American Journal of Emergency Medicine 38 (2020) 2634-2636

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American Journal of Emergency Medicine

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Desmopressin with four-factor prothrombin complex concentrate for life-threatening bleeding: A case series

Dalila Masic, PharmD ^a, Ochan Kwon, MD Candidate ^b, Megan A. Rech, PharmD, MS ^a,c,?

^a Department of Pharmacy, Loyola University Medical Center, Maywood, Illinois, United States of America

^b Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, United States of America

^c Department of Emergency Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, United States of America

Introduction

There are multiple Disease states that warrant the use of anticoagulation with one or more Antiplatelet agents. Additionally, direct oral anticoagulants (DOACs) are gradually replacing warfarin as the anticoagulants of choice [1]. A major complication of anticoagulant and Antiplatelet therapy may be life-threatening bleeding, resulting in a debilitating state or death. Current guidelines recommend the use of four-factor prothrombin complex concentrate for anticoa- gulation reversal in patients experiencing major bleeding or necessitat- ing urgent surgical intervention due to warfarin use [1,2]. There exists controversy and lack of prospective data for reversal of DOACs with 4F-PCC [3]. Ultimately, there is inadequate guidance on optimal medical therapy when a patient presents on both an anticoagulant and an anti- platelet with life-threatening bleeding.

Antiplatelet medication use at time of Intracranial Hemorrhage is associated with a higher incidence of hematoma enlargement and in- creased mortality [4]. Currently, there is no specific antidote for anti- platelet agents approved in the United States. In general, Platelet function is restored after three to five half-lives upon cessation of ticagrelor, a reversible antiplatelet. For irreversible antiplatelet agents (e.g. aspirin, clopidogrel, prasugrel) platelet activation is inhibited until new platelets are regenerated, which may take up to ten days [5]. Administration of exogenous platelets may result in temporary he- mostasis for irreversible antiplatelet agents. However, platelet transfu- sion will not reverse antiplatelet activity and may ultimately result in increased mortality [6].

Desmopressin (DDAVP) is a vasopressin analog that promotes plate- let adhesion to the endothelium by increasing the endothelial release of Von Willebrand factor [7]. Based on low-quality evidence, the Neuro- critical Care Society and the European Task Force for Advanced Bleeding Care in trauma guidelines recommend considering a single intravenous dose of DDAVP (0.3 to 0.4 ug/kg) for intracranial hemorrhages associ- ated with antiplatelet agents or Von Willebrand disease [2,8]. However, the reported efficacy of DDAVP for reversal of antiplatelet-associated

* Corresponding author at: Department of Pharmacy, Loyola University Medical Center, 2160 S First Ave, Maywood, Illinois 60153, United States of America.

E-mail address: [email protected] (M.A. Rech).

hemorrhage has been mixed [9]. The largest study to date was a retro- spective cohort study of 55 ICH patients that received DDAVP as com- pared to a control group of 69 patients. The study concluded that DDAVP use was associated with a decreased likelihood of ICH expansion during the first 24 h upon presentation [10]. Another study examined DDAVP use in patients who were on antiplatelet agents pre-injury and presented with mild Traumatic brain injury . The study concluded that DDAVP was associated with a lower incidence of hematoma expan- sion in mild TBI [11].

To our knowledge, no literature exists describing the clinical out- comes after concomitant use of DDAVP and 4F-PCC. This case series aims to report the outcomes after concomitant DDAVP and PCC for pa- tients who present to the emergency department (ED) with life- threatening bleeding on an anticoagulant and one or more antiplatelet agents.

Methods

This single-center retrospective case series included a convenient sample of all patients who received 4F-PCC and DDAVP for life- threatening bleeding from January 2014 to March 2020. We used our electronic medical record to search for all patients over the age of 18 with reported use of an oral anticoagulant and one or more oral anti- platelet agents (e.g. aspirin, clopidogrel, ticagrelor, and prasugrel) at time of bleed. All patients who confirmed the use of prior to admission medications were subsequently administered DDAVP in conjunction with 4F-PCC for life-threatening bleeding at the discretion of the neuro- surgery or trauma attending physician. The dose of 4F-PCC was preprogrammed in the electronic medical record to autopopulate 50 units/kg for DOACs and based on INR for warfarin hemorrhage. Once the order was placed, central pharmacy had the capability to ad- just the order to the nearest 4F-PCC vial size then rounded to the closest vial size within 10% of the target dose. For DDAVP, the SCCM guidelines recommend a dosing range of 0.3 to 0.4 ug/kg [2]. Epic (Verona, WI) was the electronic medical software that we utilized throughout the study period. Patients were excluded if they were transferred from an outside hospital and had missing data or if they received DDAVP and/or 4F-PCC for any indication other than life-threatening bleeding. The research protocol was approved by our institution’s Institutional Review Board.

https://doi.org/10.1016/j.ajem.2020.07.082

0735-6757/(C) 2020

We aim to describe the incidence of adverse events with concomi- tant therapies. The achievement of hemostasis was explored and deter- mined using the definition by the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria for the assessment of the effectiveness of major bleeding management to ensure assessments were objective and consistent [12]. Hemostasis for ICH was defined as stabilization or a < 35% increase in Hematoma volume on imaging. All images until discharge were analyzed. Hemosta- sis for nonvisible bleeding was defined as stable hemoglobin at 48 h after 4F-PCC administration. Adverse events evaluated included deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, arterial thrombus, hypersensitivity reaction, transfusion-related acute lung injury, and transfusion-associated circulatory overload. The following data were also collected from the electronic medical record: hospital length of stay , ICU LOS, hospital mortality, and 30-day mortality. Descriptive statistics were used to characterize the data.

