During the last decade there has been a rapid development

Safety and Efficacy of Flexible Ureterorenoscopy and Holmium:YAG Lithotripsy for Intrarenal Stones in Anticoagulated Cases Burak Turna, Robert J. Stein, Marc C. Smaldone, Bruno R. Santos, John C. Kefer, Stephen V. Jackman, Timothy D. Averch and Mihir M. Desai* From the Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio and Department of Urology, University of Pittsburgh Medical Center (MCS, SVJ, TDA), Pittsburgh, Pennsylvania Purpose: We compared perioperative outcomes in patients undergoing ureterorenoscopy and Ho:YAG lithotripsy for renal calculi with or without anticoagulation. Materials and Methods: We reviewed the records of all patients undergoing flexible ureterorenoscopy and Ho:YAG lithotripsy for renal calculi at 2 institutions from 2001 to 2007. We identified 37 patients on anticoagulation with Coumadin, clopidogrel or aspirin in whom anticoagulation therapy was not discontinued before surgery. Data on the anticoagulation group were retrospectively compared to those on a contemporary matched cohort of 37 controls without anticoagulation who underwent a similar operative procedure. The 2 groups were compared with regard to the stone-free rate, and intraoperative and postoperative complications with specific reference to bleeding and thromboembolism. Results: The 2 groups were matched for stone size, stone location, number of stones, bilateral procedures and concomitant ureteral stones. Anticoagulation group patients were older (58.2 vs 50.4 years, p 0.0209) and had a greater American Society of Anesthesiologists score (2.8 vs 1.9, p 0.0001) compared to the control group. No procedure had to be terminated in the anticoagulation group due to poor visibility from bleeding. The median postoperative hemoglobin decrease was greater in the anticoagulation group than in the control group (0.6 vs 0.2 gm/dl, p 0.0001). The stone-free rate (81.1% vs 78.4%, p 0.7725), intraoperative complications (0% vs 3%, p 0.3140), postoperative complications (11% vs 5%, p 0.3943) and hemorrhagic or thromboembolic adverse events were comparable in the 2 groups. Conclusions: When necessary, ureterorenoscopy and Ho:YAG lithotripsy can be performed safely and efficaciously for renal calculi in patients on anticoagulation therapy without the need for perioperative manipulation. Key Words: kidney, kidney calculi, lasers, anticoagulants, endoscopy During the last decade there has been a rapid development in small caliber flexible URS, Ho:YAG laser lithotripsy and various ancillary instruments for stone manipulation and retrieval. 1 Flexible URS is being increasingly used for a large number of diagnostic and therapeutic procedures involving the upper urinary tract, allowing the entire renal collecting system to be accessed safely and effectively. 2 Stone disease in patients on chronic oral AC therapy poses a difficult management problem. Many such patients on chronic AC therapy have multiple associated comorbidities, making perioperative discontinuation of AC therapy significantly risky for adverse thromboembolic events. Therapeutic modalities, such as extracorporeal shock wave lithotripsy, percutaneous nephrolithotomy, or laparoscopic or open stone treatment, are contraindicated in patients on active AC therapy. 3 5 Flexible URS may be the only surgical option available for stone disease. There is a paucity of published information regarding the safety and efficacy, Submitted for publication August 12, 2007. Supported by the Scientific and Technological Research Council of Turkey (BT). * Correspondence: Section of Endourology and Stone Disease, Glickman Urological Institute, Cleveland Clinic Foundation, 9500 Euclid Ave. /A100, Cleveland, Ohio 44195 (telephone: 216-445-1185; FAX: 216-445-2267; e-mail: desaim1@ccf.org). especially with flexible URS, in patients on AC that is not discontinued perioperatively. We evaluated the safety and efficacy of flexible URS and Ho:YAG laser lithotripsy for intrarenal calculi in patients on active oral AC. MATERIALS AND METHODS Between July 2001 and January 2007, 692 patients were treated with flexible URS and Ho:YAG laser lithotripsy for renal calculi at 2 institutions. Of these patients 37 (5.3%) were identified who underwent a procedure while on active AC. Chronic AC included Coumadin in 14 patients (37.8%), clopidogrel in 5 (13.5%), and 81 and 325 mg oral aspirin in 13 (35.2%) and 5 (13.5%), respectively. Indications for AC were coronary artery disease in 8 patients, hyperlipidemia and hypertension in 7, a mechanical cardiac