The new drug was terminated early because the effect was too obvious.

Anticoagulation is required to treat atrial fibrillation, but anticoagulation therapy is prone to carry the risk of bleeding; the new drug draws inspiration from research and observations on hemophilia and partially resolves this contradiction.

Written by Li Changqing (Doctor of Medicine, practicing physician in the United States)

A friend sent me a recent report on the progress of new drugs. The main content is that the new anticoagulant drug Abelacimab for the treatment of atrial fibrillation was terminated early in clinical trials because its effect was too obvious. This is probably the best result that a drug clinical trial can expect: not only is it successful, but it also takes much less time and money than expected.

This trial is to compare the effects of abelacizumab and rivaroxaban in patients with atrial fibrillation, and to evaluate the incidence of adverse reactions of both. Rivaroxab is one of the current standard anticoagulants for the treatment of atrial fibrillation, and the biggest adverse reaction of anticoagulant therapy is an increased risk of bleeding. The interim analysis of this trial showed that compared with rivaroxaban, abelacizumab significantly reduced the risk of bleeding while ensuring the anticoagulant effect.

To understand this new drug, we need to first understand atrial fibrillation as a disease.

How does atrial fibrillation occur?

Atrial fibrillation is short for atrial fibrillation, a very common arrhythmia. According to statistics from the American Heart Association (AHA), about 2.7% of American adults suffer from atrial fibrillation. Statistics in China vary, and the adult incidence rate is roughly between 1-5%.

To understand atrial fibrillation, we must first understand some common sense about heart beats. We all know that the heart is divided into atria and ventricles. The atria receive blood from the veins and transport the blood to the left and right ventricles through the mitral valve and tricuspid valve respectively. The latter then transports the blood to the whole body and into the pulmonary circulation. The movement of the heart is beating or pulsating. The pulse we often feel is the pulsation transmitted from the left ventricle to the radial artery.

Not only does the movement of the ventricles beat, but the atria also beat continuously. The left and right atria usually beat 0.1 seconds earlier than the corresponding ventricles. This is because the atria are upstream of the conduction of myocardial pulsation electrical signals. The starting point of the heart's pulsation signal is the sinoatrial node, which regularly sends electrical signals to the atria to generate atrial pulsation, then reaches the atrioventricular node, and then is transmitted to the ventricles through the left and right pathways to generate ventricular pulsation.

However, some heart diseases, drugs, alcohol and systemic diseases will disrupt this regularity, and the atria will no longer beat or pulse regularly, but will quiver irregularly. Under the influence of the atria, the ventricular beats also become irregular, showing different strengths and speeds. This kind of heartbeat is too characteristic and is one of the few heart diseases that can be correctly diagnosed by taking the pulse.

Why is anticoagulation necessary for the treatment of atrial fibrillation?

If atrial fibrillation causes the heart to beat too fast, reaching more than 120 beats per minute, or produces obvious symptoms such as palpitations and dyspnea, the heart rate needs to be controlled as soon as possible, otherwise it will lead to heart failure. After the heart rate is controlled, anticoagulant treatment needs to be considered.

Unlike the ventricular myocardium, the contractile force of the atrium is not strong, and it is even more difficult to generate effective power to promote blood flow in the state of atrial fibrillation. Irregular beating also increases blood turbulence. In some special corners of the atrium, such as the auricle, the blood flows more slowly, forming stagnant "dead blood". When the blood flow slows down, the blood coagulation system is activated locally. Platelets and coagulation factors in the blood form blood clots through a waterfall reaction. The blood clots fall off from the atrium to form emboli, which will flow throughout the body with the blood, blocking local blood vessels and forming infarction, also called embolism. Complications that may be caused include stroke, splenic embolism, renal embolism, intestinal ischemia, etc. According to different research results, about 15-20% of strokes are caused by atrial fibrillation.

The formation of blood clots and emboli is due to the activation of the coagulation system, so the purpose of anticoagulant therapy is to inhibit coagulation factors, prevent blood clots from forming, and thus reduce the risk of embolism.

Different patients with atrial fibrillation have different risks of accidents such as stroke. Currently, the CHA2DS2-VASc score is commonly used internationally as the basis for anticoagulant treatment. This string represents 8 risk factors, which are:

C - Congestive Heart Failure: Score 1 point if the patient has congestive heart failure.

