Thrombosis Research 135 (2015) 267–271
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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Thromboembolic and Bleeding Outcomes of Extended Duration Low-Intensity Warfarin Following Elective Total Knee Arthroplasty Stephanie E. Cho a,d, Thomas Delate b, Daniel M. Witt c, Nathan P. Clark d,⁎ a
At the time of research, Ambulatory Care Specialty Resident, Pharmacy Department, Kaiser Permanente Colorado, Aurora, CO, USA Clinical Pharmacy Research Team, Kaiser Permanente Colorado, 16601 E. Centretech ParkwayAurora, CO 80011, USA At the time of research, Clinical Pharmacy Research Team, Kaiser Permanente Colorado, Aurora, CO, USA d Clinical Pharmacy Anticoagulation and Anemia Services, Kaiser Permanente Colorado, Aurora, CO, USA b c
a r t i c l e
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Article history: Received 3 September 2014 Received in revised form 15 October 2014 Accepted 4 November 2014 Available online 13 December 2014 Keywords: Warfarin Thromboprophylaxis Deep vein thrombosis Pulmonary embolism Arthroplasty
a b s t r a c t Introduction: The purpose of this study was to describe the incidence of symptomatic venous thromboembolism (VTE), clinically-relevant bleeding, and death among a real-world population receiving warfarin prophylaxis targeting an international normalized ratio (INR) of 1.5 to 2.5 for four weeks following total knee arthroplasty (TKA). Materials and Methods: This retrospective, observational study included patients receiving warfarin following a TKA between August 1, 2005 and July 31, 2009 identified in the Kaiser Permanente Total Joint Replacement Registry. Patients b18 years, receiving warfarin for another indication, or without continuous KPCO membership during the study period were excluded. Results: There were 1487 patients with TKA included in the analysis. Mean patient age was 67.7 years and 61.7% were female. The median percent of time in therapeutic INR range during follow-up was 55% (interquartile range = 35%-75%). Nineteen cases of symptomatic VTE [1.3%; 95% confidence interval (CI) 0.8%-2.0%] including ten pulmonary emboli (PE) (0.7%) were identified within 90 days of surgery. Clinically-relevant bleeding occurred in 1.7% (95% CI 1.1%-2.5%) of patients during warfarin prophylaxis and there were no deaths within 90 days of surgery. Conclusions: The rates of symptomatic VTE and clinically-relevant bleeding following TKA in patients receiving warfarin prophylaxis with a target INR of 1.5 to 2.5 were low. Additional studies should include low-intensity warfarin to identify the regimen that optimally balances risks of bleeding and symptomatic VTE after major orthopedic surgery. © 2014 Elsevier Ltd. All rights reserved.
Introduction Venous stasis, endothelial injury, inflammation, and subsequent hypercoagulability during and following total knee arthroplasty (TKA) collectively increase the risk of post-surgical venous thromboembolism (VTE) [1–3]. The estimated baseline risk for clinically significant symptomatic VTE without thromboprophylaxis is 4.3% during the first 35 days following joint arthroplasty, with risk being greatest during
Abbreviations: TKA, total knee arthroplasty; VTE, venous thromboembolism; ACCP, American College of Chest Physicians; AAOS, American Academy of Orthopaedic Surgeons; DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist; INR, International Normalized Ratio; KPCO, Kaiser Permanente Colorado; CPAAS, Clinical Pharmacy Anticoagulation and Anemia Service; EMR, electronic medical record; LMWH, low-molecular-weight heparin; TJRR, total joint replacementregistry; TTR, time spent within the therapeutic INR range ICD-9 - International Classification of Diseases, Ninth Revision ⁎ Corresponding author at: 16601 East Centretech Parkway, Aurora, CO. Tel.: +1 303 739 4901; fax: +1 303 793 4927. E-mail address: [email protected] (N.P. Clark).
http://dx.doi.org/10.1016/j.thromres.2014.11.033 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
the first seven days after surgery [1]. Consensus guidelines, including the 9th edition of the American College of Chest Physicians (ACCP) and the American Academy of Orthopaedic Surgeons (AAOS) guidelines, recommend pharmacologic thromboprophylaxis following TKA to reduce the risk and incidence of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevent potentially lifethreatening outcomes [1,4]. Historically, the ACCP and AAOS guidelines disagreed regarding the optimal intensity of prophylaxis with vitamin K antagonists (VKAs), including warfarin. The ACCP (2008) guidelines previously emphasized preventing VTE outcomes and recommended dose-adjusted warfarin targeting a conventional international normalized ratio (INR) range of 2.0 to 3.0 [5]. Past AAOS (2009) guidelines supported a low intensity INR target of ≤ 2.0 due to concern for post-surgical bleeding complications [6]. The most recent AAOS (2011) and ACCP (2012) guidelines no longer recommend a specific INR target for warfarin therapy [1,4]. The ACCP guidelines comment that morbidity associated with symptomatic VTE is comparable to that of major post-operative bleeding following total joint arthroplasty [1].
