The Ethics of Sham PCI and the Clinical Relevance of ORBITA-2

John Mandrola asks Rasha Al-Lamee and Christopher Rajkumar to address criticisms of the ethics and clinical relevance of their pivotal ORBITA-2 trial.
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John M. Mandrola, MD: Hi, everyone. This is John Mandrola from theheart.org | Medscape Cardiology. I'm at the American Heart Association meeting in Philadelphia, and I'm so excited to present and have a conversation with two saviors of interventional cardiology, primary author Christopher Rajkumar and senior author Rasha Al-Lamee, authors of the ORBITA-2 trial, which came out positive for PCI. First of all, congratulations!
Rasha Al-Lamee, MBBS, MA, PhD: Thank you, John.
Mandrola: You've already done many interviews on this. Before we get into some of the specific things that have been going on, talking online, just give us the basic rundown of what you did and what you found.
ORBITA-2 Key Findings
Christopher A. Rajkumar, MBBS, PhD: ORBITA-2 was a placebo-controlled trial of percutaneous coronary intervention (PCI) for stable angina, just like the first ORBITA trial. Essentially, the key differences in ORBITA-2 compared with ORBITA are that we intentionally diverged from clinical guidelines in ORBITA-2 - I'm sure that will be the focus of some of the questions today - in that we wanted to test the unattenuated efficacy of PCI for angina relief. The only way we could do that is by taking patients off their antianginal medications.
There were some other differences in the trial as well. We incorporated patients with single- and multivessel disease, and evidence of ischemia and evidence of symptoms were both mandatory prior to randomization. The patients were followed up for longer - 12 weeks instead of 6. The big difference is also that we used a novel clinical endpoint called the angina symptom score, which encompassed daily reporting of angina from our patients, how much antianginal restart they needed, and any adverse clinical events like acute coronary syndrome and death.
Mandrola: ORBITA was a placebo-controlled trial of PCI as an add-on to antianginal drugs. This was totally different in that these were symptomatic patients on antianginal drugs, and then a couple of weeks before, you took them off the antianginal drugs to isolate the effect of PCI alone. Rasha, tell us what happened.
Al-Lamee: We found that angioplasty, compared with a placebo procedure, improved that angina symptom score and that patients had a far better health status on our angina symptom score. In fact, that was collected every single day. We saw that impact immediately and it was sustained throughout that 12-week period.
We also saw that patients in the PCI group were three times more likely to be free from angina and more likely to have an improvement in quality of life and an improvement in all of the various categories in terms of exercise time on the treadmill, improvement in CCS class, and also an improvement in the various domains of the SAQ questionnaire.
Mandrola: Thank goodness.
Al-Lamee: Well, I know what it's like to be negative, so it was quite nice for it to be positive this time!
Mandrola: The exercise time on the treadmill, which was the endpoint of ORBITA-1, was also positive by about 60 seconds. Is that a lot or a little?
Al-Lamee: It equates to one full-dose antianginal agent. You're thinking about a procedure with costs and potential risk - and it's not negligible either, that cost or that risk - for one antianginal agent's worth of treadmill exercise time improvement. It's still, as a blinded effect size, far smaller than the unblinded effect size that we saw from the original ACME trial of 96 seconds. Of course, it's far larger than what we saw in ORBITA, which was 16.6 seconds.
Mandrola: Chris, the slide you showed in the presentation of that gnarly lesion in the left anterior descending artery, which no one would walk away from in my neighborhood, that's only equivalent to one antianginal tablet. It's hard to believe.
Rajkumar: An important point is that, of course, that's an average treatment effect.
Mandrola: Okay, fair enough.
Rajkumar: Of course, we've got some huge responders in ORBITA-2 and we've got many patients who saw no response at all. That is a whole other subject of further research.
Al-Lamee: That's a "watch this space" moment, I think.
Is It Ethical?
Mandrola: Your trial has obviously generated many things online. One is the ethics. People ask how is it even ethical to do this. Let's answer that.
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