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 PrimaryPrevention 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

-9

-47

-9

-20

-14

-23

-8.5

-19

-11

-34

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

%+

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

N=number enrolled.

TC * CHD events *

Early Primary-Prevention Trials: Overview

WHO: ClofibrateN=15,745, P<0.05

Oslo: Diet/smoking cessation N=1,232,P=0.02

Upjohn: ColestipolN=2,278, P≤0.02LRC-CPPT: CholestyramineN=3,806, P<0.05

HHS: GemfibrozilN=4,081, P<0.02

Slide SourceLipids Online Slide Librarywww.lipidsonline.org

0

5

10

15

20

25

30

Trials of Trials of FibratesFibrates: : Effects on Cardiac EventsEffects on Cardiac Events

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.

* 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).

% C

HD

Dea

th/N

onfa

tal M

I%

CH

D D

eath

/Nonfa

tal M

I Rx

Placebo

2.72.74.1***4.1***

2.72.7

8.08.0

13.613.615.015.0

13.013.0

22.322.3

17.317.3

21.7***21.7***

66%66%

34%34%

9%9%

42%42% 22%22%

PRIMARY PREVENTIONPRIMARY PREVENTION SECONDARY PREVENTIONSECONDARY PREVENTION

HHSHHS HHSHHS(Post Hoc)*(Post Hoc)*

BIPBIP BIPBIP(Post Hoc)**(Post Hoc)**

VAVA--HITHIT

DeathsDeaths 2.22.2 2.12.1 10.410.4 9.99.9 15.715.7 17.417.4

-20

-26

5

-33

-22

-31*-35-30-25-20-15-10-505

10

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

* P<0.0005.† P=0.042.‡ P=0.051.

†

TC LDL-CHDL-C

Nonfatal MI/CHD death

CHD death

All-cause mortality

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

‡

%+

N= 6595 men45 – 64 yrsMean Baseline TC= 272 mg/dLMean Baseline LDL= 192 mg/dL5 yr durationIntervention:Pravastatin 40mg dly

WOSCOPS:Nonfatal MI and CHD Death

Years

0

1

2

4

6

8

10

12

2 3 4 5 6

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

31% relativerisk reductionP < 0.001

Per

cent

Wit h

Eve

nt

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

0.05

0.04

0.03

0.02

0.01

0.00

0 1 2 3 4 5 5+

Placebo

Lovastatin

37% risk reduction(P < 0.001)

Years of follow-up

Cum

ula

tive

inci

den

ce

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

N=660545-73 yrsHealthy subjects with low HDLLovastatin 20-40 mgvs placebo

10

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

0

2

4

6

8

10

12

14

16

≤ 34 35–39 ≥ 40

Lovastatin

Placebo

Eve

nt

rate

per

1,0

00

pat

ient-

year

s at

ris

k

HDL-C (mg/dL)

-44%risk reduction

-45%risk reduction

-15%risk reduction

Downs JR et al. JAMA 1998;279:1615–1622 Slide source: lipidsonline.org

SignificanceA 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 Eligibility: MRC/BHF Heart Protection Study 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

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


Factorial Treatment ComparisonsFactorial Treatment Comparisons

Simvastatin(40 mg daily)

5 years average duration of follow5 years average duration of follow--upup

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

VS

VSPlacebo capsules

Placebo tablets

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


VascularVascularEventEvent

SimvastatinSimvastatin(10,269)(10,269)

Placebo Placebo (10,267)(10,267)

Major coronary 898 1212

Any stroke 444 585

Revascularization 939 1205

ANY OF ABOVE2033

(19.8%)2585

(25.2%)

Simvastatin: Major Vascular EventsSimvastatin: Major Vascular Events

Risk ratio and 95% CIRisk ratio and 95% CI

STATINBetter

PLACEBOBetter

24% SE 3reduction(2P<0.00001)

0.6 0.8 1.0 1.2 1.40.4

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



Major Coronary Major Coronary EventEvent



Major coronary event

Nonfatal MI 357 574

Coronary death 587 707

CORONARY EVENTS 898 (8.7%) 1212 (11.8%)

Revascularization

Coronary 513 725

Noncoronary 450 532

REVASCULARIZATIONS 939 (9.1%) 1205 (11.7%)

Simvastatin: Coronary Events and Simvastatin: Coronary Events and RevascularizationRevascularization

