Continuous Flow Left Ventricular Assist Device Outcomes in Commercial Use Compared With the Prior Clinical Trial

Transcription

1 Continuous Flow Left Ventricular Assist Device Outcomes in Commercial Use Compared With the Prior Clinical Trial Ranjit John, MD, Yoshifumi Naka, MD, Nicholas G. Smedira, MD, Randall Starling, MD, MPH, Ulrich Jorde, MD, Peter Eckman, MD, David J. Farrar, PhD, and Francis D. Pagani, MD, PhD Cardiothoracic Surgery, University of Minnesota, Minneapolis, Minnesota; Cardiothoracic Surgery, Columbia Presbyterian Hospital, New York, New York; Cardiothoracic Surgery, Cleveland Clinic, Cleveland, Ohio; Department of Medicine, Cleveland Clinic, Cleveland, Ohio; Department of Medicine, Columbia Presbyterian Hospital, New York, New York; Department of Medicine, University of Minnesota, Minneapolis, Minnesota; Thoratec Corporation, Pleasanton, California; and Cardiothoracic Surgery, University of Michigan, Ann Arbor, Michigan Background. A multicenter clinical trial conducted from 2005 to 2008 of a continuous flow left ventricular assist device (LVAD) resulted in Food and Drug Administration approval for bridge to transplantation. The purpose of this analysis was to determine changes in posttrial outcomes in widespread commercial use since the clinical trial. Methods. We compared outcomes of 486 patients who received a continuous flow LVAD as a bridge to transplantation at 36 centers during the clinical trial (March 2005 to April 2008) with outcomes of 1,496 posttrial patients who received a continuous flow LVAD at 83 centers (April 2008 to September 2010 as reported to the Interagency Registry for Mechanically Assisted Circulatory Support). Results. Baseline data were comparable between groups. Cumulative follow-up was 511 and 1,082 patientyears for trial and posttrial patients, respectively, and average support duration was and months. Kaplan-Meier survival improved at 1 year from 76% (trial) to 85% (posttrial). The percentage of patients undergoing transplantation in the first year decreased from 48% in the trial period to 39% in the posttrial period. Quality of life metrics improved by 3 months in both groups. Conclusions. The survival rate of a large group of continuous flow LVAD patients in a real-world setting after Food and Drug Administration market approval for bridge to transplantation has improved since the clinical trial. These data show that excellent outcomes have been maintained with dissemination of new LVAD technology from a clinical trial phase to more broad based use in the period after market approval. (Ann Thorac Surg 2011;92: ) 2011 by The Society of Thoracic Surgeons The recent advent of continuous flow left ventricular assist devices (LVADs) has had an important impact on survival and quality of life for patients once considered to have terminal heart failure [1 3]. An increasing number of patients with advanced stage heart failure refractory to medical therapy are being supported by LVADs as a bridge to heart transplant (BTT) or for destination therapy. Better survival and fewer adverse events have resulted in an increased acceptance of this therapy [3, 4]. The US Food and Drug Administration (FDA) commercially approved the HeartMate II continuous flow LVAD (Thoratec, Pleasanton, CA) for BTT in 2008 and for destination therapy in 2010 [1, 5]. The survival rate for the BTT indication has steadily improved over the past 5 years and is approaching that of heart transplantation [6]. The 1-year survival rate from the HeartMate II pivotal trial for BTT in the first 133 patients implanted in 2005 to 2006 was 68% [7]. Subsequently, after including data from the next 148 patients, survival improved to 73% [5]. More recently, outcome data from the postapproval study conducted through the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) showed a further increase in 1-year survival to 85% [8].In that study, patients supported by the continuous flow LVAD had better survival rates compared with patients supported by pulsatile flow devices. In a randomized trial for destination therapy, the continuous-flow HeartMate Accepted for publication May 16, Presented at the Forty-seventh Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31 Feb 2, Address correspondence to Dr John, Division of Cardiothoracic Surgery, University of Minnesota, 420 Delaware St SE, MMC 207, Minneapolis, MN 55455; johnx008@umn.edu. Drs John, Naka, Starling, Eckman, Farrar, and Pagani disclose that they have financial relationships with Thoratec Corporation; Dr Jorde with Thoratec Corporation and Jarvik Heart Inc by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg JOHN ET AL 2011;92: TRIAL VERSUS POSTTRIAL OUTCOMES 1407 II was compared with the pulsatile-flow HeartMate XVE LVAD (Thoratec). That study demonstrated a significant survival benefit, indicating that the continuous flow LVAD technology has important advantages in the improvement of survival and reduction of adverse events [1]. Since the completion of the BTT clinical trial, there have been nearly 1,500 additional BTT patients implanted in commercial use as reported to the INTERMACS registry. The