Jennifer Cowger

Predicting Survival in Patients Receiving Continuous Flow Left Ventricular Assist Devices The HeartMate II Risk Score

OBJECTIVES The aim of this study was to derive and validate a model to predict survival in candidates for HeartMate II (HMII) (Thoratec, Pleasanton, California) left ventricular assist device (LVAD) support. BACKGROUND LVAD mortality risk prediction is important for candidate selection and communicating expectations to patients and clinicians. With the evolution of LVAD support, prior risk prediction models have become less valid. METHODS Patients enrolled into the HMII bridge to transplantation and destination therapy trials (N = 1,122) were randomly divided into derivation (DC) (n = 583) and validation cohorts (VC) (n = 539). Pre-operative candidate predictors of 90-day mortality were examined in the DC with logistic regression, from which the HMII Risk Score (HMRS) was derived. The HMRS was then applied to the VC. RESULTS There were 149 (13%) deaths within 90 days. In the DC, mortality (n = 80) was higher in older patients (odds ratio [OR]: 1.3, 95% confidence interval [CI]: 1.1 to 1.7 per 10 years), those with greater hypoalbuminemia (OR: 0.49, 95% CI: 0.31 to 0.76 per mg/dl of albumin), renal dysfunction (OR: 2.1, 95% CI: 1.4 to 3.2 per mg/dl creatinine), coagulopathy (OR: 3.1, 95% CI: 1.7 to 5.8 per international normalized ratio unit), and in those receiving LVAD support at less experienced centers (OR: 2.2, 95% CI: 1.2 to 4.4 for <15 trial patients). Mortality in the DC low, medium, and high HMRS groups was 4%, 16%, and 29%, respectively (p < 0.001). In the VC, corresponding mortality was 8%, 11%, and 25%, respectively (p < 0.001). HMRS discrimination was good (area under the receiver-operating characteristic curve: 0.71, 95% CI: 0.66 to 0.75). CONCLUSIONS The HMRS might be useful for mortality risk stratification in HMII candidates and may serve as an additional tool in the patient selection process.

The Development of Aortic Insufficiency in Left Ventricular Assist Device-Supported PatientsClinical Perspective

Background—Aortic insufficiency (AI) following left ventricular assist device (LVAD) placement can affect device performance. The aim of this study was to examine AI development following LVAD implantation. Methods and Results—Echocardiograms (n=315) from 78 subjects undergoing HeartMate-XVE (n=25 [32%]) or HeartMate-II (n=53 [68%]) implantations from 2004 to 2008 were reviewed. Studies were obtained preoperatively and at 1, 3, 6, 12, 18, and 24 months after surgery. AI was graded on an interval scale (0=none, 0.5=trivial, 1=mild, 1.5=mild-moderate, 2=moderate, 2.5=moderate-severe, 3=severe), and the change in AI at follow-up was analyzed with significance tests. Kaplan–Meier estimates for freedom from moderate or worse AI at follow-up were generated. Mixed-model linear regression was used to identify correlates of AI progression during LVAD support. The median (25th, 75th percentile) duration of LVAD support was 239 (112, 455) days, and preoperative AI grade was 0.0 (0.0, 0.0). At 6 months, 89±4% of subjects (n=49 at risk) were free from moderate or worse AI, but this was reduced to 74±7% (n=29 at risk) and 49±13% (n=13 at risk) by 12 and 18 months, respectively. Correlates (slope±SE) of AI progression included female sex (0.002±0.001; P=0.01), smaller body surface area (−0.003±0.001 per m2; P=0.0017), and HeartMate-II model type (0.002±0.001; P=0.039). Correlates (&bgr;±SE) of progressive AI on postoperative echocardiogram included increasing aortic sinus diameter (0.04±0.01 per mm; P=0.001), an aortic valve that remained closed (0.42±0.06; P<0.001) or only intermittently opened (0.34±0.09; P<0.001), and lower left ventricular diastolic (−0.002±0.0004 per cm3; P<0.001) and systolic (−0.002±0.0004 per cm3; P<0.001) volumes. Conclusions—AI progresses over time in LVAD-supported patients. As we move toward an era of long-term cardiac support, more studies are needed to determine the clinical significance of these findings.

