Advances in Neurocardiology: Focus on Anticoagulation for Valvular Heart Disease With and Without Atrial Fibrillation
2022; Lippincott Williams & Wilkins; Volume: 53; Issue: 12 Linguagem: Inglês
10.1161/strokeaha.122.039310
ISSN1524-4628
AutoresM. Edip Gurol, Luciano A. Sposato,
Tópico(s)Cardiac Arrhythmias and Treatments
ResumoHomeStrokeVol. 53, No. 12Advances in Neurocardiology: Focus on Anticoagulation for Valvular Heart Disease With and Without Atrial Fibrillation Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessArticle CommentaryPDF/EPUBAdvances in Neurocardiology: Focus on Anticoagulation for Valvular Heart Disease With and Without Atrial Fibrillation M. Edip Gurol and Luciano A. Sposato M. Edip GurolM. Edip Gurol https://orcid.org/0000-0002-2169-4457 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (M.E.G.). and Luciano A. SposatoLuciano A. Sposato Correspondence to: Luciano A. Sposato, MD, MBA, 339, Windermere Rd, Room A10-322, University Hospital, London, Ontario, Canada, N6G 5A5. Email E-mail Address: [email protected] https://orcid.org/0000-0001-6425-9343 Departments of Clinical Neurological Sciences, Anatomy and Cell Biology, and Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry (L.A.S.), Western University, London, ON, Canada. Heart and Brain Laboratory (L.A.S.), Western University, London, ON, Canada. Robarts Research Institute (L.A.S.), Western University, London, ON, Canada. Originally published7 Nov 2022https://doi.org/10.1161/STROKEAHA.122.039310Stroke. 2022;53:3763–3768Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 7, 2022: Ahead of Print The prevalence of valvular heart disease (VHD) is increasing steadily globally because of the aging population.1 Most physicians managing patients with stroke are familiar with stroke prevention in atrial fibrillation (AF), patent foramen ovale, and other cardioembolic diseases. However, they are less familiar with the management of antithrombotic agents in different types of VHD. Seven Phase II and Phase III randomized clinical trials (RCTs) of direct oral anticoagulants (DOACs) in different types of VHD have been published since 2020 (Figure).2–10 This article updates current evidence from RCTs on the use of DOACs in patients with mechanical valve replacement, moderate/severe mitral stenosis, bioprosthetic valves, and transcatheter aortic valve replacement (TAVR) from the perspective of stroke physicians. Although stroke end points were reported in most RCTs included in this update, none of the studies focused exclusively on patients with a prior cerebrovascular event. Therefore, our analysis of current evidence is based on populations with and without a prior stroke or transient ischemic attack (TIA). Ongoing RCTs are discussed in the Supplemental Material.Download figureDownload PowerPointFigure. Evidenced-based anticoagulant management in valvular heart disease. AF indicates atrial fibrillation; AHA, American Heart Association; DAPT, dual antiplatelet therapy with aspirin and clopidogrel; NCB, net clinical benefit; RCT, randomized controlled trial; and TE, thromboembolic. *Significant for any bleeding but not for major bleeding.Mitral StenosisMitral stenosis is a significant cause of heart disease globally and can be classified into 2 main types, rheumatic and calcific. Rheumatic mitral stenosis is predominant in young individuals living in low- and middle-income countries, whereas nonrheumatic calcific mitral stenosis is more common among elderly individuals in higher income countries. There are no reliable estimates of stroke risk in patients with mitral stenosis without AF not receiving anticoagulants. Stroke risk in patients with mitral stenosis and AF not receiving anticoagulants ranges between of 5 to 6 per 100 patient-years, similar to the 6 per 100 patient-years reported in the placebo arms of vitamin K antagonists (VKA) RCTs for nonvalvular AF.11 One large RCT and a small pilot RCT compared DOACs and VKAs in patients with rheumatic VHD, predominantly mitral stenosis. The INVICTUS Phase III trial (Investigation of Rheumatic AF Treatment Using Vitamin K Antagonists' Rivaroxaban or Aspirin Studies) included 4531 patients with rheumatic valvular disease and AF or atrial flutter.2 Eighty-two percent of the cohort had moderate/severe mitral stenosis.2 To be