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. 2024 Apr 21;7(4):e2044. doi: 10.1002/hsr2.2044

Safety and efficacy of direct oral anticoagulants in comparison to warfarin in obese patients with atrial fibrillation: A systematic review and meta‐analysis

Alla Adelkhanova 1, Prakash Raj Oli 2,✉, Dhan Bahadur Shrestha 1, Jurgen Shtembari 1, Vivek Jha 3, Ghanshyam Shantha 4, George Michael Bodziock 4, Monodeep Biswas 5, Muhammad Omer Zaman 6, Nimesh K Patel 7
PMCID: PMC11033493  PMID: 38650729

Abstract

Background and Aim

Obesity affects nearly 650 million adults worldwide, and the prevalence is steadily rising. This condition has significant adverse effects on cardiovascular health, increasing the risk of hypertension, coronary artery disease, heart failure, and atrial fibrillation (AF). While anticoagulation for obese patients with AF is a well‐established therapy for the prevention of thromboembolism, the safety and efficacy of different anticoagulants in this specific population are not well explored. This meta‐analysis aimed to compare direct oral anticoagulants (DOAC) to vitamin K antagonists in obese populations with AF.

Methods

The PRISMA guidelines were followed for this meta‐analysis, registered in PROSPERO (CRD42023392711). PubMed, PubMed Central, Embase, Cochrane Library, and Scopus databases were searched for relevant articles from inception through January 2023. Two independent authors screened titles and abstracts, followed by a full‐text review in Covidence. Data were extracted in Microsoft Excel and analyzed using RevMan v5.4 using odds ratio as an effect measure.

Results

Two thousand two hundred fifty‐nine studies were identified from the database search, and 18 were included in the analysis. There were statistically significant reductions in the odds of ischemic and hemorrhagic stroke in the DOAC group compared with the VKA group (OR 0.70, CI 0.66–0.75) and (OR 0.47, CI 0.35–0.62), respectively. In addition, the DOAC group exhibited lower odds of systemic embolism (OR 0.67, CI 0.54–0.83), major bleeding (OR 0.62, CI 0.54–0.72), and composite outcome (OR 0.72, CI 0.63–0.81).

Conclusion

Based on the findings from this meta‐analysis, DOACs demonstrate superior safety and efficacy in obese patients with AF compared with VKAs. These results may have significant implications for guiding anticoagulation strategies in this patient population.

Keywords: anticoagulation, apixaban, atrial fibrillation, edoxaban, obesity, rivaroxaban

1. INTRODUCTION

Obesity is a body mass index (BMI) ≥30 kg/m2 among adults. It affects nearly 650 million adults worldwide, and its prevalence has almost tripled between 1975 and 2016. 1 Obesity is known to have adverse effects on cardiovascular health, increasing the risk of hypertension, coronary artery disease, heart failure, and atrial fibrillation (AF). 2 AF is the most common sustained cardiac arrhythmia and carries considerable morbidity and mortality. 3 It has been established in the Framingham Heart Study that with every unit increase in BMI, the risk of AF increases by 4%–5%. 4 Another meta‐analysis showed that there were 10%–29% greater increased risk of incident, postoperative, and postablative AF with every 5 unit increase in BMI. 5 Given these implications, it is imperative to explore the consequences of AF in the obese population, including its complications and management.

Embolic stroke is the most dangerous complication of AF; therefore, its prevention is an essential consideration in AF management. 6 Patients with AF are advised to start anticoagulation to lower the risk of embolic stroke, following a thorough discussion of the risks and benefits. 7 Direct oral anticoagulants (DOACs) have been preferred over vitamin K antagonists (VKAs), such as warfarin, due to superior safety/efficacy, lack of required laboratory monitoring, fewer interactions with other drugs, and fewer dietary considerations. 8 Both AHA/ACC/HRS (2023) and ESC (2020) recommended the benefits of DOACs over VKAs in OAC‐eligible AF patients. Still, they have not commented on the use of DOAC in AF patients with obesity, except AHA/ACC/HRS's recommendation of DOAC use among class III obesity patients with AF. 9 , 10

Obesity affects the pharmacokinetics of drugs by altering their volume of distribution (Vd), peak concentration (Cmax), and drug exposure (area under curve, AUC), as well as drug clearance. 11 Thus, obesity also affected the pharmacokinetics and pharmacodynamics of DOACs among obese patients. 12 Due to concern about subanticoagulation with the use of fixed‐dose regimen, International Society on Thrombosis and Hemostasis (ISTH) (2016) recommended standard DOAC dosing for patients with a BMI ≤ 40 kg/m2 and weight ≤ 120 kg for prevention of ischemic stroke and systemic arterial embolism in nonvalvular AF while cautioning against DOAC use in patients with a BMI > 40 kg/m2 or weight > 120 kg due to limited data and potential pharmacokinetics or pharmacodynamic concerns. If DOACs need to be used in such patients, they are recommended to consider monitoring drug‐specific levels and, if below the expected range, consider switching to a VKA rather than adjusting the DOAC dose. 13 Zhao et al. pointed out that obesity may have a modest effect on the pharmacokinetics of dabigatran, apixaban, rivaroxaban, or edoxaban. They highlighted that the standard doses of apixaban, rivaroxaban, and edoxaban are effective and safe in morbidly obese patients with AF. At the same time, the body weight is inversely affected by the peak concentration of dabigatran, with a significantly increased risk of gastrointestinal bleeding. 12 There are now a growing number of studies studying the effectiveness and safety of the DOAC among obese or morbidly obese patients with AF, showing that they have better outcomes compared with those with normal BMI, and it's being depicted as an “obesity paradox.” 14

Earlier meta‐analyses on the use of DOAC compared with warfarin in morbidly obese patients with AF showed mixed results. 15 , 16 However, these studies were unable to fully appraise the efficacy and safety of the DOAC compared with warfarin among obese as well as morbidly obese patients with AF. Therefore, this systematic review and meta‐analysis aimed to investigate the comparative safety and efficacy of DOACs compared with VKAs in obese patients with AF, defining safety as freedom from any major bleeding event and efficacy as freedom from stroke or systemic thromboembolism.

2. METHODS

2.1. Protocol

The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines were followed for this systematic review and meta‐analysis. The protocol is registered in PROSPERO 2023 CRD42023392711. The PRISMA checklist is included in a supplementary file (Supplementary material).

