Journal of the American College of Cardiology
`© 2005 by the Society of Thoracic Surgeons, the American Association for Thoracic Surgery,
`and the Society for Cardiovascular Angiography and Interventions
`Published by Elsevier Inc.
`STS/AATS/SCAI POSITION STATEMENT
`
`Vol. 45, No. 9, 2005
`ISSN 0735-1097/05/$30.00
`doi:10.1016/j.jacc.2004.12.024
`
`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)
`Endorsed by the American College of Cardiology Foundation (ACCF)
`and the American Heart Association (AHA)
`
`THOMAS A. VASSILIADES, JR, MD
`PETER C. BLOCK, MD
`LAWRENCE H. COHN, MD
`DAVID H. ADAMS, MD
`JEFFREY S. BORER, MD
`TED FELDMAN, MD
`
`DAVID R. HOLMES, MD
`WARREN K. LASKEY, MD
`BRUCE W. LYTLE, MD
`MICHAEL J. MACK, MD
`DAVID O. WILLIAMS, MD
`
`PREAMBLE
`
`This joint position statement represents the combined
`efforts of four professional societies (Society of Thoracic
`Surgeons [STS], American Association for Thoracic Sur-
`gery [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. Percu-
`taneous 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,
`
`This document was approved by the Society for Thoracic Surgeons, the American
`Association for Thoracic Surgery, and the Society for Cardiovascular Angiography
`and Interventions. This document was endorsed by the American College of
`Cardiology Foundation and the American Heart Association.
`This document will be co-published in the Annals of Thoracic Surgery, the Journal
`of Thoracic and Cardiovascular Surgery, and Catheterization and Cardiovascular
`Interventions.
`When citing this document, please use the following citation format: Vassiliades Jr.
`TA, Block PC, Cohn LH, Adams DH, Borer JS, Feldman T, Holmes DR, Laskey
`WK, Lytle BW, Mack MJ, Williams DO. 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). J Am Coll Cardiol 2005;45:
`1554–60.
`Multiple copies, modification, alteration, enhancement, and/or distribution of this
`document are not permitted without the express permission of the authoring societies.
`Please direct requests to dmarquis@sts.org.
`Reprinted with permission from the Society of Thoracic Surgeons, the American
`Association for Thoracic Surgery, and the Society for Cardiovascular Angioplasty and
`Interventions.
`
`identify consensus and controversy, and formulate clinical
`guidelines for the continued development of PHVT.
`
`PROCESS
`
`On April 22, 2004, the STS/AATS Committee/Workforce
`for the Assessment of New Technology (Appendix 1)
`organized a workshop on PHVT. Included were represen-
`tatives 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 repre-
`sentatives (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 disclo-
`sure questionnaire documenting all outside relationships
`that might be perceived as real or potential conflicts of
`interest (1). Current crucial issues addressed were: 1) trial
`design, 2) control groups, 3) end points for assessment, 4)
`rate of technological change, 5) institutional and investiga-
`tor 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.
`
`BACKGROUND
`
`For decades, percutaneous interventional therapy has been
`an option for patients with pulmonic (2–4), mitral (5,6),
`and aortic valvular disease (7,8). For selected patients with
`pulmonic or mitral stenosis, percutaneous valvuloplasty is
`the treatment of choice (9,10). For patients with calcific
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`JACC Vol. 45, No. 9, 2005
`May 3, 2005:1554–60
`
`Vassiliades, Jr. et al.
`Clinical Development of Percutaneous Heart Valve Technology
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`1555
`
`aortic stenosis, balloon aortic valvuloplasty (BAV) (11,12)
`has been used as a bridge to aortic valve replacement as
`noted by the current ACC/American Heart Association
`(AHA) guidelines (13). 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 (14). 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
`(15). 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
`(16,17), 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 (18). 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 (19,20), significant para-
`valvular regurgitation and early mortality characterize the
`experience thus far (21). 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.
`
`GENERAL GUIDELINES REGARDING
`CLINICAL TRIAL DESIGN FOR 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 nec-
`essary 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 echocar-
`diographer. All members of the study team should be
`charged with ensuring proper patient selection to achieve
`safety and objectivity. Furthermore, such collaborative in-
`
`teraction will aid trial completion and, it is hoped, lead to
`improvement in device placement, function, and assess-
`ment.
`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 proce-
`dure. 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 (22). Participating cardiac
`surgeons should perform a minimum of 40 to 50 valve
`repairs or replacements annually (23). 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 partici-
`pate, 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 (24–26). 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 eval-
`uated? 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 (27). 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 (28). It is impor-
`tant to point out that it is statistically, and practically,
`impossible to demonstrate equivalence between two treat-
`ment arms, as some differences are always likely to exist.
