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Hemorrhagic stroke
Case series
Effect of heparin on secondary brain injury in patients with subarachnoid hemorrhage: an additional ‘H’ therapy in vasospasm treatment
  1. Markus Bruder1,
  2. Sae-Yeon Won1,
  3. Sepide Kashefiolasl1,
  4. Marlies Wagner2,
  5. Nina Brawanski1,
  6. Nazife Dinc1,
  7. Volker Seifert1,
  8. Juergen Konczalla1
  1. 1Department of Neurosurgery, Goethe University, Frankfurt am Main, Germany
  2. 2Department of Neuroradiology, Goethe University, Frankfurt am Main, Germany
  1. Correspondence to Dr Markus Bruder, Department of Neurosurgery, Goethe University, Frankfurt 60528, Germany; markus.bruder{at}kgu.de

Abstract

Objective Secondary brain injury leads to high morbidity and mortality rates in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, evidence-based treatment strategies are sparse. Since heparin has various effects on neuroinflammation, microthromboembolism and vasomotor function, our objective was to determine whether heparin can be used as a multitarget prophylactic agent to ameliorate morbidity in SAH.

Methods Between June 1999 and December 2014, 718 patients received endovascular treatment after rupture of an intracranial aneurysm at our institution; 197 of them were treated with continuous unfractionated heparin in therapeutic dosages after the endovascular procedure. We performed a matched pair analysis to evaluate the effect of heparin on cerebral vasospasm (CVS), cerebral infarction (CI), and outcome.

Results The rate of severe CVS was significantly reduced in the heparin group compared with the control group (14.2% vs 25.4%; p=0.005). CI and multiple ischemic lesions were less often present in patients with heparin treatment. These effects were enhanced if patients were treated with heparin for >48 hours, but the difference was not significant. Favorable outcome at 6-month follow-up was achieved in 69% in the heparin group and in 65% in the control group.

Conclusions Patients receiving unfractionated continuous heparin after endovascular aneurysm occlusion have a significant reduction in the rate of severe CVS, have CI less often, and tend to have a favorable outcome more often. Our findings support the potential beneficial effects of heparin as a multitarget therapy in patients with SAH, resulting in an additional ‘H’ therapy in vasospasm treatment.

  • Aneurysm
  • Coil
  • Drug
  • Hemorrhage
  • Subarachnoid

https://doi.org/10.1136/neurintsurg-2016-012925

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    Introduction

    Subarachnoid hemorrhage (SAH) is a severe life-threatening event leading to secondary brain injury and numerous adverse sequelae, often subsumed under the term ‘delayed neurological deficits’ (DNDs). Multiple pathophysiological mechanisms are held responsible for secondary brain injury such as cerebral vasospasm (CVS), neuroinflammation, microthrombi, oxidative stress, and free radical damage.1–9 As a result, patients who survive the primary brain injury develop cerebral infarctions (CI), which lead to increased mortality and severe disability.10 Nimodipine is the only evidence-based option for CVS treatment, reducing CI rates,11 ,12 and hypertensive treatment (mono-H) can prevent CI in some cases.13 However, treatment options are few and, despite many promising SAH trials in the last few years, no other treatment for secondary brain injury has shown a significant reduction in morbidity or improvement in outcome. Indeed, due to the multiple pathophysiological backgrounds, effective treatment for SAH-induced CI is still lacking.

    Heparin is widely used for prophylaxis or treatment of thromboembolism. However, heparin has various other effects: it acts as an anti-inflammatory agent, can alter vasomotor regulation, and recent studies suggest its use as a potential therapeutic inhibitor of inflammation,9 ,14–17 all relevant mechanisms for the treatment of SAH-induced brain injury. There have been a few studies of low-dose heparin treatment in patients with SAH, but the results are controversial.14 ,18 ,19 In addition, due to well justified fears of hemorrhagic complications,20 the administration of heparin in therapeutic dosages has not gained acceptance among clinicians and randomized controlled trials are difficult to justify for ethical reasons.

    We therefore performed a retrospective matched pair analysis of patients with continuous heparin treatment after endovascular occlusion of the ruptured aneurysm to analyze the effect of heparin on CVS, CI, and outcome.

    Materials and methods

    Between June 1999 and December 2014, 1664 patients with SAH were treated in our clinic. SAH was confirmed by cranial CT or lumbar puncture. Information including patient characteristics, treatment modality, and radiological findings were prospectively entered into a computerized database (IBM SPSS Statistics, V.22, Armonk, New York, USA). Treatment decision (endovascular or microsurgery) was based on an interdisciplinary approach in each individual case, as previously reported.20–22 The ruptured aneurysm in 718 patients (43.1%) was treated endovascularly. Of these, 197 (27.4%) required systemic heparinization up to 7 days after the endovascular aneurysm occlusion procedure.