2.2. Search strategy

PubMed, PubMed Central, Embase, Cochrane Library, and Scopus databases were searched in January 2023. An appropriate combination of search words such as “atrial fibrillation,” “direct oral anticoagulant,” “DOAC,” “vitamin K antagonist,” “Warfarin,” “obesity” and applicable Boolean operators were used. The search method will be described in detail in a supplemental file.

2.3. Eligibility criteria

This meta‐analysis contained prospective and retrospective studies in which obese patients with nonvalvular AF received either DOAC or Warfarin and included case‐control, cohort, and randomized control trials (RCTs). Conference abstracts, editorials, comments, qualitative and viewpoint articles, case reports, review articles, and other meta‐analyses were excluded.

2.4. Outcomes measured

The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction (MI), or any cause of death. The secondary outcomes were ischemic stroke, systemic embolism, and all‐cause mortality. The primary safety outcome was major bleeding. We also analyzed the outcome of all‐cause mortality.

2.5. Study selection

Two independent reviewers screened the titles and abstracts using Covidence, while a third reviewer resolved conflicts. Two reviewers completed the full‐text review, and conflicts were resolved by another reviewer among the list of authors. Data was then extracted for qualitative and quantitative processing.

2.6. Data extraction

A standardized form was designed in Microsoft Excel to extract pertinent data, including study authors, study details, quality, and endpoints. The endpoints of this meta‐analysis were all‐cause mortality, ischemic stroke, systemic embolism, a composite of ischemic stroke and systemic embolism, and a major bleeding event.

2.7. Study quality

The quality of individual articles was assessed using the Joanna Briggs Institute's critical appraisal (JBI) tools for the risk of bias 17  (Supporting Information: Table 1). ROB‐2 tool used for risk of bias assessment of RCTs 18 (Supporting Information: eFigure 1). Two authors independently assessed each study design and the number of patients with each outcome. A third person then resolved conflicts.

2.8. Data analysis

Data was analyzed using RevMan v5.4. 19 An odds ratio (OR) was used for outcomes such as mortality, ischemic stroke, systemic embolism, composite of ischemic stroke and systemic embolism, and a major bleeding event.

Heterogeneity was measured by the I 2 test among the included studies. A random effect model was used for analysis to consider heterogeneity.

Sensitivity analysis was performed based on the type of DOAC used and BMI class to test the robustness of the analysis.

3. RESULTS

Among 2259 studies identified from the database search, 2085 were screened for title and abstract after removing 174 duplicates. After excluding 2009 studies during title and abstract screening, full text of 76 studies were assessed for eligibility. Fifty‐eight studies were excluded from the full‐text review, and 18 were included in the analysis. Among the 18 studies included, 16 were retrospective cohort studies, and 2 were randomized controlled trials. The PRISMA flow diagram for the review is shown in Figure 1.

Figure 1.

Figure 1

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PRISMA 2020 flow diagram for the systematic review.

3.1. Qualitative analysis

Eighteen studies involving 387,205 obese patients with AF were included in this meta‐analysis. Among 387,205 patients, 193,947 (50.09%) patients received DOAC whereas 193,258 (49.91%) patients received warfarin. Among 193,947 patients who received DOAC, 130,634 (67.36%) patients received rivaroxaban, 41,540 (21.42%) patients received apixaban, 13,063 (6.74%) patients received dabigatran, 6234 (3.21%) patients received edoxaban, and 2476 (1.28%) patients received unspecified DOAC agent. Among 386,071 patients with gender data, 249,813 (64.71%) were male while 136,258 (35.29%) were female. The average mean age was 69.16 ± 9.80 years. The baseline patient characteristics, underlying comorbidities, clinical parameters, baseline medications, and clinical outcomes were collected and analyzed, as presented in Tables 1 and 2 and Supporting Information: Table 2.

Table 1.

Baseline characteristics of studies and participants, including their comorbidities.

