Response to Letter Regarding Article, “Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel: Thrombolysis in Myocardial Infarction 38”
We appreciate the letter by Drs Rosenstein and Parra about the diabetes mellitus (DM) analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel: Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38.1 We agree with the general principle that the overall results of a clinical trial should be considered to apply to those patients who were included in the clinical trial and that subgroup analyses should be interpreted with caution. The results should be considered to be hypothesis generating. Clinical trials in general are, and TRITON–TIMI 38 in specific was, not powered for efficacy end points in all individual subgroups. It is impractical to repeat an adequately powered clinical trial in each individual subgroup. We believe that the altered biology of platelet function in DM, higher rates of poor response to clopidogrel in patients with DM,2 and previous experience showing greater benefit of intensive antiplatelet therapy with glycoprotein IIb/IIIa receptor blockers in patients with DM3 all make the hypothesis-generating results of our subgroup analysis biologically plausible and clinically compelling. We too look forward to future antiplatelet therapies being tested prospectively and directly in patients with DM.
The authors of the letter state that statistical significance (presumably of the interaction term, although this is not specifically noted in the letter) should be corrected for the number of subgroups tested and interpreted in this context. Their commentary applies these criteria selectively, however. The authors challenge the results of the diabetes analysis that showed a statistically significant benefit in patients with and without DM but with a statistically greater relative benefit among diabetic patients (P = 0.05 for the outcome of death/myocardial infarction/stroke/major bleed) while highlighting the “concern” raised by subgroups without a statistical interaction for the same composite outcome (women, P interaction = 0.36; age ≤65, P = 0.16; creatinine clearance <60 mL/min, P interaction = 0.50).
Further, the authors state that the major benefit of prasugrel was associated with the loading dose only and was observed in the first 3 days, referencing a speculative editorial.4 Our previously published data have addressed this question directly in the overall TRITON–TIMI 38 population showing a similar and significant net benefit of prasugrel both within 3 days (hazard ratio [HR] = 0.85, P= 0.02) and beyond 3 days (HR = 0.87, P= 0.03), demonstrating benefit after loading and maintenance dosing.5 For the DM population, a similar net benefit of prasugrel was found both within 3 days (HR = 0.74, P= 0.06) and beyond 3 days (HR = 0.73, P= 0.005) and also within 30 days (HR = 0.68, P= 0.003) and beyond 30 days (HR = 0.76, P= 0.03).
Sources of Funding
The TRITON–TIMI 38 trial was supported by Daiichi Sankyo and Eli Lilly.
The TRITON–TIMI 38 trial was supported by Daiichi Sankyo Company LTD and Eli Lilly. Drs Wiviott and Braunwald, S.A. Murphy, and Dr Antman report receiving research grants from Daiichi Sankyo, Eli Lilly, and Sanofi-Aventis. Dr Wiviott reports receiving consulting fees or paid advisory fees from Sanofi-Aventis and lecture fees from Eli Lilly and Daiichi Sankyo; Dr Braunwald, consulting fees or paid advisory board fees from Daiichi Sankyo and Sanofi-Aventis, and lecture fees from Eli Lilly and Sanofi-Aventis; Dr Antman, consulting fees or paid advisory board fees from Sanofi-Aventis, and lecture fees from Eli Lilly and Sanofi-Aventis. Dr Angiolillo reports research grant support from Glaxo-Smith-Kline and consulting, speakers bureau, or advisory board compensation from Daiichi Sankyo, Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, Novartis, and Portola. Dr Goodman reports research grant support, speaker honoraria, or consulting income from Astra Zeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Schering-Plough, and The Medicines Company. The remaining authors report no conflicts.
Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW, Goodman SG, Corbalan R, Purdy DA, Murphy SA, McCabe CH, Antman EM. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel: Thrombolysis in Myocardial Infarction 38. Circulation. 2008; 118: 1626–1636.
Sabatine MS, Braunwald E. Will diabetes save the platelet blockers? Circulation. 2001; 104: 2759–2761.
Serebruany V. Excess rates of nonfatal myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel (preventing clinical events or chasing enzymatic ghosts?) Am J Cardiol. 2008; 9: 1364–1366.
Antman EM, Wiviott SD, Murphy SA, Voitk J, Hasin Y, Widimsky P, Chandna H, Macias W, McCabe CH, Braunwald E. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction) analysis. J Am Coll Cardiol. 2008; 51: 2028–2033.