Review Curr Urol 2013;7:169–173 DOI: 10.1159/000365670
Received: March 7, 2014 Accepted: March 21, 2014 Published online: August 20, 2014
Elective Urological Surgery Following Coronary Stent Implantation: To Whom, How To Do It? Hakan Öztürk Department of Urology, School of Medicine, Sifa University, Izmir, Turkey
Key Words Antiplatelet therapy • Coronary stent • Elective urological surgery Abstract Coronary artery disease is one of the most common diseases today and the primary cause of sudden death. The development of atherosclerosis and the incidence of symptomatic heart and vascular diseases increase depending on the average life expectancy in the elderly population. Stent applications in the treatment of coronary artery disease are quite widespread and are a standard procedure. Stent applications are applied to approximately 2 million people in the United States every year. Therefore, there is an increase in the number of patients with stents. This increase is an important and complex situation for patients who are planned for urological elective surgery. The necessity of treating the patient with the least morbidity and mortality, and supplying the balance in terms of the dose and duration of antiplatelet agents which are used for patients with stents who are planned for elective urological surgery, is main subject of our review. To whom and what should be the treatment are assessed accompanied by the literature.
Copyright © 2013 S. Karger AG, Basel
© 2013 S. Karger AG, Basel 1015–9770/13/0074–0169$38.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com
Accessible online at: www.karger.com/cur
Introduction
Currently, coronary stents are widely used in the treatment of coronary artery diseases through a percutaneous coronary intervention. In 1987, Sigwart et al. [1] first reported a successful stent implantation through percutaneous coronary intervention. Since the introduction of the earlier stents, the shape and structure of these devices, as well as implantation techniques and antiplatelet regimens, have evolved. In recent years, drug-eluting stents (DESs) have become the standard of care for the treatment of coronary artery diseases, as bare-metal stents (BMSs) are associated with a high rate of in-stent restenosis (20–30%), the need for re-stenting within three years, and possibly the need for another surgery [2]. Restenosis is a side effect of stent implantation, which is associated with scar tissue around the stent during the healing process. This is also known as neointimal hyperplasia. It peaks at three months and reaches a plateau at 6 months. The restenosis rate of the DESs, however, is 5%. These stents are impregnated with a polymer which has anti-proliferative activities to prevent neointimal hyperplasia and smooth cell proliferation. Drug-eluting stents are of 2 major types, according to their contents: Sirolimus (Cypher™ stent) and Paclitaxel (Taxus™ stent). Sirolimus (rapamycin) is a potent immunosuppressive and anti-mitotic macrolide. It is released to a great extent within 28 days and degraded within 60 days, leaving a BMS behind. Paclitaxel is, on the other hand, a potent anti-tumor agent, which is capable of Hakan Öztürk Basmane Hospital of Sifa University Fevzipasa Boulevard No: 172/2 TR–35240 Izmir (Turkey) E-Mail [email protected]
inhibiting cell division. The anti-tumor potency of the agent lasts for 12 months. Several studies have shown that DESs have a similar safety profile as BMSs. However, the 2 stents have different occlusion mechanisms. The reason for occlusion is neointimal hyperplasia for BMSs. Although DESs suppress the hyperplastic process, a higher tendency for thrombosis, which leads to endothelial dysfunction, is present, when the release is completed [3]. Furthermore, bioresorbable vascular scaffolds (BVSs) are designed to maximize all advantages of BMSs and DESs and to minimize disadvantages of these stents. Bioresorbable vascular scaffolds are everolimus eluting stents in which the drug is released immediately and leaves a permanent scaffold behind with a patent vessel lumen until the endothelium regenerates. Because of its bioresorbable characteristics over time, BVSs are considered biocompatible. Antiplatelet Therapy
