Adaptive and repeated cumulative meta-analyses of safety data during a new drug development process.

During a new drug development process, it is desirable to timely detect potential safety signals. For this purpose, repeated meta-analyses may be performed sequentially on accumulating safety data. Moreover, if the amount of safety data from the originally planned program is not enough to ensure adequate power to test a specific hypothesis (e.g., the noninferiority hypothesis of an event of interest), the total sample size may be increased by adding new studies to the program. Without appropriate adjustment, it is well known that the type I error rate will be inflated because of repeated analyses and sample size adjustment. In this paper, we discuss potential issues associated with adaptive and repeated cumulative meta-analyses of safety data conducted during a drug development process. We consider both frequentist and Bayesian approaches. A new drug development example is used to demonstrate the application of the methods.

Prospective evaluation of clinical outcomes after acute ST-elevation myocardial infarction in patients who are ineligible for reperfusion therapy: preliminary results from the TETAMI registry and randomized trial.

BACKGROUND: Treatment with lytics or primary percutaneous coronary interventions (PCI) reduces the mortality rate of patients with ST-elevation myocardial infarction (STEMI) presenting within 12 hours. Patients presenting >12 hours are generally considered to be ineligible for reperfusion therapy, and there are currently no specific treatment recommendations for this subgroup.Methods- All patients with STEMI <24 hours were included in the Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction (TETAMI) randomized trial or registry. Those patients who were ineligible for acute reperfusion, had no cardiogenic shock, and were not planned for revascularization within 48 hours were randomized to 1 of 4 antithrombotic regimens involving enoxaparin or unfractionated heparin (UFH), in combination with tirofiban or placebo for 2 to 8 days. A concurrent registry tracked STEMI patients coming in within <12 hours, and who underwent reperfusion. This registry also tracked the remaining STEMI patients who neither received reperfusion nor were enrolled in the TETAMI randomized trial. The demographics and clinical outcomes of all three groups (received reperfusion therapy, too late for reperfusion and enrolled in the randomized trial, neither received reperfusion therapy nor were enrolled in the randomized trial) were prospectively tracked. RESULTS AND CONCLUSIONS: There were 2,737 patients who presented with STEMI or a new left branch bundle block (LBBB), of which 1,654 (60%) presented < or =12 hours. There were 1,196 (72%) of 1,654 patients who received reperfusion therapy. There were 458 (28%) of the 1,654 patients deemed "ineligible" for reperfusion, mostly because of a contraindication to lytics or for being "too old." In contrast, 1,083 (40%) of 2,737 patients presented >12 hours. Apart from 34 of these patients who had a stuttering infarction and were referred for reperfusion, the remaining patients did not receive reperfusion therapy. Registry patients who received reperfusion therapy, compared with TETAMI randomized patients (all of whom received antithrombotic therapy) and registry patients who did not receive reperfusion, were younger (61 years versus 63 years and 67 years), were more likely to be male (78% versus 73% and 63%), and had persistent ST-segment elevation as opposed to LBBB or Q waves. Registry patients who received reperfusion therapy had better clinical outcomes, even after adjusting for admission Killip class, compared with TETAMI randomized patients and registry patients who did not receive reperfusion therapy. TETAMI randomized patients had better outcomes than registry patients who did not receive reperfusion therapy. The major obstacle to expanding the delivery of reperfusion therapy to patients with STEMI is the large fraction of patients who present too late for reperfusion therapy. Examination of prospectively gathered data on STEMI patients who are ineligible for reperfusion may help optimize their treatment.

The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST-segment elevation myocardial infarction patients ineligible for reperfusion (TETAMI): a randomized trial.

