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NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity

NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity
Literature review current through: Jan 2024.
This topic last updated: Jul 24, 2023.

INTRODUCTION — Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, cause considerable morbidity and mortality related to gastric and duodenal mucosal toxicity, particularly by causing gastrointestinal (GI) bleeding [1]. NSAIDs are also important causes of GI bleeding in children [2].

This topic will review the treatment of gastroduodenal toxicity associated with NSAID therapy, and the secondary prevention of recurrent gastroduodenal toxicity associated with NSAID, low-dose aspirin, or both therapies. The pathogenesis, risk factors, manifestations and primary prevention of aspirin/NSAID-related gastroduodenal toxicity are discussed separately. (See "NSAIDs: Adverse effects on the distal small bowel and colon" and "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity" and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

MANAGEMENT

Discontinuation of aspirin/NSAIDs — If a patient develops a gastric or duodenal ulcer while on an NSAID or low-dose aspirin, the NSAID or aspirin should be stopped if at all possible. If the patient has been taking low-dose aspirin for prophylaxis of cardiovascular disease, there is no consensus as to when to resume the aspirin. The indication for the low-dose aspirin should be reviewed and the severity of the ulcer presentation considered. For most patients, the author recommends low-dose aspirin, if still indicated, be restarted approximately three to five days after initiating therapy with a proton pump inhibitor (PPI).

Evaluation for and eradication of H. pylori — As in all patients with peptic ulcers, the patient's Helicobacter pylori (H. pylori) status should also be assessed (if not done previously) [3]; if positive, appropriate therapy for H. pylori should be instituted [4]. However, the sensitivity of H. pylori testing in the setting of acute GI bleeding is significantly reduced. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults", section on 'Patient undergoing upper endoscopy' and "Treatment regimens for Helicobacter pylori in adults".)

Gastric acid suppression

Choice of therapy — For patients who must remain on low-dose aspirin, NSAID therapy, or both, randomized trials have shown that ulcer healing occurs more rapidly with a PPI than an H2 receptor antagonist (H2RA), misoprostol, or sucralfate [5-11]. The table lists the available medications and their usual dose (table 1). (See "Peptic ulcer disease: Treatment and secondary prevention".)

Multiple randomized trials comparing PPIs with an H2RA have demonstrated faster healing with the use of PPIs. While these trials were usually performed with ranitidine, an H2RA that has since been withdrawn due to unacceptable levels of N-nitrosodimethylamine (NMDA), the results are generalizable to other H2RAs due to their comparable efficacy [8,9,12]. In one illustrative trial, 541 patients who had ulcers or numerous (>10) erosions in either the stomach or duodenum and who required continuous treatment with NSAIDs were randomly assigned to treatment with omeprazole (20 or 40 mg orally daily) or ranitidine for four or eight weeks [8]. At eight weeks, endoscopic healing rates were higher with both doses of omeprazole as compared with ranitidine (80 and 79 versus 63 percent). (See "Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on 'Adverse effects'.)

Duration of treatment — Treatment with a PPI is generally continued for four to eight weeks depending on the ulcer location, size, and severity of the initial clinical presentation. In general, we suggest PPI therapy (eg, omeprazole 20 to 40 mg daily or equivalent dose of an alternative PPI) for four to six weeks for ulcers <1 cm (especially for duodenal ulcers) and PPI therapy for six to eight weeks for ulcers ≥1 cm (especially for gastric ulcers) (table 1).  

Maintenance PPI therapy is indicated in patients who must remain on or resume low-dose aspirin or NSAIDs. The benefits of PPI maintenance therapy for secondary prevention of NSAID- or low-dose aspirin-associated ulcers considerably outweigh potential risks of long-term PPI therapy [13]. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Adverse effects'.)

Endoscopic follow-up — Endoscopic follow-up to assess ulcer healing is usually unnecessary for duodenal ulcers, but should be performed to assess healing of gastric ulcers if there had been any concern that malignancy had not been excluded at the initial endoscopy. (See "Peptic ulcer disease: Treatment and secondary prevention", section on 'Repeat upper endoscopy in selected patients'.)

SECONDARY PREVENTION OF GASTRODUODENAL TOXICITY — Prevention of recurrent ulcer disease becomes critically important in patients with a history of gastroduodenal toxicity from NSAIDs, low-dose aspirin, or both therapies, and who require continued therapy. Only randomized secondary prevention trials using clinical ulcer disease as the outcome (rather than an endoscopic outcome) are discussed below.

Assess the risks and benefits of continued asprin/NSAID use and risk of toxicity — In patients on aspirin and NSAIDs, the indications for use, the availability of alternatives agents, and risk factors for bleeding should be considered when deciding on their use. Assessment of gastroduodenal toxicity risk is discussed in detail separately. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity", section on 'Assessment of gastroduodenal toxicity risk'.)

As an example, patients treated with low-dose aspirin have an increased risk of gastrointestinal (GI) bleeding, which must be weighed against a possible reduction in cardiovascular mortality [14]. The risk of recurrent bleeding in aspirin users may be higher in patients without a past or current H. pylori infection [15]. Risks of stopping low-dose aspirin were addressed in a randomized trial of 156 adults with cardiovascular or cerebrovascular disease who were being treated with low-dose aspirin and developed peptic ulcer bleeding. After control of bleeding with endoscopic therapy and use of a proton pump inhibitor (PPI), patients were assigned to continue taking aspirin (80 mg per day) or to stop the aspirin and switch to a placebo for eight weeks. Stopping aspirin therapy was associated with a nonsignificant decrease in the primary endpoint of recurrent ulcer bleeding within 30 days (5.4 percent versus 10.3 percent with continued aspirin therapy). Stopping aspirin was also associated with a significant increase in the secondary endpoint of overall mortality at eight weeks (12.3 versus 1.3 percent) [16]. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease", section on 'Efficacy'.)

