Thrombosis Research 133 (2014) 42–47
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Regular Article
Effectiveness of vitamin K in anticoagulation reversal for hip fracture surgery – A prospective observational study Benjamin Buecking a,⁎, Daphne Eschbach a, Christopher Bliemel a, Ludwig Oberkircher a, Johannes Struewer b, Steffen Ruchholtz a, Ulrich J. Sachs c,d a
Department of Trauma, Hand and Reconstructive Surgery, University of Giessen and Marburg, Campus Marburg Department of Orthopaedics and Rheumatology, University of Giessen and Marburg, Campus Marburg Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany d Center for Transfusion Medicine and Hemotherapy, University Hospital Giessen and Marburg, Campus Marburg b c
a r t i c l e
i n f o
Article history: Received 17 July 2013 Received in revised form 7 October 2013 Accepted 18 October 2013 Available online 25 October 2013 Keywords: Anticoagulation Vitamin K antagonist Hip fracture Blood management Complication
a b s t r a c t Introduction: Vitamin K antagonists are often used for anticoagulant treatment in hip fracture patients. The optimal handling with such anticoagulants is unclear. We aimed to determine when anticoagulation reversal occurred after vitamin K administration and how often prothrombin complex concentrates (PCCs) were administered. We compared patients’ treatments and outcomes with those of a control group not receiving treatment for anticoagulation. Patients and Methods: A total of 402 geriatric hip fracture patients were included in this observational study. We collected data on treatment for anticoagulation, time to surgery, and reasons for delay of surgery. In patients taking vitamin K antagonists, we measured the INR (international normalized ratio) on admission and prior to surgery, along with the frequency of PCC administration. Finally, we compared in-hospital mortality and complications between patient groups. Results: A total of 62 (15%) patients received phenprocoumon prior to their fractures. Surgery was delayed in these patients compared to controls (27 h; 95%CI 23–31 vs. 16 h; 95%CI 19–19; p = 0.001), but surgery delay N 48 h (n = 5; 8%) was not due to a failure of INR reversal. The main reason for these delays was a lack of capacity for surgery. The average INR on admission was 2.1 (±0.7; range 1.0-3.5) in patients taking phenprocoumon, which decreased to 1.3 (±0.3; range 1.0-1.6) until surgery. PCCs were administered to 19% of patients. We found no differences in the in-hospital mortality (6.2% vs. 8.1%, p = 0.575) or complication rates (12.9% vs. 9.4%, p = 0.364). Conclusion: The use of vitamin K seemed to be sufficient for anticoagulation reversal in geriatric hip fracture patients, and it generally led to timely surgery; despite this success, PCCs were sometimes administered for logistical reasons. © 2013 Elsevier Ltd. All rights reserved.
Introduction Hip fractures are common in elderly people. The incidence of these fractures has risen to 439/100,000 per year in industrialized countries [1]. In 2008, nearly 140,000 fractures (ICD-10 S.72.0-72.2) were registered in Germany [2]. Demographic changes will lead to an increased incidence of these fractures over the next decade. Patients with hip fractures are often multimorbid [3]. These patients frequently suffer from cardiovascular diseases, which means that their anticoagulation treatment is often vitamin K antagonist therapy. Early surgery for hip fractures is recommended in the current guidelines [4–6]. In Germany, External Quality Assurance recommends
⁎ Corresponding author at: Department of Trauma, Hand, and Reconstructive Surgery, University of Giessen and Marburg GmbH, Campus Marburg, Baldingerstrasse, 35043 Marburg, Germany. Tel.: +49 6421 58 66216; fax: +49 6421 58 66721. E-mail address: [email protected] (B. Buecking). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.10.031
hip fracture repair during the first 48 h after admission to the hospital in most cases. The guidelines aim to minimize in-hospital mortality and medical complications, such as decubital ulcers and pneumonia, both of which have been associated with delayed surgery [7–9]. Surgical interventions under continued anticoagulation can result in an increased risk of bleeding [10,11]. Reversal of the anticoagulative effect should occur successfully prior to surgery. Vitamin K is recommended for anticoagulation reversal under the current guidelines [12,13]. It is known to reverse the international normalized ratio (INR) effectively when administered intravenously or orally prior to surgery [14,15], although due to the urgency for hip fracture surgery, the optimal strategy for INR reversal in patients with hip fractures remains controversial. Reduction of INR with vitamin K has been demonstrated, but in the same studies, the time before surgery was more than 48 h [16,18]. In a recent study in which patients on Coumadin received either vitamin K or fresh frozen plasma (FFP), the time to surgery was 1.88 days [19]. Prothrombin complex concentrates (PCCs) offer a rapid and effective alternative for anticoagulation reversal [20] and are preferable to FFP [21].
B. Buecking et al. / Thrombosis Research 133 (2014) 42–47
In our hospital, vitamin K administration is the preferred strategy for anticoagulation reversal. The aim of this study was to evaluate the efficacy of anticoagulation reversal with vitamin K in geriatric hip fracture patients. We wanted to investigate the following: when anticoagulation reversal occurred, when surgery was performed, and how often additional administration of PCCs occurred in geriatric hip fracture patients. Finally, we aimed to compare the outcomes of patients with and without anticoagulation treatment. Patients and Methods In this prospective, observational cohort study, we included 402 patients with proximal femoral fractures (ICD 10 S 72.0-72.2 [22]) aged 60 years old and older who were admitted to our university hospital for surgical fracture treatment. The exclusion criteria included polytrauma (ISS ≥ 16 [23]) and malignancy-related fractures. The recruitment period was from April 1, 2009 to September 30, 2011. Institutional review board approval from the Ethics Committee of the University of Marburg was obtained (AZ 175/08). All of the patients or their legal representatives provided written informed consent for participation in the study. Baseline data The following patient data were collected: socio-demographic data (e.g., age, sex); type of fracture, American Society of Anesthesiologists (ASA) score [24], Charlson Comorbidity Index (CCI) [25], and prefracture Barthel Index (BI) [26]. A complete medication history, with a special focus on vitamin K antagonists (e.g., warfarin, phenprocoumon), heparin, and direct oral anticoagulants (DOACs), such as rivaroxaban or dabigatran, was obtained. Medical indications for anticoagulation were also noted.
