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VERDICT & SUMMARY Atorvastatin 80 mg daily (Lipitor®) For the secondary prevention of cardiovascular events Committee’s Verdict: CATEGORY B (Q3) BNF: 2.12 Atorvastatin at the dose of 80 mg daily is suitable for restricted prescribing in primary care for secondary prevention of cardiovascular events in patients with acute coronary syndrome or established cardiovascular disease. This dose of atorvastatin should not be used routinely, because of the increased risk of adverse events. It should be reserved for patients considered to be at highest risk, after careful individual risk assessment. No trials were found assessing the efficacy for primary prevention. Q rating: The evidence for the efficacy and safety of atorvastatin 80 mg in patients with acute coronary syndrome or established cardiovascular disease was considered to be relatively strong, based on four randomised controlled trials comparing atorvastatin 80 mg daily with “moderate” statin therapy and using clinical outcomes. The evidence was stronger for patients at higher risk. The greater risk of adverse events with this dose, the absence of evidence of long-term safety, and NICE guidance give it a low place in therapy. The Q rating relates to the drug’s position on the effectiveness indicator grid. The strength of the evidence is determined by the quality and quantity of studies that show significant efficacy of the drug compared with placebo or alternative therapy. Its place in therapy in primary care takes into account safety and practical aspects of using the drug in primary care, alternative options, relevant NICE guidance, and the need for secondary care input. Place in therapy in primary care Category B: suitable for restricted prescribing under defined conditions Q2 higher place weaker evidence Q1 higher place stronger evidence Q4 lower place weaker evidence Q3 lower place stronger evidence Strength of evidence for efficacy MTRAC reviewed atorvastatin 80 mg because of concerns that its use at this dose was not supported by clinical evidence. Licensed indication Atorvastatin is indicated for the treatment of primary hypercholesterolaemia and combined (mixed) hyperlipidaemia when response to diet and other nonpharmacological measures is inadequate. It is also indicated for primary prevention of cardiovascular disease in diabetic patients with at least one additional risk factor, without clinically evident coronary heart disease, irrespective of whether cholesterol is raised.1 Background information The most common manifestation of cardiovascular disease is coronary heart disease, which is caused by narrowing of the arteries due to build-up of atheroma. This is the underlying cause of angina and myocardial infarction (MI). Other forms of cardiovascular disease include stroke and peripheral arterial disease. Acute coronary syndrome (ACS) includes unstable angina, non-ST-segment elevation myocardial infarction (non-Q wave MI), and ST-segment elevation MI. The rupture of atherosclerotic plaque, or its erosion or disruption, is the most important underlying pathophysiological mechanism in ACS. The September 2006 consequences range from unstable angina to “classical” acute MI manifest by progressive, specific ECG changes with ST-segment elevation and a rise in cardiac markers such as creatine kinase. Clinical efficacy Four RCTs compared atorvastatin 80 mg daily with “moderate” statin therapy. Two trials involved patients with ACS2,3 and two involved patients with stable cardiovascular disease.4,5 In patients with ACS, one double-blind RCT (PROVE IT-TIMI 22) compared atorvastatin 80 mg daily with pravastatin 40 mg daily (n = 4,162; mean duration of follow-up 24 months).2 The primary endpoint was a combination of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalisation, revascularisation and stroke. The other trial was a much smaller, open-label RCT (n = 81; follow-up 60 days to 12 months) which compared atorvastatin 80 mg daily with any statin titrated to achieve LDL-cholesterol < 2.6 mmol/L.3 The composite primary endpoint was cardiac death, nonfatal MI, recurrent symptomatic myocardial ischaemia Page 1 of 2 with objective evidence requiring emergency rehospitalisation. For additional information on adverse events, refer to 1 the Summary of Product Characteristics (SPC). In both studies, participants treated with atorvastatin 80 mg daily were significantly less likely to experience a primary event compared with patients in the “moderate” statin therapy group (p = 0.005, NNT = 26 over 2 years;2 p < 0.053). Additional information In patients with stable cardiovascular