Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET.

AIMS: Atrial fibrillation is common in patients with chronic heart failure (CHF). We analysed the risk associated with atrial fibrillation in a large cohort of patients with chronic heart failure all treated with a beta-blocker. METHODS AND RESULTS: In COMET, 3029 patients with CHF were randomized to carvedilol or metoprolol tartrate and followed for a mean of 58 months. We analysed the prognostic relevance on other outcomes of atrial fibrillation on the baseline electrocardiogram compared with no atrial fibrillation and the impact of new onset atrial fibrillation during follow-up. A multivariate analysis was performed using a Cox regression model where 10 baseline covariates were entered together with study treatment allocation. Six hundred patients (19.8%) had atrial fibrillation at baseline. These patients were older (65 vs. 61 years), included more men (88 vs.78%), had more severe symptoms [higher New York Heart Association (NYHA) class] and a longer duration of heart failure (all P<0.0001). Atrial fibrillation was associated with significantly increased mortality [relative risk (RR) 1.29: 95% CI 1.12-1.48; P<0.0001], higher all-cause death or hospitalization (RR 1.25: CI 1.13-1.38), and cardiovascular death or hospitalization for worsening heart failure (RR 1.34: CI 1.20-1.52), both P<0.0001. By multivariable analysis, atrial fibrillation no longer independently predicted mortality. Beneficial effects on mortality by carvedilol remained significant (RR 0.836: CI 0.74-0.94; P=0.0042). New onset atrial fibrillation during follow-up (n=580) was associated with significant increased risk for subsequent death in a time-dependent analysis (RR 1.90: CI 1.54-2.35; P<0.0001) regardless of treatment allocation and changes in NYHA class. CONCLUSION: In CHF, atrial fibrillation significantly increases the risk for death and heart failure hospitalization, but is not an independent risk factor for mortality after adjusting for other predictors of prognosis. Treatment with carvedilol compared with metoprolol offers additional benefits among patients with atrial fibrillation. Onset of new atrial fibrillation in patients on long-term beta-blocker therapy is associated with significant increased subsequent risk of mortality and morbidity.     

Carvedilol protects better against vascular events than metoprolol in heart failure: results from COMET.

OBJECTIVES: We explored whether vascular protection by carvedilol could contribute to its superior effects in the treatment of heart failure (HF) compared with metoprolol tartrate in the COMET (Carvedilol Or Metoprolol European Trial) study. BACKGROUND: Full adrenergic blockade by carvedilol and additional (e.g., antioxidative) properties may lead to vascular protection relative to beta-1 blockade alone, and contribute to its efficacy in HF treatment. METHODS: Three thousand twenty-nine patients with HF due to ischemic (51%) or idiopathic cardiomyopathy (44%) were randomized double-blind to carvedilol (n = 1,511) or metoprolol (n = 1,518) and followed for 58 months. Vascular end points were cardiovascular death, stroke, stroke death, myocardial infarction (MI), and unstable angina. RESULTS: The effect of carvedilol on cardiovascular death improved consistently in subgroups with prespecified baseline variables. Myocardial infarctions were reported in 69 carvedilol and 94 metoprolol patients (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52 to 0.97, p = 0.03). Cardiovascular death or nonfatal MI combined were reduced by 19% in carvedilol (HR 0.81, 95% CI 0.72 to 0.92, p = 0.0009 vs. metoprolol). Unstable angina was reported as an adverse event in 56 carvedilol and in 77 metoprolol patients (HR 0.71, 95% CI 0.501 to 0.998, p = 0.049). A stroke occurred in 65 carvedilol and 80 metoprolol patients (HR 0.79, 95% CI 0.57 to 1.10). Stroke or MI combined occurred in 130 carvedilol and 168 metoprolol patients (HR 0.75, 95% CI 0.60 to 0.95, p = 0.015), and fatal MI or fatal stroke occurred in 34 carvedilol and in 72 metoprolol patients (HR 0.46, 95% CI 0.31 to 0.69, p = 0.0002). Death after a nonfatal MI or stroke occurred in 61 of 124 carvedilol and in 106 of 160 metoprolol patients (HR 0.66, 95% CI 0.48 to 0.90, p = 0.0086). CONCLUSIONS: Carvedilol improves vascular outcomes better than metoprolol. These results suggest a ubiquitous protective effect of carvedilol against major vascular events.     

