Correspondence to Dr Shun Kohsaka; [email protected]
Key questions
What is already known about this subject?
Drug-eluting stent-induced vasospastic angina (DES-VSA) has emerged as a novel complication in the contemporary era of percutaneous coronary intervention (PCI). Beta blockers are widely recommended for patients with coronary heart disease; however, they can potentially induce DES-VSA. For prevention of naturally occurring vasospastic angina, calcium channel blockers are recommended which may also offer protection against DES-VSA though evidence is scarce.
What does this study add?
Occurrence of acetylcholine-induced DES-VSA did not differ at 9 months between beta blocker and calcium channel blocker groups. However, a higher incidence of 2-year repeat revascularisation was observed in the calcium channel blocker group, suggesting the importance of beta-blocker administration.
How might this impact on clinical practice?
Calcium channel blockers as an alternative to beta blockers for DES-VSA prevention should not be encouraged routinely. Concomitant use of both agents may be suitable for patients who had PCI with suspected or higher risk for coronary endothelial dysfunction, a topic which merits further study.
Background
Beta-blocker (BB) administration for patients with acute myocardial infarction (MI) after percutaneous coronary intervention (PCI) has been strongly recommended by American and European guidelines1–5 based on the results of two large randomised clinical trials, β-Blocker Heart Attack Trial6 and the Norwegian Multicenter Study Group trial,7 that demonstrated reductions in infarct size, early mortality and risk of death when continued in the long term. However, its effectiveness has been in doubt over recent years, because many trials supporting the use of BBs were conducted prior to the widespread use of PCI and because the prescription rates of currently accepted optimal medical therapies were significantly lower than in the modern era.8 A recent observational study from Medicare beneficiaries suggested limited additional benefits of BBs in patients who were prescribed statins and ACE inhibitors/angiotensin-receptor blockers for long-term cardiovascular events.9 Importantly, in the Western population with stable angina,10 a meta-analysis including results from the TIBET11 and APSIS trials,12 found that the effect of BB was equivalent in angina reduction, and that the BB rates of adverse events compared with calcium channel blockers (CCB) or long-acting nitrates lead to different recommendations among the major cardiology societies. Moreover, the risk of BB-induced vasospastic angina (VSA) has been perceived as a potential threat among the VSA-prevalent Japanese population particularly after drug-eluting stent placement.13 In Japanese society guideline, patients with coronary artery disease (CAD) presenting with coexisting atherosclerosis and VSA are recommended to start on long-acting CCB for VSA prevention and BBs if only CCBs are concurrently prescribed.14 Lastly, drug-eluting stent-induced VSA (DES-VSA) has emerged as a novel complication in the contemporary era of PCI.15 16
To study this complication, we compared the effect of BBs and CCBs monotherapy in combination with other optimal medical therapy in this prospective, multicentre, open-labelled, randomised trial; we evaluated angiography-confirmed acetylcholine (ACh)-induced VSA at 9 months as a surrogate for DES-VSA; and evaluated major adverse cardiac and cerebrovascular events (MACE) at 24 months as the secondary endpoint.
Methods
Design
This prospective, open-labelled, two-armed randomised clinical trial for optimising medical therapy after stenting compared the efficacy of CCBs and BBs for the prevention of VSA after second-generation DES implantation (figure 1). The study overview was reported to the Japanese University Hospital Medical Information Network prior to patient recruitment and is available online. The current trial enrolled patients aged ≥20 years, who had stable/unstable angina or silent ischaemia, and who underwent PCI for a single-vessel lesion with the Xience (Abbott Vascular, Santa Clara, California, USA) or Promus (Boston Scientific, Natick, Massachusetts, USA) everolimus-eluting stent (EES) placement. The assigned medical treatments were titrated to maximally tolerated doses of amlodipine (CCB) 10 mg daily or bisoprolol (BB) 10 mg daily. The incidences of ACh-induced VSA in both arms were compared at 9 months after EES implantation for elective cases.
Enlarge this image.Figure 1. Study population. ACh, acetylcholine; CAG, coronary angiography; PCI, percutaneous coronary intervention; PM, pacemaker; TLR, target lesion revascularisation.
All patients provided written informed consent before participation. The trial was conducted in accordance with the principles of the Declaration of Helsinki and adheres to Consolidated Standards of Reporting Trials guidelines. All data were collected from health records via a secure electronic database capture system from each participating hospital. Data were entered by dedicated clinical research coordinators or trained physicians deployed from Keio University Hospital.
