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Published on 20 September 2010

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Role of calcium sensitisers in the management of decompensated heart failure

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New compounds have an important role in the management of difficult to treat heart failure patients particularly when vasodilation and inotropism are needed at the same time

Fábio Vilas-Boas
MD PhD
Chief Cardiology Division
Director, Heart Failure and Transplantation Programme
Hospital Espanhol
Salvador

Christiano Pereira Silva
MD PhD
PhD in Cardiology
Heart Institute
University of São Paulo
São Paulo
Brazil

Heart failure (HF) represents the end of the spectrum of several heart diseases. It is one of the most devastating cardiovascular conditions and is prevalent in up to 16% of patients over 75 years old.
Decompensated heart failure (DHF) occurs when the heart can’t pump enough oxygen to supply the body’s demands. It generally results in a low cardiac output state, with or without lung and systemic accumulation of fluid (congestion). Three distinct clinical patterns can be identified:[1] acute HF, without previous diagnosis (first episode of decompensation); decompensated chronic HF (represents an acute exacerbation of a previously diagnosed HF); and refractory chronic HF (end-stage heart disease). Patients often present with dyspnoea at rest or at minimal exertion, and congestion is almost universally present.
Treatment for hospitalised patients varies according to the clinical presentation. Intravenous diuretics, vasodilators and inotropes are the mainstays of therapy. Generally, diuretics are used when congestion is present, vasodilators are employed to decrease blood pressure and help relieve congestion, and inotropes are indicated when a low cardiac output state is suspected to be part of the problem. Despite these well established treatments, there are many safety and efficacy limitations in the current approach. In the past few years, however, very few advances were perceived in this area.[2]
Most inotropic agents increase intracellular calcium levels. For this reason, they are commonly associated with significant side effects, such as increased myocardial oxygen consumption, arrhythmias and increased long-term mortality. The availability of new inotropic agents demands a reconsideration of its role in the management of DHF.
Inotropic agents should be reserved for patients with evidence of low cardiac output, with or without congestion, and with low or borderline blood pressures. Alternatively, they are an attractive option as rescue therapy for patients who failed initial treatment with intravenous vasodilators. Dobutamine and milrinone are available in most countries. Levosimendan, a calcium sensitiser, is available in Latin America and many countries in Europe and Asia. The role of calcium sensitisers in DHF is still controversial even after many clinical trials have been published indicating safety and efficacy.

