- Email: [email protected]
Argatroban dosing in obesity
Thrombosis Research 163 (2018) 60–63
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Full Length Article
Argatroban dosing in obesity☆ ⁎
T 1
Stephanie Elagizi, PharmD , Kyle Davis, PharmD
Department of Pharmacy, Ochsner Medical Center, 1514 East Jefferson Hwy, New Orleans, LA 70121, United States
A R T I C L E I N F O
A B S T R A C T
Keywords: Argatroban Anticoagulation Obesity Heparin induced thrombocytopenia Venous thromboembolism
Purpose: Obesity is associated with significant alterations in pharmacokinetic and pharmacodynamic properties. The use of weight based anticoagulants such as argatroban may put obese patients at an increased risk of hemorrhagic events. The purpose of this study was to evaluate argatroban dosing requirements in obese vs nonobese patients. Methods: This single-center, retrospective cohort study included patients ≥18 years with suspected HIT, treated with argatroban for ≥12 h. Patients were stratified by body mass index (BMI) into obese (BMI > 30 kg/m2) and non-obese (BMI ≤ 30 kg/m2) groups. The primary outcome was the median maintenance dose required to achieve two consecutive therapeutic activated partial thromboplastin times. Results: A total of 121 patients were included. The median BMI in the obese vs non-obese groups was 35.8 vs 24.05 kg/m2 (p < .0001). Although statistically significant, there was no clinically significant difference in median maintenance argatroban dose in obese versus non-obese patients (1 vs 1 μg/kg/min; p = .01). In-hospital major bleeding and in-hospital thrombosis also did not differ between the two groups. Conclusion: Obese patients require similar median argatroban maintenance doses when compared to non-obese patients. Based on these results argatroban should be dosed using actual body weight regardless of BMI.
1. Introduction Heparin induced thrombocytopenia (HIT) is a potentially lethal immune mediated drug reaction, caused by heparin dependent IgG antibodies produced as a result of the binding of heparin and low molecular weight heparin to platelet factor 4 (PF4). Binding of these antibodies to the heparin-PF44 complex leads to platelet activation, platelet destruction (thrombocytopenia) and the release of prothrombotic microparticles. These effects on platelets can lead to thromboembolic complications, such as deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction. In an effort to reduce the complications associated with this hypercoagulable state, current guidelines recommend immediate discontinuation of all heparin based therapies and initiation of non-heparin anticoagulation upon suspicion of HIT [1]. Argatroban is a highly selective parenteral anticoagulant indicated for the treatment and prophylaxis of thrombosis in patients with HIT. Argatroban has demonstrated the ability to improve HIT associated morbidity and mortality, without significantly increasing bleeding risk [2,3]. Argatroban reversibly binds to the active thrombin site of free and clot-associated thrombin, without interacting with PF4, and thus
☆
has no cross reactivity in HIT. Argatroban exhibits linear pharmacokinetics with weight being the most significant predictor of dosing requirements. It is recommended to initiate argatroban at a dose of 2 μg/ kg/min based on actual body weight, with dose adjustments to achieve an activated partial thromboplastin time (aPTT) within the therapeutic range of 1.5–3 times the baseline value [2,3]. However, as more than one third of adult Americans have obesity, the appropriate dosing of weight based medications such as argatroban in the obese population has been called into question [4]. Obese patients present several challenges when dosing medications, especially high risk agents such as anticoagulants. Pharmacokinetic and pharmacodynamic parameters including volume of distribution, tissue perfusion and drug clearance are often altered in this patient population [5]. Thus, the linear pharmacokinetics of argatroban may not hold true in obese patients. One of the greatest concerns surrounding the use of anticoagulants such as argatroban in this population is the potential risk of drug accumulation, leading to over anticoagulation and hemorrhagic complications. With the growing prevalence of obesity, clinicians are often faced with uncertainty surrounding the optimal dosing strategies for anticoagulants to balance achieving effective anticoagulation while minimizing bleeding complications [5].
Presented at Texas Society of Health Systems Pharmacist 2017 Alcalde Southwest Leadership Conference – April 27th, 2017. Corresponding author. E-mail address: [email protected] (S. Elagizi). 1 Present address: Wake Forest Baptist Health - 1 Medical Center Blvd, Winston-Salem, NC 27157, United States. ⁎
https://doi.org/10.1016/j.thromres.2018.01.011 Received 8 July 2017; Received in revised form 3 January 2018; Accepted 5 January 2018 Available online 09 January 2018 0049-3848/ © 2018 Elsevier Ltd. All rights reserved.
Thrombosis Research 163 (2018) 60–63
S. Elagizi, K. Davis
Fig. 1. Number of patients who were screened, assigned to a study group and included in primary analysis. SRA: serotonin release assay.
achieve two consecutive therapeutic aPTT values, in-hospital thrombosis and in-hospital major bleeding following initiation of argatroban. In-hospital thrombosis was defined as a deep vein thrombosis (DVT), pulmonary embolism (PE) or stroke confirmed via ultrasound, or computed tomography imaging. In-hospital major bleeding was defined as overt major bleeding associated with a hemoglobin decrease of ≥2 g/dL or leading to a transfusion of ≥2 units of packed red blood cells (PRBCs), symptomatic bleeding from a critical organ, or fatal bleeding [7]. Bleeding was further categorized into gastrointestinal, non-gastrointestinal, or intracranial. Both in-hospital thrombosis and major bleeding were identified via manual chart review. Statistical analysis was performed via Statistical Analysis Software (SAS). Continuous variables were analyzed using the Wilcoxan rank sum test. Chi square or Fisher's exact tests were performed to assess categorical variables. A multivariable analysis was performed a priori to determine if age, gender, weight, BMI, liver failure or multi-organ dysfunction were significant predictors of maintenance dose. Values of p < .05 were regarded as significant. Prior literature suggests that patients with multi-organ dysfunction and liver dysfunction require lower doses of argatroban; hence a subgroup analysis excluding these patients was performed to evaluate the effect on the primary outcome [8,9]. Liver failure was defined as history of liver disease documented in the electronic medical record or an aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥3× the upper limit of normal. Multi-organ dysfunction was defined as a sequential organ failure assessment (SOFA) score of ≥2 in ≥2 different organ systems [10].