Antiplatelet therapy is the mainstay of stent implantation. It allows for the uneventful transport of blood through the stent. Metallic coronary stents exert thrombogenic activities. The incidence of myocardial infarction is 50% in the case of sudden occlusion, with a mortality rate of nearly 20%. Antiplatelet therapy, thus, is critical following stent implantation. Recently, aspirin plus thienopyridines including clopidogrel, ticlopidine, prasugrel, and ticagrelor have been used. Clopidogrel is the major agent with a low side effect profile and tolerability profile. In addition, clopidogrel is a pro-drug activated by cytochrome P450 3A4 isoenzyme (CYP3A4) to a metabolite, which inhibits the P2Y12 adenosine diphosphate (ADP) platelet receptor. As a result, it has the ability to inhibit fibrinogen binding to the platelet glycoprotein IIb/IIIa receptor complex and irreversibly blocks platelet aggregation due to ADP stimulation. It also irreversibly inhibits aspirin cyclooxygenase-1 (COX-1) enzyme and blocks thromboxane A2 production. The lifespan of anuclear platelets in the peripheral circulation ranges between 7 and 10 days, which is sufficient time for aggregation inhibition. It should be kept in mind that the bioavailability of aspirin may be reduced and thromboxane production may be stimulated through decreased doses, increased metabolism, drug interactions, or various activities, resulting in resistance to aspirin. Similarly, genetic alterations may be involved in the mechanism of clopidogrel, leading to likely drug resistance. Agents which inhibit the CYP3A4 isoenzyme system including 170
Curr Urol 2013;7:169–173
Table 1. Duration for elective urological surgery
Surgery
Duration
BMSs implantation DESs implantation BVSs implantation Percutaneous transluminal coronary angioplasty After myocardial infarction (stable patients) After coronary bypass surgery
1 month 12 months 12 months 14 days 3–6 months 1 month
itraconazole, ketoconazole, erythromycin, clarithromycin, and ritonavir, as well as grapefruit juice significantly reduce the activity of clopidogrel [3]. Presently the activities of antiplatelets cannot be specifically measured. An antiplatelet therapy with aspirin plus clopidogrel is initiated for 4–6 weeks and low-dose aspirin is maintained for life, at 6 weeks after the procedure in BMS-implanted patients. However, patients with a DES or BVS receive aspirin + clopidogrel for one year and thereafter aspirin monotherapy. When is Elective Urological Surgery Performed following Stent Implantation?
Nearly 5% of the patients require a non-cardiac surgical intervention within the first year of intra-coronary stenting [4]. The incidence of major cardiac events including death, re-admission with acute coronary syndrome, or recurrent coronary revascularization is 2.1% within the first month. Furthermore, the incidence of major cardiac events is 6.7% in BMS-implanted patients within the first 45 days, while it is significantly higher, up to 20%, in DES-implanted patients [5]. Two pivotal retrospective studies showed an incidence of major cardiac events of 3–10% 30 days after BMS implantation and of 3–6% 12 months after DES implantation. Early treatment discontinuation is the major factor for thrombosis development. In addition, treatment discontinuation is an independent predictor of mortality in patients with coronary artery diseases. Discontinuation of aspirin treatment has been reported to lead to a three-fold increase in the mortality rate. Also, mortality is higher in patients with an intra-coronary stent [6]. According to the relevant guidelines, non-cardiac urological interventions are recommended to be delayed for at least 30–45 days for BMSs and one year for DESs, as well as BVSs [5]. AddiÖztürk
tionally, such interventions should be delayed for at least 14 days in patients undergoing percutaneous transluminal coronary angioplasty. Cardiac stabilization takes 3 or 6 months in patients with myocardial infarction, while it takes one month in patients undergoing coronary artery bypass grafting (table 1). Perioperative Drug Management for Elective Urological Surgery following Stent Implantation: How to Do It?
