23 November 2010
A large meta-analysis has confirmed the results of earlier meta-analyses regarding the benefits of standard dose statin therapy on cardiovascular outcomes. It also suggests additional benefits from more intensive statin therapy in selected high-risk populations. However, it did not fully explore the potential harms associated with more intensive statin therapy or examine the cost effectiveness of this approach. In addition, there are caveats regarding some aspects of the individual studies of more intensive statin treatment, and therefore the meta-analysis.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Health professionals should continue to follow NICE guidance and use simvastatin▼* 40mg for most people in whom statins are indicated, in accordance with NICE’s guidance on lipid management and care of people with type 2 diabetes. More intensive statin therapy should not be automatic but may be considered in certain circumstances, taking into account the patient’s informed preference, including the benefits and risks of treatment. The results of this MA do not provide good reasons to depart from this approach.
*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?
The Cholesterol Treatment Trialists’ (CTT) Collaboration reported a meta-analysis (MA) of 14 randomised controlled trials (RCTs) of about 90,000 patients in 2005. That MA looked at the relationship between lowering LDL-cholesterol (LDL-C) with statin therapy and reductions in risk of all-cause mortality and cardiovascular (CV) events. This MA updated that MA by considering an additional seven RCTs (39,470 patients) which compared statin therapy with control. It also looked specifically at five RCTs (39,612 patients) that compared high dose statins treatment with lower dose statin treatment. These include the SEARCH study, the results of which were published in full at the same time as this MA. SEARCH is discussed in a separate MeReC Rapid Review.
What does this study claim?
With regard to the benefits from statin therapy versus control, the results were very similar to the 2005 MA. In the 21 trials which compared statin treatment with control, the pooled rate ratio of major vascular events per year was reduced by 22% in relative terms (rate ratio 0.78, 95% confidence interval [CI] 0.76 to 0.81, P<0.0001). The authors calculate that there was a 21% relative reduction per 1mmol/L reduction in LDL-C (rate ratio per 1mmol/L reduction 0.79 (95%CI 0.77 to 0.81). Looking at all 26 trials (including the high vs lower dose trials), the authors calculate that a 1mmol/L reduction in LDL-C reduces the relative risk of any vascular event by 22%, death from cardiac causes by 16%, and death from any cause by 10% (see study details below). Reducing LDL-C with statins did not produce a statistically significant reduction in risk of death from stroke or non-vascular causes. In addition, this MA reaffirmed the findings of the 2005 MA and found no increased risk of cancer overall or by particular site.
In the comparison of high dose and lower dose statins, the rate ratio of major vascular events per year was reduced by 15% in relative terms (rate ratio 0.85, 95%CI 0.82 to 0.89, P<0.0001).
Health professionals looking after people at increased risk of, or established, CV disease are likely to have two main questions which this MA can help address: what initial dose of which statin should I offer; what are the pros and cons of using more intensive statin therapy and what dose of which statin should I use in that situation?
Regarding the first question, the largest single trial of any statin included in the MA was the Heart Protection Study (HPS). This compared simvastatin 40mg with placebo in a mixed group of people with established CV disease or at increased risk of CV disease. This found a 24% (95%CI 19% to 28%) reduction in risk of all major vascular events (and showed one of the largest mean reductions in LDL-C). The results of HPS are therefore in keeping with the overall finding of the MA. Thus, the MA results support the NICE guidance on lipid management regarding initial choice and dose of statin. This states that, in people without type 2 diabetes, simvastatin 40mg/day should be prescribed for primary and secondary prevention of cardiovascular events for most people in whom a statin is indicated. (If there are potential drug interactions, or simvastatin 40 mg is contraindicated, a lower dose or alternative preparation such as pravastatin may be chosen). It is important to note that NICE lipid guidance explicitly sets no lipid targets that patients are expected to achieve, for either primary or secondary protection. More intensive statin therapy may be considered in some circumstances. Similarly NICE guidance on lipid management in people with type 2 diabetes recommends simvastatin 40mg as the usual choice and dose of statin, with more intensive therapy as an option in some circumstances.
Regarding the second question, NICE guidance and the evidence base related to the use of higher-intensity statins is discussed in MeReC Rapid Review 1423. The results of this MA do not provide good reasons to depart from NICE guidance.
