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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 2  |  Page : 40-45

Chronic mitral regurgitation: Does atrial fibrillation impact outcome in patients managed with medical therapy only?


1 Dr. Joe Nwiloh Heart Center, St. Joseph's Hospital, Adazi Nnukwu, Anambra State, Nigeria
2 Department of Medicine, University of Nigeria Teaching Hospital, Ituku Ozalla, Enugu State, Nigeria

Date of Web Publication15-Apr-2019

Correspondence Address:
Jonathan Nwiloh
Dr. Joe Nwiloh Heart Center, St. Joseph's Hospital, Adazi Nnukwu, Anambra State, Adazi Nnukwu, Anambra State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njct.njct_2_19

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  Abstract 


Background: The AHA/ACC guideline recommends surgery for symptomatic chronic severe mitral regurgitation or percutaneous mitral valve repair for high surgical risk or inoperable patients. Although atrial fibrillation (AF) is a known predictor of survival after either of these interventional procedures, its impact on the outcome of patients treated only medically is less well defined. Materials and Methods: This was a retrospective review of adult patients with chronic mitral regurgitation seen at our heart center from August 2014 to December 2017. Results: There were 102 patients, with a mean age of 58.4 ± 15.8 years and 51% were males. Major comorbidities were AF (58.8%), hypertension (HTN) (53.9%), pulmonary HTN (18.6%), and diabetes mellitus (10.8%). Sixty-seven (65.7%) patients had primary and 35 (34.3%) had secondary mitral regurgitation. Eighty-eight (86.3%) patients were in New York Heart Association Class 3/4, 92 (90.2%) in AHA/ACC Stages C/D, and 70 (68.6%) had left ventricular (LV) dysfunction with ejection fraction (EF) <60. Patients were subdivided into Group 1 – 60 (58.8%) patients with AF and Group 2 – 42 (41.2%) patients without AF. AF frequency was higher with primary or degenerative mitral regurgitation (PMR) versus secondary mitral regurgitation (SMR), 75% versus 25%, P = 0.031, whereas HTN was higher in SMR versus PMR, 77.1% versus 41.8%, P = 0.001. Four patients underwent mitral valve replacement and two patients implantable cardioverter defibrillator. All patients were treated with the AHA/ACC guideline-directed medical therapy (GDMT). All-cause mortality for Groups 1 and 2 was 25% and 14.3%, respectively, odds ratio was 2.0, and 95% confidence interval was 0.705–5.677, P = 0.285. Overall, Kaplan–Meier survival at 30 months was 63%, and log-rank analysis survival was 56% and 79% for Groups 1 and 2, respectively, P = 0.345. Conclusion: In a cohort of patients with chronic mitral regurgitation treated only medically with GDMT in a low-resource country, all-cause mortality and intermediate survival were comparable between AF and non AF patients.

Keywords: Atrial fibrillation, chronic mitral regurgitation, survival


How to cite this article:
Nwiloh J, Okechukwu U, Adiele K, Orumwense N, Oriaku U, Ezenwajiaku V. Chronic mitral regurgitation: Does atrial fibrillation impact outcome in patients managed with medical therapy only?. Niger J Cardiovasc Thorac Surg 2018;3:40-5

How to cite this URL:
Nwiloh J, Okechukwu U, Adiele K, Orumwense N, Oriaku U, Ezenwajiaku V. Chronic mitral regurgitation: Does atrial fibrillation impact outcome in patients managed with medical therapy only?. Niger J Cardiovasc Thorac Surg [serial online] 2018 [cited 2019 Sep 18];3:40-5. Available from: http://www.nigjourcvtsurg.org/text.asp?2018/3/2/40/256252




  Introduction Top


Valvular heart disease is one of the leading causes of heart disease after coronary artery disease in adults worldwide. In most of the low-income nations present in Africa, rheumatic fever is prevalent and remains a major public health challenge. Its sequela rheumatic valvular heart disease, therefore, is the top indication for open-heart surgery in both adolescents and adults. However, because of limited access to cardiac surgery in these low-resource countries, the overwhelming majority of patients are, therefore, generally only treated medically. Even in South Africa, with the most modern health-care system in Africa, less patients are been referred for valve surgery despite the high prevalence rate of rheumatic heart disease reported as 6.9/1000 Black schoolchildren in the Soweto study.[1],[2] Chronic mitral valve regurgitation is a recognized risk factor for the development of atrial fibrillation (AF). Several studies have demonstrated improved survival outcomes with mitral valve surgery and concomitant atrial ablation versus only valve repair/replacement in patients with AF.[3] However, in patients with chronic severe mitral regurgitation and associated AF managed medically as practiced in most resource-poor countries, there are limited outcome data.[4]


