Chronic obstructive pulmonary disease does not impair responses to resistance training.

BACKGROUND: Subjects with chronic obstructive pulmonary disease (COPD) are prone to accelerated decay of muscle strength and mass with advancing age. This is believed to be driven by disease-inherent systemic pathophysiologies, which are also assumed to drive muscle cells into a state of anabolic resistance, leading to impaired abilities to adapt to resistance exercise training. Currently, this phenomenon remains largely unstudied. In this study, we aimed to investigate the assumed negative effects of COPD for health- and muscle-related responsiveness to resistance training using a healthy control-based translational approach. METHODS: Subjects with COPD (n = 20, GOLD II-III, FEV1predicted 57 ± 11%, age 69 ± 5) and healthy controls (Healthy, n = 58, FEV1predicted 112 ± 16%, age 67 ± 4) conducted identical whole-body resistance training interventions for 13 weeks, consisting of two weekly supervised training sessions. Leg exercises were performed unilaterally, with one leg conducting high-load training (10RM) and the contralateral leg conducting low-load training (30RM). Measurements included muscle strength (nvariables = 7), endurance performance (nvariables = 6), muscle mass (nvariables = 3), muscle quality, muscle biology (m. vastus lateralis; muscle fiber characteristics, RNA content including transcriptome) and health variables (body composition, blood). For core outcome domains, weighted combined factors were calculated from the range of singular assessments. RESULTS: COPD displayed well-known pathophysiologies at baseline, including elevated levels of systemic low-grade inflammation ([c-reactive protein]serum), reduced muscle mass and functionality, and muscle biological aberrancies. Despite this, resistance training led to improved lower-limb muscle strength (15 ± 8%), muscle mass (7 ± 5%), muscle quality (8 ± 8%) and lower-limb/whole-body endurance performance (26 ± 12%/8 ± 9%) in COPD, resembling or exceeding responses in Healthy, measured in both relative and numeric change terms. Within the COPD cluster, lower FEV1predicted was associated with larger numeric and relative increases in muscle mass and superior relative improvements in maximal muscle strength. This was accompanied by similar changes in hallmarks of muscle biology such as rRNA-content↑, muscle fiber cross-sectional area↑, type IIX proportions↓, and changes in mRNA transcriptomics. Neither of the core outcome domains were differentially affected by resistance training load. CONCLUSIONS: COPD showed hitherto largely unrecognized responsiveness to resistance training, rejecting the notion of disease-related impairments and rather advocating such training as a potent measure to relieve pathophysiologies. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02598830. Registered November 6th 2015, https://clinicaltrials.gov/ct2/show/NCT02598830.

Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2D). The comparative efficacy of individual SGLT2i remains unclear. We searched PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials for randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in patients with T2D. Comparators included placebo or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints were cardiovascular mortality and worsening heart failure (HF). Evidence was synthesised using network meta-analysis (NMA). Sixty-four trials reporting on 74,874 patients were included. The overall quality of evidence was high. When compared with placebo, empagliflozin and canagliflozin improved all three endpoints, whereas dapagliflozin improved worsening HF. When compared with other SGLT2i, empagliflozin was superior for all-cause and cardiovascular mortality reduction. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Ertugliflozin had no effect on any of the three endpoints investigated. Sensitivity analyses including extension periods of trials or excluding studies with a treatment duration of < 52 weeks confirmed the main results. Similar results were obtained when restricting mortality analyses to patients included in cardiovascular outcome trials (n = 38,719). Empagliflozin and canagliflozin improved survival with empagliflozin being superior to the other SGLT2i. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Prospective head-to-head comparisons would be needed to confirm these results.

Gender differences in association between uric acid and all-cause mortality in patients with chronic heart failure.

