Abstract
Background:
The effect of remote ischemic preconditioning (RIPC) on periprocedural myocardial damage (pMD) in patients undergoing percutaneous coronary intervention (PCI) is controversial. The aim of this study was to investigate the effect of RIPC or intravenous nicorandil on pMD following elective PCI in a subgroup of patients with complex coronary lesions from a multicenter randomized controlled trial.
Methods and Results:
Patients with stable angina who underwent elective PCI were assigned to 3 groups: control, upper-limb RIPC or intravenous nicorandil. The major outcome was pMD incidence following PCI, with pMD defined as an elevated level of high-sensitivity cardiac troponin T or creatine kinase myocardial band at 12 or 24 h after PCI. A total of 171 patients with complex coronary lesions (ACC-AHA coronary classification type B2 or C) were analyzed. The incidence of pMD following PCI was significantly lower in the RIPC group than in the control group (44.4% vs. 66.1%; P=0.023). The adjusted odds ratio (95% confidence interval) for pMD in the RIPC vs. the controls was 0.41 (0.18−0.94). The incidence of pMD in the nicorandil group was not significantly reduced compared with the control groups.
Conclusions:
This substudy suggested that RIPC prior to PCI prevented pMD in patients with complex coronary lesions. Further investigation in a multicenter prospective study is needed to confirm these results.
Periprocedural myocardial damage (pMD) leads to adverse cardiac events during the long-term follow-up, even though technical advances in percutaneous coronary intervention (PCI) have resulted in a safe procedure with few complications.1,2
To reduce the incidence of pMD, a promising approach is remote ischemic preconditioning (RIPC), a phenomenon wherein challenging one or more organs with reversible ischemia leads to a protective effect for other remote organs by neurohormonal transduction.3–10
Another approach is to use of nicorandil, a hybrid adenosine triphosphate-sensitive potassium channel opener with nitrates.11–14
Our recent multicenter, randomized controlled trial (RCT) showed that RIPC and intravenous nicorandil moderately, but not significantly, reduced myocardial biomarkers following elective PCI.15
However, the question of which patients would benefit from RIPC remains open.
Editorial p ????
The risk factors for biomarker release after PCI have been reported; they include PCI lesion factors (e.g., disease burden, lesion complexity), patient-related factors, and procedural factors (e.g., dissection, stent overexpansion).16
In this secondary analysis, we investigated the effect of RIPC (and nicorandil) on pMD following PCI in a prespecified subgroup based on lesion complexity defined by the American College of Cardiology-American Heart Association (ACC-AHA) coronary classification (types A, B1, B2, C) or SYNTAX (Synergy between PCI with TAXUS drug-eluting stent and Cardiac Surgery) score.17
Methods
Study Design
This study was a prespecified subgroup analysis of a RCT (Cardiac Preconditioning Effect of Remote Ischemia and Nicorandil in Patients Undergoing Elective Percutaneous Coronary Intervention: RINC trial).15
Briefly, the RINC study was a prospective, open-label, multicenter RCT conducted at 18 hospitals between February 2011 and January 2013 (Supplementary File 1). The present study was conducted according to the principles expressed in the Declaration of Helsinki and approved by Okayama University Graduate School of Medicine, Density, and Pharmaceutical Sciences and Okayama University Hospital Ethics Committee as well as the ethics committees at each research facility (research collaborators are listed in
Supplementary File 1). The study was registered with the UMIN Clinical Trials Registry, June 2011 (UMIN000005607, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006626).
This study was supported by a grant from the Okayama Medical Foundation. The trial was conducted and the manuscript written by the authors (details are provided in
Supplementary File 1), who decided to submit the manuscript for publication. The authors had no conflicts of interest in regard to this study. The funding agencies had no access to the trial data and no role in the trial design, implementation, or reporting. No sponsorship or funding from industry or for-profit sources was received for the trial.
Participants
Patients were randomly assigned in a 1:1:1 ratio to control, intravenous nicorandil, and RIPC groups. Eligible patients were adults (>20 years old) who had been diagnosed with silent myocardial ischemia or stable angina and were awaiting elective PCI. Each provided written informed consent. Patients were excluded if they had any contraindication for upper-limb compression as RIPC (e.g., aortovenous shunt in the arm), or to intravenous nicorandil administration (e.g., previous experience of pMD following PCI, acute coronary syndrome, planned elective PCI for chronic total occlusion, or therapies performed with a RotablatorTM
(Boston Scientific, Natick, MA, USA); adverse prognostic factors such as use of glibenclamide for diabetes, or survival prognosis <12 months).
