Global Cardio Vascular Market Review

The Cardiovascular Market Outlook
to 2016
Competitive landscape, global market analysis, key trends, and pipeline
analysis
1
Reference Code: BI00042-007
Publication Date: June 2011
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2
Table of Contents
About Business Insights
Disclaimer
Executive Summary
13
Overview and epidemiology of cardiovascular disorders
13
Global market analysis
13
Pipeline analysis
14
Competitive landscape
15
Chapter 1 Overview and epidemiology of cardiovascular disorders 17

Summary
17
Introduction
17
Risk factors
18
Predisposing risk factors
18
Modifiable risk factors
21
Hypertension
21
Diagnosis, treatment and management
22
Epidemiology
24
Forecast epidemiology
26
Dyslipidemia
27
Diagnosis, treatment, and management
29
Epidemiology
30
31
Cardiovascular diseases
33
Arteriosclerosis/atherosclerosis
33
Thrombosis
33
Cardiac arrhythmias
33
Myocardial infarction (MI)
33
Acute coronary syndrome (ACS)
34
Congestive heart failure (CHF)
34
Coronary artery disease (CAD)
34
Peripheral artery disease (PAD)
34
Pulmonary hypertension
34
Angina pectoris
35
Stroke
35
Epidemiology
35
36
Chapter 2 Global market analysis
38
Summary
38
Introduction
39
Market analysis by geography
40
Key events in the cardiovascular market
41
European approval for Rasilamlo
41
BMS/Pfizers apixaban likely to receive EU approval
41
Angiotensin receptor blockers (ARBs) may cause increased cancer risk
42
Crestors patent upheld in the US
43
Plavix boxed warning for poor metabolizers
43
Market analysis by drug class
44
Antihypertensives
46
Introduction
46
Antihypertensive drug classes
46
Leading treatment brands by drug class
47
4
Key brands analysis
51
Diovan/Co-Diovan
51
Cozaar
51
Benicar
53
Antidyslipidemics
54
Introduction
54
Antidyslipidemic drug classes
54
55
Key brands analysis
57
Lipitor
57
Crestor
59
Future blockbusters in the antidyslipidemic drug class
63
Antithrombotics
65
Introduction
65
Antithrombotics drug classes
66
67
Key brands analysis
68
Plavix
68
Lovenox
71
Future blockbusters in the antithrombotic drug class
Other cardiovascular agents
72
75
Introduction
75
76
Tracleer
77
Leading brands dynamics and sales forecasts
78
Product growth-share matrix for leading brands
78
Chapter 3 Pipeline analysis
81
Summary
81
5
Introduction
82
82
First advanced therapy certificate for t2cures somatic cell therapy
82
Clear evidence of safety leads to termination of apixabans Phase III AVERROES trial
83
FDA panel to review AstraZenecas Brilinta
83
Novartis presents successful Phase II results of LCZ696
84
Daiichi Sankyos CS-8635 shows promising results in pivotal trial
84
Sanofi (Genzyme)/Isis mipomersen clears second Phase III trial, but raises safety concerns
Cardiovascular pipeline
85
Leading drugs in development
86
Profiles of key pipeline products
88
Key antihypertensive pipeline drugs
90
LCZ696 Novartis
90
Cinaciguat Bayer
92
Riociguat Bayer
93
Key antidyslipidemic pipeline drugs
95
Livalo (pitavastatin) Kowa Pharmaceuticals
95
Dalcetrapib Roche
96
Anacetrapib Merck
97
Darapladib GlaxoSmithKline
99
Key antithrombotic pipeline drugs
100
Xarelto (rivaroxaban) Bayer/J&J
100
Apixaban Bristol-Myers Squibb (BMS)/Pfizer
102
Brilinta (ticagrelor) AstraZeneca
104
Betrixaban Portola/Merck
106
Chapter 4 Competitive landscape
109
Summary
109
Introduction
109
Competitive positioning of top players in the cardiovascular market
110
85
Pfizer
111
Overview
111
Marketed product portfolio
112
Lipitor (atorvastatin)
112
Norvasc (amlodipine)
114
Caduet (atorvastatin/amlodipine)
114
Revatio (sildenafil)
115
Fragmin (dalteparin)
115
R&D pipeline analysis
116
Strategic and growth analysis
116
Drivers of growth
116
Resistors of growth
117
Sanofi
118
Overview
118
119
Lovenox (enoxaparin)
120
Plavix (clopidogrel)
121
122
122
Drivers of growth
122
Resistors of growth
123
AstraZeneca
124
Overview
124
125
Crestor (rosuvastatin)
126
Atacand (candesartan cilexetil)
127
127
128
Drivers of growth
128
Resistors of growth
129
Novartis
130
7
Overview
130
130
Diovan (valsartan)
131
Exforge (amlodipine/valsartan)
132
Lescol (fluvastatin)
132
Lotrel (amlodipine/benazepril)
133
133
134
Drivers of growth
134
Resistors of growth
135
Bristol-Myers Squibb (BMS)
136
Overview
136
136
137
Avalide/Avapro (irbesartan HCT)
138
Coumadin (warfarin)
138
138
139
Drivers of growth
139
Resistors of growth
140
Merck
141
Overview
141
142
Cozaar/Hyzaar (losartan/losartan HCT)
143
Vytorin (ezetimibe/simvastatin)
143
144
145
Drivers of growth
145
Resistors of growth
146
Appendix
147
Scope and methodology
147
8
Scope
147
Methodology
148
Market size methodology
148
Epidemiology
148
Market forecast
148
Abbreviations
149
References
155
Table of figures
Figure 1:
Cardiovascular disease etiology
20
Figure 2:
Cardiovascular risk factors and definitions
21
Figure 3:
Definition and classification of hypertension
22
Figure 4:
Hypertension treatment options
24
Figure 5:
Types of lipoproteins
28
Figure 6:
Interpretation of blood lipid levels
29
Figure 7:
LDL levels and therapy patterns
30
Figure 8:
Geographical segmentation of the global cardiovascular market, 2010 and 2016
41
Figure 9:
Global market share of major cardiovascular drug classes (%), 201016
45
Figure 10: Sales of potential antidyslipidemic drugs versus Lipitor ($m), 201016
65
Figure 11: Sales of antithrombotic drugs by disease conditions in the US ($m), 201016
73
Figure 12: Forecast market share of antithrombotic drugs under development, 201016
75
Figure 13: Leading brands product growth BCG matrix
79
Figure 14: Cardiovascular pipeline by key indications and stages of development, 2010
86
Figure 15: Leading pipeline drugs in various cardiovascular sub-categories, 2010
89
Figure 16: US FDA drug approval activities, 20002010
90
Figure 17: Pfizer cardiovascular portfolio by brand (%), 2010
114
Figure 18: Sanofi cardiovascular portfolio by brand (%), 2010
120
Figure 19: AstraZeneca cardiovascular portfolio by brand (%), 2010
125
Figure 20: Novartis cardiovascular portfolio by brand (%), 2010
131
Figure 21: BMS cardiovascular portfolio by brand (%), 2010
137
Figure 22: Merck cardiovascular portfolio by brand (%), 2010
142
10
Table of tables
Table 1:
Estimated prevalence of cardiovascular disorders across the 7MM, 2010
18
Table 2:
Estimated prevalence of hypertension across the 7MM, 2010
25
Table 3:
Forecast epidemiology of hypertension across the 7MM, 201016
26
Table 4:
Estimated prevalence of dyslipidemia across the 7MM, 2010
31
Table 5:
Forecast epidemiology of dyslipidemia across the 7MM, 201016
32
Table 6:
Estimated prevalence of stroke across the 7MM, 2010
36
Table 7:
Forecast epidemiology of stroke across the 7MM, 201016
37
Table 8:
Geographical segmentation of the global cardiovascular market, 2010
40
Table 9:
Global market size of major cardiovascular drug classes ($m), 201016
44
Table 10:
Sales of leading antihypertensive drugs ($m), 2010
49
Table 11:
Sales of leading antidyslipidemic drugs ($m), 2010
56
Table 12:
Sales of leading antithrombotic drugs ($m), 2010
68
Table 13:
Snapshot of the major antithrombotic drugs under development
74
Table 14:
Sales of leading Other cardiovascular drugs ($m), 2010
76
Table 15:
Sales of leading cardiovascular brands ($m), 2010
78
Table 16:
Leading pipeline drugs in the cardiovascular market, 2010 (part 1)
87
Table 17:
Leading pipeline drugs in the cardiovascular market, 2010 (part 2)
88
Table 18:
An overview of LCZ696
91
Table 19:
An overview of cinaciguat
92
Table 20:
An overview of riociguat
94
Table 21:
An overview of Livalo
95
Table 22:
An overview of dalcetrapib
97
Table 23:
An overview of anacetrapib
98
Table 24:
An overview of darapladib
99
Table 25:
An overview of Xarelto
101
Table 26:
An overview of apixaban
103
Table 27:
An overview of Brilinta
105
Table 28:
An overview of betrixaban
106
Table 29:
Sales of leading players in the global cardiovascular market ($m), 2010
111
Table 30:
Pfizer sales of leading cardiovascular brands ($m), 2010
113
Table 31:
Pfizer late-stage cardiovascular pipeline, 2010
116
Table 32:
Sanofi sales of leading cardiovascular brands ($m), 2010
120
Table 33:
AstraZeneca sales of leading cardiovascular brands ($m), 2010
125
Table 34:
AstraZeneca late-stage cardiovascular pipeline, 2010
127
11
Table 35:
Novartis sales of leading cardiovascular brands ($m), 2010
131
Table 36:
Novartis late-stage cardiovascular pipeline, 2010
134
Table 37:
BMS sales of leading cardiovascular brands ($m), 2010
137
Table 38:
BMS cardiovascular portfolio, 2010
139
Table 39:
Merck sales of leading cardiovascular brands ($m), 2010
142
Table 40:
Merck late-stage cardiovascular pipeline, 2010
144
12
Executive Summary
Overview and epidemiology of cardiovascular disorders
Cardiovascular diseases encompass a range of ailments such as hypertension, dyslipidemia, stroke,

atherosclerosis, thrombosis, and coronary artery disease.
The risk factors for cardiovascular diseases can be classified broadly into two groups: immutable
factors such as age, sex, heredity, and modifiable factors that are largely lifestyle-related such as diet,
obesity, tobacco consumption, stress, and physical inactivity.
Dyslipidemia was the indication with the highest reported prevalence in 2010, with an estimated 336
million cases in the seven major markets (7MM).
According to World Health Organization (WHO) estimates, stroke was one of the leading causes of
mortality in 2010, and its prevalence rate across the seven major markets was estimated at
approximately 0.2%.
Global market analysis
The global cardiovascular market recorded sales of $170bn in 2010 and is set to grow to $187bn in
2016 at a CAGR of 1.6%. The US continued to be the largest market, with a share of 40% of the overall
market. After a decline in sales in 2008 due to maturity of key drug categories and the increasing
generic presence, the US witnessed a resurgence in 2009.
Antihypertensives remained the largest drug class in 2010, with global sales of $37.6bn and a global
market share of 22%. Novartiss Diovan led the antihypertensives segment with $3.6bn in sales,
followed by Benicar with sales of $2.9bn. Pfizers Norvasc, one of the blockbusters in this sub-category
suffered strong sales erosion and lost significant market share to Diovan.
Angiotensin receptor blockers (ARBs) remained the most prescribed therapeutic class within
antihypertensives, driven by key brands such as Diovan, Cozaar, and Avapro. However, the advent of
13
Cozaar generics in 2010 is expected to erode sales significantly. Angiotensin converting enzyme (ACE)
inhibitors have also been on the decline due to competition from ARBs and increased genericization.
Antidyslipidemics remained the second largest therapeutic sub-category with $29.9bn in sales and a
market share of 18% in 2010. The entry of Lipitor generics in 2011 is expected to negatively impact
future prospects of sales in this segment. Dalcetrapib, manufactured by Roche, is a potential
blockbuster in this category and could serve to offset the negative impact in the antidyslipidemic market
created by the genericization of Lipitor.
Antithrombotics recorded $18.7bn in sales in 2010 and a market share of 11%. This segment is
forecast to deliver strong growth in the next two years owing to the commercialization of recently
approved products such as Pradaxa and Xarelto and the expected launch of Pfizer/BMSs apixaban.
The antiarrythmic market is likely to remain a relatively smaller opportunity owing to the limitation of
drug therapy. However, promising products such as Sanofis Multaq are expected to provide a fillip to
the segment by 2013.
Pipeline analysis
Anticoagulants are expected to be the subject of intensive R&D activity, with the presence of promising
products such as BMS/Pfizers apixaban and Bayer/J&Js Xarelto. Since most of the factor Xa inhibitors
are in oral form, they are expected to widen the market significantly.
The superior effectiveness and better bleeding profile of Brilinta (ticagrelor) over Plavix make it a key
antithrombotic drug that could be a major player in acute coronary syndrome (ACS). Brilinta also has a
potential therapeutic advantage in atherosclerosis and can be administered to 1530% of
atherosclerosis patients who do not respond to Plavix. Moreover, its use could be initially confined to
ACS with no significant patient monitoring anticipated for respiratory or cardiac function or postmarketing surveillance requirements.
LCZ696, one of Novartiss key pipeline products, delivered favorable Phase IIb results. The data
demonstrated that LCZ696 not only improved blood pressure significantly in patients with mild-to-
14
moderate hypertension but also provided complementary action with neprilysin inhibition and ARB
blockade.
Merck/Portolas betrixaban appears to have a differentiated half-life (19 hours), competitive

bioavailability, and minimal renal excretion which theoretically could result in a superior bleeding profile
and allow recruitment of patients irrespective of renal function. In its Phase IIb results announced in
March 2010, betrixaban demonstrated strong bleeding benefits over warfarin, further strengthening its
case.
The antidyslipidemic category is set to undergo significant declines in sales owing to the patent expiry
of Lipitor. Falling sales could be rescued with the approval of dalcetrapib, a potent CETP inhibitor that
treats dyslipidemia through increasing the levels of HDL cholesterol. Early trial results indicate that
anacetrapib is a more potent CETP inhibitor than dalcetrapib. However, the early entry of dalcetrapib
could serve to establish it as a prescription drug of choice, thus giving it a significant advantage over
anacetrapib.
Competitive landscape
The global cardiovascular market registered $170bn in sales in 2010. Pfizer retained its position as the
market leader with $15.2bn in 2010 sales, led by key brands such as Lipitor, Norvasc, Caduet, and
Viagra.
The top 10 companies in the cardiovascular market registered $76.4bn in combined sales in 2010,
accounting for a substantial 44.9% of the global cardiovascular market.
Sanofi remained the second largest company, registering $10.5bn in 2010 sales and a 6.2% share of
the global cardiovascular market. The company has benefited strongly from the performance of
Lovenox and Plavix, which generated $3.8bn and $2.8bn respectively in 2010 sales.
AstraZeneca was the third largest company in the global cardiovascular market, recording sales of
$9.4bn in 2010. Sales were strongly driven by the blockbuster drugs Crestor and Atacand
15
Novartis was the fourth largest company, with 2010 sales of $8.6bn. Its position was strongly supported
by the ARBs, ARBs in combination with diuretics, and the statins. All Novartiss leading brands,
including Diovan ($3.6bn), Co-Diovan ($2.4bn), and Exforge ($904m) registered strong Y-o-Y growth in
2010.
Merck and BMS were the other leading companies, registering 2010 sales of $7.5bn and $8.4bn
respectively.
16
Chapter 1 Overview and epidemiology of

cardiovascular disorders
Summary
Cardiovascular diseases encompass a range of ailments such as hypertension, dyslipidemia, stroke,

atherosclerosis, thrombosis, and coronary artery disease.
The risk factors for cardiovascular diseases can be classified broadly into two groups: immutable
factors such as age, sex, heredity, and modifiable factors that are largely lifestyle-related such as diet,
obesity, tobacco consumption, stress, and physical inactivity.
Dyslipidemia was the indication with the highest reported prevalence in 2010, with an estimated 336
million cases in the seven major markets (7MM).
According to World Health Organization (WHO) estimates, stroke was one of the leading causes of
mortality in 2010, and its prevalence rate across the seven major markets was estimated at
approximately 0.2%.
Introduction
This chapter provides a background to the cardiovascular therapeutic category by identifying the key
indications, providing detailed overviews of each of the indications, and listing their current and forecast
prevalence through 2016. In accordance with the scope of this report, the primary focus of this chapter is
restricted to hypertension, dyslipidemia, and stroke. The chapter also provides a brief overview of the
predisposing factors that lead to cardiovascular diseases.
Among the various cardiovascular diseases, dyslipidemia had the highest prevalence in 2010, with 336
million reported cases. The following table provides the consolidated estimates of the prevalence of
cardiovascular diseases discussed in this chapter.
17
Table 1: Estimated prevalence of cardiovascular disorders across the 7MM, 2010
Country
Hypertension (000s)
Dyslipidemia (000s)
Stroke (000s)
France
16,372
31,877
80
Germany
29,612
54,780
127
Italy
22,376
20,582
112
Spain
18,715
9,712
90
UK
23,649
29,625
103
EU5
110,724
146,576
512
US
76,198
162,716
759
Japan
47,085
26,710
247
Total
234,007
336,002
1,518
Source: American Heart Association, National Health Statistics, CDC, WHO
BUSINESS INSIGHTS
Risk factors
Predisposing risk factors
Predisposing factors are those conditions and lifestyle habits that put people at a greater risk of developing
cardiovascular diseases. They can be broadly classified into two categories: immutable factors such as age,
sex, heredity, and modifiable factors that are largely lifestyle-related such as diet, tobacco consumption,
physical inactivity, obesity, and stress.
While having a certain predisposing factor or set of factors increases the likelihood of an individual
developing a cardiovascular disease, it does not always lead to the condition. Conversely, the absence of a
predisposing factor does not nullify the possibility of the individual developing a particular disease. In
essence, the factors have a cumulative effect, that is, the presence of a large number of identifiable factors
increases the probability of an individual developing cardiovascular disease.
Owing to the statistical relationship between these factors and cardiovascular disease, a treatment for the
predisposing factor may not entirely eliminate the possibility of the disease. Similarly, if the factor is very
prominent in an individual, treating it even with a very effective treatment may not reduce the disease risk.
18
However, studies have shown that the treatment of predisposing risk factors such as smoking, high blood
pressure, and high cholesterol, can reduce the likelihood of a heart attack.
Given the rather complicated nature of this association between predisposing/risk factors and cardiovascular
disease, demonstrating it is considered to be a major scientific challenge. For instance, a disease such as
atherosclerosis can be caused by various factors and is found to some degree in all individuals. Thus, it is
difficult to design and implement studies that show the effectiveness of a particular treatment.
19
Figure 1:
Cardiovascular disease etiology

Predisposing factors
Manageable
Diet
Smoking
Physical inactivity
Stress
Substance abuse
Non-manageable
Age
Sex
Heredity
Race
Risk factors
Glucose intolerance
Diabetes
Dyslipidemia
High blood pressure
Arteriosclerosis
Thrombosis
Myocardial infarction
Acute coronary syndrome
Congestive heart failure
Coronary artery disease
Peripheral artery disease
Stroke
Clinical manifestations
Angina pectoris
Aneurysm
Edema
Source: Yale Heart Book
BUSINESS INSIGHTS
20
Modifiable risk factors

Modifiable risk factors primarily include high blood pressure, high cholesterol, tobacco consumption, and type
2 diabetes. Research has indicated that the treatment of the major risk factors can greatly reduce the
possibility of a heart attack. Moreover, some of these factors are lifestyle-related, and a combination of diet
and exercise can work as a protective factor and reduce the likelihood of cardiovascular disease.
Figure 2:
Cardiovascular risk factors and definitions

Risk Factor
Definition
Impaired glucose tolerance
2 hour glucose levels of 140199mg/dL (7.8 to

11.0mmol) on the 75g oral glucose tolerance test
Type 2 diabetes
Fasting plasma glucose of 126mg/dL or 7mmol/L
Low HDL
40mg/dL
Hypertriglyceridemia
200mg/dL
High LDL
160mg/dL
Hypertension
140/90mmHg
Source: Yale Heart Book
BUSINESS INSIGHTS
Hypertension
High blood pressure or hypertension is the most important risk factor for cardiovascular disease.
Physiologically, it is defined as a condition wherein the pressure of the blood flowing through blood vessels
remains high for a prolonged period irrespective of the bodys need. An increased blood pressure leads the
heart to work harder, which makes the heart and arteries more susceptible to injury. Hypertension further
increases the risk of incidents such as heart attack, heart failure, and atherosclerosis.
21
There are several factors that lead to hypertension, such as a sedentary lifestyle, alcohol consumption, high
sodium diet, high fat diet, high alcohol intake, obesity, and age. Furthermore, people with indications such as
diabetes mellitus or kidney disease, and even those with social or occupational stress, are in the high-risk
group.
Figure 3:
Definition and classification of hypertension
Category
Blood
pressure
elevations
Risk of CVD
Systolic
blood
pressure
Diastolic
blood
pressure
Normal blood
pressure
Normal or
rare
None
Less than
130mmHg
Less than
85mm Hg
Stage I
hypertension
Occasional
or
intermittent
Low
140159mm
Hg
9099mm Hg
Stage II
hypertension
Sustained
Progressive
160mm Hg
100mm Hg
Stage III
hypertension
Marked and
sustained
Advanced
161179mm
Hg
101109mm
Hg
Source: Writing Group of The American Society of Hypertension, 2005
BUSINESS INSIGHTS
Diagnosis, treatment and management

In over 90% of cases there may be no identifiable cause of hypertension, in which case the condition is
known as essential hypertension. Some researchers believe that this may be due to hormonal factors, which
control the salt-handling ability of the kidney, while others believe that it is genetically determined and
environmentally controlled. In the remaining 10% of cases, hypertension may be secondary in nature as a
consequence of another medical problem, such as kidney disorders, adrenal tumors, or some drugs.
22
Diagnosis of hypertension involves inspection of the eyes, examination of the heart, arterial blood flow check,
examination of the kidneys, and checking for an enlarged thyroid. There are also some costly and less
frequently used diagnostic methods for hypertension, such as an echocardiogram (ECHO), 24-hour blood
pressure monitoring, and stress test.
Treatment of essential hypertension targets symptomatic relief, which implies achieving a target blood
pressure. Treatment of secondary hypertension involves symptomatic relief but also treatment of the primary
cause of elevated blood pressure. All treatment strategies include strict dietary regulations.
23
Figure 4:
Hypertension treatment options
Note: ACEI = ACE inhibitors; ARB = angiotensin II receptor blockers; BB = beta-blockers; CCB
= calcium channel blockers; TD = thiazide diuretics.
Source: Seventh Report of the Joint National Committee on the Prevention,
BUSINESS INSIGHTS
Detection, Evaluation and Treatment of High Blood Pressure
Epidemiology
As detailed in Table 2 the prevalence of hypertension was very high across all the 7MM (France, Germany,
Italy, Spain, UK, US, and Japan), with an estimated 234 million reported cases in 2010. The US accounted
for approximately 33% of the total cases, followed by Japan at 20%.
24
In terms of prevalence rate, Spain led the way at 42.1%, followed by Japan at 36.9%. The average
prevalence rate across the 5EU was around 35.6%, significantly higher than that in the US at 24.3%.
Table 2: Estimated prevalence of hypertension across the 7MM, 2010
Country
Prevalence (000s)
Prevalence (%)
Share (%)
France
16,372
26.2
Germany
29,612
35.7
13
Italy
22,376
37.9
10
Spain
18,715
42.1
UK
23,649
38.6
10
EU5
110,724
35.6
47
US
76,198
24.3
33
Japan
47,085
36.9
20
Total
234,007
31.1
100
25
BUSINESS INSIGHTS
Table 3: Forecast epidemiology of hypertension across the 7MM, 201016
Country
2010
2011(f)
2012(f)
2013(f)
2014(f)
2015(f)
2016(f)
16,372
16,495
16,619
16,744
16,869
17,051
17,149
26.2
26.3
26.4
26.4
26.5
26.7
26.7
29,612
29,701
29,791
29,881
29,971
29,994
30,112
35.7
35.8
36.0
36.1
36.2
36.2
36.4
22,376
22,388
22,401
22,413
22,426
22,474
22,471
37.9
37.9
37.9
37.8
37.9
38.0
37.9
18,715
18,818
18,922
19,026
19,131
19,392
19,428
42.1
42.3
42.7
42.5
42.7
42.8
43.0
23,649
23,795
23,942
24,089
24,237
24,450
24,567
38.6
38.7
38.8
38.9
38.6
38.8
38.9
110,724
111,197
111,675
112,153
112,634
113,361
113,727
35.6
35.7
35.7
35.8
35.9
36.0
36.0
76,198
77,335
78,488
79,659
80,847
82,584
83,475
24.3
24.4
24.5
24.7
25.3
25.6
25.7
47,085
47,396
47,709
48,024
48,341
48,667
48,973
36.9
37.2
37.5
37.8
38.4
38.8
39.1
234,007
235,928
237,872
239,836
241,822
244,612
246,175
31.1
31.2
31.3
31.4
31.8
32.1
32.1
France
Prevalence (000s)
Prevalence (%)
Germany
Prevalence (000s)
Prevalence (%)
Italy
Prevalence (000s)
Prevalence (%)
Spain
Prevalence (000s)
Prevalence (%)
UK
Prevalence (000s)
Prevalence (%)
5EU
Prevalence
(000s)
Prevalence (%)
US
Prevalence (000s)
Prevalence (%)
Japan
Prevalence (000s)
Prevalence (%)
Total
Prevalence
(000s)
Prevalence (%)
Source: American Heart Association, National Health Statistics, CDC, WHO,

Business Insights
26
BUSINESS INSIGHTS
The prevalence of hypertension is forecast to grow from 234 million in 2010 to 246 million in 2016 across the
seven major markets. In 2016, the US is still expected to be the largest market for hypertension, with an
anticipated 83 million sufferers, followed by Japan at 49 million.
In terms of prevalence rate, Spain is expected to lead the way in 2016 at 43% followed by Japan at 39.1%.
The average prevalence rate across the 5EU in 2016 is expected to be around 36%, a slight increase over
2010. Furthermore, an increase in the mean age of the population is expected to put a significant number of
individuals at hypertensive risk.
According to the International Society of Hypertension, there is a clear recognition of hypertension as a major
public health issue across all the 7MM. Although the awareness level differs from country to country, lifestyle
changes in general are expected to play a significant role in reducing the risk factors among larger
population groups.
Dyslipidemia
Dyslipidemia refers to an alteration in the level of blood lipids. It is of two types, hyperlipidemia and
hypolipidemia, with the commonest being hyperlipidemia.
27
Figure 5:
Types of lipoproteins
Type
Description
Chylomicrons
Carries triglycerides from food in intestines

to liver, skeletal muscle, and adipose tissue.
Very low density

lipoprotein (VLDL)
Carries newly synthesized triglycerides from

liver to adipose tissue.
Intermediate density
lipoprotein (IDL)
Intermediate between VLDL and LDL (very

low blood levels).
Low density
lipoproteins (LDL)
Carries cholesterol from liver to other body

parts (bad cholesterol)
High density
lipoproteins (HDL)
Collects cholesterol from body parts and

carries to the liver (good cholesterol).
Source: Business Insights
Hyperlipidemia
BUSINESS INSIGHTS
Lipids include cholesterol, cholesterol esters, phospholipids, and triglycerides, which are transported in the
blood stream as large molecules called lipoproteins. There are five major lipoprotein families, as illustrated in
the above figure.
The international committee for the evaluation of hypertriglyceridemia as a vascular risk factor has classified
hypertriglyceridemias (hyperlipidemias) into three groups:
Isolated moderate hypertriglyceridemia triglycerides 200400mg/dL, total cholesterol <200mg/dL.
Mixed hypertriglyceridemia triglycerides 200400mg/dL, LDL cholesterol >130mg/dL.
Severe hypertriglyceridemia triglycerides >400mg/dL.

