The NHLBI REVIVE-IT study: Understanding its discontinuation in the context of current left ventricular assist device therapy
2016; Elsevier BV; Volume: 35; Issue: 11 Linguagem: Inglês
10.1016/j.healun.2016.09.002
ISSN1557-3117
AutoresFrancis D. Pagani, Keith D. Aaronson, Robert L. Kormos, Douglas L. Mann, Cathie Spino, Neal Jeffries, Wendy C. Taddei‐Peters, Donna Mancini, Dennis M. McNamara, Kathleen L. Grady, John Gorcsan, Ralph J. Petrucci, Allen S. Anderson, Henry A. Glick, Michael A. Acker, J. Eduardo Rame, Daniel J. Goldstein, Salpy V. Pamboukian, Marissa A. Miller, J. Timothy Baldwin,
Tópico(s)Cardiac Arrest and Resuscitation
ResumoThe National Institutes of Health National Heart, Lung, and Blood Institute convened a working group in March 2008 to discuss how therapies for heart failure (HF) might be best advanced using clinical trials involving left ventricular assist devices (LVAD). This group opined that the field was ready for a trial to assess the use of long-term ventricular assist device therapy in patients who are less ill than patients currently eligible for destination therapy, which resulted in the Randomized Evaluation of VAD InterVEntion before Inotropic Therapy (REVIVE-IT) pilot study. The specific objective of REVIVE-IT was to compare LVAD therapy with optimal medical management in patients with less advanced HF than current LVAD indications to determine if wider application of permanent LVAD use to less ill patients would be associated with improved survival, quality of life, or functional capacity. REVIVE-IT represented an extraordinary effort to provide data from a randomized clinical trial to inform clinicians, scientists, industry, and regulatory agencies about the efficacy and safety of LVAD therapy in a population with less advanced HF. Despite significant support from the medical community, industry, and governmental agencies, REVIVE-IT failed to accomplish its goal. The reasons for its failure are instructive, and the lessons learned from the REVIVE-IT experience are likely to be relevant to any future study of LVAD therapy in a population with less advanced HF. The National Institutes of Health National Heart, Lung, and Blood Institute convened a working group in March 2008 to discuss how therapies for heart failure (HF) might be best advanced using clinical trials involving left ventricular assist devices (LVAD). This group opined that the field was ready for a trial to assess the use of long-term ventricular assist device therapy in patients who are less ill than patients currently eligible for destination therapy, which resulted in the Randomized Evaluation of VAD InterVEntion before Inotropic Therapy (REVIVE-IT) pilot study. The specific objective of REVIVE-IT was to compare LVAD therapy with optimal medical management in patients with less advanced HF than current LVAD indications to determine if wider application of permanent LVAD use to less ill patients would be associated with improved survival, quality of life, or functional capacity. REVIVE-IT represented an extraordinary effort to provide data from a randomized clinical trial to inform clinicians, scientists, industry, and regulatory agencies about the efficacy and safety of LVAD therapy in a population with less advanced HF. Despite significant support from the medical community, industry, and governmental agencies, REVIVE-IT failed to accomplish its goal. The reasons for its failure are instructive, and the lessons learned from the REVIVE-IT experience are likely to be relevant to any future study of LVAD therapy in a population with less advanced HF. In March 2008, the National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI) convened a working group in Crystal City, Virginia, to discuss how therapies for heart failure (HF) might be best advanced using clinical trials involving left ventricular assist devices (LVADs).1Baldwin J.T. Mann D.L. NHLBI's program for VAD therapy for moderately advanced heart failure: the REVIVE-IT pilot trial.J Card Fail. 2010; 16: 855-858Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Based on the ventricular assist device (VAD) technology and inpatient care and selection at that time, the working group opined that the field was ready for a trial to assess the use of long-term VAD therapy in patients who are less ill than patients currently eligible for destination therapy (DT). This interchange resulted in an initiative that became known as the Randomized Evaluation of VAD InterVEntion before Inotropic Therapy (REVIVE-IT) pilot study (see supplementary appendix for a detailed summary of the REVIVE-IT study design, available in the online version of this article at www.jhltonline.org).2Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. Randomized Evaluation of VAD InterVEntion before Inotropic Therapy Solicitation Number: NHLBI-HV-10-14. Available at: https://www.fbo.gov/?s=opportunity&mode=form&id=b48428fc701236673ae5d0ceab01c0f4&tab=core&_cview=1. Accessed April 25, 2016 [In press].Google Scholar, 3Aaronson K.D. Pagani F.D. Kormos R. et al.Design for the Randomized Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT) Study.J Heart Lung Transplant. 