ORBITA: Learning the Right Lessons From a Sham-controlled Trial of Angioplasty
By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SOURCE: Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): A double-blind, randomised controlled trial. Lancet 2017 Nov 1. pii: S0140-6736(17)32714-9. doi: 10.1016/S0140-6736(17)32714-9. [Epub ahead of print].
While percutaneous coronary intervention (PCI) produces beneficial effects on hard outcomes in acute coronary syndromes, the situation is quite different in chronic stable angina (CSA), where the primary goal of intervention is recognized to be angina reduction. Trials of PCI in CSA have not shown a benefit in terms of mortality or myocardial infarction compared with medical therapy. Also, no one has performed a placebo-controlled trial of PCI in CSA. This, in a nutshell, is what the authors of the ORBITA trial set out to accomplish. Patients were selected carefully. Each patient exhibited angiographically significant disease in a single vessel with “angina or equivalent symptoms.” Patients with disease in more than one vessel were excluded, as were patients with left main disease, prior coronary artery bypass grafting, or presentation consistent with acute coronary syndrome. Patients with severe left ventricular dysfunction also were excluded, and nearly all patients enrolled demonstrated normal ejection fraction.
All patients began with a purely diagnostic coronary angiogram that defined their eligibility. Symptoms were assessed by standard research instruments prior to an intensive six-week medical optimization phase during which medical therapy, including dual antiplatelet therapy, began. Antianginal medications were titrated aggressively in all patients through phone consultations with a cardiologist up to three times per week. Cardiopulmonary exercise testing (CPET) and dobutamine stress echocardiogram (DSE) were performed just prior to the index procedure.
For the research procedure itself, all patients underwent an assessment of fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) before randomization to PCI or placebo, although, interestingly, the operators were blinded to the results of this physiologic testing. Patients were sedated and wore headphones to assure blinding. The primary endpoint was the difference in exercise time increment between groups, assessed six weeks after the procedure. Secondary endpoints included standardized assessments of angina and quality of life, change in peak oxygen uptake, and change in DSE wall motion index.
Two hundred patients underwent randomization: 105 to PCI, and 95 to the sham procedure. Most patients were assessed as exhibiting class II or III angina, and effort tolerance pre-randomization was quite good overall, with patients averaging > 8 minutes on the treadmill. At the index procedure, coronary lesions were assessed to be physiologically severe on average, with a mean FFR value of 0.69. PCI led to improvement to a mean FFR of 0.90. Importantly, approximately 30% of lesions overall were not physiologically significant by FFR and iFR assessment. At the six-week post-procedure assessment, exercise times had increased in both groups. Although the increase was greater in the PCI group, the between-group difference was not statistically significant. The DSE peak stress wall motion score index improved more with PCI than with placebo, demonstrating an objective improvement in ischemia, but no significant differences in symptoms were seen between groups during follow up.
The authors concluded that in patients with medically treated CSA, PCI did not improve exercise time or angina symptoms significantly compared to a sham procedure despite improving hemodynamic and imaging indices of ischemia.
Predictably, reactions to the ORBITA results, both among cardiologists and in the lay press, have been relatively sensational. Some commentators have used the results to make blanket statements about the utility of PCI in CSA altogether, while others, including the study authors, caution against such overreach. The authors of an accompanying editorial took a particularly black and white view, concluding that there are “no benefits for PCI compared with medical therapy for stable angina, even when angina is refractory to medical therapy.” What can cardiologists rightfully believe?
At the base of it, ORBITA was a well-executed and difficult-to-accomplish trial, completing the first-ever study of CSA that included a sham control. The study procedures were meticulous, the blinding was well thought out and effective, and the assessment procedures were comprehensive.
Although the study benefits from numerous obvious strengths, it also featured some shortcomings that should be highlighted for better understanding of its true message and implications. The study size was relatively small, with only 100 patients in each group, and the patients demonstrated good effort capacity coming into the trial, making it difficult to show an incremental benefit of PCI. In fact, formal CPET showed that peak oxygen uptake at baseline was essentially normal for patients in this age range.
All patients underwent invasive assessment of the index lesions by FFR and iFR, but these results were not used in assessment of lesion significance and were not made available to the operators. As it turned out, although all lesions were judged to be significant angiographically, nearly one-third of patients exhibited FFR values that do not meet current thresholds for interventional treatment and would not be expected to benefit significantly from PCI. At the same time, the change in mean FFR for the entire population was highly important. This suggests a high degree of heterogeneity in lesion severity among patients in this modest-sized trial. However, there is little doubt that these functional assessments are underused in clinical practice.
In performing FFR assessments, four patients in the placebo group underwent unplanned PCI because of lesion disruption by the FFR wire. It is important to recognize that this complication is quite rare with intermediate lesions and is far more likely to occur with truly severe lesions. The end result in this case is that four placebo group patients with the most critical disease were treated by PCI, with obvious potential to skew the data in this small trial.
But the most important lessons are those we should know already, primarily that medical therapy in CSA patients can be effective when performed well, and that both patients and providers should understand that medical therapy is a viable option for clinical scenarios that fit the trial paradigm. The clinical situation studied in the trial is common in practice, and too often patients come to the cath lab on inadequate medical therapy with a plan to receive a combined diagnostic and therapeutic procedure. Such ad hoc PCI, while extremely common and often in the patient’s best interests, can also short-change the discussion of treatment options in favor of interventional therapy. The focus of the trial was more narrow than the editorialists suggested, a point worth emphasizing. The authors of ORBITA studied CSA patients with single-vessel coronary artery disease, normal left ventricular function, and very little functional limitation as defined by formal exercise testing. To extrapolate these results to all CSA patients would be both incorrect and an unfortunate disservice to patients.
In this sham-controlled trial of 200 patients with single-vessel coronary artery disease and stable angina, percutaneous coronary intervention did not increase exercise time significantly compared to a placebo procedure.
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