Antiplatelet and anticoagulative medication during shockwave lithotripsy.

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Journal of Endourology Antiplatelet and anticoagulative medication during shock wave lithotripsy (doi: 10.1089/end.2014.0162) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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Antiplatelet and anticoagulative medication during shock wave lithotripsy Schnabel MJ, Gierth M, Bründl J, Chaussy CG, Burger M, Fritsche HM Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Germany

Word count: manuscript: 3190 words; abstract: 216 words

Key words: Shock wave lithotripsy, ESWL, SWL, anticoagulation, antiplatelet therapy, acetylsalicylic acid, urolithiasis

Corresponding Author: Marco J. Schnabel, MD Department of Urology University of Regensburg [email protected]

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Abstract Introduction: Shock wave lithotripsy (SWL) is the gold standard treatment of most renal and proximal ureter calculi. Severe bleeding complications in SWL are extremely rare. Uncorrected bleeding diathesis might increase the risk and is considered to be an absolute contraindication for SWL. Objective: Perioperative management of anticoagulative and antiplatelet therapy has changed in the recent past. In particular, low-dose acetylsalicylic acid (ASA) is no longer a contraindication for many surgical procedures. Methods: A systematic Medline/Pubmed literature search of peer-reviewed scientific articles in urology and cardiovascular medicine was performed concerning the management of anticoagulative and antiplatelet medication during SWL. Results: The literature on medically acquired and pathological bleeding diathesis and SWL in general is rare, retrospective, non-standardized and of low quality. Routine cessation of obligatory indicated anticoagulative or antiplatelet medication implies a significant risk for cardiovascular adverse events (CAE). Ureterorenoscopy is recommended in patients with uncorrected bleeding diathesis although this is not based on high level evidence. Conclusion: In patients with obligatory intake of anticoagulative or antiplatelet medication the risk for CAE must be balanced against the SWL-induced bleeding risk. In patients with low-dose ASA-intake, SWL should be considered as an option instead of being disregarded as an absolute contraindication. Prospective randomized trials designed to define the optimal management of anticoagulants and antiplatelets during SWL are warranted.

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3 Introduction Shock wave lithotripsy (SWL) is the gold standard treatment modality for most renal calculi (Türk et al. 2013). Although a minimally invasive therapy with low complication rates, SWL can cause renal hematoma (RHT). To date, any medication that impairs blood coagulation is believed to increase the risk of developing RHT (Skolarikos et al. 2006). Current EAU guidelines on urolithiasis recommend stopping any kind of anticoagulative or antiplatelet therapy, including ASA, prior to beginning therapy for urolithiasis. In case of mandatory ASA intake ureterorenoscopy (URS) is suggested as the first-line therapy of choice (Türk et al. 2013). We summarize the available publications on anticoagulative and antiplatelet management during SWL treatment and provide an overview of anticoagulative and antiplatelet medication and the current standard of their perioperative management in general.

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4 Methods A systematic Medline/Pubmed literature search of peer-reviewed scientific articles published before 11/26/2013 in urology and cardiovascular medicine was performed for the management

of anticoagulative and antiplatelet medication during SWL. The search was performed using combinations of the following terms: urolithiasis, SWL, URS, antiplatelet therapy, anticoagulation, perioperative management, ASA, aspirin, Clopidogrel, Prasugrel, Ticagrelor, VKA, Coumadin, Dabigatran, Rivaroxaban, Apixanban, Tirofiban and Eptifibatide. 86 publications were obtained. 50 were selected based on title, abstract, study format, and content by consensus of all participating co-authors.

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Results The literature on medically acquired and pathological bleeding diathesis and SWL in general is rare, retrospective, non-standardized and of low quality (Table 1). Routine cessation of obligatory indicated anticoagulative or antiplatelet medication implies a significant risk for cardiovascular adverse events (CAE). The common recommendation for URS in patients with uncorrected bleeding diathesis is not based on high-level evidence.

