COMMENTARY

Lessons on AF Screening From the LOOP Study

John M. Mandrola, MD

Disclosures

August 30, 2021

At the virtual European Society of Cardiology meeting, atrial fibrillation (AF) screening finally underwent a serious test.

Danish investigators presented and published results of the LOOP trial, which randomly assigned high-risk older patients without known AF to get implantable loop recorders (ILR) or usual care. If the implanted monitor showed AF of more than 6 minutes, anticoagulation was recommended.

Unlike most AF screening studies, which measure AF detection or anticoagulation initiation, LOOP investigators measured time to first stroke and systemic embolism as the primary endpoint.

This is notable because it's not enough for screening to detect AF early; doing so must lead to improvements in an important outcome without undo harm or costs.

The LOOP Trial Results

The mean age of patients enrolled was 74 years, nearly half were female, and 91% had hypertension. Approximately 1500 patients were randomized to the ILR group and 4500 to usual care. The follow-up was slightly more than 5 years. Those in the control group were followed by their general practitioner.

AF was detected in 32% of those with the loop recorder vs 12% in the usual care group, a result that was statistically significant (hazard ratio 3.2; 95% CI, 2.8 - 3.6; P < .0001).

Among the patients with detected AF, anticoagulation was started in 91% of those in the ILR group and approximately 86% of those in the usual care group. In sum, 30% of the ILR group took anticoagulants vs 13% of the control arm.

Stroke or systemic embolism occurred in 4.5% of the ILR group vs 5.6% of the control arm. That 1.1% absolute decrease translated to a 20% relative risk reduction that did not meet statistical significance (HR, 0.80; 95% CI, 0.61 - 1.05; P = .11).

Cardiovascular death did not differ significantly and the rates of all-cause death were nearly identical in both groups.

Major bleeding occurred in 4.3% of the ILR group vs 3.5% of the control arm. The 0.8% higher absolute rate translated to a 26% relative increase that did not reach statistical significance (HR, 1.26; 95% CI, 0.95 - 1.69; P = .11).

Comments

The LOOP authors concluded that despite detecting three times more AF and a nearly threefold higher use of anticoagulants, ILR use resulted in "no significant reduction in stroke or systemic embolism."  And…"these findings might imply that not all AF is worth screening for, and not all screen-detected AF merits anticoagulation."

The clear language is laudable. We need more of it in medical journals. But LOOP is far from a "negative" trial.

Nonsignificant vs Negative Results

The rate of stroke and systemic embolism in the active group did not reach the threshold of statistical significance, but that doesn't necessarily mean that screening "did not work." The confidence intervals — for a terrible outcome — ranged from a 40% reduction to a 5% risk increase.

The bulk of the confidence interval was in favor of the screening arm, which suggests that the probability of (some degree) of a beneficial effect is strong.

But you can also say the same thing about the probability of increased major bleeding in the ILR group. Recall that the reason we use anticoagulants is because the seminal trials of warfarin found a net-benefit over placebo: more stroke reduction than major bleeding.

In LOOP, major bleeding was 26% higher in the screening group, and the bulk of the confidence interval was greater than 1, indicating that the probability of a true risk increase is also substantial.

To better know the net benefit, I would look to future analyses of LOOP to determine the severity of strokes prevented vs the severity of major bleeds caused.

The Control Arm Was Strong

A possible reason that a 20% reduction in stroke failed to reach statistical significance may have been the excellent AF detection and treatment in the control arm. I've never been to Denmark but from what I have read, the healthcare seems especially good. Plus, it's not hard to imagine that patients enrolled in an AF screening trial may be more vigilant about their heart.

AF was found in 12% of those in the usual care group, corresponding to an incidence rate of 2.5 per 100-patient years. That's nearly four times higher than AF detection in the control arm of the CRYSTAL AF trial of ILR vs usual care after cryptogenic stroke, and three times higher than a population study from Rotterdam which reported an AF rate of 0.9 - 1.7 per 100 patient-years in 70-80 year olds.

