Background

• The RIVER (Rivaroxaban for Valvular Heart Disease and Atrial Fibrillation) trial is an open-label, multicenter, non-inferiority, randomized controlled trial that was designed to assess the safety and efficacy of rivaroxaban compared to warfarin in patients with atrial fibrillation/atrial flutter and a bioprosthetic mitral valve.¹
• The trial was designed to address the paucity of data regarding the use of direct oral anticoagulants (DOAC) for long-term anticoagulation in this population. The current data that exists are for apixaban and edoxaban, however these were based on a subgroup analyses with a limited sample size.¹
• Historically, valvular atrial fibrillation was an exclusion for all the early DOAC trials, and only recently has there been a recognition that bioprosthetic valves may function more similar to native valves in this setting.
• The use of anticoagulation early post valve surgery is done in part to minimize thromboembolization from the valve annulus, which is thought to diminish with time as endothelialization of the annulus occurs.²
• The 2020 ACC/AHA valve guidelines for atrial fibrillation and mitral bioprosthetic valves still recommend warfarin for anticoagulation within the first 3 months of surgery, however recommendations after 3 months between warfarin and a DOAC should be based on shared-decision making using CHA₂DS₂-VASc score as a guide.²

Outcomes

• The primary outcome of the RIVER trial was a composite of death, major cardiovascular events, or major bleeding at 12 months, reported as restricted mean survival time with a non-inferiority margin of 8 days. The secondary outcome was a composite of death from cardiovascular causes or thromboembolic events. Primary data analysis was done according to the intention-to-treat principle.¹

Results

• A total of 1,005 patients were enrolled with the mean age of participants being 59.3 years. The mean CHA₂DS₂-VASc score was 2.6.¹
• Restricted mean survival time (RMST) analysis was used showing a mean of 347.5 days in the rivaroxaban group and 340.1 days in the warfarin group. RMST difference was 7.4 days (95%CI: −1.4 to 16.3; P_{noninferiority} <0.001) with no significant difference in major bleeding.¹

Geriatric Cardiology Focus

• Older adults ≥65 years made up about 35% of the participants and this was well balanced between the two groups.¹ It is unclear how many of these participants were ≥75 years. This is particularly important, given that most older adults will require anticoagulation based on their age alone. They are also more likely to be clinically complex and have a higher CHA₂DS₂-VASc score than the mean score in this trial, given the increased number of comorbidities with increasing age.
• Only about 19% of participants were randomized within 3 months of valve surgery.¹ Hence, in this non-US population of patients with atrial fibrillation and predominantly “chronic” mitral valve (MV) bioprostheses, a DOAC appears to be a reasonable alternative to warfarin. This may be particularly important in the older adults, where drug-drug interactions and the need for frequent international normalized ratio (INR) checks are particularly problematic.
• Baseline data on geriatric syndromes like frailty and polypharmacy, not captured, could aid the assessment of anticoagulation safety and efficacy in the older adult population. The loss of physiologic reserve in the frailty phenotype independently increases fall risk and mortality, and there is an increased risk of adverse effects from drug-drug interactions with polypharmacy.
• The appropriate dosing of rivaroxaban should be carefully considered in this population. Prior studies have shown non-recommended dosing is common. Older adults, particularly those ≥75 years are more susceptible to inappropriate dosing given their higher prevalence of renal dysfunction, especially with rivaroxaban that requires complex renal dose reduction criteria, and also in association with drug-drug interactions from polypharmacy. This is particularly important because inappropriate dosing of direct oral anticoagulants has been shown to be associated with an increase in all-cause mortality.^3-6
• It should also be noted that although rivaroxaban is noninferior to warfarin and is now being preferred over warfarin in atrial fibrillation patients, a recent study has shown that left atrial appendage occlusion has similar ischemic stroke prevention benefits but with a lower risk of major bleeding and mortality. Hence this may be considered as an alternative option long term in the older adult population, if appropriate candidates, given they are at a higher risk for stroke or bleeding, medication non-compliance and inappropriate medication dosing.^7,8
• In summary, the RIVER trial showed that rivaroxaban is a safe alternative to warfarin in this atrial fibrillation population,¹ however the extent to which this can be applied to the older adult population, particularly those ≥75-years, is yet to be determined. Further studies in the older adult population may be beneficial.
• Nevertheless, functional status, risk-benefit discussions, and goals of care discussions, including what matters most to these patients, need to be considered prior to initiating rivaroxaban or any other anticoagulants. The utilization of comprehensive geriatric assessments in a patient-centered shared decision-making process is imperative.

References

1. Guimarães HP, Lopes RD, de Barros e Silva PGM, et al. Rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve. N Engl J Med 2020;383:2117-26.
2. Otto CM, Nishimura RA, Bonow RO, 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:e72-e227.
3. Sanghai S, Wong C, Wang Z, et al. Rates of potentially inappropriate dosing of direct-acting oral anticoagulants and associations with geriatric conditions among older patients with atrial fibrillation: the SAGE-AF Study. J Am Heart Assoc 2020;9:e014108.
4. Saczynski JS, Sanghai SR, Kiefe CI, et al. Geriatric elements and oral anticoagulant prescribing in older atrial fibrillation patients: SAGE-AF. J Am Geriatr Soc 2020;68:147-54.
5. Bassand J-P, Apenteng PN, Atar D, et al. GARFIELD-AF: a worldwide prospective registry of patients with atrial fibrillation at risk of stroke. Future Cardiol 2021;17:19-38.
6. Camm AJ, Cools F, Virdone S, et al. Mortality in patients with atrial fibrillation receiving nonrecommended doses of direct oral anticoagulants. J Am Coll Cardiol 2020;76:1425-36.
7. Nielsen-Kudsk JE, Korsholm K, Damgaard D, et al. Clinical outcomes associated with left atrial appendage occlusion versus direct oral anticoagulation in atrial fibrillation. JACC Cardiovasc Interv 2021;14:69-78.
8. Freixa X, Schmidt B, Mazzone P, et al. Comparative data on left atrial appendage occlusion efficacy and clinical outcomes by age group in the Amplatzer^TM Amulet^TM Occluder Observational Study. Europace 2021;23:238-46.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Geriatric Cardiology, Valvular Heart Disease, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Geriatrics, Warfarin, International Normalized Ratio, Anticoagulants, Atrial Fibrillation, Atrial Flutter, Polypharmacy, Mitral Valve, Bioprosthesis, Prevalence, Geriatric Assessment, Brain Ischemia, Survival Rate, Intention to Treat Analysis, Atrial Appendage, Decision Making, Heart Valve Diseases, Stroke, Drug Interactions, Phenotype, Medication Adherence, Kidney Diseases, Patient-Centered Care, Patient Care Planning, Pharmaceutical Preparations, AHA Annual Scientific Sessions, AHA20

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