BACKGROUND: Elevated serum uric acid (SUA) is associated with poor prognosis in patients with cardiovascular disease, yet it is still not decided whether the role of SUA is causal or only reflects an underlying disease. The purpose of the study was to investigate if SUA was an independent predictor of 5-year all-cause mortality in a propensity score matched cohort of chronic heart failure (HF) outpatients. Furthermore, to assess whether gender or renal function modified the effect of SUA. METHODS: Patients (n = 4684) from the Norwegian Heart Failure Registry with baseline SUA were included in the study. Individuals in the highest gender-specific SUA quartile were propensity score matched 1:1 with patients in the lowest three SUA quartiles. The propensity score matching procedure created 928 pairs of patients (73.4% males, mean age 71.4 ± 11.5 years) with comparable baseline characteristics. Kaplan Meier and Cox regression analyses were used to investigate the independent effect of SUA on all-cause mortality. RESULTS: SUA in the highest quartile was an independent predictor of all-cause mortality in HF outpatients (hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.03-1.37, p-value 0.021). Gender was found to interact the relationship between SUA and all-cause mortality (p-value for interaction 0.007). High SUA was an independent predictor of all-cause mortality in women (HR 1.65, 95% CI 1.24-2.20, p-value 0.001), but not in men (HR 1.06, 95% CI 0.89-1.25, p-value 0.527). Renal function did not influence the relationship between SUA and all-cause mortality (p-value for interaction 0.539). CONCLUSIONS: High SUA was independently associated with inferior 5-year survival in Norwegian HF outpatients. The finding was modified by gender and high SUA was only an independent predictor of 5-year all-cause mortality in women, not in men.

Prevalent Diabetes Mellitus: Mortality and Management in Norwegian Heart Failure Outpatients.

OBJECTIVES: Heart failure (HF) patients with diabetes mellitus experience poor prognosis. We assessed the independent predictive effect of prevalent diabetes mellitus on all-cause mortality in HF outpatients. Furthermore, we investigated if optimized HF medication differed in diabetic versus nondiabetic patients. METHODS: From 6,289 patients included in the Norwegian HF registry during 2000-2012, 724 diabetic HF outpatients were propensity-score-matched with nondiabetic HF outpatients (1:1), based on 21 measured baseline variables. Baseline characteristics, measured comorbidities and medication were balanced in the matched sample. RESULTS: Diabetes was not an independent predictor of all-cause mortality in the propensity-matched analyses (hazard ratio 1.041; 95% confidence interval 0.875-1.240). No interactions were found between the prognostic impact of diabetes and the strata renal function, systolic function or etiology of chronic HF. Diabetic HF outpatients were independently prescribed higher doses of ß-blockers and loop diuretics (both p < 0.001) and were more prone to receive statins (p = 0.003) than nondiabetics. CONCLUSIONS: Prevalent diabetes mellitus was not an independent predictor of all-cause mortality in HF outpatients. Explanations other than tight glycemic control should be assessed to improve the prognosis of diabetic HF outpatients. The more intensive, optimized HF medication for diabetic HF outpatients may, to a certain degree, explain our results.

Changes in 6-min walk test is an independent predictor of death in chronic heart failure with reduced ejection fraction.

