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Continuing Clopidogrel During Elective Total Hip and Knee Arthroplasty: Assessment of Bleeding Risk and Adverse Outcomes
The Journal of Arthroplasty 29 (2014) 325–328
Contents lists available at ScienceDirect
The Journal of Arthroplasty journal homepage: www.arthroplastyjournal.org
Continuing Clopidogrel During Elective Total Hip and Knee Arthroplasty: Assessment of Bleeding Risk and Adverse Outcomes Adam K. Jacob, MD a, Sean P. Hurley, BSN, BS a, Sean M. Loughran, BSN a, Tyler M. Wetsch, BSN a, Robert T. Trousdale, MD b a b
Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota Departments of Orthopaedic Surgery, Mayo Clinic, Rochester, Minnesota
a r t i c l e
i n f o
Article history: Received 3 April 2013 Accepted 9 June 2013 Keywords: total hip and knee arthroplasty clopidogrel bleeding risk
a b s t r a c t Limited research assessing risks of continued clopidogrel perioperatively in patients undergoing elective orthopedic procedures exists. Patients that underwent elective primary or revision total knee arthroplasty (TKA) or total hip arthroplasty (THA) from 2007 to 2012 while taking clopidogrel at the time of surgical evaluation were retrospectively identified. Patient demographics, last dose of clopidogrel, intraoperative blood loss, blood transfusion, and presence of 30-day adverse cardiac events (ACE) were collected. Of 142 patients meeting criteria, 24 (16.9%) patients remained on clopidogrel perioperatively. Patients that continued clopidogrel were more likely to receive a blood transfusion within 24 hours of surgery (31.8% vs. 7.7%; P = 0.004) and during hospitalization (37.5% vs. 15.3%; P = 0.02), but the incidence of 30-day ACE was not significantly different. Continuation of clopidogrel perioperatively for elective THA or TKA should be carefully considered. © 2014 Elsevier Inc. All rights reserved.
From 2000 to 2009, the frequency of THA has nearly doubled and TKA has more than doubled [1]. While technology for these surgeries has vastly improved, perioperative blood loss and transfusion continue to be significant and unpredictable consequences [2]. This is especially concerning when caring for those patients with increased risk of bleeding due to prescribed antiplatelet therapy for management of cardiovascular or cerebrovascular disease. Standard prevention measures for stent thrombosis involve dual antiplatelet therapy, which typically includes aspirin in addition to clopidogrel due to its ability to inhibit platelet production of thromboxane A2. The American Heart Association (AHA) and American College of Cardiology (ACC) recommend dual antiplatelet therapy for 30–45 days status post bare metal stent placement and for 365 days status post drug eluting stent placement [3]. Discontinuation of dual antiplatelet therapy within this suggested timeframe has been shown to not only predict, but also to significantly increase the risk of acute stent thrombosis for nonsurgical patients as well as those patients undergoing non-cardiac surgery [4–6]. No specific guidelines exist for clopidogrel discontinuation beyond these timeframes. The decision to continue antiplatelet medications, such as clopidogrel, during elective orthopedic surgery has been the subject of debate. Conflicting results exist in the literature with regards to The Conflict of Interest statement associated with this article can be found at http:// dx.doi.org/10.1016/j.arth.2013.06.008. Reprint requests: Adam K. Jacob, MD, Department of Anesthesiology, Mayo Clinic, 200 First Street, S.W., Rochester, MN 55905. 0883-5403/2902-0015$36.00/0 – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.arth.2013.06.008
perioperative use of clopidogrel. Some studies show no statistical differences in cases requiring blood transfusion or hemorrhagic complications in patients that discontinued clopidogrel compared to those who continued clopidogrel perioperatively [7,8]. Other studies have found an associated increase in major blood loss and requirement for blood transfusion in patients who remained on clopidogrel throughout the perioperative period [9,10]. Given these inconsistencies, antiplatelet and anticoagulation medications are commonly discontinued during elective general surgery to reduce the risk of perioperative bleeding. Among patients that remain on clopidogrel beyond the AHA/ACC recommended timeframes, it remains unclear if continuing clopidogrel throughout the perioperative period during elective THA or TKA influences the risk of bleeding or ACE. The main objective of this retrospective cohort study was to test the hypothesis that incidence of perioperative transfusion and ACE differs between patients that continued clopidogrel and patients that discontinued clopidogrel during elective TKA or THA. Materials and Methods After Institutional Review Board approval was obtained, all patients aged ≥ 18 years who underwent elective TKA or THA from January 1, 2002 to April 30, 2012 were retrospectively identified using the Total Joint Registry and the electronic medical record (EMR). Study inclusion was restricted to the first elective primary or revision TKA or THA performed at our institution. Patients who underwent unicompartmental knee arthroplasty, underwent multiple joint procedures during the same operation, were prescribed concurrent
