Clinical outcomes after implantation of a centrifugal flow left ventricular assist device and concurrent cardiac valve procedures.

BACKGROUND: Cardiac valve procedures are commonly performed concurrently during implantation of left ventricular assist devices, but the added procedural risk has not been studied in detail. METHODS AND RESULTS: Data from patients receiving the HeartWare Ventricular Assist Device in the ADVANCE bridge to transplant (BTT) trial and continued access protocol were reviewed. Of 382 consecutive patients who completed follow-up between August 2008 and June 2013 (mean time on support 389 days, median 271 days), 262 (68.6%) underwent isolated HeartWare Ventricular Assist Device implantation, 75 (19.6%) a concurrent valve procedure, and 45 (11.8%) concurrent nonvalvular procedures. Of the concurrent valve procedures, 56 were tricuspid, 13 aortic, and 6 mitral. Survival was similar between groups (79% for concurrent valve procedures and 85% for HeartWare Ventricular Assist Device only at 1 year; P=0.33). Concurrent valve procedures were also associated with increased unadjusted early right heart failure (RHF). A multivariable analysis for death and RHF (121 total events) identified female sex (odds ratio=2.0 [95% confidence interval, 1.2-3.3; P=0.0053]) and preimplant tricuspid regurgitation severity (odds ratio=2.9 [95% confidence interval, 1.8-4.8, P<0.0001]) as independent predictors while concurrent tricuspid valve procedures (TVP) were not predictors. Furthermore, patients with significant preimplant tricuspid regurgitation who did not receive a TVP experienced an increased rate of late RHF compared with those who received TVP (0.19 versus 0.05 events per patient-year, respectively; P=0.024). CONCLUSIONS: Compared with HeartWare Ventricular Assist Device alone, survival was equivalent for the concurrent valve procedure group. Tricuspid regurgitation severity was the most important predictor of increased postoperative RHF, and concurrent TVP was not an independent predictor of RHF overall. Concurrent TVP may reduce the rate of late RHF for patients with significant preimplant tricuspid insufficiency. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751972.

Cardiac contractility modulation in heart failure with reduced ejection fraction patients with QRS duration 120-149 ms: Reduction in heart failure hospitalizations and improvement in functional outcome.

BACKGROUND: A subset of heart failure with reduced ejection fraction (HFrEF) patients qualifies for cardiac resynchronization therapy (CRT). However, a 30% CRT nonresponder rate persists, with patients having narrower QRS durations (ie, QRSd 120-149 ms) receiving less or inconsistent benefit. Cardiac contractility modulation (CCM) may be an important alternative therapy option but has largely been evaluated only in HFrEF patients with QRSd <120 ms. OBJECTIVES: The purpose of this study was to evaluate the impact of CCM on HF-related hospitalizations and on left ventricular ejection fraction (LVEF) as well as quality of life in HFrEF patients with QRSd 120-149 ms compared to QRSd <120 ms. METHODS: The CCM-REG Registry enrolled a total of 503 HFrEF patients with follow-up up to 2 years. Hospitalization rates were available for 1 year preimplant. Safety was assessed by comparison of actual vs Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score- or Seattle Heart Failure Model (SHFM)-predicted mortality. RESULTS: Among 111 of 455 patients with QRSd 120-149 ms (mean QRSd 130 ± 9 ms; 20% female; age 68 ± 11 years; LVEF 29% ± 9%; 82% New York Heart Association [NYHA] class III), CCM diminished HF-related hospitalization rate by 72% (pre- vs postimplant 0.90 vs 0.25 events per patient-year over 2 years; P <.001). LVEF improved by 7% ± 9% (P = .014 vs baseline), Minnesota Living with Heart Failure Questionnaire score by 10 ± 23 points (P = .010 vs baseline), and NYHA class by 0.5 ± 0.7 classes (<0.001 vs baseline). The effect sizes were similar to those in QRSd <120 ms patients. Mortality within the first year was 19% in QRSd 120-149 ms patients (ie, not significantly different from the MAGGIC risk score or SHFM prediction). CONCLUSIONS: CCM significantly improved HF control in NYHA class III HFrEF with reduced ejection fraction patients with moderately prolonged QRSd of 120-149 ms. The effect was comparable to that in patients with QRSd <120 ms.

Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction.

