Review of the ORBITA-2 trial

PCI vs placebo PCI for stable angina

N Engl J Med 2023;389:2319-2330

Background: Percutaneous coronary intervention (PCI) does not reduce mortality or myocardial infarction as seen in COURAGE, FAME 2, ISCHEMIA and ISCHEMIA-CKD. However, unblinded studies have indicated that revascularization may improve symptoms, which is a key factor in driving PCI decisions for many patients. ORBITA was the first blinded, placebo-controlled trial of PCI for stable angina and found no significant improvement in exercise time with PCI. The trial had a high use of anti-anginal medications, with an average of 3 medications per patient  pre-randomization. However, this level of medication use is not always achievable in clinical practice due to side effects and challenges with adherence.

The ORBITA-2 trial sought to test the hypothesis that PCI improves symptoms in patients with stable angina who are not receiving background antianginal medications.

Patients: Eligible patients had angina or angina equivalent, severe coronary stenosis of 70% or more in at least one coronary artery and evidence of ischemia on non-invasive testing or by invasive pressure wire assessment.

Main exclusion criteria were acute coronary syndrome within 6 months, previous CABG, left main disease, chronic total occlusion of target vessel, and left ventricular ejection fraction of 35% or less.

Baseline characteristics: The trial randomized 301 patients – 151 randomized to PCI and 150 to placebo PCI.

The average age of patients was 64 years and 79% were men. Approximately 63% had hypertension, 28% had diabetes, 72% had hyperlipidemia, and 62% were current or previous smokers. Left ventricular systolic function was normal in 96% of the patients.

Angina class based on the Canadian Cardiovascular Society (CCS) angina grade was 2 in 58% of the patients and 3 in 39%. Approximately 80% had single vessel disease, 17% had 2-vessel disease and 2% had 3-vessel disease. Left anterior descending coronary artery was the target vessel in 55% of the patients.

Procedures: Patients initially underwent coronary angiogram and invasive physiologic assessment was performed in each vessel with 50% or more stenosis. Patients underwent the coronary angiography while wearing headphones with music playing for auditory isolation throughout the procedure. Patients who had evidence of ischemia in at least one territory were then randomized in a 1:1 ratio to PCI or placebo PCI. Patients were sedated until they were unresponsive to verbal and tactile stimuli. In the PCI group, all target vessels were treated during the index procedure. Patients in the placebo group did not receive intervention and were kept sedated for at least 15 minutes after randomization.

The recovery room staff and all subsequent medical providers were unaware of the treatment assignments. The operator and research staff who were present during the randomization procedure had no further contact with the patients.

Anti-anginal medications were stopped at enrollment. Antihypertensive medications that has antianginal properties were replaced with different agents.

Patients were followed up for 12 weeks during which they reported daily angina symptoms using a smart phone application. New anti-anginal medications or increase in the dose of anti-anginal medications were also tracked. At the end of the 12 weeks, patients completed symptom and quality-of-life questionnaires, had an assessment of CCS class, and underwent a treadmill exercise test and dobutamine stress echocardiography. After all of these were completed, patients and medical staff were unblinded.

Endpoints: The primary endpoint was an angina symptom score calculated based on the number of angina episodes that a patient reported on a given day and the number of units of antianginal medication prescribed on that day. In this score, each episode of angina on a particular day counts as 1 point for a maximum of 6 points per day (0 points given to no angina), and each unit of anti-anginal medications counts as 7 points (0 points given for no antianginal medications prescribed that day). In supplement table 3, authors provided what counted as one unit of anti-anginal medications. For example, atenolol 25 mg counted as 1 unit and amlodipine 2.5 mg counted as one unit.

Secondary endpoints included frequency of angina, use of ant-anginal medications, exercise time on treadmill test and symptoms questionnaires.

Analysis was performed based on the intention-to-treat principle. The estimated sample size to achieve 80% power at 0.05 alpha was 284 patients. This is based on assumed standard deviation of 6 angina symptom score units and a difference of 2 units between PCI and placebo.

Results: Data were available on 99.7% of the total patient-days.

Compared to placebo, PCI reduced the mean angina symptom score (2.9 vs 5.6, OR: 2.2, 95% CI: 1.4 - 3.5; p<0.001). PCI also reduced the mean daily angina frequency (0.3 vs 0.7, OR 3.4, 95% CI: 2.0 - 5.9), improved exercise time on treadmill (700.9 seconds vs 641.4 seconds, mean difference 59.5, 95% CI: 16.0 – 103.0), led to lower CCS angina class (0.9 vs 1.7, OR: 3.8, 95% CI: 2.4 – 5.8) and improved ischemia on stress echocardiogram (mean score 0.8 vs 2.0, mean difference: -1.2, 95% CI: -1.6 - -0.8). PCI did not reduce the mean daily anti-anginal medications use as measured in units (0.2 vs 0.3, OR 1.2, 95% CI: 0.7 – 2.1).

Acute coronary syndrome occurred in 4 patients in the PCI group and 6 in the placebo group. Stroke occurred in 2 patients in the PCI group and none in the placebo group.

No subgroup analysis was provided in the main manuscript.

Conclusion: In patients with stable angina pectoris who are not taking or taking little anti-anginal medications, PCI improved angina symptom score compared to placebo PCI.

This was a well-designed and well conducted trial. The use of daily symptoms reporting on a smart phone minimized recall bias. The main reason for the divergent results between this trial and the first ORBITA trial likely stems from the fact that patients in ORBITA-2 were on minimal or no anti-anginal medications. Overall, these trials highlight that while anti-anginal medications are effective, PCI can provide symptom relief for patients who cannot tolerate these medications.

A key limitation of this trial is the short follow-up period of 12 weeks, making it uncertain whether the symptomatic improvement seen with PCI will persist over time. For example, a secondary analysis of the ISCHEMIA trial showed that the improvement in angina symptoms favoring PCI was most significant at 6 months but became less pronounced, yet still statistically significant, over time.