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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