Trials of ace inhibitors

Trials of ACE inhibitors and ARB’s in Myocardial infarction and Heart

failure

Dharam Prakash Saran

7.2. Renin-Angiotensin-Aldosterone System Inhibitors

Class I

1. An angiotensin-converting enzyme inhibitor should be administered within the first 24 hours to all patients

with STEMI with anterior location, HF, or ejection fraction less than or equal to 0.40, unless

contraindicated.174–177 (Level of Evidence: A)

2. An angiotensin receptor blocker should be given to patients with STEMI who have indications for but are

intolerant of angiotensin-converting enzyme inhibitors. 178,179 (Level of Evidence: B)

3. An aldosterone antagonist should be given to patients with STEMI and no contraindications who are

already receiving an angiotensin-converting enzyme inhibitor and beta blocker and who have an ejection

fraction less than or equal to 0.40 and either symptomatic HF or diabetes mellitus.180 (Level of Evidence:B)

Class Iia

1. Angiotensin-converting enzyme inhibitors are reasonable for all patients with STEMI and no

contraindications to their use.181–183 (Level of Evidence: A)

ACE Inhibitor ARB

HYPERTENSION ALLHAT

PROGRESS

LIFE

VALUE

CAD HOPE

EUROPA

PEACE

ONTARGET

VALUE

ACS SAVE

AIRE

TRACE

GISSI 3

ISIS 4

VALIANT

OPTIMAAL

HEART FAILURE CONSESUS

SOLVD

ATLAS

CHARM

I-PRESERVE

ValHeFT

ACE InhibitorMI Mortality Trials

Selective(higher risk, long term)

SAVE (EF 40%)

AIRE (clinical HF)

TRACE (wall motion score, EF 35%)

Broad (short term)

CONSENSUS II

GISSI-3

ISIS-4

SAVE TRIAL 1992Survival and Ventricular Enlargement Trial

Design:

Randomized placebo controlled trial.

Patients:

Total - 2231 randomly selected, 3 to 16 days after MI.

All with EF < 40% (by MUGA Scan) and no symptoms of heart failure - Class 1 to 2.

1115 recieved Captopril1116 recieved placebo.

Inclusion Criteria:

1987 to 1990 b/n 21 and 80 years of age, both sex

• Exclusion Criteria:

Failure to randomize with in 16 days of MISerum Cr > 2.5Contraindication or allergy to ACEIAnother reason to use the ACEI like HTN or CHF symptoms.Unwillingness to participate.Unstable course after MIRecurrent ischemia with in 72 hour after MI.

Average Follow-up: 42 months..

• REPEAT MUGA SCAN TO ASSES LV EJECTION FRACTION AT AN AVERAGE OF 36

MONTHS OF TIME.

Dosage:

Starting 6.25 to 12.5 tds and gradually increased to 25 tds at the time of discharge with a target dose of 50 tds.

End Points:

Primary - All cause mortality - reduced by 5 percent (20 versus 25% in placebo)

Secondary - Risk Reductions:

Death from Cardiovascular Causes - 21% risk reduction.CHF requiring hospitalization - 22% risk reductionRecurrent MI - 25% reduction in riskDeath from CV causes or MI - 22% risk reductionDeath from Cv causes, CHF or MI - 24% risk reduction.

• Conclusions:

In patient who had a recent MI addition of ACEI (Captopril) reduces all cause mortality and morbidity even on top of standard beta blockers, aspirin and nitrates.

Importance:

First trial to show mortality and morbidity reduction by ACEI in post-MI patient with LVEF of < 40% without HF symptoms.

AIRE: Acute Infarction Ramipril Efficacy study

Purpose

To determine whether the ACE inhibitor ramipril reduces mortality in patients with evidence of heart failure after MI

Design

Multicenter, multinational, randomized, double-blind, placebo-controlled

Patients

2006 patients, aged >18 years, with evidence of heart failure 3–10 days after MI;

patients with severe heart failure (usually NYHA class IV) or ongoing ischemia excluded

Follow up and primary endpoint

Average 15 months follow up. Primary endpoint all-cause mortality

Treatment

Placebo or ramipril initiated at 2.5 mg twice daily; increased to 5 mg twice daily after 2 days if tolerated

AIRE: Acute Infarction Ramipril Efficacy study- RESULTS -

• Significant reduction in all-cause mortality in ramipril group compared with placebo (17 vs. 23%, relative risk reduction 23%, P=0.002)

• Reduction in mortality apparent as early as 30 days and consistent across a wide range of subgroups

• Fewer patients in ramipril group developed severe/resistant heart failure

• No significant reduction in reinfarction or stroke

AIRE: Acute Infarction Ramipril Efficacy study- RESULTS continued-

Months after randomization

0

0

1004

982

Ramipril

Placebo

No. at risk

889

845

592

575

290

287

123

98

45

44

6 12 18 24 30

15

10

5

35

30

25

20

All-cause mortality

Placebo

Ramipril

Cumulative

mortality(%)

Relative hazard 0.73 (95% CI 0.60–0.89)P=0.002

AIRE Study Investigators. Lancet 1993;342:821–8.

