Hospital Practice
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Perioperative Anticoagulation and Renal Disease: An Update Suparna Dutta MD, MPH, Amir K. Jaffer MD, MBA, Barbara A. Slawski MD, MS, Kurt J. Pfeifer MD, Gerald W. Smetana MD & Steven L. Cohn MD To cite this article: Suparna Dutta MD, MPH, Amir K. Jaffer MD, MBA, Barbara A. Slawski MD, MS, Kurt J. Pfeifer MD, Gerald W. Smetana MD & Steven L. Cohn MD (2014) Perioperative Anticoagulation and Renal Disease: An Update, Hospital Practice, 42:5, 132-138 To link to this article: http://dx.doi.org/10.3810/hp.2014.12.1166
Published online: 30 Jun 2015.
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C L I N I C A L F E AT U R E S
Perioperative Anticoagulation and Renal Disease: An Update
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DOI: 10.3810/hp.2014.12.1166
Suparna Dutta, MD, MPH 1 Amir K. Jaffer, MD, MBA 1 Barbara A. Slawski, MD, MS 2 Kurt J. Pfeifer, MD 2 Gerald W. Smetana, MD 3 Steven L. Cohn, MD 4 1 Rush Medical College, Chicago, IL; 2Medical College of Wisconsin, Milwaukee, WI; 3Harvard Medical School, Boston, MA; 4University of Miami Miller School of Medicine, Miami, FL
Correspondence: Suparna Dutta, MD, MPH, Rush Medical College, 1717 W Congress Pkwy, 1029 Kellogg, Chicago, IL 60612. Tel: 312-942-4200 E-mail: [email protected]
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Abstract: As our surgical population becomes older and increasingly medically complex, knowledge of the most recent perioperative literature can provide guidance for physicians across multiple specialties caring for the surgical patient. Common issues many clinicians encounter in the perioperative period relate to anticoagulation and renal disease. This article identifies gaps in knowledge for the fields of perioperative anticoagulation, acute kidney injury, and chronic kidney disease and highlights recently published studies on these topics that attempt to fill these gaps and help clinicians provide excellent care for their patients. Keywords: perioperative care; anticoagulation; thromboembolism prophylaxis; acute kidney injury; chronic kidney disease
Introduction
Each year, . 200 million people undergo surgery worldwide, and this population is becoming increasingly complex.1 An estimated 33 million patients undergo surgery in the United States every year, and adverse events related to surgery affect . 1 million of these patients, at an estimated cost of $25 billion annually.2 Perioperative medicine relies on evidence-based strategies to optimize care for the surgical patient. Issues with the management of patients undergoing anticoagulation therapy or those with kidney disease are common causes of perioperative morbidity and mortality, and evidencebased strategies to identify and mitigate risk in these patients can lead to significant improvement in outcomes. This article provides a concise review of the high-impact articles published during the past year on the management of perioperative anticoagulation and renal disease. Many patients are on long-term anticoagulation therapy before surgery for stroke prevention or treatment of venous thromboembolism. Recently, novel oral anticoagulants (NOACs) such as apixaban, dabigatran, and rivaroxaban were approved for long-term oral anticoagulation, and are increasingly common in the perioperative setting. Preparation for surgery often requires interruption of anticoagulation before intervention to avoid perioperative bleeding complications. Bleeding can be associated with infections, repeat operations, delayed wound healing, and longer hospital stays.3 Given that these medications have been available for only a short time, limited literature is available regarding the optimal timing or method of interruption before surgery. Many patients are also initiated on anticoagulation postoperatively for thromboprophylaxis. Venous thromboembolism is a common cause of morbidity and mortality after surgery, and pharmacologic thromboprophylaxis reduces this risk, most notably after joint replacement surgery.4 However, pharmacologic thromboprophylaxis has also
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Perioperative Anticoagulation and Renal Disease
been associated with the development of major bleeding.4 Although vitamin K antagonists and low-molecular-weight heparin (LMWH) have long been the standard of care for thromboprophylaxis, agents such as the NOACs and aspirin are increasingly under scrutiny for their utility in this setting. The development of perioperative acute renal failure is another common complication of surgery, with an incidence between 1% and 36%, depending on type of surgery and definition of acute renal failure. It is also associated with substantial perioperative morbidity and mortality.5 Much of the literature on perioperative renal failure focuses on patients undergoing cardiovascular surgery and lacks a universal definition of acute renal failure, now referred to as acute kidney injury (AKI). The heterogeneity of this definition and previously studied surgical populations has made it difficult to draw conclusions and make comparisons between studies. In 2004, the Acute Dialysis Quality Initiative published the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria to standardize the definition and staging for AKI (Table 1).6 This standardization has helped investigators better study the incidence, risk factors, and outcomes associated with perioperative AKI, and to evaluate treatment options aimed at decreasing incidence. Chronic kidney disease (CKD) is a major health problem, with a prevalence of 13% in the United States.7 Chronic kidney disease is an independent predictor for adverse overall health outcomes, including cardiovascular complications and mortality.8 The impact of underlying CKD on postoperative outcomes in patients undergoing surgery is not clearly understood. Several reasons for this exist, with one of the most important being variations in how kidney disease is measured. For determining renal function in adults, the National Kidney Foundation currently recommends estimated glomerular filtration rate (eGFR), calculated using either the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) equations.9 This standardization has better allowed investigators to start examining the relationship between chronic kidney dysfunc-
tion and adverse outcomes after surgery.
