Safety of Prophylactic Heparin in the Prevention of Venous Thromboembolism After Spontaneous Intracerebral Hemorrhage: A Meta-analysis

Abstract

Objectives Patients with spontaneous intracerebral hemorrhage (sICH) have a nearly fourfold greater risk for venous thromboembolism (VTE) than those with acute ischemic stroke, and VTE after sICH is associated with high risk for in-hospital mortality. The benefit from prophylactic heparin for VTE remains uncertain because its safety is not documented. In this study, we used an updated meta-analysis to evaluate the safety of heparin for the prevention of VTE in patients with sICH.

Methods Electronic databases Medline and Embase from January 1990 to November 2017 and the Cochrane Library were searched using these keywords: intracerebral hemorrhage, stroke, hemorrhagic stroke, subarachnoid hemorrhage, heparin, heparinoids, low-molecular-weight heparin, anticoagulants, prophylactic, low dose, prevention, deep venous thrombosis, pulmonary embolism, venous thrombosis, randomized controlled trial, controlled clinical trial, and outcome. We evaluated the quality of included studies according to the bias risk in the Cochrane Handbook for Systematic Reviews of Interventions v.5.1.0. All statistical analyses were performed with RevMan v.5 software (Cochrane Collaboration, London, United Kingdom). Tests of heterogeneity were conducted with the Mantel-Haenszel method.

Results Nine studies involving 4,055 patients with sICH met the inclusion criteria in this meta-analysis. Of these studies, only one met all specific criteria and had a low probability of bias, whereas eight studies met only some of the criteria and had a moderate probability of bias. In comparison with non-heparin treatments, low-molecular-weight heparin or unfractionated heparin was associated with a nonsignificant increase in any hematoma enlargement, a nonsignificant reduction in extracranial hemorrhage, a nonsignificant increase in mortality, a nonsignificant increase in the number of modified Rankin Scale scores of 3 to 5, and a nonsignificant increase in numbers of Glasgow Outcome Scale scores of 2 to 3.

Conclusion Prophylactic heparin was associated with a nonsignificant increase in any hematoma enlargement and mortality, a nonsignificant reduction in extracranial hemorrhage, and a nonsignificant increase in the incidence of major disability in patients with sICH. It is probably safe to administer heparin to prevent VTE in patients with sICH.

Keywords

heparin - prophylactic - intracerebral hemorrhage - venous thromboembolism

Introduction

It was reported that as high as 40% of patients with ischemic stroke are at particularly high risk for venous thromboembolism (VTE) because of restricted mobility.[1] Acute spontaneous intracerebral hemorrhage (sICH) is an independent risk factor for VTE, and patients with sICH have a nearly fourfold greater risk for VTE than those with acute ischemic stroke.[2] VTE is associated with increased rates of mortality and morbidity. Prevention of VTE is better than treatment of it. Up to 75% of patients with stroke and resulting hemiplegia develop deep venous thrombosis (DVT) if they are not placed on prophylactic medication because weakness of the lower limb leads to alterations in blood flow and a hypercoagulable state. Most deaths from VTE are attributable to preventable negligence, rather than to failure of treatment. Reasonable precautions can reduce the risk of DVT formation by 63%.[3] [4]

Prophylaxis for VTE in patients with sICH includes nonpharmacologic and pharmacologic approaches. Common nonpharmacologic prophylactic measures include intermittent pneumatic compression (IPC) and elastic compression stockings (ECS). However, these nonpharmacologic prophylactic measures have certain limitations in clinical practice; for example, they cannot be used in cases of limb deformity, fractured limbs, or heart failure. Multiple organizations in the United States (since 2007), Europe (since 2006), and Japan (since 2011) have recommended that prophylactic doses of heparin be considered for DVT prevention. Prophylactic heparin is not recommended in the United Kingdom or Australia,[5] however, because of findings that the use of heparin will cause an enlargement of hematomas and may even increase rates of mortality.

A meta-analysis of four controlled studies suggested a significant reduction in pulmonary embolism (PE) with heparin.[6] In a trial that involved 68 patients with sICH, heparin initiation on day 2 resulted in a statistically lower rate of PE than did initiation on day 4 or day 10.[7] However, the safety of early initiation of prophylactic heparin in the prevention of VTE in patients with sICH is uncertain. Results of a randomized study in 1991 suggested that early use of heparin in ICH patients prevented DVT without increased intracranial hemorrhage.[7] A more recent trial involving 103 patients demonstrated that subcutaneous enoxaparin does not increase the risk of rebleeding or hematoma expansion.[8] In contrast, Orken et al,[9] Wasay et al,[10] and Tetri et al[11] found that hematoma enlargements occurred more often in the patients who received heparin, although the difference was not statistically significant. The European Stroke Organization (2014)[12] and the American Heart Association (2015)[13] stated that the safety of prophylactic doses of heparin for DVT prevention remains uncertain.