    Matched pair analysis

    Multivariate and propensity score matching with balance optimization was performed in the 197 patients who required systemic heparinization after endovascular treatment of the ruptured aneurysm to exclude factors with a known or potential impact on CVS, DND, and outcome.23 From the remaining endovascularly treated patients in our database (n=521), a further 197 patients who did not require heparinization were selected (using R) as the control group. To improve the balance, the following possible outcome factors were selected for matching: age, sex, admission status (according to the World Federation of Neurological Societies (WFNS) and the Hunt and Hess (H&H) scales), Fisher score, size and site of the ruptured aneurysm, early hydrocephalus (according to the need for an external ventricular drain within the first 48 hours), and smoking habits.

    Whereas before matching a number of factors (eg, hydrocephalus, Fisher score, admission status) were significantly different in the remaining cohort of 521 cases, after matching of 197 cases (38% of cases from the remaining 521), none of the factors (age, sex, admission status, Fisher score, size and site of the ruptured aneurysm, early hydrocephalus, and smoking habits) were significantly altered (table 1).

    View this table:
    Table 1

    Parameters for matching pair analysis: patient characteristics, admission status, aneurysm site, size and treatment

    Endovascular treatment and anticoagulation

    All endovascular procedures were performed at the Department of Neuroradiology, Goethe University, Frankfurt. To prevent periprocedural thrombembolism, heparin 3000–5000 IU (depending on the patient's weight) was usually administered during all endovascular procedures. The interventionist determined whether any additional heparinization was necessary. When IV heparin was used, the activated partial thromboplastin time was carefully monitored and targeted to 60 s for 24 hours up to 7 days. Indications for heparinization included thromboembolic prophylaxis, especially in the case of a broad aneurysm neck, coil dislocation into the carrier vessel, or intraprocedural thrombus formation.

    In order to prevent thrombosis and/or pulmonary embolism, all patients with SAH received low molecular weight heparin (LMWH) in a prophylactic dosage (low dose, 40 mg) subcutaneously, starting 24 hours after aneurysm treatment. LMWH was suspended while patients received IV heparinization.

    Cerebral vasospasm (CVS)

    All patients were screened for CVS by daily transcranial Doppler sonography. In cases in whom CVS was suspected, a CT or MRI scan was performed to confirm CVS. On day 7±2 after aneurysm rupture the patients received a regular control CT, MRI or digital subtraction angiogram. CVS was classified as slight, moderate, or severe by the investigating neuroradiologist according to narrowing (<33%, 33–66%, or >66% vessel constriction). In patients with CVS, until reversal of CVS (detected by an objective method such as CT angiography or MR angiography), hypertension was induced aiming at a cerebral perfusion pressure of 90–110 mm Hg.24 ,25

    Patients received nimodipine 6×60 mg/day orally during the first 3 weeks. In cases of severe hypotension, nimodipine was given 12×30 mg/day orally. Corticosteroids, statins, and anticonvulsants were not given routinely.11

    Cerebral infarction (CI) or multiple ischemic lesions

    CI was detected based on CT or MRI findings. Images were performed in awake patients with focal or cognitive deficit. In unconscious patients, a CT or MRI scan was obtained at day 7 (±2 days) or in cases where CVS was suspected, as mentioned above. All unconscious patients or patients with CVS received a control MRI or CT scan before discharge. These images were independently screened for ischemia by the following authors: MB, S-YW, SK, NB, and ND. Detection of ischemia was defined as CI, which was either CVS-dependent or independent. Hypodensities not related to infarctions were excluded. In case of ischemic lesions in more than two brain territories or both hemispheres, the lesions were defined as multiple ischemic lesions.26

    Outcome and follow-up

    Outcome was prospectively assessed 6 months after SAH at outpatient visits or by structured telephone interview of the caregiver in cases with severe disability. Functional outcome was evaluated by the modified Rankin scale (mRS), where a favorable outcome was defined as mRS 0–2 and an unfavorable outcome was defined as mRS 3–6. Furthermore, information about regaining social activity, ability to work, psychological disorders, and shunt dependency were acquired and prospectively kept in the database.