Methods
This summary of recent literature in both perioperative anticoagulation and kidney disease is derived from the “Update in Perioperative Medicine” presented at the 9th Annual Perioperative Medicine Summit and the Society of General Internal Medicine 37th Annual Meeting.10,11 A systematic search strategy was used to identify articles of particular relevance for the medical care of patients before surgery. MEDLINE was searched for the period from January 1, 2013 through April 31, 2014 for Medical Subject Heading terms, including “perioperative complications,” “intraoperative complications,” “postoperative complications,” “preoperative care,” “intraoperative care,” “perioperative care,” “postoperative care,” “intraoperative period,” and “preoperative period.” The following text words were also included in the title or abstract: “intraoperative” OR “postoperative” OR “perioperative” AND “complication” OR “event.” Articles related to transplantation, cardiac, and pediatric surgery were excluded. Selected studies were considered methodologically sound; were of interest to practicing internists/hospitalists, anesthesiologists, and/or surgeons; addressed common postoperative outcomes; and could potentially change the approach to diagnosis, risk stratification, or prevention of postoperative medical complications. The authors determined the final list through consensus based on relevance to the clinical practice of perioperative medicine.
Thromboprophylaxis
The NOACs are quickly replacing traditional agents such as heparin, LMWHs, and warfarin. Already published are a few systematic reviews which compare these agents with LMWH12; however more information is needed requiring the safety and efficacy of these agents in the perioperative period. In a new study, Adam et al3 performed a comparative effectiveness analysis to determine the effectiveness and
Table 1. Definition of RIFLE Criteria
GFR Criteria
Urine Output Criteria
Risk Injury Failure
Increased Cr by 1.5x OR GFR decrease by . 25% Increased Cr by 2x OR GFR decrease by . 50% Increased Cr by 3x OR GFR decrease by . 75% OR Cr . 4.0 mg/dL (acute increase . 0.5 mg/dL) Complete loss of renal function . 4 wk Loss of kidney function . 3 mo
Urine output , 0.5 mL/kg/h × 6 h Urine output , 0.5 mL/kg/h × 12 h Urine output , 0.3 mL/kg/h × 24 h OR Anuria × 12 h
Loss End-Stage Renal Disease
© 2004 Bellomo et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article’s original URL. http://ccforum.com/content/8/4/R204. Abbreviations: Cr, serum creatinine; GFR, glomerular filtration rate. © Hospital Practice, Volume 42, Issue 5, December 2014, ISSN – 2154-8331 133 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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safety of the NOACs compared with standard thromboprophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA). Literature review identified 6 English language systematic reviews that compared NOACs with standard thromboprophylaxis in randomized clinical trials of adults undergoing elective THA or TKA. These studies were included in the analysis that used deep venous thrombosis (DVT) and pulmonary embolism (PE) as primary outcomes and mortality and major bleeding as secondary outcomes. Factor Xa inhibitors (eg, rivaroxaban and apixaban) were associated with fewer symptomatic DVT events than LMWH (4 fewer events per 1000 patients), but no significant difference in mortality or nonfatal PE was identified. The risk for major bleeding also increased (2 more events per 1000 patients). Outcomes with the direct thrombin inhibitors (DTIs; eg, dabigatran) were similar to those with LMWH. Specific odds ratios (ORs) for the various outcomes with NOACs are illustrated in Table 2. The work of Adam et al3 confirms that NOACs are effective for thromboprophylaxis after THA and TKA. However, their clinical benefits compared with LMWH are marginal and offset by increased risk for major bleeding. Headto-head comparisons among NOACs are lacking, and real-life experience with these agents is slowly increasing. The role of aspirin for extended venous thromboembolism (VTE) prophylaxis after major joint replacement surgery also remains uncertain. The American College of Chest Physicians (ACCP) guidelines include aspirin as an acceptable form of VTE prophylaxis in joint replacement surgery.13 These guidelines also state that LMWH is a preferred form of prophylaxis over other agents. Anderson et al14 designed a study to compare aspirin and dalteparin for extended thromboprophylaxis to prevent symptomatic VTE after THA. Designed as a noninferiority study, this randomized, blinded, controlled trial was conducted at 12 tertiary care orthopedic referral centers in Canada. A total of 778 patients who had elective unilateral THA between 2007 and 2010 received 10 days of dalteparin prophylaxis and were subsequently Table 2. Comparative Effectiveness of Novel Oral Anticoagulants and LMWH in Total Joint Arthroplasty Patients Outcome
Factor Xa Inhibitors vs Dabigatran vs LMWH LMWH OR (95% CI) OR (95% CI)
Symptomatic DVT Nonfatal PE Major bleeding Mortality
0.46 (0.30–0.70) 1.07 (0.65–1.73) 1.27 (0.98–1.65) 0.95 (0.55–1.63)
0.82 (0.17–3.99) 0.69 (0.31–1.54) 0.94 (0.58–1.52) 1.54 (0.38–6.33)
Abbreviations: DVT, deep venous thrombosis; LMWH, low-molecular-weight heparin; OR, odds ratio; PE, pulmonary embolism.
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randomized to receive 28 days of dalteparin 5000 U subcutaneously (n = 400) or aspirin at 81 mg orally (n = 386). Primary outcomes were symptomatic VTE (confirmed through objective testing) and major bleeding. Five of 398 patients (1.3%) who received extended-duration dalteparin and 1 of 380 (0.3%) who received aspirin developed VTE (absolute difference, 1.0 percentage point; 95% CI, –0.5 to 2.5 percentage points). Aspirin was noninferior (P , 0.001) but not superior (P = 0.22) to dalteparin. Clinically significant bleeding occurred in 5 patients (1.3%) receiving extendedduration dalteparin and 2 (0.5%) receiving aspirin. The absolute between-group difference in a composite of all VTE and clinically significant bleeding events was 1.7 percentage points (CI, –0.3 to 3.8 percentage points; P = 0.091) in favor of aspirin. The study was halted prematurely because of difficulty with patient recruitment. In patients who initially received 10 days of prophylacticdose dalteparin, extended prophylaxis for 28 days with aspirin was noninferior (P , 0.001) but not superior (P = 0.22) to dalteparin. Furthermore, extended prophylaxis with aspirin was as safe as dalteparin. Given its low cost and greater convenience, aspirin may be considered an alternative for extended thromboprophylaxis after THA, although further study is likely needed.
