http://informahealthcare.com/plt ISSN: 0953-7104 (print), 1369-1635 (electronic) Platelets, 2015; 26(1): 93–96 ! 2015 Informa UK Ltd. DOI: 10.3109/09537104.2013.870333
SHORT COMMUNICATION
Dental procedures in 24 patients with chronic immune thrombocytopenia in prospective clinical studies of eltrombopag Michael D. Tarantino1, Patrick F. Fogarty2, Palvi Shah3, & Andre´s Brainsky4*
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1
Department of Pediatric Hematology/Oncology, The Bleeding and Clotting Disorders Institute, University of Illinois College of Medicine-Peoria, IL, USA, 2Penn Comprehensive Hemophilia and Thrombosis Program, Hospital of the University of Pennsylvania, Philadelphia, PA, USA, 3 GlaxoSmithKline, Stockley Park, UK, and 4GlaxoSmithKline, Collegeville, PA, USA Abstract
Keywords
Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by chronically low peripheral blood platelet counts. Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that increases platelet production. This report examines peri-procedural platelet counts and bleeding complications among chronic ITP patients requiring dental procedures while participating in clinical studies with eltrombopag. A total of 494 patients participated in five clinical studies of eltrombopag in chronic ITP. Information about dental procedures was collected prospectively in four studies and retrospectively in one study. Twenty-four patients (22 eltrombopag, 2 placebo) underwent 32 dental procedures (dental cleaning, tooth repair, artificial crown, dental prosthesis, tooth extraction, dental or wisdom teeth extraction, dental root extraction, and endodontic procedures, among others) during study treatment or up to 10 days later. Supplemental ITP therapy (e.g., corticosteroids, platelet transfusions) was given before the dental procedure to increase platelet counts in three eltrombopag-treated patients and both placebo-treated patients. The mean pre-procedure platelet count standard deviation for all procedures in the overall population of patients, eltrombopag group, and placebo group prior to undergoing dental procedures was 96 000 81 069/ml,103 517 81 522/ml, and 23 333 9291/ml, respectively. Two patients in each group had platelet counts below 30 000/ml before the procedure. No patient who had a dental procedure experienced a bleeding adverse event. Among patients with chronic ITP who required a dental procedure during clinical studies of eltrombopag, supplemental ITP treatment was required for both patients who received placebo but was not required for most patients who received eltrombopag. No bleeding complications were reported. These data imply that patients with chronic ITP who receive eltrombopag and experience increases in platelet counts fulfill current pre-procedural platelet count recommendations to undergo invasive dental procedures, and may have a lower risk of bleeding complications and a reduced need for supplemental ITP treatment.
Dental, hemostasis, oral hemorrhage, surgical procedures
Introduction Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by persistently low platelet counts in the absence of other causes of thrombocytopenia [1]. Chronic ITP involves platelet destruction induced by anti-platelet antibodies and impaired platelet production, resulting in chronically low platelet counts [2]. The goal of treatment in chronic ITP is to prevent bleeding by raising platelet counts to a hemostatic level between 30 000/ml and 50 000/ml [1]. Patients with chronic ITP may require dental procedures that typically would be associated with a low risk of bleeding in patients with a normal platelet count, but entail a higher risk of
*AB was an employee of GlaxoSmithKline while this research was conducted. Correspondence: Michael D. Tarantino, MD, Medical Director and President, The Bleeding and Clotting Disorders Institute, Professor of Pediatrics, University of Illinois College of Medicine-Peoria, 6811 North Knoxville Avenue, Suite A, Peoria, IL 61614, USA. Tel: +309-692-5337. Fax: +309-693-3913. E-mail: [email protected]
History Received 1 August 2013 Revised 30 October 2013 Accepted 23 November 2013 Published online 16 January 2014
bleeding in patients with chronic ITP due to their low platelet counts. Clinical guidelines for the management of chronic ITP recommend ensuring that platelet counts prior to dental procedures are 420 000/ml, or even 30 000/ml or 50 000/ml, depending on the complexity of the procedure [1]. Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that binds to the transmembrane domain of the thrombopoietin receptor, without competing with endogenous thrombopoietin [3]. Eltrombopag treatment leads to increased proliferation and differentiation of bone marrow progenitor cells into megakaryocytes and increased platelet production [3]. In clinical studies, eltrombopag was shown to increase platelet counts among healthy subjects [4] and patients with chronic ITP, hepatitis C-induced thrombocytopenia, or chronic liver diseaseinduced thrombocytopenia [5]. The efficacy and safety of eltrombopag to increase platelet counts in patients with chronic ITP has been demonstrated in three randomized, placebo-controlled studies of patients with a baseline platelet count of less than 30 000/ml: Study 773A was a 6-week, phase 2, dose-finding study [6]; Study 773B was a 6-week, phase 3 study [7]; and RAISE was a 6-month, phase
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3 study [8]. Other clinical studies of eltrombopag in patients with chronic ITP include the single-arm, open-label REPEAT study of repeated on/off dosing cycles [9] and EXTEND, an ongoing openlabel extension study that enrolled patients after they participated in one of these four studies [10]. The objective of this analysis was to evaluate peri-procedural platelet counts and bleeding complications in patients who underwent dental procedures during their participation in any of these five clinical studies [6–10]. Data from the five studies were pooled to maximize the number of dental procedures available for analysis.
