In 1959 Cobb et al published a trial of 17 patients investigating the efficacy of internal mammary artery ligation for the treatment of symptomatic angina. The authors randomized 17 patients “seriously limited by angina” to either bilateral internal mammary artery ligation or a blinded sham procedure (1). At 6-months follow up the authors reported the patients in both groups had modest increases in exercise tolerance, substantial reduction in use of nitroglycerin, and subjective improvement in angina symptoms. One patient in particular who prior to the procedure was stricken with particularly debilitating symptoms, reported 100% relief at 6-months follow up. He happened to be in the sham procedure arm of the trial. It is with this in mind that we turn our attention to the recently published ORBITA trial examining the efficacy of percutaneous coronary intervention (PCI) for the symptomatic treatment of stable angina (2).
The authors enrolled patients aged 18-85 years with angina or equivalent symptoms and at least one angiographically significant lesion (>70%) in a single vessel that was clinically appropriate for PCI. Patients were randomized following medical optimization to undergo PCI or a sham procedure. Patients in the PCI group underwent angiograpy and stent placement using drug eluding stents to treat all lesions that were deemed to be significant, with a mandate to achieve angiographic complete revascularization. While in the sham procedure group the patients were sedated for at least 15 minutes on the cath lab table and coronary catheters were removed without the patients undergoing any interventions. To assess the burden of symptomatic disease, patients underwent follow up testing at 6-weeks.
Between January 2014, and August 2017 the authors enrolled 200 patients, 103 randomized to the PCI group and 97 to the sham procedure arm. Baseline characteristics, pre and post-randomization medical therapy were similar between groups. The authors found no difference in their primary endpoint, the incremental improvement in exercise times between the patients who underwent PCI and those who had a sham procedure, 28.4 seconds vs 11.8 seconds with a difference of 16.6 seconds (95% CI –8.9 to 42.0) between the groups. Nor was there a difference in the majority of secondary endpoints measured, including time to 1 mm of ST depression, peak oxygen uptake, physical limitations, angina frequency or stability, Duke treadmill score, or assessment of quality of life. The only difference the authors noted was an incremental change in peak wall stress of 0.09 ((95% CI –0.15 to –0.04, p value 0.0011).
These results are impressively negative. Some will argue with a sample size of 200 patients, that the trial was underpowered to demonstrate a difference in outcomes. In fact, there was a 16.6 second difference in incremental improvement in exercise time favoring the PCI arm that failed to reach statistical significance. Could this be a true benefit provided by PCI? Yes, strictly from a statistical standpoint, these authors are unable to differentiate a 16 second incremental improvement from random chance. But such a perspective fails to see clinical forest for the statistical trees. When continuous variables are measured statistically significant differences can be detected with fairly low sample sizes. In such cases, differences can be identified that boast a p-value less than 0.05, but possess no clinical relevance. Such is the case with incremental improvement in exercise time. The authors powered the study to detect a 30 second difference in incremental improvement in exercise time, a value already below what is considered the minimal important difference in outcomes. And while an increased sample size may have provided a degree of statistical clarity, an incremental improvement in exercise tolerance of 16 seconds holds no clinically relevant value no matter how slight the p-value supporting its veracity, especially considering the well documented harms associated with the procedure (3).
PCI has held a fairly esteemed status in the halls of medical interventions. Its popularity seemingly resistant to mounting evidence discrediting its use for the treatment of stable angina. We have known since the publication of the COURAGE trial that PCI does not reduce the rate of death or MI in patients with stable angina (4). With the publication of ORBITA even the claims of its ability to reduce the burden of symptoms have been called into question (5, 6). If we continue to support its unrestricted use in patients with stable angina, one has to ask just who exactly are we treating. A powerful placebo effect indeed.
- Cobb LA, Thomas GI, Dillard DH, et al. An evaluation of internamammary-artery ligation by a double-blind technic. N Engl J Med. 1959;260:1115-1118.
- Al-Lamee, R, Thompson, D, Dehbi, H-M et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet. 2017; (published online Nov 2.)
- Boden WE, O'rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503-16.
- Dehmer GJ, Weaver D, Roe MT, et al. A contemporary view of diagnostic cardiac catheterization and percutaneous coronary intervention in the United States: a report from the CathPCI Registry of the National Cardiovascular Data Registry, 2010 through June 2011. J Am Coll Cardiol 2012; 60: 2017–31.
- Weintraub WS, Spertus JA, Kolm P, et al. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med. 2008;359(7):677-87.
- Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. Veterans Affairs ACME Investigators. N Engl J Med. 1992;326(1):10-6.