American Journal of Therapeutics 23, e345–e349 (2016)
Effect of Intravenous Versus Subcutaneous Phytonadione on Length of Stay for Patients in Need of Urgent Warfarin Reversal Brandon L. Mottice, PharmD, BCPS,1 Mate M. Soric, PharmD, BCPS,2* and Elizabeth Legros2
This institutional review board–approved retrospective cohort study evaluated the impact of intravenous versus subcutaneous phytonadione on length of stay in hospitalized patients requiring urgent warfarin reversal. All patients were 18 years or older, on warfarin therapy with an international normalized ratio (INR) between 3.1 and 10.0, and had warfarin therapy restarted at discharge. Patients who received intramuscular or oral phytonadione, phytonadione by more than 1 route, fresh frozen plasma, or any other blood products containing clotting factors, patients with active or severe liver disease, and patients who received other forms of anticoagulation were excluded. A total of 4425 patients receiving phytonadione were evaluated and 79 patients were included. Baseline characteristics were similar between the intravenous and subcutaneous groups, including mean age, gender, warfarin indication, Charlson comorbidity index, and indication for phytonadione. Geometric mean length of stay in the intravenous group was 211.7 hours compared with 191.0 hours in the subcutaneous group (P 5 0.47). Though intravenous phytonadione administration resulted in significantly lower INRs at all time points ,36 hours, geometric mean time to restart of warfarin therapy was not impacted (66.3 hours vs. 64.1 hours, P 5 0.72). Despite demonstrating significantly greater INR reductions, hospital length of stay and time to restart of warfarin therapy were not improved with the administration of intravenous over subcutaneous phytonadione. Keywords: phytonadione, warfarin, coagulopathy, length of stay
INTRODUCTION Warfarin-associated coagulopathy is clinically important because of adverse events of bleeding. Outpatients with international normalized ratios (INRs) greater 1
Department of Pharmacy, Medina Hospital, a Cleveland Clinic Hospital, Medina, OH; and 2Department of Pharmacy Practice, Northeast Ohio Medical University College of Pharmacy and Department of Pharmacy, University Hospitals Geauga Medical Center, Rootstown, OH. Supported by University Hospitals and Northeast Ohio Medical University College of Pharmacy. Presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting, December 12, 2013, Orlando, FL. The authors have no conflicts of interest to disclose. *Address for correspondence: Northeast Ohio Medical University College of Pharmacy, 4209 State Route 44, P.O. Box 95, Rootstown, OH 44272. E-mail: [email protected]
than 6.0 face a significant short-term risk of major hemorrhage, occurring in 4.3%–15.5% of patients.1 Over 8% of inpatients given warfarin will experience a treatmentrelated adverse event, making it one of the highest-risk medications administered in this setting.2 Simply withholding warfarin temporarily will lower INRs from 6.0– 10.0 to ,4.0 in approximately 2.5 days; however, some patients will require more rapid INR reversal.3 Phytonadione has been found to be an effective reversal agent for warfarin-associated coagulopathy and can be administered through the oral, intramuscular, intravenous, or subcutaneous routes.4 The current American College of Chest Physicians (ACCP) guidelines on Oral Anticoagulant Therapy recommend the use of intravenous over oral and subcutaneous phytonadione in patients with major bleeding because of a more rapid and predictable onset of action.5–7 Most trials show a significantly more rapid INR reduction at time points #24 hours and
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greater uniformity of response when intravenous phytonadione is compared directly with the subcutaneous route, although the studies tend to be small, retrospective, or completed in outpatient populations.4,8–10 Despite the evidence supporting the intravenous route, phytonadione continues to be administered through inappropriate routes, with studies estimating guideline compliance rates between 17.2% and 27.6%.11,12 Whether the differences in uniformity and efficacy have an impact on patient-oriented outcomes (such as length of stay or time to restart of anticoagulation therapy) has not been studied. The aim of this study is to add to the literature by evaluating the effect of intravenous versus subcutaneous phytonadione on hospital length of stay in patients in need of urgent warfarin reversal.
