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Overestimation of Stroke Risk in Rheumatic Mitral Stenosis and the Implications for Oral Anticoagulation

2020; Lippincott Williams & Wilkins; Volume: 142; Issue: 18 Linguagem: Inglês

10.1161/circulationaha.120.050347

1524-4539

Ganesan Karthikeyan, Stuart J. Connolly, Salim Yusuf,

Cardiac Valve Diseases and Treatments

HomeCirculationVol. 142, No. 18Overestimation of Stroke Risk in Rheumatic Mitral Stenosis and the Implications for Oral Anticoagulation Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBOverestimation of Stroke Risk in Rheumatic Mitral Stenosis and the Implications for Oral Anticoagulation Ganesan Karthikeyan, MD, DM, MSc Stuart J. Connolly, MD Salim YusufDPhil Ganesan KarthikeyanGanesan Karthikeyan Ganesan Karthikeyan, MD, DM, MSc, 24, Department of Cardiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. Email E-mail Address: [email protected] https://orcid.org/0000-0002-2073-2917 Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India (G.K.). , Stuart J. ConnollyStuart J. Connolly Population Health Research Institute, McMaster University, Hamilton, Canada (S.J.C., S.Y.). , Salim YusufSalim Yusuf Population Health Research Institute, McMaster University, Hamilton, Canada (S.J.C., S.Y.). Originally published2 Nov 2020https://doi.org/10.1161/CIRCULATIONAHA.120.050347Circulation. 2020;142:1697–1699Rheumatic heart disease (RHD) is an important cause of stroke in low- and middle-income countries. About 80% of the strokes in patients with RHD occur in patients with mitral stenosis (MS) and atrial fibrillation (AF). The pathophysiology and risk markers of stroke in patients with MS and AF are well recognized, but because of a paucity of good quality data, the optimal anticoagulation strategy for stroke prevention in these patients is not known.Patients with hemodynamically overt MS and AF were believed to be at very high risk of stroke, and so it was considered unethical to include them in the placebo-controlled trials of anticoagulation with vitamin K antagonists (VKA) in AF. Therefore, recommendations for anticoagulation with VKAs are based on the biological plausibility of benefit, limited observational data, and indirect evidence from trials of nonvalvular AF. The recent trials of direct oral anticoagulants (DOAC) in AF excluded patients with significant MS, mainly because of their noninferiority design. This is because, in a noninferiority trial, it is critical that the direction and magnitude of effect of the standard treatment remain similar to that in the earlier placebo-controlled trials (assay sensitivity and constancy assumptions). Enrolling patients similar to those in the placebo-controlled trials is one of the ways of preserving the effectiveness of standard treatment. Consequently, the DOAC trials restricted enrollment to patients with nonvalvular AF. As a result, there are no randomized controlled trial data on the safety and effectiveness of DOACs in patients with moderate to severe MS and AF. Current practice guidelines therefore recommend against their use in these patients.We believe that a flawed interpretation of the available data has led to substantial overestimation of stroke risk in this population. The absolute stroke risk in patients with MS and AF may in fact be similar to (if not lower than) patients with nonvalvular AF.Stroke risk in rheumatic mitral stenosis in atrial fibrillationMuch of the data on stroke-risk in MS and AF is derived from retrospective studies that were done in high-income countries several decades ago. The crude annualized stroke and systemic embolism risk estimated from the 2 largest retrospective studies of MS and AF was 5.2% per year in 1, and 2.4% per year in another. Anticoagulation was used in fewer than half the patients in either study. Estimates of stroke risk among unanticoagulated patients are in the range of 5 to 6 per 100 patient-years, similar to that seen in the placebo arms of the VKA trials of nonvalvular AF (6 per 100 patient-years). In the more recently conducted prospective studies,1–3 the risk of stroke or systemic embolism ranged between 0.4 and 4 per 100 patient-years among anticoagulated patients. The