Elsevier

The Lancet

Volume 391, Issue 10115, 6–12 January 2018, Pages 31-40
The Lancet

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

https://doi.org/10.1016/S0140-6736(17)32714-9Get rights and content

Summary

Background

Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy.

Methods

ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593.

Findings

ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI −8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group.

Interpretation

In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy.

Funding

NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

Introduction

Percutaneous coronary intervention (PCI) was originally introduced to treat stable angina.1 More than 500 000 PCI procedures are done annually worldwide for stable angina. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial showed no difference in myocardial infarction and death rates between patients with stable coronary artery disease who underwent PCI and controls.2 Meta-analyses have shown similar results.3

Angina relief remains the primary reason for PCI in stable coronary artery disease.4 Guidelines recommend antianginal medication as first line therapy, with PCI reserved for the many patients who remain symptomatic.5

Data from unblinded randomised trials have shown significant exercise time improvement, angina relief, and quality of life improvement from PCI.6, 7, 8 However, symptomatic responses are subjective and include both a true therapeutic effect and a placebo effect.9 Moreover, in an open trial, if patients randomised to no PCI have an expectation that PCI is advantageous, this might affect their reporting (and their physician's interpretation) of symptoms, artifactually increasing the rate of unplanned revascularisation in the control group.4, 10

Placebo effects are known to be larger for invasive than non-invasive treatments.11 Interventional cardiologists and patients with stable angina often think that PCI offers symptomatic relief.12 Additionally, cardiologists present a decisive approach to diagnosis and treatment, which can lead to an enhanced placebo effect.13 In the absence of blinding, the effect size of PCI on symptomatic endpoints can be overestimated because of the addition of the placebo effect to the true physiological effect of intervention.14 In all previous trials, both investigators and patients were aware of the treatment allocation.2, 8, 10

Research in context

Evidence before this study

More than 500 000 percutaneous coronary interventions (PCIs) are done annually worldwide for the relief of angina but no placebo-controlled trials have been done on the subject. Unblinded PCI is reported to increase exercise time by 96 s more than medical therapy. Single antianginal agents typically increase exercise time by more than 45 s compared with placebo so ORBITA was designed conservatively to detect an effect size of 30 s.

Added value of this study

ORBITA investigated the efficacy of PCI versus placebo to improve exercise capacity in patients with severe coronary disease who were receiving guideline-directed optimum medical therapy. The coronary stenoses were severe and had large haemodynamic effects. Despite PCI markedly improving haemodynamic and imaging indices, PCI did not improve exercise time compared with placebo.

Implications of all the available evidence

The common clinical perception is that patients with stable angina will receive substantial symptom relief from PCI. The results of ORBITA, the only blinded, randomised placebo-controlled trial of PCI, show that even with severe coronary stenosis, exercise capacity and symptoms are not improved significantly compared with a placebo intervention. Physicians advising patients on interventional treatment choices for symptom relief should favour placebo-controlled data. ORBITA shows this approach to be feasible and informative.

Cardiologists have so far been resistant to the idea of a placebo-controlled trial of angina relief from PCI for two main reasons. The first is the widespread perception that PCI unquestionably improves angina,15 a perception that is based on unblinded clinical experience. The second reason is that it might be unethical to expose patients to an invasive placebo procedure. However, no evidence of harm to placebo groups was found in a systematic review of placebo-controlled surgical trials.16

When offering an invasive intervention for symptomatic relief, it is essential to know the true efficacy of the intervention, particularly when the patient could choose to continue conservative treatment instead. Moreover, although PCI has become progressively safer, there remains a complication rate of 1–2%.17

Evidence from placebo-controlled randomised controlled trials shows that single antianginal therapies provide improvements in exercise time of 48–55 s.18, 19 The Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial was designed to assess the effect of PCI versus placebo on exercise time in patients with stable ischaemic symptoms, Given the previous evidence, ORBITA was conservatively designed to be able to detect an effect size of 30 s.

Section snippets

Study design and participants

ORBITA was a multicentre, randomised trial done at five study sites in the UK: Imperial College Healthcare NHS Trust, Essex Cardiothoracic Centre, Royal Bournemouth and Christchurch Hospitals NHS Trust, East Sussex Healthcare NHS Trust, and Royal Devon and Exeter NHS Trust. The London Central Research Ethics Committee (reference 13/LO/1340) approved the study and written consent was obtained from all patients prior to their enrolment. The trial steering committee provided overall supervision of

Results

Between Dec 18, 2013, and July 26, 2017, 368 patients with angina and single vessel coronary disease were assessed for eligibility (figure 2). Of these patients, 230 were enrolled and entered the medical therapy optimisation phase. Details of patients who were enrolled but later withdrew are shown in figure 2 and the appendix.

200 patients (table 1) were randomised to either PCI or the placebo procedure between Jan 6, 2014, and Aug 11, 2017. There were no substantial differences in the baseline

Discussion

In ORBITA, the first blinded, placebo-controlled trial of PCI for stable angina, PCI did not improve exercise time beyond the effect of the placebo. This was despite the patients having ischaemic symptoms, severe coronary stenosis both anatomically (84·4% area reduction) and haemodynamically (on-treatment FFR 0·69 and iFR 0·76), and objective relief of anatomical stenosis, invasive pressure, and non-invasive perfusion indices (FFR p<0·0001, iFR p<0·0001, stress wall motion score index

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    ORBITA investigators listed at the end of the Article

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