ORIGINAL ARTICLE
Comparison of 2 Weight-Based Heparin Dosing Nomograms in Neurology and Vascular Surgical Patients Sally B. Marotti, MClinPharm, FSHP, CGP, Michael Barras, GDipClinPharm, PhD, and Carl Kirkpatrick, BPharm(Hons), PhD
Background: Unfractionated heparin sodium (UFH) is used in neurology and vascular surgical patients to treat and prevent thromboembolic occlusions and requires weight-based dosing to achieve a therapeutic range; however, the optimal dosing strategy is not known. This study sought to determine whether an intravenous (IV) weight-based UFH dosing nomogram based on an 80-unit/kg bolus and 18-unit$kg21$h21 initial infusion rate achieves therapeutic anticoagulation [activated partial thromboplastin time (aPTT), 65–110 seconds] more rapidly than that based on a 60-unit/kg bolus and 12-unit$kg21$h21 initial infusion rate in 98 neurology and vascular surgery patients.
Methods: The study consisted of a retrospective chart review of adults prescribed and administered IV UFH for .6 hours, admitted under the neurology or vascular surgery teams and administered UFH for transient ischemic attack, stroke, acute ischemic limb, or postoperative revascularization. Results: The time to therapeutic aPTT analysis showed superiority of the higher dose (P = 0.04, log-rank test). At 6 hours, there was a significantly greater proportion of patients within the therapeutic range in the higher dose group (36.0% versus 16.7%, P = 0.03), with fewer subtherapeutic aPTTs (34.0% versus 70.8%, P , 0.001) and more supratherapeutic aPTTs (30.0% versus 12.5%, P = 0.034). Conclusions: A weight-based nomogram for IV UFH using an 80unit/kg bolus and an initial infusion rate of 18 units$kg21$h21 showed a more rapid achievement of therapeutic aPTT when compared with a 60:12 dosing nomogram. Future research assessing a 70-unit/kg bolus dose is recommended. Key Words: hemorrhage, heparin, neurology, stroke, vascular surgical procedures (Ther Drug Monit 2015;37:33–39)
Received for publication October 24, 2013; accepted April 28, 2014. From the Department of Pharmacy, The Queen Elizabeth Hospital, Woodville South, South Australia; Royal Brisbane and Women’s Hospital & School of Pharmacy, University of Queensland; and Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Australia. The authors declare no conflict of interest. Correspondence: Sally B. Marotti, MClinPharm, FSHP, CGP, Department of Pharmacy, The Queen Elizabeth Hospital, 28 Woodville Rd, Woodville South, South Australia 5011, Australia (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
INTRODUCTION The aim of treatment with unfractionated heparin sodium (UFH) is to prevent the development or extension of a thrombus without significantly increasing the risk of bleeding.1 Anticoagulant response to a dose of UFH varies between patients,2 thus it has become standard practice to monitor the measure of bleeding time to determine an optimal response. The activated partial thromboplastin time (aPTT) is the most common method used for monitoring UFH, with the dose adjusted to maintain a defined aPTT therapeutic range.3 In patients with venous thromboembolism (VTE) values below the therapeutic range, they are associated with reduced efficacy (extension of thrombi), and excessively prolonged values (above the therapeutic range) may increase the risk of bleeding.1 There is also evidence in patients with VTE that the risk of further thromboembolism is reduced if a target aPTT is achieved rapidly.4 For these reasons, it is critically important to ensure that patients with life- or limbthreatening clots achieve a therapeutic aPTT quickly and remain therapeutic until the patient is stable on oral anticoagulants, or the clot is able to be removed. As there is a diverse drug response in the population, weight-based dose strategies (units/kg) for UFH have been shown to be superior to fixed dosing.5,6 Intravenous (IV) UFH is often used in neurology and vascular surgical patients to treat or prevent thromboembolic occlusions peri-operatively. The optimal weight-based dosing strategy for UFH in neurology and vascular surgical patients is controversial because definitive studies to quantify both the therapeutic range and the corresponding dose strategy to achieve this range are lacking. In neurosurgical patients, there have been several small studies examining the efficacy of UFH in stroke or transient ischemic attack (TIA) conducted since the early sixties7–12; however, their relevance has since been questioned given the significant change in diagnosis and management of these conditions over time. Despite the lack of large randomized trials demonstrating its efficacy, UFH is still recommended in cerebral venous sinus thrombosis,13 and its use in select cases, particularly those at high short-term risk of stroke14 and those who are likely to undergo nonemergent carotid endarterectomy, may also be considered reasonable. In studies that have been conducted in stroke or TIA, weight-based dosing has been shown to be superior to other methods.15,16 In vascular surgical patients, UFH is used preoperatively and intraoperatively for acute limb ischemia and postoperatively as a bridge for commencement of oral anticoagulation.17 There are no randomized controlled studies
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examining the use of IV UFH in this patient group, and therefore it is unclear what the optimal dosage is. As data are lacking, historically, surgeons have used a variety of dosing strategies to treat or prevent embolic events in neurology and vascular surgical patients. A common strategy is to use a weight-based IV UFH nomogram developed from studies undertaken in cardiology patients.6 Given that clot burden experienced in neurology and vascular surgical patients may be considered to be similar to patients with VTE, the question has arisen as to whether the more aggressive dosing nomogram published by Raschke et al5 is better suited. In 2010, our hospital changed from the cardiology to the VTE nomogram in these patients, and this study is designed to compare the 2 methods in rapidly achieving and maintaining a therapeutic aPTT. The aim of this studywas to determine whether a weight-based IV UFH dosing nomogram (Fig. 1) using an 80-unit/kg bolus and 18-unit$kg21$h21 initial infusion rate (80:18 dosing strategy) achieves and maintains a therapeutic aPTT more effectively than that using a 60-unit/kg bolus and 12-unit$kg21$h21 initial infusion rate (60:12 dosing strategy) in neurology and vascular surgery patients.
MATERIALS AND METHODS Patients eligible for inclusion in the study were adults (older than 18 years of age) prescribed and administered IV UFH for .6 hours, admitted under the neurology or vascular surgery teams, and administered UFH for TIA, stroke, acute ischemic limb, or postoperative revascularization.
