J Thromb Thrombolysis (2016) 42:19–26 DOI 10.1007/s11239-015-1330-3
3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe Bleeding: A Multicenter, Retrospective, Propensity-Matched Pilot Study G. Morgan Jones1,2,3 • Michael J. Erdman4 • Keaton S. Smetana5 Kerry M. Mohrien6 • Joseph E. Vandigo7 • Lucas Elijovich3,8
•
Published online: 31 December 2015 Springer Science+Business Media New York 2015
Abstract Current guidelines recommend 4-factor prothrombin complex concentrate (4PCC) for emergent reversal of bleeding secondary to warfarin. While current research has demonstrated superiority of 4PCC over plasma, direct comparisons with 3-factor PCC (3PCC) are lacking. The purpose of this study is to compare the efficacy and safety of 3PCC and 4PCC. We conducted a retrospective analysis of patients who received PCC at one of four medical centers. All patients in the 3PCC group were treated at one center that utilizes a fixed, weight-based dosing protocol. After evaluation of all patients meeting inclusion criteria, propensity-score matching was used to adjust for differences in treatment characteristics. There was no difference in the primary outcome of INR B 1.4 between 3PCC and 4PCC in both the unmatched (85.7 vs. 90.6 %; p = 0.37) and matched (84.2 vs. 92.1 %;
p = 0.48) analyses. There was a significant difference in goal INR achieved favoring 4PCC (56.3 vs 90.0 %; p \ 0.02) when baseline INR [ 4.0. A total of three thrombotic events were documented, all in the 4PCC group. We found no difference in the rate of INR reversal in those treated with 3PCC and 4PCC. However, those with a baseline INR [ 4.0 may experience more successful INR reversal with 4PCC.
& G. Morgan Jones [email protected]
3
Department of Neurology and Neurosurgery, UTHSC, 920 Court Ave, Memphis, TN 38163, USA
Michael J. Erdman [email protected]
4
Department of Pharmacy, University of Florida Health, 655 West 8th Street, Jacksonville, FL 32209, USA
Keaton S. Smetana [email protected]
5
Department of Pharmacy, University of Kentucky HealthCare, 800 Rose St, Lexington, KY 40536, USA
Kerry M. Mohrien [email protected]
6
Department of Pharmacy, Temple University Hospital, 3509 N Broad St, Philadelphia, PA 19140, USA
Joseph E. Vandigo [email protected]
7
Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, 620 W Lexington St, Baltimore, MD 21201, USA
8
Semmes-Murphey Neurologic and Spine Institute, 6325 Humphreys Blvd, Memphis, TN 38120, USA
Lucas Elijovich [email protected] 1
Department of Pharmacy, Methodist University Hospital, 1265 Union Avenue, Memphis, TN 38104, USA
2
Department of Clinical Pharmacy, University of Tennessee Health Sciences Center (UTHSC), 920 Court Ave, Memphis, TN 38163, USA
Keywords Anticoagulation therapy Hematology Hemorrhagic disorders Prothrombin Abbreviations 3PCC 3-Factor prothrombin complex concentrate 4PCC 4-Factor prothrombin complex concentrate FFP Fresh frozen plasma
123
20
INR IQR PCC
G. M. Jones et al.
International normalization ratio Interquartile range Prothrombin complex concentrate
Introduction Warfarin is one of the oldest and widely used anticoagulants, accounting for more than 25 million prescriptions annually [1]. The yearly incidence of warfarin-associated major hemorrhage is estimated to be as high as 3.4 %, accounting for more than 60,000 annual visits to emergency departments in the United States alone [2, 3]. In warfarin-associated major bleeding, emergent reversal is essential given the associated high rates of mortality and potential for improved outcomes with rapid reversal [4–6]. The quickest and most reliable method to reverse the anticoagulation effects of warfarin involves the administration of prothrombin complex concentrate (PCC). In 2013, 4-factor PCC (4PCC) became the first product approved in the United States specifically for warfarin reversal, with 3-factor (3PCC) products being widely used off label prior to this date. While both formulations contain all clotting factors inhibited by warfarin (II, VII, IX, and X), 4PCC contains a larger amount of factor VII than available 3PCC agents [7, 8]. Despite the difference in factor composition, both products have been shown to be more effective than fresh frozen plasma (FFP) at rapidly reversing INR [9–11]. Available evidence comparing 3PCC to 4PCC for reversal of INR is limited to indirect evaluations that are hindered by heterogeneity in dosing, concomitant usage of vitamin K and FFP, and baseline INR values [12]. Notwithstanding this lack of comparable data, clinical guidelines recommend the use of 4PCC for rapid reversal [13, 14]. 3PCC may offer potential advantages including lower medication costs and a possible reduction in the risk of thrombosis [11]. Given the lack of direct comparisons, our pilot study sought to directly compare the rates of INR reversal and risk of thrombosis between 3PCC and 4PCC.
Materials and Methods This retrospective, propensity-matched pilot study was conducted at four major academic medicals centers in the United States and consisted of two cohorts. All patients in the 3PCC group were treated at Methodist University Hospital in Memphis, TN, which utilizes a fixed, weightbased dosing protocol for PCC administration [15]. All patients in this group received the same 3PCC product,
123
Bebulin VH (Baxter Healthcare, Deerfield, IL), which contains 0.05–0.2 units of factor VII per unit of factor IX [7]. Patients in the 4PCC group were treated with KCentra (0.5– 0.8 units of factor VII per unit of factor IX; CSL Behring, King of Prussia, PA) [8] at three institutions that use identical dosing protocols (Fig. 1): University of Florida Health (Jacksonville, FL), University of Kentucky HealthCare (Lexington, KY), and Temple University Hospital (Philadelphia, PA). Institutional review board approval was obtained at each of the participating medical centers. We conducted this pilot study in order to evaluate the approximate effect size in a real-world setting in order to determine the feasibility of conducting a full-scale comparison between the two agents. We included patients C18 years of age who were treated with PCC for reversal of warfarin due to intracranial hemorrhage, gastrointestinal hemorrhage, other bleeding associated with a fall in hemoglobin C2 g/dL, or emergent reversal for acute surgical intervention and discharged between January 1, 2012 and April 15, 2015. Exclusion criteria are listed in Fig. 2. Investigators at each site extracted all data from the institution’s electronic medical record. The primary outcome was the percent of patients achieving an INR B1.4 at initial follow-up INR after PCC administration. We also reported the number of thrombotic events after treatment with PCC as a secondary outcome measure. We planned a priori to complete a subgroup analysis of patients presenting with a baseline INR[4. Data collected included age, body weight, indication for PCC use, PCC dosing information, administration of vitamin K and/or FFP, baseline and subsequent INR results, discharge status, and incidence of any thrombotic events within 7 days of PCC administration. Initially, we evaluated all patients who received PCC and then utilized a propensity score matching approach to adjust for baseline differences and minimize bias between groups. In both the unmatched and propensity-matched analysis, continuous data were analyzed using the Student t test for parametric data and the Mann–Whitney U test for nonparametric data. Categorical data were analyzed using either the v2 test or the Fisher exact test. Normally distributed data are presented as mean (standard deviation) and non-normally distributed data as median (25–75 % interquartile range). All times are presented as minutes: seconds. All tests were 2-tailed, and p \ 0.05 was used to represent statistical significance. All analysis, other than propensity score generation, was performed using SPSS, version 21.0 for Windows (SPSS, Inc., Chicago, IL). Propensity scores were calculated via logistic regression and based upon the following variables: age, height, ideal and actual body weight, indication for PCC use, baseline INR, and use and dose of vitamin K. Model performance was assessed using the area under receiver operating
3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe…
Pre-treatment INR: 3PCC Dosing: 4PCC Dosing:
2.0 – 3.9
21
4.0 – 6.0
> 6.0
30 units/kg ABW with no maximum dose 25 units/kg ABW Max: 2,500 units
35 units/kg ABW Max: 3,500 units
50 units/kg ABW Max: 5,000 units
Fig. 1 Institution specific dosing of prothrombin complex concentrate. INR international normalized ratio, ABW actual body weight, 3PCC 3-factor prothrombin complex concentrate, 4PCC 4-factor prothrombin complex concentrate Fig. 2 Flowchart of patients. PCC prothrombin complex concentrate, INR international normalized ratio, 3PCC 3-factor prothrombin complex concentrate, 4PCC 4-factor prothrombin complex concentrate
characteristic curve. Each 3PCC patient was then matched to a 4PCC patient (1:1, nearest-neighbor, no replacement) on the logit of the propensity score using calipers equal to 0.20 of the standard deviation of the logit of the propensity score [16, 17]. The propensity score logit model and matching procedure was completed using STATA 13.1 (Stata Corporation, College Station, TX).
