cv update

© 2013 by the American Pharmacists Association. All rights reserved.

Cardiovascular Disease Update

CoraLynn Trewet, MS, PharmD, BCPS, CDEUniversity of Iowa

andMark Cziraky, PharmD, CLS, FAHA, FNLA

HealthCore, Inc.22

Supporter

Forest Laboratories, Inc.

33

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.

• 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.

44

• Target Audience: Pharmacists

• ACPE#: 0202-0000-13-008-L01-P

• Activity Type: Knowledge-based

55

Learning Objectives

1. Identify and explain important recent changes to clinical practice guidelines for the management of hypertension and dyslipidemia.

2. Summarize noteworthy recent findings from large clinical trials that have the potential to influence the care of patients with cardiovascular disease.

3. Discuss new evidence about the efficacy and safety of currently marketed therapies for cardiovascular disease.

4. Describe possible roles for new and emerging pharmacotherapy options for the prevention and treatment of cardiovascular disease.

66

Self-Assessment Questions


77

What is the systolic blood pressure goal for most patients over 80 years old?

A.<160

B.<150

C.<140

D.<130

88

Which of the following is true regarding weight and drug selection for blood pressure?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

99

Which of the following is the best diuretic for blood pressure?

A.Hydrochlorothiazide

B.Chlorthalidone

C.Furosemide

D.Bumetanide

1010

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

A.<190

B.<160

C.<130

D.<100

1111

Learning Objectives for HTN




4. Describe possible roles for new and emerging pharmacotherapy and other options for the prevention and treatment of cardiovascular disease.

1212







1313

Recent guideline changes

• Still waiting…

1414






1515

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

TREWET’S TOP 51616

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

ACCORD Study Group. N Eng J Med. 2010;362(17):1575–1585.McBrien. Arch Intern Med. 2012;172(12)1296-1303.

1717

Blood pressure in ACCORD

Average after 1st year: 133.5 Standard vs. 119.3 Intensive, 14.2

Mean # MedsIntensive: 3.2 3.4 3.5 3.4Standard: 1.9 2.1 2.2 2.3

ACCORD Study Group. N Eng J Med. 2010;362(17):1575–1585.

Baseline 139 mmHg

1818

ACCORD Outcomes Intensive Events (%/yr)

StandardEvents (%/yr) HR (95% CI) P

Primary 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20

Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55

CardiovascularDeaths

60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74

Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25

NonfatalStroke

34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03

Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01

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):1575–1585.


1919

Meta-analysis

Outcome Relative Risk CI

Mortality 0.76 0.55-1.05

Myocardial infarction 0.93 0.80-1.08

Stroke 0.65 0.48-0.86

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

Absolute risk only significant for stroke

2020

Is lower BP better?

A.Yes

B.No

2121

Something to think about…

60

82

23

46

0

10

20

30

40

50

60

70

80

90

Target <140 Target <130

<140

<130

Achieved

Treat to target2222

Treatment in mild hypertension“Mild” hypertension = 140-159/90-99

Diao. Cochrane Database Syst Rev 2012, Issue 8

Outcome Relative Risk CI

Mortality 0.85 0.63-1.15

13-26 per 1000 people

Total CV events 0.97 0.72-1.32


Withdrawal due to ADE 4.80 4.14-5.57


Estimated ARR is 0.25% for mortalityNNT = 400 people treated for 5 years to prevent 1 death

2323

“People with ‘mild benign’ hypertension, defined as blood pressures up to 210/100 mmHg, need not be treated.”

Charles Friedberg’s 1949 classic textbook “Diseases of the Heart”

2424

Treatment in mild hypertensionThe rest of the story?

Diao. Cochrane Database Syst Rev 2012, Issue 8

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 Friedberg’s 1949 classic textbook “Diseases of the Heart”


2525

Should we treat mild hypertension?

A.Yes

B.No

2626

Should we treat mild hypertension?

A.Yes

B.No

C.Need to assess risk

2727


A.<160

B.<150

C.<140

D.<130

2828

Treatment of HTN in older patients

ACCF/AHA 2011 expert consensus document on hypertension in the

elderly

Aronow. JACC 2011;57:2037-114.