This prespecified subgroup analysis sought to identify any myocardial protective effect of RIPC during elective PCI in patients with complex coronary lesions. Coronary lesions were assigned using the ACC-AHA lesion classification types (A, B1/B2 and C) or SYNTAX score. Although the aim of this study was to identify the effect of RIPC on pMD in patients with complex coronary lesions, a nicorandil group was also included in this study based on the RINC study design.
Interventions
The intervention protocol and PCI procedure are described in detail elsewhere.15
In brief, the RIPC group underwent pretreatment of upper-limb compression of 200 mmHg followed by decompression (3 cycles in total, 5-min inflation and deflation of a blood pressure cuff, at least 1 h before PCI) using a newly developed, automated continuous blood pressure device (FB-270; Fukuda Denshi, Tokyo, Japan). The nicorandil group underwent a single injection of nicorandil (4 mg) at 1 h before PCI and then a continuous infusion (6 mg/h) for not less than 8 h.
PCI was performed in a conventional manner and the exact procedure depended on the local interventional cardiologist. The complexity of the coronary lesions was assessed according to the ACC-AHA classification (types A and B1 or B2 and C). All procedures were conducted according to the protocol of each hospital. The perfusion status of the target-related coronary artery was determined in accordance with the Thrombolysis in Myocardial Infarction (TIMI) study classification.18
The final TIMI flow grade was assessed from the final angiographic image. The indications for PCI included severe coronary stenosis on coronary angiography (≥1.5 mm in diameter with ≥75% stenosis, as identified by the local interventional cardiologist). Fractional flow reserve was not assessed in the original study. PCI success was defined as <50% stenosis in the luminal diameter after balloon angioplasty or <25% after coronary stent implantation assessed by visual estimation on the angiograms after the procedure once the safety and efficacy of the procedure was confirmed by the operator.
Randomization was conducted by the Clinical Trials Unit based at Okayama University via a secure website and stratified using random permuted blocks to balance for age (<65 years or ≥ 65 years), sex, renal dysfunction [estimated glomerular filtration rate (eGFR) at baseline <60 or ≥60 mL/min/1.73 m2), and PCI center. All participants provided written informed consent before enrolling.
Outcomes
Definitions of the major outcomes in the RINC trial have been published elsewhere.15
The primary outcome was the incidence of pMD following PCI, which was defined as an elevated level of high-sensitivity cardiac troponin T (cTnT: >0.07 ng/mL) or creatine kinase myocardial band (CK-MB: >10 ng/mL) and a CK-MB/creatinine kinase ratio >5% at 12 or 24 h after PCI. The definition was based on the diagnostic criteria for myocardial injury associated with PCI from the 3rd universal definition of myocardial infarction.19
Blood samples to test for high-sensitivity cTnT (99th percentile upper reference limit 0.014) and CK-MB were collected at 12 and 24 h after PCI. To avoid inter-hospital variation in the levels of high-sensitivity cTnT and CK-MB, these markers were evaluated at a single institution (SRL Inc. Hachioji Laboratory, Tokyo, Japan). Study investigators who collected and analyzed the data were blinded to the treatment assignments.
The secondary outcomes were adverse clinical events, including ischemic events during PCI (i.e., procedural success rate, chest pain during PCI, ST segment change on ECG, ventricular arrhythmia needed for cardioversion, final TIMI flow grade) or clinical events at 8 months after PCI (all-cause death, admission for acute coronary syndrome, any revascularization, admission for heart failure, stroke).
In addition to assessing predictors related to the incidence of pMD following PCI, we performed multiple logistic regression analyses of the 3 groups. The regression models were adjusted for the risk factors of biomarker release after PCI that had been reported in a previous study.16
Statistical Analysis
Data were analyzed according to a predefined statistical analysis plan, and an independent statistician verified and replicated the analyses. Continuous variables are presented as mean±standard deviation or as median with the interquartile range, depending on the Shapiro-Wilks test for normality. Categorical variables are presented as absolute values and proportions (%).
