CAD plus atrial fib: should we use aspirin plus anticoag?

 A recent study found that aspirin was actually harmful in patients with chronic coronary syndrome who were at high atherothrombotic risk and were on long-term anticoagulation, in the AQUATIC trial (Assessment of Quitting versus Using Aspirin Therapy in Patients with Stabilized Coronary Artery Disease after Stenting Who Require Long-Term Oral Anticoagulation. a bit of a mouthful....) in this French study: see aspirin plus anticoag NEJM2025 in dropbox, or DOI: 10.1056/NEJMoa2507532

    -- "chronic coronary syndrome" is the new name for "stable coronary artery disease"

Details:

-- 872 adults were eligible who had documented chronic coronary syndrome with previous coronary stent implantation more than 6 months before enrollment, had features of high residual atherothrombotic risk, and were receiving an oral anticoagulant (either a direct oral anticoagulant DOAC or a vitamin K antagonist VKA) for any reason.

    --inclusion criteria: high-risk of atherothrombotic events included:

        -- history of percutaneous coronary intervention (PCI) during an acute coronary syndrome (ACS) involving placement of ≥1 stent(s) after >6 months

        -- history of PCI (> 6 months) outside the context of acute coronary syndrome ACS but with high-risk features of ischemic event recurrences defined as diabetes, or diffuse multivessel disease (involvement of the 3 coronary vessels), or chronic kidney disease (creatinine clearance < 50ml/min), or prior stent thrombosis, or complex PCI (defined by stenting of the last remaining patent coronary artery, left main, at least 3 stents implanted and/or 3 lesions treated, bifurcation with two stents, length of stent >60mm and chronic total coronary occlusion), or the presence of peripheral artery disease.

-- this multicenter, double-blind, randomized, placebo-controlled trial was done in 51 centers in France; patients enrolled from 2020-2024

-- these patients were randomized into 2 groups: both continued their current anticoagulation but one received aspirin 100 mg daily (433 patients) and the other placebo (439 patients)

-- mean age 72, 85% male

-- BMI mean 28, diabetes 37%, current insulin therapy in 33% of those with diabetes, history of hypertension 69%, history of dyslipidemia (undefined) 71%, current smoker 11%

-- history CABG 10% (median 9 years since last CABG), history PCI 100% (median time since last PCI of 3 years; 28% had last PCI 6-12 months before enrollment), history of MI 72%

-- history of stroke 11%, history atrial fibrillation (AF) 89%, mean CHA₂DS₂-VASc score 4 (this score reflects risk of stroke in those with AF, scores range 0-9, the higher the number is associated with higher risk), history PAD 14%, history heart failure 27%

    -- direct oral anticoagulants (DOACs) 90% (62% apixaban, 25% rivaroxaban, 3% dabagatran), the rest on vitamin K antagonists (VKA)

    -- single antiplatelet therapy at baseline in 68%, not on antiplatelet therapy 32%

-- mean hemoglobin 13.9 g/dL, creatinine clearance mean 71

-- other important characteristics were buried in the supplementary materials, with not-so-easy access:

    -- mean blood pressure 138/23, family history of CAD 77% (did many of these patients have high lipoprotein (a) levels or apolipoprotein B levels and thereby have higher cardiovascular risk than the general population??), 90% on statins (seems like a low number in this sick population, but we do not know what statins were used/what dose or the baseline LDL or non-HDL levels), only 18% were on mineralocorticoid receptor antagonists (were there lots of people having low renin levels who were not assessed/treated appropriately/and thereby prone to more adverse cardiac and renal adverse effects/overall mortality, 51% on aspirin/20% on clopidogrel (and clopidogrel seems to have lower incidence of bleeding risk than aspirin), an array of doses of DOACs (without statement of INR control if on VKA), 90% had atrial fibrillation but an array of types with paroxysmal in 55%, persistent in 16%, permanent in 25%), mechanical valves in 1%, history of PE or DVT in 5%. see the limitations below for more detail

-- primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, stroke (ischemic, hemorrhagic, or stroke of uncertain cause), transient ischemic attack (TIA), coronary revascularization, or systemic embolism/acute limb ischemia

-- secondary efficacy outcomes were net adverse clinical events defined as a composite of death from any cause, an atherothrombotic cardiovascular event, or major bleeding; death from any cause by itself; a composite of cardiovascular death, myocardial infarction, or stroke; cardiovascular death; and an atherothrombotic cardiovascular event.