`Therefore, a “clinically acceptable” difference (“delta”) be-
`tween 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).
`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
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`Clinical Development of Percutaneous Heart Valve Technology
`
`JACC Vol. 45, No. 9, 2005
`May 3, 2005:1554–60
`
`Table 1. Randomized Controlled Trial Designs
`
`Trial Design Type
`
`Superiority
`
`Non-inferiority
`
`Null Hypothesis for
`Effectiveness
`
`Treatment A success
`rate ⱕ treatment B
`rate
`Treatment A success
`rate ⱖ treatment B
`rate ⫹ “delta”
`
`Alternate
`Hypothesis for
`Effectiveness
`
`Treatment A success
`rate ⬎ treatment B
`rate
`Treatment A success
`rate ⬍ treatment B
`rate ⫹ “delta”
`
`necessary documentation, and 3) having independent core
`laboratories, blinded to the treatment assignment, adjudi-
`cate 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 deteriora-
`tion, ejection fraction, measures of reverse remodeling,
`valvular regurgitation, endocarditis, hemolysis, and func-
`tional testing. Although the timing of end point measure-
`ments 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” (29,30). 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.
`
`PERCUTANEOUS MITRAL VALVE
`REPAIR (PMVR) FOR MITRAL REGURGITATION
`
`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) (31). 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 moder-
`ate MR is seen in approximately 20% of the general
`population (32,33). The most common causes of MR in
`Western countries are degenerative, ischemic, and dilated
`cardiomyopathy (34).
`The STS National Adult Cardiac Surgery Database 2003
`notes a countrywide mortality for first time elective mitral
`valve repair of 2.5% (males) to 3.9% (females), and for
`mitral valve surgery combined with coronary artery bypass
`
`these figures are 6.1% (males) to 12.2% (females), respec-
`tively (35). Patients undergoing reoperation are also at
`increased risk (36). Mitral valve repair is considered superior
`to mitral valve replacement because of lower operative
`mortality, improved late survival, a reduced risk of endocar-
`ditis, fewer thromboembolic complications, and better pres-
`ervation of left ventricular function (37–42). However, the
`majority of mitral valve operations done in the U.S. in 2003
`remained mitral valve replacement (43). Individual surgeon
`experience remains the key factor in predicting the likeli-
`hood 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 (33). This classification is based on the opening and
`closing motions of the mitral leaflets. Patients with type I
`dysfunction have normal leaflet motion. Mitral regurgita-
`tion 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 dys-
`function have restricted leaflet motion during both diastole
`and systole. The most common lesions are leaflet thicken-
`ing/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 dis-
`placement 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 place-
`ment 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
`(44–46). Posterior annuloplasty faces multiple anatomic
`challenges including dilation of the trigone-to-trigone area
`(47,48), leaflet tethering by papillary muscle displacement
`(49), mitral annular calcification, inability to fix the annu-
`loplasty to the fibrous trigones (50), and the potential for
`compromise of the circumflex coronary artery. The edge-
`to-edge repair concept has been used in surgically treated
`patients, but the best results have been obtained when
`combined with an annuloplasty (51). The results of edge-
`to-edge repair have been suboptimal in patients with re-
`stricted leaflet motion (type III dysfunction), including a
`recent surgical series where it was used in combination with
`a posterior annuloplasty in patients with ischemic regurgi-
`tation (52).
`A feasibility study designed to evaluate PMVR with
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`JACC Vol. 45, No. 9, 2005
`May 3, 2005:1554–60
`
`Vassiliades, Jr. et al.
`Clinical Development of Percutaneous Heart Valve Technology
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`1557
`
`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, cor-
`onary artery injury, death, and leaflet damage compromising
`subsequent mitral valve repair. The secondary end points of
`the study will include quantitative echocardiographic assess-
`ment 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
`therapy (53) in non-surgical candidates with either end-stage
`cardiomyopathy and type IIIb severe MR or elderly patients
`with significant comorbidities and type II dysfunction.
`
`PERCUTANEOUS AORTIC VALVE REPLACEMENT
`(PAVR)
`
`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
`(54,55). Aortic stenosis is consistently progressive (56–59),
`and because it occurs in an elderly age group it is often
`associated with comorbid risk factors and previous bypass
`surgery (60). The goals of therapy for patients with AS
`include both improvement of symptoms and prolongation
`of life (61). Percutaneous strategies for the treatment of AS
`began with percutaneous balloon valvuloplasty, but data
`from single-center studies and the multicenter National
`Heart, Lung, and Blood Institute (NHLBI) registry noted
`only a modest improvement in early hemodynamics, a
`substantial incidence of peripheral vascular complications, a
`30-day mortality of 7%, and a high incidence of restenosis
`within 6 months (7,62).
