Article Identification

Article Title: Prothrombin Complex Concentrate Administration Timing in Warfarin-Associated Intracranial Hemorrhage☆

Authors: Brock Townsend, PharmD; Joe Slechta, PharmD; Brian W. Gilbert, PharmD, MBA

Journal: American Journal of Emergency Medicine

Year: 2024

Volume: 76

Type of Study: Retrospective, observational, single-center study

DOI: 10.1016/j.ajem.2023.11.040

Quick Reference Summary

Key Findings: The timing of 4-factor prothrombin complex concentrate (4F-PCC) administration (<45 min, 45–90 min, >90 min) in warfarin-associated intracranial hemorrhage (ICH) was not significantly associated with rates of achieving effective hemostasis (≤20% hematoma expansion) (85.7% vs. 73.3% vs. 90%, p=0.514). Secondary outcomes, including in-hospital mortality and length of stay, showed no significant differences across timing groups.

Statistical Significance: No statistically significant differences were observed in primary and secondary outcomes based on 4F-PCC administration timing.

Core Clinical Question

Primary Research Question: In adult patients with warfarin-associated intracranial hemorrhage, does the timing of 4-factor prothrombin complex concentrate (4F-PCC) administration (<45 min, 45–90 min, >90 min) compared to later administration affect the rate of achieving effective hemostasis (≤20% hematoma expansion)?

Background

Disease Overview:

Warfarin-associated bleeding is prevalent, with nearly 26% of patients experiencing a bleeding event annually.

Intracranial hemorrhage (ICH) is the most devastating bleeding event with high mortality rates (40% at 30 days, 65% at 90 days).

Prior Data on the Topic:

INR >1.4 after four hours is associated with increased hematoma expansion and worse outcomes in ICH patients.

Previous studies, including Cicci et al., have evaluated the timing of 4F-PCC administration but with limited focus on intervals <4 hours.

Current Standard of Care:

Guidelines recommend rapid and urgent reversal of anticoagulation in warfarin-associated ICH but do not specify exact time-to-administration goals.

Administration of 4F-PCC is emphasized as soon as possible for patients with elevated INR.

Knowledge Gaps Addressed by Study:

Lack of specific time-to-administration goals for 4F-PCC in warfarin-associated ICH.

Limited studies evaluating the impact of administration timing within <4-hour intervals on hematoma expansion and outcomes.

Study Rationale:

To determine if the timing of 4F-PCC administration influences hemostasis achievement and clinical outcomes in patients with warfarin-associated ICH.

Methods Summary

Study Design:

Retrospective, observational, single-center study.

Setting and Time Period:

Conducted at a large community teaching hospital from January 2017 to November 2022.

Population Characteristics:

Inclusion Criteria:

• Age ≥ 18 years.
• On warfarin with INR >1.7 on arrival.
• ICH diagnosis per radiologist report with CT scan at study site prior to 4F-PCC administration.
• Repeat CT scan within 48 hours of 4F-PCC administration.
• 4F-PCC dose of approximately 2000 units.
• Receipt of vitamin K ≤ 10 mg.

Exclusion Criteria:

• Death within 24 hours of admission.
• Developed ICH during hospitalization.
• Transferred from an outside facility with no CT performed at the study site prior to 4F-PCC administration.

Intervention Details:

4F-PCC Administration: Stratified into three groups based on time from CT diagnosis to administration: <45 min, 45–90 min, and >90 min.

Control/Comparison Group Details:

Comparison across the three timing groups to assess differences in outcomes.

Primary and Secondary Outcomes:

Primary Outcome:

Achieving effective hemostasis, defined as ≤20% increase in hematoma volume.

Secondary Outcomes:

• In-hospital mortality
• Hospital length of stay (LOS)
• Intensive care unit (ICU) LOS
• In-hospital thrombotic events within 7 days.

Statistical Analysis Approach:

• Chi-squared test for nominal variables.
• Kruskal-Wallis test for continuous non-parametric data.
• Logistic regression with time to 4F-PCC as the independent variable.
• Significance threshold set at p-value <0.05.

Sample Size Calculations:

Not specified.