Peri-Interventional Management of Anticoagulation
With the increase in overall prevalence of patients using NOACs for chronic anticoagulation, more patients on these drugs are undergoing interventional procedures. Novel oral anticoagulants have rapid onset of action and short half-lives compared with vitamin K antagonists, allowing for short periods of NOAC interruption without heparin bridging. However, outcome data for this approach to perioperative management are lacking. To this end, Beyer-Westendorf et al15 evaluated peri-interventional NOAC management in unselected patients in a European registry. Safety and efficacy outcomes data were collected from an ongoing, prospective cohort of . 2100 surgical and nonsurgical patients receiving NOACs, with adjudication of outcomes using standard event definitions. Of 2179 registered patients, 27.3% underwent 863 procedures, 15.6% of which were classified as minimal, 74.3% minor, and 10.1% as major procedures. Minimal procedures were defined as those with minimal tissue trauma, such as skin biopsies; minor procedures were those with minimal tissue trauma but a relevant risk of bleeding, such as cataract surgery; and major procedures were those with tissue trauma and high bleeding
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risk, such as abdominal and orthopedic procedures. In cases of NOAC interruption, the median duration of NOAC-free intervals was 3 days (2 days preoperatively and 1 day postoperatively). Major cardiovascular events occurred in 1.0% of patients and major bleeding complications in 1.2% within the first month after invasive procedures. Cardiovascular and major bleeding complications were highest after major procedures (4.6% and 8.0%, respectively). Heparin bridging did not reduce cardiovascular events but led to significantly higher rates of major bleeding complications (2.7%) compared with no bridging (0.5%; P = 0.010). Multivariate analysis demonstrated that major procedures (OR, 16.8) were an independent risk factor for major bleeding complications, whereas diabetes (OR, 13.2) and major procedures (OR, 7.3) were independent risk factors for cardiovascular events. This study suggests that short-term interruption of NOAC therapy is a safe strategy for most minimal or minor procedures. Heparin does not reduce the risk of cardiovascular events but does increase the rate of major bleeding; therefore, most patients likely can safely interrupt NOAC anticoagulation for a short period without heparin bridging.
Perioperative Renal Disease Acute Kidney Injury
Perioperative acute renal failure is associated with increased mortality in the perioperative period,16 but few data are available on who is at risk for developing AKI, options for mitigating progression of renal injury, and outcomes after surgery. Two new articles examine the incidence, risk factors, and outcomes of perioperative AKI, and evaluate treatment options to decrease the incidence of AKI, as defined by the RIFLE criteria. In a prospective cohort study, Biteker et al5 used the RIFLE criteria to examine the incidence, risk factors, and outcomes of postoperative AKI in patients undergoing noncardiac and nonvascular surgery at a single center in Istanbul, Turkey. Studied variables included age, sex, and comorbidities, and the primary outcome was the development of AKI within 7 days postoperatively. Of the 1200 consecutive patients studied with no preexisting renal disease, 6.7% developed postoperative AKI. When compared with the control group, patients with AKI were significantly more likely to be older (OR, 1.14; P = 0.004), and have diabetes mellitus (OR, 1.53; P , 0.001). These patients also had significantly longer length of stay (10.3 vs 8.1 days, P , 0.001) and higher mortality rates (OR, 3.83; P = 0.036), and were more likely to experience inpatient (OR,
3.56; P , 0.001) and long-term (after first 2 weeks of surgery; OR, 1.83; P = 0.36) cardiovascular complications. This article confirms the findings of previous studies regarding the incidence of and risk factors for the development of AKI in patients undergoing noncardiac surgery.16,17 Outcomes after the development of postoperative AKI also corroborate findings of previous studies showing an increase in in-hospital mortality and hospital length of stay.18,19 Although this is a single-center, observational study, its findings add to the growing body of evidence regarding risk factors for postoperative AKI and associated short- and longterm complications. Aggregating these findings with information already available on perioperative AKI, clinicians can attempt to identify and closely monitor patients at risk. Because of the need to identify effective renoprotective therapies, statins have recently gained attention for their potential protective effect in postoperative AKI secondary to their vasodilatory, antithrombotic, and anti-inflammatory properties.20 Animal models have shown that giving statins before an ischemic event significantly reduces the incidence of AKI,21,22 yet previous clinical studies have yielded mixed results. Studies demonstrating reductions in postoperative AKI with statins did not use standard criteria for AKI or included all lipid-lowering medications, whereas articles finding no benefit from statins were focused on very specific surgical populations.23–26 In this article, Argalious et al27 conducted a retrospective cohort study from 2004 to 2010 to better examine the relationship between preoperative statin therapy and the incidence of postoperative AKI in patients who had undergone noncardiac surgery. A total of 28 508 medical records were reviewed. The primary exposure of interest was preoperative statin use, and the outcome of interest was development of postoperative AKI using the RIFLE criteria. Propensity matching was used to balance baseline potential confounders between statin users and nonusers. Results indicated that the incidence of AKI in statin users compared with nonusers was not significant (7.1% vs 8.0%; OR, 0.88; P = 0.12). Secondary outcomes also were not significantly different, including the need for postoperative dialysis (OR, 0.8; P = 0.74) or in-hospital mortality (OR, 0.76; P = 0.18). This article suggests that statins do not have a significant renoprotective effect, and currently evidence is insufficient to support routine preoperative statin use for the prevention postoperative AKI. Further studies, including randomized control trials, are needed to better evaluate the impact of statins on perioperative renal function.
