BMI Mostly Doesn’t Impact DOACs, Except Maybe at the Extremes

Among patients with atrial fibrillation (AF), the relative safety and efficacy of direct oral anticoagulants (DOACs) versus warfarin are generally similar across categories of body mass index (BMI) and weight, although some of their advantages appear to be attenuated—or even reversed—at the upper ends of those scales, according to pooled data from four pivotal trials.

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Overall, DOAC therapy was associated with lower risks of stroke/systemic embolism, all-cause death, major bleeding, intracranial hemorrhage (ICH), and a net clinical outcome incorporating both safety and efficacy endpoints compared with warfarin, lead author Siddharth Patel, MD (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA), and colleagues report in a study published online recently in Circulation.

But the advantages of DOACs regarding major bleeding and the net clinical outcome—a composite of stroke/systemic embolism, major bleeding, or death—diminished at higher BMI levels. The rate of the net clinical outcome, in fact, favored warfarin among patients with a BMI of 40 kg/m² or greater (5.38% vs 6.85%; P = 0.02), mostly driven by a lower rate of all-cause mortality.

That is “somewhat surprising” and doesn’t have a clear explanation, senior author Robert Giugliano, MD (Brigham and Women’s Hospital and Harvard Medical School), told TCTMD. Prior studies have shown that warfarin performs well among patients with higher BMIs, which might be part of what’s at play, he suggested, or it could be that warfarin has protective pleiotropic effects among patients with obesity. Lastly, “this could be just a play of chance” he pointed out.

Whatever the reason, overall this study provides information that may be useful for shared decision-making discussions between patients and their doctors about anticoagulant choice, the researchers say.

“This analysis confirms the efficacy and safety of the DOACs over warfarin in patients with atrial fibrillation” across most of the range of BMI or body weight, Giugliano said. But, he added, “it does raise a question at the very high end as to whether one should use a DOAC or warfarin—so some caution there at the very, very high end.”

COMBINE AF Study

DOACs are now the preferred anticoagulant choice for prevention of stroke and systemic embolism in patients with AF and have largely replaced vitamin K antagonists (VKAs) like warfarin, Giugliano said. In the pivotal DOAC trials, however, relatively few patients at the extremes of body weight were included. That raised questions about whether drug concentrations would be too high at very low body weights, increasing the risk of bleeding, or insufficient at very high body weights, increasing the risk of ischemic events.

To explore the effects of DOACs across BMIs and body weights, investigators from the COMBINE AF study group pooled patient-level data from the four pivotal trials of DOACs versus warfarin in the setting of AF—RE-LY for dabigatran (Pradaxa; Boehringer Ingelheim), ROCKET AF for rivaroxaban (Xarelto; Bayer/Janssen), ARISTOTLE for apixaban (Eliquis; Bristol Myers Squibb), and ENGAGE AF-TIMI 48 for edoxaban (Savaysa; Daiichi Sankyo).

In total, there were 58,464 patients included, with a median BMI of 28.3 kg/m² and a median body weight of 81.0 kg. There were only 598 patients with a BMI below 18.5 kg/m², so these patients were examined separately. Of the rest, 23.1% had a normal BMI (18.5 to < 25 kg/m²), 38.5% were overweight (25 to < 30 kg/m²), 24.0% had class I obesity (30 to < 35 kg/m²), 9.4% had class II obesity (35 to < 40 kg/m²), and 5.0% had class III obesity (40 kg/m² or higher).

The primary efficacy outcome was stroke/systemic embolism, and the likelihood of this event was lower at higher BMIs irrespective of which treatment patients were receiving. Overall, DOAC therapy was associated with a lower risk compared with warfarin (adjusted HR 0.80; 95% CI 0.73-0.88), with consistent effects across BMI categories.

The primary safety outcome was ISTH major bleeding, and rates came down at higher BMIs in patients treated with warfarin but remained relatively consistent across BMI categories in those treated with DOACs. In the overall cohort, DOAC therapy was associated with a lower risk (adjusted HR 0.88; 95% CI 0.82-0.94), although the gap closed at higher BMIs.

ICH rates declined at the upper end of the BMI range regardless of treatment type, with risk lower in the DOAC-treated patients overall (adjusted HR 0.45; 95% CI 0.37-0.54).

Findings followed similar patterns when the data were analyzed by body weight.

Why the Attenuation?

Among other secondary outcomes, the attenuation of the advantages for DOAC therapy versus warfarin in terms of net clinical outcome and death at higher BMIs wasn’t explained by differences in ischemic or fatal bleeding events, which are “the two outcomes most modifiable by anticoagulation,” the investigators note.

Giugliano said that his team couldn’t come up with any definitive answers as to what explains this finding, although he pointed out that there is some evidence that warfarin could have a protective effect through a vitamin K-dependent pathway involving growth-arrest-specific 6 (gas6), a protein that is elevated in heart failure and may be related to the development of obesity. Giving a VKA like warfarin blocks this pathway and may have beneficial effects in patients with obesity, although this is a hypothesis that remains to be tested, Giugliano said.

Generally, though, “these findings should be interpreted with caution, particularly given the low number of events among patients with class III obesity and the multiple subgroups/outcomes tested,” the researchers write.

Commenting for TCTMD, Bishoy Ragheb, PharmD (VA Eastern Colorado Health Care System, Aurora), couldn’t come up with a definitive explanation either, and also suggested that warfarin might have beneficial pleiotropic effects—unrelated to its impact on ischemic events and bleeding risks—among patients with higher BMIs or body weights.

“Does warfarin have additional effects there?” Ragheb said. “This study doesn’t necessarily answer it, but it definitely raises that question and it’s something that definitely needs to be looked into over time.”

At this point, though, the finding shouldn’t be used to support avoidance of DOACs in patients at higher levels of BMI or body weight, but rather should be incorporated into shared decision-making discussions, Ragheb said. “For me, it wouldn’t preclude a patient from using a DOAC at all. I think that what it does is it provides some nuance to the discussion. . . . I wouldn’t be overly concerned using [DOACs], but this is just something in the back of our mind to say, ‘We should kind of watch out for this.’”

He called for more research on the effects of DOACs in patients with higher BMIs, and on potential differences across the DOACs, “so we can further answer these questions in the future.”