Basics on antiplatelet drugs Antiplatelet drugs are primarily indicated for diseases associated with arteriosclerosis, such as coronary heart disease (CHD) and arterial obstructive disease. This medication is mostly used metaphylactically to prevent arterial, stent or bypass thrombosis, whereby different drugs are used depending on the indication (Baron et al. 2013). All of them act by inhibiting platelet activation. The standard medication given for almost all vascular disease is low-dose acetylsalicylic acid (ASA) either 81mg or 100mg. The ASA effect continues for 7 to 10 days, until the entire platelet population has been replaced once (Douketis et al. 2012). Clopidogrel, a P2Y12 blocker like Ticlopidin, Prasugrel or Ticagrelor, is a more powerful antiplatelet drug than ASA (CAPRIE Steering Committee 1996). Dual antiplatelet therapy (DAT) as a combination of ASA and a P2Y12 blocker is even more potent than the single drug (Yusuf et al. 2001). DAT or even triple course with an additional antithrombotic drug is recommended following an acute myocardial infarction, coronary stenting or bypass surgery (Brilakis et al. 2013, Dunning et al. 2008).

Basics on anticoagulants Anticoagulative drugs are used prophylactically and metaphylactically against thrombosis as well as for stroke prevention in patients with atrial fibrillation. Different kinds of heparin are used for thrombosis prophylaxis in daily clinical practice, most commonly a subcutaneous application of lowmolecular-weight heparin (LMWH) or intravenous unfractionated heparin (UFH). The dosage depends on the risk of thromboembolism. Coumadins, such as Phenprocoumon or Warfarin, are vitamin K antagonists (VKA) and used for long-term prophylaxis (Holbrook et al. 2012). In the recent past, new oral agents (Dabigatran, Rivaroxaban and Apixaban) have been approved for thrombosis prophylaxis in clinical practice. Further information about the mechanisms of the individual drugs is provided in the appendix.

Perioperative management in general The prevalence of cardiovascular disease is higher in aging populations (Odden et al. 2011). This issue has become more critical, as 4-7% of patients who received a coronary stent undergo a surgical intervention within the first year after placement (Brilakis et al. 2013). In view of the outcome

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6 superiority of DAT compared to low-dose ASA alone, DAT is regularly used after coronary stent placement (Yusuf et al. 2001). Depending on the type of coronary stent (bare-metal or drug-eluting) DAT is mandatory for 3-12 months (Douketis et al. 2012). A premature partial or complete cessation of DAT results in a high risk (up to 29.4%) of acute stent thrombosis, which is fatal in up to 45% of cases (Poldermans et al. 2010, Iakovou et al. 2005). Even after this timeframe, which is the most critical, the perioperative cessation of low-dose ASA results in a CAE in up to 10.2% of cases (Burger et al. 2005). Similar rates were seen in intermediate and high-risk patients without coronary stent placement (Oscarsson et al. 2010). On this basis, ASA should be continued as a life-long medication course (Douketis et al. 2012). The continuation of low-dose ASA only slightly increases bleeding risk (factor of 1.5), without causing more serious bleeds (Burger et al. 2005). In light of these findings, the perioperative risk stratification of bleeding risk against the risk of CAE is recommended. As the risk of CAE outweighs the risk of bleeding in all but spinal or intracranial surgery, as well as in patients with high bleeding risk and low CAE risk, ASA should be continued perioperatively (Poldermans et al. 2010). Such a risk stratification approach is also valid for urological interventions. Kefer et al. reported five thrombotic events (10.6%) in 47 patients who discontinued their antiplatelet or anticoagulant medication prior to a partial nephrectomy, whereas no events occurred in the matched control group (Kefer et al. 2008).

Evidence on antiplatelet and anticoagulative therapy in SWL EAU guidelines recommend stopping any kind of anticoagulative or antiplatelet therapy before an intervention for urolithiasis. However, this recommendation is based on very limited data. Most studies dealing with coagulopathy and treatment for urolithiasis pool a very heterogeneous patient cohort (e.g. haemophilia, von-Willebrand disease, thrombocytopenia, VKA intake, seldom ASA or Clopidogrel) (Türk et al. 2013).

SWL treatment is classified as a procedure with a high bleeding risk (Baron et al. 2013). Bleedingrelated complications include prolonged gross hematuria and RHT. But is this classification justified? Gross hematuria is commonly seen after SWL and not very likely to cause a significant haemoglobin drop with the need for intervention (McAteer und Evan 2008). RHT is a rare complication, with many studies reporting an incidence of less than 1% (Lee et al. 2013, Collado Serra et al. 1999, Razvi et al. 2012, Torrecilla Ortiz et al. 1997, Schnabel et al. 2014). The likelihood of asymptomatic RHT can be up to 25% if a follow-up MRI or CT is performed (Rubin et al. 1987, Baumgartner et al. 1987, Kaude et al. 1985). RHT management is usually conservative (Razvi et al. 2012, Collado Serra et al. 1999). Surgical intervention or death are extremely rare (Torrecilla Ortiz et al. 1997).