Results Unmatched Analysis We included 84 patients treated with 3PCC and 64 with 4PCC and no data was missing for any included patient. A total of 100 patients were excluded (Fig. 2). While baseline
characteristics were largely similar between groups (Table 1), those treated with 3PCC were more likely to be admitted with an intracranial hemorrhage (95.2 vs. 62.5 %; p \ 0.001), have a lower median baseline INR (2.6 vs. 3.0; p = 0.006), and have fewer patients with a baseline INR [4 (19.0 vs. 34.4 %; p = 0.03) than those in the 4PCC group. The total number of INR measurements in the first 24 h after PCC administration was similar between groups (2.0 [1.0–3.0] vs. 2.0 [2.0–3.0]; p = 0.26), but time to first follow-up INR was longer in the 3PCC group (48:59 vs. 23:40; p = 0.005). Nearly all patients in both groups (90.5 vs. 92.2 %; p = 0.72) received vitamin K, with 81.1 % of all patients treated with initial doses of 10 mg. The use of adjunctive FFP was significantly higher in the 4PCC group (6.0 vs. 53.1 %; p = 0.001) with the median amount administered in both groups being 2 [2, 3] units. No patients in the 3PCC group
123
22
G. M. Jones et al.
received FFP prior to the first follow-up INR, while 14 (21.9 %) patients in the 4PCC group received FFP prior to repeat INR (Table 2). Overall, there was no difference in the primary outcome of INR B 1.4 between the 2 groups (85.7 vs. 90.6 %; p = 0.37). The actual median INR measurement was slightly lower in the 4PCC group (1.3 [1.2–1.4] vs. 1.2 [1.1–1.4]; p = 0.001) upon first follow-up, but was the same at 24 h. In the 38 patients with a baseline INR [ 4.0, 16 received 3PCC and 22 received 4PCC. There was a statistically significant difference in the rate of goal INR achieved following PCC administration favoring 4PCC (56.3 vs. 90.0 %; p \ 0.02). However, there remained a large imbalance in the receipt of FFP favoring 4PCC patients with a baseline INR [ 4 (18 of 22 patients compared to 3 of 16 patients in the 3PCC group). A total of 3 thrombotic events were documented (2 myocardial infarctions and 1 deep vein thrombosis) with all events occurring in the 4PCC group. There were no documented infusion reactions, although 1 patient in the 4PCC group was excluded after they developed hypotension shortly after initiation of the infusion resulting in the medication being stopped.
curve = 0.77). The model showed no evidence of lack of fit based on the non-significant Hosmer–Lemeshow statistic (p value [0.90). In this cohort, 36 patients in the 3PCC group were matched to an equal number of patients receiving 4PCC. All statistically significant differences in baseline characteristics in the unmatched cohort did not remain after propensity score matching, with the exception of receipt of FFP remaining higher in the 4PCC group (5.3 vs. 52.6 %; p \ 0.001). Due to the extremely small number of patients in the 3PCC group receiving FFP, we were unable to adjust for this in our statistical model. As in the unmatched analysis, patients showed no statistical difference in the primary outcome between 3PCC and 4PCC (84.2 vs. 92.1 %; p = 0.48). Median INR measurement remained the same between groups, as did the time to first follow-up INR. The same difference in reversal rates was observed (91.7 % 4PCC vs 44.4 % 3PCC; p = 0.04) in the 21 patients who presented with INR [ 4 in the propensitymatched analysis. Those in the 4PCC group continued to receive more FFP prior to first follow-up INR than those in the 3PCC group (0 vs 21.1 %;p = 0.003).
Discussion Propensity-Matched Analysis The logistic regression model used to generate the propensity score demonstrated an acceptable ability to differentiate between patients who received 3PCC and 4PCC (area under the receiver operator characteristic
We observed no difference in the rate of INR reversal achieved in both the unmatched and propensity-matched cohorts of our study. In our entire cohort, we observed rapid and complete reversal of INR for the 24-h period after PCC administration in those who received any PCC.
Table 1 Patient characteristics Unmatched cohort
Age (years)
Matched cohort
4-Factor (n = 64)
3 Factor (n = 84)
p
4-Factor (n = 36)
3 Factor (n = 36)
p
72.5 [58.5–80.0]
75.5 [64.0–83.0]
0.06
75 [66–80]
67 [57–77]
0.09
Male, n (%)
38 (59.4)
45 (53.6)
0.48
20 (52.6)
21 (55.3)
0.82
African American, n (%)
20 (31.3)
36 (42.9)
0.15
11 (28.9)
10 (26.3)
0.80
Height (centimeters)
172.7 [162.6–182.8]
172.0 [163.0–180.0]
0.99
171.5 [162.6–178.0]
173.9 [165.0–178.0]
0.74
Actual body weight (kilograms)
82.5 [72.4–100.3]
84.8 [70.2–100.8]
0.99
81.8 [72.6–99.0]
84.8 [68.0–101.6]
0.91
Reversal indication Intracranial hemorrhage, n (%)
40 (62.5)
80 (95.2)
\0.001
34 (89.5)
34 (89.5)
[0.99
Gastrointestinal hemorrhage, n (%)
11 (17.2)
2 (2.4)
0.002
2 (5.3)
2 (5.3)
[0.99
13 (20.3)
2 (2.4)
\0.001
1 (2.6)
1 (2.6)
[0.99
8.0 [3.0–14.5]
6.1 [3.8–9.5]
0.07
10.5 [2.0–14.0]
6.2 [3.8–10.8]
0.40
Other, n (%) Duration of hospitalization (days) Discharge status Morgue, n (%)
18 (28.1)
26 (31.0)
0.71
16 (42.1)
13 (34.2)
0.50
Facility, n (%)
24 (37.5)
40 (47.6)
0.08
13 (34.2)
18 (47.4)
0.24
Home, n (%)
22 (34.4)
18 (21.4)
0.08
25 (65.8)
20 (52.6)
0.24
All data are presented as median [25–75 % interquartile range] unless otherwise noted
123
3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe…
23
Table 2 Anticoagulation reversal information Unmatched
Matched
4-Factor (n = 64)
3 Factor (n = 84)
p
4-Factor (n = 36)
3 Factor (n = 36)
p
Baseline
3.0 [2.2–4.6]
2.6 [2.2–3.5]
0.006
2.9 [2.3–4.1]
2.8 [2.2–3.9]
0.43
Baseline C 4
22 (34.4)
16 (19.0)
0.03
12 (31.6)
9 (23.7)
0.44
Immediately after PCC
1.2 [1.1–1.4]
1.3 [1.2–1.4]
\0.001
1.2 [1.1–1.3]
1.3 [1.3–1.4]
0.002
24 h-post PCC
1.2 [1.0–1.4]
1.2[1.2–1.3]
0.98
1.2 [1.0–1.4]
1.2[1.2–1.3]
0.87
Time between PCC dose and follow up INR (mm:ss)
23:40 [15:33–90:00]
48:59 [31:00–91:00]
0.005
20:00 [14:01–60:00]
40:30 [30:00–88:00]
0.009
INR at goal (B1.4)
58 (90.6)
72 (85.7)
0.37
35 (92.1)
32 (84.2)
0.48
INR measurements
PCC dosing Initial (units)
2500 [2000–2852]
2454 [2228–3045]
0.29
2380 [2000–2699]
2429 [2228–3090]
0.22
Initial per kilogram actual body weight (units)
26.3 [24.7–34.3]
30.6 [28.2–32.3]
0.003
25.6 [23.5–31.7]
30.6 [28.3–32.3]
0.005
Supplemental reversal agents received Vitamin K, n (%)
59 (92.2)
76 (90.5)
0.72
36 (94.7)
37 (97.4)
0.56
FFP, n (%)
34 (53.1)
5 (6.0)
\0.001
20 (52.6)
2 (5.3)
\0.001
All data are presented as median [25–75 % interquartile range] unless otherwise noted INR international normalization ratio, PCC prothrombin complex concentrate, FFP fresh frozen plasma
The number of adverse thrombotic events was low, with only three events occurring amongst all 148 patients. In a randomized, controlled trial comparing the two agents, approximately 1450 patients would be needed to achieve 80 % power (a = 0.05, b = 0.20, continuity corrected) to detect the 5 % difference in the primary outcome observed in this pilot study. While current guidelines [13] recommend 4PCC as primary choice for emergent warfarin reversal, there is very limited evidence directly comparing the two products. Recently, a retrospective, single-center cohort study compared the efficacy of 3PCC and 4PCC in 53 patients actively bleeding due to warfarin. The primary outcome was the percentage of patients achieving INR B 1.3 at their first INR check, which was significantly higher in the 4PCC group (83.3 vs. 42.9 %) [18]. The study differs from ours in several capacities. First, the goal INR targeted was lower, which the authors justify by stating it is the goal used in previous trials [9] evaluating warfarin reversal with 4PCC and FFP. However, there is no published literature comparing the various INR goals and outcomes following warfarin-associated major bleeding. The goal of INR B 1.4 used in our study was selected based upon institutional practices, as well as previous literature and international guidelines recommending this goal [19–22]. Until more research is available regarding the impact of various INR targets on clinical outcomes, the conclusions reached by the authors that 4PCC is more effective should be interpreted cautiously considering the average post-treatment
