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22 December 2011
The SATURN study, compared treatment with two high-dose statins (atorvastatin 80 mg daily or rosuvastatin 40 mg daily). Both groups saw a regression of coronary atherosclerosis from baseline in around two thirds of patients with coronary heart disease, but there was no statistically significant difference between the two groups. Reduction in atherosclerotic plaque volume is a surrogate or disease-oriented outcome and it is unclear how this translates into patient-oriented outcomes such as reduction in risk of cardiovascular events. Other limitations in the study further reduce its application to direct patient care.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Action
Health professionals should continue to use simvastatin▼* 40 mg for most people in whom statins are indicated, in accordance with NICE guidance on lipid management and care of people with type 2 diabetes. The results of this study do not provide good reasons to depart from NICE guidance.
NICE lipid guidance explicitly sets no lipid targets that patients are expected to achieve, for either primary or secondary prevention (including those with acute coronary syndrome [ACS]). More intensive statin therapy should not be automatic but may be considered in certain circumstances, taking into account the patient’s informed preference. Any possible incremental benefit of using intensive statin therapy over standard doses (e.g. 40 mg/day simvastatin) must be considered in the context of an increased risk of adverse events.
Prescribers and prescribing managers should review local prescribing trends for statins and ezetimibe as suggested in the document ‘Key therapeutic topics – Medicines management options for local implementation. The NPC has produced e-learning resources to support organisations and prescribers in making best use of this document (see e-learning resources for statins and ezetimibe).
*Note: The MHRA has advised that the black triangle (▼) refers to intensive monitoring being requested only when simvastatin is used in children and adolescents (10–17 years), in line with the recently licensed paediatric dosing recommendation.
What is the background to this?
As discussed in MeReC Rapid Review No. 2835, although some evidence exists to support considering the use of high-dose statins in people with acute myocardial infarction or ACS, high-dose statin therapy has shown limited or no significant benefits but increased side effects in randomised controlled trials (RCTs) in people with stable cardiovascular (CV) disease, compared with standard-dose statin therapy.
This study compared atorvastatin 80 mg daily and rosuvastatin 40 mg daily to determine whether there were discernible differences in their effects on the progression of coronary atherosclerosis.
Initially, 1578 adults with coronary heart disease and who met other eligibility criteria (see study details ) were randomly assigned to two weeks of treatment with atorvastatin 40 mg or rosuvastatin 20 mg, to ascertain side effects and compliance. After this run-in period, 1385 patients were randomly assigned to high-dose treatment with atorvastatin 80 mg daily or rosuvastatin 40 mg daily (data on how many patients did not proceed to this phase because they did not meet lipid level criteria or for other reasons are not stated). After 104 weeks (two years) of treatment, 1039 of these patients (75%) remained in the study and underwent repeat intravascular ultrasonography, so that the findings on follow-up imaging could be compared with the baseline findings. The primary outcome was change in percent atheroma volume from baseline.
What does this study claim?
After two years, there was no statistically significant difference between atorvastatin and rosuvastatin in the primary outcome: percent atheroma volume decreased by 0.99% (95% confidence interval [CI] −1.19 to −0.63) from baseline with atorvastatin and 1.22% (95% CI, −1.52 to −0.90) with rosuvastatin (p for change from baseline for each <0.001, but p for between-group comparison 0.17). Both atorvastatin and rosuvastatin resulted in regression of atherosclerosis in the majority of patients (63.2% with atorvastatin and 68.5% with rosuvastatin, based on change in percent atheroma value), with no significant difference between the two treatments (p = 0.07). The clinical significance of these changes is unclear.
So what?
This study has limited application to patient care. It is not known whether the degree of plaque regression seen with both treatments is clinically significant, or whether it will lead to a clinical benefit in terms of a reduction in CV events. Although the incidence of CV events was recorded, the study was not powered to detect differences between the two treatment groups, despite being a relatively large study (n=1578).
