‘De-escalating’ P2Y12 Inhibition Possible in Acute MI Patients: PRAGUE-18

ANAHEIM, CA—Patients undergoing PCI for acute myocardial infarction have equivalent clinical outcomes at 1 year no matter whether they are treated with prasugrel (Effient; Eli Lilly) or ticagrelor (Brilinta; AstraZeneca), according to a new analysis of the PRAGUE-18 study.

Additionally, patients who quickly switched off prasugrel and ticagrelor to clopidogrel for economic reasons, citing the expense of the drug for the “de-escalation” of therapy, were not at an increased risk of ischemic events, report investigators. In fact, compared with patients who stayed on prasugrel and ticagrelor, those who switched to clopidogrel for economic reasons had a significantly lower risk of major cardiovascular events (2.5% vs 8.5%; P = 0.024) and a lower risk of bleeding (7.3% vs 13.4%; P = 0.001). 

In contrast, those who switched to clopidogrel for nonfinancial reasons had a significantly increased risk of ischemic events and bleeding compared with those who maintained therapy with prasugrel and ticagrelor.   

Zuzana Motovska, MD (Charles University/University Hospital Kralovske, Prague, Czech Republic), who presented the results at the American Heart Association 2017 Scientific Sessions, said the PRAGUE-18 study represents algorithm in which patients can safely switch to the cheaper clopidogrel during the maintenance phase of acute MI. The findings also were published online in the Journal of the American College of Cardiology.

“Most of the patients who switched because of the cost did so immediately after hospital discharge,” said Motovska. Median number of days on ticagrelor/prasugrel among the switchers was 8 days.

C. Michael Valentine, MD (Stroobants Cardiovascular Center/Centra Health, Lynchburg, VA), who was not involved in the study, said clinicians are faced all the time with clinical decisions about how and when to safely switch patients off antiplatelet therapy.

“We have patients that come in at 1, 2, or 3 months and they’re telling us, because of insurance reasons or because of cost, that they can no longer afford them,” said Valentine, vice president of the American College of Cardiology. “Their choices are either to stop and remain on aspirin alone or to choose a less expensive drug like generic clopidogrel. The huge majority are changed over in clinical practice to generic clopidogrel.”

PRAGUE-18, he said, helps alleviate some concerns physicians may have that patients who switch will fare worse than those who make a concerted effort to remain on prasugrel or ticagrelor.

Patients Informed of Drug Costs

The PRAGUE-18 study investigators presented 30-day outcomes comparing prasugrel and ticagrelor last year at the European Society of Cardiology. The study was stopped early for futility, but results showed there was no difference in early outcomes between the two antiplatelet drugs. Although investigators planned to enroll 2,500 patients, just 1,230 acute MI patients were treated with primary PCI in the study.

Patients were randomly assigned to prasugrel or ticagrelor and the intended treatment duration using the study medication was 12 months. As part of the protocol, patients were informed prior to discharge about the out-of-pocket costs of prasugrel and ticagrelor as well as the clinical benefits of long-term treatment with those drugs compared with clopidogrel. Patients who were unwilling to accept the costs of the drugs—clopidogrel is fully reimbursed by insurance in the Czech Republic—were allowed to switch to clopidogrel.

At 1 year, the risk of cardiovascular death, nonfatal MI, or stroke occurred in 6.6% of patients treated with prasugrel and 5.7% of patients treated with ticagrelor, a nonsignificant difference. There were no significant differences in any of the individual endpoints.

Overall, switching was quite common, with nearly 50% of patients switching from prasugrel to clopidogrel and 60% switching from ticagrelor to clopidogrel. The overwhelming reason for the switch was the cost of medication, said Motovska.

Patients who switched to clopidogrel because of cost were lower risk than those who remained on ticagrelor or prasugrel. For example, those who remained on the original study medication were more likely to have bundle branch block on the baseline ECG, more likely to have left main disease, and less likely to have an optimal or successful PCI result.

Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who commented on the results during the late-breaking clinical trial session, noted that prasugrel and ticagrelor are both class Ia agents recommended for STEMI patients treated with PCI. While prasugrel, ticagrelor, and clopidogrel are all recommended as part of DAPT therapy following stent implantation, the guidelines state it reasonable to choose the more potent agents in patients with prohibitive risks (class IIa).

She praised the study investigators, noting the academic study addressed an important question, that being which of the potent agents is best for patients.

To TCTMD, she said de-escalating P2Y12 inhibitor therapy after acute MI is an important clinical question, too, particularly since there is little evidence to guide such changes. “It represents the real world,” said Mehran, “as not everybody can afford these agents. It’s important to think about this de-escalation because a lot of our patients are doing it and there are conflicting findings in some of the data we current have.”

In the SCOPE observational registry, de-escalation of therapy was associated with increased ischemic events and no difference in bleeding while the TOPIC study showed that de-escalation could be safely performed without increasing patient risks. The TROPICAL-ACS study also suggested that de-escalating therapy after hospital discharge following an initial period of high ischemic risk could be a feasible option.

Recently, an international panel of experts published a consensus document on how and when to switch between P2Y12 inhibitors, which include oral agents—clopidogrel, prasugrel, and ticagrelor—and IV cangrelor (Kengreal; Chiesi USA).

For Mehran, large-scale clinical trials are still needed to address the risks and benefits of switching off potent P2Y12 inhibition to the more economically attractive clopidogrel. She noted that PRAGUE-18 was underpowered and patients were not randomized once they switched off therapy, meaning unmeasured confounding variables may have affected the results. For example, patients with fewer cardiovascular risk factors who have had a successful PCI procedure might be advised that it is safe to switch to clopidogrel.

“I think that’s what’s going on and maybe why we’re not seeing the major impact of the potent agents,” said Mehran.    

Valentine also noted the significant difference in patient characteristics between those who remained on prasugrel/clopidogrel and those who switched, which he said can help physicians make decisions about who can safely switch off those drugs.

“It allows us to individualize our therapy, which is what we always want to do,” said Valentine. “So, yes, there are certain patients I would encourage to stay on the more expensive drug because of the potentially slightly higher efficacy.” Such patients include those with complex disease, multiple stents, overlapping stents, and small vessels, for example.

Still, in the lower-risk patients, PRAGUE-18 suggests physicians “can turn patients over to the lower-priced drug, if necessary,” said Valentine.