objective of this investigation was to evaluate differences in outcomes for patients supported during the BTT clinical trial and during the posttrial phases over the past 5 years. We believe these results will help clarify the effectiveness of this new technology in real-world clinical use. Patients and Methods Patients This study is a retrospective analysis of outcome data from 1,982 patients supported by the HeartMate II LVAD as a BTT between 2005 and Patients were divided into two groups: those supported during the clinical trial (trial group; n 486) and those supported after commercial approval by the FDA (posttrial group; n 1,496). The trial group included patients at 36 centers who were enrolled in the HeartMate II BTT clinical trial from March 2005 through April 2008, including patients in the primary data cohort and patients who were enrolled in the subsequent continued-access protocol. All patients met study inclusion criteria and gave informed consent as approved by the Institutional Review Boards at the participating institutions. The posttrial group consisted of patients at 83 centers who were supported by the Heart- Mate II after FDA approval from April 2008 to October 2010 as reported to the INTERMACS registry. Data Collection For this study, the trial data was obtained from the study sponsor (Thoratec). The trial results have been published previously [5, 7]. The outcome data for the posttrial group were obtained from the INTERMACS database. All of the posttrial patients were entered into the registry as either listed or likely to be listed for heart transplant. Clinical data are entered into the INTERMACS database by each participating center according to the definitions and at the intervals published in the INTERMACS manual of operations (available at: Endpoints The outcome endpoints analyzed in this study were overall survival from the LVAD implant, ongoing LVAD support, transplant, device removal after myocardial recovery, and death. For the trial patients, the Kansas City Cardiomyopathy Questionnaire overall summary scores were used to assess quality of life. For posttrial patients, the EuroQol EQ-5D visual analog scale, as used by INTERMACS, was evaluated. Functional status was evaluated using the 6-minute walk test in both groups. In the trial period, data were collected before implant, and 1, 3, and 6 months after implant. For the posttrial period, data were collected before implant, and at 3, 6, and 12 months. Adverse events in the posttrial period are presented using INTERMACS definitions. Adverse events in the trial period were only presented for events having comparable definitions with the INTERMACS registry. Statistical Analysis All statistical comparisons were two-sided, with a p value of 0.05 considered significant. Data are given as the mean SD, or when appropriate, the median and range. Discrete variables are reported as a percentage. Differences in continuous variables between the study groups were determined with the t test. Fisher s exact test was used to determine differences in categorical variables. Survival analysis for patients remaining on LVAD support was performed by using the Kaplan-Meier method, with censoring at the time points when LVAD support was removed for transplantation or recovery with device explant. Differences in survival were determined with the log rank test. The cumulative proportion of patients reaching the endpoints of LVAD support over time was used for the competing outcomes analysis. For the posttrial period, competing outcomes were determined for the first 892 patients who all had at least 1 year of follow-up. Adverse events are provided as the number of patients with the event, the percentage of patients with the event, and the event rate (number of events divided by the patient-years). Statistical comparison of events rates between the two groups was not performed (because of differences in adverse event reporting methods). Comparisons over time for functional and quality of life measures were done with linear mixed effects modeling. Statistical analyses were performed with SAS software (SAS Institute, Cary, NC). Results Baseline Characteristics The baseline characteristics for the 486 trial patients and 1,496 posttrial patients are shown in Table 1. Demographics were similar, except that posttrial patients were larger (weight, body mass index, and body surface area). Pulmonary diastolic and capillary wedge pressures were slightly higher in the trial patients compared with posttrial patients. The difference in cardiac index was not significant between the groups. As compared with the trial patients, the posttrial group had significantly lower blood urea nitrogen and increased serum sodium. However, the total bilirubin was higher, and the platelet count was lower. A smaller percentage of posttrial patients (80%) required intravenous inotropes than did trial patients (90%; p ) or intraaortic balloon pump support (33% versus 42%, p ). More than 60% of patients in the posttrial group were in the most severely ill INTERMACS profiles 1 and 2. These data were not collected during the trial.

