Study Provides More Evidence That Having A-fib Ups Risk of Developing Dementia

A few recent studies have suggested that A-fib patients are at higher risk of dementia, including Alzheimer’s disease, but the mechanism behind this association is unclear. A new study of patients with and without A-fib who are on long-term warfarin may add another critical clue, suggesting that therapeutic efficacy is essential not only to preventing stroke but also to warding off cognitive dysfunction. 

“This study highlights a significant potential cognitive risk with long-term anticoagulation exposure, regardless of underlying disease that prompted initiation of the therapy, in those patients who have consistently poor precision in achieving target serum drug levels,” write T. Jared Bunch, MD (Intermountain Medical Center Heart Institute, Murray, UT), and colleagues.

A few years ago, the same researchers reported that A-fib was independently associated with all types of dementia, a finding that has since been confirmed in individual studies as well as meta-analyses, Bunch told TCTMD in an email.

For the new study, published online July 11, 2016, ahead of print in the Journal of the American Heart Association, Bunch and colleagues examined medical records from 10,537 patients with no history of dementia prior to the study who were taking warfarin because they had A-fib, thromboembolism, or a mechanical heart valve.

High and Increasing Risk Over Time

Compared with patients who did not have A-fib, those who did had more baseline risk factors for dementia and were more than three times as likely to develop the disease after being on warfarin for an average of 6 to 8 years (5.8% vs 1.6%, P < 0.0001). They also had more Alzheimer’s disease (2.8% vs 0.9%) and vascular dementia (1.0% vs 0.2%; P < 0.0001 for both). Even after propensity analysis for baseline differences, the risk of dementia—including Alzheimer’s disease—remained consistently higher for patients with A-fib, and continued to increase with time.

However, when time out of the therapeutic range for warfarin was analyzed, the risk of dementia grew with rising percentage of time spent in low or high therapeutic range, regardless of whether patients did or did not have A-fib. Being below therapeutic range, as opposed to above it, appeared to pose the highest risk among those not in target range.

“This confirms our findings that anticoagulation is critical to maintain brain health and function and must be carefully controlled,” Bunch observed, adding that the study holds several important messages for clinicians.

“As physicians we are used to looking at warfarin efficacy and safety by measuring large events, such as stroke or major bleeds,” he noted. “However, organ injuries are a spectrum of large and small events. Others have shown that patients on warfarin with low times in therapeutic range also have much higher rates of renal dysfunction and failure than those who are consistently in a safe therapeutic range or use a novel anticoagulant.”  

Importantly, Bunch said, it is reassuring that patients who have excellent times in therapeutic range on warfarin and who seldom need dose adjustments have low rates of dementia and other organ injury. “However, in those with poor times in therapeutic range, we as physicians need to be more aggressive in their care, with either more frequent assessments of their INR, or transitioning to a novel (direct) oral anticoagulant or considering nonpharmacologic treatments,” he said.

The novel oral anticoagulants (NOACs) are more predictable both from a stroke and intracranial/brain bleeding perspective, which is “particularly important in younger atrial fibrillation patients that may require an anticoagulant for multiple decades of time,” Bunch noted. “They need to be exposed to an agent that has little variability and predictable levels in regard to both bleeding and clotting risks.”

Another Piece of the Puzzle

Commenting on the study for TCTMD, Michael R. Gold, MD, PhD (Medical University of South Carolina, Charleston, SC), president of the Heart Rhythm Society, said the study provides more important data in this area, but he reiterated that causation has yet to be proven.

“It’s another piece of the puzzle showing that it’s likely something directly related to the atrial fibrillation that is causing the dementia,” he observed. What that “something” may be is still uncertain, but poor warfarin control may lead to microemboli that cause an accumulation of tiny strokes over time, Gold said.

“It’s further evidence that if warfarin control is not good, one should consider using a NOAC,” he added, noting that more data are needed from randomized trials such as the ongoing CABANA trial, which is looking at left atrial catheter ablation versus state-of-the-art therapy for A-fib.

“Once we have more data, we hope to more convincingly determine whether A-fib itself is contributing to cognitive dysfunction and/or dementia,” Gold said. “In the interim it reinforces our need to aggressively anticoagulate with the best method we can in these patients.”

Disclosures:

• Bunch and Gold report no relevant conflicts of interest. 

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