Jalal K. Ghali

Validation and Potential Mechanisms of Red Cell Distribution Width as a Prognostic Marker in Heart Failure

BACKGROUND Adverse outcomes have recently been linked to elevated red cell distribution width (RDW) in heart failure. Our study sought to validate the prognostic value of RDW in heart failure and to explore the potential mechanisms underlying this association. METHODS AND RESULTS Data from the Study of Anemia in a Heart Failure Population (STAMINA-HFP) registry, a prospective, multicenter cohort of ambulatory patients with heart failure supported multivariable modeling to assess relationships between RDW and outcomes. The association between RDW and iron metabolism, inflammation, and neurohormonal activation was studied in a separate cohort of heart failure patients from the United Investigators to Evaluate Heart Failure (UNITE-HF) Biomarker registry. RDW was independently predictive of outcome (for each 1% increase in RDW, hazard ratio for mortality 1.06, 95% CI 1.01-1.12; hazard ratio for hospitalization or mortality 1.06; 95% CI 1.02-1.10) after adjustment for other covariates. Increasing RDW correlated with decreasing hemoglobin, increasing interleukin-6, and impaired iron mobilization. CONCLUSIONS Our results confirm previous observations that RDW is a strong, independent predictor of adverse outcome in chronic heart failure and suggest elevated RDW may indicate inflammatory stress and impaired iron mobilization. These findings encourage further research into the relationship between heart failure and the hematologic system.

Cardiac Resynchronization Therapy Reduces the Risk of Hospitalizations in Patients With Advanced Heart Failure Results From the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) Trial

Background— In the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial, 1520 patients with advanced heart failure were assigned in a 1:2:2 ratio to optimal pharmacological therapy or optimal pharmacological therapy plus cardiac resynchronization therapy (CRT-P) or CRT with defibrillator (CRT-D). Use of CRT-P and CRT-D was associated with a significant reduction in combined risk of death or all-cause hospitalizations. Because mortality also was significantly reduced (optimal pharmacological therapy versus CRT-D only), an assessment of the true reduction in hospitalization rates must consider the competing risk of death and varying follow-up times. Methods and Results— To overcome the challenges of comparing treatment groups, we used a nonparametric test of right-censored recurrent events that accounts for multiple hospital admissions, differential follow-up time between treatment groups, and death as a competing risk. An end-point committee adjudicated and classified all hospitalizations. Compared with optimal pharmacological therapy, CRT-P and CRT-D were associated with a 21% and 25% reduction in all-cause, 34% and 37% reduction in cardiac, and 44% and 41% reduction in heart failure hospital admissions per patient-year of follow-up, respectively. Similar reductions were seen in hospitalization days per patient-year. The reduction in hospitalization rate for heart failure in the CRT groups appeared within days of randomization and remained sustained. Noncardiac hospitalization rates were not different between groups. Conclusion— Use of CRT with or without a defibrillator in advanced heart failure patients was associated with marked reductions in all-cause, cardiac, and heart failure hospitalization rates in an analysis that accounted for the competing risk of mortality and unequal follow-up time.

The Influence of Renal Function on Clinical Outcome and Response to β-Blockade in Systolic Heart Failure: Insights From Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF)

BACKGROUND Limited information is available on the risk and impact of renal dysfunction on the response to beta-blockade and mode of death in systolic heart failure (HF). METHODS AND RESULTS Renal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR(MDRD) > 60 (n = 2496), eGFR(MDRD) 45 to 60 (n = 976), and eGFR(MDRD) < 45 mL/min per 1.73 m(2) body surface area (n = 493). Hazard ratio (HR) was estimated with Cox proportional hazards models adjusted for prespecified risk factors. Placebo patients with eGFR < 45 had significantly higher risk than those with eGFR > 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR < 45 and eGFR > 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR < 45. For total mortality, metoprolol CR/XL vs placebo: HR, 0.41 (95% CI. 0.25 to 0.68; P < .001) in those with eGFR < 45 compared with HR, 0.71 (95% CI, 0.54 to 0.95; P < .021) for those with eGFR > 60; corresponding data for the combined end point was HR, 0.44 (95% CI, 0.31 to 0.63; P < .0001) and HR, 0.75 (0.62 to 0.92; P = .005, respectively; P = .095 for interaction by treatment for total mortality; P = .011 for combined end point). Metoprolol CR/XL was well tolerated in all 3 renal function subgroups. CONCLUSIONS Renal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR < 45 as in those with eGFR > 60.

Uric acid level and allopurinol use as risk markers of mortality and morbidity in systolic heart failure.

BACKGROUND Previous studies have not extensively examined the association of hyperuricemia and adverse outcomes in systolic heart failure (HF) in relation to xanthine oxidase inhibitor therapy. METHODS The Prospective Randomized Amlodipine Survival Evaluation study included New York Heart Association class IIIB or IV patients with left ventricular ejection fraction <30%. For analysis, the population was divided into uric acid quartiles among nonallopurinol users (2.2-7.1, >7.1-8.6, >8.6-10.4, >10.4 mg/dL) and those using allopurinol. Multivariate Cox regression modeling was performed to identify predictors of mortality. Uric acid quartile and allopurinol groups were referenced to the lowest uric acid quartile. RESULTS A total of 1,152 patients were included. In general, patients in the allopurinol group and in the highest uric acid quartile had indicators of more severe HF, including worse renal function and greater proportion of New York Heart Association class IV patients, and greater diuretic use. The allopurinol group and highest uric acid quartile had the highest total mortality (41.7 and 42.4 per 100 person-years, respectively) and combined morbidity/mortality (45.6 and 51.0 per 100 person-years, respectively). Allopurinol use and highest uric acid quartile were independently associated with mortality (hazard ratio [HR] 1.65, 95% CI 1.22-2.23, P = .001 and HR 1.35, 95% CI 1.07-1.72, P = .01, respectively) and combined morbidity/mortality (uric acid quartile 4 vs 1: HR 1.32, 95% CI 1.06-1.66, P = .02; allopurinol use: HR 1.48, 95% CI 1.11-1.99, P = .008). CONCLUSION Elevated uric acid level was independently associated with mortality in patients with severe systolic HF, even when accounting for allopurinol use.

