Antone Tatooles

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.)

Administration of Cardiac Stem Cells in Patients with Ischemic Cardiomyopathy (the SCIPIO Trial): Surgical Aspects and Interim Analysis of Myocardial Function and Viability by Magnetic Resonance

Background— SCIPIO is a first-in-human, phase 1, randomized, open-label trial of autologous c-kit+ cardiac stem cells (CSCs) in patients with heart failure of ischemic etiology undergoing coronary artery bypass grafting (CABG). In the present study, we report the surgical aspects and interim cardiac magnetic resonance (CMR) results. Methods and Results— A total of 33 patients (20 CSC-treated and 13 control subjects) met final eligibility criteria and were enrolled in SCIPIO. CSCs were isolated from the right atrial appendage harvested and processed during surgery. Harvesting did not affect cardiopulmonary bypass, cross-clamp, or surgical times. In CSC-treated patients, CMR showed a marked increase in both LVEF (from 27.5±1.6% to 35.1±2.4% [P=0.004, n=8] and 41.2±4.5% [P=0.013, n=5] at 4 and 12 months after CSC infusion, respectively) and regional EF in the CSC-infused territory. Infarct size (late gadolinium enhancement) decreased after CSC infusion (by manual delineation: −6.9±1.5 g [−22.7%] at 4 months [P=0.002, n=9] and −9.8±3.5 g [−30.2%] at 12 months [P=0.039, n=6]). LV nonviable mass decreased even more (−11.9±2.5 g [−49.7%] at 4 months [P=0.001] and −14.7±3.9 g [−58.6%] at 12 months [P=0.013]), whereas LV viable mass increased (+11.6±5.1 g at 4 months after CSC infusion [P=0.055] and +31.5±11.0 g at 12 months [P=0.035]). Conclusions— Isolation of CSCs from cardiac tissue obtained in the operating room is feasible and does not alter practices during CABG surgery. CMR shows that CSC infusion produces a striking improvement in both global and regional LV function, a reduction in infarct size, and an increase in viable tissue that persist at least 1 year and are consistent with cardiac regeneration. Clinical Trial Registration— This study is registered with clinicaltrials.gov, trial number NCT00474461.

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.

An analysis of pump thrombus events in patients in the HeartWare ADVANCE bridge to transplant and continued access protocol trial

BACKGROUND The HeartWare left ventricular assist device (HVAD, HeartWare Inc, Framingham, MA) is the first implantable centrifugal continuous-flow pump approved for use as a bridge to transplantation. An infrequent but serious adverse event of LVAD support is thrombus ingestion or formation in the pump. In this study, we analyze the incidence of pump thrombus, evaluate the comparative effectiveness of various treatment strategies, and examine factors pre-disposing to the development of pump thrombus. METHODS The analysis included 382 patients who underwent implantation of the HVAD as part of the HeartWare Bridge to Transplant (BTT) and subsequent Continued Access Protocol (CAP) trial. Descriptive statistics and group comparisons were generated to analyze baseline characteristics, incidence of pump thrombus, and treatment outcomes. A multivariate analysis was performed to assess significant risk factors for developing pump thrombus. RESULTS There were 34 pump thrombus events observed in 31 patients (8.1% of the cohort) for a rate of 0.08 events per patient-year. The incidence of pump thrombus did not differ between BTT and CAP. Medical management of pump thrombus was attempted in 30 cases, and was successful in 15 (50%). A total of 16 patients underwent pump exchange, and 2 underwent urgent transplantation. Five patients with a pump thrombus died after medical therapy failed, 4 of whom also underwent a pump exchange. Survival at 1 year in patients with and without a pump thrombus was 69.4% and 85.5%, respectively (p = 0.21). A multivariable analysis revealed that significant risk factors for pump thrombus included a mean arterial pressure > 90 mm Hg, aspirin dose ≤ 81 mg, international normalized ratio ≤ 2, and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile level of ≥ 3 at implant. CONCLUSIONS Pump thrombus is a clinically important adverse event in patients receiving an HVAD, occurring at a rate of 0.08 events per patient-year. Significant risk factors for pump thrombosis include elevated blood pressure and sub-optimal anti-coagulation and anti-platelet therapies. This suggests that pump thrombus event rates could be reduced through careful adherence to patient management guidelines.