INR values were 1.2 in the 4PCC group and 1.4 in the 3PCC group. Secondly, the study is a very limited sample that does not include an adjustment for differences in baseline characteristics, while our study includes a propensity-matched analysis and a sample that is three-fold larger. The study also had a significant delay in time to first follow-up INR in both groups (3.7 and 5.0 h) that may have impacted the primary outcome. The median time to follow up INR was less than 1 h in both groups in our study. All other direct comparisons between various PCC formulations are limited to abstract form. An abstract comparing 3PCC to 4PCC with the primary outcome of INR \ 1.5 demonstrated 74.3 % of patients receiving 4PCC achieved goal INR compared to 35.2 % in the 3PCC group [23]. No information is provided on dosing of either product in this abstract. A second single-center report with the same INR goal found similar results, with 4PCC treated patients having 81 % at goal compared to 73 % in the 3PCC group. This study also reported low rates of thromboembolic events (6 %) regardless of product used [24]. While the second study does report the average total PCC dose, there is no detailed information that allows clinicians to deduce if standardized doses of 3PCC were used for the comparison and no information regarding their statistical analysis is provided. Although these studies showed higher rates of INR reversal in the 4PCC group, our study found no statistically significant difference, which may be due to the dosing method utilized for 3PCC administration.
123
24
Current literature regarding the use of 3PCC is limited by the vast array of dosing strategies used that may impact the ability to achieve goal INR [25–31]. The fixed, weightbased dose of 3PCC (30 international units (IU) per kilogram of actual body weight regardless of baseline INR) used in this study has previously been shown to result in high rates of INR reversal in a population of patients with intracerebral hemorrhage [15]. Every patient in our study treated with 3PCC received the same standardized approach to dosing, which may allow for a better comparison with 4PCC dosed based upon the Kcentra package insert. Since 3PCC is not labeled for warfarin reversal, there are no clear package labeling or guideline recommendations for dosing in this population, further emphasizing the importance of the standardized dosing utilized in our study. Very few patients in the 3PCC arm of this study received supplemental FFP, while those in the 4PCC arm frequently received both. Largely, the administration of FFP was driven by one of the 4 sites in our study. We also determined the number of patients who received FFP before first INR check and found it to be higher in the 4PCC group. While the doses of FFP used were smaller than recommended for warfarin reversal, the combination of 4PCC and FFP may have impacted the INR values in this group at both initial follow-up and 24 h. Despite the fact that only 5 patients in the 3PCC group received FFP, the median INR was identical between groups at 24 h. Imberti and colleagues investigated the ability of 3PCC to reverse INR and found that only 33 % of those with an INR 4–6 were able to achieve adequate reversal [26]. While we observed no difference overall in the rate of INR reversal, the subgroup analysis of those with a baseline INR [ 4 did reveal higher rates of successful INR reversal with 4PCC. There is both a known inverse relationship between factor VII activity and INR as well as a minimum hemostatic level of factor VII activity required for coagulation, ranging from 10 to 20 % [11, 32, 33]. Yuan and colleagues demonstrated that INR values above 4 result in factor VII activity under 5–10 % [34]. A second analysis of factor activity at various INR thresholds also established variable factor VII activity as INR increased. Above 3.5, there was large ambiguity between samples, with 44 % of patients had\10 % activity [35]. From this, it is reasonable to infer that there is adequate endogenous factor VII to aid an exogenous PCC in reversing a lower baseline INR. However, as the INR increases to critical levels, factor VII activity decreases and adequate reversal may only be achieved by supplementing factor VII [11]. In our study, the lower overall baseline INR values in the 3PCC group may indicate that there was adequate endogenous factor VII to allow for complete reversal utilizing 3PCC only and may explain the high rates of efficacy seen. Further
123
G. M. Jones et al.
research is needed to determine the impact of baseline INR on differing PCC product efficacy. While cost may vary by institution and wholesaler, there are substantial differences between 3PCC and 4PCC. Based upon purchasing information from each of the institutional wholesalers at our institutions, the average cost per unit of 4PCC was 38 % higher than that of 3PCC. As our study observed no difference between rates of INR reversal between the two products, the cost savings with 3PCC has the potential to reduce drug costs particularly at high-volume centers. Even if an institution utilized 4PCC only for those with an INR [ 4.0 upon admission, the potential for cost savings still exists.
Limitations Our study is not without limitations not previously discussed. As this was a retrospective study, we are limited by sample size and observational nature of the data. There were also a low number of patients not meeting INR goal, limiting our ability to detect a statistically difference, if one existed. The low number of adverse effects confirms previous analyses that have shown an extremely low rate of thrombosis with either PCC [36]. While we were able to balance the 3PCC and 4PCC cohort on most observable characteristics, our matching approach does not balance unmeasured characteristics and confounders. Nonetheless, our study does have several strengths. It is a multicenter study including patients treated at multiple medical centers that employ standardized PCC dosing protocols. All patients in the 3PCC arm were treated at one center with a standardized dosing protocol. Patients in the 4PCC arm were treated at 3 sites that all utilize the same dosing protocol as the package insert recommendations. Our inclusion of a propensity-matched analysis that adjusted for baseline differences between the groups demonstrated similar results. Including both analyses provides a general overview of INR reversal rates in this patient population and also allows for a focus on patients with similar baseline characteristics. Our data also provides meaningful information on utilizing PCC in the real-world setting and the ability to achieve adequate INR reversal outside of the controlled trial environment. Our analysis also provides interesting exploratory data on patients with a baseline INR [ 4 who may have differential responses to 3PCC versus 4PCC. Finally, our study provides an approximate effect size that can be utilized to estimate the sample size needed to conduct a randomized, controlled trial comparing 3PCC and 4PCC. Given the large number of patients needed, the feasibility of this type of assessment is uncertain.
3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe…
Conclusions Our study revealed no difference in the rate of INR reversal between 3PCC and 4PCC with low rates of acute thromboembolic events with both agents. Due to the relatively small difference in the primary outcome observed, the feasibility of a large, randomized, controlled trial on the subject may be limited. In our subgroup analysis, those with a baseline INR [ 4.0 experienced more successful INR reversal with 4PCC. Given the significant costs of these products and the low number of patients in our study not achieving goal, further research is needed to determine the comparative efficacy between 3PCC and 4PCC before definite recommendations can be made in international guidelines. Acknowledgments No funding was obtained for the conduction of this study. The results of this study have not been presented previously. Compliance with Ethical Standards Conflict of interest All authors of this study have no direct or indirect conflict of interest to disclose.
