The last session of TCT is a half day that includes Late Breaking Clinical Trials. Often sparsely attended, in recent years trials have also been simultaneously published in a peer-reviewed journal and immediately discussed in the press and on social media.
The ORBITA study was a first: a placebo-controlled trial comparing PCI to a sham procedure in patients with stable angina. The results presented by Dr Rasha Al-Lamee on behalf of the ORBITA investigators have led to passionate debate, with fierce criticism of the trial design, and a Twitter storm. The response has been polarised with some saying the results are of little value and have no impact on current practice, and others, including the New York Times, extrapolating the results to say that thousands of patients are having unnecessary coronary stent implantation.
The abstract for this publication from the Lancet is below, together with extracts from a letter published in the Eurointervention Journal by Dr Al-Lamee and Prof Francis.
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Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial
Rasha El Lamee et al on behalf of the ORBITA Investigators
Lancet – November 2017
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.
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.
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.
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.
NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.
In December after a cascade of press and social media attention Dr Al-Lamee and Dr Francis published this commentary ORBITA, including the trial design and results.
Extracts from “Swimming against the tide: insights from the ORBITA trial
Eurointervention Journal 8/12/17”
Rasha Al-Lamee, MRCP;
Darrel P. Francis, FRC
“In the four years of conception, design, execution and completion of the Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial (ORBITA), we fell into the trap of expecting the data to speak for itself. We failed to anticipate the number of voices that would drown out ORBITA with competing choruses of over-extrapolation and denigration.
ORBITA was conceived to deliver simple evidence for what we all believed was true, namely that patients with lesions like those in the ORBITA appendix and sufficient angina on medical therapy would indeed get a large benefit from percutaneous coronary intervention (PCI).
Ninety-four percent (94%) of ORBITA patients had evidence of ischaemia on one or more non-invasive or invasive tests. However, this was not an entry requirement because the majority of PCI worldwide is based on symptoms and angiographically evidenced disease, with approximately 90% of PCI performed without invasive pressure measurements7. Enrolment to ORBITA was designed to be representative of appropriate single-vessel elective PCI.
The battle for funding came next. Applications to all major UK funding bodies and device companies were rejected for a variety of reasons. Expert reviewers informed us that:
- this trial is not important
- it does not address a clinically relevant question
- we know the answer to this question – of course PCI works
- investigators and patients will never agree to take part
- this trial cannot be done
Although their evaluation was disappointing, the planning of ORBITA continued. The trial was eventually funded internally by the Foundation for Circulatory Health and the Imperial Biomedical Research Centre with pressure wires donated by Philips Volcano.
Our fellow interventionists often marvel that we obtained ethical approval. In fact, the appraisal by the national ethics committee was as surprising as that of the funding bodies, but in the opposite direction. The committee raised three queries:
- “Is it possible that we may be implanting unnecessary stents?”
- “Does an angioplasty procedure have risks?”
- “Are there long-term complications following angioplasty?”
When our answer to each of these questions was affirmative, their final question was, “then why has this trial not already been done?”. To that, we had no response.
The results of ORBITA were a surprise to us. Since the design targeted a conservative expectation of effect size, we expected PCI, with anatomic stenosis resolution, easily to show a statistically significant effect beyond placebo. More surprising than the results themselves was the subsequent reaction to them. The lay press, medical “key opinion leaders” and social media commentators competed in the speed and ferocity with which they voiced their opinions
The reception experienced by ORBITA, and by COURAGE a decade ago, emphasises the polarity of opinions and reflects a need for more such trials. Clinical trialists should be the first to acknowledge the limitations of their research, putting their own results into perspective. Every step in medical research should be seen as exactly that, “one more step forward”. The equal servings of praise and ridicule may continue for some time but ORBITA has undoubtedly shown that placebo-controlled interventional trials can be done, do provide new information, and should be as standard for interventional procedures as they are for medication.”
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