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- J Pharm Technol
- v.38(4); 2022 Aug
- PMC9272488
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J Pharm Technol. 2022 Aug; 38(4): 202–205.
Published online 2022 May 10. doi:10.1177/87551225221094171
PMCID: PMC9272488
PMID: 35832571
Adam Dashner, PharmD, BCPS1 and Erin Siders, PharmD1
Author information Copyright and License information PMC Disclaimer
Abstract
Purpose: There is little clinical evidence comparing the safety andefficacy of prophylactic subcutaneous heparin given every 8 hours and every 12hours. We performed a retrospective analysis incorporating these dosingintervals in an inpatient rehabilitation setting. Methods: Heparinusage data was collected and patient charts were analyzed for both therapeuticfailure and bleeding events. A 2-tailed Fisher’s exact test was performed forboth outcomes, with a P-value of less than 0.05 beingconsidered significant. Odds ratios were also calculated withP-values less than 0.05 being considered significant.Study Population: A Cerner report was run to identify patientsordered prophylactic heparin in an inpatient rehabilitation setting from April7, 2020, to October 27, 2021. One hundred patients receiving heparin every 8hours and every 12 hours were randomly selected for chart review. These studygroups were further stratified by Padua risk scores. Results: Inboth groups, 4 (4.0%) patients were identified as having a documented bleedingevent and 2 (2.0%) patients from each group were identified as having a therapyfailure. Conclusion: For both endpoints, no significant differencesin bleeding rates or therapy failure rates were detected in any of thepopulation stratifications.
Keywords: anticoagulation, clinical practice, drug safety, cardiology, prophylaxis
Introduction
Many patients admitted to inpatient rehabilitation facilities have increased risks ofblood clots that can lead to deep vein thrombosis (DVT) or pulmonary embolism (PE);typically, this is related to a prolonged decrease in mobility, prior venousthromboembolism (VTE) or ischemic event, or recent trauma or surgery. It isestimated that 10% of patients in an inpatient rehabilitation facility willexperience a VTE.1 Approximately 10% to 30% of VTEs result in death, with 20% to 26% of PEsresulting in sudden death.2 Along with the high mortality rate, VTE is also a costly disease, with anannual cost believed to be of $2 billion to $10 billion.2
With the high mortality rate and cost associated with VTE, prophylaxis is imperative.To prevent VTE, patients with an increased risk for developing VTE must beidentified. The Padua VTE Risk Score is a tool that inpatient facilities can use toassess the degree of risk for developing a VTE. This tool uses 11 variables toassign a risk score; these variables are active cancer, previous VTE, decreasedmobility, thrombophilia, previous trauma or surgery within the last 4 weeks, age>70, heart and/or respiratory failure, prior ischemic stroke or myocardialinfarction (MI), acute rheumatologic disorder or acute infection, obesity, andhormonal therapy. Each of these factors has a value assigned to it and the totalnumber of points provides the patient’s risk score. This score can range from 0 (norisk factors present) to 20 (all risk factors present). Any score greater than 4 isconsidered high risk for VTE and suggests thromboprophylaxis is indicated.3
Unfractionated heparin (UFH) is commonly used in both the treatment and prevention ofVTE. Heparin is a naturally occurring glycosaminoglycan that activates antithrombinIII that, in turn, inactivates thrombin, clotting factor Xa, and several other minorclotting factors.4
When used for VTE prophylaxis, heparin is administered as a subcutaneous injection of5000 units given either every 8 hours or every 12 hours.5 There are currently no guidelines offering suggestions for when either dosinginterval is appropriate. Choosing an appropriate dosing interval is important tominimize bleeding risk without compromising the anticoagulant effect of themedication. It is also worth noting that the facility this study was conducted inuses Padua scores only to assess the need for VTE prophylaxis. There is no othertool or algorithm determining the specific agent or frequency of administration.
Permission to publish this retrospective chart review was granted by the facility atwhich it was conducted. The original intent of the data collection was for a druguse evaluation.
