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4 May 2011
A large meta-analysis (>40,000 patients) of randomised controlled trials did not find a statistically significant reduction in all-cause or cardiovascular (CV) mortality with intensive statin therapy, compared with moderate or low dose statin therapy. Furthermore, it did not find a linear relationship between LDL cholesterol lowering and CV risk reduction. In a subgroup of patients with acute coronary syndrome (ACS), there was a significant reduction in all-cause and CV mortality, but not in other CV outcomes (e.g. non-fatal myocardial infarction [MI]) with intensive therapy compared with lower doses.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria
Action
Health professionals should continue to follow NICE guidance on lipid modification and use simvastatin▼* 40mg for most people. NICE lipid guidance explicitly sets no lipid targets that patients are expected to achieve, for either primary or secondary prevention (including those with ACS). 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.
Any possible incremental benefit of using intensive statin therapy over standard doses (e.g. 40mg/day simvastatin) must be considered in the context of an increased risk of adverse events. Health professionals should also note guidance from the MHRA on the use of simvastatin 80mg, which is entirely consistent with NICE guidance.
*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?
Other previously reported randomised controlled trials (RCTs) and meta-analyses have compared the effects of intensive statin therapy, with normal statin dosing. The key RCTs are discussed in MeReC Rapid Review 1423 (IDEAL, TNT, A to Z, PROVE-IT) and MeReC Rapid Review 2138 (SEARCH study). The Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis included five RCTs (39,612 patients) that compared intensive statin therapy with lower dose statin therapy. However, as we discussed in MeReC Rapid Review 2127, this analysis had limitations, particularly regarding the different patient populations in the included studies. This new meta-analysis included further RCTs and also included a separate subgroup analysis of higher risk patients with ACS, to determine whether intensive statin therapy offers more favourable outcomes compared with moderate or low dosing.
What does this study claim?
This meta-analysis included 10 RCTs (n=41,778), although not all outcomes were reported in all studies. The authors conclude that “the available evidence suggests that intensive statin therapy reduces the risk of non-fatal events and may have a role in reducing mortality”. However, in the overall analysis of the results, there was no statistically significant reduction in all-cause mortality (relative risk [RR] 0.92, 95% confidence interval [C] 0.83 to 1.03, P=0.14), or CV mortality, with intensive statin (e.g. atorvastatin 80mg/day) dosing compared to moderate or low dosing (e.g. simvastatin 20mg/day -see study details below for dosage regimens). There was a significant reduction in non-fatal MI, a composite of coronary heart disease (CHD) death and non-fatal MI, and a composite of fatal- and non-fatal stroke (excluding TIA) – again see ‘study details’ below for more information. The authors also conducted a meta-regression analysis and did not find an association between LDL cholesterol-lowering and reduction in the risk of CHD death or non-fatal MI.
In a subgroup analysis of three RCTs in patients with ACS, there were significant reductions in all-cause mortality (RR 0.75, 95%CI 0.61 to 0.91, P=0.005) and CV mortality (RR 0.74, 95%CI 0.59 to 0.94, P=0.013, NNT over one year 119, 95%CI 63 to 1364) with intensive dosing compared to moderate or low dosing. However, there were no significant benefits in regard to either non-CVD death or non-fatal MI, or regarding a composite of CHD death or non-fatal MI.
Increased liver enzymes (AST and ALT) beyond normal were observed with intensive dosing, compared with normal dosing. There was also a significant increase in the risk of creatinine kinase (CK) beyond normal with intensive dosing, but no significantly increased risk of rhabdomyolysis.
So what?
This large meta-analysis brings together the results from previous large RCTs, and also includes new data. Unlike the CTT meta-analysis, it also analyses data in higher risk ACS patients separately. In the analysis of all of the patients in the studies, there was a significant reduction in some CV outcomes, but no significant reduction in all-cause or CV mortality with intensive statin dosing, compared with moderate or low dosing. Furthermore, as observed in previous studies, intensive dosing was associated with a significant increase in adverse events associated with liver enzyme elevations. This further supports advice from NICE 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 is also entirely consistent with MHRA guidance.
