Statin Evolution

Evidence Efficacy and Experience

This CME is brought to you by-

Atorvastatin 10/20 mg Tablets

Sun Pharmaceutical (Bangladesh) Ltd.

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Lipid-lowering Goals

Joint European Societies1

Established CHD, other atherosclerotic disease, or high absolute risk

LDL-C Goal
<115 mg/dL (3.0 mmol/L)

Wood D, et al. Atherosclerosis. 1998;140:1434-1503;

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Lipid-lowering Goals
2009 Canadian Guideline Updates
Primary target is LDL-C decrease to < 2.0 mmol/l or 50% relative reduction. A 50% relative reduction in LDL-C confers close to optimal benefit.

Canadian Cardiovascular Society. Genest J et al. Can J Cardiol 2009; 25: 567-79
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Lipid-lowering Goals

US NCEP ATP III2

0-1 CHD risk factors >2 CHD risk factors CHD or CHD risk equivalent <160 mg/dL (4.1 mmol/L) <130 mg/dL (3.4 mmol/L) <100 mg/dL (2.6 mmol/L)

NCEP Expert Panel. JAMA. 2001;285:2486-2497.

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ATP III Lipid and Lipoprotein Classification LDL Cholesterol (mg/dL)

<100 100129 130159 160189 190 Optimal Near optimal/above optimal Borderline high High Very high

ATP III Lipid and Lipoprotein Classification

HDL Cholesterol (mg/dL)

<40 60 Low High

ATP III Lipid and Lipoprotein Classification Total Cholesterol (mg/dL)

<200 200239 240 Desirable Borderline high High

Lipid-lowering Goals

High Risk Patients

All persons with CHD or CHD risk equivalents can be called high risk. LDL goal: 100 mg/dl - Reasonable optional goal: 70 mg/dl

Grundy SM, Cleeman JI, Merz CN, et al., J Am Coll Cardiol. 2004;44:720-732.
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CHD Risk Equivalents

Risk for major coronary events equal to that in established CHD 10-year risk for hard CHD >20%

Hard CHD = myocardial infarction + coronary death

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CHD Risk Equivalents

Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease) Diabetes Multiple risk factors that confer a 10-year risk for CHD >20%

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Major Risk Factors

Cigarette smoking Hypertension (BP 140/90 mmHg or on antihypertensive medication) High LDL cholesterol (>100 mg/dl) Low HDL cholesterol (<40 mg/dl) Family history of premature CHD (CHD in male first degree relative <55 years; CHD in female first degree relative <65 years) Age (men 45 years; women 55 years)

NCEP Expert Panel. JAMA. 2001;285:2486-2497.

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ATP III: Major Risk Factors That Modify LDL Goals

LDL-C goal of <70 mg/dl for severe and poorly controlled risk factors
Cigarette smoking Diabetes Hypertension Low HDL cholesterol Multiple risk factors of the metabolic syndrome

Grundy SM, Cleeman JI, Merz CN, et al., J Am Coll Cardiol. 2004;44:720-732.
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LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories
LDL Level at Which to Initiate Therapeutic LDL Goal Lifestyle Changes (mg/dL) (TLC) (mg/dL) <100 100 LDL Level at Which to Consider Drug Therapy (mg/dL) 130 (100129: drug optional)

Risk Category CHD or CHD Risk Equivalents (10-year risk >20%) 2+ Risk Factors (10-year risk 20%)

<130

130

10-year risk 1020%: 130 10-year risk <10%: 160

01 Risk Factor

<160

160

190 (160189: LDL-lowering drug optional)

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LDL-Lowering Therapy in Patients With CHD and CHD Risk Equivalents

Baseline LDL Cholesterol: 130 mg/dL

Intensive lifestyle therapies Maximal control of other risk factors Consider starting LDL-lowering drugs simultaneously with lifestyle therapies

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LDL-Lowering Therapy in Patients With CHD and CHD Risk Equivalents

Baseline (or On-Treatment) LDL-C: 100129 mg/dL

Therapeutic Options:

LDL-lowering therapy Initiate or intensify lifestyle therapies Initiate or intensify LDL-lowering drugs Treatment of metabolic syndrome Emphasize weight reduction and increased physical activity Drug therapy for other lipid risk factors For high triglycerides/low HDL cholesterol Fibrates or nicotinic acid

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LDL-Lowering Therapy in Patients With CHD and CHD Risk Equivalents