AIMS: Cardiac contractility modulation (CCM) improves symptoms and exercise tolerance and reduces heart failure (HF) hospitalizations over 6-month follow-up in patients with New York Heart Association (NYHA) class III or IV symptoms, QRS < 130 ms and 25% ≤ left ventricular ejection fraction (LVEF) ≤ 45% (FIX-HF-5C study). The current prospective registry study (CCM-REG) aimed to assess the longer-term impact of CCM on hospitalizations and mortality in real-world experience in this same population. METHODS AND RESULTS: A total of 140 patients with 25% ≤ LVEF ≤ 45% receiving CCM therapy (CCM-REG25-45 ) for clinical indications were included. Cardiovascular and HF hospitalizations, Minnesota Living with Heart Failure Questionnaire (MLHFQ) and NYHA class were assessed over 2 years. Mortality was tracked through 3 years and compared with predictions by the Seattle Heart Failure Model (SHFM). A separate analysis was performed on patients with 35% ≤ LVEF ≤ 45% (CCM-REG35-45 ) and 25% ≤ LVEF < 35% (CCM-REG25-34 ). Hospitalizations decreased by 75% (from 1.2/patient-year the year before, to 0.35/patient-year during the 2 years following CCM, P < 0.0001) in CCM-REG25-45 and by a similar amount in CCM-REG35-45 (P < 0.0001) and CCM-REG25-34 . MLHFQ and NYHA class improved in all three cohorts, with progressive improvements over time (P < 0.002). Three-year survival in CCM-REG25-45 (82.8%) and CCM-REG24-34 (79.4%) were similar to those predicted by SHFM (76.7%, P = 0.16; 78.0%, P = 0.81, respectively) and was better than predicted in CCM-REG35-45 (88.0% vs. 74.7%, P = 0.046). CONCLUSION: In real-world experience, CCM produces results similar to those of previous studies in subjects with 25% ≤ LVEF ≤ 45% and QRS < 130 ms; cardiovascular and HF hospitalizations are reduced and MLHFQ and NYHA class are improved. Overall mortality was comparable to that predicted by the SHFM but was lower than predicted in patients with 35% ≤ LVEF ≤ 45%.

Patients Awaiting Heart Transplantation on HVAD Support for Greater Than 2 Years.

Advanced heart failure patients who are classified as bridge to transplant (BTT) often remain on mechanical circulatory support (MCS) for long durations because of the limited supply of donor organs. Here, we present the outcomes of patients who have been supported by the HeartWare ventricular assist device system for more than 2 years. In the HeartWare BTT and continued access protocol trial, 74 of the 382 total patients (19.4%) had more than 2 years of MCS with a mean time of 1,045 days on device. The long-term group was more frequently female, was nonwhite, and had Interagency Registry for Mechanically Assisted Circulatory Support profiles 4-7. Postimplant adverse event rates including bleeding, cardiac arrhythmia, infection, stroke, renal dysfunction, and right heart failure were less frequent in the long-term cohort. In addition, the long-term cohort displayed significant improvements in Kansas City Cardiomyopathy Questionnaire Overall Summary Score, EuroQOL-5D Overall Health State Score, and 6 minute walk scores from baseline values. The rate of heart transplantation was lower for the long-term cohort, which may have been a result of their sex and blood type. However, most of these patients are still listed for cardiac transplantation and maintained their quality of life profiles through 3 years of support.

Gastrointestinal bleeding in recipients of the HeartWare Ventricular Assist System.

OBJECTIVES: This study evaluated gastrointestinal bleeding (GIB) in patients receiving the HeartWare HVAD System (HeartWare Inc., Framingham, Massachusetts) in the pivotal BTT (Bridge to Transplant) trial and under the continued access protocol (CAP). BACKGROUND: GIB has become a significant problem for recipients of continuous flow device left ventricular assist devices (CF-LVAD). The need for anticoagulation and antiplatelet therapies complicates the management of GIB. METHODS: Bleeding events from 382 patients with advanced heart failure (140 patients enrolled in the BTT trial, and an additional 242 CAP patients) were analyzed. Post-implant anticoagulation consisted of heparin followed by warfarin at a target international normalized ratio of 2 to 3. Acetylsalicylic acid was recommended at 81 to 325 mg. RESULTS: Overall, 59 of 382 (15.4%) patients experienced 108 GIB events (0.27 events per patient year). Mean time to first bleed was 273.1 days and 86.1% of events occurred beyond 30 days. Freedom from GIB was 84.1% at 1 year. Median international normalized ratio at the time of first bleed was 2.4 ± 1.4. The most common etiology of bleeding identified was arteriovenous malformation and the most common site was the small intestine. Repeat bleeding was infrequent, though GIB patients required more readmissions and developed nondevice infections more frequently. No patients required surgical intervention and no deaths directly related to GIB occurred. CONCLUSIONS: Recipients of the HeartWare Ventricular Assist Device System had an incidence of 0.27 GIB/patient year with a freedom from GIB of 84.1% at 1 year. All patients with GIB events were managed with medical and endoscopic therapies, although 31% of patients experienced a recurrence of GIB. No surgical intervention was required. GIB did not impact survival. (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure [ADVANCE]; NCT00751972).

