Title: Bethesda conference: conference for the design of clinical trials to study circulatory support devices for chronic heart failure
Abstract: StaffThe Conference was staffed with representatives from both The Society of Thoracic Surgeons and American College of Cardiology. Special appreciation is given to Mr David Field of the ACC and Mr Donald Turney of the STS for their efforts in conducting the conference.Because the pool of potential candidates for cardiac transplant continues to expand while donor organ availability remains critically scarce, the discrepancy between the number of patients who would benefit from heart transplant and the number of patients who actually receive a transplant continues to increase at an alarming pace. The clinical outcome for patients who receive devices as a “bridge” to transplant may well exceed medically treated status I patients and has allowed development and evaluation of devices that can be eventually used as a long-term alternative to transplant. The expectation that fully implantable ventricular assist devices (VAD) would be available by the early 1990s as an alternative to transplant has been precluded by technical regulatory difficulties in device development. In an effort to facilitate the process of bringing this remarkable therapeutic tool to widespread clinical application a cooperative effort was undertaken to bring investigators, industry, and regulatory agencies together in an attempt to prospectively define mutually agreeable and sound guidelines for clinical trials necessary to achieve pre-market approval of VADs for long-term use. The following Task Force Reports represent the culmination of these efforts and summarize the many months of dialog before and after this Bethesda Conference.Task Force 1: Trial designEric A. Rose, MD, Chairman, D. Glenn Pennington, MD, Co-Chairman, John Wallwork, MD, Lynn Warner-Stevenson, MD, Lisa Parker, MD, Gene Blackstone, MD, Victor L. Poirier, MD, Peer Portner, MD, Arthur Ciarkowski, MD, Wolf Sapierstein, MD, Harvey Boroevetz, MDGeneral philosophyThis section outlines criteria for the design of clinical trials to obtain FDA pre-marketing approval for long-term use of mechanical circulatory assist devices, beyond their current approved indications of post-cardiotomy support and bridging to cardiac transplantation.We firmly believe that clinical trials for this purpose should be scientifically sound, clinically meaningful, and achievable in a finite time frame at reasonable expense. It is anticipated that early trials will focus on well-defined patient populations, with subsequent trials including a wider spectrum of patients, once initial success is demonstrated.To meet pre-marketing approval requirements, sponsors will need to demonstrate the efficacy and safety of mechanical circulatory assist devices in the treatment of end-stage heart failure. This section discusses the target population, endpoints, and the design of clinical studies for this purpose. We shall specifically define and justify the choices of population, endpoints, and hypotheses of benefit as follows: 1.Patient population 1.1.Duration and severity of heart failure in terms of cardiac function and functional status of patient.1.2.Adequacy of current medical therapy.1.3.Potential for cardiac transplantation.1.4.Contraindications influencing predicted mortality with or without other interventions.1.5.Contraindications specifically for the device under investigation.2.Endpoints 2.1.Time-related death and its mode.2.2.Quality of life.2.3.Hemodynamic status.2.4.Quantitated exercise capacity.2.5.Functional status.2.6.Criteria and analysis for crossovers and censoring of follow-up.2.7.Device reliability and adverse events.3.Design of trials 3.1.Determination of efficacy compared to other therapies. 3.1.1.Medical therapy for non-transplant candidates (may later include other surgical therapies).3.1.2.Transplantation strategy in potential transplant candidates (may also result in testing of early vs late bridging).1.Sufficient number of events anticipated to allow endpoint comparison. 1.1.Statistically meaningful data.1.2.Clinically meaningful data.Target populationPatients participating in these clinical trials must have demonstrated evidence of severe sustained congestive heart failure despite optimal medical therapy. All patients should be receiving the optimal medical treatment as currently provided under the supervision of a team experienced in the care of patients with severe heart failure. This heart failure may be related to coronary artery disease or non-ischemic cardiomyopathy. The population involved in these trials should include an appropriate representation of minorities and women and be chosen with a sufficient number of endpoints to ensure valid conclusions.Considerations for exclusion from these studies may include: 1.Technical contraindications to device implantation.2.Patients or their representative unable to communicate effectively with the investigators, legally