Sex differences in eligibility for advanced heart failure therapies.

OBJECTIVES: We investigated sex-based differences in eligibility for and outcomes after receipt of advanced heart failure (HF) therapies. BACKGROUND: Although women are more likely to die from HF than men, registry data suggest that women are less likely to receive heart transplant (HT) or left ventricular assist device (LVAD) for largely unknown reasons. METHODS: We performed a single-center retrospective cohort study of patients evaluated for advanced HF therapies from 2012 to 2016. Logistic regression was used to determine the association of sex with eligibility for HT/LVAD. Competing risks and Kaplan-Meier analysis were used to examine survival. RESULTS: Of 569 patients (31% women) evaluated, 223 (39.2%) were listed for HT and 81 (14.2%) received destination (DT) LVAD. Women were less likely to be listed for HT (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.21-0.61; P < .0001), based on allosensitization (P < .0001) and obesity (P = .02). Women were more likely to receive DT LVAD (adjusted OR 2.29, 95% CI 1.23-4.29; P = .01). Survival was similar between men and women regardless of whether they received HT and DT LVAD or were ineligible for therapy. CONCLUSION: Women are less likely to be HT candidates, but more likely to receive DT LVAD.

Validating patient prioritization in the 2018 Revised United Network for Organ Sharing Heart Allocation System: A single-center experience.

The 2018 Revised United Network for Organ Sharing Heart Allocation System (HAS) was proposed to reclassify status 1A candidates into groups of decreasing acuity; however, it does not take into account factors such as body mass index (BMI) and blood group which influence waitlist (WL) outcomes. We sought to validate patient prioritization in the new HAS at our center. We retrospectively evaluated patients listed for heart transplantation (n = 214) at Emory University Hospital from 2011 to 2017. Patients were reclassified into the 6-tier HAS. Multistate modeling and competing risk analysis were used to compare outcomes of transplantation and WL death/deterioration between new tiers. Additionally, a stratified sensitivity analysis by BMI and blood group was performed. Compared with tier 4 patients, there was progressively increasing hazard of WL death/deterioration in tier 3 (HR: 2.52, 95% CI: 1.37-4.63, P = .003) and tier 2 (HR: 5.03, 95% CI: 1.99-12.70, P < .001), without a difference in transplantation outcome. When stratified by BMI and blood group, this hierarchical association was not valid in patients with BMI ≥30 kg/m2 and non-O blood groups in our cohort. Therefore, the 2018 HAS accurately prioritizes the sickest patients in our cohort. Factors such as BMI and blood group influence this relationship and iterate that the system can be further refined.

De novo DQ donor-specific antibodies are associated with worse outcomes compared to non-DQ de novo donor-specific antibodies following heart transplantation.

BACKGROUND: Antibody-mediated rejection (AMR) resulting from de novo donor-specific antibodies (dnDSA) leads to adverse outcomes following heart transplantation (HTx). It remains unclear what role dnDSA to specific HLA antigens play in adverse outcomes. This study compares outcomes in patients developing dnDSA to DQ antigens with those developing non-DQ dnDSA and those free from dnDSA. METHODS: The present study was a single-center, retrospective analysis of 122 consecutive HTx recipients. The primary outcome was a composite of death or graft dysfunction. RESULTS: After 3.3 years of follow-up, 31 (28%) patients developed dnDSA. Mean time to dnDSA was 539 days. Of 31 patients, 19 developed DQ antibodies and 12 developed non-DQ antibodies. Compared to non-DQ dnDSA, DQ antibodies presented with higher MFI values (P=.001) were more likely persistent (P=.001) and appeared later post-HTx (654 vs 359 days, P=.035). In a multivariable analysis, DQ dnDSA was associated with increased risk of the primary endpoint (HR 6.15, 95% CI 2.57-14.75, P=.001), whereas no increased risk was seen with non-DQ dnDSA (P=.749). CONCLUSIONS: dnDSA to DQ antigens following HTx are associated with increased risk of death and graft dysfunction.

Improved Outcomes for Women on the Heart Transplant Wait List in the Modern Era.

