antiplatelet plus anticoag in CAD with Afib???

antiplatelet plus anticoag in CAD with Afib???

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You forwarded this message on Mon 9/9/2019 8:31 AM

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Geoff A. Modest, M.D.

Mon 9/9/2019 8:29 AM

• Geoff A. Modest, M.D.

A recent Japanese multicenter, randomized, open label trial found that adding antiplatelet meds to patients with CAD on anticoagulation for atrial fibrillation increased their mortality with no evidence of improved cardiovascular outcomes (see afib and chr cad not use aspirin nejm2019 in dropbox, or DOI: 10.1056/NEJMoa1904143)

Details:

-- 2236 patients from 294 centers with atrial fibrillation and chronic coronary artery disease, the latter defined as having undergone percutaneous coronary intervention or coronary artery bypass grafting more than one year earlier, or having angiographically-confirmed CAD (at least 50% stenosis) not requiring revascularization, were randomized to rivaroxaban monotherapy or that in combination with an antiplatelet agent

    -- 70% received aspirin, 27% a P2Y₁₂ inhibitor

-- mean age 74, 79% male, BMI 25, current smoker 13%, diabetes 42%, previous stroke 14%, previous MI 35%, previous PCI 71% (70% of whom had drug-eluting stents, 24% bare-metal), creatinine clearance 62 mL/min

-- mean CHADS₂ score was 2, median CHA₂DS₂-VASc score was 4 and median HAS-BLED score was 2 (all in the moderate risk range)

-- primary efficacy endpoint: composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause, analyzed for noninferiority

-- primary safety endpoint: major bleeding, analyzed for superiority

Results:

-- trial was stopped early because of increased mortality in the combination group, with a median treatment duration of 23 months, median follow-up of 24 months

-- primary efficacy endpoint: monotherapy was noninferior to combination therapy, with event rates in 89 patients receiving monotherapy and 121 on combination therapy, 4.14% vs 5.75% per patient-year, HR 0.72 (0.55-0.95), p<0.001 for noninferiority

    -- though not a primary endpoint, monotherapy was found to be superior,  p=0.02

    -- all-cause mortality was lower in those on monotherapy than combination therapy, 1.85% vs 3.37% per patient year, HR 0.55 (0.38-0.81), due to lower incidences of both cardiovascular death, 26 vs 43 events (1.17% vs 1.99% per pt-yr, with HR 0.59) and noncardiovascular death, 15 vs 30 events (0.68% vs 1.39% per pt-yr, with HR of 0.49)

        -- most common cause of death was heart failure ( 6 vs 10 patients), stroke (2 vs 10 patients), and cancer (6 vs 13 patients)

    -- the combination of ischemic cardiovascular events or death was lower in the monotherapy group, 5.37% vs 6.77% per pt-yr, HR 0.80 (0.62-1.02)

    -- combination of all-cause death, MI, stroke, or major bleeding was lower in monotherapy group, 3.90% vs 6.28% per pt-yr, HR 0.62 (0.47-0.82)

    -- essentially every subgroup analysis found at least a trend showing monotherapy was better, including different cutpoints for the CHADS₂ and CHA₂DS₂-VASc scores, HAS-BLED scores, creatinine clearance, diabetes, type of atrial fibrillation, age, and sex

-- primary safety endpoint: monotherapy was superior to combination therapy, with event rates of 1.62% vs 2.76% per patient-year, HR 0.59 (0.39-0.89), p=0.01 for superiority

    -- this endpoint was consistent across all prespecified subgroups including those by sex, age, stroke, bleeding risk was, and renal function; this was also consistent for major bleeding events

Commentary:

-- the co-occurrence of CAD and atrial fibrillation is relatively common, 5 to 7% of patients undergoing PCI

-- this randomized trial confirms the conclusions of a few observational studies, including the Danish cohort study (see below)

-- the Canadian Cardiovascular Society and the European Society of Cardiology have both endorsed oral anticoagulant monotherapy one year after PCI, based on the Danish cohort study, without data supported by RCTs. Hence the importance of this current RCT

    -- The Danish study: (see afib and cad not help and inc bleeding circ2014 in dropbox, or  DOI: 10.1161/CIRCULATIONAHA.113.004834), of 8700 with atrial fibrillation  and stable CAD found that the addition of antiplatelet therapy to a vitamin K antagonist (eg warfarin) was not associated with decreased recurrent coronary events or VTE but the risk of bleeding was increased significantly

    -- based on the Danish study and a few other observational studies (eg, see blog below on the ORBIT HF study), i have personally avoided the combo therapy of adding aspirin to anticoagulation, given the unclear benefit and clear risks of bleeding (though with some angst: there was always a lingering question in my mind if that was the right thing to do). This new RCT helps validate this approach

-- it is difficult to explain mechanistically why the rate of ischemic events and death from any cause was better with rivaroxaban than combination therapy

-- trial limitations include: open label design, relatively high withdrawal rates of patients (though were within the 5% rate that had been anticipated), lower rivaroxaban dosing than usual (10 to 15 mg per day, though pharmacokinetic studies do suggest that Japanese patients at dose do have blood levels similar to white patients at 20mg/d), and non-randomization of the choice of which antiplatelet drug was used

    -- by the way, one of my concerns about these NOACs such as rivaroxaban is that there is no monitoriting of drug levels, which is their real selling point over warfarin used by drug companies, yet there really are blood different levels in different patients!!! (and potential issues both with efficacy and adverse effects): eg see http://gmodestmedblogs.blogspot.com/2016/10/rivaroxaban-and-increased-intracranial.html for an example of the drug company shenanigans in promoting these block-buster drugs over warfarin)

so, this study does add an RCT to the pretty significant observational literature suggesting that adding a platelet inhibitor to patients with atrial fibrillation and chronic CAD who are on an anticoagulant adds risks without benefits. 

http://gmodestmedblogs.blogspot.com/2014/11/aspirin-plus-warfarin-for-afib-and-cad.html  comments on the observational ORBIT HF study, finding that the combo of aspirin and anticoagulants was actually quite common (35% of patients), but there was no apparent benefit in terms of cardiovascular outcomes, yet much higher rates of bleeding

 

 geoff

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