Interestingly, in the CTT meta-analysis, the authors concluded that “the absolute benefit relates chiefly to an individual’s absolute risk of [CV] events and to the absolute reduction in LDL cholesterol achieved” and suggested a linear relationship exists between LDL lowering and CV risk reduction (i.e. doubling the amount of LDL lowering doubles the reduction in risk). However, this meta-analysis did not find such a linear relationship. This issue is discussed further in the MeReC Rapid Review of the SEARCH study.
As NICE advises, in secondary prevention patients without ACS, prescribers should consider increasing the dose of simvastatin to 80mg only in patients whose total cholesterol is greater than 4mmol/L and also whose LDL-cholesterol is greater than 2mmol/L: if either figure is below that level, then increasing the dose is not recommended. It is important to note that these are lipid levels which should prompt prescribers to consider increasing the dose. They are not targets patients are expected to achieve. Moreover, NICE states (in the full guideline) “most patients would not achieve a target of 4mmol/L total cholesterol [on simvastatin 80mg] and modelling suggests that it is not cost-effective to try to take more patients to target using higher cost statins such as atorvastatin.”
In patients with ACS, this meta-analysis did find a statistically significant reduction in all-cause and CV mortality, but not in other CV outcomes. NICE found that atorvastatin 80mg and simvastatin 80mg are both cost effective in ACS, if more intensive statin treatment is chosen. Again, NICE advises that the decision to offer a higher intensity statin should take into account the patient’s informed preference, as above. In addition, NICE does not recommend target lipid levels in people with ACS. NICE does not give guidance about how long ACS patients should take a higher intensity statin; that is, at what point after their ACS event they should be treated in the same way as other secondary prevention patients.
Design
Meta-analysis of 10 RCTs reporting on clinically important CV outcomes. Trials reporting surrogate outcomes (e.g. cholesterol levels) were excluded. Allocation was concealed in seven trials.
Patients
41,778 patients (average age 56 years, mean ages ranging from 56 to 74 years) taking any statin (excluding cerivastatin) for CV disease therapeutic effects.
Intervention and comparison
Moderate dose statin vs. the same or another statin of higher dose for longer than six months. Dosage regimens compared were:
- Intensive dosage group – atorvastatin 80mg/day (eight studies) or simvastatin 40mg to 80mg/day
- Moderate dosage group – simvastatin 20mg; pravastatin 40mg; atorvastatin 10mg; lovastatin 5mg
Outcomes and results
Efficacy outcomes
| Intensive vs. normal statin dosing | RR for all patients (95%CI) | RR for ACS patients only (95%CI) |
| All-cause mortality | 0.92 (0.83 to 1.03) | 0.75 (0.61 to 0.91) |
| CVD mortality | 0.89 (0.78 to 1.01) | 0.74 (0.59 to 0.94) |
| Non-fatal MI (5 RCTs) | 0.82 (0.76 to 0.90) | 0.55 (0.28 to 1.07) |
| CHD death and non-fatal MI (9 RCTs) | 0.90 (0.84 to 0.96) | 0.85 (0.71 to 1.03) |
| Fatal- and non-fatal stroke (excluding TIA) | 0.86 (0.77 to 0.96) | Not reported |
| Non CVD death (4 RCTs) | 0.97 (0.87 to 1.09) | 0.98 (0.54 to 1.08) |
Safety outcomes
| AST beyond normal | 3.15 (1.31 to 7.54) |
| ALT beyond normal | 1.57 (1.29 to 1.91) |
| CK beyond normal | 2.86 (2.02 to 4.04) |
| Rhabdomyolysis (CK >10,000 U/L) | 1.70 (0.56 to 5.19) |
Sponsorship Not stated.
More information on statins can be found on the cardiovascular disease – lipids elearning section of NPC.
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