Might screening be more effective in regions with less than Danish-level usual care?

Multimorbidity May Have Limited Anticoagulation Benefit

My first thought was that LOOP picked the perfect patients to screen for AF: older people with a median CHA₂DS₂-VASc score of 4. By email, Stanford University electrophysiologist Mintu Turakhia, MD, pointed out that many of these older patients had numerous 'vascular' risk factors, which function as competing causes of stroke.

He highlights an important point: heart rhythm clinicians sometimes forget that AF accounts for far less than half of all ischemic strokes. Intracerebral, carotid, and aortic vascular disease may also lead to stroke.

The lack of signals in the subgroup analysis suggests Turakhia may be correct about competing causes of stroke. For instance, there was zero gradient of benefit for screening in those with higher CHA₂DS₂-VASc scores. Also, University of Michigan cardiologist Venk Murthy, MD, wrote on Twitter that it was odd that the hazard ratio in the prior stroke subgroup is 1.02 while it is 0.74 without prior stroke. It's odd because you'd expect that ILR monitoring, resulting in nearly 3x more anticoagulant use, would have shown a greater effect on stroke reduction in patients with prior stroke — unless vascular disease, not AF, was the cause of their initial stroke.

The Threshold for AF Detection Was Super Low

The AF threshold that the investigators chose to initiate anticoagulation stems mostly from ASSERT, an observational study done in patients with cardiac devices which found that 6-minute episodes of atrial tachyarrhythmia associated with a 2.5-fold increased risk of stroke.

Buried within the results of that 2012 manuscript, however, was an observation that when patients were stratified (in quartiles) by duration of AF, nearly all the risk occurred in those with episodes longer than 24 hours.

Five years later, ASSERT investigators published a subanalysis confirming that only episodes above 24 hours had a statistically significant association with stroke or systemic embolism.

The duration of AF is important because having too low a bar to initiate full-dose anticoagulation in patients with competing causes of stroke may alter the net benefit. Indeed, in LOOP, the relative risk reduction in stroke was similar to the relative risk increase in major bleeding.

We can look forward to further analyses from LOOP where we learn what kind of strokes were reduced in the ILR arm and whether the net benefit was altered by duration of AF. 

Final Take

LOOP tested the best-case scenario for AF screening. No other detection tool comes close to implantable monitors, which are always on, and therefore, highly sensitive. And with two cardiologists adjudicating each AF episode, I suspect the false positive rate will be quite low.

For comparison, the Swedish STROKESTOP trial, published in the same issue of The Lancet, used handheld ECG devices twice daily for 2 weeks to screen slightly lower-risk patients. Although there are major differences in methods between the two trials — namely that STROKESTOP studied systematic screening at a population level — these handheld spot checks did not significantly change the proportion of AF episodes or anticoagulation use compared with the control arm. It's no surprise, then, that neither stroke nor bleeding rates in STROKESTOP were significantly different in the screened group compared with the control group.

The failure of always-on ILR screening to deliver a statistically significant result allows us — at minimum — to dismiss widespread adoption of expensive implantable monitors as screening tools.

But…the growth of wearable technology, and the ability of every pacemaker and defibrillator to function as an AF monitor, means that AF screening is happening whether we like it or not.

LOOP gives us a clue that 6 minutes of AF in older patients with vascular risk factors may not be the correct threshold for anticoagulation. But what about 6 hours, or 12 hours, or what if the patients were a bit younger? The oft-asked question of how much AF warrants anticoagulation remains elusive. We look forward to the Canadian-led ARTESiA study of apixaban vs aspirin in device-detected sub-clinical AF.

Until then, the offsetting stroke and bleeding signals in LOOP underscore the fact that algorithms won't displace sound decision-making and the shared understanding of the vast uncertainty inherent in stroke prevention strategies.

John Mandrola, MD, practices cardiac electrophysiology in Louisville, Kentucky and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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