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Abstract: Background: Transatlantic differences in outcomes in heart failure after acute myocardial infarction (AMI) have not been examined in propensity-matched studies. Methods: In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), there were significant imbalances in baseline characteristics between patients from North America (n =858) and Europe (n =4646). Propensity scores for North America, calculated for each patient using 64 baseline characteristics, were used to assemble 298 pairs of patients who were well balanced on all measured baseline characteristics. Matched Cox regression models were used to estimate transatlantic differences in outcomes. Results: There was no transatlantic difference in all-cause mortality during 16 months of mean follow-up of (matched hazard ratio {HR}, 1.00; 95% confidence interval {CI}, 0.64–1.57; P =1.000). All-cause hospitalization occurred in 175 (rate, 8974/10,000 person-years) and 137 (rate, 5249/10,000 person-years) patients respectively from North America and Europe (matched HR when North America was compared with Europe, 1.89; 95% CI, 1.41–2.52; P <0.0001). Matched HRs (95% CIs) for cardiovascular and non-cardiovascular hospitalization for North America were respectively 1.35 (0.92–1.97; P =0.125) and 1.89 (1.31–2.72; P <0.0001). Among 5504 pre-match patients, unadjusted, multivariable-adjusted, and propensity-adjusted HRs for all-cause hospitalization for North America were 1.52 (95% CI, 1.38–1.68; P <0.0001), 1.16 (95% CI, 1.02–1.31; P =0.020), 1.41 (95% CI, 1.17–1.70; P <0.0001). Conclusion: Despite major transatlantic differences in baseline characteristics, there was no difference in post-AMI mortality. The increased non-cardiovascular hospitalization in North America may in part be due to transatlantic differences in patient preferences and access to care. [Copyright &y& Elsevier]

Abstract: Background: Low serum magnesium levels may cause fatal ventricular arrhythmias. However, their long-term effects on mortality and morbidity in chronic heart failure patients are relatively unknown. Methods: We studied 1569 chronic systolic and diastolic heart failure patients with normal sinus rhythm who participated in the Digitalis Investigation Group trial and had serum magnesium data available at one month. Of these, 741 patients had normal (>2 mEq/L) and 828 had low (≤2 mEq/L) serum magnesium levels. Propensity scores for having low serum magnesium levels were calculated for each patient using a non-parsimonious multivariable logistic regression model, and were used to match 560 (76%) low-magnesium patients with 560 normal-magnesium patients. Effects of low-magnesium on mortality and hospitalization during a mean follow-up of 36 months were assessed using matched Cox regression analyses. Results: All-cause mortality occurred in 156 (rate, 915/10,000 person-years) normal- magnesium and 171 (rate, 1034/10,000 person-years) low-magnesium patients, respectively, during 1704 and 1653 years of follow-up (hazard ratio, 1.23; 95% confidence interval, 0.97–1.57; p =0.089). Cardiovascular mortality occurred in 110 (rate, 646/10,000 person-years) normal-magnesium and 133 (rate, 805/10,000 person-years) low-magnesium patients (hazard ratio, 1.38, 95% confidence interval, 1.04–1.83, p =0.024). Hazard ratios and 95% confidence intervals for all-cause and cardiovascular hospitalizations were respectively 1.18 (0.99–1.42; p =0.068) and 1.14 (0.94–1.39; p =0.182). Conclusions: In a propensity-matched population of ambulatory chronic heart failure patients who were balanced in all measured baseline covariates, serum magnesium level 2 mEq/L or less was associated with increased cardiovascular mortality, but had no association with cardiovascular hospitalization. [Copyright &y& Elsevier]

