Dr Paulus Kirchhof Discusses EAST-AFNET 4 Trial Results

August 29, 2020

Early rhythm control was associated with a marked reduction in cardiovascular deaths among at-risk stroke patients, said Paulus Kirchhof, MD, director of the department of cardiology at the University Heart and Vascular Center UKE Hamburg, and professor of cardiovascular medicine at the Institute of Cardiovascular Sciences at the University of Birmingham.

Early rhythm control was associated with a marked reduction in cardiovascular deaths among at-risk stroke patients, said Paulus Kirchhof, MD, director of the department of cardiology at the University Heart and Vascular Center UKE Hamburg, and professor of cardiovascular medicine at the Institute of Cardiovascular Sciences at the University of Birmingham.

Findings of the EAST-AFNET 4 trial are published in The New England Journal of Medicine.

Transcript:

The American Journal of Managed Care® (AJMC®):Can you discuss the relationship between rate control and rhythm control in atrial fibrillation (AF)?

Dr. Kirchhof: Management of patients with atrial fibrillation has made tremendous progress in the last decade. Anticoagulation now prevents most serious strokes, and rate control often renders patients asymptomatic. And on top of that, we know that treatments that reduce cardiovascular risks such as statins, treatments of heart failure, hypertension, diabetes, improve the outcomes. Nonetheless, about 5% of patients per year who receive all these important treatments suffer a stroke, cardiovascular death, or an unplanned hospitalization for heart failure or acute coronary syndrome. And if you look over a time span of 5 years, about half of patients with AF would either have died or been to the hospital. That is an unacceptably high rate of complications. Traditionally, we have used rhythm control to manage symptoms in patients with AF. So reserve rhythm control for patients who remain symptomatic despite optimal rate control therapy.

AJMC®: Can you discuss why preventing stroke is of such high importance among the cardiac events that physicians work to avoid?

Dr. Kirchhof: Stroke is one of the most devastating events that can happen to a patient with atrial fibrillation. It often leads to long term disability. It not only impairs the lives of the affected patients, but because of the need of chronic care and the adjustment of everyday lives, it will actually affect the entire household and the social environment of the patient. This is particularly important for patients with atrial fibrillation because we know that atrial fibrillation-related strokes are larger, more severe, lead to more severe disability or can even lead to death more often than other types of stroke. In addition, while the chronic effects of stroke are so devastating, we shouldn't overlook the fact that cardiovascular deaths are still common in patients with atrial fibrillation. They can be related to severe strokes, but they are also often related to death due to heart failure or to sudden death.

AJMC®: Can you discuss how therapeutic options to prevent stroke have increased, and what information doctors need to weigh choices for patients?

Dr. Kirchhof: We have seen a huge increase in our understanding of the clinical benefit of oral anti-coagulation. And with the clinical introduction of non-vitamin K antagonists or direct oral anti-coagulants, we have been able to treat more patients with anti-coagulation. We now know that most patients with stroke risk factors, basically all elderly patients with atrial fibrillation and also concomitant conditions in the younger patients, benefit from all anti-coagulations. Also, anti-coagulation prevents most serious strokes, and with the choices that we have between different vitamin K antagonists, different novel oral anticoagulant (NOACs) or direct oral anticoagulants (DOACs) we currently can anticoagulate almost all patients with atrial fibrillation. In addition, there are interventional therapies, so you can take advantage for those few patients for whom anti-coagulation is really not possible.

AJMC®: What specific questions will EAST-AFNET 4 seek to resolve for physicians?

Dr. Kirchhof: The EAST-AFNET 4 study, Early Treatment of Atrial Fibrillation for Stroke Prevention trial, tested the hypothesis that the early initiation of rhythm control therapy, on top of anti-coagulation, rate control and management of cardiovascular conditions, can further improve the prognosis of patients with atrial fibrillation compared to usual care. Usual care is what we just discussed, anti-coagulation, rate control, and treatment of concomitant cardiovascular conditions. So the best possible care based on best available evidence.

AJMC®: Why are the size and duration of EAST-AFNET 4 so important to the medical community?

Dr. Kirchhof: The EAST-AFNET 4 trial was designed as a prospective, randomized, open, blinded, end-point assessment trial. Patients with early atrial fibrillation diagnosed within a year prior to randomization and either 2 cardiovascular conditions, or aged over 75, or those who had a stroke were randomized to either usual care, receiving all guideline-conforming treatments, rate control, anti-coagulation, combined with treatment of concomitant cardiovascular conditions, or to early rhythm control therapy which consisted of the same background therapy plus either adequate antiarrhythmic drugs or catheter ablation for atrial fibrillation after randomization. The primary outcome of EAST- AFNET 4 was a composite of cardiovascular death, stroke and worsening of heart failure or acute coronary syndrome measured as hospitalizations. The trial was powered to detect a 20% difference in the first primary outcome between the 2 groups. We had a second primary outcome of nights spent at hospital that was also collected. The primary safety outcome parameter was a composite of all-cause mortality, stroke and serious adverse events related to individual outcomes.

The main finding of the EAST-AFNET 4 trial is early rhythm control therapy was associated with a marked reduction in cardiovascular events. The first primary outcome of the EAST trial was a composite of stroke, cardiovascular death, and worsening of heart failure measured as hospitalization and acute coronary syndrome measured as hospitalizations. Patients randomized to early rhythm control therapy experienced 21% less of these events.

AJMC®: What will be the most important information for payers to come out of EAST-AFNET 4?

Dr. Kirchhof: The main outcome of the EAST trial was that early rhythm control therapy initiated at randomization in all patients led to a marketed reduction of the first primary outcome. We randomized 2789 patients. In the 1395 patients randomized for the rhythm control, we found 249 patients achieved the first primary outcome over a follow-up of a median of 5 or more years. In the patients randomized to usual care, we found 316 patients with an event, a 21% hazard reduction in patients randomized to early rhythm control. There was no difference in the nights spent in hospitals. While this is not a formal cost effectiveness analysis, it shows that the main driver of costs, hospitalizations, was not different between groups. The safety outcome occurred in almost the equal number, 223 patients in rhythm control group, and 231 patients in the usual care group. So the main finding is that early initiation of rhythm control therapy improves cardiovascular outcomes on top of anti-coagulation, rate control, and therapy of concomitant cardiovascular conditions.

Now, obviously, this is one trial. It's a big trial, it enrolled a broad population of patients with recently diagnosed atrial fibrillation at risk of stroke. It was conducted in 11 countries, but it's only one trial. So we need further discussions about the value of this trial. I believe this trial will change the way that we deliver rhythm control therapy to patients with atrial fibrillation. I think that we are now in a position to say we should consider or we should offer rhythm control therapy to all patients at risk of stroke recently diagnosed with atrial fibrillation. That will also mean that reimbursement would have to follow, that adequate management of patients with atrial fibrillation should only be reimbursed if rhythm control therapy is offered. Clearly, we need to go through the proper process: the guideline writers will have to review the trial, put it in context, and with all the knowledge that we have as a community, we will have to put the trial in the context of existing findings.