Portal de Periódicos da CAPES

Clinical trial design and rationale of the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) investigational device exemption clinical study protocol

2016; Elsevier BV; Volume: 35; Issue: 4 Linguagem: Inglês

10.1016/j.healun.2016.01.021

1557-3117

Gerald J. Heatley, Poornima Sood, Daniel J. Goldstein, Nir Uriel, Joseph C. Cleveland, Don Middlebrook, Mandeep R. Mehra,

Cardiac Arrest and Resuscitation

The HeartMate 3 left ventricular assist system (LVAS; St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA) was recently introduced into clinical trials for durable circulatory support in patients with medically refractory advanced-stage heart failure. This centrifugal, fully magnetically levitated, continuous-flow pump is engineered with the intent to enhance hemocompatibility and reduce shear stress on blood elements, while also possessing intrinsic pulsatility. Although bridge-to-transplant (BTT) and destination therapy (DT) are established dichotomous indications for durable left ventricular assist device (LVAD) support, clinical practice has challenged the appropriateness of these designations. The introduction of novel LVAD technology allows for the development of clinical trial designs to keep pace with current practices. The prospective, randomized Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) clinical trial aims to evaluate the safety and effectiveness of the HeartMate 3 LVAS by demonstrating non-inferiority to the HeartMate II LVAS (also St. Jude Medical, Inc.). The innovative trial design includes patients enrolled under a single inclusion and exclusion criteria , regardless of the intended use of the device, with outcomes ascertained in the short term (ST, at 6 months) and long term (LT, at 2 years). This adaptive trial design includes a pre-specified safety phase (n = 30) analysis. The ST cohort includes the first 294 patients and the LT cohort includes the first 366 patients for evaluation of the composite primary end-point of survival to transplant, recovery or LVAD support free of debilitating stroke (modified Rankin score >3), or re-operation to replace the pump. As part of the adaptive design, an analysis by an independent statistician will determine whether sample size adjustment is required at pre-specified times during the study. A further 662 patients will be enrolled to reach a total of 1,028 patients for evaluation of the secondary end-point of pump replacement at 2 years. The HeartMate 3 left ventricular assist system (LVAS; St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA) was recently introduced into clinical trials for durable circulatory support in patients with medically refractory advanced-stage heart failure. This centrifugal, fully magnetically levitated, continuous-flow pump is engineered with the intent to enhance hemocompatibility and reduce shear stress on blood elements, while also possessing intrinsic pulsatility. Although bridge-to-transplant (BTT) and destination therapy (DT) are established dichotomous indications for durable left ventricular assist device (LVAD) support, clinical practice has challenged the appropriateness of these designations. The introduction of novel LVAD technology allows for the development of clinical trial designs to keep pace with current practices. The prospective, randomized Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) clinical trial aims to evaluate the safety and effectiveness of the HeartMate 3 LVAS by demonstrating non-inferiority to the HeartMate II LVAS (also St. Jude Medical, Inc.). The innovative trial design includes patients enrolled under a single inclusion and exclusion criteria , regardless of the intended use of the device, with outcomes ascertained in the short term (ST, at 6 months) and long term (LT, at 2 years). This adaptive trial design includes a pre-specified safety phase (n = 30) analysis. The ST cohort includes the first 294 patients and the LT cohort includes the first 366 patients for evaluation of the composite primary end-point of survival to transplant, recovery or LVAD support free of debilitating stroke (modified Rankin score >3), or re-operation to replace the pump. As part of the adaptive design, an analysis by an independent statistician will determine whether sample size adjustment is required at pre-specified times during the study. A further 662 patients will be enrolled to reach a total of 1,028 patients for evaluation of the secondary end-point of pump replacement at 2 years. Early clinical trials of durable left ventricular assist device (LVAD) support prospectively included bridge-to-transplant (BTT) candidates and compared them to historical or parallel control patients who did not undergo device implantation.1Frazier O.H. Rose E.A. McCarthy P. et al.Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system.Ann Surg. 1995; 222: 327-336Crossref PubMed Scopus (309) Google Scholar, 2Frazier O.H. Rose E.A. Macmanus Q. et al.Multicenter clinical evaluation of the HeartMate 1000 IP left ventricular assist device.Ann Thorac Surg. 1992; 53: 1080-1090Abstract Full Text PDF PubMed Scopus (361) Google Scholar, 3Frazier O.H. Rose E.A. Oz M.C. et al.Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation.J Thorac Cardiovasc Surg. 2001; 122: 1186-1195Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar After nearly a decade of successful BTT experience, the Thoratec paracorporeal VAD system and the HeartMate I devices (IP-LVAD and VE-LVAD; Thoratec Corporation, Pleasanton, CA) were commercially approved by the United States Food and Drug Administration (FDA) for this indication.1Frazier O.H. Rose E.A. McCarthy P. et al.Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system.Ann Surg. 1995; 222: 327-336Crossref PubMed Scopus (309) Google Scholar, 3Frazier O.H. Rose E.A. Oz M.C. et al.Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation.J Thorac Cardiovasc Surg. 2001; 122: 1186-1195Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar, 4Farrar D.J. Hill J.D. Pennington D.G. et al.Preoperative and postoperative comparison of patients with univentricular and biventricular support with the Thoratec ventricular assist device as a bridge to cardiac transplantation.J Thorac Cardiovasc Surg. 1997; 113: 202-209Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar The limited donor supply and consequent strict transplant candidacy criteria generated a need for such therapy in transplant-ineligible candidates with advanced heart failure who could potentially benefit from permanent, lifetime LVAD support. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, the first randomized, controlled trial with an LVAD, was thus conceived and led to FDA approval for the indication of "destination therapy" (DT).5Rose E.A. Gelijns A.C. Moskowitz A.J. et al.Long-term mechanical left ventricular assistance for end-stage heart failure.N Engl J Med. 2001; 345: 1435-1443Crossref PubMed Scopus (3375) Google Scholar, 6Rose E.A. Moskowitz A.J. Packer M. et al.The REMATCH trial: rationale, design, and end points.Ann Thorac Surg. 1999; 67: 723-730Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar On the basis of these approved indications, the Centers for Medicare and Medicaid Services in the USA established criteria for reimbursement, and the regulatory agencies used similar criteria for center accreditation. Accordingly, all successive clinical trials with new LVADs targeted these distinct BTT and DT indications. Thus, the ADVANCE trial of the HeartWare HVAD (HeartWare, Inc., Framingham, MA) enrolled a BTT population and compared outcomes with registry-derived patients implanted contemporaneously with commercially available devices.7Aaronson K.D. Slaughter M.S. Miller L.W. et al.Use of an intrapericardial, continuous flow, centrifugal pump in patients awaiting heart transplantation.Circulation. 2012; 125: 3191-3200Crossref PubMed Scopus (516) Google Scholar The HeartMate II LVAS (St. Jude Medical, Inc., formerly Thoratec Corporation, Pleasanton, CA) is currently approved for BTT and DT, whereas the HVAD remains indicated for BTT alone and trials examining the use of an HVAD in DT populations await completion. Despite improved survival and quality of life, long-term success with current devices remains partially limited by adverse effects, including infections, neurologic complications and pump thromboses.8Goldstein D.J. Naftel D. Holman W. et al.Continuous-flow devices and percutaneous site infections: clinical outcomes.J Heart Lung Transplant. 2012; 31: 1151-1157Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 9Coffin S.T. Haglund N.A. Davis M.E. et al.Adverse neurologic events in patients bridged with long-term mechanical circulatory support: a device-specific comparative analysis.J Heart Lung Transplant. 2015; 34: 1578-1585Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 10Stewart G.C. Givertz M.M. Mehra M. Pump thrombosis redux.J Heart Lung Transplant. 2015; 34: 1511-1514Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 11Stulak J.M. Davis M.E. Haglund N. et al.Adverse events in contemporary continuous-flow left ventricular assist devices: a multi-institutional comparison shows significant differences.J Thorac Cardiovasc Surg. 2016; 151: 177-189Abstract Full Text Full Text PDF Scopus (98) Google Scholar The HeartMate 3 LVAS is a centrifugal-flow pump engineered to optimize fluid dynamics and developed with wider blood-flow passages with the intent to avert thrombogenesis. The HeartMate 3 was first evaluated in humans in 50 patients in a single-arm, prospective, non-randomized clinical study outside of the USA to meet the Conformité Européenne (CE) mark requirements.12Schmitto J.D. Hanke J.S. Rojas S.V. et al.First implantation in man of a new magnetically levitated left ventricular assist device (HeartMate III).J Heart Lung Transplant. 