Methods
Trial Design
A retrospective randomized cohort study was conducted analyzing the outcomes ofprophylactic heparin used across all patients in an inpatient rehabilitationsetting.
Patient data was gathered through a Cerner report identifying all patientsordered subcutaneous heparin 5000 units either every 8 or 12 hours. This reportspanned patients started on heparin and discharged from the facility from April7, 2020, to October 27, 2021. This date range covers the time from thefacility’s adoption of the Padua Risk scale to the date of data collection.
In addition, patients were further stratified by Padua risk scores of less than 4and greater than or equal to 4.
Patient Population
All patients ordered prophylactic heparin during the time period analyzed wereeligible for assessment. No demographic qualifiers would deem a patient asineligible.
When stratified for risk scores, patients were excluded if no risk score wasdocumented or a tool other than Padua was used. Because the Padua assessment isdesigned to assess clotting risk factors, no further demographic stratificationwas performed.
As renal function does not affect heparin metabolism or clearance, this was notrecorded during date collection. Occurrence of heparin-induced thrombocytopenia(HIT) with a documented bleeding would exclude patients from the finalassessment as well. Patients receiving heparin to bridge to warfarin therapywere excluded.
Endpoints
Two primary endpoints were evaluated in this study. The first being anydocumented occurrence of bleeding regardless of severity. Reported bleedingevents included epistaxis, gastrointestinal (GI) bleeds, hematuria, injectionsite bleeding, and severe bleeding following a peripherally inserted centralcatheter (PICC) line removal. The second was documentation of a clotting orischemic event; this includes DVT, PE, or a stroke identified as ischemic innature.
Heparin-induced thrombocytopenia with bleeding was the only secondary endpointtracked.
Statistical Analysis
A 2-tailed Fisher’s exact test was used to compare the outcomes. For bleedingrisk, the every 8-hour group was compared against the every 12-hour group. Forclotting risk, the every 12-hour group was compared against the every 8-hourgroup. The results were considered significant for a P-valueless than 0.05. Odds ratios with 95% confidence intervals were also calculatedfor the date collected. P-values less than 0.05 were consideredsignificant in this analysis as well.
Bleed risk in patients with Padua scores <4 versus those with scores ≥4 werecompared using the same methods as listed above.
Results
From April 7, 2020, to October 27, 2021, 367 patients receiving prophylacticsubcutaneous heparin were identified. Of those, 160 patients were given heparin 5000units every 8 hours and 207 patients were given heparin 5000 units every 12 hours.One hundred patients were randomly selected from each of these groups for chartreview. Following the chart review, 76 patients with documented Padua scores wereordered heparin every 8 hours and 86 patients with Padua scores were ordered heparinevery 12 hours. The patients with documented Padua scores were further divided basedon Padua scores less than 4 and Padua scores greater than or equal to 4. A total of37 patients had Padua scores less than 4 while 125 patients had scores greater thanor equal to 4. The every 8-hour group had 19 patients with Padua scores less than 4and 57 patients with Padua scores greater than or equal to 4. The every 12-hourgroup had 18 patients with Padua scores less than 4 and 68 patients with Paduascores greater than or equal to 4 (Table 1).
Table 1.
Total Identified Population.
| Group | Total patients | Charts reviewed | With Padua score | Padua score <4 | Padua score ≥4 |
|---|---|---|---|---|---|
| Heparin q8 | 160 | 100 | 76 | 19 | 57 |
| Heparin q12 | 207 | 100 | 86 | 18 | 68 |
| Total | 367 | 200 | 162 | 37 | 125 |
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In all charts reviewed for both the every 8-hour and every 12-hour groups, 4 (4.0%)patients were identified as having a documented bleeding event and 2 (2.0%) patientsfrom each group were identified as having a therapy failure. No incidences of HITand bleeding were documented. No warfarin bridges were identified (Table 2).
Table 2.
