Prasugrel is a widely used ADP-receptor blocker for patients suffering from acute coronary syndrome, with or without persistent ST elevation, and undergoing myocardial revascularisation.1–3 Prasugrel is a thienopyridine given orally as a prodrug; its active metabolite binds irreversibly to platelet P2Y12 receptors. It induces stronger and faster inhibition of ADP-induced platelet aggregation than clopidogrel, both after a loading dose and during the maintenance regimen.4 As the binding of the active metabolite to the receptor is irreversible, recovery of platelet function after withdrawal of the drug depends on platelet turnover. Because of the potent antiplatelet effect of prasugrel, it is recommended to withdraw it 7 days before any elective invasive surgical procedure with a high risk of bleeding.5
In the TRITON-TIMI 38 study (TRial to Assess Improvement in Therapeutic Outcomes by Optimising Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction), prasugrel treatment significantly decreased deaths from cardiovascular causes, nonfatal myocardial infarctions or nonfatal strokes compared with clopidogrel. However, the rates of severe bleeding events, bleeding requiring transfusion and fatal bleeding were higher with prasugrel than with clopidogrel.6
The management of excessive bleeding during an invasive procedure or spontaneous and traumatic haemorrhagic events in patients treated with prasugrel is challenging, and no antidote is currently available.7 Platelet transfusion is deemed the most efficient therapy to correct the platelet defect induced by antiplatelet drugs. A large platelet transfusion (at least 15 U of platelets) was found necessary to correct ex vivo aggregation of platelets from prasugrel-treated patients8,9 and to correct prasugrel-related bleeding in a rabbit model.10 Nonspecific haemostatic drugs could be proposed as alternative therapeutic options, especially in cases of severe bleeding.5 More specifically, the usefulness of recombinant activated factor VII (rFVIIa) has been reported for some platelet functional disorders11; tranexamic acid has been proposed for its antifibrinolytic properties and for its potential effects on platelet reactivity12,13; and desmopressin (DDAVP) has been used for inherited bleeding disorders (e.g. von Willebrand disease), but also in cases of acquired platelet dysfunction (such as uraemia and aspirin treatment).14,15 To date, these three haemostatic drugs have been poorly investigated for prasugrel reversal.
We designed a placebo-controlled randomised study to investigate the efficacy and safety of rFVIIa, tranexamic acid and DDAVP to reduce blood loss after a loading dose of prasugrel in a rabbit model of microvascular bleeding and arterial thrombosis.16,17
The primary efficacy endpoint was hepatosplenic blood loss, as previously described. Secondary endpoints were ear immersion bleeding time and platelet aggregation. The safety of the three nonspecific haemostatic drugs was evaluated with a modified Folts model measuring arterial thrombotic events as cyclic flow reductions (CFRs) in a stenosed and injured carotid artery.
Materials and methods
The experiments were conducted according to the Swiss Federal Veterinary Office guidelines and the experimental protocol was approved by the Animal Welfare Committee of the Canton of Geneva, Switzerland (Ethical Committee Authorisation No. 1043/3824/1) on 27 March 2012.
The study was performed in 2013. Male New Zealand rabbits, weighing 2.6 ± 0.2 kg, were obtained from the same breeding colony (Animalerie d’Arare, Plan-les-Ouates, Switzerland) and housed, one per cage, in the animal facilities of the University of Geneva Medical Centre, under light-controlled and temperature-controlled conditions, with tap water and food ad libitum. The animals were used in the experiments after several days of acclimation. Every effort was made to minimise the number of animals used, and their pain or discomfort.
Rabbits were allocated randomly into one of five groups. The control group received 0.9% saline instead of a prasugrel-loading dose and 0.9% saline instead of a reversal agent; the placebo group received a prasugrel oral loading dose of 4 mg kg−1 and 0.9% saline instead of a reversal agent. The prasugrel dose was chosen according to data available in the literature18,19 and a previous study which showed that it increased hepatosplenic blood loss and reduced ADP-induced platelet aggregation by 75 ± 10%.10 In the three other groups, rabbits received the prasugrel-loading dose and either rFVIIa 150 μg kg−1, tranexamic acid 20 mg kg−1 or DDAVP 1 μg kg−1. The doses of these haemostatic drugs were carefully chosen according to data available in the literature. In the same rabbit model, rFVIIa 150 μg kg−1 was effective in reducing hypothermia-associated bleeding.20 DDAVP 0.3 μg kg−1 decreased ear bleeding time in rabbits treated with aspirin and streptokinase.21 Tranexamic acid has been used successfully in anticoagulated rabbits undergoing dental extractions22 and another study suggested that intravenous tranexamic acid 20 mg kg−1 would be enough to reach therapeutic serum concentrations (10 μg ml−1).23
The three haemostatic drugs were administered intravenously. The study protocol is depicted in Fig. 1.
