A Safe, Effective, and Easy to Use Warfarin Initiation Dosing Nomogram for Post–Joint Arthroplasty Patients

The Journal of Arthroplasty Vol. 25 No. 1 2010

A Safe, Effective, and Easy to Use Warfarin Initiation Dosing Nomogram for Post–Joint Arthroplasty Patients Robert C. Pendleton, MD,* Michelle Wheeler, PharmD,y Nathan Wanner, MD,* Michael B. Strong, MD,* Russell Vinik, MD,* and Christopher L. Peters, MDz

Abstract: Venous thromboembolism (VTE) is a complication after joint arthroplasty, and pharmacologic prophylaxis is recommended to reduce this risk. Warfarin is often used, but initial dosing and management can be difficult. We studied a single-center prospective cohort of consecutive (n = 351) post–joint arthroplasty/revision patients who were initiated on warfarin using a new initiation nomogram and then discharged to home with home health services. The mean time to an international normalized ratio (INR) of 2.0 or higher was 5 days, with a mean INR of 2.1 on the fifth postoperative day. Two patients (0.6%) had an INR higher than 5 in the first 10 days of therapy. Adverse events were uncommon: 4 patients (1.14%) had VTE, 1 had major bleeding episode, and 6 patients (1.7%) had minor bleeding. A specific warfarin dosing nomogram managed by an anticoagulation service and used in joint arthroplasty/revision patients who are discharged to home with home health services leads to effective anticoagulation with few associated adverse events. Keywords: warfarin, anticoagulation, joint arthroplasty, venous thromboembolism, hemorrhagic complications, nomogram. © 2010 Elsevier Inc. All rights reserved.

Venous thromboembolism (VTE), presenting as either pulmonary embolism (PE) or deep venous thrombosis (DVT), is an important complication after lower extremity joint arthroplasty [1-3]. Without primary prophylaxis, venographically proven VTE occurs in 42% to 57% of hip arthroplasty patients and 41% to 85% of knee arthroplasty patients [2,3]. Although most of these events are clinically silent, symptomatic DVT or PE still occurs in 3.4% (0.3% fatal) and 1.5% (0.2% fatal) of hip and knee arthroplasty patients, respectively, when elastic stockings are the only preventive method used [4]. Numerous trials have demonstrated that pharmacologic thromboprophylaxis is effective in reducing the risk of VTE in this population and can be achieved with low rates of clinically significant bleeding complications [2,3]. Consensus guidelines by the American College of Chest Physicians (ACCP) give warfarin (target international

From the *Department of Medicine, General Internal Medicine, University Healthcare Thrombosis Service, University of Utah, Salt Lake City, Utah; yDepartment of Pharmacy, University Healthcare Thrombosis Service, University of Utah, Salt Lake City, Utah; and zDepartment of Orthopaedics, University of Utah, Salt Lake City, Utah. Submitted June 12, 2008; accepted September 21, 2008. No benefits or funds were received in support of the study. Reprint requests: Robert C. Pendleton, MD, General Internal Medicine Division, University of Utah, 50 North Medical Drive, 4B120, Salt Lake City, UT 84132. © 2010 Elsevier Inc. All rights reserved. 0883-5403/08/2501-0024$36.00/0 doi:10.1016/j.arth.2008.09.015

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normalized ratio [INR], 2.0-3.0), low molecular weight heparins, and fondaparinux the highest level of recommendation for thromboprophylaxis after joint arthroplasty [2]. Furthermore, the American Academy of Orthopaedic Surgeons (AAOS) endorses pharmacologic prophylaxis, and warfarin (target INR, ≤2.0) is recommended as an effective option for all patient groups regardless of their estimated PE or bleeding risk [5]. These recommendations are consistent with clinical practice where warfarin is the most commonly used pharmacologic agent for prophylaxis in joint arthroplasty patients in the United States [6]. Unfortunately, individual response to warfarin is highly variable, and effective doses may range from 1 to 40 mg/d [7]. As such, weeks of dose adjustments may be required to achieve stable levels of anticoagulation. For most patients, a standard dose, often 5 to 10 mg/d, is initiated with subsequent dose adjustments based on individual response to achieve a target level of anticoagulation, as determined by the INR [3,7]. The “trial and error” of initial warfarin dosing is problematic and highly dependent on clinician experience. One solution to improve initial warfarin dosing is to use specific dosing schemes, called nomograms. Numerous nomograms have been evaluated and published, but a major limitation is that only one nomogram has been reported in post–joint arthroplasty patients, and most were studied in nonsurgical patients where excessive anticoagulation with associated bleeding risk may be less of a concern [8-13].

