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Helfand M, Carson S, Kelley C. Drug Class Review on HMG-CoA Reductase Inhibitors (Statins): Final Report [Internet]. Portland (OR): Oregon Health & Science University; 2006 Aug.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Drug Class Review on HMG-CoA Reductase Inhibitors (Statins)

Drug Class Review on HMG-CoA Reductase Inhibitors (Statins): Final Report [Internet].

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Literature Search

To identify articles relevant to each key question, we searched the Cochrane Library (2006, Issue 1), Medline (1966-March Week 5 2006), EMBASE (1980-February 4, 2005), PreMEDLINE (through April 10, 2006), and reference lists of review articles. In electronic searches, we combined terms for the included medications with terms for relevant research designs (see Appendix A for complete search strategy). Pharmaceutical manufacturers were invited to submit dossiers, including citations. All citations were imported into an electronic database (EndNote 9.0).

Eligibility Criteria and Study Selection

Studies that met the following eligibility criteria were included in the review:


Eligible populations consisted of adults (age >18 years) targeted for primary or secondary prevention of CHD or non-coronary forms of atherosclerotic disease with or without hypercholesterolemia. We excluded trials focusing on children and on rare, severe forms of hypercholesterolemia (LDL-c >250mg/dl). We included trials in inpatients with acute coronary syndrome and trials of patients undergoing revascularization if the statin was continued after hospital discharge and if health outcomes were reported.


Trials of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and/or simvastatin were included. We included studies that used one of three different strategies for dosing: fixed doses, single-dose titration, or treat (titrate dose) to a target LDL-c. We excluded multi-interventional therapies where the effect of the statin could not be separated out.


For clinical efficacy, we included studies that reported one or more of the following as primary, secondary, or incidentally reported outcomes:

Intermediate outcome measures. LDL-c reduction or the percent of patients meeting NCEP goals; HDL-c raising.

Health outcomes. Nonfatal myocardial infarction, angina, cardiovascular death, all-cause mortality, stroke, and need for revascularization (coronary artery bypass graft, angioplasty, and stenting).

We excluded studies that did not provide original data (e.g., editorials, letters), were shorter than 4 weeks in duration, did not have an English-language title or abstract, or were published only in abstract form.

We used head-to-head trials to compare the efficacy and adverse effects of different statins in a defined populations. Most head-to-head trials compare the short-term effects of different statins on LDL-c and HDL-c and on adverse events. Long-term head-to-head trials were scarce, so we relied heavily on placebo-controlled single drug trials to determine which statins have been proven to reduce mortality and the incidence of cardiovascular events. We used randomized trials as well as observational cohort studies to estimate the incidence of complications of statin therapy such as rhabdomyolysis as well as the incidence of elevations in liver enzymes or creatitine phospokinase levels. For drug interactions, we also included observational studies and individual case reports, because patients who are receiving drugs with a potential for interaction are often excluded from clinical trials. Although they do not provide comparative data, case reports were included because they may provide insight into more rare, significant interactions.

All titles and, if available, abstracts were reviewed for eligibility using the above criteria. Full-text articles of included titles and abstracts were retrieved and a second review for eligibility was conducted.

Data Abstraction

One reviewer abstracted the following data from included trials: study design, setting, population characteristics (including sex, age, ethnicity, diagnosis), eligibility and exclusion criteria, interventions (dose and duration), comparisons, numbers screened, eligible, enrolled, and lost to follow-up, method of outcome ascertainment, and results for each outcome (nonfatal myocardial infarction (MI), new CHD (new angina or unstable angina), CHD mortality, all-cause mortality, stroke or TIA, and need for revascularization). Since several of the trials grouped some of these events and referred to them as major coronary events, we also included it as a category of cardiovascular health outcomes. We recorded intention-to-treat results if available.

Validity Assessment

We assessed the internal validity (quality) of trials based on the predefined criteria listed in Appendix B. These criteria are based on those developed by the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (UK).6, 7 For Key Question 3, we rated the internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw in one or more categories were rated poor quality; trials meeting all criteria were rated good quality; the remainder were rated fair quality. As the "fair quality" category is broad, studies with this rating vary in their strengths and weaknesses: the results of some fair-quality studies are likely to be valid, while others are only probably valid. A "poor quality" trial is not valid—the results are at least as likely to reflect flaws in the study design as the true difference between the compared drugs. External validity of trials was assessed based on whether the publication adequately described the study population and how similar patients were to the target population in whom the intervention will be applied. We also recorded the funding source and role of the funder.

Dosing strategies can also affect applicability of these studies to practice. In fixed-dose studies, we note whether the doses are used in current practice and compare the rates of side effects when the dosages of the compared statins reduced LDL-c to a similar degree. We note when the dosages of the compared drugs differ in the extent to which they reduced LDL-c. For studies that titrated doses, we examined whether the methods used to decide when and how much to increase the doses were applied equally to the statins under study.

Data Synthesis

We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reported the range of estimates of LDL-c and HDL-c changes for each dosage of each drug. When possible, we also calculated pooled estimates of LDL-c reduction by drug and dosage. We considered the quality of the studies and heterogeneity across studies in study design, patient population, interventions, and outcomes, in order to determine whether meta-analysis could be meaningfully performed. If meta-analysis could not be performed, we summarized the data qualitatively.

Copyright & 2006, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK10707


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