References 1. Johnson JA (2012) Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation 125:1964–1966. doi:10.1161/CIR CULATIONAHA.112.100628 2. Shehab N, Sperling LS, Kegler SR, Budnitz DS (2010) National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med 170:1926–1933. doi:10.1001/archinternmed. 2010.407 3. Schulman S, Beyth RJ, Kearon C, Levine MN, American College of Chest P (2008) Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:257S–298S. doi:10.1378/chest.08-0674 4. Tazarourte K, Riou B, Tremey B, Samama CM, Vicaut E, Vigue B, Group Es (2014) Guideline-concordant administration of prothrombin complex concentrate and vitamin K is associated with decreased mortality in patients with severe bleeding under vitamin K antagonist treatment (EPAHK study). Crit Care 18:R81. doi:10.1186/cc13843 5. Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, Flechsenhar J, Neugebauer H, Juttler E, Grau A, Palm F, Rother J, Michels P, Hamann GF, Huwel J, Hagemann G, Barber B, Terborg C, Trostdorf F, Bazner H, Roth A, Wohrle J, Keller M, Schwarz M, Reimann G, Volkmann J, Mullges W, Kraft P, Classen J, Hobohm C, Horn M, Milewski A, Reichmann H, Schneider H, Schimmel E, Fink GR, Dohmen C, Stetefeld H, Witte O, Gunther A, Neumann-Haefelin T, Racs AE, Nueckel M, Erbguth F, Kloska SP, Dorfler A, Kohrmann M, Schwab S, Huttner HB (2015) Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulationrelated intracerebral hemorrhage. JAMA 313:824–836. doi:10. 1001/jama.2015.0846
25
6. Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J (2004) Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 63:1059–1064 7. Bebulin VH(R) [package insert]. Baxter Healthcare Corporation D, IL; April 2011 8. KCentra(R) [package insert]. CSL Behring KoP, PA; April 2013 9. Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN (2013) Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 128:1234–1243. doi:10.1161/CIRCULATIONAHA.113.002283 10. Chong CT, Lew TW, Kuperan P, Tan JJ, Tan HL, Kwek TK (2010) Rapid reversal of coagulopathy in warfarin-related intracranial haemorrhages with prothrombin complex concentrates. Anaesth Intens Care 38:474–480 11. Makris M, Van Veen JJ (2011) Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal? Blood Transfus 9:117–119. doi:10.2450/2011.0111-10 12. Voils SA, Baird B (2012) Systematic review: 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal: does it matter? Thromb Res 130:833–840. doi:10.1016/j. thromres.2012.10.001 13. Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH, American College of Chest P (2012) Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 141:e152S-84S. doi:10.1378/chest.11-2295 14. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, Kitchen S, Makris M (2011) British Committee for Standards in H. Guidelines on oral anticoagulation with warfarin—fourth edition. Br J Haematol 154:311–324. doi:10.1111/j.1365-2141. 2011.08753.x 15. Mohrien KM (2014) Morgan Jones G, Boucher AB, Elijovich L. Evaluation of a fixed, weight-based dose of 3-factor prothrombin complex concentrate without adjunctive plasma following warfarin-associated intracranial hemorrhage. Neurocrit Care 21:67–72. doi:10.1007/s12028-014-9984-9 16. Austin PC (2011) Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat 10:150–161. doi:10.1002/pst.433 17. Leuven ESB (2003) PSMATCH2: Stata Module to Perform Full Mahalanobis and Propensity Score Matching, Common Support Graphing, and Covariate Imbalance Testing 18. Al-Majzoub O, Rybak E, Reardon DP, Krause P, Connors JM (2015) Evaluation of warfarin reversal with 4-factor prothrombin complex concentrate compared to 3-factor prothrombin complex concentrate at a Tertiary Academic Medical Center. J Emerg Med. doi:10.1016/j.jemermed.2015.07.024 19. Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R, Smith EE, Greenberg SM, Rosand J (2006) Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 37:151–155. doi:10.1161/01.STR.0000195047.21562.23 20. Huttner HB, Schellinger PD, Hartmann M, Kohrmann M, Juettler E, Wikner J, Mueller S, Meyding-Lamade U, Strobl R, Mansmann U, Schwab S, Steiner T (2006) Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 37:1465–1470. doi:10.1161/01.STR.0000221786.81354.d6
123
26 21. European Stroke Initiative Writing C, Writing Committee for the EEC, Steiner T, Kaste M, Forsting M, Mendelow D, Kwiecinski H, Szikora I, Juvela S, Marchel A, Chapot R, Cognard C, Unterberg A, Hacke W (2006) Recommendations for the management of intracranial haemorrhage—part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis 22:294–316. doi:10. 1159/000094831 22. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM (2004) Warfarin Reversal Consensus G. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust 181:492–497 23. Cang WWS, Derry K, von Drygalski A, Lane J (2014) A comparison of INR reversal between 4-factor and 3-factor prothrombin complex concentrates. Crit Care Med 42:A1465 24. Voils SA, Holder M, Premraj S, Catlin J, Hinton M, Allen B (2014) Safety and effectiveness of 3- vs 4-factor PCC in patients requiring emergent Warfarin reversal. Crit Care Med 42:A1466 25. Tran H, Collecutt M, Whitehead S, Salem HH (2011) Prothrombin complex concentrates used alone in urgent reversal of warfarin anticoagulation. Internal Med J 41:337–343. doi:10. 1111/j.1445-5994.2010.02237.x 26. Imberti D, Barillari G, Biasioli C, Bianchi M, Contino L, Duce R, D’Inca M, Gnani MC, Mari E, Ageno W (2011) Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus 9:148–155. doi:10.2450/2011.0065-10 27. van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, Ploeger B, Strengers PF (2006) Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial. Thromb Res 118:313–320. doi:10.1016/j.thromres.2005.08.005 28. Khorsand N, Veeger NJ, Muller M, Overdiek JW, Huisman W, van Hest RM, Meijer K (2011) Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med 21:116–123. doi:10.1111/j. 1365-3148.2010.01050.x
123
G. M. Jones et al. 29. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R (2009) Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 49:1171–1177. doi:10.1111/j.1537-2995. 2008.02080.x 30. Switzer JA, Rocker J, Mohorn P, Waller JL, Hughes D, Bruno A, Nichols FT, Hess DC, Natarajan K, Fagan SC (2012) Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. Stroke 43:2500–2502. doi:10.1161/STROKEAHA.112.661454 31. Huynh TK, Costello JL, Rebuck JA (2014) Optimizing the dose of three-factor prothrombin complex concentrate in traumatic brain injury patients on warfarin therapy. Pharmacotherapy. 34:260–264. doi:10.1002/phar.1384 32. Jr EL (2001) Hemostatic Problems in Surgical Patients. In: Colman RWHJ, Marder VJ, Clowes AW, George JN (eds) Hemostasis and Thrombosis, 4th edn. Lippincott Williams & Wilkins, Philadelphia, p 1033 33. Bolton-Maggs PHBPD, Chalmers EA (2004) The rare coagulation disorders—review with guidelines for management from the United Kingdon Haemophilia Centre Doctors’ Organisation. Haemophilia 10:593–628 34. Yuan S, Ferrell C, Chandler WL (2007) Comparing the prothrombin time INR versus the APTT to evaluate the coagulopathy of acute trauma. Thromb Res 120:29–37. doi:10.1016/j.thromres. 2006.07.002 35. Gulati G, Hevelow M, George M, Behling E, Siegel J (2011) International normalized ratio versus plasma levels of coagulation factors in patients on vitamin K antagonist therapy. Arch Pathol Lab Med 135:490–494. doi:10.1043/2009-0474-OA.1 36. Dentali F, Marchesi C, Giorgi Pierfranceschi M, Crowther M, Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti D, Ageno W (2011) Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A metaanalysis. Thromb Haemost 106:429–438. doi:10.1160/TH11-010052
3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe Bleeding: A Multicenter, Retrospective, Propensity-Matched Pilot Study G. Morgan Jones1,2,3 • Michael J. Erdman4 • Keaton S. Smetana5 Kerry M. Mohrien6 • Joseph E. Vandigo7 • Lucas Elijovich3,8
•
Published online: 31 December 2015 Springer Science+Business Media New York 2015
Abstract Current guidelines recommend 4-factor prothrombin complex concentrate (4PCC) for emergent reversal of bleeding secondary to warfarin. While current research has demonstrated superiority of 4PCC over plasma, direct comparisons with 3-factor PCC (3PCC) are lacking. The purpose of this study is to compare the efficacy and safety of 3PCC and 4PCC. We conducted a retrospective analysis of patients who received PCC at one of four medical centers. All patients in the 3PCC group were treated at one center that utilizes a fixed, weight-based dosing protocol. After evaluation of all patients meeting inclusion criteria, propensity-score matching was used to adjust for differences in treatment characteristics. There was no difference in the primary outcome of INR B 1.4 between 3PCC and 4PCC in both the unmatched (85.7 vs. 90.6 %; p = 0.37) and matched (84.2 vs. 92.1 %;
p = 0.48) analyses. There was a significant difference in goal INR achieved favoring 4PCC (56.3 vs 90.0 %; p \ 0.02) when baseline INR [ 4.0. A total of three thrombotic events were documented, all in the 4PCC group. We found no difference in the rate of INR reversal in those treated with 3PCC and 4PCC. However, those with a baseline INR [ 4.0 may experience more successful INR reversal with 4PCC.
