Levosimendan for the treatment of acute heart failure syndromes

Levosimendan is a novel calcium-sensitising agent that has been shown to have beneficial inotropic, metabolic and vasodilatory effects in the treatment of acute and advanced chronic heart failure. Levosimendan binds to troponin-C in cardiomyocytes and, thereby, improves cardiac contractility without disturbing the metabolic status of the heart and increasing myocardial oxygen demand or provoking fatal cardiac arrhythmias. Levosimendan also opens ATP-sensitive potassium channels, causing peripheral arterial and venous dilatation, and increasing coronary flow reserve. When it is given as a short-term therapy, levosimendan enhances cardiac output, reduces systemic vascular resistance and lowers pulmonary capillary wedge pressure. Clinical outcomes were significantly reduced in decompensated or postmyocardial infarction heart failure patients who received levosimendan, compared with those on dobutamine or placebo. Recent investigations focusing on the anti-inflammatory and antiapoptotic actions of levosimendan in the failing heart indicate that improvement of cardiac contractile performance is closely related with the drug-induced reduction of circulating pro-inflammatory cytokines and apoptosis inducers. The most common adverse effects of levosimendan treatment are hypotension and headache. Overall, levosimendan represents an effective and safe option for the treatment of decompensated heart failure patients.     

左西孟旦、米力农和硝普钠治疗急性心力衰竭的对比研究

目的 探讨硝普钠、米力农以及左西孟旦治疗急性心力衰竭患者的临床效果.方法 对本院2014年1月至2015年12月收治的150例急性心力衰竭患者的临床资料进行回顾性分析,将患者分为A组、B组、C组,各50例.A组硝普钠治疗,B组米力农治疗,C组左西孟旦治疗.对比三组病死率、二次住院率、治疗效果、心血管并发症发生率以及治疗前后N端脑钠肽前体含量变化情况.结果 C组临床治疗效果、心血管并发症发生率、二次住院率、死亡率、N端脑钠肽前体含量明显优于A组、B组患者,组间差异具有统计学意义(P＜0.05).结论 左西孟旦应治疗急性心力衰竭患者效果显著,值得在临床治疗中推广应用.     

Levosimendan: a new inodilatory drug for the treatment of decompensated heart failure

Levosimendan is a new calcium sensitizer developed for the treatment of congestive heart failure. Experimental studies indicate that levosimendan increases myocardial contractility and dilates both the peripheral and coronary vessels. Its positive inotropic effect is based on calcium-dependent binding of the drug to cardiac troponin C. It also acts as an opener of ATP-dependent potassium channels in vascular smooth muscle, thus inducing vasodilation. Although levosimendan acts preferentially as a calcium sensitizer it has also demonstrated selective phosphodiesterase III inhibitory effects in vitro. However, this selective inhibition does not seem to contribute to the positive action at pharmacologically relevant concentrations. Levosimendan has an active metabolite, OR-1896. Similarly to levosimendan, the metabolite exerts its positive inotropic and vasodilatory effects on myocardium and vasculature. The elimination half-life of levosimendan is about 1 hour. Thus, with intravenous administration, the parent drug rapidly disappears from the circulation after the infusion is stopped. The active metabolite, however, has a half-life of approximately 80 hours, and can be detected in circulation up to 2 weeks after stopping a 24-hour infusion of levosimendan. The intravenous formulation of levosimendan has been studied in several randomized comparative studies in patients with decompensated heart failure. Both patients with ischemic and non-ischemic etiology have participated in the studies. Levosimendan produces significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in PCWP, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance. With a loading dose, the effects on PCWP and cardiac ouput are seen within few minutes. There is no sign of development of tolerance even with a prolonged infusion up to 48 hours. Cardiac performance is improved with no significant increases in oxygen consumption or potentially malignant rhythm disorders. Due to the formation of an active metabolite, the hemodynamic effects are maintained up to several days after stopping levosimendan infusion. Compared to dobutamine, levosimendan produces similar increase in cardiac output but profoundly greater decrease in pulmonary capillary wedge pressure. On the contrary to dobutamine, the hemodynamic effects are not attenuated with concomitant beta-blocker use. Levosimendan has been shown to have favourable effects on symptoms of heart failure superior to placebo and at least comparable to dobutamine. Mortality and morbidity in levosimendan treated patients has been shown to be significantly lower when compared to dobutamine or placebo treated patients. The most common adverse events associated with levosimendan treatment are headache and hypotension, as a likely consequence of the vasodilating properties of the compound. In conclusion, levosimendan offers a new effective option for the treatment of acutely decompensated heart failure. Unlike traditional inotropes, levosimendan seems also to be safe in terms of morbidity and mortality.     

