Initiating GLP-1 Therapy in Combination with FreeStyle Libre Provides Greater Benefit Compared with GLP-1 Therapy Alone.

Background and Aim: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy provides glycemic benefits to individuals with type 2 diabetes (T2D). However, the effects of GLP-1 RA therapy in combination with FreeStyle Libre systems (FSL) are unknown. This study aimed to compare changes in hemoglobin A1c (HbA1c) between people acquiring GLP-1 with FSL (GLP-1+FSL) versus GLP-1 without FSL (GLP-1). Methods: This real-world study used Optum's de-identified Market Clarity Data, a linked electronic health records (EHR)-claims database, and included adults with T2D and HbA1c ≥8% who acquired their first GLP-1 RA medication between 2018 and 2022. GLP-1+FSL subjects acquired their first FSL within ±30 days of their first GLP-1 acquisition. Cohorts were matched 1:5 on baseline insulin therapy, age, sex, baseline HbA1c, and GLP-1 type. Paired changes in HbA1c were compared between unmatched and matched groups at 6 months. Results: The study included 24,724 adults in the unmatched cohort (GLP-1+FSL, n = 478; GLP-1, n = 24,246). The matched cohort included 478 GLP-1+FSL users and 2,390 GLP-1 users: mean age 53.5 ± 11.8 and 53.5 ± 11.3 years, HbA1c 10.25 ± 1.68% and 10.22 ± 1.69%, respectively. HbA1c reduction was greater in the GLP-1+FSL group compared with the GLP-1 group in the unmatched cohort (-2.43% vs. -1.73%, difference 0.70%, P < 0.001, respectively) and in the matched cohort (-2.43% vs. -2.06%, difference 0.37%, P < 0.001). GLP-1+FSL vs. GLP-1 treatment was associated with greater HbA1c reduction in the intensive insulin (-2.32% vs. -1.50%), nonintensive insulin (-2.50% vs. -1.74%), and noninsulin group (-2.46% vs. -1.78%), as well as in patients using semaglutide (-2.73% vs. -1.92%) and dulaglutide (-2.45% vs. -1.71%) GLP-1 RA, all P < 0.001. Conclusions: Adults with suboptimally controlled T2D, initiating GLP-1 RA with FreeStyle Libre, had greater improvement in HbA1c compared with those treated with GLP-1 RA only. These results suggest an additional glycemic benefit of FSL when used with a GLP-1 RA in T2D treatment.

Prediction of Survival After Implantation of a Fully Magnetically Levitated Left Ventricular Assist Device.

BACKGROUND: Clinical trials inform on average efficacy, but individualized risk assessments for outcome prediction are important in guiding treatment implementation. OBJECTIVES: The authors developed and validated a patient-specific risk score to predict survival at 1 and 2 years after HeartMate 3 (HM3) left ventricular assist device (LVAD) implantation. METHODS: The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial includes 2,200 HM3 LVAD patients in the pivotal trial and Continued Access Protocol study (2014-2018). The authors randomly assigned all patients to a derivation cohort (n = 1,540) or validation cohort (n = 660). Univariate mortality predictors were screened for potential model inclusion, stepwise selection was used to build the multivariable Cox proportional hazards regression model, and performance (discrimination and calibration) was evaluated. RESULTS: Age, prior cardiac surgery (coronary artery bypass grafting [CABG] or valve procedure), lower serum sodium, higher blood urea nitrogen (BUN), small left ventricular size, and right atrial pressure-to-pulmonary capillary wedge pressure (RAP/PCWP) ratio >0.6 were significant risk factors for mortality. Receiver-operating characteristic (ROC) analysis in the validation cohort demonstrated an area under the curve (AUC) of 0.76 (95% CI: 0.70-0.81) at 1 year and 0.71 (95% CI: 0.66-0.77) at 2 years. Calibration between predicted and observed survival of the risk quintiles was high, with Pearson correlation coefficients of 0.986 and 0.994 at 1 and 2 years, respectively. Patients were successfully stratified into tertiles with higher-than-average, average, and lower-than-average survival, and observed mortality risk increased by 2-fold from one tertile to the next. CONCLUSIONS: A practical, easy-to-use HM3 Survival Risk Score with 6 components was developed to accurately predict 1- and 2-year survival after HM3 LVAD implantation. The survival risk score can be used to provide individual survival estimates to facilitate shared decision making when considering HM3 LVAD therapy. (MOMENTUM 3 Trial Portfolio; NCT02224755, NCT02892955).

Five-Year Outcomes in Patients With Fully Magnetically Levitated vs Axial-Flow Left Ventricular Assist Devices in the MOMENTUM 3 Randomized Trial.

