By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

Dr. Zimmet reports no financial relationships relevant to this field of study.

SYNOPSIS: The authors of a single-center study randomized post-acute coronary syndrome patients either to remain on higher-potency antiplatelet agents or to change to clopidogrel after one month. The results showed a benefit to de-escalation in terms of both bleeding and ischemic events, regardless of initial platelet reactivity.

SOURCE: Deharo P, Quilici J, Camoin-Jau L, et al. Benefit of switching dual antiplatelet therapy after acute coronary syndrome according to on-treatment platelet reactivity: The TOPIC-VASP pre-specified analysis of the TOPIC randomized study. JACC Cardiovasc Interv 2017;10:2560-2570.

Antiplatelet therapy plays a central role in the treatment of acute coronary syndrome (ACS) patients post-percutaneous coronary intervention (PCI), reducing the risk of recurrent ischemic events and stent thrombosis. The newer P2Y12 inhibitors prasugrel and ticagrelor have demonstrated superiority over clopidogrel in this population, albeit with significant costs, both financially and in terms of clinically significant bleeding. In response to this data, the European Society of Cardiology relegated clopidogrel to second-line status several years ago. The 2014 American College of Cardiology/American Heart Association guidelines for non-ST elevation ACS similarly gave a class IIa recommendation to the strategy of choosing ticagrelor or prasugrel over clopidogrel for ACS patients undergoing PCI. Although the usual practice is to continue the same drug for the duration of the guideline-recommended 12 months of dual antiplatelet therapy (DAPT), switching from the more potent agents to clopidogrel also is relatively common in everyday practice. Whether this happens for reasons of cost or for bleeding, the obvious concern has been that the benefits of the highly potent agents on ischemic outcomes would be lost.

Enter the Timing Of Platelet Inhibition after acute Coronary Syndrome (TOPIC) study, a single-center, open-label trial that included patients with ACS who had undergone successful coronary stenting and who were treated with either ticagrelor or prasugrel. One month after the ACS episode, patients were randomized to either remain on the more potent P2Y12 agent or to switch to clopidogrel. All patients underwent platelet function testing by platelet reactivity index vasodilator-stimulated phosphoprotein (PRI-VASP) to assess response to the initial high-potency regimen. The primary endpoint of the trial assessed a composite of ischemic and bleeding events, including cardiovascular death, unplanned coronary revascularization, and Bleeding Academic Research Consortium bleeding episodes.

In the overall group of 646 patients, those who switched from DAPT to a clopidogrel-based regimen demonstrated a significant reduction in the primary composite endpoint (9.3% vs. 23.5%; P < 0.01), driven almost entirely by a reduction in bleeding events. This occurred without a significant difference in ischemic events (9.3% vs. 11.5%; P = 0.36). Forty-seven percent of the total were classified based on platelet function testing as exhibiting low on-treatment platelet reactivity (LTPR), which has been described as “hyper-responsiveness” and is a marker for increased bleeding risk on the potent antiplatelet agents. Separating patients by platelet reactivity status showed that LTPR patients who switched from DAPT exhibited an even greater reduction in the primary endpoint at one year (11.9% vs. 33.1%; P < 0.01) compared with the overall group, and that this was related to decreased rates of both bleeding and ischemic complications. In patients without LTPR, rates of bleeding were similarly reduced by switching from DAPT, but the composite endpoint was not statistically different.

The authors concluded that switching from DAPT to a less-potent clopidogrel-based regimen at one month was associated with reduced bleeding, regardless of patients’ individual responses to the newer P2Y12 inhibitors. The benefits were greater in patients who experienced LTPR, in whom the hazard of remaining on the newer agents was especially pronounced.

COMMENTARY

The story of DAPT after stenting for ACS appears at first glance to become more complicated with each additional trial result. The use of the more potent P2Y12 inhibitors prasugrel and ticagrelor in this population has been shown to result in improved overall ischemic outcomes, leading to their adoption as first-line agents in some settings. However, with more rapid healing of current-generation drug-eluting stents, clinicians have observed a push toward shorter DAPT durations than the guideline-directed 12 months. For example, the authors of the ISAR-SAFE trial demonstrated non-inferiority of six vs. 12 months of DAPT in 1,601 ACS patients treated with aspirin and clopidogrel. The authors of the COMBO trial came to a similar conclusion. This trial included nearly 1,500 patients with ACS receiving a novel sirolimus-eluting stent in whom a three-month duration of DAPT was noninferior to 12 months (although nonsignificant trends toward higher all-cause mortality and stent thrombosis were reported with shorter duration of DAPT).

The concept of de-escalating antiplatelet therapy from the more potent agents to clopidogrel is not new, driven not by a push for improved outcomes but rather primarily by economic concerns, whereby off-patent clopidogrel is much more affordable that other drugs. This trend was well-illustrated in the PRAGUE-18 study. The authors randomized acute myocardial infarction patients to ticagrelor vs. prasugrel and found no significant difference in efficacy or safety between the two. Patients in this trial were informed prior to discharge about the out-of-pocket costs of prasugrel and ticagrelor, as well as the expected advantages of those drugs compared to clopidogrel. An unexpected finding of the trial was that a substantial proportion of the subjects switched drugs, primarily because of cost considerations, with nearly 50% of patients switching from prasugrel to clopidogrel and 60% switching from ticagrelor to clopidogrel. Although patients who switched medications exhibited lower risk profiles overall, the authors found that the (nonrandomized) de-escalation to clopidogrel resulted in a lower risk of major cardiovascular events as well as a lower risk of bleeding. In our own environment, we have seen similar issues, with some patients treated with ticagrelor switched to clopidogrel at the first post-discharge clinic visit, usually as a result of reduced cost. The authors of TOPIC set out to systematically study patients’ existing real-world habits. This trial goes beyond demonstrating the safety of this practice and suggests a clear benefit in terms of bleeding. Although this was a relatively small study, the positive results of making the switch one month after the ACS event certainly are plausible. Although these data likely are insufficient to change guidelines, the information provides reassurance about the safety of this growing practice and should prompt its consideration, at least in patients with higher bleeding risk.