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Occurrences of local complications associated with bleeding, such as seroma and hematoma, were collected, as were cardiovascular events, such as ischemic heart attack (defined as an elevation in troponin), stroke, thrombosis, or lung embolism. Statistics Data were collected in a Filemaker® database (FileMaker Inc., Santa Clara, CA, USA). A double entry with plausibility check was performed to monitor for data quality. Predictive Analysis SoftWare (PASW®), version 18.0 (SPSS Inc., Chicago, IL, USA), was used for the descriptive statistics and explorative data analysis. We determined the frequencies of dichotomous variables and the means and standard deviations intervals for continuous variables that had normal distributions. For the remaining continuous variables, we calculated the medians and ranges. The ranges were also calculated for the INR values and the LOS. First, we compared the patients being treated for anticoagulation to patients not receiving treatment. Subsequently, we analyzed a subgroup of patients receiving treatment for anticoagulation who received PCCs to patients who did not. Differences between the two groups of patients in terms of age, ASA score, BI, CCI, time from admission to surgery, LOS, laboratory values, and amount of red blood cells transfused were calculated in two manners, depending on the distribution. If the distribution was normal, Student's t-test was used; if the distribution was abnormal, Wilcoxon’s rank-sum test was used. We performed Fischer’s exact test to determine differences in sex distribution, type of surgery, transfusion rates of red blood cells and FFP, mortality, and the occurrence of complications between the patient groups. For the distribution of different fracture types, the chi-square test was performed. Results
Standard operating procedures As described previously [27], patients taking vitamin K antagonists received 10 mg of intravenous vitamin K upon admission and then twice per day until INR reversal. INR reversal was considered complete at INR b1.5. PCCs were not infused routinely but were used if anticoagulation reversal had to be accelerated. Subsequently, lowmolecular-weight heparin was administered to prevent cardiovascular complications. Patients taking vitamin K antagonists received a therapeutic dose of low-molecular-weight heparin, adapted for weight and renal function as a split dose (enoxaparin twice daily). The remaining patients received prophylactic enoxaparin (40 mg) once daily. Vitamin K antagonist therapy was restarted after wound healing.
During the study period, 539 patients with hip fractures were treated in our department. Of the 477 patients who met the inclusion criteria, 75 patients declined to participate. Thus, 402 patients were included in the study. Of 402 patients, 62 (15%) received phenprocoumon. No patients used other anticoagulants. The characteristics of patients with and without phenprocoumon are summarized in Table 1. There were no differences between the groups with regard to age, fracture location, ASA score, or prefracture BI. However, CCI was higher in patients treated with phenprocoumon (2.7 vs. 2.3, p = 0.029). The most frequent reasons for phenprocoumon treatment were cardiac arrhythmia (n = 40), coronary heart diseases (n = 15), and thrombosis (n = 14) (Table 2). In addition, there were more men in the phenprocoumon
Laboratory values We recorded the hemoglobin levels upon admission, after surgery, and at discharge. Additionally, the INRs of patients who were treated for anticoagulation were recorded both upon admission and immediately before surgery. Clinical data The amount of vitamin K administered during hospitalization was documented. If PCCs were administered preoperatively, the underlying reason and dosage were registered. The frequency and dosage of FFP administrations during the postsurgical period were also recorded. The interval between hospital admission and surgery and the type of surgery (prosthesis or internal fixation),) was documented. If surgery was delayed for more than 48 h, the particular reason was recorded. Length of stay (LOS) in our department, the frequency of red blood cell transfusion and their amounts in units, patients’ function according to the BI at discharge, and in-hospital mortality were recorded.
Table 1 Baseline Data for All Patients. Data
All (N = 402)
Anticoagulant group (N = 62)
Non-anticoagulant group (N = 340)
p-value
Age (years) ± SD Sex Men Women Fracture location Femoral neck Trochanteric Subtrochanteric ASA score ± SD Prefracture Barthel Index ± SD Charlson Comorbidity Index ± SD
81 ± 8
81 ± 7
81 ± 8
0.774 0.030
109 (27%) 293 (73%)
24 (39%) 38 (61%)
85 (25%) 255 (75%)
195 (48%) 186 (46%) 21 (5%) 2.9 ± 0.6 80 ± 25
32 (52%) 27 (44%) 3 (5%) 3.0 ± 0.5 84 ± 20
163 (48%) 159 (47%) 18 (5%) 2.9 ± 0.6 79 ± 25
0.619 0.137
2.4 ± 2.3
2.7 ± 2.0
2.3 ± 2.4
0.029
0.868
ASA = American Society of Anesthesiologists.
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B. Buecking et al. / Thrombosis Research 133 (2014) 42–47 Table 2 Reasons for Pre-fracture Anticoagulation.⁎ Diagnosis
Frequency
cardiac arrhythmia coronary heart diseases thrombosis⁎⁎ stroke cardiac valvular defect pulmonary embolism peripheral arterial disease
40 15 14 13 12 10 3
⁎ multiple indications were possible. ⁎⁎ without clinical significant stroke or pulmonary embolism.
group than among the patients not taking phenprocoumon (39% vs. 25%, p = 0.030). Surgery was delayed longer for patients taking phenprocoumon. The time between admission and surgery for these patients was 27h (±14), while it was 16 h (±12, p = 0.001) for the patients in the control group. Eighty-one percent of patients without anticoagulant treatment were operated on within 24 h, compared to 50% among patients taking phenprocoumon (p b 0.001). Eight percent (n = 5) of these patients were operated on after more than 48 h, but there were no patients for whom a delay occurred due to a failure of INR reversal. Delay of surgery was observed in 10 patients (2%) (Table 3). The reasons for these delays are listed in Table 3. The average INR on admission was 2.1 (±0.7, range 1.0-3.5) in patients taking phenprocoumon, which decreased to 1.3 (±0.3, range 1.0-1.6) at the time of surgery. The mean dose during hospitalization was 46 mg (±2.0). We did not observe any side effects due to vitamin K administration. While in 237 cases (51%), internal fixation was performed, 165 (41%) patients received prostheses without a difference in distribution between patient groups (p = 0.329). The length of hospital stay was increased in patients receiving treatment for anticoagulation (15 ± 6
d; range 2–39 vs. 13 ± 6 d; range 2–50, p = 0.005). The hemoglobin levels were 12.5 g/dl (±1.7) upon admission and 10.5 g/dl (±1.2) at discharge; more than half (58%) of the included patients required red blood cell transfusions. There were no differences in hemoglobin levels at different times or in the numbers of red blood cell transfusions between the patient groups (Table 3). PCCs were administered to 12 patients (19%) to accelerate anticoagulant reversal. The reason for providing PCC in all of these cases was capacity for surgery. There were no patients who received PCCs based on a lack of response to vitamin K treatment. The dosage of vitamin K that was administered during hospitalization was similar in both subgroups (43 ± 9 mg in patients receiving PCC and 46 ± 22 mg in patients who only received vitamin K, p = 0.596). The mean dosage of PCCs was 1500 IE or 25 IE/kg of body weight. More patients in the PCC group received FFP after surgery compared to the group that did not receive PCC (42% vs. 12%, p = 0.029) (Table 4). When PCCs were administered, surgery was performed earlier (21 ± 10 h vs. 28 ± 15 h; p = 0.029). While surgery was delayed for ≥48 h for 5 patients not receiving PCCs, patients who received PCCs were mostly operated on within 24 h. The average INR on admission was 2.3 ± 0.6 (range 1.5-3.3) in patients who received PCCs, compared to 2.0 ± 0.7 (range 1.0-3.5) in the remaining phenprocoumon patients (p = 0.210). Until surgery, the INR values decreased to 1.3 ± 0.2 (range 1.11.5) and 1.3 ± 0.2 (range 1.0-1.6, p = 0.696), respectively (Table 4). In 10% (n = 40) of all of the included patients, complications that were associated with bleeding or cardiovascular events occurred. The most frequent complications were hematomas (n=21) and myocardial infarction (n = 12) (Table 5). The incidence of complications was not higher in the group receiving anticoagulation treatment (12.9% vs. 9.4%, p = 0.364) or in the patients who received PCCs (25% vs. 10%, p = 0.177). The overall in-hospital mortality rate was 6.2% (n = 25), which included 4 patients (8.1%, p = 0.575) from the phenprocoumon group and 1 patient (of 12) from the group who received PCCs (p = 1.000) died.
