Emerging Anticoagulation Therapies: A Key “Factor” in Secondary Stroke Prevention Following an Ischemic Stroke? 

Despite decades of medical progress, the number of people who experience a secondary ischemic stroke remains unacceptably high. According to the most recent data from the World Stroke Organization, there are over 13.7 million new strokes each year globally.¹ Even more concerning, up to 25% of survivors will experience a second stroke, often leading to serious, long-term disability.^2,3 Ischemic strokes are also common after transient ischemic attacks (TIAs), which represents another opportunity for secondary prevention. Although the threat of recurrent ischemic stroke can be lowered with the current mainstays of care, residual risk remains high, and safety is also a problem. Today’s options for intensified or long-term therapy are limited by an increased risk of bleeding.⁴ The ideal secondary stroke prevention strategy should aim to achieve greater efficacy without the persistent trade-off of increased risk of bleeding that has historically been observed with the addition of more potent antithrombotic agents to background standard of care (SOC) antiplatelet therapy.

The Holy Grail: Uncoupling the Coagulation Cascade

Antiplatelet drugs form the foundation of secondary stroke prevention after non-cardioembolic stroke today. The pivotal CHANCE, POINT and THALES clinical trials established that, when combined with aspirin, both clopidogrel and ticagrelor reduce the risk of stroke during the first 30-90 days after minor ischemic stroke or high-risk TIA. However, the risk of subsequent thrombotic events remains, and safe and effective therapies are still desired to improve outcomes even further.^5,6,7 In the absence of compelling evidence for an alternative, more effective antithrombotic treatment, long-term monotherapy with aspirin is recommended.⁸

Although antiplatelet strategies have been mostly effective, blocking thrombosis through the coagulation cascade has produced more limited benefits. For cardioembolic stroke, warfarin and direct oral anticoagulants are highly effective at reducing stroke risk but with a tolerable increase in bleeding risk.  For non-cardioembolic stroke, trials have suggested that anticoagulation may be effective at reducing ischemic events, but the benefit is balanced by an increase in major hemorrhage.  

We have come to accept that the benefits of anticoagulation may be attenuated by the risk of bleeding after non-cardioembolic stroke, but our crude approach to blocking the clotting cascade may be responsible. A more precise approach could potentially be a better option. 

Figure 1. Blood clot or thrombus blocking the red blood cell stream within an artery or a vein, 3D rendering illustration. 

To illustrate this possibility, I’m afraid we must revisit details of the clotting cascade that most of us have been happy to leave behind after our hematology finals in medical school, with the distinct intrinsic and extrinsic pathways. Warfarin targets multiple clotting factors (II, VII, IX and X) that impact clotting broadly. Direct oral anticoagulants target two key enzymes at the end of the coagulation cascade (thrombin or factor X).⁹ However, these drugs cannot distinguish between the hemostasis process that produces good clots and stops bleeding from the disease process that results in bad clots and causes thrombosis. However, some exciting trials are exploring the hypothesis that the coagulation pathways can be “uncoupled”, allowing for efficacy without elevated bleeding risk and opening up the possibility that antiplatelet agents and targeted anticoagulation may potentially be used effectively and safely together for secondary stroke prevention following an ischemic stroke.¹⁰

Figure 2. Role of FX in coagulation cascade. A, Initiation and propagation. B, Amplification. 

FXI: The Fringe Factor

Compared to other enzymes in the coagulation cascade, factor XI has historically been on the fringe in terms of attention from researchers. Discovered in the early 1950s, hereditary deficiency of factor XI (hemophilia C) is linked to lower risks of thrombotic disorders without an increase in spontaneous bleeding.¹¹ More recent research offers compelling evidence of its unique dual role as an essential component of the intrinsic pathway and in the amplification loop of clot formation. By selectively impairing the clotting system, inhibition of factor XI or XIa (its activated form) may hold the key to separating thrombus formation from bleeding, which has not been achievable by inhibiting the coagulation cascade at the final step or throughout. 

There is now a surge of interest in FXI(a) inhibition as a promising new target reflected by numerous late-stage compounds in clinical development for secondary prevention in non-cardioembolic stroke or TIA:

• An investigational once-daily oral factor XIa inhibitor is currently being evaluated in a phase III trial in patients receiving SOC antiplatelet therapy after acute non-cardioembolic ischemic stroke or high-risk TIA (OCEANIC-STROKE, NCT05686070). 
• An investigational twice-daily oral factor XIa inhibitor is currently being evaluated in a phase III study in addition to SOC antiplatelet therapy for stroke prevention after an acute ischemic stroke or TIA (LIBREXIA-STROKE, NCT05702034). 

Time for a New Breakthrough in Stroke Prevention

While we have embraced the mantra “time is brain” when it comes to acute stroke treatment, the same urgency has not been applied to secondary stroke prevention. When it comes to recurrent ischemic stroke, time delay to treatment is also an enemy. The first hours and days following an initial stroke is a high-risk period for secondary events which are often more complicated and life-threatening.⁹ New drugs need to be tested as soon as possible after ischemic events. Ideal drugs will be safe and effective in both the acute and chronic periods.

It’s time for another breakthrough in secondary stroke prevention, and it may come in the form of factor XI inhibitors, an entirely new class of antithrombotics. The promise of these emerging therapies is huge, not only for secondary prevention of ischemic stroke, but for stroke prevention in atrial fibrillation and also the prevention of thrombotic events across a range of cardiovascular diseases which collectively represent a tremendous health, economic, and societal burden worldwide. Bridging the gap between efficacy and safety has long been the dream. Could it become a reality? 

This information was developed by Bristol Myers Squibb and Johnson & Johnson in conjunction with Dr. Johnston for the Librexia-STROKE trial, a paid consultant of the companies.