Currently only one study exists evaluating argatroban dosing in obese versus non-obese patients [6]. Rice and colleagues [6] found no significant difference in initial or maintenance argatroban infusion rates required to achieve the first therapeutic aPTT between the two groups. However, the study included a total of 83 patients of which only 32 were defined as obese. Given the lack of evidence available in the literature for dosing argatroban in obese patients, the results of the study by Rice and colleagues must be further evaluated. The goal of this study was to compare dosing requirements and outcomes in obese versus non-obese patients treated with argatroban for historical, suspected or confirmed HIT. 2. Methods This was an institutional review board approved single center retrospective cohort study. The study population was assembled from a pharmacy database query of all consecutive patients treated with argatroban from February 2013 through July 2016 at Ochsner Medical Center, a tertiary academic medical center in New Orleans, Louisiana. Potential cases were identified and retrieved from hospital electronic medical records. The study included patients at least 18 years of age with a diagnosis or suspicion of HIT, or a history of HIT, subsequently treated with argatroban for at least 12 h. Only those patients with a documented weight and height available for the calculation of body mass index (BMI) were included for analysis. BMI was calculated as the patient's actual body weight in kilograms, divided by the square of the patient's height in meters. Patients were stratified according to their BMI: > 30 kg/m2 (obese group) or ≤30 kg/m2 (non-obese group). Patients were excluded if they were pregnant, lacked a baseline activated partial thromboplastin time (aPTT) prior to the start of argatroban, and/or had fewer than 2 consecutive therapeutic aPTTs while on argatroban. Baseline demographics and laboratory values were collected for all patients. Pertinent characteristics that could alter dosing requirements including level of care and the presence of hepatic or multi-organ dysfunction were also collected. The primary outcome of the study was the median infusion rate required to obtain two consecutive therapeutic aPTTs (therapeutic aPTT defined as 1.5 to 2.5 times the initial baseline value per institution guidelines). Secondary outcomes included time to
3. Results A total of 210 consecutive patients received argatroban from February 2013 through July 2016 (Fig. 1). One hundred twenty-one patents met the specified inclusion criteria; 59 patients in the obese group and 62 patients in the non-obese group. Baseline characteristics comparing the obese and non-obese groups are shown in Table 1. Median actual body weights in the obese and non-obese groups were 105 kg and 70.7 kg (p < .0001), while BMI was 35.8 kg/m2 and 24.1 kg/m2 (p < .0001). There was a predominance of liver dysfunction in the obese group (44.1% vs. 25.8% p = .03). Roughly one-third of the study population was admitted to the Intensive Care Unit (ICU). 61
Thrombosis Research 163 (2018) 60–63
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Table 1 Baseline characteristics of the study patients.
Table 3 Subgroup analysis excluding patients without liver disease or multi-organ failure.
Parameter
Obese N = 59
Non-obese N = 62
p-Value
Outcomes
Obese N = 18
Non-obese N = 26
p value
Median age (years), (range) Male, n (%) Caucasian, n (%) Black, n (%) Other n (%) Weight (kg), (range)
58 (46, 66) 27 (45.8) 34 (57.6) 21 (35.6) 4 (6.8) 105 (95.3, 124.7) 35.8 (32.7, 40.9) 17 (28.8) 26 (44.1) 39 (66.1) 184 (145,270)
63 (49, 73) 31 (50.0) 37 (59.7) 20 (32.3) 5 (8.0) 70.7 (59, 78.5)
.074 .64 .99
Median maintenance dose (μg/kg/ min)a First aPTT (s)
1.5 (0.65, 2)
1.5 (1, 2)
0.5
53.6 (40.1, 58.1) 49.6 (48.1, 69.3) 11.5 (7.7, 21)
0.83
24.05 (21.7, 25.9) 19 (30.6) 16 (25.8) 31 (50) 178 (141,240)
< .0001
51.65 (41.2, 59) 56.1 (46.3, 63.6) 21.6 (11.7, 45)
.94 .03 .07 .62
81 (52, 104)
79 (49, 115)
.72
0 7 1 6 7 2
1 (3.8) 12 (46.2) 2 (7.7) 10 (38.5) 10 (38.5) 5 (19.2)
13.3 (11.5, 18) 1.3 (1.1, 1.7) 28.7 (24.9, 31.6) 3.67 (1.79, 5.9) 1(0.5, 2)
13 (11.3, 15.2) 1.3 (1.1, 1.5) 28.25 (25.2, 29.9) 3.08 (1.96, 5.64) 1 (0.5, 2)
.44 .4 .74
BMI (kg/m2), (range) ICU, n (%) Liver dysfunction, n (%) Multi-organ dysfunction, n (%) Baseline platelet count (×109/ L)a,b Platelet count at initiation of argatroban therapy (×109/L)a Prothrombin time (s)a INRa Baseline aPTT (s)a Duration of therapy (days) Initial dose (μg/kg/min)
Second aPTT (s) < .0001 Time to two consecutive therapeutic aPTT values (hours) Thrombosis and bleeding, n (%) VTE Major Bleed GI Non-GI Hgb drop ≥2 g/dL Transfusion ≥2 units
1 0.76 1 0.76 1 0.68
.60
obese cohort (11.4 vs. 16.9 h, p = .027). No difference was observed in the incidence of DVT, PE, stroke between the obese and non-obese cohorts (Table 2). While the incidence of in-hospital major bleeding were high, no difference was observed between the groups (55.9% vs. 54.8%, p = 1.0). When evaluating the components that make up this high bleeding incidence, a drop in hemoglobin by ≥2 g/dL accounted for the majority of the bleeds (55.9% vs. 54.8%, p = .78). There were no episodes of intracranial hemorrhage or fatal bleeding in either of the cohorts. Results of the multivariable analysis showed that age, gender, weight and BMI were not significant predictors of maintenance dose, whereas liver failure and multi-organ dysfunction were associated with lower median maintenance dose requirements (p = .01; p = .033). After excluding those patients with liver dysfunction and multi-organ dysfunction, a total of 44 patients remained for subgroup analysis (Table 3). There was no difference observed in the median maintenance dose between the two groups (1.5 vs 1.5 μg/kg/min p = .895). Additionally, no difference was identified in the incidence of on treatment thrombosis or in-hospital major bleeding.
