Short-Term DOAC Therapy Reduces Leaflet Thickening After TAVR: NOTION-4 Trial Results

NOTION-4 trial targets post-procedure leaflet thickening

Short-term direct oral anticoagulant therapy significantly reduces subclinical leaflet thickening following transcatheter aortic valve replacement. The benefit, however, diminishes after medication discontinuation.

Those are the findings of the NOTION-4 trial, published on August 30, 2026. The randomized controlled trial investigated antithrombotic treatment strategies for patients without an established indication for oral anticoagulation following successful valve procedures.

Evaluating risks in transcatheter aortic valve replacement

Researchers evaluated patients who underwent transcatheter aortic valve replacement without a pre-existing need for long-term oral anticoagulation, according to findings from the Nordic Aortic Valve Intervention Trial 4 presented in the journal JACC.

Severe symptomatic aortic valve stenosis carries a poor prognosis. It typically requires valve replacement using a bioprosthesis to eliminate chronic anticoagulant needs, as noted by the trial investigators led by Troels Højsgaard Jørgensen and colleagues.

Transcatheter procedures have become the most frequent approach to aortic valve replacement in Western countries, matching surgical alternatives in safety and efficacy.

The clinical puzzle of subclinical leaflet thrombosis

Following valve replacement, subclinical leaflet thrombosis—visualized on cardiac computed tomography scans as hypoattenuated leaflet thickening, or HALT—occurs in 20% to 30% of patients within the first year.

While several prior trials found no link between leaflet thickening and stroke or systemic embolism, other studies associated the finding with cerebrovascular events, retinal embolism, increased all-cause mortality, and bioprosthetic valve deterioration.

Anticoagulant therapy can lower the risk of leaflet thickening. Yet long-term use in patients without guideline-directed indications has not shown clear benefits and poses bleeding risks after transcatheter aortic valve replacement.

Randomizing 352 patients to test prevention strategies

To test prevention strategies, the NOTION-4 trial randomized 352 patients 1:1 shortly after successful procedures.

One hundred seventy-six patients were assigned to lifelong single antiplatelet therapy. Another 171 were assigned to three months of direct oral anticoagulant therapy followed by lifelong single antiplatelet therapy. Five patients were screen failures or withdrew consent.

At the three-month mark, hypoattenuated leaflet thickening was observed in 31.8% of patients receiving single antiplatelet therapy. This compared with 12.1% of those receiving the short-term direct oral anticoagulant regimen.

Discontinuation and the one-year evaluation

At the one-year evaluation, leaflet thickening occurred in 32.2% of single antiplatelet patients and 28.3% of direct oral anticoagulant patients with available computed tomography scans. This yielded a risk difference of −3.9% with a 95% confidence interval ranging from −14.4% to 6.6% and a p-value of 0.54.

The combined risk of all-cause mortality, stroke, or major and life-threatening bleeding at 12 months reached 2.3% in the single antiplatelet group versus 8.2% in the direct oral anticoagulant group. That represented a risk difference of 5.9% with a 95% confidence interval from 1.2% to 10.6%.

The trial authors concluded that three months of direct oral anticoagulant therapy successfully reduced the prevalence of leaflet thickening at three months compared with single antiplatelet therapy alone. However, investigators observed that this protective effect was attenuated by nine months after the discontinuation of the anticoagulant therapy.