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Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy
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Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2017.05.013, available online at http://www.sciencedirect.com
Clinical Paper Oral Surgery
Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy F. Buhatem Medeiros, N. Pepe Medeiros de Rezende, J. Bertoldi Franco, A. C. Porrio de Andrade, L. Timerman, M. Gallottini, I. L. Itagiba Neves, K. L. Ortega: Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy. Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx. ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. In spite of the possibility of triggering thromboembolic events, many professionals indicate the suspension of antiplatelet agents before dental surgical procedures. The aim of this study was to perform a quantitative assessment of intraoperative bleeding in patients on dual antiplatelet therapy. A case–control study was conducted in patients on dual antiplatelet therapy (APT group) and in patients who did not use these medications (control group). The following examinations were requested: complete blood cell count, blood coagulation tests, and platelet aggregation. The quantity of bleeding was measured intraoperatively by collection of aspirated blood. The mean volume of blood lost during the surgical procedure was 6.10 ml in the control group and 16.07 ml in the APT group (P = 0.002). The mean volume of blood lost per minute was 0.60 ml/min in the control group and 1 ml/min in the APT group (P = 0.001), with local haemostatic methods being sufficient to control the bleeding. There was no postoperative bleeding complication in any case. Patients on dual antiplatelet therapy presented a larger volume of bleeding, but this could be controlled by means of local haemostatic measures. Therefore, there is no need to stop either of the two dual antiplatelet therapy medications before dental extractions.
Cardiovascular diseases are one of the main causes of morbidity and mortality worldwide1. Included in this group are patients with coronary artery disease (CAD), a pathology characterized by atherosclerotic plaque accumulation that
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leads to stenosis of the coronary arteries and thus represents an important risk factor for atherothrombotic accidents2. Atherothrombotic events in patients with CAD are prevented with platelet aggregation inhibitors3. The use of these may lead
F. Buhatem Medeiros1, N. Pepe Medeiros de Rezende1, J. Bertoldi Franco2, A. C. Porrio de Andrade3, L. Timerman4, M. Gallottini1, I. L. Itagiba Neves5, K. L. Ortega1 1 School of Dentistry, Department of Oral Pathology, University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 2Division of Dentistry, Hospital das Clinicas, Medical School, University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 3Hospital Auxiliar do Cotoxo´, Hospital das Clinicas, Medical School, University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 4Department of Dentistry, Dante Pazzanese Institute of Cardiology, Sa˜o Paulo, Brazil; 5Department of Dentistry, Instituto do Corac¸a˜o (InCor), Medical School, University of Sa˜o Paulo, Sa˜o Paulo, Brazil
Key words: platelet aggregation inhibitors; coronary artery disease; blood coagulation; haemosta tic techniques; intraopera tive complications; dental care for chronically ill; tooth extraction; haemorrhage. Accepted for publication 22 May 2017
to increased bleeding in surgical procedures4. The platelet aggregation inhibitor acetylsalicylic acid (ASA) is the antiplatelet therapy most often used in patients with CAD because it is easily accessible, low
ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
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cost, and is effective against platelet aggregation by irreversibly blocking the cyclooxygenase 1 enzyme (COX-1) and thromboxane A25. Currently, therapy with ASA is usually combined with other medications, such as thienopyridine derivatives (e.g. clopidogrel, ticagrelor, and prasugrel), which are P2Y12 antagonists of the adenosine diphosphate receptors and act by blocking the activation of the glycoprotein GP II/III receptors on the surface of platelets, diminishing agglutination of fibrinogen during platelet aggregation6. The fear of bleeding complications, even with the use of single ASA therapy, led to various professionals recommending the interruption of such medications7– 11 . However, over the years and with the publication of new scientific research studies, the recommendation for interrupting the use of ASA has been re-assessed, and this is no longer indicated4,12–17. The concomitant use of ASA and clopidogrel causes irreversible blockage of the two platelet aggregation pathways, potentiating the risk of bleeding during surgical procedures18–21. Therefore, some professionals have again suggested interrupting the use of one of the two platelet aggregation inhibitors with the purpose of preventing bleeding complications21. However, interrupting or changing antiplatelet therapy is known to predispose the patient to thrombotic and thromboembolic events that may lead to cardiovascular events with a high mortality rate22. It is indicated in the literature that despite the higher risk of postoperative bleeding in patients on dual antiplatelet therapy, there is no need to interrupt either of the two medications, because bleeding may be contained with local haemostatic measures19,23–26. However, these studies presented limitations characterized by a retrospective design, opinions based on literature reviews, absence of direct evaluation of intraoperative bleeding, and lack of a control group. Only three published prospective studies were designed specifically to investigate the association between bleeding and dual antiplatelet therapy. However, they used only the duration of alveolar bleeding to define the immediate bleeding event18,27,28. Furthermore, Bajkin et al.28 and Lillis et al.18 also used the criteria proposed by Lockhart et al.29 for a late bleeding event, which is characterized by over 12 h of bleeding, need for the patient to return, presence of large haematomas or bruises, and need for a blood transfusion29. It is important to highlight that the duration of bleeding may not be directly
related to the quantity of blood lost and the risk of a real bleeding complication. Therefore, the aim of this study was to quantitatively evaluate intraoperative bleeding during dental extractions in patients on dual antiplatelet therapy. Materials and methods
This study was approved by the research ethics committees of the Dental School and the Medical School of the University of Sa˜o Paulo. All participants read, understood, accepted, and signed a written informed consent agreement. This study was performed in accordance with STROBE guidelines for observational investigations. Study design
A case–control study was conducted with CAD patients on dual antiplatelet therapy with ASA and clopidogrel (APT group) and patients with cardiovascular diseases taking no antiplatelet medication (control group), who required the extraction of up to three teeth. Patients who were alcoholics, or on therapy with warfarin, heparin, anti-inflammatory drugs (steroid or non-steroid), or oral thrombin and factor Xa inhibitors were excluded from the study. To calculate the sample size, the statistical simulations proposed by Armitage and Berry were used30. As there was no information from previous studies on the behavioural distribution of bleeding (mean and standard deviation) in the groups of patients on dual antiplatelet therapy (ASA + clopidogrel), it was assumed that the standard deviation in this group would be the same as that in the control group. Considering a two-tailed hypothesis test, 80% power, and a level of significance set at 0.05, it was determined that a sample size of 26 individuals was required for each group. To take account of possible losses during the research, two to four individuals were added to each group (8% to 15% of the sample size), resulting in a total estimated sample size of 52 (56 or 60) individuals. In total, 348 patients with cardiovascular disease were evaluated. After applying the exclusion criteria, the number of subjects was reduced to 38 in the APT group and 35 in the control group. Methods
At the first visit, all patients underwent a clinical examination and the following laboratory tests were requested: complete blood cell count, prothrombin time
