Abstract
Background and Objective
Patients with intracerebral hemorrhage (ICH) are at high risk for development of deep venous thrombosis (DVT). Current guidelines state that low dose subcutaneous (SQ) low-molecular weight heparin (LMWH) or unfractionated heparin (UH) may be considered at 3 to 4 days from onset. However, insufficient data exists on hematoma volume (HV) in patients with ICH before and after pharmacological DVT prophylaxis, leaving physicians with uncertainty regarding the safety of this practice.
Methods
We identified patients from our stroke registry (6/03 to 12/07) who presented with ICH only or ICH + intraventricular hemorrhage (IVH) and received either LMWH SQ or UH within 7 days of admission and had a repeat CT scan performed within 4 days of starting DVT prophylaxis. We calculated the change in hematoma volume (Δvol) from the admission and post treatment CTs. HV was calculated using the (ABC/2) method and IVH volumes were calculated using a published method of hand drawn regions of interest (ROI)
Results
We identified 73 patients with a mean age of 63 yo and median NIHSS 11.5. The mean baseline total HV was 25.8ml ± 23.2ml. There was an absolute Δvol from pre and posttreatment CT of −4.3ml ± 11.0ml. Two patients developed hematoma growth. Repeat analysis of patients given pharmacological DVT prophylaxis within 2 or 4 days after ICH found no increase in hematoma size.
Conclusion
Pharmacological DVT prophylaxis given SQ in patients with ICH and/or IVH in the subacute period is generally not associated with hematoma growth.
Keywords: Intracerebral Hemorrhage, Anticoagulants
Introduction
Patients with intracerebral hemorrhage (ICH) or ischemic stroke are at high risk for development of venous thromboembolism (VTE) (1). In comparison to patients with ischemic stroke, the risk for VTE is higher in the hemorrhagic stroke population (2). VTE risk is also enhanced by immobilization and paresis of the lower extremities and late recognition of subclinical thrombotic events. Without preventative measures, 53% and 16% of immobilized patients develop deep venous thrombosis (DVT) or pulmonary embolism (PE), respectively, in this population (3). One study detected DVT in 40% of ICH patients within two weeks and 1.9% of those patients had a PE (4). Development of VTE in the ICH patient adds further detrimental complications to an already lethal disease with a 1 month case fatality rate of 35-52% (5). DVT also prolongs the length of hospital stays, delays rehabilitation programs, and introduces a potential risk for PE (6).
Current AHA/ASA guidelines for acute ischemic stroke recommend the administration of subcutaneous (SQ) anticoagulants such as unfractionated heparin (UH) or low-molecular weight heparin (LMWH) to prevent DVT in immobilized patients (1). On the other hand, AHA/ASA guidelines for hemorrhagic stroke are less clear stating that subcutaneous anticoagulants may be considered at 3 to 4 days from onset, after documentation of cessation of bleeding (5). This tepid recommendation stems from the fact that there is a lack of large randomized controlled trials addressing VTE prevention in the ICH population and even less data are available for patients with intraventricular hemorrhage (IVH). As a consequence, there is no consensus on how and when to start DVT prophylaxis to prevent VTE complications in the ICH and/or IVH population.
Much hesitation arises from the concern that anticoagulants may increase hematoma size and cause neurological worsening (7). There have been 2 small prospective randomized trials published on early heparin use in ICH both showing no increased risk of bleeding (8, 9). One recent published prospective randomized trial compared early use LMWH and compression stockings in ICH patients also found no increase risk of hematoma enlargement in both groups (6). However the number of patients was small in these studies and subsequent CTs were not always routinely performed to document rebleeding. With the lack of data and concerns about hematoma expansion, physicians are left with uncertainty regarding the safety of this practice (10, 11).
This retrospective study aimed to assess the safety of subcutaneous anticoagulants in the ICH and/or IVH population and its association with hematoma growth.
Methods
Study Design and Population
A retrospective search from our prospectively gathered stroke registry from June 2003 to December 2007 identified all patients with the diagnosis of ICH. Patients were excluded who had an ICH etiology of mass lesion, AVM, aneurysm, or undetermined. Hypertensive ICH was diagnosed if patients had history of hypertension with typical hemorrhage location on imaging. Amyloid bleeds were diagnosed using clinical information including history of hypertension, blood pressure on presentation and through-out the hospitalization stay and supportive imaging. Coagulopathy associated bleeds were diagnosed if patients had ICH in the setting of elevated INRs on admission. Patients were categorized as having an undetermined etiology if it was unclear whether the etiology was hypertension, amyloid or both based on the clinical and radiological data.
