1

Cardiovascular Diseases—Unmet Needs

2

Objectives

Describe the impact of CVD on worldwide morbidity and mortality

Review the effects of LDL-C–lowering strategies on CHD risk

Explore unmet needs in CVD risk reduction

CVD=cardiovascular disease; LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease

3

Global Mortality From Cardiovascular Diseases

CHD=coronary heart disease

from World Health Organization. The atlas of heart disease and stroke. Available at: http://www.who.int/cardiovascular_diseases/resources/atlas/en. Accessed February 7, 2006.

Hypertensive 5%

Stroke33%

Other14% CHD

43%

Rheumatic 2% Inflammatory 3%

Total: 16.7 million deaths

(2002)

4

Prevalence and Impact of Hypercholesterolemia

aCardiovascular death, myocardial infarction, stroke, or hospitalization for atherothrombotic events

TC=total cholesterol

from Steg PG et al. JAMA. 2007;297:1197–1206; Bhatt DL et al. JAMA. 2006;295:180–189.

Reduction of Atherothrombosis for Continued Health (REACH) Registry

0

5

10

15

20

25

Eve

nt

Rat

e,a %

per

Yea

rNorth

AmericaLatin

AmericaWesternEurope

EasternEurope

Asia Japan

n=17,142 n=5622 n=5671 n=5021n=1835n=25,999

Adjusted Event Rate

0

10

30

50

60

70

Pat

ien

ts,

%

NorthAmerica

LatinAmerica

WesternEurope

EasternEurope

Asia Japan

n=27,746

40

20

n=1931 n=17,886 n=5656 n=5903 n=5048

Patients With TC >5.18 mmol/L

5

Managing Atherosclerosis: The First 50 Years

LDL-C=low-density lipoprotein cholesterol; HMG-CoA=hepatic hydroxymethyl glutaryl coenzyme A

from Thompson GR et al. Curr Opin Lipidol. 1999;10:521–526; Mahley RW et al. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division, 2006:933–966; Shapiro DJ et al. J Biol Chem. 1971;246:3210–3216; Goldstein JL et al. Proc Natl Acad Sci U S A. 1973;70:2804–2408; Brown MS et al. Proc Natl Acad Sci U S A. 1974;71:788–792; Endo A et al. FEBS Lett. 1976;72:323–326; Alberts AW et al. Proc Natl Acad Sci U S A. 1980;77:3957–3961; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.

1950s1950s • Beginning of lipidology

• Epidemiologic data on atherosclerotic disease available

1960s1960s• Debate over lipid hypothesis

• Existing treatment options (fibrates, resins, nicotinic acid) of limited effectiveness and poorly tolerated

1970s1970s • LDL-C receptor identified

• Characterization of HMG-CoA reductase and early development of inhibitors

1980s1980s • Statins (lovastatin and simvastatin) introduced

1990s1990s• Major statin trials confirm lipid hypothesis, transform medical practice

• LDL-C as primary treatment target

2000s2000s What more can be done?What more can be done?

6

Therapies Based on LDL-C Lowering Reduce the Risks of CHD

34

2431

24

37

27

15

36

0

20

40

60

80

100

4S CAREWOSCOPS

LIPIDAFCAPS

HPSPROSPER

ASCOT

Re

lati

ve

Ris

k R

ed

uc

tio

n

in M

ajo

r C

oro

na

ry E

ve

nts

, %

aScandinavian Simvastatin Survival Study, end point major coronary events (coronary death, nonfatal definite or probable MI, silent MI, or reassociated cardiac death); bCholesterol and Recurrent Events, fatal CHD or confirmed MI; cWest of Scotland Coronary Prevention Study, CHD and death from CHD; dLong-term Intervention with Pravastatin in Ischemic Disease, death due to CHD or nonfatal MI; eAir Force/Texas Coronary Atherosclerosis Prevention Study, fatal or nonfatal MI; fHeart-Protection Study, nonfatal MI or coronary death; gProspective Study of Pravastatin in Elderly at Risk, CHD death or nonfatal MI; hAnglo-Scandinavian Cardiac Outcomes Trial, fatal CHD and nonfatal MI

CHD=coronary heart disease; MI=myocardial infarction

Shepherd J et al. Lancet. 2002;360:1623–1630; Downs JR et al. JAMA. 1998;279:1615–1622; Sacks FM et al. N Engl J Med. 1996;335:1001–1009; Shepherd J et al. N Engl J Med. 1995;333:1301–1307; Sever PS et al. Lancet. 2003;361:1149–1158; Heart Protection Study Collaborative Group. Lancet. 2002;360:7–22; Scandinavian Simvastatin Survival Group. Lancet. 1994;344:1383–1389; LIPID Study Group. N Engl J Med. 1998;339:1349–1357.

