Background Patients with diabetes and anemia are at high risk of cardiovascular disease. The Anemia CORrection in Diabetes (ACORD) Study aimed to investigate the effect of anemia correction on ...cardiac structure, function, and outcomes in patients with diabetes with anemia and early diabetic nephropathy. Methods One hundred seventy-two patients with type 1 or 2 diabetes mellitus, mild to moderate anemia, and stage 1 to 3 chronic kidney disease were randomly assigned to attain a target hemoglobin (Hb) level of either 13 to 15 g/dL (130 to 150 g/L; group 1) or 10.5 to 11.5 g/dL (105 to 115 g/L; group 2). The primary end point was change in left ventricular mass index (LVMI). Secondary end points included echocardiographic variables, renal function, quality of life, and safety. Results Median Hb level and LVMI were similar in groups 1 and 2 (Hb, 11.9 and 11.7 g/dL 119 and 117 g/L; LVMI, 113.5 and 112.3 g/m2 , respectively). At study end, Hb levels were 13.5 g/dL (135 g/L) in group 1 and 12.1 g/dL (121 g/L) in group 2 ( P < 0.001). No significant differences were observed in median LVMI at month 15 between study groups (group 1, 112.3 g/m2 ; group 2, 116.5 g/m2 ). Multivariate analysis showed a nonsignificant decrease in LVMI ( P = 0.15) in group 1 versus group 2. Anemia correction had no effect on the rate of decrease in creatinine clearance, but resulted in significantly improved quality of life in group 1 ( P = 0.04). There were no clinically relevant differences in adverse events between study groups. Conclusion In patients with diabetes with mild to moderate anemia and moderate left ventricular hypertrophy, correction to an Hb target level of 13 to 15 g/dL (130 to 150 g/L) does not decrease LVMI. However, normalization of Hb level prevented an additional increase in left ventricular hypertrophy, was safe, and improved quality of life.
ABSTRACT
Objective: The Gain effectiveness in Anaemia treatment wIth NeoRecormon* (epoetin beta) study (GAIN) evaluated the effectiveness and safety of recombinant human erythropoietin beta in ...correcting and/or maintaining common haemoglobin (Hb) targets in routine clinical practice in Europe.
*NeoRecormon is a registered trade name of F. Hoffmann-La Roche, Basel, Switzerland
Research design and methods: European 18-month observational, prospective clinical practice study across 217 centres from 13 countries. During a 3-month retrospective period, patients received any erythropoiesis stimulating agent (ESA). For the subsequent 18-month study phase, patients receiving intravenous (IV) epoetin beta or any other ESA were recommended to be switched to subcutaneous (SC) epoetin beta. Presence of anti-erythropoietin antibodies (AEAB) and related outcomes was investigated before and during the study.
Clinical trial registration: ClinicalTrials.gov number: NCT00551603.
Main outcome measures: Correction and maintenance of Hb levels within recommended target range and mean dose requirement to correct and maintain target Hb levels.
Results: A total of 4264 patients on haemodialysis received an ESA for treatment of renal anaemia. During the study period, the number of patients who maintained Hb levels in the recommended target range of 10-12 g/dL increased from 57% to 62%. Administration of SC epoetin beta resulted in a 24% lower mean dose requirement to maintain target Hb levels compared to IV administration (p < 0.001). Considerable differences were observed between countries in the study. No patients developed pure red cell aplasia associated with AEAB during observation.
Conclusion: This observational study suggests that haemodialysis patients who are receiving any ESA via SC or IV administration for treatment of their renal anaemia can be safely and effectively switched to SC epoetin beta to achieve or maintain the currently recommended Hb targets. SC required a lower dose than IV administration to maintain similar efficacy, thereby potentially lowering the drug costs.