Study Groups The study consisted of a retrospective chart review of 2 patient populations: The first population was prescribed UFH according a 80:18 dosing strategy, and the second population a 60:12 dosing strategy. Both populations followed a dosing nomogram that required dose adjustment based on aPTT, and repeated aPTTs at least 6 hourly until therapeutic range is achieved. The patients initiated on the 80:18 dosing strategy were dosed according to the hospital’s Neurology & Vascular Surgery nomogram, which is based on the nomogram by Raschke et al,5 and implemented in the hospital in May 2010. The dose was calculated using the total body weight of patients in kilograms (kg). UFH dose adjustment and
subsequent monitoring was prescribed according to the nomogram to achieve a therapeutic aPTT range of 65–110 seconds. Data were obtained from all eligible patients between May 2010 and August 2011. The patients initiated on the 60:12 dosing strategy were dosed according to the hospital’s Acute Coronary Syndrome weight-adjusted heparin nomogram based on the nomogram published by Zimmerman et al,6 which had been in use at the hospital until May 2010. The dose was calculated using the total body weight of patients, and dose adjustment and subsequent monitoring was prescribed according to the nomogram to achieve therapeutic aPTT range of 65–110 seconds. Data were obtained from the first 52 eligible patients who fulfilled the inclusion criteria from a random selection of neurology and vascular surgery patients between January 2007 and April 2010. In both dosing strategies, aPTTs were investigated at baseline and again at 6 hours after initiation. The aPTT was tested by the local pathology service using TriniCLOT aPTT reagent S (Trinity Biotech, St Peters, Australia). The aPTT range corresponds to an anti-Xa concentration of 0.3–0.7 IU/ mL using anti-Xa assay and parallel aPTT testing in heparinized patients. This therapeutic range is equivalent to the ones used in the original studies by Raschke et al5 and Zimmerman et al.6
End Points The primary end point was the time to therapeutic aPTT from the initiation of UFH therapy. The secondary end points included the following: 1. The proportion of patients with an aPTT above, within, and below the therapeutic range and .150 seconds at 6 and 24 hours. 2. Initial compliance with the nomogram determined by adherence to the following 5 criteria: a. correct initial weight-based bolus dose. b. correct initial weight-based infusion rate. c. aPTT taken at baseline. d. aPTT taken 6 hours after commencement of IV UFH (62 hours). e. documented patient weight. 3. The proportion of patients with a major, minor, and any hemorrhagic complication. Major bleeding was defined as overt bleeding resulting in death, a bleed that was retroperitoneal, intracranial, or intraocular in location, a drop in hemoglobin concentration of 3 g/dL, or the need for transfusion of 2 or more units of blood.18,19 Minor bleeding was
FIGURE 1. Heparin dose nomograms.
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Ther Drug Monit Volume 37, Number 1, February 2015
any clinically significant bleeding that did not qualify as a major bleed, for example, bruising or rectal bleeding with only a minor drop in hemoglobin (as determined by a drop of ,3 g/dL). Any bleeding included both major and minor hemorrhages.
Comparison of Weight-Based Heparin Dosing Nomograms
Data Collection and Analysis Data was collected retrospectively through review of the patients’ medical record, laboratory data, and the electronic patient administration system. Data collected included patient demographics, length of stay, IV UFH
FIGURE 2. Flow diagram of patients included in the study of 2 weightbased IV UFH nomograms in neurology and vascular surgical patients. *Anticoagulants include warfarin, low molecular weight heparin, and unfractionated heparin. Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
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dosing, and measurement of aPTT, as well as any documented bleeding complications. The initial bolus dose and infusion rate per kilogram could only be calculated if the patients’ weight was recorded in the medical record. Statistical analysis was undertaken using NCSS 2007 (version 1). The Kaplan–Meier method was used to estimate the time to therapeutic aPTT using intention to treat analysis, and statistically compared using the log-rank test. For numerical data, a 2-sided t test (mean 6 SD) and P values were used for normally distributed data. Wilcoxon rank-sum test of medians (interquartile range) was used for nonparametric data. For nominal measures (assuming 2 independent groups), x2 test of proportions was used, and a 2-tailed Fisher exact test used in case of small expected frequencies. Intention to treat analysis was used for the primary end point. Because of limits of quantification, where aPTT was .200 seconds, the value of 200 seconds was used. This study was carried out at The Queen Elizabeth Hospital (TQEH), a 300-bed metropolitan teaching hospital in Adelaide, South Australia. Approval from TQEH Ethics Committee was sought but deemed unnecessary as the study involved deidentified retrospective data.
Exclusion Criteria Patients were excluded if they were on therapeutic anticoagulation before commencement of the IV UFH nomogram, if their medical records or IV UFH chart could not be obtained or if they were prescribed IV UFH using the incorrect nomogram during the transition period (May 2010). Patients were initially identified from laboratory data by an aPTT .50 seconds and were then confirmed to be on UFH by retrospective chart review.
RESULTS A total of 108 patients were assessed for eligibility (Fig. 2). Baseline demographics were similar when comparing
the 60:12 to 80:16 dosing strategy for median platelet counts (215 · 109 per liter versus 236 · 109 per liter, P = 0.606) and aPTT (31 versus 29 seconds, P = 0.109). As expected, the median bolus dose administered to patients was significantly greater in the 80:18 dosing strategy when compared with 60:12 dosing strategy (74.8 versus 52.34 units/kg, P , 0.001). The median initial infusion rate was also significantly higher in the 80:18 dosing strategy (17.5 versus 12.5 units/kg, P , 0.001).
Time to Event The Kaplan–Meier survival curves for both populations are shown in Figure 3. The time to achieve the first aPTT within the therapeutic range was achieved in a significantly shorter period of time after commencement of UFH infusion when the 80:18 dosing strategy is used when compared with the 60:12 dosing strategy (12.5 versus 22 hours, P = 0.04, log-rank test). The distribution of aPTTs at 6 hours is shown in Figure 4. The proportion of patients within the therapeutic range (aPTT, 65–110 seconds) at 6 hours was significantly higher in the 80:18 dosing strategy (36.0% versus 16.7%, P = 0.03). Patients in the 80:18 group were less likely to be subtherapeutic (aPTT, ,65 seconds) at 6 hours than those in the 60:12 group (34% vs 70.8%, P , 0.001), and more likely to be supratherapeutic (aPTT, .110 seconds) (30.0% vs 12.5%, P = 0.034). The distribution of aPTTs at 24 hours is shown in Figure 5. At 24 hours, there was no significant difference in the proportion of patients within the therapeutic range (52.8% versus 44.2%, P = 0.447). There were significantly more patients supratherapeutic (13.9% versus 0%, P = 0.012) and significantly fewer patients subtherapeutic (33.3% versus 56.0%, P = 0.046) in the 80:18 group. The proportion of patients with an aPTT .150 seconds at 6 hours was significantly higher in the 80:18 group (26.0% versus 6.3%, P = 0.008); however, there was no significant difference by 24 hours (5.5% versus 0%, P = 0.204).
FIGURE 3. Kaplan–Meier survival curve of time to therapeutic range.
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Ther Drug Monit Volume 37, Number 1, February 2015
Comparison of Weight-Based Heparin Dosing Nomograms
endarterectomy. He had an aPTT of 189 seconds at 6 hours after commencement of IV UFH. The case of minor bleeding in the 80:18 group was also associated with a supratherapeutic aPTT of 199 seconds at 6 hours, with the aPTT returning to 81 seconds at 24 hours. There was no association between bleeding episodes and aPTT .110 seconds at 6 hours (P = 0.443), or time to therapeutic aPTT (65–110 seconds) (P = 0.876).
