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: In a randomized trial of patients already on anticoagulation undergoing transcatheter aortic valve replacement, adding clopidogrel to oral anticoagulation increased the incidence of serious bleeding vs. oral anticoagulation alone, but did not improve cardiovascular outcomes.
SOURCE: Nijenhuis VJ, Brouwer J, Delewi R, et al. Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation. N Engl J Med 2020; Mar 29. doi: 10.1056/NEJMoa1915152. [Epub ahead of print].
The question of optimal anticoagulation regimens after transcatheter aortic valve replacement (TAVR) procedures continues to be a source of confusion and consternation. In general, there remains uncertainty about whether there is benefit to dual antiplatelet over single antiplatelet therapy. Although anticoagulants (but not antiplatelet agents) appear to be protective against imaging-defined subclinical leaflet thrombosis, the results of the recently published GALILEO trial suggested harm rather than benefit from adding rivaroxaban to a treatment strategy in post-TAVR patients without an established indication for anticoagulation.1
What about TAVR patients with an established indication for anticoagulation? Until now, the only data on this question have come from post-hoc analyses of older trials, some of which have suggested a benefit to antiplatelet therapy in reducing stroke in this population over the intermediate term. Current guidelines generally recommend a vitamin K antagonist for these patients, either alone or in combination with single antiplatelet therapy, and essentially ignore the direct-acting anticoagulant (DOAC) medications altogether. Until now, randomized trials have been lacking.
To bridge part of this knowledge gap, Nijenhuis et al published the results of cohort B of the POPular TAVI trial. Between December 2013 and August 2018, 326 patients on oral anticoagulation were enrolled at 17 sites in four European countries. These patients were randomly assigned to receive either clopidogrel or no clopidogrel for three months following the TAVR procedure. Ultimately, 157 patients were assigned to receive oral anticoagulation alone, and 156 to receive anticoagulation plus clopidogrel. Those in the first group were not administered a placebo control. The primary outcomes were any bleeding and non-procedure-related bleeding at 12 months.
Included patients were fairly typical of a TAVR population for this era; subjects were a mean age of 81 years, and 45% were women. As expected, the indication for anticoagulation was atrial fibrillation in approximately 95% of patients. Patients with recent percutaneous coronary intervention (and, thus, an absolute indication for P2Y12 inhibition) were excluded. After one year, any bleeding had occurred in 21.7% of patients on anticoagulation alone, compared with 34.6% of patients receiving anticoagulation plus clopidogrel (risk ratio [RR], 0.63; 95% confidence interval [CI], 0.43-0.90; P = 0.01). Because of the way the endpoints were defined, non-procedure-related bleeding was nearly identical to all bleeding.
A secondary composite endpoint including bleeding (cardiovascular death, bleeding, stroke, or myocardial infarction [MI]) showed a benefit for the anticoagulation-alone group (31.2% vs. 45.5%; RR, 0.69; 95% CI, 0.51-0.92). A separate secondary composite endpoint that did not include bleeding (cardiovascular death, stroke, or MI) was not significantly different between the groups. Importantly, stroke as an individual secondary outcome did not differ between the two groups, occurring in 5.7% and 5.8% of patients. The authors concluded that among patients on long-term anticoagulation for an accepted indication, the addition of clopidogrel led to a higher incidence of serious bleeding vs. anticoagulation alone.
This was a significant trial that focuses on the central importance of bleeding as a frequent and clinically relevant outcome. Although this is important work that addresses, at least in part, a common clinical question about the TAVR population, it is worthwhile to spend a moment to acknowledge its flaws. The sample size was relatively small. This was an open-label trial without a placebo control. Essential details are missing or simply left out, including information about aspirin use, and whether anticoagulants were paused periprocedurally.
The authors made the unconventional choice to use the Bleeding Academic Research Consortium type 4 definition to designate procedure-related bleeding. While this does identify severe bleeding, it excludes most episodes of what common sense would dictate to be procedure-related, including bleeding from the puncture site. Supplementary materials reveal access site bleeding accounted for approximately half of all bleeding events.
While there was no sign the anticoagulant-alone group were at higher risk for stroke or MI, the small size of the trial and the wide noninferiority margins mean this is not a conclusive result. The lack of effect on stroke hazard contradicts the previously published results of a retrospective analysis of the PARTNER II trial.2 Those researchers reported that antiplatelet therapy was associated with a significant reduction in the two-year incidence of stroke among patients with AF undergoing TAVR.
There is little doubt that bleeding is a central outcome that occurs at significant rates in post TAVR patients. As the only randomized trial published thus far in this particular group, POPular suggests withholding antiplatelet therapy as a reasonable tactic to reduce significant bleeding. Further trials will be necessary to determine whether this represents the optimal method to minimize other important outcomes, including death, stroke, and MI.
- Dangas GD, Tijssen JGP, Wöhrle J, et al. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. N Engl J Med 2020;382:120-129.
- Kosmidou I, Liu Y, Alu MC, et al. Antithrombotic therapy and cardiovascular outcomes after transcatheter aortic valve replacement in patients with atrial fibrillation. J Am Coll Cardiol Intv 2019;12:1580-1589.