Patients were included after chart reviews confirmed ICH and/or IVH on admission and received either LMWH SQ or UH SQ within 7 days of admission and had a subsequent CT scan performed within 4 days of starting DVT prophylaxis. Treatment within 7 days of admission was chosen since the guidelines for DVT prophylaxis initiation is unclear and to also capture prescribing trends at our institution. CT scans within 4 days of starting DVT prophylaxis was chosen to allow for variability in post treatment scanning since this is a retrospective analysis. Separate analysis was performed on patients that received either LMWH SQ or UH SQ within 2 and 4 days of admission and by diagnosis (ICH only, ICH +IVH). Chart review was performed on patients that fit the study criteria (figure 1) to gather baseline demographics and clinical information including admission NIHSS and discharge modified Rankin score.
Figure 1.
Study Design and Population
Management
Patients with ICH and/or IVH were treated according to AHA/ASA guidelines (5) and were not treated with Factor VII or received intraventricular tPA; however, blood pressures in the acute post-bleed period were not strictly protocolized. In patients that demonstrated obstructive hydrocephalus, an external ventricular drain was placed. Two forms of SQ anticoagulants (LMWH=enoxaparin 40mg or dalteparin 5000 Units SQ once daily, UH=heparin 5000 units SQ twice to three times a day) were employed at our institution during this period. Medication preference and timing of administration were left up to the discretion of the attending physician. Intermittent compression devices were used on all patients.
Radiological
All CT scans were performed using identical technique (slice thickness 5mm, gantry tilt—16). Admission CT scans was reviewed by the authors to confirm ICH and/or IVH. All hematoma volume calculations were performed by a single author blinded to the treatment and outcome of the study. ICH volume within the parenchyma was calculated using the (ABC/2) method (12). IVH volume was calculated using a published method of hand drawn regions of interest (ROI) around each area of intraventricular blood in every slice, multiplied by the slice thickness and added together to obtain the total IVH volume (13). The sum of the ICH volume and IVH volume was considered the total hematoma volume (HV). The change in hematoma volume (Δvol) defined as the difference between the total HV of the first post treatment CT scan and the total HV of the admission CT scan. Hematoma site was classified into deep (thalamus, putamen, caudate), lobar, and other (primary IVH, cerebellar, brainstem).
Hematoma Growth
We chose absolute hematoma growth as our primary outcome and significant hematoma growth as our secondary outcome. Significant hematoma growth was defined as change in hematoma volume >33% and an absolute change in volume ≥ 5ml. We chose a change in volume of >33% since it corresponds to a 10% increase in diameter in a sphere and it had been used in prior hematoma growth studies (14). An absolute Δvol of 5ml was chosen as the cutoff because the authors felt that a Δvol ≤ 5ml was unlikely to cause clinical deterioration and it also accounts for imprecise hematoma volume calculation using CT.
Statistical Analysis
Using the cutoff of 5ml and the SD of our data (25ml), sample size/power calculations were performed and it showed that with a correlation of 0.85, it would require 61 patients for 80% power in detecting a Δvol of 5ml. Means with standard deviations or medians for continuous variables were used. The differences were assessed using t-tests, chi-square tests, Fisher exact test or Mann-Whitney U test. A significance level of 0.05 was used to assess statistical difference. The statistical analysis was performed using SAS 9.
Results
We identified 73 patients who met study criteria. Baseline clinical and radiological characteristics are shown in table 1. The mean age was 63 and the median NIHSS on admission was 11.5. Fifty patients (69%) received enoxaparin, 20 patients (27%) received unfractionated heparin, and 3 patients (4%) received dalteparin. The time from ICH admission to DVT prophylaxis administration also varied; the majority of DVT prophylaxis was administered between days 2-5 (Figure 2). Overall, there was an absolute Δvol from pre and post-treatment CT of −4.3ml ± 11.0ml (p=0.0015). Analyzing only the ICH portion of the hematoma in all 73 patients showed absolute Δvol of −0.3ml ± 8.8ml (p=0.77). In patients without EVD placement, the absolute Δvol was −1.5ml ± 6.8ml (p=0.69).
Table 1.