3 1408 JOHN ET AL Ann Thorac Surg TRIAL VERSUS POSTTRIAL OUTCOMES 2011;92: Table 1. Baseline Characteristics of the Trial and Posttrial Groups Characteristic Trial Posttrial p Value Number Male 377 (78%) 1,154 (77%) Age, years (20%) 255 (17%) 40 to (48%) 787 (53%) (32%) 454 (30%) Height, cm Weight, kg Body surface area, m Body mass index, kg/m Body surface area 1.5 m 2 18 (3.7%) 24 (2%) INTERMACS category 1 critical cardiogenic shock, n (%) NA 252 (16.8%) 2 progressive decline, n (%) NA 667 (44.6%) 3 stable but inotrope dependent, n (%) NA 297 (19.9%) 4 resting symptoms, n (%) NA 174 (11.6%) 5 exertion intolerant, n (%) NA 42 (2.8%) 6 exertion limited, n (%) NA 33 (2.2%) 7 advanced NYHA class III, n (%) NA 31 (2.1%) Hemodynamics Heart rate Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Mean blood pressure, mm Hg Systolic PAP, mm Hg Diastolic PAP, mm Hg Mean PAP, mm Hg Pulmonary wedge pressure, mm Hg Pulmonary vascular resistance, Wood units Right atrial pressure, mm Hg Cardiac index, L/min/m Laboratory Blood urea nitrogen, mg/l Creatinine, mg/l Total bilirubin, mg/l Sodium, mg/l International normalized ratio White blood cell count, K/ L Platelets, K/ L SGOT/AST, /L Hemoglobin, mg/dl Albumin, mg/dl Concomitant procedures Intraaortic balloon pump 204 (42%) 490 (33%) Mechanical ventilation 41 (8%) 138 (9%) ACE inhibitors 134 (28%) Not reported Beta-blockers 182 (37%) Not reported Intravenous inotropic agents 436 (90%) 1203 (80%) ACE angiotensin-converting enzyme; AST aspartate aminotransferase; INTERMACS Interagency Registry for Mechanically Assisted Circulatory Support; NA not applicable; NYHA New York Heart Association; PAP pulmonary artery pressure; SGOT serum glutamic oxaloacetic transaminase.

4 Ann Thorac Surg JOHN ET AL 2011;92: TRIAL VERSUS POSTTRIAL OUTCOMES 1409 LVAD support in the Kansas City Cardiomyopathy Questionnaire (used in the trial), and the EQ-5D visual analog scale (posttrial; Fig 4A and 4B). Fig 1. Kaplan-Meier actuarial survival curves for the trial and posttrial patient groups in this study. At 12 months, the survival rate was 76% for the trial group and 85% for the posttrial group (p 0.001). Support Durations Cumulative follow-up was 511 years for trial patients and 1,082 years for posttrial patients. The average support duration was months for the trial group and months for the posttrial group. After LVAD placement, 83% of trial patients and 86.3% of posttrial patients were discharged from the hospital. Survival The 30-day operative mortality was 6.6% for the trial group and 4.5% for the posttrial group. The Kaplan- Meier survival was significantly improved for the posttrial group (p 0.001) compared with the trial group, with 1-year survival estimates increasing from 76% to 85% (Fig 1). Competing outcomes analysis showed that the percentage of patients who were transplanted, recovered, or received ongoing support increased from the trial to the posttrial period from 85% to 89% by 6 months and from 81% to 85% by 1 year (Fig 2A and 2B). The percentage of patients undergoing transplantation in the first year decreased from 48% (trial) to 39% (posttrial). Adverse Events Adverse events for the posttrial group, as reported to INTERMACS, are listed in Table 2. Bleeding and infection were the most frequently reported adverse events. Events that have the same definitions during the trial and in the INTERMACS registry are listed for comparison in Table 3. There was a trend for reduction in bleeding requiring reoperation, percutaneous lead infection, rightside heart failure requiring right ventricular assist device support, hemorrhagic stroke, and device replacement. Functional Status and Quality of Life The results of the 6-minute walk test showed similar improvements in the distance walked after LVAD support in both groups (Fig 3). Although using different instruments, there were similar improvements during Comment This study shows that survival outcomes improved in patients who received a HeartMate II LVAD for BTT after market approval in