Levosimendan, a new calcium-sensitizing inotrope for heart failure

Calcium sensitizers are a new class of inotropes that share the in vitro properties of calcium sensitization and phosphodiesterase inhibition. Levosimendan is a distinct calcium sensitizer, as it stabilizes the interaction between calcium and troponin C by binding to troponin C in a calcium-dependent manner, improving inotropy without adversely affecting lusitropy. It does not exhibit clinically relevant phosphodiesterase inhibition at therapeutic concentrations. It also exerts vasodilatory effects, possibly through activation of several potassium channels and other less well characterized mechanisms. The pharmacokinetics of levosimendan are similar in healthy subjects and patients with heart failure and remain relatively unaltered by age, sex, and organ dysfunction. In preclinical and clinical studies, levosimendan exerted potent dose-dependent positive inotropic and vasodilatory activity. Unlike conventional inotropes, levosimendan is not associated with significant increases in myocardial oxygen consumption, proarrhythmia, or neurohormonal activation. The most common adverse effects are attributable to the vasodilation. Two large, double-blind, randomized trials demonstrated favorable hemodynamic effects, improved tolerability, and a possible mortality benefit over dobutamine and placebo in patients who had acute symptoms of failure and required inotropic therapy. The long-term effect on patient outcomes is being confirmed in ongoing placebo- and inotrope-controlled trials. Levosimendan appears to be an effective inodilator devoid of the detrimental effects of conventional inotropes. In the future, levosimendan may provide a promising alternative to conventional inotropes for patients with acutely decompensated heart failure.     

Levosimendan: a review of its use in the management of acute decompensated heart failure

Levosimendan (Simdax) is a calcium-sensitising drug that stabilises the troponin molecule in cardiac muscle, thus prolonging its effects on contractile proteins, with concomitant vasodilating properties. Intravenous levosimendan (12-24 microg/kg loading dose followed by 0.1-0.2 microg/kg/min for 24 hours, adjusted for response and tolerability) is approved for the short-term treatment of acute severe decompensated heart failure. Cardiac output increased by about 30% and pulmonary capillary wedge pressure and systemic vascular resistance decreased by about 17-29% in patients with decompensated heart failure receiving intravenous levosimendan. In large, well controlled trials in patients with decompensated heart failure, intravenous levosimendan was significantly more effective than placebo or dobutamine for overall haemodynamic response rate (primary endpoint). Significant benefits were also seen for mortality (versus placebo or dobutamine) and for the combined risk of worsening heart failure or death (versus dobutamine). Improvements in key symptoms (dyspnoea and fatigue) have not been consistently demonstrated. Hospitalisation costs were similar for levosimendan and dobutamine; the total incremental (hospitalisation plus drug) cost per life-year saved (extrapolated to 3 years) for levosimendan relative to dobutamine was estimated at Euro 3205 (year of costing 2000). Levosimendan is generally well tolerated, with an adverse event profile at recommended dosages similar to that in patients receiving placebo. Cardiac rate/rhythm disorders and headache were the most common events. At higher dosages, patients receiving levosimendan had higher rates of sinus tachycardia than those in placebo recipients. More patients receiving dobutamine than those receiving levosimendan experienced angina pectoris/chest pain/myocardial ischaemia or rate/rhythm disorders. CONCLUSION: Intravenous levosimendan is an effective calcium-sensitising drug with vasodilatory and inotropic effects, and superior efficacy/tolerability to those of intravenous dobutamine in patients with acute decompensated heart failure. It may be associated with reduced mortality compared with both placebo and dobutamine. Levosimendan is generally well tolerated and may have less potential for cardiac rate/rhythm disorders than dobutamine. While evidence from well designed trials confirming the improved mortality over dobutamine and investigating haemodynamic efficacy and mortality versus other positive inotropes is required, intravenous levosimendan appears to be a useful addition to the treatment options for acute decompensated heart failure in patients with low cardiac output.     

