Evaluating an Optimal Time to Anticoagulant Reversal in Intracerebral Hemorrhage

doi:10.21203/rs.3.rs-3110987/v1

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Evaluating an Optimal Time to Anticoagulant Reversal in Intracerebral Hemorrhage

https://doi.org/10.21203/rs.3.rs-3110987/v1

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Background:

The utilization of long-term oral anticoagulation is steadily expanding due to the growing number of patients diagnosed with thromboembolic diseases, such as atrial fibrillation or venous thromboembolism. Anticoagulation use can exacerbate hematoma expansion and increase intracerebral hemorrhage (ICH) volume resulting in high mortality and severe morbidity. However, unlike the treatment of ischemic stroke, the optimal time to reversal for hemorrhagic stroke is not clearly defined in the guidelines.

Observational studies have evaluated the effect of time to reversal administration and have shown improvement on inpatient mortality and hematoma enlargement. The objective of this study was to evaluate the change in functional outcomes for intracerebral hemorrhage patients who received anticoagulant reversal within 90 minutes of presentation.

Methods:

This retrospective, observational cohort study included anticoagulated adult patients diagnosed with an intracerebral hemorrhage on a computerized tomography scan who received anticoagulant reversal at Northeast Georgia Medical Center between January 1, 2018 – September 30, 2022. Patients were excluded if diagnosed with an aneurysm, another bleed, or administered desmopressin. The primary outcome was to evaluate the change in functional outcomes for ICH patients who received anticoagulant reversal within 90 minutes of presentation. Secondary outcomes included the change in functional outcomes for ICH patients who received anticoagulation reversal within 30 or 60 minutes of presentation, time to international normalized ratio (INR) normalization if on warfarin, and to assess the incidence of thrombotic and rebleed events after reversal.

Results:

Sixty-one patients met inclusion criteria with thirty-six patients receiving reversal within 90 minutes and twenty-five receiving reversal after 90 minutes of arrival. Baseline characteristics were similar between groups. Overall, there was no change in functional outcomes for patients who received anticoagulation reversal within 90 minutes (75% vs. 52%, p=0.07); 60 minutes (71% vs. 63%, p=0.49) or 30 minutes of arrival (100% vs. 64%, p=0.3) compared to after these time points. There was a similar incidence of rebleed (3% vs. 4%) and thrombotic events (6% vs. 0%) between groups.

Conclusion:

Functional outcomes were similar for intracerebral hemorrhage patients who received anticoagulation reversal within 90 minutes compared to those who received it after 90 minutes of Emergency Department arrival.

anticoagulation reversal

intracerebral hemorrhage

critical care

emergency medicine

neurology

Intracerebral hemorrhage (ICH) is the second most common stroke type with high incidence of severe disability or death.¹ Common risk factors for ICH include advanced age, male sex, Asian ethnicity, hyperlipidemia, and hypertension. Additionally, the use of oral anticoagulation increases the risk of ICH 7 to 10-fold.² The incidence of anticoagulation related ICH is increasing as the prevalence for thromboembolic diseases such as atrial fibrillation and venous thromboembolism rises. Treatment of these conditions often includes lifelong anticoagulation. Anticoagulation use can exacerbate hematoma expansion, ICH volume, and intraventricular expansion leading to worse outcomes. Though the use of anticoagulation can increase the risk of morbidity and mortality, rapid reversal of anticoagulation may be helpful to mitigate these outcomes.

The 2022 American Heart Association/American Stroke Association management of intracerebral hemorrhage guidelines recommend “emergent reversal” for patients presenting with ICH.³ However, it is unknown if faster reversal of oral anticoagulation correlates with improved functional outcomes for ICH patients. Observational studies have evaluated the effect of earlier time to reversal administration and have shown improvement in mortality and hematoma enlargement.^4,5 A large observational study evaluated rates of hematoma enlargement in patients with INR values reversed to < 1.3. This study found significant hematoma reduction and lower in-hospital mortality when a reversal agent was given within 240 minutes of arrival.⁴ A more recent study implemented an ICH care bundle which included a goal time to reversal within 90 minutes of presentation. Anticoagulation reversal within this time frame was associated with a significantly lower 30 – day mortality than patients who did not receive the ICH care bundle.⁵ Overall the need for emergent reversal is acknowledged to minimize hematoma enlargement; however, defining the “optimal” time window remains unclear. The purpose of our study was to evaluate an optimal time to anticoagulant reversal, ideally within 90 minutes from presentation, and the associated change in functional outcomes.

