Stroke Prevalence and Risk May Be Higher in Patients With Asymptomatic Atrial Fibrillation

Atrial fibrillation (AF) accounts for a minimum of 15% of all cerebrovascular accidents. It is estimated to occur in 1% to 2% of the general population and is also the primary cause of stroke in patients aged 75 years and older.^1,2 However, data from recent studies indicate that not only does asymptomatic AF(also known as occult or subclinical AF) increase the risk of stroke, but it is also much more prevalent than previously thought.^1-3

Asymptomatic AF is diagnosed in 20% of patients who present with acute stroke. The actual prevalence and risk of subclinical AF remains unclear; AF is often undetected until after a patient experiences an ischemic event.^1-3

“AF is an ongoing epidemic that will become worse over the next decade as patients get older,” says Sandeep Gautam, MD, a cardiologist and electrophysiologist with Missouri University Health Care. “It’s more of a [health] risk in people with heart disease.”

Dr Gautam stresses the importance of increasing clinicians’ awareness of asymptomatic AF, stating, “We will see more of it in the next decade or two, so we have to become more aggressive in discussing anticoagulation [when] discussing AF. Healthcare providers have to become more vigilant in detecting and treating AF in order to prevent future cardiovascular events.”

“Asymptomatic AF is a huge problem when it comes to increased risk of stroke,” agrees Frank Peacock, MD, Professor of Emergency Medicine and Research Director at Baylor College of Medicine. “If you look at stroke literature, 700,000 people in the US have strokes, and in about one-third of those patients, we don’t know [what caused it].”

“The second [stroke] is always worse than the first one,” Dr Peacock continues. People who have had a stroke are at increased risk for experiencing additional strokes. According to the Centers for Disease Control and Prevention, nearly 25% of patients who have a stroke have a medical history of stroke, indicating a need for prevention.⁴  “If we know what caused the first stroke, then we [can] put a lot of effort into preventing the second one,” he says.

Risk Determination, Monitoring, and Screening

A 2012 study published in the New England Journal of Medicine found that subclinical atrial tachyarrhythmias were detected within 3 months after device placement in at least 10% of hypertensive patients who were aged 65 years and older and had received a pacemaker or implantable cardioverter defibrillator.⁵ The detection of this abnormality was associated with an increased risk of clinical AF (hazard ratio, 5.56; 95% confidence interval [CI], 3.78-8.17; P<.001) and subsequent increased risk of cerebrovascular accident or embolic event (hazard ratio, 2.49; 95% CI, 1.28-4.85; P=.007).⁵

Researchers also identified subclinical atrial tachyarrhythmias in another 24.5% of patients during the 2.5-year follow-up period.⁵ These findings suggest the risk of AF may actually be higher in patients with pacemakers.^1,5 However, findings from ASSERT (the Asymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing Trial) showed that patients with a CHADS₂ score of 2 or greater had a statistically significant increased risk for stroke, regardless of whether the patients’ implantable device detected arrhythmic activity.^5,6

Practicality also limits the extent to which AF can be monitored long term.¹ Even if long-term monitoring were feasible, results of the CRYSTAL-AF (Cryptogenic Stroke and Atrial Fibrillation)  trial published in the New England Journal of Medicine in 2014 failed to pinpoint AF as the sole cause of ischemic events.⁷ “It is unclear whether newly discovered AF was causally related to the index stroke, because not all strokes, even in patients with documented AF, are due to the arrhythmia,” CRYSTAL-AF researchers wrote.

The ASSERT investigators echoed similar inconclusive findings, writing that, “Asymptomatic AF episodes occur in many more [patients receiving a pacemaker for symptomatic AF], and it is unknown whether they cause stroke and whether they should be managed with anticoagulant therapy.”⁶

Determining risk presents another challenge. The authors of a 2014 cohort study that assessed prevalence, incidence, risk factors, and trends over a 50-year period write that, “Incidence and prevalence of AF vary widely… but the exact estimates have differed by sex, with higher prevalence in men and variable incidence estimates in women.”⁸

According to Dr Gautam, the risk of unfavorable outcomes from AF increases with age and family history. “Five to 10% of patients have a family history of AF, but other risk factors for AF include obstructive sleep apnea, heavy caffeine intake, and heavy alcohol consumption,” he says. “People who are highly athletic are more likely to develop a special type of AF known as vagally mediated AF when they reach their 50s.”

Current guidelines in Europe and the United States recommend that clinicians use CHA₂DS₂-VASc to help determine cardiovascular risk in patients with AF. In addition to incorporating all the criteria of CHADS₂ (hypertension, aged 75 years and older, hypertension, etc),⁹ CHA₂DS₂-VASc also takes into account vascular disease, age range between 65 and 74 years, and sex. This increased comprehensive span provides better stratification regarding risk of ischemic and thromboembolic events in patients with AF.

However, results from a new scoring tool may prove even more beneficial in helping clinicians to assess risk and utilize anticoagulant therapy more judiciously. An investigative article published in 2015 compared the performance of CHADS₂ and CHA₂DS₂-VASc against the scoring tool, ATRIA. The authors found ATRIA to be more accurate in distinguishing low-risk patients than the CHA₂DS₂-VASc score.⁹ However, according to a Danish study mentioned in the article, the CHA₂DS₂-VASc score was superior to ATRIA when determining stroke risk.