Importance: Although durable left ventricular assist device (LVAD) therapy has emerged as an important treatment option for patients with advanced heart failure refractory to pharmacological support, outcomes, including survival, beyond 2 years remain poorly characterized. Objective: To report the composite end point of survival to transplant, recovery, or LVAD support free of debilitating stroke (Modified Rankin Scale score >3) or reoperation to replace the pump 5 years after the implant in participants who received the fully magnetically levitated centrifugal-flow HeartMate 3 or axial-flow HeartMate II LVAD in the MOMENTUM 3 randomized trial and were still receiving LVAD therapy at the 2-year follow-up. Design, Setting, and Participants: This observational study was a 5-year follow-up of the MOMENTUM 3 trial, conducted in 69 US centers, that demonstrated superiority of the centrifugal-flow LVAD to the axial-flow pump with respect to survival to transplant, recovery, or LVAD support free of debilitating stroke or reoperation to replace the pump at 2 years. A total of 295 patients were enrolled between June 2019 to April 2021 in the extended-phase study, with 5-year follow-up completed in September 2021. Exposures: Of 1020 patients in the investigational device exemption per-protocol population, 536 were still receiving LVAD support at 2 years, of whom 289 received the centrifugal-flow pump and 247 received the axial-flow pump. Main Outcomes and Measures: There were 10 end points evaluated at 5 years in the per-protocol population, including a composite of survival to transplant, recovery, or LVAD support free of debilitating stroke or reoperation to replace the pump between the centrifugal-flow and axial-flow pump groups and overall survival between the 2 groups. Results: A total of 477 patients (295 enrolled and 182 provided limited data) of 536 patients still receiving LVAD support at 2 years contributed to the extended-phase analysis (median age, 62 y; 86 [18%] women). The 5-year Kaplan-Meier estimate of survival to transplant, recovery, or LVAD support free of debilitating stroke or reoperation to replace the pump in the centrifugal-flow vs axial-flow group was 54.0% vs 29.7% (hazard ratio, 0.55 [95% CI, 0.45-0.67]; P < .001). Overall Kaplan-Meier survival was 58.4% in the centrifugal-flow group vs 43.7% in the axial-flow group (hazard ratio, 0.72 [95% CI, 0.58-0.89]; P = .003). Serious adverse events of stroke, bleeding, and pump thrombosis were less frequent in the centrifugal-flow pump group. Conclusions and Relevance: In this observational follow-up study of patients from the MOMENTUM 3 randomized trial, per-protocol analyses found that receipt of a fully magnetically levitated centrifugal-flow LVAD vs axial-flow LVAD was associated with a better composite outcome and higher likelihood of overall survival at 5 years. These findings support the use of the fully magnetically levitated LVAD. Trial Registration: ClinicalTrials.gov Identifier: NCT02224755 and NCT03982979.

Center Variability in Patient Outcomes Following HeartMate 3 Implantation: An Analysis of the MOMENTUM 3 Trial.

BACKGROUND: As left ventricular assist device (LVAD) survival rates continue to improve, evaluating site-specific variability in outcomes can facilitate identifying targets for quality-improvement initiative opportunities in the field. METHODS: Deidentified center-specific outcomes were analyzed for HeartMate 3 (HM3) patients enrolled in the MOMENTUM 3 pivotal and continued access protocol trials. Centers < 25th percentile for HM3 volumes were excluded. Variability in risk-adjusted center mortality was assessed at 90 days and 2 years (conditional upon 90-day survival). Adverse event (AE) rates were compared across centers. RESULTS: In the 48 included centers (1958 patients), study-implant volumes ranged between 17 and 106 HM3s. Despite similar trial-inclusion criteria, patient demographics varied across sites, including age quartile ((Q)1-Q3:57-62 years), sex (73%-85% male), destination therapy intent (60%-84%), and INTERMACS profile 1-2 (16%-48%). Center mortality was highly variable, nadiring at ≤ 3.6% (≤ 25th percentile) and peaking at ≥ 10.4% (≥ 75th percentile) at 90 days and ≤ 10.2% and ≥ 18.7%, respectively, at 2 years. Centers with low mortality rates tended to have lower 2-year AE rates, but no center was a top performer for all AEs studied. CONCLUSIONS: Mortality and AEs were highly variable across MOMENTUM 3 centers. Studies are needed to improve our understanding of the drivers of outcome variability and to ascertain best practices associated with high-performing centers across the continuum of intraoperative to chronic stages of LVAD support.

Outcomes in Smaller Body Size Adults After HeartMate 3 Left Ventricular Assist Device Implantation.