122 The Journal of Arthroplasty Vol. 25 No. 1 January 2010 Originally, Anderson et al [8] demonstrated efficacy of their nomogram in post–joint arthroplasty patients based on the following: the average number of days to achieve an INR higher than 1.7 was 4.0 days, only 6.5% of patients had an INR higher than 3.0, and most of the patients (82%) had an INR higher than 1.7 by the day of hospital discharge. Despite the favorable degree of anticoagulation, 2.6% of patients still had a symptomatic VTE event [8]. More recently, Asnis et al [9] studied the same nomogram but had dissimilar results with only 31.3% of patients reaching an INR of 1.8 to 2.5 by the fifth postoperative day (POD), and enrollment numbers were too small to adequately assess clinical event rates. Furthermore, both of these studies were limited by hospital length-of-stay (LOS) issues. In Anderson's study, the average LOS was 9.0 days, and in Asnis's study, where the average LOS was 4.7 days, there were no postdischarge INR values reported [8,9]. These results lead to significant uncertainty about the efficacy and safety of this nomogram, especially in the current environment of shortened hospital LOSs.

The University of Utah Healthcare Thrombosis Service (UUHTS) has been initiating and managing warfarin therapy in all joint arthroplasty and revision patients since November of 2005. Before that time, VTE prevention was not uniform in that a variety of VTE prevention regimens were used by various surgeons. In an attempt to standardize a VTE prevention process and optimize outcomes, the University Hospital, UUHTS, and the Orthopaedics Department collectively agreed to form a collaborative effort to standardize management. Because of the limitations and uncertainties of currently published dosing nomograms, we sought to develop a practical specific dosing nomogram with a goal of achieving a target INR of 2.0 to 2.5 (balancing the recommendations of the ACCP and AAOS) in a minimum amount of time after surgery while avoiding excessive anticoagulation. In 2005, we implemented a modified version of the nomogram by Anderson et al [8] in a small cohort of patients. However, because of unsatisfactory results and after informal data analysis and literature review, we made substantial modifications

Fig. 1. University Healthcare joint arthroplasty/revision warfarin initiation dosing nomogram.

Safe and Effective Warfarin Nomogram  Pendleton et al

to arrive at the current reported nomogram (Fig. 1). This was implemented in all consecutive patients beginning in July 2006. This prospective cohort analysis describes the efficacy and safety of this novel warfarin dosing nomogram.