disease, one double-blind RCT (the TNT study) compared atorvastatin 80 mg daily with atorvastatin 10 mg daily (n = 10,003; median duration of follow-up 4.9 years).4 The other RCT, an open-label study with blinded endpoint assessment (the IDEAL study) compared atorvastatin 80 mg daily with simvastatin 20 mg daily (n = 8,888, mean follow-up duration 4.8 years).5 In the TNT study, the composite primary end point was the occurrence of a major cardiovascular event defined as death from CHD, non-fatal non-procedurerelated MI, cardiac arrest with resuscitation or stroke (fatal or non-fatal). In the IDEAL study, the primary composite endpoint was major coronary event, defined as coronary death, non-fatal MI or cardiac arrest with resuscitation. Stroke was not included in the composite primary end point in the IDEAL trial. In the TNT study, patients treated with atorvastatin 80 mg daily were significantly less likely to experience a primary event compared with patients who had been treated with atorvastatin 10 mg daily (p < 0.001, NNT = 45).4 However, in the IDEAL study there was no significant difference between the groups in the incidence of the composite primary endpoint (p > 0.05).5 Trials comparing atorvastatin 80 mg daily with placebo but not with an active comparator, and trials in which fewer than 50% of the patients in the “high dose” atorvastatin arm received an 80 mg daily dose, were reviewed but are not included in this summary. Adverse effects Adverse events experienced by patients treated with atorvastatin 80 mg daily included myalgia and myopathy, rhabdomyolyis, hepatic enzyme elevations, headache, back pain, depression and gastrointestinal side effects. Patients treated with atorvastatin 80 mg daily were more likely to discontinue treatment due to adverse events compared with patients receiving moderate statin therapy (p < 0.05).4,5 In some studies, a high proportion of patients had previously been exposed to statins (e.g. in the IDEAL study, 76% of patients had previously used a statin5) which may have pre-selected for patients likely to tolerate a high dose of atorvastatin. • The recommended starting dose of atorvastatin is usually 10 mg daily. Adjustment of dosage should be made at intervals of four weeks or more.1 • Contraindications to atorvastatin include active liver disease or unexplained, persistent elevations of transaminases exceeding three times the upper limit of normal. Atorvastatin is also contraindicated in breastfeeding or pregnant women (adequate contraception should be used in women of childbearing age). Liver function tests should be performed before initiation of treatment and periodically during treatment. Atorvastatin should be used with caution if patients have risk factors for myopathy or rhabdomyolysis and patients should be advised to report unexplained muscle pain. For full details, see the SPC.1 • The National Institute for Health and Clinical Excellence (NICE) issued guidelines for the prescribing of statins for the prevention of cardiovascular events in January 2006.6 The guidelines recommend that statins be used for secondary prevention of cardiovascular disease but do not address the question of dose. In a consultation document of guidelines currently in development, NICE does not recommend the routine use of statins at very high dose.7 • At current prices a year’s treatment with atorvastatin 80 mg daily costs £367. References 1. Pfizer Ltd. Lipitor. Summary of Product Characteristics 2006. 2. Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:14951504. 3. Colivicchi F, Guido V, Tubaro M et al. Effects of atorvastatin 80 mg daily early after onset of unstable angina pectoris or non-Q-wave myocardial infarction. Am J Cardiol 2002;90:872-874. 4. LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-1435. 5. Pedersen TR, Faergeman O, Kastelein JJP et al. Highdose atorvastatin vs. usual-dose simvastatin for secondary prevention after myocardial infarction. JAMA 2005;294:2437-2445. 6. NICE. Statins for the prevention of cardiovascular events. Technology Appraisal No. 94, 1-45. Jan 2006. 7. NICE. Secondary prevention in primary and secondary care for patients following myocardial infarction. Appraisal Consultation Document, Aug 2006; p.129. Launch date: August 2000 Manufacturer: Pfizer Ltd EU/16051/0005 WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. MTRAC can be contacted at the Dept. of Medicines Management, School of Pharmacy, Keele University, Keele, Staffs ST5 5BG Tel: 01782 584131 Fax: 01782 713586 Email: [email protected] Web: www.mtrac.co.uk Date: September 2006 ©Midlands Therapeutics Review & Advisory Committee VS06/17