BACKGROUND: Whether the routine use of continuous-flow left ventricular assist devices (LVAD) has affected gender differences in outcomes for patients listed for heart transplantation (HT) is unclear. METHODS AND RESULTS: We identified 20,468 adults (25% women) listed as status 1A or 1B for HT from 2000 to 2014. Sex differences in removal from the wait list during the first 365 days due to death or deterioration was assessed with the use of Kaplan-Meier survival analysis. Patients were stratified according to listing before (era 1) or after (era 2) Food and Drug Administration approval of the Heartmate II LVAD on April 22, 2008. Freedom from death or deterioration on the wait list was higher for men than for women (70% vs 64%; P < .001). After adjusting for risk factors, women had a higher risk of removal from the wait list at 365 days during both era 1 (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.10-1.36; P < .001) and era 2 (HR 1.15, 95% CI 1.01-1.31; P = .029). Further adjustment for LVAD use eliminated the higher risk for women in era 2 (HR 1.14, 95% CI 0.99-1.29; P = .053) and not in era 1 (HR 1.22, 95% CI 1.10-1.36; P < .001). CONCLUSIONS: The higher risk for death or deterioration in women waiting for HT has improved in the modern era.

Mortality in status 2 patients listed for heart transplantation in the United States: Will understanding cause of death help justify implantation of left ventricular assist devices into less sick patients?

OBJECTIVE: It remains unclear whether left ventricular assist device (LVAD) implantation in non-inotrope dependent patients is of clinical benefit. This study sought to evaluate cause of death in patients listed for heart transplant (HT) to determine the relative risks and benefits of implanting LVAD into patients who are less sick than those included in the original clinical trials. METHODS: We examined death as the primary outcome in 23,098 patients listed for HT from 2006 to 2014 using proportional subdistribution hazards modeling. Cause of death was examined as a secondary outcome using χ2 tests. RESULTS: 1859 (8.1%) patients were removed from the wait list for death, including 229 (2.7%) status 1A, 349 (4.6%) status 1B, 246 (13.2%) status 2, and 1035 (26.0%) status 7 patients (P < 0.0001). Status 2 patients who received LVAD while listed had a higher risk of death compared to those who did not (adjusted HR 1.68; 95% CI 1.09-2.59; P = 0.02), while there was no increased risk of death in status 1A (HR 1.02; 95% CI 0.68-1.51; P = 0.9) and status 1B (HR 0.89; 95% CI 0.65-1.23; P = 0.5) who received LVAD. Status 2 patients who received LVAD were more likely to die cerebrovascular causes (0.6% vs. 0.1%, P = 0.009) and organ failure (70.6% vs. 29.4%, P = 0.003). CONCLUSIONS: LVAD implantation in status 2 patients listed for HT is associated with a higher risk of death. More research is needed to determine the impact LVAD implantation will have on mortality in patients with ambulatory, non-inotrope dependent HF.

Decisional regret in left ventricular assist device patient-caregiver dyads.

BACKGROUND: The objective of this study was to investigate decisional regret among left ventricular assist device (LVAD) patients and their caregivers. METHODS: This study was a single center, cross-sectional survey of patients after LVAD implantation and their caregivers. Subjects were recruited at their outpatient heart failure appointments. Patients and caregivers at least three months from LVAD implantation completed a 5-item, validated decisional regret scale. Summative scores on a 0-100 point scale were determined for patient and caregivers (0 = no regret). Subgroup analysis included gender, LVAD indication (bridge to transplant (BTT) or destination therapy (DT)), time from LVAD implantation, and caregiver relationship. Dyad discordance was defined as a patient-caregiver difference of ≥2 points on any regret scale question. RESULTS: Fifty patients were approached for participation. Thirty-three LVAD patient-caregiver dyads were enrolled in the study (19 male, 14 female patients; 8 male, 25 female caregivers). Patients had a mean age of approximately 50 years. Caregivers had a mean age of approximately 54 years. Patients had a median regret score of 10 (Interquartile range (IQR): 0-30), while caregivers had a median regret score of 20 (IQR: 0-25). Median regret scores of female patients were significantly higher than that of male patients (27.5 vs 0, p = 0.0038). BTT patients had numerically lower regret than DT patients, but this was not statistically significant. Patients who had been implanted for greater than three years had the highest regret scores. Discordance in at least one domain of the regret scale was present in 19 out of 33 (57.6%) dyads. CONCLUSIONS: While decisional regret was reasonably low in this population, comparatively, there was significantly increased decisional regret among female patients and patients further from LVAD implantation. Differences between patients and caregivers were also observed. These findings highlight the need for robust support and continual attention to expectations before and after LVAD implantation.