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Warfarin prophylaxis targeting lower INRs is commonly used in clinical practice. A recent survey of orthopedic surgeons in the United States found that only 23% of respondents using warfarin thromboprophylaxis reported targeting an INR range of 2.0 to 3.0 [7]. A survey of American Association of Hip and Knee Surgeons found that more than 90% of respondents reported targeting an INR range lower than 2.0 to 3.0 (e.g. target INR ≤ 2.0) [8]. Despite widespread use of low-intensity warfarin thromboprophylaxis following TKA, studies reporting symptomatic VTE and bleeding with this intervention are limited. Available publications have evaluated abbreviated VKA prophylaxis durations, provide limited detail regarding anticoagulation control, report outcomes in populations intermixed with total hip and knee replacement surgeries, and do not report follow-up for VTE outcomes extending to 90 days [9–13]. The purpose of this study is to describe the incidence of symptomatic VTE, clinically-relevant bleeding, and death in a cohort of patients receiving low intensity warfarin (INR targeted to 1.5 to 2.5) for four weeks after TKA. Materials and Methods Study Design and Setting This retrospective, single group, observational study was conducted at Kaiser Permanente Colorado (KPCO), a not-for-profit integrated healthcare delivery system providing health care to over 520,000 patients in Colorado. At KPCO, orthopedic surgeons prefer warfarin with an INR target of 1.5 to 2.5 for thromboprophylaxis following TKA. Warfarin is initiated the evening of the procedure and typically continued for four weeks. Pharmacists in the KPCO Clinical Pharmacy Anticoagulation and Anemia Service (CPAAS) centrally monitor and manage over 8,000 patients receiving outpatient anticoagulants. At any given time 7% to 9% of the CPAAS census is patients receiving low-intensity warfarin after total joint arthroplasty. Orthopedic surgeons refer patients for anticoagulation management to CPAAS where clinical pharmacists practice under collaborative drug therapy management agreements and document all direct patient care activities (including warfarin dose titration and lab monitoring) in an electronic medical record (EMR) and anticoagulation tracking software program (Dawn-AC; 4S Systems, Ltd., Cumbria, United Kingdom) [14]. All study activities were reviewed and approved by the KPCO Institutional Review Board.
Haemostasis (i.e. bleeding that was fatal, symptomatic bleeding into a critical organ, bleeding that resulted in a hemoglobin decrease of greater than or equal to 2 g/dL or led to transfusion of 2 or more units of packed red blood cells) [15,16]. In addition, time spent within the therapeutic INR range (TTR) starting from the day of surgery through completion of warfarin thromboprophyalxis and rate of post-operative infection during the 90-day post-TKA time period were assessed [16]. Data Collection The KPCO study cohort was identified from the Total Joint Replacement Registry (TJRR) which includes N 90,000 joint replacement procedures from all of the Kaiser Permanente regions [17]. The TJRR was developed and maintained through administrative databases queries, physician intake forms, and manual review of EMRs. In addition to demographic data, the TJRR provides thromboprophylaxis details, intra-operative outcomes, and post-procedural complications. Bleeding, VTE and fatal outcomes were initially identified either within the TJRR or through queries of the KPCO electronic inpatient claims (for VTE, bleeding, infection outcomes) and outpatient record (for VTE outcomes) administrative databases using predefined International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes (see Appendix). Manual chart review was also undertaken for the entire sample to ensure VTE events managed in the outpatient setting were not missed. Membership datasets were used to identify fatal outcomes. Potential outcomes identified through either the TJR, administrative database queries, or manual chart review were examined and validated by at least two study team members using a standardized chart abstraction form (SEC and DMW). Any disagreements were adjudicated by a 3rd reviewer (NPC). Post-TKA target INR range and INR values during the four-week warfarin thromboprophylaxis course were obtained from the Dawn-AC database. Patient membership during the study period was identified through queries of the electronic KPCO membership database. Comorbidities (hypertension, diabetes mellitus, renal insufficiency, hepatic disease, previous VTE, and cancer [solid tumor and metastatic]) in the six months prior to TKA were identified via query of the KPCO outpatient record database using predefined ICD-9 codes. The KPCO electronic pharmacy database was used to identify prescription purchase history of nonsteroidal anti-inflammatory drugs, estrogen, and corticosteroids during the 90 days prior to and 28 days following TKA and unfractionated heparin, low-molecular-weight heparin (LMWH), or fondaparinux in the 90 days following TKA.
Study Population Data Analysis The study included patients who 1) were age ≥18 years at the time of TKA; 2) had a TKA between August 1, 2005 and July 31, 2009; 3) had continuous KPCO membership in the six months prior and three months following TKA; and 4) received warfarin targeted to an INR 1.5 to 2.5 for post-TKA thrombopropylaxis. Patients who did not receive low-intensity warfarin (defined as warfarin prophylaxis targeting INR 1.5 to 2.5) or had concurrent warfarin indication(s) other than postTKA thromboprophylaxis were excluded. Only a patient’s first TKA during the study period was included in the analysis. Study Outcomes Primary outcomes were the rates of symptomatic VTE (DVT and/or PE), all-cause mortality during the 90-day post-TKA and clinicallyrelevant bleeding during the four-week warfarin prophylaxis time periods. Clinically-relevant bleeding was defined as any unexpected bleeding following surgery documented during the index hospitalization or bleeding that resulted in rehospitalization or emergency department (ED) visit after discharge. Secondary outcomes included the rate of major hemorrhage during the four-week warfarin prophylaxis time period as defined by the International Society of Thrombosis and
Patient characteristics are reported with descriptive statistics (means, medians, standard deviations, interquartile ranges, and percentages). Venous thromboembolism, clinically-relevant bleeding, death, and infection rates were calculated by dividing the frequency of the outcome by the total count of included surgeries and reported as percentages with 95% confidence intervals. Results There were 1,725 TKA procedures identified from the TJRR during the study period. Of these, 238 procedures (13.8%) were excluded: 119 for patients with multiple procedures, 94 for chronic warfarin use prior to elective TKA, 11 received LMWH or fondaparinux instead of warfarin, eight received standard intensity warfarin (targeted INR range of 2 to 3), three for miscoded surgery type, and one each for: warfarin treatment refused, dabigatran clinical trial participation, and thromboprophylaxis being prohibited by intraoperative bleeding. Of the eight patients with INR target of 2.0 to 3.0, two cases had postoperative atrial fibrillation, five cases had history of VTE or known thrombophilia, and no rationale was readily apparent in one case. In
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total, 1,487 patients with a TKA were included in the analysis as presented in Fig. 1. The mean age at the time of TKA was 67.7 years and hypertension (59.5%) and diabetes mellitus (14.5%) were the most common comorbidities (Table 1). The majority of patients (81.1%) received some form of mechanical prophylaxis after surgery in addition to warfarin therapy (Table 2). Bridge therapy with fondaparinux or LMWH was utilized concomitantly during warfarin initiation in 5.7% of TKAs. The median duration of warfarin thromboprophylaxis was 28 (interquartile range (IQR) = 28-29) days and the median TTR was 55% (IQR = 35%-75%). The mean TTR was 54.7%. The 90-day rate of symptomatic VTE following TKA was 1.3% (19 events) including ten PE (0.7%) (two of which had concurrent DVT)
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and nine isolated DVT (0.6%) (Table 3). Sixteen VTE events occurred within 14 days of surgery (84.2%) and three (15.8%) occurred following completion of warfarin therapy. Two thrombotic events unrelated to VTE (one stroke and one arterial thromboembolism) were also identified but not included in the primary outcome. Clinically-relevant bleeding during warfarin therapy occurred following 25 (1.7%) procedures. Additional descriptions of bleeding types and locations are summarized in Table 3. Ten (0.7%) clinically-relevant bleeding events also met the definition of major hemorrhage. Eight cases of deep infection, only one of which was associated with bleeding, resulted in surgical exploration and debridement with or without hardware removal. No deaths occurred during the 90-day post-TKA time period.
