TR-05816; No of Pages 3 Thrombosis Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
New Oral Anticoagulants in the Treatment of HeparinInduced Thrombocytopenia Mohsen Sharifi a,b,⁎, Curt Bay b, Zoltan Vajo a, Wilbur Freeman b, Mirali Sharifi a, Frederic Schwartz b a b
Arizona Cardiovascular Consultants & Vein Clinic, United States A.T. Still University, Mesa, Arizona, United States
a r t i c l e
i n f o
Article history: Received 26 October 2014 Received in revised form 16 December 2014 Accepted 6 January 2015 Available online xxxx Keywords: Heparin- induced thrombocytopenia New oral anticoagulants Deep venous thrombosis
a b s t r a c t Background: Heparin induced thrombocytopenia (HIT) is a potentially catastrophic syndrome with a high incidence of vascular thrombosis. There are little data on the efficacy of new oral anticoagulants (NOAC) in this setting. This study reports on the outcome of patients with HIT, treated with NOAC. Materials and Methods: We retrospectively identified 22 patients with HIT who were treated by our group with a combination of NOAC and a short course of argatroban. These patients were evaluated in a prospective fashion for development of outcomes at a mean follow up of 19 ± 3 months. Results: There were a total of 5 deep and 2 superficial vein thromboses diagnosed at index hospitalization. No patient developed arterial thrombosis. All patients tolerated NOAC and their platelet count normalized before discharge. At 19 months of follow-up, 6 patients had died of non-thrombotic causes. There was no bleeding, limb loss or recurrent venous thromboembolism in any patient. Conclusions: In patients with HIT, a short course of parenteral treatment with argatroban followed by administration of a NOAC is highly safe and effective in prevention of thrombosis and normalization of platelet count. Development of HIT however, portends a poor prognosis independent of vascular thrombosis. © 2015 Elsevier Ltd. All rights reserved.
Introduction Heparin induced thrombocytopenia (HIT) is a potentially dangerous adverse drug reaction with a high probability for vascular thrombosis [1,2]. The risk of thrombosis in patients with isolated HIT has been as high as 50% with a mortality rate of 10-30% [1–3]. The pathophysiology of this syndrome involves the binding of predominantly IgG antibodies to a complex of heparin and platelet factor 4 [4]. The platelets are activated through the binding of antibodies to their Fc receptors leading to release of microparticles [5]. The platelets are subsequently destroyed leading to thrombocytopenia. The released microparticles are strong procoagulants resulting in thrombin generation and a hypercoagulable state [6]. Usually thrombocytopenia occurs after 5 days from exposure to heparin however the onset can be abrupt if re-exposure to heparin occurs in the presence of circulating antibodies [7]. Treatment has consisted of discontinuation of heparin and warfarin and intravenous administration of alternative anticoagulants which have predominantly been direct thrombin inhibitors such as lepirudin, argatroban and bivalirudin [3,8,9].Subcutaneous danaproid has also been used in this
⁎ Corresponding author at: Arizona Cardiovascular Consultants & Vein Clinic, 3850 E. Baseline Road, Building 1, Suite 102, Mesa, AZ 85206, United States. Tel.: +1 480 924 0006; fax: +1 480 924 0579. E-mail address: seyedmohsensharifi@yahoo.com (M. Sharifi).
condition [10].The duration of intravenous anticoagulation with argatroban has been as high as 14 days [3]. The new oral anticoagulants (NOAC) are promising drugs however there is a paucity of data on their use in the treatment of HIT. We therefore sought to investigate the role of NOAC in this setting.
Materials and Methods The study was approved by the institutional review board of A.T. Still University and informed written consent obtained from all patients.
Study design From September 2011 through June 2013 we treated 22 patients with HIT with a combination of argatroban and NOAC. This cohort was retrospectively identified and followed in a prospective fashion for development of outcomes. The patients' clinical characteristics are shown in table 1. HIT was considered to have developed if there was history of recent exposure to heparin products plus a reduction of platelet count to less than half the baseline value or b 100 X 109/L without other explainable causes. In all cases serologic assay of antibodies to heparinplatelet factor IV (Enzyme - linked immunosorbent assay = ELISA) was sought. If this test was negative serotonin release assay was performed.
