Anticoagulation key for stroke prevention in elderly AF patients

Anticoagulation treatment in the form of warfarin, shown to be highly effective at reducing stroke risk in patients with atrial fibrillation (AF), is often avoided in patients over the age of 75 years, largely due to fears of increased risk for hemorrhage in this group.

Results from the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) Study now provide convincing evidence in favor of using warfarin for stroke prevention in elderly patients with AF. MedWire reporter Helen Albert talked to Professor Jonathan Mant, the lead author of BAFTA, about the challenges of stroke prevention in elderly AF patients.

Jonathan Mant is Professor of Primary Care Research at the University of Cambridge. He is an associate director of the Stroke Research Network in the UK with responsibility for primary and community care. His current research focuses on stroke prevention and treatment in primary care settings.

A medical dilemma
AF is the most widespread cardiac arrhythmia and accounts for approximately one-third of hospitalizations for cardiac rhythm disturbances¹. It is a major risk factor for stroke, increasing the risk five fold².

AF is present in 0.95% of the overall population, rising to 3.8% in individuals over the age of 60 years². However, it is most common among elderly individuals over the age of 75 years, among whom the prevalence ranges from 9–12%^2,3.

As the overall risk for stroke in the population also increases significantly with age⁴, elderly individuals with AF are at particularly high risk for stroke.

Many previous trials have shown that anticoagulation therapy with warfarin is highly effective at reducing the risk for stroke in patients with AF. It has also been demonstrated that warfarin therapy is significantly more effective at reducing risk than antiplatelet agents such as aspirin.

However, fears of increased risk for hemorrhage in this group, among other problems, have led many clinicians to avoid treating their elderly patients with warfarin.

Addressing the problem
Despite the fact that more than half of AF patients are over the age of 75 years, prior to BAFTA they were significantly under-represented in clinical trials, with the average age of participants in earlier trials of anticoagulant and antiplatelet therapy ranging from 69–72 years³.

“One of the main drivers for doing the BAFTA trial was a concern that most of the evidence that had been previously gathered about the benefits of warfarin was actually in younger people,” explained Mant

Earlier studies indicated that treating patients over the age of 75 years with warfarin might lead to higher risk for hemorrhage compared with other treatments such as aspirin, said Mant.

“At the time we set up the trial the evidence, such as it was, in the over 75s was that yes, indeed warfarin was effective in over 75s, but the risk of harm was higher.”

“One of the main drivers for doing the BAFTA trial was a concern that most of the evidence that had been previously gathered about the benefits of warfarin was actually in younger people.”

The BAFTA trial involved 973 AF patients over the age of 75 years (average age 81 years), who were treated with warfarin or aspirin for approximately 3 years.

The results showed that warfarin treatment reduced the incidence of stroke, intracranial hemorrhage, or arterial embolism by 50% over the 3 years, with 24 reported events versus 48 in the aspirin-treated group.

Contrary to previous expectations, extracranial hemorrhage risk was similar in each group, at a yearly rate of 1.4% and 1.6% in the warfarin and aspirin groups, respectively.

“What we found really very conclusively was that in the population that we looked at, the harms of warfarin were actually no greater than the harms of aspirin and that therefore, in people who can be well controlled on warfarin, the hazards of warfarin over aspirin are minimal.”

Mant emphasized that the BAFTA findings mean, for most people over 75 years with AF who are otherwise relatively healthy, warfarin treatment should be the first port of call for the attending clinician.

Interestingly, the results did not appear to differ significantly when stratified by age. Indeed, participants aged 85 years and older appeared to gain a similar benefit from warfarin compared with aspirin, with no increase in bleeding risk.

Questions and answers
A key feature of the BAFTA trial was that it was carried out in primary care in general practice rather than in hospital settings, therefore including a group more representative of the overall elderly population.

“There are case series of reports of bleeding risks of warfarin in hospital settings that give really much higher rates of bleeding,” commented Mant.

“I think the reason for that is that when someone goes into hospital they tend to be acutely unwell, and when someone is unwell and is found to be in AF there are obviously lots of other things going on.”

Indeed, warfarin is known for interacting with many commonly used medications, which can be a problem for acutely ill patients with multiple comorbidities who are likely to be taking other drugs.

Another reason that warfarin tends to be underused in the elderly is that its activity has to be monitored by frequent blood testing to calculate the international normalized ratio (INR).

If a patient is unable to maintain an appropriate INR, for example due to non-adherence, “then perhaps you have to consider that warfarin might not be the right treatment for this individual,” said Mant.

“What we found really very conclusively was that in the population that we looked at, the harms of warfarin were actually no greater than the harms of aspirin and that therefore, in people who can be well controlled on warfarin, the hazards of warfarin over aspirin are minimal.”

