Resource
Center

Food intake with rivaroxaban is dependent on the dose. The absolute bioavailability of rivaroxaban 2.5 mg and 10 mg tablets is estimated to be between 80% to 100% and is not affected by food intake therefore can be taken with or without food. However, the absolute bioavailability of rivaroxaban 20 mg is ~66% in a fasted state. Taking rivaroxaban 20mg tablets with food increases the bioavailability (mean AUC and Cmax increasing by 39% and 76%, respectively) therefore both 20mg and 15mg tablets should be taken with food. However, there is no clearly defined guidance on how much food is sufficient to adequately increase the bioavailability of rivaroxaban 20 mg and 15 mg tablets.

A crossover, randomized, open-label study in 2006 of 10 healthy individuals evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in fasting or fed conditions. The fed conditions studied were high fat, high calorie (two large eggs fried in butter, two strips of bacon, two slices of buttered toast, 125 g hash brown potatoes and 250 mL whole milk) or high carbohydrate (4 slices buttered toast with 50 g jam, 20 g cheese, and sweetened tea) meals. Results suggested that PK and PD parameters did not differ based on type of meal.¹ Additionally, four clinical pharmacology studies assessed the maximum drug concentration and AUC of rivaroxaban 20 mg doses with different caloric intakes and meal contents (high calorie, high fat breakfast vs high carbohydrate breakfast vs applesauce followed by a low-calorie liquid diet). Kcals ranged from 578 to 1051. These studies found similar maximum drug concentrations and AUC for the differing caloric intakes and meal contents suggesting that meal content does not appear to significantly impact the PK of rivaroxaban. ^2-3 Meal timing (with breakfast, lunch, or dinner) was also assessed in a 2017 cross-study analysis which found that for a 20 mg once a day regimen, the PK of rivaroxaban are consistent regardless of meal timing.²

Resources

• Kubitza D, Becka M, Zuehlsdorf M, et al. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006;46:549-558.
• Zhang L, Peters G, Haskell L, et al. A cross-study analysis evaluating the effects of food on the pharmacokinetics of rivaroxaban in clinical studies. J Clin Pharmacol. 2017;57(12):1607-1615.
• Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther. 2013; 51(7): 549– 561.

It should first be noted that in the large pivotal trials that brought the DOACs to market, enrolled patients were assigned a dose based on renal function at study randomization without changes during the study period. Subgroup analyses of the ARISTOTLE and ROCKET-AF trials demonstrated that – in patients experiencing worsening renal function during the study period - apixaban and rivaroxaban maintained their efficacy and safety benefits as compared to warfarin. It should also be noted that studies have identified off-label DOAC dosing (including under- and over-dosing for renal function) as a common problem that significantly increases the risk of major bleeding, thromboembolic events, and all-cause mortality. As such, guidelines and experts note that patients prescribed DOACs require regular monitoring of renal function to ensure their safe and effective use – with dose adjustments made according to the renal dosing parameters for each DOAC agent. However, it may be impractical and unnecessary to frequently adjust the dose when a patient’s renal function is slightly fluctuating across parameter endpoints. DOAC dosing decisions should be based on factors such as the extent of creatinine change, the overall trend in renal function, and the clinical plan in response to the changing renal function (i.e., repeat labs, work-up, adjustments to medications which may be causative, etc). Other considerations that may sway a decision include (but are not limited to), drug-drug interactions, perceived bleeding/thrombotic risk, and patient preference. An approach that limits frequent dose changes and promotes shared decision-making between the patient and prescriber is recommended.

Resources

• JAMA Cardiol. 2016;1:451-460
• Circulation. 2016;134:37-47
• J Am Coll Cardiol. 2016;68(24);2597-604
• J Am Coll Cardiol. 2017 Jun 13;69(23):2779-2790

Since their introduction, direct oral anticoagulant (DOAC) utilization has continued to expand for patients requiring anticoagulation. However, patients with severe renal impairment (e.g., CrCl < 25-30 mL/min) were excluded from pivotal clinical trials.^1-3 Consequently, for many years, warfarin has been the preferred anticoagulant for patients with atrial fibrillation (AF) or venous thromboembolism (VTE) and with severe renal impairment.^3,4 Notwithstanding, given that chronic kidney disease (CKD) is more prevalent among patients requiring anticoagulation than in the general population,⁴ it is necessary to identify safe and effective anticoagulation options for this at-risk patient group.

