Author + information
- Received October 16, 2016
- Accepted October 20, 2016
- Published online January 16, 2017.
- Hiroki Shiomi, MDa,
- Takeshi Morimoto, MD, PhDb,
- Shoji Kitaguchi, MDc,
- Yoshihisa Nakagawa, MDd,
- Katsuhisa Ishii, MDe,
- Yoshisumi Haruna, MD, PhDc,
- Itaru Takamisawa, MDf,
- Makoto Motooka, MDg,
- Kazuhiro Nakao, MDh,
- Shintaro Matsuda, MDi,
- Satoru Mimoto, MDj,
- Yutaka Aoyama, MDk,
- Teruki Takeda, MDl,
- Koichiro Murata, MDm,
- Masaharu Akao, MDn,
- Tsukasa Inada, MDo,
- Hiroshi Eizawa, MDi,
- Eiji Hyakuna, MDp,
- Kojiro Awano, MDq,
- Manabu Shirotani, MDr,
- Yutaka Furukawa, MDs,
- Kazushige Kadota, MDt,
- Katsumi Miyauchi, MDu,
- Masaru Tanaka, MDo,
- Yuichi Noguchi, MDv,
- Sunao Nakamura, MDj,
- Satoshi Yasuda, MDh,
- Shunichi Miyazaki, MDw,
- Hiroyuki Daida, MDu,
- Kazuo Kimura, MDx,
- Yuji Ikari, MDy,
- Haruo Hirayama, MD, PhDk,
- Tetsuya Sumiyoshi, MDf,
- Takeshi Kimura, MDa,∗ (, )
- ReACT Investigators
- aDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan
- bDepartment of Clinical Epidemiology, Hyogo College of Medicine, Hyogo, Japan
- cDivision of Cardiology, Hirakata Kohsai Hospital, Hirakata, Japan
- dDivision of Cardiology, Tenri Hospital, Nara, Japan
- eDivision of Cardiology, Kansai Electric Power Hospital, Osaka, Japan
- fDepartment of Cardiology, Sakakibara Heart Institute, Japan Research Promotion Society for Cardiovascular Diseases, Tokyo, Japan
- gDivision of Cardiology, Shizuoka General Hospital, Shizuoka, Japan
- hDepartment of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
- iDivision of Cardiology, Nishikobe Medical Center, Kobe, Japan
- jDepartment of Cardiology, New Tokyo Hospital, Tokyo, Japan
- kDepartment of Cardiology, Nagoya Second Red Cross Hospital, Nagoya, Japan
- lDivision of Cardiology, Koto Memorial Hospital, Higashioumi, Japan
- mDepartment of Cardiology, Shizuoka City Shizuoka Hospital, Shizuoka, Japan
- nDepartment of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
- oCardiovascular Center Osaka Red Cross Hospital, Osaka, Japan
- pDepartment of Cardiology, Saiseikai Shimonoseki General Hospital, Yamaguchi, Japan
- qDepartment of Cardiology, Kitaharima Medical Center, Hyogo, Japan
- rDepartment of Cardiology, Kindai University Nara Hospital, Nara, Japan
- sDepartment of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Japan
- tDivision of Cardiology, Kurashiki Central Hospital, Kurashiki, Japan
- uDepartment of Cardiovascular Medicine, Juntendo University, Graduate School of Medicine, Tokyo, Japan
- vDepartment of Cardiology, Tsukuba Medical Center Hospital, Tsukuba, Japan
- wDivision of Cardiology, Kindai University, Osaka, Japan
- xDivision of Cardiology, Yokohama City University Medical Center, Yokohama, Japan
- yDepartment of Cardiology, Tokai University, Kanagawa, Japan
- ↵∗Reprint requests and correspondence:
Dr. Takeshi Kimura, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Objectives The purpose of this study was to evaluate long-term clinical impact of routine follow-up coronary angiography (FUCAG) after percutaneous coronary intervention (PCI) in daily clinical practice in Japan.
Background The long-term clinical impact of routine FUCAG after PCI in real-world clinical practice has not been evaluated adequately.
Methods In this prospective, multicenter, open-label, randomized trial, patients who underwent successful PCI were randomly assigned to routine angiographic follow-up (AF) group, in which patients were to receive FUCAG at 8 to 12 months after PCI, or clinical follow-up alone (CF) group. The primary endpoint was defined as a composite of death, myocardial infarction, stroke, emergency hospitalization for acute coronary syndrome, or hospitalization for heart failure over a minimum of 1.5 years follow-up.