Fig. 1. Disposition of total knee arthroplasty surgeries identified for study inclusion in the Kaiser Permanente Total Joint Replacement Registry. TKA – Total knee arthroplasty. KPCO - Kaiser Permanente Colorado. TJRR – Total joint replacement registry. LMWH – Low-molecular-weight heparin.
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Table 1 Baseline Characteristics of Knee Replacement Study Sample (N = 1487).
Table 3 Treatment Outcomes (N = 1487).
Characteristic
Value
Outcome
Value
Mean Age1 (SD) Age ≥ 65 Years1 (n, %) Female (n, %) Mean BMI2 (SD) Comorbid diseases2 (n, %) Hypertension Diabetes Mellitus Solid Tumor Cancer Chronic Kidney Disease History of VTE Hepatic Cirrhosis Medication history3 (n, %) Non-Steroidal Anti-Inflammatory Estrogen Corticosteroid Tobacco Use1 (n, %) Smoker Knee Surgery Side (n, %) Right Left
67.7 (9.2) 936, 63.0% 866, 61.7% 30.5 (5.3)
VTE1 (n, %, 95% CI) VTE Type (n, %2) PE DVT only Clinically Relevant Bleed (n, %, 95% CI) Major Hemorrhage2,3 (n, %) Bleed Type (n, %2) Hemarthrosis Wound Hematoma Gastrointestinal Bleed Epistaxis Hematuria Other Surgical Site Infection (n, %, 95% CI) Infection Description (n, %2) Superficial Deep
19, 1.3% (0.8%-2.0%)
884, 59.5% 216, 14.5% 65, 4.4% 17, 1.1% 15, 1.0% 13, 0.9% 361, 24.3% 138, 9.3% 79, 5.3% 63, 4.3% 752, 50.6% 735, 49.4%
SD, standard deviation; BMI, body mass index; VTE, venous thromboembolism. 1 As of surgery date. 2 Diagnosis coded in a medical office visit during the 180 days prior to surgery. 3 Purchased during the 90 days prior to or 28 days after surgery.
Discussion Despite prevalent use of low-intensity warfarin for VTE prevention following TKA in the United States, few studies have adequately evaluated the effectiveness and safety of this regimen in a real world population. Most studies evaluating the effectiveness of extended VTE prophylaxis after total joint arthroplasty (TJA) have examined LMWH or novel oral anticoagulants, not low-intensity warfarin [18–20]. Synthesis of available data by the ACCP guidelines found an estimated cumulative symptomatic VTE rate of approximately 1.8% during the first 35 days following major orthopedic surgery among patients receiving extended LMWH prophylaxis [1]. We observed 16 VTEs in 1487 patients over a comparable time frame for a numerically similar rate of 1.1%. Our overall 90-day rate of symptomatic VTE was 1.3% with three events (accounting for 15.8% of total VTE events) occurring after warfarin completion. Two retrospective studies recently highlighted the difficulty in achieving and maintaining therapeutic anticoagulation with warfarin targeting an INR of 2.0 to 3.0 after TKA. One study reported TTR of 36.6% in 295 TKA patients [21]. In this study, the mean time to the first therapeutic INR was 12.8 days and 14.9% of patients never reached their target INR [21]. Similar results were reported in another study which found a mean TTR of 29.5% among 221 TKA patients receiving warfarin with a target INR of 2 to 3 [22]. Although our study had numerically better TTR, probably owing to a lower target range, we also failed to achieve what is typically considered high-quality warfarin control [23]. It is unclear what the threshold for high-quality TTR should be Table 2 Venous Thromboembolism Prevention and Anticoagulation Characteristics (N = 1487). Characteristic
Value
Mechanical Prophylaxis (n, %) Bridge Therapy (n, %) Enoxaparin Fondaparinux Median Percent of Time In Therapeutic Range1 (IQR) Median Percent of Time Below Range1 (IQR) Median Percent of Time Above Range1 (IQR) Median Treatment Duration (days, IQR) Median Outpatient INR Counts1 (IQR)
1206, 81.1% 70, 4.7% 15, 1.0% 55% (35%-75%) 26% (9%-51%) 0% (0%-20%) 28 (28-29) 5 (4-6)
IQR, interquartile range; SD, standard deviation; INR, international normalized ratio. 1 Up to 6 weeks after surgery or until outcome.