The primary principle of drug management is to achieve the necessary time for endothelization after stenting procedure (1 month for BMSs and 12 months for DESs). Furthermore, patients with complex pathologies including a known history of stent thrombosis and major risk factors for stent thrombosis such as diabetes, renal failure, reduced ejection fractions, long and multiple stents, and bifurcation stenting should be identified. A multidisciplinary team consisting of an urologist, cardiologist, anesthetist, and hematologist should be involved in the management of such cases. An evaluation of the bleeding risk of stent thrombosis is crucial for the perioperative drug management in patients undergoing intra-coronary stenting [7]. There is limited evidenced-based data on perioperative antiplatelet regimens for patients who are scheduled for urological surgery. Patients usually are in a hypercoagulable state due to the intra-operative hemostatic reaction following major surgery. Based on thromboelastography studies, it may last at least for 7 days [3]. Early discontinuation of preventive antiplatelet therapy during perioperative hypercoagulability may lead to acute stent thrombosis in the presence of inadequate endothelization. Patients who have been recently implanted with multiple DESs are also at the highest risk of stent thrombosis. Additionally, proximal left anterior descending and the left main coronary stenting are the main high-risk group for stent thrombosis. Bleeding is another consideration for patients receiving aspirin + clopidogrel with a 3.4 fold increased bleeding time. Monitoring response to antiplatelets using coagulation tests is challenging and activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) are not conclusive. However, these tests are helpful to identify prolonged bleeding time, which is often considered irrelevant with perioperative bleeding. Today, optical light transmission platelet aggregometry is considered to be the “gold standard” of platelet funcElective Urological Surgery Following Coronary Stent Implantation
tion assay. In patients who are scheduled for elective urological surgery, the type of surgery, bleeding risk, other individual risk factors for bleeding, and outcomes of excessive bleeding should be evaluated and classified (table 2, 3 and 4). Based on the discretion of the surgeon, aspirin therapy may be maintained perioperatively in patients with intra-coronary stenting, as discontinuation of aspirin therapy is a major risk factor for acute coronary syndrome and stent thrombosis. However, aspirin therapy should be discontinued in surgeries with a potentially severe bleeding risk. Several retrospective studies on perioperative aspirin therapy for transurethral resection of the prostate (TURP) demonstrated increased postoperative bleeding [8, 9]. However, there was no significant difference in loss of blood between the patients receiving clopidogrel, aspirin, or warfarin, and controls following photoselective vaporization of the prostate [10, 11]. Another retrospective cohort study reported an increased use of blood products in patients on aspirin or non-steroidal anti-inflammatory drugs (NSAII) following TURP [12]. Furthermore, aspirin or clopidogrel regimens increased hematoma formation in patients who underwent extracorporeal shock wave lithotripsy [13]. In addition, such therapies increased the risk of rectal bleeding and hematuria in patients who underwent transrectal biopsy [14]. Aspirin, clopidogrel, and warfarin also caused increased bleeding in patients with a partial nephrectomy [15]. Similar findings were observed in patients with a percutaneous nephrolithotomy [16]. Postoperative clopidogrel use is a safe approach. When re-initiated, maximal platelet aggregation is observed at three to five days, reaching 1.5- to 3-fold within three to seven days [3]. Similar to clopidogrel, prasugrel also irreversibly blocks ADP receptors. It is a potent and rapid-onset platelet aggregation inhibitor with less individual divergences. It is more likely to be associated with clinical bleeding. On the other hand, ticagrelor, an antiplatelet agent, recently approved by the FDA, is a P2Y12 receptor inhibitor [7]. Although relevant information on the use of ticagrelor is not yet available in the guidelines, the principle of use is similar to clopidogrel. Currently, no consensus has been reached upon alternative treatments in lieu of antiplatelet regimens. Although unfractionated heparin or subcutaneous low-molecular weight heparin (LMWH) are recommended as alternatives to thienopyridines, their efficacy has not yet been established. No definitive recommendation for a target APTT value of heparin or prophylactic or therapeutic LMWH dose is available. The recommended dose Curr Urol 2013;7:169–173
171
Table 2. Low bleeding risk category
Type of procedure
Preoperative modifications
Resuming antiplatelet therapy
Cystoscopy Ureterorenoscopy Laser lithotripsy Laser prostatectomy Urethral bulking procedures
continue aspirin through perioperative period discontinue clopidogrel
concern for postoperative bleeding, if there is no bleeding, re-start clopidogrel within 24–48 h postoperatively
Table 3. Moderate bleeding risk category
Type of procedure
Preoperative modifications
Resuming antiplatelet therapy
TRUS-biospy TURB TURP ESWL Scrotal procedures Sling/urinary sphincter placements Female prolapse repair
discontinue aspirin and clopidogrel therapy 5–7 days before procedure discontinue ticlopidine therapy 14 days before procedure
concern for postoperative bleeding in coordination with cardiologist, if there is no bleeding, re-start dual antiplatelet therapy within 7 days of procedure
TRUS = Transrectal ultrasound; TURB = transurethral resection of bladder; ESWL = extracorporeal shock wave lithotripsy.
