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
Oslo: Diet/smoking
TC * CHD events * cessation N=1,232,
0 P=0.02
-5 WHO: Clofibrate
-10 -9 -9 -8.5 N=15,745, P<0.05
-11
-15 -14 Upjohn: Colestipol
-20 -19
-20 N=2,278, P≤0.02
%+ -25 -23 LRC-CPPT:
-30 Cholestyramine
-35 -34 N=3,806, P<0.05
-40
HHS: Gemfibrozil
-45 N=4,081, P<0.02
-50 -47

N=number enrolled.

* Net difference between treatment and control groups

(P values are for events).
 Trials of Fibrates: Effects on Cardiac Events
42%
30 Rx 22%
% CHD Death/Nonfatal MI

25 Placebo 9%
22.3 21.7***

17.3
20 15.0
66% 13.6 13.0
15
34%
8.0
10
4.1***
2.7 2.7
5
0
HHS HHS BIP BIP VA-HIT
(Post Hoc)* (Post Hoc)**
Deaths 2.2 2.1 10.4 9.9 15.7 17.4
PRIMARY PREVENTION 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 Slide Source
1992;85:37-45. | BIP Study Group. Circulation 2000;102:21-27. | Rubins HB et al. Lipids Online Slide Library
www.lipidsonline.org
N Engl J Med 1999;341:410-418.
WOSCOPS: Effects of Lipid Lowering on Coronary
Events in Primary Prevention Trial in Men
10 Nonfatal
5 MI/CHD CHD All-cause
5
TC LDL-C death death mortality
0
HDL-C
-5 N= 6595 men
-10 45 – 64 yrs
%+ Mean Baseline TC
-15 = 272 mg/dL
-20 Mean Baseline LDL
-20 ‡ = 192 mg/dL
-25
-22 5 yr duration
-30 -26 Intervention:
-35 † Pravastatin 40mg dly
-31*
-33
* P<0.0005.
† P=0.042.
‡ P=0.051.

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

 WOSCOPS:
Nonfatal MI and CHD Death

12
Placebo (n=3293)
10
Percent With Event

Pravastatin (n=3302) 31%

relative
8
risk
reduction
6 P < 0.001

1 2 3 4 5 6
Years

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

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

0.07

0.06
37% risk reduction
Cumulative incidence

0.05 (P < 0.001)

Placebo

0.04

0.03
Lovastatin
0.02

0.01
N=6605
0.00 45-73 yrs
Healthy subjects with
0 1 2 3 4 5 5+ low HDL
Years of follow-up
Lovastatin 20-40 mg
vs placebo
Downs JR et al. JAMA 1998;279:1615–1622
Copyright ©1998, American Medical Association.
Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS)
Event Rates by Baseline HDL-C Tertile

-45%
16
risk reduction -44%
14 risk reduction
Lovastatin
Event rate per 1,000
patient-years at risk

12
-15% Placebo
10 risk reduction

8
6
4
2
0
≤ 34 35–39 ≥ 40
HDL-C (mg/dL)

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

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: MRC/BHF Heart
Protection 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

Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
www.lipidsonline.org
Factorial Treatment Comparisons

Simvastatin Placebo
VS
(40 mg daily) tablets

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

5 years average duration of follow-up

Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
www.lipidsonline.org
Simvastatin: Major Vascular Events
Risk ratio and 95% CI
Vascular Simvastatin Placebo STATIN PLACEBO
Event (10,269) (10,267) Better Better

Major coronary 898 1212

25% SE 5
Any stroke 444 585 reduction
(2P<0.00001)
Revascularization 939 1205

24% SE 3
2033 2585
ANY OF ABOVE reduction
(19.8%) (25.2%) (2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
Reprinted with permission from Elsevier Science. www.lipidsonline.org
Simvastatin: Coronary Events and
Revascularization
Risk ratio and 95% CI
Major Coronary Simvastatin Placebo STATIN PLACEBO
Event (10,269) (10,267) Better Better

