CV Update

Supporter
Cardiovascular Disease Update

CoraLynn Trewet, MS, PharmD, BCPS, CDE University of Iowa and Mark Cziraky, PharmD, CLS, FAHA, FNLA HealthCore, Inc.
Forest Laboratories, Inc.
Disclosures
CoraLynn B. Trewet declares no conflicts of interest, real or
apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.
Target Audience: Pharmacists ACPE#: 0202-0000-13-008-L01-P Activity Type: Knowledge-based
Mark J. Cziraky declares no conflicts of interest, real or

apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.
The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. 3
Learning Objectives
1. Identify and explain important recent changes to 2. 3. 4.
clinical practice guidelines for the management of hypertension and dyslipidemia. Summarize noteworthy recent findings from large clinical trials that have the potential to influence the care of patients with cardiovascular disease. Discuss new evidence about the efficacy and safety of currently marketed therapies for cardiovascular disease. Describe possible roles for new and emerging pharmacotherapy options for the prevention and treatment of cardiovascular disease.
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Self-Assessment Questions
2013 by the American Pharmacists Association. All rights reserved.
What is the systolic blood pressure goal for most patients over 80 years old?
Which of the following is true regarding weight and drug selection for blood pressure?
A. Weight does not matter for HCTZ

or CCB
A.<160 B.<150 C.<140 D.<130
B. Weight does not matter for HCTZ C.CV events CCB > HCTZ in
obese patients D.CV events HCTZ > CCB in normal weight patients
Which of the following is the best diuretic for blood pressure? A. Hydrochlorothiazide B. Chlorthalidone C.Furosemide D.Bumetanide
What is the LDL-C goal for patients with Diabetes Mellitus?
A.<190 B.<160 C.<130 D.<100
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Learning Objectives for HTN

clinical practice guidelines for the management of hypertension and dyslipidemia. Summarize noteworthy recent findings from large clinical trials that have the potential to influence the care of patients with cardiovascular disease. Discuss new evidence about the efficacy and safety of currently marketed therapies for cardiovascular disease. Describe possible roles for new and emerging pharmacotherapy and other options for the prevention and treatment of cardiovascular disease.
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12
Recent guideline changes

Still waiting

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Noteworthy news from 2012

Intensive vs. standard blood pressure targets Treatment in mild hypertension Treatment in older patients Obese vs. Non-obese patients HTN drug selection debate continues Team base care
Intensive vs. standard blood pressure targets

130/80 vs. 140-160/85/100 ACCORD-BP trial was 140 vs. 120 5 study meta-analysis published Sept 2012
ACCORD ABCD-H, ABCD-N, ABCD-2V HOT
TREWETS TOP 5
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ACCORD Study Group. N Eng J Med. 2010;362(17):15751585. McBrien. Arch Intern Med. 2012;172(12)1296-1303.
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Blood pressure in ACCORD

Intensive: Standard: 3.2 1.9 3.4 2.1 3.5 2.2 Mean # Meds 3.4 2.3
ACCORD Outcomes
Intensive Events (%/yr) Primary Total Mortality Cardiovascular Deaths
208 (1.87) 150 (1.28) 60 (0.52) 126 (1.13) 34 (0.30) 36 (0.32)
Baseline 139 mmHg
Standard Events (%/yr)

237 (2.09) 144 (1.19) 58 (0.49) 146 (1.28) 55 (0.47) 62 (0.53)
HR (95% CI)
0.88 (0.73-1.06) 1.07 (0.85-1.35) 1.06 (0.74-1.52) 0.87 (0.68-1.10) 0.63 (0.41-0.96) 0.59 (0.39-0.89)
P
0.20 0.55 0.74 0.25 0.03 0.01
Average after 1st year: 133.5 Standard vs. 119.3 Intensive, 14.2
Nonfatal MI Nonfatal Stroke Total Stroke
ACCORD Study Group. N Eng J Med. 2010;362(17):15751585.
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Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the primary outcome, revascularization and unstable angina (HR=0.95, p=0.40)
ACCORD Study Group. N Eng J Med. 2010;362(17):15751585.
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Meta-analysis
Outcome Mortality Myocardial infarction Stroke Relative Risk 0.76 0.93 0.65 CI 0.55-1.05 0.80-1.08 0.48-0.86
Is lower BP better?
A.Yes B.No
Absolute risk only significant for stroke
McBrien. Arch Intern Med. 2012;172(12)1296-1303.
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Something to think about

90 80 70 60 50 40 30 20 10 0 Target <140 Target <130 23 60 46
Achieved
Treatment in mild hypertension

Mild hypertension = 140-159/90-99
82 Outcome Mortality 13-26 per 1000 people Total CV events 15-29 per 1000 people Withdrawal due to ADE 72-144 per 1000 people 4.80 4.14-5.57 0.97 0.72-1.32 <140 <130 Relative Risk 0.85 CI 0.63-1.15
Estimated ARR is 0.25% for mortality NNT = 400 people treated for 5 years to prevent 1 death 21 22
Treat to target
Diao. Cochrane Database Syst Rev 2012, Issue 8
Treatment in mild hypertension

The rest of the story? 4 randomized trails with ~33% of patients (~8000) Baseline BP was low in trials (140-150) Drugs used in trials bendrofluazide, reserpine, propranolol, methyldopa, chlorothiazide, chrlorthalidone, atenolol People with mild benign hypertension, defined as blood pressures up to 210/100 mmHg, need not be treated. Charles Friedbergs 1949 classic textbook Diseases of the Heart
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People with mild benign hypertension, defined as blood pressures up to 210/100 mmHg, need not be treated. Charles Friedbergs 1949 classic textbook Diseases of the Heart
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Diao. Cochrane Database Syst Rev 2012, Issue 8
Should we treat mild hypertension?
Should we treat mild hypertension?
A.Yes B.No
A.Yes B.No C.Need to assess

risk
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Treatment of HTN in older patients
A.<160 B.<150 C.<140 D.<130
ACCF/AHA 2011 expert consensus document on hypertension in the elderly

