LOOP Trial Undercuts Value of Long-term Continuous ECG Screening for Atrial Fibrillation

August 29, 2021

UPDATED AUGUST 30, 2021 // Maybe short, asymptomatic bouts of atrial fibrillation (AF) that show up on long-term, continuous monitoring aren't worth hunting for just so oral anticoagulation (OAC) can be started, even in elderly people with other stroke risk factors.

That's a potential message from a randomized trial that tested an AF screening strategy relying on an implantable loop recorder (ILR) in older adults without AF but with other stroke risk factors who were invited to participate. OAC was recommended to any participant found with even a short bout of the arrhythmia (that is, any lasting 6 minutes or longer).

More than three times as many in the monitoring group compared to a standard-care cohort were found to have AF, and nearly all were put on OAC. In fact, monitored participants were almost three times as likely to be put on OAC (P < .0001) compared with controls.

But it didn't make any apparent difference to outcomes. The risk for stroke or systemic embolism did not significantly differ between the two groups over more than 5 years in the trial of about 6000 participants, called LOOP.

"This result was seen despite a high proportion of atrial fibrillation detection, and a high acceptance of anticoagulation therapy, and might imply that not all atrial fibrillation is worth screening for, and not all screen-detected atrial fibrillation merits anticoagulation," contend the authors of the LOOP report, simultaneously published in The Lancet and presented today at the virtual European Society of Cardiology (ESC) Congress 2021.

"The rates of bleeding were modest, despite the low threshold for anticoagulation," and was not significantly different between the two groups, observed Jesper H. Svendsen, MD, DMSc, Copenhagen University Hospital, Denmark, at a media briefing before his presentation of the trial at the Congress. He is also lead author on the Lancet report.

At least 6 minutes of AF was identified in more than 30% of the ILR-monitored patients, and about 90% of those were started on OAC, Svendsen observed.

But one take-home message from LOOP, he told theheart.org | Medscape Cardiology, is that "short-lasting episodes" of AF do not necessarily pose an untoward risk for stroke compared with AF revealed by intermittent monitoring, which "primarily identifies longer-lasting atrial fibrillation episodes. So short-lasting episodes are probably not as serious as long-lasting."

Other Lessons

The LOOP trial "teaches us that perhaps short-lasting asymptomatic episodes may not benefit from being screened or found," said Stefan James, MD, PhD, Uppsala University, Sweden, who did not participate in the study.

However, that may not be the case when the monitored individual is symptomatic or has longer-lasting AF episodes, he told theheart.org | Medscape Cardiology. "But certainly, this study teaches us that we need to understand much better the relationship between short episodes versus symptoms versus medical outcomes."

The results of LOOP "are encouraging" but seem to suggest that stepwise risk-assessment strategies "that also include other risk indicators for atrial fibrillation and stroke, such as biomarkers, might lead to larger benefits and better cost-effectiveness" by reserving ambulatory electrocardiography (ECG) screening primarily for higher-risk populations," Lars Wallentin, MD, PhD, Uppsala Clinical Research Center, Sweden, also not part of the trial, commented for theheart.org | Medscape Cardiology.

LOOP was published in The Lancet simultaneously with STROKESTOP, with which it invites comparison. STROKESTOP, reported at the European Heart Rhythm Association (EHRA) 2021 sessions in April, randomly assigned all asymptomatic people age 75 or 76 years in two communities in Sweden to follow or not follow a screening protocol that differed in a critical way from the LOOP technique.

After they were declared free of AF at baseline, participants used a hand-held single-lead ECG recorder (Zenicor) for 30 seconds twice daily for 14 days. Participants found with a prespecified degree of AF during those intermittent periods were offered specialized care, including OAC.

The STROKESTOP screening group showed a modest 4% reduction (P = .045) in risk for its primary end point, which included stroke and systemic embolism but also hospitalization for severe bleeding and death, by intention to treat.

But in an as-treated analysis, screened patients showed a significant 24% drop in the prespecified secondary end point of ischemic stroke.

There are likely multiple reasons why STROKESTOP showed a screening benefit whereas LOOP did not, but one possible explanation most discussed at the ESC Congress was the difference in screening techniques.

The "simpler" intermittent short-term monitoring with a handheld ECG device in STROKESTOP was less likely than continuous ILR monitoring to catch paroxysmal AF, and it took only a 6-minute bout of AF in LOOP to qualify for OAC, observed Emma Svennberg, MD, PhD, Karolinska Institute, Stockholm, Sweden. That is, AF in LOOP participants may have been more likely to be a lower-risk form of the arrhythmia.

On the other hand, any AF discovered by intermittent ECG screening was more likely to be a higher-burden form, such as persistent or permanent AF, Svennberg, who had presented STROKESTOP at the EHRA sessions and is lead author on its publication, told theheart.org | Medscape Cardiology.

"Six minutes out of 3 years constitutes a very low AF burden," she said. "It is already known from pacemaker studies that a very low AF burden on continuous monitoring confers a lower risk of stroke compared to a higher burden, longer duration of AF. The AF detected during 2 weeks of monitoring twice daily would be of a very high burden."

In screening for AF, Svennberg said, "a simpler strategy detecting patients at true high risk is merited."

High Background AF Prevalence?