Table 4. High bleeding risk category
Type of procedure
Preoperative modifications
Resuming antiplatelet therapy
Nephrectomy Cystectomy Prostatectomy Partial Nephrectomy Penectomy Penile prosthesis placement
discontinue dual antiplatelet therapy 10 days before procedure discontinue ticlopidine therapy 14 days before procedure
concern for active bleeding in coordination with cardiologist (7–10 days after no active bleeding) and then re-start antiplatelet therapy
is 1 mg/kg enoxaparin. However, heparin, which has no antiplatelet effects, is not fully protective against stent thrombosis. In addition, early discontinuation of unfractionated heparin infusion may lead to hypercoagulation, known as heparin rebound [3]. Bridging therapy is a novel treatment modality for these patients. According to the treatment protocol, epti172
Curr Urol 2013;7:169–173
fibatide (Integrilin®; a GP IIb/IIIa inhibitor) and heparin as a potential bridge are recommended to prevent stent thrombosis. Clopidogrel therapy as a bridge is discontinued five days before surgery. The patient is admitted to hospital three days before surgery and eptifibatide in combination with a heparin infusion is initiated. Thus, thrombin formation is prevented by blocking platelet Öztürk
activation. The eptifibatide and heparin combination, which is administered intravenously, is discontinued 6 hours before surgery, and thereby offers a safe major surgical option, because of its short half-life. Eptifibatide and heparin in combination with aspirin may also significantly reduce the risk of stent thrombosis in the perioperative period [5]. Warfarin treatment should be discontinued 5 days before surgery and enoxaparin should be initiated 2 days later. The last enoxaparin dose should be administered 12 hours before surgery or maintained up to 4 hours before surgery when concomitantly used with heparin infusion. No dose adjustment is required within 2 days after surgery and a half of warfarin dose should initially be added to the treatment. Enoxaparin should be discontinued, when a therapeutic international normalized ratio (INR) is achieved. Perioperative stent thrombosis is a critical condition which requires the special attention of urologists.
Non-specific signs of thrombosis include chest pain, dyspnea, hypotension, arrhythmia, and cardiac arrest. The patient should be referred to the interventional cardiology clinic and urgent angiography should be performed to open the occluded stent. In addition, aggressive anticoagulant and antiplatelet regimens may be necessary for these patients. Stent thrombosis is a limited factor for patients recently undergoing surgery. Short-acting low-molecular weight GP IIb/IIIa inhibitors, such as eptifibatide or tirofiban, may be administered in such cases. In conclusion, the number of patients who undergo intra-coronary stenting or receive antiplatelet therapy has been steadily increasing. Urologists are thus more likely to encounter such patients in clinical practice and perform surgical interventions. Balancing thrombosis and bleeding risks relies upon a multidisciplinary approach, which is crucial for a thorough treatment of these patients. Such an approach can be standardized with the improvement of evidence-based protocols.
References 1 1-Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L: Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987;316: 701–706. 2 Popescu WM: Perioperative management of the patient with a coronary stent. Curr Opin Anaesthesiol 2010;23:109–115. 3 Howard-Alpe GM, de Bono J, Hudsmith L, Orr WP, Foex P, Sear JW: Coronary artery stents and non-cardiac surgery. Br J Anaesth 2007;98:560–574. 4 Nuttall GA, Brown MJ, Stombaugh JW, Michon PB, Hathaway MF, Lindeen KC, Hanson AC, Schroeder DR, Oliver WC, Holmes DR, Rihal CS: Time and cardiac risk of surgery after bare-metal stent percutaneous coronary intervention. Anesthesiology 2008; 109:588–595. 5 Wijeysundera DN, Wijeysundera HC, Yun L, Wąsowicz M, Beattie WS, Velianou JL, Ko DT: Risk of elective major noncardiac surgery after coronary stent insertion: a population-based study. Circulation 2012;126: 1355–1362.
Elective Urological Surgery Following Coronary Stent Implantation
6 Biondi-Zoccai GG, Lotrionte M, Agostoni P, Abbate A, Fusaro M, Burzotta F, Testa L, Sheiban I, Sangiorgi G: A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J 2006;27:2667–2674. 7 Picozzi SC, Carmignani L: Coronary stent management in elective genitourinary surgery. BJU Int 2012;109:E17–18. 8 Watson CJ, Deane AM, Doyle PT, Bullock KN: Identifiable factors in post-prostatectomy haemorrhage: the role of aspirin. Br J Urol 1990;66:85–87. 9 Thurston AV, Briant SL: Aspirin and post-prostatectomy haemorrhage. Br J Urol 1993;71:574–576. 10 Ruszat R, Wyler S, Forster T, Reich O, Stief CG, Gasser TC, Sulser T, Bachmann A: Safety and effectiveness of photoselective vaporization of the prostate (PVP) in patients on ongoing oral anticoagulation. Eur Urol 2007; 11 51:1031–1041. Sandhu JS, Ng CK, Gonzalez RR, Kaplan SA, Te AE: Photoselective laser vaporization prostatectomy in men receiving anticoagulants. J Endourol 2005;19:1196–1198.
