Mortality Lower for DOAC vs Vitamin K Antagonists in Broad VTE Registry Population

May 06, 2020

Patients in various clinical settings who were put on a direct oral anticoagulant (DOAC) for treatment of venous thromboembolism (VTE) were more likely to be alive at 1 year than those treated with a vitamin K antagonist (VKA) in a large registry study.

In the analysis, based on almost 8000 such patients in the international GARFIELD-VTE registry, adjusted all-cause mortality was 27% lower for those on a DOAC, usually rivaroxaban (Xarelto, Bayer), while their risks of major bleeding, myocardial infarction (MI), and stroke were similar to those treated with a VKA, which most often was warfarin.

The findings appeared in a report published April 28 in Thrombosis Research, with lead author Henri Bounameaux, MD, University of Geneva.

The patients were treated at more than 400 sites in 28 countries, "allowing for an analysis of real-world practices and clinical outcomes worldwide. Therefore, our conclusion that DOACs were associated with reduced all-cause mortality compared with VKA is likely to be strong," Bounameaux told | Medscape Cardiology.

Patients already faring well on warfarin "should probably stay on warfarin," he said. But the current findings "add to the growing body of evidence supporting the use of DOACs over VKA for treatment of venous thromboembolism."

Indeed, the steep mortality reduction "with no increase in bleeding risk in this large unselected population is a strong argument in favor of DOACs," Bounameaux said.

"This is more of a confirmation of what we should be doing," Gregory Piazza, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, not associated with the study, told | Medscape Cardiology.

Based on the major trials and even the guidelines, he said, it would be hard to justify using warfarin in the average patient with VTE when the DOACs are easier to take and have already been shown to reduce the risk of bleeding, including intracranial hemorrhage.

All Comers

But GARFIELD-VTE may have something new to offer, in that the registry was intended to reflect a "real world" experience and so didn't exclude some types of patients often excluded from the randomized trials. They include patients with risk factors for bleeding, as the report notes, and those from a wide range of clinical settings and with conditions that can predispose to VTE, along with other multiple comorbidities.

The analysis included 7987 patients with deep vein thrombosis (DVT), pulmonary embolism (PE), or both forms of VTE who were started on either a DOAC or a VKA (4791 and 3196 patients, respectively) and were followed on an intention-to-treat basis.

The two groups had been selected from the registry and balanced according to propensity scores. About 16% of the patients had a history of VTE. Clinical settings or possible predisposing conditions for VTE included acute illness, surgery, cancer, hospitalization, long-term immobilization, lower-limb trauma, heart failure, oral contraception, and prolonged travel, the group reports. Many had multiple comorbidities.

Patients in Europe were more likely to receive a DOAC than a VKA, "whereas the opposite was true in patients enrolled in the Middle East and South Africa," the report notes. The VKA of choice was warfarin in 85% of cases, acenocoumarol in 12%, and a few others in the remainder.

Rivaroxaban vs Warfarin?

One of the registry study's noteworthy limitations is the prevalence of rivaroxaban as the DOAC of choice for its patients, which — as the authors acknowledge — could mean the findings "may not be generalizable to the other DOACs."

Fully 80.2% of the DOAC recipients were treated with that agent, compared with 13.1% for apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), 5% for dabigatran (Pradaxa, Boehringer Ingelheim), and 1.6% for edoxaban (Savaysa, Daiichi Sankyo).

In addition, the study's sole industry backing came from rivaroxaban's manufacturer, Bayer Pharma AG, in the form of an unrestricted research grant to the registry's sponsor, the Thrombosis Research Institute, which "had no influence on the design or analyses of the study," Bounameaux said.

The predominance of rivaroxaban among DOACs in the study, he said, "is due to the early registration of this compound in the venous indication compared to the other DOACs."

Rivaroxaban was approved for VTE in both Europe and the United States in November 2012. Apixaban received the same approvals in Europe and the United States in the summer of 2014; and dabigatran in the summer and spring, respectively, of the same year.

In an interview, Bounameaux said preference for a given DOAC or VKA was "influenced by local circumstances, including drug registration characteristics, healthcare system, and insurance coverage." The analysis attempted to control for all such possible confounders, he added; other covariates included demographics, clinical history, comorbidities, type of VTE, and site of DVT.

"GARFIELD-VTE is sponsored by Bayer, which may have skewed the number of patients taking a DOAC. The steering committee apparently has recruited centers that prefer rivaroxaban as their DOAC," Freek W.A. Verheugt, MD, Onze Lieve Vrouwe Gasthuis, Amsterdam, told | Medscape Cardiology.

"Yet, I think the data are applicable to any DOAC used for VTE treatment," he said.

However, Piazza said, "the study is essentially a comparison between rivaroxaban and warfarin, so it's hard to extend it out to the other direct oral anticoagulants."

Still, "it's in a nice real-world population, the everyday patients that we see in the clinic, versus a very restricted clinical trial population," he agreed. "In that way, it's reassuring to see the benefits that we suspected with the direct oral anticoagulant rivaroxaban seem to be born out in a major way, since it impacts mortality, in this type of population."

Lower Mortality, Comparable Bleeding

The adjusted risk for death by any cause was significantly lower for those in the DOAC group, and the adjusted risks for recurrent VTE, overall bleeding, and major bleeding were similar to the those in the VKA group. Also similar were the risks for stroke or transient ischemic attack, and MI or other acute coronary syndrome.

Adjusted Hazard Ratio for Outcomes, DOAC vs VKA for VTE: GARFIELD-VTE
End Point Hazard Ratio (95% CI) P Value
Death from any cause* 0.73 (0.56–0.95) .019
Recurrent VTE* 0.91 (0.71–1.18) .489
Overall bleeding* 0.96 (0.81–1.14) .672
Major bleeding 1.03 (0.69–1.54) .887
*Coprimary end points

"Clearly, the most important finding is the significant mortality reduction," Verheugt said. Although such a difference is not surprising, "the mechanism is not clear. The authors claim a reduced risk of VTE and of fatal bleeding, yet the numbers are too small to be conclusive."

The report states that the patients who received DOACs, compared with VKAs, were less likely to die from VTE complications (2.7% vs 4.7%) or from bleeding (1.3% vs 4.2%).

Piazza questioned how the risks for recurrent VTE and major and overall bleeding between the DOACs and VKAs could be comparable, even though on DOACs there were actually fewer deaths due to VTE and bleeding.

Perhaps, he speculated, "you get more consistent anticoagulation with the direct oral anticoagulants. There are not as many episodes of low or high anticoagulation, so that tends to keep you in the target range and it reduces the risk of bleeding." Bleeding is still possible with any anticoagulant, "but if you have good control over the level of anticoagulation, it won't be a fatal bleed."

GARFIELD-VTE is supported by an unrestricted research grant from Bayer Pharma AG, from which Bounameaux discloses receiving honoraria. Disclosures for the other authors are in the report. Piazza has been a consultant to Optum, Pfizer, and Thrombolex, and he has received research funding from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Ekos, Janssen, and Portola. Verheugt has disclosed consulting, receiving royalties, or holding stock or other ownership interest in AstraZeneca, Bayer Healthcare, Bristol-Myers Squibb/Pfizer, Boehringer-Ingelheim, Daiichi-Sankyo, and Eli Lilly; he wasn't part of GARFIELD-VTE but was on the writing committee of the GARFIELD-AF trial.

Thromb Res. Published online April 28, 2020. Abstract

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