GISSI-3

Published

GISSI-3 Group. "Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction". The Lancet. 1994. 343(8906):1115-22.
PubMed • Full text

Clinical Question

Among patients with acute MI and preserved LV systolic function, does the addition of lisinopril reduce short-term mortality?

Bottom Line

Lisinopril reduces the odds of 6-week mortality by 11% when administered within 24 hours of acute MI.

Major Points

Although several studies (including the 1992 SAVE trial) have investigated the role of ACE inhibitors among patients with MI complicated by LV dysfunction, the role of the medication in those with an MI with preserved LVEF was unknown. The 1994 Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico (GISSI-3) trial randomized 19,394 patients with MI with preserved LVEF to lisinopril, nitrates, or control in a 2x2 factorial design. At 6 weeks, lisinopril was associated with a modest, but significant, 0.8% absolute reduction in mortality -- an 11% odds reduction -- when compared to placebo.

A subsequent 1998 meta-analysis 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 Guidelines (2013, adapted)

• 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 Guidelines (2014, adapted)

• 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 Guidelines (2013, adapted)

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

Design

• Multicenter, open label, 2x2 factorial design, randomized trial
• N=19,394 randomized, but 499 lost to follow-up at 6 weeks
  • Lisinopril (n=4,713)
  • Nitrates (n=4,731)
  • Lisinopril plus nitrates (n=4,722)
  • Controls (n=4,729)
• Setting: 200 coronary care units (two thirds in Italy)
• Enrollment: June 1991 to July 1993
• Follow-up: 6 months
• Analysis: Intention-to-treatment analysis

Population

Inclusion Criteria

• Typical chest pain accompanied by ST changes, either:
  • ≥1mm ST elevation or depression in ≥1 peripheral leads
  • ≥2mm ST elevation or depression in ≥1 precordial leads
• Admitted to CCU within 24h of symptom onset

Exclusion Criteria

• Severe HF requiring any of study drugs
• Killip class 4
• High risk of further serious hemodynamic deterioration after treatment with vasodilators, judged by SBP≤100 mmHg
• Contraindications to study drugs:
  • History of renal failure (creatinine ≥2mg/dl, proteinuria >500mg/24h, or both)
  • History of bilateral renal artery stenosis
  • Documented allergy to study drug
• Other life-threatening disorders

Baseline Characteristics

Comparisons are lisinopril vs. control.

• Age >70 years: 27%
• Women: 22%
• Time from symptom onset
  • ≤6 hours: 35%
  • >6-12 hours: 25%
  • >12-24 hours: 40%
• Killip class I (85%), II (14%), III (1%)
• Site of infarction
  • Anterior: 27.4%
  • Inferiorposterior: 32.3%
  • Multiple location: 3.3%
  • Non-Q-wave: 18.5%
  • Undefined: 9.7%
  • Not reported: 3.8%
  • Not confirmed AMI: 5.0%
• Heart rate
  • <60 bpm: 11.3%
  • 60-79 bpm: 49.5%
  • 80-100 bpm: 34.0%
  • >100 bpm: 5.2%
• SBP
  • 100-120 mmHg: 38.9%
  • 121-150 mmHg: 46.3%
  • >150 mmHg: 14.9%
• History
  • Previous MI: 13.9%
  • Previous angina: 34.4%
  • Treated HTN: 29.9%
  • DM: 15.6%
• Recommended treatments
  • IV &beta-blockers: 30.7%
  • Fibrinolytic treatment: 71.7%
  • Aspirin: 83.9%
  • Other antiplatelet agents: 3.5%

Interventions

• Acute treatments included thrombolysis, aspirin, and β-blockers
• Randomly assigned to four treatment groups:
  • Lisinopril alone
  • Transdermal glyceryl trinitrate (GTN) alone
  • Combined therapy with lisinopril and transdermal glyceryl trinitrate (GTN)
  • Open control, i.e. no trial therapy

Lisinopril 2.5-10 mg PO daily

Protocol: 5 mg at randomization, 5 mg after 24h, 10 mg after 48h, 10 mg daily for 6 weeks

if SBP ≤120 mmHg, initial doses could 2.5 mg

If SBP ≤100 mmHg, maintenance doses could be lowered to 5 mg with temporary reductions to 2.5 mg allowed

If SBP ≤90 mmHg, doses could be stopped

Transdermal GTN

Intravenous infusion during the first 24 hours starting at 5 µg/min every 5 mins for the first 30 mins until SBP decreased ≥10%, provided it remained above 90 mmHg

After 24 hours, intravenous infusion replaced with patch providing 10 mg daily GTN transdermally. Patch applied early every morning and removed at bedtime to provide 10 h nitrate holiday

If patch not tolerated, isosorbide mononitrate 50 mg PO daily

Outcomes

Primary Outcomes

Comparisons are lisinopril vs. control.

6-week all-cause mortality

6.3% vs. 7.1% (OR 0.88; 95% CI 0.79-0.99; 2P=0.03; NNT=125)

Composite of death, HF, LVEF ≤35%, ≥45% akinesis/dyskinesis

15.6% vs. 17.0% (OR 0.90; 95% CI 0.84-0.98; 2P=0.009)

Comparisons are nitrates vs. control.