(results were expressed in seconds (PTs), as a ratio (PTr), and as the international normalized ratio (PT/INR)), activated partial thromboplastin time (aPTT), and platelet aggregation. The PT and aPTT were used as routine preoperative coagulation screening tests31. For the APT group, platelet aggregation was evaluated by means of a point-of-care test, VerifyNow (Accumetrics, San Diego, CA, USA). The VerifyNow test cartridges contain a lyophilized preparation of human fibrinogen-coated particles, platelet agonists (adenosine diphosphate (ADP) and arachidonic acid), buffer, and preservative. The results are expressed in P2Y12 reaction units (PRU) for the response to clopidogrel, and in aspirin reaction units (ARU) for the response to ASA. For the control group, platelet aggregation was evaluated by turbidimetric assay. Platelet aggregation was measured in platelet-rich plasma by addition of ADP, arachidonic acid, and adrenaline agonists. Platelet-rich plasma was obtained by centrifugation of blood in a tube containing 3.8% sodium citrate at 1500 rpm for 6 min. The effects of stimulating agents were observed by monitoring the changes in platelet-rich plasma optical density by means of an aggregometer and an AggRAM platelet photometer (Helena Laboratories, Gateshead, Tyne and Wear, UK). Different tests were used for platelet aggregation because the APT group subjects were on antiplatelet drugs and ADPinduced platelet aggregation frequently fails to detect patients with an impaired response to clopidogrel compared to a P2Y12-specific assay32. All of the laboratory examinations were conducted immediately before the surgical procedures. Anaesthesia was performed with 2% lidocaine without a vasoconstrictor (a maximum of four cartridges of 1.8 ml each), with the lower teeth being submitted to the technique of regional block complemented with local infiltration and the upper teeth with local infiltration only. The dental extractions were performed following the procedures recommended by Peterson et al.33. During the procedure, the dental alveolus was irrigated with saline solution and a portable vacuum suction pump was used to aspirate the fluids (blood and saline solution). Bleeding was measured by subtracting the quantity of saline solution from the final quantity of aspirated fluid. The suction hand-piece of the dental equipment was used only to aspirate saliva, which was discarded and not considered34. Before suturing with 3–0 nylon thread, the dental alveolus was irrigated with
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
YIJOM-3701; No of Pages 7
Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy abundant saline solution (0.9% sodium chloride), and a paste made of a macerated tablet of tranexamic acid (250 mg) mixed with saline solution was inserted into the dental alveolus. Additional local haemostatic measures were used in the case of persistent bleeding (paste of tranexamic acid placed onto the suture). The surgical procedure was considered concluded once it was observed that there was no bleeding at all. The surgical time was measured in minutes. Standard postoperative recommendations were given to the patients after the surgical procedure. All of them were provided with analgesics (dipyrone or acetaminophen for a maximum of 3 days). The criteria of Lockhart et al. were used to define the postoperative bleeding complications29. All patients were re-assessed after 1 week, but they were instructed to return immediately in the case of bleeding.
Statistical analysis
The results were described using descriptive statistics of position and scale (mean and standard deviation, respectively) for quantitative variables and with absolute and relative frequencies for categorical variables. Comparisons between the mean values of continuous variables were performed using the Student t-test. When the supposition of normality was met or the number of cases in the subgroup analysis was very small, the Mann–Whitney test was used. Comparisons between categorical variables and the groups were evaluated using the x2 test. As the main outcome (bleeding), a generalized linear model was adjusted with gamma distribution and log link. Analyses were performed at a significance level of 5% and the results were obtained with the aid of the statistical software R 3.1.0 (R Foundation for Statistical Computing); the ggplot2 package was used to construct the graphs.
Results
Eighty-eight dental extractions were performed in 73 patients with cardiovascular disease, of whom 26 (35.6%) were female and 47 (64.4%) were male. The mean age of the subjects was 57 years. The APT group subjects underwent 52 dental extractions (27 maxillary teeth and 25 mandibular teeth) and the control group subjects underwent 36 dental extractions (14 maxillary teeth and 22 mandibular teeth). There was no statistically significant difference between the groups regarding sex, clinical condition of the teeth, or anatomical location of the teeth extracted; however the subjects differed significantly in age (Table 1). Tooth sectioning and osteotomy were necessary in four cases in the APT group and in one case in the control group, with no statistically significant difference between the groups (P > 0.05). With regard to the complete blood cell count, there was no difference between the groups in the results, with the exception of RDW (red cell distribution width), which was found to be increased in 62.9% of the control group patients compared to 18.4% of the APT group patients (P < 0.001). In the blood coagulation tests, statistically significant differences were observed between the APT and control groups for PTr, PTs, PT/INR, and aPTT (all P < 0.001) (Table 2). As six patients in the control group presented altered values of PT and aPTT after the dental surgery procedures, they were referred to a haematologist, who concluded that the patients had hepatic disorders. With regard to the main outcome, the volume of blood lost during the surgical procedure was greater in the APT group (16.07 ml) than in the control group (6.10 ml) (P = 0.002). The duration of the surgical procedure was longer in the APT group (mean 15 min, range 5–50 min) than in the control group (mean
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11 min, range 5–30 min) (P = 0.036). The mean volume of blood lost per minute was calculated as 0.6 ml/min in the control group and 1.0 ml/min in the APT group (P = 0.001) (Table 3 and Fig. 1). Of note, the maximum bleeding in the APT group was 2 ml/min and the maximum surgical time was 50 min. Although the APT group presented a significantly larger quantity of blood loss and a longer surgical procedure, there was no case of intraoperative or postoperative bleeding complication. Local bleeding was controlled with suturing associated with the intra-alveolar application of macerated tranexamic acid. Macerated tranexamic acid was also placed on the suture (extra-alveolar application) in five patients in the APT group. The platelet aggregation test in the APT group showed that 27 patients (71.1%) had values of 350–549 ARU, compatible with hypoaggregability, while 11 patients (28.9%) had values between 550 ARU to 700 ARU, considered resistance to therapy with ASA. For the P2Y12 receptor, 26 patients (68.4%) presented hypoaggregability (<230 PRU), while 12 patients (31.6%) were found not to respond to the medication (PRU >230). Five patients (13.2%) presented therapeutic failure for the two medications and 18 (47.4%) for one of the two medications. No statistically significant correlation was found between the platelet aggregation test results (using VerifyNow) and oral bleeding (P = 0.568 for ASA and P = 0.633 for P2Y12). In the control group, only the changes in hypoaggregability shown by turbidimetry for adrenaline were clinically reflected in the quantity of bleeding that occurred during the surgical procedure (P = 0.018). This did not occur for arachidonic acid (P = 0.750) or ADP (P = 0.114). As it was observed that some patients in the control group presented platelet aggregability characteristics similar to
Table 1. Homogeneity of the study groups regarding sex, clinical condition of the teeth, anatomical location of the teeth, and mean age. Sex Male Female Clinical condition of the teeth Caries Periodontal disease (PD) Residual root (RR) RR + PD Anatomical location of the teeth Maxillary Mandibular Age (years), mean SD
APT group (n = 38)
Control group (n = 35)
Total (n = 73)
27 (71.1%) 11 (28.9%)
20 (57.1%) 15 (42.9%)
47 (64.4%) 26 (35.6%)
8 (21.1%) 5 (13.2%) 24 (63.2%) 1 (2.6%)
10 (28.6%) 10 (28.6%) 15 (42.8%) 0 (0%)
18 (24.7%) 15 (20.5%) 39 (53.4%) 1 (1.4%)
27 25 61.9 10.9
14 22 51.2 17.7
41 47 57 15
P-value 0.32 0.183
0.073 0.002
APT, antiplatelet therapy; SD, standard deviation.