higher rates were seen in those with previous history of systemic embolism (Table).Despite these data, several authors maintain that patients with MS have "the highest risk of thromboembolism," perhaps influenced by results of subgroup analyses involving small numbers of patients from the retrospective studies (for example, in 1 retrospective study, stroke recurred at a rate of 7.3% per year among 32 unanticoagulated patients).Another reason for assuming that patients with MS and AF have a very high risk of stroke may be because of a focus on relative risks rather than absolute risks. For example, Wolf et al reported that the rate of stroke in patients with RHD and AF was nearly 18-fold higher than an age, sex, and hypertension matched population without AF (based on just 7 events among 154 patients).4 However, the absolute risk of stroke was 4.5 per 100 patient-years, similar to the risk in nonvalvular AF (4.2 per 100 patient-years). This high stroke risk relative to a risk-adjusted population has been cited extensively in the literature, without emphasizing the similar absolute risk (which guides clinical decision-making), and has influenced clinicians' and researchers' beliefs about stroke risk in patients with MS.Implications for anticoagulationOn the basis of pathophysiologic considerations, effective anticoagulation is likely to reduce stroke risk in patients with MS and AF. But the quality of anticoagulation with VKAs is poor in developing countries with fewer than 50% of patients receiving a prescription for a VKA, and only about 30% to 50% of patients maintaining a therapeutic international normalized ratio. Moreover, given that stroke risk in patients with MS and AF may be in the lower range of the risk spectrum, the risk–benefit trade-off with anticoagulation with VKAs may not be uniformly favorable.The DOACs achieve more consistent levels of anticoagulation and are likely to be at least as effective as VKAs, and may be more effective when anticoagulation quality with VKAs is poor. Moreover, despite their higher acquisition cost compared to VKAs, DOACs may be cost-effective even in low-resource settings, where the direct and indirect costs of frequent international normalized ratio monitoring may be prohibitive. There is promising evidence of effectiveness of the DOACs in subgroups of patients with valve disease in the large DOAC randomized controlled trials. However, the data of efficacy and safety of the DOACs, derived from these patients with mild-moderate valve disease (mainly mitral regurgitation and aortic valve disease), may not apply to those with RHD and MS. Patients with rheumatic MS are typically 10 to 30 years younger, and are much less likely to have hypertension, diabetes, or atherosclerotic vascular disease. In the subset of patients with mild to moderate valve disease enrolled in the DOAC trials, hypertension was present in nearly 90%, diabetes in 30%, and a history of myocardial infarction in more than one quarter of patients.5 In contrast, in a large ongoing randomized controlled trial of patients with MS and AF, the proportions of participants with hypertension, diabetes, and previous myocardial infarction were 23%, 6%, and 0.5%, respectively.5 Therefore, the determinants of stroke risk in this population may be distinct, with factors (such as the severity of MS) that are not affected by anticoagulation playing a greater role.Given these considerations, large randomized trials of patients with moderate to severe MS and AF are needed to make definitive recommendations regarding the efficacy and safety of DOACs. Guideline panels should therefore acknowledge the need for more data, and refrain from making strong recommendations against DOACs in moderate to severe MS and AF, until such trials are completed. It is important that the cardiology community does not prematurely abandon a potentially useful (and perhaps safer and more effective) treatment, before good quality data can be generated.Table. Risk of Stroke or Systemic Embolism in Patients With Mitral Stenosis and Atrial Fibrillation in Recent StudiesStudy, year, (region/country)Number of patientsAverage age (years)Average duration of follow-up (years)Rate of stroke or systemic embolism (per 100 patient-years)Proportion on VKA (%)/% of patients with INR 2–3Chiang et al, 1998 (South Korea)402483.13.948*/NRPengo et al, 2003 (Italy)107634.50.4100/74, 51†Perez-Gomez et al, 2006 (Spain)311632.91.4 (4.1)‡100/67‡REMEDY, 2016 (Africa, India, Yemen)554362.01.8§68/22AF indicates atrial fibrillation; INR, international normalized ratio; MVA, mitral valve area; NR, not reported; and VKA, vitamin K antagonist.