Effect of One-Cycle Remote Ischemic Preconditioning to Reduce Myocardial Injury During Percutaneous Coronary Intervention Theodoros A. Zografos, PhD, MSc, MDa,b, George D. Katritsis, MDc, Ioannis Tsiafoutis, MDa, Nikolaos Bourboulis, PhDa, Apostolos Katsivas, PhDa, and Demosthenes G. Katritsis, PhDb,* Up to 1/3 of percutaneous coronary interventions (PCIs) are complicated by troponin release. Remote ischemic preconditioning (IPC) confers effective cardioprotection; however, a 30-minute remote IPC protocol may be difficult to implement during ad hoc PCI. This study was performed to assess the ability of a brief remote IPC protocol to attenuate cardiac troponin I (cTnI) release after ad hoc PCI. Ninety-four patients undergoing ad hoc PCI for stable coronary artery disease, with undetectable preprocedural cTnI, were recruited and randomized to receive remote IPC (induced by one 5-minute inflation of a blood pressure cuff to 200 mm Hg around the upper arm) or control after the decision for PCI was made. The primary outcome was the difference between cTnI levels 24 hours after PCI and cTnI levels before coronary angiography (DcTnI). DcTnI in the remote IPC group was significantly lower compared with the control group (0.04 ng/ml [interquartile range 0.01 to 0.14] vs 0.19 ng/ml [interquartile range 0.18 to 0.59], p 0.04 ng/ml at the time of admission, (3) use of nicorandil or glibenclamide, and (4) renal dysfunction, defined as glomerular filtration rate 60 ml/min/1.73 m2. All patients had to provide a signed informed consent to be included in the study. The study was approved by the local ethics committee and was registered to the ClinicalTrials.gov database (NCT01158716). All participants had a blood pressure cuff placed around their nondominant arm. When the decision for PCI was made, patient allocation was revealed and those patients randomized to remote IPC had the cuff inflated to a pressure of 200 mm Hg for 5 minutes, followed by 1 minute of reperfusion before guiding catheter advancement. Control patients had a similar cuff placed around their arm, but it was not inflated. All patients received acetylsalicylic acid 300 mg and clopidogrel 300 mg at least 6 hours (or 600 mg of clopidogrel >2 hours) before PCI. Unfractionated heparin was administered as an intravenous bolus at a dose of 70 to 100 IU/kg after arterial sheath insertion to achieve an activated clotting time of >250 seconds. Use of glycoprotein IIb/IIIa inhibitors was at the operators’ discretion. All patients received drug-eluting stents. After the procedure, all patients received acetylsalicylic acid 100 mg and clopidogrel 75 mg. All other medication was given at the discretion of the attending physician, and the PCI strategy was at the discretion of the interventional cardiologist according to conventional practice. www.ajconline.org

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Figure 1. Flowchart of the study. CA ¼ coronary angiography; CABG ¼ coronary artery bypass graft; cTnI ¼ cardiac troponin I; IPC ¼ ischemic preconditioning; PCI ¼ percutaneous coronary intervention.

Table 1 Baseline patient characteristics Variable

Demographics Age (years) Men Risk factors Diabetes mellitus Dyslipidemia Active or ex-smoker BMI (kg/m2) Hypertension Clinical details LVEF (%) Previous MI CCS grade III/IV GFR (mL/min/1.73 m2) Medications b-blockers ACEIs/ARBs Statins

Control (n ¼ 47)

Remote Ischemic Preconditioning (n ¼ 47)

P

60.8  10.4 41 (87%)

60.2  10.9 42 (89%)

0.765 0.748

8 (17%) 35 (75%) 28 (60%) 27.6  2.8 39 (83%)

10 (21%) 32 (68%) 27 (58%) 29.1  3.5 38 (81%)

0.600 0.494 0.845 0.02 0.789

57.2  9.9 10 (21%) 10 (21%) 88.3  17.9

55.5  8.4 9 (19%) 13 (28%) 88.4  17.7

0.389 0.797 0.472 0.970

39 (83%) 33 (70%) 46 (98%)

38 (81%) 35 (75%) 44 (94%)

