Carmelo A. Milano

Advanced Heart Failure Treated with Continuous-Flow Left Ventricular Assist Device

BACKGROUND Patients with advanced heart failure have improved survival rates and quality of life when treated with implanted pulsatile-flow left ventricular assist devices as compared with medical therapy. New continuous-flow devices are smaller and may be more durable than the pulsatile-flow devices. METHODS In this randomized trial, we enrolled patients with advanced heart failure who were ineligible for transplantation, in a 2:1 ratio, to undergo implantation of a continuous-flow device (134 patients) or the currently approved pulsatile-flow device (66 patients). The primary composite end point was, at 2 years, survival free from disabling stroke and reoperation to repair or replace the device. Secondary end points included survival, frequency of adverse events, the quality of life, and functional capacity. RESULTS Preoperative characteristics were similar in the two treatment groups, with a median age of 64 years (range, 26 to 81), a mean left ventricular ejection fraction of 17%, and nearly 80% of patients receiving intravenous inotropic agents. The primary composite end point was achieved in more patients with continuous-flow devices than with pulsatile-flow devices (62 of 134 [46%] vs. 7 of 66 [11%]; P<0.001; hazard ratio, 0.38; 95% confidence interval, 0.27 to 0.54; P<0.001), and patients with continuous-flow devices had superior actuarial survival rates at 2 years (58% vs. 24%, P=0.008). Adverse events and device replacements were less frequent in patients with the continuous-flow device. The quality of life and functional capacity improved significantly in both groups. CONCLUSIONS Treatment with a continuous-flow left ventricular assist device in patients with advanced heart failure significantly improved the probability of survival free from stroke and device failure at 2 years as compared with a pulsatile device. Both devices significantly improved the quality of life and functional capacity. (ClinicalTrials.gov number, NCT00121485.)

Outcomes of Left Ventricular Assist Device Implantation as Destination Therapy in the Post-REMATCH Era Implications for Patient Selection

Background— The landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial first demonstrated that implantation of left ventricular assist devices (LVADs) as destination therapy (DT) can provide survival superior to any known medical treatment in patients with end-stage heart failure who are ineligible for transplantation. In the present study, we describe outcomes of DT in the post-REMATCH era in the United States. Methods and Results— The present study included 280 patients who underwent HeartMate XVE LVAD implantation between November 2001 and December 2005. A preoperative risk score for in-hospital mortality after LVAD implantation was established in 222 patients with complete data. All patients were followed up until death or December 2006. The 1-year survival after LVAD implantation was 56%. The in-hospital mortality after LVAD surgery was 27%. The main causes of death included sepsis, right heart failure, and multiorgan failure. The most important determinants of in-hospital mortality were poor nutrition, hematological abnormalities, markers of end-organ or right ventricular dysfunction, and lack of inotropic support. Stratification of DT candidates into low (n=65), medium (n=111), high (n=28), and very high (n=18) risk on the basis of the risk score calculated from these predictors corresponded with 1-year survival rates of 81%, 62%, 28%, and 11%, respectively. Conclusions— Appropriate selection of candidates and timing of LVAD implantation are critical for improved outcomes of DT. Patients with advanced heart failure who are referred for DT before major complications of heart failure develop have the best chance of achieving an excellent 1-year survival with LVAD therapy.

Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes.

OBJECTIVE The aim of this study was to evaluate the incidence, risk factors, and effect on outcomes of right ventricular failure in a large population of patients implanted with continuous-flow left ventricular assist devices. METHODS Patients (n = 484) enrolled in the HeartMate II left ventricular assist device (Thoratec, Pleasanton, Calif) bridge-to-transplantation clinical trial were examined for the occurrence of right ventricular failure. Right ventricular failure was defined as requiring a right ventricular assist device, 14 or more days of inotropic support after implantation, and/or inotropic support starting more than 14 days after implantation. Demographics, along with clinical, laboratory, and hemodynamic data, were compared between patients with and without right ventricular failure, and risk factors were identified. RESULTS Overall, 30 (6%) patients receiving left ventricular assist devices required a right ventricular assist device, 35 (7%) required extended inotropes, and 33 (7%) required late inotropes. A significantly greater percentage of patients without right ventricular failure survived to transplantation, recovery, or ongoing device support at 180 days compared with patients with right ventricular failure (89% vs 71%, P < .001). Multivariate analysis revealed that a central venous pressure/pulmonary capillary wedge pressure ratio of greater than 0.63 (odds ratio, 2.3; 95% confidence interval, 1.2-4.3; P = .009), need for preoperative ventilator support (odds ratio, 5.5; 95% confidence interval, 2.3-13.2; P < .001), and blood urea nitrogen level of greater than 39 mg/dL (odds ratio, 2.1; 95% confidence interval, 1.1-4.1; P = .02) were independent predictors of right ventricular failure after left ventricular assist device implantation. CONCLUSIONS The incidence of right ventricular failure in patients with a HeartMate II ventricular assist device is comparable or less than that of patients with pulsatile-flow devices. Its occurrence is associated with worse outcomes than seen in patients without right ventricular failure. Patients at risk for right ventricular failure might benefit from preoperative optimization of right heart function or planned biventricular support.