& G. Morgan Jones [email protected]
3
Department of Neurology and Neurosurgery, UTHSC, 920 Court Ave, Memphis, TN 38163, USA
Michael J. Erdman [email protected]
4
Department of Pharmacy, University of Florida Health, 655 West 8th Street, Jacksonville, FL 32209, USA
Keaton S. Smetana [email protected]
5
Department of Pharmacy, University of Kentucky HealthCare, 800 Rose St, Lexington, KY 40536, USA
Kerry M. Mohrien [email protected]
6
Department of Pharmacy, Temple University Hospital, 3509 N Broad St, Philadelphia, PA 19140, USA
Joseph E. Vandigo [email protected]
7
Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, 620 W Lexington St, Baltimore, MD 21201, USA
8
Semmes-Murphey Neurologic and Spine Institute, 6325 Humphreys Blvd, Memphis, TN 38120, USA
Lucas Elijovich [email protected] 1
Department of Pharmacy, Methodist University Hospital, 1265 Union Avenue, Memphis, TN 38104, USA
2
Department of Clinical Pharmacy, University of Tennessee Health Sciences Center (UTHSC), 920 Court Ave, Memphis, TN 38163, USA
Keywords Anticoagulation therapy Hematology Hemorrhagic disorders Prothrombin Abbreviations 3PCC 3-Factor prothrombin complex concentrate 4PCC 4-Factor prothrombin complex concentrate FFP Fresh frozen plasma
123
20
INR IQR PCC
G. M. Jones et al.
International normalization ratio Interquartile range Prothrombin complex concentrate
Introduction Warfarin is one of the oldest and widely used anticoagulants, accounting for more than 25 million prescriptions annually [1]. The yearly incidence of warfarin-associated major hemorrhage is estimated to be as high as 3.4 %, accounting for more than 60,000 annual visits to emergency departments in the United States alone [2, 3]. In warfarin-associated major bleeding, emergent reversal is essential given the associated high rates of mortality and potential for improved outcomes with rapid reversal [4–6]. The quickest and most reliable method to reverse the anticoagulation effects of warfarin involves the administration of prothrombin complex concentrate (PCC). In 2013, 4-factor PCC (4PCC) became the first product approved in the United States specifically for warfarin reversal, with 3-factor (3PCC) products being widely used off label prior to this date. While both formulations contain all clotting factors inhibited by warfarin (II, VII, IX, and X), 4PCC contains a larger amount of factor VII than available 3PCC agents [7, 8]. Despite the difference in factor composition, both products have been shown to be more effective than fresh frozen plasma (FFP) at rapidly reversing INR [9–11]. Available evidence comparing 3PCC to 4PCC for reversal of INR is limited to indirect evaluations that are hindered by heterogeneity in dosing, concomitant usage of vitamin K and FFP, and baseline INR values [12]. Notwithstanding this lack of comparable data, clinical guidelines recommend the use of 4PCC for rapid reversal [13, 14]. 3PCC may offer potential advantages including lower medication costs and a possible reduction in the risk of thrombosis [11]. Given the lack of direct comparisons, our pilot study sought to directly compare the rates of INR reversal and risk of thrombosis between 3PCC and 4PCC.
Materials and Methods This retrospective, propensity-matched pilot study was conducted at four major academic medicals centers in the United States and consisted of two cohorts. All patients in the 3PCC group were treated at Methodist University Hospital in Memphis, TN, which utilizes a fixed, weightbased dosing protocol for PCC administration [15]. All patients in this group received the same 3PCC product,
123
Bebulin VH (Baxter Healthcare, Deerfield, IL), which contains 0.05–0.2 units of factor VII per unit of factor IX [7]. Patients in the 4PCC group were treated with KCentra (0.5– 0.8 units of factor VII per unit of factor IX; CSL Behring, King of Prussia, PA) [8] at three institutions that use identical dosing protocols (Fig. 1): University of Florida Health (Jacksonville, FL), University of Kentucky HealthCare (Lexington, KY), and Temple University Hospital (Philadelphia, PA). Institutional review board approval was obtained at each of the participating medical centers. We conducted this pilot study in order to evaluate the approximate effect size in a real-world setting in order to determine the feasibility of conducting a full-scale comparison between the two agents. We included patients C18 years of age who were treated with PCC for reversal of warfarin due to intracranial hemorrhage, gastrointestinal hemorrhage, other bleeding associated with a fall in hemoglobin C2 g/dL, or emergent reversal for acute surgical intervention and discharged between January 1, 2012 and April 15, 2015. Exclusion criteria are listed in Fig. 2. Investigators at each site extracted all data from the institution’s electronic medical record. The primary outcome was the percent of patients achieving an INR B1.4 at initial follow-up INR after PCC administration. We also reported the number of thrombotic events after treatment with PCC as a secondary outcome measure. We planned a priori to complete a subgroup analysis of patients presenting with a baseline INR[4. Data collected included age, body weight, indication for PCC use, PCC dosing information, administration of vitamin K and/or FFP, baseline and subsequent INR results, discharge status, and incidence of any thrombotic events within 7 days of PCC administration. Initially, we evaluated all patients who received PCC and then utilized a propensity score matching approach to adjust for baseline differences and minimize bias between groups. In both the unmatched and propensity-matched analysis, continuous data were analyzed using the Student t test for parametric data and the Mann–Whitney U test for nonparametric data. Categorical data were analyzed using either the v2 test or the Fisher exact test. Normally distributed data are presented as mean (standard deviation) and non-normally distributed data as median (25–75 % interquartile range). All times are presented as minutes: seconds. All tests were 2-tailed, and p \ 0.05 was used to represent statistical significance. All analysis, other than propensity score generation, was performed using SPSS, version 21.0 for Windows (SPSS, Inc., Chicago, IL). Propensity scores were calculated via logistic regression and based upon the following variables: age, height, ideal and actual body weight, indication for PCC use, baseline INR, and use and dose of vitamin K. Model performance was assessed using the area under receiver operating
3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe…
Pre-treatment INR: 3PCC Dosing: 4PCC Dosing:
2.0 – 3.9
21
4.0 – 6.0
> 6.0
30 units/kg ABW with no maximum dose 25 units/kg ABW Max: 2,500 units
35 units/kg ABW Max: 3,500 units
50 units/kg ABW Max: 5,000 units
Fig. 1 Institution specific dosing of prothrombin complex concentrate. INR international normalized ratio, ABW actual body weight, 3PCC 3-factor prothrombin complex concentrate, 4PCC 4-factor prothrombin complex concentrate Fig. 2 Flowchart of patients. PCC prothrombin complex concentrate, INR international normalized ratio, 3PCC 3-factor prothrombin complex concentrate, 4PCC 4-factor prothrombin complex concentrate
characteristic curve. Each 3PCC patient was then matched to a 4PCC patient (1:1, nearest-neighbor, no replacement) on the logit of the propensity score using calipers equal to 0.20 of the standard deviation of the logit of the propensity score [16, 17]. The propensity score logit model and matching procedure was completed using STATA 13.1 (Stata Corporation, College Station, TX).