Acetylsalicylic acid Information on performing SWL during ASA intake is limited to two studies cited in the guidelines, and neither reported an increased RHT risk due to ASA exposure (Fischer et al. 2007, Klingler et al. 2003).

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7 The first is an experimental animal study on tissue damage in rat kidneys after SWL under ASA intake. RHT were found in all rat kidneys independently of ASA. The author highlights the limitation of the study's animal model - inferences to human physiology must be approached from a critical standpoint. (Fischer et al. 2007). In the second study, Klingler reported a complication rate of 33.3% in 6 of 18 patients with a coagulopathy undergoing SWL for urolithiasis. The study cohort consisted of patients with medically impaired coagulation (ASA or VKA) and other coagulation disorders (thrombocytopenia, pancytopenia, haemophilia A, factor VII deficiency, factor XI deficiency, liver cirrhosis, lupus erythematodes). In the event of treatment, ASA and VKA were paused prior to SWL, with ASA being paused 1 to 5 days prior to intervention (mean timeframe 3.6). None of the complications were related to ASA intake. The author provided no information about the 12 patients who did not suffer complications (Klingler et al. 2003). Cardiovascular guidelines recommend stopping ASA seven to 10 days prior to surgery if needed (Douketis et al. 2012). In Klingler’s study, ASA was paused 3.6 days before SWL (range 1 to 5). It can therefore be assumed that at least some of the patients experienced partial ASA effects at the time of intervention. However, no complications were reported as a result of the intake of ASA (Klingler et al. 2003). On the other hand, recent experimental studies demonstrated a completely restored PLT aggregation as early as 3 to 4 days after ASA cessation (Li et al. 2012, Zisman et al. 2010).

Our research also yielded studies concerning ASA and SWL. The largest retrospective analysis of 21699 SWL treatments revealed 31 (0.28%) cases of RHT. One of the RHT patients took ASA until 3 days before undergoing SWL (Collado Serra et al. 1999). The number of patients with ASA and without RHT was not given. Lee et al. observed 20 (0.32%) cases of RHT after SWL for kidney stones in a cohort of 6177 patients. They compared the RHT patients with 146 matched patients from the control group without RHT. Hypertension (p=0.022), a high body mass index (p=0.026) and large stones (p=0.026) were independent risk factors. Two RHT patients took ASA. They neither reported the intake of ASA in the control group, nor provided a statistical analysis (Lee et al. 2013). Our recently published data, which features 1324 SWL treatments, contrasts with Lee’s study. While the RHT rate was comparably low (0.58%), none of the RHT patients took ASA, although this was not a contraindication for SWL (Schnabel et al. 2014). There is only one retrospective study providing statistical evaluation of RHT occurrence after SWL under ASA. After 6732 SWL treatments for renal- or proximal ureteral stones, 21 RHTs (0.34%) were found and matched with 84 controls. Unfortunately, the authors pooled the intake of ASA with nonsteroidal anti-inflammatory drugs and found a significantly increased risk of RHT (Hazard ratio 4.2; p=0.0355). Additionally, hypertension was a statistically significant risk factor (hazard ratio 3.3, p=0.0384). Three of the 21 RHT patients received blood products, no further intervention was needed (Razvi et al. 2012).

In addition to these studies, several case reports refer to RHT after SWL under ASA intake. While Knorr’s patient took two Aspirin a day prior to SWL, Ruiz reported an instance of bilateral RHT

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8 following ASA intake once a day for one week before SWL (Ruiz und Saltzman 1990, Knorr und Woodside 1990).

