Management typically involves medications to control heart rate and rhythm (beta-blockers, antiarrhythmics), anticoagulants to prevent stroke, and lifestyle modifications. In some cases, procedures like electrical cardioversion or catheter ablation may be necessary to restore normal heart rhythm. Catheter ablation is a minimally invasive procedure that uses heat or cold to create small scars in the heart tissue, blocking the abnormal electrical signals that cause AFib. In a previous post, I described a new procedure, related to catheter ablation, called Pulsed Field Ablation (PFA) that uses short electrical field pulses to disrupt the cell membrane of the heart tissue, leading to cell death and scar formation at certain positions in the heart to block the abnormal electrical pathways causing AFib. The electrical pulses selectively target the cardiac cells while minimizing damage to surrounding tissues.
For those in whom the arrhythmia cannot be reversed, then medications are often prescribed to reduce stroke risk. Because AFib increases the likelihood of blood clots leading to strokes, anticoagulant medications (blood thinners) can prevent this complication. The two main types of anticoagulants (both oral) are the older Vitamin K antagonists (VKA) and the newer Direct Oral Anticoagulants (DOACs).
The main VKA is Warfarin (Coumadin) which was the standard treatment for many years. Warfarin requires regular blood tests to ensure the dose is correct i.e. it has a narrow therapeutic window (too much can cause excess bleeding, and too little may not provide enough efficacy against clotting risk). It also has many food and drug interactions, making it more challenging to manage. Warfarin's mode of action is as a vitamin K antagonist. Vitamin K is essential for the proper function of several clotting factors (specifically factors II (prothrombin), VII, IX, and X). These factors are synthesized in the liver, but they require a specific post-translational modification to become active, and this modification reaction requires the reduced form of vitamin K as a cofactor. By inhibiting the reaction that converts vitamin K to its active reduced form, Warfarin can decrease the levels of the vitamin K dependent clotting factors, reducing the ability to form blood clots.
A newer generation of drugs called Direct Oral Anticoagulants (DOACs) have been developed, and they are generally preferred over warfarin due to their:
- More predictable effects
- Fewer drug and food interactions
- No need for frequent blood tests to adjust the dose
More popular DOACs include Apixaban (Eliquis), Rivaroxaban (Xarelto), Dabigatran (Pradaxa), and Edoxaban (Savaysa). Unlike warfarin, these drugs directly target a specific step in the coagulation cascade. For example, Apixaban and Rivaroxaban bind directly and reversibly to the active site of factor Xa, which plays a critical role in the blood coagulation cascade as described below (Figure 1).
However, bleeding, particularly gastrointestinal bleeding, remains a major complication of DOACs.
This side effect leads to substantial undertreatment of patients with anticoagulants. Therefore, a need exists for safer anticoagulant options. Enter a new class of drugs that inhibit a different clotting protein, Factor XI. But first some background on the clotting process.
Hemostasis is the body's natural process of stopping bleeding and preventing excessive blood loss after an injury to a blood vessel. It involves the action of a series of enzymatic reactions in which inactive clotting factors (proteins primarily made in the liver) are sequentially activated in a cascade (Figure 1). The end result is a fibrin clot which is formed when fibrin monomers polymerize to form long, insoluble fibrin strands. These strands form a meshwork that traps red blood cells, platelets, and plasma, creating a stable blood clot.
It is important to distinguish hemostasis from thrombosis. The former stops bleeding from an injury; the latter is pathological clot formation such as stroke in which a clot forms where it is not supposed to (e.g. in an artery in the brain) and obstructs blood flow where it is needed.
Thrombin is the key enzyme that catalyzes clot formation by converting fibrinogen (Factor I) to fibrin. In addition, thrombin activates Factor XIII, which cross-links fibrin strands, stabilizing the clot. Finally, thrombin provides positive feedback by activating Factors V, VIII, and XI, amplifying the cascade (Figure 1).
There are two pathways to activate thrombin: The extrinsic pathway is initiated by tissue factor (Factor III), a protein released from damaged cells outside the blood vessel. This pathway is the "spark" that quickly generates a small amount of thrombin, i.e. initiates clotting ("initiation phase" in Figure 1). The intrinsic pathway (called "intrinsic" because all the necessary factors for activation are already present in the blood) provides the amplification so that the clot can expand to cover the wound. It involves the activation of Factor XI to Factor XIa (active form) which in turn activates Factor IX to Factor IXa. Factor IXa, in complex with Factor VIIIa (which is activated by thrombin), then activates Factor X to Factor Xa. Factor Xa in a complex with Factor Va converts prothrombin (Factor II) to thrombin (Factor IIa).