MERIT-HF mortality and morbidity data

This survival study was designed to address whether beta-1-blockade utilizing metoprolol CR/XL (controlled release/extended release) once daily added to standard therapy reduces mortality and morbidity in patients with decreased ejection fraction and symptoms of heart failure. Enrolled in a double-blind randomized study were 3991 patients with chronic heart failure in NYHA functional class II-IV and ejection fraction h 0.40 stabilized on optimal standard therapy. Randomization was preceded by a 2-week single blind placebo run-in period. The study medication was uptitrated during 8 weeks starting with 12.5 mg (NYHA functional class III-IV) or 25 mg once daily (NYHA functional class II). The target dose was 200 mg once daily. The primary endpoints were all-cause mortality and combined all-cause mortality and hospitalization (time to first event) and other objectives were cause-specific data on hospitalization, NYHA functional class and quality of life. Mean follow-up time was 1 year. All-cause mortality was reduced in the metoprolol CR/XL group compared with the placebo group, 145 versus 217 deaths, 7.2% per patient year of follow-up versus 11.0% with a relative risk of 0.66 (95% CI 0.53-0.81, nominal p = 0.00009, p adjusted for interim analysis = 0.0062). This effect was consistent across all predefined subgroups. Sudden deaths were fewer in the metoprolol group (79 versus 132 deaths), RR 0.59 (P = 0.0002). Also deaths from worsening heart failure were fewer in the metoprolol group (30 versus 58 deaths), RR 0.51 (P = 0.0023). The combined endpoint total mortality or all-cause hospitalizations was also reduced by metoprolol (641 versus 767 events), RR 0.81 (p = 0.00012). Total mortality or hospitalizations due to worsening heart failure was also reduced (311 versus 439 events), RR 0.69 (p < 0.00001). The number of hospitalizations due to worsening heart failure (317 versus 451, p < 0.00001) and days in hospital due to worsening heart failure (3401 versus 5303 days, p < 0.00001) were also reduced by metoprolol. There was also an improvement in NYHA functional class, assessed by the physicians as well as the McMaster Overall Treatment Evaluation questionnaire (OTE), assessed by the patients (p = 0.028 and p = 0.089, respectively). Permanent early discontinuation was 13.9% in the metoprolol group and 15.3% in the placebo group (RR = 0.90). In conclusion, in patients with symptomatic heart failure metoprolol CR/XL once daily improved survival by 34%, sudden death by 41%, and deaths from worsening of heart failure by 49%. In addition to improvement of survival there was also a reduced need of hospitalizations for worsening heart failure and an improved NYHA functional class and of quality of life assessed in a substudy. Metoprolol was well tolerated with no difference in early discontinuation rate from placebo treatment.     

Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial.

AIMS: We studied the influence of heart rate (HR), systolic blood pressure (SBP), and beta-blocker dose on outcome in the 2599 out of 3029 patients in Carvedilol Or Metoprolol European Trial (COMET) who were alive and on study drug at 4 months after randomization (time of first visit on maintenance therapy). METHODS AND RESULTS: By multivariable analysis, baseline HR, baseline SBP, and their change after 4 months were not independently related to subsequent outcome. In a multivariable analysis including clinical variables, HR above and SBP below the median value achieved at 4 months predicted subsequent increased mortality [relative risk (RR) for HR>68 b.p.m. 1.333; 95% confidence intervals (CI) 1.152-1.542; P<0.0001 and RR for SBP>120 mmHg 0.78; 95% CI 0.671-0.907; P<0.0013]. Achieving target beta-blocker dose was associated with a better outcome (RR 0.779; 95% CI 0.662-0.916; P<0.0025). The superiority of carvedilol as compared to metoprolol tartrate was maintained in a multivariable model (RR 0.767; 95% CI 0.663-0.887; P=0.0004) and there was no interaction with HR, SBP, or beta-blocker dose. CONCLUSION: Beta-blocker dose, HR, and SBP achieved during beta-blocker therapy have independent prognostic value in heart failure. None of these factors influenced the beneficial effects of carvedilol when compared with metoprolol tartrate at the pre-defined target doses used in COMET.     

Prognostic importance of plasma NT-pro BNP in chronic heart failure in patients treated with a beta-blocker: results from the Carvedilol Or Metoprolol European Trial (COMET) trial

BACKGROUND: Plasma levels of N-terminal pro-brain natriuretic peptide (NT-pro BNP) are increased in patients with chronic heart failure (CHF). Beta-blockers (BB) may influence these levels but it is unclear whether changes in NT-pro BNP reflect concomitant changes in prognosis. OBJECTIVES: To assess the prognostic importance of NT-pro BNP at baseline and during follow-up, in patients in whom beta-blocker therapy is initiated. METHODS: In COMET, 3029 patients with CHF in NYHA class II-IV and EF<35% were randomised to carvedilol or metoprolol tartrate and were followed for an average of 58 months. Blood samples were collected for the measurement of NT-pro BNP at baseline (n=1559) and during follow-up (n=309). RESULTS: Baseline plasma concentrations of NT-pro BNP above the median (1242 pg/ml) were associated with higher all-cause mortality (RR 2.77; 95% CI 2.33-3.3, p<0.001). Patients who achieved NT-pro BNP levels<400 pg/ml during follow-up had a lower subsequent mortality (RR 0.32; 95% CI 0.15-0.69, p=0.004). CONCLUSIONS: The plasma concentration of NT-pro BNP is a powerful predictor of mortality in patients with CHF. Patients who achieve an NT-pro BNP of <400 pg/ml subsequent to treatment with a beta-blocker have a favourable prognosis.     

