Abstract

Background

This represents the first update of this review, which was published in 2012. Atorvastatin is one of the most widely prescribed drugs and the most widely prescribed statin in the world. It is therefore important to know the dose‐related magnitude of effect of atorvastatin on blood lipids.

Objectives

Primary objective

To quantify the effects of various doses of atorvastatin on serum total cholesterol, low‐density lipoprotein (LDL)‐cholesterol, high‐density lipoprotein (HDL)‐cholesterol and triglycerides in individuals with and without evidence of cardiovascular disease. The primary focus of this review was determination of the mean per cent change from baseline of LDL‐cholesterol.

Secondary objectives

• To quantify the variability of effects of various doses of atorvastatin.

• To quantify withdrawals due to adverse effects (WDAEs) in placebo‐controlled randomised controlled trials (RCTs).

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2013), MEDLINE (1966 to December Week 2 2013), EMBASE (1980 to December Week 2 2013), Web of Science (1899 to December Week 2 2013) and BIOSIS Previews (1969 to December Week 2 2013). We applied no language restrictions.

Selection criteria

Randomised controlled and uncontrolled before‐and‐after trials evaluating the dose response of different fixed doses of atorvastatin on blood lipids over a duration of three to 12 weeks.

Data collection and analysis

Two review authors independently assessed eligibility criteria for studies to be included and extracted data. We collected information on withdrawals due to adverse effects from placebo‐controlled trials.

Main results

In this update, we found an additional 42 trials and added them to the original 254 studies. The update consists of 296 trials that evaluated dose‐related efficacy of atorvastatin in 38,817 participants. Included are 242 before‐and‐after trials and 54 placebo‐controlled RCTs. Log dose‐response data from both trial designs revealed linear dose‐related effects on blood total cholesterol, LDL‐cholesterol, HDL‐cholesterol and triglycerides. The Summary of findings table 1 documents the effect of atorvastatin on LDL‐cholesterol over the dose range of 10 to 80 mg/d, which is the range for which this systematic review acquired the greatest quantity of data. Over this range, blood LDL‐cholesterol is decreased by 37.1% to 51.7% (Summary of findings table 1). The slope of dose‐related effects on cholesterol and LDL‐cholesterol was similar for atorvastatin and rosuvastatin, but rosuvastatin is about three‐fold more potent. Subgroup analyses suggested that the atorvastatin effect was greater in females than in males and was greater in non‐familial than in familial hypercholesterolaemia. Risk of bias for the outcome of withdrawals due to adverse effects (WDAEs) was high, but the mostly unclear risk of bias was judged unlikely to affect lipid measurements. Withdrawals due to adverse effects were not statistically significantly different between atorvastatin and placebo groups in these short‐term trials (risk ratio 0.98, 95% confidence interval 0.68 to 1.40).

Authors' conclusions

This update resulted in no change to the main conclusions of the review but significantly increases the strength of the evidence. Studies show that atorvastatin decreases blood total cholesterol and LDL‐cholesterol in a linear dose‐related manner over the commonly prescribed dose range. New findings include that atorvastatin is more than three‐fold less potent than rosuvastatin, and that the cholesterol‐lowering effects of atorvastatin are greater in females than in males and greater in non‐familial than in familial hypercholesterolaemia. This review update does not provide a good estimate of the incidence of harms associated with atorvastatin because included trials were of short duration and adverse effects were not reported in 37% of placebo‐controlled trials.

Author(s)

Stephen P Adams, Michael Tsang, James M Wright

Abstract

Plain language summary

Effect of atorvastatin on cholesterol

This represents the first update of this review, which was published in 2012 (Adams 2012). Atorvastatin is one of the most widely prescribed drugs and the most widely prescribed statin in the world. It is an HMG‐CoA reductase inhibitor that is prescribed to prevent adverse cardiovascular events and to lower blood total cholesterol and LDL‐cholesterol. It is therefore important to know the magnitude of the effect that atorvastatin has on cholesterol. We searched for all evidence obtained from three‐ to 12‐week trials reporting the effect of atorvastatin on blood cholesterol. This update found 42 additional trials and reports on 296 trials in 38,817 participants. Atorvastatin showed a consistent effect in lowering blood cholesterol over the dose range of 2.5 to 80 mg daily. The effect was greater with higher doses than with lower doses. Atorvastatin works similarly to rosuvastatin in lowering cholesterol but is about three‐fold less potent. Risk of bias for all assessed trials was high. Review authors were unable to assess harms of atorvastatin because the included trials were too short, and because only 34 included trials assessed harms.

Author(s)

Stephen P Adams, Michael Tsang, James M Wright

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Specific findings of the review

• Atorvastatin 2.5 to 80 mg/d causes a linear dose‐response reduction in per cent change from control of blood total cholesterol and LDL‐cholesterol. Manufacturer‐recommended atorvastatin doses of 10 to 80 mg/d resulted in 37.1% to 51.7% decreases in LDL‐cholesterol. From the slope of the lines, it can be seen that for every two‐fold increase, a 3.6% and 4.9% decrease in blood total cholesterol and LDL‐cholesterol, respectively, was noted.
• Atorvastatin has a dose‐response effect similar to that of rosuvastatin, but it is at least three‐fold less potent than rosuvastatin in reducing total and LDL‐cholesterol.
• Subgroup analyses suggest that the LDL‐cholesterol‐lowering effect of atorvastatin is greater in females than in males and is lesser in people with familial hypercholesterolaemia than in people with non‐familial hypercholesterolaemia. These findings require confirmation by future trials.
• All doses of atorvastatin did not change WDAEs as compared with placebo (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.68 to 1.40). However, risk of bias for this outcome is high; thus this cannot be considered a reliable estimate.

Implication of these findings

This systematic review provides the best available evidence on dose‐related efficacy of atorvastatin for blood total cholesterol, LDL‐cholesterol, HDL‐cholesterol and triglycerides.

Implications for research 

• More RCTs are needed of atorvastatin at higher and lower doses to expand the estimate of dose‐response efficacy of atorvastatin over a wider dose range.
• All placebo‐controlled RCTs must accurately report withdrawals due to adverse effects and all serious adverse events.
• All trials should report effects separately in males and in females, so it is possible to better determine whether any sex differences are present.
• All trials should report effects separately for patients with familial and non‐familial hypercholesterolaemia to confirm whether efficacy is less in people with familial hypercholesterolaemia.

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