BACKGROUND: Outcomes in patients with smaller body size after HeartMate 3 left ventricular assist device (HM3) implantation are not well characterized. We sought to evaluate outcomes in smaller vs larger body surface area (BSA) patients in the MOMENTUM 3 pivotal trial and its Continued Access Protocol cohort. METHODS: The analysis cohort included 1015 HM3 patients divided into 2 groups: BSA ≤1.70 m2 (small patients, n = 82) and BSA >1.70 m2 (large patients, n = 933). The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or to remove a malfunctioning device. Adverse events were compared between groups. RESULTS: Smaller patients were more frequently women (56.1% vs 17.7%; P < .001) and had lower prevalence of diabetes (28.1% vs 43.9%; P = .005) and hypertension (51.2% vs 71.9%; P < .001), larger median indexed LVEDD (normalized by BSA, 40 vs 33 mm/m2; P < .001), and lower median serum creatinine concentration (1.1 vs 1.3 mg/dL; P < .001). The proportion of patients achieving the composite end point at 2 years was 77% in both groups (adjusted hazard ratio, 1.14; 95% CI, 0.68-1.91; P = .62). Two-year adverse event rates were also similar between groups except for sepsis (6.1% vs 14.9%; P = .029) and cardiac arrhythmias (24.4% vs 35.3%; P = .005), which were higher in the larger patients. CONCLUSIONS: Outcomes after HM3 implantation were comparable between small and large patients. Smaller body size should not be used to deny HM3 implantation in patients who are otherwise suitable candidates for durable mechanical circulatory support.

Primary results of long-term outcomes in the MOMENTUM 3 pivotal trial and continued access protocol study phase: a study of 2200 HeartMate 3 left ventricular assist device implants.

AIM: The MOMENTUM 3 pivotal trial established superiority of the HeartMate 3 (HM3) left ventricular assist device (LVAD), a fully magnetically levitated centrifugal-flow pump, over the HeartMate II axial-flow pump. We now evaluate HM3 LVAD outcomes in a single-arm prospective continuous access protocol (CAP) post-pivotal trial study. METHODS AND RESULTS: We enrolled 2200 HM3 implanted patients (515 pivotal trial and 1685 CAP patients) and compared outcomes including survival free of disabling stroke or reoperation to replace or remove a malfunctioning device (primary composite endpoint), overall survival and major adverse events at 2 years. The 2-year primary endpoint [76.7% vs. 74.8%; adjusted hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.71-1.08, P = 0.21] and overall survival (81.2% vs. 79.0%) were similar among CAP and pivotal cohorts despite sicker patients (more intra-aortic balloon pump use and INTERMACS profile 1) in CAP who were more often intended for destination therapy. Survival was similar between the CAP and pivotal trial in transplant ineligible patients (79.1% vs. 76.7%; adjusted HR 0.89, 95% CI 0.68-1.16, P = 0.38). In a pooled analysis, the 2-year primary endpoint was similar between INTERMACS profiles 1-2 ('unstable' advanced heart failure), profile 3 ('stable' on inotropic therapy), and profiles 4-7 ('stable' ambulatory advanced heart failure) (75.7% vs. 77.6% vs. 72.9%, respectively). The net burden of adverse events was lower in CAP (adjusted rate ratio 0.93, 95% CI 0.88-0.98, P = 0.006), with consequent decrease in hospitalization. CONCLUSIONS: The primary results of accumulating HM3 LVAD experience suggest a lower adverse event burden and similar survival compared to the pivotal MOMENTUM 3 trial.

Impact of left ventricular assist device implantation on mitral regurgitation: An analysis from the MOMENTUM 3 trial.

BACKGROUND: Mitral regurgitation (MR) determines pathophysiology and outcome in advanced heart failure. The impact of left ventricular assist device (LVAD) placement on clinically significant MR and its contribution to long-term outcomes has been sparsely evaluated. METHODS: We evaluated the effect of clinically significant MR on patients implanted in the MOMENTUM 3 trial with either the HeartMate II (HMII) or the HeartMate 3 (HM3) at 2 years. Clinical significance was defined as moderate or severe grade MR determined by site-based echocardiograms. RESULTS: Of 927 patients with LVAD implants without a prior or concomitant mitral valve procedure, 403 (43.5%) had clinically significant MR at baseline. At 1-month of support, residual MR was present in 6.2% of patients with HM3 and 14.3% of patients with HMII (relative risk = 0.43; 95% CI, 0.22-0.84; p = 0.01) with a low rate of worsening at 2 years. Residual MR at 1-month post-implant did not impact 2-year mortality for either the HM3 (hazard ratio [HR],1.41; 95% CI, 0.52-3.89; p = 0.50) or HMII (HR, 0.91; 95% CI, 0.37-2.26; p = 0.84) LVAD. The presence or absence of baseline MR did not influence mortality (HM3 HR, 0.86; 95% CI, 0.56-1.33; p = 0.50; HMII HR, 0.81; 95% CI, 0.54-1.22; p = 0.32), major adverse events or functional capacity. In multivariate analysis, severe baseline MR (p = 0.001), larger left ventricular dimension (p = 0.002), and implantation with the HMII instead of the HM3 LVAD (p = 0.05) were independently associated with an increased likelihood of persistent MR post-implant. CONCLUSIONS: Hemodynamic unloading after LVAD implantation improves clinically significant MR early, sustainably, and to a greater extent with the HM3 LVAD. Neither baseline nor residual MR influence outcomes after LVAD implantation.