  Materials and Methods Top


The medical records of adult patients with chronic mitral regurgitation seen at our heart center from August 2014 to December 2017 were retrospectively reviewed. Mitral regurgitation was diagnosed by transthoracic echocardiogram using a General Electric Vivid S5 echo machine (GE Healthcare, Chicago, Lllinois, USA). Mitral regurgitation was graded qualitatively from 1+ to 4+ and quantitatively as mild, moderate, or severe using regurgitant volume (RV), regurgitant fraction (RF), and effective regurgitant orifice (ERO) criteria based on the 2014 American Heart Association (AHA)/American College of Cardiology (ACC) valve guidelines.[5] The values were calculated by the Android echoCalc (the official App of the British Society of Echocardiography). Severe mitral regurgitation was ERO ≥0.4 cm2, RV ≥60 ml, and RF ≥50%. LV systolic ejection fraction (EF) was calculated using M mode, except in heart failure patients with impaired systolic function where Simpson trace (biplane method) was utilized. The MR was also staged using the 2014 AHA/ACC valve guidelines. All patients were generally treated using the AHA/ACC guideline-directed medical therapy (GDMT) as outpatients, except for acute decompensated heart failure requiring hospitalization for stabilization. Among patients recommended for surgery or device therapy, only a few could afford to undergo open-heart surgery or implantable cardioverter defibrillator (ICD). Patients were followed up through clinic visits and telephone calls to them or their relatives. Mortality was recorded as death from any cause.

Statistical analysis

Descriptive statistics were used with categorical variables reported as frequencies and percentages and continuous variables as mean ± standard deviation. Univariate analysis by unpaired Student's t-test with two-tailed distribution was used for continuous variables, and Chi-square test or Fisher's exact test was used for categorical variables. Odds ratio was used to calculate the measure of association with an estimation of 95% confidence interval. Survival was computed using the Kaplan–Meier method. Log-rank survival analysis was used to compare survival between the two groups. P < 0.05 was considered statistically significant. Statistical analysis was performed using the SigmaPlot software, version 12.5 (Systat Software, Inc., San Jose, CA, USA).


  Results Top


There were 102 patients with roughly equal sex distribution. The most frequent comorbidities were AF 58.8%, systemic hypertension (HTN) 53.9%, and pulmonary HTN (pulmonary artery systolic pressure >50 mmHg) 18.6%. Majority of the patients (68.6%) had impaired left ventricular (LV) systolic function with ejection fraction <60%. The patients were subdivided into two analytic groups: Group 1 comprised 60 (58.8%) patients with AF and Group 2 comprised 42 (41.2%) patients without AF. There was no statistically significant difference in the baseline demographics between the two groups [Table 1]. Nearly 91.7% and 78.6% of patients were in the New York Heart Association (NYHA) Classes 3 and 4, whereas 75.0% and 59.5% had impaired LV systolic function in Groups 1 and 2, respectively. Primary or degenerative mitral regurgitation (PMR) was the most common etiology in 75% and 52.4% of patients in Groups 1 and 2, respectively, whereas 93.3% and 85.7% of patients in each group, respectively, were in AHA/ACC Stages C and D [Table 2]. On comparing MR etiology, patients with secondary mitral regurgitation (SMR) tendered to be older with higher percentage of HTN compared to PMR [Table 3]. Although treatment was based on GDMT, not all patients received all classes of medications or maximal recommended doses for a variety of reasons. Diuretic therapy was the mainstay of treatment in 86.7% and 95.2% of Group 1 and 2 patients, respectively. Angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) were prescribed in about three-quarters of both groups and beta blockers in roughly a third of both groups. Angiotensin receptor-neprilysin inhibitor (ARNI) was not locally available during the study period and so was not utilized. Anticoagulation with Coumadin® or antiplatelet therapy with clopidogrel was used in 31.7% and 21.4% of Group 1 and 2 patients, respectively [Table 4]. Among patients with PMR referred for possible surgical intervention, only four underwent mitral valve surgery due to financial constraints, and they were excluded from the Kaplan–Meier survival analysis. Two patients underwent device therapy with implantation of ICD, whereas no patient had cardiac resynchronization. Overall, all-cause mortality was 20.6% during the study period. Mortality was higher as expected in patients with Stages C and D [Table 5]. All-cause mortality was 25% (15/60) and 14.3% (6/42) in Groups 1 and 2, respectively. Odds ratio was 2.0 and 95% confidence interval was 0.705–5.677, P = 0.285. Kaplan–Meier survival analysis for only medically treated patients was 63% at 30 months [Figure 1]. Kaplan–Meier log-rank analysis was 56% and 79%, P = 0.345, for Group 1 and 2 patients, respectively, at 30 months [Figure 2].
Table 1: Baseline demographics of mitral regurgitation patients

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Table 2: Characteristics of mitral regurgitation

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Table 3: Comparison between primary and secondary mitral regurgitation patients

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Table 4: Pharmacological management

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Table 5: All-cause mortality based on ejection fraction and mitral regurgitation stage

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Figure 1: Kaplan–Meier survival analysis for medically treated patients.

