The Role of Angiotensin-Converting Enzyme Inhibitors in Patients with Chronic Subdural Hematoma: A Scandinavian Population-Based Multicenter Study

doi:10.1016/j.wneu.2018.02.094

World Neurosurgery

Volume 113, May 2018, Pages e555-e560

https://doi.org/10.1016/j.wneu.2018.02.094 Get rights and content

Highlights

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Recently, conflicting reports have emerged suggesting that angiotensin-converting enzyme (ACE) inhibitors may or may not influence the risk of chronic subdural hematoma (cSDH) recurrence. Lack of power or inability to adjust for likely confounding factors likely influence the results in those previous studies.
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In a large Scandinavian multicenter population-based cohort, we investigated the risk of cSDH recurrence in users of ACE inhibitors, users of angiotensin II receptor blockers, and those without ACE inhibitor treatment (no ACE inhibitor group) using univariable analyses and adjusting for baseline differences using a regression analysis.
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After adjusting for differences in the baseline characteristics using a regression model, ACE inhibitor treatment did not influence risk for recurrence (odds ratio, 1.2; 95% confidence interval, 0.7–2.2; P = 0.46). Thus, our results argue against any significant effect of ACE inhibitors on cSDH recurrence, and other adjuvant treatment should be sought.

Objective

To investigate the role of angiotensin converting enzyme (ACE) inhibitors in the recurrence of chronic subdural hematoma (cSDH) after burr hole surgery.

Methods

A retrospective review was conducted of a Scandinavian multicenter, population-based cohort of 1252 adults with cSDH who underwent with burr hole surgery between January 1, 2005, and December 31, 2010. The risk of cSDH recurrence was assessed in users of ACE inhibitors, users of angiotensin II receptor blockers (ARBs), and those without ACE inhibitor treatment (no ACE inhibitor group) using univariable and multivariable regression analyses.

Results

The cohort included 98 (7.8%) ACE inhibitor users and 63 (5%) ARB-only users. The recurrence rate was 16.3% (n = 16) in the ACE inhibitor group, compared with 13.3% (n = 153) in the no ACE inhibitor group (P = 0.39) and 14.3% (n = 9) in the ARB group (P = 0.73). When comparing groups, age (P = 0.01), Charlson Comorbidity Index (P = 0.01), use of platelet inhibitors (P = 0.001) and use of anticoagulants (P = 0.01) differed between the ACE inhibitor and no ACE inhibitor groups. Only age differed significantly between the ACE inhibitor and ARB groups (P = 0.03). In the analyses adjusted for differences in baseline characteristics, ACE inhibitor treatment did not influence the risk of recurrence (odds ratio, 1.2; 95% confidence interval, 0.7–2.2; P = 0.46).

Conclusion

In this population-based study, the use of ACE inhibitors was not associated with the risk of recurrence following burr hole surgery for cSDH.

Introduction

As the oldest sector of the population continues to grow, chronic subdural hematoma (cSDH) is projected to become the most common cranial neurosurgical condition among adults.1, 2, 3, 4, 5, 6, 7, 8, 9 The pathogenesis of cSDH is still debated and not fully understood.10, 11, 12 One proposed theory is that hyperangiogenesis and microbleeding in the perceived neomembrane play a role in the development of cSDH.¹³ Recently, conflicting reports have emerged on whether angiotensin-converting enzyme (ACE) inhibitors influence the risk of cSDH recurrence. One study suggested that ACE inhibitors decrease the concentration of vascular endothelial growth factor in the hematoma fluid, resulting in decreased vascular permeability and reducing the risk of cSDH.¹⁴ However, a benefit of ACE inhibitors has not been reproduced in more recent, but rather small, studies.15, 16 An increased risk of recurrence in users of ACE inhibitors also has been reported, suggesting that induced bradykinin elevation causes increased vascular permeability.¹⁵ Insufficient statistical power or an inability to adjust for likely confounders might have influenced results.

A large population-based study is well suited for exploring the potential association between ACE inhibitor treatment and cSDH recurrence following burr hole surgery. Although it is difficult to establish causality from observational studies, a larger study with adjustment for potential confounding factors could allow for a better estimation of effect size than both small, underpowered randomized controlled trials and small cohort studies.

In this consecutive, population-based, multicenter study, we investigated the role of ACE inhibitor treatment on cSDH recurrence.

