More high-risk data needed on optimal antithrombotic therapy with TAVR
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Many patients undergoing transcatheter aortic valve replacement have multiple thrombotic and bleeding-related comorbidities that make optimal antiplatelet and anticoagulant management complex, leaving the question of which strategies are best open to debate.
The optimal antithrombotic strategy after implantation of any bioprosthetic valve in the aortic position is not entirely clear, George D. Dangas, MD, PhD, professor of medicine and surgery at Icahn School of Medicine at Mount Sinai and director of cardiovascular innovation at the Zena and Michael A. Wiener Cardiovascular Institute at the Icahn School of Medicine at Mount Sinai, told Healio. Guidelines vary on anticoagulation strategies in TAVR, most without a strong evidence base for their recommendations, he said. As a result, practice variation in the real world remains high.
Healio spoke with Dangas about the latest studies assessing antithrombotic therapy in TAVR and their potential impact on practice, current guideline recommendations and the need for more studies assessing the highest-risk patients.
Guideline-directed therapy
There are two distinct populations undergoing TAVR: those who require anticoagulation therapy and those who do not, according to Dangas.
“The simpler of the two are those who do not require anticoagulation,” Dangas said. “U.S. guidelines indicate the preference for aspirin alone in the short term or use of clopidogrel. In the European guideline, just aspirin alone is recommended, based on the statement issued in August. There is no statement regarding a loading dose of clopidogrel, which was very popular among TAVR practitioners, but that was always outside the guidelines.”
For those patients who do require anticoagulation, guidelines are “ambiguous,” with any recommendations covered under the indications for atrial fibrillation, Dangas said. For those patients, anticoagulation is recommended.
“Clearly, vitamin K is a default anticoagulant,” Dangas said. “The guideline is not very positive regarding the use of other anticoagulant therapies at this point. Guidance has not been updated based on the recent developments of this year.”
Benefit with aspirin alone
New data from the POPULAR TAVI trial, presented at the European Society of Cardiology Congress in August 2020, demonstrated that omitting clopidogrel after TAVR may reduce bleeding, and aspirin alone may be sufficient to prevent thromboembolic events. The study included patients who underwent TAVR but were not already on anticoagulants and had not recently undergone coronary stenting.
Investigators randomly assigned 690 patients who underwent TAVR to receive aspirin plus 3 months of clopidogrel or aspirin alone. The primary outcomes were all bleeding and nonprocedural bleeding.
Among patients who received aspirin and clopidogrel, 26.6% experienced the primary outcome of all bleeding at 1 year compared with 15.1% of the aspirin-alone group (RR = 0.57; 95% CI, 0.42-0.77). Similarly, nonprocedural bleeding occurred in 24.9% of patients assigned to aspirin plus clopidogrel vs. 15.1% of patients assigned to aspirin alone (RR = 0.61; 95% CI, 0.44-0.83).
Moreover, 31.1% of patients assigned aspirin plus clopidogrel experienced the first composite secondary outcome of CV death, MI, stroke or nonprocedural bleeding compared with 23% of those assigned aspirin alone (RR = 0.74; 95% CI, 0.57-0.95; P for noninferiority < .001).
The study’s findings challenged a common practice of dual antiplatelet therapy after TAVR.
“By the time the study was complete, the idea of adding clopidogrel to anticoagulation had already faded out because of other reports, so I would say the study confirmed what everyone was already doing,” Dangas said. “It did not really help us understand if it is worth it to initiate oral anticoagulation before the procedure, because in general, people had a lot of bleeding in this study.”
POPULAR-TAVI was not large enough to make a definitive statement about what happens after the procedure, according to Dangas.
“If, for example, we do not use a loading dose — something nearly everyone is already doing anyhow — and then start clopidogrel, does that provide benefit or not?” Dangas said. “We do not have a definitive answer on that, due to the study size. That is why there is a disparity in the U.S. vs. European guidelines, coming from the study’s shortcomings.”