On the day of the experiment, rabbits were given the oral prasugrel-loading dose in 5 ml of 0.9% saline or the same volume of saline with no drug. The rabbits were then premedicated with an intramuscular injection of xylazine (Rompun 2%; Bayer, Lyssach, Switzerland) 5 mg kg−1. A 22-gauge catheter (VasofixSafety; B Braun, Melsungen, Germany) was introduced into the marginal vein of the ear, and anaesthesia was induced using midazolam (Midazolam Sintetica; Sintetica, Mendrisio, Switzerland) 0.25 to 1 mg, intravenously. After local anaesthesia with 1.5-ml lignocaine 0.5% (Rapidocaïn; Sintetica), a median neck incision was made and a tracheostomy was performed using a cuffless cannula (3.5-mm internal diameter, Contour; Mallinckrodt, Athlone, Ireland) to ensure mechanical ventilation (Maquet Servo-i Ventilator System V4.0; Maquet, Solna, Sweden) with a respiratory rate of 40 cycles min−1, a tidal volume of 5 ml kg−1 and an inspired oxygen fraction of 0.4 in air. Mechanical ventilation was further adapted, if necessary, to obtain an end-tidal carbon dioxide level of 5.5 to 6 kPa. Subsequently, a continuous intravenous infusion of midazolam 0.3 to 0.9 mg kg−1 h−1, with fentanyl 10 to 30 μg kg−1 h−1 (Sintenyl; Sintetica) and atracurium 0.25 to 0.75 mg−1 kg−1 h−1 (Atracurium Labatec; Labatec Pharma, Meyrin, Switzerland), was administered via the ear vein for the maintenance of anaesthesia throughout the study. After dissection of the groin, a 22-gauge catheter was inserted into the femoral artery and then connected to a calibrated blood pressure (BP) monitor (Biopac MP150; BIOPAC Systems Inc., Santa Barbara, California, USA) for continuous monitoring. The heart rate was recorded from the BP wave. Rectal temperature was monitored continuously with a temperature sensor (Thermalert, Model TH-8; Physitemp, Clifton, New Jersey, USA) and was maintained within the normal range, between 38.5 and 40 °C, using a heating pad (Miostar, Zu[Combining Diaeresis]rich, Switzerland). A first arterial blood sample was taken to measure blood gases and obtain a complete blood count.
The arterial thrombosis protocol was adapted from the Folts model of coronary thrombosis to study interactions between platelets, intima and media.24 The right carotid artery was isolated and cleared of the surrounding fascia. A Doppler flow probe (PS-series; Transonic Systems Inc., Ithaca, New York, USA) was placed around the artery and linked to a flow meter for instantaneous blood flow measurements (T106; Transonic Systems Inc.). Mean and phasic flows were continuously recorded (BIOPAC MP150; BIOPAC Systems Inc.). Once carotid flow was stable, an atraumatic silicone vascular clamp (Harvard Apparatus, Kent, UK) was placed to reduce mean basal carotid artery blood flow by 10%, corresponding to a 75% circumferential stenosis. Then, an arterial injury with de-endothelialisation was induced by cross-clamping the middle of the exposed artery, on three adjacent segments, during a period of 3 s each. This was performed using a Mayo-Hegar needle-holder forceps (Harvard Apparatus) closed at the first ratchet. The stenosis clamp was then positioned over the injured segments. Carotid thrombotic events were then recorded as CFRs for a total duration of 100 min. Mean and phasic flow might decline progressively until thrombus formation. Indeed, blood flow decreases as thrombus size evolves in the injured carotid artery until the pressure gradient is such that the thrombus is released and local blood flow restored. Haemostatic drugs were administered after 20 or 50 min of observation of CRF for DDAVP, or rFVIIa, tranexamic acid and saline, respectively, to take into account that the effect of DDAVP is not immediate, in contrast to that of the other haemostatic drugs. The time elapsed between haemostatic drug administration and the bleeding challenges were thus 60 and 30 min, respectively.