Prevention strategies based on type and duration of exposure

Patients on low-dose aspirin — Patients who require low-dose aspirin for cardiovascular prophylaxis and have had a bleeding ulcer while taking low-dose aspirin should be treated with a PPI (rather than an H2-blocker), along with H. pylori eradication if they test positive for H. pylori [17]. There are no compelling data that suggest that any of the available PPIs are more effective than another. The table lists the available medications and their usual dose (table 1). Randomized trials support the efficacy of PPI therapy in preventing recurrent bleeding in both H. pylori positive and negative patients with peptic ulcers receiving low-dose aspirin therapy [17-23]. In one illustrative trial, in which 123 patients with a history of peptic ulcer complications after using low-dose aspirin were assigned to lansoprazole daily or placebo, in addition to 100 mg of aspirin daily, for 12 months, recurrence of ulcer complications (bleeding, perforation, or obstruction) were significantly lower with concurrent PPI use (2 versus 15 percent) [19].

Patients who require NSAIDs — For patients who require an NSAID and are at high risk for recurrent GI toxicity or are on concomitant low-dose aspirin, selecting celecoxib (or another COX-2 selective agent, if available) plus a PPI can reduce recurrent bleeding ulcers. Long-term maintenance PPI therapy should be continued for risk reduction while on aspirin/NSAIDs [18]. Nevertheless, recurrent GI bleeding remains a concern in such patients. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity", section on 'Assessment of gastroduodenal toxicity risk'.)

Substituting a COX-2 inhibitor for the prior nonselective NSAID in patients with NSAID-related ulcer disease and ulcer complications should not be chosen over PPI maintenance therapy. This was demonstrated in a trial of 273 arthritis patients with NSAID-related bleeding ulcers [24]. Once the ulcers had healed, substituting celecoxib 200 mg twice daily plus esomeprazole (20 mg twice daily) for a year was significantly more effective in preventing recurrent bleeding ulcers than simply substituting celecoxib (plus placebo twice daily) for the NSAID that the patient had been taking previously [24]. Ulcer rebleeding rates after a median follow-up period of 13 months were 0 percent in the celecoxib/esomeprazole group and 8.9 percent in the celecoxib/placebo group.

In patients who require both an NSAID and low-dose aspirin and are at high risk of GI toxicity, a selective COX-2 inhibitor plus a PPI is preferred over a nonselective COX inhibitor plus a PPI as this can decrease the risk of ulcer bleeding. In a randomized trial, 514 patients with bleeding gastroduodenal ulcers related to NSAID and low-dose aspirin use were placed on celecoxib (COX-2 selective) plus esomeprazole or naproxen (COX nonselective) plus esomeprazole once the ulcer had healed [25]. Patients in both groups continued taking low-dose aspirin. Rates of recurrent ulcer bleeding over the ensuing 18 months were significantly lower in the celecoxib group than in the naproxen group (5.6 versus 12.3 percent) [25]. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: NSAID-related ulcer complications".)

SUMMARY AND RECOMMENDATIONS

Management of gastroduodenal NSAID injury

Discontinue of aspirin/NSAID – For patients who develop a symptomatic gastric or duodenal ulcer while on a nonsteroidal anti-inflammatory drug (NSAID) and/or low-dose aspirin, NSAIDs and/or aspirin should be discontinued.

Acid suppression with PPI therapy – For patients with gastroduodenal toxicity (ulcers or erosions), we recommend acid suppression therapy with a proton pump inhibitor (PPI) rather than an H2 receptor antagonist (Grade 1B). The duration of acid suppression therapy with a PPI is based on whether aspirin/NSAIDs can be discontinued. In general, we use PPI therapy (eg, omeprazole 20 to 40 mg daily or equivalent dose of an alternative PPI) for four to six weeks for ulcers <1 cm (especially for duodenal ulcers) and PPI therapy for six to eight weeks for ulcers ≥1 cm (especially for gastric ulcers). (See 'Management' above.)

Test and treat H. pylori – The patient's H. pylori status should also be assessed; if positive, appropriate therapy should be instituted. Eradication of H. pylori should be confirmed. (See "Treatment regimens for Helicobacter pylori in adults" and "Indications and diagnostic tests for Helicobacter pylori infection in adults", section on 'Patient undergoing upper endoscopy'.)

Secondary prevention in patients who resume aspirin and/or NSAIDs

For patients with symptomatic gastroduodenal ulcers or multiple erosions who must continue NSAIDs or low-dose aspirin therapy, or both, we recommend treatment with a PPI (table 1) (Grade 1B). We continue PPI therapy for as long as the NSAID and/or aspirin is used.

For patients who are at high risk for gastroduodenal toxicity on low-dose aspirin for cardiovascular prophylaxis, selecting celecoxib (or another COX-2 selective agent, if available) plus a PPI may be more effective than using a nonselective NSAID plus a PPI in reducing recurrent bleeding ulcers. Nevertheless, recurrent GI bleeding remains a concern in such patients.

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