Overused and Unpredictable: A Study of Unfractionated Heparin Treatment Including Appropriateness, Safety, and Bolus Dosing

Overused and Unpredictable: A Study of Unfractionated Heparin Treatment Including Appropriateness, Safety, and Bolus Dosing | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Overused and Unpredictable: A Study of Unfractionated Heparin Treatment Including Appropriateness, Safety, and Bolus Dosing Logan Hahn, Christopher Beresh, Hadi A Goubran, William Semchuk, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4650298/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Multiple recent guidelines advocate a preference for low molecular weight heparin (LMWH) over unfractionated heparin (UFH) infusions to reduce the risk of major bleeding (MB), heparin-induced thrombocytopenia (HIT) and improve cost-effectiveness ( 1 – 6 ). This study analyzed UFH use at a tertiary centre in Canada to identify cases in which UFH could have been avoided, identify characteristics associated with bleeding, and examine the efficacy and safety of infusions where the initial bolus was administered or withheld. Methods We identified adults who received between 48 to 96 hours of a UFH infusion in a single tertiary care hospital between January 2021 and December 2023. Consecutive patients were reviewed for bleeding events, patient factors known to influence bleeding, and whether patients had a contraindication to LMWH or another anticoagulant. Patients were deemed to have “appropriate” use of UFH in preference to more desirable anticoagulants if they had recent or ongoing bleeding, required an imminent procedure or surgery, an estimated glomerular filtration rate (eGFR) less than 30mL/min, or could foreseeably require thrombolysis. Results Of 127 patients, 16 (13%) were identified to have bleeding complications, including 14 episodes of MB. Bleeding episodes were significantly associated with any measured aPTT greater than 150 seconds (s) during treatment (p = 0.0285). Omission of initial bolus dosing was not associated with reduced bleeding events or the incidence of any aPTT measurement greater than 150s. Omission of initial bolus dosing was associated with subtherapeutic aPTT measurement at 6 hours (46%) and 12 hours (25%) post-UFH administration. We identified high rates (42%) of UFH selection where an alternative anticoagulant could have been used. Conclusion Use of intravenous UFH is associated with a high risk of MB, and bleeding complications are associated with markedly elevated aPTT (> 150s). An elevated risk of bleeding does not appear to be mitigated by omitting the initial bolus. Delivery of an initial UFH bolus decreases time to therapeutic anticoagulation. Figures Figure 1 Figure 2 Background Unfractionated heparin (UFH) remains an important anticoagulant for medical and surgical indications due to its short duration of action and reversibility by protamine. UFH is used for anticoagulation in the treatment of venous thromboembolism (VTE) for patients who require thrombolysis, have severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30mL/min) or those who require anticoagulant interruption for a procedure. Multiple recent guidelines advocate a preference for low molecular weight heparin (LMWH) over UFH to reduce the risk of major bleeding (MB), heparin-induced thrombocytopenia, improve cost-effectiveness, and alleviate the burden of monitoring on nursing and laboratory staff associated with UFH use ( 1 – 6 ). UFH has a complex pharmacodynamic and pharmacokinetic profile, leading to a narrow therapeutic window and a highly variable dose-response relationship ( 7 ). Pharmacodynamically, UFH exerts its anticoagulant effect through interaction with antithrombin III, heparin cofactor II and tissue factor pathway inhibitor ( 7 ). However, UFH selectively binds several other plasma proteins such as fibronectin, platelet factor 4 (PF4), and von Willebrand factor which can vary widely in concentrations depending on nutritional and inflammatory states ( 7 – 9 ). These complexities may explain the observed clinical challenges of dosing and monitoring UFH. In clinical practice, numerous laboratory methods such as activated partial thromboplastin time (aPTT) and assays of anti-Xa activity have been employed to characterize the activity of UFH. aPTT is the most widely used method for monitoring the anticoagulant effect of UFH ( 7 ). However, aPTT monitoring has been shown to be highly discordant with anti-Xa monitoring ( 10 , 11 ). Given these issues with monitoring UFH, it is therefore unsurprising that dosing the drug has also been found to be problematic. Low rates of therapeutic aPTT measurements within the initial days of treatment are a known issue with UFH use. Prior observational studies have reported therapeutic aPTTs in less than 50% of patients during the first 24 hours of treatment ( 11 – 13 ). The narrow therapeutic window of UFH appears to have meaningful clinical consequences, especially when compared to more stable anticoagulants like LMWH. Studies have documented the superiority of LMWH over UFH in terms of VTE recurrence and thrombotic complications ( 14 , 15 ). Additionally, in the treatment of VTE, there appears to be less MB and decreased mortality with LMWH ( 6 , 16 – 25 ). An additional concern with UFH is the risk of heparin-induced thrombocytopenia (HIT). The thrombotic sequelae of HIT are the result of autoantibody formation to heparin-PF4 complexes. The mortality of HIT can approach 25% even despite treatment ( 26 – 28 ). Observational studies have demonstrated reductions in the development of HIT in patients treated with LMWH compared to UFH ( 29 – 33 ). Given the well-documented consequences of UFH, we reviewed the indications and harms associated with intravenous UFH infusions at the Royal University Hospital in Saskatoon, Saskatchewan, Canada, which is the largest tertiary hospital in the province. We performed a retrospective chart review of patients who received a UFH infusion as their initial anticoagulant between January 2021 and December 2023. We characterized bleeding events and examined indications for UFH use to determine if an alternative anticoagulation strategy could have been implemented. Additionally, given the unpredictable pharmacokinetics of UFH, we wondered if the decision to administer or withhold an initial bolus would affect aPTT lability, latency to the therapeutic target, and bleeding risk. Methods Study Design The aim of this study was to determine bleeding risks associated with UFH as an initial agent for therapeutic anticoagulation in-hospital. We chose to study consecutive patients with use from 48 to 96 hours to ensure adequate exposure to the intervention and limit cases in which UFH was used strictly as a bridging agent. We attempt to identify and describe the characteristics of patients with bleeding events, including whether these were related to markedly elevated aPTTs > 150 seconds (s) and whether the omission of bolus dosing before the infusion was correlated with delay to therapeutic anticoagulation, bleeding, or any markedly elevated aPTT. Finally, we attempt to understand whether patients at our institution had an indication for the use of UFH or if alternative anticoagulants with more favourable pharmacologic profiles could have been used. Data Capture Patients who met inclusion criteria were identified through a retrospective drug utilization report generated through a pharmacy database. Inclusion criteria consisted of adult inpatients ( ≥ 18 years of age) who were prescribed intravenous UFH at therapeutic dosing for 48 to 96 hours in a single tertiary care hospital between January 2021 and December 