edoxaban alone is better than with anti-platelet if atrial fibrillation and stable CAD

 a recent randomized control trial found that in patients with stable coronary artery disease and atrial fibrillation (AF), monotherapy with the anticoagulant edoxaban was better than dual antithrombotic therapy with an added antiplatelet drug (see afib and stable CAD NEJM2024 in dropbox, or DOI: 10.1056/NEJMoa2407362)

 

Details:

-- 1040 patients were enrolled in a multicenter, open-label, adjudicator-masked, randomized trial comparing edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with atrial fibrillation and stable coronary artery disease, in 18 sites in South Korea, with recruitment from  2019-2022

    -- coronary artery disease (CAD) was defined as being previously treated with revascularization or managed medically

        -- stable CAD was defined as having had a percutaneous coronary intervention (PCI) or CABG at least 6 months before enrollment or an acute coronary syndrome previously treated with PCI or CABG at least 12 months before enrollment , or anatomically-confirmed CAD with at least 50% stenosis of a major epicardial coronary artery on cath or CT angiography managed with medical therapy

    -- all patients were considered to be high risk of a vascular event, with a CHA₂DS₂-VASc score of at least 2

-- patients had follow-up at 6 months and 12 months

-- exclusion criteria included high incidence of major prior bleeding, prosthetic heart valves, moderate-to-severe mitral stenosis, and severe hepatic or renal dysfunction

-- mean age 72 years, 23% were women, weight 69 kg, BMI 25 

-- diabetes 40%, hypertension 81%, hyperlipidemia or taking statins 94%, current smoker 8%, previous MI 16%, heart failure 20%, history cerebrovascular disease 15%, history PAD 7%, COPD 35%, creatinine clearance 67

-- AF was paroxysmal in 55%, persistent/permanent in 45%

-- mean CHA₂DS₂-VASc score 4.3, CHADS₂ score 2.2, HAS-BLED score 2.1

-- prior PCI 60%, prior CABG 8%

 

--patients were randomized to edoxaban 60mg once a day, with or without a single antiplatelet agent (aspirin was used in 62% and clopidogrel in 38%), according to the discretion of physician

    --edoxaban dose was reduced in those with creatinine clearance of 15-50, a body weight <60kg, and the use of some meds that interact with it (eg, P-glycoprotein inhibitors, such as sertraline, nifedipine, diltiazem, clarithromycin)

 

-- the primary outcome was a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, and major bleeding or clinically relevant nonmajor bleeding at 12 months

-- secondary outcomes included a composite of major ischemic events and the safety outcome of major bleeding or clinically relevant nonmajor bleeding (as defined by the International Society on Thrombosis and Hemostasis).

 

Results:

-- at 12 months, a primary-outcome event occurred in:

    --edoxaban monotherapy: 34 patients, 6.8%

    --dual antithrombotic therapy: 79 patients, 16.2%

        -- 56% decreased risk with monotherapy, HR 0.44 (0.30 to 0.65) p<0.001

        -- number needed to treat (NNT) to avoid one primary outcome: 10.6 individuals

 

-- the cumulative incidence of major ischemic events at 12 months appeared to be similar in the trial groups

 

-- major bleeding or clinically relevant nonmajor bleeding:

    -- edoxaban monotherapy: 23 patients (4.7%) 

    -- dual antithrombotic therapy: 70 patients (14.2%)

        -- 66% decrease with monotherapy, HR 0.34 (0.22 to 0.53)

 

-- cumulative incidence of major bleeding at 12 months:

    -- edoxaban monotherapy: 1.3%

    -- dual antithrombotic therapy: 4.5%

        -- 68% decrease with monotherapy, HR 0.32 (0.14 to 0.73)

 

note that the curves splay apart within 1 month of being on the different therapies for major bleeding of clinically relevant nonmajor bleeding in those on dual therapy

 

-- sensitivity analyses:

    -- essentially no difference in per-protocol vs intention-to-treat analyses

    -- not much difference in all prespecified subgroups: age, sex, creatinine clearance, type of revascularization (PCI vs CABG vs medical treatment alone), edoxaban dose, CHA₂DS₂-VASc score above vs below 4, HAS-BLED score of above or below 3

    -- similar results in those who had past use of anti-thrombotic meds

 

Commentary:

-- AF is very common in patients with atherosclerotic coronary artery disease

-- the general medical approach to AF alone is by anticoagulation in those at higher risk of systemic embolli

-- the general medical approach to CAD is by antiplatelet meds to prevent recurrent atherosclerotic events

    -- and, of course, this combination of meds is associated with increased risk of significant bleeding

-- current guidelines reinforce the importance of this dual therapy right after a percutaneous coronary intervention or acute coronary syndrome for 6-12 months

   -- these guidelines do recommend reverting to oral anticoagulants after the dual therapy period has ended

 

-- prior trials have assessed this combination of an anticoagulant and antithrombotic med in this situation of AF plus stable CAD

    --a study with warfarin or a DOAC (direct oral anticoagulant, such as edoxaban) did not establish noninferiority for warfarin/DOAC alone vs warfarin plus an antiplatelet med, but this study was terminated early and was underpowered and inconclusive (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.036768)

    --a study with rivaroxaban in patients with atrial fibrillation and stable CAD compared to rivaroxaban plus a single antiplatelet agent, finding that rivaroxaban monotherapy was noninferior to its comparison with a single antiplatelet drug, though this study was terminated early and did not use a standard rivaroxaban dose  (https://www.nejm.org/doi/full/10.1056/NEJMoa1904143 , and https://gmodestmedblogs.blogspot.com/2019/09/antiplatelet-plus-anticoag-in-cad-with.html)