Subjects
The exclusion criteria included a history of stent restenosis or coronary bypass surgery, previous diagnosis of VSA within 1 year and/or on treatment, previous PCI within 1 year, an acute MI within 7 days, left main trunk lesion, left ventricular ejection fraction of <35%, and previous pacemaker implantation or atrioventricular block more than first degree. Additional exclusions were, systolic blood pressure <100 mm Hg or a heart rate <60 beats per minute prior to PCI, renal failure with a serum creatinine level >2.0 mg/dL or on haemodialysis, liver failure (eg, diagnosis of cirrhosis), asthma-chronic obstructive lung disease overlap, diagnosis of malignancy within 5 years, or pregnancy, and patients with ≥4 EES placements.
Eligible patients were randomly assigned centrally, in a 1:1 ratio by simple randomisation based on computer-generated numbers to receive either CCB or BB; additionally patients received within 24 hours of the baseline PCI optimal medical therapy (aspirin, P2Y12 inhibitor, statin and renin–angiotensin–aldosterone system inhibitor). EESs were implanted with ≤3 stents after a pre-dilation procedure, and at the pre-dilation site and culprit or severely stenotic coronary lesions (greater than 75% stenosis). All patients were administered oral aspirin (100 mg/day) and clopidogrel for at least 2 days before PCI, which was continued during the 24-month follow-up period.
The BB group was instructed to receive bisoprolol as a cardioselective β1-adrenergic blocking agent at an initial dose of 1.25 mg and titrated up to 5 mg per day as tolerated. Those patients already on a different type of BB shifted to the equivalent amount of bisoprolol as follows: carvedilol 5 mg to bisoprolol 1.25 mg, atenolol 25 mg to bisoprolol 2.5 mg and propranolol 80 mg to bisoprolol 5 mg, accordingly. The treating physicians were instructed to maintain the highest tolerable dose of BB during the trial. Similarly, the CCB group was instructed to receive amlodipine at an initial dose of 1.25 mg and titrated up to 10 mg per day as tolerated. The optimised medical therapy was adjusted by the treating physicians as needed.
The patients were followed at 1, 9 and 24 months after hospital discharge in the outpatient clinic of each participating hospital by the treating physicians (figure 2).
Enlarge this image.Figure 2. Study design and treatments. The Prospective Randomised Trial for Optimising Medical Therapy After Stenting: Calcium-Beta trial is a prospective, randomised, open-labelled, blinded endpoint clinical trial comparing the effects of calcium channel blocker and beta-blocker administration after second generation drug-eluting stent implantation. Patient data are collected at baseline, 9 months and 24 months after initial PCI marked as X in the figure. ACh, acetylcholine; CAG, coronary angiography; MACE, major cardiovascular events; PCI, percutaneous coronary intervention; PROBE, prospective randomised open blinded end-point; RAAS, renin-angiotensin-aldosterone system.
Outcomes
At 9 months after the initial PCI, we performed ACh provocation testing for positive vasospasm: we recorded the following three conditions and considered their occurrence as positive signs of ACh-induced VSA :(1) transient, total or subtotal coronary artery occlusion of >90% stenosis, (2) typical anginal-type with chest discomfort and (3) ischaemic ECG changes (ST segment elevation ≥0.1 mV, ST segment depression ≥0.1 mV or a new appearance of negative U-wave in at least two contiguous leads). ACh provocation testing was evaluated using 20 μg and 50 μg titration dosing of ACh for the right coronary artery, and 20, 50 and 100 μg for the left coronary artery complying with the current Japanese Circulation Society Guidelines.14
Sample size
We estimated that the assignment of 106 patients (53 patients for each of the BB and CCB arms) would provide 80% power at a one-sided alpha level of 0.05 to show the equivalence of CCB to BB with respect to the 9-month primary endpoint, with an equivalence margin of 0.05 for the upper 95% confidence limit for the between-group difference in event rates, assuming a 30% event rate in the BB group and a 15% event rate in the CCB group based on previous studies.17
Patient enrolment was terminated prematurely prior to reaching the planned sample size of 106 because of slow enrolment. The study sample size was reduced to 52 patients (26 patients in each group) to hold 80% power with an equivalence margin of 0.13 for the upper 95% confidence limit for the between-group difference in event rates, assuming a 30% event rate in the BB group and a 15% event rate in the CCB group. During the time between patient randomisation and follow-up coronary angiography (CAG), four patients in the CCB group and six in the BB group dropped out due to withdrawal of consent, a major cardiovascular event refusal to undergo CAG and ACh provocation testing, or were lost to follow-up.
