August 25, 2012

August 26, 2012 (Munich, Germany) — In TRILOGY ACS, one of the few studies to focus on high-risk patients with acute coronary syndrome (ACS) who are medically managed without revascularization, the newer antiplatelet agent prasugrel (Effient, Lilly/Daiichi-Sanyo) has failed to show a reduction in major cardiovascular events compared with clopidogrel [1]. The results were reported here at the European Society of Cardiology (ESC) 2012 Congress by Dr Matthew Roe (Duke Clinical Research Institute, Durham, NC), who is also lead author of the simultaneous online publication in the New England Journal of Medicine.

"This trial does not suggest a priori that prasugrel should be used for medically managed patients, because the results are neutral," senior author Dr Magnus Ohman (Duke Clinical Research Institute) told heartwire in an interview. Ohman discussed the findings at a press conference early Sunday morning.

But there was a surprising twist, says Ohman. The study was a median of 17 months in length, longer than most previous trials in ACS, he noted, and "the most striking thing is that there appears to be a time-dependent treatment effect."

While there was no difference in the rate of the primary composite end point or its separate components between those who received prasugrel and those who got clopidogrel in the first year of the study, thereafter the curves began to diverge, he explains. Prasugrel appeared to reduce the risk of events from 12 months onward, "an unexpected finding," says Ohman, which means that "the trial raises more questions than it answers and is going to require a lot more analysis."

This trial does not suggest a priori that prasugrel should be used for medically managed patients, because the results are neutral.

And prasugrel therapy did appear to be safe, even with the extended treatment employed in TRILOGY ACS, he says, noting that there was "no signal for increased rate of bleeding," with prasugrel. In addition, the 5-mg dose of prasugrel--which was used in those aged 75 and over and in those weighing less than 60 kg--also appeared to be safe in this regard.

Prasugrel is already approved for use during PCI in the setting of ACS, based primarily on the strength of the TRITON-TIMI 38 trial, in which it significantly reduced ischemic events compared with clopidogrel, but at the expense of an increase in major (and fatal) bleeding. Prasugrel is not currently recommended for ACS patients undergoing conservative, noninvasive (medical) management. Discussant of the study, Dr Raffaele De Caterina (G d'Annunzio University, Chieti, Italy) told the meeting that this guideline should not be changed on the basis of the TRILOGY ACS results.

Mixed Reaction to TRILOGY ACS Findings

There was a mixed response among cardiologists asked by heartwire to comment on the TRILOGY ACS results. Dr Doug Weaver (Henry Ford Hospital, Detroit, MI) said: "We are in an era when, in order to accept increased costs for therapy, we have to show increased value. So I would say that prasugrel doesn't pass muster to replace what's now generic clopidogrel. I don't think it's going to have much impact, and [Ohman] pointed that out."

Dr Gordon Tomaselli (Johns Hopkins University, Baltimore, MD) commented: "I agree with [Ohman]. I don't think it's going to change practice in this group. It's not going to make prasugrel be used much more than a drug that is off patent and is very inexpensive."

But Dr Elliott Antman (Brigham and Women's Hospital, Boston, MA) begs to differ. Antman was principal investigator of the TRITON-TIMI 38 trial but was not involved in TRILOGY ACS. "It would be superficial to regard this as an overall negative result," Antman told heartwire . "It's absolutely correct to say the primary end point didn't show a statistically significant difference between prasugrel and clopidogrel in those ACS patients managed medically, but there are several fascinating and potentially important observations."

One of these is the fact that, in TRILOGY ACS, the 5-mg dose of prasugrel used in patients aged 75 years and older and in those under 60 kg in weight appears to be safe, because there was no increased risk in bleeding, something that was seen in these patient groups when they took 10 mg of prasugrel in TRITON. This finding, says Antman, is verification of what pharmacokinetic and pharmacodynamic studies have suggested and has practical applications, because a 5-mg dose of prasugrel is available.

Weaver agrees with Antman on this point. "From the clinician's standpoint, those are very important data. If you remember, the dose of 5 mg was based on a statistical model--no patient data--so now we have some patient data that validate it is safe. There was no increase in strokes and major bleeding. We do use prasugrel in some patients, so the safety part is very important for clinicians, but it's not going to make headlines."

De Caterina also thought this was important, stating that the TRILOGY ACS results demonstrate "the successful adoption of the modified regimen [of 5 mg]" in the >75 and <60-kg patient groups.

