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. Author manuscript; available in PMC: 2016 May 1.
Published in final edited form as: AJNR Am J Neuroradiol. 2015 Aug 13;36(11):2104–2107. doi: 10.3174/ajnr.A4422

Could statin use be associated with reduced recurrence rates following coiling in ruptured intracranial aneurysms?

Waleed Brinjikji 1, Varun Shahi 2, Harry J Cloft 1, Giuseppe Lanzino 3, David F Kallmes 1, Ramanathan Kadirvel 1
PMCID: PMC4644684  NIHMSID: NIHMS682608  PMID: 26272974

Abstract

Background and Purpose

A number of studies have examined the role of matrix metalloproteinases (MMPs) in aneurysm healing following endovascular coiling. Because ruptured aneurysms are known to express higher levels of MMPs, we hypothesized that subarachnoid hemorrhage patients who were on a statin at the time of coil embolization would have lower aneurysm recanalization and retreatment rates than non-statin patients.

Materials and Methods

We performed a retrospective chart review of patients who received intrasaccular coil embolization of ruptured intracranial aneurysms≤10mm with at least 6-months of imaging follow-up. Patients were separated into two groups: 1) patients who were on an oral statin medication at the time of coiling and 2) patients who were not on a statin. Outcomes studied were aneurysm recurrence and aneurysm retreatment after endovascular coiling. Student’s t-test and chi-squared tests were used to test statistical significance of differences between groups.

Results

132 ruptured aneurysm patients with 132 ruptured aneurysms were included in our study. 16 were on statin (12.1%) and 116 were not (87.9%). Recurrence rate was 6.3% in the statin group (1/16) and 36.2% in the non-statin group (42/107) (P=0.017). Unplanned retreatment rates were 6.3% (1/16) for the statin group and 25.9% (30/116) for the non-statin group (P=0.08).

Conclusions

Statins were associated with a lower rate of aneurysm recurrence following endovascular coiling of small and medium sized ruptured aneurysms in this small retrospective study. Further studies are needed to confirm this finding to determine if statins can be used to reduce recurrence rates in these aneurysms.

Keywords: Subarachnoid Hemorrhage, Endovascular Treatment, Interventional Neuroradiology, Intracranial Aneurysm

Introduction

Approximately 20% of patients receiving endovascular coiling of intracranial aneurysms have an aneurysm recurrence and 10% require retreatment of the coiled aneurysm1. Given the risk of morbidity and mortality associated with retreatment, considerable research has been invested into determining methods to reduce the rate of aneurysm recurrence and retreatment. Statin medications are commonly prescribed medications which have been shown to have a number of beneficial health effects including reducing the risk of cardiovascular disease and stroke. Statins have been found to stimulate production of extracellular matrix and stimulate chemotactic migration and mobilization of endothelial and mesenchymal progenitor cells and stromal osteoblasts, factors important to aneurysm healing25. Statins are also effective at inhibiting chemotaxis of pro-inflammatory cells such as macrophages by inhibiting expression of adhesion molecules and decreasing macrophage expression of matrix metalloproteinases (MMPs)6. MMPs are molecules which have been shown to promote recanalization of arteries and aneurysms following endovascular embolization7.

Because statins stimulate cellular and molecular pathways known to be helpful for aneurysm healing and inhibit the expression of MMPs, molecules thought to contribute to aneurysm recanalization following endovascular coiling, it would be interesting to study the effect of statins on aneurysm recanalization and retreatment rates. We retrospectively reviewed a large series of ruptured intracranial aneurysms treated with endovascular coiling and compared the rates of aneurysm recanalization and retreatment among patients who were taking statins at the time of treatment and those who were not. We chose to specifically study ruptured aneurysms due to the fact that these aneurysms have high recanalization rates and have been shown to highly express MMPs, molecules which are inhibited by statin medications8.

Materials and Methods

Patient Selection

Following IRB approval, we conducted a retrospective chart review of all patients who received endovascular treatment of ruptured intracranial aneurysms from January 2005 to December 2013. Inclusion criteria were the following: 1) patients received intrasaccular coil embolization of an intracranial aneurysm with a maximum diameter≤10mm, 2) had follow-up imaging with either digital subtraction angiography or MR angiography at least six months later, and 3) had a recording of a medical list from the time of presentation at aneurysm rupture. Patients who did not meet all three of these criteria were excluded from the analysis.