P2Y12 blocker There is no data available about the newer P2Y12 blockers (Prasugrel, Ticagrelor) and SWL. Two case reports were found for the platelet inhibitor Clopidogrel. While one patient with RHT needed blood products, the other suffered a life-threatening RHT which resulted in a nephrectomy, the patient survived (Sare et al. 2002, Bahceci et al. 2005). In two other case reports, patients undergoing dual antiplatelet therapy (ASA and Clopidogrel) developed a RHT after SWL (Sherman and Dogon 2006). In the second publication the RHT was fatal (Toro and Kardos 2008). We found one trial reporting a significant influence of antiplatelet therapy on RHT development after SWL. However, this study needs to be interpreted with caution, since the statistical analysis is contradictory and the provided data incomplete. 17 RHTs were seen in 402 patients (4.1%). Of those 402 patients, 19 were undergoing a non-specified course of antiplatelet treatment. In this 19-patient subgroup, five developed an RHT. However, for the calculation of the RHT risk, six patients were compared with 15 patients in the control group (RHT risk 31%). In addition, out of the five RHT patients undergoing “antiplatelet therapy”, three were taking an antihypertensive drug without antiplatelet effect (Nifidipin, Alacepril and Nicardipine respectively), only two were taking Ticlopidine (P2Y12 blocker). Furthermore, the RHT incidence of 4.1% was calculated by kidney, not by session. The author used a shock-wave frequency of 1.25 to 20Hz (75 to 1200 shocks per minute), which might explain their high RHT incidence. The total energy applied was 132±124.6 J (mean±SD) in the RHT group versus 228±368.3 J in the controls (p=ns) (Ueda et al. 1993). Unfortunately, no high-quality evidence-based studies on P2Y12 blocker and SWL are available. This lack of evidence might be a reason for the interesting results of a recent study in the UK. Asked regarding their management of patients taking Clopidogrel, 54 of 297 British urologists (18.2%) indicated that they would perform SWL without suspending administration of the drug. Only 4 (1.6%) reported RHT after SWL (Mukerji et al. 2009). Due to the absence of high-quality evidence of SWL during P2Y12 blocker intake cannot be recommended.

Vitamin K antagonist (VKA) VKA are usually bridged before SWL. No publication was found that had investigated SWL during ongoing VKA intake.

New oral anticoagulative drugs No publications were found reporting SWL and the use of new oral anticoagulative agents such as Dabigatran, Rivaroxaban and Apixaban.

Bridging strategies and SWL Antiplatelet therapy

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9 In Zanetti’s study, patients with antiplatelet therapy and high-risk of CAE were bridged with UFH s.c. three times daily. The first dosage in the morning was withheld, no CEA or RHT were seen (Zanetti et al. 2001). Pharmacokinetically, no anticoagulative effect of the heparin was present at the time of SWL (Romeo et al. 1988). Nevertheless, the guidelines advise against the use of heparin as a substitute for antiplatelet therapy because it has no effect on PLT aggregation and therefore cannot prevent thrombosis of coronary stents (Grines et al. 2007, Chassot et al. 2010), an adverse event fatal in almost half of all cases (Iakovou et al. 2005). To conclude, heparin bridging is not an adequate strategy for patients undergoing antiplatelet therapy. Bridging strategies are under investigation for high-risk patients with mandatory antiplatelet therapy and the need for urgent surgery.(Savonitto et al. 2010, Ben Morrison et al. 2012, Rassi et al. 2012, Huang et al. 2012) However, none of these intravenous glycoprotein-GPIIb/IIIa blockers were tested during SWL.

Anticoagulative therapy VKA and new oral anticoagulative drugs can be bridged with heparin (Douketis et al. 2012). While LMWH is administered subcutaneously, UFH can be used intravenously or subcutaneously. In Klingler's study, 16 patients were bridged with LMWH (Enoxaparin 40mg). SWL was performed where prothrombin time >70%. Complications were seen in two patients, with gross haematuria in one and a renal vein embolism in the other (Klingler et al. 2003). In another study with eight patients over the age of 70, LMWH was selected and used as a bridging agent without any adverse event. Power ramping and a shock frequency of 60 to 80 shocks per minute were used to reduce tissue trauma (Sighinolfi et al. 2008). UFH was used as a bridging agent in two studies. Zanetti’s group had no complications when they used UFH subcutaneously in 12 patients. They applied 5000IE UFH three times a day prior to SWL (8 a.m., 4 p.m.,12 p.m.). On the day of SWL, the morning dosage was suspended and the next given at 4 p.m. on the same day (Zanetti et al. 2001). A Spanish study featuring three i.v. UFH bridged patients and one patient who only paused VKA prior to SWL starkly contrasts with this data - SWL was done with an INR of 1.3 to 1.7 depending on the risk of thrombotic events. All of the patients developed an RHT (Collado Serra et al. 1999). To summarize, bridging with heparin for SWL would appear feasible. Protective SWL settings should be used. However, the value of the studies mentioned is limited because of their very small cohorts.