28
Diagnosis, treatment, and management

Diagnosis of dyslipidemia involves the measurement of blood levels of various lipoproteins. The National
Cholesterol Education Program Adult Treatment Panel III Guidelines provide a comprehensive approach to
the treatment of dyslipidemia. It primarily focuses on controlling elevated LDL-cholesterol (LDL-C) levels.
Figure 6 illustrates the interpretation of blood lipid levels.
Figure 6:
Interpretation of blood lipid levels

Lipid
Blood levels (mg/dL)
Comment
Total cholesterol
< 200
Desirable
200239
Borderline high
> 240
High
< 100
Optimal
100129
Near optimal/ above

optimal
130159
Boderline high
160189
High
190
Very high
< 40
Low
60
High
LDL cholesterol
HDL cholesterol
Source: National Cholesterol Education Program Adult Treatment Panel III
BUSINESS INSIGHTS
Guidelines
The priority of dyslipidemia treatment is reduction of LDL-C to less than 100mg/dL and the ratio of total
cholesterol to HDL-cholesterol (HDL-C) to less than four. The American Heart Association (AHA)
recommends a set of guidelines for the treatment of dyslipidemia, which is also designed for lowering LDL
levels. The following figure illustrates LDL levels and therapy patterns.
29
Figure 7:
LDL levels and therapy patterns
LDL cholesterol
Level for drug

consideration
Therapy
Goal of therapy
220mg/dL
Diet and drug
160mg/dL
190mg/dL
Diet and drug
160mg/dL
160189mg/dL
Diet (drug therapy

optional)
160mg/dL
160mg/dL
Diet and drug
130mg/dL
130 mg/dL
Diet and drug
100mg/dL
100129mg/dL
Diet (drug therapy

optional)
100mg/dL
Without coronary
heart disease and
with < 2 risk
factors
Without coronary
heart disease
and with 2 risk
factors
With coronary
heart disease
Source: American Heart Association
BUSINESS INSIGHTS
Epidemiology
Among all the cardiovascular diseases covered in this report, dyslipidemia had the highest prevalence, with
336 million affected patients across the 7MM in 2010. The US was the largest market, accounting for 48% of
the total prevalence followed by Germany at 16%.
The highest prevalence rate was recorded by Germany at 65.7%, followed by the US at 51.8%. The average
prevalence rate in the EU5 was comparable to the US at 47.1%. Out of the 7MM, Japan had the lowest
prevalence rate at 20.9%. Table 4 shows the estimated prevalence rate of dyslipidemia across the seven
major markets in 2010.
30
Table 4: Estimated prevalence of dyslipidemia across the 7MM, 2010
Country
Prevalence (000s)
Prevalence (%)
Share (%)
France
31,877
51.0
Germany
54,780
65.7
16
Italy
20,582
34.9
9,712
21.9
UK
29,625
48.3
EU5
146,576
47.1
44
US
162,716
51.8
48
Japan
26,710
20.9
Total
336,002
44.6
100
Spain
BUSINESS INSIGHTS
The prevalence of dyslipidemia across the 7MM is forecast to increase from 336 million in 2010 to 356
million in 2016, at a CAGR of 0.97%. The US is expected to retain its position as the largest pool for
dyslipidemics, with an expected prevalence of 175 million in 2016.
In terms of prevalence rate, Germany is expected to retain its top spot in 2016, with an expected 68%,
followed by the US at 53.7% and France at 52.6%. The EU5 is forecast to have a prevalence rate of 48.4%,
lower overall than in the US. Of the 7MM, Japan is expected to have the lowest prevalence rate at 22.8% in
2016.
31
Table 5: Forecast epidemiology of dyslipidemia across the 7MM, 201016
Country
2010
2011(f)
2012(f)
2013(f)
2014(f)
2015(f)
2016(f)
31,877
32,183
32,491
32,802
33,117
33,399
33,716
51.0
51.3
51.5
51.8
52.1
52.3
52.6
54,780
55,046
55,312
55,580
55,849
56,425
56,558
65.7
65.8
66.0
66.1
67.4
68.1
68.0
20,582
20,676
20,770
20,865
20,960
21,114
21,182
34.9
35.0
35.1
35.2
35.4
35.7
37.6
9,712
9,823
9,936
10,050
10,165
10,240
10,368
21.9
22.1
22.3
22.6
22.5
22.6
22.9
29,625
29,841
30,058
30,277
30,497
30,752
30,952
48.3
48.5
48.7
48.9
48.6
48.8
49.0
146,576
147,569
148,567
149,574
150,588
151,930
152,776
47.1
47.3
47.5
47.7
48.0
48.2
48.4
162,716
164,590
166,486
168,403
170,343
173,232
174,687
51.8
51.9
52.1
52.2
53.2
53.7
53.7
26,710
27,034
27,362
27,694
28,030
28,222
28,605
20.9
21.2
21.5
21.8
22.3
22.5
22.8
336,002
339,193
342,415
345,671
348,961
353,384
356,068
44.6
44.9
45.1
45.3
46.0
46.4
46.6
France
Prevalence (000s)
Prevalence (%)
Germany
Prevalence (000s)
Prevalence (%)
Italy
Prevalence (000s)
Prevalence (%)
Spain
Prevalence (000s)
Prevalence (%)
UK
Prevalence (000s)
Prevalence (%)
5EU
Prevalence (000s)
Prevalence (%)
US
Prevalence (000s)
Prevalence (%)
Japan
Prevalence (000s)
Prevalence (%)
Total
Prevalence (000s)
Prevalence (%)

Business Insights
32
BUSINESS INSIGHTS
Cardiovascular diseases are a broad term, the definition of which includes a number of indications related to
the heart and the vascular network. These are interrelated indications, which tend to be linked in a complex
cascade; one may lead to another if not treated properly. Risk factors such as dyslipidemia and diabetes,
among others, may cause cardiovascular disease.
Arteriosclerosis/atherosclerosis
Arteriosclerosis is the thickening of the arteries and hence the loss of flexibility of the vessel walls. This leads
to a restricted supply of blood to the tissues and organs. Thickening of the vessel walls can occur for several
reasons, the most common being a build up of fats, known as plaques, on the artery walls. Arteriosclerosis
leads to complications such as coronary artery disease (CAD), stroke, peripheral artery disease (PAD),
aneurysms, and so on. Atherosclerotic plaques can also break, leading to thrombosis and probable
thromboembolism.
Thrombosis
Thrombosis is the formation of a blood clot, or thrombus, inside blood vessels, obstructing blood flow.
Thromboembolism is the condition wherein the blood clot breaks loose and is carried along the vessel, until it
clogs a narrower vessel. This may occur in the lungs (pulmonary embolism), brain (stroke), gastrointestinal
tract, or limbs (deep vein thrombosis-DVT).
Cardiac arrhythmias
Arrhythmias are heart rhythm problems, which occur when heart beats are not well coordinated owing to
improper electric impulses. This may cause the heart to beat too fast (tachycardia) or too slowly
(bradycardia). Arrhythmias are generally harmless and momentary, but frequent rhythm disturbances
increase the risk of stroke and congestive heart failure.
Myocardial infarction (MI)

Myocardial infarction, commonly known as heart attack, is a rapidly occurring myocardial necrosis due to
interruption of blood supply to a part of the heart. Angina is frequently classified according to
electrocardiogram (ECG) changes as non-ST segment elevation MI or subendocardial MI (NSTEMI
33
necrosis with no ST elevation), and ST segment elevation MI or transmural MI (STEMI necrosis with ST
elevation).
Acute coronary syndrome (ACS)

ACS is a term used to cover a group of clinical symptoms compatible with acute myocardial infarction, which
is chest pain due to insufficient blood supply to the heart muscle, resulting from coronary artery disease.
Congestive heart failure (CHF)

CHF is a condition wherein the heart fails to supply blood to the various parts of the body. This may be due
to narrowed arteries, myocardial infarction, heart valve disease, high blood pressure, cardiomyopathy, or
congenital abnormalities.
Coronary artery disease (CAD)

CAD results from the effects of atherosclerotic plaque formation in coronary arteries. The reduction in blood
supply to the heart muscles will reduce the hearts efficiency and can cause heart failure. One of the first and
major symptoms of this condition is angina.
Peripheral artery disease (PAD)

PAD is a vascular disorder in which the thickening of arteries causes reduction in blood flow to limbs, leading
to intermittent leg pain while walking. The disease is an indicator of atherosclerosis. It leads to sores (that do
not heal) and gangrenes.
Pulmonary hypertension is a disorder of the pulmonary circulatory system, wherein the pulmonary arteries
and capillaries become narrowed or blocked by emboli. This causes build up of pressure in the arteries,
which is translated to the right ventricle, unlike hypertension where the left ventricle is affected. It can also
lead to heart failure.
34
Angina pectoris
Angina pectoris is severe chest pain due to ischemia (lack of blood and oxygen supply) of the myocardium.
The main causes of ischemia are blockade or spasm of coronary vessels. Angina can occur during activity
(stable angina), which is most common, or during rest (unstable angina).
Stroke
The WHO estimates that 15 million people suffer from stroke each year worldwide, 5.7 million of whom die.
This makes stroke the second-leading cause of death globally, responsible for 9.7% of deaths. These WHO
estimates also indicate that the share of deaths due to stroke may rise to 12.1% globally in 2030. A stroke
occurs when brain cells die owing to a lack of blood supply, resulting from thrombosis, embolism, or
hemorrhage. This may lead to permanent neurological damage. Some studies have concluded that transient
ischemic attack (TIA), caused by extracranial emboli or atherosclerosis of intracranial small arteries, may be
considered a warning signal for strokes.
Strokes may be classified as ischemic or hemorrhagic. Ischemic stroke involves decreased blood supply to
parts of the brain, leading to brain cell death and thus brain dysfunction. Hemorrhagic stroke is due to rupture
of blood vessels or abnormal vascular structure, causing accumulation of blood in a part of the brain. The
majority of strokes (80%) are ischemic in nature.
Epidemiology
Table 6 shows the prevalence of stroke across the seven major markets in 2010. Epidemiological data
indicates a prevalence of 0.2% in 2010 for stroke across the major markets. Countries such as the US,
Spain, Germany, Italy, UK, and Japan had a relatively high prevalence when compared with France.
35
Table 6: Estimated prevalence of stroke across the 7MM, 2010
Country
Prevalence (000s)
Prevalence (%)
Share (%)
80
0.1
Germany
127
0.2
Italy
112
0.2
90
0.2
UK
103
0.2
EU5
512
0.2
34
US
759
0.2
50
Japan
247
0.2
16
Total
1518
0.2
100
France
Spain
BUSINESS INSIGHTS
The overall patient potential for stroke is expected to rise from 1.5 million in 2010 to 1.6 million in 2016 with
the prevalence rate remaining constant at 0.2%.
36
Table 7: Forecast epidemiology of stroke across the 7MM, 201016
Country
2010
2011(f)
2012(f)
2013(f)
2014(f)
2015(f)
2016(f)
Prevalence (000s)
80
80
80
80
80
80
80
Prevalence (%)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
Prevalence (000s)
127
127
127
127
127
127
127
Prevalence (%)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Prevalence (000s)
112
112
112
112
112
112
112
Prevalence (%)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Prevalence (000s)
90
91
91
91
91
92
92
Prevalence (%)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Prevalence (000s)
103
103
104
104
110
112
112
Prevalence (%)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Prevalence
(000s)
512
513
514
514
520
523
523
Prevalence (%)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Prevalence (000s)
759
764
769
774
779
783
788
Prevalence (%)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Prevalence (000s)
247
251
255
259
264
271
273
Prevalence (%)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1,518
1,528
1,538
1,547
1,563
1,577
1,584
0.2
0.2
0.2
0.2
0.2
0.2
0.2
France
Germany
Italy
Spain
UK
5EU
US
Japan
Total
Prevalence
(000s)
Prevalence (%)

Business Insights
37
BUSINESS INSIGHTS
Chapter 2 Global market analysis

Summary
The global cardiovascular market recorded sales of $170bn in 2010 and is set to grow to $187bn in
2016 at a CAGR of 1.6%. The US continued to be the largest market, with a share of 40% of the overall
market. After a decline in sales in 2008 due to maturity of key drug categories and the increasing
generic presence, the US witnessed a resurgence in 2009.
Antihypertensives remained the largest drug class in 2010, with global sales of $37.6bn and a global
market share of 22%. Novartiss Diovan led the antihypertensives segment with $3.6bn in sales,
followed by Benicar with sales of $2.9bn. Pfizers Norvasc, one of the blockbusters in this sub-category
suffered strong sales erosion and lost significant market share to Diovan.
Angiotensin receptor blockers (ARBs) remained the most prescribed therapeutic class within
antihypertensives, driven by key brands such as Diovan, Cozaar, and Avapro. However, the advent of
Cozaar generics in 2010 is expected to erode sales significantly. Angiotensin converting enzyme (ACE)
inhibitors have also been on the decline due to competition from ARBs and increased genericization.
Antidyslipidemics remained the second largest therapeutic sub-category with $29.9bn in sales and a
market share of 18% in 2010. The entry of Lipitor generics in 2011 is expected to negatively impact
future prospects of sales in this segment. Dalcetrapib, manufactured by Roche, is a potential
blockbuster in this category and could serve to offset the negative impact in the antidyslipidemic market
created by the genericization of Lipitor.
Antithrombotics recorded $18.7bn in sales in 2010 and a market share of 11%. This segment is
forecast to deliver strong growth in the next two years owing to the commercialization of recently
approved products such as Pradaxa and Xarelto and the expected launch of Pfizer/BMSs apixaban.
The antiarrythmic market is likely to remain a relatively smaller opportunity owing to the limitation of
drug therapy. However, promising products such as Sanofis Multaq are expected to provide a fillip to
the segment by 2013.
38
Introduction
The global cardiovascular market, valued at $170bn in 2010, continues to remain a dynamic therapy area
with excellent growth potential owing to the vast pipeline of promising products. One of the most significant
developments in this market in the recent past has been the ruling of the Plavix case in favor of the
innovators Sanofi/Bristol Myers-Squibb (BMS) in April 2010. According to this judgment, Apotex, which
briefly infringed on Plavixs 265 patent by launching clopidogrel generics, is liable to pay economic damages
to the innovators. Moreover, Plavix is patent-protected in the US until November 2011. However, widespread
generic adoption is expected to negatively impact Plavix from 2012 onwards.
The antidyslipidemics category has also been exhibiting value erosion following the entry of generic Zocor
(simvastatin) in the US in 2006. However, the imminent patent expiry of Pfizers Lipitor (atorvastatin) in 2011,
is expected have significant ramifications for the cardiovascular market. Lipitor has already been losing
market share to generic simvastatin and the entry of atorvastatin generics are likely to further contribute to
the decline. Although the agreement with Ranbaxy regarding the manufacture and sale of a generic version
of Lipitor allows Pfizer to enjoy a six month post-patent expiration exclusivity, generic versions of Lipitor will
be marketed by Ranbaxy in November 2011. Thus, the revenue loss due to Lipitor patent expiration is likely
to impact the cardiovascular pharmaceutical market in 2012. In contrast, the growth outlook for the
antithrombotics segment is very promising with the expected launch of Pfizer/BMSs apixaban and Bayer
J&Js Xarelto.
This chapter focuses on many such strategic issues concerning the global cardiovascular market, with a
comprehensive review and analysis of the current market dynamics and recent key R&D events shaping the
market. The major cardiovascular therapeutic classes such as antihypertensives, antidyslipidemics,
antithrombotics, and cardiac therapies are analyzed alongside the leading brand dynamics for each of the
indications. The sales data captured in this report are global in scope and sourced from scientific journals,
company reports, and brokerage reports. Sales forecasts were made based on regression modeling, and
cause-and-effect analysis of data (based on growth drivers and resistors).
39
Market analysis by geography

The global cardiovascular market was valued at $170bn in 2010 and is expected to grow to a value of
$187bn in 2016 at a CAGR of 1.6%. The US accounts for about 40% of the entire cardiovascular market,
while the five major EU nations (UK, Germany, Italy, Spain, and France; collectively EU5) account for 18% of
the entire market, as shown in Table 8 and Figure 8. Both the US and EU5 regions are characterized by a
negative CAGR from 2010 to 2016, based on the expected decline in sales values of major blockbuster
drugs (such as Lipitor and Cozaar) after genericization. The growth is likely to be positive in Japan and the
rest of the world (ROW), (including Asia-Pacific (APAC), Latin America, Central America, Africa, and
Canada). Sales volumes in APAC will be driven by the strong adoption of generics, following the patent
expiry of the major blockbuster drugs in the cardiovascular segment. Cardiovascular drugs are also likely to
enjoy a sustained demand in Japan, owing to the aging population, and consequently an increase in agerelated diseases.
Table 8: Geographical segmentation of the global cardiovascular market, 2010
Geographical
region
Market size 2010 ($bn)
US
Market share 2010

(%)
CAGR 201016 (%)
68
40
-8.5
EU5
30.6
18
-0.1
Japan
28.9
17
0.6
ROW
42.5
25
1.9
Total
170
100
1.6
Source: company reported sales
BUSINESS INSIGHTS
The US market delivered $68bn in sales in 2010, and continued to be the single largest market with a share
of 40% of the global market. In 200708, the US market recorded a slight decline, but it staged a remarkable
recovery in 2009, driven by the statins and beta blockers. Nonetheless, the impending patent expiration of
major cardiovascular drugs, including Lipitor and Plavix, will lead to a decline in sales values in these
regions, and the US is likely to occupy only a 27% share of the global market in 2016.
40
Figure 8:
2016
Geographical segmentation of the global cardiovascular market, 2010 and
2010
2016
25%
27%
32%
40%
17%
21%
20%
18%
100% = $170bn
US
100% = $187bn
EU5
Japan
ROW
BUSINESS INSIGHTS

European approval for Rasilamlo
Rasilamlo, a single pill combination of a rennin inhibitor (aliskiren) and a calcium channel blocker
(amlodipine), manufactured by Novartis, received approval from the European Commission in April 2011 for
the treatment of high blood pressure in patients who are not controlled by either one of the antihypertensive
molecules. The approval is based on studies in more than 5,000 patients with mild to severe blood pressure,
and establishes the superiority of the combined therapy over the use of a single therapy. Novartis also filed a
request for EU approval for a triple combination product in May 2010. The triple combination product,
Amturnide, consists of aliskiren, amlodipine, and hydrochlorothiazide (a diuretic).
BMS/Pfizers apixaban likely to receive EU approval

Bristol-Myers Squibb (BMS) and Pfizer are likely to receive EU approval for their novel factor-Xa inhibitor,
apixaban (Eliquis), after receiving positive reviews from the Committee for Medicinal Products for Human
41
Use (CHMP). If granted, the approval will be for the use of apixaban for venous thrombolic events (VTE) in
adults who have undergone knee and hip replacement surgeries. The approval will closely follow study
results published by Lassen et al. (2010), which established the clinical superiority of apixaban in reducing
the incidence of venous thromboembolism (VTE) over Sanofis Lovenox (enoxaparin). The approval is likely
to pave the way for future usage of apixaban in other indications such as atrial fibrillation (AF).
Angiotensin receptor blockers (ARBs) may cause increased cancer risk

ARBs, which form the mainstay of hypertension treatment, have recently been found to have a link to an
increased risk of cancer in a meta-analysis published by Sipahi et al. (2010). The study involved analyzing
new cancer data from 61,590 patients from five clinical trials, common types of solid organ cancers involving
68,402 patients participating in five trials, and cancer deaths for 93,515 patients in eight trials.
The results of the study revealed that patients who were undergoing treatment with ARBs had a risk of new
cancer occurrence of 7.2%, compared with 6.0% risk of new cancer occurrence in control groups. Among
different types of solid organ cancers studied, only lung-cancer occurrence was found to be significantly
higher in patients treated with ARBs. Approximately 86% of all the patients in the trial received Boehringer
Ingelheim/Astellass Micardis (telmisartan). However, enough data was not generated to ascertain if this was
a class effect shared by all ARBs or an effect specific to any particular ARB.
While the repercussions of this finding on the ARB market in the short term are expected to be minimal,
further studies are expected to be undertaken, which could potentially raise concerns among the medical
community about the safety of ARBs. With stronger results to support this theory, ARB use would be likely to
become more selective, with applications reserved to specific patient groups such as the ACE inhibitor
intolerant population.
Following this publication, Boehringer Ingelheim claimed that these findings contradicted internal safety data
that indicated that Micardis has an acceptable safety profile in over 50,000 patients. AstraZeneca is yet to
review the study and issue a statement. Other leading drugs in the ARB class include Novartiss Diovan,
Sanofi and BMSs Avapro, and Daiichi Sankyos Benicar.
42
Crestors patent upheld in the US

AstraZenecas blockbuster antidyslipidemic Crestor, the biggest growth driver within the cholesterol-lowering
drugs category received a fillip after its patent was upheld by a US district court in June 2010. The
challengers Aurobindo, Cobalt, Apotex, Mylan, Sandoz, Sun, and Par claimed that the drugs original
patent filing by AstraZenecas partner, Shionogi, omitted material information. However, after a four-month
trial that began in February 2010, the court concluded that Crestors 314 patent is valid until 2016, and none
of the generic challengers would be allowed to file abbreviated new drug approvals (ANDAs) before the
patent expiration date.
Crestor is currently the only branded statin in the US market that is witnessing positive growth and the court
judgment is expected to improve its prospects through the forecast period. The ruling also had a positive
impact on the companys stock, with a 9% increase in its share price on the London Stock Exchange (LSE)
following the news.
Plavix boxed warning for poor metabolizers

Sanofi/BMSs Plavix received a boxed warning to its US label in March 2010, indicating the diminished
effectiveness of the drug in patients with a variant of the CYP2C1P liver enzyme, which can lead to reduced
formation of the active metabolite. According to the label, this pool of patients, termed as poor metabolizers,
represents approximately 14% of Chinese, 4% of blacks, and 2% of Caucasians. The warning also includes
information about genetic tests to identify such patients.
Further, the FDA added that this group is less likely to benefit from Plavix and is at a high risk for heart
attack, stroke, and cardiovascular death. Although the information about poor metabolizers was added to the
label in May 2009 as a precaution, further evidence has prompted the companies to extend it to a warning.
This was based on a study in 40 subjects, with 10 each in the four metabolizer types, which found that the
poor metabolizers had notably lower levels of Plavix and antiplatelets (FDA Drug Safety Communication,
2010; www.fda.gov).
43
Market analysis by drug class

The global cardiovascular market registered sales of $170bn in 2010. Antihypertensives accounted for about
22% of the market, with total sales of about $37.7bn. Antithrombotics accounted for about 11% of sales in
2010, with total revenues of $18.7bn. However, the antithrombotics category is likely to experience a slower
decline than the other drug classes, owing to the relatively rapid innovation in the warfarin-replacement
market.
Sales in the major drug classes are shown in Table 9.The forecast sales of the various drug classes are
based upon the forecast sales of existing drugs only; these numbers to not take into account pipeline drugs
that are likely to be approved over the forecast period.
Table 9: Global market size of major cardiovascular drug classes ($m), 201016
Drug
class
2010
2011
2012
2013
2014
2015
2016
CAGR
2010
16 (%)
Antihyper
-tensives
37,657
36,392
34,307
30,791
29,637
29,283
28,413
-4.6
Antidyslipidemics
29,899
29,822
25,230
24,744
24,459
23,828
20,156
-6.4
Antithrom
-botics
18,687
18,185
14,403
13,030
14,294
15,360
16,126
-2.4
Others
84,216
89,306
95,240
101,544
108,238
115,199
122,206
6.4
170,460
173,706
169,179
170,109
176,629
183,671
186,901
1.6
Total
BUSINESS INSIGHTS
A comparison of the current market share of the major drug classes and future, projected market share (as
shown in Figure 9) indicates a future decline in the market share of all three major drug classes. This is
concomitant with the likely decrease in sales values after patent-expiration of major drugs, especially in the
antihypertensive (Cozaar) and antidyslipidemic (Lipitor) categories.
44
Figure 9:
Global market share of major cardiovascular drug classes (%), 201016

2010
2016
15%
22%
11%
49%
9%
18%
65%
11%
100% = $170bn
Antihypertensives
100% = $187bn
Antidyslipidemics
Antithrombotics
Total others
BUSINESS INSIGHTS
Novartiss Diovan and Daiichi Sankyos Benicar were the leading antihypertensive drugs in 2010, with sales
of $3.6bn and $2.9bn respectively. Pfizers Norvasc, which was the leading antihypertensive until 2007, has
been registering a steady decline and Diovan has taken its place as the frontrunner within this segment.
Hypertension patients have increased pressure in their arteries leading to heightened risk of indications such
as hemorrhagic stroke, congestive heart failure, myocardial infarction, and kidney damage. Diuretics, ACE
inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), beta-blockers, and calcium channel blockers
(CCBs) are the key drugs prescribed for hypertension. Whereas Norvasc is a CCB, newer blockbusters such
as Diovan, Cozaar, Blopress, and Micardis are all ARBs. ARBs have emerged as the definitive successor to
CCBs and the largest prescribed category within antihypertensives. However, the entry of Cozaar generics in
2011 is expected to restrict the growth of ARBs. ACE inhibitors are another sub-category that is witnessing a
decline in sales due to rapid genericization and competition from ARBs. Growth in the hypertension market is
likely to be driven by novel therapies such as Novartiss Tekturna and increased use of ARBs and their
combinations. Another trend observed in this market is the increased use of combination therapies, which
helps to build patience compliance by reducing the pill burden and intensity of side effects. Some frequently
45
used combinations include an ACE-I or ARB with CCB and a diuretic. Rasilamlo is one such combination
product, manufactured by Novartis. It is a combination of an ARB (aliskiren) and a CCB (amlodipine).
Antidyslipidemics were the second largest drug class within the cardiovascular market, registering global
sales of $29.9bn in 2010, with a total market share of 18%.
Antihypertensives
Introduction
Antihypertensives represent the largest drug class within the cardiovascular market, accounting for 22% of
the overall market. The major drug classes falling within this category are:
angiotensin receptor blockers (ARB)
calcium channel blockers (CCB)
ACE inhibitors (ACE-I)
diuretics
beta blockers.
ARBs are a recently introduced class of antihypertensives that are increasingly prescribed and considered to
be one of the growth drivers in this market. Angiotensin II is a blood vessel constrictor that causes
vasoconstriction throughout the body, and angiotensin II receptor antagonists are known to have good
efficacy and side-effect profiles.
The antihypertensives market is expected to undergo value erosion due to increased genericization of
leading therapies during the forecast period. However, increased adoption of recently launched novel
products such as Tekturna and Exforge is likely to provide an impetus to the market.
Antihypertensive drug classes

The antihypertensives market is complex, with the presence of an array of drug classes, ranging from
traditional therapies to novel combination products, each differing in its mechanism of action.
46
Blood pressure is maintained at a certain level by a chain of hormonal reactions in the body. The first of
these steps is the production of renin by the kidneys when they sense a lowered blood pressure. Renin, in
turn, helps in the production of angiotensin I, a protein that is converted to angiotensin II in the lungs by the
action of an enzyme (angiotensin-converting enzyme). Angiotensin II is a blood-vessel constrictor that
causes vasoconstriction throughout the body. It also leads to the secretion of aldosterone, an adrenal glands
hormone that helps in elevating blood pressure. This hormonal system is known as the renin-angiotensinaldosterone (RAA) hormonal system.
The difference between the antihypertensives drug classes lies in the step of the RAA hormonal system that
they act on. Two drug classes are known to have the maximum effect on this system, ARBs and ACE-Is.
ARBs block chemical receptors for angiotensin II so that it does not cause the arteries to constrict. ACE-Is,
on the other hand, prevent angiotensin I conversion to angiotensin II. ACE-Is may also have additional
effects, such as increasing the amount of chemicals that widen the arteries.
A third drug class, CCBs, acts on the calcium channel of the arteries. They prevent calcium from entering
into the artery muscles, keeping the arteries from contracting. One of the erstwhile leaders in the
antihypertensive market, Norvasc, is a CCB.
Beta-receptor blockers have been available for more than 35 years. They have been used for migraine,
congestive heart failure, cardiac arrhythmias, and even as a secondary prevention after myocardial
infarction. Beta blockers block sympathetic effects of the nervous system on the heart, reducing its workload,
which lowers blood pressure. Diuretics help the body in getting rid of excess fluid and salt through urine,
which helps to lower blood pressure.

