by Dr Geoffrey Modest
A prospective population-based cohort study of patients with vascular disease and on antiplatelet therapy (mainly low-dose aspirin) found a dramatic increase in the risk of bleeds in those over 75 years old, raising the question of whether we should be using proton-pump inhibitor (PPI) prophylaxis (see doi.org/10.1016/S0140-6736(17)30770-5)
Details:
— 3166 patients with vascular disease (defined as a 1st TIA, ischemic stroke, or MI and placed on antiplatelet therapy) in the Oxford Vascular Study from 2002 to 2012 were followed until 2013. 50% of the cohort were greater than 75 years old
— for the subgroup of patients < 75 years old:
— mean age 61, 65% male, 32% ischemic stroke/30% TIA/21% NSTEMI/17% STEMI, 97% on aspirin/3% nonaspirin antiplatelet therapy
— for those > 75 years old:
— mean age 83, 43% male, 42% ischemic stroke/27% TIA/23% NSTEMI/8% STEMI, 95% on aspirin/5% nonaspirin antiplatelet therapy
— the predominant aspirin formulation was 75 mg enteric-coated aspirin
Results:
— there were 405 1st bleeding events (187 major bleeds) during 13,509 patient years of follow-up in the cohort, at an average annual risk of 3.36%:
— 218 gastrointestinal
— 45 intracranial
— 142 other
— risk of non-major bleeding was unrelated to age, but major bleeding increased steeply with age, particularly in those > 75 years old, with no increase with age in patients < 70
— for those >75 yo vs <75 yo:
— major bleeding overall, HR 3.10 (2.27-4.24), p<0.0001 [ie, more than 3-fold the risk]
— fatal bleeds, HR 5.53 (2.65-11.54), p<0.0001
— major upper GI bleeds, HR 4.13 (2.60-6.57), p<0.0001; and fatal GI bleeds, HR 10.26 (4.37-24.13), p<0.0001.
— The annual risk of major bleeds increased steeply after age 70, reaching 4.1% at age 85 or older, with a similar pattern for both life-threatening and fatal bleeds. Those > 75 yo had more severe bleeds in those younger, p<0.0001. The outcome for nonfatal bleeds was also worse in the older group.
— Also, the proportion of those who survived extracranial bleeds which resulted in new or a sustained increase in disability increased with age, OR 12.8 (4.5-36.6), p<0.0001, comparing those > 75 vs <75 yo, especially in those with upper GI bleeds
— this analysis was similar if those on dual antiplatelet treatment (e.g. aspirin plus clopidogrel) were excluded
— the association of major bleeding with age were independent of sex, history of vascular disease, vascular risk factors, and history of peptic ulcer disease
— the absolute risks of major bleeding vs ischemic events increased with age. In the younger cohort this ratio was similar to those in prior aspirin trials. But the ratio increased from 0.19 in those younger than 75, to 0.32 in those 75 to 84, to 0.46 in those older than 85 [ie, the risk of major bleeds estimated to be attributable to antiplatelet treatment was approaching that of prevented ischemic events].
— The estimated number needed to treat (NNT) with routine PPIs to prevent one disabling or fatal upper GI bleed over 5 years would be 338 for individuals < 65 years old, but only 25 for individuals > 85 years old. The NNT to prevent one major upper GI bleed at 5 years was 80 for patients younger than 65, 75 for patients 65-74, 23 for patients 75-84 and 21 for patients greater than 85.
Commentary:
— given the high prevalence of vascular disease in people over 75, 40-66% of individuals in the US and Europe take aspirin or other antiplatelet drug for secondary prevention of vascular disease (and this does not include primary prevention use of aspirin!!!!). Guidelines in general do not recommend taking PPIs regularly, though a meta-analysis of randomized PPI trials vs placebo in patients on antiplatelet drugs, mostly aspirin, found a 74% reduction in upper GI bleeding (this was the number they used in estimating the preventive efficacy of PPIs above).
— The general basis for recommendations for use of antiplatelet agents is largely based on trials done in people < 75 years old (the mean age was 63, and most were < 75 yo).
— As a perspective in this study, PPIs would presumably only prevent upper GI bleeds, though 60% of all bleeds and 48% of major bleeds in the above study were non-upper GI bleeds
— assumptions in the above study, as noted by the authors, are that the efficacy of PPIs would be similar for the prevention of any bleed vs major bleed, similar at different ages, and remain consistent over time.
— I am very concerned about the role of H Pylori infections in predisposing patients to upper GI bleeds when they are on NSAIDs. An article in 1997 changed my practice to test and treat people prior to starting regular NSAID therapy (see Chan FKL Lancet 1997; 350: 975, which found that patients about to begin longterm NSAID therapy, had endoscopy, and those found to have asymptomatic H Pylori infection were then were randomized to either naproxen 750mg/d vs triple H Pylori therapy and then naproxen 750 mg/d, finding that on repeat endosopy 8 weeks later, 26% had ulcers in the naproxen only group whereas 3% had them after successful H Pylori treatment). Subsequently the 2008 Expert Consensus document by the Am Heart Assn and Am College of Gastroenterology recommended: “Testing for and eradicating H. pylori in patients with a history of ulcer disease is recommended before starting chronic antiplatelet therapy.” (see JACC 2008; 52: 1502). And another more recent article finding that those on low-dose aspirin who had H Pylori infection which had been eradicated had recurrent GI bleeds at the level of average-risk patients (see Chan FKL. GASTROENTEROLOGY 2013;144:528–535)
So, as per many prior blogs, I am concerned with long-term, wide-scale use of PPIs, in terms of significant adverse effects, as well as their profound effects on the microbiome. Given the rather compelling data from this study, it would be really great to have a randomized controlled trial in patients for both primary and secondary atherosclerotic disease prevention with aspirin, comparing PPI vs H2 blocker (fewer adverse longterm effects than PPIs) vs placebo, looking at both major GI bleeds as well as comparing them to the incidence of thromboembolic events. And, as per above comment, it would be great to either exclude those who were H Pylori positive, or treat them prior to aspirin therapy. My own practice in general, as mentioned in prior blogs, is to test and treat H Pylori infections, given their profound frequency in my patient population and the association with stomach cancer (I have had several older patients die from stomach cancer, which might have been prevented if H Pylori were diagnosed and treated earlier: eg see here ). Besides, it is always a tad unnerving when we have to prescribe a medication (which is not entirely benign) to counteract the effects of another medication. But, based on the study, it does seem reasonable to consider a PPI in those greater than 75 years old and on aspirin therapy.