NPC Archive Item: New evidence for naproxen/esomeprazole▼ combination in knee osteoarthritis.

25 November 2011

Two 12-week phase III studies found that a fixed-dose combination of naproxen and esomeprazole (Vimovo▼) had comparable upper gastrointestinal (GI) tolerability to celecoxib in people with osteoarthritis (OA) of the knee. However, there are no data to suggest that this fixed-dose combination offers any efficacy or safety advantages over the separate prescribing of naproxen 1000 mg daily plus a low-cost proton pump inhibitor (PPI) such as generic omeprazole. Separate prescribing allows for dose adjustment of individual components and is less expensive.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Action
Health professionals should follow NICE guidance on OA and our previous advice on the GI and cardiovascular (CV) risks of NSAIDs given in MeReC Extra 30 (November 2007). NICE recommends that, where an NSAID is obligatory, all NSAIDs used to treat OA (both coxibs and traditional NSAIDs) should be co-prescribed with a PPI, choosing the PPI with the lowest acquisition cost. Current low-cost PPIs are omeprazole, lansoprazole and pantoprazole.

Although coxibs (e.g. celecoxib) are associated with a lower risk of GI adverse effects than traditional NSAIDs when used without a PPI, there is no good evidence to suggest there are any differences in the GI risk of NSAIDs (coxibs or traditional NSAIDs) when prescribed with a PPI as per NICE guidance. Coxibs (and some traditional NSAIDs, particularly diclofenac) also have a higher CV risk than either ibuprofen (1200 mg daily or less) or naproxen 1000 mg daily. Therefore, prescribers should carefully consider the other potential side effects, particularly CV risks, when choosing an NSAID, taking account of individual patient risk factors. Generally, NSAIDs should be prescribed at the lowest effective dose and for the shortest period of time necessary to control symptoms, and reviewed regularly.

What is the background to this?
There are long standing and well recognised safety concerns with all NSAIDs (both coxibs and traditional NSAIDs) regarding GI, renal and CV adverse effects. Some NSAIDs have a higher GI risk than others — ibuprofen at 1200 mg daily or less is associated with the lowest risk of all traditional NSAIDs. As a class, coxibs have been found to have a lower risk of upper GI complications (e.g. perforation, ulcers, bleeding) than traditional NSAIDs as a class. However, coxibs (including celecoxib) and many traditional NSAIDs (including diclofenac) are associated with an increased risk of adverse CV events, particularly thrombotic events (e.g. myocardial infarction and stroke). Ibuprofen 1200 mg daily or less and naproxen 1000 mg daily appear to be associated with a lower CV risk.

PPIs have been shown to reduce the risk of NSAID-related gastric and duodenal ulcers, and dyspepsia. They are widely recommended to reduce the risk of GI adverse effects in obligate NSAID users, especially those at increased GI risk. NICE recommends that all NSAIDs (both coxibs and traditional NSAIDs) used to treat people with OA are co-prescribed with a PPI, choosing the PPI with the lowest acquisition cost. When a PPI is required, there is no evidence that any one PPI is more effective than the other when used at equivalent doses.

Evidence from a hospital-based, case-control study suggests that the considerable differences in the risk of GI bleeding between individual NSAIDs when used alone is negated by concomitant PPI use — i.e. there was no increased GI risk of NSAIDs plus a PPI over non-use of an NSAID. There is no good evidence to suggest that when given with a PPI, there are any differences between individual NSAIDs in terms of GI risk.

These two identical 12-week phase III studies compared the GI tolerability of a fixed-dose combination of enteric-coated naproxen 500 mg and esomeprazole 20 mg twice daily, with celecoxib 200 mg daily, and placebo, in people at least 50 years with symptomatic knee OA. This was a secondary outcome — primary efficacy outcomes were reported in a separate paper, where naproxen/esomeprazole was found to be non-inferior to celecoxib in reducing pain scores over 12 weeks.

What does this study claim?
These two 12-week studies (n= 614 and 610) claim that a fixed-dose combination of naproxen 500 mg/esomeprazole 20 mg twice daily has comparable upper GI tolerability to celecoxib 200mg daily alone in patients with OA. There were no significant differences in dyspepsia severity assessment scores and the incidence of upper GI adverse effects, but there were significantly more heartburn-free days with naproxen/esomeprazole, compared with celecoxib (all secondary outcomes – see study details for more information). There were no data on upper GI complications (e.g. perforation, ulcers, bleeding) or any CV outcomes in this study.

How does this relate to other studies?
Two other identical 6-month phase III studies (n= 434 and 420) found that the fixed-dose combination of naproxen 500 mg/esomeprazole 20 mg twice daily significantly reduced the incidence of endoscopic gastric ulcers, compared with naproxen 500 mg twice daily alone. These patients had OA, RA, ankylosing spondylitis or other conditions expected to require more than six months of NSAID therapy, and had a history of uncomplicated gastric or duodenal ulcer in the previous five years.

So what?
NICE guidance on the management of OA recommends that all NSAIDs (both coxibs and traditional NSAIDs) should be co-prescribed with a PPI, choosing the PPI with the lowest acquisition cost. There is no good evidence to suggest there are any differences in the GI risk of NSAIDs (coxibs or traditional NSAIDs) when prescribed with a PPI. Therefore, in these circumstances, it is the other potential side effects, particularly CV effects, that may concern prescribers when choosing an NSAID. Ibuprofen 1200 mg daily or less and naproxen 1000 mg daily appear to be associated with a lower CV risk. Coxibs and many traditional NSAIDs (including diclofenac) are associated with higher CV risk. See MeReC Extra 30 for more information.

