Author Affiliations: Preventive Cardiology and Therapeutics Program (Drs Eikelboom, Mehta, and Yusuf and Ms Pogue); and Department of Medicine, McMaster University (Drs Mehta and Yusuf), Hamilton, Ontario, Canada.
Context Recent studies have reported disagreement between meta-analysis of small
trials and subsequent large trials addressing the same question. However,
disagreement for uncommon but serious adverse safety outcomes has not been
Objective To explore disagreement for serious adverse safety (intracranial hemorrhage
[ICH]) and efficacy outcomes between meta-analysis of phase 2 (small) vs meta-analysis
of phase 3 (large) randomized controlled trials comparing the efficacy of
bolus thrombolytic therapy with infusion for acute myocardial infarction (AMI).
Data Sources Electronic databases (MEDLINE, Cochrane Database of Clinical Trials)
between January 1980 and December 1999 using the search terms thrombolysis, thrombolytic therapy, and myocardial
infarction; conference proceedings; and reference lists.
Study Selection Fifteen randomized trials comparing thrombolytic agents administered
by bolus injection with standard infusion therapy in patients with AMI.
Data Extraction Data on ICH, other causes of stroke, total mortality, and reinfarction
were independently extracted from each study by 2 observers.
Data Synthesis Meta-analysis of 9 phase 2 trials (n = 3956) revealed a lower risk of
ICH with bolus thrombolytic therapy (odds ratio [OR], 0.53; 95% confidence
interval [CI], 0.27-1.01), which was not statistically significant. Meta-analysis
of 6 phase 3 trials (n = 62 673) indicated a significant increase in
risk of ICH (OR, 1.25; 95% CI, 1.06-1.49). These results were significantly
different (P = .01). There was no disagreement for
efficacy outcomes. Phase 2 trials included younger and heavier patients with
lower baseline blood pressures, and were more often open-label. Subgroup analyses
suggested that each of these factors was associated with a lower estimate
of risk of ICH with bolus agents.
Conclusions Our results suggest that when therapeutic interventions are associated
with a potential for uncommon but serious adverse safety outcomes, there may
be differences between small phase 2 and large phase 3 trials that result
in their disagreement for safety but not necessarily efficacy outcomes. Further
investigation of the frequency and causes of disagreement between small and
large trials for safety outcomes is warranted.
Eikelboom JW, Mehta SR, Pogue J, Yusuf S. Safety Outcomes in Meta-analyses of Phase 2 vs Phase 3 Randomized TrialsIntracranial Hemorrhage in Trials of Bolus Thrombolytic Therapy. JAMA. 2001;285(4):444-450. doi:10.1001/jama.285.4.444