Ventricular Assist Devices for Bridge-to-Transplant and Destination Therapy

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The Centers for Medicare & Medicaid Services (CMS) makes the following changes to the current national coverage determination (NCD). Ventricular assist devices (VADs) for bridge to transplant (BTT) For the existing requirement that a patient is approved and listed as a candidate for heart transplant by a Medicare-approved heart transplant center, we clearly identify that the patient must be active on the waitlist maintained by the Organ Procurement and Transplantation Network (OPTN). Remove the existing requirement that a “Medicare-approved heart transplant center should make every reasonable effort to transplant patients on such devices as soon as medically reasonable. Ideally, the Medicare-approved heart transplant centers should determine patient-specific timetables for transplantation, and should not maintain such patients on VADs if suitable hearts become available.” VADs for destination therapy (DT) The evidence is insufficient to support changes to our current patient selection criteria for coverage of a VAD as DT; however, we are modifying the language in new section 20.9.1 to clarify that the identification of patients who are not candidates for heart transplantation is based on information available at the time of VAD implant. We will also remove the word “permanent” from the DT description as this is not part of the patient selection criteria and may lead to confusion. The evidence is sufficient to conclude that VADs implanted in facilities that meet certain criteria improve health outcomes for Medicare beneficiaries. Facilities currently credentialed by the Joint Commission for placement of VADs as DT may continue as Medicare-approved facilities until October 30, 2014. At the conclusion of this transition period, these facilities must be in compliance with the following criteria as determined by a credentialing organization. As of the effective date, new facilities must meet the following criteria as a condition of coverage of this procedure as DT under section 1862(a)(1)(A): Beneficiaries receiving VADs for DT must be managed by an explicitly identified cohesive, multidisciplinary team of medical professionals with the appropriate qualifications, training, and experience. The team embodies collaboration and dedication across medical specialties to offer optimal patient-centered care. Collectively, the team must ensure that patients and caregivers have the knowledge and support necessary to participate in shared decision making and to provide appropriate informed consent. The team members must be based at the facility and must include individuals with experience working with patients before and after placement of a VAD. The team must include, at a minimum, all of the following: At least one physician with cardiothoracic surgery privileges and individual experience implanting at least 10 durable, intracorporeal, left ventricular VADs as BTT or DT over the course of the previous 36 months with activity in the last year. At least one cardiologist trained in advanced heart failure with clinical competence in medical and device-based management including VADs, and clinical competence in the management of patients before and after heart transplant. A VAD program coordinator. A social worker. A palliative care specialist. Facilities must be credentialed by an organization approved by CMS. We remove the separate requirement that hospitals have in place staff and procedures for appropriate informed consent as this requirement is encompassed in the above team definition. The evidence is sufficient to conclude that participation in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) is no longer necessary for VADs to be reasonable and necessary. We remove this requirement. We will allow organizations that have credentialing programs specific to VADs to apply to CMS to be designated as a credentialing organization for VAD facilities for DT. These programs must ensure that credentialed facilities meet the criteria outlined in the NCD. The process for organizations to apply for CMS approval to be designated as a credentialing organization for VAD facilities for DT is posted on our web site along with a list of approved credentialing organizations, approved standard versions, and credentialed facilities. http://www.cms.gov/Medicare/Medicare-General-Information/MedicareApprovedFacilitie/VAD-Destination-Therapy-Facilities.html . The NCD does not address coverage of VADs for right ventricular support, biventricular support, use in beneficiaries under the age of 18, use in beneficiaries with complex congenital heart disease, or use in beneficiaries with acute heart failure without a history of chronic heart failure. Coverage under section 1862(a)(1)(A) for VADs in these situations will be made by local Medicare Administrative Contractors (MACs) within their respective jurisdictions. In addition to the changes above, CMS is renumbering its VAD-related policies into a sub-section of section 20.9 (Artificial Hearts and Related Devices) of the NCD Manual. The sub-section (20.9.1) will be titled Ventricular Assist Devices. This is an administrative change only to make it easier for the public to read and understand the VAD policies. Section 20.9.1 will include the existing coverage of VADs for postcardiotomy, BTT, and DT. The changes to the manual are reflected in Appendix C.

Decision Memo: To: Administrative File: CAG-00432R From: Louis Jacques, MD Director, Coverage and Analysis Group Tamara Syrek Jensen, JD Deputy Director, Coverage and Analysis Group Jyme Schafer, MD, MPH Director, Division of Medical and Surgical Services Kimberly Smith, MD, MS Lead Medical Officer, Division of Medical and Surgical Services Marie Casey, BSN, MPH Analyst, Division of Medical and Surgical Services Roya Lotfi Analyst, Division of Medical and Surgical Services Subject: Decision Memorandum for Ventricular Assist Devices Date: October 30, 2013 I. Decision The Centers for Medicare & Medicaid Services (CMS) makes the following changes to the current national coverage determination (NCD). Ventricular assist devices (VADs) for bridge to transplant (BTT) For the existing requirement that a patient is approved and listed as a candidate for heart transplant by a Medicare-approved heart transplant center, we clearly identify that the patient must be active on the waitlist maintained by the Organ Procurement and Transplantation Network (OPTN). Remove the existing requirement that a “Medicare-approved heart transplant center should make every reasonable effort to