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Aronow. JACC 2011;57:2037-114.
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Prevalence of High Blood Pressure NHANES: 2005-2008

Percentage of the Population
90 80 70 60 50 40 30 20 10 0 20-34 35-55 45-54 55-64 65-74 75+ 29
Roger. Circulation. 2012;125:e2-e220. 11.1 6.8 25.1 19.0 37.1 35.2 54.0 53.3
Initiation of Antihypertensive Drug Therapy in the Elderly

78.5
Men
Women
69.3 64.0 67.7
Consider therapy if SBP >150 mmHg Target SBP <140 for most Target SBP 140145 mmHg acceptable Start with one agent Start low and go slow Will most likely need more than one drug Frequent follow-up Watch for orthostatic hypotension (SBP decrease of > 20 mm Hg after 3 minutes of standing)
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Aronow. JACC 2011;57:2037-114.
Principles of Hypertension Treatment Target SBP 140 mm Hg in patients aged 55-79 Target SBP 140 mm Hg in patients aged 80+ Achieved values <140 mm Hg for those aged 79 are appropriate; But for those aged 80, 140 to 145 mm Hg, if tolerated, can be acceptable
Lifestyle Modifications Not at Target Blood Pressure Initial Drug Choices Without Compelling Indication Stage 1 Hypertension ACEI, ARB, CCB, Diuretic, or combination Stage 2 Hypertension Majority will require at least 2 medications to reach goal if at least 20 mm Hg above target. Initial combination therapy should be considered. The combination of amlodipine with a RAS blocker may be preferred to a diuretic combination, though either is acceptable With Compelling Indication Compelling Indication Heart Failure Post myocardial infarction CAD or High CVD risk Angina Pectoris Aortopathy/Aortic Aneurysm Diabetes Chronic Kidney Disease Recurrent Stroke Prevention Early Dementia Initial Therapy Options* Thiaz, BB, ACEI, ARB, CCB, Aldo Ant. BB, ACEI, Aldo Ant, ARB Thiaz, BB, ACEi, CCB BB, CCB BB, ARB, ACEi, Thiaz, CCB ACEi, ARB, CCB, Thiaz, BB ACEI, ARB Thiaz, ACEi, ARB, CCB Blood Pressure control *Combination Therapy
BP goals in Patients 80yrs

SBP of 150 mm Hg for treatment and first target Once SBP <150 mm Hg achieved, intensification to
<140 mm Hg could be considered
The lowest safely achieved SBP 150 mm Hg is

acceptable for patients under 3 circumstances:
1) despite taking a regimen of 4 well-selected and appropriately dosed drugs, goal has not been achieved; 2) prescribed therapy is causing unacceptable side effects 3) in attempting to reach the SBP target, the DBP is being reduced to a potentially dangerous level <65 mm Hg
Target SBP < 140 is the goal for most patients 31
Aronow. JACC 2011;57:2037-114.
Not at Target Blood Pressure Optimize dosages or add additional drugs until goal BP is achieved. Refer to a clinical hypertension specialist if unable to achieve control.
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Aronow. JACC 2011;57:2037-114.
HYVET trial continued
Leiden 85-Plus Study

572 patients more than 85 years old for ~3 years Higher SBP associated with lower disability scores Higher SBP associated with less cognitive decline Patients with higher baseline disability had best evidence for higher BP
Rates per 1000 patient yrs in main trial and extension for stroke (top panel) and total mortality
Beckett. BMJ 2012;344:bmj.d7541
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Sabayan. J Am Geriatr Soc. 2012;60:2014-2019
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Discussion: describe a patient appropriate for the following goal <160 <150 <140 <130
Hypertension and body weight
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Hypertension and weight

Obesity and high incidence of cardiovascular events
well known
ACCOMPLISH subanalysis
Event rate per 1000 person yrs
31 29 27 25 23 21 19 17 15 Normal Overweight Obese 38 19.5 17.2 24.6 All
Individuals with normal bodyweight are unexpectedly

higher than in heavier patients
Increased rates of cardiovascular outcomes seen in

lean patients with hypertension ACCOMPLISH trial
~11,000 HTN patients with high risk of CVD Patients stratified by weight (BMI <25, 25-30, >30) Benazepril + HCTZ or Benazepril + Amlodipine
Weber. Lancet 2012. Online dx.doi.org/10.1016/S0140-6736(12)61343-9.
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Difference in cardiovascular events

31 29 27 25 23 21 19 17 15 Normal 18.2 16.9 Overweight
43% risk reduction p=0.0037
30.7
Which patient is a better candidate for use of HCTZ?
21.9
B+HCTZ B+CCB
A.Normal weight B.Overweight C.Obese
18.2 16.5 Obese
HCTZ increased risk in non-obese patients

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Drug selection debate

Are all thiazide diuretics created equal? Should beta blockers be used for HTN? Is there a role for aliskiren?
Which is the preferred thiazide? A. HCTZ B. Chlorthalidone C.Either
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HCTZ
ACCOMPLISH rekindled a common debate of
diureticschlorthalidone vs. HCTZ
HCTZ compared to others (24 ABPM)