Documented Bleeding Events and Therapy Failures in All Patients With ChartReviewed.
| Group | Patients | Bleeding event | No bleeding event | Therapy failure | No therapy failure |
|---|---|---|---|---|---|
| Heparin q8 | 100 | 4 (4.0%) | 96 (96.0%) | 2 (2.0%) | 98 (98%) |
| Heparin q12 | 100 | 4 (4.0%) | 96 (96.0%) | 2 (2.0%) | 98 (98%) |
| Total | 200 | 8 (4.0%) | 193 (96.0%) | 4 (2.0%) | 196 (98%) |
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In patients with documented Padua scores, the every 8-hour group had 3 (3.9%) casesof bleeding reported and 2 (2.6%) therapy failures and the every 12-hour group had 4(4.7%) bleeding events and 0 (0.0%) therapy failures (Table 3).
Table 3.
Documented Bleeding Events and Therapy Failures in Patients With PaduaScore.
| Group | Patients | Bleeding event | No bleeding event | Therapy failure | No therapy failure |
|---|---|---|---|---|---|
| Heparin q8 | 76 | 3 (3.9%) | 73 (96.1%) | 2 (2.6%) | 74 (97.4%) |
| Heparin q12 | 86 | 4 (4.7%) | 82 (95.3%) | 0 (0.0%) | 86 (100.0%) |
| Total | 162 | 7 (4.3%) | 155 (95.7%) | 2 (1.2%) | 160 (98.8%) |
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In the every 8-hour group, there were 0 (0.0%) bleeding events and 1 (5.3%) therapyfailure in patients with scores less than 4 and 3 (5.3%) bleeding events and 1(1.8%) therapy failure in patients with scores greater than or equal to 4 (Table 3).
In the every 12-hour group, there was 1 (5.6%) bleeding event and 0 (0.0%) therapyfailures in patients with scores less than 4 and 3 (4.4%) bleeding events and 0(0.0%) therapy failures in patients with scores greater than or equal to 4 (Table 3).
There was no statistically significant increased bleeding risk in the every 8-hourgroup in all patients (P = 1.00; odds ratio [OR] = 1.00 [95%confidence interval, CI, 0.24 to 4.11]), all patients with Padua score(P = 1.00; OR = 0.84 [95% CI, 0.18 to 3.89]), patients withPadua scores less than 4 (P = 0.48; OR = 0.30 [95% CI, 0.01 to7.83]), or patients with Padua scores greater than or equal to 4 (P= 1.00; OR = 1.20 [95% CI, 0.23 to 6.21]) (Table 4).
Table 4.
Documented Bleeding Events and Therapy Failures by Padua Score.
| Group | Patients | Bleeding event | No bleeding event | Therapy failure | No therapy failure |
|---|---|---|---|---|---|
| Heparin q8 Padua <4 | 19 | 0 (0.0%) | 19 (100.0%) | 1 (5.3%) | 18 (94.7%) |
| Heparin q12 Padua <4 | 18 | 1 (5.6%) | 17 (94.4%) | 0 (0.0%) | 18 (100.0%) |
| Total Padua <4 | 37 | 1 (2.7%) | 36 (97.3%) | 1 (2.7%) | 36 (97.3%) |
| Heparin q8 Padua ≥4 | 57 | 3 (5.3%) | 54 (94.7%) | 1 (1.8%) | 56 (98.2%) |
| Heparin q12 Padua ≥4 | 68 | 3 (4.4%) | 65 (95.6%) | 0 (0.0%) | 68 (100.0%) |
| Total Padua ≥4 | 125 | 6 (4.8%) | 119 (95.2%) | 1 (0.8%) | 124 (99.2%) |
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There was no statistically significant increased therapy failure risk in the every12-hour group in all patients (P = 1.00; OR = 1.00 [95% CI, 0.14 to7.24), all patients with Padua score (P = 0.22; OR = 0.17 [95% CI,0.01 to 3.65]), patients with Padua scores less than 4 (P = 1.00;OR = 0.33 [95% CI, 0.01 to 8.73]), or patients with Padua scores greater than orequal to 4 (P = 0.46; OR = 0.27 [95% CI, 0.01 to 6.88]) (Table 4).
