Alex Spyropoulos, MD, FACP, FCCP, FRCPC
North Shore – LIJ Health System

KEY TAKEAWAYS

  • Direct oral anticoagulants (DOACs) are at least as safe and effective as warfarin in the prevention of cardioembolic stroke in patients with comorbid nonvalvular atrial fibrillation (NVAF) and obesity.
  • DOACs were specifically studied without laboratory monitoring. Monitoring anti-Xa assays in patients with obesity has not been linked to distinct clinical benefits.
  • Clinicians need to consider total healthcare costs and patient satisfaction when selecting a treatment regimen for patients with NVAF.
  • While obesity can sometimes mitigate the effects of stroke, health risks associated with obesity far outweigh any perceived benefits.

Alex Spyropoulos, MD, FACP, FCCP, FRCPC, is a professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Uniondale, New York. He is the Director of Anticoagulation and Clinical Thrombosis Services for the multi-hospital Northwell Health System in New York. He is also a professor at Feinstein Institutes for Medical Research within Northwell’s Institute of Health System Science. His areas of clinical interest include treatment of venous thromboembolic disease, patient self-testing of warfarin, and use of the novel oral anticoagulants, including their use in special patient populations.

Patients with morbid obesity, defined as a body weight of at least 120 kg or BMI of at least 40 kg/m2, were underrepresented in clinical trials of DOACs. Are DOACs considered safe and effective for stroke prevention in patients with comorbid NVAF and obesity? Does the extent of obesity — that is, a BMI of 30 to 35 kg/m2 vs a BMI of 35 to 40 kg/m2 vs BMI greater than 40 kg/m2 — affect the safety and efficacy of DOACs?

Overall, yes. Although patients with morbid obesity were underrepresented in phase 3 clinical trials of DOACs, patients who were obese and morbidly obese were definitely included.1,2 Subsequently, large observational studies have shown that, at the very least, treatment with DOACs is as safe and effective as dose-adjusted warfarin in the setting of obesity and NVAF.3-8 Taken together, these findings have led to a change in the guidance documents. Guidance in 2016 from the International Society on Thrombosis and Haemostasis (ISTH) was very conservative and recommended against using DOACs in patients weighing more than 120 kg.9 That restriction is no longer applied, and current guidelines and prescriber decisions reflect greater confidence in the use of DOACs for treatment of patients with obesity.10,11

While the extent of a patient’s obesity does not affect the choice of DOAC therapy in this setting, there are notably fewer data once BMI exceeds 40 kg/m2. This is also true of warfarin. However, unlike patients treated with DOACs, patients receiving warfarin can be monitored. In general, data on this specific group of patients with comorbid obesity and NVAF are lacking.

Pharmacokinetic studies have shown that the effect of obesity on DOAC levels in the blood varies based on the specific agent administered. Is there a benefit to using 1 DOAC rather than another in patients with obesity and NVAF?

The clinical significance of pharmacokinetic testing here is unclear. Drug levels in this setting are not meaningful currently because there are insufficient data to establish a therapeutic target value for various DOAC agents.10,11 We also know that there is tremendous individual variability in the pharmacokinetics of DOACs, independent of obesity as a comorbidity. In that regard, the difference in drug levels does not translate to greater benefit from the use of any single DOAC over another in patients with obesity. There is a slight preference for rivaroxaban, likely due to the much greater amount of observational data on use of rivaroxaban vs other DOACs in patients with obesity.

We also know that there is tremendous individual variability in the pharmacokinetics of DOACs, independent of obesity as a comorbidity. In that regard, the difference in drug levels does not translate to greater benefit from the use of any single DOAC over another in patients with obesity.”

Results of research comparing DOACs vs warfarin for stroke prevention in comorbid NVAF and obesity have varied. Several studies have demonstrated comparable efficacy and safety whereas others reported improved efficacy and safety with select DOACs, such as rivaroxaban. Can you comment on the available data?