transplant patients on such devices as soon as medically reasonable. Ideally, the Medicare-approved heart transplant centers should determine patient-specific timetables for transplantation, and should not maintain such patients on VADs if suitable hearts become available.” VADs for destination therapy (DT) The evidence is insufficient to support changes to our current patient selection criteria for coverage of a VAD as DT; however, we are modifying the language in new section 20.9.1 to clarify that the identification of patients who are not candidates for heart transplantation is based on information available at the time of VAD implant. We will also remove the word “permanent” from the DT description as this is not part of the patient selection criteria and may lead to confusion. The evidence is sufficient to conclude that VADs implanted in facilities that meet certain criteria improve health outcomes for Medicare beneficiaries. Facilities currently credentialed by the Joint Commission for placement of VADs as DT may continue as Medicare-approved facilities until October 30, 2014. At the conclusion of this transition period, these facilities must be in compliance with the following criteria as determined by a credentialing organization. As of the effective date, new facilities must meet the following criteria as a condition of coverage of this procedure as DT under section 1862(a)(1)(A): Beneficiaries receiving VADs for DT must be managed by an explicitly identified cohesive, multidisciplinary team of medical professionals with the appropriate qualifications, training, and experience. The team embodies collaboration and dedication across medical specialties to offer optimal patient-centered care. Collectively, the team must ensure that patients and caregivers have the knowledge and support necessary to participate in shared decision making and to provide appropriate informed consent. The team members must be based at the facility and must include individuals with experience working with patients before and after placement of a VAD. The team must include, at a minimum, all of the following: At least one physician with cardiothoracic surgery privileges and individual experience implanting at least 10 durable, intracorporeal, left ventricular VADs as BTT or DT over the course of the previous 36 months with activity in the last year. At least one cardiologist trained in advanced heart failure with clinical competence in medical and device-based management including VADs, and clinical competence in the management of patients before and after heart transplant. A VAD program coordinator. A social worker. A palliative care specialist. Facilities must be credentialed by an organization approved by CMS. We remove the separate requirement that hospitals have in place staff and procedures for appropriate informed consent as this requirement is encompassed in the above team definition. The evidence is sufficient to conclude that participation in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) is no longer necessary for VADs to be reasonable and necessary. We remove this requirement. We will allow organizations that have credentialing programs specific to VADs to apply to CMS to be designated as a credentialing organization for VAD facilities for DT. These programs must ensure that credentialed facilities meet the criteria outlined in the NCD. The process for organizations to apply for CMS approval to be designated as a credentialing organization for VAD facilities for DT is posted on our web site along with a list of approved credentialing organizations, approved standard versions, and credentialed facilities. http://www.cms.gov/Medicare/Medicare-General-Information/MedicareApprovedFacilitie/VAD-Destination-Therapy-Facilities.html . The NCD does not address coverage of VADs for right ventricular support, biventricular support, use in beneficiaries under the age of 18, use in beneficiaries with complex congenital heart disease, or use in beneficiaries with acute heart failure without a history of chronic heart failure. Coverage under section 1862(a)(1)(A) for VADs in these situations will be made by local Medicare Administrative Contractors (MACs) within their respective jurisdictions. In addition to the changes above, CMS is renumbering its VAD-related policies into a sub-section of section 20.9 (Artificial Hearts and Related Devices) of the NCD Manual. The sub-section (20.9.1) will be titled Ventricular Assist Devices. This is an administrative change only to make it easier for the public to read and understand the VAD policies. Section 20.9.1 will include the existing coverage of VADs for postcardiotomy, BTT, and DT. The changes to the manual are reflected in Appendix C. II. Background The following acronyms are used throughout this document. For the readers convenience they are listed here in alphabetical order. 6-MWD – six-minute walk distance 6-MWT – six-minute walk test ACC – American College of Cardiology ACCF – American College of Cardiology Foundation ACE – Angiotensin-converting enzyme inhibitor ACGME - Accreditation Council for Graduate Medical Education ACP – American College of Physicians AHA – American Heart Association ARB – angiotensin receptor blocker BiVAD – biventricular assist device BMI – body mass index BSA – body surface area BTC – bridge to candidacy BTT – bridge to transplant CAP – continued access protocol CDC – Centers for Disease Control and Prevention CMS – Centers for Medicare & Medicaid Services CRT – cardiac resynchronization therapy DNV – Det Norske Veritas Healthcare Inc. DT – destination therapy EQ-5D – EuroQuol-5D EQ-5D VAS – EuroQol-5D Visual Analog Scale FDA – Food and Drug Administration HFrEF – heart failure with reduced ejection fraction HFSA – Heart Failure Society of America HM II – HeartMate II Left Ventricular Assist System HM VE – HeartMate Vented Electric Left Ventricular Assist System HM XVE – HeartMate XVE HRQOL - health-related quality of life HRSA – Health Resources and Services Administration HW VAS – HeartWare Ventricular Assist System IABP – intraaortic balloon pump ICD – implantable cardioverter defibrillator INTERMACS – Interagency Registry for Mechanically Assisted Circulatory Support ISHLT - International Society for Heart and Lung Transplantation LVAD – left ventricular assist device LVEF – left ventricular ejection fraction KCCQ – Kansas City Cardiomyopathy Questionnaire KCCQ CSS – Kansas City Cardiomyopathy Questionnaire Clinical Summary Score KCCQ OSS – Kansas City Cardiomyopathy Questionnaire Overall Summary Score MAC - Medicare Administrative Contractor MCS – mechanical circulatory support MCSD – mechanical