Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use

Randomised controlled trials (RCTs) alone are unlikely to provide reliable estimates of the incidence of rare events because of their limited size. Co hort, case control, and other observational studies have large numbers but are vulnerable to various kinds of bias. Wanting to estimate the risk of de ath from bleeding or perforated gastroduodenal ulcers with chronic usage of non-steroidal anti-inflammatory drugs (NSAIDs) with greater precision, we developed a model to quantify the frequency of rare adverse events which fo llow a biological progression. The model combined data from both RCTs and o bservational studies. We searched systematically for any report of chronic (greater than or equal to 2 months) use of NSAIDs which gave information on gastroduodenal ulcer, bleed or perforation, death due to these complicatio ns, or progression from one level of harm to the next. Fifteen RCTs (19 364 patients exposed to NSAIDs for 2-60 months), three cohort studies (215 076 patients redeeming a NSAID prescription over a 3-12 month period), six cas e-control studies (2957 cases) and 20 case series (7406), and case reports (4447) were analysed. In RCTs the incidence of bleeding or perforation in 6 822 patients exposed to NSAIDs was 0.69%; two deaths occurred. Of 11 040 pa tients with bleeding or perforation with or without NSAID exposure across a ll reports, 6-16% (average 12%) died; the risk was lowest in RCTs and highe st in case reports. Death from bleeding or perforation in all controls not exposed to NSAIDs occurred in 18 out of 849 489 (0.002%). From these number s we calculated the number-needed-to-treat for one patient to die due to ga stroduodenal complications with chronic (greater than or equal to 2 months) NSAIDs as 1/((0.69 x {6-16%, average 12%}) - 0.002%)) = 909-2500 (average 1220). On average 1 in 1200 patients taking NSAIDs for at least 2 months wi ll die from gastroduodenal complications who would not have died had they n ot taken NSAIDs. This extrapolates to about 2000 deaths each year in the UK . (C) 2000 International Association for the Study of Pain. Published by El sevier Science B.V. All rights reserved.