25th March 2009
A pre-specified subgroup analysis of the TRITON-TIMI 38 trial suggests that prasugrel ▼ may be more effective than clopidogrel in those with STEMI ACS undergoing PCI. Major bleeding across the whole subgroup was around 2% for both treatments, but was significantly more common with prasugrel in those who had CABG surgery. However, as always, we should remain cautious about interpretation of results from sub-group analysis.
Prasugrel is to be marketed on the 27th March 2009. Area Prescribing Committees should, therefore, engage with local clinicians and agree a protocol for use. Its possible impact will depend not only upon the acquisition cost, but also upon the identification of those patients for whom it may be appropriate. The efficacy and safety data detailed in the TRITON-TIMI 38 trial should be used when making decisions.
The Summary of Product Characteristics for prasugrel emphasises that severe haemorrhagic events are more frequent in patients aged 75 years or older (including fatal events) or in those weighing less than 60kg. Use in older patients is not usually recommended but, if deemed necessary, a reduced maintenance dose should be prescribed. Patients weighing less than 60kg should also receive a lower maintenance dose.
What is the background to this?
The use of stents, thienopyridine anti-platelet agents and platelet glycoprotein IIb/IIIa inhibitors is now well established in the management of ST-elevation myocardial infarction (STEMI).
Prasugrel ▼ (Efient ® ) is to be marketed on 27th March at a price of £47.56 per 28-tablet pack of 5mg or 10mg strength. It is licensed, for use with acetylsalicylic acid (aspirin), for the prevention of atherothrombotic events in patients with acute coronary syndrome (ACS) [defined as unstable angina or non-ST segment elevation MI (NSTEMI)] or STEMI and who are undergoing primary or delayed percutaneous coronary intervention (PCI).
NICE are reviewing prasugrel plus aspirin for the treatment of ACS with PCI as part of their 17th wave of technology appraisals, with an expected publication date of October 2009. More information on the possible place in therapy of prasugrel is available from our On the Horizon Future Medicines Bulletin (NHSnet connection required). Information on ACS can be found on the cardiovascular section of NPC.
What does this study claim?
This pre-specified sub-groups analysis from the TRITON-TIMI 38 study claims that, in patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel in preventing ischaemic events with no apparent additional risk of bleeding. However, the trial was not prospectively designed or powered to show a benefit of prasugrel over clopidogrel in the STEMI cohort. At 15 months, 174 (10.0%) of patients assigned to prasugrel had met the primary endpoint compared to 216 (12.4%) allocated to clopidogrel (hazard ratio [HR] 0.79; 95% Confidence Interval [CI] 0.65 to 0.97]; P=0.02. Number needed to treat (NNT) =42). Treatments did not differ with respect to thrombolysis in myocardial infarction (TIMI) major bleeding unrelated to CABG surgery at 30 days (P=0.34) and 15 months (P=0.65). TIMI major bleeding after CABG was increased with prasugrel with a number needed to harm (NNH) of 7.
How does this relate to other studies?
A phase III randomised controlled trial (RCT) of prasugrel plus aspirin vs. clopidogrel plus aspirin in patients with moderate-to-high risk ACS undergoing scheduled PCI was published in November 2007 (TRITON-TIMI 38). This demonstrated improved efficacy for prasugrel over clopidogrel in reducing atherothrombotic events, but at the expense of an increased major, and in some cases, fatal bleeding risk.
An NPC rapid review of another sub-group analysis of TRITON-TIMI 38 looked at the claim of greater net treatment benefit with prasugrel in patients with diabetes mellitus compared to those without. However, it concluded that the results had limitations. The overall increased risk of bleeding associated with prasugrel, as shown in the full TRITON-TIMI 38 paper, remains a concern.
This latest sub-group analysis needs to be viewed with caution. It was not powered to show superiority of prasugrel over clopidogrel in the STEMI cohort alone. Therefore the effect of prasugrel on both ischaemic and haemorrhagic events should be deemed similar in STEMI and NSTEMI patients enrolled in TRITON-TIMI 38. The clopidogrel loading dose used in that trial may have been inadequate as 600mg is now considered standard of care.
As noted in an accompanying commentary, the challenge will be identifying those patients at low-to-intermediate risk of bleeding, or at high risk of atherothrombotic events, who will obtain the benefit of prasugrel with minimal bleeding complications.
Montalescot G, Wiviott SD, Braunwald E et al, for the TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373:723-31
Design: Pre-specified sub-group analysis of patients with STEMI from the multicentre, double-blind randomised TRITON-TIMI 38 trial.
Patients: TRITON–TIMI 38 included 13,608 patients with moderate–to-high risk ACS undergoing scheduled PCI. This analysis deals with the 3,534 patients who presented with STEMI. 2,438 had primary PCI (within 12 hours of onset of symptoms), 1,094 secondary PCI (between 12 hours and 14 days) and 2 patients did not receive PCI or study drug.
Intervention and Comparison: Patients were randomised to either prasugrel 60mg loading then 10mg maintenance dose (n= 1,769) or clopidogrel 300mg loading, 75mg maintenance dose (n= 1,765). Median duration of treatment was 15.2 months. Aspirin was recommended.
Outcomes: The primary efficacy endpoint was a composite of cardiovascular death, non-fatal MI, or non-fatal stroke. Follow-up was 15 months, with secondary analyses at 30 days.
Results: At 15 months 174 [10.0%] of prasugrel patients versus 216 [12.4%] clopidogrel patients reached the primary endpoint (HR 0.79; 95% CI 0.65 to 0.97; P=0.02. NNT=42). Treatments did not differ with respect to thrombolysis in myocardial infarction (TIMI) major bleeding unrelated to CABG surgery at 30 days ( prasugrel group 1.0% vs.1.3% in the clopidogrel group; P=0.34) and 15 months ( 2.4% vs. 2.0%, respectively; P=0.65). TIMI life threatening bleeding and TIMI major and minor bleeding were also similar with the two treatments. Less than 4% of patients underwent CABG surgery, but prasugrel was associated with a significantly increased risk for TIMI major bleeding after CABG surgery at 15 months compared to clopidogrel (18.8% vs. 2.7%, odds ratio [OR] 8.19; 95% CI 1.76 to 38.18; P= 0.0033. NNH=7).
Sponsorship: Daiichi Sankyo and Eli Lilly.