Materials and Methods All components of care were considered standard of care at our institution, so there was no informed consent required. Our institutional review board approved this study. Patients The inclusion group in this study consists of 351 consecutive joint arthroplasty or revision patients who were managed by the UUHTS during the period of July of 2006 to June of 2007, were prescribed warfarin for VTE prophylaxis, and were discharged to home with home health services. In total, 726 post joint arthroplasty/ revision patients were referred to the University Thrombosis Service for evaluation during the specified period. Of these, 375 (52%) were excluded from further analysis: 192 (26%) patients were discharged to inpatient rehabilitation or nursing facility, 89 (12%) were managed with an anticoagulant other than warfarin (ie, low molecular weight heparin), 75 (10%) were discharged to their primary care physician for management, and 19 (4.6%) were excluded because of a chronic warfarin indication. Procedures An initial patient clinical assessment form was filled out for all patients referred to the Thrombosis Service for management. This form standardizes the identification of important clinical conditions (age, heart failure, liver disease, poor nutritional status, prior cardiac stent placement, etc) and concomitant medications (amiodarone, trimethoprim-sulfa, metronidazole, and azole antifungals, etc), which may impact expected maintenance warfarin dose and/or the need for alternate antithrombotic agents. Warfarin was started on the evening of surgery, and the initial dose was either 3 or 5 mg based upon patient characteristics and concomitant medications according to our protocol (Fig. 1). Subsequent dosing for the remainder of the inpatient hospitalization was based upon the nomogram with oversight by the Thrombosis Service (consisting of a pharmacist and/or nurse(s) in consultation with a hospitalist) using the protocol. Target INR was 2.0 to 2.5. As an example of use, a patient without any of the abovementioned modifying factors is begun on 5 mg of warfarin on POD 0 and POD 1. If their INR on POD 3 is less than 1.5, then their average daily dose (5 mg) is increased by 150% to 7.5 mg. If on POD 4 their INR is less than 1.6, then their average daily dose ([5 mg + 5 mg + 7.5 mg)]/3 =5.8 mg, rounded to 6 mg) is increased by 150% to 9 mg. Similar methodology is followed for each day and involves simple calculations and rounding of doses.

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After discharge, patients were managed by the Thrombosis Service, with the norm being obtaining INRs twice weekly during warfarin therapy with same-day dose adjustments based on INR results. If, however, patients were discharged before POD 4, daily INRs were obtained by home health services until the fourth POD, as is specified in the nomogram (Fig. 1). After the sixth POD, further warfarin dosing was adjusted based upon clinical judgment, taking into account the patient's last INR, the trend in the previous INR measurements, and the average daily dose required to achieve the last INR. In general, if the INR was out of range, then the average daily dose was adjusted by 10% to 15% until the next INR measurement. Most of the INRs were obtained per various home health agencies; however, some patients obtained INRs per outpatient laboratory draws. At a variety of sites, home health INRs were a mixture of approved fingerstick point-of-care devices and venipuncture tests. Venipuncture verification was obtained when point-of-care INR values were greater than 4.0. The standard duration of therapy at our institution is 4 weeks for total hip arthroplasty/revision, bilateral knee arthroplasty, or patients with a history of prior VTE or underlying active cancer. All other patients, mostly uncomplicated knee arthroplasty/revision, receive 2 weeks of prophylaxis. The rationale for these lengths of therapy is supported by consensus guidelines [2]. In total, there was a mean of 7.0 INR assessments for each patient, 5.9 and 8.5 mean INR assessments for knee arthroplasty and hip arthroplasty patients, respectively. The University Thrombosis Service maintained comprehensive patient management records for all patients using individualized Microsoft Excel files, which are password protected and placed on the University Healthcare secure hard drive. Outcome data were assessed through the fourth postoperative week. Thrombosis service records and the official medical charts were used for this summation and descriptive analysis. Evaluation of Efficacy and Safety Our goal was to determine the effectiveness and safety of our institutional warfarin dosing nomogram in

Fig. 2. Mean and median international normalized ratio (INR) by postoperative day (POD) (n = 351). Patients developed timely therapeutic INR with a mean INR of 1.9 and 2.1 on PODs 4 and 5, respectively. Furthermore, the mean INR approximated target of 2 to 2.5 through the course of therapy.

INR Trends in Patient's with an Adverse Clinical Event Patient POD 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

1 – 1.2 stroke/death

2 – 1.2 1.3 1.6/PE

3 – 1.1 1.3/qgastrointestinal bleed

4 – 1.8 1.5 1.7 2 2.4 2.6 2.5 – – 2.4 – DVT

5 – 1.2 1.6 1.5 1.7/DVT

6 – 1.4 2.1 2.8/DVT

7 – 1.7 1.5 – 1.9 – – 2.6/epistaxis

8 – 2.4 2.1 1.8/hematoma

9 – 3.5 2.1 1.5 – 1.8 Hematoma

10 – 1.2 1.3 1.5 1.8 1.9 2.3 2.7 2.8 – – – Hematoma

11 – 1.3 1.5 1.9 1.9 – – 4.1 – Hematoma

Twelve of 351 patients (3.4%) had an adverse event: 1 (0.28%) stroke and death, 4 (1.14%) VTE events, 1 (0.28%) major bleeding event, and 6 (1.7%) minor bleeding events. INR, international normalized ratio; POD, postoperative day.

