Insights From Rematch and Future Directions

Comparing LVAD implantation with medical therapy in the REMATCH trial prompted consideration of a number of methodological, economic, and ethical issues.6 Conducting the pilot study proved essential, in part because it provided the patient and device-reliability data necessary to plan the larger-scale pivotal trial. The position of equipoise was strengthened by the analysis of the pilot data, which indicated no major difference in early outcomes between the device and OMM.7 A Coordinating Center gatekeeper was implemented into the study design to guarantee eligibility of each patient enrolled. This was particularly important when evaluating such an expensive intervention. Randomization in the pilot study was shown to be feasible.6 After randomization in a trial comparing surgery with medical therapy, both the investigator and the patient will immediately know the treatment assignment and have expectations regarding outcome. Patients with life-threatening diseases consenting to trials are likely biased toward the procedure and thus may perceive randomization to the control arm as a loss of hope, with possible deleterious impact on enrollment and potentially on outcome. To ameliorate these potential effects of randomization to a control arm in a nonblinded trial, an option to receive active device therapy after the achievement of a predefined time or intermediate endpoint can be implemented.7 This feature may encourage recruitment and retention, while realigning incentives for the patients and physician to continue full efforts after randomization to a control arm. In the REMATCH trial, OMM patients were given the option of crossing over to LVAD therapy in June 2001, when the primary endpoint criteria was reached and LVAD therapy was recognized to offer a survival advantage. Three of five patients crossed over, one patient withdrew from the trial, and one patient opted to continue OMM alone. Regardless, trial enrollment remained challenging owing to the reluctance of patients and families, as well as physicians, to accept randomization in the setting of a life-threatening illness when a new therapy might be lifesaving. The economic challenges and their impact on conducting innovative device trials were well illustrated in the REMATCH trial.72 The NIH and Thoratec supported the costs of data collection and analysis, the NIH covered costs of the operation, and the company provided devices free of charge. CMS agreed to support all treatment costs, except the implant hospitalization, which remained the responsibility of the participating hospitals. It was considered unethical to charge patients, especially because they had a life-threatening condition and were therefore particularly vulnerable. The economic burden of the implant hospitalization caused centers to decline participation in the trial, and participating centers imposed restrictions on enrollment. In the last quarter of 1999, the company provided extra financial support for patient care, which had a small positive effect on enrollment, but more importantly, it kept participating centers in the trial. Unlike pharmaceutical innovation, medical device research is often developed in small companies without previous product revenue to support clinical research. Thus, financial impediments have complicated the design of a sufficient research infrastructure and have profoundly impaired the conduct of clinical trials of innovative devices, for which there have been substantial treatment costs.7 The financial disincentives to enrollment increase the duration of the trial and the overall costs, delaying the time to potential recovery of development costs. This underlines the need for options of adequate clinical trial funding. A promising strategy may be conditional coverage, in which insurers pay the treatment costs for patients in an approved research protocol and sponsors cover the costs of conducting and analyzing the research. A new CMS policy, introduced September 2000, approved Medicare coverage of the routine health care costs for beneficiaries involved in clinical trials, particularly those sponsored or approved by federal agencies.20 In addition, an advisory panel to the NIH supported public-private partnerships between industry and having NIH fund clinical trials,27 as was the case in the REMATCH trial. Innovative, implantable devices are increasingly subject to rigorous coverage and reimbursement decisions by the payor community. The criteria that payers (i.e., public and private insurers) use to make these decisions vary. Although CMS has no specific statutory mandate to account for cost and cost-effectiveness when making coverage decisions, increasing fiscal pressure on CMS has made it a topic of much interest among CMS representatives. This underlines the crucial need for designing clinical trials to incorporate measures of cost and cost-effectiveness.