Clinical and Radiological Characteristics of Patients receiving Pharmacological DVT Prophylaxis within 7 days of Admission
| Baseline Characteristics | Total Patients (n=73) | Patients without EVD (n=52) |
|
|---|---|---|---|
|
Mean Age in years
(Range) |
63 (37-93) |
63 (37-87) |
|
| Sex (males/females) | 40/33 | 29/23 | |
|
Median Admission NIHSS
(Range) |
11.5 (0-40) |
10 (0-40) |
|
|
Median Discharge mRS
(Range) |
4 (0-6) |
4 (0-6) |
|
| EVD (%) | 21 (29%) | 0 | |
| DVT or PE (%) | 0 | 0 | |
|
| |||
|
Radiological
Characteristics |
Total HV | ICH Only HV | Total HV |
|
| |||
|
Mean Admit Hematoma
Volume in ml (Range) |
25.8 ± 23.2 (0.6-90) |
17.6 ± 19.3 (0- 90) |
19.5 ± 20.3 (0.6-90) |
|
Mean Post-Tx Hematoma
Volume in ml (Range) |
21.6 ± 22.6 (0.5-108) |
17.3 ± 20.4 (0-108) |
18 ± 18.9 (0.7-80) |
|
Mean Δ in Hematoma
Volume in ml (Range) |
−4.3 ± 11.0 (−41.9-23.5) (P=0.0015) |
−0.3 ± 8.8 (−35 – 38) (p=0.77) |
−1.5 ± 6.8 (−35.0 – 19.2) (P=0.69) |
|
| |||
| Location | |||
|
| |||
| Deep (%) | 47 (64%) | 31 (60%) | |
| Lobar (%) | 14 (20%) | 12 (23%) | |
| Other* (%) | 12 (16%) | 9 (17%) | |
|
| |||
| DVT Prophylaxis | |||
|
| |||
| Enoxaparin (%) | 50 (69%) | 37 (71%) | |
| Heparin (%) | 20 (27%) | 12 (23%) | |
| Dalteparin (%) | 3 (4%) | 3 (6%) | |
Other= cerebellar, brainstem, primary IVH
Figure 2.
Distribution of the Start Date for Initiating Pharmacological DVT Prophylaxis
Two patients (2.7%) showed significant hematoma growth within the study period. One patient received LMWH and one received UH, with hypertension as the etiology of the bleed in both patients. No pattern was indentified in regards to clinical and radiological characteristics for these two patients that had significant hematoma growth.
We analyzed separately patients that received DVT prophylaxis within 4 days of admission and results revealed an absolute Δvol from pre and post-treatment CT of −1.3ml ± 8.9ml (P=0.31) (Table 2). For patients that received DVT prophylaxis within 2 days of admission, data showed an absolute Δvol from pre and post-treatment CT of −0.65ml ± 5.2ml (P=0.54) (Table 2).
Table 2.
Clinical and Radiological Characteristics of Patients receiving Pharmacological DVT Prophylaxis within 4 and 2 days of Admission
| Baseline Characteristics | Within 4 Days (n=50) | Within 2 Days (n=24) |
|---|---|---|
| Mean Age in years (Range) | 62.78 (37-93) |
63.91 (40-93) |
| Sex (males/females) | 28/22 | 10/14 |
|
Median Admission NIHSS
(Range) |
9 (0-40) |
8.5 (1-40) |
|
Median Discharge mRS
(Range) |
4.5 (0-6) |
5 (1-6) |
| EVD (%) | 10 (20%) | 3 (12.5%) |
|
| ||
|
Radiological
Characteristics |
Total HV | Total HV |
|
| ||
|
Mean Initial CT Volume in
ml (Range) |
21.6 ± 22.7 (0.60-85.5) |
20.1 ± 18.9 (0.6-75) |
|
Mean Final CT Volume in
ml (Range) |
20.3 ± 24.4 (0.5-109) |
19.5 ± 19.7 (0.7-69) |
|
Mean Δ in CT Volume in
ml (Range) |
−1.3 ± 8.9 (−30.7-23.5) (p=0.31) |
−0.65 ± 5.2 (−18.5 – 12.9) (p=0.54) |
|
| ||
| Location | ||
|
| ||
| Deep (%) | 30 (60%) | 14 (58%) |
| Lobar (%) | 11 (22%) | 8 (33) |
| Other* (%) | 9 (18%) | 2 (8%) |
|
| ||
| DVT Prophylaxis | ||
|
| ||
| Enoxaparin (%) | 37 (74%) | 19 (79%) |
| Heparin (%) | 12 (24%) | 5 (21%) |
| Dalteparin (%) | 1 (2%) | 0 (0%) |
Other= cerebellar, brainstem, primary IVH
Discussion
To our knowledge, this study is the first to report hematoma growth with regards to the use of SQ anticoagulants for DVT prevention in the ICH and IVH population. In the study recently published by Orken et al, they studied the safety of LMWH and compression stocking for DVT prophylaxis and its effects on hematoma enlargement in ICH patients. They found that treatment with LMWH (n=39) and compression stocking (n=36) for DVT/PE prevention was not associated with hematoma enlargement, but did not report the frequency of IVH in their study population nor commented on time to medication administration, only that it was given after 48 hours (6). In comparison, the majority of our patients were started on anticoagulants within 2-5 days of their hemorrhage with 28% (n=20) patients receiving anticoagulants within 48 hrs of admission. In general we found that the administration of pharmacological