2015; 34: 858-860Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 13Netuka I. Sood P. Pya Y. et al.Fully magnetically levitated left ventricular assist system for the treatment of advanced HF: a multicenter study.J Am Coll Cardiol. 2015; 66: 2579-2589Crossref PubMed Scopus (175) Google Scholar Figure 1 presents the competing outcomes analysis, and Table 1 presents the adverse event data from this first-in-humans experience through 6 months of follow-up.13Netuka I. Sood P. Pya Y. et al.Fully magnetically levitated left ventricular assist system for the treatment of advanced HF: a multicenter study.J Am Coll Cardiol. 2015; 66: 2579-2589Crossref PubMed Scopus (175) Google ScholarTable 1All Adverse Events Through 6 Months for the 50 Patients Enrolled in the HeartMate 3 CE Mark Clinical Trial13Netuka I. Sood P. Pya Y. et al.Fully magnetically levitated left ventricular assist system for the treatment of advanced HF: a multicenter study.J Am Coll Cardiol. 2015; 66: 2579-2589Crossref PubMed Scopus (175) Google ScholarDays 0 to 30 (n = 50)Days >30 (n = 49)All (n = 50)Adverse eventPatients (n)Patients (%)Number of eventsPatients (n)Patients (%)Number of eventsPatients (n)Patients (%)Number of eventsBleeding15301981616193835Requiring surgery61262427148GI bleeding242364486Cardiac arrhythmias142814363173417Infection102014122414183628Sepsis4844848168Drive-line1214845105StrokeaIncludes 3 procedural-related events: 1 implant issue (difficulty engaging inflow conduit); 1 after anaphylactic shock from contrast media; and 1 after transcatheter aortic valve implantation procedure.2424846126Ischemic242242484Hemorrhagic000242242Neurologic dysfunction otherbSeizure (n = 2) and transient ischemic attack (n = 2).242242484Device thrombosis000000000Device malfunction000000000Hemolysis000000000Psychiatric episode121242363Renal dysfunction51050005105Hepatic dysfunction121000121Respiratory failure71471218168Right heart failure4841215105Requiring RVAD242000242Wound dehiscence242242363Other eventcOther adverse events include pleural effusion (n = 1), volume status (n = 5), and high/low INR (n = 7) and various (n = 10).183635193925275460GI, gastrointestinal; INR, international normalized ratio; RVAD, right ventricular assist device.a Includes 3 procedural-related events: 1 implant issue (difficulty engaging inflow conduit); 1 after anaphylactic shock from contrast media; and 1 after transcatheter aortic valve implantation procedure.b Seizure (n = 2) and transient ischemic attack (n = 2).c Other adverse events include pleural effusion (n = 1), volume status (n = 5), and high/low INR (n = 7) and various (n = 10). Open table in a new tab GI, gastrointestinal; INR, international normalized ratio; RVAD, right ventricular assist device. The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing MCS Therapy With HeartMate 3) investigational device exemption (IDE) randomized, pivotal clinical trial aims to evaluate the safety and effectiveness of the HeartMate 3 LVAS by demonstrating non-inferiority to the HeartMate II LVAS when used for the treatment of advanced, refractory left ventricular heart failure, irrespective of the primary implant strategic intent. The HeartMate 3 LVAS includes an implanted blood pump, a modular drive-line and external power and control components (Figure 2). With the exception of the system controller, all external components are identical for both the HeartMate II (HMII) and HeartMate 3 (HM3). The design strategy for the HM3 involved adopting successful elements of the HMII while pursuing a different technological path to address hemocompatibility factors associated with most clinically significant adverse events with mechanical circulatory support. Comparisons of the fundamental characteristics of the HMII and HM3 are provided in Table 2 and Figure 3. A description of the HMII has been provided elsewhere.14Miller L.W. Pagani F.D. Russell S.D. et al.Use of a continuous-flow device in patients awaiting heart transplantation.N Engl J Med. 2007; 357: 885-896Crossref PubMed Scopus (1414) Google ScholarTable 2Comparison of HeartMate II and HeartMate 3 DevicesCharacteristicHeartMate IIHeartMate 3Pump (flow)AxialCentrifugalBearingMechanical (blood washed)MagneticHydraulic capacityUp to 10.0 liters/minUp to 10.0 liters/minImplantation locationExtrathoracicIntrathoracicTypical clinical speed range8,000 to 10,000 rpm5,000 to 6,000 rpmTextured surfaces (sintered titanium)YesYesInflow graft14-mm sealed VascutekNoneOutflow