Chronic kidney disease associated mortality in diastolic versus systolic heart failure: a propensity matched study

Chronic kidney disease (CKD) is common and is associated with increased mortality in heart failure (HF). However, it is unknown whether the effect of CKD on mortality varies by left ventricular ejection fraction (LVEF). We evaluated the effect of CKD on mortality in patients with systolic (LVEF 45%) HF. Of the 7,788 patients in the Digitalis Investigation Group trial, 3,527 (45%) had CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2). We calculated the propensity score for CKD for each patient, using a multivariate logistic regression model (c statistic 0.76, postmatch absolute standardized differences <5% for all 32 co-variates). We matched 2,399 pairs of patients with and without CKD with similar propensity scores. There were 757 (rate 1,049/10,000 person-years) and 882 (rate 1,282/10,000 person-years) deaths, respectively, in patients without and with CKD (hazard ratio 1.22, 95% confidence interval 1.09 to 1.36, p <0.0001). CKD-associated mortality was higher in those with diastolic HF (371 extra deaths/10,000 person-years, hazard ratio 1.71, 95% confidence interval 1.21 to 2.41, p = 0.002) than in systolic HF (214 extra deaths/10,000 person-years, hazard ratio 1.19, 95% confidence interval 1.07 to 1.32, p = 0.001), which was significant (adjusted p for interaction = 0.034). A graded association was found between CKD-related deaths and LVEF. The hazard ratios for CKD-associated mortality for the LVEF subgroups of <35%, 35% to 55%, and >55% were 1.15 (95% confidence interval 1.02 to 1.29), 1.35 (95% confidence interval 1.11 to 1.64), and 2.33 (95% confidence interval 1.34 to 4.06). In conclusion, CKD-associated mortality was higher in those with diastolic than systolic HF. Patients with diastolic HF should be evaluated for CKD, and the role of inhibitors of the renin-angiotensin system in these patients needs to be investigated.     

Is ramipril really better than other angiotensin-converting enzyme inhibitors after acute myocardial infarction?

Whether angiotensin-converting enzyme (ACE) inhibitors are interchangeable and equally efficacious after acute myocardial infarction (AMI) is controversial. We assessed whether ramipril was superior to other ACE inhibitors after AMI as suggested by a previously published study. We performed a retrospective cohort study using linked administrative databases on >1.4 million elderly residents in the province of Ontario who were admitted to the hospital for AMI, survived >or=30 days after discharge, and were initiated on an ACE inhibitor after AMI and remained on the same ACE inhibitor from April 1, 1997 to March 31, 2000. We followed patients for 2 years and measured readmission for AMI or mortality, together or alone. Our cohort included 5,408 elderly patients. Compared with patients on enalapril, there was no significant difference for the combined end points of readmission for AMI or mortality across users of ramipril (adjusted hazard ratio 0.95, 95% confidence interval 0.79 to 1.15), lisinopril (adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.25), or other ACE inhibitors (adjusted hazard ratio 1.08, 95% confidence interval 0.88, 1.32). In conclusion, the findings of this study support a class effect among ACE inhibitors in treatment after AMI.     

Predictors of mortality in patients with heart failure and preserved systolic function in the Digitalis Investigation Group trial.

OBJECTIVES: We identified predictors of mortality in patients with preserved ejection fraction (EF) and clinical heart failure (HF). BACKGROUND: Although diastolic HF is common, the factors that predict mortality have not been clearly defined. METHODS: We studied 988 patients with HF and preserved EF enrolled in the Digitalis Investigation Group (DIG) trial. Survival analyses were employed to identify variables associated with mortality. RESULTS: During 3.1 years of follow-up, 231 (23%) patients died. Among 18 variables considered, the strongest independent predictors of death were glomerular filtration rate (adjusted hazard ratio for one standard deviation decrease 1.50, 95% confidence interval [CI] 1.35 to 1.67, p < 0.0001), New York Heart Association functional class III or IV (adjusted hazard ratio 1.64, 95% CI 1.20 to 2.18, p = 0.0011), male gender (adjusted hazard ratio 1.71, 95% CI 1.26 to 2.32, p = 0.0005), and older age (adjusted hazard ratio for one standard deviation increase of age2 1.28, 95% CI 1.08 to 1.50, p = 0.0019). A risk score was developed to estimate long-term mortality. CONCLUSIONS: Diastolic HF is associated with a high death rate. Important predictors of death include impaired renal function, worse functional class, male gender, and older age.     