Statistical analysis
All principal analyses were performed with data from the time of randomisation in the intention-to-treat population, which included all patients according to the group to which they were randomly assigned, regardless of the treatment received. Equivalence was calculated with the Farrington and Manning method,18 and sensitivity analyses were performed in the per-protocol population. Categorical variables were compared using the Χ2 test or Fisher’s exact test. Continuous variables were compared using the Student’s t-test or Wilcoxon rank-sum test for non-normally distributed data. All statistical analyses were performed using R V.3.4.3 with packages tidyverse V.1.2.1. for variable selection and ratesci V.0.3-0 for calculating, approximate Bayesian CIs.
Results
From August 2012 to May 2015, 52 patients (CCB group, n=26; BB group, n=26) were enrolled. Patient demographic, coronary lesions and procedural characteristics were basically similar and were well balanced between the two groups (table 1) (online supplemental table 1).
Table 1Baseline characteristics
| Number of patients | BB | CCB | P value | ||
| 26 | 26 | ||||
| Age (years) | 67.7±13.0 | 65.4±11.1 | 0.32 | ||
| Male (%) | 81 | 21 | 73 | 19 | 0.47 |
| Body mass index (%) | 24.1±3.3 | 25.5±4.7 | 0.24 | ||
| Medical history | |||||
| Myocardial infarction (%) | 4 | 1 | 15 | 4 | 0.23 |
| Heart failure (%) | 0 | 0 | 0 | 0 | 0.61 |
| PCI | 0% | 0 | 23% | 6 | 0.02 |
| CABG | 0% | 0 | 4% | 1 | 0.30 |
| Diabetes mellitus | 27% | 7 | 27% | 7 | 0.81 |
| Haemodialysis | 0% | 0 | 0% | 0 | 0.32 |
| Cerebrovascular disease | 12% | 3 | 4% | 1 | 0.36 |
| Peripheral vascular disease | 8% | 2 | 4% | 1 | 0.51 |
| Chronic lung disease | 0% | 0 | 0% | 0 | 0.32 |
| Hypertension | 73% | 19 | 62% | 16 | 0.40 |
| Smoking | 12% | 3 | 12% | 3 | 0.61 |
| Dyslipidaemia | 69% | 18 | 65% | 17 | 0.99 |
| Atrial fibrillation | 4% | 1 | 0% | 0 | 0.37 |
| PCI indications | |||||
| Unstable angina | 19% | 5 | 27% | 7 | 0.22 |
| Stable angina | 62% | 16 | 46% | 12 | |
| Asymptomatic/atypical | 19% | 5 | 23% | 6 | |
| Location of PCI lesion | |||||
| Left circumflex | 19% | 5 | 27% | 7 | 0.16 |
| Right coronary artery | 23% | 6 | 8% | 2 | |
| Left anterior descending | 54% | 14 | 62% | 16 | |
| Bifurcation lesion | 12% | 3 | 31% | 8 | 0.14 |
| Type C lesion | 46% | 12 | 19% | 5 | 0.048 |
| Chronic total occlusion lesion | 27% | 7 | 4% | 1 | 0.02 |
| Previous stenting to target lesion | 0% | 0 | 4% | 1 | 0.03 |
BB, beta blocker; CABG, coronary artery bypass grafting; CCB, calcium channel blocker; PCI, percutaneous coronary intervention.
Notably, there were fewer patients in the BB group than in the CCB group with a history of PCI (0% vs 23% p=0.02) or previous stenting to the target lesion (0% vs 4% p=0.03), and more patients with type C lesions (46% vs 19% p=0.048) and chronic total occlusion PCI (27% vs 4% p=0.024) (table 2).
