African-American Heart Failure Trial Research Articles

Adrenergic Polymorphisms and Survival in African Americans With Heart Failure: Results From A-HeFT

Polymorphisms in adrenergic signaling affect the molecular function of adrenergic receptors and related proteins. The β1 adrenergic receptor (ADRB1) Arg389Gly, G-protein receptor kinase type 5 (GRK5) Gln41Leu, G-protein β-3 subunit (GNB3) 825 C/T, and α2c deletion affect adrenergic tone, impact heart failure outcomes and differ in prevalence by ethnicity. Their combined effect within black cohorts remains unknown. We analyzed subjects from the African American Heart Failure Trial (A-HeFT) by assessing event-free survival, quality of life, and gene coinheritance. Significant coinheritance effects on survival included GRK5 Leu41 among subjects co-inheriting GNB3 825 C alleles (n = 166, 90.4% vs 69.0%, P < 0.001). By contrast, the impact of ADRB1 Arg389Arg genotype was magnified among subjects with GNB3 825 TT genotype (n = 181, 66.3% vs 85.7%, P = .002). The lack of the α2c deletion (ie, insertion) led to a greater impact of the ARG389Arg genotype (n = 289, 76.4% vs 86.1%, P = .007). Polymorphisms in adrenergic signaling affects outcomes in black subjects with heart failure. Coinheritance patterns in genetic variation may help determine heart failure survival.

Heart Failure With Recovered Ejection Fraction in African Americans: Results From the African-American Heart Failure Trial

BackgroundRecent studies have described the entity of heart failure with recovered ejection fraction (HFrecEF), but population-specific studies remain lacking. The aim of this study was to characterize patients enrolled in the African-American Heart Failure Trial (A-HeFT) who had significant improvement in their ejection fraction (EF) during the 1st 6 months of follow-up. Methods and ResultsSubjects with HFrecEF (improvement in EF from <35% to >40% in 6 months; n = 59) were compared with 259 subjects with heart failure and persistently reduced EF (HFrEF), defined as EF ≤40% at 6-month follow-up. The effects of improvement in EF on all-cause mortality and 1st and all hospitalizations were analyzed. Compared with HFrEF, subjects with HFrecEF had a nonsignificant trend toward lower mortality (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.02–1.15; P = .068), fewer 1st HF hospitalizations (HR 0.22, 95% CI 0.07–0.71; P = .011), fewer recurrent HF hospitalizations (HR 0.13, 95% CI 0.05–0.37; P < .001), similar 1st all-cause hospitalizations (HR 0.67, 95% CI 0.39–1.15; P = .150), and fewer recurrent all-cause hospitalizations (HR 0.41, 95% CI 0.24–0.68; P < .001). ConclusionsThese data confirm that, as in other populations, a small subgroup of black patients receiving standard care improve their EF with favorable outcomes. Further studies are required to determine whether myocardial recovery is permanent and the best management strategies in such patients.

Clinical Effectiveness of Hydralazine–Isosorbide Dinitrate in African-American Patients With Heart Failure

ObjectivesThis study sought to evaluate the effectiveness of hydralazine–isosorbide dinitrate (H-ISDN) in African Americans with heart failure (HF) with reduced ejection fraction (HFrEF). BackgroundAmong African-American patients with HFrEF, H-ISDN was found to improve quality of life and lower HF-related hospitalization and mortality rates in the A-HEFT (African-American Heart Failure Trial). Few studies have evaluated the effectiveness of this therapy in clinical practice. MethodsVeterans Affairs patients with a hospital admission for HF between 2007 and 2013 were screened. Inclusion criteria included African-American race, left ventricular ejection fraction <40%, and receipt of Veterans Affairs medications. Exclusions were documented contraindications to H-ISDN, creatinine >2.0 mg/dl, or intolerance to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Adjusted hazard ratios were calculated for patients who received H-ISDN 6-months before admission compared with patients who did not receive H-ISDN, by using inverse probability weighting of propensity scores and a time to death analysis for 18 months of follow-up. Propensity scores were generated using patients’ characteristics, left ventricular ejection fraction, laboratory values, and hospital characteristics. ResultsThe final cohort included 5,168 African-American patients with HF (mean age 65.2 years), with 15.2% treated with H-ISDN before index admission. After 18 months, there were 1,275 reported deaths (24.7%). The adjusted mortality rate at 18 months was 22.1% for patients receiving H-ISDN treatment and 25.2% for untreated patients (p = 0.009); adjusted hazard ratio: 0.85 (95% confidence interval: 0.73 to 1.00; p = 0.057). ConclusionsH-ISDN remains underused in African-American patients with HFrEF. In this cohort, the study found that H-ISDN use was associated with lower mortality rates in African-American patients with HFrEF when controlling for patient selection by using an inverse probability weighting of propensity scores.