MATERIALS AND METHODS Study Population A retrospective cohort study was conducted evaluating patients in need of urgent warfarin reversal between August 1, 2008 and November 31, 2013 within the University Hospitals Health System. Urgent warfarin reversal was defined as patients presenting with an INR between 3.1 and 10.0 requiring reversal of anticoagulation because of a potential bleed or procedure. Data were collected using the electronic medical record. The study design and protocol were approved by the University Hospitals Health System Institutional Review Board. Patients evaluated for inclusion received intravenous or subcutaneous phytonadione, were 18 years or older, were on active warfarin therapy, had an INR between 3.1 and 10.0 immediately before receiving phytonadione therapy, and were required to have warfarin therapy restarted on hospital discharge. Patients who received intramuscular or oral phytonadione, received phytonadione by more than 1 route, received other forms of anticoagulation, or had active or severe liver disease were excluded from the study. In addition to these exclusion criteria, patients who received fresh frozen plasma or any other blood products containing clotting factors were excluded because of potential interference with the impact of phytonadione on INR values. No standardized approach to phytonadione administration, dosing, or INR monitoring existed within the health system, and decisions regarding anticoagulation reversal were at the discretion of the treating health care provider.
Mottice et al
phytonadione indication, baseline INR, and total dose of phytonadione administered. The primary end point was length of stay, defined as the time of admission until the time of discharge. Secondary end points were cumulative dose of phytonadione required to achieve an INR of #1.5, time taken to achieve an INR of #1.5, time from the first phytonadione dose to restart of warfarin therapy, and the difference between initial and subsequent INRs measured at ,12 hours, 12–24 hours, .24–36 hours, and .36–48 hours. Statistics As there is no current literature assessing the impact of phytonadione route of administration on length of hospital stay, an a priori power analysis was not conducted. Statistical analysis was completed using the x2 or Fischer exact test for comparisons of nominal data and the unpaired student t-test for comparisons of continuous data, as appropriate. Data with positive skew were log (base 10) transformed before analysis, and geometric means are reported. A P value ,0.05 was deemed statistically significant. The analysis of secondary end points was not adjusted for multiple comparisons.
RESULTS This retrospective chart review evaluated 4425 patient charts to identify 79 patients who met inclusion and exclusion criteria (Figure 1). Most patients were excluded as a result of receiving vitamin K through multiple routes, receiving blood products that contain clotting factors, or having baseline INR values outside the study’s target range. As seen in Table 1, baseline characteristics were not statistically different between the intravenous and subcutaneous groups with regard to mean age, sex, or warfarin indication. The prevalence
Data Collection Baseline demographics recorded included age, gender, Charlson comorbidity index, warfarin indication, American Journal of Therapeutics (2016) 23(2)
FIGURE 1. Study population. www.americantherapeutics.com
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Intravenous Versus Subcutaneous Phytonadione
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Table 1. Patient baseline characteristics. Intravenous Subcutaneous Age, yrs Mean (SD) Sex Female, n (%) Male, n (%) Charlson comorbidity index Mean (SD) Warfarin indication Atrial fibrillation, n (%) Venous thromboembolism, n (%) Hypercoagulable state, n (%) Valvulopathy, n (%) Cerebrovascular accident, n (%) Phytonadione indication Potential bleed, n (%) Procedure, n (%) Initial INR Mean (SD) Initial phytonadione dose, mg Mean (SD)
P
70 (15)
73 (16)
0.41
23 (59) 16 (41)
23 (58) 17 (42)
0.82
5.5 (2.5)
5.2 (1.8)
0.53
21 (53.7)
26 (65)
0.31
15 (38.5)
10 (25)
0.20
3.8, P 5 0.002), 12–24 hours (1.5 vs. 2.6, P , 0.001), and .24–36 hours (1.3 vs. 1.6, P 5 0.02), although not at .36–48 hours (1.3 vs. 1.4 P 5 0.17). Geometric mean time to achieve an INR #1.5 was 21.4 hours versus 44.4 hours, respectively (P , 0.001). Cumulative dose required to achieve an INR of #1.5 was 9.3 mg of intravenous phytonadione versus 7.7 mg of subcutaneous phytonadione (P 5 0.19). Despite the more rapid reversal of anticoagulation with intravenous phytonadione, the geometric mean (95% confidence interval) time from the first phytonadione dose to restart of warfarin therapy was 66.3 (52.7–83.5) hours in the intravenous group versus 64.1 (50.2–81.9) hours in the subcutaneous group (P 5 0.84).