Drug HCTZ 12.5-25 mg HCTZ 50 mg ACE inhibitors ARBs CCB -Blockers HCTZ 50 mg SBP 6.5 12.0 12.9 13.3 11.0 11.2 12.0 DBP 4.5 5.4 7.7 7.8 8.1 8.5 5.4
Differences not well known at release of JNC7 Differences well known now Chlorthalidone twice as potent with longer duration Studies showing chlorthalidone = HCTZ
HCTZ at big doses HCTZ dosed twice daily
but Drug companies like to make HCTZ combinations Something to watch in JNC 8
Ernst. Hypertension 2006;47:352-8. Ernst. NEJM 2009;361:2153-64
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Messerli. J Am Coll Cardiol 2011;57:590-600.
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Which beta blocker is better for HTN?
Beta blockers
AHA Statement on HTN Management3rd or 4th line Outcomes data
Positive outcomes from short trials and prior to use of aspirin and lipid therapies
A.Atenolol B.Metoprolol C.Both are same D.Doesnt matter,

shouldnt use for HTN
REACH registry published in JAMA 10/2012

4 year observational study No benefit after MI (HR 0.90) No benefit in patients with CV risk without MI (HR 0.92)
Drug selection Recent study comparing atenolol vs. metoprolol

No difference (0.99 HR) between agents in CV events BP reduction 6-8 mmHg SBP and 3-5 mmHg DBP
Rosendorff Circulation 2007;115:27612788. Parker Arch Intern Med 2012:172:1406-12. Bangalore JAMA 2012;308:1340-9.
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How many aliskiren Rx have you seen this year? A. Lots! B. Few C.None D.Never heard of it
Aliskiren
Newest drug for blood pressure approved in 2007 ALTITUDE trial stopped early
SBP and DBP slightly lower (1.3/0.6 mmHg) Increased cardiovascular endpoints Increased serum creatinine and potassium
April 2012 FDA Drug Safety Communication

Do not combine aliskiren with ACE-I and ARBs Do not use in severe renal impairment
47
Parving NEJM 2012;367:2204-13
48

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New and emerging therapies

No new drug therapies Pipeline weak
Vasopeptidase inhibitor Dual-acting angiotensin receptor-neprilysin inhibitor
Promise for renal denervation

Ablation of renal sympathetic nerves by catheter Improvement in renal sympathetic outflow Studied mostly in resistant hypertension patients Blood pressure lowering effect of 32/12 mmHg Minimal procedure, minimal safety concerns Need for clinical outcome data
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Laurent S. Lancet 2012;380:591-600.
Key Points for BP
Key Points for BP

Lower may not be better for everyone Should consider risk vs. benefit when deciding to
treat mild hypertension
What do you think?
Older patients may need different goals Non-obese patients may need different drugs Drug selection is very patient specific
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Learning Objectives for Dyslipidemia

53
Recent guideline changes

Still waiting for these tooNCEP ATP IV
54
What is a Treatment Target?

3.7
LDL-C and CHD Risk

Relative Risk for CHD (Log Scale)
2.9 2.2 1.7 1.3 1.0
30 mg/dL 30 mg/dL 30 mg/dL 30 mg/dL
A variable where it is established that the presence

of this variable, or quantitative amount of this variable, is associated with incremental risk of harm or clinical benefit Therapy is guided to attain a goal value for a treatment target
Examples: LDL-C, non-HDL-C
Most other biomarkers, risk markers, or risk factors,

are not considered treatment targets
Examples: Lp(a), hs-CRP
40 55
70
100
130
160
190
LDL Cholesterol (mg/dL)

CHD=Coronary Heart Disease Grundy S et al. Circulation. 2004;110:227-239. 56
NCEP ATP III Guidelines: Dyslipidemia Targets of Treatment

Primary Target:
Goal value based on CV risk
NCEP ATP III: LDL-C Goal Values

CHD or CHD Risk Equivalent#
Yes No
LDL-C Non-HDL-C
2 major CV risk factors*

Yes No
Secondary Target:
Calculate 10-year CHD risk: Framingham Score >20%

High Risk
Only after LDL-C goal met and TG 200 mg/dL Goal is always the LDL-C goal + 30
10-20%
Moderately-High Risk
<10%
<100 mg/dL,
If Very High Risk
High Risk
<70 mg/dL is optional
<100 mg/dL
<130 mg/dL, <100 mg/dL is optional
Moderate Risk
Low Risk
<130 mg/dL
<160 mg/dL
# non-coronary atherosclerotic vascular disease (e.g., ischemic stroke, peripheral arterial disease) or diabetes Grundy SM et al. Circulation. 2004;110:227-239.
CV = Cardiovascular
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*Age (45 years men, 55 years women), hypertension, smoking, family history of premature CHD in primary relatives, HDL-C < 40 mg/dL Grundy S et al. Circulation. 2004;110:227-239.
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ATP III: Very High Risk Definition

Presence of established CVD plus:
multiple major risk factors (esp. diabetes) severe and poorly controlled risk factors (esp. continued cigarette smoking), multiple metabolic syndrome risk factors (esp. triglycerides 200 mg/dL plus non-HDL-C 130 mg/dL with HDL-C < 40 mg/dL), and patients with acute coronary syndromes
AHA/ACC Guidelines:
Secondary Prevention for Patients with Coronary and Other AVD
LDL-C goal values:

