How Safe is Long-term Antiplatelet Rx After a Vascular Event?

Should PPIs Be Routine with Aspirin?
o Guidelines recommend lifelong antiplatelet therapy after an MI or ischemic stroke[1,2]
. Recommendations mainly based on trials in people <75 years
o Aspirin (ASA) is associated with major bleeding, especially upper GI bleeds
. Concomitant proton pump inhibitors (PPIs) can decrease upper GI bleeds by 70%-90%
o PPIs not routinely co-prescribed with ASA
. Concerns about adverse effects with long-term PPI use
. GI bleeds thought to have low case-fatality rate, or mostly non-disabling
. Guidelines for secondary prevention of vascular events do not recommend concomitant PPIs

Oxford Vascular Study[3]
o Prospective cohort study in 9 general practices in Oxfordshire, UK between 2002-2012
o 3166 participants on antiplatelet therapy after first TIA, ischemic stroke, or MI:
. <75 years (n=1584): 97% on ASA
. ≥75 years (n=1582): 95% on ASA
o Overall 30% on antiplatelet therapy without concomitant PPI
o Face to face follow-up for 10 years

ASA-Associated Fatal or Disabling Bleeding Increases with Age
o Major Upper GI Bleeds: Annual risk over 4 times higher in ≥75 years vs <75 years (HR 4.13, 2.60–6.57; p<0.0001)
o Disabling Bleeds: Annual risk over 7.5 times higher in ≥75 years vs <75 years (HR 7.60, 3.74-15.47, p<0.0001)
o Fatal Bleeds: Annual risk 5.5 times higher in ≥75 years vs <75 years (HR 5.53, 2.65–11.54; p<0·0001)
o Disabling or Fatal Bleeds Combined: Annual risk over 10 times higher in ≥75 years vs <75 years (HR 10.26, 4.37-24.13; p<0.0001)

With Age Disability from Bleeds Increases, NNT with PPIs Decreases
o Odds of bleeds resulting in new or increased disability almost 13 times higher in ≥75 years vs <75 years (OR 12.8, 95% CI 4.5–36.6; p<0·0001)
. In ≥75 years, 62% (45/73) of major upper GI bleeds resulted in disability or death
. In >75 years, estimated 5-yr risk of major bleeds thought attributable to ASA approached the risk of ischemic events thought prevented by ASA
o Number needed to treat (NNT) with PPIs to prevent one disabling or fatal upper GI bleed over 5 years decreases with age:
. <65 years: NNT 338
. ≥ 85 years:  NNT 25

Limitations
o Observational design: cannot definitively say ASA caused increased risk of disabling/fatal bleeding risk with increasing age
o No estimate of number needed to harm due to adverse effects of PPIs
o Adjusted for known age, sex, risk factors for major and upper GI bleeding, residual confounding possible
. OTC NSAIDs may not have been included
o Predominant form of ASA, 75 mg enteric coated; results may not generalize to other antiplatelet therapy or countries that use other doses of ASA

People ≥75 Years Who Are on ASA Should Take PPIs
o Older patients on ASA without routine PPIs after TIA, MI, or stroke have a long-term risk for fatal or disabling bleeds that is higher than previously thought, compared to younger patients
o Risk of disabling and fatal bleeds associated with ASA increases with age, and may outweigh protective effect of ASA on ischemic events
o Authors propose an age-based criterion:
. Individuals aged 75 or older may be at high-risk for ASA-associated bleeding and should take PPIs

Take Home Points
o Real-world results from the Oxford Vascular Study showed annual risk of disabling or fatal bleeds associated with ASA for secondary prevention increases with age
o The odds that bleeds associated with ASA will result in new or increased disability are almost 13 times higher in ≥75 years vs <75 years
o Over half of major upper GI bleeds in people aged ≥75 years who are on ASA for secondary prevention result in disability or death
o The number needed to treat with PPIs to prevent one fatal or disabling upper GI bleed decreases with age
o Individuals who are age 75 or over and on ASA for secondary prevention should take PPIs

References
1. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45: 2160–2236.
2. Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113: 2363–2372.
3. Li L, Geraghty OC, Mehta Z, et al. Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study. Lancet. 2017 Jun 13. pii: S0140-6736(17)30770-5. doi: 10.1016/S0140-6736(17)30770-5.