Study Publication year Country Study design No. of patients Intervention Age (years), mean (SD) Gender BMI, % Comorbidities, %
Male, % 30.0–34.9 kg/m2 35.0–39.9 kg/m2 ≥40.0 kg/m2 Hypertension Hyperlipidemia Diabetes mellitus COPD Congestive heart failure Coronary artery disease Cerebrovascular disease Peripheral vascular disease
Alberts et al. 20 2022 USA Retrospective cohort study N = 95,875 Rivaroxaban n = 33,191 Rivaroxaban 62.97 (10.3) 65.9 49.2 15.5 35.2 85.5 64.5 53.89 13.5 22.3 16.2 11.9 12.5
Warfarin n = 62,684 Warfarin 67.72 (10.3) 62.4 52.4 15.0 32.6 81.6 60.6 70.54 19.4 34.5 16.2 18.1 18.0
Berger et al. 21 2021 USA Retrospective cohort study N = 15,635 Rivaroxaban N = 10,555 Rivaroxaban 59.3 (8.6) 69 37.7 86.6 67.9 42.5 10.1 34.0 33.4 11.15 8.1
Warfarin N = 5080 Warfarin 59.4 (8.9) 68.1 39.0 87.1 67.9 43.1 10.2 34.0 33.4 13.76 7.6
Boivin‐Proulx et al. 22 2022 Canada Retrospective cohort study N = 2195 Rivaroxaban, n = 403 Rivaroxaban 20 mg once daily 71.91 (8.09) 45.57 88.06 62.09 60.72 49.63 33.52 55.48 22.57
Apixaban n = 539 Apixaban 5 mg twice daily 74.22 (8.26) 44.45 61.99 62.26 47.24 43.71 56.51 20.0
Warfarin n = 1253 Warfarin 72.83 (11.07) 43.71 87.28 61.20 59.93 46.58 43.12 56.35 20.85
Boriani et al. 23 2018 46 countries Three‐group, randomized, double‐blind, double‐dummy study N = 8457 Higher‐dose edoxaban n = 2876 Edoxaban 60 mg dose daily 69.96 (10.52) 59.60 61.34 24.24 14.42 97.32 47.64 62.83 22.25
lower‐dose edoxaban n = 2828 Edoxaban 30 mg dose daily 69.59 (10.31) 58.10 61.60 25.32 13.08 97.21 46.92 60.08 22.70
Warfarin n = 2753 Warfarin 68.46 (10.44) 60.04 61.86 24.92 13.22 97.78 47.69 61.24 21.58
Briasoulis et al. 24 2021 USA Retrospective cohort study N = 28,011 Apixaban (n = 6052) Apixaban 5 mg or 2.5 mg twice daily 69.9 99 84.9 22 31.1 26.8 7 11.4
Dabigatran (n = 4233) Dabigatran 150 mg twice daily 65.7 99 84.5 29.1 26.2 24.8 5 8.4
Rivaroxaban (n = 4309) Rivaroxaban 20 mg or 15 mg once daily 66.7 99 83.2 25.9 27.7 24.6 4.5 8.8
Warfarin (n = 13,417) Warfarin 66.5 98.9 86.8 31.8 35.8 29 7.3 12
Costa et al. 25 2020 USA Retrospective cohort study N = 71,226 Rivaroxaban n = 35,613 Rivaroxaban 67.35 (11.12) 60.5 48.0 26.7 25.2 78.9 33.7 13.5 13.5 4.7 8.4
Warfarin n = 35,613 Warfarin 68.3 (10.38) 59.8 47.9 26.7 25.4 78.9 35.4 14.5 14.0 5.3 9.0
Deitelzweig et al. 26 2020 USA Retrospective cohort study N = 88,461 Apixaban n = 21,242 Apixaban 71.5 (9.9) 51.9 94.3 53.6 38.0
Dabigatran n = 7171 Dabigatran 69.6 (10.0) 56.2 93.0 52.7 34.7
Rivaroxaban n = 29,146 Rivaroxaban 70.0 (10.3) 53.7 93.2 52.0 35.2
Warfarin n = 30,902 Warfarin 72.8 (8.8) 51.7 95.1 61.4 47.6
Deitelzweig et al. 27 2022 USA Retrospective cohort study N = 26,522 Apixaban n = 13,604 Apixaban 5 mg or 2.5 mg twice daily 75.4 (7.6) 99 87 51 32 54 9 22
Warfarin n = 12,918 Warfarin 74.4 (7.9) 99 87 56 37 53 10 22
Huang et al. 28 2021 USA Retrospective cohort study N = 3318 Dabigatran (n = 1659) Dabigatran 66.41 (9.13) 64 5.1 23.4 71.5 68.6 54.2 47.1 4.5 35.3
Warfarin (n = 1659) Warfarin 66.43 (10.31) 62.6 4.9 23.2 71.3 69.5 54.2 47 4.6 34.9
Kido and Ngorsuraches 29 2019 USA Retrospective cohort study N = 128 DOAC (n = 64) Apixaban, dabigatran, and rivaroxaban 64.28 (10.16) 60.94 18.75
Warfarin (n = 64) Warfarin 65.88 (12.18) 54.69 15.62
Kushnir et al. 30 2019 USA Retrospective cohort study N = 429 Apixaban (n = 103) Apixaban 65·9 (10·7) 44 100
Rivaroxaban (n = 174) Rivaroxaban 60·9 (12·6) 45 100
Warfarin (n = 152) Warfarin 66·8 (13·6) 41 100
Lip et al. 31 2019 Multicenter, prospective, randomized, open, blinded endpoint trial N = 1067 Edoxaban (n = 530) Edoxaban 60 mg daily 62.9 (9.3) 84.5 25.8 48.3 19.2 4.9 2.8
Enoxaparin– Warfarin (n = 537) Warfarin 63.2 (10.1) 86.4 25.9 45.6 19.4 5.0 4.5
Nakao et al. 32 2022 UK Retrospective cohort study N = 4066 DOACs n = 2033 DOACs 74.83 (9.18) 53.91 61.44 38.56 89.87 43.53 21.94 21.50 15.59 17.81 7.97
Warfarin n = 2033 Warfarin 74.95 (8.53) 55.14 61.44 38.56 89.72 43.48 22.28 22.04 15.74 18.35 7.33
Patil and Lebrecht 33 2020 USA Retrospective cohort study N = 236 DOAC (n = 129) Dabigatran 75/150 mg twice daily, rivaroxaban 15/20 mg daily and apixaban 2.5/5 mg twice daily 70.46 (7.05) 99.22 91.47 68.22 28.68 9.30
Warfarin (n = 107) Warfarin 70.52 (6.31) 97.20 92.52 59.81 37.38 8.41
Perales et al. 34 2020 USA Retrospective cohort study N = 67 Rivaroxaban (n = 37) Rivaroxaban
Warfarin (n = 30) Warfarin
Peterson et al. 35 2019 USA Retrospective cohort study N = 9474 Rivaroxaban (n = 4543) Rivaroxaban 61.8 (10.8) 55.0 87.2 61.1 47.7 30.8 13.6
Warfarin (n = 4931) Warfarin 64.4 (10.8) 52.8 88.2 63.0 57.6 45.0 21.1
Russo et al. 36 2020 Italy Retrospective cohort study N = 960 DOACs (n = 250) Dabigatra 110/150 mg twice daily, rivaroxaban 20 mg daily, edoxaban 60 mg daily, and apixaban 5 mg twice daily 66.5 (9.1) 48.8 48.8 14.8 20 16 6
Warfarin (n = 710) Warfarin 68.8 (10.4) 48.1 49.01 13.9 20.9 15.9 5.2
Weir et al. 37 2021 USA Retrospective cohort study N = 31,078 Rivaroxaban (n = 12,663) Rivaroxaban 68.9 (9.5) 60.0 40.3 15.3 44.4 95.8 85.8 25.1 37.0 33.2 15.5 15.3
Warfarin (n = 18,415) Warfarin 70.8 (8.5) 57.9 44.2 13.6 42.2 96.1 85.2 31.2 51.2 34.8 21.5 21.0
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Table 2.

Clinical efficacy and safety outcomes among the included participants.