An examination of survival by sex and race in the HeartWare Ventricular Assist Device for the Treatment of Advanced Heart Failure (ADVANCE) Bridge to Transplant (BTT) and continued access protocol trials.

BACKGROUND: The Ventricular Assist Device for the Treatment of Advanced Heart Failure (ADVANCE) Bridge to Transplant (BTT) trial was a multicenter, prospective trial of the HeartWare Ventricular Assist Device (HVAD). The performance of the HVAD in various demographic sub-groups was evaluated. METHODS: Baseline characteristics, adverse events, and survival were compared for men vs. women and whites vs. non-whites in the combined ADVANCE BTT and continued access protocol trial. Of 332 patients enrolled in these trials, 236 were men and 96 women, with 228 whites and 104 non-whites. RESULTS: At baseline, women had a smaller body surface area (1.8 ± 0.2 vs. 2.1 ± 0.3 m2, p < 0.0001), less hypertension (50.0% vs. 61.9%, p = 0.05), and less ischemic cardiomyopathy (15.6% vs. 45.3%, p < 0.0001). Differences in Kaplan-Meier survival were not significant at 180 days (men, 91.8%; women, 91.7%) and 1 year (men, 85.3%; women, 85.1%) despite adjustment for baseline differences. Men had a lower incidence of early right heart failure and renal and respiratory dysfunction, and a shorter length of stay. In the analysis by race, non-whites were younger than whites and had less ischemic heart failure, more hypertension, and lower creatinine levels at baseline. Non-whites had lower rates of arrhythmia, bleeding requiring rehospitalization, and device malfunctions than whites. Survival was high in non-whites and whites, at 94.1% vs. 90.4% at 180 days and 89.2% vs. 82.8% at 1 year, respectively, despite adjustment for baseline differences. CONCLUSIONS: Although heart failure etiology differed between men and women and between whites and non-whites, sex and race were not factors that affected survival in patients receiving the HVAD as BTT, which was high in all sub-groups.

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).

Drive-line infections and sepsis in patients receiving the HVAD system as a left ventricular assist device.

BACKGROUND: Drive-line infections and sepsis lead to significant morbidity and even mortality in patients with ventricular assist devices (VADs). The HeartWare HVAD system is unique compared with other VAD systems in that it has a thin, flexible drive-line and is implanted directly into the pericardial space without the need for a pump pocket. We reviewed 332 patients receiving the HVAD in the pivotal ADVANCE Bridge to Transplant (BTT) trial and Continued Access Protocol (CAP) to determine the incidence of drive-line infections and sepsis. METHODS: Summary statistics of outcomes and Kaplan-Meier freedom-from-event analyses were performed. The Cochran-Mantel-Haenszel test for homogeneity was used to determine whether there was any site effect on rates of either drive-line exit-site or sepsis infections. RESULTS: Drive-line exit-site infections occurred in 16.9% (56 of 332) of patients (0.25 event per patient-year [EPPY]). These infections were primarily treated with antibiotics and most occurred >30 days post-implant (88%, or 66 of 75 drive-line infections). Sepsis occurred in 17.2% (57 of 332) of patients (0.23 EPPY), and sepsis events occurred more frequently >30 days post-implant (86%, or 60 of 70 sepsis events). Of patients with sepsis, 17.5% (10 of 57) died due to sepsis-related neurologic events (7 of 10) and multisystem organ failure (2 of 10) and cardiopulmonary failure (1 of 10), whereas there were no deaths related to drive-line infections. In addition, 17.5% (10 of 57) of patients had a stroke event while under treatment for sepsis (7 hemorrhagic and 3 ischemic strokes), and 3.5% (2 of 57 patients with sepsis) had a device exchange for VAD thrombus (4 days before and 1 day after sepsis diagnosis). Patients with drive-line infections or sepsis had a larger body mass index compared to those without infection (29.4 vs 27.6 kg/m(2), p = 0.015), and were more frequently diabetic (43.7% vs 31.2%, p = 0.034). Although there was no negative impact on survival in patients with drive-line exit-site infections, there was a trend for reduced survival in patients with sepsis events when compared to those patients without sepsis. CONCLUSIONS: The incidence of drive-line infection and sepsis was low in patients receiving the HVAD pump. Despite a trend toward reduced survival in patients with sepsis events, the overall survival of patients with either drive-line infections or sepsis was excellent.

