Landmark Trials In Preventive Cardiology

Landmark Trials in Preventive  Cardiology Ramesh Singh Veriah Cardiology Unit University Malaya Medical Centre

CLINICAL TRIALS IN  DYSLIPIDEMIA

Primary Prevention Trials • Pre‐ HMG CoA Reductase Inhibitor era ‐ Lipid Research Clinics Coronary Primary Prevention Trial ‐ Helsinki Heart Study (HHS) • Post Statin era ‐ WOSCOPS ‐ AFCAPS/TexCAPS ‐ Heart Protection Study (HPS) ‐ Collaborative Atorvastatin Diabetes Study (CARDS)  ‐ Anglo‐Scandinavian Cardiac Outcomes Trial LLA

Early Primary-Prevention Trials: Overview TC *

%+

0 -5 -10 -15 -20 -25 -30 -35 -40 -45 -50

-9

CHD events *

-8.5

-9

Oslo: Diet/smoking cessation N=1,232, P=0.02 WHO: Clofibrate N=15,745, P<0.05

-11

-14 -19

-20 -23

-34

Upjohn: Colestipol N=2,278, P≤0.02 LRC-CPPT: Cholestyramine N=3,806, P<0.05 HHS: Gemfibrozil N=4,081, P<0.02

-47

N=number enrolled.

* Net difference between treatment and control groups (P values are for events).

% CHD Death/Nonfatal MI

Trials of Fibrates: Effects on Cardiac Events 42%

30

Rx

25

Placebo

15 10 5 0

Deaths

66% 34% 2.7

22.3

9%

20 13.6

22%

15.0

21.7*** 17.3

13.0

8.0

4.1*** 2.7

HHS 2.2 2.1

HHS

(Post Hoc)*

PRIMARY PREVENTION

BIP

BIP

(Post Hoc)**

10.4 9.9

VA-HIT 15.7 17.4

SECONDARY PREVENTION

* Post hoc analysis of subgroup with TG >200 mg/dL and HDL-C <42 mg/dL. ** Post hoc analysis of subgroup with TG ≥200 mg/dL and HDL-C <35 mg/dL. *** Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05). Frick MH et al. N Engl J Med 1987;317:1237-1245. | Manninen V et al. Circulation 1992;85:37-45. | BIP Study Group. Circulation 2000;102:21-27. | Rubins HB et al. N Engl J Med 1999;341:410-418.

Slide Source Lipids Online Slide Library www.lipidsonline.org

WOSCOPS: Effects of Lipid Lowering on Coronary Events in Primary Prevention Trial in Men 10 5

5 TC

0

LDL-C

HDL-C

-5 %+

Nonfatal MI/CHD CHD All-cause death death mortality

-10 -15 -20 -25

-20

-30 -35 * P<0.0005. † P=0.042. ‡ P=0.051.

‡

-22

-26 -31*

†

N= 6595 men 45 – 64 yrs Mean Baseline TC = 272 mg/dL Mean Baseline LDL = 192 mg/dL 5 yr duration Intervention: Pravastatin 40mg dly

-33

Shepherd J et al. N Engl J Med. 1995;333:1301-1307.

WOSCOPS: Nonfatal MI and CHD Death

Percent With Event

12 Placebo (n=3293) Pravastatin (n=3302)

10

31% relative risk reduction P < 0.001

8 6 4 2 0 1

2

3

Years Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.

4

5

6

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) Primary End Point: First Acute Major Coronary Event 0.07

Cumulative incidence

0.06 0.05

37% risk reduction (P < 0.001)

Placebo

0.04 0.03

Lovastatin

0.02 0.01 0.00 0

1

2 4 3 Years of follow-up

Downs JR et al. JAMA 1998;279:1615–1622 Copyright ©1998, American Medical Association.

