Targeted therapy effect on sinus rhythm in early AF may not stand the test of time

The benefit of targeted therapy on sinus rhythm at 1 year in patients with early persistent atrial fibrillation (AF) and heart failure (HF) was not sustained at 5 years, according to results of the RACE 3* trial presented at EHRA 2021.

Participants were 216 patients (mean age 64 years, 79 percent male) with early persistent AF and HF who were causally treated for both conditions. They had been randomized 1:1 to receive conventional guideline-recommended therapies alone or in addition to targeted therapies. The targeted therapies were mineralocorticoid receptor antagonists, statins, angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs), and cardiac rehabilitation (physical activity, dietary restriction, counselling).

All patients underwent electrical cardioversion after 3 weeks and received rhythm control and HF therapies throughout the study period. Patients in the targeted therapy arm were followed up every 3 months over the 5-year study period.

Patients in the targeted and conventional therapy arms had persistent AF for 2 and 3 months, respectively, 30 and 27 percent had left ventricular ejection fraction (LVEF) <45 percent, and median NT-proBNP level was 1,057 and 1,005 pg/mL, respectively.

At 1 year, patients who received targeted therapy plus conventional therapy were more likely to be in sinus rhythm than those on conventional therapy alone (75 percent vs 63 percent; odds ratio [OR], 1.765, 95 percent confidence interval [CI], 1.021–3.051; p=0.042). [Eur Heart J 2018;39:2987-2996]

However, this benefit was lost at the 5-year follow-up with a comparable proportion of patients on targeted and conventional therapy in sinus rhythm (as per 7-day Holter monitoring; 46 percent vs 39 percent; OR, 1.297, 95 percent CI, 0.756–2.225; p=0.346). [EHRA 2021, Late Breaking Clinical Trials]

There was also no between-group difference pertaining to a composite of cardiovascular morbidity and mortality at 5-year follow-up (p=0.353).

There were significant changes in systolic blood pressure (BP), and total and LDL-cholesterol levels with targeted therapy compared with conventional therapy. Changes in other risk factors such as diastolic BP, body mass index (BMI), NT-proBNP, LVEF, and left atrial (LA) volume did not significantly differ between groups, though both groups experienced increases in BMI and LA volume.

“The RACE 3 study demonstrates that in patients with persistent AF and HF, targeted therapies on top of conventional therapy do not improve maintenance of sinus rhythm at 5-year follow-up,” presented Dr Michiel Rienstra from the University Medical Center Groningen, Groningen, the Netherlands.

“Cardiovascular morbidity and mortality were low and not different between groups,” he added.

Why the loss of benefit?

Not all risk factors were targeted in this study, pointed out Associate Professor Dennis Lau from the Royal Adelaide Hospital, University of Adelaide, Australia, who commented on the results. For instance, there was a lack of information on sleep apnoea and alcohol intake among participants, while BMI increased between baseline and follow-up.

The intensity and frequency of follow up also reduced following the first year of the study. “When patients did not meet their targets, there was no flexibility for the investigators to escalate intensity of follow-up as what we would in normal clinical practice,” said Lau.

Furthermore, three-monthly follow-up via phone call may not have been the most ideal practice. “While during this pandemic telehealth is useful, we have found in our experience in our risk factor clinics that this is quite limited,” he said. For instance, weight, waist circumference, and BP measurements could not be taken, and patient engagement was more difficult.

He also raised the question on the possibility of different results should continuous AF monitoring with loop recorder been used to assess sinus rhythm as opposed to 7-day Holter monitoring.

“So the take-home message is: when we treat patients with AF, all risk factors need to be targeted for best results. And secondly, managing AF is labour-intensive, and we need specialized AF clinics for successful treatment to provide integrated care to maximize patient engagement,” he concluded.