The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET.

AIMS: Anaemia is a common comorbidity in chronic heart failure (CHF). The predictors of new onset anaemia (NOA) and its long-term prognostic value, particularly in patients treated with beta-blockers, are not known. METHODS AND RESULTS: In COMET, 3029 patients with CHF in NYHA II-IV and EF <35% were randomized to carvedilol or metoprolol tartrate and were followed for an average of 58 months. Plasma haemoglobin (Hb) concentrations were measured at a central laboratory at randomization, at four monthly intervals for the first year and annually thereafter. According to WHO criteria, anaemia was defined when Hb measured <13 g/dL for men and <12 g/dL for women. We considered anaemia to be severe when Hb <11.5 g/dL for men and <10.5 g/dL for women. The baseline mean Hb was 14.2 +/- 1.5 g/dL (n = 2996) and 15.9% of patients had anaemia (males, 16.0%; females, 15.2%). At baseline, severe anaemia was found in 3.3% of patients (males, 3.6%; females, 2.0%). During the study, all-cause mortality (RR 1.47) death or hospitalization (RR 1.28), and heart failure hospitalization (RR 1.43, all P < 0.0001) were higher in anaemic when compared with non-anaemic patients. In patients without anaemia at baseline, at the end of the study, the cumulative frequency of NOA was 28.1% in males and 27.0% in females. NOA increased over time from 14.2% at year 1 to 27.5% at year 5. Predictors of NOA were: higher age, diuretic dose, creatinine (all P < 0.0001), higher serum potassium, lower serum sodium, body mass index, and use of aldosterone antagonists, carvedilol, and digitalis (all P < 0.03). Treatment with carvedilol (vs. metoprolol tartrate) was associated with a 24% increased risk to develop NOA (P = 0.0047), but not severe anaemia (P = 0.18). Patients with a Hb decrease of >3 g/dL (RR 3.37, P < 0.0001) or of 2.0-3.0 g/dL (RR 1.47, P = 0.011) from baseline had an increased subsequent mortality when compared with patients having Hb increases of 0-1.0 g/dL. CONCLUSION: In stable ambulatory CHF patients, development of NOA is frequent and can be predicted by a set of clinical variables. Decreases in Hb over time relate to future increased morbidity and mortality.     

Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study

OBJECTIVES: This study analyzed the effect of the beta(1)-selective beta-blocker metoprolol succinate controlled release/extended release (CR/XL) once daily on mortality, hospitalizations and tolerability in patients with severe heart failure.BACKGROUND: There continues to be resistance to the incorporation of beta-blockers into clinical care, largely due to concerns about their benefit in patients with more severe heart failure.METHOD: SA subgroup of patients from Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF) in New York Heart Association (NYHA) functional class III/IV with left ventricular ejection fraction < 0.25 were identified (n = 795). The analysis was by intention-to-treat.RESULTS: The mean ejection fraction at baseline was 0.19, and the yearly placebo mortality during follow-up was 19.1%. Treatment with metoprolol CR/XL compared to placebo resulted in significant reductions in all predefined mortality end points including: total mortality, 45 versus 72 deaths (risk reduction 39%; 95% confidence interval 11% to 58%; p = 0.0086); sudden death, 22 vs. 39 deaths (45% [7% to 67%]; p = 0.024); and death due to worsening heart failure, 13 vs. 28 deaths (55% [13% to 77%]; p = 0.015). Metoprolol CR/XL also reduced the number of hospitalizations for worsening heart failure by 45% compared with placebo (p < 0.0001). The NYHA functional class improved in the metoprolol CR/XL group compared with placebo (p = 0.0031). Metoprolol CR/XL was well tolerated, with 31% fewer patients withdrawn from study medicine (all causes) compared with placebo (p = 0.027).CONCLUSIONS: This subgroup analysis of the MERIT-HF study shows that patients with severe heart failure receive a similar mortality benefit and a similar reduction in hospitalizations for worsening heart failure with metoprolol CR/XL treatment as those patients included in the total study.     

