ORBITA investigators publish response to critics

ORBITA, the first double-blinded, placebo-controlled trial evaluating percutaneous coronary intervention (PCI) versus optimal medical therapy, has divided the interventional cardiology community.

Some cardiologists were quick to dismiss the trial’s results based on the study’s design while others believe a placebo effect may factor into symptomatic improvement after PCI, and that optimal medical therapy alone is a sufficient treatment for some patients with stable angina and single-vessel coronary stenosis.

Briefly, the randomized trial showed a statistically insignificant difference in exercise duration six weeks after treatment with either PCI or a sham procedure. Ninety-one patients were in the sham arm while 105 received PCI, a procedure that has been performed for 40 years and is considered a cornerstone of interventional cardiology.

Reactions to the provocative trial have played out in news media and on social media, which provides the ability for rapid-fire exchanges. One of ORBITA’s principal investigators, Darrel P. Francis, FRCP, even created a Twitter account in November to respond to questions about the trial, which was unveiled at the Transcatheter Cardiovascular Therapeutics scientific symposium and published simultaneously in The Lancet.

Against the chorus of criticism, Francis and co-lead investigator Rasha Al-Lamee, MRCP, provided a more comprehensive response in EuroIntervention on Dec. 8.

They reported being surprised by the trial’s findings but even more surprised by the “subsequent reaction to them.”

Critics have questioned the study’s sample size, endpoint and the types of patients it enrolled. Al-Lamee and Francis addressed each of these issues in their response, with the following highlights:

• A trial of longer than six weeks would have been unethical given the hypothesis that PCI was beneficial in these patients. The researchers also needed to make the placebo arm “sufficiently acceptable to patients and their clinicians to prevent undue selection bias and high rates of crossover or dropout.”
• The primary endpoint of treadmill exercise time was taken from FDA and European Medicines Agency recommendations for anti-anginal medicines.
• “Ninety-four percent of ORBITA patients had evidence of ischemia on one or more non-invasive or invasive tests,” Al-Lamee and Francis wrote. “However, this was not an entry requirement because the majority of PCI worldwide is based on symptoms and angiographically evidenced disease, with approximately 90 percent of PCI performed without invasive pressure measurements. Enrollment to ORBITA was designed to be representative of appropriate single-vessel elective PCI.”
• The sample size was powered to detect a 30-second difference in exercise time between the treatment arms. “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.”

Al-Lamee and Francis said, “Fellow interventionists often marvel that we obtained ethical approval.” But the process was straightforward, they reported.

The national ethics committee asked three 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, their final question was, ‘Then why has this trial not already been done?’ To that, we had no response,” the researchers wrote.

The investigators closed their argument by calling for more placebo-controlled trials. Polarizing opinions only emphasize the need for more thought-provoking studies, they said.

“Clinical trialists should be the first to acknowledge the limitations of their research, putting their own results into perspective,” Al-Lamee and Francis wrote. “Every step in medical research should be seen as exactly that, ‘one more step forward.’ The equal servings of praise and ridicule may continue for some time but ORBITA has undoubtedly shown that placebo-controlled interventional trials can be done, do provide new information, and should be as standard for interventional procedures as they are for medication.”