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Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand
HLC 1812 No. of Pages 9
Heart, Lung and Circulation (2015) xx, 1–9 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2015.02.018
ORIGINAL ARTICLE
Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand§ Unchalee Permsuwan, PhD a*, Nathorn Chaiyakunapruk, PharmD, PhD b,c,d,e, Surakit Nathisuwan, PharmD, BCPS f, Apichard Sukonthasarn, MD g Faculty of Pharmacy, Chiang Mai University[6_TD$IF], Chiang Mai, Thailand [8_TD$IF]School of Pharmacy, Monash University [9_TD$IF]Malaysia, Malaysia c Center of Pharmaceutical Outcomes Research (CPOR), Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand d School of Population Health, University of Queensland, Brisbane, Australia e School of Pharmacy, University of Wisconsin[1_TD$IF]-Madison, Madison[12_TD$IF], WI, USA f Faculty of Pharmacy, Mahidol University, Bangkok, Thailand g Department of Medicine, Faculty of Medicine, Chiang Mai University[15_TD$IF], Chiang Mai, Thailand a
b
Received 27 August 2014; received in revised form 2 February 2015; accepted 20 February 2015; online published-ahead-of-print xxx
Background
Non-ST elevation acute coronary syndrome (NSTE-ACS) imposes a significant health and economic burden on a society. Anticoagulants are recommended as standard therapy by various clinical practice guidelines. Fondaparinux was introduced and evaluated in a number of large randomised, controlled trials. This study therefore aimed to determine the cost-effectiveness of fondaparinux versus enoxaparin in the treatment of NSTE-ACS in Thailand.
Methods
A two-part construct model comprising a one-year decision tree and a Markov model was developed to capture short and long-term costs and outcomes from the perspective of provider and society. Effectiveness data were derived from OASIS-5 trial while bleeding rates were derived from the Thai Acute Coronary Syndrome Registry (TACSR). Costs data were based on a Thai database and presented in the year of 2013. Both costs and outcomes were discounted by 3% annually. A series of sensitivity analyses were performed.
Results
The results showed that compared with enoxaparin, fondaparinux was a cost-saving strategy (lower cost with slightly higher effectiveness). Cost of revascularisation with major bleeding had a greater impact on the amount of cost saved both from societal and provider perspectives. With a threshold of 160,000 THB ((4,857.3 USD) per QALY in Thailand, fondaparinux was about 99% more cost-effective compared with enoxaparin.
Conclusion
Fondaparinux should be considered as a cost-effective alternative when compared to enoxaparin for NSTE-ACS based on Thailand’s context, especially in the era of limited healthcare resources.
Keywords
Fondaparinux Enoxaparin NSTE-ACS Cost-Effectiveness Thailand
§
All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
*Corresponding author at: Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: +66 54944355; fax: +66 53222741, Email: [email protected] © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Introduction Acute coronary syndrome (ACS) encompasses a range of conditions from unstable angina (UA) to ST-segmentelevation myocardial infarction (STEMI). ACS associated with non-ST segment elevation includes UA and non-ST segment elevation MI (NSTEMI). ACS presents a unique challenge to clinicians due to the high rate of mortality and morbidity associated with these conditions [1]. UA and NSTEMI share similar pathophysiology and clinical presentations, but NSTEMI is characterised by an increase in the biochemical markers of myocardial injury; hence, nonST elevation acute coronary syndrome (NSTE-ACS) has become the preferred diagnosis for UA/NSTEMI [2]. NSTE-ACS imposes a health and economic burden on society. Patients with NSTE-ACS are also at high risk of death. According to the NICE clinical guideline 2010 for NSTE-ACS [3], treatment with anticoagulants in addition to anti-platelet agents such as aspirin and clopidogrel is recommended. Although low-molecular-weight heparins (LMWHs) have been demonstrated to reduce coronary events, they are associated with an increased risk of bleeding, which can be associated with an increased risk of death [1,4–6]. Appropriate management of NSTE-ACS is challenging, as the benefit of treatments in reducing cardiovascular associated mortality must be balanced against a risk of bleeding. Fondaparinux is a synthetic pentasaccharide that can inhibit Factor Xa leading to inhibition of thrombin generation [7]. Compared to LMWHs, this new agent possesses favourable pharmacokinetic and pharmacodynamic profiles including high selectivity and specificity against Factor Xa, complete absorption through subcutaneous injection and long half-life allowing simple once daily fix dosing. This agent has been tested and approved in a variety of conditions such as prevention and treatment of venous thromboembolism and acute coronary syndrome. Clinical effectiveness data for fondaparinux in acute coronary syndrome is primarily based on a large multi-centre pivotal trial (OASIS-5) [8] which compared fondaparinux with enoxaparin for the treatment of NSTE-ACS. Fondaparinux was demonstrated to be non-inferior to enoxaparin in preventing death, MI, and refractory ischaemia at nine days. Importantly, fondaparinux was associated with a significant reduction in the rate of major bleeding over both short- and longer term. The short-term efficacy and the reduction in the number of cases of bleeding with fondaparinux, translated to a reduction in the longer-term mortality and morbidity of patients. For Thailand, LMWHs have been the anticoagulant of choice in the ACS setting especially enoxaparin. Enoxaparin has to be administered twice daily and requires dose adjustment for weight of individual patients. This not only increases the cost of drug administration but also requires diligent effort by clinicians to measure the patient’s weight and monitor the drug dose accordingly. With limited healthcare resources in Thailand, such issues can lead to problems in care of patients. In addition, a reduction of bleeding associated with enoxaparin would provide a large cost saving to a developing
healthcare system. While data on cost-effectiveness of fondaparinux exists, such studies were done in the countries that have vast differences in healthcare environment from Thailand; hence, the application of data might be limited. Therefore, the aim of our study was to conduct a cost-effectiveness analysis comparing fondaparinux and enoxaparin in patients with NSTE-ACS in Thailand using parameters and data that reflect the local context, when available.
Methods Overall Description We used a Markov model to simulate NSTE-ACS patients receiving fondaparinux compared to enoxaparin, which was a standard treatment. We performed a cost-utility analysis with incremental cost per quality-adjusted life year (QALY) gained. The model simulated the life-time horizon to capture long-term costs and effectiveness incurred. As recommended by Thailand’s health technology assessment guidelines, the study applied an annual discount rate of 3.0% to costs and benefits [9] and was undertaken from a societal perspective [10]. Costs included drug cost, cost of major bleeding, cost of ACS first year after hospitalisation, cost of ACS in second and subsequent years, and direct non-medical costs such as transportation, care-giver time. Indirect cost was excluded to avoid double-counting since QALY already counted morbidity and mortality effect as a recommendation of Thailand’s health technology assessment guidelines [11]. We also performed analysis based on provider perspective, in which only direct medical costs were included. All above costs were adjusted with CPI [12] and presented in the year 2013. The costs were converted at a rate of 32.94 baht per USD as the average rate for 2013 [13].
