The pharmacotherapy implications of ventricular assist device in the patient with end-stage heart failure

Advances in mechanical circulatory support, such as the use of ventricular assist devices (VADs), have become a means for prolonging survival in end-stage heart failure (HF). VADs decrease the symptoms of HF and improve quality of life by replacing some of the work of a failing heart. They unload the ventricle to provide improved cardiac output and end-organ perfusion, resulting in improvement in cardiorenal syndromes and New York Heart Association functional class rating. VADs are currently used asa bridge to heart transplantation, a bridge to recovery of cardiac function, or as destination therapy. Complications of VAD include bleeding, infections, arrhythmias, multiple organ failure, right ventricular failure, and neurological dysfunction. Patients with VAD have unique pharmacotherapeutic requirements in terms of anticoagulation, appropriate antibiotic selection, and continuation of HF medications. Pharmacists in acute care and community settings are well prepared to care for the patient with VAD. These patients require thorough counseling and follow-up with regard to prevention and treatment of infections, appropriate levels of anticoagulation, and maintenance of fluid balance. A basic understanding of this unique therapy can assist pharmacists in attending to the needs of patients with VAD.     

Pharmacologic Management of Arrhythmias in Patients with Congenital Heart Disease

The management of cardiac arrhythmias has evolved rapidly over the past decade. This includes the development of more effective antiarrhythmic medications as well as catheter- and device-based therapies. Antiarrhythmic medications remain the primary treatment modality for most acute arrhythmias; however, the long term use of these medications may be accompanied by severe adverse effects. For this reason, antiarrhythmic medications are increasingly used in conjunction with other forms of therapy, such as catheter ablation or pacemaker implantation. Patients with congenital heart disease often have an increased propensity for cardiac arrhythmias due to both inherent conduction system abnormalities and impaired ventricular function. The purpose of this review is to examine the currently available antiarrhythmic drugs and assess their role in the treatment of arrhythmias in patients with congenital heart disease. It is important to emphasize that patients with congenital heart disease often have hemodynamic limitations and may be at an increased risk for developing adverse effects with antiarrhythmic agents. An awareness of the arrhythmias associated with congenital heart disease, the natural history of these arrhythmias, and the potential benefit of treatment with antiarrhythmic medications versus other forms of therapy provides a rational basis for therapy in this challenging population of patients.     

Atorvastatin and statins in the treatment of heart failure

Heart failure (HF) affects approximately five million people in the US and survival at 5 years is only 50% despite advances in medical and device therapy. Statins are of novel therapy for these patients, which may be beneficial in both ischemic and non-ischemic HF. In addition to lipid-lowering and anti-atherosclerotic effects, statins demonstrate many non-lipid or pleiotropic effects that could be beneficial in HF. They may inhibit or reverse myocardial remodeling, inhibit inflammation in HF, improve endothelial function and restore autonomic nervous system balance. Numerous observational studies of HF cohorts have linked statin therapy with significantly improved survival. Small prospective clinical studies of atorvastatin and simvastatin in systolic HF are promising, documenting improved ventricular systolic function and decreased inflammatory biomarkers with statin therapy. Definitive recommendations regarding statin therapy in all HF must await the completion of large scale outcome trials of statins in non-ischemic HF.     

Atorvastatin and statins in the treatment of heart failure

Heart failure (HF) affects approximately five million people in the US and survival at 5 years is only 50% despite advances in medical and device therapy. Statins are of novel therapy for these patients, which may be beneficial in both ischemic and non-ischemic HF. In addition to lipid-lowering and anti-atherosclerotic effects, statins demonstrate many non-lipid or pleiotropic effects that could be beneficial in HF. They may inhibit or reverse myocardial remodeling, inhibit inflammation in HF, improve endothelial function and restore autonomic nervous system balance. Numerous observational studies of HF cohorts have linked statin therapy with significantly improved survival. Small prospective clinical studies of atorvastatin and simvastatin in systolic HF are promising, documenting improved ventricular systolic function and decreased inflammatory biomarkers with statin therapy. Definitive recommendations regarding statin therapy in all HF must await the completion of large scale outcome trials of statins in non-ischemic HF.     

