Subclinical AF Common in ASSERT 2, Stroke Implications Unclear

Marlene Busko

November 28, 2016

NEW ORLEANS, LA — A third of older patients with no atrial fibrillation (AF) symptoms with a high risk for stroke (a high CHA2DS2-VASc score) and for AF (an enlarged left atrium) had short episodes of AF detected with an implantable cardiac monitor (ICM) in a 1-year period, in new study[1]. None of the patients had a pacemaker or implantable cardioverter-defibrillator (ICD).

Moreover, roughly half of these older patients with no AF symptoms had already had a stroke, transient ischemic attack (TIA), or systemic embolism, suggesting that clinical AF does not always immediately precede a stroke.

Dr Jeff Healey (McMaster University, Hamilton, ON) presented these findings from the Prevalence of Sub-Clinical Atrial Fibrillation Using an Implantable Cardiac Monitor in Patients with Cardiovascular Risk Factors (ASSERT 2) trial in an oral session at American Heart Association 2016 Scientific Sessions.

"We have one piece of the puzzle; we know how much subclinical AF [there is] in people over age 65 with elevated stroke risk factors and with atrial enlargement," he told heartwire from Medscape. "On the other side of that, we need to know how effective anticoagulants will be" in lowering the risk of stroke in patients with subclinical AF.

Two large trials are investigating this in patients with pacemakers or ICDs: the Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes (NOAH) trial led by Dr Paulus Kirchof (University of Birmingham Centre for Cardiovascular Sciences, UK) and the Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (ARTESIA) trial led by Healey.

"The cost-effectiveness of screening and treating patients with subclinical AF who do not have pacemakers will depend to a large extent on the success of anticoagulation in these trials," which are expected to present results in 3 years, he said.

Older Patients, High Stroke Risk, Without Pacemaker or ICD

Subclinical atrial tachycardia was common in in patients without AF symptoms who were implanted with a pacemaker or ICD, in the Asymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing Trial (ASSERT) trial, Healey reported. In this trial of patients aged 65 and older with hypertension, within 3 months 10% of the patients had subclinical atrial tachyarrhythmia (atrial high-rate episodes [AHRE] of >190 bpm lasting more than 6 minutes), and this was associated with a 2.5-fold increased risk of having a stroke or systemic embolism in a 2.5-year follow-up.

ASSERT 2 was designed to determine the incidence of AF lasting at least 5 minutes in patients without AF symptoms and without a pacemaker or ICD.

The trial enrolled patients attending cardiology or neurology clinics at 26 sites in Canada and the Netherlands. The patients typically had chest pain, syncope, or heart failure; were being assessed prior to cardiac surgery or an angiogram; or had had a stroke, Healey explained.

ASSERT 2 participants had to be 65 or older and have CHA2DS2-VASc >2 or obstructive sleep apnea or a body-mass index (BMI) >30. In addition, they had to have evidence of left atrial enlargement (left atrial volume >58 mL or left atrial diameter >4.4 cm) or serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) >290 pg/mL.

A total of 256 patients were implanted with the Confirm DM2100 (St Jude Medical) loop monitor and were followed for 9 to 18 months (mean follow-up 16 months).

The participants had a mean age of 74, and 34% were female.

They had a high mean CHA2DS2-VASc score of 4.1. Close to three-quarters (73%) had hypertension; a quarter had type 2 diabetes; and 9% had heart failure. They had a mean BMI of 29, and 11% had documented sleep apnea. About half (48%) had prior stroke, TIA, or spontaneous embolism.

Almost all patients (90%) had evidence of an enlarged left atrium at baseline. On average, the participants' left atrial volume was 77 mL and their NT-proBNP was 417 pg/mL.

Subclinical AF lasting at least 5 minutes was detected in 34% of the patients within a year.

Having a left atrial volume of at least 73.5 mL vs less than this was associated with almost twice the risk of having subclinical AF lasting >5 minutes within a year (hazard ratio 1.85; 95% CI 1.13–3.03; P=0.015)

However, having a prior stroke, TIA, or spontaneous embolism did not predict a greater likelihood of having subclinical AF (P=0.32)

What Does ASSERT 2 Add?

The incidence of subclinical AF in ASSERT 2 falls in the 12% to 55% range that has been reported in studies with diverse patient populations, implanted with different devices (pacemaker, ICD, loop recorder) and using diverse measures of subclinical AF, the assigned discussant, Dr NA Mark Estes III (Tufts University School of Medicine, Boston, MA), noted.

This trial "bridges a major knowledge gap" since "the major conclusion that subclinical [AF] is common in patients with or without prior stroke when they have loop monitors and high CHADS-VASc is new data."

Moreover, ASSERT 2 "substantially weakens the case that subclinical AF detected after stroke is linked to causality," he said.

"I think the important thing to take away is that [in older people] the burden and the temporal relationship for AF doesn't seem to be associated with stroke incidence," session comoderator Dr Gordon F Tomaselli (Johns Hopkins University, Baltimore, MD), agreed, in a comment to heartwire . "In fact, in older folks, there seems be something else intrinsic, perhaps in the vasculature, that's predisposing [them] to develop a stroke."

Tomaselli, Estes, and Healey all also agree that this study alone cannot tell us the value of screening for subclinical AF and treating such patients with oral anticoagulants to prevent stroke.

"Is it time to go out and implant loop monitors in everyone over age 65 to detect subclinical AF? That may be premature," said Estes. "One of the big pieces that we are missing as we are waiting for NOAH and ARTESIA is, 'What is the value of treating these patients with subclinical AF (a very distinct subform of AF)?' " he added. It is hoped that these two trials will address this in the next 3 years.

"I think that's the time when practice will change, when we have those data available," Tomaselli agreed. These trials "may lead to a more empiric approach to use of anticoagulants in older folks with risk factors for AF . . . and to figure out if screening is cost-effective."

About half of the patients with the largest left atrial diameters (in the highest quartile) developed AF within a year, "so that's positive for screening—provided that anticoagulation works," Healey pointed out.

The Medtronic-sponsored Incidence of AF in High Risk Patients (REVEAL-AF) trial (expected to have results next spring) and the Austrian Graz Study on the Risk of Atrial Fibrillation (GRAF-AF) are looking at people without left atrial enlargement, "so they will give us some complementary data about how common [subclinical AF] is in people with more normal-sized atria," he added.

ASSERT 2 is sponsored by the Population Health Research Institute and is being performed in collaboration with St Jude Medical and the Canadian Institutes of Health Research. Healey is a consultant or on an advisory board for Medtronic and Servier; has research grants from Boehringer Ingelheim, Bayer, Bristol-Meyers Squibb, Medtronic, Boston Scientific, and St Jude Medical; has received honoraria from Boston Scientific, Pfizer, and Bayer; and has been an expert witness for Bayer. Disclosures for the coauthors are listed in the abstract. Estes and Tomaselli have no relevant financial relationships.

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