Atrial fibrillation (AF) is one of the most common arrhythmias, with a particularly high prevalence in elderly patients. The risk of stroke significantly increases, and the number of patients increases with aging in many countries, including Korea. Currently, anticoagulants used primarily to treat atrial fibrillation are “non-vitamin K antagonists (NOACs)” and are recommended primarily in terms of stroke prevention and bleeding safety compared to existing vitamin K antagonists (VKAs).
Although NOAC agents were introduced into the field more than 10 years ago, there remain problems that need to be resolved. Deciding which agent to use for which patient remains a major challenge. It is also important to educate patients and healthcare professionals so that they fully understand the risks and benefits of NOAC agents and appropriately manage major side effects.
Accordingly, this article met with Professor Jan Steffel from the Department of Cardiology of the University of Zurich, Switzerland, who recently visited Korea, and heard the latest knowledge on the treatment of atrial fibrillation using NOAC agents, on the prevention of hemorrhage cerebral and on the management of hemorrhagic risk. Professor Jan Steffel was deputy editor of the European Heart Journal (EHJ) and co-authored the 2018 and 2021 European Arrhythmia Association (EHRA) NOAC prescribing guidelines for patients with atrial fibrillation as first author.
Professor Jan Steffel, Department of Cardiology, University of Zurich, Switzerland.
– Participated as first author in the guidelines on the prescription of NOACs of the European Arrhythmia Society in 2018 and 2021 for patients with atrial fibrillation. What message did you want to underline through these guidelines?
The guidelines were first published in 2013 and have been updated several times since then. To explain the context of the guidelines, NOAC agents were completely new drugs at the time. It is normal for a new drug to be released, but many people showed interest because it was the time when a new concept of anticoagulants was also introduced. However, due to a lack of information about the drug, they did not know much about optimal use and how patients taking other drugs should switch to this drug.
For example, what should be done if surgery is needed while taking this drug, how it should be prescribed to patients who have had a stroke in the past, and what should be prescribed to patients with cardiovascular diseases such as coronary artery disease (CAD)) . There was a lack of practical guidance on how to respond. Therefore, the guideline contains a lot of practical content that doctors can refer to when treating patients in clinical settings.
– The need for active management when using anticoagulants continues to be emphasized. In this regard, what are the main considerations to make when choosing a NAO agent?
When choosing the most appropriate NOAC agent for a patient, it is important to find a balance between efficacy, risk and safety, considering that the risk of bleeding may increase in addition to the stroke prevention effect. Furthermore, the four NOAC agents (apixaban, rivaroxaban, dabigatran, and edoxaban) released to date are not all the same. Although the mechanism is similar, the results are different when considering clinical trial results or real-world data (RWD) accumulated post-marketing. Therefore, it is very important to compare drugs.
Although there is no data directly comparing the drugs one-to-one, the safety of “apixaban” and “edoxaban” is slightly better than the other two drugs. In a clinical setting, if you have to decide which drug to choose for a patient at high risk of bleeding, I think choosing one of these two drugs is a data-driven decision.
– So these two drugs are also recommended for patients with kidney disease?
Clinical trial data demonstrated that the risk of major bleeding for rivaroxaban or dabigatran was similar to that for VKAs in patients with impaired renal function. On the other hand, apixaban and edoxaban have been shown to significantly reduce major bleeding compared to VKAs.
In fact, examining apixaban prescribing data, it was confirmed that the risk of major bleeding increases only slightly even in patients with reduced renal function. Therefore, the safety of apixaban may represent an advantage for patients with impaired renal function. In particular, patients with atrial fibrillation often experience worsening kidney function with long-term treatment, but if they are treated with Apixaban they can continue treatment without switching to another drug or changing the dosage. If you have been treated with another drug, you may need to reduce your dose or switch to a safer drug.
– So, what do you think about prescribing low-dose off-label apixaban to elderly patients with atrial fibrillation? In Korea, low-dose administration is permitted only in patients with non-valvular atrial fibrillation (NAVF) who have two or more of the following characteristics: age, weight, and serum creatinine level.
I have heard that there are cases where the dose is reduced to 2.5 mg instead of the existing 5 mg due to concerns about the risk of bleeding. However, attempting to reduce weight in patients who do not meet the criteria for weight reduction may actually cause greater risks. It is true that the risk of bleeding increases in frail and elderly patients, but the risk of stroke also increases in these patients. If you reduce the dose even if it does not meet the standards specified in the label, you face a lot of risks in terms of effectiveness.
Low-dose off-label prescribing is not just happening in Korea, but all over the world. However, the reason we treat with anticoagulants is not to prevent bleeding, but to prevent the patient from having a stroke. Although much attention is paid to the risk of bleeding due to anticoagulant treatment, relatively less attention is paid to stroke, which can occur if correct use and dosage are not followed. I think a change of mentality is needed.
And it has been shown that even using the standard dose the results in terms of safety are the same. Therefore, I would like to emphasize that it is very important to use a dosage that has been rigorously verified through clinical trials rather than ignoring the approved use and dosage and reducing the dosage arbitrarily.
– Last February the results of a large-scale real-world study (ATHENS) were announced that evaluated the risk of stroke, systemic embolism and major bleeding due to switching to NOAC agents (apixaban, rivaroxaban) in patients with NAVF. What do you think the research results mean?
A study was conducted on switching from rivaroxaban to apixaban or from apixaban to rivaroxaban. This is a very interesting study as it shows what results are achieved by switching to another NOAC agent after prescribing a NOAC agent.
As a result of the study, patients who switched from rivaroxaban to apixaban showed no significant difference in the risk of stroke or systemic embolism compared to patients who maintained rivaroxaban, and the risk of major bleeding was significantly reduced. On the other hand, patients who switched from apixaban to rivaroxaban had a higher risk of stroke or systemic embolism and major bleeding than patients who continued apixaban treatment.
However, one thing to be careful about is that a causal relationship should not be inferred that this outcome occurred for some reason. This is because random assignment was not done as in a randomized controlled trial (RCT). Rather than overinterpret this, it would be better to accept it as the fact that the results that can be predicted from randomized trials have been consistently confirmed in real-world studies.
– Finally, I would like to ask what changes are expected in the treatment of atrial fibrillation with NOACs and in which direction it should develop.
The prescribing environment may change with the emergence of generic drugs due to patent expiration for some NOAC agents. The launch of generic drugs has the advantage of significantly reducing medical costs, but can be problematic as the optimal NOAC agent may differ for each patient. In particular, although the original drug may represent the optimal treatment for some patients, a situation may arise where they choose a generic drug for cost-saving reasons. I would like to emphasize once again the importance of selecting the appropriate agent and personalized treatment for each situation.
Furthermore, since it has been a long time since NOAC agents were released, a lot of data has currently been accumulated. In the future, personalized treatment will be the most important task. Furthermore, active treatment is needed for very high-risk patients who have previously been unable to receive treatment due to lack of data.
When NOAC agents appeared 10 years ago, they can be said to have brought innovation to the medical world, but it will not be easy to reproduce this level of innovation again. However, I think there is still a lot of room for further development in the treatment of atrial fibrillation. It is important to discover and develop a lot of meaningful data and promote innovation, but I think it is desirable to make this data accessible to more people to make changes and ultimately benefit patients.
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