2016; ([In press])Google Scholar REVIVE-IT was designed as a 2-part study consisting of a registry and a trial, the former of which enrolled potential candidates for the trial.3Aaronson K.D. Pagani F.D. Kormos R. et al.Design for the Randomized Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT) Study.J Heart Lung Transplant. 2016; ([In press])Google Scholar The specific objective of REVIVE-IT was to compare LVAD therapy with optimal medical management (OMM) in patients with less advanced HF than current LVAD indications to determine if wider application of permanent LVAD use (i.e., destination therapy4Rose E.A. Gelijns A.C. Moskowitz A.J. et al.Long-term mechanical left ventricular assistance for end-stage heart failure.N Engl J Med. 2001; 345: 1435-1443Crossref PubMed Scopus (3363) Google Scholar) to a less ill population would be associated with improved survival, quality of life, or functional capacity.3Aaronson K.D. Pagani F.D. Kormos R. et al.Design for the Randomized Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT) Study.J Heart Lung Transplant. 2016; ([In press])Google Scholar REVIVE-IT represented an extraordinary effort to provide data from a randomized clinical trial (RCT) to inform clinicians, scientists, industry, and regulatory agencies on the efficacy and safety of LVAD therapy in a population with less advanced HF. In the end, despite significant support from the medical community, industry, and government agencies, REVIVE-IT failed to accomplish its goal. The reasons for its failure are instructive, and the lessons learned from the REVIVE-IT experience are likely to be relevant to any future study of LVAD therapy in a population with less advanced HF. Following the workshop meeting in March 2008, a Request for Proposal was released by the NHLBI on July 23, 2009, outlining requirements for the REVIVE-IT trial (Table 1).3Aaronson K.D. Pagani F.D. Kormos R. et al.Design for the Randomized Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT) Study.J Heart Lung Transplant. 2016; ([In press])Google Scholar In preparation for a proposal submission to the NHLBI, investigators from the University of Michigan (UM) and the University of Pittsburgh (UP) held a pre–investigational device exemption (IDE) meeting with the US Food and Drug Administration (FDA) on November 20, 2009, as required by the Request for Proposal. The UM-UP collaborative strategy at the time was to use the HeartWare HVAD (HeartWare, Inc., Framingham, MA) as the study device in the REVIVE-IT trial, recognizing both the pros and the cons associated with this strategy.5Wieselthaler G.M. Driscoll G. Jansz P. Khaghani A. Strueber M. HVAD Clinical Investigators. Initial clinical experience with a novel left ventricular assist device with a magnetically levitated rotor in a multi-institutional trial.J Heart Lung Transplant. 2010; 29: 1218-1225Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 6Aaronson K.D. Slaughter M.S. Miller L.W. et al.Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation.Circulation. 2012; 125: 3191-3200Crossref PubMed Scopus (512) Google Scholar, 7Slaughter M.S. Pagani F.D. McGee E.C. et al.HeartWare ventricular assist system for bridge to transplant: combined results of the bridge to transplant and continued access protocol trial.J Heart Lung Transplant. 2013; 32: 675-683Abstract Full Text Full Text PDF PubMed Scopus (272) Google ScholarTable 1NHLBI REVIVE-IT Request for Proposal (Solicitation Number: NHLBI-HV-10-14)•Study hypothesis: VAD therapy in the proposed patient population will improve functional status at 12 months post-randomization, and all-cause mortality will be no worse than that in the OMM arm of the study.•Patients for the study should be ill enough to potentially experience both functional and survival benefits from the therapy without undue risk.•The estimated mortality rate for this group should be 20%–30% at 1 year.•Patient population inclusion criteria include (1) hospitalization in past 6 months, (2) NYHA class IV or advanced class III, (3) maximal evidence-based therapies for 3 months, (4) duration of HF of at least 1 year, and (5) no inotropic support for 30 days before enrollment.•The study should be randomized between VAD and OMM arms.•The primary end-point should be a composite of survival and functional status where the improvement in functional status would need to be substantial and assessed through objective metrics.•Secondary end-points are safety, secondary functional and physiologic markers, health-related quality of life, neurocognition, and cost and cost-effectiveness.•Patients should be followed for at least 2 years.•Substantial evidence of acceptable clinical performance is required for VADs to be used in the study.HF, heart failure; NYHA, New York Heart Association; OMM, optimal medical management; VAD, ventricular assist device. Open table in a new tab HF, heart failure; NYHA, New York Heart Association; OMM, optimal medical management; VAD, ventricular assist device. The investigational HVAD pump was a relatively new technology, and significantly fewer efficacy and safety data were known about the long-term performance of the device compared with the alternative option, the HeartMate II (HMII; Thoratec Corporation, Pleasanton, CA), which was approved at that time for use in bridge-to-transplant patients.8Miller L.W. Pagani F.D. Russell S.D. et al.Use of a continuous-flow device in patients awaiting heart transplantation.N Engl J Med. 2007; 357: 885-896Crossref PubMed Scopus (1411) Google Scholar, 9Pagani F.D. Miller L.W. Russell S.D. et al.Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device.J Am Coll Cardiol. 2009; 54: 312-321Crossref PubMed Scopus (727) Google Scholar, 10Slaughter M. Rogers J.G. Milano C.A. et al.Advanced heart failure treated with continuous-flow left ventricular assist device.N Engl J Med. 2009; 361: 2241-2251Crossref PubMed Scopus (2428) Google Scholar, 11Starling R.C. Naka Y. Boyle A.J. et al.Results of the post-US Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support).J Am Coll Cardiol. 2011; 57: 1890-1898Crossref PubMed Scopus (373) Google Scholar, 12Park S.J. Milano C.A. Tatooles A.J. et al.Outcomes in advanced heart failure patients with left ventricular assist devices for destination therapy.Circ Heart Fail. 2012; 5: 241-248Crossref PubMed Scopus (274) Google Scholar, 13Jorde U.P. Kushwaha S.S. Tatooles A.J. et al.Results of the destination therapy post-Food and Drug Administration approval study with a continuous flow left ventricular assist device.J Am Coll Cardiol. 2014; 63: 1751-1757Crossref PubMed Scopus (201) Google Scholar However, the HVAD had a unique pump design with important features that were appealing for its use in a trial for less ill recipients, including smaller size, bearing-less levitation of the internal impeller, and intrapericardial placement.5Wieselthaler G.M. Driscoll G. Jansz P. Khaghani A. Strueber M. HVAD Clinical Investigators. Initial clinical experience with a novel left ventricular assist device with a magnetically levitated rotor in a multi-institutional trial.J Heart Lung Transplant. 2010; 29: 1218-1225Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 6Aaronson K.D. Slaughter M.S. Miller L.W. et al.Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation.Circulation. 2012; 125: 3191-3200Crossref PubMed Scopus (512) Google Scholar, 7Slaughter M.S. Pagani F.D. McGee E.C. et al.HeartWare ventricular assist system for bridge to transplant: combined results of the bridge to transplant and continued access protocol trial.J Heart Lung Transplant. 2013; 32: 675-683Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar Early efficacy and safety data, largely from the European and Australian experience, were encouraging, and the UM-UP collaborative initially believed these data were sufficient to propose its use to FDA.5Wieselthaler G.M. Driscoll G. Jansz P. Khaghani A. Strueber M. HVAD Clinical Investigators. Initial clinical experience with a novel left ventricular assist device with a magnetically levitated rotor in a multi-institutional trial.J Heart Lung Transplant. 2010; 29: 1218-1225Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Based on a supportive response from the FDA at the initial pre-IDE meeting, the UM-UP collaborative submitted a proposal in response to the NHLBI's Request for Proposal on December 8, 2009, incorporating the HVAD as the REVIVE-IT study device. Notification of the contract award to the UM-UP collaborative occurred on January 11, 2011. The major effort in the early period after the contract award was development of the protocol for submission to the FDA to obtain an IDE for the REVIVE-IT study. The major challenge in developing the study protocol was to identify a study population that was less ill than current DT recipients but with sufficient mortality and morbidity risk for LVAD therapy to have a reasonable probability of demonstrating success. As clinicians, we would have preferred a metric of success that incorporated survival and health-related quality of life. However, as investigators recognizing the understandable reluctance of the FDA to accept health-related quality of life as a component of a primary outcome measure in an unblinded study, we created a primary outcome measure incorporating survival, stroke disability, and improved functional capacity. The REVIVE-IT executive committee, consisting of the REVIVE-IT study principal investigators, the study chair, NHLBI program staff, and the Data and Clinical Coordinating Center (DCCC) at UM, had frequent correspondence with the FDA in the ensuing months to develop the REVIVE-IT study protocol. On June 8, 2011, the REVIVE-IT executive committee and DCCC held a pre-IDE conference call with the FDA. At that time, the FDA requested that the REVIVE-IT investigators delay submission of the IDE application to permit the FDA time to review further data on the HVAD. An IDE application for the REVIVE-IT trial was subsequently submitted to the FDA on December 11, 2011. The FDA responded to the REVIVE-IT IDE application on January 20, 2012, with disapproval of the initial IDE application, largely as a result of the absence of long-term safety data on the HeartWare HVAD. In retrospect, this initial request by the FDA to delay the IDE submission had more relevance than appreciated by the REVIVE-IT study team. REVIVE-IT investigators held a meeting with the FDA on February 27, 2011, to discuss the deficiencies of the REVIVE-IT IDE application. An amended IDE application to address the deficiencies was submitted to the FDA in April 2012. At that time, the HVAD was undergoing FDA panel review (April 25, 2012) of data from the ADVANCE trial (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure) supporting HeartWare's pre-market application for the HVAD for bridge-to-transplant indication.14Transcripts of the Food and Drug Administration Advisory Panel Meeting, Circulatory Systems Device Panel, April 25, 2012, reviewing data from ADVANCE trial (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure) supporting HeartWare, Inc.'s Premarket Application (PMA) for the HVAD for bridge to transplant (BTT) indication. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/CirculatorySystemDevicesPanel/UCM304770.pdf. Accessed April 25, 2016.Google Scholar Despite approval from the FDA panel for the HVAD for bridge-to-transplant indication, the FDA notified the REVIVE-IT study team of its disapproval of the REVIVE-IT IDE application on May 11, 2012, citing lack of long-term safety data on the use of the HVAD for DT. The ENDURANCE trial (pivotal trial of the HVAD for DT indication) was nearing completion of subject enrollment in the United States, so sufficient 2-year follow-up data on enrolled subjects were not available to satisfy the desire of the FDA for long-term performance data for the HVAD.15Pagani F.D. Milano C.A. Tatooles A.J. et al.HeartWare HVAD for the treatment of patients with advanced heart failure ineligible for cardiac transplantation: results of the ENDURANCE destination therapy trial.J Heart Lung Transplant. 2015; 34: S9Abstract Full Text Full Text PDF Google Scholar In the subsequent months, it became apparent that the REVIVE-IT trial could not be completed with the HVAD. Therefore, the REVIVE-IT study team and the industry sponsor, HeartWare, agreed to terminate their relationship. The FDA was notified of this decision on September 14, 2012. It was now clear to the REVIVE-IT study team that the only clear path to FDA approval of an IDE for REVIVE-IT was with a study device that had been approved for DT: the HMII.10Slaughter M. Rogers J.G. Milano C.A. et al.Advanced heart failure treated with continuous-flow left ventricular assist device.N Engl J Med. 2009; 361: 2241-2251Crossref PubMed Scopus (2428) Google Scholar, 12Park S.J. Milano C.A. Tatooles A.J. et al.Outcomes in advanced heart failure patients with left ventricular assist devices for destination therapy.Circ Heart Fail. 2012; 5: 241-248Crossref PubMed Scopus (274) Google Scholar, 13Jorde U.P. Kushwaha S.S. Tatooles A.J. et al.Results of the destination therapy post-Food and Drug Administration approval study with a continuous flow left ventricular assist device.J Am Coll Cardiol. 2014; 63: 1751-1757Crossref PubMed Scopus (201) Google Scholar REVIVE-IT investigators began discussions with Thoratec regarding industry support and use of the HMII as the REVIVE-IT study device. Thoratec agreed to participate as the industry partner in REVIVE-IT, and on December 20, 2012, the REVIVE-IT study team received FDA approval for IDE G120277 to complete the REVIVE-IT study with the HMII as the REVIVE-IT study device. In the second quarter of 2013, information was made available to the NHLBI and REVIVE-IT investigators of a concern for a higher incidence of pump thrombosis than previously reported from prior clinical trial data and published post-marketing surveillance data with the HMII. In response to this information, the NHLBI requested more information from the Interagency Registry of Mechanically Assisted Circulatory Support (INTERMACS) on the incidence of pump thrombosis for the HMII. On May 23, 2013, the NHLBI requested that the REVIVE-IT DCCC place all startup activities on hold until the preliminary INTERMACS analyses could be completed and made available for review and the concern for possible increased pump thrombosis could be addressed. In the ensuing months, the REVIVE-IT study team met with both the FDA and the REVIVE-IT Data Safety Monitoring Board (DSMB) to discuss findings of the INTERMACS analyses on pump thrombosis in the HMII. The preliminary INTERMACS analyses showed a modest, year-to-year increase in pump thrombosis without any change in survival after LVAD insertion.16Kirklin J.K. Naftel D.C. Kormos R.L. et al.Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device.J Heart Lung Transplant. 2014; 33: 12-22Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar Thoratec presented their root cause analysis investigation to the REVIVE-IT principal investigators and the NHLBI, a summary of which was presented by the study team to the REVIVE-IT DSMB. The root cause analysis did not identify an obvious cause for an increased rate of HMII pump thrombosis. After thorough review of the data by the FDA and the REVIVE-IT DSMB, both oversight entities supported the assessment and conclusion of the REVIVE-IT investigators that equipoise for continuation of the REVIVE-IT trial was not adversely affected by the new data on pump thrombosis. The NHLBI gave permission to resume trial startup activities on August 15, 2013. On August 28, 2013, the REVIVE-IT investigators reached their first milestone with enrollment of the first registry subject into the REVIVE-IT study (REVIVE-IT registry included patients who met a limited subset of the full trial eligibility criteria). On September 30, 2013, the REVIVE-IT DSMB held their regularly scheduled