12 – 1.1 1.2 1.2 1.6 1.9 – – 2.4 – – – 1.6 – – 1.6/hematoma

124 The Journal of Arthroplasty Vol. 25 No. 1 January 2010

Table 1. Summary of Adverse Clinical Events in Relation to Timing of Surgery and INR

Safe and Effective Warfarin Nomogram  Pendleton et al

a large cohort of joint arthroplasty patients managed by our service. Primary evaluation measures include the following: 1. Mean time in days to achieve a therapeutic INR: A. INR goal of N1.8 (consistent with AAOS recommendations) B. INR goal of N2.0 (consistent with ACCP recommendations) 2. Mean and median INR on POD 5 and POD 7 3. Percentage of patients with a therapeutic INR (INR of ≥1.8 and ≥2.0) in the first 7 PODs 4. Percentage of patients with an INR of 4 or higher and 5 or higher in the first 10 days postoperatively 5. Adverse clinical events during warfarin therapy as a percentage of total patients: A. Major bleeding defined as fatal bleeding, bleeding into a critical organ (intracranial, intraspinal, intraocular, or retroperitoneal), or bleeding requiring reoperation B. Objectively confirmed symptomatic DVT defined as proximal DVT or extensive calf vein thrombosis involving 2 or more of the calf veins demonstrated on compression ultrasound. Doppler ultrasound was obtained only in circumstances in which clinical features were suggestive of a symptomatic event (ie, there was no routine screening for asymptomatic DVT) C. Symptomatic PE defined as a high probability ventilation-perfusion study or intraluminal filling defect in the subsegmental or greater vessels as demonstrated on spiral computed tomography angiography. Objective evaluation of PE was obtained only in circumstances in which clinical features were suggestive of a symptomatic event (ie, there was no routine screening for asymptomatic PE) D. Unexplained death Adverse clinical events were adjudicated by 2 separate authors (RV and NW), and if there was a disagreement, then a third author (MS) served as the adjudication tiebreaker. Summation analysis was used for descriptive purposes in this single-arm cohort study.

Results Of the 351 patients included in the cohort analysis, the mean age was 60 years (range, 18-89 years). One hundred ninety-three (55%) were female and 158 (45%) were male. Two hundred eleven (60%) of patients underwent knee arthroplasty/revision, 125 (36%) underwent hip arthroplasty/revision, and 15 (4%) underwent other surgery (mostly bilateral knee arthroplasty). The average hospital LOS was 3.6 days (3.4 days for knee arthroplasty/revision surgery and 3.7 days for hip arthroplasty/revision surgery).

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The mean time to an INR of 1.8 or higher and 2.0 or higher was 4 and 5 days, respectively. The mean and median INR were 2.1 and 2.0 on POD 5 and 2.4 and 2.3 on POD 7, respectively (Fig. 2). Two hundred eighty-five patients (81.2%) and 256 patients (72.9%) achieved an INR of ≥1.8 and ≥2.0, respectively, in the first 7 days postoperatively. Of the 66 patients who did not achieve an INR ≥1.8 within the first 7 PODs, there were 2 symptomatic VTE events (3.0%). One PE occurring on POD 4 with an INR of 1.6 and one DVT on POD 5 with an INR of 1.7. There were no other VTE events in patients with inadequate anticoagulation. Twenty-one patients (6.0%) had an INR N4.0 in the first 10 days of therapy, and of these, only 2 patients (0.6%) had an INR higher than 5 in the first 10 days of therapy. Of these, one patient (INR of 4.1) developed a wound hematoma on POD 9. There were no additional patients with an INR higher than 5.0 after the first 10 days of warfarin initiation. Adverse clinical events were uncommon: 1 patient (0.28%) died (because of an acute ischemic stroke on the third POD), 4 patients (1.14%) had a symptomatic and objectively confirmed VTE event (1 patient with a proximal DVT, 2 patients with distal DVT, and 1 patient with a PE), 1 (0.28%) major bleeding episode, and 6 (1.7%) with a minor bleeding episode (5 patients with a wound hematoma not requiring reoperation and 1 episode of epistaxis). Of the 4 patients who had a VTE event, the mean POD of diagnosis was 6.5 (range, 4-13) and the mean INR at time of diagnosis was 2.1 (range, 1.6-2.8). One patient who had a major bleed, a peptic ulcer–related gastrointestinal bleed, had an INR at the time of event of 1.3 on POD 3. Of the 6 patients with a minor bleed, only 2 had an INR greater than 3 before the event (1.5% of those with an INR N3 at any point of their therapy). There were no clinical features identified that