DISCUSSION 1 (2.6)
2 (5)
1.00
1 (2.6) 1 (2.6)
1 (2.5) 1 (2.5)
1.00 1.00
22 (56.4)
25 (62.5)
0.58
17 (43.5)
15 (37.5)
0.58
5.1 (1.8)
5.6 (1.8)
0.25
7.7 (3.5)
6.9 (3.5)
0.35
of comorbid conditions (as measured by the Charlson comorbidity index) was not significantly different. The indication for reversal of anticoagulation, baseline INR, and phytonadione dose given was similar, as well. The primary end point of geometric mean length of stay was 211.7 hours in the intravenous group compared with 191.0 hours in the subcutaneous group (Table 2). The ratio of geometric means for the primary end point was 1.11 (95% confidence interval: 0.83–1.47) demonstrating no significant difference between groups. A separate analysis performed that defined length of stay as time of phytonadione administration to hospital discharge (to account for the impact of delayed administration of phytonadione) revealed similar results. Figure 2 shows the results of the comparison of the secondary end point of mean INR at various time points up to 48 hours after phytonadione administration. Mean INR was significantly lower with intravenous phytonadione at ,12 hours (2.1 vs. www.americantherapeutics.com
When reviewing the current ACCP guidelines, the evidence used to formulate warfarin reversal recommendations is limited in nature.5,6 One of the first studies completed was a retrospective review by Whitling et al4 comparing 33 patients with excessive anticoagulation given phytonadione for reversal. They concluded that INR reduction was more effective with intravenous phytonadione versus subcutaneous phytonadione when comparing the mean baseline INR versus the INR at 24 hours. However, it is difficult to draw firm conclusions from this study because of the variability of the dosages and the lack of statistical analysis. A randomized single-blind study by Raj et al8 evaluated the effect of 1 mg intravenous or subcutaneous phytonadione on INR of 22 asymptomatic outpatients with an INR .6.0 at baseline. They found that intravenous phytonadione showed statistically significant INR lowering at 8 hours (3.4 vs. 0.5, P 5 0.006) and 24 hours (4.9 vs. 3.5, P 5 0.009), concluding that the intravenous route was more effective than the subcutaneous phytonadione. A third study conducted by Nee et al reviewed 55 outpatients who required warfarin reversal for excessive anticoagulation. For patients with a baseline INR between 6.0 and 10.0, 0.5 mg of intravenous or subcutaneous phytonadione was administered. If the baseline INR was between 10.0 and 20.0, patients received 3 mg of phytonadione by either the intravenous or subcutaneous route. They showed a statistically significant INR reduction over a period of 24 hours in the intravenous group when compared with the subcutaneous group (24.2 vs. 23.0, P 5 0.014) along with less heterogeneity of the INR reduction in the intravenous group at 24 and 72 hours.9 When reviewing these trials, on which the current ACCP guidelines are based, the studies tend to be small outpatient trials relying on disease-oriented outcomes. American Journal of Therapeutics (2016) 23(2)
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Table 2. Outcomes.
Length of stay, h Geometric mean (95% confidence interval) Time to restart of warfarin, h Geometric mean (95% confidence interval) Time to INR #1.5, h Geometric mean (95% confidence interval) Dose required to achieve INR #1.5, mg Mean (SD) Mean (SD) INR after phytonadione dose ,12 h* 12–24 h† .24–36 h‡ .36–48 h§ *Data †Data ‡Data §Data
available available available available
for for for for
67% 59% 49% 39%
of of of of
intravenous intravenous intravenous intravenous
and and and and
35% 78% 45% 60%
of of of of
Intravenous
Subcutaneous
P
211.7 (172.6–259.5)
191 (155.8–234.1)
0.47
66.3 (52.7–83.5)
64.1 (50.2–81.9)
0.84
21.4 (17.1–26.9)
44.4 (37.9–52.1)
,0.001
7.7 (5.0)
2.1 1.5 1.3 1.3
3.8 2.6 1.6 1.4
subcutaneous subcutaneous subcutaneous subcutaneous
This study was designed in an attempt to add to the literature by assessing patient-oriented outcomes, such as length of stay, cumulative dose of phytonadione required to achieve an INR ,1.5, and time to restart of warfarin therapy in an inpatient population requiring urgent warfarin reversal. Despite demonstrating a faster onset of reversal (as was seen in other trials evaluating the route of phytonadione administration), we were unable to show any statistically significant impact on length of stay or time to restart of warfarin therapy with the intravenous group when compared with the subcutaneous group. Baseline INR, initial, and total dose of phytonadione administered to achieve an INR #1.5 was similar between groups and could not have had a significant impact on the findings. It seems that other factors of hospitalization beyond the rate of warfarin reversal play a larger role in determining length of stay and restart of anticoagulation. The study was able to add to the literature cited in the ACCP guidelines by
FIGURE 2. Secondary end point—INR change over time. American Journal of Therapeutics (2016) 23(2)
9.3 (6.1) (1.3) (0.76) (0.20) (0.24)
phytonadione phytonadione phytonadione phytonadione
(2.0) (1.1) (0.44) (0.43)
0.19 0.002 ,0.001 0.02 0.17
patients. patients. patients. patients.