    -- there have been several older studies coming to the same conclusions: the​ ORBIT-HF study assessed 10K patients from 176 US practices and found that the combination of aspirin plus warfarin was commonly used, and that there was >50% increased in major bleeding but no difference in ischemic events; and the CORONOR study, a prospective French study of 4K patients similarly found increased bleeding with no difference in atherosclerotic events. The European Society of Cardiology in 2010 suggested oral anticoagulant  monotherapy in patients with atrial fibrillation and stable vascular disease (see https://gmodestmedblogs.blogspot.com/2014/11/aspirin-plus-warfarin-for-afib-and-cad.html )

 -- this current study was designed to provide substantive evidence through a large randomized trial, finding that adding the antiplatelet agent had no effect on cardiovascular outcomes but dramatic increases in bleeding

 

--though i have never prescribed edoxaban, it seems to be a pretty great anticoagulant with the advantage of being a once-a-day medication. when not using warfarin, I have been using apixaban, though it is twice-a-day.

-- rivaroxaban, another once-a -day med, to me, should never be prescribed. it actually has about the same half-life as apixaban but received FDA clearance after pretty remarkable drug company shenanigans. the pivotal study leading to rivaroxaban approval was the ROCKET-AF study comparing rivaroxaban to warfarin; this study knowingly utilized defective INR point-of-care machines for those participants on warfarin, leading to false INR results. the drug company then was able to achieve their coveted once-a-day dosing for rivaroxaban, though it actually has basically the same half-life as the twice-a-day apixaban. This seemed to be a marketing tool, a ploy to prescribers to use the "easier" once-a-day med. BUT, studies have shown both more significant venous thromboses and more significant bleeding when comparing rivaroxaban to apixaban (for details see https://gmodestmedblogs.blogspot.com/2022/01/atrial-fib-apixaban-outperforms.html)

--edoxaban, however, has a longer half-life and is clearly better than rivaroxaban with much less bleeding:

    -- a Japanese study comparing rivaroxaban to edoxaban for patients with NVAF (nonvalvular atrial fibrillation) found excessive annual incidence of bleeding events with rivaroxaban at 4.88​ patient-yrs vs 3.73 patient-yrs; for those with eGFR >50 and body weight <60kg, there was the dramatic difference in bleeding events of 22.2% vs 2.9%. They found that on measuring peak plasma levels, 27.1% of those on rivaroxaban and 5.7% on edoxaban had peak levels above the cut-off level for developing bleeding events; similarly, trough levels were low more often in those on rivaroxaban vs edoxaban. this would support the prior-mentioned study showing both more bleeding and thromboses in those on rivaroxaban. my guess is that the drug company did increase the on-label dosing of rivaroxaban in order for it to last longer in its antithrombic state (but leading to more bleeding), but it then wore off earlier because of the once-a-day dosing so there was lower trough levels, leading to more clotting: see atrial fib edoxaban vs rivaroxaban CircReports2023 in dropbox, or doi:10.1253/circrep.CR-66-0012

    -- a meta-analysis confirmed that apixaban had the least bleeding and that major GI bleeding risk was higher with rivaroxaban (OR 1.41, 41% increase) vs edoxaban (OR 0.67 33% decrease)

-- elimination half-life of apixaban is 12 hours (8-15 hours); rivaroxaban is 5-9 hours; edoxaban is 10-24 hours

 

Limitations:

-- this was a large study done in multiple sites, but it was done in South Korea and mostly with men, and there might well be both genetic and nongenetic factors that might limit generalizability to other areas/cultures

    -- there are studies finding that East Asian individuals may have a different propensity for both ischemic and bleeding complications vs Western individuals

-- as an open-label study, there could be ascertainment or reporting biases

-- the researchers did not separate the atherosclerotic from bleeding events in their primary outcome composite, allowing the very common bleeding events to outdistance the atherosclerotic ones and muddying the waters a bit. the secondary analysis, however, did address this.

-- there was only baseline data reported. it is possible that some of these initial assessments changed during the study and might have altered the subgroup analyses

 

so, i think the data from many studies are remarkably consistent over many years in showing that patients with atrial fibrillation and chronic coronary artery disease should be on a single anticoagulant, without an antiplatelet drug. And that we clinicians should stop added antiplatelet drugs in patients on both meds, given no benefit in terms of atherosclerotic disease and very clear harms of hemorrhagic outcomes.  this conclusion is reflected in cardiovascular guidelines. That being said, a few comments:

    -- we should not be using rivaroxaban for the reasons noted above: increased atherosclerotic as well as bleeding events, in the setting of drug company malfeasance in their pivotal study that led to FDA approval for the med

    -- the best options available seem to be apixaban (for those patients able to reliably take a twice-a-day medication) or edoxaban (for the once-a-day crew)

        -- both drugs cost about $500-600/month (as does rivaroxaban), so the issue for those with insurance will likely be which are covered by insurance (and the hope that it is not just rivaroxaban...)

    -- it should be emphasized that the rather robust conclusion to avoid adding a platelet inhibitor applies so those with chronic coronary artery disease; the dual therapy is clearly indicated in those receiving a percutaneous coronary intervention (the dual therapy decreases the risk of stent thrombosis, recurrent MI, and cardiovascular death) or an acute coronary syndrome

 

 

geoff

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