meeting and reiterated their previous confirmation of support to continue the REVIVE-IT study. On November 27, 2013, new information regarding the issue of pump thrombosis in the HMII became available to the REVIVE-IT investigators with publication in The New England Journal of Medicine of an article by Starling et al17Starling R.C. Moazami N. Silvestry S.C. et al.Unexpected abrupt increase in left ventricular assist device thrombosis.N Engl J Med. 2013; 370: 33-40Crossref PubMed Scopus (616) Google Scholar reporting an abrupt and substantial increase in pump thrombosis at 3 clinical sites. Concomitantly with the report by Starling et al, the analyses from INTERMACS on the issue of pump thrombosis in the HMII previously reviewed by the REVIVE-IT investigators, NHLBI, FDA, and REVIVE-IT DSMB were published by Kirklin et al16Kirklin J.K. Naftel D.C. Kormos R.L. et al.Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device.J Heart Lung Transplant. 2014; 33: 12-22Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar online and later in print in the Journal of Heart and Lung Transplantation. Compared with the report from the 3 centers, the national INTERMACS data showed a substantially smaller increase in pump thrombosis that had modestly but steadily increased each year (rather than a precipitous increase in March 2011). On December 2, 2013, for the second time, the NHLBI suspended trial enrollment to allow the REVIVE-IT DSMB to thoroughly review the newly published data from The New England Journal of Medicine report. On December 19, 2013, a meeting was held with the REVIVE-IT DSMB and REVIVE-IT investigators to present a summary of the data, limitations of the analysis, and the questions raised by the new findings. The REVIVE-IT investigators presented plans for risk mitigation including consideration for ensuring the homogeneity of best practices across clinical sites. The REVIVE-IT investigators believed that the issue of pump thrombosis could be successfully mitigated in the REVIVE-IT trial with implementation of administrative procedures and standardized best clinical practices within the trial, including (1) modifying informed consent documents to reflect a higher concern of pump thrombosis, (2) incorporating risk mitigation clinical strategies within REVIVE-IT Medical and Surgical Management Guidelines, (3) confirming that REVIVE-IT clinical site investigators were at continued equipoise with the current trial design and use of the HMII device in the REVIVE-IT trial, and (4) modification of study enrollment criteria (reducing the screening 6-minute walk test distance from 350 m to 300 m) to identify a population with slightly higher mortality risk with HF to maintain the balance of clinical equipoise.3Aaronson K.D. Pagani F.D. Kormos R. et al.Design for the Randomized Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT) Study.J Heart Lung Transplant. 2016; ([In press])Google Scholar Concomitantly, the NHLBI staff sought guidance from the National Institutes of Health Department of Bioethics. A consultation was obtained on January 14, 2014, and guidance from the Department of Bioethics was consistent with the above-outlined approach. Risk mitigation documents and modified protocol and informed consent documents were submitted to the FDA on February 11, 2014, along with a request to resume randomization and a request to expand the number of study sites to 22. This submission included the supplemental clinical investigator agreement, risk mitigation strategies, and REVIVE-IT Best Practices document incorporated into the REVIVE-IT Medical and Surgical Management Guidelines.3Aaronson K.D. Pagani F.D. Kormos R. et al.Design for the Randomized Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT) Study.J Heart Lung Transplant. 2016; ([In press])Google Scholar At the February 18, 2014, REVIVE-IT DSMB meeting, the DSMB endorsed the risk mitigation plan, Protocol Version 4.0, and associated informed consents. The NHLBI accepted their recommendations. On March 12, 2014, the FDA approved Protocol Version 4.0, informed consents, the risk mitigation document, and the medical and surgical management guidelines. The new protocol was distributed to REVIVE-IT investigators in March 2014. An Annual Investigator Meeting was held in May 2014, during which the risk mitigation plan, administrative procedures, and clinical practices were reviewed with study investigators. Over the next several months, a series of changes were made to the REVIVE-IT study protocol to reduce the complexity of patient evaluation and optimize patient selection for the trial, including reversal of the 6-minute walk test distance back to 350 m. On December 10, 2014, the first (and only) subject was randomly assigned in the REVIVE-IT trial, specifically to the medical arm of the study. In December 2014, 3 consecutive pump thrombosis events occurred 1 month after implantation of the HMII in patients undergoing implantation of the device for approved indications outside of the context of the REVIVE-IT trial, but using the trial's risk mitigation strategies, at 1 of the REVIVE-IT clinical sites. At a second REVIVE-IT clinical site where the risk mitigation strategies had been routinely followed, thrombosis had occurred within the first 6 