showing statistically significant reductions of INR at times ,12 hours, 12–24 hours, .24–36 hours and time to INR #1.5 extend to the inpatient population receiving intravenous phytonadione. One of the strengths of this study was the choice of a patient-oriented primary end point. Existing literature relies primarily on reduction in INR without looking at the impact on the patient’s overall well-being. This study also enrolled a wide array of patients from a large urban teaching hospital, community hospitals, and rural critical access hospitals. Finally, despite the wide range of settings, the study groups were similar at baseline with regard to gender, presence of comorbidities, warfarin indication, baseline INR, and total dose of phytonadione administered. We also acknowledge the limitations of this study. Being a retrospective trial, INR draw times could not be standardized, confounders not identified in our inclusion and exclusion criteria may influence the results, and standardization of phytonadione dosing was not possible. The strict inclusion and exclusion criteria also limited our patient enrollment, potentially limiting the external validity of the study. Similar to the findings of Fan et al,11 we observed poor adherence to the current guideline recommendations for phytonadione routes of administration and dosing. Although the incidence is low, perhaps lingering fears of anaphylaxis associated with intravenous phytonadione limit its use in this patient population.13,14 A number of patients were also excluded because of the administration of fresh frozen plasma. This, however, was expected because of the www.americantherapeutics.com
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Intravenous Versus Subcutaneous Phytonadione
ACCP guideline recommendation to administer blood plasma products along with phytonadione for urgent warfarin reversal.6 This study was unable to identify an impact of intravenous versus subcutaneous phytonadione administration on length of hospital stay or time to restart of warfarin therapy in hospitalized patients requiring urgent warfarin reversal. Intravenous phytonadione administration resulted in a shorter time to achieve an INR of #1.5 and statistically significant INR reductions at ,12 hours, 12–24 hours, and .24–36 hours after administration when compared with subcutaneous phytonadione. Larger, prospective, randomized trials are warranted to better characterize the impact of route of administration of phytonadione on patientoriented outcomes such as length of stay and time to restart of warfarin therapy.
REFERENCES 1. Hylek EM, Chang YC, Skates SJ, et al. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med. 2000;160:1612–1617. 2. Classen DC, Jaser L, Budnitz DS. Adverse drug events among hospitalized medicare patients: epidemiology and national estimates from a new approach to surveillance. Jt Comm J Qual Patient Saf. 2010;36:12–21. 3. Patel RJ, Witt DM, Saseen JJ, et al. Randomized, placebocontrolled trial of oral phytonadione for excessive anticoagulation. Pharmacotherapy. 2000;20:1159–1166. 4. Whitling AM, Bussey HI, Lyons RM. Comparing different routes and doses of phytonadione for reversing excessive anticoagulation. Arch Intern Med. 1998;158:2136–2140. 5. Ageno W, Gallus A, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians
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6.
7.
8.
9.
10.
11.
12.
13.
14.
Evidenced-Based Clinical Practice Guidelines. Chest. 2012;141:e44S–e88S. Holbrook A, Schulman S, Witt DM, et al. Evidence-based Management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidenced-Based Clinical Practice Guidelines. Chest. 2012;141:e152S–e184S. Lubetsky A, Yonath H, Olchovsky D, et al. Comparison of oral vs intravenous phytonadione (vitamin K) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med. 2003;163: 2469–2473. Raj G, Kumar R, McKinney P. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med. 1999;159: 2721–2724. Nee R, Doppenschmidt D, Donovan DJ, et al. Intravenous versus subcutaneous vitamin K1 in reversing excessive oral anticoagulation. Am J Cardiol. 1999;83: 286–288. Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized, controlled trial. Ann Intern Med. 2002;137:251–254. Fan J, Armistead JA, Adams AG, et al. A retrospective evaluation of vitamin K1 therapy to reverse the anticoagulant effect of warfarin. Pharmacotherapy. 2003;10: 1245–1250. Van Berkel MA, Crannage AJ, Murphy JA. Evaluation of education on the appropriate use of vitamin K in warfarin reversal in adult inpatients. Hosp Pharm. 2013;48:662–667. Riegert-Johnson DL, Volcheck GW. The incidence of anaphylaxis following intravenous phytonadione (vitamin K): a 5-year retrospective review. Ann Allergy Asthma Immunol. 2002;89:400–406. Fiore LD, Scola MA, Cantillon CE, et al. Anaphylactoid reactions to Vitamin K. J Thromb Thrombolysis. 2001;11: 175–183.
