Although rheumatic heart disease is now uncommon in the United States, valvular heart disease remains a common cause of morbidity and mortality. With the dramatic aging of the American population over the past several decades, degenerative lesions of the mitral and aortic valves, resulting in mitral regurgitation (MR), aortic stenosis (AS), or aortic regurgitation (AR) have become the most prevalent valvular disorders requiring surgery. All three valve lesions contribute to the current heart failure epidemic. Over 90% of the 96,000 annual cardiac valve operations performed in 2002 involved the aortic and mitral valves.1
Despite the important contributions of NHLBI multicenter clinical trials to define the therapy of cardiovascular disease, valvular heart disease remains a "gap area" in this regard. No prior or ongoing NHLBI clinical trial specifically addresses this area. The continued rapid expansion of the elderly population and the strong predilection of MR, AS, and AR for this age group insure that these valvular disorders will continue to increase for the foreseeable future.
A Working Group on Valvular Heart Disease was convened to provide advice to the NHLBI and to define and prioritize promising avenues of research in this area. This report summarizes the discussion and recommendations of the Working Group.
Summary of Discussion
There is a general dearth of randomized controlled trials (RCT?s) testing interventions for valvular heart disease to guide treatment of these common disorders. Most of the prior comparisons of various prosthetic valves and their need for anticoagulation are outdated because the valves studied are no longer widely used. Other trials, such as those examining the benefit of vasodilator therapy in AR and MR, are limited by their small sample size. The multiple observational studies comparing medical versus surgical therapy for common valve disorders are severely limited by their non-randomized design and the significant selection biases involved in selecting patients for surgery. Thus, there is a clear need for RCT?s designed to address the major unanswered questions in valvular disease.
The following were selected as high priority issues in valvular heart disease for which RCTs are needed to define optimal therapy. They are listed in order of importance, highest first.
1. Mitral valve repair for MR in dilated cardiomyopathy. There was a consensus that this issue has the highest priority for a RCT. Among the large population with dilated cardiomyopathy, approximately half have functional MR.2, 3 When hemodynamically significant, MR results in progressive dilation of the mitral annulus, which worsens MR, leading to further left ventricular (LV) enlargement.4, 5 Multiple studies have shown that significant MR in patients with LV dysfunction reduces survival.6-10 In several nonrandomized series, mitral valve repair, usually consisting of annuloplasty, was accomplished with low mortality and was associated with improved functional status and greater survival than seen in medically treated patients.11-15
The group favored a RCT that would include patients with both ischemic and non-ischemic cardiomyopathy to allow maximal generalizability of the results. Stratification based on etiology was recommended. The optimal primary outcome was felt to be total mortality, although composite primary outcomes may be considered in order to reduce the size of such a study. Important secondary outcomes include heart failure hospitalizations, exercise capacity, and cost-effectiveness. Percutaneous mitral valve repair16 was discussed but was thought to be inadequately studied and therefore not appropriate to incorporate into a RCT at present. A core echocardiography laboratory was recommended for quantification of MR and LV function. The need for a study on this topic and possible design characteristics were discussed separately by NHLBI staff with Dr. Stephen Bolling, who could not attend the Working Group because of other commitments. He endorsed the seminal importance of a RCT to optimize MR therapy, noting that his group has switched from a flexible mitral annuloplasty ring to a rigid ring for this purpose during the past 2 years. He agreed that valvular heart disease is an understudied area in need of RCTs and expressed great enthusiasm for such trials.
2. Valve replacement in patients with severe asymptomatic AS. Although there is general agreement that aortic valve replacement should be performed in patients with severe AS once angina, syncope or heart failure symptoms appear,17 the optimal treatment strategy for those with severe AS without associated symptoms is unclear. Among 622 patients from the Mayo Clinic with severe asymptomatic AS, the 5-year probability of remaining free of valve surgery or cardiac death was only 25%.18Within the overall group, greater AS severity conferred a greater likelihood of developing symptoms, having aortic valve replacement, or cardiac death. Thus, the current strategy of waiting for symptoms to develop before referring patients with AS for valve surgery may be suboptimal and should be addressed in a RCT.