graft14-mm sealed Vascutek14-mm sealed VascutekQuick pump attachmentNoYesModular drive-lineNoYesElectronics incorporated in pumpNoYesSoftware incorporated in pumpNoYesArtificial pulseNoYesFlow estimator hematocrit adjustmentNoYesPower efficiency (battery run-time)—20% longer than that of HMII Open table in a new tab Figure 3(A) Cross-section of the HeartMate II. Arterial blood passes from the left ventricle into the pump through the inflow (IF) conduit; blood flow direction is straightened by the inflow stator (IS); the rotor (R) controlled by the motor (M) spins to generate the needed force for blood to pass through the outflow stator (OS), then through the outflow (OF) conduit. (B) Cross-section of the HeartMate 3. The rotor (R) is magnetically levitated via electromagnetic coils (C) and rotated via motor drive coils (D). The levitated rotor produces wide recirculation passages radially (P1) and axially (P2). A second axial passage beneath the rotor is hidden in this view. Motor electronics (E) are incorporated into the implantable pump.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The engineering technology in the HM3 involves a magnetically levitated rotor and wide blood-flow passages that are designed with the intent to reduce blood shear stress exposure. In addition, the wide blood-flow passages facilitate rapid rotor speed changes, allowing for the introduction of an artificial pulse. The artificial fixed pulse is intended to disrupt regions of stasis within the pump and to provide a degree of physiologic normalcy in cases of otherwise chronically attenuated native pulsatility. These engineering differences also alter the hemodynamic pressure and flow relationships in the HM3 as compared with the HMII pump. Both devices demonstrate the expected inverse relationship between the pressure head across the pump and flow through the pump, and generally follow the convention that the slope of this relationship is steeper for the axial-flow HMII than for the centrifugal HM3 (Figure 4). However, a closer examination near the typical design point suggests the opposite. Thus, within the typical ranges of clinical operation, a change in pressure head across the pump results in a greater change in flow for the HMII than for the HM3. The clinical effects of these engineering and technological characteristics in the HM3 will be validated in the MOMENTUM 3 study and other mechanistic trials. The MOMENTUM 3 IDE clinical trial is an ongoing, prospective, multicenter, randomized, pivotal study, comparing the HM3 LVAS with the HMII LVAS in advanced-stage heart failure patients (Figure 5). The study will enroll 1,028 patients in up to 60 centers throughout the USA. The MOMENTUM 3 trial proposes a paradigm shift for regulatory bodies on the basis of today's clinical reality. It diverges from previous clinical studies and has an innovative trial design with the following characteristics: 1. It is an all-comer study, with patients enrolled in the trial under a single inclusion and exclusion criteria, regardless of the intended use of the device (short-term [ST], such as BTT, and long-term [LT], such as DT). 2. There is a pre-specified safety phase (N = 30) in lieu of a pilot study while maintaining randomization. 3. There is an ST cohort consisting of the first 294 patients for evaluation of outcomes to 6 months of support, powered to demonstrate the non-inferiority of the HM3 compared with the HMII. 4. There is an LT cohort consisting of the first 366 patients for evaluation of outcomes to 2 years of support, powered to demonstrate the non-inferiority of the HM3 compared with the HMII. 5. There is ongoing enrollment of a further 662 patients (to a full sample size of 1,028) for evaluation of a secondary end-point of pump replacement at 2 years, powered to demonstrate the superiority of the HM3 over the HMII. 6. The study has an adaptive design, with an interim pre-specified analysis conducted by an independent statistician to determine ongoing power and sample size requirements. The primary objective of the MOMENTUM 3 study is to evaluate the safety and effectiveness of the HM3 LVAS by demonstrating its non-inferiority to the HMII when used for the treatment of advanced, refractory heart failure. Secondary objectives include: assessment of adverse events; quality of life as measured by the EuroQol-5D-5L and Kansas City Cardiomyopathy Questionnaire; functional status as measured by the 6-minute walk test and New York Heart Association (NYHA) class; assessment of device malfunction rates; and determination of need for reoperation or rehospitalization. The study will also be powered to evaluate a secondary end-point to determine whether the incidence of pump replacement at 24 months is significantly different