The top ten products in the cardiovascular market predominantly belong to the ARB sub-category, a trend
that is expected to continue up to 201213. However, rapid genericization across other sub-categories is
expected to negatively affect the prospects of ARBs. The popularity of ARBs has been primarily due to their
favorable side-effect profile, which has given them a competitive edge over several ACE inhibitors. In
addition, the ARB class has benefited from positive outcomes data from key studies such as VAL-HeFT and
47
LIFE, which have clearly demonstrated the superiority of ARBs over other sub-categories. The calcium
channel blockers, another leading sub-category is currently in decline due to the patent expiration of
Norvasc, the former top-selling drug.
Growth in the antihypertensive category is likely to be driven by products with novel mechanisms of action,
and combination therapies involving the use of multiple drugs with different mechanisms that complement
each other. Novartiss Tekturna, launched in March 2007 was initially approved as an add-on therapy for
hydrochlorothiazide, ARBs, and ACE inhibitors and as a monotherapy for uncontrolled hypertensives.
However, a fixed dose combination of Tekturna/hydrochlorothiazide (HCT) was approved in 2009 for patients
likely to receive multiple therapies, thus boosting the growth prospects. In addition, Novartis is expected to
file two other Tekturna combinations in 2010 (Tekturna/amlodipine, and Tekturna/amlodipine/HCT), which if
approved could further help Tekturna consolidate its position as a potential blockbuster. Table 10 shows the
leading antihypertensive drugs in 2010.
48
Table 10: Sales of leading antihypertensive drugs ($m), 2010
Brand
name
Generic
name
Category
Sales 2010
($m)
Market
share 2010
(%)
CAGR
201016
(%)
Patent
expiry
Diovan
valsartan
ARB
3,632
9.6
-14.6
2012
Benicar
olmesartan
ARB
2,891
7.7
0.8
2016
Blopress
candesartan
ARB
2,449
6.5
-3.8
2014*
CoDiovan
valsartan
/HCT
ARB
2,421
6.4
-8.8
2012
Cozaar
losartan
ARB
2,105
5.6
-14.0
Expired
2010
Aprovel
irbesartan
ARB
1,758
4.7
-3.3
NA
Norvasc
amlodipine
CCB
1,506
4.0
-7.5
Expired
Micardis
telmisartan
ARB
1,329
3.5
-10.8
2017*
Seloken
metoprolol
Beta
blocker
1,210
3.2
0.5
NA
Exforge
amlodipine/
valsartan
CCB
904
2.4
3.4
2017
Total
leading
20,205
53.6
Others
17,452
46.4
Grand
total
37,657
100
* Japanese patent expiry

Source: company reported sales, FDA Orange Book
BUSINESS INSIGHTS
Novartiss Diovan led the antihypertensives market in 2010, registering sales of $3.7bn. Its HCT combination,
Co-Diovan achieved $2.4bn in sales and was the fourth largest selling antihypertensive drug in 2010. Pfizers
former blockbuster Norvasc, which was the market leader in 2007, has suffered severe sales erosion due to
genericization and is expected to exhibit a negative CAGR of -7.5% from 2010 to 2016.
Diovans market position has been strengthened further by its label expansion, supported by clinical
programs such as Val-HeFT (Valsartan Heart Failure Trial). This trial supported the use of Diovan for the
49
treatment of heart failure in cases where patients are not able to tolerate ACE-I. Another study, VALIANT
(VALsartan In Acute Myocardial Infarction Trial), supported its label expansion for patients who have suffered
a heart attack, to reduce cardiovascular death. A third study, VALUE (Valsartan Antihypertensive Long-term
Use Evaluation), supports its long-term use in preference to Norvasc. In 2007, Novartis launched Exforge
(Diovan/amlodipine), an expanded formulation of Diovan. The drug is a fixed dose combination, which is also
approved in the US for first-line use in the treatment of high blood pressure. As the revenues indicate,
Exforge has performed well in the US market, where fixed dose combinations have had moderate success at
best.
The second largest ARB, Benicar, generated $2.9bn in 2010. Blopress was the third largest selling
antihypertensive drug in 2010 and achieved $2.5bn in sales. Sales of Blopress can be attributed to the fact
that it is the first ARB to be approved for the treatment of chronic heart failure in three major markets (Japan,
US, and Europe). Cozaar was the fifth largest selling drug and generated revenues of $2.1bn. Over the past
few years, Cozaars sales have been largely driven by positive data from clinical trials such as LIFE
(Losartan Intervention For Endpoint Reduction in Hypertension) and RENAAL (Reduction of Endpoints in
Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II antagonist Losartan). However, following its
patent expiry in 2011, Cozaars sales are expected to erode significantly. One of the biggest drawbacks for
Cozaar has been the lack of a first-line congestive heart failure (CHF) claim worldwide, thus losing out to key
competitor brands such as Diovan.
Beta blockers are dominated by generics of atenolol, metoprolol, nadolol, pindolol, and propranolol. In 2008,
Forest laboratories launched a third-generation beta blocker, Bystolic (nebivolol) with a differentiated
mechanism of action. Bystolic was also being tested in patients with chronic heart failure, an indication for
which the FDA declined approval in February 2010. Despite this setback, there is still a potential market for
Bystolic in the elderly heart failure patient population, owing to positive data from a European pivotal CHF
trial (SENIORS). However, the biggest challenge for Bystolic is expected to be from generic Seloken
(metoprolol) and Coreg (carvedilol), which are known to have better safety profiles.
50
Key brands analysis

Diovan/Co-Diovan
Novartiss Diovan franchise collectively generated sales of $6bn in 2010. Diovan and Co-Diovan have both
grown largely by capturing Norvasc sales following its patent expiry in 2007. Additionally, positive outcomes
data from key clinical studies such as Val-HeFT, VALIANT, and VALUE covering over 55,000 patients has
helped in extending the Diovan label beyond hypertension, thus consolidating its position in the market.
Clinical
The Val-HeFT trial supported Diovans claim in heart failure treatment for patients who cannot tolerate ACE-I
(Cohn et al., 1999) while VALIANT supported the drugs label expansion for the reduction of cardiovascular
death in patients at high risk (with left ventricular failure or dysfunction) following a heart attack (Pfeffer et al.,
2000), and VALUE (Julius et al., 2004) supported long-term use when compared with Norvasc. The ABCD2V study (Bedigian et al., 2000) demonstrated that intensive diastolic blood pressure control also returned
diabetic patients return to normoalbuminuria.
Regulatory/commercial
Novartis launched two versions of Diovan HCT in the EU in 2009 with higher doses of diuretic (12.5mg and
25mg). The Diovan/amlodipine fixed-dose combination Exforge is one of the key products in the
antihypertensive market, registering $904m in sales in 2010. Exforge/HCT consists of a CCB (amlodipine),
an ARB (valsartan), and a diuretic (HCT), making it the first three-in-one combination treatment in the
antihypertensives market. These Diovan line extensions are part of Novartiss strategy to offset lost sales
due to generic erosion following the loss of patent exclusivity in major EU markets in mid 2011.
Cozaar
Cozaar belongs to the ARBs, the most prescribed antihypertensive class. Angiotensin-II is a powerful bloodvessel constrictor, and can cause vasoconstriction throughout the body. In general, angiotensin-II receptor
antagonists have very good efficacy and side-effect profiles. Their major advantage is a favorable side-effect
profile, such as the absence of cough.
51
Clinical
Cozaar is supported by indications for reduction in end-stage renal disease in diabetic patients, stemming
from the results of the RENAAL trial, and a stroke indication based on the LIFE study. RENAAL (Reduction
of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan) was a
1,513 patient study of type 2 diabetics that assessed Cozaars impact on renal insufficiency and diabetic
nephropathy. Patients received Cozaar 50mg, 100mg, or placebo once daily, and were studied for 3.4 years.
Cozaar reduced the primary endpoint of either a doubling of serum creatinine, kidney failure, or death by
16% compared with placebo (p = 0.024). It also reduced the risk of progression to end-stage renal disease
requiring dialysis or kidney transplantation by 28% compared with placebo (p = 0.002) (Brenner et al., 2001).
LIFE (Losartan Intervention For Endpoint Reduction in Hypertension) was revealed at the American College
of Cardiology meeting in March 2002. The trial compared Cozaar (Losartan) with atenolol (beta blocker) and
was designed to conclude after 1,040 cardiovascular events and a duration of four years. The overall results
were positive for Cozaar, as it showed a 13% risk reduction in the primary endpoint of cardiovascular
mortality, stroke, and myocardial infarction (p = 0.009) (Dalhf et al., 1997). Cozaar reduced total mortality in
diabetics by 39% versus atenolol (p < 0.05). However, the data raised some questions. Stroke was the only
component of the primary endpoint that contributed a statistically significant improvement when assessed
separately, with risk of stroke reduced by 25% for patients taking Cozaar compared with atenolol (p = 0.001)
(Dalhf et al., 1997). Data assessing Cozaar versus atenolol for the reduction of cardiovascular death and MI
were not statistically significant. Overall, the results of LIFE are viewed as impressive, given the sizable
mortality benefit that was observed with Cozaar, particularly in diabetics. Furthermore, LIFE was the first
outcomes study which showed that mechanisms are important; Cozaar led to similar blood pressure
reduction versus atenolol, yet delivered more powerful reductions in events. Cozaar will likely become the
ARB of choice in patients with hypertension and left ventricular hypertrophy, the latter being sometimes
viewed as a proxy for high-risk hypertension. Beta blockers are considered to be less effective than ACE-I
due to a lack of impact on the kidney. Cozaar received an expanded indication approval for the prevention of
stroke based on the LIFE data.
52
Cozaar lacks a first-line CHF claim worldwide, giving Diovan a significant competitive advantage.
Furthermore, the loss of patent protection in 2011 will further erode its sales and alter the dynamics of the
ARB market.
Benicar
Scientific
Benicar (olmesartan) is an ARB in the same class as Diovan and Co-Diovan, launched by a joint venture
between Forest and Sankyo in 2002. The results of a clinical study sponsored by Sankyo, and announced at
the American Society of Hypertension meetings in 2000, demonstrated Benicars statistically significant
superiority in starting doses over other ARBs, including Cozaar, Diovan, and Avapro, in the reduction of
diastolic pressure.
Clinical
Benicar is currently undergoing a trial called ROADMAP (Randomised Olmesartan and Diabetes
MicroAlbuminuria Prevention Study), a first-of-its-kind trial in which the effect of an ARB on the prevention of
microalbuminuria in patients with type 2 diabetes is being studied. The final results of this study are expected
in 2012.
Although Benicar was launched in 2002, it underwent an upsurge in sales after the commercialization of its
diuretic combination version with HCT (hydrochlorothiazide) in September 2003. Despite the lack of
significant differentiation from other ARBs, aggressive marketing has allowed Benicar to capture $2.9bn in
sales in 2010, making it the second largest selling drug in the cardiovascular category. Mylan challenged the
Benicar HCT combination in February 2007, but in March 2009 a lower court found the patent valid. The
Benicar patent is currently valid up to 2016, with peak sales expected in 2013. Sales are expected to
diminish after 2014 owing to increasing competition from the genericization of key brands, including
Blopress.
53
Antidyslipidemics
Introduction
Antidyslipidemics remain the second-largest drug class in the cardiovascular market, generating $29.9bn in
sales in 2010, and accounting for a market share of 18%. The antidyslipidemics drug class includes the
following sub-categories:
statins
fibrates
non-statins.
The current outlook of the dyslipidemia market has been shaped by several key events:
the appearance of Zocor generics in 2006
torcetrapibs clinical setback in 2006
the FDAs not approvable letter given to Mercks Tredaptive in April 2008
Vytorins clinical data from the ENHANCE and SEAS trials.
In addition to all these developments, generic simvastatin has captured a significant share of the statins
market, leading to a decline in the sales of its branded counterparts Genericization of leading dyslipidemic
drugs such as Lipitor is likely to offset the growth driven by factors such as Crestors expanded approval
following the JUPITER (Justification for the Use of Statins in Primary Prevention ) trial data, which has the
potential to expand the market to include patients with normal levels of LDL and high C-reactive protein
(CRP). The market share of branded statins is declining due to recent patent expirations of key products
such as that of Zocor (2006).
Antidyslipidemic drug classes

The antidyslipidemics market consists of statins, fibrates, and a few other non-statin products, such as Zetia
(ezetimibe; Merck), and Niaspan (niacin; Abbott). Statins dominate the market, with most of the key drugs
falling into this class. Statins reduce blood cholesterol by lowering its production from the liver. Scientifically
54
referred to as HMG-CoA reductase inhibitors, statins block hydroxymethylglutaryl-coenzyme A reductase

(HMG-CoA reductase), the enzyme responsible for making cholesterol. They are prescribed for the treatment
of atherosclerosis (which causes stroke, heart attack, and chest pain) or for people with high blood
cholesterol levels.
Individual statins differ in their ability to lower blood cholesterol. Lipitor (atorvastatin) and Crestor
(rosuvastatin), for instance, are the most potent statins, while Lescol (fluvastatin) is the least potent. Statins
also differ in their interactions with other drugs, several of which are known to block the enzymes that
eliminate statins. When taken with statins, these may lead to increased statin levels, leading to inflammation
of the muscles, a condition called myopathy. Pravachol (pravastatin) and Crestor (rosuvastatin) are two
statins that are less likely to increase in level when taken with other drugs.
Fibrates are fibric acid derivatives that help in lowering blood triglyceride levels. Two ways in which fibrates
act are by reducing very low density lipoprotein (VLDL) (a triglyceride-carrying particle in blood) production in
the liver and speedy removal of triglycerides from the blood. They may also help in increasing HDL
cholesterol, although they are not effective in reducing LDL cholesterol levels.

The antidyslipidemics market is dominated by statins, which are predominant among the top 10 brands. The
top ten brands in the market recorded sales of $27.8bn accounting for over 90% of the market. Lipitor was
the top-selling drug, occupying 39.7% of the market. However, Lipitors growth has stagnated in the past four
years. Other than Lipitor, some of the top brands include Crestor at $6.8bn and Zetia at $2.3bn. Table 11
illustrates the leading antidyslipidemic brands in 2010.
55
Table 11: Sales of leading antidyslipidemic drugs ($m), 2010
Brand
name
Generic
name
Category
Sales 2010
($m)
Market
share 2010
(%)
CAGR
201016
(%)
Patent
expiry
Lipitor
atorvastatin
statin
11,873
39.7
-23.9
2011
Crestor
rosuvastatin
statin
6,767
22.6
3.8
2016
Zetia
ezetimibe
others
2,298
7.7
-1.8
2016
Vytorin
ezetimibe/
simvastatin
statin
2,014
6.7
-8.2
2017
TriCor/TRI
LIPIX
fenofibrate
fibrate
1,582
5.3
-7.4
Expired
Niaspan
niacin
GPR109
agonist
927
3.1
-53.0
2013
Lovaza
omega-3acid ethyl
esters
819
2.7
-8.0
Mevalotin
parvastatin
statin
538
1.8
-6.9
Expired
Caduet
amlodipine/
atorvastatin
statin
527
1.8
-6.1
2018
Zocor
simvastatin
statin
468
1.6
-13.6
Expired
Total
leading
27,813
93
Others
2,086
Grand
total
29,899
100
BUSINESS INSIGHTS
Sales of Lipitor have exhibited a steady decline in the past three to four years owing to the availability of
generic simvastatin since 2006 and also the emergence of Crestor as a leading treatment alternative. Sales
of Lipitor are set to decline at a CAGR of -23.9% from 2010 to 2016. AstraZenecas Crestor (rosuvastatin) is
another leading statin, with 2010 sales of $6.7bn. The sales of Crestor have continually risen since launch
and are likely to grow at a strong positive CAGR of 3.8%. Favorable clinical trial results, diminishing safety
concerns, and heavy promotions have assisted in boosting Crestors uptake. Furthermore, the increasing
use of high-potency statins among primary care physicians continues to drive growth for Crestor.
56
Pfizers Caduet (amlodipine and atorvastatin) registered sales of $527m in 2010 and is set to experience a
decline in sales at the rate of -6.1% from 2010 to 2016. The drug is a fixed dose combination of Lipitor and
Norvasc, and is one of the many options for treating high blood pressure and high cholesterol. Overall,
Caduets launch has been disappointing owing to slow managed-care acceptance, as the drug is viewed by
many formulary managers as a franchise extension strategy for Norvasc, which suffers from generic
competition.
Key brands analysis

Lipitor
Scientific
Lipitor (atorvastatin) is the largest selling drug globally, a mega blockbuster with 2010 sales of $11.8bn. It is
a liver-selective HMG-CoA reductase inhibitor and also one of the most researched drugs, backed by over
15 years of research data. The drug is estimated to lower LDL levels by 3960%, depending on dosage. It
has received additional FDA approval for stroke, heart attack, chest pain (in patients with risk factors for
heart diseases), and some types of heart surgeries.
Clinical
Observational studies undertaken by Pfizer after the launch of generic Zocor have indicated that patients on
Lipitor had a 12% lower risk of a cardiovascular event compared with simvastatin. Lipitor patients also had a
15% lower risk of heart attack. Pfizer aggressively promoted the uptake of Lipitor 80mg formulations based
on the data from the REVERSAL (Reversal of atherosclerosis with aggressive lipid lowering), PROVEIT
(pravastatin or atorvastatin evaluation and infection therapy) and TNT (Treating to New Targets) studies. The
TNT results indicated a 22% reduction in cardiovascular events with 80mg, relative to 10mg, as well as only
a slight difference in muscle-related side effects including rhabdomyolysis (Waters et al., 2004). However, in
the IDEAL study Lipitor 80mg versus Zocor 20mg and 40mg indicated only an 11% relative reduction (nonsignificant) in cardiovascular events, the primary composite endpoint (Pedersen et al., 2005). The trial
provided support for managed care to push generic Zocor over branded statins.
An analysis conducted after IDEAL indicated that patients taking Lipitor 80mg had their risk of experiencing
another heart attack reduced by 46%. Additionally, the risk of experiencing major coronary events, such as
57
heart attack, cardiac arrest, and cardiac death, was found to be reduced by 34% relative to simvastatin 20
40mg doses. Lipitor 80mg also significantly reduced the risk of stroke, unstable angina, death, and
revascularization by 18% relative to 2040 mg simvastatin. The safety profiles of the two groups were found
to be comparable.
The REVERSAL (Cannon et al., 2004) and PROVE-IT (Nissen et al., 2004) studies that compared Lipitor
80mg to Pravachol 40mg found Lipitor to be superior to Pravachol in reducing cardiovascular events
(PROVE-IT) and plaque volume (REVERSAL). Both the trials data showed Lipitor 80mg to be very safe over
the two-year period.
ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events) compared the effects of an
aggressive lipid-lowering regimen with atorvastatin in patients after myocardial infarction versus a control
group receiving the usual care (lipid lowering drugs including statins at a dosage of 2040mg, diet
modifications, and lifestyle changes). The results showed a reduction in non-fatal MI with atorvastatin by
47%, relative to the alternative therapeutic options (Koren et al., 2004).
The availability of generic simvastatin in the market, as well as competition from AstraZenecas Crestor, has
led to increasing therapeutic substitution and a declining market share for Lipitor. All this has resulted in a
waning of Lipitors dominance in the lipid control market, though it still continues to be the top-selling statin
globally. The drug is expected to lose patent exclusivity in the US in November 2011, which will lead to
severe erosion of sales.
Pfizer has recently filed a 5mg formulation of the drug in the EU for pediatric use. This filing is for the use of
Lipitor in six to 18 year-old patients who have familial hypercholesterolemia. The filing was supported by data
from new studies of the drug in heterozygous familial hypercholesterolemia (HeFH) patients in the age group
of six to 18 years, together with older data that was used to support its US pediatric filing. This is an effort by
the company to extend Lipitors patent protection; if approved, the drug would be eligible for patent term
extensions in some EU nations such as France and the UK. In the US, the drug has been approved for use
in adolescent HeFH patients since 2002.
58
Pfizer had been contesting Ranbaxy in a bid to delay generic competition for Lipitor until 2016. The two
companies finally entered into a settlement in June 2008. According to the settlement, Ranbaxy will not sell
the drugs generic version until November 30, 2011. After this date, Ranbaxy will share a six-month market
exclusivity period with Cobalt (a subsidiary of Watson). Cobalt had filed an ANDA for the approval of a
product containing atorvastatin sodium, a salt form that is different from the atorvastatin calcium used in
Lipitor. In 2007, Pfizer filed a suit against Cobalt, leveling allegations of infringement of the enantiomer
patent. Pfizer and Cobalt had then (April 2008) entered into an agreement which gave Cobalt the right to
make authorized generics for a period of five years, wherein Pfizer will provide API through its subsidiary
Greenstone. In April 2009, Teva had also entered into a settlement with Pfizer.
Ranbaxys ability to manufacture generic Lipitor has become unclear owing to safety concerns raised by the
FDA. Inspections of Ranbaxy plants in India have found several quality control issues such as the lack of
proper GMPs and falsification of stability data. This has led to the halting of pending and future drug review
applications for drugs manufactured at Ranbaxys Paonta Sahib plant, the originally intended site of
atorvastatin manufacture. Ranbaxy has now requested permission to manufacture atorvastatin from its plant
in New Jersey (US), but it is unclear whether it will be granted. These regulatory issues have made it
uncertain whether Ranbaxy will be in a position to begin marketing atorvastatin in November 2011. Since
Ranbaxy was the first to file its application for the manufacture of generic Lipitor, the lack of a clear
regulatory decision from FDA would also prevent other generic manufacturers from manufacturing the drug.
Meanwhile, Pfizer intends to manufacture its own generic version of Lipitor, which will be distributed through
Watson Pharmaceuticals. The lack of a generic entry from other manufacturers would mean that Pfizer could
sell generic Lipitor at about 70-80% of the current Lipitor price even after the expiration of the patent
exclusivity period in November 2011. This in turn could be disadvantageous for managed care providers,
who are under pressure to contain costs.
Crestor
Scientific
Crestor (rosuvastatin calcium), a statin from AstraZeneca, registered 2010 sales of $6.7bn and holds a
market share of 22.6%. The drug is considered a preferred therapeutic option for high-risk patients owing to
59
its potency in lowering LDL-C, while raising HDL-C. In October 2009, Crestor received FDA approval for
pediatric use (patients aged 1017 years) in treating those suffering from HeFH. This extended approval for
the drug was based on 12-week PLUTO (pediatric lipid-reduction trial of rosuvastatin) trial data. Based on
this data, the FDA also granted an additional six-month licensing exclusivity to Crestor for its approved
atherosclerosis and cholesterol indications through to July 2016. Further, in February 2010 Crestor received
FDA approval for use in the prevention of heart disease in individuals with normal LDL (low density
lipoprotein) levels and no clinically relevant heart disease in the presence of other risk factors.
In November 2007, the FDA approved Crestor for atherosclerosis, demonstrating its efficacy in slowing the
disease progression in adult patients with elevated cholesterol, as an adjunct to diet. This approval was
based on the METEOR trial data. Currently, Crestor is the only statin in the US with a broad atherosclerosis
indication.
In April 2010, the EU approved Crestor for patients with a high risk of experiencing a cardiovascular event.
The European Medicines Agency (EMA) approval followed a similar move by the FDA in 2009, and was
based on positive evidence from the 18,000-patient JUPITER trial.
Crestor has been shown to reduce LDL-C by up to 52% and raise HDL-C by up to 14% (Ridker et al., 2008).
Sales of Crestor grew over the period 200509, likely driven by several factors including:
new clinical data from trials such as JUPITER
expanded label approval as a result of the METEOR trial
increasing use of high potency statins
the ENHANCE and SEAS trial data that caused a shift away from Vytorin.
Clinical
JUPITER trial data released in November 2008 indicated that rosuvastatin lowered strokes and heart attacks
in people with elevated high-sensitivity C-reactive protein (hsCRP) levels, but not high cholesterol. The trial
tested Crestor versus placebo in people with low to normal LDL but an elevated hsCRP, who therefore
exhibit an increased cardiovascular risk profile.
60
AstraZeneca announced a new clinical trial for Crestor, SATURN, in January 2008. SATURN is designed to
measure the impact of 40mg Crestor and 80mg Lipitor (atorvastatin) on the progression of atherosclerosis in
high-risk patients. This study will enroll more than 1,000 patients globally and should be completed in 2011.
Data from the multinational study CORONA were presented at the AHA in November 2007. CORONA
examined the effect on cardiovascular mortality and morbidity of the addition of 10mg Crestor to optimized
treatment. It further studied overall survival from advanced heart failure in older patients who were not on
statin therapy. The study failed to show an improvement in morbidity and mortality when Crestor was added
on top of standard-of-care heart failure medication in CHF patients.
Patients who were on 10mg Crestor experienced an 8% reduction in the combined primary endpoint of
myocardial infarction or stroke, or cardiovascular death, which was statistically insignificant (Kjekshus et al.,
2007). The majority of deaths in this study were sudden, or due to non-ischemic causes, neither of which
appeared to be impacted by statin therapy.
GALAXY, a long-term global clinical research program that started in 2002, investigates the effect of Crestor
on cardiovascular risk reduction and patient outcomes. The study showed an 8% reduction in the combined
primary endpoint of myocardial infarction, stroke, or cardiovascular death, which was not statistically
significant. This reduction was driven by decreased atherosclerotic events (stroke and myocardial infarction).
Additionally, fewer hospitalizations were observed in patients on Crestor in comparison with placebo.
Furthermore, Crestor 10mg was well tolerated and had a safety profile similar to placebo. Additional clinical
trials as part of the GALAXY program are continuing and are likely to be reported in the next few years.
METEOR data indicated that Crestor slowed the progression of atherosclerosis significantly in comparison
with placebo in people who are at a lower risk of coronary heart disease and those with early signs of carotid
artery disease. Additionally, LDL-C reduced by 48.8%, in comparison with 0.3% with placebo, while HDL-C
increased by 8.0%, as against 2.8% with placebo (Crouse et al., 2007). The study met its primary endpoint,
slowing plaque progression, although treatment did not result in plaque reversal. In July 2007, Crestor
prescribing information was updated in the EU to incorporate positive atherosclerosis data from the
METEOR study.
61
In February 2010, Crestor received FDA approval for the prevention of cardiovascular disease. The drug is
now approved for use to reduce the risk of heart attack, stroke, and arterial revascularization procedures in
individuals without any clinically evident heart disease but at a high risk. This was based on the JUPITER
trial data which had shown that the disease prevention benefits of the drug outweighed the risks of adverse
effects. According to FDA documents, the drugs wider indication is likely to increase the statin therapy target
populations size by 15%.
Following this approval, Crestor would be the first statin for which hsCRP (high sensitivity C-reactive protein)
levels would be considered during prescribing. Individuals with hsCRP levels of greater than 2mg/L are at a
high risk of developing heart disease. In light of this expanded approval, the drug could experience higher
sales growth through 2011 until Lipitor generics reach the market. The upside for Crestor could be significant
if AstraZeneca is able to significantly promote the drugs expanded indication with physicians as a
compound-specific advantage such that it is not viewed as a class effect.
Crestors US patent was upheld in June 2010 by a US district court after a trial that began in February 2010.
The challenge was raised by generic manufacturers Aurobindo, Cobalt, Apotex, Mylan, Sandoz, Sun, and
Par on claims that the drugs original patent filing by AstraZenecas partner, Shionogi, omitted material
information. This is considered to be a major victory for Crestor and is expected to provide a boost to the
overall antidyslipidemics market.
There are some concerns over the drugs expanded approval. One of the key issues is that the expanded
patient base results are due to the inclusion of individuals with increased CRP levels (and normal LDL
levels). Elevated CRP is not a very good indicator of cardiovascular risk. Individuals who have higher than
normal CRP do have a higher risk of heart attack (as well as diseases such as cancer and diabetes), and
statins have been shown to lower circulating CRP levels. But CRP is a marker for several other indications
as well, such as arthritis, vitamin D deficiency, viral infections, and excess weight, which implies that high
CRP levels may not necessarily equate to cardiovascular risk.
62
Besides this, there are concerns about the JUPITER trial as well. In the study, 13 deaths occurred due to
gastrointestinal disorders among the Crestor group of patients (compared with one in the placebo group).
There were also 18 cases of neurocognitive dysfunction (as against four in the placebo group). Additionally,
there was a 27% rise in reported cases of diabetes in the Crestor group of patients. Based on this data, the
FDA committee had concluded that Crestors benefits outweighed the risks. However, diabetes itself is a risk
factor for cardiovascular disease. This further raises concern over whether Crestor could increase
cardiovascular risk in some cases.
Further to this, muscle pain is also one of the side-effects of Crestor. Therefore, if asymptomatic individuals
are given the medication only as a preventive measure, compliance is likely to be low. Appearance of any
side effects may act as a further deterrent toward compliance. There is also the question of reimbursement,
as insurers may not be keen to pay for the drugs administration in otherwise healthy individuals. Another
question that arises is whether the ability to reduce cardiovascular risk is limited to Crestor or extends to
other statins as well (a class effect). If the effectiveness of other statins in preventing cardiovascular disease
is proved, Crestors commercial prospects are likely to be jeopardized. This is especially so because
generics of Mercks Zocor (simvastatin) and Bristol-Myers Squibbs Pravachol (pravastatin) are already
available and may encroach on Crestor sales. Another issue that plagues the drug is whether physicians
would order a CRP assay for all potential patients, as primary care physicians do not routinely screen CRP
levels.
Future blockbusters in the antidyslipidemic drug class

Lipitor was a major blockbuster drug in the cardiovascular market segment, with worldwide sales of $11.8bn
in 2010. The impending patent expiry of Lipitor is likely to impact the antidyslipidemic market severely.
Torcetrapib, developed by Pfizer, showed early promise of being a potential replacement for Lipitor.
Torcetrapib acts as an inhibitor of cholesteryl ester transfer protein (CETP) and the expectation was that this
would raise HDL levels and reduce LDL to provide improvement in cardiovascular health. However,
torcetrapib failed in Phase III clinical trials owing to an unexpected increase in cardiovascular events
associated with its use. Although this initially cast doubt on the potential for CETP inhibitors to replace
statins, extensive studies of newer lipid-lowering compounds developed by Roche and GSK show that they
63
may not necessarily suffer the same toxicities as torcetrapib, and thus may be in contention to replace
Lipitor. The three major blockbuster candidates for the replacement of Lipitor are:
Dalcetrapib This is manufactured by Roche, and acts through the mechanism of cholesteryl ester
transfer protein (CETP) inhibition. CETP is an enzyme that leads to the transfer of cholesteryl ester
molecules from low-density lipoprotein (LDL) to high-density lipoprotein (HDL), and inhibition leads to a
build-up in HDL. HDL is actively involved in reverse-cholesterol transfer processes and thus removes
excess cholesterol (lipid) from the body and also has cardio-protective properties. Roche is expected to
report Phase III data for dalcetrapib by the end of 2012.
Darapladib This is manufactured by GSK, and acts through the mechanism of lipoprotein associated
phospholipase A2 (Lp-PLA2) inhibition. Lp-PLA2 makes an atherosclerotic plaque vulnerable to rupture
due to its inflammation promoting properties. Inhibition of Lp-PLA2 stabilizes the plaque and thus
reduces the risk of cardiovascular events such as myocardial infarction or stroke. Due to the lack of
lipid-lowering properties, darapladib is unlikely to replace Lipitor by itself but would rather emerge as a
strong complement to drugs such as dalcetrapib. GSK is likely to announce Phase III results by 2012 or
2013.
Aleglitazar This is manufactured by Roche and acts as a peroxisome proliferator activated receptor
(PPAR) agonist. PPAR agonists can assist cardiovascular (CV) risk management through multiple
modes of actions, including lipid lowering, blood pressure lowering, and hyperglycemia management.
The glucose-lowering mechanisms of aleglitazar prevent it from being used as a general lipid-lowering
agent such as dalcetrapib. However, Roche is targeting the development of aleglitazar for high risk type
2 diabetes patient sub-groups, where it may prove more useful than dalcetrapib.
An analysis of the sales forecasts of the potential antidyslipidemic blockbusters vis--vis Lipitor (Figure 10),
shows that the slump in sales of Lipitor once it is genericized could in fact be rescued through the new
antidyslipidemic drugs. Together, these could account for $14bn in sales in 2016.
64
Figure 10:
Sales of potential antidyslipidemic drugs versus Lipitor ($m), 201016
12,000
Global sales ($m)
10,000
8,000
6,000
4,000
2,000
0
2010
2011
Lipitor [PFE]
2012
2013
Dalcetrapib
2014
2015
Aleglitaxar
2016
Darapladip
BUSINESS INSIGHTS
Antithrombotics
Introduction
The antithrombotics market registered $18.7bn in sales in 2010, accounting for an 11% share of the global
cardiovascular market. In the period from 200510, the antithrombotics market grew strongly, driven by
leading products such as Plavix, Lovenox, and Asasantin. The market growth over the next few years will be
positively impacted by the recent commercialization of key products such as Bayer/J&Js Xarelto, and the
future approval of others such as Pfizer/BMSs apixaban and Daiichi Sankyos Effient. In 2008, Xarelto was
approved in the EU and launched in Germany and the UK. However, in the US Xarelto received a complete
response letter from the FDA in May 2009, and it may suffer owing to a higher than expected bleeding risk in
atrial fibrillation, considering a once daily dosing and also the dose variability needed in patients with poor
kidney function.
The antithrombotics market can be broadly categorized into the following drug classes:
65
antiplatelets
heparins
vitamin K antagonists
fibrinolytics.
The anticoagulants market is dominated by low-molecular-weight heparins (LMWHs), which offer benefits
such as ease of administration and an improved therapeutic profile. LMWHs have thus far been able to
replace unfractionated heparin (UFH) in all patient populations, except those with renal insufficiency. Sanofis
Lovenox is the dominant LMWH, with 2010 sales of $3.8bn. Adenosine diphosphate (ADP) receptor
antagonists dominate the antiplatelet agents market in terms of revenue and market share, followed by
platelet cyclic adenosine monophosphate (cAMP) enhancers and Gp2b/3a inhibitors.
Antithrombotics drug classes

The antithrombotics market consists of antiplatelets, heparins, vitamin K antagonists, and fibrinolytics.
Antiplatelets are drugs that interfere with the bloods ability to clot, thereby preventing the formation of blood
clots that can lead to stroke or heart attack. A blood clot is formed when blood platelets clump together
where plaque is formed in a blood vessel. Plaque is formed when cholesterol and other such substances
accumulate in the inner lining of arteries, a process called atherosclerosis. Antiplatelet agents such as
aspirin, clopidogrel, ticlopidine, and dipyridamole prevent blood platelets from clumping.
Heparin is an anionic mucopolysaccharide that acts as an anticoagulant. It forms a complex with
antithrombin and then catalyzes the inhibition of blood coagulation factors such as IXa, Xa, XIa, XIIa, and
thrombin. Heparins are used for the prevention and treatment of thromboembolism, both venous and arterial.
LMWHs are typically the treatment of choice for venous thromboembolism, yet UFHs are administered by
continuous intravenous infusion in patients with massive pulmonary embolism, or in cases where patients
are unstable and require interventional procedures or thrombolysis. Intravenous heparins are used in
cardiovascular disease, after coronary artery bypass surgery, angioplasty, peripheral vascular surgery, or
thrombolysis. In these cases intravenous heparin is the therapy of choice because its effect can be quickly
66
reversed once the intravenous infusion has been discontinued, and where necessary by taking protamine
sulfate.