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Chronic Kidney Disease
Chronic kidney disease is a common medical problem in the United States, and is an independent predictor for poor long-term medical outcomes.28 However, no association has been documented between early kidney disease and adverse perioperative outcomes (Revised Cardiac Risk Index criteria only apply for a serum creatinine level . 2.0 mg/dL). The goal of both of the following studies was to examine the relationship between chronic kidney dysfunction and adverse outcomes after surgery, using eGFR as a measure of kidney function. Gaber et al28 conducted a case-control, observational trial to examine the association between chronic kidney dysfunction and postoperative morbidity and mortality. Data from 260 352 patients undergoing general or vascular surgery were gathered from the American College of Surgeons National Surgical Quality Improvement Program database between 2005 and 2007. Estimated GFR was calculated for each patient using the MDRD formula, and kidney function at the time of surgery was staged using the National Kidney Foundation definitions for stages 1 through 5 CKD.8 The primary outcome was postoperative death within 30 days of the procedure. Secondary outcomes included the incidence of postprocedural major complications, such as surgical site infection, pneumonia, unplanned intubation, PE, stroke, cardiac arrest, and acute myocardial infarction. Decreased eGFR (defined as , 90 mL/min) was reported in 63.7% of patients in the cohort, and 19.4% had an eGFR , 60 mL/min (stage 3, 4, or 5 CKD). Using the Cox proportional hazard model, those with stages 3, 4, and 5 CKD had longer hospital length of stay and significantly higher 30-day mortality compared with patients with no CKD (hazard ratio [HR] of 2.30, 3.37, and 3.05, respectively; all P values , 0.001). In addition, more-advanced stages of CKD were independently associated with increased odds of having a major postoperative complication (ORs for stages 3–5 CKD, 1.24, 1.65,1.40, respectively; all P values , 0.001). Serum creatinine level did not identify impaired renal function as accurately as eGFR and was within the normal laboratory reference range for 99.5% of patients. In a nested case-control analysis, patients with stage 4 CKD undergoing colectomy procedures were matched to those with no CKD. The stage 4 CKD group had a significantly lower 30-day survival rate compared with the no CKD group (77.8% vs 94.6%; P , 0.0001). This study used a large, multi-institutional dataset to document the prevalence of preoperative renal impairment using eGFR. The prevalence of CKD captured by this study 136
is higher than that reported in some previously published studies.28 However, this may be because eGFR is a more sensitive marker of renal impairment than serum creatinine, and much of the previous data are from patients undergoing cardiac surgery. In addition, a significant relationship was found between preoperative impaired renal function and adverse postoperative outcomes. These results confirm that preoperative renal insufficiency may be underrecognized in the surgical population when using serum creatinine level as a marker, and CKD is a strong predictor of short- and long-term postoperative morbidity and mortality. The work of Gaber et al28 also makes a strong case for the use of eGFR instead of serum creatinine level to assess renal function before surgery, and for close postoperative monitoring of patients with impaired renal function. In another recent article, Mooney et al29 also aimed to evaluate the association between preoperative renal dysfunction and postoperative outcomes. The authors conducted a systematic review and meta-analysis to determine the nature, strength, and consistency of the relationship between preoperative eGFR and adverse outcomes after any type of surgery. Thirty studies were selected for inclusion in the analysis, and these included prospective or retrospective cohort studies with data on preoperative eGFR. Outcome measures included all-cause mortality (both short- and long-term) and a composite endpoint of cardiovascular events (acute myocardial infarction, heart failure, cardiac arrest, cardiovascular death, and stroke). The authors found that an eGFR , 60 mL/min was associated with an increased risk of all-cause mortality in the short-term (adjusted relative risk [RR], 2.98; P = 0.055) and long-term (adjusted RR, 1.61; P = 0.15; subgroup analysis for mortality . 60 months; RR, 1.4; P = 0.03). The estimated RRs for death within 30 days of surgery associated with an eGFR of 60, 30, and 15 mL/min were 2.04, 4.17, and 6.00, respectively. Although not statistically significant, the RR for death trended upward for each 10 mL/min decline in eGFR , 90 mL/min (P = 0.5). Long-term major adverse cardiovascular events were also more likely to occur in patients with an eGFR , 60 mL/min, although this trend also was not statistically significant (RR, 1.49; P = 0.9). This meta-analysis validates previous findings that decreased preoperative eGFR is associated with adverse postoperative outcomes. Although a relationship was found between eGFR and cardiac events, the results were likely not significant secondary to the small number of studies with the requisite endpoints. Most notable is the fact that even a mild
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Perioperative Anticoagulation and Renal Disease
reduction in eGFR by 10 mL/min below 90 mL/min seems to trend toward an increased mortality risk, widening the pool of patients who could potentially be considered at risk for adverse postoperative complications. The findings presented in this article also adds to the increasing evidence that eGFR is a more sensitive marker of impaired renal function as opposed to serum creatinine in the perioperative setting.
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Discussion
Both anticoagulation and kidney disease are associated with significant perioperative morbidity and mortality. This new body of literature provides evidence that, when used appropriately, can assist the physician and patient with preoperative decision-making. Most notably, these articles provide guidance for clinicians regarding perioperative management of NOACs, and use of aspirin, LMWH, and NOACs for venous thromboprophylaxis. These recent data also help identify patients at increased risk for developing postoperative AKI, provide no evidence for the use of statins in preventing AKI, advocate for the use of eGFR instead of serum creatinine level for measuring renal function, and demonstrate the association of AKI and CKD with adverse perioperative outcomes. Further studies may provide additional guidance regarding interventions to improve those outcomes.
Conflict of Interest Statement
Barbara A. Slawski, MD, MS, Kurt J. Pfeifer, MD, Gerald W. Smetana, MD, and Steven L. Cohn, MD, have no conflict of interests to declare. Suparna Dutta, MD, MPH, is a member of the advisory board for Otsuka Pharmaceuticals. Amir K. Jaffer, MD, MBA, is a consultant for BoehringerIngelheim, Janssen Pharmaceuticals, Pfizer, AstraZeneca, and Marathon; has received research funding from the NHLBI and AstraZeneca; and is a member of the advisory board for the Society of Perioperative Assessment and Quality Improvement (SPAQI).
