An analysis of TRITON-TIMI 38, based on the 12 month recommended length of therapy in the European label for prasugrel

Abstract

Background:

In TRITON-TIMI 38, patients with acute coronary syndromes were treated with prasugrel or clopidogrel, with aspirin, for a median of 14.5 (maximum of 15) months. Based on this trial, the EU label for prasugrel recommends treatment for up to 12 months and excludes patients with prior stroke/transient ischemic attack (TIA). Furthermore, the EU label recommends the 10 mg maintenance dose (MD) for patients with body weight ≥60 kg and age <75 years. A lower MD of 5 mg is recommended for those with body weight <60 kg; although generally not recommended, 5 mg can be prescribed to patients ≥75 years after individual risk–benefit evaluation. This paper presents the one-year outcome data for this ‘10 mg indicated cohort’.

Methods and results:

From the overall cohort of 13,608 patients in TRITON-TIMI 38, 10,804 fulfilled inclusion criteria for the 10 mg indicated cohort, of whom 22% had a history of diabetes, 73% an index diagnosis of unstable angina/non-ST-segment-elevation myocardial infarction (UA/NSTEMI), and 27% an index diagnosis of ST-segment-elevation myocardial infarction (STEMI). In this cohort at 12 months, those given prasugrel experienced significantly fewer ischemic events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, 7.8% vs 10.5%, hazard ratio (HR) = 0.73, p < 0.001, than those given clopidogrel, with a non-significant increase in non-coronary artery bypass graft (CABG) TIMI major bleeding, 1.7% vs 1.5%, HR = 1.15, p = 0.40; similarly, in the overall cohort these frequencies were 9.4% vs 11.4%, HR = 0.81, p < 0.001, for cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, and 2.2% vs 1.8%, HR = 1.24, p = 0.10, for non-CABG TIMI major bleeding. There was a significant reduction in stent thrombosis in the prasugrel group, with similar mortality rates and no excess of strokes.

Conclusions:

Treatment with prasugrel according to EU label recommendations results in a significant 27% and 57% relative risk reduction (absolute risk reductions of 2.7% and 1.2%) in ischemic events and stent thromboses respectively compared with clopidogrel, with a 15% relative risk increase (absolute risk increase of 0.2%) for major bleeds (p = 0.40), and no excess of strokes.

Limitations:

Although restricted to 365 days of follow-up, this analysis encapsulates 1366 of 1424 (95.9%) of all primary endpoint events and 244 of 257 (94.9%) of all first non-CABG TIMI major bleeds reported in the pivotal manuscript. Furthermore, the 10 mg indicated cohort was not a pre-specified subgroup in the study protocol, but due to European labeling restrictions, results for all outcomes in this cohort are presented through 12 months.

Keywords::

• Acute coronary syndrome
• Clopidogrel
• Diabetes
• One-year
• Prasugrel
• TRITON-TIMI 38

Transparency

Declaration of funding

This study was supported by Daiichi Sankyo and Eli Lilly and Company.

Declaration of financial/other relationships

R.W. has disclosed that he has collaborated in trials of anti-thrombotic treatments in ACS and has received meeting support from Daiichi Sankyo and Eli Lilly. RW holds no shares in the company. K.I. and Y.R. have disclosed that they are employees of Daiichi Sankyo, but hold no shares in the company. T.C. has disclosed that he is employed by Lilly Research Laboratories and owns shares in Eli Lilly. J.L.-S. has disclosed that he has received research grants from Lilly-Daiichi Sankyo and Astra Zeneca, and has acted as a consultant for Lilly-Daiichi Sankyo and Astra Zeneca. P.W. has disclosed that he did not receive any support for his work on this manuscript, but he has received occasional lecture honoraria and consultancy fees from Daiichi Sankyo, Eli Lilly, Bayer, Boehringer Ingelheim and Astra Zeneca. He was also the national coordinator (Czech Republic) of the TRITON TIMI 38 trial and received the study honoraria for that work during the trial period. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Notice of Correction:

The version of this article published online ahead of print on 06 Aug 2014 contained an error in Figure 2B and 4A. In Figure 2B, the value 7.9 was changed to 7.8 for the Prasugrel efficacy Kaplan Meier curve. The values for the numbers at risk for Prasugrel and Clopidogrel were incorrect in Figure 4A. The errors have been corrected for this version.