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Methods Data were analyzed for the 494 patients with previously treated chronic ITP who participated in the five clinical studies: Study 773A (n ¼ 117) [6], Study 773B (n ¼ 114) [7], RAISE (n ¼ 197) [8], REPEAT (n ¼ 66) [9], and EXTEND (n ¼ 299 as of the data cutoff date of December 2008 for this analysis) [10]. Information about dental procedures was collected retrospectively in Study 773A and prospectively in the other studies. Investigators were asked to record information about any surgical or medical procedure. The level of detail collected on many procedures, including dental ones, was not standardized. Data collection included basic demographic information, platelet counts before and after procedures, type of procedure, need for supplemental treatment to increase platelet counts (within 1 week before and 1 week after the intervention), use of blood products, and reported bleeding complications. Supplemental ITP treatments were defined as receiving a new ITP medication, an increase in dose from baseline of a concomitant ITP medication, a platelet or other blood product transfusion, or a splenectomy. The ethics committee at each institution approved the protocol and amendments, and all patients provided written informed consent before enrolment. Each study was undertaken in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.
Results A total of 24 of 676 patients enrolled in the five trials underwent a dental procedure and were included in this study. No patient underwent a dental procedure during Study 773A [6], and only 1 of 114 patients in Study 773B reported having a dental procedure. The 24 included patients received a total of 32 procedures categorized as dental cleaning, tooth repair, dental caries, artificial crown, dental treatment, dental prosthesis, tooth extraction, dental extraction, wisdom teeth removal, dental root extraction, dental operation, or endodontic procedure (Table I). Prior to dental treatment, the overall mean SD platelet count calculated from all dental procedures was 96 000 81 069/ml with a median (range) of 80 000/ml (9000/ml–412 000/ml), the mean SD platelet count for all procedures in the placebo group was 23 333 9292/ml with a median (range) of 19 000/ml (17 000/ml–34 000/ml), and the mean SD platelet count for all procedures in the eltrombopag group was 103 517 81 522/ml with a median (range) of 81 000/ml (9000/ml–412 000/ml). Two patients were on placebo; both received supplemental ITP treatment perioperatively. One patient received platelet transfusion and hydrocortisone following a platelet count of 17 000/ml prior to a tooth extraction. After the procedure his platelet count was 7000/ml. The second patient on placebo had a platelet count of 19 000/ml prior to a ‘‘dental operation’’ (no additional details provided by the investigator). Preceding a second dental operation, this patient received IVIg which raised her platelet count from 20 000/ml to 34 000/ml.
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All of the remaining patients undergoing dental procedures were in the eltrombopag group. One of these patients did not respond to eltrombopag and was placed on danazol prior to his procedure. The platelet count prior to the procedure was 9000/ml and he received a peri-procedural platelet transfusion. Following the procedure, his platelet count was 12 000/ml. The remaining patients received a total of 28 procedures of varying complexity, and had platelet counts that ranged from 19 000/ml to 270 000/ml. Only two of these patients received supplemental ITP treatment (platelet counts of 39 000/ml, and 64 000/ml, respectively). None of the patients who underwent dental procedures experienced a bleeding complication associated with the procedure.
