Author + information
- Rishi Puri, MBBS, PhDa,b,c,∗ ( )(, )
- Jose M. de la Torre Hernandez, MD, PhDd and
- Vincent Auffret, MD, MSce,f
- aQuebec Heart & Lung Institute, Laval University, Quebec City, Quebec, Canada
- bCleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio
- cDepartment of Medicine, University of Adelaide, Adelaide, Australia
- dInterventional Cardiology Unit, Hospital Universitario Marques de Valdecilla, IDIVAL, Santander, Spain
- eDepartment of Cardiology, Rennes University Hospital, Rennes, France
- fDepartment of Signal and Image Processing Laboratory, Rennes 1 University, Rennes, France
- ↵∗Reprint requests and correspondence:
Dr. Rishi Puri, Québec Heart and Lung Institute, 2725 Chemin Ste-Foy, Québec City, Québec G1V 4G5, Canada.
Surveillance coronary angiography post–percutaneous coronary intervention (PCI) has served as an important tool characterizing and comparing the serial behavior of a range stent types, as well as the biology and mechanisms underscoring restenosis (1). Although essentially abandoned by societal guidelines on both sides of the Atlantic (2,3), surveillance angiography post-PCI is still believed to represent the optimal means of detecting restenosis, remaining an integral part of clinical interventional practice in Japan. The clinical impact of angiographically detectable asymptomatic restenosis, however, remains controversial, with a range of studies yielding contradictory findings. Although some analyses point to an association between asymptomatic restenosis (on surveillance post-PCI angiography) and long-term mortality (4,5), others have failed to identify meaningful associations (6–9). These studies were not, however, dedicated randomized trials designed to test the hypothesis of the potential benefit of surveillance angiography post-PCI versus symptom- or ischemia-driven follow-up. Moreover, differing methodologies were used with respect to their emphasis on routine surveillance angiography versus the actual impact of restenosis per se, on subsequent cardiovascular events. As such, the potential link between angiographically detectable silent restenosis and late clinical events remains mechanistically elusive. Moreover, largely a result of the oculostenotic reflex, surveillance coronary angiography significantly increases coronary revascularization rates (6–9), and some would argue that these procedures are unnecessary in the absence of symptoms and/or documented ischemia.
With this in mind, published in this issue of JACC: Cardiovascular Interventions, the ReACT (Randomized Evaluation of Routine Follow-Up Coronary Angiography After Percutaneous Coronary Intervention) trial, undertaken by Shiomi et al. (10), was designed to evaluate the long-term clinical impact of surveillance coronary angiography post-PCI, testing the hypothesis that this approach would prove superior to clinically driven follow-up in associating with significant reductions in long-term clinical events. The key features of ReACT are as follows: 1) the study was a prospective, open-label trial involving 22 Japanese centers; 2) patients were randomized in a 1:1 fashion to surveillance coronary angiography at 8 to 12 months post-PCI versus simple clinical follow-up; 3) the primary endpoint was the combined endpoint of death, myocardial infarction, stroke, hospitalization for acute coronary syndrome, and hospitalization for heart failure; 4) an independent clinical events committee was used for endpoint adjudication; 5) the original plan was to enroll 3,300 patients, with 80% power to detect a 15% relative risk reduction in the surveillance angiography group versus those undergoing routine clinical follow-up, on the basis of an estimated 3-year primary endpoint rate of 25%; and 6) enrollment began in May 2010, but by June 2014, the investigators amended the protocol to enroll 700 patients with 5-year follow-up, with an estimated primary endpoint rate of 48% in the control group to detect a 25% relative risk reduction in favor of the surveillance angiography group. Median follow-up was 4.6 years, and approximately 85% of stents used were second-generation drug-eluting stents. The primary endpoint occurred in 22.4% and 24.7% in the surveillance angiography and control groups, respectively (p = 0.70). Within the first year post-PCI, revascularization rates were unsurprisingly higher in the surveillance angiography group compared with the control group (12.8% vs. 3.8%; p < 0.001), but these differences were mitigated over 5 years (19.6% vs. 18.1%, respectively; p = 0.92). The investigators rightfully conclude that routine surveillance coronary angiography 8 to 12 months post-PCI yielded no net clinical benefit compared with standard clinical follow-up.