Analysis of variance or the Kruskal-Wallis test was used to compare continuous variables among the study groups. The χ2
test was used to compare categorical variables among the groups. A post-hoc test was not applied because we did not directly compare the RIPC group with the nicorandil group. In the primary analysis, the χ2
test was used to compare the proportion of pMD following PCI between the control and RIPC groups or the control and nicorandil groups. A logistic regression model or Cox’s proportional hazard model was used to estimate hazard ratios between treatment groups.
We also assessed cTnT and CK-MB as continuous variables. To account for correlations among repeated measurements, we used a repeated-measures linear mixed-effects model. Independent variables in this model were log-transformed baseline cTnT or CK-MB, age category, sex, chronic kidney disease status, treatment arm, scheduled visit as a class variable (12 h, 24 h), and the interaction between the arm and the visit, with the use of an unstructured covariance matrix.
A multiple logistic regression model was used to calculate the odds ratio (OR) among study groups with adjustments for conventional pMD risk factors.16
Risk factors included PCI lesion factors, such as the total stent length in the PCI (centimeters), with or without the stent after dilation; patient factors such as age (<65 vs. ≥65 years), with or without diabetes, with or without hypertension, and with or without chronic kidney disease (baseline eGFR <60 or ≥60 mL/min/1.73 m2
because no data reflecting albuminuria were collected in the RINC study); and procedural factors, such as the final TIMI flow grade during PCI and maximum dilation pressure (atmospheres).
All analyses were performed with R version 3.2.3 software (The R Foundation for Statistical Computing, Vienna, Austria) and SAS version 9.3 software (SAS Institute Inc., Cary, NC, USA). Values of P<0.05 were considered to indicate statistical significance.
Results
Study Population
Figure 1
shows the flow diagram for the study. The RINC study consisted originally of 391 patients who were suitable for full analysis including the control (n=133), RIPC (n=129), and nicorandil groups (n=129). Of the 171 patients who underwent PCI for complex coronary lesions (ACC-AHA types B2 and C), 56 served as the control group, 54 were in the RIPC group, and 61 were in the nicorandil group (Figure 1). Baseline patient characteristics of those with ACC-AHA type B2 and C lesions among those groups are shown in
Table 1. There were no significant differences among the 3 groups, except for oral nicorandil use (control: 67.9%, RIPC: 42.6%, nicorandil: 36.1%, P=0.045). Procedural characteristics also were not significantly different among the groups (Table 2). In addition to ACC-AHA classification, we also assessed SYNTAX scores before PCI. Because the median SYNTAX score was 7 (interquartile range: 4–13), a high SYNTAX score was defined as >7 in this study. Of the 147 patients with high SYNTAX scores, 52 served as the control group, 49 constituted the RIPC group, and 46 constituted the nicorandil group (Figure 1). Patients’ characteristics in the high SYNTAX score group were also well-balanced (Tables S1,S2). PCI was performed successfully in all groups.
Table 1.