Abstract 13157: Relationship Between Body Mass Index and Mortality in the African-American Heart Failure Trial

Introduction: In patients with heart failure and reduced ejection fraction (HFrEF), increasing body mass index (BMI) is not associated with worsening prognosis, termed the obesity paradox. Although this phenomenon has been studied extensively, data on the African-American population are limited. The aim of this study was to examine the relationship between BMI and all-cause mortality in African Americans with HFrEF. Methods and Results: The African-American Heart Failure Trial (A-HeFT) database was utilized to conduct a retrospective analysis. In A-HeFT, 1050 self-identified black patients with BMI range of 15.7 to 69.4 kg/m 2 (median 30.3 kg/m 2 ) were followed for a median of 15 months, with 86 deaths. BMI was modeled as a curvilinear continuous variable using restricted cubic splines. Unadjusted Cox regression analysis of the relationship between BMI and all-cause mortality revealed a significant (p = 0.001) inverse relationship, with an increase in mortality risk below the median BMI of approximately 30 kg/m 2 (HR&gt; 1.0) without an upward trend in mortality risk above a BMI &gt; 30 kg/m 2 (Figure1). Adjustment for other variables including age, sex, comorbidities, and clinical assessments did not reveal an increase in HR above the median BMI. Conclusion: Consistent with the obesity paradox, the mortality risk increased with decreasing BMI and did not increase when the BMI exceeded the definition of obesity. Until the mechanisms of the obesity paradox are better understood, these results question whether weight reduction would be beneficial in the African American population with HFrEF.

Dilemmas With Race and Heart Failure Treatment.

The combination of hydralazine and isosorbide dinitrate (H+ISDN) provides balanced vasodilatation, resulting in afterload and preload reductions in heart failure (HF). Both the V-HeFT (Vasodilator Heart Failure Trials) I and II showed improvement in functional capacity and ejection fraction with the use of this combination in HF patients with reduced ejection fraction.1 Subsequent secondary analysis of the V-HeFT data suggested that there might be a race-dependent response to H+ISDN therapy, with blacks deriving more benefit.1 In parallel, there was progress in understanding the role of oxidative stress in HF, varying racial trends in oxidative stress, and the role of H+ISDN in this respect, with ISDN donating nitric oxide and hydralazine being an antioxidant. The hypothesis drawn from these observations was tested in A-HeFT (African-American Heart Failure Trial), which was terminated early because of a 43% relative risk reduction in mortality with H+ISDN observed during data monitoring and led to the approval of BiDil (fixed-dose H+ISDN formulation used in A-HeFT) for the treatment of HF in self-identified blacks.2 This approval was the first where race was used to identify the target population. Although A-HeFT showed the efficacy of H+ISDN in blacks, it did not show H+ISDN to be nonefficacious in non-blacks. Although non-blacks patients did not seem to derive mortality benefit in a retrospective analysis of V-HeFT I, this subgroup finding should be viewed with caution. Rather than reviewing an individual subgroup, the statistical standard is to assess treatment-by-subgroup interaction, which was not …

Composite outcome measures in a pragmatic clinical trial of chronic heart failure management: A comparative assessment

BackgroundA number of composite outcomes have been developed to capture the perspective of the patient, clinician and objective measures of health in assessing heart failure outcomes. To date there has been a limited examination in the composition of these outcomes. Methods and resultsThree commonly used scoring systems in heart failure trials: Packer's composite, Patient Journey and the African American Heart Failure Trial (A-HeFT) scores were compared in assessing outcomes from the Which heart failure intervention is most cost-effective & consumer friendly in reducing hospital care (WHICH(?)) Trial. Comparability and interpretability of these outcomes and the influence of each component to the final outcome were examined. Despite all three composite outcomes incorporating mortality, hospitalisation and quality of life (QoL), the contribution of each individual component to the final outcomes differed. The component with the most influence in deteriorating condition for the Packer's composite was hospitalisation (67.7%), while in Patient Journey it was QoL (61.5%) and for A-HeFT composite score it was mortality (45.4%). ConclusionsThe contribution made by each component varied in subtle, but important ways. This study emphasises the importance of understanding the value system of the composite outcomes to enable meaningful interpretation of results.