Certain biases may also have contributed to the null effect of screening on the primary endpoint in LOOP, Svennberg proposed. Invitees who chose to participate in the trial "had to accept getting a device implanted for 3 years in case of randomization to the intervention arm. This likely created a control group that was highly interested in their heart rhythm," possibly encouraging greater detection rates.

Indeed, "a striking 12% of the control group received a diagnosis of atrial fibrillation, compared to the expected rate of 3%," Svennberg observed. "With such high background detection of AF, the study would have a difficult time meeting its primary endpoint."

Consideration of LOOP and STROKESTOP together would suggest that AF detected by intermittent ECG "in higher-risk patients may identify more accurately those who will benefit from anticoagulation, because they have clinical AF," Isabelle C. Van Gelder, MD, PhD, University Medical Center Groningen, the Netherlands, said as an invited discussant of the Svendsen LOOP presentation.

"The LOOP study contributes to the evidence that short episodes of subclinical AF are not worth screening for," she said.

In LOOP, 6004 people age 70 to 90 years without AF but with at least one other stroke risk factor, which could include hypertension, diabetes, a history of stroke, or heart failure, were implanted with an ILR, the Reveal LINQ (Medtronic).

They were randomly assigned at four centers in Denmark to a monitoring group or a usual care group in a 1:3 ratio. Overwhelmingly, most had hypertension. Almost half the population were women.

OAC was recommended for all persons in the monitoring group who showed an episode of AF lasting at least 6 minutes.

Atrial fibrillation was diagnosed in 31.8% of the 1501 participants in the monitored group and 12.2% of the 4503 assigned to usual care, for a hazard ratio (HR) of 3.17 (95% CI, 2.81 - 3.59; P < .0001).

OAC was started in 29.7% of monitored participants and 13.1% of the control cohort, for an HR of 2.72 (95% CI, 2.41 - 3.08; P < .0001).

There were 315 strokes and three systemic arterial embolisms observed in the entire trial, for primary-end point rates of 4.5% in the ILR monitoring group and 5.6% in the control group (HR, 0.80; 95% CI, 0.61 - 1.05; P = .11). Adding transient ischemic attack (TIA) or cardiovascular death to the endpoint did not make for a significant difference. The rates of major bleeding were 4.3% and 3.5%, respectively (P = .11).

Consistent Across Subgroups, Almost

"In general, the findings were consistent across subgroups," including by age, sex, diabetes and heart failure status, stroke history, antiplatelet therapy, renal function, and even CHA2DS2–VASc score, Svendsen noted.

But, he said, participants in the highest tertile for baseline systolic blood pressure (BP), that is, at least 157 mm Hg, "seemed to benefit from being screened," with a 49% reduction in risk for the primary endpoint (P = .0066). The interaction between systolic BP and outcome was significant (P = .007).

Only 9.3% of participants in LOOP did not have a baseline diagnosis of hypertension and so had to have another risk factor to enroll, the published report notes. However, the significant interaction with systolic BP "suggests that patients with dysregulated hypertension could benefit from this type of screening and concomitant anticoagulation."

"There is a tight association between our primary end point and hypertension," Svendsen told theheart.org | Medscape Cardiology. "But I think it's very important to say that this subgroup analysis is only hypothesis-generating."

Still, proposed Svennberg, the finding could point to a particular high-risk subgroup, the elderly with hypertension, that might especially benefit from AF screening and — even for detected paroxysmal AF — initiation of OAC.

An editorial accompanying the LOOP publication agrees that "shorter atrial fibrillation episodes found by long-term ILRs might not have the same stroke risk as atrial fibrillation detected through single-timepoint or less intense monitoring."

If much of the paroxysmal AF observed in LOOP and other studies with similar monitoring methods "is not the actual cause of stroke and is instead predominantly a risk marker, further research is warranted to establish whether a different screening focus and treatment paradigm are required to prevent stroke and other vascular brain injury related to atrial fibrillation," write editorialists Ben Freedman, MBBS, PhD, and Nicole Lowres, BPhty, PhD, University of Sydney, Australia.

LOOP was partially supported by Medtronic. Svendsen "is a member of Medtronic advisory boards and has received speaker honoraria and research grants from Medtronic in relation to this work and outside the submitted work." Disclosures for the other authors are in the report. STROKESTOP was partially supported by Carl Bennet AB, Boehringer-Ingelheim, Bayer, Bristol-Meyers Squibb, and Pfizer. Svennberg discloses receiving fees for lectures or consulting from Bayer, Bristol-Meyers Squibb, Pfizer, Boehringer-Ingelheim, Merck Sharp & Dohme, and Sanofi; and institutional grants from Roche Diagnostics and Carl Bennett Ltd. Freedman "reports grants to the Heart Research Institute, speaker's fees and non-financial support from the Bristol-Myers Squibb-Pfizer Alliance, speaker's fees and non-financial support from Daiichi Sankyo, non-financial support from AliveCor, and speaker's fees and non-financial support from Omron unrelated to the topic of this Comment but related to atrial fibrillation and screening for atrial fibrillation." Lowres reports "grants to the Heart Research Institute from the Bristol-Myers Squibb-Pfizer Alliance unrelated to the topic of this comment but related to atrial fibrillation and screening for atrial fibrillation."

European Society of Cardiology (ESC) Congress 2021. Presented August 29, 2021.

Lancet. Published online August 29, 2021. Abstract, Commentary

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