100 mg/dL Further reduction to 70 mg/dL is reasonable 70 mg/dL if baseline LDL-C is 70-100 mg/dL
If LDL-C <70 mg/dL is not possible

because of a high baseline LDL-C:
Achieve LDL-C reduction of 50% with statins or combination regimens.
Smith SC, Jr, et al. J Am Coll Cardiol. 2006;47:21302139. AHA= American Heart Association. ACC= American College of Cardiology AVD= Atherosclerotic Vascular Disease
Optional goal of <70 mg/dL does not apply to

individuals who are not at least high risk
Grundy SM et al. Circulation. 2004; 110:227-39.
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Which of the following patients is considered by the ATP III as very high risk and has an optional LDL goal of < 70 mg/dL? 1. A 50-year-old man, family history of premature CHD (father), smoker, Framingham score is 25% 2. A 30-year-old woman, type 1 diabetes 3. A 60-year-old man, history of myocardial infarction, smoker, uncontrolled hypertension 4. A 70-year-old man, uncontrolled hypertension, Framingham score is 30%
Which is the preferred initial agent for treating high LDL-C? A. Statin B. Niacin C.BAR D.Fibrates
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Patients Experiencing Major CHD Events, %
Cardiovascular Risk Reduction in Major Statin Trials

CHD events occur in patients treated with statins
28.0
ATP III: 2004 Update

Doses that Attain 30-40% LDL-C Reductions
Drug Atorvastatin (Lipitor) Lovastatin (Mevacor) Pravastatin (Pravachol) Dose (mg/d) 10 40 40 20-40 40-80 5-10 LDL-C reduction (%) 39 31 34 35-41 25-35 39-45
Placebo Statin 19.4

15.9
12.3
13.2
10.2
11.8
8.7
10.9 7.9
5.5
6.8
AFCAPS/ TexCAPS6 6605 -25% Primary
Simvastatin (Zocor) Fluvastatin (Lescol) Rosuvastatin (Crestor)
4S1 N LDL 4444 -35%
LIPID2 9014 -25% Secondary

14S
CARE3 4159 -28%
HPS4 20 536 -29% High Risk
WOSCOPS5 6595 -26%
Pitavastatin (Livalo) 1 mg daily provides ~ 32% LDL-C reduction

Grundy S et al. Circulation. 2004;110:227-239. Livalo [package insert] Kowa Pharmaceuticals; 2010.
2LIPID
3Sacks
Group. Lancet. 1994;344:1383-1389. Study Group. N Engl J Med. 1998;339:1349-1357. FM et al. N Engl J Med. 1996;335:1001-1009.
4HPS 6
5Shepherd
Collaborative Group. Lancet. 2002;360:7-22. J et al. N Engl J Med. 1995;333:1301-1307. 63 Downs JR et al. JAMA. 1998;279:1615-1622.
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HDL AND CARDIOVASCULAR RISK
66
Framingham Heart Study

Risk of Coronary Artery Disease in Men Aged 50-70 by LDL and HDL Cholesterol Levels
Potential Antiatherogenic Actions of HDL

Vasodilatory Activity Antithrombotic Activity Anti-inflammatory Activity
Reverse Anti-infectious Antioxidative Cholesterol Activity Activity Antiapoptotic Transport Activity Cellular Cholesterol Efflux Apo A-I Endothelial Repair Apo A-II
Castelli W. Can J Cardiol. 1988;4(suppl A):5a-10a.
67
Chapman MJ et al. Curr Med Res Opin. 2004;20:1253-1268. Assmann G et al. Annu Rev Med. 2003;53:321-341.
68
Low HDL-C Predicts CV Events After ACS: In 1032 Patients Undergoing PCI
Death 15
%
P=0.033 P<0.01 Target lesion revasc. or MACE
Evidence from Prior Placebo-Controlled Trials Supporting Niacin or Fibrate Benefit
Coronary Drug Project (1975) 5-year follow-up

Immediate-release niacin (3,000 mg/day) Reduced CHD Death/MI by 14% Reduced non-fatal MI by 26% Reduced stroke/TIA by 21%
5 0
0-30 days 30 days to 1 year
Low HDL-C
Wolfram RM et al. Am J Cardiol. 2006;98:711-717.
10
25 20 15 10 5 0
P=0.005
VA-HIT (1999) 5-year follow-up

P=0.002 0-30 days 30 days to 1 year Gemfibrozil vs. placebo (no statin therapy) Reduced CHD Death/MI by 22%
HATS (2001) 3-year follow-up

niacin + simvastatin regression of angiographic coronary stenoses and reductions in clinical events
Not Low HDL

69 70
AIM HIGH Study: Primary Objective

To determine whether the residual risk associated with low levels of HDL-C in patients with established CHD whose LDL-C therapy was optimized with statins ezetimibe would be mitigated with extended-release niacin vs. placebo during long-term follow-up
Study Hypothesis
Combination dyslipidemic therapy with high-dose extended-release niacin (1,500-2,000 mg/day), when added to intensive LDL-C lowering therapy, will be superior to intensive LDL-C lowering therapy alone in reducing the risk of CV events in patients with established atherosclerotic cardiovascular disease and low baseline levels of HDL-cholesterol
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Study Design
Open-Label Run-In: Up-Titrate Niacin from 500mg to 2,000mg/day 4-8 weeks Adjust simva to LDL 40 80 mg/dL ER Niacin + 40-80 mg/day simvastatin Follow to end of study
Statistical Analyses
Event-driven trial with projected 800 primary
outcomes; 2.5-7 year follow-up (mean 4.6 years) component primary endpoint (one-sided test of significance; alpha level=0.025)
85% power to detect a 25% reduction in the revised 5-
R Placebo + 40-80 mg/day simvastatin
Pre-specified, conservative asymmetric boundaries for

potential early stopping based on efficacy/lack of efficacy
Trial stopped on 5/25/11: lack of efficacy and concern

-2 -1 0 1 2 3 6 Months Relative to Randomization 12
73
of ischemic stroke imbalance with niacin after a 36month average follow-up
74
Concomitant Medications at Baseline

On a Statin Duration of Statin Therapy* 1 year 5 years Prior Niacin Use ASA/Antiplatelet Therapy eta-Blocker ACEI / ARB 94% 76% 40% 20% 98% 80% 74%
Baseline Lipids (mg/dL)

