William E. Boden, MD, FACC, FAHA

The ORBITA findings are incredible when one considers that stenting a coronary artery with a mean 84% stenosis should impart an immediate clinical and physiologic benefit — yet there was none observed across the board between the PCI and sham PCI groups: Canadian Cardiovascular Society (CCS) angina class, Seattle Angina Questionnaire scores, the EQ-5D quality of life score, all exercise indices, and Duke Treadmill scores were neutral, though the peak stress wall motion score index did improve in the PCI group as one would expect — meaning that the PCI was technically successful.

A 2014 editorial in JACC: Cardiovascular Interventions after FAME-2 was published (King SB, et al. JACC Cardiovasc Interv. 2014;doi:10.1016/j.jcin.2014.02.001) addressed the need for a sham control trial in stable CAD, and cites how this was accomplished in the late 1950’s with internal mammary artery ligations to improve angina, so this paper highlighted many of the shortcomings of more recent unblinded trials in the PCI era like COURAGE, BARI-2D and FAME-2, in which preconceived treatment biases led to assumptions of procedural treatment superiority and clinical benefit and which likely introduced bias into the less rigorous/soft endpoints like “unplanned revascularization” in FAME-2 that drove the composite primary endpoint in favor of FFR-guided PCI, and angina relief in all of these trials. This same limitation will apply to the large, ongoing ISCHEMIA trial, which is also unblinded, but won’t end until 2019. Both the JACC: Cardiovascular Interventions editorial and ORBITA underscore the powerful placebo/nocebo effect on both physicians and patients who undergo a procedure that is supposed to impart significant symptomatic improvement — yet remarkably, ORBITA found no between-group differences.

The narrative in the aftermath of COURAGE was a glib dismissal of the trial findings by many in the interventional community who stated simply: “COURAGE taught us nothing new,” which were the talking points for months/years as many tried to downplay the COURAGE trial results. What we were told repeatedly was: “We’ve known for decades that PCI doesn’t reduce death or MI in stable CAD, but that’s not why we do PCI in these patients — we do it to improve symptoms and quality of life, and PCI is better than optimal medical therapy for angina relief. Plus, many patients don’t like to take medications or don’t want to wait for medications to work, so PCI is a more effective treatment for angina, and that’s what we can offer to our patients.” Moreover, this prevailing view has been firmly espoused by cardiology professional society guidelines internationally for the past 8 to 10 years.

So now, along comes ORBITA, which confronted this “angina superiority with PCI hypothesis” head-on with a sham-controlled trial, the results of which emphatically underscored the powerful placebo/nocebo effect of a PCI procedure that both physicians and patients assumed — and have for 40 years — would be of unquestioned benefit. These results are a “Back to the Future” requiem in an earlier era some 60 years ago when the sham-controlled internal mammary artery ligation studies of the late 1950s showed the unexpected findings of a lack of benefit of this procedure.

How will the results of ORBITA be viewed? It will be a combination of love and hate. ORBITA was rigorously designed and undertaken with great care and painstaking attention to detail using objective exercise and physiologic outcome measures before and after stabilization on optimal medical therapy, combined with the use of well-validated quality of life metrics before and after randomization. Overall, the results were stunningly negative, which ORBITA supporters have cited. By contrast, many in the interventional community have been quick to pounce on and discredit this study. There certainly hasn’t been an opportunity since COURAGE was published 10 years ago in 2007 to potentially discredit a trial that now confronts the last remaining sacred cow of PCI benefit for angina relief as the sole basis to justify PCI in patients with stable CAD. Many in the interventional community will likely cite the limitations of small numbers, only 200 patients; that the study was woefully underpowered; the potential ethical conundrum of subjecting patients with significant flow-limiting CAD to a sham procedure (or deferred PCI for clinical need); that 28% to 32% of randomly assigned patients had either normal FFR or iFR, and therefore didn’t have a “physiologically significant” or flow-limiting stenosis that PCI would otherwise benefit; that the study was undertaken only in stable patients with single-vessel CAD; that the short duration of follow-up, only 6 weeks, was too brief to assess potential benefit (though this actually favored the PCI group); and, of course, who would have the time or patience to call patients three times per week to assess their response to intensifying medical therapy — it is deemed “not real-world”, just like the optimal medical therapy used in COURAGE was said to be unachievable in the real world.

