Statins are drugs to lower cholesterol to prevent strokes and heart attacks. Although generally well tolerated, statins can cause muscular side effects, primarily muscle pain, which may lead to treatment termination. The risk of developing such side-effects increases with higher prescribed doses of a statin. Whether the choice of statin type influences the risk of muscle-related problems remains controversial. It has been suggested that hydrophilic, or water-soluble, statins, which are one subgroup of statin drugs, cause less muscle problems than lipophilic, or fat-soluble, statins because they are less likely to enter muscle cells. However, studies comparing hydrophilic with lipophilic statins, irrespective of prescribed doses, reported no difference in the risk of muscle problems. Still, it is possible that, at comparable doses, hydrophilic statins cause less muscle problems than lipophilic statins. Surprisingly, a study, which analysed the risk of severe but rare muscle inflammation during statin treatment, found that the different doses of the hydrophilic statin called rosuvastatin were more toxic than comparable doses of other lipophilic statins.
Analyses that evaluated the risk of any muscle problems, either severe or mild, reported that comparable doses of hydrophilic and lipophilic statins were similarly safe. Although these analyses evaluated statin-related muscle problems more broadly, they might have failed to detect differences in the risk of side-effects between statin types, as patients analysed were sometimes known to have tolerated statin treatment before. We aim to compare the risk of any muscle problems between hydrophilic and lipophilic statins of comparable doses in patients who newly receive statins.
We will apply a propensity score matched sequential cohort study design to compare the risk of muscular events between new users of hydrophilic statins (i.e. pravastatin, rosuvastatin) vs lipophilic statins (i.e. simvastatin, atorvastatin, fluvastatin) at comparable lipid-lowering doses. Five comparisons between individual statins are planned; pravastatin vs simvastatin or fluvastatin, and rosuvastatin vs atorvastatin, simvastatin, or fluvastatin, although we may need to drop the latter two because of small sample size. We will conduct analyses separately in patients taking statins for primary cardiovascular prevention (i.e. no previous ischemic stroke or myocardial infarction) and those taking statins for secondary prevention.
We will identify patients aged 40 to 80 years with a first-time prescription for a hydrophilic or lipophilic statin between 2000 and 2017 (cohort entry date). In each comparative analysis, hydrophilic statin users will be (1:1) matched to lipophilic statin users on a propensity score. We will conduct matching within 2 year enrolment blocks to avoid time-trend bias (expanding statin indications over time). After concatenating all matched patients into one cohort, we will follow them from day 1 after cohort entry until the first Read code for myalgia, myositis, or rhabdomyolysis or until they are censored due to treatment cessation, treatment switch to another statin, death, leaving the CPRD, a Read code for an exclusion criterion or reaching the end of study period. We will follow patients for a maximum of 1 year since statin-associated myotoxic events occur predominately shortly after treatment start. We will perform Cox-proportional hazard analyses to calculate hazard ratios with 95% confidence intervals for the risk of muscular events in new users of hydrophilic vs lipophilic statins. We plan to quantify time-specific hazard ratios by duration of follow-up and to conduct subgroup analyses by sex, age, and daily comparable lipid-lowering dose.
The rate of muscular events, defined as a composite outcome of myalgia, myositis, and rhabdomyolysis
Susan Jick - Chief Investigator - BCDSP - Boston Collaborative Drug Surveillance Program
Alexandra Mueller - Corresponding Applicant - University of Basel
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Christoph Meier - Collaborator - University of Basel
Evangelia Liakoni - Collaborator - Bern University Hospital
Stephan Krähenbühl - Collaborator - University of Basel
Theresa Burkard - Collaborator - University of Basel
Christoph Meier - Collaborator - University of Basel
Cornelia Schneider - Collaborator - University of Basel
Julia Spoendlin - Collaborator - University of Basel