A Fully Magnetically Levitated Left Ventricular Assist Device - Final Report.

BACKGROUND: In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device were less likely to have pump thrombosis or nondisabling stroke than were patients treated with a mechanical-bearing axial-flow left ventricular assist device. METHODS: We randomly assigned patients with advanced heart failure to receive either the centrifugal-flow pump or the axial-flow pump irrespective of the intended goal of use (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or remove a malfunctioning device. The principal secondary end point was pump replacement at 2 years. RESULTS: This final analysis included 1028 enrolled patients: 516 in the centrifugal-flow pump group and 512 in the axial-flow pump group. In the analysis of the primary end point, 397 patients (76.9%) in the centrifugal-flow pump group, as compared with 332 (64.8%) in the axial-flow pump group, remained alive and free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years (relative risk, 0.84; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 for superiority). Pump replacement was less common in the centrifugal-flow pump group than in the axial-flow pump group (12 patients [2.3%] vs. 57 patients [11.3%]; relative risk, 0.21; 95% CI, 0.11 to 0.38; P<0.001). The numbers of events per patient-year for stroke of any severity, major bleeding, and gastrointestinal hemorrhage were lower in the centrifugal-flow pump group than in the axial-flow pump group. CONCLUSIONS: Among patients with advanced heart failure, a fully magnetically levitated centrifugal-flow left ventricular assist device was associated with less frequent need for pump replacement than an axial-flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.).

Postmarket Experience With HeartMate 3 Left Ventricular Assist Device: 30-Day Outcomes From the ELEVATE Registry.

BACKGROUND: The HeartMate 3 left ventricular assist device (Abbott, Chicago, IL) is designed to provide circulatory support with enhanced hemocompatibility for patients with advanced heart failure. The purpose of this study was to compare the surgical outcomes between patients treated during the European Conformity Mark (CE Mark [CEM]) clinical trial and those treated in the postmarket era. METHODS: The prospective, observational, multinational ELEVATE (Evaluating the HeartMate 3 with Full MagLev Technology in a Post-Market Approval Setting) registry includes patients receiving the HeartMate 3 following CEM approval. Outcomes of patients in the ELEVATE registry are compared with patients in the CEM trial. RESULTS: Compared with the CEM trial (N = 50), the ELEVATE registry group (N = 463) was more severely ill, with more patients classified as INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 1 to 2 (32% versus 10%; p < 0.001). The CEM trial group was younger and underwent fewer concomitant valve procedures. After adjustment for differences in baseline characteristics, the 30-day survival was comparable between the ELEVATE registry and CEM trial groups (95% versus 98%; p = 0.46). Length of intensive care unit stay was similar between the ELEVATE registry (7 days) and CEM trial (6 days) groups. Most adverse event rates were comparable between the 2 groups. ELEVATE registry patients had a lower rate of cardiac arrhythmias (13% versus 28%; p = 0.009). With increasing experience, the implant technique has evolved to include more versatile approaches such as less invasive and off-pump implantation. CONCLUSIONS: The 30-day outcomes for ELEVATE registry patients are comparable despite being sicker than CEM trial patients. Adverse event rates remain low, with no cases of pump thrombosis within the first 30 days. Implant techniques have evolved to include more versatile approaches.

Pump Position Impacts HeartMate II Left Ventricular Assist Device Thrombosis.

The PREVENtion of HeartMate II pump Thrombosis through clinical management (PREVENT) study was a multicenter, prospective investigation to evaluate the rate of pump thrombosis (PT) with adoption of a uniform set of surgical and medical practices for left ventricular assist device implantation. We sought to quantify pump position at baseline and retrospectively define a pump position associated with poor clinical outcomes. Chest x-rays at baseline were prospectively obtained per protocol. Pump pocket depth, inflow cannula (IC) angle relative to the pump, and IC angle relative to the vertical were measured. Pumps falling in the tail-ends of the IC angle and pump pocket depth distributions were categorized as having an extreme pump position within the PREVENT study. Patients with extreme pump position had a significantly higher risk of confirmed and suspected PT, hemolysis, and elevated lactate dehydrogenase. In a multivariable analysis of survival free of confirmed PT, extreme pump position was an independent risk factor (hazard ratio = 3.6; 95% confidence interval = 1.5-8.9; p = 0.006) when adjusting for differences in pump speed and anticoagulation level. Our analysis shows that HeartMate II pump position at implant can significantly impact event-free survival and the incidence of adverse events at 6 months.