2929

Prevalence of High Blood PressureNHANES: 2005-2008

11.1

25.1

37.1

54.0

64.067.7

6.8

19.0

35.2

53.3

69.3

78.5

0

10

20

30

40

50

60

70

80

90

20-34 35-55 45-54 55-64 65-74 75+

Per

cen

tag

e o

f th

e P

op

ula

tio

n Men Women

Roger. Circulation. 2012;125:e2-e220.3030

Initiation of Antihypertensive Drug Therapy in the Elderly

• Consider therapy if SBP >150 mmHg

• Target SBP <140 for most

• Target SBP 140—145 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)

Aronow. JACC 2011;57:2037-114.


3131

Principles of Hypertension TreatmentTarget SBP ≤140 mm Hg in patients aged 55-79Target 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 With Compelling Indication

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.

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

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

Aronow. JACC 2011;57:2037-114.3232

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

Aronow. JACC 2011;57:2037-114.

Target SBP < 140 is the goal for most patients

3333

Rates per 1000 patient yrs in main trial and extension for stroke (top panel) and total mortality

Beckett. BMJ 2012;344:bmj.d7541

HYVET trial continued…

3434

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

Sabayan. J Am Geriatr Soc. 2012;60:2014-2019

3535

Discussion: describe a patient appropriate for the following goal

<160

<150

<140

<130

3636

Hypertension and body weight


3737

Hypertension and weight

• Obesity and high incidence of cardiovascular events well known

• 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. 3838

ACCOMPLISH subanalysis

24.6

19.5

17.2

15

17

19

21

23

25

27

29

31

Normal Overweight Obese

All

Event rate per 1000 person yrs

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

3939

Difference in cardiovascular events

30.7

21.9

18.218.2

16.9 16.5

15

17

19

21

23

25

27

29

31

Normal Overweight Obese

B+HCTZ

B+CCB

43% risk reductionp=0.0037



HCTZ increased risk in non-obese patients

Weber. Lancet 2012. Online dx.doi.org/10.1016/S0140-6736(12)61343-9. 4040

Which patient is a better candidate for use of HCTZ?

A.Normal weight

B.Overweight

C.Obese

4141

Drug selection debate

• Are all thiazide diuretics created equal?

• Should beta blockers be used for HTN?

• Is there a role for aliskiren?

4242

Which is the preferred thiazide?

A.HCTZ

B.Chlorthalidone

C.Either


4343

HCTZ

• ACCOMPLISH rekindled a common debate of diuretics—chlorthalidone vs. HCTZ

• 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

Ernst. Hypertension 2006;47:352-8.Ernst. NEJM 2009;361:2153-64

4444

HCTZ compared to others (24 ABPM)

Drug SBP DBP

HCTZ 12.5-25 mg 6.5 4.5

HCTZ 50 mg 12.0 5.4

ACE inhibitors 12.9 7.7

ARBs 13.3 7.8

CCB 11.0 8.1

ß-Blockers 11.2 8.5

HCTZ 50 mg 12.0 5.4

Messerli. J Am Coll Cardiol 2011;57:590-600.

Something to watch in JNC 8…

4545

Which beta blocker is better for HTN?

A.Atenolol

B.Metoprolol

C.Both are same

D.Doesn’t matter, shouldn’t use for HTN

4646

Beta blockers• AHA Statement on HTN Management—3rd or 4th line

• Outcomes data– Positive outcomes from short trials and prior to use of aspirin

and lipid therapies

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;115:2761–2788.Parker Arch Intern Med 2012:172:1406-12.Bangalore JAMA 2012;308:1340-9.

4747

How many aliskiren Rx have you seen this year?

A.Lots!

B.Few

C.None

D.Never heard of it

4848

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

Parving NEJM 2012;367:2204-13


4949






5050

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

Laurent S. Lancet 2012;380:591-600.

5151

Key Points for BP

What do you think?

5252

Key Points for BP

• Lower may not be better for everyone

• Should consider risk vs. benefit when deciding to treat mild hypertension

• Older patients may need different goals

• Non-obese patients may need different drugs

• Drug selection is very patient specific

5353

Learning Objectives for Dyslipidemia





5454

Recent guideline changes

• Still waiting for these too…NCEP ATP IV


5555

What is a Treatment Target?

• 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

5656

LDL-C and CHD Risk

30 mg/dL

30 mg/dL

30 mg/dL

30 mg/dL

Grundy S et al. Circulation. 2004;110:227-239.