G-Protein Beta-3 Subunit Genotype Predicts Enhanced Benefit of Fixed-Dose Isosorbide Dinitrate and Hydralazine: Results of A-HeFT

ObjectivesThe purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial). BackgroundGNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans. MethodsA total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets. ResultsThe GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 ± 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 ± 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H = 0.50 ± 1.6; placebo = −0.11 ± 1.8, p = 0.02), QoL (FDC I/H = 0.69 ± 1.4; placebo = 0.24 ± 1.5, p = 0.04), and event-free survival (hazard ratio: 0.51, p = 0.047), but not in subjects with the C allele (for CS, FDC I/H = −0.05 ± 1.7; placebo = −0.09 ± 1.7, p = 0.87; for QoL, FDC I/H = 0.28 ± 1.5; placebo = 0.14 ± 1.5, p = 0.56; and for event-free survival, p = 0.35). ConclusionsThe GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.

Effect of fixed-dose combination of isosorbide dinitrate and hydralazine on all hospitalizations and on 30-day readmission rates in patients with heart failure: results from the African-American Heart Failure Trial.

Fixed-dose combination of isosorbide dinitrate and hydralazine (FDC-I/H) reduced mortality by 43% and death or first hospitalization for heart failure (HF) by 37% in the African-American Heart Failure Trial (A-HeFT). Reduction in mortality makes it difficult to determine the effect on hospitalizations unless the analysis adjusts for death as a competing risk. In A-HeFT, 1050 self-identified black patients with moderate to severe HF were randomized to FDC-I/H or placebo. The effects of FDC-I/H on first and all hospitalizations and 30-day readmission rates were analyzed. Deaths as competing risks were adjusted using Fine-Gray regression and joint models of hospitalizations and mortality. There were 558 all-cause and 251 HF hospitalizations in placebo compared with 435 and 173 hospitalizations in the FDC-I/H group. Adjusting for deaths as a competing risk, the effect of FDC-I/H on the first hospitalization for HF, expressed in hazard ratio (95% confidence interval), was 0.61 (0.47-0.80; P<0.001) and 0.88 (0.72-1.06; P=0.18) on the first all-cause hospitalization. The effect of FDC-I/H on all recurrent hospitalizations for HF was 0.66 (0.52-0.83; P=0.0005), similar to the effect on the first hospitalizations for HF, whereas the effect on all hospitalizations for any cause was 0.75 (0.63-0.91; P=0.003). The 30-day all-cause readmission rate after the first hospitalization for HF was 23.6% (29 of 123) in placebo versus 14.8% (12 of 81) in the FDC-I/H group, but the effect (0.59; 0.30-1.16; P=0.12) in this small subgroup was not significant. Treatment with FDC-I/H was associated with a substantial reduction in the first and recurrent HF hospitalizations, and in total all-cause hospitalizations, reducing the total burden of costly and distressing hospitalizations. http://www.clinicaltrials.gov. Unique identifier: NCT00047775.

BiDil in the Clinic: An Interdisciplinary Investigation of Physicians’ Prescription Patterns of a Race-Based Therapy

Background: The African American Heart Failure Trial (A-HeFT) and the Food and Drug Administration (FDA) approval of BiDil for race-specific prescription have stirred the debate about the scientific and medical status of race. Yet there is no assessment of the potential fallout of this dispute on physicians’ willingness to prescribe the drug. We present here an analysis of the factors influencing physicians’ prescription of BiDil and investigate whether exposure to the controversy has an impact on their therapeutic judgments about the drug. Methods: We conducted an electronic survey with physicians in the department of internal medicine at the University of Cincinnati. Participants were randomly assigned to two groups, with one group receiving information about the controversy over BiDil. We used various statistical tests, including a linear mixed effects model, to analyze the results. Results: Twenty-seven percent of the participants reported using patients’ race as a major factor in making treatment decisions. Thirty-three percent reported the inefficacy of standard therapies, 25% the severity of the disease, and 15% other unspecified factors as primary determining criteria in prescribing BiDil. With respect to the controversy, 68% of physicians reported that they were not aware of any controversy surrounding BiDil. Physicians’ willingness to prescribe BiDil as a therapy was associated with their awareness of the controversy surrounding A-HeFT (p < .003). But their willingness to prescribe the therapy along racial lines did not vary significantly with exposure to the controversy. Conclusions: Overall, physicians prescribe and are willing to prescribe BiDil more to black patients than to white patients. However, physicians’ lack of awareness about the controversial scientific status of A-HeFT suggests the need for more efficient ways to convey scientific information about BiDil to clinicians. Furthermore, the uncertainties about the determination of clinical utility of BiDil for the individual patient raise questions about whether this specific race-based therapy is in patients’ best interests.