Of all DOACs, apixaban has the least degree of renal elimination,^1-3 and apixaban package labeling contains language describing its use in patients with AF or VTE and with end-stage renal disease (CrCl <15 ml/min; ESRD) or on hemodialysis (HD). Apixaban exposure appears to be modestly increased in patients with renal dysfunction.^5,6 However, this information is based on pharmacokinetic data and has not been correlated with clinical outcomes.^1,7

For AF, limited, randomized clinical trial and real-world evidence and some guidance support apixaban as a comparably safe and effective alternative to warfarin for the prevention of stroke or systemic embolism in patients with AF and with ESRD or are on HD.^8-10 Regarding specific dosing for patients with AF and on HD, there is limited high-quality data to inform decision making. Results from the AXADIA-AFNET 8 randomized clinical trial, comparing apixaban 2.5 mg twice daily to the vitamin K antagonist phenprocoumon in patients with AF and on HD, found comparable safety and efficacy outcomes. It is important to note that this study did not meet prespecified noninferiority test requirements due to slow enrollment, and there may be clinically relevant differences between the groups.⁹ Pokorney et al. (2022), in the RENAL-AF randomized clinical trial comparing apixaban (using standard dose reduction criteria) to warfarin in patients with AF and on HD, were unable to draw conclusions regarding safety outcomes due to enrollment challenges. Interestingly, pharmacokinetic results revealed that serum levels of apixaban were similar among patients with or without bleeding events.¹¹ A recent cohort study by Welander et al. (2023) evaluated safety and effectiveness outcomes of DOACs compared to warfarin in patients with AF and CKD including on HD. For patients on apixaban dosed using standard dose reduction criteria, they found a lower risk of bleeding and no difference in the risk of ischemic stroke compared to warfarin.¹² Based on available evidence, for patients with AF and ESRD or on HD, if anticoagulation were to be used, generally using standard dose reduction criteria for apixaban would be reasonable.

For the treatment or prevention of VTE, there are limited studies evaluating the safety and effectiveness of apixaban in patients with ESRD or on HD. Results from observational studies comparing apixaban to warfarin in patients with VTE and with ESRD or on HD suggest that apixaban may be a safe and effective alternative to warfarin. However, these studies included patients on varying doses of apixaban, including off-label doses, and did not specifically assess or had limited use of loading doses (i.e., apixaban 10 mg twice daily for 7 days).^13-16 While the package insert for apixaban does not recommend dosing changes in this patient population, the optimal dosing regimen for apixaban for the treatment or prevention of VTE in patients with ESRD or on HD remains unknown because of limited available evidence.

Resources

1. Allen A, Ansell J, Clark N, et al. Direct Oral Anticoagulant (DOAC) Playbook. Anticoagulation Forum. Published 2021. Accessed May 12, 2022. https://acforum-excellence.org/Resource-Center/downloads/DOAC%20Playbook%20_07-2021.pdf
2. Steffel J, Collins R, Antz M, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Eur Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol Eur Soc Cardiol. 2021;23(10):1612-1676. doi:10.1093/europace/euab065
3. Chen A, Stecker E, A. Warden B. Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges. J Am Heart Assoc. 2020;9(13):e017559. doi:10.1161/JAHA.120.017559
4. Aursulesei V, Costache II. Anticoagulation in chronic kidney disease: from guidelines to clinical practice. Clin Cardiol. 2019;42(8):774-782. doi:10.1002/clc.23196
5. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):628-636. doi:10.1002/jcph.628
6. Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clin Pharmacokinet. 2019;58(10):1265-1279. doi:10.1007/s40262-019-00775-z
7. Apixaban [Eliquis - Package Insert]. Princeton, NJ: Bristol-Myers Squibb. Published online September 2021. Accessed February 28, 2023. https://packageinserts.bms.com/pi/pi_eliquis.pdf
8. Memon RA, Hamdani SSQ, Usama A, et al. Comparison of the Efficacy and Safety of Apixaban and Warfarin in the Prevention of Stroke in Patients With Non-valvular Atrial Fibrillation: A Meta-Analysis. Cureus. 2022;14(8):e27838. doi:10.7759/cureus.27838
9. Reinecke H, Engelbertz C, Bauersachs R, et al. A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study. Circulation. 2023;147(4):296-309. doi:10.1161/CIRCULATIONAHA.122.062779
10. 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. doi:10.1161/CIR.0000000000000665
11. Pokorney SD, Chertow GM, Al-Khalidi HR, et al. Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial. Circulation. 2022;146(23):1735-1745. doi:10.1161/CIRCULATIONAHA.121.054990
12. Welander F, Renlund H, Dimény E, Holmberg H, Själander A. Direct oral anticoagulants versus warfarin in patients with non-valvular atrial fibrillation and CKD G3–G5D. Clin Kidney J. Published online January 5, 2023:sfad004. doi:10.1093/ckj/sfad004
13. Reed D, Palkimas S, Hockman R, Abraham S, Le T, Maitland H. Safety and effectiveness of apixaban compared to warfarin in dialysis patients. Res Pract Thromb Haemost. 2018;2(2):291-298. doi:10.1002/rth2.12083
14. Sy J, Hsiung JT, Edgett D, Kalantar-Zadeh K, Streja E, Lau WL. Cardiovascular and Bleeding Outcomes with Anticoagulants across Kidney Disease Stages: Analysis of a National US Cohort. Am J Nephrol. 2021;52(3):199-208. doi:10.1159/000514753
15. Wetmore JB, Herzog CA, Yan H, Reyes JL, Weinhandl ED, Roetker NS. Apixaban versus Warfarin for Treatment of Venous Thromboembolism in Patients Receiving Long-Term Dialysis. Clin J Am Soc Nephrol. 2022;17(5):693-702. doi:10.2215/CJN.14021021
16. Ellenbogen MI, Ardeshirrouhanifard S, Segal JB, Streiff MB, Deitelzweig SB, Brotman DJ. Safety and effectiveness of apixaban versus warfarin for acute venous thromboembolism in patients with end‐stage kidney disease: A national cohort study. J Hosp Med. 2022;17(10):809-818. doi:10.1002/jhm.12926