Study Groups Composite of stroke, systemic embolic event, major bleeding, or death Ischemic stroke Hemorrhagic stroke Systemic embolism Major bleeding Intracranial bleeding GI bleeding All‐cause mortality
Total 30.0–34.9 kg/m2 35.0–39.9 kg/m2 ≥40.0 kg/m2 Total 30.0–34.9 kg/m2 35.0–39.9 kg/m2 ≥40.0 kg/m2 Total 30.0–34.9 kg/m2 35.0–39.9 kg/m2 ≥40.0 kg/m2 Total 30.0–34.9 kg/m2 35.0–39.9 kg/m2 ≥40.0 kg/m2
Alberts et al. 20 Rivaroxaban 926/21,442 473/10,755 121/3040 332/7647 742/21,442 374/10,755 99/3040 269/7647 194/21,442 72/21,442 34/10,755 11/3040 27/7647 421/21,442 223/10,755 53/3040 145/7647
Warfarin 1199/21,442 620/10,755 185/3040 394/7647 936/21,442 479/10,755 137/3040 320/7647 311/21,442 110/21,442 55/10,755 20/3040 35/7647 422/21,442 200/10,755 54/3040 168/7647
Berger et al. 21 Rivaroxaban 366/10,555 366/10,555 186/10,555 46/10,555 26/10,555 366/3958 288/3792
Warfarin 222/5080 222/5080 106/5080 39/5080 14/5080 312/2604 230/2094
Boivin‐Proulx et al. 22 Rivaroxaban 43/403 3/403 0/403 5/403 9/403 1/403 0/403 20/403
Apixaban 41/539 3/539 0/539 1/539 6/539 0/539 2/539 24/539
Warfarin 96/1253 9/1253 2/1253 2/1253 33/1253 5/1253 15/1253 70/1253
Boriani, G. et al. 23 Higher dose edoxaban 508/2876 318/1764 117/697 73/415 185/2876 119/1764 36/697 30/415 284/2876
Lower dose edoxaban 445/2828 285/1742 112/716 48/370 122/28,282 69/1742 40/716 15/370 244/28,282
Warfarin 498/2753 324/1703 114/686 60/364 214/2753 130/1703 54/686 28/364 265/2753
Briasoulis et al. 24 Apixaban 32/6052 7/6052 99/6052 68/6052 328/6052
Dabigatran 29/4233 2/4233 64/4233 50/4233 183/4233
Rivaroxaban 26/4309 7/4309 91/4309 59/4309 177/4309
Warfarin 124/13,417 53/13,417 583/13,417 381/13,417 1047/13,417
Costa et al. 25 Rivaroxaban 429/35,613 212/16,821 115/9428 105/9161 399/35,613 196/16,821 106/9428 100/9161 877/35,613 420/16,821 231/9428 226/9161 79/35,613
Warfarin 668/35,613 343/16,821 163/9428 157/9161 586/35,613 307/16,821 142/9428 137/9161 1382/35,613 630/16,821 352/9428 392/9161 164/35,613
Deitelzweig et al. 26 Apixaban 132/21,242 107/21,242 23/21,242 399/21,242 38/21,242 195/21,242
Dabigatran 67/7171 56/7171 174/7171 17/7171 110/7171
Rivaroxaban 226/29,146 170/29,146 41/29,146 17/29,146 1050/29,146 67/29,146 612/29,146
Warfarin 406/30,902 276/30,902 115/30,902 20/30,902 1491/30,902 190/30,902 721/30,902
Deitelzweig et al. 27 Apixaban 147/13,604 109/13,604 29/13,604 11/13,604 398/13,604 68/13,604 210/13,604
Warfarin 218/12,918 148/12,918 56/12,918 17/12,918 779/12,918 163/12,918 384/12,918
Huang et al. 28 Dabigatran 118/1659 118/1659 10/1659 37/1659 329/1659 142/1659
Warfarin 224/1659 224/1659 13/1659 77/1659 395/1659 570/1659
Kido and Ngorsuraches 29 DOAC 4/64 5/64
Warfarin 3/64 12/64
Kushnir et al. 30 Apixaban 1/103 3/103
Rivaroxaban 4/174 5/174
Warfarin 2/152 12/152
Lip et al. 31 Edoxaban 4/530 2/517
Warfarin 5/537 4/528
Nakao et al. 32 DOAC 51/2033 38/1249 70/2033 47/1249
Warfarin 67/2033 42/1249 99/2033 63/1249
Patil et al. 33 DOAC 3/129 7/129
Warfarin 5/107 9/107
Perales et al. 34 Rivaroxaban 4/37 0/37
Warfarin 0/30 3/30
Peterson et al. 35 Rivaroxaban 52/3563 52/3563 77/3563 77/3563
Warfarin 59/3563 59/3563 96/3563 96/3563
Russo et al. 36 DOAC 5/248 8/248 1/248
Warfarin 19/496 34/496 3/496
Weir et al. 37 Rivaroxaban 272/9999 120/4086 40/1485 112/4344 216/9999 94/4086 35/1485 87/4344 59/9999 19/9999 9/4086 2/1485 8/4344 262/9999 103/4086 41/1485 123/4344
Warfarin 396/9999 168/4086 54/1485 152/4344 322/9999 129/4086 39/1485 119/4344 93/9999 29/9999 18/4086 8/1485 13/4344 285/9999 116/4086 39/1485 124/4344
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3.2. Quantitative analysis

3.2.1. Composite outcome

Twelve studies reported the composite events with an incidence rate of 2.71% (N = 7775/287,125) [DOAC group (2.34%; N = 3779/161,299) vs. Warfarin group (3.17%; N = 3996/125,826)]. Pooled data analysis showed a 28% lower occurrence of the composite events in the DOAC group compared with the Warfarin group (OR 0.72, 95% CI 0.63–0.81; n = 287,125; I 2 = 81%) (Figure 2). In the subanalysis comparing the specific DOACs to warfarin, the composite events had significantly lower occurrence in rivaroxaban (OR 0.74, 95% CI 0.65–0.85), apixaban (OR 0.65, 95% CI 0.45–0.93), and dabigatran (OR 0.59, 95% CI 0.41–0.84), but not so for the edoxaban subgroup despite favoring it (OR 0.91, 95% CI 0.81–1.02), (Supporting Information: eFigure 2).

Figure 2.

Figure 2

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Forest plots show a significantly lower occurrence of composite events in the DOAC group than in the Warfarin group using the random effect model.

3.2.2. Stroke

Twelve studies reported the ischemic stroke (IS) events with an incidence rate of 1.65% (N = 5006/302,868) [DOAC group (1.33%; N = 2246/168,336) vs. Warfarin group (2.05%; N = 2760/134,532)]. Pooled data analysis showed a 30% lower occurrence of IS events in the DOAC group compared with Warfarin group (OR 0.70, 95% CI 0.66–0.75; n = 302,868; I 2 = 16%). Seven studies reported hemorrhagic stroke events with and incidence rate of 0.48% (N = 1077/223,701) [DOAC group (0.32%; N = 408/128,690) vs. Warfarin group (0.70%; N = 669/95,011)] and pooled data showed a 53% lower occurrence of the hemorrhagic stroke in the DOAC group compared with the Warfarin group (OR 0.47, 95% CI 0.35–0.62; n = 223,701; I 2 = 74%) (Figure 3).

