Article Identification

Article Title: GISSI-3: Effect of Lisinopril and Transdermal Glyceryl Trinitrate on Survival and Ventricular Function After Acute Myocardial Infarction

Authors: [Not specified in the abstract]

Journal Name, Year, Volume, Issue: [Not specified in the abstract]

Type of Study: Multicentre Randomised Clinical Trial

DOI/PMID: [Not provided]

Quick Reference Summary

Lisinopril initiated within 24 hours of AMI significantly reduced 6-week mortality (OR 0.88, 95% CI 0.79-0.99) and the combined outcome of mortality and severe ventricular dysfunction (OR 0.90, 95% CI 0.84-0.98).

The combination of lisinopril and transdermal GTN further decreased overall mortality (OR 0.83, 95% CI 0.70-0.97) and the combined endpoint (OR 0.85, 95% CI 0.76-0.94), whereas GTN alone showed no independent effect.

Core Clinical Question

Does early administration of lisinopril, transdermal glyceryl trinitrate (GTN), or their combination improve 6-week survival and ventricular function in patients after acute myocardial infarction (AMI)?

Background

Disease Overview

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. Post-AMI management aims to improve survival and ventricular function.

Prior Data

• ACE inhibitors like lisinopril have been shown to reduce mortality post-AMI.
• Nitrates are commonly used to manage chest pain in AMI but their impact on survival is less clear.

Current Standard of Care

Includes thrombolysis, beta-blockers, aspirin, and ACE inhibitors for eligible patients.

Knowledge Gaps Addressed

• Efficacy of lisinopril and transdermal GTN initiated within 24 hours of AMI.
• Combined effect of lisinopril and GTN on survival and ventricular function.

Study Rationale

To determine whether early intervention with lisinopril and/or GTN can further improve outcomes in a population already receiving recommended treatments.

Methods Summary

Study Design

Multicentre randomised clinical trial with a factorial design.

Setting and Time Period

200 coronary care units in Italy; June 1991 – July 1993.

Population Characteristics

19,394 patients presenting within 24 hours of AMI symptom onset.

Inclusion/Exclusion Criteria

Eligible patients had no clear indications against the study treatments.

Intervention Details

• Lisinopril Group: 6 weeks of oral lisinopril (5 mg initial dose, then 10 mg daily).
• GTN Group: Intravenous nitrates for the first 24 hours followed by transdermal GTN 10 mg daily.

Control/Comparison Group Details

Open control for lisinopril and GTN.

Primary and Secondary Outcomes

• Primary: Overall 6-week mortality.
• Secondary: Combined outcome of mortality and severe ventricular dysfunction.

Statistical Analysis Approach

Odds ratios with 95% confidence intervals to assess significance.

Sample Size Calculations

Based on expected mortality reductions; exact calculations not specified.

Ethics and Funding Information

Not specified in the abstract.

Detailed Results

Participant Flow and Demographics

• Total Randomised: 19,394 patients.
• Complete Clinical Data: 18,895 (97.4%).
• Echocardiographic Data: 14,209 patients.

Primary Outcome Results

• Overall 6-Week Mortality: 6.7%.
• Lisinopril vs. Control: OR 0.88 (95% CI 0.79-0.99, p < 0.05).
• Combined Lisinopril and GTN vs. Control: OR 0.83 (95% CI 0.70-0.97, p < 0.05).

Effect Sizes and Confidence Intervals

• Lisinopril: 12% relative risk reduction in mortality.
• Lisinopril + GTN: 17% relative risk reduction in mortality.

Secondary Outcome Results

• Mortality and Severe Ventricular Dysfunction:
  • Lisinopril vs. Control: OR 0.90 (95% CI 0.84-0.98, p < 0.05).
  • Lisinopril + GTN vs. Control: OR 0.85 (95% CI 0.76-0.94, p < 0.05).
• GTN Alone: No significant effect (OR 0.94, 95% CI 0.84-1.05; OR 0.94, 95% CI 0.87-1.02).

Subgroup Analyses

• High-Risk Populations (Elderly, Women): Significant reductions in combined endpoints with lisinopril alone or combined with GTN.

Adverse Events/Safety Data

No excess of unfavorable clinically relevant events reported in treated groups.

Results Tables

Authors’ Conclusions

• Primary Conclusions: Early administration of lisinopril, alone or in combination with transdermal GTN, significantly reduces 6-week mortality and the combined outcome of mortality and severe ventricular dysfunction in AMI patients.
• Interpretation of Results: Lisinopril provides a clear survival benefit, which is enhanced when combined with GTN. GTN alone does not independently affect mortality or ventricular function.
• Clinical Implications: Initiating lisinopril within 24 hours of AMI can improve survival rates, including in high-risk groups such as elderly patients and women.
• Future Research Recommendations: Further studies could explore long-term outcomes and the mechanisms by which lisinopril confers mortality benefits post-AMI.

Critical Analysis

A. Strengths

• Large Sample Size: Involving 19,394 patients increases the power and generalizability of the findings.
• Multicentre Design: Conducted across 200 coronary care units, enhancing external validity.
• High Follow-Up Rate: 97.4% complete clinical data minimizes potential attrition bias.
• Factorial Design: Allows assessment of both individual and combined effects of lisinopril and GTN.
• Inclusion of High-Risk Populations: Results are applicable to elderly patients and women.

B. Limitations

• Abstract Lacks Specific Details: Information on authors, exact journal, and full methodology is missing.
• Potential Selection Bias: Patients without clear indications for or against treatments may not represent all AMI patients.
• Short Follow-Up Duration: Only 6-week outcomes are reported; long-term effects are unknown.
• Limited Adverse Events Reporting: Abstract mentions no excess unfavorable events but lacks detailed safety data.
• Generalizability Issues: Study conducted in Italy; results may vary in different healthcare settings or populations.

C. Literature Context

Previous Studies and Meta-Analyses

Previous trials have shown ACE inhibitors reduce mortality post-AMI. (e.g., N Engl J Med. 1990;322(3): 143-150.)

Nitrates have been traditionally used for symptom relief in AMI but their impact on survival is debated. (e.g., Lancet. 1988;1(8601): 869-874.)

Contrasting Methodological Quality

GISSI-3 employed a larger sample size compared to earlier studies, enhancing reliability. (e.g., comparison with smaller trials like TRACE study)

Comparisons with Guidelines

Current guidelines recommend ACE inhibitors post-AMI for eligible patients. (e.g., American Heart Association, 2020.)

This Trial’s Contribution

• Provides robust evidence for the early use of lisinopril in a broad AMI population.
• Demonstrates additional mortality benefits when combining ACE inhibitors with nitrates.

Clinical Application

• Lisinopril should be initiated within the first 24 hours of AMI to reduce mortality and improve ventricular function, especially in high-risk groups such as the elderly and women.
• Combining lisinopril with transdermal GTN may offer additional survival benefits, though GTN alone does not significantly impact mortality.
• Implementation should consider patient-specific factors and existing treatment protocols to integrate these findings effectively into practice.

How to Use This Info in Practice

Clinicians should consider initiating lisinopril within 24 hours of AMI in eligible patients to enhance survival and ventricular outcomes.