In 2016, the International Society on Thrombosis and Haemostasis (ISTH) published guidance advising caution when using direct oral anticoagulants (DOACs) in patients with high weight or BMI (>120 kg or BMI >40 kg/m2) due to the limited efficacy and safety data in this patient population.¹ Since that time, emerging evidence suggests that DOACs may have comparable safety and effectiveness in venous thromboembolism (VTE)² and atrial fibrillation (AF)^3,4 patient populations with high weight or BMI. Furthermore, more recent guidance suggests apixaban and rivaroxaban may be considered in the treatment and prevention of thrombosis in VTE and AF regardless of high BMI or weight.^5-7 Dabigatran or edoxaban should continue to be avoided in patients with high weight or BMI due to mixed and/or limited available data.⁵ Shared decision-making remains essential to ensure risks vs benefits are discussed and that a collective decision is made regarding therapy selection.

It is important to note the despite growing supportive evidence at higher weight and BMI, there remains a paucity of evidence at extremely high weight (e.g., BMI ≥ 50 kg/m2 and weight > 150 kg). DOAC use in this patient population may require unique considerations of thrombotic/bleeding risks and the potential role of quantitative DOAC serum level measurement.^5-8 Of note, due to a lack of clinically validated therapeutic ranges, routine monitoring of DOAC levels should be avoided;⁵ however, there may be unique circumstances where laboratory assessment of levels may aid management decisions (e.g., post-bariatric surgery).^5,9 Additionally, there remains little evidence for reduced-intensity dosing for the secondary prevention of VTE (apixaban 2.5 mg twice daily and rivaroxaban 10 mg daily) for patients at high weight or BMI (>120 kg or BMI >40 kg/m3 ), and it would be reasonable to continue these patients on therapeutic-intensity dosing until more data is available.^5,7

References:

1. 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 Haemost. 2016;14(6):1308-1313. doi:10.1111/jth.13323
2. Katel A, Aryal M, Neupane A, et al. Efficacy and Safety of Direct Oral Anticoagulants in Venous Thromboembolism Compared to Traditional Anticoagulants in Morbidly Obese Patients: A Systematic Review and Meta-Analysis. Cureus. Published online April 20, 2021. doi:10.7759/cureus.14572
3. Wang SY, Giugliano RP. Non-Vitamin K Antagonist Oral Anticoagulant for Atrial Fibrillation in Obese Patients. Am J Cardiol. 2020;127:176-183. doi:10.1016/j.amjcard.2020.04.016
4. Zhou Y, Ma J, Zhu W. Efficacy and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation Across BMI Categories: A Systematic Review and Meta-Analysis. Am J Cardiovasc Drugs Drugs Devices Interv. 2020;20(1):51-60. doi:10.1007/s40256-019-00362-4
5. 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
6. Mocini D, Di Fusco SA, Mocini E, et al. Direct Oral Anticoagulants in Patients with Obesity and Atrial Fibrillation: Position Paper of Italian National Association of Hospital Cardiologists (ANMCO). J Clin Med. 2021;10(18):4185. doi:10.3390/jcm10184185
7. Rosovsky RP, Kline-Rogers E, Lake L, et al. Direct Oral Anticoagulants in Obese Patients with Venous Thromboembolism: Results of an Expert Consensus Panel. The American Journal of Medicine. 2023;136(6):523-533. doi:10.1016/j.amjmed.2023.01.010
8. Pandey AK, Eikelboom JW. Direct Oral Anticoagulant Dosing in Extremes of Body Weight: Time to Revisit the Guidelines? Thromb Haemost. 2021;121(02):118-120. doi:10.1055/s-0040-1716753
9. Akpan IJ, Cuker A. Laboratory assessment of the direct oral anticoagulants: who can benefit? Kardiol Pol. Published online May 24, 2021:VM/OJS/J/83811. doi:10.33963/KP.a2021.0021