Table 3 Clinical Data. Data
All (N = 402)
Anticoagulant group (N = 62)
Non-anticoagulant group (N = 340)
p-value
Time between admission and surgery (h) ± SD Surgery within b24 h ≥24 and b48 h ≥48 h Reasons for delay of surgery (≥48 h)
18 ± 13
27 ± 14
16 ± 12
b0.001
307 (76) 85 (21) 10 (2)
31 (50) 26 (42) 5 (8) 1x delayed diagnosis
276 (81) 59 (17) 5 (2) 1x surgery of symptomatic stenosis of carotid artery prior to hip fracture surgery 1x non displaced femoral neck fracture 2x waiting for capacity for surgery
INR Level on admission ± SD (range) INR Level prior to surgery ± SD (range) Kind of surgery Internal fixation (%) Prosthesis (%) Length of stay in acute care hospital (days) ± SD (range) Hemoglobin level on admission ± SD Hemoglobin level post surgery ± SD Hemoglobin level at discharge ± SD Transfusion of red blood cells (%) Median units of red blood cells ± SD (range) Mortality (%) Barthel Index on discharge ± SD
b0.001
1x non displaced femoral neck fracture 1x preoperative preparation for symptomatic coronary heart disease 2x waiting for capacity for surgery 2.1 ± 0.7 (1.0-3.5) 1.3 ± 0.3 (1.0-1.6)
1x unknown reason
0.329 237 (59) 165 (41) 14 ± 6 (2–50)
33 (53) 29 (47) 15 ± 6 (2–39)
204 (60) 136 (40) 13 ± 6 (2–50)
12.5 ± 1.7 10.5 ± 1.5 10.5 ± 1.2 231 (58)
12.7 ± 1.6 10.7 ± 1.5 10.7 ± 1.4 38 (61)
12.5 ± 1.7 10.5 ± 1.5 10.5 ± 1.1 193 (57)
0.303 0.164 0.308 0.577
2 ± 3.5 (1–34) 25 (6.2) 49 ± 28
3 ± 3.0 (1–14) 4 (8.1) 49 ± 28
2 ± 3.5 (1–34) 20 (5.9) 49 ± 28
0.210
0.005
0.575 0.823
B. Buecking et al. / Thrombosis Research 133 (2014) 42–47 Table 4 Subgroup Analysis of Patients Taking Vitamin K Antagonists. Data
With PCC treatment (N = 12)
Without PCC treatment (N = 50)
p-value
Age (years) ± SD Sex Men Women Fracture location Femoral neck Trochanteric Subtrochanteric ASA score ± SD Prefracture Barthel Index ± SD Charlson Comorbidity Index ± SD Time between admission and surgery (h) ± SD Surgery within b24 h (%) ≥24 and b48 h (%) ≥48 h (%) Dosage of vitamin K (± SD) INR Level on admission ± SD (range) INR Level prior to surgery ± SD (range) Reason for PCC administration Median dosage of PCC (range)
81 ± 6
81 ± 7
0.849 0.752
4 (33%) 8 (67%)
20 (40%) 30 (60%)
6 (50%) 6 (50%) 0 (0%) 2.8 ± 0.5 85 ± 16
26 (52%) 21 (42%) 3 (6%) 3.0 ± 0.6 84 ± 21
0.156 0.729
3.3 ± 2.4
2.6 ± 1.9
0.549
21 ± 10
28 ± 15
0.029
10 (83) 2 (17) 0 (0) 43 mg (9)
21 (42) 24 (48) 5 (10) 46 mg (22)
2.3 ± 0.6 (1.5-3.3)
2.0 ± 0.7 (1.0-3.5)
0.210
1.3 ± 0.2 (1.1-1.5) Early surgery required (e.g. surgical capacity) 1500 IE (1000-3500E) 25 IE/kg body weight (20–41) 5 (42) 2 (2–10)
1.3 ± 0.2 (1.0-1.6) -
0.696 -
-
-
6 (12) 2 (2–8)
0.029 0.721
Transfusion of FFP⁎ (%) Median Units of FFP (range)
0.647
b0.061
0.596
⁎ after surgery.
Discussion With this study, we aimed to evaluate our treatment of patients receiving anticoagulation with phenprocoumon. Vitamin K alone seemed to be sufficient for INR reversal within 48 h in geriatric hip fracture patients. To the best of our knowledge, there have been only a few studies that have described the effects of vitamin K treatment on geriatric hip fracture patients who were on vitamin K antagonists prior to surgery. The characteristics of the patients included in our study (Table 1) were comparable to other studies of geriatric hip fractures regarding age; distribution of the sexes; and fracture type, ASA score, and function. However, the patients in our study were on phenprocoumon instead of warfarin, which has a longer half-life (6.5 days vs. 35–45 h
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[28]). In our cohort, 16% of all hip fracture patients were taking phenprocoumon, which was a large proportion compared to other studies, in which 3.2 to 12% of patients took warfarin [17,19,29]. In our and other studies, the most frequent reason for taking vitamin K antagonists was cardiac arrhythmia [17,18,30] (Table 2). Because we aimed to normalize the INR by vitamin K supplementation, an increase in clotting factor activity from 20-25% to 60-80% was intended [31]. While Woods and co-workers reported that 1 mg of oral vitamin K was as effective in the normalization of INR in patients with an INR of 1.4-1.9 [14], Steib and colleagues found that 66% of patients with an INR of 2.6 failed to normalize [15]. We preferred intravenous administration because patients with hip fractures often have inadequate dietary intake, and the i.v. route circumvents this problem and other reasons for vitamin K malabsorption. Tsu et al. demonstrated that intravenous vitamin K reduced the INR more rapidly than oral vitamin K; in addition, a dose-dependent effect of vitamin K on anticoagulation reversal was observed, and higher doses for more rapid and complete anticoagulation reversal were therefore proposed [32]. We used a dosage of 10mg to ensure complete vitamin K saturation, although this dose is double the recommended amount of 5 mg [13,33]. Based on in-hospital procedures, this dose was administered repeatedly, leading to an average overall dose of 46 mg of vitamin K. No adverse events were observed, indicating that vitamin K is safe. Of course, there are reasonable concerns about re-establishing effective anticoagulation after surgery. The authors are unable to comment on this issue because all of the patients left the hospital with risk-adjusted low-molecularweight heparin and were re-introduced to phenprocoumon while in rehabilitation facilities. With this high dose of intravenous vitamin K, the mean time to surgery was 27 h. In other recent studies assessing the effects of intravenous vitamin K, the mean times to surgery were 67.4 h after 1–2 mg [16], 63 h after 1 mg [18], and 57.6 h after 5–10 mg [17]. However, the first study included orally and intravenously administered vitamin K and, in some cases, repeated doses. In the second study, the mean time to surgery was significantly delayed, although the target INR of 1.5 was