Randomised controlled trials (RCTs) alone are unlikely to provide reliable estimates of the incidence of rare events because of their limited size. Cohort, case control, and other observational studies have large numbers but are vulnerable to various kinds of bias. Wanting to estimate the risk of death 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 follow a biological progression. The model combined data from both RCTs and observational studies. We searched systematically for any report of chronic (>/=2 months) use of
NSAIDs which gave information on
gastroduodenal ulcer, bleed or perforation, death due to these complications, or progression from one level of harm to the next. Fifteen RCTs (19364 patients exposed to
NSAIDs for 2-60 months), three cohort studies (215076 patients redeeming a
NSAID prescription over a 3-12 month period), six case-control studies (2957 cases) and 20 case series (7406), and case reports (4447) were analysed. In RCTs the incidence of
bleeding or perforation in 6822 patients exposed to
NSAIDs was 0.69%; two deaths occurred. Of 11040 patients with
bleeding or perforation with or without
NSAID exposure across all reports, 6-16% (average 12%) died; the risk was lowest in RCTs and highest in case reports. Death from
bleeding or perforation in all controls not exposed to
NSAIDs occurred in 18 out of 849489 (0.002%). From these numbers we calculated the number-needed-to-treat for one patient to die due to gastroduodenal complications with chronic (>/=2 months)
NSAIDs as 1/((0.69x¿6-16%, average 12%¿)-0.002%))=909-2500 (average 1220). On average 1 in 1200 patients taking
NSAIDs for at least 2 months will die from gastroduodenal complications who would not have died had they not taken
NSAIDs. This extrapolates to about 2000 deaths each year in the UK.