American Journal of Emergency Medicine xxx (2014) xxx–xxx

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Brief Report

Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED Mehmet Ali Karaca a,⁎, Bulent Erbil a, Mehmet Mahir Ozmen b a b

Emergency Medicine Department, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey General Surgery Department, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey

a r t i c l e

i n f o

Article history: Received 8 January 2014 Received in revised form 13 February 2014 Accepted 15 February 2014 Available online xxxx

a b s t r a c t Objectives: High International Normalized Ratio (INR) level resulting from warfarin use increases the risk of gastrointestinal hemorrhages. We aimed to compare the efficacy of prothrombin complex concentrates (PCC) and fresh frozen plasma (FFP) at lowering the INR level, decreasing active hemorrhages visible by endoscopy, and shortening the length of stay at the emergency department (ED). Method: This study is a prospective cohort study of consecutive patents with gastrointestinal hemorrhages that received either PCC or FFP. With strict exclusion criteria, only patients over 18 years of age with a high INR level (N 2.1) due to warfarin usage were included. Results: A total of 40 patients (18 female) were included in the study, 20 each in the PCC and FFP groups. For the PCC group, the mean INR levels at the second and sixth hours were lower than those for the FFP group (second hour INR: 1.53 vs 4.50, P b .01, sixth hour INR: 1.52 vs 2.41, P b .01). Seven patients experienced active bleeding (Forrest 1) in the FFP group, whereas no patient experienced active bleeding in the PCC group based on the Forrest classification (35% vs 0%, P b .01), and only 3 patients in the FFP group underwent invasive/ surgical treatment (15% vs 0%, P b .01). The ED length of stay was lower for the PCC group (1.62 days vs 3.46 days, P b .01). Conclusion: For patients experiencing a gastrointestinal hemorrhage, INR levels were reversed more quickly, there was less active bleeding on endoscopy, and the ED length of stay was lower in the PCC group than in the FFP group. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Warfarin is currently the most commonly used oral anticoagulant, and it inhibits the biosynthesis of factor II, VII, IX, and X, which are vitamin K dependent procoagulant factors [1]. Warfarin has a narrow therapeutic window and can cause a variety of frequent hemorrhages, including life threatening major hemorrhages [2]. Major hemorrhages are typically witnessed in the gastrointestinal system, urinary system and soft tissues, and their annual occurrence rate in patients receiving anti-coagulation medications is 6.5% [3]. Approximately one in 10 major hemorrhages are fatal [4]. This hemorrhage risk increases in parallel with an increase in the International Normalized Ratio (INR) level [5,6]. The principle behind immediately reversing the warfarin effect is to increase or replace vitamin K dependent coagulation factors quickly ⁎ Corresponding author. Tel.: +90 532 5918202 (GSM). E-mail addresses: [email protected], [email protected] (M.A. Karaca), [email protected] (B. Erbil), [email protected] (M.M. Ozmen).

and efficiently [1]. For this purpose, fresh frozen plasma (FFP) is commonly used allowing for quick but partial correction of coagulopathy [7]. FFP has isohemagglutinins, and blood-group specific FFP should be given to patients. Therefore, time is required to prepare FFP, which may result in delayed treatment. Additionally, FFP generates a risk of infection, and large quantities of FFP are necessary for patients with a high INR level. Adequate FIX levels cannot be achieved with the currently suggested FFP doses because FFP contains various amount of FIX (FIX levels in Turkey in 96% of FFP: N0.70 IU/mL) [6,8-10]. Prothrombin complex concentrates (PCC) provide a quick and effective correction of deficient coagulation factors and were first used in 1976. PCC includes factors II, VII, IX and X, which are obtained as recombinants. PCC has a low infusion volume, can be prepared quickly, and does not carry the risk of infection; therefore, it is used to reverse the warfarin effect immediately at many centers [1,11]. Despite the fact that PCC has been used to reverse the warfarin effect for 35 years, there are very few studies that compare the efficiency of PCC and FFP. This is the first prospective study to compare the effects of PCC and FFP in patients with gastrointestinal bleeding due to warfarin usage. The present study was aimed to compare the

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Please cite this article as: Karaca MA, et al, Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin us..., Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.02.016

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M.A. Karaca et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx

Fig. 1. Patient selection and treatment algorithm.

efficacy of PCC and FFP on decreasing INR, reducing active hemorrhage noted on endoscopy, and shortening patients’ length of stay at the emergency department (ED).

