The ORBITA trial, presented at TCT 2017 and simultaneously published in The Lancet¹ (see Journal Wrap) has generated much controversy. In short, in stable patients with single-vessel coronary artery disease, maximally treated with medical therapy, the salient outcomes at six weeks after randomization are:

1. PCI did not improve exercise time by more than the effect of a placebo procedure.
2. PCI reduced ischemic burden.
3. No significant differences between the PCI and placebo groups were seen in measures of symptom improvement and quality of life.

However, no trial should be taken simply at the face value of its outcomes. ORBITA is no exception. High praise goes to the ORBITA investigators for following a complex blinding procedure that allowed a sham PCI procedure and for their careful, conservative reporting of the trial results.

Nonetheless, the list of problems with the trial is not short: only 200 patients were included; angina definition and classification is difficult and subjective, especially in patients with single-vessel disease; and follow-up was only six weeks.

More problematic are the coronary lesion characteristics of the patients. Although all were reported at >70 percent, almost a third had a fractional flow reserve (FFR) and invasive FFR measurement of >0.80 and >0.89 respectively (and still underwent PCI). In reviewing the angiographic images that were provided, we agree they are the kind of lesions most of us would simply have treated with PCI in the past.

However, in contemporary practice, we’ve recognized the inaccuracy of angiography in determining the ischemic potential of coronary artery lesions. We’ve moved towards treating lesions with PCI only after some demonstration of physiologic significance (per the 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease).

With an FFR value of ≤0.80 having a high sensitivity for noninvasively detected ischemia, it seems that many PCIs in ORBITA may not have treated ischemia-producing coronary lesions. Despite this, PCI was still associated with significantly improved exercise time in the PCI group over baseline (28.4 seconds; 95 percent confidence interval [CI], 11.6-45.1 seconds). However, the increase was not significantly more than in the sham-treated group, whose smaller and nonsignificant improvement in exercise time (11.8 seconds; 95 percent CI, −7.8-31.3 seconds) prevented the trial from reaching its primary endpoint goal of a thirty second difference in exercise time.

Reaction to ORBITA was dramatized by an article on page A8 of the New York Times on Nov. 3, 2017. Unbelievable: Heart Stents Fail to Ease Chest Pain in British Study, croaked the headline, followed by the subtitle, Findings Leave Doctors Stunned. Are we stunned? Actually, not at all. And there is more than one reason we’re not.

First, the problems with ORBITA outlined above may alone have influenced the outcomes enough to render the trial a “negative” one. With only 200 patients and roughly a third of those who underwent PCI having a negative FFR (and therefore not expected to have any ischemic or angina benefit from the PCI), the study had a low power to detect clinically important differences.

Second, the placebo effect on symptoms of coronary disease has been well known for more than half a century; six weeks of follow-up might not be nearly long enough to counter it. In the 1950s and 1960s, surgeons devised operations for coronary heart disease, which in retrospect were either useless or at best possibly beneficial.

The potentially most useful procedure was devised by Vineberg, who developed a technique for implantation of a cut internal mammary artery (IMA) into an anterior myocardial tunnel, which he hoped would bring new blood supply to ischemic myocardium. Most of his work was done before the development of coronary angiography, so there was no proof of improved myocardial perfusion. Controversy over the usefulness of his procedure was fueled by the absence of an objective endpoint — the argument being that the placebo effect of the surgery was producing symptom improvement.

Reaction to ORBITA was dramatized by an article on page A8 of the New York Times on Nov. 3, 2017. Unbelievable: Heart Stents Fail to Ease Chest Pain in British Study, croaked the headline, followed by the subtitle, Findings Leave Doctors Stunned. Are we stunned? Actually, not at all.

Vineberg’s procedure was never studied in a randomized trial with a sham control. But, in 1959 and 1960, Dimond, et al., and Cobb, et al., performed sham-controlled surgical studies in a total of 35 patients having IMA ligation. Dimond and colleagues reported that all the sham-operated patients had less need for nitroglycerin and improved exercise tolerance.² So did three-fourths of the IMA-ligated patients. In Cobb’s report, more than half of both groups had subjective improvement six months after surgery.³ A more recent review in 2014 showed sham operations, compared with elective surgical procedures, provided improvement in approximately three-fourths of the trials and were equivalent to the real operations in half of the studies.⁴

We also know that paying a lot of attention to patients (frequent calls, office visits and even conversations) can improve anginal symptoms. In ORBITA, in which patients were intensively followed, this was certainly the case with both sham and PCI patients. Whether longer follow-up, allowing the placebo effect to “wear off,” would result in the emergence of a greater difference in symptoms and function between the PCI and sham-treated groups remains to be seen.