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25. Kor DJ, Brown MJ, Iscimen R, et al. Perioperative statin therapy and renal outcomes after major vascular surgery: a propensity-based analysis. J Cardiothorac Vasc Anesth. 2008;22:210–216. 26. Argalious M, Xu M, Sun Z, Smedira N, Koch CG. Preoperative statin therapy is not associated with a reduced incidence of postoperative acute kidney injury after cardiac surgery. Anesth Analg. 2010;111(2):324–330. 27. Argalious MY, Dalton JE, Sreenivasalu T, O’Hara J, Sessler DI. Association of preoperative statin use and acute kidney injury after noncardiac surgery. Anesth Analg. 2013;117(4):916–923.
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Perioperative Anticoagulation and Renal Disease: An Update Suparna Dutta MD, MPH, Amir K. Jaffer MD, MBA, Barbara A. Slawski MD, MS, Kurt J. Pfeifer MD, Gerald W. Smetana MD & Steven L. Cohn MD To cite this article: Suparna Dutta MD, MPH, Amir K. Jaffer MD, MBA, Barbara A. Slawski MD, MS, Kurt J. Pfeifer MD, Gerald W. Smetana MD & Steven L. Cohn MD (2014) Perioperative Anticoagulation and Renal Disease: An Update, Hospital Practice, 42:5, 132-138 To link to this article: http://dx.doi.org/10.3810/hp.2014.12.1166
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C L I N I C A L F E AT U R E S
Perioperative Anticoagulation and Renal Disease: An Update
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DOI: 10.3810/hp.2014.12.1166
Suparna Dutta, MD, MPH 1 Amir K. Jaffer, MD, MBA 1 Barbara A. Slawski, MD, MS 2 Kurt J. Pfeifer, MD 2 Gerald W. Smetana, MD 3 Steven L. Cohn, MD 4 1 Rush Medical College, Chicago, IL; 2Medical College of Wisconsin, Milwaukee, WI; 3Harvard Medical School, Boston, MA; 4University of Miami Miller School of Medicine, Miami, FL
Correspondence: Suparna Dutta, MD, MPH, Rush Medical College, 1717 W Congress Pkwy, 1029 Kellogg, Chicago, IL 60612. Tel: 312-942-4200 E-mail: [email protected]
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Abstract: As our surgical population becomes older and increasingly medically complex, knowledge of the most recent perioperative literature can provide guidance for physicians across multiple specialties caring for the surgical patient. Common issues many clinicians encounter in the perioperative period relate to anticoagulation and renal disease. This article identifies gaps in knowledge for the fields of perioperative anticoagulation, acute kidney injury, and chronic kidney disease and highlights recently published studies on these topics that attempt to fill these gaps and help clinicians provide excellent care for their patients. Keywords: perioperative care; anticoagulation; thromboembolism prophylaxis; acute kidney injury; chronic kidney disease
Introduction
Each year, . 200 million people undergo surgery worldwide, and this population is becoming increasingly complex.1 An estimated 33 million patients undergo surgery in the United States every year, and adverse events related to surgery affect . 1 million of these patients, at an estimated cost of $25 billion annually.2 Perioperative medicine relies on evidence-based strategies to optimize care for the surgical patient. Issues with the management of patients undergoing anticoagulation therapy or those with kidney disease are common causes of perioperative morbidity and mortality, and evidencebased strategies to identify and mitigate risk in these patients can lead to significant improvement in outcomes. This article provides a concise review of the high-impact articles published during the past year on the management of perioperative anticoagulation and renal disease. Many patients are on long-term anticoagulation therapy before surgery for stroke prevention or treatment of venous thromboembolism. Recently, novel oral anticoagulants (NOACs) such as apixaban, dabigatran, and rivaroxaban were approved for long-term oral anticoagulation, and are increasingly common in the perioperative setting. Preparation for surgery often requires interruption of anticoagulation before intervention to avoid perioperative bleeding complications. Bleeding can be associated with infections, repeat operations, delayed wound healing, and longer hospital stays.3 Given that these medications have been available for only a short time, limited literature is available regarding the optimal timing or method of interruption before surgery. Many patients are also initiated on anticoagulation postoperatively for thromboprophylaxis. Venous thromboembolism is a common cause of morbidity and mortality after surgery, and pharmacologic thromboprophylaxis reduces this risk, most notably after joint replacement surgery.4 However, pharmacologic thromboprophylaxis has also
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been associated with the development of major bleeding.4 Although vitamin K antagonists and low-molecular-weight heparin (LMWH) have long been the standard of care for thromboprophylaxis, agents such as the NOACs and aspirin are increasingly under scrutiny for their utility in this setting. The development of perioperative acute renal failure is another common complication of surgery, with an incidence between 1% and 36%, depending on type of surgery and definition of acute renal failure. It is also associated with substantial perioperative morbidity and mortality.5 Much of the literature on perioperative renal failure focuses on patients undergoing cardiovascular surgery and lacks a universal definition of acute renal failure, now referred to as acute kidney injury (AKI). The heterogeneity of this definition and previously studied surgical populations has made it difficult to draw conclusions and make comparisons between studies. In 2004, the Acute Dialysis Quality Initiative published the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria to standardize the definition and staging for AKI (Table 1).6 This standardization has helped investigators better study the incidence, risk factors, and outcomes associated with perioperative AKI, and to evaluate treatment options aimed at decreasing incidence. Chronic kidney disease (CKD) is a major health problem, with a prevalence of 13% in the United States.7 Chronic kidney disease is an independent predictor for adverse overall health outcomes, including cardiovascular complications and mortality.8 The impact of underlying CKD on postoperative outcomes in patients undergoing surgery is not clearly understood. Several reasons for this exist, with one of the most important being variations in how kidney disease is measured. For determining renal function in adults, the National Kidney Foundation currently recommends estimated glomerular filtration rate (eGFR), calculated using either the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) equations.9 This standardization has better allowed investigators to start examining the relationship between chronic kidney dysfunc-
tion and adverse outcomes after surgery.