American Journal of Therapeutics (2016) 23(2)
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Effect of Intravenous Versus Subcutaneous Phytonadione on Length of Stay for Patients in Need of Urgent Warfarin Reversal Brandon L. Mottice, PharmD, BCPS,1 Mate M. Soric, PharmD, BCPS,2* and Elizabeth Legros2
This institutional review board–approved retrospective cohort study evaluated the impact of intravenous versus subcutaneous phytonadione on length of stay in hospitalized patients requiring urgent warfarin reversal. All patients were 18 years or older, on warfarin therapy with an international normalized ratio (INR) between 3.1 and 10.0, and had warfarin therapy restarted at discharge. Patients who received intramuscular or oral phytonadione, phytonadione by more than 1 route, fresh frozen plasma, or any other blood products containing clotting factors, patients with active or severe liver disease, and patients who received other forms of anticoagulation were excluded. A total of 4425 patients receiving phytonadione were evaluated and 79 patients were included. Baseline characteristics were similar between the intravenous and subcutaneous groups, including mean age, gender, warfarin indication, Charlson comorbidity index, and indication for phytonadione. Geometric mean length of stay in the intravenous group was 211.7 hours compared with 191.0 hours in the subcutaneous group (P 5 0.47). Though intravenous phytonadione administration resulted in significantly lower INRs at all time points ,36 hours, geometric mean time to restart of warfarin therapy was not impacted (66.3 hours vs. 64.1 hours, P 5 0.72). Despite demonstrating significantly greater INR reductions, hospital length of stay and time to restart of warfarin therapy were not improved with the administration of intravenous over subcutaneous phytonadione. Keywords: phytonadione, warfarin, coagulopathy, length of stay
INTRODUCTION Warfarin-associated coagulopathy is clinically important because of adverse events of bleeding. Outpatients with international normalized ratios (INRs) greater 1
Department of Pharmacy, Medina Hospital, a Cleveland Clinic Hospital, Medina, OH; and 2Department of Pharmacy Practice, Northeast Ohio Medical University College of Pharmacy and Department of Pharmacy, University Hospitals Geauga Medical Center, Rootstown, OH. Supported by University Hospitals and Northeast Ohio Medical University College of Pharmacy. Presented at the American Society of Health-System Pharmacists Midyear Clinical Meeting, December 12, 2013, Orlando, FL. The authors have no conflicts of interest to disclose. *Address for correspondence: Northeast Ohio Medical University College of Pharmacy, 4209 State Route 44, P.O. Box 95, Rootstown, OH 44272. E-mail: [email protected]
than 6.0 face a significant short-term risk of major hemorrhage, occurring in 4.3%–15.5% of patients.1 Over 8% of inpatients given warfarin will experience a treatmentrelated adverse event, making it one of the highest-risk medications administered in this setting.2 Simply withholding warfarin temporarily will lower INRs from 6.0– 10.0 to ,4.0 in approximately 2.5 days; however, some patients will require more rapid INR reversal.3 Phytonadione has been found to be an effective reversal agent for warfarin-associated coagulopathy and can be administered through the oral, intramuscular, intravenous, or subcutaneous routes.4 The current American College of Chest Physicians (ACCP) guidelines on Oral Anticoagulant Therapy recommend the use of intravenous over oral and subcutaneous phytonadione in patients with major bleeding because of a more rapid and predictable onset of action.5–7 Most trials show a significantly more rapid INR reduction at time points #24 hours and
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greater uniformity of response when intravenous phytonadione is compared directly with the subcutaneous route, although the studies tend to be small, retrospective, or completed in outpatient populations.4,8–10 Despite the evidence supporting the intravenous route, phytonadione continues to be administered through inappropriate routes, with studies estimating guideline compliance rates between 17.2% and 27.6%.11,12 Whether the differences in uniformity and efficacy have an impact on patient-oriented outcomes (such as length of stay or time to restart of anticoagulation therapy) has not been studied. The aim of this study is to add to the literature by evaluating the effect of intravenous versus subcutaneous phytonadione on hospital length of stay in patients in need of urgent warfarin reversal.
