Journal of Cardiac Failure Vol. 13 No. 7 2007 A 6-Month Follow-up of Intermittent Levosimendan Administration Effect on Systolic Function, Specific Activity Questionnaire, and Arrhythmia in Advanced Heart Failure SOPHIE MAVROGENI, MD, FESC, GREGORY GIAMOUZIS, MD, EVANGELIA PAPADOPOULOU, MD, SOPHIA THOMOPOULOU, MD, ATHANASIOS DRITSAS, MD, GEORGE ATHANASOPOULOS, MD, ELIAS ADREANIDES, MD, IOANNIS VASSILIADIS, MD, KONSTANTINOS SPARGIAS, MD, DIMOSTHENIS PANAGIOTAKOS, MD, AND DENNIS V. COKKINOS, PROF. Athens, Greece ABSTRACT Background: Levosimendan (LS) improves cardiac contractility without increasing myocardial oxygen demand. We administrated LS on a monthly intermittent 24-hour protocol and evaluated the clinical effect after 6 months in a randomized, open, prospective study. Methods and Results: Fifty patients (age 45e65 years) with LV systolic dysfunction and New York Heart Association (NYHA) III or IV were randomized in 2 groups. LS group (n 5 25) was compared with a control group (n 5 25) matched for sex, age, and NYHA class. LS was given monthly on a 24-hour intravenous protocol for 6 months. Patients were evaluated by specific activity questionnaire (SAQ) and echocardiography (ECHO) before and 3 to 5 days after last drug administration, whereas 24-hour Holter recording was performed before and during last drug administration. Patients in LS and control group had same baseline SAQ, ECHO, and Holter parameters. At the end of the study, a larger proportion of patients in the levosimendan group reported improvement in symptoms (dyspnea and fatigue) (65% versus 20% in controls, P ! .01). After 6 months, the LS group had a significant increase in LV ejection fraction versus controls (28 6 7 versus 21 6 4 %, P 5 .003), LV shortening fraction (15 6 3 versus 11 6 3 %, P 5 .006) and a decrease in mitral regurgitation (1.5 6 0.8 versus 2.7 6 0.6, P 5 .0001). There was no increase in supraventricular or ventricular beats or supraventricular tachycardia and VT episodes in LS group, compared with controls. Two patients from the LS group died in the 6-month follow-up period, compared with 8 patients in the control group (8% versus 32%, P ! .05). Conclusions: A 6-month intermittent LS treatment in patients with decompensated advanced heart failure improved symptoms and LV systolic function. (J Cardiac Fail 2007;13:556e559) Key Words: Heart failure, levosimendan. Levosimendan (LS), a novel calcium sensitizer, improves cardiac contractility (inotropic effect) without increasing myocardial oxygen demand (vasodilatory properties).1,2 This is due possibly to stabilization of troponin-C in a configuration that enhances the calcium sensitivity of cardiac myofilaments3,4 and activation of adenosine triphosphatesensitive Kþ channels in the heart and systemic arteries5 In severe low-output heart failure, levosimendan improves cardiac function and has been reported to decrease mortality in some6 but not all studies. Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy Versus Placebo in the Short-Term Treatment of Decompensated Heart Failure (REVIVE-1) revealed that LS induced a significantly higher rate of clinical improvement compared with placebo. REVIVE-2 showed improvement of clinical signs and symptoms of acute decompensated heart failure with neutral effects on mortality at 90 days. Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) revealed no significantly different effects compared with dobutamine on mortality.1 The results of these studies provide now some more firm conclusions regarding the potential beneficial effects of levosimendan on clinical status of patients with acute decompensated heart failure. Additionally, LS administration offers renal protection, improves hemodynamics, From the Onassis Cardiac Surgery Center, Athens, Greece. Manuscript received April 29, 2006; revised manuscript received March 24, 2007; revised manuscript accepted April 17, 2007. Reprint requests: Sophie Mavrogeni, MD, FESC, 50 Esperou Street, 175-61 P. Faliro, Athens, Greece. Data were presented in abstract form in the 2005 ESC Heart Failure meeting. 1071-9164/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2007.04.004 556 Follow-up of Levosimendan in Heart Failure myocardial wall stress and peripheral organ perfusion,7 and is beneficial even in patients whose syndrome is refractory to traditional inotropes.8 Our aim was to apply the administration of levosimendan in end-stage heart failure patients and repeat the drug administration on a monthly base for 6 months. Evaluation of patients was performed at baseline (immediately before the drug administration) and 3 to 5 days after the last drug administration using echocardiography and specific activity questionnaire (SAQ). A 24-hour Holter recording was performed at baseline and during the last drug administration.  