Discussion Postoperative bleeding occurs in approximately 10% of patients with compromised hemostasis (e.g., von Willebrand disease, hemophilia A) who undergo oral surgery [11]. To increase preprocedural platelet counts in patients with chronic ITP, different treatments are available, including IVIg, corticosteroids, and/or platelet transfusion [1]. There have been few case reports of the peri-procedural care of patients with ITP who undergo dental procedures [12–14]. One of these reports described dental procedures in two young girls diagnosed with ITP: a 5-year-old girl who had dental treatment postponed for 2 months due to a low platelet count and a 7-year-old girl who had a platelet count of 54 000/ml at presentation and no complications despite extensive dental treatment [12]. In another report, a 20-year-old woman with ITP and a pre-operative platelet count of 60 000/ml was hospitalized pre-operatively and received tranexamic acid infusions before molar extraction; no bleeding complications were reported [13]. In a third report, a 13-year-old boy with ITP presented to the emergency room after a fall that dislocated two teeth [14]. Because his platelet count was 15 000/ml at admission, surgery was delayed 2 days until the platelet count rose to 70 000/ml. Partial healing had occurred and general anesthesia and some force were required to reposition the teeth. The teeth eventually lost vitality and he required endodontic treatment. In these case reports, dental procedures in ITP patients were delayed until platelet counts were 450 000/ml [12] and/or the patient was hospitalized peri-operatively [13, 14]. These approaches may reduce the risk of bleeding complications, but may also lead to delays before necessary dental care can be provided [12, 14]. Delaying dental procedures because of low platelet counts may lead to more complicated procedures, potentially increasing healthcare costs, and jeopardizing the outcome of the procedure. Several other reports have described patients who presented to dentists to manage oral complications of undiagnosed ITP [15–21]. However, the primary purpose of those reports was to aid dentists in the recognition and diagnosis of ITP based on oral symptomatology. To the best of our knowledge, this is the first report of dental procedures and bleeding complications among a large population of patients with ITP. Guidelines for the treatment of ITP have stipulated that simple dental prophylaxis (e.g., cleaning) can be undertaken at platelet counts of 20 000/ml to 30 000/ml; simple dental extractions should be done only if platelet counts are 430 000/ml; and more complex procedures require platelet counts 450 000/ml [1]. Given the frequency of dental procedures in patients with ITP, it is important for dentists to be familiar with these guidelines. The present report suggests that dentists generally follow these parameters in the management of patients with ITP, and none of the patients who had a dental procedure during the
Dental procedures in patients with cITP
DOI: 10.3109/09537104.2013.870333
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Table I. Dental procedures among patients with ITP in pivotal eltrombopag studies. Platelet count (/ml) Dental procedure Treatment
Procedure
Before
After
Day
Day
Count
Day
Count
88
85
17 000
92
7000
69 106
50 106
19 000 34 000
71 113
22 000 31 000
29 601 13 99 102
29 580 8 96 78
34 000 65 000 81 000 93 000 270 000
36 609 15 102 106
43 365 603
43 353 580
31 000 58 000 65 000
113
109
105 140
Supplemental ITP treatment Day
Treatment
Sex/Age
Study
Placebo Tooth extraction 85, 87, 88 87–88
Transfusion Hydrocortisone
M/67
RAISE
None IVIgc
F/77* F/77*
RAISE RAISE
56 000 38 000 490 000 84 000 313 000
None None None None None
M/53* F/82* F/61 F/33* F/45
EXTEND EXTEND REPEAT EXTEND EXTEND
50 385 609
26 000 54 000 38 000
None None None
F/43 M/42* F/82*
EXTEND EXTEND EXTEND
167 000
116
171 000
None
F/33*
EXTEND
88 135
93 000 412 000
114 148
109 000 54 000
None None
F/68* F/68*
EXTEND EXTEND
83
79
131 000
85
166 000
None
M/30*
EXTEND
106
101
137 000
111
219 000
None
F/42
RAISE
156
156
9000
184
12 000
M/43
RAISE
101 72 260 227 51a 431 272 29
87 72 260 225 50 430 253 29
19 000 39 000 62 000 64 000 80 000 112 000 132 000 150 000
NA 105 267 232 57 435 280 37
NA 30 000 44 000 73 000 82 000 120 000 118 000 128 000
Danazol Transfusion None IVIg None Methylprednisoloned None None None None
F/52 F/29 M/53* F/57 F/68e F/60 M/63 F/59
EXTEND RAISE EXTEND EXTEND 773B EXTEND EXTEND REPEAT
128
105
53 000
135
60 000
None
M/53*
EXTEND
341
337
92 000
365
63 000
None
F/52
EXTEND
503
503
80 000
531
80 000
None
M/53*
EXTEND
490
484
149 000
508
79 000
None
M/71
EXTEND
379 48 134
353 43 134
58 000 82 000 184 000
385 71 140
54 000 140 000 100 000
None None None
M/42* F/31 M/30*
EXTEND RAISE EXTEND
Dental operation 99, 103
Eltrombopag
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Dental cleaning
Tooth repair
Dental caries Artificial crown Dental treatment (drainage) Dental prosthesis replacement Tooth extraction 67b 156 72 221–224
Dental extraction Wisdom teeth removal Dental root extraction Dental operation Endodontic procedure
NA, not available. Eltrombopag dose was 50 mg/day. b The last platelet count prior to IVIg treatment was 20 000/ml on day 99. c Danazol treatment was ongoing at the time of the analysis; the last platelet count prior to danazol treatment was 10 000/ml on day 42. d The last platelet count prior to methylprednisolone treatment was 48 000/ml on day 220. e Patient stopped study treatment on day 43, with a platelet count of 129 000/ml. *Patients received more than one type of procedure and appear in multiple categories. a
eltrombopag studies experienced a bleeding complication associated with the procedure. The fact that only two patients in the placebo arms of the randomized studies underwent a dental procedure limits the comparison between the eltrombopag and placebo arms. This may reflect the fact that patients taking placebo had lower median platelet counts and may not have been able to schedule procedures potentially associated with a risk of bleeding. However, no
information is available to clarify how many patients required procedures that could not be undertaken because of thrombocytopenia. No dental procedures were reported for the 117 patients in Study 773A. It is possible that this finding was the result of the retrospective analysis of dental procedures in that study. However, in Study 773B, dental procedures were recorded prospectively, and only 1 of 114 patients in that study had a dental procedure.