Abstract: Background: In heart failure (HF), digoxin at low serum digoxin concentrations (SDC) reduces all-cause mortality and HF hospitalizations. However, the effects of digoxin on other cause-specific outcomes have not been studied in a propensity-matched cohort. Methods: The Digitalis Investigation Group trial, conducted during 1991–1993, enrolled 7788 ambulatory chronic HF patients. This analysis focuses on 4843 patients: 982 receiving digoxin with low (0.5–0.9 ng/ml) SDC at one month, and 3861 receiving placebo and alive at one month. Propensity scores for low SDC, calculated using a non-parsimonious multivariable logistic regression model, were used to match 982 low-SDC patients with 982 placebo patients. Matched Cox regression analyses were used to determine the effect of digoxin at low SDC on outcomes. Results: All-cause mortality occurred in 315 placebo (rate, 1071/10,000 person-years) and 288 low-SDC digoxin (rate, 871/10,000 person-years) patients, respectively, during 2940 and 3305 years of follow up (hazard ratio {HR}, 0.81, 95% confidence interval {CI}, 0.68–0.98; p =0.028). Cardiovascular hospitalizations occurred in 493 placebo (2359/10,000 person-year) and 471 low-SDC digoxin (1963/10,000 person-year) patients, respectively during 2090 and 2399 years of follow up (HR, 0.82, 95% CI, 0.70–0.95; P =0.010). Low-SDC digoxin to placebo HR (95%CI) for HF mortality and HF hospitalizations were respectively, 0.65 (0.45–0.92; P =0.015) and 0.63 (0.52–0.77; P <0.0001). Low-dose digoxin (≤0.125 mg/day) was the strongest independent predictor of low SDC (adjusted odd ratio, 2.07, 95% CI 1.54–2.80). Conclusions: Digoxin at low SDC significantly reduced mortality and hospitalizations in ambulatory chronic systolic and diastolic HF patients. [Copyright &y& Elsevier]

Spironolactone might improve the prognosis of patients with heart failure with preserved left ventricular ejection fraction (HFpEF), but the mechanisms by which it acts are uncertain. Serum concentrations of procollagen type I carboxy-terminal propeptide (PICP) reflect the synthesis of type I collagen and correlate well with histologically proven cardiac fibrosis. To investigate the effect of spironolactone on serum PICP concentration in patients with stage B and C HFpEF across three trials (HOMAGE, ALDO-DHF, and TOPCAT) for which measurements of serum PICP were available. Random-effects meta-analysis. A total of 1038 patients with PICP measurements available both at baseline and 9–12 months were included in this analysis: 488 (47.0%) from HOMAGE, 386 (37.2%) from ALDO-DHF, and 164 (15.8%) from TOPCAT. The median (percentile 25 – 75) serum PICP was 98 (76–128) ng/mL. Compared to placebo or usual care, administration of spironolactone for 9 to 12 months reduced serum PICP by −7.4 ng/mL, 95%CI -13.9 to −0.9, P -value =0.02. The effect was moderately heterogeneous (I2 = 64%) with the most pronounced effect seen in TOPCAT where PICP was reduced by −27.0 ng/mL, followed by HOMAGE where PICP was reduced by −8.1 ng/mL, and was least marked in ALDO-DHF where PICP changed by −2.9 ng/mL. The association between spironolactone and serum PICP was not mediated substantially by blood pressure. Spironolactone reduced serum concentrations of PICP in patients with HFpEF with different severity and stages of disease. These findings are consistent with spironolactone having an anti-fibrotic effect. • Serum concentrations of procollagen type I carboxy-terminal propeptide (PICP) reflect the synthesis of type I collagen and correlate with cardiac fibrosis. • Administration of spironolactone for 9 to 12 months reduced serum PICP by −7.4 ng/mL, 95%CI -13.9 to −0.9, P-value =0.02, in HFpEF. • The association between spironolactone and serum PICP was not mediated substantially by blood pressure, findings consistent with spironolactone having an anti-fibrotic effect. [ABSTRACT FROM AUTHOR]

Inflammation plays a central role in the genesis and progression of heart failure with preserved ejection fraction (HFpEF). C-reactive protein (CRP) is widely used as means to assess systemic inflammation, and elevated levels of CRP have been associated with poor HF prognosis. Identification of chronic low-grade inflammation in outpatients can be performed measuring high-sensitivity CRP (hsCRP). The clinical characteristics and outcome associations of a pro-inflammatory state among outpatients with HFpEF requires further study. Using a biomarker subset of TOPCAT-Americas (NCT00094302), we aim to characterize HFpEF patients according to hsCRP levels and study the prognostic associations of hsCRP. hsCRP was available in a subset of 232 participants. Comparisons were performed between patients with hsCRP <2 mg/L and ≥ 2 mg/L. Cox regression models were used to study the association between hsCRP and the study outcomes. Compared to patients with hsCRP <2 mg/L (n = 89, 38%), those with hsCRP ≥2 mg/L (n = 143, 62%) had more frequent HF hospitalizations prior to randomization, chronic obstructive pulmonary disease, orthopnea, higher body mass index, and worse health-related quality-of-life. A hsCRP level ≥ 2 mg/L was associated with an increased risk of cardiovascular death and HF hospitalizations: hsCRP ≥2 mg/L vs <2 mg/L adjusted HR 2.36, 95%CI 1.27–4.38, P = 0.006. Spironolactone did not influence hsCRP levels from baseline to month 12: gMean ratio = 1.11, 95%CI 0.87–1.42, P = 0.39. A hsCRP ≥2 mg/L identified HFpEF patients with a high risk of HF events and cardiovascular mortality. Spironolactone did not influence hsCRP levels at 12 months. • Inflammation plays a central role in the progression of heart failure with preserved ejection fraction (HFpEF). • hsCRP was available in a subset of TOPCAT-Americas. Comparisons were performed between hsCRP <2 mg/L and ≥ 2 mg/L. • Patients with hsCRP ≥2 mg/L experienced an increased risk of HF events. Spironolactone did not change hsCRP levels. [ABSTRACT FROM AUTHOR]