Clots tend to form in the venous and the arterial systems, and both are due to various underlying pathologies
and result in a variety of clinical manifestations. Arterial clots manifest as ischemic diseases such as stroke,
PAD, and acute coronary syndrome. Venous thrombi or clots result from stasis or the slowing of blood flow.
There is a slight difference in the way these two categories of indications are managed. Plavix and aspirin
focus on antiplatelet activity and are the mainstay of ischemic disease management, while LMWHs, such as
Sanofis Lovenox and Pfizers Fragmin, and vitamin K antagonists such as warfarin are all anticoagulants
and are used in venous thromboembolic disease. These drugs interact with different elements of the clotting
cascade, such as the platelets, and help to prevent further thrombus formation. Yet whatever the mechanism
used, preventing the formation of clots leads to increased bleeding. The requirement for monitoring bleeding
risks has resulted in a significant unmet clinical need. This safety hurdle has been particularly significant
following the clinical setback experienced by AstraZenecas Exanta, which was found after approval to cause
liver toxicity. These factors further imply that commercial penetration in this therapeutic area is likely to be
limited to the approved indications and extensive clinical data would be required for a broader adoption.
Factors that have worked to the benefit of LMWH include expanding the use of anticoagulation therapy to
include newer indications, replacement of UFH in existing indications, and a recent incident of heparin
contamination. Table 12 shows the leading antithrombotics brands in the global cardiovascular market in
2010.
67
Table 12: Sales of leading antithrombotic drugs ($m), 2010
Brand
Generic
Category
Sales 2010
($m)
Market
share 2010
(%)
CAGR
2010-16
(%)
Patent
expiry
Plavix
clopidogrel
AP
9,426
50.4
-7.8
2011
Lovenox
enoxaparin
heparin
3,754
20.1
-12.3
2012
Pletaal
cilostazol
PAI
628
3.4
2.2
Expired
Aggrenox
dipyridamole
PAI
608
3.2
-5.2
2017
Aspirin
Bayer
ASA
PAI
474
2.5
3.6
N/A
Arixtra
fondaparinux
others
465
2.5
-10.4
2012
Activase
alteplase
TPA
441
2.4
3.6
2018
Fraxiparine
nadroparine
heparin
343
1.8
-1.6
2017
Intergrilin
eptifibatide
PAI
266
1.4
-14.9
2015
Coumadin
warfarin
VKA
217
1.2
5.4
Expired
Totalleading
16,622
88.9
Others
2,065
11.1
Grand
total
18,687
100
AP = antiplatelet; PAI = platelet aggregation inhibitor; TPA = tissue plasminogen activator; VKA
= vitamin-K antagonist; ASA = acetylsalicylic acid
BUSINESS INSIGHTS
Key brands analysis

Plavix
Sanofi/BMSs Plavix (clopidogrel bisulfate) is the top-selling antiplatelet agent in the market, with sales of
$9.4bn in 2010. The drug is jointly developed and marketed by BMS and Sanofi. The two companies have
set up the REACH (REduction of Atherothrombosis for Continued Health) registry for the study of
atherothrombosis and the risk factors associated with it. In August 2006 the drug was approved in S-T
elevation myocardial infarction (STEMI) based on the COMMIT/CLARITY data. Plavix is one of the
68
mainstays of ischemic disease management due to its potent antiplatelet activity. The drug causes
irreversible blockade of ADP receptor P2Y12, inhibiting the ADP-mediated GPIIb/IIIa complex.
Growth of Plavix in the US market was driven by factors such as growing disease incidence (for indications
where Plavix has approval) and target markets that have not yet been fully penetrated. However, competition
from recently launched products such as Eli Lilly/Daiichi Sankyos Effient and AstraZenecas Brilinta and the
fact that Plavix has no major line extension studies planned before its patent expiry in November 2011, mean
that the drugs future growth is likely to be stifled. In the EU, Plavix generics manufactured by the generic
drug maker Acino have been in the German market since 2009. According to company sources, this generic
version has already captured a quarter of the products market share by volume.
Furthermore, in May 2009 the EMA gave a positive recommendation to six generic versions of the drug.
Also, the potential for atrial fibrillation (ACIVE-A) and the CURRENT/OASIS-7 trials missed the primary endpoint, which has led to concerns about the safety and effectiveness of the drug in a high loading dose.
Plavix is expected to experience negative growth at a CAGR of -7.8% from 2010 to 2016, due to the
decrease in sales values with the patent expiration of Plavix from 2010 to 2016, and the availability of newer
alternative anticoagulants such as apixaban and Xarelto.
Clinical
Plavix has been reviewed in eight major clinical trials, leading to Class I recommendations for the indications
ACS, PAD, and stroke. The randomized, double-blind study of patients with acute STEMI, CLARITY
(CLopidogrel as Adjunctive Reperfusion Therapy), showed that Plavix reduced the odds of acute MI patients
having a second heart attack or another occluded artery, or death, by 36%. The drug was also found to
reduce the rate of cardiovascular death, recurrent myocardial infarction, and recurrent ischemia leading to
urgent revascularization (MACE) by 20%. However, data from the CHARISMA study has reduced the drugs
prevention opportunity as it failed to meet the primary endpoint. The data showed that when Plavix was
added to aspirin it resulted in a heightened rate of cardiovascular mortality in patients with multiple
cardiovascular risk factors but no history of cardiovascular symptoms (Bhatt et al., 2006).
69
Another trial, CLASSICS (Clopidogrel Aspirin Stent International Cooperative Study), showed that the
effectiveness of a combination of Plavix and aspirin, after the implantation of coronary stents, was
comparable to Ticlid (ticlopidine) and aspirin combination, and that the former had better tolerance. COMMIT
(Comprehensive Multidisciplinary Interventional Trial for regression of coronary artery disease), a trial by the
Oxford Group (an independent body), compared Plavix and aspirin with aspirin alone for acute myocardial
infarction. In this trial, patients were not given a loading dose of Plavix and the drug was found to reduce the
relative risk of death by 7% at 28 days. The drug also reduced by 9% the relative risk of the combined
endpoint (stroke, recurrent MI, and death) in the same patient population (Chen et al., 2005).
In late 2009, the US Supreme Court turned down an appeal made by Apotex regarding the 265 patent
covering Plavix, declining without comment to hear the case. An earlier patent covering Plavix had expired in
2003 and since then Apotex had been trying to challenge the 265 patents validity, which had been upheld
by both a US Court of Appeals for the Federal Circuit and a US district court judge. Both the courts had ruled
that Apotex had failed to prove through clear and convincing evidence that the 265 patent should not have
been granted by the US Patent and Trademark Office (USPTO). In early 2009, Apotex also filed a request
with the USPTO to re-examine the 265 patent. The USPTO had accepted the companys request but the reexamination could go on for several years and so even negative conclusions may not affect Plavixs
exclusivity.
In the US, Plavix enjoys patent protection through 2011, while in the EU its bisulfate salt formulation is
protected in most countries through 2013. In the EU, however, generics of Plavix with a different salt
formulation, such as clopidogrel hydrochloride or besylate, have received positive opinion from regulators.
These may not infringe the primary patent covering Plavix.
Generic firms such as Teva, Pharmathen, and Acino have had their versions of generic Plavix recommended
by the CHMP. Sanofi is set to be market-ready with its own generic version of the drug to be launched in
case there is a threat from competitor versions. In Germany, Plavix lost significant market share within six
months of a generic version of the drug being launched. Thus Sanofi is launching its own generic version of
70
Lovenox to prevent a rapid decline in its clopidogrel market share in other EU nations, in order to prevent a
scenario similar to that which occurred in Germany.
Lovenox
Sanofis Lovenox/Clexane is one of the market-leading anticoagulants, with 2010 sales of $3.8bn, but it is
projected to decline at a CAGR of -12.3% from 2010 to 2016. The drug is a LMWH used to prevent clot
formation in veins and arteries, thus helping to prevent likely acute and chronic complications associated with
arterial and deep vein thrombosis. Lovenox is approved for the prevention of deep vein thrombosis (DVT) in
medical patients, prevention of post-surgical DVT, treatment of DVT with or without pulmonary embolism,
morbidity prevention (heart attacks or further strokes), and prevention of mortality following unstable angina
with non-Q wave myocardial infarction.
Lovenox is a complex mixture of purified heparin chains derived from natural sources such as pig intestines.
Therefore, the drug has characteristics of a biologic, such as a lack of complete characterization, and is
difficult to replicate. In May 2007, Lovenox received an FDA approval for treating the most severe type of
heart attack (ST segment elevation myocardial infarction), making it the only LMWH in the US approved for a
wide array of indications.
Clinical
SYNERGY, an 8,000-patient study, showed Lovenox to be as effective as unfractionated heparins (UFH)
when administered with an early aggressive, invasive therapy. A sub-analysis of the study also showed that
patients who started treatment with Lovenox before randomization and continued with Lovenox treatment for
the entire course of the therapy showed an 18% relative risk reduction in the incidence of myocardial
infarction and death, as against a score of 12.8% for patients who started on UFH and continued on it.
EXTRACT-TIMI 25 demonstrated that the risk of recurrent non-fatal heart attack or death was reduced
significantly (17%) in patients on Lovenox therapy, relative to those on UFH treatment. The advantages of
Lovenox therapy were evident in a span of 48 hours. After a period of one month, the risk of recurrent, nonfatal heart attack reduced by 33% in patients on Lovenox therapy, relative to those on UFH.
71
Lovenox was launched in the US in 1993 before the inception of the Biologic License Application (BLA), the
current procedure for approval of biologics, came into effect. The drug was thus registered under a New
Drug Application (NDA), although it did fulfill many characteristics of biologics.
Lovenox came under generic attack in 2003, with ANDA filings by generic makers Teva and Amphastar.
Sanofi filed lawsuits against the two companies, but lost these cases in 2007. In May 2009, the US Supreme
Court declined an appeal by Sanofi regarding a patent challenge to Lovenox by Amphastar. The justices held
that Lovenoxs main patent is unenforceable as a scientist from the company withheld material information
on the drug from the US Patent and Trademark Office. This further implied that there is no legal impediment
for the entry of generic Lovenox in the US. Teva and Amphastar have both had an ANDA pending with the
FDA since April 2003.
However, in July 2010, the FDA approved a generic version of Lovenox (enoxaparin), manufactured and
distributed jointly by Sandoz (a subsidiary of Novartis) and Momenta. This is seen as a significant victory for
Novartis, as Lovenox is one of the highest selling anticoagulant drugs other than Plavix. Amphastar has now
filed a lawsuit against the FDA, asking the Federal Court to force the FDA to approve Amphastars generic
Lovenox. Amphastar has claimed that although it was the first to file the ANDA for generic Lovenox, the FDA
has continually delayed its application without requisite justification.
Future blockbusters in the antithrombotic drug class

With the impending patent expiration of the majority of blockbuster drugs, pharmaceutical companies are
turning to different growth strategies to protect their revenues. These include agreements with generic
manufacturers to protect patent exclusivity for an extended time period (such as the one between Pfizer and
Ranbaxy for an extended six-month exclusivity for Lipitor), and licensing of R&D from third party
manufacturers/developers, so as to shorten the innovation timelines. Licensing has played a very important
role in sustaining top-line growth in pharmaceutical companies such as Roche. However, to maintain
sustained growth once drugs fall off the patent cliff, it is required that pharmaceutical companies generate
novel therapeutic products which could act as potential replacements for the existing blockbuster drugs.
72
The antithrombotic category is characterized by a relatively strong developmental pipeline, with several
products that could prove to be the future blockbusters. Most of these drugs are anticoagulants, which are
aimed at replacing warfarin. Together, they could exhibit potential sales of about $11-12bn in 2021.
Among the various disease conditions, atrial fibrillation shows the greatest potential for sales of the new
antithrombotics (as shown in Figure 11). These drugs are likely to capture significant market share from
Lovenox, which will lose patent exclusivity by 2012.
Figure 11:
16
Sales of antithrombotic drugs by disease conditions in the US ($m), 2010

4,500
Global sales ($m)
4,000
3,500
3,000
2,500
2,000
1,500
1,000
500
0
2011
2012
2013
2014
2015
Atrial fibrillation
Venous thromboembolism
Short-term surgical use
2016
Other medical uses

BUSINESS INSIGHTS
Currently only 30% of atrial fibrillation conditions are treated with warfarin. Thus, stress would be laid on
those antithrombotic drugs with lower bleeding risks than warfarin, as these could be used to treat atrial
fibrillation. Table 13 provides a summary of the major antithrombotic drugs under development.
73
Table 13: Snapshot of the major antithrombotic drugs under development
Drug
Company
Approval
Target
Dose frequency
Pradaxa
(dabigartan)
Boehringer
Ingelheim
Approved ex-US
Direct thrombin
inhibitor
Twice daily
Xarelto
(rivarobaxan)
Bayer/ J&J
Approved ex-US
Direct FXa
inhibitor
Once/Twice daily
Apixaban
BMS/Pfizer
Approval filing by
end 2011
Direct FXa
inhibitor
Twice daily
DU176b
(edoxaban)
Daiichi Sankyo
NA
Direct FXa
inhibitor
Once daily
AZD0837
AstraZeneca
NA
Direct thrombin
inhibitor
Twice/once daily
Betrixaban
Portola/Merck
NA
Direct FXa
inhibitor
Once daily
Source: Eriksson et al.,2009; Business Insights
BUSINESS INSIGHTS
Owing to the twice daily dosing regimen and low potential for drug-drug interactions (as the mechanism of
metabolism involves multiple pathways), apixaban is likely to emerge as the most preferred candidate for
treatment of atrial fibrillation. DU176b and betrixaban require an aggressive once-a-day dosage which poses
a significantly greater bleeding risk than twice-a-day dosing and is thus dangerous to use in low-risk patient
sub-groups. Pradaxa, Xarelto, and AZDO837 can also be used in a twice-a-day dosage regimen, but they
pose a greater risk of interacting with other drugs especially amiodarones and ketoconazole. Thus, these are
less likely to be preferred than apixaban for the treatment of atrial fibrillation. A market-share forecast of
these antithrombotic drugs (as shown in Figure 12), indicates that apixaban is likely to emerge as the largestselling drug in this segment, with an expected market share of about 52% in 2016.
74
Figure 12:
16
Forecast market share of antithrombotic drugs under development, 2010

1
3
100
17
90
24
80
47
Market share (%)
70
60
79
52
52
34
32
10
10
2015
2016
82
63
50
54
40
37
30
20
10
3
3
21
18
20
22
2010
2011
2012
2013
16
Pradaxa
Xarelto
Apixaban
2014
Du-176b
Betrixaban
BUSINESS INSIGHTS
Other cardiovascular agents

Introduction
Other cardiovascular agents include drugs falling under the classes systemic and topical varicose therapy
(products used for the topical/systemic treatment of varicose veins), cerebral and peripheral
vasotherapeutics, cardiac therapies (including medications for angina, heart failure, arrhythmia, and atrial
fibrillation), and some other products recommended for diseases of the cardiovascular system. Table 14
illustrates the top ten other cardiovascular treatments in the global cardiovascular market.
75
Table 14: Sales of leading Other cardiovascular drugs ($m), 2010
Brand name
Generic
name
Company
Sales 2010
($m)
Market share
2010 (%)
CAGR 2010
16 (%)
Tracleer
bosentan
Actelion
1,569
1.9
-1.1
Daflon
diosmin
flavonoids
Servier
448
0.5
1.3
Lexiscan
regadenoson
Astellas
Pharma
433
0.5
3.8
Vastarel
trimetazidine
Servier
422
0.5
-0.1
EpiPen
epinephrine
Mylan
258
0.3
5.9
Letairis
ambrisentan
Gilead
Sciences
240
0.3
4.3
Ranexa
ranolazine
Gilead
Sciences
240
0.3
12.5
Multaq
dronedarone
Sanofi
228
0.3
27.8
Cordarone
amiodarone
Sanofi
209
0.2
-0.5
Sigmart
nicorandil
Roche
169
0.2
-1.7
4,216
5.0
Others
80,000
95.0
Grand total
84,216
100
Total leading
BUSINESS INSIGHTS

The leading drug in the Other cardiovascular agents category was Actelions Tracleer, which generated
$1.6bn in sales in 2010 and accounted for 1.9% of the market. The next top-selling brand in this class was
Serviers Daflon, which registered sales of $448m in 2010, occupying a share of 0.5%.
Tracleer is one of the key oral therapies for pulmonary hypertension used in less severe patients. The FDA
approved Tracleer in 2001 as a treatment for Class III and IV pulmonary arterial hypertension (PAH). The
drug is indicated to reduce the rate of clinical worsening in pulmonary hypertension patients and improve
exercise ability. Following the US launch, the drug received marketing approval in the EU in 2002.
76
Tracleer
Actelions Tracleer (bosentan) is an oral endothelin-1 antagonist. Endothelin-1 is a potent vasoconstrictive
peptide that also plays a role in vascular remodeling. Tracleer binds to both the ETA and ETB endothelin
receptors, resulting in vasodilation of the pulmonary arterial system. Tracleer may also ameliorate vascular
remodeling. With a half-life of roughly five hours, Tracleer is administered twice a day, with an indication to
improve exercise ability and alleviate the rate of clinical worsening in PAH patients with significant limitation
of physical activity.
Clinical
In 2001, Tracleer was approved by the FDA for the treatment of class III and IV pulmonary arterial
hypertension (PAH). In late 2001, the FDA approved Tracleer for the treatment of Class III and IV PAH. The
US launch was followed by EU marketing approval in mid-2002. Tracleer was approved on the basis of data
presented in its 213-patient BREATHE-1 study, which demonstrated an improvement in the primary endpoint
of six-minute walking distance at both doses tested (125mg bid and 250mg bid). After 16 weeks, treatment
with 125mg bid Tracleer led to a 35m placebo-adjusted treatment improvement, and treatment with 250mg
bid led to a 54m improvement.
In the US market, there are currently eight drugs available for PAH therapy, which can broadly be divided
based on their route of administration. Besides Tracleer, the other oral therapies include Pfizers Revatio
(sildenafil), Gileads Letairis (ambrisentan), and United Therapeutics Adcirca (tadalafil). All these therapies
are used in less severe and new cases. The US market also has two branded infused prostacyclins: GSKs
Flolan (epoprostenol) and United Therapeutics Remodulin (treprostinil). Additionally, Teva launched a
generic version of Flolan in 2008. Both of these therapies are very potent and are used in severe patients.
Two inhaled options are also available: United Therapeutics Tyvaso (treprostinil) and Actelions Ventavis
(iloprost). These two therapies are used when disease severity is not high enough for an infused prostanoid
and not mild enough for an oral therapy. The choice of initial therapy thus depends on degree of severity.
Tracleer is forecast to grow at a CAGR of 1.9% from 2010 to 2016. Its growth is likely to be impeded by
several newer endothelin antagonists expected to enter the market during the forecast period.
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Leading brands dynamics and sales forecasts

The following table summarizes the leading brands in the global cardiovascular market in 2010.
Table 15: Sales of leading cardiovascular brands ($m), 2010
Brand
Company
Drug Class
Sales
2010
($m)
Market
share 2010
(%)
CAGR
200510
(%)
CAGR
201016
(%)
Lipitor
Pfizer
antidyslipidemic
11,873
-2.5
-23.90%
Plavix
BMS/Sanofi
antithrombotic
9,426
5.6
0.6
-7.80%
AstraZeneca
antidyslipidemic
6,767
35.0
3.80%
Sanofi
antithrombotic
3,754
2.2
5.7
-12.30%
Diovan
Novartis
antihypertensive
3,632
2.1
10.5
-14.60%
Benicar
Daiichi
Sankyo
antihypertensive
2,891
1.7
22.4
0.80%
Blopress
Takeda
antihypertensive
2,449
1.4
5.5
-3.80%
Novartis
antihypertensive
2,421
1.4
10.5
-8.80%
Merck
(ScheringPlough)
antidyslipidemic
2,298
1.4
19.9
-1.80%
Merck
antihypertensive
2,105
1.2
-7.2
-14.0
Crestor
Lovenox
Co-Diovan
Zetia
Cozaar
BUSINESS INSIGHTS
The top ten brands collectively generated $47.6bn in sales in 2010, accounting for 28% of the global
cardiovascular markets sales. Owing to the presence of leading blockbusters such as Lipitor and Crestor,
antidyslipidemics constituted the largest share within the top ten brands (44%), generating $20.9bn in sales
in 2010. The antihypertensive class was the next largest, with $13.4bn in sales and a 28.4% market share.
Product growth-share matrix for leading brands

A product-growth share matrix analysis of the leading brands (Figure 13) shows that the top products are
predominantly concentrated in the question-marks quadrant (high growth rate but low market share) and
the dogs (low growth rate and low market share) quadrant.
78
Figure 13:
Leading brands product growth BCG matrix
10
Question marks
Stars
Growth rate 2009 10 (%)
5
0
-5
-10
-15
-20
-25
Dogs
-30
0
Crestor
Cash cows
10
Benicar
Cozaar
20
30
40
Market share 2010 (%)
Zetia
Blopress
Diovan
Plavix
50
Co-Diovan
60
Lovenox
Lipitor
BUSINESS INSIGHTS
If the drugs in the question-marks quadrant fail to increase their market share, they will eventually exhibit a
declining Y-o-Y growth and fall into the dogs quadrant. The drugs in the dogs quadrant represent declining
growth categories, and all three of these drugs (Lovenox, Cozaar, and Diovan) are facing patent expirations
in 2012. This is likely to decrease their market share and growth rates even further. Lipitor falls into the cash
cow quadrant, due to its relatively large market share. It is the single largest selling drug in the
cardiovascular category and accounts for 7% of the entire cardiovascular market. However, the growth rates
of Lipitor are low, as sales values are set to decline with its patent expiration in late 2011. Eventually, with
the emergence of generic forms, its market share is further likely to decrease and it would fall into the dogs
category.
Drugs in the dogs category represent low potential for future growth. Thus, companies manufacturing these
drugs should aim to increase market share, using strategies such as expansion into emerging markets.
79
Drugs such as Benicar fall into the question marks category. Benicar has maintained a high growth rate
through aggressive marketing strategies, despite the lack of significant product differentiation when
compared with other ARBs. Manufacturers of these drugs should also attempt to increase the drug-market
share through geographical expansion and aggressive marketing, so that the drugs move toward the stars
category.
Lipitor falls into the cash cow category, owing to its large market share and sales revenues. However, Lipitor
has been exhibiting a continuous Y-o-Y decline in sales and may fall into the dogs category after patent
expiry.
80
Chapter 3 Pipeline analysis

Summary
Anticoagulants are expected to be the subject of intensive R&D activity, with the presence of promising
products such as BMS/Pfizers apixaban and Bayer/J&Js Xarelto. Since most of the factor Xa inhibitors
are in oral form, they are expected to widen the market significantly.
The superior effectiveness and better bleeding profile of Brilinta (ticagrelor) over Plavix make it a key
antithrombotic drug that could be a major player in acute coronary syndrome (ACS). Brilinta also has a
potential therapeutic advantage in atherosclerosis and can be administered to 1530% of
atherosclerosis patients who do not respond to Plavix. Moreover, its use could be initially confined to
ACS with no significant patient monitoring anticipated for respiratory or cardiac function or postmarketing surveillance requirements.
LCZ696, one of Novartiss key pipeline products, delivered favorable Phase IIb results. The data
demonstrated that LCZ696 not only improved blood pressure significantly in patients with mild-tomoderate hypertension but also provided complementary action with neprilysin inhibition and ARB
blockade.
Merck/Portolas betrixaban appears to have a differentiated half-life (19 hours), competitive

bioavailability, and minimal renal excretion which theoretically could result in a superior bleeding profile
and allow recruitment of patients irrespective of renal function. In its Phase IIb results announced in
March 2010, betrixaban demonstrated strong bleeding benefits over warfarin, further strengthening its
case.
The antidyslipidemic category is set to undergo significant declines in sales owing to the patent expiry
of Lipitor. Falling sales could be rescued with the approval of dalcetrapib, a potent CETP inhibitor that
treats dyslipidemia through increasing the levels of HDL cholesterol. Early trial results indicate that
anacetrapib is a more potent CETP inhibitor than dalcetrapib. However, the early entry of dalcetrapib
81
could serve to establish it as a prescription drug of choice, thus giving it a significant advantage over
anacetrapib.
Introduction
This chapter covers key late-stage pipeline drugs, providing analysis of completed and ongoing clinical trials,
with information on launch dates and forecast sales. Hypertension, stroke, thrombosis, and heart failure are
the major cardiovascular indications with the strongest pipeline. The thrombosis market has seen a lot of
upheaval, with promising new drugs such as J&J/Bayers Xarelto (launched in 2008) and Pfizer/BMSs
apixaban (approved in Q2 2011). These oral drugs are expected to widen the thrombosis market significantly
while also extending the prescription period, and they are set to undermine Lovenoxs (Sanofi) monopoly in
the thrombosis market.