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A likely explanation for the lower numbers of procedures in these two studies is that each was only 6 weeks in duration, as compared with the longer duration of the RAISE, REPEAT, and EXTEND studies, in which more patients underwent dental procedures. This study has several limitations. While data on hemostatic challenges were prospectively collected, the details of dental procedures recorded were not standardized. Therefore, some details of procedures are missing. The study also has the inherent limitations of all retrospective studies, limiting the interpretation of the results. A prospective controlled trial would be necessary to address questions about what a safe level of platelets would be for ITP patients undergoing dental work.
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Conclusion Although the studies described herein were not designed to address bleeding complications with dental procedures, these data suggest that patients with chronic ITP who are being treated with eltrombopag and experience increases in platelet counts fulfill current pre-procedural platelet count recommendations to undergo dental procedures. These patients may have a lower risk of bleeding complications, a reduced need for other supplemental ITP treatment, and an increased likelihood of successful hemostatic outcomes. Prospective studies evaluating the utility of increasing pre-procedural platelet counts and the potential use of ancillary therapies would be useful to establish treatment algorithms.
Acknowledgements The authors would like to thank Kimberly Marino of GlaxoSmithKline who provided critical review. Portions of this work were presented at the American Society of Hematology 52nd Annual Meeting and Exposition, Orlando, FL, USA, December 4–7, 2010.
Declaration of interest This work was supported by GlaxoSmithKline (GSK), Collegeville, PA, USA. Michael D. Tarantino provided consultancy for Amgen, is a Study Investigator with GSK in the EXTEND REPEAT Studies; his institution received royalties. Patrick F. Fogarty received research funding from GSK and provided consultancy for Amgen. Palvi Shah is an employee of and holds equity ownership in GSK. Andres Brainsky is a former employee of and held equity ownership in GSK. Editorial support was provided by Jonathan Latham of PharmaScribe, LLC. Editorial support for this Short Communication was provided by AOI Communications, L.P.
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4.
5.
6.
7.
8.
9.
10.
11.
12. 13. 14. 15. 16. 17.
References 1. Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, Chong BH, Cines DB, Gernsheimer TB, Godeau B, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010;115:168–186. 2. Aledort LM, Hayward CP, Chen MG, Nichol JL, Bussel J. Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies. Am J Hematol 2004;76:205–213. 3. Erickson-Miller CL, Delorme E, Tian SS, Hopson CB, Landis AJ, Valoret EI, Sellers TS, Rosen J, Miller SG, Luengo JI, et al.