Patients with low body weight (≤60 kg) and extremely low body weight (<50 kg) were under-represented in pivotal DOAC RCTs. There is currently no direct societal guidance on use of DOACs in those with low body weight. Pharmacokinetic data suggests only a modest increase in Cmax and AUC in those with low body weight, but this has not consistently correlated with worsening clinical outcomes. A 2017 meta-analysis of phase III RCTs evaluated DOAC safety and efficacy in those with low body weight (≤60 kg). The study concluded that dose adjustment of DOACs outside of that recommended by package inserts is unlikely to improve safety or efficacy.¹ A 2019 retrospective cohort study of more than 14,000 low body weight (≤60kg) Asian patients treated with DOACs for atrial fibrillation found that regular doses of DOACs showed comparable results as reduced dosages in both efficacy and safety.² It also showed DOACs were safer and more effective than warfarin. The benefits were consistent in those <50 kg as well except for hospitalization for GIB.

Although there is limited guidance on DOAC use within a low body weight population, current available evidence suggests that it can be considered a comparable alternative to warfarin. Additionally, evidence suggests that dosage adjustments outside of those recommended by package inserts is unlikely to improve efficacy or safety.

1. Boonyawat K, Caron F, Li A, et al. Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis. J Thromb Haemost. 2017;15:1322-1333.

2. Lee S, Choi E, Park C, et al. Direct Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation and Low Body Weight. J Am Coll Cardiol. 2019 Mar, 73 (8) 919–931.

Recent publications have highlighted that “off-label” DOAC dose reductions correspond with higher incidence of thromboembolic events. Presently, “off-label” dose reductions should be avoided.

Resources

• Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes
• Non-Vitamin K Anticoagulant Dose Selection: It’s Best to Read and Follow the Directions

Direct oral anticoagulants (DOACs) have a rapid onset and offset of action which obviates the need for parenteral bridging.¹ Additionally, results from a large, prospective cohort study showed that patients on DOAC therapy for atrial fibrillation utilizing an interruption strategy without bridging had low rates of bleeding and thrombosis.² Generally, the use of parenteral bridging during typical interruptions of DOAC therapy for procedures should be avoided.^3,4

References

1. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood. 2012;120(15):2954-2962. doi:10.1182/blood-2012-06-415943
2. Douketis JD, Spyropoulos AC, Duncan J, et al. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med. 2019;179(11):1469. doi:10.1001/jamainternmed.2019.2431
3. Douketis JD, Spyropoulos AC, Murad MH, et al. Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline Executive Summary. Chest. Published online August 10, 2022:S0012-3692(22)01364-2. doi:10.1016/j.chest.2022.08.004
4. Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation. J Am Coll Cardiol. 2017;69(7):871-898. doi:10.1016/j.jacc.2016.11.024

Recent evidence and guidance support interrupting warfarin without perioperative bridging with parenteral anticoagulation in most patients due to increased bleeding risk without reducing thrombotic risk.^1,2 However, bridging is suggested in select patients with a history of VTE considered high risk for thromboembolism including those with:

• Recent (within 3 months and especially 1 month) VTE;
• Strong thrombophilia (protein C, S, or antithrombin deficiency; homozygous factor V Leiden or prothrombin gene mutation; heterozygous factor V Leiden AND heterozygous prothrombin gene mutation; multiple thrombophilias; antiphospholipid antibodies);
• Active cancer associated with high VTE risk, including pancreatic cancer, myeloproliferative disorders, primary brain cancer, gastric cancer, and esophageal cancer;
• Previous therapeutic failure or VTE during short-term interruption of anticoagulation.^2,3

References

1. Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial. Thromb Haemost. 2015;113(3):625-632. doi:10.1160/TH14-04-0305
2. Douketis JD, Spyropoulos AC, Murad MH, et al. Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline Executive Summary. Chest. Published online August 10, 2022:S0012-3692(22)01364-2. doi:10.1016/j.chest.2022.08.004
3. Rose AJ, Allen AL, Minichello T. A Call to Reduce the Use of Bridging Anticoagulation. Circ Cardiovasc Qual Outcomes. 2016;9(1):64-67. doi:10.1161/CIRCOUTCOMES.115.002430

Prophylactic-intensity anticoagulation for venous thromboembolism (VTE) prophylaxis is frequently utilized after major orthopedic surgery (total hip or knee replacement)¹ and is recommended for patients whose anticoagulation was interrupted and until therapeutic-intensity anticoagulation is resumed.² For patients on a direct oral anticoagulant (DOAC), VTE prophylaxis would typically be continued until resumption of DOAC therapy. For patients on warfarin therapy who did not use therapeutic-intensity bridging, VTE prophylaxis would typically be continued for 2 to 3 days while warfarin takes effect. For patients on warfarin therapy who used therapeutic-intensity bridging (see below for further description), VTE prophylaxis would be continued until therapeutic-intensity bridging was resumed.²