circulatory support device MEDCAC – Medicare Evidence Development and Coverage Advisory Committee METS – metabolic equivalent task score MLHFQ – Minnesota Living with Heart Failure Questionnaire NCA – National Coverage Analysis NCD – National Coverage Determination NHLBI – National Heart, Lung and Blood Institute NIH – National Institutes of Health NYHA – New York Heart Association OPTN – Organ Procurement and Transplantation Network PMA – premarket approval PROs – patient-reported outcomes QOL – quality of life REMATCH – Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure UNOS – United Network for Organ Sharing VAD – ventricular assist device The scope of this national coverage analysis (NCA) includes a review of the evidence for patient selection and facility criteria for the use of durable VADs for end-stage congestive heart failure. Specifically, we review the evidence for whether it supports changes to our current criteria. Heart failure is a condition in which the heart cannot pump blood adequately to meet the body’s needs at rest or with exertion. Around 5.7 million people in the United States have heart failure with a higher prevalence at older ages. In the Framingham Heart Study, the incidence of heart failure doubled for each additional ten years of age (Lloyd-Jones, et al., 2002). In addition to age, which is an independent risk factor for heart failure, older adults often have additional risk factors such as high blood pressure, diabetes mellitus, coronary heart disease, tobacco use, and overweight/obesity and may have been exposed to these risk factors for many years. When the heart fails to adequately pump blood, patients retain excess fluid and tissues do not get enough oxygen. This results in symptoms such as shortness of breath, swelling of the legs, and fatigue and causes substantial morbidity and, in the most serious circumstances, mortality. Heart failure leads to over one million hospitalizations each year and 20% of hospitalizations in persons over the age of 65 (Go, et al., 2013) (Jessup & Brozena, 2003). It causes over 55,000 deaths and contributes to at least 275,000 deaths annually in the United States (CDC, 2012 (Go, et al., 2013). While there are objective measures of the severity of heart failure such as ejection fraction and cardiopulmonary exercise testing, care is most often driven by symptom-based classifications including the New York Heart Association (NYHA) classification, INTERMACS profiles, and the American Heart Association and American College of Cardiology (AHA/ACC) Stages of Heart Failure. The NYHA classification is a subjective measure of the severity of heart failure symptoms which some have criticized as being unresponsive to change, having a high degree of interobserver variability, and providing the perspective of the doctor rather than the patient (Green, et al., 2000) (Miller & Guglin, 2013). The four NYHA classes include: Class I: Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. Class II: Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea or anginal pain. Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort increases. INTERMACS profiles were recently developed to further classify patients with advanced NYHA class III and class IV heart failure into one of seven profiles (Stevenson, et al., 2009): Profile 1 - Critical cardiogenic shock: Patient with life-threatening hypotension despite rapidly escalating inotropic support, critical organ hypoperfusion, often confirmed by worsening acidosis and/or lactate levels. Profile 2 – Progressive decline: Patient with declining function despite intravenous inotropic support, may manifest with worsening renal function, nutritional depletion, or inability to restore volume balance. Also describes declining status in patients unable to tolerate inotropic therapy. Profile 3 - Stable but inotrope dependent: Patient with stable blood pressure, organ function, nutrition, and symptoms on continuous intravenous inotropic support (or a temporary circulatory support device or both), but demonstrating repeated failure to wean from support due to recurrent symptomatic hypotension or renal dysfunction. Profile 4 - Resting symptoms: Patient who can be stabilized close to normal volume status but experiences daily symptoms of congestion at rest or during activities of daily living. Doses of diuretics generally fluctuate at very high levels. Profile 5 - Exertion intolerant: Patient who is comfortable at rest and with activities of daily living but is unable to engage in any other activity, living predominantly within the house. Profile 6 - Exertion limited: Patient without evidence of fluid overload who is comfortable at rest, and with activities of daily living and minor activities outside the home but fatigues after the first few minutes of any meaningful activity. Profile 7 - Advanced NYHA class III: Patient who is clinically stable with a reasonable level of comfortable activity, usually able to walk more than a block. Has a history of previous decompensation but any decompensation requiring intravenous diuretics or hospitalization within the previous month should make this person a patient profile 6 or lower. The AHA/ACC Stages emphasize the development and progression of heart failure ranging from Stage A (risk factors but no current cardiac abnormality) to Stage D (refractory heart failure, may be eligible for advanced treatments such as continuous inotropes, heart transplant, ventricular assist device placement (VAD), or end-of-life care) (Hunt, 2009). Therapeutic interventions include modification of diet and lifestyle (such as restricting dietary sodium intake or increasing exercise) and medications including diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), aldosterone antagonists, beta-blockers, or digoxin. In the most severe cases, intravenous inotropic medications can be used. Inotropic medications do not reverse heart failure but may improve symptoms by making the heart beat stronger or reducing strain on the heart by reducing blood pressure. Device therapies include implantable cardioverter defibrillators (ICD) for patients at risk for sudden cardiac death; pacemakers and cardiac resynchronization devices for patients with abnormalities in the heart’s electrical conduction system; and VADs which are the subject of this analysis. Heart failure can be a progressive disease with increasing symptoms over time despite optimal medical management, though the time course is difficult to predict. Eventually, the heart fails completely and can no longer pump enough blood to sustain life. At this end-stage, eligible patients can undergo heart