ASSERT: Device-Detected Atrial Tachyarrhythmias Are Common, Raise Stroke Risk

Susan Jeffrey

November 17, 2010

November 17, 2010 (Chicago, Illinois) — A new study suggests that in patients with pacemakers, the rate of stroke associated with otherwise asymptomatic atrial tachyarrhythmias may be higher than was previously thought.

Results of the ASymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing Trial (ASSERT) showed in this population of pacemaker patients with hypertension but no history of atrial fibrillation (AF), episodes of device-detected atrial tachycardia greater than 6 minutes were found in approximately one-third during almost 3 years of mean follow-up.

Further, these arrhythmias were associated with a 2.5-fold increase in the risk for ischemic stroke and systemic embolism. Among the subgroup of patients with a CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score of 2 or higher, device-detected atrial tachyarrhythmias increased the absolute risk for stroke to 2.1% per year.

"The clinical implication of this is that the risk of stroke among patients with device detected tachyarrhythmias and a CHADS2 score of 2 or higher is similar to the risk in patients with actual atrial fibrillation, where guidelines would recommend physicians to consider oral anticoagulation," Jeff S. Healey, MD, MSc, associate professor at McMaster University, Hamilton, Ontario, Canada, said.

"Among pacemaker patients without any prior history of atrial arrhythmias, 35% of all strokes and systemic emboli were preceded by device-detected atrial tachyarrhythmias."

The ASSERT results were presented here at the American Heart Association 2010 Scientific Sessions. The study was sponsored by St. Jude Medical.

Monitoring 24/7/365

Dr. Jeff Healey

Modern pacemakers can pick up very precisely short asymptomatic episodes of atrial tachyarrhythmia, Dr. Healey told Medscape Medical News, "but we're not clear what this means — how closely are they related to stroke, both in terms of their stroke risk and their temporal association."

These devices also store a lot of data that may allow researchers to clarify the connection between these brief asymptomatic atrial tachyarrhythmias and stroke. "The main goal of ASSERT was to quantify that, to see if there is an association, and measure what the risk is," Dr. Healey said.

ASSERT was a prospective cohort study. Patients with a history of hypertension and age of 65 years or older were enrolled after implantation of a new dual-chamber pacemaker or implantable cardioverter defibrillator (ICD). They wanted a "relatively clean study," he said, "whereby we'd exclude everybody who had known atrial tachyarrhythmias and everyone who was on warfarin or other anticoagulants because this would dull the association, if any, between atrial tachyarrhythmias and stroke."

The primary analysis was to monitor from enrollment to the 3-month visit for episodes of atrial tachycardia defined as longer than 6 minutes, at an atrial rate of greater than 190 beats per minute (bpm). All of these atrial high-rate episodes (AHREs) were adjudicated.

A total of 2580 patients from 136 centers in 23 countries were enrolled, most (2451) when a pacemaker was implanted and 129 when an ICD was implanted.

They found that AHREs occurred commonly, he said; by 3 months, 10% of ASSERT patients had had at least 1 episode greater than 6 minutes, and by mean follow-up of 2.8 years, 36% had had one.

For the primary clinical outcome, they found the presence of a device-detected atrial tachyarrhythmia was associated with a 2.5-fold increase in the risk for stroke and systemic embolism, "which in epidemiologic terms, is a relatively strong association," Dr. Healey said.

They also found the risk of developing clinical AF or flutter, detected by surface electrocardiography (ECG) and lasting more than 5 minutes, was highly significantly increased for those with device-detected atrial tachyarrhythmias in the first 3 months.

Table. ASSERT Endpoints

Endpoint Device-Detected AT Absent, No. (% per Year) Device-Detected AT Present, No. (% per Year) Relative Risk (95% CI) P
Ischemic stroke or systemic embolism 40 (0.69) 11 (1.69) 2.49 (1.28 – 4.85) .007
Vascular death 153 (2.62) 19 (2.92) 1.11 (0.69 – 1.79) .67
Stroke, MI, or vascular death 206 (3.53) 29 (4.45) 1.25 (0.85 – 1.84) .27
Clinical AF or flutter 71 (1.22) 41 (6.29) 5.56 (3.78 – 8.17) .001

AF = atrial fibrillation; AT = atrial tachyarrhythmia; CI = confidence interval; MI = myocardial infarction

Kaplan-Meier curves for the time to first ischemic stroke or systemic embolus showed no significant separation between groups for about the first year, at which point more events began to occur in the patients with device-detected AHREs.

Because the stroke risk associated with clinical AF or flutter is already well understood, they undertook an analysis that censored these patients once they had a surface ECG documenting one of these conditions. "So this analysis really isolates the effect of just having device-detected atrial tachyarrhythmias," Dr. Healey told the meeting here, "and as you can see, the results for the primary outcome do not change very much."

The relative risk for stroke and systemic embolism for the presence vs absence of device-detected arrhythmias was still significant at 2.41 (P = .01).

Another analysis adjusted for other baseline stroke risk factors, including hypertension, diabetes, and heart failure, he added, and again showed "a remarkably similar result," with a relative risk of 2.50 (P = .008).

