All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- updated June 6, 2002 INTRO Levosimendan is an IV drug being tested in patients with acute decompensated heart failure - in other words, CHFers having a real nasty 'episode.' Levosimendan makes your heart more sensitive to calcium. It is called a calcium sensitizer. Calcium is heavily involved in making your heart beat and helping to control its pumping power. The drug increases the heart's pumping strength without increasing oxygen demand, and it relaxes blood vessels (vasodilation). A plus for this drug is that it does not affect free calcium levels. Current inotropic drugs increase pumping power by increasing levels of free calcium. However, this increases the heart's energy demand, which increases risk of irregular heart beats. Levosimendan avoids these problems and still increases pumping strength. In trials, levosimendan reduced risk of worsening CHF or death compared to dobutamine and placebo in CHFers. The drug is well tolerated, does not cause irregular heart beats, does not interact strongly with other drugs, and may improve survival. TECHNICALLY SPEAKING The drug increases the sensitivity of the cardiac myofilament to calcium, rather than increasing the level of free calcium. By binding to cardiac troponin C, levosimendan stabilizes troponin C and the action of actin-myosin cross-bridges without increasing the heart's consumption of ATP (adenosine triphosphate). RESULTS FROM SOME TRIALS Giving levosimendan at 8 or 24 micrograms/kg by IV in 23 patients having elective heart surgery increased cardiac output and heart rate without increasing the heart's oxygen demand. Levosimendan dilates (expands) arteries. Continuous 24-hour IV levosimendan lowered lung pressures and blood pressure in patients with moderate to severe heart failure. The drug did not increase tachycardias and did not increase already existing tachycardias in 386 CHFers treated. The drug's half life is about one hour. In patients with decompensated CHF, levosimendan significantly reduced worsening CHF or death, and improved heart function. The LIDO trial included 203 patients with severe, decompensated CHF. More levosimendan patients saw cardiac index increase over 30% (28% of patients) pulmonary pressure decrease more than 25% (15% of patients) than in the dobutamine group. More dobutamine (17%) than levosimendan patients (7%) had worsening heart failure or died by 30 day follow-up when the drug was given as a 24 microgram/kg loading dose followed by 0.1 to 0.2 microgram/kg/minute for 24 hours. When 18 patients got either low or high dose levosimendan or placebo 15 minutes before bypass surgery and then for 6 hours after surgery, both doses of the drug increased cardiac output 15 and 60 minutes after surgery compared to placebo. Levosimendan was well tolerated, with most adverse events - mainly headache and low blood pressure - caused by the vasodilation. SUMMARY 1) In the LIDO trial, levosimendan (7%) caused fewer serious adverse events than dobutamine (18%) 2) Levosimendan caused no arrhythmias even in patients taking higher doses than would normally be given. 3) Levosimendan does not interact with ACE inhibitors, calcium channel blockers, beta-blockers, felodipine, digoxin, warfarin, isosorbide mononitrate, or alcohol. DOSE The usual IV levosimendan dose used in clinical trials of CHFers is a 6 to 12 microgram/kg loading dose over 10 minutes, followed by 0.05 to 0.2 microgram/kg/minute as continuous IV infusion. Heart function usually responds within 5 minutes of starting the loading dose. Peak effects are seen in 10 to 30 minutes. The drug continues to act for about one to 2 hours. No dose adjustments are needed for patients with moderate kidney or liver failure. Currently available IV drugs for serious acute heart failure episodes are vasodilators like nitro, inotropes like dobutamine, inodilators like milrinone, and now Natrecor (nesiritide). When given long-term though, oral inotropes have not been successful. Digoxin reduces complications but not risk of death. Milrinone increases risk of death although it definitely raises quality of remaining life. An oral form of levosimendan is being developed. Levosimendan has been approved only in Sweden to date. BENEFITS 1) Increases heart pumping strength without increasing heart oxygen demand, and also relaxes arteries, easing the heart's work load 2) Significantly improves survival and prevents worsening of hear failure in patients with decompensated CHF 3) No evidence of causing irregular heart beats POTENTIAL LIMITATIONS 1) Vasodilation can cause adverse effects such as headache and low blood pressure 2) Must currently be given by IV 3) We don't have a lot of experience with the drug so far since it has not yet been FDA approved Feature Levosimendan Milrinone Dobutamine Drug class Calcium Phosphodies- Catecholamine sensitizer terase inhibitor Increases intracellular calcium levels? No Yes Yes Increases heart's pumping strength? Yes Yes Yes Vasodilator? Coronary Peripheral Mild and systemic peripheral Increase heart's oxygen demand? No No Yes Causes arrhythmia? None seen yet Ventricular Ventricular (12%) and ectopic activity supra- (5%) - less ventricular than milrinone arrhythmias (4%) Available formulations IV IV, oral IV Drug interactions? None Few None significant significant significant Can be given with beta- blockers? Yes Yes Yes Adverse events Headache, Ventricular Tachycardia, low blood irregularities, high BP pressure headache, low blood pressure Title : Levosimendan: A New Dual-Acting, Non- Arrhythmogenic