There was no statistically significant increased risk in bleeding in any patientsreceiving any heparin with a Padua score less than 4 (P = 1.00; OR= 0.55 [0.06 to 4.73]) (Table5).
Table 5.
Fisher’s Exact Test and OR for Bleeding Risk and Therapy Failure.
| Group | All patients bleeding risk (q8 vs q12) | All with Padua score bleeding risk (q8 vsq12) | Padua <4 bleeding risk (q8 vs q12) | Padua ≥4 bleeding risk (q8 vs q12) | All patients therapy failure (q12 vs q8) | All with Padua therapy failure (q12 vs q8) | Padua <4 therapy failure (q12 vs q8) | Padua ≥4 therapy failure (q12 vs q8) | Bleed risk any Padua <4 vs Padua ≥4 |
|---|---|---|---|---|---|---|---|---|---|
| Fischer P-value | 1.00 | 1.00 | 0.48 | 1.00 | 1.00 | 0.22 | 1.00 | 0.46 | 1.00 |
| OR (P-value) | 1.00 (1.00) | 0.84 (0.83) | 0.30 (0.47) | 1.20 (0.82) | 1.00 (1.00) | 0.17 (0.26) | 0.33 (0.51) | 0.27 (0.43) | 0.55 (0.59) |
| OR 95% CI | 0.24 to 4.11 | 0.18 to 3.89 | 0.01 to 7.83 | 0.23 to 6.21 | 0.14 to 7.24 | 0.01 to 3.65 | 0.01 to 8.73 | 0.01 to 6.88 | 0.06 to 4.73 |
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Abbreviations: CI, confidence interval; OR, odds ratio.
*Data considered significant for P-value <0.05.
Discussion
Rates of bleeding events and therapy failures were similar across all groups in thisanalysis with no significant statistical difference in any endpoint found in anypopulation. The limited population size is a weakness of this study, especially whenstratified for Padua scores less than 4 and greater than or equal to 4. A largersample size may have detected a significant difference in at least one of thestudied outcomes and would have allowed the Padua scores to be furtherstratified.
Another limitation is the quality of event documentation. This study was dependent onproper documentation of bleeding events and therapy failures; it is possible thatmore events occurred than what was documented in the patient charts.
Conclusion
In conclusion, this study showed no difference in treatment groups implying thatthere is little benefit to more frequent dosing of prophylactic heparin regardlessof risk for VTE. We also found no evidence of increased bleeding risk whenprophylactic heparin is given to patients with a low risk for VTE.
Stephens and Young’s analysis of heparin for prophylaxis in dialysis patients haveconcluded similar results.6
Our findings conflict with a meta-analysis by King et al7 of prophylactic heparin in the general medical population that found anincrease in therapeutic failures from every 12-hour dosing and an increase inbleeding events in every 8-hour dosing.
Without a larger patient population or confirmed significance in any outcome, wecannot recommend one dosing schedule over the other. Every 12-hour dosing may bepreferred for patient convenience without compromising safety.
The largest limitation of this study was the limited data collected from eachpatient. As the scope of this study was limited to the relationship of heparinprophylaxis outcomes and Padua scores only, other demographic information was notgathered such as age, sex, weight, and renal function. A future exploration of thistopic would certainly benefit from broadening its scope to include more demographicinformation.
Footnotes
Contributed by
Author Contributions: AD contributed to conception and design; contributed to acquisition, analysis,and interpretation; drafted manuscript; critically revised manuscript; gavefinal approval; and agrees to be accountable for all aspects of work ensuringintegrity and accuracy. ES contributed to design; contributed to acquisition,analysis, and interpretation; critically revised manuscript; gave finalapproval; and agrees to be accountable for all aspects of work ensuringintegrity and accuracy.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to theresearch, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/orpublication of this article.
ORCID iD: Adam Dashner 
https://orcid.org/0000-0002-7424-7271
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Articles from The Journal of Pharmacy Technology : JPT : Official Publication of the Association of Pharmacy Technicians are provided here courtesy of SAGE Publications
