Oral anticoagulation alone reduces bleeding after TAVR vs. dual therapy
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The incidence of serious bleeding after transcatheter aortic valve replacement was lower in patients assigned oral anticoagulation alone compared with those assigned oral anticoagulation and clopidogrel, according to data from the POPULAR-TAVI trial presented at the American College of Cardiology Scientific Session.
The findings were simultaneously published in The New England Journal of Medicine.
“Oral anticoagulants alone as compared to oral anticoagulants with clopidogrel reduces the rate of bleeding events including major, life-threatening or disabling bleeding, and it does not increase the rate of thrombotic events,” Vincent Nijenhuis, MD, resident cardiologist at St. Antonius Hospital in Nieuwegein, the Netherlands, said during the presentation.
Patients scheduled for TAVR
Researchers analyzed data from patients from 17 European sites who were undergoing TAVR and had an established indication for long-term oral anticoagulation. Patients were assigned clopidogrel on top of their existing oral anticoagulation therapy (n = 156; mean age, 81 years; 47% women) or oral anticoagulation therapy alone (n = 157; mean age, 81 years; 44% women). The oral anticoagulation therapy that continued throughout the trial included a direct-acting oral anticoagulant or a vitamin K antagonist.
Patients assigned clopidogrel were given an initial loading dose of 300 mg 1 day before or on the day of the procedure. This was followed by a 75 mg once-daily dose for 3 months.
Follow-up for routine care was conducted at 30 days, 6 months and 12 months. Other follow-up visits were conducted throughout the trial for at least 1 year after TAVR and included transthoracic echocardiography and a questionnaire to collect information on prescribed medication, quality of life, health status and occurrence of primary and secondary outcomes.
The primary outcomes were nonprocedure-related bleeding and all bleeding. Events related to the procedure were defined as Bleeding Academic Research Consortium type 4 severe bleeding, so most access-site bleeding events were not considered related to the procedure. Secondary outcomes included a composite of nonprocedural-related bleeding, CV death, MI or all-cause stroke and a composite of CV death, MI or ischemic stroke.
The adherence rate during at 3 months was 95.5%.
The incidence of bleeding was higher in patients assigned clopidogrel plus oral anticoagulation compared with oral anticoagulation alone (34.6% vs. 21.7%; RR = 0.63; 95% CI, 0.43-0.9). Most bleeding events occurred at the access site for TAVR.
Nonprocedure-related bleeding was also higher in the clopidogrel group compared with the no clopidogrel group (34% vs. 21.7%; RR = 0.64; 95% CI, 0.44-0.92). Most bleeding events were minor and occurred in the first month after TAVR.
The composite of nonprocedural-related bleeding, CV death, MI or all-cause stroke occurred in 45.5% of patients assigned clopidogrel and 31.2% of those assigned oral anticoagulation alone (difference, 14.3 percentage points; 95% CI for noninferiority, 25 to 2.6; RR = 0.69; 95% CI for superiority, 0.51-0.92).
Another secondary outcome — composite of CV death, MI or ischemic stroke — was observed in 13.4% of patients assigned oral anticoagulation alone and 17.3% of those assigned clopidogrel with oral anticoagulation (difference, 3.9 percentage points; 95% CI for noninferiority, 11.9 to 4; RR = 0.77; 95% CI for superiority, 0.46-1.31).
“The study was not designed to directly compare outcomes between both regimens with vitamin K antagonists or [direct oral anticoagulants],” Nijenhuis said during the discussion portion of the presentation. “We performed a prespecified subgroup analysis, and we noticed a numerically lower rate of bleeding with novel anticoagulants compared to [vitamin K antagonists], but due to small numbers and possible biases, this sign could only be interpreted as hypothesis-generating only.”
‘Good start’
Joseph C. Cleveland Jr., MD, professor of surgery-cardiothoracic at University of Colorado School of Medicine in Aurora, said during a press conference that “This confirms what we have seen in other patient populations; for example, the ischemic heart disease population patients when you combine oral anticoagulants with platelet inhibition, particularly with clopidogrel, one observes more bleeding,” he said. “This trial certainly suggests that these patients in the TAVR population with atrial fibrillation, when challenged with both oral anticoagulation and clopidogrel, are going to bleed more.”
In addition, Cleveland said this is a “good start in helping us understand the management of these patients and realizing that probably it is safe to reinitiate oral anticoagulation and patients can be maintained on oral anticoagulation alone. That’s a bit of a strong statement. We will still need further data.”
In a related editorial in NEJM, Frederick Feit, MD, associate professor in the department of medicine and director of the cardiac catheterization laboratory at NYU Langone Health, wrote: “The ideal would be an anticoagulant regimen that minimizes the risk of death, stroke, myocardial infarction or permanent disability, whether resulting from thrombosis or bleeding. These are the events that matter most to patients. Future trials assessing antithrombotic regimens for patients undergoing TAVR should be powered to evaluate these adverse outcomes.” – by Darlene Dobkowski
References:
Nijenhuis V, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).
Feit F. N Engl J Med. 2020;doi:10.1056/NEJMe2003031.
Nijenhuis V, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1915152.
Disclosures: The trial was funded by the Netherlands Organization for Health Research and Development ZonMW. Nijenhuis reports no relevant financial disclosures. Feit reports he received personal fees from Abbott Vascular and other support from Boston Scientific, Medtronic and Sapheon. Healio could not confirm relevant financial disclosures for Cleveland at the time of publication. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Michael J. Rinaldi, MD
POPULAR TAVI is an important trial and will likely change practice. Currently, most patients undergoing TAVR who also have an indication for oral anticoagulation therapy receive additional antiplatelet therapy with either aspirin or clopidogrel, but data supporting this strategy are lacking.
In this study, patients undergoing TAVR with an indication for oral anticoagulation therapy, primarily AF, received oral anticoagulation with either warfarin or direct oral anticoagulation and were randomly assigned to 3 months of clopidogrel monotherapy or no clopidogrel. Aspirin was not administered.
This study showed a significant reduction in bleeding, as one would expect, but no increase in ischemic events such as MI or stroke. In fact, while the trial was underpowered to look at these events, these ischemic events were numerically lower in the oral anticoagulation therapy alone arm, which makes it unlikely that underpowering is missing an ischemic disadvantage.
Currently, most centers use 81 mg of aspirin as an adjuvant to oral anticoagulation therapy following TAVR, and how the disadvantage of adding clopidogrel in comparison to aspirin is unknown, but likely the outcomes would be similar.
While it would be nice to have additional studies that corroborate this, I would feel very comfortable eliminating antiplatelet therapy post-TAVR in patients receiving oral anticoagulation therapy who do not have a recently placed coronary stent.
These findings fit nicely with a variety of other studies in interventional cardiology that suggest less combination therapy results in less bleeding without the expense of higher ischemic events.
Perspective
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B. Hadley Wilson, MD, FACC
It appears that for patients who have TAVR and need anticoagulation for other reasons like AF or other thromboembolic conditions, they should continue that. Adding an antiplatelet agent only increased bleeding and did not really decrease complications.
Although the researchers admit that the power of looking at these secondary endpoints was not great enough to make the absolute determination, it does appear that events were the same whether an antiplatelet agent was added onto anticoagulation in these post-TAVR patients. More importantly, bleeding was significantly higher when you added the antiplatelet agent onto anticoagulation.
The findings would suggest that we should practice continuing anticoagulation in these patients that require it prior to TAVR and not add an antiplatelet agent on afterward.
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