2. Patients and methods This is a prospective cohort study of consecutive patients alternately selected by the authors. After approval from the local ethics committee, a total of 40 (18 F) patients over 18 years of age with high INR (N2.1) levels due to warfarin usage and upper gastrointestinal system hemorrhage were included in the study. Patients with chronic liver disease, any history of acute thromboembolic disease, disseminated intravascular coagulation, sepsis, pregnancy, cancer, or hemorrhagic diathesis due to causes other than warfarin usage were excluded from the study. The patients included in the study were divided into FFP and PCC groups by the authors (MAK, BE) at triage unit, and informed consent was obtained from all participants. For all patients, demographic characteristics, laboratory values, blood and FFP transfusion counts, endoscopy findings, including active hemorrhage presence, sclerotherapy requirements, Forrest scores, length of stays in the emergency department and Table 1 Forrest classification [14] Forrest 1a: Spurting hemorrhage Forrest 1b: Oozing hemorrhage Forrest 2a: Visible vessel Forrest 2b: Adherent clot Forrest 2c: Flat pigmented hematin on ulcer base Forrest 3: Lesions without signs of recent hemorrhage or fibrin-covered clean ulcer base.

wards, admission ratios to wards and intensive care units, complications, and mortality rates were evaluated. While calculating the PCC dosage for patients, the “Cofact Individualized Dosage Regime Calculation Guide” [12] (Sanquin, Amsterdam, The Netherlands) was used. For minor (immediate) surgery or serious overdosing, the aim was to decrease the target INR Table 2 Patients' characteristics Demographic features

PCC (n = 20)

FFP (n = 20)

Sex (Male/Female) Age (mean) (years) Concomitant diseases Hypertension Diabetes mellitus Coronary artery disease CVA Valvular disease/replacement PE/DVT, thrombosis Dysrhythmia Main complaints Hematemesis Melena Hematochezia Syncope Hematemesis + melena Initial laboratory results Hb (mg/dl) Htc (%) Plt X1000

12/8 68.3 (48-86)

10/10 66.5 (40-88)

10 5 8 4 10 5 8

10 3 8 0 7 2 9

3 8 2 3 4

1 12 2 0 5

6.74 (4.1-11.5) 20.22 (12.2-33.9) 263.90 (107–352)

7.3 (4.3-13) (P = .426) 21.69 (13–37) (P = .470) 275.35 (108–440) (P = .63)

CVA, cerebrovascular accident; PE, pulmonary embolism; DVT, deep venous thrombosis.

Please cite this article as: Karaca MA, et al, Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin us..., Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.02.016

M.A. Karaca et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx

FFP (n = 20)

13.20 1.53 1.52 3.15 1.62 5.60

9.97 4.50 2.41 4.30 3.46 7.36

(4.45-21.0) (1.14-2.30) (1.09-2.13) (0–6) (0.5-3) (2-14)

PCC

12

PCC (n = 20)

FFP

9.97

(2.96-21) (P = .076) (2.18-12.2) (P = .000) (1.19-5.0) (P = .000) (1-9) (P = .058) (2-13) (P = .000) (2–40) (P = .583)

Plt, Platelet; INR1, INR level at admission; INR2, INR level at the second hour after admission; INR3, INR level at the sixth hour after admission; RBC, red blood cell.

INR LEVEL

INR1 INR2 INR3 RBC transfusion (U) Length of stay in ED (d) Length of stay at hospital (d)

