The European Journal of Heart Failure 5 (2003) J.G.F. Cleland *, A. Takala, M. Apajasalo, N. Zethraeus, G. Kobelt

The European Journal of Heart Failure 5 (2003) 101 108 Intravenous levosimendan treatment is cost-effective compared with dobutamine in severe low-output heart failure: an analysis based on the international LIDO trial a, b b c d J.G.F. Cleland *, A. Takala, M. Apajasalo, N. Zethraeus, G. Kobelt Abstract a Department of Cardiology, Castle Hill Hospital, Castle Road, Cottingham, University of Hull, Kingston upon Hull HU16 5JQ, UK b Orion Pharma Research Centre, Espoo, Finland c Centre for Health Economics, Stockholm School of Economics, Stockholm, Sweden d Health Dynamics International, London, UK Received 24 June 2001; received in revised form 24 September 2002; accepted 22 October 2002 Background: Levosimendan, a novel calcium sensitiser, improves cardiac performance and symptoms without increasing oxygen consumption, and decreases the mortality of patients with low-output heart failure. Aims: To estimate the cost-effectiveness of intravenous treatment with levosimendan compared with dobutamine in patients with severe low-output heart failure. Methods: This economic evaluation was based on a European clinical trial (LIDO), in which 203 patients with severe heart failure randomly received a 24 h infusion with either levosimendan or dobutamine. Survival and resource utilisation data were collected for 6 months; survival was extrapolated assuming a mean additional lifetime of 3 years based on data from the Cooperative North Scandinavian Enalapril Survival Study trial. Costs were based on study drug usage and hospitalisation in the 6-month follow-up. A sensitivity analysis on dosage of drug and duration of survival was performed. Results: The mean survival over 6 months was 157"52 days in the levosimendan group and 139"64 days in the dobutamine group (P-0.01). When extrapolated up to 3 years, the gain in life expectancy was estimated at 0.35 years (discounted at 3%). Levosimendan increased the mean cost per patient by 71108, which was entirely due to the cost of the study drug. The incremental cost per life-year saved (LYS) was 73205 at the European level; in the individual countries the cost per LYS ranged between 73091 and 73331. The result was robust in the sensitivity analysis. Conclusions: Although the patients in the levosimendan group were alive for more days and thus at risk of hospitalisation for longer, there was no increase in hospitalisation or hospitalisation costs with levosimendan treatment. The cost per LYS using levosimendan compares favourably with other cost-effectiveness analyses in cardiology. 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved. Keywords: 1. Introduction LIDO trial; Heart failure; Cost-effectiveness; Levosimendan; Dobutamine Heart failure is a common and growing problem causing a burden to the individual and to society w1,2x. Approximately 40% of patients with severe heart failure die within 1 year of an acute exacerbation of the disease w3,4x. In addition to poor prognosis, heart failure is associated with a high rate of hospital admissions and early readmissions w5,6x. The aims of treating heart failure are to improve symptoms and reduce mortality, and to do so without increasing the need for hospitalis- *Corresponding author. Tel.: q44-1482-624084; fax: q44-1482- 624085. E-mail address: j.g.cleland@hull.ac.uk (J.G.F. Cleland). ation one of the major factors contributing to the high cost of managing patients with heart failure. Levosimendan, developed specifically for the treatment of decompensated heart failure, is a new intravenous calcium sensitiser with a novel mechanism of action w7 11x. Levosimendan improves cardiac performance and symptoms without significantly increasing oxygen consumption w12 15x. Most importantly, randomised controlled trials have shown that levosimendan is effective in reducing the mortality of patients with low-output heart failure w16,17x. This is in contrast to a wide range of inotropicagents, which have shown increased mortality despite favourable haemodynamic properties w18x. Thus, levosimendan seems to be the 1388-9842/03/$30.00 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved. PII: S1388-9842Ž02.00246-5