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Figure 2: Kaplan–Meier log-rank analysis for atrial fibrillation versus nonatrial fibrillation patients.

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  Discussion Top


Mitral regurgitation is fairly common and is the leading cause of valvular heart disease in the United States, affecting more than 2 million people with increasing incidence with advancing age.[6] In Europe, mitral regurgitation was the second most common valvular disease requiring surgery after aortic stenosis in the Euro Heart Survey study.[7] Mitral regurgitation is usually classified as either primary or secondary. PMR results from intrinsic disease of the mitral valve leaflets or subvalvular apparatus, whereas secondary or functional mitral regurgitation is a disease of the left ventricle with ventricular remodeling from ischemic or nonischemic dilated cardiomyopathy resulting in leaflet tethering and malcoaptation of structurally normal valves. Over the last half-century, there has been a transition in the incidence of valvular heart disease from rheumatic to degenerative in the developed countries, while in low-income nations, rheumatic heart disease still remains the leading etiology. Furthermore, in the Western nations, valvular heart disease generally affects more of the older population compared to low-resource nations where the younger population is more commonly afflicted. Mitral regurgitation may go unrecognized and clinically silent for years until the insidious onset of symptoms or even the development of irreversible ventricular dysfunction. The natural history of severe mitral regurgitation from early series reported widely varying 5-year mortality rates ranging from 27% to 97%, perhaps due to poorly defined severity criteria.[8],[9] In a more recent series, Ling et al.[10] in a review of 229 patients treated medically with PMR found that the mortality rate was significantly higher than expected at 6.3% yearly compared to that of the US population. Another review of 456 patients with asymptomatic PMR treated medically had a 5-year all-cause mortality of 22% and cardiac mortality of 14%.[11] The present series consistent with the poor socioeconomic status of our population shows that about two-thirds of the patients had PMR predominantly from rheumatic valvular heart disease. Because of lower life expectancy averaging 52–54 years in most of the sub-Saharan Africa, many do not live long enough to develop degenerative valvular heart disease common in the developed nations. The rest of the patients had SMR which was predominantly from nonischemic dilated cardiomyopathy secondary to HTN as compared to mainly ischemic cardiomyopathy seen in the Western nations. Our patients with SMR were generally older than PMR patients, although it did not attain statistical significance. There were no observed differences in left atrial and ventricular dimensions and ejection fractions between PMR and SMR groups. HTN was more frequently associated with SMR compared to PMR patients, P = 0.001. HTN is a major cause of nonischemic cardiomyopathy and remains a major public health challenge needing more public education in low-resource nations. Many hypertensive patients go undiagnosed and even when diagnosed, many asymptomatic patients often neglect care or are noncompliant with their medications due to a false sense of security, while end-organ damage continues unabated silently. Majority of the patients in low-resource nations with mitral regurgitation, therefore, tend to present late with Stages C and D and often with severe LV systolic dysfunction. Atrial fibrillation, a known sequela of chronic severe mitral regurgitation, was present in about 59% of our patients and was more frequently associated with PMR than SMR, P = 0.031. In recent registries and reviews of mitral regurgitation, the incidence of AF has ranged from 31.7% to 67.7%,[12] whereas in a surgical series of patients undergoing mitral valve surgery, AF has been reported in 30%–50% and has been shown to be an independent predictor of postoperative survival and stroke.[3],[13] Coutinho et al. in a 20-year follow-up of 382 patients after mitral valve surgery for asymptomatic or mildly symptomatic PMR and preserved LV function observed poorer long-term outcome and event-free survival in patients with AF and pulmonary HTN.[14] Similarly, Kebler et al. reported on 355 patients with severe MR and either high surgical risks or considered inoperable who underwent transcatheter mitral clip implantation. They found that AF patients compared to non-AF patients had a significantly higher mortality and major adverse cardiovascular and cerebral events (MACCE) at 3-year follow-up. All-cause mortality was 50.3% and 32.2%, P = 0.032, cardiovascular death was 35.1% and 24.2%, P = 0.10, and MACCE was 66.7% and 46.7%, P = 0.003, in the AF and non-AF groups, respectively.[12] Another multi-institutional review reported on 618 patients who were either inoperable or high surgical risk with severe MR who underwent percutaneous mitral valve repair. There was no survival difference at 1 year between patients with AF and non-AF, 82% and 85%, P = 0.3, but at 5 years, there was a significant difference, 34% and 47%, P = 0.006, respectively.