The clinical development of percutaneous heart valve technology: A position statement of the Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), and the Society for Cardiovascular Angiography and Interventions (SCAI)

Abstract

This joint position statement represents the combined efforts of four professional societies (Society of Thoracic Surgeons [STS], American Association for Thoracic Surgery [AATS], American College of Cardiology [ACC], and Society for Cardiovascular Angiography and Interventions [SCAI]), two government agencies (the U.S. Food and Drug Administration [FDA] and the Centers for Medicare and Medicaid Services [CMS]), and numerous industry representatives to assess the foreseeable directions of a class of emerging technologies being developed to enable the percutaneous treatment of cardiac valve dysfunction. Percutaneous heart valve technology (PHVT) is a less invasive means of treating valvular heart disease. The goals of the interdisciplinary group have been to establish cooperation, identify consensus and controversy, and formulate clinical guidelines for the continued development of PHVT. On April 22, 2004, the STS/AATS Committee/Workforce for the Assessment of New Technology (Appendix 1) organized a workshop on PHVT. Included were representatives from the STS, the AATS, the ACC, and SCAI. Also in attendance were representatives from the FDA’s Division of Cardiovascular Devices, Circulatory Support and Prosthetic Devices Branch, CMS, and industry representatives (Appendix 2). Clinical aspects of PHVT were initially addressed in small groups with representatives from each of the constituencies followed by a summary report and discussion amongst the entire group. All participants of the workshop and writing group members completed a disclosure questionnaire documenting all outside relationships that might be perceived as real or potential conflicts of interest.1The Society of Thoracic Surgeons Disclosure Policy and Guidelines Regarding Conflicts of Interest, 2002. Available at: www.sts.org. Accessed April 18, 2004.Google Scholar Current crucial issues addressed were: 1) trial design, 2) control groups, 3) end points for assessment, 4) rate of technological change, 5) institutional and investigator requirements, and 6) safety. Consideration of these issues is undertaken with the acknowledgement that for most patients with heart valve disease, open cardiac surgical procedures provide an established form of treatment. For decades, percutaneous interventional therapy has been an option for patients with pulmonic,2Jarrar M. Betbout F. Rarhat M.B. et al.Long-term invasive and non-invasive results of percutaneous balloon pulmonary valvuloplasty in children, adolescents, and adults.Am Heart J. 1999; 138: 950-954Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 3Kan J.S. White Jr, R.J. Mitchell S.E. 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Analysis of late clinical deterioration: frequency, anatomic findings, and predictive factors.Circulation. 1999; 99: 3272-3278Crossref PubMed Scopus (203) Google Scholar and aortic valvular disease.7NHLBI Balloon Valvuloplasty Registry ParticipantsPercutaneous balloon aortic valvuloplasty acute and 30-day follow-up results in 674 patients.Circulation. 1991; 84: 2383-2397Crossref PubMed Scopus (268) Google Scholar, 8Cribier A. Savin T. Saoudi N. et al.Percutaneous balloon aortic valvuloplasty of acquired aortic stenosis in elderly patients an alternative to valve replacement?.Lancet. 1986; 1: 63-67Abstract PubMed Google Scholar For selected patients with pulmonic or mitral stenosis, percutaneous valvuloplasty is the treatment of choice.9Palacios I. Block P.C. Brandi S. Percutaneous balloon valvotomy for patients with severe mitral stenosis.Circulation. 1987; 75: 778-784Crossref PubMed Scopus (279) Google Scholar, 10Babic U.U. Pejcic P. Dgurisiz Z. Percutaneous transarterial balloon valvuloplasty for mitral valve stenosis.Am J Cardiol. 1986; 57: 1101-1104Abstract Full Text PDF PubMed Scopus (103) Google Scholar For patients with calcific aortic stenosis, balloon aortic valvuloplasty (BAV)11O’Neill W.W. Predictors of long-term survival after percutaneous aortic valvuloplasty report of the Mansfield Scientific Balloon Aortic Registry.J Am Coll Cardiol. 1991; 17: 193-198Abstract Full Text PDF PubMed Scopus (90) Google Scholar, 12Sholler G.F. Keane J.F. Perry S.B. Balloon dilation of congenital aortic valve stenosis results and influence of technical and morphological features on outcome.Circulation. 1988; 78: 351-360Crossref PubMed Scopus (140) Google Scholar has been used as a bridge to aortic valve replacement as noted by the current ACC/American Heart Association (AHA) guidelines.13Bonow R.O. Carabello B. De Leon Jr, A.C. et al.ACC/AHA Task Force Report.J Am Coll Cardiol. 