transplant; however, only around 2,000 heart transplants are performed annually in the United States (HRSA, 2012). In addition, older patients are often not eligible for heart transplant due to comorbid conditions which greatly increase the risk of poor outcomes. A ventricular assist device (VAD), also referred to as a mechanical circulatory support (MCS) device, is a mechanical pump that can assist a damaged or weakened heart in pumping blood. It does not replace the heart like a heart transplant but instead is surgically connected to the failing right or left ventricle of the native heart and the aorta. If both ventricles are failing, sometimes two devices are implanted for biventricular support. The mechanical pump is outside the body for temporary devices used in the hospital. The pump is implanted in the abdomen or chest for devices which allow patient mobility and hospital discharge, known as durable devices. All devices require a driveline that goes from the pump to an external power source and control unit. Initial pumps were pulsatile, mimicking the pulsations of the native heart, but clinical use was limited by issues such as large pump size, high rates of adverse events, and poor device durability. Newer continuous-flow pumps have almost entirely replaced pulsatile pumps for longer-term use. Patients who may be candidates for VAD implant undergo extensive clinical testing to ensure an adequate severity of heart failure but acceptable severity of comorbidities. This evaluation attempts to balance the benefits that might be achieved by VAD implant with the significant risks of the surgery and prolonged device support. Initially, VADs were used in the hospital as short-term support for patients with acute heart failure caused by temporary conditions such as infection or open heart surgery. With the development of smaller implantable pumps, patients could be ambulatory, discharged from the hospital, and supported on device for longer periods of time. These durable VADs were first introduced in patients on the heart transplant waitlist as a “bridge to transplant (BTT)” since the duration of support was intended to be finite. With heart transplants in limited supply and additional clinical experience gained, devices were subsequently implanted as “destination therapy (DT)” in patients ineligible for heart transplant who required permanent support. Heart failure patients that may be candidates for VAD therapy who are not classified as either BTT or DT at the time of VAD implant are referred to as bridge to decision or bridge to candidacy (BTC). Some patients transition between the categories of BTT, BTC, and DT over time with the development or resolution of comorbid conditions. In addition, this categorization can be inconsistent due to differences in the transplant approval and listing processes at individual transplant hospitals. The use of VADs as a therapeutic tool has continued to evolve since our last national coverage analyses for BTT and DT. Based on this and ten years of mandatory registry participation, CMS has decided to review our current BTT and DT policies. This national coverage analysis reviews the available evidence for patient selection and facility criteria for the use of durable VADs for end-stage congestive heart failure. III.History of Medicare Coverage Bridge to Transplant In 1996, CMS began covering VADs implanted as BTT at Medicare-approved heart transplant centers. In 2001, CMS covered implantation at sites other than Medicare-approved heart transplant centers. Currently, devices are only covered if they have received approval from the FDA for BTT, are used according to the FDA-approved labeling instructions, and all of the following criteria are fulfilled: The patient is approved and listed as a candidate for heart transplant by a Medicare-approved heart transplant center; and The implanting site, if different than the Medicare-approved transplant center, must receive written permission from the Medicare-approved heart transplant center under which the patient is listed prior to implantation of the VAD. The Medicare-approved heart transplant center should make every reasonable effort to transplant patients on such devices as soon as medically reasonable. Ideally, the Medicare-approved heart transplant centers should determine patient-specific timetables for transplant, and should not maintain such patients on VADs if suitable hearts become available. Destination Therapy In 2003, CMS began covering VADs implanted as DT at Medicare-approved heart transplant centers meeting specific facility criteria including participation in a national, audited registry. We believed these criteria were necessary due to the technical nature of the procedure, the high-risk patient population, and the need to ensure reasonable dissemination of new technology. In 2007, CMS allowed implantation at sites other than Medicare-approved heart transplant centers, named INTERMACS as the required registry, and required facilities to be credentialed by the Joint Commission based on standards dated February 2007. INTERMACS is a North American registry of VAD recipients “established as a joint effort of the National Heart, Lung and Blood Institute (NHLBI), the Centers for Medicare and Medicaid Services (CMS), the Food and Drug Administration (FDA), clinicians, scientists and industry representatives” ( http://www.uab.edu/intermacs/ ). Currently, devices are only covered if they have received approval from the FDA for DT, are used according to the FDA-approved labeling instructions, and are implanted at a facility meeting the following criteria: Facilities must have at least one member of the VAD team with experience implanting at least 10 VADs (as bridge-to-transplant or destination therapy) or artificial hearts over the course of the previous 36 months; Facilities must be a member of the INTERMACS Registry; and, All facilities must meet the above facility criteria and be credentialed by the Joint Commission under the Disease Specific Certification Program for Ventricular Assist Devices (standards dated February 2007). Facilities also must have in place staff and procedures that ensure that prospective VAD recipients receive all information necessary to assist them in giving appropriate informed consent for the procedure so that they and their families are fully aware of the aftercare requirements and potential limitations, as well as benefits, following VAD implantation. In 2003, CMS required patients implanted as DT to meet specific criteria which were developed based on the study that led to FDA approval of a pulsatile-flow device for DT (the pivotal study) (Rose, et