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

Background—Aortic insufficiency (AI) following left ventricular assist device (LVAD) placement can affect device performance. The aim of this study was to examine AI development following LVAD implantation. Methods and Results—Echocardiograms (n=315) from 78 subjects undergoing HeartMate-XVE (n=25 [32%]) or HeartMate-II (n=53 [68%]) implantations from 2004 to 2008 were reviewed. Studies were obtained preoperatively and at 1, 3, 6, 12, 18, and 24 months after surgery. AI was graded on an interval scale (0=none, 0.5=trivial, 1=mild, 1.5=mild-moderate, 2=moderate, 2.5=moderate-severe, 3=severe), and the change in AI at follow-up was analyzed with significance tests. Kaplan–Meier estimates for freedom from moderate or worse AI at follow-up were generated. Mixed-model linear regression was used to identify correlates of AI progression during LVAD support. The median (25th, 75th percentile) duration of LVAD support was 239 (112, 455) days, and preoperative AI grade was 0.0 (0.0, 0.0). At 6 months, 89±4% of subjects (n=49 at risk) were free from moderate or worse AI, but this was reduced to 74±7% (n=29 at risk) and 49±13% (n=13 at risk) by 12 and 18 months, respectively. Correlates (slope±SE) of AI progression included female sex (0.002±0.001; P=0.01), smaller body surface area (−0.003±0.001 per m2; P=0.0017), and HeartMate-II model type (0.002±0.001; P=0.039). Correlates (&bgr;±SE) of progressive AI on postoperative echocardiogram included increasing aortic sinus diameter (0.04±0.01 per mm; P=0.001), an aortic valve that remained closed (0.42±0.06; P<0.001) or only intermittently opened (0.34±0.09; P<0.001), and lower left ventricular diastolic (−0.002±0.0004 per cm3; P<0.001) and systolic (−0.002±0.0004 per cm3; P<0.001) volumes. Conclusions—AI progresses over time in LVAD-supported patients. As we move toward an era of long-term cardiac support, more studies are needed to determine the clinical significance of these findings.

Hemolysis: A harbinger of adverse outcome after left ventricular assist device implant

BACKGROUND The clinical relevance of elevated serum markers of hemolysis during left ventricular assist device (LVAD) support has not been fully ascertained. METHODS Lactate dehydrogenase (LDH) and serum free hemoglobin (sfHg) values were tallied monthly in 182 patients on HeartMate II (Thoratec, Pleasanton, CA) LVAD support. Peak values for each marker were identified, and 2 hemolysis definitions were applied to the cohort: Hemolysis according to Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) criteria (sfHg > 40 mg/dl with signs/symptoms) and/or hemolysis defined by an LDH ≥ 600 IU/liter (2.5-times the upper limit of laboratory normal). Kaplan-Meier survival free from death, urgent United Network of Organ Sharing 1A transplant for thrombosis, device exchange for thrombosis, and stroke/peripheral embolism was estimated, and Cox hazard ratios (HR) with the 95% confidence interval (95% CI) were calculated. Areas under the receiver-operating characteristic curves (AUCs) for predicting 1-year event-free survival were calculated. RESULTS Hemolysis occurred in 32 patients (18%) by INTERMACS criteria and in 68 (37%) patients by LDH criteria. Over a median (25(th), 75(th)) support of 427 days (245, 793 days), there were 78 events. One year event-free survival after the onset of INTERMACS-defined hemolysis was 16% ± 8.3% compared with 85% ± 3.2% in non-hemolyzers (HR, 14.7; 95% CI, 7.9-27; AUC 0.70 ± 0.05; p < 0.001; ). One year event-free survival after the onset of LDH-defined hemolysis was 32% ± 7.2% compared with 89% ± 3.2% in those with persistent LDH values < 600 IU/liter (HR, 8.0; 95% CI, 4.4-14; AUC 0.87 ± 0.04; p < 0.001). Patients who met the LDH hemolysis definition had longer times from hemolysis onset to clinical events and larger magnitudes of risk for embolism and device exchange for thrombosis than those with INTERMACS hemolysis. CONCLUSIONS Serum hemolysis marker elevations are associated with increased events in LVAD patients. LDH monitoring provides an earlier diagnosis of adverse events than sfHg, supporting need for a new INTERMACS definition of VAD-associated hemolysis.

