Broad, Early AF Risk-Factor Intervention Preserves Sinus Rhythm: RACE-3

August 28, 2017

BARCELONA, SPAIN — A broad-scale risk-factor intervention program appeared to successfully keep atrial fibrillation (AF) at bay for up to a year after electric cardioversion compared with standard care in a randomized trial, a small one but one of the first to confirm such a benefit lately seen in a number of observational studies[1].

The aggressive intervention in the trial's patients with recent-onset persistent AF and mild to moderate heart failure included intensive drug therapy, dietary management, cardiac rehabilitation and other exercise, and counseling. Drug therapy emphasized aldosterone inhibitors and other blood-pressure–lowering agents but also included statins.

Patients following the intervention showed a 76% greater likelihood of being in sinus rhythm at 12 months compared with those managed conventionally. Their significant reductions in natriuretic peptides during the trial were not associated with improvements in adverse atrial remodeling.

Dr Isabelle C van Gelder

The observed benefit of "risk-factor–driven upstream therapy" shows how an approach that attacks the underlying causes of AF can work with rhythm control to keep patients in sinus rhythm, "if you catch the patients early," principal investigator Dr Isabelle C van Gelder (University Medical Center Groningen, the Netherlands) told | Medscape Cardiology.

Preclinical atrial stretch as a response to elevated blood pressure may explain the intervention's apparent failure to improve atrial volume, a main measure of myocardial remodeling, observed van Gelder. "The remodeling process starts long before the first episode of atrial fibrillation," she said. "Although we intended it to be early in the remodeling process, I think we weren't that early."

The odds ratio (OR) for the primary end point of sinus rhythm at 1 year, assessed by continuous 7-day Holter monitoring read at a core lab, was 1.765 (P=0.021) for superiority in the intervention group, reported van Gelder when presenting the Routine vs Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure (RACE-3) trial here at the European Society of Cardiology (ESC) 2017 Congress.

The trial follows a number of mostly small observational studies pointing to a salutary effect from exercise and lifestyle changes on AF and its symptoms or need for AF ablation, including LEGACY and REVERSE-AF, which saw benefits from healthy-eating and weight-loss interventions, and CARDIO-FIT, which correlated improved AF outcomes with greater cardiorespiratory fitness.

It also supports the development of comprehensive AF prevention and management efforts similar to HF disease management programs, to increase focus on the arrhythmia's causes and counter the predominant way AF is approached clinically, according to van Gelder. "Everyone wants to focus on the arrhythmia, on performing an ablation, but they forget the associated conditions."

Clinics that use secondary-prevention principles to maintain stable sinus rhythm in patients with AF have become increasingly common in Europe in recent years, and that is "exactly the model that we envision for future comprehensive atrial fib care," Prof Dan Atar (Oslo University Hospital Ulleval, Norway) said in an interview.

"So RACE-3 fits extremely well into this evolving development of how we approach atrial fibrillation, by and large," said Atar, who is a coauthor on the ESC guidelines for AF management, most recently in 2016.

"Probably Applies to AF in General"

The trial randomized 245 patients with symptomatic AF that had been persistent for less than 6 months; the average was 3 months. Their total AF history had to be less than 5 years. They also had mild to moderate HF of less than 1 year in duration, but the average was only 2 months. They were enrolled at 14 centers in the Netherlands and three in the UK between 2009 and 2015.

Patients had HF with reduced LVEF (HFpEF) in 30% of cases, and a full 70% of the cohort had HF with preserved LVEF (HFpEF), according to van Gelder.

Those who developed recurrent AF during the follow-up could undergo repeat cardioversion, be started on antiarrhythmic drugs, or be referred for catheter ablation.

Noting that the trial required patients to have recent-onset HF along with their AF, Atar said this was a limitation of the trial in that it made the cohort a more select group. He said, however, that the upstream risk-factor–management approach "probably applies nevertheless to atrial fibrillation in general."

The program would be appropriate for patients with AF in whom HF has not been identified, van Gelder agreed, noting, however, that unrecognized HFpEF is very common in patients with AF.

As assigned discussant for van Gelder's RACE-3 presentation, Dr Josep Brugada Terradellas (University of Barcelona, Spain), also said the inclusion criteria made for a highly selected cohort, noting it took 6 years for 17 centers to recruit less than 250 patients.

"That's how difficult it is to find this type of patient, a kind of de novo patient to prove the hypothesis that by treating them aggressively you avoid progression," he said.

And, he pointed out, the intervention group showed significant reductions (P<0.05) from baseline to 1 year, compared with standard care, in systolic and diastolic BP, natriuretic peptides, and LDL cholesterol, but not in LVEF or left-atrial volumes or, somewhat oddly, in BMI.

Something was lacking in the success of the weight-loss interventions, Brugada Terradellas noted, proposing that the results might have been more striking had weight-loss efforts been more successful in group started on upstream therapy.

Still, RACE-3, on the heels of the observational studies, "opens the door to scientific evidence that aggressive upstream therapy is reducing the number of patients with atrial fibrillation and the progression of atrial fibrillation," he said.

Nature of the Upstream Risk-Factor Management

The upstream intervention, which started at least 3 weeks before electric cardioversion and continued for a year, consisted of aldosterone inhibitors, primarily for their antifibrosis effects and secondarily for their diuretic effect in helping reduce blood pressure, van Gelder said when interviewed. Statins were given for their anti-inflammatory effect, she said, and ACE inhibitors or angiotensin-receptor blockers for lowering BP and for the heart failure.

Blood-pressure meds were given to a target of <120/80 mm Hg.

The intervention also included a cardiac rehabilitation program, two to three times per week, supervised for the first few months and followed by recommendations to engage in sports-related exercise for at least 30 minutes a day, she said. And it included dietary changes including sodium reduction and calorie restriction for everyone with a BMI of at least 27 kg/m2.

Plus, patients received counseling to promote exercise, diet, and drug adherence starting 1 week after enrollment.

Rhythm Control and Interventions to Maintain Sinus Rhythm by 1 Year in RACE 3

End points Upstream intervention, n=119 (%) Standard management, n=126 (%)
Sinus rhythm maintained 75 63*
Repeat cardioversion 56 51
Antiarrhythmic drug therapy 45 43
Amiodarone 22 25
AF ablation 4 2
* P=0.02

The trial wasn't powered for clinical events, but 16% of patients on the intervention and 17% on standard care met a composite primary end point of all-cause mortality or admission for CV causes including AF or HF.

"We are now showing the beneficial effects of upstream intervention on sinus rhythm," van Gelder said when interviewed, adding hopefully, "but we'll come back in 4 years' time with a 5-year follow-up, when possibly cardiovascular morbidity and mortality will also be different between the groups."

RACE-3 was supported by Medtronic, Boehringer Ingelheim, Biotronik, St Jude Medical (now Abbott), Boston Scientific, AstraZeneca, Sanofi, and Bayer. Van Gelder discloses receiving grants for her institution from Medtronic. Brugada and Atar had no relevant financial relationships.

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