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CONSENSUS CONFERENCE REPORT

Mechanical cardiac support 2000: current applications and future trial design

June 15–16, 2000 Bethesda, Maryland

	Steering Committee members

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

	Writing group participants

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
MARK L. BARR, MD MARIA ROSA COSTANZO, MD, FACC PATRICE DESVIGNE-NICKENS, MD ARTHUR MICHAEL FELDMAN, MD, PHD, FACC O. HOWARD (BUD) FRAZIER, MD, FACC LAWRENCE FRIEDMAN, MD J. DONALD HILL, MD, FACC MARVIN A. KONSTAM, MD, FACC PATRICK McGUANE McCARTHY, MD ROBERT E. MICHLER, MD, FACC MEHMET C. OZ, MD, FACC BRUCE R. ROSENGARD, MD WOLF SAPIRSTEIN, MD RHONA SHANKER CRAIG R. SMITH, MD RANDALL C. STARLING, MD, MPH, FACC DAVID O. TAYLOR, MD, FACC ALISON WICHMAN, MD

	Invited representatives of industry

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
DALLAS W. ANDERSON KEN CHARHUT LAURA DAMME, RN, MPH MICHAEL R. DEVRIES LORENZO DICARLO, MD, FACC DAVID J. FARRAR, PHD LEONARD A. R. GOLDING, MD, FACC STEVEN A. KOLENIK TIM KRAUSKOPF DOUGLAS MCNAIR, MD, PHD TOFY MUSSIVAND, PHD CHISATO NOJIRI, MD, PHD GEORGE P. NOON, MD STEVEN J. PHILLIPS, MD, FACC PEER M. PORTNER, PHD, FACC ERIC SCHORSCH JOSEPH J. SCHWOEBEL, MBA WINSTON UMEMURA ROBERT L. WHALEN, PHD HELENE ZINTAK, PA

	Sponsoring organizations

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
The conference was conducted with financial and other support from the following organizations: American College of Cardiology, American Heart Association, International Society for Heart and Lung Transplantation, American Society of Transplantation, Heart Failure Society of America, American Association for Thoracic Surgery, the Society of Thoracic Surgeons, and the American Society of Transplant Surgeons.^* Additionally, participants included members of these agencies: Food and Drug Administration, National Institutes of Health, and the American Society for Artificial Internal Organs.

	Table of contents

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
Impact Statement......341

Introduction......342

Executive Summary......342

I. Current Status of Mechanical Cardiac Support......346

II. Evolution of Therapies for Heart Failure......348

A. Medical Therapies for Heart Failure......348

B. Surgical Therapies for Heart Failure......350

C. Downshifting of Risk for New Surgical Therapies......350

III. Target Populations and End Points for Mechanical Circulatory Support......351

A. Indications for Device Support......351

1. Cardiogenic shock......351

a. Critical low output state from exacerbation of chronic heart failure......351

b. Cardiogenic shock after acute myocardial infarction......352

c. Post-cardiotomy shock......352

2. Heart failure dependent on intravenous inotropic support......352

3. Outpatients with symptomatic heart failure— who is at intermediate risk?......353

4. Uncontrollable ventricular arrhythmias......353

5. Cardiac allograft dysfunction and/or cardiac allograft vasculopathy......354

B. Evaluation for Exclusion Criteria......354

C. Selection of Devices......355

D. End Points for Outcomes......355

1. The end points for critical populations......355

2. Ambulatory heart failure on oral therapy......356

IV. Establishing Efficacy for Devices: Ethical and Practical Challenges......357

A. Therapies for Life-threatening Illness......357

B. Differences Between Development of Drugs and Devices......357

C. The Potential for "Breakthrough" Devices......358

D. Ethical Considerations Governing Trials of Mechanical Circulatory Support......358

1. Requirement for clinical equipoise......358

2. Ethical issues in patient selection for mechanical circulatory support......359

3. Ethical issues surrounding randomization......359

4. Ethical issues after randomization......360

5. Future ethical issues for equipoise......360

E. Design of Clinical Trials for Mechanical Circulatory Support......360

1. Randomized clinical trials......361

2. The REMATCH trial......361

3. Modifications of the randomized controlled trial for mechanical circulatory support devices......362

a. Option of later "compassionate" use of device......362

b. Potential influence of initial patient preference......362

4. Comparison of non-randomized cohorts......362

a. Historical controls......363

b. Prospective controls......363

i. Timed graduation from control cohort to active therapy......363

ii. Patient preference cohort studies......363

iii. Risk-based allocation cohort studies......363

F. The Vital Importance of Registries......363

1. Outcomes database for advanced heart failure......363

2. Registries for implantable devices......364

V. Future Devices Entering Clinical Development......364

A. Existing Minimum Standards for Pre-Clinical Device Evaluation......364

B. Devices Currently in Clinical Development......366

1. Continuous flow left ventricular assist devices......366

a. Axial flow pumps......366

b. Centrifugal flow pumps......366

2. Pulsatile flow devices......367

3. Total artificial hearts......367

4. Devices without blood contact......367

C. Conclusions......368

	Impact statement

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
Heart failure presents an increasing public health burden of morbidity and mortality even as the mortality from coronary artery disease and hypertension is decreasing. While effective pharmacologic therapies have improved outcomes for mild-moderate heart failure, the impact of newer therapies and mechanical circulatory support for advanced heart failure has not yet been realized. Implantable devices have been shown to be safe and effective as bridges to cardiac transplantation, but further work is needed to establish the role of mechanical support for myocardial recovery and for long-term support. This conference was held to assess current mechanical support applications and future trial designs for investigation affecting this public health issue.