MATERIALS AND METHODS Study Population A retrospective cohort study was conducted evaluating patients in need of urgent warfarin reversal between August 1, 2008 and November 31, 2013 within the University Hospitals Health System. Urgent warfarin reversal was defined as patients presenting with an INR between 3.1 and 10.0 requiring reversal of anticoagulation because of a potential bleed or procedure. Data were collected using the electronic medical record. The study design and protocol were approved by the University Hospitals Health System Institutional Review Board. Patients evaluated for inclusion received intravenous or subcutaneous phytonadione, were 18 years or older, were on active warfarin therapy, had an INR between 3.1 and 10.0 immediately before receiving phytonadione therapy, and were required to have warfarin therapy restarted on hospital discharge. Patients who received intramuscular or oral phytonadione, received phytonadione by more than 1 route, received other forms of anticoagulation, or had active or severe liver disease were excluded from the study. In addition to these exclusion criteria, patients who received fresh frozen plasma or any other blood products containing clotting factors were excluded because of potential interference with the impact of phytonadione on INR values. No standardized approach to phytonadione administration, dosing, or INR monitoring existed within the health system, and decisions regarding anticoagulation reversal were at the discretion of the treating health care provider.
Mottice et al
phytonadione indication, baseline INR, and total dose of phytonadione administered. The primary end point was length of stay, defined as the time of admission until the time of discharge. Secondary end points were cumulative dose of phytonadione required to achieve an INR of #1.5, time taken to achieve an INR of #1.5, time from the first phytonadione dose to restart of warfarin therapy, and the difference between initial and subsequent INRs measured at ,12 hours, 12–24 hours, .24–36 hours, and .36–48 hours. Statistics As there is no current literature assessing the impact of phytonadione route of administration on length of hospital stay, an a priori power analysis was not conducted. Statistical analysis was completed using the x2 or Fischer exact test for comparisons of nominal data and the unpaired student t-test for comparisons of continuous data, as appropriate. Data with positive skew were log (base 10) transformed before analysis, and geometric means are reported. A P value ,0.05 was deemed statistically significant. The analysis of secondary end points was not adjusted for multiple comparisons.
RESULTS This retrospective chart review evaluated 4425 patient charts to identify 79 patients who met inclusion and exclusion criteria (Figure 1). Most patients were excluded as a result of receiving vitamin K through multiple routes, receiving blood products that contain clotting factors, or having baseline INR values outside the study’s target range. As seen in Table 1, baseline characteristics were not statistically different between the intravenous and subcutaneous groups with regard to mean age, sex, or warfarin indication. The prevalence
Data Collection Baseline demographics recorded included age, gender, Charlson comorbidity index, warfarin indication, American Journal of Therapeutics (2016) 23(2)
FIGURE 1. Study population. www.americantherapeutics.com
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Table 1. Patient baseline characteristics. Intravenous Subcutaneous Age, yrs Mean (SD) Sex Female, n (%) Male, n (%) Charlson comorbidity index Mean (SD) Warfarin indication Atrial fibrillation, n (%) Venous thromboembolism, n (%) Hypercoagulable state, n (%) Valvulopathy, n (%) Cerebrovascular accident, n (%) Phytonadione indication Potential bleed, n (%) Procedure, n (%) Initial INR Mean (SD) Initial phytonadione dose, mg Mean (SD)
P
70 (15)
73 (16)
0.41
23 (59) 16 (41)
23 (58) 17 (42)
0.82
5.5 (2.5)
5.2 (1.8)
0.53
21 (53.7)
26 (65)
0.31
15 (38.5)
10 (25)
0.20
3.8, P 5 0.002), 12–24 hours (1.5 vs. 2.6, P , 0.001), and .24–36 hours (1.3 vs. 1.6, P 5 0.02), although not at .36–48 hours (1.3 vs. 1.4 P 5 0.17). Geometric mean time to achieve an INR #1.5 was 21.4 hours versus 44.4 hours, respectively (P , 0.001). Cumulative dose required to achieve an INR of #1.5 was 9.3 mg of intravenous phytonadione versus 7.7 mg of subcutaneous phytonadione (P 5 0.19). Despite the more rapid reversal of anticoagulation with intravenous phytonadione, the geometric mean (95% confidence interval) time from the first phytonadione dose to restart of warfarin therapy was 66.3 (52.7–83.5) hours in the intravenous group versus 64.1 (50.2–81.9) hours in the subcutaneous group (P 5 0.84).