Results Unmatched Analysis We included 84 patients treated with 3PCC and 64 with 4PCC and no data was missing for any included patient. A total of 100 patients were excluded (Fig. 2). While baseline
characteristics were largely similar between groups (Table 1), those treated with 3PCC were more likely to be admitted with an intracranial hemorrhage (95.2 vs. 62.5 %; p \ 0.001), have a lower median baseline INR (2.6 vs. 3.0; p = 0.006), and have fewer patients with a baseline INR [4 (19.0 vs. 34.4 %; p = 0.03) than those in the 4PCC group. The total number of INR measurements in the first 24 h after PCC administration was similar between groups (2.0 [1.0–3.0] vs. 2.0 [2.0–3.0]; p = 0.26), but time to first follow-up INR was longer in the 3PCC group (48:59 vs. 23:40; p = 0.005). Nearly all patients in both groups (90.5 vs. 92.2 %; p = 0.72) received vitamin K, with 81.1 % of all patients treated with initial doses of 10 mg. The use of adjunctive FFP was significantly higher in the 4PCC group (6.0 vs. 53.1 %; p = 0.001) with the median amount administered in both groups being 2 [2, 3] units. No patients in the 3PCC group
123
22
G. M. Jones et al.
received FFP prior to the first follow-up INR, while 14 (21.9 %) patients in the 4PCC group received FFP prior to repeat INR (Table 2). Overall, there was no difference in the primary outcome of INR B 1.4 between the 2 groups (85.7 vs. 90.6 %; p = 0.37). The actual median INR measurement was slightly lower in the 4PCC group (1.3 [1.2–1.4] vs. 1.2 [1.1–1.4]; p = 0.001) upon first follow-up, but was the same at 24 h. In the 38 patients with a baseline INR [ 4.0, 16 received 3PCC and 22 received 4PCC. There was a statistically significant difference in the rate of goal INR achieved following PCC administration favoring 4PCC (56.3 vs. 90.0 %; p \ 0.02). However, there remained a large imbalance in the receipt of FFP favoring 4PCC patients with a baseline INR [ 4 (18 of 22 patients compared to 3 of 16 patients in the 3PCC group). A total of 3 thrombotic events were documented (2 myocardial infarctions and 1 deep vein thrombosis) with all events occurring in the 4PCC group. There were no documented infusion reactions, although 1 patient in the 4PCC group was excluded after they developed hypotension shortly after initiation of the infusion resulting in the medication being stopped.
curve = 0.77). The model showed no evidence of lack of fit based on the non-significant Hosmer–Lemeshow statistic (p value [0.90). In this cohort, 36 patients in the 3PCC group were matched to an equal number of patients receiving 4PCC. All statistically significant differences in baseline characteristics in the unmatched cohort did not remain after propensity score matching, with the exception of receipt of FFP remaining higher in the 4PCC group (5.3 vs. 52.6 %; p \ 0.001). Due to the extremely small number of patients in the 3PCC group receiving FFP, we were unable to adjust for this in our statistical model. As in the unmatched analysis, patients showed no statistical difference in the primary outcome between 3PCC and 4PCC (84.2 vs. 92.1 %; p = 0.48). Median INR measurement remained the same between groups, as did the time to first follow-up INR. The same difference in reversal rates was observed (91.7 % 4PCC vs 44.4 % 3PCC; p = 0.04) in the 21 patients who presented with INR [ 4 in the propensitymatched analysis. Those in the 4PCC group continued to receive more FFP prior to first follow-up INR than those in the 3PCC group (0 vs 21.1 %;p = 0.003).
Discussion Propensity-Matched Analysis The logistic regression model used to generate the propensity score demonstrated an acceptable ability to differentiate between patients who received 3PCC and 4PCC (area under the receiver operator characteristic
We observed no difference in the rate of INR reversal achieved in both the unmatched and propensity-matched cohorts of our study. In our entire cohort, we observed rapid and complete reversal of INR for the 24-h period after PCC administration in those who received any PCC.
Table 1 Patient characteristics Unmatched cohort
Age (years)
Matched cohort
4-Factor (n = 64)
3 Factor (n = 84)
p
4-Factor (n = 36)
3 Factor (n = 36)
p
72.5 [58.5–80.0]
75.5 [64.0–83.0]
0.06
75 [66–80]
67 [57–77]
0.09
Male, n (%)
38 (59.4)
45 (53.6)
0.48
20 (52.6)
21 (55.3)
0.82
African American, n (%)
20 (31.3)
36 (42.9)
0.15
11 (28.9)
10 (26.3)
0.80
Height (centimeters)
172.7 [162.6–182.8]
172.0 [163.0–180.0]
0.99
171.5 [162.6–178.0]
173.9 [165.0–178.0]
0.74
Actual body weight (kilograms)
82.5 [72.4–100.3]
84.8 [70.2–100.8]
0.99
81.8 [72.6–99.0]
84.8 [68.0–101.6]
0.91
Reversal indication Intracranial hemorrhage, n (%)
40 (62.5)
80 (95.2)
\0.001
34 (89.5)
34 (89.5)
[0.99
Gastrointestinal hemorrhage, n (%)
11 (17.2)
2 (2.4)
0.002
2 (5.3)
2 (5.3)
[0.99
13 (20.3)
2 (2.4)
\0.001
1 (2.6)
1 (2.6)
[0.99
8.0 [3.0–14.5]
6.1 [3.8–9.5]
0.07
10.5 [2.0–14.0]
6.2 [3.8–10.8]
0.40
Other, n (%) Duration of hospitalization (days) Discharge status Morgue, n (%)
18 (28.1)
26 (31.0)
0.71
16 (42.1)
13 (34.2)
0.50
Facility, n (%)
24 (37.5)
40 (47.6)
0.08
13 (34.2)
18 (47.4)
0.24
Home, n (%)
22 (34.4)
18 (21.4)
0.08
25 (65.8)
20 (52.6)
0.24
All data are presented as median [25–75 % interquartile range] unless otherwise noted
123
3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe…
23
Table 2 Anticoagulation reversal information Unmatched
Matched
4-Factor (n = 64)
3 Factor (n = 84)
p
4-Factor (n = 36)
3 Factor (n = 36)
p
Baseline
3.0 [2.2–4.6]
2.6 [2.2–3.5]
0.006
2.9 [2.3–4.1]
2.8 [2.2–3.9]
0.43
Baseline C 4
22 (34.4)
16 (19.0)
0.03
12 (31.6)
9 (23.7)
0.44
Immediately after PCC
1.2 [1.1–1.4]
1.3 [1.2–1.4]
\0.001
1.2 [1.1–1.3]
1.3 [1.3–1.4]
0.002
24 h-post PCC
1.2 [1.0–1.4]
1.2[1.2–1.3]
0.98
1.2 [1.0–1.4]
1.2[1.2–1.3]
0.87
Time between PCC dose and follow up INR (mm:ss)
23:40 [15:33–90:00]
48:59 [31:00–91:00]
0.005
20:00 [14:01–60:00]
40:30 [30:00–88:00]
0.009
INR at goal (B1.4)
58 (90.6)
72 (85.7)
0.37
35 (92.1)
32 (84.2)
0.48
INR measurements
PCC dosing Initial (units)
2500 [2000–2852]
2454 [2228–3045]
0.29
2380 [2000–2699]
2429 [2228–3090]
0.22
Initial per kilogram actual body weight (units)
26.3 [24.7–34.3]
30.6 [28.2–32.3]
0.003
25.6 [23.5–31.7]
30.6 [28.3–32.3]
0.005
Supplemental reversal agents received Vitamin K, n (%)
59 (92.2)
76 (90.5)
0.72
36 (94.7)
37 (97.4)
0.56
FFP, n (%)
34 (53.1)
5 (6.0)
\0.001
20 (52.6)
2 (5.3)
\0.001
All data are presented as median [25–75 % interquartile range] unless otherwise noted INR international normalization ratio, PCC prothrombin complex concentrate, FFP fresh frozen plasma
The number of adverse thrombotic events was low, with only three events occurring amongst all 148 patients. In a randomized, controlled trial comparing the two agents, approximately 1450 patients would be needed to achieve 80 % power (a = 0.05, b = 0.20, continuity corrected) to detect the 5 % difference in the primary outcome observed in this pilot study. While current guidelines [13] recommend 4PCC as primary choice for emergent warfarin reversal, there is very limited evidence directly comparing the two products. Recently, a retrospective, single-center cohort study compared the efficacy of 3PCC and 4PCC in 53 patients actively bleeding due to warfarin. The primary outcome was the percentage of patients achieving INR B 1.3 at their first INR check, which was significantly higher in the 4PCC group (83.3 vs. 42.9 %) [18]. The study differs from ours in several capacities. First, the goal INR targeted was lower, which the authors justify by stating it is the goal used in previous trials [9] evaluating warfarin reversal with 4PCC and FFP. However, there is no published literature comparing the various INR goals and outcomes following warfarin-associated major bleeding. The goal of INR B 1.4 used in our study was selected based upon institutional practices, as well as previous literature and international guidelines recommending this goal [19–22]. Until more research is available regarding the impact of various INR targets on clinical outcomes, the conclusions reached by the authors that 4PCC is more effective should be interpreted cautiously considering the average post-treatment
