Dr Niraj Sharma: Welcome back to the critical appraisal issue of EP Edge Journal Watch, Background and Breakthrough, where we bridge science to practice. I'm Doctor. Niraj Sharma. Today we explore the aquatic trial published in the New England Journal of Medicine 2025. It asks a deceptively simple question.
For patients with atrial fibrillation and chronic coronary syndrome long after stenting, does adding aspirin to oral anticoagulation still help or does it only harm? To answer that we will walk through four decades of progress from warfarin to DOACs, from dual therapy to monotherapy culminating in the aquatic trial. Let's have a quick pathophysiologic background. Atrial fibrillation promotes atrial stasis, endothelial dysfunction, and a thrombin dominant state that drives clot formation and stroke. Coronary artery disease, by contrast, is platelet driven, triggered by plaque rupture and local inflammation.
When both coexist, therapy becomes a balancing act. One process demands anticoagulation, the other antiplatelet therapy. The shared foundation, inflammation, oxidative stress, and tissue factor activation explains why we have historically combined drugs and why bleeding so often followed. Our challenge has always been to find equilibrium protecting both the brain and the coronaries without overwhelming hemostasis. And to appreciate how we reached that equilibrium, we have to go back to the early trials that first taught us what worked and what didn't.
From warfarin to DOACS, let s start in the 1980s and 1990s, the warfarin era. A Fasak (Lancet nineteen eighty nine) showed warfarin reduced stroke by about sixty percent versus aspirin or placebo. BAT F. New England Journal 1990 confirmed benefit in non valvular AF. SPF one and two, stroke '19 ninety one-ninety four, refined stroke risk stratification.
Cafe JAC 1991 and ACTIVE W Lancet 2006 sealed the verdict oral anticoagulation outperforms dual antiplatelet therapy. But warfarin came at a cost two-three percent per year major bleeding and roughly one percent intracranial hemorrhage. When coronary disease entered the scene, triple therapy, warfarin plus aspirin and clopidogrel, became routine and bleeding skyrocketed to ten to fifteen percent. We needed a safer, simpler anticoagulant. That search opened the door to a revolution, the era of the DOAC.
The DOAC revolution between 2009 and 2013, four New England Journal trials evaluating non valvular atrial fibrillation and systemic embolism transformed the field. ReLi tested dabigatran in 2009, non inferior to warfarin with seventy percent fewer brain bleeds. ROCCAT AF 2011 brought rivaroxaban, similar efficacy, less intracranial hemorrhage. That same year, Aristotle showed apixaban reduced stroke, major bleeding and mortality. And finally, ENGAGE AFTME forty eight-twenty thirteen confirmed class consistency with edoxaban.
Together they delivered predictable dosing, no INR checks and half the brain bleeds of warfarin. By 2014, DOACs had replaced warfarin as first line therapy. But for AF patients undergoing PCI, another question remained, could we safely drop aspirin? That question defined the next chapter, the era of AFPCI trials, AFPCI and the AFIRE prelude. Modern trials answered that question.
Wovist, Lancet, 2013 Warfarin plus Clopidogrel, without aspirin, cut bleeding by nearly half No increase in stent thrombosis Pioneer AF PCI New England Journal 2016 Rivaroxaban dual therapy reduced bleeding by 40% versus triple therapy Re Dual PCI New England Journal 2017 Debigatran dual therapy 50% less bleeding Augustus New England Journal 2019 Apixaban was safer than VKA Aspirin nearly double bleeding Entrust AF PCI Lancet 2019 Edoxaban Dual Therapy non inferior for efficacy and safer overall. By 2020, the message was clear: dual therapy is enough. Aspirin's role ends early. Then came AFIRE, the Japanese trial that set the stage for aquatic. AFIRE (New England Journal twenty nineteen) tested rivaroxaban monotherapy versus rivaroxaban plus an antiplatelet in AF with stable coronary artery disease.
It was stopped early for excess mortality and bleeding in the combination arm. Monotherapy was non inferior for ischemia and superior for safety. Limitations however remained. Japanese only lower doses of Rivaroxaban open label but the direction was set. After one year, DOAC alone may be enough.