3. Neurohormonal antagonism in chronic MR. Small clinical and experimental studies suggest that sympathetic activation occurs in chronic MR19 and that angiotensin converting enzyme inhibitors (ACEI) and beta blockers reduce MR severity and improve LV performance.20-22 Prospective observation of 76 persons with chronic MR revealed that pharmacologic afterload reduction with the ACEI ramipril was associated with regression of MR.22 Taken together, these findings suggest that long-term therapy with ACEI and/or beta blockers may retard the progression of MR and help preserve LV function. A RCT is needed to assess these therapies.
4. Afterload reduction in chronic asymptomatic AR. In chronic asymptomatic AR, studies spanning 6 to 24 months have shown beneficial hemodynamic effects of afterload reduction with nifedipine, felodipine and ACEI?s.23-25 In one study, nifedipine delayed the need for aortic valve replacement from 85% to 65% over 6 years.25 The myocardial fibrosis observed in chronic severe AR suggests a potential role for aldosterone antagonists or other anti-proliferative agents.26 A RCT examining the role of medical therapy for chronic AR should be considered.
5. Anticoagulation in patients with prosthetic heart valves. Although a few RCT?s have examined this issue,27, 28 they are outdated because most of the valves studied are no longer used. Thus, RCT?s examining this issue with the newer generation of prosthetic valves should be considered.
6. Statins for retarding progression of aortic stenosis. Recent experimental and observational studies suggest that statins, used routinely to reduce serum LDL-cholesterol, retard the progression of AS.29-32 In several recent observational clinical studies, statins appeared to retard progression or mild-to-moderate AS by 50-60%.30-32 However, a recently published single center RCT failed to show a benefit for statins in such patients.33 This finding, in addition to an ongoing multicenter RCT in Europe to address this issue, tempered the enthusiasm of the Working Group for another RCT in this area.
- Heart Disease and Stroke Statistics?2003 Update, American Heart Association
- Blondheim D, Jacobs L, Kolter M, et al. Dilated cardiomyopathy with mitral regurgitation: Decreased survival despite a low frequency of left ventricular thrombus. Am Heart J 1991;122;763-777.
- Strauss R, Stevenson L, Dadourium B, Child J. Predictability of mitral regurgitation detected by Doppler echocardiography in patients referred for cardiac transplantation. Am J Cardiol 1987;59:892-894.
- Yiu SF, Enriquez Sarano M, Tribouilloy C, Seward JB, TajikAJ. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: a quantitative clinical study. Circulation 2000;102:1400-1406.
- Boltwood CM, Tei C, Wong M, Shah PM. Quantitative echocardiography of the mitral complex in dilated cardiomypathy: the mechanism of functional mitral regurgitation. Circulation 1983;68:498-508.
- Anguitta M, Arizon J, Bueno G, Latre J, Sancho M, Torres F. Clinical and hemodynamic predictors of survival in patients aged less than 65 years with severe congestive heart failure secondary to ischemic or nonischemic dilated cardiomypathy. Am J Cardiol 1993;72:413-417.
- Koelling TM, Aaronson KD, Cody RJ, Bach DS, Armstrong WF. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am Heart J 2002;144:524-529.
- Cabell CH, Trichon BH, Velasquez EJ, et al. Importance of echocardiography in patients with severe nonischemic heart failure: The Second Prospective Randomized Amlodipine Survival Evaluation (PRAISE-2) Echocardiographic Study. Am Heart J 2004;147:151-157.
- Venturi F, Gianfaldoni ML, Melina G, et al. Mitral effective regurgitant orifice area versus left ventricular ejection fraction as prognostic indicators in patients with dilated cardiomypathy and heart failure. Ital Heart J 2004;5:755-761.
- Junker A, Thayssen P, Nielsen B, Anderson PE. The hemodynamic and prognostic significance of echo-Doppler-proven mitral regurgitation in patients with dilated cardiomyopathy. Cardiology 1993;83:14-20.
- Bolling S, Pagani F, Deeb G, Bach D. Intermediate-term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg 1998;115:381-388.