Baseline Characteristics of Patients With ACC-AHA Type B2/C Lesions
| |
Control
(n=56) |
RIPC
(n=54) |
Nicorandil
(n=61) |
P value |
| Age, years |
71.6±8.9 |
70.7±8.6 |
69.4±9.4 |
0.41 |
| Male, n (%) |
41 (73.2) |
40 (74.1) |
49 (80.3) |
0.61 |
| BMI (kg/m2) |
23.9±2.9 |
24.6±3.2 |
25.0±3.2 |
0.138 |
| Stable angina, n (%) |
| Symptomatic |
38 (67.9) |
39 (72.2) |
41 (67.2) |
0.82 |
| Asymptomatic |
18 (32.1) |
15 (27.8) |
20 (32.8) |
|
| Prior diagnoses, n (%) |
| Diabetes |
31 (55.4) |
30 (55.6) |
29 (47.5) |
0.61 |
| Use of insulin |
7 (12.5) |
5 (9.3) |
7 (11.5) |
0.86 |
| Hypertension |
46 (82.1) |
45 (83.3) |
54 (88.5) |
0.59 |
| Dyslipidemia |
43 (76.8) |
49 (90.7) |
51 (83.6) |
0.142 |
| Renal dysfunction |
24 (42.9) |
23 (42.6) |
25 (41.0) |
0.98 |
| CCV event history |
35 (62.5) |
22 (40.7) |
29 (47.5) |
0.064 |
| Smoking history, n (%) |
| Current smoker |
6 (10.7) |
6 (11.1) |
6 (9.8) |
1.00 |
| Ex-smoker |
29 (51.8) |
29 (53.7) |
32 (52.5) |
|
| Echocardiographic parameters at randomization |
| LVEF (%) |
60.0±10.2 |
62.7±10.7 |
62.7±9.5 |
0.30 |
| E/e’ |
13.6 (9.7–15.5) |
13.5 (10.4–16.6) |
12.9 (9.9–16.1) |
0.73 |
| Laboratory data at randomization |
| Hemoglobin (g/dL) |
12.8±1.7 |
14.0±4.0 |
13.5±3.6 |
0.170 |
| Platelets (104/μL) |
20.1±6.0 |
21.0±6.4 |
20.9±5.5 |
0.66 |
| Total cholesterol (mg/dL) |
158 (136–176) |
158 (140–172) |
157 (136–174) |
0.90 |
| eGFR (mL/min/1.73 m2) |
65.0±17.7 |
65.3±19.2 |
63.8±20.8 |
0.92 |
| HbA1c (%) |
6.0 (5.4–6.5) |
6.1 (5.5–6.8) |
5.9 (5.3–6.5) |
0.28 |
| CRP (mg/dL) |
0.12 (0.05–0.33) |
0.10 (0.06–0.30) |
0.12 (0.07–0.22) |
0.85 |
| BNP (pg/mL) |
37.9 (21.5–64.4) |
33.4 (18.1–97.8) |
38.8 (18–72.8) |
0.98 |
| Myocardial biomarkers at randomization |
| cTnT (ng/mL) |
0.013 (0.009–0.022) |
0.010 (0.006–0.022) |
0.012 (0.007–0.019) |
0.42 |
| CK-MB (ng/mL) |
3.8 (2.7–4.9) |
3.5 (2.2–4.5) |
3.7 (2.7–4.9) |
0.48 |
| Medications at randomization, n (%) |
| Antiplatelet drugs |
56 (100) |
53 (98.1) |
61 (100) |
0.34 |
| β-blockers |
25 (44.6) |
29 (53.7) |
31 (50.8) |
0.62 |
| ACEI/ARB |
38 (67.9) |
30 (55.6) |
43 (70.5) |
0.21 |
| CCB |
24 (42.9) |
27 (50) |
31 (50.8) |
0.65 |
| Statins |
47 (83.9) |
46 (85.2) |
51 (83.6) |
0.97 |
| Oral nicorandil |
38 (67.9) |
23 (42.6) |
22 (36.1) |
0.045 |
Data are mean±standard deviation, n (%) or median (interquartile range). Renal dysfunction is defined as baseline eGFR <60 mL/min/1.73 m2. ACC, American College of Cardiology; ACEI, angiotensin-converting enzyme inhibitor; AHA, American Heart Association; ARB, angiotensin II receptor blocker; BMI, body mass index; BNP, B-type natriuretic peptide; CCB, calcium-channel blocker; CCV, cardio-cerebrovascular; CK, creatine kinase myocardial band; CRP, C-reactive protein; cTnT, cardiac troponin T; DM, diabetes mellitus; E, peak velocity of early diastolic filling wave; e’, mitral annulus velocity; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; LVEF, left ventricular ejection fraction; RIPC, remote ischemic preconditioning.
Table 2.