incompetent to give written informed consent, or unable to reliably follow a prescribed course of medical or other therapy.3.Presence of active systemic infection.4.Presence of bleeding or coagulation disorder.5.Presence of severe end organ dysfunction in other body systems (renal, hepatic, cerebral, or pulmonary).6.Any other condition that, in the opinion of the investigators, would disqualify the patient for inclusion in the study, limit survival, or not permit valid consideration.EndpointsThe objective of implanting a device is to provide improvement in survival and quality of life when compared to alternative therapy. The primary endpoints that need to be measured are all cause mortality and impact severely on health-related quality of life. Secondary endpoints that need to be measured include cardiovascular mortality and functional cardiac status.Device safety is also an important endpoint. Monitoring the safety of the device requires measurement of the incidence of adverse effects, including (in particular) infections, thromboembolic complications, bleeding, end organ dysfunction, right heart failure, emotional and psychiatric complications, and mechanical failure (see Task Force 2: Adverse Events).Clinical trial designThe separation of transplantable from non-transplantable patients is an important consideration in minimizing the incidence of patient crossover from device therapy to transplantation or vice versa, which may confound the analysis of trial results and reduce the statistical power of the trial to detect effects. However, the competing risk of death may confound the analysis of non-fatal events.Non-transplant patientsIn the case of patients who are not candidates for transplantation, it is feasible to conduct prospective, randomized, controlled clinical trials with a parallel study design. A non-randomized concurrent control group could also be considered, with adequate justification. It should be recognized that patients who are not transplant candidates may also be at greater risk of complications and death when receiving devices compared to transplant candidates. In the following paragraphs, we will specify the features that such trials should address.Nature of comparisonAt this time, pre-marketing approval of applicant devices should be based on a comparison to the survival and quality of life of patients who are randomly assigned to remain on medical therapy. The follow-up time should be sufficient to establish appropriate survival in the control group. This may be an inadequate amount of time to monitor device failure. Long-term safety and effectiveness data will be captured by post-marketing surveillance. The criteria for approving such devices should not be directly based on the absolute working life and failure rate of the device but rather on the relative improvement of quality of life or survival of the recipient population.BlindingIt will be impossible for care-giving investigators or patients to be blinded to the nature of treatment received. However, to the extent that it is possible, outcome determinations should be made or at least confirmed by investigators that are blinded to the patients’ treatment allocations. Sham operations performed in support of the concept of blinded trials are surely unethical.RandomizationRandomization is useful to ensure equitably constituted comparative groups and, when feasible, it would be employed. Because practical considerations dictate relatively small sample sizes, the efficacy of these devices should be high if they are to have a meaningful impact on survival and quality of life. Investigators may consider blocking by center to ensure approximately equivalent numbers of patients in each arm of the trial throughout its course.Sample sizeThe determination of sample size to conduct any clinical trial is based upon the differences in the primary outcome event that the investigator is attempting to establish. For comparisons to standard medical therapy, sample size should be sufficient to establish clinical utility. For example, a study might be designed to establish a 33% survival gain and improved quality of life by two years with a significance level of 0.05 with 80% power. The goal of a 33% reduction in mortality is roughly equivalent to double the effect seen with angiotensin-converting enzyme inhibitors for heart failure and thrombolytic drugs for acute myocardial infarction.Candidates for cardiac transplantationIt is widely recognized that donor hearts are becoming relatively more scarce due to the increasing population of potential recipients and a stagnation in the number of donors. Thus, the strategy of transplantation today often includes a prolonged waiting period and the inability to be transplanted before death from heart failure. In many areas of the country, this waiting period is in the range of 100 days for United Network for Organ Sharing (UNOS) Status I patients and much longer for UNOS Status II patients. An undefined number of potential transplant candidates