Methods
This summary of recent literature in both perioperative anticoagulation and kidney disease is derived from the “Update in Perioperative Medicine” presented at the 9th Annual Perioperative Medicine Summit and the Society of General Internal Medicine 37th Annual Meeting.10,11 A systematic search strategy was used to identify articles of particular relevance for the medical care of patients before surgery. MEDLINE was searched for the period from January 1, 2013 through April 31, 2014 for Medical Subject Heading terms, including “perioperative complications,” “intraoperative complications,” “postoperative complications,” “preoperative care,” “intraoperative care,” “perioperative care,” “postoperative care,” “intraoperative period,” and “preoperative period.” The following text words were also included in the title or abstract: “intraoperative” OR “postoperative” OR “perioperative” AND “complication” OR “event.” Articles related to transplantation, cardiac, and pediatric surgery were excluded. Selected studies were considered methodologically sound; were of interest to practicing internists/hospitalists, anesthesiologists, and/or surgeons; addressed common postoperative outcomes; and could potentially change the approach to diagnosis, risk stratification, or prevention of postoperative medical complications. The authors determined the final list through consensus based on relevance to the clinical practice of perioperative medicine.
Thromboprophylaxis
The NOACs are quickly replacing traditional agents such as heparin, LMWHs, and warfarin. Already published are a few systematic reviews which compare these agents with LMWH12; however more information is needed requiring the safety and efficacy of these agents in the perioperative period. In a new study, Adam et al3 performed a comparative effectiveness analysis to determine the effectiveness and
Table 1. Definition of RIFLE Criteria
GFR Criteria
Urine Output Criteria
Risk Injury Failure
Increased Cr by 1.5x OR GFR decrease by . 25% Increased Cr by 2x OR GFR decrease by . 50% Increased Cr by 3x OR GFR decrease by . 75% OR Cr . 4.0 mg/dL (acute increase . 0.5 mg/dL) Complete loss of renal function . 4 wk Loss of kidney function . 3 mo
Urine output , 0.5 mL/kg/h × 6 h Urine output , 0.5 mL/kg/h × 12 h Urine output , 0.3 mL/kg/h × 24 h OR Anuria × 12 h
Loss End-Stage Renal Disease
© 2004 Bellomo et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article’s original URL. http://ccforum.com/content/8/4/R204. Abbreviations: Cr, serum creatinine; GFR, glomerular filtration rate. © Hospital Practice, Volume 42, Issue 5, December 2014, ISSN – 2154-8331 133 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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safety of the NOACs compared with standard thromboprophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA). Literature review identified 6 English language systematic reviews that compared NOACs with standard thromboprophylaxis in randomized clinical trials of adults undergoing elective THA or TKA. These studies were included in the analysis that used deep venous thrombosis (DVT) and pulmonary embolism (PE) as primary outcomes and mortality and major bleeding as secondary outcomes. Factor Xa inhibitors (eg, rivaroxaban and apixaban) were associated with fewer symptomatic DVT events than LMWH (4 fewer events per 1000 patients), but no significant difference in mortality or nonfatal PE was identified. The risk for major bleeding also increased (2 more events per 1000 patients). Outcomes with the direct thrombin inhibitors (DTIs; eg, dabigatran) were similar to those with LMWH. Specific odds ratios (ORs) for the various outcomes with NOACs are illustrated in Table 2. The work of Adam et al3 confirms that NOACs are effective for thromboprophylaxis after THA and TKA. However, their clinical benefits compared with LMWH are marginal and offset by increased risk for major bleeding. Headto-head comparisons among NOACs are lacking, and real-life experience with these agents is slowly increasing. The role of aspirin for extended venous thromboembolism (VTE) prophylaxis after major joint replacement surgery also remains uncertain. The American College of Chest Physicians (ACCP) guidelines include aspirin as an acceptable form of VTE prophylaxis in joint replacement surgery.13 These guidelines also state that LMWH is a preferred form of prophylaxis over other agents. Anderson et al14 designed a study to compare aspirin and dalteparin for extended thromboprophylaxis to prevent symptomatic VTE after THA. Designed as a noninferiority study, this randomized, blinded, controlled trial was conducted at 12 tertiary care orthopedic referral centers in Canada. A total of 778 patients who had elective unilateral THA between 2007 and 2010 received 10 days of dalteparin prophylaxis and were subsequently Table 2. Comparative Effectiveness of Novel Oral Anticoagulants and LMWH in Total Joint Arthroplasty Patients Outcome
Factor Xa Inhibitors vs Dabigatran vs LMWH LMWH OR (95% CI) OR (95% CI)
Symptomatic DVT Nonfatal PE Major bleeding Mortality
0.46 (0.30–0.70) 1.07 (0.65–1.73) 1.27 (0.98–1.65) 0.95 (0.55–1.63)
0.82 (0.17–3.99) 0.69 (0.31–1.54) 0.94 (0.58–1.52) 1.54 (0.38–6.33)
Abbreviations: DVT, deep venous thrombosis; LMWH, low-molecular-weight heparin; OR, odds ratio; PE, pulmonary embolism.
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randomized to receive 28 days of dalteparin 5000 U subcutaneously (n = 400) or aspirin at 81 mg orally (n = 386). Primary outcomes were symptomatic VTE (confirmed through objective testing) and major bleeding. Five of 398 patients (1.3%) who received extended-duration dalteparin and 1 of 380 (0.3%) who received aspirin developed VTE (absolute difference, 1.0 percentage point; 95% CI, –0.5 to 2.5 percentage points). Aspirin was noninferior (P , 0.001) but not superior (P = 0.22) to dalteparin. Clinically significant bleeding occurred in 5 patients (1.3%) receiving extendedduration dalteparin and 2 (0.5%) receiving aspirin. The absolute between-group difference in a composite of all VTE and clinically significant bleeding events was 1.7 percentage points (CI, –0.3 to 3.8 percentage points; P = 0.091) in favor of aspirin. The study was halted prematurely because of difficulty with patient recruitment. In patients who initially received 10 days of prophylacticdose dalteparin, extended prophylaxis for 28 days with aspirin was noninferior (P , 0.001) but not superior (P = 0.22) to dalteparin. Furthermore, extended prophylaxis with aspirin was as safe as dalteparin. Given its low cost and greater convenience, aspirin may be considered an alternative for extended thromboprophylaxis after THA, although further study is likely needed.