[15] In our series, there was no statistically significant difference in the baseline demographics of AF and non-AF patients. In the absence of a government-sponsored health insurance scheme, most of our patients who are indigents despite been in NYHA Class III or IV, and Stage C or D, could not undergo guideline-recommended interventional therapies. The current ACC/AHA guidelines recommend mitral valve surgery for symptomatic patients with severe chronic primary mitral regurgitation Stage D and LV EF >30 (Class 1 recommendation, level of evidence B). The treatment for SMR, however, remains controversial as mitral regurgitation adds volume overload to an already decompensated left ventricle consequently worsening the prognosis. Correcting MR, therefore, addresses only one component of the disease.[16] A recent Cardiothoracic Surgical Trials Network multi-institutional trial of 251 patients with severe ischemic secondary MR randomized to mitral valve annuloplasty repair versus chordal-sparing mitral valve replacement found no significant difference in LV reverse remodeling or survival at 12 months. Although there was no group difference in clinical outcomes, recurrence of moderate or severe mitral regurgitation was more in the repair than replacement groups (32.6% vs. 2.3%, P = 0.001).[17] Based on this study, the 2017 ACC/AHA guidelines suggest that it is reasonable to choose chordal-sparing mitral valve replacement over downsized annuloplasty in SMR NYHA 3 or 4, Stage D, and persistent symptoms despite GDMT for heart failure (class of recommendation 1, level of evidence B).[18] Only four of our patients underwent mitral valve surgery and two ICD implants due to financial constraints. GDMT medical therapy was, therefore, the only therapeutic option available for the majority of patients regardless of whether they met guideline criteria for mitral valve surgery. Percutaneous mitral valve repair is presently not available in Nigeria. Our inability to attain a higher rate of GDMT guidelines was multifactorial. Many patients with LV dysfunction presented with low baseline blood pressure and so, there was often reluctance to add vasodilator agents such as ACEI/ARBs and beta-blockers or attempt reaching maximal guideline doses. Furthermore, many patients were often fluid overloaded and needed diuretic therapy (incidentally, the cheapest affordable drug for the patients), which not infrequently further lowers their blood pressure. In addition, the cost of GDMT medications was unaffordable to some patients which resulted in sporadic compliance. Moreover, the costs of escalating the drug doses are uniformly higher and discourage compliance. Although ARNI is now available in the Nigerian market, it remains too expensive for a majority of patients, thus denying them its known survival benefits. Because these challenges were across board, there was no statistically significant difference in the percentage of the prescribed drug class between the AF and non-AF patients. Due to our largely indigent patient population, the current practice is not to initiate anticoagulation with the mere presence of AF. Patients are usually risk stratified, and higher risk groups offered either antiplatelet agents or anticoagulation. Younger patients without HTN, diabetes mellitus, etc., are less likely to be anticoagulated and mostly placed on aspirin or clopidogrel. Monitoring of chronic Coumadin therapy can be difficult in our environment as many patients either do not start or eventually stop compliance over time. All-cause mortality between the AF and non-AF groups at 30 months was 56% and 79%, P = 0.345, respectively. The lack of any significant difference between the two groups treated only medically could possibly be due to the smaller size and shorter duration of follow-up compared to the observed differences seen in the series with patients who underwent surgical mitral valve repair/replacement or percutaneous transcatheter mitral valve repair. However, another plausible explanation could be that medical therapy alone may have no major impact on the natural history of severe MR (Stages C and D present in 92% of our patients) regardless of the presence or absence of AF. The ventricles may be so severely damaged that, without a procedure to reduce the severity of MR and LV volume overload, the outcome will be uniformly unsatisfactory. While surgery is beneficial for PMR, its role for SMR has, however, not been validated in clinical trials and its benefits remain unclear.[16] The current guidelines state that GDMT and device therapy with cardiac resynchronization can help reduce the severity of SMR (Class 1 recommendation, level of evidence A). Primary care physicians in low-resource nations need better education to refer patients with uncontrolled HTN, heart murmurs, and heart failure symptoms to specialist cardiologists (where available) for baseline echocardiogram. Early detection of MR and institution of appropriate GDMT treatment may delay or avoid progression and improve outcomes. In addition, both primary and specialist physicians need to be educated against overaggressive diuretic therapy in attempting to dry out the patient and eliminate all traces of edema. This approach may further drop the blood pressure too low, thereby preventing adding the drugs known to actually improve survival.