A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study

PURPOSE: To describe the effect of atrial fibrillation on long-term morbidity and mortality. SUBJECTS AND METHODS: The Renfrew/Paisley Study surveyed 7052 men and 8354 women aged 45-64 years between 1972 and 1976. All hospitalizations and deaths occurring during the subsequent 20 years were analyzed by the presence or absence of atrial fibrillation at baseline. Lone atrial fibrillation was defined in the absence of other cardiovascular signs or symptoms. Cox proportional hazards models were used to adjust for age and cardiovascular conditions. RESULTS: After 20 years, 42 (89%) of the 47 women with atrial fibrillation had a cardiovascular event (death or hospitalization), compared with 2276 (27%) of the 8307 women without this arrhythmia. Among men, 35 (66%) of 53 with atrial fibrillation had an event, compared with 3151 (45%) of 6999 without atrial fibrillation. In women, atrial fibrillation was an independent predictor of cardiovascular events (rate ratio [RR] = 3.0; 95% confidence interval [CI]: 2.1-4.2), fatal or nonfatal strokes (RR = 3.2; 95% CI: 1.0-5.0), and heart failure (RR = 3.4; 95% CI: 1.9-6.2). The rate ratios among men were 1.8 (95% CI: 1.3-2.5) for cardiovascular events, 2.5 (95% CI: 1.3-4.8) for strokes, and 3.4 (95% CI: 1.7-6.8) for heart failure. Atrial fibrillation was an independent predictor of all-cause mortality in women (RR = 2.2; 95% CI: 1.5-3.2) and men (RR = 1.5; 95% CI: 1.2-2.2). However, lone atrial fibrillation (which occurred in 15 subjects) was not associated with a statistically significant increase in either cardiovascular events (RR = 1.5; 95% CI: 0.6-3.6) or mortality (RR = 1.8; 95% CI: 0.9-3.8). CONCLUSIONS: Atrial fibrillation is associated with an increased long-term risk of stroke, heart failure, and all-cause mortality, especially in women.     

Hypertrophic cardiomyopathy. Long-term clinical development in a regional cohort of 243 patients

This retrospective study was undertaken to assess the long-term clinical outcome of hypertrophic cardiomyopathy (HCM) in a regional cohort of 243 patients aged 40.4 years on average at the time of diagnosis and followed up for 12.3 +/- 8.1 years. Forty-one deaths were recorded during the follow-up period directly related to HCM (including 20 sudden deaths and 17 deaths due to cardiac failure), an annual cardiac mortality rate of 1.37%. In multivariate analysis, two factors were associated with extra mortality: occurrence of the first symptoms before the age of 20 (RR x 2.35) (p = 0.006) and NYHA functional classes III: IV at the latest clinical assessment (p = 0.005). The risk of sudden death increased significantly with septal wall thickness: RR x 2.34 (p = 0.05), RR x 3.27 (p = 0.007) and RR x 3.67 (p = 0.02) respectively, for septal thickness equal to or greater than 25, 30 and 35 mm. Eighty-three patients (34%) had major cardiovascular events (sudden death, congestive cardiac failure, cerebrovascular accident) during follow-up. However, at the latest clinical assessment, 79% were relatively unaffected by their disease, without treatment (12%) or with drug therapy alone (60%). In a minority of patients (28%) a more aggressive therapeutic approach was necessary: cardiac pacing (N = 48), implantable cardiac defibrillators (N = 2) myomectomy (N = 27) or cardiac transplantation (N = 6). The authors conclude that HCM is a complex disease, less serious than initially thought in the majority of patients, but the cause of major cardiovascular events and premature deaths which still remain difficult to prevent.     

Effects of long-term beta-blocker (metoprolol or carvedilol) therapy on QT variability in subjects with chronic heart failure secondary to ischemic cardiomyopathy

Chronic heart failure (CHF) is a risk factor for sudden death. Temporal and spatial changes in repolarization are among the most studied mechanisms for inducing fatal ventricular arrhythmias. Beta blockers effectively reduce the risk of sudden death in CHF. Our aim in this study was to investigate changes induced by metoprolol and carvedilol on the QT variability index (QTVI), a new measure reflecting the temporal heterogeneity of cardiac repolarization. A total of 82 subjects, who were in New York Heart Association functional class II or III, underwent short-term spectral analysis of RR and QT variability before and after a 1-year course of high-dose metoprolol (40 subjects) or carvedilol (42 subjects) at baseline (rest) and after sympathetic stress (head-up tilt). At rest, both drug-treated groups had lower QTVI (p <0.001) than after placebo, but during tilt patients treated with carvedilol had a lower QTVI than those treated with metoprolol (p <0.05). Although both beta-blocker treatments helped to normalize the QTVI measured in normal subjects at rest, they each differentially altered the index after tilt. Carvedilol seemed to improve the QTVI more than metoprolol.     

