Remote Hemodynamic Monitoring Equally Reduces Heart Failure Hospitalizations in Women and Men in Clinical Practice: A Sex-Specific Analysis of the CardioMEMS Post-Approval Study.

BACKGROUND: Response to pharmacological and device-based therapy for heart failure (HF) may vary by sex. We examined sex differences in response to ambulatory hemodynamic monitoring in clinical practice using the CardioMEMS PAS (Post-Approval Study). METHODS: The CardioMEMS PAS was a prospective, single-arm, multicenter, open-label study of 1200 adults with New York Heart Association class III HF and at least 1 HF hospitalization (HFH) within 12 months who underwent pulmonary artery pressure sensor implantation between 2014 and 2017. Changes in pulmonary artery pressure over time were stratified by ejection fraction <40% and sex. Clinical outcomes including HFH rate at 12 months, 1-year mortality, and quality of life were examined in women and men. RESULTS: Four hundred fifty-two women (38% of total) enrolled in the PAS were less likely to be White (78% versus 86%) and more likely to have nonischemic cardiomyopathy (44% versus 34%) and had significantly higher SBP (132 versus 124 mm Hg), mean ejection fraction (44% versus 36%), and pulmonary vascular resistance (3.2 versus 2.6 WU) than men (P<0.001 for all). There were similar reductions in pulmonary artery pressure from baseline to 12 months in both men and women for the whole cohort and for subgroups with HF with reduced ejection fraction and HF with preserved ejection fraction. Both sexes experienced significant decreases in HFH over 12 months (men: HR, 0.46 [95% CI, 0.40-0.52]; women: HR, 0.39 [95% CI, 0.33-0.46]). In adjusted models, there were no significant differences in change in HFH between men and women (interaction P=0.13) or all-cause mortality at 1 year (adjusted HR, 1.25 [95% CI, 0.88-1.77]). CONCLUSIONS: Women and men enrolled in the CardioMEMS PAS had similar reductions from baseline in pulmonary artery pressure over 1 year and experienced similar reductions in HFH. Hemodynamic monitoring provides similar benefit with regard to HF events in both women and men. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02279888.

Causes of Cardiovascular Hospitalization and Death in Patients With Transthyretin Amyloid Cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]).

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT. Clinical trial registration ClinicalTrials.gov: NCT01994889.

Cause of Death in Patients With Acute Heart Failure: Insights From RELAX-AHF-2.

OBJECTIVES: This study sought to better understand the discrepant results of 2 trials of serelaxin on acute heart failure (AHF) and short-term mortality after AHF by analyzing causes of death of patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF-2) trial. BACKGROUND: Patients with AHF continue to suffer significant short-term mortality, but limited systematic analyses of causes of death in this patient population are available. METHODS: Adjudicated cause of death of patients in RELAX-AHF-2, a randomized, double-blind, placebo-controlled trial of serelaxin in patients with AHF across the spectrum of ejection fraction (EF), was analyzed. RESULTS: By 180 days of follow-up, 11.5% of patients in RELAX-AHF-2 died, primarily due to heart failure (HF) (38% of all deaths). Unlike RELAX-AHF, there was no apparent effect of treatment with serelaxin on any category of cause of death. Older patients (≥75 years) had higher rates of mortality (14.2% vs. 8.8%) and noncardiovascular (CV) death (27% vs. 19%) compared to younger patients. Patients with preserved EF (≥50%) had lower rates of HF-related mortality (30% vs. 40%) but higher non-CV mortality (36% vs. 20%) compared to patients with reduced EF. CONCLUSIONS: Despite previous data suggesting benefit of serelaxin in AHF, treatment with serelaxin was not found to improve overall mortality or have an effect on any category of cause of death in RELAX-AHF-2. Careful adjudication of events in the serelaxin trials showed that older patients and those with preserved EF had fewer deaths from HF or sudden death and more deaths from other CV causes and from noncardiac causes. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778).

Ten-Year Outcomes After Coronary Artery Bypass Grafting According to Age in Patients With Heart Failure and Left Ventricular Systolic Dysfunction: An Analysis of the Extended Follow-Up of the STICH Trial (Surgical Treatment for Ischemic Heart Failure).