2023. Patients on UFH with cardiovascular dosing (lower aPTT target) were excluded. Data retrieved from computerized records included age, weight, gender, indication for anticoagulation, troponin, imaging evidence of right heart strain, HIT testing, known bleeding history before hospitalization, known bleeding events while in hospital but prior to UFH use, platelet count, decompensated cirrhosis, and eGFR. In our centre aPTT is performed using Synthesil (IL) reagents and the validated therapeutic range is 70–99 seconds at the treatment dose. All patients had a normal baseline aPTT. All available aPTTs while on UFH infusion were examined. It was documented if the patient experienced at least one markedly elevated aPTT at > 150s. According to our institutional UFH nomogram, the initial aPTT is measured 6 hours after starting the infusion. If this initial aPTT is within the target (aPTT = 70-99s), a subsequent or second PTT is checked after 24 hours. If the initial aPTT is not within the target range, then the subsequent aPTT is checked in an additional 6 hours. First and second aPTT measurements were classified as subtherapeutic if the measured value was at least 10 seconds shorter than the lower limit of the therapeutic range (< 60 seconds). Definitions and Endpoints We relied on available discharge summaries, progress notes, and laboratory results to identify and classify bleeding episodes. We defined MB according to the International Society on Thrombosis and Haemostasis (ISTH) criteria, which defines MB as fatal and/or symptomatic bleeding in a critical area or organ, bleeding causing a hemoglobin fall of 20g/L or greater and/or bleeding requiring a transfusion of 2 or more units of whole blood or packed red blood cells ( 34 ). Other bleeding was defined as all other reported bleeding which did not meet the criteria for MB. Patients were deemed to have “appropriate” use of UFH if they had recent (defined as bleeding during current admission) or ongoing bleeding, required an imminent procedure or surgery, had an eGFR < 30mL/min, or could foreseeably require thrombolysis through classification of patients as either “intermediate-high” or “high” risk per the European Society of Cardiology 2019 treatment of VTE guidelines ( 5 ). This definition uses imaging (CT or echocardiogram) and biochemical evidence of right heart strain (elevated Troponin T Cardiac; High Sensitivity assay) to define patients as “intermediate-high” risk. High risk was defined as cardiac arrest, obstructive shock (systolic BP < 90 mmHg or vasopressors required to achieve a BP ≥ 90 mmHg despite an adequate filling status, in combination with end-organ hypoperfusion), or persistent hypotension (systolic BP 15 min, not caused by new-onset arrhythmia, hypovolaemia, or sepsis). All patients who were administered systemic thrombolysis were considered appropriate for use of UFH. Statistical Analysis Univariate analysis using Fisher’s Exact test was applied (GraphPad Prism version 10.2.3 for Windows, GraphPad Software, Boston, Massachusetts USA) to determine if associations between any markedly elevated aPTT, bolus dosing prior to infusion, systemic thrombolysis, or concurrent anti-platelet use were significantly associated with bleeding events. A two-sided p-value of < 0.05 was considered statistically significant. Figures were constructed using GraphPad Prism. Results We identified 131 consecutive patients prescribed intravenous UFH for 48 to 96 hours between 2021 and 2023. Four patients were excluded due to incomplete data with no aPTT or anti-Xa measurements, likely due to non-standard use of the order set to prescribe low, fixed doses of UFH. The population for analysis included 127 patients (Table 1 ), of which 16 patients (13%) had a bleeding event recorded. Criteria for ISTH MB were met in 14/16 identified bleeding complications (11% of the total population). An episode of GI bleeding and a significant bleed around a central venous catheter during UFH treatment did not meet the criteria for MB, but both necessitated discontinuation of anticoagulation until bleeding was controlled. None of the bleeding events were classified as fatal bleeding. In 53/127 charts reviewed, an indication for UFH as opposed to an alternative anticoagulant could not be identified (42%). Four patients in this series were tested for HIT using a rapid HemosIL® HIT-Ab(PF4-H) (HemosILAb) latex-particle immunoassay, and none were positive. Table 1 Patient Characteristics in Bolus and No Bolus Cohorts Bolus (n = 61) No Bolus (n = 66) Bleeding (n = 16) Age, mean (SD) 63.1 (17.0) 65.0 (16.1) 70.1 (14.1) Age, range 19–98 24–91 34–84 Male, n (%) 29 (47.5) 39 (59.1) 7 (43.8) Female, n (%) 32 (52.5) 27 (40.9) 9 (56.3) Weight (kg) Weight, mean (SD) 87.4 (28.0) 85.4 (25.6) 80.7 (17.4) Weight, range 45–208 43–194 45–118 eGFR (mL/min) GFR, mean (SD) 67.4 (36.7) 67.8 (35.4) 59.5 (41.0) GFR < 60, n (%) 23 (37.7) 24 (36.4) 8 (50.0) GFR < 30, n (%) 6 (9.8) 7 (10.6) 3 (18.8) Platelet count (10 9 /L), mean (SD) 266 (137) 271 (134) 274 (140) ASA, n (%) 4 (6.6) 14 (21.2) 5 (31.3) Use of other antiplatelet, n (%) 3 (4.9) 9 (13.6) 4 (25.0) History of bleeding prior to current admission, n (%) 3 (4.9) 7 (10.6) 4 (25.0) Bleeding during current admission prior to UFH, n (%) 7 (11.5) 12 (18.2) 5 (31.3) Decompensated cirrhosis, n (%) 1 (1.6) 2 (3.0%) 0 (0) VTE indication for AC n (%) 42 (68.9) 36 (54.5) 13 (81.3) Indication for AC other than VTE, n (%) 19 (31.1) 30 (45.5) 3 (18.8) Duration on UFH infusion in hours, mean (SD) 68 (14.9) 70 (14.1) 72 (16.9) Table 1 : Patient characteristics in bolus and no bolus cohorts. Characteristics of patients who had a bleeding event are also displayed. Abbreviations: SD: standard deviation; eGFR: estimated glomerular filtration rate; ASA: acetylsalicylic acid; UFH: unfractionated heparin; VTE: venous thromboembolism; AC: anticoagulation. Observing at least one markedly elevated aPTT at > 150s while on UFH treatment was significantly associated with bleeding p = 0.0285 (Odds ratio 3.614 95% CI 1.267 to 9.796). Use of any anti-platelet treatment was significantly associated with bleeding p = 0.0339 (OR 3.564 CI 1.064 to 11.27). Four patients required thrombolysis within 24 hours of IV UFH (3 high-risk PE and one stroke), and 2/4 were classified as having bleeding events. No significant association was observed between thrombolysis and bleeding. In our centre, the initial “bolus” dose of 80 units/kg IV UFH is listed beside “no bolus” as an optional component of IV UFH treatment prior to standardized 18 units/kg/hour infusion. No bolus was selected for 66/127 (52%) of infusions, and the bolus was given in 61/127 (48%) of cases. Use of the initial bolus was not associated with a statistically significant risk of bleeding p = 0.186 (Bolus and Bleeding OR 0.446 OR 0.165 to 1.262), with 11/16 (69%) of bleeding events occurring in the group where bolus dosing was omitted (Fig. 1 ). A very high proportion of patients in this study were noted to have at least one aPTT measurement > 150s, including 27/61 (44%) of patients given the initial bolus and 26/66 (39%) patients in the “no bolus” group p = 0.594 (OR 1.222 95% CI 0.5976 to 2.519) (Fig. 1 ). The omission of initial bolus was significantly associated with an initial subtherapeutic aPTT at 6 hours p = < 0.001OR 8.119 95% CI 3.209 to 20.74) and at subsequent aPTT (p = 0.0444 95% CI 1.007 to 6.736) (Fig. 2 ). Discussion A high incidence of MB events (11%) was observed in patients who received a UFH infusion as their initial anticoagulant. A 2005 meta-analysis of patients randomized to UFH as part of VTE-treatment trials found that 2.0% of patients had MB at 10 days and 4.3% had MB at 3 months ( 20 ). In randomized studies of anticoagulation, where episodes of bleeding are diligently recorded, clinically relevant non-major bleeding episodes are approximately three times more common than episodes of MB ( 35 , 36 ). The high rate of MB (11%) and low rate of all other types of bleeding (1.5%) in our study may suggest significant underrepresentation of non-MB events when captured by retrospective review of discharge summaries and progress notes. MB events may be over-represented in our study due to the short duration of heparin administration. Bleeding events were not significantly associated with the use or omission of the initial bolus. However, there were higher rates of historical bleeding and antiplatelet use in the “no bolus” cohort. We found a significant association between bleeding events and any markedly elevated aPTT > 150s. In our study, markedly elevated aPTTs were seen at least once in 44% of those with an initial bolus dose and in 39% of those where the initial bolus was omitted. Clinicians may be intending to limit excess anticoagulation by withholding the initial bolus. Omission of the bolus does not appear to be effective in avoiding markedly supratherapeutic measurements within the first 96 hours. To our knowledge, only one previous study examined the effect of initial heparin boluses on aPTT lability. This study reported an association between withholding the initial bolus and recording supratherapeutic aPTTs at 24 hours ( 12 ). The authors theorize that this could be related to the phenomenon that patients who do not receive an initial bolus are more prone to being administered inappropriately high infusion rates ( 12 ). Our study found that omission of the initial bolus was associated with significant delays in achieving therapeutic levels of anticoagulation compared to a cohort who received an initial bolus. Subtherapeutic aPTTs are commonly reported during initial treatment with UFH infusions ( 12 , 13 , 37 ). The delay in therapeutic anticoagulation may have significant clinical consequences in the treatment of those with VTE. For instance, a large retrospective study of patients with acute PE found an association between failing to obtain a therapeutic aPTT within 24 hours and increased mortality ( 37 ). Altogether, our findings suggest that the high bleed rates of UFH may not be mitigated by foregoing the initial bolus and that withholding the initial bolus may come at the expense of increased latency to therapeutic levels of anticoagulation. Currently, there is little uniformity with how intravenous UFH is administered between centres in Canada. In cases where the bleeding risk is felt to be excessively high, omission of the bolus might be considered a strategy to provide deliberately subtherapeutic anticoagulation with gradual escalation over the first 6 to 12 hours with early reconsideration for alternative anticoagulation if bleeding is not seen. Outside of these rare examples, our findings indicate the omission of the bolus is frequently associated with significant delay to therapeutic levels and not associated with protection against markedly supratherapeutic levels of anticoagulation in the first 96 hours. Based on these preliminary findings, we hypothesize that limiting UFH use and mandating the bolus dose in most cases would result in net clinical benefit by increasing efficacy with limited effects on markedly supratherapeutic aPTTs and bleeding complications. We identified a high proportion of cases within our institution (42%) with no identified indication for UFH. Therefore, UFH might have been replaced with a potentially safer and more effective anticoagulant in these instances. This finding may provide impetus for local education efforts or increased institutional oversight. Initiatives which limit UFH use already exist in Canada and have demonstrated good uptake and effectiveness. Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada launched the Avoid-Heparin Initiative in 2005. The program was a multi-faceted, institution-wide approach directed at replacing UFH with LMWH wherever possible. A retrospective analysis of the program has noted a significant decrease of 42% in the annual HIT rate with substantial cost savings since its inception ( 33 ). Aside from HIT, there is mounting evidence that LMWH is more efficacious than UFH and safer from a bleeding perspective ( 14 , 15 , 18 , 22 , 23 ). Compared with the administration of LMWH injections, the monitoring required for UFH infusions places an additional burden on patients, bedside nurses, and laboratory staff. There are several limitations of the present study. Retrospective chart review was utilized to determine the appropriateness of clinical decisions, and perhaps undocumented reasons for using UFH were not accounted for by the authors. This may overestimate the number of instances in which UFH administration was deemed to be inappropriate. While a duration of 48 to 96 hours is likely ideal for examining appropriateness of initial anticoagulant choice and the kinetics of initial aPTTs, it is insufficient to capture cases of the most feared complication of UFH use, namely HIT, and may bias the sample toward high rates of bleeding if UFH was stopped after an observed bleeding event. We are unable to determine whether omission of initial bolus is a consequence of this being considered an equivalent option on our current order set, or a deliberate choice for patients deemed to be at high risk of bleeding. Therefore, all comparisons should be considered hypothesis-generating rather than causal. Conclusion UFH plays an important, albeit increasingly limited, role as an anticoagulant. There is mounting evidence that LMWH is safer and more efficacious than UFH in the treatment of acute VTE, which is likely related to the known challenges in dosing and monitoring UFH. This study adds to a growing body of literature demonstrating high rates of MB events when using IV UFH treatment outside of randomized controlled trials. We suspect that many institutions, like our own, continue to overuse UFH by way of clinical inertia. 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Reducing the hospital burden of heparin-induced thrombocytopenia: impact of an avoid-heparin program. Blood. 2016;127(16):1954–9. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361(24):2342–52. Franco L, Becattini C, Vanni S, Sbrojavacca R, Nitti C, Manina G, et al. Clinically relevant non-major bleeding with oral anticoagulants: non-major may not be trivial. Blood Transfus. 2018;16(4):387–91. Smith SB, Geske JB, Maguire JM, Zane NA, Carter RE, Morgenthaler TI. Early Anticoagulation Is Associated With Reduced Mortality for Acute Pulmonary Embolism. Chest. 2010;137(6):1382–90. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4650298","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":325648492,"identity":"f7d513e2-ebfe-4ba7-a71c-bbac599e002e","order_by":0,"name":"Logan Hahn","email":"","orcid":"","institution":"University of Saskatchewan","correspondingAuthor":false,"prefix":"","firstName":"Logan","middleName":"","lastName":"Hahn","suffix":""},{"id":325648493,"identity":"16b5e449-4d0e-44ca-9381-1b39f7ab6144","order_by":1,"name":"Christopher Beresh","email":"","orcid":"","institution":"University of Saskatchewan","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Beresh","suffix":""},{"id":325648494,"identity":"a27f6159-6057-4772-a503-4059289d9326","order_by":2,"name":"Hadi A Goubran","email":"","orcid":"","institution":"Saskatchewan Cancer Agency, University of Saskatchewan","correspondingAuthor":false,"prefix":"","firstName":"Hadi","middleName":"A","lastName":"Goubran","suffix":""},{"id":325648495,"identity":"724b3587-a5dc-47a9-951c-5ce4a1b28b86","order_by":3,"name":"William Semchuk","email":"","orcid":"","institution":"University of Saskatchewan","correspondingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"Semchuk","suffix":""},{"id":325648496,"identity":"4c04e470-1146-4807-bfa2-def9c5fcafde","order_by":4,"name":"Matthew Nicholson","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABJklEQVRIie3Qv2qDQBzA8Z8IulzpahDsExROBCWU2ldRBCeHjIGKFYR26QMIeYlbuwkHugiuF7KkHKSrJUu6tL1Am0JF6djhvsOP4+DD/QGQyf5p6tfUABZioediVJNAKX4IFgtU/ZXANzGCaXL50DV8saTg6epu2+PM8mYvz6+H1r/wdFr3kPq/idtGSlG2FOaF5tklps58lTgmYpH99BhHJdTRgFSCnN1vAFOkmQhXIdkkYEJfKYQhB5RcHZCOC/J+IllI1g1/O/TVDWHne0HuBoQdT8lPRA0JA9dATBzHkCoIHRJur1D9gTDV3NnxLbhN3CvURhFpYweCuhleLNzuURpbuKM7o19mFm4avj7U/jVpKIc+vR37bDSyH4wBmUwmk031Cd3+cSAHMWpvAAAAAElFTkSuQmCC","orcid":"","institution":"Saskatchewan Cancer Agency, University of Saskatchewan","correspondingAuthor":true,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Nicholson","suffix":""}],"badges":[],"createdAt":"2024-06-27 17:02:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4650298/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4650298/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60168249,"identity":"9986785f-bd59-43b8-ace6-2744104d6374","added_by":"auto","created_at":"2024-07-12 14:38:05","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":220744,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of Initial Bolus on Any Markedly Elevated aPTT \u0026gt; 150 seconds and Bleeding Complications In Hospital After Starting UFH Infusion\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4650298/v1/aa997943bbea136ebc59894e.jpeg"},{"id":60168251,"identity":"14607d82-ee08-48e0-a3e8-d712d2eac184","added_by":"auto","created_at":"2024-07-12 14:38:05","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":212823,"visible":true,"origin":"","legend":"\u003cp\u003eImpact of Initial Bolus on Subtherapeutic aPTTs as Measured By First and Second aPTT After Starting UFH Infusion\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4650298/v1/cdf0a91b8eede25b6d5f446d.jpeg"},{"id":61275707,"identity":"ece1c212-2f80-4a48-9fa5-00ec8297deae","added_by":"auto","created_at":"2024-07-29 03:39:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":777151,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4650298/v1/a088bccd-b746-4a3b-aeb4-473140b7f976.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Overused and Unpredictable: A Study of Unfractionated Heparin Treatment Including Appropriateness, Safety, and Bolus Dosing","fulltext":[{"header":"Background","content":"\u003cp\u003eUnfractionated heparin (UFH) remains an important anticoagulant for medical and surgical indications due to its short duration of action and reversibility by protamine. UFH is used for anticoagulation in the treatment of venous thromboembolism (VTE) for patients who require thrombolysis, have severe renal dysfunction (estimated glomerular filtration rate [eGFR]\u0026thinsp;\u0026lt;\u0026thinsp;30mL/min) or those who require anticoagulant interruption for a procedure. Multiple recent guidelines advocate a preference for low molecular weight heparin (LMWH) over UFH to reduce the risk of major bleeding (MB), heparin-induced thrombocytopenia, improve cost-effectiveness, and alleviate the burden of monitoring on nursing and laboratory staff associated with UFH use (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUFH has a complex pharmacodynamic and pharmacokinetic profile, leading to a narrow therapeutic window and a highly variable dose-response relationship (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Pharmacodynamically, UFH exerts its anticoagulant effect through interaction with antithrombin III, heparin cofactor II and tissue factor pathway inhibitor (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). However, UFH selectively binds several other plasma proteins such as fibronectin, platelet factor 4 (PF4), and von Willebrand factor which can vary widely in concentrations depending on nutritional and inflammatory states (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). These complexities may explain the observed clinical challenges of dosing and monitoring UFH.\u003c/p\u003e \u003cp\u003eIn clinical practice, numerous laboratory methods such as activated partial thromboplastin time (aPTT) and assays of anti-Xa activity have been employed to characterize the activity of UFH. aPTT is the most widely used method for monitoring the anticoagulant effect of UFH (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). However, aPTT monitoring has been shown to be highly discordant with anti-Xa monitoring (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Given these issues with monitoring UFH, it is therefore unsurprising that dosing the drug has also been found to be problematic. Low rates of therapeutic aPTT measurements within the initial days of treatment are a known issue with UFH use. Prior observational studies have reported therapeutic aPTTs in less than 50% of patients during the first 24 hours of treatment (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe narrow therapeutic window of UFH appears to have meaningful clinical consequences, especially when compared to more stable anticoagulants like LMWH. Studies have documented the superiority of LMWH over UFH in terms of VTE recurrence and thrombotic complications (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Additionally, in the treatment of VTE, there appears to be less MB and decreased mortality with LMWH (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). An additional concern with UFH is the risk of heparin-induced thrombocytopenia (HIT). The thrombotic sequelae of HIT are the result of autoantibody formation to heparin-PF4 complexes. The mortality of HIT can approach 25% even despite treatment (\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Observational studies have demonstrated reductions in the development of HIT in patients treated with LMWH compared to UFH (\u003cspan additionalcitationids=\"CR30 CR31 CR32\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e Given the well-documented consequences of UFH, we reviewed the indications and harms associated with intravenous UFH infusions at the Royal University Hospital in Saskatoon, Saskatchewan, Canada, which is the largest tertiary hospital in the province. We performed a retrospective chart review of patients who received a UFH infusion as their initial anticoagulant between January 2021 and December 2023. We characterized bleeding events and examined indications for UFH use to determine if an alternative anticoagulation strategy could have been implemented. Additionally, given the unpredictable pharmacokinetics of UFH, we wondered if the decision to administer or withhold an initial bolus would affect aPTT lability, latency to the therapeutic target, and bleeding risk.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThe aim of this study was to determine bleeding risks associated with UFH as an initial agent for therapeutic anticoagulation in-hospital. We chose to study consecutive patients with use from 48 to 96 hours to ensure adequate exposure to the intervention and limit cases in which UFH was used strictly as a bridging agent. We attempt to identify and describe the characteristics of patients with bleeding events, including whether these were related to markedly elevated aPTTs\u0026thinsp;\u0026gt;\u0026thinsp;150 seconds (s) and whether the omission of bolus dosing before the infusion was correlated with delay to therapeutic anticoagulation, bleeding, or any markedly elevated aPTT. Finally, we attempt to understand whether patients at our institution had an indication for the use of UFH or if alternative anticoagulants with more favourable pharmacologic profiles could have been used.