Modest Clinical Gain for AF Screening of Asymptomatic Elderly: STROKESTOP

April 26, 2021

Some, perhaps many, previously unrecognized cases of atrial fibrillation (AF) will come to light in a screening program aimed at older asymptomatic adults. The key question is whether the challenges of such systematic but age-restricted AF screening in the community, with oral anticoagulation (OAC) offered to those found to have the arrhythmia, is worthwhile in preventing events like death or stroke.

Now there is evidence supporting such a clinical benefit from a large, prospective, randomized trial. A screening program restricted to people 75 or 76 years of age in two Swedish communities, which called on them to use a hand-held single-lead ECG system at home intermittently for 2 weeks, was followed by a slight drop in clinical events over about 7 years.

The 4% decline in risk (P = .045) in the STROKESTOP trial's "intention-to-treat" (ITT) analysis yielded a number needed to treat of 91; that is, that many people had to be targeted by the screening program to prevent one primary-endpoint clinical event.

Those included ischemic stroke, systemic thromboembolism, hospitalization for severe bleeding, and death from any cause, investigators reported April 23 during the virtual European Heart Rhythm Association (EHRA) 2021 congress.

If that benefit and its significance seem marginal, some secondary findings might be reassuring. Half the population of the target age in the two communities — 13,979 randomly selected people — were invited to join the trial and follow the screening protocol, comprising the ITT cohort. The other half, numbering 13,996, was not invited and served as control subjects.

However, only 51% of the ITT cohort accepted the invitation and participated in the trial; they represented the "as-treated" cohort, observed Emma Svennberg, MD, PhD, Karolinska Institute, Danderyd Hospital, Stockholm, who presented the analysis at the EHRA sessions.

The screening protocol identified untreated AF, whether previously known or unknown, in about 5% of the 7165 as-treated screening participants; OAC was initiated in about three-fourths of those cases.

The as-treated group, on their own, benefited with a 24% drop in the prospectively defined secondary endpoint of ischemic stroke, compared with the entire control group.

The clinical benefit in the ITT population was "small but significant," but over the same period in the as-treated cohort, there was a highly significant drop in risk for ischemic stroke, Svennberg told | Medscape Cardiology.

The trial's lead message, she said, is that "screening for atrial fibrillation in an elderly population reduces the risk of death and ischemic stroke without increasing the risk of bleeding."

Caveats: As-Treated vs ITT

But there are caveats that complicate interpretation of the trial and, Svennberg proposed, point to the importance of that interpretation of both the ITT and as-treated analyses.

"We detected significantly more atrial fibrillation in the group that was randomized to screening. A major strength of our study was that we referred all of those individuals for a structured follow-up within the study," she said. "Although the focus of the follow-up was oral anticoagulant therapy, other risk factors were also assessed and managed, such as hypertension and diabetes."

It's possible that increased detection of AF followed by such structured management contributed to the observed benefit, Svennberg proposed.

However, the exclusion of those in the prespecified ITT population who declined to be screened or otherwise didn't participate left an as-treated cohort that was healthier than either the ITT population or the control group.

Indeed, the nonparticipating invitees were sicker, with significantly more diabetes, vascular disease, hypertension, and heart failure, and higher CHA2DS2VASc stroke risk scores than those who agreed to participate.

"We took a more difficult route in setting up this study, in that we identified all individuals aged 75 to 76 residing in our two regions and excluded no one," Svennberg said in an interview. "That means even individuals with end-stage disease, severe dementia, bedridden in nursing homes, et cetera, were also randomized but perhaps not likely or eligible to participate."

Therefore, some invitees were unable to join the study even as others might have declined "out of low interest" or other personal reasons, she said. "We believe that this mimics how a population-based screening program would be performed if done in our country."

In the ITT analysis, screening successfully identified previously unknown or untreated cases of AF, which led to expanded OAC use and intensified risk-factor management, "which was key to a successful outcome."