AIRE: Acute Infarction Ramipril Efficacy study - SUMMARY -

In patients with non-severe heart failure after MI, ramipril started 3–10 days after MI and continued for a mean 15-month period:

• Significantly reduced all-cause mortality

• Conferred benefit independent of age, sex, hypertension, angina or concomitant therapy

• No significant reduction in reinfarction or stroke

TRACE (1995)Trandolapril Cardiac Evaluation Study

A clinical trial of the trandolapril in patients with left ventricular dysfunction after myocardial

infarction.

BACKGROUND:

• Treatment with ACE inhibitors reduces mortality among survivors of acute myocardial infarction, but whether to use ACE inhibitors in all patients or only in selected patients is uncertain.

METHODS:

• Screened 6676 consecutive patients with 7001 myocardial infarctions confirmed by enzyme studies.

• A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction, < or = 35%).

• On days 3 to 7 after infarction, 1749 patients were randomly assigned to receive oral trandolapril (876 patients) or placebo (873 patients).

• Trandolapril 1 mg daily initial dose, up to 4 mg daily vs placebo.

• The duration of follow-up was 24 to 50 months.

CONCLUSIONS:

• Long-term treatment with trandolapril in patients with reduced left ventricularfunction soon after myocardial infarction significantly reduced the risk of overallmortality, mortality from cardiovascular causes, sudden death, and thedevelopment of severe heart failure but not that of recurrent myocardialinfarction.

TRACEEchocardiographicEF 35%

AIREClinical and/or radiographic signs of HF

SAVERadionuclideEF 40%

SAVE AIRE TRACE

DURATION 1987-1990 1989-1992 1991-1993

DRUG CAPTOPRIL RAMIPRIL TRANDOLAPRIL

Target dose 50 mg tds 5 mg bd 4 mg od

NO. OF PATIENTS 2231 Patients 2006 patients 1749 patients

SELECTION DAY 3 to 16 days after MI 3 to 10 days after MI 3 to 7 days after infarction

SELECTION CRITERIA EF < 40% (by

Radionucleotide MUGA

Scan) and no symptoms of

heart failure

Patients with evidence of

heart failure (Clinical or

Radiographic)

Echocardiographic evidence

of left ventricular systolic

dysfunction (ejection

fraction, < or = 35%).

AGE GROUP b/n 21 and 80 years >18 years of age

Average Follow-up 42 months 15 months 24 to 50 months

Effects of ACE Inhibition in Early Myocardial Infarction: Results of GISSI-3

The third Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico

(GISSI-3) study was a controlled, randomized, multicenter, open study undertaken to

investigate the effects of early intervention (within 24 h of symptom onset) with an

angiotensin-converting enzyme (ACE) inhibitor in the management of acute myocardial

infarction (MI).

A total of 19,394 patients were treated with oral lisinopril 10 mg/day, glyceryl

trinitrate (GTN) (intravenous followed by transdermal 10 mgday) or their

combination for 6 weeks.

VALIANT TRIALVALsartan In Acute myocardial iNfarcTion

AimsVALIANT was designed as a mortality trial in high-risk MI patients who

derived particular benefits from an ACE inhibitor (SAVE, AIRE, TRACE).To determine whether:

• the ARB valsartan was superior to captopril in improving survival

and

• the addition of the ARB valsartan to captopril was superior to the proven dose of captopril in improving survival

If valsartan was not superior to captopril, a non-inferiority analysis was prespecified to determine whether valsartan could be considered “as effective as” captopril

Primary Endpoint: All-Cause Mortality

Secondary Endpoints: CV Death, MI, or HF

Other Endpoints: Safety and Tolerability

Captopril 50 mg tid(n = 4909)

Valsartan 160 mg bid(n = 4909)

Captopril 50 mg tid + Valsartan 80 mg bid

(n = 4885)

Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible(either clinical/radiologic signs of HF or LV systolic dysfunction)

ExExclusion:— Serum creatinine > 2.5 mg/dL— BP < 100 mm Hg— Prior intolerance of an ARB or ACE-I— Nonconsent

median duration: 24.7 months

Cap 6.25 mg

Val 20 mg

Cap 12.5 mg

Val 20 mg

Cap 25 mg

Val 40 mg

Cap 50 mg (tid)

Val 80 mg (bid)

COMBINATION

Cap 6.25 mg

Cap 12.5 mg

Cap 25 mg

Cap 50 mg (tid)

CAPTOPRIL (tid)

Val 20 mg

Val 40 mg

Val 80 mg

Val 160 mg (bid)

VALSARTAN (bid)

Step I

GOAL by 3 months

Step IVStep IIIStep II

Study DrugDose Titration

Am Heart J. 2000;140:727–734.