DISCUSSION 1 (2.6)
2 (5)
1.00
1 (2.6) 1 (2.6)
1 (2.5) 1 (2.5)
1.00 1.00
22 (56.4)
25 (62.5)
0.58
17 (43.5)
15 (37.5)
0.58
5.1 (1.8)
5.6 (1.8)
0.25
7.7 (3.5)
6.9 (3.5)
0.35
of comorbid conditions (as measured by the Charlson comorbidity index) was not significantly different. The indication for reversal of anticoagulation, baseline INR, and phytonadione dose given was similar, as well. The primary end point of geometric mean length of stay was 211.7 hours in the intravenous group compared with 191.0 hours in the subcutaneous group (Table 2). The ratio of geometric means for the primary end point was 1.11 (95% confidence interval: 0.83–1.47) demonstrating no significant difference between groups. A separate analysis performed that defined length of stay as time of phytonadione administration to hospital discharge (to account for the impact of delayed administration of phytonadione) revealed similar results. Figure 2 shows the results of the comparison of the secondary end point of mean INR at various time points up to 48 hours after phytonadione administration. Mean INR was significantly lower with intravenous phytonadione at ,12 hours (2.1 vs. www.americantherapeutics.com
When reviewing the current ACCP guidelines, the evidence used to formulate warfarin reversal recommendations is limited in nature.5,6 One of the first studies completed was a retrospective review by Whitling et al4 comparing 33 patients with excessive anticoagulation given phytonadione for reversal. They concluded that INR reduction was more effective with intravenous phytonadione versus subcutaneous phytonadione when comparing the mean baseline INR versus the INR at 24 hours. However, it is difficult to draw firm conclusions from this study because of the variability of the dosages and the lack of statistical analysis. A randomized single-blind study by Raj et al8 evaluated the effect of 1 mg intravenous or subcutaneous phytonadione on INR of 22 asymptomatic outpatients with an INR .6.0 at baseline. They found that intravenous phytonadione showed statistically significant INR lowering at 8 hours (3.4 vs. 0.5, P 5 0.006) and 24 hours (4.9 vs. 3.5, P 5 0.009), concluding that the intravenous route was more effective than the subcutaneous phytonadione. A third study conducted by Nee et al reviewed 55 outpatients who required warfarin reversal for excessive anticoagulation. For patients with a baseline INR between 6.0 and 10.0, 0.5 mg of intravenous or subcutaneous phytonadione was administered. If the baseline INR was between 10.0 and 20.0, patients received 3 mg of phytonadione by either the intravenous or subcutaneous route. They showed a statistically significant INR reduction over a period of 24 hours in the intravenous group when compared with the subcutaneous group (24.2 vs. 23.0, P 5 0.014) along with less heterogeneity of the INR reduction in the intravenous group at 24 and 72 hours.9 When reviewing these trials, on which the current ACCP guidelines are based, the studies tend to be small outpatient trials relying on disease-oriented outcomes. American Journal of Therapeutics (2016) 23(2)
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Table 2. Outcomes.
Length of stay, h Geometric mean (95% confidence interval) Time to restart of warfarin, h Geometric mean (95% confidence interval) Time to INR #1.5, h Geometric mean (95% confidence interval) Dose required to achieve INR #1.5, mg Mean (SD) Mean (SD) INR after phytonadione dose ,12 h* 12–24 h† .24–36 h‡ .36–48 h§ *Data †Data ‡Data §Data
available available available available
for for for for
67% 59% 49% 39%
of of of of
intravenous intravenous intravenous intravenous
and and and and
35% 78% 45% 60%
of of of of
Intravenous
Subcutaneous
P
211.7 (172.6–259.5)
191 (155.8–234.1)
0.47
66.3 (52.7–83.5)
64.1 (50.2–81.9)
0.84
21.4 (17.1–26.9)
44.4 (37.9–52.1)
,0.001
7.7 (5.0)
2.1 1.5 1.3 1.3
3.8 2.6 1.6 1.4
subcutaneous subcutaneous subcutaneous subcutaneous
This study was designed in an attempt to add to the literature by assessing patient-oriented outcomes, such as length of stay, cumulative dose of phytonadione required to achieve an INR ,1.5, and time to restart of warfarin therapy in an inpatient population requiring urgent warfarin reversal. Despite demonstrating a faster onset of reversal (as was seen in other trials evaluating the route of phytonadione administration), we were unable to show any statistically significant impact on length of stay or time to restart of warfarin therapy with the intravenous group when compared with the subcutaneous group. Baseline INR, initial, and total dose of phytonadione administered to achieve an INR #1.5 was similar between groups and could not have had a significant impact on the findings. It seems that other factors of hospitalization beyond the rate of warfarin reversal play a larger role in determining length of stay and restart of anticoagulation. The study was able to add to the literature cited in the ACCP guidelines by
FIGURE 2. Secondary end point—INR change over time. American Journal of Therapeutics (2016) 23(2)
9.3 (6.1) (1.3) (0.76) (0.20) (0.24)
phytonadione phytonadione phytonadione phytonadione
(2.0) (1.1) (0.44) (0.43)
0.19 0.002 ,0.001 0.02 0.17
patients. patients. patients. patients.
