Osteoarthritis is the most common joint disease and a major cause of functional disability and impaired quality of life.1 It is one of the most common reasons for visits to primary care and has a high socioeconomic impact2 with an estimated annual cost of € 1502 per patient, resulting in a total expense of 511billion euros a year in Spain.3 It occurs in all populations and its incidence increases with age. It is estimated to affect 85% of the elderly population and disables 10% of people over 60 years, mainly women.2 The prevalence of knee and hands osteoarthritis in the Spanish population was estimated at 10.2% and 6.2%, respectively.1

The goals of osteoarthritis treatment are to relieve pain, improve joint function and delay disease progression in terms of structural joint damage, preventing the toxic effects of treatment. In choosing the therapeutic strategy, clinicians can turn to the recommendations of the European League Against Rheumatism (EULAR),4 and the American College of Rheumatology (ACR),5 as well as the consensus documents of the Spanish Society of Rheumatology (SER)6 or to the guidelines of the Osteoarthritis Research Society International (OARSI).7

Most of the therapeutic goals can be achieved by treatment with various non-selective nonsteroidal anti-inflammatory drugs (NSAIDs). However, NSAID use is frequently associated with gastrointestinal disorders (GI) which can range from mild discomfort to severe adverse events such as perforations and bleeding; this is associated with a high consumption of health resources.8 Concomitant administration of proton pump inhibitors (PPIs) has shown an inverse relationship with the development of GI episodes, strongly influenced by the adherence to PPIs.9

The introduction of selective cyclooxygenase inhibitors 2 (ICOX-2) of similar efficacy provided an interesting alternative for improving the toxicity profile in terms of GI events compared to traditional NSAIDs. However, their widespread use has been associated to an increase of cardiovascular events (CV), some of which also involve traditional NSAIDs, with the possible exception of naproxen, which has not been associated with increased cardiovascular events.10

Therefore, strategies can be employed with NSAID use, both traditional and ICOX-2 of similar efficacy but different safety profiles, which affect the quality of life related to the health of patients with osteoarthritis.

The fact that health care resources are limited requires that prescription be an act that considers the most effective among the available drugs and selects the most effective in treating the disease in question, prescribing that which enables a lower incremental cost per additional unit of effectiveness.

The fixed dose combination of naproxen and esomeprazolea (naproxen/esomeprazole) combines the efficiency of naproxen as an NSAID, with a lower incidence of NSAID-associated ulcers and better tolerated in the upper digestive tract, due to its association to esomeprazole, a PPI.11 Its efficacy in osteoarthritis is equivalent to ICOX-2 and has proven to maintain its profile of GI and CV safety, even in the long term.12

The objective of this analysis was to conduct an assessment of the efficiency of naproxen/esomeprazole as an alternative therapy in patients with osteoarthritis compared to other NSAIDs available in Spain, both traditional and ICOX-2, alone or administered with a PPI.

At the end of the 12-month simulation and 6 months of treatment, naproxen/esomeprazole resulted in a (more effective and less associated cost) than the celecoxib, etoricoxib and diclofenac+PPI dominant strategy. Whereas an efficiency threshold € 30000/QALY is an acceptable additional value of willingness to pay, naproxen/esomeprazole would be cost-effective regarding ibuprofen+PPI and naproxen+PPI strategy. Celecoxib+PPI and etoricoxib+PPI were more effective than naproxen/esomeprazole strategies, which prevented the calculation of the ICER of naproxen/esomeprazole with respect to them with the proposed formula for this calculation. These results are detailed in Table 5.

In all deterministic sensitivity analysis performed (Table 6), the results of naproxen/esomeprazole remained: dominant vs celecoxib and etoricoxib, cost-effective compared to ibuprofen+PPI and naproxen+PPI and showing no change vs diclofenac+PPI, becoming cost-effective in reducing treatment to 3 months and reducing the costs of episodes by 10%. We performed two separate PSA vs the options for naproxen/esomeprazole and that proved cost-effective in the baseline case, ibuprofen+PPI and naproxen+PPI. In the PSA, after 10000 simulations, the average ICER, naproxen/esomeprazole stood at 18436 and € 6367/additional QALY vs+ibuprofen+PPI and naproxen+PPI respectively, 66.4% and 98.3% of cases were considered cost-effective (below the threshold of € 30000/additional QALY), respectively for each strategy (Figs. 2 and 3).

Fig. 2.

Plot of cost-effectiveness of naproxen/esomeprazole. The cost-effectiveness plane represents the results of the PSA. Each point represents a value of ICER, of each of the 10000 Monte Carlo simulations performed.

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Fig. 3.

Acceptability curve of naproxen/esomeprazole. The acceptability curve reflects certain thresholds for willingness to pay (from 0 to 50000 € represented on the horizontal axis), the proportion (on the vertical axis) of the 10000 ICER values obtained in the PSA that would be less than that determined threshold, considered cost effective.