DVT prophylaxis SQ in the acute (2-4 days) to subacute period (≤7days) was not associated with hematoma growth. Our patients in this study had variable sizes of hematoma from 0.5 cc to 90 cc. In the subacute period, however, two patients did develop significant hematoma expansion but no pattern or factors could be found that were associated with hematoma growth. Hematoma growth was also not observed when the patient population was partitioned by diagnosis (ICH only and ICH + IVH) and by the presence of an EVD. However, the difference in Δvol in the ICH only group was much smaller than the ICH +IVH group confirming that IVH plays a role in hematoma resolution. Of the 36 ICH +IVH patients, 21 of them had an EVD placed and we only identified one patient that developed bleeding around the catheter. Therefore, starting SQ anticoagulants in patients with EVDs may be safe with low rates of complications. Our data, however, does indicate that patients that were treated in the acute period had lower median admission NIHSS scores (9 within day 4, 8.5 within day 2) compared to a median NIHSS of 11.5 for those treated within day 7 of admission. This may indicate that there is a tendency to delay SQ anticoagulation in the sicker ICH patients or possibly those patients with higher admission NIHSS tend to have early rebleeding leading to later SQ anticoagulation administration.
Current guidelines for ICH management recommend intermittent pneumatic compression for prevention of VTE, and its use has been demonstrated to be effective (15). Even though no randomized data exist, the addition of SQ anticoagulants to intermittent pneumatic compression devices should provide added protection against the development VTE. The widespread availability, low cost and proven efficacy of SQ anticoagulants for VTE prevention can potentially reduce VTE complications in the highly vulnerable ICH/IVH population. Our study adds to the existing limited literature and further supports the safety of anticoagulants in the acute and subacute period after ICH.
Our study is limited, however, by its retrospective nature, small sample size and the inherent inaccuracy of measuring hematoma volume on CT scan. With the small sample, we were also unable to assess the efficacy of SQ LMWH or SQ UH in preventing DVT or PE, however, there were no PE or DVT observed in the study population. The observed overall hematoma reduction may be largely contributed by ventriculostomy drainage and/or natural hematoma regression; however, when looking at the ICH portion of all 73 study patients, hematoma growth was not observed. Another major confounder may be blood pressure control, as some have postulated that hematoma growth is associated with the degree of hypertension control in ICH patients (16).
The inclusion criteria of the study may have also affected our data and results. First, we only included patients that received DVT prophylaxis. This selection bias may have excluded patients that had more severe hemorrhages, with the potential for early hematoma growth in which the attending physician may have chosen to withhold anticoagulants. Conversely, by only including patients that had follow up imaging, we may also have neglected a population of stable patients that received SQ anticoagulants and were clinically stable, hence not necessitating follow up CT scans. This may have over-represented patients with hematoma enlargements in this study since those that clinically deteriorate are more likely to have follow-up imaging. Lastly, by choosing to only analyze the hematoma volume of the first post-treatment CT scan, we were limited in our ability to detect delayed hematoma expansion.
In conclusion, data from this study suggest that administration of SQ LMWH or UH in patients with ICH and/or IVH for DVT prophylaxis in the acute to subacute period is generally safe. A prospective safety and efficacy study of SQ anticoagulants in ICH patients is warranted.
Acknowledgments and Funding
This study was funded by NIH Training Grant: 5 T32 NS007412-12, SPOTRIAS Grant: P50 NS 044227, the Howard Hughes Medical Institute, and the American Heart Association 0475008N.