are never listed for transplantation because of the severe shortage of donor hearts.It may be feasible to conduct prospective randomized clinical trials of parallel study design; however, a non-randomized concurrent group could also be considered with adequate justification. A trial to demonstrate the utility of devices in ambulatory candidates might include all those candidates with a designated severity of disease, or it could be limited to patients with a low probability of being transplanted such as large type O patients, or patients with multiple antibodies. However, accruing enough patients of this type may be difficult and may necessitate a non-randomized, prospective cohort study. The device group might then consist of transplantation candidates with a low likelihood of being transplanted while the controls would be selected from the general group of candidates. Study design in this population requires careful consideration of the patients’ options for crossover to transplantation and devices as bridges and the impact such crossovers may have on analysis and interpretation of results. In addition, extensive multivariant analysis would be required to ensure the validity of group comparisons.Hybrid trial: Transplant candidates and non-candidatesHybrid trials, including patients who are and patients who are not candidates for transplantation, might also be considered. Design of such trials is confounded by issues of crossovers between groups and the necessity for a large number of patients to be enrolled. However, such trials may be justified if these obstacles can be overcome. The advantage of this hybrid trial would be to provide an increased number of patients, more generalizability, and the opportunity to test the devices simultaneously against medical therapy and the strategy of cardiac transplantation.Task Force 2: Adverse eventsJ. Donald Hill, MD, Chairman, O. Howard Frazier, MD, Co-Chairman, Kurt Daase, MD, Howard Leven, MD, James M. Anderson, MD, Rhona Shanker, MD, Benjamen H. Eidleman, MD, Maria Rosa Costanzo, MDThe following set of recommendations regarding adverse event definitions was written by the Task Force for inclusion in the Guidelines for the Design of Clinical Trials to Study Circulatory Support Devices for Chronic Heart Failure. The Task Force recognizes the dynamic nature of medicine and surgery and wishes to qualify these definitions: 1.The definitions for adverse events are global. They are meant to take into account clinical practice and to be used for both current and future studies. Therefore, the definitions are more qualitative than quantitative in nature.2.The definitions have been chosen and written to be appropriate for use in device trials that may include possible control groups; standard medical therapy for end stage heart disease, cardiac transplantation, or both; and/or another support device approved by the Food and Drug Administration (FDA) for the same indication.3.The definitions are not fixed and should be reviewed at least every 2 years by The Society of Thoracic Surgeons (STS) Ad Hoc Committee on Circulatory Support and Thoracic Transplantation and the FDA.4.These adverse events definitions are as free as possible of inconsistencies and ambiguity without the benefit of a pilot study. Situations may arise which are not covered by these definitions. In these situations the intent of the FDA’s adverse event policy should be followed rather than adhering to an inadequate definition.5.The adverse events as defined do not include a relationship to origin of the event. In the absence of objective diagnostic tests that accurately identify the source of a specific event, it should be regarded as device-related.6.New diagnostic technologies which improve the assessment of the origin of adverse events may be developed. When this occurs, the definitions should be updated to allow assessment with the new diagnostic technology, if appropriate. Retrospective analyses of adverse events with technologies which were previously unavailable will not be required.7.Good data collection, in accordance with the study data collection schedule, is essential in order to determine changes that may occur as a result of the intervention. Therefore, data should be gathered at baseline (that is, at the time of a complete history and physical examination, hemodynamic measurements, and clinical laboratory parameters of end organ function) to determine the pre-intervention status of the patient. Collection of this information should continue in accordance with the study protocol at appropriate intervals throughout the trial in order to assess device/intervention performance (Table 1).8.A complete autopsy should be pursued to confirm the identification of adverse events and to assist in the identification of clinical/pathological correlations.9.The frequency origin of adverse events will be compared in treatment and control groups using the appropriate analysis.10.An independent Clinical Evaluation Committee to review the