Risk ratio and 95% CIRisk ratio and 95% CI

STATINBetter

PLACEBOBetter


0.6 0.8 1.0 1.2 1.40.4






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

ALL STROKES 444 (4.3%) 585 (5.7%)

Simvastatin: Stroke IncidenceSimvastatin: Stroke IncidenceRisk ratio and 95% CIRisk ratio and 95% CI

STATINBetter

PLACEBOBetter


0.6 0.8 1.0 1.2 1.40.4



Cause of DeathCause of DeathSimvastatinSimvastatin

(10,269)(10,269)Placebo Placebo (10,267)(10,267)

Vascular

Coronary 587 707

Other vascular 194 230

ANY VASCULAR 781 (7.6%) 937 (9.1%)

Nonvascular

Neoplastic 359 345

Respiratory 90 114

Other medical 82 90

Nonmedical 16 21

NONVASCULAR 547 (5.3%) 570 (5.6%)

ALL CAUSES 1328 (12.9%) 1507 (14.7%)

Simvastatin: CauseSimvastatin: Cause--Specific MortalitySpecific MortalityRisk ratio and 95% CIRisk ratio and 95% CI

STATINBetter

PLACEBOBetter


5% SE 6reduction (NS) 13% SE 4

reduction(2P<0.001)

0.6 0.8 1.0 1.2 1.40.4



0

5

10

15

20

25

30

Simvastatin: Major Vascular Events by YearSimvastatin: Major Vascular Events by Year

0 1 2 4 5Years of Follow-up

63

Placebo

Simvastatin

Peo

ple

Suff

erin

g E

vents

(%

)

5 (3) 20 (4) 46 (5) 54 (7) 60 (18)35 (5)Benefit/1000 (SE):



HPS: ConclusionsHPS: 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

20Colhoun 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.

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.

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

A primary preventive study of CVD with a ‘cardiovascular equivalent’ risk factor

21

Design

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/LAged 40-75 years

Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211.

2838 patients

Atorvastatin 10 mg/day

Placebo

304 primary end points6-week placebo lead-in

prerandomization

Placebo

N =1428

N =1410

Mean follow-up of 3.7 years65% on OHA83% Hypertensive

Mean baseline LDL-C entry is 3.0 mmol/L

22

Primary End Point

RRR 37%

Years

328305

694651

10741022

13611306

13921351

AtorvaPlacebo

14281410

Placebo127 events

Atorvastatin83 events

Cum

ulat

ive

haza

rd (%

)

0

5

10

15

0 1 2 3 4 4.75

P=0.001

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

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

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.

All patients in ASCOT have hypertension plus ≥ 3 risk factors for CHD

No previous MI or current clinical CHD

Patients with risk factor (%)0 10 20 30 40 50 60 70 80 90 100

Hypertension

Age ≥ 55 years

Male

Microalbuminuria/proteinuria

Smoker

Family history of CHD

Plasma TC:HDL-C ≥ 6

Type 2 diabetes

Certain ECG abnormalities

LVH

Previous cerebrovascular events

Peripheral vascular disease

8477

6130

272424

1413

116

ASCOT patient population risk factor profileASCOT patient population risk factor profileASCOT patient population risk factor profile

100

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT): A Study in Hypertensive Patients at Low to Moderate CV Risk

The AngloThe Anglo--Scandinavian Cardiac Outcomes Trial (ASCOT): A Scandinavian Cardiac Outcomes Trial (ASCOT): A Study in Hypertensive Patients at Low to Moderate CV RiskStudy in Hypertensive Patients at Low to Moderate CV Risk

GITS=gastrointestinal therapeutic system.GITS=gastrointestinal therapeutic system.Adapted from Sever PS et al, for the ASCOT Investigators. Adapted from Sever PS et al, for the ASCOT Investigators. J J HypertensHypertens. 2001;19:1139. 2001;19:1139--1147. Sever PS et al, 1147. Sever PS et al, for the ASCOT Investigators. for the ASCOT Investigators. Lancet. Lancet. 2003;361:11492003;361:1149--1158. 1158. DahlDahlööff B et al, for the ASCOT Investigators. B et al, for the ASCOT Investigators. LancetLancet. . 2005;366:8952005;366:895--906.906.