Comparison of outcomes of illicit drug users and nonusers hospitalized with heart failure

The long-term effects of illicit drug use (IDU) on the clinical outcome of patients with heart failure (HF) are not well described. The objective of the present study was to describe the characteristics of patients with HF who used illicit drugs and to determine the effects of IDU on the clinical outcomes such as in-hospital mortality and hospital readmission for HF. A retrospective cohort study was conducted that included all patients admitted with HF from June 2003 to September 2004 and followed up until 2008 at a university hospital serving an at-risk population. The patients were divided into 2 groups: IDU and non-IDU according to self-reported use or positive laboratory results. The outcome measures were in-hospital mortality, HF readmission rate, interval to readmission for HF, and average brain natriuretic peptide and troponin levels throughout the follow-up period. Of 646 reviewed records, 542, representing 357 patients, were included in the present analysis. Of the 357 patients, 53 patients were in the IDU group and 304 were in the non-IDU group. Kaplan-Meier log-rank analysis and Cox proportional hazard analysis showed that IDU was associated with a shorter interval to readmission for HF (hazard ratio 3.8, 95% confidence interval 2.3 to 10.7, p <0.0001) but not with in-hospital mortality (hazard ratio 0.7, 95% confidence interval 0.3 to 1.7, p = 0.4). Multiple linear regression analysis identified IDU as an independent variable for the HF readmission rate (p = 0.0001) but not for average brain natriuretic peptide or average troponin levels. In conclusion, the results of the present study have demonstrated that IDU was associated with a decreased interval to readmission for HF and greater HF readmission rates.     

Warfarin use and outcomes in patients with advanced chronic systolic heart failure without atrial fibrillation, prior thromboembolic events, or prosthetic valves

Warfarin is often used in patients with systolic heart failure (HF) to prevent adverse outcomes. However, its long-term effect remains controversial. The objective of this study was to determine the association of warfarin use and outcomes in patients with advanced chronic systolic HF without atrial fibrillation (AF), previous thromboembolic events, or prosthetic valves. Of the 2,708 BEST patients, 1,642 were free of AF without a history of thromboembolic events and without prosthetic valves at baseline. Of these, 471 patients (29%) were receiving warfarin. Propensity scores for warfarin use were estimated for each patient and were used to assemble a matched cohort of 354 pairs of patients with and without warfarin use who were balanced on 62 baseline characteristics. Kaplan-Meier and Cox regression analyses were used to estimate the association between warfarin use and outcomes during 4.5 years of follow-up. Matched participants had a mean age ± SD of 57 ± 13 years with 24% women and 24% African-Americans. All-cause mortality occurred in 30% of matched patients in the 2 groups receiving and not receiving warfarin (hazard ratio 0.86, 95% confidence interval 0.62 to 1.19, p = 0.361). Warfarin use was not associated with cardiovascular mortality (hazard ratio 0.97, 95% confidence interval 0.68 to 1.38, p = 0.855), or HF hospitalization (hazard ratio 1.09, 95% confidence interval 0.82 to 1.44, p = 0.568). In conclusion, in patients with chronic advanced systolic HF without AF or other recommended indications for anticoagulation, prevalence of warfarin use was high. However, despite a therapeutic international normalized ratio in those receiving warfarin, its use had no significant intrinsic association with mortality and hospitalization.     

Usefulness of body mass index to characterize nutritional status in patients with heart failure

The obesity paradox in heart failure (HF) is criticized because of the limitations of body mass index (BMI) in correctly characterizing overweight and obese patients, necessitating a better evaluation of nutritional status. The aim of this study was to assess nutritional status, BMI, and significance in terms of HF survival. Anthropometry and biochemical nutritional markers were assessed in 55 HF patients. Undernourishment was defined as the presence of ≥2 of the following indexes below the normal range: triceps skinfold, subscapular skinfold, arm muscle circumference, albumin, and total lymphocyte count. Patients were also stratified by BMI and followed for a median of 26.7 months. Across BMI strata, no patient was underweight, 31% were normal weight, 42% were overweight, and 27% were obese. Undernourishment was present in 53% of normal-weight patients, 22% of overweight patients, and none of the obese patients (p = 0.001). Undernourished patients had significantly higher mortality (p = 0.009) compared to well-nourished patients. In multivariate analysis, only undernutrition (hazard ratio 3.149, 95% confidence interval 1.367 to 7.253), New York Heart Association functional class (hazard ratio 3.374, 95% confidence interval 1.486 to 7.659), and age (hazard ratio 1.115, 95% confidence interval 1.045 to 1.189) remained in the model. Among nutritional indicators, subscapular skinfold was the best predictor of mortality; patients with subscapular skinfold in the fifth percentile had higher mortality (p = 0.0001). In conclusion, BMI does not indicate true nutritional status in HF. Classifying patients as well nourished or undernourished may improve risk stratification.     