al., 2001). In 2010, CMS modified these criteria after review of the pivotal study that led to FDA approval of a continuous-flow device for DT (Slaughter, et al., 2009). Currently devices are only covered as DT for patients with chronic end-stage heart failure (New York Heart Association Class IV end-stage left ventricular failure) who are not candidates for heart transplant, and meet all of the following conditions: Have failed to respond to optimal medical management (including beta-blockers and ACE inhibitors if tolerated) for at least 45 of the last 60 days, or have been balloon pump-dependent for 7 days, or IV inotrope-dependent for 14 days; and Have a left ventricular ejection fraction (LVEF) < 25%; and Have demonstrated functional limitation with a peak oxygen consumption of ≤ 14 ml/kg/min unless balloon pump- or inotrope-dependent or physically unable to perform the test. A. Current Reconsideration On February 7, 2013, CMS accepted a formal request from Det Norske Veritas Healthcare Inc. (DNV) to reconsider Section 20.9 of the NCD Manual. Specifically, DNV requested that the facility criteria be amended to include the DNV Mechanical Circulatory Support Certification Program as an acceptable credential for facilities implanting devices as DT. The request is available at http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id268.pdf . CMS has also included a review of the existing evidence for patient selection and facility criteria for the use of durable VADs for end-stage congestive heart failure B. Benefit Category For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act (the Act). VADs may fall within the Inpatient Hospital Services benefit category (section 1861(b) (2) of the Social Security Act (the Act)), which describes supplies, appliances, and equipment furnished by the hospital, for use in the hospital, for the care and treatment of inpatients. After a VAD has been surgically implanted into the patient and when the patient is not a hospital patient, the replacement of an external part or parts may be covered under Medicare Part B within the Prosthetic Device benefit category (section 1861(s)(8) of the Act). This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. IV. Timeline of Recent Activities Date Action February 7, 2013 CMS initiates this national coverage analysis. March 9, 2013 The initial 30-day public comment period closes. August 1, 2013 CMS posts the proposed decision memorandum. The 30-day public comment period begins. August 30, 2013 The 30-day public comment period closes. V. FDA Status The FDA is aware of several durable VADs which are currently FDA-approved and commercially marketed for use as BTT and/or DT for single-ventricle support in adults. The same VAD may also be FDA-approved for additional Indications for Use which will not be discussed here. The FDA approved the pulsatile HeartMate Vented Electric Left Ventricular Assist System (HM VE) for BTT in 1994 and the modified HM XVE for DT in 2003 (Premarket Approval (PMA) P920014). This device has since been replaced by the continuous-flow HeartMate II Left Ventricular Assist System (HM II) which received FDA approval for BTT in 2008 and DT in 2010 (PMA P060040; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTopic/pma/pma.cfm?num=P060040). The HM II Summary of Safety and Effectiveness Indications for Use states: “The HeartMate II LVAS is intended for use as a bridge to transplantation in cardiac transplant candidates at risk of imminent death from non-reversible left ventricular failure. The HeartMate II LVAS is also indicated for use in patients with New York Heart Association (NYHA) Class IIIB or IV end-stage left ventricular failure who have received optimal medical therapy for at least 45 of the last 60 days, and who are not candidates for cardiac transplantation.” The FDA approved the continuous-flow HeartWare Ventricular Assist System (HW VAS) for BTT in 2012 (PMA P100047; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=P100047). The HW VAS Summary of Safety and Effectiveness Indications for Use states: “The HeartWare Ventricular Assist System (HeartWare VAS) is indicated for use as a bridge to cardiac transplantation in patients who are at risk of death from refractory end stage left ventricular heart failure.” VI. General Methodological Principles When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A. Public commenters sometimes cite the published clinical evidence and provide CMS with useful information. Public comments that provide information based on unpublished evidence, such as the results of individual practitioners or patients, are less rigorous and, therefore, less useful for making a coverage determination. CMS uses the initial comment period to inform its proposed decision. CMS responds in detail to the public comments that were received in response to the proposed decision when it issues the final decision memorandum. VII. Evidence A. Introduction This examination of evidence focuses upon whether new clinical evidence from peer-reviewed published literature or INTERMACS data analyses supports a change to our current NCD’s patient selection criteria or facility criteria. Key health outcomes of interest to CMS are mortality; morbidity including adverse events such as bleeding, infection, stroke, or device malfunction; and patient-centered measures of physical function and quality of life (QOL). Mortality in VAD recipients is generally reported using the Kaplan-Meier method. With this statistical technique, patients are censored at the time of VAD removal for heart transplant or recovery of native heart function and, therefore, their outcomes following device removal are not incorporated into subsequent data points. Measures of patient function in heart failure include the NYHA classification, INTERMACS profiles, and the AHA/ACC Stages of Heart Failure which were discussed in section II. Additional measures include the six-minute walk test (6-MWT) and the metabolic equivalent task score (METS). The 6-MWT measures the distance a patient walks in six minutes (the six-minute walk distance; 6-MWD) (American Thoracic Society, 2002). While the testing is standardized, results are effort dependent. METS are a subjective rating of a patient’s highest self-reported activity level during the reporting period ranging from 1 (bedridden, unable to care for self or participate in any physical activity) to 6 (dancing, climbing stairs, heavy shoveling). Several instruments are available to assess QOL (Grady, et al., 2012) (Dunderdale, et al., 2005). Generic instruments such as the SF-36 or EuroQol-5D (EQ-5D) provide a broad overview and allow comparisons