Gastrointestinal bleeding and subsequent risk of thromboembolic events during support with a left ventricular assist device

BACKGROUND Modern left ventricular assist devices (LVAD) require anti-coagulation (AC) with warfarin and anti-platelet therapy to prevent thromboembolic complications in patients. Gastrointestinal bleeding (GI) is a significant adverse event in these patients and treatment typically requires reduction or elimination of AC or anti-platelet therapy. It is not known whether alterations in AC to treat GI bleeding influence subsequent risk of thromboembolic (TE) events during LVAD support. METHODS Between July 2003 and September 2011, 389 patients (308 male) underwent implantation of a continuous-flow LVAD at the University of Michigan Health System and the Mayo Clinic. Median age at implant was 60 years (range 18 to 79 years). Outcomes were analyzed for the association of GI bleeding events and subsequent TE events, defined as stroke, transient ischemic attack, hemolysis or suspected or confirmed pump thrombosis. RESULTS Median survival was 10 months (maximum 7.2 years, total 439 patient-years). TE events occurring within the first 30 days were not counted. Overall survival and freedom from an outcome event were assessed using the Kaplan-Meier method. Associations between GI bleeding and subsequent TE events and survival impact were analyzed as time-dependent covariates. One hundred ninety-nine GI bleeding episodes occurred in 116 of 389 patients (30%) for an event rate of 0.45 GI bleed/patient-year of support. One hundred thirty-eight TE events occurred in 97 of 389 patients (25%) for an event rate of 0.31 TE event/patient-year of support. Median time from LVAD implant to first GI bleed was 5 months (range 1 to 116 months) and to first TE event was 6 months (range 1 to 29 months). For patients who had a TE event after GI bleed, the median interval was 5 months (range 0.5 to 25 months). TE events were 7.4-fold more likely in patients who had a prior GI bleed (range 4.9- to 11.1-fold) (p < 0.001); however, neither the presence of GI bleeding (0.7 to 1.2) nor a TE event (0.8 to 2.0) portended a lower overall survival. CONCLUSIONS Patients who had GI bleeding were at significantly higher risk for a subsequent TE event. Although the exact cause of this relationship is unknown, it suggests that a reduction in anti-coagulation and anti-platelet management to treat GI bleeds may contribute to this risk.

Diagnosis of hemolysis and device thrombosis with lactate dehydrogenase during left ventricular assist device support

Diagnosis of hemolysis and device thrombosis with lactate dehydrogenase during left ventricular assist device support Palak Shah, MD, MS, Vivek M. Mehta, BS, Jennifer A. Cowger, MD, Keith D. Aaronson, MD, MS, and Francis D. Pagani, MD, PhD From the Division of Cardiovascular Medicine; College of Literature, Science and Arts; and the Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan

Device exchange after primary left ventricular assist device implantation: Indications and outcomes

BACKGROUND Patients are being supported for longer periods with implantable left ventricular assist devices (LVADs) owing to longer transplantation wait times and approval of LVADs for destination therapy. This comes with an increased potential need for device exchange when complications arise. There are few data examining this patient population. METHODS Between August 1998 and January 2012, 45 patients (34 men) underwent 57 device exchanges after primary pulsatile or continuous-flow LVAD implantation. The median age at the initial LVAD implantation was 58 years (range, 28-78 years) and the median time to first device exchange was 15 months (range, immediate-56 months). Indications for primary LVAD included bridge to transplantation in all but 10 patients, and devices included the HeartMate I (Thoratec, Pleasanton, CA) in 16 patients, the HeartMate II (Thoratec) in 21 patients, the HeartWare HVAD (HeartWare, Framingham, MA) in 2 patients, the DuraHeart I (Terumo Heart, Ann Arbor, MI) in 1 patient, and other devices in 5 patients. Indications for reoperation included device/component failure (n=24), major driveline infection (n=15), pump thrombus (n=15), and other indications (n=2). RESULTS Pumps implanted in 57 reoperations included the HeartMate I in 15 patients, the HeartMate II in 35 patients, the HeartWare HVAD in 2 patients, the DuraHeart I in 2 patients, and other devices in 3 patients. Early mortality occurred in 2/57 (3.5%) patients. Median follow-up was 18 months (range, 1-113 months); median length of LVAD therapy after the first device exchange was 13 months (range, 1-59 months). Actuarial 1-year survival and freedom from repeated device exchange after the first exchange was 89% and 79%, respectively. CONCLUSIONS Device exchange may be required after LVAD implantation. This can be performed with low early mortality and no adverse effect on late survival. Multiple reoperations may be required in some patients.

