Introduction: Literature regarding the safety and efficacy of antithrombotic (antiplatelet or anticoagulant) therapy and statins in patients with cavernous malformations (CMs) of the central nervous system is sparse, resulting in uncertainty about its use in clinical practice. The aim of this study was to analyze the impact of antithrombotic therapy and statins on the risk of hemorrhage and focal neurological deficit in patients with CMs. Methods: The authors’ institutional database was screened for all patients with CMs of the central nervous system treated at their institution between 2006 and 2018. Patients with radiological and/or histological diagnosis of CMs, clinical baseline characteristics, available patient’s medication history, and follow-up data were included in this study. Time-to-event probability (hemorrhage or focal neurological deficit) as well as the number of events (hemorrhage or focal neurological deficit) during follow-up were assessed in patients who were categorized according to their medical treatment (antithrombotic therapy, statins, combined therapy, or no treatment). Results: Four hundred twenty-eight patients with CMs were eligible and included in the final analysis. Sixty-nine (16.1%) patients were on long-term antithrombotic therapy and 46 (10.6%) on long-term statins, of whom 31 patients were on a combination of both. The probability of experiencing first hemorrhage or focal neurological deficit was less likely in patients on antiplatelet therapy (HR 0.09, 95% CI 0.021–0.39, p = 0.001), anticoagulant therapy (HR 0.12, 95% CI 0.016–0.85, p = 0.034), or the combination thereof (HR 0.12, 95% CI 0.016–0.93, p = 0.043) compared to patients with no antithrombotic treatment. The number of hemorrhages and focal neurological deficits were significantly lower in patients on antithrombotic therapy compared to patients on no treatment during follow-up. In patients on statins alone, the time-to-event probability was comparable to that of patients on no treatment (HR 0.91, 95% CI 0.438–1.91, p = 0.812), and the number of events was similar to patients on no treatment. Conclusion: The results of our study provide further evidence that antithrombotic therapy alone or in combination with statins in patients with CMs of the central nervous system does not increase the risk of hemorrhage or focal neurological deficit but, on the contrary, may have some benefit.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Cavernous malformations (CMs) are the second most common vascular malformations of the central nervous system with a prevalence of 0.1–0.8% in the general population [1, 2]. Nonetheless, the literature regarding the safety and efficacy of drugs, especially, antithrombotic (antiplatelet or anticoagulant) agents and statins in patients with CMs is sparse, resulting in uncertainty about its use in clinical practice [3-6]. Antithrombotic agents are, therefore, often withheld from patients harboring CMs, even in the presence of strong medical indication, since it is still widely believed that they may increase the hemorrhage risk in such patients [2, 6].

However, recent studies have initiated a paradigm shift in the understanding of the pathophysiology underlying CM hemorrhages [4]. There is increasing evidence that the pathogenesis of hemorrhage and focal neurological deficit in patients with CMs might be different to what is commonly thought and is most likely triggered by thrombosis in the CM or an associated venous anomaly [7]. CMs are endothelium-lined cavities containing blood of different ages; those dilated caverns may cause the blood to flow slowly, which makes them more susceptible to thrombus formations [7, 8] and, consequently, a potential source of new or progressive focal neurological deficit or hemorrhage [9, 10]. This raises the hypothesis that antithrombotic agents and statins might be beneficial in these patients due to inhibition of venous outflow thrombosis.

Accordingly, there is first evidence that long-term antithrombotic treatment does not increase the frequency of CM-related hemorrhages but is even beneficial in these patients [4, 11-13]. In addition, early evidence suggests that statins reduce the risk of hemorrhages in patients with CMs [11, 14]. By acting on the vessel wall, statins are known to prevent lesion initiation and repair injuries, enhance myocardial perfusion, slow lesion progression, and prevent coronary occlusion and, therefore, are used in daily clinical practice [15, 16]. Given the paucity of literature regarding the safety and efficacy of antithrombotic agents and statins in patients with CMs, the aim of this study was to quantify the association between antithrombotic and statin therapy and hemorrhages or focal neurological deficit attributable to CMs in a large patient cohort with 428 patients and to further define the role of these medications alone and in combination in the management of patients with CMs.