Procedural Characteristics of Patients With ACC-AHA Type B2/C Lesions
| |
Control
(n=56) |
RIPC
(n=54) |
Nicorandil
(n=61) |
P value |
| ACC-AHA coronary classification |
| Type C, n (%) |
16 (28.6) |
16 (29.6) |
15 (24.6) |
0.81 |
| SYNTAX score |
7.5 (4.0–16.0) |
8.0 (5.0–11.8) |
7.0 (4.3–13.0) |
0.82 |
| Target vessel, n (%) |
| LAD |
21 (37.5) |
25 (46.3) |
17 (27.9) |
0.187 |
| LCX |
8 (14.3) |
7 (13.0) |
17 (27.9) |
|
| RCA |
21 (37.5) |
20 (37.0) |
22 (36.1) |
|
| Multiple |
6 (10.7) |
2 (3.7) |
5 (8.2) |
|
| Amount of contrast medium (mL) |
114 (70–110) |
101 (80–127) |
106 (82–140) |
0.46 |
| PCI operation time (min) |
83 (61–111) |
77 (58–95) |
83 (60–105) |
0.40 |
| Puncture site, n (%) |
| Radial artery |
25 (44.6) |
27 (50) |
37 (60.7) |
0.34 |
| Brachial artery |
11 (19.6) |
6 (11.1) |
8 (13.1) |
|
| Femoral artery |
20 (35.7) |
21 (38.9) |
16 (26.2) |
|
| Catheter size, n (%) |
| 6Fr |
44 (78.6) |
41 (75.9) |
54 (88.5) |
0.119 |
| 7Fr |
10 (17.9) |
13 (24.1) |
7 (11.5) |
|
| 8Fr |
2 (3.6) |
0 |
0 |
|
| Device information |
| No. of stents used |
1 (1–2) |
1 (1–2) |
1 (1–2) |
0.25 |
| DES, n (%) |
50 (89.3) |
48 (88.9) |
55 (90.2) |
0.86 |
| Maximal stent diameter (mm) |
3.0 (2.5–3.5) |
3.0 (2.5–3.5) |
3.0 (2.5–3.5) |
0.89 |
| Total stent length (mm) |
33 (19–47) |
28 (23–40) |
24 (18–38) |
0.24 |
| Post dilatation, n (%) |
45 (80.4) |
45 (83.3) |
47 (77.1) |
0.77 |
| Maximal dilatation pressure (atm) |
16.5±4.5 |
16.8±4.6 |
16.6±4.1 |
0.95 |
Data are mean (standard deviation) or n (%) or median (interquartile range). atm, atmospheres; DES, drug-eluting stent; LAD, left anterior descending artery; LCX, left circumflex artery; PCI, percutaneous coronary intervention; RCA, right coronary artery; SYNTAX, Synergy between PCI with TAXUS drug-eluting stent and Cardiac Surgery. Other abbreviations as in Table 1.
Figure 2
shows the incidence of pMD in patients classified by complexity of coronary artery disease (CAD). The incidence of pMD was significantly different between patients with ACC-AHA coronary classification type A/B1 and B2/C [62/168 patients (36.9%) vs. 91/171 patients (53.2%), respectively; P=0.002]. The incidence of pMD in the RIPC group was significantly lower in patients with ACC-AHA coronary classification B2/C than in the control group [24/54 patients (44.4%) vs. 37/56 patients (66.1%), respectively; P=0.023]. These proportions in the nicorandil group, however, were not significantly different from those in the control group [30/61 patients (49.2%) vs. 37/56 patients (66.1%), respectively; P=0.065]. In contrast, the incidence of pMD was not significantly different among the 3 groups for patients with ACC-AHA coronary classification A/B1 (RIPC: 39.3%, nicorandil: 31.3%, vs. controls: 39.3%; P=0.99 and 0.38, respectively) (Figure 2A).
In the SYNTAX score analysis, the incidence of pMD was not significantly different between patients with low (≤7) and high (>7) SYNTAX scores [69/165 patients (41.8%) vs. 72/147 patients (49.0%); P=0.20]. We also found no significant difference in the incidence of pMD among the 3 groups for patients with high SYNTAX score (RIPC: 42.9%, nicorandil: 54.3%, vs. control: 50.0%; P=0.47 and 0.67, respectively). In contrast, in the low SYNTAX score group, the incidence of pMD was significantly different among the 3 groups (RIPC: 42%, nicorandil: 31.6%, vs. control: 51.7%; P=0.31 and 0.029, respectively) (Figure 2B).
In addition, the quantitative analyses of cTnT and CK-MB in a repeated-measures linear mixed-effects model were performed using data from patients with ACC-AHA coronary classification B2/C (Figure 3). Interactions between the time period and the 3 treatment arms for cTnT and CK-MB were not statistically significant (P=0.53 and P=0.54, respectively).