It is important to bear in mind that “efficacy” does not apply to observational studies. The most appropriate outcome to evaluate is “effectiveness.” I am very conservative in the way I interpret observational studies because often the quality of the data is very poor. That said, an advantage is that such studies typically include more patients than could otherwise be evaluated, and therefore include a large amount of data.
 
I believe we can say that treatment with DOACs in patients with obesity is, at the very least, equivalent to warfarin in terms of effectiveness and safety.
 
Although a large recently published study suggested better safety parameters with DOACs,12 I think that the investigators may be overly optimistic in their conclusions. I would rather be conservative. We all know warfarin is problematic and a target warfarin dose is more difficult to reach in patients who are obese vs nonobese, so that is important to consider as well.

How big of a role does total healthcare cost play in treatment selection for patients with NVAF and obesity? Does patient satisfaction with treatment outcomes or pill burden influence the prescribing of certain medications?

Although patients with obesity treated with warfarin have the same bleeding risk as those who receive DOACs, healthcare resource utilization is much lower with warfarin.4 On the other hand, when considering DOACs, much of the decision-making is dictated by insurance coverage. At this time, most private insurers are reasonable regarding use of DOACs rather than warfarin.
 
Of course, patient satisfaction is another key factor in choosing a particular treatment regimen, and it can play a critical role in patients with obesity. The ability to offer patients DOAC therapy can have a notable impact on patient satisfaction and ease of use, because — unlike warfarin — treatment monitoring is not required. In choosing among DOACs, I prefer to use rivaroxaban rather than apixaban because of its once-daily, as opposed to twice-daily, dosing.

What additional monitoring, if any, is recommended for patients with obesity receiving treatment with warfarin or a DOAC for stroke prevention in NVAF?

For warfarin, the target internal normalized ratio and required monitoring remain the same in a patient with obesity. As I mentioned, it can be more difficult to get patients with obesity into the goal range, but the end target is still typically 2 to 3 for NVAF.
 
Regarding DOACs, I am not a big believer in monitoring because there is no evidence that monitoring drug levels or performing DOAC anti-Xa assays leads to better hard clinical outcomes. That said, I may obtain a 1-time DOAC trough level to ensure that the DOAC is at least “on board.” I would also measure a trough in select cases, such as in a patient who requires neurosurgery or is taking prohibitive medications that pose the risk of a drug-drug interaction. Again, the obvious advantage of DOACs is that they do not need to be monitored, since DOAC monitoring was not performed in the pivotal clinical trials.


Which anticoagulant(s) requires monitoring in patients with obesity and NVAF?
Flip
Warfarin. Routine monitoring is not needed for DOACs.

What role does weight loss play in reducing stroke risk for patients with comorbid NVAF and obesity?

This is an interesting question because of the obesity paradox, which is a U-shaped curve.13 Studies have found that obesity actually protects against stroke. Nevertheless, obesity is an independent risk factor for venous thromboembolism, so the relationship between obesity and stroke is paradoxical in some ways.14
 
Obesity is a chronic, low-grade inflammatory condition. In the setting of stroke and NVAF, the health risks of obesity far outweigh any potential benefits.15 I always tell my patients that it is a good idea to lose weight since a lower weight is much better from a metabolic and cardiovascular point of view. I am a big advocate of weight loss, and having a patient achieve a BMI of 30 kg/m2 or lower would be ideal.

Disclosures

Dr Spyropoulos has had consulting relationships with Alexion Pharmaceuticals, Inc.; Bayer HealthCare Pharmaceuticals Inc.; Boehringer Ingelheim Pharmaceuticals. Inc.; Bristol-Myers Squibb Company; Daiichi Sankyo Company, Limited.; and Janssen Pharmaceuticals, Inc.

This Q&A was edited for clarity and length.

References

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2. Granger CB, Alexander JH, McMurray JJV, et al; on behalf of the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992. doi:10.1056/NEJMoa1107039
 
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10. Martin KA, Beyer- Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8): 1874-1882. doi:10.1111/jth.15358
 
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Reviewed July 2022