The NOAH Study Provides Evidence That Aids Decision-Making in Atrial Fibrillation
The Study of the Week was inducing pessimism so last week I promised to present a study done well. I am at the ESC meeting, and I have found one
This weekend at the European Society of Cardiology, I watched Professor Paulus Kirchhof present results of the NOAH AFNET 6 trial, which is also published in the New England Journal of Medicine.
I describe it here for two reasons: it is an example of well-conducted unbiased study, and it deals with an increasingly common problem of short-duration episodes of atrial fibrillation.
The digital revolution, wherein we now have tools to monitor our heart rhythm, has brought new challenges for treatment.
In patients with certain risk factors, AF increases the risk of having a stroke. The increase in risk parallels the presence of risk factors, such as age, high blood pressure, diabetes, coronary disease, and previous stroke.
Oral anticoagulant drugs, such as warfarin, and now direct acting oral anticoagulants, have been shown to provide a net benefit in patients with AF and risk factors. Net benefit means stroke reduction > bleeding increase.
In the past, patients had to have AF long enough (or symptomatic enough) to present to a doctor who then did a standard ECG. These were the patients who benefited from oral anticoagulant drugs. We call this clinical AF.
Times have changed. Devices, such as pacemakers, defibrillators, and implantable loop recorders, can detect minutes to hours of AF, which is often not felt by the patient. We give these episodes names like atrial high rate episodes or subclinical AF. (These can also be detected on smart watches.)
Not every day, but most days, I receive a notification that a patient with a pacemaker had a short run of AF. The note also often includes a phrase—”patient not on anticoagulant.”
These were the patients studied in NOAH AFNET 6.
Investigators randomized about 2500 patients who had short duration AF detected on a device to two arms: one got the anticoagulant edoxaban and the other got placebo. These were older patients in the their late 70s. The median duration of AF was about 3 hours.
The primary endpoint was a composite of stroke, systemic embolism or death from cardiovascular causes.
The plan was to follow these patients until they collected 220 primary outcome events.
But the trial had to be terminated early, because a safety monitoring committee noted both a high chance of futility of benefit and an increased rate of bleeding in the anticoagulation arm.
The results at the time of termination were as follows:
A primary endpoint occurred at a rate of 3.2% per patient-year in the edoxaban group vs 4.0% in the placebo group. Even though the rate was lower in the edoxaban group, the difference did not reach statistical significance (HR, 0.81; 95% CI, 0.60 - 1.08; P = .15).
The incidence of stroke was 0.9% vs 1% per patient-year in the edoxaban vs placebo arms, respectively.
Adverse events, defined as major bleeding or death, were significantly higher in the edoxaban group (5.9% vs 4.5% per patient-year; HR, 1.31; 95% CI, 1.02 - 1.67).
Here is a picture of the main finding:
The authors concluded:
Among patients with atrial high rate episodes detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo, but it led to a higher incidence of a composite of death or major bleeding. The incidence of stroke was low in both groups.
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The first thing to say is that medical studies can run well. NOAH AFNET 6 addressed an important question. It was well-conducted and it delivered both actionable clinical results and it advanced knowledge of AF.
Professor Kirchhof called it “practice changing.” What he means is that the common practice of treating patients with short-duration AF should stop. This may be somewhat premature because another similar study, one called ARTESIA, will soon present its results. It may or may not come to different conclusions.
That said, the findings of increased bleeding and little difference in stroke from NOAH AFNET 6 does change my view of short-duration AF. Before heading to ESC, I struggled with the decision to treat or not treat when getting these messages.
On the one hand, you read in the chart that “this patient has AF.” This makes you think: “gosh, I don’t want her to have a stroke.” So, you lean toward using anticoagulants. But, on the other hand, you know that AF detected on a pacer or defibrillator may be different (shorter, mainly) from the AF in which anticoagulants were established as beneficial.
This is where the results of NOAH AFNET 6 come in. It suggests, strongly, that subclinical AF is different from AF of the old days. And that net benefit (stroke reduction > bleeding increase) is not a given. For now, I will hold off treating these shorter episodes in most patients.
This is exactly what we want evidence to do for us. And, it is a good story about medical science.