Opposing effects of β blockers and angiotensin-converting enzyme inhibitors on development of new-onset diabetes mellitus in patients with stable coronary artery disease

We used data from patients with stable coronary artery disease (CAD) to assess the risk of new-onset diabetes mellitus (NOD) with β blockers and to determine whether angiotensin-converting enzyme (ACE) inhibition would modify this risk. The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial randomized 8,290 patients with stable CAD to trandolapril or placebo. Presence of NOD was assessed at each study visit over a median follow-up time of 4.8 years. We examined the risk of NOD associated with β-blocker use with Cox regression models adjusting for 25 baseline covariates and tested whether this risk was modified by randomization to the ACE inhibitor. Of 6,910 patients without diabetes mellitus at enrollment (1,179 women and 5,731 men, mean age 64 ± 8 years), 4,147 (60%) were taking β blockers and 733 (8.8%) developed NOD. We observed a significant interaction between β-blocker use and randomization to ACE inhibitor with respect to NOD (p = 0.028). Participants taking β blockers assigned to the placebo group (n = 2,090) were at increased risk for NOD adjusting for baseline covariates (hazard ratio 1.63, 95% confidence interval 1.29 to 2.05, p <0.001), and this risk was attenuated in those assigned to trandolapril (n = 2,057, hazard ratio 1.11, 95% confidence interval 0.87 to 1.42, p = 0.39). β blocker use was associated with increased risk for NOD in patients with stable CAD, and this risk was decreased in patients treated concurrently with an ACE inhibitor. In conclusion, these data suggest that ACE inhibition may attenuate the risk for glucose abnormalities observed in patients taking β blockers.     

Effect of statin therapy on survival in patients with nonischemic dilated cardiomyopathy (from the Beta-blocker Evaluation of Survival Trial [BEST])

To determine whether statin therapy improves survival in patients with heart failure (HF) secondary to nonischemic dilated cardiomyopathy (non-IDC), data from 1,024 patients with non-IDC (New York Heart Association functional class III and IV HF) and left ventricular ejection fraction < or =0.35 who were enrolled in the BEST were analyzed. The association of statin therapy at the initial screening visit with all-cause and cardiovascular mortality was evaluated using multivariate Cox proportional hazards models. After adjusting for age, gender, race, systolic blood pressure, total cholesterol, New York Heart Association functional class IV, estimated glomerular filtration rate, current cigarette smoking, left ventricular ejection fraction, angiotensin-converting enzyme inhibitor use, antiplatelet therapy, diabetes mellitus, treatment group (beta blocker or placebo), and hypertension, statin use was independently associated with decreased all-cause mortality (hazard ratio 0.38, confidence interval 0.18 to 0.82, p = 0.0134) and also with decreased cardiovascular death (hazard ratio 0.42, confidence interval 0.18 to 0.95, p = 0.037). In conclusion, in patients with moderate or severe HF due to non-IDC entered into BEST, statin therapy at entry was independently associated with a decrease in all-cause and cardiovascular mortality.     

Relation of beta(2)-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure

Heart failure (HF) is characterized by neurohormonal activation of the sympathetic nervous and renin-angiotensin systems. Genetic polymorphisms in these systems could alter the prognosis in HF. We hypothesized the genetic polymorphisms in the sympathetic nervous and renin-angiotensin systems are associated with adverse outcomes, defined as death or heart transplantation in patients with HF. A total of 227 patients with HF were enrolled from a tertiary care clinic and followed for outcomes for < or =4 years. Eight polymorphisms in 6 genes were genotyped: beta(1)-adrenergic receptor (ADRB1, S49G, R389G), beta(2)-adrenergic receptor (ADRB2, G16R, Q27E), alpha(2c)-adrenergic receptor (ADRA2C, insertion/deletion 322-325), angiotensinogen (AGT, M235T), angiotensin receptor type 1 (AGTR1, 1166A>C), and angiotensin-converting enzyme (ACE, insertion/deletion in intron 16). Most patients were treated according to consensus guidelines. Male gender (hazard ratio 2.24, 95% confidence interval 1.27 to 3.94), higher New York Heart Association functional class (hazard ratio 2.54, 95% confidence interval 1.84 to 3.52), and 2 copies of ADRB2 Arg16Gln27 haplotype (hazard ratio 1.91, 95% confidence interval 1.09 to 3.36) increased the risk of adverse outcomes. In contrast, a higher serum sodium level (hazard ratio 0.91, 95% confidence interval 0.86 to 0.97) and higher creatinine clearance (hazard ratio 0.99, 95% confidence interval 0.98 to 0.99) decreased the risk of adverse outcomes. None of the other genotypes/haplotypes were associated with adverse outcomes. In conclusion, ADRB2 Arg16Gln27 haplotype may significantly increase the risk of adverse outcomes in patients with HF receiving contemporary HF pharmacotherapy.     