Intervention and Comparators We compared fondaparinux (at a dose of 2.5 mg once daily) with enoxaparin (at a dose of 1 mg/kg body weight twice daily) for six days in the treatment of patients with NSTEACS. Due to the report from the OASIS-5 trial [8] regarding a few cases of coronary and catheter-related thrombosis in patients who underwent PCI, patients receiving fondaparinux who underwent revascularisation would receive 100 IU/kg of unfractionated heparin (UFH) to flush the catheters. Enoxaparin is the most commonly prescribed LMWH in Thailand. It is therefore considered to be the most appropriate comparator as the treatment most likely to be displaced by fondaparinux.
Study Cohort The study cohort included only patients with NSTE-ACS. The mean age of patients recruited in the OASIS-5 trial [8] was 66.6 years so that we assumed our study cohort with age started at 60 years and older. We also excluded the patients with creatinine clearance (CrCl) < 30 ml/min. The dose of medications was calculated based on 60 kg body weight for our Thai patients.
Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Economic Model
from the TACSR which demonstrated the average hospitalisation of 8.6 days for UA patients and 11.8 days for NSTEMI patients [14]. A decision tree began with cohort patients with NSTEACS. Patients would receive either fondaparinux or enoxaparin. After receiving medication, they underwent revascularisation or continued receiving conservative medication treatment. The revascularisation included percutaneous coronary intervention (PCI) or/and coronary artery bypass graft (CABG). Patients would further have a
The model in this study was a two-part construct with a one-year decision tree, based effectiveness data on the OASIS-5 trial [8], and a Markov model for capturing longterm costs and benefits (Figure 1). A one-year decision tree model was used in the first part because the efficacy of fondaparinux in terms of the reduction of major bleeding occurs rapidly after treatment. The OASIS-5 trial [8] provided the safety outcome at day 9, day 30, and day 180. The result at day 9 was used in this analysis owing to the clinical evidence
Survive No major bleeding Die No revascularization
Death
Survive Major bleeding Die
Fondaparinux No major bleeding
Death
Survive Die
Revascularization
Death
Survive Major bleeding Die NSTE-ACS
Death
Survive No major bleeding Die No revascularization
Death
Survive Major bleeding Die Enoxaparin
Death
Survive No major bleeding Die Revascularization
Death
Survive Major bleeding Die A A one-year decision tree model
ACS
Death
Death
B A long-term Markov model Figure 1 Model structure comparing fondaparinux and enoxaparin in non-ST elevation acute coronary syndrome patients. Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Likelihood of Events We derived the probability of revascularisation and major bleeding from the TACSR which was the largest cohort study ever conducted in Thailand [2,15]. The probability of major bleeding in patients undergoing revascularisation was 5.8% which was very consistent with the report of 6% in the OASIS-5 trial. In the case of no revascularisation, the probability of major bleeding was still close to that from OASIS-5 trial (4.2% vs 3%) respectively. Based on the safety data from the OASIS-5 trial [8], the fondaparinux group had a significantly lower rate of major bleeding at nine days than the enoxaparin group (2.2% vs 4.1% respectively; hazard ratio 0.52; 95%CI 0.44-0.61; p<0.001). We used the finding from the OASIS-5 trial [8] to calculate the probability of major bleeding for the fondaparinux arm in a decision tree model. The finding from the OASIS-5 trial [8] and the TACSR [2] showed that patients who had major bleeding during hospitalisation had higher rates of death. However, the mortality rate with major bleeding reported in the TACSR was double compared with the OASIS-5 trial (27.9% vs 13.2%). In the same way, without major bleeding the mortality rate was higher in the TACSR than that from the OASIS-5 trial (8.6% vs 2.8%). We decided to choose the data based on Thai database because it reflected current clinical practice in Thailand[2_TD$IF].
possibility of major bleeding occurrence. At the end of one year, patients would be either alive or dead. After the first year, fondaparinux or enoxaparin treatment was discontinued. We assumed that there was no remaining treatment effect in the subsequent years. Therefore, each treatment arm had similar transition probabilities in a Markov model which comprised only two health states (ACS or death). The difference occurred directly from the number of patients entering into a Markov model. Patients might continue staying in ACS health state or pass to death. The model was run until patients aged 100 years or 40 cycles. The cycle length was one year.
Input Parameters Effectiveness data were obtained from the OASIS-5 trial [8]. Costs were based on the Thai database. Major bleeding rates and mortality were derived from the Thai Acute Coronary Syndrome Registry (TACSR). The TACSR is a multi-centre prospective project of nationwide registration in Thailand. A total of 17 tertiary care hospitals located in different regions in Thailand initially participated in the registry. The enrolment of the patients started in August 2002. After three years, records of 9,373 patients had been collected. Of those, 59.1% were NSTE-ACS patients [14]. All input parameters and sources of information used in the model are shown in Table 1.
Table 1 Input parameters. Parameters
Base case
Range
Source
Probabilities Revascularisation
0.274
0.267-0.282
[15]
Major bleeding after revascularisation
0.058
0.052-0.064
[15]
Major bleeding without revascularisation
0.042
0.038-0.045
[15]
Death with major bleeding Death without major bleeding
0.279 0.086
0.251-0.308 0.082-0.090
[2] [2]
0.52
0.44-0.61
[8]
Fondaparinux1
1,320
352-2,112
GSK
Enoxaparin2
2,712
723.2-4,339.2
[18]
Heparin3
128
102.4-153.6
[18]
Revascularisation with major bleeding Revascularisation with no major bleeding
386,130 315,422
295,536-1,067,795 305,612-325,232
[19] [19]
No revascularisation with major bleeding
75,377
54,721-96,033
[19]
No revascularisation with no major bleeding
55,826
53,726-57,924
[19]
Direct non-medical cost 1st year
3,382
2,706-4,059
[20]
Direct non-medical cost 2nd year
4,4892
3,913-5,870
[20]
Cost of ACS 1st year
59,405
47,524-71,286
[20]
Cost of ACS 2nd year
13,584
10,867-16,300
[20]
0.605
0.509-0.920
[21]
Effectiveness of fondaparinux (RR) On major bleeding Costs (THB, year of costing: 2013)
Utility ACS 1
Unit cost of fondaparinux sodium prefill syringe 2.5 mg/0.5 ml was 220 THB; Total six day treatment was 1,320 (220*6).
2
Unit cost of enoxaparin sodium 60 mg/0.6 ml was 226 THB; Total six day treatment was 2,712 (226*2*6).
3
Unit cost of heparin 5000 IU/ml was 128 THB.
Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Long-term mortality rate in the Markov model was based on the age- and sex-specific mortality rate (ASMR) for the Thai population [16]. However, ACS is a serious medical condition associated with high morbidity and mortality [14]. The additional mortality risk in ACS patients was quantified in terms of a relative risk compared to the general Thai population. This relative risk was based on a secondary analysis of the Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS) study which followed-up 490 ACS patients for four years [17]. Therefore, we calculated transition probability for ACS to death by multiplying [18_TD$IF]ASMR of Thai population by 1.8. Healthcare Resources and Costs Parameters Drug costs comprised fondaparinux, enoxaparin, and heparin. The unit price was 220 THB (6.68 USD)/2.5 mg/0.5 ml tube, obtained from GSK. The reference prices of enoxaparin and heparin were obtained from Drug and Medical Supply Information Center (DMSIC), Ministry of Public Health (http://dmsic.moph.go.th/price.htm) [18]. The standard price of enoxaparin sodium 60 mg/0.6 ml was 226 THB (6.86 USD) and heparin 5,000 IU/ml were 128 THB (3.88 USD). Based on the OASIS-5 trial [8], the treatment duration lasted for six days. Enoxaparin was administered twice daily while fondaparinux was once daily. Therefore, total costs of enoxaparin and fondaparinux treatment were 2,712 THB (82.33 USD) and 1,320 THB (40.07 USD) respectively. Patients receiving fondaparinux who underwent revascularisation would receive UFH 100 IU/kg to flush the catheters. Costs of major bleeding were derived from the study by Saokaew S. [19] which used the database of a Universityaffiliated hospital in Bangkok. This study was a retrospective cohort study of hospitalised patients with acute coronary syndrome (n=346) comparing cost and length of stay between those with and without bleeding. The cost of major bleeding for patients who underwent revascularisation and not revascularisation was 386,130 THB (SD=75,870) and 75,377 THB (SD=12,980), respectively. Patients who underwent revascularisation, but did not have major bleeding incurred 315,422 THB (SD=49,946), while the medical care cost of those patients who did not undergo revascularisation and no major bleeding was 55,826 THB (SD=10,523). The attributable cost of major bleeding among those with revascularisation was 70,708 THB (SD=25,923) and those without revascularisation was 19,552 THB (SD=2,458). Costs of ACS first year, second year, and direct non-medical costs were obtained from the study by Anukoolsawat P. [20]. The first year ACS cost accounted for the costs incurred after hospitalisation. Since this cost was not actually reported in the study, we used the difference between the first year average cost and the first year average admission cost. For the second year and onward, we assumed the indifferent costs were due to a paucity of cost data beyond the second year. Utility Due to the lack of direct utility elicitation from the Thai population, we derived a utility based on the disability weight of ACS patients used in a study by Tamteerano Y.
[21] from the Health Intervention and Technology Assessment Program (HITAP). The utility was 0.605 with a range from 0.509 to 0.92.
Analyses The two alternatives were compared on the basis of the increments in costs and effectiveness. The ICER was calculated by incremental cost divided by incremental effectiveness yielding cost per QALY.
Sensitivity Analyses A series of sensitivity analyses were performed. One-way sensitivity analysis was carried out by varying each variable while keeping other variables constant. Those varied variables were costs, relative risks, probabilities, and utility value. Number of days that patients received either fondaparinux or enoxaparin was also varied. This was due to the fact that the treatment would last only three days for the treatment of patients with NSTE-ACS as the routine clinical practice in Thailand. For cost variables, we used 20% for upper and lower range except for costs of major bleeding, for which data were available [19]. For probability parameters, the range would be mean standard error. For other variables, the study provided the base case value and its range. The results of one-way sensitivity analysis [19_TD$IF]were displayed as the tornado diagram. In addition, probabilistic sensitivity analysis (PSA) was undertaken to address uncertainty in the assumptions underlying the model by allowing all of the input parameters’ values to vary simultaneously over their respective feasible ranges within the model. All input parameters were assigned a probability distribution to reflect their feasible range of values. A beta distribution was chosen for probability and utility parameters. A log-normal distribution was used for RRs’ parameters. A gamma distribution, which ensures positive values, was assigned for all cost parameters. A thousand iterations were performed. The results [19_TD$IF]were displayed as a cost-effectiveness acceptability curve which illustrates the relationship between the willingness to pay for a unit of outcome and the probability of favouring each strategy [22].
Results Base Case Analysis We found that fondaparinux treatment was a cost saving strategy compared to enoxaparin treatment in both perspectives. This was the result from less total cost of 962 THB (29.2 USD) and 1,286 THB (39.0 USD) from the perspectives of society and provider respectively. Furthermore, NSTE-ACS patients who received fondaparinux gained 0.04 more QALY than those who received enoxaparin from both perspectives[20_TD$IF] (Table 2).
Sensitivity Analyses A series of one-way sensitivity analyses from both provider and societal perspectives (Figure 2 and 3) showed that fondaparinux treatment was still a cost-saving strategy compared with enoxaparin treatment. This was the result from
Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Table 2 Base case analyses. Variable
Societal Perspective
Provider Perspective
Fondaparinux
Enoxaparin
Fondaparinux
Enoxaparin
Costs (THB)
451,070
452,031
379,122
380,408
QALY
9.03
8.99
9.03
ICER (THB/QALY)
8.99 Cost saving
Cost saving
-1,60,000.00 -1,20,000.00 -80,000.00
-40,000.00
0.00
Cost of revas with bleeding (295,5361,067,795) Discount rate (0-6) Unit cost of enoxaparin (181-271) Death with major bleeding (0.251-0.308) Cost of no revas with bleeding (54,721-96,033) Unit cost of fondaparinux (176-264)
Using the lower value
Using the upper value
Utility (0.509-0.920) RR of major bleeding (0.44-0.61) RR of death from ACS (1.233-2.367)
Figure 2 One-way sensitivity analyses considering societal perspective. ACS: acute coronary syndrome; bleeding: major bleeding; RR: relative risk; revas: revascularisation.
-1,60,000.00 -1,20,000.00 -80,000.00
-40,000.00
0.00
Cost of revas with bleeding (295,5361,067,795) Discount rate (0-6) Unit cost of enoxaparin (181-271) Utility (0.509-0.92) Death with major bleeding (0.251-0.308) Using the lower value Cost of no revas with bleeding (54,721-96,033) Unit cost of fondaparinux (176-264)
Using the upper value
RR of major bleeding (0.44-0.61) RR of death from ACS (1.233-2.367)
Figure 3 One-way sensitivity analyses considering provider perspective. ACS: acute coronary syndrome; bleeding: major bleeding; RR: relative risk; revas: revascularisation. Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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the less incremental cost with a slightly higher gain in QALY. Among 22 varied parameters, cost of revascularisation with major bleeding had the high impact on cost saving. When it was increased, fondaparinux treatment was more likely to be a cost-saving strategy.
The result of PSA showed that at a 160,000 THB (4,857.3 USD) per QALY threshold in Thailand, fondaparinux treatment was approximately 99% cost-effective compared with enoxaparin from both provider and societal perspectives as shown in Figures 4 and 5.
1.2
Probability of being cost-effective
Fondaparinux 1
0.8
0.6
0.4
0.2 Enoxaparin 0
Willingness to pay per QALY
Figure 4 Cost-effectiveness acceptability curve from societal perspective.