Patients with heart failure with preserved ejection fraction (HFpEF) have poor health-related quality of life (HR-QoL). However, the relationship between HR-QoL measures and the alterations of cardiac structure and function that are present in patients with HFpEF remains unknown. To study the associations between HR-QoL and echocardiographic parameters in HFpEF. Regression modelling in patients from TOPCAT-Americas who had both HR-QoL questionnaires and a baseline echocardiogram. A total of 631 patients (36% of the TOPCAT-Americas population) had both echocardiographic and HR-QoL at baseline. KCCQ-23 Overall Summary Score (OSS; 0–100 points) was negatively (higher echocardiographic values-poorer/lower HR-QoL scores) associated with left ventricular end-diastolic diameter (LVEDD: β = −3.56 [−7.00 to −0.13] points-per-1 cm, P = 0.042), interventricular septum thickness (β = −1.31 [−2.19 to −0.42] points-per-1 mm, P = 0.004), posterior wall thickness (β = −1.57 [−2.52 to −0.63] points-per-1 mm, P = 0.001 and left atrial width (β = −3.27 [−6.39 to −0.15], P = 0.040) points-per-1 cm, and positively (higher echocardiographic values-better/higher HR-QoL scores) associated with left ventricular end-diastolic volume index (LVEDVi: β = 0.23 [0.09 to 0.37] points-per-1 ml/m2, P = 0.002) and left ventricular end-systolic volume index (LVESVi: β = 0.41 [0.18 to 0.63] points-per-1 ml/m2, P < 0.001). Body mass index (BMI: β = −0.74 [−1.02 to −0.47] points-per-1Kg/m2, P < 0.001), diabetes (β = −6.01 [−10.05 to −1.97], P = 0.004), and asthma (β = −6.78 [−13.52 to −0.04], P = 0.049) were negatively associated with OSS. A similar pattern of associations was observed for KCCQ-23 Clinical Summary Score, EQ5D-VAS and NYHA class. In patients with HFpEF, HR-QoL measures were associated with cardiac structure and function alterations. Extra-cardiac factors were also associated with HR-QoL, which may influence HR-QoL results when testing cardiovascular drugs. • Patients with HFpEF have poor quality of life. • The relationship between HR-QoL measures and the alterations of cardiac structure and function remain unknown. • In TOPCAT-Americas HR-QoL was associated with cardiac structure and function alterations, particularly measures reflection cardiac mass and atrial volume. • Extra-cardiac factors were also associated with HR-QoL, which may influence HR-QoL results when testing cardiovascular drugs. [ABSTRACT FROM AUTHOR]

Numerous registries, including the most recent ESC Euro-observational registry, have reported a large and persistent gap between real-life practice in the use of life-saving evidence-based therapies (such as renin angiotensin antagonists, beta-blockers, mineralocorticoid receptor antagonists) and recommended practices in international guidelines. Although the use of multiple renin angiotensin aldosterone system-inhibitors is associated with the development of worsening renal function and hyperkalemia in patients with heart failure and reduced ejection fraction, increased efforts should be expended to initiate and maintain target doses of these agents so as to provide their benefits on mortality and hospitalizations for heart failure. [ABSTRACT FROM AUTHOR]