13.2

14

Table 3 INR levels, transfusion rates, and hospital length of stay

3

10 8 6

4.5

4 2 0

0.hour

1.53

2.41 1.52

2nd.hour

6th hour

TIME to 2.1 (Situation A), and for cases requiring major surgery or cases with a life threatening hemorrhage, the aim was to decrease the target INR to 1.5 (Situation B). In the present study, the target INR level was determined as b 1.5. However, an INR level of b2.1 was accepted as a sufficient reversal of oral anticoagulant treatment (OAT) to allow endoscopy to be performed on the patient (Fig. 1). Based on guides [13] and the “Cofact® Individualized Dosage Regime Calculation Guide” [12], patients in the PCC group were administered 25-50 IU/kg of body weight PCC [Cofact® (Sanquin, Amsterdam, The Netherlands) (FII = 140-350 IU, FVII = 70-200 IU, FIX = 250 IU, FX = 140-350 IU)]. Diluted vials of 10 mL = 250 IU were administered intravenously at a rate of 2 mL/min. The FFP dosage was calculated as 10-15 ml/kg (FIX levels in FFP = 0.81-0.89 IU/mL) [10]. All patients were administered 10 mg vitamin K1 intravenously (Fig. 1). PCC infusion was completed in approximately 1 h and 45 min (lab results of INR levels: ~ 1 h, PCC infusion: ~ 45 min), and FFP infusion was completed in approximately 5 h after admission. Therefore, to determine the efficiency of the treatment, INR levels were measured in all patients at the time of admission (INR1) (before the treatment), 2 h after admission (INR2) (15 min after PCC infusion) and 6 h later (INR3) (1 h after the completion of FFP infusion). Hemoglobin (Hb) and hematocrit (Htc) level monitoring was performed at approximately 2-h intervals, and if there was an indication of bleeding, an erythrocyte (ES) transfusion was performed to attain Hb levels of ≥ 10 mg/dl. Upper endoscopy was performed on patients after their INR reached an efficient level (INR b 2.1) (Fig. 1). Based on the endoscopy results, the patients' risk categories were determined according to the Forrest classification [14], in which Forrest 1a and 1b indicate acute hemorrhage, Forrest 2a, 2b, and 2c indicate signs of recent hemorrhage, and Forrest 3 indicates lesions without active bleeding (Table 1). For statistical analysis, SPSS for Windows® version 21 was used, and P b .05 was considered significant. The normality of the numeric variants in the groups was checked with the Shapiro Wilks test. An Independent t test was applied for the normally distributed variants, and a Mann–Whitney U test was applied for the non-normally distributed variants. The relation of the categorical variants was 30 25 20 15 10 5 0

1

2

PCC Hb (mg/dl)

FFP Hb (mg/dl)

3 PCC Htc (%)

Fig. 2. Time dependent change of Hb and Htc levels.

4 FFP Htc (%)

0 hour p=0.076, 2nd hour p=0.00, 3rd hour p=0.00 Fig. 3. Time dependent change of mean INR levels.

evaluated with a χ 2 test. For the Hb and Htc changes in time within the groups, the data were analyzed using 2-way repeated measures. 3. Results There were a total of 40 patients (18 Female), with 20 in the FFP group and 20 in the PCC group. The mean (range) age of the patients was 67 (40-88) years. The patients' demographic characteristics and initial laboratory results are listed in Table 2, and there were no differences between the groups. The INR levels are listed in Table 3. The INR levels at hours 2 and 6 were lower in the PCC group than in the FFP group, and there was a significant difference between the groups (Table 3, Fig. 3). For 17 of the 20 patients who received PCC (85%), the INR level at the second hour was b 2.1, while none of the patients who received FFP had an INR level at or below 2.1; there was a statistically significant difference in this value between the groups (P b .001). The INR level at the sixth hour was b2.1 for 17 patients who received PCC (85%) and six (30%) in the FFP group; there was a significant difference in this value between the groups (P b .0001). In the PCC group, patients received 7.65 ± 1.26 vials (1 vial = 10 ml = 250 IU) (min = 5, max = 9) of PCC. The groups were analyzed based on patient need for FFP transfusion. For three patients in the PCC group, efficient INR reversal was not achieved at the second hour. In addition, there was a rebound INR level increase in two of the PCC patients at 48 h, and PCC cessation

Table 4 Endoscopic findings PCC (n = 20) Diagnosis Normal Gastric bleeding Gastric ulcer Gastric ulcer with adherent Clot Duodenal bleeding Duodenal ulcer Active bleeding Yes No Sclerotherapy Yes No Endoscopic Forrest classification Forrest 1a Forrest 1b Forrest 2a Forrest 2b Forrest 2c Forrest 3

FFP (n = 20)

N (%) 3 (15%) 0 11 (55%) 1 (5%)

N (%) 0 2 (10%) 8 (40%) 1 (5%)

0 5 (25%)

5 (25%) 4 (20%)

0 20 (100%)

7 (35%) 13 (65%)

(P = .008)

1 (5%) 19 (95%)

10 (50%) 10 (50%)

(P = .005)

0 0 1 (5%) 0 1 (5%) 18 (90%)

6 (30%) 1 (5%) 0 1 (5%) 2 (10%) 10 (50%)

g

(P = .005)

(P = .01)

Please cite this article as: Karaca MA, et al, Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin us..., Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.02.016

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M.A. Karaca et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx

Table 5 Patients' disposition Disposition

PCC

FFP

ED-treated and discharged Hospitalization in wards Hospitalization in ICU Patient died Total

8 8 3 1 20

7 (35%) 8 (40%) 4 (20%) 1 (5%) 20 (100%)

(40%) (40%) (15%) (5%) (100%)

ICU, intensive care unit.

