Statins after stroke: the SPARCL study

The SPARCL study¹ was a prospective, double-blind, randomised controlled clinical trial that compared the effect of atorvastatin 80mg daily with placebo in 4,731 patients who had recently (within six months) suffered a stroke or transient ischaemic attack (TIA) (67% ischaemic stroke, 2% haemorrhagic stroke, 31% TIA). Patients had a low-density lipoprotein (LDL)-cholesterol level of 2.6–4.9mmol/l, with no previous history of coronary heart disease (CHD), although most had one or more CHD risk factors, such as smoking, hypertension, and diabetes. Patients with atrial fibrillation were excluded.

Over a median follow-up of 4.9 years, the incidence of fatal or non-fatal stroke (primary outcome events) was lower in the atorvastatin group compared with the placebo group (11.2% vs. 13.1%). The five-year absolute rate reduction for these events was 2.2% (adjusted hazard ratio [HR] 0.84; 95%CI 0.71 to 0.99, unadjusted P=0.05, adjusted P=0.03), which equates to a number needed to treat of 45 (95%CI 24 to 500). The incidences of TIA (6.5% vs. 8.8%, adjusted P=0.004) and major cardiovascular (CV) events (14.1% vs. 17.2%, adjusted P=0.002) were significantly reduced in the atorvastatin group. There was no significant difference in mortality between groups (9.1% atorvastatin, 8.9% placebo, adjusted P=0.98), although the study was not powered to demonstrate a difference in this outcome. Persistently raised liver enzyme levels were more frequent with atorvastatin than placebo (2.2% vs. 0.5%, P<0.001; number needed to harm 59), although there were no significant differences between groups with regard to other adverse effects. Mean LDL-cholesterol levels were significantly lower in the atorvastatin group than the placebo group during the study (1.9mmol/l vs. 3.3mmol/l, P<0.001).

What does this mean?

The SPARCL study suggests that atorvastatin 80mg reduces the risk of ischaemic stroke, TIA, and other CV events in patients who have recently suffered an ischaemic stroke or TIA. Any benefit obtained for atorvastatin in reducing ischaemic stroke (9.2% vs. 11.6%; adjusted HR 0.78, 95%CI 0.66 to 0.94) is slightly offset by an increased risk of haemorrhagic stroke (2.3% vs. 1.4%; adjusted HR 1.66, 95%CI 1.08 to 2.55), and by increased liver enzyme levels.

The study supports the use of statins in patients who have suffered an ischaemic stroke or TIA, which is consistent with the recent NICE Technology Appraisal Guidance for the use of statins for secondary prevention of CV disease.² The Royal College of Physicians stroke guidelines also recommend initiating statin treatment (e.g. simvastatin 40mg) following an ischaemic stroke or TIA if total cholesterol level is above 3.5mmol/l, unless contraindicated.³ Further studies are required to identify whether atorvastatin 80mg daily offers any clinical or cost-effectiveness advantage over less aggressive, and less costly, statin regimens such as simvastatin 40mg daily.

References

1. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) investigators. High-dose atorvastatin after stroke or transient ischaemic attack. N Engl J Med 2006;355:549–59
2. National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events. Technology Appraisal 94. January 2006. Accessed from www.nice.org.uk on 30/10/06
3. Intercollegiate Stroke Working Party. National clinical guidelines for stroke. Second Edition. Royal College of Physicians 2004. Accessed from www.rcplondon.ac.uk/pubs/brochure.aspx?e=130 on 30/10/06

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MeReC Bulletin on hypertension: now available online

A new MeReC Bulletin on the management of hypertension,¹ including the updated clinical guideline from NICE,² is now available. The Bulletin supersedes the previous MeReC Briefing on the same subject in 2005.³

The Bulletin is divided into three parts, each of which is freely available on the NPC website (www.npc.co.uk/merec.htm) to download for personal use. Part 1 is a summary of the key points. Part 2 provides an extensive overview of the management of hypertension and covers assessment of risk, measurement of blood pressure, treatment thresholds and targets, lifestyle interventions, and drug treatment. Part 3 contains a more detailed review of the drug treatment aspects of the updated NICE guideline. It includes information on how the guideline was developed, and the differences from the previous guideline.⁴ It also points out some limitations of the analyses of clinical and cost-effectiveness used in preparation of the updated NICE guideline.