Table 2Hospital discharge medications
| Number of patients | BB | CCB | P value | ||
| 26 | 26 | ||||
| Aspirin | 92% | 24 | 96% | 25 | 1 |
| Clopidogrel | 92% | 24 | 96% | 25 | 1 |
| Anticoagulation use | 0% | 0 | 8% | 2 | |
| Warfarin | 0% | 0 | 4% | 1 | 1 |
| Rivaroxaban | 0% | 0 | 4% | 1 | 1 |
| ACEi/ARB | 42% | 11 | 46% | 12 | 1 |
| BB | 77% | 20 | 12% | 3 | <0.001 |
| Carvedilol | 0% | 0 | 4% | 1 | |
| Bisoprolol | 73% | 19 | 4% | 2 | |
| Propranolol | 4% | 1 | 0% | 0 | |
| CCB | |||||
| Amlodipine | 15% | 4 | 77% | 20 | <0.001 |
| Statin | 85% | 22 | 73% | 19 | 0.42 |
| Atorvastatin | 12% | 3 | 15% | 4 | |
| Pitavastatin | 19% | 5 | 12% | 3 | |
| Pravastatin | 4% | 1 | 0% | 0 | |
| Rosuvastatin | 50% | 13 | 46% | 12 | |
| Other lipid-lowering agents | 4% | 1 | 12% | 3 | 0.70 |
Values are mean_SD or n (%).
ACEi, ACE inhibitor; ARB, angiotensin II receptor blocker ; BB, beta blocker; CCB, calcium channel blocker.
At the time of 1-month visit post-discharge, the randomised medications were prescribed to 24/26 (92.3%) in the BB group and 24/26 (92.3%) in the CCB group (online supplemental table 2). At 9 months after PCI, 42 (84.6%) patients underwent follow-up CAG and ACh stress testing. The primary outcome of definite vasospasm occurred in seven patients (intention-to-treat analysis, 26.9%; per-protocol analysis, 31.8%) in the CCB group and seven patients (intention-to-treat analysis, 26.9%; per-protocol analysis, 35.0%) in the BB group (table 3).
Table 3Primary endpoints at 9 months
| Number of patients | BB | CCB | P value | ||
| 26 | 26 | ||||
| Positive Ach-induced spasm | |||||
| Intention-to-treat analysis | 26.9% | 7 | 26.9% | 7 | 1 |
| Per-protocol analysis | 35% | 7 | 31.8% | 7 | 0.21 |
| Coronary angiographic findings | |||||
| 75% spasm | 8% | 2 | 4% | 1 | 0.71 |
| 90% spasm | 15% | 4 | 15% | 4 | |
| 99% spasm | 23% | 6 | 27% | 7 | |
| 100% spasm | 4% | 1 | 0% | 0 | |
| QCA | 3.25 | 19.5 | 0.04 | ||
| Improvement with nitroglycerin administration | 46% | 12 | 42% | 11 | 0.34 |
| Chest discomfort | 42% | 11 | 46% | 12 | 0.27 |
| Typical chest discomfort during test | 27% | 7 | 27% | 7 | 0.89 |
| Time required for symptom alleviation (minutes) | |||||
| Under 5 | 42% | 11 | 58% | 15 | 0.48 |
| Above 5 | 23% | 6 | 4% | 1 | |
| Ambiguous or unknown | 35% | 9 | 27% | 7 | |
| ECG change during provocation | 46% | 12 | 27% | 7 | 0.18 |
| Non-specific STT change | 0% | 0 | 8% | 2 | 0.23 |
| ST elevation >0.5 mm | 15% | 4 | 8% | 2 | |
| ST depression >0.5 mm | 31% | 8 | 15% | 4 | |
| Time required for ECG recovery (minutes) | |||||
| Under 5 | 31% | 8 | 19% | 5 | 0.54 |
| Above 5 | 15% | 4 | 8% | 2 | |
Values are mean_SD or n (%).
Ach, acetylcholine; BB, beta blocker; CCB, calcium channel blocker; QCA, quantitative coronary analysis.
The risk difference point estimate and 95% CIs calculated by the Farrington and Manning method were 0 (−0.241 to 0.241) under the intention-to-treat analysis and 0.0318 (−0.317, 0.254) under the per-protocol analysis, both demonstrating inconclusive results due to CIs wider than the equivalence margin set as 0.13 (adjusted ORs shown in online supplemental table 3). Meanwhile, the secondary endpoint, 24-month MACE, was higher in the CCB group (19.2%) than in the BB group (3.8%) (p=0.01). In detail, coronary revascularisation for stable CAD was the predominant endpoint that contributed to the greater proportion of MACE in the CCB group (CCB (19.2%) vs BB (3.8%), p=0.03) (table 4).