AFIRE raised the question that Aquatic was destined to answer: Can we drop aspirin for good in a global high risk population? And so DEFINITIVE trial arrived in 2025. The ACQUATIC trial, published in New England Journal 2025 but presented earlier at the European Cardiology Society Late Breaker session, was a multicenter, double blind, placebo controlled study across France. It enrolled eight seventy two patients with chronic coronary syndrome on long term oral anticoagulation, mostly for AF, whose last stent was more than six months old. Patients were randomized to oral anticoagulant alone, or oral anticoagulant plus aspirin eighty one mg daily.
To capture a high risk population, eligibility required either PCI for an acute coronary syndrome more than six months prior or a non acute coronary syndrome PCI more than six months ago plus at least one of these features: diabetes, chronic kidney disease, multi vessel coronary disease, complex PCI included, bifurcation stents, long segments, equal to or more than two overlaps, or peripheral artery disease. Median time since last PCI was about three years. Seventy two percent had prior myocardial infarction. Almost ninety percent were on a DOAC. After two years of follow-up, the data safety monitoring board stopped the trial early for harm.
Aspirin increased mortality thirteen point four percent versus eight point four percent. Major bleeding tripled ten point two percent versus three point four percent ). The primary composite endpoint was worse with aspirin sixteen point nine versus twelve point one percent. Even among the highest risk patients diabetes, CKD, multi vessel disease complex stents, aspirin added no benefit and clear harm. The verdict was unequivocal.
Before we sign off, let's take a step back and look at what the aquatic trial didn't tell us. Because every study, even a landmark one, leaves some questions on the table. First, sample size. Only eight seventy two patients were enrolled, far smaller than the massive DOAC trials that shaped our field. That means less power to explore important subgroups, renal impairment, complex PCI, or heavy atrial disease burden.
Small numbers can exaggerate effects or hide nuance. Second, the trial was stopped early for harm. While that was the right ethical decision, early termination can inflate risk difference and leave long term ischemic trends unknown. We may have seen a signal amplified by timing rather than true magnitude. Third, geography.
Aquatic was conducted almost entirely in France, a homogeneous European population. That limits generalizability to East Asian or South Asian cohorts, Africans where bleeding and thrombosis behave differently, and DOAC dosing strategies vary. Fourth, drug heterogeneity. Nearly ninety percent of patients took a DOAC, but multiple agents were allowed without randomization by type. Apixaban, rivaroxaban, dabigatran, edoxaban all behave a little differently.
Without stratification, we can't tell if one drives the bleeding curve more than another. Fifth, anatomy and procedure complexity. Despite labeling this a high atherothrombotic risk cohort, only a fraction had truly complex PCI, multiple overlapping stents, bifurcation work, or long segment disease. That means for our patients with diffuse coronary disease or recurrent restenosis, we're still extrapolating. Sixth, event adjudication.
Bleeding was defined by ISTH criteria, but minor and non major events were underreported, and there was no centralized imaging core for confirming stroke or myocardial infarction. In a world where silent cerebral events are common in AF, that leaves room for uncertainty. Seventh, mechanistic insight. The study didn't include biomarkers, no D dimer, no platelet reactivity, no CRP or endothelial markers. We don't know who bleeds because of biology versus who bleeds because of chance.
Eighth, a small subset, about ten percent were on anticoagulation for reasons other than AF, venous thromboembolism, left ventricular thrombus, other indications but outcomes weren't separated. That heterogeneity muddies the pure AF plus coronary disease signal we'd like to see. Ninth, adherence and dose verification. Therapy compliance was self reported, not plasma validated. Even minor crossovers, stopping aspirin, missing DOAC doses could bias results toward showing harm.
And finally, duration. Two year follow-up captures early safety, but not the full chronic risk of AF plus coronary disease, patients who live a decade or more. Whether event curves converge or whether some late ischemic penalty emerges, we simply don't know. So what do we take from all this? Aquatic is confirmatory, but not conclusive.
It strengthens the case for DOAC only therapy in most stable AF plus coronary artery disease patients, but it also reminds us that simplification must remain individualized. The patient with three stents, chronic kidney disease, or diffuse diabetes may still need a bespoke approach. In other words, this trial refines the story but it doesn't close the book. And that's exactly where thoughtful electrophysiologists and thoughtful clinicians should live, at the intersection of evidence and individualization. Thank you all for listening and joining me for this EP Edge Journal Watch podcast background and breakthrough the aquatic trial.
I'm Dr Niraj Sharma. Take care and bye for now.