Cost Effectiveness of Biventricular Pacemakers in Heart Failure Patients

BACKGROUND: Biventricular pacemakers have been shown to reduce mortality and hospitalizations in heart failure (HF) patients and are indicated for those with a New York Heart Association functional class of III or IV and a QRS interval of >130 ms. However, these devices currently cost in the region of dollar US 33,500 and require replacement upon battery depletion. Therefore, determination of the cost effectiveness of resynchronization therapy is important, although little data have been published to date on this topic. METHODS AND RESULTS: A cost-utility analysis from the healthcare perspective was performed using HF patients who received a biventricular pacing device in the Cleveland Clinic Foundation. The comparator was a similarly profiled group of patients who did not receive the device but were treated medically. A Markov model was used to investigate the cost effectiveness at 1 and 5 years. Second-order Monte-Carlo simulation was used to determine the variability in results, using probabilistic sensitivity analysis. Medical treatment was dominated by biventricular pacemaker treatment at both 1 and 5 years of follow-up. CONCLUSION: Biventricular device insertion is an economically attractive treatment option for clinically indicated HF patients.     

Safe and Effective Use of Pharmacologic and Device Therapy for Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is an uncommon, idiopathic complication of pregnancy associated with significant (10–30%) mortality. The disease occurs late in pregnancy or in the months following delivery, resulting in reduced systolic function and heart failure (HF) symptoms. Limited direction is provided for the management of PPCM, and the safe and effective use of medications in pregnant and breastfeeding women with PPCM presents a unique challenge. Although several HF therapies in pregnant and lactating women are supported by robust evidence, evidence to support the use of other therapies is significantly lacking. Current guidelines recommend treatment as in other forms of HF with reduced left ventricular ejection fraction (LVEF) but with consideration for the important nuances in this population as well as the unique and potential teratogenic effects of these therapies. Since most patients with PPCM recover their LVEF, the duration of therapy is currently unknown and warrants further study. We review the available literature surrounding pharmacologic and device therapy for PPCM and provide insight into managing patients with the condition.     

降糖药物对糖尿病合并心衰患者的影响

糖尿病（DM）合并心力衰竭（HF）患者在临床上治疗和生存状态较差,而不同的降糖药物导致HF的风险不同。本文综述总结了目前各类降糖药物临床实验中对HF的影响：二甲双胍是一种相对安全的降糖药物;钠-葡萄糖共转运体-2（SGLT-2）抑制剂类降糖药可以降低危重心血管病和HF的风险,未来有望用于一线治疗,以改善HF患者的预后。     

Potential Mechanisms of Benefit with Thalidomide in Chronic Heart Failure

This review considers the recent clinical and relevant preclinical evidence that thalidomide may have therapeutic benefit in chronic heart failure (HF), and considers some of the mechanisms by which thalidomide may elicit potentially beneficial effects. Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic HF by influencing heart contractility, inducing matrix degradation and fibrosis, and promoting apoptosis, contributing to myocardial remodeling. On the basis of these issues, immunomodulating therapy has emerged as an option in the management of chronic HF. Failure of anti-tumor necrosis factor (TNF) therapy has lead to further interest in a more general immunomodulatory approach, directed against the imbalanced cytokine network rather than at one particular cytokine.Some recent studies suggest that thalidomide, a glutamic acid derivative with proposed antiangiogenic, anti-inflammatory, and immunomodulatory properties, should be added to the list of potential immunomodulating agents in chronic HF. Thus, in a recent double-blind, placebo-controlled study in patients with chronic HF, thalidomide was found to significantly improve left ventricular ejection fraction. Although thalidomide has been regarded as an anti-TNF drug, it was found to increase plasma levels of TNFalpha in a placebo-controlled study in patients with HF, suggesting that other mechanisms may contribute to its beneficial effects. Such mechanisms could involve inhibition of neutrophils, matrix stabilizing, and antifibrotic effects, as well as a thalidomide-mediated decrease in the heart rate. However, our knowledge of the mechanisms of action of this drug is still scarce and will have to be further examined in forthcoming studies. Such studies should include experiments in animal models of HF as well as further preclinical trials, attempting to identify the potential mechanisms by which thalidomide may be beneficial in human HF.     

