Introduction

The secondary prevention of cardiovascular events in patients with known SIHD is key to improving their overall outcomes. Despite the use of effective anti-atherosclerotic and antithrombotic strategies, 12% of patients with SIHD have recurrent events after 4 years.¹ Recently, the DOAC rivaroxaban was approved for the secondary prevention of atherosclerotic cardiovascular disease based on the results of the COMPASS trial.² Specifically, the COMPASS trial demonstrated that the combination of low-dose rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily reduced the risk of myocardial infarction, stroke, or cardiovascular death for patients with SIHD compared with aspirin 100 mg daily alone (hazard ratio [HR] 0.76; 95% confidence interval [CI], 0.66-0.86). Low-dose rivaroxaban plus aspirin was associated with an increased rate of major bleeding events (3.1%) compared with aspirin alone (1.9%), but there was no significant difference for fatal bleeding.

Despite these promising results, concerns have persisted about the safety and efficacy of DOACs in specific subgroups, namely patients with obesity and morbid obesity. This is largely driven by a scarcity of data regarding the pharmacokinetics and pharmacodynamics of DOACs at this level of body weight. With the ever-increasing prevalence of obesity in the United Sates, the increased cardiovascular risk associated with obesity, and the growing list of indications for DOAC therapy, the use of DOACs in patients with obesity has become an important clinical question.

The Use of DOACs in Patients With SIHD and Obesity

The investigators of the COMPASS trial published an important follow-up study examining the efficacy of dual antithrombotic therapy with the combination of an antiplatelet and a DOAC for SIHD by conducting a post-hoc subgroup analysis across BMI categories. The results showed a consistent reduction in cardiovascular death, stroke, and myocardial infarction for patients with a BMI of 18.5-39.9 kg/m². Further analysis stratifying patients according to their category of obesity showed similar outcomes with HR 0.70 (95% credible interval, 0.56-0.87) for Class I obesity (BMI = 30.0-34.9 kg/m²) and HR 0.71 (95% credible interval, 0.52-0.87) for Class 2 obesity (BMI = 35.0-39.9 kg/m²). Patients with obesity in the dual antithrombotic arm had higher rates of major bleeding (3.2%) compared with aspirin alone (2.1%) but without increased risk for fatal bleeding as seen in the non-obese cohort.³

This sub-analysis provides critical data supporting the benefit of DOACs in preventing secondary events for patients with obesity (up to a BMI = 39.9 kg/m²) and SIHD. The hesitancy toward generalizing these results to patients in extreme BMI categories stems from prior concerns that severe obesity (BMI ≥40 kg/m²) may alter the pharmacokinetics and pharmacodynamics of orally available medications, leading to potential underdosing.⁴ Specifically, dabigatran has been shown to have variable blood level concentrations based upon body weight, though this variability did not lead to differences in clinical outcomes for patients anticoagulated for non-valvular atrial fibrillation (AF).⁵ On the other hand, previous studies of rivaroxaban did not exhibit changes in blood level concentrations in relation to BMI when used for the treatment of venous thromboembolism (VTE).⁶ This leads to the important question of whether the results of the COMPASS trial can be extrapolated to DOACs as a class effect or reserved for low-dose rivaroxaban alone.

The Use of DOACs in Patients with SIHD and Morbid Obesity

Although the COMPASS trial demonstrated a reduction in major cardiovascular events for most patients with SIHD, it has yet to be seen if this benefit extends to patients at the greatest extreme of BMIs. For patients with Class 3 obesity (BMI ≥40 kg/m²), there was no statistical benefit seen in the dual antithrombotic therapy arm compared with aspirin alone (HR 0.79; 95% CI, 0.56-1.11).³ This was likely driven by an underpowered analysis in this subgroup because only 174 patients were included in the rivaroxaban/aspirin arm and 182 patients in the aspirin-only arm.