Results Between May 2010 and July 2014, 700 patients were enrolled in the trial among 22 participating centers and were randomly assigned to the AF group (n = 349) or the CF group (n = 351). During a median of 4.6 years of follow-up (interquartile range [IQR]: 3.1 to 5.2 years), the cumulative 5-year incidence of the primary endpoint was 22.4% in the AF group and 24.7% in the CF group (hazard ratio: 0.94; 95% confidence interval: 0.67 to 1.31; p = 0.70). Any coronary revascularization within the first year was more frequently performed in AF group than in CF group (12.8% vs. 3.8%; log-rank p < 0.001), although the difference between the 2 groups attenuated over time with a similar cumulative 5-year incidence (19.6% vs. 18.1%; log-rank p = 0.92).
Conclusions No clinical benefits were observed for routine FUCAG after PCI and early coronary revascularization rates were increased within routine FUCAG strategy in the current trial. (Randomized Evaluation of Routine Follow-up Coronary Angiography After Percutaneous Coronary Intervention Trial [ReACT]; NCT01123291)
In several previous studies, routine follow-up coronary angiography (FUCAG) after percutaneous coronary intervention (PCI) increased the rate of coronary revascularization, but did not improve clinical outcomes (1–4). Based on these study results, the current clinical guidelines in the United States have already disregarded routine FUCAG, even after PCI for left main coronary artery disease, whereas the current clinical guidelines in Europe regarded routine FUCAG after high-risk PCI as Class IIb (5,6). However, previous studies in the drug-eluting stents (DES) era were conducted in the context of pivotal randomized trials of DES and there have been no randomized clinical trial evaluating long-term clinical impact of routine FUCAG after PCI in the real-world clinical practice, including in high-risk patients for cardiovascular events risk such as complex coronary artery disease and acute myocardial infarction (AMI) presentation (3,7,8). The current randomized clinical trial, therefore, was conducted to evaluate the long-term clinical impact of routine FUCAG after PCI in real-world clinical practice in Japan, where routine FUCAG after PCI is still performed commonly as usual care (4,9,10).
Study design and patient selection
The ReACT (Randomized Evaluation of Routine Follow-up Coronary Angiography After Percutaneous Coronary Intervention Trial) is a prospective, multicenter, open-label, randomized trial comparing the routine angiographic follow-up (AF) strategy with the clinical follow-up (CF) strategy in daily clinical practice in Japan. In this all-comer design trial, patients who underwent successful PCI without planned staged PCI were enrolled from 22 participating centers (List A in the Online Appendix) without any exclusion criteria. The study protocol was approved by the institutional review board at each participating center. Written informed consent was obtained from all the study patients. The trial was registered with NCT01123291.
Patients were randomly allocated in a 1:1 ratio to the routine AF group or CF group. Randomization was performed before hospital discharge after the index PCI and stratified by centers and bare-metal stent use. In the AF group, patients were scheduled to undergo routine FUCAG at 8 to 12 months after the index PCI, whereas in the CF group, patients were scheduled to receive CF without routine FUCAG. During follow-up, any physiological stress tests such as treadmill exercise test or stress nuclear study were allowed to be performed, but coronary computed tomography angiography was not allowed in either group. Clinically indicated coronary angiographic studies, such as those for acute coronary syndrome (ACS), for recurrence of angina, and/or for objective evidence of myocardial ischemia, were allowed based on the decision by the attending physicians.
Follow-up data were collected by the clinical research coordinators belonging to the participating centers, or to the academic research organization (Research Institute for Production Development, Kyoto, Japan). Follow-up assessments were performed by means of hospital visit or telephone contact with the patient and/or the referring physician at 1 year and final follow-up. Data collection for the final follow-up was started at February 1, 2016, which was 1.5 years after the last patient was enrolled.
Primary and secondary endpoints
The primary endpoint was defined as a composite of death, myocardial infarction (MI), stroke, emergency hospitalization for ACS, or hospitalization for heart failure (HF) during the minimum of 1.5 years CF after the index PCI.
The secondary endpoints included all-cause death, MI, stroke, emergency hospitalization for ACS, hospitalization for HF, definite stent thrombosis, major bleeding, target lesion revascularization (TLR), clinically driven TLR, any coronary revascularization, and clinically driven coronary revascularization.