Reduced ejection fraction, sudden cardiac death, and heart failure death in the mode selection trial (MOST): implications for device selection in elderly patients with sinus node disease

Background: The purpose of this study was to describe the incidence and predictors of sudden cardiac death (SCD) and heart failure (HF) death, and coexisting indications for ICDs and CRT, in patients with sinus node disease (SND) treated with pacemakers. Methods and Results: Baseline variables were used to predict SCD and HF death among 1,135 patients in the Mode Selection Trial, a 6‐year trial of pacing mode in SND. There were 73 deaths among 177 patients with EF ≤ 35% (41.2%), 46/156 (29.5%) with EF 36–49%, and 147/802(18.3%) with EF ≥ 50%. SCD accounted for 21.9%, 23.9%, and 14.3% of deaths with EF ≤ 35%, 36–49%, and ≥ 50%. HF deaths accounted for 23.3%, 19.6%, and 3.4% of deaths with EF ≤ 35%, 36‐49%, and ≥ 50%. EF ≤ 35% predicted SCD (hazard ratio [HR] 3.68, 95% confidence interval [CI] 1.72‐7.89, P = 0.002) and HF death (HR 10.17, 95% CI 3.35, 30.82, P = 0.001). Four‐year SCD rate with EF ≤ 35% was 15.5% (3.9% annually). Nearly one‐fifth of patients qualified for ICDs (EF ≤ 35%) and half of these had QRS ≥ 120 ms. However, >40% died within 33 months (4‐year noncardiac death rate ～22%). Conclusions: Reduced EF predicts SCD and HF death in SND treated with pacemakers. SCD rates among patients with EF ≤ 35% are similar to control arms of primary prevention ICD trials, but mortality rates are significantly higher. Whether ICDs or CRT to provide bradycardia support would prolong life in elderly patients with EF ≤ 35% and SND merits prospective investigation.     

Presence and development of atrial fibrillation in chronic heart failure. Experiences from the MERIT-HF Study

BACKGROUND: Atrial fibrillation is common in heart failure, but data regarding beta-blockade in these patients and its ability to prevent new occurrence of atrial fibrillation are scarce. METHODS: Baseline ECGs in MERIT-HF were coded regarding baseline rhythm, and outcome was analyzed in relation to rhythm. Occurrence of atrial fibrillation during follow-up was also analyzed. RESULTS: At baseline atrial fibrillation was diagnosed in 556 patients (13.9%). Mean metoprolol CR/XL dose in patients in atrial fibrillation (154 mg) and sinus rhythm (158 mg) was similar, as well as decrease in heart rate (14.8 and 13.7 bpm, respectively). Only 61 (total of 362) deaths occurred in those in atrial fibrillation at baseline, 31 on placebo and 30 on metoprolol (RR 1.0; 95% CI 0.61-1.65). During follow-up, new atrial fibrillation was observed in 85 patients on placebo and 47 patients on metoprolol (RR 0.53; 95% CI 0.37-0.76; p=0.0005). CONCLUSION: First, given the wide confidence interval, it was impossible to detect an interaction between metoprolol and mortality in patients with atrial fibrillation and heart failure. Second, in patients with sinus rhythm at baseline, metoprolol reduced the incidence of atrial fibrillation during follow-up. However, we must be extremely cautious in over-interpreting effects in these subgroups.     

Depressed Heart Rate Variability as an Independent Predictor of Death in Chronic Congestive Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy

After acute myocardial infarction, depressed heart rate variability (HRV) has been proven to be a powerful independent predictor of a poor outcome. Although patients with chronic congestive heart failure (CHF) have also markedly impaired HRV, the prognostic value of HRV analysis in these patients remains unknown. The aim of this study was to investigate whether HRV parameters could predict survival in 102 consecutive patients with moderate to severe CHF (90 men, mean age 58 years, New York Heart Association [NYHA] class II to IV, CHF due to idiopathic dilated cardiomyopathy in 24 patients and ischemic heart disease in 78 patients, ejection fraction [EF], 26%; peak oxygen consumption, 16.9 ml/kg/min) after exclusion of patients in atrial fibrilation with diabetes or with chronic renal failure. In the prognostic analysis (Cox proportional-hazards model, Kaplan-Meier survival analysis), the following factors were investigated: age, CHF etiology, NYHA class, EF, peak oxygen consumption, presence of ventricular tachycardia on Holter monitoring, and HRV measures derived from 24-hour electrocardiography monitoring, calculated in the time (standard deviation of all normal RR intervals [SDNN], standard deviation of 5-minute RR intervals [SDANN], mean of all 5-minute standard deviations of RR intervals [SD], root-mean-square of difference of successive RR intervals [rMSSD], and percentage of adjacent RR intervals >50 ms different [pNN50]) and frequency domain (total power [TP], power within low-frequency band [LF], and power within high-frequency band [HF]). During follow-up of 584 ± 405 days (365 days in all who survived), 19 patients (19%) died (mean time to death: 307 ± 315 days, range 3 to 989). Cox's univariate analysis identified the following factors to be predictors of death: NYHA (p = 0.003), peak oxygen consumption (p = 0.01), EF (p = 0.02), ventricular tachycardia on Holter monitoring (p = 0.05), and among HRV measures: SDNN (p = 0.004), SDANN (p = 0.003), SD (p = 0.02), and LF (p = 0.003). In multivariate analysis, HRV parameters (SDNN, SDANN, LF) were found to predict survival independently of NYHA functional class, EF, peak oxygen consumption, and ventricular tachycardia on Holter monitoring. The Kaplan-Meier survival curves revealed SDNN <100 ms to be a useful risk factor; 1-year survival in patients with SDNN <100 ms was 78% when compared with 95% in those with SDNN >100 ms (p = 0.008). The coexistence of SDNN <100 ms and a peak oxygen consumption <14 ml/kg/min allowed identification of a group of 18 patients with a particularly poor prognosis (1-year survival 63% vs 94% in the remaining patients, p <0.001). We conclude that depressed HRV on 24-hour ambulatory electrocardiography monitoring is an independent risk factor for a poor prognosis in patients with CHF. Whether analysis of HRV could be recommended in the risk stratification for better management of patients with CHF needs further investigation.

In 102 consecutive patients with stable chronic congestive heart failure and sinus rhythm, several heart rate variability measures derived from 24-hour electrocardiographic recording were significant prognostic risk markers, independent of clinical variables (New York Heart Association class, peak oxygen consumption, left ventricular ejection fraction). The coexistence of the standard deviation of all normal RR intervals <100 ms and peak oxygen consumption <14 ml/kg/min had the worst prognosis, and it is concluded that heart rate variability analysis is useful for noninvasive heart transplant assessment.     

Mode of death in patients with newly diagnosed heart failure in the general population

BACKGROUND: Early prognosis for incident (new) heart failure (HF) patients in the general population is poor. Clinical trials suggest approximately half of chronic HF patients die suddenly but mode of death for incident HF cases in the general population has not been evaluated. AIMS: To describe mode of death in the first six months after a new diagnosis in the general population. METHODS: Two-centre UK population-based study. RESULTS: 396 incident HF patients were prospectively identified. Overall mortality rates were 6% [3-8%], 11% [8-14%] and 14% [11-18%] at 1, 3 and 6months respectively. There were 59 deaths over a median follow-up of 10months; 86% (n = 51) were cardiovascular (CV) deaths. Overall, the mode of death was progressive HF in 52% (n = 31), sudden death (SD) in 22% (n = 13), other CV death in 12% (n = 7), and non-CV death in 14% (n = 8). On multivariable analysis, progressive HF deaths were associated with older age, lower serum sodium, systolic hypotension, prolonged QRS duration at baseline and absence of ACE inhibitor therapy at the time of discharge or death. CONCLUSION: Early prognosis after a new diagnosis of HF in the general population is poor and progressive HF, rather than sudden death, accounts for the majority of deaths.     

美托洛尔和卡维地洛对慢性心力衰竭的影响

目的比较选择性β1受体阻滞剂美托洛尔和非选择性β受体阻滞剂卡维地洛治疗对慢性心力衰竭(CHF)代谢底物、细胞因子及心脏功能的影响。方法选择CHF患者86例(CHF组)及健康体检者25例(正常对照组)。CHF组患者又随机分为美托洛尔组(43例)和卡维地洛组(43例)。记录两组CHF患者治疗前后心功能分级及不良事件次数及TNF-α、白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)含量。所有入选者均测定血清游离脂肪酸(FFA)含量。结果美托洛尔组和卡维地洛组患者经过治疗后心功能明显改善(P<0.01),其中卡维地洛组更加明显(P<0.01)。美托洛尔组不良事件40次,卡维地洛组不良事件24次(P<0.01)。血浆TNF-α、IL-1β和IL-6较治疗前显著降低(P<0.05)。卡维地洛组较美托洛尔组TNFα和IL-1β降低更明显(P<0.01,P<0.05)。CHF组患者血清FFA含量同正常对照组比较明显升高(P<0.01)。治疗后卡维地洛组血清FFA较美托洛尔组降低更明显(P<0.01)。结论β受体阻滞剂可以改善CHF患者心功能,降低血浆细胞因子及FFA水平,非选择性的β受体阻滞剂卡维地洛优于选择性的β1受体阻滞剂美托洛尔。     

Effect of Beta-blockade and ACE Inhibition on B-type Natriuretic Peptides in Stable Patients with Systolic Heart Failure