hb

c

de

f

g

a

7

Substantial Risk of CHD Events Remains for Many Patients on Statin Therapy

Trial (N) Statin Treatment

Clinical Eventsa

Relative Risk Reduction vs Placebo, %

Remaining Relative

Risk

WOSCOPSb (6595) Pravastatin 40 mg 31

AFCAPS/TexCAPSb (6605) Lovastatin 20 or 40 mg 37

ASCOT-LLAb (10,305) Atorvastatin 10 mg 36

4Sb (4444) Simvastatin 20 mg 26

CAREc (4159) Pravastatin 40 mg 24

LIPIDc (9014) Pravastatin 40 mg 24

HPSc (20,536) Simvastatin 40 mg 27

PROSPERc (5804) Pravastatin 40 mg 19

TNT (10,001) Atorvastatin 80 mg (vs 10 mg atorvastatin) 22d

IDEAL (8888) Atorvastatin 80 mg (vs 20 mg simvastatin) 11d

PROVE IT–TIMI 22 (4162) Atorvastatin 80 mg (vs 40 mg pravastatin) 16d

aNonfatal myocardial infarction and coronary heart death; bPrimary prevention trial; cSecondary prevention trial; dRisk reduction vs comparator

WOSCOPS=West of Scotland Coronary Prevention Study; AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol and Recurrent Events; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; HPS=Heart Protection Study; PROSPER=Prospective Study of Pravastatin in the Elderly at Risk; TNT=Treating to New Targets study; IDEAL=Incremental Decrease in End Points Through Aggressive Lipid Lowering study; PROVE IT–TIMI 22=Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 study

from Mahley RW et al. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division, 2006:933–966; Bays HE. Expert Rev Cardiovasc Ther. 2004;2:485–501; Shepherd J et al. N Engl J Med. 1995;333:1301–1307; Downs JR et al. JAMA. 1998;279:1615–1622; Sever PS et al. Lancet. 2003;361:1149–1158; Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383–1389; Sacks FM et al. N Engl J Med. 1996;335:1001–1009; Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349–1357; Heart Protection Study Collaborative Group. Lancet. 2002;360:7–22; Shepherd J et al. Lancet. 2002;360:1623–1630. LaRosa JC et al. N Engl J Med. 2005;352:1425–1435; Pedersen TR et al. JAMA. 2005;294:2437–2445; Cannon CP et al. N Engl J Med. 2004;350:1495–1504.

SIGNIFICANT

8

Post Hoc Analysis of Predictive Value of HDL-C for Major CV Events

Treating to New Targets (TNT) Trial (N=10,001)

Design: randomized, double-blind, parallel-group comparison of atorvastatin 80 mg vs 10 mg once daily

Primary end point: occurrence of major CV eventsa

Participants: men and women 35 to 75 years of age with CHDb and LDL-C <130 mg/dL at baseline

Post Hoc Analysis (N=9770)

Objective: evaluate relationship between HDL-C and risk of major CV events

aCHD death, nonfatal/nonprocedure-related myocardial infarction, resuscitation after cardiac arrest, fatal/nonfatal stroke.bOne or more of: previous myocardial infarction, previous/current angina with objective evidence of atherosclerotic CHD, history of revascularization.

LaRosa JC et al. N Engl J Med. 2005;352(14):1425–1435; Barter P, et al. N Engl J Med. 2007;357(13):1301–1310.

9

5-Year Risk of Major CV Events Stratified by HDL-C and LDL-C

Reprinted with permission from Barter P et al. N Engl J Med. 2007;357(13):1301–1310.

Quintile of HDL-C, mg/dL

5-Y

ear

Ris

k o

f M

ajo

r C

V E

ven

ts, %

LDL-C Level

<70 mg/dL (n=2,661)70–100 mg/dL (n=4,537)>100 mg/dL (n=2,571)

Hazard ratio (95% CI) vs Quintile 1

Quintile 2 1.00 (0.82–1.21)Quintile 3 0.80 (0.65–0.99)Quintile 4 0.92 (0.74–1.13)Quintile 5 0.75 (0.60–0.95)

P=0.050

2

4

6

8

10

12

Quintile 1(<38)

Quintile 2(38 to <43)

Quintile 3(43 to <48)

Quintile 4(48 to <55)

Quintile 5(≥55)

10

5-Year Risk of Major CV Events Stratified by HDL-Cin Patients With LDL-C <70 mg/dL

Reprinted with permission from Barter P et al. N Engl J Med. 2007;357(13):1301–1310.

Quintile of HDL-C, mg/dL

5-Y

ear

Ris

k o

f M

ajo

r C

V E

ven

ts, %

P=0.030

2

4

6

8

10

12

Quintile 1(<37)

Quintile 2(37 to <42)

Quintile 3(42 to <47)

Quintile 4(47 to <55)

Quintile 5(≥55)

Hazard ratio (95% CI) vs Quintile 1

Quintile 2 0.85 (0.57–1.25)Quintile 3 0.57 (0.36–0.88)Quintile 4 0.55 (0.35–0.86)Quintile 5 0.61 (0.38–0.97)

No. of events 57 50 34 34 35No. of patients 473 525 550 569 544

11

5-Year Risk of Major CV Events According to LDL-C:HDL-C Ratio

Reprinted with permission from Barter P et al. N Engl J Med. 2007;357(13):1301–1310.

