The biggest challenge in preventing stroke in older patients with non-valvular atrial fibrillation (NVAF) still remains that many who would benefit from anticoagulation are not receiving it say experts who argue that age alone should not be the only criterion guiding the decision of whether to offer the blood thinning medication to the elderly.
“Data consistently shows, with all of the DOACs [direct oral anticoagulants], that the lower dose is used more frequently than you would expect from the parameters for dose reduction seen in clinical practice,” said director of the Heart Failure Unit and Department of Cardiac Rehabilitation at Concord Hospital Professor Andrew Sindone.
Speaking to the limbic about the evidence surrounding use of the therapy in elderly and frail patients he said clinicians too often opt for a lower dose to counter the risk of bleeding without recognising that they may be compromising the effectiveness of the drug in reducing stroke.
“That kind of conservatism shouldn’t be part of your thinking,” he told the limbic adding that, for elderly patients especially, the DOACs improved safety profile compared to warfarin has changed the way clinicians balance the risk-benefit coagulation equation.
“Atrial fibrillation is the biggest risk factor for stroke – around 75% of these strokes are directly related to atrial fibrillation and 35% or more of stroke in patients over 80 years of age is mostly due to AF. You accept some extra bleeding risk because the clinical consequence of having a stroke is far greater than the clinical consequences of a bleeding event.”
The burden of stroke in AF
Neurologist and Regional Director of Stroke Medicine at Adelaide Health Service, Professor Andrew Lee, sees the impact of AF-related stroke in patients who either haven’t been offered anticoagulation or who have been treated with an insufficient therapeutic dose in a bid to stave off a major bleeding event.
Talking to the limbic he said the biggest challenge in managing AF in the elderly is being appropriately aggressive with anticoagulation in the modern era of DOACs.
“Most clinicians involved in treating AF don’t see the outcome of stroke,” he said explaining that stroke mortality ranges from about 20% at one year to around 30-50% at five years.
“The key issue is this: you don’t die because of the stroke; you die because of the medical complications of your immobility – you die of pneumonia, DVT, pressure sores and sepsis you have a very poor quality of life leading up to death and that’s the consequence of stroke.”
Today, Professor Lee says clinicians need to consider in which NVAF patients anticoagulation should not be used rather than, as in the warfarin era, deciding in which patients it should be used.
“There are still a lot of clinicians who are just unwilling to put older people on an anticoagulant and I think the problem arises when there’s a perception that the DOACs are the same or similar to warfarin when they are not. These are completely different chemical structures, they act differently on the coagulation cascade and the risk of bleeding on these agents is so much less than warfarin. I’ve had people in their 90’s who I would never dream of putting on warfarin but who I would put on a DOAC and wouldn’t see any problem with that.”
According to Professor Lee, the introduction of the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban and apixaban almost a decade ago as an alternative to warfarin for preventing stroke or systemic embolism in patients with NVAF has completely changed the way the condition is managed in Australia.
“There are a couple of things that we noticed straight away in our stroke units since the DOACs have come on board – one is that the risk of bleeding into the brain seems to be less. In the past when warfarin was used a lot invariably every week we’d have a warfarin related bleed coming into a stroke service. Nowadays with the DOACs you hardly see that at all.
The second of course is that with more patients moving onto DOACs we don’t see as many patients with AF coming in for acute interventions because they’ve had a stroke. With warfarin it was very common for patients to present with stroke because their INR was too low.”
Who to anticoagulate
The most widely used tool for stroke risk assessment is the CHA2DS2-VASc score while the HASBLED score is used to determine a patients bleeding risk.
According to Professor Lee, while the CHA2DS2-VASc score is important for measuring the risk of stroke in an untreated non-anticoagulated population, using HASBLED to guide decisions about initiating anticoagulation treatment is not as clear-cut.
“It’s important to understand that these scores were derived in the era when we only had warfarin in terms of stroke prevention. The HASBLED is a bleeding score derived from the risk of bleeding taken from multiple different RCTs comparing warfarin in atrial fibrillation – it doesn’t factor DOACs in AF at all.