between treatment arms (superiority analysis). The primary end-point is a composite of survival free of debilitating stroke (modified Rankin score >3) or the need for a pump exchange. The ST end-point will be assessed at 6 months and the LT end-point at 24 months. Patients who are urgently transplanted due to a device complication before a pre-specified end-point will be considered study failures. All other transplants or device explants due to myocardial recovery that occur before a pre-specified end-point will be considered study successes. All patients meeting the study entry criteria will be enrolled regardless of the planned use of the device (BTT or DT). Patients with advanced heart failure classified as NYHA Class III with dyspnea upon mild physical activity, or NYHA Class IV who are refractory to advanced heart failure management are candidates for the study. A detailed listing of the study inclusion and exclusion criteria is shown in Table 3.Table 3Study Inclusion and Exclusion CriteriaInclusion criteria:1.Subject or legal representative has signed ICF.2.Age ≥18 years.3.BSA ≥1.2 m2.4.NYHA Class III with dyspnea upon mild physical activity or NYHA Class IV.5.LVEF ≤ 25%.6.(a) Inotrope-dependent; OR (b) CI <2.2 liters/min/m2, while not on inotropes and subjects must also meet one of the following:•On optimal medical management, based on current HF practice guidelines for at least 45 of the last 60 days and are failing to respond.•Advanced heart failure for at least 14 days and dependent on IABP for ≥7 days.7.Females of childbearing age must agree to use adequate contraception.Exclusion criteria:1.Etiology of HF due to or associated with uncorrected thyroid disease, obstructive cardiomyopathy, pericardial disease, amyloidosis or restrictive cardiomyopathy.2.Technical obstacles which pose an inordinately high surgical risk, in the judgment of the investigator.3.Existence of ongoing MCS other than IABP.4.Positive pregnancy test if of childbearing potential.5.Presence of mechanical aortic cardiac valve that will not be either converted to a bioprosthesis or oversewn at the time of LVAD implant.6.History of any organ transplant.7.Platelet count < 100,000 × 103/liter ( 5 cm in diameter within 6 months of enrollment.10.Presence of an active, uncontrolled infection.11.Intolerance to anti-coagulant or anti-platelet therapies or any other peri-/post-operative therapy that the investigator will require based upon the patient's health status.12.Presence of any one of the following risk factors for indications of severe end-organ dysfunction or failure:•An INR ≥2.0 not due to anti-coagulation therapy.•Total bilirubin >43 µmol/liter (2.5 mg/dl), shock liver, or biopsy-proven liver cirrhosis•History of severe COPD defined by FEV1/FVC < 0.7, and FEV1 80%) uncorrected carotid artery stenosis•Serum creatinine ≥221 μmol/liter (2.5 mg/dl) or the need for chronic renal replacement therapy.•Significant PVD accompanied by rest pain or extremity ulceration.13.Patient has moderate to severe aortic insufficiency without plans for correction during pump implant.14.Pre-albumin <150 mg/liter (15 mg/dl) or albumin <30 g/liter (3 g/dl) (if only one available); pre-albumin <150 mg/liter (15 mg/dl) and albumin <30 g/liter (3 g/dl) (if both available).15.Planned Bi-VAD support prior to enrollment.16.Patient has known hypo- or hypercoagulable states such as disseminated intravascular coagulation and heparin-induced thrombocytopenia.17.Participation in any other clinical investigation that is likely to confound study results or affect the study.18.Any condition other than HF that could limit survival to <24 months.AAA, abdominal aortic aneurysm; Bi-VAD, biventricular assist device; BSA, body surface area; CI, cardiac index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HF, heart failure; IABP, intra-aortic balloon pump; ICF, informed consent form; INR, international normalized ratio; LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support; NYHA, New York Heart Association; PVD, peripheral vascular disease; PVR, pulmonary vascular resistance. Open table in a new tab AAA, abdominal aortic aneurysm; Bi-VAD, biventricular assist device; BSA, body surface area; CI, cardiac index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HF, heart failure; IABP, intra-aortic balloon pump; ICF, informed consent form; INR, international normalized ratio; LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support; NYHA, New York Heart Association; PVD, peripheral vascular disease; PVR, pulmonary vascular resistance. Qualified study candidates will be randomized 1:1 between the HMII and the HM3. The randomization will be stratified by study center and blocked to maintain the 1:1 ratio over time. Randomization will be implemented through