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NSAIDs, both non-selective as well as those selective for inhibition of COX-2, are effective therapeutic alternative in the treatment of osteoarthritis. However, tolerability and GI and CV safety factors associated with its use in certain populations contraindicate their use or require appraisal of the individual profile of benefit/risk for each patient. Thus, although ICOX-2 reduces the risk of gastrointestinal complications, they have not shown, on occasion, a suitable CV safety profile. Conversely, naproxen is a therapeutic agent with a good CV safety profile at doses of 500mg/12h, but does not have this profile regarding the digestive tract. It seems logical that the latter risk reduction (with the addition of esomeprazole) would give naproxen a role in the symptomatic treatment of osteoarthritis, and that this would be an efficient therapeutic choice.

The many potential variables in the GI and CV risk for each patient makes assignment of the best therapeutic strategy based on existing resources difficult, so that an indicator such as ICER, which combines clinical and economic outcomes relative to different therapies, is very interesting.

The ICER of naproxen/esomeprazole was favorable, even in the analysis of sensitivity compared to other options, except for the treatment ICOX-2+PPI. The initial advantage of ICOX-2 came from the lack of need, due to their lower rate of GI events, of concomitant use of a PPI, although in recent times there has been a change in clinical practice, with the recommendation of using ICOX-2+PPI in elderly patients with a history of gastrointestinal bleeding and the presence of multiple risk factors.26

The results are important from the point of view of clinical practice. The patient with osteoarthritis is usually elderly and has chronic multiple comorbidities including pathologies, usually CV and include gastrointestinal manifestations. Numerous studies have stratified these risks in said population and have established indication for NSAIDs in order to minimize the impact of adverse events.26,27 The availability of a fixed combination of a highly effective NSAID with excellent CV profile, such as naproxen, along with a powerful PPI, might be able to mitigate its digestive impact by itself, according to the authors, becoming a good alternative. The analysis performed in this study further corroborates, from the pharmacoeconomic point of view, its favorable clinical medicine perspective.

This work is not without some limitations, some inherent to the theoretical association or to the use of decision analytic models, simulations that may not be an accurate reflection of clinical practice.

The validity and quality of decision analytical studies lie in their programming, as well as in the assumptions made and the values for the parameters included under consideration. In the development of economic evaluations it is crucial that the model has clinical sense and that the data comes from reliable and verifiable, preferably published sources.

This model was developed with the baseline assumption of equivalence in terms of efficacy of all treatments included, so that the differences between the evaluated strategies lie in the differences in costs and rates of adverse events. The decision on inclusion of clinical episodes was made considering the clinically relevant and data availability required13 for the episodes. The equivalence in efficacy, if not exact, could be a bias of the design, but in the absence of proven evidence from controlled head-to-head trials it has to be understood as a reasonable premise.13 The adjustment made in relation to the dose and the occurrence of clinical events that are handled in the model represents a limitation, although the methodology is consistent with that used in other studies which concluded that the uncertainty associated with this parameter did not influence the14 results.

In the absence of specific data concerning Spanish population it was necessary to use utility values per age obtained from the UK population. Utilities, associated with cultural factors, may differ even between countries in the same environment, but the sensitivity analysis, changing the values of earnings per episode, showed no influence of this parameter on the results.

Additionally, the fact that in each 3 month cycle the patient may only experience one GI or CV episode must be considered. This assumption may not be entirely realistic, but its adoption was necessary to build the model, also considering the generation of no significant impact on the results.13

The limitations described were offset by conservative assumptions and tested in sensitivity analyzes, showing no significant influence on the meaning of the results.

There are several publications on economic evaluations of treatments used in osteoarthritis, both internationally and in the14 Spanish context,20,28,29 although, to the authors’ knowledge, this is the first cost-utility analysis of naproxen/esomeprazole over other ICOX-2 NSAIDs or adapted to Spain, also individualized for each NSAID, instead of treating all NSAIDs as a group.

The results obtained from the analysis of a hypothetical cohort of patients with a decision analytic model suggest that naproxen/esomeprazole is an appropriate therapeutic option that is dominant over other strategies available, such as celecoxib, etoricoxib and diclofenac+PPI; and also using the standard reference threshold € 30000/additional QALY,30,31 showing it as a cost-effective strategy against both the option prescribed in clinical practice (ibuprofen+PPI) compared to the option of separate single-components (naproxen+PPI).

IO and MAC are PORIB employees, a consultant agency specialized in the area of economic evaluation of health technologies, have received unconditional funding for this analysis from AstraZeneca.

JSC and MC are employees of AstraZeneca.

JT, AL and JLZ have worked as clinical experts in the validation of the values of the parameters used in the analysis, and therefore claim to have received unconditional funding from AstraZeneca, which never influenced the participation and results obtained.