1998; 32: 1486-1582Abstract Full Text Full Text PDF PubMed Google Scholar Hospital mortality for BAV varies from 3.5% to 13.5%, and as many as 25% of the patients have at least one serious complication.14McKay R.G. The Mansfield Scientific Aortic Valvuloplasty Registry overview of acute hemodynamic results and procedural complications.J Am Coll Cardiol. 1991; 17: 485-491Abstract Full Text PDF PubMed Scopus (131) Google Scholar The durability of BAV is limited. Therefore, open aortic valve replacement remains the definitive therapy for aortic stenosis in patients who are viable candidates for surgery. Currently, multiple new concepts for the percutaneous treatment of valvular heart disease are under evaluation in a variety of stages from bench testing to early clinical trials.15Vahanian A. Palacios I.F. Percutaneous approaches to valvular disease.Circulation. 2004; 109: 1572-1579Crossref PubMed Scopus (91) Google Scholar Most involve either mitral valve repair via annular or leaflet manipulation, or percutaneous valve insertion for pulmonic or aortic valve disease. Using a stent-based valve,16Wright K.C. Wallace S. Charnasangavej C. Percutaneous endovascular stents an experimental evaluation.Radiology. 1985; 156: 68-72Google Scholar, 17Bonhoeffer P. Boudjemline Y. Saliba Z. et al.Transcatheter implantation of a bovine valve in pulmonary position a lamb study.Circulation. 2000; 102: 813-816Crossref PubMed Scopus (236) Google Scholar percutaneous pulmonary valve insertion has been successfully carried out in more than 60 cases, primarily outside the U.S., usually for the treatment of conduit stenosis.18Bonhoeffer P. Boudjemline Y. Saliba Z. et al.Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonary-artery prosthetic conduit with valve dysfunction.Lancet. 2000; 356: 1403-1405Abstract Full Text Full Text PDF PubMed Scopus (752) Google Scholar However, late follow-up is limited and future trials will need to focus on the issues of patient selection with degenerated conduits, durability and the inability of the device to grow. Although percutaneous aortic valve insertion has been carried out on a compassionate use for extremely high-risk patients,19Cribier A. Eltchaninoff H. Bash A. et al.Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis first human case description.Circulation. 2002; 106: 3006-3008Crossref PubMed Scopus (2341) Google Scholar, 20Eltchaninoff H. Tron C. Cribier A. Percutaneous implantation of aortic valve prosthesis in patients with calcific aortic stenosis technical aspects.J Interv Cardiol. 2003; 16: 515-521Crossref PubMed Scopus (38) Google Scholar significant para-valvular regurgitation and early mortality characterize the experience thus far.21Cribier A. Eltchaninoff H. Tron C. et al.Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis.J Am Coll Cardiol. 2004; 43: 698-703Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar Currently, there are no approved percutaneous aortic valve devices in the U.S. The goal of the following discussion is to provide a framework for clinical research directed at further testing of PHVT. The testing of new medical technology usually begins with bench testing (in vitro) and in vivo animal testing, followed by clinical investigation. Initial clinical investigation begins with a feasibility study: a small, unblinded, and uncontrolled trial designed to test safety. Following the feasibility trials, a larger, prospective, controlled trial is performed to evaluate both safety and efficacy (Pivotal trial). The most rigorous design for establishing the safety and effectiveness of new technology is the controlled, randomized trial. It is the consensus of the participants of the Workshop that no adequate historical controls exists for the evaluation of PHVT sufficient to eliminate the influence of confounding variables. Therefore, randomized controlled trials are necessary to evaluate safety and efficacy properly for these devices. At each institution participating in clinical trials, the study team should include at least an interventionalist, a cardiac surgeon, a non-interventional clinical investigator charged with monitoring patient welfare, and an echocardiographer. All members of the study team should be charged with ensuring proper patient selection to achieve safety and objectivity. Furthermore, such collaborative interaction will aid trial completion and, it is hoped, lead to improvement in device placement, function, and assessment. Use of PHVT requires skill sets independent of the operator’s base discipline, and specific training should be required before engaging in any percutaneous valve procedure. Those individuals eligible for the procedural