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23 November 2010
The SEARCH study has been published in full. It found no significant reduction in major vascular events among people randomised to simvastatin▼* 80mg vs 20mg per day for secondary prevention. The higher dose was associated with an increased risk of muscle side effects, but even on this higher dose myopathy was uncommon (NNH 118) and rhabdomyolysis was rare (NNH 862, both over 6.7 years).
*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.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
Health professionals should continue to follow NICE guidance and use simvastatin 40mg for most people in whom statins are indicated, in accordance with its 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 study do not provide good reasons to depart from this. Health professionals should also note MHRA guidance on the use of simvastatin 80mg, which is entirely consistent with NICE guidance.
What is the background to this?
Four other previously reported randomised controlled trials (RCTs) have compared the effects of higher and lower intensity statins. Those trials are discussed in MeReC Rapid Review 1423. The SEARCH study compared the risks and benefits of 80mg/day versus 20mg/day simvastatin in 12,064 people with a history of myocardial infarction (MI), over a mean follow-up period of 6.7 years. It also examined the effects of vitamin therapy designed to lower homocysteine levels, but those apparently negative results are not reported here. The study results were originally presented in 2008 and have now been published in full.
What does this study claim?
There was no statistically significant difference in the primary endpoint of major vascular events (defined as coronary death, myocardial infarction, any stroke, or any arterial revascularization): risk ratio (80mg vs 20mg) 0.94 (95% confidence interval [CI] 0.88 to 1.01 P=0.10). This was despite the LDL-cholesterol (LDL-C) in the simvastatin 80mg group being lower than in the 20mg group by an average of 0.35mmol/L (SE 0.01).
At each follow-up visit, about 7% of participants reported unexplained muscle pain or weakness, but at no time was there any significant difference between the treatment groups. Myopathy occurred more often in the 80mg group but was uncommon: 0.88% vs 0.03%, 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).
So what?
Relevant NICE guidance is discussed in MeReC Rapid Review 1423. In summary, NICE recommends simvastatin 40mg as the statin and dose of first choice in most people in whom a statin is indicated i.e. those with existing CVD 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 80mg, or with other statins in particular circumstances), taking into account the patient’s informed preference, including the benefits and risks of treatment. SEARCH does not provide any reason to depart from this guidance.
Serious muscle adverse effects were seen more frequently in the high dose group in SEARCH, and the MHRA have issued guidance on the use of simvastatin 80mg. The product information for simvastatin now recommends that the 80mg dose should be considered only in patients with severe hypercholesterolaemia at high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks. This is entirely consistent with NICE guidance. In addition, health professionals should note that 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.
SEARCH did not find a statistically significant difference in the risk of major vascular events, even though it had 90% power at P<0.05 to detect a 10% relative reduction. However, the authors presented this result as “Major vascular events occurred in 1477 (24·5%) participants allocated 80 mg simvastatin versus 1553 (25·7%) of those allocated 20 mg, corresponding to a 6% proportional reduction (risk ratio 0·94, 95% CI 0·88—1·01; p=0·10). Richard Lehman, reviewing this, has pointed out:
“As for The Lancet: this is the second time in two weeks that they’ve let triallists write a summary which misrepresents the result of a trial which was negative for its primary end-point (SEARCH this week, VITAL last) – not good enough”
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 Richard Lehman commented, on SEARCH and the meta-analysis, “……the writing committees of these two studies, sharing a number of Oxford notables, behave more like theologians than logicians. LDL-cholesterol to them is an infallible surrogate, and anything that lowers it must be good…”.
Fortunately this hypothesis has already been examined in the IDEAL study, but that RCT did not support it. IDEAL compared atorvastatin 80mg with simvastatin 20mg in 8,888 people with a history of MI, over a median of 4.8 years. After 24 weeks, the atorvastatin dose could be reduced to 40mg if there were adverse events, and the simvastatin dose could be increased to 40mg if total cholesterol levels were greater than 5mmol. By the end of the study, 23% of the simvastatin group was taking 40mg, and 13% of the atorvastatin group was taking 40mg.
The mean LDL-C level in the IDEAL study was lower in the atorvastatin 80mg group than in the simvastatin 20/40mg group (2.1 vs. 2.7mmol/l, difference 0.6mmol/L). This was nearly double the difference seen in SEARCH (0.35mmol/L). Nevertheless, IDEAL failed to identify a statistically significant difference between treatments in its primary composite endpoint (coronary death, hospitalisation for non-fatal acute MI, or cardiac arrest with resuscitation): hazard ratio [HR] 0.89, 95% CI 0.78 to 1.01, P=0.07. There was no significant difference in the rates of myopathy or rhabdomyolysis, 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).
Design Double-blind RCT
Patients Men and women aged 18–80 years with a history of previous MI either currently taking a statin or with a clear indication for this treatment, a total cholesterol of at least 3∙5mmol/L if already on a statin or 4∙5mmol/L if not.
Intervention and comparison Simvastatin 80mg daily or simvastatin 20mg daily. Mean follow-up 6.7 years.
Outcomes and results. There was no statistically significant difference in the primary endpoint of major vascular events (defined as coronary death, MI, any stroke, or any arterial revascularization): risk ratio 0.94 (95%CI 0.88 to 1.01 P=0.10).
The total cholesterol in 80mg group was lower than that in the 20mg by an average of 0.40mmol/L (SE 0.01) over the study, the LDL-C was lower by an average of 0.35mmol/L (SE 0.01) and the HDL was greater by an average of 0.02mmol/L (SE 0.01).
Myopathy (defined as creatine kinase concentration more than ten times the upper limit of normal plus unexplained muscle symptoms) was more common in the 80mg group: 0.88% vs 0.03%, relative risk [RR] 26·6, 95% CI 6·5–109·3; P<0·0001, NNH 118 over 6.7 years (95%CI 92 to 165). Rhabdomyolysis (defined as creatine kinase more than 40 times the upper limit of normal plus evidence of end-organ damage e.g. doubling of plasma creatinine) was more common in the 80mg group: 7 cases (0.12%) vs 0 cases, NNH over 6.7 years 862 (95%CI 495 to 3319).
Sponsorship The study was supported by a grant from Merck, and the Clinical Trial Service Unit also receives core support from the UK Medical Research Council and the British Heart Foundation.
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