Ethics and Funding Information:

Ethics: Study was IRB exempt per HealthONE IRB.

Funding: Supported by HCA Healthcare and/or an HCA-affiliated entity. No financial conflicts of interest reported.

Detailed Results

Participant Flow and Demographics:

• Screened Patients: 227
• Included Patients: 39
• Exclusion Reasons: Primarily omission of outpatient warfarin therapy.
• Stratification:
  • <45 minutes: 14 patients
  • 45–90 minutes: 15 patients
  • >90 minutes: 10 patients (p <0.001 for time stratification)

Baseline Characteristics:

• Age: Median ~79-82 years across groups
• Gender: 70-80% male
• Glasgow Coma Scale (GCS) on Arrival: Median 14-15 across groups
• INR on Arrival: Median 3.0-3.8
• Antihypertensive Required: 40-57%
• Neurosurgical Intervention: 7-27%
• Administration of 10 mg IV Vitamin K: 100% in <45 and 45–90 min groups; 100% in >90 min group
• 4F-PCC Dose: Median ~1581-1638 units
• Repeat INR: Median ~1.4-1.45
• Admitting Service: Trauma and Neurocritical Care evenly distributed
• Warfarin Indication: Primarily atrial fibrillation, clotting disorder, mechanical heart valve, other/unknown
• Antiplatelet Regimen: Majority not on antiplatelets

Primary Outcome Results:

Effective Hemostasis Achieved:

• <45 min: 85.7%
• 45–90 min: 73.3%
• >90 min: 90%
• P-value: 0.514 (Not statistically significant)

Secondary Outcome Results:

• In-Hospital Mortality:
  • <45 min: 14%
  • 45–90 min: 33%
  • >90 min: 10%
  • P-value: 0.283 (Not statistically significant)
• Hospital Length of Stay (LOS):
  • <45 min: 10 days
  • 45–90 min: 8 days
  • >90 min: 6 days
  • P-value: 0.101 (Not statistically significant)
• ICU Length of Stay (LOS):
  • <45 min: 4.5 days
  • 45–90 min: 4.5 days
  • >90 min: 2.5 days
  • P-value: 0.255 (Not statistically significant)
• In-Hospital Thrombotic Event within 7 Days:
  • <45 min: 14% (2 patients)
  • 45–90 min: 0%
  • >90 min: 0%
  • P-value: Not applicable

Statistical Significance: No statistically significant differences observed in primary or secondary outcomes based on timing of 4F-PCC administration.

Results Tables

Outcome	<45 min Group (n=14)	45–90 min Group (n=15)	>90 min Group (n=10)	Difference (95% CI)	P-value
Effective Hemostasis Achieved (%)	85.7	73.3	90	-4.3 (−25.6 to 17.0)	0.514
In-Hospital Mortality (%)	14	33	10	+19 (−9 to 47)	0.283
Hospital Length of Stay (days)	10 (4.5–14)	8 (4.5–12.5)	6 (4–7)	−4 (−10 to +2)	0.101
ICU Length of Stay (days)	4.5 (2.5–5)	4.5 (2.3–8.5)	2.5 (2–3)	−2 (−7 to +3)	0.255
In-Hospital Thrombotic Event within 7 Days (%)	14	0	0	—	—

Authors' Conclusions

Primary Conclusions: Timing of 4F-PCC administration (<45 min, 45–90 min, >90 min) in warfarin-associated ICH was not associated with rates of achieving effective hemostasis (≤20% hematoma expansion).

Interpretation of Results: The administration time of 4F-PCC within the studied intervals does not significantly impact hemostasis achievement or secondary clinical outcomes in this patient population.

Clinical Implications Stated by Authors: Current guidelines emphasizing rapid reversal may not require specific time-to-administration targets within the intervals studied (<4 hours) for effective hemostasis in warfarin-associated ICH.

Future Research Recommendations: Further studies with larger sample sizes and multicenter designs are needed to identify optimal timing goals for 4F-PCC administration in managing warfarin-associated ICH.