valve in 5, atrial fibrillation in 4, myocardial infarction in 3, cerebrovascular disease in 3, DVT in 2, and lupus anticoagulant, ischemic colitis, factor V Leiden, total hip replacement and an unknown reason in 1 each (table 1). The median duration of AC therapy was 15 months (range 1 to 120). Data on the AC group were retrospectively compared to those on a contemporary cohort of 37 control patients not on AC therapy who underwent flexible URS and Ho:YAG laser lithotripsy for intrarenal calculi. Control patients were matched for stone size, stone location, the number of stones, 0022-5347/08/1794-1415/0 1415 Vol. 179, 1415-1419, April 2008 THE JOURNAL OF UROLOGY Printed in U.S.A. Copyright 2008 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2007.11.076

1416 FLEXIBLE URETERENOSCOPY FOR INTRARENAL STONES TABLE 1. Anticoagulation therapy etiology Coumadin Clopidogrel Aspirin Overall 14 5 18 Mechanical prosthetic heart valve 5 Chronic atrial fibrillation 4 Coronary artery disease 2 6 Myocardial infarction stenting 1 2 DVT 2 Lupus anticoagulant 1 Ischemic colitis 1 Cerebrovascular disease 3 Hyperlipidemia hypertension 1 6 Factor V Leiden 1 Total hip replacement 1 Unknown 1 the number of bilateral simultaneous procedures, and the number and size of concomitant ipsilateral ureteral stones. Preoperative clotting parameters were available in all patients. Intraoperative and postoperative outcomes were compared between the 2 groups. Specifically the groups were compared for clotting parameters (normal prothrombin time less than 13 seconds, normal partial thromboplastin time less than 34 seconds and normal INR less than 1.1), changes in preoperative and postoperative hemoglobin, the stonefree rate, and intraoperative and postoperative complications, including hemorrhagic and thromboembolic adverse events. All patients underwent noncontrast computerized tomography before surgery. Any associated ipsilateral ureteral stones or contralateral renal stones were treated at the same setting when indicated. All patients underwent flexible URS using a 7.5Fr Karl Storz 11278 AUA1 Flex-X, 8.7Fr ACMI DUR-8 Elite or 6.9Fr Olympus URF-P3 flexible ureterorenoscope. Ureteral balloon dilatation was performed when necessary. A ureteral access sheath was used based on individual surgeon preference. Lower pole stones were typically relocated to a more favorable location using a 2.4Fr nitinol basket before laser lithotripsy. Ho:YAG laser lithotripsy was performed using a 200 or 365 m laser fiber set at 10 W (1.0 Joule 10 Hz). Stone(s) were completely fragmented into a gravel size of less than 2 mm. Basket retrieval at the end of laser lithotripsy was performed based on individual surgeon preference. A systematic inspection of the collecting system was performed at the end of the procedure to confirm adequate fragmentation. A 6Fr Double-J stent was routinely inserted in all patients and removed a minimum of 1 week after the procedure. All patients were discharged home within 24 hours after the procedure following postoperative hemoglobin determination, urine color assessment and confirmation of stable vital signs. Any residual fragment greater than 2 mm on postoperative computerized tomography followup at 1 month was considered treatment failure. Summary statistics are reported using the mean or median for continuous variables and percents for categorical variables. Statistical comparison of the 2 groups (AC vs control) was performed using the Wilcoxon rank sum test for continuous data and the chi-square test for categorical data with SPSS software. For further analysis the 4 subgroups (Coumadin vs clopidogrel vs aspirin vs control) were also compared using the Kruskal-Wallis test for continuous data and the chi-square test for categorical data with statistical significance considered at p 0.05. RESULTS Compared to the 37 patients in the control group the 37 in the AC group were older (58.2 vs 50.4 years, p 0.0209) and had a greater American Society of Anesthesiologists score (2.8 vs 1.9, p 0.0001, table 2). The 2 groups were comparable in terms of the number of lower pole stones (32% vs 32%, p 1.0), number of multiple stones (43% vs 46%, p 0.3636) and concomitant ureteral stones (22% vs 19%, p 0.7725) requiring simultaneous treatment. The groups were also similar in terms of preoperative flank pain/colic (57% vs 70% of patients), baseline hemoglobin (13.8 vs 13.5 gm/dl), baseline serum creatinine (1.0 vs 0.9 mg/dl), a preexisting Double-J stent (46% vs 35% of patients), renal stone size (13.2 vs 11.1 mm) and associated ureteral