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preoperative heparin or low-molecular weight heparin therapy, or had a preexisting diagnosis of end-stage renal failure, liver failure, or inherited bleeding disorder were excluded. Documented cases of noncompliance with antiplatelet therapy or medical charts missing the date of last clopidogrel intake were excluded on the basis of inconclusive evidence for which clopidogrel was continued or discontinued preoperatively. Patients with chronic angina were excluded due to the inability to assess probable causation. Finally, patients who denied research authorization were excluded as per government statute. Patient demographics (gender, date of birth, height, weight), date of surgery, joint replaced (knee, hip), surgeon, type of surgery (primary, revision), and total surgical time were recorded from the Total Joint Registry. Type of postoperative anticoagulation (warfarin, unfractionated heparin, low molecular weight heparin, aspirin only) and presence of postoperative bleeding or infectious complications within 30 days requiring hospital readmission were collected during manual review of the medical record. Preoperative clopidogrel use was identified using a free-text electronic query of the EMR. The medication list of all clinical notes within the EMR preceding the surgical date was searched for the terms “clopidogrel” or “Plavix.” Medical records were manually reviewed for the indication for clopidogrel use, presence of concomitant preoperative aspirin use, and date of last clopidogrel dose. In addition, the following perioperative variables were manually collected from the EMR: preoperative hemoglobin, postanesthesia care unit hemoglobin, postoperative day 1 hemoglobin, last hemoglobin prior to hospital discharge, estimated intraoperative blood loss, postoperative administration of low-molecular weight heparin, warfarin, clopidogrel and/or anti-inflammatory medications, and length of hospital stay. Patients were categorized as discontinuing clopidogrel if the last dose was taken 7 or more days before the date of surgery, and categorized as continuing clopidogrel if the last dose was taken b 7 days before the date of surgery. The primary outcome variable was defined as the incidence of allogenic red cell transfusion during the hospital admission (including intraoperative period). Presence of any blood product transfusion (packed red blood cells, intraoperative blood salvage, platelets, fresh frozen plasma) was collected from manual review of the anesthesia record and EMR. The secondary outcome was defined as the presence of any major ACE (stent thrombosis requiring PCI, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, or death) within 30 days of hospital discharge. All analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC). Continuous variables were compared using the Wilcoxon rank sum test. Nominal variables were compared using Fisher's exact test. Two-tailed P-values ≤ 0.05 were considered to be statistically significant. Continuous variables (e.g., age, body mass index, and surgical duration) are reported as median and interquartile range unless indicated otherwise. Categorical variables are reported as frequency percentages. Results A total of 197 patients were initially identified that met our inclusion criteria. Of these, 55 patients met one or more exclusion criteria. Therefore, 142 patients (48 females, 94 males) were included in the final analysis. Twenty-four (16.9%) and 118 (83.1%) patients had continued and discontinued clopidogrel throughout the perioperative period, respectively. The median timeframe (25th, 75th quartiles) for discontinuation of clopidogrel prior to surgery was 9 (7, 11) days. No significant difference in gender, age, ASA status, joint replaced, type of procedure, type of postoperative anticoagulation, preoperative hemoglobin, estimated blood loss, or length of hospital stay was detected between patients continuing clopidogrel compared to patients that discontinued clopidogrel perioperatively (Table 1). Three patients developed a complication (2 bleeding complications, 1
Table 1 Patient Demographics. Continued Clopidogrel Discontinued Clopidogrel (N = 24) (N = 118) P-value Age (years) Gender Female Male ASA physical statusa 2 3 4 Joint Total knee arthroplasty Total hip arthroplasty Type of surgery Primary Revision Postoperative DVT prophylaxis Warfarin Unfractionated heparin Dalteparin Enoxaparin Aspirin Preoperative hemoglobin (g/dL) Duration of surgery (minutes) Estimated blood loss (mL) Hospital length of stay (days)
72.9 (67.4, 79.4)
74.7 (66.0, 80.8)
9 (37.5%) 15 (62.5%)
39 (33.1%) 87 (66.9%)
3 (12.5%) 20 (83.3%) 1 (4.2%)
27 (23.3%) 87 (75.0%) 2 (1.7%)
9 (37.5%)
63 (53.4%)
15 (62.5%)
55 (46.6%)
20 (83.3%) 4 (16.7%)
95 (80.5%) 23 (19.5%)
5 (20.8%) 2 (8.3%)
46 (40.0%) 3 (2.5%)
0.70 0.67
0.32
0.16
1.0
0.09 0.20
12 (50.0%) 0 (0%) 5 (20.8%) 13.4 (12.8, 14.1)
52 (44.1%) 2 (1.7%) 15 (12.7%) 13.6 (12.6, 14.6)
0.59 1.0 0.32 0.50
80.5 (59.0, 100.5)
102.0 (83.0, 132.0)
b0.01b
200 (50, 350) 4 (3.5, 5.5)
200 (0, 355)
0.68
4 (4, 5)
0.97
Values presented at median (25th, 75th) unless otherwise specified; ASA = American Society of Anesthesiologists, DVT = deep venous thrombosis. a ASA score missing in 2 patients in the Discontinued Clopidogrel group. b Wilcoxon Rank Sum test.
