TOPIC: Replacing P2Y12 Inhibitors With Clopidogrel 1 Month After PCI Saves Money, Prevents Bleeding in ACS

PARIS, France (UPDATED)—Switching the antiplatelet regimen in ACS patients from newer, more potent P2Y12 inhibitors to clopidogrel at 1 month post-PCI may reduce bleeding without increasing the risk of later ischemic events, the TOPIC trial suggests.

These findings may pose a challenge to current guidelines, which state that 1 year of dual antiplatelet therapy (DAPT) using prasugrel (Effient; Eli Lilly) or ticagrelor (Brilinta; AstraZeneca) in combination with aspirin is preferable to the older, cheaper combination of clopidogrel plus aspirin.

As presenter Thomas Cuisset, MD PhD (CHU Timone, Marseille, France), explained here, the advent of more potent P2Y12 inhibitors has provided patients better protection from ischemic events in the first weeks after an ACS event—when they are most vulnerable—but at the expense of higher bleeding risk over the long term than if they were treated with clopidogrel and aspirin. That conundrum has led some centers to adopt a non-guideline-supported strategy of using the more potent P2Y12 regimen in the first few months, but switching to the cheaper, less potent strategy thereafter.

For the TOPIC trial, presented in the opening Hot Line session here at EuroPCR 2017 and simultaneously published in the European Heart Journal, Cuisset and colleagues randomized 646 ACS patients at their institution who were being treated with prasugrel or ticagrelor and aspirin to either stay on that regimen (n = 323) or switch to clopidogrel plus aspirin (n = 323) at 1 month after PCI.

Originally, 43% of patients were being treated with ticagrelor and 57% with prasugrel. Most patients were treated with the radial approach and 91% received DES.

At 1 year, risk of the combined primary endpoint (death, urgent revascularization, stroke, and BARC ≥ 2 bleeding) dropped by half in patients who switched their DAPT therapy (26.3% vs 13.4%; HR 0.48; 95% CI 0.34-0.68). While there was no difference in ischemic endpoints between the study arms (11.5% vs 9.3%; HR 0.80; 95% CI 0.50-1.29), BARC ≥ 2 bleeding was substantially lower in the switch therapy cohort (14.9% vs 4.0%; HR 0.30; 95% CI 0.18-0.50). All BARC bleeding as well as TIMI minor bleeding also favored the patients whose DAPT regimen was switched to clopidogrel, while TIMI major bleeds were no different between groups.

The Superior Switch

A strategy of switching from prasugrel or ticagrelor to clopidogrel 1 month after PCI for ACS is “superior” to keeping patients on the same combination of drugs for 12 months, Cuisset concluded. “This could have important clinical implications with providing to the physician new potential strategy integrating the dynamic risk after ACS with potent DAPT in the early phase to prevent early ischemic events including stent thrombosis,” he said in a press briefing.

Cuisset commented that while operators are “really afraid” of early stent thrombosis, after several months “we had the feeling that we see more often patients coming to us for bleeding events than for thrombotic events.”

As such, he said, many physicians around the globe already prescribe DAPT for their ACS patients in this fashion—either because of personal preference or because P2Y12 inhibitors are only reimbursed for a shortened period of time. “That's why . . . we tried to do this randomized study, to try to validate what was already applied by many physicians around the world.”

The economic implications of the TOPIC findings are substantial, Cuisset noted. “Indeed there was a huge difference” between total DAPT cost between the study arms over the course of a year, which makes sense given how much more money prasugrel and ticagrelor cost over clopidogrel. Responding to a question from TCTMD, Cuisset acknowledged that although pharmaceutical companies might not be pleased with his single-center results, “hopefully I think the patients will like it.”

Clashing With the Guidelines

During the session where TOPIC was presented, panel discussant Upendra Kaul, MD (Escorts Heart Institute, New Delhi, India), praised the trial’s “brilliant hypothesis” that “reflects the vision of many interventional cardiologists.”

Kaul had several caveats, however, pointing out that the power calculation for TOPIC, as well as the choice of bleeding definitions and ischemic endpoints, are somewhat at odds with the major ACS trials in this space, namely TRYTON and PLATO. In particular, Kaul said, the decision to exclude revascularization from the composite endpoint was “glaringly absent.”

In response, Cuisset said this was extensively discussed at the time of trial design; ultimately, investigators felt that limiting their scope to urgent revascularizations would capture all of the clinically meaningful revascularizations in this cohort.

Panelists Runlin Gao, MD (National Center for Cardiovascular Diseases, Fu Wai Hospital), and Chaim Lotan, MD (Hadassah-Hebrew University Medical Center, Jerusalem, Israel), also praised Cuisset’s study, with Gao saying that TOPIC’s strategy is already widely used in China, where prasugrel and ticagrelor are not reimbursed. “This study provides evidence for this kind of treatment, [in addition to] its economic value,” he said.

Lotan, similarly, said that he himself had planned a study of this strategy but ultimately abandoned those plans after pushback from industry and his institutional review board, which noted that this would fly in the face of the guidelines. TOPIC, said Lotan, argues strongly for guideline writers to rethink the current DAPT recommendations.

A Closer Look at Safety

Commenting on the study, Dean Kereiakes, MD (The Christ Hospital, Cincinnati, OH), said he “often” treats patients using the TOPIC strategy, usually making the switch between 1 and 3 months. “The majority of ischemic event benefit difference between these drugs is in the first 30 days and the majority of the bleeding event risk difference is beyond 30 days,” he said in an email to TCTMD.

Kereiakes said his concern with designing a similar trial for US Food and Drug Administration (FDA) approval was the issue of switching to clopidogrel at 30 days in patients with genetic polymorphisms that render the drug ineffective. “These patients would get only 30 days of effective DAPT therapy,” he explained. “At the time, about 2 years ago, the FDA was pushing to recommend CYP2C19 testing on all patients who might be switched at 30 days from prasugrel/ticagrelor to clopidogrel.”

In the press briefing, Cuisset acknowledged the need for a larger study or registry to ensure safety for all patients. “We also need to be able to identify which patients should be kept on more potent DAPT after 1 month because I think [this is] a very good strategy but maybe not applicable for [all] ACS patients.”

For TOPIC specifically, Kereiakes said he would have liked to have seen MI included in the composite endpoint as well. “In the DAPT trial, we observed a 53% reduction in MI between randomized treatment strategies and 55% of the MIs prevented were not related to the stented segment,” Kereiakes explained. “Further, DAPT discontinuation was associated with a significant increase in MI during the 12-15 month observation period. Obviously, this study ‘switches’ drugs much earlier and there is no ‘placebo,’ but the propensity for MI to occur following a switch from more effective platelet inhibition to less effective inhibition at 30 days after PCI for ACS should be present.”Alternately, Marco Valgimigli, MD (Bern University Hospital), who also was not involved in the study, told TCTMD in an email that he never switches patients to clopidogrel “unless there was a clinical reason” for it like bleeding or intolerance. “I am very skeptical about this treatment strategy, and I think this study is likely too small to make me change my mind,” he said. “The confidence intervals [around] ischemic events after switching are too wide and not conclusive as far as I am concerned.”

Shelley Wood contributed to the reporting of this story.