1.2 Fondaparinux Probability of being cost-effective
1
0.8
0.6
0.4
0.2 Enoxaparin 0
Willingness to pay per QALY
Figure 5 Cost-effectiveness acceptability curve from provider perspective. Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Discussion Summary of Findings Our findings demonstrate that fondaparinux is a costeffective strategy compared with enoxaparin in treating patients with NSTE-ACS from both provider and societal perspectives. We believe that the cost-effective or cost-saving findings in our study are due mainly to two reasons. Firstly, both medicines have no significant difference in acquisition cost (226 vs 220 THB for enoxaparin and fondaparinux respectively). Enoxaparin has a slightly higher total drug cost compared with fondaparinux due to its twice daily administration. Secondly, avoidance of costs associated with major bleeding results in substantial saving. The study by Saokaew S. [19] reported that the attributable cost of major bleeding among those with revascularisation was 70,708 THB (2,146.6 USD) and those without revascularisation was 19,552 THB (593.6 USD). Based on the result of one-way sensitivity analysis, we found that cost of revascularisation with major bleeding was the most influential parameter. When this cost was increased, fondaparinux showed even better cost-saving. In addition to our research work, another cost-effectiveness study conducted by Pepe et al. [23] in Brazil reported similar findings. From the Ministry of Health of Brazil, it was found that fondaparinux resulted in cost-saving based on less than one-year time horizon. However, this study used a Markov model to simulate for the life-time horizon to capture long-term costs and effectiveness incurred. Our results are also consistent with findings of other cost-effectiveness studies [24–26] which reported that fondaparinux was a dominant strategy compared with enoxaparin. However, those studies have different aspects from this study such as differences in construct model and costs.
Strengths and Limitations This study used clinical effectiveness based on a well-known landmark clinical trial, the OASIS-5 trial [8], specifically designed to evaluate non-inferiority of fondaparinux and enoxaparin. The highly internal valid findings from this trial suit well as inputs in our cost-effectiveness analysis. To make our results applicable to the local context, we used local inputs to reflect clinical practice and consequences associated with bleeding. Most local inputs were derived from a large registry of ACS patients receiving care in a number of hospitals in Thailand. Furthermore, the cost of major bleeding used in our model was obtained from a cohort study of 346 Thai ACS patients. This cost analysis was undertaken using a standard generalised linear model with log-transformation and Duan’s smearing estimator. Based on these, we believe that our findings provide key relevant information aiding policy makers to make informed decisions regarding resource allocation, especially treating NSTE-ACS patients in Thailand. A number of key limitations of this study should be noted. First, the study finding is limited to NSTE-ACS and may not be applicable to all ACS patients. Second, the population
included in this study is those with CrCl 30 ml/min. There remains limited evidence on the use of fondaparinux in ACS patients with renal insufficiency. Third, costs of bleeding were obtained from a single hospital. This would[3_TD$IF] affect overall generalisability of our findings. Fourth, we assume lack of difference of both short- and long-term adverse effects. Despite current evidence of no difference, clinicians and policy makers should be aware of the changes in cost-effectiveness value when new information related to adverse effects becomes available.
Conclusions In summary, our cost-effectiveness results show that, compared with enoxaparin, fondaparinux is a cost-effective strategy for treating only patients with NSTE-ACS in Thailand from both provider and societal perspectives. Fondaparinux should be considered as another cost-effective anticoagulant alternative in Thailand during the era of limited healthcare resources.
Funding Sources This study was supported by GSK (Thailand). However, the supporter did not have a role in directing the design, conducting model analyses, interpreting the data, and preparing this manuscript.
Conflict of Interest All authors have no conflict of interest.
Acknowledgements The authors would like to thank Dr. Surasak Saokaew for providing assistance on cost analysis, and Dr. Naiyana Praditsitthikorn and Ms. Pitsaphun Werayingyong for their advice and comments on this cost-effectiveness[4_TD$IF] study[5_TD$IF].
References [1] Campbell CL. New treatment options for acute coronary syndromes. Am J Manag Care 2006;12(16 Suppl):S435–43. [2] Kiatchoosakun S, Wongvipaporn C, Buakhamsri A, Sanguanwong S, Moleerergpoom W, Sarakarn P, et al. Predictors of in-hospital mortality in non-ST elevation acute coronary syndrome in Thai Acute Coronary Syndrome Registry (TACSR). J Med Assoc Thai 2007;90(suppl 1):41–50. [3] National Institute for Health and Clinical Excellence. Unstable angina and NSTEMI: The early management of unstable angina and non-STsegment-elevation myocardial infarction. March 2010.[21_TD$IF] [February 15, 2014]; Available from: http://www.nice.org.uk/guidance/cg94. [4] Mehta SR. Clinical benefit and practical use of Fondaparinux in the invasive management of patients with acute coronary syndromes. Eur Heart J 2008;10(Suppl C):C14–21. [5] Wienbergen H, Zeymer U. Management of acute coronary syndromes with Fondaparinux. Vasc Health Risk Manag 2007;3(3):321–9. [6] Bassand J-P, Richard-Lordereau I, Cadroy Y. Efficacy and safety of Fondaparinux in patients with acute coronary syndromes. Expert Rev Cardiovasc Ther 2007;5(6):1013–26.
Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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[7] Nadar SK, Goyal D, Shantsila E, Banerjee P, Lip GY. Fondaparinux: an overview. Expert Rev Cardiovasc Ther 2009;7(6):577–85. [8] Fifth Organization to Access Strategies in Acute Ischemic Syndromes Investigators, Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, et al. Comparison of Fondaparinux and Enoxaparin in acute coronary syndromes. N Engl Med 2006;354(14):1464–76. [9] Permsuwan U, Guntawongwan K, Buddhawongsa P. Handling time in economic evaluation studies. J Med Assoc Thai 2008;91(Suppl 2):s53–8. [10] Chaiyakunapruk N. Defining the scope of economic evaluation study and selection of comparators. J Med Assoc Thai 2008;91(Suppl 2):S16–20. [11] Riewpaiboon A. Measurement of costs. J Med Assoc Thai 2008;91(Suppl 2): S28–37. [12] Bureau of Trade and Economics Indices, Ministry of Commerce. CPI (Medical Care). 2014 [March[2_TD$IF] 1, 2014]; Available from: http://www.price. moc.go.th/price/cpi/index_new_e.asp. [13] Bank of Thailand. Foreign exchange rates year 2013. [March[2_TD$IF] 1, 2014]; Available from: http://www.bot.or.th/english/statistics/financialmarkets/ exchangerate/_layouts/Application/ExchangeRate/ExchangeRate.aspx. [14] Srimahachota S, Kanjanavanit R, Boonyaratavej S, Boonsom W, Veerakul C, Tresukosol D. Demographic, management practices and in-hospital outcomes of Thai Acute Coronary Syndrome Registry (TACSR): the difference from the western world. J Med Assoc Thai 2007;90(suppl 1):1–11. [15] Phrommintikul A, Kuanprasert S, Limpijankit T, Hengrassamee K. Inhospital invasive strategy and outcomes in non-ST elevation acute coronary syndrome management from Thai Acute Coronary Syndrome Registry. J Med Assoc Thai 2007;90(suppl 1):74–80. [16] World Health Organization. Global Health Observatory Data Repository. 2011 [March[2_TD$IF] 1, 2014]; Available from: http://apps.who.int/ghodata/? vid=61640. [17] Taneja AK, Collinson J, Flather MD, Bakhai A, deArenaza DP, Wang D, et al. Mortality following non-ST elevation acute coronary syndrome: 4 years follow-up of PRAIS UK Registry (Prospective Registry of Acute Ischaemic Syndromes in the UK). European Heart J 2004;5:2013–8.
