In patients with stable angina and evidence of ischemia who are not on antianginal medication, percutaneous coronary intervention (PCI) improved angina symptoms score, an effect driven by a reduction in angina frequency. These results were presented by Christopher Rajkumar, MBBS, of Imperial College London, on behalf of the ORBITA-2 investigators during a late-breaking trial session Saturday at the American Heart Association Scientific Sessions 2023 conference in Philadelphia. A manuscript reporting these results was simultaneously published online in The New England Journal of Medicine. During a news conference, ORBITA-2 chief investigator Rasha Al-Lamee, MB BS, PhD, of Imperial College London, cited the revascularization guidelines, “for patients with stable angina, our first line approach should be to optimize the antianginal medication, and only when they remain refractory with ongoing symptoms should we consider an angioplasty procedure as an add-on therapy,” in describing the investigators’ goal in performing the study. She continued by saying “guidelines may not reflect our real-world clinical practice, and in fact, the vast majority of patients coming to the cath lab for elective PCI [percutaneous coronary intervention] worldwide will have zero or one antianginal medication.” The first ORBITA study was published in The Lancet in 2017 and was the first randomized controlled trial that studied this guideline recommendation. In that study, the authors compared PCI versus placebo in patients with stable angina and severe single-vessel coronary disease. The patients underwent a 6-week period of optimization of their antianginal medication, and only then were they randomized. Most patients were on three anti-anginal medications after this optimization period and during follow-up. In that study, at 6 weeks of follow-up, there was no statistical difference between the groups regarding the primary endpoint of exercise time increment. When discussing this trial results, the authors believe that “perhaps angioplasty on a high level of background anti-anginal therapy may potentially attenuate its effect”. ORBITA-2 was a randomized clinical trial and included patients with single-vessel or multivessel disease. All patients had to have stable angina with severe anatomical disease and evidence of ischemia. The primary outcome was the angina symptom score at 12 weeks of follow-up. For the calculation of the angina symptom score, the researchers used a dedicated smartphone application. This score was based on daily reporting of three constituent factors: the number of episodes of angina on a given day, the number of standardized doses or units of antianginal medications prescribed on that day. Also, adverse events such as intolerable angina, acute coronary syndromes, and death were included. Importantly, and different from the first ORBITA study, anti-anginal medication was stopped in both groups. Al-Lamee explained, “We had one primary question, which was to ask, does coronary angioplasty without antianginal medication improve angina compared to placebo.” After enrollment, the patienst underwent a 2-week pre-randomization period, during which they documented their daily angina symptom score and then underwent exercise treadmill tests and dobutamine stress echocardiography (DSE). At the randomization visit, all patients underwent coronary angiography, including invasive physiologic assessment. For blinding purposes, all patients were medicated to a deep level of conscious sedation, and over-the-ear headphones were worn throughout the procedure for auditory isolation. After 1:1 randomization, in the PCI group, all ischemia-causing lesions were treated, and in the placebo arm, no intervention was done, and patients remained sedated in the catheterization laboratory table for a minimum of 15 minutes. All patients were discharged with dual antiplatelet therapy and entered a 12-week blinded follow-up period, during which they continued to report their angina symptoms score through the dedicated application. At the final follow-up assessment visit, they also underwent an exercise treadmill test and DBE. Among 439 patients enrolled in the trial, 301 were eventually randomized. Patients left the study mainly because they did not meet the inclusion criteria or because they were referred to coronary artery bypass graft surgery. Among randomized patients, 151 were randomized to the PCI arm and 150 to the placebo arm. PCI improved the primary outcome of angina symptom score compared with the placebo procedure (odds ratio [OR]: 2.21; 95% confidence interval [CI]: 1.41-3.47; p<0.001). Interestingly, immediately following randomization, the proportion of patients with an angina symptom score of zero, meaning no angina, on no antianginal therapy, was significantly higher in the PCI compared to the placebo group, a difference that was sustained for the whole follow-up period. This difference was mainly driven by a reduction in angina frequency in the PCI group, with no significant difference in antianginal medication use between the groups. PCI also improved the secondary endpoint of the physician-assessed Canadian Cardiovascular Society (CCS) angina classification (OR 3.76; 95% CI: 2.43-5.82; p<0.001) and treadmill exercise time (+59.5 seconds, 16-113 seconds, p=0.008). Al-Lamee concluded: “We have shown that in stable angina with evidence of ischemia without antianginal medication, PCI improves the angina symptoms scores, reduces angina frequency, increases exercise capacity, and improves the quality of life.” She added that “the effect of PCI was immediate, sustained over 12 weeks, consistent across all endpoints, and smaller than comparable unblinded data.” Al-Lamee pointed out the significance of these findings: “It is the first placebo-controlled trial to demonstrate the efficacy of PCI for angina relief.” She continued, “PCI as an antianginal monotherapy procedure is feasible and effective.” However, she acknowledged that “residual symptoms persist in many around 59% of patients still have symptoms despite successful PCI and resolution of ischemia.” When interpreting the trial data, Al-Lamee said, “it’s now an option to use either antianginal medication or PCI as upfront strategies,” and that “the guidelines that currently reserve PCI for those with optimal antianginal medication may systematically select patients with the least to gain”. Image Credit: Jason Wermers/CRTonline.org Image Caption: Rasha Al-Lamee, MB BS, PhD, presents findings from the ORBITA-2 trial during a news conference at the American Heart Association Scientific Sessions 2023 conference in Philadelphia.