After myocardial infarction (MI) complicated by heart failure (HF), eplerenone reduced serum concentrations of amino-terminal propeptide of type III collagen (PIIINP) and carboxy-terminal propeptide of type I collagen (PICP). Determining a subgroup who are more prone to decrease their collagen content and to respond better to the antifibrotic effects of mineralocorticoid receptor antagonists (MRA) may be relevant for a personalized treatment approach. Whether circulating microRNAs may identify a subgroup that have experienced a more pronounced antifibrotic effect of eplerenone as measured by a PICP and PIIINP decrease is unclear. A set of circulating microRNAs linked to cardiac fibrosis (mir-1, mir-21, mir-29a, mir-29b, mir-101, mir-122, mir-133a) were measured at baseline in 198 patients in the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Associations between baseline microRNA levels and changes in both PIIINP and PICP from baseline to month 9 were studied using multivariable analysis of covariance, adjusting for age, sex, history of hypertension and diabetes mellitus, prescription of ACE-inhibitors or angiotensin receptor blockers, baseline PIIINP or PICP, and eplerenone treatment. Furthermore, a treatment-by-microRNA interaction was studied. From the selected microRNAs, only mir-133a was associated with a PICP decrease (ß-6.43, 95%CI-12.71 to −0.15, p = 0.045). None of the microRNAs was associated with a PIIINP change. The microRNAs did not predict an effect of eplerenone on PICP and PIIINP changes. Although serum mir-133a was associated with PICP change, none of the microRNAs previously linked to cardiac fibrosis predicted an antifibrotic response to eplerenone. Further study is needed to identify other suitable targets for a personalized treatment approach. • MicroRNAs previously linked to cardiac fibrosis were measured in patients after an acute myocardial infarction complicated by heart failure. • Higher mir-133a levels were independently associated with a PICP decrease, which may suggest an antifibrotic response. • None of these microRNAs predicted an antifibrotic response to eplerenone in these patients. [ABSTRACT FROM AUTHOR]

Hyperkalemia is a common clinical problem, especially in patients with chronic kidney disease, diabetes mellitus, or heart failure. Treatment with renin angiotensin aldosterone system inhibitors exacerbates the risk of hyperkalemia in these patients. Concern about hyperkalemia can result in the failure to initiate, suboptimal dosing, or discontinuation of renin angiotensin aldosterone system inhibitor therapy in patients; effective treatments for hyperkalemia might mitigate such undertreatment. New treatments for hyperkalemia in development may offer better efficacy, tolerability and safety profiles than do existing approved treatments. These compounds might enable more eligible patients to receive renin angiotensin aldosterone system inhibitor therapy or to receive renin angiotensin aldosterone system inhibitors at target doses. The evidence needed to support a treatment claim (reduction in serum potassium) differs from that needed to support a prevention claim (preventing hyperkalemia to allow renin angiotensin aldosterone system inhibitor treatment). Thus, several issues related to clinical trial design and drug development need to be considered. This paper summarizes and expands upon a discussion at the Global Cardiovascular Clinical Trialists 2014 Forum and examines methodologic considerations for trials of new potassium binders for the prevention and management of hyperkalemia in patients with renin angiotensin aldosterone system inhibitor indications. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To examine the prevalence of peripheral artery disease (PAD) and the relationship between PAD and cardiovascular (CV) outcomes in subjects with left ventricular systolic dysfunction, heart failure or both after acute myocardial infarction (MI). Background: PAD is associated with poorer prognosis in patients with stable and unstable coronary heart disease but whether PAD is associated with worse outcomes following substantial acute MI is unknown. Methods: Univariate and multivariate Cox proportional hazards modelling was used to compare clinical outcomes in an individual-patient meta-analysis of 4 trials (CAPRICORN, EPHESUS, OPTIMAAL and VALIANT). Results: Of the 28,771 patients randomized, 2357 (8.2%) had PAD. These patients were older and had more co-morbidity and were less likely to be prescribed aspirin or a beta-blocker compared to patients without PAD. Over a mean follow-up of 2.7years, 5121 (17.8%) patients died and 15,055 (52.3%) experienced CV death or hospitalization. PAD was an independent predictor of all individual and composite CV outcomes examined (including heart failure), with the exception of stroke. In patients with PAD (compared to those without PAD), the adjusted hazard ratio (HR) for all-cause mortality was 1.25 (95% CI 1.15–1.37; p<0.001) and the HR for CV death, non-fatal MI, non-fatal stroke or heart failure hospitalization was 1.24 (1.16–1.33; p<0.001). Conclusions: PAD is common and is an independent predictor of worse outcomes in patients already at high risk after MI because of left ventricular systolic dysfunction, heart failure or both. These patients represent an important group for intensive application of secondary preventive therapies. [Copyright &y& Elsevier]