Dr Gautam reveals an underutilized opportunity to screen for occult or symptomatic AF in patients with sleep apnea, and he also indicated that the ability to detect AF through genetic testing may be forthcoming. The Detection of Occult Paroxysmal AF in Cryptogenic Stroke or TIA Patients Using an Implantable Loop Recorder and Correction with Genetic Markers trial is an example of one such study and is currently recruiting subjects.¹⁰

Another clinical trial currently in the recruitment phase is the Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Sub-Clinical Atrial Fibrillation (ARTTESiA) study, which will investigate how apixaban, a novel oral anticoagulant, compares to aspirin in reducing the risk of ischemic and thromboembolic events in patients with subclinical AF detected by medical devices.¹¹  

Where Do We Go From Here?

Both experts agree that impending risk of undetected asymptomatic AF raises the need for educating both the public and healthcare providers. It also brings attention to the increased utilization of electrocardiograms (ECGs) for screening. Currently, the 12-lead ECG is the gold standard for diagnosing AF.³

The physicians maintain that it is neither practical nor financially feasible to provide the constant monitoring required to diagnose patients with occult AF, but their opinions differ on how to improve screening.

Dr Gautam recommends placement of an implantable loop recorder inside the skin to record the patient’s heart rhythm for 3 years while Dr Peacock reports being optimistic about technological advances that allow patients to monitor their heart rhythm at home by using mobile devices.

Dr Peacock also remains adamant about the importance of prophylactically treating with anticoagulants. “It’s ridiculous that there are lots of patients walking around out there who are known to have AF who are not getting treated because … [many doctors] are hesitant to give them certain drugs because there are no reversing agents for them,” Dr Peacock stresses. “That’s the most common reason [some patients don’t receive treatment], and the solution is that it’s safer to be on a drug without a reversing agent than nothing at all….”  On October 16, 2015, the US Food and Drug Administration granted accelerated approval to idarucizumab as the first reversal agent for dabigatran, a non-Vitamin K antagonist oral anticoagulant, in emergency settings.¹²

“Even the older agents [like warfarin] are better than being on no agent at all,” Dr Peacock says. “The older agents may not be as effective as the newer ones, but if you’re not on some sort of [anticoagulant], the question is not whether you’re going to have a stroke, it’s a question of when,” Dr Peacock maintains. 

References

1. Healey JS, Lopes RD, Connolly SJ. The detection and treatment of subclinical atrial fibrillation: evaluating the IMPACT of a comprehensive strategy based on remote arrhythmia monitoring. Eur Heart J.2015;36(26):1640-1642. doi: http://dx.doi.org/10.1093/eurheartj/ehv159. 
2. Xiong Q, Proietti M, Senoo K, Lip GK. Asymptomatic versus symptomatic atrial fibrillation: a systematic review of age/gender differences and cardiovascular outcomes. Int Journal of Card. 2015;191:172-177. doi:10.1016/j.ijcard.2015.05.011.
3. Keach JW, Bradley SM, Turakhia MP, Maddox TM. Early detection of occult atrial fibrillation and stroke prevention. Heart. 2015;101(14)1097-102. doi:10.1136/heartjnl-2015-307588.
4. Stroke Facts. The Centers for Disease Control website.  http://www.cdc.gov/stroke/facts.htm. Updated March 24, 2015. Accessed on October 19, 2015.
5. Healey JS, Connolly JC, Gold MR, et al; for the ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366:120-129. doi:10.1056/NEJMoa1105575.
6. Hohnloser SH, Capucci A, Fain E, et al; ASSERT Investigators and Committees. Asymptomatic atrial fibrillation and stroke evaluation in pacemaker patients and the atrial fibrillation reduction atrial pacing trial (ASSERT). Am Heart J. 2006; 152:442-447. doi:10.1016/j.ahj.2006.02.016.
7. Sanna T, Diener H-C, Passman RS, et al; for the CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014; 370:2478-2486. doi:10.1056/NEJMoa1313600.
8. Schnabel RB, Yin X, Gona P, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. The Lancet. 2015; 386:154-162. doi: 10.1016/s0140-6736(14)61774-8.
9. Van den Ham HA, Klungel OH, Singer DE, Leufkens HGM, van Staa TP. Comparative performance of ATRIA, CHADS, and CHA₂DS₂-VASc risk scores predicting stroke in patients with atrial fibrillation. J Am Coll Cardiol. 2015;66:1851-1859. doi: 10.1016/j.jacc.2015.
10. US National Institutes of Health. Detection of occult paroxysmal AF in cryptogenic stroke or TIA patients using an implantable loop recorder and correction with genetic markers. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02216370?term=atrial+fibrillation+AND+genetic&rank=3. Accessed October 13, 2015.
11. US National Institutes of Health. Apixaban for the reduction of thrombo-embolism in patients with device-detected sub-clinical atrial fibrillation (ARTTESiA). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01938248. Accessed on October 13, 2015.
12. FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. October 16, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm. Accessed October 29, 2015.