Usefulness of pulmonary artery pressure by echocardiography to predict outcome in patients receiving cardiac resynchronization therapy heart failure

Secondary pulmonary hypertension is a marker of advanced heart failure (HF) that confers a poor prognosis. Consecutive patients from 2004 through 2005 who underwent echocardiographic assessments of systolic pulmonary arterial pressure (SPAP) before the implantation of cardiac resynchronization therapy defibrillators were included. Patients were divided into tertiles according to baseline SPAP. Patients in the lowest (group I, 20 to 29 mm Hg) and highest (group III, 45 to 88 mm Hg) tertiles were compared for the end points or death or transplantation and for HF hospital admission. Two hundred seventy patients were evaluated, of whom 95% were Caucasians and 91% men. The mean age was 66.5 +/- 11.6 years, the mean QRS duration was 155 +/- 30 ms, the mean left ventricular ejection fraction was 22.6 +/- 9.7%, and the mean New York Heart Association functional class was 3.0 +/- 0.4. In a multivariate model, death or transplantation was significantly more likely in group III (hazard ratio 2.62, 95% confidence interval 1.1 to 6.4, p = 0.036), as was HF admission (hazard ratio 6.35, 95% confidence interval 2.6 to 15.8, p <0.001). In patients with follow-up echocardiographic assessments, a reduction in SPAP was a significant predictor of freedom from the combined end point (hazard ratio 0.29, 95% confidence interval 0.12 to 0.76, p = 0.011). In conclusion, elevated baseline SPAP in patients who underwent cardiac resynchronization therapy is an independent predictor of all-cause mortality or transplantation and HF admission. A decrease in SPAP on follow-up echocardiography is an independent positive prognostic marker.     

Renal insufficiency as an independent predictor of mortality among women with heart failure

OBJECTIVES: We sought to explore the association between renal insufficiency and mortality among women with heart failure (HF) and to evaluate this risk by the presence of preserved or depressed systolic function. BACKGROUND: Although HF is common in older women, little is known about their risk factors for mortality. METHODS: This prospective cohort study retrospectively analyzed data from the Heart and Estrogen/progestin Replacement Study (HERS). Of the 2,763 women in HERS, 702 had HF. Renal function was categorized as creatinine clearance (CrCl) >60 ml/min, 40 to 60 ml/min, and <40 ml/min. We used proportional hazards models to evaluate the association between renal insufficiency and mortality. RESULTS: Over a mean 5.8 years, 228 women with HF died (32%). Renal insufficiency was strongly associated with mortality, even after adjustment for co-morbid conditions, systolic function, and medications (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.09 to 2.16 for CrCl 40 to 60 ml/min; adjusted HR 2.40, 95% CI 1.60 to 3.62 for CrCl <40 ml/min). Preserved or depressed systolic function did not modify the association between renal insufficiency and mortality risk, but the use of angiotensin-converting enzyme (ACE) inhibitors did modify this risk (ACE users: adjusted HR = 0.9, 95% CI 0.6 to 1.6; ACE nonusers: adjusted HR 2.1, 95% CI 1.3 to 3.2; p = 0.02 for interaction). Compared with other risk factors for mortality, renal insufficiency had the highest population attributable risk (27%). CONCLUSIONS: Renal insufficiency was a major predictor of mortality among women with HF and preserved or depressed systolic function. This risk was attenuated by the use of ACE inhibitors.     