102 J.G.F. Cleland et al. / The European Journal of Heart Failure 5 (2003) 101 108 first inotropicagent that it is both effective and safe w19x. The aim of this analysis, which was based on the randomised and double-blind LIDO trial w16x, was to estimate the cost-effectiveness of treatment with levosimendan compared with dobutamine in patients with severe low-output heart failure. 2. Methods 2.1. LIDO trial The detailed design and principal results of the LIDO trial have been reported w16x. In brief, hospitalised patients with severe low-output heart failure were randomised to receive a 24-h infusion with either levosimendan (an initial loading dose of 24 mgykg infused over 10 min, followed by a continuous infusion of 0.1 mgykgymin for 24 h) or dobutamine (at an initial dose 5 mgykgymin without a loading dose). Infusion rates of either drug were doubled if responses remained inadequate after 2 h. The primary endpoint was the proportion of patients with haemodynamicimprovement at 24 h. The timing of other cardiovascular medications, such as digitalis, diuretics and angiotensin converting enzymeinhibitors, was standardised, and the dose of these concomitant medications held constant, unless necessary modifications were needed on clinical or haemodynamic grounds. One of the prospectively defined secondary endpoints of the LIDO trial was days alive and out of hospital without receiving intravenous medications during the first month after initial treatment. It also included an analysis of all-cause mortality at 31 days. All-cause mortality as well as hospitalisations were also retrospectively followed up for 180 days w16x. 2.2. Extrapolated survival for the health economic analysis Survival after the 180-day follow-up period was extrapolated assuming a mean additional survival time of 3 years. This assumption was based on data on similar patient group with severe heart failure from the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial w20x. 2.2.1. CONSENSUS and LIDO trial populations The general characteristics, age, and gender of patients in the LIDO trial were similar to that of patients in the CONSENSUS trial w16,21x. At 30 days the mortality rates were 9% and 12%, respectively, for all CONSENSUS and LIDO patients similarities that extended to the 180-day findings in which 71% and 68% of study patients survived, respectively. Based on these findings, the CONSENSUS data were used to extrapolate the life expectancy beyond 6 months for the LIDO patients. 2.2.2. CONSENSUS vs. LIDO survival rates In the CONSENSUS trial the survival of the patients was analysed at the end of the 10-year follow-up period when 5 out of 253 patients (2.0%) were still alive w20x. Assuming that these long-term survivors died immediately at the end of the 10-year follow-up, the mean survival time for the patients who were alive after the double-blind study period of 6 months, was 941 days (2.6 years) and 774 days (2.1 years) in the enalapril and placebo groups, respectively. As approximately 87% of LIDO patients received an ACE inhibitor, the survival rate from the enalapril-treated group of the CONSEN- SUS trial was applied to the LIDO trial patients. The survival after the clinical study was modelled assuming that a constant proportion of the population surviving 180 days would then die each year. In the base case the mean expected additional lifetime was 3 years, giving a range of survival 0 6 years for individual patients. Sensitivity analysis for the mean survival was also performed for 2 and 4 years of expected additional lifetime. 2.3. Health economic analysis This health economic analysis is based on those patients who actually received either levosimendan or dobutamine. Therefore, 4 patients were excluded from this analysis leading to 102 and 97 patients treated with levosimendan and dobutamine, respectively (Table 1). The primary effectiveness measure in the health economic analysis was the gain in life expectancy (lifeyears saved, LYS) with two data components: the first based on the 180-day survival from the LIDO trial and the second using the extrapolated data. LYS was calculated on the difference between the Kaplan Meyer curves for the levosimendan and dobutamine treatment groups at 180 days using actual study data (Fig. 1) and the extrapolated mean survival of 3 years based on the CONSENSUS trial data (Fig. 2). Because future benefits and costs are typically valued less than the ones in the present, both outcomes and costs are discounted in economical analysis. In this costeffectiveness analysis life expectancy was discounted at an annual rate of 3%. The incremental cost per LYS was calculated as follows: Costs(drugqhospitalisation) Levosimendany Costs(drugqhospitalisation) Dobutamine LYS ylys Levosimendan Dobutamine All calculations were conducted in Euros (7). Levosimendan is available in 5-ml vials (12.5 mg active