Ear-immersion bleeding time was measured as follows. A 5-mm-long, 1-mm-deep incision was made on the outer surface of the shaved ear using an automated blade device (Surgicutt, Elitech, Estavayer-le-Lac. Switzerland). The ear was then immersed in a glass filled with 0.9% saline at 39 °C. Bleeding time was defined as the time between the incision and the complete visual cessation of bleeding, as previously described.25
After the second blood sampling, a xyphopubic laparotomy was performed. The liver and spleen were isolated. A 2-cm incision was made at the anterior extremity of the spleen along its inferior border. Ten standardised 1-cm sections were made on the left and right lobes of the liver. Swabs were placed close to the liver and the spleen and into the right and left parietocolic spaces before transections. The total amount of hepatosplenic blood loss was measured by weighing these swabs 15 min later, as previously described.26 Finally, rabbits were sacrificed by an injection of a lethal dose of pentobarbital 150 mg kg−1 (Thiopental Inresa; Inresa Arzneimittel, Freiburg, Germany).
Blood samples were collected via the femoral artery catheter. Arterial blood gases were analysed from blood collected into a heparinised syringe 15 min after the beginning of mechanical ventilation (EG6+ Cartridge, i-stat; Abbott, The Hague, The Netherlands). Complete blood count was assessed in EDTA-anticoagulated blood (EDTA Microvette; Sarstedt, Nümbrecht, Germany) after femoral artery catheterisation, and before hepatic bleeding (pocH-100iv; Sysmex Digitana, Yverdon-les-Bains, Switzerland). Platelet function was evaluated using light transmittance aggregometry. Platelet-rich plasma (PRP) was prepared from whole blood collected just before the laparotomy, into tubes containing 3.2% sodium citrate (BD Vacutainer; Becton Dickinson, Meylan, France), by centrifugation at 200 × g for 10 min at room temperature. Platelet-poor plasma, used to calibrate the aggregometer, was obtained by further centrifugation at 2000 × g for 10 min. Platelet aggregation assays were performed with unadjusted PRP27 within 1 h of blood collection, using an eight-channel aggregometer (TA-8V; SD Medical, Heillecourt, France) and in response to ADP 10 μmol l−1 (ADP; Sigma-Aldrich, Buchs, Switzerland) or collagen 10 μg ml−1 (Horm; Nycomed, Pfäffikon, Switzerland). The concentration of collagen was chosen to serve as a control as it is unaffected by ADP inhibition. Platelet aggregation was recorded for 6 min and maximal light transmission (expressed in percentages) was used for analysis.
The sample size was calculated for the primary endpoint by assuming that a 30% decrease in hepatosplenic blood loss would be clinically relevant and that the prasugrel-loading dose would double hepatosplenic bleeding compared with control rabbits.16,18 Twelve rabbits per group were necessary for a 5% α risk and a 20% β risk, with eight rabbits in the control group.
Discrete variables (CFRs) and variables with non-Gaussian distributions were expressed as median with interquartile range [IQR]. Other data were expressed as mean ± SD. Normally distributed data were compared using a one-way analysis of variance test. Nonnormally distributed data were compared using the Kruskal–Wallis test, followed, when significant, by the Mann–Whitney U test. Statistical analyses were performed using R software (Vienna, Austria, URL http://www.R-project.org/).
A P value less than 0.05 was considered statistically significant.
The current study included 57 rabbits. One died during preparation for anaesthesia. Thus, a total of 56 rabbits underwent the entire protocol.
Prasugrel decreased ADP-induced maximal platelet aggregation from 66 ± 4% in the control group to 41 ± 7% in the prasugrel-treated rabbits from the placebo group (P < 0.001). Neither tranexamic acid, DDAVP nor rFVII improved ADP-induced aggregation (40 ± 11%, 42 ± 10% and 41 ± 11%, respectively) compared with placebo.
As expected, collagen-induced aggregation (maximal aggregation and lag-time) was comparable in all five groups (Table 1).
Hepatosplenic blood loss
As expected, prasugrel doubled the hepatosplenic blood loss from 10.7 g (10.1 to 12.7) (median and IQR) in the control group to 20.0 g (17.0 to 24.4) in the prasugrel–placebo group (P = 0.003). Blood loss in the prasugrel–rFVIIa group was very similar, 19.7 g (14.0 to 27.6). Neither tranexamic acid nor DDAVP had any significant impact on hepatosplenic blood loss [25.2 g (22.6 to 28.7) and 22.9 g (16.8 to 8.8), respectively] (Table 2 and Fig. 2).
Ear-immersion bleeding time
Bleeding time was also affected by prasugrel administration, being significantly longer in the placebo (prasugrel-treated) group [146 s (120 to 203)] than in the control group [92 s (73 to 119), P < 0.05]. None of the three haemostatic drugs reduced bleeding time in prasugrel-treated rabbits (Table 2).