Mavrogeni et al 557 Table 1. Baseline Clinical Characteristics of Patients Treated With Levosimendan (LS) and Controls Male/female Age (y) Cardiomyopathy type (%): ischemic/dilated/valvular Medication (%): Angiotensin-converting enzyme inhibitor or AT1 b-blockers Diuretics Digitalis Aldosterone antagonist Amiodarone Nitrates LS Controls 20/5 62 6 20 52/32/16 20/5 61 6 19 50/33/17 96 97 92 100 32 52 25 30 94 100 35 49 28 26 Patients and Methods The study population consisted of 50 patients with systolic LV dysfunction and New York Heart Association Class III or IV symptoms of heart failure. Patients were currently on treatment with angiotensin-converting enzyme inhibitors, b-blockers, aldosterone antagonist, amiodarone, and diuretics. They had documented LV ejection fraction of !30% and a cardiac index !2.5 L/min/m2. Exclusion criteria were acute or chronic infectious or inflammatory diseases, recent myocardial infarction (!8 weeks) or active ischemia, hepatic or renal impairment (creatinine O2.5 mg/d), use of immunosuppressive drugs, serious arrhythmias, and supine systolic blood pressure !85 mm Hg. The investigation conformed to the principles outlined in the Declaration of Helsinki. The study was approved by Onassis Cardiac Surgery Center ethics committee, and written consent was given by each patient. The patients who received LS were informed about the drug effect, while the staff that performed the study and analyzed the data was blinded to drug given and to group characteristics. The design of the study was open, prospective. Of the 50 patients, 25 were randomized to receive additionally to standard treatment intravenous levosimendan; the rest (n 5 25) served as controls and did not receive any additional infusion. Controls underwent monthly visits for routine clinical evaluation. Randomization was based on a sequence of binary numbers. In detail, for each consecutive patient of our clinic we assigned a sequence of random binary numbers (ie, 1,1,1,0,1,0,1,1,0,1.) that assisted to allocate participants into the 2 treatment arms. For example if a patient was assigned to number 1, he/she was treated with levosimendan, if he/she was assigned to number 0, he/she was not treated with levosimendan. No blocking or stratification was performed. The treatment code was not known to the physician of the study. The randomization system was created by a special software (STATA, STATA Corp, College Station, Texas 77845 USA, data command: sample # [if exp] [in range] [, count by (groupvars)])’’. The 2 groups had similar baseline clinical characteristics (Table 1). Levosimendan was given as a 10-minute intravenous bolus of 6 mg/kg followed by continuous infusion, initially at a rate of 0.1 mg/ kg/min. Up-titration was done until a maximum rate of 0.2 mg/kg/ min was achieved or a dose-limiting event occurred, as previously described.9 The same protocol was applied every month for six months in the levosimendan group. Diuretics dose was halved on the day of infusion. Symptoms (evaluated using SAQ) and left ventricular volumes per body surface area (mL/m2), LV ejection fraction (%), mitral regurgitation grade (scale 1e4), and right ventricular systolic pressure (mm Hg) were analyzed at baseline and 3 to 5 days after the last drug administration over a 6-month study period. A 24-hour Holter recording was performed and analyzed at baseline and during the last dose of drug administration for LS group and during hospitalization after 6 months for the control group. A Vivid General Electric Ultrasound System was used to perform the study. Complete 2-dimensional echocardiographic study was performed by the use of a mechanical and phased-array sector-scanner with a 3.5-MHz transducer. Long axis and parasternal short axis views at the mid-ventricular level were used to derive the left-ventricular end-systolic and end-diastolic diameters. The echocardiographic study was read by 1 experienced cardiologist, who was blinded to the treatment group. Ambulatory 24-hour Holter echocardiographic recording were obtained in a standard fashion with a portable tape recorder and modified V1 and V5 leads. Holter echocardiographic recordings were scanned on a DelMar Reynolds AccuPlus (Del Mar Reynolds Medical, Irvine, California). In each case the arrhythmias were verified by an experienced cardiologist, who was blinded to the clinical, echocardiographic, and follow-up data. The SAQ is composed of 13 questions based on everyday activities. Each activity corresponds to metabolic equivalents, 