There was no significant difference in the incidence of adverse clinical events between the RIPC/nicorandil and control groups for patients with ACC-AHA coronary classification B2/C (Table 3).
Table 3.
Adverse Clinical Events in Patients With ACC-AHA Type B2/C Lesions
| |
Control
(n=56) |
RIPC
(n=54) |
OR/HR
(95% CI) |
P value |
Nicorandil
(n=61) |
OR/HR
(95% CI) |
P value |
| Ischemic events during PCI, n (%)† |
| Procedural success rate |
56 (100) |
54 (100) |
|
|
61 (100) |
|
|
| Chest pain during PCI |
7 (12.5) |
7 (13.0) |
1.04
(0.34–3.2) |
0.94 |
6 (9.8) |
0.76
(0.24–2.43) |
0.29 |
| ST-segment change on ECG |
9 (16.1) |
10 (18.5) |
1.19
(0.44–3.19) |
0.73 |
11 (18.0) |
1.15
(0.44–3.02) |
0.61 |
Ventricular arrhythmia needing
cardioversion |
0 |
0 |
|
|
0 |
|
|
| Final TIMI grade |
| 3 |
54 (96.4) |
53 (98.1) |
1.47
(0.24–9.13) |
0.68 |
60 (98.4) |
0.95
(0.19–4.83) |
0.95 |
| 0–2 |
2 (3.6) |
1 (1.9) |
|
|
1 (1.6) |
|
|
Adverse clinical events at
8 months after PCI, n (%)‡ |
5 (8.9) |
6 (11.1) |
1.28
(0.39–4.18) |
0.69 |
4 (6.6) |
0.76
(0.20–2.84) |
0.69 |
| All-cause death |
0 |
0 |
|
|
0 |
|
|
| Acute coronary syndrome |
0 |
0 |
|
|
0 |
|
|
| Revascularization |
4 (7.1) |
4 (7.4) |
1.07
(0.27–4.27) |
0.93 |
3 (4.9) |
0.72
(0.16–3.20) |
0.66 |
| PCI |
4 |
4 |
|
|
3 |
|
|
| CABG |
0 |
0 |
|
|
0 |
|
|
| Unknown |
0 |
0 |
|
|
0 |
|
|
| Admission for heart failure |
1 (1.8) |
2 (3.7) |
2.11
(0.19–23.3) |
0.54 |
1 (1.6) |
0.94
(0.06–15.1) |
0.97 |
| Stroke |
0 |
1 (1.9) |
0.85
(0.37–1.97) |
0.70 |
0 |
|
|
Data are n (%). †Logistic regression model was used to calculate ORs between study groups for perioperative myocardial injury and ischemic events during PCI. ‡Cox’s proportional hazard model was used to estimate HRs between treatment groups for adverse clinical events for 8 months after PCI. CABG, coronary artery bypass grafting; CI, confidence interval; HR, hazard ratio; OR, odds ratio; TIMI, Thrombolysis in Myocardial Infarction. Other abbreviations as in Tables 1,2.
In an analysis adjusted for conventional pMD risk factors, RIPC was also effective in reducing the incidence of pMD when compared with the control group (Table 4). The adjusted analysis suggested that RIPC was a myocardial protective factor following PCI [adjusted OR (95% confidence interval (CI): 0.41 (0.18−0.94); P=0.035], and that the use of longer stents was an independent predictor of pMD following PCI [adjusted OR (95% CI): 1.33 (1.09−1.64); P=0.006].
Table 4.