12 Wierød FS, Frandsen NJ, Jacobsen JD, Hartvigsen A, Olsen PR: Risk of Haemorrhage form transurethral prostatectomy in acetylsalicylic acid and NSAID-treated patients. Scand J Urol Nephrol 1998;32:120–122. 13 Sare GM, Lloyd FR, Stower MJ: Life-threatening Haemorrhage after extracorporeal shockwave lithotripsy in a patient taking clopidogrel. BJU Int 2002;90:469. 14 Maan Z, Cutting CW, Patel U, Kerry S, Pietrzak P, Perry MJ, Kirby RS: Morbidity of transrectal ultrasonography-guided prostate biopsies in patients after continued use of low-dose aspirin. BJU Int 2003;91:798–800. 15 Kefer JC, Desai MM, Fergany A, Novick AC, Gill IS: Outcomes of partial nephrectomy in patients on chronic oral anticoagulant therapy. J Urol 2008;180:2370–2374. 16 Kefer JC, Turna B, Stein RJ, Desai MM: Safety and efficacy of percutaneous nephrostolithotomy in patients on anticoagulant therapy. J Urol 2009;181:144–148.
Curr Urol 2013;7:169–173
173
Received: March 7, 2014 Accepted: March 21, 2014 Published online: August 20, 2014
Elective Urological Surgery Following Coronary Stent Implantation: To Whom, How To Do It? Hakan Öztürk Department of Urology, School of Medicine, Sifa University, Izmir, Turkey
Key Words Antiplatelet therapy • Coronary stent • Elective urological surgery Abstract Coronary artery disease is one of the most common diseases today and the primary cause of sudden death. The development of atherosclerosis and the incidence of symptomatic heart and vascular diseases increase depending on the average life expectancy in the elderly population. Stent applications in the treatment of coronary artery disease are quite widespread and are a standard procedure. Stent applications are applied to approximately 2 million people in the United States every year. Therefore, there is an increase in the number of patients with stents. This increase is an important and complex situation for patients who are planned for urological elective surgery. The necessity of treating the patient with the least morbidity and mortality, and supplying the balance in terms of the dose and duration of antiplatelet agents which are used for patients with stents who are planned for elective urological surgery, is main subject of our review. To whom and what should be the treatment are assessed accompanied by the literature.
Copyright © 2013 S. Karger AG, Basel
© 2013 S. Karger AG, Basel 1015–9770/13/0074–0169$38.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com
Accessible online at: www.karger.com/cur
Introduction
Currently, coronary stents are widely used in the treatment of coronary artery diseases through a percutaneous coronary intervention. In 1987, Sigwart et al. [1] first reported a successful stent implantation through percutaneous coronary intervention. Since the introduction of the earlier stents, the shape and structure of these devices, as well as implantation techniques and antiplatelet regimens, have evolved. In recent years, drug-eluting stents (DESs) have become the standard of care for the treatment of coronary artery diseases, as bare-metal stents (BMSs) are associated with a high rate of in-stent restenosis (20–30%), the need for re-stenting within three years, and possibly the need for another surgery [2]. Restenosis is a side effect of stent implantation, which is associated with scar tissue around the stent during the healing process. This is also known as neointimal hyperplasia. It peaks at three months and reaches a plateau at 6 months. The restenosis rate of the DESs, however, is 5%. These stents are impregnated with a polymer which has anti-proliferative activities to prevent neointimal hyperplasia and smooth cell proliferation. Drug-eluting stents are of 2 major types, according to their contents: Sirolimus (Cypher™ stent) and Paclitaxel (Taxus™ stent). Sirolimus (rapamycin) is a potent immunosuppressive and anti-mitotic macrolide. It is released to a great extent within 28 days and degraded within 60 days, leaving a BMS behind. Paclitaxel is, on the other hand, a potent anti-tumor agent, which is capable of Hakan Öztürk Basmane Hospital of Sifa University Fevzipasa Boulevard No: 172/2 TR–35240 Izmir (Turkey) E-Mail [email protected]