Figure 3.

Figure 3

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Forest plot showing significantly lower occurrence of stroke events in the DOAC group compared with Warfarin group using random effect model.

In subanalysis comparing different DOAC agents with the warfarin group, the occurrences of ischemic stroke as well as hemorrhagic stroke were significantly lower in the rivaroxaban subgroup (ischemic stroke: OR 0.72, 95%CI 0.66–0.78 and hemorrhagic stroke: OR 0.55; 95% CI 0.45–0.66), apixaban subgroup (ischemic stroke: OR 0.61; 95% CI 0.52–0.71 and hemorrhagic stroke: OR 0.36; 95% CI 0.27–0.49), and dabigatran subgroup (ischemic stroke: OR 0.71; 95%CI 0.54–0.93 and hemorrhagic stroke: OR 0.12, 95% CI 0.03–0.49)] (Supporting Information: eFigure 3a,b).

3.2.3. Systemic embolic events

Eight studies reported systemic embolism events with an incidence rate of 0.20% (N = 390/199,752) (DOAC group: 0.14%; N = 166/116,003 vs. Warfarin group: 0.27%; N = 224/83,749). Pooled data analysis showed a 33% lower occurrence of systemic embolism in the DOAC group compared with the warfarin group (OR 0.67, 95% CI 0.54–0.83; n = 199752; I 2 = 5%) (Figure 4). In the subanalysis comparing different DOAC agents with the warfarin group, there were no significant difference occurrence of systemic embolic events for three DOAC agents: rivaroxaban, apixaban, and dabigatran (Supporting Information: eFigure 4).

Figure 4.

Figure 4

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Forest plot showing significantly lower occurrence of systemic embolic events in the DOAC group compared with the Warfarin group using the random effect model.

3.2.4. Major bleeding

Eighteen studies reported major bleeding events with an incidence rate of 3.84% (N = 12,295/320,548) [DOAC group: 3.14%; N = 5612/178,539 vs. Warfarin group: 4.7%; N = 6683/142,009). Pooled data showed a 37% lower occurrence of the major bleeding events in DOAC group compared with warfarin group (OR 0. 63, 95% CI 0.55–0.73; n = 320,548; I 2 = 88%) (Figure 5). Among different bleeding event types, the DOAC group had significantly lower occurrences of these bleeding types compared with the warfarin group [Intracranial Hemorrhage (ICH): OR 0.40, 95% CI 0.35–0.46; n = 192,466; I 2 = 0% and Gastrointestinal (GI) bleeding: OR 0.57, 95% CI 0.44–0.73; n = 148,507; I 2 = 89%] (Supporting Information: eFigure 5).

Figure 5.

Figure 5

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Forest plot showing significantly lower occurrence of major bleeding events in the DOAC group compared with VKA group using random effect model.

In the subanalysis comparing different DOAC agents with the warfarin group, there were significantly lower occurrences of the major bleedings in rivaroxaban (OR 0.73, 95% CI 0.63–0.85) apixaban (OR 0.41, 95% CI 0.35–0.47) and edoxaban (OR 0.67, 95% CI 0.56–0.81) subgroups, but not in the dabigatran (OR 0.91, 95% CI 0.51–1.62) subgroup (Supporting Information: eFigure 6). In the subanalysis comparing different DOAC agents with the warfarin group, there was a significantly lower occurrences of GI bleeding in the rivaroxaban (OR 0.58, 95% CI 0.37–0.91) apixaban (OR 0.39, 95% CI 0.34–0.44) and dabigatran (OR 0.61, 95% CI 0.43–0.85) subgroups (Supporting Information: eFigure 7).

In the subanalysis comparing different DOAC agents with the warfarin group, there was significantly lower occurrences of intracranial hemorrhages in the rivaroxaban (OR 0.43, 95% CI 0.35–0.52) apixaban (OR 0.35, 95% CI 0.28–0.43) and dabigatran (OR 0.43, 95% CI 0.32–0.59) subgroups (Supporting Information: eFigure 8).

3.2.5. All‐cause mortality

Seven studies reported the all‐cause mortality events, and the pooled data showed a significantly lower occurrence of all‐cause mortality in the DOAC group by 44% compared with the warfarin group (OR 0.56, 95% CI 0.34–0.94; n = 46,858; I 2 = 97%) (Supporting Information: eFigure 9). In the subanalysis comparing the different DOAC agents with the warfarin group, there was a significant reductions of the all‐cause mortality in the rivaroxaban (OR 0.65, 95% CI 0.46–0.91) and apixaban (OR 0.66, 95% CI 0.48–0.91) subgroups but not in dabigatran (OR 0.32, 95% CI 0.10–1.04) and edoxaban (OR 0.96, 95% CI 0.82–1.12) subgroups (Supporting Information: eFigure 10).

3.2.6. Subanalysis based on BMI classes

Subanalysis of the clinical efficacy and safety of DOAC agents compared with warfarin use was performed based on the obesity classification: obesity class I (30–34.9 kg/m2), obesity class II (35–39.9 kg/m2), and obesity class III (>40.0 kg/m2). We found that the use of DOACs was associated with statistically significant reductions in the composite outcome of ischemic stroke, systemic embolism, and major bleeding across all three obesity classes. However, the individual outcomes of systemic embolism in obesity classes I and III and the major bleeding in obesity classes I and II were not significant.

3.2.7. Composite outcome

In the subanalysis across different obesity classes, there was a significantly lower occurrence of the composite outcomes in all three obesity classes: obesity class I (OR 0.74, 95% CI 0.62–0.90), obesity class II (OR 0.76, 95% CI 0.59–0.97) and obesity class III (OR 0.72, 95% CI 0.60–0.87) in comparison to the warfarin group (Supporting Information: eFigure 11).

3.2.8. Ischemic stroke

In the subanalysis across different obesity classes, there was a significantly lower occurrence of ischemic stroke in all three obesity classes: obesity class I (OR 0.73, 95% CI 0.64–0.82), class II (OR 0.75, 95% CI 0.63–0.89), and class III (OR 0.73, 95% CI 0.63–0.85) on comparison with warfarin group (Supporting Information: eFigure 12).