already obtained after 38 h, with the reason for this discrepancy being unclear. It should also be noted that definitions of “acceptable INR” differed among the three studies, and the INRs were 2.0, 1.5, and not given, respectively. However, these data do seem to indicate that 5–10 mg of vitamin K is favorable to 1–2 mg. A fourth study, with a focus on clopidogrel, reported a group of patients on warfarin with a mean time to surgery of 45h [19]; 72% received vitamin K or fresh frozen plasma, but the dosage, regimen, and use of FFP were not reported. Hip fracture repair should be performed within 48 h [7–9]; unfortunately, the percentage of patients being operated on within this time frame could not be calculated from the studies mentioned above. In our cohort, 8% of patients on phenprocoumon had a delay of surgery of more than 48 h, which is less than the 17% in the UK national hip fracture database [34] and the 9.6% in the German External Quality
Table 5 Complications Associated with Bleeding, Cardiovascular Events and in-Hospital Mortalities. Data
All (N = 402)
Anticoagulant group (N = 62)
Non-anticoagulant group (N = 340)
p-value⁎
Hematomas (%) Seromas (%) Myocardial infarction (%) Stroke (%) Thrombosis (%) Pulmonary Embolism (%) Sum (%) Mortality (%)
21 (5.2%) 9 (2.2) 12 (3.0) 2 (0.5) 1 (0.2) 2 (0.5) 40 (10.0) 25 (6.2)
6 (9.7) 0 (0) 2 (3.2) 0 (0) 0 (0) 0 (0) 8 (12.9) 4 (8.1)
15 (4.4) 9 (2.6) 10 (2.9) 2 (0.6) 1 (0.3) 2 (0.6) 32 (9.4) 20 (5.9)
0.113 0.366 1.000 1.000 1.000 1.000 0.364 0.575
p-value⁎⁎
With anticoagulant With PCC treatment
Without PCC treatment
2 (16.7) 0 (0) 1 (8.3) 0 (0) 0 (0) 0 (0) 3 (25.0) 1 (8.3)
4 (7.3) 0 (0) 1 (2.0) 0 (0) 0 (0) 0 (0) 5 (10) 4 (8.0)
⁎ Patients with anticoagulation treatments as compared to patients without anticoagulation treatments. ⁎⁎ Patients with anticoagulation treatments who received PCC in comparison to patients with anticoagulation treatment who did not receive PCC.
0.287 0.326 0.177 1.000
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B. Buecking et al. / Thrombosis Research 133 (2014) 42–47
Assurance Program [35]. As noted in Table 3, the primary reason for delay was a lack of capacity for surgery. In our opinion, every effort should be undertaken to reduce surgery delay and thus minimize complication rates. This philosophy, combined with the limited resources available during the study, might account for the fact that 19% of patients received PCCs when surgery was more appropriate. We used a PCC dosage (25 IE/kg of body weight) that was comparable to dosages used in other studies [21,36]. As demonstrated in Table 4, we found no substantial differences in the characteristics of patients who received PCCs and patients who did not, though patients who received PCCs were operated on earlier than patients who did not (21 h vs. 28 h), most likely because of rapid anticoagulation reversal. In our opinion, vitamin K administration is a safe and effective method to reverse the effects of phenprocoumon in patients with hip fractures. Vitamin K should be administered intravenously immediately after hospital admission. Patients after phenprocoumon reversal were not different from the other patients with regard to hemoglobin levels at different time points or transfusion rates (Table 3), indicating sustainable anticoagulation reversal. Our study had several limitations. First, we investigated a limited number of patients on phenprocoumon. However, the prospective design and the few exclusion criteria were advantages in our study. Second, because this study was not a randomized, controlled trial, a causal relationship between PCC administration and the patients’ outcomes cannot be proved. Well-designed studies with appropriate sample sizes are necessary to prove this causal relationship. Finally, the total dose of vitamin K in this trial was very high. Although we did not observe any adverse events, a 5 to 10 mg vitamin K dose, administered once or twice preoperatively, is very likely to produce comparably convincing results [13,17,33]. In conclusion, vitamin K treatment sufficiently reversed anticoagulant treatment in geriatric hip fracture patients and allowed for timely surgery. Conflict of interest statement Each author certifies that he or she and the members of his/her immediate family have no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the content of the submitted article. Acknowledgments We thank Monika Balzer-Geldsetzer and Richard Dodel for their assistance in planning this study. Special thanks go to Anne Hemesath, Kristin Horstmann, Renate Marschall, Natalie Schubert, Anna Waldermann, and Lutz Waschnick, who contributed to the acquisition of the data. Finally, we thank Teresa Riedl-Seifert for valuable guidance in preparing the manuscript. References [1] Kanis JA, Odén A, McCloskey EV, Johansson H, Wahl DA, Cooper C. Life obotIWGoEaQo. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporos Int 2012. http://dx.doi.org/10.1007/s00198-0121964-3. [2] Federal. bureau of statistics. Germany. Hospital statistics. Wiesbaden. https://http:// www.destatis.de/DE/Publikationen/Thematisch/Gesundheit/Krankenhaeuser/ DiagnosedatenKrankenhaus2120621097004.pdf?__blob=publicationFile; 2011 . [Accessed May 2, 2012]. [3] Kannegaard PN, van der Mark S, Eiken P, Abrahamsen B. Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival. Age Ageing 2010;39:203–9. [4] Network GR. Acute care Hip Fracture Clinical Pathway. http://www.gtarehabnetwork. ca/clinical-care-guidelines-hip-fracture; October 2011. [Accessed May 2, 2012]. [5] (SIGN) SIGN. Management of hip fracture in older people - a national clinical guideline. http://www.sign.ac.uk/pdf/sign111.pdf. [Download 25.12.2011]. [6] National Institute for Health and Clinical Excellence (NICE). The management of hip fracture in adults. http://www.nice.org.uk/nicemedia/live/13489/54919/54919.pdf. [Accessed May 2, 2012].