with healthy populations or those with other chronic conditions. Heart failure-specific instruments such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Minnesota Living with Heart Failure Questionnaire (MLHFQ) are more relevant to the specific disease and may be more responsive to change but do not allow comparisons with other groups. No instruments have been designed or validated specifically for VAD recipients; however, the EQ-5D, KCCQ, and MLHFQ are most commonly reported. The EQ-5D scores patient-reported health-related quality of life (HRQOL) across different dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). A higher value on a scale of 0 to 100 represents better quality of life. The KCCQ quantifies physical limitations, symptoms, self-efficacy, social limitations, and quality of life. The KCCQ Overall summary score (OSS) combines scores from all domains while the clinical summary score (CSS) combines the physical function and symptom scores. For both, a higher value on a range of 0 to 100 represents a better quality of life. The MLHFQ quantifies the impact of heart failure and its treatment on physical and emotional domains. A lower value on range of 0 to 105 represents a better quality of life. Well-designed, double-blind randomized controlled trials provide the highest quality of evidence regarding patient outcomes as subjects are allocated to comparison groups in an unbiased way and outcomes are assessed without knowledge of the treatment. Our search did not identify any randomized trials reported since the last analyses for BTT and DT and none were identified by the public commenters; therefore, we expanded our search to include study types lower in the evidence hierarchy such as non-randomized trials or observational cohorts. B. Discussion of Evidence 1. Questions: The development of an assessment in support of Medicare coverage decisions is based on the same general question for almost all national coverage analyses (NCAs): "Is the evidence sufficient to conclude that the application of the item or service under study will improve health outcomes for Medicare patients?" For this NCA, the specific questions of interest are: 1. Is the evidence adequate to conclude that maintaining the current patient selection criteria for VAD implantation will provide improved health outcomes for Medicare beneficiaries? 2. Is the evidence adequate to conclude that maintaining the current facility criteria for VAD implantation will provide improved health outcomes for Medicare beneficiaries? 2. External Technology Assessment (TA) CMS did not commission an external TA for this NCA; however, we identified one external TA published since the last NCA. Rector TS, Taylor BC, Greer N, Rutks I, and Wilt TJ. Use of Left Ventricular Assist Devices as Destination Therapy in End-Stage Congestive Heart Failure: A Systematic Review. VA-ESP Project #09-009; May 2012. (Rector, et al., 2012) The Department of Veteran’s Affairs Health Services Research & Development Service Evidence-based Synthesis Program performed a systematic review on the use of VADs as DT in end-stage congestive heart failure. They reviewed articles published through October 2011 addressing three key questions, one of which is relevant to the scope of this NCA. “Key Question #2. What patient or site characteristics have been associated with patient benefits or harms when the FDA-approved, current generation LVAD is used as destination therapy? Conclusion: The available evidence is insufficient to refine patient or site selection criteria for use of the HeartMate II as destination therapy. A few studies have identified risk factors for mortality and complications and developed or applied mortality prediction models to this particular patient population. Further studies are needed to validate use of different criteria to improve patient outcomes. An ongoing clinical trial is selecting less severely ill patients and may expand the criteria for use of a newer generation continuous flow device (HeartWare) as destination therapy. In the meantime, the approved FDA indication and CMS criteria for coverage are available to guide patient selection.” The authors noted that “Patients who die in the hospital soon after implantation of a ventricular assist device do not benefit. A validated prediction model for early/postoperative mortality could be applied to avoid high risk and costly attempts to use ventricular assist devices as destination therapy. Ideally clinical trials would be done to show that use of an outcome prediction model improves patient outcomes. This review did not find any established or proposed threshold for predicted risk of post-operative mortality that would preclude use of destination therapy or generally be acceptable to patients and health care providers.” 3. Internal Technology Assessment CMS examined the evidence regarding the impact of VADs on mortality, morbidity, QOL, and functional status in patients with end-stage congestive heart failure. Specifically, we assessed whether the evidence is adequate to support changes to our current patient selection or facility criteria. We included studies with publication dates between August 1, 2007 and March 28, 2013 to include the first pivotal trial for FDA approval of a continuous-flow device and later studies. For DT, we included studies with publication dates between January 2010 and March 28, 2013 to only include studies published since our last NCA. We searched the PubMed database using the terms ventricular assist device, mechanical circulatory support device, or INTERMACS. We limited our search to English language publications in humans over the age of 18. We reviewed the titles and abstracts of peer-reviewed publications and all potentially relevant articles were reviewed in full. We identified additional references from the bibliographies of key articles. We excluded studies of devices not currently approved by the FDA, devices that are no longer marketed, pre-pivotal studies of approved devices, studies of fewer than 50 VAD recipients, retrospective single-center case series, studies reporting only intermediate or surrogate outcomes, studies only reporting outcomes following heart transplant, or studies of cost or cost effectiveness. We also excluded studies focused only on pulsatile, temporary (non-durable), percutaneous, right-sided, biventricular, or partial-support devices and studies of artificial hearts. We identified three trials of the use of continuous-flow VADs meeting the above criteria: the pivotal HM II BTT trial (Miller, et al., 2007) (Pagani, et al., 2009) (Bogaev, et al., 2011), follow-up analyses of the pivotal