3.7

2.9

2.2

1.7

1.3

1.0

40 70 100 130 160 190

LDL Cholesterol (mg/dL)

Rel

ativ

e R

isk

fo

r C

HD

(Lo

g S

cale

)

CHD=Coronary Heart Disease

5757

NCEP ATP III Guidelines:Dyslipidemia Targets of Treatment

• Primary Target: LDL-C– Goal value based on CV risk

• Secondary Target: Non-HDL-C– Only after LDL-C goal met and TG 200 mg/dL

– Goal is always the LDL-C goal + 30

Grundy SM et al. Circulation. 2004;110:227-239. CV = Cardiovascular 5858

CHD or CHD Risk Equivalent#

High Risk

<100 mg/dL, If Very High Risk

<70 mg/dL is optional

Yes

Low Risk

<160 mg/dLModerate Risk

<130 mg/dLHigh Risk

<100 mg/dL

No 2 major CV risk factors*

10-20% <10%

NoYes

NCEP ATP III: LDL-C Goal Values

Moderately-High Risk

<130 mg/dL, <100 mg/dLis optional

>20%

# non-coronary atherosclerotic vascular disease (e.g., ischemic stroke, peripheral arterial disease) or diabetes

*Age (45 years men, 55 years women), hypertension, smoking, family history of premature CHD in primary relatives, HDL-C < 40 mg/dL

Framingham Score

Calculate 10-year CHD risk:

Framingham Score

Grundy S et al. Circulation. 2004;110:227-239.

5959

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

• 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.

6060

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;47:2130–2139.

AHA= American Heart Association. ACC= American College of Cardiology AVD= Atherosclerotic Vascular Disease


6161

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%

6262

Which is the preferred initial agent for treating high LDL-C?

A.Statin

B.Niacin

C.BAR

D.Fibrates

6363

Cardiovascular Risk Reduction in Major StatinTrials

4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333:1301-1307.

6 Downs JR et al. JAMA. 1998;279:1615-1622.

14S Group. Lancet. 1994;344:1383-1389.2LIPID Study Group. N Engl J Med. 1998;339:1349-1357.

3Sacks FM et al. N Engl J Med. 1996;335:1001-1009.

LDL

N 4444 4159 20 536 6595 66059014-35% -28% -29% -26% -25%-25%

Secondary High Risk Primary

Patie

nts

Expe

rienc

ing

Maj

or C

HD

Eve

nts,

%

4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/TexCAPS6

Placebo

Statin

19.4

12.310.2

8.75.5 6.8

28.0

15.913.2

11.8

7.910.9

CHD events occur in patients treated with statins

6464

ATP III: 2004 Update Doses that Attain 30-40% LDL-C Reductions

DrugDose

(mg/d)LDL-C

reduction (%)

Atorvastatin (Lipitor) 10 39

Lovastatin (Mevacor) 40 31

Pravastatin (Pravachol) 40 34

Simvastatin (Zocor) 20-40 35-41

Fluvastatin (Lescol) 40-80 25-35

Rosuvastatin (Crestor) 5-10 39-45

Grundy S et al. Circulation. 2004;110:227-239.Livalo [package insert] Kowa Pharmaceuticals; 2010.

Pitavastatin (Livalo) 1 mg daily provides ~ 32% LDL-C reduction

6565






6666

HDL AND CARDIOVASCULAR RISK


6767

Framingham Heart StudyRisk of Coronary Artery Disease in Men Aged 50-70by LDL and HDL Cholesterol Levels

Castelli W. Can J Cardiol. 1988;4(suppl A):5a-10a. 6868

Potential Antiatherogenic Actions of HDL

Chapman MJ et al. Curr Med Res Opin. 2004;20:1253-1268.Assmann G et al. Annu Rev Med. 2003;53:321-341.

Apo A-I

Apo A-II

Antioxidative Activity

AntithromboticActivity

Anti-infectious Activity

EndothelialRepair

AntiapoptoticActivity

ReverseCholesterol

TransportCellular

CholesterolEfflux

Anti-inflammatoryActivity

VasodilatoryActivity

6969

Low HDL-C Predicts CV Events After ACS: In 1032 Patients Undergoing PCI

Wolfram RM et al. Am J Cardiol. 2006;98:711-717.