inhibiting cell division. The anti-tumor potency of the agent lasts for 12 months. Several studies have shown that DESs have a similar safety profile as BMSs. However, the 2 stents have different occlusion mechanisms. The reason for occlusion is neointimal hyperplasia for BMSs. Although DESs suppress the hyperplastic process, a higher tendency for thrombosis, which leads to endothelial dysfunction, is present, when the release is completed [3]. Furthermore, bioresorbable vascular scaffolds (BVSs) are designed to maximize all advantages of BMSs and DESs and to minimize disadvantages of these stents. Bioresorbable vascular scaffolds are everolimus eluting stents in which the drug is released immediately and leaves a permanent scaffold behind with a patent vessel lumen until the endothelium regenerates. Because of its bioresorbable characteristics over time, BVSs are considered biocompatible. Antiplatelet Therapy
Antiplatelet therapy is the mainstay of stent implantation. It allows for the uneventful transport of blood through the stent. Metallic coronary stents exert thrombogenic activities. The incidence of myocardial infarction is 50% in the case of sudden occlusion, with a mortality rate of nearly 20%. Antiplatelet therapy, thus, is critical following stent implantation. Recently, aspirin plus thienopyridines including clopidogrel, ticlopidine, prasugrel, and ticagrelor have been used. Clopidogrel is the major agent with a low side effect profile and tolerability profile. In addition, clopidogrel is a pro-drug activated by cytochrome P450 3A4 isoenzyme (CYP3A4) to a metabolite, which inhibits the P2Y12 adenosine diphosphate (ADP) platelet receptor. As a result, it has the ability to inhibit fibrinogen binding to the platelet glycoprotein IIb/IIIa receptor complex and irreversibly blocks platelet aggregation due to ADP stimulation. It also irreversibly inhibits aspirin cyclooxygenase-1 (COX-1) enzyme and blocks thromboxane A2 production. The lifespan of anuclear platelets in the peripheral circulation ranges between 7 and 10 days, which is sufficient time for aggregation inhibition. It should be kept in mind that the bioavailability of aspirin may be reduced and thromboxane production may be stimulated through decreased doses, increased metabolism, drug interactions, or various activities, resulting in resistance to aspirin. Similarly, genetic alterations may be involved in the mechanism of clopidogrel, leading to likely drug resistance. Agents which inhibit the CYP3A4 isoenzyme system including 170
Curr Urol 2013;7:169–173
Table 1. Duration for elective urological surgery
Surgery
Duration
BMSs implantation DESs implantation BVSs implantation Percutaneous transluminal coronary angioplasty After myocardial infarction (stable patients) After coronary bypass surgery
1 month 12 months 12 months 14 days 3–6 months 1 month
itraconazole, ketoconazole, erythromycin, clarithromycin, and ritonavir, as well as grapefruit juice significantly reduce the activity of clopidogrel [3]. Presently the activities of antiplatelets cannot be specifically measured. An antiplatelet therapy with aspirin plus clopidogrel is initiated for 4–6 weeks and low-dose aspirin is maintained for life, at 6 weeks after the procedure in BMS-implanted patients. However, patients with a DES or BVS receive aspirin + clopidogrel for one year and thereafter aspirin monotherapy. When is Elective Urological Surgery Performed following Stent Implantation?
Nearly 5% of the patients require a non-cardiac surgical intervention within the first year of intra-coronary stenting [4]. The incidence of major cardiac events including death, re-admission with acute coronary syndrome, or recurrent coronary revascularization is 2.1% within the first month. Furthermore, the incidence of major cardiac events is 6.7% in BMS-implanted patients within the first 45 days, while it is significantly higher, up to 20%, in DES-implanted patients [5]. Two pivotal retrospective studies showed an incidence of major cardiac events of 3–10% 30 days after BMS implantation and of 3–6% 12 months after DES implantation. Early treatment discontinuation is the major factor for thrombosis development. In addition, treatment discontinuation is an independent predictor of mortality in patients with coronary artery diseases. Discontinuation of aspirin treatment has been reported to lead to a three-fold increase in the mortality rate. Also, mortality is higher in patients with an intra-coronary stent [6]. According to the relevant guidelines, non-cardiac urological interventions are recommended to be delayed for at least 30–45 days for BMSs and one year for DESs, as well as BVSs [5]. AddiÖztürk
tionally, such interventions should be delayed for at least 14 days in patients undergoing percutaneous transluminal coronary angioplasty. Cardiac stabilization takes 3 or 6 months in patients with myocardial infarction, while it takes one month in patients undergoing coronary artery bypass grafting (table 1). Perioperative Drug Management for Elective Urological Surgery following Stent Implantation: How to Do It?
