Standard dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor for 12 months after stenting for an acute coronary syndrome (ACS) is under increasing fire from studies showing that varying the duration and intensity of DAPT can reduce bleeding risk without compromising ischemic protection.
A novel meta-analysis of 29 studies indirectly compares short DAPT and de-escalation in 50,602 patients, providing new insights into the relative safety and efficacy of the two strategies and further challenging current guideline recommendations.
Results show no difference in the risk of death between short DAPT with aspirin or P2Y12 inhibitor discontinuation 1 to 6 months after percutaneous coronary intervention and de-escalation to clopidogrel (Plavix) or lower dose prasugrel (Effient) or ticagrelor (Brilinta) after the initial high-risk period for ischemic events (risk ratio [RR] 0.98).
“However, there are some differentiating characteristics between the two. De-escalation seems to reduce NACE — net adverse cardiovascular events — likely because of a reduction in major adverse cardiac events, while short DAPT decreases bleeding,” senior author Davide Capodanno, MD, PhD, University of Catania, Italy, told theheart.org | Medscape Cardiology.
The findings, published today in JACC: Cardiovascular Interventions, are clinically plausible because patients remain on two antiplatelet drugs with de-escalation, but are on only one drug at the point of shortening DAPT, he said. “So, of course, if you have only one antiplatelet drug instead of two, you reduce bleeding. On the other hand, having two antiplatelets probably reduces the thrombotic and ischemic events.”
The study failed to show statistically significant differences in ischemic endpoints between strategies, likely due to few events and wide confidence intervals, Capodanno said. “In fact, when we look at each single component of this NACE, we see a directional difference in favor of de-escalation, which is what you would expect from two drugs.”
All-cause death was also similar among strategies in an alternative 5-node analysis that split short DAPT and de-escalation into four groups and included standard DAPT.
Compared with short DAPT with P2Y12 inhibitor discontinuation, both de-escalation to clopidogrel and to half-dose prasugrel or ticagrelor reduced the risk for NACE. De-escalation to half dose also reduced the risk for minor bleeding compared with short DAPT with aspirin discontinuation.
The overall results were similar in multiple sensitivity analyses and a Bayesian meta-analysis, according to the authors, led by Claudio Laudani, MD, also with the University of Catania.
The Bayesian analysis suggested a greater than 95% probability that de-escalation is the best strategy for NACE, MI, stroke, stent thrombosis and minor bleeding, whereas short DAPT ranks first for major bleeding with a greater than 95% probability.
Guidelines Upside Down?
In the absence of a head-to-head comparison, the authors say the results warrant a change in current guidelines, which give a class 2a recommendation for short DAPT and a weak class 2b for de-escalation.
“The two strategies have both merits and caveats but, overall, they are very similar; so this is why we believe they should be similar [in status],” Capodanno said.
In an accompanying editorial, Dean Kereiakes, MD, Christ Hospital Heart and Vascular Center, Cincinnati, Ohio, and Robert Yeh, MD, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, suggest the guideline recommendations are upside down.
“The class 1 recommendation should be for short DAPT or DAPT de-escalation vs standard DAPT based on this meta-analysis and, frankly, based on the independent analyses from Bangalore [et al] and from Shoji [et al],” Kereiakes told theheart.org | Medscape Cardiology.
“When you look at the meta-analyses that have been done, what you see is a reduction of bleeding and either no change or a slight numeric reduction in ischemic events, which magnifies the net clinical benefit, favoring short DAPT or DAPT de-escalation in comparison to standard 12-month, guideline-compliant DAPT,” he said. “So for me, it’s kind of like, game over. When will the guidelines catch up?”
Commenting for theheart.org | Medscape Cardiology, Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York City, said in an email that “both approaches warrant a class 1 recommendation in patients at high bleeding risk, and both a 2a in non-high bleeding risk patients. With contemporary drug-eluting stents, the prognosis is more strongly determined by bleeding risk and the occurrence of hemorrhagic complications than ischemic risk.”
Not All Strategies Are “Created Equal”
The editorialists caution that while viable, not all short DAPT or de-escalation strategies are “created equal.” In the five-node analysis, for example, the relative risk of stent thrombosis is highest following a short DAPT regimen with extended aspirin monotherapy (RR, 1.45) and lowest following de-escalation to half-dose prasugrel/ticagrelor (RR, 0.45).
Although not universally observed, the signal of harm with aspirin is consistent with studies such as TWILIGHT, HOST EXAM, and a 2020 meta-analysis, in which stopping aspirin 1 to 3 months after PCI cut bleeding by 50% compared with DAPT in patients with ACS, noted Kereiakes.
He also hinted that more data are forthcoming showing that short DAPT followed by aspirin single antiplatelet therapy (SAPT) has relatively higher ischemic and bleeding event rates compared with short DAPT followed by P2Y12 SAPT, with or without an anticoagulant on board.
The key going forward, all agree, is to formally incorporate ischemic/bleeding risk stratification tools into practice guidelines to allow personalized antiplatelet therapy. To that end, Kereiakes and Yeh offer a detailed graphic of rank-order recommendations for each strategy by clinical risk strata, with de-escalation generally best for those at greatest ischemic risk and short DAPT best applied to those at greatest bleeding risk.
“The biggest incremental knowledge provided by Davide and Laudani is that they gave us more insight into the granularity of platelet inhibition strategies,” Kereiakes said. “And it is mechanistically possible to be applied in clinical practice. It’s what I personally see in high-volume clinical practice.”
Before it can be determined which of these strategies is safer and/or more effective, a large, direct head-to-head comparative randomized trial is necessary, Stone cautioned.
“There are still many variables that were not adjusted for in this excellent study, including the timing of DAPT discontinuation or de-escalation, the specific agent used, etc,” he added. “Finally, as implied by these results, the optimal regimen may vary based on the balance of ischemic and bleeding risk. Thus, the specific population enrolled in such a randomized trial might importantly affect its outcome.”
As a man “who likes science and statistics,” Capodanno said he’d also like a large, randomized trial directly comparing the two strategies to confirm these indirect findings. “But it’s very difficult to imagine the power for a trial like that, so it’s not something that’s easy to do.”
Capodanno reports consulting and speaker fees from Amgen, Arena, Biotronik, Daiichi-Sankyo, and Sanofi outside the present work. Co-author disclosures are listed in the original article. Kereiakes reports consulting fees from SINO Medical Sciences Technologies, Svelte Medical Systems, Elixir Medical, and Caliber Therapeutics/Orchestra Biomed. Yeh reports consulting fees and grant support from Abbott Vascular, AstraZeneca, Boston Scientific, and Medtronic . Stone reported having no disclosures relevant to the study.