First advanced therapy certificate for t2cures somatic cell therapy
Germany based t2cure is a biopharmaceutical company working to develop progenitor cell-based
regenerative therapies to provide new treatment options to patients suffering from various cardiovascular
diseases. The company is currently developing a product called t2c001, which is a somatic cell therapy
product derived from bone marrow. In May 2010 t2c001 was certified under the European Medicines Agency
(EMA) regulations for Advanced Therapy Medicinal Products (ATMPs), a framework intended to ensure the
quality of data associated with advanced biotechnology products ahead of marketing authorization.
Based on data published from its two pivotal trials, TOPCARE-AMI and REPAIR-AMI, t2c001 is currently in
Phase III trials in severe acute myocardial infarction (MI). In addition, it is also part of pilot studies in chronic
ischemic heart disease and in non-ischemic dilative cardiomyopathy.
Compelling five-year safety and efficacy data from the Phase II trial allowed the EMAs committee on
advanced therapeutics (CAT) to rule its decision in favor of the company. This approval is likely to provide a
boost to small and medium-sized companies to pursue research based on novel approaches such as
somatic cell therapy and gene therapy, encouraging them to have an early dialogue with regulators.
82
Clear evidence of safety leads to termination of apixabans Phase III AVERROES

trial
In June 2010, BMS halted its Phase III AVERROES trial in vitamin K antagonist intolerant patients with atrial
fibrillation. Interim data from the trial revealed that the drug reduced stroke and systemic embolism in
comparison with aspirin, in addition to demonstrating sufficient safety, prompting the company to take this
decision.
The AVERROES trial included 5,600 patients randomized to 5mg apixaban twice daily or 81324mg of
aspirin once daily. The primary endpoint of this study was time from first dose of study drug to first
occurrence of ischemic stroke, hemorrhagic stroke, or systemic embolism. Although BMS has not yet
announced the extent of apixabans efficacy, it is currently working on recruiting patients for an open-label
safety extension study.
On the basis of results from the ADVANCE-3 trial, Apixaban has already been approved in the EU for
prevention of VTE in adults who are undergoing elective hip or knee replacement therapies. It is also
undergoing a Phase III trial for use in atrial fibrillation the ARISTOTLE trial which recently ended in Q2
2011. This study is considered to be critical to the success of apixaban as it involves 18,000 patients
randomized to apixaban or warfarin.
FDA panel to review AstraZenecas Brilinta

AstraZenecas Brilinta (ticagrelor), the novel P2Y12 antagonist for the treatment of arterial thrombosis in
patients with ACS, underwent a review by the FDAs cardiovascular and renal drug advisory committee in
July 2010. AstraZeneca filed for an NDA for Brilinta in November 2009, based on the PLATO trial, involving
18,000 patients hospitalized with ACS.
The results of this trial indicated that ticagrelor significantly reduced the composite endpoints of vascular
death, myocardial infarction, or stroke in comparison with clopidogrel. However, in a sub-trial involving 1,814
North American patients, clopidogrel was found to have better efficacy over ticagrelor, raising some minor
concerns. AstraZeneca received a response letter from the FDA in Q4 2010, indicating that the FDA was not
satisfied with the efficacy data provided. This has further delayed the launch of the drug in the US, which is
expected in Q4 2011.
83
Novartis presents successful Phase II results of LCZ696

Novartiss LCZ696 is a novel dual-acting molecule that blocks the activity of ARB and neutral endopeptidase
(NEP), and forms a potential option to replace ACE inhibitors as a standard therapy in heart failure. In March
2010, Novartis presented Phase II results that demonstrated that the product not only improved blood
pressure significantly in patients with mild-to-moderate hypertension but also provided complementary action
with neprilysin inhibition and ARB blockade.
The trial involved 1,328 patients with mild-to-moderate hypertension randomized for eight weeks of treatment
on one of eight strengths: 100mg, 200mg, or 400mg LCZ696; 80mg, 160mg or 320mg Diovan; 200mg
AHU377; or placebo. Novartis is currently planning to pursue the development of the drug for hypertension in
specific populations such as diabetics and elderly patients.
Daiichi Sankyos CS-8635 shows promising results in pivotal trial

Daiichi Sankyos CS-8635 is a triple combination antihypertensive consisting of olmesartan with amlodipine
and hydrochlorothiazide and is currently under FDA review for the treatment of hypertension. The company
released Phase III results at the American Society of Hypertension meeting at New York in May 2010, which
demonstrated that CS-8635 met its primary endpoint. The product was approved in the US, Germany, and
UK in 2010 and is expected to add an edge to Daiichi Sankyos cardiovascular franchise.
In the pivotal trial involving 2,500 patients with moderate-to-severe hypertension, for the first 12 weeks of
treatment the subjects received blinded doses of CS-8635, olmesartan plus amlodipine, olmesartan plus
hydrochlorothiazide, or amlodipine plus hydrochlorothiazide, followed by 40 weeks of open-label treatment.
The results indicated that percentage of patients reaching the current recommended blood pressure target
was greater with the triple combination therapy than with the dual combination therapies, regardless of
gender, age, race, and hypertension severity (p < 0.0001).
Although, there are other triple combination antihypertensives in the market, such as Novartiss Exforge HCT
(approved in the EU and US) and Tekturna (approved in the US and EU), there is expected to be further
room for combination antihypertensives that provide supplemental benefits to patients.
84
Sanofi (Genzyme)/Isis mipomersen clears second Phase III trial, but raises safety
concerns
Mipomersen is a second-generation antisense inhibitor of apolipoprotein B-100 (ApoB-100) synthesis,
designed to prevent the formation of atherogenic lipoproteins. ApoB-100 is a critical element of LDLs, which
contain cholesterol and are considered to be an important risk factor for cardiovascular disease when
elevated. By preventing the formation of the ApoB-100 protein, mipomersen reduces LDL levels and
represents a potential therapeutic strategy for patients with high cholesterol. In fact, because atherogenicity
is determined as much by the number of circulating LDL particles as it is by their size, ApoB-100 levels may
be a better predictor of cardiac risk. This is an important differentiating fact, given that mipomersen appears
to reduce ApoB-100 levels to a greater extent than statins.
Phase III results presented in February 2010 demonstrated that mipomersen was effective in patients with a
less severe form of homozygous familial hypercholesterolemia (hoFH), a rare and fatal genetic condition in
which patients have extremely high cholesterol levels. These results supplement the first set of Phase III
results in November 2009, which showed that mipomersen reduced LDL-C levels significantly (28%
decrease in LDL-C with mipomersen when compared with a 5% increase with placebo after 26 weeks of
treatment) in patients with severe hoFH (Raal et al., 2010). However, both these trials involved elevations in
liver enzymes, which has raised concerns about the drugs safety. Although some analysts believe that
safety data is in line with other commonly used statins, mipomersen will need to vindicate itself through its
future studies to establish itself as a key competitor in the dyslipidemia market.
Cardiovascular pipeline
Among the major cardiovascular disorders, hypertension has the strongest pipeline, with around 112
products under development in 2010. Out of these, eight products were approved, while 30 products were in
the pending approval stage. Thrombosis had the next largest pipeline with 31 products in the Phase II/III
stages, and 30 in the pre-clinical stage. Factor Xa inhibitors such as Xarelto and apixaban have given a
strong boost to the thrombosis market. The two major indications driving growth in this market are prevention
of DVT and prevention of strokes in patients with atrial fibrillation. Other leading cardiovascular indications
with strong pipelines included congestive heart failure, myocardial infarction, dyslipidemia, and pulmonary
85
arterial hypertension, with respectively a total of 85, 64, 56, and 51 products in development. Figure 14
illustrates the number of compounds in the R&D pipeline across major indications in the cardiovascular
therapeutic area progressing through different stages of development in 2010.
Figure 14:
2010
Cardiovascular pipeline by key indications and stages of development,
Other CV diseases
Hypertension
Stroke
Thrombosis
Atherosclerosis
Preclinical
Phase I
Dyslipidemia
Phase II
Phase III
Hypercholesterolemia
NDA
Approved
Total
Angina
Peripheral arterial disease
Ischemia
Hypotension
Arrhythmia
Lipid disorders
Hypertriglyceridemia
0
50
100
150
200
250
Number of pipeline compounds

Source: MedTRACK, 2010
BUSINESS INSIGHTS
Leading drugs in development

The following section analyzes the performance and potential of some of the recently launched and most
promising late-stage drugs in development for the treatment of various cardiovascular disorders. Table 16
and Table 17 illustrate the key drugs in late-stage development and recently launched status in the
cardiovascular market.
86
Table 16: Leading pipeline drugs in the cardiovascular market, 2010 (part 1)
Product
Company
Mechanism of action
Development
phase
Drug class
Apixaban
Pfizer/BMS
Direct factor Xa
inhibitor
Phase III
Antithrombotic
Betrixaban
Merck
Direct factor Xa
inhibitor
Phase II
Antithrombotic
Xarelto
Bayer
Direct factor Xa
inhibitor
NDA
Antithrombotic
YM150
Astellas
Direct factor Xa
inhibitor
Phase II (US),
Phase III (Japan)
Antithrombotic
Edoxaban
(DU 176b)
Daiichi Sankyo
Direct factor Xa
inhibitor
Phase III for

treatment of
atrial fibrillation,
NDA for
treatment of VTE
Antithrombotic
Darapladib
GSK
Lp-PLA2 inhibitor
Phase III
Antidyslipidemic
Anacetrapib
Merck
CETP inhibitor
Phase III
Antidyslipidemic
Tredaptive
(niacin +
laropiprant)
Merck
HDL increase through

niacin and flushing
pathway inhibitor
Phase III
Antidyslipidemic
Aleglitazar
Roche
PPAR co-agonist
Phase III
Antidyslipidemic
E5555
Eisai
Protease activated
receptor (PAR-1)
antagonist
Phase II
Antithrombotic
AVE5026
Sanofi
Low molecular weight

heparin
Phase III
Antithrombotic
Ellinorgel
Novartis
P2Y12 reversible
antagonist
Phase II
Antithrombotic
AZDO837
AstraZeneca
Direct thrombin
(reversible) inhibitor
Phase III
Antithrombotic
Dalcetrapib
Roche
CETP inhibitor
Phase III
Antidyslipidemic
Mipomersen
Genzyme
(Sanofi)/Isis
Antisense
apolipoprotein B
synthesis inhibitor
NDA
Antidyslipidemic
Cinaciguat
Bayer
Guanylate cyclase
activator
Phase II
Antihypertensive
Source: company reports, Business Insights
BUSINESS INSIGHTS
87
Table 17: Leading pipeline drugs in the cardiovascular market, 2010 (part 2)
Product
Company
Mechanism of action
Development
phase
Drug class
Riociguat
Bayer
Guanylate cyclase
activator
Phase III
Antihypertensive
Terguride
Pfizer with
Ergonex
Pharma
5HT2 receptor
antagonist
Phase II
Antihypertensive
Livalo
Kowa
HMG-CoA reductase
inhibitor
Launched
Antidyslipidemic
Effient
Daiichi Sankyo
and Eli Lilly
P2Y12 antagonist
Phase III
Antithrombotic
TAK 491
Takeda
A2 receptor antagonist
NDA
Antihypertensive
Brilinta
AstraZeneca
P2Y12 inhibitor
Approved EU,
NDA in US
Antithrombotic
MK-0524B
(simvastatin
+ niacin +
laropiprant)
Merck
HMG-CoA reductase
inhibitor + niacin to
increase HDL + DP1
antagonist to reduce
flushing
Phase II
Antidyslipidemic
LCZ696
Novartis
Angiotensin receptor II
blocker
Phase II for
hypertension,
Phase III for
other CV
disorders
Antihypertensive,
Other
cardiovascular
Otamixaban
Sanofi
Direct factor Xa
inhibition
Phase III
Antithrombotic
Pradaxa
Boehringer
Ingelheim
Heparin
Launched
Antithrombotic
Varespladib
Anthera
Secretory
phospholipase A2
inhibitor
Phase III
Antidyslipidemic
BUSINESS INSIGHTS
Profiles of key pipeline products

Figure 15 shows the key pipeline products across various therapeutic sub-categories in various phases of
development. The developmental timelines are an indicator that these pipeline molecules could serve to
soften the patent cliff caused by the expiry of several blockbuster drugs in the cardiovascular space.
88
Figure 15:
Leading pipeline drugs in various cardiovascular sub-categories, 2010

Phase I
Phase II
Phase III
NDA
Already on
market
Antithrombotics
Antidyslipidemics
Antihypertensives
Apixaban
Betribaxan
Xarelto
Darapladib
Anecetaprib
Dalcetrapib
Cinaciguat
Riociguat
Livalo
Brillinta
LCZ696
BUSINESS INSIGHTS
Pipeline activity is driven both by R&D (including in-licensed drug candidates) and through mergers and
acquisitions. An analysis of the pipelines of the major companies shows that companies with the largest
number of pipeline products (Pfizer, GSK, Novartis, and AstraZeneca) have undergone at least one major
merger/acquisition in the last decade. In-licensed drug candidates also contribute to a robust pipeline.
89
However, several pipeline drugs which were being relied on to become the new blockbusters, such as
torcetrapib (antidyslipidemic) and vorapaxar (antithrombotic) failed to gain regulatory approval due to
unsatisfactory Phase III results. Thus, despite a large number of late-stage drugs in the pipeline of major
companies, it is unclear whether these drugs could off-set the decrease in sales due to genericization. This is
reflected in the analysis of drug approval activities by the FDA, from 20002010, as shown in Figure 16.
While the number of NDAs has decreased from 2000 to 2010, there has been a relatively steady increase in
the number of generic drug (ANDAs) approvals.
Figure 16:
US FDA drug approval activities, 20002010

500
450
Number of approvals
400
350
300
250
200
150
100
50
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
New Drug Approvals (NDAs)
Generic approvals (ANDAs)
Source: FDA, company and investment analysis reports, Business Insights
BUSINESS INSIGHTS
Key antihypertensive pipeline drugs

LCZ696 Novartis
Overview
LCZ696 is a single molecule NEP/ARB inhibitor, currently undergoing Phase III trials for chronic heart failure
and Phase II trials for hypertension. It is a dual-acting molecule that blocks the activity of ARB and NEP. This
compound forms a potential option to replace ACE inhibitors as a standard therapy of heart failure.
90
Table 18: An overview of LCZ696
Brand name
n/a
Generic name
LCZ696
Company
Novartis
Indication
Chronic heart failure, hypertension
Mechanism of action
ARB (angiotensin receptor blocker)/NEP

(neural endopeptidase inhibitor)
Status
Phase III trials for chronic heart failure, Phase

II trials for hypertension
Source: company reports
BUSINESS INSIGHTS
Clinical
In a Phase II hypertension trial of around 1,000 patients (510% of which were African Americans), a 400mg
dose of LCZ696 resulted in superior blood pressure reduction than Diovan and was well-tolerated with no
reported cases of angioedema (swelling) (Ruilope et al., 2010). Some of the other key trials include:
In December 2009, Novartis initiated a Phase III study to determine the safety and efficacy of LCZ696
compared with enalapril on morbidity and mortality in patients with chronic heart failure.
In November 2009, a 12-week Phase II study was initiated to evaluate the safety, efficacy, and
tolerability of LCZ696 compared to valsartan in patients with chronic heart failure and preserved leftventricular ejection fraction.
In May 2009, Novartis also started an open-label Phase II pharmacokinetic and pharmacodynamic
study of LCZ696 in patients with stable heart failure.
In March 2010, Novartis presented Phase II results which demonstrated that the product not only improved
blood pressure significantly in patients with mild-to-moderate hypertension but also provided complementary
action with neprilysin inhibition and ARB blockade.
The trial involved 1,328 patients with mild-to-moderate hypertension randomized for eight weeks of treatment
on one of eight doses: 100mg, 200mg, or 400mg LCZ696; 80mg, 160mg, or 320mg Diovan; 200mg AHU377;
91
or placebo. Novartis is also planning to pursue development of the drug for hypertension in specific
populations such as diabetics and elderly patients.
Cinaciguat Bayer
Overview
Cinaciguat is the first member of a new class of antihypertensive drugs that work through guanylate cyclase
(sCG) activation. It is especially used for the treatment of acute decompensated heart failure (ADHF), which
is an advanced cardiac condition that has poor prognosis. ADHF is one of the leading causes of death
among patients with cardiac conditions. It has been found that 45% of patients hospitalized with ADHF are
re-hospitalized within a period of 12 months (Allen et al., 2007). Thus, cinaciguat has a high market potential
as it aims to address a highly unmet medical need.
Table 19: An overview of cinaciguat
Brand name
n/a
Generic name
cinaciguat (BAY 58-2667)
Company
Bayer
Indication
Hypertension, acute decompensated heart

failure
Mechanism of action
sCG activation in the nitric oxide (NO)

pathway, which in turn stimulates cyclic
guanosine monophosphate (cGMP), a
vasodilator.
Status
Phase II trials
BUSINESS INSIGHTS
Clinical
In 2009, Cinaciguat was evaluated in a non-randomized, uncontrolled, proof-of-concept study, using a
starting dose of 100g/h, to measure periodic hemodynamic response. The starting dose was titrated to
different concentrations depending on the hemodynamic response. Patients were categorized as responders
if their pulmonary capillary wedge pressure decreased by 4mm Hg compared with baseline. Compared with
baseline, a 6-hour infusion of cinaciguat led to significant reductions in pulmonary capillary wedge pressure
92
(-7.9mm Hg), mean right atrial pressure (-2.9mm Hg), mean pulmonary artery pressure (-6.5mm Hg),
pulmonary vascular resistance (-43.4dynesscm-5), and systemic vascular resistance (-597dynesscm-5),
while increasing heart rate by 4.4bpm and cardiac output by 1.68L/min. The responder rate was 53% after 2
hours, 83% after 4 hours, and 90% after 6 hours (Lapp et al., 2009).
Phase II trials are underway in the US to measure the efficacy and tolerance to intravenously administered
cinaciguat. Phase II data is likely to be available by end of Q2 2011.
Riociguat Bayer
Overview
Riociguat is also a sCG activator, which effects vasodilation through the nitric oxide (NO) pathway. It is
currently being investigated to treat chronic thromboembolic pulmonary hypertension (CEPH) and pulmonary
arterial hypertension (PAH). Phase II trial results of riociguat showed an improvement in parameters such as
pulmonary vascular resistance, arterial pressure, and cardiac output (Ghofrani et al., 2010). This, along with
a favorable safety profile, is likely to lead to the positioning of Riociguat as a promising drug in the
antihypertensive segment.
Riociguat is currently undergoing Phase III trials. A positive Phase III result should provide the drug with the
necessary differentiation vis--vis other antihypertensive drugs. Business Insights estimates that sales of
Riociguat are likely to reach a value of $380m by 2016.
93
Table 20: An overview of riociguat
Brand name
n/a
Generic name
riociguat (BAY 63-2521)
Company
Bayer
Indication
Chronic thromboembolic pulmonary

hypertension (CEPH), pulmonary arterial
hypertension (PAH)
Mechanism of action
sCG activation in the nitric oxide (NO) pathway

which in turn stimulates cGMP, a vasodilator.
Status
Phase III trials
BUSINESS INSIGHTS
Clinical
A Phase II trial of Riociguat was carried out in 2009 to evaluate the safety and tolerability of riociguat in
patients with CETPH or PAH. Riociguat resulted in significant improvements in both CETPH and PAH
patients in exercise capacity, which was evident as early as 14 days after initiation of treatment. Significant
improvements were also seen in other hemodynamic parameters such as echochardiographic parameters,
WHO functional class, and patient heart failure (Ghofrani et al., 2010).
Riociguat is currently undergoing Phase III trials which consist of two pivotal trials, as follows:
Chronic Thromoboembolic Pulmonary Hypertension sGC Stimulator Trial (CHEST) The

randomized, placebo-controlled pivotal trial CHEST-1 will investigate the effect of riociguat in patients
with CTEPH. The primary outcome measure after 16 weeks of treatment will be patients exercise
capacity, measured by the change from baseline in the six-minute walk test (6-MWT). All patients
having completed CHEST-1 will enter the extension trial CHEST-2.
Pulmonary Arterial Hypertension sGC-Stimulator Trial (PATENT) PATENT-1 will investigate the
efficacy and safety of riociguat in patients with PAH. The primary outcome measure after 12 weeks of
treatment will be the same as the CHEST-1 outcome measure, namely the patients exercise capacity,
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measured by the change from baseline in the 6-MWT. All patients having completed PATENT-1 will
enter the extension trial PATENT-2.
Key antidyslipidemic pipeline drugs

Livalo (pitavastatin) Kowa Pharmaceuticals
Overview
Livalo (pitavastatin) is a fully synthetic and highly potent inhibitor of HMG-CoA reductase used for primary
hypercholesterolemia and combined dyslipidemia. Following a launch in 2003 in Japan, pitavastatin has
generated voluminous data on patient groups, particularly those with co-morbidities and on multiple
medications. Livalo was later launched in South Korea (2005), Thailand (2008), and China (2009). Kowa filed
an NDA with the FDA in mid- 2009, and secured an approval in August 2009. Following this approval, Kowa
launched the product in 1mg, 2mg, and 4mg tablet formulations on the US market in June 2010 in
association with Eli Lilly. To improve its market reach, the company also struck several alliances with
companies such as Abbott and Recordati in markets such as Australia, New Zealand, and Europe, where it
expects to launch the product by 2012.
Livalo is a particularly attractive option for physicians treating patients taking multiple medications because of
its low potential for cytochrome P450-mediated drug-drug interaction in the liver, which is the major
metabolic pathway for the degradation of most drugs.
Table 21: An overview of Livalo
Brand name
Livalo
Generic name
pitavastatin
Company
Kowa
Indication
Adult primary hyperlipidemia/mixed

dyslipidemia
Mechanism of action
HMG-CoA reductase inhibitor
Status
Launched in the US (June 2010), Japan (2003)
BUSINESS INSIGHTS
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Clinical
Livalo was approved by the FDA on the basis of five different 12-week comparative trials with Lipitor
(atorvastatin), Zocor (simvastatin), and Pravachol (pravastatin). The Phase III active-controlled study
involved patients aged more than or equal to 65 years with primary hypercholesterolemia or combined
dyslipidemia. While half the patients had hypertension, 5% had diabetes and about 80% were on
concomitant medications. The results of these trials demonstrated that pitavastatin was statistically superior
to the other statins across all three dosages (1mg, 2mg, and 4mg), and a higher percentage of patients
achieved lower LDL-C levels with pitavastatin than any other drug (Hayashi et al., 2007). In addition, the drug
also exhibited a robust safety and tolerability profile, helping its approval.
Kowa is currently positioning Livalo as an adjunctive therapy for the treatment of adult primary hyperlipidemia
and mixed dyslipidemia, in patients who have not responded to other statins or are receiving other
medications.
Dalcetrapib Roche
Overview
Dalcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that helps control dyslipidemia through the
increase of high-density lipoprotein (HDL). CETP is a plasma glucoprotein that facilitates transfer of
cholesteryl esters from HDL to low-density lipoprotein (LDL), thus increasing the levels of blood HDL. HDL is
involved in reverse cholesteryl ester transfer processes and thereby removes excess cholesterol from the
body, resulting in cardio-protection. However, it is also thought that the cardio-protective properties of HDL
are attributable to its antioxidant and anti-inflammatory properties. Thus, although HDL increase is implicated
in negating the harmful effects of dyslipidemia, the exact pharmacological impact of HDL increase is not
clear.
CETP inhibitors are a novel class of compounds, and a favorable Phase III result would lead to their rapid
uptake and adoption in the market. The recent Phase III failure of the CETP inhibitor torcetrapib has led to
much skepticism about the efficacy and safety of dalcetrapib. Thus, Roche has undertaken a well-planned
de-risking strategy before moving into Phase III trials with dalcetrapib. These de-risking strategies involve
several structural and pharmacokinetic studies that establish that dalcetrapib follows a different mechanism
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of CETP inhibition (through a different binding site) when compared with other molecules in its class, and
unlike torcetrapib it is able to activate a fully functional reverse cholesterol transport system.
Table 22: An overview of dalcetrapib
Brand name
n/a
Generic name
dalcetrapib
Company
Roche
Indication
Hyperlipidemia, mixed dyslipidemia,

atherosclerosis
Mechanism of action
HDL increase through CETP inhibition
Status
Phase III trials
BUSINESS INSIGHTS
Clinical
Dalcetrapib has recently moved into Phase III clinical trials. The following are the major trials involving
dalcetrapib:
Dal-VESSEL This is a Phase II safety study that looked at endothelial function and was completed in
Q4 2010; results will be announced in Q2 2011.
Dal-PLAQUE This is a Phase II imaging study (n = 181) that used innovative imaging techniques to
visualize plaque changes and was completed in Q1 2011; results will be announced in Q2 2011.
Dal-PLAQUE 2 This is a Phase III imaging study (n = 906) that is estimated to be completed in 2015
but early data may be available by 2013.
Dal-OUTCOME This is a Phase III outcome study of CR morbidity/mortality and is expected to be

complete by late 2012/2013.
Anacetrapib Merck
Overview
Anacetrapib is a CETP inhibitor with a mechanism of action similar to dalcetrapib. It is indicated for use in
treating mixed lipidemia, hypercholesterolemia, and atherosclerosis. Anacetrapib has shown a more
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significant increase in HDL when compared with dalcetrapib, but the pharmacological implications of HDL
increase through anacetrapib are yet to be determined.
Table 23: An overview of anacetrapib
Brand name
n/a
Generic name
anacetrapib
Company
Merck
Indication
Mixed lipidemia, hypercholesterolemia,

atherosclerosis
Mechanism of action
HDL increase through CETP inhibition
Status
Phase III trials
BUSINESS INSIGHTS
Clinical
Early results from the Phase III trial DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition
with Anacetrapib) was presented at the American Heart Association meeting in Chicago in November 2010.
The data showed that anacetrapib reduced LDL by 40% relative to placebo. The levels of HDL have also
shown a significant increase of more than 50% (company reports). Patients undergoing anacetrapib
treatment did not show an increase in blood pressure, which was particularly significant as an increase in
blood pressure was one of the side effects of torcetrapib.
In the reverse phase study, treatment with anacetrapib was stopped and patients continued to receive either
a placebo or atorvastatin for 8 weeks. The effect of withdrawal of drug on lipid efficacy and safety was
assessed, and there were no adverse reactions observed. Although, anacetrapib has provided significant
clinical trial results, the dalcetrapib Phase III study began earlier than that of anacetrapib. Since dalcetrapib
shows reasonably good efficacy and safety profiles, it is likely to receive approval and will be marketed
earlier than anacetrapib. Business insights considers that the early market entry would prove to be a
significant advantage for dalcetrapib as it will already be established as a prescription drug of choice prior to
anacetrapib entry, and dalcetrapib is thus likely to hold a greater percentage of the market share in 2016
than anacetrapib.
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Darapladib GlaxoSmithKline
Overview
Darapladib is a lipoprotein-associated phospholipid A2 (Lp-PLA2) inhibitor which is primarily indicated for use
in treating atherosclerotic plaques. Lp-PLA2 makes an atherosclerotic plaque vulnerable to rupture by
initiating inflammatory processes in the plaque. Since plaque rupture is implicated in a number of CV
disorders, including myocardial Infarction (MI) and stroke, Lp-PLA2 inhibition could serve to prevent these
conditions. Inflammation has long been known to be one of the causative factors of CV events but no
inflammation-inhibiting prescription drugs currently exist in this space. Thus, Business Insights believes that
darapladib exhibits significant market potential both in terms of a sufficiently differentiated product profile and
in addressing a largely unmet clinical need. A differentiated mechanism of action will allow darapladib to act
as a complimentary therapy along with CETP inhibitors/statins, thus allowing it capture as much as 20% of
the market share by 2016.
Table 24: An overview of darapladib
Brand name
n/a
Generic name
darapladib
Company
GlaxoSmithKline
Indication
Mixed lipidemia/Hypercholesterolemia/
atherosclerosis
Mechanism of action
Atherosclerotic plaque stabilization through LpPLA2 inhibition
Status
Phase III trials
BUSINESS INSIGHTS
Clinical
Darapladib was evaluated in a randomized 959-patient Phase II study for 12 weeks, wherein both the
inhibition of Lp-PLA2 and the reduction of circulating levels of inflammatory biomarkers were assessed. At a
dose of 160mg of darapladib, a 66% reduction in Lp-PLA2, a 21.5% reduction of interleukin-6, and a 20.2%
reduction in hs-CRP (C-reactive protein) was observed relative to placebo (Mohler et al., 2008). However,
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whether a decrease in circulating inflammatory biomarkers is actually indicative of plaque stabilization

remains unclear.
Subsequently, another Phase II study was carried out that evaluated the hypothesis that darapladib
stabilizes atherosclerotic plaques by measuring the level of plaque deformation using intravascular
ultrasound (IVUS) imaging technology. However, no reduction in plaque deformation (primary endpoint) was
seen. On the other hand, the study did produce promising results with respect to its secondary end-point,
namely a significant increase in necrotic core volume (Serruys et al., 2008). Based on the secondary
endpoint, GSK has now moved into Phase III trials, the results of which are expected in early 2012.
Key antithrombotic pipeline drugs