Regarding identifying patients on warfarin who may benefit from bridging anticoagulation, recent evidence and guidance support interrupting warfarin without perioperative bridging with parenteral anticoagulation in most patients due to increased bleeding risk without reducing thrombotic risk.^2,3 However, bridging anticoagulation (typically with therapeutic-intensity anticoagulation) is suggested in select patients considered high risk for thromboembolism including those with:

• recent (within 3 months) VTE, stroke, or TIA;
• strong thrombophilia (protein C, S, or antithrombin deficiency; homozygous factor V Leiden or prothrombin gene mutation; heterozygous factor V Leiden AND heterozygous prothrombin gene mutation; multiple thrombophilias; antiphospholipid antibodies);
• active cancer associated with high VTE risk, including pancreatic cancer, myeloproliferative disorders, primary brain cancer, gastric cancer, and esophageal cancer;
• atrial fibrillation with a CHA2DS2VASc ≥ 7 or CHADS2 score of 5 or 6;
• rheumatic valvular heart disease;
• caged ball valve or tilting disc valve in aortic/mitral position;
• mechanical mitral valve with high-risk stroke factors including multiple prior strokes, prior perioperative stroke, or prior valve thrombosis;
• previous therapeutic failure or VTE during short-term interruption of anticoagulation.^2,4

Given the complexity and risks inherent to periprocedural management of antithrombotic therapies, shared decision making with the patient, care team, and proceduralist is recommended.

References

1. Anderson DR, Morgano GP, Bennett C, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3(23):3898-3944. doi:10.1182/bloodadvances.2019000975
2. Douketis JD, Spyropoulos AC, Murad MH, et al. Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline Executive Summary. Chest. Published online August 10, 2022:S0012-3692(22)01364-2. doi:10.1016/j.chest.2022.08.004
3. Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial. Thromb Haemost. 2015;113(3):625-632. doi:10.1160/TH14-04-0305
4. Rose AJ, Allen AL, Minichello T. A Call to Reduce the Use of Bridging Anticoagulation. Circ Cardiovasc Qual Outcomes. 2016;9(1):64-67. doi:10.1161/CIRCOUTCOMES.115.002430

In patients on long-term OAC with stable CAD, is antiplatelet therapy also indicated?
It is well known that the addition of APT to an oral anticoagulant (OAC) substantially increases the risk of major bleeding. While indications for long-term oral anticoagulation include atrial fibrillation and venous thromboembolism (VTE), it is important to note most of the evidence surrounding the combination of OAC and APT is in atrial fibrillation patients with stable CAD. There is very limited evidence evaluating this combination in patients being treated for VTE with stable CAD.

The 2018 CHEST guidelines state "in atrial fibrillation patients with stable coronary artery disease (eg, no acute coronary syndrome within the previous year), there is no evidence that adding APT to an OAC reduces stroke/systemic embolism, death, or MI. However, the risk of major bleeding and intracranial hemorrhage is substantially increased with the addition of APT to an OAC."¹ In accordance with these recommendations, the 2020 ACC Expert Consensus Pathway for Anticoagulant and Antiplatelet Therapy, the 2020 ESC Guidelines, and the 2023 ACC/AHA/ACCP/HRS Guidelines also recommend OAC monotherapy in patients with stable CAD (also referred to as chronic coronary disease), defined as no new cardiovascular event in the past 12 months or CAD not requiring coronary revascularization.^2-4 The 2020 ESC Guidelines and 2023 ACC/AHA Guidelines also give consideration for atrial fibrillation patients with stable PAD (defined as no new vascular event in the past 12 months) stating they should be managed with OAC monotherapy as well.^3,4

Data from the AFIRE landmark clinical trial is cited by the 2023 Guidelines supporting the use of OAC monotherapy in patients with stable CAD.⁴ The investigators concluded that rivaroxaban monotherapy was non-inferior to rivaroxaban plus APT for cardiovascular events and death and superior in terms of major bleeding.⁵ It was also terminated early due to increased mortality in the rivaroxaban plus APT group. Furthermore, a 2018 pooled analysis of the data collected from the PREFER in AF and PREFER in AF PROLONGATION registries concluded that combination therapy did not provide any added protection against coronary events but did increase major bleeding.⁶

While most data surround atrial fibrillation patients with stable CAD, the ACC Expert Consensus Pathway also recommends OAC monotherapy in patients with stable CAD on long term anticoagulation for prevention of VTE.² However, the evidence evaluating this patient population is limited.

While OAC monotherapy is generally recommended in stable CAD, the ACC Expert Consensus Pathway also states if thrombotic risk is high and bleeding risk is low, it is reasonable to continue combined APT with an OAC beyond 12 months.²

Resources

1. Lip G, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation. CHEST. 2018; 154(5), 1121-1201.
2. Kumbhani D, Cannon C, Beavers C, et al. 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or With Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021 Feb, 77(5): 629–658.
3. 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). European Heart Journal. 2020 Aug, 42(5):373-498.
4. 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. Circulation. 2024;149(1). doi:10.1161/CIR.0000000000001193
5. Yasuda S, Kaikita K, Akao M, et al. Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease. N Engl J Med. 2019; 381:1103-1113.
6. Patti G, Pecen L, Lucerna M, et al. Outcomes of anticoagulated patients with atrial fibrillation treated with or without antiplatelet therapy - A pooled analysis from the PREFER in AF and PREFER in AF PROLONGATON registries. Int J Cardiol. 2018 Nov;270:160–166.