BACKGROUND: Advancing age is associated with a greater prevalence of coronary artery disease in heart failure with reduced ejection fraction and with a higher risk of complications after coronary artery bypass grafting (CABG). Whether the efficacy of CABG compared with medical therapy (MED) in patients with heart failure caused by ischemic cardiomyopathy is the same in patients of different ages is unknown. METHODS: A total of 1212 patients (median follow-up, 9.8 years) with ejection fraction ≤35% and coronary disease amenable to CABG were randomized to CABG or MED in the STICH trial (Surgical Treatment for Ischemic Heart Failure). RESULTS: Mean age at trial entry was 60 years; 12% were women; 36% were nonwhite; and the baseline ejection fraction was 28%. For the present analyses, patients were categorized by age quartiles: quartile 1, ≤54 years; quartile, 2 >54 and ≤60 years; quartile 3, >60 and ≤67 years; and quartile 4, >67 years. Older versus younger patients had more comorbidities. All-cause mortality was higher in older compared with younger patients assigned to MED (79% versus 60% for quartiles 4 and 1, respectively; log-rank P=0.005) and CABG (68% versus 48% for quartiles 4 and 1, respectively; log-rank P<0.001). In contrast, cardiovascular mortality was not statistically significantly different across the spectrum of age in the MED group (53% versus 49% for quartiles 4 and 1, respectively; log-rank P=0.388) or CABG group (39% versus 35% for quartiles 4 and 1, respectively; log-rank P=0.103). Cardiovascular deaths accounted for a greater proportion of deaths in the youngest versus oldest quartile (79% versus 62%). The effect of CABG versus MED on all-cause mortality tended to diminish with increasing age (Pinteraction=0.062), whereas the benefit of CABG on cardiovascular mortality was consistent over all ages (Pinteraction=0.307). There was a greater reduction in all-cause mortality or cardiovascular hospitalization with CABG versus MED in younger compared with older patients (Pinteraction=0.004). In the CABG group, cardiopulmonary bypass time or days in intensive care did not differ for older versus younger patients. CONCLUSIONS: CABG added to MED has a more substantial benefit on all-cause mortality and the combination of all-cause mortality and cardiovascular hospitalization in younger compared with older patients. CABG added to MED has a consistent beneficial effect on cardiovascular mortality regardless of age. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.

A novel method to predict the proportional risk of sudden cardiac death in heart failure: Derivation of the Seattle Proportional Risk Model.

BACKGROUND: Patients with heart failure are at increased risk of both sudden death and pump failure death. Strategies to better identify those who have greatest net benefit from implantable cardioverter-defibrillator (ICD) implantation could reduce morbidity and maximize cost-effectiveness of ICDs. OBJECTIVE: We aimed to identify baseline variables in patients with cardiomyopathy that are independently associated with a disproportionate fraction of mortality risk attributable to sudden death vs nonsudden death. METHODS: We used data from 9885 patients with heart failure without ICDs, of whom 2552 died during an average follow-up of 2.3 years. Using commonly available baseline clinical and demographic variables, we developed a multivariate regression model to identify variables associated with a disproportionate risk of sudden death. RESULTS: We confirmed that lower ejection fraction and better functional class were associated with a greater proportion of mortality due to sudden death. Younger age, male sex, and higher body mass index were independently associated with a greater proportional risk of sudden death, while diabetes mellitus, hyper/hypotension, higher creatinine level, and hyponatremia were associated with a disproportionately lower risk of sudden death. The use of several heart failure medications, left ventricular end-diastolic dimension, or NT-pro brain natriuretic peptide concentrations were not associated with a disproportionate risk of sudden death. CONCLUSION: Several easily obtained baseline demographic and clinical variables, beyond ejection fraction and New York Heart Association functional class, are independently associated with a disproportionately increased risk of sudden death. Further investigation is needed to assess whether this novel predictive method can be used to target the use of lifesaving therapies to populations who will derive greatest mortality benefit .

Clinical characteristics and outcomes of patients with and without diabetes in the Surgical Treatment for Ischemic Heart Failure (STICH) trial.