In addition, the study has several important limitations in its design and execution. Patients recruited to the study were undergoing clinically indicated coronary angiography, and it is unknown whether the results are applicable to asymptomatic people. About 60% of patients were receiving statins at study entry. The type, dose and duration of therapy with these are not stated, although people who had taken intensive lipid-lowering therapy for more than three months in the previous year, such as simvastatin 80 mg or statin therapy combined with ezetimibe were excluded. It is therefore not possible to know how the observed reductions in atheroma volume compare with what had been produced by previous, non-intensive statin therapy. There was also no group randomised to standard dose statin (e.g. simvastatin 40 mg), so as to compare the effects on atheroma volume of high dose versus standard dose statin during the trial period.
In addition, 12% of patients did not proceed from the run in period to the main trial, but the reasons for them leaving the study are not stated. Furthermore, 25% of patients who did enter the main trial did not receive follow-up intravascular ultrasonography. These patients may have had rates of progression that were different from those who completed the study.
As discussed in MeReC Rapid Review No. 2835, although some evidence exists to support considering the use of high-dose statins in people with acute myocardial infarction or ACS, high-dose statin therapy has shown limited or no significant benefits but increased side effects in RCTs in people with stable CV disease, compared with standard-dose therapy. This new study does not provide any reason to change practice and healthcare professionals should continue to follow NICE guidance on lipid management.
Relevant NICE guidance is discussed in MeReC Rapid Review 1423. In summary, NICE recommends simvastatin 40 mg as the statin and dose of first choice in most people in whom a statin is indicated i.e. those with existing CV disease or for primary prevention in those with a CV risk of 20% or greater. In some circumstances NICE advises considering intensifying therapy (usually with simvastatin 80 mg, or with other statins in particular circumstances), taking into account the patient’s informed preference, including the benefits and risks of treatment.
See the QIPP e-learning resources on statins and ezetimibe for more information on:
- What NICE advises about statin doses and lipid targets for primary and secondary prevention of CV disease, and for people with type 2 diabetes and ACS.
- The evidence for high-dose statin therapy.
- How statins compare in terms of safety and efficacy
- The evidence for ezetimibe and what NICE recommends.
Study details
Nicholls SJ, et al. Effect of Two Intensive Statin Regimens on Progression of Coronary Disease. N Engl J Med 2011:365:2078–87
Design: Randomised, double-blind trial at 208 centres
Patients: 1578 adults aged18 to 75 years of age with at least one vessel with 20% stenosis on clinically indicated coronary angiography and a target vessel for imaging with less than 50% obstruction. Patients were excluded if they had received intensive lipid-lowering therapy for more than 3 months in the previous year or had uncontrolled hypertension, heart failure, renal dysfunction, or liver disease.
Intervention and comparison: patients were randomised to receive atorvastatin 40 mg daily or rosuvastatin 20 mg daily for two weeks to ascertain side effects and compliance. After the run-in period, 1385 patients with an LDL cholesterol level <3.0 mmol/L and a triglyceride level of < 5.6 mmol/L were randomised to receive atorvastatin 80 mg daily or rosuvastatin 40 mg daily for 104 weeks. A clinical events committee whose members were unaware of the treatment assignments adjudicated cardiovascular events at a central location.
Outcomes and results
After 104 weeks, 1039 patients (75%) remained in the study. there was no statistically significant difference between atorvastatin and rosuvastatin in the primary outcome: percent atheroma volume decreased by 0.99% (95% confidence interval [CI] −1.19 to −0.63) from baseline with atorvastatin and 1.22% (95% CI, −1.52 to −0.90) with rosuvastatin (p for change from baseline for each <0.001, but p for between-group comparison 0.17). Both atorvastatin and rosuvastatin resulted in regression of atherosclerosis in the majority of patients (63.2% with atorvastatin and 68.5% with rosuvastatin, based on change in percent atheroma value). Despite statistically significantly lower levels of LDL cholesterol (1.62 vs. 1.82 mmol/L, p<0.001) and higher levels of HDL cholesterol (1.30 vs. 1.26 mmol/L, p=0.01) in the rosuvastatin group, compared with the atorvastatin group, there was no significant difference in regression between the treatments (p=0.07). The rate of abnormal laboratory values was low and the frequency of CV events was similar in the two groups: the rates of myocardial infarction, stroke and CV death were 1.6%, 0.4% and 0.3%, respectively.
Study sponsorship: Astra Zeneca Pharmaceuticals
Further information can be found on NHS Evidence and in the cardiovascular disease – lipids e-learning section of the NPC website
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