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Is famotidine effective for preventing ulcers in patients receiving low-dose aspirin?

Introduction
Antiplatelet therapy is commonly used for the prevention of thrombotic events in patients with acute coronary syndrome (ACS).^1,2 To prevent recurrent cardiovascular events following unstable angina/non-ST elevation myocardial infarction, current guidelines recommend the use of aspirin with clopidogrel in patients treated either medically or with percutaneous coronary intervention.¹ There are safety precautions for aspirin and clopidogrel that warrant close monitoring in patients.² When used alone, aspirin and clopidogrel can cause gastrointestinal (GI) injury resulting in GI bleeding or impaired healing of gastric ulcers. The American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents, the American College of Gastroenterology, and the American Heart Association recommend treatment with a gastroprotective agent, preferably a proton pump inhibitor (PPI), to reduce GI complications associated with aspirin and clopidogrel in patients with risk factors such as dual antiplatelet therapy, GI bleeding, or history of ulcers.

It is important to note that proton pump inhibitors may interfere with the activation of clopidogrel by inhibiting cytochrome P450 (CYP) 2C19 enzymes.³ Consequently, PPIs may reduce the antiplatelet effects of clopidogrel resulting in diminished cardiac protection. Of the PPIs, omeprazole is said to be a potent CYP 2C19 inhibitor; whereas, pantoprazole is considered the weakest inhibitor. Data are conflicting regarding the presence of an interaction; the reader is referred to the Drug Information Group’s website for a review of the available literature (http://dig.pharm.uic.edu/faq/antiplatelet.aspx). In addition to the drug interaction with clopidogrel, there are concerns regarding long-term PPI use.⁴ Long-term treatment with PPIs has been associated with cancer, enteric infections, community-acquired pneumonia, nutritional deficiencies, and osteoporosis.

Due to the lack of CYP 2C19 inhibition, histamine H₂-receptor antagonists (H₂RAs) such as ranitidine, famotidine, and nizatidine have been suggested as possible alternatives to PPIs in patients taking clopidogrel; however, no data exist to support the efficacy of the H₂RAs for this purpose.³

Literature Review: the FAMOUS Trial
The objective of the FAMOUS trial was to assess the efficacy of famotidine for the prevention of peptic ulcers and esophagitis in adult patients taking low-dose aspirin (75 to 325 mg daily).⁵ In this randomized, double-blind, placebo-controlled trial, a total of 404 patients received either famotidine 20 mg twice daily (n=204) or matching placebo twice daily (n=200) for 12 weeks. Eligible patients included those who were in stable condition, had an indication for aspirin use for at least 12 weeks with or without mild to moderate dyspeptic or reflux symptoms, scars (gastric or duodenal), or erosions at baseline. Patients with current malignancy, a history of esophageal, gastric, or duodenal surgery, Zollinger-Ellison syndrome, or primary esophageal motility disorder were excluded from the study. Patients could continue other antiplatelet therapy such as clopidogrel. However, patients who used PPIs, H₂RAs, or sucralfate within 1 week of the first endoscopy, had been previously treated for Helicobacter pylori, or used warfarin, non-steroidal anti-inflammatory drugs, and other agents were disqualified for participation. Patients were excluded if the endoscopic findings revealed malignancy, erosive esophagitis, esophageal strictures, or ulcers (gastric or duodenal).

As the primary endpoint, the authors assessed the formation of new ulcers (size ≥3 mm) in the stomach or duodenum or erosive esophagitis week 12.⁵ The Lanza scores (grade 0: no abnormality; grade 1: single erosion; grade 2: 2 to 9 erosions; grade 3: ≥10 erosions; grade 4: ulcer)⁶ for gastric and duodenal erosions, abdominal and vascular symptom score, overall treatment assessment, and antacid consumption were evaluated as secondary endpoints. Endoscopic examinations were performed at baseline and week 12, and clinical assessments were performed at baseline and weeks 6 and 12.

Based on endoscopic findings at week 12, seven (3.4%) patients in the famotidine group developed gastric ulcers ≥3 mm compared to 30 (15%) of patients in the placebo group (odds ratio [OR] 0.20; 95% CI 0.09 to 0.47, p=0.0002).⁵ When compared to placebo, there were fewer patients in the famotidine group who developed duodenal ulcers ≥3 mm (1 [0.5%] vs. 17 [8.5%], OR 0.05; 95% CI 0.01 to 0.40, p=0.0045), erosive esophagitis (9 [4.4%] vs. 38 [19%], OR 0.20; 95% CI 0.09 to 0.42, p<0.0001), and erosive esophagitis and/or ulcer (12 [5.9%] vs. 66 [33%], OR 0.13; 95% CI 0.07 to 0.24, p<0.0001) as compared to placebo. For the secondary outcomes, more patients in the famotidine group had a Lanza score of 0 (no erosions or ulcers) in the stomach (p<0.0001) and in the duodenum (p<0.0001) than patients in the placebo group, and 40 (23.5%) of 170 patients who received famotidine reported better treatment assessment compared to 21 (14.6%) of 144 patients who received placebo (p=0.012). According to the appendix of the article, there were no differences between treatment groups in terms of antacid use or vascular and abdominal symptoms (numbers not provided). There were no significant differences between groups in terms of adverse events. The authors also evaluated adverse events in the patients taking concurrent clopidogrel; 5 (55.6%) of 9 patients in the famotidine group experienced adverse events compared to 6 (40%) of 15 patients in the placebo group (OR 0.90; 95% CI 0.58 to 1.40, p=0.6412). It is important to note that <20% of patients in both groups were receiving clopidogrel. The authors concluded that famotidine is effective for the prevention of peptic ulcers and esophagitis in patients taking low-dose aspirin, and that famotidine may be a potential alternative to PPIs.

Conclusions
The results from the FAMOUS trial were favorable for famotidine in the prevention of peptic ulcers and esophagitis thereby, increasing the therapeutic options for GI protection in patients taking low-dose aspirin. A majority of the patients (>90%) included in the trial were taking the lowest dose aspirin (75 mg). Therefore, these data cannot readily be applied to patients taking higher doses of aspirin. This trial was not powered to detect a difference in GI complications in patients taking aspirin plus clopidogrel. Finally, depsite the authors’ suggestion that famotidine may be a potential alternative to PPIs, the trial did not compare efficay of famotidine to that of the PPIs. Further comparative trials are need to establish such efficacy.

References