Response to Letter Regarding Article, “Cost-Effectiveness of Prasugrel Versus Clopidogrel in Patients With Acute Coronary Syndromes and Planned Percutaneous Coronary Intervention: Results From the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction TRITON-TIMI 38”
Dr Serebruany raises 3 issues with regard to our analysis1: (1) Failure to account for an increased incidence of cancer; (2) use of the Saskatchewan Health database for prognostic modeling; and (3) differential effects across patient subgroups.
With regard to cancer, Dr Serebruany is correct that we have not explicitly accounted for the impact of cancer in our analysis. There are several reasons behind this approach. First of all, our analysis plan was developed prospectively, long before the trial results were available. For reasons of expediency, our data collection focused on those events that were expected to be impacted by the treatments under consideration (ie, cardiovascular events and bleeding). Consequently, we did not collect specific data on resource utilization associated with cancer and were unable to include this information in our analysis. More importantly, however, it should be noted that the excess risk of cancer that Dr Serebruany alludes to was not actually identified in the Food and Drug Administration analysis, and the trend toward an increase in newly diagnosed cancer (1.6% versus 1.2%, relative risk 1.29, 95% confidence interval 0.96 to 1.72) was reviewed thoroughly by the Food and Drug Administration and its advisory committee and found to be highly unlikely.2 Moreover, any excess mortality related to cancer (or any other cause) was explicitly accounted for in our study by means of a sensitivity analysis that incorporated all-cause mortality in the life-expectancy projections. The results of this analysis (described in Table III of the online-only Data Supplement to our article) demonstrated only a trivial change in life expectancy compared with our original projections (0.1021 versus 0.1024 life years gained with prasugrel) and no meaningful change in our overall results.
Previous analyses from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) have identified a consistent reduction in myocardial infarction with prasugrel regardless of size or provocation of myocardial infarction (MI).3 Regarding the impact of periprocedural MIs on subsequent life expectancy, we included a sensitivity analysis in which we assumed that such events had no prognostic impact (possibly a biased assumption, in the opposite direction). Results from this sensitivity analysis (in which the estimate of life years gained with prasugrel was reduced from 0.1024 to 0.0940 years) were also presented in Table III of the online-only Data Supplement to our article and did not differ substantively from the main finding of economic dominance for the overall analysis.
On the basis of our published analysis, the estimated mortality benefit of prasugrel tended to be greater among patients with ST-elevation MI (0.1447 life years gained with prasugrel versus clopidogrel in ST-elevation MI patients compared with 0.0991 life years gained among non–ST-elevation MI/unstable angina patients, respectively). Nonetheless, even among the non–ST-elevation MI/unstable angina subset, although there was no difference in survival over the duration of the trial, we projected a modest gain in life expectancy related predominantly to prevention of recurrent MI and stent thrombosis. Thus, although the cost-effectiveness was more favorable in the ST-elevation MI group (because of greater cost savings and greater projected life expectancy gains), even among the non–ST-elevation MI/unstable angina subset, we found that prasugrel was economically dominant and reasonably cost-effective (<$50 000 per life year gained in more than 98% of the bootstrap replications).
Ultimately, all health economic analyses can be criticized because they invariably require certain assumptions to project long-term costs and outcomes based on the relatively short duration of observation encompassed in any clinical trial. Unfortunately, the alternative approach (waiting for all patients in a clinical trial to die so that costs and life expectancy can be calculated rather than estimated) is rarely feasible or desirable. By adhering to a prespecified analysis plan and by making any assumptions explicit, we believe that rigorous economic analyses such as ours can provide an important additional perspective on the results of any clinical trial and lead to better-informed clinical guidelines and healthcare policy.
Dr Mahoney has received grant support from Eli Lilly, Daiichi Sankyo, Sanofi-Aventis, and Bristol-Myers Squibb and has received lecture fees from Sanofi-Aventis and Bristol-Myers Squibb. Dr Cohen has received grant support from Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, Daiichi Sankyo, Schering-Plough, The Medicines Company, Accumetrics, Cordis, and Boston Scientific. Drs Wiviott, Antman, and Braunwald have received research grants from Daiichi Sankyo, Eli Lilly, and Sanofi Aventis. In addition, Dr Braunwald has received consulting or paid advisory board fees from Daiichi Sankyo and Sanofi-Aventis and lecture fees from Eli Lilly and Daiichi Sankyo. Dr Wiviott has received consulting or advisory board fees from Daiichi Sankyo and Sanofi-Aventis and lecture fees from Eli Lilly and Daiichi Sankyo. Dr Antman has received consulting or advisory board fees from Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis. The remaining authors report no conflicts.
Mahoney EM, Wang K, Arnold SV, Proskorovsky I, Wiviott S, Antman E, Braunwald E, Cohen DJ. Cost-effectiveness of prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention: results from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction TRITON-TIMI 38. Circulation. 2010; 121: 71–79.
Morrow DA, Wiviott SD, White HD, Nicolau JC, Bramucci E, Murphy SA, Bonaca MP, Ruff CT, Scirica BM, McCabe CH, Antman EM, Braunwald E. Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38: an application of the classification system from the universal definition of myocardial infarction. Circulation. 2009; 119: 2758–2764.