PRAGUE-18 Hints at Risk-Based Personalized DAPT After STEMI-PCI Discharge

November 15, 2017

ANAHEIM, CA — Switching to clopidogrel postdischarge after starting on a more potent P2Y12 inhibitor as part of dual antiplatelet therapy (DAPT) after primary PCI apparently doesn't lead to a greater risk of ischemic events over a year, at least in selected low-risk patients[1].

That was a secondary finding in the 12-month follow-up report from PRAGUE-18 trial, which had primarily compared prasugrel (Effient, Efient, Lilly/Daiichi-Sankyo) vs ticagrelor (Brilinta, Brilique, Possia, AstraZeneca) in DAPT after PCI for STEMI.

Also at 1 year, there was no significant difference between the two agents for the primary clinical end point that previously had not been different at the 7-day mark, a composite of reinfarction, urgent target vessel revascularization, stroke, bleeding requiring transfusion, or prolonged hospitalization. It was seen at 12 months in 6.6% of patients who received prasugrel and 5.7% of those getting ticagrelor (P=0.93) in the trial, which had randomized 1230 patients.

Patients who switched to clopidogrel postdischarge didn't show excess ischemic events compared with patients in the trial who continued on either prasugrel or ticagrelor. Such a risk might have been a concern, as the influential PLATO and TRITON studies saw that ischemic events were fewer on the latter two antiplatelets, although at the cost of possibly more bleeding complications.

Importantly, the PRAGUE-18 protocol allowed a postdischarge switch to clopidogrel for patients unwilling to pay out-of-pocket for costlier long-term prasugrel or ticagrelor, subject case-by-case to the approval of trial physicians.

That is, they went with clopidogrel for "economic" reasons and tended to be at low enough risk that their doctors agreed to it, Dr Zuzana Motovska (Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic) told | Medscape Cardiology.

A Highly Selected Group

Indeed, both ischemic events and bleeding complications were significantly fewer (57% risk reduction, P=0.024; and 58% risk reduction, P=0.001, respectively) for those who were economically moved to switch to clopidogrel, compared with those who continued on the other agents. But the reduction in ischemic events in those who switched, Motovska said, was explained by their lower-risk status. Also, the trial was greatly underpowered for these outcomes.

Dr Zuzana Motovska

The more potent P2Y12 inhibitors are fully reimbursable during hospitalization for STEMI in the Czech Republic, and prasugrel is reimbursable after discharge in some cases; otherwise, she said, patients foot the bill for postdischarge prasugrel or ticagrelor.

Of those who had been assigned to prasugrel, 34.1% switched to clopidogrel for such "economic" reasons. Significantly more of those on ticagrelor, 44.4% (P=0.003), made such a switch. Overwhelmingly in both cases, the change was made soon after discharge, at a median of 8 days.

Motovska presented the PRAGUE-18 analysis here at the American Heart Association (AHA) 2017 Scientific Sessions and is lead author on its simultaneous publication in the Journal of the American College of Cardiology.

Deescalated DAPT: A Thing

The dilemma of which antiplatelet to take with aspirin for long-term DAPT after primary PCI would exist in any country where patients pay for the newer agents themselves. But switching to clopidogrel for economic reasons, Motovska said, is probably more common in the Czech Republic than in other European countries.

Still, the strategy of making clopidogrel the long-term choice after primary PCI, following in-hospital prasugrel or ticagrelor, which the field is calling deescalated DAPT, has garnered wide interest and was explored recently in several studies, including TROPICAL-ACS and TOPIC.

"A lot our patients are doing this," said Dr Roxana Mehran (Mount Sinai School of Medicine, New York, NY) about such deescalation from prasugrel or ticagrelor to clopidogrel. Yet the studies are conflicted about whether it can attenuate the risk of bleeding on long-term DAPT while not raising the risk of ischemic complications.

And PRAGUE-18, unfortunately, doesn't provide the answer either, Mehran said as the assigned discussant following Motovska's presentation of the study. "The economically driven, physician-directed deescalation seems feasible, we see that it was done, but the study is underpowered to evaluate the safety and efficacy of this strategy." PRAGUE-18, she pointed out, had been terminated prematurely "for futility" after enrolling only 1230 of a planned 2500 patients.

Moreover, the clopidogrel-switching part of the study wasn't randomized, and "there are lots of confounders," she said, adding that the issue will only be settled by large prospective randomized trials.

Personalized DAPT

The clopidogrel-switching results "support personalization in antiplatelet therapy," Motovska said when interviewed. "I think the therapy has to be individualized according to the ischemic and bleeding risk of each patient."

In PRAGUE-18, patients who switched to clopidogrel, compared with those who didn't, displayed their lower-risk status with a more favorable Killip risk-classification profile (P=0.004), with significantly fewer in Killip class II or higher (P<0.001), and were less likely to have had left-main disease at their acute procedure or to have had failed PCI (P<0.001) or a suboptimal result (P=0.028).

Although by far most switching to clopidogrel was for economic reasons, other reasons for going with the less potent antiplatelet included a requirement for oral anticoagulation or complications on prasugrel or ticagrelor.

Such patients tended to be higher-risk, perhaps with a history of bleeding or other complications, and generally made the switch with the blessing of their personal physician but without the okay of PRAGUE-18 clinicians, Motovska said.

"The switch in these patients was not a good choice," she observed. Those who switched for other than economic reasons had more than triple the risk of the study's primary composite end point (P<0.001) compared with patients who maintained either prasugrel or ticagrelor.

Motovska reports receiving modest honoraria from AstraZeneca. The coauthors report no relevant financial relationships. Mehran reports research grants from the Medicines Company, Bristol-Myers Squibb/Sanofi, Eli Lilly/Daiichi Sankyo, OrbusNeich, Bayer, and CSL Behring; consulting for Janssen Pharmaceuticals and Osprey Medical; and consulting for/being on an advisory board for Abbott Laboratories.

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