DISCUSSION
There was no significant difference between populations in the proportion of patients that developed hemorrhagic complications. In the 80:18 group, there were 5 major bleeds: 4 patients with a drop in hemoglobin concentration of .3 g/dL (1 neurology patient and 3 vascular surgery patients) and 1 patient (vascular surgery patient) required transfusion of 2 units of blood. There was a single patient who developed hematuria. In the 60:12 group, there were 6 major bleeds: 5 patients with a drop in hemoglobin concentration of .3 g/dL (2 neurology patients and 3 vascular surgery patients) and 2 (vascular surgery patients) required transfusion of 2 units of blood (1 patient had a drop in hemoglobin concentration of 59 g/dL). Only 1 case of major bleeding was associated with an aPTT .110 seconds in the 80:18 group. This patient was admitted under neurology for a stroke and underwent a carotid
This study sought to determine if a weight-based nomogram for IV UFH that recommends 80 units/kg of bolus and an initial infusion rate of 18 units$kg21$h21 achieved a therapeutic aPTT (65–110 seconds) more rapidly than a weight-based nomogram of 60 units/kg of bolus and an initial infusion rate of 12 units$kg21$h21. We also sought to test for prescribing compliance with the nomogram on initiation and adverse events such as bleeding. Our main finding was that patients who were prescribed the higher dose strategy achieved a more rapid time to therapeutic aPTT (65–110 seconds) (P = 0.04, log-rank test). In the clinical setting, it is common to test aPTT at 6 hours (approximately 5 half-lives) to assess the effectiveness of the dosing strategy. The aPPT at 6 hours is the most frequently studied indicator of appropriate dosing throughout the literature because the risk of extension of thrombosis and development of further thromboembolic events is high particularly early in the treatment period. A study in 2005 by Camerlingo et al20 revealed that reducing the time from the onset of stroke to initiation of IV UFH is beneficial, particularly in acute hemispheric cerebral infarction, and highlighted the importance of achieving a therapeutic aPTT quickly in this patient group. Our results indicate that the 80:18 dosing strategy was more likely to achieve the therapeutic aPTT at 6 hours after commencement of IV UFH, but also more likely to have supratherapeutic aPTT (.110 seconds) and less likely to have subtherapeutic aPTTs (,65 seconds). This suggests that a lower loading dose, for instance, 70 units/kg may be more appropriate. We did not attempt any population modeling of our data; however, a population pharmacokinetic and pharmacodynamic analysis would help identify patient specific factors that influence the time course of aPTTs. Nonparametric population models would be best suited to this data, which would allow the use of multiple model dosage design methods to aid the development of maximally precise dosing regimens to a target aPTT.21–23 This should be the next phase of research. The results from our study do vary from the literature. Kang et al16 used a similar dose of IV UFH (80 units/kg bolus, 17.5 units$kg21$h21 infusion) to the 80:18 group, and found that only 5.6% of patients were within the therapeutic range at 6 hours compared with 36% of patients in our study. However, this study was much smaller, used a lower initial infusion rate and did not include vascular surgical patients. The study by Raschke et al5 shows similar results to our study. Despite the recruitment of patients predominantly for
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FIGURE 4. Box plot of patients with aPPT 6 hours after the commencement of IV UFH. Box length represents interquartile range (middle, 50% of data), midpoint represents the median time taken to achieve a therapeutic aPTT, and the dots represent outlying values. Gray lines indicate therapeutic range.
Prescribing Compliance Prescribing compliance, as determined by adherence to all 5 criteria, was significantly better in the 80:18 group than in the 60:12 group (48% versus 25%, P = 0.018); primarily, driven by noncompliance in the bolus dose (68.2% versus 46%, P = 0.043) and initial infusion rate (77.3% versus 54%, P = 0.027). For the other 3 criteria, the groups were not significantly different, with a similar proportion of patients with a baseline aPTT (78.0% versus 68.8%, P = 0.300), a recorded patient weight (86.0% versus 77.1%, P = 0.254), and an aPTT taken at 6 hours (62 hours) (88% versus 85.4%, P = 0.706). An analysis of patients who were compliant with the nomograms demonstrated that significantly fewer patients in the 80:18 group had a subtherapeutic aPTT (,65 seconds) at 6 hours when compared with those in the 60:12 group (29.2% vs 66.7%, P = 0.031) and at 24 hours (33.3% versus 55.8%, P = 0.046).
Bleeding Complications
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Marotti et al
FIGURE 5. Box plot of patients aPPT 24 hours after the commencement of IV UFH. For patients prescribed IV UFH for 24 hours or greater and with an aPTT measured at 24 hours (62 hours): 80:18 dosing strategy (n = 36) and 60:12 dosing strategy (n = 43). Box length represents interquartile range (middle, 50% of data), midpoint represents the median time taken to achieve a therapeutic aPTT, and the dots represent outlying values. Gray lines indicate therapeutic range.
