ORBITA: Sham Comparison Casts Doubt on PCI for Stable Angina

DENVER, CO — Among patients with stable angina, even with severe coronary stenosis, exercise capacity and symptom relief were no better after PCI for single-vessel disease than a sham procedure in the first-ever sham-controlled PCI trial^[1].

Dr Rasha Al Lamee

"I think that the correlation between a tight epicardial stenosis that we see, relieving ischemia, and hopefully improving symptoms may be more complex than just performing angioplasty," lead investigator Dr Rasha Al-Lamee (Imperial College London, UK) told theheart.org | Medscape Cardiology. "Perhaps some of these patients have microvascular disease, they may have noncardiac chest pain, they may have other reasons why they come back."

She stressed that the results of ORBITA, presented amid a 40th anniversary celebration for PCI at TCT 2017 and simultaneously published in the Lancet, need to be taken in context. The patients had single-vessel disease, and to extrapolate the results to patients with multivessel disease and a higher ischemic burden would be a mistake.

The results may also have been different if they had added an invasive physiological assessment rather than using angiography alone to guide PCI, albeit in line with common practice, she said.

Reaction to the trial was swift, with headlines splashed across national news outlets and a tsunami of Tweets fiercely debating its merits. In an accompanying editorial^[2], Dr David L Brown (Washington University School of Medicine, St Louis, MO) and Dr Rita Redberg (University of California, San Francisco) write that the implications of ORBITA are "profound and far-reaching."

"Based on these data, all cardiology guidelines should be revised to downgrade the recommendation for PCI in patients with angina despite use of medical therapy," they argue.

Speaking during a press briefing, Al-Lamee countered that the results "will stimulate debate and may even be used in guidelines discussions, but I think the guidelines are based on thinking about the whole population.

"Therefore, to use this to downgrade angioplasty in the guidelines, and I say this as one of the investigators, would be an incredibly large overreach."

Dr Ajay Kirtane (New York-Presbyterian Hospital/Columbia University Medical Center, New York City) called the editorial "unfortunate" and said it contained factual inaccuracies. For example, it claims there's a 15% MI rate after stable-angina PCI, which is "off by a factor of 10," and that PCI provided no benefits even when angina is refractory to medical therapy, when "these patients weren't studied in this trial."

"It does a disservice to the trial investigators . . . and more important, it does a disservice to patients," he said in an interview. "For folks who aren't refractory, if they were to read that or if it comes out in the lay press, then they're not going seek help when help could be provided in a thoughtful and less invasive way."

The COURAGE trial also showed no benefit of PCI over optimal drugs in reducing the risk of hard CV events in stable coronary artery disease, but what's often underappreciated is that patients with the most frequent angina had a crossover rate of nearly 50% to PCI, Kirtane added.

Panelist Dr Carl Tommaso (NorthShore University Health-Evanston Hospital, Chicago, IL) said the ORBITA investigators showed PCI improved patients' exercise times and ischemia, but still their symptoms didn't go away.

"Why does your patient after a successful angioplasty that you know you've had a great result with come back? Because their symptoms weren't angina to begin with. I think that was one of the problems in COURAGE and may be a problem you have here," he added.

The Right End Point?

ORBITA investigators at five UK sites enrolled 200 patients with angina and at least one angiographically significant lesion (>70% stenosis) in a single vessel to 6 weeks of medical optimization and uptitration of angina therapy before randomization to PCI with drug-eluting stents or a sham procedure with auditory isolation (headphones) and sedation.

At 6 weeks of follow-up, exercise time increased from baseline by a mean of 28.4 seconds in the PCI group (P=0.001) and by 11.8 seconds in the sham group (P=0.235). However, the primary end point of between-group change in exercise time based on an conservative estimate of 30 seconds was not significant (+16.6 sec; P=0.200).

PCI was associated with a significantly reduction in ischemia, assessed by dobutamine stress echocardiography change in wall-motion stress index (P=0.0011).

"In fact, the stress echo burden has essentially normalized in the angioplasty arm," Al-Lamee said.

Although both groups had improved outcomes, there was no between-group difference in Seattle Angina Questionnaire angina frequency or physical-limitation scores or in quality of life on the EQ-5D-5L.

At enrollment, 98% of patients had Canadian Cardiovascular Society class II or III angina, but by randomization 9% of PCI patients and 14% of sham patients were free of angina, improving at follow-up to 39% and 29%, respectively.

Panelist Dr Martin Leon (Columbia University Medical Center, New York City) applauded the investigators efforts for a "remarkable study" but said it's a much, much higher bar to achieve when the end points are differences from baseline between two groups.