The Critical Link of Hypervolemia and Hyponatremia in Heart Failure and the Potential Role of Arginine Vasopressin Antagonists

BACKGROUND Hypervolemia and hyponatremia resulting from activation of the neurohormonal system and impairment of renal function are prominent features of decompensated heart failure. Both conditions share many pathophysiologic and prognostic features and each has been associated with increased morbidity and mortality. When both conditions coexist, therapeutic options are limited. METHODS AND RESULTS This review presents a concise digest of the pathophysiology, clinical significance, and pharmacological therapy of hyponatremia complicating heart failure with a special emphasis on vasopressin antagonists and their aquaretic effects in the absence of neurohormonal activation along with their ability to correct hyponatremia. CONCLUSIONS Hypervolemia and hyponatremia share many pathophysiologic and prognostic features in heart failure. Vasopressin antagonists provide a viable option for their management and a potentially unique role when both conditions coexists.

Prospective evaluation of the association between hemoglobin concentration and quality of life in patients with heart failure

BACKGROUND Reduced hemoglobin has been associated with adverse outcomes in heart failure, but the relationship of hemoglobin to health-related quality of life in outpatients with this syndrome has not been well studied. METHODS We used data from the prospective, observational Study of Anemia in a Heart Failure Population Registry, which randomly selected outpatients with heart failure from specialty or community cardiology clinics. Hemoglobin was determined by finger stick at baseline and during medically indicated follow-up visits. Health-related quality of life was assessed using the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire at 3-month intervals for 12 months. RESULTS Adjusted regression analysis demonstrated a significant, direct, linear relationship between hemoglobin and health-related quality of life from baseline through 12 months follow-up on all Kansas City Cardiomyopathy Questionnaire domains (all P < .001) and the Summary and Physical domains of the Minnesota Living with Heart Failure Questionnaire (all P < .05). Adjusted categorical analysis of the change in Kansas City Cardiomyopathy Questionnaire Clinical scores associated with change in hemoglobin from baseline to 6 months also showed a significant relationship between increasing hemoglobin and improved health status (5.9 +/- 1.8 units for a hemoglobin increase of >or=1 g/dL, 0.7 +/- 1.2 units for change in hemoglobin <1 g/dL, and -2.6 +/- 1.4 units for a >or=1 g/dL decrease in hemoglobin, P < .001). CONCLUSIONS These prospective, observational results indicate that reduced hemoglobin is associated with poorer quality of life in patients with heart failure. Additional studies will be required to establish if this is a cause-and-effect relationship.

The safety and tolerability of darbepoetin alfa in patients with anaemia and symptomatic heart failure

To assess the safety and tolerability of darbepoetin alfa (DA) in the treatment of anaemia in heart failure (HF).

Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial

Many patients with heart failure and reduced EF remain at high risk for hospitalization despite evidence‐based therapy. Digoxin may decrease hospitalization; however, uncertainty persists concerning its proper administration and effect on mortality. This study investigated whether using dose response concepts to re‐evaluate the relationship between serum digoxin concentration and key mortality outcomes in patients with reduced EF in the Digitalis Investigation Group trial would help clarify efficacy and safety.

The efficacy and safety of lixivaptan in outpatients with heart failure and volume overload: results of a multicentre, randomized, double-blind, placebo-controlled, parallel-group study.

Volume overload is the dominant feature of decompensated heart failure (HF) and it often results in adverse clinical outcomes. Vasopressin receptor antagonists such as lixivaptan may provide effective volume unloading. This study assessed weight loss after 1 day and 8 weeks of treatment with lixivaptan in outpatients with HF and volume overload.

Does aspirin use adversely influence intermediate-term postdischarge outcomes for hospitalized patients who are treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers? Findings from Organized Program to Facilitate Life-Saving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF).

BACKGROUND Conflicting data exist regarding a potential deleterious association between aspirin (ASA) and angiotensin-converting enzyme inhibitors (ACEIs) when used concurrently in patients with heart failure (HF). How such an interaction may be influenced by underlying etiology of HF and whether it extends to patients treated with angiotensin receptor blockers (ARBs), however, are not known. METHODS Eligible patients from the OPTIMIZE-HF registry were dichotomized into those with ischemic or nonischemic HF. Potential associations between ASA and ACEI or ARB use and 60- to 90-day postdischarge outcomes were assessed using Cox proportional and logistic regression modeling. Models were adjusted for factors known to influence the outcome of interest and by propensity score for ACEI or ARB prescription after an index HF admission. RESULTS Mortality was not increased (hazard ratio [95% CI]) when ASA was used in conjunction with ACEI (0.51 [0.29-0.87]) or ARB (0.29 [0.09-0.96]) in patients with ischemic or nonischemic (ACEI 0.71 [0.42-1.21], ARB 1.42 [0.74-2.74]) HF. Regression model parameter estimates trended toward harm reduction, but interaction terms for mortality and a composite of mortality or rehospitalization were nonsignificant (P for all >.05). CONCLUSIONS When combined with ACEI or ARB, ASA had no demonstrable adverse effect on intermediate-term postdischarge outcomes for patients with ischemic or nonischemic HF.