Even following left main coronary artery PCI (a notoriously high-risk patient group), societal guidelines in the United States and Europe fail to strongly endorse surveillance coronary angiography, with a Class IIb (Level of Evidence: C) recommendation (2). However, the evidence base for these recommendations has stemmed largely from numerous post hoc analyses. Taking advantage of the typical work flow and interventional cardiology culture in Japan, Shiomi et al. (10) are to be congratulated for attempting to provide a more solid evidence base in this area. Although the ReACT data do not support routine surveillance post-PCI coronary angiography, several caveats of this trial warrant consideration, prior to us putting the final nail in the coffin for surveillance coronary angiography during routine clinical practice.
First, ReACT was grossly underpowered to make meaningful conclusions, and as such should be considered inconclusive in nature. Designed as an all-comers approach, only about 8 patients per center per year were ultimately enrolled. Perhaps this reflects either the reluctance of Japanese patients to abstain from having their stents dutifully reevaluated (as is the norm in Japan) or the reluctance of Japanese physicians to enroll their patients in a trial that offers the chance of only clinical follow-up, thus deviating from their clinical comfort. Furthermore, randomization was performed post-PCI but prior to hospital discharge, potentially adding further bias toward study inclusion.
Second, this in turn precluded the ability to enroll sufficient patient numbers with high-risk lesion subsets (i.e., left main lesions, chronic total occlusions) in which routine surveillance angiography may indeed harbor a specific niche. In fact, more than 60% of study participants had stable coronary disease, which perhaps fails to reflect real-world practice, whereby patients with acute coronary syndromes normally constitute a majority of PCIs.
Third, whether such data can be generalized to other geographic regions remains unknown, especially given the known interregional heterogeneity of the natural history of coronary atherosclerosis as well as interventional practice patterns (11).
Fourth, ReACT yet again highlights the ever present and controversial oculostenotic reflex phenomenon, despite the sound performance of these second-generation drug-eluting stents, with target lesion revascularization rates at 1 year post-PCI hovering at about 2% in the control group, being 8.5% at 5 years in this same patient group. Although on-treatment cholesterol levels and statin use were not provided by the ReACT investigators, these impressive patient outcomes data in the control arm likely speak to not only the efficacy of newer generation stents, which are often meticulously implanted with liberal use of intracoronary imaging by our Japanese colleagues, but also the value of optimal medical therapy in vastly improving cardiovascular event rates.
For those of us living and practicing outside Japan, how should we “react to ReACT?” Is it time to once and for all throw the concept of surveillance angiography under the bus, if it hadn’t already been done so by many? It will be quite intriguing to see how our Japanese colleagues will react to ReACT and whether this may alter clinical practice somewhat in Japan. Perhaps the inconclusive nature of ReACT will unlikely dent the culture of post-PCI surveillance angiography in Japan, where it remains ingrained among interventional clinicians. However, the publication of ReACT does seem to evoke a range of intriguing questions for which we do not yet have answers. For example, in patients with clinically silent angiographic restenosis, are long-term clinical events driven by the in-stent stenotic lesion per se or by the manifestations of systemic plaque progression and instability? Let us not forget that in the widely acclaimed DAPT (Dual Antiplatelet Therapy) trial, about 50% of follow-up events were not target lesion related (12). The fact that a landmark analysis from ReACT identified a “catch-up” phenomenon from a target lesion revascularization perspective within the control group suggests that 1-year follow-up for stent trials is insufficient, and a minimum of 3 years of follow-up is required to truly understand their efficacy. These data also reopen the ongoing debate regarding symptom- and/or ischemia-driven invasive coronary investigation versus reacting to asymptomatic plaque progression evident on a screening plaque imaging test. Are we prepared to tolerate target lesion revascularization for silent or occult restenosis at 1 year post–index PCI or accept a clinically driven endpoint (which could be a manifestation of a stent thrombosis, harboring greater attributable clinical risk) 3 to 4 years down the track? Delving deeper into the ReACT data, it seems that patients undergoing left main coronary or chronic total occlusion revascularization demonstrated trends toward a clinical benefit, whereby the lack of significant interaction p values seems to be a function of small patient numbers rather than lack of efficacy. Given recent advances in computed tomographic imaging technology coupled with flow-dynamic iterations, systematic computed tomographic angiographic follow-up in high-risk patient subsets may be worth exploring further.
At first glance, especially to those practicing outside of Japan, the ReACT data may superficially seem a little less relevant and exciting. However, progress in medicine has often been made from keeping an open mind and leaving the door open to explore new avenues to improve our understanding of disease and the treatments we use. Perhaps a similar mind-set should be adopted to the way in which we react to ReACT, whereby many intriguing questions from this trial could stimulate investigators to continue to push the envelope and challenge clinical convention to improve the outcomes of our patients.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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