AIMS: Hypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an LVEF of ≤35% and CAD amenable to coronary artery bypass grafting (CABG). Patients were randomized to CABG and optimal medical therapy (MED) or MED alone. The objective was to assess whether or not patients with diabetes mellitus (DM) enrolled in the STICH trial would have greater benefit from CABG than patients without DM. METHODS AND RESULTS: The characteristics and clinical outcomes of patients with and without DM randomized to CABG and MED or MED alone were compared. DM was present in 40%. At baseline, patients with DM had more triple vessel CAD, higher LVEF, and smaller left ventricular volumes. In patients with DM, the primary outcome of all-cause mortality occurred in 39% of patients in the MED group and 39% in the CABG group [hazard ratio (HR) with CABG 0.96, 95% confidence interval (CI) 0.73-1.26]. In patients without DM, the primary outcome occurred in 41% of patients in the MED group and 32% in the CABG group (HR with CABG 0.80, 95% CI 0.63-1.02). While numerically it would appear that the treatment effect of CABG is blunted in patients with DM, there was no significant interaction between DM and treatment group on formal statistical testing. CONCLUSIONS: Patients with DM enrolled in the STICH trial had more triple vessel disease, smaller hearts, and higher LVEF than those without DM. CABG did not exert greater benefit in patients with DM.

Pulmonary hypertension related to left heart disease: insight from a wireless implantable hemodynamic monitor.

BACKGROUND: Pulmonary hypertension (PH) associated with left heart disease (World Health Organization [WHO] Group II) has previously been linked with significant morbidity and mortality. However, there are currently no approved therapies or hemodynamic monitoring systems to improve outcomes in WHO Group II PH. METHODS: We conducted a retrospective analysis of the CHAMPION trial of an implantable hemodynamic monitor (IHM) in 550 New York Heart Association (NYHA) Functional Class III HF patients, regardless of left ventricular ejection fraction (LVEF) or heart failure (HF) etiology. We evaluated clinical variables, changes in medical therapy, HF hospitalization rates and survival in patients with and without WHO Group II PH. RESULTS: Data were obtained for 314 patients (59%) who had WHO Group II PH. Patients without PH were at significantly lower risk for mortality than PH patients (hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.19 to 0.52, p < 0.0001). PH patients had higher HF hospitalization rates than non-PH patients (0.77/year vs 0.37/year; HR 0.49, 95% CI 0.39 to 0.61, p < 0.001). In patients with and without PH, ongoing knowledge of hemodynamic data resulted in a reduction in HF hospitalization for PH patients (HR 0.64, 95% CI 0.51 to 0.81, p = 0.002) and for non-PH patients (HR 0.60, 95% CI 0.41 to 0.89, p = 0.01). Among PH patients, there was a reduction in the composite end-point of death and HF hospitalization with ongoing knowledge of hemodynamics (HR 0.74, 95% CI 0.55 to 0.99, p = 0.04), but no difference in survival (HR 0.78, 95% CI 0.50 to 1.22, p = 0.28). CONCLUSIONS: WHO Group II PH is prevalent and identifies HF patients at risk for adverse outcomes. Ongoing knowledge of hemodynamic variables may allow for more effective treatment strategies to reduce the morbidity of this disease.

Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study.

BACKGROUND: Little is known about mode of death after acute heart failure (AHF) hospitalization. In the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study, serelaxin, the recombinant form of human relaxin-2, reduced post-discharge mortality at 180 days in selected patients with AHF. OBJECTIVES: The goal of this study was to assess the effect of serelaxin on specific modes of death in patients with AHF. METHODS: The RELAX-AHF study randomized 1,161 patients with AHF to 48 h of therapy with intravenous serelaxin or placebo. Patients were followed for vital status through 180 days. A blinded clinical events committee reviewed all deaths and adjudicated a cause of death on the basis of pre-specified criteria. Cox proportional hazard models were used to assess the effect of serelaxin on each mode of death, on the basis of pre-specified groupings of mode of death. RESULTS: There were 107 deaths (9.3%): 37 (35%) due to HF, 25 (23%) due to sudden death, 15 (14%) due to other cardiovascular (CV) causes, 19 (18%) due to non-CV causes, and 11 (10%) classified as unknown. The treatment effect of serelaxin was most pronounced on other CV deaths (hazard ratio [HR]: 0.29; 95% CI: 0.12 to 0.73; p = 0.005) and sudden death (HR: 0.46; 95% CI: 0.20 to 1.07; p = 0.065). There was no apparent impact of serelaxin treatment on HF deaths or non-CV deaths. CONCLUSIONS: In the RELAX-AHF study, the effects of serelaxin on mortality were primarily driven by reduction in mortality from other CV causes and sudden death, without apparent impact on HF deaths. (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure [RELAX-AHF]; NCT00520806).

PA32540 (a coordinated-delivery tablet of enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) versus enteric-coated aspirin 325 mg alone in subjects at risk for aspirin-associated gastric ulcers: results of two 6-month, phase 3 studies.