Xarelto (rivaroxaban) Bayer/J&J
Overview
Xarelto (rivaroxaban) is a factor Xa inhibitor indicated for the treatment of thrombosis and stroke. It was
approved in the EU for the prevention of VTE in patients who have had hip or knee replacement surgery, but
in May 2009 it was rejected for the same indication in the US. Moreover, the US FDA also issued a complete
response letter (CRL) requesting additional data from completed and ongoing studies and market
surveillance data from countries outside the US. Xarelto is a Bayer compound licensed to J&J, which shares
worldwide development costs and is responsible for making upfront, milestone, and royalty payments.
Xarelto has also been approved for treatment of VTE in Australia, Canada and Mexico, where it is marketed
by Bayer. If approved in the US, it will be marketed by J&Js Ortho-McNeil subsidiary.
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Table 25: An overview of Xarelto
Brand name
Xarelto
Generic name
rivaroxaban
Company
J&J/Bayer
Indication
Prevention of VTE in hip and knee

replacement surgery
Mechanism of action
Direct factor Xa inhibitor
Status
Approved in the EU; received a complete

response letter from the FDA in May 2009
BUSINESS INSIGHTS
Clinical
The RECORD (REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE)
trial series for rivaroxaban demonstrated statistically significant reductions in VTE following orthopedic
surgery, in comparison to enoxaparin. This was coupled with no increased risk of bleeding or elevated liver
enzymes (Turpie et al., 2009).
RECORD 4 data combined with those from RECORD 1, 2, and 3, showed Xareltos superiority over
Lovenox. Xarelto was observed to have a higher efficacy benefit without the cost of an increased bleeding
risk. RECORD 4 results showed a 31% relative risk reduction (RRR) in comparison with Lovenox, which is
also statistically significant. Symptomatic VTE was also found to be numerically better, 0.7% versus 1.2%,
but failed to achieve statistical significance because of the small number of events. Major bleeding was found
to be in line with Lovenox at 0.7% versus 0.3%. Clinically relevant non-major bleeding was also found to be
similar, at 2.6% versus 2.0%, further indicating that Xareltos bleeding profile is comparable to Lovenox
(Komajda et al., 2008). Xarelto showed a lower incidence of cardiovascular events in comparison with
Lovenox (seven versus 11), although these events occurred after discontinuation of treatment. This is in line
with the background rate expected.
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In December 2009, Bayer/J&Js positioning in the VTE market was further strengthened by a positive Phase
III outcome from EINSTEIN-EXT study. The trial data presented at the American Society of Hematology
meeting in New Orleans 2009 showed that the anticoagulant reduced the relative risk of potentially fatal clots
by 82% compared with placebo in patients who had completed 612 months of treatment with warfarin after
suffering an acute VTE or a pulmonary embolism (PE) (Buller et al., 2010). Xarelto is also being studied for
the prevention of stroke in atrial fibrillation patients, the results of which are due by the second half of 2010.
Xarelto was launched in Canada in 2008 for the prevention of VTE in patients who have had elective total hip
or knee replacement surgery. The drug recently received European approval and was subsequently
launched in the UK and Germany. If approved in the US (the NDA was filed in Q1 2011), Xarelto will
compete with several other potential factor Xa inhibitors such as Eli Lilly/Daiichi Sankyos Effient,
BMS/Pfizers apixaban, Astellass YM150, and Daiichi Sankyos DU-176b.
Apixaban Bristol-Myers Squibb (BMS)/Pfizer
Overview
Apixaban (BMS-562247) is the follow-on compound to BMSs oral factor Xa inhibitor razaxaban both of
which have been in development for the treatment of thrombosis. BMS and Pfizer are jointly developing
apixaban. The two companies have entered into an agreement that is believed to be one of the most
expensive joint development agreements in the industry. As part of the agreement, Pfizer has agreed to pay
$1bn to acquire the products development and marketing rights. Moreover, both the companies have also
agreed to share the commercialization expenses and profits/losses equally on a global basis.
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Table 26: An overview of apixaban
Brand name
n/a
Generic name
apixaban
Company
BMS/Pfizer
Indication
VTE, ACS, atrial fibrillation
Mechanism of action
Factor Xa inhibitor
Status:
US filing expected in Q2/Q3 2011, approved in

the EU for VTE
BUSINESS INSIGHTS
Clinical
The EU approval of apixaban in Q2 2011 was mainly supported by two Phase III trials, namely ADVANCE-2
and ADVANCE-3. Results of the ADVANCE-2 study showed that apixaban reduces the risk of deep vein
thrombosis (DVT) and pulmonary embolism (PE) much more efficiently compared with Sanofis low
molecular weight heparin enoxaparin (Lovenox/Clexane). In addition, apixaban also showed a trend toward
less bleeding in patients undergoing hip replacement surgery (Lassen et al., 2010). The Phase III VTE
prevention study, ADVANCE-1, compared apixaban, administered at a dose of 2.5mg twice daily, with the
FDA-approved enoxaparin (30mg, twice daily). The data indicated that apixaban could not meet its primary
efficacy endpoint as a composite of symptomatic or asymptomatic DVT, pulmonary embolism, or death by
other causes (Lassen et al., 2009). Although the rate was found to be numerically similar to enoxaparin, it did
not meet the primary endpoint which, in turn, led to the delay in US filing. Similarly, with respect to adverse
events, the major bleeding rate was found to be lower with the use of apixaban but the result was not
statistically significant. However, the composite rate of major and non-major bleeding was found to be
significantly lower in apixaban patients.
BMS and Pfizer are also conducting several Phase IIII trials of apixaban in ACS, atrial fibrillation (AF), VTE
treatment, and VTE prevention, the results of which are expected by the end of 2011. BMS and Pfizer are
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also exploring a once-daily modified-release formulation of apixaban that is dependent on colonic absorption
levels.
Apixabans twice-daily regimen, low renal clearance, and relatively low potential for drug interactions implies
that it could potentially have the lowest bleeding risk among other factor Xa inhibitors, which would be an
advantage in penetrating the low to medium risk patient population.
In a major development, BMS announced in June 2010 that it had decided to terminate its Phase III
AVERROES trial in vitamin K antagonist intolerant patients with atrial fibrillation, as sufficient efficacy of the
drug had already be proven and further continuation of the trial was deemed unnecessary by the Data
monitoring committee. Interim data from the trial revealed that the drug reduced stroke and systemic
embolism in comparison with aspirin, in addition to demonstrating sufficient safety.
Brilinta (ticagrelor) AstraZeneca
Overview
AstraZenecas Brilinta (ticagrelor) is currently being developed for the treatment of arterial thrombosis in
patients with ACS. It is the first reversible oral P2Y12 receptor antagonist and is under development as an
alternative to clopidogrel, the current market-leading antiplatelet drug. Brilinta belongs to a different chemical
class: the cyclopentyl-triazolopyrimidines. It provides faster, greater and more consistent P2Y12 inhibition
than does clopidogrel and exhibits reversible binding to receptors. Its onset of action is rapid, at two hours
and it also has a plasma half-life of approximately 12 hours.
104
Table 27: An overview of Brilinta
Brand name
Brilinta
Generic name
ticagrelor
Company
AstraZeneca
Indication
Arterial thrombosis, ACS
Mechanism of action
P2Y12 inhibitor
Status
Filed in the US (November 2009), received

approval in EU (Q4 2010)
BUSINESS INSIGHTS
Clinical
Results of the DISPERSE trial (Phase IIa) showed that ticagrelor is a more potent and consistent inhibitor of
platelet aggregation than clopidogrel in patients with stable atherosclerotic disease in any vascular bed. The
DISPERSE-2 trial (Phase IIb) assessed the antiplatelet effects of Brilinta against Plavix (clopidogrel) in ACS
patients with either unstable angina or NSTEMI ACS (Cannon et al., 2007). It is indicated that Brilinta and
Plavix were associated with a similar rate of bleeding events and a comparable reduction in the incidence of
cardiovascular events.
The recent US filing of Brilinta was mainly based on the promising Phase III results of PLATO (Platelet
inhibition and patient outcomes) trial. This large, randomized, multinational trial comparing Brilinta with Plavix
in ACS patients showed that Brilinta had a faster onset of action. Trial results also showed that 9.8% of
Brilinta patients experienced death from vascular causes, MI (myocardial infarction), or stroke compared with
11.7% of Plavix patients at 12 months (p < 0.001) (Steg et al., 2010). Although there was no difference in the
rate of overall bleeding between the two groups, Brilinta outperformed Plavix in the severe heart attack
STEMI (segment elevation myocardial infarction) patient subgroup. The PLATO study also suggested that
Brilinta reduces the risk of CV events by 16% but, unlike Eli Lilly/Daiichi Sankyos Effient, without increased
risk of major bleeding.
105
Brilinta has a potential therapeutic advantage in atherosclerosis and can be administered to 1530% of
atherosclerosis patients who do not respond to Plavix. Owing to its short offset period, it is also applicable to
patients who have to undergo surgery. The drug will be indicated for use in percutaneous coronary
intervention (PCI), as well as secondary prevention of MACE.
A major drawback of the drug is that it requires twice-daily dosing, in contrast with Plavix, which only requires
once-daily administration. If approved, Brilinta would compete not only with Plavix but also with Eli
Lilly/Daiichi Sankyos Effient, an irreversible P2Y12 receptor antagonist that was launched in 2009 in both
the US and the EU.
AstraZeneca received a response letter from the FDA in Q4 2010, indicating that Brilintas efficacy data was
unsatisfactory. This has created a further setback for Brilinta, which may now receive approval in Q4 2011.
Betrixaban Portola/Merck
Overview
Betrixaban is a once-daily factor Xa inhibitor with 1924 hours of terminal half-life. The product recently
completed Phase II trials for stroke prevention in patients with atrial fibrillation and multiple indications in
venous thromboembolism (VTE). It also appears to have low (15%) renal clearance, with the promise of
relatively low bleeding risk, and potentially forms the drug of choice in patients with moderate to severe renal
impairment. Moreover, betrixaban is also seen as a novel oral factor Xa inhibitor that could address the
limitations of current anticoagulants such as warfarin (risks of bleeding, food-drug interactions).
Table 28: An overview of betrixaban
Brand name
n/a
Generic name
betrixaban
Company
Portola/Merck
Indication
Atrial fibrillation, renal impairment
Mechanism of action
Direct factor Xa inhibitor
Status
Phase II completed in the US
BUSINESS INSIGHTS
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In July 2009, Merck and Portola signed an exclusive global collaboration and licensing agreement for
betrixaban, whereby Merck will assume all development and commercialization costs of Phase III trials and
pay Portola royalties on worldwide sales of the drug. Portola received an upfront fee of $50m and could
receive additional payment of up to $420m on achievement of certain development, regulatory, and
commercialization milestones. Furthermore, Portola has also retained an option to co-fund Phase III trials in
exchange for additional royalties and co-promotion rights to betrixaban with Merck in the US.
Clinical
Betrixaban recently concluded its Phase II trial (EXPLORE-Xa) for atrial fibrillation. The key objective of this
trial was to assess the safety and tolerability of betrixaban at doses of 40mg, 60mg, and 80mg given orally
once a day for at least three months, compared with dose-adjusted warfarin in patients with non-valvular
atrial fibrillation. While predictive modeling of thrombin generation suggested that the 40mg dose should
maintain patients in the anticipated therapeutic range, 60mg and 80mg doses were also studied to explore
the bleeding-dose relationship and, potentially, a flexible dosing strategy for Phase III trials (Portola press
releases).
Betrixaban has also been reported to have minimal (about 15%) renal excretion and a low risk of drug
interactions, implying highly predictable dosing, even in patients with renal impairment. Thus, betrixaban has
the potential to be the only agent indicated for patients with severe renal impairment (around 4% to 11% of
patients in target indications) and the only agent without warnings and precautions for increased bleeding in
patients with moderate renal impairment (12%25% of patients in target indications).
Although Pradaxa, Xarelto, and apixaban are all rapidly absorbed with broadly comparable plasma half-lives,
betrixaban appears to have a differentiated half-life (19 hours), competitive bioavailability, and minimal renal
excretion, which theoretically could result in a superior bleeding profile and allow recruitment of patients
irrespective of renal function.
In March 2010, Merck/Portola released Phase IIb results from the EXPLORE-Xa study at the American
College of Cardiology (ACC) meeting in Atlanta. The study demonstrated that betrixaban was associated
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with significantly less clinically relevant bleeding than warfarin at a dosage of 40mg/day to patients with atrial
fibrillation.
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Chapter 4 Competitive landscape

Summary
The global cardiovascular market registered $170bn in sales in 2010. Pfizer retained its position as the
market leader with $15.2bn in 2010 sales, led by key brands such as Lipitor, Norvasc, Caduet, and
Viagra.
The top 10 companies in the cardiovascular market registered $76.4bn in combined sales in 2010,
accounting for a substantial 44.9% of the global cardiovascular market.
Sanofi remained the second largest company, registering $10.5bn in 2010 sales and a 6.2% share of
the global cardiovascular market. The company has benefited strongly from the performance of
Lovenox and Plavix, which generated $3.8bn and $2.8bn respectively in 2010 sales.
AstraZeneca was the third largest company in the global cardiovascular market, recording sales of
$9.4bn in 2010. Sales were strongly driven by the blockbuster drugs Crestor and Atacand
Novartis was the fourth largest company, with 2010 sales of $8.6bn. Its position was strongly supported
by the ARBs, ARBs in combination with diuretics, and the statins. All Novartiss leading brands,
including Diovan ($3.6bn), Co-Diovan ($2.4bn), and Exforge ($904m) registered strong Y-o-Y growth in
2010.
Merck and BMS were the other leading companies, registering 2010 sales of $7.5bn and $8.4bn
respectively.
Introduction
This chapter focuses on the performance of the leading players in the cardiovascular market in 2010. It
provides a detailed description of each companys portfolio, sales data of leading products, key brand
analysis, and strategic growth analysis.
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Competitive positioning of top players in the cardiovascular

market
The top ten companies in the cardiovascular market generated $76.4bn in sales in 2010, a 44.9% share of
the overall market, clearly demonstrating their domination. The revenues of the top 10 players is set to
decline at a CAGR of -5.2%, and reach the value of $29.6bn in 2016. The biggest reasons for this are the
patent expiry of key products within their portfolios and the absence of new blockbusters to propel growth.
Pfizer led the cardiovascular market, with sales of $15.2bn in 2010 and a market share of 8.9%. Sanofi was
the next largest, registering $10.5bn in sales and a market share of 6.2%. Various generic drug majors such
as Sandoz, Teva, Mylan, and Ratiopharm also reported strong revenues from their cardiovascular
franchises.
Pfizers leading blockbusters, Norvasc and Lipitor, diminished in sales, registering Y-o-Y declines of 23.6%
and 6.1% respectively. Mercks top-selling cardiovascular drugs, including Vytorin, Zetia, Cozaar, and Zocor
also suffered significant sales erosion.
AstraZeneca was the third largest company in the global cardiovascular market, recording sales of $9.4bn in
2010. AstraZeneca benefited from the strong performance of its blockbusters Crestor and Atacand. Novartis
registered 2010 sales of $8.6bn. Its growth was on the back of a strong performance by its ARB blockbusters
Diovan, Co-Diovan, and relatively newer brands such as Exforge and Tekturna. Other leading companies in
the market include Bristol-Myers Squibb (BMS) and Daiichi Sankyo with $8.4bn and $5.5bn in sales
respectively. Daiichi Sankyo received a boost from the Benicar franchises increased sales.
Table 29 illustrates the sales performance of the leading players in the cardiovascular market in 2010.
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Table 29: Sales of leading players in the global cardiovascular market ($m), 2010
Company
Sales 2010 ($m)
Sales 2016 ($m)
Market share
2010 (%)
Market share
2016 (%)
Pfizer
16,661
5,915
8.9
3.2
Sanofi
10,527
8,699
6.2
4.6
AstraZeneca
9,365
12,133
5.5
6.5
Novartis
8,574
5,690
5.1
3.1
Bristol-Myers
Squibb
8,383
1,055
4.9
0.6
Merck
7,478
6,036
4.4
3.2
Daiichi Sankyo
5,502
6,505
3.2
3.5
Abbott
3,734
2,681
2.2
1.4
Boehringer
Ingelheim
3,291
3,621
1.9
1.9
Servier
2,848
2,996
1.7
1.6
Total leading
76,363
55,331
44.8
29.6
Others
94,097
131,570
55.2
70.4
170,460
186,901
100
100
Grand total
BUSINESS INSIGHTS
Pfizer
Overview
Pfizer led the cardiovascular market in 2010 with sales of $15.2bn. The companys dominant position in the
cardiovascular market has been driven primarily by the worlds largest selling drug, Lipitor, which accounted
for 65% of the companys cardiovascular franchise sales. In the past, Pfizer had depended heavily on its
blockbuster antihypertensive Norvasc, and ever since it lost patent protection in 2007 overall sales have
been declining. Despite its current leadership position, the impending patent expiry of Lipitor in 2011 is
expected to impact Pfizer significantly and challenge its leadership position within the cardiovascular market.
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Pfizers leading brands across antihypertensives and antidyslipidemics face several challenges due to
changing market dynamics. Despite continuing losses in sales due to genericization, Pfizers calcium
channel blocker Norvasc is the current leader in its antihypertensives franchise. Calcium channel blockers,
which are also used in angina, are expected to continue their decline through the forecast period (2010 to
2016).
In antidyslipidemics, Pfizer has two leading products: Lipitor, the megablockbuster, and Caduet, a
combination product of atorvastatin and amlodipine. Caduet, which is widely considered to be a Norvasc
franchise extension, recorded sales of $413m in 2010. The impending patent expiry of Lipitor in 2011 is the
most significant challenge to Pfizers leadership position in the cardiovascular market, as there are no
products in Pfizers near-term pipeline to offset the losses due to Lipitors patent loss. Torcetrapib, developed
by Pfizer, was thought to be a potential Lipitor replacement, but it failed in Phase III of its clinical studies
owing to the development of off-target toxicity (Vergeer et al., 2008; Vergeer and Stroes 2009; Sofat et al.,
2010).
Fragmin, a heparin, is Pfizers leading antithrombotic drug, with 2010 sales of $341m. Another major drug in
Pfizers cardiovascular portfolio is Revatio, which falls under the other cardiovascular category. Revatio is
one of the preferred first-line therapies for PAH and registered 2010 sales of $481m.

Lipitor (atorvastatin)
The best selling drug for Pfizer is also the leading drug in the global pharmaceutical market, recording 2010
sales of $10.7bn, and making up 65% of the companys cardiovascular sales. Lipitor is already facing strong
competition from generic simvastatin and AstraZenecas Crestor as indicated by its 2010 decline of 6.1%.
Owing to Pfizers strong dependence on Lipitor, its patent expiry in 2011 is a major threat for the company
through the forecast period. In November 2009, Pfizer filed a pediatric formulation (5mg) of Lipitor (branded
as Sortis) with the EMA for the treatment of six to 18 year old patients with familial hypercholesterolemia (a
rare genetic disorder that causes high LDL-cholesterol levels and increased heart disease risk). Following
this application, in March 2010 the CHMP recommended a product line extension to add chewable tablets
suitable for the pediatric population for the treatment of hypercholesterolemia. In addition, it also
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recommended that this indication be approved for film-coated tablets of Sortis. These recommendations
were based on data generated in accordance with an agreed pediatric investigation plan (PIP). Lipitor
suffered a setback recently with the launch by Ranbaxy (now a part of Daiichi Sankyo) of generic atorvastatin
in Canada and South Africa. Ranbaxy is also set to launch Lipitor generics in other European markets such
as Belgium, the Netherlands, Germany, Sweden, Italy, and Australia.
Table 30 summarizes the sales data of the leading cardiovascular brands manufactured by Pfizer, and their
relative market shares are shown in Figure 17.
Table 30: Pfizer sales of leading cardiovascular brands ($m), 2010
Brand Name
Generic name
Lipitor
atorvastatin
10,733
Norvasc
amlodipine
1,506
Caduet
amlodipine/atorvastatin
527
Revatio
sildenafil
481
Cardura
doxazosin mesylate
413
Fragmin
dalteparin
341
Total leading
Sales 2010 ($m)
14,001
Others
1,213
Total sales
15,214
BUSINESS INSIGHTS
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Figure 17:
Pfizer cardiovascular portfolio by brand (%), 2010

2%
3%
8%
3%
Lipitor
3%
Norvasc
Caduet
10%
Revatio
Cardura
71%
Fragmin
Others
BUSINESS INSIGHTS
Norvasc (amlodipine)
Norvasc is an antihypertensive and was Pfizers second top-selling cardiovascular brand in 2010. Following
its patent expiry in 2007, Norvasc has had falling sales and is largely responsible for the companys reduced
share of the cardiovascular market. In 2010, Norvasc registered $1.5bn in sales a Y-o-Y decline of 23.7%.
Growth in the hypertension and congestive heart failure markets is being fuelled by changing demographics,
an increasing focus on prevention of cardiac events, and growing adoption of newer, more expensive
therapies. Norvasc belongs to a mature class of drugs, the calcium channel blockers, whereas growth in this
market is likely to be driven by novel therapies such as Tekturna, a renin inhibitor from Novartis, as well as
an increase in the use of ARBs and their combinations.
Caduet (atorvastatin/amlodipine)
Caduet, a combination of atorvastatin and amlodipine, was the third largest selling drug in Pfizers
cardiovascular portfolio in 2010, with sales of $527m. Pfizer commercialized Caduet with the intention of
shifting patients from Norvasc to Caduet, a strategy that did not materialize. Moreover, Caduets marketing
authorization in 12 European countries, including Germany, Italy, and the UK, was withdrawn following
doubts over the demonstration of its benefits as a fixed-dose combination.
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Caduets uptake in the US has been hindered by slow managed-care acceptance. Most formulary managers
within the US perceive Caduet as a Norvasc franchise extension that offers no significant benefit over
Norvasc, leading to a modest uptake so far. Additionally, Caduets future prospects appear grim due to
several ongoing patent challenges. In 2008, Pfizer settled a worldwide litigation with Ranbaxy allowing it to
launch generic Caduet in the US from November 30, 2011. Sandoz and Mylan have also filed abbreviated
new drug approvals (ANDAs) on Caduet, challenging the combination patent that expires in 2018. In
retaliation, Pfizer filed an infringement suit against Mylan in February 2010, challenging the companys 180day exclusivity claim. Given the current market dynamics, Caduet sales are expected to decline strongly
through the forecast period.
Revatio (sildenafil)
In 2005, Pfizer launched Revatio for the treatment of pulmonary arterial hypertension (PAH). Revatio has
brought about a significant improvement in the quality and survival of PAH patients. It is used orally in newly
presenting, less severe patients, and is one of the first-line preferred therapies for the indication. In January
2010, the European Medicines Agency (EMA) approved an intravenous formulation of Revatio for patients
who are temporarily unable to take oral medications. Revatio is the first and currently only injectable
phosphodiesterase-5 (PDE5) inhibitor approved for the treatment of PAH in the EU.
In March 2010, Pfizer challenged Teva after the latter had filed an ANDA challenging Revatios use patent
that expires in 2019. Following this, the court adjudicating this case granted a 30 month stay running into
September 2012.
Fragmin (dalteparin)
Fragmin is a low-molecular-weight heparin (LMWH) used in venous thromboembolic disease and was one of
the other leading drugs for Pfizers cardiovascular portfolio with 2010 sales of $341m. It is considered to be
the gold standard for DVT treatment and prophylaxis, with a superior clinical profile when compared with
other LMWHs; however, its penetration in the US is far behind the EU. Unfractionated heparins (UFHs) take
precedence over LMWHs in the US, mainly owing to their lower cost. However, LMWH and UFH tend to be
almost equal in their cost implications if the extensive monitoring required while using UFH is factored in.
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Pfizers cardiovascular R&D pipeline features numerous products at different stages of development, with
varying market potential. The most prominent late-stage compound in Pfizers cardiovascular pipeline is
apixaban, a factor Xa inhibitor that is in the pre-registration stage for VTE treatment and prevention, and in
Phase II/III for acute coronary syndrome. The company is developing and will commercialize this compound
in collaboration with BMS. A detailed profile of this compound is available in the pipeline section of this
report. Table 31 summarizes Pfizers late-stage cardiovascular pipeline in 2010.
Table 31: Pfizer late-stage cardiovascular pipeline, 2010
Compound name
Indication
Stage
Expected year of launch
Apixaban
Venous thromboembolism
prevention/treatment
Pre-registration
2011
Apixaban
Phase II
2011
PD-348292
Thrombosis
Phase II
2014
Source: Pfizer pipeline (www.pfizer.com)
BUSINESS INSIGHTS

Drivers of growth
Despite the loss of significant revenues due to patent expiry of its key blockbuster Norvasc and declining
sales of Lipitor, Pfizer continued to lead the cardiovascular market in 2010. A large degree of this success
can be attributed to the domination of its mega blockbuster, Lipitor. Recent favorable outcomes from the
CHMP for the use of Lipitor in familial hypercholesterolemia highlight Pfizers efforts to extend the patent
protection for Lipitor.
Apixaban, an oral Factor Xa inhibitor (being developed in collaboration with BMS) for a broad range of
cardiovascular indications, including venous thromboembolism (VTE), atrial fibrillation, and acute coronary
syndromes, is considered to be one of Pfizers most promising pipeline products. In June 2010, Bristol-Myers
Squibb, Pfizers development partner for apixaban, halted the pivotal Phase III Apixaban versus
Acetylsalicylic Acid to Prevent Strokes (AVERROES) trial, citing clear evidence of efficacy. In AVERROES,
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apixaban was being tested in vitamin K antagonist intolerant patients with atrial fibrillation (AF), and interim
data demonstrated that the drug reduced stroke and systemic embolism relative to aspirin, prompting the
company to end the trial abruptly.
Although apixaban has already been approved in the EU for VTE prevention following surgery, a similar
approval in the US is likely to take more time. AF is considered to be a highly lucrative market and
apixabans performance in the first-line Apixaban for the Prevention of Stroke in Subjects With Atrial
Fibrillation (ARISTOTLE) trial, which recently ended in Q2 April 2011, is expected to set the tone for Pfizers
future prospects in the cardiovascular market.
From Pfizers marketed portfolio, its biggest drivers in the near-term are likely to be Revatio and Inspra.
Revatio is a preferred first-line therapy for PAH and recorded $481m in sales in 2010. More recently, the US
FDA (November 2009) and the EMA (January 2010) approved an intravenous formulation of Revatio for PAH
treatment making it the only FDA-approved phosphodiesterase-5 (PDE5) inhibitor available in both tablet and
intravenous formulation.
Resistors of growth
The greatest impediment to Pfizers growth over the forecast period is generic erosion and a limited latestage pipeline. Lipitor, its largest selling drug globally, is expected to go off patent in November 2011, which
is likely to change the antidyslipidemic market significantly. The presence of generic simvastatin has already
resulted in generic substitution and, regardless of aggressive efforts by the company with its Lipitor message
of "flexible contracting" to achieve optimal tier II access, Lipitor has been losing market share in the major
markets.
In the past three years, one of the key reasons for Pfizers decline has been the continued sales erosion to
its leading antihypertensive Norvasc. In the period from 2005-10, Norvasc recorded a negative CAGR of
20.4%, and the negative sales trajectory (CAGR of -7.5% from 2010 to 2016) is expected to continue, with
further competition from newer combination therapies, ARBs, and generic amlodipine. By launching Caduet
in June 2004, the company sought to switch patients from Norvasc to Caduet, but Caduet was not a great
success. Indeed, its marketing authorization has been withdrawn in 12 EU nations, including Germany, Italy,
117
and the UK, owing to reservations as to whether the required benefits of fixed combinations had been
demonstrated.
Pfizers product development also suffered a major setback when the company discontinued its development
program for torcetrapib owing to the unexpected number of patient deaths during clinical trials. Torcetrapib,
which was expected to reach market in 2009, was seen as the successor to Lipitor and had the potential to
generate revenues that could largely offset the loss of Lipitor. Pfizers R&D productivity has been weak, as
reflected in the setback associated with the commercialization of torcetrapib, and the company has not been
able to successfully commercialize products with significant revenue potential in the cardiovascular therapy
area lately.
Following the failure of torcetrapib, in late 2008 Pfizer formally announced its exit from the cardiovascular
market in confirming that it would internally not develop any new products. Moreover, the subsequent
acquisition of Wyeth indicates a wider strategy with a re-aligned therapeutic area focus and a diminishing
focus on cardiovascular therapy.
Sanofi
Overview
Sanofi is the second leading company in the cardiovascular market, with 2010 sales of $10.5bn. Lovenox
and Plavix continue to be the companys key revenue contributors, accounting for 61% of the companys
overall cardiovascular sales, while also giving it a leadership position in the antithrombotics category. In
addition to thrombosis, the company has a strong position in the hypertension market, with several key
marketed products such as CoAprovel.
Lovenox and Plavix, the market leaders in the current thrombosis market led Sanofis antithrombotics
portfolio. Thrombosis is a dynamic market and is likely to see a lot of activity over the forecast period, with
promising drugs in the pipeline. One such drug is Bayer and J&Js Xarelto, a Factor Xa inhibitor that has
blockbuster potential and would be a challenger to Lovenox. Xarelto has already been approved for venous
thromboembolism (VTE) surgery in Europe and is awaiting an expected US approval in 2011.
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BMS/Pfizers apixaban is another potential threat to Lovenox, but Sanofi has a pipeline that could help it to
retain its dominance in the market. The company has deliberately opted to keep its focus on injectable drugs,
and with a strong pipeline it now seems to be equipped to handle the competition following the patent expiry
of its leading drugs. Even though the new drugs from other companies are oral and are slated to expand the
market for this delivery method, Sanofi is set to maintain its focus on injectable versions. Considering that
these drugs are for hospital indications, the method of administration may not be a concern or a significant
differentiating factor. In fact, an injectable drug may facilitate monitoring of treatment compliance and
dosage, as well as limiting drug interactions, owing to the fact that it will usually be administered in a hospital
setting.
CoAprovel and Aprovel were the leading antihypertensives for Sanofi in 2010, with combined sales of
$1.8bn, and a combined market share of 17% of the companys overall cardiovascular franchise. Triatec
(ramipril), Lasix (furosemide), and Delix plus (ramipril/HCT) are the other leading antihypertensives in
Sanofis marketed portfolio. Triatec/Altace is the only ACE inhibitor with an indication for the reduction of risk
of cardiovascular death, stroke, and myocardial infarction. The drug lost its composition-of-matter patent in
September 2007, long before its scheduled patent expiry in October 2008, due to a ruling of the US court of
appeals. This led to significant sales erosion during the 200809 period.

