In Defense Of ORBITA

–The trial investigators respond to their numerous critics.

If you’ve been reading about ORBITA then you probably know that the first ever placebo-controlled trial of PCI was interesting and provocative. But you’ve also probably heard that the trial was too small, too short and performed in patients who should not have been studied. Simultaneously, you also probably heard from the same critics— without any sense of self awareness— that the trial both reaffirmed what interventional cardiologists already knew and were already doing. So the message was it was a bad trial except for the fact that it confirmed the obvious.

Until now it has not been easy to understand the defense of the trial by the ORBITA investigators. Most of the fiery debate has taken place on Twitter, which is opaque or inscrutable for most cardiologists and other interested parties. An added difficulty is that many US critics may have had additional trouble understanding the language of the UK-based ORBITA investigators, who are prone to speak with sarcasm, irony, and subtlety.

The good news is that the two lead investi  gators of ORBITA, Rasha Al-Lamee and Darrel Francis, have now published a relatively brief and comprehensible response to their critics in EuroIntervention. Americans can celebrate the fact that it is almost free of irony. (Actually there’s a fair amount of irony but you can ignore it and still grasp all the main points, just as a tone deaf person can understand the words of Handel’s Messiah.) Perhaps now, finally, we can have an intelligent discussion about the merits and implications of the trial.

If you have any interest in ORBITA you should read the whole thing. Here are some of their main points:

• The sham design meant that the trial was not plagued by selection bias and high crossover or dropout rates. The authors point out that most of the events in the earlier FAM  E 2 trial “occurred soon after the physician had explained that there was a haemodynamically significant lesion that had not been stented.” This is a profound and easily missed point.
• The primary endpoint, treadmill exercise time, was taken from FDA and EMA recommendations for anti-angina drugs. (I would add that critics have been quick to assail this endpoint, but have failed to propose any better endpoint.)
• The sample size of 200 patients was designed to detect a 30-second improvement in exercise time beyond placebo. “The only reason to carry out a larger study would have been the belief that a smaller effect size than 30 seconds was clinically relevant,” the authors write.
• Evidence of ischemia was not an entry requirement “because the majority of PCI worldwide is based on symptoms and angiographically evidenced disease, with approximately 90% of PCI performed without invasive pressure measurements. Enrolment to ORBITA was designed to be representative of appropriate single-vessel elective PCI.” Nevertheless, 94% of ORBITA patients did have evidence of ischemia.
• Since there was a widespread belief that PCI would be beneficial it would have been unethical to ask patients to remain blinded to their treatment allocation for more than 6 weeks, especially since they sought to study a representative sample of patients including those with high-grade lesions.

In other words, ORBITA was designed to ethically test, for the first time, in a rigorous placebo-controlled fashion, a clinically significant question in a representative and clinically important population.

Perhaps the most important point the ORBITA authors make involves their effort to obtain ethical approval for the trial. Some have raised ethical questions about the trial. But, they recall, when they sought approval from a national ethics committee they were asked 3 questions:

1. “Is it possible that we may be implanting unnecessary stents?”
2. “Does an angioplasty procedure have risks?”
3. “Are there long-term complications following angioplasty?”

“When our answer to each of these questions was affirmative,” they write, “their final question was, ‘then why has this trial not already been done’? To that, we had no response.”

More on ORBITA:

• What If PCI Is Just A Sham?
• Small Trial Raises Big Concerns That PCI In Stable Angina Is Just A Placebo
• ORBITA Trial Puts Interventional Cardiologists On The Defensive
• Diving Deep Into The ORBITA Trial
• The Story Behind The NY Times ORBITA Anecdote