-- key secondary safety outcome was major bleeding according to International Society on Thrombosis and Hemostasis (ISTH) criteria:

    -- the ISTH criteria for nonsurgical patients: fatal bleeding and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome and/or bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells.

-- the study was discontinued early at median of 1.7 years (was supposed to have minimum follow-up of 24 months, with total duration ranging from 24 to 48 months), on the recommendation of the members of the data and safety monitoring board, who observed an excess of deaths from any cause in the aspirin group; followup continued at the next 1-to-3 months after discontinuation of the aspirin or placebo

    -- as a result of the monitoring board's decision, the median follow-up was 2.2 years

Results:

-- primary efficacy outcome (composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization, or acute limb ischemia):

    -- aspirin group: 73 patients (16.9%)

    -- placebo group: 53 patients (12.1%)

        -- adjusted hazard ratio 53% increase if on aspirin, aHR 1.53 (1.07 to 2.18), P = 0.02)

-- net adverse clinical event occurred in 124 patients (28.6%) in the aspirin group and in 76 patients (17.3%) in the placebo group HR 1.85 (1.39 to 2.46), P<0.001

    -- death from any cause occurred in 58 patients (13.4%) in the aspirin group and in 37 patients (8.4%) in the placebo group, aHR 1.72 (1.14 to 2.58),  P = 0.01

    -- cardiovascular death occurred in 33 patients (7.6%) in the aspirin group and in 19 patients (4.3%) in the placebo group, aHR 1.90 (1.07 to 3.35)

        -- causes of death are summarized in Table S4 in the supplement, though there was no significant difference in any of the specific causes (heart failure, MI, ischemic stroke, sudden death, acute limb ischemia, mesenteric ischemic)

        -- the only major difference between groups was in the "unknown category", with a total of 18 events (2.1% of the population), with 14 (3.2%) in the aspirin group and 4 (0.9%) in the placebo group

    -- atherothrombotic events occurred in 46 patients (10.6%) in the aspirin group and in 40 patients (9.1%) in the placebo group, aHR ratio 1.27 (0.83 to 1.95)

    -- stent thrombosis occurred in 1 patient in each group (ie, no evidence that stopping the aspirin led to increase in stent thrombosis)

-- subgroup analyses (also squirreled away in their supplementary material, specifically their Figures S6 and S7 found that all subgroups favored the placebo group, including use of DOAC or vitamin K antagonist, age >75 or <75, sex, diabetes or not, chronic kidney disease or not, history of MI or not, if the PCI was done more recently (within the prior 6-12 months) or not

-- the results of sensitivity analyses appeared to be consistent with those of the intention-to-treat analyses

-- Safety outcomes:

    -- major bleeding according to ISTH criteria (the key secondary safety endpoint) occurred in 44 patients (10.2%) in the aspirin group and 15 patients (3.4%) in the placebo group, >3-fold with aHR ratio 3.35 (1.87 to 6.00), P<0.001

    -- major or clinically relevant nonmajor bleeding according to ISTH criteria occurred in 65 patients (15%) vs 36 patients (8%), aHR 2.06 (1.36-3.11), p<0.001

    -- any bleeding occurred in 70 patients (16.2%) in the aspirin group and in 41 patients (9.3%) in the placebo group, aHR 1.97 (1.34 to 2.89),  P<0.001

    -- a total of 467 serious adverse events occurred in 201 patients in the aspirin group, and 395 serious adverse events occurred in 192 patients in the placebo group

        -- per their table S9 in the supplement: there were more people in the aspirin group who had atypical chest pain (12 vs 5 people) and new onset of heart failure (77 vs 48)

-- here is the graph of the outcomes, with notable separation of the curves at under 12 months:

Commentary: 

-- several prior studies comparing oral anticoagulation (OAC) with or without aspirin therapy for atrial fibrillation and venous thromboembolic disease have found increased bleeding with the addition of aspirin to the OAC no clear benefit, though these studies have been open-label, included low risk populations, or were based on data-mining of large databases (eg https://gmodestmedblogs.blogspot.com/2021/04/aspirin-plus-doacs-equals-more-bleeding.html)

-- there have been studies looking at lower dose DOACs plus aspirin showing cardiovascular benefit with nonmajor bleeding adverse effects. in particular there are 2 relatively new studies on lower dose rivaroxaban with aspirin finding benefit (https://www.nature.com/articles/s41569-019-0314-y) However, there needs to be more information on this approach, preferably with apixaban, the best of the DOACs  (and cheapest per our pharmacy). see below for more information on this. edoxaban does seem to be great, is once a day, but is very expensive and not covered by the insurance companies i deal with. a recent study also found that edoxaban by itself is better than if combined with anti-platelet therapy in patients with atrial fibrillation and stable CAD: https://gmodestmedblogs.blogspot.com/2025/02/edoxaban-alone-is-better-than-with-anti.html)

-- this double-blind, placebo-controlled trial found that the use of aspirin in addition to anticoagulation increased the risk of adverse cardiovascular outcomes/mortality over anticoagulation alone, and also had a significant increase in major bleeding outcomes as well.