Baseline LDL-C: <100 mg/dL

Further LDL lowering not required Therapeutic Lifestyle Changes (TLC) recommended Consider treatment of other lipid risk factors Elevated triglycerides Low HDL cholesterol Ongoing clinical trials are assessing benefit of further LDL lowering

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LDL-Lowering Therapy in Patients With Multiple (2+) Risk Factors and 10-Year Risk 20% 10-Year Risk 1020%

LDL-cholesterol goal <130 mg/dL Aim: reduce both short-term and long-term risk Immediate initiation of Therapeutic Lifestyle Changes (TLC) if LDL-C is 130 mg/dL Consider drug therapy if LDL-C is 130 mg/dL after 3 months of lifestyle therapies

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LDL-Lowering Therapy in Patients With Multiple (2+) Risk Factors and 10-Year Risk 20% 10-Year Risk <10%

LDL-cholesterol goal: <130 mg/dL Therapeutic aim: reduce long-term risk Initiate therapeutic lifestyle changes if LDL-C is 130 mg/dL Consider drug therapy if LDL-C is 160 mg/dL after 3 months of lifestyle therapies

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LDL-Lowering Therapy in Patients With 01 Risk Factor Most persons have 10-year risk <10% Therapeutic goal: reduce long-term risk LDL-cholesterol goal: <160 mg/dL Initiate therapeutic lifestyle changes if LDL-C is 160 mg/dL If LDL-C is 190 mg/dL after 3 months of lifestyle therapies, consider drug therapy If LDL-C is 160189 mg/dL after 3 months of lifestyle therapies, drug therapy is optional

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Atherosclerosis Timeline

Media Intima

Phase I: Initiation
Lumen

LDL-C plays a major role in initiating the development of atherosclerotic plaque. LDL-C

Unstable

Phase II: Progression

Disease progression results in the remodeling of the vascular wall so that the size of the lumen does not change significantly.

Stable

Phase III: Complication

Extensive lipid accumulation and a greater inflammatory component can pose the threat of plaque rupture.

Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co; 2001:995-1009; Libby P. J Intern Med. 2000;247:349-358.

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Potential plaque stabilizing effects of cholesterol lowering

Lumen
Lipid Core

STATINS

Lumen
Lipid Core

Macrophage number Smooth muscle cell maturation Interstitial collagen Matrix metalloproteinase expression (MMP-1, MMP-3, MM-9) Tissue factor expression Adhesion molecule expression CRP Endothelial function Cytokines
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Libby P, Aikawa M. Mechanisms of plaque stabilization with statins. Am J Cardiol. 2003;91(suppl 4A):4B-8B.

Benefits of Statins

Arrests as well as prevents the process of atherosclerosis Reduces total and cardiovascular mortality Reduces CHD events such as nonfatal myocardial infarction, angina Reduces incidence of heart failure Reduces the risk of cerebrovascular events such as stroke Reduces need for revascularization procedures such as angioplasty / bypass surgery Reduces number of hospitalizations/duration of hospital stay

Ann Pharmacother 1998; 32: 10301043 Atheroscler 1999; 143 (suppl 1): S17S21
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Mode of Action
Staitin Lowers cholesterol by inhibiting the enzyme HMG CoA reductase in the liver. Acetate Statin Mevalonic acid 20 steps Cholesterol
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HMG CoA HMG CoA

reductase

Continue.

Inhibition of HMG CoA reductase in liver --- Intracellular cholesterol synthesis --- Upregulation of LDL Receptors --- Binding of LDL-Receptors --- LDL catabolism in liver --- Clearance of LDL from circulation --- LDL in blood VLDL (TG) synthesis in liver Total lipid in blood

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Indication & Usages

To reduce elevated total-Cholesterol, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia As an adjunct to diet for the treatment of patients with elevated serum TG levels For the treatment of patients with primary dysbetalipoproteinemia To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia
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Adverse effects
Treating to New Targets Study (TNT )

In TNT was involved 10,001 patients with clinically evident CHD during a median follow-up of 4.9 years. The adverse effects was following in low & high dose of atorvastatin.