RandomisedRandomisedN=19,257N=19,257

•• 55--year planned followyear planned follow--upup

•• Primary end point: nonfatal MI Primary end point: nonfatal MI and fatal CHDand fatal CHD

Amlodipine ± perindopril ±doxazosin GITS

Hypertensive patients with additional risk factorsHypertensive patients with additional risk factors

Atenolol ± bendroflumethiazide-K+

± doxazosin GITS

BPLA

n=5137Placebo

n=5168Atorvastatin

10 mg

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

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

Double-blind randomisationLLA

ASCOT-BPLA: Primary End Point Not Significant Due to Significant Benefit on Secondary End Point

of All-Cause Mortality

ASCOTASCOT--BPLA: BPLA: Primary End Point Not Significant Primary End Point Not Significant Due to Significant Benefit on Secondary End Point Due to Significant Benefit on Secondary End Point

of Allof All--Cause MortalityCause Mortality

0.0 1.0 2.0 3.0 4.0 5.00.0

1.0

2.0

3.0

4.0

5.0

HR=0.90 (0.79-1.02)Prop

ortio

n of

Eve

nts

(%)

Years

Atenolol Atenolol ±± bendroflumethiazidebendroflumethiazide

Amlodipine Amlodipine ±± perindoprilperindopril

Primary End Point: Nonfatal MI and Fatal CHDPrimary End Point: Nonfatal MI and Fatal CHD

6.0

Trial stoppedTrial stoppedearlyearly

PP=.1052=.1052

DahlDahlööf B et al, for the ASCOT Investigators. f B et al, for the ASCOT Investigators. LancetLancet. 2005;366:895. 2005;366:895--906.906.

ASCOT-BPLA: Reduction in fatal and nonfatal stroke

ASCOTASCOT--BPLA: BPLA: Reduction in fatal and nonfatal strokeReduction in fatal and nonfatal stroke

Number at riskAmlodipine-based regimen 9639 9483 9331 9156 8972 7863(327 events)Atenolol-based regimen 9618 9461 9274 9059 8843 7720(422 events)

Proportionof events

(%)

6

2

4

01 2 3 4

8

10

50Time (years)

6

Atenolol-based regimen*Amlodipine-based regimen†

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

Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366

VBWG

*Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn†Amlodipine 5–10 mg ± perindopril 4–8 mg prn

ASCOT-LLA: 36% RRR in Nonfatal MI and Fatal CHD When Atorvastatin Added to BP TreatmentASCOTASCOT--LLA: 36% RRR in Nonfatal MI and Fatal LLA: 36% RRR in Nonfatal MI and Fatal CHD When Atorvastatin Added to BP TreatmentCHD When Atorvastatin Added to BP Treatment

00

11

22

33

44

HR=0.64 (0.50-0.83)Prop

ortio

n of

Pat

ient

s (%

) Atorvastatin 10 mg (n=5168)

Originally planned length of trial: 5 yearsOriginally planned length of trial: 5 years

Actual length of trial: median 3.3 yearsActual length of trial: median 3.3 years

Trial stopped earlyTrial stopped earlyPP=.0005=.0005

Placebo (n=5137)

RRR=relative risk reduction.RRR=relative risk reduction.Sever PS et al for the ASCOT Investigators. Sever PS et al for the ASCOT Investigators. Lancet. Lancet. 2003;361:11492003;361:1149--1158. Sever PS et al, for the 1158. Sever PS et al, for the ASCOT Investigators. ASCOT Investigators. Am J Cardiol. Am J Cardiol. 2005;96:39F2005;96:39F--44F.44F.

Years0.0 0.5 1.0 1.5 2.0 2.5 3.0 5.03.3

Significant Significant benefits benefits

observed in observed in 90 days90 days

ASCOT-LLA: 27% RRR in Fatal and Nonfatal Stroke When Atorvastatin Added to

BP Treatment

ASCOTASCOT--LLA: 27% RRR in Fatal and Nonfatal LLA: 27% RRR in Fatal and Nonfatal Stroke When Atorvastatin Added to Stroke When Atorvastatin Added to

BP TreatmentBP TreatmentAtorvastatin 10 mg (n=5168)Placebo (n=5137)

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

Years0.0 0.5 1.0 1.5 2.0 2.5 3.0 5.03.5

HR=0.73 (0.56-0.96)

Trial stopped earlyTrial stopped earlyPP=.0236=.0236

Prop

ortio

n of

Eve

nts

(%)

Prop

ortio

n of

Eve

nts

(%)

