The Lancet November 02, 2017

Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial

Rasha Al-Lamee, David Thompson, Hakim-Moulay Dehbi, Sayan Sen, Kare Tang, John Davies, Thomas Keeble, et al.

Bottom Line

In patients with medically treated stable angina and severe single-vessel coronary stenosis, percutaneous coronary intervention did not significantly increase exercise time or improve symptoms more than a sham placebo procedure.

Key Findings

1. There was no significant difference in the primary endpoint of exercise time increment between the PCI and placebo groups (PCI minus placebo difference of 16.6 seconds, 95% CI -8.9 to 42.0, p=0.200).

2. Both groups showed an increase in exercise time from baseline (PCI mean increase 28.4 seconds; placebo mean increase 11.8 seconds).

3. There were no significant differences in patient-reported symptom scores, including the Seattle Physical Limitation Score, Angina Frequency, or Angina Stability.

4. PCI significantly improved objective measures of ischemia compared to placebo, specifically the dobutamine stress echocardiography peak stress wall motion score index (difference of -0.07, 95% CI -0.11 to -0.04, p<0.0001).

5. There were no deaths. Major bleeding occurred in 3 patients (2 in the PCI group, 1 in the placebo group), and 4 patients in the placebo group had pressure-wire related complications requiring PCI.

Study Design

Design

Double-Blind RCT

Double-Blind

Sample

200

Patients

Duration

6 wk

Median

Setting

5 centers, UK

Population Patients aged 18-85 years with stable angina and severe (at least 70% stenosis) single-vessel coronary artery disease clinically appropriate for PCI, following a 6-week optimal medical therapy phase.

Intervention Percutaneous coronary intervention (PCI) using drug-eluting stents.

Comparator Sham (placebo) procedure involving sedation and catheter insertion without balloon inflation or stent placement.

Outcome Difference in the increment of treadmill exercise time between the PCI and placebo groups at 6 weeks.

Study Limitations

• The 6-week follow-up period was relatively short for assessing long-term symptomatic changes.

• The trial was restricted to a highly selected population with strictly single-vessel disease, meaning the findings may not extrapolate to patients with multi-vessel disease or a higher ischemic burden.

• The relatively small sample size (N=200 randomized) was powered to detect a 30-second difference in exercise time, which might have missed smaller but clinically relevant improvements.

• The intensive 6-week medical optimization phase prior to randomization achieved a level of antianginal therapy up-titration that may not reflect real-world clinical practice or medication tolerance.

• Reliance on treadmill exercise time as a surrogate primary outcome might not fully capture all subjective dimensions of angina relief.

Clinical Significance

ORBITA profoundly challenged the widespread assumption that the symptomatic relief experienced by patients undergoing PCI for stable single-vessel angina is entirely due to the physical relief of ischemia. By revealing a substantial placebo effect associated with the invasive procedure, the trial highlighted the necessity of sham-controlled designs in interventional cardiology and reinforced optimal medical therapy as the foundational strategy for managing stable coronary artery disease symptoms.

Historical Context

Historically, PCI was frequently performed for stable angina primarily for symptomatic relief, even after landmark trials like COURAGE (2007) and BARI 2D (2009) demonstrated no mortality or myocardial infarction benefits over optimal medical therapy. The subjective improvement in symptoms post-PCI was universally accepted by clinicians but had never been rigorously tested against a placebo (sham) procedure. ORBITA was a groundbreaking study as the first true sham-controlled trial of PCI for stable angina, initiating intense debate over the role of PCI and paving the way for further placebo-controlled interventional trials such as ORBITA-2.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Based on the pathophysiology of stable angina, why might optimal medical therapy be just as effective as mechanically opening a severely stenotic vessel, and what role does the placebo effect play in the perception of angina symptoms?

Key Response

This question tests foundational knowledge of myocardial oxygen supply and demand, collateral circulation, and the pharmacological mechanisms of antianginals. It also highlights the subjective nature of angina, explaining why a sham control is critical to isolate the true physiological benefit of a stent from the psychological relief of receiving a procedure.

Resident

If a patient presents to your clinic with stable angina and a known 85% proximal LAD lesion but is only taking low-dose metoprolol, how does the ORBITA trial influence your next management step before considering referral for PCI?