Section snippets

Patient Population

All patients age ≥18 years treated with burr hole evacuation of primary cSDH between January 1, 2005, and December 31, 2010, at the Departments of Neurosurgery at Karolinska University Hospital (Stockholm, Sweden), University Hospital of North Norway (Tromsø, Norway) and St. Olav's University Hospital (Trondheim, Norway) were identified using the hospitals' patient administrative databases and operating room logs. Patients having undergone any other form of intracranial surgery during the 6

Primary Endpoint

There were 98 ACE inhibitor users, including 62 (63.3%) with enalapril, 1 (1.0%) with captopril, 15 (15.3%) with lisinopril, and 20 (20.4%) with ramipril. Although significant differences were observed between users and nonusers of ACE inhibitor in terms of age (mean, 73.7 years vs. 77.0 years; P = 0.01), Charlson Comorbidity Index >1 (32.7% vs. 45.9%; P = 0.01), use of platelet inhibitors (25.9% vs. 40.8%; P = 0.001), and use of anticoagulants (16.6% vs. 27.6; P = 0.01), there was no

Discussion

In this multicenter study, we found no association between the use of ACE inhibitors and recurrence of cSDH, demonstrating that the theoretical effect of ACE inhibitors on cSDH recurrence appears to be very limited in clinical practice. The theory behind the supposed role of ACE in cSDH is related to one of the theories of the pathophysiology of cSDH, namely highly vascularized neomembranes with fragile capillaries and subsequent microbleeding.10, 12, 17, 18 ACE inhibitors are well-established

Conclusions

The use of ACE inhibitors was not associated with a decreased risk of recurrence following burr hole surgery for cSDH in this population-based study. The cumulative evidence, including our present results, argues against any significant effect of ACE inhibitors on cSDH recurrence, and thus other treatment should be sought to reduce recurrence rates.

Acknowledgments

We thank Helena Kristiansson, Fredrik Ståhl, Lisa M. Sagberg, and Marte Lødemel Henriksen for their invaluable assistance with data gathering.

