The optimal timing for non-cardiac surgery after percutaneous coronary intervention with drug-eluting stents

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The optimal timing for non-cardiac surgery after percutaneous coronary intervention with drug-eluting stents Cheol Ung Choi a , Seung-Woon Rha a,⁎, Zhe Jin a , Kang-yin Chen a , Yoshiyasu Minami a , Ji Hoon Kim a , Jin Oh Na a , Soon Yong Suh b , Jin Won Kim a , Eung Ju Kim a , Chang Gyu Park a , Hong Seog Seo a , Dong Joo Oh a a

Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea b Cardiovascular Center, Konkuk University Hospital, Seoul, Republic of Korea Received 29 May 2008; accepted 31 October 2008 Available online 14 December 2008

Abstract This study was to assess the optimal timing for non-cardiac surgery (NCS) after drug-eluting stents (DES) implantation in patients who are scheduled for NCS. In conclusions, patients undergoing early NCS within 3 months after the PCI with DES may associate with adverse outcomes. Therefore we suggest that NCS should be deferred at least 3 months after the DES implantation. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Drug-eluting stent; Percutaneous coronary intervention; Non-cardiac surgery

1. Introduction Although the introduction of drug-eluting stent (DES) has dramatically reduced the restenosis and related repeat percutaneous coronary intervention (PCI), however, the safety issue regarding stent thrombosis has recently been raised. If this safety issue is not obvious in patients who are scheduled for non-cardiac surgery (NCS), especially for the cancer patients strongly waiting early surgery, DES implantation may more durable and beneficial compared with bare metal stents (BMS). It has been suggested that NCS should be delayed six weeks after BMS implantation whenever possible because BMS are generally endothelialized after a course of antiplatelet therapy to prevent stent thrombosis [1,2]. However, in a DES environment, should further modifications be made to the clinical guidelines? Delayed endothelialization has been suggested with both sirolimus – (SES, Cypher™) and paclitaxel – (PES, Taxus™) eluting stents [3,4]. Elution of antiproliferative agents delays endothelialization [5,6], which, consequently, may increase the risk of stent thrombosis. Therefore, a prolonged course of antiplatelet therapy has been recommended with the use of DES [7]. However, there was no definite guideline about the optimal timing for NCS after PCI with DES. The aim of our study was to assess the safety and durability of DES in patients waiting ⁎ Corresponding author. Cardiovascular Center, Korea University Guro Hospital, 80, Guro-dong, Guro-gu, Seoul, 152-703, Republic of Korea. Tel.: +82 2 2626 3020; fax: +82 2 864 3062. E-mail address: [email protected] (SW Rha).

NCS, especially cancer patients requiring early surgery and to determine the optimal timing for elective NCS. 2. Methods 2.1. Subjects and study design A total 27 consecutive patients who were scheduled for elective NCS, were enrolled for the study. Pre-operative cardiac work up of the enrolled patients showed angiographically significant coronary lesions requiring elective revascularization before the NCS. All patients who were undergoing PCI with DES assigned to receive SES, PES or Zotarolimus-eluting stents (ZES; Endeavor™) before elective NCS. The choice of DES and deployment pressure was at the operator's discretion. All patients received pre-procedural oral aspirin (200 mg) and clopidogrel (Plavix®, 300–600 mg) was given as a loading dose either immediately before or during the PCI followed by aspirin 100 mg and clopidogrel 75 mg daily as the maintenance dose. Patients were assigned into two groups: The early surgery group was scheduled to receive NCS within 90 days after the index PCI and the late surgery group after 90 days. All the patients were encouraged to temporarily discontinue aspirin and clopidogrel 5 to 7 days before surgery and resume within 3 days after the surgery unless there were significant risks of postoperative bleeding complications. The written informed consent was obtained from all patients. From immediate after the surgery, serial post-operative cardiac enzymes including creatine kinase (CK) MB,

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Troponin T, and NT-pro BNP, Chest X-ray, ECG and cardiac echocardiography, if needed, were routinely followed up to post-operative 3 days. Type and details of surgery, use of antiplatelet therapy during the perioperative period, and the occurrence of in-hospital death, Q- and non-Q-wave myocardial infarction (MI), stent thrombosis, post-operative congestive heart failure, significant surgical bleeding complications, bleeding associated transfusions and repeat revascularization procedures with either CABG or repeat angioplasty of the target vessel were compared between the two groups. Special attention was given to assess the time of the discontinuation as well as restart of antiplatelet regimen during the peri-operative period.

when at least two of the following three criteria were met: 1) chest pain N30 min; 2) persistent electrocardiographic changes suggestive of ischemia; 3) characteristic elevations in serum CK MB (N 2 times normal). Q-wave MI and non-Qwave MI were defined as two above criteria with presence or absence of significant ST segment elevation in two or more consecutive leads or pathologic Q-waves on electrocardiogram. Bleeding complications were difficult to grade as many of the surgical procedures performed are considered inherently associated with high blood loss. Therefore, major bleeding episodes were defined as the postoperative need for transfusion or bleeding that necessitated for repeat surgical explorations.