occurred for one patient; therefore, FFP transfusion after PCC was necessary for three patients in the PCC group. The mean FFP transfusion volume in the FFP group was 5.05 [2-10] U. The mean ES transfusion volumes were 3.15 (0-6) units in the PCC group and 4.30 [1-9] U in the FFP group, but this difference was not significant (P = .058) (Table 3). When the graphs of Hb and Htc levels showing changes over time were examined, no significant difference was found between the groups (P = .094) (Fig. 2). When the INR level decreased to 2.1 or below, upper endoscopy was performed on all patients. On average, upper endoscopy was performed 8 h (range: 6-12 h) after admission in the PCC group and 12 h (range: 8-24 h) in the FFP group; the difference in that value was statistically significant (P = .015). Endoscopy revealed active hemorrhage in seven patients (35%, Forrest 1a and 1b) in the FFP group, but no active hemorrhage (Forrest 1) was observed in the PCC group (P = .008). Sclerotherapy was performed in one patient (5%) (Forrest 2a) in the PCC group and in 10 patients (50%) in the FFP group, and the difference in the frequency of sclerotherapy between the groups was statistically significant (P = .005) (Table 4). The hospitalization ratios and the lengths of the hospital stays are given in Tables 3 and 5. The length of stay at the emergency department in the PCC group was shorter than that in the FFP group (P = .000), whereas the total length of stay at the hospital was not different between the groups (P = .583). In three (15%) patients in the FFP group, the gastrointestinal hemorrhage recurred. Angio-embolization was performed on the gastroepiploic artery of one patient because of an active hemorrhage (Forrest 1a) in the duodenal bulbus. Surgery was performed in one patient because of an active hemorrhage in the bulbus (Forrest 1a) and in other patient because of an ulcerous lesion covered with coagulum and mass (Forrest 2b). There was no need for invasive/ surgical treatment in any patients in the PCC group, and the difference in the number of invasive/surgical treatments required between groups was statistically significant (P b .001). One patient in each group died. 4. Discussion This is the first prospective study to compare PCC and FFP treatment in patients with gastrointestinal hemorrhage who were treated with warfarin and had a high INR level. PCC was found to be more effective than FFP in decreasing INR, reducing active hemorrhage noted on endoscopy and reducing the need for invasive/surgical procedures, with less hemorrhage recurrences and shorter ED stays. Patients with gastrointestinal hemorrhages resulting from high INR due to warfarin treatment are an at risk group in terms of morbidity and mortality; therefore, they require immediate treatment. Deficient coagulation factors resulting from warfarin usage are commonly replaced with FFP. However, preparation of FFP takes time and this causes a delay in the treatment. Although the optimal FFP dose has not yet been clearly identified, the frequently recommended FFP dose is 15 ml/kg [13,15]. Patients with a high INR level require a high volume FFP transfusion in a short time