inclusion and exclusion of complications and to audit the completeness and accuracy of data collected and entered into the database is recommended. This would be made up of peers who are experienced and knowledgeable in the field and chosen together by the sponsor and the FDA. Table 1Clinical Data to Be CollectedHemodynamicCardiac/pump indexBlood dataRBCsWBCHematocritHemoglobinPlateletsPlasma HemoglobinTransfusionsBlood chemistryBilirubinSGOTBUNCreatinineSGPTLDHSerum cholesterolCPKECGAnticoagulation dataTypeDosePT, PTT, ACTBone densityNeurological assessmentCT scan every three monthsNutritional intakeBody weightAutopsy dataBrainLiverHeartKidneysLungsGIDevice analysisAnalyze surface for thrombus and adhesions, and evidence of adhesions that have become dislodgedMechanical integrity of the pump Open table in a new tab Definition of adverse events1.Bleeding: Blood loss resulting in: 1.1.Death1.2.Reoperation1.3.Red blood cell transfusion (greater than or equal to 6 units within 24 hours) or1.4.Treatment or intervention for bleeding2.Hemolysis: Three plasma free hemoglobin values > 40 mg/dL (measured by standard clinical pathology or laboratory medicine methods). The final two readings taken within 12 hours of each other as confirmation of the first reading.3.Cardiac tamponade: Accumulation of undrained fluid resulting in hemodynamic compromise requiring reoperation or intervention.4.Reoperation: Any unscheduled return to the operating room.5.Wound dehiscence: Disruption of the opposed surfaces of a surgical incision, excluding infectious etiology.6.Infection: 6.1.Local infection: Positive tissue or swab culture (from the device or other sites) requiring intervention.6.2.Systemic infection: Any instance in which intravenous (IV) antimicrobial treatment is instituted (excluding routine prophylactic treatment dictated by hospital protocol). This includes treatment of culture negative symptoms.6.3.Bacterial, viral, fungal, or protozoan infection (documented by standard clinical pathology or laboratory medicine methods), treated with antimicrobial agents (excluding routine prophylactic treatment dictated by hospital protocol).7.Myocardial infarction: The presence of two of the following three criteria: 7.1.Creatine phosphokinase (CPK) (measured by standard clinical pathology or laboratory medicine methods) greater than the normal range for that hospital with a positive MB fraction;7.2.ECG with a pattern or changes consistent with a myocardial infarction;7.3.A history and timing consistent with either of the above events.8.Arrhythmias: Any documented arrhythmia that requires intervention or results in the signs and symptoms of vital organ hypoperfusion, such as dizziness, syncope, or lightheadedness.9.Hypotension: Hypotension requiring treatment or manifesting signs and symptoms of vital organ hypoperfusion, such as dizziness, syncope, or loss of peripheral pulses.10.Hypertension: A blood pressure greater than or equal to 140/90 mm Hg, measured on three separate days.11.Right heart failure: Cardiac index less than 2.2 L/min/m2, for greater than or equal to 6 hours, resulting in death, or requiring intervention, in the absence of anatomical structural reasons, left sided dysfunction, or hypovolemia.12.Left heart failure: Cardiac index less than 2.2 L/min/m2, for greater than or equal to 6 hours or resulting in death, or requiring intervention, in the absence of anatomical structural reasons, right-sided dysfunction, or hypovolemia.13.Device malfunction: Any instance when any component of the system fails to perform according to specifications. To use these data in calculating reliability for the device, an event must be evaluated using the definitions for failure that are included in the ASAIO-STS Long Term Blood Pump Reliability Recommendation.14.Device system failure: The inability of the device system, including redundant, external back-up components, to provide adequate circulatory support. For example, the inability to provide pump output of X for Y period of time under ZZZ conditions (eg, rest, exercise). The definition may be modified to address the indicated use of a specific device. However, the definitions must include measurable criteria, and must be applicable to the in vitro, in vivo, and clinical environment in order to use the data in calculating the reliability of the device.15.Renal failure: Abnormal kidney function requiring hemodialysis or hemofiltration in patients who did not require these procedures prior to mechanical circulatory support/transplant/medical therapy. Renal function laboratory data (measured by standard clinical pathology or laboratory medicine methods) will be collected and recorded as part of specific protocols.16.Hepatic failure: Greater than two times increase above baseline values in any two of the four liver function studies (bilirubin, SGPT, SGOT, or LDH), measured by standard clinical pathology or laboratory medicine methods, or if hepatic dysfunction is the primary cause of death.17.Respiratory failure: Impairment of respiratory function requiring reintubation or tracheostomy, or inability to discontinue ventilatory support after postoperative day six.18.Neurological dysfunction: The advent of a neurological deficit, whether it be transient or prolonged, that is not present at baseline as determined by a standard neurological examination and appropriate special investigations. The investigation of new neurological deficits will be determined by the clinical presentation. However, should a new event occur and the clinical features indicate a cerebral localization, particularly in the case of a stroke-like syndrome, a repeat computerized axial tomographic (CT) scan of the head will be indicated. A CT scan of the head and clinical examination to be carried out at entry, and this together with a further neurological examination will be repeated at appropriate intervals (interval determined by sponsor).19.Psychiatric problems: Any change in mood or behavior that requires an intervention that is outside the standard management protocol.20.Rejection: A clinical event, usually but not always accompanied by an abnormal myocardial biopsy, which results in augmentation of a patient’s immunosuppression.21.Cardiac allograft vasculopathy: An accelerated form of cardiac allograft coronary vascular disease leading to retransplantation, death or therapy for cardiac allograft dysfunction.22.Post transplantation lympho-proliferative disorder: Lymphocyte tumor in patients receiving chronic immunosuppression.23.Hyperlipemia: A total serum cholesterol (measured by standard clinical pathology or laboratory medicine methods) of 200 mg/dL.24.Glucose intolerance: An adverse event manifested by new onset of diabetes mellitus or pre-existing diabetes mellitus requiring increased intensity of medical intervention.25.Obesity: A weight 20% greater than ideal body weight. For patients meeting the definition of obesity at baseline, an increase in body weight of greater than 10% from baseline will qualify as an adverse event.26.Osteoporosis: Any decrease in bone density compared to baseline, determined by nuclear bone densitometry.27.Reproductive system dysfunction: Any new sexual or menstrual dysfunction.28.Malignancy: Occurrence of any malignancy (excluding squamous or basal cell of the skin) not present at time of entrance into the study.29.Pain: Necessity for chronic pain medication or other pain management interventions.30.Thrombotic vascular complications (excluding central nervous system events): Any mural thrombus or thromboembolism in the vasculature or device confirmed by standard clinical and laboratory testing that requires intervention.31.Loss of limb: Loss of a limb or any portion thereof.32.Aneurysm: Any aneurysm, pseudoaneurysm, or dissection requiring medical or surgical intervention, or resulting in death.33.Herniation: Protrusion of an organ, part of an organ, or other structure through the wall of a cavity in which it normally resides.34.Cholelithiasis: Gall bladder dysfunction causing clinical symptoms requiring medical or surgical intervention.35.Pancreatitis: Pancreatic dysfunction causing clinical symptoms requiring medical or surgical intervention.36.Bowel obstruction/perforation: Intestinal obstruction or perforation requiring intervention.37.Dysphagia: Eating disorder causing symptoms requiring medical or surgical intervention.38.Loss of appetite: Reduction of food intake severe enough to require hyperalimentation or nasogastric feeding that persists after 14 days of any surgical intervention.39.Hematoma: A collection of clotted blood requiring aspiration or surgical intervention.40.Persistent malnutrition: Inability to attain or maintain desired body weight due to inadequate intake of calories and protein following the intervention.41.Unscheduled hospital readmittance: A readmission to the hospital that is unscheduled or outside the protocol.Task Force 3: Cardiovascular function evaluationJack G. Copeland, MD, Chairman, Patrick M. McCarthy, MD, Co-Chairman, Robert L. Kormos, MD, David Farrar, MD, Donna Mancini, MD, Michael J. Domanski, MD, Ramiah Subramanian, MDIntroductionIt must be recognized at the outset that these guidelines are evolving as clinical experience accrues. In particular, predicting the need for additional right ventricular support, response of the right ventricle to implantable left ventricular assist device (LVAD) support, and the possibility for successfully removing the LVAD after cardiac recovery are areas that are still under study. These are areas of active clinical research and more specific answers should be forthcoming in the future.Areas for reviewFour areas of cardiovascular function will be reviewed: 1.The minimally acceptable degree of circulatory support provided by the LVAD.2.Effects of the device on native heart function.3.Exercise capacity of device-supported patients.4.Possible myocardial “recovery,” allowing removal of the device.Acceptable hemodynamic function with the deviceThe implantable LVAD is placed