.14
Table 2 Results. Outcomes
Obese N = 59
Non-obese N = 62
p value
Median maintenance dose (μg/kg/ min)a First aPTT (s)
1 (0.5, 1)
1 (0.75, 2)
0.01
50 (42.4, 67.5) 52.3 (47.7, 69.5) 0.5 (0.5, 1) 2 (1, 3) 11.4 (7.2, 21.9)
50.5 (38, 58.5) 54.5 (44, 61.6) 0.95 (0.5, 1) 2 (1.5, 2.5) 16.9 (9.7, 30.1)
0.25
2 (3.4) 1 (1.7) 0 (0)
3 (4.8) 0 (0) 0 (0)
1 0.49 –
33 (55.9) 0 (0) 5 (8.5) 28 (47.5) 32 (54.2) 21 (35.6)
34 (54.8) 0 (0) 6 (9.7) 28 (45.2) 32 (51.6) 20 (32.3)
1 – 0.818 0.8 0.78 0.698
Min rate (μg/kg/min) Max rate (μg/kg/min) Time to two consecutive therapeutic aPTT values (hours) Thrombosis event, n (%) DVT PE Stroke Bleeding, n (%) Major bleed ICH GI Non-GI Hgb drop ≥2 g/dL Transfusion ≥2 units
0.033
Values are reported as median and interquartile ranges unless stated otherwise. ICH: intracranial hemorrhage; GI: gastrointestinal; Non-GI: non-gastrointestinal; Hgb: hemoglobin. a Based on actual body weight.
Values are reported as median and interquartile ranges. INR: international normalized ratio. a Normal ranges for reported laboratory values: platelet count 150–350 × 109/L, prothrombin time 9–12.5 s, INR 0.8–1.2, aPTT 21–32 s. b Baseline platelet count refers to value at admission.
Second aPTT (s)
(0) (38.9) (5.6) (33.3) (38.9) (11.1)
0.63
0.38 0.12 0.38 0.027
4. Discussion The results of this study demonstrated no clinically significant difference in the argatroban median maintenance dose requirements, despite statistical significance, between obese and non-obese patients. Time to achieve 2 consecutive therapeutic aPTTs was however significantly greater in the non-obese cohort. Additionally, thrombosis and in hospital major bleeding did not differ significantly between the two groups. On the basis of the results of this study, it appears that the current practice of dosing argatroban based on actual body weight is appropriate for obese and non-obese patients. Studies evaluating the dosing strategies of anticoagulants in obesity are lacking. However, a few studies have assessed the use of heparin in this patient population. Barletta and colleagues [11] found that morbidly obese patients (BMI ≥ 40 kg/m2) had significantly higher aPTT values at 6 and 12 h compared to non-morbidly obese patients (BMI < 40 kg/m2) who received heparin using a weight base nomogram utilizing actual body weights. Increasing BMI and age were found to be independent predictors of supratherapeutic aPTTs. Riney and colleagues [12] found that morbidly obese patients (BMI ≥ 40 kg/m2) required significantly lower mean heparin infusion rates to achieve the first therapeutic aPTT (11.5 units/kg/min), compared to patients with BMI < 40 kg/m2 (12.5–13.5 units/kg/min). These findings contradict
Values are reported as median and interquartile ranges unless otherwise stated. ICH: intracranial hemorrhage; GI: gastrointestinal; Non-GI: non-gastrointestinal; Hgb: hemoglobin. a Based on actual body weight.
There were no differences detected with respect to median duration of therapy, the first measured aPTT or the second measured aPTT (Table 2). The primary outcome of median maintenance dose to achieve two consecutive therapeutic aPTTs was statistically different between the two groups (1 μg/kg/min IQR 0.5, 1) vs 1 μg/kg/min (IQR 0.75, 2), (p = .01) (Table 2). However this result is not clinically significant as the median rates in both groups were identical. Time to achieve 2 consecutive therapeutic aPTTs was significantly greater in the non62
Thrombosis Research 163 (2018) 60–63
S. Elagizi, K. Davis
obese cohort had liver dysfunction and multi-organ dysfunction. As these patients often require smaller doses of argatroban, a subgroup analysis excluding such patients was performed which yielded similar results to the total cohort [8,9]. In conclusion, obese patients require similar median argatroban maintenance doses compared to non-obese patients, and experience similar incidence of thrombosis and bleeding. The results of this study support the use of actual body weight when dosing argatroban, while results should be applied cautiously to morbidly obese patients.