J.G.F. Cleland et al. / The European Journal of Heart Failure 5 (2003) 101 108 103 substance); for the purpose of this analysis, the values for mg of levosimendan were based on the use of 5-ml vials. As the cost for levosimendan was not yet fixed, an assumed cost of USD 600 for a 5 ml vial (USD 48.0ymg) was assigned giving an equivalent cost of 7668 per vial (753.4ymg) (exchange rate of December 15, 2000). Dobutamine is available in 20 ml ampoules containing 250 mg of active substance; the local list price for a 20 ml ampoule in the largest pack size in local currency was obtained from the countries included in the analysis, i.e. Denmark, Finland, France, Germany, The Netherlands, Norway, Sweden and the UK. The European mean cost of dobutamine was 714.7 (range 712.3 20.0; 70.059ymg). Calculations on the mean cost of hospital stay on a general ward, coronary care unit (CCU), and intensive care unit (ICU) were based on country-specific unit costs. Because the hospitalisation data did not differentiate CCU and ICU days, only CCU unit costs were used. In the main analysis, total cost per patient in every country was calculated as: Cost of study drug (mg)q number of CCU days=ccu day unit costqnumber of ward days=ward day unit cost. The European wide cost estimate was calculated as a mean of the country-specific figures after being transformed to Euros. Study drug calculations were based on the drug consumptions as reported in the clinical study; patients received a mean of 19.2 mg (range 1.1 40.8 mg) of levosimendan or a mean of 700 mg (range 14 1841 mg) of dobutamine during the 24-h infusion. Although in-patient drugs are generally included in the cost of a hospital day, because of the large difference in price between the two drugs, the cost of levosimendan was added separately into this analysis. A sensitivity analysis was performed by calculating the drug usage in full vials, i.e. 2.0"0.7 vials of levosimendan and 3.2"1.4 Table 1 Demographics and clinical characteristics Fig. 1. Kaplan Meier estimates (time-to-first event analysis) of risk of death during first 180 days after randomisation. Characteristics at baseline Dobutamine Levosimendan Patients randomised 100 103 Patients in economic evaluation (i.e. received either study drug) 97 102 Age (years) (mean"s.d.) 61"11 57"11 Gender male: n (%) 82 (85) 90 (88) Aetiology of heart failure Ischaemicyother: n (%) 49 (51)y48 (49) 46 (45)y56 (55) 2 Cardiacindex (lyminym )(mean"s.d.) 1.9"0.4 1.9"0.4 Pulmonary capillary wedge pressure (mmhg) (mean"s.d.) 24"7 25"8 Ejection fraction (%) (mean"s.d.) 21"7 20"7 At the end of infusion (%) (%) Patients on ACE-inhibitors 87 86 Patients on anticoagulants 45 45 Patients on beta-blockers 37 37 Patients on digitalis 77 75 Patients on diuretics 91 95 Patients on organicnitrates 47 27 ACE, angiotensin converting enzyme. vials of dobutamine. In this analysis it was assumed that partly used vials were wasted. All patients were hospitalised at the study onset; over the 180 days after randomisation, both levosimendanand dobutamine-treated patients experienced a mean of 2.3 admissions. The ward to which the patient was admitted was recorded over the first 31 days; the average stay in the CCU per admission was approximately 2 days. For the 180-day follow-up period, only the number of admissions and the length of hospital stay were recorded. Therefore, for hospital stays of less than 2 days, the whole duration of the stay was assigned to the CCU. For stays exceeding 2 days, an assumption was made that 2 days were spent in a CCU with the remainder of the stay spent on a general ward. The use of concomitant medications was not recorded after the initial drug infusion and, therefore, this was not considered in this analysis. However, there were no discernible differences between the groups in the concomitant medications at baseline w16x or at the end of

104 J.G.F. Cleland et al. / The European Journal of Heart Failure 5 (2003) 101 108 infusion (Table 1). As outpatient consultations were protocol driven, they were not considered in this analysis. 3. Results The patient characteristics of both the levosimendanand dobutamine-treated patients are summarised in Table 1. All patients were hospitalised with NYHA III IV class heart failure and both groups were considered similar with no differences in age, disease history and for use of concomitant medications. The vital status of all the patients was reliably obtained for the 6-month retrospective follow-up. For date of death, 58 out of 63 (92%) were confirmed using official written records, 5 deaths (8%) were confirmed by a GP or other physician or by relatives over the telephone. The hospitalisation status of 99% of patients was reliably obtained, for 96% of the cases from the official patient records. 