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Pharmacological interventions for treating heart failure in patients with Chagas cardiomyopathy.
Martí-Carvajal, AJ, Kwong, JS
The Cochrane database of systematic reviews. 2016;(7):CD009077
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Abstract
BACKGROUND Chagas disease-related cardiomyopathy is a major cause of morbidity and mortality in Latin America. Despite the substantial burden to the healthcare system, there is uncertainty regarding the efficacy and safety of pharmacological interventions for treating heart failure in people with Chagas disease. This is an update of a Cochrane review published in 2012. OBJECTIVES To assess the clinical benefits and harms of current pharmacological interventions for treating heart failure in people with Chagas cardiomyopathy. SEARCH METHODS We updated the searches in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 1), MEDLINE (Ovid; 1946 to to February Week 1 2016), EMBASE (Ovid; 1947 to 2016 Week 07), LILACS (1982 to 15 February 2016), and Web of Science (Thomson Reuters; 1970 to 15 February 2016). We checked the reference lists of included papers. We applied no language restrictions. SELECTION CRITERIA We included randomised clinical trials (RCTs) that assessed the effects of pharmacological interventions to treat heart failure in adult patients (18 years or older) with symptomatic heart failure (New York Heart Association classes II to IV), regardless of the left ventricular ejection fraction stage (reduced or preserved), with Chagas cardiomyopathy. We did not apply limits to the length of follow-up. Primary outcomes were all-cause mortality, cardiovascular mortality at 30 days, time-to-heart decompensation, disease-free period (at 30, 60, and 90 days), and adverse events. DATA COLLECTION AND ANALYSIS Two authors independently performed study selection, 'Risk of bias' assessment and data extraction. We estimated relative risk (RR) and 95% confidence intervals (CIs) for dichotomous outcomes. We measured statistical heterogeneity using the I² statistic. We used a fixed-effect model to synthesize the findings. We contacted authors for additional data. We developed 'Summary of findings' (SoF) tables and used GRADE methodology to assess the quality of the evidence. MAIN RESULTS In this update, we identified one new trial. Therefore, this version includes three trials (108 participants). Two trials compared carvedilol against placebo and another assessed rosuvastatin versus placebo. All trials had a high risk of bias.Meta-analysis of two trials showed a lower proportion of all-cause mortality in the carvedilol groups compared with the placebo groups (RR 0.69; 95% CI 0.12 to 3.88, I² = 0%; 69 participants; very low-quality evidence). Neither of the trials reported on cardiovascular mortality, time-to-heart decompensation, or disease-free periods.One trial (30 participants) found no difference in hospital readmissions (RR 1.00; 95% CI 0.31 to 3.28; very low-quality of evidence) or reported adverse events (RR 0.92; 95% CI 0.67 to 1.27; very low-quality of evidence) between the carvedilol and placebo groups.There was very low-quality evidence from two trials of inconclusive effects on quality of life (QoL) between the carvedilol and placebo groups. One trial (30 participants) assessed QoL with the Minnesota Living With Heart Failure Questionnaire (21 items; item scores range from 0 to 5; a lower MLHFQ score is better). The MD was -14.74; 95% CI -24.75 to -4.73. The other trial (39 participants) measured QoL with the Medical Outcomes Study 36-item short-form health survey (SF-36; item scores range from 0 to 100; higher SF-36 score is better). Data were not provided.One trial (39 participants) assessed the effect of rosuvastatin versus placebo. The trial did not report on any primary outcomes or adverse events. There was very low-quality evidence of uncertain effects on QoL (no data were provided). AUTHORS' CONCLUSIONS This first update of our review found very low-quality evidence for the effects of either carvedilol or rosuvastatin, compared with placebo, for treating heart failure in people with Chagas disease. The three included trials were underpowered and had a high risk of bias. There were no conclusive data to support or reject the use of either carvedilol or rosuvastatin for treating Chagas cardiomyopathy. Unless randomised clinical trials provide evidence of a treatment effect, and the trade-off between potential benefits and harms is established, policy-makers, clinicians, and academics should be cautious when recommending or administering either carvedilol or rosuvastatin to treat heart failure in people with Chagas disease. The efficacy and safety of other pharmacological interventions for treating heart failure in people with Chagas disease remains unknown.