Table 2. International Normalized Ratio and Adverse Event Comparison of the 5- and 3-mg Dose Initiation Groups

Mean age (y) Mean time (d) to INR ≥1.8 Mean time (d) to INR ≥2.0 INR ≥1.8 by POD 7 INR ≥2.0 by POD 7 INR ≥4.0 in first 10 days Deep vein thrombosis PE Major bleeding Minor bleeding Wound hematoma Epistaxis

5-mg Initiation (n = 308)

3-mg Initiation (n = 43)

57 4 5 249 (80.8%) 223 (72.4%) 15 (4.9%) 3 (1.0%) 1 (0.3%) 1 (0.3%) 6 (1.9%) 5 (1.6%) 1 (0.3%)

75 5 6 36 (83.7%) 33 (76.7%) 4 (9.3%) 0 0 0 0

Because of the small numbers of patients who required modified initial dosing, there is no statistical difference between groups. However, trends suggest better INR control in the patient without modifying factors (advanced age, major interacting medications, etc) who were started on 5 mg. All adverse clinical events, however, occurred in the 5-mg initiation group. These events, though, were infrequent.

126 The Journal of Arthroplasty Vol. 25 No. 1 January 2010 appeared to correlate with these adverse complications. Table 1 summarizes the adverse clinical events in relation to date of surgery and degree of anticoagulation. As per our protocol, of the 351 total patients, 308 (88%) received the 5-mg initial dose and 43 (12%) received the modified 3-mg initial dose (see protocol Fig. 1). Results of INR and adverse event rates in the 3- and 5-mg groups are listed in Table 2.

Discussion In this study, we demonstrate a safe, effective, and easyto-use warfarin dosing nomogram in a large cohort of consecutive joint arthroplasty/revision patients. Our results demonstrate that this dosing scheme is highly effective in achieving a target INR in a timely fashion with an acceptably low rate of excessive anticoagulation and very low rate of adverse clinical events. It is important to note that consensus recommendations regarding target INR are varied. The ACCP guidelines recommend an INR target of 2.0 to 3.0. However, the AAOS guidelines recommend an INR target of 2.0 or lower. These divergent recommendations reflect the legitimate concerns of orthopedic surgeons regarding postoperative bleeding complications. In an attempt to balance these concerns, our nomogram targets an INR of 2.0 to 2.5. Importantly, we demonstrate that with our nomogram, the mean time to achieve target INR is only 4 to 5 days with a mean INR on the fourth and fifth PODs of 1.9 and 2.1, respectively. Equal in importance is that there were relatively few patients who had excessive anticoagulation. In contrast to other studies where nomograms were used in nonorthopedic populations, 3% to 20% of patients had excessive anticoagulation (INR in excess of 45) [10,11,13]. The high rates of excessive anticoagulation in these studies limit their application to a postoperative population. Importantly, our efficacy and safety results compare favorably with the few studies using prespecified dosing schemes in orthopedic surgery patients. Anderson et al reported a mean INR of 1.9 on the fourth POD with little excessive anticoagulation. However, using the same nomogram, Asnis et al reported a mean INR of only 1.55 on POD 4, and only 31% of patients achieved an INR higher than 1.7 by POD 5. Further limiting the applicability of Anderson's nomogram is LOS issues. In Anderson's original study, the mean LOS was 9.0 days, whereas LOS was 4.7 days in Asnis's study (with no postdischarge INR data reported). The difference in LOS and reporting in these 2 studies leads to uncertainty about the use of this dosing scheme in the modern era of shortened hospitalization. In contrast, our nomogram proved to be practical in patients with a 3.6-day LOS. The strengths of our current study include a specific and straightforward dosing nomogram that was evaluated in a large consecutive cohort of patients with complete follow-up and thorough reporting of INR values. We also report thorough and specific evaluation of adverse clinical