10, 52.6% 9, 47.4% 25, 1.7% (1.1%-2.5%) 10, 37.0% 12, 48.0% 8, 32.0% 2, 8.0% 1, 4.0% 1, 4.0% 1, 4.0% 8, 0.5% (0.2%-1.1%) 3, 37.5% 5, 62.5%
CI, confidence interval; DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism. 1 Within 90 days of surgery. 2 Percent of those with the outcome. 3 Percent of those having a clinically relevant bleed fitting International Society of Thrombosis and Haemostasis definition of major hemorrhage.
for short term prophylaxis with warfarin, but achieving a TTR similar to chronic indications, like atrial fibrillation, may not be readily achievable. The aforementioned studies each reported difficulty in achieving and maintaining therapeutic anticoagulation; however, their findings were divergent for the primary outcome of symptomatic VTE. The 30day incidence of symptomatic VTE of 1% found by Barnes and colleagues is comparable to our results as well as ACCP estimates [1,21]. In contrast, Netescu et al reported symptomatic VTE in 5% of their population with the majority of VTE associated with INR values less than 1.5 [22]. Comparing our results to earlier prospective studies examining standard intensity warfarin prophylaxis (INR 2.0 to 3.0) following TJA is difficult because these studies examined varying durations of therapy and follow up, and included asymptomatic DVT in the primary outcome [24, 25]. Warfarin is preferred by some orthopedic surgeons due to its delayed anticoagulant effect, which theoretically should minimize the risk of early postoperative bleeding at the expense of greater risk for early VTE [7,8]. A review of VTE prophylaxis studies using enoxaparin following TKA found major hemorrhage rates range from 0.2% to 1.4% during 6 to 15 days of prophylaxis which is comparable to the risk of major hemorrhage we identified for low-intensity warfarin during 28 days of prophylaxis (0.6%) [26]. Analysis in the 9th edition of the ACCP guidelines suggests that compared to LMWH, use of warfarin during initial major orthopedic prophylaxis would result in 3 more VTE events and 4 fewer major bleeding events per 1000 patients [1]. Their analysis of extended prophylaxis is hampered by availability of only one trial comparing LMWH and VKA for extended orthopedic prophylaxis which evaluated products not commercially available in the United States [27]. This underscores the need for future studies comparing warfarin to LMWH as well as newer oral anticoagulant options after major orthopedic surgery to identify the drug regimen that optimally balances risk of bleeding and VTE. Overall, the ACCP panelists suggest LMWH over dose-adjusted VKA for prophylaxis after major orthopedic surgery (Grade 2C recommendation) [1]. At KPCO, the decision to use LMWH or fondaparinux during warfarin initiation was at the discretion of the referring orthopedic surgeon and was not common (5.7%). The majority of VTE outcomes in our study occurred during the initial warfarin titration period within the first week following TKA when VTE risk is highest and patients may not have achieved a target INR or a complete antithrombotic warfarin effect
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[28]. It is therefore possible that the use of rapid-acting parenteral anticoagulants as bridge therapy could have mitigated the risk of early VTE during warfarin initiation. Among the 85 patients receiving bridge therapy in our study, there were no cases of symptomatic VTE and only one clinically-relevant (non-major) wound hematoma occurred (1.2% of bridged patients). The majority of patients in our study were prescribed mechanical thromboprophylaxis. The usual protocol at KPCO includes pneumatic compression devices during hospitalization followed by compression stockings for up to six weeks after hospital discharge. Pneumatic compression has been shown to decrease the rate of VTE after major orthopedic surgery [1]. The use of these devices in patients receiving warfarin for prophylaxis may be particularly important given warfarin’s delayed onset of anticoagulant effect [7,8]. There are limitations to our study. We mitigated the potential risk of missed clinical events by leveraging administratively collected electronic registry, medical record, and claims data with manual EMR review for the entire identified patient population for up to 90 days following TKA. Patients receiving warfarin in this study were managed by a centralized anticoagulation service of clinical pharmacists with specialized training. Our findings may not be generalizable to settings without comparable anticoagulation services. Comparing the event rates we observed in this retrospective evaluation to event rates from randomized, controlled studies may not be valid but does provide insights into real-world vs. experimental clinical experiences. The impact of warfarin on preventing symptomatic VTE after TKA cannot be definitively determined within the present analysis as there was no untreated control population.
[5]
[6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15] [16]
Conclusions
[17]
Low-intensity warfarin prophylaxis with a target INR of 1.5 to 2.5 for four weeks after TKA resulted in low rates of symptomatic VTE and bleeding. Future studies evaluating VTE prophylaxis after major orthopedic surgery should include low-intensity warfarin to identify the regimen that optimally balances risk of symptomatic VTE and post-operative bleeding. This study was funded by the Kaiser Permanente Colorado Pharmacy Department. The authors have no conflicts of interest to report.
[18]
Conflict of Interest The authors have no conflicts of interest to report.
[19]
[20]
[21]
[22]
Acknowledgments Author contributions: SEC, TD, DMW and NPC contributed to study design and implementation. TD, SEC, Sara Byrnes, Allison Berch, Gale Albrecht and Charlyn Wong were responsible for data collection. SEC and DMW validated study outcomes. All authors provided critical revisions to the manuscript. Role of sponsors: N/A.