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ISRN Hematol 2011;2011:294628. http:// dx.doi.org/10.5402/2011/294628. [18] Bhatia M, Talawadekar G, Parihar S, Smith A. An audit of the role of vitamin K in the reversal of International Normalised Ratio (INR) in patients undergoing surgery for hip fracture. Ann R Coll Surg Engl 2010;92:473–6. http://dx.doi.org/10.1308/ 003588410X12664192075774 [31, pii]. [19] Collinge CA, Kelly KC, Little B, Weaver T, Schuster RD. The effects of clopidogrel (Plavix) and other oral anticoagulants on early hip fracture surgery. J Orthop Trauma 2012;26:568–73. http://dx.doi.org/10.1097/BOT.0b013e318240d70f. [20] Majeed A, Eelde A, Agren A, Schulman S, Holmström M. Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy. Thromb Res 2012;129:146–51. http://dx.doi.org/10.1016/ j.thromres.2011.07.024. [21] Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H, et al. 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Regular Article
Effectiveness of vitamin K in anticoagulation reversal for hip fracture surgery – A prospective observational study Benjamin Buecking a,⁎, Daphne Eschbach a, Christopher Bliemel a, Ludwig Oberkircher a, Johannes Struewer b, Steffen Ruchholtz a, Ulrich J. Sachs c,d a
Department of Trauma, Hand and Reconstructive Surgery, University of Giessen and Marburg, Campus Marburg Department of Orthopaedics and Rheumatology, University of Giessen and Marburg, Campus Marburg Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany d Center for Transfusion Medicine and Hemotherapy, University Hospital Giessen and Marburg, Campus Marburg b c
a r t i c l e
i n f o
Article history: Received 17 July 2013 Received in revised form 7 October 2013 Accepted 18 October 2013 Available online 25 October 2013 Keywords: Anticoagulation Vitamin K antagonist Hip fracture Blood management Complication
a b s t r a c t Introduction: Vitamin K antagonists are often used for anticoagulant treatment in hip fracture patients. The optimal handling with such anticoagulants is unclear. We aimed to determine when anticoagulation reversal occurred after vitamin K administration and how often prothrombin complex concentrates (PCCs) were administered. We compared patients’ treatments and outcomes with those of a control group not receiving treatment for anticoagulation. Patients and Methods: A total of 402 geriatric hip fracture patients were included in this observational study. We collected data on treatment for anticoagulation, time to surgery, and reasons for delay of surgery. In patients taking vitamin K antagonists, we measured the INR (international normalized ratio) on admission and prior to surgery, along with the frequency of PCC administration. Finally, we compared in-hospital mortality and complications between patient groups. Results: A total of 62 (15%) patients received phenprocoumon prior to their fractures. Surgery was delayed in these patients compared to controls (27 h; 95%CI 23–31 vs. 16 h; 95%CI 19–19; p = 0.001), but surgery delay N 48 h (n = 5; 8%) was not due to a failure of INR reversal. The main reason for these delays was a lack of capacity for surgery. The average INR on admission was 2.1 (±0.7; range 1.0-3.5) in patients taking phenprocoumon, which decreased to 1.3 (±0.3; range 1.0-1.6) until surgery. PCCs were administered to 19% of patients. We found no differences in the in-hospital mortality (6.2% vs. 8.1%, p = 0.575) or complication rates (12.9% vs. 9.4%, p = 0.364). Conclusion: The use of vitamin K seemed to be sufficient for anticoagulation reversal in geriatric hip fracture patients, and it generally led to timely surgery; despite this success, PCCs were sometimes administered for logistical reasons. © 2013 Elsevier Ltd. All rights reserved.
Introduction Hip fractures are common in elderly people. The incidence of these fractures has risen to 439/100,000 per year in industrialized countries [1]. In 2008, nearly 140,000 fractures (ICD-10 S.72.0-72.2) were registered in Germany [2]. Demographic changes will lead to an increased incidence of these fractures over the next decade. Patients with hip fractures are often multimorbid [3]. These patients frequently suffer from cardiovascular diseases, which means that their anticoagulation treatment is often vitamin K antagonist therapy. Early surgery for hip fractures is recommended in the current guidelines [4–6]. In Germany, External Quality Assurance recommends
⁎ Corresponding author at: Department of Trauma, Hand, and Reconstructive Surgery, University of Giessen and Marburg GmbH, Campus Marburg, Baldingerstrasse, 35043 Marburg, Germany. Tel.: +49 6421 58 66216; fax: +49 6421 58 66721. E-mail address: [email protected] (B. Buecking). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.10.031
hip fracture repair during the first 48 h after admission to the hospital in most cases. The guidelines aim to minimize in-hospital mortality and medical complications, such as decubital ulcers and pneumonia, both of which have been associated with delayed surgery [7–9]. Surgical interventions under continued anticoagulation can result in an increased risk of bleeding [10,11]. Reversal of the anticoagulative effect should occur successfully prior to surgery. Vitamin K is recommended for anticoagulation reversal under the current guidelines [12,13]. It is known to reverse the international normalized ratio (INR) effectively when administered intravenously or orally prior to surgery [14,15], although due to the urgency for hip fracture surgery, the optimal strategy for INR reversal in patients with hip fractures remains controversial. Reduction of INR with vitamin K has been demonstrated, but in the same studies, the time before surgery was more than 48 h [16,18]. In a recent study in which patients on Coumadin received either vitamin K or fresh frozen plasma (FFP), the time to surgery was 1.88 days [19]. Prothrombin complex concentrates (PCCs) offer a rapid and effective alternative for anticoagulation reversal [20] and are preferable to FFP [21].
B. Buecking et al. / Thrombosis Research 133 (2014) 42–47
In our hospital, vitamin K administration is the preferred strategy for anticoagulation reversal. The aim of this study was to evaluate the efficacy of anticoagulation reversal with vitamin K in geriatric hip fracture patients. We wanted to investigate the following: when anticoagulation reversal occurred, when surgery was performed, and how often additional administration of PCCs occurred in geriatric hip fracture patients. Finally, we aimed to compare the outcomes of patients with and without anticoagulation treatment. Patients and Methods In this prospective, observational cohort study, we included 402 patients with proximal femoral fractures (ICD 10 S 72.0-72.2 [22]) aged 60 years old and older who were admitted to our university hospital for surgical fracture treatment. The exclusion criteria included polytrauma (ISS ≥ 16 [23]) and malignancy-related fractures. The recruitment period was from April 1, 2009 to September 30, 2011. Institutional review board approval from the Ethics Committee of the University of Marburg was obtained (AZ 175/08). All of the patients or their legal representatives provided written informed consent for participation in the study. Baseline data The following patient data were collected: socio-demographic data (e.g., age, sex); type of fracture, American Society of Anesthesiologists (ASA) score [24], Charlson Comorbidity Index (CCI) [25], and prefracture Barthel Index (BI) [26]. A complete medication history, with a special focus on vitamin K antagonists (e.g., warfarin, phenprocoumon), heparin, and direct oral anticoagulants (DOACs), such as rivaroxaban or dabigatran, was obtained. Medical indications for anticoagulation were also noted.
