Girard, R.

Background A recent randomized prospective controlled trial demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter rebleeding in cerebral cavernous malformations. However, any consequences of discontinuing atorvastatin remain unknown. We hypothesized that symptomatic hemorrhage (SH) recurs more frequently in cerebral cavernous malformations after discontinuation of atorvastatin than placebo. Methods We conducted a 12‐month posttreatment follow‐up of patients enrolled in the Atorvastatin Therapy in Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) trial (41 randomized to atorvastatin, 39 to placebo) to identify potential recurrent SH after trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded from follow‐up for <90% compliance with study drug, for its discontinuation <3 months after trial enrollment, for statin reinitiation <3 months after discontinuation, or for lack of follow‐up. Cases were censored during follow‐up upon cerebral cavernous malformation resection/radiation or later statin reinitiation. Results Follow‐up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin. Four SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and 1 SH at 395 days after discontinuing placebo. There was significantly lower symptomatic hemorrhage‐free survival in the atorvastatin‐discontinuation group (log‐rank χ 2 =4.136, P =0.042). The hazard ratio was 0.162 (95% CI, 0.027–0.977) for placebo versus atorvastatin discontinuation. Conclusions Discontinuation of atorvastatin was associated with a higher risk of recurrent SH compared with placebo discontinuation. Additional studies are warranted to confirm this hypothesis‐generating observation, examine potential mechanisms, and how best to mitigate this risk. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02603328.

Background: There is much interest in drug development to prevent rebleeding after symptomatic hemorrhage (SH) in cerebral cavernous malformations (CCM) and its neurologic sequelae. A recent randomized prospective controlled trial (AT CASH EPOC clinicaltrials.gov NCT02603328) demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter CCM iron deposition or SH rates. However, the consequences of discontinuing atorvastatin in CCM patients remain unknown. Given reports of rebound effects with discontinuation of statins, we here hypothesize that SH recurs more frequently in hemorrhagic CCMs after discontinuation of atorvastatin than placebo. Methods: We conducted 12-month (±1 month) post-treatment follow-up of all 80 patients randomized in the AT CASH EPOC trial (41 atorvastatin, 39 placebo) to identify potential recurrent SH from the date of trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded for < 90% compliance with study drug or its discontinuation <3 months during the trial, and for lack of follow-up. Cases were censored during follow-up upon CCM resection/radiation or atorvastatin initiation/re-initiation. Results: Follow-up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin.During follow-up, 4 SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and only 1 SH 395 days after discontinuing placebo. Kaplan–Meier curves demonstrated significantly lower symptomatic hemorrhage-free survival in the atorvastatin-discontinuation group (log-rank chi=4.136, p=0.042). The Gehan–Breslow–Wilcoxon test (chi=4.080, p=0.043) highlighted early divergence in recurrent SH risk. The hazard ratio was 0.162 (95% CI 0.027–0.977) for placebo vs. atorvastatin discontinuation. Conclusion: While there was no difference in SH rates during 2 years of treatment with atorvastatin versus placebo in randomized clinical trial, discontinuation of atorvastatin was associated with a significantly higher and earlier risk of recurrent SH compared with placebo discontinuation. This raises concern for a rebound effect during the year after statin withdrawal in hemorrhagic CCM patients, potentially mediated by reactivation of Rho-associated kinase. Additional studies are warranted to confirm these observations and to assess whether statin tapering or maintenance therapy can mitigate the risk of discontinuation in hemorrhagic CCM.