Drug in Decompensated Congestive Heart Failure Source : Drug and Ther Perspect 17(20)1-5, 2001 =================================================== INTRO Levosimendan is a calcium sensitizer. The drug also increases heart relaxation and relaxes arteries by opening potassium channels. To study its effects, we did PET scans in patients with decompensated chronic heart failure. THE TRIAL 8 hospitalized class 3 to class 4 CHFers got either levosimendan or placebo by IV in a randomized double- blind cross-over study. During PET scan, acetate was used to measure the heart's oxygen use (demand) and also to measure blood flow. Heart performance and size were measured by pulmonary artery cath and echo. Compared to healthy volunteers, heart oxygen use went up with placebo in the right ventricle but was the same in the left ventricle. With IV levosimendan, heart output increased 32%. Heart and lung pressures (resistance) went down. Average blood flow increased from 0.76 to 1.02 milliliters/minute/gram. Levosimendan did not increase or decrease the heart's demand for oxygen. It had no effect on left ventricular efficiency, but it improved right ventricular efficiency by 24%. CONCLUSIONS Levosimendan is a good drug to treat acute CHF in the short-term. It improves heart output without making the heart work harder, and it improves right ventricle efficiency. Title: Myocardial efficiency during levosimendan infusion in congestive heart failure. Authors: Ukkonen H, Saraste M, Akkila J, Knuuti J, Karanko M, Iida H, Lehikoinen P, Nagren K, Lehtonen L, Voipio-Pulkki LM. Source: Clin Pharmacol Ther 2000 Nov;68(5):522-31 PMID: 11103755 =================================================== INTRO We wanted to define a safe and effective dose range for levosimendan in ischemic class 2 to class 4 CHFers. This was a double-blind, placebo-controlled, randomized, parallel-group study. THE TRIAL Our study included 151 adult patients. Levosimendan was given as a 10 minute IV dose of 3, 6, 12, 24 or 36 micrograms/kilogram, followed by a 24 hour IV of 0.05, 0.1, 0.2, 0.4 or 0.6 micrograms/kilogram/minute. Dobutamine was used for comparison, given by IV at 6 micrograms/kilogram/minute. The main goal for dose effectiveness was the number of patients to reach at least one of the following : 1) more than 14% increase in stroke volume (SV) at 23 to 24 hours 2) more than 24% decrease in lung pressure (PCWP) or 4 mmHg at 23 to 24 hours 3) more than 39% increase in cardiac output without more than a 20% change in heart rate 4) more than 49% decrease in PCWP during 2 consecutive measurements. Response to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose. Placebo = 14% and dobutamine = 70%. The higher the dose, the greater the drug's effect on cardiac output, stroke volume and PCWP. Headache (9%), nausea (5%) and low blood pressure (5%) were the most common side effects at higher doses. CONCLUSIONS Levosimendan at a 10 minute dose of 6 to 24 micrograms/kilogram followed by IV at 0.05 to 0.2 micrograms/kilogram/minute is well tolerated and gives good results in acute heart failure episodes. Title: Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. Authors: Nieminen MS, Akkila J, Hasenfuss G, Kleber FX, Lehtonen LA, Mitrovic V, Nyquist O, Remme WJ. Source: J Am Coll Cardiol 2000 Nov 15;36(6):1903-12 PMID: 11092663 =================================================== INTRO We studied short-term effects of levosimendan in patients with decompensated heart failure. This was a double-blind, placebo-controlled study. THE TRIAL 146 class 3 to class 4 CHFers with an average EF of 21% who had PCWP over 15 mmHg and cardiac index less than 2.5 L/min/m2 were enrolled. Patients got either IV levosimendan or placebo. Drug infusion dose was raised over 4 hours from 0.1 micrograms/kg/minute to 0.4 micrograms/kg/minute and then maintained at the maximum dose tolerated for another 2 hours. Levosimendan increased heart function beginning with the lowest dose. Final increases were 28% in stroke volume and 39% in cardiac index. Heart rate went up slightly at 8% at the maximum dose but stayed level at lower doses. Levosimendan lowered pulmonary pressures, right atrial pressure, and blood pressure. The drug improved shortness of breath and fatigue, and caused no significant side effects. CONCLUSIONS Levosimendan rapidly improved heart function in these decompensated heart failure patients. Symptoms improved. This drug may be valuable for short-term management of these patients. Title: Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure Authors: Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, Haeusslein E, Hare J, Hutchins S, Leier CV, LeJemtel TH, Loh E, Nicklas J, Ogilby D, Singh BN, Smith W Source: Circulation 2000 Oct 31;102(18):2222-7 PMID: 11056096 =================================================== INTRO Calcium sensitizers increase the heart's pumping strength. Levosimendan may also help diastolic dysfunction. THE STUDY We studied the effects of levosimendan on diastolic and systolic function in heart muscle preparations made from failing human hearts. Levosimendan improved systolic function. Diastolic function also improved quite a bit with levosimendan. CONCLUSIONS Levosimendan improves both systolic and diastolic function in failing human hearts. Effects are more pronounced at higher heart rates and when diastolic dysfunction is present. Title: Levosimendan improves diastolic and systolic function in failing human myocardium Authors: Janssen PM, Datz N, Zeitz O, Hasenfuss G Source: Eur J Pharmacol 2000 Sep 15;404(1-2):191-9 PMID: 10980279