http://dx.doi.org/10.1016/j.thromres.2015.01.009 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: Sharifi M, et al, New Oral Anticoagulants in the Treatment of Heparin- Induced Thrombocytopenia, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.01.009
2
M. Sharifi et al. / Thrombosis Research xxx (2015) xxx–xxx
Results
Table 1 Clinical Characteristics of patients. n = 22(%) Male Age (yr) BMI Previous or concomitant disease- n (%) Hypertension Diabetes mellitus Cardiovascular Hypercholesterolemia Pulmonary Renal Autoimmune Current smoker Surgery or trauma (within previous 3 m) Estrogen/testosterone therapy Cancer Active History Known prothrombotic state Previous VTE
15 (68) 72 ± 8 29 ± 5 8 (36) 6 (27) 7 (32) 4(18) 4 (18) 5 (23) 3 (14) 6 (27) 4 (18) 3(14) 5 (23) 2 (9) 3 (14) 5 (23)
± denotes mean ± standard deviation; VTE = venous thromboembolism.
Fluctuations in platelet count All patients tolerated the combination of argatroban and NOAC. In 20 patients HIT antibody was diagnosed with ELISA or serotonin release assay. There were therefore 2 patients who were considered to have HIT on clinical grounds only without serologic diagnosis. The mean period from presumed exposure to heparin product to diagnosis of HIT was 4.2 ± 1 day. The changes in platelet count are shown in Fig. 1. At baseline the mean ± SD platelet count was 168.8 ± 87.1 X 109/L (range 88-to-450 X 109/L); at nadir, 82.1 ± 38.6 X 109/L (range 37-to-202 X 109/L); and at discharge, 188.4 ± 52.5 X 109/L (range 125-to-369 X 109/L). Due to the moderate positive skew of the data, a non-parametric approach was used for inferential analysis. Friedman’s test indicated a significant difference across the three measurement periods. Followup pairwise testing (Wilcoxon) showed significant differences between baseline and nadir measurements (p b 0.001) and nadir and discharge (p b 0.001); however, the difference between baseline and discharge did not reach statistical significance ((p b 0.057). Thrombotic outcomes
Exposure to parenteral anticoagulation Of the 22 patients, there were 6 who had recent exposure to heparin, 12 to enoxaparin and 4 to a combination of the two. The indications for anticoagulation were: coronary artery bypass surgery in 2; other surgeries in 2; initiation of anticoagulation for atrial fibrillation in 3; treatment for confirmed VTE in 4; suspicion for VTE in 5 and prophylactic anticoagulation during previous hospitalizations in 6 patients.
There were 5 patients with new onset of deep venous thrombosis (DVT): 4 in the lower extremities and 1 in an upper extremity. One of them had prior history of DVT. There were 2 other patients with superficial thrombosis in the great saphenous vein. There was no arterial thrombosis. Two patients had developed a small non necrotizing rash at the site of previous enoxaparin injection which resolved without sequelae. Mortality and other outcomes
Treatment With suspicion for HIT, all heparin products were discontinued and argatroban without a bolus was initiated at 0.3-0.5 mcg/Kg/min and continued for a mean of 32 ± 4 hours. The dosage was adjusted to keep the activated partial thromboplastin time (PTT) between 50– 90 seconds. The first PTT was obtained 3 hours after initiation of argatroban and every 3 hours if a change in dose was made. If no change in dosing was made, PTT was obtained every 24 hours. Two hours after discontinuation of argatroban, a NOAC was initiated. Dabigatran was given at 150 mg twice daily to 6 patients, rivaroxaban at 20 mg daily to 11 patients and apixaban at 5 mg twice daily to 5 patients. Administration of NOAC was based on its availability at the time of presentation. Later in the course of the study, patients with a glomerular filtration rate of b30 mL/min, bleeding tendencies and recent surgeries were given apixaban over other NOAC. No warfarin or other vitamin K antagonists were used in any patient. The mean follow up was 19 ± 3 months. The patients were evaluated for mortality, venous thromboembolism (VTE), arterial thrombosis, limb loss and bleeding during this period. The NOACs were continued for a minimum of 3 months although in most patients, anticoagulation was extended to 6 months.
