Evidence suggests that overstated concerns about bleeding with non-vitamin K antagonist oral anticoagulants (NOACs) are leaving many patients with non-valvular atrial fibrillation (NVAF) with renal dysfunction under-anticoagulated and therefore at risk for stroke.¹ To help put the risk of major bleeding associated with NOACs versus the risk of stroke due to NVAF into perspective, the limbic spoke with neurologist Associate Professor Andrew Lee, Director of the centre for neuroscience innovation and stroke, Flinders University College of Medicine and Public Heath, Calvary Wakefield Hospital.

Atrial fibrillation (AF) causes up to one in four ischaemic strokes, and when compared with ischaemic strokes due to other causes, these are often more severe and disabling.² NOACs have become standard of care for preventing new or recurrent ischaemic events in patients with NVAF, but evidence suggests that their benefits are not being accurately weighed up against the associated increased risk of major bleeding.^1,3

Fear of major bleeding with NOACs is leaving some patients at risk for stroke³

It has been suggested by some clinicians that using reduced doses of NOACs in various clinical scenarios, including those often associated with a frail state (e.g. age >75 years old, renal impairment), is prudent.⁴

However, in a propensity weighted nationwide study by Nielsen and colleagues assessing the effectiveness and safety of reduced dose NOAC regimens, apixaban 2.5 mg twice daily was associated with a non-significant trend towards higher rates of ischaemic stroke/systemic embolism compared with warfarin, while rivaroxaban 15 mg once daily and dabigatran 110 mg twice daily showed a non-significant trend towards lower thromboembolic rates compared with warfarin.⁵ In terms of bleeding rates, these were significantly lower for dabigatran, but not significantly different for apixaban and rivaroxaban, compared with warfarin.⁵

Furthermore, the two-year results from a retrospective claims database analysis by Martinez and colleagues showed that outcomes in frail NVAF patients treated with NOACs were generally consistent with the overall study population findings from phase III randomised trials.⁴ In this study, 56.1% of patients treated with apixaban received a reduced dose compared with 56.5% treated with rivaroxaban and 41.3% treated with dabigatran.⁴ Results showed that rivaroxaban, but not apixaban or dabigatran, was associated with reduced stroke/systemic embolism versus warfarin. None of the NOACs demonstrated a significant difference in major bleeding versus warfarin.⁴

A recently published, large, retrospective analysis by Yao and colleagues also demonstrated that in routine clinical practice in the USA, use of reduced dose apixaban among patients with no renal indication for dose reduction was associated with a nearly 5-fold higher risk of stroke (HR: 4.87; 95% CI: 1.30 to 18.26), but a similar risk of major bleeding (HR: 1.29; 95% CI: 0.48 to 3.42) compared with standard dose apixaban.¹ In contrast, there were no statistically significant relationships in dabigatran- or rivaroxaban-treated patients without a renal indication.¹

Associate Professor Lee highlighted, “A significant proportion of patients seem to be on a lower dose NOAC when there is no clinical reason for this… In general, the only reason to put a patient on a lower NOAC dose is not because of frailty or age, but because of reduced eGFR.”

Putting the risk of major bleeding with NOACs versus risk of stroke due to NVAF into perspective

According to the National Heart Foundation of Australia (NHFA) and Cardiac Society of Australia and New Zealand (CSANZ) Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018, “the net clinical benefit almost always favours stroke prevention over major bleeding, so bleeding risk scores should not be used to avoid anticoagulation in patients with AF. Higher scores might be used to alert the clinician to a greater need to attend to any modifiable bleeding risk factors.”³

Indeed, Associate Professor Lee highlighted, “If you look at any patient with an elevated CHA₂DS₂VASc score, there is an increased risk of stroke over 1 year of up to around 15%,⁶ but with a NOAC this risk drops down to around 2% or less regardless of how high the initial risk was.”⁴

Associate Professor Lee continued, “The risk of intracranial bleeding, my main concern as a neurologist, is then only around 0.2–0.5% with NOACs, which is actually similar to the risk associated with aspirin.⁷ The risk of major extracranial bleeding is higher than this, but it can generally be dealt with effectively by a surgeon.”