A critical evaluation of the NICE guidelines for post-myocardial infarction prophylaxis. National Institute for Clinical Excellence

The UK National Institute for Clinical Excellence (NICE) has recently published guidelines on prophylaxis for patients who have experienced a myocardial infarction (MI). Based on a previously commissioned extensive review of the literature, the recommendations are antiplatelet therapy, beta-blockers and angiotensin converting enzyme inhibitors (ACEIs) for all patients; statins for those with hypercholesterolaemia; spironolactone for those with moderate-to-severe heart failure (HF); and insulin for those with diabetes. While there may be concerns about some of the details (eg., the possible adverse interaction between aspirin and ACEIs), comments on the use of statins for those with HF, the lack of advice on the choice of lipid-lowering therapy for those intolerent of statins, the dangers of spironolactone therapy and the practicality of intensive insulin treatment, the guidelines are firmly based on sound evidence of efficacy and cost effectiveness. The NICE guidelines should therefore stimulate the provision of resources to address the gap between current practice and these recommendations.     

A critical evaluation of the NICE guidelines for post-myocardial infarction prophylaxis

The UK National Institute for Clinical Excellence (NICE) has recently published guidelines on prophylaxis for patients who have experienced a myocardial infarction (MI). Based on a previously commissioned extensive review of the literature, the recommendations are antiplatelet therapy, β-blockers and angiotensin converting enzyme inhibitors (ACEIs) for all patients; statins for those with hypercholesterolaemia; spironolactone for those with moderate-to-severe heart failure (HF); and insulin for those with diabetes. While there may be concerns about some of the details (eg., the possible adverse interaction between aspirin and ACEIs), comments on the use of statins for those with HF, the lack of advice on the choice of lipid-lowering therapy for those intolerent of statins, the dangers of spironolactone therapy and the practicality of intensive insulin treatment, the guidelines are firmly based on sound evidence of efficacy and cost effectiveness. The NICE guidelines should therefore stimulate the provision of resources to address the gap between current practice and these recommendations.     

ACE Inhibitors in Heart Failure

ACE inhibitors have significantly decreased cardiovascular mortality, myocardial infarction (MI), and hospitalizations for heart failure (HF) in patients with asymptomatic or symptomatic left ventricular (LV) systolic dysfunction. Furthermore, the extended 12-year study of the SOLVD (Studies Of Left Ventricular Dysfunction) Prevention and Treatment trials (X-SOLVD) demonstrated a significant benefit with a reduction of cumulative all-cause death compared with placebo (50.9% vs 56.4%) [hazard ratio (HR) 0.86; 95% CI 0.79, 0.93; p < 0.001]. The survival benefits and significant reductions in cardiovascular morbidity related to treatment with ACE inhibitors are likely achieved by titrating the dose of ACE inhibitors to the target dose achieved in clinical trials. Although the ATLAS (Assessment of Treatment with Lisinopril And Survival) study, which randomly allocated HF patients to low- or high-dose lisinopril, showed no significant difference between groups for the primary outcome of all-cause mortality (HR 0.92; 95% CI 0.82, 1.03), the predetermined secondary combined outcome of all-cause mortality and HF hospitalization was reduced by 15% for the patients receiving high-dose lisinopril compared with low-dose (p < 0.001) with a 24% reduction in HF hospitalization (p = 0.002). Despite the use of ACE inhibitors, blockade of the renin angiotensin aldosterone system (RAAS) remains incomplete, with evidence of continued production of angiotensin II by non-ACE-dependent pathways. The safety and potential benefits of angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) in patients with impaired systolic function have been assessed in moderate to large clinical trials. In patients with impaired LV systolic function and HF, combination therapy with ARBs with recommended HF therapy including ACE inhibitors in patients who remain symptomatic may be considered for its morbidity benefit. Based on the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity)-Added data, candesartan cilexetil in addition to standard HF therapy results in a further reduction of cardiovascular mortality. Close monitoring of renal function and serum potassium levels is needed in this setting. The VALIANT (VALsartan In Acute myocardial iNfarction Trial) results suggest that valsartan is as effective as captopril in patients following an acute MI with HF and/or LV systolic dysfunction and may be used as an alternative treatment in ACE inhibitor-intolerant patients. There was no survival benefit with valsartan-captopril combination compared with captopril alone in this trial. Despite these results, ACE inhibitors remain the first-choice therapeutic agent in post-MI patients, and ARBs can be used in patients with clear intolerance. Although the use of ACE inhibitors may be appealing in patients with HF and preserved LV systolic function, there is currently no evidence from large clinical trials to support this.     