Results

Of the 60 patients that were screened for inclusion, there were seven patients that received concomitant 4F-PCC and DDAVP for life- threatening bleeding. The most common reasons for exclusion included outside hospital transfer with missing data (n = 20) and receipt of ther- apies in the operating room for routine surgical procedure rather than life-threatening bleeding (n = 33). Table 1 lists the patient characteris- tics and outcomes of all included patients. Six patients (86%) presented with an ICH with median Glasgow Coma Scale score of 15 (+- in- terquartile range 0) with a stable ICH Score, while one patient (14%) had non-visible bleeding due to trauma. Patient 1 had a 9 mm traumatic subdural hematoma along the lateral cerebral convexities. Pa- tient 2 had an 8 mm atraumatic intraventricular hemorrhage (IVH) in the septum pellucidum. Patient 3 had a 5 mm traumatic intrapare- nchymal hemorrhage (IPH) in the left frontal lobe. Patient 4 had a 2 mm traumatic subarachnoid hemorrhage in the right temporal lobe. Patient 5 had a 4 mm Traumatic SAH in the right cerebral hemi- sphere. Patient 6 had a 4 mm traumatic SDH in the temporal lobe. Pa- tient 7 had a traumatic pelvic fracture with a hematoma which was classified as “non-visible bleeding”. The initial hemoglobin for the non-visible trauma patient was 12, from a baseline of 13.9 prior to presentation.

The indication for anticoagulation was Atrial fibrillation for three patients (43%), deep vein thrombosis for one patient (14%), me- chanical valve replacement for one patient (14%), and left ventricular assist device for one patient (14%). Four (57%) patients presented on warfarin, one patient (14%) on apixaban, and two patients (29%) on rivaroxaban. Concomitant antiplatelet therapy consisted of aspirin 81 mg alone for three patients (43%), clopidogrel alone for one patient (14%), aspirin 81 mg with clopidogrel for two patients (29%), and aspi- rin 325 mg with clopidogrel for one patient (14%).

The 4F-PCC dose was appropriately administered according to inter- national normalized ratio (INR) on presentation for warfarin-induced hemorrhage and approximately 50 units/kg for hemorrhage on rivaroxaban or apixaban. All patients received concomitant intravenous

(IV) phytonadione if the anticoagulant on presentation was warfarin. The median time from ED admission to 4F-PCC administration was 135 (+-106.5) minutes. Furthermore, median DDAVP dose was 0.3 (+- 0.08) mcg/kg. The median time from ED admission to DDAVP adminis- tration was 224 (+-159) minutes. No patients received any additional reversal agents (e.g. tranexemic acid). There were no thrombotic ad- verse Drug reactions reported up to 30 days post-discharge.

Of the six patients that presented with an ICH, all six patients (100%) had computed tomography scan showing a stable or less than 35% increase in hematoma volume within 12 h of concomitant 4F-PCC and DDAVP therapy. For the one patient that presented with non-visible bleeding due to trauma, a stable hemoglobin and hemodynamics were both achieved within 24 h of therapy. The median ICU LOS was

2 (+-1.5) days, while the median hospital LOS was 5 (+-7.5) days. Four patients (57%) were discharged to a long-term care facility, while three patients (43%) were discharged home. All patients survived to hospital discharge and there were no patients that died 30 days after discharge.

Discussion

This exploratory analysis for the administration of concomitant DDAVP and 4F-PCC seems to be safe for life-threatening bleeding. To our knowledge, this is the first case series to describe concomitant use of anticoagulant and antiplatelet Reversal strategies. The findings of this case series demonstrate that patients who received both therapies were not at increased risk of thrombotic Adverse drug reactions.

There are multiple disease states that warrant the use of anticoa- gulation with one or more antiplatelet agents. For instance, in AF patients who develop acute coronary syndrome, anticoagulation is the mainstay of therapy for AF Stroke prevention whereas antiplatelet agents are necessary to prevent in-Stent thrombosis and restenosis of a newly placed coronary artery stent. While guidelines offer separate recommendations for reversal of anticoagulation and antiplatelet agents for life-threatening bleeding, there are no recommendations on optimal management when a patient presents on both agents [1,2,8].

