Viewpoint: Statins in ischaemic stroke prevention

Professor Peter Sever and Professor Neil Poulter discuss the role of statins in stroke prevention.

CT scans of 52 year old patient who has had a stroke (Photo: SPL)
CT scans of 52 year old patient who has had a stroke (Photo: SPL)

European1,2 and US3 guidelines state that patients who have an ischaemic stroke should have long-term statin therapy as secondary prevention.

The European Society of Cardiology (ESC) guidelines1 state that ‘patients with ischaemic cerebrovascular disease merit the same degree of attention to treatment of plasma lipids as do patients with CHD’.

The only evidence-based dose of statin to demonstrate a reduction in morbidity/mortality in patients with ischaemic stroke is atorvastatin 80mg,4 but guidelines have been less clear on the specific dose of statin that should be prescribed.

Some guidelines propose target LDL cholesterol goals for optimal risk reduction, while others simply advocate highly effective statin therapy, regardless of LDL levels.

In the most recent US guidelines,5 the authors concluded from a review of current evidence that in a secondary prevention context, there are no trial data to provide a scientific basis for treating to a specific LDL target. Instead, all patients with ischaemic stroke should receive high-intensity statin treatment.

Implications for the UK

A 2007 audit6 highlighted that despite clear guidelines, only about 50% of UK patients with ischaemic stroke were receiving statin therapy.

Only a proportion of those would have had high-intensity therapy. Whether future UK and European guidelines will follow the US lead remains to be seen. However, the new NICE guidance on lipid modification, currently out for consultation, suggests this will be the case.7

NICE advocates the use of atorvastatin 80mg in all patients with established cardiovascular disease, with provision for a lower dose of atorvastatin in the event of adverse effects, drug interactions or patient preference. It warns not to delay initiation of statin therapy to manage modifiable risk factors. For patients on low- or middle-intensity statins, NICE recommends discussing the benefits of high-intensity statins.

Critically, the draft NICE guidance states that the most important measure of success in minimising population risk will no longer be cholesterol levels, it will be the proportion of patients taking high-intensity statins for secondary prevention.

Impact on GPs

For GPs, this would seem to simplify decision-making as it removes uncertainties over which statin to use and avoids dose titration.

However, some critics believe abolition of lipid goals will confuse physicians and miss the opportunity for adherence and patient engagement in self-management.8

In addition, the absence of lipid goals in high-risk patients with high cholesterol levels will discourage clinicians from considering the addition of other lipid-modifying drugs or treatments.

The Fourier study

This study is investigating whether lowering LDL by an additional 50% with evolocumab (a PCSK9 inhibitor, not yet licensed for use) on top of optimal statin therapy can reduce the risk of a further cardiovascular event in patients who have had an ischaemic stroke, MI or peripheral arterial disease and are considered to be at high risk of a further event.

The study will include patients with LDL ≥1.8mmol/L (the ESC guidelines target for very high risk cardiovascular patients). SPARCL only included those with LDL ≥2.6mmol/L (and <4.9mmol/L).4

Additional studies

Two other PCSK9 inhibitors are undergoing phase III studies – bococizumab and alirocumab.9

SPIRE-1 and SPIRE-2 will include more than 22,000 patients to evaluate bococizumab in high-risk subjects on background lipid-lowering therapy. Patients will be randomised to subcutaneous bococizumab or placebo every two weeks.

The main outcome is time from randomisation to first confirmed occurrence of a major cardiovascular event, including cardiovascular death, MI, stroke and unstable angina requiring urgent revascularisation.

Patients in SPIRE-1 will have LDL ≥1.8mmol/L and <2.6mmol/L or non-HDL >2.6mmol/L and <3.4mmol/L. In SPIRE-2, they will have LDL ≥2.6mmol/L or non-HDL ≥3.4mmol/L.

ODYSSEY Outcomes
ODYSSEY Outcomes is a trial of 18,000 patients recruited within one year of an acute coronary syndrome, who have an LDL >1.8mmol/L despite high-intensity or maximum tolerated dose of statin.
Patients are randomised to alirocumab or placebo as a two-weekly subcutaneous injection.

The principal outcome is the composite of CHD death, non-fatal MI, ischaemic stroke or unstable angina.

  • Professor Sever is professor of clinical pharmacology and therapeutics, Professor Poulter is professor of preventive cardiovascular medicine, both at Imperial College London
  • Conflict of interest: The Fourier study is supported by the Imperial Clinical Trials Unit and sponsored by Amgen Pharmaceuticals

1. Perk J, De Backer G, Gohlke H et al. Eur Heart J 2012; 33: 1635-701.
2. European Stroke Organisation (ESO) Executive Committee, ESO Writing Committee. Cerebrovasc Dis 2008; 25: 467-507.
3. Sacco RL, Adams R, Albers G et al. Stroke 2006; 37: 577-617.
4. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med 2006; 355: 549-59.
5. Stone NJ, Robinson J, ?Lichtenstein AH et al.? Circulation 2013; Nov 12.
6. Ramsay SE, Whincup PH, ?Wannamethee SG et al. J Public Health (Oxf) 2007; 29: 251-7.
7. NICE. Draft guideline on lipid modification (update): guideline ?consultation. London, NICE, in progress 2014.
8. Ray KK, Kastelein JJ, Matthijs Boekholdt S et al. Eur Heart J 2014; 35: 960-8.

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