BACKGROUND: Discontinuations and/or interruptions in aspirin therapy for secondary cardioprotection due to upper gastrointestinal (UGI) complications or symptoms have been shown to increase the risk for subsequent cardiovascular events. PA32540 is a coordinated-delivery, combination tablet consisting of enteric-coated aspirin (EC-ASA) 325 mg and immediate-release (IR) omeprazole 40 mg. METHODS: Two identically-designed, 6-month, randomized, double-blind trials evaluated PA32540 vs. EC-ASA 325 mg in a secondary cardiovascular disease prevention population taking aspirin 325 mg daily for ≥3 months and at risk for ASA-associated gastric ulcers (GUs). The combined study population was 1049 subjects (524 randomized to PA32540, 525 to EC-ASA 325 mg). The primary endpoint was the occurrence of endoscopically-determined gastric ulceration over 6 months. Safety outcomes included the rates of major adverse cardiovascular events (MACE) and UGI symptoms. RESULTS: Significantly fewer PA32540-treated subjects (3.2%) developed endoscopic GUs vs. EC-ASA 325 mg-treated subjects (8.6%) (P < .001). Overall occurrence of MACE was low (2.1%), with no significant differences between treatments in types or incidence of MACE. PA32540-treated subjects had significantly fewer UGI symptoms (P < .001) and significantly fewer discontinuations due to pre-specified UGI adverse events (1.5% vs. 8.2%, respectively; P < .001). CONCLUSIONS: PA32540 reduced the incidence of endoscopic GUs compared to EC-ASA 325 mg, but with a similar cardiovascular event profile. Due to fewer UGI symptoms, continuation on aspirin therapy was greater in the PA32540 treatment arm.

Association of cardiac events with coronary artery disease detected by 64-slice or greater coronary CT angiography: a systematic review and meta-analysis.

BACKGROUND: The value of ≥64-slice coronary CT angiography (CCTA) to determine odds of cardiac death or non-fatal myocardial infarction (MI) needs further clarification. METHODS: We performed a systematic review and meta-analysis using publications reporting events/severity of coronary artery disease (CAD) in patients with suspected CAD undergoing CCTA. Patients were divided into: no CAD, non-obstructive CAD (maximal stenosis <50%), and obstructive CAD (≥50% stenosis). Odds ratios with 95% confidence intervals were calculated using a fixed or random effects model. Heterogeneity was assessed using the I(2) index. RESULTS: We included thirty-two studies comprising 41,960 patients with 363 all-cause deaths (15.0%), 114 cardiac deaths (4.7%), 342 MI (14.2%), 69 unstable angina (2.8%), and 1527 late revascularizations (63.2%) over 1.96 (SD 0.77) years of follow-up. Cardiac death or MI occurred in 0.04% without, 1.29% with non-obstructive, and 6.53% with obstructive CAD. OR for cardiac death or MI was: 14.92 (95% CI, 6.78 to 32.85) for obstructive CAD, 6.41 (95% CI, 2.44 to 16.84) for non-obstructive CAD versus no CAD, and 3.19 (95% CI, 2.29 to 4.45) for non-obstructive versus obstructive CAD and 6.56 (95% CI, 3.07 to 14.02) for no versus any CAD. Similar trends were noted for all-cause mortality and composite major adverse cardiovascular events. CONCLUSIONS: Increasing CAD severity detected by CCTA is associated with cardiac death or MI, all-cause mortality, and composite major adverse cardiovascular events. Absence of CAD is associated with very low odds of major adverse events, but non-obstructive disease significantly increases odds of cardiac adverse events in this follow-up period.

Association of low body temperature and poor outcomes in patients admitted with worsening heart failure: a substudy of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial.