[23]
[24]
[25]
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Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Thromboembolic and Bleeding Outcomes of Extended Duration Low-Intensity Warfarin Following Elective Total Knee Arthroplasty Stephanie E. Cho a,d, Thomas Delate b, Daniel M. Witt c, Nathan P. Clark d,⁎ a
At the time of research, Ambulatory Care Specialty Resident, Pharmacy Department, Kaiser Permanente Colorado, Aurora, CO, USA Clinical Pharmacy Research Team, Kaiser Permanente Colorado, 16601 E. Centretech ParkwayAurora, CO 80011, USA At the time of research, Clinical Pharmacy Research Team, Kaiser Permanente Colorado, Aurora, CO, USA d Clinical Pharmacy Anticoagulation and Anemia Services, Kaiser Permanente Colorado, Aurora, CO, USA b c
a r t i c l e
i n f o
Article history: Received 3 September 2014 Received in revised form 15 October 2014 Accepted 4 November 2014 Available online 13 December 2014 Keywords: Warfarin Thromboprophylaxis Deep vein thrombosis Pulmonary embolism Arthroplasty
a b s t r a c t Introduction: The purpose of this study was to describe the incidence of symptomatic venous thromboembolism (VTE), clinically-relevant bleeding, and death among a real-world population receiving warfarin prophylaxis targeting an international normalized ratio (INR) of 1.5 to 2.5 for four weeks following total knee arthroplasty (TKA). Materials and Methods: This retrospective, observational study included patients receiving warfarin following a TKA between August 1, 2005 and July 31, 2009 identified in the Kaiser Permanente Total Joint Replacement Registry. Patients b18 years, receiving warfarin for another indication, or without continuous KPCO membership during the study period were excluded. Results: There were 1487 patients with TKA included in the analysis. Mean patient age was 67.7 years and 61.7% were female. The median percent of time in therapeutic INR range during follow-up was 55% (interquartile range = 35%-75%). Nineteen cases of symptomatic VTE [1.3%; 95% confidence interval (CI) 0.8%-2.0%] including ten pulmonary emboli (PE) (0.7%) were identified within 90 days of surgery. Clinically-relevant bleeding occurred in 1.7% (95% CI 1.1%-2.5%) of patients during warfarin prophylaxis and there were no deaths within 90 days of surgery. Conclusions: The rates of symptomatic VTE and clinically-relevant bleeding following TKA in patients receiving warfarin prophylaxis with a target INR of 1.5 to 2.5 were low. Additional studies should include low-intensity warfarin to identify the regimen that optimally balances risks of bleeding and symptomatic VTE after major orthopedic surgery. © 2014 Elsevier Ltd. All rights reserved.
Introduction Venous stasis, endothelial injury, inflammation, and subsequent hypercoagulability during and following total knee arthroplasty (TKA) collectively increase the risk of post-surgical venous thromboembolism (VTE) [1–3]. The estimated baseline risk for clinically significant symptomatic VTE without thromboprophylaxis is 4.3% during the first 35 days following joint arthroplasty, with risk being greatest during
Abbreviations: TKA, total knee arthroplasty; VTE, venous thromboembolism; ACCP, American College of Chest Physicians; AAOS, American Academy of Orthopaedic Surgeons; DVT, deep vein thrombosis; PE, pulmonary embolism; VKA, vitamin K antagonist; INR, International Normalized Ratio; KPCO, Kaiser Permanente Colorado; CPAAS, Clinical Pharmacy Anticoagulation and Anemia Service; EMR, electronic medical record; LMWH, low-molecular-weight heparin; TJRR, total joint replacementregistry; TTR, time spent within the therapeutic INR range ICD-9 - International Classification of Diseases, Ninth Revision ⁎ Corresponding author at: 16601 East Centretech Parkway, Aurora, CO. Tel.: +1 303 739 4901; fax: +1 303 793 4927. E-mail address: [email protected] (N.P. Clark).
http://dx.doi.org/10.1016/j.thromres.2014.11.033 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
the first seven days after surgery [1]. Consensus guidelines, including the 9th edition of the American College of Chest Physicians (ACCP) and the American Academy of Orthopaedic Surgeons (AAOS) guidelines, recommend pharmacologic thromboprophylaxis following TKA to reduce the risk and incidence of symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevent potentially lifethreatening outcomes [1,4]. Historically, the ACCP and AAOS guidelines disagreed regarding the optimal intensity of prophylaxis with vitamin K antagonists (VKAs), including warfarin. The ACCP (2008) guidelines previously emphasized preventing VTE outcomes and recommended dose-adjusted warfarin targeting a conventional international normalized ratio (INR) range of 2.0 to 3.0 [5]. Past AAOS (2009) guidelines supported a low intensity INR target of ≤ 2.0 due to concern for post-surgical bleeding complications [6]. The most recent AAOS (2011) and ACCP (2012) guidelines no longer recommend a specific INR target for warfarin therapy [1,4]. The ACCP guidelines comment that morbidity associated with symptomatic VTE is comparable to that of major post-operative bleeding following total joint arthroplasty [1].