AIMS: Functional capacity provides important clinical information in patients with heart failure (HF) and reduced ejection fraction (HFrEF). The 6-min walk test (6MWT) is a simple and inexpensive tool for assessing functional capacity and risk. Although change in 6MWT is frequently used as a surrogate outcome in HF trials, the association with mortality is unclear. We aimed to assess the prognostic importance of changes in 6MWT. METHODS AND RESULTS: Patients with chronic HFrEF referred to HF outpatient clinics in Norway completed a 6MWT at the first visit (baseline) and at a stable follow-up visit after treatment optimization (follow-up). Absolute and relative changes in 6MWT were analysed in association with mortality risk using Cox regression models and flexible cubic splines. The study included 3636 HFrEF patients aged 67.3 ± 11.6 years, 23% women, with left ventricular ejection fraction 30 ± 7%. At baseline, mean 6MWT was 438 ± 125 m, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1574 (732-3093) ng/L, and 27% had New York Heart Association (NYHA) class III/IV. After optimization of guideline-directed medical therapy (median 147 [86-240] days), 6MWT increased by mean 40 ± 74 m, NT-proBNP decreased by median 425 (14-1322) ng/L, and NYHA class improved in 38% of patients. Patients with greater improvements in 6MWT were younger, with greater improvements in NYHA class (r = 0.27, p < 0.001) and larger reductions in NT-proBNP concentrations (r = 0.19, p < 0.001). After mean 845 ± 595 days, 419 (11.5%) patients were dead. Both absolute and relative changes in 6MWT were non-linearly associated with survival, attenuating as 6MWT increased. A 50 m increase in 6MWT was associated with a 17% lower mortality risk (hazard ratio 0.84, 95% confidence interval 0.77-0.90, p < 0.001) in the fully adjusted model, including changes in NYHA class, NT-proBNP concentrations, and other established risk factors. The associations were more pronounced in patients with lower baseline 6MWT and higher age. CONCLUSION: Improvement in 6MWT in patients with HFrEF is associated with increased survival, independent of changes in NT-proBNP and NYHA class. These findings support 6MWT change as a surrogate outcome in HF trials.

Glycaemic control and insulin therapy are significant confounders of the obesity paradox in patients with heart failure and diabetes mellitus.

BACKGROUND: A high body mass index (BMI) confers a paradoxical survival benefit in patients with heart failure (HF) or diabetes mellitus (DM). There is, however, controversy whether an obesity paradox is also present in patients with HF and concomitant DM. In addition, the influence of glycaemic control and diabetes treatment on the presence or absence of the obesity paradox in patients with HF and DM is unknown. METHODS: We identified 2936 patients with HF with reduced ejection fraction (HFrEF) in the HF registries of the universities of Heidelberg, Germany, and Hull, UK (general sample). Of these, 598 (20%) were treated for concomitant DM (DM subgroup). The relationship between BMI and all-cause mortality was analysed in both the general sample and the DM subgroup. Patients with concomitant DM were stratified according to HbA1c levels or type of diabetes treatment and analyses were repeated. RESULTS: We found an inverse BMI-mortality relationship in both the general sample and the DM subgroup. However, the obesity paradox was less pronounced in patients with diabetes treated with insulin and it disappeared in those with poor glycaemic control as defined by HbA1c levels > 7.5%. CONCLUSION: In patients with HFrEF, a higher BMI is associated with better survival irrespective of concomitant DM. However, insulin treatment and poor glycaemic control make the relationship much weaker.

Patients with micro or other myocardial infarctions have equal long-term survival.

OBJECTIVES: To investigate differences in prognosis after myocardial infarction (MI) in patients classified according to the old and new definitions of MI. Patients not fulfilling the old definitions were classified as having a micro MI. DESIGN: Data on 1216 consecutive patients with a diagnosis of first MI (38.3% women) and who were discharged from or died in one hospital in the 5-year period from 2001 were included in the study. Surviving patients were followed for a mean of 8.2 years. Risk factors and death after MI were analysed according to MI classification. RESULTS: Of the patients, 20.1% were classified as having a micro MI. During follow-up, 47.2% of all the patients died. Patients with micro MI were older and fewer were current smokers than patients with other MI. In multivariate Cox regression analysis for the total risk of mortality, age, diabetes mellitus, a positive smoking history, history of stroke and living alone were significantly related to long-term prognosis, and there was no difference in long-term survival between the two types of MI (p 0.50). CONCLUSIONS: After adjustment for confounders, patients with micro MI had no significant difference in long-term survival compared with those with other MI.

Influence of receptor selectivity on benefits from SGLT2 inhibitors in patients with heart failure: a systematic review and head-to-head comparative efficacy network meta-analysis.