Results of the post-market Registry to Evaluate the HeartWare Left Ventricular Assist System (ReVOLVE).

BACKGROUND: The post-market Registry to Evaluate the HeartWare Left Ventricular Assist System (ReVOLVE) is an investigator-initiated registry established to collect post-CE Mark Trial clinical data on patients receiving a HeartWare ventricular assist device (HVAD) in the European Union and Australia. METHODS: The ReVOLVE is a multi-center, prospective, single-arm registry performed at seven centers in Europe and two in Australia. Herein we describe a total of 254 commercial HVAD implants according to labeled indications between February 2009 and November 2012. Summary statistics included patients' demographics, adverse events, length of support and outcomes. RESULTS: Compared with the clinical trial supporting the CE Mark of the HeartWare system, patient selection differed in that patients were older, and there were higher proportions of females and patients with idiopathic cardiomyopathies in the ReVOLVE cohort. Duration of support ranged from 1 to 1,057 days, with a mean of 363 ± 280 days (median 299.5 days). Transplantation was done in 56 patients (22%), explant for recovery was performed in 3 patients (1%), 43 died while on support (17%), and 152 (60%) remain on the device. Success in patients with the HeartWare system was 87% at 6 months, 85% at 1 year, 79% at 2 years and 73% at 3 years. Adverse event rates were low, comparable or improved when compared to the CE Mark Trial. CONCLUSION: Real-world use of the HeartWare system continues to demonstrate excellent clinical outcomes in patients supported with the device.

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.

HeartWare ventricular assist system for bridge to transplant: combined results of the bridge to transplant and continued access protocol trial.

BACKGROUND: The HeartWare Ventricular Assist System (HeartWare Inc, Framingmam, MA) is a miniaturized implantable, centrifugal design, continuous-flow blood pump. The pivotal bridge to transplant and continued access protocols trials have enrolled patients with advanced heart failure in a bridge-to-transplant indication. METHODS: The primary outcome, success, was defined as survival on the originally implanted device, transplant, or explant for ventricular recovery at 180 days. Secondary outcomes included an evaluation of survival, functional and quality of life outcomes, and adverse events. RESULTS: A total of 332 patients in the pivotal bridge to transplant and continued access protocols trial have completed their 180-day primary end-point assessment. Survival in patients receiving the HeartWare pump was 91% at 180 days and 84% at 360 days. Quality of life scores improved significantly, and adverse event rates remain low. CONCLUSIONS: The use of the HeartWare pump as a bridge to transplant continues to demonstrate a high 180-day survival rate despite a low rate of transplant. Adverse event rates are similar or better than those observed in historical bridge-to-transplant trials, despite longer exposure times due to longer survival and lower transplant rates.

Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.

PURPOSE: To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. PATIENTS AND METHODS: Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13). RESULTS: Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. CONCLUSION: Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.

Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma.

The prompt response to bortezomib observed in a 63-year-old woman with multiple myeloma was associated with a significant increase in alkaline phosphatase (ALP). After similar elevations were noted in patients responding to bortezomib, thalidomide, dexamethasone combination, ALP levels were analysed in two large bortezomib trials. A statistically significant elevation of ALP from baseline was observed in responding patients (complete and partial responders) within three cycles of therapy. The rise in ALP after bortezomib in three patients was explained by a parallel increase in bone-specific ALP and parathyroid hormone, suggesting that response to bortezomib in myeloma is closely associated with osteoblastic activation.