All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- NOTE: You can make the print bigger with the font button on your browser! (It's usually a big "A") ----------------------------------------------------------- Jon's note: I updated this article June 6, 2002 and again August 13, 2006. Oral levosimendan (pill form) does not work for heart failure and trials for it have been stopped. The articles below are about IV levosimendan for acute decompensated heart failure. ========================= Levosimendan is an IV drug being tested in patients with acute decompensated heart failure. This drug 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. IV levosimendan increases the heart's pumping power without increasing oxygen demand and it relaxes blood vessels (vasodilation). This drug does not affect free calcium levels in your body. Current inotropic drugs increase pumping power by increasing levels of free calcium. However, this increases the heart's energy demand, which raises risk of irregular heart beats. Levosimendan avoids these problems while still increasing pumping power. 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 IV levosimendan increases 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). TRIAL RESULTS Giving levosimendan at 8 or 24 micrograms/kg by IV in 23 patients having elective heart surgery raised 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 tachycardia and did not increase already existing tachycardia 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 had cardiac index increase over 30% (28% of patients) and 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 side effects - mainly headache and low blood pressure - caused by 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 HF trials is a 6 to 12 microgram/kg loading dose given over 10 minutes, followed by 0.05 to 0.2 microgram/kg/ minute 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. ========================= BENEFITS 1. Increases heart pumping strength with- out increasing the heart's oxygen demand, and also relaxes arteries, which eases the heart's work load. 2. Significantly improves survival and prevents worsening of CHF in decompensated patients. 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 because it has not yet been FDA approved. Title: Levosimendan: A New Dual-Acting, Non- Arrhythmogenic Drug in Decompensated Congestive Heart Failure. Source: Drug and Ther Perspect 17(20)1-5, 2001. ========================= 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 CHF. 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 ml/minute/gram. Levosimendan did not increase or decrease the heart's demand for oxygen. It had no effect on left heart efficiency, but it improved right heart efficiency by 24%. Researchers conclude the levosimendan is a good drug for acute CHF in the short-term. It raises 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. ========================= Researchers wanted to find a safe and effective dose range for IV levosimendan in ischemic class 2 to class 4 CHFers. This was a double-blind, placebo-controlled, randomized, parallel-group study. The trial included 151 adult patients. Levosimendan was given as a 10 minute IV dose of 3, 6, 12, 24 or 36 micrograms/kg, followed by a 24 hour IV of 0.05, 0.1, 0.2, 0.4 or 0.6 micrograms/kg/minute. Dobutamine was used for comparison, given by IV at 6 micrograms/kg/minute. The main goal for dose effectiveness was the number of patients to reach at least one of the following endpoints: 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 (CO) 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 gave a 14% improvement and dobutamine 70%. The higher the dose, the greater the improvement in CO, SV, and PCWP. Headache (9%), nausea (5%) and low blood pressure (5%) were the most common side effects at higher doses. 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. ========================= Researchers studied short-term effects of levosimendan in patients with decompensated heart failure. This was a double-blind, placebo-controlled study. 146 class 3 to class 4 CHFers with an average EF of 21%, PCWP over 15 mmHg, and cardiac index less than 2.5 L/min/m2 were included. Patients got either IV levosimendan or IV 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 (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. 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. ========================= Calcium sensitizers increase the heart's pumping power. Levosimendan may also help diastolic dysfunction. We studied its effects on both diastolic and systolic function in heart muscle preparations made from failing human hearts. Levosimendan improved both systolic and diastolic function. 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.