2.2. Study definition

2.3. Statistical analysis

Death was defined as all-cause mortality. Peri-operative myocardial infarction (MI) was considered to have occurred

Continuous variables are presented as mean value ± S.D. and compared by Mann–Whitney U test. Categorical

Table 1 Baseline clinical characteristic and procedural details of the study population. Variables

NCS b 3 months (n = 17)

NCS N 3 months (n = 10)

Total (n = 27)

p-value

Age, years Interval between PCI and OP, days Male, n (%) Diabetes mellitus, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Smoking, n (%) Previous myocardial infarction, n (%) Previous PCI or CABG, n (%) CVA history, n (%) PVD history, n (%) Ejection fraction (%) Target vessel LAD, n (%) LCX, n (%) RCA, n (%) Multivessel, n (%) Saphenous vein, n (%) Lesion type B2, n (%) C, n (%) Stent type Cypher, n (%) Taxus, n (%) Endeavor, n (%) Cypher + Taxus, n (%) Number of stent, n (%) Number of target vessel, n (%) Stent diameter, n (%) Stent length, n (%) Diagnosis on PCI Myocardial infarction, n (%) Stable angina, n (%) Unstable angina, n (%) Others, n (%)

67.12 ± 7.89 44.59 ± 9.43 12 (70.6) 4 (23.5) 8 (47.1) 13 (76.5) 4 (23.5) 3 (17.6) 1 (5.9) 0 (0) 0 (0) 55.88 ± 8.68

68.5 ± 14.22 186.10 ± 88.45 7 (70.0) 4 (40.0) 7 (70.0) 7 (70.00) 4 (40.0) 1 (10.0) 1 (10.0) 1 (10) 0 (0) 54.50 ± 15.29

67.63 ± 10.43 97.00 ± 87.25 19 (70.4) 8 (29.6) 15 (55.6) 20 (74.2) 8 (29.6) 4 (14.8) 2 (7.4) 1 (3.7) 0 (0) 55.37 ± 11.30

0.359 b0.001 0.974 0.415 0.424 1.000 0.415 1.000 1.000 0.37 1.000 0.786

11 (64.7) 6 (35.3) 8 (47.1) 6 (35.3) 0 (0)

5 (50.0) 1 (10.0) 3 (30.0) 2 (20.0) 1 (10)

16 (3859.3) 7 (25.9) 11 (40.7) 8 (29.6) 1 (3.7)

0.687 0.204 0.448 0.666 0.370

4 (23.5) 13 (76.5)

2 (20.0) 8 (80.0)

6 (22.2) 21 (77.8)

1.000 1.000

6 (35.3) 12 (70.6) 1 (5.9) 2 (11.8) 2.24 ± 1.52 1.53 ± 0.72 2.72 ± 0.45 24.74 ± 4.04

5 (50.0) 5 (50.0) 0 (0) 0 (0) 1.20 ± 0.42 1.20 ± 0.42 2.97 ± 0.38 28.00 ± 6.18

11 (40.7) 17 (63.0) 1 (3.7) 2 (7.4) 1.85 ± 1.32 1.41 ± 0.64 2.81 ± 0.44 25.94 ± 5.08

0.687 0.415 1.000 0.516 0.059 0.334 0.264 0.155

1 (5.9) 12 (70.6) 4 (23.5) 0 (0)

0 (0) 6 (60.0) 3 (30) 1 (10)

1 (3.7) 18 (66.7) 7 (25.9) 1 (3.7)

1.000 0.683 1.000 0.370

NCS = non-cardiac surgery; OP = operation; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; CVA = cerebrovascular accident; PVD = peripheral vascular disease; LAD = left anterior descending coronary artery; LCX = left circumflex coronary artery; RCA = right coronary artery; PCI = percutaneous coronary intervention.

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Table 2 Duration of peri-operative discontinuation of antiplatelet agents and post-operative bleeding and clinical manifestations. Interval, days

NCS b 3 months (n = 17)

NCS N 3 months (n = 10)

Total (n = 27)

p-value

Duration of stop of antiplatelet agents (before surgery) Duration of stop of antiplatelet agents (after surgery) Duration of stop of antiplatelet agents (total duration) Bleeding Cx (Transfusion), n (%) Chest pain, n (%) ECG change, n (%) CK-MB N 2× normal, n (%) BNP elevation, n (%) Repeat CAG, n (%) ICU stays, days Hospital days, days

4.94 ± 0.89 7.35 ± 6.41 12.29 ± 6.96 4 (23.5) 2 (11.8) 0 (0) 3 (27.3) 2 (11.8) 1 (5.9) 0.53 ± 1.18 12.65 ± 9.16

5.00 ± 0.00 4.78 ± 3.19 9.78 ± 43.19 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0±0 12.80 ± 11.20

4.96 ± 0.71 6.46 ± 5.58 11.42 ± 5.98 4 (14.8) 2 (7.4) 0 (0) 3 (21.4) 2 (7.4) 1 (3.7) 0.33 ± 0.96 12.70 ± 9.75