3.2.9. Systemic embolism

In the subanalysis across different obesity classes, there was a significantly lower occurrence of systemic embolic events only in obesity class II (OR 0.47, 95% CI 0.24–0.92) but not in obesity class I (OR 0.81, 95% CI 0.37–1.79) of class III (OR 0.73, 95% CI 0.47–1.13), in comparison to warfarin group (Supporting Information: eFigure 13).

3.2.10. Major bleeding

In the subanalysis across different obesity classes, there was a significantly lower occurrence of systemic embolic events only in obesity class III (OR 0.75, 95% CI 0.62–0.90), however not in obesity class I (OR 0.80, 95% CI 0.64–1.01) or class II (OR 0.78, 95% CI 0.61–1.00), in comparison to warfarin group (Supporting Information: eFigure 14).

3.2.11. Publication bias

Publication bias for the composite outcome, stroke, major bleeding, and all‐cause mortality was checked with a Funnel plot, which showed the asymmetric distribution of studies signifying significant publication bias (Supporting Information: eFigure 15).

4. DISCUSSION

Obesity is a well‐established risk factor for AF, which itself carries a high risk of major life‐threatening thromboembolism and ischemic stroke. 38 Thus, primary as well as secondary prevention of the thromboembolism and ischemic stroke risk with anticoagulation is one of the cornerstones of AF management in suitable AF patients. 39 Due to the better clinical efficacy profile (systemic embolism and the stroke) as well as the clinical safety (major bleeding and intracranial hemorrhage), thus higher mortality benefit, of DOACs over the warfarin, DOACs are recommended over warfarin for the anticoagulation in AF patients in the 2023 ACC/AHA/ACCP/HRS guideline. However, there was little clinical evidence to support this clinical safety and efficacy superiority profiles of DOACs over warfarin among obese patients with AF. So, 2023 ACC/AHA/ACCP/HRS guideline recommends DOAC among AF patients with class III obesity (class of recommendation 2a and the level of evidence B‐NR) only while no comments regarding which type of anticoagulants is suitable for AF patients with class I or II obesity. 10 Therefore, it is imperative to investigate the safety and efficacy of anticoagulation in AF patients with obesity. This comprehensive systematic review and meta‐analysis evaluated the efficacy and safety of DOACs, as compared with VKAs, within the obese patient population suffering from nonvalvular AF.

Our meta‐analysis revealed that obese patients with AF who received DOACs, as compared with VKAs, had significantly lower occurrences of composite events as well as individual events: stroke (ischemic as well as hemorrhagic) and systemic embolic events, in overall. The DOACs also significantly lowered major bleeding rates, including GI bleeding, ICH, and all‐cause mortality in this patient cohort. Among different DOAC agents, rivaroxaban and apixaban use had significantly lower occurrence of composite events, ischemic as well as hemorrhagic strokes, major bleeding including GI bleeding as well as ICH, and all‐cause mortality compared with warfarin use. Dabigatran use had a significantly lower occurrence of composite events, GI bleeding, and ICH than warfarin use. Across all three classes of obesity, the DOAC had significantly lower occurrences of composite events as well as ischemic stroke events. Whereas only class II obesity and class III obesity had a significantly lower occurrence of systemic embolism events and major bleeding, respectively, when using DOACs compared with warfarin. None of the DOAC agents were associated with a significant reduction of systemic embolic events on individual comparison with warfarin use. Similar findings were reported on this topic in the previous other studies.

A real‐world electronic health record study by Costa et al. demonstrated a significant reduction in stroke and systemic embolism, along with a reduction in major bleeding, with rivaroxaban in comparison to warfarin use in obese patients with AF. 40 In this study, there were no significant reductions in stroke and systemic embolism, and major bleeding events across different BMI classes. In contrast, in our study, there was a statistically significant reduction in both systemic embolism and major bleeding across obesity classes in the DOAC group, except the systemic embolism in obesity classes I and III, and the major bleeding in obesity classes I and II, where reduction was not statistically significant. These disparities in our findings and by Costa et al. among different BMI classes seem to be due to the type of DOACs used, differences in the number of patients in different BMI classes, and differences in the statistical analysis used.

The post‐hoc analysis of the ARISTOTLE trial based on the obesity performed by Deitelzweig et al. showed a lower risk of stroke and systemic embolism in apixaban and rivaroxaban groups compared with the warfarin group; however, the dabigatran group had similar rates of stroke and systemic embolism as the warfarin group, while all three DOACs were associated with lower major bleeding rates than warfarin. 26 These findings contrast with our subanalysis, which showed that compared with warfarin, apixaban, rivaroxaban, and dabigatran all have significantly lower stroke rates; however, major bleeding rates were only significantly lower in apixaban and rivaroxaban groups. One potential explanation for the discrepancy in outcomes could be the mechanism of action of DOACs, as dabigatran is a factor IIa inhibitor while apixaban and rivaroxaban are factor Xa inhibitors. 41 The pharmacokinetics of dabigatran also differ from apixaban and rivaroxaban since dabigatran undergoes hepatic glucuronidation, while apixaban and rivaroxaban are metabolized through the cytochrome P450 system. 41

A retrospective study by Briasoulis et al. interestingly reported that in patients weighing over 120 kg, apixaban had a higher risk of stroke than warfarin, while rivaroxaban and dabigatran had a similar risk as warfarin, and all three DOACs had a lower bleeding risk. 24 This differs from the results of our study and may be partially explained by the diversity in comorbidity burden among the various DOACs and the differences in the patient population. 42

Our results do have some limitations. First, we did not make a comparison of obese to nonobese or underweight populations. Second, the data set did not include INR levels in patients on warfarin, and it's possible that subtherapeutic or supratherapeutic warfarin effects could influence the rates of stroke and bleeding. Despite these limitations, the meta‐analysis has multiple strengths, including a large number of studies and a large patient population, increasing the power of the results. The analysis also compared different individual DOACs to warfarin and allowed subanalysis of various obesity classes.

5. CONCLUSION

DOACs appear to show superior safety and efficacy (stroke, systemic embolism, MI, bleeding, or death) when compared with VKAs (warfarin) in obese populations with AF. As the totality of this evidence mostly came from observational studies, additional data from larger randomized controlled trials will be required to discern the appropriate DOACs, dosage regimens, and BMI extremes.

