Safety outcomes in meta-analyses of phase 2 vs phase 3 randomized trials -Intracranial hemorrhage in trials of bolus thrombolytic therapy

Context Recent studies have reported disagreement between meta-analysis of small trials and subsequent large trials addressing the same question. Howe ver, disagreement for uncommon but serious adverse safety outcomes has not been examined. Objective To explore disagreement for serious adverse safety (intracranial hemorrhage [ICH]) and efficacy outcomes between mete-analysis of phase 2 (s mall) vs metaanalysis of phase 3 (large) randomized controlled trials compa ring the efficacy of bolus thrombolytic therapy with infusion for acute myo cardia[ infarction (AMI). Data Sources Electronic databases (MEDLINE, Cochrane Database of Clinical T rials) between January 1980 and December 1999 using the search terms thromb olysis, thrombolytic therapy, and myocardial infarction; conference proceed ings; and reference lists. Study Selection Fifteen randomized trials comparing thrombolytic agents adm inistered by bolus injection with standard infusion therapy in patients wit h AMI. Data Extraction Data on [CH, other causes of stroke, total mortality, and r einfarction 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% con fidence interval [CI], 0.27-1.01), which was not statistically significant, Meta-analysis of 6 phase 3 trials (n=62673) indicated a significant increa se in risk of ICH (OR, 2.25; 95% CI, 1.06-1.49). These results were signifi cantly different (P =.01). There was no disagreement for efficacy outcomes. Phase 2 trials included younger and heavier patients with lower baseline b lood 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 ass ociated with a potential for uncommon but serious adverse safety outcomes, there may be differences between small phase 2 and large phase 3 trials tha t result in their disagreement for safety but not necessarily efficacy outc omes. Further investigation of the frequency and causes of disagreement bet ween small and large trials for safety outcomes is warranted.