Few results are more definitive than the decidedly negative AQUATIC trial of aspirin plus anticoagulation vs anticoagulation alone in patients with indications for both drug classes. 

The large number of patients who take this combination make AQUATIC the most important trial from this year’s European Society of Cardiology meeting in my opinion. The findings should lead to a major reversal of the common practice of combining aspirin with anticoagulation, so called dual pathway therapy. 

Aspirin Plus Anticoagulation: A Common Prescription

That these drugs are so often used together stems from four factors: One is that chronic coronary artery disease and atrial fibrillation (AF) are common and often co-exist. Second is that — individually — both conditions have an indication for one of the drugs. Third, doctors often consider conditions in isolation. Fourth, aspirin has a benign reputation, and inertia can inhibit the work it takes to stop aspirin when using anticoagulation; call this the why bother reason.

AQUATIC randomized patients who had chronic coronary disease and a condition warranting oral anticoagulation to a dual pathway arm of anticoagulation plus aspirin vs a single pathway arm of anticoagulation plus a placebo pill. 

The trial enrolled nearly 900 patients who were most likely to benefit from aspirin. These were high-thrombotic risk patients who had undergone coronary stenting more than 6 months before enrollment. 

The mean age of patients was 72 years, 85% were male, and nearly three quarters had had a previous myocardial infarction (MI). The mean CHA2DS2VASc score was 4. Anticoagulation could be with direct oral anticoagulants (DOACs, used in 89%) or vitamin K antagonists, primarily warfarin. AF was the indication for anticoagulation in nearly 90% of patients. 

The primary efficacy outcome was a composite of cardiovascular death, MI, stroke, systemic embolism, coronary revascularization, or acute limb ischemia. The key safety outcome was major bleeding.

AQUATIC Results 

After 2 years of follow-up, the trial was stopped early for harm in the dual pathway arm. 

A primary efficacy outcome event occurred in 16.9% in the aspirin group vs 12.1% in the placebo group (hazard ratio [HR] = 1.53; 95% CI, 1.07-2.18; P =.02)

Death from any cause occurred in 13.4% vs 8.4% in the placebo arm (HR = 1.72; 95% CI, 1.14-2.58; P =.01). The rate of major bleeding was 10.2% vs 3.4%, respectively (HR = 3.3; 95% CI, 1.9-6.0). 

The authors concluded the only thing possible: Combination therapy was clearly worse. 

Five Important Lessons From the AQUATIC Trial

First, the effect sizes from both the efficacy and safety endpoints were large. The absolute risk increase for thrombotic events in the dual pathway arm was nearly 5%, a number needed to harm of only 21. Bleeding risk was even more striking; the number needed to harm was 15. 

Second, the safety signal was statistically robust with the 95% CI ranging from a 2- to 6-fold increase in major bleeding in the dual pathway arm. You might argue that the efficacy signal was statistically weaker, but this was likely due to early termination of the trial — an ethically correct decision. The Kaplan-Meier curves for major adverse cardiac events were clearly separating over time. 

Third, previous trial results of dual vs single pathway strategies bolster our confidence in the AQUATIC results. The AFIRE and the EPIC-CAD trials also found worse outcomes with the dual pathway strategy. 

Fourth, AQUATIC authors have shown that trials can actually answer true scientific questions. Too often, randomized trials are designed to find positive results for a new (and profitable) intervention. AQUATIC, on the other hand, picked patients most likely to benefit from the combination and they chose a relevant efficacy and safety endpoint. No one made any money on these results. The winners were anyone interested in caring for these patients. 

Taken together with previous trial results, I see a clear answer: Outside of the 6to 12-month post-stent interval, in patients with chronic coronary artery disease and an indication for anticoagulation, just use anticoagulants. Dual pathway therapy is clearly the wrong answer for AQUATIC-like patients. 

The fifth and final message is that the human body is unlike a machine where you can independently tweak systems. Aspirin is indicated in patients with chronic coronary disease. But when this patient also has a reason to take oral anticoagulants, the combination of the two drug classes is not simply the sum of two beneficial therapies. 

The coagulation system is a delicate balance between thrombosis and bleeding. Blocking both platelets and coagulation should have always required separate testing. 

AQUATIC shines not only because it informs a common clinical scenario, but also because it infuses us with humility regarding the translation of evidence. 

When in doubt, which should be often, the answer is to randomize. 

John Mandrola practices cardiac electrophysiology in Louisville Kentucky and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.Â