H - Hypertension: Score 1 point if the patient has high blood pressure.

A2 - Age ≥75 years: 2 points if the patient is 75 years old or older.

D - Diabetes Mellitus: Score 1 point if the patient has diabetes mellitus.

S2 - Prior Stroke or TIA: If the patient has a history of stroke or transient ischemic attack (TIA), 2 points are awarded.

V - Vascular Disease: 1 point if the patient has a history of cardiovascular disease (such as myocardial infarction, peripheral arterial disease, etc.) or aortic valve disease.

A - Age 65-74 years: Score 1 point if the patient is between 65 and 74 years old.

Sc - Sex Category: Score 1 point if the patient is female.

The higher the score, the greater the risk of atrial fibrillation combined with unexpected events such as stroke, and the more likely the doctor will be to recommend anticoagulant therapy.

The principles and side effects of anticoagulation

There are many types of anticoagulant therapy, all based on the understanding of coagulation reactions. Factors related to coagulation are represented by Roman numerals, and different anticoagulant drugs often target one or more coagulation factors.

Our human body has so many coagulation factors, not to cause trouble and create blood clots, but to have important physiological functions, the most important of which is to stop bleeding. Therefore, the main adverse reaction of anticoagulant therapy is bleeding. The most common is gastrointestinal bleeding, and the most serious is intracranial hemorrhage.

Corresponding to CHA2DS2-VASc, the HAS-BLED score is generally used internationally to predict the bleeding risk of anticoagulant therapy. The score includes:

H (Hypertension): If the patient has high blood pressure, score 1 point.

A (Abnormal Renal/Liver Function): If the patient has abnormal renal or liver function, get 1 point.

S (Stroke): If the patient has a history of stroke or transient ischemic attack, 1 point is given.

B (Bleeding History): 1 point if the patient has a bleeding tendency or history of bleeding.

L (Labile International Normalized Ratio, unstable international normalized ratio): If the patient's international normalized ratio (INR, which is an indicator of the patient's coagulation function, the higher the value, the longer the coagulation time) is unstable, 1 point will be awarded.

E (Elderly): If the patient is 65 years old or older, score 1 point.

D (Drugs/Alcohol Concomitantly): 1 point if the patient's anticoagulant therapy is used concurrently with other anticoagulant drugs or alcohol.

Compared with the previous CHA2DS2-VASc score, it can be found that some factors are high-risk factors for both thromboembolism and bleeding, such as advanced age and hypertension. It is not uncommon for the two scores to give almost the same risk in clinical practice, which poses a difficult choice for both patients and doctors.

Optimal anticoagulation therapy

There is no doubt that the ideal anticoagulant should be both an anticoagulant and not affect hemostasis. Rivaroxaban is a relatively new oral anticoagulant, and has considerable advantages over more traditional anticoagulants such as heparin and warfarin. For example, it does not require regular monitoring of coagulation indicators and is more convenient to use. However, it still increases the risk of bleeding, and even compared with other new oral anticoagulants, such as apixaban, rivaroxaban has a higher risk of bleeding. However, rivaroxaban only needs to be taken once a day, and this advantage cannot be ignored for drugs that need to be taken for a long time and compliance is crucial to the effect.

The site of action of rivaroxaban, a conventional treatment, is coagulation factor X, while the experimental new drug abelasimab mentioned at the beginning of this article targets coagulation factor XI.

The inspiration for the development of this drug comes from clinical observations of hemophiliacs. Hemophilia is a bleeding disease caused by the lack of a certain coagulation factor in the blood. According to the type of factor deficiency, it is divided into three types: A, B and C. The first two are due to the deficiency of coagulation factors VIII and IX, respectively, and the third type of hemophilia C is due to the deficiency of coagulation factor XI. Clinically, it has been found that patients with hemophilia C have a milder tendency to bleed, while at the same time the risk of thromboembolism is lower than that of ordinary people. So people think that coagulation factor XI may be mainly involved in the formation of blood clots, but it has little effect on hemostasis. Artificial inhibition of coagulation factor XI has become an ideal anticoagulant treatment. At present, there are many ways to treat factor XI, including antibodies, small molecule drugs, antisense oligonucleotides, etc. Abelacizumab is one of the antibodies. As early as August 2021, in a report published in the New England Journal of Medicine, abelacizumab was shown to reduce venous thromboembolism in patients undergoing knee replacement by 80%.

