Maros Elsik

Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis

BACKGROUND Recombinant human erythropoietin is commonly used for treatment of anaemia. Our aim was to determine whether targeting different haemoglobin concentrations with such treatment is associated with altered all-cause mortality and cardiovascular events in patients with anaemia caused by chronic kidney disease. METHODS We did a meta-analysis of randomised controlled clinical trials that were identified in medical databases and trial registration websites. Trials were eligible for inclusion if they assessed the effects of targeting different haemoglobin concentrations in patients with anaemia caused by chronic disease who were randomly assigned to treatment with recombinant human erythropoietin, recruited at least 100 patients, and had a minimum follow-up of 12 weeks. FINDINGS We analysed nine randomised controlled trials that enrolled 5143 patients. There was a significantly higher risk of all-cause mortality (risk ratio 1.17, 95% CI 1.01-1.35; p=0.031) and arteriovenous access thrombosis (1.34, 1.16-1.54; p=0.0001) in the higher haemoglobin target group than in the lower haemoglobin target group in the fixed effects model without heterogeneity between studies. There was a significantly higher risk of poorly controlled blood pressure (1.27, 1.08-1.50; p=0.004) in the higher haemoglobin target group than in the lower target haemoglobin group with the fixed effects model; however, this was not significant in the random effects model (1.31, 0.97-1.78; p=0.075). The incidence of myocardial infarction was much the same in the two groups. INTERPRETATION To target higher haemoglobin concentrations when treating patients with anaemia caused by chronic kidney disease with recombinant human erythropoietin puts such patients at increased risk of death. Current guidelines do not include an upper limit for the target haemoglobin concentration; such an upper limit should be considered in future recommendations.

Differences Between Beta-Blockers in Patients With Chronic Heart Failure and Chronic Obstructive Pulmonary Disease A Randomized Crossover Trial

OBJECTIVES The purpose of this study was to determine the respiratory, hemodynamic, and clinical effects of switching between beta1-selective and nonselective beta-blockers in patients with chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD). BACKGROUND Carvedilol, metoprolol succinate, and bisoprolol are established beta-blockers for treating CHF. Whether differences in beta-receptor specificities affect lung or vascular function in CHF patients, particularly those with coexistent COPD, remains incompletely characterized. METHODS A randomized, open label, triple-crossover trial involving 51 subjects receiving optimal therapy for CHF was conducted in 2 Australian teaching hospitals. Subjects received each beta-blocker, dose-matched, for 6 weeks before resuming their original beta-blocker. Echocardiography, N-terminal pro-hormone brain natriuretic peptide, central augmented pressure from pulse waveform analysis, respiratory function testing, 6-min walk distance, and New York Heart Association (NYHA) functional class were assessed at each visit. RESULTS Of 51 subjects with a mean age of 66 +/- 12 years, NYHA functional class I (n = 6), II (n = 29), or III (n = 16), and left ventricular ejection fraction mean of 37 +/- 10%, 35 had coexistent COPD. N-terminal pro-hormone brain natriuretic peptide was significantly lower with carvedilol than with metoprolol or bisoprolol (mean: carvedilol 1,001 [95% confidence interval (CI): 633 to 1,367] ng/l; metoprolol 1,371 [95% CI: 778 to 1,964] ng/l; bisoprolol 1,349 [95% CI: 782 to 1,916] ng/l; p < 0.01), and returned to baseline level on resumption of the initial beta-blocker. Central augmented pressure, a measure of pulsatile afterload, was lowest with carvedilol (carvedilol 9.9 [95% CI: 7.7 to 12.2] mm Hg; metoprolol 11.5 [95% CI: 9.3 to 13.8] mm Hg; bisoprolol 12.2 [95% CI: 9.6 to 14.7] mm Hg; p < 0.05). In subjects with COPD, forced expiratory volume in 1 s was lowest with carvedilol and highest with bisoprolol (carvedilol 1.85 [95% CI: 1.67 to 2.03] l/s; metoprolol 1.94 [95% CI: 1.73 to 2.14] l/s; bisoprolol 2.0 [95% CI: 1.79 to 2.22] l/s; p < 0.001). The NYHA functional class, 6-min walk distance, and left ventricular ejection fraction did not change. The beta-blocker switches were well tolerated. CONCLUSIONS Switching between beta1-selective beta-blockers and the nonselective beta-blocker carvedilol is well tolerated but results in demonstrable changes in airway function, most marked in patients with COPD. Switching from beta1-selective beta-blockers to carvedilol causes short-term reduction of central augmented pressure and N-terminal pro-hormone brain natriuretic peptide. (Comparison of Nonselective and Beta1-Selective Beta-Blockers on Respiratory and Arterial Function and Cardiac Chamber Dynamics in Patients With Chronic Stable Congestive Cardiac Failure; Australian New Zealand Clinical Trials Registry, ACTRN12605000504617).