[18] Drug and Medical Supply Information Center. Prices of drugs and medical supply. 2012 [[23_TD$IF]February 20, [24_TD$IF]2013]; Available from: http:// dmsic.moph.go.th/price.htm. [19] Saokaew S, Khaisombat N, Chaiyakunapruk N, Likittanasombat K, Nathisuwan S. Attributable cost and length of stay for patients with enoxaparin associated bleeding. Value Health Regional Issues 2012;(1):41–5. [20] Anukoolsawat P, Sritara P, Teerawattananon Y. Costs of lifetime treatment of acute coronary syndrome at Ramathibodi hospital. Thai Heart J 2006;19:132–43. [21] Tamteerano Y, Khonputsa P, Chaikledkaew U, Teerawattananon Y, Lim S. Economic evaluation of HMG-CoA reductase inhibitors (statin) for primary prevention of cardiovascular diseases among Thai population (in Thai language). Bangkok: Health Intervention and Technology Assessment Program (HITAP), Ministry of Public Health; 2008. [22] Zethraeus N, Johannesson M, Jonsson B, Lothgren M, Tambour M. Advantages of using the net-benefit approach for analysing uncertainty in economic evaluation studies. Pharmacoeconomics 2003;21(1):39–48. Epub 2002/12/18. [23] Pepe C, Machado M, Olimpio A, Ramos R. Cost-effectiveness of fondaparinux in patients with acute coronary syndrome without ST-segment elevation. Arq Bras Cardiol 2012;99(1):613–22. [24] Davies A, Stamuli E, Sculpher M. Fondaparinux versus enoxaparin in acute coronary syndromes (OASIS-5): UK (Scotland) cost-effectiveness analysis. Oxford Outcomes Ltd; 2007. [25] Latour-Perez J, de-Miguel-Balsa E. Cost effectiveness of Fondaparinux in non-ST-elevation acute coronary syndrome. Pharmacoecomics 2009;27 (7):585–95. [26] Sculpher MJ, Lozano-Ortega G, Sambrook J, Palmer S, Ormanidhi O, Bakhai A, et al. Fondaparinux versus Enoxaparin in non-ST-elevation acute coronary syndromes: Short-term cost and long-term cost-effectiveness using data from the Fifth Organization to Assess Strategies in Acute Ischemic Syndrome Investigators (OASIS-5) trial. Am Heart J 2009;157: 845–52.
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Heart, Lung and Circulation (2015) xx, 1–9 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2015.02.018
ORIGINAL ARTICLE
Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand§ Unchalee Permsuwan, PhD a*, Nathorn Chaiyakunapruk, PharmD, PhD b,c,d,e, Surakit Nathisuwan, PharmD, BCPS f, Apichard Sukonthasarn, MD g Faculty of Pharmacy, Chiang Mai University[6_TD$IF], Chiang Mai, Thailand [8_TD$IF]School of Pharmacy, Monash University [9_TD$IF]Malaysia, Malaysia c Center of Pharmaceutical Outcomes Research (CPOR), Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand d School of Population Health, University of Queensland, Brisbane, Australia e School of Pharmacy, University of Wisconsin[1_TD$IF]-Madison, Madison[12_TD$IF], WI, USA f Faculty of Pharmacy, Mahidol University, Bangkok, Thailand g Department of Medicine, Faculty of Medicine, Chiang Mai University[15_TD$IF], Chiang Mai, Thailand a
b
Received 27 August 2014; received in revised form 2 February 2015; accepted 20 February 2015; online published-ahead-of-print xxx
Background
Non-ST elevation acute coronary syndrome (NSTE-ACS) imposes a significant health and economic burden on a society. Anticoagulants are recommended as standard therapy by various clinical practice guidelines. Fondaparinux was introduced and evaluated in a number of large randomised, controlled trials. This study therefore aimed to determine the cost-effectiveness of fondaparinux versus enoxaparin in the treatment of NSTE-ACS in Thailand.
Methods
A two-part construct model comprising a one-year decision tree and a Markov model was developed to capture short and long-term costs and outcomes from the perspective of provider and society. Effectiveness data were derived from OASIS-5 trial while bleeding rates were derived from the Thai Acute Coronary Syndrome Registry (TACSR). Costs data were based on a Thai database and presented in the year of 2013. Both costs and outcomes were discounted by 3% annually. A series of sensitivity analyses were performed.
Results
The results showed that compared with enoxaparin, fondaparinux was a cost-saving strategy (lower cost with slightly higher effectiveness). Cost of revascularisation with major bleeding had a greater impact on the amount of cost saved both from societal and provider perspectives. With a threshold of 160,000 THB ((4,857.3 USD) per QALY in Thailand, fondaparinux was about 99% more cost-effective compared with enoxaparin.
Conclusion
Fondaparinux should be considered as a cost-effective alternative when compared to enoxaparin for NSTE-ACS based on Thailand’s context, especially in the era of limited healthcare resources.