included, patients had to fulfill at least one of the following criteria: a CHA2DS2-VASc score ≥ 2 points, a mitral-valve area <2 cm2, left atrial spontaneous echo contrast, or a left atrial thrombus. The study evaluated whether rivaroxaban 20 mg daily was noninferior to VKA in preventing the composite of stroke, systemic embolism, myocardial infarction, and death from a vascular or unknown cause. INVICTUS was terminated earlier because the primary question had been satisfactorily answered as per a pre-planned blinded interim analysis. The rivaroxaban arm showed a 25% higher rate of the composite of cardiovascular events and death (primary end point) than VKA, with 29% increase in vascular deaths, a 53% higher ischemic stroke rate, and no difference in major bleeding events. Higher rates of death (HR, 1.23 [95% CI, 1.09–1.40]) were observed in the rivaroxaban arm. Additionally, the proportion of patients with permanent discontinuation at the end of the study was 22.6% for rivaroxaban versus 6.0% for VKA. RISE-MS (Rivaroxaban in Mitral Stenosis) was an open-label, single-center, pilot RCT including 37 patients with moderate or severe mitral stenosis and AF.3 The primary composite end point was stroke or systemic embolism at 1 year. The study was underpowered for identifying significant differences in the primary outcome. There were no primary outcome or major bleeding events in either study arm.Mechanical Valve ReplacementPatients with a mechanical valve exhibit a substantial risk of stroke and systemic embolism, thus anticoagulation with VKAs has been the standard of care for this population. In a Swedish population-based study of patients with mechanical valve replacement on VKAs, the rate of stroke or thromboembolism was 1.36 100 patient-years.12 Importantly, the risk of major bleeding was more than twice higher (3.20 patient-years). Two RCTs compared DOACs to VKAs in patients with mechanical mitral valve replacement, with and without AF. The RE-ALIGN trial (Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement) aimed to validate a novel dabigatran dosing scheme, compared with VKAs, for preventing thromboembolic events in patients with mitral or aortic mechanical valve replacement, with and without AF.4 Dabigatran was administered in doses of 150, 220, or 300 mg twice daily, adjusted to obtain a plasma level ≥50 ng/ml. Since this was a Phase II trial, the primary outcome was the trough plasma level of dabigatran. RE-ALIGN was terminated prematurely after enrolling 252 patients, due to excessive thromboembolic and hemorrhagic events in the dabigatran arm (Table 1).4 There were 9 ischemic strokes in the dabigatran arm (5%) and none in the warfarin group (0%). An exhaustive analysis of this trial can be found elsewhere.13 The RE-ALIGN study findings resulted in a black box warning issued by FDA against the use of DOACs in patients with mechanical heart valve. The RIWA study (Rivaroxaban Versus Warfarin in Patients With Mechanical Heart Valves) was a small open-label, proof-of-concept trial.5 It randomized 44 patients to rivaroxaban 15 mg daily versus dose-adjusted warfarin. There were no differences in thromboembolic events and ischemic stroke, and there were no bleeding events in either arm (Table 1). This study was underpowered to find significant differences between treatment arms. Two ongoing clinical trials are comparing DOACs versus warfarin in patients with mechanical aortic valve replacement. The RENOVATE trial (Randomized, Evaluation of Long-term Anticoagulation With Oral Factor Xa Inhibitor Versus Vitamin K Antagonist After Mechanical Aortic Valve Replacement) plans to enroll 1300 participants with mechanical aortic valve replacement to rivaroxaban 20 mg daily versus VKA (NCT04258488). The primary efficacy end point is the composite of cardiac death, valve thrombosis, valve-related thromboembolic event, major bleeding, and clinically relevant nonmajor bleeding at 1 year.Table 1. Summary of Main Randomized Controlled Trials of Anticoagulants in Patients With Valvular Heart DiseaseInterventionsPrior stroke or TIAAtrial fibrillation or flutterPrimary efficacy end pointPrimary safety end pointIschemic stroke riskModerate/severe mitral stenosisWith AFINVICTUS (2022)2Rivaroxaban 20 mg/d (n=2275)VKA (n=2256)652/4531 (14.4%)4531/4531 (100%)Mean