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Warfarin prophylaxis targeting lower INRs is commonly used in clinical practice. A recent survey of orthopedic surgeons in the United States found that only 23% of respondents using warfarin thromboprophylaxis reported targeting an INR range of 2.0 to 3.0 [7]. A survey of American Association of Hip and Knee Surgeons found that more than 90% of respondents reported targeting an INR range lower than 2.0 to 3.0 (e.g. target INR ≤ 2.0) [8]. Despite widespread use of low-intensity warfarin thromboprophylaxis following TKA, studies reporting symptomatic VTE and bleeding with this intervention are limited. Available publications have evaluated abbreviated VKA prophylaxis durations, provide limited detail regarding anticoagulation control, report outcomes in populations intermixed with total hip and knee replacement surgeries, and do not report follow-up for VTE outcomes extending to 90 days [9–13]. The purpose of this study is to describe the incidence of symptomatic VTE, clinically-relevant bleeding, and death in a cohort of patients receiving low intensity warfarin (INR targeted to 1.5 to 2.5) for four weeks after TKA. Materials and Methods Study Design and Setting This retrospective, single group, observational study was conducted at Kaiser Permanente Colorado (KPCO), a not-for-profit integrated healthcare delivery system providing health care to over 520,000 patients in Colorado. At KPCO, orthopedic surgeons prefer warfarin with an INR target of 1.5 to 2.5 for thromboprophylaxis following TKA. Warfarin is initiated the evening of the procedure and typically continued for four weeks. Pharmacists in the KPCO Clinical Pharmacy Anticoagulation and Anemia Service (CPAAS) centrally monitor and manage over 8,000 patients receiving outpatient anticoagulants. At any given time 7% to 9% of the CPAAS census is patients receiving low-intensity warfarin after total joint arthroplasty. Orthopedic surgeons refer patients for anticoagulation management to CPAAS where clinical pharmacists practice under collaborative drug therapy management agreements and document all direct patient care activities (including warfarin dose titration and lab monitoring) in an electronic medical record (EMR) and anticoagulation tracking software program (Dawn-AC; 4S Systems, Ltd., Cumbria, United Kingdom) [14]. All study activities were reviewed and approved by the KPCO Institutional Review Board.
Haemostasis (i.e. bleeding that was fatal, symptomatic bleeding into a critical organ, bleeding that resulted in a hemoglobin decrease of greater than or equal to 2 g/dL or led to transfusion of 2 or more units of packed red blood cells) [15,16]. In addition, time spent within the therapeutic INR range (TTR) starting from the day of surgery through completion of warfarin thromboprophyalxis and rate of post-operative infection during the 90-day post-TKA time period were assessed [16]. Data Collection The KPCO study cohort was identified from the Total Joint Replacement Registry (TJRR) which includes N 90,000 joint replacement procedures from all of the Kaiser Permanente regions [17]. The TJRR was developed and maintained through administrative databases queries, physician intake forms, and manual review of EMRs. In addition to demographic data, the TJRR provides thromboprophylaxis details, intra-operative outcomes, and post-procedural complications. Bleeding, VTE and fatal outcomes were initially identified either within the TJRR or through queries of the KPCO electronic inpatient claims (for VTE, bleeding, infection outcomes) and outpatient record (for VTE outcomes) administrative databases using predefined International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes (see Appendix). Manual chart review was also undertaken for the entire sample to ensure VTE events managed in the outpatient setting were not missed. Membership datasets were used to identify fatal outcomes. Potential outcomes identified through either the TJR, administrative database queries, or manual chart review were examined and validated by at least two study team members using a standardized chart abstraction form (SEC and DMW). Any disagreements were adjudicated by a 3rd reviewer (NPC). Post-TKA target INR range and INR values during the four-week warfarin thromboprophylaxis course were obtained from the Dawn-AC database. Patient membership during the study period was identified through queries of the electronic KPCO membership database. Comorbidities (hypertension, diabetes mellitus, renal insufficiency, hepatic disease, previous VTE, and cancer [solid tumor and metastatic]) in the six months prior to TKA were identified via query of the KPCO outpatient record database using predefined ICD-9 codes. The KPCO electronic pharmacy database was used to identify prescription purchase history of nonsteroidal anti-inflammatory drugs, estrogen, and corticosteroids during the 90 days prior to and 28 days following TKA and unfractionated heparin, low-molecular-weight heparin (LMWH), or fondaparinux in the 90 days following TKA.
Study Population Data Analysis The study included patients who 1) were age ≥18 years at the time of TKA; 2) had a TKA between August 1, 2005 and July 31, 2009; 3) had continuous KPCO membership in the six months prior and three months following TKA; and 4) received warfarin targeted to an INR 1.5 to 2.5 for post-TKA thrombopropylaxis. Patients who did not receive low-intensity warfarin (defined as warfarin prophylaxis targeting INR 1.5 to 2.5) or had concurrent warfarin indication(s) other than postTKA thromboprophylaxis were excluded. Only a patient’s first TKA during the study period was included in the analysis. Study Outcomes Primary outcomes were the rates of symptomatic VTE (DVT and/or PE), all-cause mortality during the 90-day post-TKA and clinicallyrelevant bleeding during the four-week warfarin prophylaxis time periods. Clinically-relevant bleeding was defined as any unexpected bleeding following surgery documented during the index hospitalization or bleeding that resulted in rehospitalization or emergency department (ED) visit after discharge. Secondary outcomes included the rate of major hemorrhage during the four-week warfarin prophylaxis time period as defined by the International Society of Thrombosis and