Cardiac output (CO) is an important parameter for diagnosis and therapy of heart diseases, but it is still difficult to determine. Innocor, a novel noninvasive inert gas rebreathing (IGR) system, has ...shown promising results. However, the impact of pulmonary diseases on IGR remains unclear. The aim of the study therefore was to assess the accuracy and reliability of IGR in patients with distinct chronic lung disease. A total of 96 patients were enrolled, including 48 consecutive patients with variant lung diseases (group A) and 48 pair-matched pulmonary healthy patients (group B). CO was measured with cardiac magnetic resonance imaging (CMR) and IGR. Lung function testing was done by spirometry FEV₁/FVC (forced expiratory volume in one second/forced vital capacity), VC (vital capacity) and determination of the diffusing capacity of the lung for carbon monoxide divided by alveolar volume (DLCO/VA). In group A we found a mean CO of 4.7 ± 1.3 L/min by IGR and 4.9 ± 1.2 L/min by CMR. Group B showed a mean CO of 4.8 ± 1.4 L/min by IGR and 5.0 ± 1.3 L/min by CMR. Bland-Altman analysis revealed good correspondence between CMR and IGR, with an average deviation of 0.1 ± 1.0 L/min in group A and 0.1 ± 1.0 L/min in group B (p = 0.99). Multiple regression analysis for the pulmonary parameters did not show a statistically significant impact on the mean bias of CO measurements (FEV₁/FVC: r = 0.01, p = 0.91; VC: r = −0.2, p = 0.13; and DLCO/VA: r = 0.04, p = 0.82). IGR allows a feasible determination of CO even in patients with lung diseases. The accuracy of the IGR method is not influenced by either pulmonary obstructive and restrictive diseases or a reduced DLCO.
Abstract Background Uncertainty persists about the safety and efficacy of amiodarone for the management of heart failure. Methods and Results We randomized 3029 patients with chronic heart failure to ...receive carvedilol or metoprolol and followed patients for a median of 58 months. One hundred fifty-five of 1466 patients in New York Heart Association (NYHA) Class II and 209 of 1563 in Class III or IV received amiodarone at baseline. Persistence with amiodarone treatment was high and 66% received amiodarone after 4 years. During follow-up, 38.7% and 58.9% of patients receiving amiodarone in NYHA Classes II and III + IV died versus 26.2% and 43.3% not receiving amiodarone ( P < .001). This difference was maintained in multivariable analysis (hazard ratio HR 1.5, 95% confidence interval CI 1.2–1.7, P < .001). The difference was explained by an increased risk of death due to circulatory failure (HR 2.4, CI 1.9–3.1, P < .001) in patients receiving amiodarone. Sudden death was not different (HR 1.07, CI 0.8–1.4, P = .7). The increased risk was similar across NYHA classes with HR of 1.60 (CI 1.2–2.1, P < .001) in NYHA Class II versus 1.58 (CI 1.3–1.9, P < .001) in Classes III + IV. Conclusions Treatment with amiodarone was associated with an increased risk of death from circulatory failure independent of functional class.
Background:
Management guidelines for heart failure recommend ACE‐I and β‐blockers. The perception of difficult up‐titration might have added to the slow uptake of β‐blockers despite their mortality ...and morbidity benefits.
Aims:
CARMEN offered a possibility to study safety and tolerability of enalapril against carvedilol and their combination.
Methods:
Five hundred and seventy‐two patients were blindly up‐titrated on carvedilol (target 25 mg bid) and/or enalapril (target 10 mg bid), and continued for 18 months. In the combination arm, carvedilol was up‐titrated before enalapril.
Results:
There was no group related difference in adverse events during up‐titration. Withdrawal rates were 31, 30 and 30%, and serious adverse events 28, 29 and 34% in the combination, carvedilol and enalapril arms. Mortality was similar in all groups (all‐cause N=14, 14 and 14; cardiovascular N=9, 13 and 14). All‐cause and cardiovascular hospitalizations occurred in 26, 27 and 32%, and in 12, 16 and 22% in the combination, carvedilol and enalapril arms, respectively.
Conclusion:
The safety profile was similar in all treatment arms. In contrast to common perception, there was no difference in tolerability between the ACE‐I and carvedilol. This result is even more remarkable as the high prestudy use of ACE‐I (65%) might have introduced a bias by selecting ACE‐I tolerant patients, who were only switched from their former ACE‐I to enalapril.
Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established.
We randomly assigned 603 patients with an estimated glomerular ...filtration rate (GFR) of 15.0 to 35.0 ml per minute per 1.73 m2 of body-surface area and mild-to-moderate anemia (hemoglobin level, 11.0 to 12.5 g per deciliter) to a target hemoglobin value in the normal range (13.0 to 15.0 g per deciliter, group 1) or the subnormal range (10.5 to 11.5 g per deciliter, group 2). Subcutaneous erythropoietin (epoetin beta) was initiated at randomization (group 1) or only after the hemoglobin level fell below 10.5 g per deciliter (group 2). The primary end point was a composite of eight cardiovascular events; secondary end points included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease.
