The Lancet JANUARY 06, 2018

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

Rasha Al-Lamee, David Thompson, Hakim-Moulay Dehbi, et al.

Bottom Line

The ORBITA trial demonstrated that in patients with stable angina and severe single-vessel coronary artery disease, percutaneous coronary intervention (PCI) did not result in a statistically significant improvement in exercise time compared to a placebo sham procedure.

Key Findings

1. The primary endpoint, change in treadmill exercise time from baseline to 6 weeks, did not differ significantly between the PCI group (increase of 28.4 s) and the sham-procedure group (increase of 11.8 s), with a between-group difference of 16.6 s (95% CI -8.9 to 42.0; p=0.200).

2. PCI resulted in a significant reduction of ischemic burden as assessed by dobutamine stress echocardiography compared to the sham procedure (p=0.001).

3. Both the PCI and the sham groups experienced significant improvements in exercise capacity from baseline, highlighting a substantial placebo effect in patients with stable angina.

4. Adverse events were reported in both groups, including four wire-related complications in the placebo group requiring emergent PCI and five major bleeding events (two in PCI, three in placebo).

Study Design

Design

RCT

Double-Blind

Sample

200

Patients

Duration

6 wk

Median

Setting

Multicenter, UK

Population Patients with stable angina and evidence of severe (≥70%) single-vessel coronary stenosis.

Intervention Percutaneous coronary intervention (PCI) with drug-eluting stent implantation.

Comparator Placebo sham procedure involving coronary angiography without stenting, with auditory isolation and sedation.

Outcome Difference in the change in treadmill exercise time from baseline to 6 weeks between the intervention and control groups.

Study Limitations

• The trial had a relatively small sample size, which may have limited the power to detect smaller, yet potentially clinically meaningful, differences between the groups.

• The follow-up period was short (6 weeks), which does not provide insight into the longer-term clinical impact or durability of symptoms.

• The study population was highly selected, consisting specifically of patients with single-vessel coronary artery disease, which may limit the generalizability of these findings to broader populations, such as those with multi-vessel disease.

• The primary endpoint, treadmill exercise time, may not fully capture the subjective experience of angina or quality of life compared to patient-reported outcomes.

Clinical Significance

The ORBITA trial challenged the long-held assumption that the symptomatic benefit of PCI for stable angina is primarily due to the mechanical relief of coronary stenosis, suggesting that a significant portion of the observed clinical improvement in unblinded practice may be attributable to a placebo effect. It emphasizes the importance of optimal medical therapy as a first-line treatment for stable angina.

Historical Context

Prior to ORBITA, the efficacy of PCI for stable angina in preventing cardiovascular events had been questioned by trials like COURAGE, but the symptomatic benefit of the procedure remained widely accepted based on unblinded data. ORBITA was the first randomized, double-blind, sham-controlled trial to test this symptomatic benefit, providing a landmark methodology for interventional cardiology that allowed for the isolation of the procedural effect from the patient and physician expectation.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How can a coronary stenosis of >70% exist without providing a significant improvement in exercise duration after percutaneous coronary intervention (PCI) compared to a sham procedure?

Key Response

This highlights the distinction between anatomical severity and clinical symptoms. In stable angina, symptoms are not purely a function of flow limitation in a large vessel; they are also influenced by microvascular function, the efficacy of optimal medical therapy (OMT), and the significant placebo effect associated with invasive procedures. ORBITA demonstrated that when OMT is maximized, the marginal gain of PCI on exercise capacity is surprisingly small.

Resident

Given the ORBITA results, what is the role of intensive medical therapy versus early PCI in a patient with stable single-vessel coronary artery disease and a positive stress test?

Key Response

ORBITA reinforces that for stable angina, 'Optimal Medical Therapy' (OMT) is the foundational treatment. The study showed that even in hemodynamically significant lesions (mean FFR 0.69), PCI did not outperform sham when medications were aggressively up-titrated. Therefore, initial management should focus on 2-3 anti-anginal medications before proceeding to PCI, unless symptoms are refractory or there is high-risk anatomy.

