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Cost-effectiveness of allopurinol versus febuxostat in the treatment of gout patients: A systematic review

Background: In recent years, increased longevity, poor dietary habits, and the rising prevalence of metabolic syndrome and hypertension have increased the prevalence of gout. Gout significantly increases direct and indirect costs and reduces the quality of life. Allopurinol and febuxostat are the most commonly used drugs for reducing uric acid levels and controlling this disease with different cost-effectiveness. The present systematic review compares the cost-effectiveness of these drugs. Methods: This was a systematic review of economic evaluations. Cochrane CENTRAL, Web of Science, PubMed, Embase, and the Cost-Effectiveness Analysis (CEA) Registry were searched up to April 30, 2018, based on the specific search strategy of each database. Keywords used in the search include gout, cost-effectiveness, allopurinol, and febuxostat in MeSH and free-text forms. Screening of identified studies, data extraction, and quality assessment were done independently by 2 reviewers. The quality of studies was assessed based on Drummond Checklist. Finally, a qualitative analysis was done to analyze the results. Results: A total of 94 studies were identified through database search and the review of references. After screening the titles, abstracts, and full-texts, 6 economic evaluations were included in the review. The majority of the studies had been conducted in the US using the Markov model, within a 5-year horizon, and from the payer’s perspective, with the quality of life as a measure of effectiveness. In most studies, the incremental cost-effectiveness ratios (ICERs) of febuxostat per quality-adjusted life year (QALY) were below the threshold (10 000$/QALY and 30 000€/QALY). Conclusion: Febuxostat has been shown to be more cost-effective than allopurinol in all treatment sequences in studies that have used uric acid levels as the measure of effectiveness. Furthermore, in studies with the quality of life as the measure of effectiveness, febuxostat has been shown to be very cost-effective as the second-line treatment.


Introduction
Gout is a debilitating and painful disease that can cause acute or chronic arthritis due to hyperuricemia. In recent 2 years, the prevalence of gout has increased due to increased longevity, poor dietary habits, and increase in related diseases such as metabolic syndrome and hypertension. The prevalence of this disease doubled between 1990 and 2010 (1)(2)(3). Epidemiological studies have shown that the prevalence of gout in all countries increases with age, with the highest prevalence observed in people over 40 and, especially, over 60 years (2)(3)(4)(5)(6)(7)(8). A study in Hong Kong found that 5% of individuals aged 45-59 years and 6% of those older than 60 years had gout (4). There has been a recent renewal of interest in gout and its management and costs due to the following factors: the rise in its incidence and prevalence; recognition of its unfavorable long-term outcomes (debilitation and reduced quality of life); new knowledge about mechanisms underlying the expression of the disease; and new interventions to control painful acute episodes and the chronic progressive and disabling features of gout (9,10). This disease has a significant impact on direct costs (outpatient visits, diagnosis, medication, and inpatient stays) and indirect costs such as productivity loss. These costs (over 90%) are mostly direct medication costs (11,12). Therefore, the best approach to deal with this disease is to implement strategies to improve patient outcomes while reducing the economic burden of gout for patients, payers, and governments. The most important strategies for cost reduction are as follow: increasing awareness of adherence to treatment, as noncompliance can cause progression of the disease and increase its costs; raising awareness in primary care physicians about the latest guidelines and interventions for treatment of gout; and prescription of optimal (traditional and modern) treatments to prevent and manage gout flares (10).
Medications used in the treatment of gout include antiinflammatory and urate-lowering drugs that are prescribed to alleviate the symptoms of an acute flare and prevent recurrences. Urate-lowering drugs such as probenecid, which increases uric acid excretion, and allopurinol and febuxostat, which lower uric acid levels, are used for longterm treatment (10,(13)(14)(15). Febuxostat was introduced in 2009 in the US as an alternative to allopurinol (16). Studies on the effectiveness of allopurinol and febuxostat in reducing serum urate concentration and alleviating gout flares have found different results, with most studies indicating that febuxostat is more effective than allopurinol in reducing serum urate concentration (17,18). Costeffectiveness analyses have also shown differences in the costs of these drugs, with most studies reporting that treatment with febuxostat is more expensive than allopurinol by more than $1000 (15,(19)(20)(21)(22). On the other hand, the only systematic review on the cost-effectiveness of gout medications by Kydd et al (2014) showed that the evidence on urate-lowering drugs was very limited and only 3 studies were included in the review (23). Therefore, a review of various studies on the costs and effects of allopurinol and febuxostat on gout outcomes seems necessary. Given that numerous studies have been done on the cost-effectiveness of these drugs, and the necessity to make the final decision about the suitable drug for the treatment and control of gout, this study aimed to compare the cost-effectiveness of gout medications through a systematic review of the relevant economic evaluations.

