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PHILADELPHIA -- Patients were harmed when given rivaroxaban (Xarelto) to prevent valve surface thromboembolism after transcatheter aortic valve replacement (TAVR) if they had no established indication for it, according to the phase III trial GALILEO.

These patients were at significantly higher risk of the primary composite outcome, death or thromboembolic events, on intention-to-treat analysis comparing rivaroxaban and antiplatelet therapy over a median 17 months of follow-up (9.8 vs 7.2 per 100 person-years, HR 1.35, 95% CI 1.01-1.81).

This finding was consistent across prespecified subgroups, said George Dangas, MD, PhD, of Icahn School of Medicine at Mount Sinai in New York City, at the American Heart Association (AHA) meeting. The results were published online in the

Death rates alone put the anticoagulation group at a disadvantage (5.8 vs 3.4 per 100 person-years, HR 1.69, 95% CI 1.13-2.53).

As for safety, rivaroxaban was tied to numerically more life-threatening, disabling, or major bleeds (4.3 vs 2.8 per 100 person-years, HR 1.50, 95% CI 0.95-2.37).

Yet how rivaroxaban might lead to higher mortality compared to antiplatelets is unclear, the GALILEO investigators said.

"The higher number of deaths in the rivaroxaban group than in the antiplatelet group did not appear to be directly attributable to the higher risk of bleeding in the rivaroxaban group," they pointed out.

"Among patients assigned to rivaroxaban who died, only a minority had a major bleeding event, MI, or stroke within 30 days before death, and most deaths occurred long after discontinuation of the trial drug," they wrote. "Most of the adjudicated causes of death in the rivaroxaban group were sudden or from unknown causes, as well as due to noncardiovascular causes."

A secondary efficacy analysis revealed that rivaroxaban after TAVR was associated with numerical, non-significant excesses in death from cardiovascular causes or any thromboembolic event (7.8 vs 6.3 per 100 person-years, HR 1.22, 95% CI 0.89-1.69).

"Understanding cause of death in a study like this is difficult," but the fact that rivaroxaban did not lead to a clinical benefit while there was also more severe bleeding is enough to "close the door" on this oral anticoagulant at the dose tested, commented Robert Bonow, MD, of Northwestern University Feinberg School of Medicine in Chicago, and AHA past president.

Early Termination

A major limitation of GALILEO was that it was terminated early by the data and safety monitoring board due to safety concerns.

The open-label trial was conducted at 136 centers in 16 countries. Randomization occurred before hospital discharge and at a median 2 days after successful TAVR. Study participants were assigned to rivaroxaban 10 mg daily plus aspirin for the first 3 months (followed by rivaroxaban monotherapy) or aspirin plus clopidogrel 75 mg daily for the first 3 months (followed by aspirin monotherapy).

Included were 1,644 adults, average age 80.6, who were roughly split between the sexes.

Notably, there was an imbalance in the proportion of patients who prematurely discontinued their assigned drug regimen: 307 in the rivaroxaban arm and 194 in the antiplatelet arm. This left the anticoagulation group with a median 428 days of exposure to rivaroxaban and the antiplatelet group 474 days of aspirin use.

On-treatment analysis attenuated the difference between rivaroxaban and antiplatelet therapy after TAVR in terms of the primary composite endpoint (8.1 vs 6.6 per 100 person-years, HR 1.21, 95% CI 0.86-1.70).

"These results underscore the challenge of antithrombotic therapy in the TAVR population, which includes patients who are generally elderly, potentially frail, or affected by multiple coexisting conditions associated with an increased risk of both bleeding and thromboembolic events," the authors noted.

In this trial, anticoagulation did not reduce the risk of symptomatic valve thrombosis over what was seen with antiplatelets (0.3 vs 0.6 per 100 person-years, HR 0.43, 95% CI 0.11-1.66).

Subclinical Leaflet Thrombosis

However, a substudy did find that rivaroxaban lowered the incidence of subclinical valve leaflet thickening and reduced leaflet motion after TAVR.

Presented at the same AHA session, the GALILEO-4D imaging substudy showed fewer rivaroxaban recipients presenting with prosthetic valve leaflets with ≥grade 3 motion reduction (2.1% vs 10.9%, P=0.01), a finding that held up on per-protocol analysis (0 vs 9.6%).

Similarly, the risk of developing thickening of at least one leaflet was lower in the experimental arm (12.4% vs 32.4%), according to Ole De Backer, MD, PhD, of Rigshospitalet, Copenhagen University Hospital. The findings were also published in NEJM.

Again, anticoagulation managed to reduce the risk of leaflet thickening, and reduced leaflet motion, as well as potentially improve long-term valve function, said Danny Dvir, MD, of the University of Washington Medical Center in Seattle.

Yet, "we still don't know what the clinical significance is of the subclinical thrombosis ... it doesn't seem to be related to stroke," Bonow said. "Occasionally it may alter the TAVR valve function but not usually in a clinically meaningful way."

Ultimately, the question is whether leaflet thickening (interpreted as leaflet thrombosis) leads to structural valve deterioration and limits valve durability, he told 口袋女优.

The GALILEO substudy included 231 patients with available 4-D CT scans from their 3-month follow-up visit.

Investigators generally noted similar patient characteristics between the overall GALILEO study population and the substudy cohort, the exception being there were fewer high-risk patients in the latter.

The small sample was a limitation of this imaging analysis. People were also imaged at just one time point, De Backer's group acknowledged.

Rivaroxaban is approved for the prevention of venous thromboembolism and for stroke prophylaxis in atrial fibrillation.

Several randomized trials are ongoing in the study of TAVR patients who fall under an established indication for oral anticoagulation. These trials include , , , and , according to the GALILEO investigators.

Lower-risk patients in particular, recently made eligible for TAVR by the FDA, may or may not see the same subgroups benefiting from anticoagulation, according to Dvir.

"Younger patients will have less bleeding and will require longer valve durability," he stated. "Selected scenarios that are significantly associated with clinical thrombosis, such as valve in valve, may still be considered for anticoagulation."

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