Abstract: The renin–angiotensin aldosterone system (RAAS) is central to the pathogenesis of cardiovascular disease. RAAS inhibition can reduce blood pressure, prevent target organ damage in hypertension and diabetes, and improve outcomes in patients with heart failure and/or myocardial infarction. This review presents the history of RAAS inhibition including a summary of key heart failure, myocardial infarction, hypertension and atrial fibrillation trials. Recent developments in RAAS inhibition are discussed including implementation and optimization of current drug therapies. Finally, ongoing clinical trials, opportunities for future trials and issues related to the barriers and approvability of novel RAAS inhibitors are highlighted. [Copyright &y& Elsevier]

Abstract: Background: Angiotensin-converting enzyme inhibitors improve outcomes in systolic heart failure (SHF). However, doubts linger about their effect in SHF patients with chronic kidney disease (CKD). Methods: In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, 2569 ambulatory chronic HF patients with left ventricular ejection fraction ≤35% and serum creatinine level ≤2.5mg/dl were randomized to receive either placebo (n=1284) or enalapril (n=1285). Of the 2502 patients with baseline serum creatinine data, 1036 had CKD (estimated glomerular filtration rate <60ml/min/1.73m2). Results: Overall, during 35months of median follow-up, all-cause mortality occurred in 40% (502/1252) and 35% (440/1250) of placebo and enalapril patients, respectively (hazard ratio {HR}, 0.84; 95% confidence interval {CI}, 0.74–0.95; p=0.007). All-cause mortality occurred in 45% and 42% of patients with CKD (HR, 0.88; 95% CI, 0.73–1.06; p=0.164), and 36% and 31% of non-CKD patients (HR, 0.82; 95% CI, 0.69–0.98; p=0.028) in the placebo and enalapril groups, respectively (p for interaction=0.615). Enalapril reduced cardiovascular hospitalization in those with CKD (HR, 0.77; 95% CI, 0.66–0.90; p<0.001) and without CKD (HR, 0.80; 95% CI, 0.70–0.91; p<0.001). Among patients in the enalapril group, serum creatinine elevation was significantly higher in those without CKD (0.09 versus 0.04mg/dl in CKD; p=0.003) during first year of follow-up, but there was no differences in changes in systolic blood pressure (mean drop, 7mm Hg, both) and serum potassium (mean increase, 0.2mEq/L, both). Conclusions: Enalapril reduces mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD. [Copyright &y& Elsevier]

Abstract: Background: Older age is an independent predictor of all-cause mortality in patients with mild to moderate heart failure (HF). Whether older age is also an independent predictor of mortality in patients with more advanced HF is unknown. Methods: Of the 2707 Beta-Blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF (New York Heart Association class III/IV and left ventricular ejection fraction <35%), 1091 were elderly (≥65years). Propensity scores for older age, estimated for each of the 2707 patients, were used to assemble a cohort of 603 pairs of younger and older patients, balanced on 66 baseline characteristics. Results: All-cause mortality occurred in 33% and 36% of younger and older matched patients respectively during 4years of follow-up (hazard ratio {HR} associated with age ≥65years, 1.05; 95% confidence interval {CI}, 0.87–1.27; P =0.614). HF hospitalization occurred in 38% and 40% of younger and older matched patients respectively (HR, 1.01; 95% CI, 0.84–1.21; P =0.951). Among 603 pairs of unmatched and unbalanced patients, all-cause mortality occurred in 28% and 36% of younger and older patients respectively (HR, 1.34; 95% CI, 1.10–1.64; P =0.004) and HF hospitalization occurred in 34% and 40% of younger and older unmatched patients respectively (HR, 1.24; 95% CI, 1.03–1.50; P =0.024). Conclusion: Significant bivariate associations suggest that older age is a useful marker of poor outcomes in patients with advanced chronic systolic HF. However, lack of significant independent associations suggests that older age per se has no intrinsic effect on outcomes in these patients. [Copyright &y& Elsevier]