There was no in hospital death. Within one month after discharge 3 patients died of cancer, heart failure and systemic sclerosis. None of these deaths were thrombosis-related. At 19 months, 3 other patients had died of cancer, heart and renal failure. There was no bleeding, limb loss or recurrent VTE in any patient. At 6 months, 18 patients were still on NOAC. Indefinite anticoagulation was recommended to 10 patients. Discussion The results indicate that a short course of argatroban followed by administration of NOAC is highly safe and effective in the treatment of HIT. Interestingly no bleeding, recurrent VTE or arterial thrombosis
Statistical Analysis Analyses were conducted using SPSS version 22 (IBM Corp, Armonk, NY). Values are shown as mean ± SD. Friedman’s test was used to assess differences in platelet count across the three measurement periods within the index hospitalization. Follow-up pairwise comparisons were conducted using Wilcoxon tests. An alpha of 0.05, two-tailed, was adopted for statistical significance.
Fig. 1. Fluctuations in the patients’ platelet count during hospitalization.
Please cite this article as: Sharifi M, et al, New Oral Anticoagulants in the Treatment of Heparin- Induced Thrombocytopenia, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.01.009
M. Sharifi et al. / Thrombosis Research xxx (2015) xxx–xxx
was observed at intermediate follow up. This is a rather striking finding in comparison with other studies. In a prospective trial, 304 patient with HIT (with and without thrombosis), were compared with 193 historical controls [3]. At 37 days, the incidence of the primary efficacy end point (a composite of all-cause death, all-cause amputation, or new thrombosis), was significantly reduced in the argatroban-treated patients vs. control subjects (25.6% versus 38.8%, P = 0.014 for HIT without thrombosis). In those patients with thrombosis, this composite endpoint was 43.8% in the argatroban group vs. 56.5% in control subjects (P = 0.13). Major bleeding was similar for both groups: 6.9% in the argatroban treated group vs. 6.8% in the control group. Minor bleeding was at about 40% in both groups [3]. In another prospective study using lepirudin, the 35-day combined primary end-point of death, limb amputations and new thromboembolic complications was reduced from 52.1 % observed in historical controls to 20.8% with lepirudin p = 0.0146 [2]. In our study there was no major or minor bleeding. This may have been in part due to absence of a loading dose for argatroban and administration of a relatively low maintenance dose. Furthermore the mean duration of argatroban infusion was limited to 32 ± 4 h. We have previously reported on the efficacy of low dose argatroban during catheter-directed thrombolysis for extensive lower extremity DVT in patients without HIT [11]. The use of NOAC which was started 2 hours after completion of argatroban, eliminated the inconveniences associated with parenteral anticoagulation. In the conventional approach, warfarin is started when platelet count has normalized which may take an average of 3–5 days. Furthermore a minimum of 4 days of overlap with warfarin is recommended in patients on lepirudin [2]. Despite absence of thrombosis, 6 of the 22 (27%) patients died within 19 months after discharge and half the deaths occurred in the first month. This is in keeping with a 37-day total mortality of 17.5% in the argatroban group vs. 23% in the control group in the study by Lewis et al. [3]. In that study thrombosis related mortality in the argatroban group occurred in only 1 patient (0.3%) [3]. We did not witness any thrombus related mortality. Nonetheless development of HIT was associated with a relatively high total mortality rate, irrespective of normalization of platelet count and absence of vascular thrombosis. In this study all available NOACs were used based on their availability and operator's discretion. The United States Food and Drug Administration (FDA) approved dabigatran, rivaroxaban and apixaban for treatment of non-valvular atrial fibrillation on October 2010, November 2011 and December 2012 respectively. Rivaroxaban, dabigatran and apixaban were approved for treatment of VTE on November 2012, April and August 2014 respectively. Later in the course of the study, patients with renal insufficiency, bleeding tendencies and recent surgeries received apixaban. Earlier dabigatran was the only available NOAC. In this study the starting dose of rivaroxaban and apixaban was less than the recommended initial dose for treatment of DVT. This was due to the fact that all patients had received a short course of treatment with argatroban and we postulated that with this approach the lower maintenance dose of rivaroxaban and apixaban would be reasonable.
