Effects of Lisinopril and Transdermal Glycerol Trinitrate Singly and Together on 6-week Mortality and Ventricular Function after AMI - GISSI-3

Description:

Lisinopril and/or nitrates for mortality in acute myocardial infarction.

Hypothesis:

Vasodilator with ACE inhibitor and nitrates, alone or in combination is effective following acute myocardial infarction.

Study Design

Study Design:

Patients Screened: 43,047
Patients Enrolled: 18,895
NYHA Class: not given
Mean Follow Up: 4 years
Female: 22

Patient Populations:

Chest pain accompanied by elevation or depression of ST segment by at least 1 mm in one or more peripheral leads or 2 mm in precordial leads.
Admitted within 24 hours of symptom onset.
Diagnoses of acute myocardial infarction by two of the following:
typical chest pain
typical evaluation of CE
positive enzymes

Exclusions:

Severe heart failure
Killip class IV
High risk for hemodynamic compromise with vasodilators
Other life-threatening disorders

Primary Endpoints:

Mortality (all cause)
Death plus heart failure or extensive left ventricular dysfunction (EF < 35%) (combined endpoint)

Secondary Endpoints:

Change in left ventricular ejection fraction

Drug/Procedures Used:

6 weeks nitrates, ACE, both, or neither. Nitrates: IV glyceryl trinitrate x 24 hours, then transdermal glyceryl trinitrate or oral isosorbide mononitrate. ACE: Oral lisinopril, 2.5-5 mg po qd x 24 hours, then increased to 10 mg po qd

Concomitant Medications:

Aspirin (84%)
Beta-blockers (31%)
Thrombolytics (72%)

Principal Findings:

Overall six week mortality was 6.7%.

Lisinopril started within 24 hours of acute myocardial infarction symptoms produced significant reductions in mortality (11%) and combined endpoint of mortality and left ventricular dysfunction.

Transdermal nitroglycerin did not affect the outcome measured.

Combined administration of lisinopril and nitroglycerin significantly reduced overall mortality as well as the combined endpoint.

Efficacy of lisinopril alone or with nitroglycerin also evident in high-risk populations for the combined endpoint.

The most important factor in administration of thrombolytic therapy was that less than 6 hours elapse from symptom onset to hospital admission (odds ratio [OR] 14.05; 95% confidence interval [CI] 12.3 to 16.0).

A 4-year follow-up was conducted on approximately 95% of the patients. The data showed that the absolute benefit observed earlier was preserved. The subgroups showing the greatest benefit were patients with diabetes, anterior MI, and Killip class greater than 1 during the acute phase.

Interpretation:

Lisinopril administered early post infarction alone or in combination with nitrates has a favorable effect on mortality and left ventricular dysfunction. The GISSI-3 experience confirmed a high rate of prescription of thrombolytic therapy to patients admitted within 6 hours of symptom onset and those with ST-segment elevation on entrance electrocardiogram. It demonstrated that patients admitted to coronary care units with catheterization laboratories or cardiac programs or both have higher chances of receiving thrombolytic treatment than those admitted to hospitals without these capabilities.

Dosage may be important to avoid the hypotension observed in earlier trials of acute enalaprilat administration. The reduction in mortality is extended, though not expanded, after the early treatment.

References:

1. Am J Cardiol 1992;70:62C-69C. Study design
2. Lancet 1995;343:1115-22. Final results
3. J Am Coll Cardiol 1996;27:337-44. 6-month outcomes
4. Am Heart J 1998;135:443-8. Thrombolytic administration
5. 4-year follow-up Presented at the XXth Congress of the European Society of Cardiology, Vienna, 1998

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Thrombolytic Therapy, Myocardial Infarction, Coronary Care Units, Hypotension, Electrocardiography, Vasodilator Agents, Isosorbide Dinitrate, Lisinopril, Chest Pain, Nitrates, Catheterization, Ventricular Dysfunction, Left, Diabetes Mellitus, Nitroglycerin


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