Most Important

(The CAST Trial is) "literally the most important trial of modern medicine. Period. End of story.” Tweet by John Mandrola, MD

It is July 1^st, 1988, Cara’s first day as a medicine intern on my ward team. She meets her existing patients and picks up a new one, Bill. Bill is 35 and has a severe cardiomyopathy. He is waiting a heart transplant but has been having worsening episodes of ventricular tachycardia (VT). He was a direct admission after an electrophysiologic (EP) study. During the study the cardiologists used electric impulses to induce VT. They found a medication that made it harder to induce VT and sent him up to the medical floor for admission and monitoring with instructions to initiate that medication. Cara meets Bill, a man only slightly older than herself, performs a history and physical, and orders the medication: encainide.

The next morning when I came in to round as the 3^rd year resident on the team, I found Cara quietly crying at one of the desks behind the nurses’ station. Bill had coded and died overnight. A nurse had a needlestick during the code. She had called Cara in the middle of the night to find out whether Bill had any HIV risk factors. Cara, on her first night as an intern, had learned of Bill’s death when she received this panicked call.

I learned from the nursing staff that Bill’s family was in his hospital room, hoping to speak with someone about what had gone wrong. I called down to the EP lab to see how the cardiologists wanted to handle the conversation. Ever so thoughtfully, they suggested I take care of speaking with the family since they were busy doing EP procedures. I brought Cara with me and met Bill’s parents and brother.

“Can you tell us what happened?” the brother asked after we’d told the family how sorry we were.

“We know,” I said, “that sometimes the medications we use to try to prevent arrhythmias can make them worse. We call this a ‘proarrhythmic effect’.”

“So, you think the medication he received is what caused this?”

“I think that’s the most likely explanation. The team that took care of him last night was run by two of the best residents you could possibly have in a situation like this, and they couldn’t break his arrhythmia. It was probably the medication.”

As an aside, I wasn’t lying about the residents. One was a future interventional cardiologist who was so calm and determined that you would have been happy to have her leading your tribe during a zombie apocalypse; the other is now a world-famous cardiologist, researcher, and educator.

After we left the room, Cara looked at me and said, “So that means I killed him.”

I’ve thought about these events many times over the years, but particularly one year later when the preliminary results of the CAST trial became known. I was, to put it mildly, not shocked.

The medical center where I was a resident had a major EP program. I had been learning about the procedure since I was an intern. As with Bill, patients with ventricular arrhythmias would be tried on various antiarrhythmic drugs until one was found that suppressed arrhythmias (or at least made them harder to induce) in the lab. The evidence that this was beneficial was observational. Patients who were found to have a drug that suppressed inducible arrhythmias and were treated with that drug had much better survival compared with patients for whom no suppressing drug could be found. As a 2^nd year resident, I’d learned enough to ask the EP attendings and fellows how they could know that they weren’t just finding people who would have had better survival even if they weren’t given the suppressing drug. That is, maybe these EP studies were just a diagnostic procedure for finding those people who were more or less likely to survive, rather than a therapeutic procedure to find a life-saving drug therapy. (I expect you can imagine how my challenges to their bread-and-butter procedure were received – especially coming from a resident.)

The CAST investigators set out to answer this question. Patients whose ventricular arrhythmias could be suppressed by one of three medications were randomized to receive that medication or placebo. All three medications were eventually shown to increase mortality, and the portion of the trial involving encainide (and the closely related drug flecainide) was stopped for harm in April 1989. After a mean follow-up of 10 months, 8.3% of patients receiving encainide or flecainide had died, compared with 3.5% of those receiving placebo.

CAST was an extremely important trial because it stopped electrophysiologists from continuing to kill people like Bill.

I doubt, though, that this is why Dr. Mandrola feels it is the most important trial ever. Recurrent ventricular arrhythmias aren’t that common; they don’t kill that many people. Obviously, every avoidable death is a tragedy, but a small absolute increase in death rates with a drug that is treating a rare disease makes little difference.

What makes the trial important has to do with cardiologists learning a lesson about the importance of good evidence.

Even with regard to lessons about evidence, though, I would argue that the HERS and WHI trials are far more important. They showed that the observational data suggesting cardiac benefits from hormone replacement therapy were wrong.

Did cardiologists (and everyone else) really learn a lesson about the importance of robust evidence before the widespread adoption of a procedure? Dr. Mandrola also wrote about the stunning ORBITA trial showing that many of the benefits ascribed to stenting a coronary lesion in patients with stable angina were likely never real. This wasn’t published until three decades after CAST.

Bill never got to receive a new heart and, as best I could tell, Cara never recovered from his death. She was smart and compassionate, but she never developed confidence in her medical skills. With pretty much every other new doctor I’ve worked with on their first night as an intern, no matter how badly the shift went, I could always reassure them, “everyone you cared for lived.”

David Rind is an academic primary care physician at Beth Israel Deaconess Medical Center and Chief Medical Officer of the Institute for Clinical and Economic Review. He was previously Vice President of Editorial and Evidence-Based Medicine at UpToDate.