3
Limitations of the study This study was an open label single arm study from our center which prospectively followed patients for outcomes after being treated by our group. The identification of the cohort was in a retrospective fashion. Consequently it did not have the rigor of a prospective randomized trial. Specifically there was no control group and in two patients the diagnosis was made clinically and without serologic confirmation. All available NOACs were included and their use was governed by their availability and the discretion of the treating physician. The study population was small and none of the patients had their presentation as arterial thrombosis which potentially could have led to a graver outcome. Nonetheless this report was a reflection of treatment in the "real world" and for all comers. Due to the existing limitations, further studies are required to explore the role of NOACs in the treatment of HIT. We conclude that in patients with HIT a short course of parenteral treatment with low dose argatroban followed by administration of a NOAC is highly safe and effective in prevention of thrombosis and normalization of platelet count. This approach obviates the inconveniences associated with prolonged parenteral anticoagulation. Development of HIT portends a poor prognosis independent of vascular thrombosis. Conflict of interest statement There are no conflicts of interest by any author pertaining to this submission. References [1] Warkentin T, Kelton J. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996;101:502–7. [2] Greinacher A, Völpel H, Janssens U, Hach-Wunderle V, Kemkes-Matthes B, Eichler P, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999;99:73–80. [3] Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001;103:1838–43. [4] Horsewood P, Warkentin T, Hayward C, Kelton J. The epitope specificity of heparininduced thrombocytopenia. Br J Haematol 1996;95:161–7. [5] Chong B, Fawaz I, Chesterman C, Berndt M. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989;73:235–40. [6] Warkentin TE, Hayward CP, Boshkov LK, Santos AV, Sheppard JA, Bode AP, et al. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood 1994;84:3691–9. [7] Warkentin T, Kelton J. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286–92. [8] Reilly M, Weiss R, Askenase A, Tuite C, Soulen M, Mohler E. Hirudin therapy during thrombolysis for venous thrombosis in heparin-induced thrombocytopenia. Vasc Med 2000;5:239–42. [9] Singla A, Amini MR, Alpert MA, Gornik HL. Fatal anaphylactoid reaction associated with heparin-induced thrombocytopenia. Vasc Med 2013;18:136–8. [10] Greinarcher A. Treatment of heparin-induced thrombocytopenia. Thromb Haemost 1999;82:457–67. [11] Sharifi M, Bay C, Nowroozi S, Bentz S, Valeros G. Catheter Directed Thrombolysis with Argatroban and tPA for Extensive Iliac and Femoropopliteal Vein Thrombosis. Cardiovasc Intervent Radiol 2013;36:1586–90.
Please cite this article as: Sharifi M, et al, New Oral Anticoagulants in the Treatment of Heparin- Induced Thrombocytopenia, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.01.009
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
New Oral Anticoagulants in the Treatment of HeparinInduced Thrombocytopenia Mohsen Sharifi a,b,⁎, Curt Bay b, Zoltan Vajo a, Wilbur Freeman b, Mirali Sharifi a, Frederic Schwartz b a b
Arizona Cardiovascular Consultants & Vein Clinic, United States A.T. Still University, Mesa, Arizona, United States
a r t i c l e
i n f o
Article history: Received 26 October 2014 Received in revised form 16 December 2014 Accepted 6 January 2015 Available online xxxx Keywords: Heparin- induced thrombocytopenia New oral anticoagulants Deep venous thrombosis
a b s t r a c t Background: Heparin induced thrombocytopenia (HIT) is a potentially catastrophic syndrome with a high incidence of vascular thrombosis. There are little data on the efficacy of new oral anticoagulants (NOAC) in this setting. This study reports on the outcome of patients with HIT, treated with NOAC. Materials and Methods: We retrospectively identified 22 patients with HIT who were treated by our group with a combination of NOAC and a short course of argatroban. These patients were evaluated in a prospective fashion for development of outcomes at a mean follow up of 19 ± 3 months. Results: There were a total of 5 deep and 2 superficial vein thromboses diagnosed at index hospitalization. No patient developed arterial thrombosis. All patients tolerated NOAC and their platelet count normalized before discharge. At 19 months of follow-up, 6 patients had died of non-thrombotic causes. There was no bleeding, limb loss or recurrent venous thromboembolism in any patient. Conclusions: In patients with HIT, a short course of parenteral treatment with argatroban followed by administration of a NOAC is highly safe and effective in prevention of thrombosis and normalization of platelet count. Development of HIT however, portends a poor prognosis independent of vascular thrombosis. © 2015 Elsevier Ltd. All rights reserved.