5

N=6605 45-73 yrs Healthy subjects with 5+ low HDL Lovastatin 20-40 mg vs placebo

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) Event Rates by Baseline HDL-C Tertile

Event rate per 1,000 patient-years at risk

16

-45% risk reduction

14

-44% risk reduction

12

Lovastatin Placebo -15% risk reduction

10 8 6 4 2 0

≤ 34

35–39 HDL-C (mg/dL)

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

≥ 40 Slide source: lipidsonline.org 10

Significance „ A landmark study involving subjects with no evidence of heart disease and would not ordinarily be considered for statin therapy according to the NCEP giudelines at that time. „ But it was a group that will eventually go on to develop CAD with time if not treated.

11

Eligibility: Protection

MRC/BHF Heart Study

„ Role of lipid lowering in individuals with diabetes

or at high risk for vascular events

„ Age 40–80 years „ Total cholesterol >3.5 mmol/l (>135 mg/dl) „ Statin not considered clearly indicated or

contraindicated by patient’s own doctors

Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.

Slide Source Lipids Online Slide Library www.lipidsonline.org

Factorial Treatment Comparisons Simvastatin (40 mg daily)

VS

Placebo tablets

Vitamins (600 mg E, 250 mg C, VS and 20 mg β-carotene)

Placebo capsules

5 years average duration of follow-up

Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.

Slide Source Lipids Online Slide Library www.lipidsonline.org

Simvastatin: Major Vascular Events Risk ratio and 95% CI Vascular Event

Simvastatin (10,269)

Placebo (10,267)

Major coronary

898

1212

Any stroke

444

585

Revascularization

939

1205

2033 (19.8%)

2585 (25.2%)

ANY OF ABOVE

STATIN Better

PLACEBO Better 25% SE 5 reduction (2P<0.00001)

24% SE 3 reduction (2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Reprinted with permission from Elsevier Science.

Slide Source Lipids Online Slide Library www.lipidsonline.org

Simvastatin: Coronary Events and Revascularization

Risk ratio and 95% CI

Major Coronary Event

Simvastatin (10,269)

Placebo (10,267)

STATIN Better

PLACEBO Better

Major coronary event Nonfatal MI

357

574

Coronary death

587

707

CORONARY EVENTS

27% SE 4 reduction (2P<0.00001)

898 (8.7%) 1212 (11.8%)

Revascularization Coronary

513

725

Noncoronary

450

532

24% SE 4 reduction (2P<0.00001)

REVASCULARIZATIONS 939 (9.1%) 1205 (11.7%)

0.4

0.6

0.8

Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Reprinted with permission from Elsevier Science.

1.0

1.2

1.4

Slide Source Lipids Online Slide Library www.lipidsonline.org

Simvastatin: Stroke Incidence

Risk ratio and 95% CI

Simvastatin (10,269)

Placebo (10,267)

290

409

51

53

103

134

Fatal

96

119

Severe

42

51

Moderate

107

155

Mild

138

189

61

71

STATIN Better

PLACEBO Better

Type Ischemic Hemorrhagic Unknown Severity

Unknown ALL STROKES

25% SE 5 reduction (2P<0.00001)

444 (4.3%) 585 (5.7%) 0.4

0.6

0.8

Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Reprinted with permission from Elsevier Science.

1.0

1.2

1.4

Slide Source Lipids Online Slide Library www.lipidsonline.org

Simvastatin: Cause-Specific Mortality Risk ratio and 95% CI Simvastatin (10,269)

Placebo (10,267)

Coronary

587

707

Other vascular

194

230

Cause of Death Vascular

ANY VASCULAR

781 (7.6%)

937 (9.1%)

359

345

Respiratory

90

114

Other medical

82

90

Nonmedical

16

21

STATIN Better

PLACEBO Better

17% SE 4 reduction (2P<0.0001)

Nonvascular Neoplastic

NONVASCULAR ALL CAUSES

547 (5.3%)

5% SE 6 reduction (NS)

570 (5.6%)

1328 (12.9%) 1507 (14.7%) 0.4

0.6

0.8

Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Reprinted with permission from Elsevier Science.