Table 4Secondary endpoints at 24 months
| Number of patients | BB | CCB | P value | ||
| 26 | 26 | ||||
| MACE | |||||
| Intention to treat | 3.8% | 1 | 19.2% | 5 | 0.01 |
| Per-protocol | 5.0% | 1 | 13.6% | 3 | 0.1 |
| Individual endpoints of MACE | |||||
| All-cause death | 0% | 0 | 0% | 0 | NA |
| Hospitalisation for non-fatal MI and unstable angina | 0% | 0 | 0% | 0 | NA |
| Coronary revascularisation for stable CAD | 4% | 1 | 19% | 5 | 0.03 |
| CVD | 0% | 0 | 0% | 0 | NA |
| Bleeding complication | 0% | 0 | 0% | 0 | NA |
| Severe side effects due to medication | 0% | 0 | 4% | 1 | 0.18 |
Values are mean_SD or n (%).
BB, beta blocker; CAD, coronary artery disease; CCB, calcium channel blocker; CVD, cerebrovascular disease; MACE, major adverse cardiac events; MI, myocardial infarction; NA, not applicable.
Discussion
To study the novel complication of DES-VSA, in this prospective, multicentre, open-labelled, randomised trial, we compared the effect of BBs and CCBs on angiography-confirmed ACh-induced VSA at 9 months as a surrogate for DES-VSA. We found that the incidence of ACh-induced VSA among patients randomly receiving BB was not inferior to CCB at the 9-month angiography, in addition to other optimal medical therapies, they received after the initial PCI. Notably, CCB administration was associated with a higher incidence of coronary revascularisation for stable CAD at 24 months than BB administration.
In this study, BBs did not significantly increase the incidence of ACh-induced VSA, compared with CCBs, in contrast to the common belief regarding VSA. Nishigaki et al have demonstrated the effectiveness of CCB in ‘spontaneous’ VSA prevention in a meta-analysis. Four major CCBs, benidipine, amlodipine, nifedipine and diltiazem, were shown to suppress recurrent spontaneous VSA attacks, with benidipine showing the most beneficial effect on long-term MACE.19 Our results showed that BBs are certainly as effective compared with CCBs for VSA prevention after EES implantation, which is believed to be a risk factor for VSA among patients with non-obstructive CAD.
Conversely, we found that BBs do not essentially increase the incidence of VSA among the Japanese population compared with CCB administration. Importantly, we observed a trend in a higher incidence of 24-month hospitalisation for stable CAD in the CCB group, suggesting the presence of protective effects provided by BB. Although this may be due to the higher proportion of patients with a history of PCI and previous stenting, this is an important finding since post-PCI BB administration on discharge, particularly in East Asians, has been reported to be lower than that in Western countries.20–22 This is based on previous observational studies reporting a vulnerability in the occurrence of spontaneous VSA as well as DES-VSA after PCI. In a prospective observational study, Kohno et al studied 615 consecutive patients with VSA-suspected CAD undergoing ACh provocation testing, including those with and without previous PCI; they reported that patients with a history of PCI were significantly associated with higher risks of positive results on provocation; although, its relationship was not illustrated in terms of spontaneous and DES-VSA separately.23 Moreover, these patients were less likely to receive BBs on discharge, although, a higher proportion of these patients presented with unstable angina.
Previous trials have shown mixed results regarding the efficacy of CCBs on DES-VSA and incident MACE. Moreover, these have not been compared with the efficacy of BBs, except in the Japanese Beta-blockers and Calcium Antagonists Myocardial Infarction Study conducted in the pre-DES era.24 The study did not show any significant difference between the BB and CCB groups. In the first-generation DES era, Terashima et al demonstrated that telmisartan, an angiotensin II receptor blocker, significantly reduces the incidence of ACh-induced VSA compared with amlodipine after coronary DES implantation.17 In our study, approximately 40% of the patients received optimal medical therapy after PCI, including angiotensin-receptor blockers, in both arms, and the proportions did not differ significantly. More recently, in the second-generation DES era, the Nifedipine on Coronary Vascular Function after Drug-Eluting Stent Implantation (NOVEL) Study,25 found that nifedipine was effective for DES-VSA prevention compared with that in patients without CCB or BB administration in patients with stable CAD who had EES implantations to the left anterior descending artery 8–10 months prior to follow-up CAG. Among the 50 patients receiving nifedipine in the NOVEL Study, 38 patients underwent follow-up CAG with ACh provocation testing and 9 (23.7%) patients presented with DES-VSA; this was slightly lower than the present study results. The higher than expected DES-VSA observed in the CCB group may have been caused by difference in patient selection and study protocol resulting in higher proportion of patients with a history of PCI or previous stenting to the target lesion in the CCB group.