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Mechanisms and Treatment of Intradialytic Hypertension.
Van Buren, PN, Inrig, JK
Blood purification. 2016;(1-3):188-93
Abstract
BACKGROUND Intradialytic hypertension is a condition where there is an increase in blood pressure (BP) from pre- to post-hemodialysis; this condition has been recently identified as an independent mortality risk factor in hypertensive hemodialysis patients. The mechanisms and management of intradialytic hypertension have been explored in numerous research studies over the past few years. SUMMARY Patients with intradialytic hypertension have been found to be more chronically volume overloaded compared to other hemodialysis patients, although no causal role has been established. Patients with intradialytic hypertension have intradialytic vascular resistance surges that likely explain the BP increase during dialysis. Acute intradialytic changes in endothelial cell function have been proposed as etiologies for the increase in vascular resistance, although it is unclear if endothelin-1 or some other vasoconstrictive peptide is responsible. There is an association between dialysate to serum sodium gradients and BP increase during dialysis in patients with intradialytic hypertension, although it is unclear if this is related to endothelial cell activity or acute osmolar changes. In addition to probing the dry weight of patients with intradialytic hypertension, other management strategies include lowering dialysate sodium and changing antihypertensives to include carvedilol or other poorly dialyzed antihypertensives. KEY MESSAGES Hemodialysis patients with intradialytic hypertension have an increased mortality risk compared to patients with modest decreases in BP during dialysis. Intradialytic hypertension is associated with extracellular volume overload in addition to acute increases in vascular resistance during dialysis. Management strategies should include reevaluation of dry weight and modification of both the dialysate prescription and medication prescription.
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Carvedilol's antiarrhythmic properties: therapeutic implications in patients with left ventricular dysfunction.
Naccarelli, GV, Lukas, MA
Clinical cardiology. 2005;(4):165-73
Abstract
Carvedilol is a beta- and alpha-adrenergic-blocking drug with clinically important antiarrhythmic properties. It possesses anti-ischemic and antioxidant activity and inhibits a number of cationic channels in the cardiomyocyte, including the HERG-associated potassium channel, the L-type calcium channel, and the rapid-depolarizing sodium channel. The electrophysiologic properties of carvedilol include moderate prolongation of action potential duration and effective refractory period; slowing of atrioventricular conduction; and reducing the dispersion of refractoriness. Experimentally, carvedilol reduces complex and repetitive ventricular ectopy induced by ischemia and reperfusion. In patients, carvedilol is effective in controlling the ventricular rate response in atrial fibrillation (AF), with and without digitalis, and is useful in maintaining sinus rhythm after cardioversion, with and without amiodarone. In patients with AF and heart failure (HF), carvedilol reduces mortality risk and improves left ventricular (LV) function. Large-scale clinical trials have demonstrated that combined carvedilol and angiotensin-converting enzyme inhibitor therapy significantly reduces sudden cardiac death, mortality, and ventricular arrhythmia in patients with LV dysfunction (LVD) due to chronic HF or following myocardial infarction (MI). Despite intensive neurohormonal blockade, mortality rates remain relatively high in patients with post-MI and nonischemic LVD. Recent trials of implantable cardioverter-defibrillators added to pharmacologic therapy, especially beta blockers, have shown a further reduction in arrhythmic deaths in these patients.
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Carvedilol: a new candidate for reversal of MDR1/P-glycoprotein-mediated multidrug resistance.