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
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Table 2. Laboratory coagulation values for the APT group and control group, and the results of platelet aggregation tests. APT group (n = 38)
PTs PT/INR PTr aPTT (s) PLT (cells/mm3)
Control group (n = 35)
Min
Max
Mean
SD
Min
Max
Mean
SD
13.00 0.90 0.92 22.80 149,000
18.50 1.30 1.27 41.20 406,000
15.00 1.10 1.05 28.80 244,600
1.30 0.10 8.70 3.40 59.40
13.90 1.00 0.98 24.40 64,000
21.20 1.60 1.50 42.60 644,000
16.50 1.20 1.00 32.00 270,700
1.90 0.10 37.96 4.40 123.70
Min
Max
Mean
SD
Hypo
Normo
Hyper
98 224
342 662
222.28 478.73
67.67 110.11
26 27
12 11
0 0
– – –
– – –
– – –
– – –
20 9 13
15 26 22
0 0 0
Platelet aggregation VerifyNowa P2Y12 (PRU) ASA (ARU) Turbidimetryb Arachidonic acid ADP Adrenaline
APT, antiplatelet therapy; PTs, prothrombin time in seconds (reference value 14.1 s); PT/INR, international normalized ratio (reference range 1–1.2); PTr, prothrombin time ratio (reference range 1–1.20); aPTT, activated partial thromboplastin time (reference value 30 s); PLT, platelets (reference range 140,000 to 450,000 cells/mm3); PRU, P2Y12 reaction units; ARU, aspirin reaction units; Min, minimum; Max, maximum. a Used for the APT group patients: tests for ASA (acetylsalicylic acid) and P2Y12 receptor (clopidogrel); P2Y12 <230 PRU and ASA 350–549 ARU considered to indicate hypoaggregability. b Used for the control group patients: the number of patients who presented with hypoaggregability (hypo), normal aggregability (normo), and hyperaggregability (hyper), according to the reference values, for each of adenosine diphosphate (ADP), arachidonic acid, and adrenaline agonists. Table 3. Comparison of the mean volume of blood lost during the surgical procedure between the APT group and the control group.
Mean volume of bleeding (ml) Mean surgical time (min) Mean volume of blood lost per minute (ml/min)
APT group (n = 38)
Control group (n = 35)
Total (n = 73)
P-value
16.07 15 1.00
6.10 11 0.60
11.3 13 0.80
0.002 0.036 0.001
APT, antiplatelet therapy.
those of the APT group patients, and considering that this characteristic of platelet aggregability influenced the final outcome of bleeding, a generalized linear model was constructed with gamma distribution and log link to compare the mean values of bleeding (ml/min) in the APT group patients, control group patients with
hypoaggregability (control-H), and control group patients with normal aggregability (control-N) (Table 4). The model showed that the mean oral bleeding in the control-H group (0.81 ml/min) was similar to that in the APT group (0.97 ml/min), with no statistically significant difference between these two groups (P = 0.32).
However, as the model was adjusted with the log link, it was estimated that the patients in the control-N group reduced the logarithm of bleeding by 0.67 ml/min; hence, the mean estimate of bleeding in the control-N group was e 0.7 = 0.49 ml/ min compared to 0.97 ml/min in the APT group (P < 0.001). Discussion
Fig. 1. Box plot of the volume of blood lost per minute in the two study groups: antiplatelet therapy group and control group.
Dental interventions resulting in bleeding in patients on medications that change haemostasis have been the subject of multiple studies and publications, reflecting the fear dental practitioners feel in managing this group of patients35–37. Different clinical research studies have shown that the use of ASA does not constitute a risk for uncontrollable bleeding during invasive dental procedures12,17,34. However, single therapy has since been replaced by dual therapy (ASA + clopidogrel), elevating the risk of bleeding. Once again it appears necessary to ensure that although there may be a risk of bleeding, it is unlikely to be uncontrollable. This study quantified bleeding during dental extractions in patients on dual anti-
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
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Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy
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Table 4. Comparison of the mean values of bleeding (ml/min) between the APT group and the control group, divided into those showing hypoaggregability (control-H) and normal aggregability (control-N). 95% CI for mean bleeding b
Group
Parameter
Estimate
SE
P-value
Estimated mean bleeding (e )
Mandibular
Maxillary
APT group Control-H Control-N
b0 b1 b2 f
0.03 0.18 0.67 0.31
0.09 0.18 0.15
0.74 0.32 <0.001
0.97 0.81 0.49
0.78 0.56 0.38
1.20 1.17 0.66
APT, antiplatelet therapy; SE, standard error; CI, confidence interval.
