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European Journal of Heart Failure 2003 5(1):101-108; doi:10.1016/S1388-9842(02)00246-5
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© 2002 European Society of Cardiology

Intravenous levosimendan treatment is cost-effective compared with dobutamine in severe low-output heart failure: an analysis based on the international LIDO trial

J.G.F. Clelanda,*, A. Takalab, M. Apajasalob, N. Zethraeusc and G. Kobeltd

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

* Corresponding author. Tel.: +44-1482-624084; fax: +44-1482-624085 Email address: j.g.cleland{at}hull.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
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 {euro}1108, which was entirely due to the cost of the study drug. The incremental cost per life-year saved (LYS) was {euro}3205 at the European level; in the individual countries the cost per LYS ranged between {euro}3091 and {euro}3331. 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.

Key Words: LIDO trial • Heart failure • Cost-effectiveness • Levosimendan • Dobutamine

Received June 24, 2001; Revised September 24, 2002; Accepted October 22, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure is a common and growing problem causing a burden to the individual and to society [1,2]. Approximately 40% of patients with severe heart failure die within 1 year of an acute exacerbation of the disease [3,4]. In addition to poor prognosis, heart failure is associated with a high rate of hospital admissions and early readmissions [5,6]. The aims of treating heart failure are to improve symptoms and reduce mortality, and to do so without increasing the need for hospitalisation—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 [7–11]. Levosimendan improves cardiac performance and symptoms without significantly increasing oxygen consumption [12–15]. Most importantly, randomised controlled trials have shown that levosimendan is effective in reducing the mortality of patients with low-output heart failure [16,17]. This is in contrast to a wide range of inotropic agents, which have shown increased mortality despite favourable haemodynamic properties [18]. Thus, levosimendan seems to be the first inotropic agent that it is both effective and safe [19].

The aim of this analysis, which was based on the randomised and double-blind LIDO trial [16], was to estimate the cost-effectiveness of treatment with levosimendan compared with dobutamine in patients with severe low-output heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. LIDO trial
The detailed design and principal results of the LIDO trial have been reported [16]. 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 µg/kg infused over 10 min, followed by a continuous infusion of 0.1 µg/kg/min for 24 h) or dobutamine (at an initial dose 5 µg/kg/min 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 haemodynamic improvement at 24 h. The timing of other cardiovascular medications, such as digitalis, diuretics and angiotensin converting enzyme-inhibitors, 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 [16].

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 [20].

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 [16,21]. 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 [20]. 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 CONSENSUS 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).


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  		Table 1 Demographics and clinical characteristics

 
The primary effectiveness measure in the health economic analysis was the gain in life expectancy (life-years 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).


Figure 1
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  		Fig. 1 Kaplan–Meier estimates (time-to-first event analysis) of risk of death during first 180 days after randomisation.

 


Figure 2
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  		Fig. 2 Life expectancy during and beyond the clinical trial. The graphs represent the percentage of patients who survived. LY, life-years.

 
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 cost-effectiveness analysis life expectancy was discounted at an annual rate of 3%.

The incremental cost per LYS was calculated as follows:


Formula

All calculations were conducted in Euros ({euro}). Levosimendan is available in 5-ml vials (12.5 mg active 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 48.0/mg) was assigned giving an equivalent cost of {euro}668 per vial ({euro}53.4/mg) (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 {euro}14.7 (range {euro}12.3–20.0; {euro}0.059/mg).

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)+number of CCU daysxCCU day unit cost+number of ward daysxward 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 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 levosimendan- and 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 [16] or at the end of infusion (Table 1). As outpatient consultations were protocol driven, they were not considered in this analysis.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The patient characteristics of both the levosimendan- and 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% (75/102) of levosimendan patients and 63% (61/97) 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 months in favour of levosimendan. With the extrapolation assuming 3 expected additional life-years, levosimendan saved 0.37 life-years/patient more than dobutamine (Table 2). Discounting by 3% reduced this difference minimally from 0.37 to 0.35 years/patient.


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  		Table 2 Mean values for LYS with levosimendan vs. dobutamine assuming additional mean survival of 3 years

 
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 {euro}1108 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 {euro}1069 and {euro}1152 (Table 5).


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  		Table 3 Hospitalisations over 180 days

 


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  		Table 4 Study drug use and European wide hospitalisation costs per patient

 


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  		Table 5 Costs, Euro ({euro}) and local currencies, for levosimendan and dobutamine treatments together with their cost differences

 
Based on the assumptions and a theoretical price for levosimendan of {euro}53.4/mg, the mean incremental cost per LYS over 3-year survival was {euro}3205 at European level (Table 6), ranging from {euro}3091 to {euro}3331 in different countries (Table 7). In a sensitivity analysis using drug costs in vials, and mean survival of 2 and 4 years, the incremental cost/LYS ranged from {euro}3170 to {euro}5855 in different countries (Table 8).


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  		Table 6 Cost-effectiveness analysis at the European level

 


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  		Table 7 Country-specific cost-effectiveness analysis including sensitivity analysis

 


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  		Table 8 Country-specific cost-effectiveness analysis, drug in vials

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
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 ({euro}1024 vs. {euro}41 for one treatment of levosimendan vs. dobutamine), the cost per LYS (3% discounted) with levosimendan was only {euro}3205 at the European level ({euro}3091–{euro}3331 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 [22–27]. 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 [28].


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  		Table 9 Incremental cost-effectiveness estimates for various medical interventions

 
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 [29]. 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 {euro}20 000 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 (P=0.01), as well as rate and rhythm disorders (P=0.02) than patients treated with levosimendan [16].

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.


   Acknowledgements
 
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.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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