Hydralazine and Organic Nitrates Restore Impaired Excitation-Contraction Coupling by Reducing Calcium Leak Associated with Nitroso-Redox Imbalance*

Although the combined use of hydralazine and isosorbide dinitrate confers important clinical benefits in patients with heart failure, the underlying mechanism of action is still controversial. We used two models of nitroso-redox imbalance, neuronal NO synthase-deficient (NOS1(-/-)) mice and spontaneously hypertensive heart failure rats, to test the hypothesis that hydralazine (HYD) alone or in combination with nitroglycerin (NTG) or isosorbide dinitrate restores Ca(2+) cycling and contractile performance and controls superoxide production in isolated cardiomyocytes. The response to increased pacing frequency was depressed in NOS1(-/-) compared with wild type myocytes. Both sarcomere length shortening and intracellular Ca(2+) transient (Δ[Ca(2+)]i) responses in NOS1(-/-) cardiomyocytes were augmented by HYD in a dose-dependent manner. NTG alone did not affect myocyte shortening but reduced Δ[Ca(2+)]i across the range of pacing frequencies and increased myofilament Ca(2+) sensitivity thereby enhancing contractile efficiency. Similar results were seen in failing myocytes from the heart failure rat model. HYD alone or in combination with NTG reduced sarcoplasmic reticulum (SR) leak, improved SR Ca(2+) reuptake, and restored SR Ca(2+) content. HYD and NTG at low concentrations (1 μm), scavenged superoxide in isolated cardiomyocytes, whereas in cardiac homogenates, NTG inhibited xanthine oxidoreductase activity and scavenged NADPH oxidase-dependent superoxide more efficiently than HYD. Together, these results revealed that by reducing SR Ca(2+) leak, HYD improves Ca(2+) cycling and contractility impaired by nitroso-redox imbalance, and NTG enhanced contractile efficiency, restoring cardiac excitation-contraction coupling.

Effect of Fixed-Dose Combined Isosorbide Dinitrate/Hydralazine in Elderly Patients in the African-American Heart Failure Trial

BackgroundFixed-dose combined isosorbide dinitrate/hydralazine (FDC I/H) significantly improved outcomes in patients with advanced heart failure (HF) receiving background neurohormonal therapy in the African-American Heart Failure Trial (A-HeFT). In this analysis, we investigated treatment effects by age <65 or ≥65 years. Methods and ResultsTime-to-event curves were produced by the Kaplan-Meier method. Hazard ratios were calculated with the Cox proportional hazards model. Baseline characteristics showed that patients ≥65 years old had less hypertensive and more ischemic HF, better quality of life (QoL) scores, higher plasma B-type natriuretic peptide and creatinine levels, and received less background neurohormonal therapy. Kaplan-Meier curves showed that FDC I/H improved mortality and event-free survival in elderly patients. The hazard ratios for mortality, first heart failure hospitalization, and event-free survival (both unadjusted and adjusted for baseline differences), were similar quantitatively and in direction of effect in both age groups. ConclusionsIn A-HeFT, FDC I/H improved outcomes in HF patients aged <65 or ≥65 years, despite significant baseline differences between these age groups. Patients aged ≥65 years, a group at greater mortality risk, had the greatest survival benefit from FDC I/H.

