Role of statins in preventing another stroke

Alison Turner and Dr Nigel Jowett examine the dangers and preventative measures of recurring stroke

Stroke is a common condition, that affects about 200 people per 100,000 of the UK population each year, accounting for 11 per cent of all deaths.

Over three quarters of cases are caused by cerebral infarction secondary to large intra- or extra-cranial artery atherosclerosis, embolism from a cardiac source or small vessel disease (lacunar infarcts).

The remainder are caused by intra-cerebral haemorrhage or other uncertain types. In addition, transient ischaemic attacks (TIA) affect 35 people per 100,000 of the population annually and are associated with a high risk of stroke within the first 72 hours of the event: 10-20 per cent will have a stroke within a month.

The distinction between TIA and ischaemic stroke has become less important in recent years because they share pathogenic mechanisms, and many of the preventive approaches are applicable to both groups. However, the relevance of these interventions to haemorrhagic and cardio-embolic stroke is not necessarily the same.

Traditional cardiovascular risk factors, such as hypertension, smoking, and diabetes independently increase the probability of stroke. The role of lipids is more difficult to understand. In patients who had not suffered a stroke, the Heart Protection Study (HPS) demonstrated that simvastatin reduced the rate of ischaemic strokes by between a quarter and a third. However, if participants already had pre-existing cerebrovascular disease, statin therapy offered no protection against recurrence. Reducing the serum cholesterol did reduce other vascular events, and gives good reason for routine statin therapy.

Another stroke occurs in a third of patients within five years. There are several interventions that can help prevent recurrence (see box right).

With respect to cholesterol, the latest guidelines from the American Heart Association recommend that patients with ischaemic stroke or TIA should be treated with a statin to reduce the risk of vascular events, although not specifically recurrent stroke.

However, subsequent publication of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial may modify this advice. This placebo controlled trial was specifically designed to see whether a more potent statin (atorvastatin 80mg) would help prevent stroke recurrence.

Reducing risks
During a median follow-up of 4.9 years, of patients 11.2 per cent receiving atorvastatin and of patients 13.1 per cent receiving placebo had a fatal or non-fatal stroke, an absolute reduction in risk over the five years of 2.2 per cent.

As expected, there was a significant reduction in other major cardiovascular events. Despite the high dose of atorvastatin, there was no difference in serious side-effects between the groups.

Patients with atrial fibrillation and other cardiac sources of emboli were excluded from the trial, so the SPARCL results cannot apply to the roughly one in five ischaemic strokes where emboli originate in the heart.

There is some concern for patients who present with cerebral haemorrhage. Curiously, these patients were not excluded from the trial, and the relative risk of haemorrhagic stroke was increased by 66 per cent in those patients in the atorvastatin group.

On the basis of HPS, the current UK stroke guidelines suggest treatment with a statin (40mg simvastatin) for all patients with ischaemic stroke or TIA, and a total cholesterol of more than 3.5mmol/l to reduce cardiovascular events. Patients in SPARCL were entered into the trial at one and six months following their first stroke.

Reducing cholesterol
While in the HPS this was on average 4.3 years later, and it may have been this delay that adversely affected outcome.

Whether earlier administration of less potent generic statins, or lower doses of atorvastatin may produce similar benefits is unknown. What is important to prevent all recurrent vascular disease is that the serum cholesterol is reduced sufficiently (see box on opposite page).

Following a stroke, the risk of recurrence remains high for at least a year, but remains higher than for the general population for the rest of patient's life, so they need regular review and appropriate treatment of cardiovascular risk factors. Chronic disease clinics in primary care should ensure that the dose of the chosen statin is titrated to achieve optimum blood cholesterol levels. The current GMS contract points ‘weighting' does not reflect the importance of both lipid and BP control in the prevention of second stroke.

Perhaps in the light of recent evidence such as SPARCL, GMS targets and stroke management guidelines may change at the next review. 

  • Alison Turner is a cardiovascular research nurse and Dr Jowett is a consultant in cardiovascular medicine, Pembrokeshire & Derwen NHS Trust, Wales

CHOLESTEROL TARGETS FOLLOWING STROKE

Total cholesterol < 4 mmol/l 

OR 

LDL-cholesterol < 2 mmol/l 

OR 

25 per cent reduction in total cholesterol 

OR 

30 per cent reduction in LDL-cholesterol of these results in the lowest cholesterol level

SECONDARY PREVENTION OF ISCHAEMIC STROKE OR ITA 

General measures

  • Stop smoking .
  • Regular exercise and eat a healthy diet, achieving a satisfactory weight. 
  • Reduced salt intake. Avoid excess alcohol.

Blood pressure

  • Elevated BP persisting for over two weeks should be treated (ACE-inhibitor/thiazide combination preferred).
  • BP targets <140/85mmHg (<130/80mmHg in patients with diabetes).

Anti-platelet therapy

  • Aspirin (50-300mg) or aspirin 75mg and modified-release dipyridamole (200mg bd).
  • Clopidogrel 75mg if aspirin is not tolerated.

Anticoagulation

  • Anticoagulation with warfarin (INR 2-3) in patients with persistent or paroxysmal atrial fibrillation.

Statins

  • Treatment with statins should be given to patients with ischaemic stroke or TIA, and a total cholesterol of >3.5mmol/l.

Surgery

  • Any patient with a carotid artery territory stroke without severe disability should be considered for carotid endarterectomy.

References

  •  Allender S, Peto V, Scarborough P, et al. Coronary heart disease statistics. British Heart Foundation Statistics database, 2006. London. http://www.heartstats.org..
  •  Wolfe C D. The impact of stroke. British Medical Bulletin 2000; 56: 275-86.
  • Royal College of Physicians. National clinical guidelines for stroke, 2004; RCP. London
  • Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363: 757-67.
  • Sacco R L, Adams R, Albers G, et al (2006). Guidelines for prevention of stroke in patients with ischaemic stroke or transient ischaemic attack: A statement for healthcare professionals from the American Heart Association. Stroke 2006; 37: 577-617.

 

  • Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators (2006). High-dose atorvastatin after stroke or transient ischaemic attack. N Engl J Med 2006; 355:549-59.

 

  • LaRosa J C. Is aggressive lipid-lowering effective and safe in the older adult? Clin Cardio, 2005; 28: 404-7.

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