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Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells 2009;27:424–430. Jenkins JM, Williams D, Deng Y, Uhi J, Kitchen V, Collins D, Erickson-Miller CL. Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood 2007;109: 4739–4741. McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, Berg T, Gordon SC, Campbell FM, Theodore D, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007;357: 2227–2236. Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007;357:2237–2247. Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: A randomised, double-blind, placebo-controlled trial. Lancet 2009;373:641–648. Cheng G, Saleh MN, Marcher C, Vasey S, Mayer B, Aivado M, Arning M, Stone NL, Bussel JB. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): A 6-month, randomised, phase 3 study. Lancet 2011;377:393–402. Bussel JB, Psaila B, Saleh MN, Vasey S, Mayer B, Stone NL, Arning M. Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura. Blood 2008;112:3431. Saleh MN, Bussel JB, Cheng G, et al. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: Results of the long-term, open-label EXTEND study. Blood 2013; 121:537–545. Reich W, Kriwalsky MS, Wolf HH, Schubert J. Bleeding complications after oral surgery in outpatients with compromised haemostasis: Incidence and management. Oral Maxillofac Surg 2009;13: 73–77. Vaisman B, Medina AC, Ramirez G. Dental treatment for children with chronic idiopathic thrombocytopaenic purpura: A report of two cases. Int J Paediatr Dent 2004;14:355–362. Inchingolo F, Crincoli V, Di Palma G, Inchingolo AM. Patient at high hemorrhagic risk. Surgical management of three cases and review of the literature. Miner Stomatol 2005;54:247–253. Finucane D, Fleming P, Smith O. Dentoalveolar trauma in a patient with chronic idiopathic thrombocytopenic purpura: A case report. Pediatr Dent 2004;26:352–354. Yeager DA. Idiopathic thrombocytopenic purpura: report of case. J Am Dent Assoc 1975;90:640–643. Benson P, Macpherson DW. Idiopathic thrombocytopenic purpura presenting with infraorbital nerve paraesthesia. Int J Oral Maxillofac Surg 1990;19:263–265. Reddy VV, Rawal YB. Childhood thrombocytopenic purpura: Review and a case report. Indian J Dent Res 1996;7:103–106. Hunter ML, Hunter B, Lesser S. Acute idiopathic thrombocytopaenic purpura in childhood: Report of a case presenting in general dental practice. Br Dent J 1997;183:27–29. Hegde RJ, Parimala K, Shivaprakash. Acute idiopathic thrombocytopenic purpura in childhood: A case report. J Indian Soc Pedod Prev Dent 2003;21:42–44. Owais Z, Dane J, Cumming CG. Unprovoked periodontal hemorrhage, life-threatening anemia and idiopathic thrombocytopenia purpura: An unusual case report. Spec Care Dentist 2003;23:58–62. Themistocleous E, Ariyaratnam S, Duxbury AJ. Acute idiopathic thrombocytopenic purpura: A case report. Dent Update 2004;31: 92–96.
SHORT COMMUNICATION
Dental procedures in 24 patients with chronic immune thrombocytopenia in prospective clinical studies of eltrombopag Michael D. Tarantino1, Patrick F. Fogarty2, Palvi Shah3, & Andre´s Brainsky4*
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1
Department of Pediatric Hematology/Oncology, The Bleeding and Clotting Disorders Institute, University of Illinois College of Medicine-Peoria, IL, USA, 2Penn Comprehensive Hemophilia and Thrombosis Program, Hospital of the University of Pennsylvania, Philadelphia, PA, USA, 3 GlaxoSmithKline, Stockley Park, UK, and 4GlaxoSmithKline, Collegeville, PA, USA Abstract
Keywords
Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by chronically low peripheral blood platelet counts. Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that increases platelet production. This report examines peri-procedural platelet counts and bleeding complications among chronic ITP patients requiring dental procedures while participating in clinical studies with eltrombopag. A total of 494 patients participated in five clinical studies of eltrombopag in chronic ITP. Information about dental procedures was collected prospectively in four studies and retrospectively in one study. Twenty-four patients (22 eltrombopag, 2 placebo) underwent 32 dental procedures (dental cleaning, tooth repair, artificial crown, dental prosthesis, tooth extraction, dental or wisdom teeth extraction, dental root extraction, and endodontic procedures, among others) during study treatment or up to 10 days later. Supplemental ITP therapy (e.g., corticosteroids, platelet transfusions) was given before the dental procedure to increase platelet counts in three eltrombopag-treated patients and both placebo-treated patients. The mean pre-procedure platelet count standard deviation for all procedures in the overall population of patients, eltrombopag group, and placebo group prior to undergoing dental procedures was 96 000 81 069/ml,103 517 81 522/ml, and 23 333 9291/ml, respectively. Two patients in each group had platelet counts below 30 000/ml before the procedure. No patient who had a dental procedure experienced a bleeding adverse event. Among patients with chronic ITP who required a dental procedure during clinical studies of eltrombopag, supplemental ITP treatment was required for both patients who received placebo but was not required for most patients who received eltrombopag. No bleeding complications were reported. These data imply that patients with chronic ITP who receive eltrombopag and experience increases in platelet counts fulfill current pre-procedural platelet count recommendations to undergo invasive dental procedures, and may have a lower risk of bleeding complications and a reduced need for supplemental ITP treatment.