months in routine clinical practice in 2 additional patients. REVIVE-IT investigators subsequently reported these events to the NHLBI and REVIVE-IT DSMB in early January 2015. For a third time, the REVIVE-IT study was placed on clinical hold by the NHLBI, and the FDA was notified on January 29, 2015. Over the ensuing months, REVIVE-IT investigators held meetings with the NHLBI and REVIVE-IT DSMB. Ultimately, recognizing the futility of trial enrollment as a result of (1) a loss of equipoise among a significant number of clinical site investigators with respect to placing the study device in a less ill population and (2) the inability to enroll subjects into a complex trial within the remaining time frame of the NHLBI contract, the REVIVE-IT DSMB endorsed terminating the REVIVE-IT study in April 2015. The NHLBI accepted their recommendation (Table 2).Table 2REVIVE-IT Timeline2008 March 2008NHLBI Workshop2009 November 20, 2009Pre-IDE meeting with FDA December 8, 2009UM-UP collaborative application submitted to NHLBI20102011 January 11, 2011Contract awarded to UM-UP collaborative January 14, 2011Contract award signed by UM and returned to NHLBI February 2011–May 2011Teleconferences and e-mail correspondence with FDA for development of REVIVE-IT IDE March 2011–September 2011Protocol development committee meetings April 28, 2011UM institutional review board approval DCCC activities May 27, 2011Protocol review committee meeting June 8, 2011Pre-IDE meeting with FDA September 22, 2011DSMB meeting December 12, 2011DSMB meeting December 19, 2011REVIVE-IT IDE application submitted to FDA2012 January 20, 2012REVIVE-IT received disapproval of IDE application February 27, 2012Meeting with FDA to discuss deficiencies of REVIVE-IT IDE November 26, 2012REVIVE-IT investigators submit new IDE application to FDA with HMII as REVIVE-IT study device December 20, 2012REVIVE-IT investigators receive approval from FDA for IDE G120277 to complete REVIVE-IT study December 21, 2012UM executes contract with Thoratec Corporation as industry partner for REVIVE-IT study2013 January 31, 2013REVIVE-IT investigators submit supplemental IDE to FDA to address minor non-hold issues and increase number of clinical sites from 14 to 182014 February 11, 2014Protocol Version 4.0 containing modified informed consent documents and risk mitigation procedures submitted to FDA February 18, 2014At DSMB meeting, DSMB endorsed risk mitigation plan and Protocol Version 4.0 and associated informed consent documents February 28, 2014NHLBI acceptance of DSMB recommendations May 30, 2014Annual investigator meeting presenting risk mitigation strategy and REVIVE-IT Best Practices September 26, 2014DSMB meeting and endorsement of Protocol Version 5.0 October 8, 2014NHLBI acceptance of DSMB recommendations October 16, 2014Protocol Version 5.0 amendment submitted to FDA November 14, 2014Protocol Version 5.0 amendment approved by FDA December 10, 2014First subject randomized into medical arm of REVIVE-IT trial2015 January 29, 2015FDA notified that REVIVE-IT trial was being placed on clinical hold after series of consecutive pump thrombus events observed in patients receiving the device for current FDA-approved labeling indications outside of the context of REVIVE-IT study at a REVIVE-IT clinical site March 19, 2015DSMB meeting to discuss issues leading to clinical hold and equipoise April 13, 2015REVIVE-IT study discontinued after NHLBI acceptance of DSMB recommendationsDCCC, Data and Clinical Coordinating Center; DSMB, Data Safety Monitoring Board; FDA, US Food and Drug Administration; HMII, HeartMate II; IDE, investigational device exemption; NHLBI, National Heart Lung and Blood Institute; REVIVE-IT, Randomized Evaluation of VAD InterVEntion before Inotropic Therapy; UM, University of Michigan; UP, University of Pittsburgh. Open table in a new tab DCCC, Data and Clinical Coordinating Center; DSMB, Data Safety Monitoring Board; FDA, US Food and Drug Administration; HMII, HeartMate II; IDE, investigational device exemption; NHLBI, National Heart Lung and Blood Institute; REVIVE-IT, Randomized Evaluation of VAD InterVEntion before Inotropic Therapy; UM, University of Michigan; UP, University of Pittsburgh. The failure of the REVIVE-IT trial represented a "perfect storm" of (1) the inability of current technology and still-evolving patient and pump management strategies to meet safety expectations of clinicians, patients, and regulatory agencies to perform an RCT in a population with less advanced HF, leading to a lack of clinical equipoise by the community and the REVIVE-IT investigators, and (2) the complexities of identifying and recruiting trial subjects on OMM who had sufficiently advanced HF and who could potentially benefit from VAD therapy, yet did not have such advanced HF that they would already be a candidate for a DT. The lack of long-term safety data and concern for stroke with the HVAD and the concern for pump thrombosis with the HMII significantly delayed progress in the REVIVE-IT trial. The recurring issue of pump thrombosis in the HMII led some clinical sites to withdraw from the trial and ultimately led to a loss of clinical equipoise for most, but not all, study investigators. There were many aspects of the REVIVE-IT trial that worked well, deserve