Material and MethodsStudy Design

A retrospective single-center study was conducted, comprising all patients with CMs who were followed between 2006 and 2018 at the Department of Neurosurgery at the University Hospital Zurich, a tertiary reference center. Patients fulfilling the following criteria were eligible and included: (1) radiological and/or histological diagnosis of CMs, (2) available clinical baseline characteristics, (3) medication history, and (4) follow-up data with available magnetic resonance imaging and consultation with a board-certified neurosurgeon or neurologist. Radiological and histological diagnoses of CMs were confirmed either by a board-certified neuroradiologist and/or neuropathologist.

Data Collection

The charts of all patients were screened for baseline characteristics: date and age at initial diagnosis, sex, date of surgery for CM, medical history, family history (familial CM [FCCM]), cardiovascular and non-cardiovascular comorbidities, and date of last follow-up. Magnetic resonance imaging results were reviewed and assessed for CM location (supratentorial, brainstem, cerebellum, and spinal cord) as well as occurrence of multiple CCMs (mCCMs). The diagnosis of FCCM was established in a patient with either or both of the following findings: (1) mCCMs or one CCM and at least one other family member with ≥1 CCMs; and/or (2) a heterozygous pathogenic variant in KRIT1, CCM2, or PDCD1 [17].Cardiovascular comorbidities were distinguished as (1) hypertension, (2) coronary heart disease/myocardial ischemia, (3) transient ischemic attack/stroke, (4) atrial fibrillation and other cardiac arrhythmias, and (5) artificial heart valves.

We collected medical history from medical records at baseline and identified treatment and outcomes using annual prospective surveillance of hospital records and available primary care practitioner records. We retrospectively collected data for long-term antithrombotic therapy and statin therapy (HMG-CoA reductase inhibitors) use from these data sources. Antithrombotic therapy is used in our study as the generic term for the intake of either antiplatelet or anticoagulant therapy. Antiplatelet therapy was further subdivided into the intake of (1) acetylsalicylic acid (aspirin), (2) clopidogrel (Plavix), and (3) other antiplatelets, whereas with anticoagulant therapy, we distinguished between (1) rivaroxaban (Xarelto), (2) apixaban (Eliquis), and (3) other anticoagulants. Long-term antithrombotic and statin therapy use were both defined as the prescription and receipt of anticoagulant or antiplatelet therapy for at least 90 days at any time after the starting point but before the first outcome event or the end of follow-up (if an outcome event did not occur).

The starting point was the time of the first clinical presentation. In the final analysis, we included every individual with a first-in-a-lifetime diagnosis of CMs which fulfilled the abovementioned inclusion criteria and categorized the type of the first clinical presentation by the symptoms that led to the initial diagnosis into (1) incidental finding, (2) focal neurological deficits, or (3) seizures (regardless of earlier events that might, in retrospect, have been attributable to a CM). We noted as well whether hemorrhage did or did not occur at the initial diagnosis.

The primary outcome was defined by a new hemorrhage (confirmed by acute/subacute hemorrhage on brain imaging consistent with the time of symptom onset) or a new focal neurological deficit attributable to the location of the CM (but without evidence of a new hemorrhage on brain imaging). Focal neurological deficits without evidence of a new hemorrhage on brain imaging were included as primary outcome since they might be due to an undetected hemorrhage on imaging or triggered by thrombosis and, thus, might be affected by medical treatment [13, 18]. The type of new focal neurological deficit during follow-up was further categorized into (1) sensory deficit, (2) motoric deficit, (3) seizures, (4) cranial nerve deficit, and (5) headache.

Dates and number of outcome events (new hemorrhage or focal neurological deficit) were quantified during follow-up. Two investigators (SW and SN) assessed outcome events using available clinical, radiological, and pathological information, masked to antithrombotic therapy and statin use. Patients who had undergone surgery were censored on the day of CM removal, and patients with loss of follow-up were censored on the day of the last follow-up. The electronic patient chart was screened for causes and occurrence of death.