Literature Search
Cochrane CENTRAL, Web of Science, PubMed, Embase, and the Cost-Effectiveness Analysis (CEA) Registry were searched between January 1, 2000 and April 30, 2018, based on the specific search strategy of each database (Appendix 1) and using a combination of keywords and Medical Subject Headings (MeSH). In addition to electronic search, the reference lists of relevant studies were reviewed to find more studies.

Study selection
First, the titles and abstracts of the identified studies were independently examined by 2 reviewers, and economic evaluations related to gout treatments were selected. Next, the full-texts of all eligible studies were examined in the screening phase and discrepancies between the reviewers were resolved by consulting a third person and consensus.

Eligibility criteria
Eligible studies included randomized controlled trials (RCT) studies conducted between 2000 and 2018 that have examined the cost-effectiveness of allopurinol (as the comparator) and febuxostat (as the intervention) in elderly patients in the last 3 stages of gout (acute, intercritical, and chronic). The followings were excluded from this review: studies on other than economic evaluations; studies on adolescents' populations and on patients with asymptomatic hyperuricemia; other reviews; subjects related to the safety and effectiveness of gout medications; conference abstracts; book chapters; and letters/editorials. However, cost-effectiveness studies were included because the effects of the medicines used to treat gout are different and the aim of the present study was to consider nonmonetary outcomes and all health outcomes, not just a measure of utility.

Data extraction and quality assessment
Data were extracted from eligible studies based on the objectives of the study and were independently checked by a third reviewer. Data included author, publication year, country of study, model, perspective, time horizon, outcome measures (effectiveness outcomes), demographic characteristics, intervention type, comparator, costs, incremental cost-effectiveness ratios (ICERs), and key findings. Data extraction was done independently by the 2 researchers (ZF & NJH) and discrepancies were resolved by consulting a third person (RM) and consensus. ICERs were reported accurately, as they were presented in the articles and were not adjusted by a year or purchasing power parity. Qualitative data analysis was performed following data extraction.
Quality of the studies was assessed using the Drummond 10-item Checklist, which is one of the most comprehensive tools for quality assessment of economic evaluations and has been recommended by the Cochrane http://mjiri.iums.ac.ir Med J Islam Repub Iran. 2020 (30 Apr); 34.41.

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Handbook for Systematic Reviews of Interventions. It consists of 10 items with 4 options: yes, no, not clear (NC), and not appropriate (NA). The quality score of each study is based on the number of yes answers, and studies with a score above 7 are of high quality. Studies with quality scores between 3 and 7 or less than 3 are, respectively, of medium or low quality (24,25). Quality assessment was performed by 2 researchers independently (NKH, RM, ZF, and/or SA), and discrepancies were resolved by consulting a third person and consensus.

Study selection
A total of 89 studies were identified through database searches and 5 studies through reference lists of relevant studies. After removing redundant cases, the titles and abstracts of 51 studies were examined by 2 researchers independently and based on the research question; finally, the full-texts of 15 economic evaluations were examined. At this stage, noneconomic evaluations, such as efficacy and safety studies (n=20), conference abstracts (n=3), reports (n=2), economic evaluations other than costeffectiveness analysis (n=2), and studies examining either allopurinol or febuxostat (n=2), were removed, and the 6 remaining studies were systematically reviewed. The PRISMA flowchart is presented in Figure 1.

Quality of the studies
Quality was assessed using the Drummond 10-item Checklist. The results showed that all studies were of relatively high quality, with 4 high-quality studies (scores higher than 7) and 2 moderate quality studies (a score of 6 out of 10). The results of the quality assessment are presented in Table 1 by each item in the Drummond Checklist.