The participants concluded that important differences between devices and drugs may warrant novel study designs characterized by innovation and flexibility. While the randomized clinical trial remains the most powerful tool for unambiguous comparison of interventions, variations may include timed graduation from control to investigational therapies, assignment influenced by patient risk or patient preferences and criteria for an optional crossover to compassionate device use. A major impact would result from a national outcomes database for advanced heart failure that identifies high-risk populations with the greatest potential for benefit from newer therapies and thus facilitates the design of devices and device trials. A separate registry with industry of outcomes after device placement would help to identify "breakthrough" device therapies and facilitate the refinement and acceptance of this new technology. As represented in this conference, progress in mechanical circulatory support will be accelerated by the continued coordination of scientists, engineers, industry, clinical investigators and regulatory and payment agencies in prospective partnership.

	Introduction

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
Over the past five years, mechanical circulatory support devices have evolved from the earlier investigational stages to become standard therapy for bridging to transplantation, in some cases extending beyond original indications. As the first randomized controlled trial of mechanical circulatory support, the Randomized Evaluation of Mechanical Assistance in the Treatment of Congestive Heart Failure (REMATCH) trial began in 1998 and has undergone regular protocol modifications resulting from experiences gained with the patient population and the devices themselves. In 1999, an expert review panel for the National Heart, Lung and Blood Institute (NHLBI) recommended continued support for the development of total artificial heart programs. Refinement of currently available left ventricular (LV) devices continues steadily, and many new types of support devices are in or approaching clinical trials. Ethical and practical issues have emerged regarding the design and funding of these future clinical trials. Challenges for optimal application are being compounded as the separation between indications for recovery, bridge to transplantation and permanent use is becoming less distinct.

As in the original conference on trial design for mechanical circulatory support led by Pae in 1995, the goals of investigators, governmental agencies and industry remain the establishment of clinical trials that are "scientifically sound, clinically meaningful and achievable in a finite time frame at reasonable expense." With the rapid increase in experience with populations of advanced heart failure, broader clinical application of available devices and the promise of new technology for future support, members of the steering group for the NHLBI, the Food and Drug Administration (FDA), the American College of Cardiology Committee on End-Stage Heart Failure and the International Society for Heart and Lung Transplantation sought broad representation from professional societies and industry to address the issues involved in trial design for mechanical circulatory support looking ahead from 2000.

The professional societies with significant interest in this field were invited to co-sponsor this conference and to select delegates to participate in the discussion and writing of the draft document. The writing groups established the basis of their conclusions for discussion and subsequent revision by all participants during the conference at the Heart House in Bethesda, Maryland, to which representatives of industry were also invited. The published document represents the consensus of the participants, as approved by the Steering Committee, and does not imply formal acceptance by any of the societies represented. New developments will render the specifics of this document obsolete, but it is hoped that the fundamental considerations established here will help to guide trial design and clinical decisions for the near future.

	Executive summary

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
Present status of devices for heart failure.   Current use of mechanical circulatory support devices is dominated by the indications of post-cardiotomy shock and bridging to cardiac transplantation. In the U.S., about 6,000 patients a year receive support devices after cardiac surgery, with hospital survival of 20% to 40%. Sustained improvement of native heart function after support also occurs in 5% to 15% of transplant candidates, with greater frequency of recovery in patients with fulminant myocarditis. Bridging to cardiac transplantation occurs in 300 to 400 patients yearly in the U.S., with an overall discharge rate of 50% to 70% from device implantation through transplantation.

Limitations in our current conception of device indications need to be recognized. First, the need for biventricular versus univentricular support is difficult to determine. Second, the ultimate utility of a total artificial heart versus ventricular assist device(s) (VAD) has not been established. Third, the intended duration of mechanical support is a moving target. The time and type of device utilization is influenced by external factors such as the time to myocardial recovery, donor organ availability, the potential of outpatient therapy and the unpredictability of adverse events associated with new technology. Thus, even within the field of currently used devices, evolving indications mandate flexible guidelines for utilization.

Development of drugs and surgical devices for advanced heart failure.   Observation provided the basis for early therapies of heart failure, many of which have subsequently been abandoned. A systematic approach to testing pharmacologic therapies in heart failure has arisen only within the last 20 years. The basis of evidence supporting the current medical therapy with angiotensin-converting enzyme inhibitors and beta-adrenergic receptor antagonists has arisen from double-blind, randomized controlled trials in hundreds to thousands of patients with mild to moderate heart failure. Except for digoxin, oral inotropic agents have been shown in controlled trials to increase mortality, despite sound theoretical rationale. The template of the double-blind, randomized control trial has emerged as the gold standard for evaluating new pharmacologic therapies. It has not been applied to urgent therapies such as diuretics for relief of pulmonary edema and intravenous inotropic agents for cardiogenic shock (CS), during which placebo therapies might be regarded as unacceptable.

Many surgical approaches have been introduced for heart failure. The coronary artery surgery trial demonstrated benefit in patients with reduced left ventricular ejection fractions (LVEFs) but did not target patients with symptomatic heart failure. Requiring five years to complete enrollment, the trial of revascularization for acute CS demonstrated benefit in patients <75 years of age. Revascularization, valve surgery and other remodeling techniques are being employed for some patients with more severe chronic heart failure (HF). The inability to provide comparable placebo therapy, strong patient preferences regarding invasive procedures, and the front-loaded risk of operative procedures have complicated the evaluation of these new approaches.

Fundamental differences between drugs and devices
As therapies for heart failure advance beyond drugs into procedures and devices, fundamental differences emerge in the evaluation of efficacy. By contrast with drug development, progress with devices is more incremental, with experience leading to progressive device modifications. The impact of devices is more transparent, in part because the most obvious risks are front-loaded compared with those from new drugs. It is harder for the effects of devices to be masked or mimicked by the natural history of heart failure. Practical considerations relate to the higher order of magnitude of expense per patient in a trial, which can be prohibitive for companies without major revenue from previous products. The clinically meaningful benefit, however, is projected to be larger than the benefit of new drugs, such that estimated sample sizes are in hundreds rather than thousands of subjects. The experience and skill necessary to achieve optimal outcomes restrict center participation in trials and limit the generalizability of results. A crucial difference between drugs and devices is the inability to blind patients or physicians to therapy, a limitation with both ethical and practical implications for clinical trials.