13% SE 4 reduction (2P<0.001) 1.0

1.2 1.4

Slide Source Lipids Online Slide Library www.lipidsonline.org

People Suffering Events (%)

Simvastatin: Major Vascular Events by Year 30 25

Placebo

20 15

Simvastatin

10 5 0 0

1

2

3

4

5

6

54 (7)

60 (18)

Years of Follow-up Benefit/1000 (SE): 5 (3)

20 (4)

35 (5)

46 (5)

Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Reprinted with permission from Elsevier Science.

Slide Source Lipids Online Slide Library www.lipidsonline.org

HPS: Conclusions „ After allowance for noncompliance, 40 mg

daily simvastatin safely reduces the risk of heart attack, of stroke, and of revascularization by about one third.

„ In diabetic patients, glycemia alone will not

completely eliminate the excess CHD risk.

„ Statin therapy should now be considered

rountinely for all diabetic patients irrespective of the initial cholesterol levels

Slide Source Lipids Online Slide Library www.lipidsonline.org

The Collaborative AtoRvastatin Diabetes Study Whether Diabetics with normal to mildly elevated cholesterol levels and no history of CVD would benefit from further lipid reduction. A primary preventive study of CVD with a ‘cardiovascular equivalent’ risk factor

Geiss LS, et al. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1995:233-257. Haffner SM, Lehto S, Rönnemaa T, et al. N Engl J Med. 1998;339:229-234 Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211. Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211.

20

Design Placebo

Atorvastatin 10 mg/day

N= 1428

Placebo

N= 1410

2838 patients

6-week placebo lead-in prerandomization

304 primary end points

Patient population: „

Type 2 diabetes with no previous MI or CHD

≥1 other CHD risk factor plus LDL-C ≤4.14 mmol/L and TG ≤6.78 mmol/L „ Aged 40-75 years „

Mean baseline LDL-C entry is 3.0 mmol/L Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211.

„ Mean follow-up of 3.7 years „ 65% on OHA „ 83% Hypertensive

21

Cumulative hazard (%)

Primary Endpoint: -Acute CHD death -Nonfatal MI, including silent MI -Unstable angina 15 -CABG or other coronary revascularization -Resuscitated cardiac arrest -Stroke 10

Primary End Point

Placebo 127 events

RRR 37% P=0.001

Atorvastatin 83 events 5

0 0 Placebo 1410 Atorva 1428

1

2

3

4

4.75

1351 1392

1306 1361

1022 1074

651 694

305 328

Colhoun HM, Betteridge DJ, Durrington PN, et al. Lancet. 2004;364:685-696.

Years

22

Atorvastatin 10mg provided impressive benefits in patients with type 2 diabetes with no history of CVD and with normal to mildly-elevated cholesterol levels

LLA: Identify the benefits of lowering lipids in well-controlled hypertensive patients not conventionally considered dyslipidemic Primary Objective of the ASCOT BPLA To compare the effect on non-fatal myocardial infarction (MI) and fatal CHD of the standard antihypertensive regimen (B-blocker ± diuretic) with a more contemporary regimen (CCB ± ACE inhibitor) Dahlof et al. Lancet 2005; 366: 895-906.

ASCOT patient population risk factor profile All patients in ASCOT have hypertension plus ≥ 3 risk factors for CHD No previous MI or current clinical CHD 100

Hypertension Age ≥ 55 years

84

Male

77

Microalbuminuria/proteinuria

61

Smoker

30 27 24 24

Family history of CHD Plasma TC:HDL-C ≥ 6 Type 2 diabetes Certain ECG abnormalities

14 13 11

LVH Previous cerebrovascular events Peripheral vascular disease

6 0

10

20

30 40 50 60 70 80 Patients with risk factor (%)

90 100

The Anglo -Scandinavian Cardiac Outcomes Trial (ASCOT): A Anglo-Scandinavian Study in Hypertensive Patients at Low to Moderate CV Risk Hypertensive patients with additional risk factors Randomised N=19,257

BPLA Amlodipine ± perindopril ± doxazosin GITS

LLA

Atenolol ± bendroflumethiazide-K+ ± doxazosin GITS

Eligible for lipid-lowering arm (TC ≤6.5 mmol/L [≤250 mg/dL]) (n=10,305) Double-blind randomisation n=5168 Atorvastatin 10 mg

n=5137 Placebo

Not eligible for lipid-lowering arm (TC >6.5 mmol/L [>250 mg/dL])

• 5-year planned follow-up • Primary end point: nonfatal MI and fatal CHD

GITS=gastrointestinal therapeutic system. Adapted from Sever PS et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147. Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158. Dahlöf B et al, for the ASCOT Investigators. Lancet. 2005;366:895-906.

