aspirin in elderly may increase serious falls

 A recent randomized clinical trial found that low-dose aspirin is associated with increased risk of serious falls in the elderly (see aspirin elderly inc serious falls jama2022 in dropbox, or doi:10.1001/jamainternmed.2022.5028) 

 

Details: 

-- the ASPREE-FRACTURE study was a sub-study of the Australian component of the larger ASPREE study 

-- 16,703 community-dwelling volunteers aged at least 70 were recruited from 2010-2014; all were free of cardiovascular disease, dementia, or physical disability at baseline

-- median age of 74 (IQR 72-78), 50% were 70-74 years old, 46% 75-84 yo, 5% >84 yo; 55% women; 32% living at home alone, 68% living with family/friends/spouse; BMI 27 

-- current smokers 3.4% , current alcohol use 84%, depression 24%, cancer history 20%, hypertension 75%, osteoarthritis 56%, history of a prior broken bone 38% 

-- frailty (as defined by the Fried criteria):  not frail 62%/pre-frail 36%/frail 2%, 98% reported no difficulty with walking or bathing, 14% reported their health status as excellent/48% very good/33% good 

-- intervention: daily enteric-coated aspirin 100 mg versus an identical enteric-coated placebo 

 

-- all participants had to adhere to a 4-week run-in medication trial before being enrolled into the study 

-- primary outcome: occurrence of any fracture, including vertebral, hip, and other fractures (including traumatic and pathological), confirmed by medical imaging 

-- secondary outcome: serious fall resulting in hospital presentation

-analysis was adjusted for age, use of medications that affect bone structure and mineralization, malignant neoplasm, alcohol intake, and smoking status; predefined subgroups for analysis included osteoarthritis, age group, gender, BMI, alcohol use, smoking, frailty, health status by self-report, use of medication affecting bone mineral density, and use of antihypertensives 

 

Results: 

-- annual pill counts (medication adherence) were similar in both the aspirin and placebo groups, approximately 73% 

-- 2865 fractures and 1688 serious falls occurred over a median follow-up of 4.6 years (yielding 76,219 total person-years of follow-up) 

    -- risk of first fracture: no difference, HR 0.97 (0.87-1.06), p=0.50 

        -- no difference was seen for either first or recurrent fracture events 

        -- none of the predefined subgroups had a significant difference in comparing aspirin with placebo 

    -- risk of serious falls, aspirin versus placebo: 884 versus 800 falls, 17% more if on aspirin, incidence rate ratio 1.17 (1.03-1.33), p=0.01 

    -- the aspirin group had increases for either one or two serious falls 

    -- the risk of falls associated with fracture was not different between groups, though there was a 29% increased risk in falls without fracture, HR 1.29 (1.07-1.55), p=0.004 

        -- there was a statistically increased risk of serious falls in those 75-84 years old (17% increased risk), those underweight (82% increased risk) and those who stated their health status was fair to poor (52% increased risk). However the vast majority of all of the subgroups assessed had strong trends to higher risk with aspirin though not reaching statistical significance 

-- the above results for fractures and serious falls remained unchanged in analyses that adjusted for the covariates (noted above) known to influence fracture and fall risk 

 

Commentary: 

-- falls and fractures are quite frequent in the elderly population; the Global Burden of Disease Study in 2017 estimated that the burden of disease ranked falls 17^th for the male population and 25^th for the female population 

    -- it is estimated that globally there are more than 1.6 million people annually with fractures and 700,000 related deaths, with 95% of the fractures being due to falls. And these numbers are likely to increase with the increasingly aging population 

-- prior literature had suggested that aspirin was protective from fracture: a recent systematic review of observational trials found a 17% lower odds of fractures, though there was not much difference in bone mineral density (though it should be pointed out that BMD is a gross measurement of bone mineralization and does not provide information about the important bone microarchitecture which provides a lot of structural support). see https://bmjopen.bmj.com/content/10/2/e026876 , a study done by the same lead author as the ASPREE-FRACTURE one above

 

-- this large ASPREE-FRACTURE study found that those receiving aspirin were more likely to have a fall-related hospital presentation than those on placebo, with no significant change in actual fractures (as opposed to the apparent 17% protection found in the systematic review noted above). And their results were reinforced by the large number of people in the study, near-complete endpoint ascertainment and participant retention in the study, and the quality of their data. 

    -- In addition, the confidence intervals in their statistical calculations were quite narrow, also reinforcing the validity of the conclusions 

-- the findings in the study were not anticipated: to the extent aspirin decreased cardiovascular and cerebrovascular events, as well as perhaps reducing cognitive decline (though with mixed results for Alzheimer’s and vascular dementias), the fall risk shoud be less with aspirin. [The ASPREE trial, as one example, did not find any decrease in dementia: see aspirin not dec dementia Neurol2020 in dropbox, or doi.org/10.1212/WNL.0000000000009277]

-- it is possible that the increased risk of falls necessitating hospital presentation was a result of aspirin leading to increased bleeding after the fall and the subsequent increased patient concern and hospital visitation

 

-- perhaps the most important conclusion for this study is that it reinforces another potential harm of aspirin therapy in those at high risk for cardiovascular disease. It is clear from more recent recommendations that aspirin should be reserved for those with documented cardiovascular disease and not as primary prevention in those at higher risk (see http://gmodestmedblogs.blogspot.com/2022/05/uspstf-aspirin-for-primary-cvd.html ) 

-- as another aspirin-related issue, several studies have suggested that the use of anticoagulation along with aspirin leads to more harms without benefit, except in the setting of a recent acute coronary syndrome or coronary stent placement, see http://gmodestmedblogs.blogspot.com/2021/04/aspirin-plus-doacs-equals-more-bleeding.html 

 

-- The authors do comment on the fact that US participants were not included in the study because we do not have sufficient available granular documentation here to verify fracture and serious fall events in the community (our system is so fragmented that there is no consistent, reliable, all-inclusive database for assessing important epidemiologic issues in the US, despite our having the most expensive health care system in the world, e.g. see https://www.hsph.harvard.edu/news/hsph-in-the-news/the-most-expensive-health-care-system-in-the-world/ ) 

 

Limitations: 

-- the study population above included basically white Australian patients who were pretty healthy. Unclear how this would generalize to other areas of the world or patients who were less healthy. It was notable that the relatively few people who thought their baseline health was fair to poor did seem to have higher fall risk with aspirin 

-- no granular data on the specifics of the falls, their intensity (eg traumatic vs with minor provocation), limiting a more complete understanding of the people who had the falls (and our ability to generalize the results to our patients)

-- since one quarter of participants did not adhere to their aspirin or placebo, it would be useful to know the results for those who did adhere (the "per protocol" group)

 

So, as happens relatively frequently, this well done RCT undercut the systematic review of 12 observational studies finding that aspirin had benefit in decreasing fracture risk (ie there was no reduction, though there was a decrease in falls), as well as undercutting data from in vitro studies suggesting that aspirin increased the lifespan of osteoblasts, impaired osteoclast activity, and promoted bone regeneration (all suggesting bone benefit). So, a few take-home messages here: 

-- observational studies are important and useful, but they do not rise to the level of import of good randomized controlled trials 

-- this study deflated the argument that aspirin was beneficial for bone health, and thereby added increased validity to avoiding aspirin for primary prevention of cardiovascular disease 

    -- and, it adds yet another reason to avoid aspirin use except for specific indications.  ie, we should probably stop the aspirin as primary prevention in our current patient caseload, as was based on older recommendations...

geoff

 

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