Introduction Heparin induced thrombocytopenia (HIT) is a potentially dangerous adverse drug reaction with a high probability for vascular thrombosis [1,2]. The risk of thrombosis in patients with isolated HIT has been as high as 50% with a mortality rate of 10-30% [1–3]. The pathophysiology of this syndrome involves the binding of predominantly IgG antibodies to a complex of heparin and platelet factor 4 [4]. The platelets are activated through the binding of antibodies to their Fc receptors leading to release of microparticles [5]. The platelets are subsequently destroyed leading to thrombocytopenia. The released microparticles are strong procoagulants resulting in thrombin generation and a hypercoagulable state [6]. Usually thrombocytopenia occurs after 5 days from exposure to heparin however the onset can be abrupt if re-exposure to heparin occurs in the presence of circulating antibodies [7]. Treatment has consisted of discontinuation of heparin and warfarin and intravenous administration of alternative anticoagulants which have predominantly been direct thrombin inhibitors such as lepirudin, argatroban and bivalirudin [3,8,9].Subcutaneous danaproid has also been used in this
⁎ Corresponding author at: Arizona Cardiovascular Consultants & Vein Clinic, 3850 E. Baseline Road, Building 1, Suite 102, Mesa, AZ 85206, United States. Tel.: +1 480 924 0006; fax: +1 480 924 0579. E-mail address: seyedmohsensharifi@yahoo.com (M. Sharifi).
condition [10].The duration of intravenous anticoagulation with argatroban has been as high as 14 days [3]. The new oral anticoagulants (NOAC) are promising drugs however there is a paucity of data on their use in the treatment of HIT. We therefore sought to investigate the role of NOAC in this setting.
Materials and Methods The study was approved by the institutional review board of A.T. Still University and informed written consent obtained from all patients.
Study design From September 2011 through June 2013 we treated 22 patients with HIT with a combination of argatroban and NOAC. This cohort was retrospectively identified and followed in a prospective fashion for development of outcomes. The patients' clinical characteristics are shown in table 1. HIT was considered to have developed if there was history of recent exposure to heparin products plus a reduction of platelet count to less than half the baseline value or b 100 X 109/L without other explainable causes. In all cases serologic assay of antibodies to heparinplatelet factor IV (Enzyme - linked immunosorbent assay = ELISA) was sought. If this test was negative serotonin release assay was performed.
http://dx.doi.org/10.1016/j.thromres.2015.01.009 0049-3848/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: Sharifi M, et al, New Oral Anticoagulants in the Treatment of Heparin- Induced Thrombocytopenia, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.01.009
2
M. Sharifi et al. / Thrombosis Research xxx (2015) xxx–xxx
Results
Table 1 Clinical Characteristics of patients. n = 22(%) Male Age (yr) BMI Previous or concomitant disease- n (%) Hypertension Diabetes mellitus Cardiovascular Hypercholesterolemia Pulmonary Renal Autoimmune Current smoker Surgery or trauma (within previous 3 m) Estrogen/testosterone therapy Cancer Active History Known prothrombotic state Previous VTE
15 (68) 72 ± 8 29 ± 5 8 (36) 6 (27) 7 (32) 4(18) 4 (18) 5 (23) 3 (14) 6 (27) 4 (18) 3(14) 5 (23) 2 (9) 3 (14) 5 (23)
± denotes mean ± standard deviation; VTE = venous thromboembolism.
Fluctuations in platelet count All patients tolerated the combination of argatroban and NOAC. In 20 patients HIT antibody was diagnosed with ELISA or serotonin release assay. There were therefore 2 patients who were considered to have HIT on clinical grounds only without serologic diagnosis. The mean period from presumed exposure to heparin product to diagnosis of HIT was 4.2 ± 1 day. The changes in platelet count are shown in Fig. 1. At baseline the mean ± SD platelet count was 168.8 ± 87.1 X 109/L (range 88-to-450 X 109/L); at nadir, 82.1 ± 38.6 X 109/L (range 37-to-202 X 109/L); and at discharge, 188.4 ± 52.5 X 109/L (range 125-to-369 X 109/L). Due to the moderate positive skew of the data, a non-parametric approach was used for inferential analysis. Friedman’s test indicated a significant difference across the three measurement periods. Followup pairwise testing (Wilcoxon) showed significant differences between baseline and nadir measurements (p b 0.001) and nadir and discharge (p b 0.001); however, the difference between baseline and discharge did not reach statistical significance ((p b 0.057). Thrombotic outcomes
Exposure to parenteral anticoagulation Of the 22 patients, there were 6 who had recent exposure to heparin, 12 to enoxaparin and 4 to a combination of the two. The indications for anticoagulation were: coronary artery bypass surgery in 2; other surgeries in 2; initiation of anticoagulation for atrial fibrillation in 3; treatment for confirmed VTE in 4; suspicion for VTE in 5 and prophylactic anticoagulation during previous hospitalizations in 6 patients.
