Prescribing Advice for GPs

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Lancet reopens intensive statin debate

The Lancet has published two studies this week that have the potential to reopen the debate about standard versus intensive lipid lowering. The first of these studies is a meta-analysis of statin trials and the second is a randomised controlled trial of simvastatin 80mg versus simvastatin 20mg. Both studies have been reported in the general media (BBC, Telegraph).

The meta-analysis included 26 trials involving 169,138 participants. All of these studies recruited at least 1,000 participants and ran for at least 2 years. 5 of the studies compared a standard statin dose with an intensive dose with the remaining 21 studies comparing statin therapy with a placebo control. This study also compared rates of some adverse events between the study groups. The analysis of the 5 studies with active comparators identified a 15% relative risk reduction (95% CI 11%-18%, p<0.0001) in cardiovascular events. The comparison of adverse effects focussed on haemorrhagic strokes and cancers and found no difference in event rates between the groups.

The authors conclude that, "further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke". They also indicate that for each 1mmol/L reduction in LDL there is a reduction in cardiovascular risk of approximately 20%.

This study does have some limitations. While it did assess adverse events there was no assessment of mild reactions or of liver dysfunction, myopathy and rhabdomyolysis. The conclusions are also based on clinical data alone without any consideration of the relative benefit in terms of additional acquisition costs that would be involved in using more intensive statin therapies.

The second study is the results of the SEARCH study, a randomised controlled trial involving 12,064 participants aged 18 to 80 years with a history of myocardial infarction. Participants were randomly assigned to treatment with either simvastatin 20mg daily or simvastatin 80mg daily. The study ran for a mean of 6.7 years with a composite primary endpoint of coronary death, myocardial infarction, stroke or arterial revascularisation..

At the end of follow up there was a non-significant reduction in major vascular events of 6% (relative risk ratio 0.94, 95% CI 0.88-1.01, p=0.10). There was no apparent difference in the rates of haemorrhagic stroke, vascular death or non-vascular death. There was a higher rate of myopathy (0.9%) in patients taking simvastatin 80mg compared to those taking simvastatin 20mg (0.03%).

The authors conclude that, "the 6% reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials". They also suggest that the higher rate of myopathy could be avoided by using other regimens to intensively lower LDL.

The conclusions of this study are restricted as it did not reach statistical significance in the primary outcomes. The authors also note that over the duration of the study, the introduction of more aggressive targets had the effect of reducing the net difference in LDL cholesterol between the two groups as more non-study treatments were started. The suggestion that alternative intensive lipid regimens could be used to reach lower targets and avoid the risk of myopathy seen with simvastatin 80mg does not consider the relative benefits in terms of higher acquisition costs.

Action: These two studies both appear to champion treating LDL to lower levels to prevent cardiovascular events. Neither study has assessed the impact of milder adverse drug reactions nor has any assessment be made of the relative benefits of more intensive lipid lowering treatments versus the acquisition costs to the NHS.

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2 Comments to “Lancet reopens intensive statin debate”

  1. Would this apply to all statins even though they have different kinetics, and what are the benefits of combination therapy

    Comment by Xavier Nel — November 11, 2010 #
    Reply

    1. @Xavier,

      The RCT only looked at simvastatin but the meta-analysis included studies for all statins. The authors are suggesting that treating cholesterol to lower levels reduces cardiovascular events irrespective of the agent used - the type of analysis would not be able to detect differences between agents.

      In terms of combination therapy, again this study did not aim to assess the relative risks and benefits of treatments other than statins. There are RCT studies ongoing examining exactly this for the newer lipid lowering therapies.

      Comment by Matthew Robinson — November 11, 2010 #
      Reply

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