Statistical Analysis

All statistical analyses were performed using R 4.0.0 (R Core Team, 2020). The statistical code is provided in the supplemental materials, including the versions of the R packages used. Descriptive statistics are presented as absolute numbers (n) and proportions (%) for categorical variables, whereas continuous variables are shown as mean and standard deviation (SD). Group differences in the number of outcome events (hemorrhages and focal neurological deficits) were assessed using the Kruskal-Wallis and the Wilcoxon rank sum tests. The strength of association between the number of outcome events (hemorrhages and focal neurological deficit) and patient age, antithrombotic therapy, statins, location of the CM, and the presence of mCCM was assessed using a generalized additive model (GAM). Time-to-event probabilities were plotted using the Kaplan-Meier method [19]. For multivariable survival analysis, the Cox proportional hazards regression model was used [20].

ResultsBaseline Characteristics

Four hundred thirty-two individuals with CMs of the central nervous system were treated at our institution between 2006 and 2018. Four hundred twenty-eight patients were eligible and included in the final analysis; 4 patients were excluded as there were no follow-up data available. The median age at initial presentation that led to CM diagnosis was 44.5 ± 18.3 years; 201 individuals were female (47.0%) (Table 1). CMs were located in the supratentorial compartment in 239 patients (55.8%), in the brainstem in 81 patients (18.9%), in the cerebellum in 29 patients (6.8%), in the spinal cord in 26 patients (6.1%), and in multiple anatomical compartments in 53 patients (12.4%). The diagnosis of FCCM was established in 78 patients (18.2%).

Table 1.

Patients’ baseline characteristics stratified by the use of antithrombotic therapy and statins

Onset of focal neurological deficit or seizures led to the initial presentation and diagnosis of CM in 241 patients (56.3%) and 87 patients (20.3%), respectively. Incidental finding of CMs occurred in 100 patients (23.4%). Detailed information on the cardiovascular and non-cardiovascular comorbidities of our patient cohort can be found in Table 1. Of the 428 patients, 208 patients (48.6%) underwent surgical resection of at least one CM.

Of these 428 patients, 69 patients (16.1%) were on long-term antithrombotic therapy, 46 (10.8%) patients were on statins, while 31 patients (7.2%) were on a combination of both. 49 patients (11.4%) were on antiplatelet therapy with most of them on aspirin monotherapy (35/49 patients). Thirty-three patients (7.7%) were on anticoagulation monotherapy or a combination of antithrombotic treatment. Detailed information on the medical treatment of this patient cohort can be found in Table 2.

Table 2.

Detailed information on the long-term antithrombotic and statin treatment in our patient cohort

Patients on antithrombotic therapy and/or statins were older (61.2 vs. 41.3 years and 62.0 vs. 42.4 years), and the type of CM presentation was more likely to be incidental and less likely due to onset of neurological deficits or hemorrhage. Patients on antithrombotic therapy and/or on statins were less likely to undergo resection of CMs. There were no relevant differences in CM multiplicity, location of CM, or sex compared to the control groups (Table 1). Patients on antithrombotic therapy and/or on statins were more likely to have cardiovascular comorbidities such as hypertension, coronary heart disease/myocardial ischemia, transient ischemic attack/stroke, atrial fibrillation and other cardiac arrhythmia, and an artificial heart valve than patients never using antithrombotic or statin therapy (Table 1).

Reduced Risk of First Hemorrhage and Focal Neurological Deficit in Patients with CMs on Antithrombotic Therapy