Six-month outcomes after treatment of advanced heart failure with a full magnetically levitated continuous flow left ventricular assist device: report from the ELEVATE registry.

Aims: The ELEVATE registry was planned to study post-approval outcomes with HeartMate 3™ (HM3), a fully magnetically levitated continuous flow left ventricular assist device (LVAD). Methods and results: A total of 482 patients provided consent to participate in ELEVATE (enrolled cohort). Data collection included baseline demographics, survival, adverse events, quality of life (QOL) [EuroQoL-5 Dimensions visual analogue scale (VAS), and 6-minute walk distance (6MWD)]. An additional 58 patients were implanted with HM3 during the same period but expired or were explanted prior to consent, and only survival data were collected (anonymized cohort). We report the 6-month outcomes of the patients who received HM3 as their primary implant (n = 463) and the survival of the 540 patients in the full cohort (enrolled + anonymized). Baseline characteristics included a mean age of 55.6 ± 11.7 years, 89% male, 48% ischaemic aetiology, and 70% on inotropes. The majority of patients (66%) were bridge-to-transplantation (BTT) and 32% were INTERMACS profile 1-2. Full cohort survival at 6 months was 82 ± 2%. In the enrolled primary implant patients, there was no incidence of pump thrombosis, major bleeding was 25%, major infection 35%, and any stroke type 5%. Functional capacity improved significantly (Δ6MWD 230 ± 191 m) as did QOL (ΔVAS 31 ± 23). Freedom from unplanned rehospitalizations at 6 months was 68 ± 2%. Conclusion: The 6-month outcomes of the HM3 LVAD demonstrate a highly reliable, thrombosis free, device with low incidence of stroke and improved functional capacity, and QOL. ClinicalTrials. gov Identifier: NCT02497950.

Healthcare Resource Use and Cost Implications in the MOMENTUM 3 Long-Term Outcome Study.

BACKGROUND: The MOMENTUM 3 trial compares the centrifugal HeartMate 3 (HM3) with the axial HeartMate II (HMII) continuous-flow left ventricular assist system in patients with advanced heart failure, irrespective of the intended goal of therapy. The trial's 2-year clinical outcome (n=366) demonstrated superiority of the HM3 for the primary end point (survival free of a disabling stroke or reoperation to replace or remove a malfunctioning pump). This analysis evaluates health resource use and cost implications of the observed differences between the 2 devices while patients were enrolled in the trial. METHODS: We analyzed all hospitalizations and their associated costs occurring after discharge from the implant hospitalization until censoring (study withdrawal, heart transplantation, and pump exchange with a nonstudy device or death). Each adjudicated episode of hospital-based care was used to calculate costs (device-attributable and non-device-attributable event costs), estimated by using trial data and payer administrative claims databases. Cost savings stratified by subgroups (study outcome [transplant, death, or ongoing on device], intended goal of therapy, type of insurance, or sex) were also assessed. RESULTS: In 366 randomly assigned patients, 361 comprised the as-treated group (189 in the HM3 group and 172 in the HMII group), of whom 337 (177 in the HM3 group and 160 in the HMII group) were successfully discharged following implantation. The HM3 arm experienced fewer total hospitalizations per patient-year (HM3: 2.1±0.2 versus HMII: 2.7±0.2; P=0.015) and 8.3 fewer hospital days per patient-year on average (HM3: 17.1 days versus HMII: 25.5 days; P=0.003). These differences were driven by patients hospitalized for suspected pump thrombosis (HM3: 0.6% versus HMII: 12.5%; P<0.001) and stroke (HM3: 2.8% versus HMII: 11.3%; P=0.002). Controlled for time spent in the study (average cumulative cost per patient-year), postdischarge HM3 arm costs were 51% lower than with the HMII (HM3: $37 685±4251 versus HMII: $76 599±11 889, P<0.001) and similar in either bridge to transplant or destination therapy intent. CONCLUSIONS: In this 2-year outcome economic analysis of the MOMENTUM 3 trial, the HM3 demonstrated a reduction in rehospitalizations, hospital days spent during rehospitalizations, and a significant cost savings following discharge in comparison with the HMII left ventricular assist system, irrespective of the intended goal of therapy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02224755.

Left ventricular assist devices versus medical management in ambulatory heart failure patients: An analysis of INTERMACS Profiles 4 and 5 to 7 from the ROADMAP study.