Results of the Destination Therapy Post-Food and Drug Administration Approval Study With a Continuous Flow Left Ventricular Assist Device: A Prospective Study Using the INTERMACS Registry (Interagency Registry for Mechanically Assisted Circulatory Support)

OBJECTIVES A post-approval (PA) study for destination therapy (DT) was required by the Food and Drug Administration (FDA) to determine whether results with the HeartMate (HM) II (Thoratec, Pleasanton, California) left ventricular assist device (LVAD) in a commercial setting were comparable to results during the DT multicenter pivotal clinical trial. BACKGROUND New device technology developed in the clinical research setting requires validation in a real-world setting. METHODS The PA study was a prospective evaluation of the first 247 HM II patients identified pre-operatively as eligible for DT in the national INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) registry. Patients were enrolled from January to September 2010 at 61 U.S. centers and followed for 2 years. A historical comparison group included patients (n = 133 at 34 centers) enrolled in the primary data cohort in the DT pivotal trial (TR). Survival rates and adverse events for the PA group were obtained from the INTERMACS registry. RESULTS Baseline characteristics were similar for PA versus TR. Forty-five percent of PA patients were in INTERMACS profiles 1 to 2 and 28% were in profile 3. Adverse events in the PA group were similar or lower than those in the TR group, including improvements in device-related infection (0.22 vs. 0.47) and post-operative bleeding requiring surgery (0.09 vs. 0.23) events per patient-year. Kaplan-Meier survival at 2 years was 62% (PA group) versus 58% (TR group). PA group survival at 1 and 2 years was 82 ± 5% and 69 ± 6% for INTERMACS profiles 4 to 7 (n = 63) versus 72 ± 3% and 60 ± 4% for profiles 1 to 3 (n = 184). The median length of stay after surgery was reduced by 6 days in the PA group versus the TR group. CONCLUSIONS Results in a commercial patient care setting for the DT population supported the original pivotal clinical trial findings regarding the efficacy and risk profile of the HM II LVAD. Survival was best in patients who were not inotrope-dependent (INTERMACS profiles 4 to 7).

Intrapericardial Left Ventricular Assist Device for Advanced Heart Failure.

Background Mechanical circulatory support with a left ventricular assist device (LVAD) is an established treatment for patients with advanced heart failure. We compared a newer LVAD design (a small intrapericardial centrifugal‐flow device) against existing technology (a commercially available axial‐flow device) in patients with advanced heart failure who were ineligible for heart transplantation. Methods We conducted a multicenter randomized trial involving 446 patients who were assigned, in a 2:1 ratio, to the study (centrifugal‐flow) device or the control (axial‐flow) device. Adults who met contemporary criteria for LVAD implantation for permanent use were eligible to participate in the trial. The primary end point was survival at 2 years free from disabling stroke or device removal for malfunction or failure. The trial was powered to show noninferiority with a margin of 15 percentage points. Results The intention‐to treat‐population included 297 participants assigned to the study device and 148 participants assigned to the control device. The primary end point was achieved in 164 patients in the study group and 85 patients in the control group. The analysis of the primary end point showed noninferiority of the study device relative to the control device (estimated success rates, 55.4% and 59.1%, respectively, calculated by the Weibull model; absolute difference, 3.7 percentage points; 95% upper confidence limit, 12.56 percentage points; P=0.01 for noninferiority). More patients in the control group than in the study group had device malfunction or device failure requiring replacement (16.2% vs. 8.8%), and more patients in the study group had strokes (29.7% vs. 12.1%). Quality of life and functional capacity improved to a similar degree in the two groups. Conclusions In this trial involving patients with advanced heart failure who were ineligible for heart transplantation, a small, intrapericardial, centrifugal‐flow LVAD was found to be noninferior to an axial‐flow LVAD with respect to survival free from disabling stroke or device removal for malfunction or failure. (Funded by HeartWare; ENDURANCE ClinicalTrials.gov number, NCT01166347.)

Incidence and Management of Gastrointestinal Bleeding With Continuous Flow Assist Devices

BACKGROUND Continuous flow left ventricular assist devices (CF-LVADs) have emerged as the standard of care for patients in advanced heart failure (HF) requiring long-term mechanical circulatory support. Gastrointestinal (GI) bleeding has been frequently reported within this population. METHODS A retrospective analysis of 101 patients implanted with the Heart Mate II from January 2005 to August 2011 was performed to identify incidence, etiology, and management of GI bleeding. Univariate and multivariate regression analysis was conducted to identify related risk factors. RESULTS A significant incidence of GI bleeding (22.8%) occurred in our predominantly destination therapy (DT) (93%) population. Fifty-seven percent of the patients with bleeding episodes bled from the upper GI (UGI) tract (with 54% bleeding from gastric erosions and 37% from ulcers/angiodysplasias), whereas 35% of patients bled from the lower GI (LGI) tract. Previous history of GI bleeding (odds ratio [OR], 22.7; 95% CI, 2.2-228.6; p=0.008), elevated international normalized ratio (INR) (OR, 3.9; CI, 1.2-12.9; p=0.02), and low platelet count (OR, -0.98; CI, 0.98 -0.99; p=0.001) were independent predictors of GI hemorrhage. Recurrent bleeding was more common in older patients (mean, 70 years; p=0.01). The majority of bleeders (60%) rebled from the same site. Management strategies included temporarily withholding anticoagulation, decreasing the speed of LVADs, and using octreotide. Octreotide did not impact the amount of packed red blood cells used, rebleeding rates, length of hospital stay, or all-cause mortality. Only 1 patient died as a direct consequence of GI bleeding. CONCLUSIONS Multiple factors account for GI bleeding in patients on CF-VADs. A previous history of bleeding increases risk significantly and warrants careful monitoring.