COMBINATION OF ISOSORBIDE DINITRATE AND HYDRALAZINE REDUCES 30 DAY HOSPITAL READMISSIONS AND INCREASES TIME TO HOSPITAL READMISSION IN BLACKS WITH HEART FAILURE

A fixed dose combination of isosorbide dinitrate plus hydralazine (FDC I/H) reduced mortality in black patients with moderate to severe heart failure in the African-American Heart Failure Trial (A-HeFT). We further examined its effect on hospital readmissions. A total of 1050 black patients with

Letter by Taylor et al Regarding Article, “Hydralazine and Isosorbide Dinitrate in Heart Failure: Historical Perspectives, Mechanisms, and Future Directions”

To the Editor: Cole et al1 are to be congratulated on a thoughtful, thorough, and especially timely review of hydralazine and nitrates in heart failure. The timeliness is of particular relevance: 2011 marks the 25th anniversary of the publication of the first Vasodilator in Heart Failure Trial (V-HeFT-I),2 which demonstrated that a vasodilator drug could confer a survival benefit in heart failure. Although the precise mechanism of the benefit of combined hydralazine and nitrate was not known at the time (and still requires elucidation), this was nonetheless a sentinel observation. Twenty-five years later, with the outcomes of the African American Heart Failure Trial (A-HeFT)3 as evidence of survival …

Atrial fibrillation and mortality in African American patients with heart failure: Results from the African American Heart Failure Trial (A-HeFT)

Atrial fibrillation (AF) is common in patients with heart failure (HF) and portends a worsened prognosis. Because of the low enrollment of African American subjects (AAs) in randomized HF trials, there are little data on AF in AAs with HF. This post hoc analysis reviews characteristics and outcomes of AA patients with AF in A-HeFT. A total of 1,050 AA patients with New York Heart Association class III/IV systolic HF, well treated with neurohormonal blockade (87% β-blockers, 93% angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker), were randomized to an added fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H) or placebo. Atrial fibrillation was confirmed in 174 (16.6%) patients at baseline and in an additional 9 patients who developed AF during the study, for a final cohort of 183 (17.4%). Comparison of patients with AF versus no AF revealed the following: mean age 61 ± 12 versus 56 ± 13 years (P < .001), systolic blood pressure (BP) 124 ± 18 versus 127 ± 18 mm Hg (P = .044), diastolic BP 74 ± 11 versus 77 ± 10 mm Hg (P = .002), creatinine level 1.4 ± 0.5 versus 1.2 ± 0.5 mg/dL (P < .001), and brain natriuretic peptide 431 ± 443 versus 283 ± 396 pg/mL (P < .001). No significant difference was observed in ejection fraction, left ventricular end-diastolic diameter, or quality-of-life scores. However, AF increased the risk of mortality significantly among AA patients (P = .018), and the use of FDC I/H reduced the risk of mortality in patients with AF (HR 0.21, P = .002). African Americans with HF and AF (vs no AF) were older, had lower BP, and had higher creatinine and brain natriuretic peptide levels. Mortality and morbidity were worse when AF was present, and these data suggest that there may be an enhanced survival benefit with the use of FDC I/H in AA patients with HF and AF.

Hydralazine and Isosorbide Dinitrate in Heart Failure

Until the 1970s, treatment options for heart failure were limited to digitalis and diuretics.1 Although effective for symptoms, there was no evidence of mortality benefit with this combination, and it was an inadequate option for many patients with advanced symptoms. The search for more effective options led to strategies that modulated hemodynamics.1 Numerous physiological studies showed the dependence of ventricular function on vascular resistance, and drugs that reduced systemic vascular resistance improved cardiac performance.2,–,5 A pivotal study by Franciosa et al6 showed that sodium nitroprusside in patients with heart failure in the setting of acute myocardial infarction reduced left ventricular filling pressures from 22.7±2.0 to 11.3±1.6 mm Hg and led to a modest increase in cardiac output. A subsequent study revealed more striking improvements in patients with refractory heart failure, in whom nitroprusside reduced systemic vascular resistance by 50%, increased cardiac output by 56%, and reduced left ventricular filling pressure by 47%.7 These hemodynamic benefits with nitroprusside led to studies with oral agents, including hydralazine, isosorbide dinitrate (ISDN), prazosin, phentolamine, and minoxidil. Although these drugs did affect hemodynamics, none was as effective as nitroprusside individually.8,–,12 In 1977, Massie et al13 studied the combination of 2 oral agents, hydralazine and ISDN (H-ISDN) in class III to IV heart failure patients, proposing that simultaneously reducing preload with ISDN and afterload with hydralazine would result in a better response than with either drug individually. They found that H-ISDN reduced left ventricular filling pressure by 36%, increased cardiac index by 58%, and reduced systemic vascular resistance by 34%. Later, Pierpont et al14 compared H-ISDN with nitroprusside and showed that the 2 therapies had similar effects on wedge pressure reduction and cardiac index increase. Considering these hemodynamic benefits with …

