De-escalation Tops Other DAPT Tactics for ACS: Meta-analysis

De-escalation of dual antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor to clopidogrel or low-dose prasugrel 1 month after PCI is the most effective strategy for reducing bleeding without paying a price in ischemic events for patients with ACS, according to a new meta-analysis.

Multiple strategies have been proposed for how to manage antiplatelet therapy following ACS, but a consensus hasn’t yet been established. To date, three randomized trials have looked at de-escalation and shown promise—TOPIC, HOST-REDUCE-POLYTECH-ACS, and most recently TALOS-AMI—with the idea that the first month following PCI is the most vulnerable time for patients to report ischemic events.

“In daily practice [people] just continue ticagrelor or prasugrel plus aspirin for 1 year, but our study might trigger physicians need to rethink needing to de-escalate to clopidogrel for these patients or something like that,” study co-lead author Toshiki Kuno, MD, PhD (Icahn School of Medicine at Mount Sinai, New York, NY), told TCTMD. “Of course, this is a meta-analysis of randomized trials for patients who could be eligible for randomized trial. It depends on patients’ ischemic events or bleeding incidents.”

The results were published online yesterday ahead of print in the Journal of the American College of Cardiology.

“The finding that if you go to less-intense antithrombotic therapy there's less bleeding and you don't have a penalty with respect to ischemic events” has been shown in prior research, said Usman Baber, MD (University of Oklahoma Health Sciences Center, Oklahoma City), who commented on the study for TCTMD. “So the fact that the aggregate data when pooled shows the same is not, to me at least, particularly surprising.”

European guidelines have also endorsed a strategy of de-escalation for NSTE ACS patients, either guided by platelet function or genetic testing or unguided based on clinical judgment.

The novelty here, said Baber, “was more the analytic approach where they performed network-based comparisons to different studies and different trials.”

Comparison of Strategies

For the study, also led by Satoshi Shoji, MD, PhD (Keio University School of Medicine, Tokyo, Japan), the researchers looked at 15 randomized trials of DAPT strategies inclusive of 55,798 patients with ACS.

Compared with four other antiplatelet strategies—aspirin plus either clopidogrel, ticagrelor, standard-dose prasugrel, or low-dose prasugrel—one that involved de-escalation from aspirin plus standard-dose ticagrelor/prasugrel to aspirin plus clopidogrel or low-dose prasugrel after 1 month was associated with a reduced risk of the primary bleeding endpoint (trial-defined major or minor bleeding). There were no significant differences observed in the primary efficacy endpoint (composite of cardiovascular death, myocardial infarction, and stroke).

Other Strategies vs De-escalation

Additionally, DAPT de-escalation was linked with a reduction in cardiovascular death compared with all other strategies, as was ticagrelor compared with clopidogrel. Standard-dose prasugrel was associated with less MI compared with clopidogrel, and there were no differences in stroke rates among all five strategies.

Sensitivity analyses confirmed that de-escalation to either clopidogrel or low-dose prasugrel were each associated with less bleeding without increasing ischemic events. Also, there were no differences between the de-escalation strategies with regard to any ischemic or bleeding endpoints.

Delving Further Into De-escalation

“Our findings are reassuring, as de-escalation to clopidogrel is common (15%-28% of patients with ACS), despite the absence of any scientific evidence for its efficacy in real-world clinical practice,” the authors write. “De-escalation to clopidogrel is common for several reasons: 1) the reduced cost of off-patent clopidogrel; 2) concerns about increased risks of bleeding with potent P2Y12 inhibitors; and 3) concerns about nonbleeding side effects caused by ticagrelor, such as dyspnea. Our study indicates that de-escalation from potent antiplatelet agents to the less potent and off-patent clopidogrel is a promising and potentially optimal DAPT strategy from both scientific and economic perspectives.”

They point out that data are limited regarding de-escalation to monotherapy, genotype- or platelet function-guided selection of antiplatelets, and de-escalation to low-dose ticagrelor, so further research is needed to help further tease out the best strategy.

Also, “we did not consider racial or regional differences when performing the meta-analysis,” Shoji and colleagues write. “East-Asian individuals are known to have a higher risk of bleeding events than Western individuals, and further studies are needed to identify optimal antiplatelet therapies in various areas and for various populations.”

A next step would be to further home in on bleeding reduction strategies and deciding which is right for each individual patient, Baber said. “We now know DAPT de-escalation is one such strategy and guidelines even endorse that. Another one is aspirin withdrawal. Another one is just shortening the duration of DAPT to aspirin alone, which has been studied in high-bleeding-risk patients.”

One practical challenge to implementing DAPT de-escalation “is just the concern about clopidogrel responsiveness,” he continued. “In patients with acute coronary syndrome, I would favor de-escalating based upon either genotype or phenotype platelet function testing . . . . I would want to make sure they're responding if that's going to be my strategy.”