  Conclusion Top


Medical therapy is presently the only option available to the majority of patients with chronic severe mitral regurgitation in low-resource countries. Our review showed no difference in intermediate-term survival between AF and non-AF patients with chronic severe mitral regurgitation treated only with medical therapy. This is in contrast to the superior survival in patients without AF compared to with AF undergoing surgical mitral valve surgery or percutaneous mitral valve repair. The study limitation include small sample size retrospective study nature and limited follow up.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Commerford PJ. Valvular heart disease in South Africa in 2005. S Afr Med J 2005;95:568, 570, 572-4.  Back to cited text no. 1
    
2.
McLaren MJ, Hawkins DM, Koonhof HJ. Epidemiology of rheumatic heart disease in black school children of Soweto, Johannesburg. Br Med J 1975;3:474-8.  Back to cited text no. 2
    
3.
Bando K, Kasegawa H, Okada Y, Kobayashi J, Kada A, Shimokawa T, et al. Impact of preoperative and postoperative atrial fibrillation on outcome after mitral valvuloplasty for nonischemic mitral regurgitation. J Thorac Cardiovasc Surg 2005;129:1032-40.  Back to cited text no. 3
    
4.
Kingué S, Ba SA, Balde D, Diarra MB, Anzouan-Kacou JB, Anisubia B, et al. The VALVAFRIC study: A registry of rheumatic heart disease in Western and Central Africa. Arch Cardiovasc Dis 2016;109:321-9.  Back to cited text no. 4
    
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Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57-185.  Back to cited text no. 5
    
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Apostolidou E, Maslow AD, Poppas A. Primary mitral valve regurgitation: Update and review. Glob Cardiol Sci Pract 2017;3:1-7.  Back to cited text no. 6
    
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Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Bärwolf C, Levang OW, et al. Aprospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24:1231-43.  Back to cited text no. 7
    
8.
Wilson MG, Lim WN. The natural history of rheumatic heart disease in the third, fourth, and fifth decades of life. I. Prognosis with special reference to survivorship. Circulation 1957;16:700-12.  Back to cited text no. 8
    
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Horstkotte D, Loogen F. The influence of heart valve replacement on the natural history of isolated mitral, aortic and multivalvular disease. J Cardio 1883;72:494-503.  Back to cited text no. 9
    
10.
Ling L, Enriquez-Sarano M. Early surgery in patients with mitral regurgitation due to flail leaflets. N Engl J Med 1996;335:1417-23.  Back to cited text no. 10
    
11.
Enriquez-Sarano M, Avierinos JF. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med 2005;352:875-83.  Back to cited text no. 11
    
12.
Keßler M, Pott A, Mammadova E, Seeger J, Wöhrle J, Rottbauer W, et al. Atrial fibrillation predicts long-term outcome after transcatheter edge-to-edge mitral valve repair by MitraClip implantation. Biomolecules 2018;8. pii: E152.  Back to cited text no. 12
    
13.
Gillinov AM, Gelijns AC, Parides MK, DeRose JJ Jr., Moskowitz AJ, Voisine P, et al. Surgical ablation of atrial fibrillation during mitral-valve surgery. N Engl J Med 2015;372:1399-409.  Back to cited text no. 13
    
14.
Coutinho GF, Garcia AL, Correia PM, Branco C, Antunes MJ. Negative impact of atrial fibrillation and pulmonary hypertension after mitral valve surgery in asymptomatic patients with severe mitral regurgitation: A 20-year follow-up. Eur J Cardiothorac Surg 2015;48:548-55.  Back to cited text no. 14
    
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Velu JF, Kortlandt FA, Hendriks T, Schurer RA, van Boven AJ, Koch KT, et al. Comparison of outcome after percutaneous mitral valve repair with the MitraClip in patients with versus without atrial fibrillation. Am J Cardiol 2017;120:2035-40.  Back to cited text no. 15
    
16.
Nishimura RA, Bonow RO. Percutaneous repair of secondary mitral regurgitation – A tale of two trials. N Engl J Med 2018;379:2374-6.  Back to cited text no. 16
    
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Acker MA, Parides MK, Perrault LP, Moskowitz AJ, Gelijns AC, Voisine P, et al. Mitral-valve repair versus replacement for severe ischemic mitral regurgitation. N Engl J Med 2014;370:23-32.  Back to cited text no. 17
    
18.
Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Fleisher LA, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252-89.  Back to cited text no. 18
    


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