AIMS: Risk stratification in patients admitted with worsening heart failure (HF) is essential for tailoring therapy and counselling. Risk models are available but rarely used, in part because many require laboratory and imaging results that are not routinely available. Body temperature is associated with prognosis in other illnesses, and we hypothesized that low body temperature would be associated with worse outcomes in patients admitted with worsening HF. METHODS AND RESULTS: The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial was an event-driven, randomized, double-blind, placebo-controlled study of tolvaptan in 4133 patients hospitalized for worsening HF with an EF <40%. Co-primary endpoints were all-cause mortality and cardiovascular (CV) death or HF rehospitalization. Body temperature was measured orally at randomization and entered in analyses both as a continuous variable and categorized into three groups (<36 °C, 36-36.5 °C, and >36.5 °C) using Cox regression models. The composite of CV death or HF rehospitalization occurred in 1544 patients within 1 year. For every 1 °C decrease in body temperature, the risk of adverse outcomes increased by 16% [hazard raio (HR) 1.16, 95% confidence interval (CI) 1.04-1.28], after adjustment for age, gender, race, systolic blood pressure, EF, blood urea nitrogen, and serum sodium. In fully adjusted analysis, the risk of adverse outcomes in the lowest body temperature group (<36 °C) was 51% higher than that of the index group (>36.5 °C) (HR 1.35, 95% CI 1.15-1.58). CONCLUSIONS: Low body temperature is an independent marker of poor cardiovascular outcomes in patients admitted with worsening HF and reduced EF.

Cardiovascular safety of varenicline: patient-level meta-analysis of randomized, blinded, placebo-controlled trials.

Smoking is a major modifiable risk factor for cardiovascular (CV) disease. Varenicline is a pharmacological aid for smoking cessation. To explore the CV safety of varenicline, we investigated the incidence of CV events in varenicline-treated subjects across all phase 2-4 randomized placebo-controlled clinical trials of ≥12-week treatment duration conducted in smokers aged ≥18 years and sponsored by the drug manufacturer. This manuscript reports a subject-level meta-analysis of time to major adverse cardiovascular events (MACE; defined as CV-related death, nonfatal myocardial infarction, nonfatal stroke) and time to MACE+ (defined as MACE plus worsening or any procedure for peripheral vascular disease, hospitalization for angina, or performance of coronary revascularization). All events were adjudicated by an independent adjudication committee, blind to treatment assignment. Events were assessed during treatment and up to 30 days after the last treatment dose. The primary analytical method was a stratified logrank time-to-event analysis; secondary analyses were meta-analyses of incidence rate ratios and rate differences. Overall, 7002 subjects were included (varenicline: 4190; placebo: 2812) from 15 studies. MACE were reported by 13 varenicline subjects (0.31%) and 6 placebo subjects (0.21%) [hazard ratio, 1.95; 95% confidence interval (CI): 0.79-4.82; P = 0.15; risk difference, 0.006 events per subject-year; 95% CI: -0.003, 0.015, P = 0.19]. MACE+ were reported by 26 varenicline subjects (0.62%) and 12 placebo subjects (0.43%) (hazard ratio, 1.74; 95% CI: 0.91-3.34, P = 0.10; risk difference, 0.010; 95% CI: -0.002, 0.022, P = 0.11). This subject-level meta-analysis of MACE or MACE+ up to 30 days posttreatment in placebo-controlled clinical trials of varenicline found a trend toward increased incidence of these events in varenicline-treated patients that did not reach statistical significance. The overall number of events was low and the absolute risk of CV events with varenicline was small.

Association between bilirubin and mode of death in severe systolic heart failure.

The bilirubin level has been associated with worse outcomes, but it has not been studied as a predictor for the mode of death in patients with systolic heart failure. The Prospective Randomized Amlodipine Evaluation Study (PRAISE) cohort (including New York Heart Association class IIIB-IV patients with left ventricular ejection fraction <30%, n = 1,135) was analyzed, divided by bilirubin level: ≤0.6 mg/dl, group 1; >0.6 to 1.2 mg/dl, group 2; and >1.2 mg/dl, group 3. Multivariate Cox proportional hazards models were used to determine the association of bilirubin with the risk of sudden or pump failure death. Total bilirubin was entered as a base 2 log-transformed variable (log2 bilirubin), indicating doubling of the bilirubin level corresponding to each increase in variable value. The higher bilirubin groups had a lower ejection fraction (range 19% to 21%), sodium (range 138 to 139 mmol/L), and systolic blood pressure (range 111 to 120 mm Hg), a greater heart rate (range 79 to 81 beats/min), and greater diuretic dosages (range 86 to 110 furosemide-equivalent total daily dose in mg). The overall survival rates declined with increasing bilirubin (24.3, 31.3, and 44.3 deaths per 100 person-years, respectively, for groups 1, 2, and 3). Although a positive relation was seen between log2 bilirubin and both pump failure risk and sudden death risk, the relation in multivariate modeling was significant only for pump failure mortality (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82, p = 0.0004), not for sudden death mortality (hazard ratio 1.21, 95% confidence interval 0.98 to 1.49, p = 0.08). In conclusion, an increasing bilirubin level was significantly associated with the risk of pump failure death but not for sudden death in patients with severe systolic heart failure.