0.789 0.645 0.617

During PCI, chest pain severity was assessed with a 10point scale (0: no pain, 10: most severe discomfort ever experienced) and the electrocardiogram was monitored for ST-segment deviation. Venous blood samples were obtained before coronary angiography and at 24 hours after PCI. cTnI was analyzed with an automated immunoassay (Bayer ADVIA IMS Troponin-I Ultra method; Bayer, Berlin, Germany). The

ninety-ninth percentile of the cTnI level in a reference population (upper reference limit) of healthy volunteers was below the lower limit of detection of 0.04 ng/ml. The coefficient of variation of the assay was 0.20 ng/ml was predetermined (5 times the upper reference limit). Serum creatinine at the time of admission was used to estimate the glomerular filtration rate with the Modification of Diet in Renal Disease formula. The volume of myocardium subtended by a stenosis, that is, the myocardium at risk, was assessed by reference to the target vessel using the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) lesion score.12 Angiographic lesion characteristics were classified according to the modified American Heart Association/American College of Cardiology classification.13 The final result of stent implantation was assessed by quantitative coronary angiography. Postprocedural assessment of Thrombolysis In Myocardial Infarction flow score was performed by 2 interventional cardiologists, blinded to the cTnI results.14 Other periprocedural factors, such as length and type of implanted stent, duration and pressure of balloon inflations, or complications (coronary artery dissection, perforation, or jailed side branch with compromised flow), were recorded. The primary outcome measure was DcTnI, defined as cTnI at 24 hours after PCI minus cTnI before coronary angiography. Secondary outcomes were the effect of remote IPC on ischemic symptoms and electrocardiographic evidence of ischemia during coronary balloon occlusion. The sample size was determined assuming periprocedural DcTnI in the remote IPC group equal to 0.06 ng/ml, according to available evidence during study design.2 A sample size of 74 patients would be needed to detect a 2 times higher periprocedural DcTnI in the control group (a ¼ 0.05, b ¼ 0.2, statistical power ¼ 80%). Patients were allocated to treatment groups according to a computer-generated randomization procedure. The allocations were kept in sealed envelopes. Once a decision for PCI was made for an eligible patient, the group allocation was released to the study coordinator. Continuous variables are summarized as mean  SD or median (interquartile range) and were compared using Student t test or Mann-Whitney U test, as appropriate. Categorical data are expressed as frequencies (percentages) and were compared using Pearson chi-square test or Fisher’s exact test. Spearman correlation coefficient (rs) was used to assess variable relations. Using multiple linear regression and logistic regression, we investigated the association of DcTnI and type 4a MI with several parameters identified by univariate analysis. All analyses were performed with SPSS, version 21 (IBM Corporation, Armonk, New York). Results One hundred forty-three patients undergoing coronary angiography were assessed for eligibility. After excluding patients meeting prespecified criteria, a decision for ad hoc

Coronary Artery Disease/One-Cycle Remote Ischemic Preconditioning Table 2 Angiographic and procedural characteristics Variable

Control (n ¼ 47)

Angiographic parameters Target coronary artery Left anterior descending 23 (49%) Circumflex 6 (13%) Right 6 (13%) Combined 12 (26%) APPROACH score 37.4  18.3 Modified Rentrop score 0 36 (77%) 1 9 (19%) 2/3 2 (4%) Lesion type (AHA/ACC) A 14 (30%) B 23 (49%) C 10 (21%) Stenosis severity, % 85.8  8.6 Side branch >2 mm 16 (34%) Total Stent Length (mm) 23 (15-28) Systolic blood pressure (mm Hg) 132  18 Diastolic blood pressure (mm Hg) 76  9 Heart rate (bpm) 68.9  9.9 Chest pain score >1 28 (60%) ECG ST deviation >1 mm 18 (38%) Complications Dissection 2 (4%) Jailed side branch 4 (9%) Post-procedural coronary flow TIMI flow score 0-2 7 (15%) 3 40 (85%)

Remote Ischemic Preconditioning (n ¼ 47)

P

20 (43%) 5 (11%) 11 (23%) 11 (23%) 32.0  18.0

0.612

Remote Ischemic Preconditioning Stenosis severity

39 (83%) 7 (15%) 1 (2%) 0.492 13 (28%) 19 (40%) 15 (32%) 83.6  8.1 20 (43%) 26 (12-32) 129  14 73  9 71.2  8.6 22 (47%) 13 (28%)

0.203 0.396 0.713 0.371 0.174 0.237 0.301 0.380

1 (2%) 3 (6%)

1.00 0.677

1 (2%) 46 (98%)

0.059

Table 3 Multiple regression analysis of factors related to peri-procedural cTnI release

DcTnI Independent variables

APPROACH score Stenosis severity Remote Ischemic Preconditioning

Table 4 Logistic regression analysis with the occurrence of type 4a myocardial infarction as the dependent variable Variable

0.158 0.704

R2 ¼ 0.375

3

exp(B)

95% Confidence Interval

P-Value

3.43 1.22

1.03 e 11.37 1.09 e 1.37

0.044 0.001

balloon inflation in the remote IPC group was 4.06  0.55 minutes. At 24 hours after PCI, the increase in cTnI concentration (DcTnI) in the remote IPC group was significantly lower compared with the control group (0.04 ng/ml [interquartile range 0.01 to 0.14] vs 0.19 ng/ml [interquartile range 0.18 to 0.59], p