Treatment of Heart Failure in African Americans— A Call to Action

Advances in heart failure treatment have not necessarily translated into equity in improved outcomes for African Americans. Heart failure in African Americans is characterized by a higher prevalence, especially at younger ages; more-adverse course with more frequent hospitalizations; and higher mortality rates compared to the general population. Despite this distinct disease profile, African Americans are remarkably underrepresented in large heart failure trials. This paper reviews the unique course of heart failure in African Americans and discusses treatment in the context of clinical trial evidence. African Americans with heart failure may respond differently to some standard therapies compared to whites, but low levels of enrollment of AAs in large clinical trials preclude valid conclusions in certain cases. An important exception is the African American Heart Failure Trial (AHeFT), a well-designed, prospective, randomized, placebo-controlled, double-blind study, that added a combination of fixed-dose isosorbide dinitrate/hydralazine (ISDN/ HYD) to standard therapy and showed a 43% improvement in survival and a 33% reduction in first hospitalizations. Despite compelling evidence from AHeFT, post hoc secondary analyses, and recommendations from current practice guidelines, ISDN/HYD remains underutilized in African Americans with heart failure. In this paper, we put forth a call to action for racial equity in clinical research and treatment in African Americans with heart failure.

Adherence to Guideline-Recommended Adjunctive Heart Failure Therapies Among Outpatient Cardiology Practices (Findings from IMPROVE HF)

Although previous studies have documented adherence with certain established heart failure (HF) quality metrics in outpatient cardiology practices, the extent to which there is conformity with other evidence-based, guideline-driven quality metrics in outpatients with HF is unknown. IMPROVE HF is a prospective cohort study designed to characterize the current management of patients with chronic HF and left ventricular ejection fraction <or=35% in outpatient cardiology practices. We evaluated baseline data for conformity with adjunctive HF therapies including pneumococcal vaccinization, hydralazine/isosorbide dinitrate (HYD/ISDN) for Black patients, statin therapy, antiplatelet therapy, smoking-cessation counseling, low-density lipoprotein cholesterol levels (<100 mg/dl), and systolic blood pressure decrease (all patients <140 mm Hg or [optimal] <130 mm Hg). Baseline data were available for 15,381 patients attending 167 cardiology practices. Patient characteristics included a median age 70 years, 71.0% men, 9.1% Black patients, 65.2% with ischemic HF cause, and 61.7% with a history of hypertension. Mean adherences or documentations of adherence were only 7.3% for HYD/ISDN and 1.0% for pneumococcal vaccination. Adherence to other adjunctive therapies ranged from 27.4% to 82.0% but none of the adjunctive treatment interventions were associated with high levels of adherence. Conformity with guideline-recommended, adjunctive HF therapies is deficient in the management of outpatients with HF. Critical gaps in documentation or delivery of care exist, especially for the use of pneumococcal vaccination and HYD/ISDN. In conclusion, improved processes of care, better documentation, and/or increased measures to promote adherence to all primary and adjunctive therapies for HF are needed.

Relationship of Quality of Life Scores With Baseline Characteristics and Outcomes in the African-American Heart Failure Trial

Background To characterize the quality of life (QOL) in the African-American Heart Failure Trial (A-HeFT) for factors associated with baseline score, relation of score to prognosis, and response to therapy with a fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H). Limited data exist on QOL scores in African-American heart failure patients or on the prognostic value of theses scores in any population. Finally, the effect of FDC I/H on QOL scores, particularly in A-HeFT, is not known. Methods and Results A-HeFT randomized 1050 African-American patients with New York Heart Association (NYHA) Class III-IV heart failure and systolic dysfunction. QOL measurements using Minnesota Living with Heart Failure Questionnaire (MLHFQ) were done at baseline and 3-month intervals. At baseline, worse MLHFQ scores were associated with younger age, female sex, greater body mass index, nonischemic etiology, high heart rate and NYHA Class, low systolic blood pressure, and chronic obstructive pulmonary disease. Both baseline and change in MLHFQ score were associated with a higher risk for combined all-cause mortality or heart failure hospitalization (baseline P < .0001, change at 3 months P = .001, and at 6 months P = .0008), but not mortality. Treatment with FDC I/H significantly improved MLHFQ score compared with placebo. Conclusions In A-HeFT, baseline QOL (MLHFQ) scores and change in score were predictive of combined HF morbidity and mortality outcomes. FDC I/H consistently improved QOL scores in A-HeFT compared with placebo.