    Statistical methods

    Statistical analyses were performed using the Student's t-test, χ2 test, or Fisher's exact test as indicated. Results with a p value <0.05 were considered statistically significant. Statistical analyses and calculations were made using standard commercial software (IBM SPSS Statistics, V.22, Armonk, New York, USA). For the matched-pair analysis, the statistical computing program R (The R Foundation for Statistical Computing; V.3.0.3) was used.

    Results

    In 197 patients, postinterventional heparinization was recommended by the interventionist to prevent thromboembolic complications; 141 patients (71.6%) received a therapeutic dosage of heparin 24–48 hours after the endovascular procedure while 56 patients (28.4%) were treated with heparin for 48 hours up to 7 days after the intervention. The mean age was 53.8±13.7 years and 69.5% of the patients were women. 62.4% had a good admission status (WFNS 1–3) and 37.6% had a poor admission status (WFNS 4–5). In 75.1% of cases a significant amount of blood was present in the subarachnoid spaces on the CT scan according to Fisher grade 3,27 and 14.2% had additional intracerebral hemorrhage. The mean size of the ruptured aneurysms was 6.5±3.4 mm, and the most frequent site of aneurysm rupture was the anterior cerebral artery (38.6%), followed by the internal carotid artery (30%), the posterior circulation (23.9%), and the middle cerebral artery (7.6%). According to the inclusion criteria, all patients received endovascular aneurysm treatment.

    All 197 patients in the heparin group were matched to 197 patients without heparinization after endovascular aneurysm occlusion (control group). Due to the matching algorithm, there was no difference in age, sex, admission status, bleeding pattern, size or site of the ruptured aneurysm, rate of early hydrocephalus, or smoking between the heparin and control groups (table 1).

    Course of treatment and outcome

    The overall rate of CVS occurrence was slightly lower in patients with heparinization than in patients without postinterventional heparinization, but the difference was not significant (40.1% vs 47.2%; p=0.16; OR 1.34; 95% CI 0.9 to 2.0). CVS was classified as severe in 28 patients (14.2%) in the heparin group and in 50 patients (25.4%) in the control group. This difference was statistically significant (p=0.005; OR 2.1; 95% CI 1.23 to 3.43) (figure 1). CI was observed in 54 patients (27.4%) in the heparin group and in 63 patients (32%) in the control group (p=0.32; OR 1.25; 95% CI 0.81 to 1.92). Multiple ischemic lesions were present in 14 patients (7.1%) in the heparin group and in 20 patients (10.2%) in the control group (p=0.28; OR 1.48; 95% CI 0.72 to 3.02).

    Figure 1
    Figure 1

    Comparison of cerebral vasospasm (CVS) classification between patients with post-interventional heparinization (heparin group) and patients without post-interventional heparinization (control group) (mild CVS, vessel constriction <33%; moderate CVS, vessel constriction 33–66%; severe CVS, >66% of the vessel diameter constricted).

    In 141 patients (71.6%) with postinterventional heparinization, heparin was administered for 24–48 hours and, in 56 patients (28.4%), heparin was given for >48 hours up to 7 days in single cases. The rate of severe CVS was significantly lower in patients given heparin for ≤48 hours and in those treated with heparin for >48 hours than in patients without heparinization (control group). The overall rates of CVS, CI, and multi-ischemic syndromes were lower in patients given heparin for >48 hours than in those treated with heparinization for ≤48 hours or patients in the control group. Even though there was no significant difference in patients given heparin for ≤48 hours, CVS rates and CI rates tended to be significantly lower when heparin was administered for >48 hours (table 2).

    View this table:
    Table 2

    Rate of cerebral vasospasm (CVS) and cerebral infarction (CI) in patients with heparinization for ≤48 hours and patients with heparinization for >48 hours after the endovascular procedure compared with patients without heparinization

    At 6 months, an overall favorable outcome (mRS 0–2) was achieved in 263 cases (66.8%). Patients in the heparin group achieved a favorable outcome slightly more often than patients in the control group (69.0% vs 64.5%; p=0.57; OR 1.14; 95% CI 0.73 to 1.78). Mortality rates at 6-month follow-up were 12.2% in the heparin group and 13.2% in the control group (p=0.65; OR 1.14; 95% CI 0.64 to 2.06).

    Predictors for a favorable outcome of heparinized patients in univariate analysis were good admission status, younger age, Fisher 3-like bleeding pattern, signs of early hydrocephalus, necessity of ventriculoperitoneal shunt, presence of CVS, severe CVS, as well as CI or multi-ischemic syndrome. However, independent predictors for a favorable outcome after multivariate analysis were young age and good admission status (table 3).