the results of our study and further support the individual evaluation of high risk medications such as anticoagulants in the morbidly obese patient population. The results of this study are consistent with the study by Rice and colleagues, which also found no difference in argatroban mean maintenance dose requirements based on actual body weight, in obese (BMI > 30 kg/m2) versus non-obese (BMI ≤ 30 kg/m2) patients [6]. Given the difference in results between the studies evaluating the effects of obesity on heparin versus the results seen with argatroban, it appears that obesity may have differing effects on different anticoagulants. These findings stress the importance of researching the effect of weight based medications on obesity, especially for high risk anticoagulants, and suggests that generalized recommendations regarding anticoagulant use in obesity should only be made with adequate investigation. It is important to note that the studies involving unfractionated heparin found a difference between morbidly obese patients (BMI ≥ 40 kg/m2) and non-morbidly obese patients (BMI < 40 kg/m2), while our study, as well as the study by Rice and colleagues, focused on obese (BMI > 30 kg/m2) versus non-obese (BMI ≤ 30 kg/m2) patients. Thus, there is the possibility that a difference in argatroban dose requirements may exist in patients who are morbidly obese. Delineating the groups in our study into morbidly obese and non-morbidly obese categories would have resulted in a small sample size of morbidly obese patients and a significant imbalance in sample size between the two groups. This study is not without limitations. The retrospective single centered approach has inherent limitations including variability with regards to health care provider compliance with the nomogram and consistency of use, as well as the use of a nomogram which may differ from other institutions. Given the retrospective design of this study, it was also difficult to accurately assess the use of medications that could alter coagulation parameters. However, this is the largest study of its kind with similar patients enrolled in each cohort at baseline. In contrast to the Rice and colleagues study, which assessed argatroban dosing requirements based on first therapeutic aPTT, our study defined maintenance dose as the dose required to achieve two consecutive therapeutic aPTTs [6]. We recognize that argatroban requires significant monitoring and titration, and including two consecutive therapeutic aPTTs in the definition strengthens the focus on attaining a more precise median maintenance dose. With regards to major bleeding, we acknowledge that our incidence of major bleeding is higher than previously reported in the literature, recognizing that major bleeding is difficult to assess in retrospect based upon chart review. A drop in hemoglobin by > 2 g/dL accounted for approximately half of bleeding events in contrary to overt bleeding events. In addition, about one-third of the patient population were ICU patients, who often have large amounts of blood drawn as part of their routine care, putting them at risk for major bleeding. Lastly, significantly more patients in the
Conflict of interest All authors have no conflict of interest to disclose. References [1] L.A. Linkins, A.L. Dans, L.K. Moores, et al., Treatment and prevention of heparininduced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 141 (Suppl. 2) (Feb 2012) e495S–530S, http://dx.doi.org/10. 1378/chest.11-2303. [2] B.E. Lewis, D.E. Wallis, S.D. Berkowitz, et al., ARG-911 study investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia, Circulation 103 (14) (Apr 10 2001) 1838–1843, http://dx.doi.org/10.1161/ 01.CIR.103.14.1838. [3] B.E. Lewis, D.E. Wallis, F. Leya, et al., Argatroban anticoagulation in patients with heparin-induced thrombocytopenia, Arch. Intern. Med. 163 (15) (Aug 11–25 2003) 1849–1856, http://dx.doi.org/10.1001/archinte.163.15.1849. [4] M.A. Smythe, J. Priziola, P.P. Dobesh, et al., Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism, J. Thromb. Thrombolysis 41 (2016) 165–186, http://dx.doi.org/10.1007/s11239015-1315-2. [5] M.A. Smythe, J.L. Stephens, J.M. Koerber, et al., A comparison of lepirudin and argatroban outcomes, Clin. Appl. Thromb. Hemost. 11 (2005) 371–374. [6] L. Rice, M. Hursting, M. Baillie, et al., Argatroban anticoagulation in obese versus nonobese patients: implications for treating heparin-induced thrombocytopenia, J. Clin. Pharmacol. 47 (2007) 1028–1034, http://dx.doi.org/10.1177/ 0091270007302951. [7] S. Schulman, C. Kearon, Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients, J. Thromb. Haemost. 3 (4) (Apr 2005) 692–694, http://dx.doi.org/10.1111/j.1538-7836.2005.01204.x. [8] S. Kim, N. Tran, J.C. Schewe, et al., Safety and economic considerations of argatroban use in critically ill patients: a retrospective analysis, J. Cardiothorac. Surg. 10 (2015) 19, , http://dx.doi.org/10.1186/s13019-015-0214-0. [9] B. Saugel, V. Phillip, G. Moessmer, et al., Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study, Crit. Care 14 (3) (2010) R90, http://dx.doi.org/10.1186/ cc9024. [10] M. Singer, C.S. Deutschman, C.W. Seymour, et al., The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA 315 (8) (2016 Feb 23) 801–810, http://dx.doi.org/10.1001/jama.2016.0287. [11] J.F. Barletta, J.L. DeYoung, K. McAllen, et al., Limitations of a standardized weightbased nomogram for heparin dosing in patients with morbid obesity, Surg. Obes. Relat. Dis. 4 (2008) 748–753, http://dx.doi.org/10.1016/j.soard.2008.03.005. [12] J. Riney, J. Hollands, J. Smith, et al., Identifying optimal initial infusion rates for unfractionated heparin in morbidly obese patients, Ann. Pharmacother. 44 (2010) 1141–1151, http://dx.doi.org/10.1345/aph.1P088.