in patients with end-stage heart disease to reverse cardiogenic shock or to restore more effective hemodynamic parameters. As a minimum requirement, therefore, use of the device should result in a cardiac index greater than or equal to 2.2 L/min/m2 with a pulmonary capillary wedge pressure (or left atrial pressure, or pulmonary artery diastolic pressure) less than or equal to 18 mm Hg during periods of proper function.In the early postoperative period, the effects of hypovolemia, transient right heart dysfunction, tamponade, or other problems related to surgery may interfere with the ability of the device to meet these demands. However, these are “patient-related” failures, and not failure of the device, per se. Inadequate function of the device itself has been defined by the task force on adverse events (see Task Force 2: Adverse Events).Under optimal conditions, the design of the device should allow increased device output with exercise or other physiologic demands. Devices functioning in the automatic fill mode meet this requirement. [1McCarthy P.M. Sabik J.F. Implantable circulatory support devices as a bridge to heart transplantation.Semin Thorac Surg. 1994; 6: 174-180PubMed Google Scholar] Devices in a fixed rate mode should allow external adjustment so that device output can be increased as needed. Also the system should have a monitor that displays pump output. This does not need to be a continuous display monitor, but such a monitor is useful in the early postoperative period. For patients who are chronically supported, periodic measurements of device output are important for troubleshooting, or determining proper device function.Left ventricular assist device effects on left and right ventricular functionThere was initial concern that the implantable LVAD would induce left ventricular atrophy. This has not been shown to be the case. Histologic findings in the bridge-to-transplant experience show resolution during support of acute changes from cardiac decompensation at implant. Eventually fibrosis and otherwise viable and healthy myocytes appear [2Frazier O.H. Radovancevic B. Abou-Awdi N.L. et al.Ventricular remodeling after prolonged ventricular unloading “heart rest” experience with the HeartMate left ventricular assist device.J Heart Lung Transplant [Abstract]. 1994; 13: S51Google Scholar, 3McCarthy P.M. Nakatani S. Vargo R. et al.Structural and left ventricular histologic changes after implantable LVAD insertion.Ann Thorac Surg. 1995; 59: 609-613Abstract Full Text PDF PubMed Scopus (139) Google Scholar]. Echocardiographic studies show a decrease in left ventricular chamber size immediately after the onset of LVAD function, while left ventricular dimensions remain stable during the period of support [3McCarthy P.M. Nakatani S. Vargo R. et al.Structural and left ventricular histologic changes after implantable LVAD insertion.Ann Thorac Surg. 1995; 59: 609-613Abstract Full Text PDF PubMed Scopus (139) Google Scholar, 4Levin H.R. Oz M.C. Chen J.M. et al.Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading.Circulation. 1995; 91: 2717-2720Crossref PubMed Scopus (355) Google Scholar, 5Charron M. Follansbee W. Ziady G.M. Kormos R.L. Assessment of biventricular cardiac function in patients with a Novacor left ventricular assist device.J Heart Lung Transplant. 1994; 13: 263-267PubMed Google Scholar]. Left ventricular wall thickness increases.Depending upon the device synchronization with left ventricular systole, pressures within the left ventricular cavity typically reach 40 mm Hg maximum on LVAD support. This continued left ventricular pressure (although greatly reduced from pre-LVAD levels) may help explain the absence of left ventricular myocyte atrophy. Because the histologic picture improves on support, successfully weaning and removing the LVAD following LV recovery may be possible. This concept will be dealt with in the section “Potential Cardiac Recovery While on Device Support.”The effect of LVAD support on the right ventricle and the right-sided circulation is a complex issue and not always predictable [6Chow E. Farrar D.J. Right heart function during prosthetic left ventricular assistance in a porcine model of congestive heart failure.J Thorac Cardiovasc Surg. 1992; 104: 569-578PubMed Google Scholar, 7Pennington D.G. Reedy J.E. Swartz M.T. et al.Univentricular versus biventricular assist device support.J Heart Lung Transplant. 1991; 10: 258-263PubMed Google Scholar, 8Chow E. Farrar D.J. Effects of left ventricular pressure reductions on right ventricular systolic performance.Am J Physiol. 1989; 257: H1878-H1885PubMed Google Scholar, 9Farrar D.J. Ventricular interactions during mechanical circulatory support.Semin Thorac Cardiovasc Surg. 1994; 6: 163-168PubMed Google Scholar, 10Mandarino W.A. Morita S. Kormos R.L. et al.Quantitation of right ventricular shape chan
Publication Year: 1998
Publication Date: 1998-10-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 13
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