This trial has several limitations. First, the current trial was underpowered to detect equivalence for the primary endpoint because of the reduced final sample size owing to slow patient enrolment. Although BBs were not inferior to CCB, the number of patients with the positive ACh response, seven in each group, was small. Therefore, the current trial results may be ‘inconclusive’, warranting future, larger-scale studies. Second, the pathophysiology of clinically observed DES-induced vasospasms may differ from that of vasospasms observed during ACh provocation testing. High concentrations of ACh infused into the coronary artery may have overly diagnosed subclinical DES-VSA as those observed in the real world. Also, ACh provocative testing prior to PCI was not performed. Third, although randomisation was successful for other clinical features, there were fewer patients in the BB group with a history of PCI or prior stenting to the target lesion and more patients with type C lesions, including chronic total occlusion. These factors may have led to a higher incidence of 24-month MACE in the CCB group, mainly driven by elective PCI hospitalisations; although, the exact indications and characteristics of the treated coronary lesions are unknown. Fourth, we did not study the concomitant use of both agents, which may be suitable for patients who had PCI with suspected, or higher risk for coronary endothelial dysfunction. Fifth, the recent findings from the 2020 International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial have questioned the need for PCI in patients with stable angina with moderate or more subjectively proven myocardial ischaemia,26 however, our protocol and enrolment was registered in 2012. Sixth, because this study challenges the conventional use of CCB in DES-VSA by suggesting BBs may be equally effective, replicating this study for validation may be difficult: (1) criteria for PCI has become more restrictive for stable angina since this protocol was started in 2012; (2) obtaining informed consent for voluntary cardiac catheterisation in Western countries may be more challenging than in Japan with its cultural differences.
Conclusion
In this study of novel complication of DES-VSA, no significant difference in the incidence of ACh-induced coronary artery spasms was observed for routine administration of BBs compared with routine CCB administration in elective patients who had PCI who underwent EES implantation in a DES-VSA-vulnerable Japanese population.
The authors thank the members of the cardiac catheterisation laboratories of the participating centres and the clinical research coordinators: YM, Shunsuke Yuasa, Hideaki Kanazawa, Kentaro Hayashida and Takashi Kawakami (Keio University School of Medicine); Yukihiko Momiyama, Munehisa Sakamoto, Jun Fuse, Kojiro Tanimoto, YI and Kohei Inagawa (National Hospital Organization Tokyo Medical Center).
Twitter @MitsuakiSawano
MS, TK and SK contributed equally.
Contributors IU, AE and SK conceived and designed the research. MS and TK performed the statistical analysis. AE and SK handled funding and supervision. TK, KT, KO, YI, TY, IU, YM and AK acquired the data. MS, TK and SK drafted the manuscript. TK, YM, AK and KF made critical revision of the manuscript for key intellectual content. All authors have approved the final article.
Funding This study was supported in part by the grants-in-aid from the Ministry of Health, Labour, and Welfare (Award number: 24790538) and Pfizer Japan Inc. (Tokyo, Japan; award number: 04-013-0455), based on the research contract between the company and the Keio University School of Medicine. SK has received grants from Bayer Yakuhin and Daiichi-Sankyo, lecture fees from Bayer Yakuhin and Bristol-Myers Squibb, and consulting fees from Pfizer. The equipment and drugs used in the study were purchased by the participating hospitals.
Competing interests MS reports grants from Japan Promotional Society for Cardiovascular Disease Sakakibara Memorial Research Grant, grants from Japan Heart Foundation Japan Heart Foundation Research Grant, and grants from Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (18K17332) during the conduct of the study; grants from Takeda Pharma, Takeda Japan Medical Office Funded Research Grant 2018 outside the submitted work. TI has a research grant from Boston Scientific. SK reports investigator-initiated grant funding from Bayer and Daiichi Sankyo and personal fees from Bayer and Bristol-Myers Squibb. HI receives lecture fees from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, Otsuka Pharma, Pfizer, Mochida Pharma and MSD.
Patient consent for publication Not required.
Ethics approval The institutional review boards at each participating hospital approved the trial protocol: Keio University Hospital, Kobe City Medical Center General Hospital, Nishinomiya Watanabe Cardiovascular Center, Tokyo Bay Urayasu Ichikawa Medical Center, National Hospital Organization Tokyo Medical Center and Saiseikai Central Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available according to the 'Act on the Protection of Personal Information' Law (as of May 2017) and the 'Ethical Guidelines for Medical and Health Research Involving Human Subjects' (as of March 2015). The current study data were obtained from the JCD-KiCS PCI registry and are available upon request to The Institutional Review Board of Keio University School of Medicine ([email protected]).