stone size (8.3 vs 6.7 mm) (table 2). However, clotting parameters, such as prothrombin time (14 vs 10.7 seconds, p 0.0051), partial thromboplastin time (31.9 vs 28.4 seconds, p 0.0419) and INR (1.3 vs 0.9, p 0.0284) were significantly prolonged in the AC group compared to those in controls. Table 3 lists perioperative outcomes. A ureteral access sheath was used more frequently (22% vs 3%, p 0.0128) and mean operative time was significantly longer (69.9 vs 57.8 minutes, p 0.0146) in the AC group. Intraoperative visibility was satisfactory for allowing successful completion of the procedure in all patients on AC. No patient required blood transfusion in either group. The median postoperative hemoglobin decrease was 0.7, 0.65, 0.3, 0.6 and 0.2 gm/dl in patients on aspirin, Coumadin, clopidogrel and overall AC, and in controls, respectively (AC vs control p 0.0001). The figure shows the changes in preoperative and postoperative hemoglobin. No patients in either group experienced major bleeding complications perioperatively. Table 4 lists detailed hemorrhagic and thromboembolic adverse events. The single intraoperative complication in the entire series (superficial proximal ureteral perforation) occurred in the control group. Four patients in the AC group experienced postoperative complications, including macroscopic hematuria 3 days or longer in duration in 3 and urinary tract infection in 1, compared to 2 in the control group, including urinary tract infection and DVT in 1, and severe dysuria in 1. The stone-free rate at 1 month did not differ significantly among the 4 subgroups or between the 2 groups (81.1% vs 78.4%, p 0.7725). DISCUSSION Currently there are several alternatives for the surgical treatment of renal and ureteral calculi. Factors such as stone characteristics, anatomical detail, patient factors and surgeon preference typically determine the choice of surgical intervention. Uncorrected bleeding diathesis is an absolute contraindication to stone treatment with shock wave lithotripsy, percutaneous nephrolithotomy, open surgery or laparoscopy. 3 5 Several indications, therapeutic goals and recommended durations of therapy exist for the use of aspirin, clopidogrel and Coumadin. The prevention of thromboembolic complications from DVT, atrial fibrillation, valvular heart disease and coronary stenting are the main indications for AC therapy,

FLEXIBLE URETERENOSCOPY FOR INTRARENAL STONES 1417 TABLE 2. Baseline demographrics Coumadin Clopidogrel Aspirin Overall AC Control Coumadin vs Clopidogrel vs Aspirin vs Control p Value* Overall AC vs Control p Value pts 14 5 18 37 37 Age: Mean SD 61.5 16.6 55.8 8.7 56.4 9.5 58.2 12.5 50.4 15.1 0.1131 0.0209 Range 35 86 45 68 41 75 35 86 17 80 Median 60 54 55 56 50 American Society of Anesthesiologists score: Mean SD 2.9 0.5 3.0 0 2.6 0.7 2.8 0.6 1.9 0.8 0.004 0.0001 Range 2 4 3 3 2 4 2 4 1 3 Median 3 3 2.5 3 2 INR: Mean SD 1.8 0.7 1.0 0.1 0.9 0.1 1.3 0.6 0.9 0.1 0.0001 0.0284 Range 1.1 3.3 0.9 1.1 0.9 1.1 0.9 3.3 0.9 1.1 Median 1.7 1.0 0.9 1.0 1.0 pts with previous stents (%) 7 (50) 3 (60) 7 (39) 17 (46) 13 (35) 0.6206 0.3436 bilat stones/simultaneous procedures 1 (7) 0 5 (28) 6 (16) 5 (14) 0.5583 0.5722 (%) Kidney stone size (mm): Mean SD 17.2 9.2 8.4 5.5 11.4 5.4 13.2 7.6 11.1 6.6 0.0666 0.1501 Range 7 35 5 14 5 22 5 35 4 30 Median 13 10 10 12 10 pts with multiple kidney stones (%) 7 (50) 1 (20) 8 (44) 16 (43) 17 (46) 0.8637 0.3636 pts with associated ureteral stones (%) 2 (14) 2 (40) 4 (22) 8 (22) 7 (19) 0.6597 0.7725 Associated ureteral stone size (mm): Mean SD 8.0 1.4 10.5 6.4 7.3 1.9 8.3 3.1 6.7 2.4 0.7818 0.4133 Range 7 9 6 15 6 10 6 15 4 10 Median 8 10.5 6.5 7 7 * Kruskal-Wallis test for continuous data and chi-square test for categorical data. Wilcoxon rank sum test for continuous data and chi-square test for categorical data. which often requires long-term or indefinite use. 6 Coumadin and aspirin were shown to dramatically decrease the risk of stroke with a pooled relative risk reduction of 68% and 21%, respectively, compared to that in an untreated group of patients with atrial fibrillation. 7 The rate of recurrent DVT in patients at high risk for DVT without AC is 7.2% per year. 8 Arnold et al reported that physicians could have prevented 17.4% of 253 episodes of venous thromboembolism if they had applied adequate prophylaxis according to the recommended guidelines. 9 Aspirin decreases the risk of death after myocardial infarction and decreases mortality in those at high risk for cardiovascular disease, ie previous angina, stroke or a transient ischemic attack. 