Captopril

0

0.05

0.1

0.15

0.2

0.25

0.3

0 6 12 18 24 30 36

Pro

ba

bil

ity o

f E

ve

nt

Mortality by Treatment

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

Valsartan 4909 4464 4272 4007 2648 1437 357

Months

Valsartan vs. Captopril: HR = 1.00; P = 0.982

Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726

Captopril 4909 4428 4241 4018 2635 1432 364

Valsartan + Cap 4885 4414 4265 3994 2648 1435 382

Valsartan

Valsartan + Captopril

Mortality in SAVE,TRACE, AIRE, and VALIANT

Hazard Ratio for Mortality

FavorsActive Drug

FavorsPlacebo


0.5 1 2

Combined

TRACE

SAVE

AIRE

VALIANT

Valsartan

preserves

99.6% of

mortality

benefit of

captopril.

Captopril

CV Death, MI, or HFby Treatment


Months

Valsartan vs. Captopril: HR = 0.96; P = 0.198

Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.369

0

0.1

0.2

0.3

0.4

0 6 12 18 24 30 36

Pro

ba

bil

ity o

f E

ve

nt

Valsartan

Valsartan + Captopril

Conclusion

In patients with MI complicated by heart failure, leftventricular dysfunction or both:

Valsartan is as effective as a proven dose of captopril in reducing the risk of:

—Death

—CV death or nonfatal MI or heart failure admission

Combining valsartan with a proven dose of captopril produced no further reduction in mortality—and more adverse drug events.

Implications:In these patients, valsartan is a clinically effectivealternative to an ACE inhibitor.

ACE Inhibitor ARB

HYPERTENSION ALLHAT

PROGRESS

LIFE

VALUE

CAD HOPE

EUROPA

PEACE

ONTARGET

VALUE

ACS SAVE

AIRE

TRACE

GISSI 3

ISIS 4

VALIANT


SOLVD

ATLAS

CHARM

I-PRESERVE

ValHeFT

Class I

1. ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, unless

contraindicated, to reduce morbidity and mortality (343, 412-414). (Level of Evidence: A)

7.3.2.3. ARBs: Recommendations

Class I

1. ARBs are recommended in patients with HFrEF with current or prior symptoms who areACE

inhibitor intolerant, unless contraindicated, to reduce morbidity and mortality (108, 345, 415,

450). (Level of Evidence:A)

Class IIa

1. ARBs are reasonable to reduce morbidity and mortality as alternatives to ACE inhibitors as

firstline

therapy for patients with HFrEF, especially for patients already taking ARBs for other

indications, unless contraindicated (451-456). (Level of Evidence: A)

Class llb

1. Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are

already being treated with an ACE inhibitor and a beta blocker in whom an aldosterone

antagonist is not indicated or tolerated (420, 457). (Level of Evidence: A)

Class III: Harm

1. Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially

harmful for patients with HFrEF. (Level of Evidence: C)

Landmark trials with ACE inhibitors in HF

Trial n EF% Drug Death Hospitalisation Follow up NNT

(death)

CONSENSUS

1987

253 <35%

(IV)

enalapril 36 vs 50 reduced 1 year 6

SOLVD-P

1992

4228 <35

(I)

enalapril trend to

reduction

reduced 4 years 104

SOLVD – T

1991

2500 < 40

(II-III)

enalapril 12.3 vs 15.5 reduced 3 years 31

ATLAS

1997

3164 <35

(II-IV)

lisinopril no difference reduced 4 years -

The CONSENSUS trial

• NEJM 1987

• Show prognostic improvement by an ACE inhibitor.

• STUDIED TREATMENT: Enalapril (2.5 to 40 mg per day)

• CONTROL TREATMENT: Placebo

The CONSENSUS trial

• RANDOMIZED EFFECTIVES: 127/126 (Enp. vs Cnt.)