Peri-Interventional Management of Anticoagulation
With the increase in overall prevalence of patients using NOACs for chronic anticoagulation, more patients on these drugs are undergoing interventional procedures. Novel oral anticoagulants have rapid onset of action and short half-lives compared with vitamin K antagonists, allowing for short periods of NOAC interruption without heparin bridging. However, outcome data for this approach to perioperative management are lacking. To this end, Beyer-Westendorf et al15 evaluated peri-interventional NOAC management in unselected patients in a European registry. Safety and efficacy outcomes data were collected from an ongoing, prospective cohort of . 2100 surgical and nonsurgical patients receiving NOACs, with adjudication of outcomes using standard event definitions. Of 2179 registered patients, 27.3% underwent 863 procedures, 15.6% of which were classified as minimal, 74.3% minor, and 10.1% as major procedures. Minimal procedures were defined as those with minimal tissue trauma, such as skin biopsies; minor procedures were those with minimal tissue trauma but a relevant risk of bleeding, such as cataract surgery; and major procedures were those with tissue trauma and high bleeding
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risk, such as abdominal and orthopedic procedures. In cases of NOAC interruption, the median duration of NOAC-free intervals was 3 days (2 days preoperatively and 1 day postoperatively). Major cardiovascular events occurred in 1.0% of patients and major bleeding complications in 1.2% within the first month after invasive procedures. Cardiovascular and major bleeding complications were highest after major procedures (4.6% and 8.0%, respectively). Heparin bridging did not reduce cardiovascular events but led to significantly higher rates of major bleeding complications (2.7%) compared with no bridging (0.5%; P = 0.010). Multivariate analysis demonstrated that major procedures (OR, 16.8) were an independent risk factor for major bleeding complications, whereas diabetes (OR, 13.2) and major procedures (OR, 7.3) were independent risk factors for cardiovascular events. This study suggests that short-term interruption of NOAC therapy is a safe strategy for most minimal or minor procedures. Heparin does not reduce the risk of cardiovascular events but does increase the rate of major bleeding; therefore, most patients likely can safely interrupt NOAC anticoagulation for a short period without heparin bridging.
Perioperative Renal Disease Acute Kidney Injury
Perioperative acute renal failure is associated with increased mortality in the perioperative period,16 but few data are available on who is at risk for developing AKI, options for mitigating progression of renal injury, and outcomes after surgery. Two new articles examine the incidence, risk factors, and outcomes of perioperative AKI, and evaluate treatment options to decrease the incidence of AKI, as defined by the RIFLE criteria. In a prospective cohort study, Biteker et al5 used the RIFLE criteria to examine the incidence, risk factors, and outcomes of postoperative AKI in patients undergoing noncardiac and nonvascular surgery at a single center in Istanbul, Turkey. Studied variables included age, sex, and comorbidities, and the primary outcome was the development of AKI within 7 days postoperatively. Of the 1200 consecutive patients studied with no preexisting renal disease, 6.7% developed postoperative AKI. When compared with the control group, patients with AKI were significantly more likely to be older (OR, 1.14; P = 0.004), and have diabetes mellitus (OR, 1.53; P , 0.001). These patients also had significantly longer length of stay (10.3 vs 8.1 days, P , 0.001) and higher mortality rates (OR, 3.83; P = 0.036), and were more likely to experience inpatient (OR,
3.56; P , 0.001) and long-term (after first 2 weeks of surgery; OR, 1.83; P = 0.36) cardiovascular complications. This article confirms the findings of previous studies regarding the incidence of and risk factors for the development of AKI in patients undergoing noncardiac surgery.16,17 Outcomes after the development of postoperative AKI also corroborate findings of previous studies showing an increase in in-hospital mortality and hospital length of stay.18,19 Although this is a single-center, observational study, its findings add to the growing body of evidence regarding risk factors for postoperative AKI and associated short- and longterm complications. Aggregating these findings with information already available on perioperative AKI, clinicians can attempt to identify and closely monitor patients at risk. Because of the need to identify effective renoprotective therapies, statins have recently gained attention for their potential protective effect in postoperative AKI secondary to their vasodilatory, antithrombotic, and anti-inflammatory properties.20 Animal models have shown that giving statins before an ischemic event significantly reduces the incidence of AKI,21,22 yet previous clinical studies have yielded mixed results. Studies demonstrating reductions in postoperative AKI with statins did not use standard criteria for AKI or included all lipid-lowering medications, whereas articles finding no benefit from statins were focused on very specific surgical populations.23–26 In this article, Argalious et al27 conducted a retrospective cohort study from 2004 to 2010 to better examine the relationship between preoperative statin therapy and the incidence of postoperative AKI in patients who had undergone noncardiac surgery. A total of 28 508 medical records were reviewed. The primary exposure of interest was preoperative statin use, and the outcome of interest was development of postoperative AKI using the RIFLE criteria. Propensity matching was used to balance baseline potential confounders between statin users and nonusers. Results indicated that the incidence of AKI in statin users compared with nonusers was not significant (7.1% vs 8.0%; OR, 0.88; P = 0.12). Secondary outcomes also were not significantly different, including the need for postoperative dialysis (OR, 0.8; P = 0.74) or in-hospital mortality (OR, 0.76; P = 0.18). This article suggests that statins do not have a significant renoprotective effect, and currently evidence is insufficient to support routine preoperative statin use for the prevention postoperative AKI. Further studies, including randomized control trials, are needed to better evaluate the impact of statins on perioperative renal function.