During the 3-year study, complete correction of anemia did not affect the likelihood of a first cardiovascular event (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95% confidence interval, 0.53 to 1.14; P=0.20). Left ventricular mass index remained stable in both groups. The mean estimated GFR was 24.9 ml per minute in group 1 and 24.2 ml per minute in group 2 at baseline and decreased by 3.6 and 3.1 ml per minute per year, respectively (P=0.40). Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P=0.03). General health and physical function improved significantly (P=0.003 and P<0.001, respectively, in group 1, as compared with group 2). There was no significant difference in the combined incidence of adverse events between the two groups, but hypertensive episodes and headaches were more prevalent in group 1.
In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events. (ClinicalTrials.gov number, NCT00321919 ClinicalTrials.gov.).
β blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to ...compare the effects of carvedilol and metoprolol on clinical outcome.
In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II–IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0·35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat.
The mean study duration was 58 months (SD 6). The mean ejection fraction was 0·26 (0·07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0·83 95% CI 0·74–0–93, p=0–0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0·94 0·86–1–02, p=0·122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups.
Our results suggest that carvedilol extends survival compared with metoprolol.
Carvedilol Protects Better Against Vascular Events Than Metoprolol in Heart Failure: Results From COMET Willem J. Remme, Christian Torp-Pedersen, John G. F. Cleland, Philip A. Poole-Wilson, Marco ...Metra, Michel Komajda, Karl Swedberg, Andrea Di Lenarda, Phillip Spark, Armin Scherhag, Christine Moullet, Mary Ann Lukas Comprehensive adrenergic blockade by carvedilol and additional properties, including antioxidant effects, may lead to improved vascular function and vascular protection relative to beta-1 blockade alone. We compared vascular protective effects of carvedilol and metoprolol in the COMET (Carvedilol Or Metoprolol European Trial) study in 3,029 heart failure patients during 58 months of therapy. Carvedilol reduced myocardial infarctions (MI) by 21%, cardiovascular death or nonfatal MI by 19%, unstable angina by 29%, stroke or MI by 25%, fatal MI or fatal stroke by 54%, and death after nonfatal MI or stroke by 33% (all p < 0.05 vs. metoprolol). These results suggest a ubiquitous protective effect of carvedilol against major cardiovascular events.
Recent studies, in which the cardiovascular risk and mortality associated with high and low hemoglobin target values, respectively, have been investigated, challenged the concept that hemoglobin ...normalization improves prognosis.
The results of these studies are reviewed with respect to differences in study populations, study design and methodological limitations to provide guidance for their interpretation and relevance for clinical practice.
There are important differences with respect to enrolled populations, design and conduct of the studies. Each study has its specific, inherent methodological limitations. Importantly, there is no statistically significant and consistent pattern of negative results for cardiovascular and mortality outcomes, although in general outcomes are not in favor of hemoglobin normalization. On the other hand, the reported data on quality of life are consistently and significantly better with higher hemoglobin values.
Recent evidence from large outcome studies suggested an increased risk associated with hemoglobin normalization. On the other side, several study-inherent and methodological limitations must be considered before simply extrapolating the negative findings of these studies into clinical practice. However, until new evidence becomes available from ongoing and future clinical studies, an upper Hb limit of 12 g/dl should not be exceeded.
Partial correction of anemia in patients with chronic kidney disease (CKD) reduces left ventricular hypertrophy (LVH), which is a risk factor for cardiovascular (CV) morbidity, but complete ...correction of anemia does not improve CV outcomes. Whether LV geometry associates with CV events in patients who are treated to different hemoglobin (Hb) targets is unknown. One of the larger trials to study the effects of complete correction of anemia in stages 3 to 4 CKD was the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial. Here, we analyzed echocardiographic data from CREATE to determine the prevalence, dynamics, and prognostic implications of abnormal LV geometry in patients who were treated to different Hb targets. The prevalence of LVH at baseline was 47%, with eccentric LVH more frequent than concentric. During the study, LVH prevalence and mean left ventricular mass index did not change significantly, but LV geometry fluctuated considerably within 2 yr in both groups. CV event-free survival was significantly worse in the presence of concentric LVH and eccentric LVH compared with the absence of LVH (P = 0.0009 and P < or = 0.0001, respectively). Treatment to the higher Hb target associated with reduced event-free survival in the subgroup with eccentric LVH at baseline (P = 0.034). In conclusion, LVH is common and associates with poor outcomes among patients with stages 3 to 4 CKD, although both progression and regression of abnormal LV geometry occur. Complete anemia correction may aggravate the adverse prognosis of eccentric LVH.
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