Levosimendan overview
Levosimendan, a calcium sensitiser, improves myocardial contractility by stabilising troponin C and enhancing calcium sensitivity of cardiac myofilaments. Even with a cardiac inotropic effect it has no effect on myocardial oxygen demand and does not induce critical arrhythmias. Several studies have demonstrated that levosimendan improves haemodynamic performance more effectively than dobutamine in patients with severe HF, and it is neutral regarding long-term survival. Recent evidence indicates that patients on chronic beta-blocker treatment gain a special benefit when treated with levosimendan. Although levosimendan has a short half-life, the improvement in cardiac output after a single 24-hour intravenous infusion, has been shown to last for more than five days.
Pivotal, large, randomised, double-blind trials have investigated the efficacy of intravenous levosimendan.[3] Intravenous levosimendan at these dosages was more haemodynamically effective than placebo or intravenous dobutamine. A significant improvement in dyspnoea symptoms (a secondary endpoint) was seen in levosimendan recipients in one of the two placebo-controlled trials. In the LIDO trial,[4] patients with severe low-output HF were treated with levosimendan or dobutamine. A significantly higher proportion of levosimendan patients experienced haemodynamic improvement compared to dobutamine. For the first time, a subgroup analysis demonstrated that the use of beta-blockers enhanced the haemodynamic effects of levosimendan but reduced the haemodynamic effects of dobutamine. Levosimendan treatment was associated with a significant improvement in overall survival at 31 days. The number of days alive and out of the hospital at 31 days was also reduced, almost entirely related to the lower mortality rate rather than a reduction in re-admissions. Also at 180 days, the retrospective analysis revealed a significant improvement in survival for patients treated with levosimendan compared with dobutamine.
Two other studies assessed the effects of levosimendan versus dobutamine or placebo on worsening HF or death (as secondary endpoints). Mortality with levosimendan was significantly lower than with dobutamine. Morbidity and mortality results were not dose-related.
The REVIVE trial, conducted in the USA, compared levosimendan with placebo in patients considered refractory to the initial treatment with intravenous diuretics.[5] The primary endpoint of symptomatic improvement over the course of hospitalisation was achieved in 33% more levosimendan patients than with placebo. In a similar way, 29% fewer patients worsened over the same time period. B-type natriuretic peptide levels decreased significantly more with levosimendan and the length of hospital stay was almost two days shorter. In contrast, hypotension episodes were more frequent with levosimendan, and also there was an excess of ventricular and atrial arrhythmias. A trend towards higher number of deaths was observed, which didn’t reach statistical significance. These data should be considered in the light of the initial bolus and high uniform maintenance doses employed in this particular study, which doesn’t resemble what is done in clinical practice. Also, levosimendan was used together with other vasodilators and phosphodiesterase inhibitors after intense diuresis, which may have led to unrecognised hypovolaemia and massive vasodilatation.
Those previous benefits over mortality (as secondary endpoints) led to the largest trial with levosimendan, termed The SURVival of Patients with Acute HF in Need of IntraVEnous Inotropic Support (SURVIVE).[6] This was the first prospective, double-blind, randomised trial utilising mortality as the primary endpoint in evaluating the efficacy of levosimendan as compared with dobutamine. This trial comprised 1,327 hospitalised patients with severe acute DHF and clinical need for intravenous inotropic support after intravenous diuretics and/or vasodilators had failed. The primary endpoint of this study was mortality during 180 days after the start of treatment. This was debated in many opportunities, due to the long period between the infusion and the target (180 days). It is very improbable that any intravenous drug, administered as a single dose during the decompensated phase of chronic HF, could influence such a relevant endpoint over such a long time period. At 180 days, no differences in mortality have been observed between patients treated with levosimendan and dobutamine (26 vs 28%, respectively, hazard ratio [HR] 0.91 [0.74–1.13]; p ¼ 0.401). However, a trend in favour of levosimendan in the initial phase of treatment (4 vs 6%, HR 0.72 [0.44–1.16] at five days and 12 vs 14%, HR 0.85 [0.63–1.15] at 31 days), especially among patients with previous episodes of HF (HR 0.58 [0.33–1.01] at five days) was present. No significant differences in the incidence of hypotension, cardiac failure, AF, ventricular tachycardia or renal adverse events were found after levosimendan treatment compared with dobutamine.
In all, the most common adverse events were cardiac rate/rhythm disorders (10%) and headache (up to 14%). The proportion of patients experiencing clinically significant hypotension and/or ischaemia (the primary endpoint in one pivotal trial) was similar in levosimendan (pooled dosage groups) and placebo (13% and 11%) recipients. At higher dosage levels, sinus tachycardia occurred more often with levosimendan (5% vs 2%; p<0.05 vs placebo).
Again, one has to consider the low dose of dobutamine employed in this trial (5mcg/kg/min) and the high standardised maintenance dose of levosimendan (0.2mcg/kg/min), which is different from the use of levosimendan in countries already using this drug. In both trials, haemodynamic monitoring was not carried out despite the inclusion of critically ill patients, which doesn’t reflect clinical practice in the real world.
Taken together, the accumulated evidence on levosimendan suggests that its maintenance doses should be reduced to 0.1mcg/kg/min and that it should be avoided in hypotensive patients. In our experience there is no benefit with the loading dose, and sometimes this can even be deleterious for the patient. If needed, it should also be reduced to 6–12 mcg/kg infused over 10 minutes, and restricted to those patients with systolic pressure higher than 110mmHg and in whom an immediate response is needed. Special care has to be taken with the potassium level, since the urine output generally increases, causing hypokalaemia.