platelet therapy. A control group consisting of patients with similar clinical conditions (cardiovascular changes), but not on antiplatelet aggregation therapy, was established to make it possible to evaluate whether patients on dual therapy would present bleeding events, or a quantitatively higher volume of bleeding. The two groups were shown to be similar regarding the sex distribution, clinical condition of the teeth, and anatomical location of the teeth; however, they differed for the variable age. The higher mean age in the APT group can be explained by the selection of the sample of patients. Coronary pathologies requiring percutaneous coronary interventions with the placement of stents and use of dual antiplatelet therapy occur more frequently in the older population. In the blood coagulation tests, statistically significant differences were observed between the APT group and control group for PT (PTs, PTr, and PT/ INR) and aPTT; however, the mean values in each group were within the normal therapeutic range. The results for platelet aggregation showed that APT group patients, on average, were within the therapeutic range for both medications, i.e. they presented hypoaggregability. Interestingly, it was found that 57.1% of the control group patients presented hypoaggregability for arachidonic acid, 25.7% for ADP, and 37.1% for adrenaline, although they were not on any antiplatelet aggregation medication. This may be explained by the presence of other alterations capable of acting on platelet aggregation, such as liver and kidney alterations, idiopathic hypoaggregation, congenital platelet syndromes, and adverse reactions to medications (e.g. beta-blockers, statins, tricyclic antidepressants, antiemetic agents, and proton pump inhibitors)38–40. Other laboratory evidence was that some patients in the APT group were found to be unresponsive to antiplatelet therapy: 28.9% for ASA and 31.6% for P2Y12. This variability in platelet aggre-
gation may be related to several clinical factors, such as the patient’s body mass index, under-dosing of the medication, poor adherence to treatment, low absorption, and drug–drug interactions, or even to genetic factors (e.g. polymorphisms in the CYP3A4, CYP2C19, P2Y12, or COX1 receptors, or in other genes involved in the biosynthesis of thromboxane, or also individual variations in the activity of cytochrome P450)41–43. The APT group patients had more intense intraoperative bleeding than the control group patients, and this difference was statistically significant. Although the intraoperative bleeding was much more intense in the APT group, the quantity of blood lost by the patients did not exceed 100 ml, which could hardly be characterized as a bleeding event that would justify the interruption of antiplatelet medications. The use of simple local haemostatic measures was sufficient to prevent intraoperative and postoperative bleeding complications. None of the patients involved in the study presented a postoperative bleeding complication according to the criteria proposed by Lockhart et al. in 201329. Local haemostatic measures were used in this study, consisting of the intra-alveolar application of tranexamic acid associated with the use of non-resorbable sutures. This is a simple, low cost technique that is easily available and it provided good results. Even in the five cases in which there was a larger quantity of bleeding, the use of the same medication in the extra-alveolar region (on the suture) associated with a compressive gauze dressing was sufficient for local haemostasis control. When the quantity of bleeding was correlated with the duration of the surgical procedure, irrespective of the group studied, the authors found that bleeding was directly proportional to the operative time and this was statistically significant. However, the operative time was longer in the APT group, by virtue of the hypoaggregability caused by the antiplatelet therapy.
The results of this study confirm the initial hypothesis that there is no need to interrupt the use of either of the two medications used as dual antiplatelet therapy before dental extractions, provided that the dental surgeon is qualified to control intraoperative bleeding of greater intensity and to resolve a possible postoperative bleeding complication. A thromboembolic event is a more serious health threat than the volume of blood lost during dental extractions involving up to three teeth. Funding
This work was supported by the Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo (FAPESP) – grant 2012/16523-0. Competing interests
None. Ethical approval
This project was approved by the Research Ethics Committee of the Dental School of the University of Sa˜o Paulo (Protocol No. 47816) and by the Ethics Commission for the Analysis of Research Projects of the ‘‘Hospital das Clı´nicas’’, Medical School, University of Sa˜o Paulo (HCFMUSP) (Protocol No. 35879). Patient consent
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16. Krishnan B, Shenoy NA, Alexander M. Exodontia and antiplatelet therapy. J Oral Maxillofac Surg 2008;66:2063–6. 17. Morimoto Y, Niwa H, Minematsu K. Hemostatic management of tooth extractions in patients on oral antithrombotic therapy. J Oral Maxillofac Surg 2008;66:51–7. 18. Lillis T, Ziakas A, Koskinas K, Tsirlis A, Giannoglou G. Safety of dental extractions during uninterrupted single or dual antiplatelet treatment. Am J Cardiol 2011;108:964–7. 19. Napen˜as JJ, Oost FC, DeGroot A, Loven B, Hong CH, Brennan MT, Lockhart PB, van Diermen DE. Review of postoperative bleeding risk in dental patients on antiplatelet therapy. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:491–9. 20. Mingarro-de-Leo´n A, Chaveli-Lo´pez B, Gavalda´-Estece C. Dental management of patients receiving anticoagulant and/or antiplatelet treatment. J Clin Exp Dent 2014;6: e155–61. 21. Harder S, Klinkhardt U, Alvarez JM. Avoidance of bleeding during surgery in patients receiving anticoagulant and/or antiplatelet therapy: pharmacokinetic and pharmacodynamic considerations. Clin Pharmacokinet 2004;43:963–81. 22. Wahl MJ. Dental surgery and antiplatelet agents: bleed or die. Am J Med 2014;127:260–7. 23. Napen˜as JJ, Hong CH, Brennan MT, Furney SL, Fox PC, Lockhart PB. The frequency of bleeding complications after invasive dental treatment in patients receiving single and dual antiplatelet therapy. J Am Dent Assoc 2009;140:690–5. 24. Schreuder WH, Peacock ZS. Antiplatelet therapy and exodontia. J Am Dent Assoc 2015;146:851–6. 25. Nathwani S, Martin K. Exodontia in dual antiplatelet therapy: the evidence. Br Dent J 2016;220:235–8. 26. Lu SY, Tsai CY, Lin LH, Lu SN. Dental extraction without stopping single or dual antiplatelet therapy: results of a retrospective cohort study. Int J Oral Maxillofac Surg 2016;45:1293–8. 27. Olmos-Carrasco O, Pastor-Ramos V, Espinilla-Blanco R, Ortiz-Za´rate A, Garcı´a-Avila I, Rodrı´guez-Alonso E, Herrero-Sanjua´n R, Ruiz-Garcı´a MM, Gallego-Beuter P, Sa´nchez-Delgado MP, Tera´n-Agustı´n AI, Ferna´ndez-Behar M, Pen˜a-Sainz I. Hemorrhagic complications of dental extractions in 181 patients undergoing double antiplatelet therapy. J Oral Maxillofac Surg 2015;73:203–10. 28. Bajkin BV, Urosevic IM, Stankov KM, Petrovic BB, Bajkin IA. Dental extractions and risk of bleeding in patients taking single and dual antiplatelet treatment. Br J Oral Maxillofac Surg 2015;53:39–43. 29. Lockhart PB, Gibson J, Pond SH, Leitch J. Dental management considerations for the patient with an acquired coagulopathy. Part