`The disappointing results of BAV have led to investiga-
`tion of the possibility of percutaneous placement of pros-
`thetic aortic valves. Such devices have been used clinically in
`a small number of cases in high-risk patients (63). A
`feasibility study designed to evaluate PAVR might consist
`of 20 to 30 patients with severe symptomatic AS (aortic
`valve area ⱕ0.70 cm2), or severe aortic valve regurgitation
`(AR). Initial feasibility trials have treated only AS patients
`because AR treatment is more problematic for the first
`generation of PAVR devices. Therefore, it is envisioned that
`
`feasibility trials will initially enroll only patients with severe
`AS.
`In addition, differences in the age and comorbidity
`between patients with AS and AR dictate each study
`population be fairly pure, with a cohort of one or the other
`but not a mixture. These initial patients should be judged to
`be at extremely high operative risk as calculated by an
`established risk scoring system (64–67). Selection of a risk
`scoring system as well as the definition of inoperability
`should be clearly defined in the protocol. Such inoperability
`will almost always be caused by non-cardiac morbid condi-
`tions. In such a feasibility trial it is not acceptable to use
`such devices for patients who simply refuse open surgery on
`the basis of personal preference. Study end points will
`include death, stroke, myocardial infarction, para-prosthetic
`leak, device migration, symptom status, angiographic gra-
`dient, and rehospitalization. Pivotal trials will depend upon
`the safety data from the feasibility trial, and a variety of
`control groups may be possible including patients having
`balloon valvuloplasty and high-risk open surgery.
`
`MINIMALLY INVASIVE VALVE SURGERY
`
`The procedural goal of PHVT is to reliably repair or replace
`dysfunctional heart valves percutaneously and without the
`need for cardiopulmonary bypass (CPB). An alternate
`approach has been to repair or replace valves off-pump
`through small incisions, thereby simplifying device delivery.
`Concepts along these lines include anterior and posterior
`pads connected by a subvalvular cord designed to draw the
`posterior leaflet and annulus of the mitral valve toward the
`anterior leaflet (68); a transatrial off-pump edge-to-edge
`mitral valve repair (69); and off-pump AR antegrade
`through the ascending aorta or retrograde through the left
`ventricular apex (70). The minimally invasive surgical ap-
`proach is an avenue of treating heart valve disease that not
`only has benefit on its own merit but also supports devel-
`opment of PHVT.
`
`REGULATORY CONSIDERATIONS
`
`At this Workshop, the general considerations of the FDA,
`as expressed by Bram Zuckerman, Director of Cardiovas-
`cular Devices, Office of Device Evaluation (ODE), Center
`for Devices and Radiologic Health, were as follows. Percu-
`taneous heart valve systems are considered class III devices;
`they will be reviewed as pre-market approval (PMA) appli-
`cations (71) and, as such, controlled, randomized clinical
`trials will be the gold standard for meeting FDA require-
`ments. Industry or independent study investigators should
`solicit the assistance and guidance of the FDA before
`designing any clinical trial for PHVT (72). Post-market
`approval studies may be required.
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`Clinical Development of Percutaneous Heart Valve Technology
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`JACC Vol. 45, No. 9, 2005
`May 3, 2005:1554–60
`
`SUMMARY
`
`Although percutaneous devices for the repair or replacement
`of heart valves appear promising, they are clearly in an early
`stage of development. Many critical questions remain un-
`answered, including the durability of these devices and the
`potential adverse effects they may have on subsequent heart
`valve surgery. Therefore, one cannot justify the use of these
`experimental technologies in patients for whom published
`guideline indications do not exist or in situations of pro-
`phylactic therapy until data on safety and effectiveness are
`gathered from well-designed clinical trials. Study candidates
`should consist of symptomatic patients in whom long-term
`survival is already severely compromised. Such a strategy
`would allow the collection of mid-term device durability
`data while providing much needed clinically relevant safety
`and effectiveness data.
`Prospective, randomized, clinical trials provide the most
`reliable evidence of the effectiveness of the treatment.
`Without such trials, ineffective treatments (or worse, harm-
`ful treatments) may be accepted in medical practice. Our
`collective enthusiasm for new, less-invasive cardiovascular
`approaches should not divert us from the importance of
`evaluating these devices in the context of a controlled
`clinical trial environment. Success of these clinical trials
`ultimately depends upon a sincere commitment to collabo-
`ration between cardiology and cardiac surgery.
`
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`ENDOHEART AG, EX. 2030 Page 5
`EDWARDS LIFESCIENCES CORPORATION (PETITIONER) v. ENDOHEART AG (PATENT OWNER)
`Case No.: IPR2016-00299, U.S Patent No. 8,182,530
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