In these two studies, choosing celecoxib alone as the comparator provides no useful information on whether or not the fixed-dose combination is more effective or better tolerated than either celecoxib or naproxen when prescribed separately with a low-cost PPI (as recommended by NICE). Furthermore, All NSAIDs should be prescribed at the lowest effective dose and for the shortest period of time necessary to control symptoms. There is a lack of flexibility of dosing with the fixed-dose combination andnaproxen 1000 mg daily may not be appropriate, or needed at that dose in some people. The Summary of Product Characteristics (SPC) states that in patients not treated with an NSAID previously, a lower daily dose of naproxen or of another NSAID should be considered. When the total daily dose of 1000 mg of naproxen is not considered appropriate, alternative therapeutic regimens should be utilised. In addition, the recommended dose of esomeprazole for NSAID prophylaxis is 20 mg daily, but patients using the combination product would receive 40 mg daily — double the recommended dose.

It has been suggested that there is poor adherence with concomitant gastroprotection and the combination ensures adherence to the PPI. This may potentially result in fewer upper GI complications and hospital admissions. However, there is no evidence to support this assumption. These two studies mainly reported outcomes related to tolerability (i.e. minor GI symptoms such as dyspepsia severity and heartburn-free days), but dyspeptic symptoms are a poor predictor of significant GI disease. We also do not know the clinical significance of lower dyspepsia severity scores, or fewer heartburn-free days.

Furthermore, NICE recommends the use of a PPI with lowest acquisition cost. Current low cost PPIs are omeprazole, lansoprazole, or pantoprazole. When used at doses recommended for NSAID prophylaxis, the cost of a low cost PPI plus generic naproxen 500 mg twice daily is approximately £5–6 for one months supply, compared with £14.95 for the combination naproxen/esomeprazole product (Source: BNF 62, September 2011). There is no evidence to suggest enteric-coated naproxen offers any advantages over generic naproxen when prescribed separately with a PPI.

The Scottish Medicines Consortium has not recommended the naproxen/esomeprazole fixed-dose combination (Vimovo) for use in NHS Scotland as the manufacturer did not present a sufficiently robust economic analysis. Note: SMC recommendations only apply in Scotland. The fixed-dose combination is licensed for the symptomatic treatment of OA, rheumatoid arthritis and ankylosing spondylitis, in patients who are at risk for developing NSAID-associated gastric and/or duodenal ulcers and where treatment with lower doses of naproxen or of other NSAIDs is not considered sufficient. It is under intensive surveillance by the MHRA and all suspected adverse drug reactions should be reported via the Yellow Card Scheme.

Study details
Cryer BL, Sostek MB, Fort JG, et al. A fixed-dose combination of naproxen and esomeprazole magnesium has comparable upper gastrointestinal tolerability to celecoxib in patients with osteoarthritis of the knee: Results from two randomized, parallel-group, placebo-controlled trials. Ann Med 2011;43:594–605

Design
Two identical 12-week double-blind, randomised, placebo-controlled, phase III studies.

Patients
614* patients (Study 1: PN400-307) and 610* patients (Study 2: PN400-309) aged at least 50 years with a 6-month history of symptomatic knee OA, who had been receiving a stable dose of NSAIDs (traditional NSAIDs or coxibs), or other oral analgesic therapy for at least six weeks. Exclusion criteria included patients with a history of hypersensitivity, allergy or intolerance to any PPI or NSAID (including aspirin), any GI disorder or surgery, history of peptic ulcer disease within six months prior to screening.

* The modified intention to treat population – i.e. all randomised patients who received at least one dose of study medication and provided at least one post-baseline efficacy evaluation.

Intervention and comparison
Enteric-coated naproxen 500 mg/esomeprazole magnesium 20 mg fixed-dose combination twice daily, compared with celecoxib 200 mg daily, or placebo.

Outcomes
Tolerability end-points included: dyspepsia severity (measured by a modified Severity Of Dyspepsia Assessment [mSODA tool]*), heartburn severity (measured by proportion of heartburn-free days on the heartburn severity patient questionnaire), incidence of patient reported pre-defined NSAID-associated upper GI adverse events, and discontinuations due to any adverse event or pre-defined NSAID-associated upper GI adverse event (all secondary outcomes).

* The mSODA tool consisted of six questions assessing dyspepsia-related upper abdominal pain intensity. Lower scores equate to lower dyspepsia severity.

Results
There were no significant differences in mean change from baseline to week 12 mSODA scores between groups, or in NSAID-associated upper GI adverse events. Discontinuations due to any adverse event were similar across all groups in study 1, but in study 2, fewer patients receiving placebo discontinued due to any adverse event, compared with naproxen/esomeprazole and celecoxib. There were also no differences in the incidence of adverse events. The greatest proportion of heartburn-free days was in the naproxen/esomeprazole groups of both studies.

Table 1. Results from study 1

Table 2. Results from study 2

Sponsorship: Pozen Inc. Pharmaceuticals. All authors were consultants or employees of Pozen or the UK manufacturer Astra Zeneca.

Further information can be found on NHS Evidence and in the musculoskeletal pain e-learning section of the NPC website.

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