The COMPASS trial, like many of the other landmark DOAC trials before it, enrolled few patients with morbid obesity (BMI ≥40 kg/m²), though this subgroup now represents nearly 10% of the US population.⁷ Despite the lack of evidence in patients with morbid obesity, the use of DOACs as antithrombotic therapy for VTE treatment and prevention is not uncommon. A recent analysis of Medicare and US commercial claims databases found that of the 34,910 patients with morbid obesity (BMI ≥40 kg/m²) on anticoagulation for non-valvular AF, 63.4% of them were anticoagulated with a DOAC.⁸

Although there are no large, randomized trials demonstrating the safety and efficacy of DOACs in patients with morbid obesity, recent retrospective studies have lent some support to the use of DOACs in these understudied populations. In a study of 1,840 patients who were diagnosed with an acute VTE and had a body weight >100 kg and <300 kg, there was no significant difference in recurrence of VTE for DOAC-treated patients compared to vitamin K antagonist (VKA) (6.5% vs. 6.4%; p = 0.93).⁹ Likewise, there was no significant difference in major bleeding events between the 2 groups (1.2% vs. 1.7%; p = 0.31). For patients with non-valvular AF who are on anticoagulation, a large analysis compared the efficacy and safety of DOAC versus VKA in patients specifically with BMI ≥40 kg/m². Overall, 18,548 patients were included in the study, and, again, no statistically significant difference was seen in thromboembolic events between DOAC and VKA for morbidly obese patients (relative risk 0.85; 95% CI, 0.56-1.29).¹⁰

It also remains to be seen if it is safe to use DOACs in patients with morbid obesity. Though there appears to be a signal toward safety in retrospective studies, it is feasible that these retrospective data are likely to be confounded by selection bias because clinicians may be more likely to choose a DOAC for patients with morbid obesity with fewer risk factors for major bleeding events and treat their more at-risk patients with better known VKA. The COMPASS trial demonstrated no increase in major bleeding or fatal bleeding events for patients with BMI ≥40 kg/m² (HR 1.03; 95% CI, 0.26-4.14), though the sample size remains limited.3 Data remain sparse on the safety of oral anticoagulants in patients with morbid obesity for the prevention of atherosclerotic cardiovascular disease. It is important to comprehensively study the safety of DOACs in this population because obesity is also an independent risk factor for major bleeding events such as intracranial hemorrhage.¹¹

Conclusion

The COMPASS trial has demonstrated a reduction in major cardiovascular events using dual-pathway antithrombotic therapy for patients with SIHD. This benefit was confirmed in a post-hoc subgroup analysis in patients with BMIs ranging from 18.5 kg/m² to 39.9 kg/m². However, it is yet to be seen if this benefit extends to patients at the greatest extremes of BMIs, both with severe obesity and underweight status. Given the increasing population of patients with severe obesity within the United States, the increased cardiovascular risk associated with obesity, and the growing list of indications for DOAC use, future research should prioritize equitable recruitment and enrollment of representative clinical trial populations, including individuals with severe obesity, to address these unanswered questions.

References

1. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;304:1350-7.
2. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017;377:1319-30.
3. Guzik TJ, Ramasundarahettige C, Pogosova N, et al. Rivaroxaban Plus Aspirin in Obese and Overweight Patients With Vascular Disease in the COMPASS Trial. J Am Coll Cardiol 2021;77:511-25.
4. Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol 2013;76:908-16.
5. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014;63:321-8.
6. Di Nisio M, Vedovati MC, Riera-Mestre A, et al. Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies. Thromb Haemost 2016;116:739-46.
7. Ogden CL, Fryar CD, Martin CB, et al. Trends in Obesity Prevalence by Race and Hispanic Origin-1999-2000 to 2017-2018. JAMA 2020;324:1208-10.
8. Deitelzweig S, Keshishian A, Kang A, et al. Effectiveness and Safety of Oral Anticoagulants among NVAF Patients with Obesity: Insights from the ARISTOPHANES Study. J Clin Med 2020;9:1633.
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10. Thangjui S, Kewcharoen J, Yodsuwan R, et al. Efficacy and safety of direct oral anticoagulant in morbidly obese patients with atrial fibrillation: systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother 2021;Mar 17:[Epub ahead of print].
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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Stable Ischemic Heart Disease

Keywords: Obesity, Morbid, Fibrinolytic Agents, Antithrombins, Retrospective Studies, Follow-Up Studies, Cardiovascular Diseases, Body Mass Index, Atrial Fibrillation, Venous Thromboembolism, Aspirin, Secondary Prevention, Confidence Intervals, Selection Bias, Risk Factors, Medicare, Anticoagulants, Stroke, Myocardial Infarction, Intracranial Hemorrhages, Vitamin K

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