Author + information
- aSchool of Medicine, University of California, Irvine, Orange, California
- bVeterans Administration Long Beach Health Care System, Long Beach, California
- cDepartment of Cardiology, Veterans Administration Long Beach Health Care System, Long Beach, California
- ↵∗Address for correspondence:
Dr. Morton J. Kern, School of Medicine, Veterans Administration Long Beach Health Care System, 5901 East 7th Street, Long Beach, California 90822.
In early 2018, a landmark study (1) comparing percutaneous coronary intervention (PCI) to a sham PCI procedure (with patients and treating physicians blinded to results) found no significant difference in the primary outcome of exercise treadmill time after 6 weeks, leading to the conclusion that PCI does not increase exercise time any more than continued medical therapy and a placebo procedure. To quote the editorialists (2), “…these data put PCI in the category of other abandoned therapies for cardiovascular disease…” and generated almost as many headlines as the number of patients enrolled, citing the lack of value of stenting, reinforcing the belief of some cardiology and lay literati that stents do not relieve ischemia or angina (better than medicines/placebo alone). Many national and internationally renowned interventionalists have respectfully, but strongly, disagreed with the emotional and premature condemnation of PCI. It was noteworthy that on further analysis of the same data (3), the same group of investigators recently reported that PCI relieved “patient-reported” angina more than sham control and reduced exercise stress echocardiographic ischemic responses compared with continued medical therapy. Moreover, the more severe the ischemia (i.e., lower fractional flow reserve [FFR] or instantaneous wave-free ratio [iFR]), the greater the magnitude of stress echocardiographic improvement.
Mechanisms of Stents
The fundamental mechanism of stents is the scaffolding and enlargement of a stenotic lumen, permitting any needed demand-mediated increase in coronary blood flow. Innumerable PCI studies have demonstrated clinical benefit, presumably through this obvious mechanism. In this issue of the Journal, Cook et al. (4) now provide data that should definitively dispel any doubts that opening a significantly stenotic coronary vessel improves exercise-induced increases in coronary blood flow, eliminates exercise-related ischemic systemic hemodynamic responses, and relieves anginal symptoms. Perhaps the only surprising part of this extremely well-conducted study is that it confirms what every interventionalist believes, that PCI works, in contrast to the sensational headlines suggesting the contrary (1).
Exercise Coronary and Systemic Hemodynamics
Cook et al. (4) measured coronary and systemic hemodynamics in 21 patients with stable single-vessel coronary artery disease at rest and after exercise, before and after stenting of the stenosis. In the cardiac catheterization laboratory, transradial access without conscious sedation allowed supine bicycle exercise to be performed to rate-limiting angina or exhaustion. Translesional pressure and flow were measured with a sensor angioplasty guidewire, along with systemic hemodynamics, blood lactate levels, and coronary wave intensity analysis. After pre-PCI resting/exercise measurements, stent implantation was then performed and the rest/exercise measurements repeated.
The stenoses examined were hemodynamically significant with FFR and iFR values of 0.59 ± 0.18 and 0.61 ± 0.27, respectively (where ≤0.80 and ≤0.89 are considered ischemic threshold values). The stenoses were abolished after stent implantation with FFR and iFR increasing to 0.91 ± 0.07 and 0.96 ± 0.05, respectively (normal values are 1.0 for both FFR and iFR). Stenting increased coronary flow reserve from 1.7 to 3.1 after PCI. Compared with the pre-PCI state, stenting improved all peak-exercise parameters including average peak coronary flow velocity, coronary perfusion pressure, systolic blood pressure, accelerating wave energy, and myocardial work rate-pressure product. These effects are attributable almost exclusively to reducing the calculated stenosis resistance to negligible values after stenting.
Clinically, stenting improved exercise time by 67 s (95% confidence interval: 31 to 102 s; p < 0.0001) from pre-PCI exercise time. Importantly and pertinent to the controversy over the effect of PCI on functional status, PCI reduced rate-limiting anginal symptoms in 18 of 18 anginal patients. Exercised was stopped because of fatigue (19 of 21 subjects) or dyspnea (2 of 21).
Hemodynamic Patterns Associated With Exercise-Induced Ischemia
This study (4) elegantly illustrates coronary hemodynamics during ischemia and validates many of the basic concepts from earlier animal models of ischemia. Across a critical stenosis, coronary blood flow increased minimally during exercise and plateaued early, consistent with flow limitation from the stenosis resistance. Systemic arterial pressure rose rapidly with exercise and then fell (as did the rate-pressure product) in response to exercise-induced ischemia at peak exertion, events that corresponded to the onset of anginal symptoms.
After relief of the stenosis resistance, coronary blood flow increased across all stages of exertion in a nonlinear fashion and without a plateau. At peak exercise, coronary flow velocity was 65% higher than before PCI. Peak systolic blood pressure and rate-pressure product were also higher after PCI, consistent with the higher level of exercise performance allowed by PCI. Before PCI, diastolic microvascular resistance was low and reached its minimum value earlier during exercise, indicative of near-maximal distal coronary vasodilatation at rest (to compensate for the stenosis resistance), and reduced physiological capacity to increase coronary flow further (i.e., read, impaired coronary flow reserve). After PCI, diastolic microvascular resistance was higher and more normal at rest, thus retaining the capacity to decrease further and increase coronary blood flow during exercise.
The net wave-intensity analysis was also in concert with directly measured flow responses. Although the backward expanding wave intensity was similar, the forward contracting wave intensity was significantly higher during exercise following PCI, suggesting increased net flow responses and improved perfusion-generating waves. Stenting did not change pulse pressure, tension time index, diastolic time index, or diastolic time fraction during exercise, suggesting these myocardial functional indices require a greater duration, magnitude, or extent of ischemia to register abnormalities.
Given the relatively complex exercise and translesional sensor wire measurement protocol, the study population is understandably small and limited to patients with single-vessel disease with relatively severe ischemia. Patients and operators were unblinded. Any reduction in symptoms or observed increase in exercise capacity is a function of both physiological and psychological factors with their potential inherent bias. Blinding would have required sedation, which would have impaired the exercise portion of the study. Any reduction in symptoms or observed increase in exercise capacity conceivably could have been the result of a placebo effect, but this explanation seems somewhat implausible given the changes in objective hemodynamics. Some clinicians have expressed concern over the risk of exercise performed immediately following the stent implantation period. Whether this concern can be alleviated remains to be seen, but no complications were reported. It appeared safe to perform such a complicated exercise study immediately after PCI in this population. From Cook et al.’s data (4), although it appears indisputable that PCI restores blood flow in single-vessel coronary artery disease, for the majority of symptomatic patients with more complex and diffuse atherosclerotic disease, stenting may not be able to relieve ischemia/angina because of the confounding influences of untreatable small-branch disease, coexistent microvascular dysfunction, or in patients with prior remote myocardial infarction, residual ischemia in the border zones. Nonetheless, these scenarios do not negate PCI’s therapeutic effect.
The Bottom Line is More Important Than a Headline
This study represents one of the best human physiological studies demonstrating the mechanisms of benefit from stenosis relief by stenting. The measured objective findings demonstrate that for truly ischemic lesions, PCI works, relieving ischemia and angina, and likely works much better than medical therapy. Although this study will not make the front page of the New York Times, it should go a long way to restoring confidence in the physiological basis for PCI and supporting its continued use for patients with stable angina.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Kern has been a consultant and speaker for Abbott/St. Jude, Philips/Volcano, Acist Medical Inc., Opsens Inc., and Heartflow Inc. Dr. Seto has been a speaker for and received research funding from Acist Medical and Philips/Volcano.
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