DOACs may reduce thromboembolic events in patients with mitral stenosis and AF

Outcomes of Direct Oral Anticoagulants in Patients With Mitral Stenosis

Literature - Kim JY, Kim S-H, Myong J-P et al. - JACC 2019;73:1123–31

Introduction and methods

Direct oral anticoagulants (DOACs) effectively reduce thromboembolic events in patients with AF, but AF patients with mitral stenosis or mechanic prosthetic heart valves have been excluded from trials [1-5], leaving warfarin as the only oral anticoagulant option for these patients. Mitral stenosis combined with AF increased risk of stroke >20 times, likely due to stasis in the left atrium [6]. Efficacy of warfarin in patients with mitral stenosis and AF can be reduced by the poor quality of therapy (quality of international normalized ratio control measured by time in therapeutic range), especially in developing countries [7].

Therefore, it is interesting to investigate the efficacy of DOACs in patients with mitral stenosis and AF. DOACs are used in these patients as some physicians are unclear of the definition ‘nonvalvular AF’ and others prescribe DOACs off-label in patients with mitral stenosis.

This study analyzed data of 2230 patients with AF and mitral stenosis who were prescribed oral anticoagulation for >3 weeks between February 2008 and January 2017. Medical records from the Health Insurance Review and Assessment Service of the Republic of Korea database were reviewed and a case-control analysis was performed using data of patients with off-label use of DOACs and those with propensity score matched warfarin use (1:1 ratio). Patients with a history of mitral valve surgery were excluded.

Primary outcome was defined as the first hospitalization with a diagnosis of an ischemic stroke or systemic embolism after 3 weeks of DOAC use. Safety endpoint was intracranial hemorrhage. Mean follow-up was 27 months.

Main results

  • There was a greater reduction in strokes or systemic embolisms the DOAC group (2.22%/year) than in the warfarin group (4.19%/year) (adjHR: 0.28; 95%CI: 0.18- 0.45, log-rank P<0.0001 for difference in cumulative incidence).
  • Incidence of intracranial hemorrhages was nonsignificant between groups (DOAC group: 0.49%/year, warfarin group: 0.93%/year; adjHR: 0.53; 95% CI: 0.22 to 1.26).
  • All-cause death was reduced in the DOAC group vs the warfarin group (3.45%/year vs 8.08%/year, adjHR:0.41; 95%CI:0.30-0.56, log-rank P<0.0001 for difference in cumulative incidence).

Conclusion

This study of insurance data showed that in patients with mitral stenosis and AF, use of DOACs resulted in reduced rates of thromboembolism compared to warfarin group, whereas DOACs and warfarin had similar efficacy in reducing hemorrhagic strokes. These findings justify randomized clinical trials to investigate the superiority of DOACs over warfarin in patients with mitral stenosis and AF.

Editorial comment

Giugliano and O’Gara first explain why use of DOACs in patients with AF and mitral stenosis or mechanical heart valve replacement is not supported in guidelines or by regulatory authorities: these patients were excluded from trials because they are at very high risk for thromboembolism without the use of anticoagulation and in addition, a phase 2 trial of dabigatran was prematurely stopped because of harm.

After summarizing the results they say that ‘given the paucity of information regarding the use of DOACs in patients with MS, these observational data are welcome and should be viewed as hypothesis-generating’. They do think though that some of the HRs are too optimistic (72% reduction in thromboembolic events, 59% reduction in mortality) compared to those seen in other studies, which is most likely due to confounding. One of the limitations of this study is that most likely a high number of patients received subtherapeutic levels of warfarin therapy and those with mitral valve surgery were excluded making it difficult to extrapolate these findings to patient groups with high level of time-in-therapeutic range with VKA or those who had prior valve surgery.

They list some of the differences between an observational analysis of insurance data and a randomized controlled trial (inclusion criteria, reporting on outcomes), and ‘agree with the authors and others that the time has come to answer this question with an adequately powered RCT with significant implications for the health of vulnerable populations’.

References

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.

2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.

3. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92.

4. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493–503.

5. Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation 2012;125:2298–307.

6. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–8.

7. Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008;118:2029–37.

8. Giugliano RP and O’Gara PT. DOACs in patients with mitral stenosis and atrial fibrillation -time for a randomized clinical trial. JACC 2019;73:132-34.

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