Data extraction
The results showed a limited number of economic evaluations that compared the cost-effectiveness of allopurinol and febuxostat in patients with gout. Four studies (67%) have been conducted in the US, one in Spain (17%), and one in Scotland (17%). The majority of the studies were conducted from a health care payer perspective (67%), while the rest were conducted from a health system perspective. Four studies had a 5-year time horizon, while the other 2 were conducted in a 1-year and lifetime horizon.  Table 2.

Data analysis
To compare allopurinol with febuxostat, ICERs were calculated in every study, except in Smolen et al's study (2015), and in all these studies, medication cost was considered as the most important direct cost of patients with gout. Other direct costs, including costs related to sideeffects, and other nonmedication costs, including the costs of outpatient, inpatient, and emergency visits, have been examined in a number of studies. In all these studies, the ICER for febuxostat as the second-line treatment was less than that of allopurinol, indicating the high costeffectiveness of this drug as a complimentary line for allopurinol. However, studies have shown that using this drug as the first-line treatment or increasing its dose in subsequent stages is not cost-effective. However, in the study of Smolen et al, its cost-effectiveness for 2 ICERs, eg, per patient reaching target sUA and per flare avoided, has been established (22). The results of economic evaluations reviewed in this study are presented in Table 3.

Discussion
The aim of the present study was to systematically review economic evaluations that examine the costeffectiveness of allopurinol and febuxostat in the treatment of gout. The results showed that 6 studies have examined the cost-effectiveness of these 2 drugs in the population of interest.
Evidence suggests that in most economic evaluations related to gout medications, quality of life is examined as the measure of effectiveness, and only a limited number of studies have mentioned clinical indicators and the sideeffects of drugs. Allopurinol and febuxostat have different effects on clinical outcomes and quality of life, and the high effectiveness of febuxostat in lowering serum urate levels has been observed. The results of most studies re- 6 vealed that other clinical outcomes, including gout flares and side-effects (eg, diarrhea, headache), are similar in febuxostat and allopurinol treatments (16,17,28). However, some studies have reported conflicting results, suggesting that febuxostat has fewer side-effects than allopurinol (14), while some studies have reported a higher prevalence of gout flares in patients receiving febuxostat compared to allopurinol, which may be due to the very fast reduction in serum uric acid levels (29,30). A 2011 systematic review, which included 21 studies, examined achieving target used as a clinical outcome, along with the side-effects of allopurinol and febuxostat, and showed that the latter has no effect on the risk of gout flares (14). In addition, a 2013 systematic review and meta-analysis was conducted on the efficacy and safety of febuxostat versus allopurinol, with 7 studies and 25 associated publications.
The results of that systematic review showed that although febuxostat increases the likelihood of achieving a target serum uric acid of < 6 mg/dL, there is no evidence suggesting that it is superior to allopurinol for clinical outcomes, and given its higher cost, febuxostat should not be routinely used for acute gout. Given the limitations of this review and the high heterogeneity of the studies, the reported results must be cited with caution (30). Studies included in the present systematic review addressed the direct costs of gout medications and examined other costs such as those related to side-effects, gout flares, diagnosis, and outpatient visits. However, indirect costs were not included in the calculations for a variety of reasons. The results of these studies showed that the cost of per patient who took febuxostat was higher than that the cost per patient who tool allopurinol, and it included all direct costs associated with each treatment (medication costs and nonmedication costs related to disease control and management). The costs were mainly medication costs rather than diagnostic or management costs (21). The results of Smolen et al study (2016) showed that the total cost per patient was $1264 higher for febuxostat than for allopurinol (22).
The results of Beard et al (2014) on the costeffectiveness of febuxostat in chronic gout patients showed that the ICER per QALY of febuxostat in a 5-year horizon was $3578, which is below the accepted threshold. Accordingly, they suggested febuxostat as a costeffective and suitable second-line option after allopurinol (26). Other studies that examined the quality of life as the measure of effectiveness have found febuxostat as a costeffective drug for second-line treatment. Smolen et al (2016) showed that the cost-effectiveness ratio of febuxostat to allopurinol is $ 5377 per patient who has reached the required uric acid level, $1773 per flare avoided, $221 795 per incident CKD avoided, and $29 063 per CKD progression avoided, indicating that febuxostat may be a cost-effective alternative to allopurinol, especially for patients with CKD stages 3 or 4 (22,29).
Studies have shown that limiting gout treatment to the first-line option, eg, the use of either allopurinol or febuxostat, is not clinically and economically cost-effective, and a combination of these drugs can be used at different stages of the disease and based on the conditions of the pa-tient. The results of Jutkowitz et al (2014) suggested that administration of allopurinol or febuxostat alone are not cost-effective; however, allopurinol-febuxostat sequential therapy increases the cost-effectiveness of the treatment (20).
Some studies have shown that febuxostat is more costeffective as a second-line option and choosing it as the first-line treatment is not cost-effective. However, studies that have examined the reduction in serum uric acid as the measure of effectiveness have shown that febuxostat is more cost-effective than allopurinol in all conditions and its ICER is lower than the efficiency threshold (9). The results of these studies are consistent with the conclusion of the National Institute for Clinical Effectiveness (NICE) that febuxostat is used as an option for the management of chronic hyperuricemia in gout only for those who are intolerant to allopurinol or for whom allopurinol is contraindicated (31).
Although studies included in the present review were of high quality, it must be noted that this review had some limitations. First, it only focused on the cost-effectiveness of the 2 interventions in elderly gout patients and excluded other economic evaluations. In addition, the small number of studies performed in this area (primarily due to the introduction of febuxostat in 2009) limited the scope of the review, and the results must be interpreted with caution. Generalization of the results of studies with small samples to those of larger populations requires that numerous variables be taken into account, which could not be achieved due to the scarcity of relevant studies. Moreover, the outcomes examined in the scant literature are very limited; thus, only some of the effects of these interventions were addressed in this review.