Irrespective of these findings the current bridging strategy of VKA patients has been challenged by a recently published meta-analysis that showed an increased incidence of bleeding without a reduction of periprocedural thromboembolic events.(Siegal et al. 2012)

Alternative therapeutic approaches Ureterorenoscopy

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10 EAU guidelines recommend URS for stone treatment in the event of mandatory anticoagulation or antiplatelet therapy on the basis of two retrospective feasibility studies (Türk et al. 2013). A current review pools these two studies with a third and underlines the possibility of performing URS in uncorrected bleeding diathesis with a very low likelihood of bleeding complications (4.1%, 3 of 70 patients) (Aboumarzouk et al. 2012). We also found another recently published retrospective analysis of 176 patients who underwent URS with ongoing antithrombotic medication (11 VKA, 11 VKA + ASA, 4 Clopidogrel, 13 DAT, 137 ASA). There was no significant difference in bleeding complications and CAE compared to the control group (460 patients) (Toepfer et al. 2013).

It must, however, be borne in mind that URS is the more invasive treatment, entailing more complications compared to SWL (Aboumarzouk et al. 2011). RHT can even occur during laser URS for proximal ureteral stones with a comparable rate of incidence (about 0.40%), although these RHTs seem to be more severe. In two retrospective studies featuring 3962 patients, 15 RHT were seen. Five RHTs were managed conservatively, seven RHTs were drained percutaneously and three patients underwent open surgery, 11 patients received blood products (Bai et al. 2012, Chiu et al. 2013). There is also a 2-5 % risk of perioperative coronary stent thrombosis within the first two years after placement, irrespective of antiplatelet therapy management. Coronary stent thrombosis is lethal in approximately 50% of cases (Douketis et al. 2012).

Cessation of antiplatelet therapy In cases where a cessation of the antiplatelet therapy is justifiable, ASA should be paused at least four days prior to SWL (Zisman et al. 2010, Li et al. 2012). In the case of DAT, ASA needs to be continued (Poldermans et al. 2010, Douketis et al. 2012). Clopidogrel should be paused five to seven days prior to an intervention, the period for Prasugrel should be seven to nine days (Price et al. 2012).

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11 Conclusion In patients with the obligatory intake of anticoagulative or antiplatelet medication, the risk of CAE must be balanced against that of SWL-induced bleeding. There is a low risk of RHT after SWL, which could be increased by low-dose ASA intake. RHT management is mostly conservative. Risk stratification for patients with obligatory low-dose ASA-intake based on individual patient characteristics is necessary. SWL should at least be considered as an option instead of being disregarded an absolute contraindication. Furthermore, the continuation of other platelet inhibitors or high-dose ASA during SWL must be discouraged, since there is no reliable data available on this and the risk for RHT would therefore be incalculable. SWL in heparin-bridged patients appears feasible. In patients with medically impaired coagulation a protective SWL setting with power ramping and a low frequency (60 shocks/min) is essential. RHT and other bleeding complications are even less likely to occur after SWL of ureteric stones. Nevertheless, current guidelines recommend cessation of anticoagulative or antiplatelet medication prior to ESWL in general, without distinguishing between ureteral and renal calculi. Further refinements of the guidelines with regard to the suspension of anticoagulative or antiplatelet medication under distinction of renal and ureteral stones are necessary. Prospective randomized trials aimed at defining the optimal management of anticoagulants and antiplatelets during SWL are warranted. Due of its clinical relevance, the risks and benefits of continuation or cessation of low-dose ASA during SWL should be the primary subject of investigation. Furthermore, experimental studies evaluating the bleeding risk during SWL with other anticoagulative or antiplatelet drugs than ASA would also be of interest.


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Acknowledgment

The authors would like to thank Patrick Goldsworthy for his assistance.

Journal of Endourology Antiplatelet and anticoagulative medication during shock wave lithotripsy (doi: 10.1089/end.2014.0162) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Page 13 of 22

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Author Disclosure Statement

The authors have no conflicts of interest, especially none of a competing financial nature.