In my opinion I think the HASBLED score hasn’t been validated in DOACs – I don’t think it’s actually relevant in terms of bleeding risk – in fact we don’t actually have a bleeding risk score for the DOACs at this point.”
Speaking with the limbic, cardiologist and AF expert Professor John Amerena agreed that while HASBLED does stratify patients into high, intermediate and low risk for bleeding it shouldn’t be used as a reason not to anticoagulate or to use the appropriate dose for patients who have NVAF and a high CHA2DS2-VASc score.
“The ESC is now saying to use HASBLED as an indicator of what you can do to reduce the risk of bleeding but it shouldn’t be used as a reason not to initiate appropriate anticoagulation.
So look for reversible causes of bleeding: control blood pressure, stop the aspirin, stop non steroidal anti inflammatory medications, and reduce alcohol intake,” Professor Amerena advised.
Professor Andrew Sindone echoed similar sentiments adding that the algorithm should be used to look at factors that may predispose someone to bleeding – particularly uncontrolled blood pressure medications and any drugs that may interfere with a DOAC.
“If you can reverse or control these risk factors then your bleeding risk is very low That’s what HASBLED is all about. A high score should not be stopping you from prescribing – it’s just informing you of risk. I do it less and less nowadays because it’s not so useful with the DOACs”.
The updated European Society of Cardiology Atrial Fibrillation Guideline1 has recommended that, if men have a CHA2DS2-VASc score of 2 or more, anticoagulation should be used for stroke prevention, but if the CHA2DS2-VASc score is 1, it should be considered, depending on patient characteristics and preferences1.
Meanwhile if a female has a CHA2DS2-VASc score of three or more, anticoagulation is recommended and should be considered if the score is 2.
If the CHA2DS2-VASc score is 0 in men and women or is 1 in a woman, neither anti-coagulation nor aspirin is necessary.
But in terms of the elderly and frail patient in particular, Professor Lee acknowledged that risk scores aren’t enough to capture the complexity of the patient.
“When I look at somebody that I’m about to put on a DOAC or any stroke prevention I ask the question: if they have a stroke would that alter that persons trajectory?”
Supposing I see a patient who is bed bound in a nursing home who has severe dementia with a [mini mental state examination] score of 10 out of 30 …if that person were to have a stroke they may not even know they’ve had a stroke because their baseline is already extremely poor. In that situation putting them on a DOAC doesn’t make any sense.”
On the other hand, he argues that a person with a MMSE score of 12 or 13 who is in a nursing home but who has some mobility and can still interact with their family will have a greater net clinical benefit from stroke prevention therapy.
“If that person had a stroke then absolutely that would make a massive difference to their life so it’s that value judgement that is never ever captured in any one of these algorithms purely because you really can’t capture that level of complexity.”
Is age a barrier to anticoagulation?
Is age ever a barrier to anticoagulation? Professor Lee and Professor Amerena argue that in the current era of DOACs, for most patients, it shouldn’t be.
“People fail to appreciate that [elderly patients] are the ones who would get the most benefit from having anticoagulation to reduce the risk of stroke; so again there’s a disconnect between what the evidence says and what happens in clinical practice,” said Professor Amerena.
He was referring to a recent US study2 that assessed the effectiveness and safety of apixaban, dabigatran and rivaroxaban versus warfarin in frail NVAF patients.
The US authors used claims data from 2011 to 2016 to identify frail NVAF patients; 2700 patients were prescribed apixaban, 2784 were on dabigatran, and 5270 patients were taking rivaroxaban. They were propensity matched 1:1 with warfarin users and followed for two years2.
At 2-years follow-up, apixaban and dabigatran were not associated with a significant hazard reduction in stroke or systemic embolism or ischemic stroke versus warfarin in frail nonvalvular atrial fibrillation patients.2
Rivaroxaban, however, significantly reduced the risk of stroke or systemic embolism (SSE) and ischemic stroke versus warfarin by 32% and 31%, respectively at two years while apixaban and dabigatran were not associated with a significant hazard reduction in SSE or ischemic stroke versus warfarin at final follow up. No significant differences were observed between the direct-acting oral anticoagulants and warfarin in rates of major bleeding at 2 years. 2
Professor Amerena noted that the study offered “valuable information on real-world outcomes” and suggests that clinicians are “successfully identifying elderly patients who can be given anticoagulation therapy with relative safety.”