1: Coagulopathies from systemic disease. Br Dent J 2003;195:439–45. 30. Armitage P, Berry G. Statistical methods in medical research. Second edition. England: Blackwell Scientific; 1987: 527–38. 31. Lippi G, Pasalic L, Favaloro EJ. Detection of mild inherited disorders of blood coagulation: current options and personal recomExpert Rev Hematol mendations. 2015;8:527–42. 32. Scha¨fer A, Weinberger S, Flierl U, Eigenthaler M, Sto¨rk S, Walter U, Ertl G, Bauersachs J. ADP-induced platelet aggregation frequently fails to detect impaired clopidogrel-responsiveness in patients with coronary artery disease compared to a P2Y12-specific assay. Thromb Haemost 2008;100:618–25. 33. Peterson LJ, Ellis E, Hupp JR, Tucker MR. Contemporary oral and maxillofacial surgery. Fourth edition. St. Louis: Mosby; 2003: 126. 34. Medeiros FB, de Andrade AC, Angelis GA, Conrado VC, Timerman L, Farsky P, Dib LL. Bleeding evaluation during single tooth extraction in patients with coronary artery disease and acetylsalicylic acid therapy suspension: a prospective, double-blinded, and randomized study. J Oral Maxillofac Surg 2011;69:2949–55. 35. van Diermen DE, Bruers JJ, Hoogstraten J, Bovenlander M, van den Bosch A, van der Waal I. Treating dental patients who use oral antithrombotic medication: a survey of dentists in the Netherlands. J Am Dent Assoc 2011;142:1376–82. 36. Park MW, Her SH, Kwon JB, Lee JB, Choi MS, Cho JS, Kim DB, Chung WS, Seung KB, Kim KY. Safety of dental extractions in coronary drug-eluting stenting patients without stopping multiple antiplatelet agents. Clin Cardiol 2012;35:225–30. 37. van Diermen DE, van der Waal I, Hoogstraten J. Management recommendations for invasive dental treatment in patients using oral antithrombotic medication, including novel oral anticoagulants. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:709–16. 38. McKay H, Derome F, Haq MA, Whittaker S, Arnold E, Adam F, Heddle NM, Rivard GE, Hayward CP. Bleeding risks associated with inheritance of Quebec platelet disorder. Blood 2004;104:159–65. 39. Zhou L, Schmaier AH. Platelet aggregation testing in platelet-rich plasma: description of procedures with the aim to develop standards in the field. Am J Clin Pathol 2005;123:172– 83. 40. Neunert CE, Journeycake JM. Congenital platelet disorders. Hematol Oncol Clin North Am 2007;21:663–84. 41. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet 2006;367:606–17. [42] Geisler T, Langer H, Wydymus M, Go¨hring K, Zu¨rn C, Bigalke B, Stellos K, May AE, Gawaz M. Low response to clopidogrel is
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
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Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006;27:2420–5. 43. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D. Impact of platelet reactivity after clopidogrel
administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312–7.
Address: Karem L. Ortega Universidade de Sa˜o Paulo Faculdade de Odontologia Disciplina de Patologia Bucal
Av. Professor Lineu Prestes 2227 CEP 05508-000 Sa˜o Paulo – SP Brazil Tel.: +55 11 30917859; 30917838 E-mail: [email protected]
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Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2017.05.013, available online at http://www.sciencedirect.com
Clinical Paper Oral Surgery
Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy F. Buhatem Medeiros, N. Pepe Medeiros de Rezende, J. Bertoldi Franco, A. C. Porrio de Andrade, L. Timerman, M. Gallottini, I. L. Itagiba Neves, K. L. Ortega: Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy. Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx. ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Abstract. In spite of the possibility of triggering thromboembolic events, many professionals indicate the suspension of antiplatelet agents before dental surgical procedures. The aim of this study was to perform a quantitative assessment of intraoperative bleeding in patients on dual antiplatelet therapy. A case–control study was conducted in patients on dual antiplatelet therapy (APT group) and in patients who did not use these medications (control group). The following examinations were requested: complete blood cell count, blood coagulation tests, and platelet aggregation. The quantity of bleeding was measured intraoperatively by collection of aspirated blood. The mean volume of blood lost during the surgical procedure was 6.10 ml in the control group and 16.07 ml in the APT group (P = 0.002). The mean volume of blood lost per minute was 0.60 ml/min in the control group and 1 ml/min in the APT group (P = 0.001), with local haemostatic methods being sufficient to control the bleeding. There was no postoperative bleeding complication in any case. Patients on dual antiplatelet therapy presented a larger volume of bleeding, but this could be controlled by means of local haemostatic measures. Therefore, there is no need to stop either of the two dual antiplatelet therapy medications before dental extractions.
Cardiovascular diseases are one of the main causes of morbidity and mortality worldwide1. Included in this group are patients with coronary artery disease (CAD), a pathology characterized by atherosclerotic plaque accumulation that
0901-5027/000001+07
leads to stenosis of the coronary arteries and thus represents an important risk factor for atherothrombotic accidents2. Atherothrombotic events in patients with CAD are prevented with platelet aggregation inhibitors3. The use of these may lead
F. Buhatem Medeiros1, N. Pepe Medeiros de Rezende1, J. Bertoldi Franco2, A. C. Porrio de Andrade3, L. Timerman4, M. Gallottini1, I. L. Itagiba Neves5, K. L. Ortega1 1 School of Dentistry, Department of Oral Pathology, University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 2Division of Dentistry, Hospital das Clinicas, Medical School, University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 3Hospital Auxiliar do Cotoxo´, Hospital das Clinicas, Medical School, University of Sa˜o Paulo, Sa˜o Paulo, Brazil; 4Department of Dentistry, Dante Pazzanese Institute of Cardiology, Sa˜o Paulo, Brazil; 5Department of Dentistry, Instituto do Corac¸a˜o (InCor), Medical School, University of Sa˜o Paulo, Sa˜o Paulo, Brazil
Key words: platelet aggregation inhibitors; coronary artery disease; blood coagulation; haemosta tic techniques; intraopera tive complications; dental care for chronically ill; tooth extraction; haemorrhage. Accepted for publication 22 May 2017
to increased bleeding in surgical procedures4. The platelet aggregation inhibitor acetylsalicylic acid (ASA) is the antiplatelet therapy most often used in patients with CAD because it is easily accessible, low
ã 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
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cost, and is effective against platelet aggregation by irreversibly blocking the cyclooxygenase 1 enzyme (COX-1) and thromboxane A25. Currently, therapy with ASA is usually combined with other medications, such as thienopyridine derivatives (e.g. clopidogrel, ticagrelor, and prasugrel), which are P2Y12 antagonists of the adenosine diphosphate receptors and act by blocking the activation of the glycoprotein GP II/III receptors on the surface of platelets, diminishing agglutination of fibrinogen during platelet aggregation6. The fear of bleeding complications, even with the use of single ASA therapy, led to various professionals recommending the interruption of such medications7– 11 . However, over the years and with the publication of new scientific research studies, the recommendation for interrupting the use of ASA has been re-assessed, and this is no longer indicated4,12–17. The concomitant use of ASA and clopidogrel causes irreversible blockage of the two platelet aggregation pathways, potentiating the risk of bleeding during surgical procedures18–21. Therefore, some professionals have again suggested interrupting the use of one of the two platelet aggregation inhibitors with the purpose of preventing bleeding complications21. However, interrupting or changing antiplatelet therapy is known to predispose the patient to