infectious complication) within 30 days of surgery that required either readmission with re-operation or joint aspiration. All 3 complications occurred in patients that had discontinued clopidogrel N 7 days preoperatively. The median (25th, 75th) postoperative day 1 hemoglobin level for patients that continued clopidogrel was 9.6 (8.7, 10.8) g/dL, compared to 10.6 (9.8, 11.4) g/dL in patients that discontinued clopidogrel. This was not statistically significantly different (P = 0.06), nor was the change in hemoglobin from preoperative to postoperative day 1 levels (P = 0.46). The last documented hemoglobin level prior to hospital discharge was not significantly different in patients that continued clopidogrel compared to patients that discontinued clopidogrel (10.1 [9.6, 11.3] g/dL vs. 10.2 [9.5, 11.0] g/dL; P = 0.92]. Compared to patients that discontinued clopidogrel, patients remaining on clopidogrel were more likely to receive a salvaged blood transfusion intraoperatively (29.2% vs. 10.2%; P = 0.02), but the incidence of intraoperative packed red blood cell transfusion was not statistically significantly different (20.8% vs. 11.9%; P = 0.32). Patients who continued clopidogrel were more likely to receive an allogenic blood transfusion than patients who discontinued clopidogrel in the first 24 hours after surgery (31.8% vs. 7.7%; P = 0.004; Fig. 1) and overall during the entire hospital admission (37.5% vs. 15.3%; P = 0.02; Fig. 2). The incidence of ACE within 30-days was greater among patients that continued clopidogrel, but the difference was not statistically significant (16.7% vs. 5.1%; P = 0.07). Callaghan and Spitzer suggested that total joint revision procedures are more likely to require a blood transfusion compared to total joint primary procedures [11]. Therefore as a secondary analysis, we limited the comparison to only those 115 patients (20 continued clopidogrel, 95 discontinued clopidogrel) who underwent primary
A.K. Jacob et al. / The Journal of Arthroplasty 29 (2014) 325–328 Clopidogrel Continued
35
Percent of Patients
*
30
Clopidogrel Discontinued
25 20 15 10 5 0 PRBC
Cell Saver
Type of Blood Product Fig. 1. Intraoperative and postanesthesia care unit blood product administration. Significant difference in blood product administration in patients that continued clopidogrel. PRBC = Packed Red Blood Cell. *P = 0.02 using Fisher's exact test.
joint arthroplasty. The change in hemoglobin from preoperative to postoperative day 1 levels was not significantly different for patients that continued clopidogrel compared to patients that discontinued clopidogrel (3.4 g/dL vs. 3.0 g/dL; P = 0.46), nor was the change in hemoglobin from preoperative to hospital discharge levels (2.8 g/dL vs. 3.3 g/dL; P = 0.34). Compared to patients that discontinued clopidogrel, patients remaining on clopidogrel were again more likely to receive a salvaged blood transfusion intraoperatively (20% vs. 0%; P b 0.001), but the incidence of intraoperative allogenic packed red blood cell transfusion was not statistically significantly different (10.0% vs. 5.3%; P = 0.35). Patients who continued clopidogrel were more likely to receive an allogenic blood transfusion than patients who discontinued clopidogrel in the first 24 hours after surgery (25.0% vs. 6.3%; P = 0.02) and overall during the entire hospital admission (30.0% vs. 9.5%; P = 0.02). Similarly, the incidence of ACE within 30-days was greater among patients that continued clopidogrel, but the difference was not statistically significant (10.0% vs. 4.2%; P = 0.28).
Discussion No current guidelines exist beyond the recommended ACC/AHA timeframes to direct healthcare providers in the decision-making process of whether or not to continue clopidogrel throughout the perioperative period during elective orthopedic procedures. Arguments exist in favor of discontinuation of clopidogrel in order to
**
Percent of Patients
40 35
Clopidogrel Continued Clopidogrel Discontinued
*
30 25 20 15 10 5 0
24 hour postop
Entire admission
Time of PRBC Transfusion Fig. 2. Postoperative blood product administration. Significant difference in blood product administration in patients that continued clopidogrel. Entire admission inclusive of intraoperative, PACU, and postoperative data. PRBC = Packed Red Blood Cell. *P = 0.004 using Fisher's exact test. **P = 0.02 using Fisher's exact test.
