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CLINICAL STATEMENTS AND GUIDELINES

January 2, 2024 Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 e56

Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

6.8.5 AF in VHD

Recommendations for AF in VHD Referenced studies that support the recommendations are summarized in the Online Data Supplement. COR LOE Recommendations

1 B-R 1 In patients with rheumatic mitral stenosis or mitral

stenosis of moderate or greater severity and history of AF, long-term anticoagulation with warfarin is recommended over DOACs, independent of the CHA2DS2-VASc score to prevent cardiovascular events, including stroke or death.1

1 B-NR 2 In patients with AF and valve disease other than

moderate or greater mitral stenosis or a mechanical heart valve, DOACs are recommended over VKAs.2–8

Synopsis At least one-third of patients with AF have some degree of VHD. Patients with AF and VHD have a higher prevalence of stroke and systemic thromboembolism than those patients with AF without VHD.9 Patients with VHD and AF should be evaluated for risk of thromboembolic events and treated with oral anticoagulation if they are at high risk or if they have significant mitral stenosis or a mechanical heart valve. VKAs are the anticoagulation drugs of choice for patients with rheumatic mitral stenosis, mechanical heart valves, and new-onset AF within 3 months after mechanical aortic or mitral valve surgery.10 Recommendation-Specific Supportive Text 1.	 Historical data have reported that in patients

with mitral stenosis and AF, stroke risk was nearly 18-fold higher than an age-, sex-, and hypertension-matched population without AF.11 More recently, stroke or systemic embolism rates ranged between 0.4 and 4 per 100 patient-years among anticoagulated patients and were highest in those with previous embolism. Warfarin is generally prescribed, but it has been questioned whether a DOAC may be an alternative. A retrospective cohort study from Korea examined 2230 individuals with mitral stenosis and AF who were prescribed either warfarin or a DOAC, using propensity matching on 10 clinical variables. Thromboembolic events in the DOAC group were 2.22% per year compared with 4.19% per year in the warfarin group (HR, 0.28 [95% CI, 0.18-0.45]).12 However, in the INVICTUS (The Investigation of Rheumatic AF Treatment Using VKAs, Rivaroxaban or Aspirin Studies) RCT,1 patients with AF, rheumatic heart disease, and mitral stenosis had a mean survival time to a primary outcome event of stroke, systemic embolism, MI, or death from vascular or unknown cause of 1 675 days if treated with a VKA compared with 1 599 days if with rivaroxaban (difference, –76 days [95% CI, –121 to –31]; P<0.001). 2.	 Although patients with moderate to severe mitral

stenosis or mechanical valve were excluded from DOAC trials, other forms of VHD were allowed, such as aortic stenosis or mitral regurgitation. Bioprosthetic valves and valve repair were allowed in the edoxaban (ENGAGE AF) and apixaban (ARISTOTLE) trials, and valve repair in the rivaroxaban (ROCKET AF) trial. A systematic review13 of patients with VHD (other than moderate to severe mitral stenosis or mechanical valve) concluded that DOACs were safe. A meta-analysis confirmed that DOACs decreased the risk of stroke/systemic embolism compared with warfarin in patients with (HR, 0.70 [95% CI, 0.58-0.86]) and without VHD (HR, 0.84 [95% CI, 0.75-0.95]).14 However, for patients with mechanical heart valves,15 the RE-ALIGN (Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement)10 trial was halted during phase II after enrolling 252 subjects due to increased thromboembolism and bleeding in the dabigatran arm. PROACT Xa (A Trial to Determine if Participants with an On-X Aortic Valve Can be Maintained Safely on Apixaban) was also terminated early due to higher thromboembolic events with apixaban in patients who were >3 months after mechanical On-X aortic valves.

Table 19.  Recommended Doses of Currently Approved DOACs According to Renal Function

CrCl (mL/min)

DOAC >95 51-95 31-50 15-30 <15 or on dialysis Apixaban 5 or 2.5 mg twice daily* 5 or 2.5 mg twice daily* 5 or 2.5 mg twice daily* 5 or 2.5 mg twice daily* 5 or 2.5 mg twice daily* Dabigatran 150 mg twice daily 150 mg twice daily 150 mg twice daily 75 mg twice daily Contraindicated Edoxaban Contraindicated 60 mg once daily 30 mg once daily 30 mg once daily Contraindicated Rivaroxaban 20 mg once daily 20 mg once daily 15 mg once daily 15 mg once daily 15 mg once daily† Note that other, nonrenal considerations such as drug interactions may also apply. The gray area indicates doses not studied in the pivotal clinical trials of these agents. *If at least 2 of the following are present: serum creatinine ≥1.5 mg/dL, age ≥80 y, or body weight ≤60 kg, the recommended dose is 2.5 mg twice daily. The ARIS- TOTLE trial excluded patients with either a creatinine of >2.5 mg/dL or a calculated CrCl <25 mL/min. †Rivaroxaban is not recommended for other indications in patients with a CrCl <15 mL/min, but such a recommendation is not made for the AF indication. However, pharmacokinetic data are limited. AF indicates atrial fibrillation; ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; CrCl, creatinine clearance; and DOAC, direct oral anticoagulant.

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