1.2 / IAGS 2019
Session 1: Coronary Session 1: Elective PCI
Elective PCI is Not Dead: How to Take ORBITA Out of Orbit
Problem Presenter: Alfredo Rodriguez
Statement of problem or issue
The ORBITA trial continues to generate interest and controversy. This blinded trial compared two groups of patients with stable angina, a positive exercise treadmill stress test (ETT), and an angiographically severe stenosis in a single coronary artery to either optimal medical therapy (OMT) or percutaneous coronary intervention (PCI). Outcome was assessed by a 6-week ETT. The result was a non-significant improvement in exercise time in both the OMT and PCI groups (11 seconds vs 28 seconds, respectively). The conclusion was that PCI in this setting was a mere placebo. Some commentators called for a change in guidelines and restrictions on PCI in patients like these. The study was hailed by some as a new standard in clinical trials, altering the spectrum of future research. However, a perplexing problem was that in prior studies, OMT patients improved exercise time by 55 seconds while PCI patients improved by about 120 seconds. Why ORBITA patients behaved so differently remains unexplained, as admitted even by the study authors.
Gaps in knowledge
Several major limitations in ORBITA have been identified. A conservative estimate of the enrolled patients at the 5 participating centers reveals they were less than 1% of the total screened. So, enrollees were a highly selected group. Careful analysis of the angiograms reveals that many lesions were less than the prespecified requirement of >70% severity. This finding could also explain the fact that 30% of enrolled patients had a normal FFR before the PCI.
Importantly, due to blinding, none of the treated patients were told they had received a stent. However, patients in both groups were told that they had a severe stenosis in a major heart artery, possibly inducing a “nocebo” response. What exactly is a nocebo response? It is the opposite of placebo (favorable response) and has been defined as “negative expectations or threats to the patients in response to the clinical encounter.” This uncertainty about the status of their severe narrowing could very well have led patients in both groups to proceed cautiously and hold back on the 6-week ETT in case their artery was not stented. This might explain the markedly reduced exercise response of both OMT and PCI patients relative to all previous trials.
The same investigators subsequently aimed to answer these questions in a small but eloquently performed trial in similar, ORBITA-like patients, in which they replicated the ORBITA protocol but implanted stents in both study arms and informed all patients that they had received a stent, thus effectively removing any possible nocebo response. These patients exercised for an additional 65 seconds at follow-up. The investigators also used a special pressure sensor to perform an eloquent hemodynamic study pre- and post-PCI, which proved that post-PCI FFR, iFR, coronary perfusion pressure, as well as coronary flow velocity at peak exercise, significantly increased and were normalized relative to the pre-PCI measurements. They concluded “PCI for single-vessel stable coronary artery disease shows clear physiological evidence of meeting all that could be demanded of a therapy for ischemia.” The calls for changing the guidelines became much more subdued after the ORBITA investigators acknowledged the original study limitations.
Possible solutions and future directions
The ORBITA trial was a landmark because it was the first to attempt to study the psychological placebo response to PCI. However, it highlighted the potential pitfalls encountered when studying the complexities of human reactions. Future studies in other fields of percutaneous interventions will undoubtedly become subject to this type of trial but would have to circumvent the obstacles encountered in ORBITA:
- The placebo response is part of any medical therapy and to test an intervention, it must provide evidence of efficacy above and beyond the placebo effect. Accordingly, all measures should be taken to increase the placebo response, while at the same time minimizing any possible nocebo effects. This would be done through reassuring and comforting verbal communications.
- Psychological tendencies of patients are highly varied, with some more prone to a placebo (positive) response than others who may be more prone to a nocebo (negative) response. Control and assessment of these responses remain quite elusive on subjective tests such as the ETT or Seattle Angina Questionnaire (SAQ). For this reason, all efforts should be made to include objective hard endpoints in these trials.
- The ongoing ISCHEMIA trial will shed further light on the issue of PCI in patients with stable angina regarding hard endpoints.