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Impact of Statins on Hematoma, Edema, Seizures, Vascular Events, and Functional Recovery After Intracerebral Hemorrhage. Maximilian I. Sprügel, Joji B. Kuramatsu et al. Stroke 2021 Mar;52(3):975-984. doi: 10.1161/STROKEAHA.120.029345
Background: Statins play an important role in the treatment and prevention of ischemic cerebrovascular and cardiovascular disease. The debate on statin therapy and ICH risk is one that is ongoing, ever since the Stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study published in 2006 showed an increase in incidence of ICH with statin therapy. The effect of statin therapy on perihematoma edema (PHE), seizure risk and long-term outcomes are unclear. The aims of this study were to assess the effect of statin use on hematoma volumes, PHE, remote symptomatic seizures and outcomes pertaining cardiovascular adverse events and functional recovery after ICH.
Methods: Authors queried the single-center UKER-ICH registry, which contained a prospective cohort of ICH patients admitted to the University Hospital Erlangen, Germany, between 2006 and 2015. Data on laboratory and clinical parameters were extracted directly from medical charts. Patients with secondary causes of ICH and patients on oral anticoagulation were excluded. All imaging scans during hospitalization were assessed to determine location of ICH (Deep vs. lobar) and to measure PHE volumes, which was done using a semiautomatic volumetric algorithm. Peak PHE was defined as the maximum PHE in any scan during hospitalizations and ICH volume was measured using the ABC/2 method. Statin use was defined as daily statin medication regardless of dose or type of medication and further divided into <1, 1-2 or >2 years of duration. Primary outcome measures were (1) association between statin use and hematoma location/size; (2) extent of PHE depending on statin continuation, discontinuation or initiation; (3) statin use and association with remote symptomatic seizures; and (4) long term cardiovascular outcomes and functional outcomes. Remote symptomatic seizures were defined as seizures >7 days after ICH based on clinical or electrographic seizure activity. Appropriate two--sided statistical analysis was done for all variables. Propensity score matching (PSM) was performed for parameters (baseline characteristics, coronary disease, baseline mRS and ICH characteristics) that showed significant between-group differences.
Results: 1275 patients with primary spontaneous ICH were analyzed. 277 patients (21.7%) with ICH were on statin therapy. Patients on statins were older (76 vs. 72 years; p<0.001), had more medical comorbidities such as hypertension, prior TIA/ischemic stroke, coronary artery disease, and had lower total cholesterol levels compared to patients not on prior statin therapy. The incidence of lobar ICH was higher among patients with statin premedication (56.8% Vs. 45.6%; p=0.037). There were no differences in the admission ICH volumes (measured by ABC method), rates of hematoma expansion (defined as relative ICH volume increase >33% from baseline) or IVH. Binary logistic regression subgroup analyses in the PSM cohort revealed (1) a significant association between statin use and lobar hematoma (odds ratio [OR] 1.57 [1.03-2.40]; p=0.038); (2) association with lobar hematoma after adjusting for anti-platelet medication use, age, statin type, duration and dosage (OR 1.40 [0.84-2.34]); and (3) association with lobar hematoma after adjusting for average atorvastatin equivalent daily dose of >=20 mg/d (OR 1.85 [1.01-3.40]). While there was no significant association between peak PHE and statin therapy on admission, new initiation of statin was associated with increased PHE (β =0.12, SE=0.06; p=0.008). Continuation of statin therapy versus discontinuation, however, was not significantly associated with increased PHE. Remote symptomatic seizures, while numerically more frequently in the statin therapy group, were not significantly different at 1 and 5 years (11.5% Vs. 7.8%, p=0.512 and 17.6% Vs. 12.2%, p=0.25 respectively).
In the analysis of outcome events, the incidence of cardiovascular adverse events was lower in the statin group at 1 year, albeit not reaching statistical significance (crude incidence 11.6% Vs. 18.5%; HR 0.6, p=0.058). Cardiovascular events were significantly lower at 5 years in the statin group (20.9% Vs. 33.3%; HR, 0.56, p=0.004. A higher proportion of patients with statin treatment achieved functional recovery after 1 year (defined as at least 1 point improvement in mRS) (57.7% Vs. 45%; OR 1.67, p=0.019).
Commentary: The key findings of this study are that the continuation of statin premedication did not aggravate PHE, while new initiation of statin therapy in the acute phase of ICH was associated with PHE however outcomes at one year were better in the statin group. Additionally, lobar ICH was more common in patients taking a statin, with a stronger association after adjusting for average daily dose. This study adds to the evidence on the incidence of ICH, and association between lobar ICH location and statin therapy. Authors postulate that microglial activation and accelerated RBC phagocytosis in the hematoma boundary zone may increase peak PHE. Statins are effective for >24 hrs after last dose, which could explain why continuation did not affect PHE formation. Statin therapy prevented secondary cardiovascular events beyond the first 3 months after index ICH, which may in part drive improvement in neurological function at 12 months. Limitations of this study include a single-center non-randomized study design which could result in bias, varying statin regimens and timing of neuro imaging, using ABC/2 method for hematoma volume which approximates all shapes of ICH to that of a sphere. The ongoing Statins in Intracerebral Hemorrhage (SATURN) multi-center prospective randomized controlled trial will aim to clarify the effect of early continuation vs. discontinuation of statins after lobar ICH and its effects on recurrent ICH or major adverse cerebro/cardiovascular events.