• DESIGN: Parallel Groups

• TYPE: Double Blind

• DURATION: 188 days

• AREA: Finland, Sweeden, Norway

• PRIMARY ENDPOINT: Mortality

Method and design

• Severe congestive heart failure (new york heart association [NYHA] functional class IV)

PATIENTS

ISCHEMIC ORIGIN: 73%

FEMALE: 30%

AGE: 70

DILATED CARDIOMYOPATHY: 16%

HYPERTENSION: 21%

• Mortality was reduced by 31 percent at one year

• A significant improvement in NYHA classification was observed in the enalaprilgroup, together with a reduction in heart size and a reduced requirement for other medication for heart failure.

• the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms.

RESULTS

• Surviving CONSENSUS patients were followed for an additional 10 years after termination of the trial, at which time five patients remained alive, all from the enalapril group.

SOLVDEffect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure

SOLVD

• Enalapril vs placebo in 6,794 patients

• Ejection fraction < 35%

• End points include:

– Delaying the progression of heart failure

– Improving signs and symptoms

– Reducing mortality

• Treatment arm - 2,568 symptomatic class II-III patients most on digitalis and diuretics

• Prevention arm - 4,226 asymptomatic class I-II patients, most on no concomitant therapy

N Engl J Med 1991:325:293-302

SOLVD Treatment Trial

All Cause Mortality

0

10

20

30

40

50

0 6 12 18 24 30 36 42 48

Months

Mo

rtal

ity%

Placebo

Enalapril

N Engl J Med 1991;325:293-302

16% Risk Reduction

p = 0.0036

Benefits of Enalapril

• Patients: Symptomatic HF patients with LVD (EF < 35%)

• 11% reduction of overall mortality at end of study (P=0.0036)

The SOLVD Investigators, N Engl J Med. 1991;325:293


Mortality or Hospitalization for CHF

0

10

20

30

40

50

60

70

0 6 12 18 24 30 36 42 48

Months

Even

ts %

Placebo

Enalapril

N Engl J Med 1991;325:293-302

26% Risk Reduction

p<0.0001


• Implications:

– Treating 1,000 patients for 3 years

• Prevents about 50 deaths

• Prevents about 350 hospitalizations

SOLVD Treatment Trial Conclusions

• Hospitalizations:

– Risk reduced by 20% (p<0.001)

– Significant reduction in CHF hospitalization by 1/3 (p<0.0001)

– Sustained benefit over 4 years

N Engl J Med 1991;325:293-302

SOLVD Prevention Trial

All Cause Mortality

0

5

10

15

20

25

0 6 12 18 24 30 36 42 48

Months

Mort

alit

y fr

om

All

Cause

s (%

)

Placebo

EnalaprilRisk Reduction 8%

P=0.30

N Engl J Med 1992;327:685-91


Death or Development of CHF

0

5

10

15

20

25

30

35

40

45

50

0 6 12 18 24 30 36 42 48

Months of Follow-up

% E

ven

ts

Placebo

Enalapril

Risk Reduction 29%

p<0.001

N Engl J Med 1992;327:685-91


First Hospitalization for CHF

0

2

4

6

8

10

12

14

16

18

0 6 12 18 24 30 36 42 48

Months of Follow-up

% E

ven

ts

Placebo

Enalapril

Risk Reduction 36%

p<0.001

N Engl J Med 1992;327:685-91


Morbidity and Combined Outcomes

Endpoint Placebo %

Enalapril %

RR P value

Development of CHF 30.2 20.7 37% <0.001

Development of CHF and anti-CHF Rx

22.5 13.9 43% <0.001

First Hospitalization for CHF 12.9 8.7 36% <0.001

Multiple Hospitalization for CHF

4.8 2.7 44% <0.001

Death or Development of CHF 38.6 29.8 29% <0.001

Death or Hospitalization for CHF

24.5 20.6 20% <0.001

Comparative Effects of Low and High Doses of the Angiotensin-Converting

Enzyme Inhibitor, Lisinopril, on Morbidity and Mortality in Chronic Heart

Failure

ATLAS Study

Background

Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by

physicians in doses lower than the large doses that have been shown to reduce

morbidity and mortality in patients with heart failure.

It is unclear, however, if low doses and high doses of ACE inhibitors have similar

benefits.

Methods

3164 patients with New York Heart Association class II to IV heart failure

an ejection fraction <30%

double-blind treatment with either low doses (2.5 to 5.0 mg daily, n51596) or high

doses (32.5 to 35 mg daily, n51568) of the ACE inhibitor, lisinopril, for 39 to 58

months,

while background therapy for heart failure was continued.

When compared with the low-dose group, patients in the high-dose group had a

•Nonsignificant 8% lower risk of death (P=0.128) but

•A significant 12% lower risk of death or hospitalization for any reason (P=0.002)

and

•24% fewer hospitalizations for heart failure (P=0.002).

