Systematic Review and Meta-Analysis of Randomised Trials to Ascertain Fatal Gastrointestinal Bleeding Events Attributable to Preventive Low-Dose Aspirin: No Evidence of Increased Risk

Abstract

BackgroundAspirin has been shown to lower the incidence and the mortality of vascular disease and cancer but its wider adoption appears to be seriously impeded by concerns about gastrointestinal (GI) bleeding. Unlike heart attacks, stroke and cancer, GI bleeding is an acute event, usually followed by complete recovery. We propose therefore that a more appropriate evaluation of the risk-benefit balance would be based on fatal adverse events, rather than on the incidence of bleeding. We therefore present a literature search and meta-analysis to ascertain fatal events attributable to low-dose aspirin.MethodsIn a systematic literature review we identified reports of randomised controlled trials of aspirin in which both total GI bleeding events and bleeds that led to death had been reported. Principal investigators of studies in which fatal events had not been adequately described were contacted via email and asked for further details. A meta-analyses was then performed to estimate the risk of fatal gastrointestinal bleeding attributable to low-dose aspirin.ResultsEleven randomised trials were identified in the literature search. In these the relative risk (RR) of ‘major’ incident GI bleeding in subjects who had been randomised to low-dose aspirin was 1.55 (95% CI 1.33, 1.83), and the risk of a bleed attributable to aspirin being fatal was 0.45 (95% CI 0.25, 0.80). In all the subjects randomised to aspirin, compared with those randomised not to receive aspirin, there was no significant increase in the risk of a fatal bleed (RR 0.77; 95% CI 0.41, 1.43).ConclusionsThe majority of the adverse events caused by aspirin are GI bleeds, and there appears to be no valid evidence that the overall frequency of fatal GI bleeds is increased by aspirin. The substantive risk for prophylactic aspirin is therefore cerebral haemorrhage which can be fatal or severely disabling, with an estimated risk of one death and one disabling stroke for every 1,000 people taking aspirin for ten years. These adverse effects of aspirin should be weighed against the reductions in vascular disease and cancer.

Incidence of Upper and Lower Gastrointestinal Bleeding in New Users of Low-Dose Aspirin

“…A higher incidence of hospitalized UGIB was reported among low-dose aspirin users in Denmark (3.64 per 1000 person-years) using a prescription database and hospital discharge registry records with data collected from 1991 to 1995. 12 As expected by the low case fatality rates, the incidence of fatal UGIB and LGIB in our study cohort was substantially lower than the incidence of nonfatal events, in line with data from aspirin randomized controlled trials 14 and observational data from secondary prevention aspirin users. 8 The absolute rate of fatal GIBs in Elwood's meta-analysis of randomized controlled trial data was much higher at 0.37 per 1000 person-years than in our study cohort; the incidence of all GIBs was also substantially higher, at 8 cases per 1000 personyears.…”

“…Low case-fatality rates for GIBs have also been shown among individuals randomized to low-dose aspirin in clinical trials, especially among those without ischemic vascular disease. 14…”

“…There are few studies from observational cohorts of preventative low-dose aspirin users reporting incidence rates for UGIBs, [8][9][10][11][12] and even fewer for lower GIBs (LGIBs). 10,11,13 Furthermore, most have reported data only for hospitalized events in individuals without GI antecedents, [10][11][12][13] and while separate estimates for fatal and nonfatal GIBs are available from clinical trials, 14 there are few estimates from observational data. 8 There is therefore a need to obtain UGIB and LGIB incidence data, including by age and bleed severity, among real-world low-dose aspirin users, including those with previous GIBs or taking concomitant medications known to increase bleeding risk.…”

General Aspects of Primary Cancer Prevention

“…Longer use is likely to have greater benefits. The predominant adverse event caused by aspirin is GI bleeding, and there appears to be no valid evidence that the overall frequency of fatal GI bleeding is increased by daily low-dose aspirin [36,57,58]. On the other hand, recent populationbased study from the United Kingdom showed that lowdose aspirin was not associated with increased survival of patients diagnosed with esophageal or gastric cancer [59].…”

Low-dose aspirin and risk of upper/lower gastrointestinal bleeding by bleed severity: a cohort study with nested case-control analysis using primary care electronic health records from the United Kingdom

“…In addition to assessing bleeding risks according to the target population (primary or secondary CVD prevention), a full evaluation of low-dose aspirin-associated GI bleeding would cover the severity of bleeds (case-fatality, need for hospitalization) and the bleed location (upper or lower GI tract)data on low-dose aspirin-associated risks of lower GI bleeding are scarce. A recent metaanalysis of data from aspirin clinical trials (where doses ranged from 75 mg to 1900 mg daily) found no significant increase in the risk of fatal GI bleeds in subjects randomized to aspirin compared with placebo [14]. Using data from a validated UK primary care database -The Health Improvement Network (THIN)we aimed to quantify the association between new use of low-dose aspirin and risk of upper and lower gastrointestinal bleeding (UGIB/LGIB), including by level of healthcare assistance received (hospitalized or referred only), case-fatality, specific GI tract location, characteristics of aspirin (dose and duration) and according to primary/secondary CVD prevention population.…”