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData Capture\u003c/h2\u003e \u003cp\u003ePatients who met inclusion criteria were identified through a retrospective drug utilization report generated through a pharmacy database. Inclusion criteria consisted of adult inpatients (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;18 years of age) who were prescribed intravenous UFH at therapeutic dosing for 48 to 96 hours in a single tertiary care hospital between January 2021 and December 2023. Patients on UFH with cardiovascular dosing (lower aPTT target) were excluded. Data retrieved from computerized records included age, weight, gender, indication for anticoagulation, troponin, imaging evidence of right heart strain, HIT testing, known bleeding history before hospitalization, known bleeding events while in hospital but prior to UFH use, platelet count, decompensated cirrhosis, and eGFR.\u003c/p\u003e \u003cp\u003eIn our centre aPTT is performed using Synthesil (IL) reagents and the validated therapeutic range is 70\u0026ndash;99 seconds at the treatment dose. All patients had a normal baseline aPTT. All available aPTTs while on UFH infusion were examined. It was documented if the patient experienced at least one markedly elevated aPTT at \u0026gt;\u0026thinsp;150s. According to our institutional UFH nomogram, the initial aPTT is measured 6 hours after starting the infusion. If this initial aPTT is within the target (aPTT\u0026thinsp;=\u0026thinsp;70-99s), a subsequent or second PTT is checked after 24 hours. If the initial aPTT is not within the target range, then the subsequent aPTT is checked in an additional 6 hours. First and second aPTT measurements were classified as subtherapeutic if the measured value was at least 10 seconds shorter than the lower limit of the therapeutic range (\u0026lt;\u0026thinsp;60 seconds).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDefinitions and Endpoints\u003c/h2\u003e \u003cp\u003eWe relied on available discharge summaries, progress notes, and laboratory results to identify and classify bleeding episodes. We defined MB according to the International Society on Thrombosis and Haemostasis (ISTH) criteria, which defines MB as fatal and/or symptomatic bleeding in a critical area or organ, bleeding causing a hemoglobin fall of 20g/L or greater and/or bleeding requiring a transfusion of 2 or more units of whole blood or packed red blood cells (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Other bleeding was defined as all other reported bleeding which did not meet the criteria for MB.\u003c/p\u003e \u003cp\u003ePatients were deemed to have \u0026ldquo;appropriate\u0026rdquo; use of UFH if they had recent (defined as bleeding during current admission) or ongoing bleeding, required an imminent procedure or surgery, had an eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30mL/min, or could foreseeably require thrombolysis through classification of patients as either \u0026ldquo;intermediate-high\u0026rdquo; or \u0026ldquo;high\u0026rdquo; risk per the European Society of Cardiology 2019 treatment of VTE guidelines (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This definition uses imaging (CT or echocardiogram) and biochemical evidence of right heart strain (elevated Troponin T Cardiac; High Sensitivity assay) to define patients as \u0026ldquo;intermediate-high\u0026rdquo; risk. High risk was defined as cardiac arrest, obstructive shock (systolic BP\u0026thinsp;\u0026lt;\u0026thinsp;90 mmHg or vasopressors required to achieve a BP\u0026thinsp;\u0026ge;\u0026thinsp;90 mmHg despite an adequate filling status, in combination with end-organ hypoperfusion), or persistent hypotension (systolic BP\u0026thinsp;\u0026lt;\u0026thinsp;90 mmHg or a systolic BP drop\u0026thinsp;\u0026ge;\u0026thinsp;40 mmHg for \u0026gt;\u0026thinsp;15 min, not caused by new-onset arrhythmia, hypovolaemia, or sepsis). All patients who were administered systemic thrombolysis were considered appropriate for use of UFH.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eUnivariate analysis using Fisher\u0026rsquo;s Exact test was applied (GraphPad Prism version 10.2.3 for Windows, GraphPad Software, Boston, Massachusetts USA) to determine if associations between any markedly elevated aPTT, bolus dosing prior to infusion, systemic thrombolysis, or concurrent anti-platelet use were significantly associated with bleeding events. A two-sided p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. Figures were constructed using GraphPad Prism.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWe identified 131 consecutive patients prescribed intravenous UFH for 48 to 96 hours between 2021 and 2023. Four patients were excluded due to incomplete data with no aPTT or anti-Xa measurements, likely due to non-standard use of the order set to prescribe low, fixed doses of UFH. The population for analysis included 127 patients (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), of which 16 patients (13%) had a bleeding event recorded. Criteria for ISTH MB were met in 14/16 identified bleeding complications (11% of the total population). An episode of GI bleeding and a significant bleed around a central venous catheter during UFH treatment did not meet the criteria for MB, but both necessitated discontinuation of anticoagulation until bleeding was controlled. None of the bleeding events were classified as fatal bleeding. In 53/127 charts reviewed, an indication for UFH as opposed to an alternative anticoagulant could not be identified (42%). Four patients in this series were tested for HIT using a rapid HemosIL\u0026reg; HIT-Ab(PF4-H) (HemosILAb) latex-particle immunoassay, and none were positive.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Characteristics in Bolus and No Bolus Cohorts\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBolus (n\u0026thinsp;=\u0026thinsp;61)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo Bolus (n\u0026thinsp;=\u0026thinsp;66)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBleeding (n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63.1 (17.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.0 (16.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70.1 (14.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u0026ndash;98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u0026ndash;91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u0026ndash;84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (47.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (59.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (43.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (52.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (40.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (56.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87.4 (28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85.4 (25.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80.7 (17.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u0026ndash;208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43\u0026ndash;194\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45\u0026ndash;118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR (mL/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFR, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.4 (36.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.8 (35.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59.5 (41.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (37.