showing statistically significant reductions of INR at times ,12 hours, 12–24 hours, .24–36 hours and time to INR #1.5 extend to the inpatient population receiving intravenous phytonadione. One of the strengths of this study was the choice of a patient-oriented primary end point. Existing literature relies primarily on reduction in INR without looking at the impact on the patient’s overall well-being. This study also enrolled a wide array of patients from a large urban teaching hospital, community hospitals, and rural critical access hospitals. Finally, despite the wide range of settings, the study groups were similar at baseline with regard to gender, presence of comorbidities, warfarin indication, baseline INR, and total dose of phytonadione administered. We also acknowledge the limitations of this study. Being a retrospective trial, INR draw times could not be standardized, confounders not identified in our inclusion and exclusion criteria may influence the results, and standardization of phytonadione dosing was not possible. The strict inclusion and exclusion criteria also limited our patient enrollment, potentially limiting the external validity of the study. Similar to the findings of Fan et al,11 we observed poor adherence to the current guideline recommendations for phytonadione routes of administration and dosing. Although the incidence is low, perhaps lingering fears of anaphylaxis associated with intravenous phytonadione limit its use in this patient population.13,14 A number of patients were also excluded because of the administration of fresh frozen plasma. This, however, was expected because of the www.americantherapeutics.com
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Intravenous Versus Subcutaneous Phytonadione
ACCP guideline recommendation to administer blood plasma products along with phytonadione for urgent warfarin reversal.6 This study was unable to identify an impact of intravenous versus subcutaneous phytonadione administration on length of hospital stay or time to restart of warfarin therapy in hospitalized patients requiring urgent warfarin reversal. Intravenous phytonadione administration resulted in a shorter time to achieve an INR of #1.5 and statistically significant INR reductions at ,12 hours, 12–24 hours, and .24–36 hours after administration when compared with subcutaneous phytonadione. Larger, prospective, randomized trials are warranted to better characterize the impact of route of administration of phytonadione on patientoriented outcomes such as length of stay and time to restart of warfarin therapy.
REFERENCES 1. Hylek EM, Chang YC, Skates SJ, et al. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med. 2000;160:1612–1617. 2. Classen DC, Jaser L, Budnitz DS. Adverse drug events among hospitalized medicare patients: epidemiology and national estimates from a new approach to surveillance. Jt Comm J Qual Patient Saf. 2010;36:12–21. 3. Patel RJ, Witt DM, Saseen JJ, et al. Randomized, placebocontrolled trial of oral phytonadione for excessive anticoagulation. Pharmacotherapy. 2000;20:1159–1166. 4. Whitling AM, Bussey HI, Lyons RM. Comparing different routes and doses of phytonadione for reversing excessive anticoagulation. Arch Intern Med. 1998;158:2136–2140. 5. Ageno W, Gallus A, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians
www.americantherapeutics.com
e349
6.
7.
8.
9.
10.
11.
12.
13.
14.
Evidenced-Based Clinical Practice Guidelines. Chest. 2012;141:e44S–e88S. Holbrook A, Schulman S, Witt DM, et al. Evidence-based Management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidenced-Based Clinical Practice Guidelines. Chest. 2012;141:e152S–e184S. Lubetsky A, Yonath H, Olchovsky D, et al. Comparison of oral vs intravenous phytonadione (vitamin K) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med. 2003;163: 2469–2473. Raj G, Kumar R, McKinney P. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med. 1999;159: 2721–2724. Nee R, Doppenschmidt D, Donovan DJ, et al. Intravenous versus subcutaneous vitamin K1 in reversing excessive oral anticoagulation. Am J Cardiol. 1999;83: 286–288. Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized, controlled trial. Ann Intern Med. 2002;137:251–254. Fan J, Armistead JA, Adams AG, et al. A retrospective evaluation of vitamin K1 therapy to reverse the anticoagulant effect of warfarin. Pharmacotherapy. 2003;10: 1245–1250. Van Berkel MA, Crannage AJ, Murphy JA. Evaluation of education on the appropriate use of vitamin K in warfarin reversal in adult inpatients. Hosp Pharm. 2013;48:662–667. Riegert-Johnson DL, Volcheck GW. The incidence of anaphylaxis following intravenous phytonadione (vitamin K): a 5-year retrospective review. Ann Allergy Asthma Immunol. 2002;89:400–406. Fiore LD, Scola MA, Cantillon CE, et al. Anaphylactoid reactions to Vitamin K. J Thromb Thrombolysis. 2001;11: 175–183.
American Journal of Therapeutics (2016) 23(2)
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