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Chronic Kidney Disease
Chronic kidney disease is a common medical problem in the United States, and is an independent predictor for poor long-term medical outcomes.28 However, no association has been documented between early kidney disease and adverse perioperative outcomes (Revised Cardiac Risk Index criteria only apply for a serum creatinine level . 2.0 mg/dL). The goal of both of the following studies was to examine the relationship between chronic kidney dysfunction and adverse outcomes after surgery, using eGFR as a measure of kidney function. Gaber et al28 conducted a case-control, observational trial to examine the association between chronic kidney dysfunction and postoperative morbidity and mortality. Data from 260 352 patients undergoing general or vascular surgery were gathered from the American College of Surgeons National Surgical Quality Improvement Program database between 2005 and 2007. Estimated GFR was calculated for each patient using the MDRD formula, and kidney function at the time of surgery was staged using the National Kidney Foundation definitions for stages 1 through 5 CKD.8 The primary outcome was postoperative death within 30 days of the procedure. Secondary outcomes included the incidence of postprocedural major complications, such as surgical site infection, pneumonia, unplanned intubation, PE, stroke, cardiac arrest, and acute myocardial infarction. Decreased eGFR (defined as , 90 mL/min) was reported in 63.7% of patients in the cohort, and 19.4% had an eGFR , 60 mL/min (stage 3, 4, or 5 CKD). Using the Cox proportional hazard model, those with stages 3, 4, and 5 CKD had longer hospital length of stay and significantly higher 30-day mortality compared with patients with no CKD (hazard ratio [HR] of 2.30, 3.37, and 3.05, respectively; all P values , 0.001). In addition, more-advanced stages of CKD were independently associated with increased odds of having a major postoperative complication (ORs for stages 3–5 CKD, 1.24, 1.65,1.40, respectively; all P values , 0.001). Serum creatinine level did not identify impaired renal function as accurately as eGFR and was within the normal laboratory reference range for 99.5% of patients. In a nested case-control analysis, patients with stage 4 CKD undergoing colectomy procedures were matched to those with no CKD. The stage 4 CKD group had a significantly lower 30-day survival rate compared with the no CKD group (77.8% vs 94.6%; P , 0.0001). This study used a large, multi-institutional dataset to document the prevalence of preoperative renal impairment using eGFR. The prevalence of CKD captured by this study 136
is higher than that reported in some previously published studies.28 However, this may be because eGFR is a more sensitive marker of renal impairment than serum creatinine, and much of the previous data are from patients undergoing cardiac surgery. In addition, a significant relationship was found between preoperative impaired renal function and adverse postoperative outcomes. These results confirm that preoperative renal insufficiency may be underrecognized in the surgical population when using serum creatinine level as a marker, and CKD is a strong predictor of short- and long-term postoperative morbidity and mortality. The work of Gaber et al28 also makes a strong case for the use of eGFR instead of serum creatinine level to assess renal function before surgery, and for close postoperative monitoring of patients with impaired renal function. In another recent article, Mooney et al29 also aimed to evaluate the association between preoperative renal dysfunction and postoperative outcomes. The authors conducted a systematic review and meta-analysis to determine the nature, strength, and consistency of the relationship between preoperative eGFR and adverse outcomes after any type of surgery. Thirty studies were selected for inclusion in the analysis, and these included prospective or retrospective cohort studies with data on preoperative eGFR. Outcome measures included all-cause mortality (both short- and long-term) and a composite endpoint of cardiovascular events (acute myocardial infarction, heart failure, cardiac arrest, cardiovascular death, and stroke). The authors found that an eGFR , 60 mL/min was associated with an increased risk of all-cause mortality in the short-term (adjusted relative risk [RR], 2.98; P = 0.055) and long-term (adjusted RR, 1.61; P = 0.15; subgroup analysis for mortality . 60 months; RR, 1.4; P = 0.03). The estimated RRs for death within 30 days of surgery associated with an eGFR of 60, 30, and 15 mL/min were 2.04, 4.17, and 6.00, respectively. Although not statistically significant, the RR for death trended upward for each 10 mL/min decline in eGFR , 90 mL/min (P = 0.5). Long-term major adverse cardiovascular events were also more likely to occur in patients with an eGFR , 60 mL/min, although this trend also was not statistically significant (RR, 1.49; P = 0.9). This meta-analysis validates previous findings that decreased preoperative eGFR is associated with adverse postoperative outcomes. Although a relationship was found between eGFR and cardiac events, the results were likely not significant secondary to the small number of studies with the requisite endpoints. Most notable is the fact that even a mild
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Perioperative Anticoagulation and Renal Disease
reduction in eGFR by 10 mL/min below 90 mL/min seems to trend toward an increased mortality risk, widening the pool of patients who could potentially be considered at risk for adverse postoperative complications. The findings presented in this article also adds to the increasing evidence that eGFR is a more sensitive marker of impaired renal function as opposed to serum creatinine in the perioperative setting.
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Discussion
Both anticoagulation and kidney disease are associated with significant perioperative morbidity and mortality. This new body of literature provides evidence that, when used appropriately, can assist the physician and patient with preoperative decision-making. Most notably, these articles provide guidance for clinicians regarding perioperative management of NOACs, and use of aspirin, LMWH, and NOACs for venous thromboprophylaxis. These recent data also help identify patients at increased risk for developing postoperative AKI, provide no evidence for the use of statins in preventing AKI, advocate for the use of eGFR instead of serum creatinine level for measuring renal function, and demonstrate the association of AKI and CKD with adverse perioperative outcomes. Further studies may provide additional guidance regarding interventions to improve those outcomes.
Conflict of Interest Statement
Barbara A. Slawski, MD, MS, Kurt J. Pfeifer, MD, Gerald W. Smetana, MD, and Steven L. Cohn, MD, have no conflict of interests to declare. Suparna Dutta, MD, MPH, is a member of the advisory board for Otsuka Pharmaceuticals. Amir K. Jaffer, MD, MBA, is a consultant for BoehringerIngelheim, Janssen Pharmaceuticals, Pfizer, AstraZeneca, and Marathon; has received research funding from the NHLBI and AstraZeneca; and is a member of the advisory board for the Society of Perioperative Assessment and Quality Improvement (SPAQI).
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