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (10.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet count (10\u003csup\u003e9\u003c/sup\u003e/L), mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e266 (137)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e271 (134)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e274 (140)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASA, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (31.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of other antiplatelet, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of bleeding prior to current admission, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (10.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding during current admission prior to UFH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (31.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecompensated cirrhosis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVTE indication for AC n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (68.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (81.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndication for AC other than VTE, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (31.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (18.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration on UFH infusion in hours, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (14.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 (14.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72 (16.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e: Patient characteristics in bolus and no bolus cohorts. Characteristics of patients who had a bleeding event are also displayed. Abbreviations: SD: standard deviation; eGFR: estimated glomerular filtration rate; ASA: acetylsalicylic acid; UFH: unfractionated heparin; VTE: venous thromboembolism; AC: anticoagulation.\u003c/p\u003e \u003cp\u003eObserving at least one markedly elevated aPTT at \u0026gt;\u0026thinsp;150s while on UFH treatment was significantly associated with bleeding p\u0026thinsp;=\u0026thinsp;0.0285 (Odds ratio 3.614 95% CI 1.267 to 9.796). Use of any anti-platelet treatment was significantly associated with bleeding p\u0026thinsp;=\u0026thinsp;0.0339 (OR 3.564 CI 1.064 to 11.27). Four patients required thrombolysis within 24 hours of IV UFH (3 high-risk PE and one stroke), and 2/4 were classified as having bleeding events. No significant association was observed between thrombolysis and bleeding.\u003c/p\u003e \u003cp\u003eIn our centre, the initial \u0026ldquo;bolus\u0026rdquo; dose of 80 units/kg IV UFH is listed beside \u0026ldquo;no bolus\u0026rdquo; as an optional component of IV UFH treatment prior to standardized 18 units/kg/hour infusion. No bolus was selected for 66/127 (52%) of infusions, and the bolus was given in 61/127 (48%) of cases. Use of the initial bolus was not associated with a statistically significant risk of bleeding p\u0026thinsp;=\u0026thinsp;0.186 (Bolus and Bleeding OR 0.446 OR 0.165 to 1.262), with 11/16 (69%) of bleeding events occurring in the group where bolus dosing was omitted (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). A very high proportion of patients in this study were noted to have at least one aPTT measurement\u0026thinsp;\u0026gt;\u0026thinsp;150s, including 27/61 (44%) of patients given the initial bolus and 26/66 (39%) patients in the \u0026ldquo;no bolus\u0026rdquo; group p\u0026thinsp;=\u0026thinsp;0.594 (OR 1.222 95% CI 0.5976 to 2.519) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The omission of initial bolus was significantly associated with an initial subtherapeutic aPTT at 6 hours p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001OR 8.119 95% CI 3.209 to 20.74) and at subsequent aPTT (p\u0026thinsp;=\u0026thinsp;0.0444 95% CI 1.007 to 6.736) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eA high incidence of MB events (11%) was observed in patients who received a UFH infusion as their initial anticoagulant. A 2005 meta-analysis of patients randomized to UFH as part of VTE-treatment trials found that 2.0% of patients had MB at 10 days and 4.3% had MB at 3 months (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In randomized studies of anticoagulation, where episodes of bleeding are diligently recorded, clinically relevant non-major bleeding episodes are approximately three times more common than episodes of MB (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). The high rate of MB (11%) and low rate of all other types of bleeding (1.5%) in our study may suggest significant underrepresentation of non-MB events when captured by retrospective review of discharge summaries and progress notes. MB events may be over-represented in our study due to the short duration of heparin administration. Bleeding events were not significantly associated with the use or omission of the initial bolus. However, there were higher rates of historical bleeding and antiplatelet use in the \u0026ldquo;no bolus\u0026rdquo; cohort.\u003c/p\u003e \u003cp\u003eWe found a significant association between bleeding events and any markedly elevated aPTT\u0026thinsp;\u0026gt;\u0026thinsp;150s. In our study, markedly elevated aPTTs were seen at least once in 44% of those with an initial bolus dose and in 39% of those where the initial bolus was omitted. Clinicians may be intending to limit excess anticoagulation by withholding the initial bolus. Omission of the bolus does not appear to be effective in avoiding markedly supratherapeutic measurements within the first 96 hours. To our knowledge, only one previous study examined the effect of initial heparin boluses on aPTT lability. This study reported an association between withholding the initial bolus and recording supratherapeutic aPTTs at 24 hours (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The authors theorize that this could be related to the phenomenon that patients who do not receive an initial bolus are more prone to being administered inappropriately high infusion rates (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur study found that omission of the initial bolus was associated with significant delays in achieving therapeutic levels of anticoagulation compared to a cohort who received an initial bolus. Subtherapeutic aPTTs are commonly reported during initial treatment with UFH infusions (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). The delay in therapeutic anticoagulation may have significant clinical consequences in the treatment of those with VTE. For instance, a large retrospective study of patients with acute PE found an association between failing to obtain a therapeutic aPTT within 24 hours and increased mortality (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Altogether, our findings suggest that the high bleed rates of UFH may not be mitigated by foregoing the initial bolus and that withholding the initial bolus may come at the expense of increased latency to therapeutic levels of anticoagulation.\u003c/p\u003e \u003cp\u003eCurrently, there is little uniformity with how intravenous UFH is administered between centres in Canada. In cases where the bleeding risk is felt to be excessively high, omission of the bolus might be considered a strategy to provide deliberately subtherapeutic anticoagulation with gradual escalation over the first 6 to 12 hours with early reconsideration for alternative anticoagulation if bleeding is not seen. Outside of these rare examples, our findings indicate the omission of the bolus is frequently associated with significant delay to therapeutic levels and not associated with protection against markedly supratherapeutic levels of anticoagulation in the first 96 hours. Based on these preliminary findings, we hypothesize that limiting UFH use and mandating the bolus dose in most cases would result in net clinical benefit by increasing efficacy with limited effects on markedly supratherapeutic aPTTs and bleeding complications.