00

11

22

33

ASCOT: SummaryASCOT: SummaryASCOT: Summary

•• AmlodipineAmlodipine ±± perindoprilperindopril based therapy confers an based therapy confers an advantage over advantage over atenololatenolol ±± thiazidethiazide based therapy on all based therapy on all major CV end points, allmajor CV end points, all--cause mortality and newcause mortality and new--onset onset diabetesdiabetes

•• Compared with standard antihypertensive therapy without Compared with standard antihypertensive therapy without statinstatin therapy, the therapy, the amlodipineamlodipine ±± perindoprilperindopril regimen plus regimen plus atorvastatinatorvastatin reduced coronary and stroke events by almost reduced coronary and stroke events by almost 50%50%

•• StatinStatin therapy should be considered in hypertensive patients therapy should be considered in hypertensive patients with multiple risk factors and no history of CAD irrespective ofwith multiple risk factors and no history of CAD irrespective oftheir initial cholesterol values.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 StudyVA-HIT Study

•• Study designStudy design−− DoubleDouble--blind, placeboblind, placebo--controlled trial controlled trial −− 2531 men with CHD2531 men with CHD, , HDLHDL--C C ≤≤ 40, 40,

LDLLDL--CC ≤≤ 140, and TG 140, and TG ≤≤ 300300

•• Study interventionStudy intervention−− Gemfibrozil 1200 mg/day or placeboGemfibrozil 1200 mg/day or placebo

•• Primary endpointPrimary endpoint−− Nonfatal MI or death from coronary causesNonfatal MI or death from coronary causes

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

VA-HIT Study (cont.)VA-HIT Study (cont.)

ResultsResults•• Median followMedian follow--up, 5.1 yearsup, 5.1 years•• Primary endpoint reached in 21.7% of placebo Primary endpoint reached in 21.7% of placebo

group and 17.3% of gemfibrozil groupgroup and 17.3% of gemfibrozil group–– 22% relative risk reduction in CHD death (22% relative risk reduction in CHD death (PP = =

0.07) and 23% reduction in nonfatal MI (0.07) and 23% reduction in nonfatal MI (PP = = 0.02)0.02)

–– 24% relative risk reduction in combined 24% relative risk reduction in combined outcome outcome of CHD death, nonfatal MI, or confirmed stroke of CHD death, nonfatal MI, or confirmed stroke ((PP ≤≤ 0.001)0.001)

•• ↑↑ HDLHDL--C 6%C 6%•• ↓↓ TG 31%TG 31%•• No change in LDLNo change in LDL--CC

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

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

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

25

22

19

16

13

1024 28 32 36 40 44 80 95 110 125 140 155

HDL-C

5-Y

ear C

HD

Eve

nt R

ate,

% LDL-C

Quintile Trial Concentrations, mg/dLGemfibrozilPlacebo

VA-HIT: Beneficial Effects of Gemfibrozil Are UnexplainedVA-HIT: Beneficial Effects of Gemfibrozil Are Unexplained

Analysis of Lipid ParametersAnalysis of Lipid Parameters•• LDLLDL--C (baseline or on treatment) did not predict eventsC (baseline or on treatment) did not predict events

•• TG (baseline or on treatment) did not predict eventsTG (baseline or on treatment) did not predict events

•• Increases in HDLIncreases in HDL--C account for part of the benefitC account for part of the benefit−− 5 mg/dL increase in HDL5 mg/dL increase in HDL--C decreases RR by 11%C decreases RR by 11%−− HDLHDL--C increased 2 mg/dL but RR decreased 22%C increased 2 mg/dL but RR decreased 22%

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

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

CLINICAL TRIALS IN HYPERTENSIONCLINICAL TRIALS IN HYPERTENSIONCLINICAL TRIALS IN HYPERTENSION

•• Systolic Hypertension in Europe Trial (Systolic Hypertension in Europe Trial (SystSyst--EurEur))

•• Systolic Hypertension in the Elderly Program Trial Systolic Hypertension in the Elderly Program Trial (SHEP)(SHEP)

•• ASCOTASCOT--BPLABPLA

Syst-Eur trial SystSyst--Eur trial Eur trial

•• 4695 patients over age 59 with a mean initial sitting blood pres4695 patients over age 59 with a mean initial sitting blood pressure of sure of 174/86 randomnized to therapy with placebo or nitrendipine plus,174/86 randomnized to therapy with placebo or nitrendipine plus, if if necessary, enalapril and hydrochlorothiazide necessary, enalapril and hydrochlorothiazide

•• The fall in blood pressure was greater with active therapy, 23/7The fall in blood pressure was greater with active therapy, 23/7 versus versus 13/2 mmHg13/2 mmHg

•• At four years, significant reductions were noted in stroke (7.9 At four years, significant reductions were noted in stroke (7.9 versus versus 13.7 total endpoints per 1000 patient years), and fatal and non13.7 total endpoints per 1000 patient years), and fatal and non--fatal fatal cardiac endpointscardiac endpoints

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

Syst-Eur trial - contSystSyst--Eur trial Eur trial -- contcont

•• Mortality increased with a higher systolic blood Mortality increased with a higher systolic blood pressure.pressure.