To clarify the safety of prophylactic heparin in the prevention of VTE in patients with sICH, we performed an updated meta-analysis of studies (randomized or not) in which low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) was compared with non-heparin treatments. Study outcomes included any hematoma enlargement, major extracranial hemorrhage, and major disability as defined by modified Rankin Scale (mRS) scores of 3 to 5 or Glasgow Outcome Scale (GOS) scores of 2 to 3 and death.

Methods

We prospectively developed a protocol in which specific objectives, selection criteria, assessment of study quality, clinical outcomes, and statistical methods were compared in detail.

Study Identification

All relevant comparisons of LMWH or UFH with non-heparin treatments for prevention of VTE in patients with sICH that were published from January 1990 to November 2017 were identified from electronic databases (Medline and Embase), as well as from the Cochrane Library. Keywords were intracerebral hemorrhage, stroke, hemorrhagic stroke, subarachnoid hemorrhage, heparin, heparinoids, low-molecular-weight heparin, prophylactic, low dose, anticoagulants, prevention, deep venous thrombosis, pulmonary embolism, venous thrombosis, randomized controlled trial, controlled clinical trial, and outcome. The relevance of studies to the prevention of VTE after sICH was determined on the basis of title, abstract, and full manuscript. If any of these data were not available in a particular publication, further information was sought through correspondence with the authors of the reference.

Study Selection

Inclusion criteria were as follows: (1) patient: patients with spontaneous intracerebral hemorrhage; (2) intervention: LMWH or UFH treatment, or LMWH or UFH treatment plus non-heparin therapy (IPC, ECS, or placebo); (3) comparison: non-heparin treatment (IPC, ECS, or placebo); (4) outcome: any hematoma enlargement, major extracranial hemorrhage, and major disability as defined by mRS scores of 3 to 5 or GOS scores of 2 to 3 and death; and (5) prophylactic doses of LMWH (≤ 40 mg/day) or UFH (5,000 IU/8 hours or less). Exclusion criteria were ICH caused by surgery or traumatic brain injury, noncontrolled studies, animal experiments, case studies, reviews, and appraised topics.

Study Quality

The quality of studies was evaluated according to the bias risk described in the Cochrane Handbook for Systematic Reviews of Interventions, v.5.1.0.[14] The evaluation parameters included random sequence (selection bias), degree of hidden (performance) bias, use of blind methods for implementers and participants (detection bias), use of blind methods for outcome evaluator (loss to follow-up bias), incomplete data report (attrition bias), selective reporting data (reporting bias), and other bias (other bias). If a study referred to all these criteria and indicated low risk of bias, its quality was considered “A”; if a study met part of the criteria and the probability of bias was moderate, its quality was considered “B.” If a study did not meet the any of the criteria, indicating the possibility of a high risk of bias, its quality was considered “C.”

Data Extraction

Two investigators independently extracted data on study design, study quality, and the following safety outcomes within 3 months: (1) population (inclusion and exclusion criteria, sample size); (2) intervention (LMWH or UFH, treatment initiation, duration of treatment, dose of heparin, comparator); and (3) study outcomes (any hematoma enlargement, major extracranial hemorrhage, death, and major disability according to mRS scores of 3–5 or GOS scores of 2–3). The data abstracted for each trial were confirmed by a third investigator, and any disagreements were resolved by consensus.

Statistical Analysis

All statistical analyses were performed with RevMan v.5 software (Cochrane Collaboration, London, United Kingdom). Tests of heterogeneity were conducted with the Mantel-Haenszel method. A p value ≤ 0.05 was considered statistically significant except in heterogeneity testing, for which a p value of 0.10 was accepted as statistically significant. If p > 0.10 and the proportion of variation across studies that was due to heterogeneity (I²) was < 50%, a fixed-effects model was used. If p > 0.10 and I² ≥ 50%, a random-effects model based on the Mantel-Haenszel method was used to combine results from individual studies. If p > 0.10 and the source of the heterogeneity could not be judged, the descriptive analysis was used. In addition, the risk ratios (RRs) and 95% confidence intervals (CIs) were calculated.