Keywords
Fondaparinux Enoxaparin NSTE-ACS Cost-Effectiveness Thailand
§
All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
*Corresponding author at: Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: +66 54944355; fax: +66 53222741, Email: [email protected] © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Introduction Acute coronary syndrome (ACS) encompasses a range of conditions from unstable angina (UA) to ST-segmentelevation myocardial infarction (STEMI). ACS associated with non-ST segment elevation includes UA and non-ST segment elevation MI (NSTEMI). ACS presents a unique challenge to clinicians due to the high rate of mortality and morbidity associated with these conditions [1]. UA and NSTEMI share similar pathophysiology and clinical presentations, but NSTEMI is characterised by an increase in the biochemical markers of myocardial injury; hence, nonST elevation acute coronary syndrome (NSTE-ACS) has become the preferred diagnosis for UA/NSTEMI [2]. NSTE-ACS imposes a health and economic burden on society. Patients with NSTE-ACS are also at high risk of death. According to the NICE clinical guideline 2010 for NSTE-ACS [3], treatment with anticoagulants in addition to anti-platelet agents such as aspirin and clopidogrel is recommended. Although low-molecular-weight heparins (LMWHs) have been demonstrated to reduce coronary events, they are associated with an increased risk of bleeding, which can be associated with an increased risk of death [1,4–6]. Appropriate management of NSTE-ACS is challenging, as the benefit of treatments in reducing cardiovascular associated mortality must be balanced against a risk of bleeding. Fondaparinux is a synthetic pentasaccharide that can inhibit Factor Xa leading to inhibition of thrombin generation [7]. Compared to LMWHs, this new agent possesses favourable pharmacokinetic and pharmacodynamic profiles including high selectivity and specificity against Factor Xa, complete absorption through subcutaneous injection and long half-life allowing simple once daily fix dosing. This agent has been tested and approved in a variety of conditions such as prevention and treatment of venous thromboembolism and acute coronary syndrome. Clinical effectiveness data for fondaparinux in acute coronary syndrome is primarily based on a large multi-centre pivotal trial (OASIS-5) [8] which compared fondaparinux with enoxaparin for the treatment of NSTE-ACS. Fondaparinux was demonstrated to be non-inferior to enoxaparin in preventing death, MI, and refractory ischaemia at nine days. Importantly, fondaparinux was associated with a significant reduction in the rate of major bleeding over both short- and longer term. The short-term efficacy and the reduction in the number of cases of bleeding with fondaparinux, translated to a reduction in the longer-term mortality and morbidity of patients. For Thailand, LMWHs have been the anticoagulant of choice in the ACS setting especially enoxaparin. Enoxaparin has to be administered twice daily and requires dose adjustment for weight of individual patients. This not only increases the cost of drug administration but also requires diligent effort by clinicians to measure the patient’s weight and monitor the drug dose accordingly. With limited healthcare resources in Thailand, such issues can lead to problems in care of patients. In addition, a reduction of bleeding associated with enoxaparin would provide a large cost saving to a developing
healthcare system. While data on cost-effectiveness of fondaparinux exists, such studies were done in the countries that have vast differences in healthcare environment from Thailand; hence, the application of data might be limited. Therefore, the aim of our study was to conduct a cost-effectiveness analysis comparing fondaparinux and enoxaparin in patients with NSTE-ACS in Thailand using parameters and data that reflect the local context, when available.
Methods Overall Description We used a Markov model to simulate NSTE-ACS patients receiving fondaparinux compared to enoxaparin, which was a standard treatment. We performed a cost-utility analysis with incremental cost per quality-adjusted life year (QALY) gained. The model simulated the life-time horizon to capture long-term costs and effectiveness incurred. As recommended by Thailand’s health technology assessment guidelines, the study applied an annual discount rate of 3.0% to costs and benefits [9] and was undertaken from a societal perspective [10]. Costs included drug cost, cost of major bleeding, cost of ACS first year after hospitalisation, cost of ACS in second and subsequent years, and direct non-medical costs such as transportation, care-giver time. Indirect cost was excluded to avoid double-counting since QALY already counted morbidity and mortality effect as a recommendation of Thailand’s health technology assessment guidelines [11]. We also performed analysis based on provider perspective, in which only direct medical costs were included. All above costs were adjusted with CPI [12] and presented in the year 2013. The costs were converted at a rate of 32.94 baht per USD as the average rate for 2013 [13].
Intervention and Comparators We compared fondaparinux (at a dose of 2.5 mg once daily) with enoxaparin (at a dose of 1 mg/kg body weight twice daily) for six days in the treatment of patients with NSTEACS. Due to the report from the OASIS-5 trial [8] regarding a few cases of coronary and catheter-related thrombosis in patients who underwent PCI, patients receiving fondaparinux who underwent revascularisation would receive 100 IU/kg of unfractionated heparin (UFH) to flush the catheters. Enoxaparin is the most commonly prescribed LMWH in Thailand. It is therefore considered to be the most appropriate comparator as the treatment most likely to be displaced by fondaparinux.
Study Cohort The study cohort included only patients with NSTE-ACS. The mean age of patients recruited in the OASIS-5 trial [8] was 66.6 years so that we assumed our study cohort with age started at 60 years and older. We also excluded the patients with creatinine clearance (CrCl) < 30 ml/min. The dose of medications was calculated based on 60 kg body weight for our Thai patients.
Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Economic Model
from the TACSR which demonstrated the average hospitalisation of 8.6 days for UA patients and 11.8 days for NSTEMI patients [14]. A decision tree began with cohort patients with NSTEACS. Patients would receive either fondaparinux or enoxaparin. After receiving medication, they underwent revascularisation or continued receiving conservative medication treatment. The revascularisation included percutaneous coronary intervention (PCI) or/and coronary artery bypass graft (CABG). Patients would further have a
The model in this study was a two-part construct with a one-year decision tree, based effectiveness data on the OASIS-5 trial [8], and a Markov model for capturing longterm costs and benefits (Figure 1). A one-year decision tree model was used in the first part because the efficacy of fondaparinux in terms of the reduction of major bleeding occurs rapidly after treatment. The OASIS-5 trial [8] provided the safety outcome at day 9, day 30, and day 180. The result at day 9 was used in this analysis owing to the clinical evidence
Survive No major bleeding Die No revascularization
Death
Survive Major bleeding Die
Fondaparinux No major bleeding
Death
Survive Die
Revascularization
Death
Survive Major bleeding Die NSTE-ACS
Death
Survive No major bleeding Die No revascularization
Death
Survive Major bleeding Die Enoxaparin
Death
Survive No major bleeding Die Revascularization
Death
Survive Major bleeding Die A A one-year decision tree model
ACS
Death
Death
B A long-term Markov model Figure 1 Model structure comparing fondaparinux and enoxaparin in non-ST elevation acute coronary syndrome patients. Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Likelihood of Events We derived the probability of revascularisation and major bleeding from the TACSR which was the largest cohort study ever conducted in Thailand [2,15]. The probability of major bleeding in patients undergoing revascularisation was 5.8% which was very consistent with the report of 6% in the OASIS-5 trial. In the case of no revascularisation, the probability of major bleeding was still close to that from OASIS-5 trial (4.2% vs 3%) respectively. Based on the safety data from the OASIS-5 trial [8], the fondaparinux group had a significantly lower rate of major bleeding at nine days than the enoxaparin group (2.2% vs 4.1% respectively; hazard ratio 0.52; 95%CI 0.44-0.61; p<0.001). We used the finding from the OASIS-5 trial [8] to calculate the probability of major bleeding for the fondaparinux arm in a decision tree model. The finding from the OASIS-5 trial [8] and the TACSR [2] showed that patients who had major bleeding during hospitalisation had higher rates of death. However, the mortality rate with major bleeding reported in the TACSR was double compared with the OASIS-5 trial (27.9% vs 13.2%). In the same way, without major bleeding the mortality rate was higher in the TACSR than that from the OASIS-5 trial (8.6% vs 2.8%). We decided to choose the data based on Thai database because it reflected current clinical practice in Thailand[2_TD$IF].
possibility of major bleeding occurrence. At the end of one year, patients would be either alive or dead. After the first year, fondaparinux or enoxaparin treatment was discontinued. We assumed that there was no remaining treatment effect in the subsequent years. Therefore, each treatment arm had similar transition probabilities in a Markov model which comprised only two health states (ACS or death). The difference occurred directly from the number of patients entering into a Markov model. Patients might continue staying in ACS health state or pass to death. The model was run until patients aged 100 years or 40 cycles. The cycle length was one year.