References

1. National Prescribing Centre. The management of hypertension in primary care: updated guidance from NICE. MeReC Bulletin 2006;17:1–20. Accessed from www.npc.co.uk/merec.htm on 30/10/06
2. National Institute for Health and Clinical Excellence. Hypertension: management of hypertension in adults in primary care (partial update of NICE clinical guideline 18). Clinical Guideline 34. June 2006. Accessed from www.nice.org.uk on 30/10/06
3. National Prescribing Centre. Hypertension management in primary care. MeReC Briefing 2005;29:1–8. Accessed from www.npc.co.uk/merec.htm on 30/10/06
4. National Institute for Health and Clinical Excellence. Hypertension: management of hypertension in adults in primary care. Clinical Guideline 18. August 2004. Accessed from www.nice.org.uk on 30/10/06

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Glitazones for preventing type 2 diabetes: the DREAM study

The Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study aimed to find out whether rosiglitazone or ramipril could prevent the development of type 2 diabetes in people at high risk of developing this condition. This article focuses on the rosiglitazone part of the study.¹ The results for ramipril are available elsewhere.²

In DREAM, 5,269 people with impaired glucose regulation (an intermediate state between normal glucose homeostasis and diabetes mellitus) and no previous history of diabetes or cardiovascular (CV) disease were randomised to receive either 8mg rosiglitazone daily or placebo. All participants were provided with advice about healthy diets and lifestyles, which was reinforced at each visit.

After a median of three years, rosiglitazone significantly reduced the composite primary endpoint of diabetes or death (rosiglitazone 11.6% vs. placebo 26.0%; hazard ratio [HR] 0.40; 95%CI 0.35 to 0.46, P<0.0001, number needed to treat [NNT] 7). This was mainly due to a reduction in the incidence of diabetes. There was no significant difference between the groups in the number of deaths or CV events, although the study was not sufficiently powered to assess these secondary endpoints.

Heart failure was significantly increased with rosiglitazone compared with placebo (0.5% vs. 0.1%, HR 7.03; 95%CI 1.60 to 30.9, P=0.01, number needed to harm [NNH] 250 over three years). More people also withdrew from treatment with rosiglitazone compared with placebo because of oedema (4.8% vs. 1.6%, respectively) and weight gain (1.9% vs. 0.6%, respectively).

What does this mean?

The observation that rosiglitazone reduces the incidence of type 2 diabetes in this study is interesting. However, it is unclear whether rosiglitazone prevents the onset of type 2 diabetes or merely lowers blood sugar concentrations in those with new onset diabetes.³ The risk of heart failure is also a concern, particularly as this study was carried out in a population at low CV risk.

Lifestyle interventions, such as a healthy diet and exercise, remain the mainstay in the prevention of type 2 diabetes. In the Diabetes Prevention Program, intensive lifestyle interventions (weight loss and increased physical activity) showed similarly impressive reductions in the incidence of diabetes, with seven people with impaired glucose regulation needing to participate in the programme to prevent one person developing type 2 diabetes.⁴

References

1. The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096–105
2. The DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006;355:1551–2
3. Heneghan C,Thompson M, Perera R. Prevention of diabetes. Drug trials show promising results, but have limitations. BMJ 2006;333:764–5
4. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403

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SIGN guidance for UTI

The Scottish Intercollegiate Guidelines Network (SIGN) has recently issued guidance on the management of suspected bacterial urinary tract infection (UTI) in adults, including pregnant women, men, patients with catheters and those with co-morbidities such as diabetes.¹

SIGN advises that antibiotics should only be used when there is evidence that eradicating a bacterial infection in the urine will result in meaningful health gains, e.g. relief of symptoms. For example, there is evidence that bacteriuria is common in asymptomatic elderly patients and that treating such patients does more harm than good. In contrast, treatment of bacteriuria is beneficial in pregnancy.

The guideline aims to minimise unnecessary use of tests and antibiotic treatment by the use of simple decision rules. In non-pregnant women with multiple signs and symptoms of lower UTI (e.g. dysuria, urgency and frequency, with no vaginal irritation or discharge) it is not necessary to use a urine dipstick and SIGN recommends empirical antibiotic treatment. If diagnosis is uncertain based on signs and symptoms alone, nitrite and leucocyte esterase tests may be useful to determine whether bacteriuria is present and guide management.

References

1. Scottish Intercollegiate Guidelines Network. Management of suspected bacterial urinary tract infection in adults. SIGN guideline No.88. July 2006. Accessed fromwww.sign.ac.uk on 26/10/06

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