6-week all-cause mortality

6.5% vs. 6.9% (OR 0.94; 95% CI 0.84-1.05; 2P=0.28)

Composite of death, HF, LVEF ≤35%, ≥45% akinesis/dyskinesis

15.9% vs. 16.7% (OR 0.94; 95% CI 0.87-1.02; 2P=0.12)

"Comparisons are lisinopril plus nitrates vs. control.

6-week all-cause mortality

6.0% vs. 7.2% (OR 0.83; 95% CI 0.70-0.97; 2P=0.021)

Composite of death, HF, LVEF ≤35%, ≥45% akinesis/dyskinesis

14.8% vs. 17.0% (OR 0.85; 95% CI 0.76-0.94; 2P=0.0028)

Secondary Outcomes

Comparisons are lisinopril vs. control.

Clinical HF

3.9% vs. 3.7%

LVEF ≤35%

4.8% vs. 5.3%

≥45% akinesis/dyskinesis

0.6% vs. 0.6%

Reinfarction

3.2% vs. 3.1% (OR 1.04; 95% CI 0.88-1.23; P=NS)

Postinfarction angina

21.0% vs. 20.2% (OR 1.05; 95% CI 0.98-1.13, P=NS)

CABG

1.6% vs. 1.5% (OR 1.08; 95% CI 0.86-1.36)

PTCA

1.7% vs. 1.6% (OR 1.08; 95% CI 0.87-1.36)

SBP <90 mmHg for ≥1 h

9.0% vs. 3.7% (OR 2.44; 95% CI 2.17-2.74)

Cardiogenic shock

2.5% vs. 2.2% (OR 1.13; 95% CI 0.94-1.37, P=NS)

Renal dysfunction

2.4% vs. 1.1% (OR 2.09; 95% CI 1.68-2.60)

Stroke

0.8% vs. 0.7% (OR 1.06; 95% CI 0.76-1.48, P=NS)

Comparisons are nitrates vs. control.

Clinical HF

3.8% vs. 3.8%

LVEF ≤35%

5.1% vs. 5.3%

≥45% akinesis/dyskinesis

0.5% vs. 0.7%

Reinfarction

3.1% vs. 3.2% (OR 0.96; 95% CI 0.82-1.13)

Postinfarction angina

20.0% vs. 21.2% (OR 0.93; 95% CI 0.86-0.99)

CABG

1.5% vs. 1.6% (OR 0.94; 95% CI 0.74-1.18)

PTCA

1.6% vs. 1.7% (OR 0.94; 95% CI 0.75-1.17)

SBP <90 mmHg for ≥1 h

6.6% vs. 6.2% (OR 1.07; 95% CI 0.95-1.20)

Cardiogenic shock

2.1% vs. 2.6% (OR 0.78; 95% CI 0.64-0.94)

Renal dysfunction

1.8% vs. 1.8% (OR 1.00; 95% CI 0.80-1.24)

Stroke

0.9% vs. 0.6% (OR 1.45; 95% CI 1.04-2.02)

Comparisons are lisinopril plus nitrates vs. control.

Clinical HF

3.7% vs. 3.7%

LVEF ≤35%

4.6% vs. 5.5%

≥45% akinesis/dyskinesis

0.5% vs. 0.6%s

Reinfarction

3.3% vs. 3.3% (OR 1.00; 95% CI 0.80-1.26)

Postinfarction angina

20.3% vs. 20.7% (OR 0.98; 95% CI 0.88-1.08)

CABG

1.6% vs. 1.6% (OR 1.01; 95% CI 0.74-1.40)

PTCA

1.5% vs. 1.5% (OR 1.02; 95% CI 0.73-1.42)

SBP <90 mmHg for ≥1 h

9.3% vs. 3.6% (OR 2.59; 95% CI 2.20-3.05)

Cardiogenic shock

2.2% vs. 2.5% (OR 0.88; 95% CI 0.67-1.15)

Renal dysfunction

2.4% vs. 1.1% (OR 2.11; 95% CI 01.55-2.87)

Stroke

0.9% vs. 0.6% (OR 1.53; 95% CI 0.96-2.45)

Subgroup Analysis

Comparisons are lisinopril vs. control.

>70 years

Composite endpoint

24.8% vs. 28.3% (OR 0.83; 95% CI 0.74-0.94, 2P=0.0039)

Deaths: 14.0% vs. 15.6%

HF: 5.9% vs. 5.9%

LVEF ≤35%: 4.4% vs. 6.0%

≥45% akinesis/dyskinesis: 0.4% vs. 0.8%

Women

Composite endpoint

20.8% vs. 23.4% (OR 0.86; 95% CI 0.74-0.99, 2P=0.039)

Deaths: 10.7% vs. 12.9%

HF: 5.5% vs. 5.5%

LVEF ≤35%: 3.8% vs. 4.5%

≥45% akinesis/dyskinesis: 0.8% vs. 0.6%

Comparisons are combination of lisinopril plus nitrates vs. control.

Composite endpoint in >70 years

22.8% vs. 28.8% (RR 0.79; 2P=0.0004)

Composite endpoint in women

19.0% vs. 24.0% (RR 0.79; 2P=0.0051)

Criticisms

• Use of odds ratio overestimates the benefit of lisinopril.

Funding

• Zeneca Pharmaceutical, the manufacturers of Zestril, the brand name of lisinopril
• Schwarz Pharma suppliers of IV and transdermal NTG