AUTHOR CONTRIBUTIONS

Alla Adelkhanova: Conceptualization; data curation; methodology; project administration; resources; software; writing—original draft; writing—review and editing. Prakash Raj Oli: Data curation; formal analysis; methodology; project administration; resources; software; validation; writing—original draft; writing—review and editing. Dhan Bahadur Shrestha: Conceptualization; data curation; formal analysis; methodology; project administration; resources; software; validation; writing—original draft; writing—review and editing. Jurgen Shtembari: Data curation; methodology; project administration; resources; software; writing—original draft; writing—review and editing. Vivek Jha: Data curation; methodology; resources; software; writing—original draft; writing—review and editing. Ghanshyam Shantha: Methodology; project administration; supervision; writing—review and editing. George Michael Bodziock: Investigation; project administration; supervision; validation; writing—review and editing. Monodeep Biswas: Methodology; project administration; supervision; validation; writing—review & editing. Muhammad Omer Zaman: Investigation; project administration; supervision; validation; writing—review and editing. Nimesh K. Patel: Conceptualization; investigation; methodology; project administration; supervision; validation; visualization; writing—review and editing.

TRANSPARENCY STATEMENT

The lead author Prakash Raj Oli affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Supporting information

Supporting information.

HSR2-7-e2044-s001.docx (6.5MB, docx)

Supporting information.

HSR2-7-e2044-s002.docx (31.7KB, docx)

Adelkhanova A, Oli PR, Shrestha DB, et al. Safety and efficacy of direct oral anticoagulants in comparison to warfarin in obese patients with atrial fibrillation: a systematic review and meta‐analysis. Health Sci Rep. 2024;7:e2044. 10.1002/hsr2.2044

DATA AVAILABILITY STATEMENT

The data that supports the findings of this study are available in the supplementary material of this article.

