Eikelboom J W, Mehta S R, Pogue J, Yusuf S
McMaster University, Hamilton General Hospital-McMaster Clinic, 237 Barton St E, Hamilton, Ontario, Canada L8L 2X2.
JAMA. 2001;285(4):444-50. doi: 10.1001/jama.285.4.444.
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 examined.
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).
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.
Fifteen randomized trials comparing thrombolytic agents administered by bolus injection with standard infusion therapy in patients with AMI.
Data on ICH, other causes of stroke, total mortality, and reinfarction were independently extracted from each study by 2 observers.
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.
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.
近期研究报告称，针对同一问题的小型试验的荟萃分析与后续大型试验之间存在分歧。然而，对于罕见但严重的不良安全结局的分歧尚未得到研究。
探讨在比较急性心肌梗死（AMI）大剂量溶栓治疗与静脉输注疗效的2期（小型）随机对照试验的荟萃分析与3期（大型）随机对照试验的荟萃分析之间，严重不良安全结局（颅内出血[ICH]）和疗效结局的分歧。
1980年1月至1999年12月期间的电子数据库（MEDLINE、Cochrane临床试验数据库），使用搜索词溶栓、溶栓治疗和心肌梗死；会议论文集；以及参考文献列表。
15项比较AMI患者大剂量注射溶栓剂与标准静脉输注治疗的随机试验。
2名观察者分别从每项研究中独立提取关于ICH、其他中风原因、总死亡率和再梗死的数据。
对9项2期试验（n = 3956）的荟萃分析显示，大剂量溶栓治疗的ICH风险较低（优势比[OR]，0.53；95%置信区间[CI]，0.27 - 1.01），差异无统计学意义。对6项3期试验（n = 62673）的荟萃分析表明，ICH风险显著增加（OR，1.25；95% CI，1.06 - 1.49）。这些结果差异有统计学意义（P = 0.01）。疗效结局方面没有分歧。2期试验纳入的患者更年轻、体重更重、基线血压更低，且更多为开放标签试验。亚组分析表明，这些因素中的每一个都与大剂量药物降低ICH风险的估计值相关。
我们的结果表明，当治疗干预措施存在罕见但严重的不良安全结局的可能性时，2期小型试验和3期大型试验之间可能存在差异，导致它们在安全结局上存在分歧，但在疗效结局上不一定如此。有必要进一步研究小型试验和大型试验在安全结局上分歧的频率和原因。