Relation of Peripheral Collagen Markers to Death and Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction Results of the I-PRESERVE Collagen Substudy

Background— Heart failure with preserved ejection fraction (HFPEF) is a common and increasing public health problem. Myocardial fibrosis is a key pathological feature of HFPEF. Peripheral collagen markers may reflect this excess fibrosis; however, the relation of these markers to prognosis in patients with HFPEF has not as yet been determined. Methods and Results— This substudy of the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial measured plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide, and osteopontin in 334 patients with HFPEF. Measurements were performed at baseline and 6 months after randomization to placebo or irbesartan 300 mg/day. The relation of baseline collagen markers to the I-PRESERVE primary end point (all-cause death and hospitalization for prespecified cardiovascular causes) was evaluated by single and multivariable analysis. Similar evaluations were performed for all-cause death alone as well as heart failure events (death or hospitalization because of heart failure). Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers. For each 10-&mgr;g/L increase in procollagen type I amino-terminal peptide, the hazard ratio (HR) for the primary end point was 1.09 (95% CI, 1.052 to 1.13; P<0.0001); for each 10-&mgr;g/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide, the HR was 2.47 (95% CI, 0.97 to 6.33; P=0.059); and for each 10-nmol/L increase in osteopontin, the HR was 1.084 (95% CI, 1.026 to 1.15; P=0.004). No variable remained significant as an independent predictor when introduced into a multivariable model. Both treatment groups tended to reduce collagen markers, with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only (P=0.0185). Conclusions— Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis. These findings provide some support to the hypothesis that pathological fibrosis in the heart, and possibly the peripheral vasculature, may be contributory to adverse clinical outcomes in patients with HFPEF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

A new anti-fibrotic drug attenuates cardiac remodeling and systolic dysfunction following experimental myocardial infarction

BACKGROUND Pathological deposition of extracellular matrix in the non-infarct zone (NIZ) of the ventricle post myocardial infarction (MI) is a key contributor to cardiac remodeling and heart failure. FT011, a novel antifibrotic compound, was evaluated for its efficacy in neonatal cardiac fibroblasts (NCF) and in an experimental MI model. METHODS AND RESULTS Collagen synthesis in NCF was determined by (3)H-proline incorporation following stimulation with TGF-β or angiotensin II (Ang II). FT011 inhibited collagen synthesis to both agents in a dose dependent manner. In vivo, Sprague Dawley rats underwent left anterior descending coronary artery ligation or sham surgery and were randomized one week later to receive either FT011 (200mg/kg/day) or vehicle for a further 4 weeks. Echocardiography and cardiac catheterization were performed, and tissues were collected for histological analysis of collagen, myocyte hypertrophy, interstitial macrophage accumulation and Smad2 phosphorylation. mRNA expression of collagens I and III and TGF-β was measured using in situ hybridization and RT-PCR, respectively. FT011 treatment was associated with improved cardiac function (increased ejection fraction, fraction shortening and preload recruitable stroke work) and myocardial remodeling (reduced left ventricular diameter and volume at both end diastolic and systolic) compared with vehicle treatment. FT011 significantly reduced collagen matrix deposition, myocyte hypertrophy and interstitial macrophage infiltration, and mRNA expression of collagens I and III in NIZ compared with vehicle treatment. CONCLUSION Anti-fibrotic therapy with FT011 in MI rats attenuated fibrosis and preserved systolic function.

Relation of Peripheral Collagen Markers to Death and Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction

Background— Heart failure with preserved ejection fraction (HFPEF) is a common and increasing public health problem. Myocardial fibrosis is a key pathological feature of HFPEF. Peripheral collagen markers may reflect this excess fibrosis; however, the relation of these markers to prognosis in patients with HFPEF has not as yet been determined. Methods and Results— This substudy of the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial measured plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide, and osteopontin in 334 patients with HFPEF. Measurements were performed at baseline and 6 months after randomization to placebo or irbesartan 300 mg/day. The relation of baseline collagen markers to the I-PRESERVE primary end point (all-cause death and hospitalization for prespecified cardiovascular causes) was evaluated by single and multivariable analysis. Similar evaluations were performed for all-cause death alone as well as heart failure events (death or hospitalization because of heart failure). Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers. For each 10-&mgr;g/L increase in procollagen type I amino-terminal peptide, the hazard ratio (HR) for the primary end point was 1.09 (95% CI, 1.052 to 1.13; P<0.0001); for each 10-&mgr;g/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide, the HR was 2.47 (95% CI, 0.97 to 6.33; P=0.059); and for each 10-nmol/L increase in osteopontin, the HR was 1.084 (95% CI, 1.026 to 1.15; P=0.004). No variable remained significant as an independent predictor when introduced into a multivariable model. Both treatment groups tended to reduce collagen markers, with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only (P=0.0185). Conclusions— Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis. These findings provide some support to the hypothesis that pathological fibrosis in the heart, and possibly the peripheral vasculature, may be contributory to adverse clinical outcomes in patients with HFPEF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.