Hessel F. Groenveld

Lenient versus Strict Rate Control in Patients with Atrial Fibrillation

BACKGROUND Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation. METHODS We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years. RESULTS The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups. CONCLUSIONS In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.)

Anemia and Mortality in Heart Failure Patients: A Systematic Review and Meta-Analysis

OBJECTIVES The aim of this study was to assess the effect of anemia on mortality in chronic heart failure (CHF). BACKGROUND Anemia is frequently observed in patients with CHF, and evidence suggests that anemia might be associated with an increased mortality. METHODS A systematic literature search in MEDLINE (through November 2007) for English language articles was performed. In addition, a manual search was performed. We included cohort studies and retrospective secondary analyses of randomized controlled trials whose primary objective was to analyze the association between anemia and mortality in CHF. Of a total of 1,327 initial studies, we included 34 studies, comprising 153,180 patients. Information on study design, patient characteristics, outcome, and potential confounders were extracted. RESULTS Anemia was defined by criteria used in the original articles. Of the 153,180 CHF patients, 37.2% were anemic. After a minimal follow-up of 6 months, 46.8% of anemic patients died compared with 29.5% of nonanemic patients. Crude mortality risk of anemia was odds ratio 1.96 (95% confidence interval: 1.74 to 2.21, p < 0.001). Lower baseline hemoglobin values were associated with increased crude mortality rates (r = -0.396, p = 0.025). Adjusted hazard ratios showed an increased adjusted risk for anemia (hazard ratio 1.46 [95% confidence interval: 1.26 to 1.69, p < 0.001]). Subgroup analysis showed no significant difference between mortality risk of anemia in diastolic or systolic CHF. CONCLUSIONS Anemia is associated with an increased risk of mortality in both systolic and diastolic CHF. Anemia should, therefore, be considered as a useful prognosticator, and therapeutic strategies aimed to increase hemoglobin levels in CHF should be investigated.

Erythropoietin treatment in patients with chronic heart failure: a meta-analysis

Background: Anaemia is common in patients with chronic heart failure (HF), and erythropoiesis stimulating proteins (ESPs) are frequently used for its treatment. However, recent studies in patients with malignancies and renal failure have raised concerns about the safety of these agents. Objective: To determine whether treatment of anaemic patients with chronic HF with ESPs is associated with an effect on morbidity and mortality. Data sources: A systematic literature search in Medline, the Cochrane Controlled Trials Register Database and ClinicalTrials.gov through July 2008 was performed. Study selection: Randomised clinical trials comparing the effect of ESP treatment with placebo or usual care in anaemic patients with HF were included. Results: Seven randomised controlled trials were identified that enrolled 650 patients, of whom 363 were treated with ESPs and 287 with placebo. ESP treatment had a significantly lower risk of HF hospitalisation (risk ratio (RR) = 0.59; 95% CI 0.41 to 0.86; p = 0.006).There was no significant difference in the mortality risk between the two groups (RR = 0.69; 95% CI 0.39 to 1.23; p = 0.21). No significant differences were observed in the occurrence of hypertension or venous thrombosis. Conclusions: In chronic HF, treatment with ESPs is not associated with a higher mortality rate or more adverse events, whereas a beneficial effect on HF hospitalisation is seen. These outcomes are in contrast with studies in cancer and kidney disease, and support a large phase III morbidity and mortality trial of anaemia correction in patients with chronic HF.

The Effect of Rate Control on Quality of Life in Patients With Permanent Atrial Fibrillation Data From the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) Study

OBJECTIVES The aim of this study was to investigate the influence of rate control on quality of life (QOL). BACKGROUND The RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) trial showed that lenient rate control is not inferior to strict rate control in terms of cardiovascular morbidity and mortality. The influence of stringency of rate control on QOL is unknown. METHODS In RACE II, a total of 614 patients with permanent atrial fibrillation (AF) were randomized to lenient (resting heart rate [HR] <110 beats/min) or strict (resting HR <80 beats/min, HR during moderate exercise <110 beats/min) rate control. QOL was assessed in 437 patients using the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) questionnaire, AF severity scale, and Multidimensional Fatigue Inventory-20 (MFI-20) at baseline, 1 year, and end of study. QOL changes were related to patient characteristics. RESULTS Median follow-up was 3 years. Mean age was 68 ± 8 years, and 66% were males. At the end of follow-up, all SF-36 subscales were comparable between both groups. The AF severity scale was similar at baseline and end of study. At baseline and at end of study there were no differences in the MFI-20 subscales between the 2 groups. Symptoms at baseline, younger age, and less severe underlying disease, rather than assigned therapy or heart rate, were associated with QOL improvements. Female sex and cardiovascular endpoints during the study were associated with worsening of QOL. CONCLUSIONS Stringency of heart rate control does not influence QOL. Instead, symptoms, sex, age, and severity of the underlying disease influence QOL. (Rate Control Efficacy in Permanent Atrial Fibrillation; NCT00392613).

Lenient vs. strict rate control in patients with atrial fibrillation and heart failure: a post-hoc analysis of the RACE II study

It is unknown whether lenient rate control is an acceptable strategy in patients with AF and heart failure. We evaluated differences in outcome in patients with AF and heart failure treated with lenient or strict rate control.