The sum of evidence guiding therapy with drugs is dominated by evidence from large trials completed prior to drug approval. Once it is approved, it is difficult to identify use and attribute effects of any particular drug because of variable prescription, adherence and combination with other medications. For this reason, post-marketing surveillance provides limited information regarding drugs for heart failure, except for non-cardiovascular side effects. By contrast, the very complexity and undisguised impact of devices render their use and outcomes easier to track, as long as appropriate registries are maintained. The cumulative body of evidence guiding the ultimate use of devices may be drawn more from information gained after initial approval.

Target populations and end points for mechanical circulatory support.   Target populations for mechanical circulatory support can be defined by the expected natural history of heart failure. Patients with CS have an in-hospital mortality of >50% but also carry high risk for patient-related operative complications. Ambulatory patients without resting symptoms on standard oral therapy often survive for two years or longer. Despite various approaches to risk stratification, it remains hard to specify an intermediate-risk population. For patients receiving outpatient intravenous inotropic therapy, the six-month mortality is currently in the range of 50%. However, without objective indications for and restrictions on this therapy, it may encroach on the population with less advanced disease. Another target population might be cardiac transplant patients with triple vessel coronary artery disease (CAD) and decreased ejection fraction, with <50% one-year survival, but mechanical devices in the post-transplant population may be complicated by previous surgery and immunosuppression. The target population for trials should be defined widely to include patients with the best natural history compatible with the degree of certainty that a given device will provide an improvement. This would be greatly facilitated by a multicenter registry of advanced heart failure. After approval, ongoing re-evaluation of a successful device should reflect the observed trend for downshifting risks, in which procedures with proven benefit in a high-risk population become generalized to patients with less risk of post-operative complications but potentially less benefit.

End points for clinical trials will be chosen according to the severity of disease in the population selected. For patients with the most severe disease, early survival will be a fundamental end point. A combination of early survival and functional end points may be most appropriate for trials allowing eventual device placement in patients randomized to medical therapy. As the risk of death becomes imminent, measurements of functional capacity, quality of life and survival adjusted for patient preferences become increasingly relevant. At all levels, measures of efficacy will need to be supplemented by measures of cost-effectiveness. It should be emphasized, however, that cost-effectiveness for a successful device is likely to improve after approval, as experience is gained and costs are decreased.

The spectrum including "breakthrough" devices.   In the future, initial studies could identify a therapy with such an obvious impact on survival that it would be considered a "breakthrough" for a population with otherwise high early mortality (Fig. 1). In retrospect, cardiac transplantation was considered a breakthrough that has been widely accepted without a controlled study. Most new therapies do not enter the breakthrough realm during preliminary testing but fall somewhere else along the spectrum before approval. Outside of breakthroughs, there may be some therapies that are not yet approved but are considered by experienced clinicians to be so effective that waiting for a controlled trial would not be ethical. The best way to bridge this gap to expedite approval from regulatory agencies has not yet been determined for any of the life-threatening diseases. The focus of this conference is not on the approval process but on designing trials of devices for which there is reasonable doubt regarding efficacy. Even for devices in the breakthrough realm for end-stage disease, the design of trials would remain relevant for extension to those populations with lesser severity of illness, in whom the benefit of the device could not be assumed.

View larger version (16K): [in this window] [in a new window]   Figure 1 Line depicting the relationship between equipoise and efficacy of a new therapy, as perceived after initial clinical testing. It is possible that the early experience could be so dramatic that both the scientific and regulatory community regard it as a "breakthrough" therapy that should be approved without further investigation for the defined population. Initial experience could also demonstrate sufficient success that the scientific community is convinced of efficacy, while the regulatory agencies require further information. This gap might be bridged by continued clinical investigation at limited sites, with prospective definition of a non-randomized cohort for comparison. In the majority of cases, initial testing does not establish efficacy, and clinical equipoise can be maintained for the performance of randomized controlled trials. It is anticipated that patient preference regarding new therapies will most often lie to the right of clinical equipoise, complicating trials of therapies that cannot be blinded. The asymmetry of the line to the right of equipoise reflects the enthusiasm necessary to drive any therapy through clinical evaluation.

The randomized controlled trial (RCT) remains widely regarded as the most powerful and sensitive tool for comparing therapeutic interventions and the most persuasive force for the acceptance of new technology. Many of the differences between drugs and devices, as detailed in the preceding text, complicate the translation of RCTs from pharmaceutical trials to trials of mechanical support devices.

Ethics of randomized controlled trials for mechanical circulatory support
Special emphasis was placed by this conference on consideration of the ethics of RCTs for mechanical support devices. A fundamental tenet of the ethical RCT is that equipoise exists for the treatment being tested; it would thus not be ethical to do an RCT of a device already determined from initial testing to be in the breakthrough realm for the population being considered. Theoretical equipoise, in which available data and investigator preference are exactly balanced, may in fact never be located for the individual clinician. Clinical equipoise, in which genuine debate and uncertainty exist among the clinical community, is more feasible and relevant. Although it was initially challenged for the REMATCH trial, the position of equipoise was strengthened by the analysis of pilot data from the pilot trial for REMATCH (PRE-MATCH), in which no clear survival benefit from the LVAD could be seen at three months.