Unexpected Abrupt Increase in Left Ventricular Assist Device Thrombosis

BACKGROUND We observed an apparent increase in the rate of device thrombosis among patients who received the HeartMate II left ventricular assist device, as compared with preapproval clinical-trial results and initial experience. We investigated the occurrence of pump thrombosis and elevated lactate dehydrogenase (LDH) levels, LDH levels presaging thrombosis (and associated hemolysis), and outcomes of different management strategies in a multi-institutional study. METHODS We obtained data from 837 patients at three institutions, where 895 devices were implanted from 2004 through mid-2013; the mean (±SD) age of the patients was 55±14 years. The primary end point was confirmed pump thrombosis. Secondary end points were confirmed and suspected thrombosis, longitudinal LDH levels, and outcomes after pump thrombosis. RESULTS A total of 72 pump thromboses were confirmed in 66 patients; an additional 36 thromboses in unique devices were suspected. Starting in approximately March 2011, the occurrence of confirmed pump thrombosis at 3 months after implantation increased from 2.2% (95% confidence interval [CI], 1.5 to 3.4) to 8.4% (95% CI, 5.0 to 13.9) by January 1, 2013. Before March 1, 2011, the median time from implantation to thrombosis was 18.6 months (95% CI, 0.5 to 52.7), and from March 2011 onward, it was 2.7 months (95% CI, 0.0 to 18.6). The occurrence of elevated LDH levels within 3 months after implantation mirrored that of thrombosis. Thrombosis was presaged by LDH levels that more than doubled, from 540 IU per liter to 1490 IU per liter, within the weeks before diagnosis. Thrombosis was managed by heart transplantation in 11 patients (1 patient died 31 days after transplantation) and by pump replacement in 21, with mortality equivalent to that among patients without thrombosis; among 40 thromboses in 40 patients who did not undergo transplantation or pump replacement, actuarial mortality was 48.2% (95% CI, 31.6 to 65.2) in the ensuing 6 months after pump thrombosis. CONCLUSIONS The rate of pump thrombosis related to the use of the HeartMate II has been increasing at our centers and is associated with substantial morbidity and mortality.

Continuous Flow Left Ventricular Assist Device Improves Functional Capacity and Quality of Life of Advanced Heart Failure Patients

OBJECTIVES This study sought to assess the impact of continuous flow left ventricular assist devices (LVADs) on functional capacity and heart failure-related quality of life. BACKGROUND Newer continuous-flow LVAD are smaller and quieter than pulsatile-flow LVADs. METHODS Data from advanced heart failure patients enrolled in the HeartMate II LVAD (Thoratec Corporation, Pleasanton, California) bridge to transplantation (BTT) (n = 281) and destination therapy (DT) (n = 374) trials were analyzed. Functional status (New York Heart Association [NYHA] functional class, 6-min walk distance, patient activity scores), and quality of life (Minnesota Living With Heart Failure [MLWHF] and Kansas City Cardiomyopathy Questionnaires [KCCQ]) were collected before and after LVAD implantation. RESULTS Compared with baseline, LVAD patients demonstrated early and sustained improvements in functional status and quality of life. Most patients had NYHA functional class IV symptoms at baseline. Following implant, 82% (BTT) and 80% (DT) of patients at 6 months and 79% (DT) at 24 months improved to NYHA functional class I or II. Mean 6-min walk distance in DT patients was 204 m in patients able to ambulate at baseline, which improved to 350 and 360 m at 6 and 24 months. There were also significant and sustained improvements from baseline in both BTT and DT patients in median MLWHF scores (by 40 and 42 U in DT patients, or 52% and 55%, at 6 and 24 months, respectively), and KCCQ overall summary scores (by 39 and 41 U, or 170% and 178%). CONCLUSIONS Use of a continuous flow LVAD in advanced heart failure patients results in clinically relevant improvements in functional capacity and heart failure-related quality of life.