Racial differences in the development of de-novo donor-specific antibodies and treated antibody-mediated rejection after heart transplantation.

BACKGROUND: Despite improvements in outcomes after heart transplantation, black recipients have worse survival compared with non-black recipients. The source of such disparate outcomes remains largely unknown. We hypothesize that a propensity to generate de-novo donor-specific antibodies (dnDSA) and subsequent antibody-mediated rejection (AMR) may account for racial differences in sub-optimal outcomes after heart transplant. In this study we aimed to determine the role of dnDSA and AMR in racial disparities in post-transplant outcomes. METHODS: This study was a single-center, retrospective analysis of 137 heart transplant recipients (81% male, 48% black) discharged from Emory University Hospital. Patients were classified as black vs non-black for the purpose of our analysis. Kaplan-Meier and Cox regression analyses were used to evaluate the association between race and selected outcomes. The primary outcome was the development of dnDSA. Secondary outcomes included treated AMR and a composite of all-cause graft dysfunction or death. RESULTS: After 3.7 years of follow-up, 39 (28.5%) patients developed dnDSA and 19 (13.8%) were treated for AMR. In multivariable models, black race was associated with a higher risk of developing dnDSA (hazard ratio [HR] 3.65, 95% confidence interval [CI] 1.54 to 8.65, p = 0.003) and a higher risk of treated AMR (HR 4.86, 95% CI 1.26 to 18.72, p = 0.021) compared with non-black race. Black race was also associated with a higher risk of all-cause graft dysfunction or death in univariate analyses (HR 2.10, 95% CI 1.02 to 4.30, p = 0.044). However, in a multivariable model incorporating dnDSA, black race was no longer a significant risk factor. Only dnDSA development was significantly associated with all-cause graft dysfunction or death (HR 4.85, 95% CI 1.89 to 12.44, p = 0.001). CONCLUSION: Black transplant recipients are at higher risk for the development of dnDSA and treated AMR, which may account for racial disparities in outcomes after heart transplantation.

Novel therapies for heart failure: vasopressin and selective aldosterone antagonists.

Despite favorable improvements in mortality, heart failure (HF) remains a problematic illness due to the ever-present burden of hospitalization. Clearly, novel treatment strategies are needed. This review focuses on two newer pharmacologic targets: arginine vasopressin and aldosterone. Arginine vasopressin receptor antagonists will most likely serve as an adjunct to or replacement of standard diuretic therapy in selected patients. The safety and efficacy of chronic therapy with oral arginine vasopressin receptor antagonists in large groups of congestive HF patients is currently under investigation. Aldosterone antagonism is emerging as a treatment of severe congestive HF. Recent large-scale clinical trials using aldosterone antagonists have proven that those with HF or left ventricular dysfunction postmyocardial infarction derive a survival benefit from aldosterone antagonism. Whether aldosterone antagonism should be prescribed in all patients with HF is unclear; however, in carefully selected and managed patients, aldosterone antagonism is helpful.

Gender differences in the risk of stroke during support with continuous-flow left ventricular assist device.

BACKGROUND: There is increasing recognition that the risk of stroke after left ventricular assist device (LVAD) implantation varies based on gender, with a higher risk in female patients. We reviewed our own data to determine gender differences in the risk of stroke. METHODS: Frequency of stroke, including intracranial hemorrhage and ischemic stroke, was retrospectively evaluated in 110 heart failure patients (mean age 49.6 ± 13.6 years, 32% women) discharged from the hospital after implantation of a HeartMate II (N = 74) or HeartWare (N = 36) LVAD. Competing outcomes analysis was used to determine which clinical risk factors were associated with the risk of stroke and death, with the primary end-point being time to first stroke event. RESULTS: During a median follow-up of 1.3 years, 26 patients had a stroke (23.6%, 0.14 case per person-year). The median time to first stroke was 0.7 (interquartile range 0.3 to 1.4) years. After adjusting for covariates, risk of stroke was higher for women than for men (hazard ratio 3.1, 95% confidence interval 1.4 to 6.9; p = 0.007). There was no difference in overall survival between men and women. CONCLUSION: The risk of stroke after LVAD varies based on gender, with a higher risk in female patients. More research is needed to fully understand these differences, and whether device management strategies should be tailored based on gender.