the electronic data capture (EDC) system (Merge Healthcare, Morrisville, NC). Study centers will be allowed a maximum of 50 randomized patients. Patients will be considered enrolled in the study upon signing informed consent; all randomized patients will be included in the intent-to-treat analysis. The investigation will be conducted as a staged, pivotal study that includes a pre-specified early assessment for safety that is consistent with the FDA's new guideline for a staged approval process.15U.S. Department of Health and Human Services; Food and Drug Administration; Center for Devices and Radiological Health; Center for Biologics Evaluation and Research. Draft guidance for industry and Food and Drug Administration staff: adaptive designs for medical device clinical studies. [email protected], May 18, 2015.Google Scholar The study was initially limited to 5 study sites during the early safety assessment. Safety data were analyzed when the first 10 patients, randomly assigned to HM3, achieved 30 days of support. Data included the status of each patient, a summary of adverse events, and a description of any device malfunction. The data were presented to an independent data safety monitoring board (DSMB) and the FDA, with a request to expand the trial to up to a total of 60 study centers. The first 5 study sites continued to enroll and randomize up to a total of 30 patients during the FDA review of the safety data. This phase began in October 2014 and, after review of the initial data, the FDA granted unrestricted expansion to the planned 60 sites. Thus, the expanded phase of enrollment began in April 2015 and is ongoing. A total of 1,028 patients will be enrolled in the study. Three hundred sixty-six patients (randomized 1:1) will be enrolled and randomized to evaluate the primary end-point for assessment of non-inferiority. Of these, the first 294 patients will be evaluated at 6 months for the primary end-point. An additional 662 patients will be randomized to achieve the total of 1,028 needed for the powered secondary superiority end-point analysis. On the basis of a review of recent data from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) and Thoratec, it is assumed that the HMII population will achieve a composite success rate of 85% at 6 months.16Kirklin J.K. Naftel D.C. Pagani F.D. et al.Seventh INTERMACS annual report: 15,000 patients and counting.J Heart Lung Transplant. 2015; 34: 1495-1504Abstract Full Text Full Text PDF PubMed Scopus (1048) Google Scholar, 17John R. Naka Y. Smedira N.G. et al.Continuous flow left ventricular assist device outcomes in commercial use compared with the prior clinical trial.Ann Thorac Surg. 2011; 92: 1406-1413Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar It is also assumed that the HM3 population will have a composite success rate of 87% due to fewer pump replacements at 6 months caused by thrombus or drive-line problems. We estimate that 138 patients in each group will be required to achieve 80% power to demonstrate that the HM3 is non-inferior to HMII at a margin of non-inferiority of –10% (= Δ in the previously noted null and alternative hypotheses) using the Farrington–Manning risk difference approach to non-inferiority with a one-sided α = 0.025. INTERMACS data were reviewed from 26 sites likely to participate in the study. Eight hundred twenty (820) patients were implanted with an HMII in 2012 at these sites, and 52 (6%) received a transplant or explant due to myocardial recovery before 6 months. Based on this, and to have sufficient data to evaluate the 6-month success rate, an additional 9 patients will be randomized per arm (6% of 138) to account for these early outcomes. This requires 147 patients to be randomized in each arm (294 total patients) for the ST cohort analysis. On the basis of the results from the HMII destination therapy IDE study, it is assumed that 50% of the HMII patients will successfully achieve the composite primary end-point.18Slaughter M.S. Rogers J.G. Milano C.A. et al.Advanced heart failure treated with continuous-flow left ventricular assist device.N Engl J Med. 2009; 361: 2241-2251Crossref PubMed Scopus (2436) Google Scholar It is also assumed that the HM3 patients will have a composite success rate of 55% due to fewer pump replacements at 24 months caused by thrombus or drive-line–related complications. It will require 174 HM3 and 174 HMII patients (348 total patients) to achieve 80% power to demonstrate that the HM3 is non-inferior to the HMII when the margin of non-inferiority (= Δ in the above null and alternative hypotheses) is –10% using the Farrington–Manning risk difference approach to non-inferiority with a one-sided α = 0.025. The 9 additional patients added per treatment arm for the ST indication wi