the treatment of VTE and the inclusion of only 4 patients with vascular surgery or neurology indications, the patients dosed using the 80:18 weight-based nomogram took a mean of 14.1 hours to reach therapeutic aPTT, which is consistent with our study (median time of 12.5 hours). Raschke et al also reported that 86% of patients achieved the therapeutic threshold (equivalent to .65 seconds) on the first aPTT, whereas our study found that 66% of patients achieved this threshold at 6 hours. This difference may be a result of the different patient populations and the variation in the timing of the first aPTT. Unfortunately, there are no studies undertaken specifically in vascular surgery patients to compare our results. In comparison to the 60:12 dose group, we saw a significantly greater proportion of patients with supratherapeutic aPPTs in the 80:18 dose group. It would be expected that this may be accompanied by an increase in bleeding events; however, we did not observe this in our study. It is important to note that most supratherapeutic patients quickly returned to the therapeutic range within 24 hours after application of the nomogram-based dose adjustment. Although overanticoagulation of patients is of concern and has the potential to increase the risk of brain hemorrhage in patients with ischemic stroke,24–26 and of postoperative bleeding in vascular surgical patients, few studies have actually shown an association. A recent study in patients treated with IV UFH for TIA or ischemic stroke showed no difference in bleeding rates amongst 3 patient groups (0, 30, and 80 units/kg bolus dosing).16 In vascular surgery patients, no studies have examined supratherapeutic aPTTs and the incidence of bleeding. It is also not known how long patients need to have supratherapeutic aPTTs to increase their risk in bleeding, for instance, a single spike in aPTT may not be of concern if there is a subsequent dose adjustment. It is likely that the small sample size of this study does not provide sufficient power for
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a valid comparison of bleeding between the 2 groups, and a larger randomized controlled trial is required. Prescribing compliance tends to be notoriously difficult with many nomograms for anticoagulants in the busy clinical setting, particularly in the surgical setting where clinicians may empirically adjust doses based on the perceived risk of bleeding. Compliance did improve with the introduction of the new nomogram, but still remains quite poor (48%), and further improvements could be made. This can partly be explained by a lack of documentation, with weight not being recorded for 14% of patients in the 80:18 group and 22.9% in the 60:12 group. Strategies such as audit and feedback and education are being used at our hospital to improve compliance with the nomogram. Administration compliance was not measured in this study, nor was compliance with dose adjustment guidelines, including compliance with aPTT measurement recommendations beyond 6 hours, and these may have also had an impact on time to therapeutic aPTT. A limitation of this study is the retrospective method of data collection. A lack of sufficient detail in the patients’ notes was noted during data collection, such as the recording of patient weight (although compliance was similar between groups) and the presence of minor bleeding, which is reliant on clinician documentation. The retrospective issues could be overcome by undertaking a prospective randomized controlled trial; however, the limited patient numbers available for recruitment meant that this was not feasible in the timeframe available to undertake this study. It should also be recognized that rapid attainment of a therapeutic aPTT is a surrogate measure of effectiveness; however, it makes pharmacological sense to ensure therapeutic treatment as soon as possible if the decision to prescribe is made. Of importance, this study has shown that the 60:12 dose strategy is inadequate in achieving a therapeutic aPTT at 6 hours in a large proportion of patients and clearly indicates that this strategy is not optimal in this population. The 80:18 strategy results in a therapeutic threshold in a shorter time period and results in fewer patients being under dosed early in the treatment period when compared with the 60:12 strategy. There is an increased risk of supratherapeutic aPTTs at 6 hours, and physicians should be aware that ongoing monitoring is essential to ensure early detection, with the dose adjusted accordingly. Future dosing studies looking at a bolus dose of 70 units/kg with an initial infusion rate of 18 units$kg21$h21 are recommended to determine if fewer patients are likely to achieve a supratherapeutic aPTT in this patient group, without compromising efficacy. Much research is required in vascular surgery and neurology to determine which patient groups are most likely to benefit from therapy. Although this study answers some pertinent dosing questions, further research is necessary to answer clinical questions such as when IV UFH should be commenced and to quantify the target range for each indication.
CONCLUSIONS A weight-based nomogram for IV UFH using 80 units/kg of bolus and an initial infusion rate of 18 units$kg21$h21 showed a more rapid achievement of therapeutic aPTT when Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
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Ther Drug Monit Volume 37, Number 1, February 2015
compared with the 60:12 dosing nomogram. At 6 hours after dose, there were significantly more patients within the therapeutic range, less subtherapeutic aPTTs, and more supratherapeutic aPTTs in the higher dose group, although there was no increase in bleeding events.
Comparison of Weight-Based Heparin Dosing Nomograms
1. Basu D, Gallus A, Hirsh J, et al. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med. 1972;287:324–327. 2. Hirsh J, van Aken WG, Gallus AS, et al. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation. 1976;53:691–695. 3. Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:257S–298S. 4. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1986;315:1109–1114. 5. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med. 1993;119:874–881. 6. Zimmermann AT, Jeffries WS, McElroy H, et al. Utility of a weightbased heparin nomogram for patients with acute coronary syndromes. Intern Med J. 2003;33:18–25. 7. Putman SF, Adams HP Jr. Usefulness of heparin in initial management of patients with recent transient ischemic attacks. Arch Neurol. 1985;42: 960–962. 8. Haley EC Jr, Kassell NF, Torner JC. Failure of heparin to prevent progression in progressing ischemic infarction. Stroke. 1988;19:10–14. 9. Biller J, Bruno A, Adams HP Jr, et al. A randomized trial of aspirin or heparin in hospitalized patients with recent transient ischemic attacks. A pilot study. Stroke. 1989;20:441–447. 10. Carter AB. Anticoagulant treatment in progressing stroke. Br Med J. 1961;2:70–73. 11. Baker RN. Anticoagulant therapy in cerebral infarction. Report on cooperative study. Neurology. 1962;12:823–835. 12. Duke RJ, Bloch RF, Turpie AG, et al. Intravenous heparin for the prevention of stroke progression in acute partial stable stroke. Ann Intern Med. 1986;105:825–828. 13. Swain S, Turner C, Tyrrell P, et al. Diagnosis and initial management of acute stroke and transient ischaemic attack: summary of NICE guidance. National Institute for Health and Clinical Excellence; 2008.
14. Cucchiara B, Ross M. Transient ischemic attack: risk stratification and treatment. Ann Emerg Med. 2008;52:S27–S39. 15. Toth C, Voll C. Validation of a weight-based nomogram for the use of intravenous heparin in transient ischemic attack or stroke. Stroke. 2002; 33:670–674. 16. Kang K, Dong Wook K, Park HK, et al. Optimal dosing of intravenous unfractionated heparin bolus in transient ischemic attack or stroke. Clin Appl Thromb Hemost. 2010;16:126–131. 17. Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th edition). Chest. 2008;133: 815S–843S. 18. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety subcutaneous enoxaparin non-Q-wave Coronary Events Study Group. N Engl J Med. 1997;337: 447–452. 19. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results thrombolysis myocardial infarction (timi) 11B trial. Circulation. 1999;100:1593–1601. 20. Camerlingo M, Salvi P, Belloni G, et al. Intravenous heparin started within the first 3 hours after onset of symptoms as a treatment for acute nonlacunar hemispheric cerebral infarctions. Stroke. 2005;36:2415–2420. 21. Jelliffe R, Bayard D, Milman M, et al. Achieving target goals most precisely using nonparametric compartmental models and “multiple model” design of dosage regimens. Ther Drug Monit. 2000;22:346–353. 22. Macdonald I, Staatz CE, Jelliffe RW, et al. Evaluation and comparison of simple multiple model, richer data multiple model, and sequential interacting multiple model (IMM) Bayesian analyses of gentamicin and vancomycin data collected from patients undergoing cardiothoracic surgery. Ther Drug Monit. 2008;30:67–74. 23. Jelliffe RW, Schumitzky A, Bayard D, et al. Model-based, goal-oriented, individualized drug therapy. Linkage Population Modelling, new “multiple model” dosage design, Bayesian feedback individualised target goals. Clin Pharmacokinet. 1998;34:57–77. 24. Cerebral Embolism Study Group. Cardioembolic stroke, early anticoagulation, and brain hemorrhage. Arch Intern Med. 1987;147:636–640. 25. Chamorro A, Vila N, Ascaso C, et al. Heparin in acute stroke with atrial fibrillation: clinical relevance of very early treatment. Arch Neurol. 1999; 56:1098–1102. 26. Swedenborg J, Nydahl S, Egberg N. Low molecular mass heparin instead of unfractionated heparin during infrainguinal bypass surgery. Eur J Vasc Endovasc Surg. 1996;11:59–64.