Logistic Regression Models for Remote Ischemic Preconditioning and Risk Factors for Periprocedural Myocardial Damage Following PCI in Patients With ACC-AHA Types B2/C Lesions (n=171)
| Factor |
Unadjusted |
Adjusted |
| OR (95% CI) |
P value |
OR (95% CI) |
P value |
| Intervention |
| Control |
Ref. |
– |
Ref. |
– |
| Remote ischemic preconditioning |
0.41 (0.19–0.89) |
0.024 |
0.41 (0.18–0.94) |
0.035 |
| Nicorandil |
0.50 (0.24–1.05) |
0.067 |
0.54 (0.24–1.20) |
0.131 |
| Lesion factor |
| Stent total length (per 10 mm) |
1.36 (1.11–1.65) |
0.002 |
1.33 (1.09–1.64) |
0.006 |
| Stent post dilatation |
1.92 (0.86–4.30) |
0.111 |
1.46 (0.59–3.62) |
0.41 |
| Patient factor |
| Age (≥65 years) |
1.11 (0.55–2.24) |
0.77 |
0.73 (0.33–1.63) |
0.45 |
| Diabetes |
1.47 (0.81–2.70) |
0.21 |
1.29 (0.66–2.53) |
0.45 |
| Hypertension |
1.40 (0.60–3.23) |
0.43 |
1.42 (0.54–3.75) |
0.48 |
| CKD (<60 mL/min/1.73 m2) |
1.30 (0.70–2.39) |
0.41 |
1.42 (0.72–2.80) |
0.32 |
| Procedural factor |
| Final TIMI grade |
1.68 (0.57–4.95) |
0.35 |
1.68 (0.52–5.43) |
0.38 |
| Maximal dilatation pressure (mmHg) |
1.06 (0.98–1.13) |
0.131 |
1.03 (0.95–1.11) |
0.49 |
CKD, chronic kidney disease; OR, odds ratio. Other abbreviations as in Tables 1,3.
Discussion
In this prespecified subgroup analysis of a multicenter RCT, we found that the incidence of pMD following PCI in patients with stable angina and complex coronary lesions (ACC-AHA types B2/C) was significantly higher than the incidence in patients with simple lesions (types A/B1). RIPC significantly reduced the incidence of pMD following PCI in patients with ACC-AHA type B2/C lesions and intravenous nicorandil moderately reduced the incidence of pMD following PCI in this same population, although the difference was not statistically significant. In the adjusted analysis, RIPC also showed a myocardial protective effect, whereas stent length had a contrasting effect on myocardial injury. Finally, there was no significant difference among the study groups in the incidence of pMD following PCI for patients with high SYNTAX score (>7).
These substudy results are reasonable outcomes for our hypothesis that RIPC could effectively reduce the incidence of pMD following PCI in patients with ACC-AHA type B2/C lesions. Such patients have numerous patient-related risk factors for pMD16
and a number of lesion-related risk factors as well, including disease burden, calcification, lesion eccentricity, and thrombus,20,21
which explains the high incidence of pMD in this study. Previous basic studies have reported that RIPC offers an organ-protective effect partly by stimulating the neurohumoral pathway.3,22
Protective signals can be transferred with plasma-derived dialysate and the transfers involve nitric oxide, stromal-derived factor-1α, microribonucleic acid-144, and other factors. Intracardiac signal transduction involves specific receptors (adenosine, bradykinin, cytokines, chemokines), intracellular signal transduction (e.g., nitric oxide) and mitochondrial function. Although the mechanism of pMD reduction by RIPC in patients with complex coronary lesions has not been fully clarified, RIPC may be more appropriate for such patients than for those with simple coronary lesions.
In contrast to the analysis by ACC-AHA type, our study failed to demonstrate a beneficial effect of RIPC in patients with high SYNTAX scores. We believe there are several reasons for this result. First, overall SYNTAX scores in this study were low. Because this was a RCT, patients with a high risk for PCI may have been excluded. Second, even in patients with high SYNTAX scores with multivessel disease, revascularization with PCI was performed for a single coronary disease in the original study. Therefore, the incidence of pMD did not differ between patients with low vs. high SYNTAX scores. Finally, the SYNTAX score does not assess the severity of single-target lesions, but instead predicts the prognosis based on the anatomy of the entire coronary vasculature.23
Therefore, the ACC-AHA coronary lesion classification may better reflect lesion complexity at the PCI site and predict pMD following PCI for single-target lesions, compared with the SYNTAX score.
Only a few single-center studies with small sample sizes have used RIPC in patients undergoing elective PCI, and the subgroup or exploratory analysis in those studies has been insufficient. The RINC study was the largest multicenter clinical trial for patients with elective PCI, which allowed us to conduct this subanalysis to identify the patient group for which RIPC was most effective during elective PCI. RIPC is a favorable, low-cost, safe treatment that provides myocardial protection. It does, however, cause more stress (e.g., pain, compression, and discomfort) to patients. The results of this study suggested that RIPC might be more effective for a specific patient group: those with complex coronary lesions (ACC-AHA types B2/C). Therefore, further prospective studies to evaluate the effect of RIPC on myocardial protection in these patients are needed.