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16 Morris TA, Jacobson A, Marsh JJ, Lane JR. 2005. Pharmacokinetics of UH and LMWH are similar with respect to antithrombin activity. Thromb Res, 115 (1-2):45-51. Mukerji G, Munasinghe I, Raza A. 2009. A survey of the peri-operative management of urological patients on clopidogrel. Ann R Coll Surg Engl, 91 (4):313-320. Odden MC, Coxson PG, Moran A, Lightwood JM, Goldman L, Bibbins-Domingo K. 2011. The impact of the aging population on coronary heart disease in the United States. Am J Med, 124 (9):827-833.e825. Oscarsson A, Gupta A, Fredrikson M, Järhult J, Nyström M, Pettersson E, Darvish B, Krook H, Swahn E, Eintrei C. 2010. To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial. Br J Anaesth, 104 (3):305-312. Poldermans D, Bax JJ, Boersma E, De Hert S, Eeckhout E, Fowkes G, Gorenek B, Hennerici MG, Iung B, Kelm M, Kjeldsen KP, Kristensen SD, Lopez-Sendon J, Pelosi P, Philippe F, Pierard L, Ponikowski P, Schmid J-P, Sellevold OF, Sicari R, Van den Berghe G, Vermassen F, Hoeks SE, Vanhorebeek I, Vahanian A, Auricchio A, Ceconi C, Dean V, Filippatos G, FunckBrentano C, Hobbs R, Kearn P, McDonag T, McGregor K, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P, De Caterina R, Agewall S, Al Attar N, Andreotti F, Anker SD, Baron-Esquivias G, Berkenboom G, Chapoutot L, Cifkova R, Faggiano P, Gibbs S, Hansen HS, Iserin L, Israel CW, Kornowski R, Eizagaechevarria NM, Pepi M, Piepoli M, Priebe HJ, Scherer M, Stepinska J, Taggart D, Tubaro M, Assessment TFfPCR, Cardiology PCMiN-cSoESo, Anaesthesiology ESo. 2010. Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery: the Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Noncardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of Anaesthesiology (ESA). Eur J Anaesthesiol, 27 (2):92-137. Price MJ, Walder JS, Baker BA, Heiselman DE, Jakubowski JA, Logan DK, Winters KJ, Li W, Angiolillo DJ. 2012. Recovery of platelet function after discontinuation of prasugrel or clopidogrel maintenance dosing in aspirin-treated patients with stable coronary disease: the recovery trial. J Am Coll Cardiol, 59 (25):2338-2343. Quinlan DJ, Eriksson BI. 2013. Novel oral anticoagulants for thromboprophylaxis after orthopaedic surgery. Best Pract Res Clin Haematol, 26 (2):171-182. Rassi AN, Blackstone E, Militello MA, Theodos G, Cavender MA, Sun Z, Ellis SG, Cho L. 2012. Safety of "bridging" with eptifibatide for patients with coronary stents before cardiac and non-cardiac surgery. Am J Cardiol, 110 (4):485-490. Razvi H, Fuller A, Nott L, Méndez-Probst CE, Leistner R, Foell K, Davé S, Denstedt JD. 2012. Risk factors for perinephric hematoma formation after shockwave lithotripsy: a matched casecontrol analysis. J Endourol, 26 (11):1478-1482. Romeo G, Salanitri G, Catania G. 1988. Time-course of anti-Xa effects of calcium heparin and lowmolecular-weight heparin given s.c.: insights for thrombosis prevention. Drugs Exp Clin Res, 14 (6):423-427.