BACKGROUND: Receptor selectivity of sodium-glucose cotransporter-2 inhibitors (SGLT2i) varies greatly between agents. The overall improvement of cardiovascular (CV) outcomes in heart failure (HF) patients varies between trials. We, therefore, evaluated the comparative efficacy of individual SGLT2i and the influence of their respective receptor selectivity thereon. METHODS: We identified randomized controlled trials investigating the use of SGLT2i in patients with HF-either as the target cohort or as a subgroup of it. Comparators included placebo or any other active treatment. The primary endpoint was the composite of hospitalization for HF or CV death. Secondary outcomes included all-cause mortality, CV mortality, hospitalization for HF, worsening renal function (RF), and the composite of worsening RF or CV death. Evidence was synthesized using network meta-analysis. In addition, the impact of receptor selectivity on outcomes was analysed using meta-regression. RESULTS: We identified 18,265 patients included in 22 trials. Compared to placebo, selective and non-selective SGLT2i improved fatal and non-fatal HF events. Head-to-head comparisons suggest superior efficacy with sotagliflozin as compared to dapagliflozin, empagliflozin or ertugliflozin. No significant difference was found between canagliflozin and sotagliflozin. Meta-regression analyses show a decreasing benefit on HF events with increasing receptor selectivity of SGLT2i. In contrast, receptor selectivity did not affect mortality and renal endpoints and no significant difference between individual SGLT2i was noted. CONCLUSION: Our data point towards a class-effect of SGLT2i on mortality and renal outcomes. However, non-selective SGLT2i such as sotagliflozin may be superior to highly selective SGLT2i in terms of HF outcomes.

Mortality after myocardial infarction: impact of gender and smoking status.

We have shown previously that smoking causes a first myocardial infarction (MI) to occur significantly more prematurely in women than in men. The aim of the study was to investigate mortality after MI with special emphasis on the impact of smoking and gender. The study included 2,281 consecutive patients (36.8% women) who died or were discharged from a central hospital with a diagnosis of MI from 1998 to 2005; the median follow-up of survivors was 7 years. Death after MI was adjusted for confounders. Mean age for women was 5.8 years older than for men (76.0 vs. 70.2 years) and women were less likely to have been smokers. In-hospital mortality for the first MI was 8.9% for men and 13.3% for women, and total mortality rates for all indexed MI after 7 years were 47% for men and 61% for women. Using Cox regression analysis, with all indexed MIs included, the after-discharge mortality for women was significantly lower than for men (hazard ratio 0.82; 95% confidence interval 0.70-0.96; P = 0.015). Compared with non-smokers, patients who were smokers on admission had significantly increased seven-year mortality after discharge (hazard ratio 1.30; 95% confidence interval 1.03-1.63; P = 0.002). In conclusion, current smoking at the time of the indexed MI was associated with increased mortality after 7 years follow-up. The smoking effect was independent of gender. Female gender was associated with a moderately lower risk of death during the same follow-up period.

Renal function in outpatients with chronic heart failure.

BACKGROUND: Impaired renal function confers an adverse prognosis in patients with heart failure (HF). The aims of the present study were to identify factors associated with and predictive of impaired renal function and to assess the relationship between estimated glomerular filtration rate (eGFR) and all-cause mortality in outpatients with HF. METHODS AND RESULTS: Baseline data on 3605 patients (median age 73 years, 70.1% men) from 24 outpatient HF clinics in Norway were analyzed. Median follow-up time was 9 months. Renal dysfunction (eGFR < 60 mL/min) was present in 44.9%. The population was randomized into equal-sized model-building and validation samples to enhance model stability. eGFR was an independent predictor of all-cause mortality (HR 0.94 per 5 mL/min increase, P = .001). Use of spironolactone (P = .002), higher blood pressure (P < .001), and lower hemoglobin levels (P = .002) were predictors of impaired renal function. Increasing doses of loop diuretics were strongly associated with eGFR at baseline (P < .001), but only tended to predict worsening renal function during follow-up (P = .08). CONCLUSIONS: Clinically significant reduction in renal function was prevalent in outpatients with HF, and was a strong predictor of all-cause mortality. Use of loop diuretics and spironolactone should be carefully evaluated as these agents may adversely affect renal function.

ß-Blocker Doses and Heart Rate in Patients with Heart Failure: Results from the National Norwegian Heart Failure Registry.