There were 5 patients with new onset of deep venous thrombosis (DVT): 4 in the lower extremities and 1 in an upper extremity. One of them had prior history of DVT. There were 2 other patients with superficial thrombosis in the great saphenous vein. There was no arterial thrombosis. Two patients had developed a small non necrotizing rash at the site of previous enoxaparin injection which resolved without sequelae. Mortality and other outcomes
Treatment With suspicion for HIT, all heparin products were discontinued and argatroban without a bolus was initiated at 0.3-0.5 mcg/Kg/min and continued for a mean of 32 ± 4 hours. The dosage was adjusted to keep the activated partial thromboplastin time (PTT) between 50– 90 seconds. The first PTT was obtained 3 hours after initiation of argatroban and every 3 hours if a change in dose was made. If no change in dosing was made, PTT was obtained every 24 hours. Two hours after discontinuation of argatroban, a NOAC was initiated. Dabigatran was given at 150 mg twice daily to 6 patients, rivaroxaban at 20 mg daily to 11 patients and apixaban at 5 mg twice daily to 5 patients. Administration of NOAC was based on its availability at the time of presentation. Later in the course of the study, patients with a glomerular filtration rate of b30 mL/min, bleeding tendencies and recent surgeries were given apixaban over other NOAC. No warfarin or other vitamin K antagonists were used in any patient. The mean follow up was 19 ± 3 months. The patients were evaluated for mortality, venous thromboembolism (VTE), arterial thrombosis, limb loss and bleeding during this period. The NOACs were continued for a minimum of 3 months although in most patients, anticoagulation was extended to 6 months.
There was no in hospital death. Within one month after discharge 3 patients died of cancer, heart failure and systemic sclerosis. None of these deaths were thrombosis-related. At 19 months, 3 other patients had died of cancer, heart and renal failure. There was no bleeding, limb loss or recurrent VTE in any patient. At 6 months, 18 patients were still on NOAC. Indefinite anticoagulation was recommended to 10 patients. Discussion The results indicate that a short course of argatroban followed by administration of NOAC is highly safe and effective in the treatment of HIT. Interestingly no bleeding, recurrent VTE or arterial thrombosis
Statistical Analysis Analyses were conducted using SPSS version 22 (IBM Corp, Armonk, NY). Values are shown as mean ± SD. Friedman’s test was used to assess differences in platelet count across the three measurement periods within the index hospitalization. Follow-up pairwise comparisons were conducted using Wilcoxon tests. An alpha of 0.05, two-tailed, was adopted for statistical significance.
Fig. 1. Fluctuations in the patients’ platelet count during hospitalization.
Please cite this article as: Sharifi M, et al, New Oral Anticoagulants in the Treatment of Heparin- Induced Thrombocytopenia, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.01.009
M. Sharifi et al. / Thrombosis Research xxx (2015) xxx–xxx
was observed at intermediate follow up. This is a rather striking finding in comparison with other studies. In a prospective trial, 304 patient with HIT (with and without thrombosis), were compared with 193 historical controls [3]. At 37 days, the incidence of the primary efficacy end point (a composite of all-cause death, all-cause amputation, or new thrombosis), was significantly reduced in the argatroban-treated patients vs. control subjects (25.6% versus 38.8%, P = 0.014 for HIT without thrombosis). In those patients with thrombosis, this composite endpoint was 43.8% in the argatroban group vs. 56.5% in control subjects (P = 0.13). Major bleeding was similar for both groups: 6.9% in the argatroban treated group vs. 6.8% in the control group. Minor bleeding was at about 40% in both groups [3]. In another prospective study using lepirudin, the 35-day combined primary end-point of death, limb amputations and new thromboembolic complications was reduced from 52.1 % observed in historical controls to 20.8% with lepirudin p = 0.0146 [2]. In our study there was no major or minor bleeding. This may have been in part due to absence of a loading dose for argatroban and administration of a relatively low maintenance dose. Furthermore the mean duration of argatroban infusion was limited to 32 ± 4 h. We have previously reported on the efficacy of low dose argatroban during catheter-directed thrombolysis for extensive lower extremity DVT in patients without HIT [11]. The use of NOAC which was started 2 hours after completion of argatroban, eliminated the inconveniences associated with parenteral anticoagulation. In the conventional approach, warfarin is started when platelet count has normalized which may take an average of 3–5 