ASCOT -BPLA: Primary End Point Not Significant ASCOT-BPLA: Due to Significant Benefit on Secondary End Point of All -Cause Mortality All-Cause Primary End Point: Nonfatal MI and Fatal CHD Proportion of Events (%)

5.0

Trial stopped early

Atenolol ± bendroflumethiazide Amlodipine ± perindopril

4.0

P=.1052

3.0 2.0 1.0 HR=0.90 (0.79-1.02) 0.0 0.0

1.0

2.0

3.0 Years

4.0

5.0

6.0

Dahlöf B et al, for the ASCOT Investigators. Lancet. 2005;366:895-906.

VBWG

ASCOT -BPLA: ASCOT-BPLA: Reduction Reduction in in fatal fatal and and nonfatal nonfatal stroke stroke 10 8

HR = 0.77 (95% CI, 0.66–0.89) RRR = 23% P = 0.0003

6

Proportion of events 4 (%)

Atenolol-based Amlodipine-based regimen* regimen†

2 0

0

1

2

3

4

Time (years)

5

6

Number at risk Amlodipine-based regimen 9639 9483 9331 9156 8972 7863 (327 events) Atenolol-based regimen 9618 9461 9274 9059 8843 7720 (422 events) *Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn †Amlodipine 5–10 mg ± perindopril 4–8 mg prn Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366

ASCOT -LLA: 36% RRR in Nonfatal MI and Fatal ASCOT-LLA: CHD When Atorvastatin Added to BP Treatment Originally planned length of trial: 5 years Actual length of trial: median 3.3 years

Proportion of Patients (%)

4

Atorvastatin 10 mg (n=5168) Placebo (n=5137)

3

Trial stopped early P=.0005

2

1 Significant benefits observed in 0 90 days

HR=0.64 (0.50-0.83)

0.0

0.5

1.0

1.5

2.0 2.5 Years

3.0 3.3

5.0

RRR=relative risk reduction. Sever PS et al for the ASCOT Investigators. Lancet. 2003;361:1149-1158. Sever PS et al, for the ASCOT Investigators. Am J Cardiol. 2005;96:39F-44F.

ASCOT -LLA: 27% RRR in Fatal and Nonfatal ASCOT-LLA: Stroke When Atorvastatin Added to BP Treatment Atorvastatin 10 mg (n=5168) Placebo (n=5137)

Proportion of Events (%)

3

Trial stopped early P=.0236

2

1

HR=0.73 (0.56-0.96) 0 0.0

0.5

1.0

1.5

2.0 2.5 Years

3.0

3.5

5.0

Sever PS et al for the ASCOT Investigators. Lancet. 2003;361:1149-1158.

ASCOT: Summary • Amlodipine ± perindopril based therapy confers an

advantage over atenolol ± thiazide based therapy on all major CV end points, all-cause mortality and new-onset diabetes

• Compared with standard antihypertensive therapy without

statin therapy, the amlodipine ± perindopril regimen plus atorvastatin reduced coronary and stroke events by almost 50%

• Statin therapy should be considered in hypertensive patients

with multiple risk factors and no history of CAD irrespective of their initial cholesterol values.

ASCOT results support the use of newer drugs, in multi-drug combinations, to modify risk factors and/or metabolic disturbances, especially in patients with complicated hypertension

VA-HIT Study • Study design − Double-blind, placebo-controlled trial − 2531 men with CHD, HDL-C ≤ 40, LDL-C ≤ 140, and TG ≤ 300

• Study intervention − Gemfibrozil 1200 mg/day or placebo

• Primary endpoint − Nonfatal MI or death from coronary causes

Rubins HB et al. N Engl J Med. 1999;341:410-418.