BACKGROUND: Use of ß-blockers and titration to the highest tolerated dose are highly recommended by the European Society of Cardiology (ESC) guidelines for treatment of chronic heart failure (HF) with a reduced ejection fraction (HFrEF), but little attention has been paid to the achieved heart rate (HR) during this treatment. OBJECTIVES: The aim of the present study was to examine the achieved HR in relation to the use of ß-blockers in these patients. METHODS: All of the patients (n = 2,689) in the National Norwegian Heart Failure Registry as part of the Norwegian Cardiovascular Disease Registry with a sinus rhythm and left ventricular ejection fraction (LVEF) <40% at stable follow-up visiting specialised hospital outpatient HF clinics in Norway were included. The ß-blocker doses were calculated as a percent of the target dose according to ESC HF guidelines. Differences between baseline variables according to the achieved HR were analysed by the Student's t test for continuous variables and Pearson's χ2 test for categorical variables. Linear regression was used to determine the predictors of HR ≥70 beats/min (bpm) in the multivariate analysis. RESULTS: One third of the patients had a resting HR ≥70 bpm. Of the patients with an HR ≥70 bpm, 72.3% used less than the target dose of ß-blocker; they were younger and had a higher NYHA class, more diabetes mellitus and chronic obstructive pulmonary disease (COPD), and higher N-terminal pro-B type natriuretic peptide (NT-proBNP) levels and estimated glomerular filtration rates compared to the patients with an HR <70 bpm. The 1-year mortality was 3.1, 3.7, 5.8, and 9.1% among the patients with an HR <70, 70-79, 80-89, and >89 bpm, respectively. Only 2 patients used ivabradine. CONCLUSIONS: In patients with HFrEF and sinus rhythm, an HR ≥70 bpm was associated with worse clinical variables and outcomes. A high proportion of the patients who had an HR ≥70 bpm was not treated with or/did not tolerate the target dose of a ß-blocker, although the ß-blocker dose was higher than in patients with an HR <70 bpm. This may suggest that increased efforts should be made to further increase the ß-blocker dose, and treatment with ivabradine could be considered among patients with an HR ≥70 bpm.

6 min walk test is a strong independent predictor of death in outpatients with heart failure.

AIMS: The aim of this study was to examine the prognostic value of the 6 min walk test (6MWT) in a large cohort of outpatients with heart failure. METHODS AND RESULTS: A total of 5519 outpatients with heart failure from the National Norwegian Heart Failure Registry (NNHFR), which is part of the Norwegian Cardiovascular Disease Registry, were included in this analysis. The NNHFR recommended the use of the 6MWT for prognostic assessment of all patients included in the registry. Patients were categorized according to the 6MWT: Category 1 walked the longest and Category 3 the shortest. During a median (25th-75th percentiles) follow-up of 24 (14-36), 12.9% of the patients died. Patients in Category 3 had the overall worst outcome than had patients in Categories 1 and 2. 6MWT used as a continuous variable was a highly significant independent predictor for mortality in a multivariate Cox regression model adjusted for 16 other variables with a hazard ratio of 0.979 [(95% confidence interval 0.972-0.986), P < 0.001]. The four most important predictors for mortality were active cancer in the last 5 years, age, 6MWT, and natriuretic peptides (all P < 0.001). CONCLUSIONS: 6MWT is a strong independent predictor of mortality in outpatients with HF. The findings support the use of the 6MWT in the prognostic assessment of patients with HF irrespective of HF aetiology.

Sex-based differences in premature first myocardial infarction caused by smoking: twice as many years lost by women as by men.