There are two major limitations to the MA of the higher dose versus lower dose statins. Firstly, two of the trials (PROVE-IT and the A to Z study) were conducted in people with acute coronary syndromes (ACS). There are good pathophysiological reasons for suggesting that this may represent a different patient population from patients with more stable disease and so results from trials in this group are not necessarily predictive of effects in the latter. Secondly, only one study (the TNT study) compared intensive statin therapy with a standard dose of statin (80mg vs 10mg atorvastatin in this case). The other studies either used a low dose of simvastatin (A to Z and IDEAL), or pravastatin – less potent than simvastatin or atorvastatin at standard doses (PROVE-IT). In addition, only two of the five studies (PROVE-IT and TNT) identified a statistically significant difference in their primary outcome. It is, therefore, a matter of judgement whether combining these trials in a meta-analysis is entirely appropriate.
Notwithstanding these caveats, the observed extra benefit from more intensive statins does not support treatment to a particular target. As the related editorial states:
“Only a minor proportion of patients who were treated with more-intensive therapy achieved an LDL-cholesterol concentration less than 2mmol/L. Today’s results do not imply that an LDL-cholesterol concentration of less than 2mmol/L should be achieved; they suggest that patients at risk of cardiovascular events would benefit from intensive statin therapy, even if their baseline LDL cholesterol is already less than 2mmol/L.”
NICE advises that any decision to offer a higher intensity statin should not be automatic, but should take into account the patient’s informed preference, including the benefits and risks of treatment. This MA did not consider statin related adverse effects, except rhabdomyolysis (for which there were few occurrences). It is reassuring in that it found no increase in incidence of non-vascular mortality or site-specific cancer, but some relevant outcomes, such as diabetes, liver dysfunction, cataract development and myopathy, have not been covered.
As we discussed in MeReC Rapid Review 370, the risk of statin-related myopathy appears to increase with higher doses. The MHRA have noted the increased risk of myopathy with simvastatin 80mg compared with 20mg. However, dose-related myopathy is a risk with all statins. There is no good evidence to suggest that any one statin has any advantages over another in this regard at a population level.
On the basis of this relationship between LDL-C reduction and CV risk, the authors suggest that using a statin more potent than simvastatin 80mg would reduce the risks of CV events compared to 20mg simvastatin, by achieving greater reductions in LDL-C, and at the same time would be less likely to increase the risk of muscle adverse effects like simvastatin 80mg. As discussed in the MeReC Rapid Review of the SEARCH study, this hypothesis has already been examined in the IDEAL study, but that RCT did not support it.
Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81
Design Meta-analysis of patient level data
Patients 169,138 patients from 26 RCTs. Trials included patients with or without established CVD but had to include at least 1000 participants and be scheduled to last at least two years
Intervention and comparison Five trials (n=39,612) compared intensive and less intensive statin therapy. Twenty-one trials (n=129,526) compared statin therapy (with different degrees of lipid lowering) with control. All analysis was based on intention to treat.
Outcomes and results
Rate ratio of events per annum (95%CI)
Rate Ratio per 1mmol reduction in LDL-C (95%CI)
|Statin vs control (N = 21)|
|Any major vascular event*||0.78 (0.76 to 0.81) P<0.0001||0.79 (0.77 to 0.81) P<0.0001|
|Higher vs lower dose statin (N = 5)|
|Any major vascular event*||0.85 (0.82 to 0.89) P<0.0001||0.72 (0.66 to 0.78) P<0.0001|
|All trials combined (N = 26)|
|Any major vascular event||Not reported||0.78 (0.76 to 0.80)*|
|Cardiac death||Not reported||0.84 (0.80 to 0.88)*|
|Stroke||Not reported||0.96 (0.84 to 1.09) NS|
|Any vascular death (stroke or cardiac cause)||Not reported||0.86 (0.82 to 0.90)*|
|Non-vascular death||Not reported||0.97 (0.92 to 1.03) NS|
|All cause death||Not reported||0.90 (0.87 to 0.93)*|
|Any site specific cancer incidence**||Not reported||1.00 (0.96 to 1.04) NS|
* statistically significant (P<0.05)
NS = not statistically significant (P>0.05)
N = number of trials included
Sponsorship UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation
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