In the as-treated analysis, Svennberg said, "I think a combination of the intervention and the population being overall more healthy was driving the secondary endpoint."

Systematic vs Opportunistic Screening

Although "opportunistic screening in individuals aged 65 and older" is recommended by current European Society of Cardiology guidelines, systematic screening, such as that used in STROKESTOP, has a much weaker evidence base, observed Renate B. Schnabel, MD, PhD, University Heart & Vascular Center, Hamburg, Germany, as the invited discussant after the STROKESTOP presentation.

STROKESTOP "is one of the first studies, if not the first study," to show a clinical benefit from screening for AF, Schnabel said.

Fewer-than-projected primary outcome events were seen during the trial, and event curves for screened and control participants didn't start to separate until about 4 years into the study, she said. It therefore might take a long time for the screened elderly to realize the clinical benefits of screening.

Studies such as the recent SCREEN-AF and mSTOPS have amply shown that AF screening in the asymptomatic elderly can reveal previously unrecognized AF far more often than would be detected in routine practice, allowing them the opportunity to go on OAC. But the trials weren't able to show whether the benefits of such management outweigh the risks or costs.

Indeed, on April 20 the US Preventive Services Task Force (USPSTF) released a draft recommendation statement concluding that "the current evidence is insufficient to assess the balance of benefits and harms" associated with AF screening in asymptomatic people at least 50 years of age.

In STROKESTOP, however, benefit for the primary outcome reached significance in the prespecified ITT analysis and "appeared to be driven by the reduction in ischemic stroke incidence," Schnabel said.

"The future guidelines have gained strong evidence to judge on systematic atrial fibrillation screening" as it was performed in the trial, she said. "How to implement atrial fibrillation screening, including systematic screening in healthcare systems across Europe and beyond, remains an open question."

A Randomized Population

STROKESTOP considered all 75- and 76-year-olds living in Sweden's Stockholm County (n = 23,888) and the Halland region (n = 4,880) and randomly assigned them to the ITT group or a control group, with stratification by sex, birth year, and geographic region. In both groups, 54.6% were female and the mean CHA2DS2VASc score was 3.5.

People assigned to the ITT cohort were invited to be screened and followed. Those who agreed to participate underwent a baseline ECG assessment to detect or rule out permanent AF. Guideline-based OAC and follow-up was offered to those found with the arrhythmia. Those in sinus rhythm with no history of AF used a handheld single-lead ECG recorder (Zenicor) for 30 seconds twice daily for 14 days.

Structured management, including OAC, was offered to anyone demonstrating sufficient AF, that is, at least one bout without p waves in one 30-second recording or at least two such episodes lasting 10 to 29 seconds during the 2-week screening period.

In the ITT analysis, the hazard ratio (HR) for the composite clinical primary endpoint was 0.96 (95% CI, 0.920 - 0.999; = .045), but in the as-treated analysis, the HR for ischemic stroke was 0.76 (95% CI, 0.68 - 0.87; P < .001).

"I believe that this will likely be generalizable to most countries' elderly residents," Svennberg said. "I think if we can find a significant difference in our elderly population in Sweden, most countries will be able to do so, or find even more significant results."

That's because "baseline detection of AF in Sweden is high," she said, "so new detection is likely more difficult." Also in Sweden, "care can be sought without monetary concern, and prescriptions are provided at low costs to the patients." Therefore, patients newly identified with AF, whether in studies or not, "would likely be started on therapy."

It will be important to know whether the screening strategy is cost-effective, Schnabel said, because "the overall effect, with a hazard ratio of 0.96, is not too big, and costs incurred by systematic screening are comparatively high."

STROKESTOP "now provides sound information for cost-effectiveness analyses, which to date have largely relied on assumptions."

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.

European Heart Rhythm Association (EHRA) Congress 2021. Late Breaking Clinical Trials. Presented April 23, 2021.

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