Dental, hemostasis, oral hemorrhage, surgical procedures
Introduction Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by persistently low platelet counts in the absence of other causes of thrombocytopenia [1]. Chronic ITP involves platelet destruction induced by anti-platelet antibodies and impaired platelet production, resulting in chronically low platelet counts [2]. The goal of treatment in chronic ITP is to prevent bleeding by raising platelet counts to a hemostatic level between 30 000/ml and 50 000/ml [1]. Patients with chronic ITP may require dental procedures that typically would be associated with a low risk of bleeding in patients with a normal platelet count, but entail a higher risk of
*AB was an employee of GlaxoSmithKline while this research was conducted. Correspondence: Michael D. Tarantino, MD, Medical Director and President, The Bleeding and Clotting Disorders Institute, Professor of Pediatrics, University of Illinois College of Medicine-Peoria, 6811 North Knoxville Avenue, Suite A, Peoria, IL 61614, USA. Tel: +309-692-5337. Fax: +309-693-3913. E-mail: [email protected]
History Received 1 August 2013 Revised 30 October 2013 Accepted 23 November 2013 Published online 16 January 2014
bleeding in patients with chronic ITP due to their low platelet counts. Clinical guidelines for the management of chronic ITP recommend ensuring that platelet counts prior to dental procedures are 420 000/ml, or even 30 000/ml or 50 000/ml, depending on the complexity of the procedure [1]. Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that binds to the transmembrane domain of the thrombopoietin receptor, without competing with endogenous thrombopoietin [3]. Eltrombopag treatment leads to increased proliferation and differentiation of bone marrow progenitor cells into megakaryocytes and increased platelet production [3]. In clinical studies, eltrombopag was shown to increase platelet counts among healthy subjects [4] and patients with chronic ITP, hepatitis C-induced thrombocytopenia, or chronic liver diseaseinduced thrombocytopenia [5]. The efficacy and safety of eltrombopag to increase platelet counts in patients with chronic ITP has been demonstrated in three randomized, placebo-controlled studies of patients with a baseline platelet count of less than 30 000/ml: Study 773A was a 6-week, phase 2, dose-finding study [6]; Study 773B was a 6-week, phase 3 study [7]; and RAISE was a 6-month, phase
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3 study [8]. Other clinical studies of eltrombopag in patients with chronic ITP include the single-arm, open-label REPEAT study of repeated on/off dosing cycles [9] and EXTEND, an ongoing openlabel extension study that enrolled patients after they participated in one of these four studies [10]. The objective of this analysis was to evaluate peri-procedural platelet counts and bleeding complications in patients who underwent dental procedures during their participation in any of these five clinical studies [6–10]. Data from the five studies were pooled to maximize the number of dental procedures available for analysis.
Platelets Downloaded from informahealthcare.com by University of Ulster at Jordanstown on 04/03/15 For personal use only.
Methods Data were analyzed for the 494 patients with previously treated chronic ITP who participated in the five clinical studies: Study 773A (n ¼ 117) [6], Study 773B (n ¼ 114) [7], RAISE (n ¼ 197) [8], REPEAT (n ¼ 66) [9], and EXTEND (n ¼ 299 as of the data cutoff date of December 2008 for this analysis) [10]. Information about dental procedures was collected retrospectively in Study 773A and prospectively in the other studies. Investigators were asked to record information about any surgical or medical procedure. The level of detail collected on many procedures, including dental ones, was not standardized. Data collection included basic demographic information, platelet counts before and after procedures, type of procedure, need for supplemental treatment to increase platelet counts (within 1 week before and 1 week after the intervention), use of blood products, and reported bleeding complications. Supplemental ITP treatments were defined as receiving a new ITP medication, an increase in dose from baseline of a concomitant ITP medication, a platelet or other blood product transfusion, or a splenectomy. The ethics committee at each institution approved the protocol and amendments, and all patients provided written informed consent before enrolment. Each study was undertaken in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.
Results A total of 24 of 676 patients enrolled in the five trials underwent a dental procedure and were included in this study. No patient underwent a dental procedure during Study 773A [6], and only 1 of 114 patients in Study 773B reported having a dental procedure. The 24 included patients received a total of 32 procedures categorized as dental cleaning, tooth repair, dental caries, artificial crown, dental treatment, dental prosthesis, tooth extraction, dental extraction, wisdom teeth removal, dental root extraction, dental operation, or endodontic procedure (Table I). Prior to dental treatment, the overall mean SD platelet count calculated from all dental procedures was 96 000 81 069/ml with a median (range) of 80 000/ml (9000/ml–412 000/ml), the mean SD platelet count for all procedures in the placebo group was 23 333 9292/ml with a median (range) of 19 000/ml (17 000/ml–34 000/ml), and the mean SD platelet count for all procedures in the eltrombopag group was 103 517 81 522/ml with a median (range) of 81 000/ml (9000/ml–412 000/ml). Two patients were on placebo; both received supplemental ITP treatment perioperatively. One patient received platelet transfusion and hydrocortisone following a platelet count of 17 000/ml prior to a tooth extraction. After the procedure his platelet count was 7000/ml. The second patient on placebo had a platelet count of 19 000/ml prior to a ‘‘dental operation’’ (no additional details provided by the investigator). Preceding a second dental operation, this patient received IVIg which raised her platelet count from 20 000/ml to 34 000/ml.