The patient cohort with 428 patients was followed from the initial diagnosis of CMs for the primary outcome of hemorrhage or focal neurological deficit related to CMs. Time-to-event probabilities were visualized using the Kaplan-Meier method (Fig. 1a–d). The probability of experiencing first hemorrhage (Fig. 1a) or focal neurological deficit (Fig. 1c) after initial presentation was less likely in patients on antiplatelet (HR 0.09, 95% CI 0.021–0.39, p = 0.001), anticoagulant therapy (HR 0.12, 95% CI 0.016–0.85, p = 0.034), or the combination thereof (HR 0.12, 95% CI 0.016–0.93, p = 0.043) compared to patients with no antithrombotic treatment (Fig. 1e). Patients on antithrombotic therapy and statins were less likely to experience a first hemorrhage (Fig. 1b) or focal neurological deficit (Fig. 1d) compared to patients receiving no medical treatment or on statins alone. Multivariate Cox regression analysis (Fig. 1e) provided evidence for an independent association between the use of antithrombotic therapy and a lower risk of the primary outcome (hemorrhage or focal neurological deficit). This did not hold true for the use of statins (HR 0.91, 95% CI 0.438–1.91, p = 0.812) (Fig. 1e). Patients with CMs in the brainstem (HR 1.72, 95% CI 1.136–2.60, p = 0.01), the spinal cord (HR 2.62, 95% CI 1.363–5.02, p = 0.004), or multiple compartments (HR 2.53, 95% CI 1.212–5.26, p = 0.013) were more likely to experience first intracranial hemorrhage or focal neurological deficit due to CMs (Fig. 1e).

Fig. 1.

Time-to-event probabilities for a first hemorrhage or focal neurological deficit. Kaplan-Meier curve visualizing the probability of a first hemorrhage (a) or focal neurological deficit (c) over time in patients on antiplatelets, anticoagulants, or the combination thereof. Kaplan-Meier curves visualizing the probability of a first hemorrhage (b) or focal neurological deficit (d) over time in patients on antithrombotic therapy, statins, or the combination thereof. e Multivariable time-to-event analysis (first hemorrhage or first focal neurological deficit) based on the Cox proportional hazards regression model. AC, anticoagulant therapy; AP, antiplatelet therapy; AT, antithrombotic therapy.

Fewer Hemorrhages and Focal Neurological Deficits during Follow-Up in Patients on Antithrombotic Therapy

The mean number of hemorrhages during follow-up was 0.4 ± 1.0 in the overall patient cohort of 428 patients. Antithrombotic therapy was associated with fewer numbers of hemorrhages (p < 0.001) and focal neurological deficits (p < 0.001) during follow-up, while there was no association between statin therapy and the number of hemorrhages (p = 0.032) and focal neurological deficits (p = 0.953) (Table 3).

Table 3.

Clinical outcome stratified by antithrombotic and statin therapy

In addition, the number of hemorrhages during follow-up showed a negative association with the use of antiplatelets (p < 0.001), anticoagulants (p = 0.022), or a combination of both (p = 0.096) (Fig. 2a). Patients on statins did not show a reduced number of hemorrhages during follow-up (p = 0.45, Fig. 2b). Multivariable analysis based on a GAM (Fig. 2c) supported an independent negative association between the number of hemorrhages during follow-up and the use of antithrombotic therapy (pantiplatelets = 0.026, panticoagulants = 0.072, pantiplatelets and anticoagulants = 0.14) or multiple cavernoma locations (p < 0.001), while there was no association to statins (p = 0.54) or specific anatomical locations (pbrainstem = 0.23, pcerebellum = 0.87, pspinal = 0.86).

Fig. 2.

Number of new hemorrhages or new neurological deficits during follow-up. a, b Group differences in the number of new hemorrhages during follow-up quantified using the Kruskal-Wallis and the Wilcoxon rank sum tests. AC, anticoagulant therapy; AP, antiplatelet therapy; AT, antithrombotic therapy. c Strength of association between the number of new hemorrhages during follow-up and patient age, antithrombotic treatment, statin treatment, location of the CM, and the presence of mCCM based on a generalized additive model (GAM). d, e Group differences in the number of new focal neurological deficits during follow-up quantified using the Kruskal-Wallis and the Wilcoxon rank sum tests. f Strength of association between the number of new focal neurological deficits during follow-up and patient age, antithrombotic treatment, statin treatment, location of the CM, and the presence of mCCM based on a GAM.