The Development of Aortic Insufficiency in Continuous-Flow Left Ventricular Assist Device–Supported Patients

BACKGROUND Significant aortic insufficiency (AI) after left ventricular assist device (LVAD) placement affects device performance and end-organ perfusion. This study examined the development and progression of AI after implantation of continuous-flow LVAD. METHODS Seventy-nine patients undergoing Heart Mate II (Thoratec Corp, Pleasanton, CA) LVAD implantation for predominantly destination therapy (n = 69 [87%]) were examined. Preoperative and postoperative echocardiograms for all patients were reviewed at the intervals of 0 to 3, 3 to 6, 6 to 12, 12 to 18, and 18 to 24 months. AI was graded on an interval scale of 0, none; 0.5, trivial; 1, mild; 1.5, mild to moderate; 2, moderate; 2.5, moderate to severe; and 3, severe. Development and progression of AI were analyzed. RESULTS The incidence of significant AI (mild or greater) was 52% (n = 41). Median time to AI development was 187 days. The median duration of VAD support was 761 days. Mild AI developed in 41 patients (52%). No severe AI developed. In the Cox regression model (hazard ratio [95% confidence interval]), aortic valve closure (2.51 [1.06 to 5.89]; p = 0.03), and age (1.04 [1.008 to 1.08]; p = 0.01) were independent predictors of AI development. There was no difference in mortality rates in the two groups (p = 0.40 by log-rank test). A mixed-model linear regression analysis showed a significant overall progression of AI over time (β ± standard error, 0.06 ± 0.02; p = 0.006). CONCLUSIONS AI develops over time in a significant number of Heart Mate II LVAD patients. AI is more common in patients with closed aortic valves and in the older age group. As more patients require long-term VAD support, the development of AI will need careful attention and monitoring.

A new method of monitoring recovery and weaning the thoratec left ventricular assist device

BACKGROUND Recent scientific and clinical data suggest that chronic mechanical ventricular unloading may lead to myocardial recovery. Evaluating and monitoring patients for myocardial recovery and the optimal methods of weaning the left ventricular assist device are not well defined. METHODS Six patients with advanced heart failure and severe mitral regurgitation have undergone successful bridge to recovery using a Thoratec left ventricular assist device. Data that details their monitoring for myocardial recovery and weaning from the left ventricular assist device were prospectively collected. RESULTS Clinical data collected during the recovery phase included chest roentgenogram, echocardiography, plasma norepinephrine, tumor necrosis factor-alpha, bioimpedance, and cardiopulmonary exercise testing (peak oxygen consumption). Normalization of these variables with a 10% increase in the peak oxygen consumption was obtained before weaning. The Thoratec device rate and percent systole were manipulated to allow gradual reloading of the ventricle. The weaning process occurred for more than 5 to 10 days to allow time for observation of the ventricle and its response to the increasing workload. CONCLUSIONS Select patients with advanced congestive heart failure and severe mitral insufficiency can benefit from mechanical device support. We describe our technique of monitoring for myocardial recovery using clinical variables. Our technique of weaning allows for gradual reloading of the ventricle and a longer period of observation before device removal. Additional research is needed to determine which variables will accurately predict long-term myocardial recovery and the optimal weaning method.

Are Blood Stream Infections Associated With an Increased Risk of Hemorrhagic Stroke in Patients With a Left Ventricular Assist Device

Blood stream infections (BSIs) are an important cause of morbidity and mortality in patients with left ventricular assist devices (LVADs). The aim of this study was to examine the correlation between hemorrhagic cerebrovascular accident (CVA) and BSI after implantation of LVAD for advanced heart failure (HF). This was a retrospective descriptive review of 87 patients with end-stage HF, who underwent implantation of HeartMate II continuous-flow LVAD over a 4 year period. Blood stream infections were diagnosed by serial blood cultures, and suspected neurological complications including CVAs were confirmed by neuroimaging. Extensive patient chart review was performed, and descriptive characteristics were analyzed using SPSS statistical software. The mean age of our study population was 62.3 ± 12.8 years, and the majority of our patients were males (n = 75, 86.2%). The baseline characteristics were comparable in the patients with and without CVAs. Patients with BSI had a much greater incidence of CVA compared to patients without BSI (n = 13, 43.3% vs. n = 5, 10.0%; p < 0.0001). There was an increased mortality in patients with BSI than those without (n = 57, 65.5% vs. n = 30, 34.5%; p = 0.003). The risk of all CVAs (hemorrhagic/ischemic) was eightfold (odds ratio [OR] = 7.9; 95% confidence interval [CI] = 2.4–25.5; p = 0.001] in patients with BSI. Patients with BSI had a >20-fold risk of hemorrhagic CVA (OR = 24; 95% CI = 2.8–201.1; p = 0.03). Advanced HF patients with LVAD support who developed BSI need urgent evaluation and close monitoring for suspected neurological complications, particularly hemorrhagic CVA.