Assessing risk of stroke versus bleeding prior to initiation of a NOAC

According to the National Heart Foundation of Australia (NHFA) and Cardiac Society of Australia and New Zealand (CSANZ) as highlighted in their Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018, the CHA₂DS₂-VA score (i.e. the sexless CHA₂DS₂-VASc score) is recommended for predicting stroke risk in AF and this should be re-evaluated yearly in low-risk patients who are not anticoagulated.³ Oral anticoagulation therapy to prevent stroke and systemic embolism is recommended in all patients with NVAF whose CHA₂DS₂-VA score is 2 or more, unless there are contraindications to anticoagulation.³ To predict and minimise risk of bleeding associated with anticoagulation, the guidelines recommend that reversible bleeding factors should be identified and corrected.³

Associate Professor Lee explained, “I use the CHA₂DS₂-VA score to predict risk of stroke in my patients, but when it comes to bleeding, I don’t tend to use the HAS-BLED score as this was calibrated to a population using warfarin… The NOAC bleeding risk is different to that associated with warfarin, therefore, what I look at is how the patient would perceive the outcome of a bleed versus the outcome of a stroke.”

“For example, when I talk to a patient I usually say to them that if you had an ischaemic stroke, the chances are that you would end up disabled before dying and that the disability may last anywhere between 1 and 5 years before you would die from complications of the stroke. In contrast, if you had an intracranial haemorrhage, then chances are that you would die quickly or, if not, you would survive with minimal deficit.”

“This changes the way that the patient looks at the risks. And if they are concerned about GI bleeding, then you can explain to them that a surgeon can usually resolve this. What sticks in their mind then is the serious disabling impact of a stroke and that they would likely need institutional care as a result.”

Strategies for minimising risk of bleeding in patients with NVAF treated with a NOAC

Treating reversible bleeding risk factors such as hypertension, falls and peptic ulceration should be prioritised to minimise the bleeding rate in patients on anticoagulants.³ Furthermore, appropriate selection of NOAC dosage according to renal function is critical to reduce bleeding risk.³

According to Associate Professor Lee, “The major factor that causes bleeding in the brain is elevated blood pressure. In patients treated with a NOAC, I always make sure that blood pressure management is aggressive… I try to maintain blood pressure below 140/80 mmHg, preferably around 120/80 mmHg, and I also do 24-hour blood pressure monitoring every six months to make sure that average blood pressure is within the therapeutic range.”

“There are also potential issues around medication compliance so you want to use the simplest regimen. Obviously once daily dosing is simpler for patients than dosing more often than this. Finally, I monitor kidney function at least every six months.”

Conclusions

Stroke is a major cause of death and lifelong disability worldwide.^8,9 Stroke survivors may face severe movement restriction, paralysis, loss of speech, and loss of vision.^8,9 Family members may also experience loss of independence due to permanent physical and cognitive disabilities of stroke survivors.^8,9 Anticoagulants are critical in reducing this risk of stroke in patients with AF.³

Associate Professor Lee concluded, “For clinicians who are concerned about bleeding risk with NOACs, I recommend that they spend some time in a stroke unit so they better understand the serious consequences that these patients face over many years.”

For further information on the growing body of evidence supporting the use of NOACs for stroke prevention in AF, the Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018 can be accessed here.

This article was sponsored by Bayer Australia Ltd, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Bayer Australia Ltd.

References:

1. Yao X et al. J Am Coll Cardiol 2017;69:2779–90.
2. Wong CX et al. Heart Lung Circ 2017;26:870–9.
3. NHFA CSANZ Atrial Fibrillation Guideline Working Group. Heart Lung Circ 2018;27:1209–66.
4. Martinez BK et al. J Am Heart Assoc 2018;7:e008643.
5. Nielsen PB et al. BMJ 2017;356:j510.
6. Lip GY et al. Stroke 2010;41:273–8.
7. Hankey GJ. Curr Cardiol Rep 2014;16:480.
8. Wolfe C, Rudd A. The Burden of Stroke White Paper: Raising awareness of the global toll of stroke-related disability and death. March 2019. Available at: http://safestroke.eu/wp-content/uploads/2016/07/FINAL_Burden_of_Stroke.pdf. Accessed April 2019.
9. Atrial Fibrillation Society. The AF Report Atrial Fibrillation: Preventing a Stroke Crisis. Available at: http://www.preventaf-strokecrisis.org/files/files/The%20AF%20Report%2014%20April%202012.pdf. Accessed March 2019.