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17 Rubin JI, Arger PH, Pollack HM, Banner MP, Coleman BG, Mintz MC, VanArsdalen KN. 1987. Kidney changes after extracorporeal shock wave lithotripsy: CT evaluation. Radiology, 162 (1 Pt 1):21-24. Ruiz H, Saltzman B. 1990. Aspirin-induced bilateral renal hemorrhage after extracorporeal shock wave lithotripsy therapy: implications and conclusions. J Urol, 143 (4):791-792. Sare GM, Lloyd FR, Stower MJ. 2002. Life-threatening haemorrhage after extracorporeal shockwave lithotripsy in a patient taking clopidogrel. BJU Int, 90 (4):469. Savonitto S, D'Urbano M, Caracciolo M, Barlocco F, Mariani G, Nichelatti M, Klugmann S, De Servi S. 2010. Urgent surgery in patients with a recently implanted coronary drug-eluting stent: a phase II study of 'bridging' antiplatelet therapy with tirofiban during temporary withdrawal of clopidogrel. Br J Anaesth, 104 (3):285-291. Schnabel MJ, Gierth M, Chaussy CG, Dötzer K, Burger M, Fritsche HM. 2014. Incidence and risk factors of renal hematoma: a prospective study of 1,300 SWL treatments. Urolithiasis. Sherman SC, Dogon A. 2006. Subcapsular renal hematoma after shock wave lithotripsy. J Emerg Med, 30 (4):437-439. Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. 2012. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation, 126 (13):1630-1639. Sighinolfi MC, Micali S, Grande M, Mofferdin A, De Stefani S, Bianchi G. 2008. Extracorporeal shock wave lithotripsy in an elderly population: how to prevent complications and make the treatment safe and effective. J Endourol, 22 (10):2223-2226. Skolarikos A, Alivizatos G, de la Rosette J. 2006. Extracorporeal shock wave lithotripsy 25 years later: complications and their prevention. Eur Urol, 50 (5):981-990. Toepfer NJ, Baylor K, Henry Y, Simmons J, Berger PB. 2013. The Effect of Antiplatelet and Anticoagulant Therapy on the Clinical Outcome of Patients Undergoing Ureteroscopy. Urology. Toro K, Kardos M. 2008. Fatal renal hemorrhage after extracorporeal shock wave lithotripsy. J Forensic Sci, 53 (5):1191-1193. Torrecilla Ortiz C, Matías López JJ, Contreras García J, Aguiló Luciá F, Camps Lloveras N, Riera Canals L, Serrallach Mila N. 1997. [Renal hematoma after shockwave extracorporeal lithotripsy]. Actas Urol Esp, 21 (8):752-757. Türk C, Knoll T, Petrik A, Sarica K, Skolarikos A, Straub M, Seitz C 08 August 2013. The EAU Guidelines on Urolithiasis http://www.uroweb.org/guidelines/online-guidelines/. Ueda S, Matsuoka K, Yamashita T, Kunimi H, Noda S, Eto K. 1993. Perirenal hematomas caused by SWL with EDAP LT-01 lithotripter. J Endourol, 7 (1):11-15. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, Investigators CiUAtPRET. 2001. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med, 345 (7):494-502. Zanetti G, Kartalas-Goumas I, Montanari E, Federici AB, Trinchieri A, Rovera F, Pisani E. 2001. Extracorporeal shockwave lithotripsy in patients treated with antithrombotic agents. J Endourol, 15 (3):237-241.


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Zisman E, Erport A, Kohanovsky E, Ballagulah M, Cassel A, Quitt M, Pizov R. 2010. Platelet function recovery after cessation of aspirin: preliminary study of volunteers and surgical patients. Eur J

Anaesthesiol, 27 (7):617-623.

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19

Abbreviations ASA

acetylsalicylic acid

DAT

dual antiplatelet therapy

CAE

cardiovascular adverse event

LWMH

low weight molecular heparin

PLT

thrombocyte

RHT

renal hematoma

SWL

shock wave lithotripsy

UFH

unfractioned heparin

URS

ureterorenoscopy

VKA

vitamin K antagonist

Table 1: Overview of studies concerning SWL and RHT incidence.

Study

Design

Coagulopathy

Collado Serra et al.

R (n = 21699)

ASA

Klingler et al.

R (n = 6827)

ASA

†

RHT associated

RHT overall

n=1

0.28% (n = 31)

None

(n = 11) †

Lee et al.

R (n = 6177)

ASA

Razvi et al.

R (n = 6723)

ASA and NSAID

Schnabel et al.

P (n = 1324)

ASA

Torrecilla et al.

R (n = 12000)

None

Ueda et al.

R (n = 402)

Antiplatelet therapy

†

n=2

n=8

0.32% (n =21) ††

0.34% (n = 21)

n=0

0.58% (n = 7)

0.078% (n = 10)

n = 5 (31%)

‡

4.1% (n = 17)

(n = 19) Collado Serra et al.

R (n = 21699)

UFH iv

n = 3 (100%)

0.28% (n = 31)

(n = 3) Klingler et al.

R (n = 6827)

Enoxaparin 40mg

None

‡‡

(n =16) Sighinolfi et al.

R (n = 140)

LMWH sc

None

(n = 8) Zanetti et al.