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All of the remaining patients undergoing dental procedures were in the eltrombopag group. One of these patients did not respond to eltrombopag and was placed on danazol prior to his procedure. The platelet count prior to the procedure was 9000/ml and he received a peri-procedural platelet transfusion. Following the procedure, his platelet count was 12 000/ml. The remaining patients received a total of 28 procedures of varying complexity, and had platelet counts that ranged from 19 000/ml to 270 000/ml. Only two of these patients received supplemental ITP treatment (platelet counts of 39 000/ml, and 64 000/ml, respectively). None of the patients who underwent dental procedures experienced a bleeding complication associated with the procedure.
Discussion Postoperative bleeding occurs in approximately 10% of patients with compromised hemostasis (e.g., von Willebrand disease, hemophilia A) who undergo oral surgery [11]. To increase preprocedural platelet counts in patients with chronic ITP, different treatments are available, including IVIg, corticosteroids, and/or platelet transfusion [1]. There have been few case reports of the peri-procedural care of patients with ITP who undergo dental procedures [12–14]. One of these reports described dental procedures in two young girls diagnosed with ITP: a 5-year-old girl who had dental treatment postponed for 2 months due to a low platelet count and a 7-year-old girl who had a platelet count of 54 000/ml at presentation and no complications despite extensive dental treatment [12]. In another report, a 20-year-old woman with ITP and a pre-operative platelet count of 60 000/ml was hospitalized pre-operatively and received tranexamic acid infusions before molar extraction; no bleeding complications were reported [13]. In a third report, a 13-year-old boy with ITP presented to the emergency room after a fall that dislocated two teeth [14]. Because his platelet count was 15 000/ml at admission, surgery was delayed 2 days until the platelet count rose to 70 000/ml. Partial healing had occurred and general anesthesia and some force were required to reposition the teeth. The teeth eventually lost vitality and he required endodontic treatment. In these case reports, dental procedures in ITP patients were delayed until platelet counts were 450 000/ml [12] and/or the patient was hospitalized peri-operatively [13, 14]. These approaches may reduce the risk of bleeding complications, but may also lead to delays before necessary dental care can be provided [12, 14]. Delaying dental procedures because of low platelet counts may lead to more complicated procedures, potentially increasing healthcare costs, and jeopardizing the outcome of the procedure. Several other reports have described patients who presented to dentists to manage oral complications of undiagnosed ITP [15–21]. However, the primary purpose of those reports was to aid dentists in the recognition and diagnosis of ITP based on oral symptomatology. To the best of our knowledge, this is the first report of dental procedures and bleeding complications among a large population of patients with ITP. Guidelines for the treatment of ITP have stipulated that simple dental prophylaxis (e.g., cleaning) can be undertaken at platelet counts of 20 000/ml to 30 000/ml; simple dental extractions should be done only if platelet counts are 430 000/ml; and more complex procedures require platelet counts 450 000/ml [1]. Given the frequency of dental procedures in patients with ITP, it is important for dentists to be familiar with these guidelines. The present report suggests that dentists generally follow these parameters in the management of patients with ITP, and none of the patients who had a dental procedure during the
Dental procedures in patients with cITP
DOI: 10.3109/09537104.2013.870333
95
Table I. Dental procedures among patients with ITP in pivotal eltrombopag studies. Platelet count (/ml) Dental procedure Treatment
Procedure
Before
After
Day
Day
Count
Day
Count
88
85
17 000
92
7000
69 106
50 106
19 000 34 000
71 113
22 000 31 000
29 601 13 99 102
29 580 8 96 78
34 000 65 000 81 000 93 000 270 000
36 609 15 102 106
43 365 603
43 353 580
31 000 58 000 65 000
113
109
105 140
Supplemental ITP treatment Day
Treatment
Sex/Age
Study
Placebo Tooth extraction 85, 87, 88 87–88
Transfusion Hydrocortisone
M/67
RAISE
None IVIgc
F/77* F/77*
RAISE RAISE
56 000 38 000 490 000 84 000 313 000
None None None None None
M/53* F/82* F/61 F/33* F/45
EXTEND EXTEND REPEAT EXTEND EXTEND
50 385 609
26 000 54 000 38 000
None None None
F/43 M/42* F/82*
EXTEND EXTEND EXTEND
167 000
116
171 000
None
F/33*
EXTEND
88 135
93 000 412 000
114 148
109 000 54 000
None None
F/68* F/68*
EXTEND EXTEND
83
79
131 000
85
166 000
None
M/30*
EXTEND
106
101
137 000
111
219 000
None
F/42
RAISE
156
156
9000
184
12 000
M/43
RAISE
101 72 260 227 51a 431 272 29
87 72 260 225 50 430 253 29