Based on the above description, Factor XI stands out as an attractive target for a new generation of anticoagulants that do not target Factor X in a condition like AFib where the primary goal is to prevent thrombosis (stroke) while minimizing the risk of bleeding. More specifically, inhibiting Factor XI may disrupt the amplification of the coagulation cascade that contributes to pathological clot formation from a random clotting signal without severely impairing the body's ability to form clots in response to a more sustained clotting signal from an injury. Indeed, individuals with a genetic deficiency in Factor XI (hemophilia C) typically experience mild bleeding, often only after surgery or trauma. This is in stark contrast to deficiencies in Factor VIII (hemophilia A) or Factor IX (hemophilia B), which cause severe bleeding
With this in mind, the biotechnology company Anthos Therapeutics developed the monoclonal antibody abelacimab which binds to factor XI, locking it in its inactive state, as well as inhibiting activated factor XI (XIa). Abelacimab is quite potent rapidly suppressing factor XI activity within 1 hour and maintaining near-maximal inhibition for up to 30 days. It is delivered by a subcutaneous injection once a month.
A new study reported in The New England Journal of Medicine performed a randomized controlled trial in which patients with atrial fibrillation who were at a moderate-to-high risk of stroke were either given abelacimab or one of the standard-of-care DOACs, rivaroxaban (Xarelto). Patients were randomly assigned to one of three groups (1:1:1 ratio): 1) Abelacimab 150 mg (subcutaneous injection, once monthly); 2) Abelacimab 90 mg (subcutaneous injection, once monthly); and 3) Rivaroxaban 20 mg (oral, once daily).
There were 1287 patients with a median age of 74. Abelacimab reduced Factor XI levels by 99% in the 150 mg dose group, and by 97% in the 90 mg dose group. The median follow-up time was approximately 2 years. The primary outcome measured was the occurrence of major or clinically relevant nonmajor bleeding. Thrombotic events were also monitored.
The results were striking with a significant decline in clinically relevant nonmajor bleeding (per 100 person-years) in the abelacimab-treated patients. The incidence rates (Hazard Ratios , HR, with respect to rivaroxaban, and statistical significance) were:
- Abelacimab 150 mg: 3.2 events (HR = 0.38, P<0.001)
- Abelacimab 90 mg: 2.6 events (HR = 0.31, P<0.001)
- Rivaroxaban: 8.4 events
28 patients experienced stroke or systemic embolism (blockage in blood vessel) with the abelacimab groups exhibiting a higher incidence rate than the control rivaroxaban group: 150-mg abelacimab (1.21), 90-mg abelacimab (1.24), and Rivaroxaban (0.59). However, the small number of events resulted in wide confidence intervals so that the differences were not statistically significant.
Altogether, there were 78 deaths from all causes with mortality incidence rates per 100 person-years of
2.65 (abelacimab 150 mg), 3.20 (abelacimab 90 mg), and 3.52 (rivaroxaban).
Combining all of these results into a single net clinical outcome (composite of ischemic stroke, systemic embolism, major or clinically relevant nonmajor bleeding, or death from any cause) favored abelacimab in a statistically significant fashion over rivaroxaban: 1) 150-mg abelacimab, HR = 0.55 (95% CI, 0.39 to 0.77), and 90-mg abelacimab, HR = 0.58 (95% CI, 0.41 to 0.81).
In summary, the authors concluded somewhat conservatively (NEJM):
"Among patients with atrial fibrillation who were at moderate-to-high risk for stroke, treatment with abelacimab resulted in markedly lower levels of free factor XI and fewer bleeding events than treatment with rivaroxaban."
One reason for the understated conclusion was that the overall efficacy of abelacimab with respect to atrial fibrillation presents a somewhat mixed picture depending on which outcome is emphasized, i.e. excessive bleeding or thrombosis prevention. This uncertainty is a reflection of the balance that must be struck between too much and too little coagulation. One can imagine for patients who are experienceing bleeding events on a DOAC may want to switch to abelacimab, but those who are tolerating the DOAC well may want to stay on the DOAC. Regardless, having more options available is a good thing to discuss with one's doctor.
Figure 1. Blood coagulation pathway which is divided into the extrinsic (initiation) and intrinsic (amplification) branches. Factor XI acts in the intrinsic pathway in an outer feedback loop that helps to strengthen clotting without being absolute essential, making it a good target for an anti-coagulant treatment (Wikipedia).
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