•• More More pronounced in the subset of patients with diabetespronounced in the subset of patients with diabetes

-- mortality reduced 55%mortality reduced 55%

-- cardiovascular events reduced 26%cardiovascular events reduced 26%

-- strokes reduced 38%strokes reduced 38%

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

Prevention of Dementia in ISH: Syst-Eur Trial

Prevention of Dementia in ISH: Prevention of Dementia in ISH: SystSyst--EurEur Trial Trial

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

Systolic Hypertension in the Elderly Program (SHEP) trial

Systolic Hypertension in the Elderly Systolic Hypertension in the Elderly Program (SHEP) trialProgram (SHEP) trial

•• 4736 patients with mean entry BP of 170/77 randomized to 4736 patients with mean entry BP of 170/77 randomized to chlorthalidone and placebo. chlorthalidone and placebo.

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

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

The Systolic Hypertension in the Elderly Program

The The SSystolic ystolic HHypertension in ypertension in the the EElderly lderly PProgramrogram

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

Cohort 4,736; 43% men

Age ≥ 60 yrs old; mean 71.6 yrs old

Eligibility 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

The Antihypertensive and Lipid-Lowering Treatment

to Prevent Heart Attack Trial

The The AAntihypertensive and ntihypertensive and LLipidipid--LLowering Treatment owering Treatment

to Prevent to Prevent HHeart eart AAttack ttack TTrialrialALLHAT study overviewALLHAT study overviewDoubleDouble--blind, randomized trial to determine whether theblind, randomized trial to determine whether theoccurrence of fatal CHD or nonfatal MI is lower for highoccurrence of fatal CHD or nonfatal MI is lower for high--risk risk hypertensive patients treated with newer agents (amlodipine,hypertensive patients treated with newer agents (amlodipine,lisinopril, or doxazosin) compared with a diuretic (chlorthalidolisinopril, or doxazosin) compared with a diuretic (chlorthalidone)ne)

CohortCohort•• 42,418 patients (42,418 patients (≥≥55 years old) from 623 sites in North America55 years old) from 623 sites in North America

−− Stage 1 or 2 hypertension Stage 1 or 2 hypertension −− 1 additional risk factor for CHD1 additional risk factor for CHD

•• Comparisons between chlorthalidone and amlodipine and Comparisons between chlorthalidone and amlodipine and chlorthalidone and lisinopril have been reported together, chlorthalidone and lisinopril have been reported together, excluding the doxazosin arm (n=9,062), which was terminated excluding the doxazosin arm (n=9,062), which was terminated earlyearly

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

CHD=coronary heart disease; MI=myocardial infarction

ALLHAT Study DesignALLHAT Study DesignALLHAT Study Design

n=13,854n=13,8542,235 (16.1%) stopped drug

Chlorthalidone Chlorthalidone n=15,255n=15,255

AmlodipineAmlodipinen=9,048n=9,048

Randomizedn=42,418

n=15,255 n=15,255 339 (2.2%) lost to follow-up80 (0.5%) refused follow-up

n=9,048n=9,048200 (2.2%) lost to follow-up58 (0.6%) refused follow-up

n=6,210n=6,2101,873 (30.2%) stopped drug

n=9,054 n=9,054 218 (2.4%) lost to follow-up58 (0.6%) refused follow-up

n=8,215n=8,2151,357 (16.5%) stopped drug

n=3,769n=3,7691,052 (27.9%)stopped drug

YEAR 1n=8,158n=8,158

1,842 (22.6%) stopped drug

n=3,605n=3,6051,399 (38.8%) stopped

drug

LisinoprilLisinopriln=9,054n=9,054

YEAR 5


Intent-to-Treat

Analysis

Doxazosinn=9,062

Discontinuedearly at 3.3 yrs

ALLHAT EndpointsALLHAT EndpointsALLHAT Endpoints

Primary endpointPrimary endpoint•• Composite of fatal coronary heart disease (CHD) or nonfatal Composite of fatal coronary heart disease (CHD) or nonfatal

myocardial infarction (MI)myocardial infarction (MI)