Adverse events in contemporary continuous-flow left ventricular assist devices: A multi-institutional comparison shows significant differences

OBJECTIVES We review differences in the incidence and timing of adverse events in patients implanted with continuous-flow left ventricular assist devices (LVADs), using the Mechanical Circulatory Support Research Network registry. METHODS From May 2004 to September 2014, a total of 734 patients (591 men; median age: 59 years) underwent primary continuous-flow LVAD implantation at our institutions. Patients implanted with the HeartMate II (HMII) (560 [76%] patients), compared with the HeartWare ventricular assist device (HVAD; 174 [24%]) were more often receiving destination therapy (47% vs 20%; P < .01), had a lower preoperative creatinine level (1.2 vs 1.3; P = .01), and had less median preoperative right ventricular dysfunction (mild vs moderate; P < .01). Ischemic etiology, prior sternotomy, and median INTERMACS profile were similar. RESULTS Overall mortality was 54 of 734 (7.4%); 41 of 560 (7.3%) in the HMII group, and 13 of 174 (7.5%) in the HVAD group (P = .95). Follow-up was available in 100% of early survivors for a median of 1 year (max: 10 years) and a total of 1120 patient-years of support (HMII: 940 patient-years [median: 1.1 years, max: 5.3 years] and HVAD: 180 patient-years [median: 0.6 year, max: 10.4 years]). On multivariable analysis, GI bleeding (P = .63), any infection (P = .32), driveline infection (P = .10), and pump thrombus (P = .64) were similar between devices while HeartWare HVAD was associated with higher risk of stroke (HR: 1.8, [1.25, 2.5], P = .003). CONCLUSIONS In this pooled analysis, a trend was found for higher incidence of percutaneous driveline infections in patients treated with the HMII; a higher incidence of stroke and time-related cumulative risk of any infection and stroke was found in patients treated with the HVAD, which was independently associated with higher stroke risk.

A contemporary review of mechanical circulatory support

Mechanical circulatory support has seen numerous advances in the recent years, with important observations made to guide patient selection for the therapy, indications for use, and management of devices after implantation. There is rapid growth in the use of left ventricular assist device therapy (LVAD) for advanced heart failure, with a movement to pursue device intervention earlier in the disease spectrum before comorbidities escalate. With this increase in LVAD use have come new challenges, including unanticipated adverse events and high readmission rates. Simultaneously, complications encountered during LVAD support and an increased number of patients supported with a goal for transplant have had an important effect on the allocation of cardiac allografts. Still, the field continues to evolve and address these challenges in systematic fashion to provide novel solutions and meet the needs of a growing population with advanced heart failure. This has led to an extensive body of literature, ranging from case reports to multicenter clinical trials, which will enhance the future of LVAD technology and patient outcomes. This review summarizes important publications in mechanical circulatory support during the past 24 months.

Consequences of aortic insufficiency during long-term axial continuous-flow left ventricular assist device support

BACKGROUND Although left ventricular assist device (LVAD) management strategies are undertaken to reduce the development of aortic insufficiency (AI), the effect of AI on patient morbidity and mortality is not known. METHODS Patients undergoing HeartMate II (Thoratec, Pleasanton, CA) implant were prospectively monitored with serial echocardiograms. Kaplan-Meier methods and log-rank testing were used to estimate and compare mortality and freedom from moderate or worser right ventricular hypokinesis (RVHK), moderate or worse mitral regurgitation (MR), and hemolysis according to AI severity. Mixed modelling was used to examine for correlates of AI development in the pre-operative and post-operative setting and to investigate the effect of AI on post-operative MR and RVHK. RESULTS There were 930 echocardiograms completed in 166 patients. During 291 person-years of follow-up, mild-moderate or worse AI developed in 70 (0.38 persons per year [PPY]), moderate or worse AI in 36 (0.17 PPY), moderate-severe AI in 11 (0.039 PPY), and severe AI in 2 (0.0069 PPY). Overall 2-year survival and 2-year survival after onset of moderate or worse AI was 87% ± 6.2% and 65% ± 11%, respectively, compared with 76% ± 5.1% and 76% ± 5.1%, respectively, in those with less AI (p = 0.57). Patients with moderate AI were not more likely to develop MR, hemolysis events, or worsening RVHK, but patients with pre-existing RVHK appeared to be less tolerant of AI. Three of 35 deaths were directly attributed to AI. No reoperations were performed solely for AI. CONCLUSIONS AI is common after LVAD implant but did not affect survival in this cohort. Except in those with significant RV dysfunction, this calls into question need for echocardiogram-guided device settings to ensure aortic valve opening.