My Pick of the Most Important Study from the European Society of Cardiology Meeting

Last week I attended the European Society of Cardiology congress in Amsterdam. ESC is one of the largest cardiology meetings.

I attend mostly in the role of a physician journalist. Well, not really a journalist, more like an opinion writer and critical appraiser.

For me, one study stood out at ESC. This randomized controlled trial had it all—an important question, good trial conduct, surprising results and no spin in the conclusions. But these are not the only reasons why I want to tell you about it.

I feature the FRAIL AF study because it speaks to one of the most important jobs of a modern-day clinician: taking evidence from trials and applying it to the patient in front of us in the clinic.

The journal CIRCULATION published FRAIL AF, and it is open access.

FRAIL AF addressed the question of changing oral anticoagulation medications in frail mostly homebound elderly patients in the Netherlands. Specifically, if a frail patient was doing well on Vitamin K antagonists (similar to warfarin), should they be switched to the newer direct acting oral anticoagulant (DOACs, such as apixaban or rivaroxaban).

Senior author, Geert-Jan Geersing, MD, PhD, from the University Medical Center Utrecht, told me that he designed the trial a bit out of frustration. He saw colleagues switching patients, and felt frustrated because they were applying evidence collected in trials of much younger patients and applying it to a different type of patient.

The newer DOAC drugs have been compared to VKAs (warfarin or warfarin-like) in multiple trials with over 50K patients. These trials reveal clear DOAC superiority in stroke prevention and strong trends for less bleeding. This, plus convenience—no INR testing—has led to DOAC dominance of the market. The average age of patients in these trials was in the low 70s, and few were considered frail.

And that is THE issue. Do average effects from these trials apply to elderly people with frailty?

First author of FRAIL AF, Dr. Linda Joosten, told the packed auditorium during her presentation that frailty is a complex syndrome that includes multiple domains, such as weight loss, communication difficulties, physical fitness, and polypharmacy, all of which may affect the benefit/harm ratio of DOACs.

FRAIL AF enrolled older patients (average 83) recruited from out-patient clinics in the Netherlands. They had to meet frailty criteria and be stable on a VKA. Half the group stayed on VKAs and the other half switched to a DOAC. The treating clinician chose one of the four DOAC drugs.

Their primary endpoint was major bleeding. They designed the trial to show DOACs were better—as shown in the seminal trials.

The results surprised the investigators.

The first interim analysis (trials are analyzed regularly by data safety monitoring boards) found a rate of major bleeding in the DOAC arm of 15.3% vs 9.4% in the VKA arm. The hazard ratio was 1.69 (95% confidence intervals (CI) 1.23-2.32; P = 0.0012.

Read that again.

FRAIL AF did not find that DOACs were better. The trial showed that conventional wisdom was harmful. Very harmful. Major bleeding was 69% higher in the group that switched. The surprise finding led investigators to stop the trial.

Three Big Lessons of FRAIL AF

The most obvious take-home is that if your frail patient is doing well on a standard VKA, such as warfarin, do not switch to a DOAC. This is good to know. But it is a quite specific medical question. This is not the most important lesson.

The second lesson from this trial speaks to how we know things in medicine. Senior author Geersing did not try to convince his colleagues with stories of frail elders who did poorly on DOACs. He did not set out to do retrospective observational studies. No. He designed and conducted a proper randomized trial. RCTs are how we should answer questions in medicine.

The third, and by far most critical lesson, from FRAIL AF speaks to the translation of evidence in the clinic. The evidence that established DOACS as preferred over VKAs came from trials that enrolled younger healthier patients. FRAIL AF teaches us to be super careful applying that evidence to more complicated older patients.

Trials provide evidence. Use of evidence is what separates doctors from palm readers. But use of evidence can never be algorithmic. You have to consider your patient vs those in the trials.

FRAIL AF shows the danger of soft-thinking and blindly following the fashion of the day. It also demonstrates the folly of thinking you can design a quality measure such as the prescription of a specific drug for a specific diagnosis—which is common now.

No trial at ESC infuses us more with humility. And for that, FRAIL AF tops my list as most important.

JMM

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