Weekly journal scan: angina severity reduced by percutaneous coronary intervention in the ORBITA-2 trial

Comment on the article ‘A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina’ which was published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2310610. The ORBITA-2 (Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina), an investigator-initiated, multicentre, double-blind, randomized, placebo-controlled trial, aimed to evaluate the effectiveness of percutaneous coronary intervention (PCI) compared to placebo in patients with stable angina who were not receiving antianginal medications.1 Patient eligibility criteria included the presence of angina or angina-equivalent symptoms, evidence of severe coronary stenosis confirmed by invasive coronary angiography or coronary computed tomographic angiography, ischaemia demonstrated by non-invasive imaging or invasive physiological tests, and clinical indication for PCI by the referring heart team. Upon enrolment, patients discontinued antianginal medications and utilized a smartphone application for daily symptom reporting, including the presence and number of episodes. The 2-week pre-randomization phase involved patient-initiated contact for angina, with eligibility confirmed if at least one angina episode had occurred. This was followed by coronary angiography and invasive physiological assessments of stenoses. Patients showing evidence of ischaemia in at least one cardiac territory were then randomly assigned to either PCI or a placebo procedure, with complete blinding maintained throughout. The PCI group underwent complete revascularization of target vessels, while the placebo group remained sedated for at least 15 min without intervention. During the 12-week follow-up period, patients continued symptom reporting and antianginal medication management. Follow-up evaluations included symptom questionnaires, treadmill exercise tests, and stress echocardiography. The primary endpoint, the angina symptom score, was an ordinal clinical outcome scale based on the number of angina episodes and prescribed antianginal medications. Secondary endpoints included: angina frequency, use of antianginal medication, exercise duration, severity of angina based on the Canadian Cardiovascular Society (CCS) scale, and quality of life. Serious adverse events were monitored, with blinding effectiveness confirmed through blinding index assessment at various stages. From a total of 923 patients assessed for eligibility across 14 sites in the UK between November 2018 and June 2023, 439 were enrolled in the pre-randomization symptom assessment phase, and 301 (mean age, 64 years; 21% female) were subsequently randomized to PCI (151 patients) or placebo procedure (150 patients). At enrolment, 96% of patients had angina of CCS severity class II or III. Radial artery access was utilized in 96% of cases, with a median of 1 vessel undergoing invasive physiological assessment per patient. At 12-week follow-up, the PCI group showed significantly lower mean angina symptom scores compared to the placebo group (2.9 vs. 5.6, respectively; odds ratio 2.21; 95% confidence interval 1.41–3.47; P < .001). Favourable outcomes for PCI were also evident in angina frequency, antianginal medication usage, exercise duration, CCS class, and quality of life. One patient in the placebo group experienced unacceptable angina leading to unblinding. Periprocedural myocardial infarction (MI) occurred in four patients in the PCI group. Spontaneous MI occurred in none of the PCI group patients and in six patients in the placebo group. In the placebo group, two major periprocedural bleeding events and two spontaneous bleeding events occurred in four patients receiving dual antiplatelet therapy (DAPT). Over the past four decades, PCI has experienced significant advancements, with evidence that it is able to prevent death, cardiac death, and MI in patients with unstable CAD.2 PCI is also widely performed to treat patients with stable ischaemic heart disease, and a number of randomized clinical trials (RCTs) have been conducted to test its potential prognostic benefit over medical therapy alone in this lower risk population, without definitive results.3–5 Recent meta-analyses have tried to summarize this inconclusive evidence, suggesting that routine revascularization does not improve survival, but it may lower the risk of spontaneous MI, at the expense of higher rates of periprocedural MI.6 One of the primary objectives of performing PCI in patients with stable angina, therefore, remains the relief of symptoms. Current guidelines recommend antianginal medications as first line therapy, reserving PCI for those patients who remain symptomatic.7 While several unblinded RCTs have shown improvements in angina, exercise duration, and quality of life after PCI,3,4,8 these subjective outcomes may include both genuine therapeutic responses and a placebo effect. The ORBITA trial