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Issue No 22 May 2006

ASTEROID: what is the impact?
New developments for MeReC
Clopidogrel found lacking in CHARISMA
NRT, pregnancy and congenital malformations: unproven concerns

ASTEROID: what is the impact?

The ASTEROID study (A Study To Evaluate the effect of Rosuvastatin^▼ On Intravascular ultrasound-Derived coronary atheroma burden) aimed to find out whether intensive statin therapy could regress coronary atherosclerosis.¹ The study involved 507 patients who had coronary angiography for a clinical indication (e.g. stable or unstable angina) or as a result of abnormal functional studies (e.g. exercise testing). All patients received open-label, active treatment with rosuvastatin 40mg daily in this prospective cohort study. There was no control group.

After two years, only 349 patients had baseline and follow-up results suitable for evaluation. Analysis of the results was not by intention to treat. The primary outcome variables showed statistically significant atheroma regression; a reduced percentage of atheroma volume was demonstrated in 63.6% of patients and, in the most diseased segment of the artery, reduction in total atheroma volume was seen in 78.1% of patients. Drug-related adverse events resulted in 49 (9.7%) patients being withdrawn from the trial.

So what does this mean?

Although rosuvastatin appeared to reverse atherosclerosis in ASTEROID, there is no evidence that this will lead to a reduction in heart attacks and strokes, or save lives. Further studies are needed to determine the effect of the observed changes on clinical outcomes, and to find out whether similar effects are seen with equivalent doses of other statins.

There remain concerns regarding the muscle toxicity of rosuvastatin, especially at the high dose (40mg) used in ASTEROID. Rosuvastatin is still subject to post marketing surveillance and the Committee on Safety of Medicines has issued advice regarding its use.²

A summary of advice² on the use of rosuvastatin^▼:

• All patients must start on an initial dose of rosuvastatin 10mg daily; increase to 20mg if considered necessary after a four-week trial of 10mg
• The 40mg dose is contraindicated in patients with predisposing risk factors for muscle toxicity e.g. underlying muscle disorders, renal impairment, untreated hypothyroidism, alcohol abuse, age >70 years, Asian patients³
• Specialist supervision is recommended when the 40mg dose is given (through local lipid, diabetic or cardiac clinics)
• The 40mg dose should only be necessary for the minority of patients with severe hypercholesterolaemia at high cardiovascular risk.

In summary, the ASTEROID study does not provide evidence to support a change in practice. Rosuvastatin has no clinical outcome data and prescribing restrictions apply to higher doses. Therefore, it should be reserved for cautious use in difficult-to-treat cases. A statin which has been shown to reduce mortality and morbidity (e.g simvastatin 40mg) is a more appropriate first choice.

References

1. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA 2006;295:1556–65. Accessed from www.jama.com on 20/03/2006
2. MHRA/CSM. Statins and cytochrome P450 interactions. Curr Probl Pharmacovigilance 2004;30:1–2. Accessed from www.mhra.gov.uk on 20/03/2006
3. Summary of Product Characteristics. Crestor. Accessed from www.medicines.org.uk on 24/04/2006

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New developments for MeReC

To better meet your needs in the ever-changing environment of the NHS, we are making some changes to MeReC Publications. From volume 17, each MeReC Bulletin will be accompanied by a range of complementary education and implementation resources, such as slide sets, case studies and learning quizzes. These aim to provide support for continuing professional development and local implementation of the evidence base..

In response to requests for evaluated information about key new clinical trials or guidance, as soon as they are published, we are producing a new web-based publication, MeReC Rapid Review. This will offer an appraisal of the evidence, set into the context of the current evidence base and healthcare practice, shortly after new findings are first published.

To provide a wider audience with more timely access to an increasingly interactive portfolio of MeReC resources, we are discontinuing the MeReC Briefing and moving towards greater electronic distribution. Future MeReC Bulletins and accompanying resources, and the new MeReC Rapid Review, will be available in electronic format only on our website, where you can download print-friendly versions. We will continue to distribute MeReC Extra in paper copy this year, and we will send out a CD-ROM containing the entire MeReC portfolio produced during 2006/07 at the end of the year.

To ensure you continue to be aware of all MeReC support available to you, please register to receive an email alert when a new MeReC resource is added to the NPC website. Register at www.npc.co.uk/merec.htm.

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Clopidogrel found lacking in CHARISMA

The CHARISMA (Clopidogrel for High Athero-thrombotic Risk and Ischemic Stabilization, Management, and Avoidance) study found that, in a broad population of patients at high risk of cardiovascular (CV) events, clopidogrel plus aspirin was no more effective than aspirin alone in preventing major CV events.¹ However, it increased the risk of moderate bleeding.