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REFERENCES
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Comparison of 2 Weight-Based Heparin Dosing Nomograms in Neurology and Vascular Surgical Patients Sally B. Marotti, MClinPharm, FSHP, CGP, Michael Barras, GDipClinPharm, PhD, and Carl Kirkpatrick, BPharm(Hons), PhD
Background: Unfractionated heparin sodium (UFH) is used in neurology and vascular surgical patients to treat and prevent thromboembolic occlusions and requires weight-based dosing to achieve a therapeutic range; however, the optimal dosing strategy is not known. This study sought to determine whether an intravenous (IV) weight-based UFH dosing nomogram based on an 80-unit/kg bolus and 18-unit$kg21$h21 initial infusion rate achieves therapeutic anticoagulation [activated partial thromboplastin time (aPTT), 65–110 seconds] more rapidly than that based on a 60-unit/kg bolus and 12-unit$kg21$h21 initial infusion rate in 98 neurology and vascular surgery patients.
Methods: The study consisted of a retrospective chart review of adults prescribed and administered IV UFH for .6 hours, admitted under the neurology or vascular surgery teams and administered UFH for transient ischemic attack, stroke, acute ischemic limb, or postoperative revascularization. Results: The time to therapeutic aPTT analysis showed superiority of the higher dose (P = 0.04, log-rank test). At 6 hours, there was a significantly greater proportion of patients within the therapeutic range in the higher dose group (36.0% versus 16.7%, P = 0.03), with fewer subtherapeutic aPTTs (34.0% versus 70.8%, P , 0.001) and more supratherapeutic aPTTs (30.0% versus 12.5%, P = 0.034). Conclusions: A weight-based nomogram for IV UFH using an 80unit/kg bolus and an initial infusion rate of 18 units$kg21$h21 showed a more rapid achievement of therapeutic aPTT when compared with a 60:12 dosing nomogram. Future research assessing a 70-unit/kg bolus dose is recommended. Key Words: hemorrhage, heparin, neurology, stroke, vascular surgical procedures (Ther Drug Monit 2015;37:33–39)
Received for publication October 24, 2013; accepted April 28, 2014. From the Department of Pharmacy, The Queen Elizabeth Hospital, Woodville South, South Australia; Royal Brisbane and Women’s Hospital & School of Pharmacy, University of Queensland; and Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Australia. The authors declare no conflict of interest. Correspondence: Sally B. Marotti, MClinPharm, FSHP, CGP, Department of Pharmacy, The Queen Elizabeth Hospital, 28 Woodville Rd, Woodville South, South Australia 5011, Australia (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
INTRODUCTION The aim of treatment with unfractionated heparin sodium (UFH) is to prevent the development or extension of a thrombus without significantly increasing the risk of bleeding.1 Anticoagulant response to a dose of UFH varies between patients,2 thus it has become standard practice to monitor the measure of bleeding time to determine an optimal response. The activated partial thromboplastin time (aPTT) is the most common method used for monitoring UFH, with the dose adjusted to maintain a defined aPTT therapeutic range.3 In patients with venous thromboembolism (VTE) values below the therapeutic range, they are associated with reduced efficacy (extension of thrombi), and excessively prolonged values (above the therapeutic range) may increase the risk of bleeding.1 There is also evidence in patients with VTE that the risk of further thromboembolism is reduced if a target aPTT is achieved rapidly.4 For these reasons, it is critically important to ensure that patients with life- or limbthreatening clots achieve a therapeutic aPTT quickly and remain therapeutic until the patient is stable on oral anticoagulants, or the clot is able to be removed. As there is a diverse drug response in the population, weight-based dose strategies (units/kg) for UFH have been shown to be superior to fixed dosing.5,6 Intravenous (IV) UFH is often used in neurology and vascular surgical patients to treat or prevent thromboembolic occlusions peri-operatively. The optimal weight-based dosing strategy for UFH in neurology and vascular surgical patients is controversial because definitive studies to quantify both the therapeutic range and the corresponding dose strategy to achieve this range are lacking. In neurosurgical patients, there have been several small studies examining the efficacy of UFH in stroke or transient ischemic attack (TIA) conducted since the early sixties7–12; however, their relevance has since been questioned given the significant change in diagnosis and management of these conditions over time. Despite the lack of large randomized trials demonstrating its efficacy, UFH is still recommended in cerebral venous sinus thrombosis,13 and its use in select cases, particularly those at high short-term risk of stroke14 and those who are likely to undergo nonemergent carotid endarterectomy, may also be considered reasonable. In studies that have been conducted in stroke or TIA, weight-based dosing has been shown to be superior to other methods.15,16 In vascular surgical patients, UFH is used preoperatively and intraoperatively for acute limb ischemia and postoperatively as a bridge for commencement of oral anticoagulation.17 There are no randomized controlled studies
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examining the use of IV UFH in this patient group, and therefore it is unclear what the optimal dosage is. As data are lacking, historically, surgeons have used a variety of dosing strategies to treat or prevent embolic events in neurology and vascular surgical patients. A common strategy is to use a weight-based IV UFH nomogram developed from studies undertaken in cardiology patients.6 Given that clot burden experienced in neurology and vascular surgical patients may be considered to be similar to patients with VTE, the question has arisen as to whether the more aggressive dosing nomogram published by Raschke et al5 is better suited. In 2010, our hospital changed from the cardiology to the VTE nomogram in these patients, and this study is designed to compare the 2 methods in rapidly achieving and maintaining a therapeutic aPTT. The aim of this studywas to determine whether a weight-based IV UFH dosing nomogram (Fig. 1) using an 80-unit/kg bolus and 18-unit$kg21$h21 initial infusion rate (80:18 dosing strategy) achieves and maintains a therapeutic aPTT more effectively than that using a 60-unit/kg bolus and 12-unit$kg21$h21 initial infusion rate (60:12 dosing strategy) in neurology and vascular surgery patients.
MATERIALS AND METHODS Patients eligible for inclusion in the study were adults (older than 18 years of age) prescribed and administered IV UFH for .6 hours, admitted under the neurology or vascular surgery teams, and administered UFH for TIA, stroke, acute ischemic limb, or postoperative revascularization.