VA-HIT Study (cont.) Results • Median follow-up, 5.1 years • Primary endpoint reached in 21.7% of placebo group and 17.3% of gemfibrozil group – 22% relative risk reduction in CHD death (P = 0.07) and 23% reduction in nonfatal MI (P = 0.02) – 24% relative risk reduction in combined outcome of CHD death, nonfatal MI, or confirmed stroke (P ≤ 0.001) • ↑ HDL-C 6% • ↓ TG 31% • No change in LDL-C Rubins HB et al. N Engl J Med. 1999;341:410-418.

5-Year CHD Event Rate, %

VA-HIT: Relation of 5-Year CHD Rates to On-Treatment Lipid Values

HDL-C

25

LDL-C

22 19 16 13 10

24

28

Gemfibrozil Placebo

32

36

40

44

80

95

110

Quintile Trial Concentrations, mg/dL

Robins SJ et al. JAMA. 2001;285:1585-1591.

125

140

155

VA-HIT: Beneficial Effects of Gemfibrozil Are Unexplained Analysis of Lipid Parameters

• LDL-C (baseline or on treatment) did not predict events • TG (baseline or on treatment) did not predict events • Increases in HDL-C account for part of the benefit − 5 mg/dL increase in HDL-C decreases RR by 11% − HDL-C increased 2 mg/dL but RR decreased 22%

• Changes in all lipid values account for 23% of the benefit

Robins SJ et al. JAMA. 2001;285:1585-1591.

CLINICAL TRIALS IN HYPERTENSION • Systolic Hypertension in Europe Trial (Syst-Eur) • Systolic Hypertension in the Elderly Program Trial (SHEP)

• ASCOT-BPLA

Syst -Eur trial Syst-Eur • 4695 patients over age 59 with a mean initial sitting blood pressure of 174/86 randomnized to therapy with placebo or nitrendipine plus, if necessary, enalapril and hydrochlorothiazide

• The fall in blood pressure was greater with active therapy, 23/7 versus 13/2 mmHg

• At four years, significant reductions were noted in stroke (7.9 versus 13.7 total endpoints per 1000 patient years), and fatal and non-fatal cardiac endpoints

The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350:757.

Syst -Eur trial - cont Syst-Eur • Mortality increased with a higher systolic blood pressure. • More pronounced in the subset of patients with diabetes - mortality reduced 55% - cardiovascular events reduced 26% - strokes reduced 38%

The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350:757.

Prevention of Dementia in ISH: Syst -Eur Trial Syst-Eur

Forette et al, Arch Int Med 2002: 162: 2046

Systolic Hypertension in the Elderly Program (SHEP) trial • 4736 patients with mean entry BP of 170/77 randomized to chlorthalidone and placebo.

• Other drugs can be added to achieve the aim of therapy of at least a 20 mmHg reduction in systolic pressure to a level below 160 mmHg.

•

SHEP Cooperative Research Group. JAMA 1991; 265:3255.

The S ystolic H ypertension in Systolic Hypertension the E lderly P rogram Elderly Program Cohort Age Eligibility

4,736; 43% men ≥ 60 yrs old; mean 71.6 yrs old Systolic BP 160−219 mmHg and Diastolic BP <90 mmHg

Design

Double blind; placebo control

Therapy

Chlorthalidone (atenolol as step 2)

Duration

4.5 years

BP change

Systolic BP –12 mmHg

SHEP Research Group. JAMA. 1991;265:3255-3264.

