Publication Bias and Therapeutic Fashion

The Study of the Week goes back in history to explore the matter of how our beliefs affect what can be known in Medicine

The story begins in Nottingham UK in 1980. It was a small study at one hospital. But its lessons are large.

First the background.

I believe the CAST trial (1991) was the most important trial in all of modern medicine.

It showed that the common practice of using drugs to suppress rhythm disturbances (anti-arrhythmics) in patients after heart attack (myocardial infarction) led to higher death rates. Anti-arrhythmic drugs killed 1 patient for every 29 we treated.

CAST shocked the world of cardiology because suppression of rhythm disturbances after MI had been an accepted practice. We had observational studies that associated rhythm disturbances with higher death rates and we had drugs that suppressed arrhythmias. It made perfect sense that suppressing bad things would help people.

But our belief was wrong. And that is why CAST was so important. Not only did it change the management of patients with MI, the trial began the evidence-based practice movement. CAST established the importance of randomization and it strongly demoted the value of expert opinion and causal inference from observational studies.

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The question for this column is why it took a decade of using antiarrhythmic drugs to do the CAST trial—and learn that we were killing people with our belief?

Dr John Hampton, a cardiologist in Nottingham, UK, tells the story of a study that he and his group performed in 1980—a decade before CAST.

In 1980, his group decided to perform a small study of a drug called lorcainide, which is similar to the rhythm-suppressing drugs used in the CAST trial. They did this trial of 100 patients to detect a 25% reduction in ventricular rhythm disturbances.

They randomized patients with suspected MI to either the drug or placebo. They quickly learned that lorcainide suppressed arrhythmias. It was an effective arrhythmia drug.

But they also observed that 9 of 48 patients died in the lorcainide group vs only 1 of 47 in the placebo arm. They did not expect this 9-fold higher death rate.

Here is what Dr Hampton wrote in a 2015 editorial:

This difference did not worry us particularly: the overall death rate (10%) was about what we had expected, we had become used to the confusion caused by small trials with few outcomes, and we assumed that the excess deaths in the lorcainide group had probably occurred by chance because there did not seem to be any pattern in the causes of death.

Our lorcainide study faithfully followed all the rules of clinical trials as they were then understood. One of those rules was (and remains) that if differences are observed in outcomes that were not pre-specified these should be regarded merely as generating hypotheses for testing in further studies

But then something happened. They tried to publish their study.

Full of enthusiasm we started with The Lancet and then tried two or three cardiology journals. The result was always the same – immediate rejection. We lost interest, the company which produced lorcainide decided for commercial reasons (not because of our study) not to continue with the drug – and we forgot about it.

Hampton writes, and I remember, that in the mid 1980s our interest turned to thrombolytic therapy (clot-busting) of MI. The therapeutic fashion of the day had changed.

Then, two years after the CAST trial had been published, the Nottingham group sent in their old manuscript for publication.

The big journals were not interested, but they found a home for it in the International Journal of Cardiology. The title of the paper included the phrase—”an example of publication bias.”

Hampton’s conclusion to this story is beautiful:

The moral of this story is that evidence-based medicine often depends on evidence that has been collected according to the fashion of the day. It depends on what can be funded and on what interests journal editors and reviewers, and this too is often a matter of fashion. Perhaps we should talk about ‘opinion-based’ or ‘fashion-based’ rather than evidence-based medicine.

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I am not sure whether publication of this small trial 10 years before the CAST trial would have helped break our deadly belief in anti-arrhythmic drugs. The 9x higher death rate could have been put off to the play of chance—as the authors did at the time.

But, in retrospect, with the results of CAST now known, the higher death rate was likely an early sign of trouble rather than a play of chance.

Yet denial of publication meant no one was given the chance to even consider the danger of this class of drugs. Also, not having the study published meant not having the deaths added to meta-analyses.

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I share Dr Hampton’s lorcainide story because it highlights many of the timeless lessons of medical practice: the power of randomization over observational studies, the value of publishing surprising or non-significant results, and, mostly, the absolute need to remain humble about what we believe to be true.

It seems a great exercise to consider what practices we believe in today might be overturned in the future. Some things will surely hold up: PCI for MI, fixing displaced fractures, antibiotics for bacterial infection, and of course, caring and empathy.

But due to my age, I can testify that we were quite sure that ventricular arrhythmias needed to be suppressed after an MI.

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I spoke at the University of British Columbia and the Therapeutics Initiative in Vancouver last week. I was shocked at how many people said that they read Sensible Medicine. Adam, Vinay and I appreciate your support. We believe that independent and industry-free thinking needs a home. Sensible Medicine grows because of your support. Thank you. JMM