a broad range of centers in commercial use compared with the earlier clinical trial. Kaplan- Meier survival improved at 1 year from 76% (trial) to 85% (posttrial). This finding is consistent with steady improvements reported in survival from 68% to 73% as experience was gained from the early to mid stages of the clinical trial [5, 7]. Another important finding in this study was the decrease in the percentages of patients undergoing heart transplant from the trial to the posttrial period. After 6 months of LVAD support, 32% of patients had undergone transplantation in the trial as compared with only 22% of the posttrial patients. Similarly, by 12 months, 48% of trial patients had received a transplant, compared with 39% of posttrial patients. After market approval of the device, there was an increase in the Fig 2. (A) Competing outcomes analysis for the clinical trial patients (n 486). (B) Competing outcomes analysis for the posttrial patients (n 892 patients with at least 1 year of follow-up).

5 1410 JOHN ET AL Ann Thorac Surg TRIAL VERSUS POSTTRIAL OUTCOMES 2011;92: Table 2. Adverse Events for the Posttrial Patients (n 1,496) a Adverse Event Patients No. of Events Events per Patient-Year Arterial non-cns 8 (1%) thromboembolism Bleeding 539 (36%) 1, Bleeding requiring 101 (7%) surgery Gastrointestinal 157 (10%) bleeding Cardiac arrhythmia 418 (28%) Device malfunction 156 (10%) Hemolysis 45 (3%) Hepatic dysfunction 59 (4%) Hypertension 78 (5%) Infection b 566 (38%) 1, Driveline 192 (13%) Pump pocket 28 (2%) Pump interior 4 (0%) Blood 167 (11%) Line sepsis 38 (3%) Other infection 386 (26%) Myocardial infarction 10 (1%) Stroke 97 (6%) Hemorrhagic stroke 23 (2%) Ischemic stroke 57 (4%) Unknown 17 (1%) Other neurologic 64 (4%) dysfunction Pericardial drainage 91 (6%) Psychiatric episode 125 (8%) Rehospitalization 744 (50%) 1, Renal dysfunction 129 (9%) Respiratory failure 241 (16%) Right-side heart 173 (12%) failure Right ventricular 14 (1%) assist device Venous 88 (6%) thromboembolism Wound dehiscence 19 (1%) Device replacement 21 (1%) a Cumulative support patient-years. have multiple sites. CNS central nervous system. b Infection events can number of centers that performed HeartMate II implants, thereby increasing the number of BTT patients on heart transplant waiting lists. That may have increased competition for a limited number of donors, which could have resulted in the longer waiting time for transplantation. The HeartMate II has also proven to be very reliable for extended durations. Studies have shown that the development of continuous flow LVAD technology has had an important impact in reducing adverse events and improving survival with better quality of life [1, 3, 9]. Experience from the trial and posttrial studies and that of more than 7,000 HeartMate II LVADs that have been implanted worldwide since 2005 (cumulative support time, more than 5,000 patient-years, and more than 80 patients with more than 4 years of support) have yielded additional lessons regarding patient selection, perioperative management, operative techniques, and long-term management of outpatients [10]. This experience has likely resulted in the improved outcomes seen in the posttrial patients. For example, over the course of the clinical study, it was determined that anticoagulation therapy could be decreased because of the low rates of thrombogenicity [11 13]. Studies showed that postoperative heparin may not be required in transitioning patients to warfarin [13], and that the international normalized ratio could be lowered to 1.5 to 2.5 [12]. Subsequent to these changes in anticoagulation regimens, the overall bleeding adverse event rates have decreased. However, late gastrointestinal bleeding events are being observed in many patients supported by continuous flow LVADs [14, 15]. Gastrointestinal bleeding due to factors such as angiodysplasias and acquired von Willebrand disease in this population requires further research to develop measures for prevention and treatment [16]. The