TRA 2°P-TIMI 50: Future Possible for Vorapaxar in Patients With Prior MI

March 24, 2012

Updated March 24, 2012 (Chicago, Illinois) Full results of the TRA 2°P TIMI-50 study suggest that the novel antiplatelet agent vorapaxar (Merck) appears to have a net clinical benefit in selected secondary-prevention patients [1].

Patients who did best on the drug were those with a prior MI without a history of stroke or transient ischemic attack (TIA) and who weighed over 60 kg. But many observers expressed concerns about the bleeding risk with the drug, with suggestions that it may not be suitable for general availability.

The top-line results of the trial, announced earlier this year, reported that vorapaxar, which blocks the protease-activated receptor 1 (PAR-1) on the platelet, was successful in reducing the primary ischemic end point of the study, but at the cost of increased bleeding, including intracranial hemorrhage (ICH).

The detailed results were presented today at the American College of Cardiology (ACC) 2012 Scientific Sessions by lead investigator Dr David Morrow (Brigham and Women's Hospital, Boston, MA). It was also published online simultaneously in the New England Journal of Medicine.

Morrow commented to heartwire : "There are definitely some important--even practice-changing--messages from this trial. The most compelling benefits were seen in the subgroup of patients with previous MI, where we saw a 20% reduction in the primary end point of cardiovascular death/MI/stroke."

However, those not involved in the trial were not nearly as enthusiastic about the current results or the future of vorapaxar as the TRA 2°P investigators (see sidebar below).

Sufficient for Approval?

Asked whether he thought this would be sufficient for approval of the drug, Morrow said: "While I can't speak for the FDA, I can say that the overall trial did meet its primary end point; the MI subgroup was a very large one--close to 18 000 patients, like a trial unto itself; and this was a prespecified group. So we think this result is valid."

The benefit does have to be weighed against the risk of increased bleeding, but Morrow believes doctors should be able use known factors that are associated with increased bleeding risk to select patients who will be suitable for this drug.

"Vorapaxar will not be an option in patients with a history of stroke or TIA, and it also appears unsuitable for patients with low body weight (<60 kg). These patients have a higher bleeding risk. But taking these caveats into account, there is clearly a large group of patients who have great potential for benefit," he added.

TRA 2°P TIMI 50 was conducted to investigate whether vorapaxar could reduce thrombotic events in stable patients with atherosclerosis treated for one year or more in addition to standard therapy.

The trial included three types of patients: those who had had an MI within the past year (67% of patients); those who had an ischemic stroke or TIA within the past year (19%); and those with peripheral arterial disease (PAD) (14%).

In total, 26 449 were randomized to vorapaxar 2.5 mg per day or placebo. In January 2011, the data safety and monitoring board (DSMB) recommended that patients with a history of stroke should stop taking vorapaxar after an increase in ICH was seen in this group. The trial continued in the other patient groups.

After a median follow-up of 2.5 years, there was a significant 13% relative reduction in the primary efficacy end point (CV death/MI/stroke) for the whole patient population. The reduction was slightly larger in the patients without a history of stroke.

Primary End Point: CV Death/MI/Stroke

Group Vorapaxar (%) Placebo (%) HR (95% CI) p
All patients (n=26 449) 9.3 10.5 0.87 (0.80–0.94) <0.001
No prior stroke (n=20 699) 8.3 9.6 0.84 (0.76–0.93) <0.001

Among the three subgroups of patients, this primary end point was significantly reduced in the post-MI patients and there was a small trend toward benefit in the PAD patients and a neutral effect in patients with a previous cerebrovascular event. The reduction was significant in both patients taking and those not taking a thienopyridine at baseline.

Primary End Point: Subgroups

Subgroup HR (95% CI) for CV death/MI/stroke with vorapaxar vs placebo
MI (n=17 779) 0.80 (0.72–0.89)
PAD (n=3787) 0.94 (0.78–1.14)
Stroke (n=4883) 1.03 (0.85–1.25)
Thienopyridine at entry (n=16 442) 0.88 (0.79–0.98)
No thienopyridine (n=10 007) 0.85 (0.74–0.98)

Now for the Bad News . . . 

In terms of bleeding, there was a significant increase in all measures of major bleeding, including ICH, with vorapaxar in the total population. But bleeding was less severe with vorapaxar in patients with no history of stroke.

Increase in Bleeding With Vorapaxar vs Placebo in Patients With History of Stroke (n=5746)

Outcome Absolute increase (%) HR p
TIMI non–CABG-related major bleeding 2.0 1.87 <0.001
ICH 1.5 2.55 <0.001
Fatal 0.2 1.48 0.46

Increase in Bleeding With Vorapaxar vs Placebo in Patients Without History of Stroke (n=20 699)

Outcome Absolute increase (%) HR p
TIMI non–CABG-related major bleeding 0.7 1.35 0.005
ICH 0.2 1.55 0.049
Fatal 0.1 1.44 0.30

 

In terms of GUSTO moderate or severe bleeding, this again was increased with vorapaxar in all patient groups and was particularly problematic in patents with prior stroke and those with a low body weight.