training should be confined to experienced interventionalists and surgeons. Feasibility studies in adults should be restricted to a small number of high-volume cardiology and cardiac surgery programs where at least 100 to 150 surgical valve operations per year are performed.22Petersen E.D. Coombs L.P. DeLong E.R. et al.Procedure volume as a marker of quality for CABG surgery.JAMA. 2004; 291: 195-201Crossref PubMed Scopus (247) Google Scholar Participating cardiac surgeons should perform a minimum of 40 to 50 valve repairs or replacements annually.23Crawford F.A. Anderson R.P. Clark R.E. et al.Volume requirements for cardiac surgery credentialing a critical examination of the ad hoc committee on cardiac surgery credentialing of the Society of Thoracic Surgeons.Ann Thorac Surg. 1996; 61: 12-16Abstract Full Text PDF PubMed Scopus (54) Google Scholar In addition, the surgeon’s valve experience should be specific for the device under consideration (i.e., a surgeon with a large volume of aortic valve replacement and minimal mitral valve repair would only qualify for an aortic device study). Although most interventionalists are likely to be cardiologists, or rarely interventional radiologists, surgeons with appropriate training in percutaneous procedures may directly participate, in addition to providing patient selection, guidance, and back-up services. Interventionalists should perform at least 100 percutaneous procedures each year, and have experience with the catheter-based techniques required for PHVT (e.g., trans-septal and/or coronary sinus access techniques) and with the assessment and management of valvular heart disease.24Advisory Council for Cardiothoracic Surgery, American College of SurgeonsGuidelines for standards in cardiac surgery.Bull Am Coll Surg. 1997; 82: 27-29Google Scholar, 25Beller GA, Winters WL Jr., Carver JR, et al. Task force 3: Guidelines for Credentialing Practicing Physicians. American College of Cardiology 2000. Available at: www.acc.org. Accessed July 14, 2004.Google Scholar, 26Cameron A.A. Laskey W.K. Sheldon W.C. SCAI Ad Hoc Task Force on Ethics in Invasive and Interventional Cardiology.Catheter Cardiovasc Interv. 2004; 61: 157-162Crossref PubMed Scopus (28) Google Scholar Clinical trials should also be limited to centers with a proven track record of close collaboration between the aforementioned disciplines and experience in trials. A major problem with all new devices is how to evaluate a first-generation product against the established “gold standard,” in this case the open cardiac surgical procedure. How should a new device that avoids cardiac surgery but perhaps is less effective—especially initially—be best evaluated? At the design stage of a clinical trial it is essential to state clearly the purpose of the study and the specific hypothesis to be evaluated.27Hulley S.B. Cummings S.R. Browner W.S. Designing Clinical Research.2nd edition. Lippinicott Williams and Wilkins, Philadelphia, PA2001Google Scholar Randomized controlled trial designs can be broadly viewed as evaluating the superiority or non-inferiority (clinical equivalence) of the test arm with regard to effectiveness. Critical differences exist between these two approaches, which affect sample size, study feasibility, and credibility of conclusions.28Friedman L.M. DeMets D.L. Furbeerg C. Fundamentals of Clinical Trials.3rd edition. Mosby-Year Book, St. Louis, MO1996Google Scholar It is important to point out that it is statistically, and practically, impossible to demonstrate equivalence between two treatment arms, as some differences are always likely to exist. Therefore, a “clinically acceptable” difference (“delta”) between the two treatment arms must be specified at the outset and the null hypothesis constructed such that its rejection supports the claim of non-inferiority (Table 1).TABLE 1Randomized controlled trial designsTrial design typeNull hypothesis for effectivenessAlternate hypothesis for effectivenessSuperiorityTreatment A success rate ≤ treatment B rateTreatment A success rate > treatment B rateNon-inferiorityTreatment A success rate ≥ treatment B rate + “delta”Treatment A success rate < treatment B rate + “delta” Open table in a new tab Sample size estimation would be most appropriately determined by power calculations for the specific end point and study results published in the literature. Study end points should be chosen that can be assessed objectively by: 1) creating clear criteria for the outcome, 2) collecting the necessary documentation, and 3) having independent core laboratories, blinded to the treatment assignment, adjudicate the cases whenever possible. Meaningful outcome measurements could include components such as death, myocardial infarction, need for