Table 32 summarizes the recent performance of Sanofis major cardiovascular brands. The contribution of
the leading brands to Sanofis cardiovascular portfolio is shown in Figure 18.
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Table 32: Sanofi sales of leading cardiovascular brands ($m), 2010
Brand name
Generic name
Sales 2010 ($m)
Lovenox
enoxaparin
3,754
Plavix
clopidogrel
2,760
Coaprovel/Aprovel
irbesartan
1,758
Triatec
ramipril
543
Lasix
furosemide
267
Cordarone
amiodarone
209
Total leading
9,291
Others
1,236
Grand total
10,527
Figure 18:
BUSINESS INSIGHTS
Sanofi cardiovascular portfolio by brand (%), 2010

2%
12%
3%
35%
5%
Lovenox
Plavix
Coaprovel/Aprovel
Triatec
17%
Lasix
Cordarone
Others
26%
BUSINESS INSIGHTS
Lovenox (enoxaparin)
Sanofis cardiovascular franchise is led by sales from Lovenox, which registered 2010 sales of $3.8bn.
Lovenox is the worlds best selling LMWH, indicated for the prevention and treatment of DVT with or without
pulmonary embolism, prevention of post-surgical deep vein thrombosis, and prevention of morbidity and
mortality following unstable angina. Lovenoxs domination of the antithrombotics market is the result of an
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array of factors acting together. Lovenox is a very complex compound that is difficult to characterize and so
not easily genericized. However, other market factors have helped the drug to maintain its market-leading
position over the years, including the price positioning of Arixtra, and the reluctance of the FDA to approve
new drugs However, a generic Lovenox (enoxaparin), manufactured by Sandoz (a division of Novartis) and
Momenta has recently been approved by the FDA. This generic enoxaparin could capture significant market
share from Lovenox by 2012. Among the future threats to Lovenox, Xarelto is the most noteworthy. The
products critical RECORD-3 and RECORD-4 trials, demonstrating its superiority over Lovenox, provided a
compelling reason for its approval in the EU. Xarelto also has the benefit of use outside the hospital setting
owing to its oral administration, which would facilitate treatment compliance by the patient. Additionally,
unlike other existing oral drugs, Xarelto does not present a huge risk of bleeding and does not require
patients coagulation to be monitored.
Plavix is the second major drug in Sanofis cardiovascular portfolio, with 2010 sales of $2.8bn. It is marketed
by BMS (in the US) and Sanofi (in other markets) through a joint venture between them. Although Plavixs
US patent is set to expire only in 2011, its sales have already begun to contract in the EU, particularly in
markets such as Germany, where generic versions of Plavix with different salts of clopidogrel have already
begun to make inroads. To counter competition, Sanofi has developed its own generic versions of Plavix for
launch in various markets including Belgium, Denmark, Germany, Netherlands, and the UK, which may
offset losses to an extent.
In November 2009, Plavix received a new warning regarding omeprazole interaction. According to the US
FDA, when omeprazole (a PPI) is used with Plavix it decreases the level of Plavixs active metabolite through
inhibition of the CYP2C19 enzyme.
Plavix prevents blood platelets from sticking together, thereby preventing clot formation, and it is also
recommended for patients diagnosed with peripheral artery disease. The antithrombotics/antiplatelet market
is set to expand substantially, with promising oral drugs such as Bayers Xarelto (already launched in the EU
and awaiting US approval), BMS/Pfizers apixaban (pre-registration) and Eli Lilly/Daiichi Sankyos Effient
(recently approved in the EU, awaiting US approval).
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Sanofis cardiovascular R&D pipeline features numerous products at different stages of development,
ranging across several different cardiovascular indications. The company is developing celivarone, an antiarrhythmic agent which does not lead to pro-arrhythmic events or signs of organ toxicity. This agent is
designed to be easier to use, ensuring better patient compliance.
Multaq, one such new anti-arrhythmic agent, has already been approved both in the US and the EU. Its
performance in the US has been fairly modest so far, with 2010 sales of $282m, with future prospects
depending on managed care acceptance. Multaq was launched in the UK in March 2010, after a positive
recommendation from NICE, and in France it is currently undergoing an evaluation by the transparency
commission (HAS) of the CEPS (Comit Economique des Produits de Sant; the economic committee on
healthcare products in France, which fixes drug prices in consultation with manufacturers). In January 2011,
the FDA released a safety announcement stating that acute liver failure may be one of the possible side
effects of Multaq usage. This announcement follows the release of multiple reports of hepatocellular liver
injury and hepatic failure among Multaq users.
Sanofi also has some key compounds in its antithrombotics pipeline in a bid to retain its supremacy in this
market segment. Of these, AVE5026 (Phase III) and otamixaban (Phase II completed) form the key
compounds under development. AVE5026 is an ultra LMWH which has shown a lower thrombosis risk than
Lovenox in Phase II. It is currently undergoing Phase III trials for VTE prevention in abdominal surgery and
cancer patients. Otamixaban is a Factor Xa inhibitor that is currently in Phase III for the treatment of
moderate to high risk patients with unstable angina (UA)/non-ST elevated myocardial infarction (NSTEMI)
with planned early invasive surgery. Phase II results showed clinically significant reduction in complications
in the invasive management of ACS, with a similar safety profile to that of existing therapies.

Drivers of growth
In 2010, Sanofi was the leading company in the EU, primarily due to its leadership position in France. Within
the 7MM, the company recorded the strongest growth in Japan due to the excellent performance of leading
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brands such as Plavix. In addition, Sanofi grew its sales in the BRIC (Brazil, Russia, India, and China)
markets, further consolidating its position in the emerging markets.
Sanofis growth over the years has been driven by three of its major franchises: vaccines, insulins, and the
antithrombotics portfolio. These three franchises made up the majority of its earnings in 2010 and are likely
to do so throughout the forecast period. Being shielded from generic competition, profits from vaccines tend
to be sustainable and this has put the company in a strong position.
A major drug in Sanofis cardiovascular pipeline that is likely to drive its growth is Multaq. Supported by
positive results from the ATHENA study, the drug received its EU approval for atrial fibrillation in November
2009, after receiving US approval in July 2009. Multaq is expected to further consolidate Sanofis position in
the atrial fibrillation disease area. The drug has a good side effects profile and is aimed at being a first-line
treatment, unlike the companys existing amiodarone which, due to numerous side effects, has been
indicated as a second-line treatment.
Additionally, although the threat of sales decline in the Lovenox and Plavix franchises after the patent
expirations looms large, the reduction in Lovenox sales may not be as significant as would normally be
expected. Being a biologic, Lovenox is considered to be less susceptible to rapid generic erosion compared
with traditional small-molecule drugs.
Resistors of growth
The patent expiries of Lovenox and Plavix are the most apparent resistors to Sanofis growth over the
forecast period. The two drugs made a combined $6.5bn in sales, or 61% of the companys cardiovascular
franchise in 2010. The recent FDA approval of generic Lovenox (enoxaparin), manufactured jointly by
Sandoz and Momenta, is likely to negatively impact future Lovenox sales.
Plavix, the other key drug in Sanofis portfolio, also faces some strong competition in Germany following a
May 2008 decision approving clopidogrel salt as different from the specific clopidogrel salt (expressly
claimed by the companys EU patent). Moreover, the drug also lost its EU data exclusivity in July 2008,
which has led to generic competition in several markets. Although Sanofi has launched its own generic
version of Plavix to tackle competition, it is unlikely to offset the revenue loss due to generics.
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In terms of pipeline developments, Sanofi does not have a strong cardiovascular portfolio to make up for
revenue loss from expected generic erosion, after the patent expiry of key products. Moreover, otamixaban,
one of Sanofis key antithrombotic compounds is likely to face some significant competition from other
recently launched or late-stage drugs, such as Xarelto and apixaban, both of which have the potential to
generate substantial sales. Besides Lovenox and Plavix, the company has no other drugs with such
significant market potential in its existing cardiovascular portfolio.
AstraZeneca
Overview
AstraZeneca was the third largest company in the global cardiovascular market, with $9.4bn in sales in 2010.
Amongst the top players in the cardiovascular market, the company recorded the fastest growth on the back
of strong performances by its leading antidyslipidemics and antihypertensives. Crestor remains the
companys leading cholesterol-lowering drug, with rising commercial potential supported by the positive
results from the JUPITER study. The company has a nominal presence in cardiac therapies and other
cardiovascular agents, and there are no antithrombotics in its franchise.
AstraZenecas presence in the cardiovascular market is wide ranging across indications, although it is led by
antihypertensives and antidyslipidemics. Among its leading brands, Crestor is the only antidyslipidemic,
contributing 61% of AstraZenecas total cardiovascular sales. Beta blockers and ARBs formed the other
leading drug classes for the company.
Growth in the dyslipidemia market has historically been driven by, the proven benefits of cholesterol-lowering
drugs and the growing number of patients needing lipid modulation. Although ENHANCE data had
threatened the growth of this market, recent JUPITER (Justification for the Use of statins in Prevention: an
Intervention Trial Evaluating Rosuvastatin) results are likely to continue to drive growth. The JUPITER trial
tested Crestor versus placebo on people with low-to-normal LDL, but with an elevated high sensitivity CRP
and, therefore, an increased cardiovascular risk. Although the study still leaves room for questions
concerning the effect of statins on people who are otherwise healthy, and whether the observed benefits
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were a consequence of lowering CRP or lowering LDL cholesterol, it does have the potential to widen the
dyslipidemia market.

Table 33 summarizes the performance of AstraZenecas major cardiovascular brands in 2010. Their relative
contributions to AstraZenecas cardiovascular portfolio are shown in Figure 19.
Table 33: AstraZeneca sales of leading cardiovascular brands ($m), 2010
Brand name
Generic name
Sales 2010 ($m)
Crestor
rosuvastatin
5,691
Atacand
candesartan
890
Atacand Plus
candesartan
593
Tenormin
atenolol
139
Plendil
felodipine
255
Total leading
7,568
Others
1,797
Grand total
9,365
Figure 19:
BUSINESS INSIGHTS
AstraZeneca cardiovascular portfolio by brand (%), 2010

19%
Crestor
1%
Atacand
3%
Atacand Plus
6%
Plendil
61%
10%
Tenormin
Others
BUSINESS INSIGHTS
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Crestor (rosuvastatin)
Crestor was the leading drug in AstraZenecas portfolio, with 2010 sales of $5.7bn. It is also the second topselling statin drug in the global cardiovascular market after Lipitor. Crestors commercial potential has been
further enhanced by the positive JUPITER trial results, which showed that Crestor, when administered to
people with normal LDL cholesterol levels and increased C-reactive protein, helped in reducing
cardiovascular events and reduced consequent deaths by 44% relative to placebo (Ridker et al., 2008).
Crestor was found to reduce the combined risk of heart attack, stroke, or cardiovascular death by 47%
relative to placebo. Total mortality reduced by 20% and there was a median drop of 50% in LDL cholesterol
on taking Crestor, relative to placebo.
In December 2009 the US FDAs Endocrine and Metabolic Drugs Advisory Committee (EMDAC) also voted
positively in supporting the use of Crestor in individuals meeting the following criteria:
men 50 years and women 60 years
fasting LDL < 130 mg/dL, hsCRP 2.0 mg/L, triglycerides < 500 mg/dL
patients with no prior history of cardiovascular or cerebrovascular events or coronary heart disease risk
equivalent as defined by NCEP ATP-III guidelines.
Thus, Crestor is now approved (based on February 2010 US approval) to reduce the risk of heart attack,
stroke, and arterial revascularization procedures in patients who have no clinically evident heart disease but
are at an increased risk of heart disease due to the combined effect of the above-mentioned criteria.
Following this judgment, Crestor received a similar broadening of indication in the EU as well in April 2010.
While giving a new dimension to the statins market (efficacy in people with low-to-normal LDL cholesterol),
the study results further reinforce Crestors market position in the global cardiovascular market. Other factors
contributing to the drugs prescription growth are the increasing usage of high potency statins and
diminishing safety concerns. Furthermore, in October 2009, Crestor also received US approval for use in
pediatric patients aged 1017 years with heterozygous familial hypercholesterolemia (when diet alone has
failed to reduce elevated cholesterol levels). However, the company has no plans to actively promote this
indication for Crestor, at least in the near-term.
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Atacand (candesartan cilexetil)

Atacand is an ARB that remained AstraZenecas second largest selling drug in 2010 with $890m in sales. It
is indicated only for patients who require more than a monotherapy. Atacand was unable to generate
significant market share owing to a tempered commercial effort, a consequence of unfavorable economics
deriving from royalties paid to Merck and Takeda, and competition from Novartiss Diovan. Atacand had very
low growth in 200910, and it is expected to decline significantly following its patent expiry in 2012.
Moreover, the threat of substitution from Cozaar/Hyzaar generics could further accelerate its decline.
Atacand Plus, AstraZenecas other leading drug, is a combination of candesartan and hydrochlorothiazide,
and registered $593m in 2010 sales.

The following table summarizes the late-stage cardiovascular pipeline of AstraZeneca in 2010.
Table 34: AstraZeneca late-stage cardiovascular pipeline, 2010
Compound name
Indication
Stage
Brilinta (ticagrelor)
Thrombosis
Approved in EU (2011), US
registration
Launched in Europe, expected to

be launched in US in Q4 2011
AZD0837
Thrombosis
Phase II
NA
AZD1305
Arrhythmias
Phase II
NA
AZD6482
Thrombosis
Phase I
NA
Source: AstraZeneca pipeline (www.astrazeneca.com)
BUSINESS INSIGHTS
AstraZeneca has several investigational clinical compounds in the cardiovascular therapy area. Key
therapeutic categories being investigated by AstraZeneca include antithrombotics, dyslipidemia, and cardiac
therapies, such as for arrhythmia.
Brilinta (AZD6140/ticagrelor), a reversible ADP receptor blocker and a novel antithrombotic, is among the
leading antithrombotics compounds in development. It was approved in the EU in Q4 2010. AstraZeneca
received a response letter from the US FDA in Q4 2010, indicating that Brilintas efficacy data was
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unsatisfactory. This has created a further setback for Brilinta, which may now not receive approval in the US
until Q4 2011.
The drug selectively inhibits the P2Y12 receptor, a major ADP receptor on the surface of platelets. Its
reversible receptor-binding properties differentiate it from Plavix, Effient (prasugrel), and Ticlid. However, this
reversible binding property may not actually translate to a clinical advantage, considering the compliance
concerns for a twice-a-day drug, which may increase clotting.
AZD0837 is an oral thrombin inhibitor, undergoing Phase II trials for stroke prevention and other embolic
events in atrial fibrillation patients. The safety and effectiveness of this compound will be studied in over 35
countries, using a once-daily extended release formulation. AstraZenecas other major developmental
compound, AZD1305, is an ion channel blocker which has progressed into Phase II trials for atrial fibrillation
in both oral and intravenous form.

Drivers of growth
AstraZenecas biggest growth driver lies in the commercial potential of its cardiovascular franchise, led by
Crestor, which is a high-potency statin that has steadily gained market share over the years. Positive
JUPITER trial results are expected to further consolidate its market position in the coming years. The
company is also planning to invest in fast-growing economies to strengthen its platform for growth in the
emerging markets.
Crestor also received US (February 2010) and EU (April 2010) approvals to reduce the risk of stroke, heart
attack, and arterial revascularization procedures in patients who have no clinically evident heart disease but
are at an increased risk of heart disease. Additionally, Crestor got a boost in June 2010 after a US court
upheld its US patent, allowing it to retain exclusivity until 2016. This judgment has re-affirmed Crestors
status as the only statin that is expected to achieve positive growth through the forecast period.
The company has a maturing pipeline, which seems to have been underappreciated. Its leading
cardiovascular pipeline drug, Brilinta (ticagrelor/AZD6140), an antiplatelet agent, was filed in the US in 2010.
However, the FDA response letter released in December 2010 indicated that the FDA was not entirely
128
satisfied regarding the efficacy data, indicating that the approval maybe delayed. This has represented a
significant setback for AstraZeneca, as Brilinta was thought to be one of its future blockbuster drugs.
AstraZeneca had also developed Certriad, a fixed-dose combination of Crestor and Abbotts TriLipix, in a
collaboration agreement with Abbott. This combination product was a new approach to help dyslipidemic
patients achieve their treatment goals, using a single pill targeting all three major blood lipids LDL-C, HDL-C,
and triglycerides. Phase III trial data presented at the National Lipid Associations 2008 Scientific Sessions
demonstrated that patients treated with the combination of TriLipix 135mg and Crestor 20mg had an
increase in HDL of 19% and a decrease in triglycerides of 42.9% compared with 10.3% and 25.6%,
respectively, with Crestor 20mg monotherapy. However, the development of Certriad was discontinued in Q4
2010, in a mutual agreement between AstraZeneca and Abbott, as it was deemed commercially unattractive
due to the long regulatory delays.
Resistors of growth
AstraZenecas cardiovascular franchise is highly concentrated toward its top five brands, which constitute up
to 81% of the franchises total sales. Currently, Crestor is the only drug in AstraZenecas marketed portfolio
that is forecast to record sales growth through to 2016. Furthermore, AstraZenecas blockbuster focus in
terms of sustainable sales growth opportunity will narrow markedly over the next few years and the company
is expected to become increasingly dependent on the Crestor franchise to drive revenue expansion in the
cardiovascular space.
AstraZenecas hypertension franchise is likely to become a resistor of growth over the forecast period, with
Atacand going off patent in 2011 (US) and 2012 (EU). Atacand has been unable to gain a significant market
share in recent years. The reasons for poor performance include a tempered commercial effort due to
unfavorable economics because of royalties paid to Merck (contingent payment) and Takeda, and strong
competition from Diovan. Moreover, Betaloc, the other leading drug in the companys hypertension franchise,
also lost its market exclusivity in 2007 and is exposed to generic competition.
129
Novartis
Overview
Novartis is the fourth largest company in the cardiovascular market, with 2010 sales of $8.6bn. The company
has a strong presence in antihypertensives and antidyslipidemics categories, as well as a modest presence
in the other cardiovascular market segments.
Novartiss cardiovascular franchise is dominated by ARBs, followed by ARBs in combination with
antihypertensives and/or diuretics. Diovan and Co-Diovan, which together generated sales of $6bn in 2010,
led Novartiss antihypertensive franchise.
ARBs are considered to be the drug class with the greatest market potential in the antihypertensives market,
and Novartiss leading antihypertensives Diovan/Co-Diovan both fall under this category. Additionally, the
company has some other promising antihypertensives such as Exforge, which is the only drug to combine
the complementary actions of an ARB (valsartan) and a CCB (amlodipine). Tekturna (aliskiren) is the other
major hypertension drug from Novartis and is the first in a class of drugs called direct renin inhibitors.
Tekturna generated sales of $438m in 2010. Novartis also launched a combination of Tekturna with the
diuretic hydrochlorothiazide (HCT). The Tekturna franchise has delivered promising results so far and is
expected to be one of Novartiss key antihypertensives
Alongside the ARBs, the hypertension market is currently shifting toward combination therapies as they
provide the multiple advantages of providing effective control for hypertension, while reducing pill burdens
and facilitating patient compliance. In line with this market trend, Exforge and Tekturna are likely to have
significant market potential through to 2016. Other than the antihypertensives, Novartis has dyslipidemia
drugs such as Lescol among its top brands.

Table 35 summarizes the recent performance of Novartiss leading cardiovascular brands in 2010. The
relative contributions to Novartiss cardiovascular portfolio are shown in Figure 20.
130
Table 35: Novartis sales of leading cardiovascular brands ($m), 2010
Brand Name
Generic name
Sales 2010 ($m)
Diovan
valsartan
3,632
Co-Diovan
Valsartan/ HCT
2,421
Exforge
amlodipine/valsartan
904
Lescol
fluvastatin
333
Lotrel
Amlodipine/benazepril
266
Tekturna
aliskiren
438
Total leading
7,994
Others
580
Grand total
8,574
Figure 20:
BUSINESS INSIGHTS
Novartis cardiovascular portfolio by brand (%), 2010

3%
7%
4%
Diovan
5%
42%
11%
Co-Diovan
Exforge
Tekturna
Lescol
Lotrel
Others
28%
BUSINESS INSIGHTS
Diovan (valsartan)
Diovan was the leading antihypertensive in Novartiss portfolio, generating 2010 sales of $3.6bn. The next
largest drug, Co-Diovan, an HCT salt version of Diovan also performed strongly with $2.4bn in sales in 2010.
Diovan has maintained its leadership position owing to increasing generic substitution in other
antihypertensive classes. Diovan is expected to continue on a growth trajectory until the loss of its patent
exclusivity in 2012.
131
Over the years, Diovan has continued to generate revenue growth owing to the accumulation of impressive
clinical data and its approval across several indications. The VAL-HeFT trial data revealed that Diovan is
superior to conventional therapy for the treatment of congestive heart failure, which has helped in expanding
its label beyond hypertension and establishing its market position. The VALIANT trial results supported its
label expansion for the reduction of cardiovascular death in high-risk patients following a heart attack, while
VALUE supported long-term use, in preference to Norvasc. Moreover, the approval of Valturna (a
combination of Diovan and Tekturna) in the US in September 2009 also forms a key prospect for the
company. In April 2010, Diovan gained a pediatric indication in the EU after it was approved for hypertension
in children and adolescents aged 6 to 18. Novartis is also actively pushing for a diabetes prevention
indication with Diovan based on data from its Phase III NAVIGATOR trial in patients with impaired glucose
tolerance. Despite only meeting one co-primary endpoint in this study, Novartis is currently in talks with the
FDA to convince it of a label change for Diovan, which would add another line extension to this highly
successful brand. However, given that the drug failed to prevent CV events in patients with impaired glucose
tolerance (IGT) (McMurray et al., 2010), Business Insights is of the opinion that the label change would only
lead to a modest increase in sales. As such, the sales increase due to the prescription of Diovan to delay the
onset of type 2 diabetes would be outweighed by the loss of sales values after genericization.
Exforge (amlodipine/valsartan)
Exforge is a single pill combination of valsartan and amlodipine. Since its launch in 2007, Exforge has
emerged as one of the strongest brands within the high blood pressure treatments market. Despite the trend
of fixed-dose combinations not performing well in the US, Exforge has demonstrated excellent growth.
Exforge HCT, which added a diuretic to the original, was launched in the US in April 2009 and the EU in July
2009 and is a single pill therapy containing three medicines (amlodipine, valsartan, and hydrochlorothiazide).
Exforge received approval in Japan in January 2010, a market which is expected to aid the brands overall
growth. Exforge registered worldwide sales of $904m in 2010.
Lescol (fluvastatin)
Lescol is an extended-release tablet formulation of fluvastatin, indicated for hypercholesterolemia and
dyslipidemia. The drug is marketed as Lescol XL for primary hypercholesterolemia and mixed dyslipidemia in
132
countries such as Italy, Spain, France, the UK, and the US. Its prolonged-release formulation has been
launched in France as Lescol LP. Additionally, it has also been approved in Mexico, Germany, the US, and
the UK for secondary prevention of cardiovascular events following percutaneous intervention, such as
angioplasty. Novartiss positioning in the cholesterol market has historically been tied to its Lescol and
Labistatin franchise. Despite its leading position among the top 10 brands of Novartis, Lescol has always
been a relatively minor product in the global statin market. Furthermore, the franchise will act as a sales
growth resistor through to 2016, mainly due to the impact of other statin patent expirations and the loss of
Lescol exclusivity in 2008 (EU markets). In 2010, Lescol was the fourth best-selling drug for the company in
its cardiovascular portfolio, registering sales of $333m.
Lotrel (amlodipine/benazepril)
Lotrel is a fixed-dose combination of two hypertension drugs, amlodipine (CCB) and benazepril (ACE
inhibitor), which have complementary modes of action. The drug lost patent protection long before its slated
patent expiry when Teva received an approval for its generic version of Lotrel in May 2007. This is because
the patent filed by Novartis specifies that the two component drugs of Lotrel must be separated physically,
that is, using a barrier. However, Teva separates the two components using an excipient, and hence claimed
that its version of Lotrel did not infringe the Novartis patent. Although Novartis managed to gain a temporary
stay order, it could not secure a preliminary injunction, which would have barred Teva from the continued
launch of the generic drug. Subsequently, Novartis launched its own generic version, creating a co-exclusive
period with Teva through the first quarter of 2009, when the 30 month stay on the remaining generic
companies expired. In February 2010, Indian generic major Lupin received FDA approval for generic Lotrel
capsules in various doses.

Novartiss cardiovascular pipeline has four important compounds under development, which are LCZ696,
QTI571 and PRT128. LCZ696 is in Phase III trials and is a dual-acting ARB/neprilysin inhibitor for systolic
heart failure. The Phase II results of LCZ696 indicated that the product improved blood pressure significantly
in patients with mild to moderate hypertension. These results were presented at the American College of
Cardiology meeting and published in the Lancet by Ruilope et al., (2010). On the basis of this data, Novartis
133
is currently planning to pursue testing of the drug for hypertension in specific patient populations including
diabetics, patients with renal failure, and elderly patients.
In December 2009, Novartis announced plans to acquire Corthera (a US-based biopharmaceutical company)
for $120m upfront and up to $500m in development and commercialization milestones. This acquisition
allowed Novartis to access Cortheras lead product relaxin, a recombinant version of a naturally occurring
peptide (currently undergoing Phase III trials for the treatment of acute decompensated heart failure
patients). Acute decompensated heart failure (ADHF) is the leading cause of hospitalization in people over
the age of 65. In addition, relaxin is used to relax the female reproductive tract and mediate the
cardiovascular and renal changes during pregnancy.
Table 36 summarizes the late-stage cardiovascular pipeline of Novartis in 2010.
Table 36: Novartis late-stage cardiovascular pipeline, 2010
Compound name
Indication
Stage
LCZ696
Heart failure
Phase III
>2012
QTI571
PAH
Phase III
NA
PRT128
ACS/CCHD
NA
NA
Note: ACS = acute coronary syndrome; CCHD = chronic coronary heart disease
Source: company pipeline (www.novartis.com)
BUSINESS INSIGHTS

Drivers of growth
The antihypertensive portfolio led by the Diovan franchise is expected to continue being Novartiss biggest
growth driver in the near-term. Diovan is best in class among the ARBs, and it is likely to maintain its
domination of this category until its patent expiry in 2012.
Yet another key product with strong growth potential is Tekturna/Rasilez, a novel, first-in-class direct renin
inhibitor to treat hypertension. Tekturna is likely to be the only renin inhibitor in the market in the near-term
134
giving Novartis a strong competitive advantage. Since its launch in 2007, the brand has had a high growth
rate due to its single pill combinations Tekturna HCT and Valturna, and increasing geographic expansion.
Another combination Amturnide, involving Tekturna, amlodipine, and HCT was approved by the FDA in
December 2010. Tekturna is also part of a major label-extension study program, across myriad indications
such as ACS and CHF, through the ASTRONAUT and ATMOSPHERE studies respectively. Although the
results of these studies are expected in 201213, success in any of these indications is expected to provide
a major boost to Novartis. More recently, Tekturna suffered a minor setback after Phase II results of the
ASPIRE study demonstrated its failure to reduce heart remodeling when used as a post myocardial-infarction
(MI) treatment. However, the overall prospects of Tekturna are considered to be very promising.
Exforge is another brand boosting Novartiss prospects in the antihypertensives market. It has performed
well in the market since its launch in 2007, closely following the benchmark Benicar launch in the US.
Moreover, the recent approval of Exforge HCT (the first three-in-one combination of amlodipine, valsartan
and hydrochlorothiazide) in both the US and the EU will further strengthen Novartiss hypertensive portfolio in
the coming years. The drug also has patent exclusivity in the EU until 2016, unlike the US, where it goes off
patent at the same time as Diovan, in 2012. Therefore, Exforge is expected to have significant market
potential in the EU over the forecast period, becoming a growth driver for the company.
The recent acquisition of Corthera (a US biopharmaceutical company) allowed Novartis to access Cortheras
lead product, relaxin (a recombinant version of a naturally occurring peptide, currently undergoing Phase III
trials for the treatment of acute decompensated heart failure patients).
Resistors of growth
Novartiss cardiovascular franchise is mostly dependent on Diovan and Co-Diovan, both of which are
expected to lose their patent exclusivity by 2012 in the US (2011 in the EU). Exforge and Tekturna may be
able to offset this loss to an extent but, given current prescribing trends, the drugs do not seem to have the
potential to completely stem the decline in the companys cardiovascular revenues.
Furthermore, with the recent patent expiry of Cozaar in 2010, it is surmised that the entire structure of the
antihypertensives market will change. Generic substitution and money-saving healthcare strategies, which
135
have been taking a toll on other markets, may begin to have an adverse effect on the antihypertensives
market in the US. Lotrels earlier-than-expected patent expiry has also triggered a decline in the companys
revenues. Lotrel sales fell sharply after an at risk launch in mid-2007 by Teva.
Bristol-Myers Squibb (BMS)

Overview
BMS was the fifth-largest player in the cardiovascular market in 2010, with $8.4bn in sales. The company
has a strong presence in the antithrombotics market, primarily driven by the strong performance of the
antiplatelet drug Plavix. The company also maintains a significant therapeutic presence in the hypertension
and dyslipidemia markets.
The companys leading antithrombotic drugs include Plavix, Coumadin, and Capoten. Apixaban, a follow-on
compound to the oral Factor Xa inhibitor razaxaban, is in pre-registration in the US. Products such as
apixaban are expected to help BMSs dominance in the thrombosis market over the forecast period.
Developed in a partnership with Pfizer, apixaban is believed to be BMSs most important strategic product in
the cardiovascular market.