Other predefined endpointsOther predefined endpoints−− allall--cause mortalitycause mortality−− strokestroke−− combined CHD combined CHD –– nonfatal MI, CHD death, coronary nonfatal MI, CHD death, coronary

revascularization, hospitalized anginarevascularization, hospitalized angina−− combined cardiovascular disease combined cardiovascular disease –– combined CHD, stroke, combined CHD, stroke,

lower extremity revascularization, treated angina, fatal/ lower extremity revascularization, treated angina, fatal/ hospitalized/treated congestive heart failure, hospitalized or hospitalized/treated congestive heart failure, hospitalized or outpatient peripheral arterial diseaseoutpatient peripheral arterial disease

−− other other –– renalrenal


ALLHAT ConclusionsALLHAT ConclusionsALLHAT Conclusions

•• Better control of systolic BP was achieved with Better control of systolic BP was achieved with chlorthalidonechlorthalidone than with than with amlodipineamlodipine or or lisinoprillisinopril

•• There were no differences in risk for CHD There were no differences in risk for CHD death/nonfatal MI between death/nonfatal MI between chlorthalidonechlorthalidone and and amlodipineamlodipine or or lisinoprillisinopril

•• In secondary endpoints, In secondary endpoints, chlorthalidonechlorthalidone was was associated with lower risk for associated with lower risk for −− stroke, combined CVD, and HF compared with stroke, combined CVD, and HF compared with

lisinoprillisinopril−− HF compared with HF compared with amlodipineamlodipine

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

ALLHAT ImplicationsALLHAT ImplicationsALLHAT Implications

•• Unless contraindicated, or unless specific Unless contraindicated, or unless specific indications are present that would favor use of indications are present that would favor use of another drug class, diuretics should be the initial another drug class, diuretics should be the initial drug of choice in antihypertensive regimensdrug of choice in antihypertensive regimens

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

•• Many highMany high--risk hypertensive patients will require risk hypertensive patients will require 2 or more drugs for BP control2 or more drugs for BP control


Prevention of New Onset DiabetesPrevention of New Onset DiabetesPrevention of New Onset Diabetes

•• Heart Outcomes Prevention Evaluation Study Heart Outcomes Prevention Evaluation Study (HOPE)(HOPE)

•• VALUEVALUE

•• LIFELIFE

HOPEHeart Outcomes Prevention Evaluation

Study

HOPEHOPEHeart Outcomes Prevention Evaluation Heart Outcomes Prevention Evaluation

StudyStudyDoes the addition of ramipril to the ongoing and optimized Does the addition of ramipril to the ongoing and optimized medication of a broad range of medication of a broad range of 'high'high--risk' patientsrisk' patients with with

preserved left ventricular functionpreserved left ventricular function reduce cardiovascular reduce cardiovascular morbidity and mortality?morbidity and mortality?

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

9297 patients > 55 years oldHistory 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

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

HOPESecondary and other outcomes

HOPEHOPESecondary and other outcomesSecondary and other outcomes

*Including nephropathy (UAE ≥ 300 mg/day), need for dialysis, retinopathy requiring laser therapy.

†All cases (hospitalised and non-hospitalised).

Outcome Ramipril Placebo Relative risk p(n = 4645) (n = 4652) (95% CI)

Diabetes 299 (6.4%) 354 (7.6%) 0.84 (0.72-0.98) 0.03complications*†

Revascular- 742 (16.0%) 852 (18.3%) 0.85 (0.77-0.94) 0.002isationCardiac arrest 37 (0.8%) 59 (1.3%) 0.62 (0.41-0.94) 0.02

Hospitalisationfor unstable AP 554 (11.9%) 565 (12.1%) 0.98 (0.87-1.10) 0.68Worsening AP† 1107 (23.8%) 1220 (26.2%) 0.89 (0.82-0.96) 0.004

HF† 417 (9.0%) 535 (11.5%) 0.77 (0.67-0.87) < 0.001

Hospitalisationfor HF 141 (3.0%) 160 (3.4%) 0.88 (0.70-1.10) 0.25

New diabetes 102 (3.6%) 155 (5.4%) 0.66 (0.51-0.85) < 0.001

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

Total mortality 482 (10.4%) 569 (12.2%) 0.84 (0.75-0.95) 0.005

HOPE-TOO: Additional reduction in new-onset diabetesHOPEHOPE--TOO: Additional reduction TOO: Additional reduction in newin new--onset diabetesonset diabetes