Importance and usage
The best indication of levosimendan is for patients with DHF who are under previous beta-blocker treatment. For patients with chronic HF, all international guidelines recommend beta-blockers as first-line chronic therapy, as that can improve survival, lower risk for morbidity and reduce rates of hospitalisation. However, when a patient receiving a beta-blocker is hospitalised for DHF, the response to treatment with an inotrope such as dobutamine, can be blunted or unpredictable. Recently,[7] a sub-analysis of the SURVIVE trial was published, demonstrating that all-cause mortality was lower in the levosimendan group than in the dobutamine group, with treatment differences by HR at days 5 (3.4 vs 5.8%; HR, 0.58, confidence interval [CI] 0.33–1.01, p = 0.05) and 14 (7.0 vs 10.3%; HR, 0.67, CI 0.45–0.99, p = 0.045). For patients on beta-blockers (n = 669), mortality was significantly lower for levosimendan than dobutamine at day 5 (1.5 vs 5.1% deaths; HR, 0.29; CI 0.11–0.78, p = 0.01).
The number of patients undergoing beta-blockers treatment has risen worldwide. One of the biggest challenges to the emergency physician is how to proceed when a severe decompensated patient taking beta-blockers is admitted. In our experience, we try to keep the same beta-blockers dose, starting levosimendan without loading dosage. The volume status must be checked and optimised before starting the infusion, and all laboratorial parameters must be followed every 6 hours, especially the potassium level. If deemed necessary, we reduce the beta-blockers dose by 50%.
Perioperative usage of levosimendan has grown quickly. Patients with severe HF who will be admitted for elective cardiac surgery have been treated with pre-operative infusion 24 to 48 hours earlier, and better recovery has been demonstrated. Lilleberg et al[8] first demonstrated that levosimendan improves systemic and coronary haemodynamics without increasing myocardial oxygen consumption or changing myocardial substrate utilisation in 23 low-risk patients after coronary artery bypass grafting (CABG). Plochl and Rajek[9] described a significant increase in cardiac output and stroke volume with decreases in systemic vascular resistance in 10 critically ill post-operative patients. Also Labriola et al[10] evaluated the effects of levosimendan in 11 patients with severely impaired cardiac output and haemodynamic compromise low-output syndrome following cardiac surgery. Of the 11 post-operative patients enrolled, eight showed evidence of combined haemodynamic improvement within 3 hours after the start of levosimendan infusion. In another randomised study, 31 patients were treated with a low or a high dose of levosimendan or placebo administered over 10 minutes and started 20 minutes before off-pump CABG. All patients also received an initial volume load of 500ml before levosimendan. After the infusions, cardiac output and LVEF were significantly higher and systemic vascular resistances were lower in patients receiving levosimendan at both dosages. These peri-operative studies indicate that levosimendan is a potentially useful drug in preventing and/or improving haemodynamics and post-operative ischaemic cardiac depression. However, further and broader studies must be developed to establish this clinical indication.
Patients taking dobutamine over a long period could also benefit from levosimendan infusion. Our experience has demonstrated that the process of dobutamine weaning is more effective when levosimendan is administered concomitantly. Our protocol does not include a loading dose in this situation. Levosimendan infusion is commenced with dobutamine, and then the dose of the latter drug should be decreased carefully, according to clinical and haemodynamic parameters. Usually dobutamine is totally out of infusion during the 24-hour levosimendan administration. If successful, this represents a substantial cost-effective approach.[11]
Hospital costs of levosimendan are similar to dobutamine, despite higher costs of the medication, indicating that the acquisition costs alone should not influence which agent should be used.[12,13]

Conclusion
Levosimendan represents a real advance in the treatment of DHF patients. We are convinced that existing evidence provides enough support for using this drug in selected patients. Mortality data should be interpreted as a safety and not as an efficacy endpoint. The best indications for levosimendan in DHF patients are the following: in patients previously treated with beta-blockers; in patients with concomitant right and left ventricular dysfunction; and as concomitant infusion during the weaning process of dobutamine infusion.

References
1. Vilas-Boas F and Follath F. Arq Bras Cardiol 2006;87:369–77.
2. Vilas-Boas F. Expert Rev Cardiovasc Ther 2009;7(2):159–67.
3. De Luca L et al. Eur Heart Journal 2006;27:1908–20.
4. Follath F et al. Lancet 2002;360:196–202.
5. Packer M. Program and abstracts from the American Heart Association Scientific Sessions 2005; November 13–16, 2005; Dallas, Texas. Late Breaking Clinical Trials II.
6. Mebazaa A et al. JAMA 2007;297:1883–91.
7. Mebazaa A et al. Eur J Heart Fail 2009;11:304–11.
8. Lilleberg J et al. Eur Heart Journal 1998;19:660–68.
9. Plochl W and Rajek A. Anaesth Intensive Care 2004;32:471–75.
10. Labriola C et al. Int J Clin Pharmacol Ther 2004;42:204–11.
11. Bocchi E et al. Arq Bras Cardiol 2008;90(3):182–190.
12. Cleland J et al. Eur J Heart Fail 2003;5;101–08.
13. Oliveira M Jr et al. Arq Bras Cardiol 2005;85(1):9–14.



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