63
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Full Length Article
Argatroban dosing in obesity☆ ⁎
T 1
Stephanie Elagizi, PharmD , Kyle Davis, PharmD
Department of Pharmacy, Ochsner Medical Center, 1514 East Jefferson Hwy, New Orleans, LA 70121, United States
A R T I C L E I N F O
A B S T R A C T
Keywords: Argatroban Anticoagulation Obesity Heparin induced thrombocytopenia Venous thromboembolism
Purpose: Obesity is associated with significant alterations in pharmacokinetic and pharmacodynamic properties. The use of weight based anticoagulants such as argatroban may put obese patients at an increased risk of hemorrhagic events. The purpose of this study was to evaluate argatroban dosing requirements in obese vs nonobese patients. Methods: This single-center, retrospective cohort study included patients ≥18 years with suspected HIT, treated with argatroban for ≥12 h. Patients were stratified by body mass index (BMI) into obese (BMI > 30 kg/m2) and non-obese (BMI ≤ 30 kg/m2) groups. The primary outcome was the median maintenance dose required to achieve two consecutive therapeutic activated partial thromboplastin times. Results: A total of 121 patients were included. The median BMI in the obese vs non-obese groups was 35.8 vs 24.05 kg/m2 (p < .0001). Although statistically significant, there was no clinically significant difference in median maintenance argatroban dose in obese versus non-obese patients (1 vs 1 μg/kg/min; p = .01). In-hospital major bleeding and in-hospital thrombosis also did not differ between the two groups. Conclusion: Obese patients require similar median argatroban maintenance doses when compared to non-obese patients. Based on these results argatroban should be dosed using actual body weight regardless of BMI.
1. Introduction Heparin induced thrombocytopenia (HIT) is a potentially lethal immune mediated drug reaction, caused by heparin dependent IgG antibodies produced as a result of the binding of heparin and low molecular weight heparin to platelet factor 4 (PF4). Binding of these antibodies to the heparin-PF44 complex leads to platelet activation, platelet destruction (thrombocytopenia) and the release of prothrombotic microparticles. These effects on platelets can lead to thromboembolic complications, such as deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction. In an effort to reduce the complications associated with this hypercoagulable state, current guidelines recommend immediate discontinuation of all heparin based therapies and initiation of non-heparin anticoagulation upon suspicion of HIT [1]. Argatroban is a highly selective parenteral anticoagulant indicated for the treatment and prophylaxis of thrombosis in patients with HIT. Argatroban has demonstrated the ability to improve HIT associated morbidity and mortality, without significantly increasing bleeding risk [2,3]. Argatroban reversibly binds to the active thrombin site of free and clot-associated thrombin, without interacting with PF4, and thus
☆
has no cross reactivity in HIT. Argatroban exhibits linear pharmacokinetics with weight being the most significant predictor of dosing requirements. It is recommended to initiate argatroban at a dose of 2 μg/ kg/min based on actual body weight, with dose adjustments to achieve an activated partial thromboplastin time (aPTT) within the therapeutic range of 1.5–3 times the baseline value [2,3]. However, as more than one third of adult Americans have obesity, the appropriate dosing of weight based medications such as argatroban in the obese population has been called into question [4]. Obese patients present several challenges when dosing medications, especially high risk agents such as anticoagulants. Pharmacokinetic and pharmacodynamic parameters including volume of distribution, tissue perfusion and drug clearance are often altered in this patient population [5]. Thus, the linear pharmacokinetics of argatroban may not hold true in obese patients. One of the greatest concerns surrounding the use of anticoagulants such as argatroban in this population is the potential risk of drug accumulation, leading to over anticoagulation and hemorrhagic complications. With the growing prevalence of obesity, clinicians are often faced with uncertainty surrounding the optimal dosing strategies for anticoagulants to balance achieving effective anticoagulation while minimizing bleeding complications [5].
Presented at Texas Society of Health Systems Pharmacist 2017 Alcalde Southwest Leadership Conference – April 27th, 2017. Corresponding author. E-mail address: [email protected] (S. Elagizi). 1 Present address: Wake Forest Baptist Health - 1 Medical Center Blvd, Winston-Salem, NC 27157, United States. ⁎
https://doi.org/10.1016/j.thromres.2018.01.011 Received 8 July 2017; Received in revised form 3 January 2018; Accepted 5 January 2018 Available online 09 January 2018 0049-3848/ © 2018 Elsevier Ltd. All rights reserved.
Thrombosis Research 163 (2018) 60–63
S. Elagizi, K. Davis
Fig. 1. Number of patients who were screened, assigned to a study group and included in primary analysis. SRA: serotonin release assay.
achieve two consecutive therapeutic aPTT values, in-hospital thrombosis and in-hospital major bleeding following initiation of argatroban. In-hospital thrombosis was defined as a deep vein thrombosis (DVT), pulmonary embolism (PE) or stroke confirmed via ultrasound, or computed tomography imaging. In-hospital major bleeding was defined as overt major bleeding associated with a hemoglobin decrease of ≥2 g/dL or leading to a transfusion of ≥2 units of packed red blood cells (PRBCs), symptomatic bleeding from a critical organ, or fatal bleeding [7]. Bleeding was further categorized into gastrointestinal, non-gastrointestinal, or intracranial. Both in-hospital thrombosis and major bleeding were identified via manual chart review. Statistical analysis was performed via Statistical Analysis Software (SAS). Continuous variables were analyzed using the Wilcoxan rank sum test. Chi square or Fisher's exact tests were performed to assess categorical variables. A multivariable analysis was performed a priori to determine if age, gender, weight, BMI, liver failure or multi-organ dysfunction were significant predictors of maintenance dose. Values of p < .05 were regarded as significant. Prior literature suggests that patients with multi-organ dysfunction and liver dysfunction require lower doses of argatroban; hence a subgroup analysis excluding these patients was performed to evaluate the effect on the primary outcome [8,9]. Liver failure was defined as history of liver disease documented in the electronic medical record or an aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥3× the upper limit of normal. Multi-organ dysfunction was defined as a sequential organ failure assessment (SOFA) score of ≥2 in ≥2 different organ systems [10].