thrombotic and thromboembolic events that may lead to cardiovascular events with a high mortality rate22. It is indicated in the literature that despite the higher risk of postoperative bleeding in patients on dual antiplatelet therapy, there is no need to interrupt either of the two medications, because bleeding may be contained with local haemostatic measures19,23–26. However, these studies presented limitations characterized by a retrospective design, opinions based on literature reviews, absence of direct evaluation of intraoperative bleeding, and lack of a control group. Only three published prospective studies were designed specifically to investigate the association between bleeding and dual antiplatelet therapy. However, they used only the duration of alveolar bleeding to define the immediate bleeding event18,27,28. Furthermore, Bajkin et al.28 and Lillis et al.18 also used the criteria proposed by Lockhart et al.29 for a late bleeding event, which is characterized by over 12 h of bleeding, need for the patient to return, presence of large haematomas or bruises, and need for a blood transfusion29. It is important to highlight that the duration of bleeding may not be directly
related to the quantity of blood lost and the risk of a real bleeding complication. Therefore, the aim of this study was to quantitatively evaluate intraoperative bleeding during dental extractions in patients on dual antiplatelet therapy. Materials and methods
This study was approved by the research ethics committees of the Dental School and the Medical School of the University of Sa˜o Paulo. All participants read, understood, accepted, and signed a written informed consent agreement. This study was performed in accordance with STROBE guidelines for observational investigations. Study design
A case–control study was conducted with CAD patients on dual antiplatelet therapy with ASA and clopidogrel (APT group) and patients with cardiovascular diseases taking no antiplatelet medication (control group), who required the extraction of up to three teeth. Patients who were alcoholics, or on therapy with warfarin, heparin, anti-inflammatory drugs (steroid or non-steroid), or oral thrombin and factor Xa inhibitors were excluded from the study. To calculate the sample size, the statistical simulations proposed by Armitage and Berry were used30. As there was no information from previous studies on the behavioural distribution of bleeding (mean and standard deviation) in the groups of patients on dual antiplatelet therapy (ASA + clopidogrel), it was assumed that the standard deviation in this group would be the same as that in the control group. Considering a two-tailed hypothesis test, 80% power, and a level of significance set at 0.05, it was determined that a sample size of 26 individuals was required for each group. To take account of possible losses during the research, two to four individuals were added to each group (8% to 15% of the sample size), resulting in a total estimated sample size of 52 (56 or 60) individuals. In total, 348 patients with cardiovascular disease were evaluated. After applying the exclusion criteria, the number of subjects was reduced to 38 in the APT group and 35 in the control group. Methods
At the first visit, all patients underwent a clinical examination and the following laboratory tests were requested: complete blood cell count, prothrombin time
(results were expressed in seconds (PTs), as a ratio (PTr), and as the international normalized ratio (PT/INR)), activated partial thromboplastin time (aPTT), and platelet aggregation. The PT and aPTT were used as routine preoperative coagulation screening tests31. For the APT group, platelet aggregation was evaluated by means of a point-of-care test, VerifyNow (Accumetrics, San Diego, CA, USA). The VerifyNow test cartridges contain a lyophilized preparation of human fibrinogen-coated particles, platelet agonists (adenosine diphosphate (ADP) and arachidonic acid), buffer, and preservative. The results are expressed in P2Y12 reaction units (PRU) for the response to clopidogrel, and in aspirin reaction units (ARU) for the response to ASA. For the control group, platelet aggregation was evaluated by turbidimetric assay. Platelet aggregation was measured in platelet-rich plasma by addition of ADP, arachidonic acid, and adrenaline agonists. Platelet-rich plasma was obtained by centrifugation of blood in a tube containing 3.8% sodium citrate at 1500 rpm for 6 min. The effects of stimulating agents were observed by monitoring the changes in platelet-rich plasma optical density by means of an aggregometer and an AggRAM platelet photometer (Helena Laboratories, Gateshead, Tyne and Wear, UK). Different tests were used for platelet aggregation because the APT group subjects were on antiplatelet drugs and ADPinduced platelet aggregation frequently fails to detect patients with an impaired response to clopidogrel compared to a P2Y12-specific assay32. All of the laboratory examinations were conducted immediately before the surgical procedures. Anaesthesia was performed with 2% lidocaine without a vasoconstrictor (a maximum of four cartridges of 1.8 ml each), with the lower teeth being submitted to the technique of regional block complemented with local infiltration and the upper teeth with local infiltration only. The dental extractions were performed following the procedures recommended by Peterson et al.33. During the procedure, the dental alveolus was irrigated with saline solution and a portable vacuum suction pump was used to aspirate the fluids (blood and saline solution). Bleeding was measured by subtracting the quantity of saline solution from the final quantity of aspirated fluid. The suction hand-piece of the dental equipment was used only to aspirate saliva, which was discarded and not considered34. Before suturing with 3–0 nylon thread, the dental alveolus was irrigated with
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
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Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy abundant saline solution (0.9% sodium chloride), and a paste made of a macerated tablet of tranexamic acid (250 mg) mixed with saline solution was inserted into the dental alveolus. Additional local haemostatic measures were used in the case of persistent bleeding (paste of tranexamic acid placed onto the suture). The surgical procedure was considered concluded once it was observed that there was no bleeding at all. The surgical time was measured in minutes. Standard postoperative recommendations were given to the patients after the surgical procedure. All of them were provided with analgesics (dipyrone or acetaminophen for a maximum of 3 days). The criteria of Lockhart et al. were used to define the postoperative bleeding complications29. All patients were re-assessed after 1 week, but they were instructed to return immediately in the case of bleeding.
Statistical analysis
The results were described using descriptive statistics of position and scale (mean and standard deviation, respectively) for quantitative variables and with absolute and relative frequencies for categorical variables. Comparisons between the mean values of continuous variables were performed using the Student t-test. When the supposition of normality was met or the number of cases in the subgroup analysis was very small, the Mann–Whitney test was used. Comparisons between categorical variables and the groups were evaluated using the x2 test. As the main outcome (bleeding), a generalized linear model was adjusted with gamma distribution and log link. Analyses were performed at a significance level of 5% and the results were obtained with the aid of the statistical software R 3.1.0 (R Foundation for Statistical Computing); the ggplot2 package was used to construct the graphs.
