Would Tirofiban Have Been Shown Non‐Inferior to Abciximab Had the TENACITY Trial Not Been Terminated for Financial Reasons?

Abstract

Objectives To investigate whether tirofiban would have been non-inferior to abciximab had the trial completed enrollment, and we place the termination of this trial in a broader research ethics context. Background TENACITY was terminated by the sponsor for financial reasons. At the time, event rates for the 2 treatment arms were unknown. Methods TENACITY was designed to compare tirofiban with abciximab in approximately 8000 patients; however, enrollment was terminated after 383 (4.8%) patients. The primary endpoint was a composite of 30-day death, myocardial infarction, and urgent target vessel revascularization. Non-inferiority was defined as the likelihood that tirofiban would preserve at least 50% of the ability of abciximab to reduce the primary endpoint at 30 days, based on abciximab’s demonstrated ability to reduce such events by 43% (relative risk, 0.573; 95% confidence interval [CI], 0.507–0.648; P<0.001). To determine the probability of non-inferiority given the patients already enrolled, a Bayesian approach was used. Results The primary composite endpoint occurred in 8.8% of patients randomized to abciximab vs. 6.9% receiving high-bolus-dose tirofiban (odds ratio, 0.77; 95% CI, 0.37–1.64). The estimated conditional power for the test that tirofiban would be non-inferior to abciximab if all patients been enrolled is 93.7%. Using the estimated predictive power method, the likelihood was 84.8%. Conclusions TENACITY was well-powered to identify non-inferiority with tirofiban vs. abciximab, and the patients enrolled strengthened the probability that this would have been the outcome had the trial been completed. When a clinical trial is terminated solely for financial reasons, it is incumbent upon the sponsor to provide proper patient follow-up and publication of the findings.

A randomized trial assessing the impact of three different glycoprotein IIb/IIIa antagonists on glycoprotein IIb/IIIa platelet receptor inhibition and clinical endpoints in patients with acute coronary syndromes

“…also found a small nonstatistically significant increase in minor bleeding and major bleeding requiring transfusion in the high‐dose tirofiban group. Although ceased prematurely, another recent trial would have likely demonstrated noninferiority of tirofiban over abciximab in terms of MACEs had it been completed . More recently, abciximab and high‐dose, double‐bolus eptifibatide have been shown to have a comparable effect on outcomes in a large number of patients (n=1710) undergoing primary PCI for STEMI, with similar rates of MACEs and major bleeding at 30 days and 3 years .…”

“…Although ceased prematurely, another recent trial would have likely demonstrated noninferiority of tirofiban over abciximab in terms of MACEs had it been completed. 24,25 More recently, abciximab and high-dose, double-bolus eptifibatide have been shown to have a comparable effect on outcomes in a large number of patients (n=1710) undergoing primary PCI for STEMI, with similar rates of MACEs and major bleeding at 30 days and 3 years. 26 Although not powered to compare these events, we have consistent results with these larger studies.…”

Glycoprotein IIb/III Inhibition During Acute Percutaneous Coronary Intervention: Tool or Talisman?

“…The MULTISTRATEGY study is one of the larger reports showing non‐inferiority of tirofiban compared to abciximab in primary PCI . This was also suggested in a recent statistical extrapolation of the TENACITY trial . Despite this apparent equivalence, 2 meta‐analyses of abciximab and tirofiban trials were conflicting in their conclusions as to the efficacy of these agents .…”

“…4 This was also suggested in a recent statistical extrapolation of the TENACITY trial. 5 Despite this apparent equivalence, 2 meta-analyses of abciximab and tirofiban trials were conflicting in their conclusions as to the efficacy of these agents. 6,7 In the high-dose P2Y 12 inhibitors pretreatment era, trials of GPI similarly resulted in differing outcome benefits, ON-TIME 2 8 favoring pretreatment with tirofiban with no benefit from upstream abciximab in BRAVE-3.…”