Study Design

This retrospective observational cohort study utilized the electronic health record of patients at a comprehensive stroke and level I trauma community teaching hospital in Georgia from January 1, 2018, through September 30, 2022. Patient lists were created from an established internal stroke database generated by the Neurology and Trauma departments. Eligible patients included those who were diagnosed with a spontaneous or traumatic intracerebral hemorrhage while on prior anticoagulation and administered a reversal agent within the hospital system. Spontaneous hemorrhages were defined through ICD- 10 I61.xx and traumatic were further defined through ICD 10 sequela codes S06340A- S06369A. Patients who were diagnosed with a subarachnoid, subdural hemorrhage, or aneurysm and administration of desmopressin were excluded. Vulnerable subjects were also excluded from the study. The study design was approved by the Western Institutional Review Board – Copernicus Group (WCG-IRB) and waived the requirement for informed consent.

Data Collection

Baseline data collection included patient demographics, prior comorbidities including atrial fibrillation, hypertension, hyperlipidemia, diabetes mellitus, congestive heart failure, prior intracerebral hemorrhage, prior transient ischemic attack or stroke, use of home anticoagulation or antiplatelet agents, indication for oral anticoagulation, baseline serum creatinine, baseline INR, and arrival systolic blood pressure. To evaluate potential barriers to expedited anticoagulation reversal the following time windows were collected for further assessment: admission to imaging, admission to anticoagulation reversal, admission to blood pressure ≤ 160 mmHg, and imaging interpretation to anticoagulation reversal administration. To further assess the appropriate use of anticoagulation reversal we recorded administration of reversal agent and dose as well as the date and time of administration as documented on the medication administration record. If more than one reversal agent was administered, then the first agent given was utilized for reversal time. For warfarin patients, the first INR after reversal and the time to INR < 1.3 was also collected. For the association with elevated blood sugar and blood pressure with hematoma enlargement, we documented if blood glucose ≥ 180 mg/dL within the first 24 hours of admission and time to systolic blood pressure ≤ 160 mmHg. Neurological status was assessed through National Institutes of Health Stroke Scale (NIHSS), Intracerebral Hemorrhage (ICH) score, and Modified Rankin Score (mRS). The intracerebral hemorrhage score was identified through progress notes or calculated by the research team. Functional outcomes were assessed upon presentation and at discharge using mRS. A mRS 0–2 represented favorable outcomes and 3–6 represented non favorable outcomes. We define in hospital mortality as not being discharged alive from the hospital stay.

Outcomes

The primary outcome of the study was a change in functional outcomes for ICH patients who received anticoagulation reversal within 90 minutes of presentation. Secondary outcomes included the change in functional outcomes for ICH patients who received anticoagulation reversal within 60 or 30 minutes of presentation, incidence of thrombotic events after anticoagulation reversal during hospitalization, rebleed rates during hospitalization, and time to INR normalization. A subgroup analysis comparing patients with an ICH score < 3 or ICH score ≥ 3 was completed to determine if the severity of ICH at presentation impacted functional outcomes when the patient received reversal within 90 minutes.

Statistical Analysis

The primary outcomes were analyzed using the Man Whitney test. Discrete data were analyzed using the Chi- Squared test or Fischer’s exact respectively. P values of less than 0.05 were considered significant. Discrete variables are reported as a value and the percent of the total; continuous variables are reported as a median and interquartile range.

From January 1, 2018 – September 30, 2023, 623 patients were identified with an intracerebral hemorrhage from the Trauma and Neurology stroke data set. Five hundred and sixty-two patients were excluded; therefore 61 patients were included in the study (Fig. 1).