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

12

4

6

2

0

1 2 3 4

8

10

5 6 7

Placebo

Ramipril

Years

RRR 31% P = 0.0006

HOPE-TOO begins

Main HOPE study ends

28832837

28032763

27042672

26002587

23922431

18131853

12691324

10211092

New-onsetdiabetes

(% HOPE-TOO patients)

PlaceboRamipril

n

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

New

-On

set

Dia

bete

s (%

of

pati

ents

in

trea

tmen

t gr

oup)

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

0

2

4

6

8

10

12

14

Valsartan-based Regimen

(n = 5254)

Amlodipine-based Regimen

(n = 5168)

13.1%

16.4%

23% Risk Reduction With Valsartan

16

18

P < 0.0001

New-Onset Diabetes(hypertensive patients with LVH)NewNew--Onset DiabetesOnset Diabetes

(hypertensive patients with LVH)(hypertensive patients with LVH)

Losartan

AtenololAtenolol (N=3979)Losartan (N=4019)

Study Month 0 6 12 18 24 30 36 42 48 54 60 660.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

25% lower incidence in losartan groupP<0.001

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

Endp

oint

Rat

e

European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease

Lancet 2003; 362:782-8Br J Cardiol 2004;11:195-204

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 studyAim of studyTo investigate whether longTo investigate whether long--term administrationterm administration

of the ACE inhibitor perindopril, added toof the ACE inhibitor perindopril, added tostandard therapy, leads to a reduction ofstandard therapy, leads to a reduction ofcardiovascular events in all patients withcardiovascular events in all patients with

documented coronary diseasedocumented coronary disease

DesignDesignDesign

PlaceboPlacebo00 1212 2424--1/21/2--11

MonthsMonths3636 4848

RunRun--in periodin period

RandomisationRandomisation

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

4 mg4 mg 8 mg8 mgPerindoprilPerindopril

Perindopril 8 mg once dailyPerindopril 8 mg once daily

6060

N=12 218

Primary endpointPrimary endpointPrimary endpoint

Composite of CV death, nonComposite of CV death, non--fatal MI or resuscitated cardiac arrestfatal MI or resuscitated cardiac arrest

Placebo annual event rate: 2.4%Placebo annual event rate: 2.4%

Perindopril Perindopril

PlaceboPlacebo

p = 0.0003p = 0.0003RRR: 20%RRR: 20%

YearsYears00

22

44

66

88

1010

1212

1414

00 11 22 33 44 55

Secondary Endpoint:Hospitalisation for heart failure

Secondary Endpoint:Secondary Endpoint:Hospitalisation for heart failureHospitalisation for heart failure

Perindopril Perindopril

PlaceboPlacebo

5500 11 22 33 44 YearsYears

p = 0.002p = 0.002RRR: 39%RRR: 39%

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0(%)(%)

Stroke PreventionStroke PreventionStroke Prevention

•• PROGRESS StudyPROGRESS Study

•• HOPE StudyHOPE Study

•• ASCOT StudyASCOT Study

•• JIKEI HEART StudyJIKEI HEART Study

•• LIFE StudyLIFE Study

•• To determine the effects To determine the effects of an ACEIof an ACEI--based based blood blood pressure loweringpressure loweringregimen on the risk of regimen on the risk of recurrent stroke among recurrent stroke among patients with a history of patients with a history of stroke or TIA.stroke or TIA.

•• History of History of cerebrovascular cerebrovascular disease within the disease within the previous 5 yearsprevious 5 years

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

Lancet 2001; 358: 1033-41

Prop

ortio

n w

ith e

vent

PlaceboActive*

0.20

0.15

0.10

0.05

0.000 1 2 3

Follow-up time (years)4

28% risk reduction

P<0.0001

*Active: Coversyl 4 mg ± NatrilixReference: Lancet 2001; 358: 1033-41

Primary Endpoint:Stroke (fatal or non fatal)

3/2mmHg

Reduction in fatal and nonfatal strokeReduction in fatal and nonfatal strokeReduction in fatal and nonfatal stroke

Number at riskAmlodipine-based regimen 9639 9483 9331 9156 8972 7863(327 events)Atenolol-based regimen 9618 9461 9274 9059 8843 7720(422 events)

Proportionof events

(%)

6

2

4

03 4

8

1 2

10

50Time (years)

6

Atenolol ±bendroflumethiazideAmlodipine ± perindopril

RRR = 23%P = 0.0003

A

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

nglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm

N = 19,257 with hypertension and ≥3 other CV risk factors

The JIKEI HEART StudyThe JIKEI HEART StudyThe JIKEI HEART Study•• The First LargeThe First Large--scale Intervention Trial of an ARB in a Japanese scale Intervention Trial of an ARB in a Japanese

Population (representative of the Asian population).Population (representative of the Asian population).