43
Occurrences of local complications associated with bleeding, such as seroma and hematoma, were collected, as were cardiovascular events, such as ischemic heart attack (defined as an elevation in troponin), stroke, thrombosis, or lung embolism. Statistics Data were collected in a Filemaker® database (FileMaker Inc., Santa Clara, CA, USA). A double entry with plausibility check was performed to monitor for data quality. Predictive Analysis SoftWare (PASW®), version 18.0 (SPSS Inc., Chicago, IL, USA), was used for the descriptive statistics and explorative data analysis. We determined the frequencies of dichotomous variables and the means and standard deviations intervals for continuous variables that had normal distributions. For the remaining continuous variables, we calculated the medians and ranges. The ranges were also calculated for the INR values and the LOS. First, we compared the patients being treated for anticoagulation to patients not receiving treatment. Subsequently, we analyzed a subgroup of patients receiving treatment for anticoagulation who received PCCs to patients who did not. Differences between the two groups of patients in terms of age, ASA score, BI, CCI, time from admission to surgery, LOS, laboratory values, and amount of red blood cells transfused were calculated in two manners, depending on the distribution. If the distribution was normal, Student's t-test was used; if the distribution was abnormal, Wilcoxon’s rank-sum test was used. We performed Fischer’s exact test to determine differences in sex distribution, type of surgery, transfusion rates of red blood cells and FFP, mortality, and the occurrence of complications between the patient groups. For the distribution of different fracture types, the chi-square test was performed. Results
Standard operating procedures As described previously [27], patients taking vitamin K antagonists received 10 mg of intravenous vitamin K upon admission and then twice per day until INR reversal. INR reversal was considered complete at INR b1.5. PCCs were not infused routinely but were used if anticoagulation reversal had to be accelerated. Subsequently, lowmolecular-weight heparin was administered to prevent cardiovascular complications. Patients taking vitamin K antagonists received a therapeutic dose of low-molecular-weight heparin, adapted for weight and renal function as a split dose (enoxaparin twice daily). The remaining patients received prophylactic enoxaparin (40 mg) once daily. Vitamin K antagonist therapy was restarted after wound healing.
During the study period, 539 patients with hip fractures were treated in our department. Of the 477 patients who met the inclusion criteria, 75 patients declined to participate. Thus, 402 patients were included in the study. Of 402 patients, 62 (15%) received phenprocoumon. No patients used other anticoagulants. The characteristics of patients with and without phenprocoumon are summarized in Table 1. There were no differences between the groups with regard to age, fracture location, ASA score, or prefracture BI. However, CCI was higher in patients treated with phenprocoumon (2.7 vs. 2.3, p = 0.029). The most frequent reasons for phenprocoumon treatment were cardiac arrhythmia (n = 40), coronary heart diseases (n = 15), and thrombosis (n = 14) (Table 2). In addition, there were more men in the phenprocoumon
Laboratory values We recorded the hemoglobin levels upon admission, after surgery, and at discharge. Additionally, the INRs of patients who were treated for anticoagulation were recorded both upon admission and immediately before surgery. Clinical data The amount of vitamin K administered during hospitalization was documented. If PCCs were administered preoperatively, the underlying reason and dosage were registered. The frequency and dosage of FFP administrations during the postsurgical period were also recorded. The interval between hospital admission and surgery and the type of surgery (prosthesis or internal fixation),) was documented. If surgery was delayed for more than 48 h, the particular reason was recorded. Length of stay (LOS) in our department, the frequency of red blood cell transfusion and their amounts in units, patients’ function according to the BI at discharge, and in-hospital mortality were recorded.
Table 1 Baseline Data for All Patients. Data
All (N = 402)
Anticoagulant group (N = 62)
Non-anticoagulant group (N = 340)
p-value
Age (years) ± SD Sex Men Women Fracture location Femoral neck Trochanteric Subtrochanteric ASA score ± SD Prefracture Barthel Index ± SD Charlson Comorbidity Index ± SD
81 ± 8
81 ± 7
81 ± 8
0.774 0.030
109 (27%) 293 (73%)
24 (39%) 38 (61%)
85 (25%) 255 (75%)
195 (48%) 186 (46%) 21 (5%) 2.9 ± 0.6 80 ± 25
32 (52%) 27 (44%) 3 (5%) 3.0 ± 0.5 84 ± 20
163 (48%) 159 (47%) 18 (5%) 2.9 ± 0.6 79 ± 25
0.619 0.137
2.4 ± 2.3
2.7 ± 2.0
2.3 ± 2.4
0.029
0.868
ASA = American Society of Anesthesiologists.
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B. Buecking et al. / Thrombosis Research 133 (2014) 42–47 Table 2 Reasons for Pre-fracture Anticoagulation.⁎ Diagnosis
Frequency
cardiac arrhythmia coronary heart diseases thrombosis⁎⁎ stroke cardiac valvular defect pulmonary embolism peripheral arterial disease
40 15 14 13 12 10 3
⁎ multiple indications were possible. ⁎⁎ without clinical significant stroke or pulmonary embolism.
group than among the patients not taking phenprocoumon (39% vs. 25%, p = 0.030). Surgery was delayed longer for patients taking phenprocoumon. The time between admission and surgery for these patients was 27h (±14), while it was 16 h (±12, p = 0.001) for the patients in the control group. Eighty-one percent of patients without anticoagulant treatment were operated on within 24 h, compared to 50% among patients taking phenprocoumon (p b 0.001). Eight percent (n = 5) of these patients were operated on after more than 48 h, but there were no patients for whom a delay occurred due to a failure of INR reversal. Delay of surgery was observed in 10 patients (2%) (Table 3). The reasons for these delays are listed in Table 3. The average INR on admission was 2.1 (±0.7, range 1.0-3.5) in patients taking phenprocoumon, which decreased to 1.3 (±0.3, range 1.0-1.6) at the time of surgery. The mean dose during hospitalization was 46 mg (±2.0). We did not observe any side effects due to vitamin K administration. While in 237 cases (51%), internal fixation was performed, 165 (41%) patients received prostheses without a difference in distribution between patient groups (p = 0.329). The length of hospital stay was increased in patients receiving treatment for anticoagulation (15 ± 6
d; range 2–39 vs. 13 ± 6 d; range 2–50, p = 0.005). The hemoglobin levels were 12.5 g/dl (±1.7) upon admission and 10.5 g/dl (±1.2) at discharge; more than half (58%) of the included patients required red blood cell transfusions. There were no differences in hemoglobin levels at different times or in the numbers of red blood cell transfusions between the patient groups (Table 3). PCCs were administered to 12 patients (19%) to accelerate anticoagulant reversal. The reason for providing PCC in all of these cases was capacity for surgery. There were no patients who received PCCs based on a lack of response to vitamin K treatment. The dosage of vitamin K that was administered during hospitalization was similar in both subgroups (43 ± 9 mg in patients receiving PCC and 46 ± 22 mg in patients who only received vitamin K, p = 0.596). The mean dosage of PCCs was 1500 IE or 25 IE/kg of body weight. More patients in the PCC group received FFP after surgery compared to the group that did not receive PCC (42% vs. 12%, p = 0.029) (Table 4). When PCCs were administered, surgery was performed earlier (21 ± 10 h vs. 28 ± 15 h; p = 0.029). While surgery was delayed for ≥48 h for 5 patients not receiving PCCs, patients who received PCCs were mostly operated on within 24 h. The average INR on admission was 2.3 ± 0.6 (range 1.5-3.3) in patients who received PCCs, compared to 2.0 ± 0.7 (range 1.0-3.5) in the remaining phenprocoumon patients (p = 0.210). Until surgery, the INR values decreased to 1.3 ± 0.2 (range 1.11.5) and 1.3 ± 0.2 (range 1.0-1.6, p = 0.696), respectively (Table 4). In 10% (n = 40) of all of the included patients, complications that were associated with bleeding or cardiovascular events occurred. The most frequent complications were hematomas (n=21) and myocardial infarction (n = 12) (Table 5). The incidence of complications was not higher in the group receiving anticoagulation treatment (12.9% vs. 9.4%, p = 0.364) or in the patients who received PCCs (25% vs. 10%, p = 0.177). The overall in-hospital mortality rate was 6.2% (n = 25), which included 4 patients (8.1%, p = 0.575) from the phenprocoumon group and 1 patient (of 12) from the group who received PCCs (p = 1.000) died.