BACKGROUND: It has been debated whether smoking increases the risk of heart disease relatively more in women than in men. It is not known whether there are sex differences with regard to how many years prematurely smoking causes acute myocardial infarction (AMI) to occur. We aimed to determine how smoking affects the age of onset of first myocardial infarction in both the sexes. DESIGN: Clinical data were consecutively entered into a database and were analysed with a multivariate regression technique. METHODS: In the years 1998-2005, data on 1784 consecutive patients (38.3% women) who were discharged from or died in a district general hospital with a diagnosis of first myocardial infarction were included in the study. Age at first AMI was analysed. RESULTS: Unadjusted mean ages were 76.2 years for women and 69.8 years for men, a difference of 6.4 years (P<0.001). Mean age within the various groups was: women nonsmokers 80.7 years, women smokers 66.2 years, difference 14.4 years (P<0.001); men nonsmokers 72.2 years, men smokers 63.9 years, difference 8.3 years (P<0.001). After adjustment for risk factors (hypertension, cholesterol levels, diabetes) and patient characteristics (history of angina, history of stroke) 13.7 years of the age difference in women were attributed to smoking; the corresponding figure in men was 6.2 years (P<0.001). CONCLUSION: First AMI occurred significantly more prematurely in women than in men smokers, implying that twice as many years were lost by women as by men smokers.

Epidemiology and long-term outcome in outpatients with chronic heart failure in Northwestern Europe.

OBJECTIVE: To describe the epidemiology, long-term outcomes and temporal trends in mortality in ambulatory patients with chronic heart failure (HF) with reduced (HFrEF), mid-range (HFmrEF) or preserved ejection fraction (HFpEF) from three European countries. METHODS: We identified 10 312 patients from the Norwegian HF Registry and the HF registries of the universities of Heidelberg, Germany, and Hull, UK. Patients were classified according to baseline left ventricular ejection fraction (LVEF) and time of enrolment (period 1: 1995-2005 vs period 2: 2006-2015). Predictors of mortality were analysed by use of univariable and multivariable Cox regression analyses. RESULTS: Among 10 312 patients with stable HF, 7080 (68.7%), 2086 (20.2%) and 1146 (11.1%) were classified as having HFrEF, HFmrEF or HFpEF, respectively. A total of 4617 (44.8%) patients were included in period 1, and 5695 (55.2%) patients were included in period 2. Baseline characteristics significantly differed with respect to type of HF and time of enrolment. During a median follow-up of 66 (33-105) months, 5297 patients (51.4%) died. In multivariable analyses, survival was independent of LVEF category (p>0.05), while mortality was lower in period 2 as compared with period 1 (HR 0.81, 95% CI 0.72 to 0.91, p<0.001). Significant predictors of all-cause mortality regardless of HF category were increasing age, New York Heart Association functional class, N-terminal pro-brain natriuretic peptide and use of loop diuretics. CONCLUSION: Ambulatory patients with HF stratified by LVEF represent different phenotypes. However, after adjusting for a wide range of covariates, long-term survival is independent of LVEF category. Outcome significantly improved during the last two decades irrespective from type of HF.

Comparative effectiveness of loop diuretics on mortality in the treatment of patients with chronic heart failure - A multicenter propensity score matched analysis.

BACKGROUND: Loop diuretics are given to the majority of patients with chronic heart failure (HF). Whether the different pharmacological properties of the three guideline-recommended loop diuretics result in differential effects on survival is unknown. METHODS: 6293 patients with chronic HF using either bumetanide, furosemide or torasemide were identified in three European HF registries. Patients were individually matched on both the respective propensity scores for receipt of the individual drug and dose-equivalents thereof. RESULTS: During a follow-up of 35,038 patient-years, 652 (53.7%), 2179 (51.9%), and 268 (30.4%) patients died amongst those prescribed bumetanide, furosemide, and torasemide, respectively. In univariable analyses of the general sample, bumetanide and furosemide were both associated with higher mortality as compared with torasemide treatment (HR 1.50, 95% CI 1.31-1.73, p < 0.001, and HR 1.34, CI 1.18-1.52, p < 0.001, respectively). Mortality was higher in bumetanide users when compared to furosemide users (HR 1.11, 95% CI 1.02-1.20, p = 0.01). However, there was no significant association between loop diuretic choice and all-cause mortality in any of the matched samples (bumetanide vs. furosemide, HR 1.03, 95% CI 0.93-1.14, p = 0.53; bumetanide vs. torasemide, HR 0.98, 95% CI 0.78-1.24, p = 0.89; furosemide vs. torasemide, HR 1.02, 95% CI 0.84-1.24, p = 0.82). The results were confirmed in subgroup analyses with respect to age, sex, left ventricular ejection fraction, NYHA functional class, cause of HF, rhythm, and systolic blood pressure. CONCLUSIONS: In patients with HF, mortality is not affected by the choice of individual loop diuretics.

