Scott C. Silvestry

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.

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.

Algorithm for the diagnosis and management of suspected pump thrombus

Pump thrombosis is a dreaded complication of long-term implantable ventricular assist devices. No guidance exists regarding the diagnosis and management of this entity despite its significant morbidity. After considerable thought and deliberation, a group of leading investigators in the field of mechanical support propose an algorithm for the diagnosis and management of this vexing entity based on clinical symptoms and serologic and imaging studies.

Benefits of a novel percutaneous ventricular assist device for right heart failure: The prospective RECOVER RIGHT study of the Impella RP device

BACKGROUND Right ventricular failure (RVF) increases morbidity and mortality. The RECOVER RIGHT study evaluated the safety and efficacy of a novel percutaneous right ventricular assist device, the Impella RP (Abiomed, Danvers, MA), in a prospective, multicenter trial. METHODS Thirty patients with RVF refractory to medical treatment received the Impella RP device at 15 United States institutions. The study population included 2 cohorts: 18 patients with RVF after left ventricular assist device (LVAD) implantation (Cohort A) and 12 patients with RVF after cardiotomy or myocardial infarction (Cohort B). The primary end point was survival to 30 days or hospital discharge (whichever was longer). Major secondary end points included indices of safety and efficacy. RESULTS The patients (77% male) were a mean age of 59 ± 15 years, 53% had diabetes, 88.5% had a history of congestive heart failure, and 37.5% had renal dysfunction. Patients were on an average of 3.2 inotropes/pressors. Device delivery was achieved in all but 1 patient. Hemodynamics improved immediately after initiation of Impella RP support, with an increase in cardiac index from 1.8 ± 0.2 to 3.3 ± 0.23 liters/min/m(2) (p < 0.001) and a decrease in central venous pressure from 19.2 ± 4 to 12.6 ± 1 mm Hg (p < 0.001). Patients were supported for an average of 3.0 ± 1.5 days (range, 0.5-7.8 days). The overall survival at 30 days was 73.3%. All patients discharged were alive at 180 days. CONCLUSIONS In patients with life-threatening RVF, the novel percutaneous Impella RP device was safe, easy to deploy, and reliably resulted in immediate hemodynamic benefit. These data support its probable benefit in this gravely ill patient population.

Results of Valve Replacement With Mechanical and Biological Prostheses in Chronic Renal Dialysis Patients

BACKGROUND Whether biological or mechanical valves should be used in patients on chronic dialysis therapy remains to be clearly defined. METHODS A retrospective review was performed on 19 consecutive patients from our institution with end-stage renal disease on chronic peritoneal or hemodialysis undergoing aortic (n = 12), mitral (n = 5), or aortic-mitral (n = 2) valve replacement. RESULTS The 9 biological and 10 mechanical valve patients had similar ages (56.5 versus 56.6 years) and cardiovascular risk factors. The overall estimated Kaplan-Meier survival was 60% +/- 12% at 12 months and 42% +/- 14% at 60 months. Mechanical valve patients had a significantly higher rate of postoperative cerebrovascular accidents or bleeding complications (10/10 versus 0/9; chi 2 = 17.0; p < 0.001). No subsequent reoperations were required for biological valve failure at a mean follow-up of 32 +/- 53 months. CONCLUSIONS These results demonstrate that in patients with end-stage renal disease, use of mechanical valves is associated with significant risk of complications, whereas biological valve failure from prosthetic dysfunction is unusual. Overall survival is poor in both groups of patients. Therefore, preference should be given to biological valve instead of mechanical valve prostheses in patients on chronic renal dialysis.

The HVAD Left Ventricular Assist Device: Risk Factors for Neurological Events and Risk Mitigation Strategies.