After randomization has taken place, the patient and his physician are aware of the selected therapy, unlike participation in the placebo arm of a double-blinded drug trial. The combination of life-threatening disease and unblinded therapy raises ethical issues beyond that of physician equipoise at the start of the trial. The visible impact of the device may threaten maintenance of equipoise for investigators following patients during the course of a trial. Responding as individuals to unfiltered information, patients are less likely to be in positions of equipoise even before randomization. Patients consenting to new trials are likely to be already biased toward the procedure and thus may perceive randomization to the control arm as a loss of hope, with potentially deleterious impacts on individual outcomes.

Practical issues of randomized controlled trials for mechanical circulatory support
Patient preference for specific therapies perceived to be life-saving may limit enrollment, particularly when a similar therapy is perceived to be offered by other routes. From a methodologic aspect, randomization does not eliminate evaluation bias when all parties know the treatment received. Patient dissatisfaction regarding treatment choice threatens compliance with follow-up and increases the likelihood of off-protocol therapy that could compromise the trial results, as was seen in early trials of AZT for AIDS.

The cost of initiating a randomized trial for a new device greatly exceeds that of continuing to report uncontrolled experience. For this effort to be undertaken, the ultimate value in terms of acceptance as an effective device must be consistently endorsed. Financial impediments have profoundly impaired the conduct of clinical trials of devices, for which there have been substantial unreimbursed costs. These disincentives to enrollment increase the duration and overall cost of the study, delaying the time to potential recovery of development costs. Government support for reimbursement of routine Medicare treatment costs and "conditional coverage" of treatment costs in recognized scientifically-designed trials are strongly endorsed by this conference.

Despite a number of obstacles, an RCT of classical design is nearing completion to determine the impact of an implantable mechanical circulatory support device as destination therapy compared with optimal medical therapy. If the REMATCH trial proves a survival benefit for devices in this population, similar devices may be tested against this benchmark. Regardless of the outcome of this trial, both the lessons learned during its conduct and the ultimate results will have a profound influence on the design of future trials.

Modifications of the randomized controlled trial for mechanical cardiac support
It should be recognized that the gold standard methodology for evaluating the impact of a treatment on outcome remains the randomized, double-blinded, placebo-controlled trial. It should also be recognized, however, that surgical interventions in advanced illness may not appropriately lend themselves to all aspects, such as blinding, of this methodological gold standard. With increasing appreciation for the unique aspects of mechanical circulatory support for advanced heart failure, variations in the design of randomized trials merit consideration.

The aspects of randomization and a control arm can be retained in a non-blinded trial with an option to receive active device therapy as "compassionate use" after the achievement of a predefined time or intermediate end points. (Because only the original cohorts would be compared, this does not represent a true crossover design.) This feature may encourage recruitment and retention, while re-aligning incentives for the patient and physician to continue full efforts after randomization to a control arm. Models for randomized trials that allow some degree of patient preference could improve recruitment and patient satisfaction while providing more information on outcomes for patients not desiring device therapy. The degree to which patient preference should influence the choice of therapy remains a major ethical issue for this and other life-threatening conditions. From a more practical standpoint, it is not clear to what extent the advantages of design modifications would outweigh the increase in sample size that would be required.

Comparison of non-randomized cohorts
In the absence of a randomized control group, there are no large historical groups that could be considered for comparison. Contemporary cohort studies offer better information than observational reports without comparison, but they are compromised by a major bias in favor of new treatments. Data provided by a cohort analysis of the bridge-to-transplant experience indicated a major benefit from the device for that indication. While this cohort data were often cited to suggest that a randomized trial of therapy in non-transplant candidates was not ethical, its relevance to this different population was questioned when the small randomized pilot trial indicated no major difference in early outcomes between the device and optimal medical therapy.

Alternatively, to generate prospective control groups, cohorts could be defined by an obligatory control period prior to enrollment that could provide short-to-intermediate-term information, after which, however, subjects entering surgery might be either better or worse than at initial evaluation. Comparison of patients preferring surgery to patients preferring medical therapy would require an extensive adjustment for baseline factors influencing outcome, not all of which can be identified. For non-randomized cohorts, it is not possible to adjust for all of the factors that lead to the provision of a therapy to one patient and not another. A different approach to outcomes adjusted for severity of illness is being investigated for therapy of breast cancer, in which therapy is allocated only to the patients at highest risk, whose outcome is then compared with that projected from a less compromised population on standard therapy, according to a mathematical model. This technique and all of the regression models used to control for cohort differences would require a deeper knowledge of risk profiles and outcomes for advanced heart failure than that which currently exists.

Vital role of registries.   The absence of broad-based data and the magnitude of mortality, morbidity and resource utilization argue strongly for the creation of a registry of advanced heart failure. Such a multicenter registry would advance both risk stratification for outcome prediction and the development of a multivariate regression model to help adjust for differences between cohorts. Greater confidence in our ability to identify high-risk populations would sharpen trial design and accelerate recognition of devices in the breakthrough realm. Design of RCTs would be streamlined by better selection of target populations and better prediction of event rates.

There is now broad consensus that responsible progress in the field of mechanical circulatory support requires the establishment and maintenance of a mandatory registry that includes all implantable devices, both before and after approval. It should be possible to require specific baseline data collection on patients with mechanical assist devices after device approval if that stipulation is formally linked to the initial approval. By contrast to pharmaceutical therapies, which are easier to study before approval and harder to track afterward, mechanical circulatory support devices may, with appropriate registry documentation, be supported by a weight of evidence distributed differently between pre- and post-approval experiences.