Levosimendan: a novel agent in heart failure

Heart failure is characterised by decreased cardiac output, which results in the development of both peripheral hypoperfusion and pulmonary congestion and can lead to the development of acute pulmonary edema. The primary objective in treating a patient with decompensated heart failure is hemodynamic stabilization, which is usually achieved by inotropic support. Classic inotropic agents provide short-term hemodynamic improvement, but their use has been correlated with poor prognosis. Levosimendan, a new calcium sensitizer, offers hemodynamic and symptomatic improvement without increasing cAMP and intracellular calcium concentrations. This agent improves contractility without increasing the risk of cardiac events such as arrhythmias. By combining a positive inotropic action mediated via calcium sensitization and a vasodilatory effect via ATP-dependent potassium channels, it appears to be superior than classic positive inotropic agents. Furthermore, it seems to have prolonged benefit in heart failure patients, and it also has anti-inflammatory and antiapoptotic properties. In conclusion, levosimendan seems to be a particularly promising agent for the treatment of decompensated heart failure, as in addition to improving cardiac output, it has a more favorable side-effect profile than classic inotropic agents, and it affects multiple pathways with key role in the pathophysiology of heart failure.     

Serelaxin a novel treatment for acute heart failure

Acute heart failure (AHF) represents a major healthcare burden with a high risk of in-hospital and post-discharge mortality, which remained almost unchanged in the last few decades, underscoring the need of new treatments. Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone and has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. Recently, the new molecule serelaxin, a recombinant form of the naturally occurring hormone relaxin has been studied in patients hospitalized for AHF. In addition to vasodilation, serelaxin has anti-oxidative, anti-inflammatory and connective tissue regulating properties. In preclinical studies, it reduced both systemic and renal vascular resistance and, in the clinical trials Pre-RELAX-AHF and RELAX-AHF, it improved dyspnea and signs of congestion. In addition, serelaxin was associated with a reduction of 180-day mortality. The aim of this review is to summarize the pharmacological properties of serelaxin and the results of the preclinical and clinical studies.     

左西孟旦注射液治疗老年重度心力衰竭的疗效及安全性分析

目的 评价对常规治疗（如利尿剂、血管紧张素转换酶抑制剂和洋地黄类药物等）疗效不佳的老年重度失代偿性心力衰竭患者,静脉注射左西孟旦（Levosimendan Injection）的有效性及安全性。方法：40例常规纠正心衰治疗无好转的老年重度心力衰竭患者随机分为试验组（20例,给予左西孟旦治疗）和对照组（20例,给予米力农治疗）。观察两组治疗前后临床症状、BNP和血流动力学改变情况。结果：两组比较,经过治疗,左西孟旦组患者BNP下降、呼吸困难好转方面较米力农组更显著（P﹤0.01）,而米力农组患者血压降低则更显著（P﹤0.01）。二者之间在改善心衰症状方面的差异具有显著性（P﹤0.01）。结论：左西孟旦在治疗老年重度心力衰竭患者疗效和安全性均优于米力农。     

急性心力衰竭急诊救治的临床观察

目的：观察急性心力衰竭患者急诊抢救的综合治疗措施及其疗效、安全性。方法对78例急性心力衰竭患者给予端坐位、双腿下垂、吸氧、镇静、快速利尿、血管扩张、强心等综合性抢救措施,同时对抢救效果、生命体征变化等进行观察与数据分析。结果78例患者经抢救治疗后其中72例症状好转,呼吸困难减轻,两肺啰音减少或消失,抢救成功率达92.31%。结论对于急性心力衰竭的抢救应及时并且要给予综合性治疗措施方能提高疗效、降低死亡率。     