Effect of bucindolol on heart failure outcomes and heart rate response in patients with reduced ejection fraction heart failure and atrial fibrillation.

AIMS: There is little evidence of beta-blocker treatment benefit in patients with heart failure and reduced left ventricular ejection fraction (HFREF) and atrial fibrillation (AF). We investigated the effects of bucindolol in HFREF patients with AF enrolled in the Beta-blocker Evaluation of Survival Trial (BEST). METHODS AND RESULTS: A post-hoc analysis of patients in BEST with and without AF was performed to estimate the effect of bucindolol on mortality and hospitalization. Patients were also evaluated for treatment effects on heart rate and the influence of beta1-adrenergic receptor position 389 (ß(1)389) arginine (Arg) vs. glycine (Gly) genotypes. In the 303/2708 patients in AF, patients receiving bucindolol were more likely to achieve a resting heart rate ≤ 80 b.p.m. at 3 months (P < 0.005) in the absence of treatment-limiting bradycardia. In AF patients and sinus rhythm (SR) patients who achieved a resting heart rate ≤ 80 b.p.m., there were beneficial treatment effects on cardiovascular mortality/cardiovascular hospitalization [hazard ratio (HR) 0.61, P = 0.025, and 0.79, P = 0.002]. Without achieving a resting heart rate ≤ 80 b.p.m., there were no treatment effects on events in either group. ß(1)389-Arg/Arg AF patients had nominally significant reductions in all-cause mortality/HF hospitalization and cardiovascular mortality/hospitalization with bucindolol (HR 0.23, P = 0.037 and 0.28, P = 0.039), whereas Gly carriers did not. There was no evidence of diminished heart rate response in ß(1)389-Arg homozygotes. CONCLUSION: In HFREF patients with AF, bucindolol was associated with reductions in composite HF endpoints in those who achieved a resting heart rate ≤ 80 b.p.m. and nominally in those with the ß(1)389-Arg homozygous genotype.

Combinatorial pharmacogenetic interactions of bucindolol and ß1, α2C adrenergic receptor polymorphisms.

BACKGROUND: Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a ß-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (ß(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. METHODOLOGY: In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of ß(1)389 and α(2C)322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for ß(1)389 AR variants was measured in human explanted left ventricles. PRINCIPAL FINDINGS: The combination of ß(1)389 Arg+α(2C)322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in ß(1)389 Arg homozygotes+α(2C)322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in ß(1)389 Arg vs. Gly ARs, which converts α(2C)Del minor allele-associated NE lowering from a therapeutic liability to a benefit. CONCLUSIONS: On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (ß(1)389 Arg homozygotes), intermediate (ß(1)389 Gly carriers+α(2C)322-325 Wt homozygotes), and no (ß(1)389 Gly carriers+α(2C)322-325 Del carriers) efficacy.

The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT.

BACKGROUND: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes. OBJECTIVE: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure. METHODS: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days. RESULTS: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group. CONCLUSIONS: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure.

A case of caffeine-induced coronary artery vasospasm of a 17-year-old male.

The intentional consumption and use of stimulants, such as caffeine, are known to have numerous interactions with the human cardiovascular system. Ex vivo studies have shown caffeine-induced vasoconstriction of coronary arteries (Forman et al. in Ann Emerg Med 29:178-180, 1997). We report on a case of a 17-year-old male who presented with angina and an abnormal electrocardiogram (ECG) concerning for ST elevation myocardial infarct. He was found to have diffuse ECG changes and markedly elevated cardiac enzymes. A transthoracic echocardiogram revealed a reduced left ventricular (LV) systolic function as well as segmental wall motion abnormalities consistent with an ischemic insult. The patient admitted to consuming near lethal doses of caffeine immediately preceding his angina. He was diagnosed with coronary vasospasms as a result of stimulant use. During hospitalization, ECG changes resolved, cardiac enzymes started trending downward, and LV systolic function returned to normal, all consistent with stunned myocardium that fully recovered. This case strongly suggests that overuse of stimulants, such as caffeine, should be considered in patients presenting with coronary vasospasms, particularly in teenagers and young adults.

The relationship between aortic stiffness and E/A filling ratio and myocardial strain in the context of left ventricular diastolic dysfunction in heart failure with normal ejection fraction: insights from magnetic resonance imaging.

