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Thrombolysis in non-ST-elevation myocardial infarction: systematic review and meta-analysis of randomised controlled
José Nunes de Alencar1, Márcio Henrique de Jesus Oliveira2, Elisio Bulhoes3
1Cardiology, Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil jose.alencar@dantepazzanese.org.br.
Insights
Thrombolysis reduced mortality in non-ST-elevation acute coronary syndromes (ACS), contrary to prior meta-analyses. Re-evaluating historical trials suggests current guidelines may overlook benefits due to flawed data.
Area of Science:
- Cardiology
- Clinical Trials
- Evidence-Based Medicine
Background:
- Current guidelines recommend reperfusion therapy for ST-elevation myocardial infarction (STEMI) but not for most non-ST-elevation acute coronary syndromes (NSTE-ACS).
- This practice is based on the Fibrinolytic Therapy Trialists (FTT) meta-analysis, which found no benefit in NSTE-ACS patients.
- The FTT analysis included a problematic subgroup from the ISIS-3 trial, potentially skewing results.
Purpose of the Study:
- To systematically review and meta-analyze randomized controlled trials (RCTs) of thrombolysis in ACS, specifically examining outcomes based on ECG findings.
- To reassess the impact of thrombolysis in NSTE-ACS, particularly addressing the influence of the ISIS-3 trial's 'uncertain diagnosis' subgroup.
Main Methods:
- Conducted a systematic review and meta-analysis of RCTs comparing thrombolysis versus placebo or no thrombolysis in ACS patients.
- Grouped patients by ECG findings: ST-elevation (STE), ST-depression (STD), or absence of STE.
- Extracted all-cause mortality data from short-term follow-up and analyzed outcomes with and without the ISIS-3 'uncertain diagnosis' subgroup.
Main Results:
- Analyzed nine RCTs involving 40,226 patients.
- Thrombolysis significantly reduced mortality in NSTE-ACS patients (excluding isolated STD) (RR: 0.799; 95% CI 0.668 to 0.956; I²=0%).
- Including the ISIS-3 'uncertain diagnosis' subgroup eliminated statistical significance for NSTE-ACS (RR: 0.928; 95% CI 0.694 to 1.242) and increased heterogeneity (I²=71%).
Conclusions:
- Historical RCTs indicate thrombolysis lowers short-term mortality in NSTE-ACS, excluding isolated STD.
- Isolated STD showed no mortality benefit from thrombolysis.
- Current guideline conclusions may be based on outdated methods and flawed data, highlighting an evidence gap and the need for contemporary trials.
Background:
Guidelines strongly recommend reperfusion therapy, including thrombolysis and percutaneous coronary intervention, for ST-elevation myocardial infarction but contraindicate its use in most non-ST-elevation acute coronary syndromes (ACS). This practice largely stems from the landmark fibrinolytic therapy trialists (FTT) meta-analysis, which reported no benefit in patients without ST elevation (STE). However, the FTT included a subgroup from the ISIS-3 trial with substantial methodological issues, potentially obscuring a genuine treatment effect.
Methods:
We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing thrombolysis vs placebo or no thrombolysis in ACS. Patients were grouped by ECG findings: STE, ST depression (STD) or absence of STE. All-cause mortality was extracted from each trial's short-term follow-up (typically 21-35 days). We reassessed outcomes with and without inclusion of the ISIS-3 'uncertain diagnosis' subgroup.
Results:
Nine RCTs (40 226 patients) were analysed. Thrombolysis significantly reduced mortality in patients without STE (excluding isolated STD) (risk ratio (RR): 0.799; 95% CI 0.668 to 0.956; I²=0%). Including the ISIS-3 'uncertain diagnosis' subgroup (representing 42% of the non-STE population) would have eliminated the statistical significance in non-STE patients (RR: 0.928; 95% CI 0.694 to 1.242) and markedly increased heterogeneity (I²=71%).
Conclusion:
In historical RCTs, thrombolysis was associated with lower short-term mortality in non-STE presentations excluding isolated ST-segment depression, while isolated STD showed no benefit. Legacy conclusions hinge on outdated methods, delayed treatment and heterogeneous ECG definitions (and are sensitive to ISIS-3). This study exposes a material evidence gap in the foundation of current guidelines. Contemporary randomised trials with prespecified ECG criteria, rapid treatment windows and rigorous safety adjudication are needed.
Prospero Registration Number:
CRD42024573681.
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