19 000 39 000 62 000 64 000 80 000 112 000 132 000 150 000
NA 105 267 232 57 435 280 37
NA 30 000 44 000 73 000 82 000 120 000 118 000 128 000
Danazol Transfusion None IVIg None Methylprednisoloned None None None None
F/52 F/29 M/53* F/57 F/68e F/60 M/63 F/59
EXTEND RAISE EXTEND EXTEND 773B EXTEND EXTEND REPEAT
128
105
53 000
135
60 000
None
M/53*
EXTEND
341
337
92 000
365
63 000
None
F/52
EXTEND
503
503
80 000
531
80 000
None
M/53*
EXTEND
490
484
149 000
508
79 000
None
M/71
EXTEND
379 48 134
353 43 134
58 000 82 000 184 000
385 71 140
54 000 140 000 100 000
None None None
M/42* F/31 M/30*
EXTEND RAISE EXTEND
Dental operation 99, 103
Eltrombopag
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Dental cleaning
Tooth repair
Dental caries Artificial crown Dental treatment (drainage) Dental prosthesis replacement Tooth extraction 67b 156 72 221–224
Dental extraction Wisdom teeth removal Dental root extraction Dental operation Endodontic procedure
NA, not available. Eltrombopag dose was 50 mg/day. b The last platelet count prior to IVIg treatment was 20 000/ml on day 99. c Danazol treatment was ongoing at the time of the analysis; the last platelet count prior to danazol treatment was 10 000/ml on day 42. d The last platelet count prior to methylprednisolone treatment was 48 000/ml on day 220. e Patient stopped study treatment on day 43, with a platelet count of 129 000/ml. *Patients received more than one type of procedure and appear in multiple categories. a
eltrombopag studies experienced a bleeding complication associated with the procedure. The fact that only two patients in the placebo arms of the randomized studies underwent a dental procedure limits the comparison between the eltrombopag and placebo arms. This may reflect the fact that patients taking placebo had lower median platelet counts and may not have been able to schedule procedures potentially associated with a risk of bleeding. However, no
information is available to clarify how many patients required procedures that could not be undertaken because of thrombocytopenia. No dental procedures were reported for the 117 patients in Study 773A. It is possible that this finding was the result of the retrospective analysis of dental procedures in that study. However, in Study 773B, dental procedures were recorded prospectively, and only 1 of 114 patients in that study had a dental procedure.
96
M. D. Tarantino et al.
A likely explanation for the lower numbers of procedures in these two studies is that each was only 6 weeks in duration, as compared with the longer duration of the RAISE, REPEAT, and EXTEND studies, in which more patients underwent dental procedures. This study has several limitations. While data on hemostatic challenges were prospectively collected, the details of dental procedures recorded were not standardized. Therefore, some details of procedures are missing. The study also has the inherent limitations of all retrospective studies, limiting the interpretation of the results. A prospective controlled trial would be necessary to address questions about what a safe level of platelets would be for ITP patients undergoing dental work.
Platelets Downloaded from informahealthcare.com by University of Ulster at Jordanstown on 04/03/15 For personal use only.
Conclusion Although the studies described herein were not designed to address bleeding complications with dental procedures, these data suggest that patients with chronic ITP who are being treated with eltrombopag and experience increases in platelet counts fulfill current pre-procedural platelet count recommendations to undergo dental procedures. These patients may have a lower risk of bleeding complications, a reduced need for other supplemental ITP treatment, and an increased likelihood of successful hemostatic outcomes. Prospective studies evaluating the utility of increasing pre-procedural platelet counts and the potential use of ancillary therapies would be useful to establish treatment algorithms.
Acknowledgements The authors would like to thank Kimberly Marino of GlaxoSmithKline who provided critical review. Portions of this work were presented at the American Society of Hematology 52nd Annual Meeting and Exposition, Orlando, FL, USA, December 4–7, 2010.
Declaration of interest This work was supported by GlaxoSmithKline (GSK), Collegeville, PA, USA. Michael D. Tarantino provided consultancy for Amgen, is a Study Investigator with GSK in the EXTEND REPEAT Studies; his institution received royalties. Patrick F. Fogarty received research funding from GSK and provided consultancy for Amgen. Palvi Shah is an employee of and holds equity ownership in GSK. Andres Brainsky is a former employee of and held equity ownership in GSK. Editorial support was provided by Jonathan Latham of PharmaScribe, LLC. Editorial support for this Short Communication was provided by AOI Communications, L.P.
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