Effect of lenient versus strict rate control on cardiac remodeling in patients with atrial fibrillation data of the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) study

OBJECTIVES The aim of this study was to evaluate echocardiographic remodeling in permanent atrial fibrillation (AF) patients treated with either lenient or strict rate control. BACKGROUND It is unknown whether in permanent AF, lenient rate control is associated with more adverse cardiac remodeling than strict rate control. METHODS Echocardiography was conducted at baseline and at follow-up in 517 patients included in the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) trial. Echocardiographic parameters were compared between patients randomized to lenient rate control (n = 261) or strict rate control (n = 256). RESULTS Baseline echocardiographic parameters were comparable between patients randomized to lenient and strict rate control. Between baseline and follow-up, significant adverse atrial or ventricular remodeling was not observed in either group. There were also no significant differences in atrial and ventricular remodeling between patients who continuously had heart rates between 80 and 110 beats/min and patients who continuously had heart rates <80 beats/min during follow-up. Lenient rate control was not independently associated with changes in echocardiographic parameters: mean adjusted effect on left atrial size was 1.6 mm (p = 0.09) and 1.1 mm on left ventricular end-diastolic diameter (p = 0.23). Instead, female sex was independently associated with adverse remodeling: mean adjusted effect on left atrial size was 2.4 mm (p = 0.02) and 6.5 mm on left ventricular end-diastolic diameter (p < 0.0001). CONCLUSIONS Female sex, not lenient rate control, seemed to be associated with significant adverse cardiac remodeling in patients with permanent AF such as those enrolled in the RACE II study. (RAte Control Efficacy in Permanent Atrial Fibrillation [RACE II]; NCT00392613).

Rate Control Efficacy in Permanent Atrial Fibrillation: Successful and Failed Strict Rate Control Against a Background of Lenient Rate Control

OBJECTIVES This study sought to investigate differences in outcome between patients treated with successful strict, failed strict, and lenient rate control. BACKGROUND The RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation) study showed no difference in outcome between lenient and strict rate control in patients with permanent atrial fibrillation (AF). However, in the strict group not all patients achieved the pre-defined heart rate target. METHODS The primary outcome was a composite of cardiovascular morbidity and mortality. For the current analysis outcome events were analyzed from end of the dose-adjustment phase until end of follow-up (median 2.9 years [interquartile range: 2.4 to 3.0 years]). Of 614 patients, 608 completed the dose-adjustment phase-301 in the strict (resting heart rate <80 beats/min, and during moderate exercise <110 beats/min) and 307 in the lenient group (resting heart rate <110 beats/min). In the strict group, 203 of 301 patients achieved the rate control target, and 98 failed. RESULTS Heart rate was different after the dose-adjustment phase between the successful strict (72 ± 7 beats/min), failed strict (86 ± 14 beats/min), and lenient (93 ± 8 beats/min) group (p < 0.001) and remained significantly different during follow-up. The primary outcome was reached in 27 of 203 (14.2% KM estimate) in the successful strict versus 14 of 98 (15%) in the failed strict versus 35 of 307 (12.1%) in the lenient group (p = 0.5). The components of the primary outcome and quality of life were similar in the groups. CONCLUSIONS In patients with permanent AF, successful strict rate control does not improve outcome. Therefore, lenient rate control might be frontline therapy.

Does intensity of rate control influence outcome in persistent atrial fibrillation? : Data of the RACE study

BACKGROUND Large trials have demonstrated that rate control is an acceptable alternative for rhythm control. However, optimal heart rate during atrial fibrillation (AF) remains unknown. Aim of this analysis was to compare outcome between rate control > or =80 and <80 beat/min in patients with persistent atrial fibrillation. METHODS In the RAte Control versus Electrical cardioversion for persistent atrial fibrillation study, 522 patients were included, and 256 were randomized to rate control. This post hoc analysis included patients randomized to rate control. Patients were divided according to their mean resting heart rate during follow-up, <80 beat/min (n = 75) or > or =80 beat/min (n = 139). The end point, a composite of cardiovascular mortality, heart failure, thromboembolic complications, bleeding, pacemaker implantation, and severe drug side effects, was compared between both groups. RESULTS During follow-up (2.3 +/- 0.6 years), a significant difference between both groups in heart rate was observed (72 +/- 5 vs 90 +/- 8 beat/min; P < .001). Rate control drugs were not significantly different between both groups. New York Heart Association class and fractional shortening remained unchanged in both groups. There were 17 (23%) end points in the low heart rate group and 24 (17%) in the higher heart rate group (absolute difference, 5.4 [-7.3 to 8.2]; P = ns). Independent predictors for the primary end point were coronary artery disease, digoxin use, and interrupted anticoagulation, not high heart rate. Quality of life was comparable in both groups during follow-up. CONCLUSIONS In patients treated with a rate control strategy, no differences were observed in terms of cardiovascular morbidity, mortality, and quality of life between the observed differences in level of rate control throughout follow-up.

Rate control in Atrial fibrillation

Rate control may now be adopted as a first-choice therapy in a variety of patients, especially older relatively asymptomatic patients with hypertension or other underlying heart diseases. The goal of rate control therapy is to minimize symptoms, improve quality of life, decrease the risk of development of heart failure, and prevent thromboembolic complications. A lenient rate control approach may be the initial therapeutic strategy. If symptoms persist, a stricter rate control approach may be adopted. Although long-term randomized studies are lacking, the evidence available suggests that a β-blocker with or without digoxin is the first-choice rate control therapy.