The combined use of NSAIDs and anticoagulants is discouraged given the significant increase in risk of bleeding when used concomitantly. A 2020 meta-analysis found a nearly twofold increased risk of gastrointestinal bleeding (GIB) when warfarin is combined with an NSAID vs warfarin alone.¹ A 2020 Danish registry review also found a twofold increased risk of GIB when DOACs are combined with NSAIDs in atrial fibrillation patients.² An even higher risk has been quoted by the Agency for Healthcare Research and Quality (AHRQ) stating concomitant use of anticoagulants and nonselective NSAIDs increases the risk of GIB three- to six fold compared to anticoagulant use alone.

When first encountering a patient with this combination, exploring alternative therapies for pain relief should be a priority. Oral NSAIDs are commonly used for the treatment of osteoarthritis (OA). The 2019 American College of Rheumatology (ACR) OA treatment guidelines recommend topical NSAID use over oral NSAID use due to less systemic exposure. They also strongly or conditionally recommend the use of non-pharmacological interventions (exercise, weight loss, tai chi, yoga, cognitive-behavioral therapy, acupuncture, etc.) and alternative pharmacological therapies (topical capsaicin, acetaminophen, duloxetine, tramadol, intraarticular glucocorticoid injections, etc.) for the treatment of OA depending on affected joint.³

If alternative therapies have been exhausted and a patient’s quality of life is severely impacted in the absence of oral NSAIDs, a risk vs benefit discussion should be conducted if concomitant anticoagulation and NSAID therapy is continued. Patients must be well educated on the risks of the combination and instructed when to seek medical attention if abnormal bleeding does occur. For acute pain, lowest doses and shortest durations of NSAIDs should be used. Choice of anticoagulant should be considered as well. DOACs have a lower bleeding risk compared to warfarin. Among DOACs, apixaban appears to have a more favorable safety profile in terms of GIB while rivaroxaban appears to have the least favorable.^4-5 Additionally, studies have found that when combined with a PPI, the risk of GIB is significantly decreased.

COX selectivity of NSAIDs can be considered as well. In general, NSAIDs with greater COX-2 selectivity (celecoxib, etodolac, meloxicam) are associated with less GIB but have also been associated with an increased risk in CV events and should be used with caution in those with underlying CV disease. A meta-analysis found that upper GIB rates of COX-2 selective agents were similar with that of diclofenac and ibuprofen and that naproxen is not associated with an increased risk of CV events but does have a higher risk of GIB as compared with COX-2 selective agents.⁶ Naproxen may also inhibit p-glycoprotein thereby increasing apixaban exposure.⁷

Resources

• Zapata L, Hansten P, Panic J, et al. Risk of Bleeding with Exposure to Warfarin and Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review and Meta-Analysis. Thromb Haemost. 2020 Jul: 120(7):1066-1074.
• Olsen A, McGettigan P, Gerds T, et al. Risk of gastrointestinal bleeding associated with oral anticoagulation and nonsteroidal anti-inflammatory drugs in patients with atrial fibrillation: a nationwide study. Eur Heart J Cardiovasc Pharmacother. 2020 Sept 1;6(5):292-300.
• Kolasinski S, Neogi T, Hochberg M, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care & Research. Feb 2020: 72(2):149-162.
• Vinogradova Y, Coupland C, Hill T, et al. Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care. BMJ. 2018;362:k2505.
• Van Ganse E, Danchin N, Mahe I, et al. Comparative Safety and Effectiveness of Oral Anticoagulants in Non-valvular Atrial Fibrillation: The NAXOS Study. Stroke. 2020;51:2066-2075.
• Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non‐steroidal anti‐inflammatory drugs: meta‐analyses of individual participant data from randomized trials. Lancet 2013;9894:769–79.
• Frost C, Shenker A, Gandhi MD, et al. Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban [published online ahead of print April 2, 2014]. Br J Clin Pharmacol. 2014 Oct; 78(4):877-885.