3.1. Gain in life expectancy The mean survival over 6 months was 157"52 days in the levosimendan group and 139"64 days in the dobutamine group (P-0.01). At 6 months, 74% (75y 102) of levosimendan patients and 63% (61y97) of the dobutamine patients were alive, representing a 0.027- year gain in life expectancy per patient in favour of levosimendan (Figs. 1 and 2). The risk of death was reduced by 41% in relative terms (hazard ratio 0.594, 95% CI (0.356, 0.991)) with levosimendan treatment and the absolute difference in mortality was 11% at 6 Table 2 Mean values for LYS with levosimendan vs. dobutamine assuming additional mean survival of 3 years Dobutamine Levosimendan Difference LYS (undiscounted) 2.27 2.64 0.37 * LYS (discounted 3%) 2.13 2.48 0.35 ** * Equivalent to 135 days. ** Equivalent to 128 days. months in favour of levosimendan. With the extrapolation assuming 3 expected additional life-years, levosimendan saved 0.37 life-yearsypatient more than dobutamine (Table 2). Discounting by 3% reduced this difference minimally from 0.37 to 0.35 yearsypatient. 3.2. Cost-effectiveness analysis Despite the increased survival in the levosimendan group, there was no difference in the number of hospital admissions or in the number of hospital days per patient between the groups (Table 3). Thus, the mean incremental cost of 71108 per patient in the levosimendan group at the European level was entirely due to the drug costs (Table 4). In the selected countries, levosimendan increased the mean cost per patient between 71069 and 71152 (Table 5). Based on the assumptions and a theoretical price for levosimendan of 753.4ymg, the mean incremental cost per LYS over 3-year survival was 73205 at European level (Table 6), ranging from 73091 to 73331 in different countries (Table 7). In a sensitivity analysis using drug costs in vials, and mean survival of 2 and 4 Fig. 2. Life expectancy during and beyond the clinical trial. The graphs represent the percentage of patients who survived. LY, life-years.

J.G.F. Cleland et al. / The European Journal of Heart Failure 5 (2003) 101 108 105 Table 3 Hospitalisations over 180 days Dobutamine Levosimendan All hospitalisations Total number of patients readmitted: n (%) 62 (64) 63 (62) Admissions per patient (mean"s.d. (range)) 2.3"1.3 (1 6) 2.3"1.7 (1 9) Inpatient days per patient (mean (range)) 29 (1 168) 29 (1 181) Hospitalisations due to worsening heart failure Total number of patients readmitted: n (%) 48 (49) 51 (50) Admissions per patient (mean"s.d. (range)) 1.9"1.2 (0 5) 1.9"1.4 (0 8) Inpatient days per patient (mean (range)) 26 (1 168) 27 (1 181) Table 4 Study drug use and European wide hospitalisation costs per patient Cost Dobutamine Levosimendan (7) (7) Drug cost Base case in mg (mean"s.d.) 41.2"20.7 1024"404 Number of ampoulesyvials (mean"s.d.) 47.6"20.9 1349"448 Hospitalisation cost Base case, 2 CCU daysyadmission (mean"s.d.) 12 728"12 643 12 853"12 259 Total costs Base case (mean"s.d.) 12 769"12 639 13 877"12 327 Incremental cost Base case (mean) 1108 CCU, coronary care unit. Table 5 Costs, Euro (7) and local currencies, for levosimendan and dobutamine treatments together with their cost differences Country DO cost (7) LS cost (7) Difference, LSyDO DO cost LS cost mean"s.d. mean"s.d. (7); local currency mean mean Denmark 9860"9739 10 940"9519 1081; DKK 8057 DKK 73 511 DKK 81 568 Finland 10 751"11 236 11 833"10 896 1082; FIM 6432 FIM 63 925 FIM 70 356 France 8734"8692 9803"8495 1069; FRF 7011 FRF 57 293 FRF 64 304 Germany 10 301"9138 11 412"9108 1111; DEM 2173 DEM 20 148 DEM 22 320 Netherlands 16 027"15 777 17 174"15 382 1147; NLG 2529 NLG 35 318 NLG 37 846 Norway 15 263"15 083 16 381"14 700 1119; NOK 9105 NOK 124 238 NOK 133 343 Sweden 13 186"13 135 14 293"12 797 1107; SEK 9501 SEK 113 161 SEK 122 663 UK 18 029"18 353 19 181"17 804 1152; GBP 701 GBP 10 976 GBP 11 677 DO, dobutamine; LS, levosimendan. Table 6 Cost-effectiveness analysis at the European level Incremental cost per LYS (7) Conditional survival 3 years (base case) 2 years 4 years Base case (drug in mg) 3205 4421 2535 Sensitivity (drug in vials) 4127 5693 3264 years, the incremental costylys ranged from 73170 to 75855 in different countries (Table 8). 4. Discussion The LIDO study suggests that in patients with severe, low-output heart failure the use of levosimendan instead of dobutamine is associated with a reduction in mortality without an increase in the need for hospitalisation. Accordingly, health economic analysis suggests that levosimendan is cost-effective in terms of LYS in this patient group. Although the absolute difference in drug costs was relatively high (71024 vs. 741 for one treatment of

