Shane J. LaRue

Decreased Cardiac Functional Reserve in Heart Failure with Preserved Systolic Function

BACKGROUND Heart failure in patients with preserved left ventricular systolic function (HFpEF) is a prevalent disease characterized by exercise intolerance with poorly understood pathophysiology. We hypothesized that recruitable contractility is impaired in HFpEF, accounting for the appearance of symptoms with exertion. METHODS AND RESULTS Echocardiographic analysis of myocardial performance was performed at baseline and after a modified dobutamine protocol (max dose 16 μg/kg/min) in participants with known HFpEF and age- and gender-matched controls. The primary outcome variable was change in contractile reserve, measured as a change in ejection fraction (EF). Recruitable contractility was decreased in HFpEF participants compared with control subjects (HFpEF 0.4 ± 1.9% vs control 19.0 ± 1.4%; P < .001). During dobutamine infusion, velocities increased in control participants but remained unchanged in the HFpEF group, yielding a significant difference between groups (P < .05) for both longitudinal displacement and velocity. CONCLUSIONS Patients with HFpEF have an impaired contractile response to adrenergic stimulation. The blunted response to adrenergic stimulation in the HFpEF group suggests that these patients may be unable to respond to periods of increased cardiac demand. This inability to increase contractility appropriately suggests abnormalities of systolic function in this disease and may contribute to exertional intolerance in HFpEF.

Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial.

Importance Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. Objective To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. Design, Setting, and Participants Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites. Interventions Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. Main Outcomes and Measures The primary end point was a change in peak oxygen uptake (V[Combining Dot Above]O2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). Results Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V[Combining Dot Above]O2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V[Combining Dot Above]O2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs −2 mL/min; difference, 21 mL/min [95% CI, −34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (−13 m; 95% CI, −32 to 6 m), NT-proBNP levels (159; 95% CI, −280 to 599 pg/mL), or KCCQ score (1; 95% CI, −2.4 to 4.4), all P > .05. Conclusions and Relevance Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. Trial Registration clinicaltrials.gov Identifier: NCT02188784

Systolic blood pressure on discharge after left ventricular assist device insertion is associated with subsequent stroke

BACKGROUND Stroke is a significant complication in patients supported with continuous-flow left ventricular assist devices (CF-LVAD) and hypertension is a significant risk factor for stroke, but the association between blood pressure and stroke in LVAD patients is not well characterized. METHODS We identified 275 consecutive patients who survived implant hospitalization between January 2005 and April 2013. Patients were grouped according to systolic blood pressure (SBP) as above a median and below a median of 100 mm Hg by their averaged systolic blood pressure during the 48 hours before discharge from implantation hospitalization. The groups were compared for the primary outcome of time to stroke. RESULTS The above-median SBP group had mean SBP of 110 mm Hg and the below-median SBP group had mean SBP of 95 mm Hg. There were no significant between-group differences in body mass index, smoking, vascular disease, hypertension, atrial fibrillation, or prior stroke. During a mean follow-up of 16 months, stroke occurred in 16% of the above-median SBP group vs in 7% of the below-median SBP group (hazard ratio, 2.38; 95% confidence interval, 1.11-5.11), with a similar proportion of hemorrhagic and ischemic strokes in each group. In Cox proportional hazard models adjusting for age, diabetes, or prior stroke, the hazard ratio remained statistically significant. SBP as a continuous variable predictor of stroke had an area under the curve of 0.64 in a receiver operating characteristic curve analysis. CONCLUSIONS In this large, CF-LVAD cohort, elevated SBP was independently associated with a greater risk of subsequent stroke. These results identify management of hypertension as a potential modifiable risk factor for reducing the incidence of stroke in patients supported by CF-LVAD.

Relationship Between Anticoagulation Intensity and Thrombotic or Bleeding Outcomes Among Outpatients With Continuous-Flow Left Ventricular Assist Devices

Background—We evaluated thrombotic and bleeding outcomes in patients with continuous-flow left ventricular assist devices (CF-LVADs), stratified by anticoagulation intensity. Previous studies of outpatients with CF-LVADs have suggested that target international normalized ratio (INR) values <2.5 (range, 2–3) may be used. However, recent studies reported an increase in pump thrombosis among CF-LVADs, especially within the first 6 months of implant. Methods and Results—We retrospectively reviewed 249 outpatients at our center who received a CF-LVAD between January 2005 and August 2013. Using Poisson models, we analyzed their 10 927 INRs to determine INR-specific rates of thrombotic (ischemic stroke and suspected pump thrombosis) and hemorrhagic (gastrointestinal bleeding and hemorrhagic stroke) events occurring outside of the hospital. In multivariate analyses, we adjusted for age, sex, atrial fibrillation, coronary disease, and LVAD type as time-dependent Cox proportional hazard models. During a mean follow-up of 17.6±13.6 months, thrombotic events occurred in 46 outpatients. The highest event rate (0.40 thrombotic events per patient-year) was in the INR range of <1.5, but INR values of 1.5 to 1.99 also had high rates (0.16 thrombotic events per patient-year). INR was inversely associated with thrombotic events (hazard ratio, 0.40; 95% confidence interval, 0.22–0.72; P=0.002). The optimal INR based on weighted mortality of thrombotic and bleeding events was 2.6. Conclusions—INR is inversely related to thrombotic events occurring outside of the hospital among patients supported with CF-LVADs. INR values <2.0 increase the rate of thrombotic events occurring outside of the hospital among patients supported with CF-LVADs.