Stent thrombosis and MI were defined according to the Academic Research Consortium definitions (11). Stroke during follow-up was defined as ischemic or hemorrhagic stroke requiring hospitalization with symptoms lasting >24 hrs. ACS was diagnosed according to clinical symptoms, electrocardiographic changes compatible with acute myocardial ischemia, and elevation of cardiac biomarkers. AMI (ST-segment elevation AMI and non–ST-segment elevation AMI) and unstable angina were distinguished according to the presence or absence of cardiac biomarker elevation. Unstable angina was adjudicated only in the presence of an angiographically evident culprit lesion. Hospitalization for HF was defined as hospitalization due to worsening HF requiring intravenous drug therapy. Major bleeding was defined as moderate or severe bleeding according to the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) classification (12). TLR was defined as either PCI or coronary artery bypass grafting due to restenosis or thrombosis of the target lesion that included the proximal and distal edge segments as well as the ostium of the side branches. Only those lesions treated at the time of the index PCI procedure were regarded as target lesions. Any coronary revascularization was defined as either PCI or coronary artery bypass grafting for any reasons. A coronary revascularization was considered clinically indicated if one of the following occurred: 1) a positive history of recurrent angina pectoris; 2) objective signs of ischemia at rest (changes in the electrocardiograph) or during exercise test (or the equivalent); and 3) abnormal results of any invasive functional diagnostic test (e.g., fractional flow reserve).
Adjudication of endpoint events by an independent clinical event committee (List B in the Online Appendix) was conducted in a blinded fashion regarding the assigned study groups. Clinical outcomes are analyzed according to the intention-to-treat principle.
Categorical variables were expressed as number (%), and were compared with the chi-square test or Fisher’s exact test. Continuous variables were expressed as mean ± SD or median with interquartile range (IQR). Continuous variables were compared using the Student t test or Wilcoxon rank-sum test based on their distributions. The cumulative incidence of a clinical event was assessed by the Kaplan-Meier method and compared by the log-rank test. We developed the Cox proportional hazard model incorporating the random effect of center to take the differences in management between facilities into consideration. The effect of routine follow-up angiography for the primary endpoint was expressed by hazard ratio with its 95% confidence interval. As a subgroup analysis, the treatment effect of routine AF strategy relative to CF strategy was evaluated in several clinically relevant subgroups, including those patients with diabetes mellitus, restenotic lesion, left main coronary artery disease, chronic total occlusion lesion, bifurcation lesion, multivessel disease, total stent length ≥40 mm, and “post hoc” high-risk group defined as having ≥1 high-risk features, such as left main coronary artery disease, bifurcation lesion, multivessel disease, and total stent length ≥40 mm.
The trial was originally designed to enroll 3,300 patients to ensure a power of 80% to detect a 15% relative reduction of the primary endpoint rate at 3 years in the AF group as compared with that in the CF group, in which the estimated primary endpoint event rate was 25% at 3 years based on the data from the j-Cypher registry (13). The enrollment of study patients was started at May 2010. In June 2014, however, the protocol was amended to have a target enrollment of 700 patients with an estimated median follow-up duration of 5 years, because of slow enrollment, and resulting in longer follow-up interval. The sample size calculation were based on an estimated primary event rate of 47.7% in CF group, with a power of 80% to detect a relative reduction of 25% in AF group as compared with CF group for the primary endpoint, assuming 25% crossover and loss to follow-up. Interim analysis was not performed during the study period.
All statistical analyses were performed using JMP 8.0 (SAS Institute Inc., Cary, North Carolina) and SAS 9.4 (SAS Institute, Inc.) software. All reported p values were 2-sided and p < 0.05 were regarded as statistically significant.
Between May 2010 and July 2014, a total of 700 patients were enrolled in the trial among 22 participating centers and were randomly assigned to AF group (n = 349) or CF group (n = 351) (Figure 1). The 2 study groups were balanced with regard to clinical, angiographic, and procedural characteristics (Table 1). The study population reflected the real-world clinical practice in Japan, including large proportions of patients with advanced age, diabetes mellitus, prior PCI, and multivessel disease, and a significant proportions of patients with AMI presentation, target of bifurcation lesion, and target of chronic total occlusion. Regarding the PCI procedure, DES was used in 85% of patients, in whom second-generation DES was used in 89% of patients (Table 1).
