By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
SYNOPSIS: In this randomized trial of patients with stable angina and objective evidence of ischemia, percutaneous coronary intervention resulted in a significant reduction in angina compared to a placebo procedure.
SOURCE: Rajkumar CA, Foley MJ, Ahmed-Jushuf F, et al. A placebo-controlled trial of percutaneous coronary intervention for stable angina. N Engl J Med 2023; Nov 11. doi: 10.1056/NEJMoa2310610. [Online ahead of print].
Stable ischemic heart disease is an extremely common condition that often is marked by symptoms of limiting angina. However, despite its frequent use in the treatment of ischemic symptoms, percutaneous coronary intervention (PCI) has until recently lacked hard evidence demonstrating its efficacy. Specifically, prior trials examining the effectiveness of PCI for amelioration of angina have struggled to separate the influence of the intervention from the placebo effect.
The first Objective Randomized Blinded Investigation with Optimal Medical Therapy or Angioplasty in Stable Angina (ORBITA) trial, published in 2018, compared PCI to a placebo (formerly referred to as “sham”) procedure and showed no significant effect of PCI on treadmill exercise time. That small trial was marked by multiple limitations that hindered its broad applicability, however. For example, patients had very good baseline effort capacity with low angina burden at baseline, making it very difficult to show incremental benefit. In addition, approximately 30% of coronary lesions were negative by functional testing (instantaneous wave-free ratio [iFR] or fractional flow reserve [FFR]) and would not meet conventional criteria for interventional treatment. Despite these limitations, PCI in ORBITA resulted in more patient-reported freedom from angina than placebo.
In the first ORBITA trial, antianginal medications were mandated by the protocol and were aggressively titrated during the trial period. The ORBITA-2 trial was designed to investigate the antianginal effects of PCI using a similar placebo procedure comparator, but without the background of antianginal medication. To this end, over the course of nearly five years at 14 sites in the United Kingdom, a total of 301 patients were randomly assigned 1:1 to either PCI or placebo. All patients underwent coronary angiography and invasive physiological assessment prior to randomization.
Eligible patients were sedated, and patients assigned to placebo remained sedated for at least 15 minutes after randomization. Patients assigned to the PCI group subsequently underwent complete revascularization of the target vessels. Any antianginal medications — a median of one agent per patient — that previously had been started were stopped at the time of randomization. Enrolled patients had a mean age of 64 years, and 21% were women. Ninety-six percent of patients were judged to have Canadian Cardiology Society (CCS) class II or III symptoms. Eighty percent of patients had single-vessel disease, while 17.0% and 2.3% had two- and three-vessel disease, respectively.
The primary outcome was a scale known as the angina symptom score, which was calculated based on the number of angina episodes reported daily, units of antianginal medications, and the occurrence of unblinding as the result of intolerable angina, acute coronary syndrome (ACS), or death. At 12 weeks, this score was significantly lower among patients who underwent PCI than among those treated with placebo (2.9 vs. 5.6; P < 0.001). The most significant difference was in the number of daily angina episodes (0.3 vs. 0.7; odds ratio, 3.44; 95% confidence interval, 2.0-5.9). Among secondary endpoints, treadmill exercise time was approximately 60 seconds greater in the PCI group (700.9 seconds vs. 641.4 seconds). Physician-assessed CCS class also was lower in the PCI group, and significant improvements also were seen in symptoms assessed by the Seattle Angina Questionnaire and in quality of life measured with the EuroQol questionnaire. The investigators concluded that, among patients with stable angina not on antianginal medications, PCI resulted in a lower burden of angina and improved health status compared with a placebo procedure.
COMMENTARY
While ORBITA-2 undoubtedly is a very interesting study, its interpretation depends entirely on the lens through which one observes the results. The one point about which all commentators seem to agree is that this trial — with its placebo/sham procedure arm, and meticulous assessment of both ischemia and symptoms — represents a fantastic achievement in trial design and implementation. But will it (or should it) change practice?
ORBITA-2 was a very impressive experiment that was designed to quantify the treatment effects of PCI alone. In this it succeeded admirably, demonstrating a clear and consistent result over placebo. Unlike the first ORBITA trial, all patients were required to have significant objective ischemic testing to be enrolled. Patients had higher baseline angina scores as well, making discrimination between groups easier and more meaningful. The actual scoring system used as the primary endpoint is a novel one that has not been reported previously, however; therefore, the clinical interpretation of the observed differences is not intuitive.
Although freedom from angina was nearly threefold higher in the PCI group, a significant proportion of patients — 59% — continued to have symptoms despite successful PCI, and despite testing demonstrating resolution of ischemia. Whether this indicates symptoms were the result of microvascular disease or noncardiac causes was not elucidated, but this represents a diagnostic dilemma in cardiology. Namely, which patients with significant epicardial coronary disease are likely to have symptomatic benefit from revascularization?
As before, there remains a lack of evidence suggesting a benefit of PCI in stable angina for hard endpoints, including death and myocardial infarction. And, also, as before, the cardiologist’s response to a patient with symptomatic ischemic heart disease will need to consider multiple factors, including disease complexity, response to (and side effects from) medications, risks of interventional revascularization, and the patient’s treatment wishes. For most practitioners, this trial result cements the position of PCI as one option for symptomatic control of angina but will not greatly alter their approach to these patients.