Patient characteristics are reported with descriptive statistics (means, medians, standard deviations, interquartile ranges, and percentages). Venous thromboembolism, clinically-relevant bleeding, death, and infection rates were calculated by dividing the frequency of the outcome by the total count of included surgeries and reported as percentages with 95% confidence intervals. Results There were 1,725 TKA procedures identified from the TJRR during the study period. Of these, 238 procedures (13.8%) were excluded: 119 for patients with multiple procedures, 94 for chronic warfarin use prior to elective TKA, 11 received LMWH or fondaparinux instead of warfarin, eight received standard intensity warfarin (targeted INR range of 2 to 3), three for miscoded surgery type, and one each for: warfarin treatment refused, dabigatran clinical trial participation, and thromboprophylaxis being prohibited by intraoperative bleeding. Of the eight patients with INR target of 2.0 to 3.0, two cases had postoperative atrial fibrillation, five cases had history of VTE or known thrombophilia, and no rationale was readily apparent in one case. In
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total, 1,487 patients with a TKA were included in the analysis as presented in Fig. 1. The mean age at the time of TKA was 67.7 years and hypertension (59.5%) and diabetes mellitus (14.5%) were the most common comorbidities (Table 1). The majority of patients (81.1%) received some form of mechanical prophylaxis after surgery in addition to warfarin therapy (Table 2). Bridge therapy with fondaparinux or LMWH was utilized concomitantly during warfarin initiation in 5.7% of TKAs. The median duration of warfarin thromboprophylaxis was 28 (interquartile range (IQR) = 28-29) days and the median TTR was 55% (IQR = 35%-75%). The mean TTR was 54.7%. The 90-day rate of symptomatic VTE following TKA was 1.3% (19 events) including ten PE (0.7%) (two of which had concurrent DVT)
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and nine isolated DVT (0.6%) (Table 3). Sixteen VTE events occurred within 14 days of surgery (84.2%) and three (15.8%) occurred following completion of warfarin therapy. Two thrombotic events unrelated to VTE (one stroke and one arterial thromboembolism) were also identified but not included in the primary outcome. Clinically-relevant bleeding during warfarin therapy occurred following 25 (1.7%) procedures. Additional descriptions of bleeding types and locations are summarized in Table 3. Ten (0.7%) clinically-relevant bleeding events also met the definition of major hemorrhage. Eight cases of deep infection, only one of which was associated with bleeding, resulted in surgical exploration and debridement with or without hardware removal. No deaths occurred during the 90-day post-TKA time period.
Fig. 1. Disposition of total knee arthroplasty surgeries identified for study inclusion in the Kaiser Permanente Total Joint Replacement Registry. TKA – Total knee arthroplasty. KPCO - Kaiser Permanente Colorado. TJRR – Total joint replacement registry. LMWH – Low-molecular-weight heparin.
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Table 1 Baseline Characteristics of Knee Replacement Study Sample (N = 1487).
Table 3 Treatment Outcomes (N = 1487).
Characteristic
Value
Outcome
Value
Mean Age1 (SD) Age ≥ 65 Years1 (n, %) Female (n, %) Mean BMI2 (SD) Comorbid diseases2 (n, %) Hypertension Diabetes Mellitus Solid Tumor Cancer Chronic Kidney Disease History of VTE Hepatic Cirrhosis Medication history3 (n, %) Non-Steroidal Anti-Inflammatory Estrogen Corticosteroid Tobacco Use1 (n, %) Smoker Knee Surgery Side (n, %) Right Left
67.7 (9.2) 936, 63.0% 866, 61.7% 30.5 (5.3)
VTE1 (n, %, 95% CI) VTE Type (n, %2) PE DVT only Clinically Relevant Bleed (n, %, 95% CI) Major Hemorrhage2,3 (n, %) Bleed Type (n, %2) Hemarthrosis Wound Hematoma Gastrointestinal Bleed Epistaxis Hematuria Other Surgical Site Infection (n, %, 95% CI) Infection Description (n, %2) Superficial Deep
19, 1.3% (0.8%-2.0%)
884, 59.5% 216, 14.5% 65, 4.4% 17, 1.1% 15, 1.0% 13, 0.9% 361, 24.3% 138, 9.3% 79, 5.3% 63, 4.3% 752, 50.6% 735, 49.4%
SD, standard deviation; BMI, body mass index; VTE, venous thromboembolism. 1 As of surgery date. 2 Diagnosis coded in a medical office visit during the 180 days prior to surgery. 3 Purchased during the 90 days prior to or 28 days after surgery.
Discussion Despite prevalent use of low-intensity warfarin for VTE prevention following TKA in the United States, few studies have adequately evaluated the effectiveness and safety of this regimen in a real world population. Most studies evaluating the effectiveness of extended VTE prophylaxis after total joint arthroplasty (TJA) have examined LMWH or novel oral anticoagulants, not low-intensity warfarin [18–20]. Synthesis of available data by the ACCP guidelines found an estimated cumulative symptomatic VTE rate of approximately 1.8% during the first 35 days following major orthopedic surgery among patients receiving extended LMWH prophylaxis [1]. We observed 16 VTEs in 1487 patients over a comparable time frame for a numerically similar rate of 1.1%. Our overall 90-day rate of symptomatic VTE was 1.3% with three events (accounting for 15.8% of total VTE events) occurring after warfarin completion. Two retrospective studies recently highlighted the difficulty in achieving and maintaining therapeutic anticoagulation with warfarin targeting an INR of 2.0 to 3.0 after TKA. One study reported TTR of 36.6% in 295 TKA patients [21]. In this study, the mean time to the first therapeutic INR was 12.8 days and 14.9% of patients never reached their target INR [21]. Similar results were reported in another study which found a mean TTR of 29.5% among 221 TKA patients receiving warfarin with a target INR of 2 to 3 [22]. Although our study had numerically better TTR, probably owing to a lower target range, we also failed to achieve what is typically considered high-quality warfarin control [23]. It is unclear what the threshold for high-quality TTR should be Table 2 Venous Thromboembolism Prevention and Anticoagulation Characteristics (N = 1487). Characteristic
Value
Mechanical Prophylaxis (n, %) Bridge Therapy (n, %) Enoxaparin Fondaparinux Median Percent of Time In Therapeutic Range1 (IQR) Median Percent of Time Below Range1 (IQR) Median Percent of Time Above Range1 (IQR) Median Treatment Duration (days, IQR) Median Outpatient INR Counts1 (IQR)
1206, 81.1% 70, 4.7% 15, 1.0% 55% (35%-75%) 26% (9%-51%) 0% (0%-20%) 28 (28-29) 5 (4-6)
IQR, interquartile range; SD, standard deviation; INR, international normalized ratio. 1 Up to 6 weeks after surgery or until outcome.