1 Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American heart association Task force on practice guidelines (Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). Circulation 2004; 110: e82–292. http://www.ncbi.nlm.nih.gov/pubmed/15339869
2 O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of cardiology Foundation/American heart association Task force on practice guidelines. Circulation 2013; 127: e362–425. doi:10.1161/CIR.0b013e3182742cf6 http://www.ncbi.nlm.nih.gov/pubmed/23247304
3 Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American heart association Task force on practice guidelines. Circulation 2014; 130: e344–426. doi:10.1161/CIR.0000000000000134 http://www.ncbi.nlm.nih.gov/pubmed/25249585
4 Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of cardiology Foundation/American heart association Task force on practice guidelines, and the American College of physicians, American association for thoracic surgery, preventive cardiovascular nurses association, Society for cardiovascular angiography and interventions, and society of thoracic surgeons. Circulation 2012; 126: e354–471. doi:10.1161/CIR.0b013e318277d6a0 http://www.ncbi.nlm.nih.gov/pubmed/23166211
5 Ibanez B, James S, Agewall S, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of cardiology (ESC). Eur Heart J 2018; 39: 119–77. doi:10.1093/eurheartj/ehx393 http://www.ncbi.nlm.nih.gov/pubmed/28886621
6 A randomized trial of propranolol in patients with acute myocardial infarction. I. mortality results. JAMA 1982; 247: 1707–14. doi:10.1001/jama.1982.03320370021023 http://www.ncbi.nlm.nih.gov/pubmed/7038157
7 Pedersen TR. The Norwegian multicenter study of timolol after myocardial infarction. Circulation 1983; 67: I49–53. http://www.ncbi.nlm.nih.gov/pubmed/6342838
8 Borden WB, Redberg RF, Mushlin AI, et al. Patterns and intensity of medical therapy in patients undergoing percutaneous coronary intervention. JAMA 2011; 305: 1882–9. doi:10.1001/jama.2011.601 http://www.ncbi.nlm.nih.gov/pubmed/21558519
9 Korhonen MJ, Robinson JG, Annis IE, et al. Adherence tradeoff to multiple preventive therapies and all-cause mortality after acute myocardial infarction. J Am Coll Cardiol 2017; 70: 1543–54. doi:10.1016/j.jacc.2017.07.783 http://www.ncbi.nlm.nih.gov/pubmed/28935030
10 Heidenreich PA, McDonald KM, Hastie T, et al. Meta-Analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA 1999; 281: 1927–36. doi:10.1001/jama.281.20.1927 http://www.ncbi.nlm.nih.gov/pubmed/10349897
11 Dargie HJ, Ford I, Fox KM. Total ischaemic burden European trial (Tibet). Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. The Tibet Study Group. Eur Heart J 1996; 17: 104–12. doi:10.1093/oxfordjournals.eurheartj.a014668 http://www.ncbi.nlm.nih.gov/pubmed/8682116
12 Forslund L, Hjemdahl P, Held C, et al. Prognostic implications of results from exercise testing in patients with chronic stable angina pectoris treated with metoprolol or verapamil. A report from the angina prognosis study in Stockholm (APSIS). Eur Heart J 2000; 21: 901–10. doi:10.1053/euhj.1999.1936 http://www.ncbi.nlm.nih.gov/pubmed/10806014
13 Shibutani H, Akita Y, Matsui Y, et al. The potential hazard of drug-eluting stent-induced coronary vasospasm causing subacute stent thrombosis: a case report. BMC Cardiovasc Disord 2016; 16: 236. doi:10.1186/s12872-016-0410-4 http://www.ncbi.nlm.nih.gov/pubmed/27887648
14 JCS Joint Working Group. Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2013). Circ J 2014; 78: 2779–801. doi:10.1253/circj.CJ-66-0098 http://www.ncbi.nlm.nih.gov/pubmed/25273915
15 Brott BC, Anayiotos AS, Chapman GD, et al. Severe, diffuse coronary artery spasm after drug-eluting stent placement. J Invasive Cardiol 2006; 18: 584–92. http://www.ncbi.nlm.nih.gov/pubmed/17197707