New apixaban data
Data from the randomized, open-label ATLANTIS trial, presented in May at the American College of Cardiology Scientific Session, demonstrated that apixaban (Eliquis, Bristol Myers Squibb/Pfizer) was not superior to standard of care antithrombotic treatment for preventing thrombotic or bleeding events after successful TAVR, regardless of indication for oral anticoagulation.
In ATLANTIS, about one-third of patients required anticoagulation for a reason other than the TAVR procedure. Patients with an indication for oral anticoagulation were randomly assigned to twice-daily apixaban 5 mg or a vitamin K antagonist and patients with no indication for oral anticoagulation were assigned twice-daily apixaban or single or dual antiplatelet therapy when needed for a coronary indication.
In the intent-to-treat analysis, apixaban was not superior to standard care for the primary endpoint, which was a composite of all-cause death, transient ischemic attack/stroke, MI, valve thrombosis, pulmonary embolism, deep venous thrombosis, systemic embolism or major bleeding at 1 year (HR = 0.92; 95% CI, 0.73-1.16), including in patients with an indication for oral anticoagulation other than TAVR (HR = 0.88; 95% CI, 0.66-1.17) and for patients without an indication for oral anticoagulation (HR = 1.02; 95% CI, 0.68-1.51; P value for interaction = .57).
“ATLANTIS is again two studies in one: those who do vs. do not need anticoagulation,” Dangas said. “Unfortunately, when you subdivide these populations, it becomes two smaller studies. The results are limited by that fact, particularly in the anticoagulation arm, which has a pilot study flavor, because it is just a few hundred people in each group. It did not show much difference between the anticoagulant over apixaban and the anticoagulant over warfarin.”
In ATLANTIS, there were significantly higher mortality trends in the anticoagulation arm, accompanied by only a slight decrease in the study’s imaging endpoint, Dangas said. “Unfavorable trends in mortality, obviously, are not reassuring to anyone,” Dangas said. “For this reason, the findings from ATLANTIS are difficult to comprehend, just because of the compiling together of two different populations. We need to tell those stories separately.”
An ‘unusual patient group’
Increased longevity has resulted in an increase in diagnoses of aortic stenosis. Prevalence is low in patients aged 60 years and younger; however, it rises to approximately 10% among adults aged at least 80 years, according to a 2016 analysis published in the Journal of Geriatric Cardiology. The severity of aortic stenosis also increases with age.
“Everyone undergoing TAVR is in the elderly range; the question is are they very elderly or just elderly?” Dangas said. “This is an unusual patient group to deal with. Older adults, in general, are not well represented in typical CV outcomes studies conducted for any drug or condition.”
To have a condition dominated by predominantly older patients poses some interesting questions, Dangas said.
“How sure are we that the drugs or the dosing regimen derived from a middle-aged group of patients translate to these older adults with additional risk factors?” Dangas said. “They may not, and we have not been able to find out, because we have not had a condition where the patient population was so much older.”
Similarly, lower-risk patients who are relatively younger — in their 70s — may tolerate some drugs better, Dangas noted.
“These issues make us think about the term of any therapy,” Dangas said. “Sometimes doctors start medicines and then never stop them. The older patient group should make all of us stop and think: Are all the drugs they are prescribed worthy of long durations? Perhaps for some drugs, for some conditions, it is good to reevaluate.”
Dangas said there is a need for trials that enroll older, higher-risk patients who are at greater risk for bleeding.
“Previously, it has been too easy to say, “Oh, high-risk or very elderly patients are excluded,” Dangas said. “Then, you end up with so many people that are out there in the real world, yet somehow, clinical studies have not looked at them carefully. Now, it comes back to haunt us. Maybe what has been viewed as a patient minority is perhaps not a minority at all. There are many people with some seemingly rare causes, and we must study them because they are a considerable chunk of the patient population.”
References:
Brouwer J, et al. N Engl J Med. 2020; doi:10.1056/NEJMoa2017815.
Capodanno D, et al. JACC Cardiovasc Interv. 2021;doi:10.1016/j.jcin.2021.06.020.
Collet JP, et al. Joint American College of Cardiology/Journal of the American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).
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