    View this table:
    Table 3

    Univariate analysis comparing favorable and unfavorable outcome in patients with heparinization after the aneurysm occluding procedure

    Discussion

    Patients with continuous IV heparin administration after endovascular aneurysm occlusion had severe vasospasm significantly less often, even when heparin was administered for only ≤48 hours. This effect was enhanced in patients treated with heparin for >48 hours. However, the clinical outcome at 6 months did not improve significantly with heparin treatment. To clarify this issue, more data are needed to improve the statistical power (sample size of n=1720 according to power analysis). Therefore, a multicenter evaluation or further reports may show a benefit by meta-analysis in the future.

    Heparin or LMWH are widely used for the prophylaxis or treatment of thromboembolism. Interestingly, heparin is the highest negatively charged biological molecule existing and has various effects. Due to the negative charges, it can bind to positively charged proteins and surfaces including various growth factors, cytokines, and chemokines, acting as an anti-inflammatory agent.9 ,14 Furthermore, heparin can bind oxyhemoglobin, block free radical activity, and antagonize endothelin, resulting in reduction of endothelin-related vasoconstriction.9 ,14 ,15 ,17 All these effects are intimately related to mechanisms implicated in SAH-induced DND. Therefore heparin seems to be attractive as a multitarget prophylactic agent to ameliorate secondary brain injury and morbidity after SAH.9

    In a translational approach, Hochart et al28 showed that unfractionated heparin as well as LMWH has an anti-inflammatory effect by inhibiting nuclear factor NF-κB activity, suggesting heparin as a potential therapeutic inhibitor of inflammation. Simard et al16 showed in a rat SAH model that heparin treatment reduced neuroinflammation, demyelination, and neuronal apoptosis, indicating a reduction of adverse effects in SAH. Furthermore, Altay et al29 recently showed improvement in neurobehavioral function and a decrease in brain edema in mice pretreated with low-dose unfractionated heparin before SAH induction.

    A few studies have been published on the use of low-dose heparin treatment in humans with SAH, but the results are contradictory. Wurm et al19 studied the effects of daily subcutaneous administration of 20 mg enoxaparin in a placebo controlled trial of patients with SAH, Hunt and Hess grades 1–3. Patients with enoxoparin had a significant reduction in CVS and DND and a significantly better outcome according to the Glasgow Outcome Scale and Karnofsky score 1 year after SAH. There was no higher risk of rebleeding or other hemorrhagic complications between enoxaparin-treated and placebo-treated patients. Interestingly, patients treated with enoxaparin also had a lower rate of shunt-dependent hydrocephalus. The rate of shunt dependency in the present series was the same in both groups (17% in patients with heparin vs 18% in patients without heparin). In a placebo controlled trial on the effects of LMWH on patients with SAH, Siironen et al18 observed contrasting results. Even though they administered a higher dosage of enoxaparin (40 mg/day subcutaneously), the rates of DND and outcome after 3 months were not different in the two groups, with a tendency toward a higher risk of hemorrhagic complications in the enoxoparin group. It is important to note that LMWH was mostly injected subcutaneously, which has different pharmacological dynamics and kinetics in each patient depending on the location of the injection and the mass of fat cells. Some of the patients might have local accumulation whereas other patients might have a direct effect through systemic transfer. The level of anticoagulation might therefore vary between patients, which could lead to the controversial results. It might be important to measure the drug level in case of LMWH to reduce this bias.

    However, the biological effects of LMWH are different from those of unfractionated heparin. Unfractionated heparin is suggested to be more effective in limiting the inflammatory response involving the endothelial surface, as binding of unfractionated heparin to thrombin activated endothelial cells is significantly higher than the binding of LMWH.9 ,30 Furthermore, the antiproliferative activity of heparin on smooth muscle cells is maximal in its high molecular weight component, and LMWH has a lower affinity than unfractionated heparin for cell receptors.9 Rats with focal temporal ischemia receiving unfractionated heparin showed a significantly better outcome than animals with an equivalent dose of LMWH.31 Therefore, opposing reports of the effects of LMWH on SAH-induced DNDs may be due to the absence of high molecular weight components which are present only in unfractionated heparin.9

    The present study cannot address the effect of low-dose LMWH on the treatment course and outcome of SAH because all patients in the present study received LMWH subcutaneously daily to prevent DVT and pulmonary embolism if they were not heparinized at that time. However, the present study showed a reduction in severe vasospasm and a tendency for an improved outcome when unfractionated heparin was administered continuously even for a short time compared with patients receiving LMWH once daily. The continuous administration of heparin seems to be another important factor. Animal studies showed that heparin has adverse effects on growth factors when administered subcutaneously twice a day, but has beneficial effects when administered by continuous IV infusion.32 Therefore, continuous IV infusion seems to be important to enable the beneficial effects of heparin, and these effects seem to be enhanced in patients receiving heparinization for >48 hours.

