A separate study looked at the efficacy and safety of the DOACs apixaban, dabigatran, and rivaroxaban in comparison with warfarin in patients with severe obesity, measured as the frequency of thromboembolic and major bleeding events. The researchers examined data from 180 patients, with 41 patients receiving apixaban, 11 receiving dabigatran, 33 receiving rivaroxaban, and 90 receiving warfarin. There were 11 ischemic stroke and systemic embolic events in the DOAC groups and 10 such events in the warfarin group.2 The researchers concluded that anticoagulation therapy with DOACs in extremely obese patients appeared to be safe and effective for preventing thromboembolic events. However, they wrote that further studies are warranted.2

George H Crossley, MD, professor of medicine and the director of the electrophysiology laboratory at the Vanderbilt Heart and Vascular Institute in Nashville, Tennessee, told Hematology Advisor that clinicians are in a difficult position because of a lack of prospective data. “I don’t think the data support a change in guidelines or a change in practice. When you look at the pharmacokinetics, some of the drugs make more sense than others, so there is no one-size approach,” Dr Crossley explained. “All the data we have would suggest the therapeutic index of these drugs is quite wide, and so that leaves us in a good situation with efficacy and safety, and we would need new data to change practice.”

He added that none of the recent retrospective studies are powered enough to change clinical practice or change the guidelines currently offered by various medical societies and organizations. “I don’t think anything about this suggests that we need to change our practice. There are no significant data that are new since [DOACs] were approved,” said Dr Crossley.


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John Higgins, MD, professor of cardiovascular medicine at the University of Texas Health Science Center at Houston, said that in patients with extreme obesity who need anticoagulation for management of VTE, or for prevention of stroke in patients with AF, a CHA2DS2-VASc score of 2 or higher, and a HAS-BLED score no higher than 3, clinicians should consider a different approach. “After starting the DOAC, a blood test should be performed to make sure [the patient is] being adequately anticoagulated,” Dr Higgins told Hematology Advisor. “If testing reveals insufficient anticoagulation with [the] DOAC, [the patient] should be anticoagulated with coumadin to a target international normalized ratio (INR) [of] 2.0 to 3.0. Although this is more labor intensive and requires blood testing, this approach will provide more optimal anticoagulation and prevent [the patient from] having an event.”

Dr Higgins added that DOACs are still relatively new, and there is a lack of knowledge about the established clear dosage intervals for some of these agents. “For those with extreme obesity, the evidence is lacking, and so we should be cautious [about] using DOACS in this group. For those with obesity, DOACs are probably okay based on the available data. When in doubt, or if the [patient] has had a recurrent event while on a DOAC, [it is] probably best to use coumadin,” he noted.

Sandeep Jain, MD, director of the Center for Atrial Fibrillation at the University of Pittsburgh Medical Center Heart and Vascular Institute in Pennsylvania, agreed that prospective studies looking at outcomes in patients with extreme obesity receiving DOACs are urgently needed. “However,” he added, “there are several reports from subanalyses of the randomized trials as well as real-world data supporting DOAC use in this population. Though a ‘softer’ stance on obesity in DOACs may be warranted, there is currently not enough data for a strong recommendation in the BMI greater than 40 group.” He said that given the difficulties and well documented challenges in maintaining therapeutic INRs with warfarin, it is reasonable based on the available data to treat obese patients with DOACs.

Currently, the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis recommends against the use of DOACs in patients with severe obesity except in certain situations. However, Paul L den Exter, MD, PhD, of the department of thrombosis and hemostasis at Leiden University Medical Center in the Netherlands, told Hematology Advisor there have been several observational studies on the use of DOACs in obese populations, and, although they should be regarded as indirect evidence, they do not suggest inferior efficacy of DOACs in these patients.

“For an update of the guidelines, it would be important to consider the results of these studies as well. Although the reported incidences of thromboembolic events under DOAC treatment appear to be comparable [with those in] patients receiving vitamin K antagonists, it remains uncertain whether peak and trough levels in patients with extreme body weight are adequate. In cases where the levels are monitored and inadequate, vitamin K antagonists remain the therapy of choice,” concluded Dr den Exter.

References

1.     Kushnir M, Choi Y, Eisenberg R, et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data [published online May 24, 2019]. Lancet Haematol. doi:10.1016/s2352-3026(19)30086-9

2.     Kalani C, Awudi Henry E, Alexander T, Udeani G, Surani S. Efficacy and safety of direct oral anticoagulants (DOACs) in morbidly obese patients [published online October 1, 2018]. Poster presentation at: American College of Chest Physicians 2018 Annual Meeting; October 10, 2018; San Antonio, TX. doi:10.1016/j.chest.2018.08.093