Dose Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995)

Aderse events 1.4%

Discontinuatio n 8.1%

1.8%

9.9%
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Statin Evolution

Evidence Efficacy Experience

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Statin Evidence: ASCOT-LLA

ASCOT is a multicenter, international trial that involves 2 treatment comparisons in a factorial design:

A Prospective, Randomized, Open, Blinded End point (PROBE) design comparing 2 antihypertensive regimens

A double-blind, placebo-controlled trial of atorvastatin 10 mg in a large prospective cohort of those hypertensive patients studied (lipid-lowering arm [ASCOT-LLA])

ASCOT is composed of almost 20,000 hypertensive patients with multiple risk factors for CHD
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Statin Evidence: ASCOT-LLA

Blood Pressure Changes
170
SBP (mm Hg)

Atorvastatin 10 mg Placebo
Baseline 164/95 mm Hg Treated 138/80 mm Hg

160 150 140 130 0

100 95 90 85 80 75 0 1
Years

LLA Close-out

DBP (mm Hg)

LLA Close-out

Sever PS, et al. Lancet. 2003;361:1149-1158.

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Statin Evidence: ASCOT-LLA

6

Total cholesterol (mmol/L)

4 Atorvastatin 10 mg Placebo 2 0 1 2 3

150 100

150 46.5 mg/dL (1.2 mmol/L) 38.7 mg/dL (1.0 mmol/L) 125 100 75

LDL cholesterol (mmol/L)

3 2 1 0 1

LLA Close-out

Years
Sever PS, et al. Lancet. 2003;361:1149-1158.
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(mg/dL)

(mg/dL)

50 mg/dL (1.3 mmol/L)

38.7 mg/dL (1.0 mmol/L)

200

Statin Evidence: ASCOT-LLA

Primary Endpoint: Nonfatal MI and Fatal CHD
4 Cumulative Incidence (%) 3

Secondary Endpoint: Fatal and Nonfatal Stroke

3

Cumulative Incidence (%)

36% reduction

27% reduction

0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years

1
HR = 0.73 (0.56-0.96) P = .0236

HR = 0.64 (0.50-0.83) P = .0005

0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years

Atorvastatin 10 mg Placebo

Number of events Number of events

100 154

Atorvastatin 10 mg Placebo

Number of events Number of events

89 121

Sever PS, et al. Lancet. 2003;361:1149-1158.

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Statin Evidence: ASCOT-LLA

Secondary Endpoint: All CV Events and Procedures
12

Secondary Endpoint: All Coronary Events

6

Cumulative Incidence (%)

Cumulative Incidence (%)

10 8 6 4 2 0 0.0

21% reduction

5 4 3 2 1 0

29% reduction

HR = 0.79 (0.69-0.90) P = .0005

HR = 0.71 (0.59-0.86) P = .0005

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Years Atorvastatin 10 mg Placebo Number of events Number of events 389 486 Atorvastatin 10 mg Placebo

Years Number of events Number of events 178 247

Sever PS, et al. Lancet. 2003;361:1149-1158.

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Statin Evidence: ASCOT-LLA

Safety

No significant difference between atorvastatin and placebo in:

Incidence of fatal cancers Incidence of serious adverse events Incidence of liver enzyme abnormalities

Sever PS, et al. Lancet. 2003;361:1149-1158.

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Statin Evidence: MIRACL Study

Double-blind period

Atorvastatin 80 mg/day
Randomization (1-4 days) 3086 patients

Initial hospitalization

Placebo plus usual care

16-week treatment phase

Schwartz GG, et al. JAMA. 2001;285:1711-1718.

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Statin Evidence: MIRACL Study

Primary Efficacy Measure

Placebo
15

17.4% 14.8%

Cumulative Incidence (%)

Atorvastatin
10 Time to first occurrence of: Death (any cause) Nonfatal MI Resuscitated cardiac arrest Worsening angina with new objective evidence and urgent rehospitalization 0 4 8

Relative risk = 0.84 P = .048 95% CI 0.701-0.999

12 16

Time Since Randomization (weeks)

Schwartz GG, et al. JAMA. 2001;285:1711-1718.
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Statin Evidence: MIRACL Study

Fatal and Nonfatal Stroke
2

Cumulative Incidence (%)

1.5

Placebo

Atorvastatin
Relative risk = 0.49 P = .04 95% CI 0.24-0.98
0 4 8 12 16

0.5

Time Since Randomization (weeks)

Waters DD, et al. Circulation. 2002;106:1690-1695.
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Statin Evidence: GREACE Study

10
Usual Care Structured Care

Mean % Change From Baseline

0 -10 -20 -30 -40 -50 -60 Total-C LDL-C TG HDL-C VLDL-C Non-HDL-C
*P < .0001; P = .0028. Mean atorvastatin dose, 24 mg/day.