Also commenting on the study neurologist Professor Andrew Lee suggested that compliance rates might have been different across the three DOAC populations over the follow up periods.
“You don’t need an RCT to work out that the less you have to take of a medication the more likely you are to comply with it.”
According to Professor Lee this is one area – the pharmacokinetics and pharmacodynamics of a drug, or how a drug is taken – where he would say there is a ‘major difference’ between the DOAC agents.
“Rivaroxaban is taken once daily and clearly once a day would have a better compliance rate. You would then hypothesise that because of that better compliance at two years that you would be more likely to still be on the rivaroxaban and hence the better effect in terms of stroke prevention whereas a twice a day intervention would probably have a lesser compliance rate.”
But he added that was speculation because the study didn’t capture compliance data.
Investigating bleeding risk – the evidence
During the past five years, large randomised trials have established that DOACs have a similar efficacy to warfarin but have a superior safety profile, largely driven by a substantial reduction in associated risk of intracranial haemorrhage.3
The findings of these clinical trials have been backed up in various observational cohort studies based on data from clinical practice.4-7
And, according to the most recent European Society of Cardiology guidelines1 released in March this year experts in the field of anticoagulation agreed that DOACs should be preferred over warfarin for stroke prevention in NVAF.
Speaking about the reduced risk of intracranial haemorrhage (IC) afforded by the DOACs compared to warfarin cardiologist Professor Sindone said it’s the DOACs ability to inhibit single clotting factors that puts them out in front.
“Warfarin causes around 68% more IC bleeding because warfarin inhibits a transmembrane factor called Tissue Factor, which is important in maintaining the blood brain barrier. The DOACs on the other hand act on a single coagulation factor so unless you hit your head you are much less likely to get bleeding to your head and that’s the one catastrophic bleed that both patients and doctors are worried about.”
Also weighing in on the evidence surrounding bleeding risk Professor Andrew Lee said the risk of bleeding associated with DOACs was ‘almost the same’ as aspirin.
“When you look at the randomised control trials between the DOACs your risk of bleeding is about 0.4-0.7% roughly speaking depending upon which RCT you’re in and if you look at the risk of bleeding in aspirin in the early stroke trials in 1991 that risk was about 0.9%.”
But he added that there is a caveat noting a slightly higher risk of extracranial bleeding with DOACs compared to warfarin.
“Is that a bad thing? Well of course but it’s important to realise when you’re balancing the equation that a surgeon can reach an extracranial space and stop the bleeding far more effectively than they can with intracranial bleeding so that’s a reason why you do want to go to the DOACs over warfarin,” he added.
Meanwhile, the focus on potential bleeding as a result of falls – which is the most common reason for not prescribing warfarin to elderly patients with AF – may be overstated, Professor Lee said, citing data suggesting that a patient would have to fall more than 200 times8 to tip the risk-benefit analysis in favour of fall risk.
“If you do have a patient who is falling that much then there’s something seriously wrong with this particular individual medically speaking and in that situation being on a DOAC probably doesn’t make any sense however, if a patient is at risk for a couple of falls in a month then that should not prevent them from being on a DOAC.”
Low dose vs high dose
According to drug manufacturer guidelines reduced doses of DOACs are recommended for patients who are older, have low body weight or have impaired kidney function. Of the 3 NOACs, only rivaroxaban has a pre-specified dose specifically for patients with moderate renal impairment (CrCl 30-40ml/min).10
For dabigatran (110 mg twice a day) that’s an an eGFR of 30-50 mL/min while rivaroxaban (15 mg once a day) is CrCl 30-49 mL/min, meanwhile apixaban’s low dose (2.5 mg twice a day) should be used if two of the three following criteria are present: age ≥80 or an eGRF of 15-29 mL/min or body weight ≤60 kg.
And while those recommendations are based on subgroup analyses of elderly patients with AF and patients with impaired renal function who were included in the landmark DOAC trials, their numbers were small making ‘real world’ evidence confirming the safety and efficacy of low dose regimens all the more important.