Table 3 Clinical Data. Data
All (N = 402)
Anticoagulant group (N = 62)
Non-anticoagulant group (N = 340)
p-value
Time between admission and surgery (h) ± SD Surgery within b24 h ≥24 and b48 h ≥48 h Reasons for delay of surgery (≥48 h)
18 ± 13
27 ± 14
16 ± 12
b0.001
307 (76) 85 (21) 10 (2)
31 (50) 26 (42) 5 (8) 1x delayed diagnosis
276 (81) 59 (17) 5 (2) 1x surgery of symptomatic stenosis of carotid artery prior to hip fracture surgery 1x non displaced femoral neck fracture 2x waiting for capacity for surgery
INR Level on admission ± SD (range) INR Level prior to surgery ± SD (range) Kind of surgery Internal fixation (%) Prosthesis (%) Length of stay in acute care hospital (days) ± SD (range) Hemoglobin level on admission ± SD Hemoglobin level post surgery ± SD Hemoglobin level at discharge ± SD Transfusion of red blood cells (%) Median units of red blood cells ± SD (range) Mortality (%) Barthel Index on discharge ± SD
b0.001
1x non displaced femoral neck fracture 1x preoperative preparation for symptomatic coronary heart disease 2x waiting for capacity for surgery 2.1 ± 0.7 (1.0-3.5) 1.3 ± 0.3 (1.0-1.6)
1x unknown reason
0.329 237 (59) 165 (41) 14 ± 6 (2–50)
33 (53) 29 (47) 15 ± 6 (2–39)
204 (60) 136 (40) 13 ± 6 (2–50)
12.5 ± 1.7 10.5 ± 1.5 10.5 ± 1.2 231 (58)
12.7 ± 1.6 10.7 ± 1.5 10.7 ± 1.4 38 (61)
12.5 ± 1.7 10.5 ± 1.5 10.5 ± 1.1 193 (57)
0.303 0.164 0.308 0.577
2 ± 3.5 (1–34) 25 (6.2) 49 ± 28
3 ± 3.0 (1–14) 4 (8.1) 49 ± 28
2 ± 3.5 (1–34) 20 (5.9) 49 ± 28
0.210
0.005
0.575 0.823
B. Buecking et al. / Thrombosis Research 133 (2014) 42–47 Table 4 Subgroup Analysis of Patients Taking Vitamin K Antagonists. Data
With PCC treatment (N = 12)
Without PCC treatment (N = 50)
p-value
Age (years) ± SD Sex Men Women Fracture location Femoral neck Trochanteric Subtrochanteric ASA score ± SD Prefracture Barthel Index ± SD Charlson Comorbidity Index ± SD Time between admission and surgery (h) ± SD Surgery within b24 h (%) ≥24 and b48 h (%) ≥48 h (%) Dosage of vitamin K (± SD) INR Level on admission ± SD (range) INR Level prior to surgery ± SD (range) Reason for PCC administration Median dosage of PCC (range)
81 ± 6
81 ± 7
0.849 0.752
4 (33%) 8 (67%)
20 (40%) 30 (60%)
6 (50%) 6 (50%) 0 (0%) 2.8 ± 0.5 85 ± 16
26 (52%) 21 (42%) 3 (6%) 3.0 ± 0.6 84 ± 21
0.156 0.729
3.3 ± 2.4
2.6 ± 1.9
0.549
21 ± 10
28 ± 15
0.029
10 (83) 2 (17) 0 (0) 43 mg (9)
21 (42) 24 (48) 5 (10) 46 mg (22)
2.3 ± 0.6 (1.5-3.3)
2.0 ± 0.7 (1.0-3.5)
0.210
1.3 ± 0.2 (1.1-1.5) Early surgery required (e.g. surgical capacity) 1500 IE (1000-3500E) 25 IE/kg body weight (20–41) 5 (42) 2 (2–10)
1.3 ± 0.2 (1.0-1.6) -
0.696 -
-
-
6 (12) 2 (2–8)
0.029 0.721
Transfusion of FFP⁎ (%) Median Units of FFP (range)
0.647
b0.061
0.596
⁎ after surgery.