Results
Eighty-eight dental extractions were performed in 73 patients with cardiovascular disease, of whom 26 (35.6%) were female and 47 (64.4%) were male. The mean age of the subjects was 57 years. The APT group subjects underwent 52 dental extractions (27 maxillary teeth and 25 mandibular teeth) and the control group subjects underwent 36 dental extractions (14 maxillary teeth and 22 mandibular teeth). There was no statistically significant difference between the groups regarding sex, clinical condition of the teeth, or anatomical location of the teeth extracted; however the subjects differed significantly in age (Table 1). Tooth sectioning and osteotomy were necessary in four cases in the APT group and in one case in the control group, with no statistically significant difference between the groups (P > 0.05). With regard to the complete blood cell count, there was no difference between the groups in the results, with the exception of RDW (red cell distribution width), which was found to be increased in 62.9% of the control group patients compared to 18.4% of the APT group patients (P < 0.001). In the blood coagulation tests, statistically significant differences were observed between the APT and control groups for PTr, PTs, PT/INR, and aPTT (all P < 0.001) (Table 2). As six patients in the control group presented altered values of PT and aPTT after the dental surgery procedures, they were referred to a haematologist, who concluded that the patients had hepatic disorders. With regard to the main outcome, the volume of blood lost during the surgical procedure was greater in the APT group (16.07 ml) than in the control group (6.10 ml) (P = 0.002). The duration of the surgical procedure was longer in the APT group (mean 15 min, range 5–50 min) than in the control group (mean
3
11 min, range 5–30 min) (P = 0.036). The mean volume of blood lost per minute was calculated as 0.6 ml/min in the control group and 1.0 ml/min in the APT group (P = 0.001) (Table 3 and Fig. 1). Of note, the maximum bleeding in the APT group was 2 ml/min and the maximum surgical time was 50 min. Although the APT group presented a significantly larger quantity of blood loss and a longer surgical procedure, there was no case of intraoperative or postoperative bleeding complication. Local bleeding was controlled with suturing associated with the intra-alveolar application of macerated tranexamic acid. Macerated tranexamic acid was also placed on the suture (extra-alveolar application) in five patients in the APT group. The platelet aggregation test in the APT group showed that 27 patients (71.1%) had values of 350–549 ARU, compatible with hypoaggregability, while 11 patients (28.9%) had values between 550 ARU to 700 ARU, considered resistance to therapy with ASA. For the P2Y12 receptor, 26 patients (68.4%) presented hypoaggregability (<230 PRU), while 12 patients (31.6%) were found not to respond to the medication (PRU >230). Five patients (13.2%) presented therapeutic failure for the two medications and 18 (47.4%) for one of the two medications. No statistically significant correlation was found between the platelet aggregation test results (using VerifyNow) and oral bleeding (P = 0.568 for ASA and P = 0.633 for P2Y12). In the control group, only the changes in hypoaggregability shown by turbidimetry for adrenaline were clinically reflected in the quantity of bleeding that occurred during the surgical procedure (P = 0.018). This did not occur for arachidonic acid (P = 0.750) or ADP (P = 0.114). As it was observed that some patients in the control group presented platelet aggregability characteristics similar to
Table 1. Homogeneity of the study groups regarding sex, clinical condition of the teeth, anatomical location of the teeth, and mean age. Sex Male Female Clinical condition of the teeth Caries Periodontal disease (PD) Residual root (RR) RR + PD Anatomical location of the teeth Maxillary Mandibular Age (years), mean SD
APT group (n = 38)
Control group (n = 35)
Total (n = 73)
27 (71.1%) 11 (28.9%)
20 (57.1%) 15 (42.9%)
47 (64.4%) 26 (35.6%)
8 (21.1%) 5 (13.2%) 24 (63.2%) 1 (2.6%)
10 (28.6%) 10 (28.6%) 15 (42.8%) 0 (0%)
18 (24.7%) 15 (20.5%) 39 (53.4%) 1 (1.4%)
27 25 61.9 10.9
14 22 51.2 17.7
41 47 57 15
P-value 0.32 0.183
0.073 0.002
APT, antiplatelet therapy; SD, standard deviation.
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
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Table 2. Laboratory coagulation values for the APT group and control group, and the results of platelet aggregation tests. APT group (n = 38)
PTs PT/INR PTr aPTT (s) PLT (cells/mm3)
Control group (n = 35)
Min
Max
Mean
SD
Min
Max
Mean
SD
13.00 0.90 0.92 22.80 149,000
18.50 1.30 1.27 41.20 406,000
15.00 1.10 1.05 28.80 244,600
1.30 0.10 8.70 3.40 59.40
13.90 1.00 0.98 24.40 64,000
21.20 1.60 1.50 42.60 644,000
16.50 1.20 1.00 32.00 270,700
1.90 0.10 37.96 4.40 123.70
Min
Max
Mean
SD
Hypo
Normo
Hyper
98 224
342 662
222.28 478.73
67.67 110.11
26 27
12 11
0 0
– – –
– – –
– – –
– – –
20 9 13
15 26 22
0 0 0
Platelet aggregation VerifyNowa P2Y12 (PRU) ASA (ARU) Turbidimetryb Arachidonic acid ADP Adrenaline
APT, antiplatelet therapy; PTs, prothrombin time in seconds (reference value 14.1 s); PT/INR, international normalized ratio (reference range 1–1.2); PTr, prothrombin time ratio (reference range 1–1.20); aPTT, activated partial thromboplastin time (reference value 30 s); PLT, platelets (reference range 140,000 to 450,000 cells/mm3); PRU, P2Y12 reaction units; ARU, aspirin reaction units; Min, minimum; Max, maximum. a Used for the APT group patients: tests for ASA (acetylsalicylic acid) and P2Y12 receptor (clopidogrel); P2Y12 <230 PRU and ASA 350–549 ARU considered to indicate hypoaggregability. b Used for the control group patients: the number of patients who presented with hypoaggregability (hypo), normal aggregability (normo), and hyperaggregability (hyper), according to the reference values, for each of adenosine diphosphate (ADP), arachidonic acid, and adrenaline agonists. Table 3. Comparison of the mean volume of blood lost during the surgical procedure between the APT group and the control group.
