Atrial fibrillation (AF) is the most common cardiac arrhythmia and an important risk factor for stroke. It increases the risk of stroke by 5-fold. Non-vitamin K antagonist oral anticoagulants (NOACs) offer a new standard of care in preventing AF-related strokes.

From 2000 to 2016, the prevalence of recorded AF in the UK increased in all age groups and both sexes. Anticoagulant treatment of eligible patients with AF has more than doubled, with marked improvements since 2011 when NOACs became more available. However there had been a lack of consensus on the safety of NOACs for high risk patients with comorbidities before the 2017 European Society of Cardiologist guidelines were published, and even a year later some doctors are hesitant to prescribe NOACs to high risk patients despite the new guidelines.

We caught up with Professor Sylvia Haas, the grand doyenne of NOACs at the Asian Pacific Society of Cardiology (APSC) 2018 Congress in Taipei. Haas is Emeritus Professor of Medicine and Former Director of the Haemostasis and Thrombosis Research Group at the Institute for Experimental Oncology and Therapy Research, Technical University of Munich. She has been involved in the research and development of direct Factor Xa inhibitor NOACs for more than 25 years.

During her presentation, Haas pointed out that although the use of NOACs for stroke prevention has increased some doctors are still not prescribing them to patients with comorbidities, potentially putting millions of patients at greater risk of stroke than they need be. Like in any anticoagulant medications, major bleeding is a consideration of doctors when prescribing NOACs for AF patients. Haas discussed how patient characteristics drive bleeding risk and what doctors should consider when assessing a NOAC’s evidence and experience in patients with varying risk profiles.

What are the key things to consider when choosing a NOAC for AF patients in stroke prevention?

I would look at the pivotal phase III trials of the NOAC and then compare its design and findings with that of its phase IV studies, which provide data in real-world clinical practice. In this regard, I would give more weight to real-world prospective studies. Of course, whilst retrospective data analysis can inform our decision-making, my main concern with these studies is that we often do not have all the relevant information. For instance, we know what dose was prescribed but we don’t know how the medication was taken. Was it a once daily or twice daily dosage, and what were the compliance rates? This type of information, which could affect the accuracy of the study results, is usually missing. That’s why I prefer to base my decisions on prospective real-world data.

Next, we must consider the individual patient’s characteristics. Does the patient have comorbidities (like uncontrolled hypertension or heart failure) which affect the risks for stroke and bleeding? Another important factor to consider is the patient’s kidney function. If kidney function is impaired, we can make a clear decision to not use a NOAC mainly excreted via the kidneys and select a NOAC which is more suitable.

For high-risk AF patients with impaired kidney function, what are your challenges in prescribing NOACs to prevent stroke in these patients?

My view is that kidney impairment is not a challenge for a NOAC, it is an opportunity. When compared to the traditional Warfarin therapy, which is not suitable for these patients, the Factor Xa inhibitor NOACs are much better options for these patients. In this regard, we should distinguish between the NOACs available so far. The Factor Xa inhibitor NOACs, which act directly upon Factor X in the coagulation cascade are much less excreted via the kidneys than another NOAC directly inhibiting thrombin. This direct thrombin inhibitor is mainly excreted via the kidneys unchanged. Therefore, any reduction in kidney function can affect the plasma concentration of the medicine and its action. This naturally narrows our choice amongst the available Factor Xa inhibitor NOACs for patients with kidney impairment.

Would body weight, age, and frailty be also reasons to consider a lower dosage of NOAC for AF stroke prevention?

This is something that is intuitively done by many doctors. But I would again refer to the Phase III ROCKET AF study, which included elderly patients with higher risk of both stroke and bleeding. In this group, the standard 20mg dose of rivaroxaban performed very well. Hence, age would not be a major factor in my choice of dosing.

As for body weight, whilst we don’t have a specific subgroup analysis, low body weight is often associated with reduced kidney function. In particular, some doctors intuitively prescribe lower doses of NOACs for smaller-sized ladies. However, I would always recommend testing the patient’s renal function first before deciding on a dose reduction. We have clear guidance that impaired kidney function should be the key consideration for a lower dose of a NOAC. Specifically for rivaroxaban, its dosing guidelines recommend a reduced dose of 15 mg for patients impaired kidney function regardless of other patient risk factors.

Is there any evidence that higher doses of NOACs significantly increase the risk of bleeding?

The bleeding risk of an AF patient is not exclusively correlated with the dose of the anticoagulant used by the patient. In fact, it is the patient’s characteristics which drive the bleeding risk. CHADS2 or CHADS2VaSC scores determine the stroke risk of an AF patient, and these scores largely correlate with the bleeding risk of the patient when taking a NOAC. Patients with higher CHADS2 or CHADS2VaSC scores tend to also have higher rates of bleeding. One should also consider other factors which could increase a patient’s bleeding risk, such as concomitant medications, and alcohol consumption.

Professor Sylvia Haas is a Professor of Medicine and the former Director of the Haemostasis and Thrombosis Research Group at the Institute for Experimental Oncology and Therapy Research, Technical University of Munich in Germany. Professor Haas’s extensive research focused on the development of innovative anticoagulant therapies, laboratory monitoring of anticoagulants, biomarkers, and tumour-associated thrombosis. She is actively involved in several clinical trials centred around the prevention and treatment of arterial and venous thromboembolism.

John Battersby has been a science and technical writer for more than 20 years. For the last decade he has focused on medical and healthcare issues writing on diverse topics including dentistry, cardiology, immunology and pharmaceuticals. He has lived in South East Asia for twenty years, mainly in Singapore, working as a freelance journalist and media adviser to the pharmaceutical industry.