During the first year, FUCAG, including those due to clinical reasons, were actually performed in 298 patients (85.4%) in the AF group and in 42 patients (12.0%) in the CF group. Median time to FUCAG in patients receiving FUCAG within 1 year after index PCI was 287 days (IQR: 253 to 322 days) in the AF group (n = 298 of 349) and 235 days (IQR: 174 to 299 days) in the CF group (n = 42 of 351). In the AF group, 21 patients (7%) underwent coronary angiography for clinical reasons. In the CF group, the reasons for coronary angiography within the first year included 6 patients (14%) for ACS, 25 patients (60%) for recurrence of angina, 6 patients (14%) for other clinical reasons, and 5 patients (12%) without any clinical reason (protocol violation) (Figure 1). Noninvasive physiological stress tests such as treadmill exercise test and stress nuclear study were more often performed in the CF group than the AF group within the first year after PCI (33.6% and 25.2%; p = 0.01), and during the entire follow-up period (52.7% and 40.1%; p < 0.001).
Median follow-up duration after the index PCI was 4.6 (IQR: 3.1 to 5.2) years in the entire study population (AF group 4.5 [IQR: 3.1 to 5.2] years, and CF group: 4.6 [IQR: 3.1 to 5.2] years; p = 0.87). The CF rate was 98.6% at 1 year and 95.5% at 3 years (277 eligible patients) in the AF group, and 99.4% at 1 year and 96.2% at 3 years (279 eligible patients) in the CF group. The cumulative 5-year incidence of the primary endpoint was 22.4% in the AF group and 24.7% in the CF group (hazard ratio: 0.94, 95% confidence interval: 0.67 to 1.31; p = 0.70) (Table 2, Figure 2).
The cumulative 5-year incidences of the individual components of the primary endpoint such as all-cause death, MI, stroke, emergency hospitalization for ACS, and hospitalization for HF were also not significantly different between the AF and CF groups (Table 2). The cumulative 5-year incidence of major bleeding was also not different between the 2 groups (Table 2).
TLR within the first year after the index PCI was performed more frequently in AF group than in CF group (7.0% vs. 1.7%; log-rank p < 0.001) (Figure 3A, Online Figure 1A). However, the cumulative 5-year incidence of TLR in the AF group was not significantly different with that in the CF group (10.4% vs. 8.5%; log-rank p = 0.12) (Table 2, Figure 3A). Any coronary revascularization within the first year after the index PCI was also more frequently performed in the AF group than in the CF group (12.8% vs. 3.8%; log-rank p < 0.001) (Figure 3B). However, any coronary revascularization beyond the first year after the index PCI was performed more frequently in the CF group than in the AF group, and the difference in any coronary revascularization between the 2 groups attenuated over time with similar cumulative 5-year incidence (19.6% vs. 18.1%; log-rank p = 0.92) (Table 2, Figure 3B, Online Figure 1B).
Regarding the subgroup analyses, there was no interaction between the subgroup factors and the effect of AF relative to CF on the primary endpoint (Figure 4).
The main findings of the current trial were as follows: 1) routine FUCAG after PCI did not provide any clinical benefits as compared with CF alone; and 2) an increased 1-year rate of repeat coronary revascularization with routine AF attenuated with long-term follow-up.
Previous randomized trials in the balloon angioplasty or bare-metal stent era and nonrandomized studies in the DES era consistently reported that routine FUCAG increased repeat coronary revascularization, but did not reduce major adverse cardiac events, although the rate of MI was slightly lower in AF than in CF alone in the substudies of the BAAS (Balloon Angioplasty and Anticoagulation Study) and the TAXUS-IV trial (1–3,7,8). However, the impact of routine FUCAG for high-risk patients in real-world practice has not been evaluated fully, because all the previous studies included patients with relatively low-risk profile in terms of comorbidity and lesion complexity. Cassese et al. (14) reported that the presence of restenosis at FUCAG after PCI was predictive of 4-year mortality in their cohort of 10,004 patients with routine FUCAG. However, as the authors correctly stated in their article, the understanding of a potential role for routine follow-up angiography was beyond the scope of their study. According to the findings of the current trial, which included high-risk patients in real clinical practice, routine FUCAG did not provide any clinical benefit, including preventive effect of MI. Routine FUCAG after PCI is still commonly performed as usual care in Japan without evidence of clinical benefit (4,9,10). Considering the invasive nature of coronary angiography and increased medical expenses, routine FUCAG after PCI would not be considered usual clinical practice, unless patients have recurrent symptom or objective evidence of ischemia. In contrast, there was no excess of adverse clinical events with a routine AF strategy, except for the increased rate of 1-year repeat coronary revascularization. Therefore, the scheduled AF would still be acceptable in a first-in-man coronary device trials, or as the mechanistic substudy in the pivotal coronary device trials.