INR values were 1.2 in the 4PCC group and 1.4 in the 3PCC group. Secondly, the study is a very limited sample that does not include an adjustment for differences in baseline characteristics, while our study includes a propensity-matched analysis and a sample that is three-fold larger. The study also had a significant delay in time to first follow-up INR in both groups (3.7 and 5.0 h) that may have impacted the primary outcome. The median time to follow up INR was less than 1 h in both groups in our study. All other direct comparisons between various PCC formulations are limited to abstract form. An abstract comparing 3PCC to 4PCC with the primary outcome of INR \ 1.5 demonstrated 74.3 % of patients receiving 4PCC achieved goal INR compared to 35.2 % in the 3PCC group [23]. No information is provided on dosing of either product in this abstract. A second single-center report with the same INR goal found similar results, with 4PCC treated patients having 81 % at goal compared to 73 % in the 3PCC group. This study also reported low rates of thromboembolic events (6 %) regardless of product used [24]. While the second study does report the average total PCC dose, there is no detailed information that allows clinicians to deduce if standardized doses of 3PCC were used for the comparison and no information regarding their statistical analysis is provided. Although these studies showed higher rates of INR reversal in the 4PCC group, our study found no statistically significant difference, which may be due to the dosing method utilized for 3PCC administration.
123
24
Current literature regarding the use of 3PCC is limited by the vast array of dosing strategies used that may impact the ability to achieve goal INR [25–31]. The fixed, weightbased dose of 3PCC (30 international units (IU) per kilogram of actual body weight regardless of baseline INR) used in this study has previously been shown to result in high rates of INR reversal in a population of patients with intracerebral hemorrhage [15]. Every patient in our study treated with 3PCC received the same standardized approach to dosing, which may allow for a better comparison with 4PCC dosed based upon the Kcentra package insert. Since 3PCC is not labeled for warfarin reversal, there are no clear package labeling or guideline recommendations for dosing in this population, further emphasizing the importance of the standardized dosing utilized in our study. Very few patients in the 3PCC arm of this study received supplemental FFP, while those in the 4PCC arm frequently received both. Largely, the administration of FFP was driven by one of the 4 sites in our study. We also determined the number of patients who received FFP before first INR check and found it to be higher in the 4PCC group. While the doses of FFP used were smaller than recommended for warfarin reversal, the combination of 4PCC and FFP may have impacted the INR values in this group at both initial follow-up and 24 h. Despite the fact that only 5 patients in the 3PCC group received FFP, the median INR was identical between groups at 24 h. Imberti and colleagues investigated the ability of 3PCC to reverse INR and found that only 33 % of those with an INR 4–6 were able to achieve adequate reversal [26]. While we observed no difference overall in the rate of INR reversal, the subgroup analysis of those with a baseline INR [ 4 did reveal higher rates of successful INR reversal with 4PCC. There is both a known inverse relationship between factor VII activity and INR as well as a minimum hemostatic level of factor VII activity required for coagulation, ranging from 10 to 20 % [11, 32, 33]. Yuan and colleagues demonstrated that INR values above 4 result in factor VII activity under 5–10 % [34]. A second analysis of factor activity at various INR thresholds also established variable factor VII activity as INR increased. Above 3.5, there was large ambiguity between samples, with 44 % of patients had\10 % activity [35]. From this, it is reasonable to infer that there is adequate endogenous factor VII to aid an exogenous PCC in reversing a lower baseline INR. However, as the INR increases to critical levels, factor VII activity decreases and adequate reversal may only be achieved by supplementing factor VII [11]. In our study, the lower overall baseline INR values in the 3PCC group may indicate that there was adequate endogenous factor VII to allow for complete reversal utilizing 3PCC only and may explain the high rates of efficacy seen. Further
123
G. M. Jones et al.
research is needed to determine the impact of baseline INR on differing PCC product efficacy. While cost may vary by institution and wholesaler, there are substantial differences between 3PCC and 4PCC. Based upon purchasing information from each of the institutional wholesalers at our institutions, the average cost per unit of 4PCC was 38 % higher than that of 3PCC. As our study observed no difference between rates of INR reversal between the two products, the cost savings with 3PCC has the potential to reduce drug costs particularly at high-volume centers. Even if an institution utilized 4PCC only for those with an INR [ 4.0 upon admission, the potential for cost savings still exists.
Limitations Our study is not without limitations not previously discussed. As this was a retrospective study, we are limited by sample size and observational nature of the data. There were also a low number of patients not meeting INR goal, limiting our ability to detect a statistically difference, if one existed. The low number of adverse effects confirms previous analyses that have shown an extremely low rate of thrombosis with either PCC [36]. While we were able to balance the 3PCC and 4PCC cohort on most observable characteristics, our matching approach does not balance unmeasured characteristics and confounders. Nonetheless, our study does have several strengths. It is a multicenter study including patients treated at multiple medical centers that employ standardized PCC dosing protocols. All patients in the 3PCC arm were treated at one center with a standardized dosing protocol. Patients in the 4PCC arm were treated at 3 sites that all utilize the same dosing protocol as the package insert recommendations. Our inclusion of a propensity-matched analysis that adjusted for baseline differences between the groups demonstrated similar results. Including both analyses provides a general overview of INR reversal rates in this patient population and also allows for a focus on patients with similar baseline characteristics. Our data also provides meaningful information on utilizing PCC in the real-world setting and the ability to achieve adequate INR reversal outside of the controlled trial environment. Our analysis also provides interesting exploratory data on patients with a baseline INR [ 4 who may have differential responses to 3PCC versus 4PCC. Finally, our study provides an approximate effect size that can be utilized to estimate the sample size needed to conduct a randomized, controlled trial comparing 3PCC and 4PCC. Given the large number of patients needed, the feasibility of this type of assessment is uncertain.
3-Factor Versus 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal in Severe…
Conclusions Our study revealed no difference in the rate of INR reversal between 3PCC and 4PCC with low rates of acute thromboembolic events with both agents. Due to the relatively small difference in the primary outcome observed, the feasibility of a large, randomized, controlled trial on the subject may be limited. In our subgroup analysis, those with a baseline INR [ 4.0 experienced more successful INR reversal with 4PCC. Given the significant costs of these products and the low number of patients in our study not achieving goal, further research is needed to determine the comparative efficacy between 3PCC and 4PCC before definite recommendations can be made in international guidelines. Acknowledgments No funding was obtained for the conduction of this study. The results of this study have not been presented previously. Compliance with Ethical Standards Conflict of interest All authors of this study have no direct or indirect conflict of interest to disclose.