Major coronary event

Nonfatal MI 357 574

Coronary death 587 707

27% SE 4
CORONARY EVENTS 898 (8.7%) 1212 (11.8%) reduction
(2P<0.00001)

Revascularization
Coronary 513 725
Noncoronary 450 532
24% SE 4
reduction
REVASCULARIZATIONS 939 (9.1%) 1205 (11.7%) (2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
www.lipidsonline.org
Reprinted with permission from Elsevier Science.
Simvastatin: Stroke Incidence
Risk ratio and 95% CI
Simvastatin Placebo STATIN PLACEBO
(10,269) (10,267) Better Better
Type
Ischemic 290 409
Hemorrhagic 51 53
Unknown 103 134

Severity
Fatal 96 119
Severe 42 51
Moderate 107 155
Mild 138 189
Unknown 61 71
25% SE 5
reduction
ALL STROKES 444 (4.3%) 585 (5.7%) (2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
www.lipidsonline.org
Reprinted with permission from Elsevier Science.
Simvastatin: Cause-Specific Mortality
Risk ratio and 95% CI
Simvastatin Placebo STATIN PLACEBO
Cause of Death (10,269) (10,267) Better Better
Vascular
Coronary 587 707
Other vascular 194 230
17% SE 4
ANY VASCULAR 781 (7.6%) 937 (9.1%) reduction
(2P<0.0001)
Nonvascular
Neoplastic 359 345
Respiratory 90 114
Other medical 82 90
Nonmedical 16 21
5% SE 6
NONVASCULAR 547 (5.3%) 570 (5.6%) reduction
(NS) 13% SE 4
reduction
ALL CAUSES 1328 (12.9%) 1507 (14.7%) (2P<0.001)

0.4 0.6 0.8 1.0 1.2 1.4

Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
www.lipidsonline.org
Reprinted with permission from Elsevier Science.
 Simvastatin: Major Vascular Events by Year
People Suffering Events (%)

30

25
Placebo
20

15 Simvastatin

10

0
0 1 2 3 4 5 6
Years of Follow-up
Benefit/1000 (SE): 5 (3) 20 (4) 35 (5) 46 (5) 54 (7) 60 (18)
Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
www.lipidsonline.org
Reprinted with permission from Elsevier Science.
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.
20
Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211.
 Design
Atorvastatin 10 mg/day N=
1428
Placebo 2838
patients
N=
Placebo 1410
6-week placebo lead-in
prerandomization 304 primary end points

Patient population:
„ Type 2 diabetes with no previous MI or CHD
„ Mean follow-up of 3.7 years
„ ≥1 other CHD risk factor plus LDL-C ≤4.14 mmol/L
„ 65% on OHA
and TG ≤6.78 mmol/L
„ 83% Hypertensive
„ Aged 40-75 years

Mean baseline LDL-C entry is 3.0 mmol/L

21
Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211.
 Primary Endpoint:
-Acute CHD death Primary End Point
-Nonfatal MI, including silent
MI
-Unstable angina
15 -CABG or other coronary
revascularization Placebo
Cumulative hazard (%)

-Resuscitated cardiac arrest

RRR 37% 127 events
-Stroke
10 P=0.001
Atorvastatin
83 events
5

0
0 1 2 3 4 4.75 Years
Placebo 1410 1351 1306 1022 651 305
Atorva 1428 1392 1361 1074 694 328

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

Hypertension 100
Age ≥ 55 years 84
Male
77
Microalbuminuria/proteinuria
61
Smoker
30
Family history of CHD
27
Plasma TC:HDL-C ≥ 6 24
Type 2 diabetes 24
Certain ECG abnormalities
14
LVH 13
Previous cerebrovascular events
11
Peripheral vascular disease
6
0 10 20 30 40 50 60 70 80 90 100
Patients with risk factor (%)
 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 ± Atenolol ± bendroflumethiazide-K+
doxazosin GITS ± doxazosin GITS