Key Response

This focuses on clinical application. ORBITA emphasizes the necessity of maximizing optimal medical therapy (OMT) before pursuing invasive strategies. Residents must recognize that PCI in stable single-vessel disease without optimizing anti-anginal agents first may yield no more symptomatic benefit than a placebo.

Fellow

The ORBITA trial evaluated a highly selected population with single-vessel disease and preserved LV function. How should these findings be contextualized when evaluating patients with multi-vessel disease, left main disease, or ischemic cardiomyopathy?

Key Response

Fellows must understand the limits of trial extrapolation. While ORBITA challenges the symptomatic benefit of PCI in stable single-vessel disease, patients with multi-vessel, left main disease, or LV dysfunction often have prognostic (survival) indications for revascularization, supported by trials like STICH, which must not be conflated with ORBITA's symptom-driven endpoints.

Attending

How do you use the results of ORBITA to counsel a highly symptomatic patient who strongly believes that a 'blockage' inevitably requires a 'stent' to prevent a heart attack, while managing their expectations regarding medical therapy versus PCI?

Key Response

Attendings must navigate patient psychology, the 'oculostenotic reflex,' and shared decision-making. Translating trial data to bedside practice requires explaining that stents in stable disease do not prevent myocardial infarctions (as seen in COURAGE/ISCHEMIA) and, per ORBITA, might not even provide superior symptom relief compared to medical therapy and placebo effect.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

ORBITA utilized a relatively small sample size (n=200) and a very short follow-up period (6 weeks) to assess the primary endpoint of exercise time. How does this short follow-up impact the statistical power, the risk of a Type II error, and the ability to detect late divergence in clinical endpoints?

Key Response

This critiques the study design. Six weeks is extremely short for a cardiovascular trial. A researcher must evaluate whether the trial was underpowered to detect smaller but clinically meaningful differences in treadmill time or symptoms, and whether a Type II error occurred due to the limited sample size and brief observation window.

Journal Editor

A critical reviewer might argue that the ORBITA trial's intensive 6-week medical optimization phase prior to randomization does not reflect real-world clinical practice, threatening external validity. How should an editor weigh this artificial pre-randomization optimization against the internal validity gained by the sham control?

Key Response

This highlights the tension between efficacy and effectiveness. The rigorous OMT run-in phase ensures that PCI is tested strictly for its incremental benefit over perfect medical therapy, maximizing internal validity. However, an editor must question if the results apply to standard clinical settings where medication adherence and titration are often suboptimal.

Guideline Committee

Given that current ACC/AHA and ESC guidelines provide a Class I recommendation for PCI to improve symptoms in patients with stable ischemic heart disease refractory to medical therapy, does the ORBITA trial provide sufficient evidence to downgrade this recommendation, or does its highly specific patient population preclude sweeping guideline changes?

Key Response

This addresses evidence integration for guidelines. The committee must decide if a single sham-controlled trial of 200 single-vessel patients is enough to alter a Class I recommendation. It forces an evaluation of whether guidelines should mandate a trial of rigorous, documented OMT before PCI can be reimbursed or recommended for symptom relief.

Clinical Landscape

Noteworthy Related Trials

2007

COURAGE Trial

n = 2,287 · NEJM

Tested

PCI + Optimal Medical Therapy

Population

Patients with stable coronary artery disease

Comparator

Optimal Medical Therapy alone

Endpoint

Death from any cause and nonfatal myocardial infarction

Key result: PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy.

2020

ISCHEMIA Trial

n = 5,179 · NEJM

Tested

Initial invasive strategy (angiography and revascularization)

Population

Patients with stable coronary disease and moderate to severe ischemia

Comparator

Initial conservative strategy (medical therapy)

Endpoint

Composite of cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest

Key result: Among patients with stable coronary disease and moderate or severe ischemia, an initial invasive strategy did not reduce the risk of ischemic cardiovascular events or death.

2023

ORBITA-2 Trial

n = 301 · NEJM

Tested

Percutaneous coronary intervention

Population

Patients with stable angina taking little or no antianginal medication

Comparator

Sham procedure (placebo)

Endpoint

Angina symptom score

Key result: PCI resulted in a lower angina symptom score than a placebo procedure among patients taking no background antianginal medication.

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