PubMed · 1894860
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S M Lieberman. 1991. ISIS-3.. https://doi.org/10.1016/0735-1097(91)90781-4
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Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (-3.47, -3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [-0.05 mg/dl per year, (-0.07, -0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.
Severe intraventricular hemorrhage caused by extension from subarachnoid hemorrhage or intracerebral hemorrhage leads to hydrocephalus and often to poor outcome. We conducted a systematic review to compare conservative treatment, extraventricular drainage, and extraventricular drainage combined with fibrinolysis. We carried out a search in Medline of the literature between January 1966 and December 1998 and an additional hand-search from January 1990 to December 1998. Pharmaceutical companies were contacted to gather unpublished data. We reviewed the reference lists of all relevant articles. Two authors independently assessed eligibility of the studies and extracted data on characteristics of study design, patients, and treatment. Patients with primary intraventricular hemorrhage were excluded. Main outcome measures were death and poor outcome (defined as death or dependency) at the end of follow-up. No randomized clinical trial has yet been conducted so far, and we therefore reviewed only observational studies. The case fatality rate for conservative treatment (ten studies) was 78%. For extraventricular drainage (seven studies) it was 58% [relative risk versus conservative treatment (RR) 0.74; 95% confidence interval (CI) 0.55-0.99]. For extraventricular drainage with fibrinolytic agents (five studies) the case fatality rate was 6% (RR 0.08; 95% CI 0.02-0.24). The poor outcome rate for conservative treatment was 90%, that for extraventricular drainage 89% (RR 0.98; 95% CI 0.75-1.30) and that for extraventricular drainage with fibrinolytic agents 34% (RR 0.38; 95% CI 0.21-0.68). All RR values remained essentially the same after adjusting for age, sex, World Federation of Neurological Surgeons scale, study design, and year of publication for the studies that provided these data. Outcome is thus poor in patients with intraventricular extension of subarachnoid or intracerebral hemorrhage. This meta-analysis suggests that treatment with ventricular drainage combined with fibrinolytics may improve outcome for such patients, although this impression is derived only from an indirect comparison between observational studies. A randomized clinical trial is warranted.
UNLABELLED: To evaluate the incidence of neonatal complications among infants exposed to indomethacin antenatally, postnatally or both ante-and postnatally (combined), the records of 240 infants of gestational ages between 23 to 32 weeks were analysed retrospectively. Antenatal indomethacin treatment for longer than 2 days with a daily or cumulative dosage >/=150 mg correlated with a significantly higher incidence of grade I-II intraventricular haemorrhage. Combined exposure, cumulative antenatal exposure >/=150 mg and duration of antenatal exposure of more than 2 days was associated with necrotising enterocolitis and a cumulative exposure with sepsis. There was no independent association between indomethacin exposure and pneumothorax, bronchopulmonary dysplasia or respiratory distress syndrome. CONCLUSION: Preterm infants with exposure to antenatal indomethacin might be at increased risk of grade I and II intraventricular haemorrhage and those with both ante- and postnatal exposure at an increased risk of necrotising enterocolitis and sepsis.