The question of whether percutaneous coronary intervention (PCI) relieves angina may seem an odd one to operators who observe this effect or patients who are dramatically relieved. Severely symptomatic patients with high-grade obstructions and ischemia as the cause of their discomfort do experience dramatic relief when flow is restored by surgery or PCI. So there is little question that revascularization relieves angina. But does it do it better than medical therapy without revascularization? Three recent trials that set out, at least in part, to address this question are ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina),¹ FAME II (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation 2) at 5 years,² and EUROCTO (Randomized Multicentre Trial to Compare Revascularization With Optimal Medical Therapy for the Treatment of Chronic Total Occlusions).³ It is highly unlikely that the most severely symptomatic patients with the most severe obstructive disease were included in these trials, but many with angina who are representative of a subset of patients undergoing percutaneous intervention were investigated in all three trials. In other words, these patients are undergoing PCI, and the question of whether PCI relieved their symptoms more than medical therapy alone is an entirely valid one.

In the ORBITA trial,¹ 200 patients with single-vessel disease and obstructions that were significant as manifest by the average area stenosis of 84.4% and a fractional flow reserve of 0.69 were included. Exercise time, which was a primary endpoint, was not significantly different between the two groups, and the Seattle Angina Questionnaire about physical limitation also did not reach significance. The failure of this trial to show improvement in the defined endpoints at 30 days deserves some comment. Because this was a randomized sham-controlled trial, it was necessary to continue the same medical therapy throughout the 30-day observation period. This probably does not reflect what happens in actual practice because a patient revascularized with only single-vessel disease would likely have the medical therapy modified, especially as it relates to beta-blocker and calcium-blocker therapy. These interventions were continued in both the PCI group and the medical therapy-only group and may have moderated the exercise performance. A paper investigating the physiologic responses of these patients was subsequently published with interesting results.⁴ PCI clearly improved stress echocardiography more than placebo, and the effect of PCI on the wall motion score increased progressively with decreased fractional flow reserve. Although PCI did not improve angina frequency score more than placebo, it did result in more patient-reported freedom from angina (49.5% vs. 31.5%). Therefore, the number of patients needed to be treated to achieve total freedom from angina is 5. That is a highly significant difference in a trial that was designed to try to eliminate, as much as possible, the placebo effect on angina relief.

The second bit of evidence that angina is relieved was provided by the 5-year follow-up of the FAME II trial.² In this trial, fractional flow reserve was used to identify lesions with flow limitation, and these patients were then randomized between PCI and medical therapy compared with medical therapy alone. The endpoint, which included revascularization, was less than half as frequent in the PCI group compared with the medical therapy group. This was not surprising because urgent revascularization was expected to be more common, but there was also a reduction in myocardial infarction that was revealed only in this 5-year outcome. Angina was dramatically improved in both the medical therapy and PCI groups, but PCI retained a significant advantage on follow-ups ranging from 30 days to 3 years. By 5 years, there was no significant difference in freedom from significant angina, but a large number of the patients in the medical group had undergone subsequent PCI by that time. Therefore, this trial, which has the limitation of being an open-label study without blinding, did result in early and sustained relief of angina that which was superior in the PCI group.

The third study addressing this issue was the EUROCTO trial,³ which was a randomized trial comparing revascularization to optimal medical therapy for patients with chronic total occlusions (CTOs). This trial included patients with single-vessel disease and patients with multi-vessel disease who had the non-CTO lesions treated prior to randomization. In other words, the comparison was between opening the CTO, which was the only remaining obstruction, and leaving the CTO unopened. The 2:1 randomization resulted in 259 patients randomized to the PCI arm and 137 to the optimal medical therapy arm. At the 1-year follow-up, there was significant difference in freedom from angina with an absolute difference of 13%. There was also a dramatic improvement in the Canadian Angina Score classifications in the PCI group compared with the medical therapy-only group. Once again, the limitations, of course, are that this is an open-label study, bringing into question the placebo effect, and many severely symptomatic patients were not included. In addition, this trial was discontinued prematurely due to slow enrollment. We concluded in an editorial accompanying the EUROCTO publication that CTOs causing significant symptoms are more likely to have relief with PCI than medical therapy alone.⁵

Together, these three recent trials may seem to be addressing a question that was already answered in the minds of interventional cardiologists. However, it is reassuring to have randomized data supporting our belief that PCI indeed relieves angina pectoris. We should remember that enrollment in all of these trials required a willingness to assume equipoise and, therefore, likely excluded patients with the most limiting angina pectoris. Therefore, documentation of the relief of angina in these three trials is even more compelling. Patients should also understand that the mortality risk is not reduced in any of these trials; therefore, symptomatic relief is still the primary goal for patients with these characteristics. That message apparently was not clear to the patients in the ORBITA trial because 85% of the control group patients selected have stenting done even though many of them had their symptoms relieved by medical therapy alone. We physicians must be aware that once patients know that they have coronary obstructions, many of them will believe that opening those obstructions will improve their chance of survival. On the one hand, proper informed consent should include information that no improvement in survival is anticipated; on the other hand, we should not discount the value of placebo effect in improving subjective endpoints such as angina relief. After all, from the patient's perspective, it may be less important what the mechanism of relief is than that their symptoms are indeed relieved.

References

1. Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet 2018;391:31-40.
2. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-Year Outcomes with PCI Guided by Fractional Flow Reserve. N Engl J Med 2018;379:250-9.
3. Werner GS, Martin-Yuste V, Hildick-Smith D, et al. A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions. Eur Heart J 2018:39:2484-93.
4. Al-Lamee R, Howard JP, Shun-Shin MJ, et al. Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Single-Vessel Coronary Artery Disease: Physiology-Stratified Analysis of ORBITA. Circulation 2018;May 22:[Epub ahead of print].
5. King SB 3rd, Gogas BD. Opening chronic coronary total occlusions: light in the tunnel or sleeping in Seattle? Eur Heart J 2018;39:2494-6.

Keywords: Percutaneous Coronary Intervention, Angina, Stable, Echocardiography, Stress, Placebo Effect, Constriction, Pathologic, Angioplasty, Myocardial Infarction, Angiography

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