The near future.   The lessons learned through the use of current technology have led to formative strategies regarding the timing of implantation, rehabilitative potential and discharge management in patients supported with circulatory assist devices. However, limitations of systems requiring external power sources connected through percutaneous drivelines have led to the development of numerous systems that are as completely implanted in the body as possible. This has resulted in developments along two broad approaches. The first is a refinement of implantable pulsatile systems, including the Abiomed and Penn State/3M total artificial hearts, the Thoratec IVAD, the Novacor II, the World Heart Heartsaver VAD and the Arrow LionHeart VAD. The majority of these systems utilize transcutaneous power transmission and either an integral or component volume compensatory mechanism. A second thrust utilizes a completely new concept of axial flow technology for chronic support and includes the Nimbus/TCI HeartMate II, Intracorporeal Ventricular Assist System (IVAS), the Jarvik 2000 IVAS and the DeBakey/Micromed IVAS. These systems also depend on transcutaneous power transmission but eliminate the need for volume compensation. The AB-180 Circulatory Support System, the HeartMate III LVAD and the CorAide are devices based on centrifugal principles. In many ways our limited understanding of the impact of this latter group of devices may dictate newer study design principles.

Although there are no specific standards for the pre-clinical evaluation of newer mechanical circulatory support systems, guidelines do exist. A Preliminary Draft Guidance for Ventricular Assist Devices and Total Artificial Hearts issued by the FDA in December 1987 needs to be updated. The joint paper developed by the American Society for Artificial Organs (ASAIO) and the Society of Thoracic Surgeons (STS) addresses only reliability concerns for long-term devices and does not address emerging technology for which a comprehensive standard with criteria for pre-clinical testing is still needed. The revision of these guidelines becomes even more important as distinctions between short-, intermediate- and long-term support become increasingly blurred during clinical application. An interdisciplinary effort needs to address the development of a comprehensive standard for the pre-clinical evaluation of blood pumps, taking into account the uniqueness of each system and its intended use, yet remaining sufficiently flexible to incorporate new clinical experience.

As the field moves ahead, it has become clear that no one trial design or set of standards will be ideal or appropriate for all of these devices, populations and stages of development. This document represents both consensus and controversy from leading scientists, clinical investigators, representatives of industry and regulatory agencies. One of the most important achievements of this conference may be the recognition that the pace of real progress in mechanical circulatory support will be accelerated by ongoing collaboration.

[END OF EXECUTIVE SUMMARY]

	I. Current status of mechanical cardiac support

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
A variety of devices are available to patients depending on the indications for support (1). In Table 1, the devices that have been used in more than 100 patients in the U.S. are listed, along with the chief characteristics that determine present use. Currently, specific device use is governed by the FDA.

The acute heart failure patients are still comprised primarily of those requiring support after cardiac operations and represent about 1.5% of the 400,000 patients who undergo cardiac operations in the U.S. each year. Post-cardiotomy patients may require support for a variety of problems, often relating to the sequelae of perioperative MI, valve disease or problems of myocardial preservation. Several devices are available to support post-cardiotomy shock patients. The simplest device is extracorporeal membrane oxygenation (ECMO), a cardiopulmonary bypass system with venoarterial cannulation placed either through the femoral or intrathoracic vessels. These systems are limited by their short-term usefulness of <1 week and by problems with bleeding and coagulation. The systems have been improved recently by heparin coating of the circuits, which may reduce the incidence of thromboembolism as well as the bleeding caused by anticoagulation. However, these systems do not always provide adequate LV decompression, a primary determinant of recovery. Often the ECMO system, the centrifugal or the Abiomed VADs are used as systems for acute resuscitation to salvage severely ill patients, who are subsequently determined to be transplant candidates and are converted to a bridge to transplant device (Thoratec, Cardiowest, Novacor and HeartMate), thus creating a "bridge to a bridge." Four centrifugal pumps are currently available and provide the advantage of biventricular support, but they also present problems of anticoagulation (3). Two VADs, the Abiomed (4) and the Thoratec (5), offer the advantages of pulsatility, specially integrated cannulas for a variety of cannulation options, and more sophisticated control systems. The Thoratec VAD allows for ambulation and management out of an ICU setting. Currently, none of these systems allows for hospital discharge of patients in the U.S. However, clinical trials with a portable driver (Thoratec) are ongoing, and the driver is approved for use in other countries.

Outcomes of post-cardiotomy support are similar regardless of the device employed (1) and relate primarily to age of recipient, timing of insertion and degree of completed MI (3,4). Survival rates range from 20% to 40% with complications of bleeding (25% to 45%), renal failure (20% to 30%), multiorgan failure (20% to 25%), thromboembolism (4% to 20%), neurological deficit (5% to 20%) and infections (35% to 60%), of which only 5% to 10% are actually device related. A small group of patients in the post-cardiotomy group undergo support for a period of time without recovery of cardiac function and become candidates for cardiac transplantation. With the Thoratec VAD, the only device approved for both post-cardiotomy support and bridge to transplantation, there were 34 patients who underwent bridge to transplantation after a recent cardiac operation. Seventy-one percent were transplanted and 53% were actually discharged from the hospital. By comparison, of 536 patients primarily implanted with Thoratec VADs as a bridge to transplantation, 328 or 61% were transplanted, and of those, 284 survived (87% of those transplanted), with an overall survival rate of 53%. However, it is important to note that in the post-cardiotomy group, only 75% of those transplanted survived, while in the primary VAD bridge-to-transplant group, 87% of those transplanted survived.

Post-MI support represents about 10% of all patients treated with VADs. This application has not been widely employed, because of the wide range of co-morbidities encountered by such patients, many of whom succumb before surgery can be performed. Of those implanted with VADs after acute MI with CS, the majority have been considered unsuitable for coronary revascularization. However, the VAD in this population, either post-cardiotomy or after failed medical management, may serve either as a bridge to transplant or bridge to recovery, providing an emerging potential application. Recent experiences when LVADs were implanted within 14 days after acute MI have shown a survival rate of 74% to transplantation or explantation (6). This experience suggests that VAD implantation for post-MI CS may be able to reduce the mortality of 65% to 80% currently associated with medical management.