time until stroke, SE, MI, vascular/U-C death*Major bleedingHR, 1.53 (95%CI, 1.06–2.20)RMST difference, −76 d (95% CI, −121 to −31) days; P<0.001 for superiorityHR, 0.76 (95% CI, 0.51–1.15)HR, 1.25 (95% CI, 1.10–1.41)With AFRISE-MS (2022)3Rivaroxaban 20 mg/d (n=18)VKA (n=19)NA37/37 (100%)Ischemic stroke or SEMajor bleedingNo eventsNo eventsNo eventsAny mechanical valve replacementWith and without AFRE-ALIGN (2013)4Dabigatran 150, 220, or 300 mg twice daily (n=168)Warfarin (n=84)17/252 (6.8%)71/252 (28.2%)Stroke, TIA, SE, MI, death (secondary composite end point)Major bleeding9 (5%) for dabigatran and 0 for VKA (0%)HR, 1.94 (95% CI, 0.64–5.86)HR, 1.76 (95% CI, 0.37–8.46)RIWA (2021)5Rivaroxaban 15 mg/d (n=23)Warfarin (n=21)10/44 (22.7%)12/44 (27.3%)Ischemic stroke, TIA, SBI, SEMajor bleedingRR, 0.90 (95%CI, 0.78–1.03)RR, 0.27 (95% CI, 0.02–2.85)No events in either groupMitral or aortic bioprosthetic valveWith AFRIVER (2020)6Rivaroxaban 20 mg/d (n=500)Warfarin (n=505)47/1005 (4.5%)1005/1005 (100%)Mean time until death, stroke, TIA, valve thrombosis, SE, hospitalization for HF, or major bleedingMajor bleeding was part of the primary efficacy end pointHR, 0.43 (95%CI, 0.11–1.66)RMST difference, +7.4 d (95% CI, −1.4–16.3); P 30 seconds after successful TAVR for severe aortic stenosis.8 The study included 1426 patients, and the primary efficacy outcome was the composite of death from any cause, myocardial infarction, ischemic stroke, systemic embolism, valve thrombosis, or major bleeding. Edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio for the composite primary outcome but showed a 40% higher rate of major bleeding than VKA (Table 1). There were no differences in the rate of ischemic stroke between groups. In the ATLANTIS trial (Antithrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Transaortic Valve Implantation for Aortic Stenosis), 1500 patients with a recent (>2 weeks) TAVR were randomized to receive open-label apixaban 5 mg twice daily versus standard of care.9 The trial was organized in 2 strata. Stratum 1 included patients with an indication for anticoagulation, and the standard of care arm was a VKA. In this stratum, 84% of the participants had AF (Table 1). Stratum 2 included patients without an indication for anticoagulation, and the standard of care group in this stratum received antiplatelet agents. The primary outcome was the composite of death, myocardial infarction, stroke or TIA, systemic embolism, intracardiac or valve thrombosis, deep vein thrombosis or pulmonary embolism, or life-threatening, disabling, or major bleeding at 1 year. The primary safety end point was the composite of fatal, life-threatening, disabling, or major bleeding. Overall, apixaban was not superior to the standard-of-care antithrombotic treatment in the rate of the primary efficacy outcome at 1 year in the whole cohort, without significant interactions for study strata (concurrent need for anticoagulation). Apixaban met the non-inferiority threshold for the primary end point. There were no differences in the rates of major bleeding and stroke or TIA between treatment arms in the whole cohort (Table 1). However, in patients without an indication for anticoagulation, apixaban resulted in higher non-cardiovascular mortality compared with antiplatelet therapy (HR, 2.99 [95% CI, 1.07–8.36]). The GALILEO trial (Global Study Comparing a Rivaroxaban-Based Antithrombotic Strategy to an Antiplatelet-Based Strategy After Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes) included patients with a TAVR and no indication for anticoagulation.10 The study randomized 1644 patients to rivaroxaban 10 mg daily (plus aspirin 75 to 100 mg daily during the first 3 months) versus antiplatelet therapy (aspirin 75 to 100 mg daily+clopidogrel 75 mg daily for the first 3 months).10 The primary efficacy outcome was the composite of death from any cause or thromboembolic events, including any stroke, myocardial infarction, symptomatic valve thrombosis, systemic embolism, deep-vein thrombosis, or pulmonary embolism. The primary safety outcome was the composite of life-threatening, disabling, or major bleeding. The study was terminated prematurely because rivaroxaban resulted in a higher risk of death or thromboembolic complications and a non-significantly higher risk of