Educational Resources for Patients Considering a Left Ventricular Assist Device

Background—Left ventricular assist devices (LVADs) are being used with increasing frequency to treat severe heart failure. Patients seek out informational resources when considering implantation. The primary study objective was to characterize the scope and quality of available LVAD educational materials. Methods and Results—In July 2013, we performed a cross-sectional search of Internet, print, and multimedia resources available to patients considering LVAD. Written materials <10 sentences, videos <2 minutes, and materials clearly directed to healthcare professionals were excluded. Seventy-seven materials met inclusion criteria. Potential benefits of LVAD therapy were discussed in all (n=77), whereas less often mentioned were risks (n=43), lifestyle considerations (n=29), surgical details (n=26), caregiver information (n=9), and hospice or palliative care (n=2). Of the 14 materials that recognized a decision or alternate treatment option, 7 used outdated statistics, 12 scored above an eighth grade reading comprehension level, and 12 met <50% of International Patient Decision Aid Standards criteria. In the survey participants rated all but one as biased toward accepting LVAD therapy. Conclusions—Although many resources exist for patients considering an LVAD, the content is suboptimal. Benefits of LVADs are often presented in the absence of risks, alternative options, and caregiver considerations. Most materials use outdated statistics, are above the reading level of average Americans, and are biased toward accepting LVAD therapy. There is no tool that would qualify as a formal decision aid.

Timing and Causes of Readmission After Acute Heart Failure Hospitalization—Insights From the Heart Failure Network Trials

BACKGROUND Readmission or death after heart failure (HF) hospitalization is a consequential and closely scrutinized outcome, but risk factors may vary by population. We characterized the risk factors for post-discharge readmission/death in subjects treated for acute heart failure (AHF). METHODS AND RESULTS A post hoc analysis was performed on data from 744 subjects enrolled in 3 AHF trials conducted within the Heart Failure Network (HFN): Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE-AHF), Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), and Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF). All-cause readmission/death occurred in 26% and 38% of subjects within 30 and 60 days of discharge, respectively. Non-HF cardiovascular causes of readmission were more common in the ≤30-day timeframe than in the 31-60-day timeframe (23% vs 10%, P = .016). In a Cox proportional hazards model adjusting a priori for left ventricular ejection fraction <50% and trial, the risk factors for all-cause readmission/death included: elevated baseline blood urea nitrogen, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) non-use, lower baseline sodium, non-white race, elevated baseline bicarbonate, lower systolic blood pressure at discharge or day 7, depression, increased length of stay, and male sex. CONCLUSIONS In an AHF population with prominent congestion and prevalent renal dysfunction, early readmissions were more likely to be due to non-HF cardiovascular causes compared with later readmissions. The association between use of ACEI/ARB and lower all-cause readmission/death in Cox proportional hazards model suggests a role for these drugs to improve post-discharge outcomes in AHF.

A Multicenter Trial of a Shared Decision Support Intervention for Patients and Their Caregivers Offered Destination Therapy for Advanced Heart Failure: Decide-lvad

Background:Shared decision making is important to ensure that patients receive therapies aligned with their goals and values. Based upon a detailed needs assessment with diverse stakeholders, pamphlet and video decision aids for destination therapy left ventricular assist devices (DT LVAD) were developed to help patients and their caregivers think through, forecast, and deliberate their options. These decision aids are the foundation of the Multicenter Trial of a Shared Decision Support Intervention for Patients and their Caregivers Offered Destination Therapy for End-Stage Heart Failure (DECIDE-LVAD) study, a multicenter, randomized trial aimed at understanding the effectiveness and implementation of a shared decision support intervention for patients considering DT LVAD. Methods/Design:A stepped-wedge randomized controlled trial was designed, guided by the RE-AIM framework and modeled after an effectiveness-implementation hybrid type II design. Six DT LVAD programs from across the United States will participate. Primary outcomes include knowledge and values-treatment concordance. Patients with advanced heart failure who are being considered for DT LVAD and their caregivers are eligible with a target enrollment of 168 dyads. From August 2014 to January 2015, an acceptability and feasibility pilot study was performed, which clarified opportunities and challenges around decision support for DT LVAD and resulted in significant modifications to the DECIDE-LVAD study. Discussion:Study findings will provide a foundation for implementing decision support interventions, including decision aids, with patients who have chronic progressive illness facing end-of-life decisions involving invasive, preference-sensitive therapy options.