Input Parameters Effectiveness data were obtained from the OASIS-5 trial [8]. Costs were based on the Thai database. Major bleeding rates and mortality were derived from the Thai Acute Coronary Syndrome Registry (TACSR). The TACSR is a multi-centre prospective project of nationwide registration in Thailand. A total of 17 tertiary care hospitals located in different regions in Thailand initially participated in the registry. The enrolment of the patients started in August 2002. After three years, records of 9,373 patients had been collected. Of those, 59.1% were NSTE-ACS patients [14]. All input parameters and sources of information used in the model are shown in Table 1.
Table 1 Input parameters. Parameters
Base case
Range
Source
Probabilities Revascularisation
0.274
0.267-0.282
[15]
Major bleeding after revascularisation
0.058
0.052-0.064
[15]
Major bleeding without revascularisation
0.042
0.038-0.045
[15]
Death with major bleeding Death without major bleeding
0.279 0.086
0.251-0.308 0.082-0.090
[2] [2]
0.52
0.44-0.61
[8]
Fondaparinux1
1,320
352-2,112
GSK
Enoxaparin2
2,712
723.2-4,339.2
[18]
Heparin3
128
102.4-153.6
[18]
Revascularisation with major bleeding Revascularisation with no major bleeding
386,130 315,422
295,536-1,067,795 305,612-325,232
[19] [19]
No revascularisation with major bleeding
75,377
54,721-96,033
[19]
No revascularisation with no major bleeding
55,826
53,726-57,924
[19]
Direct non-medical cost 1st year
3,382
2,706-4,059
[20]
Direct non-medical cost 2nd year
4,4892
3,913-5,870
[20]
Cost of ACS 1st year
59,405
47,524-71,286
[20]
Cost of ACS 2nd year
13,584
10,867-16,300
[20]
0.605
0.509-0.920
[21]
Effectiveness of fondaparinux (RR) On major bleeding Costs (THB, year of costing: 2013)
Utility ACS 1
Unit cost of fondaparinux sodium prefill syringe 2.5 mg/0.5 ml was 220 THB; Total six day treatment was 1,320 (220*6).
2
Unit cost of enoxaparin sodium 60 mg/0.6 ml was 226 THB; Total six day treatment was 2,712 (226*2*6).
3
Unit cost of heparin 5000 IU/ml was 128 THB.
Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Long-term mortality rate in the Markov model was based on the age- and sex-specific mortality rate (ASMR) for the Thai population [16]. However, ACS is a serious medical condition associated with high morbidity and mortality [14]. The additional mortality risk in ACS patients was quantified in terms of a relative risk compared to the general Thai population. This relative risk was based on a secondary analysis of the Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS) study which followed-up 490 ACS patients for four years [17]. Therefore, we calculated transition probability for ACS to death by multiplying [18_TD$IF]ASMR of Thai population by 1.8. Healthcare Resources and Costs Parameters Drug costs comprised fondaparinux, enoxaparin, and heparin. The unit price was 220 THB (6.68 USD)/2.5 mg/0.5 ml tube, obtained from GSK. The reference prices of enoxaparin and heparin were obtained from Drug and Medical Supply Information Center (DMSIC), Ministry of Public Health (http://dmsic.moph.go.th/price.htm) [18]. The standard price of enoxaparin sodium 60 mg/0.6 ml was 226 THB (6.86 USD) and heparin 5,000 IU/ml were 128 THB (3.88 USD). Based on the OASIS-5 trial [8], the treatment duration lasted for six days. Enoxaparin was administered twice daily while fondaparinux was once daily. Therefore, total costs of enoxaparin and fondaparinux treatment were 2,712 THB (82.33 USD) and 1,320 THB (40.07 USD) respectively. Patients receiving fondaparinux who underwent revascularisation would receive UFH 100 IU/kg to flush the catheters. Costs of major bleeding were derived from the study by Saokaew S. [19] which used the database of a Universityaffiliated hospital in Bangkok. This study was a retrospective cohort study of hospitalised patients with acute coronary syndrome (n=346) comparing cost and length of stay between those with and without bleeding. The cost of major bleeding for patients who underwent revascularisation and not revascularisation was 386,130 THB (SD=75,870) and 75,377 THB (SD=12,980), respectively. Patients who underwent revascularisation, but did not have major bleeding incurred 315,422 THB (SD=49,946), while the medical care cost of those patients who did not undergo revascularisation and no major bleeding was 55,826 THB (SD=10,523). The attributable cost of major bleeding among those with revascularisation was 70,708 THB (SD=25,923) and those without revascularisation was 19,552 THB (SD=2,458). Costs of ACS first year, second year, and direct non-medical costs were obtained from the study by Anukoolsawat P. [20]. The first year ACS cost accounted for the costs incurred after hospitalisation. Since this cost was not actually reported in the study, we used the difference between the first year average cost and the first year average admission cost. For the second year and onward, we assumed the indifferent costs were due to a paucity of cost data beyond the second year. Utility Due to the lack of direct utility elicitation from the Thai population, we derived a utility based on the disability weight of ACS patients used in a study by Tamteerano Y.
[21] from the Health Intervention and Technology Assessment Program (HITAP). The utility was 0.605 with a range from 0.509 to 0.92.
Analyses The two alternatives were compared on the basis of the increments in costs and effectiveness. The ICER was calculated by incremental cost divided by incremental effectiveness yielding cost per QALY.
Sensitivity Analyses A series of sensitivity analyses were performed. One-way sensitivity analysis was carried out by varying each variable while keeping other variables constant. Those varied variables were costs, relative risks, probabilities, and utility value. Number of days that patients received either fondaparinux or enoxaparin was also varied. This was due to the fact that the treatment would last only three days for the treatment of patients with NSTE-ACS as the routine clinical practice in Thailand. For cost variables, we used 20% for upper and lower range except for costs of major bleeding, for which data were available [19]. For probability parameters, the range would be mean standard error. For other variables, the study provided the base case value and its range. The results of one-way sensitivity analysis [19_TD$IF]were displayed as the tornado diagram. In addition, probabilistic sensitivity analysis (PSA) was undertaken to address uncertainty in the assumptions underlying the model by allowing all of the input parameters’ values to vary simultaneously over their respective feasible ranges within the model. All input parameters were assigned a probability distribution to reflect their feasible range of values. A beta distribution was chosen for probability and utility parameters. A log-normal distribution was used for RRs’ parameters. A gamma distribution, which ensures positive values, was assigned for all cost parameters. A thousand iterations were performed. The results [19_TD$IF]were displayed as a cost-effectiveness acceptability curve which illustrates the relationship between the willingness to pay for a unit of outcome and the probability of favouring each strategy [22].
