TRILOGY ACS: Does it raise new questions about the advantages of prasugrel over clopidogrel?

One of the landmark trials to emerge from the proceedings of the European Society of Cardiology 2012 meeting was TRILOGY ACS, the long-awaited comparison of prasugrel and clopidogrel in patients with acute coronary syndrome (ACS) for whom a medical management strategy is selected [1]. Prior to its publication, the use of prasugrel was recommended only in patients for whom percutaneous coronary intervention (PCI) was intended, based on the results of TRITON TIMI 38 [2].

In TRILOGY ACS, patients with unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI) for whom a medical management strategy was selected were randomized to receive prasugrel or clopidogrel, added to background therapy with aspirin. Patients randomized to prasugrel were given a 30 mg loading dose followed by 10 mg daily, and patients over the age of 75 or under 60 kg were given 5 mg daily (a maintenance dose already available but previously unstudied in large clinical trials).  Patients randomized to clopidogrel received a 300 mg loading dose followed by 75 mg daily, a regimen already known to reduce cardiovascular events in a similar patient population [3]. The primary analysis of TRILOGY ACS was intended for those patients under the age of 75, while analyses for older patients were only exploratory.

No differences in the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke were observed (13.9% versus 16.0%, p = 0.21), a stark contrast to the results of TRITON TIMI 38. Interestingly, no significant differences in bleeding events were observed either, although this may have been due to the use of lower prasugrel maintenance doses in older and lower weight patients, two groups that were at higher risk of bleeding complications in previous trials.

While patients enrolled in TRILOGY ACS were unquestionably different from those included in TRITON TIMI 38 (e.g., no PCI performed, patients with ST-elevation myocardial infarction [STEMI] excluded), for me, this trial raises several questions about the long-term advantages of prasugrel over clopidogrel, even in those patients for whom an invasive strategy is selected.

First, nearly 95% of patients in TRILOGY ACS were pre-treated with clopidogrel prior to randomization, with the majority of them receiving at least 4 days of therapy. Based on the results of TRITON TIMI 38, where significant benefit was observed in the first few days after randomization, some might contend that the window for observing maximal benefit with prasugrel was missed, as patients randomized to prasugrel did not receive it until several days after their index event. On the other hand, it may also indicate that there is minimal to no incremental benefit with the use of prasugrel in patients who are already receiving dual antiplatelet therapy, a hypothesis previously untested in earlier trials.

Which brings me to my next point -- how the lack of benefit observed in TRILOGY ACS highlights several important limitations in the design of TRITON TIMI 38 and how it may have given prasugrel an unfair advantage over clopidogrel in the PCI population.

As mentioned above, much of the proposed benefit of prasugrel in TRITON TIMI 38 was observed in the first few hours after randomization, with nearly half of the 2.2% difference in the primary endpoint being observed at only 3 days after randomization (5.6% versus 4.7%, or a difference of 0.9%, p = 0.01) [2]. While the appearance of these differences so early in the trial have been cited as one of the major advantages of prasugrel, a couple of important limitations should also be considered:

• Clopidogrel loading dose. While the appropriate loading dose of clopidogrel prior to PCI remains somewhat controversial, current guidelines recommend 600 mg, as this dose has demonstrated a faster onset of antiplatelet activity, a reduction in cardiovascular events at 30 days (a difference that emerges only days after randomization), and minimal (if any) differences in bleeding compared to a 300 mg loading dose [4]. However, patients in TRITON TIMI 38 only received a 300 mg loading dose prior to PCI, a practice that probably represented the standard of care at the time but is now thought to be inferior to a 600 mg loading dose.
• Timing of clopidogrel administration. One of the major pharmacokinetic advantages of prasugrel is that its antiplatelet effects emerge as early as 30 minutes after oral administration (peak of around 4 hours).  For clopidogrel, even at doses of 600 mg, these effects do not emerge until around 2 hours. In TRITON TIMI 38, nearly 75% of patients received their loading doses during PCI (or immediately thereafter), so it is unlikely that the antiplatelet effects of clopidogrel were even realized in the first few hours after randomization.

So it should be no surprise that such a significant difference in efficacy emerged as soon as hours after randomization.  However, the question is -- can those differences be attributed to prasugrel being a superior drug, or was clopidogrel simply not administered early enough (or at an appropriate dose) to observe its beneficial effects?

Furthermore, we now know that genetic variations in the expression of CYPC19 correspond to differences in clopidogrel response, likely due to a reduction in the biotransformation of clopidogrel to its active metabolite.  Carriers of at least one CYP2C19 reduced-function allele (*2 or *3) are less responsive to clopidogrel when compared to non-carriers (wild-type, or *1). A cohort of patients receiving clopidogrel in TRITON TIMI 38 were genotyped for loss-of-function alleles (n = 1477); of the patients who were carriers of a loss-of-function allele (i.e., non-responders), the primary endpoint occurred in 12% compared to only 8.0% of non-carriers (i.e., responders) (p = 0.01), a result comparable to the incidence observed with prasugrel in the overall population. Similar results were observed for stent thrombosis, where 2.6% of carriers experienced an event compared to only 0.8% of non-carriers (p = 0.02) [5]. 

In summary, I believe TRILOGY ACS raises several important questions about the advantages, and thus, the cost-effectiveness, of prasugrel for the long-term management of ACS, irrespective the management strategy selected (i.e., invasive or medical management).  The trial I would like to see performed is one that compares prasugrel to an adequate loading dose of clopidogrel (600 mg) administered at least 1-2 hours prior to PCI; all patients would be genotyped to see if any differences could be attributed to CYP2C19 polymorphisms. 

That being said, I do think prasugrel has some pharmacokinetic advantages over clopidogrel and should be considered first-line in certain clinical scenarios.  For example, I think it should be considered over clopidogrel in patients who require immediate revascularization (e.g., STEMI) or in other high-risk patients for whom the delayed onset of antiplatelet activity observed with clopidogrel might pose a risk to therapeutic outcomes. However, would that same patient continue to derive benefit from the use of prasugrel in the long-run (versus transitioning to clopidogrel)?

Of that I am the most doubtful, but will probably never know for sure.

References

1. Roe MT, Armstrong PW, Ohman EM, et al; for the TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012 Oct 4;367(14):1297-309. 
2. Wiviott SD, Braunwald E, Antman EM, et al; for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. 
3. Yusuf S, Zhao F, Fox KK, et al; for the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502. 
4. Cuisset T, Frere C, Alessi MC, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol. 2006 Oct 3;48(7):1339-45.  
5. Mega JL, Close SL, Sabatine MS, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62.