Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina - ORBITA

Jun 29, 2022
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Presenter/Author:
Rasha Al-Lamee, MD
Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.
Date Presented:
11/16/2019
Date Published:
05/26/2022
Date Updated:
06/29/2022
Original Posted Date:
11/02/2017
References

Contribution To Literature:

Highlighted text has been updated as of June 29, 2022.

The ORBITA trial showed that among patients with stable angina, PCI does not result in greater improvements in exercise times or anginal frequency compared with a sham procedure, despite the presence of anatomically and functionally significant stenoses.

Description:

The goal of the trial was to assess the efficacy of percutaneous coronary intervention (PCI) compared with a sham placebo procedure for angina relief among patients with stable angina.

Study Design

Patients with stable angina and evidence of severe single-vessel stenosis were randomized in a 1:1 fashion to either PCI or a placebo sham procedure. After enrollment, patients received 6 weeks of medication optimization. Coronary angiography was done via a radial or femoral arterial approach with auditory isolation achieved by placing over-the-ear headphones playing music on the patient throughout the procedure. In all patients, a research invasive physiological assessment of fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) was done. The operator was blinded to the physiology values and therefore did not use them to guide treatment. Randomization occurred after this physiological assessment.

For patients allocated to PCI, the clinical operator used drug-eluting stents (DES) to treat all lesions that were deemed to be angiographically significant, with a mandate to achieve angiographic complete revascularization. After PCI, iFR and FFR were measured again. In the placebo group, patients were kept sedated for at least 15 minutes on the catheter laboratory table and the coronary catheters were withdrawn with no intervention having been done.

  • Total number of enrollees: 200
  • Duration of follow-up: 6 weeks
  • Mean patient age: 66 years
  • Percentage female: 27%

Inclusion criteria:

  • Age 18-85 years
  • Stable angina/angina equivalent
  • At least one angiographically significant lesion (≥70%) in a single vessel that was clinically appropriate for PCI

Exclusion criteria:

  • Angiographic stenosis ≥50% in a nontarget vessel
  • Acute coronary syndrome
  • Previous coronary artery bypass graft surgery
  • Left main stem coronary disease
  • Contraindications to DES
  • Chronic total coronary occlusion
  • Severe valvular disease
  • Severe left ventricular systolic impairment
  • Moderate-to-severe pulmonary hypertension
  • Life expectancy <2 years
  • Inability to give consent

Other salient features:

  • Previous PCI: 13%
  • Left ventricular ejection fraction normal: 92%
  • Canadian Cardiovascular Society angina severity grading class: I (3%), II (59%), III (39%)
  • Angina duration: 9 months
  • Vessel involved: left anterior descending (69%)
  • Median area stenosis by quantitative coronary angiography: 85%
  • Median baseline FFR value: 0.72; median post-PCI FFR value: 0.9

Principal Findings:

The primary outcome, change in exercise time from baseline for PCI vs. sham, was 28.4 vs. 11.8 seconds, p = 0.2.

Secondary outcomes for PCI vs. sham:

  • Change in Seattle Angina Questionnaire (SAQ)-physical limitation from baseline: 7.4 vs. 5.0, p = 0.42
  • Change in SAQ-angina frequency from baseline: 14.0 vs. 9.6, p = 0.26
  • Change in Duke treadmill score from baseline: 1.22 vs. 0.1, p = 0.10
  • Complete freedom from angina: 49.5% vs. 31.5%, p < 0.05

Compared with placebo, PCI improved stress echocardiography by 1.07 segment units (p < 0.00001). There was a significant interaction with both FFR and iFR values, with larger improvements in stress echo with lower levels of FFR and iFR (p for interaction < 0.00001 for both). There was no interaction between angina relief with PCI vs. placebo and FFR/iFR values.

Risk-stratification based on baseline dobutamine echocardiogram: Prerandomization dobutamine stress echocardiograms were available in 183 of the 200 randomized patients. The mean prerandomization stress echo score was 1.56 ± 1.77 in the PCI arm and 1.61 ± 1.73 in the placebo arm. A strong linear association was noted between greater number of ischemic myocardial segments and lower FFR and iFR values (p < 0.0001). There was a detectable interaction between prerandomization stress echo score and the effect of PCI on angina frequency score with a larger placebo-controlled effect of PCI in patients with the highest stress echo score (p for interaction = 0.031). Patients with prerandomization echo score ≥1 were more likely to have lower angina frequency score (odds ratio [OR] 3.18, 95% confidence interval [CI] 1.38-7.34, p = 0.007) and freedom from angina (OR 4.62, 95% CI 1.70-12.6, p = 0.003) with PCI than with placebo.