The concomitant use of dexamethasone and direct-acting oral anticoagulants (DOACs) therapy is not a clinically significant issue. There are limited human/in vivo studies investigating the interaction between DOACs and dexamethasone. COVID-19 patients are at a higher risk of thrombotic events and frequently receive extended courses of dexamethasone, however, the use of dexamethasone is reserved for the critically ill COVID-19 patients requiring oxygen supplementation.¹ Some institutions may use DOAC therapy to prevent VTE in acutely-ill patients while many patients are already taking DOAC therapy for concomitant conditions like prior venous thromboembolism (VTE) or atrial fibrillation (Afib). Because corticosteroids increase the risk of gastrointestinal bleeding or perforation by forty percent,² monitoring serum concentrations of DOACs may be warranted if concomitant use is unavoidable.³

Apixaban and rivaroxaban exploit CYP3A4 metabolism and all DOACs are substrates of p-gp efflux transporters.⁴ Drugs that are strong modifiers for p-gp or CYP3A4 can have clinically significant reactions with DOACs leading to increased risk of thrombosis or bleeding.⁴ Lexicomp classifies dexamethasone as a weak CYP3A4 inducer with no p-gp induction.⁵ Current recommendations demonstrate that there is no interaction between dexamethasone and DOACs. Most recommendations either do not use dexamethasone and DOACs concomitantly, did not discuss interactions between dexamethasone and DOACs, or are review articles/guidelines that recommend against concomitant use of dexamethasone and DOACs based on a theoretical interaction.⁴ Therefore, given the low quality of the data and uncertainty on the degree or duration of a potential prothrombotic state with COVID-19 patients, the concomitant use of DOACs and dexamethasone is not a clinically significant issue.

Resources

• COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.
• Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open. 2014;4(5):e004587. Published 2014 May 15. doi:10.1136/bmjopen-2013-004587
• Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic of the Week. J Am Coll Cardiol. 2020;75(11):1341-1350. doi:10.1016/j.jacc.2019.12.068
• Vasquez S, Fleming R. Direct Oral Anticoagulant (DOAC) Drug-Drug Interaction Guidance: Anticoagulation Forum. 2020.
• Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2020; November 17, 2020.

Aspirin is not recommended for the prevention of thromboembolism in NVAF due to decreased efficacy and no difference in bleeding risk compared to anticoagulant therapy. The Garfield-AF registry reports that NVAF patients on antiplatelet monotherapy for stroke prevention tend to have higher HAS-BLED scores suggesting that clinicians may be unfamiliar with guidelines and studies revealing similar bleeding risks of anticoagulants and antiplatelet agents. The AVERROES trial showed no significant difference in bleeding with apixaban vs. aspirin. A recent meta-analysis of 4 randomized controlled trials with greater than 20,000 patients, showed no significant difference in outcomes of major bleeding with therapeutic direct oral anticoagulant (DOAC) dosing vs. aspirin. Guidelines from the United States and Europe (CHEST 2018, ESC 2020 and AHA/ACC/HRS 2019) all recommend anticoagulants over antiplatelets and the ESC recommends against antiplatelet therapy used for stroke prevention in NVAF patients.

Resources

• Verheugt, European Heart Journal. 2018; 39(5):464-473
• Dimitrios Sagris, et al., European Journal of Internal Medicine. https://doi.org/10.1016/j.ejim.2020.05.001
• Connoly, NEJM 2011; 364:806-817.
• Lipp, CHEST 2018;154(5):1121-1201.
• European Society of Cardiology 2021; 42(5):373-498.
• January, Circulation.2019;140:e125–e151.

Prior to the release of the 2020 ACC/AHA Valvular Heart Disease Guidelines, aspirin was routinely recommended in addition to a VKA in patients with MHV per 2014 ACC/AHA and 2012 CHEST guidelines. However, this stance has recently changed. The 2020 ACC/AHA Guidelines state "for patients with a mechanical surgical aortic valve replacement or mitral valve replacement who are managed with a VKA and have an indication for antiplatelet therapy, adding aspirin 75 to 100 mg daily may be considered when the risk of bleeding is low."" The guidelines state the prior recommendation to add aspirin to a VKA for MHV was based on studies performed decades ago that included many patients with older-generation valves who also had thromboembolic and vascular risk factors. A 2013 Cochrane Systematic Review using low quality evidence showed that the addition of antiplatelet therapy to a VKA reduced the risk of thromboembolic events and the total mortality rate but at the cost of increased major bleeding. An individualized approach that takes the risk of bleeding into account is recommended.

There is however one mechanical valve for which addition of low-dose aspirin to a VKA is routinely recommended. The 2020 ACC/AHA guidelines state that for mechanical On-X aortic valve replacements, a VKA targeted to a lower INR goal (1.5-2.0) may be reasonable starting 3 months after surgery with low-dose aspirin used concomitantly.

The guidelines also comment on patients with MHV that experience thromboembolic events in the setting of a therapeutic INR. Guidelines state is it reasonable to increase the INR goal range or add low-dose aspirin with assessment of bleeding risk.