It has been suggested that use of lower doses of warfarin, for example aiming to achieve a target INR of 1.5–2.7 versus the standard target INR of 2–3, could combine the benefits of warfarin treatment on stroke risk reduction with lower risk for hemorrhage or bleeding.

However, Mant pointed out: “There is quite a lot of evidence from looking at large databases, such as the big HMO databases in the USA, that if you allow the INR to fall below 2.0 then the protection against ischemic stroke falls off fairly rapidly.

“Also, the bleeding risk with an INR of 3.0 is the same as with an INR of 2.0, so in other words, if you aim for a lower INR you are not actually substantially increasing the safety, but you are reducing the efficacy.”

Memory can also be a problem in older individuals. “You do require someone to take warfarin regularly, when they should do and to take the right dose,” explained Mant. “Clearly one of the concerns with elderly people is whether their memory is up to taking the drug.”

Convincing the skeptics
Since their publication, the BAFTA study results have been taken up by various international guidelines. “But obviously changes of guidelines of itself don’t change practice and I think that maybe clinicians might in general overestimate the harms of warfarin,” Mant said.

“I think one of the general problems, which is just one of those things about medicine, is that if warfarin is effective then you don’t notice any difference because basically the person doesn’t have a stroke, whereas if it’s harmful then you notice that because you see the hemorrhage.”

“I think it’s a question of making clear that the benefits are really very great and that the harms, with proper control of the INR, can be minimized.”

When considering how to treat elderly patients with AF, Mant suggested that GPs should try to be more analytical, and recognize that evidence from randomized controlled trials is actually much stronger than clinical experience, which can be misleading.

“The other issue is being clear about what the benefits of warfarin are,” he added. “For a lot of elderly people what they fear is having something like a stroke and leading the last few years of their life severely disabled.

“So I think it’s a question of making clear that the benefits are really very great and that the harms, with proper control of the INR, can be minimized.”

In addition, it is important to note that the alternative treatment to warfarin, which tends to be aspirin, has also been associated with detrimental side effects in the over-75 age group when taken long term.

The future
Novel anticoagulants that could eventually take the place of warfarin, such as direct thrombin inhibitors (DTIs), are currently in development. But “the alternatives to date have yet to demonstrate an advantage over warfarin,” Mant said.

For example, “there was a big trial published the year before BAFTA, called the ACTIVE-W trial, which showed that warfarin was much more effective than the combination of aspirin and clopidogrel.”

The phase III trial of the DTI ximelagatran was initially promising as it seemed to be as effective as warfarin with a similar risk for bleeding. It also had the potential additional advantage that it did not appear to need dose monitoring like warfarin, but then there were concerns about liver damage and it was withdrawn.

The more recently developed DTI dabigatran does not appear to have the same adverse effects as ximelagatran and has already been licensed for treatment of deep vein thrombosis.

Phase III trials for use of dabigatran in AF patients at high risk for stroke have been completed and results are due to be presented at the upcoming 2009 annual European Society of Cardiology congress.

Mant commented: “My guess is that the role for dabigatran, if it’s demonstrated to be as effective as warfarin, is likely to be in the first instance in people who you have tried to get on warfarin but can’t, such as in patients in whom warfarin is very difficult to control and is not safe.”

The Embolic Protection in Patients with Atrial Fibrillation (PROTECT-AF) study used a device called Watchman to close the left atrial appendage (LAA) as a stroke-prevention strategy in patients with nonvalvular AF, with some success⁵.

Recent results presented at the 58th Annual Scientific Session of the American College of Cardiology showed Watchman to be comparable to warfarin for stroke prevention in individuals with AF, but whether this is a viable option for the elderly population with the condition is yet to be seen.

Another approach in AF management is maintaining a sinus rhythm with anti-arrhythmic drugs.

“Trying to maintain sinus rhythm isn’t a bad idea, but that needs to be thought of as complementary to a strategy to prevent thromboembolism in AF,” according to Mant.

Most patients with AF, particularly the elderly, have an underlying cause which cannot be treated purely by rhythm control, such as ischemic heart disease.

“A rhythm control strategy is a symptomatic treatment and doesn’t really treat the underlying cause in many cases, so even if you have a successful electrical cardioversion there is a concern that that person will slip back into AF,” Mant explained.

He noted that techniques such as radiofrequency ablation of AF may be useful in younger people, in whom the cause of AF may well be an electrical disturbance rather than underlying ischemic heart disease.

But, Mant said: “I can’t see this sort of surgical technique becoming a mainstay of the treatment of the vast majority of people in AF, which are the elderly.”