Because nicorandil activates a potassium channel in mitochondria, which plays a beneficial role in ischemic preconditioning, it could protect against pMD. Oral administration of nicorandil in patients with stable angina significantly reduced the number of major coronary events in a RCT.11
In addition, previous studies have shown that periprocedural intravenous nicorandil reduced both myocardial biomarkers following PCI and the slow-flow phenomenon.12–14
The RINC study, however, did not show a significantly reduced incidence of pMD following PCI when periprocedural intravenous nicorandil was administered to patients with stable CAD. We believe that the particular population of stable angina patients and the high incidence of pMD in the control group might have affected the results for intravenous nicorandil and pMD in the original study.15
In the current substudy, we found a lower but not significant incidence of pMD in patients in the nicorandil group compared with the control group. Although the populations in this substudy included high-risk patients, each group size was smaller than in the original study. Therefore, statistical under-power might have affected the results for the effect of intravenous nicorandil on pMD in this substudy.
Study Limitations
First, the study was a prespecified subgroup analysis of a RCT. Although the RINC study was the largest RCT of RIPC in patients with elective PCI, the study sample size was somewhat small because of the subgroup analysis. Second, because the RINC study was designed to separately compare RIPC and nicorandil groups with a control group, we could not evaluate the difference between them in this prespecified subgroup analysis. Third, because the ACC-AHA coronary classification was not performed in a core laboratory, the definition depended on each hospital’s assessment. Finally, although there are other coronary classification systems available,24
coronary lesion complexity in the present study was defined by the ACC-AHA classification or SYNTAX score system because our study did not provide the data needed for the other systems. In addition, intravascular imaging data were not available in this study.
In conclusion, this secondary analysis of the RINC study, conducted as a multicenter RCT, revealed that upper-limb RIPC significantly reduced the incidence of pMD following PCI in patients with complex coronary lesions (ACC-AHA types B2/C). These results suggested that RIPC might offer effective myocardial protection for patients undergoing PCI. Further investigation in a multicenter prospective study is needed to confirm the favorable effect of RIPC on pMD following PCI in patients with complex coronary lesions.
Acknowledgments
We thank Tetsutaro Hamano, MS, for his assistance in the study design and statistics.
Disclosures
This study was supported by a grant from the Okayama Medical Foundation. The authors had no conflicts of interest in regard to this study.
Presented in part at the European Society of Cardiology congress 2016, Rome, Italy on August 29, 2016, and as Late-Breaking Clinical Trial at the 81st Annual Scientific Meeting of the Japanese Circulation Society, Kanazawa, Japan on March 17, 2017.
K.E., T.M., and K.K. contributed to the study design. K.E., T.M., K.K., T.H., K.N., and H.I. contributed to data interpretation and drafting of the manuscript. All authors have read, and confirm that they meet, ICMJE criteria for authorship.
Conflict of Interest Statement
The investigators had no conflict of interest about this study. This study was funded by the Okayama Medical Foundation, which is a nonprofit institution. It was not involved in the design of the protocol, the conduct of the study, or the analyses or reporting of the data.
Appendix
The RINC study collaborators, in addition to the authors, are Yusuke Kawai, MD, PhD; Tetsuya Satoh, MD, PhD; Katsumasa Satoh, MD, PhD; Takefumi Oka, MD, PhD; Natsuki Takahashi, MD, PhD; Satoru Sakuragi, MD, PhD; Atsushi Mima, MD, PhD; Kenki Enko, MD, PhD; Shingo Hosogi, MD, PhD; Seiji Nanba, MD, PhD; Ryoichi Hirami, MD, PhD, Yasukazu Fujiwara, MD; Yoshimasa Morimoto, MD; Shunji Suemaru, MD; and Toshiaki Yamanaka, MD.
Supplementary Files
Supplementary File 1
Trial Protocol
Table S1.
Characteristics of patients in the high SYNTAX score group
Table S2.
Procedural characteristics of the patients in the high SYNTAX score group
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-17-1000
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