Study Groups The study consisted of a retrospective chart review of 2 patient populations: The first population was prescribed UFH according a 80:18 dosing strategy, and the second population a 60:12 dosing strategy. Both populations followed a dosing nomogram that required dose adjustment based on aPTT, and repeated aPTTs at least 6 hourly until therapeutic range is achieved. The patients initiated on the 80:18 dosing strategy were dosed according to the hospital’s Neurology & Vascular Surgery nomogram, which is based on the nomogram by Raschke et al,5 and implemented in the hospital in May 2010. The dose was calculated using the total body weight of patients in kilograms (kg). UFH dose adjustment and
subsequent monitoring was prescribed according to the nomogram to achieve a therapeutic aPTT range of 65–110 seconds. Data were obtained from all eligible patients between May 2010 and August 2011. The patients initiated on the 60:12 dosing strategy were dosed according to the hospital’s Acute Coronary Syndrome weight-adjusted heparin nomogram based on the nomogram published by Zimmerman et al,6 which had been in use at the hospital until May 2010. The dose was calculated using the total body weight of patients, and dose adjustment and subsequent monitoring was prescribed according to the nomogram to achieve therapeutic aPTT range of 65–110 seconds. Data were obtained from the first 52 eligible patients who fulfilled the inclusion criteria from a random selection of neurology and vascular surgery patients between January 2007 and April 2010. In both dosing strategies, aPTTs were investigated at baseline and again at 6 hours after initiation. The aPTT was tested by the local pathology service using TriniCLOT aPTT reagent S (Trinity Biotech, St Peters, Australia). The aPTT range corresponds to an anti-Xa concentration of 0.3–0.7 IU/ mL using anti-Xa assay and parallel aPTT testing in heparinized patients. This therapeutic range is equivalent to the ones used in the original studies by Raschke et al5 and Zimmerman et al.6
End Points The primary end point was the time to therapeutic aPTT from the initiation of UFH therapy. The secondary end points included the following: 1. The proportion of patients with an aPTT above, within, and below the therapeutic range and .150 seconds at 6 and 24 hours. 2. Initial compliance with the nomogram determined by adherence to the following 5 criteria: a. correct initial weight-based bolus dose. b. correct initial weight-based infusion rate. c. aPTT taken at baseline. d. aPTT taken 6 hours after commencement of IV UFH (62 hours). e. documented patient weight. 3. The proportion of patients with a major, minor, and any hemorrhagic complication. Major bleeding was defined as overt bleeding resulting in death, a bleed that was retroperitoneal, intracranial, or intraocular in location, a drop in hemoglobin concentration of 3 g/dL, or the need for transfusion of 2 or more units of blood.18,19 Minor bleeding was
FIGURE 1. Heparin dose nomograms.
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Ther Drug Monit Volume 37, Number 1, February 2015
any clinically significant bleeding that did not qualify as a major bleed, for example, bruising or rectal bleeding with only a minor drop in hemoglobin (as determined by a drop of ,3 g/dL). Any bleeding included both major and minor hemorrhages.
Comparison of Weight-Based Heparin Dosing Nomograms
Data Collection and Analysis Data was collected retrospectively through review of the patients’ medical record, laboratory data, and the electronic patient administration system. Data collected included patient demographics, length of stay, IV UFH
FIGURE 2. Flow diagram of patients included in the study of 2 weightbased IV UFH nomograms in neurology and vascular surgical patients. *Anticoagulants include warfarin, low molecular weight heparin, and unfractionated heparin. Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
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dosing, and measurement of aPTT, as well as any documented bleeding complications. The initial bolus dose and infusion rate per kilogram could only be calculated if the patients’ weight was recorded in the medical record. Statistical analysis was undertaken using NCSS 2007 (version 1). The Kaplan–Meier method was used to estimate the time to therapeutic aPTT using intention to treat analysis, and statistically compared using the log-rank test. For numerical data, a 2-sided t test (mean 6 SD) and P values were used for normally distributed data. Wilcoxon rank-sum test of medians (interquartile range) was used for nonparametric data. For nominal measures (assuming 2 independent groups), x2 test of proportions was used, and a 2-tailed Fisher exact test used in case of small expected frequencies. Intention to treat analysis was used for the primary end point. Because of limits of quantification, where aPTT was .200 seconds, the value of 200 seconds was used. This study was carried out at The Queen Elizabeth Hospital (TQEH), a 300-bed metropolitan teaching hospital in Adelaide, South Australia. Approval from TQEH Ethics Committee was sought but deemed unnecessary as the study involved deidentified retrospective data.
Exclusion Criteria Patients were excluded if they were on therapeutic anticoagulation before commencement of the IV UFH nomogram, if their medical records or IV UFH chart could not be obtained or if they were prescribed IV UFH using the incorrect nomogram during the transition period (May 2010). Patients were initially identified from laboratory data by an aPTT .50 seconds and were then confirmed to be on UFH by retrospective chart review.
RESULTS A total of 108 patients were assessed for eligibility (Fig. 2). Baseline demographics were similar when comparing
the 60:12 to 80:16 dosing strategy for median platelet counts (215 · 109 per liter versus 236 · 109 per liter, P = 0.606) and aPTT (31 versus 29 seconds, P = 0.109). As expected, the median bolus dose administered to patients was significantly greater in the 80:18 dosing strategy when compared with 60:12 dosing strategy (74.8 versus 52.34 units/kg, P , 0.001). The median initial infusion rate was also significantly higher in the 80:18 dosing strategy (17.5 versus 12.5 units/kg, P , 0.001).
Time to Event The Kaplan–Meier survival curves for both populations are shown in Figure 3. The time to achieve the first aPTT within the therapeutic range was achieved in a significantly shorter period of time after commencement of UFH infusion when the 80:18 dosing strategy is used when compared with the 60:12 dosing strategy (12.5 versus 22 hours, P = 0.04, log-rank test). The distribution of aPTTs at 6 hours is shown in Figure 4. The proportion of patients within the therapeutic range (aPTT, 65–110 seconds) at 6 hours was significantly higher in the 80:18 dosing strategy (36.0% versus 16.7%, P = 0.03). Patients in the 80:18 group were less likely to be subtherapeutic (aPTT, ,65 seconds) at 6 hours than those in the 60:12 group (34% vs 70.8%, P , 0.001), and more likely to be supratherapeutic (aPTT, .110 seconds) (30.0% vs 12.5%, P = 0.034). The distribution of aPTTs at 24 hours is shown in Figure 5. At 24 hours, there was no significant difference in the proportion of patients within the therapeutic range (52.8% versus 44.2%, P = 0.447). There were significantly more patients supratherapeutic (13.9% versus 0%, P = 0.012) and significantly fewer patients subtherapeutic (33.3% versus 56.0%, P = 0.046) in the 80:18 group. The proportion of patients with an aPTT .150 seconds at 6 hours was significantly higher in the 80:18 group (26.0% versus 6.3%, P = 0.008); however, there was no significant difference by 24 hours (5.5% versus 0%, P = 0.204).
FIGURE 3. Kaplan–Meier survival curve of time to therapeutic range.
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Comparison of Weight-Based Heparin Dosing Nomograms
endarterectomy. He had an aPTT of 189 seconds at 6 hours after commencement of IV UFH. The case of minor bleeding in the 80:18 group was also associated with a supratherapeutic aPTT of 199 seconds at 6 hours, with the aPTT returning to 81 seconds at 24 hours. There was no association between bleeding episodes and aPTT .110 seconds at 6 hours (P = 0.443), or time to therapeutic aPTT (65–110 seconds) (P = 0.876).