Baseline characteristics were similar between treatment groups (Table 1), except for a significant difference with blood glucose ≥ 180 mg/dL in 24 hours (50% vs. 4%, p = 0.0001). Past medical history was similar between groups with hypertension, atrial fibrillation, and hyperlipidemia being the most prevalent. At baseline, patients with reversal greater than 90 minutes had more favorable mRS of 0,1,2, a lower NIHSS, and a lower ICH score. All 36 patients administered reversal within 90 minutes were diagnosed with a spontaneous ICH. Eighty-two percent of patients required anticoagulation for atrial fibrillation. While not significantly different, anticoagulation agents varied between groups with a higher utilization of warfarin in the group receiving a reversal agent within 90 minutes (42% vs 32%, p = 0.44) and higher utilization of apixaban in the group receiving a reversal agent after 90 minutes (36% vs 56%, p = 0.12). Of those on warfarin, more patients were supratherapeutic when reversal was given after 90 minutes, although it should be noted, this group had less patients on warfarin altogether (14% vs 24%, p = 0.31). Concurrent antiplatelet therapy was similar between groups (33 vs 32%, p = 0.74).

Table 1

Baseline Characteristics by Treatment Group
	≤ 90 minutes (n = 36)	> 90 minutes (n = 25)
Age (years)	79 (18)	78 (16)
Sex (male)	21 (58%)	11 (44%)
Race White Black/African American Asian	34 (94%) 1 (3%) 1 (3%)	22 (88%) 1 (4%) 2 (8%)
Ethnicity (Non-Hispanic)	35 (97%)	24 (96%)
Weight (kg)	75 (26)	72 (23)
Past Medical History Hypertension Atrial Fibrillation Hyperlipidemia Congestive Heart Failure Diabetes Mellitus Prior Ischemic Stroke Prior Intracerebral Hemorrhage	30 (83%) 29 (81%) 19 (53%) 14 (39%) 14 (39%) 9 (25%) 2 (6%)	22 (88%) 21 (84%) 12 (48%) 6 (24%) 5 (20%) 7 (28%) 3 (12%)
Serum Creatinine, mg/dL	1.05 (0.5)	1 (0.3)
Systolic blood pressure, mmHg	173 (49)	160 (28)
Glucose ≥ 180 mg/dL*	18 (50%)	1 (4%)
Modified Rankin Score 0,1,2	22 (61%)	20 (80%)
Intracerebral Hemorrhage Score National Institute of Health Stroke Scale^¥	2 (2) 17 (20)	1 (1) 4 (9)
Type of Hemorrhage Traumatic Spontaneous	0 36 (100%)	5 (20%) 20 (80%)
Anticoagulation Indication Atrial Fibrillation Deep vein thrombosis/Pulmonary Embolism Other	28 (78%) 5 (14%) 8 (22%)	21 (84%) 3 (12%) 5 (20%)
Anticoagulation Prior to Admission Warfarin Apixaban Rivaroxaban Dabigatran	15 (42%) 13 (36%) 8 (22%) 0	8 (32%) 14 (56%) 3 (12%) 0
INR^◊ Subtherapeutic Therapeutic Supratherapeutic	2 (6%) 8 (22%) 5 (14%)	1 (4%) 1 (4%) 6 (24%)
Concurrent Antiplatelet Use	12 (33%)	8 (32%)
Values listed as median (IQR) or value (percentage)
*Indicates statistically significant difference
^¥not all NIHSS were documented, N-9 for ≤ 90 minutes and N-11 for > 90 minutes
^◊Number may not equal 100% due to a subset of the sample on warfarin therapy

Table 2

Secondary Outcomes and Subgroup Analysis
Secondary Outcomes	≤ 90 minutes (n = 36)	> 90 minutes (n = 25)
Incidence of thrombotic event	2 (6%)	0
Incidence of rebleed	1 (3%)	1 (4%)
Time to INR normalization if on warfarin, hours*	(n = 15) 3.1 (6.5)	(n = 8) 11.5 (19.2)
Subgroup Analysis
Incidence of devastating bleed	12 (33%)	6 (24%)
Values listed as median (IQR) or value (percentage)
*Time to INR < 1.3, ≤ 90 minutes group 4 did not have INR values; >90 minutes group 1 did not have INR value