327
prevent excessive bleeding or the need for a blood transfusion [2,12,13]. Conversely, arguments also are made in favor of continuation of clopidogrel for prevention of stent thrombosis or reinfarction [14,15]. The results of this investigation demonstrated that patients who continued clopidogrel throughout the perioperative period were more likely to receive a blood transfusion compared to patients that discontinued clopidogrel. Interestingly, there may be additional risk for ACE among patients that continue clopidogrel. Therefore, healthcare providers must be prepared for the increased potential requirement for blood transfusion as well as ACE in the perioperative period. Clopidogrel is a thienopyridine class glycoprotein IIB/IIIA inhibitor that causes irreversible competitive inhibition of adenosine diphosphate by blocking its binding capability to the P2Y12 platelet receptor. In effect, the platelet is rendered incapable of clot formation and thus unable to contribute to thrombosis for its lifespan. Clopidogrel was approved by the Food and Drug Administration in 1997 with its primary indication for the reduction of atherothrombotic events. It is most commonly prescribed for patients with history of a recent myocardial infarction or stroke, established peripheral arterial disease, acute coronary syndrome, or stent placement. Conflicting results exist in the literature with regards to perioperative use of clopidogrel. Some studies show no statistical differences in cases requiring blood transfusion or return to the operating room for hemorrhagic complications in patients that discontinued clopidogrel at least 7 days prior to general, orthopedic, vascular, and cardiovascular surgery as compared to those who continued clopidogrel perioperatively [7,8]. Other studies have found an associated increase in major blood loss and requirement for blood transfusion in patients who remained on clopidogrel throughout the perioperative period [9,10]. We demonstrated an increased incidence of allogenic blood transfusion without an increase in intraoperative blood loss when patients continue clopidogrel throughout the perioperative period. These results appear discordant, but may illustrate the variation that occurs while recording estimated blood loss and the potential for ongoing postoperative blood loss after PACU dismissal. It is important to note that based on our definition, some patients may have still discontinued clopidogrel fewer than 7 days before surgery. Therefore, it is possible that the discrepancy in perioperative transfusion may be greater if the medication is continued up to and including the day of surgery as well as the immediate postoperative period. Although the incidence of ACE within 30 days of surgery was not statistically significant, there was a trend toward increased incidence of ACE among patients that continued clopidogrel perioperatively. The exact reason for this observation is unclear. Because recommendations listed within the medical charting system lacked rationale for continuation of clopidogrel perioperatively, it is possible that patients at greater risk for perioperative ACE were recommended to continue clopidogrel, thus creating a treatment bias. Alternatively, exposure to allogenic blood, specifically leukocytes within stored blood, may release potentially harmful proinflammatory and prothrombotic mediators during storage [16]. Therefore, it is possible that the greater incidence of allogenic blood transfusion may increase the risk of transfusion-related thrombotic ACE. If this is the case, it will be important for healthcare providers to carefully monitor these patients for at least 30 days after surgery if clopidogrel is continued perioperatively. As with all studies, this study was not without limitations. First, the natural tendency of a retrospective study presents inherent weaknesses. For example, data recorded in charts are vulnerable to subjectivity, which may lead to inaccuracies (i.e., estimated blood loss) or lack of adequate documentation (i.e., date of last clopidogrel). Second, our institution commonly attracts many patients with primary care providers outside the medical charting system. In effect, a patient may have experienced an ACE within a year of the elective
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THA or TKA procedure, but this event may have gone undocumented within the charting system and ultimately be unaccounted for in our study. Third, there was no blood transfusion protocol to assist healthcare providers in decision-making consistency of when to administer a blood transfusion. The absence of a blood transfusion protocol allowed healthcare providers to make individual decisions regarding the need of blood transfusion on a case by case basis. Finally, this study was limited due to the small size of our convenience sample of patients meeting inclusion criteria, which limits the robustness of the statistical analysis and limits our ability to draw firm conclusions based on the data. In conclusion, if it is felt that perioperative discontinuation of clopidogrel beyond the suggested timeframes outlined by the AHA/ ACC would increase the risk of adverse cardiovascular events, these data support the notion that it may be reasonable to operate on patients who require hip or knee replacement surgery while remaining on clopidogrel, recognizing the potential increase in transfusion requirements or adverse cardiovascular events. However, we recommend cautious consideration when recommending a patient to continue clopidogrel throughout the perioperative period for elective THA or TKA. Though our results are provocative, the limitations of the study prevent us from drawing firm conclusions. Further research is necessary to clarify the association of perioperative clopidogrel discontinuation and perioperative bleeding risk and cardiovascular morbidity.
Acknowledgments The authors would like to acknowledge the assistance of W. Scott Harmsen (Statistician, Department of Biostatistics and Health Sciences Research, Mayo Clinic, Rochester, MN) and Mary Shirk Marienau Ph.D., C.R.N.A. (Assistant Professor of Anesthesiology, School of Health Sciences Master of Nurse Anesthesia Program, Rochester, MN).