The primary principle of drug management is to achieve the necessary time for endothelization after stenting procedure (1 month for BMSs and 12 months for DESs). Furthermore, patients with complex pathologies including a known history of stent thrombosis and major risk factors for stent thrombosis such as diabetes, renal failure, reduced ejection fractions, long and multiple stents, and bifurcation stenting should be identified. A multidisciplinary team consisting of an urologist, cardiologist, anesthetist, and hematologist should be involved in the management of such cases. An evaluation of the bleeding risk of stent thrombosis is crucial for the perioperative drug management in patients undergoing intra-coronary stenting [7]. There is limited evidenced-based data on perioperative antiplatelet regimens for patients who are scheduled for urological surgery. Patients usually are in a hypercoagulable state due to the intra-operative hemostatic reaction following major surgery. Based on thromboelastography studies, it may last at least for 7 days [3]. Early discontinuation of preventive antiplatelet therapy during perioperative hypercoagulability may lead to acute stent thrombosis in the presence of inadequate endothelization. Patients who have been recently implanted with multiple DESs are also at the highest risk of stent thrombosis. Additionally, proximal left anterior descending and the left main coronary stenting are the main high-risk group for stent thrombosis. Bleeding is another consideration for patients receiving aspirin + clopidogrel with a 3.4 fold increased bleeding time. Monitoring response to antiplatelets using coagulation tests is challenging and activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) are not conclusive. However, these tests are helpful to identify prolonged bleeding time, which is often considered irrelevant with perioperative bleeding. Today, optical light transmission platelet aggregometry is considered to be the “gold standard” of platelet funcElective Urological Surgery Following Coronary Stent Implantation
tion assay. In patients who are scheduled for elective urological surgery, the type of surgery, bleeding risk, other individual risk factors for bleeding, and outcomes of excessive bleeding should be evaluated and classified (table 2, 3 and 4). Based on the discretion of the surgeon, aspirin therapy may be maintained perioperatively in patients with intra-coronary stenting, as discontinuation of aspirin therapy is a major risk factor for acute coronary syndrome and stent thrombosis. However, aspirin therapy should be discontinued in surgeries with a potentially severe bleeding risk. Several retrospective studies on perioperative aspirin therapy for transurethral resection of the prostate (TURP) demonstrated increased postoperative bleeding [8, 9]. However, there was no significant difference in loss of blood between the patients receiving clopidogrel, aspirin, or warfarin, and controls following photoselective vaporization of the prostate [10, 11]. Another retrospective cohort study reported an increased use of blood products in patients on aspirin or non-steroidal anti-inflammatory drugs (NSAII) following TURP [12]. Furthermore, aspirin or clopidogrel regimens increased hematoma formation in patients who underwent extracorporeal shock wave lithotripsy [13]. In addition, such therapies increased the risk of rectal bleeding and hematuria in patients who underwent transrectal biopsy [14]. Aspirin, clopidogrel, and warfarin also caused increased bleeding in patients with a partial nephrectomy [15]. Similar findings were observed in patients with a percutaneous nephrolithotomy [16]. Postoperative clopidogrel use is a safe approach. When re-initiated, maximal platelet aggregation is observed at three to five days, reaching 1.5- to 3-fold within three to seven days [3]. Similar to clopidogrel, prasugrel also irreversibly blocks ADP receptors. It is a potent and rapid-onset platelet aggregation inhibitor with less individual divergences. It is more likely to be associated with clinical bleeding. On the other hand, ticagrelor, an antiplatelet agent, recently approved by the FDA, is a P2Y12 receptor inhibitor [7]. Although relevant information on the use of ticagrelor is not yet available in the guidelines, the principle of use is similar to clopidogrel. Currently, no consensus has been reached upon alternative treatments in lieu of antiplatelet regimens. Although unfractionated heparin or subcutaneous low-molecular weight heparin (LMWH) are recommended as alternatives to thienopyridines, their efficacy has not yet been established. No definitive recommendation for a target APTT value of heparin or prophylactic or therapeutic LMWH dose is available. The recommended dose Curr Urol 2013;7:169–173