BACKGROUND: The ROADMAP study showed survival with improved functional status was better with left ventricular assist device (LVAD) therapy compared with optimal medical management (OMM) in ambulatory, non-inotrope-dependent (INTERMACS [IM] Profile 4 to 7) patients. To study more balanced cohorts and better define which patients may benefit from implantation of an LVAD, we re-evaluated the patients enrolled in ROADMAP when stratified by INTERMACS profile (Profile 4 and Profiles 5 to 7). METHODS: The primary end-point (survival on original therapy with improvement in 6-minute walk distance ≥75 meters at 1 year), actuarial survival, adverse events (AEs) and health-related quality of life (HRQoL) were evaluated. RESULTS: For INTERMACS Profile 4 (IM4), more LVAD patients met the primary end-point compared with OMM patients (40% vs 15%; odds ratio = 3.9 [1.2 to 12.7], p = 0.024), but there was no statistically significant difference for INTERMACS Profiles IM 5 to 7 (IM5-7). Event-free survival on original therapy at 2 years was greater for LVAD than for OMM patients in both IM4 (67% vs 28%; p < 0.001) and IM5-7 (76% vs 49%; p = 0.025) profile groups. Composite end-points of survival on original therapy with improved HRQoL or depression were better with LVAD than OMM in IM4, but not IM5-7. AEs trended higher in LVAD compared with OMM patients in both profile groups. Rehospitalization rates for LVAD vs OMM were similar between treatment arms in IM4 (82% vs 86%; p = 0.780), but were higher for LVAD in IM5-7 (93% vs 71%; p = 0.016). CONCLUSIONS: LVAD patients in IM4, but not IM5-7, are more likely to meet the primary end-point and have improvements in HRQoL and depression compared with OMM, even with AEs generally being more frequent. LVAD therapy with current technology may be beneficial in select IM4 patients, but can be deferred for most IM5-7 patients, who should be followed closely due to the high frequency of treatment failures.

Novel Cardiac Coordinate Modeling System for Three-Dimensional Quantification of Inflow Cannula Malposition of HeartMate II LVADs.

Optimal function of left ventricular assist devices (LVADs) depends on proper alignment of the inflow cannula (IC). Quantitative guidelines for IC angulation are lacking because of variation in cardiac geometry and difficulty in analyzing three-dimensional (3D) cannula orientation relative to the left ventricle (LV). Based on contrast-enhanced computed tomography images from five normal and five clinically malpositioned IC cases in patients with HeartMate II LVADs, we developed a method for 3D quantification of IC malpositioning. Using Mimics image software (Materialise, Leuven, Belgium), the native heart, major arteries, and LVAD were segmented to create patient-specific 3D models, allowing LV cavity volume and long-axis length to be measured directly. The deviation of the IC was quantified in a cylindrical coordinate system at the IC insertion point relative to the mitral valve and septum, and IC occlusion was assessed by the distance between cannula inlet and the proximal endocardium. Compared with normal cases, patients with malpositioned pumps had shorter LV length (p = 0.03) and reduced pump pocket depth (p = 0.009). Malpositioned pumps may experience greater obstruction by the nearby myocardium. This quantitative 3D modeling tool may help identify different modes of pump malalignment and migration and may facilitate preoperative planning and minimally invasive approaches via virtual LVAD implantation.

Early intervention for lactate dehydrogenase elevation improves clinical outcomes in patients with the HeartMate II left ventricular assist device: Insights from the PREVENT study.

BACKGROUND: Hemolysis, assessed by elevated serum lactate dehydrogenase (LDH), is strongly associated with HeartMate II pump thrombosis (PT). However, it is unknown whether early intervention for elevated LDH circumvents the risk of serious PT requiring pump exchange. We sought to evaluate the relationship between elevated LDH and clinical outcomes, the effectiveness of early medical intervention, and risk factors for elevated LDH. METHODS: We studied 268 patients in the prospective, multicenter PREVENT study who had 2 or more LDH measurements at ≥30 days post-implant. Elevated LDH was defined as LDH ≥2.5× upper limit of normal (ULN) for 2 consecutive measurements. RESULTS: Fourteen percent of patients had elevated LDH. Stroke-free survival at 6 months was lower in patients with elevated LDH vs patients with normal LDH (83 ± 6% vs 93 ± 2%, p = 0.035). Elevated LDH resolved without intervention in 19% of patients, with intensified medical therapy in 43% and required surgical intervention in 38%. For patients receiving only medical therapy, survival was 94 ± 6% at 6 months post-treatment. In this subgroup, resolution of symptoms with intensified medical therapy was sustained in 15 of 16 patients, with PT occurring in 1 patient at 171 days after initial treatment for elevated LDH (202 days post-implant). Early medical intervention at moderately elevated LDH (2.5× to 3.2× ULN), as compared with higher levels (>3.2× ULN), led to more sustained resolution of symptoms without subsequent PT or need for surgical intervention (91% vs 26% at 6 months post-treatment, p = 0.002). CONCLUSIONS: Early medical intervention can successfully resolve moderate LDH elevations (2.5× to 3.2× ULN) with a low incidence of death or PT at 6 months post-treatment.