-4

-5

-3

-3

-6

-36

-31

-32

-46

-44

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

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Statin Evidence: GREACE Study

8
P = .0001

Usual Care Structured Care

P = .0011

6.4

P = .0021

P = .0017

5.6

% of Patients

4.8

4
2.9
P = .0032

P = .021

2.5

2.6

2.6 1.2

2.7

2.7 1.3

P = .034

2.1 1.1

Total Mortality

Coronary Mortality

Nonfatal MI

Unstable Angina

PTCA/CABG

CHF

Stroke

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

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Statin Evidence: GREACE Study

Structured Care Group

95% of patients reached the NCEP LDL-C goal

Mean dose of atorvastatin 24 mg/day

96% of patients reached the European LDL-C goal

Mean dose of atorvastatin was 22 mg/day

Usual Care Group

3% of patients reached the NCEP LDL-C goal 5.5% of patients reached the European LDL-C goal

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228; Athyros VG, et al. Data on file.
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Statin Evidence: Benefits

The statin trials have demonstrated significant decreases in CVD morbidity and mortality.

Reduction in CVD events has been demonstrated in patients with stable CHD as well as acute coronary syndrome patients.

Additionally, lowering LDL-C to target levels has beneficial effects in patients with normal or moderately elevated LDL-C.

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Statin Evidence: SPARCL

Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial

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SPARCL: High-dose statin treatment reduces fatal/nonfatal stroke

Primary outcome
16 Placebo 16% RRR* HR 0.84 (0.710.99) P = 0.03 NNT = 46 patients for 5 years

12 Fatal/ nonfatal stroke (%)

Atorvastatin

0 0 1 2 3 4 5 Time since randomization (years) 6

*Adjusted

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

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SPARCL: Treatment effect on stroke and TIA

N = 4731
Aggressive statin therapy Primary outcome Stroke (total) Fatal Nonfatal Better Worse 0.84 (0.710.99) 0.57 (0.350.95) 0.87 (0.731.03) 0.03 0.03 0.11 HR* (95% CI) P

Secondary outcomes Stroke or TIA TIA 0.3

*Adjusted

0.77 (0.670.88) 0.74 (0.600.91) 1.0 Hazard ratio 1.7

<0.001 0.004

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

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SPARCL: High-dose statin reduces major coronary events and stroke

30 20% RRR HR 0.80 (0.690.92) P = 0.002

20 Major CV events* (%)

Placebo

NNT = 29 patients for 5 years

10

Atorvastatin

0 0 1 2 3 4 5 Time since randomization (years) 6

*Cardiac death, MI, resuscitated cardiac arrest, and stroke

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

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SPARCL: Reductions in major coronary events

10 8 6 Major coronary events* 4 (%) 2 0 0 1 2 3 4 5 Time since randomization (years) 6 35% RRR HR 0.65 (0.490.87) P = 0.003

Placebo

Atorvastatin

*Cardiac death, MI, resuscitated cardiac arrest

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

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SPARCL: Summary
Atorvastatin 80 mg yielded: Primary end point
16% fatal/nonfatal stroke (P = 0.03)
Significant benefit despite small hemorrhagic stroke with atorvastatin (2.3%) vs placebo (1.4%)

Secondary end points

35% major coronary events (P = 0.003) 20% major CV events (P = 0.002) 42% any coronary events (P < 0.001) 26% any CV events (P < 0.001) 45% revascularizations (P < 0.001)

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

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SPARCL: Implications

Aggressive statin therapy should be strongly considered soon after stroke or TIA Magnitude of benefit may vary depending on baseline stroke subtype SPARCL results support the concept of stroke or TIA as a CHD risk equivalent

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

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Statin Evolution

Evidence Efficacy Experience

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Statin Efficacy: Lipid Lowering

Drug Class Statins* Bile Acid Sequestrants Nicotinic Acid Fibric Acids

LDL-C 18% to 60%*** 15% to 30%

HDL-C 5% to 15% 3% to 5%

Triglycerides 7% to 37%*** No change or increase

5% to 25% 5% to 20%**

15% to 35% 10% to 20%

20% to 50% 20% to 50%

*Lovastatin (20 to 80 mg), pravastatin (20 to 40 mg), simvastatin (20 to 80 mg), fluvastatin (20 to 80 mg), atorvastatin (10 to 80 mg), and rosuvastatin (10 to 40 mg). **May be increased in patients with high triglycerides. ***Up to 60% reduction in LDL-C, and 37% reduction in triglycerides, as indicated in the atorvastatin PI. Adapted from NCEP Expert Panel. JAMA. 2001;285:2486-2497.