On Statin (n=3,196) LDL-C (mean) HDL-C (mean) Triglycerides
(median)
Off Statin (n=218) 119 33 215 165 111

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71 35 161 107 81
Use of all secondary prevention therapies were well-balanced between treatment groups
*Duration of statin therapy not ascertained in 6%
Non-HDL (mean) Apo-B

75
(mean)
HDL-C at Baseline & Follow-up

55 50 45
mg/dL
LDL-C at Baseline & Follow-up

80 Combination Therapy 75 70
mg/dL
Combination Therapy
Monotherapy
40 35 30 25 Baseline Year 1 Year 2 Year 3

77
65 60 55 50 Baseline Year 1 Year 2 Year 3

78
Primary & Secondary Endpoints

Cumulative % with Primary Outcome
Primary Outcome
50 40 30 20 10 0 0 N at risk 1 1581 1606 2 3 Time (years) 910 903 4 436 42880 HR 1.02, 95% CI 0.87, 1,21 Logrank p-value= 0.79 Combination Therapy Monotherapy
Hazard Ratio Primary Endpoint Secondary Endpoints CHD Death, MI, Ischemic Stroke, High-Risk ACS CHD Death, MI, Ischemic Stroke Cardiovascular Death 1.08 1.02
95% CI 0.87, 1.21
0.87, 1.34
1.13 1.17
0.90, 1.42 0.76, 1.80

79
Monotherapy 1696 Combination Therapy 1718
1381 1366
Primary & Secondary Endpoints

Hazard Ratio
Primary Endpoint Secondary Endpoints CHD Death, MI, Ischemic Stroke, HighRisk ACS CHD Death, MI, Ischemic Stroke 1.08 0.87, 1.34 1.02
HPS 2-THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events
95% CI
0.87, 1.21 Primary Endpoint Secondary Endpoints CHD Death, MI, Ischemic Stroke, HighRisk ACS CHD Death, MI, Ischemic Stroke
Hazard Ratio
1.02
Study Design:
25,673 high-risk patients with occlusive arterial disease from China, Scandinavia and UK Patients randomized to ER niacin/laropiprant (ERN/LRPT) 2g daily versus placebo Patients on simvastatin 40mg (+/- ezetimibe 10mg) daily Primary end point - Major vascular events after median follow-up of 4 years Pre-specified safety analyses: Median follow-up of 3.4 years (to January 2012)
1.08
1.13
0.90, 1.42
1.13
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HPS2-THRIVE: Design and randomization
HPS2-THRIVE summary

Largest ever randomized trial of effects of ER niacin on safety and CV events in diverse high-risk patients Effects of 4 years of ERN/LRPT on vascular events in HPS2-THRIVE scheduled to be released in 2013 Study was stopped in late 2012
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84

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UnmetNeedsintheTreatmentofHomozygous FamilialHypercholesterolemia
PREVALENCE
Homozygotes occur with a frequency of
approximately 1 in 1 million. Serum cholesterol ranges from 650-1000 mg/dL. Homozygotes have near total or total loss of LDLR functionality. Homozygotes can inherit two copies of the same mutant allele, or may be classified as compound homozygotes due to the inheritance of two different mutant alleles.
GENETICS
Defined as an autosomal dominant trait with
complete penetrance causing congenitally elevated levels of LDL cholesterol due to loss of function mutations in the LDL receptor. There is a gene dosage effect with homozygotes having significantly greater elevations of LDL-C and earlier cardiovascular disease onset than subjects who are heterozygotes.
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The Spectrum of Familial Hypercholesterolemia

Mean LDL-C In US Adults Typical LDL-C Range for Untreated HeFH Patients Typical LDL-C Range for Untreated HoFH Patients
Defective LDL Receptors in HoFH Leads to Impaired LDL Catabolism
0-100
100-200
200-300
300-400
400-500
500-600
600-700
700-800
800-900
900-1,000+
apoB
VLDL
Estimated Prevalence
Heterozygous FH: 1:500 Homozygous FH: 1:1 million
TG
LDLR
X
B B
LDL
Goldstein, J. L., H. H. Hobbs, et al. (2001). The Metabolic and Molecular Basis of Inherited Disease. Moorjani, S., M. Roy, et al. (1993). Lancet 341(8856): 1303-1306.
CM-008
89
B
CM-012
90
Patients With HoFH Respond Poorly to Currently Available Therapies
Efficacy of Current CholesterolLowering Interventions in HoFH

Class Major Effect LDLR activity LDLR activity LDLR activity LDLR activity Unknown Typical LDL-C-Lowering Response <10% <10% <10% <10% <10%
apoB
VLDL
Low-fat diet Statins (e.g. atorvastatin, rosuvastatin) Bile Acid Sequestrants (e.g. cholestyamine, colestipol)
TG
LDLR
X
B B B B
CM-013
LDL
Cholesterol Absorption Inhibitors (e.g. ezetimibe ) Nicotinic acid (ie, niacin) 91
Statins CAI BAS
Rader DJ, et al. J Clin Invest. 2003;111:1796-1803. Konrad RJ, et al. Lipids Health Dis. 2011;10:38. 92
CM-014
LDL Apheresis is Current Standard of Care for HoFH

Heparin Pump Re-Priming Solution Regeneration Solution Regeneration Pump Blood Pump Plasma Pump
LDL Apheresis Centers in the US: Limited Geographical Access
Plasma Separator
Dextran sulfate columns
Blood Return
Plasma Line
Waste Line
93
94
LDL-C Levels Acutely Decrease and then Rebound Following Apheresis