continuous arterial blood flow generated by these new LVADs has changed the traditional approach to managing hemodynamics. Over the course of the Heart- Mate II study experience, investigators realized the importance of having a more conservative rotor speed setting. With continuous unloading of the left ventricle, cardiac output is augmented during diastole, resulting in increased diastolic pressure, reduced pulse pressure and potentially less aortic valve opening. Aortic valve insufficiency has been observed to develop or worsen during LVAD support when the aortic valve remains closed for prolonged periods [17 20]. Pump speed settings that result in some degree of constant aortic valve opening may be beneficial [11]. Furthermore, the reduced pulse pressure has somewhat complicated the routine measurement and management of arterial blood pressure in ambulatory patients [21]. Blood pressure is difficult to measure with conventional automated devices. Many clinicians now use a Doppler to listen to the first sound of flow while the sphygmomanometer pressure is released, but the value obtained may be somewhere between true systolic or diastolic pressure. Thus, a cautious approach to using these values in managing vasodilator therapy is prudent. In addition, pump speed settings that are high relative to the available blood volume of the left ventricle may result in a suck-down effect within the ventricle, with possible effects on right ventricular function or obstruction of the opening of the inflow cannula with ventricular arrhythmias. When the clinical trials with continuous flow LVADs began just over a decade ago, there was concern over the uncertainty of the long-term effects of arterial blood flow with low pulsatility. However, the large amount of cumulative experience with the HeartMate II indicates that long-term support does not carry detrimental effects on organ function [22]. Although it appears that the reliability issues of the past have been largely addressed with

6 Ann Thorac Surg JOHN ET AL 2011;92: TRIAL VERSUS POSTTRIAL OUTCOMES 1411 Table 3. Adverse Events Comparable by Definition for Trial Group (n 486) and Posttrial Group (n 1496) Trial (n 486) Patient-Years Posttrial (n 1,496) Patient Years Adverse Event Incidence a Event Rate b Incidence a Event Rate b Bleeding requiring reexploration 21% % 0.12 Infection Percutaneous lead 20% % 0.28 Pump pocket 3% % 0.03 Right-side HF requiring RVAD 7% % 0.01 Stroke Ischemic 5% % 0.06 Hemorrhagic 5% % 0.02 Other 0% % 0.02 Device replacement 5% % 0.02 a Percent of patients. HF heart failure; b Events per patient-year. RVAD right ventricular assist device. the newer continuous flow LVADs, some adverse events continue to limit the overall effectiveness of the technology. Although infection rates have decreased with the smaller LVADs, infection continues to be an important risk factor for long-term survival [23]. Aggressive strategies for prevention and treatment of infection need to be refined. Because trauma to the percutaneous lead exit site is a frequent cause of many device-related infections, preventative stabilization of the lead is important to minimize risk of infection. For long durations, a totally implantable LVAD with a transcutaneous energy transmission system may offer the best option for preventing infection [24]. There are several limitations to this study. First, individual centers had their own variations in patient selec- Fig 3. Six-minute walk test results for the trial group (black bars) and posttrial group (gray bars). There were improvements during left ventricular assist device support from baseline for both groups. Data for the 12-month interval was not determined for the trial group. The percentage of patients able to complete the test is listed below the x-axis. Fig 4. (A) Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score for the trial group. (B) EuroQoL EQ-5D visual analog scale results for the posttrial cohort. Note: The EuroQol and KCCQ reporting intervals are different.