•Dizziness and renal insufficiency was observed more frequently in the high-dose

group, but

•The 2 groups were similar in the number of patients requiring discontinuation of

the study medication.

Results

Patients with heart failure should not generally be maintained on very low doses of

an ACE inhibitor (unless these are the only doses that can be tolerated)

The difference in efficacy between intermediate and high doses of an ACE inhibitor

(if any) is likely to be very small.

Conclusions

Candesartan in Heart Failure

CHARM Trial

CHARM Added

Patients with LVEF

<40% and treated with an

ACE-inhibitor

CHARM Alternative

Patients with LVEF

<40% and ACE-inhibitor

intolerant

Endpoints (follow-up minimum 2 years):

Primary – Component trials: cardiovascular mortality or CHF

hospitalization

Primary – Overall trial results: All-cause mortality

CHARM Trial

European Society of Cardiology 2003

7,601 patients with heart failure

3 Individual component randomized trials with the ARB candesartan (4

or 8 mg/day, titrated to target dose of 32 mg) or placebo

CHARM Preserved

Patients with LVEF

>40% with or without

ACE-inhibitor

CHARM Overall Program

All-cause mortalityHR 0.91

95% CI 0.83-1.00

p=0.055

23.3%24.9%

0%

10%

20%

30%

Candesartan Placebo

30.2%

34.5%

0%

10%

20%

30%

40%

Candesartan Placebo


CV Mortality or

CHF HospitalizationHR 0.84

p<0.0001

CHARM Added Trial

CV Mortality or

CHF hospitalizationHR 0.85

p=0.011

37.9%

42.3%

0%

10%

20%

30%

40%

50%

Candesartan Placebo

23.7%

27.3%

0%

10%

20%

30%

Candesartan Placebo


CV MortalityHR 0.84

p=0.02

CHARM Alternative Trial

CV Mortality or


p=0.0004

33.0%

40.0%

0%

10%

20%

30%

40%

50%

Candesartan Placebo

21.6%

24.8%

0%

10%

20%

30%

Candesartan Placebo


CV MortalityHR 0.85

p=0.072

CHARM Preserved Trial

CV Mortality or


p=0.118

22.0%

24.3%

0%

10%

20%

30%

Candesartan Placebo

11.2% 11.3%

0%

5%

10%

15%

Candesartan Placebo


CV MortalityHR 0.99

p=0.918

ACE Inhibitors and ARB in HFpEF

Class IIa

The use of beta-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is

reasonable to control blood pressure in patients with HFpEF. (Level of Evidence: C)

Class IIb

1. The use of ARBs might be considered to decrease hospitalizations for patients with HFpEF (589).

(Level of Evidence: B)

Thank you

Chart showing randomized clinical trials on ACE inhibitors from CHF to coronary artery disease.

Latini R et al. Circulation. 1995;92:3132-3137

Copyright © American Heart Association, Inc. All rights reserved.

Effects of an Angiotensin-Converting Enzyme Inhibitor, Ramipril, on Death from

Cardiovascular Causes, Myocardial

Infarction, and Stroke in High-Risk Patients

The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators

N Engl J Med, January 20, 2000

HOPE - Background

• ACEIs improve the outcome in patients with LV dysfunction, whether or not they have symptomatic heart failure.

• This study assessed the role of an ACEI, ramipril, in patients who were at high risk for cardiovascular events but who did not have LV dysfunction or heart failure.


HOPE (Heart Outcome Prevention Evaluation)

• 9297 Patients

• Age >55

• DM + 1 other CV factor

• Normal EF (>40%)

• Ramipril (10mg) vs. Placebo

HOPE (Primary endpoints)

• Death (CV) - 6.1 vs 8.1 P<0.001 RR=0.75

• MI - 9.9 vs 12.2 P<0.001 RR=0.80

• Stroke - 3.4 vs 4.9 P<0.001 RR=0.69

HOPE - Design

• A total of 9,297 high-risk patients,

• > 55 years old,

• who had evidence of vascular disease

• or diabetes plus one other cardiovascular risk factor and who were not known to have a low EF or heart failure were randomly assigned to receive ramipril (10 mg per day) or matching placebo for a mean of 5 years.

• The primary outcome was a composite of MI, stroke or death from cardiovascular causes.

• Secondary endpoints were death from any cause, the need for revascularization, hospitalization for unstable angina or heart failure, and complications related to diabetes.