\u003c/p\u003e \u003cp\u003eWe identified a high proportion of cases within our institution (42%) with no identified indication for UFH. Therefore, UFH might have been replaced with a potentially safer and more effective anticoagulant in these instances. This finding may provide impetus for local education efforts or increased institutional oversight. Initiatives which limit UFH use already exist in Canada and have demonstrated good uptake and effectiveness. Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada launched the Avoid-Heparin Initiative in 2005. The program was a multi-faceted, institution-wide approach directed at replacing UFH with LMWH wherever possible. A retrospective analysis of the program has noted a significant decrease of 42% in the annual HIT rate with substantial cost savings since its inception (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Aside from HIT, there is mounting evidence that LMWH is more efficacious than UFH and safer from a bleeding perspective (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Compared with the administration of LMWH injections, the monitoring required for UFH infusions places an additional burden on patients, bedside nurses, and laboratory staff.\u003c/p\u003e \u003cp\u003eThere are several limitations of the present study. Retrospective chart review was utilized to determine the appropriateness of clinical decisions, and perhaps undocumented reasons for using UFH were not accounted for by the authors. This may overestimate the number of instances in which UFH administration was deemed to be inappropriate. While a duration of 48 to 96 hours is likely ideal for examining appropriateness of initial anticoagulant choice and the kinetics of initial aPTTs, it is insufficient to capture cases of the most feared complication of UFH use, namely HIT, and may bias the sample toward high rates of bleeding if UFH was stopped after an observed bleeding event. We are unable to determine whether omission of initial bolus is a consequence of this being considered an equivalent option on our current order set, or a deliberate choice for patients deemed to be at high risk of bleeding. Therefore, all comparisons should be considered hypothesis-generating rather than causal.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eUFH plays an important, albeit increasingly limited, role as an anticoagulant. There is mounting evidence that LMWH is safer and more efficacious than UFH in the treatment of acute VTE, which is likely related to the known challenges in dosing and monitoring UFH. This study adds to a growing body of literature demonstrating high rates of MB events when using IV UFH treatment outside of randomized controlled trials. We suspect that many institutions, like our own, continue to overuse UFH by way of clinical inertia. When treatment with UFH is necessary, it appears as though administering the initial bolus dose may reduce latency to therapeutic effect with a similar tendency to lability and markedly elevated aPTT. In this small retrospective sample, omission of the bolus was not associated with a reduced risk of bleeding.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eFunding\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eEthics declarations\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved for data acquisition and publication by the affiliated University of Saskatchewan Research Ethics Board (OA-UofS-4552).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCOVID-19 Treatment Guidelines Panel. National Institutes of Health. 2019. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.covid19treatmentguidelines.nih.gov/\u003c/span\u003e\u003cspan address=\"https://www.covid19treatmentguidelines.nih.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 2024 May 15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCossette B, Pelletier M\u0026Egrave;, Carrier N, Turgeon M, Leclair C, Charron P, et al. Evaluation of Bleeding Risk in Patients Exposed to Therapeutic Unfractionated or Low-Molecular Weight Heparin: A Cohort Study in the Context of a Quality Improvement Initiative. Ann Pharmacother. 2010;44(6):994\u0026ndash;1002.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFowler RA, Mittmann N, Geerts W, Heels-Ansdell D, Gould MK, Guyatt G, et al. Cost-effectiveness of Dalteparin vs Unfractionated Heparin for the Prevention of Venous Thromboembolism in Critically Ill Patients. JAMA. 2014;312(20):2135.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLyman GH, Carrier M, Ay C, Di Nisio M, Hicks LK, Khorana AA, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021;5(4):927\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKonstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543\u0026ndash;603.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eErkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. In: Prins MH, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley \u0026amp; Sons, Ltd; 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDerbalah A, Duffull S, Newall F, Moynihan K, Al-Sallami H. Revisiting the Pharmacology of Unfractionated Heparin. Clin Pharmacokinet. 2019;58(8):1015\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoletti LF, Bird KE, Marques D, Harris RB, Suda Y, Sobel M. Structural Aspects of Heparin Responsible for Interactions With von Willebrand Factor. Arterioscler Thromb Vasc Biol. 1997;17(5):925\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaitman I, Huang ML, Williams SA, Friedman B, Godula K, Schwarzbauer JE. Heparin-fibronectin interactions in the development of extracellular matrix insolubility. Matrix Biol. 2018;67:107\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Roessel S, Middeldorp S, Cheung YW, Zwinderman AH, de Pont ACJM. Accuracy of aPTT monitoring in critically ill patients treated with unfractionated heparin. Neth J Med. 2014;72(6):305\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRhoades R, Leong R, Kopenitz J, Thoma B, McDermott L, Dovidio J, et al. Coagulopathy monitoring and anticoagulation management in COVID-19 patients on ECMO: Advantages of a heparin anti-Xa-based titration strategy. Thromb Res. 2021;203:1\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonenfant F, Cossette B, Nault V, Turgeon M, Paulin M, Echenberg D, et al. 241 Risk of supratherapeutic APTT in the absence of an initial unfractionated heparin bolus. Can J Cardiol. 2011;27(5):S149.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrucnal CK, Jansson PS, Deadmon E, Rosovsky RP, Zheng H, Kabrhel C. Analysis of Partial Thromboplastin Times in Patients With Pulmonary Embolism During the First 48 Hours of Anticoagulation With Unfractionated Heparin. Acad Emerg Med. 2020;27(2):117\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: Results of a meta-analysis. Am J Med. 1996;100(3):269\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobertson L, Jones LE. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Reviews. 2017;2017:2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGould MK. Low-Molecular-Weight Heparins Compared with Unfractionated Heparin for Treatment of Acute Deep Venous Thrombosis. Ann Intern Med. 1999;130(10):800.