To Anticoagulate or Not? Debating Secondary Stroke Prevention in an A-fib Patient With Microbleeds

A 73-year old man presents to the hospital with an ischemic stroke and is later diagnosed with atrial fibrillation—the question is whether or not he should be treated with oral anticoagulation. Complicating matters is the fact that magnetic resonance imaging reveals a small cortical infarct and a series of incidental cortical microbleeds.

That was the hypothetical scenario 2 experts grappled with last week at the International Stroke Conference (ISC) in Los Angeles, CA, with Hans-Christoph Diener, MD, of University Hospital (Essen, Germany), arguing that oral anticoagulation, specifically one of the newer agents, should be prescribed to prevent a second stroke.

Taking the other side, Steven Greenberg, MD, of Massachusetts General Hospital (Boston, MA), took the opposite position, arguing that oral anticoagulation should be avoided. In Circulation, where the case vignette was published to coincide with the ISC meeting, Greenberg quoted neurologist C. Miller Fisher, stating that “if you are treating even 1 patient in your practice with oral anticoagulation, you should wake up once a week or so in a cold sweat.”

Speaking with TCTMD, Greenberg said that even when physicians do their best for their patients, there is a risk of unintended adverse events, and with warfarin, that concern is the potential risk of major bleeding, particularly in the brain. The morbidity and mortality from warfarin-related intracranial hemorrhage comprises the “major weight on the risk side” in the risk-versus-benefit calculation.

“Anybody who does not have a healthy respect for the danger of anticoagulation has never seen somebody with anticoagulation-related intracerebral hemorrhage,” said Greenberg. “It can be absolutely devastating. They come in basically dead or deteriorate quickly over the first few days. Even when we reverse treatment, they often keep bleeding.”

In debating the pros and cons of anticoagulation in the hypothetical 73-year-old ischemic stroke patient, Greenberg acknowledges that warfarin is “extraordinarily effective” in reducing the risk of stroke in nonvalvular atrial fibrillation but it does carry more risk than benefit in a subset of patients at higher risk for intracerebral hemorrhage. In their hypothetical test case, the presence of 8 microbleeds detected by MRI suggests the patient might have cerebral small vessel disease, such as hypertensive vasculopathy or cerebral amyloid angiopathy (CAA). The risk of intracerebral hemorrhage in patients with microbleeds and CAA is “substantial,” according to Greenberg.

Arguing in Favor of Anticoagulation

For his part, Diener argues that A-fib patients have a high risk of ischemic stroke and need to be anticoagulated. In the hypothetical 73-year-old, the MRI suggested a cortical embolic stroke, which indicates it was likely the result of the arrhythmia. Like Greenberg, he acknowledges the detection of 8 microbleeds should give physicians pause, writing that patients with a large number of cortical microbleeds, in addition to severe white matter disease on MRI, might be suggestive of amyloid angiopathy. These patients should not be anticoagulated, according to Diener.

Microbleeds, he acknowledges, do bring uncertainty into the decision about oral anticoagulation, but on their own, the presence of a small number of cerebral microbleeds does not constitute a contraindication to anticoagulation.

As for what drug to prescribe, Diener notes that the major clinical trials involving the novel oral anticoagulants—dabigatran (Pradaxa, Boehringer Ingelheim), apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), and rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals)—included subgroup analyses testing the safety and effectiveness of the agents against warfarin in patients with prior transient ischemic attack or ischemic stroke. In these analyses, there was a trend toward higher efficacy with the new anticoagulants, while a meta-analysis of the 3 studies showed that these new agents were associated with a significantly reduced risk of major bleeding compared with warfarin, including a significant reduction in the risk of hemorrhagic stroke.

Taken all together, Diener believes the hypothetical patient with the embolic stroke should be treated with a novel oral anticoagulant for secondary stroke prevention. He notes that stroke neurologists typically fall into 2 camps: those who trained in critical care and worked in emergency rooms have the primary goal of preventing devastating cardioembolic strokes, while others are stroke physicians who moved from general neurology. The latter group tends to fear major bleeding complications from antithrombotic therapy more than the former, suggests Diener.

“They know that the family of a patient who had a major bleed on oral anticoagulation will blame the prescribing physician,” he writes. “Therefore, they prefer a wait and see policy.”

‘A Complicated Decision’

To TCTMD, Greenberg said that while he argued against anticoagulation during the ISC debate, he takes a more measured response in real-world practice. In fact, even during the debate, he simply reminded physicians to be aware of the risks of anticoagulation. Individuals with cerebral microbleeds are at a higher risk of intracerebral hemorrhage, generally speaking, and while this is not a contraindication necessarily, the number of bleeds and their location impacts the decision.

“It’s a complicated decision,” said Greenberg. “In general, I don’t want to avoid anticoagulation unless there’s really a good enough reason because we know the benefit is real.”

Like Diener, Greenberg believes the novel oral anticoagulants do have a role to play in these types of patients, particularly since their biggest advantage is the lower risk of intracranial hemorrhage. He noted that some would question the decision to prescribe a novel oral anticoagulant given the lack of commercially available reversal agents, but the goal of oral anticoagulation is preventing the stroke and reducing the risk of bleeding. Even with warfarin, where there are reversal agents, short-term mortality is approximately 50% if the patient has an intracerebral hemorrhage.

“What really counts in terms of weighing out the risks and benefits is lowering the risk of a hemorrhage happening rather than what you’ll do once the hemorrhage happens,” said Greenberg. “Once the hemorrhage happens, the outcome is often quite bad.”

The bottom line, he stressed, is that the decision about whether or not to anticoagulate should follow the direction again of the quotable C. Miller Fisher: Don’t hurt your patient if you can avoid it.

“I will say to the residents sometimes that we worry about decisions that are very low stakes,” said Greenberg. “The dose of aspirin you use probably doesn’t matter very much, things like that. It’s probably not worth losing sleep over. The decision about anticoagulation is a very serious situation. It is a decision worth obsessing over.”