References 1. Johnson JA (2012) Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation 125:1964–1966. doi:10.1161/CIR CULATIONAHA.112.100628 2. Shehab N, Sperling LS, Kegler SR, Budnitz DS (2010) National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med 170:1926–1933. doi:10.1001/archinternmed. 2010.407 3. Schulman S, Beyth RJ, Kearon C, Levine MN, American College of Chest P (2008) Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:257S–298S. doi:10.1378/chest.08-0674 4. Tazarourte K, Riou B, Tremey B, Samama CM, Vicaut E, Vigue B, Group Es (2014) Guideline-concordant administration of prothrombin complex concentrate and vitamin K is associated with decreased mortality in patients with severe bleeding under vitamin K antagonist treatment (EPAHK study). Crit Care 18:R81. doi:10.1186/cc13843 5. Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, Flechsenhar J, Neugebauer H, Juttler E, Grau A, Palm F, Rother J, Michels P, Hamann GF, Huwel J, Hagemann G, Barber B, Terborg C, Trostdorf F, Bazner H, Roth A, Wohrle J, Keller M, Schwarz M, Reimann G, Volkmann J, Mullges W, Kraft P, Classen J, Hobohm C, Horn M, Milewski A, Reichmann H, Schneider H, Schimmel E, Fink GR, Dohmen C, Stetefeld H, Witte O, Gunther A, Neumann-Haefelin T, Racs AE, Nueckel M, Erbguth F, Kloska SP, Dorfler A, Kohrmann M, Schwab S, Huttner HB (2015) Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulationrelated intracerebral hemorrhage. JAMA 313:824–836. doi:10. 1001/jama.2015.0846
25
6. Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J (2004) Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 63:1059–1064 7. Bebulin VH(R) [package insert]. Baxter Healthcare Corporation D, IL; April 2011 8. KCentra(R) [package insert]. CSL Behring KoP, PA; April 2013 9. Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, Goldstein JN (2013) Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 128:1234–1243. doi:10.1161/CIRCULATIONAHA.113.002283 10. Chong CT, Lew TW, Kuperan P, Tan JJ, Tan HL, Kwek TK (2010) Rapid reversal of coagulopathy in warfarin-related intracranial haemorrhages with prothrombin complex concentrates. Anaesth Intens Care 38:474–480 11. Makris M, Van Veen JJ (2011) Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal? Blood Transfus 9:117–119. doi:10.2450/2011.0111-10 12. Voils SA, Baird B (2012) Systematic review: 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal: does it matter? Thromb Res 130:833–840. doi:10.1016/j. thromres.2012.10.001 13. Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH, American College of Chest P (2012) Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 141:e152S-84S. doi:10.1378/chest.11-2295 14. Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, Kitchen S, Makris M (2011) British Committee for Standards in H. Guidelines on oral anticoagulation with warfarin—fourth edition. Br J Haematol 154:311–324. doi:10.1111/j.1365-2141. 2011.08753.x 15. Mohrien KM (2014) Morgan Jones G, Boucher AB, Elijovich L. Evaluation of a fixed, weight-based dose of 3-factor prothrombin complex concentrate without adjunctive plasma following warfarin-associated intracranial hemorrhage. Neurocrit Care 21:67–72. doi:10.1007/s12028-014-9984-9 16. Austin PC (2011) Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat 10:150–161. doi:10.1002/pst.433 17. Leuven ESB (2003) PSMATCH2: Stata Module to Perform Full Mahalanobis and Propensity Score Matching, Common Support Graphing, and Covariate Imbalance Testing 18. Al-Majzoub O, Rybak E, Reardon DP, Krause P, Connors JM (2015) Evaluation of warfarin reversal with 4-factor prothrombin complex concentrate compared to 3-factor prothrombin complex concentrate at a Tertiary Academic Medical Center. J Emerg Med. doi:10.1016/j.jemermed.2015.07.024 19. Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R, Smith EE, Greenberg SM, Rosand J (2006) Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 37:151–155. doi:10.1161/01.STR.0000195047.21562.23 20. Huttner HB, Schellinger PD, Hartmann M, Kohrmann M, Juettler E, Wikner J, Mueller S, Meyding-Lamade U, Strobl R, Mansmann U, Schwab S, Steiner T (2006) Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 37:1465–1470. doi:10.1161/01.STR.0000221786.81354.d6
123
26 21. European Stroke Initiative Writing C, Writing Committee for the EEC, Steiner T, Kaste M, Forsting M, Mendelow D, Kwiecinski H, Szikora I, Juvela S, Marchel A, Chapot R, Cognard C, Unterberg A, Hacke W (2006) Recommendations for the management of intracranial haemorrhage—part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis 22:294–316. doi:10. 1159/000094831 22. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM (2004) Warfarin Reversal Consensus G. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust 181:492–497 23. Cang WWS, Derry K, von Drygalski A, Lane J (2014) A comparison of INR reversal between 4-factor and 3-factor prothrombin complex concentrates. Crit Care Med 42:A1465 24. Voils SA, Holder M, Premraj S, Catlin J, Hinton M, Allen B (2014) Safety and effectiveness of 3- vs 4-factor PCC in patients requiring emergent Warfarin reversal. Crit Care Med 42:A1466 25. Tran H, Collecutt M, Whitehead S, Salem HH (2011) Prothrombin complex concentrates used alone in urgent reversal of warfarin anticoagulation. Internal Med J 41:337–343. doi:10. 1111/j.1445-5994.2010.02237.x 26. Imberti D, Barillari G, Biasioli C, Bianchi M, Contino L, Duce R, D’Inca M, Gnani MC, Mari E, Ageno W (2011) Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus 9:148–155. doi:10.2450/2011.0065-10 27. van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, Ploeger B, Strengers PF (2006) Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial. Thromb Res 118:313–320. doi:10.1016/j.thromres.2005.08.005 28. Khorsand N, Veeger NJ, Muller M, Overdiek JW, Huisman W, van Hest RM, Meijer K (2011) Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med 21:116–123. doi:10.1111/j. 1365-3148.2010.01050.x
123
G. M. Jones et al. 29. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R (2009) Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 49:1171–1177. doi:10.1111/j.1537-2995. 2008.02080.x 30. Switzer JA, Rocker J, Mohorn P, Waller JL, Hughes D, Bruno A, Nichols FT, Hess DC, Natarajan K, Fagan SC (2012) Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. Stroke 43:2500–2502. doi:10.1161/STROKEAHA.112.661454 31. Huynh TK, Costello JL, Rebuck JA (2014) Optimizing the dose of three-factor prothrombin complex concentrate in traumatic brain injury patients on warfarin therapy. Pharmacotherapy. 34:260–264. doi:10.1002/phar.1384 32. Jr EL (2001) Hemostatic Problems in Surgical Patients. In: Colman RWHJ, Marder VJ, Clowes AW, George JN (eds) Hemostasis and Thrombosis, 4th edn. Lippincott Williams & Wilkins, Philadelphia, p 1033 33. Bolton-Maggs PHBPD, Chalmers EA (2004) The rare coagulation disorders—review with guidelines for management from the United Kingdon Haemophilia Centre Doctors’ Organisation. Haemophilia 10:593–628 34. Yuan S, Ferrell C, Chandler WL (2007) Comparing the prothrombin time INR versus the APTT to evaluate the coagulopathy of acute trauma. Thromb Res 120:29–37. doi:10.1016/j.thromres. 2006.07.002 35. Gulati G, Hevelow M, George M, Behling E, Siegel J (2011) International normalized ratio versus plasma levels of coagulation factors in patients on vitamin K antagonist therapy. Arch Pathol Lab Med 135:490–494. doi:10.1043/2009-0474-OA.1 36. Dentali F, Marchesi C, Giorgi Pierfranceschi M, Crowther M, Garcia D, Hylek E, Witt DM, Clark NP, Squizzato A, Imberti D, Ageno W (2011) Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A metaanalysis. Thromb Haemost 106:429–438. doi:10.1160/TH11-010052