7 1412 JOHN ET AL Ann Thorac Surg TRIAL VERSUS POSTTRIAL OUTCOMES 2011;92: tion, implantation techniques, and postoperative management of patients, which is a limitation of any multicenter study. In addition, there are important differences in reporting and collection of data in a carefully monitored clinical trial and from a registry. There were differences in adverse event definitions between the clinical trial and the INTERMACS registry that do not permit comparative analyses of all variables. However, for events with the same definition, there was a trend toward lower adverse event rates for the posttrial patients. Quality of life assessment tools used in the clinical trial and by the INTERMACS registry were also different. Although not directly comparable, the EuroQoL results from the posttrial patients and the Kansas City Cardiomyopathy Questionnaire results for the trial patients both showed improvements at 3 months with sustained measures out to 6 months. In a recent study by Rogers and colleagues [3], the functional status and quality of life measures from 655 patients supported by the HeartMate II demonstrated early and sustained improvements up to 2 years. In summary, the results of this study demonstrate that outcomes of patients bridged to transplant with the HeartMate II LVAD have improved since the clinical trial. Results were determined from one of the largest datasets ever evaluated in mechanical circulatory support from a broad range of clinical centers. The findings indicate that excellent outcomes have been maintained with dissemination of new LVAD technology from a clinical trial phase to more broad based use in the postmarket-approval period. This study was sponsored by Thoratec Corporation. References 1. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361: Fang JC. Rise of the machines left ventricular assist devices as permanent therapy for advanced heart failure. N Engl J Med 2009;361: Rogers JG, Aaronson KD, Boyle AJ, et al. Continuous flow left ventricular assist device improves functional capacity and quality of life of advanced heart failure patients. J Am Coll Cardiol 2010;55: John R, Kamdar F, Liao K, Colvin-Adams M, Boyle A, Joyce L. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg 2008;86: Pagani FD, Miller LW, Russell SD, et al. Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device. J Am Coll Cardiol 2009;54: Williams ML, Trivedi JR, McCants KC, et al. Heart transplant versus left ventricular assist device in heart transplanteligible patients. Ann Thorac Surg 2011;91: Miller LW, Pagani FD, Russell SD, et al. Use of a continuousflow device in patients awaiting heart transplantation. N Engl J Med 2007;357: Starling RC, Naka Y, Boyle AJ, et al. Results of the post-fdaapproval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS registry. J Am Coll Cardiol 2011;57: Osorio J. Continuous-flow LVAD improves quality of life. Nat Rev Cardiol 2010;7: Slaughter MS, Pagani FD, Rogers JG, et al. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010; 29(Suppl): John R, Kamdar F, Liao K, et al. Low thromboembolic risk for patients with the Heartmate II left ventricular assist device. J Thorac Cardiovasc Surg 2008;136: Boyle AJ, Russell SD, Teuteberg JJ, et al. Low thromboembolism and pump thrombosis with the HeartMate II left ventricular assist device: analysis of outpatient anticoagulation. J Heart Lung Transplant 2009;28: Slaughter MS, Naka Y, John R, et al. Post-operative heparin may not be required for transitioning patients with a Heart- Mate II left ventricular assist system to long-term warfarin therapy. J Heart Lung Transplant 2010;29: Letsou GV, Shah N, Gregoric ID, Myers TJ, Delgado R, Frazier OH. Gastrointestinal bleeding from arteriovenous malformations in patients supported by the Jarvik 2000 axial-flow left ventricular assist device. J Heart Lung Transplant 2005;24: Crow S, John R, Boyle A, et al. Gastrointestinal bleeding rates in recipients of nonpulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg 2009;137: John R, Panch SR, Hrabe J, et al. Activation of endothelial and coagulation systems in left ventricular assist device recipients. Ann Thorac Surg 2009;88: Pak SW, Uriel N, Takayama H, et al. Prevalence of de novo aortic insufficiency during long-term support with left ventricular assist devices. J Heart Lung Transplant 2010; 29: Cowger J, Pagani FD, Haft JW, Romano MA, Aaronson KD, Kolias TJ. The development of aortic insufficiency in left ventricular assist device-supported patients. Circ Heart Fail 2010;3: Mudd JO, Cuda JD, Halushka M, Soderlund KA, Conte