The purpose of this study is to investigate the relationship between aortic stiffness and diastolic dysfunction in heart failure with normal ejection fraction (HFNEF) and compare the results to normal subjects using magnetic resonance imaging (MRI). Sixteen human subjects (eight HFNEF and eight volunteers) were scanned on a 3.0-T MRI system. Aortic stiffness was assessed using pulse wave velocity (PWV). Left ventricle (LV) diastolic function was assessed by the early/atrial (E/A) filling ratio and different myocardial strain components. The results showed that, in HFNEF, a major part of LV filling occurred later during the atrial filling phase. The E/A ratio was less than 1 in HFNEF and greater than 1 in volunteers. Left ventricular myocardial dynamic strain range (difference between end-diastolic and end-systolic strains) was reduced in HFNEF, with less relaxation (strain rate) during the diastolic phase. Aortic PWV was higher in HFNEF than in volunteers due to less vessel compliance. The E/A ratio and myocardial strain measurements showed inverse correlations with aortic stiffness in HFNEF. The resulting inter- and intraobserver variabilities showed no bias between repeated cardiovascular measurements. In conclusion, a comprehensive MRI exam was developed for assessing patients with HFNEF. Heart failure with normal EF is associated with impaired LV diastolic function and significant ventricular and aortic stiffening. The degree of aortic stiffness involvement suggests reduced aortic compliance as a major factor in HFNEF.

Importance of blood pressure control in left ventricular mass regression.

Blood pressure (BP) reduction to 140/90 mm Hg or lower using renin-angiotensin-system blockers reportedly provides the greatest left ventricular (LV) mass regression; ß-blockers have less effect. This study examined whether combination antihypertensive therapy would provide greater benefit. With a double-blind, parallel-group design, the effects of 3 different combinations, carvedilol controlled-release (CR)/lisinopril, atenolol/lisinopril, and lisinopril, on left ventricular mass index (LVMI) were assessed by MRI after 12 months. Patients were treated to achieve guideline-recommended BP (<140 mm Hg/<90 mm Hg; diabetes: <130 mm Hg/<80 mm Hg). Sample size was calculated to achieve 90% power to detect a 5 g/m(2) difference in mean change from baseline in LVMI between the carvedilol CR/lisinopril group and each of the other treatment groups. Of 287 patients randomized, more than 50% were titrated to maximum dosage; 73% reached targeted BP. At month 12 (last observation carried forward ≥ month 9) for 195 evaluable subjects, mean BP was similar in all groups (carvedilol CR/lisinopril: 128.8/77.9; atenolol/lisinopril: 128.7/76.5; lisinopril: 126.3/80.3 mm Hg). Compared with baseline, mean LVMI decreased to a similar extent in all groups (carvedilol CR/lisinopril: -6.3; atenolol/lisinopril: -6.7; lisinopril: -7.9 g/m(2)). Achievement of targeted BP control is more important than treatment regimen in achieving LV mass reduction.

Implantable cardioverter-defibrillators in patients hospitalized for heart failure with chronically reduced left ventricular ejection fraction.

The aim of this study was to investigate the association between implantable cardioverter-defibrillator (ICD) status at the time of hospitalization for worsening heart failure (HF) with postdischarge events in patients with reduced left ventricular ejection fraction. We conducted an analysis of 4133 patients hospitalized for HF with left ventricular ejection fraction 40% or less in EVEREST. The final analysis included patients without an electrophysiological device (n = 3102) and those with an ICD (n = 600) at the time of enrollment. During a median follow-up of 300 days, all-cause mortality was 22.9% in the no device group and 35.2% in the ICD group (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.39-1.89). Rehospitalization for HF was 27.0% in the no device group and 46.8% in the ICD group (HR, 2.20; 95% CI, 1.92-2.52). After adjustment for multiple variables, the rates for all-cause mortality were similar (HR, 1.01; 95% CI, 0.83-1.22), but the ICD group had elevated rates of HF hospitalizations compared with the no device group (HR, 1.35; 95% CI, 1.14-1.60). In patients with reduced left ventricular ejection fraction, an ICD at presentation for hospitalization for worsening HF was associated with similar rates of death but higher rates of rehospitalization for HF. Given our findings, further studies should investigate optimization of care in patients already implanted with an ICD as well as the role of ICD implantation during or soon after hospitalization for HF in patients not yet implanted.