-- of note, unlike prior studies, the patients involved in this one had chronic coronary syndromes (the new name for "stable coronary artery disease") as well as prior PCI and ongoing very high risk of an atherothrombotic event

    -- their mean CHA₂DS₂-VASc score was quite high at 4, putting them at very high risk of  developing atrial fibrillation (no specific data in the study on that) as well as reflecting their very high atherosclerotic risk;  this study group had high prevalence of prior MI (72%), atrial fibrillation (89%), hypertension (69%), dyslipidemia (71%), diabetes (37%)

        -- the patients in this AQUATIC study had about 10-fold the number of clinical events as in the prior studies

    -- prior studies have not included patients at such a high cardiovascular risk, and included different groups (some had only patients with atrial fibrillation), and involved patients on different medications at different doses

Limitations:

-- the patients in this study were really at high risk for cardiovascular events. it is unclear how generalizable the results are for those at lower risk

-- much of the study data was buried in the supplementary materials, a very important issue here since:

    -- prior studies have found that a large % of medical article readers just read the abstract, a reality given that there is such a plethora of new and potentially very important clinical articles that appear on a daily basis: a 2000 study of self-administered surveys to 143 internists in the AMA master file found that 63% read only the article abstracts: https://pubmed.ncbi.nlm.nih.gov/11119185/.

    -- in my reviews, it is not-so-uncommon for me to find that the abstracts skew the conclusions (? to reinforce the conclusion wanted by the funding drug company, ?to make the conclusions seem clearer/less equivocal and thereby make the study seem to be more important??,...)

    -- and, access to the supplementary material is inaccessible in most journals (NEJM is bad, JAMA is good): one needs to either have a subscription to the journal (costs lots) or have library access to an institution that does have access, and also have the time/interest to log in for the article. this barrier would exclude many clinicians from being able to evaluate this often important material (for example, not knowing that the "cardiac events" in a study included many that were guesses by the study authors and not necessarily reliable: eg https://gmodestmedblogs.blogspot.com/2015/12/empagliflozin-good-and-bad.html ) as well as was done in this study above where of the 7 "cardiovascular causes" of deaths, the largest single category was "unknown", with 2.1% of the causes (18 patients and 35% of the total 52 patients with cardiovascular deaths!!!). perhaps the overall outcomes identified in the main article were just wrong because the cardiac death totals included this large category of patients were without confirmed cardiovascular deaths???

     -- as noted above in the Details section above, important information was buried in the supplementary materials: mean blood pressure 138/23, family history of CAD 77%, 90% were on statins (seems like a low number in this sick population), low use of mineralocorticoid receptor antagonists at 18% (were there lots of people having low renin levels that were not assessed/treated appropriately/thereby prone to more adverse cardiac/renal/overall mortality), 51% on aspirin/20% on clopidogrel (and clopidogrel seems to have lower incidence of bleeding risk: https://pubmed.ncbi.nlm.nih.gov/39602157/), an array of doses of DOACs, 90% had atrial fibrillation but an array of types with paroxysmal in 55%, persistent in 16%, permanent in 25%), mechanical valves in 1%, history of PE or DVT in 5%

        -- and, in particular, no information on the actual lipid levels in the study groups; no information on lipoprotein (a), an important marker of cardiovascular risk (https://gmodestmedblogs.blogspot.com/2025/06/high-lpa-increases-risk-of-recurrent.html) or apolipoprotein B (https://gmodestmedblogs.blogspot.com/2023/05/cad-presumed-mechanism-and-apob-was.html), no information on plasma renin levels, an important cardiovascular risk factor independent of blood pressure control  (https://gmodestmedblogs.blogspot.com/2025/12/hyperaldosteronism-targeting-renin-level.html and https://gmodestmedblogs.blogspot.com/2025/09/new-hypertension-guidelines.html). i do realize that some of this testing has become more mainstream since this current study was done, but these should be analyzed as potential confounders in the results this study found and hopefully addressed in future studies. but the issue here is that is this study of very high cardiovascular risk individuals comparable and generalizable to the general population since they may well be very high risk because of their (unmeasured) lipoprotein a, apoB, and renin levels conferring their higher risk????