171
Table 2. Low bleeding risk category
Type of procedure
Preoperative modifications
Resuming antiplatelet therapy
Cystoscopy Ureterorenoscopy Laser lithotripsy Laser prostatectomy Urethral bulking procedures
continue aspirin through perioperative period discontinue clopidogrel
concern for postoperative bleeding, if there is no bleeding, re-start clopidogrel within 24–48 h postoperatively
Table 3. Moderate bleeding risk category
Type of procedure
Preoperative modifications
Resuming antiplatelet therapy
TRUS-biospy TURB TURP ESWL Scrotal procedures Sling/urinary sphincter placements Female prolapse repair
discontinue aspirin and clopidogrel therapy 5–7 days before procedure discontinue ticlopidine therapy 14 days before procedure
concern for postoperative bleeding in coordination with cardiologist, if there is no bleeding, re-start dual antiplatelet therapy within 7 days of procedure
TRUS = Transrectal ultrasound; TURB = transurethral resection of bladder; ESWL = extracorporeal shock wave lithotripsy.
Table 4. High bleeding risk category
Type of procedure
Preoperative modifications
Resuming antiplatelet therapy
Nephrectomy Cystectomy Prostatectomy Partial Nephrectomy Penectomy Penile prosthesis placement
discontinue dual antiplatelet therapy 10 days before procedure discontinue ticlopidine therapy 14 days before procedure
concern for active bleeding in coordination with cardiologist (7–10 days after no active bleeding) and then re-start antiplatelet therapy
is 1 mg/kg enoxaparin. However, heparin, which has no antiplatelet effects, is not fully protective against stent thrombosis. In addition, early discontinuation of unfractionated heparin infusion may lead to hypercoagulation, known as heparin rebound [3]. Bridging therapy is a novel treatment modality for these patients. According to the treatment protocol, epti172
Curr Urol 2013;7:169–173
fibatide (Integrilin®; a GP IIb/IIIa inhibitor) and heparin as a potential bridge are recommended to prevent stent thrombosis. Clopidogrel therapy as a bridge is discontinued five days before surgery. The patient is admitted to hospital three days before surgery and eptifibatide in combination with a heparin infusion is initiated. Thus, thrombin formation is prevented by blocking platelet Öztürk
activation. The eptifibatide and heparin combination, which is administered intravenously, is discontinued 6 hours before surgery, and thereby offers a safe major surgical option, because of its short half-life. Eptifibatide and heparin in combination with aspirin may also significantly reduce the risk of stent thrombosis in the perioperative period [5]. Warfarin treatment should be discontinued 5 days before surgery and enoxaparin should be initiated 2 days later. The last enoxaparin dose should be administered 12 hours before surgery or maintained up to 4 hours before surgery when concomitantly used with heparin infusion. No dose adjustment is required within 2 days after surgery and a half of warfarin dose should initially be added to the treatment. Enoxaparin should be discontinued, when a therapeutic international normalized ratio (INR) is achieved. Perioperative stent thrombosis is a critical condition which requires the special attention of urologists.
Non-specific signs of thrombosis include chest pain, dyspnea, hypotension, arrhythmia, and cardiac arrest. The patient should be referred to the interventional cardiology clinic and urgent angiography should be performed to open the occluded stent. In addition, aggressive anticoagulant and antiplatelet regimens may be necessary for these patients. Stent thrombosis is a limited factor for patients recently undergoing surgery. Short-acting low-molecular weight GP IIb/IIIa inhibitors, such as eptifibatide or tirofiban, may be administered in such cases. In conclusion, the number of patients who undergo intra-coronary stenting or receive antiplatelet therapy has been steadily increasing. Urologists are thus more likely to encounter such patients in clinical practice and perform surgical interventions. Balancing thrombosis and bleeding risks relies upon a multidisciplinary approach, which is crucial for a thorough treatment of these patients. Such an approach can be standardized with the improvement of evidence-based protocols.
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