Takara, K, Sakaeda, T, Okumura, K
Anti-cancer drugs. 2004;(4):303-9
Abstract
In 1983, carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-propanol] was designed and developed as a beta-adrenoceptor antagonist with vasodilating activity for efficacious and safe treatment of hypertension and coronary artery disease. Carvedilol belongs to the 'third generation' of beta-adrenoceptor antagonists and shows selectivity for the beta1- rather than beta2-adrenoceptor. Carvedilol is also an alpha1-blocking agents, with around 2- to 3-fold more selectivity for beta1- than alpha1-adrenoceptors. This degree of alpha1-blockade is responsible for the moderate vasodilator properties of carvedilol, being different from other beta-adrenoceptor antagonists. In addition, carvedilol is a potent antioxidant, with a 10-fold greater activity than vitamin E. Some carvedilol metabolites found in human plasma also exhibit antioxidative activity approximately 50- to 100-fold greater than carvedilol and other antioxidants. These unique properties of carvedilol, i.e. adrenergic (beta1, beta2 and alpha1) blockade and antioxidative activity, may be important in preventing progressive deterioration of left ventricular dysfunction and chronic heart failure. Recently, carvedilol has been demonstrated to reverse multidrug resistance (MDR) to anticancer drugs in tumor cells in vitro and its reversal effects were comparable with verapamil, which has been used in the first clinical trial for the reversal of MDR. This review introduces the reversal activity and usefulness against MDR, as well as an overview of the pharmacological and pharmacokinetic properties, of carvedilol.
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Advantages of a third-generation beta-blocker in patients with diabetes mellitus.
Bell, DS
The American journal of cardiology. 2004;(9A):49B-52B
Abstract
beta-Blocker use improves outcomes even more for the patient with diabetes mellitus than for the patient without diabetes with a history of acute myocardial infarction or coronary artery disease. beta-Blockers facilitate shifting the metabolism of the myocardium away from free fatty acid toward glucose utilization, thereby reducing the cardiac workload and myocardial ischemia. beta-Blockers are also able to reverse the fetal gene induction program to reverse myocardial remodeling and improve ventricular function. Side effects of beta-blockers in the patient with diabetes include increased insulin resistance with worsening glycemic control, elevated triglyceride levels, and lowered levels of high-density lipoprotein cholesterol. Increased frequency of hypoglycemia and its lack of recognition can also be a problem in the insulin-deficient patient but is a minimal problem with the patient with type 2 diabetes. In addition, vasoconstriction, caused by unopposed alpha-activity, can worsen peripheral vascular disease. However, carvedilol, a nonselective beta-blocker with vasodilating and insulin-sensitizing properties, can largely circumvent these problems and is the ideal beta-blocker for the patient with diabetes.
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Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001.
Louis, A, Cleland, JG, Crabbe, S, Ford, S, Thackray, S, Houghton, T, Clark, A
European journal of heart failure. 2001;(3):381-7
Abstract
This is a synopsis of presentations made at the American College of Cardiology (ACC) in 2001 summarising recent research developments relating to heart failure. Clinical studies of particular interest to physicians with an interest in heart failure and its prevention are reviewed. The COPERNICUS trial lends further support to the use of the beta-blocker, carvedilol, in severe heart failure and the CAPRICORN trial to its use in patients with post-infarction left ventricular systolic dysfunction. The MIRACLE study reinforces the evidence from three smaller trials that cardiac resynchronisation therapy is an effective treatment for the relief of symptoms in patients with severe heart failure and cardiac dyssynchrony. The STAF trial casts further doubt on the wisdom of cardioversion as a routine strategy for the management of chronic atrial fibrillation. The RITZ-2 trial suggests that an intravenous, non-selective endothelin antagonist is effective in improving haemodynamics and symptoms and possibly in reducing morbidity in severe heart failure. Observational studies in heart failure suggest that a moderate excess of body fat and elevated blood cholesterol may be desirable in patients with heart failure, challenging the current non-evidenced-based vogue for cholesterol lowering therapy in heart failure. The RENAISSANCE and RECOVER outcome studies of etanercept, a tumour necrosis factor (TNF) receptor analogue that blocks the effect of TNF, were stopped because of lack of evidence of benefit shortly after the ACC.