References 1. National Center for Health Statistics. Center for Disease Control, 2011: Discharges with at least one procedure in nonfederal short-stay hospitals, by sex, age, and selected procedures: United States, selected years 1990 through 2009–2010. Accessed on December 27, 2012. 2. Guerin S, Collins C, Kapoor H, et al. Blood transfusion requirement prediction in patients undergoing primary total hip and knee arthroplasty. Transfus Med 2007;17:37. 3. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Anesth Analg 2008;106:685. 4. Brown MJ, Long TR, Brown DR, et al. Acute coronary syndrome and myocardial infarction after orthopedic surgery in a patient with a recently placed drug-eluting stent. J Clin Anesth 2006;18:537. 5. Kaluza GL, Joseph J, Lee JR, et al. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000;35:1288. 6. Rabbitts JA, Nuttall GA, Brown MJ, et al. Cardiac risk of noncardiac surgery after percutaneous coronary intervention with drug-eluting stents. Anesthesiology 2008;109:596. 7. Grujic D, Martin D. Perioperative clopidogrel is seven days enough? Am Surg 2009;75:909. 8. Kang W, Theman TE, Reed III JF, et al. The effect of preoperative clopidogrel on bleeding after coronary artery bypass surgery. J Surg Educ 2007;64:88. 9. Maltais S, Perrault LP, Do QB. Effect of clopidogrel on bleeding and transfusions after off-pump coronary artery bypass graft surgery: impact of discontinuation prior to surgery. Eur J Cardio-Thorac Surg 2008;34:127. 10. Pickard AS, Becker RC, Schumock GT, et al. Clopidogrel-associated bleeding and related complications in patients undergoing coronary artery bypass grafting. Pharmacotherapy 2008;28:376. 11. Callaghan JJ, Spitzer AI. Blood management and patient specific transfusion options in total joint replacement surgery. Iowa Orthop J 2000;20:36. 12. Bierbaum BE, Callaghan JJ, Galante JO, et al. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Joint Surg Am 1999;81:2. 13. Rosencher N, Kerkkamp HE, Macheras G, et al. Orthopedic Surgery Transfusion Hemoglobin European Overview (OSTHEO) study: blood management in elective knee and hip arthroplasty in Europe. Transfusion 2003;43:459. 14. Oh JJ, Robon MJ, Akers WS. Optimizing antiplatelet and anticoagulant agents in the perioperative orthopedic surgery patient. Orthopedics 2005;28:453. 15. Palan J, Odutola A, White SP. Is clopidogrel stopped prior to hip fracture surgery–A survey of current practice in the United Kingdom. Injury 2007;38:1279. 16. Lannan KL, Sahler J, Spinelli SL, et al. Transfusion immunomodulation—the case for leukoreduced and (perhaps) washed transfusions. Blood Cells Mol Dis 2013;50:61.
Contents lists available at ScienceDirect
The Journal of Arthroplasty journal homepage: www.arthroplastyjournal.org
Continuing Clopidogrel During Elective Total Hip and Knee Arthroplasty: Assessment of Bleeding Risk and Adverse Outcomes Adam K. Jacob, MD a, Sean P. Hurley, BSN, BS a, Sean M. Loughran, BSN a, Tyler M. Wetsch, BSN a, Robert T. Trousdale, MD b a b
Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota Departments of Orthopaedic Surgery, Mayo Clinic, Rochester, Minnesota
a r t i c l e
i n f o
Article history: Received 3 April 2013 Accepted 9 June 2013 Keywords: total hip and knee arthroplasty clopidogrel bleeding risk
a b s t r a c t Limited research assessing risks of continued clopidogrel perioperatively in patients undergoing elective orthopedic procedures exists. Patients that underwent elective primary or revision total knee arthroplasty (TKA) or total hip arthroplasty (THA) from 2007 to 2012 while taking clopidogrel at the time of surgical evaluation were retrospectively identified. Patient demographics, last dose of clopidogrel, intraoperative blood loss, blood transfusion, and presence of 30-day adverse cardiac events (ACE) were collected. Of 142 patients meeting criteria, 24 (16.9%) patients remained on clopidogrel perioperatively. Patients that continued clopidogrel were more likely to receive a blood transfusion within 24 hours of surgery (31.8% vs. 7.7%; P = 0.004) and during hospitalization (37.5% vs. 15.3%; P = 0.02), but the incidence of 30-day ACE was not significantly different. Continuation of clopidogrel perioperatively for elective THA or TKA should be carefully considered. © 2014 Elsevier Inc. All rights reserved.
From 2000 to 2009, the frequency of THA has nearly doubled and TKA has more than doubled [1]. While technology for these surgeries has vastly improved, perioperative blood loss and transfusion continue to be significant and unpredictable consequences [2]. This is especially concerning when caring for those patients with increased risk of bleeding due to prescribed antiplatelet therapy for management of cardiovascular or cerebrovascular disease. Standard prevention measures for stent thrombosis involve dual antiplatelet therapy, which typically includes aspirin in addition to clopidogrel due to its ability to inhibit platelet production of thromboxane A2. The American Heart Association (AHA) and American College of Cardiology (ACC) recommend dual antiplatelet therapy for 30–45 days status post bare metal stent placement and for 365 days status post drug eluting stent placement [3]. Discontinuation of dual antiplatelet therapy within this suggested timeframe has been shown to not only predict, but also to significantly increase the risk of acute stent thrombosis for nonsurgical patients as well as those patients undergoing non-cardiac surgery [4–6]. No specific guidelines exist for clopidogrel discontinuation beyond these timeframes. The decision to continue antiplatelet medications, such as clopidogrel, during elective orthopedic surgery has been the subject of debate. Conflicting results exist in the literature with regards to The Conflict of Interest statement associated with this article can be found at http:// dx.doi.org/10.1016/j.arth.2013.06.008. Reprint requests: Adam K. Jacob, MD, Department of Anesthesiology, Mayo Clinic, 200 First Street, S.W., Rochester, MN 55905. 0883-5403/2902-0015$36.00/0 – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.arth.2013.06.008