Start of LDL apheresis Baseline LDL
LDL-C Target Treatment Goals
Pre-treatment LDL level
0-100
LDL cholesterol
100-200
200-300
300-400
400-500
500-600
600-700
700-800
800-900 900-1,000
<100 mg/dL for subjects at high-risk

2-week interval Post-treatment LDL level
<70 mg/dL for subjects at very high-risk

Time
Thompsen J & Thompson PD. Atherosclerosis. 2006;189: 31-8.
CM-017
95
CM-019
96
Treated HoFH Patients are Still Far from LDL-C Target Treatment Goals
Typical LDL-C Range for Treated HoFH Patients*
HoFH Represents a Major Unmet Medical Need

HoFH patients have inadequate response to existing
pharmacologic cholesterol-lowering therapies
While LDL-apheresis provides some benefit, LDL-C reduction is

700-800 800-900 900-1,000
0-100
100-200
200-300
300-400
400-500
500-600
600-700
not sustained, LDL-C is not optimally-controlled, and the procedure is not widely available
New approaches to reducing LDL-C in patients with HoFH are <100 mg/dL for subjects at high-risk
needed
<70 mg/dL for subjects at very high-risk

* Raal J, et al. Circulation. (2011).
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New and Emerging Therapies

PCSK9 Monoclonal Antibody
Increases LDL-C removal by decreasing inhibitor of LDL clearance receptor
Mipomersen

Manufacturer: ISIS Entered clinical trials in December 2003 Indication: Add-on therapy Populations studied in clinical trials: Heterozygous and homozygous FH Polygenic hypercholesterolemia Statin intolerant Add-on therapy Varying degrees of hyperlipidemia (Liver triglycerides) Side effects seen in clinical trials: Injection-site reactions (most common) decribed as typically mild, painless erythema which resolve in 5 days (median) and dosedependent. Fatty liver (300 mg dosing) remains an important concern
Mipomersen
Antisense agent that inhibits ApoB synthesis
Anacetrapib, Evacetrapib, Dalcetrapib

Inhibits cholesterol ester transfer protein (CETP)
Lomitapide
Mitochondrial trifunctional protein enzyme inhibitor that decreases lipoprotein production
99 99
100
A New Mechanism of Action

Antisense Oligonucleotide DNA
Transcription
Mipomersen: Overview of Phase 3

Phase 3 Trials:
Traditional Drug
mRNA
Translation
Disease-Associated Protein
Homozygous Familial Hypercholesterolemia (HoFH) Heterozygous Familial Hypercholesterolemia (HeFH) and Coronary Artery Disease Severe Hypercholesterolemia in HeFH Hypercholesterolemia and High Risk of CHD Phase 3 long term extension study for FH Patients Safety database ~775 subjects receiving mipomersen
Transcription
RNaseH Degrades RNA No Translation
Antisense Drug
(Oligonucleotide)
No Disease-Associated Proteins Produced

101
1.Lancet. 2010 Mar 20;375(9719):998-1006. (NCT00607373) 2.J. Am Coll. Cardiol. 2011;57(14):E492. (NCT00794664). 3.Eur. Heart J. 2010;31(Suppl.1):898 (NCT007684). 4.J. Am. Coll. Cardiol. 2011;57(14):E504. (NCT00770146).
Goldberg AC. J Clin Lipidol. 2010;4:350-6.
102
Study Design
Across Four Phase 3 Studies
Efficacy Endpoints
Across Four Phase 3 Studies
Randomized, double-blind, placebo-controlled, multi-center All patients on stable maximally tolerated LLT Weekly subcutaneous injections of mipomersen 200 mg or placebo for 26
weeks (option to self-administer) Primary efficacy endpoint: % change in LDL-C from baseline to week 28, or 2 weeks after the last dose
Primary endpoint: % change in LDL-C from baseline

Primary efficacy time point (PET) = Week 28 or 2 weeks after the last dose
Secondary endpoints: % change at PET

Apo B Total cholesterol Non-HDL-C
Tertiary endpoints: % change at PET

Mipomersen 200 mg/wk All Studies Enroll Patients
R
Screening
4 weeks
2:1 mipomersen:placebo
Placebo Treatment Period
26 weeks
Safety Follow-up
Triglycerides Lp(a) VLDL-C
Apo A1
Safety Follow-up Primary efficacy timepoint
24 weeks
HDL-C
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1.Lancet. 2010 Mar 20;375(9719):998-1006. (NCT00607373) 2.J. Am Coll. Cardiol. 2011;57(14):E492. (NCT00794664). 3.Eur. Heart J. 2010;31(Suppl.1):898 (NCT007684). 4.J. Am. Coll. Cardiol. 2011;57(14):E504. (NCT00770146).
LDL/HDL ratio
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Phase 3 Trials of Mipomersen Efficacy

Patient Population Dose (N) Homozygous FH1 200 mg SC weekly (n=51) Severe heterozygous hypercholesterolemi a2 200 mg SC weekly (n=58) Heterozygous FH3 200 mg SC weekly (n-124) High cholesterol at high risk for CAD (n=158)
1. Lancet. 2010 Mar 20;375(9719):998-1006. (NCT00607373) 2. J. Am Coll. Cardiol. 2011;57(14):E492. (NCT00794664). 3. Eur. Heart J. 2010;31(Suppl.1):898 (NCT007684). 4. J. Am. Coll. Cardiol. 2011;57(14):E504. (NCT00770146).
#NS
Phase 3: Efficacy on top of Max Tolerated Lipid Lowering Therapies Primary End Point Achieved in All Four Phase 3 Trials
Change in TG (%)
Treated Baseline LDL-C (mg/dL)*
Change in LDL-C (%)
Change in ApoB (%)
Change in Lp(a) (%)
Change in HDL-C (%)
LDL-C
Phase 3 Study Homozygous FH
Mipomersen
Avg Baseline (mg/dL) Avg Change (mg/dL)
Placebo % Change
Mipomersen % Change *
439 276
-25 -36
-27 -36
-31 -33
+15 NC
-17
439 276
-113 -101
-3 +13
-25 -36
Severe Hypercholesterolemia
Average Reduction >100 mg/dL

153 123 -28 -37 -26 -38 -21 -24 +3# +2# -14 -25
Heterozygous FH
153
-49
+5
-28
45% of Patients Achieved Target <100 mg/dL
High Risk 105

* All P Values <0.001
123
-47
-5
-37 106
51% of Patients Achieved Target <70 mg/dL
*maximally tolerated dose of a lipid-lowering drug
Long-term effects of Mipomersen in Extension Study Interim Data Analysis March 2011
Change from Baseline in Lipids
Phase 3 Trials of Mipomersen Side-effects

Patient Population Dose (N) Injection-site reactions Placebo vs mipomersen 24% vs 76% 32% vs 90% Influenza-like symptoms Placebo vs mipomersen 24% vs 29% 21% vs 46% ALT 3x ULN Placebo vs mipomersen
Mean % Change (95% CI)
Homozygous FH1 200 mg SC weekly (n=51) Severe hypercholesterolemia2 200 mg SC weekly (n=58) Heterozygous FH3 200 mg SC weekly (n-124) High cholesterol at high risk for CAD4
0% vs 12% 0% vs 15%
42% vs 93% 31% vs 78%
39% vs 42% 21% vs 34%
0% vs 6% 0% vs 10%
26 n=130
Source: Table 14.2.1a; Table 14.3.6
Safety profile remains consistent with all phase 3 studies

52 n=110 76 n=58 104 n=26
(n=158)
4MRI
fat fraction, increase from baseline 5%: 8% vs 35%
Study Week
*Dallas Heart Study General Population: 5.6% liver fat median
107
107
1. Lancet. 2010 Mar 20;375(9719):998-1006. (NCT00607373) 2. J. Am Coll. Cardiol. 2011;57(14):E492. (NCT00794664). 3. Eur. Heart J. 2010;31(Suppl.1):898 (NCT007684). 4. J. Am. Coll. Cardiol. 2011;57(14):E504. (NCT00770146).
108
Summary
Mipomersen significantly lowers LDL-C (from 25 to 37%), apo B
(from 26 to 38%), as well as Lp(a) (from 21 to 33%) in addition to maximally tolerated doses of statins.
10% in mipomersen-treated group developed mild hepatic steatosis at 15 weeks IHTG increased from 1.2% to 2.1% at 13 weeks (P=0.051)
Limitations: Small study Short study duration Patients at increase risk of steatosis were excluded (TG<200 mg/dL, IHTG<5%, HgA1c <6%)
Average LDL-C reduction > 100 mg/dL in severe FH populations Increase or no change (+2 to +15%) in HDL
Mipomersen does not interact with statin, ezetimibe, and does

not effect major cytochrome P450 enzymes (1A2, 2C9, 2C19, 2D6, and 3A4).1 ALT elevations ( 3 times ULN) occurred in 8 to 15% of patients, but have not been associated with changes in PT, albumin, bilirubin, or alkaline phospatase.2-5 Long-term outcome trials are needed.
1. Geary RS, et al. Clin Pharmacokinet 2006;45:789-801. 2. Lancet. 2010 Mar 20;375(9719):998-1006. (NCT00607373) 3. J. Am Coll. Cardiol. 2011;57(14):E492. (NCT00794664). 4.Eur. Heart J. 2010;31(Suppl.1):898 (NCT007684). 5. J. Am. Coll. Cardiol. 2011;57(14):E504. (NCT00770146).
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110
MTP-inhibition reduces apoB-containing lipoprotein production
MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN INHIBITION
B100
apoB
TG
MTP
VLDL
TG LDLR
X
IDL LDL TG
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Lomitapide

Manufacturer: Aegerion FDA Approved : December 2012 Brand Name : Juxtapid Indication: Add-on therapy Black box risk of hepatotoxicity Contraindications;
Category X Concomitant use with strong or moderate CYP3A4 inhibitors Moderate to severe hepatic impairment or active liver disease CYP3A4 Inhibitors including grapefruit juice Warfarin Simvastatin & Lovastatin
Lomitapide
Manufacturer: Aegerion
Initiate treatment at 5 Mg once daily Titrate dose based on acceptable safety/tolerability:
Increase to 10 mg daily after at least 2 weeks Increase to 20 mg after 4 weeks Increase to 40 mg after 4 weeks Increase to 60 mg after 4 weeks ( Max dose)
Drug Interactions
Adverse reactions ( 28%):

Diarrhea Nausea Vomiting Dyspepsia Abdominal pain
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Pharmacologic MTP inhibition reduces LDL-C levels in HoFH
New Agents Summary

Statins have revolutionized the treatment of lipid disorders.
Despite their efficacy, many patients fail to reach their LDL-C and non-HDL-C targets due to high baseline levels or tolerability issues. Residual risk remain in some patients despite statin therapy.
Ezetimibe was the last new class of lipid-lowering agent to be

introduced back in October 2002 until 2012 when lomitapide was approved. Novel new pharmacologic strategies are promising, but have potentially significant limitations
SC or IV dosing (injection site reactions) Steatorrhea fatty liver potential off-target effects
The effects of each of these strategies on morbidity and

mortality has not been demonstrated.
Cuchel, M. et al. NEJM 2007; 356:148-56.
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Key Points for Dyslpidemia
Key Points for Dyslipidemia

