When A Negative Trial Takes 11 Years to Publish

The BioPace trial boldly challenged a new cardiac pacing technique, which was hot at the time. The trial was negative. But then not published for more than a decade.

It was my second ever ESC meeting. In Barcelona in 2014.

The BioPace trial comparing standard RV pacing vs biventricular pacing was presented as a hot-line trial. BiV pacing was all the rage at the time. The three lead system (one lead in the RA, one in the RV and the third in the coronary sinus to pace the LV) had been shown to improve patients with heart failure and left bundle branch block.

Everyone expected positive results. But the results were negative. This is a story about what happened—or did not happen.

First Some Background

BiV pacing equals electrical therapy for heart failure. Many patients with HF have a left bundle branch block. The problem with LBBB is that the RV contracts first, then the LV contracts later. That (150 msec) dyssynchrony can weaken the heart and cause heart failure.

But. But. When you pace both chambers simultaneously, you correct the electrical delay. We say that you have given this patient cardiac resynchronization therapy or CRT.

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Trial Idea

The thinking behind BioPace is that when you put a standard RV pacing lead, you create the same situation as a LBBB. Think about it. An RV pacing lead paces the RV first, then the signal has to traverse heart muscle to get to the LV. That is exactly what happens in a standard LBBB. In days of old, this is all we had. The other option was no pacing; and death.

An RV pacing lead, therefore, creates dyssynchrony. Pacing-induced cardiomyopathy occurs in a debatable number of new RV pacing systems. Estimates range from 10-25%.

BioPace tested preventive biV pacing in patients who required cardiac pacing. One group received a standard RV pacing system. The other group got biV pacing.

The trial was sponsored by a pacing company, and had it been positive, it would have massively expanded the market for BiV pacing systems—which are more costly, rightly so, because there are three vs two leads.

Trial Results

Over a mean follow-up of nearly 6 years, a primary outcome of death or hospitalization (HHF) occurred in 38.4% in the BiV arm vs 40% of the RV pacing arm. The HR was 0.78 but CI went from 0.76-1.02 and the p-value was 0.09, so non-significant. The second co-primary endpoint of survival was also not different, with both groups having a death rate of 33.8%.

Trials like this have crossovers, and the authors provide an as-treated analysis which also showed no sig differences.

You might wonder if the patients with lower baseline EFs did better with BiV pacing. Nope. Subgroup analyses showed no heterogeneity of treatment effect for any endpoint.

For secondary endpoints, there was no difference in 6 min-walk, and QOL questionnaires.

There were, however, more adverse events in the BiV pacing arm: 115 vs 72 procedure related. And 87 vs 54 lead related AE noted in the BiV vs RV group.

The authors concluded, rightly I think, that

“in patients with preserved EF who require pacing and will pace in the RV, BiV pacing did not prove superior and was associated with numerically more AE.”

The authors add that

RV pacing may be less harmful for this type of patient than previously thought.

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My Comments

BioPace was a well-conducted and bold trial. It recruited 1800 patients and tested an important question. At the time, in 2014, many of us hated giving a patient a single RV lead, because we knew it would create dyssynchrony and possible cardiomyopathy.

Plus, many of us loved BiV pacing because it had been shown to help patients with heart failure. It was more fun to do three leads; and we were paid more to do the extra lead.

What is more, one year before, the BLOCK HF trial, had shown that biV pacing improved outcomes over RV pacing if patients had some degree of left ventricular dysfunction.

But BioPace studied a different group. An all-comers group who did not have to have LV dysfunction. These are the patients we see almost every day.

And the results were non-significant. Not only did BiV pacing not prove efficacious compared to standard RV pacing, there were many more adverse events.

The journal Europace published the trial last week. Last week!.

What gives? Why would such a well-conducted important trial sit ideal 11 years after it was presented in a featured session at the world’s biggest cardiology conference?

Think of the counter-factual wherein biV pacing crushed standard pacing. Say it reduced death or hospitalizations, improved quality of life etc. Do you think the trialists and sponsors would wait more than a decade to publish the trial results?

I really worry about stories like this. What do you say? JMM

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Bonus Content for Subscribers (The Nuance of Conduction System Pacing)