After preliminary animal and phase 2a clinical trials, the multicenter, randomized controlled phase 2b trial was officially launched. Abelacizumab only needs to be injected subcutaneously once a month, and it cannot be compared with the oral drug rivaroxaban in a double-blind manner. However, the experimenters set up two test groups of abelacizumab 90mg and 150mg, and implemented a double-blind comparison between the two test groups.

Why the trial was terminated early

So, why did an experiment that was going well suddenly stop and not continue?

This involves one of the prerequisites that must be adhered to in clinical drug trials, clinical equipoise, which can be translated into Chinese as clinical equilibrium or clinical balance. It means that when designing a clinical trial, the designer does not really know which of the two or more therapies being compared is more effective. In this way, when the patients participating in the trial are divided into different treatment groups using a random method, the benefits that everyone may obtain and the risks and opportunities they face are equal, reflecting the three principles of respect, benefit, and fairness in clinical research.

For clinical trials with patients as subjects, it is also necessary to ensure that patients receive appropriate treatment. Unless there is a consensus that there is no effective treatment, try not to use a placebo control. The current common trial design is to compare with a drug that has been approved and widely used, but has various defects, just like the trial described in this article.

There have been many cases where trials were stopped because of a break in clinical equilibrium, and most of them were not good, such as a lack of patient recruitment, lack of significant results, too many adverse reactions, insufficient funding for the trial, etc. As mentioned earlier, early termination because the trial was too effective is what everyone wants to see the most.

In order to maximize the benefits of trial participants and reduce risks, many clinical trials will entrust an independent data monitoring committee to conduct real-time analysis of the trial data. When the committee finds that the current data is sufficient to draw a conclusion, the trial can be terminated early - because the clinical equilibrium of the comparative therapy has been broken by the existing data. If it continues, it will violate the assumption of clinical equilibrium. For newly recruited and continuing patients in the trial, patients assigned to the treatment group with low efficacy will obviously face unfair treatment. The early termination of this trial was because the analysis found that the bleeding events of patients using abelacizumab were much lower than those of patients using rivaroxaban. Those patients who are currently using rivaroxaban should be informed and provided with the opportunity to switch to abelacizumab.

Since the test data is so optimistic, is it certain that the new drug will replace many of the currently commonly used anticoagulants? Not necessarily. This first depends on whether the pharmaceutical company submits a new drug application based on Phase II clinical trials to the FDA, and the FDA's decision. Even if it is really approved, it is unlikely to completely replace existing drugs. Just like traditional anticoagulants such as warfarin, although the risk of bleeding is high, there are large individual differences, and frequent blood draws are required, but because of its low price, it is still in use. The most likely scenario is that it will first pass the indication for use in patients with a higher risk of bleeding (such as those with a history of gastrointestinal bleeding).

The exploration of anticoagulation therapy for patients with atrial fibrillation can be seen as one of the typical examples of "preventive treatment" in modern medicine. Basic medicine (pathophysiology of bleeding and coagulation) is still the premise of exploration, clinical medicine (different clinical manifestations of hemophilia patients) provides new ideas, evidence-based medicine provides tools to solve problems (discovering problems that need to be solved, designing and interpreting clinical trials), and medical ethics runs through it all (patient-centered, maximizing benefits and minimizing risks).

Health issues are so complex and significant that they undoubtedly deserve such serious exploration.

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

Special Tips

1. Go to the "Featured Column" at the bottom of the menu of the "Fanpu" WeChat public account to read a series of popular science articles on different topics.

2. Fanpu provides a function to search articles by month. Follow the official account and reply with the four-digit year + month, such as "1903", to get the article index for March 2019, and so on.

Copyright statement: Personal forwarding is welcome. Any form of media or organization is not allowed to reprint or excerpt without authorization. For reprint authorization, please contact the backstage of the "Fanpu" WeChat public account.