急性心力衰竭内科治疗的循证医学

在急性心力衰竭的内科治疗措施中,无创呼吸支持和超滤等新技术的效果获得了循证医学的支持,无创呼吸支持可有效缓解急性心源性肺水肿患者的症状,降低气管插管和呼吸机的使用率,降低住院死亡率。超滤可有效缓解钠水潴留的相关症状,效果优于利尿药,不良事件两组相似。人重组脑钠肽和左西孟旦等新药的疗效和安全性也有了初步的循证医学证据。而传统药物如袢利尿药、吗啡、硝酸甘油等基本用药对急性心力衰竭预后的影响还缺乏循证医学的评价。需要开展相应的循证医学研究来进一步明确其对急性心力衰竭患者近期和远期预后的影响。     

Medications for the treatment of acute coronary syndromes

Patients presenting with acute coronary syndromes without ST elevation on their electrocardiogram continue to contribute an important healthcare burden. Medical treatments to control symptoms include nitrates and beta-blockers. Morphine is a very effective analgesic although its use may be associated with adverse outcomes. Oral antiplatelet therapies including aspirin and clopidogrel form a cornerstone of prognostically modifying therapy. Similarly, the intravenous IIb/IIIa antagonists have emerged as having an important role in patients undergoing coronary intervention. Low molecular weight heparins are more convenient to use than unfractionated heparin and may be more effective. Care should be taken to avoid mixing the two antithrombins as this contributes to increased bleeding risk. Statins can impact on short-term outcomes when given during the acute admission; and this benefit is augmented if high doses are used.     

Medications for the treatment of acute coronary syndromes

Patients presenting with acute coronary syndromes without ST elevation on their electrocardiogram continue to contribute an important healthcare burden. Medical treatments to control symptoms include nitrates and β-blockers. Morphine is a very effective analgesic although its use may be associated with adverse outcomes. Oral antiplatelet therapies including aspirin and clopidogrel form a cornerstone of prognostically modifying therapy. Similarly, the intravenous IIb/IIIa antagonists have emerged as having an important role in patients undergoing coronary intervention. Low molecular weight heparins are more convenient to use than unfractionated heparin and may be more effective. Care should be taken to avoid mixing the two antithrombins as this contributes to increased bleeding risk. Statins can impact on short-term outcomes when given during the acute admission; and this benefit is augmented if high doses are used.     

Rivaroxaban for the treatment of acute coronary syndromes

Both lung cancer and mesothelioma are malignancies with increasing incidence, and both are primarily due to inhalation of an external carcinogen. The occurence of both diseases is expected to rise worldwide, although a stabilisation and/or decrease may be anticipated in some developed countries. There are other common similarities to both cancers, including the median age of their patients, the advanced stage at presentation, the outcome and the treatments given. This review focuses on the available evidence of a novel antifolate agent, pemetrexed, in the treatment of both of these thoracic malignancies. Current status, persisting controversies and future developments are discussed.     

急性左心衰13例应用无创通气支持的疗效观察

目的分析13例急性左心衰患者应用无创通气支持的疗效。方法观察13例病人在药物治疗的基础上应用BiPAP正压通气1小时后心率、血压、血氧饱和度、平均动脉压、呼吸频率、血气分析的变化，经统计学处理后比较通气前后各指标的差异。结果12例急性左心衰患者应用无创通气后1小时，心率、血压、血氧饱和度、平均动脉压、血氧分压、呼吸频率均有非常明显的改善，而血pH值和PaCO2则无明显变化。结论急性左心衰早期积极的无创正压通气支持能改善左心功能，改善通气血流比值，提高氧分压和血氧饱和度，保证重要脏垂的氧供，大大提高抢救的成功率。     

Istaroxime, a novel luso-inotropic agent for the treatment of acute heart failure

Sigma-Tau Ind Farm Riunite SpA and Debiopharm SA are developing istaroxime, the lead in a series of Na(+)/K(+)-ATPase inhibitors, for the potential treatment of cardiac failure. By September 2005, phase I/II trials of istaroxime were ongoing.     

