PubMed · 4069342
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P Merlob. 1985. Craniosynostosis.. https://doi.org/10.1097/00006123-198511000-00026
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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.
Strategies for managing acute myocardial infarction (AMI), with a focus on thrombolytics, are reviewed. Revised guidelines published by the American College of Cardiology and the American Heart Association strongly recommend the use of thrombolytic therapy in carefully selected patients to promote reperfusion of ischemic myocardium. Thrombolytics reduce in-hospital mortality, and the mortality benefit is maintained for at least one year. Which patients are the best candidates for thrombolytics has been debated; variables that have been analyzed include infarct location, time after onset of symptoms, age, sex, blood pressure, and prior AMI. Clinicians should be thoroughly familiar with the absolute and relative contraindications to thrombolytic therapy to minimize potential hemorrhagic complications. The diagnosis of AMI should be clearly established. All patients should receive thrombolytic therapy if they arrive for treatment within 12 hours of the onset of symptoms of AMI and have appropriate ECG changes. Aspirin should be given to all patients, and beta-blockers should also be given if there are no contraindications. Heparin may be given as antithrombotic therapy in patients not receiving thrombolytics or as adjuvant therapy in those receiving thrombolytics. Other adjuvant treatments, notably angiotensin-converting-enzyme inhibitors, are used as indicated. Primary angioplasty may have a role in selected patients. Long-term interventions are intended to prevent recurrence of AMI. Thrombolytic therapy can substantially improve survival and function in patients with AMI, especially when it is given within six hours of the onset of symptoms.
BACKGROUND: Thrombolytic therapy can be life-saving in patients with acute myocardial infarction. However, if given too late or insufficiently selectively, it may provide little benefit but still cause serious complications and incur substantial costs. OBJECTIVE: To develop a thrombolytic predictive instrument for real-time use in emergency medical service settings that could 1) identify patients likely to benefit from thrombolysis and 2) facilitate the earliest possible use of this therapy. DESIGN: Creation and validation of logistic regression-based predictive instruments based on secondary analysis of clinical data. PATIENTS: 4911 patients who had acute myocardial infarction and ST-segment elevation on electrocardiogram; 3483 received thrombolytic therapy. MEASUREMENTS: Data were obtained from 13 major clinical trials and registries and directly from medical records, including electrocardiograms obtained at presentation. Input variables include presenting clinical and electrocardiography features; predictive models generate probabilities for acute (30-day) mortality if and if not treated with thrombolysis, 1-year mortality rates if and if not treated with thrombolysis, cardiac arrest if and if not treated with thrombolysis, thrombolysis-related intracranial hemorrhage, and thrombolysis-related major bleeding episode requiring transfusion. Together, these models constitute the thrombolytic predictive instrument. RESULTS: The predictive models generated the following mean predictions for patients in the Thrombolytic Predictive instrument Database: 30-day mortality rate, 7.1%; 1-year mortality rate, 10.9%; rate of cardiac arrest, 3.7%; rate of thrombolysis-related intracranial hemorrhage. 0.6%; and rate of other thrombolysis-related major bleeding episodes, 5.0%. They discriminated with between persons having and those not having the predicted outcome; areas under the receiver-operating characteristic (ROC) curve were between 0.77 and 0.84 for the five outcomes. Calibration between each instrument's predicted and observed served rates was excellent. Validation of the predictive instruments of 30-day and 1-year mortality, done on a separate test dataset, yielded areas under the ROC curve of 0.76 for each CONCLUSIONS: After the basic features of a clinical presentation are entered into a computerized electrocardiograph, the predictions of the thrombolytic predictive instrument can be printed on the electrocardiogram report. This decision aid may facilitate earlier and more appropriate use of thrombolytic therapy in patients with acute myocardial infarction.