    -- also, there is no information on the INR level of those patients on vitamin K antagonists, and high or low levels could affect the clinical outcomes

-- i have clinical concerns about the use of composites as the primary outcome assessed as opposed to important individual outcomes:

    -- composite outcomes, i assume, are employed since it is much easier to find statistical validity of a result if there is a combination of many individual outcomes: the combination will achieve more positive findings than just looking at one of them alone

    -- in many studies, there is the combination of really bad adverse events (stroke, MI, mortality) along with less bad adverse events (coronary revascularization) as in this study. My guess is that most people would prefer a revascularization vs a disabling stroke. and adding the revascularization to the mix just adds numbers to the totals (making the total more significant) but blurs over the real import of the adverse events

-- several of the prior studies were conducted in Japan and Korea. This study was in France. And it is likely that the approved doses of several antithrombotic agents (eg clopidogrel) used in several of these studies are different and have different metabolism based on genetic differences that vary by population. And other risk factors, such as diet and exercise, also likely differ significantly across different populations/cultures. all of this limiting the generalizability of the results.

-- there are likely different outcomes by the choice of DOACs. several studies used rivaroxaban (eg the AFIRE study, ROCKET-AF) and was used in 25% of the participants in this current study

    -- there are studies revealing the drug company shenanigans in getting rivaroxaban FDA-approved as a once-a-day medication: https://gmodestmedblogs.blogspot.com/2016/02/rivaroxaban-is-it-really-better-than.html

    -- and, apixaban pretty clearly outperforms rivaroxaban: https://gmodestmedblogs.blogspot.com/2022/01/atrial-fib-apixaban-outperforms.html ; rivaroxaban is associated with more thrombotic as well as hemorrhagic events: https://www.acpjournals.org/doi/10.7326/M21-0717 (and, to my interpretation, rivaroxaban should be prescribed pretty rarely)

    -- so including the documented use of the inferior rivaroxaban likely distorts the results of this and other studies on the issue of single DOAC treatment without an antithrombotic agent

-- there is also a bias in results when a study is designed to be a certain length (up to 4 years in this study) but ends early (1.7 years, with 2.2 years of followup). there are usually very clear statistical calculations that lead to the initial proposed length of a study. stopping early could distort this if, in the case of this study, some of the large cardiovascular benefits take much more or much less time to manifest themselves, distorting the risk/benefit ratio by early study termination

-- 33% of the patients with diabetes were on insulin, a prothrombotic and proatherosclerotic agent, also affecting the results (though one would expect it to lead to increasing both cardiac and bleeding events in the group off aspirin??)

-- and, as per many studies, they used creatinine-based measurements of renal function, though it is pretty clear that cystatin-based measurements are much better predictors of adverse cardiovascular outcomes: https://gmodestmedblogs.blogspot.com/2023/12/cystatin-c-better-predictor-of-bad.html and  https://gmodestmedblogs.blogspot.com/2024/03/cystatin-c-more-evidence-of-its-benefit.html

so,

-- this study, as a randomized controlled trial, presents a more rigorous evaluation of the problems with dual therapy with an anticoagulant and an anti-thrombotic medication when a patient has a rational for each based on the individual diagnoses (ie, has AF needing anticoagulation but also bad heart disease needing anti-platelet meds)

    -- though, as with all studies, there are important limitations to the study design, how the data is presented, the patient selection (where done, how done), etc.  And the above study did have its fair share of limitations

    -- these limitations do muddy the water, so we clinicians need to guess whether they apply to patients we see who are either not included (outside the age group of the study, occurring in a different location with different cultures/diet/exercise/etc, having clinical conditions such as kidney disease that excludes them, etc)

    -- so, we just make the decision based on the individual we are treating, likely following more closely the clinical differences of that patient from that of the study (eg, following renal function more closely in those with chronic kidney disease)

-- i personally have not been using the dual therapy based on several older observational studies over the past few decades that have come to the above study's conclusions that harms exceed benefits. and i chose to review this current study as further support of this, especially since they enrolled such high-risk patients and still found no benefit to adding aspirin. But given the above limitations, this all still adds to the usual editorial comment that "more studies need to be done:"... 

geoff

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