Eligible for lipid-lowering arm

Not eligible for lipid-lowering arm
(TC ≤6.5 mmol/L [≤250 mg/dL]) (n=10,305)
(TC >6.5 mmol/L [>250 mg/dL])
LLA Double-blind randomisation

• 5-year planned follow-up

n=5168
n=5137
Atorvastatin
Placebo
• Primary end point: nonfatal MI
10 mg 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
5.0 Atenolol ± bendroflumethiazide Trial stopped
early
Proportion of Events (%)

Amlodipine ± perindopril P=.1052

4.0

3.0

2.0

1.0
HR=0.90 (0.79-1.02)
0.0
0.0 1.0 2.0 3.0 4.0 5.0 6.0
Years
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%
6 P = 0.0003
Proportion
of events 4
(%)
2 Atenolol-based
Amlodipine-based
regimen* regimen†
0
0 1 2 3 4 5 6
Time (years)
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
4
Atorvastatin 10 mg (n=5168)
Proportion of Patients (%)

Placebo (n=5137)
3
Trial stopped early
P=.0005
2

1
Significant
benefits HR=0.64 (0.50-0.83)
observed in
90 days 0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.3 5.0
Years
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)
3 Placebo (n=5137)
Proportion of Events (%)

Trial stopped early

P=.0236
2

HR=0.73 (0.56-0.96)

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 5.0
Years

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

25 HDL-C LDL-C
5-Year CHD Event Rate, %

22

19

16

13

10
24 28 32 36 40 44 80 95 110 125 140 155

Quintile Trial Concentrations, mg/dL

Gemfibrozil
Placebo

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

 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 Systolic H
Systolic ypertension in
Hypertension
the Elderly P
Elderly rogram
Program
Cohort 4,736; 43% men
Age ≥ 60 yrs old; mean 71.6 yrs old
Systolic BP 160−219 mmHg and
Eligibility
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
Heart ttack T
Attack rial
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 Discontinued Randomized
early at 3.3 yrs
n=9,062 n=42,418

Chlorthalidone Amlodipine Lisinopril

n=15,255 n=9,048 n=9,054

n=13,854 n=8,215 n=8,158

YEAR 1 2,235 (16.1%) 1,357 (16.5%) 1,842 (22.6%) stopped
stopped drug stopped drug drug

n=6,210 n=3,769 n=3,605

YEAR 5 1,873 (30.2%) 1,052 (27.9%) 1,399 (38.8%) stopped
stopped drug stopped drug drug

Intent-to-
n=15,255 n=9,048 n=9,054
Treat 339 (2.2%) lost to follow-up 200 (2.2%) lost to follow-up 218 (2.4%) lost to follow-up
Analysis 80 (0.5%) refused follow-up 58 (0.6%) refused 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 HF=heart failure

ALLHAT Research Group. JAMA. 2002;288:2981-2997.
 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 Placebo Relative risk p
(n = 4645) (n = 4652) (95% CI)
Revascular- 742 (16.0%) 852 (18.3%) 0.85 (0.77-0.94) 0.002
isation
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
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 299 (6.4%) 354 (7.6%) 0.84 (0.72-0.98) 0.03
complications*†
Total mortality 482 (10.4%) 569 (12.2%) 0.84 (0.75-0.95) 0.005

*Including nephropathy (UAE ≥ 300 mg/day), need for

dialysis, retinopathy requiring laser therapy.
HOPE Study Investigators New Engl J Med 2000;342:145-153. †
All cases (hospitalised and non-hospitalised).
 HOPE -TOO: Additional reduction
HOPE-TOO:
in new-onset diabetes
new-onset
12 HOPE-TOO begins
Main HOPE
10 study ends

New-onset 8
diabetes
(% HOPE-TOO 6 Placebo
patients)
4
RRR 31%
P = 0.0006
2
Ramipril
0

n 1 2 3 4 5 6 7 Years
Placebo 2883 2803 2704 2600 2392 1813 1269 1021
Ramipril 2837 2763 2672 2587 2431 1853 1324 1092

