PHILADELPHIA – The results of the first randomized prospective trial of an anticoagulation strategy versus standard dual antiplatelet (DAPT) therapy for patients undergoing transcatheter aortic valve replacement (TAVR) show that routine anticoagulation is not suitable for all comers in a high-risk population.
In the main GALILEO trial of elderly patients after TAVR, those who received an investigational anticoagulation strategy with the direct factor Xa inhibitor rivaroxaban (Xarelto; Bayer/Janssen) had worse survival and more thromboembolic and bleeding events than patients who received standard DAPT.
However, in the GALILEO 4D substudy of patients who underwent four-dimensional computed tomography (4DCT) randomized to the two therapies, those in the rivaroxaban arm were less likely to show subclinical leaflet motion abnormalities and leaflet thickening.
Preliminary results from GALILEO were disclosed in an October 3, 2018, “Dear Healthcare Professional” letter from Bayer, and the trial was stopped after a median of 17 months due to safety concerns.
The full data analysis from GALILEO as well as the results from GALILEO 4D were presented at the American Heart Association scientific sessions to coincide with their publication on Nov. 16, 2019, in the New England Journal of Medicine.
The takeaway message is that, despite the positive imaging finding in GALILEO 4D, “there is no reason to give 10 mg rivaroxaban-based treatment routinely after TAVR in patients who don’t need anticoagulation anyhow,” lead author in the main GALILEO trial, George D. Dangas, MD, PhD, Mount Sinai Hospital, New York, said in an interview.
However, because rivaroxaban had an effect in reducing the clots on leaflets, he said, further investigation is required to determine the optimal therapeutic strategy after TAVR.
Similarly, the assigned discussant for GALILEO, Elaine Hylek, MD, of Boston University said in an interview that “we just don’t know right now what the overall added benefit of an oral anticoagulant would be in this high-risk patient population after having a TAVR.”
Ole De Backer, MD, PhD, of Rigshospitalet University Hospital, Copenhagen, lead author of the GALILEO 4D substudy, concluded that, although the rivaroxaban-based strategy was associated with fewer valve abnormalities in this analysis, those positive outcomes need to be taken in context with worse clinical outcomes in the main GALILEO trial.
Guidelines recommend DAPT after TAVR, but this advice is based on expert consensus or small studies, the GALILEO study authors noted. Several years ago, there were random case reports and then case series of patients who had undergone TAVR or surgical aortic valve replacement (SAVR) and developed clots around the valve, Dr. Dangas explained.
These developments coincided with the first available high-quality CT angiography images that captured valve abnormalities that had not been seen before.
In parallel, there were rare reports of stroke and transient ischemic attack (TIA) that may have been associated with TAVR or SAVR. This triggered a series of studies to investigate an anticoagulation strategy after TAVR.
From December 2015 to May 2018, GALILEO enrolled 1,644 patients at 136 sites in 16 countries who had undergone successful TAVR, and had no indication for an anticoagulant (e.g., no atrial fibrillation).
The patients had a mean age of 80.6 years (plus or minus 6.6 years) and 49.5% were female. The median time from TAVR to randomization was 2 days (range, 0-8 days).
Half were randomized to receive an antithrombotic strategy, rivaroxaban 10 mg once daily plus aspirin 75-100 mg once daily for the first 90 days followed by rivaroxaban alone. The other half received an antiplatelet-based strategy, aspirin 75-100 mg once daily plus clopidogrel 75 mg once daily for the first 90 days followed by aspirin alone.
In the intention-to-treat analysis, death or first thromboembolic event, the primary efficacy outcome, occurred in 105 patients in the rivaroxaban group and 78 patients in the antiplatelet group (hazard ratio, 1.35; 95% CI, 1.01-1.81; P = .04).
Major, disabling, or life-threatening bleeding, the primary safety outcome, occurred in 46 and 31 patients, respectively (HR, 1.50; P = .08).
A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (HR, 1.69; 95% CI, 1.13-2.53).
The individuals who were enrolled in this study were 80 and older, Dr. Hylek pointed out. “The age in and of itself is an uncontested risk factor for everything, whether it be bleeding, embolic event, or obviously mortality.”
Although the dose was half that used to prevent stroke in patients with atrial fibrillation, perhaps a “twice-daily lower dose” might be the way to go, moving forward, she said.
Patients who did not have atrial fibrillation may have developed atrial fibrillation in the interim, and “you would have to change the dose of the rivaroxaban.”
Also, patients who may have been taking aspirin for 5 or 10 years and “survived” aspirin, who were then newly exposed to an anticoagulant, would be more likely to experience bleeding.
“I certainly wouldn’t close the door on novel anticoagulants,” she concluded. “There are still other drug trials that are out there with this TAVR population. We’ll wait for that,” and see if the results corroborate these findings.
The high-risk patients may turn out to be a potential niche group for drugs being developed to inhibit factor XIa, she speculated.