Comparative effectiveness of enalapril, lisinopril, and ramipril in the treatment of patients with chronic heart failure: a propensity score-matched cohort study.

Aims: Angiotensin-converting enzyme inhibitors (ACEIs) are recommended as first-line therapy in patients with heart failure with reduced ejection fraction (HFrEF). The comparative effectiveness of different ACEIs is not known. Methods and results: A total of 4723 outpatients with stable HFrEF prescribed enalapril, lisinopril, or ramipril were identified from three registries in Norway, England, and Germany. In three separate matching procedures, patients were individually matched with respect to both dose equivalents and their respective propensity scores for ACEI treatment. During a follow-up of 21 939 patient-years, 360 (49.5%), 337 (52.4%), and 1119 (33.4%) patients died among those prescribed enalapril, lisinopril, and ramipril, respectively. In univariable analysis of the general sample, enalapril and lisinopril were both associated with higher mortality when compared with ramipril treatment [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.30-1.65, P < 0.001 and HR 1.38, 95% CI 1.22-1.56, P < 0.001, respectively). Patients prescribed enalapril or lisinopril had similar mortality (HR 1.06, 95% CI 0.92-1.24, P = 0.41). However, there was no significant association between ACEI choice and all-cause mortality in any of the matched samples (HR 1.07, 95% CI 0.91-1.25, P = 0.40; HR 1.12, 95% CI 0.96-1.32, P = 0.16; and HR 1.10, 95% CI 0.93-1.31, P = 0.25 for enalapril vs. ramipril, lisinopril vs. ramipril, and enalapril vs. lisinopril, respectively). Results were confirmed in subgroup analyses with respect to age, sex, left ventricular ejection fraction, New York Class Association functional class, cause of HFrEF, rhythm, and systolic blood pressure. Conclusion: Our results suggest that enalapril, lisinopril, and ramipril are equally effective in the treatment of patients with HFrEF when given at equivalent doses.

Spironolactone Treatment and Effect on Survival in Chronic Heart Failure Patients with Reduced Renal Function: A Propensity-Matched Study.

BACKGROUND/AIMS: Spironolactone may be hazardous in heart failure (HF) patients with renal dysfunction due to risk of hyperkalemia and worsened renal function. We aimed to evaluate the effect of spironolactone on all-cause mortality in HF outpatients with renal dysfunction in a propensity-score-matched study. METHODS: A total of 2,077 patients from the Norwegian Heart Failure Registry with renal dysfunction (eGFR <60 mL/min/1.73 m2) not treated with spironolactone at the first visit at the HF clinic were eligible for the study. Patients started on spironolactone at the outpatient HF clinics (n = 206) were propensity-score-matched 1:1 with patients not started on spironolactone, based on 16 measured baseline characteristics. Kaplan-Meier and Cox regression analyses were used to investigate the independent effect of spironolactone on 2-year all-cause mortality. RESULTS: Propensity score matching identified 170 pairs of patients, one group receiving spironolactone and the other not. The two groups were well matched (mean age 76.7 ± 8.1 years, 66.4% males, and eGFR 46.2 ± 10.2 mL/min/1.73 m2). Treatment with spironolactone was associated with increased potassium (delta potassium 0.31 ± 0.55 vs. 0.05 ± 0.41 mmol/L, p < 0.001) and decreased eGFR (delta eGFR -4.12 ± 12.2 vs. -0.98 ± 7.88 mL/min/1.73 m2, p = 0.006) compared to the non-spironolactone group. After 2 years, 84% of patients were alive in the spironolactone group and 73% of patients in the non-spironolactone group (HR 0.59, 95% CI 0.37-0.92, p = 0.020). CONCLUSION: In HF outpatients with renal dysfunction, treatment with spironolactone was associated with improved 2-year survival compared to well-matched patients not treated with spironolactone. Favorable survival was observed despite worsened renal function and increased potassium in the spironolactone group.