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Tranexamic Acid for Prevention of Postoperative Recurrence of Chronic Subdural Hematoma After Burr Hole Craniotomy: Comment on Recent Global Neurosurgery Article in Neurosurgery
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Renin-angiotensin-aldosterone system inhibitors as a risk factor for chronic subdural hematoma recurrence: A matter of debate
2023, Journal of Stroke and Cerebrovascular Diseases
Chronic subdural hematoma (cSDH) is a common central nervous system condition. Recent reports indicate that cSDH affects long-term prognosis; however, its definitive risk factors remain unknown. An antihypertensive drug, renin–angiotensin–aldosterone system inhibitors (RAASi), can affect vascular permeability and cell proliferation processes, which may suppress the recurrence of cSDH. However, several studies have reported negative results to this effect. Therefore, we aimed to evaluate antihypertensive drugs, including RAASi, as risk factors for recurrent cSDH.
A total of 203 consecutive cases of surgically treated cSDH were retrospectively reviewed. Clinical and radiological parameters were compared between the groups with and without cSDH recurrence to identify risk factors.
Of the included cases, 68 (33.5%) used RAASi and 37 (18.2%) developed recurrence within 60 days of surgery. In the multiple logistic regression analysis adjusted by composite risk score, the odds ratios (95% confidence interval) of RAASi, calcium channel blockers, diuretics, β and α blockers, for the recurrent risk of cSDH after surgery were 2.49 (1.16, 5.42), 1.79 (0.84, 3.82), 1.83 (0.62, 4.87), 0.90 (0.28, 2.44), and 0.96 (0.21, 3.20), respectively. The Cox proportional hazard model also demonstrated that RAASi-use was an independent risk factor for cSDH recurrence.
Present series suggests RAASi-use as a risk factor for cSDH recurrence, although the role of RAASi-use in cSDH remains debatable. Further studies for deeper understanding of the microenvironment of hematoma and the surroundings are preferable. (235 words)
Efficacy and Safety of Glucocorticoids Versus Placebo as an Adjuvant Treatment to Surgery in Chronic Subdural Hematoma: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials
2022, World Neurosurgery
Citation Excerpt :
The increasing incidence and high recurrence rate of CSDH have emphasized the need for improved understanding of both the pathophysiology of CSDH and the optimal treatment options. During the past few decades, several therapies, including atorvastatin,12,13 angiotensin-converting enzyme inhibitors,14 glucocorticoids,15-18 tranexamic acid,19 and middle meningeal artery embolization,20,21 have been used for the medical treatment of CSDH. Of these treatments, glucocorticoids have been widely used as an adjunct or as an alternative to surgery for patients with mild neurological impairment.
Chronic subdural hematoma (CSDH) is a common neurosurgical disease with a high recurrence rate, especially among the elderly. Glucocorticoids have been tested for the treatment of CSDH in observational studies and randomized clinical trials.
We systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials database for randomized trials from the earliest date available to May 23, 2021 that had compared glucocorticoids and placebo as a postoperative treatment of CSDH. Trials were included if the study participants were aged ≥18 years and had had CSDH after surgery. The relative risk (RR) was used to evaluate the clinical outcomes.
We included 5 eligible randomized controlled trials with a total of 1251 patients. The findings showed that the use of adjuvant glucocorticoid therapy can effectively reduce the recurrence risk of CSDH compared with placebo (RR, 0.40; 95% confidence interval [CI], 0.28–0.58; P < 0.001). No significant differences were found between the glucocorticoid and placebo groups regarding favorable neurological outcomes (RR, 1; 95% CI, 0.93–1.08; P = 0.92). We found that the use of adjuvant glucocorticoids resulted in a significant increase in psychiatric symptoms (RR, 3.22; 95% CI, 1.83–5.64; P < 0.001). No significant differences were found for infection between the 2 groups (RR, 1.86; 95% CI, 0.56–6.14; P = 0.31).
Glucocorticoid therapy can effectively reduce the recurrence risk of CSDH after surgery without an increase in the postoperative infection rate. However, significantly increased psychiatric symptoms were reported in the glucocorticoid group.
History and current progress of chronic subdural hematoma
2021, Journal of the Neurological Sciences
Citation Excerpt :
A comparative study of 310 patients suggested that ACE inhibitors decrease the recurrence risk in CSDH patients [54]. In contrast, other studies have demonstrated the inability of ACE inhibitors in reducing the CSDH recurrence rate [55,56]. Tranexamic acid is an antifibrinolytic drug.
Chronic subdural hematoma (CSDH) is characterized by an encapsulated collection of old blood. Although CSDH has become the most frequent pathologic entity in daily neurosurgical practice, there are some unresolved research questions. In particular, the causes and recurrent risk factors of CSDH remain as an object of debate. The split of the dural border layer forms a few tiers of dural border cells over the arachnoid layer. Tissue plasminogen activator plays an important role as a key factor of defective coagulation. Historically, CSDH has often been treated via burr hole craniostomy using a closed drainage system. Several different operative strategies and peri-operative strategies such as the addition of burr holes, addition of cavity irrigation, position of drain, or postural position, have been described previously. Although the direction of the drainage tube, residual air, low intensity of T1-weighted images on MRI, and niveau formation have been reported as risk factors for recurrence, antiplatelet or anticoagulant drug use has not yet been verified as a risk factor. Recently, pharmaceutical strategies, including atorvastatin, significantly improved the neurological function in CSDH patients. Many case series, without randomization, have been reported; and given its promising result, several randomized clinical trials using pharmaceutical as well as operative and perioperative strategies were initiated to obtain sufficient data. In contrast, relatively fewer basic studies have achieved clinical applications in CSDH, although it is one of the most common clinical entities. Further scientific basic research may be essential for achieving a novel treatment strategy for CSDH.
Chronic Subdural Hematomas and Pursuit of Nonsurgical Treatment Alternatives
2019, World Neurosurgery
Effect of postoperative tranexamic acid on recurrence rate and complications in chronic subdural hematomas patients: preliminary results of a randomized controlled clinical trial
2023, Neurosurgical Review

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: Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Original ArticleThe Role of Angiotensin-Converting Enzyme Inhibitors in Patients with Chronic Subdural Hematoma: A Scandinavian Population-Based Multicenter Study

Highlights

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Patient Population

Primary Endpoint

Discussion

Conclusions

Acknowledgments

World Neurosurg

J Chronic Dis

World Neurosurg

J Clin Neurosci

Clin Neurol Neurosurg

J Clin Neurosci

Surg Neurol

Lancet

Chronic subdural haematoma in the elderly

Postgrad Med J

Chronic subdural haematoma in the elderly–a North Wales experience

J R Soc Med

Actual and projected incidence rates for chronic subdural hematomas in United States Veterans Administration and civilian populations

J Neurosurg

Original Article
The Role of Angiotensin-Converting Enzyme Inhibitors in Patients with Chronic Subdural Hematoma: A Scandinavian Population-Based Multicenter Study