Results Base Case Analysis We found that fondaparinux treatment was a cost saving strategy compared to enoxaparin treatment in both perspectives. This was the result from less total cost of 962 THB (29.2 USD) and 1,286 THB (39.0 USD) from the perspectives of society and provider respectively. Furthermore, NSTE-ACS patients who received fondaparinux gained 0.04 more QALY than those who received enoxaparin from both perspectives[20_TD$IF] (Table 2).
Sensitivity Analyses A series of one-way sensitivity analyses from both provider and societal perspectives (Figure 2 and 3) showed that fondaparinux treatment was still a cost-saving strategy compared with enoxaparin treatment. This was the result from
Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Table 2 Base case analyses. Variable
Societal Perspective
Provider Perspective
Fondaparinux
Enoxaparin
Fondaparinux
Enoxaparin
Costs (THB)
451,070
452,031
379,122
380,408
QALY
9.03
8.99
9.03
ICER (THB/QALY)
8.99 Cost saving
Cost saving
-1,60,000.00 -1,20,000.00 -80,000.00
-40,000.00
0.00
Cost of revas with bleeding (295,5361,067,795) Discount rate (0-6) Unit cost of enoxaparin (181-271) Death with major bleeding (0.251-0.308) Cost of no revas with bleeding (54,721-96,033) Unit cost of fondaparinux (176-264)
Using the lower value
Using the upper value
Utility (0.509-0.920) RR of major bleeding (0.44-0.61) RR of death from ACS (1.233-2.367)
Figure 2 One-way sensitivity analyses considering societal perspective. ACS: acute coronary syndrome; bleeding: major bleeding; RR: relative risk; revas: revascularisation.
-1,60,000.00 -1,20,000.00 -80,000.00
-40,000.00
0.00
Cost of revas with bleeding (295,5361,067,795) Discount rate (0-6) Unit cost of enoxaparin (181-271) Utility (0.509-0.92) Death with major bleeding (0.251-0.308) Using the lower value Cost of no revas with bleeding (54,721-96,033) Unit cost of fondaparinux (176-264)
Using the upper value
RR of major bleeding (0.44-0.61) RR of death from ACS (1.233-2.367)
Figure 3 One-way sensitivity analyses considering provider perspective. ACS: acute coronary syndrome; bleeding: major bleeding; RR: relative risk; revas: revascularisation. Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin
the less incremental cost with a slightly higher gain in QALY. Among 22 varied parameters, cost of revascularisation with major bleeding had the high impact on cost saving. When it was increased, fondaparinux treatment was more likely to be a cost-saving strategy.
The result of PSA showed that at a 160,000 THB (4,857.3 USD) per QALY threshold in Thailand, fondaparinux treatment was approximately 99% cost-effective compared with enoxaparin from both provider and societal perspectives as shown in Figures 4 and 5.
1.2
Probability of being cost-effective
Fondaparinux 1
0.8
0.6
0.4
0.2 Enoxaparin 0
Willingness to pay per QALY
Figure 4 Cost-effectiveness acceptability curve from societal perspective.
1.2 Fondaparinux Probability of being cost-effective
1
0.8
0.6
0.4
0.2 Enoxaparin 0
Willingness to pay per QALY
Figure 5 Cost-effectiveness acceptability curve from provider perspective. Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018
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Discussion Summary of Findings Our findings demonstrate that fondaparinux is a costeffective strategy compared with enoxaparin in treating patients with NSTE-ACS from both provider and societal perspectives. We believe that the cost-effective or cost-saving findings in our study are due mainly to two reasons. Firstly, both medicines have no significant difference in acquisition cost (226 vs 220 THB for enoxaparin and fondaparinux respectively). Enoxaparin has a slightly higher total drug cost compared with fondaparinux due to its twice daily administration. Secondly, avoidance of costs associated with major bleeding results in substantial saving. The study by Saokaew S. [19] reported that the attributable cost of major bleeding among those with revascularisation was 70,708 THB (2,146.6 USD) and those without revascularisation was 19,552 THB (593.6 USD). Based on the result of one-way sensitivity analysis, we found that cost of revascularisation with major bleeding was the most influential parameter. When this cost was increased, fondaparinux showed even better cost-saving. In addition to our research work, another cost-effectiveness study conducted by Pepe et al. [23] in Brazil reported similar findings. From the Ministry of Health of Brazil, it was found that fondaparinux resulted in cost-saving based on less than one-year time horizon. However, this study used a Markov model to simulate for the life-time horizon to capture long-term costs and effectiveness incurred. Our results are also consistent with findings of other cost-effectiveness studies [24–26] which reported that fondaparinux was a dominant strategy compared with enoxaparin. However, those studies have different aspects from this study such as differences in construct model and costs.
Strengths and Limitations This study used clinical effectiveness based on a well-known landmark clinical trial, the OASIS-5 trial [8], specifically designed to evaluate non-inferiority of fondaparinux and enoxaparin. The highly internal valid findings from this trial suit well as inputs in our cost-effectiveness analysis. To make our results applicable to the local context, we used local inputs to reflect clinical practice and consequences associated with bleeding. Most local inputs were derived from a large registry of ACS patients receiving care in a number of hospitals in Thailand. Furthermore, the cost of major bleeding used in our model was obtained from a cohort study of 346 Thai ACS patients. This cost analysis was undertaken using a standard generalised linear model with log-transformation and Duan’s smearing estimator. Based on these, we believe that our findings provide key relevant information aiding policy makers to make informed decisions regarding resource allocation, especially treating NSTE-ACS patients in Thailand. A number of key limitations of this study should be noted. First, the study finding is limited to NSTE-ACS and may not be applicable to all ACS patients. Second, the population
included in this study is those with CrCl 30 ml/min. There remains limited evidence on the use of fondaparinux in ACS patients with renal insufficiency. Third, costs of bleeding were obtained from a single hospital. This would[3_TD$IF] affect overall generalisability of our findings. Fourth, we assume lack of difference of both short- and long-term adverse effects. Despite current evidence of no difference, clinicians and policy makers should be aware of the changes in cost-effectiveness value when new information related to adverse effects becomes available.
Conclusions In summary, our cost-effectiveness results show that, compared with enoxaparin, fondaparinux is a cost-effective strategy for treating only patients with NSTE-ACS in Thailand from both provider and societal perspectives. Fondaparinux should be considered as another cost-effective anticoagulant alternative in Thailand during the era of limited healthcare resources.
Funding Sources This study was supported by GSK (Thailand). However, the supporter did not have a role in directing the design, conducting model analyses, interpreting the data, and preparing this manuscript.
Conflict of Interest All authors have no conflict of interest.
Acknowledgements The authors would like to thank Dr. Surasak Saokaew for providing assistance on cost analysis, and Dr. Naiyana Praditsitthikorn and Ms. Pitsaphun Werayingyong for their advice and comments on this cost-effectiveness[4_TD$IF] study[5_TD$IF].
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Please cite this article in press as: Permsuwan U, et al. Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. Heart, Lung and Circulation (2015), http://dx.doi.org/10.1016/j. hlc.2015.02.018