心力衰竭患者高凝状态与抗栓治疗

心力衰竭(HF)患者脑卒中、肺栓塞及外周静脉血栓等血栓栓塞事件的发生率明显高于非HF患者。其抗栓治疗一直存在争议,主要权衡抗栓(抗凝和抗血小板)治疗、血栓栓塞风险降低的获益和出血的风险。多项研究已证实,有心房颤动或血栓栓塞史的HF患者需要进行常规抗凝治疗,但窦性心律HF患者是否需要进行预防性抗栓治疗目前还没有达成共识。     

心力衰竭治疗新靶点-Galectins．3

尽管心力衰竭（HF）的药物治疗近年来有了较大进展,但HF患者预后仍很差。针对HF发病早期行药物治疗是近年来研究的一个重点。Galectin．3（Gal-3）在心室重塑和HF病理生理发展过程中起重要作用,可作为HF治疗的靶点。Gal-3水平升高的HF患者可从醛固酮拮抗剂治疗中获益。本文简要综述以Gal-3水平为指导的HF患者个体化治疗。     

Rationale, design and organisation of an efficacy and safety study of oxypurinol added to standard therapy in patients with NYHA class III - IV congestive heart failure

Oxypurinol, the active metabolite of allopurinol and a potent xanthine oxidase inhibitor (XOI), is under evaluation as a novel agent for the treatment of congestive heart failure (HF). Several lines of evidence provide the rationale for the hypothesis that XOIs will improve clinical outcomes in patients with HF. First, XOIs have unique positive inotropic effects, improving myocardial contraction and performance while simultaneously improving myocardial energy metabolism. Second, XOIs ameliorate endothelial dysfunction in humans with HF. Finally, XO activity is upregulated in the heart and vasculature of subjects with HF, which may in turn contribute to oxidative stress and/or increased uric acid levels. Together these findings form the rationale for the Controlled Efficacy and Safety Study of Oxypurinol Added to Standard Therapy in Patients with New York Heart Association (NYHA) class III - IV Congestive Heart Failure (OPT-CHF) trial (Food and Drug Administration IND 65,125), a Phase II - III prospective, randomised, double-blind, placebo-controlled trial, which will include patients with stable symptomatic HF in NYHA class III - IV congestive HF who are deemed clinically stable on a standard and appropriately maximised heart failure therapy regimen. The efficacy end point for OPT-CHF is a composite that incorporates measures of patient outcome and well-being.     

Rationale,design and organisation of an efficacy and safety study of oxypurinol added to standard therapy in patients with NYHA class III – IV congestive heart failure

Oxypurinol, the active metabolite of allopurinol and a potent xanthine oxidase inhibitor (XOI), is under evaluation as a novel agent for the treatment of congestive heart failure (HF). Several lines of evidence provide the rationale for the hypothesis that XOIs will improve clinical outcomes in patients with HF. First, XOIs have unique positive inotropic effects, improving myocardial contraction and performance while simultaneously improving myocardial energy metabolism. Second, XOIs ameliorate endothelial dysfunction in humans with HF. Finally, XO activity is upregulated in the heart and vasculature of subjects with HF, which may in turn contribute to oxidative stress and/or increased uric acid levels. Together these findings form the rationale for the Controlled Efficacy and Safety Study of Oxypurinol Added to Standard Therapy in Patients with New York Heart Association (NYHA) class III – IV Congestive Heart Failure (OPT-CHF) trial (Food and Drug Adminstration IND 65,125), a Phase II – III prospective, randomised, double-blind, placebo-controlled trial, which will include patients with stable symptomatic HF in NYHA class III – IV congestive HF who are deemed clinically stable on a standard and appropriately maximised heart failure therapy regimen. The efficacy end point for OPT-CHF is a composite that incorporates measures of patient outcome and well-being.     

New therapeutic options for onychomycosis

INTRODUCTION: Onychomycosis is a fungal infection of the nail apparatus that affects 10 - 30% of the global population. Current therapeutic options for onychomycosis have a low to moderate efficacy and result in a 20 - 25% rate of relapse and reinfection. New therapeutic options are needed to broaden the spectrum of treatment options and improve the efficacy of treatment. AREAS COVERED: This review discusses the emerging pharmacotherapeutics; including topical reformulations of terbinafine, new azole molecules for systemic and topical administration, topical benzoxaboroles and topical polymer barriers. The paper also discusses device-based options, which may be designed to activate a drug or to improve drug delivery, such as photodynamic therapy and iontophoresis; laser device systems have also begun to receive regulatory approval for onychomycosis. EXPERT OPINION: Device-based therapeutic options for onychomycosis are expanding more rapidly than pharmacotherapy. Systemic azoles are the only class of pharmacotherapy that has shown a comparable efficacy to systemic terbinafine; however terbinafine remains the gold standard. The most notable new topical drugs are tavaborole, efinaconazole and luliconazole, which belong to the benzoxaborole and azole classes of drugs. Photodynamic therapy, iontophoresis and laser therapy have shown positive initial results, but randomized controlled trials are necessary to determine the long-term success of these devices.     