1.000 0.287 0.339 0.264 0.516 1.000 1.000 1.000 1.000 0.473 0.902

NCS = non-cardiac surgery; Cx = complications; ECG = electrocardiogram; BNP = b-type natriuretic peptide; CAG = coronary angiography; ICU = intensive care unit.

variables are described as frequencies and percentages and were compared by Fisher exact test. A p-value of less than 0.05 was considered as statistically significant. 3. Results 3.1. Baseline characteristics Among 27 enrolled patients, 17 patients underwent surgery within 90 days (The early surgery group; average 44.59 ± 9.43 days) following DES implantation and 10 patients after 90 days (The late surgery group; average 186.10 ± 88.45 days, p b 0.001). Baseline characteristics and coronary risk factors were similar between the two groups and the baseline clinical presentation, lesion and procedural characteristics were similar between the two groups. There were no significant differences in target vessel, lesion type, lesion number, DES type, diameter and length of implanted DES and diagnosis on PCI between two groups (Table 1). 3.2. Post-operative complications and clinical outcomes Although there were no significant differences between the two groups, the incidence of clinical events including bleeding-related complications presented with transfusion, chest pain, and post-operative pro-BNP and CK-MB elevations was numerically higher in the early surgery group. There is no significant difference in duration of discontinuation of aspirin and clopidogrel before surgery, restart time after surgery and total duration of temporal discontinuation between the two groups (Table 2). 3.3. Surgical procedures There were no significant differences in type of surgical procedure, type of anesthesia and malignancy between the two groups. Characteristically, 41% of the enrolled patients were waiting cancer surgery that needs early surgery.

4. Discussion The most important finding of this study is that elective NCS at least 3 months after DES implantation appears to be safe and feasible without obvious adverse events. DES implantation in patients who were scheduled for early NCS (b 3 months after the PCI) such as cancer surgery might be associated with adverse clinical outcomes including postoperative bleeding and ischemic complications. Although there were no statistically significant differences in the rate of post-operative bleeding complications, stent thrombosis and adverse cardiac events between the two groups, patients in early surgery group showed numerically higher incidence of all the adverse events. Because we decided to quit the study due to safety concerns, thus a limited number of study patients were enrolled and lead statistically insignificant differences in terms of post-operative adverse events. Based on the design of the clinical trials that led to approval of such stents, dual antiplatelet therapy has been prescribed on an empirical basis, at least for 3 months after implantation of SES, and for 6 months after implantation of PES, with life-long aspirin [8]. A recommendation regarding stent selection in relation to the timing of NCS after the PCI was reported [9]. In case of the emergency surgery required within 4 weeks, the use of BMS possibly with Hepacoat or phophoryline coating seems helpful because of the antithrombotic milieu for preventing stent thrombosis. In case of urgent surgery during 1–3 months after the PCI, a standard BMS would be safe and feasible. In case of elective surgery at least 3 months after the PCI, DES might be a preferred option in terms of reducing repeat revascularization and similar safety with BMS after reendothelialization. Weber et al. [10] found that after discontinuation of clopidogrel treatment, platelet function gradually recovers and that a complete restoration of ADP-induced platelet responses occurs 7 days after the last clopidogrel dose. Assays of platelet aggregation can be abnormal for up to 10 days after a single dose of aspirin, given the average platelet life span of 7–10 days [11]. We hypothesized that the

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antiplatelet effect will be remained before and after NCS despite of discontinuation aspirin and clopidogrel 7 to 10 days. Therefore, in this study we strongly encouraged to discontinue aspirin and clopidogrel 5 to 7 days before surgery and resume dual antiplatelets at post-operative 3 days unless there are significant post-operative bleeding complications. Satler et al. [9] also suggested that in patients who are undergoing elective NCS, DES might be a preferred option because of its substantial reduction in restenosis and the fact that most endothelialization has probably occurred in 3 months after the index PCI with DES. We arbitrarily divided our study groups as early versus late surgery group with 3 months after the PCI on the basis of these previous reports. The main reported causes of stent thrombosis after DES implantation are as follows; stent length, stent diameter, number of implanted stents, lesion location, patient and lesion characteristics and premature antiplatelet therapy discontinuation [12–14]. From our results, we can deduce that premature antiplatelet therapy discontinuation after DES implantation is the main risk factor for the numerically different incidence of post-operative chest pain, CK-MB elevations and BNP elevations between the early surgery and late surgery group because there were no differences in stent length, stent diameter, number of implanted stents, location of lesion, patient and lesion characteristics. These results, despite the small number of enrolled patients because of the premature termination of the study due to the safety issue, may provide a clue to decide the optimal timing for NCS after PCI with DES. Our study contained small number of study populations to make a generalization and we need more study with larger study populations. We need to investigate the safety of other newly developing DES except the first generation DES for the patients who are undergoing major NCS, especially when they need early surgery. In conclusion, we suggest that early NCS within 3 months after DES implantation may associate with adverse clinical outcomes and specifically, delaying the elective NCS at least 3 months after DES implantation appears to be safe and feasible without significant post-operative adverse cardiac events.

0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.10.050

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