Discussion With this study, we aimed to evaluate our treatment of patients receiving anticoagulation with phenprocoumon. Vitamin K alone seemed to be sufficient for INR reversal within 48 h in geriatric hip fracture patients. To the best of our knowledge, there have been only a few studies that have described the effects of vitamin K treatment on geriatric hip fracture patients who were on vitamin K antagonists prior to surgery. The characteristics of the patients included in our study (Table 1) were comparable to other studies of geriatric hip fractures regarding age; distribution of the sexes; and fracture type, ASA score, and function. However, the patients in our study were on phenprocoumon instead of warfarin, which has a longer half-life (6.5 days vs. 35–45 h
45
[28]). In our cohort, 16% of all hip fracture patients were taking phenprocoumon, which was a large proportion compared to other studies, in which 3.2 to 12% of patients took warfarin [17,19,29]. In our and other studies, the most frequent reason for taking vitamin K antagonists was cardiac arrhythmia [17,18,30] (Table 2). Because we aimed to normalize the INR by vitamin K supplementation, an increase in clotting factor activity from 20-25% to 60-80% was intended [31]. While Woods and co-workers reported that 1 mg of oral vitamin K was as effective in the normalization of INR in patients with an INR of 1.4-1.9 [14], Steib and colleagues found that 66% of patients with an INR of 2.6 failed to normalize [15]. We preferred intravenous administration because patients with hip fractures often have inadequate dietary intake, and the i.v. route circumvents this problem and other reasons for vitamin K malabsorption. Tsu et al. demonstrated that intravenous vitamin K reduced the INR more rapidly than oral vitamin K; in addition, a dose-dependent effect of vitamin K on anticoagulation reversal was observed, and higher doses for more rapid and complete anticoagulation reversal were therefore proposed [32]. We used a dosage of 10mg to ensure complete vitamin K saturation, although this dose is double the recommended amount of 5 mg [13,33]. Based on in-hospital procedures, this dose was administered repeatedly, leading to an average overall dose of 46 mg of vitamin K. No adverse events were observed, indicating that vitamin K is safe. Of course, there are reasonable concerns about re-establishing effective anticoagulation after surgery. The authors are unable to comment on this issue because all of the patients left the hospital with risk-adjusted low-molecularweight heparin and were re-introduced to phenprocoumon while in rehabilitation facilities. With this high dose of intravenous vitamin K, the mean time to surgery was 27 h. In other recent studies assessing the effects of intravenous vitamin K, the mean times to surgery were 67.4 h after 1–2 mg [16], 63 h after 1 mg [18], and 57.6 h after 5–10 mg [17]. However, the first study included orally and intravenously administered vitamin K and, in some cases, repeated doses. In the second study, the mean time to surgery was significantly delayed, although the target INR of 1.5 was already obtained after 38 h, with the reason for this discrepancy being unclear. It should also be noted that definitions of “acceptable INR” differed among the three studies, and the INRs were 2.0, 1.5, and not given, respectively. However, these data do seem to indicate that 5–10 mg of vitamin K is favorable to 1–2 mg. A fourth study, with a focus on clopidogrel, reported a group of patients on warfarin with a mean time to surgery of 45h [19]; 72% received vitamin K or fresh frozen plasma, but the dosage, regimen, and use of FFP were not reported. Hip fracture repair should be performed within 48 h [7–9]; unfortunately, the percentage of patients being operated on within this time frame could not be calculated from the studies mentioned above. In our cohort, 8% of patients on phenprocoumon had a delay of surgery of more than 48 h, which is less than the 17% in the UK national hip fracture database [34] and the 9.6% in the German External Quality
Table 5 Complications Associated with Bleeding, Cardiovascular Events and in-Hospital Mortalities. Data
All (N = 402)
Anticoagulant group (N = 62)
Non-anticoagulant group (N = 340)
p-value⁎
Hematomas (%) Seromas (%) Myocardial infarction (%) Stroke (%) Thrombosis (%) Pulmonary Embolism (%) Sum (%) Mortality (%)
21 (5.2%) 9 (2.2) 12 (3.0) 2 (0.5) 1 (0.2) 2 (0.5) 40 (10.0) 25 (6.2)
6 (9.7) 0 (0) 2 (3.2) 0 (0) 0 (0) 0 (0) 8 (12.9) 4 (8.1)
15 (4.4) 9 (2.6) 10 (2.9) 2 (0.6) 1 (0.3) 2 (0.6) 32 (9.4) 20 (5.9)
0.113 0.366 1.000 1.000 1.000 1.000 0.364 0.575
p-value⁎⁎
With anticoagulant With PCC treatment
Without PCC treatment
2 (16.7) 0 (0) 1 (8.3) 0 (0) 0 (0) 0 (0) 3 (25.0) 1 (8.3)
4 (7.3) 0 (0) 1 (2.0) 0 (0) 0 (0) 0 (0) 5 (10) 4 (8.0)
⁎ Patients with anticoagulation treatments as compared to patients without anticoagulation treatments. ⁎⁎ Patients with anticoagulation treatments who received PCC in comparison to patients with anticoagulation treatment who did not receive PCC.
0.287 0.326 0.177 1.000
46
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Assurance Program [35]. As noted in Table 3, the primary reason for delay was a lack of capacity for surgery. In our opinion, every effort should be undertaken to reduce surgery delay and thus minimize complication rates. This philosophy, combined with the limited resources available during the study, might account for the fact that 19% of patients received PCCs when surgery was more appropriate. We used a PCC dosage (25 IE/kg of body weight) that was comparable to dosages used in other studies [21,36]. As demonstrated in Table 4, we found no substantial differences in the characteristics of patients who received PCCs and patients who did not, though patients who received PCCs were operated on earlier than patients who did not (21 h vs. 28 h), most likely because of rapid anticoagulation reversal. In our opinion, vitamin K administration is a safe and effective method to reverse the effects of phenprocoumon in patients with hip fractures. Vitamin K should be administered intravenously immediately after hospital admission. Patients after phenprocoumon reversal were not different from the other patients with regard to hemoglobin levels at different time points or transfusion rates (Table 3), indicating sustainable anticoagulation reversal. Our study had several limitations. First, we investigated a limited number of patients on phenprocoumon. However, the prospective design and the few exclusion criteria were advantages in our study. Second, because this study was not a randomized, controlled trial, a causal relationship between PCC administration and the patients’ outcomes cannot be proved. Well-designed studies with appropriate sample sizes are necessary to prove this causal relationship. Finally, the total dose of vitamin K in this trial was very high. Although we did not observe any adverse events, a 5 to 10 mg vitamin K dose, administered once or twice preoperatively, is very likely to produce comparably convincing results [13,17,33]. In conclusion, vitamin K treatment sufficiently reversed anticoagulant treatment in geriatric hip fracture patients and allowed for timely surgery. Conflict of interest statement Each author certifies that he or she and the members of his/her immediate family have no commercial associations (e.g., consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the content of the submitted article. Acknowledgments We thank Monika Balzer-Geldsetzer and Richard Dodel for their assistance in planning this study. Special thanks go to Anne Hemesath, Kristin Horstmann, Renate Marschall, Natalie Schubert, Anna Waldermann, and Lutz Waschnick, who contributed to the acquisition of the data. Finally, we thank Teresa Riedl-Seifert for valuable guidance in preparing the manuscript. References [1] Kanis JA, Odén A, McCloskey EV, Johansson H, Wahl DA, Cooper C. Life obotIWGoEaQo. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporos Int 2012. http://dx.doi.org/10.1007/s00198-0121964-3. [2] Federal. bureau of statistics. Germany. Hospital statistics. Wiesbaden. https://http:// www.destatis.de/DE/Publikationen/Thematisch/Gesundheit/Krankenhaeuser/ DiagnosedatenKrankenhaus2120621097004.pdf?__blob=publicationFile; 2011 . [Accessed May 2, 2012]. [3] Kannegaard PN, van der Mark S, Eiken P, Abrahamsen B. Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival. Age Ageing 2010;39:203–9. [4] Network GR. Acute care Hip Fracture Clinical Pathway. http://www.gtarehabnetwork. ca/clinical-care-guidelines-hip-fracture; October 2011. [Accessed May 2, 2012]. [5] (SIGN) SIGN. Management of hip fracture in older people - a national clinical guideline. http://www.sign.ac.uk/pdf/sign111.pdf. [Download 25.12.2011]. [6] National Institute for Health and Clinical Excellence (NICE). The management of hip fracture in adults. http://www.nice.org.uk/nicemedia/live/13489/54919/54919.pdf. [Accessed May 2, 2012].
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