Third, there is more to PCI effects than just exercise time and angina control. Trials in the past have shown that medical therapy and revascularization strategies in patients have similar outcomes of death and myocardial infarction. COURAGE and BARI 2-D are the most cited. Despite different patient characteristics, etc., the primary outcomes of both of these large trials showed no difference between medical therapy and revascularization. Arguably the BARI 2D ischemia substudy indicated that more ischemia and more myocardial scar were associated with poorer outcomes, but the study was a post-hoc analysis.⁵ It’s hard to argue that myocardial ischemia is “not bad” for patients. Surprisingly there has yet to be a study to show that intervening, and thereby reducing ischemia in stable angina patients, makes a clinical difference.

We know so much, but really so little about the interaction of ischemia, angina, PCI and adverse cardiac events.

So, where does ORBITA leave us in the understanding of the merits/benefits of PCI versus intensive medical therapy? We all know that intensive medical therapy is beneficial for patients with angina – and certainly so for a short six-week follow-up. But on a more basic level, we’re stuck with our assumption that epicardial vessel stenosis causes ischemia. However, coronary vasomotor tone, microembolic events from plaque, and most importantly, microvascular coronary dysfunction all may play varying roles. We cannot tease these out either in our patients or in the trials.

We’re also stuck with our assumption that reducing ischemia (which PCI effectively does) should improve angina and other ischemic outcomes. Finally, like the BARI-2D ischemia substudy, ORBITA also shows that PCI plus medical therapy reduces ischemia better than medical therapy alone. It follows that PCI should help patient outcomes in the long-term. But does it? And if so, in which patients? And why? Stenting an epicardial lesion likely has little, if any, effect on microvascular dysfunction. Or does it? We know so much, but really so little about the interaction of ischemia, angina, PCI and adverse cardiac events.

The soon-to-be-finished ISCHEMIA trial hopefully will help sort out some of the issues that ORBITA raises. In ISCHEMIA, patients are randomized following noninvasive ischemia testing that shows at least moderate ischemia – but before cardiac catheterization – to one of two groups: a conservative management group, given optimal medical therapy, with catheterization and possibly revascularization performed only if the patient is not responding to therapy; and an invasive management group, given optimal medical therapy and immediate cardiac catheterization with coronary revascularization performed either by PCI or CABG (as clinically determined), with the goal of complete revascularization. The endpoints will be “hard” ones of death and myocardial infarction at three years. Patients in ISCHEMIA will be limited to those with stable coronary artery disease and ≤CCS III angina. Unstable patients and those with left main disease and other factors that have been shown to be benefitted by revascularization are excluded.

Candidly, we doubt that ISCHEMIA will lay to rest all the controversy that ORBITA has generated. We hope it will help answer the vexing question the results of ORBITA could not answer: Is PCI or medical therapy the better strategy for patients with stable angina?

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References

1. Al-Lamee R, Thompson D, Dehbi HM, et al. Lancet 2017;Nov 2:[Epub ahead of print].
2. Dimond EG, Kittle CF, Crockett JE. Am J Cardiol 1960;5:483-6.
3. Cobb LA, Thomas GI, Dillard DH, et al. N Engl J Med 1959;260:1115-8.
4. Wartolowska K, Judge A, Hopewell S, et al. BMJ 2014;348:g3253.
5. Shaw LJ, Cerqueira MD, Brooks MM, et al. J Nucl Cardiol 2012;19:658-69.

Peter C. Block, MD, FACC, is editor-in-chief of Cardiology: Interventions and Kreton Mavromatis MD, FACC, is director of the cardiac catheterization laboratory at Atlanta Veterans Administration Medical Center and assistant professor of medicine in the division of cardiology at Emory University School of Medicine.

Keywords: ACC Publications, Cardiology Interventions, Angina Pectoris, Angina, Stable, Angina, Unstable, Cardiac Catheterization, Cicatrix, Constriction, Pathologic, Coronary Angiography, Coronary Artery Disease, Elective Surgical Procedures, Follow-Up Studies, Ligation, Mammary Arteries, Myocardial Infarction, Myocardial Ischemia, Myocardium, Nitroglycerin, Placebo Effect, Quality of Life, Random Allocation, Research Personnel, Stents, Surgeons

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