Conclusion
Studies that have examined reduction in serum uric acid as the measure of effectiveness have shown that febuxostat is more cost-effective than allopurinol in all treatment sequences. However, studies that have used quality of life as the measure of effectiveness have shown that febuxostat was very cost-effective as the second-line option, but prescribing it as the first-line treatment, increasing its dose, or switching to allopurinol is not cost-effective. However, given the limited number of studies conducted in this area, further primary studies with larger sample sizes are needed to achieve more accurate results. Embase allopurinol:ab,ti OR allohexal:ab,ti OR allohexan:ab,ti OR alloprin:ab,ti OR allopurin:ab,ti OR allorin:ab,ti OR allpargin:ab,ti OR allural:ab,ti OR apulonga:ab,ti OR apurin:ab,ti OR atisuri:ab,ti OR bleminol:ab,ti OR caplenal:ab,ti OR capurate:ab,ti OR cellidrin:ab,ti OR embarin:ab,ti OR foligan:ab,ti OR hamari:ab,ti OR jenapurinol:ab,ti OR lopurin:ab,ti OR lysuron:ab,ti OR milurit:ab,ti OR milurite:ab,ti OR novopurol:ab,ti OR progout:ab,ti OR 'pan quimica':ab,ti OR pureduct:ab,ti OR purinol:ab,ti OR remid:ab,ti OR rimapurinol:ab,ti OR roucol:ab,ti OR suspendol:ab,ti OR tipuric:ab,ti OR uribenz:ab,ti OR uridocid:ab,ti OR uripurinol:ab,ti OR urosin:ab,ti OR urtias:ab,ti OR xanthomax:ab,ti OR xanturic:ab,ti OR zyloprim:ab,ti OR zyloric:ab,ti AND febuxostat:ab,ti AND gout:ab,ti AND ('cost-benefit analysis':ab,ti OR 'cost benefit':ab,ti OR 'cost benefit analysis':ab,ti OR 'cost effectiveness':ab,ti OR 'cost-benefit data':ab,ti OR 'cost-effectiveness analysis':ab,ti OR 'cost-utility analysis':ab,ti OR 'economic evaluation':ab,ti OR 'marginal analysis':ab,ti 20