10 Similarly the oral antiplatelet agent clopidogrel has been widely used predominately as adjunct therapy to prevent subacute thrombosis after coronary stenting. 11 The decision to stop/modulate chronic AC therapy preoperatively depends on the etiology requiring AC and the subsequent risk of stopping AC therapy. This issue is becoming more relevant in patients who have drug eluting vascular stents that necessitate some form of AC therapy, potentially lifelong, to minimize the risk of stent thrombosis. Major concerns of discontinuing and re-initiating AC therapy in patients at high risk are 3-fold. 1) During the correction of bleeding diathesis patients requiring AC are at risk for thromboembolic events. 2) Drug therapy need not be altered, which provides greater simplicity of the medication regimen and likely improves compliance in elderly patients with common polypharmacy. 3) The expense of bridging therapy (temporary use of intravenous unfractionated heparin or low molecular weight heparin) is considerable. In our experience referring physicians are increasingly reluctant to discontinue AC even temporarily. TABLE 3. Perioperative parameters Overall AC Control p Value* Operative time (mins): Mean SD 69.9 25.4 57.8 15.9 0.0146 Range 35 149 40 100 Median 60 50 balloon dilatation (%) 1 (3) 3 (8) 0.3039 ureteral access sheath (%) 8 (22) 1 (3) 0.0128 intraop complications (%) 0 1 (3) 0.3140 Postop hemoglobin (gm/dl): Mean SD 13.2 1.7 13.3 1.9 0.9957 Range 9.3 16 9.3 17.8 Median 13.3 13.1 postop complications (%) 4 (11) 2 (5) 0.3943 % Stone-free 81.1 78.4 0.7725 Total of 37 patients per group. * Wilcoxon rank sum test for continuous data and chi-square test for categorical data. Hemoglobin changes in 4 groups

1418 FLEXIBLE URETERENOSCOPY FOR INTRARENAL STONES TABLE 4. Hemorrhagic and/or thromboembolic related adverse events in patients undergoing flexible URS and Ho:YAG laser lithotripsy on active oral AC vs controls Coumadin Clopidogrel Aspirin Overall AC Control Overall pts 14 5 18 37 37 Transient macroscopic 2 1 0 3 0 hematuria 3 days or greater Severe dysuria 0 0 0 0 1 Urinary tract 0 0 1 1 1* infection Thromboembolic event 0 0 0 0 1* No patients had clot retention, blood transfusion, discharge home with an indwelling stent, reoperation or conversion to open surgery. * Urinary tract infection and DVT in the same patient. Flexible URS with laser lithotripsy remains the only potential surgical treatment alternative in patients on AC in whom therapy cannot be discontinued perioperatively. However, due to the paucity of published data on the safety and efficacy of flexible URS and laser lithotripsy in patients on active AC urologists may be hesitant to proceed with definitive treatment. In our study we noted that despite active AC patients were not at increased risk for associated intraoperative (0% vs 3%) or postoperative (11% vs 5%) complications and stone-free rates were comparable to those in patients undergoing flexible URS and laser lithotripsy without AC (81.1% vs 78.4%). A concern, especially with flexible ureteroscopy due to lower irrigant flow and optical resolution compared to those of semirigid ureteroscopy, is the impact of AC therapy on oozing and intraoperative visibility. In this regard in our study no procedure had to be prematurely terminated because of poor visibility from bleeding. Nevertheless, there was a significant increase in operative time (69.9 vs 57.8 minutes) and a greater, though clinically insignificant decrease in hemoglobin in the AC group compared to controls. This comparative study attests to the technical feasibility, effectiveness and safety of flexible URS and Ho:YAG laser lithotripsy in patients on active AC. Our findings confirm the 2 available descriptive studies in the literature in an objective manner. Kuo et al first reported the safety and efficacy of ureteroscopy and holmium laser treatment in 6 patients receiving Coumadin, 2 with thrombocytopenia and 1 with von Willebrand s disease. 12 In the study 8 patients had upper tract calculi and 1 had transitional cell carcinoma. Only 1 patient had a postoperative bleeding complication, which resolved without surgical intervention. None of the bleeding diatheses were corrected before surgery. Watterson et al assessed the safety and efficacy of ureteroscopy and Ho:YAG laser lithotripsy for upper urinary tract calculi in 25 patients with known and uncorrected bleeding diathesis from 2 tertiary care centers. 