"Baseline data demonstrating that these patients had very good functional capacity, had infrequent angina, had very little ischemia, means that regardless of what you did to the coronary artery there was going to be very little you could demonstrate in terms of clinical therapeutic benefit. So I'm really glad that PCI had a statistically significant benefit in both echos and the stress tests," Leon said.

"The concern here is the results will be distorted and sensationalized to apply to other patient populations where this kind of outcome very likely would not occur," he added.

Panelist Dr Manish Parikh (New York-Presbyterian Hospital/Columbia University Medical Center, New York City) agreed. "Let's not sensationalize this. These are the types of patients that we usually don't bring into the lab. We do physiology and if it's negative, we don't treat. So it's not going to change my practice at all."

Commenting for theheart.org | Medscape Cardiology, Dr Roxana Mehran (Ichan School of Medicine at Mount Sinai, New York City) said, "To me actually this study shows angioplasty is quite effective in reducing ischemia, improving [fractional flow reserve] FFR, and in fact I'm actually very pleased with this. It's exactly what I want to do for my patients—improve their blood supply."

Asked whether this isn't just a positive spin on a negative study, Mehran quickly responded, "No," adding that whenever a primary end point is a change in a value, showing an important difference is very hard to do when baseline values are so good, especially with only 200 patients.

"I promise you, had she studied 400 patients this would be positive because everything was in the right direction," she said.

Lessons Learned

Panelist Dr Allen Jeremias (St Francis Hospital, Rosyln, NY) said "One of the lessons of this is that we cannot guide our therapy solely by the angiogram, but we have to get physiologic data, patient symptoms, and basically the context that the patient presents with."

Al-Lamee responded that the investigators plan to look at the FFR and instantaneous wave-free ratio (iFR) results, assessed in all patients before randomization, to see whether there is a subgroup that may gain a greater benefit from PCI.

"The point is well made that across all cath labs we only report physiology in 20% of our cases; perhaps we can do more," she said.

During the press briefing Dr Robert Yeh (Beth Israel Deaconess Medical Center, Boston, MA) congratulated the authors on a courageous, bold, and well-executed trial but said the results reaffirm in many ways those from COURAGE.

"To extrapolate that this means that elective PCI is not an indicated procedure is the furthest overreach that I can possibly imagine from a very small and I think hypothesis-generating trial with an interesting result," he said.

On the other hand, Yeh said one of the takeaways is that in this type of population with this particular level of intensive medical care, "It is likely that medical therapy is quite effective for a large number of patients, and the interventional community should take note of these findings and do a better job of offering it."

Notably, the mean number of antianginal medications in the PCI group was 0.90 at enrollment, 2.8 at prerandomization, and 2.9 at follow-up, compared with 1.0, 3.1, and 2.9, respectively, in the sham group. All patients had blood-pressure machines at home and were called by a consulting cardiologist several times per week to introduce and uptitrate medical therapy.

"The problem with medical management is that patients won't stay on it because we're not talking about just a beta-blocker; we're talking about two or three or four medications," Dr Molly Szerlip (Heart Hospital Baylor Plano, Texas) said in an interview.

She added, "It's really not inferior, and a lot of people would prefer to get the stent and not have to take four or five, which becomes really expensive. Optimal medical therapy means medicines like Ranexa [ranolazine, Gilead], which insurance companies don't reimburse and is an over-$1000/month drug."

"We know that it's quite hard to achieve this kind of medical therapy," Al-Lamee acknowledged in our interview. "In the UK, the cost of prescription is a different thing, but clearly regular consultations with a physician if you were going to do it in normal clinical practice and also the issues around side effects and having to see patients for side effects has a cost implication."

She noted that the investigators plan to publish an analysis on medical therapy alone including compliance, discontinuation, and side effects.

Finally, Society for Cardiovascular Angiography and Intervention president Dr Kirk N Garratt said in a statement, "ORBITA was undertaken because the investigators were concerned about the placebo effect. Of course, the placebo effect can be very powerful in the short term, but ischemia remained for these sham-treated patients. Since the hearts of sham-treated patients were still struggling with ischemia, I worry about the longer term."

He continued, "Andreas Gruentzig, the inventor of angioplasty, advocated for rigorous study of the technique from the start. He would approve of using a sham procedure, but I think he would have demanded a larger, longer study with less subjective end points."

ORBITA was funded by grants from National Institute for Health Research Imperial Biomedical Research Centre, Foundation for Circulatory Health, and Imperial College Healthcare Charity. Philips Volcano supplied the coronary pressure wires. Al-Lamee has received speaker's honoraria from Philips Volcano. Disclosures for the authors are listed in the paper. Brown and Redberg declare no relevant financial relationships.

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