HOPE - Kaplan-Meier Estimates of the Composite Endpoint of CV Death, MI or Stroke in the Ramipril and

Placebo Groups

0

0.05

0.1

0.15

0.2

0 500 1000 15000

Days of Follow-up

% o

f P

atie

nts

Ramipril

Placebo


P<0.001

HOPE - Primary Endpoint Results

14.1

6.1

9.9

3.44.3

10.4

17.7

8.1

12.2

4.94.1

12.2

0

5

10

15

20

25%

with a

n e

vent

Ramipril

Placebo

MI/Stroke/

CV Death

CV Death MI Stroke Total

Mortality

22% Risk Reduction

p<0.001

25% Risk Reduction

p<0.001

20% Risk Reduction

p=<0.001

31% Risk Reduction

p=<0.001

16% Risk

Reduction

p=0.006


Non CV Death

0% Risk Reduction

p=0.78

HOPE - Secondary and Other Endpoint Results

16

6.2

3.3

9.2

3.7

18.6

7.4

3.8

11.7

5.3

0

5

10

15

20

25%

with a

n e

vent

Ramipril

Placebo

Revascularization DM

Complications

New diagnosis of

Diabetes Mellitus

16% Risk Reduction

p<0.001

16% Risk Reduction

p=0.03

23% Risk Reduction

p<0.001

HF

Hospitalization

Heart Failure


13% Risk Reduction

p=0.19

32% Risk Reduction

p=0.002

HOPE - Results in Patients with Diabetes

Endpoint Ramipril Placebo RR P value

n=1808 n=1770

Primary Endpoint 15.3% 19.6% 0.76 0.0007

CV Death 6.0% 9.6% 0.62

G. Dagenais, ESC 1999

HOPE - Results in Patients with Diabetes

15.3

6

19.6

9.6

0

5

10

15

20

25%

with a

n e

vent

Ramipril

Placebo

MI/Stroke/CV Death CV Death

34% Risk Reduction

p=0.0007

38% Risk Reduction

G. Dagenais, ESC 1999

HOPE - Summary of Results

• Patients randomized to ramipril had risk reductions of:

MI, stroke, CV death -22%

CV death -25%

MI -20%

Stroke -31%

Revascularization procedures* -16%

New onset of diabetes -32%

*Revascularization procedures included PTCA, CABG or peripheral angioplasty


HOPE - Summary of Results (continued)

• The beneficial effect of treatment with ramipril on the composite outcome was consistently observed among the following predefined subgroups:

patients with and without diabetes

men and women

those with and without evidence of cardiovascular disease

those < 65 years of age and those > 65 year of age

those with and without hypertension at baseline*

those with and without microalbuminuria

*A reduction of 2 mm Hg in diastolic blood pressure (as seen in this trial) might at best

account for about 40% of the reduction in the rate of stroke and about 25% of the reduction of MI.


HOPE - Conclusions

• “Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure”


CV mortality + non fatal MI + cardiac arrest

Primary endpoint

Secondary endpoints

Total mortality + non fatal MI + unstable angina +

cardiac arrest

Heart failure

Revascularisation (PCI/CABG)

Stroke

Design

Placebo

0 12 24-1/2-1

Run-in period

Randomisation

Follow-up

Months36 48

4 mg 8 mg

Perindopril

Perindopril 8 mg once daily

60

Selection criteria

Male or female > 18 years of age

Documented coronary disease

Not scheduled for revascularisation

No clinical signs of heart failure

Documented coronary disease

Previous MI > 3 months

PCI / CABG > 6 months

Angiographic evidence ( 70% stenosis)

In males with chest pain: positive exercise or

stress test

Primary endpoint

% CV death, MI or cardiac arrest

Placebo annual event rate: 2.4%

Perindopril

Placebop = 0.0003

RRR: 20%

Years

0

2

4

6

8

10

12

14

0 1 2 3 4 5

Primary and first secondary endpoint

0.5 1.0 2.0

20

14

22

46

14

RRR (%)Perindopril

better

Placebo

better

CV mortality, MI, CA

CV mortality

Non fatal MI

Cardiac arrest

Total mortality, MI, UAP,CA

Fatal and non fatal MI

Perindopril

Placebo

0

2

4

6

8

10

0 1 2 3 4 5 Years

(%)

p < 0.001

RRR: 24%

Heart Failure

Perindopril

Placebo

50 1 2 3 4 Years

p = 0.002

RRR: 39%

0.0

0.5

1.0

1.5

2.0(%)

-1 -1/2 0 3 6 12 18 24 30 36 42 48 54 60

Months

70

80

90

100

110

120

130

140

mmHg

Blood pressure

SBP: 5 mmHg

DBP: 2 mmHg

Perindopril 8mg Placebo

Summary of results

In EUROPA, the largest and longest trial of stable,

low risk CAD patients, perindopril 8 mg/d

significantly reduced:

CV mortality + non fatal MI + cardiac arrest: 20%

CV mortality and non fatal MI: 19%

Fatal + non fatal MI: 24%

Heart failure: 39%

Summary of results

Benefits occurred on top of recommended therapy (92% platelet inhibitors, 58% lipid

lowering drugs, 62% -blockers) and are consistent across predefined sub-groups

Perindopril should be considered for chronic therapy in all patients with coronary

disease

The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial

A double-blind, placebo-controlled, randomized trial

Sponsored by the National Heart, Lung, and Blood Institute

Inclusion Criteria

• Age 50 years

• Coronary artery disease

MI, or

CABG or PCI, or

Coronary angiogram with obstruction of 50% luminal diameter in at least one native vessel

• LVEF > 40%

• Tolerated 2 week run-in of 2 mg/day trandolapril

1º OutcomeCV Death, MI, CABG, or PCI

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0 1 2 3 4 5 6

Years from Randomization

Inci

den

ce o

f P

rim

ary

Ou

tcom

e

Placebo

Trandolapril

Number of Patients

Placebo 4132 3992 3722 3491 3034 1941 906

Active 4158 4019 3758 3515 3093 1981 985

HR=0.96 (95% CI, 0.88-1.06) P=0.43

PEACE was conducted in a population with CAD and preserved LV function who received intensive contemporary management.

— This usually included coronary revascularization, lipid lowering and blood pressure control

In this population, which represents the majority of patients with CAD, the addition of an ACE inhibitor did not reduce further clinical atherosclerotic events.

Conclusions

Conclusions

In patients with stable CHD and preserved LV function who are receiving contemporary management, there is no evidence of further benefit from the addition of an ACE inhibitor for

CV death, MI or coronary revascularization.

0

5

10

15

20

0 1 2 3 4 5

HOPE, placebo

HOPE, active drug (ramipril)

PEACE, placebo

ACE Inhibitor Evidence: Secondary Prevention

Comparison between the HOPE and PEACE trials

Patients enrolled in the PEACE trial were at lower risk*

MI,

Car

dia

c dea

th,

or

Str

oke

(%)

The PEACE Trial Investigators. NEJM 2004;351:2058-68

CHD=Coronary heart disease, MI=Myocardial infarction

*Reflects better blood pressure control, revascularization, and use of other risk-reducing medications (i.e., antiplatelet

therapy, -blocker, lipid-lowering medication)

Years

ONTARGET

• Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events

• Effects of ARB, ACE-Inhibitors, combination therapy in death from cardiovascular causes, MI, stroke, or hospitalization for heart failure.

ONTARGET

ONTARGET

• 29,019 patients were recruited from 733 centers in 40 countries.

Single-Blind run in-period

2.5mg ramipril daily x 3days

40mg telmisartan and 2.5mg ramipril daily x 7 days

5mg ramipril and 40mg telmisartan x 11-18 days

ONTARGET• Blood pressure

Telmisartin and combination group maintained slightly lower blood pressure levels

• Serum Creatinine

Number of patients with increased levels was similar in three groups

• Potassium

Similar number of patients with levels more then 5.5 mmmol per liter in monotherapy groups. (283/287)

Significantly higher levels in combination group

480 patients

p=<0.001

ONTARGET

• Primary Outcomes

1412 (16.5%) in Ramipril group,

1423 (16.7%) patients in Telmisartan group

1386 (16.3) patients in combination group

ONTARGET

Telmisartan was noninferior to Ramipril, nor was it superior

Upper boundary of CI for RR of primary outcome was lower then predetermined (noninferiority)

Lower boundary of CI (not superior)

No significant difference in total number of deaths between mono therpaygroups.

Higher number of deaths in combination group, but not statistically significant.

Kaplan-Meier Curves for the Primary Outcome in the Three Study Groups

104

ACE Inhibitor ARB

HYPERTENSION ALLHAT

PROGRESS

LIFE

VALUE

CAD HOPE

EUROPA

PEACE

ONTARGET

VALUE

ACS SAVE

AIRE

TRACE

GISSI 3

ISIS 4

VALIANT


SOLVD

CHARM

I-PRESERVE

ValHeFT

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

JAMA 2002;288:2981-2997

ALLHAT

42,418 patients with hypertension SBP >140mmHg and/or DBP >90 mmHg OR

Took medication for hypertension and had at least one additional risk factor for CHD

Age >55 years

NHLBI funded trial

Diuretic

Chlorthalidone

12-25 mg/day (n=15,255)