5-Y

ear

Ris

k o

f M

ajo

r C

V E

ven

ts, %

Atorvastatin 10 mgAtorvastatin 80 mgTotal

P=0.0060

2

4

6

8

10

12

Quintile 1(<1.33)

Quintile 2(1.33 to <1.66)

Quintile 3(1.66 to <1.98)

Quintile 4(1.98 to <2.41)

Quintile 5(≥2.41)

Quintile of LDL-C:HDL-C Ratio

12

5-Year Risk of Major CV Events According to TC:HDL-C Ratio

TC=total cholesterol.

Reprinted with permission from Barter P et al. N Engl J Med. 2007;357(13):1301–1310.

5-Y

ear

Ris

k o

f M

ajo

r C

V E

ven

ts, %

0

2

4

6

8

10

12

Quintile 1(<2.76)

Quintile 2(2.76 to <3.19)

Quintile 3(3.19 to <3.63)

Quintile 4(3.63 to <4.23)

Quintile 5(≥4.23)

Quintile of TC:HDL-C Ratio

Atorvastatin 10 mgAtorvastatin 80 mgTotal

13

Patients at or Below LDL-C of 2.6 mmol/L Had Vascular Events

67%

33%

LDL-C <2.6 mmol/L

LDL-C >2.6 mmol/L

Retrospective cohort study conducted in the UK of 19,882 patients >35 years of age

Of 2191 statin-treated patients who experienced a CV/CB event, 67% were at LDL-C of 2.6 mmol/L

– 33% of the 2191 patients who had a CV event were not at LDL-C of 2.6 mmol/L

Among patients with a CV/CB event and

– With LDL-C <2.6 mmol/L, 38.6% had low HDL-C and/or elevated triglycerides

– With LDL-C >2.6 mmol/L, 43.9% had low HDL-C and/or elevated triglycerides

Patients were on statin therapy ≥6 weeks; >2 years pre- and post-statin history with laboratory data; no concomitant lipid-lowering drugs; and ≥1 complete lipid profile pre- and post-statin initiation. Patients were followed for up to 5 years LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; CV=cardiovascular; CB=cerebrovascularPhatak H et al. Poster presented at the European Atherosclerosis Society Congress; 10–13 June 2007: Helsinki, Finland. Poster P016-441.

n=2191

14

Proportion of European Patients on Lipid-Lowering Therapy Achieving Lipid Goals

aNational Cholesterol Education Program (NCEP) ATP III (LDL-C <2.6 mmol/L with CHD/CHD risk equivalent); bTC <5.2 mmol/L; cLDL-C <3.0 mmol/L, TC <5.0 mmol/L; dDetermined by treating physician or according to NCEP ATP IIITC=total cholesterol; LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease

from Van Ganse E et al. Curr Med Res Opin. 2005;21:1389–1399.

Return on Expenditure Achieved for Lipid Therapy (REALITY) Study

TOTAL (LDL-C or TC)UKc

Switzerlandd

Sweden (TC)c

Spaina

Norwayc

Netherlandsb

Italy (LDL-C)b,c

Italy (TC)b,c

Hungaryb

Germanya

Francea

Patients Achieving Goal, %

0 10 20 30 40 50 60

54.924

26.428

1430.2

32.926.3

29.734.2

50

40.5

15

The Need to Treat Beyond LDL-C

Intensive lipid lowering with high-dose statin therapy on a population basis has reduced relative risk by a third, improved clinical outcomes, confirming that “lower is better” on a population basis, however

– Substaintial risk remains

Development of new approaches may include targeting a broad lipoprotein profile, eg, HDL-C + triglycerides, and modifying other established cardiovascular risk factors that may address the substantial risk that remains

LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease; HDL-C=high-density lipoprotein cholesterol

from Brown BG. Eur Heart J Suppl. 2005;7(suppl F):F34–F40; Pedersen TR et al. JAMA. 2005;294:2437–2445; LaRosa JC et al. N Engl J Med. 2005;352:1425–1435; Cannon CP et al. N Engl J Med. 2004;350:1495–1504; Cannon CP. JAMA. 2005;294:2492–2494; Assmann G. Curr Med Res Opin. 2005;21(suppl 6):S3–S8.

16

Summary

Atherosclerosis is recognized as the leading cause of death and disability in developed nations worldwide

LDL-C–lowering therapy reduces the relative risk of CHD-related events by about 30%

Significant CVD risk remains in treated patients with LDL-C below 2.6 mmol/L

Further risk reduction may need to focus on other CVD risk factors

LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease; CVD=cardiovascular disease

17

Bibliography

18

Bibliography (continued)

19

Cardiovascular Diseases—Unmet Needs

Before prescribing, please consult the manufacturers’ prescribing information.

Merck does not recommend the use of any product in any different manner than as described

in the prescribing information.

Copyright © 2007 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

12-08 M524A-2007-W-1245910-SS

01-10-CVT-2009-IT-2651 Dep.Aifa 12/02/09

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