* The proportion is for all patients in the study including those without AF.1† While all patients in the study by Pengo et al2 received VKAs, patients were randomized to a target INR of 2 or 3; the percentages refer to the proportion of patients with INR 1.5–2.5 (n=52), and INR 2.5–3.5 (n=55), respectively.‡ In the study by Perez-Gomez et al, 3 147 patients received a combination of VKA with Triflusal (a salicylic acid analogue). Stroke rate and proportion in therapeutic range are for the remaining patients who received anticoagulation alone. The higher rate is for patients with a previous stroke or systemic embolism. The target INR range in patients on VKA plus Triflusal was 1.4-2.4, with 75% of patients being in that range.§ Rate is for patients with AF and MVA ≤2 cm2 (Ganesan Karthikeyan, MD, DM, MSc, unpublished data, 2012) in the Rheumatic heart disease Global Registry (REMEDY).AcknowledgmentThe authors thank Professor Mpiko Ntsekhe MD, PhD, University of Cape Town, Cape Town, South Africa, for comments on an earlier version of the article.DisclosuresThe authors are the key leads of the INVICTUS-VKA (The INVestIgation of rheumatiC atrial fibrillation Treatment Using VKAs and rivaroxaban) trial (NCT02832544) which is funded through a grant from Bayer AG (Germany). Dr Connolly reports grants and personal fees from Bayer, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Portola, and grants and personal fees from Daiichi Sankyo, outside of the scope of the submitted work. Dr Yusuf reports grants and personal fees from Bayer for the conduct of the INVICTUS trial. Dr Karthikeyan does not have any conflicts of interest.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circGanesan Karthikeyan, MD, DM, MSc, 24, Department of Cardiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. Email [email protected]comReferences1. Chiang CW, Lo SK, Ko YS, Cheng NJ, Lin PJ, Chang CH. Predictors of systemic embolism in patients with mitral stenosis. A prospective study.Ann Intern Med. 1998; 128:885–889. doi: 10.7326/0003-4819-128-11-199806010-00001CrossrefMedlineGoogle Scholar2. Pengo V, Barbero F, Biasiolo A, Pegoraro C, Noventa F, Iliceto S. Prevention of thromboembolism in patients with mitral stenosis and associated atrial fibrillation: effectiveness of low intensity (INR target 2) oral anticoagulant treatment.Thromb Haemost. 2003; 89:760–764.CrossrefMedlineGoogle Scholar3. Pérez-Gómez F, Salvador A, Zumalde J, Iriarte JA, Berjón J, Alegría E, Almería C, Bover R, Herrera D, Fernández C. Effect of antithrombotic therapy in patients with mitral stenosis and atrial fibrillation: a sub-analysis of NASPEAF randomized trial.Eur Heart J. 2006; 27:960–967. doi: 10.1093/eurheartj/ehi667CrossrefMedlineGoogle Scholar4. Wolf PA, Dawber TR, Thomas HE, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study.Neurology. 1978; 28:973–977. doi: 10.1212/wnl.28.10.973CrossrefMedlineGoogle Scholar5. Karthikeyan G, Connolly SJ, Ntsekhe M, Benz A, Rangarajan S, Lewis G, Yun Y, Sharma SK, Maklady F, Elghamrawy AE, et al.; INVICTUS Investigators. The INVICTUS rheumatic heart disease research program: rationale, design and baseline characteristics of a randomized trial of rivaroxaban compared to vitamin K antagonists in rheumatic valvular disease and atrial fibrillation.Am Heart J. 2020; 225:69–77. doi: 10.1016/j.ahj.2020.03.018CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails November 3, 2020Vol 142, Issue 18Article InformationMetrics Download: 1,557 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.050347PMID: 33136507 Originally publishedNovember 2, 2020 Keywordsstrokerheumatic heart diseaseatrial fibrillationanticoagulantsmitral valve stenosisPDF download SubjectsRheumatic Heart DiseaseIschemic StrokeValvular Heart DiseaseAtrial Fibrillation