ACE inhibitors post-MI (CCS-1, CONSENSUS II, GISSI-3, ISIS-4, SMILE; AIRE, SAVE, TRACE)

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Bottom line:

  • Short-term use of ACE inhibitors reduces the risk of death post-MI regardless of HF signs/symptoms or LVEF at time of initiation (NNT 125-200).

    • Note: The previously-reviewed HOPE trial then supports continuing ACE inhibitors in patients without HF or LV dysfunction. 

  • In patients with either clinical HF or reduced LVEF post-MI, long-term use of ACE inhibitors reduce the risk of death (NNT 14-20) and severe HF.

 

Short-term use of ACEI in MI all-comers:

  • Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: Interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995;345:686-7.
  • ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995;345:669-85.
  • Swedberg K, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992;327:678-84.
  • Gruppo Italiano per lo Study della Sopravvivenza nell'infarcto Miocardico. GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after myocardial infarction. Lancet 1994;343:1115-22.
  • The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995;332:80-5.

Long-term use of ACEI started shortly post-MI with LV dysfunction or clinical HF:

  • 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. N Engl J Med 1992;327:669-77.
  • The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.
  • Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-6.

Issues with internal validity?

  • No: All but 1 trial double-blind (GISSI-3) with measurement of objective outcome (all-cause mortality) and consistency between all trials.

Patients

5 trials enrolled "all-comer" acute MI patients, regardless of the presence/absence of clinical HF or LVEF

About 20% of patients in the "all comer" trials had clinical HF. LVEF was not routinely measured & is not reported in the original trial reports

3 trials enrolled patients early after an MI if they had either clinical HF (AIRE) or reduced LVEF (SAVE, TRACE) for enrolment

The majority of patients in the 2 trials of patients with LV dysfunction (SAVE, TRACE) did not have any clinical signs of HF at baseline despite an average LVEF ~30%

Generalizability: Who do these results apply to?

  • Taken together, these 8 trials enrolled any patient within ~2 weeks of an MI with or without clinical HF or LV dysfunction in the fibrinolytic/pre-early invasive management era, as long as they did not have an absolute contraindication to ACEI such as SBP <90, AKI or hyperkalemia (exclusion criteria common to 2+ trials)
  • Baseline use of concomitant medications (ASA, beta-blockers, etc) was variable, & overall suboptimal (ASA use ranged 55-94%)

Interventions

  • Captopril studies
    • CCS-1: 6.25 mg PO test dose, followed by 12.5 mg PO TID x28 days
    • ISIS-4: 6.25 mg PO test dose, then 12.5 mg 2h later, then 25 mg 10h later, then 50 mg PO BID x28 days
      • 17% discontinued captopril before discharge
    • SAVE: Initial dose 6.25-12.5 mg PO TID, titrated up to 25 mg PO TID by hospital discharge, then increased to 50 mg PO TID & continued for trial duration (mean 3.3 y)
  • Enalaprilat/enalapril (CONSENSUS II)
    • Enalaprilat 1 mg IV over 2h, then enalapril 2.5 mg PO BID, doubled daily as tolerated up to 20 mg PO BID on day 5 onward & continued for trial duration (41-180 days)
  • Lisinopril (GISSI-3)
    • 5 mg PO daily x2 days, then 10 mg PO daily x6 weeks
    • 18% discontinued by week 6
  • Ramipril (AIRE)
    • 2.5 mg PO BID x2 days, then 5 mg PO BID for trial duration (mean 1.25 y)
      • 86% discharged on 10 mg/d
  • Trandolapril (TRACE)
    • 1 mg PO daily x2 days, then 2 mg PO daily x4 weeks, then 4 mg PO daily for trial duration (2-5.1 y)
  • Zofenopril (SMILE)
    • 7.5 mg PO BID x1 day, doubled daily to target 30 mg PO BID, continued for total 6 weeks

Results

The 5 all-comer trials all evaluated outcomes in the short term, & all but CONSENSUS II (which initiated ACEI therapy as IV) demonstrated a reduction in the incidence of death +/- HF with NNT ~125-200 for death at 4-6 weeks

The trials of patients with clinical HF/LV dysfunction post-MI all evaluated outcomes beyond 1 year, with all trials demonstrating a mortality benefit that ranged from NNT 14-20 at ~1-5 y. Superficially, the greatest absolute benefit was seen in the AIRE trial, which enrolled only patients with clinical HF