Mediastinitis After Coronary Artery Bypass Graft Surgery Risk Factors and Long-term Survival

This study from Duke University Medical Center addresses both the risk factors for the development of mediastinitis, as well as the long-term impact of mediastinal infection on survival in 6459 consecutive patients undergoing coronary artery bypass graft (CABG) surgery at that institution from 1987 to 1994. Data on 20 preoperative and intraoperative variables were collected prospectively and analyzed using univariate and multivariate analyses, with evaluation of long-term survival in the infected and uninfected groups. Eight-three patients (1.3%) developed mediastinitis, defined as deep sternal wound infection requiring extensive debridement and drainage. The mean postoperative hospital stay was prolonged in the mediastinitis group (25 versus 10 days, no statistical analysis provided). Variables associated with an increased incidence of mediastinitis by univariate analysis included obesity (P =.009), New York Heart Association congestive heart failure (NYHA CHF) class (P =.002), diabetes mellitus (P =.009), priorsternotomy (P =.009), duration of cardiopulmonary bypass (P =.02), presence of comorbid conditions (P =.03) and poor hemostasis at sternotomy closure (P =.09). Multivariate logistic regression analysis revealed four independent predictors of mediastinitis development: NYHA CHF class (P =.002), obesity (P =.0002), prior sternotomy (P =.008), and duration of cardiopulmonary bypass (P =.05). Variables without significant influence included age, number of internal mammary artery grafts utilized, duration of preoperative stay, and chronic obstructive pulmonary disease. The median duration of follow-up in the mediastinitis group was 1.5 years, with a follow-up of 3.4 years in the patients without mediastinitis. Interval and cumulative mortality rates were higher in the mediastinitis group up to 2 years following CABG surgery, a difference which persisted when controlled for variables associated with late postoperative mortality, including age, ejection fraction, cere-brovascular disease, and mitral insufficiency. Patients developing mediastinitis suffered a nearly fourfold increase in mortality in the 1–2 postoperative years (8.1% versus 2.3%). The authors provide a review of the literature addressing risk factors for mediastinitis development. In addition, they propose a model of preoperative risk assessment in individual patients, using NYHA CHF class III or IV, obesity, and prior heart surgery as variables. According to their data, patients possessing one factor have a threefold increased incidence of postoperative mediastinitis, and those possessing all three have a nearly 20-fold increased risk of this postoperative complication.

Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device

BACKGROUND Pump thrombosis remains an uncommon but potentially catastrophic complication of durable continuous-flow left ventricular assist devices (LVAD). A perceived increase in the incidence of pump thrombosis in the HeartMate II (HMII) LVAD (Thoratec, Pleasanton, CA) by clinicians prompted this analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database. METHODS Between 2006 and June 2013, 8,988 United States patients aged older than 18 years received a durable LVAD. Of these, 6,910 adult patients from 132 institutions who received a HMII LVAD were entered in the INTERMACS database and constitute the study group for this analysis. RESULTS Overall survival (with censoring at transplant or explant for recovery) with the HMII LVAD was 80% at 1 year and 69% at 2 years and was not significantly different when stratified by era of implant. Freedom from device exchange or death due to thrombosis decreased from 99% at 6 months in 2009 to 94% in 2012 (p < 0.0001). Multivariable hazard function analysis showed risk factors for pump thrombosis included later implant year (p < 0.0001), younger age (p < 0.0001), higher creatinine (p = 0.002), larger body mass index (p = 0.004), white race (p = 0.0004), left ventricular ejection fraction above 20% (p = 0.02), and higher lactate dehydrogenase level at 1 month (p < 0.0001). Survival (p < 0.0001) and freedom from infection (p = 0.008) and cerebrovascular accident (p < 0.0001) were lower after pump exchange than after primary implant. CONCLUSIONS Pump exchange or death due to pump thrombosis increased during 2011 and 2012, but the magnitude of the increase remained relatively small. Survival remains high (80% at 1 year) with the HMII LVAD. Risk factor analysis suggests that a number of patient-related factors contribute to the risk of thrombosis. Markedly elevated lactate dehydrogenase in the first month is a predictor of pump thrombosis. This analysis could not examine the potential role of technical factors during implant, such as sub-optimal pump or graft positioning, changes in patient management paradigms with pump speed settings, improved recognition and change in the threshold for pump exchange, or design or production changes with the pump, as contributors to the risk of pump thrombosis.