A propensity-matched study of outcomes of chronic heart failure (HF) in younger and older adults

The majority of heart failure (HF) patients are older adults and most HF-related adverse events occur in these patients. However, the independent association of age and outcomes in HF is not clearly determined. We categorized 7788 ambulatory HF patients who participated in the Digitalis Investigation Group (DIG) trial as younger (< 65 years) and older (> or = 65 years). Propensity scores for older age were calculated for each patient and used to match 2381 pairs of younger and older patients. The associations of older age with mortality and hospitalization during a median 40 months of follow-up were assessed using matched Cox regression models. All-cause mortality occurred in 877 older patients versus 688 younger patients (hazard ratio when older age was compared with younger age (HR)=1.26; 95% confidence interval (CI)=1.12-1.41; p<0.0001). Older patients, when compared with propensity-matched younger patients, also had significantly higher mortality rates due to cardiovascular causes (HR=1.14; 95% CI=1.00-1.30; p=0.044) and worsening heart failure causes (HR=1.32; 95% CI=1.07-1.62; p=0.009). No significant association was found between age and hospitalization due to all causes (HR=1.08; 95% CI=0.99-1.18; p=0.084) and cardiovascular causes (HR=1.03; 95% CI=0.93-1.13; p=0.622). However, hospitalization due to HF was significantly increased in older patients (HR=1.14; 95% CI=1.01-1.28; p=0.041). In ambulatory HF patients, older age although associated with increased mortality, was not associated with increased hospitalizations except for those due to worsening HF.     

A propensity-matched study of the association of physical function and outcomes in geriatric heart failure

Most heart failure (HF) patients are older adults. However, the association of functional status and outcomes in ambulatory older adults with chronic HF has not been well studied. Of the 7788 Digitalis Investigation Group (DIG) trial participants, 4036 were > or =65 years. Of these, 1369 (34%) had New York Heart Association (NYHA) class III-IV symptoms. We calculated propensity scores for NYHA III-IV symptoms for all 4036 patients using a non-parsimonious logistic regression model. We used propensity scores to match 1010 (74% of 1369) NYHA III-IV patients with 1010 of NYHA I-II patients. Kaplan-Meier and matched Cox proportion hazard analyses were used to estimate associations of NYHA class III-IV with mortality and hospitalizations. Patients had a mean age of 73 years, 31% were female, and 11% were nonwhites. All-cause mortality occurred in 394 (rate, 1385/10000 person-years) NYHA I-II and 452 (rate, 1654/10000 person-years) NYHA III-IV patients, respectively, during 2967 and 2733 years of follow up (hazard ratio: {HR}, 1.28; 95% confidence interval {CI}, 1.09-1.50; p=0.002). NYHA III-IV class was associated with increased cardiovascular (HR, 1.25; 95% CI, 1.04-1.49; p=0.016) and HF mortality (HR, 1.51; 95% CI, 1.16-1.97; p=0.002). NYHA III-IV class was not significantly associated with hospitalizations due to all causes (HR, 1.10; 95% CI, 0.96-1.25; p=0.165), cardiovascular causes (HR, 1.11; 95% CI, 0.96-1.29; p=0.150), or worsening HF (HR, 1.09, 95% CI, 0.92-1.30; p=0.330). Baseline NYHA functional class was associated with mortality but not with hospitalization in ambulatory older adults with chronic HF.     

Outcomes of preoperative Angiotensin-converting enzyme inhibitor therapy in patients undergoing isolated coronary artery bypass grafting

The association between preoperative use of angiotensin-converting enzyme (ACE) inhibitors and outcomes after coronary artery bypass grafting (CABG) remain controversial. Our aim was to study in-hospital outcomes after isolated CABG in patients on preoperative ACE inhibitors. A retrospective analysis of 8,889 patients who underwent isolated CABG from 2000 through 2011 was conducted. The primary outcome of interest was the incidence of major adverse events (MAEs) defined as a composite of mortality, postoperative renal dysfunction, myocardial infarction, stroke, and atrial fibrillation during index hospitalization. The secondary outcome was the incidence of individual outcomes included in MAEs. Logistic regression analyses were performed. Of 8,889 patients, 3,983 (45%) were on preoperative ACE inhibitors and 4,906 (55%) were not. Overall incidence of MAEs was 38.1% (n = 1,518) in the ACE inhibitor group compared to 33.6% (n = 1,649) in the no-ACE inhibitor group. Preoperative use of ACE inhibitors was independently associated with MAEs (odds ratio 1.13, 95% confidence interval 1.03 to 1.24), most of which was driven by a statistically significant increase in postoperative renal dysfunction (odds ratio 1.18, 95% confidence interval 1.03 to 1.36) and atrial fibrillation (odds ratio 1.15, 95% confidence interval 1.05 to 1.27). In-hospital mortality, postoperative myocardial infarction, and stroke were not significantly associated with preoperative ACE inhibitor use. Analyses performed after excluding patients with low ejection fractions yielded similar results. In conclusion, preoperative ACE inhibitor use was associated with an increased risk of MAEs after CABG, in particular postoperative renal dysfunction and atrial fibrillation.