Do Not Confuse Novelty With Progress: What Failed Anticoagulant Trials Teach Us About Modern Drug Development

Medicine is often attracted to novelty. A new molecular target, a different biological pathway, or a drug described as “first in class” can create understandable excitement among researchers, clinicians, investors, and patients.

But novelty is not the same as progress.

Recent trials of new anticoagulants provide a timely reminder. For more than a decade, four direct oral anticoagulants—apixaban, rivaroxaban, dabigatran, and edoxaban—have formed the practical foundation of oral anticoagulation for atrial fibrillation and venous thromboembolism. They are not identical, but they have created a mature and highly effective therapeutic class.

New factor XI inhibitors were designed to improve upon them. The scientific rationale was attractive: reduce pathologic thrombosis while preserving enough normal hemostasis to cause less bleeding. If successful, this might have been a major advance, especially for older people and patients at high bleeding risk.

The first results, however, show why biological elegance alone is not enough.

In OCEANIC-AF, asundexian produced substantially less major bleeding than apixaban. Yet it was clearly inferior for the outcome that makes anticoagulation necessary: prevention of stroke and systemic embolism. The study was stopped early because patients receiving asundexian had considerably more thromboembolic events. A safer drug is not a better drug if it no longer provides adequate protection against the disease it is intended to prevent.

 Abelacimab has produced a more encouraging safety signal. In AZALEA-TIMI 71, it markedly reduced bleeding compared with rivaroxaban. But the trial ended early for that safety advantage and was not able to establish whether stroke prevention was comparable over the longer term. That distinction matters. Less bleeding is a valuable achievement, but anticoagulation is a balance between hemorrhage and thrombosis—not a competition to produce the lowest bleeding rate. 

A lesson beyond anticoagulants

The broader principle is familiar throughout pharmacology. Once a medication class has achieved a high level of clinical effectiveness, the burden on any successor becomes much greater.

A new medicine should demonstrate one or more meaningful advantages:

• Better survival, fewer strokes, fewer heart attacks, or fewer recurrent disease events.
• Better quality of life or functional capacity.
• A clearly lower risk of important harm.
• Simpler dosing that improves real-world adherence.
• Greater usefulness in people often excluded from trials, such as older adults, patients with kidney disease, frailty, multimorbidity, or polypharmacy.
• Lower cost and better access.

If it does not improve one of these outcomes, a new medicine may be pharmacologically interesting but clinically redundant.

The same pattern occurs with ACE inhibitors, proton-pump inhibitors, statins, beta-blockers, and many other mature classes. The class often produces the main therapeutic benefit. Individual drugs may differ in dose schedule, metabolism, renal clearance, interactions, tolerability, or price; these details can be decisive for a particular patient. But they should not be confused with evidence that every new member of the class is a therapeutic breakthrough.

The hidden cost of “me-too” innovation

Large late-stage trials are expensive. OCEANIC-AF involved nearly 15,000 participants across an international research program. Although its total cost has not been publicly disclosed, a study of this scale almost certainly required hundreds of millions of dollars when global coordination, study visits, laboratory testing, monitoring, data management, drug supply, and earlier development work are considered.

Negative trials are not useless. They protect patients from ineffective or inferior treatments and teach us important biological lessons. In this case, they suggest that reducing bleeding through factor XI inhibition may not automatically preserve sufficient protection against embolic stroke.

Yet the opportunity cost deserves attention. How many strokes could be prevented if comparable resources were invested in identifying untreated atrial fibrillation, ensuring affordable access to proven DOACs, helping patients adhere to therapy, preventing dangerous drug interactions, and studying anticoagulation in frail older adults and people with advanced kidney disease?

Progress must be patient-centered

The next major change in anticoagulation may come not from a new mechanism, but from affordability. Generic rivaroxaban 2.5-mg tablets received FDA approval in 2025, while broad U.S. generic competition for apixaban remains constrained until at least April 2028. The current 2.5-mg generic approval does not itself create a generic option for standard full-dose atrial-fibrillation therapy, but it signals an eventual shift in the economic landscape. For clinicians and patients, the essential question is not, “Is this drug new?” It is: “Will this drug help this patient live longer, avoid stroke or thrombosis, experience less harm, take treatment reliably, and afford it?”

That is the standard medicine should apply to every promising new drug.

Do not confuse novelty with progress.

More about this topic can be found in the Index.

Mykola Iabluchanskyi together with Andriy Yabluchanskiy