Currently only one study exists evaluating argatroban dosing in obese versus non-obese patients [6]. Rice and colleagues [6] found no significant difference in initial or maintenance argatroban infusion rates required to achieve the first therapeutic aPTT between the two groups. However, the study included a total of 83 patients of which only 32 were defined as obese. Given the lack of evidence available in the literature for dosing argatroban in obese patients, the results of the study by Rice and colleagues must be further evaluated. The goal of this study was to compare dosing requirements and outcomes in obese versus non-obese patients treated with argatroban for historical, suspected or confirmed HIT. 2. Methods This was an institutional review board approved single center retrospective cohort study. The study population was assembled from a pharmacy database query of all consecutive patients treated with argatroban from February 2013 through July 2016 at Ochsner Medical Center, a tertiary academic medical center in New Orleans, Louisiana. Potential cases were identified and retrieved from hospital electronic medical records. The study included patients at least 18 years of age with a diagnosis or suspicion of HIT, or a history of HIT, subsequently treated with argatroban for at least 12 h. Only those patients with a documented weight and height available for the calculation of body mass index (BMI) were included for analysis. BMI was calculated as the patient's actual body weight in kilograms, divided by the square of the patient's height in meters. Patients were stratified according to their BMI: > 30 kg/m2 (obese group) or ≤30 kg/m2 (non-obese group). Patients were excluded if they were pregnant, lacked a baseline activated partial thromboplastin time (aPTT) prior to the start of argatroban, and/or had fewer than 2 consecutive therapeutic aPTTs while on argatroban. Baseline demographics and laboratory values were collected for all patients. Pertinent characteristics that could alter dosing requirements including level of care and the presence of hepatic or multi-organ dysfunction were also collected. The primary outcome of the study was the median infusion rate required to obtain two consecutive therapeutic aPTTs (therapeutic aPTT defined as 1.5 to 2.5 times the initial baseline value per institution guidelines). Secondary outcomes included time to
3. Results A total of 210 consecutive patients received argatroban from February 2013 through July 2016 (Fig. 1). One hundred twenty-one patents met the specified inclusion criteria; 59 patients in the obese group and 62 patients in the non-obese group. Baseline characteristics comparing the obese and non-obese groups are shown in Table 1. Median actual body weights in the obese and non-obese groups were 105 kg and 70.7 kg (p < .0001), while BMI was 35.8 kg/m2 and 24.1 kg/m2 (p < .0001). There was a predominance of liver dysfunction in the obese group (44.1% vs. 25.8% p = .03). Roughly one-third of the study population was admitted to the Intensive Care Unit (ICU). 61
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S. Elagizi, K. Davis
Table 1 Baseline characteristics of the study patients.
Table 3 Subgroup analysis excluding patients without liver disease or multi-organ failure.
Parameter
Obese N = 59
Non-obese N = 62
p-Value
Outcomes
Obese N = 18
Non-obese N = 26
p value
Median age (years), (range) Male, n (%) Caucasian, n (%) Black, n (%) Other n (%) Weight (kg), (range)
58 (46, 66) 27 (45.8) 34 (57.6) 21 (35.6) 4 (6.8) 105 (95.3, 124.7) 35.8 (32.7, 40.9) 17 (28.8) 26 (44.1) 39 (66.1) 184 (145,270)
63 (49, 73) 31 (50.0) 37 (59.7) 20 (32.3) 5 (8.0) 70.7 (59, 78.5)
.074 .64 .99
Median maintenance dose (μg/kg/ min)a First aPTT (s)
1.5 (0.65, 2)
1.5 (1, 2)
0.5
53.6 (40.1, 58.1) 49.6 (48.1, 69.3) 11.5 (7.7, 21)
0.83
24.05 (21.7, 25.9) 19 (30.6) 16 (25.8) 31 (50) 178 (141,240)
< .0001
51.65 (41.2, 59) 56.1 (46.3, 63.6) 21.6 (11.7, 45)
.94 .03 .07 .62
81 (52, 104)
79 (49, 115)
.72
0 7 1 6 7 2
1 (3.8) 12 (46.2) 2 (7.7) 10 (38.5) 10 (38.5) 5 (19.2)
13.3 (11.5, 18) 1.3 (1.1, 1.7) 28.7 (24.9, 31.6) 3.67 (1.79, 5.9) 1(0.5, 2)
13 (11.3, 15.2) 1.3 (1.1, 1.5) 28.25 (25.2, 29.9) 3.08 (1.96, 5.64) 1 (0.5, 2)
.44 .4 .74
BMI (kg/m2), (range) ICU, n (%) Liver dysfunction, n (%) Multi-organ dysfunction, n (%) Baseline platelet count (×109/ L)a,b Platelet count at initiation of argatroban therapy (×109/L)a Prothrombin time (s)a INRa Baseline aPTT (s)a Duration of therapy (days) Initial dose (μg/kg/min)
Second aPTT (s) < .0001 Time to two consecutive therapeutic aPTT values (hours) Thrombosis and bleeding, n (%) VTE Major Bleed GI Non-GI Hgb drop ≥2 g/dL Transfusion ≥2 units
1 0.76 1 0.76 1 0.68
.60
obese cohort (11.4 vs. 16.9 h, p = .027). No difference was observed in the incidence of DVT, PE, stroke between the obese and non-obese cohorts (Table 2). While the incidence of in-hospital major bleeding were high, no difference was observed between the groups (55.9% vs. 54.8%, p = 1.0). When evaluating the components that make up this high bleeding incidence, a drop in hemoglobin by ≥2 g/dL accounted for the majority of the bleeds (55.9% vs. 54.8%, p = .78). There were no episodes of intracranial hemorrhage or fatal bleeding in either of the cohorts. Results of the multivariable analysis showed that age, gender, weight and BMI were not significant predictors of maintenance dose, whereas liver failure and multi-organ dysfunction were associated with lower median maintenance dose requirements (p = .01; p = .033). After excluding those patients with liver dysfunction and multi-organ dysfunction, a total of 44 patients remained for subgroup analysis (Table 3). There was no difference observed in the median maintenance dose between the two groups (1.5 vs 1.5 μg/kg/min p = .895). Additionally, no difference was identified in the incidence of on treatment thrombosis or in-hospital major bleeding.