Chronic Heart Failure

Heart failure (HF) is a complex syndrome characterized by the inability of the heart to maintain a normal cardiac output without elevated intracardiac filling pressures, resulting in signs of pulmonary and peripheral edema and symptoms of dyspnea and fatigue. Central to the management of HF is a multifaceted pharmacological intervention to abate the harmful counter-regulatory effects of neurohormonal activation and avid salt and water retention. Whereas up to 40 years ago HF was managed with diuretics and leaf of digitalis, the cornerstones of therapy for HF patients with systolic dysfunction now include ACE inhibitors or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers), β-adrenoceptor antagonists (β-blockers), and aldosterone antagonists, which have significantly improved survival. However, with the increasing number of beneficial therapies, there are challenges to implementing all of them. Specific cardiomyopathies also merit specific considerations with respect to treatment, and — unfortunately — there is no therapy for HF with preserved left ventricular ejection fraction that has been shown to improve survival. Although mortality has improved in HF, the biggest challenge to treatment lies in addressing the morbidity of this disease, which is now the most common reason for hospital admission in our aged population. As such, there are many therapies that may serve to improve the quality of life of HF patients. Future HF treatment regimens may include direct cellular therapy via hormone and cytokine signaling or cardiac regeneration through growth factors or cell therapy.     

Indications for heart transplantation in current era of left ventricular assist devices

Although both heart transplantation and left ventricular assist device therapy have enjoyed clinical success in the treatment of patients with end-stage heart disease, newer left ventricular assist devices currently undergoing testing are likely to have a tremendous impact on the management of these patients. Smaller, more durable devices with improved safety profiles will allow for longer duration of therapy and make biventricular support more feasible, obviating the need for the total artificial heart. In this article we review the historical aspects of both forms of therapy and highlight the current use of left ventricular assist device therapy on patients awaiting heart transplantation.     

Tolvaptan for Volume Management in Heart Failure

Volume management in acute decompensated and chronic heart failure (HF) remains a significant challenge. Although progress has been made in the development of mortality-reducing neurohormonal regimens in the reduced ejection fraction population, no clinical trial has yet demonstrated anything more than symptomatic relief or biomarker reduction with pharmacotherapeutic volume-based interventions made in the acutely decompensated individual or those with evolving outpatient congestion. As the number of patients with HF continues to grow, in addition to HF-related hospitalizations, identifying therapies that have the potential to aid in diuresis more safely and efficaciously is paramount to decreasing inpatient length of stay and preventing unnecessary admissions. More recently, a significant amount of research has been dedicated to the use of vasopressin antagonists, specifically tolvaptan, as adjunctive therapy to loop and thiazide diuretics. Although these agents do not seem to have a pervasive role in fluid management in the acute decompensated and chronic HF populations, they are effective tools to have available for specific clinical situations. This review summarizes the literature surrounding the use of tolvaptan for volume management in congestive HF, as well as offering practical guidance for use of this agent.     

辛伐他汀联合缬沙坦对慢性心力衰竭患者血清TNF-α、IL-1、BNP水平和心功能的影响

目的观察辛伐他汀联合缬沙坦对慢性充血性心力衰竭患者血清TNF-α、IL-1、BNP水平和心功能的影响。方法68例慢性充血性心力衰竭患者随机分为治疗组和对照组。对照组给予缬沙坦及常规治疗,治疗组在此基础上加用辛伐他汀,疗程均为1年。比较两组治疗前后血清TNF-α、IL-1、BNP水平的变化和心功能疗效及心脏彩超指标。结果治疗组1年后血清TNF-α、IL-1、BNP水平较对照组显著下降（P〈0．05）;心功能改善总有效率显著优于对照组（P〈0．05）;左心室射血分数（LVEF）、左室收缩末内径（LVSD）、左室舒张末内径（LVDD）和左室内径缩短率（FS）均较对照组有明显改善（P〈0．01）。结论辛伐他汀联合缬沙坦治疗慢性充血性心力衰竭能显著降低患者血清TNF-α、IL－1、BNP水平,明显改善心功能,疗效优于单加缬沙坦。