Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in ...patients with chronic systolic heart failure and mild symptoms.
In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.
The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval CI, 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).
Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).
Heart failure Krum, Henry, Prof; Abraham, William T, Prof
The Lancet (British edition),
03/2009, Letnik:
373, Številka:
9667
Journal Article
Recenzirano
Summary Despite advances in management of heart failure, the condition remains a major public-health issue, with high prevalence, poor clinical outcomes, and large health-care costs. Risk factors are ...well known and, thus, preventive strategies should have a positive effect on disease burden. Treatment of established systolic chronic heart failure includes use of agents that block the renin-angiotensin-aldosterone and sympathetic nervous systems to prevent adverse remodelling, to reduce symptoms and prolong survival. Diuretics are used to achieve and maintain euvolaemia. Devices have a key role in management of advanced heart failure and include cardiac resynchronisation in patients with evidence of cardiac dyssynchrony and implantation of a cardioverter defibrillator in individuals with low ejection fraction. Approaches for treatment of acute heart failure and heart failure with preserved ejection fraction are supported by little clinical evidence. Emerging strategies for heart failure management include individualisation of treatment, novel approaches to diagnosis and tracking of therapeutic response, pharmacological agents aimed at new targets, and cell-based and gene-based methods for cardiac regeneration.
Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure.
Patients with ...New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction < or =0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375) or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per week (n=308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE (P=0.17) or RECOVER (P=0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, P=0.33).
The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.
Eplerenone is known to reduce time to first hospitalization for heart failure or cardiovascular death in patients with heart failure and mild symptoms. In chronic diseases such as heart failure, ...characterized by repeat hospitalizations, analyzing all heart failure hospitalizations, not just the first, should give a more complete picture of treatment benefits.
The Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF) trial compared eplerenone with placebo in 2737 patients with mild heart failure, followed for a median 2.08 years (interquartile range, 1.08-3.10 years). Data were collected on all hospitalizations, with a focus on those due to heart failure. Heart failure hospitalization rates in the eplerenone and placebo groups were 10.70 and 16.99 per 100 patient-years, respectively. Allowing for skewness in the frequency of hospitalizations by using the negative binomial generalized linear model, the rate ratio (eplerenone versus placebo) was 0.53 (95% confidence interval, 0.42-0.66; P<0.0001). A plot of cumulative hospitalization rates over time revealed that most of the reduced risk on eplerenone occurred in the first year of follow-up. Several baseline variables strongly predicted the risk of hospitalization. More complex statistical methods, adjusting for mortality (as informative censoring), made a negligible difference in these findings.
Eplerenone markedly reduces the risk of heart failure hospitalizations in patients with heart failure and mild symptoms to a greater extent than is captured by only studying the time to first hospitalization. Future clinical trials in heart failure would gain from incorporating repeat hospitalizations into their primary evaluation of treatment effects.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00232180.
Our objective was to review all published trials of coenzyme Q10 for hypertension, assess overall efficacy and consistency of therapeutic action and side effect incidence. Meta-analysis was performed ...in 12 clinical trials (362 patients) comprising three randomized controlled trials, one crossover study and eight open label studies. In the randomized controlled trials (n=120), systolic blood pressure in the treatment group was 167.7 (95% confidence interval, CI: 163.7-171.1) mm Hg before, and 151.1 (147.1-155.1) mm Hg after treatment, a decrease of 16.6 (12.6-20.6, P<0.001) mm Hg, with no significant change in the placebo group. Diastolic blood pressure in the treatment group was 103 (101-105) mm Hg before, and 94.8 (92.8-96.8) mm Hg after treatment, a decrease of 8.2 (6.2-10.2, P<0.001) mm Hg, with no significant change in the placebo group. In the crossover study (n=18), systolic blood pressure decreased by 11 mm Hg and diastolic blood pressure by 8 mm Hg (P<0.001) with no significant change with placebo. In the open label studies (n=214), mean systolic blood pressure was 162 (158.4-165.7) mm Hg before, and 148.6 (145-152.2) mm Hg after treatment, a decrease of 13.5 (9.8-17.1, P<0.001) mm Hg. Mean diastolic blood pressure was 97.1 (95.2-99.1) mm Hg before, and 86.8 (84.9-88.8) mm Hg after treatment, a decrease of 10.3 (8.4-12.3, P<0.001) mm Hg. We conclude that coenzyme Q10 has the potential in hypertensive patients to lower systolic blood pressure by up to 17 mm Hg and diastolic blood pressure by up to 10 mm Hg without significant side effects.
Skeletal muscle NKA preferentially utilises ATP derived from glycogenolytic and glycolytic origins, therefore the aim of this study was to determine whether digoxin effects on muscle NKA would reduce ...systemic lactate Lac- with intense exercise and exacerbate fatigue in healthy humans. During FF, plasma Lac-a and Lac-v increased at fatigue compared to rest (P<0.001); Lac-a-v became more negative during each exercise bout (EB) to fatigue (P<0.001); Lac-a-v (corrected for corresponding ∆PVa-v) decreased below rest, indicating a net Lac- entry into plasma during each EB (P<0.001); Lac- flux became more negative (i.e. flux into plasma) during each EB (P<0.001; fatigue, ~157-fold). DIG induced compensatory NKA upregulation was likely in skeletal muscle NKA (data not presented here), thus the observed small DIG effects on plasma lactate during exercise are not surprising.
Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure.
We evaluated 2289 ...patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded.
There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.00013, unadjusted; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol (95 percent confidence interval, 13 to 33 percent; P<0.001). The favorable effects on both end points were seen consistently in all the subgroups we examined, including patients with a history of recent or recurrent cardiac decompensation. Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons (P=0.02).
The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also apparent in the patients with severe heart failure who were evaluated in this trial.
In patients with chronic heart failure (CHF), a beta-blocker is generally added to a regimen containing an angiotensin-converting-enzyme (ACE) inhibitor. It is unknown whether beta-blockade as ...initial therapy may be as useful.
We randomized 1010 patients with mild to moderate CHF and left ventricular ejection fraction < or =35%, who were not receiving ACE inhibitor, beta-blocker, or angiotensin receptor blocker therapy, to open-label monotherapy with either bisoprolol (target dose 10 mg QD; n=505) or enalapril (target dose 10 mg BID; n=505) for 6 months, followed by their combination for 6 to 24 months. The 2 strategies were blindly compared with regard to the combined primary end point of all-cause mortality or hospitalization and with regard to each of these end point components individually. Bisoprolol-first treatment was noninferior to enalapril-first treatment if the upper limit of the 95% confidence interval (CI) for the absolute between-group difference was <5%, corresponding to a hazard ratio (HR) of 1.17. In the intention-to-treat sample, the primary end point occurred in 178 patients allocated to bisoprolol-first treatment versus 186 allocated to enalapril-first treatment (absolute difference -1.6%, 95% CI -7.6 to 4.4%, HR 0.94; 95% CI 0.77 to 1.16). In the per-protocol sample, 163 patients allocated to bisoprolol-first treatment had a primary end point, versus 165 allocated to enalapril-first treatment (absolute difference -0.7%, 95% CI -6.6 to 5.1%, HR 0.97; 95% CI 0.78 to 1.21). With bisoprolol-first treatment, 65 patients died, versus 73 with enalapril-first treatment (HR 0.88; 95% CI 0.63 to 1.22), and 151 versus 157 patients were hospitalized (HR 0.95; 95% CI 0.76 to 1.19).
Although noninferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, our results indicate that it may be as safe and efficacious to initiate treatment for CHF with bisoprolol as with enalapril.
Obstructive coronary artery disease (CAD) is evident in only half of patients referred for diagnostic angiography. Five-minute heart rate variability (HRV) is a non-invasive marker for autonomic ...control of the vasculature, which this study hypothesised could risk-stratify cardiac patients and reduce unnecessary angiograms.
A prospective observational study (the Alternative Risk Markers in Coronary Artery Disease (ARM-CAD) study).
Three cardiac centres in Melbourne, Australia.
470 consecutive patients undergoing elective angiography (with predominantly normal cardiac rhythm), regardless of co-morbidity.
The presence of obstructive CAD (≥50% stenosis) on angiography.
Patients with obstructive CAD had significantly reduced HRV, particularly in the low frequency (LF) range (median 180 vs 267 ms(2) without CAD; p<0.001). There was a linear trend with the severity of CAD; median LF power (IQR) in patients with normal coronaries was 275 (612), with minor coronary irregularities 255 (400), single-vessel CAD 212 (396) and more severe disease 170 (327) ms(2); p value for trend 0.003. There was a similar reduction in LF power regardless of the anatomical location of coronary stenoses. Comparing patients with LF less than 250 and 250 ms(2) or greater, the adjusted OR for obstructive CAD using multivariate regression was 2.42, 95% CI 1.33 to 4.38 (p=0.004). No interactions were noted in subgroup analysis and HRV added to risk prediction irrespective of the baseline Framingham risk (p<0.0001).
Low HRV is strongly predictive of angiographic coronary disease regardless of other co-morbidities and is clinically useful as a risk predictor in patients with sinus rhythm.
http://clinicaltrials.gov/ct2/show/NCT00403351 www.armcad.com.
Diuretic Use in Heart Failure and Outcomes von Lueder, T G; Atar, D; Krum, H
Clinical pharmacology and therapeutics,
October 2013, Letnik:
94, Številka:
4
Journal Article
Recenzirano
Diuretics are frequently administered to relieve congestive symptoms in patients with heart failure (HF). Despite their widespread use, prospective data on the potential of diuretics to modulate ...HF‐related morbidity and mortality are scarce. Diuretic efficacy may be limited by adverse neurohormonal activation and by “congestion‐like” symptoms that may occur in the absence of fluid overload. Herein, we review the current knowledge on diuretic use and outcomes in HF.
Clinical Pharmacology & Therapeutics (2013); 94 4, 490–498. doi:10.1038/clpt.2013.140
PDF