.14
Table 2 Results. Outcomes
Obese N = 59
Non-obese N = 62
p value
Median maintenance dose (μg/kg/ min)a First aPTT (s)
1 (0.5, 1)
1 (0.75, 2)
0.01
50 (42.4, 67.5) 52.3 (47.7, 69.5) 0.5 (0.5, 1) 2 (1, 3) 11.4 (7.2, 21.9)
50.5 (38, 58.5) 54.5 (44, 61.6) 0.95 (0.5, 1) 2 (1.5, 2.5) 16.9 (9.7, 30.1)
0.25
2 (3.4) 1 (1.7) 0 (0)
3 (4.8) 0 (0) 0 (0)
1 0.49 –
33 (55.9) 0 (0) 5 (8.5) 28 (47.5) 32 (54.2) 21 (35.6)
34 (54.8) 0 (0) 6 (9.7) 28 (45.2) 32 (51.6) 20 (32.3)
1 – 0.818 0.8 0.78 0.698
Min rate (μg/kg/min) Max rate (μg/kg/min) Time to two consecutive therapeutic aPTT values (hours) Thrombosis event, n (%) DVT PE Stroke Bleeding, n (%) Major bleed ICH GI Non-GI Hgb drop ≥2 g/dL Transfusion ≥2 units
0.033
Values are reported as median and interquartile ranges unless stated otherwise. ICH: intracranial hemorrhage; GI: gastrointestinal; Non-GI: non-gastrointestinal; Hgb: hemoglobin. a Based on actual body weight.
Values are reported as median and interquartile ranges. INR: international normalized ratio. a Normal ranges for reported laboratory values: platelet count 150–350 × 109/L, prothrombin time 9–12.5 s, INR 0.8–1.2, aPTT 21–32 s. b Baseline platelet count refers to value at admission.
Second aPTT (s)
(0) (38.9) (5.6) (33.3) (38.9) (11.1)
0.63
0.38 0.12 0.38 0.027
4. Discussion The results of this study demonstrated no clinically significant difference in the argatroban median maintenance dose requirements, despite statistical significance, between obese and non-obese patients. Time to achieve 2 consecutive therapeutic aPTTs was however significantly greater in the non-obese cohort. Additionally, thrombosis and in hospital major bleeding did not differ significantly between the two groups. On the basis of the results of this study, it appears that the current practice of dosing argatroban based on actual body weight is appropriate for obese and non-obese patients. Studies evaluating the dosing strategies of anticoagulants in obesity are lacking. However, a few studies have assessed the use of heparin in this patient population. Barletta and colleagues [11] found that morbidly obese patients (BMI ≥ 40 kg/m2) had significantly higher aPTT values at 6 and 12 h compared to non-morbidly obese patients (BMI < 40 kg/m2) who received heparin using a weight base nomogram utilizing actual body weights. Increasing BMI and age were found to be independent predictors of supratherapeutic aPTTs. Riney and colleagues [12] found that morbidly obese patients (BMI ≥ 40 kg/m2) required significantly lower mean heparin infusion rates to achieve the first therapeutic aPTT (11.5 units/kg/min), compared to patients with BMI < 40 kg/m2 (12.5–13.5 units/kg/min). These findings contradict
Values are reported as median and interquartile ranges unless otherwise stated. ICH: intracranial hemorrhage; GI: gastrointestinal; Non-GI: non-gastrointestinal; Hgb: hemoglobin. a Based on actual body weight.
There were no differences detected with respect to median duration of therapy, the first measured aPTT or the second measured aPTT (Table 2). The primary outcome of median maintenance dose to achieve two consecutive therapeutic aPTTs was statistically different between the two groups (1 μg/kg/min IQR 0.5, 1) vs 1 μg/kg/min (IQR 0.75, 2), (p = .01) (Table 2). However this result is not clinically significant as the median rates in both groups were identical. Time to achieve 2 consecutive therapeutic aPTTs was significantly greater in the non62
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obese cohort had liver dysfunction and multi-organ dysfunction. As these patients often require smaller doses of argatroban, a subgroup analysis excluding such patients was performed which yielded similar results to the total cohort [8,9]. In conclusion, obese patients require similar median argatroban maintenance doses compared to non-obese patients, and experience similar incidence of thrombosis and bleeding. The results of this study support the use of actual body weight when dosing argatroban, while results should be applied cautiously to morbidly obese patients.
