Maintenance treatment with esomeprazole following initial relief of non-steroidal anti-inflammatory drug-associated upper gastrointestinal symptoms: the NASA2 and SPACE2 studies

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 (COX-2) inhibitors, cause upper gastrointestinal (GI) symptoms that are relieved by treatment with esomeprazole. We assessed esomeprazole for maintaining long-term relief of such symptoms. Six hundred and ten patients with a chronic condition requiring anti-inflammatory therapy who achieved relief of NSAID-associated symptoms of pain, discomfort, or burning in the upper abdomen during two previous studies were enrolled and randomly assigned into two identical, multicentre, parallel-group, placebo-controlled studies of esomeprazole 20 mg or 40 mg treatment (NASA2 [Nexium Anti-inflammatory Symptom Amelioration] and SPACE2 [Symptom Prevention by Acid Control with Esomeprazole] studies; ClinicalTrials.gov identifiers NCT00241514 and NCT00241553, respectively) performed at various rheumatology, gastroenterology, and primary care clinics. Four hundred and twenty-six patients completed the 6-month treatment period. The primary measure was the proportion of patients with relapse of upper GI symptoms, recorded in daily diary cards, after 6 months. Relapse was defined as moderate-to-severe upper GI symptoms (a score of more than or equal to 3 on a 7-grade scale) for 3 days or more in any 7-day period. Esomeprazole was significantly more effective than placebo in maintaining relief of upper GI symptoms throughout 6 months of treatment. Life-table estimates (95% confidence intervals) of the proportion of patients with relapse at 6 months (pooled population) were placebo, 39.1% (32.2% to 46.0%); esomeprazole 20 mg, 29.3% (22.3% to 36.2%) (p = 0.006 versus placebo); and esomeprazole 40 mg, 26.1% (19.4% to 32.9%) (p = 0.001 versus placebo). Patients on either non-selective NSAIDs or selective COX-2 inhibitors appeared to benefit. The frequency of adverse events was similar in the three groups. Esomeprazole maintains relief of NSAID-associated upper GI symptoms in patients taking continuous NSAIDs, including selective COX-2 inhibitors.

Figures

Figure 1

Flow diagram of patients through the studies. E20, esomeprazole 20 mg; E40, esomeprazole 40 mg; ITT, intention-to-treat; NSAID, non-steroidal anti-inflammatory drug.

Figure 2

Estimated proportion of patients with relapse of upper gastrointestinal symptoms. Kaplan-Meier life-table analyses of the proportion of patients with relapse of pain, discomfort, or burning in the upper abdomen throughout 6 months of treatment with esomeprazole 20 mg (E20), esomeprazole 40 mg (E40), or placebo (a) for all patients, (b) according to treatment in the acute and maintenance studies, (c) for non-selective non-steroidal anti-inflammatory drug (NSAID) users, and (d) for selective cyclo-oxygenase-2 (COX-2) NSAID users (pooled intention-to-treat population). Diary card data were not available for 10 patients (placebo, n = 2; esomeprazole 20 mg, n = 6; esomeprazole 40 mg, n = 2). §p = 0.006, ¥p = 0.001, ‡p = 0.03, *p = 0.02, ¶p = 0.08, †p = 0.01, all versus placebo. CI, confidence interval.

Figure 3

Proportion of patients with investigator-assessed symptoms in the week preceding the 6-month visit (pooled intention-to-treat population). Numbers (n) relate to patients without the individual symptom upon entering the 6-month maintenance phase. †p = 0.02, ¥p = 0.002, ‡p = 0.003, §p = 0.0001, ****p < 0.0001, all versus placebo.

Figure 4

Score changes in patient-reported outcome scales. Mean (and standard error) score change in (a) Gastrointestinal Symptom Rating Scale (GSRS) and (b) Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire (pooled intention-to-treat population).