13 The overall stonefree rate was 96% and all except 1 procedure were completed successfully. Significant retroperitoneal hemorrhage occurred in 1 patient who was treated with electrohydraulic lithotripsy. The investigators concluded that upper tract urinary calculi in patients with uncorrected bleeding diathesis can be safely managed by small caliber ureteroscopes and the holmium laser. Certain technical details may be of even greater importance during ureteroscopy in patients on AC. If there is difficulty in inserting the ureteroscope, or accessing or fragmenting a stone, or if there is bleeding that impedes visibility, there should be a lower threshold for placement of an indwelling stent and planning for stage 2 URS treatment. Also, no procedure should be performed without having fluoroscopy and a safety guidewire to maintain ureteral access. Lastly, familiarity with and the availability of appropriate endoscopes and ancillary instruments are crucial. Ureteral access sheaths were used in 8 patients and ureteral balloon dilatation was done in 1 without any hemorrhagic complications, confirming their safety in patients on AC. Of all intracorporeal lithotriptors the Ho: YAG laser provides the ability to fragment stones of any composition with minimal complications. 14 The precise ablation, decreased collateral damage and hemostatic effects of laser energy make it an ideal method in patients on active AC. Nevertheless, special care should be exercised while using the Ho:YAG laser in anticoagulated cases and attempts to minimize contact with the mucosa are noteworthy. To our knowledge this is the largest study assessing the safety and efficacy of flexible URS in anticoagulated cases. Nevertheless, a sample size of 37 patients may be underpowered for detecting clinically significant differences, specifically between the 4 subgroups. As such, there were 18 patients in the aspirin group, 14 in the Coumadin group and only 5 in the clopidogrel group. This limitation should be considered when interpreting our results. CONCLUSIONS URS and Ho:YAG laser lithotripsy can be performed safely and effectively for intrarenal stones in anticoagulated cases. Our data suggest no increased risk of hemorrhagic adverse events or decreased stone-free rates when compared to those in a matched cohort group undergoing URS and Ho:YAG laser lithotripsy. Thus, it should be considered the ideal treatment modality in this setting without discontinuing and re-initiating AC. This may further increase the already growing popularity of retrograde intrarenal surgery for renal stones. Abbreviations and Acronyms AC anticoagulation DVT deep vein thrombosis INR international normalized ratio URS ureterorenoscopy REFERENCES 1. Grasso M and Bagley D: Small diameter, actively deflectable, flexible ureteropyeloscopy. J Urol 1998; 160: 1648. 2. Monga M and Beeman WW: Advanced intrarenal ureteroscopic procedures. Urol Clin North Am 2004; 31: 129. 3. Streem SB: Contemporary clinical practice of shock wave lithotripsy: a reevaluation of contraindications. J Urol 1997; 157: 1197.

FLEXIBLE URETERENOSCOPY FOR INTRARENAL STONES 1419 4. Lee WJ, Smith AD, Cubelli V, Badlani GH, Lewin B, Vernace F et al: Complications of percutaneous nephrolithotomy. AJR Am J Roentgenol 1987; 148: 177. 5. Albqami N and Janetschek G: Indications and contraindications for the use of laparoscopic surgery for renal cell carcinoma. Nat Clin Pract Urol 2006; 3: 32. 6. du Breuil AL and Umland EM: Outpatient management of anticoagulation therapy. Am Fam Physician 2007; 75: 1031. 7. Fang MC and Singer DE: Anticoagulation for atrial fibrillation. Cardiol Clin 2004; 22: 47. 8. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH and Raskob GE: Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 401S. 9. Arnold DM, Kahn SR and Shrier I: Missed opportunities for prevention of venous thromboembolism: an evaluation of the use of thromboprophylaxis guidelines. Chest 2001; 120: 1964. 10. McAlister FA, Lawson FM, Teo KK and Armstrong PW: Randomised trials of secondary prevention programmes in coronary heart disease: systematic review. BMJ 2001; 323: 957. 11. Doggrell SA: Clopidogrel use with stenting. Expert Opin Pharmacother 2007; 8: 1399. 12. Kuo RL, Aslan P, Fitzgerald KB and Preminger GM: Use of ureteroscopy and holmium:yag laser in patients with bleeding diatheses. Urology 1998; 52: 609. 13. Watterson JD, Girvan AR, Cook AJ, Beiko DT, Nott L, Auge BK et al: Safety and efficacy of holmium:yag laser lithotripsy in patients with bleeding diatheses. J Urol 2002; 168: 442. 14. Leveillee RJ and Lobik L: Intracorporeal lithotripsy: which modality is best? Curr Opin Urol 2003; 13: 249