GALILEO, GALILEO 4D: Mixed Results in Post-TAVR Anticoagulation

PHILADELPHIA ― The results of the first randomized prospective trial of an anticoagulation strategy vs standard dual antiplatelet therapy (DAPT) 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 experienced more thromboembolic and bleeding events than patients who received standard DAPT.

However, in the GALILEO 4D substudy of patients who underwent four-dimensional CT (4DCT), in which patients were randomly assigned to the two therapies, those in the rivaroxaban arm were less likely to show subclinical leaflet motion abnormalities and leaflet thickening.

As reported earlier, 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 because of safety concerns.

The full data analysis from GALILEO as well as the results from GALILEO 4D were presented here at the American Heart Association (AHA) Scientific Sessions 2019 to coincide with their publication November 16 in the New England Journal of Medicine.

The take-away 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," the lead author in the main GALILEO trial, George D. Dangas, MD, PhD, Mount Sinai Hospital, New York City, told theheart.org | Medscape Cardiology .

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, Boston University, Massachusetts, told theheart.org | Medscape Cardiology 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, Rigshospitalet University Hospital, Copenhagen, Denmark, 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.

GALILEO

Guidelines recommend DAPT after TAVR, but this advice is based on expert consensus or small studies, the GALILEO study authors note. 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, 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 1644 patients at 136 sites in 16 countries. The patients had successfully undergone TAVR and had no indication for an anticoagulant (eg, no atrial fibrillation).

The mean age of the patients was 80.6 years (±6.6 years), and 49.5% were women. The median time from TAVR to randomization was 2 days (range, 0 – 8 days).

Half of the patients were randomly assigned 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 [HR], 1.35; 95% confidence interval [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 occurred in the antiplatelet group (HR, 1.69; 95% CI, 1.13 – 2.53).

The individuals who were enrolled in this study were aged 80 years or older, 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 AF may have developed AF in the interim, and "you would have to change the dose of the rivaroxaban," she said.

Also, patients who may have been taking aspirin for 5 or 10 years and "survived" aspirin and who were then newly exposed to an anticoagulant would be more likely to experience bleeding.

"I certainly wouldn't close the door on NOACs [novel oral anticoagulants]," she concluded. "There are still other drug trials that are out there with this TAVR population. We'll wait for that" and see whether 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.

GALILEO 4D

Despite the negative results of the overall GALILEO study, results from the substudy that used 4DCT to evaluate function of the bioprosthetic aortic valves suggested rivaroxaban may have potentially beneficial effects on valve function.

The results showed that for patients who received the rivaroxaban–low-dose aspirin regimen, rates of subclinical reduced leaflet motion and leaflet thickening were lower than for patients who received the antiplatelet strategy, said De Backer, reporting on behalf of the GALILEO-4D investigators.

The substudy evaluated 205 patients who underwent 4DCT 90 days after TAVR. The primary substudy endpoint was at least one prosthetic valve leaflet with a grade 3 or higher motion reduction. Such a reduction occurred in 2 of 97 patients in the rivaroxaban group (2.1%) vs 11 of 101 in the antiplatelet group (10.9%; P = .01).

"This indicated an 80% greater reduction of the primary endpoint in the rivaroxaban arm," De Backer said. The chief secondary endpoint, the proportion of patients with at least one thickened leaflet, was met by 12.4% of the rivaroxaban group and 32.4% of the antiplatelet group, "a 60% significant reduction by rivaroxaban," De Backer said.

However, after the 10 patients in each group who had not adhered to the study drug regimen were excluded, he said, "we see no single patient had reduced leaflet motion of grade 3 or more in the rivaroxaban arm."

Another take-away from the substudy is the ineffectiveness of transthoracic echocardiography as opposed to 4DCT in TAVR patients. Echocardiography (ECG) failed to show any significant differences in the mean valve gradient between the treatment groups, De Backer said.

For the 11 patients who didn't have leaflet thickening (7.3%) and for the seven patients who did (15.9%), there was an increase of 5 mmHg or more in the mean valve gradient on ECG. ECG also showed a similar increase in the mean valve gradient for 14 patients who had no to moderate reduced leaflet motion (grade 3 or lower, 7.7%) and in four patients (30.8) who had reduced leaflet motion of grade 3 or higher.

"This basically confirms results from observational studies that transthoracic echocardiography is often not good enough to detect these phenomena," De Backer said.

The percentage of substudy patients who had major clinical events — major bleeding, thromboembolic events, or death at 90 days — was less than 3% for each type of event, DeBacker said. "There were too few clinical events to permit any assessment of the impact of leaflet thickening or reduced leaflet motion on clinical outcomes," he said.

That lack of clarity with regard to clinical events was addressed by discussant Victoria Delgado, MD, PhD, of Leiden University Medical Center in the Netherlands.

"With stroke or TIA, there are too few events to draw any conclusions," she said of the substudy. "We don't know when we need to use CT, when we need to evaluate these patients, or maybe when we should go for more advanced imaging techniques where we can see the biology of those changes in the leaflets." Hopefully, she said, future studies will provide those insights.

"CT can be more sensitive than ECG to see these subclinical changes," she said, "but the open questions that we have are to see if there is a correlation between thrombosis rate on imaging vs the stroke rate."

The substudy's conclusion regarding ECG, however, has been borne out by previous retrospective studies, Delgado added.

Robert A. Harrington, MD, of Stanford Medicine, who is the current AHA president, tried to put the seemingly conflicting findings of the main GALILEO study and the 4D substudy into context.

"There you have the disconnect between the mechanism and the clinical observation, and those are sometimes difficult to reconcile because the assumption is that the mechanism leads to the clinical outcome," he said.

Although the main study shows that routine anticoagulation after TAVR is not indicated, the findings raise questions about the risk for clots forming on bioprosthetic valves. "Yes, maybe there are clots forming on these valves, but maybe that's not causing the bad clinical outcomes," Harrington said.

The findings also raise questions about the use of newer anticoagulants to prevent stroke after TAVR, he said. "It appears that warfarin is better than the newer anticoagulants for reasons that aren't entirely clear."

Dangas, lead author of the main GALILEO trial, said the substudy results could help with respect to the design of future trials of even lower doses of anticoagulation in a more selective group of TAVR patients.

"In order to decrease the clots, first of all, you don't need the full dose of anticoagulation; even a low dose may do the trick," he said. Further investigations can evaluate the clinical significance of having a blood clot in the valve as an indication for anticoagulation vs antiplatelet therapy.

"Even though this obviously doesn't mean you're going to have a stroke in a year or two," Dangas said, "could it perhaps mean that the valve is not going to have such a good durability later on?"

Perhaps future studies of anticoagulation in TAVR should concentrate on patients who actually experience clotting in the valve, he said.

The trial was supported by Bayer and Janssen. Dangas reports receiving grants from Bayer during the conduct of the study; personal fees from Bayer, Janssen; grants and personal fees from Daiichi-Sankyo; and other compensation from Medtronic outside the submitted work. De Backer reports receiving grants from Bayer during the conduct of the study and personal fees from Abbott and Boston Scientific outside the submitted work.

American Heart Association (AHA) Scientific Sessions 2019: Presented November 16, 2019.

N Engl J Med. Published online November 16, 2019. GALILEO study, Abstract; GALILEO 4D study, Abstract

This report also appears on MDEdge Cardiology.

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