Literature Review

Comparisons to Other Studies:

• Cicci et al.: Evaluated timing of 4F-PCC administration in warfarin-associated ICH but did not stratify groups in 45-minute intervals.
• Kuramatsu et al.: Demonstrated reduced hematoma expansion if INR was reversed to <1.3 within 4 hours.

Guidelines Comparison:

• AHA/ASA Guidelines: Recommend rapid administration of 4F-PCC for patients with INR ≥1.3 but do not specify exact time-to-administration goals.
• SCCM Guidelines: Recommend urgent reversal with 4F-PCC but lack specific timing targets.

Critical Analysis

A. Strengths:

Methodological Strengths:

• Clear stratification of 4F-PCC administration timing into specific intervals (<45 min, 45–90 min, >90 min).
• Use of radiologist-determined hematoma expansion as a primary outcome.

Internal Validity Considerations:

• Similar baseline characteristics across timing groups enhance comparability.
• Use of logistic regression to control for potential confounders.

External Validity Considerations:

• Conducted in a real-world community teaching hospital setting, enhancing applicability to similar clinical environments.

B. Limitations:

Study Design Limitations:

• Retrospective and observational nature may introduce inherent biases and confounders.

Potential Biases:

• Selection bias due to retrospective data collection.
• Reliance on the accuracy of medical record charting.

Generalizability Issues:

• Single-center study with a small sample size (39 patients) limits broader applicability.

Statistical Limitations:

• Lack of statistical power to detect significant differences due to small sample size.

Missing Data Handling:

• Did not collect data on bleed volume, location, or underlying structural abnormalities, which may influence outcomes.

C. Literature Context:

Previous Studies and Meta-Analyses:

• Cicci CD, Weiss A, Dang C, Stanton M, Feldman R. Impact of timing and dosing of 4-factor prothrombin complex concentrate administration on outcomes in warfarin-associated intracranial hemorrhage. Pharmacotherapy. 2022;42(5):366–74. https://doi.org/10.1002/phar.2680.
• Kuramatsu J, Gerner S, Schellinger P, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA. 2015;313(8):824–36. https://doi.org/10.1001/jama.2015.0846.

Contrasting Methodological Quality:

• Cicci et al. utilized broader time intervals and a composite primary outcome, which may differ in sensitivity compared to the current study’s focused timing and single outcome measure.

Comparisons with Guidelines:

• Current study supports existing AHA/ASA and SCCM guidelines on the urgency of 4F-PCC administration without delineating specific time targets.

This Trial's Contribution:

• Adds evidence that strict timing (<45 min vs. 45–90 min vs. >90 min) within the first few hours may not significantly impact hemostasis in warfarin-associated ICH, contrasting with studies suggesting INR reversal within 4 hours improves outcomes.

Clinical Application

Practice Changes:

The findings suggest that within the first few hours, the exact timing of 4F-PCC administration may be flexible without compromising hemostatic efficacy in warfarin-associated ICH.

Applicable Populations/Scenarios:

Particularly relevant for elderly patients presenting with warfarin-associated ICH where rapid administration within the studied intervals is feasible.

Implementation Considerations:

Focus may be placed on ensuring overall timely reversal rather than adhering to stringent minute-by-minute targets within the first 90 minutes.

Integration with Existing Evidence:

Supports guidelines advocating for urgent reversal of anticoagulation while providing flexibility in administration timing.

How to Use This Info in Practice

Practical Use for Practitioners: Clinicians should prioritize rapid reversal of warfarin in ICH patients but may have flexibility in exact timing within the first few hours without adversely affecting hemostasis outcomes.

Notes for Clarity

• Statistical Significance: All p-values >0.05 were not statistically significant.
• Confidence Intervals: Provided in Results Tables where applicable.
• Conflicts of Interest: Authors reported no financial conflicts of interest.
• Areas of Uncertainty: Optimal timing goals for 4F-PCC administration beyond the first few hours remain unclear.
• Funding Sources: Supported by HCA Healthcare and/or an HCA-affiliated entity.
• Sample Size Consideration: Small sample size may limit the detection of significant differences.
• Generalizability: Findings may not be applicable to all clinical settings due to single-center design.