perioperative use of clopidogrel. Some studies show no statistical differences in cases requiring blood transfusion or hemorrhagic complications in patients that discontinued clopidogrel compared to those who continued clopidogrel perioperatively [7,8]. Other studies have found an associated increase in major blood loss and requirement for blood transfusion in patients who remained on clopidogrel throughout the perioperative period [9,10]. Given these inconsistencies, antiplatelet and anticoagulation medications are commonly discontinued during elective general surgery to reduce the risk of perioperative bleeding. Among patients that remain on clopidogrel beyond the AHA/ACC recommended timeframes, it remains unclear if continuing clopidogrel throughout the perioperative period during elective THA or TKA influences the risk of bleeding or ACE. The main objective of this retrospective cohort study was to test the hypothesis that incidence of perioperative transfusion and ACE differs between patients that continued clopidogrel and patients that discontinued clopidogrel during elective TKA or THA. Materials and Methods After Institutional Review Board approval was obtained, all patients aged ≥ 18 years who underwent elective TKA or THA from January 1, 2002 to April 30, 2012 were retrospectively identified using the Total Joint Registry and the electronic medical record (EMR). Study inclusion was restricted to the first elective primary or revision TKA or THA performed at our institution. Patients who underwent unicompartmental knee arthroplasty, underwent multiple joint procedures during the same operation, were prescribed concurrent
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preoperative heparin or low-molecular weight heparin therapy, or had a preexisting diagnosis of end-stage renal failure, liver failure, or inherited bleeding disorder were excluded. Documented cases of noncompliance with antiplatelet therapy or medical charts missing the date of last clopidogrel intake were excluded on the basis of inconclusive evidence for which clopidogrel was continued or discontinued preoperatively. Patients with chronic angina were excluded due to the inability to assess probable causation. Finally, patients who denied research authorization were excluded as per government statute. Patient demographics (gender, date of birth, height, weight), date of surgery, joint replaced (knee, hip), surgeon, type of surgery (primary, revision), and total surgical time were recorded from the Total Joint Registry. Type of postoperative anticoagulation (warfarin, unfractionated heparin, low molecular weight heparin, aspirin only) and presence of postoperative bleeding or infectious complications within 30 days requiring hospital readmission were collected during manual review of the medical record. Preoperative clopidogrel use was identified using a free-text electronic query of the EMR. The medication list of all clinical notes within the EMR preceding the surgical date was searched for the terms “clopidogrel” or “Plavix.” Medical records were manually reviewed for the indication for clopidogrel use, presence of concomitant preoperative aspirin use, and date of last clopidogrel dose. In addition, the following perioperative variables were manually collected from the EMR: preoperative hemoglobin, postanesthesia care unit hemoglobin, postoperative day 1 hemoglobin, last hemoglobin prior to hospital discharge, estimated intraoperative blood loss, postoperative administration of low-molecular weight heparin, warfarin, clopidogrel and/or anti-inflammatory medications, and length of hospital stay. Patients were categorized as discontinuing clopidogrel if the last dose was taken 7 or more days before the date of surgery, and categorized as continuing clopidogrel if the last dose was taken b 7 days before the date of surgery. The primary outcome variable was defined as the incidence of allogenic red cell transfusion during the hospital admission (including intraoperative period). Presence of any blood product transfusion (packed red blood cells, intraoperative blood salvage, platelets, fresh frozen plasma) was collected from manual review of the anesthesia record and EMR. The secondary outcome was defined as the presence of any major ACE (stent thrombosis requiring PCI, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, or death) within 30 days of hospital discharge. All analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC). Continuous variables were compared using the Wilcoxon rank sum test. Nominal variables were compared using Fisher's exact test. Two-tailed P-values ≤ 0.05 were considered to be statistically significant. Continuous variables (e.g., age, body mass index, and surgical duration) are reported as median and interquartile range unless indicated otherwise. Categorical variables are reported as frequency percentages. Results A total of 197 patients were initially identified that met our inclusion criteria. Of these, 55 patients met one or more exclusion criteria. Therefore, 142 patients (48 females, 94 males) were included in the final analysis. Twenty-four (16.9%) and 118 (83.1%) patients had continued and discontinued clopidogrel throughout the perioperative period, respectively. The median timeframe (25th, 75th quartiles) for discontinuation of clopidogrel prior to surgery was 9 (7, 11) days. No significant difference in gender, age, ASA status, joint replaced, type of procedure, type of postoperative anticoagulation, preoperative hemoglobin, estimated blood loss, or length of hospital stay was detected between patients continuing clopidogrel compared to patients that discontinued clopidogrel perioperatively (Table 1). Three patients developed a complication (2 bleeding complications, 1
Table 1 Patient Demographics. Continued Clopidogrel Discontinued Clopidogrel (N = 24) (N = 118) P-value Age (years) Gender Female Male ASA physical statusa 2 3 4 Joint Total knee arthroplasty Total hip arthroplasty Type of surgery Primary Revision Postoperative DVT prophylaxis Warfarin Unfractionated heparin Dalteparin Enoxaparin Aspirin Preoperative hemoglobin (g/dL) Duration of surgery (minutes) Estimated blood loss (mL) Hospital length of stay (days)
72.9 (67.4, 79.4)
74.7 (66.0, 80.8)
9 (37.5%) 15 (62.5%)
39 (33.1%) 87 (66.9%)
3 (12.5%) 20 (83.3%) 1 (4.2%)
27 (23.3%) 87 (75.0%) 2 (1.7%)
9 (37.5%)
63 (53.4%)
15 (62.5%)
55 (46.6%)
20 (83.3%) 4 (16.7%)
95 (80.5%) 23 (19.5%)
5 (20.8%) 2 (8.3%)
46 (40.0%) 3 (2.5%)
0.70 0.67
0.32
0.16
1.0
0.09 0.20
12 (50.0%) 0 (0%) 5 (20.8%) 13.4 (12.8, 14.1)
52 (44.1%) 2 (1.7%) 15 (12.7%) 13.6 (12.6, 14.6)
0.59 1.0 0.32 0.50
80.5 (59.0, 100.5)
102.0 (83.0, 132.0)
b0.01b
200 (50, 350) 4 (3.5, 5.5)
200 (0, 355)
0.68
4 (4, 5)
0.97
Values presented at median (25th, 75th) unless otherwise specified; ASA = American Society of Anesthesiologists, DVT = deep venous thrombosis. a ASA score missing in 2 patients in the Discontinued Clopidogrel group. b Wilcoxon Rank Sum test.
