Data from the first blinded, placebo-controlled trial of percutaneous coronary intervention (PCI) in patients with stable angina call into question its efficacy compared to placebo.
Symptomatic relief is the primary goal for PCI in patients with stable coronary artery disease. Currently, guidelines recommend antianginal medication as first-line therapy and PCI for those who remain symptomatic. Although over half a million PCI procedures are performed yearly for angina, there is "no evidence from blinded, placebo-controlled randomised trials to show its efficacy," explained lead author Dr Rasha Al-Lamee, from the Imperial College London, UK.
ORBITA was a double-blind, randomised controlled trial that evaluated PCI vs a placebo procedure for improved exercise capacity in patients with severe coronary disease who were receiving optimum medical therapy. Researchers recruited 230 patients (aged 18–85 years) with severe (≥70%) single-vessel stenoses who were entered into a 6-week medication optimisation phase. Then prior to randomisation, patients underwent a cardiopulmonary exercise assessment, symptom questionnaire, and a dobutamine stress echocardiography. All of the patients were pre-treated with dual antiplatelet therapy, which was continued until the final visit.
The primary endpoint was difference in treadmill exercise time increment between the treatment arms at a follow-up of 6 weeks; a total of 200 patients were randomised (PCI: 105; Placebo: 95) between January 6, 2014 and August 11, 2017. Some secondary endpoints included change in peak oxygen uptake, change in exercise time to 1mm ST segment depression, and angina severity.
In the PCI group, 98% were taking aspirin, 94% were taking a statin, and 98% were taking a second antiplatelet, compared to 98%, 96%, and 99% in the placebo group, respectively. About three-quarters (78%) of the whole study population were taking beta-blockers and 91% were taking calcium channel blockers.
The data indicated no significant difference in the primary endpoint of exercise time increment between groups (28.4 seconds vs. 11.8 seconds; difference in increment: 16.6 seconds, 95% CI: –8.9 to 42.0; P=0.200). "This was despite the patients having ischemic symptoms, severe coronary stenosis both anatomically (84.4% area reduction) and haemo-dynamically, and objective relief of anatomical stenosis, invasive pressure, and non-invasive perfusion indices," the authors write.
There was also no significant difference between the groups in the secondary endpoints of change in time to 1mm ST depression (P=0.164) or change in peak oxygen uptake (P=0.741). Moreover, the authors reported no significant difference in the proportion of patients with improved angina severity of 1 class or ≥2 classes from enrollment to pre-randomisation (P=0.916) and from pre-randomisation to follow-up (P=0.633).
Serious adverse events included 4 pressure-wire related complications requiring PCI in the placebo group, as well as major bleeding events seen in both the PCI (2) and placebo groups (3).
Findings from ORBITA showed that for patients with medically treated angina and severe coronary stenosis, PCI did not improve exercise time any more than the effect of the placebo procedure. In addition, no improvement beyond placebo was seen for other exercise and patient-centered effects.
Although the data may "seem to contradict the real-world experience that patients report relief of angina after PCI," the authors note that some patients may prefer the invasive procedure over taking multiple antianginal drugs. Therefore, the findings of this study "do not mean that patients should never undergo PCI for stable angina."
As ORBITA only evaluated PCI efficacy for stable angina, these results do not apply to patients undergoing PCI for acute coronary syndrome, including STEMI. In addition, the study's short duration also limits the evaluation of long-term endpoints such as myocardial infarction and mortality endpoints. The findings "suggest[s] that the common clinical observation of symptomatic improvement from PCI might well contain a large placebo component," according to the authors.
In a separate commentary, David L Brown and Rita F Redberg from the Washington University School of Medicine in St Louis, describe the findings from ORBITA to be "profound and far-reaching" and call for a revision of cardiology guidelines downgrading the recommendation for PCI in patients with angina despite use of medical therapy.
"ORBITA highlights the importance of including sham controls and double blinding in a trial to avoid being fooled by illusory improvements due to the powerful placebo effect of procedures such as PCI," conclude Brown and Redberg.
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.
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.
Authors
Rasha Al-Lamee, David Thompson, Hakim-Moulay Dehbi, Sayan Sen, Kare Tang, John Davies, Thomas Keeble, Michael Mielewczik, Raffi Kaprielian, Iqbal S Malik, Sukhjinder S Nijjer, Ricardo Petraco, Christopher Cook, Yousif Ahmad, James Howard, Christopher Baker, Andrew Sharp, Robert Gerber, Suneel Talwar, Ravi Assomull, Jamil Mayet, Roland Wensel, David Collier, Matthew Shun-Shin, Simon A Thom, Justin E Davies, Darrel P Francis
[link url="http://www.empr.com/news/percutaneous-coronary-intervention-pci-angina-medication/article/705137/"]EMPR material[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32714-9/fulltext"]The Lancet article summary[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32757-5/fulltext"]The Lancet commentary[/link]