Not Low HDLNot Low HDL

DeathDeathTarget lesion revasc. or

MACETarget lesion revasc. or

MACE

Low HDL-C

05

10152025

0

5

10

15

P<0.01P<0.01

P=0.033P=0.033

P=0.002P=0.002

P=0.005P=0.005

0-30 days0-30 days

0-30 days0-30 days

30 days to 1 year30 days to 1 year

30 days to 1 year

30 days to 1 year

%% %%

7070

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%

• VA-HIT (1999) 5-year follow-up – 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

7171

AIM HIGH Study: Primary Objective

To determine whether the residual risk associated with lowlevels of HDL-C in patients with established CHD whose LDL-C therapy was optimized with statins ± ezetimibewould be mitigated with extended-release niacin vs. placebo during long-term follow-up

7272

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


7373

Adjust simva to LDL 40 – 80 mg/dL

Study Design

Months Relative to Randomization

-2 -1 0 1 2 3 6 12

Open-Label Run-In: Up-Titrate Niacin from 500mg to 2,000mg/day

4-8 weeks

Follow to end

of study

ER Niacin + 40-80 mg/day simvastatin

Placebo + 40-80 mg/day simvastatin

R

7474

Statistical Analyses

• Event-driven trial with projected 800 primary outcomes; 2.5-7 year follow-up (mean 4.6 years)

• 85% power to detect a 25% reduction in the revised 5-component primary endpoint (one-sided test of significance; alpha level=0.025)

• 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 of ischemic stroke imbalance with niacin after a 36-month average follow-up

7575

Concomitant Medications at Baseline

On a Statin 94%

Duration of Statin Therapy*

≥ 1 year 76%

≥ 5 years 40%

Prior Niacin Use 20%

ASA/Antiplatelet Therapy 98%

Βeta-Blocker 80%

ACEI / ARB 74%

Use of all secondary prevention therapies were

well-balanced between treatment groups*Duration of statin therapy not ascertained in 6%

7676

Baseline Lipids (mg/dL)

On Statin Off Statin

LDL-C (mean)

(n=3,196)

71

(n=218)

119

HDL-C (mean) 35 33

Triglycerides (median)

161 215

Non-HDL (mean) 107 165

Apo-B (mean) 81 111

7777

HDL-C at Baseline & Follow-up

25

30

35

40

45

50

55

Baseline Year 1 Year 2 Year 3

mg

/dL

CombinationTherapy

7878

LDL-C at Baseline & Follow-up

50

55

60

65

70

75

80

Baseline Year 1 Year 2 Year 3

mg

/dL

Combination Therapy

Monotherapy


7979

Primary & Secondary Endpoints

Hazard Ratio

95% CI

Primary Endpoint 1.02 0.87, 1.21

Secondary Endpoints

CHD Death, MI, Ischemic Stroke, High-Risk ACS

1.08 0.87, 1.34

CHD Death, MI, Ischemic Stroke

1.13 0.90, 1.42

Cardiovascular Death

1.17 0.76, 1.80

8080

Time (years)

Cu

mul

ativ

e %

wit

h P

rim

ary

Ou

tcom

e

0

10

20

30

40

50

0 1 2 3 4

MonotherapyCombination Therapy

HR 1.02, 95% CI 0.87, 1,21Logrank p-value= 0.79

N at risk

Monotherapy

Combination Therapy

1696

1718

1581

1606

1381

1366

910

903

436

428

Primary Outcome

8181

Primary & Secondary Endpoints

Hazard Ratio

95% CI Hazard Ratio

Primary Endpoint

1.02 0.87, 1.21 Primary Endpoint

1.02

Secondary Endpoints

Secondary Endpoints

CHD Death, MI, IschemicStroke, High-Risk ACS

1.08 0.87, 1.34 CHD Death, MI, IschemicStroke, High-Risk ACS

1.08

CHD Death,MI, Ischemic Stroke

1.13 0.90, 1.42 CHD Death,MI, Ischemic Stroke

1.13

8282

HPS 2-THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events

• 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)

8383

HPS2-THRIVE: Design and randomization

8484

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


8585






Unmet Needs in the Treatment of Homozygous Familial Hypercholesterolemia

8787

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.

8888

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.

8989

The Spectrum of Familial Hypercholesterolemia

• Estimated Prevalence

– Heterozygous FH: 1:500†

– Homozygous FH: 1:1 million‡

0-100 100-200 200-300 300-400 400-500 500-600 600-700 700-800 800-900 900-1,000+

Mean LDL-C In US Adults

CM-008

Typical LDL-C Range for Untreated HeFH Patients

Typical LDL-C Range for Untreated HoFH Patients

† 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.