The number of new focal neurological deficits during follow-up also exhibited a negative association with the use of antiplatelets (p = 0.0021), anticoagulants (p = 0.01), or a combination of both (p = 0.037) (Fig. 2d). Patients on statins did not show a reduced number of new focal neurological deficits during follow-up (p = 0.97, Fig. 2e). Multivariable analysis based on a GAM (Fig. 2f) supported an independent negative association between the number of new focal neurological deficits during follow-up and the use of antithrombotic therapy (pantiplatelets = 0.001, panticoagulants = 0.017, pantiplatelets and anticoagulants = 0.008).

Discussion

Great uncertainty remains in clinical practice regarding the use and safety of medication in patients with CMs of the central nervous system due to the unknown pathogenesis of CM hemorrhage and focal neurological deficit [6, 21]. However, recent studies have initiated a paradigm shift in the understanding of the pathophysiology underlying CM hemorrhages [4]. A recently published landmark study showed that patients with CMs who were on antithrombotic therapy had a decreased risk of hemorrhage and focal neurological deficit [13]. These findings are consistent with the results of this study, which showed that long-term antithrombotic therapy reduces the risk of hemorrhage and focal neurological deficit in patients with CMs, not only regarding the time-to-event probability but moreover on the number of events (hemorrhage and focal neurological deficit) during life. This patient cohort is the largest case series published so far analyzing the effect of antithrombotic therapy and statins in patients with CMs of the central nervous system and provides further reassurance about the use of any type of antithrombotic therapy in these patients.

Preclinical studies have shown that statins reduce the hemorrhage risk in CMs due to their capacity to stabilize the cerebral vascular system via the prenylation-dependent signaling pathway [12]. Zuurbier et al. [14] were the first to show in a prospective, population-based study of adults with CMs that the risk of a new hemorrhage or persistent/progressive focal neurological deficit in patients using statins was insignificantly lower. In our cohort, patients on antithrombotic therapy and statins were less likely to experience hemorrhage and focal neurological deficit, whereas patients solely on statins were equally likely to present with hemorrhage or focal neurological deficit compared to patients under no medical treatment (Fig. 1, 2).

The findings of our study have strong implications for clinical practice and provide reassurance for antithrombotic therapy alone or in combination with statins in patients with strong indication for its use due to, e.g., cardiovascular comorbidities. The increasing evidence that antithrombotic therapy reduces the risk of hemorrhage and focal neurological deficit in patients with CMs, most likely due to the prevention of thrombus formation in these lesions, raises a hypothesis that needs to be tested in a randomized controlled trial in patients with CMs with or without other indications for antithrombotic therapy.

The strengths of our study include the large sample size of 428 patients, which is the largest study cohort so far analyzing the impact of antithrombotic therapy and statins in patients with CMs of the central nervous system; the overall very long follow-up time of 1,608.9 person-years in total, and outcome assessment masked to antithrombotic and statin use. The limitations of our study are the inherent limitations of retrospective cohorts and incomplete patient information; the potential selection given the retrospective study design with a bias toward the use of antithrombotic and statin therapy (i.e., patients without a history of hemorrhage were more likely to use antithrombotic therapy) and the overall low number of patients on antithrombotic therapy or statins (16.1% and 10.8%, respectively).

Conclusion

The results of our study provide further reassurance that antithrombotic therapy alone or in combination with statins in patients with CMs is safe and does not increase the risk of hemorrhage or focal neurological deficit but, on the contrary, may have some benefit.

Statement of Ethics

The study was reviewed and approved by the Cantonal Ethics Committee and has been granted an exemption from requiring written informed consent of each patient (KEK-ZH; application number 2017-00330). Generalized patient consent was used, written informed consent was waived, and patients or children’s parents could oppose the use of their health-related data for the purpose of research. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of Interest Statement

There are not conflicts of interests.

Funding Sources

This study did not receive any funding.

Author Contributions

Saskia Wildi and Selina Nager: acquisition of data and drafting the article. Kevin Akeret: statistical analysis, analysis and interpretation of data, and critically revising the article. Sena Özkaratufan, Niklaus Krayenbühl, Oliver Bozinov, and Luca Regli: acquisition of data and critically revising the article. Julia Velz: conception and design, acquisition of data, analysis and interpretation of data, drafting the article, and critically revising the article.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.

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