GUSTO Moderate to Severe Bleeding in Major Subgroups

Subgroup Vorapaxar (%) Placebo (%) HR
Age >75 8.4 5.5 1.69
Age <75 3.7 2.2 1.65
Weight <60 kg 7.7 3.7 1.95
Weight >60 kg 4.0 2.4 1.64
Stroke 4.2 2.4 1.93
PAD 7.4 4.5 1.62
MI 3.4 2.1 1.61

There was no interaction in terms of bleeding between vorapaxar and clopidogrel in the study, with patients taking clopidogrel showing no increased bleeding risk with vorapaxar compared with patients not taking clopidogrel. Morrow suggested this may be explained by physicians "doing a good job selecting patients who were reasonable candidates for long-term clopidogrel therapy."

Net Clinical Benefit

Net clinical benefit was defined in two ways:

1. The combination of CV death/MI/stroke/urgent revascularization/GUSTO moderate or severe bleeding.

2. The combination of CV death/MI/stroke/GUSTO severe bleeding.

With both definitions, the net clinical benefit of vorapaxar was greatest in patients with no history of stroke or TIA and with a body weight above 60 kg.

Net Clinical Benefit of Vorapaxar

Group Vorapaxar (%) Placebo (%) Relative risk reduction (%) p
All patients        
Definition 1 13.4 14.0 4 0.20
Definition 2 11.9 12.8 8 0.020
No prior stroke        
Definition 1 12.8 13.4 6 0.16
Definition 2 10.8 11.8 11 0.010
No prior stroke/TIA and weight >60 kg        
Definition 1 12.0 13.4 12 0.004
Definition 2 10.0 11.7 16 <0.001

 

Morrow calculated that for every 1000 patients with no history of stroke/TIA and weight over 60 kg treated with vorapaxar, these results would translate into 11 fewer MIs, six fewer cardiovascular deaths, and five fewer strokes, at the cost of two ICHs and 10 GUSTO moderate or severe bleeds.

"This is the first time we have seen a definitive additional benefit on top of aspirin in post-MI patients with stable atherosclerotic disease," he commented to heartwire . Although a benefit was suggested for clopidogrel on top of aspirin in a similar population in the CHARISMA trial, Morrow pointed out that the overall CHARISMA result was neutral and unlike TRA 2°P, the MI subgroup was not prospectively defined.

Reaction to Presentation: Others Not So Impressed

Unsurprisingly, experts not involved in TRA 2°P or its sibling trial TRACER were not nearly as enthusiastic about the current results or the future of vorapaxar as the TRA 2°P investigators.

Dr Steven Nissen (Cleveland Clinic, OH) was aghast at the notion of there being anything positive to say about TRA 2°P. "There were 148 fewer adverse cardiovascular events and 171 greater moderate or severe bleeds, including 49 ICH. It doesn't get much more negative than that," he commented to heartwire .

Others had similar, albeit maybe less direct, points of view.

One of the official panel of discussants for the trial, Dr Eduardo Marban (Cedars-Sinai Medical Center, Los Angeles, CA), said: "It would not be in my personal medical chest. The number need to treat (to prevent one event) is high and the risks are not minor."

But Morrow countered that for the group with no prior history of stroke or TIA and body weight over 60 kg the numbers were better. In this population, the number need to treat to prevent one event was 53, the number needed to treat to cause a severe bleed was 333, and the number need to treat to cause an ICH was 500, he noted.

But still many seemed unconvinced. Dr David Holmes (Mayo Clinic, Rochester, MN), president of the ACC, commented: "I would rather think about individual patients than numbers needed to treat. This is clearly a drug that needs individualized treatment."

Asked at the ACC press conference on the trial whether he thought vorapaxar was safe enough to be made generally available, Holmes answered: "That's up to the FDA, but this may be one of those drugs that they decide may be too dangerous to make available for everyone. I would think it would be better to restrict it to specialist centers. In selected patients at selected centers it may have a role in improving outcomes, but it also has an important safety hazard."

Dr Doug Weaver (Henry Ford Hospital, Detroit, MI) was also concerned about the bleeding. "It’s hard to get too excited. I don't think this drug is going to make prime time. The reduction in mortality is very small and less than the increase in ICH in the overall population," he told heartwire .

Weaver also pointed out that the vast majority of patients on a thienopyridine in TRA 2°P were on clopidogrel, which raises the question of whether similar benefits could have been seen with ticagrelor or prasugrel without such a high bleeding risk. Morrow said it was impossible to know that, but "our belief is that this drug is doing something completely different to clopidogrel, which probably accounts for its incremental benefit."

Dr Shamir Mehta (McMaster University, Hamilton, ON) said he thought the results could potentially have a clinical impact. "The reduction in the primary outcome was modest but clear. It was driven by a lower rate of spontaneous MIs, which are clinically important events.  It is puzzling why a similar reduction was not also observed in the TRACER trial. What is also clear is that vorapaxar increases the risk of serious bleeding, including ICH, findings that were consistently observed in both trials. If approved, patients considered for vorapaxar will be relatively stable outpatients who have suffered an event at some time in the past. Balancing the benefit with the risk in this relatively stable group is challenging and very different from in the acute situation," he commented to heartwire .

Dr Robert Califf (Duke University, Durham, NC), who was involved in the TRACER trial with vorapaxar in ACS, which did not meet its primary end point and showed worse bleeding than in TRA-2°P, described the TRA 2°P data as "very provocative." He commented to Morrow: "You suggest if you select the right patients you can find a good group for net clinical benefit. But this would be greatly strengthened if you can back up the findings with data from the other trial [TRACER]."

Morrow pointed out that in TRACER, although the primary end point wasn't significant, the key secondary end point--CV death/MI/stroke (which was the same as the TRA 2°P primary end point)--was significantly reduced. "So there is some synergy."

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