the results of our study and further support the individual evaluation of high risk medications such as anticoagulants in the morbidly obese patient population. The results of this study are consistent with the study by Rice and colleagues, which also found no difference in argatroban mean maintenance dose requirements based on actual body weight, in obese (BMI > 30 kg/m2) versus non-obese (BMI ≤ 30 kg/m2) patients [6]. Given the difference in results between the studies evaluating the effects of obesity on heparin versus the results seen with argatroban, it appears that obesity may have differing effects on different anticoagulants. These findings stress the importance of researching the effect of weight based medications on obesity, especially for high risk anticoagulants, and suggests that generalized recommendations regarding anticoagulant use in obesity should only be made with adequate investigation. It is important to note that the studies involving unfractionated heparin found a difference between morbidly obese patients (BMI ≥ 40 kg/m2) and non-morbidly obese patients (BMI < 40 kg/m2), while our study, as well as the study by Rice and colleagues, focused on obese (BMI > 30 kg/m2) versus non-obese (BMI ≤ 30 kg/m2) patients. Thus, there is the possibility that a difference in argatroban dose requirements may exist in patients who are morbidly obese. Delineating the groups in our study into morbidly obese and non-morbidly obese categories would have resulted in a small sample size of morbidly obese patients and a significant imbalance in sample size between the two groups. This study is not without limitations. The retrospective single centered approach has inherent limitations including variability with regards to health care provider compliance with the nomogram and consistency of use, as well as the use of a nomogram which may differ from other institutions. Given the retrospective design of this study, it was also difficult to accurately assess the use of medications that could alter coagulation parameters. However, this is the largest study of its kind with similar patients enrolled in each cohort at baseline. In contrast to the Rice and colleagues study, which assessed argatroban dosing requirements based on first therapeutic aPTT, our study defined maintenance dose as the dose required to achieve two consecutive therapeutic aPTTs [6]. We recognize that argatroban requires significant monitoring and titration, and including two consecutive therapeutic aPTTs in the definition strengthens the focus on attaining a more precise median maintenance dose. With regards to major bleeding, we acknowledge that our incidence of major bleeding is higher than previously reported in the literature, recognizing that major bleeding is difficult to assess in retrospect based upon chart review. A drop in hemoglobin by > 2 g/dL accounted for approximately half of bleeding events in contrary to overt bleeding events. In addition, about one-third of the patient population were ICU patients, who often have large amounts of blood drawn as part of their routine care, putting them at risk for major bleeding. Lastly, significantly more patients in the
Conflict of interest All authors have no conflict of interest to disclose. References [1] L.A. Linkins, A.L. Dans, L.K. Moores, et al., Treatment and prevention of heparininduced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest 141 (Suppl. 2) (Feb 2012) e495S–530S, http://dx.doi.org/10. 1378/chest.11-2303. [2] B.E. Lewis, D.E. Wallis, S.D. Berkowitz, et al., ARG-911 study investigators. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia, Circulation 103 (14) (Apr 10 2001) 1838–1843, http://dx.doi.org/10.1161/ 01.CIR.103.14.1838. [3] B.E. Lewis, D.E. Wallis, F. Leya, et al., Argatroban anticoagulation in patients with heparin-induced thrombocytopenia, Arch. Intern. Med. 163 (15) (Aug 11–25 2003) 1849–1856, http://dx.doi.org/10.1001/archinte.163.15.1849. [4] M.A. Smythe, J. Priziola, P.P. Dobesh, et al., Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism, J. Thromb. Thrombolysis 41 (2016) 165–186, http://dx.doi.org/10.1007/s11239015-1315-2. [5] M.A. Smythe, J.L. Stephens, J.M. Koerber, et al., A comparison of lepirudin and argatroban outcomes, Clin. Appl. Thromb. Hemost. 11 (2005) 371–374. [6] L. Rice, M. Hursting, M. Baillie, et al., Argatroban anticoagulation in obese versus nonobese patients: implications for treating heparin-induced thrombocytopenia, J. Clin. Pharmacol. 47 (2007) 1028–1034, http://dx.doi.org/10.1177/ 0091270007302951. [7] S. Schulman, C. Kearon, Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients, J. Thromb. Haemost. 3 (4) (Apr 2005) 692–694, http://dx.doi.org/10.1111/j.1538-7836.2005.01204.x. [8] S. Kim, N. Tran, J.C. Schewe, et al., Safety and economic considerations of argatroban use in critically ill patients: a retrospective analysis, J. Cardiothorac. Surg. 10 (2015) 19, , http://dx.doi.org/10.1186/s13019-015-0214-0. [9] B. Saugel, V. Phillip, G. Moessmer, et al., Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study, Crit. Care 14 (3) (2010) R90, http://dx.doi.org/10.1186/ cc9024. [10] M. Singer, C.S. Deutschman, C.W. Seymour, et al., The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA 315 (8) (2016 Feb 23) 801–810, http://dx.doi.org/10.1001/jama.2016.0287. [11] J.F. Barletta, J.L. DeYoung, K. McAllen, et al., Limitations of a standardized weightbased nomogram for heparin dosing in patients with morbid obesity, Surg. Obes. Relat. Dis. 4 (2008) 748–753, http://dx.doi.org/10.1016/j.soard.2008.03.005. [12] J. Riney, J. Hollands, J. Smith, et al., Identifying optimal initial infusion rates for unfractionated heparin in morbidly obese patients, Ann. Pharmacother. 44 (2010) 1141–1151, http://dx.doi.org/10.1345/aph.1P088.
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