JV, Russell SD. Fusion of aortic valve commissures in patients supported by a continuous axial flow left ventricular assist device. J Heart Lung Transplant 2008;27: John R, Mantz K, Eckman P, Rose A, Joyce L. Aortic valve pathophysiology during left ventricular assist device support. J Heart Lung Transplant 2010;29: Myers TJ, Bolmers M, Gregoric ID, Kar B, Frazier OH. Assessment of arterial blood pressure during support with an axial flow left ventricular assist device. J Heart Lung Transplant 2009;28: Russell SD, Rogers JG, Milano CA, et al. Renal and hepatic function improve in advanced heart failure patients during continuous-flow support with the HeartMate II left ventricular assist device. Circulation 2009;120: Topkara VK, Kondareddy S, Malik F, et al. Infectious complications in patients with left ventricular assist device: etiology and outcomes in the continuous-flow era. Ann Thorac Surg 2010;90: Slaughter MS, Myers TJ. Transcutaneous energy transmission for mechanical circulatory support systems: history, current status, and future prospects. J Card Surg 2010;25:

8 Ann Thorac Surg JOHN ET AL 2011;92: TRIAL VERSUS POSTTRIAL OUTCOMES 1413 DISCUSSION DR MICHAEL A. ACKER (Philadelphia, PA): Thank you. The significantly improved survival of nearly 1,500 postmarket approved bridge to transplant HeartMate II patients over already excellent results of the pivotal trail demonstrate several things. One, that new VAD technology that utilizes continuous flow, a disruptive concept compared with pulsatile flow, can be taught along with appropriate patient selection and disseminated to a broad range of clinical centers. If similar successful dissemination occurs after the destination therapy approval, small continuous flow pumps will constitute a paradigm shift for the treatment of end-stage heart failure. Two, that the regulations governing this dissemination put in place by a combination of the FDA, CMS, JACHO, and, most importantly the manufacturer, actually does insure safety on dissemination; it works. And finally, that mandatory prospective databases such as INTERMACS are essential for monitoring outcomes and providing feedback needed to improve results. My first question is, despite the impressive overall results seen with HeartMate II, we all know that gastrointestinal bleeding from arteriovenous malformations occurs often. What was the exact incidence seen in this group of patients, what is your hypothesis on its etiology, and what is your recommendation on how to treat it when it occurs? DR JOHN: Thank you. We did not have the exact incidence of gastrointestinal bleeding. It was part of the overall bleeding of 36%. Again, my feeling from many single-center studies, including ours, is that the incidence of bleeding ranges from about 10% to 20%, closer to the 20% range, and as you have pointed out, I think bleeding along with infection clearly represents the two Achilles heels of currently available technology. I think the phenomenon of the acquired von Willebrand syndrome has garnered much attention and has been reported in as high as 100% of these patients; however, all these patients with the acquired syndrome don t bleed. So, clearly, I think the acquired von Willebrand syndrome is only part of the puzzle. Many of these patients have preexisting arteriovenous malformations, and there is a lot of suggestion, akin to the literature from aortic stenosis, that the narrowed pulse pressure with these continuous flow pumps might predispose to the further development of arteriovenous malformations. And I think the last piece of the puzzle is anticoagulation. I still think a lot of work needs to be done on who needs aspirin, are we dosing these patients with coumadin, and so forth. DR ACKER: Ranjit, do you think that these results and the destination therapy pivotal trial results justify currently placing HeartMate II in class IIIb patients? Your manuscript indicated that only 2% of these 1,500 patients actually were IIIb. Or do we need a new randomized study to medical therapy in this less sick group of patients? DR JOHN: I do believe, while the device has been approved for IIIb, regulatory agencies like the CMS do not pay for it, and part of the reason is that the target of IIIb and class IV is a shifting one. A patient might come into an intensive care unit as class IV, inotrope dependent, a few days later he is optimized and now he is a IIIb, and a week later he may be going home as a III. So I am not sure whether the classical NYHA classification is a good one to decide whether earlier implantation is feasible. Thank you.