And Antman believes this finding will play well with regulatory authorities. "The FDA is very interested in dose modification," he notes. He also says he "would not be surprised" if Lilly/Daiichi-Sankyo filed for a supplemental new drug application for prasugrel for medically managed ACS. "Of course, they will need to look carefully at the data."

Time-Dependent Effect With Multiple Recurrent Ischemic Events, Too

The trial raises more questions than it answers and is going to require a lot more analysis.

In the double-blind, randomized TRILOGY ACS trial, patients were eligible if they were selected for a final treatment strategy of medical management without revascularization within 10 days of their index ACS event. The study was conducted from June 2008 through September 2011, and participants were enrolled at 966 sites in 52 countries.

Roe explained that around 40% to 60% of ACS patients worldwide are managed medically, for a multitude of reasons--for example, because of poor renal function, diabetes, or advanced age. Hence, as a patient group, they are at higher risk than the overall ACS population, he notes.

The 7243 ACS patients age <75 years taking aspirin were randomized to 30 months of treatment with prasugrel 10 mg daily or clopidogrel 75 mg daily (prasugrel 5 mg was employed for those weighing <60 kg). There was a secondary analysis of patients aged >75 years (n=2083), who also received 5 mg of prasugrel or clopidogrel.

"We believed it was important to follow people for more than one year," Ohman noted, adding, "I'm glad that we did, because much of the information came after one year."

Through a median follow-up of 17 months, the primary end point of cardiovascular death, MI, or stroke among those <75 years occurred in 13.9% of those treated with prasugrel vs 16.0% of those treated with clopidogrel (hazard ratio 0.91; p=0.21). Similar results were observed in the overall population.

The researchers also performed a prespecified analysis of multiple recurrent ischemic events (all components of the primary end point), which hinted at a lower risk with prasugrel than clopidogrel among those under 75 years (HR 0.85; p=0.044). Again, this suggested a time-dependent treatment effect in favor of prasugrel, says Ohman, "with much of the reduction in recurrent events being after one year," which he notes is "consistent with the time dependence seen with the primary end point."

The primary end point and the outcome of multiple recurrent ischemic events are the only efficacy end points for which results were reported for the overall population, says Ohman, explaining that most of the findings with regard to those aged 75 and over will be presented at a future date, most likely at the Canadian Cardiovascular Congress in October.

What About Ticagrelor?

Tomaselli commented to heartwire that "the elephant in the room" is ticagrelor (Brilinta, AstraZeneca). He also commented about how the TRILOGY ACS results play out with regard to this other new antiplatelet agent. "I don't think this changes the choice between prasugrel and clopidogrel, but the real issue is how does ticagrelor fit into this?"

De Caterina compared and contrasted the findings of TRILOGY ACS with those of a subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) study in ACS patients who were managed medically, published in the BMJ in 2011 [2]. There are two important things to note here, he said. First, he reiterated the higher overall risk of medically managed ACS patients, and second, the fact that "there is an important difference in favor of ticagrelor in noninvasive, medically managed patients."

Safety Profile of the Two Treatments Similar

Roe emphasized there were no differences between rates of GUSTO severe/life-threatening and TIMI major, fatal, and intracranial bleeding between the prasugrel and clopidogrel groups in participants <75 years and the overall population.

But those in the prasugrel group did have slightly higher rates of non-CABG-related GUSTO severe/life-threatening or moderate bleeding (1.4% vs 1% with clopidogrel; p=0.06) and TIMI major or minor bleeding (1.9% vs 1.3% with clopidogrel; p=0.02).

The frequency of nonhemorrhagic serious adverse events was similar by treatment except for a higher frequency of heart failure in the clopidogrel group. There was no difference between the two groups in terms of cancers.

TRILOGY ACS was supported by Eli Lilly and Daiichi Sankyo. Roe reports receiving grant support from Eli Lilly, Bristol-Myers Squibb, Hoffmann-La Roche, Novartis, Schering-Plough, and KAI Pharmaceuticals; consulting fees from Eli Lilly, Daiichi Sankyo, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Janssen Pharmaceuticals, KAI Pharmaceuticals, Sanofi, Helsinn Pharmaceuticals, Regeneron, Novartis, AstraZeneca, and Orexigen; and lecture fees from AstraZeneca and Janssen Pharmaceuticals. Ohman reports receiving grant support and travel expenses from Daiichi Sankyo and Eli Lilly; consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Liposcience, Merck, Pozen, Hoffman-La Roche, Sanofi, the Medicines Company, and WebMD; grant support from Gilead Sciences; and lecture fees from Gilead Sciences, Boehringer Ingelheim, and the Medicines Company. Disclosures for the coauthors are listed in the paper.