Serelaxin: a potential new drug for the treatment of acute heart failure

The wide media coverage given recently to a study correlating higher selenium levels with a reduced risk of advanced prostate cancer is but the latest addition to a growing body of epidemiological findings which link dietary selenium deficiency to diseases as diverse as cancer, heart disease, arthritis and AIDS. Indeed, selenium has a long history of association with human health and disease. Moreover, direct evidence is now emerging for specific beneficial effects of dietary selenium supplementation. Thus, the pharmacology, biology and biochemistry of selenium metabolism have become subjects of intense current interest. At the molecular level, selenium (as selenocysteine) is an essential component of the active sites of the enzymes glutathione peroxidase, iodothyronine 5′-deiodinase and mammalian thioredoxin reductase, and is also present in several other mammalian selenoproteins. Both glutathione peroxidase and thioredoxin reductase catalyse reactions essential to the protection of cellular components against oxidative and free radical damage. As a consequence of the growing recognition of the important biological role of selenium, a number of novel pharmaceutical agents, either selenium-based or which target specific aspects of selenium metabolism, are under development. Among these are orally active selenium-based antihypertensive agents, anticancer, antiviral, immunosuppressive and antimicrobial agents, and organoselenium compounds which reduce oxidative tissue damage and oedema. It can be anticipated that as our understanding of the basic biology and biochemistry of selenium increases, future efforts will uncover even more sophisticated approaches for the rational development of new selenium-based pharmaceutical agents.     

Valsartan for the treatment of heart failure

Heart failure (HF) still has a discouraging prognosis. Therapeutic strategies aim to reduce mortality as well as slow the progression of the disease, improve symptoms and reduce the frequency of hospital admission. Activation of the renin-angiotensin-aldosterone system (RAAS) is a hallmark of several cardiocirculatory diseases, including HF. Drugs for evidence-based therapy of HF are angiotensin-coverting enzyme inhibitors (ACEIs), β-blockers and aldosterone antagonists. A promising alternative is a more complete action on the RAAS through selective blockade of the angiotensin type 1 (AT₁) receptors, taking into account not only physiopathological issues but also pharmacological, experimental and clinical data. The effect of valsartan, an orally-active, selective antagonist of AT₁ receptors, on the outcome in patients with chronic and symptomatic HF was evaluated in a large-scale, international, placebo-controlled clinical study, the Valsartan in Heart Failure Trial (Val-HeFT). In this study, overall mortality was similar in the valsartan and placebo groups (19.7 and 19.4%, respectively). However, valsartan, in addition to recommended therapy of HF including an ACEI, significantly reduced the combined end point of mortality and morbidity, with a significant reduction in the risk of hospitalisation, paralleled by improvements in New York Heart Association (NYHA) functional class, signs and symptoms and quality of life. Valsartan also improved left ventricular anatomy and function and significantly reduced neurohormonal activation. These results were confirmed and extended by the CHARM trial, where the benefits of candesartan were proved not only in all 7599 patients with HF, but also in the 2548 given an ACEI, the 2028 not given an ACEI and in the 3023 patients with an ejection fraction of > 40%. In conclusion, the first choice for HF remains an ACEI with a β-blocker, but two new options are emerging. In patients intolerant to ACEI, the combination of valsartan or candesartan with a β-blocker is proposed, whereas an ACEI with either valsartan or candesartan can be considered in patients intolerant to or with contraindications to β-blockers.     