R (n = 749)

UFH sc (n =12)

P – prospective study; R – retrospective study

None

None


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20

†

††

‡

‡‡

intake in control group not reported 21 RHT cases matched with 84 controls, hazard ratio 4.2 for ASA and NSAID intake 2 patient with PY12 blocker, 3 with antihypotensive drug without antiplatelet effect 1 patient with gross hematuria, 1 with renal vein embolism

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21

Appendix Antiplatelet drugs - Mechanism of action Antiplatelet drugs impair blood coagulation by inhibition of PLT activity. PLT activation leads to a selfamplifying process of mediator production and activation of other PLT which finally results in the formation of a PLT clot. All antiplatelet drugs act by inhibiting PLT activation.

ASA ASA irreversibly blocks the cyclooxygenases (COX) 1 and 2 located in the endoplasmatic reticulum of the PLT. This prevents the production of Thromboxan A2 which is an activating mediator of the PLT. Since PLT lack a nucleus, they are unable to reproduce COX. Thus the irreversible ASA receptor blockage lasts the whole lifespan of a PLT. The whole PLT population is replaced after seven to ten days. Recent findings suggest an unimpaired PLT population of 30 to 40% is sufficient to provide normal PLT clot formation (Zisman et al. 2010, Li et al. 2012).

P2Y12 blocker P2Y12 is a receptor for the PLT activating ligand ADP which is expressed on PLT surface. It is spilled out by destroyed cells and secreted by activated PLT.

Anticoagulative drugs - Mechanism of action This group of drugs impairs blood clotting by inhibiting single factors of the coagulation cascade.

Heparin Heparin binds to antithrombin III and activates it. Actived antithrombin III is a protease which inactivates clotting-factor IIa (thrombin) and clotting-factor Xa (Morris et al. 2005).

Coumadin Coumadins are VKA and inhibit the synthesis of vitamin K depending clotting-factors (II, VII, IX, X).

New oral anticoagulative drugs Rivaroxaban and Apixaban are direct factor Xa blockers. The inhibited Xa is unable to facilitate prothrombin to the active form thrombin (IIa). Thrombin activates PLT and catalyzes the conversion of fribrinogen to fibrin. Dabigatran on the other hand follows a new approach by directly blocking fibrinbound and free IIa (Quinlan und Eriksson 2013).

Appendix


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22

Re: Antiplatelet and Anticoagulative Medication During Shockwave Lithotripsy.

Complementary approaches to decreasing discomfort during shockwave lithotripsy (SWL).

Renal Vasoconstriction Occurs Early During Shockwave Lithotripsy in Humans.

[Sonography and biliary extracorporeal shockwave lithotripsy (ESWL)].

Extracorporeal shockwave lithotripsy of primary intrahepatic stones.

[Extracorporeal shockwave lithotripsy in gallstone perforation].

Extracorporeal shockwave lithotripsy for upper tract urolithiasis.

Shockwave lithotripsy of salivary duct stones.

[Extrasystoles during extracorporeal biliary shockwave lithotripsy. Their incidence and clinical significance].

[Extracorporeal shockwave lithotripsy: what system and for what purpose?].

[Imaging procedures prior to the extracorporeal shockwave lithotripsy of gallstones].

Extracorporeal shockwave lithotripsy monotherapy for treating patients with bladder stones.

Spleen injury following left extracorporeal shockwave lithotripsy (ESWL).

Optical coupling control: an important step toward better shockwave lithotripsy.

Does lithotripsy increase stone recurrence? A comparative study between extracorporeal shockwave lithotripsy and non-fragmenting percutaneous nephrolithotomy.

Quantification of the Range of Motion of Kidney and Ureteral Stones During Shockwave Lithotripsy in Conscious Patients.

[Endoscopy, shockwave lithotripsy and local lysis in complicated pigmentary calculi of extra- and intrahepatic bile ducts].

Comparison of treatment outcomes according to output voltage during shockwave lithotripsy for ureteral calculi: a prospective randomized multicenter study.

Does Stepwise Voltage Ramping Protect the Kidney from Injury During Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial.

Shockwave lithotripsy with renoprotective pause is associated with renovascular vasoconstriction in humans.

Efficacy of extracorporeal shockwave lithotripsy using Dornier SII in different levels of ureteral stones.

Impact of ureteric stent on outcome of extracorporeal shockwave lithotripsy: A propensity score analysis.

Evolution of shockwave lithotripsy (SWL) technique: a 25-year single centre experience of >5000 patients.

Immediate versus delayed shockwave lithotripsy for inaccessible stones after uncomplicated percutaneous nephrolithotomy.