The study was a double-blind, randomised, placebo-controlled trial of 15,603 patients (median age 64, 30% women) with either clinically evident (78%), or multiple risk factors for, CV disease. Patients received low-dose aspirin (75 to 162mg daily) or low-dose aspirin plus clopidogrel (75mg daily) and were followed-up for a median of 28 months. The proportion of patients who suffered a primary outcome event (myocardial infarction [MI], stroke, or death from CV causes) was similar in both groups (clopidogrel plus aspirin 6.8% vs. aspirin 7.3%, P=0.22). Although there was no significant difference in severe bleeding between the groups (1.7% clopidogrel plus aspirin vs. 1.3% aspirin, P=0.09), the risk of moderate bleeding was significantly higher in the clopidogrel plus aspirin group (2.1% vs. 1.3%, P<0.001, number needed to harm [NNH] 125).¹

Clopidogrel was associated with a small reduction in primary outcomes in patients who had existing CV disease (6.9% vs. 7.9%, P=0.046, number needed to treat 100). However, in asym-ptomatic patients it increased the risk of death from CV causes (3.9% vs. 2.2%, P=0.01, NNH 59) and from any cause (5.4% vs. 3.8%, P=0.04, NNH 63).¹ These subgroup analyses should only be regarded as a basis for future research² and not as a reason to change practice.

Clopidogrel plus aspirin has shown benefit in the acute treatment of patients following an MI.^2,3 However, the CHARISMA study does not support the general use of clopidogrel plus aspirin for subsequent prevention of CV events, or for primary prevention in high-risk patients. NICE recommends use of clopidogrel plus aspirin in patients with unstable angina or non-ST-segment-elevation MI, who are at moderate to high risk of MI or death, for 12 months following an acute episode (before reverting to low-dose aspirin alone).⁴ Evidence also supports use of clopidogrel plus aspirin following a percutaneous coronary intervention with stent placement.⁵

References

1. Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. New Engl J Med 2006;354:1706–17
2. Pfeffer MA, Jarcho JA. The charisma of subgroups and the subgroups of CHARISMA. Editorial. New Engl J Med 2006;354:1744–6
3. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo- controlled trial. Lancet 2005;366:1607–21
4. The National Institute for Health and Clinical Excellence. TA80: Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome (July 2004) and clarification of recommendation 1.3 (July 2005). Accessed from http://www.nice.org.uk/page.aspx?o=TA080 on 17/03/06
5. Popma JJ, Berger P, Ohman EM, et al. Antithrombotic therapy during percutaneous coronary intervention. Chest 2004;126(Suppl 3):576S–99S

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NRT, pregnancy and congenital malformations: unproven concerns

Pregnant women who smoke should be informed of the risk of smoking to the foetus and themselves and encouraged to stop (e.g. by referral to a smoking cessation service).¹ Stopping smoking without nicotine replacement therapy (NRT) is preferable. However, if this is not possible, NRT may be recommended to assist a quit attempt, as it is considered less harmful to the foetus than continuing to smoke.²

A recent, retrospective cohort study raised concerns about an increased risk of congenital malformations when using NRT in pregnancy.³ The study evaluated the association between congenital malformations of the first child born to 76,768 women in Denmark (1997–2003) and self-reported maternal smoking habits in the first 12 weeks of pregnancy (20,603 smokers; 56,165 non-smokers — 250 used NRT). The prevalence of abnormalities for smokers (5.0%) and non-smokers (4.9%) was similar, but the prevalence for NRT users was higher (7.6%): relative prevalence rate ratio vs. other non-smokers 1.61, 95% CI 1.01 to 2.58, NNH 36). However, no direct evidence or plausible explanation was provided for the apparent increased risk of NRT when compared with smoking. Because of the small number (19) of malformations in children of women using NRT relative to other non-smokers (2,719), the study was statistically underpowered to detect the difference, which may have occurred by chance. Furthermore, as the study was observational, the results may have been influenced by uncontrolled confounding factors.

The following advice is appropriate:⁴

"Pregnant smokers should always be encouraged first to give up smoking without using NRT. However, these research findings do not mean that pregnant smokers are better off smoking than using NRT. The risks of premature birth or stillbirth caused by smoking are far higher than any potential higher risk of congenital malformation caused by NRT use."

References

1. Sowerby Centre for Health Informatics at Newcastle. Prodigy guidance: smoking cessation 2006. Accessed from www.prodigy.nhs.uk on 20/03/06
2. Duff G. New advice on use of nicotine replacement therapy (NRT): wider access in at-risk populations. Healthcare professional letter 29/12/05. Accessed from www.mhra.gov.uk on 20/03/06
3. Morales-Suárez-Varela MM, Bille C, Christensen K, et al. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol 2006;107:51–7
4. Action on Smoking and Health. ASH Response: Pregnant women using NRT. Accessed from www.ash.org.uk/html/cessation/pregnancyNRT060113.html on 20/03/06

The National Institute for Health and Clinical Excellence (NICE) is associated with MeReC Publications published by the NPC through a funding contract. This arrangement provides NICE with the ability to secure value for money in the use of NHS funds invested in its work and enables it to influence topic selection, methodology and dissemination practice. NICE considers the work of this organisation to be of value to the NHS in England and Wales and recommends that it be used to inform decisions on service organisation and delivery. This publication represents the views of the authors and not necessarily those of the Institute.

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