surgical repair (including the need for valve replacement when repair was the preoperative intent), stroke or embolic events, hemodynamic deterioration, ejection fraction, measures of reverse remodeling, valvular regurgitation, endocarditis, hemolysis, and functional testing. Although the timing of end point measurements was discussed at the Workshop, the consensus was that it is too early in PHVT development to answer this question. Finally, in any trial designed to evaluate an intervention, “crossovers” are likely to occur. Crossover patients can be analyzed using several methods, including “intent to treat,” “as treated,” and “per protocol”.29Newell D. Intention-to-treat analysis implications for quantitative and qualitative research.Int J Epidemiol. 1992; 21: 837-841Crossref PubMed Scopus (473) Google Scholar, 30Senn S.J. The Design and Analysis of Crossover Trials. Wiley, Chichester1992Google Scholar In addition, a large amount of missing end point data can make interpretation of trial results difficult and threaten the success of the trial. Every effort should be made to collect all data specified in the trial. Additionally, the importance of a knowledgeable and active Data Safety and Monitoring Board cannot be overemphasized. This board should be independent of the investigators, of the company sponsoring the trial, and of any contracted data analysis organizations involved in the trial. The pathophysiologic triad describing mitral regurgitation (MR) is composed of etiology (cause of the disease), valve lesions (resulting from the disease), and valve dysfunction (resulting from the lesion).31Carpentier A. Cardiac valve surgery the “French Correction.”.J Thorac Cardiovasc Surg. 1983; 86: 323-337PubMed Google Scholar These distinctions are relevant because long-term prognosis depends on etiology, whereas surgical treatment strategy—and future PMVR—depends on valve dysfunctions and lesions. Mild to moderate MR is seen in approximately 20% of the general population.32Singh J.P. Evans J.C. Levy D. et al.Prevalence and clinical determinants of mitral, tricuspid, and aortic regurgitation (the Framingham Heart Study).Am J Cardiol. 1999; 83: 897-902Abstract Full Text Full Text PDF PubMed Scopus (729) Google Scholar, 33Jones E.C. Devereaux R.B. 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Accessed August 23, 2004.Google Scholar Patients undergoing reoperation are also at increased risk.36Edwards F.H. Petersen E.D. Coombs L.P. DeLong E.R. et al.Prediction of operative mortality following valve replacement surgery.J Am Coll Cardiol. 2001; 37: 885-892Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar Mitral valve repair is considered superior to mitral valve replacement because of lower operative mortality, improved late survival, a reduced risk of endocarditis, fewer thromboembolic complications, and better preservation of left ventricular function.37Cohn L.H. Mitral valve repair for ischemic mitral regurgitation.Adv Cardiol. 2002; 39: 153-156Crossref PubMed Scopus (9) Google Scholar, 38Enriquez-Sarano M. Schaff H.V. Orszulak T.A. et al.Valve repair improves the outcome of surgery for mitral regurgitation.Circulation. 1995; 91: 1022-1028Crossref PubMed Scopus (613) Google Scholar, 39Jamieson W.R. Edwards F.H. 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Ferguson Jr, T.B. DiSesa V.J. Use of mitral valve repair analysis of contemporary United States experience reported to the Society of Thoracic Surgeons National Cardiac Database.Ann Thorac Surg. 2003; 75: 820-825Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Individual surgeon experience remains the key factor in predicting the likelihood of mitral valve repair or replacement for any given patient. To discuss patient selection for PMVR for MR and to consider comparative outcomes with surgical approaches, it is possible to consider two classifications: one focusing on etiology and the other on leaflet dysfunction, realizing that both can influence patient outcome. For the purposes of this discussion, we will focus on leaflet dysfunction as opposed to etiology.33Jones E.C. Devereaux R.B. Roman M.J. et al.Prevalence and correlates of mitral regurgitation in a population-based sample (the Strong Heart Study).Am J Cardiol. 