Bisoprolol compared with carvedilol and metoprolol succinate in the treatment of patients with chronic heart failure.

AIMS: Beta-blockers are recommended for the treatment of chronic heart failure (CHF). However, it is disputed whether beta-blockers exert a class effect or whether there are differences in efficacy between agents. METHODS AND RESULTS: 6010 out-patients with stable CHF and a reduced left ventricular ejection fraction prescribed either bisoprolol, carvedilol or metoprolol succinate were identified from three registries in Norway, England, and Germany. In three separate matching procedures, patients were individually matched with respect to both dose equivalents and the respective propensity scores for beta-blocker treatment. During a follow-up of 26,963 patient-years, 302 (29.5%), 637 (37.0%), and 1232 (37.7%) patients died amongst those prescribed bisoprolol, carvedilol, and metoprolol, respectively. In univariable analysis of the general sample, bisoprolol and carvedilol were both associated with lower mortality as compared with metoprolol succinate (HR 0.80, 95% CI 0.71-0.91, p < 0.01, and HR 0.86, 95% CI 0.78-0.94, p < 0.01, respectively). Patients prescribed bisoprolol or carvedilol had similar mortality (HR 0.94, 95% CI 0.82-1.08, p = 0.37). However, there was no significant association between beta-blocker choice and all-cause mortality in any of the matched samples (HR 0.90; 95% CI 0.76-1.06; p = 0.20; HR 1.10, 95% CI 0.93-1.31, p = 0.24; and HR 1.08, 95% CI 0.95-1.22, p = 0.26 for bisoprolol vs. carvedilol, bisoprolol vs. metoprolol succinate, and carvedilol vs. metoprolol succinate, respectively). Results were confirmed in a number of important subgroups. CONCLUSION: Our results suggest that the three beta-blockers investigated have similar effects on mortality amongst patients with CHF.

Statins attenuate but do not eliminate the reverse epidemiology of total serum cholesterol in patients with non-ischemic chronic heart failure.

BACKGROUND: In patients with chronic heart failure (CHF) increasing levels of total serum cholesterol are associated with improved survival - while statin usage is not. The impact of statin treatment on the "reverse epidemiology" of cholesterol is unclear. METHODS: 2992 consecutive patients with non-ischemic CHF due to left ventricular systolic dysfunction from the Norwegian CHF Registry and the CHF Registries of the Universities of Hull, UK, and Heidelberg, Germany, were studied. 1736 patients were individually double-matched on both cholesterol levels and the individual propensity scores for statin treatment. All-cause mortality was analyzed as a function of baseline cholesterol and statin use in both the general and the matched sample. RESULTS: 1209 patients (40.4%) received a statin. During a follow-up of 13,740 patient-years, 360 statin users (29.8%) and 573 (32.1%) statin non-users died. When grouped according to total cholesterol levels as low (≤3.6mmol/L), moderate (3.7-4.9mmol/L), high (4.8-6.2mmol/L), and very high (>6.2mmol/L), we found improved survival with very high as compared with low cholesterol levels. This association was present in statin users and non-users in both the general and matched sample (p<0.05 for each group comparison). The negative association of total cholesterol and mortality persisted when cholesterol was treated as a continuous variable (HR 0.83, 95%CI 0.77-0.90, p<0.001 for matched patients), but it was less pronounced in statin users than in non-users (F-test p<0.001). CONCLUSIONS: Statins attenuate but do not eliminate the reverse epidemiological association between increasing total serum cholesterol and improved survival in patients with non-ischemic CHF.