aspirin plus DOACs equals more bleeding, no benefit

 

A recent data-mining study found that the combination of direct oral anticoagulants (DOACs) plus aspirin (ASA) did not improve outcomes, but did increase the risk of bleeding (see cad aspirin and DOACs bleeding jamaintmed2021 in dropbox, or doi:10.1001/jamainternmed.2021.1197) 

 

Details: 

-- 3280 patients with atrial fibrillation or venous thromboembolic (VTE) disease, but without a recent MI or history of heart valve replacement, were followed in 4 anticoagulation clinics in Michigan, from January 2015 to December 2019 

-- mean age 68, 51% men, BMI>30 in 50%, alcohol or drug use 6%, tobacco current 9%/former 33% 

-- indications for DOAC: atrial fibrillation/flutter 61%, DVT/PE 40% 

-- comorbidities: CAD 15%, cancer 22%, heart failure 15%, CKD 16%, diabetes 22%, hypertension 53% 

-- modified HAS-BLED 2.0 (mod risk of bleed, approx 2/100 patient-yrs), Charlson Comorbidity Index 4.0  (10-year survival 53%)

-- DOACs used included apixaban 55%, dabagatran  8%, rivaroxaban 38% 

-- >90% were on low-dose aspirin, < 100 mg/ day 

-- propensity score-matched cohorts, each with 1047 patients, were analyzed (DOAC plus aspirin, and DOAC only) 

-- patients were excluded from the study if they had an MI in the past 6 months prior to DOAC initiation and/or had a history of heart valve replacement 

 

--Main outcomes:  

    -- primary outcome: rate of bleeding events (patient-reported, regardless of severity)  

    -- secondary bleeding outcomes: major bleeds, nonmajor bleeds, emergency department visits for bleeding and hospitalizations related to bleeding  

        -- major bleeding: fatal bleeding, life-threatening bleeding, and intracranial or intraspinal bleeding  

        -- life-threatening bleeding: intracranial bleeding, 5g/dL drop in hemoglobin, or more than 4 units of blood needed  

    -- secondary thrombotic outcomes:  ischemic strokes, TIAs, VTE, ACS/MI, ED visits for thrombosis, and hospitalizations for thrombosis rates, and death 

 -- follow-up 12 months 

 

Results: 

-- bleeding episodes: 

    -- DOAC plus ASA, vs DOAC monotherapy: 26.0 vs 31.6 bleeds/100 patient-yrs, p=0.01 

-- by bleeding type: 

    -- non-major bleeds: DOAC plus ASA vs DOAC monotherapy: 26.1 vs 21.7 bleeds/100 patient-yrs, p=0.02 

    -- major bleeds, ED visits for bleeding, hospitalizations for bleeding, and death: all trended to worse outcomes with the combination (e.g. major bleed was 3.59/100 patient-yrs with DOAC alone and 4.95/100 patient-yrs for DOAC plus ASA; ED visits were 10.40 vs 13.00/100 patient-yrs for bleeding) 

    -- minor GI bleeds: increased with a combination therapy at 4.6 vs 3.0 bleeds/100 patient-yrs

--thrombotic event rates overall were similar between the cohorts, DOAC plus ASA vs DOAC monotherapy: 2.5 events vs 2.3 events/100 patient-yrs 

    -- ED visits for thromboses in those on DOAC monotherapy, 1.47 vs 0.83 ED visits/100 patient-yrs, p=0.04 

    -- but for other endpoints there were trends to fewer new thromboses and deaths in those with DOAC alone, except increased trend for DOAC alone for hospitalizations for thrombosis 

-- hospitalizations: DOAC plus aspirin vs DOAC alone: 9.1 vs 6.5 admissions per 100 patient years, p=0.02 

 

-- excluding patients with any history of MI, CAD, PAD or PCI/CABG did not affect outcomes, other than that bleeding rates were elevated but no longer statistically significant (the numbers of patients were significantly decreased, making statistical significance less likely)

 

-- there was no clear indication for ASA therapy in 1107 (34%) of the patients who were on DOACs and ASA together 

 

 

Commentary: 

-- so, this study found that these patients on DOACs seemed to have a significantly increased risk of bleeding without clear evidence for thrombotic benefit 

-- there are clinical indications for the combination of DOAC plus  aspirin, including patients with left ventricular assist devices, or patients with non-valvular atrial fibrillation and/or VTE who experience an acute coronary syndrome (ACS), or those undergoing percutaneous coronary intervention (PCI) 

-- there have been a few studies suggesting that warfarin plus aspirin is associated with increased bleeding and no benefit for thrombotic events (eg see http://gmodestmedblogs.blogspot.com/2014/11/aspirin-plus-warfarin-for-afib-and-cad.html , as well as what was found in a recent publication by the same Michigan group as the DOAC one above looking at aspirin plus warfarin therapy:  see JAMA Intern Med. 2019;179(4):533-541. doi:10.1001/jamainternmed.2018.7816

-- the 2019 ACC/AHA guidelines on the primary prevention of cardiovascular disease recommends against use of aspirin with either warfarin or or DOACs: 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines | Circulation (ahajournals.org)

-- this Michigan study assessed DOACs specifically, since these may have a better safety profile than warfarin. but, alas, same conclusion…

-- and, a recent Japanese study (AFIRE) randomized 2236 patients with atrial fibrillation and stable coronary disease (having undergone PCI or CABG >1 yr earlier, or had angiographically confirmed CAD not requiring revascularization) to the DOAC rivaroxaban vs rivaroxaban plus an antiplatelet agent, finding that the rivaroxaban alone was noninferior to the combination therapy for the composite of stroke, systemic embolism, MI, unstable angina requiring revascularization, or death from any cause; but there was increased risk of bleeding with the combination (see afib and CAD DOAC+ASA more bleeding no benefit AFIRE nejm2019 in dropbox, or DOI: 10.1056/NEJMoa1904143)

-- and, despite all of this information to the contrary over this 5 year Michigan study, there was no substantial decline in the number of patients on combination therapy (anticoagulant and antiplatelet drug) over time

 

Limitations: 

-- one significant benefit of the study was it was a review of real-world patients using sophisticated statistical methods. However, this is still a data-mining study with little granular data on other cardiovascular risk factors, psychosocial issues, medications (including nonprescription medications, etc). Such studies allow for broad generalizations, but limit the ability to draw definitive conclusions

    -- and, the propensity matching is a mathematical tool to try to equalize different populations, but they are not really comparing actual patients who are matched as in a randomized controlled trial. and sometimes propensity matching, depending on the algorithm used, can lead to wrong conclusions, eg see http://gmodestmedblogs.blogspot.com/2020/03/tramadol-fo-oa-inc-mortalityprobs-with.html 

--in addition, as with any retrospective analysis, it is not possible to know if all outcomes were captured or coded appropriately 

-- all of the bleeding endpoints at least trended to worse outcomes with the combination of the DOAC plus ASA, though the only one that reached statistical significance was nonmajor bleeding. This may well have been due to the low number of outcomes for all these other specific bleeding events 

-- there were very few thrombotic events in either group, thereby undercutting the possibility of a statistically significant comparison: but, the numbers were quite similar between groups

 

So, yet another study finding that the interaction between anticoagulants and aspirin in most cases is inappropriate and leads to increased bleeding without evident benefit. this is a consistently dangerous combination and should really only be used in very limited, well-defined clinical scenarios, as noted above.

geoff

 

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