•• Investigator initiated, Investigator initiated, independentindependent, investigator, investigator--led, multicentre and led, multicentre and controlled trialcontrolled trial

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

•• 3,081 Japanese patients with heart failure, coronary heart disea3,081 Japanese patients with heart failure, coronary heart disease, se, hypertension, or a combination of these cardiovascular diseases.hypertension, or a combination of these cardiovascular diseases.

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

Baseline characteristicsBaseline characteristicsBaseline characteristics

Medical history

Valsartan arm

(n=1,541)

Non-ARB arm(n=1,540)

Hypertension 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%)

Primary endpointCombined endpoint of CV morbidity and

mortality

Primary endpointPrimary endpointCombined endpoint of CV morbidity and Combined endpoint of CV morbidity and

mortalitymortality

0 6 12 18 24 30 36 42 48Time

15

10

5

0

Even

t rat

e (%

)

Valsartan arm 92 eventsNon-ARB arm 149 events

p=0.0002195% CI 0.47–0.79

39%

Stroke/TIAStroke/TIAStroke/TIA

0 6 12 18 24 30 36 42 48Time

40%

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Even

t rat

e (%

)

Valsartan arm 29 eventsNon-ARB arm 48 events

p=0.02895% CI 0.38–0.95

Losartan Intervention For Endpoint Reduction in Hypertension Study

LLosartan osartan IIntervention ntervention FFor or EEndpoint ndpoint Reduction in Hypertension StudyReduction in Hypertension Study

•• 9193 hypertensive patients with left ventricular 9193 hypertensive patients with left ventricular hypertrophy (LVH)hypertrophy (LVH)

•• Compared to atenolol. Compared to atenolol.

•• The primary endpoint was a composite of:The primary endpoint was a composite of:−− Cardiovascular mortality Cardiovascular mortality −− StrokeStroke−− Myocardial infarctionMyocardial infarction

Secondary Endpoint:Fatal and Non-Fatal Stroke

Secondary Endpoint:Secondary Endpoint:Fatal and NonFatal and Non--Fatal StrokeFatal Stroke

0 6 12 18 24 30 36 42 48 54 60 66Study Month

0

2

4

6

8Pe

rcen

t of P

atie

nts

Losartan (n) 4605 4469 4332 4224 4117 1928n at risk

Atenolol (n) 4588 4424 4317 4180 4055 1901

with

Firs

t Eve

nt

Adjusted risk reduction 24.8%, p=0.001

LosartanAtenolol

Prevention of New Onset AFPrevention of New Onset AFPrevention of New Onset AF

•• LIFE StudyLIFE Study

•• ValVal--Heft StudyHeft Study

New Onset Atrial Fibrillation New Onset Atrial Fibrillation New Onset Atrial Fibrillation

Post-Hoc Analysis

Atrial Fibrillation

Atrial Fibrillation by ECG

Atrial Fibrillation by Inv./ECG

Endpoints

No. of Events

by Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigatorby Investigator

Los

304

165

346

Atl

360

240

416416416416416416416416416416416416416

0.5 1 1.5 2Favors Favors

Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)Hazard Ratio (95% CI)

← Losartan Atenolol →

Addition of DIOVAN to Standard HF Therapy Significantly Reduces Incidence of AF

Occurrence by 37%

Addition of DIOVAN to Standard HF Therapy Addition of DIOVAN to Standard HF Therapy Significantly Reduces Incidence of AF Significantly Reduces Incidence of AF

Occurrence by Occurrence by 37%37%Es

timat

ed p

roba

bilit

y of

AF

Time post-randomisation (months)0 126 8 10 14 16 18

0.05

0.15

DIOVAN 160 mg bd (n= 2,511)

242 4 20 22

0.10Log rank test p=0.0001

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

0

Placebo (n=2,499)

landmark trials in preventive cardiology

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