Emergency department visits and hospitalizations for digoxin toxicity: United States, 2005 to 2010.

BACKGROUND: Recent data on digoxin prescribing and adverse events are lacking but could help inform the management of digoxin in contemporary heart failure treatment. METHODS AND RESULTS: We determined nationally representative numbers and rates of emergency department (ED) visits for digoxin toxicity in the United States using 2005 to 2010 reports from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project and the National Ambulatory (and Hospital Ambulatory) Medical Care Surveys. Based on 441 cases, an estimated 5156 (95% confidence interval [CI], 2663-7648) ED visits for digoxin toxicity occurred annually in the United States; more than three fourths (78.8% [95% CI, 73.5%-84.1%]) resulted in hospitalization. Serum digoxin level was ≥2.0 ng/mL for 95.8% (95% CI, 93.2%-98.4%) of estimated ED visits with levels reported (n=251 cases). The rate of ED visits per 10 000 outpatient prescription visits among patients≥85 years was twice that of patients 40 to 84 years (rate ratio, 2.4 [95% CI, 1.2-5.0]); among women, the rate was twice that of men (rate ratio, 2.3 [95% CI, 1.1-4.7]). Digoxin toxicity accounted for an estimated 1.0% (95% CI, 0.6%-1.4%) of ED visits for all adverse drug events among patients≥40 years, but an estimated 3.3% (95% CI, 2.3%-4.4%) of ED visits and 5.9% (95% CI, 4.0%-7.9%) of hospitalizations for all adverse drug events among patients≥85 years. Estimated annual ED visits and hospitalizations remained relatively constant from 2005 to 2010. CONCLUSIONS: Digoxin toxicity is not declining; more careful prescribing to high-risk groups and improved monitoring of serum levels might be needed to reduce morbidity from outpatient digoxin use.

Influence of race/ethnic differences in pre-transplantation panel reactive antibody on outcomes in heart transplant recipients.

OBJECTIVES: This study sought to investigate post-transplantation outcomes as a function of race and panel reactive antibody (PRA). BACKGROUND: PRA screening is used to determine the presence of pre-formed antibodies to population-wide human leukocyte antigens (HLAs) in patients being evaluated for heart transplantation (HT). Racial/ethnic differences in long-term survival after HT have been described. However, whether there are significant racial/ethnic differences in PRA among adults awaiting HT is poorly characterized. METHODS: We identified patients age ≥18 years in the Organ Procurement and Transplantation database with race/ethnicity of white, black, Hispanic, or Asian and listed for HT between 2000 and 2012 (N = 19,704). A PRA value of ≥10% was used to define clinically meaningful sensitization. RESULTS: Blacks had a higher peak PRA than did all other groups and were more likely to be sensitized. Black HT recipients were more likely to experience graft failure than were Hispanic, white, and Asian recipients (31% vs. 27%, 26%, and 21%, respectively; p < 0.001). The median follow-up was 1,207 days (interquartile range: 373 to 2,364 days), with a trend toward a shorter median time to graft failure in the Asian group than in the black, Hispanic, and white groups (p = 0.065). Sensitized blacks had the lowest rate of allograft survival, whereas nonsensitized Asians had the highest survival. Using Cox proportional regression to adjust for other clinical variables, black race (HR: 1.3; 95% confidence interval [CI]: 1.2 to 1.5), Hispanic ethnicity (HR: 1.2; 95% CI: 1.0 to 1.5), and sensitization (HR: 1.2; 95% CI: 1.1 to 1.4) remained predictors of higher rates of graft failure. CONCLUSIONS: Race/ethnicity and level of sensitization are important predictors of graft survival.

The prognostic significance of renal dysfunction in patients with chronic systolic heart failure.

Renal insufficiency is an independent powerful predictor of morbidity and mortality in a number of cardiovascular disorders. A number of retrospective analyses of large heart failure trials have shown that even mild renal insufficiency has powerful negative predictive power in patients with both mild and severe heart failure. We discuss the available data on the prognostic value of mild renal insufficiency in heart failure, as well as possible mechanisms of this phenomenon. Future research should focus on its possible pathophysiology.