ASSERT: Device-detected atrial tachyarrhythmias are common, raise stroke risk

Susan Jeffrey

November 17, 2010

Chicago , IL - 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 that, in this population of pacemaker patients with hypertension but no history of atrial fibrillation (AF), episodes of device-detected atrial tachycardia greater than six minutes were found in approximately one-third over almost three years of mean follow-up.

Further, these arrhythmias were associated with a 2.5-fold increase in the risk of ischemic stroke and systemic embolism. Among the subgroup of patients with a CHADS2 score >2, device-detected atrial tachyarrhythmias increased the absolute risk of stroke to 2.1% per year.

Dr Jeff S Healey

"The clinical implication of this is that the risk of stroke among patients with device-detected tachyarrhythmias and a CHADS2 score of >2 is similar to the risk in patients with actual atrial fibrillation, where guidelines would recommend physicians to consider oral anticoagulation," Dr Jeff S Healey (McMaster University, Hamilton, ON) 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 (AHA) 2010 Scientific Sessions .

Monitoring 24/7/365

Modern pacemakers can pick up very precisely short asymptomatic episodes of atrial tachyarrhythmia, Healey said in an interview, "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 whether there is an association, and measure what the risk is," Healey said.

ASSERT was a prospective cohort study. Patients with a history of hypertension and age 65 years or older were enrolled after implantation of a new dual-chamber pacemaker or implantable cardioverter defibrillator (ICD); patients who had known atrial tachyarrhythmias or were on warfarin or other anticoagulants were excluded.

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

A total of 2580 patients from 136 centers in 23 countries were enrolled at the implant of a pacemaker in 2451 or an ICD in 129.

At three months, 10% of ASSERT patients had had at least one atrial high-rate episode greater than six minutes, and at a 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 of stroke and systemic embolism, "which in epidemiologic terms, is a relatively strong association," Healey said.

They also found the risk for developing clinical atrial fibrillation or flutter, detected by surface ECG and lasting more than five minutes, was highly significantly increased for those with device-detected atrial tachyarrhythmias in the first three months.

ASSERT end points

End point Device-detected AT absent, n (%/year) Device-detected AT p resent , n (%/year) Relative r isk (95% CI) p
Ischemic stroke or systemic embolism 40 (0.69) 11 (1.69) 2.49 (1.28-4.85) 0.007
Vascular d eath 153 (2.62) 19 (2.92) 1.11 (0.69-1.79) 0.67
Stroke, MI or vascular death 206 (3.53) 29 (4.45) 1.25 (0.85-1.84) 0.27
Clinical AF or flutter 71 (1.22) 41 (6.29) 5.56 (3.78-8.17) 0.001

 

AT=atrial tachyarrhythmia

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 atrial high-rate episodes.

In an analysis that censored patients once they had a surface ECG documenting either clinical AF or flutter, thereby isolating device-detected atrial tachyarrhythmias, the relative risk for stroke and systemic embolism for the presence vs absence of device-detected arrhythmias was still significant at 2.41 (p=0.01)

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=0.008).

In a predefined analysis looking at stroke and systemic embolic risk in patients with a CHADS2 score of >2, who 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<0.001).

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

"Overall, there was about a 1%-per-year absolute increase in the risk for stroke or embolism," 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, called IMPACT , sponsored by Biotronik, is ongoing, he said.

"The question now, though, is, since ASSERT has defined the risk of these [atrial tachyarrhythmias] and . . . gives a number that one can relate to atrial fibrillation, 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," Healey added.

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 six 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 one oral agent already on the market, there'll be fewer barriers to treating according to risk," Healey said.

Important clinical ramifications

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

He pointed out that ASSERT is one of four 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, Camm noted, at 1.5 years, and the trial used a different definition of AHREs at 175 bpm for >20 seconds.

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[1].

The ASSERT trial provides a significant result, but Camm had several questions about "who these patients are" and how hypertension and events 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 six 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, Camm noted. "We've heard a little of that today and I'm sure there is more to come."

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

The ASSERT trial was sponsored by St Jude Medical. Healey reports receiving grants/research support from Boston Scientific, St Jude Medical, Boehri nger Ingelheim, and AstraZeneca and has served on advisory boards for Sanofi-Aventis and Boehr inger Ingelheim. 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 & Johnson, and Solvay Pharma.

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