- Bishay E, McCarthy P, Cosgrove D, et al. Mitral valve surgery in patients with severe left ventricular dysfunction. Eur J Cardiothorac Surg 2000;17:213-221.
- Chen F, Adams D, Aranki S, et al. Mitral valve repair in cardiomyopathy. Circulation 1998;98:II-124 ? II-127.
- Stanley AW, Athanasuleas CI, Buckberg GD: RESTORE Group. Left ventricular remodeling and functional mitral regurgitation:mechanisms and therapy. Semin Thorac Cardiovasc Surg 2001;121:675-682.
- Wu AH, Aaronson KD, Bolling SF, Pagani FD, Welch K, Koelling TM. Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction. J Am Coll Cardiol 2005;45:381-387.
- Feldman T, Wasserman HS, Hermann HC, et al. Percutaneous mitral valve repair using the edge-to-edge technique. Six-month results of the EVEREST phase I clinical trial. J Am Coll Cardiol 2005;46:2134-2140.
- Pellikka P, Sarano ME, Nishimura RA, et al. Outcome of 622 adults with asymptomatic, hemodynamically severe aortic stenosis during prolonged follow-up. Circulation 2005;111:3290-3295.
- Bonow RO, Carabello B, de Leon AC, et al. Guidelines for the management of patients with valvular heart disease: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). Circulation 1998;98:1949-1984.
- Mehta RH, Supiano MA, Oral H, et al. Compared with control subjects, the sympathetic nervous system is activated in patients with mitral regurgitation. Am Heart J. 2003;145:1078-1085.
- Nemoto S, Hamawaki M, DeFreitas G, Carabello BA. Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation. J Am Coll Cardiol 2002;40:149-154.
- Tichler MD, Rowen M, LeWinter MM. Effect of enalapril therapy on left ventricular mass and volumes in asymptomatic chronic, severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 1998;82:242-245.
- Host U, Kelbaek H, Hildebrant P, et al. Effect of ramipril on mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 1997;80:655-658.
- Alehan D, Ozkutlu S. Beneficial effects of 1-year captopril therapy in children with chronic aortic regurgitation who have no symptoms. Am Heart J 1998;135: 598-605.
- Sondergaard L, Aldersville J, Hildebrandt P, et al. Vasodilation with felodipine in chronic asymptomatic aortic regurgitation. Am Heart J 2000;139:667-674.
- Scognamiglio R, Rahimtoola SH, Fasoli G, et al. Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. N Engl J Med 1994;331:689-694.
- Borer JS, Truter S, Herrold EM, et al. Myocardial fibrosis in chronic aortic regurgitation: Molecular and cellular responses to volume overload. Circulation 2002;105:1837-1842.
- Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995;333:11-17.
- Laffort p, Roudaut R, Roques X, et al. Early and long-term (1 year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude Medical Prosthesis. J Am Coll Cardiol 2000;34:739-746.
- Rajamannan NM, Subramaniam M, Springett M, et al. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation 2002;105:2660-2665.
- Novaro GM, Tiong IY, Pearce GL, et al. Effect of hydroxymethylglutaryl coenzyme A reductase inhibitors on the progression of calcific aortic stenosis. Circulation 2001;104:2205-2209.
- Shavelle DM, Takasu J, Budoff MJ, et al. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 2002;359:1125-1126.
- Rosenhek R, Rader F, Loho N, et al. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004;110:1291 -1295.
- Cowell SJ, Newby DE, Prescott RJ, et al. A randomized trial of intensive lipid- lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389-2397.
Working Group Members
- Stephen Bolling, M.D., University of Michigan Medical Center
- Robert Bonow, M.D., Northwestern University School of Medicine
- Blase Carabello, M.D., Baylor University School of Medicine
- Maurice Sarano, M.D., Mayo School of Medicine
- Michael Domanski, M.D., National Heart, Lung, and Blood Institute
- Jerome Fleg, M.D., National Heart, Lung, and Blood Institute
- Denise Simons-Morton M.D., Ph.D., National Heart, Lung, and Blood Institute