Will ORBITA change practice?  Likely not, because the narrative will likely be that rates of PCI for stable ischemic heart disease are declining, while more recent data from American College of Cardiology’s National Cardiovascular Data Registry show that, based on appropriate use criteria, the percentage of patients undergoing inappropriate PCI — or the more recently sanitized term “rarely appropriate PCI” — is likewise declining. But, what isn’t entirely clear at present is whether, in the post-appropriate use criteria era, there has been an increase in “coding creep” to up-classify or re-classify patients with “stable angina” to “unstable angina” so as blur these distinctions — is it CCS Class 2 angina or CCS Class 3 angina? So, by re-classifying stable angina as “unstable angina,” such up-coding then flies under the radar of public reporting requirements. Recall also that the large ACC NCDR registry is voluntary and represents self-reported information. It is not an objectively validated data set.

We thought that COURAGE was an appropriate acronym for a large, almost 2,300-patient study where patients were followed up to 7 years after randomization with no clinical benefit on any hard endpoints. ORBITA required even more “courage” than our trial did, and the results are very important to advancing our understanding of how procedures may elicit powerful effects, but not necessarily the effect of angina relief most have long-assumed to be a benefit of PCI. It is — or should be — a wake-up call that we always need to challenge long-held assumptions, unless they have been subjected to rigorous, prospective, blinded study.

There is another very important aspect of ORBITA that fundamentally addresses the patient perspective on what undergoing PCI means, and what message patients take away. Most importantly, we need to be honest that our biases and pre-existing beliefs about the benefits of PCI color the way we approach this discussion with patients. When even a patient with stable CAD is found to have a flow-limiting coronary stenosis during angiography, what is conveyed to the patient in real time in the cath lab (along with the frightening appearance of an angiographic obstruction) is an impending catastrophic event: If we don't intervene and "fix this blockage" right here and now, something very bad could happen. In this context, who could blame a patient for acquiescing to PCI? But, I suspect there is little discussion about the lack of PCI benefit on improved survival or reduced MI in this setting — though well there should be. And, in this context, when an interventional cardiologist says to a patient: “I can fix that blockage,” what the patient may hear and take away is: “He can cure that coronary disease.” Inflated expectations and misperceptions of clinical benefit are critically important at this physician-patient interface.

Lastly, the looming question post-ORBITA is: Will we need to start informing our patients that PCI may not necessarily improve their angina either? Only time will tell. 

Arnold H. Seto, MD, MPA

The ORBITA Trial is a milestone in the study of the placebo effect in cardiology. In this first-ever sham-controlled study of angioplasty, 200 patients with stable angina with low-risk clinical features (single vessel disease, normal ejection fraction, normal exercise tolerance) were treated during run-in phase of optimal medical therapy, then randomly assigned to either PCI or a sham-controlled procedure. Despite a very high-risk lesion profile (average 85% angiographic stenosis, FFR of 0.69, and iFR of 0.76), the trial showed no statistically significant differences in exercise time, angina or quality of life between PCI and placebo.

Although the headline results of the study might appear to be negative for PCI in stable angina, a closer look suggests several reasons why PCI should remain an option, even with optimal medical therapy. Ischemia was clearly relieved with PCI as measured by dobutamine stress echo and FFR/iFR, and from the FAME 2 study, we know that the outcomes for ischemic patients is unfavorable, especially due to unplanned urgent revascularization. In ORBITA, over only a 6-week observation period, unplanned revascularization occurred in five patients assigned placebo compared with zero patients assigned PCI. Although the trial was underpowered for clinical endpoints, this represents a significant difference, with a P value of .02. 

The primary endpoint of exercise time was significantly different for patients before and after PCI (28.4 seconds improvement after PCI, P = .001), whereas this was not significantly different before and after sham PCI (11.8 seconds, P = .235). Only the between-group comparison proved to be non-significant (16.6 seconds, P = .2), indicating that while PCI reduces symptoms, this trial was unable to show that it did so more than a sham-PCI control.
This trial demonstrates both the effectiveness of medical therapy and the power of the placebo, as reductions in angina occurred after both interventions. The effectiveness of PCI on a background of aggressive medical therapy would naturally be more difficult to demonstrate with a small number of low-risk stable angina patients. Symptom relief and exercise tolerance may be less-sensitive markers of the effect of an intervention than ischemia. The durability of the placebo effect is also of concern. A larger, longer-term trial of higher-risk patients would have a greater potential of showing a difference between PCI and placebo.

The ideal treatment for any symptom would be inexpensive, highly effective and completely harmless. If we could ethically prescribe such a placebo, it would cure many of the world’s ills. However, in the real world, we have to treat patients and their symptoms. While patients with stable angina should first be given medical therapy, for the 77% of patients with persistent Class II to III angina despite medical therapy, PCI clearly works and should continue to be a choice for angina relief.