Acute dilated cardiomyopathy has a variety of etiologies, the most common of which is myocarditis (7). This has been an indication for LVAD implantation in about 15% of all patients on VADs. The outcomes are quite variable, but the potential for recovery is increased in younger patients, patients who have had shorter periods of heart failure and patients who have improved more rapidly after LVAD implantation (8). Intermediate or long-term device support (30 days to >1 year) has been employed largely for candidates for cardiac transplantation whose condition deteriorates before hearts become available. Of approximately 2,400 cardiac transplants performed in the U.S. in 1997, 15% of those patients required circulatory support devices to be bridged to transplantation. The types of devices used to bridge patients include extracorporeal VADs, implantable wearable LVADs and implantable biventricular replacement devices. The most important evolution in this group of patients has been the ability to discharge them from the hospital with implantable wearable LVADs. However, these LVADs do not provide for right ventricular (RV) support. If severe right heart failure occurs, another device must be implanted for the RV. Consequently, patients with severe concomitant RV failure have usually been implanted with extracorporeal VADs or implantable biventricular replacement devices. Approximately 10% to 15% of all patients implanted with wearable VADs have required right heart support with another device.

Of the more than 3,000 patients who have been implanted with circulatory support devices as a bridge to transplantation, approximately 60% to 70% actually received a transplant. Of those who received a transplant, 85% to 90% survived to be discharged from the hospital (9–11). Among those implanted as a bridge to transplantation, approximately 5% recovered ventricular function and survived without cardiac transplantation. Approximately 25% of patients from one series of more than 100 patients implanted with VADs for bridge to transplantation recovered ventricular function, and of those survivors, 14 retained good cardiac function while the others later died or required cardiac transplantation (8).

During the last year, at least 50% of patients receiving implantable wearable LVADs have been able to be discharged from the hospital, and patients have been supported from periods of a few weeks to >4 years. Although patients discharged from the hospital may require readmission for problems of infection, anticoagulation or bleeding, the cost of caring for these patients has been significantly reduced by the out-of-hospital option. Currently, that option is available only with the implantable wearable LVADs and is not available with the extracorporeal LVADs or the implantable biventricular replacement devices. However, this option has potentially important economic implications.

Complications occurring during bridge to transplantation are well documented in individual series, but unfortunately a reliable common registry is not currently available to determine outcomes. From individual series, it is reported that bleeding requiring reoperation occurs in 5% to 30%, infections occur in 40%, and device-related infections occur in only 5% to 30%. Thromboembolism has been reported in 5% to 25% of patients, with a stroke rate of 2.7% to 25%. Elevated panel reactive antibodies (PRA) may complicate the LVAD bridge to transplantation. These are presumed to be due to anti-HLA antibodies induced by blood products, cross-reactive antibodies to the device itself or antiphospholipid antibodies due to exposure to fibrin glue (topical bovine thrombin) or perioperative blood transfusions. The consequent elevation of PRAs cause "positive" donor-specific crossmatches that may delay transplantation. In one large series (12) with the TCI HeartMate device, PRA elevation to greater than 10% occurred in 66% of patients post-LVAD but persisted in only 22% at the time of transplantation. However, several patients required immunosuppressive therapy and plasmapheresis to reduce the PRA.

The final group of patients, who are not yet well defined, are patients who have apparently irreversible cardiac failure but are not good candidates for cardiac transplantation. Enrollment is almost completed in the randomized, controlled REMATCH trial, in which the TCI HeartMate vented electric LVAD is compared with optimal medical therapy in patients who are not candidates for cardiac transplantation (13). The FDA has recently given permission for Novacor to begin a similar study of the permanent implantation as "destination therapy" for patients with severe cardiac failure who are not candidates for cardiac transplantation. Unlike the REMATCH trial, the Novacor study will not include a randomized control group. The obvious impediments to the success of such long-term device therapy are the risks of infection related to externalized energy sources, the threat of thromboembolic events and mechanical failure. Although we do not have data from the current studies to address these questions, it is apparent that the long-term result will depend on solving these problems. If these trials can demonstrate efficacy, it will be appropriate to consider this therapy for similar patients among the 50,000 to 100,000 patients in the U.S. who have been estimated to potentially benefit from this technology (14).

	II. Evolution of therapies for heart failure

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
A. Medical therapies for heart failure.   The evolution of therapy for heart failure presently includes many strategies never tested by properly controlled clinical trials (Table 2). Many treatments have been abandoned without formal testing after unrewarding anecdotal experience. Over two millennia ago, treatment for what was once termed "dropsy" was aimed at restoring a balance of fundamental elements and complementary humors (15,16). A historical overview of more modern therapies (17) reveals that in 1683, Thomas Sydenham recommended bleeding, purges, blistering, garlic and wine. A century later, William Withering provided a precise description of the benefits of foxglove in the Shropshire maid’s cure for dropsy. Catharsis and venesection continued through the nineteenth century, with amyl nitrate, mercurial diuretics and digitalis glycosides becoming available in the early part of the twentieth century.

Trials have also demonstrated the lack of sustained clinical benefit from many therapies with sound theoretical rationale. Although acute hemodynamic improvements in heart failure patients were readily demonstrated with dopamine in 1972 and dobutamine in 1974, inotropic agents have not been associated with sustained hemodynamic benefit or mortality reduction during chronic therapy. In fact, mortality is increased in these patients, as suggested by early experiences and confirmed in larger trials (29). Although excess myocyte calcium concentrations have been implicated in progression and death, calcium channel blockers have worsened heart failure and survival in retrospective analyses and prospective trials. Many anti-arrhythmic agents that suppress ventricular arrhythmias were shown in large trials to increase death in patients with heart failure. Amiodarone, the only currently available anti-arrhythmic agent that does not increase mortality in heart failure, may in fact have more benefit for heart failure end points than for sudden death. Beta-adrenergic blocking agents worsen hemodynamics initially but, when tolerated, lead eventually to improved hemodynamics and survival in recent large trials of mild-to-moderate heart failure.