Left ventricular assist device in pregnancy.

BACKGROUND: Left ventricular assist devices have become increasingly common for the treatment of acute and chronic heart failure. It is unclear whether these devices can handle the increased stresses caused by pregnancy. CASE: An 18-year-old woman received a left ventricular assist device after peripartum cardiomyopathy. The patient was not adherent to prescribed medical regimens until she returned 11 months later, at 33 weeks of gestation. She underwent anticoagulation and inpatient surveillance until a cesarean delivery at approximately 34 weeks (based on ultrasound estimates). CONCLUSION: Left ventricular assist devices are allowing patients to live with minimal symptoms of heart failure and return to a good quality of life.

Clinical outcomes associated with INTERMACS-defined right heart failure after left ventricular assist device implantation

Background: Left Ventricular Assist Device (LVAD) pump thrombosis (PT) is a devastating complication of mechanical circulatory support. The diagnosis of LVAD thrombus is difficult in vivo, often only suggested by markers of hemolysis and echocardiographic features, which lack sensitivity. We sought to test a probe with high avidity anti-fibrin 99mTc to localize and quantify thrombus within the high shear environment of titanium axial-flow pumps. Methods: Monomeric bifunctional ligands with a fibrin-specific peptide, a short spacer, and technetium chelating amino acid sequence (F1A) were covalently inter-coupled via a 4-arm-PEG2000 tetramer to form F4A. Each was radiolabeled with 99mTc using the IsoLink procedure. We collected 20 explanted HeartMate II LVADs, of which 9 were explanted for suspected pump thrombosis and 11 were explanted during heart transplant or exchange for other complications. Ex-vivo imaging of explanted pumps was conducted in plasma using a mock circulatory loop running at 9400 RPM for 30 minutes as has previously been described. After imaging the devices were sent to the manufacturer for disassembly and thorough inspection for thrombus. Results: The majority of patients were male (85%) with a mean age of 54.1 6 9.8 and a median INTERMACS profile of 2. The median time of LVAD support prior to explant was 7.6 6 7.2 months. Of the 9 patients exchanged for suspected pump thrombosis all had undetectable haptoglobin levels and mean LDH levels of 3520 6 2596. All 9 had CT scans prior to LVAD exchange without any visualized thrombus or kinking of the inflow or outflow cannulas. Two of the pumps have been disassembled and inspected by the manufacturer. Both pumps were in patients with suspected pump thrombosis and both the pumps had thrombus found on SPECT imaging and on visual inspection (Figure 1A and 1B). Conclusions: A novel, fibrin-specific 99mTc small tetrameric probe offers the potential to detect, localize, and quantify intra-LVAD thrombus noninvasively. Once verified in a large cohort this agent offers the opportunity to diagnose LVAD pump thrombosis at an earlier stage. Definite and early diagnosis may confer therapeutic options to avoid pump failure and/or costly and morbid LVAD exchange.

Video capsule endoscopy in left ventricular assist device recipients with obscure gastrointestinal bleeding.

AIM To assess whether video capsule endoscopy (VCE) affects the outcomes of left ventricular assist devices (LVADs) recipients with gastrointestinal bleeding. METHODS This is a retrospective study of LVAD recipients with obscure gastrointestinal bleeding (OGIB) who underwent VCE at a tertiary medical center between 2005 and 2013. All patients were admitted and monitored with telemetry and all VCE and subsequent endoscopic procedures were performed as inpatients. A VCE study was considered positive only when P2 lesions were found and was regarded as negative if P1 or P0 were identified. All patients were followed until heart transplant, death, or the end of the study. RESULTS Between 2005 and 2013, 30 patients with LVAD underwent VCE. Completion rate of VCE was 93.3% and there was no capsule retention. No interference of VCE recording or the function of LVAD was found. VCE was positive in 40% of patients (n = 12). The most common finding was active small intestinal bleeding (50%) and small intestinal angiodysplasia (33.3%). There was no difference in the rate of recurrent bleeding between patients with positive and negative VCE study (50.0% vs 55.6%, P = 1.00) during an average of 11.6 ± 9.6 mo follow up. Among patients with positive VCE, the recurrent bleeding rate did not differ whether subsequent endoscopy was performed (50% vs 50%, P = 1.00). CONCLUSION VCE can be safely performed in LVAD recipients with a diagnostic yield of 40%. VCE does not affect recurrent bleeding in LVAD patients regardless of findings.