REFERENCES

  • 1. Obesity and overweight. Accessed April 28, 2023. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
  • 2. Lavie CJ, De Schutter A, Parto P, et al. Obesity and prevalence of cardiovascular diseases and prognosis—the obesity paradox updated. Prog Cardiovasc Dis. 2016;58(5):537‐547. 10.1016/J.PCAD.2016.01.008 [DOI] [PubMed] [Google Scholar]
  • 3. Patel NJ, Deshmukh A, Pant S, et al. Contemporary trends of hospitalization for atrial fibrillation in the United States, 2000 through 2010 implications for healthcare planning. Circulation. 2014;129(23):2371‐2379. 10.1161/CIRCULATIONAHA.114.008201 [DOI] [PubMed] [Google Scholar]
  • 4. Nalliah CJ, Sanders P, Kottkamp H, Kalman JM. The role of obesity in atrial fibrillation. Eur Heart J. 2016;37(20):1565‐1572. 10.1093/eurheartj/ehv486 [DOI] [PubMed] [Google Scholar]
  • 5. Wong CX, Sullivan T, Sun MT, et al. Obesity and the risk of incident, post‐operative, and post‐ablation atrial fibrillation: a metaanalysis of 626,603 individuals in 51 studies. JACC Clin Electrophysiol. 2015;1(3):139‐152. 10.1016/J.JACEP.2015.04.004 [DOI] [PubMed] [Google Scholar]
  • 6. Alkhouli M, Friedman PA. Ischemic stroke risk in patients with nonvalvular atrial fibrillation: JACC review topic of the week. J Am Coll Cardiol. 2019;74(24):3050‐3065. 10.1016/J.JACC.2019.10.040 [DOI] [PubMed] [Google Scholar]
  • 7. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circulation. 2019;140(2):e125‐e151. 10.1161/CIR.0000000000000665 [DOI] [PubMed] [Google Scholar]
  • 8. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non‐Vitaminnon‐vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330‐1393. 10.1093/eurheartj/ehy136 [DOI] [PubMed] [Google Scholar]
  • 9. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio‐Thoracic Surgery (EACTS). Eur Heart J. 2021;42(5):373‐498. 10.1093/eurheartj/ehaa612 [DOI] [PubMed] [Google Scholar]
  • 10. Joglar JA, Chung MK, Armbruster AL, et al. 2023. ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 149:e1‐e156. 10.1016/J.JACC.2023.08.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010;49(2):71‐87. 10.2165/11318100-000000000-00000 [DOI] [PubMed] [Google Scholar]
  • 12. Zhao Y, Guo M, Li D, et al. Pharmacokinetics and dosing regimens of direct oral anticoagulants in morbidly obese patients: an updated literature review. Clin Appl Thromb Hemost. 2023;29:107602962311536. 10.1177/10760296231153638 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Martin K, Beyer‐Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemostasis. 2016;14(6):1308‐1313. 10.1111/jth.13323 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Lima Filho AIN, do Rego Barros MC, de Barros Guimarães AA, Celestino Sobral Filho D. Obesity paradox in atrial fibrillation and its relation with the new oral anticoagulants. Curr Cardiol Rev. 2022;18(5):8‐10. 10.2174/1573403x18666220324111343 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Shaikh F, Wynne R, Castelino RL, Inglis SC, Ferguson C. Effectiveness of direct oral anticoagulants in obese adults with atrial fibrillation: a systematic review of systematic reviews and meta‐analysis. Front Cardiovasc Med. 2021;8:732828. 10.3389/fcvm.2021.732828 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Mhanna M, Beran A, Al‐Abdouh A, et al. Direct oral anticoagulants versus warfarin in morbidly obese patients with nonvalvular atrial fibrillation: a systematic review and meta‐analysis. Am J Ther. 2021;28(5):e531‐e539. 10.1097/MJT.0000000000001403 [DOI] [PubMed] [Google Scholar]
  • 17. critical‐appraisal‐tools ‐Critical Appraisal Tools . JBI.
  • 18. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed.). 2019;366:4898. 10.1136/bmj.l4898 [DOI] [PubMed] [Google Scholar]
  • 19.RevMan. Cochrane Training. Accessed October 15, 2022. https://training.cochrane.org/online-learning/core-software/revman
  • 20. Alberts MJ, He J, Kharat A, Ashton V. Effectiveness and safety of rivaroxaban versus warfarin among nonvalvular atrial fibrillation patients with obesity and polypharmacy. Am J Cardiovasc Drugs. 2022;22(4):425‐436. 10.1007/s40256-021-00520-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Berger JS, Laliberté F, Kharat A, et al. Real‐world effectiveness and safety of rivaroxaban versus warfarin among non‐valvular atrial fibrillation patients with obesity in a US population. Curr Med Res Opin. 2021;37(6):881‐890. 10.1080/03007995.2021.1901223 [DOI] [PubMed] [Google Scholar]
  • 22. Boivin‐Proulx LA, Potter BJ, Dorais M, Perreault S. Comparative effectiveness and safety of direct oral anticoagulants vs warfarin among obese patients with atrial fibrillation. CJC Open. 2022;4(4):395‐405. 10.1016/j.cjco.2022.01.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Boriani G, Ruff CT, Kuder JF, et al. Relationship between body mass index and outcomes in patients with atrial fibrillation treated with edoxaban or warfarin in the ENGAGE AF‐TIMI 48 trial. Eur Heart J. 2019;40(19):1541‐1550. 10.1093/eurheartj/ehy861 [DOI] [PubMed] [Google Scholar]
  • 24. Briasoulis A, Mentias A, Mazur A, Alvarez P, Leira EC, Sarrazin MSV. Comparative effectiveness and safety of direct oral anticoagulants in obese patients with atrial fibrillation. Cardiovasc Drugs Ther. 2021;35:261‐272. 10.1007/s10557-020-07126-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Costa OS, Beyer‐Westendorf J, Ashton V, et al. Effectiveness and safety of rivaroxaban versus warfarin in obese nonvalvular atrial fibrillation patients: analysis of electronic health record data. Curr Med Res Opin. 2020;36(7):1081‐1088. 10.1080/03007995.2020.1762554 [DOI] [PubMed] [Google Scholar]
  • 26. 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(6):1633. 10.3390/jcm9061633 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Deitelzweig S, Sah J, Kang A, et al. Effectiveness and safety of Apixaban versus warfarin in obese patients with Nonvalvular atrial fibrillation enrolled in Medicare and veteran affairs. Am J Cardiol. 2022;163:43‐49. 10.1016/j.amjcard.2021.09.047 [DOI] [PubMed] [Google Scholar]
  • 28. Huang CW, Duan L, An J, Sim JJ, Lee MS. Effectiveness and safety of dabigatran in atrial fibrillation patients with severe obesity: a real‐world retrospective cohort study. J Gen Intern Med. 2022;37(12):2982‐2990. 10.1007/s11606-021-07114-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Kido K, Ngorsuraches S. Comparing the efficacy and safety of direct oral anticoagulants with warfarin in the morbidly obese population with atrial fibrillation. Ann Pharmacother. 2019;53(2):165‐170. 10.1177/1060028018796604 [DOI] [PubMed] [Google Scholar]
  • 30. 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. Lancet Haematol. 2019;6(7):e359‐e365. 10.1016/S2352-3026(19)30086-9 [DOI] [PubMed] [Google Scholar]
  • 31. Lip GYH, Merino JL, Banach M, et al. Impact of body mass index on outcomes in the edoxaban versus warfarin therapy groups in patients underwent cardioversion of atrial fibrillation (from ENSURE‐AF). Am J Cardiol. 2019;123(4):592‐597. 10.1016/j.amjcard.2018.11.019 [DOI] [PubMed] [Google Scholar]
  • 32. Nakao YM, Nakao K, Wu J, Nadarajah R, Camm AJ, Gale CP. Risks and benefits of oral anticoagulants for stroke prophylaxis in atrial fibrillation according to body mass index: nationwide cohort study of primary care records in England. EClinicalMedicine. 2022;54:101709. 10.1016/j.eclinm.2022.101709 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Patil T, Lebrecht M. A single center retrospective cohort study evaluating use of direct oral anticoagulants (DOACs) in morbidly obese veteran population. Thromb Res. 2020;192:124‐130. 10.1016/j.thromres.2020.04.015 [DOI] [PubMed] [Google Scholar]
  • 34. Perales IJ, San Agustin K, DeAngelo J, Campbell AM. Rivaroxaban versus warfarin for stroke prevention and venous thromboembolism treatment in extreme obesity and high body weight. Ann Pharmacother. 2020;54(4):344‐350. 10.1177/1060028019886092 [DOI] [PubMed] [Google Scholar]
  • 35. Peterson ED, Ashton V, Chen YW, Wu B, Spyropoulos AC. Comparative effectiveness, safety, and costs of rivaroxaban and warfarin among morbidly obese patients with atrial fibrillation. Am Heart J. 2019;212:113‐119. 10.1016/j.ahj.2019.02.001 [DOI] [PubMed] [Google Scholar]
  • 36. Russo V, Bottino R, Rago A, et al. Clinical performance of nonvitamin K antagonist oral anticoagulants in real‐world obese patients with atrial fibrillation. Semin Thromb Hemost. 2020;46(8):970‐976. 10.1055/s-0040-1715792 [DOI] [PubMed] [Google Scholar]
  • 37. Weir MR, Chen YW, He J, Bookhart B, Campbell A, Ashton V. Effectiveness and safety of rivaroxaban versus warfarin among nonvalvular atrial fibrillation patients with obesity and diabetes. J Diabetes Complications. 2021;35(11):108029. 10.1016/j.jdiacomp.2021.108029 [DOI] [PubMed] [Google Scholar]
  • 38. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370(26):2478‐2486. 10.1056/nejmoa1313600 [DOI] [PubMed] [Google Scholar]
  • 39. Choi SE, Sagris D, Hill A, Lip GYH, Abdul‐Rahim AH. Atrial fibrillation and stroke. Expert Rev Cardiovasc Ther. 2023;21(1):35‐56. 10.1080/14779072.2023.2160319 [DOI] [PubMed] [Google Scholar]
  • 40. Costa OS, Beyer‐Westendorf J, Ashton V, et al. Effectiveness and safety of rivaroxaban versus warfarin in obese nonvalvular atrial fibrillation patients: analysis of electronic health record data. Curr Med Res Opin. 2020;36(7):1081‐1088. 10.1080/03007995.2020.1762554 [DOI] [PubMed] [Google Scholar]
  • 41. Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost. 2009;15(1_suppl):9S‐16S. 10.1177/1076029609343004 [DOI] [PubMed] [Google Scholar]
  • 42. Patel JP, Roberts LN, Arya R. Anticoagulating obese patients in the modern era. Br J Haematol. 155:137‐149. 10.1111/j.1365-2141.2011.08826.x [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting information.

HSR2-7-e2044-s001.docx (6.5MB, docx)

Supporting information.

HSR2-7-e2044-s002.docx (31.7KB, docx)

Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.

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