Endpoints:

Primary – Fatal coronary heart disease and nonfatal MI

Secondary – All-cause mortality, stroke, and major cardiovascular

disease events (CHF, coronary revascularization, angina, and

peripheral artery disease)

Mean follow-up 4.9 years

JAMA 2002;288:2981-2997

Calcium Channel Blocker

Amlodipine

2.5-10 mg/day

(n=9,048)

ACE Inhibitor Lisinopril

10-40 mg/day

(n=9,054)

Alpha Blocker

Doxazosin*

2-8 mg/day

(n=9,061)

* Discontinued prior to study completion

ALLHAT: Primary Endpoint*

11.5% 11.3%

0%

5%

10%

15%

Chlorthalidone vs Amlodipine

Primary Endpoint

RR = 0.98

p = 0.65

Chlorthalidone

JAMA 2002;288:2981-2997

Amlodipine

11.5% 11.4%

0%

5%

10%

15%

* Primary Endpoint = Fatal CHD or nonfatal MI

Chlorthalidone vs Lisinopril

Primary Endpoint

RR = 0.99

p = 0.81

Chlorthalidone Lisinopril

ALLHAT: Secondary Endpoints

17.3% 16.8%

0%

5%

10%

15%

20%

All Cause Mortality

RR = 0.96

p = 0.20

Chlorthalidone

JAMA 2002;288:2981-2997

Amlodipine

7.7%

10.2%

0%

5%

10%

15%

Heart Failure

RR = 1.38

p < 0.001

Chlorthalidone Amlodipine

Chlorthalidone vs Amlodipine

5.6%

6.3%

0%

2%

4%

6%

8%

10%

ALLHAT: Secondary Endpoints

17.3% 17.2%

0%

5%

10%

15%

20%

All Cause Mortality

RR = 1.00

p = 0.90

Chlorthalidone

JAMA 2002;288:2981-2997

Lisinopril

7.7%

8.7%

0%

5%

10%

15%

Heart Failure

RR = 1.19

p < 0.001

Chlorthalidone vs Lisinopril

Chlorthalidone Lisinopril Chlorthalidone Lisinopril

Stroke

RR = 1.15

p = 0.02

Second Australian National Blood Pressure Study (ANBP-2)

• Enalapril/ACEI vs. HCTZ, n = 6,083

• Randomized, open-label (blinded endpoint review)

110NEJM 2003;348:583-92

Second Australian National Blood Pressure Study (ANBP-2)

• All CV events or death from any cause

HR = 0.89 (0.79-1.00), p=0.05

• First events

CVD: HR = 0.88 (0.77-1.01), p = 0.07

CHD: HR = 0.86 (0.70-1.06), p = 0.16

Stroke: HR = 1.02 (0.78-1.33), p = 0.91

HF: HR = 0.85 (0.62-1.18), p = 0.33

111NEJM 2003;348:583-92

The LIFE Trial

Losartan Intervention For Endpoint reduction in hypertension study (LIFE)

Patients with hypertension (blood pressure 160-200/ 95-115 mm Hg)

and left ventricular hypertrophy

Atenolol

Beta-blockerDose titrated to BP <140/90 mm Hg

(n=4,588)

Losartan

Angiotensin II antagonist Dose titrated to BP <140/90 mm Hg

(n=4,605)

Followed for >4 years - Mean follow-up 4.8 years

Cardiovascular death, MI, stroke

LIFE: Study Design

11.0%

12.8%

0%

5%

10%

15%

Losartan Atenolol

P=0.021

Composite of CV Death / MI / Stroke

LIFE: Primary Composite Endpoint

Adjusted

Hazard

Ratio = 0.87

Rate 23.8/1,000

patient yrsRate 27.9/1,000

patient yrs

n=508 n=588

4.4%

5.1%

0%

2%

4%

6%

8%

5.0%

6.7%

0%

2%

4%

6%

8%

4.3% 4.1%

0%

2%

4%

6%

8%

P=0.206 P=0.491

Cardiovascular Death Myocardial Infarction

P=0.001

Stroke

LIFE: Individual Endpoint Results

Adjusted

HR 0.89

Adjusted HR

1.07

Adjusted

HR 0.75

Losartan Atenolol Losartan Atenolol Losartan Atenolol

5.2%

7.0%

0%

2%

4%

6%

8%

10%

Losartan Atenolol

P=0.001

LIFE: New-onset diabetes

Adjusted

Hazard

Ratio = 0.75

Rate 13.0/1,000

patient yrsRate 17.4/1,000

patient yrs

n=241 n=319

Health & Medicine

Trials of ace inhibitors