2001; 87: 298-304Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar This classification is based on the opening and closing motions of the mitral leaflets. Patients with type I dysfunction have normal leaflet motion. Mitral regurgitation in these patients is due to annular dilatation or leaflet perforation. There is increased leaflet motion in patients with type II dysfunction with the free edge of the leaflet overriding the plane of the annulus during systole (leaflet prolapse). The most common lesions responsible for type II dysfunction are chordal elongation or rupture and papillary muscle elongation or rupture. Patients with type IIIa dysfunction have restricted leaflet motion during both diastole and systole. The most common lesions are leaflet thickening/retraction, chordal thickening/shortening or fusion, and commissural fusion. The mechanism of MR in type IIIb dysfunction is restricted leaflet motion during systole: left ventricular enlargement with apical papillary muscle displacement due to ischemic or idiopathic cardiomyopathy causes this type of valve dysfunction. Currently, there are two concepts for percutaneous mitral valve repair: 1) partial mitral annuloplasty by device placement in the coronary sinus to reduce the circumference of the posterior mitral annulus; and 2) anterior and posterior leaflet attachment using an edge-to-edge clip or suture.44Fucci C. Sandrelli L. Pardini A. et al.Improved results with mitral valve repair using new surgical techniques.Eur J Cardiothor Surg. 1995; 9: 621-626Crossref PubMed Scopus (226) Google Scholar, 45Maisano F. Torraca L. Oppizzi M. et al.The edge-to-edge technique a simplified method to correct mitral insufficiency.Eur J Cardiothor Surg. 1998; 13: 240-245Crossref PubMed Scopus (310) Google Scholar, 46Maisano F. Schreuder J.J. 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DeBonis M. et al.The double-orifice technique in mitral valve repair a simple solution for complex problems.J Thorac Cardiovasc Surg. 2001; 122: 674-681Abstract Full Text Full Text PDF PubMed Scopus (624) Google Scholar The results of edge-to-edge repair have been suboptimal in patients with restricted leaflet motion (type III dysfunction), including a recent surgical series where it was used in combination with a posterior annuloplasty in patients with ischemic regurgitation.52Bhudia S.K. McCarthy P.M. Smedira N.G. et al.Edge-to-edge (Alfieri) mitral repair results in diverse clinical settings.Ann Thorac Surg. 2004; 77: 1598-1606Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar A feasibility study designed to evaluate PMVR with annular remodeling technology should consist of 20 to 30 patients with severe symptomatic MR caused by annular dilation with normal leaflet motion (type I dysfunction) or by restricted leaflet motion (type IIIb dysfunction), or by a combination of these two mechanisms. A feasibility study to evaluate PMVR with leaflet edge-to-edge repair should consist of 20 to 30 patients with excessive leaflet motion (type II dysfunction). These studies will have safety as the primary end point and will assess adverse events including residual (equal or worse) MR, myocardial infarction, stroke, tamponade, coronary artery injury, death, and leaflet damage compromising subsequent mitral valve repair. The secondary end points of the study will include quantitative echocardiographic assessment of MR diminution, left ventricular function, and symptom status. The design of Pivotal trials will need to await safety and durability data from the feasibility study, but will include: 1) comparison of PMVR to open surgical mitral valve repair in patients with types I, II, and IIIb dysfunction; or 2) comparison of PMVR to optimal medical therapy53Bonow R.O. Carabello B. de Leon A.C. et al.ACC/AHA guidelines for the management of patients with valvular heart disease: executive summary. A report of the ACC/AHA Task Force on Practice Guidelines (Committee on Management of Patients With Valvular Heart Disease).J Heart Valve Dis. 1998; 7: 672-707PubMed Google Scholar in non-surgical candidates with either end-stage cardiomyopathy and type IIIb severe MR or elderly patients with significant comorbidities and type II dysfunction. Aortic valve replacement is the most common heart valve operation. Aortic stenosis (AS) affects from 2% to 7% of individuals older than 65 years in the U.S., a prevalence that will continue to increase as more people live to older ages.54Ross Jr, J. Braunwald E. Aortic stenosis.Circulation. 1968; 37: V61-V67Google Scholar, 55Horstkotte D. Logan F. The natural history of aortic valve stenosis.Eur Heart J. 1988; 9: 57-64Crossref PubMed Google Scholar Aortic stenosis is consistently progressive,56Kennedy K.D. Nishimura R.A. Holmes D.R. et al.Natural history of moderate aortic stenosis.J Am Coll Cardiol. 1991; 17: 313-319Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 57Pellika P.A. Nishimura R.A. Bailey K.R. et al.The natural history of adults with asymptomatic, hemodynamically significant aortic stenosis.J Am Coll Cardiol. 1990; 15: 1018-1020Abstract Full Text PDF PubMed Scopus (62) Google Scholar, 58O’Keefe J.H. Vliestra R.E. Bailey K.R. Holmes D.R. 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