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

 Incidence of New-onset Diabetes
(hypertensive, high risk patients)
23% Risk Reduction
18 With Valsartan
16 P < 0.0001
14
New-Onset Diabetes

treatment group)
(% of patients in

12
10
16.4%
8
13.1%
6
4
2
0
Valsartan-based Amlodipine-based
Regimen Regimen
(n = 5254) (n = 5168)

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

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

0.09
Atenolol
0.08 Atenolol (N=3979)
Losartan (N=4019)
0.07
Endpoint Rate

0.06

0.05 Losartan
0.04

0.03

0.02
25% lower incidence in losartan group
0.01 P<0.001

0.00
Study Month 0 6 12 18 24 30 36 42 48 54 60 66
B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002.
 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

12 Placebo
10
Perindopril
8

4 RRR: 20%
2 p = 0.0003

0
0 1 2 3 4 5 Years

Placebo annual event rate: 2.4%

 Secondary Endpoint:
Hospitalisation for heart failure

(%) 2.0 RRR: 39% Placebo

p = 0.002
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 • No definite indication
stroke or TIA.
• History of
cerebrovascular
disease within the
previous 5 years
for treatment with an
ACE inhibitor (e.g.
heart failure)

Lancet 2001; 358: 1033-41

 Primary Endpoint:
Stroke (fatal or non fatal)

0.20
28% risk reduction
P<0.0001
Proportion with event

0.15
Placebo
Active*
0.10

0.05

0.00
0 1 2 3 4
*Active: Coversyl 4 mg ± Natrilix Follow-up time (years)
Reference: Lancet 2001; 358: 1033-41
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

6 RRR = 23%
Proportion P = 0.0003
of events 4
(%)
Atenolol ±
2 bendroflumethiazide
Amlodipine ± perindopril
0
0 1 2 3 4 5 6
Time (years)
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)

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

 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
Non-ARB arm
arm
Medical history (n=1,540)
(n=1,541)
Hypertension 1,358 (88%) 1,341 (87%)
Coronary heart
514 (33%) 522 (34%)
disease
Heart failure 176 (11%) 174 (11%)
Hyperlipidaemia 812 (53%) 813 (53%)
Diabetes mellitus 315 (20%) 314 (20%)
 Primary endpoint
Combined endpoint of CV morbidity and
mortality
15
Valsartan arm 92 events
Non-ARB arm 149 events

10
Event rate (%)

5 39%

p=0.00021
95% CI 0.47–0.79

0
0 6 12 18 24 30 36 42 48
Time
 Stroke/TIA

3.5
Valsartan arm 29 events
3.0 Non-ARB arm 48 events

2.5
Event rate (%)

2.0
40%
1.5

1.0
p=0.028
0.5 95% CI 0.38–0.95

0.0
0 6 12 18 24 30 36 42 48
Time
 Losartan IIntervention
Losartan ntervention For E
For ndpoint
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
8
Losartan
Atenolol
Percent of Patients

6
with First Event

2
Adjusted risk reduction 24.8%, p=0.001
0
0 6 12 18 24 30 36 42 48 54 60 66
n at risk Study Month
Losartan (n) 4605 4469 4332 4224 4117 1928
Atenolol (n) 4588 4424 4317 4180 4055 1901
Prevention of New Onset AF

• LIFE Study
• Val-Heft Study
 New Onset Atrial Fibrillation
Post-Hoc Analysis

No. of Events
Endpoints Los Atl Hazard Ratio (95% CI)

Atrial Fibrillation by Investigator 304 360

Atrial Fibrillation by ECG 165 240
Atrial Fibrillation by Inv./ECG 346 416

0.5 1 1.5 2
Favors Favors
← Losartan Atenolol →
 Addition of DIOVAN to Standard HF Therapy
Significantly Reduces Incidence of AF
Occurrence by 37%
0.15
Estimated probability of AF

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 22 24
Time post-randomisation (months)
AF = atrial fibrillation
Val-HeFT: Valsartan in Heart Failure Trial
Maggioni et al. Am Heart J 2005;149:548–57