INTRODUCTION: The long-term effect of beta-blockade on the plasma levels of natriuretic peptides BNP and its N-terminal counterpart, NT-proBNP, as risk markers in heart failure (HF) is obscure. METHODS: Stable systolic HF patients from the CARMEN study were divided in groups matching their randomised treatment allocation: Carvedilol, enalapril or carvedilol+enalapril. Changes in BNP and NT-proBNP from baseline to 6 months maintenance visit were evaluated in each treatment arm. Furthermore, the prognostic value of BNP and NT-proBNP during monotherapy with carvedilol was assessed with univariate Cox proportional hazards models using a combined endpoint of all cause mortality and cardiovascular hospitalisation. RESULTS: NT-proBNP and BNP were significantly reduced after six months treatment with enalapril (NT-proBNP 1,303 to 857 pg/ml (P < 0.001), BNP 119 to 85 pg/ml (P < 0.001)) or carvedilol+enalapril (NT-proBNP 1,223 to 953 pg/ml (P = 0.003), BNP 117 to 93 pg/ml (P = 0.01)). In contrast, no change was observed in the carvedilol group (NT-proBNP 907 to 1,082 pg/ml (P = 0.06), BNP 114 to 130 pg/ml (P = 0.15). The prognostic value of NT-proBNP and BNP was maintained in the carvedilol group (NT-proBNP HR 1.018 95% CI (1.005-1.032), BNP 1.171 (1.088-1.260)). CONCLUSION: Treatment of HF patients with carvedilol alone does not reduce levels of natriuretic peptides, but treatment with enalapril does. Both BNP and NT-proBNP predict death and hospitalisation in HF patients treated with carvedilol for six months. The clinical implication of our results is that NT-proBNP and BNP can be used as risk markers of death and cardiovascular hospitalisations in systolic HF patients receiving carvedilol without ACE inhibition.     

Sudden cardiac death risk factors in patients with heart failure treated with carvedilol

BACKGROUND: Chronic heart failure (CHF) is associated with a high risk of sudden cardiac death (SCD). Most frequently SCD occurs in patients with NYHA class II and III. AIM: To evaluate the influence of prolonged carvedilol therapy on SCD risk in CHF patients. METHODS: The study included 86 patients (81 men and 5 women) aged 56.8+/-9.19 (35-70) years with CHF in NYHA class II and III receiving an ACE inhibitor and diuretics but not beta-blockers. At baseline and after 12 months of carvedilol therapy the following risk factors for SCD were analysed: in angiography - occluded infarct-related artery; in echocardiography - left ventricular ejection fraction (LVEF) <30%, volume of the left ventricle (LVEDV) >140 ml; in ECG at rest - sinus heart rate (HRs) >75/min, sustained atrial fibrillation, increased QTc; in 24-hour ECG recording - complex arrhythmia, blunted heart rate variability (SDNN <100 ms) and abnormal turbulence parameters (TO and TS or one of them); in signal-averaged ECG - late ventricular potentials and prolonged fQRS >114 ms. The analysis of SCD risk factors in basic examination in patients who suddenly died was also performed. RESULTS: During one-year carvedilol therapy heart transplantation was performed in 2 patients; 5 patients died. At 12 months the following risk factors for SCD were significantly changed: HRs >75/min (50 vs. 16 patients, p=0.006), LVEF <30% (37 vs. 14 patients, p=0.01), SDNN <100 ms (19 vs. 9 patients, p=0.04). At 12 months the number of risk factors for SCD in each patient was significantly reduced (p=0.001). In patients who suddenly died we found a greater amount of SCD risk factors in basic examination (7 vs. 5) as compared to alive patients. CONCLUSIONS: Prolonged beta-adrenergic blockade reduces risk of sudden cardiac death through significant LVEF increase, reduction of HR at rest and improvement of HRV.     

Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids

BACKGROUND: Sudden death (SD) has a major impact on mortality (M) in patients with left ventricular systolic dysfunction (SyD). In GISSI-Prevenzione, treatment with n-3 polyunsaturated fatty acids (PUFA) reduced M and SD in post-MI patients, but their effect in patients with SyD is unknown. METHODS: 11,323 patients with prior MI and NYHA class < or = II were recruited. After excluding patients with no ejection fraction (EF) measurement (1684), and those with missing data (n=9), 9630 patients were available for analysis. Multivariate Cox regression adjusted models were fitted. RESULTS: Compared to patients with EF > 50%, SyD patients had higher M (12.3% vs. 6.0%) and SD (3.4% vs. 1.4%) rates. PUFA reduced M similarly in patients with (RR 0.76 (0.60-0.96) P=0.02) and without SyD (RR 0.81 (0.59-1.10) P=0.17) (heterogeneity tests P=0.55). In contrast, the effect on SD was markedly asymmetrical: PUFA produced a marked reduction (RR 0.42 (0.26-0.67) P=0.0003) of risk in SyD patients whereas the effect was less evident (RR 0.89 (0.41-1.69) P=0.71) in patients with EF > 50% (heterogeneity tests P=0.07). There was a significant increase in SD with worsening EF (P test for trend=0.02), the benefit on SD in patients with EF < or = 40% being 4-fold higher than in those with EF > 50%. CONCLUSIONS: Increasing SyD is associated with elevated risk of SD and with increasing benefit from PUFA. The effect of PUFA on SD reduction was greater in patients with SyD. Prospective trials testing the effect of PUFA in populations with SyD are required.     