9090

LDLR

apoB

TG

BVLDL

BLDL

XX

B

B

B

Defective LDL Receptors in HoFHLeads to Impaired LDL Catabolism

CM-012


9191

LDLR

apoB

TG

BVLDL

BLDL

XX

B

B

B

StatinsCAIBAS

Patients With HoFH Respond Poorly to Currently Available Therapies

CM-0139292

Rader DJ, et al. J Clin Invest. 2003;111:1796-1803.Konrad RJ, et al. Lipids Health Dis. 2011;10:38.

Efficacy of Current Cholesterol-Lowering Interventions in HoFH

Class Major Effect

Typical LDL-C-Lowering

Response

Low-fat diet ↑ LDLR activity <10%

Statins (e.g. atorvastatin, rosuvastatin)

↑ LDLR activity <10%

Bile Acid Sequestrants(e.g. cholestyamine, colestipol)


Cholesterol Absorption Inhibitors (e.g. ezetimibe )


Nicotinic acid (ie, niacin) Unknown <10%

CM-014

9393

LDL Apheresis is Current Standard of Care for HoFH

Plasma Line

Dextran sulfatecolumns

Plasma PumpBlood Pump

Heparin Pump

Blood Return

PlasmaSeparator

RegenerationPump

Re-PrimingSolution

RegenerationSolution

Waste Line

9494

LDL Apheresis Centers in the US:Limited Geographical Access

9595

LDL-C Levels Acutely Decrease and then Rebound Following Apheresis

CM-017Thompsen J & Thompson PD. Atherosclerosis. 2006;189: 31-8.

Pre-treatment LDL level

2-week interval

LDL

chol

este

rol

Start of LDL apheresis

Baseline LDL

Time

Post-treatment LDL level

9696

LDL-C Target Treatment Goals

0-100 100-200 200-300 300-400 400-500 500-600 600-700 700-800 800-900 900-1,000

CM-019

<100 mg/dL for subjects at high-risk

<70 mg/dL for subjects at very high-risk


9797

Treated HoFH Patients are Still Far from LDL-C Target Treatment Goals

0-100 100-200 200-300 300-400 400-500 500-600 600-700 700-800 800-900 900-1,000

<100 mg/dL for subjects at high-risk

<70 mg/dL for subjects at very high-risk

Typical LDL-C Range for Treated HoFH Patients*

* Raal J, et al. Circulation. (2011). 9898

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 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 needed

9999

New and Emerging Therapies

• PCSK9 Monoclonal Antibody– Increases LDL-C removal by decreasing inhibitor of LDL

clearance receptor

• 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 100100

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 dose-dependent.

– Fatty liver (300 mg dosing) remains an important concern

101101

A New Mechanism of ActionAntisense Oligonucleotide

DNA mRNA Disease-Associated Protein

Transcription Translation

Antisense Drug(Oligonucleotide)

Transcription

Traditional Drug

No Disease-Associated Proteins Produced

RNaseHDegrades RNA No Translation

Goldberg AC. J Clin Lipidol. 2010;4:350-6. 102102

Mipomersen: Overview of Phase 3

• Phase 3 Trials:– 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

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).


103103

Study Design 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

All Studies

Enroll

Patients

Mipomersen 200 mg/wk

Placebo

RR 2:1 mipomersen:placebo

Screening

≤ 4 weeks

Treatment Period

26 weeks

Safety Follow-up

24 weeks

Safety Follow-up

Primary efficacy

timepoint1.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).

104104

• 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– Triglycerides

– Lp(a)

– VLDL-C

– Apo A1

– HDL-C

– LDL/HDL ratio

Efficacy EndpointsAcross Four Phase 3 Studies

105105

Phase 3 Trials of MipomersenEfficacy

Patient Population Dose (N)

Treated Baseline LDL-C

(mg/dL)*

Change in LDL-C

(%)

Change in ApoB(%)

Change in Lp(a)(%)

Change in HDL-C

(%)

Change in TG(%)

Homozygous FH1

200 mg SC weekly(n=51)

439 -25 -27 -31 +15 -17

Severe heterozygous hypercholesterolemia2


276 -36 -36 -33 NC

Heterozygous FH3

200 mg SC weekly(n-124)

153 -28 -26 -21 +3# -14

High cholesterol at high risk for CAD

(n=158)

123 -37 -38 -24 +2# -25

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).