    Siimard et al14 reported a dramatic reduction in clinically relevant vasospasm and an absence of delayed cerebral ischemia when low-dose IV heparin was continuously administered up to day 14 after SAH. The clinical outcome was assumed according to discharge status (discharge to rehabilitation center vs discharge to home). Patients with low-dose IV heparin treatment were discharged home significantly more often than patients without heparin.

    Patients with continuous unfractionated heparin treatment in the present series had significantly lower rates of severe CVS but, unlike Simard et al,14 we observed CI in heparin-treated patients. However, the CI rates were lower, especially in patients receiving heparin for >48 hours, and these patients tended to have a better outcome than patients treated with LMWH. Simard et al14 used low-dose heparin with a partial thromboplastin time targeted to normal or minimally elevated. On the contrary, in the present series unfractionated heparin was given to a therapeutic level with a carefully adjusted partial thromboplastin time of 60 s, but most often for <48 hours. However, the outcome tended to be better in the heparin group, but the difference did not reach a significant level.

    CVS rates were lower even in patients with heparin administered for <48 hours. This may be due to an effect of heparin on the initial inflammation process. However, as secondary brain damage usually occurs within several days after SAH,33 it is not surprising that patients receiving heparin for >48 hours had the lowest rates of CVS, severe CVS, CI, and multi-ischemic syndrome (table 2). From a combination of our findings and the results of Simard et al,14 we consider the protective effect of heparin to be dependent on treatment duration.

    When using anticoagulant agents one should focus on hemorrhagic complications, especially in patients with SAH for whom multiple surgical interventions may be necessary during the treatment course. As we have previously reported, patients with heparin administration after endovascular procedures are at a higher risk of ventriculostomy-related hemorrhage.20 However, we did not encounter any clinically relevant hemorrhage due to ventricular drain placement in either group in the present series, but suggest that ventriculostomy should be performed before starting anticoagulation whenever possible.

    Rebleeding rates of the treated aneurysm were low and did not differ between the two groups (6 patients (3.0%) in the heparin group vs 9 patients (4.6%) in the control group). Nevertheless, heparin should be used with caution and only in a neurointensive care setting.

    The reduction in CVS rates in the heparin group did not reach a significant level, most probably due to the small number of patients. However, the rate of CI was low, equal to the rate presented in the series of Pickard et al (11%) investigating the effect of nimodipine34 and leading to a standard of care principle.

    To prove a clinical impact on the long-term outcome of low-dose unfractionated heparin treatment, a standardized treatment scheme needs to be implemented and a multicentre analysis in a prospective setting should be performed.

    Study limitations

    This study has several limitations. The main limitation is its retrospective and single-center design, as well as the various and most often only short durations of IV heparin administration. The retrospective design has typical restrictions such as lack of data initially not documented in the medical records. Moreover, there is a potential bias in case selection of patients who received IV heparin. CI rates in conscious patients could be underestimated as detection depends on neurological deficits. However, we performed a matched-pair analysis so the restrictions apply to both groups. Furthermore, the structured treatment and diagnostic course together with the prospective outcome assessment might counteract these disadvantages.

    Conclusion

    Patients with SAH administered heparin after endovascular treatment of the ruptured aneurysm have a significant reduction in the rate of severe CVS, less often have CI, and tend to have a better outcome after 6 months according to the mRS. This effect was enhanced when heparin was administered for >48 hours. Our findings support the potential beneficial effects of heparin as a multitarget ‘H’ therapy in patients with SAH, resulting in additional ‘H’ therapy for vasospasm treatment.

    Acknowledgments

    We thank Anne Sicking and Marina Heibel for their excellent technical support.

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    Footnotes

    • MB and S-YW are joint first authors and contributed equally.

    • Contributors MB and S-YW made equal substantial contributions to the conception and design of the work and acquisition and analysis of data (shared first authors). SK, NB and ND made substantial contributions to acquisition of data. MW made substantial contributions to the analysis of data. VoS and JK made substantial contributions to the conception and design of the work. All authors revised the article critically for important intellectual content and gave their final approval of the version to be published. All authors agreed to be accountable for all aspects of the work ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

    • Competing interests None declared.

    • Ethics approval Ethics approval was obtained from the Ethics Committee of the Hospital of the Goethe University Frankfurt.

    • Provenance and peer review Not commissioned; externally peer reviewed.