This is a special edition summarizing three studies from the recent European Society of Cardiology (ESC) Conference hosted from August 29 to September 1, 2025.
Preamble: If my math is correct, there were at least five practice-changing trials published at ESC. All were published simultaneously in either NEJM, Lancet, or JAMA. Below is a brief summary of three of these trials.
The headliner: Anticoagulants + Aspirin = death.
Ok, maybe that headline is a slight exaggeration. However, the AQUATIC trial was stopped early because of an increased risk of all-cause mortality for patients randomized to receive both an anticoagulant and aspirin compared to an anticoagulant and placebo. Specifically, death from any cause occurred in 13.4% of the aspirin group and in 8.4% of the placebo group (HR 1.72, 95% CI 1.14-2.58). AQUATIC was a double-blind trial of patients (N=872) who had undergone a previous stent at least 6 months before enrollment and also had an indication for full dose anticoagulation (most often afib). The primary efficacy outcome (composite of CV death, MI, stroke, among others) event occurred in 73 patients (16.9%) in the aspirin group and in 53 patients (12.1%) in the placebo group (adjusted hazard ratio 1.53, 95% CI 1.07-2.18, P=0.02). The final nail in the coffin was a higher risk of major bleeding which occurred in 10.2% of the aspirin group and in 3.4% of the placebo group.
The 2nd headliner: Digitoxin (not digoxin) improved outcomes in adults with heart failure and reduced ejection fraction.
While digitoxin sounds a lot like digoxin, it is not renally cleared, and thus has the potential to be safer than digoxin. This international double-blind trial evaluated digitoxin versus placebo in 1212 patients with heart failure and reduced ejection fraction already on guideline-directed therapy. Over a median of 36 months, digitoxin significantly reduced the composite outcome of death or first hospitalization for worsening heart failure (HR 0.82, 95% CI 0.69-0.98, p=0.03). Serious adverse events were infrequent but somewhat higher with digitoxin (4.7% vs. 2.8%). I need to consult a friendly pharmacist to see if we can access digitoxin in Canada. The next call will be to a friendly cardiologist to see if they think this is a good idea!
The 3rd headliner: Following a provoked VTE, an additional 12mo of low dose apixaban appears to be superior for high risk patients.
As we know, most patients with a VTE are treated for 3 to 6 months with a DOAC like apixaban. But what if the patients have ongoing risk factors for a recurrent VTE such as obesity, inflammatory conditions (e.g., lupus), or chronic respiratory disease (e.g., COPD)? Enter the HI-PRO trial. It was a randomized, double-blind trial that evaluated whether extended low-dose apixaban reduces recurrent VTE in patients with a transient provoking factor and at least one enduring risk factor. Six hundred patients who had completed at least 3 months of anticoagulation were randomized to apixaban 2.5 mg twice daily or placebo for 12 months. Recurrent VTE occurred in 1.3% of apixaban-treated patients versus 10% of those on placebo (HR 0.13, 95% CI 0.04-0.36). Major bleeding was rare, though clinically relevant nonmajor bleeding was more frequent with apixaban. While this feels practice-changing, the fact that the trial was single-centre is a major limitation, and this internist thinks the results require confirmation before changing practice.
The take home points:
[1] In patients with a prior coronary stent and an indication for anticoagulation, continuing aspirin beyond the initial 6 months increased death, CV events, and major bleeding.
[2] Digitoxin (think digoxin, but not renally cleared) reduced death or HF hospitalization in HFrEF patients already on guideline-directed therapy.
[3] In high-risk patients with provoked VTE, 12 months of low-dose apixaban cut recurrent VTE from 10% to 1.3% with little major bleeding.