bleeding than antiplatelets. There were no differences in the risk of ischemic stroke between treatment arms.Other Valvular AbnormalitiesPatients with other valvular abnormalities, including mitral or aortic insufficiency, and aortic and mild mitral stenosis, were included in RCTs comparing DOACs versus VKAs in patients with non-valvular AF.13 These trials were underpowered to evaluate clinical outcomes in patients with VHD, but the primary efficacy and safety outcome in patients with valvular abnormalities did not differ significantly from the overall study populations.13In summary, the antithrombotic management of patients with VHD is complex and often influenced by comorbid conditions, mainly AF.16,17 In general, VKAs should be used in patients with rheumatic moderate to severe mitral stenosis, mechanical valve replacement with or without AF, and sometimes, during the first months after surgical or transcatheter bioprosthetic valve replacement in patients without AF. DOACs may be used in patients with bioprosthetic valves who have AF, although they have never shown superiority to VKAs. Finally, patients with bioprosthetic valves or TAVR without AF or other concomitant clear indication for anticoagulants (such as occasional hypercoagulable state), antiplatelet monotherapy is used in the long run.Article InformationSources of FundingDr Gurol is supported by NIH grants (NINDS/NIA R01NS11452, NS 083711, 5R01NS096730-04, 5R01AG026484). Dr Sposato is supported by the Kathleen & Dr Henry Barnett Research Chair in Stroke Research (Western University, London, ON, Canada) and the Edward and Alma Saraydar Neurosciences Fund (London Health Sciences Foundation).Supplemental MaterialTables S1–S2Supplemental search strategySupplemental description of trialsNonstandard Abbreviations and AcronymsATLANTISAntithrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Transaortic Valve Implantation for Aortic StenosisDAWADabigatran Versus Warfarin After Bioprosthetic Valve Replacement for the Management of Atrial Fibrillation PostoperativelyDOACdirect oral anticoagulantENVISAGE-TAVI AFEdoxaban Versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation–Atrial FibrillationGALILEOGlobal Study Comparing a Rivaroxaban-Based AntiThrombotic Strategy to an Antiplatelet-Based Strategy After Transcatheter Aortic Valve Replacement to Optimize Clinical OutcomesINVICTUSInvestigation of Rheumatic AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin StudiesPROACT XaProspective, Randomized, Active (Warfarin) Controlled, Parallel-Arm Clinical Trial to Determine if Participants With an On-X Aortic Valve Can Be Maintained Safely and Effectively on ApixabanRE-ALIGNPhase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve ReplacementRISE-MSRivaroxaban in Mitral StenosisRIVERRivaroxaban for Valvular Heart Disease and Atrial FibrillationRIWARivaroxaban Versus Warfarin in Patients With Mechanical Heart ValvesVHDvalvular heart diseaseVKAvitamin K antagonistDisclosures Dr Gurol's hospital received research grants from AVID, Pfizer, and Boston Scientific Corporation. Dr Sposato received speaker/consulting honoraria from Boehringer Ingelheim, Pfizer, Bayer, Gore, and Daiichi Sankyo; research grants from Boehringer Ingelheim and Bayer; member of the Editorial Board of Neurology, Stroke, and JAHA; co-editor, Neurocardiology section of Stroke. Guest Associate Editor, JAHA.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.122.039310.For Sources of Funding and Disclosures, see page 3768.Correspondence to: Luciano A. Sposato, MD, MBA, 339, Windermere Rd, Room A10-322, University Hospital, London, Ontario, Canada, N6G 5A5. Email luciano.sposato@LHSC.on.caReferences1. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP, et al; GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group. 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Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails December 2022Vol 53, Issue 12 Advertisement Article Information Metrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.122.039310PMID: 36337056 Originally publishedNovember 7, 2022 Keywordsatrial fibrillationanticoagulationdirect oral anticoagulantsheart and brainstroke preventionPDF download Advertisement Subjects Atrial Fibrillation
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