As LVADs for destination therapy are an emerging procedure, opportunities exist for reducing costs and improving outcome with experience. First, the REMATCH analysis revealed that sepsis was the most important predictor of cost and the most common cause of death in the device group.73 Improvements in the design of devices offer a sizeable opportunity to reduce infections and consequent costs of future patients. Newer devices have smaller, more flexible drivelines or use a totally implantable device, which eliminates this portal of infection. Malnutrition, another major factor that predisposes this population to infection, may be reduced with newer axial flow devices, which do not have an intra-abdominal component, and with newer approaches to nutritional management and chronic inflammation.73 Second, improved surgical proficiency and innovative approaches to management of bleeding address important factors that could also improve outcomes and reduce overall costs. Device-related bleeding has already been reduced by two significant modifications to the approved HeartMate device. Third, device reliability is essential to improve the outcome and minimize the cost of readmisssion. The REMATCH experience, as of July 2001, revealed that 17 devices in 52 patients needed replacement. In addition to sepsis, the leading causes of replacement were mechanical pump failure and inflow valve incompetence.73 There have been more than 40 modifications made to the device that was initially employed in the REMATCH trial. These changes were approved by the FDA73 and may continue to improve device reliability and outcomes. Modifications to devices that may alter the cost and outcome of RCTs take place during the trial and continue thereafter. Even over the 2-year course of the REMATCH trial, device modifications and implementation of an infection management guideline were associated with a significant improvement in survival and occurrence of adverse events in patients enrolled during the second half of the trial, as compared with those enrolled in the first half of the trial. This suggests that we will continue to see further improvements as we mature in our experience with LVAD as destination therapy. Finally, patient selection offers another opportunity to improve out come and reduce costs. Survivors of the index hospitalization after LVAD implantation cost noticeably less to manage than nonsurvivors do. Moreover, those surviving more than 1 year had substantially less hospital resource utilization than the rest of the cohort, although in the predictive model of the REMATCH trial, there were no significant predictors of costs among the baseline patient characteristics.73 This might be in part a result of the small sample size. Similar to the bridge to transplant trials, in which preimplant patient characteristics have been identified that are independent risk factors for survival, larger LVAD destination therapy trials or continued postmarketing data collection in the future could help identify patient profiles of high-risk and high-cost patients that would assist in the patient selection process. With the growing number of different destination therapy trials, the recognized success of LVAD therapy for end-stage heart failure may be followed by a cycle of improving results and expanding the patient population definition.

Surgical therapies for heart failure carry front-loaded risk that is easier to absorb for patients expecting high early mortality.7 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 at lower costs.7 Regarding the LVAD population, it can be assumed that with increasing reliability of devices, in the long term, the bridge to transplant and the destination-therapy population will merge and the distinction of short- and long-term indications for therapy will become less relevant. Thus, in the future, those bridge to transplant patients not receiving a donor organ may stay on long-term LVAD support as an alternative to transplantation. Of the estimated 60,000 patients who could benefit from cardiac transplantation each year but are not necessary candidates, it is conjectured that approximately 20% would be candidates for long-term LVAD therapy at present.73 The number of devices and patients who form the basis of approval is of necessity relatively small, and extensive further experience is required to optimize the clinical use of new devices in long-term circulatory support. Because rare events or complications that require years to develop may not yet be appreciated and the duration in observation is more limited when severity of illness is higher (as in current populations with end-stage heart failure), efforts have focused on trying to shorten the premarketing clinical trial and FDA review processes, while shifting more emphasis to rigorous postmarketing studies and implementing registries both for advanced heart failure and LVADs. The former creates the potential for a larger number of patients to be rapidly exposed to a newly approved product, whereas registries would track changes in patient management and device modifications, as well as patient outcomes, as we continue to learn to care for LVAD patients and as device modifications continue to be introduced into practice.

References

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8. McLoughlin, M. P., Chapman, J. R., Gordon, S. V., et al. 1991. "Go on—say yes": a publicity campaign to increase commitment to organ donation on the driver's license in New South Wales. Transplant. Proc. 23:2693.

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16. Thoratec Inc. What is Destination Therapy? Available from: www.thoratec.com/ /heartmate-destination-therapy/heartmate_faqs.htm. Assessed September 9, 2004.

17. Gillick, M. R. 2004. Medicare coverage for technology innovations—time for new criteria? N. Engl. J. Med. 350:2199-2203.

18. Medicare Coverage Advisory Committee meetings for ventricular assist devices as destination therapy. Minutes. March 12, 2003. Available from www.cms.hhs.gov/mcac/id79-2.pdf?origin=globalsearch&page=/med/ viewmcac.asp&id=79. Accessed July 16, 2004.

19. Goldstein, D. J., Oz, M. C., Rose, E. 1998. Implantable left ventricular assist devices. N. Engl. J. Med. 339:1522-1533.

20. Centers for Medicare and Medicaid Services, Health and Human Services. Medicare Coverage for Clinical Trials. Available from: www.cms.hhs.gov/coverage/ 8d2.asp. Accessed September 7, 2004.

21. National Institutes of Health Director's Panel on Clinical Research, Executive Summary. Available from: www.nih.gov/news/crp/97report/execsum.htm. Accessed September 7, 2004.

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