10, 52.6% 9, 47.4% 25, 1.7% (1.1%-2.5%) 10, 37.0% 12, 48.0% 8, 32.0% 2, 8.0% 1, 4.0% 1, 4.0% 1, 4.0% 8, 0.5% (0.2%-1.1%) 3, 37.5% 5, 62.5%
CI, confidence interval; DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism. 1 Within 90 days of surgery. 2 Percent of those with the outcome. 3 Percent of those having a clinically relevant bleed fitting International Society of Thrombosis and Haemostasis definition of major hemorrhage.
for short term prophylaxis with warfarin, but achieving a TTR similar to chronic indications, like atrial fibrillation, may not be readily achievable. The aforementioned studies each reported difficulty in achieving and maintaining therapeutic anticoagulation; however, their findings were divergent for the primary outcome of symptomatic VTE. The 30day incidence of symptomatic VTE of 1% found by Barnes and colleagues is comparable to our results as well as ACCP estimates [1,21]. In contrast, Netescu et al reported symptomatic VTE in 5% of their population with the majority of VTE associated with INR values less than 1.5 [22]. Comparing our results to earlier prospective studies examining standard intensity warfarin prophylaxis (INR 2.0 to 3.0) following TJA is difficult because these studies examined varying durations of therapy and follow up, and included asymptomatic DVT in the primary outcome [24, 25]. Warfarin is preferred by some orthopedic surgeons due to its delayed anticoagulant effect, which theoretically should minimize the risk of early postoperative bleeding at the expense of greater risk for early VTE [7,8]. A review of VTE prophylaxis studies using enoxaparin following TKA found major hemorrhage rates range from 0.2% to 1.4% during 6 to 15 days of prophylaxis which is comparable to the risk of major hemorrhage we identified for low-intensity warfarin during 28 days of prophylaxis (0.6%) [26]. Analysis in the 9th edition of the ACCP guidelines suggests that compared to LMWH, use of warfarin during initial major orthopedic prophylaxis would result in 3 more VTE events and 4 fewer major bleeding events per 1000 patients [1]. Their analysis of extended prophylaxis is hampered by availability of only one trial comparing LMWH and VKA for extended orthopedic prophylaxis which evaluated products not commercially available in the United States [27]. This underscores the need for future studies comparing warfarin to LMWH as well as newer oral anticoagulant options after major orthopedic surgery to identify the drug regimen that optimally balances risk of bleeding and VTE. Overall, the ACCP panelists suggest LMWH over dose-adjusted VKA for prophylaxis after major orthopedic surgery (Grade 2C recommendation) [1]. At KPCO, the decision to use LMWH or fondaparinux during warfarin initiation was at the discretion of the referring orthopedic surgeon and was not common (5.7%). The majority of VTE outcomes in our study occurred during the initial warfarin titration period within the first week following TKA when VTE risk is highest and patients may not have achieved a target INR or a complete antithrombotic warfarin effect
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[28]. It is therefore possible that the use of rapid-acting parenteral anticoagulants as bridge therapy could have mitigated the risk of early VTE during warfarin initiation. Among the 85 patients receiving bridge therapy in our study, there were no cases of symptomatic VTE and only one clinically-relevant (non-major) wound hematoma occurred (1.2% of bridged patients). The majority of patients in our study were prescribed mechanical thromboprophylaxis. The usual protocol at KPCO includes pneumatic compression devices during hospitalization followed by compression stockings for up to six weeks after hospital discharge. Pneumatic compression has been shown to decrease the rate of VTE after major orthopedic surgery [1]. The use of these devices in patients receiving warfarin for prophylaxis may be particularly important given warfarin’s delayed onset of anticoagulant effect [7,8]. There are limitations to our study. We mitigated the potential risk of missed clinical events by leveraging administratively collected electronic registry, medical record, and claims data with manual EMR review for the entire identified patient population for up to 90 days following TKA. Patients receiving warfarin in this study were managed by a centralized anticoagulation service of clinical pharmacists with specialized training. Our findings may not be generalizable to settings without comparable anticoagulation services. Comparing the event rates we observed in this retrospective evaluation to event rates from randomized, controlled studies may not be valid but does provide insights into real-world vs. experimental clinical experiences. The impact of warfarin on preventing symptomatic VTE after TKA cannot be definitively determined within the present analysis as there was no untreated control population.
[5]
[6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15] [16]
Conclusions
[17]
Low-intensity warfarin prophylaxis with a target INR of 1.5 to 2.5 for four weeks after TKA resulted in low rates of symptomatic VTE and bleeding. Future studies evaluating VTE prophylaxis after major orthopedic surgery should include low-intensity warfarin to identify the regimen that optimally balances risk of symptomatic VTE and post-operative bleeding. This study was funded by the Kaiser Permanente Colorado Pharmacy Department. The authors have no conflicts of interest to report.
[18]
Conflict of Interest The authors have no conflicts of interest to report.
[19]
[20]
[21]
[22]
Acknowledgments Author contributions: SEC, TD, DMW and NPC contributed to study design and implementation. TD, SEC, Sara Byrnes, Allison Berch, Gale Albrecht and Charlyn Wong were responsible for data collection. SEC and DMW validated study outcomes. All authors provided critical revisions to the manuscript. Role of sponsors: N/A.
[23]
[24]
[25]
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