In a predefined analysis looking at stroke and systemic embolic risk in patients with a CHADS2 score of 2 or higher, that made up nearly 80% of the patients in ASSERT, those without device-detected atrial tachyarrhythmias had a rate of 0.7% per year, rising to 2.1% per year for those with these episodes (relative risk, 2.67; P < .001).

In none of these analyses was there a significant effect on vascular death or the composite of stroke, myocardial infarction, or vascular death.

"Overall, there was about a 1% per year absolute increase in the risk for stroke or embolism," Dr. Healey noted. When they designed the study, this rate of 1% per year was considered the threshold that would trigger physicians to consider treatment with warfarin, he said. In CHADS2 patients, the absolute risk rose by more than 2%, a risk level similar to that in clinical AF patients with a CHADS2 score of 1, for whom guidelines would recommend treatment.

The strongest evidence for the role of anticoagulation in these patients would come from a randomized trial, one of which, called IMPACT, sponsored by Biotronik, is ongoing, he said.

"The question though now is since ASSERT has defined the risk of these (atrial tachyarrhythmias) and...gives a number which one can relate to atrial fibrillation, there is this philosophic question of are these things actually short episodes of atrial fibrillation or are they something different?" he said.

"Our interpretation on the steering committee is [that] this is a continuum, starting with a few atrial extrasystoles, short runs of tachycardia, and then all up to full-blown permanent atrial fibrillation," Dr. Healey added.

"It'll be interesting to see how physicians take this information — will they anticoagulate just based on the results of ASSERT and knowing what the stroke rate is and comparing it to atrial fibrillation, or will some people wait for the results of an intervention study?"

Their group actually discussed doing a trial themselves, but felt that there may now be difficulties randomizing patients with prior stroke or those with a high CHADS2 score, who have device-detected atrial tachyarrhythmias to potentially receive no therapy or aspirin alone, given the stroke rates as high as they have found in ASSERT." It will be interesting to see how well the IMPACT trial recruits."

He speculated that treatment thresholds may now be lowered still further given the recent approval of an oral anticoagulant, dabigatran (Pradaxa, Boehringer Ingelheim), with other agents in hot pursuit. Data showing noninferiority of rivaroxaban (Xarelto, Bayer/Johnson & Johnson) were presented here in the ROCKET AF trial.

"Had we presented the results of ASSERT 6 years ago when all we had was warfarin, there would probably be more resistance to looking at the numbers and saying okay I'm going to do something about it, whereas now when we have at least 1 oral agent already on the market, there'll be fewer barriers to treating according to risk," Dr. Healey said.

Important Clinical Ramifications

Invited discussant for this trial was John Camm, MD, from St. George's University of London, United Kingdom, who called this an "interesting, well-planned and well-executed study, with important clinical ramifications."

He pointed out that ASSERT is 1 of 4 studies looking at this issue. The TRENDS study, reported a year ago, was also a prospective observational study including more than 2400 patients with CHADS2 scores of 1 or greater. Follow-up was relatively short, Dr. Camm noted, at 1.5 years and used a different definition of AHREs at 175 bpm for 20 seconds or more.

In TRENDS, an AF burden greater than 5.5 hours was associated with a higher stroke plus TIA rate, but the analysis for stroke only was not significant (Circ Arrhythmia Electrophysiol. 2009;2:474-480).

The ASSERT trial provides a significant result, but Dr. Camm had several questions about "who these patients are" and how hypertension and AHREs were defined.

"Hypertension seems to be relatively generally defined, and the risk stratification in the atrial fibrillation arena is littered with relatively loose definitions," he said. He speculated on whether the results might have been different if a definition other than 190 bpm for greater than 6 minutes had been used. Would consideration rather of the burden of AF been "more interesting than simply the attainment of an episode of AF?" he asked.

Particularly relevant is the interaction between thromboembolic risk stratification factors and the burden of AF incidence, Dr. Camm noted. "We've heard a little of that today and I'm sure there is more to come.

"But importantly, this trial does have important clinical implications," he concluded. "It asks first, whether we should be considering anticoagulation in patients who have devices which record atrial fibrillation at a rate of 190 bpm for 6 minutes or more. More generally, it offers us a challenge to consider continuous monitoring of patients with atrial fibrillation with risk factors in order to define whether they are at more risk of stroke and systemic embolus."

The ASSERT trial was sponsored by St. Jude Medical. Dr. Healey reports receiving grants/research support from Boston Scientific, St. Jude Medical, Boehringer Ingelheim, and AstraZeneca and has served on advisory boards for Sanofi-Aventis and Boehringer Ingelheim. Dr. Camm reports that he has served as an advisor/speaker for Ambit, Servier, Novartis, Sanofi-Aventis, AstraZeneca, Cardiome, Prism, Astellas, Menarini, Xention, ARYx, Bristol Myers Squibb, Daiichi, Bayer, Merck, Medtronic, St. Jude, Biotronik, Boehringer Ingelheim, Takeda, GlaxoSmithKline, Boston Scientific, Pfizer, Actelion, Johnson and Johnson, and Solvay Pharma.

American Heart Association (AHA) 2010 Scientific Sessions: Abstract 21838. Presented November 15, 2010.

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