Issue No 48 February 2011
Two related pieces of evidence on statins have been published. The first, the SEARCH1 study, found no significant reduction in major vascular events among people randomised to simvastatin▼* 80mg/day versus 20mg/day for the secondary prevention of cardiovascular (CV) events for 6.7 years. The 80mg dose was associated with an increased risk of myopathy, although this was uncommon; and rhabdomyolysis, but this was rare.
The second was a large meta-analysis,2 which included SEARCH,1 and confirmed the benefits of standard dose statin therapy on CV outcomes. The authors suggested that more intensive statin therapy in selected high-risk populations might bring additional benefits. However, the meta-analysis did not fully explore the potential harms or cost effectiveness of this approach. In addition, the studies included were dissimilar and it is a matter of judgment whether combining them in a meta-analysis is entirely appropriate.
*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.
Health professionals should continue to follow NICE guidance and use simvastatin 40mg/day for most people in whom statins are indicated, in accordance with NICE guidance on lipid management3 and type 2 diabetes.4 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.3 The results of these studies do not provide good reasons to depart from these recommendations. Health professionals should also note that MHRA guidance on the use of simvastatin 80mg5 is entirely consistent with NICE guidance.3,4 Dose-related myopathy is a risk with all statins.5 There is no good evidence that any one statin has any advantages over another in this regard at a population level.
What did SEARCH claim?
The SEARCH study, a double-blind randomised controlled trial (RCT), compared simvastatin 80mg/day and 20mg/day in 12,064 adults with a history of myocardial infarction (MI), followed up for a mean of 6.7 years. There was no statistically significant difference in the primary endpoint of major vascular events (coronary death, MI, any stroke, or any arterial revascularisation): risk ratio (80mg vs. 20mg) 0.94 (95% confidence interval [CI] 0.88 to 1.01, P=0.10). This was despite a lower average LDL-cholesterol (LDL-C) in the simvastatin 80mg group than the 20mg group. About 7% of participants in both groups reported unexplained muscle pain or weakness (difference not significant). Myopathy occurred more often in the 80mg group but was relatively uncommon: 0.88% vs. 0.03%, number needed to harm (NNH) 118 over 6.7 years (95%CI 92 to 165). Similarly, rhabdomyolysis occurred more often in the 80mg group, but was rare: 7 cases (0.12%) vs 0 cases, NNH over 6.7 years 862 (95%CI 495 to 3319).1
What did the meta-analysis claim?
The meta-analysis (MA) assessed 26 RCTs (n=169,138) in patients with or without established CV disease. Twenty-one RCTs (n=129,526) compared statin therapy with control. Among these, the mean reduction in LDL-C at one year was 1.07mmol/L and the authors calculated that the average relative reduction in the rate of major vascular events per 1mmol/L reduction in LDL-C was 21% (95%CI 19% to 23%, P<0.0001). Five trials, including SEARCH,1 compared intensive and less intensive statin therapy. In these trials, the additional mean reduction in LDL-C at one year was 0.51mmo/L (range 0.30 to 0.65 mmol/L) and the relative rate of major vascular events was reduced by a further 15% overall (95%CI 11% to 18%, P<0.0001).2 However, there are caveats to this comparison which limit its usefulness (see below).
Health professionals looking after people at increased CV risk, or who have established CV disease, are likely to have four main questions which these studies can help address:
What initial dose of which statin should I offer?
The largest single trial of any statin included in the MA was the Heart Protection Study. This compared simvastatin 40mg/day with placebo and found a 24% (95%CI 19% to 28%, P<0.0001) relative reduction in risk of all major vascular events.6 Its results are in keeping with the overall finding of the MA. Thus, the MA results provide no reason to depart from NICE guidance as described above.
What are the pros and cons of using more intensive statin therapy and what dose of which statin should I use in that situation?
The MA findings might suggest that intensive therapy to achieve maximum lipid lowering may be desirable. However, there are some important caveats to be considered.
In the MA of higher dose versus lower dose statins, two of the five trials were conducted in people with acute coronary syndrome (ACS).2 This may represent a different patient population from patients with more stable disease. Moreover, only one study compared intensive statin therapy with a standard dose of statin and only two studies (one in ACS) found a statistically significant difference in their primary outcomes. It is, therefore, a matter of judgement whether combining these trials in a meta-analysis is entirely appropriate (see MeReC Rapid Review No. 2127 for more details).
The authors of both studies1,2 assume a linear relationship between LDL-C reduction and CV risk reduction. Richard Lehman, commenting on the writing committees of both studies, said that that 'LDL-cholesterol to them is an infallible surrogate, and anything that lowers it must be good'.7 The SEARCH authors state in their abstract that 'the 6% (standard error [SE] 3.5%) reduction in major vascular events with a further 0.35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials' but they do not highlight that this observed reduction is not statistically significant. They suggest that using a statin more potent than simvastatin 80mg would further reduce the risks of CV events compared with 20mg simvastatin by achieving greater reductions in LDL-C.1
That hypothesis has already been tested in the IDEAL study,8 but that RCT did not support it. IDEAL compared atorvastatin 80mg/day with simvastatin 20mg to 40mg/day in 8,888 people with a history of MI, over a median of 4.8 years. Despite a mean difference in LDL-C nearly double that seen in SEARCH, IDEAL found no statistically significant difference in its primary composite endpoint (coronary death, hospitalisation for non-fatal acute MI, or cardiac arrest with resuscitation). Rates of myopathy and of rhabdomyolysis were also not significantly different, but twice as many people in the atorvastatin group withdrew due to myalgia compared to the simvastatin group (2.2 vs. 1.1%, P<0.001), and more than twice as many withdrew due to adverse effects overall (9.6% vs. 4.2%, P<0.001).8
For more information on these studies and how they fit with what we know already see MeReC Rapid Review No. 2138 and MeReC Rapid Review No. 2127. The place in therapy of simvastatin 80mg is discussed in MeReC Rapid Review No. 1423 and on the lipids section of NPC.
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