Multicenter Evaluation of Octreotide as Secondary Prophylaxis in Patients With Left Ventricular Assist Devices and Gastrointestinal Bleeding.

BACKGROUND: Gastrointestinal (GI) bleeding is one of the most common complications after continuous-flow left ventricular assist device implantation. More than one third of patients with incident bleed go on to develop recurrent GI bleeding. Octreotide, a somatostatin analog, is proposed to reduce the risk of recurrent GI bleeding in this population. METHODS AND RESULTS: This multicenter, retrospective analysis evaluated 51 continuous-flow left ventricular assist device patients who received secondary prophylaxis with octreotide after their index GI bleed from 2009 to 2015. All patients had a hospitalization for GI bleed and received octreotide after discharge. Patient demographics, medical and medication history, and clinical characteristics of patients who rebled after receiving octreotide were compared with non-rebleeders. These data were also compared with matched historical control patients previously enrolled in the HMII (HeartMate II) clinical trials, none of whom received octreotide, to provide a context for the bleeding rates. Twelve patients (24%) who received secondary octreotide prophylaxis developed another GI bleed, whereas 39 (76%) did not. There were similar intergroup demographics; however, significantly more bleeders had a previous GI bleeding history before left ventricular assist device placement (33% versus 5%; P=0.02) and greater frequency of angiodysplasia confirmed during endoscopy (58% versus 23%; P=0.03). Fewer patients in this study experienced a recurrent GI bleed compared with a matched historical control group that did not receive octreotide (24% versus 43%; P=0.04). CONCLUSIONS: Patients with continuous-flow left ventricular assist device receiving secondary prophylaxis with octreotide had a significantly lower GI bleed recurrence compared with historical controls not treated with octreotide. Additional prospective studies are needed to confirm these data.

Patient-Reported Health-Related Quality of Life Is a Predictor of Outcomes in Ambulatory Heart Failure Patients Treated With Left Ventricular Assist Device Compared With Medical Management: Results From the ROADMAP Study (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management).

BACKGROUND: The prospective observational ROADMAP study (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management) demonstrated that ambulatory advanced heart failure patients selected for left ventricular assist device (LVAD) were more likely to be alive at 1 year on original therapy with ≥75-m improvement in 6-minute walk distance compared with patients assigned to optimal medical management. Whether baseline health-related quality of life (hrQoL) resulted in a heterogeneity of this treatment benefit is unknown. METHODS AND RESULTS: Patient-reported hrQoL was assessed with EuroQol questionnaire and visual analogue scale (VAS). We aimed to identify predictors of event-free survival and survival with acceptable hrQoL (VAS≥60). LVAD patients had significant improvement in 3 of 5 EuroQol dimensions (P<0.05), but no significant changes were observed with optimal medical management. Among patients with baseline VAS<55, survival on original treatment was lower for optimal medical management patients compared with those assigned to LVAD (58±7% versus 82±5%; P=0.004). No such difference was seen if baseline VAS was ≥55 (70±7% versus 75±9%; P=0.79). Survival on original therapy with acceptable quality of life was also more likely with LVAD versus optimal medical management if baseline VAS was <55, whereas outcomes in patients with higher baseline VAS scores were similar regardless of treatment assignment (P=0.046 for treatment arm and baseline VAS interaction). CONCLUSIONS: LVAD therapy resulted in improvement of patient health status in heart failure patients with low self-reported hrQoL, but not in patients with acceptable quality of life at the time of LVAD implantation. Patient-reported hrQoL should be integrated into decision making concerning the use and timing of LVAD therapy in heart failure patients who are symptom limited but remain ambulatory. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01452802.

Accuracy of Seattle Heart Failure Model and HeartMate II Risk Score in Non-Inotrope-Dependent Advanced Heart Failure Patients: Insights From the ROADMAP Study (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients).