period, which can cause cardiac decompensation in patients with a limited cardiac reserve [5,6,9]. Additionally, because the dilution and factor levels in FFP are not standard, sufficient factor replacement is not guaranteed with FFP treatment [16]. On the other hand, PCC provides a fast and efficient replacement of factors that are deficient due to warfarin usage. Furthermore, its infusion volume is low, it can be prepared quickly and it does not carry the risk of infection [8,17,18]. There are many studies that have shown the efficiency of PCC at providing normal hemostasis at different doses. In our study, the PCC doses used were within the range of 25 to 50 IU/kg according to the guides used (Australasian guidelines [13] and “Individualized Dosage Regime Calculation Guide” [12]), and the dose was administered intravenously at a rate of 2 ml/min. We determined that mean the INR level in 85% of the patients in the PCC group at the second hour after admission regressed from 13.20 to 1.53, and the INR levels at the sixth hour regressed to 1.52. At the dose of PCC we administered, we observed an efficient and quick recovery of patient INR levels, similar to those reported in previous publications. In contrast, Wozniak et al. retrospectively examined 213 patients who were administered the standard PCC dose of 40 ml (14 IU/kg) to reverse the warfarin effect; they reported that the INR levels dropped below 1.5 in 76% of the patients and that this dose is sufficient in patients without hemorrhages [19]. Additionally, Lubetsky et al reported that, in 20 patients who either had a major hemorrhage or required emergency surgery, INR levels dropped within 10 min after injecting a 25–30 IU/kg PCC dose. Of those patients, 85% responded well to PCC treatment (hemorrhage stopped immediately), and the remaining patients responded at a medium level (hemorrhage continued for 24–36 h and a RBC transfusion was necessary) [20]. Studies in the literature have compared the collective usage of PCC and FFP to FFP usage exclusively and reported that INR levels were more efficiently recovered with the collective usage of PCC and FFP than with FFP usage alone [8,17]. In our study, there was a faster and more effective recovery in INR levels with PCC treatment, but an additional FFP transfusion was needed in three patients in the PCC group due to the occurrence of additional co-morbidities (inefficient reversal and rebound high INR in one patient with acute renal failure, and one patient with a hematoma in the jejunum). The INR levels of a patient with acute renal failure and a patient with a hematoma in the jejunum dropped to an efficient level with additional FFP treatment, but a rebound INR level increase developed in those patients within 48 h. In a third patient who had hepatic vein thrombosis in the inferior vena cava and mesenteric vascular occlusion, although his INR levels had decreased to an efficient level with additional FFP treatment, he died due to multiple organ failure. Hickey et al. showed that the coadministration of vitamin K prevents rebound INR increases; however, in our study, we administered vitamin K to all patients and could not find any explanation for the observed rebound increase in INR level [21]. In previously published studies that compared FFP and PCC efficiencies, gastrointestinal hemorrhage events were found to be sub-groups of major hemorrhage events. No isolated prospective study of patients with gastrointestinal hemorrhage due to warfarin usage has been conducted previously. Our study is the first to examine PCC and FFP efficiency and clinical prognoses of patients with isolated upper gastrointestinal hemorrhage due to over anticoagulation resulting from warfarin usage. In our study, upper endoscopy was performed on the patients after their INR values dropped below 2.1. Following the PCC/FFP infusion, an active hemorrhage was diagnosed in seven patients (35%, Forrest 1a and 1b) in the FFP group, whereas no active hemorrhages were found in the PCC group. Sclerotherapy was performed based on endoscopy results. Sclerotherapy was performed on only one patient (5%) in the

Please cite this article as: Karaca MA, et al, Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin us..., Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.02.016

M.A. Karaca et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx

PCC group due to a visible vessel lesion, whereas in the FFP group, it was performed on 10 patients (50%) due to active hemorrhages and visible vessel lesions. Three patients in the FFP group experienced a hemorrhage recurrence, and these patients were treated with invasive/surgical methods; no recurrent hemorrhages was observed in the PCC group. These results show that, in addition to decreasing INR levels quickly, PCC causes less active bleeding on endoscopy and prevents bleeding recurrences. When the ES transfusion ratios between the groups were examined, even though there was no significant difference between the two groups, the ratio was lower in the PCC group (3.15 vs 4.30 U). This shows that PCC treatment generated hemostasis sooner than FFP treatment. Similarly, Hackey et al found that PCC lowers the required volume of red cell transfusions (3.2 vs 1.4 U) [21]. PCC shortens a patient's length of stay at the emergency department significantly because it generates hemostasis early and fast. The mean length of stay at the emergency department was 1.62 days in the PCC group, whereas it was 3.46 days in the FFP group. The early hemostasis generated by PCC usage allows for an earlier endoscopy, and this increases the speed of bed turnover at the emergency department, a critical factor in ED management. The mortality ratios were the same in both groups. One patient in the PCC group was admitted with a gastrointestinal hemorrhage and abdominal pain; an abdominal computed tomography (CT) revealed a hepatic vein, inferior vena cava thrombosis and mesenteric vascular occlusion, and the patient died due to multiple organ failure. In the literature, it has been reported that potentially fatal thromboembolic events can develop as a result of PCC usage. Such thromboembolic events may be caused by malignancies, coagulation defects and fast infusions of PCC. Pulmonary emboli and disseminated intravascular coagulation were reported by these studies [22-24]. In our study, one patient in the PCC group underwent an abdominal CT at the time of admission due to abdominal pain, and upon examining the thromboembolic findings, the PCC infusion was ceased and the FFP infusion was initiated. Thromboembolic determination through abdominal CT in addition to the initial examination, leads us to believe that the thromboembolic event and disseminated intravascular coagulation were present in the patient before administering the PCC infusion. One patient in the FFP group died due to a hematoma growth around the aortofemoral graft. 5. Conclusion In patients with gastrointestinal hemorrhage, PCC treatment reversed INR levels more quickly, resulted in less active bleeding on endoscopy, and lowered the ED length of stay compared with FFP treatment.

5

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Please cite this article as: Karaca MA, et al, Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin us..., Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.02.016

Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED.

High International Normalized Ratio (INR) level resulting from warfarin use increases the risk of gastrointestinal hemorrhages. We aimed to compare th...
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