Valsartan for the treatment of heart failure

Heart failure (HF) still has a discouraging prognosis. Therapeutic strategies aim to reduce mortality as well as slow the progression of the disease, improve symptoms and reduce the frequency of hospital admission. Activation of the renin-angiotensin-aldosterone system (RAAS) is a hallmark of several cardiocirculatory diseases, including HF. Drugs for evidence-based therapy of HF are angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers and aldosterone antagonists. A promising alternative is a more complete action on the RAAS through selective blockade of the angiotensin type 1 (AT(1)) receptors, taking into account not only physiopathological issues but also pharmacological, experimental and clinical data. The effect of valsartan, an orally-active, selective antagonist of AT(1) receptors, on the outcome in patients with chronic and symptomatic HF was evaluated in a large-scale, international, placebo-controlled clinical study, the Valsartan in Heart Failure Trial (Val-HeFT). In this study, overall mortality was similar in the valsartan and placebo groups (19.7 and 19.4%, respectively). However, valsartan, in addition to recommended therapy of HF including an ACEI, significantly reduced the combined end point of mortality and morbidity, with a significant reduction in the risk of hospitalisation, paralleled by improvements in New York Heart Association (NYHA) functional class, signs and symptoms and quality of life. Valsartan also improved left ventricular anatomy and function and significantly reduced neurohormonal activation. These results were confirmed and extended by the CHARM trial, where the benefits of candesartan were proved not only in all 7599 patients with HF, but also in the 2548 given an ACEI, the 2028 not given an ACEI and in the 3023 patients with an ejection fraction of > 40%. In conclusion, the first choice for HF remains an ACEI with a beta-blocker, but two new options are emerging. In patients intolerant to ACEI, the combination of valsartan or candesartan with a beta-blocker is proposed, whereas an ACEI with either valsartan or candesartan can be considered in patients intolerant to or with contraindications to beta-blockers.     

Torasemide for the treatment of heart failure

Diuretics play an essential role in modern cardiovascular therapy, and are currently recommended for the treatment of congestive heart failure. Torasemide has been developed as a newer type of loop diuretic with a longer half-life, longer duration of action, and higher bioavailability compared to the most commonly used loop diuretic, furosemide. Torasemide also appears to have additional actions beyond the pure diuretic effect, such as anti-aldosterone effect and vasorelaxation effect. Studies have also investigated whether the superior pharmacokinetics and pharmacological activity of torasemide result in a favorable clinical outcome. Their results have indicated that, in comparison with furosemide, torasemide improves left ventricular function, reduces mortality as well as the frequency and duration of heart failure-related hospitalization, and improves quality of life, exercise tolerance and NYHA functional class in patients with congestive heart failure. Thus, torasemide appears to be a promising loop diuretic that contributes to a better management of patients with heart failure. Definitive clinical trials in a double-blind fashion are warranted.     

Nebivolol for the treatment of heart failure

INTRODUCTION: Heart failure (HF) is a common and disabling disease with a high prevalence in the elderly. Beta-blockers are among the mainstay therapies of HF because they antagonize the deleterious effects of the chronic activation of sympathetic nervous system. In large randomized clinical trials, bisoprolol, carvedilol and metoprolol reduced mortality and cardiovascular hospital admission and, hence, are included in current guidelines for HF treatment. AREAS COVERED: Nebivolol is a third-generation β-blocker with high selectivity for β1-adrenoceptors selectivity and vasodilating effects. It also shows antioxidant, antiproliferative and antithrombotic properties. Nebivolol is generally well tolerated. Typical β-blocker-related adverse events are same as that with placebo, except for bradycardia. In addition, it shows no negative effects on chronic obstructive pulmonary disease, erectile function, and glucose and lipid metabolism. The benefits of nebivolol for HF treatment have been evaluated in the SENIORS trial, where it reduced the composite endpoint of mortality and cardiovascular hospital admission. EXPERT OPINION: Nebivolol is a β-blocker with distinctive characteristics. Initiated at 1.25 mg and titrated up to 10 mg/day, it has shown safety and efficacy in one large outcome trial, when added to standard medical therapy, in elderly patients (≥ 70 years) affected by HF.