Overall data supporting the use of DDAVP with or without platelets for antiplatelet-associated hemorrhage remains limited and conflicting. Multiple retrospective studies report that the administration of platelets and DDAVP may cause harm and ultimately increase mortality [4,9]. Al- most half of our patient population received a concomitant platelet transfusion per the decision of the neurosurgery or trauma attending. We do not believe that it is considered a failure of hemostasis as all ther- apies were administered concomitantly upon patient arrival. In patients with acute non-traumatic ICH on aspirin, the PATCH trial showed that administration of platelet transfusion as compared to usual Standard care increased the risk of death or Modified Rankin scale (mRS)-defined dependence (OR 2.05; 95% CI 1.18-3.56) [6]. Unfortunately, mRS was not well-documented in the electronic medical record for our case se- ries. However, there were no patients that died on hospital discharge or 30 days after discharge. Hemostasis cannot be justified with this case series as patients in our case series who presented with an ICH were relatively healthy and had no data to suggest sustained hyperco- agulability. Therefore, it was unlikely that they were going to have he- matoma expansion regardless.

Moreover, one retrospective study showed a decreased likelihood ICH expansion with DDAVP alone compared to the standard of care in patients who presented on an antiplatelet agent [10]. This study con- firmed the safety of DDAVP noting that there were no significant changes in serum sodium or any thrombotic events during the study pe- riod. Our case series also evaluated Thrombotic adverse events and found that there were no patients that experienced thrombotic events up to 30 days post discharge. However, we feel that efficacy of concom- itant therapies should be explored further, including the effect of hema- toma expansion in a more critically ill population and how that would result in patient outcomes.

There are several limitations worthy of discussion given the na- ture of this small case series. Over the study period, we only identi- fied seven patients who received concomitant DDAVP and 4F-PCC for life-threatening bleeding. The decision to administer both agents was ultimately guided by preference of the neurosurgery or trauma attending physician. This exploratory analysis is hypothesis generat- ing and further studies are warranted to study the efficacy of combi- nation therapy. The next limitation is the relatively mild nature of the cases in the series, with a baseline median GCS of 15 and ICH score of one [13]. As the administration of 4F-PCC and DDAVP from ED admission was delayed, there is a risk of survivor bias. It remains uncertain if both reversal agents were needed or if there is benefit in less severe ICH cases. Although the patients in our

Table 1

Patient characteristics and outcomes.

Patient	Age/Sex	Weight (kg)	Type of bleed	Admit GCS	ICH score	Anti-coagulant	4F-PCC dose (units/kg)	Anti-platelet	DDAVP dose (mcg/kg)	PRBC in 24 h	Platelet in 24 h	Dis-charge GCS	ADR	30 Day mortality
1	91/M	106.1	Trauma-tic SDH (9 mm)	15	1	Apixaban	46.9	Aspirin 81 mg	0.18	0	0	15	No	No
2 3	75/M 67/M	88.3 103.4	Atrauma-tic IVH (8 mm) Trauma-tic IPH	15 15	1 1	Warfarin Warfarin	25.7 26.4	Aspirin 81 mg & Clopidogrel Aspirin 81 mg	0.41 0.29	0 0	1 0	15 15	No No	No No
4	70/M	53.3	(5 mm) Trauma-tic SAH	15	0	Rivaroxaban	50.6	Aspirin 81 mg	0.30	0	0	15	No	No
5	74/M	105.1	(2 mm) Trauma-tic SAH	15	1	Warfarin	10.4	Aspirin	0.41	0	1	15	No	No
6	76/M	70.7	(4 mm) Trauma-tic SDH	15	2	Rivaroxaban	48.5	325 mg & Clopidogrel Aspirin 81 mg	0.29	0	1	15	No	No
7	59/M	83.1	(4 mm) Non-visible	15	N/A	Warfarin	26.1	& Clopidogrel Clopidogrel	0.24	3	0	15	No	No
Total	74	88.3	bleeding (pelvic fracture) -	15	1	-	26.4	-	0.30	0	0	15	-	-
	(+-7.5)	(+-27.4)		(+-0)	(+-0)		(+- 21.9)		(+- 0.08)	(+- 0)	(+- 1)	(+-0)

GCS = Glasgow Coma Score; SDH = Subdural Hematoma; IVH = Intraventricular Hemorrhage; IPH = Intraparenchymal hemorrhage; SAH = Subarachnoid Hemorrhage; 4F-PCC = 4-factor prothrombin complex concentrate; DDAVP = Desmopressin; PRBC = Packed red blood cells; ADR = Adverse Drug Reaction (Thrombotic). All results are reported as median (+-interquartile range).

case series did not receive thromboelastometry, there may be bene- fit of using thromboelastometry to guide reversal when a patient presents on both anticoagulation and antiplatelet agents. Also, rou- tine CYP-2C19 genetic testing for clopidogrel responsiveness was not conducted at our institution.

Conclusions

Although guidelines recommend 4F-PCC for reversal of anticoagulant-induced hemorrhage and DDAVP for reversal of antiplatelet-associated hemorrhage, there is no available evidence to guide concomitant reversal. This exploratory case series demonstrates that both agents were administered to mild cases of life-threatening bleeding without an increased risk of thrombosis at 30-days post dis- charge. Larger, prospective studies are warranted to confirm these find- ings and explore the efficacy of Combination therapy.

Author statement

DM- conceptualization of the case series, writing - original draft, writing - review & editing; OK- writing - original draft, writing - review & editing; MR: conceptualization, visualization, supervision, writing - review & editing

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

None.

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