The A ntihypertensive and Antihypertensive L ipid-Lowering Treatment Lipid-Lowering to Prevent H eart A ttack T rial Heart Attack Trial

ALLHAT study overview

Double-blind, randomized trial to determine whether the occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (amlodipine, lisinopril, or doxazosin) compared with a diuretic (chlorthalidone)

Cohort

• 42,418 patients (≥55 years old) from 623 sites in North America − Stage 1 or 2 hypertension − 1 additional risk factor for CHD • Comparisons between chlorthalidone and amlodipine and chlorthalidone and lisinopril have been reported together, excluding the doxazosin arm (n=9,062), which was terminated early

CHD=coronary heart disease; MI=myocardial infarction ALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT Study Design Doxazosin n=9,062

YEAR 1

YEAR 5

Intent-toTreat Analysis

Discontinued early at 3.3 yrs

Randomized n=42,418

Chlorthalidone n=15,255

Amlodipine n=9,048

Lisinopril n=9,054

n=13,854

n=8,215

n=8,158

2,235 (16.1%) stopped drug

1,357 (16.5%) stopped drug

1,842 (22.6%) stopped drug

n=6,210

n=3,769

n=3,605

1,873 (30.2%) stopped drug

1,052 (27.9%) stopped drug

1,399 (38.8%) stopped drug

n=15,255

n=9,048

n=9,054

339 (2.2%) lost to follow-up 80 (0.5%) refused follow-up

200 (2.2%) lost to follow-up 58 (0.6%) refused follow-up

218 (2.4%) lost to follow-up 58 (0.6%) refused follow-up

ALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT Endpoints Primary endpoint

• Composite of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI)

Other predefined endpoints − all-cause mortality − stroke − combined CHD – nonfatal MI, CHD death, coronary revascularization, hospitalized angina − combined cardiovascular disease – combined CHD, stroke, lower extremity revascularization, treated angina, fatal/ hospitalized/treated congestive heart failure, hospitalized or outpatient peripheral arterial disease − other – renal ALLHAT Research Group. JAMA. 2002;288:2981-2997.

ALLHAT Conclusions • Better control of systolic BP was achieved with

chlorthalidone than with amlodipine or lisinopril

• There were no differences in risk for CHD

death/nonfatal MI between chlorthalidone and amlodipine or lisinopril

• In secondary endpoints, chlorthalidone was associated with lower risk for

− stroke, combined CVD, and HF compared with lisinopril − HF compared with amlodipine MI=myocardial infarction

CHD=coronary heart disease

ALLHAT Research Group. JAMA. 2002;288:2981-2997.

HF=heart failure

ALLHAT Implications • Unless contraindicated, or unless specific

indications are present that would favor use of another drug class, diuretics should be the initial drug of choice in antihypertensive regimens

• Only 30 percent of patients achieve both systolic BP <140 mmHg and diastolic BP <90 mmHg on monotherapy

• Many high-risk hypertensive patients will require 2 or more drugs for BP control

ALLHAT Research Group. JAMA. 2002;288:2981-2997.

Prevention of New Onset Diabetes • Heart Outcomes Prevention Evaluation Study (HOPE)

• VALUE • LIFE

HOPE Heart Outcomes Prevention Evaluation Study Does the addition of ramipril to the ongoing and optimized medication of a broad range of 'high-risk' patients with preserved left ventricular function reduce cardiovascular morbidity and mortality? 9297 patients > 55 years old History of - CVD (CAD, stroke, PVD) or diabetes plus - at least 1 other CV risk factor: - Hypertension - Total cholesterol > 5.2 mmol/L - HDL cholesterol ≤ 0.9 mmol/L - Microalbuminuria - Current smoking

HOPE Study Investigators New Engl J Med 2000;342:145-153.

This landmark trial was halted early, after an average treatment duration of 4.5yrs, due to significant risk reductions achieved with Tritace for the primary endpoint.Time to significance : 2 years

HOPE Secondary and other outcomes Outcome

Ramipril (n = 4645)

Placebo (n = 4652)

742 (16.0%)

852 (18.3%)

0.85 (0.77-0.94)

0.002

Cardiac arrest

37 (0.8%)

59 (1.3%)

0.62 (0.41-0.94)

0.02

Hospitalisation for unstable AP

554 (11.9%)

565 (12.1%)

0.98 (0.87-1.10)

0.68

Worsening AP† 1107 (23.8%)

1220 (26.2%)

0.89 (0.82-0.96)