Abstract: Background: Compared with serum potassium levels 4–5.5 mEq/L, those <4 mEq/L have been shown to increase mortality in chronic heart failure (HF). Expert opinions suggest that serum potassium levels >5.5 mEq/L may be harmful in HF. However, little is known about the safety of serum potassium 5–5.5 mEq/L. Methods: Of the 7788 chronic HF patients in the Digitalis Investigation Group trial, 5656 had serum potassium 4–5.5 mEq/L. Of these, 567 had mild hyperkalemia (5–5.5 mEq/L) and 5089 had normokalemia (4–4.9 mEq/L). Propensity scores for mild hyperkalemia were used to assemble a balanced cohort of 548 patients with mild hyperkalemia and 1629 patients with normokalemia. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for association between mild hyperkalemia and mortality during a median follow-up of 38 months. Results: All-cause mortality occurred in 36% and 38% of matched patients with normokalemia and mild hyperkalemia respectively (HR, 1.07; 95% CI, 0.90–1.26; P =0.458). Unadjusted, multivariable-adjusted, and propensity-adjusted HRs for mortality associated with mild hyperkalemia were 1.33 (95% CI, 1.15–1.52; P <0.0001), 1.16 (95% CI, 1.01–1.34; P =0.040) and 1.13 (95% CI, 0.98–1.31; P =0.091) respectively. Mild hyperkalemia had no association with cardiovascular or HF mortality or all-cause or cardiovascular hospitalization. Conclusion: Serum potassium 4–4.9 mEq/L is optimal and 5–5.5 mEq/L appears relatively safe in HF. Despite lack of an intrinsic association , the bivariate association of mild-hyperkalemia with mortality suggests that it may be useful as a biomarker of poor prognosis in HF. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hypokalemia is common in heart failure (HF) and is associated with increased mortality. Potassium supplements are commonly used to treat hypokalemia and maintain normokalemia. However, their long-term effects on outcomes in chronic HF are unknown. We used a public-use copy of the Digitalis Investigation Group (DIG) trial dataset to determine the associations of potassium supplement use with outcomes using a propensity-matched design. Methods: Of the 7788 DIG participants with chronic HF, 2199 were using oral potassium supplements at baseline. We estimated propensity scores for potassium supplement use for each patient and used them to match 2131 pairs of patients receiving and not receiving potassium supplements. Matched Cox regression models were used to estimate associations of potassium supplement use with mortality and hospitalization during 40 months of median follow-up. Results: All-cause mortality occurred in 818 (rate, 1327/10,000 person-years) and 802 (rate, 1313/10,000 person-years) patients respectively receiving and not receiving potassium supplements (hazard ratio {HR} when potassium supplement use was compared with nonuse, 1.05; 95% confidence interval {CI}, 0.94–1.18; P =0.390). All-cause hospitalizations occurred in 1516 (rate, 4777/10,000 person-years) and 1445 (rate, 4120/10,000 person-years) patients respectively receiving and not receiving potassium supplements (HR, 1.15; 95% CI, 1.05–1.26; P =0.004). HRs (95% CI) for hospitalizations due to cardiovascular causes and worsening HF were respectively 1.19 (95% CI, 1.08–1.32; P =0.001) and 1.27 (1.12–1.43; P <0.0001). Conclusion: The use of potassium supplements in chronic HF was not associated with mortality. However, their use was associated with increased hospitalization due to cardiovascular causes and progressive HF. [Copyright &y& Elsevier]

Abstract: Background: There is minimal evidence that HMG-CoA reductase inhibitors (statins) are beneficial in patients with chronic heart failure (CHF). Treatment with statins may lead to a lower mortality in CHF, independent of cholesterol levels, CHF etiology and clinical status. Methods: In a first study, we included 3132 patients with CHF from the ELITE 2 study in whom information on body mass index (BMI) and statin use at baseline were available. In a second study, we pooled the databases of 5 tertiary referral centers with 2068 CHF patients. In this cohort 705 patients were on a statin (34%), 585 of 1202 (49%) patients with ischemic etiology, and 120 of 866 (14%) patients with non-ischemic etiology (established by coronary angiography). Findings: Patients in ELITE 2 who received statin therapy at baseline (n =397, 13%) had lower mortality (hazard ratio [HR] 0.61, 95% CI 0.45–0.83; p =0.0007). In univariate analysis, increasing age, NYHA class, creatinine, and decreasing BMI, LVEF, and cholesterol, as well as lack of beta-blocker treatment and ischemic etiology (all p <0.002) related to higher mortality. In multivariable analysis, statin therapy related to lower mortality independently of all these variables (adjusted HR 0.66, 95% CI 0.47–0.93; p =0.017). In the second study CHF patients on statins had lower mortality (adjusted HR 0.58, 95% CI 0.44–0.77; p =0.0001). Both in patients with ischemic (p <0.0001) and non-ischemic etiology (p =0.028) statin treatment related to better survival. Interpretation: In chronic heart failure, treatment with statins is related to lower mortality, independent of cholesterol levels, disease etiology and clinical status. [Copyright &y& Elsevier]