Baseline Characteristics

Patients were then stratified into two groups: 1) patients on statin medications and 2) patients not on statin medications. Use of statin medications was determined from the patient’s medical chart from the time of admission for subarachnoid hemorrhage. Discharge notes were searched to ensure that the patient was not taken off of the statin upon hospital discharge. Thus, all patients in the statin group were on statins at the time of rupture and during the follow-up period. No patients were started on statins at the time of aneurysm rupture or at discharge. In addition to statin use, the following information were obtained: type and dose of statin, age, gender, comorbidities (hypertension, diabetes mellitus and current smoking), aneurysm location, aneurysm maximum size, initial degree of occlusion, and use of balloon assistance. Current smokers were defined as patients who were smoking at the time of aneurysm rupture and continued to smoke on follow-up.

Outcomes

The two primary outcomes of this study were aneurysm recurrence and unplanned aneurysm retreatment following endovascular aneurysm treatment. Initial aneurysm occlusion was categorized based on the Raymond scale into: 1) residual aneurysm, 2) residual neck and 3) complete occlusion. Follow-up aneurysm occlusion was categorized into two outcomes: 1) stable occlusion and 2) aneurysm recurrence defined as coil compaction and/or recanalization. Retreatments were categorized as unplanned and planned-staged. A retreatment was considered planned-staged if the treating team mentioned in the operative note or follow-up clinical notes that further treatment was recommended to improve aneurysm occlusion (i.e. planned coiling of an aneurysm followed by PED placement). Planned-staged retreatments were excluded from our analysis.

Statistical Analysis

Continuous variables were presented as mean (SD) and categorical variables as frequency (percentage). Student’s T-test and chi-square tests were used to test statistical significance in aneurysm recurrence and/or retreatment in relation to patient statin use. We also performed a multivariate logistic regression analysis to determine if statin use was independently associated with recanalization and retreatment. Any baseline variables which were significantly different between the two groups were included in this model.

Results

Baseline Characteristics

When considering patients with ruptured aneurysms 10mm or smaller, 16 patients were on statin medications at the time of treatment and 116 patients were not. Mean age of the statin group was higher than that of the non-statin group (70.2 versus 57.0, P<0.0001). Mean aneurysm size was similar between groups (5.4mm versus 5.6mm, P=0.63). Baseline occlusion status (P=0.51) and use of balloon assistant were similar between groups (P=0.31). There were similar rates of hypertension (P=0.59), diabetes mellitus (P=0.20) and smoking (P=0.19) between groups. Mean follow-up was 23.4 months for the statin group and 25.1 months for the non-statin group (P=0.59).

Among patients in the statin group, the most common statin medication used was simvastatin (6 patients, dose 20mg–40mg), followed by atorvastatin (5 patients, dose 10mg–20mg), rosuvastatin (3 patients, dose 5mg–20mg), and pravastatin (2 patients, 20mg–80mg). All patients were on statin therapy for the duration of their follow-up (25 months–96 months). The indication for statin therapy was hyperlipidemia in all cases.

Outcomes

Recurrence rates were significantly lower in the statin group than in the non-statin group. Recurrence rates were 6.3% (1/16) for the statin group and 36.2% (41/116) for the non-statin group (P=0.017). There was a trend towards lower retreatment rate in the statin group. Unplanned retreatment rates were 6.3% (1/16) for the statin group and 25.9% (30/116) for the non-statin group (P=0.08). Among patients in the non-statin group, 16 patients were recoiled, 5 underwent flow diverter treatment and nine underwent clipping. One patient in the statin group was retreated with a flow diverter. These data are summarized in Table 1.

Table 1.

Baseline Characteristics and Recurrence and Retreatment Rates: Ruptured Aneurysms≤10mm

Statin Group Non-Statin Group P
N 16 116 -
Mean Age (SD) 70.2 (9.0) 57.0 (11.7) <.0001
N (%) Female 12 (75.0) 77 (66.4) 0.58
N (%) Hypertension 10 (62.5) 61 (52.6) 0.59
N (%) Diabetes 3 (18.8) 10 (8.6) 0.20
N (%) Current Smoker 3 (18.8) 41 (35.3) 0.19
Aneurysm Location
 ICA N (%) 6 41
 ACA/Acom N (%) 9 50
 MCA N (%) 0 7 0.88
 VBA N (%) 1 16
 Other N (%) 0 2
Mean Size (SD) 5.4 (1.8) 5.6 (2.0) 0.63
Initial Occlusion
 Complete 8 (50.0) 60 (51.7)
 Residual Neck 6 (37.5) 50 (43.1)
 Residual Aneurysm 2 (12.5) 6 (5.2) 0.51
Balloon Assistance 4 (25.0) 18 (15.5) 0.31
Mean Follow-up 23.4 (14.4) 25.1 (25.4) 0.59
N(%) Recurrence 1 (6.3) 42 (36.2) 0.017
N (%) Retreatment 1 (6.3) 30 (25.9) 0.08

The only baseline characteristics that differed between the statin and non-statin groups were mean age. When considering patients with ruptured aneurysms 10mm or small and adjusting for age, statin use was associated with a significantly lower odds of recurrence (OR=0.13, 95%CI=0.01–0.72, P=0.016) and a non-statistically significant lower odds of retreatment (OR==0.29, 95%CI=0.01–1.55, P=0.16).