0.004

Revascularisation

Relative risk (95% CI)

p

Hospitalisation for HF

141 (3.0%)

160 (3.4%)

0.88 (0.70-1.10)

0.25

HF†

417 (9.0%)

535 (11.5%)

0.77 (0.67-0.87)

< 0.001

New diabetes

102 (3.6%)

155 (5.4%)

0.66 (0.51-0.85)

< 0.001

Diabetes complications*†

299 (6.4%)

354 (7.6%)

0.84 (0.72-0.98)

0.03

Total mortality

482 (10.4%)

569 (12.2%) 0.84 (0.75-0.95)

HOPE Study Investigators New Engl J Med 2000;342:145-153.

0.005

*Including nephropathy (UAE ≥ 300 mg/day), need for dialysis, retinopathy requiring laser therapy. † All cases (hospitalised and non-hospitalised).

HOPE -TOO: Additional reduction HOPE-TOO: in new -onset diabetes new-onset HOPE-TOO begins

12 Main HOPE study ends

10 New-onset diabetes (% HOPE-TOO patients)

8 6

Placebo

4

RRR 31% P = 0.0006

2

Ramipril

0 n Placebo Ramipril

2883 2837

1

2

3

4

5

6

7

2803 2763

2704 2672

2600 2587

2392 2431

1813 1853

1269 1324

1021 1092

Years

HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

Incidence of New-onset Diabetes (hypertensive, high risk patients) 18

New-Onset Diabetes (% of patients in treatment group)

16

23% Risk Reduction With Valsartan P < 0.0001

14 12 10 8 6

16.4% 13.1%

4 2 0

Valsartan-based Regimen (n = 5254)

Julius S et al. Lancet. June 2004;363:2022–31.

Amlodipine-based Regimen (n = 5168)

New -Onset Diabetes New-Onset (hypertensive patients with LVH) 0.10 0.09

Atenolol Atenolol (N=3979) Losartan (N=4019)

0.08

Endpoint Rate

0.07 0.06

Losartan

0.05 0.04 0.03 0.02

25% lower incidence in losartan group P<0.001

0.01 0.00 Study Month 0

6

12

18

24

30

36

42

48

B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002.

54

60

66

European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease Randomised, double-blind, placebo-controlled, multi-center study Stable CAD, age 18 and above with no clinical heart failure or LV systolic dysfunction with one of the below: - MI > 3 months before study entery - PCI or surgical revascularisation > 6 months before - ≥ 70% angiographic lesion of major coronary vessel or - men with angina and positive exercise, echocardiographic or nuclear stress test Aim of study To investigate whether long-term administration of the ACE inhibitor perindopril, added to standard therapy, leads to a reduction of cardiovascular events in all patients with documented coronary disease Lancet 2003; 362:782-8 Br J Cardiol 2004;11:195-204

Design Perindopril 8 mg once daily Perindopril 4 mg 8 mg

N=12 218

Placebo -1 -1/2

0

12

24

36

48

60 Months

Randomisation Run-in period

Follow-up ( study to run at least 3 years)

Primary endpoint Composite of CV death, non-fatal MI or resuscitated cardiac arrest 14

Placebo

12 10

Perindopril

8 6

RRR: 20% p = 0.0003

4 2 0 0

1

2

3

Placebo annual event rate: 2.4%

4

5 Years

Secondary Endpoint: Hospitalisation for heart failure

RRR: 39% p = 0.002

(%) 2.0

Placebo

1.5

Perindopril 1.0

0.5

0.0 0

1

2

3

4

5 Years

Stroke Prevention • • • • •

PROGRESS Study HOPE Study ASCOT Study JIKEI HEART Study LIFE Study

• To determine the effects

of an ACEI-based blood pressure lowering regimen on the risk of recurrent stroke among patients with a history of stroke or TIA.