OBJECTIVES: The aims of the Safety and Efficacy of Subcutaneous Enoxaparin Versus Intravenous Unfractionated Heparin and Tirofiban Versus Placebo in the Treatment of Acute ST-Segment Elevation Myocardial Infarction Patients Ineligible for Reperfusion (TETAMI) study were to demonstrate that enoxaparin was superior to unfractionated heparin (UFH) and that tirofiban was better than placebo in patients with acute ST-segment elevation myocardial infarction (STEMI) who do not receive timely reperfusion. BACKGROUND: An optimal treatment strategy has not been identified for the many STEMI patients ineligible for acute reperfusion. METHODS: A total of 1224 patients were enrolled in 91 centers in 14 countries between July 1999 and July 2002. Patients with STEMI ineligible for reperfusion were randomized to enoxaparin, enoxaparin plus tirofiban, UFH, or UFH plus tirofiban. All patients received oral aspirin. The primary efficacy end point was the 30-day combined incidence of death, reinfarction, or recurrent angina; the primary analysis was the comparison of the pooled enoxaparin and UFH groups. RESULTS: The incidence of the primary efficacy end point was 15.7% enoxaparin versus 17.3% for UFH (odds ratio 0.89 [95% confidence interval CI = 0.66 to 1.21]) and 16.6% for tirofiban versus 16.4% for placebo (odds ratio 1.02 [95% CI 0.75 to 1.38]). The Thrombolysis In Myocardial Infarction (TIMI) major hemorrhage rate was 1.5% for enoxaparin versus 1.3% for UFH (odds ratio 1.16 [95% CI 0.44 to 3.02]) and 1.8% versus 1% for tirofiban versus placebo (odds ratio 1.82 [95% CI 0.67 to 4.95]). CONCLUSIONS: This study did not show that enoxaparin significantly reduced the 30-day incidence of death, reinfarction, and recurrent angina compared with UFH in non-reperfused STEMI patients. However, enoxaparin appears to have a similar safety and efficacy profile to UFH and may be an alternative treatment. Additional therapy with tirofiban did not appear beneficial.

Prospective evaluation of clinical outcomes after acute ST-elevation myocardial infarction in patients who are ineligible for reperfusion therapy: Preliminary results from the TETAMI registry nd randomized trial

BACKGROUND: Treatment with lytics or primary percutaneous coronary interventions (PCI) reduces the mortality rate of patients with ST-elevation myocardial infarction (STEMI) presenting within 12 hours. Patients presenting >12 hours are generally considered to be ineligible for reperfusion therapy, and there are currently no specific treatment recommendations for this subgroup.Methods- All patients with STEMI 12 hours. Apart from 34 of these patients who had a stuttering infarction and were referred for reperfusion, the remaining patients did not receive reperfusion therapy.Registry patients who received reperfusion therapy, compared with TETAMI randomized patients (all of whom received antithrombotic therapy) and registry patients who did not receive reperfusion, were younger (61 years versus 63 years and 67 years), were more likely to be male (78% versus 73% and 63%), and had persistent ST-segment elevation as opposed to LBBB or Q waves...

The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST-segment elevation myocardial infarction Patients ineligible for reperfusion (TETAMI): a randomized trial

The aims of the Safety and Efficacy of Subcutaneous Enoxaparin Versus Intravenous Unfractionated Heparin and Tirofiban Versus Placebo in the Treatment of Acute ST-Segment Elevation Myocardial Infarction Patients Ineligible for Reperfusion (TETAMI) study were to demonstrate that enoxaparin was superior to unfractionated heparin (UFH) and that tirofiban was better than placebo in patients with acute ST-segment elevation myocardial infarction (STEMI) who do not receive timely reperfusion. BACKGROUND: An optimal treatment strategy has not been identified for the many STEMI patients ineligible for acute reperfusion. METHODS: A total of 1224 patients were enrolled in 91 centers in 14 countries between July 1999 and July 2002. Patients with STEMI ineligible for reperfusion were randomized to enoxaparin, enoxaparin plus tirofiban, UFH, or UFH plus tirofiban. All patients received oral aspirin. The primary efficacy end point was the 30-day combined incidence of death, reinfarction, or recurrent angina; the primary analysis was the comparison of the pooled enoxaparin and UFH groups. REULTS: The incidence of the primary efficacy end point was 15.7% enoxaparin versus 17.3% for UFH (odds ratio 0.89 [95% confidence interval CI = 0.66 to 1.21]) and 16.6% for tirofiban versus 16.4% for placebo (odds ratio 1.02 [95% CI 0.75 to 1.38]). The Thrombolysis In Myocardial Infarction (TIMI) major hemorrhage rate was 1.5% for enoxaparin versus 1.3% for UFH (odds ratio 1.16 [95% CI 0.44 to 3.02]) and 1.8% versus 1% for tirofiban versus Placebo (odds ratio 1.82 ([95% CI 0.67 to 4.95])...