days. Furthermore a minimum of 4 days of overlap with warfarin is recommended in patients on lepirudin [2]. Despite absence of thrombosis, 6 of the 22 (27%) patients died within 19 months after discharge and half the deaths occurred in the first month. This is in keeping with a 37-day total mortality of 17.5% in the argatroban group vs. 23% in the control group in the study by Lewis et al. [3]. In that study thrombosis related mortality in the argatroban group occurred in only 1 patient (0.3%) [3]. We did not witness any thrombus related mortality. Nonetheless development of HIT was associated with a relatively high total mortality rate, irrespective of normalization of platelet count and absence of vascular thrombosis. In this study all available NOACs were used based on their availability and operator's discretion. The United States Food and Drug Administration (FDA) approved dabigatran, rivaroxaban and apixaban for treatment of non-valvular atrial fibrillation on October 2010, November 2011 and December 2012 respectively. Rivaroxaban, dabigatran and apixaban were approved for treatment of VTE on November 2012, April and August 2014 respectively. Later in the course of the study, patients with renal insufficiency, bleeding tendencies and recent surgeries received apixaban. Earlier dabigatran was the only available NOAC. In this study the starting dose of rivaroxaban and apixaban was less than the recommended initial dose for treatment of DVT. This was due to the fact that all patients had received a short course of treatment with argatroban and we postulated that with this approach the lower maintenance dose of rivaroxaban and apixaban would be reasonable.
3
Limitations of the study This study was an open label single arm study from our center which prospectively followed patients for outcomes after being treated by our group. The identification of the cohort was in a retrospective fashion. Consequently it did not have the rigor of a prospective randomized trial. Specifically there was no control group and in two patients the diagnosis was made clinically and without serologic confirmation. All available NOACs were included and their use was governed by their availability and the discretion of the treating physician. The study population was small and none of the patients had their presentation as arterial thrombosis which potentially could have led to a graver outcome. Nonetheless this report was a reflection of treatment in the "real world" and for all comers. Due to the existing limitations, further studies are required to explore the role of NOACs in the treatment of HIT. We conclude that in patients with HIT a short course of parenteral treatment with low dose argatroban followed by administration of a NOAC is highly safe and effective in prevention of thrombosis and normalization of platelet count. This approach obviates the inconveniences associated with prolonged parenteral anticoagulation. Development of HIT portends a poor prognosis independent of vascular thrombosis. Conflict of interest statement There are no conflicts of interest by any author pertaining to this submission. References [1] Warkentin T, Kelton J. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996;101:502–7. [2] Greinacher A, Völpel H, Janssens U, Hach-Wunderle V, Kemkes-Matthes B, Eichler P, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999;99:73–80. [3] Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001;103:1838–43. [4] Horsewood P, Warkentin T, Hayward C, Kelton J. The epitope specificity of heparininduced thrombocytopenia. Br J Haematol 1996;95:161–7. [5] Chong B, Fawaz I, Chesterman C, Berndt M. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989;73:235–40. [6] Warkentin TE, Hayward CP, Boshkov LK, Santos AV, Sheppard JA, Bode AP, et al. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood 1994;84:3691–9. [7] Warkentin T, Kelton J. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286–92. [8] Reilly M, Weiss R, Askenase A, Tuite C, Soulen M, Mohler E. Hirudin therapy during thrombolysis for venous thrombosis in heparin-induced thrombocytopenia. Vasc Med 2000;5:239–42. [9] Singla A, Amini MR, Alpert MA, Gornik HL. Fatal anaphylactoid reaction associated with heparin-induced thrombocytopenia. Vasc Med 2013;18:136–8. [10] Greinarcher A. Treatment of heparin-induced thrombocytopenia. Thromb Haemost 1999;82:457–67. [11] Sharifi M, Bay C, Nowroozi S, Bentz S, Valeros G. Catheter Directed Thrombolysis with Argatroban and tPA for Extensive Iliac and Femoropopliteal Vein Thrombosis. Cardiovasc Intervent Radiol 2013;36:1586–90.
Please cite this article as: Sharifi M, et al, New Oral Anticoagulants in the Treatment of Heparin- Induced Thrombocytopenia, Thromb Res (2015), http://dx.doi.org/10.1016/j.thromres.2015.01.009
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