Prasugrel protected against CFRs, as their number was 7 (4 to 8) in the control group vs. 0 (0 to 0), with a maximum of two, in the placebo (prasugrel-treated) group, P < 0.001 (Fig. 3). In the prasugrel–rVIIa group, there were three CFRs or more for 5/12 rabbits vs. 0/12 in the placebo group (P = 0.037). Tranexamic acid and DDAVP were not associated with an increase in CFRs (Fig. 3).
The current study aimed to evaluate the efficacy of three nonspecific haemostatic agents to reduce prasugrel-related bleeding in a rabbit model, as well as safety regarding the thrombotic risk. We had previously shown that platelet transfusion was effective in reducing prasugrel-related bleeding in this model, provided that a sufficient amount of platelets was delivered.10 In the current study, we found that neither rFVIIa, tranexamic acid nor DDAVP were able to significantly reduce prasugrel-related bleeding. Moreover, rabbits treated with rFVIIa were more prone to thrombotic events.
DDAVP increases plasma von Willebrand factor and factor VIII concentrations, promotes interactions between platelets and the subendothelium via the Glycoprotein Ib receptor and may also increase interactions between platelets themselves via the Glycoprotein IIbIIIa receptor.28–30 DDAVP may also be effective in correcting the platelet dysfunction induced by aspirin. No studies in humans have shown it to be effective in correcting platelet inhibition induced by ADP inhibitors (clopidogrel, prasugrel or ticagrelor).31 In rats exposed to clopidogrel, lower doses of DDAVP (0.6 μg kg−1) were associated with fewer animals suffering a prolonged bleeding time.32 Our study with rabbits did not confirm this potential benefit.
Tranexamic acid is an antifibrinolytic drug with potential effects on platelets.33 In the specific setting of cardiac surgery, and when testing using multiple electrode aggregometry with whole blood from patients treated with aspirin and clopidogrel, tranexamic acid has been shown to increase platelet aggregation in response to arachidonic acid and ADP.34 We did not observe such an effect on platelet aggregation when testing with light transmittance aggregometry. Furthermore, in our model, tranexamic acid was ineffective at reducing bleeding time and hepatosplenic blood loss.
By promoting thrombin generation, rFVIIa has been suggested as a means to improve haemostasis in patients treated with thienopyridines.35,36 The results of animal studies with bleeding as the primary endpoint have nevertheless differed. At very high doses (10 mg kg−1), rFVIIa decreased blood loss in a tail bleeding model in rats treated with clopidogrel37 but did not decrease hepatosplenic blood loss in rabbits treated with the same antiplatelet drug.17 One study in mice treated with ticagrelor showed that injection of very high doses of rFVIIa (1 mg kg−1) reduced the duration of bleeding and blood loss induced by a tail section.38 In the current study, we found that a dose of rFVIIa 150 μg kg−1 in rabbits failed to decrease hepatosplenic blood loss but did lead to an increase in thrombotic events, suggesting that this dose has effects on haemostasis in vivo. The reasons for such a dissociation remain obscure, but could be linked to the type of the vascular bed and lesion.
Our study has some limitations. The main concern is that only one dose of each haemostatic drug was tested, and we cannot preclude underdosing. Nevertheless, doses were carefully selected and quite high. The doses of the three haemostatic agents were chosen based on the available relevant data in the literature, as specified above. In particular, rFVIIa 150 μg kg−1 has been shown to be effective in reducing hypothermia-associated bleeding in the same rabbit model.20 Moreover, the presence of thrombotic side-effects observed in the current study does not favour the use of higher doses of rFVIIa.
In conclusion, with this rabbit model of bleeding, neither rFVIIa, tranexamic acid nor DDAVP at the studied doses significantly reduced prasugrel-related bleeding. Regarding safety, rabbits treated with rFVIIa were more prone to thrombotic events. Although the extrapolation to humans of results obtained with animals should always be cautious, our data do not support the use of any of the studied haemostatic drugs to improve the haemostatic competence of prasugrel-treated patients. Hence, the transfusion of a suitable amount of platelets seems to be the unique resort in case of worrisome bleeding.
Acknowledgement relating to this article
Assistance with the study: we wish to thank Severine Nolli and Xavier Belin for their excellent technical assistance during this study and Sylvie Roullet for her invaluable support.
Financial support and sponsorship: the current study was funded by a Research and Development Project grant from the Geneva University Hospitals and by the Department of Anaesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland.
Conflicts of interest: none.
Comment from the Editor: CMS is an associate editor of the European Journal of Anaesthesiology.
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