‘Low-dose, off-label prescription of NOACs is a risky, misleading choice’

Atrial fibrillation (AF) is one of the most common arrhythmias, with a higher prevalence in older adults. It significantly increases the risk of stroke, and the number of patients is increasing with the aging population in many countries, including Korea. Currently, the main anticoagulants used to treat atrial fibrillation are “non-vitamin K NOACs (novel oral anticoagulants),” which are preferred over existing vitamin K antagonists (VKAs) for stroke prevention and bleeding safety.

Although NOACs have been in the field for over a decade, questions remain. Determining which formulation should be used in which patient remains a major challenge. It is also important to educate patients and healthcare providers so that they fully understand the risks and benefits of NOACs and can appropriately manage major side effects.

Korea Biomedical Review recently met with Professor Jan Steffel of the Department of Cardiology at the University of Zurich, Switzerland, during his recent visit to Korea to listen to the latest views on the treatment of atrial fibrillation with NOACs, the prevention of cerebral hemorrhage, and the management of bleeding risks. Professor Steffel is an associate editor of the European Heart Journal (EHJ) and the first author and co-author of the 2018 and 2021 European Heart Rhythm Association (EHRA) guidelines for prescribing NOACs in patients with atrial fibrillation.

Question: You were the first author of the European Heart Rhythm Association’s NOAC prescribing guidelines for patients with atrial fibrillation in 2018 and 2021. What was the message you wanted to emphasize with the guidelines?

Answer: The guidelines were first published in 2013 and updated several times. To put the guidelines in context, NOACs were brand new then. It's not uncommon for new drugs to come out, but this was a new concept in anticoagulation, so there was a lot of interest. However, there was a lack of information about the drugs, so people didn't know how best to use them or how to switch from other medications.

For example, there was a lack of practical guidance on what to do if a patient was taking the drug and needed surgery, how to prescribe it for patients who had had a stroke in the past, and how to handle patients with cardiovascular conditions, such as coronary artery disease (CAD). So, the guidelines contain much practical information that clinicians can use in their clinical practice.

Q: The need for active management of anticoagulation continues to be emphasized. With that in mind, what are the key considerations when choosing a NOAC agent?

A: When choosing the most appropriate NOAC for a patient, it is important to balance efficacy, risk, and safety, given that there may be an increased risk of bleeding in addition to the stroke-preventing benefits. Also, the four NOACs available to date—apixaban, rivaroxaban, dabigatran, and edoxaban—are not all the same. Despite similar mechanisms of action, clinical trial results and post-marketing real-world data (RWD) show different outcomes, so it is important to compare the drugs head-to-head.

Although there are no direct head-to-head comparisons, the safety profiles of Apixaban and Edoxaban are slightly better than those of the other two agents. In clinical practice, if you have a patient at risk of bleeding and you have to decide which agent to choose, I think it's a data-driven decision to choose one of these two agents.

Q: Are these two agents recommended for patients with kidney disease?

A: Clinical trial data suggest that rivaroxaban and dabigatran have a similar risk of major bleeding to VKAs in patients with reduced renal function. However, apixaban and edoxaban have been associated with significantly fewer major bleeds than VKAs.

Apixaban prescribing data shows a very small increase in the risk of major bleeding in patients with reduced renal function, suggesting that the safety of apixaban may be advantageous in patients with reduced renal function. In particular, patients with atrial fibrillation often develop renal deterioration over time. If they are already on apixaban, they may not need to switch to another drug or change their dose. If you were treated with another drug, you may need to reduce the dose or switch to a safer drug.

Q: So, what do you think about prescribing an off-label lower-dose apixaban in frail elderly atrial fibrillation patients? In Korea, the lower dose is only authorized for patients with non-valvular atrial fibrillation (NVAF) who have at least two of the following characteristics -- age, weight, and serum creatinine level.

A: I've heard of some patients reducing the dose to 2.5 mg instead of 5 mg due to concerns about bleeding risk, but attempting to reduce the dose in patients who don't meet the criteria for reducing the dose may create more risks. While it is true that the risk of bleeding is increased in frail or elderly patients, the risk of stroke is also increased in these patients. Dose reductions that don't meet the labeled criteria come at the expense of efficacy.

Off-label low-dose prescribing is not unique to Korea. It's happening worldwide. However, the reason we treat with anticoagulants is not to prevent bleeding but to prevent patients from having a stroke. We pay a lot of attention to the risk of bleeding with anticoagulant therapy, but we tend to pay less attention to the strokes that can occur if we don't adhere to the proper use and dosage. I think there needs to be a shift in thinking.

It's been proven that standardized doses have the same safety outcomes. That's why I want to emphasize the importance of using the dose rigorously validated in clinical trials rather than ignoring the licensed dose and arbitrarily reducing it.

Q: In February, the results of a large real-world study (ATHENS) were published that evaluated the risk of stroke, systemic embolism, and major bleeding events after switching to NOACs (apixaban, rivaroxaban) in patients with NVAF. What do these findings mean?

A: The study looked at switching from rivaroxaban to apixaban and from apixaban to rivaroxaban. It is interesting because it shows what happens when you switch to a different NOAC after being prescribed one.

The results showed that patients who switched from rivaroxaban to apixaban had no significant difference in the risk of stroke or systemic embolism compared to those who remained on rivaroxaban and had a significantly lower risk of major bleeding. Still, patients who switched from apixaban to rivaroxaban had a higher risk of stroke or systemic embolism and a higher risk of major bleeding compared to patients who remained on apixaban.

However, it is important to note that no causal relationship should be inferred from these findings. The study was not randomized like a randomized controlled trial (RCT). Instead of overinterpreting the results, it's best to take them as confirmation that the results predicted by RCTs have been consistently confirmed in real-world studies.

Q: Finally, we'd like to ask you what changes you expect to see in treating atrial fibrillation with NOACs and where you think they should go.

A: The patent expiration of some NOACs may change the prescribing landscape with the introduction of generic drugs. While the introduction of generics has the potential to reduce healthcare costs significantly, it can be problematic in that the optimal NOAC formulation for each patient may be different. In particular, some patients may choose a generic drug to save costs, even though the original drug may be the optimal treatment for them. It is important to emphasize the importance of selecting the appropriate formulation and personalizing treatment for each situation.

In addition, given that NOACs have been on the market for a considerable amount of time, there is now a large body of data. In the future, personalization of treatment will be the most important challenge, and we need to aggressively treat ultra-high-risk patients who may not have been treated in the past due to lack of data.

The introduction of NOACs a decade ago revolutionized medicine, and replicating that level of innovation won't be easy. Nevertheless, there is much room for further advances in treating atrial fibrillation. While it is important to discover and advance meaningful data and innovate, it is also important to make this data accessible to a broader audience to drive change and ultimately benefit patients.