infectious complication) within 30 days of surgery that required either readmission with re-operation or joint aspiration. All 3 complications occurred in patients that had discontinued clopidogrel N 7 days preoperatively. The median (25th, 75th) postoperative day 1 hemoglobin level for patients that continued clopidogrel was 9.6 (8.7, 10.8) g/dL, compared to 10.6 (9.8, 11.4) g/dL in patients that discontinued clopidogrel. This was not statistically significantly different (P = 0.06), nor was the change in hemoglobin from preoperative to postoperative day 1 levels (P = 0.46). The last documented hemoglobin level prior to hospital discharge was not significantly different in patients that continued clopidogrel compared to patients that discontinued clopidogrel (10.1 [9.6, 11.3] g/dL vs. 10.2 [9.5, 11.0] g/dL; P = 0.92]. Compared to patients that discontinued clopidogrel, patients remaining on clopidogrel were more likely to receive a salvaged blood transfusion intraoperatively (29.2% vs. 10.2%; P = 0.02), but the incidence of intraoperative packed red blood cell transfusion was not statistically significantly different (20.8% vs. 11.9%; P = 0.32). Patients who continued clopidogrel were more likely to receive an allogenic blood transfusion than patients who discontinued clopidogrel in the first 24 hours after surgery (31.8% vs. 7.7%; P = 0.004; Fig. 1) and overall during the entire hospital admission (37.5% vs. 15.3%; P = 0.02; Fig. 2). The incidence of ACE within 30-days was greater among patients that continued clopidogrel, but the difference was not statistically significant (16.7% vs. 5.1%; P = 0.07). Callaghan and Spitzer suggested that total joint revision procedures are more likely to require a blood transfusion compared to total joint primary procedures [11]. Therefore as a secondary analysis, we limited the comparison to only those 115 patients (20 continued clopidogrel, 95 discontinued clopidogrel) who underwent primary
A.K. Jacob et al. / The Journal of Arthroplasty 29 (2014) 325–328 Clopidogrel Continued
35
Percent of Patients
*
30
Clopidogrel Discontinued
25 20 15 10 5 0 PRBC
Cell Saver
Type of Blood Product Fig. 1. Intraoperative and postanesthesia care unit blood product administration. Significant difference in blood product administration in patients that continued clopidogrel. PRBC = Packed Red Blood Cell. *P = 0.02 using Fisher's exact test.
joint arthroplasty. The change in hemoglobin from preoperative to postoperative day 1 levels was not significantly different for patients that continued clopidogrel compared to patients that discontinued clopidogrel (3.4 g/dL vs. 3.0 g/dL; P = 0.46), nor was the change in hemoglobin from preoperative to hospital discharge levels (2.8 g/dL vs. 3.3 g/dL; P = 0.34). Compared to patients that discontinued clopidogrel, patients remaining on clopidogrel were again more likely to receive a salvaged blood transfusion intraoperatively (20% vs. 0%; P b 0.001), but the incidence of intraoperative allogenic packed red blood cell transfusion was not statistically significantly different (10.0% vs. 5.3%; P = 0.35). Patients who continued clopidogrel were more likely to receive an allogenic blood transfusion than patients who discontinued clopidogrel in the first 24 hours after surgery (25.0% vs. 6.3%; P = 0.02) and overall during the entire hospital admission (30.0% vs. 9.5%; P = 0.02). Similarly, the incidence of ACE within 30-days was greater among patients that continued clopidogrel, but the difference was not statistically significant (10.0% vs. 4.2%; P = 0.28).
Discussion No current guidelines exist beyond the recommended ACC/AHA timeframes to direct healthcare providers in the decision-making process of whether or not to continue clopidogrel throughout the perioperative period during elective orthopedic procedures. Arguments exist in favor of discontinuation of clopidogrel in order to
**
Percent of Patients
40 35
Clopidogrel Continued Clopidogrel Discontinued
*
30 25 20 15 10 5 0
24 hour postop
Entire admission
Time of PRBC Transfusion Fig. 2. Postoperative blood product administration. Significant difference in blood product administration in patients that continued clopidogrel. Entire admission inclusive of intraoperative, PACU, and postoperative data. PRBC = Packed Red Blood Cell. *P = 0.004 using Fisher's exact test. **P = 0.02 using Fisher's exact test.