HM II DT trial (initial trial reviewed previously in CAG-00119R2) (Park, et al., 2012), and the pivotal HW VAS BTT trial (Aaronson, et al., 2012). We identified two studies reporting additional analyses of data from these trials and their associated continued access protocols (CAP) (Adamson, et al., 2011) (Cowger, et al., 2013). Additionally, we identified several published analyses of INTERMACS registry data: an FDA-required post-approval study of the HM II as BTT (Starling, et al., 2011), a retrospective analysis of HM II BTT implants (John, et al., 2011), a comparison of outcomes in men and women (Hsich, et al., 2012) and, a comparison of device durability (Holman, et al., 2013). We also identified published (Kirklin, et al., 2012) (Kirklin, et al., 2013) and unpublished (INTERMACS Q4, 2012) (INTERMACS CMS Q4, 2012) (INTERMACS CMS Report, 2013) reports from the INTERMACS investigators. Public commenters identified a comparison of outcomes by device implant strategy published after the posting of our proposed decision (Teuteberg, et al., 2013). We identified one study of a program intervention (Pamboukian, et al., 2011). Lastly, we identified one systematic review of the literature on patient-reported outcomes (Brouwers, et al., 2011). Question #1: Is the evidence adequate to conclude that maintaining the current patient selection criteria for VAD implantation will provide improved health outcomes for Medicare beneficiaries? We note that the studies identified to inform this first question are limited to pivotal trials which led to FDA device approvals, follow-up analyses of pivotal trial data, and INTERMACS analyses. Some of the INTERMACS analyses are not in the peer-reviewed published literature. We have reported a focused review of the population studied (e.g. inclusion/exclusion criteria) and their outcomes, specifically mortality, morbidity (adverse events), functional status, and QOL. Miller LW, Pagani FD, Russell SD, John R, Boyle AJ, Aaronson KD, Conte JV, Naka Y, Mancini D, Delgado RM, MacGillivray TE, Farrar DJ, Frazier OH; Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med. 2007 Aug 30; 357(9): 885-96. PMID: 17761592. (Miller, et al., 2007) Pagani FD, Miller LW, Russell SD, Aaronson KD, John R, Boyle AJ, Conte JV, Bogaev RC, MacGillivray TE, Naka Y, Mancini D, Massey HT, Chen L, Klodell CT, Aranda JM, Moazami N, Ewald GA, Farrar DJ, Frazier OH. Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device. J Am Coll Cardiol. 2009 Jul 21;54(4):312-21. PMID: 19608028. (Pagani, et al., 2009) Miller et al. and Pagani et al. reported the results of a pivotal, manufacturer-sponsored, single-arm, prospective study and CAP which assessed outcomes for the HM II in a BTT population. Miller et al. reported results from 133 patients enrolled in the initial study. Pagani et al. reported follow-up outcomes for these patients combined with an additional 148 patients enrolled through a CAP. Patients had NYHA class IV heart failure and were listed for heart transplant with United Network for Organ Sharing (UNOS) status 1A or 1B. Patients were excluded for severe renal, pulmonary, or hepatic dysfunction; active uncontrolled infection; a mechanical aortic valve; aortic insufficiency; an aortic aneurysm; the presence of other mechanical circulatory support, except for an intraaortic balloon pump (IABP); and technical obstacles thought by the investigator to pose an increased surgical risk. Ninety percent of patients were receiving intravenous inotropes with the remaining 10% intolerant due to arrhythmias. Forty-five percent were on an IABP. Of the 281 total patients, 222 (79%) had either undergone heart transplant (n = 157), device explant for cardiac recovery (n = 7), or remained alive with ongoing mechanical support (n = 58) at 18 months. Kaplan-Meier survival for patients continuing on device support was 82% at six months (number at risk = 133) and 72% at 18 months (number at risk = 58). Adverse event rates were compared with previous studies of pulsatile devices and included bleeding requiring surgery (0.45 events/patient-year vs. 1.47), driveline infection (0.26 vs. 3.49), stroke (0.14 vs. 0.44), non-stroke neurological events (0.09 vs. 0.67), and right heart failure requiring a right-sided VAD (0.09 vs. 0.30) (Frazier, et al., 2001). The authors noted, “differences in rates of adverse events may have been influenced by differences in acuity of patient illness or improvements in patient management over time.” From the initial 133 patients, 82 remained alive and on device support at the three month assessment of functional status and QOL. All reported NYHA class IV symptoms prior to implant. By three months (number tested =78) this fell to 3% with 32% reporting class I symptoms, 51% class II, and 14% class III. The number of patients able to perform the 6-MWT increased from 25 to 56 at three months and the mean 6-MWD increased from 42 ± 97 meters to 292 ± 212 meters. The mean score on the MLHFQ fell from 73 ± 25 (n = 114) to 45 ± 25 (n = 77). The mean KCCQ OSS rose from 33 ± 19 (n = 113) to 57 ± 20 (n = 77). Data collection was reportedly incomplete “because of issues related to staff availability, scheduling, or oversight.” Pagani et al. concluded, “A continuous-flow rotary pump LVAD with axial design provides safe, reliable, and effective hemodynamic support in patients awaiting transplantation with improved quality of life and functional capacity. Furthermore, LVAD therapy with continuous-flow rotary pumps with extended support is associated with a very low rate of device malfunction or infection requiring device exchange. Continuous-flow rotary pumps provide a superior alternative to pumps with a pulsatile design in patients awaiting transplantation.” Bogaev RC, Pamboukian SV, Moore SA, Chen L, John R, Boyle AJ, Sundareswaran KS, Farrar DJ, Frazier OH; Comparison of outcomes in women versus men using a continuous-flow left ventricular assist device as a bridge to transplantation. J Heart Lung Transplant. 2011 May; 30(5): 515-22. PMID: 21257321. (Bogaev, et al., 2011) Bogaev et al. reported on “a sex-based analysis of the combined 465 patients who have received the HeartMate II as a bridge to cardiac transplantation.” Specifically, they compared outcomes of 104 women and 361 men implanted with the HM II device during the BTT trial and CAP who either completed study endpoints or reached 18-month follow-up after implant. Kaplan-Meier survival and adverse event rates were similar, but hemorrhagic stroke occurred more frequently in women (0.10 events/patient-year vs. 0.04) and device-related infections occurred less frequently (0.23 vs. 0.44). The authors concluded, “continuous-flow LV assistance as a bridge to transplantation is associated with similar survival rates in women and men. Differences observed in higher stroke rates and fewer infections among women require further study.” Aaronson KD, Slaughter MS, Miller LW, McGee EC, Cotts WG, Acker MA, Jessup ML, Gregoric ID, Loyalka P, Frazier OH, Jeevanandam V, Anderson AS, Kormos RL, Teuteberg JJ, Levy WC, Naftel DC, Bittman RM, Pagani FD, Hathaway DR, Boyce SW. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation. 2012 Jun 26; 125(25): 3191-200. PMID: 22619284. (Aaronson, et al., 2012) Aaronson et al. reported the results of a pivotal, manufacturer-sponsored, non-randomized, prospective noninferiority trial comparing outcomes of 140 patients implanted with the HW VAS as BTT with outcomes of a contemporaneous INTERMACS registry control group (>95% HM II). HW VAS patients were ≥ 18 years of age with a body surface area (BSA) of ≥ 1.2 m 2 , had NYHA class IV symptoms, and were listed for heart transplant with UNOS status 1A or 1B. Patients were excluded for ongoing mechanical circulatory support with the exception of an IABP, a history of heart transplant, prior valve replacement, cirrhosis, portal hypertension, pulmonary hypertension unresponsive to medical management, untreated aortic aneurysm, symptomatic cerebrovascular disease or >80% carotid stenosis, severe right ventricular failure, active uncontrolled infection, thrombocytopenia, coagulopathy, intolerance to anticoagulant or antiplatelet therapy, serum creatinine greater than three times upper limit of normal or requirement for dialysis, liver enzymes greater than three times upper limit of normal, or recent cardiothoracic surgery, acute myocardial infarction, ventilator support, or pulmonary embolus. 95% of patients had NYHA class IV symptoms, 82% were on intravenous inotropes, and 25% of were on an IABP. The INTERMACS control group included 499 adult patients who received a primary left-sided device during the study period, were prospectively enrolled in the registry, had a BSA of ≥ 1.2 m 2 , and were listed for heart transplant. Patients were excluded for a creatinine > 5 mg/dl, dialysis, or ventilator support within 24 hours of implant. Ninety and seven tenths percent of HW VAS and 90.1% of control patients reached the primary endpoint of the proportion of patients who, at 180 days, had undergone transplant, had cardiac recovery, or remained on mechanical support with the originally implanted device. One year Kaplan-Meier survival was 86% for the HW VAS (number at risk = 63) and 85% for the INTERMACS control (number at risk = 186). Adverse event rates for the HW VAS were generally comparable to the published literature (INTERMACS control data were unavailable). The authors noted that any adverse event comparisons were “solely hypothesis generating unless confirmed in a randomized clinical trial.” QOL was measured with the KCCQ and EQ-5D VAS. Ninety-one percent of patients completed the KCCQ at baseline and 76% of patients alive on device support completed it at six months. Available data demonstrated improvement in the KCCQ OSS from 35 ± 19 to 67 ± 21 and in the KCCQ CSS from 44 ± 22 to 74 ± 21. Ninety-three percent of patients completed the EQ-5D VAS at baseline and 78% of patients alive on device support completed it at six months. Available data demonstrated improvement in the EQ-5D VAS from 40 ± 24 to 70 ± 20. Functional capacity was measured using the NYHA classification and 6-MWT. Changes in NYHA class were not reported due to significant missing data. Ninety-four percent of patients had a 6-MWD recorded at baseline and 80% of patients alive on device support had one recorded at six months. Available data demonstrated an improvement in median 6-MWD from 0 to 274.2 meters. The authors concluded, “a small, continuous-flow, centrifugal pump with a single magnetically and hydrodynamically levitated moving part, implanted directly in the left ventricle and positioned within the pericardial space, was associated with high rates of 180-day success and survival and a favorable adverse event profile when used as a bridge to transplantation. Perioperative mortality was 1%, and survival at 1 year was 86%. Quality-of-life and functional capacity improvements were much larger than those seen with any drug or device therapy for advanced heart failure and were similar to those obtained with cardiac transplantation.” Park SJ, Milano CA, Tatooles AJ, Rogers JG, Adamson RM, Steidley DE, Ewald GA, Sundareswaran KS, Farrar DJ, Slaughter MS. Outcomes in advanced heart failure patients with left ventricular assist devices for destination therapy. Circ Heart Fail. 2012 Mar 1; 5(2):241-8. PMID: 22282104. (Park, et al., 2012) Park et al. reported extended follow-up for 133 patients who received the HM II device during the pivotal HM II DT trial (“early-trial”) compared with 281 patients enrolled in the CAP (“mid-trial”) who had reached two-year follow-up. The authors stated, “The goal of this report is to compare outcomes in patients enrolled later in the trial under continued access protocol with outcomes of the initial primary patient cohort. The main hypothesis is that patients implanted in the later part of the trial would have better clinical outcomes compared with those who were implanted earlier.” We previously reviewed the pivotal HM II DT trial (CAG-00119R2) (Slaughter, et al., 2009). In brief, patients were enrolled with advanced heart failure refractory to medical management who were ineligible for heart transplant. Patients had an ejection fraction of < 25%, a peak VO 2 < 14 mL/kg per minute or < 50% of predicted, NYHA Class IIIB or IV symptoms for at least 45 of 60 days, or dependence on an IABP for seven days or inotropes for 14 days before enrollment. Exclusion criteria included severe renal impairment (serum creatinine > 3.5 mg/dl or dialysis), hepatic or pulmonary dysfunction, uncontrolled infection, history of stroke, mechanical aortic valve, irreparable aortic insufficiency, aortic aneurysm > 5.0 cm, or other mechanical circulatory support (except IABPs). For this follow-up analysis, 71% of early-trial and 63% of mid-trial patients had NYHA class IV symptoms, 77% and 78% were receiving intravenous inotropes, and 23 and 19% were on an IABP respectively. Kaplan-Meier survival in the early-trial group was 68% at one year (number at risk = 82) and 58% at two years (number at risk = 62) and in the mid-trial group survival was 73% (number at risk = 187) and 63% respectively (number at risk = 146). Adverse events rates were compared between the early and mid-trial periods including hemorrhagic strokes