BACKGROUND: Timing of left ventricular assist device (LVAD) implantation in advanced heart failure patients not on inotropes is unclear. Relevant prediction models exist (SHFM [Seattle Heart Failure Model] and HMRS [HeartMate II Risk Score]), but use in this group is not established. METHODS AND RESULTS: ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) is a prospective, multicenter, nonrandomized study of 200 advanced heart failure patients not on inotropes who met indications for LVAD implantation, comparing the effectiveness of HeartMate II support versus optimal medical management. We compared SHFM-predicted versus observed survival (overall survival and LVAD-free survival) in the optimal medical management arm (n=103) and HMRS-predicted versus observed survival in all LVAD patients (n=111) using Cox modeling, receiver-operator characteristic (ROC) curves, and calibration plots. In the optimal medical management cohort, the SHFM was a significant predictor of survival (hazard ratio=2.98; P<0.001; ROC area under the curve=0.71; P<0.001) but not LVAD-free survival (hazard ratio=1.41; P=0.097; ROC area under the curve=0.56; P=0.314). SHFM showed adequate calibration for survival but overestimated LVAD-free survival. In the LVAD cohort, the HMRS had marginal discrimination at 3 (Cox P=0.23; ROC area under the curve=0.71; P=0.026) and 12 months (Cox P=0.036; ROC area under the curve=0.62; P=0.122), but calibration was poor, underestimating survival across time and risk subgroups. CONCLUSIONS: In non-inotrope-dependent advanced heart failure patients receiving optimal medical management, the SHFM was predictive of overall survival but underestimated the risk of clinical worsening and LVAD implantation. Among LVAD patients, the HMRS had marginal discrimination and underestimated survival post-LVAD implantation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01452802.

Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients: The ROADMAP Study 2-Year Results.

OBJECTIVES: The authors sought to provide the pre-specified primary endpoint of the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) trial at 2 years. BACKGROUND: The ROADMAP trial was a prospective nonrandomized observational study of 200 patients (97 with a left ventricular assist device [LVAD], 103 on optimal medical management [OMM]) that showed that survival with improved functional status at 1 year was better with LVADs compared with OMM in a patient population of ambulatory New York Heart Association functional class IIIb/IV patients. METHODS: The primary composite endpoint was survival on original therapy with improvement in 6-min walk distance ≥75 m. RESULTS: Patients receiving LVAD versus OMM had lower baseline health-related quality of life, reduced Seattle Heart Failure Model 1-year survival (78% vs. 84%; p = 0.012), and were predominantly INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 4 (65% vs. 34%; p < 0.001) versus profiles 5 to 7. More LVAD patients met the primary endpoint at 2 years: 30% LVAD versus 12% OMM (odds ratio: 3.2 [95% confidence interval: 1.3 to 7.7]; p = 0.012). Survival as treated on original therapy at 2 years was greater for LVAD versus OMM (70 ± 5% vs. 41 ± 5%; p < 0.001), but there was no difference in intent-to-treat survival (70 ± 5% vs. 63 ± 5%; p = 0.307). In the OMM arm, 23 of 103 (22%) received delayed LVADs (18 within 12 months; 5 from 12 to 24 months). LVAD adverse events declined after year 1 for bleeding (primarily gastrointestinal) and arrhythmias. CONCLUSIONS: Survival on original therapy with improvement in 6-min walk distance was superior with LVAD compared with OMM at 2 years. Reduction in key adverse events beyond 1 year was observed in the LVAD group. The ROADMAP trial provides risk-benefit information to guide patient- and physician-shared decision making for elective LVAD therapy as a treatment for heart failure. (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients [ROADMAP]; NCT01452802).

Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) termed a 'disease of the desmosome' is an inherited cardiomyopathy that recently underwent reclassification owing to the identification of left-dominant and biventricular disease forms. Homozygous loss-of-function mutations in the desmosomal component, desmoplakin, are found in patients exhibiting a biventricular form of ARVC; however, no models recapitulate the postnatal hallmarks of the disease as seen in these patients. To gain insights into the homozygous loss-of-function effects of desmoplakin in the heart, we generated cardiomyocyte-specific desmoplakin-deficient mice (DSP-cKO) using ventricular myosin light chain-2-Cre mice. Homozygous DSP-cKO mice are viable but display early ultrastructural defects in desmosomal integrity leading to a cardiomyopathy reminiscent of a biventricular form of ARVC, which includes cell death and fibro-fatty replacement within the ventricle leading to biventricular dysfunction, failure and premature death. DSP-cKO mice also exhibited ventricular arrhythmias that are exacerbated with exercise and catecholamine stimulation. Furthermore, DSP-cKO hearts exhibited right ventricular conduction defects associated with loss of connexin 40 expression and electrical wavefront propagation defects associated with loss of connexin 43 expression. Dose-dependent assessment of the effects of loss of desmoplakin in neonatal ventricular cardiomyocytes revealed primary loss of connexin 43 levels, phosphorylation and function independent of the molecular dissociation of the mechanical junction complex and fibro-fatty manifestation associated with ARVC, suggesting a role for desmoplakin as a primary stabilizer of connexin integrity. In summary, we provide evidence for a novel mouse model, which is reminiscent of the postnatal onset of ARVC while highlighting mechanisms underlying a biventricular form of human ARVC.