Results

Study Selection

[Fig. 1] illustrates the process of study selection. From a database search of citations, 1,443 records were identified, and 9 additional records were identified through other sources. Of these records, 684 were retained for further evaluation after duplicates were removed. After screening of titles and abstracts, 668 citations were excluded, and 17 citations were retained for further evaluation. Eight additional studies were excluded for these reasons: One study was a critically appraised topic[15]; a control group was not included in three studies[16] [17] [18]; one study was not a controlled study of heparin and other measures[19]; IPC, ECS, and placebo were not used in the control group in one study[20]; and ICH was caused by traumatic brain injury in two studies.[21] [22] [Table 1] summarizes the designs of the nine studies[7] [8] [9] [10] [11] [23] [24] [25] [26] included in this meta-analysis.

Table 1 Characteristics of studies included in the meta-analysis

Study	Treatment	Treatment initiation	Duration of treatment	Dose	Control	Follow-up	Outcomes
Paula[23]	UFH or LMWH	7 d	NR	Prophylactic	Placebo	90 d	mRS; death
Yu[8]	LMWH	1 d	14 d	4,000 IU/d	Placebo	14 ds	Hematoma enlargement; death
Gu et al[24]	LMWH and IPC	4 d	10 d	0.4 mL/d	IPC	14 d	Hematoma enlargement; extracranial hemorrhage; death
Orken et al[9]	LMWH and CS	48 h	NR	40 mg/d	CS	21 d	Hematoma enlargement; death
Wasay et al[10]	UFH and CS	Day 1–6	7–14 d	2,500–5,000 IU/12 h	CS	NR	Hematoma enlargement; extracranial hemorrhage; death
Tetri et al[11]	LMWH	24 h	NR	20–40 mg/d	Placebo	3 mo	Hematoma enlargement; GOS; death
Wurm et al[25]	LMWH	Day 3	3 wk	20 mg/d	Placebo	1 y	Extracranial hemorrhage; death
Siironen et al[26]	LMWH	24 h	10 d	40 mg/d	Placebo	3 mo	mRS; GOS; extracranial hemorrhage; death
Boeer et al[7]	UFH and CS	96 h	10 d	5,000 IU/8 h	CS	10 d	Hematoma enlargement; death

Abbreviations: CS, compression stockings; GOS, Glasgow Outcome Scale; IPC, intermittent pneumatic compression; LMWH, low-molecular-weight heparin; mRS, modified Rankin Scale; NR, not reported; UFH, unfractionated heparin.

Fig. 1 Process of study selection. ECS, elastic compression stockings; IPC, intermittent pneumatic compression.

Study Quality

[Table 2] summarizes the quality data of the nine studies. Of these studies, only one study was of “A” quality; the other eight studies were of “B” quality. Most studies were deficient in the blind method, and their data reports were incomplete. Although loss to follow-up was reported, an intent-to-treat analysis was not conducted, and the reasons for the loss to follow-up were not explained.

Table 2 Quality of studies included in the meta-analysis

	Selection bias	Performance bias	Detection bias	Attrition bias	Reporting bias	Other reporting bias	Other bias	Level
Paula (2016)	NR	NR	NR	NR	Low bias	Low bias	NR	B
Yu (2015)	NR	NR	NR	NR	Low bias	Low bias	NR	B
Gu et al[24]	NR	NR	NR	NR	Low bias	Low bias	NR	B
Orken et al[9]	NR	NR	Low bias	Low bias	Low bias	Low bias	NR	B
Wasay et al[10]	NR	NR	NR	NR	Low bias	Low bias	NR	B
Tetri et al[11]	NR	NR	Low bias	Low bias	Low bias	Low bias	NR	B
Wurm et al[25]	Low bias	Low bias	Low bias	Low bias	Low bias	Low bias	NR	A
Siironen et al[26]	NR	Low bias	Low bias	NR	Low bias	Low bias	NR	B
Boeer et al[7]	NR	NR	NR	NR	Low bias	Low bias	NR	B

Abbreviation: NR, not reported.

Study Outcomes

Incidence of Intracranial Hemorrhage

Six trials that involved 1,082 patients yielded data on ICH ([Fig. 2]). There was no statistically significant heterogeneity among the studies (I² = 8%; p = 0.36). In comparison with non-heparin treatments, heparin treatment was associated with a nonsignificant increase in any hematoma enlargement (6.6% versus 3.2%; RR: 1.48; 95% CI, 0.88–2.50; p = 0.14).