had questioned the favourable effect of PCI on exercise duration,9 although the absence of benefit might have been related to the high number of background antianginal medications. Yet, antianginal medications are often underused in everyday clinical practice.10 In fact, despite guideline recommendation of escalating antianginal medications in case of symptom recurrence,7 about half of patients undergoing elective cardiac catheterization receive only one or no antianginal medication.10 The ORBITA-2 is the first trial with a double-blind, randomized, placebo-controlled design demonstrating the effectiveness of PCI in improving angina in patients with stable CAD and objective evidence of ischaemia who were not receiving background antianginal medications.1 A major strength of the trial is that contemporary PCI was performed with complete revascularization in almost all patients and frequent use of intravascular imaging (∼70% of cases). The trial was very rigorous in ensuring blindness, although loss of blinding during the course of a study with these characteristics cannot be totally excluded. For instance, patients randomized to receive the placebo procedure were hold in the catheterization laboratory, under deep conscious sedation, for ∼15 min, which is significantly shorter than the average procedural time reported in contemporary PCI trials.11 Therefore, trial personnel, patients and their relatives may have become aware of the treatment status in some cases, although the overall results of blinding assessment were reassuring. Another potential source of bias is that patients were informed of the relatively short trial duration (12 weeks), and they were therefore aware that, after trial termination and unblinding, they could have undergone PCI, if not received yet. This knowledge might have had an impact on symptom perception and reporting, in particular in the placebo group, potentially underestimating the true effect size of PCI. Data on the prevalence of PCI performed in patients randomized to placebo after study termination might provide valuable insights into this issue. The relatively small sample of patients enrolled over a period of almost 5 years at 14 institutions poses risk of potential selection bias. It is possible that patients with severe or unacceptable angina might have been less frequently screened for eligibility and/or less prone to accept participation in the trial, as suggested by the relatively high proportion of patients who declined participation (more than one-third). Of note, patients with severe angina are those more likely to benefit from PCI.8 The trial enrolled a relatively low-risk population, as documented by the high prevalence (80%) of single-vessel disease, and the inclusion of secondary coronary branches as target vessels in a non-trivial proportion of cases (15%), which might have diluted the difference in outcome between the two groups. An interesting finding was that, although PCI led to improvement of symptoms, longer exercise duration (by 60 s) and reduced evidence of myocardial ischaemia, angina persisted in a large proportion (59%) of patients in the PCI group. Some symptoms might have been unrelated to epicardial vessel stenoses, potentially stemming from other mechanisms like microvascular disease. A full physiological assessment of each component of the coronary circulation, including epicardial, microvascular, and vasomotor function, which can be rapidly performed in the catheterization laboratory with a single pressure wire,12 was not obtained in this trial. Finally, it is worth noting that six spontaneous MI occurred in patients randomized to placebo. Although the study was not powered for the evaluation of clinical outcomes, this appears to be a high rate considering the short follow-up duration (12 weeks), the low background risk of patients, and the use of DAPT. In addition, four bleeding events occurred in the placebo group. The inclusion of sham control in interventional cardiology trials is matter of debate.13 In fact, individual patients assigned to a sham procedure are exposed solely to risks without any potential for benefit. Therefore, the possible advantages for the general population must be carefully balanced against the risks faced by individuals undergoing exposure within the trial. In conclusion, the ORBITA-2 trial confirms that PCI improves symptoms in untreated patients with stable angina and evidence of ischaemia. The persistence of symptoms in more than half of patients treated with PCI and the multifactorial pathogenesis of angina underscore the importance of a comprehensive functional assessment and treatment of these patients, tailoring interventional and medical therapies. R.V. received consulting or lecturing fees from Abbott Vascular, Abiomed, Amgen, Daiichi Sankyo, Medtronic, and Terumo, outside the submitted work. L.G. has nothing to disclose.

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