OBJECTIVES The purpose of this study was to determine the risk factors for ischemic in hemorrhage cerebrovascular events in patients supported by the HeartWare ventricular assist device (HVAD). BACKGROUND Patients supported with left ventricular assist devices are at risk for both ischemic and hemorrhagic cerebrovascular events. METHODS Patients undergoing implantation with a HVAD as part of the bridge-to-transplant trial and subsequent continued access protocol were included. Neurological events (ischemic cerebrovascular accidents [ICVAs] and hemorrhagic cerebrovascular accidents [HCVAs]) were assessed, and the risk factors for these events were evaluated in a multivariable model. RESULTS A total of 382 patients were included: 140 bridge-to-transplant patients from the ADVANCE (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure) clinical trial and 242 patients from the continued access protocol. Patients had a mean age of 53.2 years; 71.2% were male, and 68.1% were white. Thirty-eight percent had ischemic heart disease, and the mean duration of support was 422.7 days. The overall prevalence of ICVA was 6.8% (26 of 382); for HCVA, it was 8.4% (32 of 382). Pump design modifications and a protocol-driven change in the antiplatelet therapy reduced the prevalence of ICVA from 6.3% (17 of 272) to 2.7% (3 of 110; p = 0.21) but had a negligible effect on the prevalence of HVCA (8.8% [24 of 272] vs. 6.4% [7 of 110]; p = 0.69). Multivariable predictors of ICVA were aspirin ≤81 mg and atrial fibrillation; predictors of HCVA were mean arterial pressure >90 mm Hg, aspirin ≤81 mg, and an international normalized ratio >3.0. Eight of the 30 participating sites had established improved blood pressure management (IBPM) protocols. Although the prevalence of ICVA for those with and without IBPM protocols was similar (5.3% [6 of 114] vs. 5.2% [14 of 268]; p = 0.99), those with IBPM protocols had a significantly lower prevalence of HCVA (1.8% [2 of 114] vs. 10.8% [29 of 268]; p = 0.0078). CONCLUSIONS Anticoagulation, antiplatelet therapy, and blood pressure management affected the prevalence of cerebrovascular events after implantation of the HVAD. Attention to these clinical parameters can have a substantial impact on the occurrence of serious neurological events. (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure [ADVANCE]; NCT00751972).

Preoperative Aspirin Use and Outcomes in Cardiac Surgery Patients

Background: The effects of preoperative aspirin use on outcomes of cardiac surgery patients remain uncertain. This study was aimed to evaluate the effect of preoperative aspirin use on major outcomes in cardiac surgery patients. Methods: An observational cohort study was performed on consecutive patients (n = 4256) undergoing cardiac surgery in 2 tertiary hospitals. Of all patients, 2868 patients met the inclusion criteria and were divided into 2 groups: those taking (n = 1923) or not taking (n = 945) aspirin within 5 days preceding surgery. Results: Patients in the aspirin group presented significantly more with comorbidities including hypertension, diabetes, peripheral arterial disease, previous myocardial infarction, angina, cerebrovascular disease, older age, and male gender. With propensity scores adjusted and multivariate logistic regression, however, the results of this study showed that preoperative aspirin therapy (vs nonaspirin) significantly reduced the risk of 30-day mortality (3.5% vs 6.5%, OR: 0.611, 95% CI: 0.391–0.956, P = 0.031), postoperative renal failure (3.7% vs 7.1%, OR: 0.384, 95% CI: 0.254–0.579, P < 0.001), dialysis required (1.9% vs 3.6%, OR: 0.441, 95% CI: 0.254–0.579, P < 0.001), intensive care unit stay (mean 107.2 vs 136.1 h, P < 0.001) and a composite outcome-major adverse cardiocerebral events (8.7% vs 10.8%, OR: 0.662, 95% CI:: 0.482–0.909, P = 0.011) in the patients undergoing cardiac surgery. However, readmissions did not show a significant difference between the 2 groups (14.5% vs 12.8%, P = 0.944). Conclusions: Preoperative aspirin therapy is associated with a significant decrease in the risk of major cardiocerebral complications, renal failure, intensive care unit stay and 30-day mortality but does not increase the risk of readmissions in patients undergoing cardiac surgery.

S100A1 Genetically Targeted Therapy Reverses Dysfunction of Human Failing Cardiomyocytes