Acquired von Willebrand Syndrome in Continuous-Flow Ventricular Assist Device Recipients

BACKGROUND Bleeding is a major cause of morbidity in recipients of continuous-flow left ventricular assist devices (CF-LVAD). A better understanding of the impact of CF-LVAD support on the hemostatic profile is necessary to establish better strategies for anticoagulation therapy and risk assessment for bleeding complications. A prospective multicenter study was conducted to characterize von Willebrand factor (vWF) profiles in patients undergoing CF-LVAD implantation. METHODS Blood samples were collected before and after CF-LVAD implantation from 37 patients between July 2008 and April 2009 at Duke University and the University of Minnesota. Blood samples were analyzed for vWF, platelet and collagen-binding ability. The presence of high-molecular-weight (HMW) vWF multimers were detected through gel electrophoresis, and deficiency was graded on a scale of 0 (normal) to 3 (severe loss). RESULTS All 37 patients exhibited significant loss of HMW vWF multimers within 30 days of CF-LVAD implantation. Ten of the 37 patients experienced bleeding complications after CF-LVAD placement. CONCLUSIONS All CF-LVAD recipients had acquired von Willebrand syndrome after LVAD placement, demonstrated by reduced or absent HMW vWF multimer levels. However, not all recipients had bleeding complications. These findings suggest that loss of HMW vWF multimers alone cannot predict bleeding risk. Further refinement of laboratory techniques and a larger follow-up is required to identify risk factors for bleeding in CF-LVAD recipients.

Outcomes in Advanced Heart Failure Patients with Left Ventricular Assist Devices for Destination Therapy

Background—The HeartMate II (HMII) destination therapy (DT) trial demonstrated significant improvements in outcomes in continuous-flow left ventricular assist devices compared with patients implanted with the pulsatile-flow HeartMate XVE. The primary hypothesis of the current study is that trial patients enrolled after the initial data cohort would have better clinical outcomes. Methods and Results—Two hundred eighty-one patients who underwent HMII for DT from May 2007 to March 2009 (Mid Trial [MT] group) were compared with the initial 133 HMII patients from March 2005 to May 2007 (Early Trial [ET] group). Patient entry criteria were the same during the 2 time periods. Survival, adverse events, and quality of life were compared between the 2 groups. Baseline characteristics were similar between the groups. Compared with the ET group, patients in the MT group had reduced adverse event rates for bleeding requiring transfusions (1.66 versus 1.13 events per patient-year, P<0.001), sepsis (0.38 versus 0.27, P=0.025), device-related infections (0.47 versus 0.27, P<0.001), and hemorrhagic stroke (0.07 versus 0.03, P=0.01). Other event rates were similar between groups including ischemic stroke (0.06 versus 0.05 events per patient-year, P=0.57). Survival at 1 year in the MT group was 73% versus 68% in the ET group (P=0.21). Additionally, there was a significant reduction in deaths caused by hemorrhagic stroke (P=0.01). Quality of life improvements were significant in both the groups (P<0.001). Conclusions—The benefit of DT therapy with the HMII is confirmed in subsequent trial patients, with improved adverse event rates and a strong trend for improvements in survival. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00121485.

Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation

BACKGROUND In a trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve repair in patients with moderate ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI) or survival after 1 year. Concomitant mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation, but patients had more adverse events. We now report 2-year outcomes. METHODS We randomly assigned 301 patients to undergo either CABG alone or the combined procedure. Patients were followed for 2 years for clinical and echocardiographic outcomes. RESULTS At 2 years, the mean (±SD) LVESVI was 41.2±20.0 ml per square meter of body-surface area in the CABG-alone group and 43.2±20.6 ml per square meter in the combined-procedure group (mean improvement over baseline, -14.1 ml per square meter and -14.6 ml per square meter, respectively). The rate of death was 10.6% in the CABG-alone group and 10.0% in the combined-procedure group (hazard ratio in the combined-procedure group, 0.90; 95% confidence interval, 0.45 to 1.83; P=0.78). There was no significant between-group difference in the rank-based assessment of the LVESVI (including death) at 2 years (z score, 0.38; P=0.71). The 2-year rate of moderate or severe residual mitral regurgitation was higher in the CABG-alone group than in the combined-procedure group (32.3% vs. 11.2%, P<0.001). Overall rates of hospital readmission and serious adverse events were similar in the two groups, but neurologic events and supraventricular arrhythmias remained more frequent in the combined-procedure group. CONCLUSIONS In patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not lead to significant differences in left ventricular reverse remodeling at 2 years. Mitral-valve repair provided a more durable correction of mitral regurgitation but did not significantly improve survival or reduce overall adverse events or readmissions and was associated with an early hazard of increased neurologic events and supraventricular arrhythmias. (Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988.).