16 Minami Y, Kaneda H, Inoue M, et al. Endothelial dysfunction following drug-eluting stent implantation: a systematic review of the literature. Int J Cardiol 2013; 165: 222–8. doi:10.1016/j.ijcard.2012.03.084 http://www.ncbi.nlm.nih.gov/pubmed/22459395
17 Terashima M, Kaneda H, Nasu K, et al. Protective effect of telmisartan against endothelial dysfunction after coronary drug-eluting stent implantation in hypertensive patients. JACC Cardiovasc Interv 2012; 5: 182–90. doi:10.1016/j.jcin.2011.09.022 http://www.ncbi.nlm.nih.gov/pubmed/22361603
18 Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med 1990; 9: 1447–54. doi:10.1002/sim.4780091208 http://www.ncbi.nlm.nih.gov/pubmed/2281232
19 Nishigaki K, Inoue Y, Yamanouchi Y, et al. Prognostic effects of calcium channel blockers in patients with vasospastic angina--a meta-analysis. Circ J 2010; 74: 1943–50. doi:10.1253/circj.CJ-10-0292 http://www.ncbi.nlm.nih.gov/pubmed/20668353
20 Yasuda S, Nakao K, Nishimura K, et al. The current status of cardiovascular medicine in Japan - analysis of a large number of health records From a nationwide claim-based database, JROAD-DPC. Circ J 2016; 80: 2327–35. doi:10.1253/circj.CJ-16-0196 http://www.ncbi.nlm.nih.gov/pubmed/27725417
21 Ni Z, Dardas L, Wu B, et al. Cardioprotective medication adherence among patients with coronary heart disease in China: a systematic review. Heart Asia 2019; 11: e011173. doi:10.1136/heartasia-2018-011173 http://www.ncbi.nlm.nih.gov/pubmed/31297162
22 Won H, Suh Y, Kim GS, et al. Clinical impact of beta blockers in patients with myocardial infarction from the Korean National health insurance database. Korean Circ J 2020; 50: 499–508. doi:10.4070/kcj.2019.0231 http://www.ncbi.nlm.nih.gov/pubmed/32096355
23 Kohno T, Kohsaka S, Ueda I, et al. Frequency and safety of intracoronary acetylcholine provocation testing compared to coronary interventions: analysis of a contemporary Japanese multicenter PCI registry. Int J Cardiol 2015; 183: 171–2. doi:10.1016/j.ijcard.2015.01.064 http://www.ncbi.nlm.nih.gov/pubmed/25666126
24 Japanese beta-Blockers and Calcium Antagonists Myocardial Infarction (JBCMI) Investigators. Comparison of the effects of beta blockers and calcium antagonists on cardiovascular events after acute myocardial infarction in Japanese subjects. Am J Cardiol 2004; 93: 969–73. doi:10.1016/j.amjcard.2004.01.006 http://www.ncbi.nlm.nih.gov/pubmed/15081437
25 Tsuburaya R, Takahashi J, Nakamura A, et al. Beneficial effects of long-acting nifedipine on coronary vasomotion abnormalities after drug-eluting stent implantation: the novel study. Eur Heart J 2016; 37: 2713–21. doi:10.1093/eurheartj/ehw256 http://www.ncbi.nlm.nih.gov/pubmed/27354043
26 Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020; 382: 1395–407. doi:10.1056/NEJMoa1915922 http://www.ncbi.nlm.nih.gov/pubmed/32227755
© 2020 Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Details
; Katsuki, Toshiomi 2 ; Kitai, Takeshi 3 ; Tamita, Koichi 4 ; Obunai, Kotaro 5 ; Ikegami, Yukinori 6 ; Yamane, Takafumi 3 ; Ueda, Ikuko 2 ; Endo, Ayaka 7 ; Maekawa, Yuichiro 8 ; Kawamura, Akio 9 ; Fukuda, Keiichi 2 ; Kohsaka, Shun 2 1 Department of Cardiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan
2 Department of Cardiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
3 Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Japan
4 Department of Cardiology, Nishinomiya Watanabe Cardiovascular Center, Nishinomiya, Hyogo, Japan
5 Department of Cardiology, Tokyo Bay Urayasu Ichikawa Medical Center, Ichikawa, Japan
6 Department of Cardiology, National Hospital Organisation Tokyo Medical Center, Meguro-ku, Tokyo, Japan
7 Department of Cardiology, Saiseikai Central Hospital, Minato-ku, Tokyo, Japan
8 Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
9 Department of Cardiology, International University of Health and Welfare Faculty of Medicine Graduate School of Medicine, Narita, Chiba, Japan