Fig. 2 Any hematoma enlargement in studies comparing low-molecular-weight heparin or unfractionated heparin with non-heparin treatments (elastic compression stockings, intermittent pneumatic compression, or placebo) for the prevention of venous thromboembolism.

Incidence of Major Extracranial Hemorrhage

Three trials involving 618 patients yielded data on extracranial hemorrhage ([Fig. 3]). There was no statistically significant heterogeneity among the studies (I² = 32%; p = 0.22). In comparison with non-heparin treatments, heparin treatment was associated with a nonsignificant reduction in extracranial hemorrhage (1.8% versus 2.8%; RR: 0.71; 95% CI, 0.25–2.05; p = 0.53).

Fig. 3 Any extracranial hemorrhage in studies comparing low-molecular-weight heparin or unfractionated heparin with non-heparin treatments (elastic compression stockings, intermitted pneumatic compression, or placebo) for the prevention of venous thromboembolism. CI, confidence interval; M-H, Mantel-Haenszel.

Incidence of Death

Seven trials involving 3,848 patients yielded data on mortality ([Fig. 4]). There was no statistically significant heterogeneity among the studies (I² = 1%; p = 0.42). In comparison with non-heparin treatments, heparin treatment was associated with a nonsignificant increase in mortality (12.0% versus 11.8%; RR: 0.90; 95% CI, 0.74–1.09; p = 0.29).

Fig. 4 Death due to any cause in studies comparing low-molecular-weight heparin or unfractionated heparin with non-heparin treatments (elastic compression stockings, intermitted pneumatic compression, or placebo) for the prevention of venous thromboembolism.

Incidence of Major Disability

Modified Rankin Scale Scores

Two trials involving 2,695 patients yielded data on mRS scores ([Fig. 5]). There was statistically significant heterogeneity between the studies (I² = 83%; p = 0.01). The random-effects model was used for analysis. In comparison with nonpharmacologic treatments, heparin treatment was associated with a nonsignificant increase in the numbers of mRS scores of 3 to 5 (58.3% versus 42.8%; RR: 1.55; 95% CI, 0.57–4.20; p = 0.39).

Fig. 5 Major disability at 90 days, according to scores 3 to 5 on the modified Rankin Scale comparing low-molecular-weight heparin or unfractionated heparin with non-heparin treatments (elastic compression stockings, intermitted pneumatic compression, or placebo) for the prevention of venous thromboembolism.

Glasgow Outcome Scale Scores

Three trials involving 694 patients yielded data on GOS scores. However, descriptive analysis was used because the observation time point in one study[25] was different from those in the other studies, and the data in that study could not be combined with the data in other studies for analysis. In Wurm's study,[25] patients received one subcutaneous injection per day of either 20 mg enoxaparin or placebo for 3 weeks after ICH. Patients treated with enoxaparin had significantly more favorable GOS scores than patients treated with placebo at 1-year follow-up. Moreover, the other two articles were meta-analyzed. There was statistically significant heterogeneity between the studies (I² = 80%; p = 0.03) ([Fig. 6]). The random-effects model was used for analysis. In comparison with other treatments, heparin treatment was associated with a nonsignificant increase in the numbers of GOS scores of 2 to 3 (31.9% versus 16.9%; RR: 1.95; 95% CI, 0.74–5.11; p = 0.18).

Fig. 6 Major disability at 90 days, according to scores 2 to 3 on the Glasgow Outcome Scale comparing low-molecular-weight heparin or unfractionated heparin with non-heparin treatments (elastic compression stockings, intermitted pneumatic compression, or placebo) for the prevention of venous thromboembolism.

Discussion

The safety of heparin treatment to prevent VTE in patients with sICH is always controversial largely because of concerns about bleeding, particularly the extension of the ICH and deterioration of neurologic function that would offset any potential benefits of the treatment.[17] The main conclusion of our analysis across different studies was that prophylactic heparin for VTE might be relatively safe with regard to hematoma enlargement, death, and functional outcome.