DISCUSSION
There was no significant difference between populations in the proportion of patients that developed hemorrhagic complications. In the 80:18 group, there were 5 major bleeds: 4 patients with a drop in hemoglobin concentration of .3 g/dL (1 neurology patient and 3 vascular surgery patients) and 1 patient (vascular surgery patient) required transfusion of 2 units of blood. There was a single patient who developed hematuria. In the 60:12 group, there were 6 major bleeds: 5 patients with a drop in hemoglobin concentration of .3 g/dL (2 neurology patients and 3 vascular surgery patients) and 2 (vascular surgery patients) required transfusion of 2 units of blood (1 patient had a drop in hemoglobin concentration of 59 g/dL). Only 1 case of major bleeding was associated with an aPTT .110 seconds in the 80:18 group. This patient was admitted under neurology for a stroke and underwent a carotid
This study sought to determine if a weight-based nomogram for IV UFH that recommends 80 units/kg of bolus and an initial infusion rate of 18 units$kg21$h21 achieved a therapeutic aPTT (65–110 seconds) more rapidly than a weight-based nomogram of 60 units/kg of bolus and an initial infusion rate of 12 units$kg21$h21. We also sought to test for prescribing compliance with the nomogram on initiation and adverse events such as bleeding. Our main finding was that patients who were prescribed the higher dose strategy achieved a more rapid time to therapeutic aPTT (65–110 seconds) (P = 0.04, log-rank test). In the clinical setting, it is common to test aPTT at 6 hours (approximately 5 half-lives) to assess the effectiveness of the dosing strategy. The aPPT at 6 hours is the most frequently studied indicator of appropriate dosing throughout the literature because the risk of extension of thrombosis and development of further thromboembolic events is high particularly early in the treatment period. A study in 2005 by Camerlingo et al20 revealed that reducing the time from the onset of stroke to initiation of IV UFH is beneficial, particularly in acute hemispheric cerebral infarction, and highlighted the importance of achieving a therapeutic aPTT quickly in this patient group. Our results indicate that the 80:18 dosing strategy was more likely to achieve the therapeutic aPTT at 6 hours after commencement of IV UFH, but also more likely to have supratherapeutic aPTT (.110 seconds) and less likely to have subtherapeutic aPTTs (,65 seconds). This suggests that a lower loading dose, for instance, 70 units/kg may be more appropriate. We did not attempt any population modeling of our data; however, a population pharmacokinetic and pharmacodynamic analysis would help identify patient specific factors that influence the time course of aPTTs. Nonparametric population models would be best suited to this data, which would allow the use of multiple model dosage design methods to aid the development of maximally precise dosing regimens to a target aPTT.21–23 This should be the next phase of research. The results from our study do vary from the literature. Kang et al16 used a similar dose of IV UFH (80 units/kg bolus, 17.5 units$kg21$h21 infusion) to the 80:18 group, and found that only 5.6% of patients were within the therapeutic range at 6 hours compared with 36% of patients in our study. However, this study was much smaller, used a lower initial infusion rate and did not include vascular surgical patients. The study by Raschke et al5 shows similar results to our study. Despite the recruitment of patients predominantly for
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FIGURE 4. Box plot of patients with aPPT 6 hours after the commencement of IV UFH. Box length represents interquartile range (middle, 50% of data), midpoint represents the median time taken to achieve a therapeutic aPTT, and the dots represent outlying values. Gray lines indicate therapeutic range.
Prescribing Compliance Prescribing compliance, as determined by adherence to all 5 criteria, was significantly better in the 80:18 group than in the 60:12 group (48% versus 25%, P = 0.018); primarily, driven by noncompliance in the bolus dose (68.2% versus 46%, P = 0.043) and initial infusion rate (77.3% versus 54%, P = 0.027). For the other 3 criteria, the groups were not significantly different, with a similar proportion of patients with a baseline aPTT (78.0% versus 68.8%, P = 0.300), a recorded patient weight (86.0% versus 77.1%, P = 0.254), and an aPTT taken at 6 hours (62 hours) (88% versus 85.4%, P = 0.706). An analysis of patients who were compliant with the nomograms demonstrated that significantly fewer patients in the 80:18 group had a subtherapeutic aPTT (,65 seconds) at 6 hours when compared with those in the 60:12 group (29.2% vs 66.7%, P = 0.031) and at 24 hours (33.3% versus 55.8%, P = 0.046).
Bleeding Complications
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Marotti et al
FIGURE 5. Box plot of patients aPPT 24 hours after the commencement of IV UFH. For patients prescribed IV UFH for 24 hours or greater and with an aPTT measured at 24 hours (62 hours): 80:18 dosing strategy (n = 36) and 60:12 dosing strategy (n = 43). Box length represents interquartile range (middle, 50% of data), midpoint represents the median time taken to achieve a therapeutic aPTT, and the dots represent outlying values. Gray lines indicate therapeutic range.