Cardiopulmonary exercise testing (CPET): Available for 195 patients. Patients in whom an oxygen-pulse plateau was observed during CPET had a higher (more ischemic) dobutamine stress echocardiography score (+0.82 segments; 95% CI 0.40-1.25, p = 0.0068) and lower FFR (-0.07; 95% CI -0.12 to -0.02, p = 0.011) compared with those without. At 6-week follow-up, there was no significant effect of PCI compared with placebo on peak VO2 (-8.03 ml/min, p = 0.83), presence of O2-pulse plateau (OR 1.13, 95% CI 0.56-2.26, p = 0.74), or other CPET parameters during exercise. However, PCI was more likely to result in improvement in Duke treadmill score compared with placebo (OR 1.73, 95% CI 1.05-2.85, p = 0.032). Among patients with paired dobutamine stress echocardiography data, the presence of an O2-pulse plateau (p for interaction = 0.026) and the O2-pulse gradient (p for interaction = 0.023) predicted progressively larger improvement of dobutamine stress echocardiography scores with PCI at lower (more abnormal) O2-pulse slopes. Although PCI did not improve SAQ physical-limitation score (p = 0.14), the presence of an O2-pulse plateau significantly modified this effect (p for interaction = 0.037).

Interpretation:

The results of this trial indicate that among patients with stable angina, PCI does not result in greater improvements in exercise times or anginal frequency compared with a sham procedure. This was despite the presence of anatomically and functionally significant stenoses. PCI did however resolve ischemia more effectively, as ascertained by follow-up stress echocardiography. Patients with higher echo score on dobutamine stress echocardiography at baseline were more likely to manifest improvements in angina.

CPET analysis suggested that the presence of an O2-pulse plateau during CPET was associated with more ischemia. The presence of an O2-pulse plateau also predicted greater reduction of dobutamine stress echocardiography ischemia and greater improvement in angina physical-limitation score at 6 weeks following placebo-controlled PCI.

This is clearly a landmark trial, but several issues need to be considered. The trial was extremely well done, with careful assessments of ischemia pre- and post-procedure, and appropriate use of antianginal medications. Although powered for exercise treadmill-based endpoints, the trial appears to be too small to address a question of this magnitude. The COURAGE trial, for instance, enrolled 2,300 patients with stable angina. Moreover, changes in Duke treadmill score and exercise time were both numerically higher in the PCI arm, and it is unknown if a larger sample size would have detected more modest improvements in exercise capacity.

Accordingly, these findings need to be validated in a larger randomized controlled trial. This trial also highlights the value of sham controls for procedure-oriented trials, where a procedural placebo effect is balanced out. A similar benefit of using sham controls was noted in the SYMPLICITY HTN-3 trial earlier.

References:

Ganesananthan S, Rajkumar CA, Foley M, et al. Cardiopulmonary exercise testing and efficacy of percutaneous coronary intervention: a substudy of the ORBITA trial. Eur Heart J 2022;May 26:[Epub ahead of print].

Al-Lamee RK, Shun-Shin MJ, Howard JP, et al. Dobutamine Stress Echocardiography Ischemia as a Predictor of the Placebo-Controlled Efficacy of Percutaneous Coronary Intervention in Stable Coronary Artery Disease: The Stress Echocardiography-Stratified Analysis of ORBITA. Circulation 2019;140:1971-80.

Presented by Dr. Rasha Kadem Al-Lamee at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019.

Al-Lamee R, Howard JP, Shun-Shin NJ, et al. Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Single-Vessel Coronary Artery Disease: Physiology-Stratified Analysis of ORBITA. Circulation 2018;138:1780-92.

Editorial: Kirtane AJ. ORBITA2: Bringing Some Oxygen Back to PCI in Stable Ischemic Heart Disease? Circulation 2018;138:1793-6.

Al-Lamee R, Thompson D, Dehbi HM, et al., on behalf of the ORBITA Investigators. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet 2018;391:31-40.

Editorial Comment: Brown DL, Redberg RF. Last nail in the coffin for PCI in stable angina. Lancet 2018;391:3-4.

Presented by Dr. Rasha Al-Lamee at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2017), Denver, CO, November 2, 2017.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Stable Ischemic Heart Disease, Aortic Surgery, Cardiac Surgery and SIHD, Interventions and Imaging, Angiography, Echocardiography/Ultrasound, Nuclear Imaging, Chronic Angina

Keywords: AHA Annual Scientific Sessions, AHA19, Angina, Stable, Cardiac Catheters, Constriction, Pathologic, Coronary Angiography, Coronary Stenosis, Drug-Eluting Stents, Echocardiography, Echocardiography, Stress, Exercise Test, Fractional Flow Reserve, Myocardial, Ischemia, Myocardial Revascularization, Percutaneous Coronary Intervention, Stents, TCT17, Transcatheter Cardiovascular Therapeutics


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