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Statin Efficacy: CURVES Trial

Atorvastatin Significantly Lowered LDL-C
Atorvastatin Simvastatin* Pravastatin Lovastatin Fluvastatin
10 mg (n = 73) 20 mg (n = 51) 40 mg (n = 61) 80 mg (n = 10) 10 mg (n = 70) 20 mg (n = 49) 40 mg (n = 61) 10 mg (n = 14) 20 mg (n = 41) 40 mg (n = 25) 20 mg (n = 16) 40 mg (n = 16) 80 mg (n = 11)

-38%** -46%** -51%** -54% -28% -35% -41% -19% -24% -34% -29% -31% -48% -17% -23%

20 mg (n = 12) 40 mg (n = 12)

-10

-20

-30

-40

-50

-60

*Simvastatin 80 mg not available at time of study. **Significantly greater than mg-equivalent doses of comparative agents (P <.01). Significantly less than atorvastatin 10 mg (P <.02). Significantly less than atorvastatin 20 mg (P <.01).

% LDL-C reduction

Jones P, et al, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.

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Statin Efficacy: ACCESS study

Atorvastatin Effectively Lowered LDL-C
10
5% 6% 5% 6% 6%

0 -10 -20 -30 -40

-42% -29% -28% -19% -7% -12% -9% -13%

-36%

-36%

Atorvastatin 10 to 80 (avg 24) mg (n = 1902) Fluvastatin 20 to 80 (avg 62) mg (n = 477) Lovastatin 20 to 80 (avg 52) mg (n = 476) Pravastatin 10 to 40 (avg 31) mg (n = 462) Simvastatin 10 to 80 (avg 23) mg (n = 468)

% Change

-50

LDL-C

TG

HDL-C

*P < .01 vs all other treatments

Andrews TC, et al. Am J Med. 2001;111:185-191.

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Statin Efficacy: ACCESS study

100

Percent of patients achieving goal

NCEP Goal Attainment

75

* *

* *

50

25

0 Atorvastatin
10 to 80 mg

Simvastatin
10 to 80 mg

Pravastatin
10 to 40 mg

Lovastatin
20 to 80 mg

Fluvastatin
20 to 80 mg

*Significant difference vs atorvastatin (P < 0.05)

Andrews TC, et al. Am J Med. 2001;111:185-191.

NCEP ATP II LDL-C Goals

< 2 CHD risk factors is < 160 mg/dL (4.1 mmol/L) > 2 CHD risk factors is < 130 mg/dL (3.4 mmol/L) 53

Statin Efficacy: NASDAC Study

NASDAC study88% of dyslipidemic patients receiving a starting dose of 10 to 40 mg atorvastatin once daily reached their NCEP ATP III LDL-C goal.
Patients without CHD and no CHD equivalents

88%

Percentage of patients reaching LDL-C goal at 10, 20, or 40 mg

10 mg

20 mg

40 mg

79%
(n = 76)
Pfizer Inc. Data on file: NASDAC study.

88%
(n = 68)

98%
(n = 64)

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Statin Efficacy: Atorvastatin

Excellent efficacy across the dose range for all lipid parameters: LDL-C HDL-C -39% to -60% -19% to -37% +5% to +9%

Triglycerides

In clinical trials, the vast majority of patients on atorvastatin reached LDL-C goal.

Lipitor-Pfizer Inc. Data on file.

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Statin Evolution

Evidence Efficacy Experience

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Atorvastatin Experience: Summary

A recent analysis of 44 completed clinical trials demonstrated that atorvastatin is well tolerated and has excellent safety across the 10 mg to 80 mg atorvastatin dose range. The overall incidence of AEs with atorvastatin in clinical trials does not increase across the dose range, and is similar to that observed with placebo, and in patients treated with other statins. Specific analysis of musculoskeletal and hepatic AEs showed that these occurred infrequently and rarely resulted in treatment discontinuation.

Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.

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Atorvastatin Evolution
When choosing a Statin consider:

Evidence Efficacy Experience

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