PROFID EHRA: The Most Important Trial of the Decade in Cardiology

The PROFID EHRA trial will test the benefit of an implantable cardioverter defibrillator in patients who have LV dysfunction after an MI.

You might think I mistyped the teaser sentence, as an ICD has a Class I recommendation in this type of patient. But it was not. PROFID EHRA will retest the ICD in this highest-risk patient.

ICD benefit was established in two clinical trials published in the early 2000s. In SCD-HeFT, an ICD added to optimal medical therapy reduced mortality over placebo by 7% in absolute terms. In MADIT 2, which recruited only patients with LV dysfunction due to previous MI, the ICD reduced mortality by 5.6%.

By today’s standards, these are large effect sizes. Plus, it’s in mortality, not a composite endpoint. Yet, still, the vast majority (≈13 of 14) of patients implanted with an ICD for primary prevention never receive a shock, and therefore gain no benefit.

Both of these seminal trials recruited patients more than 20 years ago. The treatment of heart failure has improved. In fact, heart failure trialists have shown a 44% decline in sudden arrhythmic death from their oldest trials to the newest ones. That’s huge, because ICDs extend life only by reducing arrhythmic death. If the proportion of death caused by arrhythmia goes down, so does the chance for ICD benefit.

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In the DANISH trial (2016), which recruited only patients with heart failure not due to CAD, the ICD no longer reduced death over optimal heart failure therapy.

Here is a slide of the two trials’ survival curves.

As I wrote here on Sensible Medicine, cardiologists have mostly ignored DANISH results. I explain why in the linked piece. Yet, to smart and impartial judges, ICD benefit in patients with non-ischemic heart failure has always been dubious.

Ischemic heart failure (think scar) confers a higher risk of arrhythmia and sudden death than non-ischemic disease. The higher the risk of arrhythmia the higher the probability of ICD benefit. Keep in mind that the ICD is a dumb device—as it saves lives by shocking a malignant arrhythmia back to normal. That is (pretty much) it.

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You might be wondering about the ethics of doing such a study. Is there equipoise or uncertainty?

I think there is. Here are a few reasons. Essentially, change has come to both the comparison (medical) and treatment (medical + ICD) arms.

Toughening of the comparator arm: Medical therapy of heart failure has improved over the past decade. We have new drugs and a heightened sense of getting patients on these drugs. Interventional therapy of coronary disease has also improved. Fewer patients have huge heart attacks due to early revascularization with stents.

Lower probability of ICD benefit. The heart failure trialists have clearly shown a decline in sudden cardiac death over the past 3 decades. Since everyone dies of something, a lower proportion of sudden to non-sudden death makes it harder for the ICD to make a difference.

This past weekend I had the pleasure to sit in on an investigators’ meeting in Berlin, Germany. Sadly, the trial has slow enrollment of patients. They need more than 3000 patients to sort signal from noise. It’s early yet but the recruitment pace is low.

Potential reasons for slow enrollment include the boldness of the study question. Doctors have had 20 years to get accustomed to the ICD. What is more, European practice relies heavily on guideline documents. Going against a therapy that has the highest recommendation takes effort. Class I equals “you should do this.”

Another reason is reimbursement. Most of the PROFID centers are in Germany, where procedures are lucrative. Doctors who enroll a patient in the trial stand to lose income. Patients randomized to no ICD means no procedural payments. Hospitals, too, lose money when fewer ICDs are implanted. Financial disincentives should not be underrated.

A third reason for challenging enrollment is that fewer patients have bad enough LV function after an MI. Emergent stenting to stop an MI from causing damage is the norm and it saves heart muscle. The pool of ICD eligible patients after an MI is smaller than it was 20 years ago.

Finally, most of the PROFID enthusiasts work in academic centers. While most of the MIs and heart failure occur in the community. Community doctors may be less enthusiastic about the effort it takes to explain the pros and cons of being in a clinical trial. Far easier is to implant an ICD and skip the science.

Slow enrollment is dangerous because PROFID EHRA is funded by the European commission. The obvious reason for public funding is that industry does not sponsor trials that may result in fewer units sold. That’s not nefarious; it’s just a fact.

Government funding will not continue if recruitment stays low. Trials are expensive. And they need to recruit enough patients to have enough statistical power to detect differences. Underpowered trials border on being unethical—because if you are going to enroll patients in an experiment, it should be able to answer the clinical question.

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My talk at the Kardiologie Symposium on Saturday focused on the future of knowledge transfer in cardiology.

I initially thought I would speak about AI or preprint servers, or independent media (like this site), but thinking about PROFID the day before convinced me that randomized controlled trials will remain the best way to transfer knowledge, now, and well into the future.

Think about it: a completed fully-powered PROFID EHRA trial will transfer a bunch of knowledge. If positive for the ICD (or in this case, medical therapy is not noninferior), we will continue recommending these devices in PROFID-like patients. Although the effect size is likely to be lower than in the seminal trials, so patients may be less convinced than they used to be.

But if the ICD does not prove to be better than optimal medical therapy, then we will have learned two lessons—one modest and one huge.

The modest lesson involves better treatment of patients with one selective type of condition. It will be great news for patients because avoiding hardware and its potential complications is a positive.

The big lesson of a “negative” PROFID comes in the teaching of evidence-based practice. An ICD reversal will show physicians the need for skepticism—even for therapies with strong guideline support. Specifically, that trial results and the guideline recommendations that follow, should have expiration dates.

Diseases and background therapy change and so can the benefits of additional therapy. Here is another slide I made for beta-blockers in the post-MI setting. In 1992, there was clear benefit. In 2024, no benefit. The drug is the same. The disease changed.

I write to urge my European colleagues to be bold. Think skeptically and get your patients enrolled in this trial.

Congratulations to Professors Hindricks and Dagres for having the courage to ask such a question and the energy to plan and conduct this important trial. It must not fail.