Resources

• Otto C, Nishimura R, Bonow R, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American college of cardiology/American heart association joint committee on clinical practice guidelines. Circulation. 2021; 143(5):e72-e227.
• Massel D, Little S. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev. 2013 Jul; 2013(7):CD003464.
• Puskas J, Gerdisch M, Nichols D, et al. Reduced anticoagulation after mechanical aortic valve replacement: interim results from the prospective randomized on-X valve anticoagulation clinical trial randomized Food and Drug Administration investigational device exemption trial. J Thorac Cardiovasc Surg. 2014; 147:1202–10.

The 9th edition of the ACCP Antithrombotic guidelines (CHEST 2012) states the following:

For patients with stable therapeutic INRs presenting with a single subtherapeutic INR value, we suggest against routinely administering bridging with heparin (Grade 2C).

It should be noted that this is not specific to MHVs, does not speak to repeatedly subtherapeutic INR, and does not speak specifically to high-risk indications. One could extrapolate from current recommendations about bridging for intentional interruptions, but this does not add much clarity to the issue if the guidelines and available literature are taken in context. First, the annualized stroke risk associated with MHVs has been estimated at 2-4% so one can assume a daily risk of no more than 0.01% - quite low. While some societies still encourage periprocedural bridging for certain patients with MHVs, it should be clear that all available literature would suggest net HARM from bridging in all patient populations represented in studies to date. Across the board, the data demonstrates no significant reduction in the risk of thromboembolic events, with significant increase in the risk of major bleeding. Clear data on the risk and benefit of bridging in the highest risk population (including the highest risk patients with MHVs) are lacking, but the net harm from other populations seems so clear that the likelihood of any population exhibiting net benefit is low. As such, bridging for a single subtherapeutic INR should likely be avoided in most cases. For the highest risk patients and/or those with multiple subtherapeutic INRs, the above should be taken into consideration and decisions should ultimately favor the patients’ informed decision.

Resources

• CHEST 2012; 141(2)(Suppl):7S–47S.
• Circulation. 2017;135:e1159–e1195.
• European Heart Journal (2017) 38, 2739–2791.
• J Am Coll Cardiol 2000; 86:1097–101.

For most patients on anticoagulation who experience gastrointestinal (GI) bleeding, resumption of anticoagulation after the GI bleeding event likely confers a thrombosis risk reduction and mortality benefit but may increase the risk of rebleeding.^1-5 While high-quality evidence on optimal resumption timing is lacking, given that thromboembolic risk increases over time, expert opinion and recent guidance suggests resuming anticoagulation after 7 days from the GI bleeding event is reasonable.^6,7 Earlier resumption of anticoagulation within 3-7 days from the GI bleeding event may be considered in patients at high-risk for thrombosis (e.g., mechanical mitral valve, VTE within previous 3 months, etc.).^3,4,8 Previous bleeding, index major bleeding, and lower glomerular filtration rate have been identified as predictors of recurrent clinically relevant bleeding.⁹ If the risks of resuming anticoagulation outweigh the benefits, consulting with relevant specialists is advised.

References

1. Qureshi W, Mittal C, Patsias I, et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol. 2014;113(4):662-668. doi:10.1016/j.amjcard.2013.10.044
2. Sengupta N, Feuerstein JD, Patwardhan VR, et al. The risks of thromboembolism vs. recurrent gastrointestinal bleeding after interruption of systemic anticoagulation in hospitalized inpatients with gastrointestinal bleeding: a prospective study. Am J Gastroenterol. 2015;110(2):328-335. doi:10.1038/ajg.2014.398
3. Tapaskar N, Pang A, Werner DA, Sengupta N. Resuming Anticoagulation Following Hospitalization for Gastrointestinal Bleeding Is Associated with Reduced Thromboembolic Events and Improved Mortality: Results from a Systematic Review and Meta-Analysis. Dig Dis Sci. 2021;66(2):554-566. doi:10.1007/s10620-020-06248-9
4. Zappulla P, Calvi V. Gastrointestinal Bleeding and Direct Oral Anticoagulants among Patients with Atrial Fibrillation: Risk, Prevention, Management, and Quality of Life. TH Open. 2021;05(02):e200-e210. doi:10.1055/s-0041-1730035
5. Triantafyllou K, Gkolfakis P, Gralnek IM, et al. Diagnosis and management of acute lower gastrointestinal bleeding: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2021;53(08):850-868. doi:10.1055/a-1496-8969
6. Abraham NS, Barkun AN, Sauer BG, et al. American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period. Am J Gastroenterol. 2022 Apr 1;117(4):542-558
7. Senguta N, Feuerstein JD, Jairath V, et al. Management of Patients With Acute Lower Gastrointestinal Bleeding: An Updated ACG Guideline. Am J Gastroenterol. 2023 Feb 1;118(2):208-231
8. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330-1393. doi:10.1093/eurheartj/ehy136
9. Candeloro M, van Es N, Cantor N, et al. Recurrent bleeding and thrombotic events after resumption of oral anticoagulants following gastrointestinal bleeding: Communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021 Oct;19(10):2618-2628