106 J.G.F. Cleland et al. / The European Journal of Heart Failure 5 (2003) 101 108 Table 7 Country-specific cost-effectiveness analysis including sensitivity analysis Incremental cost per LYS 3 years 3 years (7) 2 years (7) 4 years (7) (local currency) Denmark DKK 23 301 3125 4311 2471 Finland FIM 18 600 3128 4315 2474 France FRF 20 276 3091 4264 2444 Germany DEM 6283 3212 4431 2540 Netherlands NLG 7313 3318 4577 2624 Norway NOK 26 331 3235 4462 2558 Sweden SEK 27 477 3202 4416 2532 UK GBP 2028 3331 4594 2634 Table 8 Country-specific cost-effectiveness analysis, drug in vials Incremental cost per LYS levosimendan vs. dobutamine), the cost per LYS (3% discounted) with levosimendan was only 73205 at the European level (73091 73331 in different countries). These findings compare favourably with other cardiovascular therapies (Table 9), which although more expensive than the alternative therapy, are still considered to be cost-effective w22 27x. A widely held view is that an incremental cost-effectiveness ratio (with an adjustment for quality-adjusted life-years) is very attractive if less than USD 20 000 w28x. It is possible that we have underestimated the true costs of levosimendan. Improved survival and late deterioration beyond the 6-month follow-up may have led to higher costs. Analysis of costs in added years of life is recommended in economic evaluations carried out from a societal perspective w29x. Therefore, a separate analysis of costs in added years of life was performed for Sweden, including estimates of future healthcare and nonhealth-related consumption and production in the study population. In this analysis, the cost per LYS increased to 720 000 with levosimendan treatment, still indicating that levosimendan treatment is cost-effective. In the clinical setting, further exacerbations of heart failure may well be managed by further administration of levosimendan. Although this might increase costs it may also extend the benefits of treatment with levosimendan on survival. On the other hand, we may have overestimated the costs of inotropic therapy. The needs of the study protocol may have increased costs above those observed in normal clinical practice. However, we used a conservative estimate of hospital costs, as CCU costs were used for all ICU days. It is also possible that we underestimated the true costs of dobutamine. Adverse drug events may demand additional monitoring which itself contributes to increased costs. Patients treated with dobutamine experienced more angina pectoris, chest pain or myocardial ischaemia (Ps0.01), as well as rate and rhythm disorders (Ps0.02) than patients treated with levosimendan w16x. In conclusion, although the patients in the levosimendan group were alive for more days and thus at risk of hospitalisation for longer, there was no increase in resource utilisation. The cost per LYS using levosimendan compares favourably with other cost-effectiveness analyses in cardiology. Acknowledgments We thank the LIDO trial investigators and are indebted to Professor J.K. Kjekshus, Oslo, Norway, for making the CONSENSUS data available. This study was funded by Orion Pharma. 3 years 3 years (7) 2 years (7) 4 years (7) (local currency) Denmark DKK 30 160 4045 5580 3199 Finland FIM 23 963 4030 5559 3187 France FRF 26 293 4008 5529 3170 Germany DEM 8079 4131 5698 3266 Netherlands NLG 9316 4228 5831 3343 Norway NOK 34 183 4199 5792 3321 Sweden SEK 35 473 4133 5701 3269 UK GBP 2584 4245 5855 3357

Table 9 Incremental cost-effectiveness estimates for various medical interventions Intervention Incremental cost per LYS Source t-pa treatment compared with streptokinase in the GUSTO trial $32 678 (736 381) w22x Revascularisation for coronary multivessel disease $50 000 (755 667) w23x ACE inhibitors or b-blockers for chronic heart failure compared with conventional therapy Ranges from cost-saving to $12 799 per LYS(714 250) w23 26x Heart transplantation for patients aged 50 years with terminal heart disease $100 000 (7111 333) w27x Median cost-effectiveness of life-saving interventions in the US $42 000 (746 760) w27x ACE, angiotensin converting enzyme; t-pa, tissue plasminogen activator. J.G.F. Cleland et al. / The European Journal of Heart Failure 5 (2003) 101 108 107 Downloaded from http://eurjhf.oxfordjournals.org/ at Pennsylvania State University on March 4, 2014

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