Fellow

The mean FFR in ORBITA was 0.69 and the mean iFR was 0.76. How do you reconcile these physiological markers of ischemia with the lack of improvement in exercise time in the PCI arm relative to sham?

Key Response

This discrepancy suggests that while PCI effectively treats the physiological 'bottleneck' (ischemia relief), exercise duration is a multifaceted endpoint. The 6-week timeframe might be too short to see physiological adaptation, or more likely, the symptomatic relief attributed to PCI in prior unblinded trials (like FAME-2) was heavily driven by the placebo effect rather than the reversal of the pressure gradient itself.

Attending

How does the ORBITA trial change the way you conduct the informed consent process for an elective PCI in a patient with stable angina?

Key Response

The trial creates an ethical imperative to inform patients that PCI, while excellent for acute coronary syndromes, may not improve exercise capacity or symptom-free time more than tablets alone in the setting of stable disease. The discussion should pivot from 'fixing a blockage' to 'symptom management,' emphasizing that PCI is an option if medications are not tolerated or are insufficient, rather than a mandatory curative step.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of 'change in treadmill exercise time' as a primary endpoint in a 6-week study: what are the implications of the 'training effect' and the choice of follow-up duration on the study's power?

Key Response

A 6-week window captures the peak placebo effect of a sham procedure but may be too short to observe the 'de-conditioning' reversal that might occur if a patient becomes more active post-PCI. Furthermore, the 'training effect' (patients performing better on a second treadmill test simply due to familiarity) can create noise that masks the small delta between the treatment and sham arms, requiring a larger sample size than ORBITA provided.

Journal Editor

The ORBITA trial featured a 6-week 'medical optimization' phase where patients were contacted 1-3 times per week to up-titrate medications. Does this level of intensive OMT compromise the external validity (generalizability) of the results?

Key Response

A tough reviewer would argue that the 'control' arm in ORBITA received a level of medical attention and adherence monitoring that is non-existent in real-world clinical practice. Therefore, while the internal validity is high due to the sham control, the results might only apply to patients who are truly 'optimized,' potentially underestimating the benefit of PCI in typical 'real-world' patients who are non-adherent or poorly managed.

Guideline Committee

Based on ORBITA and ISCHEMIA, should the Class I recommendation for PCI in stable CAD be restricted only to patients who have failed a documented trial of at least two anti-anginal classes?

Key Response

Current guidelines (e.g., 2021 ACC/AHA/SCAI) already emphasize OMT as the first-line (Class 1) for stable CAD. ORBITA provides 'Level A' evidence that the placebo-controlled effect size for PCI is small. This supports strengthening the language to ensure that revascularization is specifically reserved for symptom relief in patients with 'refractory' symptoms, rather than being used as a first-line surrogate for ischemia reduction in stable single-vessel disease.

Clinical Landscape

Noteworthy Related Trials

2007

COURAGE Trial

n = 2,287 · NEJM

Tested

PCI plus optimal medical therapy

Population

Patients with stable coronary artery disease

Comparator

Optimal medical therapy alone

Endpoint

Death from any cause or nonfatal myocardial infarction

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

2012

FAME 2 Trial

n = 888 · NEJM

Tested

FFR-guided PCI plus medical therapy

Population

Patients with stable coronary artery disease and at least one functionally significant stenosis

Comparator

Medical therapy alone

Endpoint

Composite of death, nonfatal myocardial infarction, or urgent revascularization

Key result: Patients with FFR-guided PCI had a significantly lower rate of urgent revascularization compared to those receiving medical therapy alone.

2020

ISCHEMIA Trial

n = 5,179 · NEJM

Tested

Invasive strategy (angiography and revascularization) plus medical therapy

Population

Patients with stable coronary disease and moderate to severe ischemia

Comparator

Conservative strategy (medical therapy alone)

Endpoint

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

Key result: An invasive strategy did not result in a lower rate of ischemic cardiovascular events or death than a conservative strategy over a median of 3.2 years.

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