events throughout the patient's course of therapy. In our study, 0.28% of patients developed a PE, 0.28% a major bleeding event, and 1.4% a wound hematoma. These results compare favorably with patients who received warfarin in recent clinical trials (mostly comparing warfarin with low molecular weight heparins) wherein 0.5%, 3.2%, and 8.5% had a PE, major bleed, or wound hematoma, respectively [14]. These comparisons support that our nomogram is demonstrated to be safe, effective, and associated with very few adverse clinical events. There are several important limitations of our study that need mention. First, our results are reported only in patients who are discharged home with home health services. Incomplete data acquisition in patients discharged to rehabilitation or subacute care facilities precluded us from including these patients in our analysis. It is possible that in patients who are not discharged home (perhaps because of greater concomitant medical problems, advanced age, or debility), our nomogram may be less effective and/or safe. This is an important issue that warrants further study. In addition, we excluded patients who were known to be particularly sensitive or resistant to warfarin or who had a recent known established warfarin dose. Consequently, these patient groups should not be managed with this nomogram until further study. It is also important to recognize that oversight of this nomogram and subsequent management after hospital discharge were performed by a dedicated hospital-based anticoagulation service who was allowed to deviate from the nomogram if clinical events such as the development of an adverse event dictated. It is possible that management by less experienced anticoagulant providers would not yield the same favorable results. However, because most of our analysis was focused on the efficacy and safety during the time most affected by the nomogram (POD 0-10), our results are likely applicable to other settings. It is also important to recognize that our study involves a predominantly white patient population. With recent advances in understanding of the ethnic variation of warfarin pharmacogenetics, it is possible that this nomogram would be less effective in other ethnic groups [15]. As an example, Lenzini et al [16] recently proposed a method for initial warfarin dose adjustment taking into account patient ethnicity, demographics, concomitant medications, and estimated intraoperative blood loss using a computerized dosing algorithm. They found a strong correlation between predicted and actual warfarin dosing to achieve a therapeutic INR but found that, on average, it took 6 days to reach a therapeutic INR, and 9.5% of patients had an INR higher than 4.0 [16]. The results of our initiation scheme in a predominantly Caucasian population appear more favorable. For other ethnic groups, and Asian populations in particular, the efficacy of our nomogram is uncertain, and until further study, its use should be with caution.

Safe and Effective Warfarin Nomogram  Pendleton et al

Future comparative studies comparing our dosing algorithm with other strategies, incorporating routine pharmacogenetic testing, evaluating our nomogram in a more ethnically diverse patient population, confirmation of safety and efficacy in other studies, and evaluating outcomes in patients who are discharged to subacute care facilities would all be important.

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Conclusion We present a novel and easy-to-use warfarin dosing nomogram that is effective in achieving timely effective anticoagulation with acceptable rates of excessive anticoagulation and very low adverse events in a large cohort of post–joint arthroplasty patients who were discharged home and subsequently managed by a hospital-based anticoagulation service. Importantly, the use of this nomogram is feasible in an era of shortened postsurgery hospitalization.

Acknowledgments

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The authors would like to thank Pamela Proctor, MSN, Julie Harper, RpH, Sara Vazquez, PharmD, and Sharla Watts for their invaluably helpful patient assistance, data collection and coordination, and editorial assistance.

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