Mean volume of bleeding (ml) Mean surgical time (min) Mean volume of blood lost per minute (ml/min)
APT group (n = 38)
Control group (n = 35)
Total (n = 73)
P-value
16.07 15 1.00
6.10 11 0.60
11.3 13 0.80
0.002 0.036 0.001
APT, antiplatelet therapy.
those of the APT group patients, and considering that this characteristic of platelet aggregability influenced the final outcome of bleeding, a generalized linear model was constructed with gamma distribution and log link to compare the mean values of bleeding (ml/min) in the APT group patients, control group patients with
hypoaggregability (control-H), and control group patients with normal aggregability (control-N) (Table 4). The model showed that the mean oral bleeding in the control-H group (0.81 ml/min) was similar to that in the APT group (0.97 ml/min), with no statistically significant difference between these two groups (P = 0.32).
However, as the model was adjusted with the log link, it was estimated that the patients in the control-N group reduced the logarithm of bleeding by 0.67 ml/min; hence, the mean estimate of bleeding in the control-N group was e 0.7 = 0.49 ml/ min compared to 0.97 ml/min in the APT group (P < 0.001). Discussion
Fig. 1. Box plot of the volume of blood lost per minute in the two study groups: antiplatelet therapy group and control group.
Dental interventions resulting in bleeding in patients on medications that change haemostasis have been the subject of multiple studies and publications, reflecting the fear dental practitioners feel in managing this group of patients35–37. Different clinical research studies have shown that the use of ASA does not constitute a risk for uncontrollable bleeding during invasive dental procedures12,17,34. However, single therapy has since been replaced by dual therapy (ASA + clopidogrel), elevating the risk of bleeding. Once again it appears necessary to ensure that although there may be a risk of bleeding, it is unlikely to be uncontrollable. This study quantified bleeding during dental extractions in patients on dual anti-
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
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Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy
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Table 4. Comparison of the mean values of bleeding (ml/min) between the APT group and the control group, divided into those showing hypoaggregability (control-H) and normal aggregability (control-N). 95% CI for mean bleeding b
Group
Parameter
Estimate
SE
P-value
Estimated mean bleeding (e )
Mandibular
Maxillary
APT group Control-H Control-N
b0 b1 b2 f
0.03 0.18 0.67 0.31
0.09 0.18 0.15
0.74 0.32 <0.001
0.97 0.81 0.49
0.78 0.56 0.38
1.20 1.17 0.66
APT, antiplatelet therapy; SE, standard error; CI, confidence interval.
platelet therapy. A control group consisting of patients with similar clinical conditions (cardiovascular changes), but not on antiplatelet aggregation therapy, was established to make it possible to evaluate whether patients on dual therapy would present bleeding events, or a quantitatively higher volume of bleeding. The two groups were shown to be similar regarding the sex distribution, clinical condition of the teeth, and anatomical location of the teeth; however, they differed for the variable age. The higher mean age in the APT group can be explained by the selection of the sample of patients. Coronary pathologies requiring percutaneous coronary interventions with the placement of stents and use of dual antiplatelet therapy occur more frequently in the older population. In the blood coagulation tests, statistically significant differences were observed between the APT group and control group for PT (PTs, PTr, and PT/ INR) and aPTT; however, the mean values in each group were within the normal therapeutic range. The results for platelet aggregation showed that APT group patients, on average, were within the therapeutic range for both medications, i.e. they presented hypoaggregability. Interestingly, it was found that 57.1% of the control group patients presented hypoaggregability for arachidonic acid, 25.7% for ADP, and 37.1% for adrenaline, although they were not on any antiplatelet aggregation medication. This may be explained by the presence of other alterations capable of acting on platelet aggregation, such as liver and kidney alterations, idiopathic hypoaggregation, congenital platelet syndromes, and adverse reactions to medications (e.g. beta-blockers, statins, tricyclic antidepressants, antiemetic agents, and proton pump inhibitors)38–40. Other laboratory evidence was that some patients in the APT group were found to be unresponsive to antiplatelet therapy: 28.9% for ASA and 31.6% for P2Y12. This variability in platelet aggre-
gation may be related to several clinical factors, such as the patient’s body mass index, under-dosing of the medication, poor adherence to treatment, low absorption, and drug–drug interactions, or even to genetic factors (e.g. polymorphisms in the CYP3A4, CYP2C19, P2Y12, or COX1 receptors, or in other genes involved in the biosynthesis of thromboxane, or also individual variations in the activity of cytochrome P450)41–43. The APT group patients had more intense intraoperative bleeding than the control group patients, and this difference was statistically significant. Although the intraoperative bleeding was much more intense in the APT group, the quantity of blood lost by the patients did not exceed 100 ml, which could hardly be characterized as a bleeding event that would justify the interruption of antiplatelet medications. The use of simple local haemostatic measures was sufficient to prevent intraoperative and postoperative bleeding complications. None of the patients involved in the study presented a postoperative bleeding complication according to the criteria proposed by Lockhart et al. in 201329. Local haemostatic measures were used in this study, consisting of the intra-alveolar application of tranexamic acid associated with the use of non-resorbable sutures. This is a simple, low cost technique that is easily available and it provided good results. Even in the five cases in which there was a larger quantity of bleeding, the use of the same medication in the extra-alveolar region (on the suture) associated with a compressive gauze dressing was sufficient for local haemostasis control. When the quantity of bleeding was correlated with the duration of the surgical procedure, irrespective of the group studied, the authors found that bleeding was directly proportional to the operative time and this was statistically significant. However, the operative time was longer in the APT group, by virtue of the hypoaggregability caused by the antiplatelet therapy.
The results of this study confirm the initial hypothesis that there is no need to interrupt the use of either of the two medications used as dual antiplatelet therapy before dental extractions, provided that the dental surgeon is qualified to control intraoperative bleeding of greater intensity and to resolve a possible postoperative bleeding complication. A thromboembolic event is a more serious health threat than the volume of blood lost during dental extractions involving up to three teeth. Funding
This work was supported by the Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo (FAPESP) – grant 2012/16523-0. Competing interests
None. Ethical approval
This project was approved by the Research Ethics Committee of the Dental School of the University of Sa˜o Paulo (Protocol No. 47816) and by the Ethics Commission for the Analysis of Research Projects of the ‘‘Hospital das Clı´nicas’’, Medical School, University of Sa˜o Paulo (HCFMUSP) (Protocol No. 35879). Patient consent
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Address: Karem L. Ortega Universidade de Sa˜o Paulo Faculdade de Odontologia Disciplina de Patologia Bucal
Av. Professor Lineu Prestes 2227 CEP 05508-000 Sa˜o Paulo – SP Brazil Tel.: +55 11 30917859; 30917838 E-mail: [email protected]
Please cite this article in press as: Buhatem F, et al. Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.05.013
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