Prophylactic heparin for VTE was associated with a nonsignificant increase in hematoma enlargement and a nonsignificant reduction in extracranial hemorrhage. Clinically evident VTE occurs in up to 13% of patients with sICH, the incidence peaks between days 2 and 7 of hospitalization, and the risk of death from PE is high.[27] [28] The incidence of intracerebral hemorrhage with DVT after initiation of prophylactic heparin may be increased, but this effect is not obvious after late treatment. In radiologic studies and multiple studies, hematoma expansion occurs in 18 to 38% of patients with sICH within 3 hours, in 70% within 24 hours, and infrequently after 24 hours.[29] [30] [31] Therefore, in theory, it could be safe to initiate the heparin treatment between days 2 and 7 after ICH onset and cessation of active bleeding. However, blood pressure should be closely monitored during this period because the patient is still at risk for repeated ICH. In comparison, most patients in our studies received heparin within 2 to 7 days after ICH onset. At the same time, computed tomography of the head was repeated more frequently in patients receiving heparin, and this might be a more cautious approach for physicians when administering heparin.

Several observational studies indicated that heparin prophylaxis does not result in hematoma expansion after ICH. In a trial involving 68 patients with ICH, heparin initiation on day 2 led to a statistically lower rate of PE than did initiation on day 4 or day 10.[7] A more recent trial involving 103 patients demonstrated that subcutaneous enoxaparin does not increase risk of rebleeding or hematoma expansion.[8] A meta-analysis of four controlled studies[6] suggested that prophylactic heparin results in a significant reduction in PE, although no effect on bleeding was observed.

The nonsignificance of the reduction in mortality among patients receiving prophylactic heparin in our analysis could be attributed to lower rates of PE and a nonsignificant increase in hematoma enlargement. Our findings were consistent with those of other studies and meta-analyses, showing that prophylactic doses of heparin do not increase mortality after ICH.[7] [8] [10] [11] [23] Standard prophylaxis for patients at high risk includes twice/day dosing with 30 mg enoxaparin. However, previous observations suggested that the incidence of DVT was increased in patients who received 40 mg enoxaparin daily in comparison with a dosage of 30 mg twice/day or lower.[32] [33] Therefore, the use of lower prophylactic doses was considered justified in an attempt to improve outcome after ICH. However, a trial involving 170 patients[26] demonstrated a higher rate of mortality among the ICH patients who received heparin treatment. Such a higher mortality rate in enoxaparin recipients could be attributed to primary bleeding or rebleeding before enoxaparin treatment and to pneumonia that had nothing to do with heparin treatment.

The major disability, reflected by mRS and GOS scores, of surviving patients among those receiving prophylactic heparin was associated with a nonsignificant increase than those in patients not receiving heparin. However, as mentioned, Wurm and colleagues[25] showed that patients treated with enoxaparin had significantly more favorable GOS scores at 1-year follow-up than patients treated with placebo. Moreover, in experimental mouse models of ischemic stroke, enoxaparin seems to offer good neuroprotection and reduce ischemic lesion size by 49%.[34] Similarly, Yi et al[35] showed that LMWH improved outcome in a dose-dependent manner after stroke, as clinically confirmed at 6 months, and was more effective than aspirin alone in preventing early neurologic deterioration and improving the 6-month outcome in patients with ischemic stroke. However, Paula Muñoz-Venturelli et al[23] showed that patients who received subcutaneous heparin had greater major disability at 90 days. Major disability was evaluated in only two reports in our study, and there was heterogeneity between those studies. Relevant randomized controlled clinical trials are needed to assess the major disability of prophylactic heparin in patients with sICH.

In addition to the limitations shared by all meta-analyses, our study had some further limitations. On one hand, the sample sizes were small, and most of these studies were of quality “B” or worse, according to the classification scheme of the Centre for Evidence-Based Medicine. On the other hand, anticoagulants include heparin, oral anticoagulants, and thrombin inhibitors. In our study, only the preventive effect of heparin on VTE in sICH was considered. Therefore, large randomized controlled clinical trials are needed to assess the safety of heparin therapy in the prevention of VTE after sICH.

Conclusions

Our findings indicated that in patients with acute hemorrhagic stroke, prophylactic heparin was associated with a nonsignificant increase in any hematoma enlargement and in mortality, a nonsignificant reduction in extracranial hemorrhage, and a nonsignificant increase in the incidence of major disability in patients with sICH. In clinical practice, prophylactic heparin could be used safely to prevent VTE in patients with sICH. This meta-analysis provided valuable insights into the design of large randomized controlled clinical trials and offers useful information on the safety of prophylactic heparin administration in patients with sICH.

Conflict of Interest

None declared.

^* Xi Pan and Jihui Li contributed equally to this article as first co-authors.

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