There was no significant difference in change in mRS between groups who received anticoagulation reversal within 90 minutes of presentation vs after 90 minutes of presentation (75% vs. 52%, p = 0.07). Of the mRS change observed, no patients moved from an unfavorable mRS to a favorable mRS; therefore, all changes documented were to a higher, non-favorable mRS (Fig. 2). Similar results were seen with our secondary outcomes evaluating reversal given within 60 minutes (71% vs. 63%, p = 0.49) or 30 minutes of arrival (100% vs. 64%, p = 0.3) compared to after these time points (Figs. 3 and 4). Similar incidence of rebleed (3% vs. 4%) and thrombotic events (6% vs. 0%) occurred. As expected, patients on warfarin that received faster anticoagulation reversal had a faster time to INR normalization (3 hours vs 11.5 hours).

The most frequent anticoagulant reversal agent given was 4 Factor-Prothrombin Complex Concentrate (61% vs 72%). Approximately 91% of patients given reversal within 90-minutes received appropriate reversal according to the established hospital protocol. The 9% who received inappropriate reversal were all patients on warfarin where only Vitamin K was given instead of combination 4 Factor-Prothrombin Complex Concentrate and Vitamin K. Incidence of hematoma expansion was higher in the group who received reversal within 90 minutes (25% vs 4%).

As our primary outcome was time dependent, different time windows were evaluated to determine where delays to anticoagulation reversal may occur (Table 3). Most notably, the median time for admission to anticoagulation reversal was 58 minutes vs 195 minutes for patients receiving reversal within 90 minutes vs after 90 minutes. The change in stroke accreditation likely increased provider awareness of the signs and symptoms of ICH and having neurology at bedside in the emergency room likely strengthened the following time intervals admission to CT, to interpretation, and door to reversal time.

Table 3

Time Windows by Treatment Group
	≤ 90 minutes (n = 36)	> 90 minutes (n = 25)
Time windows, minutes (IQR) Admission to imaging Admission to anticoagulation reversal Admission to blood pressure ≤ 160 mmHg Imaging interpretation to anticoagulation reversal	12 (-30) 58 (22) 49 (46) 24 (21)	62 (56) 195 (119) 37 (115) 80 (109)

Table 4

Additional Outcomes
	≤ 90 minutes (n = 36)	> 90 minutes (n = 25)
Mode of anticoagulation reversal, n (%) 4F-PCC 4F-PCC + Vitamin K Vitamin K only	22 (61%) 12 (33%) 2 (6%)	18 (72%) 6 (24%) 1 (4%)
Appropriate anticoagulation reversal administered, n (%)	32 (91%)	22 (88%)
Multiple doses of 4F-PCC	0	1 (4%)
Hematoma expansion noted, n (%)	9 (25%)	1 (4%)
Level of care of reversal administration Emergency Department Intensive Care Unit Operating Room	35 (97%) 0 1 (3%)	24 (96%) 1(4%) 0
In hospital mortality, n (%)	16 (46%)	8 (32%)
Hospital length of stay, days (IQR)	5 (7)	4 (8)
4F-PCC: Four Factor Prothrombin Complex Concentrate

In our study, no significant differences were found regarding a change of functional outcomes for patients who received earlier anticoagulant reversal. However, a high percentage of patients received appropriate anticoagulant reversal within an hour from admission. This demonstrates establishing a goal to reverse anticoagulation in ICH patients within 90 minutes of presentation is realistic and feasible. The medical team’s ability to appropriately diagnose, obtain diagnostic imaging, and treat within a 90-minute time frame provides evidence that with the appropriate recognition, hemorrhagic stroke care can be conducted in a timely manner. Regarding the safety of patients, the incidence of thrombotic events and rebleed events were low between groups. This low incidence of adverse events supports our position to give anticoagulation reversal quickly after ICH is identified.

While our study did not find functional outcome differences, Parry-Jones et al. found that implementation of a care bundle with a door to reversal time of less than 90 minutes, rapid blood pressure lowering, and strict adherence to neurosurgical referral was significantly associated with lower 30-day case fatality.⁵ In addition to rapid anticoagulation reversal, their trial focused on intensive blood pressure lowering within 6 hours of admission to a SBP of 130–140 mmHg. The effect of a rapid blood pressure lowering, and maintenance has been shown to reduce disability and improve quality of life.⁶ Overall the authors comprehensive management approach may have led to improved outcomes as compared to our focus on expedited anticoagulation reversal alone in this patient population.

