1. CRITICAL APPRAISAL OF ARTICLE ON HARM

2. Among patients with acute rheumatic fever, will administration of non steroidal anti- inflammatory drugs have adverse effects? Clinical question patients with rheumatic fever taking NSAIDs Population: non steroidal anti-inflammatory drugs Intervention: Harm, complications Outcome: Incidence of Serious Upper Gastrointestinal Bleeding in patients taking Non Steroidal Anti-inflammatory Drugs in Japan Ishikawa SIshikawa S, Inaba T, Mizuno M, Okada H, Kuwaki K, Kuzume T,Inaba TMizuno MOkada HKuwaki KKuzume T Search terms: gastrointestinal bleeding, non steroidal anti-inflammatory drugs, salicylates, rheumatic fever

3. Relevance Yes. The objective of the study is to determine the annual incidence of serious upper gastrointestinal bleeding among Japanese patients in whom NSAIDs were used while the recommended treatment for our patient in this case which is salicylate falls under this drug family. (page 29,Abstract,1 st paragraph) Is the objective of the article similar to your dilemma?

4. Validity Yes. The investigator only included patients who were 30 – 70 yrs old, from both sexes who were taking NSAIDs for cardiovascular disease, cerebrovascular disease, arthritis, fever and pain control. The subjects were categorized as a) patients on low dose aspirin and b)patients on non aspirin NSAIDs. (page 30,Materials and Methods, 2 nd paragraph) (page 31,Results, 1 st paragraph) Were there clearly identified comparison groups? Yes. The exposures and outcomes were measured in the same way in the groups compared. The outcomes of all groups were determined through endoscopic examination of bleeding ulcers in all groups. (page 30, Materials and Methods, 4 th paragraph) Were the exposures and outcomes measured in the same way in the groups compared?

5. Yes. Follow up was done after two years from the start of administration of non steroidal anti – inflammatory drugs which is from June 2003 to June 2005. (page 30, Materials and Methods, 2 nd paragraph) 18,048 subjects were identified in the study. 629 were lost to follow up whie 148 died of other causes. Of the remaining 17,270, 8,815 periodically came for hospital visits, 7,613 returned after their last NSAID prescription, 992 were interviewed by telephone. They therefore have a 96 % follow up. (page 31, Results, 2 nd paragraph) Was follow-up sufficiently long and complete?

6. Yes. The study administered NSAIDs before any event of bleeding ulcer so the temporal relationship was correct. (page 30, Table 1) NSAIDs used in this study were low dose aspirin (80- 325 m; Bufferin 81mg and Bayaspirin, a 100mg enteric coated tablet) and other NSAID (page 30, Table 2) Is the temporal relationship between the exposure and outcome correct and dose response gradient present? Since all the answers for the validity guides are valid, the study can be considered valid. Overall, is the study valid?

7. Results Incidence rate for bleeding: 2.65 (95% CI, 2.56-2.74) per 1,000 patient years for low dose aspirin 1.29 (95% CI, 1.32) per 1,000 patient years non- aspirin NSAID users (page 33, Results, 2 nd paragraph) Incidence rate for bleeding: 2.65 (95% CI, 2.56-2.74) per 1,000 patient years for low dose aspirin 1.29 (95% CI, 1.32) per 1,000 patient years non- aspirin NSAID users (page 33, Results, 2 nd paragraph) What is the magnitude of the association between exposure and outcome? Was the estimate of the risk precise?

8. Clinical Applicability Yes. (page 30, Materials & Methods, 1 st paragraph) anti-inflammatory agent in the treatment of symptomatic acute rheumatic fever Incidence of assoc. upper GI ulcer bleeding was low and outcomes did not become serious when adequate measures were taken to prevent bleeding (page 33-34, Discussion) no alternative treatments mentioned recommended that anti-ulcer agents like PPIs or H2RA be co-administered to prevent serious adverse events associated with NSAID use (page 33, Discussion, 1 st paragraph) 28 year-old female cardiovascular problem chest pain, fever and arthritis mean age : 51.5± 20.7 years indications for NSAID (fever, pain, arthritis, CV disease Are the study patients similar to my own? What is our patient’s risk of benefit and harm from the exposure? What alternative treatments are available?

9. Resolution to the Scenario Based on the appraisal, the patient will be advised to continue treatment with aspirin or other non-aspirin NSAIDs provided that anti- ulcer agents like proton-pump inhibitors and H2 blockers are also administered.