327
prevent excessive bleeding or the need for a blood transfusion [2,12,13]. Conversely, arguments also are made in favor of continuation of clopidogrel for prevention of stent thrombosis or reinfarction [14,15]. The results of this investigation demonstrated that patients who continued clopidogrel throughout the perioperative period were more likely to receive a blood transfusion compared to patients that discontinued clopidogrel. Interestingly, there may be additional risk for ACE among patients that continue clopidogrel. Therefore, healthcare providers must be prepared for the increased potential requirement for blood transfusion as well as ACE in the perioperative period. Clopidogrel is a thienopyridine class glycoprotein IIB/IIIA inhibitor that causes irreversible competitive inhibition of adenosine diphosphate by blocking its binding capability to the P2Y12 platelet receptor. In effect, the platelet is rendered incapable of clot formation and thus unable to contribute to thrombosis for its lifespan. Clopidogrel was approved by the Food and Drug Administration in 1997 with its primary indication for the reduction of atherothrombotic events. It is most commonly prescribed for patients with history of a recent myocardial infarction or stroke, established peripheral arterial disease, acute coronary syndrome, or stent placement. Conflicting results exist in the literature with regards to perioperative use of clopidogrel. Some studies show no statistical differences in cases requiring blood transfusion or return to the operating room for hemorrhagic complications in patients that discontinued clopidogrel at least 7 days prior to general, orthopedic, vascular, and cardiovascular surgery as compared to those who continued clopidogrel perioperatively [7,8]. Other studies have found an associated increase in major blood loss and requirement for blood transfusion in patients who remained on clopidogrel throughout the perioperative period [9,10]. We demonstrated an increased incidence of allogenic blood transfusion without an increase in intraoperative blood loss when patients continue clopidogrel throughout the perioperative period. These results appear discordant, but may illustrate the variation that occurs while recording estimated blood loss and the potential for ongoing postoperative blood loss after PACU dismissal. It is important to note that based on our definition, some patients may have still discontinued clopidogrel fewer than 7 days before surgery. Therefore, it is possible that the discrepancy in perioperative transfusion may be greater if the medication is continued up to and including the day of surgery as well as the immediate postoperative period. Although the incidence of ACE within 30 days of surgery was not statistically significant, there was a trend toward increased incidence of ACE among patients that continued clopidogrel perioperatively. The exact reason for this observation is unclear. Because recommendations listed within the medical charting system lacked rationale for continuation of clopidogrel perioperatively, it is possible that patients at greater risk for perioperative ACE were recommended to continue clopidogrel, thus creating a treatment bias. Alternatively, exposure to allogenic blood, specifically leukocytes within stored blood, may release potentially harmful proinflammatory and prothrombotic mediators during storage [16]. Therefore, it is possible that the greater incidence of allogenic blood transfusion may increase the risk of transfusion-related thrombotic ACE. If this is the case, it will be important for healthcare providers to carefully monitor these patients for at least 30 days after surgery if clopidogrel is continued perioperatively. As with all studies, this study was not without limitations. First, the natural tendency of a retrospective study presents inherent weaknesses. For example, data recorded in charts are vulnerable to subjectivity, which may lead to inaccuracies (i.e., estimated blood loss) or lack of adequate documentation (i.e., date of last clopidogrel). Second, our institution commonly attracts many patients with primary care providers outside the medical charting system. In effect, a patient may have experienced an ACE within a year of the elective
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THA or TKA procedure, but this event may have gone undocumented within the charting system and ultimately be unaccounted for in our study. Third, there was no blood transfusion protocol to assist healthcare providers in decision-making consistency of when to administer a blood transfusion. The absence of a blood transfusion protocol allowed healthcare providers to make individual decisions regarding the need of blood transfusion on a case by case basis. Finally, this study was limited due to the small size of our convenience sample of patients meeting inclusion criteria, which limits the robustness of the statistical analysis and limits our ability to draw firm conclusions based on the data. In conclusion, if it is felt that perioperative discontinuation of clopidogrel beyond the suggested timeframes outlined by the AHA/ ACC would increase the risk of adverse cardiovascular events, these data support the notion that it may be reasonable to operate on patients who require hip or knee replacement surgery while remaining on clopidogrel, recognizing the potential increase in transfusion requirements or adverse cardiovascular events. However, we recommend cautious consideration when recommending a patient to continue clopidogrel throughout the perioperative period for elective THA or TKA. Though our results are provocative, the limitations of the study prevent us from drawing firm conclusions. Further research is necessary to clarify the association of perioperative clopidogrel discontinuation and perioperative bleeding risk and cardiovascular morbidity.
Acknowledgments The authors would like to acknowledge the assistance of W. Scott Harmsen (Statistician, Department of Biostatistics and Health Sciences Research, Mayo Clinic, Rochester, MN) and Mary Shirk Marienau Ph.D., C.R.N.A. (Assistant Professor of Anesthesiology, School of Health Sciences Master of Nurse Anesthesia Program, Rochester, MN).
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