Such data has been scarce but in 2017 a nation wide cohort study9 from Denmark showed that reduced-dose DOACs performed as well as warfarin in preventing ischaemic stroke and systemic embolism in 56,000 older patients with AF.
Patients received warfarin (69.9%), apixaban (7.9%), dabigatran (15.9%), or rivaroxaban (6.3%) and were monitored through registries that followed the onset of treatment9.
After 1 year, apixaban was linked with slightly higher, but not statistically significant, rates of ischaemic stroke/systemic embolism (4.8%), followed by warfarin (3.7%), rivaroxaban (3.5%), and dabigatran (3.3%)9.
Stroke and bleeding rates were shown to be slightly higher (4.8%) with apixaban 2.5 mg than with warfarin, but not statistically significant. The lowest event rate was dabigatran (3.3%), which was only slightly lower than rivaroxaban (3.5%) and warfarin (3.7%)9.
Thromboembolic rates were slightly lower with dabigatran 110 mg and rivaroxaban 15 mg than warfarin.
And while bleeding rates were not significantly different for apixaban and rivaroxaban, they were significantly lower for dabigatran compared with warfarin.
“It might be important to review concerns about safety of oral anticoagulant treatment in atrial fibrillation,” said the authors commenting on their findings while also referencing the now historical trials in stroke prevention that show treatment with an DOAC compared with warfarin in patients with AF reduced the risk of ischaemic stroke as well as all cause death.
“Ineffective or insufficient treatment for stroke prevention should be viewed as a safety issue itself, while the increase in the risk of bleeding is an inevitable consequence of a necessary treatment,” they added.
Meanwhile Professor Lee highlighted the importance for clinicians to be vigilant of kidney function when selecting or adjusting DOAC dose.
He noted that, because DOACs are preventive, clinicians can’t be certain the medication prevented a stroke, but they can link bleeding events to the drugs – which could cause some doctors to be cautious and prescribe a lower dose.
“I think physicians often choose to reduce the dose when they anticipate their patients are at a particularly high bleeding risk – independent of kidney function. The key message is that when using DOACs you need to know what the estimated GFR is and dose according to that – if it’s normal then you need to use the appropriate highest dose but on the other hand if the GFR is low then you need to use the appropriate low dose.”
He added: “If you decide that you want to use the dose that is not appropriate to the GFR then you are placing your patient at risk of either having a stroke by using too low a dose or a risk of bleeding if you’re using a dose that is higher than recommended for the GFR.”
- Steffel J, Verhamme P , Potpara T, et al, The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. European Heart Journal (2018) 39, 1330–1393 doi:10.1093/eurheartj/ehy136
- Brandon K. Martinez, Nitesh A. Sood, Thomas J. Bunz, et al, Effectiveness and Safety of Apixaban, Dabigatran, and Rivaroxaban Versus Warfarin in Frail Patients With Nonvalvular Atrial Fibrillation. J Am Heart Assoc. 2018;7:e008643. DOI: 10.1161/JAHA.118.008643
- C. Ruff et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014 Mar 15;383(9921):955-62. doi: 10.1016/S0140-6736(13)62343-0.
- Larsen TB, Skjøth F, Nielsen PB, Kjældgaard JN, Lip GYH. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2016;353:i3189. doi:10.1136/bmj.i3189.
- Larsen TB, Rasmussen LH, Skjøth F, et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013;61:2264-73. doi:10.1016/j.jacc.2013.03.020.
- Avgil-Tsadok M, Jackevicius CA, Essebag V, et al. Dabigatran use in elderly patients with atrial fibrillation. Thromb Haemost 2016;115:152-60. doi:10.1160/TH15-03-0247.
- Gorst-Rasmussen A, Lip GYH, Bjerregaard Larsen T. Rivaroxaban versus warfarin and dabigatran in atrial fibrillation: comparative effectiveness and safety in Danish routine care. Pharmacoepidemiol Drug Saf 2016;25:1236-44. doi:10.1002/pds.4034.
- Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med. 1999;159(7):677-685
- Nielsen P, Skjøth F, Søgaard M, Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2017;356:j510 http://dx.doi.org/10.1136/bmj.j510
- Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91.