小剂量阿司匹林对心血管病一级预防效果及安全性的系统评价

目的 系统评价小剂量阿司匹林在高危人群中一级预防心血管病的有效性和安全性.方法 计算机检索MEDLINE、EMbase、Cochrane图书馆(2008年第3期)、中国生物医学文献数据库、中国学术期刊全文数据库,同时筛检了纳入文献的参考文献.收集小剂量阿司匹林(75～150 mg)一级预防心血管病的随机对照试验(RCT),2名评价员独立评价文献质量和提取资料,并采用RevMan4.2软件对资料进行荟萃分析.结果 共纳入6个研究(TPT,HOT,PPP,WHS,POPADAD,JPAD),72 466例患者.(1)小剂量阿司匹林总的心血管事件的发生率(RR=0.85,95% CI:0.80～0.92)、卒中发生率(RR=0.87,95% CI:0.77～0.98)、非致死性卒中发生率(RR=0.81,95%CI:0.70～0.95)、短暂脑缺血发作发生率(RR=0.76,95%CI:0.64～0.90)均低于安慰剂(均P＜0.05).(2)小剂量阿司匹林非致死性心肌梗死(RR=0.89,95%CI:0.77～1.02)、心血管性死亡(RR=0.98,95% CI:0.86～1.13)、全因死亡发生率(RR=0.95,95%CI:0.88～1.02)与安慰剂比较,差异无统计学意义(P＞0.05).(3)在老年人群中分析显示,小剂量阿司匹林冠心病的发生率低于安慰剂(RR=0.81,95%CI:0.70～0.94,P＜0.01).(4)在安全性方面,与安慰剂比较,小剂量阿司匹林有出血并发症的风险(RR=1.15,95%CI:1.12～1.18,P＜0.01),而在过敏反应方面差异无统计学意义(P＞0.05).结论 小剂最阿司匹林能降低总的心血管事件、短暂脑缺血发作、卒中、非致死性卒中的发生率;对降低非致死性心肌梗死、心血管性死亡、全因死亡方面效果不明显;在老年人群中小剂量阿司匹林能降低冠心病的发牛率;长期应用无明显过敏反应,但存在出血并发症的风险.     

The Prognostic Significance of Bundle Branch Block in High-Risk Chronic Stable Vascular Disease Patients: A Report from the HOPE Trial

Objective: The prognostic significance of left and right bundle branch block (LBBB and RRBB) in patients with chronic stable cardiovascular (CV) disease is not well characterized and was evaluated in the Heart Outcomes Prevention Evaluation (HOPE) study cohort.
Design: Observational analysis of data prospectively collected in the HOPE trial.
Setting and Patients: HOPE was a multicenter, international trial, which evaluated ramipril and vitamin E in 9,541 patients aged ≥55 years with CV disease or diabetes with ≥1 CV risk factor(s) but without heart failure (HF) or known left ventricular systolic dysfunction. Follow-up extended for a median of 4.5 years. Electrocardiograms were obtained at baseline in all study participants and were read centrally.
Main Outcome Measures: Major CV events (defined as CV death, myocardial infarction, or stroke), heart failure, CV death, all-cause death, and sudden death.
Results: Baseline LBBB was present in 246 (2.6%) patients and was associated with increased risk for major CV events (HR = 1.54; 95% CI, 1.18–2.02), CV death (HR 2.29; 95% CI, 1.63–3.20), heart failure (HR 2.99; 95% CI, 2.31–3.87), sudden death (HR 3.17; 95% CI, 2.13–4.73), and all-cause death (HR = 2.10; 95% CI, 1.59–2.77). In multivariate models, LBBB remained an independent predictor of heart failure, sudden death, CV death, and all-cause death (P ≤ 0.002 for all). Baseline RBBB was present in 428 (4.5%) of patients and was not associated with increased CV risk.
Conclusions: In patients with stable chronic CV disease, LBBB but not RBBB is an independent predictor of heart failure, sudden death, CV death, and all-cause death.