Footnotes
Conflicts of interest Authors have no conflicts of interest to disclose
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References
- 1).Adams HP, Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF. Guidelines for the early management of adults with ischemic stroke: A Guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary. Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:1655–1711. doi: 10.1161/STROKEAHA.107.181486. [DOI] [PubMed] [Google Scholar]
- 2).Skaf E, Stein PD, Beemath A, Sanchez J, Bustamante MA, Olson RE. Venous Thromboembolism in Patients with Ischemic and Hemorrhagic Stroke. The American Journal of Cardiology. 96:1731–1733. doi: 10.1016/j.amjcard.2005.07.097. [DOI] [PubMed] [Google Scholar]
- 3).Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of legs after strokes: Part I – Incidence and predisposing factors. Part II – Natural history. Br Med J. 1976:1178–83. doi: 10.1136/bmj.1.6019.1178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4).Ogata T, Yasaka M, Wakugawa Y, Inoue T, Ibayashi S, Okada Y. Deep Venous Thrombosis After Acute Intracerebral Hemorrhage. Journal of the Neurological Sciences. 2008;272:83–86. doi: 10.1016/j.jns.2008.04.032. [DOI] [PubMed] [Google Scholar]
- 5).Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D, Mayberg M, Morgenstern L, Ogilvy CS, Vespa P, Zuccarello M. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults 2007 Update: A Guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke. 2007;38:2001–2023. doi: 10.1161/STROKEAHA.107.183689. [DOI] [PubMed] [Google Scholar]
- 6).Orken DN, Kenangil G Gulay, Ozkurt H, Guner C, Gundogdu L, Basak M, Forta H. Prevention of Deep Venous Thrombosis and Pulmonary Embolism in Patients with Acute Intracerebral Hemorrhage. The Neurologist. 2009;15:329–331. doi: 10.1097/NRL.0b013e3181a93bac. [DOI] [PubMed] [Google Scholar]
- 7).Kiphuth IC, Staykov D, Kohrmann M, Struffert T, Ricter G, Bardutzky J, Kollmar R, Maurer M, Schellinger PD, Hilz MJ, Doerfler A, Schwab S, Huttner HB. Early Administration of Low Molecular Weight Heparin after Spontaneous Intracerebral Hemorrhage–A Safety Analysis. Cerebrovascular Diseases. 2009;27:146–150. doi: 10.1159/000177923. [DOI] [PubMed] [Google Scholar]
- 8).Boeer A, Voth E, Henze TH, Prange HW. Early Heparin Therapy in Patients with Spontaneous Intracerebral Haemorrhage. Journal of Neurology, Neurosurgery, and Psychiatry. 1991;54:466–467. doi: 10.1136/jnnp.54.5.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9).Dickman U, Voth E, Schicha H, Henze TH, Prange HW, Emrich D. Heparin Therapy, Deep-Vein Thrombosis and Pulmonary Embolism after Intracerebral Hemorrhage. Klinische Wochenschrift. 1988:1182–1183. doi: 10.1007/BF01727666. [DOI] [PubMed] [Google Scholar]
- 10).Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of Spontaneous Intracerebral hemorrhage: incidence and time course. Stroke. 1996;27:1783–1787. doi: 10.1161/01.str.27.10.1783. [DOI] [PubMed] [Google Scholar]
- 11).Lim JK, Hwang HS, Cho BM, Lee HK, Ahn SK, Oh SM, Choi SK. Multivariate analysis of risk factors of hematoma expansion in spontaneous intracerebral hemorrhage. Surg Neurol. 2008;69:40–45. doi: 10.1016/j.surneu.2007.07.025. [DOI] [PubMed] [Google Scholar]
- 12).Huttner HB, Steiner T, Hartmann M, Köhrmann M, Juettler E, Mueller S, Wikner J, Meyding-Lamade U, Schramm P, Schwab S, Schellinger PD. Comparison of ABC/2 Estimation Technique to Computer-assisted Planimetric Analysis in Warfarin-related Intracerebral Parenchymal Hemorrhage. Stroke. 2006;37:404–408. doi: 10.1161/01.STR.0000198806.67472.5c. [DOI] [PubMed] [Google Scholar]
- 13).Zimmerman RD, Maldjian JA, Brun NC, Horvath B, Skolnick BE. Radiologic Estimation of Hematoma Volume in Intracerebral Hemorrhage Trial by CT Scan. AJNR. 2006;27:666–670. [PMC free article] [PubMed] [Google Scholar]
- 14).Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, Spilker J, Duldner J, Khoury J. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997;28:1–5. doi: 10.1161/01.str.28.1.1. [DOI] [PubMed] [Google Scholar]
- 15).Lacut K, Bressollette L, Le Gal G, Etienne E, De Tinteniac A, Renault A, Rouhard F, Besson G, Garcia JF, Mottier D, Oger E. Prevention of Venous Thrombosis in Patients with Acute Intracerebral Hemorrhage. Neurology. 2005;65:865–869. doi: 10.1212/01.wnl.0000176073.80532.a2. [DOI] [PubMed] [Google Scholar]
- 16).Kazui SMK, Sawada T, Yamaguchi T. Predisposing factors to enlargement of spontaneous intracerebral hematoma. Stroke. 1997;28:2370–75. doi: 10.1161/01.str.28.12.2370. [DOI] [PubMed] [Google Scholar]