*maximally tolerated dose of a lipid-lowering drug

#NS

106106

LDL-C

Phase 3 Study

Mipomersen Placebo MipomersenAvg Baseline

(mg/dL)Avg Change

(mg/dL) % Change % Change *

Phase 3: Efficacy on top of Max Tolerated Lipid Lowering TherapiesPrimary End Point Achieved in All Four Phase 3 Trials

* All P Values <0.001

Average Reduction >100 mg/dL

51% of Patients Achieved Target <70 mg/dL

Heterozygous FH 153 -49 +5 -28

Homozygous FH 439 -113 -3 -25

Severe Hypercholesterolemia

276 -101 +13 -36

High Risk 123 -47 -5 -37

45% of Patients Achieved Target <100 mg/dL

107107 107

Safety profile remains consistent with all phase 3

studies

*Dallas Heart Study General Population: 5.6% liver fat median

Source: Table 14.2.1a; Table 14.3.6

Me

an

% C

ha

ng

e (

95

% C

I)

Change from Baseline in Lipids

Study Week

26n=130

52n=110

104n=26

76n=58

Long-term effects of Mipomersen in Extension Study Interim Data Analysis – March 2011

108108

Phase 3 Trials of MipomersenSide-effects

Patient Population Dose (N)

Injection-sitereactions

Placebo vsmipomersen

Influenza-likesymptomsPlacebo vs

mipomersen

ALT ≥ 3x ULNPlacebo vs

mipomersen

Homozygous FH1


24% vs 76% 24% vs 29% 0% vs 12%

Severe hypercholesterolemia2


32% vs 90% 21% vs 46% 0% vs 15%

Heterozygous FH3

200 mg SC weekly(n-124)

42% vs 93% 39% vs 42% 0% vs 6%

High cholesterol at high risk for CAD4

(n=158)

31% vs 78% 21% vs 34% 0% vs 10%

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).

4MRI fat fraction, increase from baseline ≥5%: 8% vs 35%


109109

Limitations:•Small study

•Short study duration•Patients at increase risk of

steatosis were excluded (TG<200 mg/dL, IHTG<5%, HgA1c <6%)

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)

110110

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.

– 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).

111111

MICROSOMAL TRIGLYCERIDE TRANSFER

PROTEIN INHIBITION

112112

LDLR

apoB

TG

B100

VLDL

LDL

TG

IDL

TG

X

MTP-inhibition reduces apoB-containing lipoprotein production

MTP

113113

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

• Drug Interactions– CYP3A4 Inhibitors including grapefruit juice

– Warfarin

– Simvastatin & Lovastatin

• Adverse reactions ( 28%):

– Diarrhea

– Nausea

– Vomiting

– Dyspepsia

– Abdominal pain114114

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)


115115

Pharmacologic MTP inhibition reduces LDL-C levels in HoFH

Cuchel, M. et al. NEJM 2007; 356:148-56. 116116

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 lomitapidewas 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.

117117

Key Points for Dyslpidemia

What do you think?

118118

Key Points for Dyslipidemia

• Statins are still considered drug of choice for patients

• New treatment guidelines should be available 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

119119

Patient CaseA 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 patient’s 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 patient’s BMI is 33 kg/m2. Her office blood pressure is 178/106 mm Hg and her heart rate if 82 bpm.

Blood pressure medications: HCTZ 25 mg qday

Verapamil 180 mg qdayOlmesartan 20 mg qdayAliskiren 150 mg qdayClonidine 0.2 mg tid 120120

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, HDL-C = 30 mg/dL, TG = 250 mg/dL, LDL-C = 170 mg/dL

• He does not have coronary heart disease, non-coronary 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


121121

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. LDL-C < 70 mg/dL

2. LDL-C < 100 mg/dL



121 122122

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. His non-HDL-C is already low enough

2. His triglycerides are not ≥ 500 mg/dL

3. His HDL-C should be raised first

4. His LDL-C is not yet at goal

122

123123

Self-Assessment Questions

124124


A.<160

B.<150

C.<140

D.<130

125125

Which of the following is true regarding weight and drug selection for blood pressure?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

126126

Which of the following is the best diuretic for blood pressure?

A.Hydrochlorothiazide

B.Chlorthalidone

C.Furosemide

D.Bumetanide


127127

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

A.<190

B.<160

C.<130

D.<100

cv update

Documents

care of patients

important recent changes

noteworthy recent findings

recent guideline changes

new evidence

pharmacists acpe

older patients obese

mild hypertension treatment