Early AF Rhythm-Control Advantage Climbs With Comorbidity Burden: EAST-AFNET4

August 23, 2022

Although an early rhythm-control strategy outperformed a primarily rate-control approach for cardiovascular (CV) outcomes in patients with recent-onset atrial fibrillation (AF) in a recent trial, the strategy may be more likely to reward some kinds of patients while others miss out, at least over the short term.

Patients in the randomized EAST-AFNET4 trial with a higher burden of comorbidities and stroke risk factors benefited from early rhythm control, compared with a rate-control-first usual-care approach, with significantly fewer CV events in a prespecified secondary analysis. Those with fewer comorbidities fared about the same regardless of AF management strategy.

The findings suggest "that patients with recently diagnosed atrial fibrillation and multiple comorbidities are the ones who would benefit more from early rhythm control," Paulus Kirchhof, MD, University Medical Center Hamburg-Eppendorf, Germany, told theheart.org | Medscape Cardiology.

"That goes a bit counter to our past practice of offering rhythm control for those in whom we considered it to be most successful — the young and those without comorbidities," observed Kirchhof, who is senior author on the secondary analysis published August 15 in Circulation with lead author Andreas Rillig, MD, also of University Medical Center Hamburg-Eppendorf.

The EAST-AFNET4 trial's primary results, published in 2020, saw a 21% drop in risk for the composite primary efficacy outcome for the early rhythm-control strategy vs usual care across all of its patients with recent-onset AF and other CV risk factors.

That efficacy endpoint included CV death, stroke, or hospitalization with worsening heart failure (HF) or acute coronary syndrome. Early rhythm control consisted of catheter ablation, antiarrhythmic therapy, or cardioversion. Usual care, as reported, called for initial rate-control therapy without rhythm control, the latter reserved primarily for patients with persisting symptoms on rate control.

The benefit from early rhythm control in EAST-AFNET4, Kirchhof said, "raised questions, because it was an unexpected finding. It was contrary to clinical practice at the time, and also contrary to earlier trials, mainly AFFIRM."

The 2002 AFFIRM trial, in which neither strategy showed a survival advantage, was among a series of major randomized trials to shift practice toward greater use of ostensibly safer rate control as an initial strategy.

But in the new EAST-AFNET4 analysis, the risk for CV events plunged 36% in the rhythm-control group, compared with those on rate control, among patients with an initial CHA2DS2-VASc score of 4 or higher. Management strategy didn't significantly affect risk for those with CHA2DS2-VASc scores less than 4.

The CHA2DS2-VASc scoring system, typically used to guide antithrombotic therapy in AF, reflects comorbidity burden by assigning points for specific stroke risk factors: HF, vascular disease, hypertension, diabetes, stroke history, age, and sex.

The new results, which "call for independent validation," the report states, "underline the importance of not withholding rhythm control therapy in patients with recently diagnosed AF and multiple comorbidities."

But the opposite conclusion should not be made for those with fewer comorbidities, observed Jonathan P. Piccini, MD, MHS, Duke University Medical Center, Durham, North Carolina, who isn't connected with the analysis.

It "makes sense" that patients at greatest risk gain the most benefit from early rhythm-control implementation, he told theheart.org | Medscape Cardiology. But it makes less sense to infer that "there's no benefit or that it could be harmful to initiate early rhythm control in less-sick patients."

Among patients with fewer comorbidities, Piccini noted, "it just may be that their horizon is longer. Patients who had less disease may have just taken longer to manifest a benefit." In such cases, "maybe whether you start rhythm control right away, or you wait a year, doesn't matter as much for that patient."

Another caution, he said, is that EAST-AFNET4 "wasn't powered to look at subgroups."

Of the trial's 2789 patients with AF diagnosed within the past year and at least 2 CHA2DS2-VASc risk factors, 1093 and 1696 had a CHA2DS2-VASc score of at least 4 or less than 4, respectively.

The primary efficacy outcome endpoint hazard ratio (HR), early rhythm control vs usual care, was 0.64 (95% CI, 0.51 - 0.81, P < .001) among patients with the higher CHA2DS2-VASc score and 0.93 (95% CI, 0.73 - 1.19, P = .56) for the lower-score group (interaction P = .037).

The HR for the trial's primary safety outcome was flat in the higher-score group, 0.84 (95% CI, 0.65 - 1.08, P = .175) but increased at 1.39 (95% CI, 1.05 - 1.82, P = .019) for those with scores less than 4 (interaction P = .008). The safety endpoint consisted of death, stroke, or serious adverse events related to rhythm-control therapy.

Symptoms of AF improved significantly regardless of assigned management strategy for patients in both CHA2DS2-VASc score groups, the report states. Yet quality of life measures improved on early rhythm control compared with usual care for those with higher CHA2DS2-VASc scores. They were unaffected by management strategy for those with lower scores.

It's unknown why the early rhythm-control approach would yield better survival in EAST-AFNET4 but not in trials like AFFIRM from an earlier era. Although the intervening period was notable for the rise of catheter ablation as a foremost treatment for AF, that likely doesn't explain it, Kirchhof said.

EAST-AFNET4 tested early rhythm-control as a strategy without mandating or encouraging how it would be achieved, he said. "About three-quarters of the patients randomized to early rhythm-control were not treated with AF ablation. They were only treated with antiarrhythmic drugs."

But other management practices have also changed since AFFIRM, with positive outcome effects that could have made the difference. When that trial was conducted, "we all were trained to stop anticoagulation after cardioversion once sinus rhythm was established," Kirchhof noted. "Basically, successful rhythm control led to withdrawal of anticoagulation, and of course we now know that was wrong."

Another driver of apparently improved early-rhythm-control outcomes, he said, may have been progress between AFFIRM and EAST-AFNET4 in using rhythm control agents. "It's difficult to measure, but I think we have, as a community, learned how to use antiarrhythmic drugs safely."

Piccini agreed. It's "not that we have more safe and effective methods of rhythm control today. I would say that we're smarter about using antiarrhythmics, and now we have medications like dronedarone (Multaq) with better safety profiles than, say, the class IC agents."

Kirchhof discloses holding patents relating to AF markers and treatment that are licensed to the University of Birmingham, United Kingdom. Rillig discloses receiving consultant fees from Medtronic, KODEX-EPD, and Biosense Webster; and travel grants and lecture fees from Medtronic, CardioFocus, Biosense Webster, Abbott, Boehringer Ingelheim, Philips KODEX-EPD, Ablamap, Bayer, and Novartis. Disclosures for the other authors are in the report.

Piccini has disclosed consultant fees or honoraria from Abbott, AbbVie, ARCA Biopharma, Biotronik, Bristol-Myers Squibb, ElectroPhysiology Frontiers, Itamar, Medtronic, Milestone, Philips, Recor, sanofi-aventis, and UpToDate; serving on a data safety monitoring board for Element Science; and receiving research Grants from Abbott Laboratories, Bayer Healthcare Pharmaceuticals, Boston Scientific, iRhythm, and Philips.

Circulation. Published online August 15. Full text

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