Table 37 summarizes the recent performance of BMSs major cardiovascular brands in 2010. Their relative
contributions to BMSs cardiovascular portfolio are shown in Figure 21.
136
Table 37: BMS sales of leading cardiovascular brands ($m), 2010
Brand Name
Generic name
Sales 2010 ($m)
Plavix
clopidogrel
Avalide
irbesartan
565
Coumadin
warfarin
188
Pravachol
pravastatin
111
Monopril
fosinopril sodium
6,666
62
Total leading
7,592
Others
791
Grand total
8,383
Figure 21:
BUSINESS INSIGHTS
BMS cardiovascular portfolio by brand (%), 2010

1%
1%
9%
2%
7%
Plavix
Avalide
Coumadin
Pravachol
Monopril
Others
80%
BUSINESS INSIGHTS
Plavix was the key revenue driver in BMSs portfolio, registering $6.7bn in sales in 2010. This growth was
primarily due to a line extension approval for treatment of non-ST-segment elevation ACS in combination
with aspirin in Europe in 2008. Additionally, Plavix is awaiting approval in Europe (where it is marketed by
Sanofi) for prophylaxis against atherothrombotic events in patients suffering from MI, ischemic stroke, and
137
established PAD (peripheral arterial disease). However, sales are forecast to erode significantly following its
patent expiration in 2012, and a recent restrictive labeling (US) with the PPI omeprazole (AstraZenecas
Prilosec/Prilosec OTC). The potential launch of AstraZenecas Brilinta in 2011, and increasing competition
from Eli Lillys Effient are also expected to pose a threat to Plavixs future prospects.
Avalide/Avapro (irbesartan HCT)
Avalide was the second-largest drug for BMS in 2010, with $565m in sales. It is also marketed as Avapro by
Sanofi in some leading markets. Avalide is an ARB that has a significant share of the ARB market within the
US. Beyond hypertension, Avapro also received approval for the treatment of diabetic neuropathy based on
results from the PRIME study, which demonstrated that it reduces morbidity and mortality for patients with
type 2 diabetes and hypertension with early or late alteration of renal function. Avalide/Avapro sales
decreased by 3.3% in 2010 when compared with 2009, with the introduction of Cozaar generics and they are
further expected to decline significantly after patent expiry in 2012.
Coumadin (warfarin)
Coumadin was BMSs third best-selling drug, with 2010 sales of $188m. Vitamin K antagonists, such as
Coumadin, and its generic bioequivalents and derivatives (acenocoumarol and phenprocoumon, and
indanediones such as phenindione and fluindione), are the only representatives of the oral anticoagulants
class. Coumadin sales have been declining over the years, primarily driven by some product attributes that
make the therapy time-consuming and cumbersome. Warfarin has numerous drug-drug and food-drug
interactions, which lead to an unpredictable dosage response, necessitating continuous monitoring of
coagulation. Furthermore, maintenance doses have to be adjusted regularly to prevent overtreatment, which
can cause severe bleeding, or under treatment, which can result in a failure to prevent clot formation. Poorly
monitored warfarin therapy can be potentially dangerous, exposing the patient to a risk of internal bleeding.
In October 2006, prompted by an FDA recommendation, BMS introduced a black box warning highlighting
the risk of major or fatal bleeding.

Apixaban, the oral Factor Xa inhibitor being developed (in collaboration with Pfizer) for a broad range of
cardiovascular indications including VTE, atrial fibrillation, and acute coronary syndrome is BMSs most
138
promising pipeline product. It is also part of one of the most expensive joint development agreements in the
industry. As a result of this agreement, Pfizer has agreed to pay $1bn to acquire the product development
and marketing rights, while also committing to finance 40% of the R&D outlay. It is believed that the product
has peak sales potential similar to Xarelto (rivaroxaban). With Lipitor sales declining sharply, Pfizers
commercial machine is likely to be focused on ensuring that apixaban is a commercial success, and
therefore can probably make up for the time lag in its launch relative to Xarelto. Table 38 summarizes BMSs
cardiovascular pipeline in 2010.
Table 38: BMS cardiovascular portfolio, 2010
Compound name
Indication
Stage
Expected year of
launch
Apixaban
Venous
thromboembolism
prevention/treatment
Pre-registration in the EU
2011
CCR2 antagonist
Cardiovascular
NA
NA
DGAT inhibitor
Cardiovascular
NA
NA
LXR agonists
Cardiovascular
NA
NA
PCSK9 inhibitor
Cardiovascular
NA
NA
CCR2/CCR5 antagonist
Cardiovascular
NA
NA
Delta PKC inhibitor
Cardiovascular
NA
NA
IKACh inhibitor
Cardiovascular
NA
NA
Source: BMS pipeline (www.bms.com)
BUSINESS INSIGHTS

Drivers of growth
BMS entered into a collaborative agreement with Isis Pharmaceutical in May 2007 for discovering,
developing, and commercializing novel antisense drugs targeting proprotein convertase subtilisin kexin 9 for
the prevention and treatment of cardiovascular disease. The company made an upfront payment of $15m to
Isis as part of this agreement and will provide Isis with at least $9m in research funding over a period of three
years. This agreement may become a key growth driver for the company in the cardiovascular arena.
139
To further broaden its partnering strategy, in May 2008 BMS announced an agreement with Kai
Pharmaceuticals for the global development and commercialization of KAI-9803, a delta protein kinase C
pathway inhibitor to reduce heart attack and improve clinical outcomes during the treatment of acute MI
(myocardial infarction). In December 2008, both companies also started a Phase II trial to determine the
safety and efficacy of the drug in subjects with ST elevation myocardial infarction undergoing a percutaneous
coronary intervention (PCI).
Plavix has been the major revenue contributor for the company, and its additional EU approval (in March
2008) for the treatment of non-ST-segment elevation ACS in combination with aspirin has continued to drive
additional growth. Backed by positive clinical data, the compound presents significant commercial potential.
Apixaban, the other leading Factor Xa inhibitor from BMS and Pfizer is undergoing Phase III trials in ACS,
AF, VTE treatment, and VTE prevention. In June 2010, BMS halted the pivotal Phase III AVERROES trial of
its apixaban in vitamin K antagonist intolerant patients with atrial fibrillation (AF), based on interim data that
showed that the drug reduced stroke and systemic embolism compared with aspirin. Although apixaban has
already been approved in the EU for VTE prevention following surgery, a similar approval in the US is likely
to take more time. AF is considered to be a highly lucrative market and apixabans performance in the firstline ARISTOTLE trial which is due to ended in Q2 2011 is expected to set the tone for BMSs future
prospects in the cardiovascular market.
Resistors of growth
Near-term patent expiration of Plavix and Avalide will be the primary factors resulting in erosion of BMSs
cardiovascular franchise sales. Most of the other leading products in the companys cardiovascular portfolio
are off patent and have been losing sales.
Furthermore, the company does not have a strong pipeline, apart from apixaban, to offset this loss. Although
BMS is set to enjoy significant profits out to 2011, the company must brace itself for a significant downturn in
revenues beyond this time (as happened after the patent expiry of Pravachol in 2006, when the drug lost
over $1bn in sales over previous year). This scenario was worsened by the failure of Pravachol in head-tohead trials (REVERSAL and PROVE IT) against Pfizers market leader Lipitor, which showed that Lipitor was
better at reducing both LDL cholesterol and secondary cardiac events.
140
Merck
Overview
Merck was the sixth largest company in the global cardiovascular market, with $7.5bn in 2010 sales. From
200510 Merck has been gradually losing its market share within the cardiovascular market. However,
despite the continued shrinkage in sales, Merck retained its position in the top ten cardiovascular companies
in 2010. One of the biggest reasons for Mercks declining performance over the past five years has been the
loss of patent exclusivity for its former blockbuster Zocor (simvastatin) in 2006. More recently, other
blockbusters in its portfolio such as Vytorin, with 2010 sales of $2bn, and Zetia, with 2010 sales of $2.3bn,
have also been declining over the past two years, affecting Mercks prospects in the cardiovascular market.
Vytorins decline can be attributed to the safety and efficacy issues in the ENHANCE (Ezetimibe and
Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) and SEAS (Simvastatin and
Ezetimibe in Aortic Stenosis) trials. Besides dyslipidemia, the company has a significant presence in the
hypertension market and a modest presence in thrombosis.
Mercks cardiovascular portfolio is dominated by antidyslipidemics. Statins have dominated the dyslipidemia
market, but lately, with cost saving policies coming into play in most of the major markets, generic drugs
have begun to replace their branded counterparts. This is further accentuated by the patent expiry of key
statins in the recent past, such as Mercks Zocor and the imminent expiry of Lipitor in 2011, as well as safety
concerns raised by data from the ENHANCE clinical trial. ENHANCE raised regulatory concerns over the
validity of LDL as a surrogate marker and is likely to temper the adoption of new agents that lack outcomes
data. However, statins such as Mercks Vytorin may remain the mainstay treatment for cholesterol reduction,
supported partly by recent positive results from the JUPITER study
Drugs that raise HDL cholesterol remain another area of interest in the dyslipidemia market. CETP inhibitors
such as torcetrapib showed early promise in this segment. However, data from ILLUMINATE trials indicated
an increased risk of CV events with torcetrapib, due to off-target toxicity. This has lead to the cautious
development of the CETP inhibitors manufactured by Merck and Roche.
141
Merck also has a strong presence in the hypertension market, led by the ARB and ARB combination drugs
Cozaar and Hyzaar, respectively. However, the loss of exclusivity to Cozaar/Hyzaar in April 2010 in the US is
expected to impact Mercks position further. Among Mercks other antihypertensives, Renitec is an ACE
inhibitor and Vaseretic is an angiotensin I converting enzyme inhibitor.

Table 39 summarizes the recent performance of Mercks major cardiovascular brands in 2010. Their relative
contributions to Mercks cardiovascular portfolio are shown in Figure 22.
Table 39: Merck sales of leading cardiovascular brands ($m), 2010
Brand name
Generic name
Sales 2010 ($m)
Zetia
ezetimibe
2,298
Vytorin
ezetimibe/simvastatin
2,014
Cozaar
losartan
2,105
Zocor
simvastatin
468
Total leading
6,885
Others
593
Grand total
7,478
Figure 22:
BUSINESS INSIGHTS
Merck cardiovascular portfolio by brand (%), 2010

8%
6%
31%
Zetia
Cozaar
Vytorin
27%
Zocor
Others
28%
BUSINESS INSIGHTS
142
Cozaar/Hyzaar (losartan/losartan HCT)

Cozaar/Hyzaar is a first-in-class ARB that registered $2.1bn sales in 2010. It is a leading antihypertensive,
following Diovan and Norvasc. Hyzaar is a fixed-dose combination of losartan with the diuretic
hydrochlorothiazide (HCT) and is primarily indicated for the treatment of patients with hypertension who have
not benefited from losartan monotherapy. The Reduction of Endpoints in NIDDM [non-insulin dependant
diabetes mellitus].with the Angiotensin II Antagonist Losartan (RENAAL) and the Losartan Intervention For
Endpoint Reduction in Hypertension (LIFE) trial data have supported Cozaars use over the years, with
RENAAL results indicating a reduction in end-stage renal disease in diabetic patients, and LIFE supporting
its efficacy in stroke. However, Cozaar does not have a first-line congestive heart failure claim worldwide,
giving an edge to other leading ARBs such as Novartiss Diovan and AstraZenecas Atacand. On April 2010,
the primary Cozaar patent (the 197 patent) expired, exposing it to generic losartan. Following this
development, the FDA granted final approval to Tevas generic versions of Cozaar and Hyzaar in various
strengths, declaring it eligible for 180 days exclusivity. Furthermore, Sandoz also announced the launch of
authorized generic versions of both Cozaar and Hyzaar. Sales of Cozaar/Hyzaar are expected to decline
considerably through the forecast period.
Vytorin (ezetimibe/simvastatin)
Vytorin is one of Mercks leading cardiovascular products, with 2010 sales of $2.0bn. The drug is jointly
developed and promoted by Merck and Schering-Plough and is a fixed-dose combination of a high efficacy
statin and the cholesterol absorption inhibitor ezetimibe. Vytorin was the only branded statin with sales
growth up to 2007, even after the launch of generic simvastatin. This was because many patients cannot
meet their cholesterol-lowering targets on simvastatin alone. However, following the January 2008
ENHANCE results, which raised concerns over the increased cancer risk on using Vytorin, its sales have
steadily declined. Furthermore, competition to the drug has increased following the recent positive results
from the JUPITER trial supporting Crestor. This scenario may change with the IMPROVE-IT trial results, due
in 2013.
143

Mercks R&D pipeline features numerous products at different stages of development, and across diseases
such as atherosclerosis, stroke, and ACS. The companys most promising cardiovascular pipeline compound
is vorapaxar, an orally active pyridine derivative thrombin (PAR-1) receptor antagonist (also known as TRA),
which is currently undergoing Phase III trials for the prevention of heart disease in patients with ischemic
heart disease. Merck inherited the drug from Schering-Plough. The Phase III trials were halted in Q1 2011 by
the Data and Safety monitoring board, owing to excessive bleeding. The drug usage in patient populations
who had suffered a stroke prior to participation in the clinical trial has been immediately discontinued. Clinical
trials are continuing only in those sub-groups who had suffered a pervious heart attack or peripheral arterial
disease, Cordaptive (MK-0524A) is another promising drug that has already been approved in the EU under
the brand name Tredaptive. In the US, however, the FDA issued a non-approvable letter for the compound in
April 2008. Moreover, FDA regulators also suggested that Merck may have to wait until 2012 to reapply
when the THRIVE study is scheduled to complete. Table 40 summarizes the late-stage cardiovascular
pipeline of Merck and Schering-Plough as of June 2010.
Table 40: Merck late-stage cardiovascular pipeline, 2010
Compound name
Indication
Stage
Vorapaxar
ACS
Phase III
Uncertain; Phase III continuing

only in certain sub-groups
Cordaptive/Tredaptive
(niacin + laropiprant)
Atherosclerosis
Phase III
Approved in the EU
MK-0524B
Atherosclerosis
Phase III
>2012
MK-0859/ anacetrapib
Atherosclerosis and
hypercholesterolemia
Phase III
>2012
Acadesine
IRI
Phase III
>2013
MK-0736
cardiovascular
Phase II
>2014
MK-4448/ betrixaban
cardiovascular
Phase II
>2014
MK-6621/ vernakalant
Atrial fibrillation
Phase II
>2014
TRA = thrombin receptor antagonist; IRI = ischemia reperfusion injury; ACS = acute coronary syndrome.
Source: company pipeline (www.merck.com)
BUSINESS INSIGHTS
144
Cordaptive is a combination of extended-release niacin (ERN) with laropiprant, a prostaglandin D2 receptor 1

(DP1) antagonist. It is indicated for the treatment of atherosclerosis and also helps in reducing flushing by
antagonism of the DP1 receptor. This is a common side effect of niacin therapy and a factor that can lead to
discontinuation. The drug delivers a 2g dose of niacin and can be used in combination with a statin. Merck is
investigating a fixed-dose combination of Cordaptive with simvastatin, designated MK-0524B.
Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor indicated for the treatment of
atherosclerosis, is another Merck compound in Phase III development. Merck/Portolas betrixaban (currently
undergoing Phase II trials), an anticoagulant drug, appears to have the most compelling profile of its class,
with a once-daily dosing profile.

Drivers of growth
Mercks biggest advantage over its competitors is its extensive cardiovascular pipeline with compounds for
various indications. The company intends to maintain its focus on cardiovascular R&D, with eight drugs
under development. In the long term, this will give the company an edge in the cardiovascular market over
competitors such as Pfizer, which recently announced that it is ending development of early-stage
cardiovascular compounds.
Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor indicated for the treatment of
atherosclerosis showed no increase in blood pressure and no changes in aldosterone and serum electrolyte
levels in Phase III studies. Additionally, its impressive lipid modulator properties make it a key potential
growth driver for the company. In terms of recent alliances, Merck and Portola entered into a licensing
agreement for betrixaban (an anticoagulant), whereby Merck will assume all development and
commercialization costs of Phase III trials and pay Portola double digit royalties on worldwide sales of the
drug. According to the agreement, Portola has the option to co-fund Phase III studies in exchange for
additional royalties, and also to co-promote betrixaban with Merck in the US.
145
Resistors of growth
Merck is primarily a small-molecule company, generating over 70% of its sales from this type of drug (while
the rest of the sales are from its vaccine division). With an increasing industry-wide focus on biologics
research, it is not surprising that big pharma has been increasing its presence in the sector through
acquisitions and licensing deals. R&D-based firms such as Merck see their traditional strengths in innovative
research, clinical development, and marketing as valuable assets. Although the recent merger with ScheringPlough and a definitive agreement with Insmed have increased its biologics platform and infrastructure, the
deals have only a limited impact on the cardiovascular therapeutic area.
Furthermore, the cholesterol drugs Vytorin and Zetia (the leading cardiovascular drugs for Merck), marketed
through a Merck/Schering-Plough partnership, have also been facing large sales declines, which was mainly
due to safety and efficacy issues from ENHANCE and SEAS trials. In November 2009, Mercks Zetia also
suffered a further blow after it was shown to be less effective than Abbotts extended-release niacin product,
Niaspan, in the prematurely terminated ARBITER 6 HALTS trial. In December 2009, Merck also decided to
discontinue the development of MK-1903 (an investigational niacin receptor agonist to treat atherosclerosis),
which was being developed under its research collaboration with Arena Pharmaceuticals.
The loss of patent protection earlier this year for Mercks leading antihypertensive drug, Cozaar/Hyzaar, is
the other major threat for the company during the forecast period. Cozaar also lacks a first-line congestive
heart failure (CHF) claim worldwide, giving an advantage to Novartiss Diovan and AstraZenecas Atacand.
In November 2009, the US FDA refused to approve an NDA submitted by Merck for its lipid-lowering product
MK-0653C, which combines Pfizers Lipitor and Schering-Plough's Zetia. In addition, the FDA also requested
additional manufacturing and stability data before its re-filing.
146
Appendix
Scope and methodology
Scope
This report provides comprehensive coverage of the cardiovascular market, incorporating a disease
overview and detailed epidemiological analyses of the major indications. It makes a wide-ranging
assessment of the marketed product portfolio, R&D pipeline, market share data, sales forecast, and
competitive landscape for the major players. Furthermore, it highlights the key market and R&D trends that
may influence treatment sales and includes a thorough analysis of the competitive dynamics of leading
brands within each indication, enabling the reader to identify growth brands, key drug classes, and leading
players through 2016.
Key cardiovascular sub therapy areas covered in this report are:
antihypertensives
antidyslipidemics
antithrombotics
cardiac therapies
other cardiovascular agents.
This report provides the following:
An overview and summary of significant developments and key R&D and market events in the global
cardiovascular market that have impacted treatment algorithms and sales potential across the major
cardiovascular drug classes.
Epidemiological analysis and forecast prevalence for cardiovascular indications to 2016.
Forecasts and analysis of the key products in the major indications over the period 201016 to
benchmark the forecast performance of the leading players.
147
Methodology
Market size methodology
The leading products and companies in the global cardiovascular market were identified using companyreported sales sourced from PharmaVitae and company annual reports. Where applicable, reference was
also made to multiple secondary resources, in-house databases, scientific journals, and analyst reports to
derive additional insights into currently marketed drugs.
Epidemiology
The epidemiology of relevant indications is derived from the cohort studies referenced in the report. The
epidemiology forecast is extrapolated based on the cohort studies and forecast population changes sourced
from the US Census Bureau. The forecast does not take into account any genetic, cultural, environmental,
social, or racial changes to population demographics that could have an impact on disease epidemiology in
the various markets.
Market forecast
To forecast future market sizes, regression analysis was used to establish a forward-looking baseline trend.
This baseline was then adjusted to take into account future events that are not reflected by the historical
trend. Examples of these events include:
The launch of new products, with peak sales forecasts based on expected patient numbers and
expected price.
Patent expirations, generic competition, any ongoing patent litigation, or restricted label warnings (black
box warnings).
Product extensions based on superior administration/dosage profiles, expanded indications, or postmarketing studies.
For biologics, the likely entry of biosimilars/follow-on biologics in the developed (mostly the US and EU)
and developing countries, and the competitive dynamics that these may introduce post-approval.
Special consideration is also given to the impact of first-in-class, novel drugs that result in a paradigm
shift in the treatment algorithm in therapy areas and diseases with significant unmet medical need.
148
Abbreviations
ABCD-2V: Appropriate Blood pressure Control in Diabetes Part II with Valsartan
ACC: American College of Cardiology
ACE-I: ACE inhibitors
ADHF: acute decompensated heart failure
ADP: adenosine diphosphate
ALLIANCE: Aggressive Lipid Lowering Initiation Abates New Cardiac Events
ANDA: Abbreviated new drug approval
ApoB: apolipoprotein B
ACS: acute coronary syndrome
ARB: Angiotensin receptor blockers
ARISTOTLE: Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation
AVERROES: Apixaban versus Acetylsalicylic Acid to Prevent Strokes
BI: Boehringer Ingelheim
BMS: Bristol-Myers Squibb
BREATHE-1: Bosentan Randomized trial of Endothelin Antagonist Therapy for pulmonary hypertension
CAD: coronary artery disease
cAMP: cyclic adenosine monophosphate
CAGR: compounded annual growth rate
CCB: Calcium Channel Blockers
149
CETP: cholesteryl ester transfer protein

CHD: coronary heart disease
CEPS: Comit Economique des Produits de Sant
CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and
Avoidance
CHF: congestive heart failure
CHMP: Committee for Medicinal Products for Human Use
CLARITY: Clopidogrel as Adjunctive ReperfusIon Therapy
COMMIT: Comprehensive Multidisciplinary Interventional Trial for regression of coronary artery disease
CORONA: Controlled Rosuvastatin multinational trial in heart failure
CURRENT/OASIS-7: Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal
Antiplatelet Strategy for Interventions
CHEST: Chronic Thromboembolic Pulmonary Hypertension sGC Stimulator Trial (CHEST)
CRL: complete response letter
DVT: Deep vein thrombosis
DEFINE: Determining the Efficacy and Tolerability of CETP Inhibition with anacetrapib
EMA: European Medicines Agency
ENHANCE: Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression
ERN: extended release niacin
EXTRACT-TIMI 25: Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction TreatmentThrombolysis In Myocardial Infarction Study 25
150
HCT: hydrochlorothiazide
HDL: high density lipoprotein
HeFH: heterozygous familial hypercholesterolemia
HoFH: homozygous familial hypercholesterolemia
HMG-CoA: hydroxy-methylglutaryl-coenzyme A
HsCRP: high-sensitivity C-reactive protein
IDEAL: Individualized Dosing Efficacy vs. flat dosing to Assess optimal PEGylated interferon therapy
IVUS: intravascular ultrasound
JUPITER: Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating
Rosuvastatin
LDL: low density lipoprotein
LIFE: Losartan Intervention For Endpoint Reduction in Hypertension
LMWH: low molecular weight heparins
Lp-PLA2: lipoprotein associated phospholipase 2
METEOR: Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin
MI: myocardial infarction
NAVIGATOR: Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research
NDA: New Drug Application
NEP: neutral endopeptidase
NIDDM: non-insulin dependant diabetes mellitus
151
PAH: pulmonary arterial hypertension

PAD: peripheral artery disease
PAI: platelet aggregation inhibitor
PIP: pediatric investigation plan
PAR-1: pyridine derivative thrombin (PAR-1) receptor
PATENT: Pulmonary arterial hypertension sGC Stimulator Trial (CHEST)
PDE5: phosphodiesterase-5
PLUTO: Pediatric Lipid-redUction Trial of rOsuvastatin
PPAR: peroxisome proliferator activated receptor
PROVE-IT: Pravastatin or atorvastatin evaluation and infection therapy.
RAA: renin-angiotensin-aldosterone
RECORD: REcognition of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE
RENAAL: Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus
ROW: Rest of the World, including Asia-Pacific (APAC), Latin and Central America, Africa and Canada
RAODMAP: Randomised Olmesartan and Diabetes MicroAlbuminuria Prevention Study
SATURN: Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin Versus
AtorvastatiN
sCG: Guanylate cyclase
7MM: 7 major markets US, Japan, UK, Germany, France, Italy and Spain
STEMI: S-T elevation myocardial infarction
152
SYNERGY: Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa
inhibitors
TNT: Treating to New Targets
UFH: unfractionated heparin
Val-HeFT: Valsartan Heart Failure Trial
VALIANT: VALsartan In Acute Myocardial Infarction Trial
VALUE: Valsartan Antihypertensive Long-term Use Evaluation
VKA: vitamin-K antagonists
VLDL: very low density lipoprotein
VTE: venous thromboembolism
WHO: World Health Organization
Angina
Angina is a type of chest pain occurring when the heart muscle (myocardium) does not receive enough
oxygen-rich blood.
Arrhythmias
Heart rhythm problems (arrhythmias) occur when the electrical impulses in the heart that coordinate
heartbeats do not function properly, causing the heart to beat too fast, too slow, or irregularly.
Atherosclerosis
Atherosclerosis refers to the build-up of fats in and on the artery walls (plaques), which can restrict blood
flow.
153
Thrombosis
Thrombosis is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood
through the circulatory system.
Congestive heart failure occurs when the heart loses the capacity to pump enough blood for the whole
bodys needs.
Coronary artery disease develops when the coronary arteries (the arteries that supply blood to the heart)
become damaged or diseasedusually due to a build-up of plaques.
Dyslipidemia
Disrupted levels of lipids in the body, usually elevated LDL and low HDL.
Familial hypercholesterolemia
A rare genetic disorder that leads to high levels of LDL-cholesterol and increased risk of heart disease.
Hypercholesterolemia
High blood levels of cholesterol.
Cardiac ischemia
Cardiac ischemia occurs when blood flow to the heart muscle (myocardium) is decreased by a partial or
complete blockage of a coronary artery.
A heart attack caused by severe and sudden blockade of a coronary artery, causing ischemia.
154
Peripheral arterial disease

A circulatory problem in which narrowed arteries reduce blood flow to limbs.
A condition wherein the pulmonary arteries and capillaries become narrowed, blocked, or destroyed. This
causes an increase in blood pressure in the pulmonary arteries, veins, or capillaries.
Stroke
A stroke occurs when the blood supply to a part of the brain is interrupted or severely reduced, depriving
brain tissue of oxygen and nutrients. Within a few minutes, brain cells begin to die.
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160

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The Cardiovascular Market Outlook

About Business Insights

Overview and epidemiology of cardiovascular disorders

Global market analysis

Chapter 1 Overview and epidemiology of cardiovascular disorders 17

Predisposing risk factors

Modifiable risk factors

Diagnosis, treatment and management

Diagnosis, treatment, and management

Myocardial infarction (MI)

Acute coronary syndrome (ACS)

Congestive heart failure (CHF)

Coronary artery disease (CAD)

Peripheral artery disease (PAD)

Chapter 2 Global market analysis

Market analysis by geography

Key events in the cardiovascular market

European approval for Rasilamlo

BMS/Pfizers apixaban likely to receive EU approval

Angiotensin receptor blockers (ARBs) may cause increased cancer risk

Crestors patent upheld in the US

Plavix boxed warning for poor metabolizers

Market analysis by drug class

Antihypertensive drug classes

Leading treatment brands by drug class

Key brands analysis

Antidyslipidemic drug classes

Leading treatment brands by drug class

Key brands analysis

Future blockbusters in the antidyslipidemic drug class

Antithrombotics drug classes

Leading treatment brands by drug class

Key brands analysis

Future blockbusters in the antithrombotic drug class

Other cardiovascular agents

Leading treatment brands by drug class

Leading brands dynamics and sales forecasts

Product growth-share matrix for leading brands

Chapter 3 Pipeline analysis

Key events in the cardiovascular market

First advanced therapy certificate for t2cures somatic cell therapy

FDA panel to review AstraZenecas Brilinta

Novartis presents successful Phase II results of LCZ696

Daiichi Sankyos CS-8635 shows promising results in pivotal trial

Leading drugs in development

Profiles of key pipeline products

Key antihypertensive pipeline drugs

Key antidyslipidemic pipeline drugs

Livalo (pitavastatin) Kowa Pharmaceuticals

Key antithrombotic pipeline drugs

Xarelto (rivaroxaban) Bayer/J&J

Apixaban Bristol-Myers Squibb (BMS)/Pfizer

Brilinta (ticagrelor) AstraZeneca

Chapter 4 Competitive landscape

Competitive positioning of top players in the cardiovascular market

Marketed product portfolio

R&D pipeline analysis

Strategic and growth analysis

Marketed product portfolio

R&D pipeline analysis

Strategic and growth analysis

Marketed product portfolio

Atacand (candesartan cilexetil)

R&D pipeline analysis