The Symptom-Stratified Analysis of ORBITA-2

Published in Congress: Euro PCR 2024

Link:  https://www.jacc.org/doi/10.1016/j.jacc.2024.04.016

 Dr. Yusuf Bozkurt Şahin

Background:
The ORBITA-2 trial compared the effects of percutaneous coronary intervention (PCI) versus placebo in the relief of angina. In the PCI group, patients experienced three times more relief from angina symptoms compared to the placebo group. However, despite complete revascularization in the PCI group, 60% of patients still reported symptoms during follow-up.

Objective:
This secondary analysis of ORBITA-2 aims to investigate the relationship between current symptoms and disease severity (both anatomical and ischemic, non-invasive, and invasive) and to evaluate the ability of symptoms to predict the efficacy of PCI.

Methods:
Before randomization, symptom severity and nature were assessed using symptom and quality of life questionnaires, including the ORBITA smartphone app and the Rose angina questionnaire. Lesion severity was evaluated using quantitative coronary angiography (QCA), stress echocardiography, fractional flow reserve (FFR), and instantaneous wave-free ratio (iFR). The study included 301 patients from 14 centers in the United Kingdom. All antianginal medications were discontinued at enrollment. Patients were then randomized to PCI or placebo groups. Both patients and medical staff, except those in the catheter lab, were blinded to the treatment. Both groups received dual antiplatelet therapy. Patients underwent a 12-week blinded follow-up phase during which they reported their angina daily using the ORBITA app. Subsequently, patients returned for a blinded follow-up evaluation, including symptom and quality of life questionnaires, Canadian Cardiovascular Society classification, stress echocardiography, and treadmill exercise testing. Symptom severity; Patient-reported symptom severity was assessed using the ORBITA application and symptom and quality of life questionnaires (SAQ, EQ-5D-5L and MacNew). Symptom nature; the nature of symptoms was recorded using the Rose angina questionnaire, the short form McGill pain questionnaire and the MRC Dyspnoea Scale.

Results:
A total of 301 patients were randomized. The median number of daily angina attacks before randomization was 0.8 (0.4-1.6). The median angina symptom score was 1.4 (0.5-6.1). The median stress echocardiography score was 10 (0.0-27). The median percent diameter stenosis was 61% (49-74), FFR was 0.63 (0.49-0.75), and iFR was 0.78 (0.55-0.87).

Relationship between symptoms and disease severity
There was little correlation between the severity and nature of symptoms (daily ORBITA-app data and symptom and quality of life questionnaires) and anatomical and ischemic indicators of disease severity.

Symptom severity as a predictor of the placebo-controlled effect of PCI
No strong interaction was found between pre-randomization symptom severity and the benefit of PCI over placebo.

Symptom nature as a predictor of the placebo-controlled effect of PCI;
Data from the Rose angina questionnaire were available for 89% (n=267/301) of patients. Of these, 64% (n=171/267) met Rose angina criteria. Patients with Rose angina were more likely to benefit from PCI compared to placebo in terms of angina symptom score and angina episodes than those without Rose angina (OR 1.9, 95% CrI 1.6-2.1). Typical angina, defined by guideline-based criteria, was present in 66% (n=176/267) and atypical angina in 34% (n=91/267). There was strong evidence that patients with typical angina were more likely to have a better angina symptom score (OR 1.8, 95% CrI 1.6-2.1) and fewer angina attacks (OR 2.0, 95% CrI 1.7) with PCI compared to those with atypical angina.

Conclusion:
The nature of symptoms is a strong predictor of the placebo-controlled efficacy of PCI. Rose angina and typical angina are excellent predictors of the efficacy of PCI compared to placebo. Other symptoms, such as shortness of breath, are poor predictors of efficacy.

Interpretations:  
This symptom-stratified analysis of the ORBITA-2 trial surprisingly shows little relationship between the severity or nature of symptoms and the anatomical severity of coronary disease and ischemia. This study highlights the importance of the nature of symptoms in selecting the right patients for PCI. Using coronary anatomy, stress-induced wall motion abnormalities, and hemodynamic pressure gradient measurements as criteria alone does not provide sufficient clinical benefit. The more typical the angina, the greater the reduction in angina with PCI.