Lancet 2001; 358: 1033-41

• History of

cerebrovascular disease within the previous 5 years

• No definite indication for treatment with an ACE inhibitor (e.g. heart failure)

Primary Endpoint: Stroke (fatal or non fatal) 0.20

28% risk reduction

Proportion with event

P<0.0001

0.15

Placebo Active*

0.10

0.05

0.00

0

1

2

*Active: Coversyl 4 mg ± Natrilix Follow-up time (years) Reference: Lancet 2001; 358: 1033-41

3

4

3/2mmHg

Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm

Reduction in fatal and nonfatal stroke N = 19,257 with hypertension and ≥3 other CV risk factors 10 8 6

RRR = 23% P = 0.0003

Proportion of events 4 (%)

Atenolol ± bendroflumethiazide Amlodipine ± perindopril

2 0 Number at risk Amlodipine-based regimen (327 events) Atenolol-based regimen (422 events)

0

1

9639

9483

9618

9461

2

4

5

9331 9156

8972

7863

9274 9059

8843

7720

3

Time (years)

Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.

6

The JIKEI HEART Study • The First Large-scale Intervention Trial of an ARB in a Japanese Population (representative of the Asian population).

• Investigator initiated, independent, investigator-led, multicentre and controlled trial

• Prospective, randomised, open-label, blinded endpoint (PROBE) morbidity-mortality study.

• 3,081 Japanese patients with heart failure, coronary heart disease, hypertension, or a combination of these cardiovascular diseases.

Seibu et al. Lancet 2007; 369: 1431-1439.

Baseline characteristics Valsartan arm (n=1,541)

Non-ARB arm (n=1,540)

1,358 (88%)

1,341 (87%)

Coronary heart disease

514 (33%)

522 (34%)

Heart failure

176 (11%)

174 (11%)

Hyperlipidaemia

812 (53%)

813 (53%)

Diabetes mellitus

315 (20%)

314 (20%)

Medical history Hypertension

Primary endpoint Combined endpoint of CV morbidity and mortality 15

Event rate (%)

Valsartan arm 92 events Non-ARB arm 149 events

10

5

39% p=0.00021 95% CI 0.47–0.79

0 0

6

12

18

24 Time

30

36

42

48

Stroke/TIA 3.5 Valsartan arm 29 events Non-ARB arm 48 events

3.0

Event rate (%)

2.5 2.0 40% 1.5 1.0 p=0.028 95% CI 0.38–0.95

0.5 0.0 0

6

12

18

24 Time

30

36

42

48

osartan IIntervention ntervention F or E ndpoint L Losartan For Endpoint Reduction in Hypertension Study • 9193 hypertensive patients with left ventricular hypertrophy (LVH)

• Compared to atenolol. • The primary endpoint was a composite of: − − −

Cardiovascular mortality Stroke Myocardial infarction

Secondary Endpoint: Fatal and Non -Fatal Stroke Non-Fatal Percent of Patients with First Event

8

Losartan Atenolol

6 4 2

Adjusted risk reduction 24.8%, p=0.001 0

0

n at risk Losartan (n) 4605 Atenolol (n) 4588

6

12 18 24 30 36 42 48 54 60 66 Study Month 4469 4424

4332 4317

4224 4180

4117 4055

1928 1901

Prevention of New Onset AF • LIFE Study • Val-Heft Study

New Onset Atrial Fibrillation Post-Hoc Analysis

No. of Events Endpoints

Los

Atl

Atrial Fibrillation by Investigator 304

360

Atrial Fibrillation by ECG

165

240

Atrial Fibrillation by Inv./ECG

346

416

Hazard Ratio (95% CI)

0.5

Favors ← Losartan

1

1.5 2 Favors Atenolol →

Addition of DIOVAN to Standard HF Therapy Significantly Reduces Incidence of AF Occurrence by 37%

Estimated probability of AF

0.15

Log rank test p=0.0001 0.10

Placebo (n=2,499)

0.05 DIOVAN 160 mg bd (n= 2,511) 0 0

2

4

6 8 10 12 14 16 18 20 Time post-randomisation (months)

AF = atrial fibrillation Val-HeFT: Valsartan in Heart Failure Trial Maggioni et al. Am Heart J 2005;149:548–57

22

24