Reviewing the history of introduction, adoption and, in some cases, abandonment of therapies for heart failure, reveals the contribution of large controlled trials in defining the additive impact of our interventions. In the process of establishing a basis of evidence to guide current medical therapy for heart failure, a template has been created for the rigorous testing of medications that can be administered in parallel with placebo therapy. End points of survival, clinical status, cardiovascular function and cost-effectiveness can be evaluated using this template without either patient or physician knowing who has received the new therapy being tested.

However, the randomized placebo-controlled trials have, in general, not included patients desperate for relief from severe heart failure symptoms or hoping to be rescued from imminent death. For example, the rapid impact of intravenous diuretics in treating dyspnea from pulmonary edema in heart failure, and the rapid benefit of inotropic therapy to improve perfusion acutely in CS have not been put to the test of placebo-controlled, randomized trials. The immediate cause-effect response typically observed renders a physician unlikely to substitute placebo therapy in these situations. Even in a less compromised group of hospitalized patients, placebo-controlled trials have either excluded patients with urgent indications for intravenous therapy or limited placebo therapy to a short period with early crossover to active treatment.

B. Surgical therapies for heart failure.   Early surgical procedures for heart failure included thyroidectomy, pericardiectomy and valve replacement. Subsequent procedures, such as intra-aortic balloon counterpulsation for CS (30), proposed in 1961, and LV aneurysmectomy introduced for chronic HF in 1962 (31), were more systemically studied and reported but without specific control groups against which to compare benefit. As soon as orthotopic cardiac transplantation was performed in humans, it was tried in many centers with poor initial results. In large part through the perseverance of the Stanford team, outcomes steadily improved. Approval by Medicare of heart transplant as standard therapy was based on careful description of outcomes for a cohort of patients assumed to have over 50% six-month mortality without transplantation (estimates based on early waiting list deaths, but not on any control groups). Increasing waiting times for transplantation have led to expanding use of mechanical circulatory support as bridging devices for cardiac transplantation. Comparisons with patient cohorts without bridging devices suggested better survival to transplantation and discharge, but no randomized trials were done before the widespread acceptance of bridging strategies.

With a limited supply of donor hearts, research continued into other surgical options for heart failure. Coronary revascularization and valvular heart surgery, once thought to be contraindicated in the presence of a low ejection fraction, were extended into the heart failure population, where their roles are not yet defined. A variety of cardiac remodeling procedures (aneurysmorrhaphy/aneurysmectomy, infarct exclusion, application of cardiac restraining and ventricular splinting devices) have recently been introduced and reported in small numbers. More systematic evaluations have been recommended (31). In fact, there are developing plans for a national randomized trial in ischemic heart failure to compare medical therapy with surgical therapy, with further randomization of the surgical arm with or without ventricular reconstruction.

Despite the obstacles, large randomized clinical trials have been performed with surgical therapies of advanced cardiac disease. Three landmark trials of coronary artery bypass surgery clarified its role in ameliorating morbidity and mortality from coronary heart disease (32–34). The smaller analyses of patients with three-vessel disease with decreased LVEF demonstrated particular benefit but included few patients with typical heart failure. With enthusiasm generated by uncontrolled experiences of cardiomyoplasty, the Cardiomyoplasty-Skeletal Muscle Assist Randomized Trial (C-SMART) was an ambitious trial (35) that included a non-blinded, control arm of patients without cardiomyoplasty. Due to early problems with patient recruitment and withdrawal to receive active therapy, the protocol was changed to allow crossover to active treatment after one year. After recruitment of only 100 patients over five years because of ongoing problems with both patient recruitment and reimbursement, the trial was terminated, despite a trend for improved outcomes in the surgical group.

Revascularization is commonly employed as standard therapy for CS due to an acute ischemic event. The Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock? (SHOCK) trial (36) of revascularization for acute coronary syndromes causing CS was completed in 302 patients only after five years. Survival benefit from revascularization was not apparent at one month but shown by the six-month evaluation for patients under 75 years. At the same time, the Swiss Multicenter Angioplasty for Shock Trial was terminated because of inadequate enrollment (37).

The ongoing REMATCH trial (13) faces the double challenge posed by both a surgical trial and study of a more compromised heart failure population than was ever enrolled in a controlled trial. Candidate criteria were originally designed to include patients with an expected 25% two-year survival. Considering previous information from cohort experiences suggesting a large benefit from "bridging" in transplant candidates, concern was raised that this trial was unethical because it denied patients a life-saving therapy. In fact, the 21-patient pilot trial prior to REMATCH demonstrated a three-month mortality of almost 30% without apparent difference between the medical and surgical arms. Attempting to find a population with intermediate risk, the inclusion criteria for REMATCH were subsequently expanded to require 60 rather than 90 days of severe symptoms and either dependence on intravenous inotropic agents or a peak oxygen consumption <14 ml/kg/min, compared with the previous limit of 12 ml/kg/min. Enrollment in the trial has been limited by issues of reimbursement for the surgical procedures, difficulty in regional recruitment at designated centers and reluctance of patients and families as well as physicians to accept randomization in the setting of a life-threatening illness for which a new therapy might be life-saving. Still, it is anticipated that the completion of this trial in 2001 will provide new benchmarks for both the medical and device arms of future trials.