Discussion

Our small, retrospective study demonstrated that patients with ruptured aneurysms 10mm or smaller who were on a statin at the time of aneurysm treatment had lower rates of aneurysm recurrence and had a trend towards lower retreatment rates when compared to those who were not on a statin. These findings are important as they suggest that statin therapy may represent a low cost and efficacious therapy in reducing recurrence rates in some patients with ruptured aneurysms. However, these results need to be confirmed in future, larger studies before they can be applied in routine clinical practice.

We chose to specifically study the recanalization rates of ruptured aneurysms receiving endovascular coiling because of the fact that MMPs are expressed at significantly higher levels in ruptured compared to unruptured aneurysms810. MMPs, specifically MMP-2 and MMP-9, are proteases which are thought to play a role in aneurysm formation, growth, rupture, and recanalization1114. Statins are potent inhibitors of MMP-2 and MMP-9 formation and expression1518. We hypothesize that by inhibiting MMPs early in the healing process, statins can prevent any further growth of the aneurysm, thus reducing recurrence rates. This hypothesis is supported by work from Hasan et al who demonstrated that aneurysm sac growth, not coil compaction, is the primary mechanism associated with post-coiling aneurysm recurrence19. In addition, statins likely enhance many other facets of the aneurysm healing process such as cellular infiltration of the aneurysm dome, deposition of extracellular matrix and endothelialization of the aneurysm neck5, 15, 20. Statins upregulate expression of TGF-B and BMP-2, factors important in stimulating migration of osteoblasts and mesenchymal progenitor cells to the aneurysm dome21.

There are some other, previously reported preclinical data to suggest that statins could improve aneurysm healing following endovascular treatment of intracranial aneurysms. One previous study comparing statin-coated coils to bare metal coils in coil embolization of rat aneurysms demonstrated that aneurysms treated with statin covered coils had improved aneurysm occlusion due to increased tissue organization about the coils and increased collagen deposition in the aneurysm dome. In addition, this same previous study demonstrated increased endothelialization of the aneurysm neck in statin-covered coil treated aneurysms compared to non-statin covered coil aneurysms22. A number of previous clinical studies of patients receiving endovascular aortic aneurysm repair (EVAR) have demonstrated that statin therapy can promote aneurysm sac regression and healing. A study by Raux et al demonstrated that EVAR patients on statins had a significantly higher rate of aneurysm sac regression compared to their non-statin using counterparts23. These results were confirmed by a later study performed by Gray et al who demonstrated that statin use was independently associated with aneurysm sac regression following EVAR24.

Limitations

Our study has limitations. First, we only included patients with aneurysms 10mm or less. We excluded patients with large and giant aneurysms as these patients much higher recanalization rates than small and medium sized aneurysms due to difficulties in achieving high packing densities25. As such, inclusion large aneurysms may mask the benefit isolated to small and medium-sized aneurysms. Our study only included ruptured aneurysms as it is known that ruptured aneurysms have different biology from unruptured aneurysms as evidenced by elevated recurrence rates in many series26. In our study, only 16 patients were on statin medication. This low number of patients on statin medications may have limited our ability to detect differences between the statin and non-statin groups in aneurysm retreatment rates. In addition, the low number of statin-using patients in our study makes our conclusions unreliable as if only one additional patient had a recurrence in the statin group, statistical significance would be lost. Another limitation is the fact that patients were on various statin agents and on various doses. It is known that there are differences in statin efficacy by type and dose.

Given the small size and limitations of our study, our study should not serve to alter clinical management of patients with ruptured aneurysms. Ultimately, this study sought to determine whether systemic statin therapy warrants further study as a potential therapy to reduce aneurysm recanalization for patients with ruptured aneurysms. Future studies, including animal studies examining the effects of statins on the cellular response to endovascular coiling, large retrospective reviews combining data with multiple centers and prospective clinical trials studying the impact of statins on angiographic outcomes of ruptured intracranial aneurysm patients are needed to confirm these findings.

Conclusions

Our study found that patients with ruptured aneurysms 10mm or smaller had significantly lower aneurysm recanalization rates than those who were not on a statin. In addition, there was a trend towards lower retreatment rates in the statin groups. These results suggest that the role of systemic statin therapy in reducing aneurysm recanalization rates in patients with ruptured aneurysms undergoing aneurysm coiling should be further studied. More data from pre-clinical and retrospective and prospective clinical studies are needed to determine if statins do in fact reduce aneurysm recanalization in the ruptured aneurysm population.

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