The consensus statement  was proposed by the chairperson in the session, Professor Eivind Berge, Oslo, the session secretary dr Nikolaos Kostulas, Stockholm, together with the speakers in the session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The speakers in this session were Dr Philippa Lavallée, Paris, Professor Bo Norrving, Lund and dr Manuel Rodriguez Yañez, Santiago de Compostela.

Is there sufficient evidence to recommend aggressive cholesterol-lowering therapy for secondary prevention of stroke?

Is there sufficient evidence to recommend that cholesterol-lowering therapy should not be withdrawn at the onset of stroke? Are further clinical trials warranted?

Evidence about risk reduction of stroke by statins

In patients with high risk of cardiovascular events, there is reliable evidence that statin treatment results in a modest but important reduction in the risk of stroke (relative risk reduction 21%, 95% confidence interval [1].

In the Heart Protection Study (HPS) more than 20.000 patients at high risk of vascular events and with total plasma cholesterol of ≥3.5 mM were treated with simvastatin 40 mg or placebo daily [2]. 3280 patients (16% of all patients) had a previous stroke or TIA, out of whom 1820 had no known coronary artery disease (CAD). For all patients there was a 20% relative reduction (and a 5.1% absolute reduction) of the risk for a major vascular event during the 5 years follow-up period. For patients with previous stroke/TIA there was a 23% relative risk reduction (absolute risk reduction 4.9%). Statin treatment was initiated on average more than 4 years after stroke onset.

In the Prospective Study of Pravastin in the Elderly at Risk (PROSPER) trial, 638 of 5804 (11%) patients aged 70-82 years had a previous stroke. Overall, there was a 15% relative risk reduction of vascular events during 3.2 years (absolute risk reduction 2.1%), but no risk reduction for stroke (although this study was underpowered for this estimate)[3].

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial 4,731 patients with recent (<6 months) noncardioembolic stroke or TIA and with no known CAD were randomised to atorvastatin 80 mg per day or placebo [4]. After 4.9 years of follow-up, there was a statistically significant 16% relative reduction in the risk of stroke (primary end-point) in the atorvastatin group compared to the placebo group (absolute risk reduction 2.2 %), despite a small increase in the risk of haemorrhagic stroke. There was also a statistically significant 35% reduction in major coronary events, 42% reduction in all coronary events, and a 45% reduction in revascularization procedures.

Epidemiological studies have suggested that low blood cholesterol may increase the risk of haemorrhagic stroke. However, a recent large observational study has suggested that the increased risk of haemorrhagic stroke is confined to people with low concentrations of blood cholesterol and markers of high alcohol consumption. It is therefore still uncertain whether low blood cholesterol levels increase risk of haemorrhagic stroke [5].

Conclusions

Based on the above-mentioned studies we recommend that statins should be part of a standard secondary prophylactic treatment after an ischaemic stroke or a TIA if LDL cholesterol is 2.6 mmol/l (100 mg/dl) or above, or if total cholesterol levels are 5.0 mmol/l or above. Benefits were observed both with atorvastatin 80mg [4] (Grade A evidence) and with simvastatin 40mg [2] (Grade B evidence).

Statin treatment should be started during the first 6 months after stroke (grade B evidence) [1-2]. There is no reliable evidence to support the routine use of statins in the acute phase of stroke (first 2 weeks). However, to ensure that patients are started on prophylactic treatment, we recommend that treatment be started before discharge from hospital.

It appears reasonable to avoid discontinuation of statin therapy in the acute phase of ischaemic stroke. However this conclusion is not based on firm evidence from randomised studies.

Statins should be used with caution in patients with previous haemorrhagic stroke, and in patients with ischaemic stroke or TIA with markers of alcohol excess [5].

References

1. No authors listed. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994 Nov 19;344(8934):1383-9. 
2. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004; 363:757-67.
3. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360:1623-1630
4. High-dose atorvastatin after stroke or transient ischemic attack.
   N Engl J Med 2006 Aug 10;355(6):549-59
5. Woo D, Kissela BM, Khoury JC, Sauerbeck LR, Haverbusch MA, Szaflarski JP, Gebel JM, Pancioli AM, Jauch EC, Schneider A, Kleindorfer D, Broderick JP. Hypercholesterolemia, HMG-CoA reductase inhibitors, and risk of intracerebral hemorrhage: a case-control study. Stroke. 2004;35(6):1360-4