C. Downshifting of risk for new surgical therapies.   The recognized success of new surgical procedures for advanced disease may be followed in some cases by a cycle of improving results and expanding population definition. The evolution of such therapy contrasts with the development of pharmacologic and exercise interventions, which have usually been initiated in patients with mild disease, validated in trials of moderate disease and ultimately extended to patients with severe disease who would have been excluded from the landmark trials (38). Surgical therapies for heart failure carry front-loaded risk that is easier to absorb for patients expecting high early mortality. As survival and improved function are realized by these desperate patients, the procedure is then sought by patients at earlier stages of the disease. These patients are more likely than the initial subjects to obtain good results from the procedure. With the downshifting of risk, however, the actual benefit, calculated as the difference between outcome with the procedure and outcome without the procedure, may become less significant. An appropriate example of "downshifting" the risk is the evolution of cardiac transplantation (39–41). Candidates were originally expected to have "less than six months to live," at which time survival with transplantation was 60% to 70% at one year. The current one-year survival rate after heart transplant is 80% to 85%, with a 10-year survival rate of about 50%. For ambulatory heart failure patients not requiring intravenous inotropic agents, the survival without transplantation has also improved to 60% to 70% without death or urgent transplantation at one year in many studies, leaving a smaller margin of early benefit. The positive impact of heart transplant remains striking, however, for patients in critical status or dependent on inotropic infusion. After initial experiences, risk can shift up as well, as has happened for candidates developing organ failure while awaiting transplantation, such that procedures may be extended to patients who are more severely ill than their predecessors. As new surgical therapies for heart failure are introduced and accepted into broadening populations, it remains crucial to monitor the target populations and ensure that the benefits expected from earlier experience are being derived.

	III. Target populations and end points for mechanical circulatory support

Top Steering Committee members Writing group participants Invited representatives of... Sponsoring organizations Table of contents Impact statement Introduction Executive summary I. Current status of... II. Evolution of therapies... III. Target populations and... IV. Establishing efficacy for... V. Future devices entering... Staff References

 
A. Indications for device support.   The appropriate population for a trial of mechanical circulatory support is comprised of the patients whose current quality of life and prognosis are measurably worse than expected outcomes for the device being tested. The population should be defined as broadly as possible to maximize generalization of the results. Although the specific entry criteria will vary for each device and indication, there are general categories of patients who can be considered along a scale of disease severity (Table 3). As the severity of disease increases, there is greater certainty regarding imminent death, and less certainty is required regarding the device performance and patient outcome after device implantation. In general, however, increasing disease severity also increases the risk of adverse outcomes attributable more to the patient than to the device. At lesser grades of severity, when death is not imminent, details regarding the expected function and quality of life with mechanical circulatory support become more critical. In one study, a majority of patients anticipating continued heart failure symptoms at rest expressed willingness to trade >50% of their remaining time, or take >50% risk of death, for a chance to return to more normal function (42).

The frequency of CS complicating HF in transplant candidates is difficult to estimate from the 15% of recipients of "bridges" to transplantation, as the increased recognition of the benefits of mechanical support have broadened the application to patients with impending or anticipated circulatory failure. In addition, this population also includes patients bridged for more common causes of CS, such as MI and post-cardiotomy failure.

b. Cardiogenic shock after acute myocardial infarction
It is estimated that 1.1 million patients suffer an acute MI in the U.S. each year. Of these, approximately one third die prior to presentation (46). In the large multicenter Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, CS occurred in 7.2% of patients, but it accounted for 58% of all deaths in the entire trial (47). The estimated yearly incidence in the U.S. is 50,000 in the hospital with post-infarction CS. In the SHOCK registry, in-hospital mortality was approximately 60% in patients with post-MI CS (48). Of the patients developing shock, it was present initially in 10.6% and developed after admission in the remaining 89.4%, usually within 48 h (49). In one sub-study of GUSTO a prognostic algorithm predicted with high accuracy the 30-day mortality in patients with CS complicating an acute MI. Increased age was the strongest demographic variable predicting 30-day mortality, and shock at presentation had better outcome than shock presenting later. Clinical predictors focused on findings of peripheral hypoperfusion such as an altered sensorium, cold and clammy skin and oliguria. Significant hemodynamic predictors were a cardiac output <1.5 L/min or a pulmonary arterial wedge pressure >20 mm Hg. A serious limitation of this prognostic algorithm is the lack of consideration of revascularization, found in another GUSTO substudy to reduce the 30-day mortality rate and in the SHOCK trial to reduce six-month mortality (36). Based on these data, a patient with CS after MI, especially if not a candidate for revascularization, could be a candidate for long-term mechanical support.

c. Post-cardiotomy shock
Post-cardiotomy shock is described in approximately 1.5% of the 400,000 patients undergoing cardiac operations each year in the U.S. As discussed above, survival to discharge is in the range of 20% to 40% (1–6). In the minority of patients who proceeded through bridging devices to transplantation, the overall survival rate to discharge was 40% to 60%. Patients who are not candidates for transplantation could be considered for trials of permanent mechanical support, but it should be recognized that the factors rendering them ineligible for transplantation would also affect outcome on devices. The post-surgical state may also predispose to worse outcome because the results of mechanical bridging to transplant have been slightly less favorable in this population than in primary bridging experiences.

2. Heart failure dependent on intravenous inotropic support
The population of patients requiring intravenous inotropic support is increasingly being considered as a potential candidate group for newer heart failure therapies, particularly those that carry significant risk. This population definition is less precise, however, than others based on immediately measurable parameters. Many patients hospitalized for heart failure exacerbations receive brief courses of intravenous inotropic therapy to facilitate diuresis or redesign an effective oral regimen, following which the inotropic therapy is discontinued. Persistent efforts to achieve fluid balance, the substitution or combination of different vasodilators to avoid symptomatic hypotension and severe renal dysfunction, and