SAVE

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Pfeffer MA, et al. "Effect of Captopril on Mortality and Morbidity in Patients with Left Ventricular Dysfunction after Myocardial Infarction — Results of the Survival and Ventricular Enlargement Trial". The New England Journal of Medicine. 1992. 327(10):669-677.
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Clinical Question

What is the effect of captopril on mortality among patients with acute MI complicated by asymptomatic LV dysfunction?

Bottom Line

In patients with acute MI complicated by asymptomatic LV dysfunction, captopril led to a 19% reduction in all-cause mortality.

Major Points

The 1992 Survival and Ventricular Enlargement (SAVE) trial demonstrated a 19% reduction in mortality with captopril compared to placebo among patients with acute MI complicated by asymptomatic LV dysfunction. This study echoed the results of the prior CONSENSUS (1987) and SOLVD (1991) studies of ACE inhibitors in chronic HF, and is the basis of recommendations for the addition of ACE inhibitors in LV dysfunction complicating acute MI. The related GISSI-3 study (1994) demonstrated that ACE inhibitors have a mortality benefit following an MI regardless of subsequent LV function.

A subsequent 1998 meta-analysis[1] demonstrated an absolute reduction of mortality of 0.5% -- a 7.1% odds reduction -- when ACE-inhibitors were used post-MI. This correlated with a NNT of 200. This mortality benefit was offset by higher rates of persistent hypotension and renal dysfunction in the treatment groups. Of note, subgroup analysis demonstrated more robust mortality benefit in those in Killip class II or III, heart rate ≥100 BPM, and anterior MI. ACE-inhibitors also reduced rates of development of non-fatal HF.

Guidelines

ACCF/AHA STEMI (2013, adapted)[2]

  • ACE-inhibitor administration within 24 hours after STEMI if its location was anterior, if there is a history of HF, or an LVEF ≤40% unless if otherwise contraindicated (class I, level A)
  • ACE inhibitor for all patients with STEMI if no contraindications (class IIa, level A)

ACCF/AHA NSTE-ACS (2014, adapted)[3]

  • Unless contraindicated, indefinite ACE-inhibitor therapy for patients with LVEF <40% and those with HTN, DM, or stable CKD (class I, level A)
  • ARBs in patients with HF or MI with LVEF <40% if intolerant to ACE-inhibitors (class I, level A)
  • ACE-inhibitors may be reasonable in all patients with cardiac or vascular disease (class IIb, level B)
    • ARBs are reasonable in patients with cardiac or vascular disease who are intolerant to ACE-inhibitors (class IIa, level B)

AHA/ACCF Heart Failure (2013, adapted)[4]

  • ACE-inhibitors for all patients with HFrEF with with current or prior symptoms unless contraindicated (class I, level A)

Design

  • Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
  • N=2,231
    • Captopril (n=1,115)
    • Placebo (n=1,116)
  • Setting: 45 centers in 112 hospitals in US and Canada
  • Analysis: Intention-to-treat
  • Enrollment: 1987-1990
  • Mean follow-up: 42 months
  • Primary outcome: All-cause mortality

Population

Inclusion Criteria

  • Age ≥21 years
  • MI within prior 3 days
  • New onset LVEF ≤40%
  • Absence of overt signs of CHF

Exclusion Criteria

  • Age >80 years
  • Failure to undergo randomization within 16 days after AMI
  • Relative contraindication to ACE inhibitors
  • Symptomatic CHF or HTN requiring ACE inhibitor
  • Serum creatinine level >2.5mg/dl
  • Other conditions believed to limit survival
  • Unstable course after infarction

Baseline Characteristics

  • Demographics: Age 59 years, male 82%
  • Baseline health data: SBP 113 mmHg, LVEF 31%
  • PMH: MI 35%, HTN 43%, DM 22%, current smoker 53%
  • PSH: CABG 9%
  • Days to randomization: 11
  • Events between MI and randomization:
    • Killip class I MI: 59%
    • Treatment with thrombolytics: 33%
    • Cardiac catheterization: 55.5%
    • PTCA: 17%
  • Prior medications: Aspirin 59%, nitrates 52%, CCB 42%, Beta-blockers 36%, diuretics 35%, anticoagulants 28%, digitalis 26%, antiarrhythmics 13%

Interventions

  • Randomized to captopril or placebo achieved by computer-generated assignment and stratified according to center
  • Initial dose of blinded medication was 12.5mg with target dose of 25mg PO BID by end of in-hospital phase
  • Outpatient visits scheduled at intervals of 3-4 months

Outcomes

Comparisons are captopril vs. placebo.

Primary Outcome

All-cause mortality
20% vs. 25% (RR 0.81, 95% CI 0.68-0.97, P=0.019)

Secondary Outcomes

CHF requiring hospitalization or recurrent MI
Not explicitly stated.
CHF hospitalization
14% vs. 17% (RR 0.78, 95% CI 0.63-0.96, P=0.019)
CHF requiring ACE inhibitors
11% vs. 16% (RR 0.63, 95% CI 0.50-0.80, P<0.001)
Recurrent MI
11.9% vs. 15.2% (RR 0.75, 95% CI 0.60-0.95, P=0.015)
CV death, CHF requiring ACE inhibitor, CHF hospitalization, or recurrent MI
32% vs. 40% (RR 0.76, 95% CI 0.66-0.87, P<0.001)

Subgroup analysis

  • Regardless of treatment assignment, advanced age, history of MI, lower LVEF, higher Killip class were each associated with higher incidence of adverse events.
  • When these subgroups were analyzed, effect of captopril on risk reduction showed consistent benefit independent of age, LVEF, history of MI, sex, baseline BP, use of thrombolytic therapy, ASA, beta-blockers (P=0.013).

Adverse events

Following symptoms reported significantly more often by captopril-treated patients:

  • Dizziness (5%)
  • Alteration in taste (2%)
  • Cough (6%; prompting discontinuation of study drug)
  • Diarrhea (2%)

Funding

Supported by a grant from the Bristol-Myers Squibb Institute for Pharmaceutical Research.

Further Reading

  1. ACE Inhibitor Myocardial Infarction Collaborative Group. "Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials." Circulation. 1998;97:2202-2212.
  2. O'Gara PT, et al. "2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines." Circulation. 2013;127(4):e362-e425.
  3. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes." Journal of the American College of Cardiology. 2014;epublished 2014-09-23. Accessed 2014-09-24.
  4. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.