Statins are still considered drug of choice for
patients
New treatment guidelines should be available
What do you think?
soon.
Recent clinical trial results with HDL-lowering

products missed primary outcomes
Newer classes of agents are becoming available

focused on special populations
Continue to focus on adherence to therapies and

appropriate dosing in your patients
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Patient Case
A 58 year-old African American female is referred for blood pressure and lipid control. The patient reports an approximately 25-year history of hypertension and cholesterol that have become more difficult to treat over the last 5-6 years. Prior medications have included atenolol, valsartan, furosemide, and hydralazine. The medications were stopped because of adverse effects or ineffectiveness. The patients renal function is normal. Co-morbidities include type II diabetes and osteoarthritis. Home blood pressure readings are generally 150-180/90-110 mm Hg. She reports being adherent with her prescribed medications. The patients BMI is 33 kg/m2. Her office blood pressure is 178/106 mm Hg and her heart rate if 82 bpm.
Patient Case
Sam is a 47-year-old man with a history of
hypertension and dyslipidemia has been treated with lifestyle modifications for the past two years Present fasting lipid panel is: TC = 240 mg/dL, HDLC = 30 mg/dL, TG = 250 mg/dL, LDL-C = 170 mg/dL He does not have coronary heart disease, noncoronary atherosclerosis (e.g., ischemic stroke, peripheral arterial disease) or diabetes He has pre diabetes calculated 10-year risk of coronary heart disease (Framingham Risk score) is 7%
TC= Total Cholesterol
Blood pressure medications: HCTZ 25 mg qday Verapamil 180 mg qday Olmesartan 20 mg qday Aliskiren 150 mg qday Clonidine 0.2 mg tid
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Case Scenario 1, cont.

According to the NCEP ATP III, which of the
following is the most appropriate primary target of therapy for Sam at this time?
1. 2. 3. 4. LDL-C < 70 mg/dL LDL-C < 100 mg/dL LDL-C < 130 mg/dL LDL-C < 160 mg/dL
Case Scenario 1, cont.

Which of the following best explains why targeting
non-HDL-C lowering to a goal value is not yet needed in this patient?
1. 2. 3. 4. His non-HDL-C is already low enough His triglycerides are not 500 mg/dL His HDL-C should be raised first His LDL-C is not yet at goal
121 121
122 122
Self-Assessment Questions
A.<160 B.<150 C.<140 D.<130
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Which of the following is true regarding weight and drug selection for blood pressure?
Which of the following is the best diuretic for blood pressure? A. Hydrochlorothiazide B. Chlorthalidone C.Furosemide D.Bumetanide
A. Weight does not matter for HCTZ
or CCB B. Weight does not matter for HCTZ C.CV events CCB > HCTZ in obese patients D.CV events HCTZ > CCB in normal weight patients
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What is the LDL-C goal for patients with Diabetes Mellitus?
A.<190 B.<160 C.<130 D.<100
127

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Target Audience: Pharmacists ACPE#: 0202-0000-13-008-L01-P Activity Type: Knowledge-based

Mark J. Cziraky declares no conflicts of interest, real or

2013 by the American Pharmacists Association. All rights reserved.

A. Weight does not matter for HCTZ

A.<160 B.<150 C.<140 D.<130

What is the LDL-C goal for patients with Diabetes Mellitus?

A.<190 B.<160 C.<130 D.<100

Learning Objectives for HTN

Learning Objectives for HTN

2013 by the American Pharmacists Association. All rights reserved.

Recent guideline changes

Learning Objectives for HTN

Noteworthy news from 2012

Intensive vs. standard blood pressure targets

Blood pressure in ACCORD

Baseline 139 mmHg

Standard Events (%/yr)

Nonfatal MI Nonfatal Stroke Total Stroke

ACCORD Study Group. N Eng J Med. 2010;362(17):15751585.

2013 by the American Pharmacists Association. All rights reserved.

Absolute risk only significant for stroke

McBrien. Arch Intern Med. 2012;172(12)1296-1303.

Something to think about

Treatment in mild hypertension

Diao. Cochrane Database Syst Rev 2012, Issue 8

Treatment in mild hypertension

Diao. Cochrane Database Syst Rev 2012, Issue 8

2013 by the American Pharmacists Association. All rights reserved.

Should we treat mild hypertension?

Should we treat mild hypertension?

A.Yes B.No C.Need to assess

Treatment of HTN in older patients

A.<160 B.<150 C.<140 D.<130

ACCF/AHA 2011 expert consensus document on hypertension in the elderly

Prevalence of High Blood Pressure NHANES: 2005-2008

Initiation of Antihypertensive Drug Therapy in the Elderly

Aronow. JACC 2011;57:2037-114.

2013 by the American Pharmacists Association. All rights reserved.

BP goals in Patients 80yrs

The lowest safely achieved SBP 150 mm Hg is

Aronow. JACC 2011;57:2037-114.

HYVET trial continued

Leiden 85-Plus Study

Hypertension and body weight

2013 by the American Pharmacists Association. All rights reserved.

Hypertension and weight

Individuals with normal bodyweight are unexpectedly

Increased rates of cardiovascular outcomes seen in

Weber. Lancet 2012. Online dx.doi.org/10.1016/S0140-6736(12)61343-9.

Weber. Lancet 2012. Online dx.doi.org/10.1016/S0140-6736(12)61343-9.

Difference in cardiovascular events

Which patient is a better candidate for use of HCTZ?

A.Normal weight B.Overweight C.Obese

18.2 16.5 Obese

11% risk reduction p=0.3189

HCTZ increased risk in non-obese patients

Drug selection debate

Which is the preferred thiazide? A. HCTZ B. Chlorthalidone C.Either

2013 by the American Pharmacists Association. All rights reserved.

HCTZ compared to others (24 ABPM)