1 metabolic equivalent 5 3.5 mL O2$kg$min, predicted for a given type of activity (Table 2). SAQ was performed in person during hospitalization and subsequently analyzed by personnel blinded to the treatment group. Death and its cause, at any time during the 6-month interval, were recorded. All values are mean 6 SD. Repeated measures analysis of variance was used to evaluate the differences in variables (inclusion versus 6 months) between levosimendan and control group. Comparisons between qualitative variables were performed by chi-square test. A P value ! .05 was considered statistically significant. Results All of the patients in the levosimendan group achieved the maximum rate of 0.2 mg$kg$min. Only 2 patients presented a dose-limiting event (hypotension), but this was temporary and they managed to reach also the maximum infusion rate. All LS patients completed successfully the 6 cycles of drug administration. Patients in the LS and the control groups had same baseline SAQ, echocardiogram, and Holter parameters 558 Journal of Cardiac Failure Vol. 13 No. 7 September 2007 Table 2. The Specific Activity Questionnaire (SAQ) Can you Complete the Following Activities Without Symptoms? MET Values 1. Dress without stopping because of symptoms? 2. Do moderate work around the house like vacuum, sweep floors, or carry groceries? 3. Walk down a flight of stairs unassisted and without stopping? 4. Do heavy work around the house like make the beds, hang out washing, or wash the car? 5. Do moderate gardening like weed or rake the leaves? 6. Push an electric or petrol mower on level ground? 7. Participate in moderate activities like walk at a normal pace (4 km/h) or play golf and carry the clubs? 8. Walk briskly around an oval? 9. Do outdoor work like split wood or dig in the garden? 10. Carry an 8-kg weight (load of wet washing) up 8 steps? 11. Carry at least 10 kg (eg, a suitcase) up 8 steps? 12. Carry objects that weight at least 35 kg 13. Participate in vigorous activities like swimming (crawl), jogging (8 km/h), cycling (17 km/h), singles tennis? 2.00 2.50 3.00 3.25 4.25 4.50 4.75 5.00 5.50 6.00 7.00 7.50 9.00 (Table 3). After 6 months of treatment, the mean SAQ values improved in the LS group, but were not significantly different after repeated measures analysis of variance analysis. However, a larger proportion of patients in the levosimendan group reported improvement in symptoms (dyspnea and fatigue) (65% versus 20% in controls, P ! .01). At the end of the 6 months, the LS group had a significant increase in LV ejection fraction versus controls (28 6 7 versus 21 6 4 %, P 5 .003) and LV shortening fraction (15 6 3 versus 11 6 3 %, P 5 .006), respectively. There was also a decrease in end-systolic volume versus controls (82 6 20 versus 107 6 21 mL/m2, P 5 .044), end-diastolic volume (120 6 20 versus 157 6 25 mL/m2, P 5 .0001), mitral regurgitation (1.5 6 0.8 versus 2.7 6 0.6, P 5 .0001), and a borderline decrease in RV systolic pressure (50 6 13 versus 63 6 14 mm Hg, P 5 .052), respectively. There was no increase in supraventricular or ventricular beats or supraventricular tachycardia and ventricular tachycardia episodes in LS group, compared with controls. Two patients from the LS group died in the 6-month follow-up period, compared with 8 patients in the control group (8% versus 32%, P ! .05). In the control group, there was a worsening at the end of the 6-month study period (versus baseline) of both mitral regurgitation grade (2.7 6 0.6 versus 2.5 6 0.6, P ! .05) and RV systolic pressure (63 6 14 versus 61 6 14, P ! .05). Concerning mortality, 2 patients from the LS group died in the 6-month follow-up period because of acutely decompensated heart failure and cardiac arrest, compared with 8 patients in the control group (8% versus 32%, P ! .05). Discussion This study focused on the follow-up of patients with endstage heart failure after intermittent administration of levosimendan during a 6-month period. We evaluated clinical symptoms, echocardiographic indexes of cardiac contractility, and 24-hour Holter recording. Clinical symptoms, such as dyspnea and fatigue, were improved in a larger proportion of our patients in the levosimendan group compared with controls. Score derived from SAQ is strongly correlated with maximal overall aerobic capacity expressed by peak VO2 measured by exercise spirometry.10 This effect, already described after acute administration,11,12 is also observed after an intermittent 6-month levosimendan administration. A decrease in mean pulmonary artery pressure in the levosimendan group was considered responsible for the improvement of symptoms.13,14 In this study, the mean SAQ values improved in the levosimendan group, but the difference did not reach statistical significance. This may be explained by the small population of the study. An increase in shortening and injection fraction with simultaneous improvement of functional mitral regurgitation Table 3. Comparison of ECHO, Holter, and SAQ Parameters in Patients Treated With Levosimendan and Controls at Inclusion and After 6 Months Treatment Levosimendan Parameter FS (%) LVEF (%) EDV (mL/m2) ESV (mL/m2) MR grade RVSP (mm Hg) Max HR Min HR Mean HR SVB PVB Couplets NSVT SAQ (METS) Inclusion 12 22 138 98 2.4 61 95 61 78 393 1535 89 8 1.7 6 6 6 6 6 6 6 6 6 6 6 6 6 6 3 6 20 25 1.0 16 21 10 13 115 1256 57 5 1.6 Controls 6 Months 15 28 120 82 1.5 50 108 58 79 358 2010 104 12 2.7 6 6 6 6 6 6 6 6 6 6 6 6 6 6 3 7 20 20 0.8 13 16 19 6 63 1188 88 6 1.2 Inclusion 12 22 145 99 2.5 61 93 58 80 402 1610 95 10 2.2 6 6 6 6 6 6 6 6 6 6 6 6 6 6 3 5 30 28 0.6 14 15 8 13 120 1150 40 7 1.1 RANOVA 6 Months 11 21 157 107 2.7 63 98 61 82 415 1710 100 13 1.7 6 6 6 6 6 6 6 6 6 6 6 6 6 6 3 4 25 21 0.6 14 20 8 10 180 1190 45 6 1.6 P Value* .006 .003 .0001 .044 .0001 .052 .134 .917 .348 .319 .689 .899 .190 .423 ECHO, echocardiogram; SAQ, specific activity questionnaire; FS, shortening fraction of left ventricle; LVEF, left ventricular ejection fraction; EDV, enddiastolic volume of left ventricle; ESV, end-systolic volume of left ventricle; MR, mitral regurgitation; RVSP, right ventricular systolic pressure; HR, heart rate; SVB, supraventricular beats; PVB, premature ventricular beats; NSVT, nonsustained ventricular tachycardia (*P value for repeated measures analysis of variance [RANCOVA] [inclusion vs. 6 months] between levosimendan and controls). Follow-up of Levosimendan in Heart Failure was documented in levosimendan-treated patients. This might be the result of drug-induced increase of myocardial contractility.15 There were no dose-limiting events in the levosimendan group, except for 2 patients that presented transient hypotension. This may be explained by the reduction of diuretic dose during levosimendan infusion. In the levosimendan group, no increase in heart rate or arrhythmias on Holter recording was found. This is in agreement with previous studies, showing that levosimendan has no significant effects on heart rate, when data were pooled from the 24-hour electrocardiograms of patients receiving various dose levels.16 The absence of tachycardia may also be attributed to the fact that the patients were already on maximal doses of bblockers. However, these findings are notably different from the REVIVE experience,1 where there was a significant excess of atrial fibrillation, ventricular tachycardia, and death. In view of the conflicting findings, there is need for more information to establish safety. At the moment, there is rarity of studies on the effects of an intermittent long-term protocol of intravenous administration of levosimendan. However, a recent study17 confirmed the beneficial effects of our protocol in LV performance, neurohormonal, and immune indices. It should be noted that the 2 major trials, REVIVE and SURVIVE, failed to provide much evidence of efficacy and both raise concerns of safety. In REVIVE, the primary outcome was substantially driven by the lesser use of diuretics rather than real evidence of clinical improvement. The previously impressive LIDO trial probably reflects excessively high doses of dobutamine, because the mortality data were not reproduced in SURVIVE. Other published studies are not as well blinded or controlled and only included small numbers of outcomes or very short followup. Overall, the clinical (versus hemodynamic) efficacy of this agent remains uncertain and needs to be confirmed in a large randomized, double-blind, placebo-controlled outcome study. In this perspective, our data support the potential use of intermittent infusions in such a trial. Limitations of the Study This is a report of an intermittent protocol of levosimendan administration in decompensated heart failure and the results seem encouraging. Although the small number of patients is not powerful to perform risk assessment, these findings suggest that a double-blind, placebo-controlled study with larger number of patients should be performed. The open design of the current study may have influenced the SAQ response. Although mortality rate was smaller in the LS group, no early conclusions should be drawn. Further studies are needed to establish the exact duration of such a protocol, the possible benefit in different New York Heart Association classes and the long-term survival. 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