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlsagaff MY, Mulia EPB, Maghfirah I, Azmi Y, Rachmi DA, Yutha A, et al. Low molecular weight heparin is associated with better outcomes than unfractionated heparin for thromboprophylaxis in hospitalized COVID-19 patients: a meta-analysis. Eur Heart J Qual Care Clin Outcomes. 2022;8(8):909\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G. A Meta-analysis Comparing Low-Molecular-Weight Heparins With Unfractionated Heparin in the Treatment of Venous Thromboembolism. Arch Intern Med. 2000;160(2):181.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpinler SA, Inverso SM, Cohen M, Goodman SG, Stringer KA, Antman EM. Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Am Heart J. 2003;146(1):33\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMismetti P, Quenet S, Levine M, Merli G, Decousus H, Derobert E, et al. Enoxaparin in the Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism. Chest. 2005;128(4):2203\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnoxaparin vs Unfractionated. Heparin in High-Risk Patients With Non\u0026ndash;ST-Segment Elevation Acute Coronary Syndromes Managed With an Intended Early Invasive Strategy. JAMA. 2004;292(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCostantino G, Ceriani E, Rusconi AM, Podda GM, Montano N, Duca P, et al. Bleeding Risk during Treatment of Acute Thrombotic Events with Subcutaneous LMWH Compared to Intravenous Unfractionated Heparin; A Systematic Review. PLoS ONE. 2012;7(9):e44553.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUcar EY, Akgun M, Araz O, Tas H, Kerget B, Meral M, et al. Comparison of LMWH Versus UFH for Hemorrhage and Hospital Mortality in the Treatment of Acute Massive Pulmonary Thromboembolism After Thrombolytic Treatment. Lung. 2015;193(1):121\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetersen JL, Mahaffey KW, Hasselblad V, Antman EM, Cohen M, Goodman SG et al. Efficacy and Bleeding Complications Among Patients Randomized to Enoxaparin or Unfractionated Heparin for Antithrombin Therapy in Non\u0026ndash;ST-Segment Elevation Acute Coronary Syndromes. JAMA. 2004;292(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen M, Blaber R, Demers C, Gurfinkel EP, Langer A, Fromell G, et al. The Essence Trial: Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI: A Double-Blind, Randomized, Parallel-Group, Multicenter Study Comparing Enoxaparin and Intravenous Unfractionated Heparin: Methods and Design. J Thromb Thrombolysis. 1997;4(2):271\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStoll F, G\u0026ouml;dde M, Leo A, Katus HA, M\u0026uuml;ller OJ. Characterization of hospitalized cardiovascular patients with suspected heparin-induced thrombocytopenia. Clin Cardiol. 2018;41(12):1521\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGallo T, Curry SC, Padilla-Jones A, Heise CW, Ramos KS, Woosley RL, et al. A computerized scoring system to improve assessment of heparin‐induced thrombocytopenia risk. J Thromb Haemost. 2019;17(2):383\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArepally GM, Padmanabhan A. Heparin-Induced Thrombocytopenia. Arterioscler Thromb Vasc Biol. 2021;41(1):141\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106(8):2710\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWarkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, et al. Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin. N Engl J Med. 1995;332(20):1330\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJunqueira DR, Zorzela LM, Perini E. Unfractionated heparin versus low molecular weight heparins for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Reviews. 2017;2017:4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWarkentin TE, Sheppard JAI, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006;108(9):2937\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcGowan KE, Makari J, Diamantouros A, Bucci C, Rempel P, Selby R, et al. Reducing the hospital burden of heparin-induced thrombocytopenia: impact of an avoid-heparin program. Blood. 2016;127(16):1954\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361(24):2342\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranco L, Becattini C, Vanni S, Sbrojavacca R, Nitti C, Manina G, et al. Clinically relevant non-major bleeding with oral anticoagulants: non-major may not be trivial. Blood Transfus. 2018;16(4):387\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith SB, Geske JB, Maguire JM, Zane NA, Carter RE, Morgenthaler TI. Early Anticoagulation Is Associated With Reduced Mortality for Acute Pulmonary Embolism. Chest. 2010;137(6):1382\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4650298/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4650298/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMultiple recent guidelines advocate a preference for low molecular weight heparin (LMWH) over unfractionated heparin (UFH) infusions to reduce the risk of major bleeding (MB), heparin-induced thrombocytopenia (HIT) and improve cost-effectiveness (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This study analyzed UFH use at a tertiary centre in Canada to identify cases in which UFH could have been avoided, identify characteristics associated with bleeding, and examine the efficacy and safety of infusions where the initial bolus was administered or withheld.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe identified adults who received between 48 to 96 hours of a UFH infusion in a single tertiary care hospital between January 2021 and December 2023. Consecutive patients were reviewed for bleeding events, patient factors known to influence bleeding, and whether patients had a contraindication to LMWH or another anticoagulant. Patients were deemed to have \u0026ldquo;appropriate\u0026rdquo; use of UFH in preference to more desirable anticoagulants if they had recent or ongoing bleeding, required an imminent procedure or surgery, an estimated glomerular filtration rate (eGFR) less than 30mL/min, or could foreseeably require thrombolysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf 127 patients, 16 (13%) were identified to have bleeding complications, including 14 episodes of MB. Bleeding episodes were significantly associated with any measured aPTT greater than 150 seconds (s) during treatment (p\u0026thinsp;=\u0026thinsp;0.0285). Omission of initial bolus dosing was not associated with reduced bleeding events or the incidence of any aPTT measurement greater than 150s. Omission of initial bolus dosing was associated with subtherapeutic aPTT measurement at 6 hours (46%) and 12 hours (25%) post-UFH administration. We identified high rates (42%) of UFH selection where an alternative anticoagulant could have been used.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eUse of intravenous UFH is associated with a high risk of MB, and bleeding complications are associated with markedly elevated aPTT (\u0026gt;\u0026thinsp;150s). An elevated risk of bleeding does not appear to be mitigated by omitting the initial bolus. Delivery of an initial UFH bolus decreases time to therapeutic anticoagulation.\u003c/p\u003e","manuscriptTitle":"Overused and Unpredictable: A Study of Unfractionated Heparin Treatment Including Appropriateness, Safety, and Bolus Dosing","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-12 14:38:01","doi":"10.21203/rs.3.rs-4650298/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"85973629-4cbd-4efe-9409-a3c35b9502b3","owner":[],"postedDate":"July 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-29T03:31:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-12 14:38:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4650298","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4650298","identity":"rs-4650298","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}