Introduction: Functional outcome scales are commonly used in neurological clinical trials. Prior studies suggested that these scales may reflect symptomatic hemorrhage (SH), but their performance in detecting treatment effects has not been assessed in clinical trials of cerebral cavernous malformations (CCM). And they have not been correlated with CCM bleeding as reflected by lesional iron content assessed by quantitative susceptibility mapping (QSM) MRI. Hypothesis: We hypothesized that functional outcome measures would detect differences between treatment arms in a randomized clinical trial of hemorrhagic CCM, and reflect new SH or a ≥6% increase in mean lesional QSM reflective of CCM bleeding. Methods: Eighty adults with CCM-related SH in the prior 12 months of enrollment were randomized 1:1 to atorvastatin 80 mg/day or placebo for 2 years. Functional outcomes, including mRS, EQ-5D index, EQ-VAS, and PROMIS-29 domains, were collected at baseline, Year 1, and Year 2. Analyses were conducted in 63 participants (32 atorvastatin, 31 placebo) in the modified intention-to-treat trial cohort who had contributed at least one paired annual clinical and imaging assessment. Results: No significant differences were found between atorvastatin and placebo groups in any functional outcome measure across timepoints. Rates of functional decline and improvement were comparable, except for PROMIS Fatigue which improved more in the atorvastatin than placebo patients from baseline to Year 1 (p=0.019). Pooled analyses showed that several functional domains had strong specificity for identifying SH. PROMIS Sleep Disturbance decline from baseline to Year 2 was associated with SH (p=0.0045; specificity 92.3%, sensitivity 57.1%). A ≥10-point drop in EQ-VAS from baseline to Year 1 identified all SH cases during that interval (p=0.007; sensitivity 100%, specificity 83.6%). Functional decline had low sensitivity in detecting CCM bleeding on QSM, though specificity was high (>75%) across domains. Conclusions: Atorvastatin did not influence functional change over 2 years by any measure. PROMIS Sleep Disturbance and EQ-VAS demonstrated high specificity, and in the case of EQ-VAS also a high sensitivity for identifying SH. Functional outcomes across domains also had high specificity for occult bleeding in CCMs as measured by QSM. Poor sensitivity and consistent improvements over time demonstrate the limitations of functional outcome measures as endpoints of drug effects on CCM bleeding.

Background: It is not clear if changes in lesion volume might represent a clinically relevant and statistically advantageous outcome parameter in early phase trials of novel drugs aimed at preventing bleeding in cerebral cavernous malformations (CCM). Methods: We analyzed the modified intention to treat cohort (33 patients receiving atorvastatin and 31 placebo) who contributed at least one paired imaging biomarker in the recently completed double-blinded randomized controlled AT CASH EPOC trial (clinicaltrials.gov NCT02603328). We examined prospective changes in CCM lesion volume and correlated these with symptomatic hemorrhage (SH) events. We contemporaneously assessed changes in lesional iron content by quantitative susceptibility mapping (QSM) on MRI, and objective (mRS) and subjective (EQ-VAS) functional status. We also simulated sample sizes needed to detect potential effects of a drug on lesion volume. Results: There was excellent correlation between independently assessed maximum lesion diameter and CCM lesion volume (R 2 = 0.68, P<0.0001). The mean (SD) percentage change in lesion volume per year was +6 (65) and +18 (94) in atorvastatin and placebo patients, respectively (P= 0.43). All cases with SH had increases in lesion volume as well as increases in mean lesional iron content by QSM, and most had declines in functional status on mRS and EQ-VAS. But there were many cases with increases in lesion volume with improved functional status or decreased mean lesional QSM, and other cases with worsening in function or increased lesional QSM and decreased lesion volume. There were no significant correlations of changes in lesion volume with concomitant changes in mean lesional QSM, mRS or EQ-VAS (all R/R 2 <0.5 and Bonferroni corrected P>0.05), including in brainstem lesions analyzed separately. Sample size simulations indicate larger numbers of cases needed to demonstrate a drug effect on changes in lesion volume than those needed to detect an effect on QSM change with a=0.05 and b=0.8, and even larger samples to detect effects on the proportion of cases with increased or decreased lesion volume. Conclusion: Changes in lesion volume occur frequently in CCM lesions after recent SH, but do not correlate with measures of bleeding in the lesions, nor appear to reflect functional changes. And they are not statistically advantageous in comparison to QSM measures for detecting potential drug effects.