For reduction of hematoma expansion, the guidelines recommend achieving an INR of < 1.3 for warfarin patients and expedited reversal for direct oral anticoagulants. Hematoma expansion in ICH patients is typically seen within the first 4 to 24 hours after symptom onset.¹ Concurrent anticoagulant use places the patient at a higher risk of rebleed events and can increase mortality or lead to worse functional outcomes.⁷ These risks emphasize the need to obtain imaging and administer anticoagulant reversal quickly to help reduce further hematoma expansion.⁸ In our study, hematoma expansion was noted at a higher rate in the less than 90 minutes group. of One might consider that the CT assessment patients before 90 minutes showed an expansion on repeat CT, because compared to patients who received reversal after 90 minutes the initial CT scan could have bypassed the original bleed, therefore only capturing the completed expansion.This finding differs from a previous study by Kuramatsu et al, where hematoma expansion was reduced when warfarin reversal was given within 4 hours.⁴ Of note, the time frame for reversal agent administration does differ between the two studies with our study targeting a stricter goal of reversal within 90 minutes vs 4 hours for Kuramatsu. Fitting the time with the prior study to our data, a majority (86%) of our patients received anticoagulation reversal within 4 hours. All hematoma expansions are noted when reversal was given within the 4-hour time frame. Thirty-six percent of patients were on warfarin and sixteen percent had a documented hematoma expansion CT scan. These results emphasize that earlier time to anticoagulation reversal may capture an early expansion on CT scan but can allow for the benefits of earlier anticoagulation reversal.

There were several limitations to this study, the first being the retrospective study design. Additionally, the hospital underwent changes in stroke accreditation within the study timeline. The varying stroke accreditation over time could have altered recorded stroke documentation. The small sample size limits the ability to see true differences between groups. Patients who received reversal within 90 minutes had non-significant but elevated baseline NIHSS, ICH, and mRS scores representing higher dysfunction at presentation than the comparator group. This might have affected our outcomes due to a higher baseline debility. Lastly, due to absence of documentation we were unable to assign a trauma severity prognosis (Injury Severity Score) score to our traumatic ICH population. This score would have provided insight into the severity of traumatic injury to the patient and help identify if trauma sequala contributed to a change in functional outcome.

In our study, functional outcome change was similar between groups who received anticoagulant reversal within or after 90 minutes of presentation to the Emergency Department. Incidence of thrombotic events and rebleed rates were similar between groups and clinically no harm was noted in patients who received expedited anticoagulation reversal. Additionally, this study demonstrated anticoagulant reversal within 90 minutes of presentation is a feasible goal for ICH management. Therefore, faster anticoagulation reversal should be considered for patients who present with anticoagulant associated ICH. Overall, more research is needed to identify the relationship between faster anticoagulation reversal and improved functional outcomes in this patient population.

This manuscript complies with all instructions to authors.
Authorship requirements have been met and final manuscript is approved by all authors.
Authors contributions are as follows:
1. Study conception: E. Harman, L. Roebuck
2. Study design: H. Peters, E. Harman, L. Roebuck
3. Data collection: H. Peters
4. Analysis and interpretation of results: H. Peters, E. Harman
5. Draft manuscript preparation: H. Peters
6. Revised manuscript for critically important content: E. Harman, L. Roebuck
This manuscript has not been published elsewhere and is not under consideration by another journal.
The authors confirm the use of a reporting checklist.
IRB approval: The study design was approved by the Western Institutional Review Board – Copernicus Group (WCG-IRB) and waived the requirement for informed consent.
Conflict of interest: The authors declare that they have no conflicts of interest.

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Evaluating an Optimal Time to Anticoagulant Reversal in Intracerebral Hemorrhage

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Abstract

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Introduction

Methods

Study Design

Data Collection

Outcomes

Statistical Analysis

Results

Discussion

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