OBJECTIVES This study investigated the hypothesis whether S100A1 gene therapy can improve pathological key features in human failing ventricular cardiomyocytes (HFCMs). BACKGROUND Depletion of the Ca²⁺-sensor protein S100A1 drives deterioration of cardiac performance toward heart failure (HF) in experimental animal models. Targeted repair of this molecular defect by cardiac-specific S100A1 gene therapy rescued cardiac performance, raising the immanent question of its effects in human failing myocardium. METHODS Enzymatically isolated HFCMs from hearts with severe systolic HF were subjected to S100A1 and control adenoviral gene transfer and contractile performance, calcium handling, signaling, and energy homeostasis were analyzed by video-edge-detection, FURA2-based epifluorescent microscopy, phosphorylation site-specific antibodies, and mitochondrial assays, respectively. RESULTS Genetically targeted therapy employing the human S100A1 cDNA normalized decreased S100A1 protein levels in HFCMs, reversed both contractile dysfunction and negative force-frequency relationship, and improved contractile reserve under beta-adrenergic receptor (β-AR) stimulation independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 reversed underlying Ca²⁺ handling abnormalities basally and under β-AR stimulation shown by improved SR Ca²⁺ handling, intracellular Ca²⁺ transients, diastolic Ca²⁺ overload, and diminished susceptibility to arrhythmogenic SR Ca²⁺ leak, respectively. Moreover, S100A1 ameliorated compromised mitochondrial function and restored the phosphocreatine/adenosine-triphosphate ratio. CONCLUSIONS Our results demonstrate for the first time the therapeutic efficacy of genetically reconstituted S100A1 protein levels in HFCMs by reversing pathophysiological features that characterize human failing myocardium. Our findings close a gap in our understanding of S100A1s effects in human cardiomyocytes and strengthen the rationale for future molecular-guided therapy of human HF.

Hemolysis in left ventricular assist device: A retrospective analysis of outcomes

BACKGROUND Hemolysis is becoming increasingly recognized as a major complication of left ventricular assist device (LVAD) support. Data regarding risk factors, prevalence, and outcomes are limited. To better define the characteristics and prognosis of hemolysis, we present a retrospective case-control study of LVAD patients in our institution. METHODS A detailed record review was conducted of 18 patients supported with the HeartMate II (HMII; Thoratec Corp, Pleasanton, CA) who were diagnosed with hemolysis, and their data were compared with 82 patients who received an LVAD implant during the same period who did not develop hemolysis. Patients were excluded if they did not survive hospitalization at the time of LVAD implantation. The primary end points of this analysis were time to death and time to first hospitalization. RESULTS Of 100 total patients, 18 HMII patients (18%) were diagnosed with hemolysis. Those with hemolysis were younger, had significantly higher lactate dehydrogenase and bilirubin levels, lower international normalized ratio, and no difference in cannula velocities by transthoracic echocardiography. Patient survival in the hemolysis group was markedly decreased at 1 year (38.9% vs 89.3%, p < 0.001), but no differences in hospitalization (p = 0.57) were observed. Partial to complete thrombosis was noted in all of the pumps at explant. CONCLUSIONS These findings demonstrate that hemolysis is associated with high mortality, likely serving as a marker of pump thrombosis. Elevated lactate dehydrogenase and bilirubin levels are important indicators for hemolysis, and lower international normalized ratio may pre-dispose for this worrisome condition. Diagnosis should prompt clinicians to consider pump exchange or explant, listing for transplantation, or intensifying anti-coagulation.

Aspirin and clopidogrel use in the early postoperative period following on-pump and off-pump coronary artery bypass grafting

OBJECTIVE Preoperative use of clopidogrel increases the risk of bleeding, but its postoperative use has not been studied. We studied early postoperative clopidogrel use in on-pump and off-pump coronary artery bypass grafting. METHODS Data were obtained from the University HealthSystem Consortium database. We conducted a retrospective analysis of data of 15,067 adults who had coronary artery bypass grafting between 2003 and 2006 and received perioperative aspirin alone or in combination with clopidogrel, with the latter administered within 2 days after coronary artery bypass grafting. Logistic regression was used to analyze in-hospital mortality, 30-day readmission, ischemic or thrombotic events, and bleeding events, with propensity score adjustment for clopidogrel treatment. RESULTS Combined aspirin and clopidogrel were used in 3268 patients (22%). Compared with aspirin alone, aspirin plus clopidogrel was associated with reductions of in-hospital mortality (0.95% vs 1.78%; adjusted odds ratio: 0.50; 95% confidence interval: 0.25, 0.99) and bleeding events (4.19% vs 5.17%; adjusted odds ratio: 0.70; 95% confidence interval: 0.51, 0.97). Ischemic or thrombotic events were not significantly different (1.29% vs 1.53%; adjusted odds ratio, 0.99; 95% confidence interval: 0.59, 1.64). The relative effect of combined treatment did not differ between on-pump and off-pump coronary artery bypass grafting. CONCLUSIONS Early postoperative clopidogrel combined with aspirin may be safe and beneficial compared with perioperative aspirin treatment alone, in both on-pump and off-pump coronary artery bypass grafting. However, a possibility of selection bias calls for randomized controlled trials to confirm our findings.