“Oculostenotic reflex” phenomenon, which means coronary revascularization for angiographic stenosis without objective evidence of ischemia, was reported as a negative aspect of routine FUCAG, which resulted in approximately 2-fold higher rate of repeat coronary revascularization as compared with CF alone in several previous studies (1–3). In a substudy of the SPIRIT III (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions) trial evaluating newer generation DES; however, the cumulative incidence of repeat coronary revascularization was not significantly different between routine FUCAG and CF alone in 3-year CF (12.4% vs. 11.3%; log-rank p = 0.45) (8). Consistent with the results of the SPIRIT III trial, long-term risks for TLR and any coronary revascularization were not significantly different between AF and CF groups in the current trial. Despite the 3-fold higher 1-year rate of TLR and any coronary revascularization in AF group, this large difference gradually attenuated with long-term follow-up in the current trial. The annual 1.7% rate of late TLR beyond 1 year after PCI in the CF group, which resulted in the attenuation of the difference in TLR between the 2 groups, was consistent with the annual 2.0% to 2.2% rate of late TLR beyond 1 year reported in first-generation and newer generation DES studies (15,16). In contrast, the relatively lower 0.9% annual rate of late TLR in AF group might suggest that many of the lesions with late TLR in CF group actually had early restenosis within 1 year. Late TLR is one of the unsolved issues in contemporary PCI using DES. It would be a clinically relevant question as to whether the fully bioresorbable coronary scaffold could overcome the late adverse events related to the target-lesion after complete resorption of the scaffold (17). The other possible reason for the attenuation of the between group difference in the coronary revascularization rate during long-term follow-up was the higher rate of coronary revascularization for new lesions or progression of nontarget lesions in the CF group. The lesions treated at the time of FUCAG might undergo clinically driven revascularization with long-term follow-up, even if not detected by FUCAG within 1 year.
First, the current trial was underpowered to detect modest differences in the primary endpoint due to the reduced final sample size and the actual event rate lower than anticipated, although the size of the present study was similar to previous studies. Therefore, the current trial result might be “inconclusive” rather than “negative,” warranting future, larger scale studies. Furthermore, we were unable to address the role of routine AF in the high-risk subgroups, such as left main or multivessel coronary artery disease. Future dedicated studies are warranted to evaluate the role of routine AF in these high-risk subsets of patients. Second, slow patient enrollment might indicate patient selection bias that would potentially influence the study results. Finally, because patient demographics, practice patterns including the indication of coronary revascularization, and clinical outcomes in Japan may be different from those outside Japan, generalizing the present study results to populations outside Japan should be done with caution.
No clinical benefits were observed for routine FUCAG after PCI and early revascularization rates were increased within this approach in the current trial. Thus, routine FUCAG cannot be recommended as a clinical strategy. However, the present study was underpowered to detect modest benefits (or harm) of routine FUCAG, and larger scale trials (especially in high-risk patients) are warranted to definitively address this issue.
WHAT IS KNOWN? Routine FUCAG after PCI could not improve clinical outcomes but increased the rate of coronary revascularization due to “oculostenotic reflex” in the previous studies. However, there have been no randomized clinical trials evaluating the clinical impact of routine FUCAG after PCI in real-world clinical practice, including high-risk patients for cardiovascular events risk.
WHAT IS NEW? In this trial, which included a large proportion of high-risk patients for cardiovascular events risk in daily clinical practice in Japan, no clinical benefits were observed for routine FUCAG after PCI and early revascularization rates were increased within this approach.
WHAT IS NEXT? Future, larger scale trials (especially in high-risk patients) are warranted to address definitively the role of routine FUCAG after PCI in high-risk subsets of patients, such as those with left main or multivessel coronary artery disease.
The authors thank the members of the cardiac catheterization laboratories of the participating centers and the clinical research coordinators.
For supplemental materials and figures, please see the online version of this article.
Supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan).
Dr. Morimoto received honoraria for education consulting from Boston Scientific Corporation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- acute myocardial infarction
- drug-eluting stent(s)
- follow-up coronary angiography
- heart failure
- interquartile range
- myocardial infarction
- percutaneous coronary intervention
- target lesion revascularization
- Received October 16, 2016.
- Accepted October 20, 2016.
- American College of Cardiology Foundation
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