The Pros and Cons of Studying Strategies with RCTs - EAST AFNET 4
The EAST AF Net trial ambitiously attempted to sort out the best way to treat people with new onset atrial fibrillation. There were positives and negatives.
Atrial fibrillation is one of the most common reasons people get admitted to a hospital. As Western society grows larger and less active, AF incidence continues to rise.
In short, few questions in cardiology are more relevant than the treatment of patients with new-onset AF. There are two paths of treating patients with AF. (After initiation of stroke prevention regimens—often with oral anticoagulation.)
Choice A: Give rate-controlling medicines, which are generic, inexpensive and many decades old. Rate-control strategies let AF continue.
Choice B: Rhythm-control strategies try to convert AF to regular sinus rhythm and then maintain SR. Rhythm control is harder because it often requires more drugs and procedures.
The EAST AFNET 4 investigators set out to compare these two strategies in a large (N - 2789 patients) multicenter trial. The authors boldly chose hard endpoints. The first primary endpoint was a composite of CV death, stroke, hospitalization for heart failure or acute coronary syndrome. The second primary endpoint was days in the hospital.
First some history: You might think this is dumb question because of course it would be better to maintain regular rhythm. That’s how we came out of our mothers; SR must be the better strategy.
Well, here is where intuition falls apart.
More than 20 years ago, the AFFIRM trial studied the rate vs rhythm control question in 4000 patients with AF. And…patients in the rhythm control arm had a 15% higher rate of death. The 95% confidence intervals went from 0.99-1.34, so the EP world got to say “there was no difference.”
While AFFIRM was often badly translated to mean no AF patients should have rhythm control, the trial clearly showed the potential challenges of rhythm control.
The EAST Trial
The open-label trial randomized patients with new AF to either strategy. (I used italics because open-label will be critical.)
Trial procedures are important: Patients in the rhythm control arm were given antiarrthymic drugs, cardioversion (shocks) or ablation in attempts to maintain SR. They transmitted single-lead ECGs twice per week or when symptomatic. AF recurrence triggered an in-person visit. Patients in the rate-control arm took simple tablets. Both groups received oral anticoagulation. Note the different intensity of the strategies.
Patients were 70 years old, about half female, and had a mean CHADSVASC score of 3.4. This was a typical group of AF patients.
EAST is often cited as an ablation trial, but it was not. Less than 20% of patients received ablation as a rhythm control strategy. The figure shows that most rhythm control was done with drugs.
The Results:
EAST was stopped early for efficacy. Over 5 years, a primary outcome event occurred in 249 patients in the rhythm control arm vs 316 in the rate control arm. That’s 3.9 per 100 patient years vs 5.0 per 100 patient years. The relative risk reduction was 21% [HR 0.79 (0.66 to 0.94) P = 0.005].
All components of the primary outcome directionally favored rhythm control. CV death were quite low at 1.0% vs 1.3%. Stroke was even lower at 0.6% and 0.9%. The second primary endpoint of days in the hospital was not different.
Quality of life components however were not different. Nor was left ventricular function. A key finding was that the number of asymptomatic patients at 2 years were 74% vs 73%. IOW: symptoms from AF were not different.
Adverse effects
Here things get tricky. Look at the picture of the table from the NEJM.
This looks like there is no penalty for the early rhythm control. But there is a problem. Two of the most common adverse events were also primary outcome events (stroke and death). Double counting primary outcome events as adverse events is problematic.
Here is a slide. If you exclude the primary outcome events, you are left with “serious adverse events of special interest related to the rhythm-control arm.”
I calculated this as nearly 4x odds of having an adverse event in the rhythm control arm.
The authors concluded that “early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions.”
It is a compelling finding because a reduction of hard events is a positive finding. Few strategy trials lead to such positive results. But, of course, there are caveats.
EAST has given tailwind to the notion of aggressive early treatment of patients with AF.
Opinion alert: It’s had almost the opposite effect of AFFIRM. Whereas AFFIRM led to too many patients not offered rhythm control, EAST has led to too many patients treated with rhythm control.
Critical Appraisal
The main problem with EAST is also seen in many open-label strategy trials.
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