Soluble Guanylate Cyclase

Arthur Kornberg, who shared with Severo Ochoa the 1959 Nobel Prize for Physiology or Medicine, stated in his autobiography that he had never met a dull enzyme.1 We strongly believe that soluble guanylate cyclase (sGC; E.C.4.6.1.2) is no exception to this. Article see p 2781 Nitric oxide (NO) plays an important physiological role as a signaling molecule as well as a cytotoxic agent. It is produced by 3 distinct NO synthases, specifically endothelial, neuronal, and inducible NO synthase. In the vasculature, endothelial NO synthase plays an important role in vascular homeostasis because NO generated in endothelial cells promotes vascular smooth muscle cell relaxation and inhibits platelet aggregation. Importantly, bioavailability of NO can be reduced in cardiovascular diseases, a condition which has been termed “endothelial dysfunction.” This phenomenon provides a rationale for therapeutic intervention. The primary target of NO is sGC, which is a heterodimeric enzyme consisting of an α- and β-subunit and a prosthetic heme group, which is located in the β-subunit. The heme group contains a ferrous iron atom (Fe2+). Binding of NO to this iron changes the conformation of the enzyme and leads to a >100-fold increase in catalytic rate (ie, the conversion of guanosine triphosphate to the second messenger cyclic guanosine monophosphate [cGMP]). The NO-induced cGMP signal modulates intracellularly the activity of several effector molecules: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cGMP-gated ion channels. Of note, both heme iron oxidation (Fe3+) and heme removal render sGC unresponsive to NO (Figure). These 2 conditions could therefore provide a mechanism for “vascular smooth muscle cell dysfunction” in cardiovascular disease states, which are often characterized by marked vasoconstriction either systemically or in specific organs. Figure. Schematic illustrating 3 different forms of soluble guanylate cyclase and their respective responsiveness to nitrovasodilators, sGC stimulators (eg, BAY 41–2272), and sGC …

Effectiveness of hydralazine/isosorbide dinitrate in racial/ethnic subgroups with heart failure

Background: The addition of hydralazine/isosorbide dinitrate (H-ISDN) to a standard heart failure treatment regimen in the African-American Heart Failure Trial was associated with a 43% reduction in mortality. However, the effectiveness of H-ISDN in a community sample of African-American patients and other racial/ethnic groups is unknown. Objective: The aim of this study was to assess the associations between treatment with H-ISDN and mortality or hospitalization for heart failure in veterans with the disease. Methods: For this retrospective cohort study, electronic data on outpatient prescriptions, comorbidity, and other heart failure risk factors were analyzed in veterans with heart failure. Patients were classified based on whether they were prescribed H-ISDN and subclassified based on race/ethnicity (African American, Hispanic, or white). Patients who were prescribed H-ISDN were subclassified based on time of initiation of H-ISDN treatment (0–121, 122–365, or >365 days after diagnosis). Data were analyzed using propensity-adjusted Cox regression analyses, with exposure to H-ISDN modeled as a time-varying covariate. Results: Data from 76,828 veterans were analyzed (98% men, 2% women). H-ISDN prescription was not associated with the risk of death in 5 of the 9 subgroups predefined by race/ethnicity or time of initiation of H-ISDN; however, H-ISDN was associated with an increased risk of death in the 4 subgroups with longer times to initiation. H-ISDN was associated with a significantly increased risk of heart failure hospitalization in all but 1 of the 9 subgroups. The risk of both mortality and hospitalization associated with H-ISDN was significantly lower in African-American patients than in those who were Hispanic or white. Concurrent prescription of other, evidence-based heart failure therapies (eg, angiotensin-converting enzyme inhibitors, β-blockers, and combinations) had strong, statistically significant associations with reduced mortality. Conclusions: In this population of veterans with heart failure, H-ISDN prescription was not associated with significant reductions in mortality or hospitalization in any of the subgroups defined by race/ethnicity and time of initiation of H-ISDN analyzed compared with the group that did not receive H-ISDN. It is possible, or even likely, that unmeasured differences in important risk factors—particularly heart failure severity and left ventricular dysfunction—between the group that received H-ISDN and the one that did not masked a beneficial effect of H-ISDN. Therefore, our conclusions must be regarded as hypothesis generating and need to be tested in subsequent randomized trial(s).