further mention, and should be considered for inclusion in any future RCT of LVAD therapy in a population with less advanced HF. First, REVIVE-IT was a collaborative effort, reflecting a strong commitment from clinicians, scientists, and regulatory agencies. The administrative and organizational structure of REVIVE-IT was strong and benefited by inclusion of a vast amount of expertise from multiple clinical sites, core laboratories, and the DCCC. The REVIVE-IT investigators were supported with strong NHLBI resource commitments, both financially and intellectually, with sustained and substantial contributions from NHLBI personnel throughout the study. Additionally, both industry partners during their respective periods of involvement provided significant financial resources and a negotiated agreement of independence from the conduct of the study. From the start, governmental regulatory agencies including the FDA and the Centers for Medicare and Medicaid Services were open to early dialogue and collaboration with REVIVE-IT investigators that contributed to important insights into the trial design and assisted progress with development of the study protocol. We believe that establishing and using collaborations with these groups will be critical to the success of any similar future study aiming to expand LVAD therapy into a less ill population. For a trial similar to REVIVE-IT to move forward in the future, several important issues need to be addressed, including (1) identification of a study device with a safety profile that satisfies clinical equipoise for trial investigators and regulatory agencies and (2) an improved understanding of patient characteristics that will permit more accurate assessment of HF prognosis. It is unlikely that current technology will ever satisfy the first requirement, and new technology will be required to advance LVAD therapy into a population with less advanced HF. Concerns for current LVAD technology were highlighted by a safety communication (August 5, 2015) issued by the FDA highlighting adverse events with current durable LVADs and emphasized the importance of restricting current device use to currently approved populations to justify the benefit and risk profile.18Food and Drug Administration. Serious adverse events with implantable left ventricular assist devices (LVADs): FDA safety communication. Available at: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm457327.htm. Accessed April 25, 2016Google Scholar Results from the ENDURANCE trial, a prospective RCT evaluating the HVAD and HMII for DT demonstrated non-inferiority of the HVAD to the HMII with respect to the primary efficacy end-point.15Pagani F.D. Milano C.A. Tatooles A.J. et al.HeartWare HVAD for the treatment of patients with advanced heart failure ineligible for cardiac transplantation: results of the ENDURANCE destination therapy trial.J Heart Lung Transplant. 2015; 34: S9Abstract Full Text Full Text PDF Google Scholar However, the ENDURANCE trial highlighted the limitations of the presently available devices in the context of a trial in a population with less advanced HF. There was a substantial risk of pump exchange, explant, or need for urgent transplant with both devices, but especially with the HMII (16.2%) compared with the HVAD (8.8%). However, the risk of stroke was prohibitively high for the HVAD (28.7% vs 12.1% for the HM II). These results confirmed concerns of the FDA, NHLBI, and REVIVE-IT study leadership with respect to conducting REVIVE-IT with the current generation of mechanical circulatory support devices. To better understand which patients might have the most to gain from earlier implementation of future iterations of LVAD therapy, the REVIVE-IT study has been rescoped from the trial and corresponding registry of patients with HF who did not meet the entry criteria or opted not to participate to that of a more comprehensive long-term registry to study the prognosis of patients with lesser degrees of advanced HF. This effort has been called REVIVAL (REgistry of Vital Information for VADs in Ambulatory Life) and expands on the commitment of the NHLBI to understanding HF prognosis in patients receiving OMM in the Medical Arm of Mechanically Assisted Circulatory Support (MEDAMACS), the medical registry arm for patients not receiving mechanical circulatory support in INTERMACS. Validation of the underlying hypothesis of REVIVE-IT that earlier use of LVADs can improve outcomes and the need for a future RCT were endorsed by the REVIVE-IT DSMB at the final DSMB meeting. Whether a trial of LVAD therapy in patients with less advanced HF will ever be completed in the future is unknown. There is some debate as to whether an RCT studying LVAD therapy in patients with less advanced HF is necessary. Some thought experts assert that the data necessary to offer LVAD therapy to patients with less advanced HF can be obtained from registry data or non-randomized observations trials. More recently, data were reported from the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) study, a multi-center, non-randomized observational study evaluating LVAD therapy in ambulatory non–inotrope-dependent patients compared with OMM.19Estep J.D. Starling R.C. Horstmanshof D.A. et al.Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients.J Am Coll Cardiol. 2015; 66: 1747-1761Crossref PubMed Scopus (246) Google Scholar ROADMAP demonstrated improved survival free from urgent transplant or subsequent LVAD placement for patients assigned to LVAD therapy compared with OMM (80% ± 4 vs 63% ± 5; p = 0.022) when the data were analyzed according to initial treatment assignment. However, this outcome was completely driven by the need for LVAD in 22% of the OMM arm. Moreover, overall survival free of urgent transplant at 1 year (when change of therapy from OMM to LVAD was removed from the composite outcome) was not statistically different for LVAD compared with OMM (82% ± 4 vs 81% ± 4; p = 0.931), with very similar risks for both death within 1 year (22% for OMM vs 20% for LVAD) and urgent transplant (0% for OMM vs 2% for LVAD). Adverse events were higher in patients with LVADs (1.89 events/patient-year [EPPY], primarily driven by bleeding [1.22 EPPY]) than in patients with OMM (0.83 EPPY, mainly worsening HF [0.68 EPPY]). More LVAD recipients required subsequent hospitalization, but hospitalization was common in both groups (80% LVAD vs 62% OMM; p < 0.001). It is unknown whether REVIVE-IT would have demonstrated similar findings in an RCT enrolling patients with less advanced HF. However, the results of ROADMAP clearly demonstrate the potential for bias in the study population without randomization and speak to the need for an RCT to more definitively evaluate the use of LVAD therapy in a population with less advanced HF. New LVAD technology is being evaluated at the present time in trial designs not incorporating a randomized medical comparator group.20Netuka I. Sood P. Pya Y. et al.Fully magnetically levitated left ventricular assist system for treating advanced heart failure. A multicenter study.J Am Coll Cardiol. 2015; 66: 2579-2589Crossref PubMed Scopus (174) Google Scholar The enrollment criteria for the HeartMate 3 (Thoratec Corporation, now St. Jude, Minneapolis, MN) study (ClinicalTrials.gov Identifier: NCT02224755) are designed to allow inclusion of ambulatory, non–inotrope-dependent patients with New York Heart Association class III or IV limitations (in addition to patients with more severely advanced HF).21Heatley G. Sood P. Goldstein D. et al.Clinical trial design and rationale of the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) investigational device exemption clinical study protocol.J Heart Lung Transplant. 2016; 35: 528-536Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar These criteria eschew objective evaluations of functional limitations using established methodologies (i.e., 6-minute walk test distance or peak exercise oxygen consumption) in favor of either subjective assessments (i.e., New York Heart Association functional class) or hemodynamic criteria. However, the limitations of New York Heart Association assessment and hemodynamic criteria in assessing prognosis in advanced HF are well established. Assessing the benefits of VAD therapy in the recipients of VADs with less advanced HF who enter this trial will be impossible, as their natural history on continued medical therapy alone is unclear. We believe that the inclusion of a randomized medical comparator group in VAD trial designs is essential to fully understand the tradeoff of benefit and harm of LVAD therapy in a less ill group of patients. Design of such a study should incorporate information on the natural history and risks to patients with advanced HF on medical therapy alone that is expected to be gleaned from REVIVAL. In conclusion, the underlying hypothesis of REVIVE-IT remains valid and should be the basis for a future trial of LVAD therapy in a population with less advanced HF with newer generations of LVADs with a lower adverse-event profile. We believe that the chances of success of any such future trial would be improved by considering the lessons learned from the REVIVE-IT study. R.K. has received educational support (<$3000) from HeartWare, Inc. D.L.M. has been a consultant for Novartis, Bristol-Myers Squibb, and Corvia Medical, Inc., and a member of miRagen Therapeutics, Inc., Scientific Advisory Board. D.M.M. has been a speaker for Novartis and Amgen. K.L.G. has been a speaker for the American Heart Association and a speaker and expert witness for INTERMACS. D.J.G. has received travel reimbursement from St. Jude Medical, Inc., to attend research meetings in his role as National Co-principal Investigator in the MOMENTUM 3 Trial and has been a consultant and medical monitor for Terumo Corporation. REVIVE-IT (ClinicalTrials.gov identifier: NCT01369407) was supported by funding from the National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI Contract Number: HHSN268201100026C). Additional funding in the early study period was provided by HeartWare, Inc., and in the later study period by Thoratec Corporation. The REVIVE-IT investigators acknowledge the intellectual contributions of David Farrar, PhD, Donald Middlebrook, and David Hathaway, MD. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; National Institutes of Health; US Department of Health and Human Services; or US Government. Download .pdf (.91 MB) Help with pdf files Supplementary material
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