the treatment of VTE and the inclusion of only 4 patients with vascular surgery or neurology indications, the patients dosed using the 80:18 weight-based nomogram took a mean of 14.1 hours to reach therapeutic aPTT, which is consistent with our study (median time of 12.5 hours). Raschke et al also reported that 86% of patients achieved the therapeutic threshold (equivalent to .65 seconds) on the first aPTT, whereas our study found that 66% of patients achieved this threshold at 6 hours. This difference may be a result of the different patient populations and the variation in the timing of the first aPTT. Unfortunately, there are no studies undertaken specifically in vascular surgery patients to compare our results. In comparison to the 60:12 dose group, we saw a significantly greater proportion of patients with supratherapeutic aPPTs in the 80:18 dose group. It would be expected that this may be accompanied by an increase in bleeding events; however, we did not observe this in our study. It is important to note that most supratherapeutic patients quickly returned to the therapeutic range within 24 hours after application of the nomogram-based dose adjustment. Although overanticoagulation of patients is of concern and has the potential to increase the risk of brain hemorrhage in patients with ischemic stroke,24–26 and of postoperative bleeding in vascular surgical patients, few studies have actually shown an association. A recent study in patients treated with IV UFH for TIA or ischemic stroke showed no difference in bleeding rates amongst 3 patient groups (0, 30, and 80 units/kg bolus dosing).16 In vascular surgery patients, no studies have examined supratherapeutic aPTTs and the incidence of bleeding. It is also not known how long patients need to have supratherapeutic aPTTs to increase their risk in bleeding, for instance, a single spike in aPTT may not be of concern if there is a subsequent dose adjustment. It is likely that the small sample size of this study does not provide sufficient power for
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a valid comparison of bleeding between the 2 groups, and a larger randomized controlled trial is required. Prescribing compliance tends to be notoriously difficult with many nomograms for anticoagulants in the busy clinical setting, particularly in the surgical setting where clinicians may empirically adjust doses based on the perceived risk of bleeding. Compliance did improve with the introduction of the new nomogram, but still remains quite poor (48%), and further improvements could be made. This can partly be explained by a lack of documentation, with weight not being recorded for 14% of patients in the 80:18 group and 22.9% in the 60:12 group. Strategies such as audit and feedback and education are being used at our hospital to improve compliance with the nomogram. Administration compliance was not measured in this study, nor was compliance with dose adjustment guidelines, including compliance with aPTT measurement recommendations beyond 6 hours, and these may have also had an impact on time to therapeutic aPTT. A limitation of this study is the retrospective method of data collection. A lack of sufficient detail in the patients’ notes was noted during data collection, such as the recording of patient weight (although compliance was similar between groups) and the presence of minor bleeding, which is reliant on clinician documentation. The retrospective issues could be overcome by undertaking a prospective randomized controlled trial; however, the limited patient numbers available for recruitment meant that this was not feasible in the timeframe available to undertake this study. It should also be recognized that rapid attainment of a therapeutic aPTT is a surrogate measure of effectiveness; however, it makes pharmacological sense to ensure therapeutic treatment as soon as possible if the decision to prescribe is made. Of importance, this study has shown that the 60:12 dose strategy is inadequate in achieving a therapeutic aPTT at 6 hours in a large proportion of patients and clearly indicates that this strategy is not optimal in this population. The 80:18 strategy results in a therapeutic threshold in a shorter time period and results in fewer patients being under dosed early in the treatment period when compared with the 60:12 strategy. There is an increased risk of supratherapeutic aPTTs at 6 hours, and physicians should be aware that ongoing monitoring is essential to ensure early detection, with the dose adjusted accordingly. Future dosing studies looking at a bolus dose of 70 units/kg with an initial infusion rate of 18 units$kg21$h21 are recommended to determine if fewer patients are likely to achieve a supratherapeutic aPTT in this patient group, without compromising efficacy. Much research is required in vascular surgery and neurology to determine which patient groups are most likely to benefit from therapy. Although this study answers some pertinent dosing questions, further research is necessary to answer clinical questions such as when IV UFH should be commenced and to quantify the target range for each indication.
CONCLUSIONS A weight-based nomogram for IV UFH using 80 units/kg of bolus and an initial infusion rate of 18 units$kg21$h21 showed a more rapid achievement of therapeutic aPTT when Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
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Ther Drug Monit Volume 37, Number 1, February 2015
compared with the 60:12 dosing nomogram. At 6 hours after dose, there were significantly more patients within the therapeutic range, less subtherapeutic aPTTs, and more supratherapeutic aPTTs in the higher dose group, although there was no increase in bleeding events.
Comparison of Weight-Based Heparin Dosing Nomograms
1. Basu D, Gallus A, Hirsh J, et al. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med. 1972;287:324–327. 2. Hirsh J, van Aken WG, Gallus AS, et al. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation. 1976;53:691–695. 3. Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:257S–298S. 4. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1986;315:1109–1114. 5. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med. 1993;119:874–881. 6. Zimmermann AT, Jeffries WS, McElroy H, et al. Utility of a weightbased heparin nomogram for patients with acute coronary syndromes. Intern Med J. 2003;33:18–25. 7. Putman SF, Adams HP Jr. Usefulness of heparin in initial management of patients with recent transient ischemic attacks. Arch Neurol. 1985;42: 960–962. 8. Haley EC Jr, Kassell NF, Torner JC. Failure of heparin to prevent progression in progressing ischemic infarction. Stroke. 1988;19:10–14. 9. Biller J, Bruno A, Adams HP Jr, et al. A randomized trial of aspirin or heparin in hospitalized patients with recent transient ischemic attacks. A pilot study. Stroke. 1989;20:441–447. 10. Carter AB. Anticoagulant treatment in progressing stroke. Br Med J. 1961;2:70–73. 11. Baker RN. Anticoagulant therapy in cerebral infarction. Report on cooperative study. Neurology. 1962;12:823–835. 12. Duke RJ, Bloch RF, Turpie AG, et al. Intravenous heparin for the prevention of stroke progression in acute partial stable stroke. Ann Intern Med. 1986;105:825–828. 13. Swain S, Turner C, Tyrrell P, et al. Diagnosis and initial management of acute stroke and transient ischaemic attack: summary of NICE guidance. National Institute for Health and Clinical Excellence; 2008.
14. Cucchiara B, Ross M. Transient ischemic attack: risk stratification and treatment. Ann Emerg Med. 2008;52:S27–S39. 15. Toth C, Voll C. Validation of a weight-based nomogram for the use of intravenous heparin in transient ischemic attack or stroke. Stroke. 2002; 33:670–674. 16. Kang K, Dong Wook K, Park HK, et al. Optimal dosing of intravenous unfractionated heparin bolus in transient ischemic attack or stroke. Clin Appl Thromb Hemost. 2010;16:126–131. 17. Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th edition). Chest. 2008;133: 815S–843S. 18. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety subcutaneous enoxaparin non-Q-wave Coronary Events Study Group. N Engl J Med. 1997;337: 447–452. 19. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results thrombolysis myocardial infarction (timi) 11B trial. Circulation. 1999;100:1593–1601. 20. Camerlingo M, Salvi P, Belloni G, et al. Intravenous heparin started within the first 3 hours after onset of symptoms as a treatment for acute nonlacunar hemispheric cerebral infarctions. Stroke. 2005;36:2415–2420. 21. Jelliffe R, Bayard D, Milman M, et al. Achieving target goals most precisely using nonparametric compartmental models and “multiple model” design of dosage regimens. Ther Drug Monit. 2000;22:346–353. 22. Macdonald I, Staatz CE, Jelliffe RW, et al. Evaluation and comparison of simple multiple model, richer data multiple model, and sequential interacting multiple model (IMM) Bayesian analyses of gentamicin and vancomycin data collected from patients undergoing cardiothoracic surgery. Ther Drug Monit. 2008;30:67–74. 23. Jelliffe RW, Schumitzky A, Bayard D, et al. Model-based, goal-oriented, individualized drug therapy. Linkage Population Modelling, new “multiple model” dosage design, Bayesian feedback individualised target goals. Clin Pharmacokinet. 1998;34:57–77. 24. Cerebral Embolism Study Group. Cardioembolic stroke, early anticoagulation, and brain hemorrhage. Arch Intern Med. 1987;147:636–640. 25. Chamorro A, Vila N, Ascaso C, et al. Heparin in acute stroke with atrial fibrillation: clinical relevance of very early treatment. Arch Neurol. 1999; 56:1098–1102. 26. Swedenborg J, Nydahl S, Egberg N. Low molecular mass heparin instead of unfractionated heparin during infrainguinal bypass surgery. Eur J Vasc Endovasc Surg. 1996;11:59–64.
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REFERENCES
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