Download Lipid-modifying treatment

VOLUME 19
NUMBER 3
Lipid-modifying treatment
SUMMARY
• This MeReC Bulletin summarises the NICE guidance on lipid modification and addresses some
important supplementary clinical questions.
• Statin therapy should usually be considered for all adults who have established cardiovascular
(CV) disease or who have a 20% or greater 10-year risk of developing it. Use a suitable risk
calculator to estimate risk and explain likely risks and benefits to patients in absolute terms (see
the patient decision aid on the lipids floor of NPCi).
• A single cholesterol reading may well under- or over-estimate a person’s true average cholesterol
by as much as 14%, so health professionals should be wary of making treatment decisions on
the basis of single readings.
NICE lipid
guidance sets no
lipid targets
patients are
expected to attain
• Simvastatin 40mg daily is the usual first-choice statin for most patients for primary and secondary
prevention. If this is contraindicated or not tolerated, or if there are potential drug interactions, offer
a lower dose or an alternative preparation, such as pravastatin.
• For primary prevention in people without type 2 diabetes, no target for total or LDL-cholesterol
is recommended. Do not use higher intensity statinsa routinely.
• For secondary prevention in people without type 2 diabetes, consider increasing to simvastatin
80mg if both the total cholesterol and the LDL-cholesterol are greater than 4mmol/L and
2mmol/L, respectively, on simvastatin 40mg. These figures are intended to guide treatment
and are not targets all patients are expected to attain. Most patients will not attain these levels
on simvastatin 80mg and it is not cost-effective to try to take more patients to target using higher
cost statins such as atorvastatin.
• Offer people with acute coronary syndrome treatment with higher intensity statins but note that
no target for total or LDL-cholesterol is recommended.
• Any decision to offer a higher intensity statin should take into account the patient's informed
preference, comorbidities, multiple drug therapy, and the benefits and risks of treatment.
• Recommendations for primary and secondary prevention in people with type 2 diabetes are
slightly different from those without diabetes (see text).
• In the only published randomised controlled trial (RCT) of ezetimibeq which examined patientoriented CV outcomes, ezetimibeq plus simvastatin did not produce beneficial effects compared
with double placebo treatment but raised safety concerns relating to cancer.
• Statins are usually well tolerated, but due consideration should be given to possible side-effects
and the need for monitoring of enzyme levels (e.g. transaminases and creatine kinase) in certain
circumstances.
Introduction
Panel: What NICE guidance is there relating to lipid modification?
This MeReC Bulletin summarises NICE
guidance on lipid modification1-5 (see Panel)
and addresses some important supplementary
clinical questions. More information on lipid
modification can be found on the
cardiovascular floors of NPCi.
What does NICE advise about primary
prevention of cardiovascular diseaseb?
Primary prevention refers to reducing the
risk of developing cardiovascular (CV)
a
b
This publication was
correct at the time of
preparation:
December 2008
The NICE clinical guideline on lipid modification was published in
May 2008. It provides comprehensive guidance on CV risk
assessment and lipid modifying treatment1. This guidance
included and updated relevant previously published technology
appraisals on statins2 and ezetimibeq3. At the same time, NICE
published updated guidance on management of type 2 diabetes.4
This included specific recommendations on management of lipids
in people with diabetes (who were not included in the general
lipid modification guidance). Finally, in August 2008, NICE
published its clinical guideline on management of familial
hypercholesterolaemia.5
‘Higher intensity statins’ are statins used in doses that produce greater cholesterol lowering than simvastatin 40mg, for example simvastatin 80mg.
In people without diabetes or familial hypercholesterolaemia
This MeReC Publication is produced by the NHS for the NHS
MeReC Bulletin Volume 19, Number 3
1
Lipid-modifying treatment
Simvastatin 40mg
daily is the usual
first-choice statin
for most patients
disease in the future (e.g. myocardial
infarction [MI], stroke, angina, etc) in people
who do not currently have it. NICE advises
that all adults who have a 20% or greater
10-year risk of developing CV disease
should be considered for statin therapy. 1
More information on CV risk assessment
can be found in a separate MeReC Bulletin6
and on the relevant floor of NPCi.
Healthcare professionals should consider
the
possibility
of
familial
hypercholesterolaemia (FH) in adults with raised
cholesterol (total cholesterol typically
greater than 7.5mmol/L), especially when
there is a personal or a family history of
coronary
heart
disease. 5
premature
Diagnosis and management of FH is
addressed in a separate NICE clinical
guideline and is not discussed further in this
MeReC Bulletin.5
If statin treatment is appropriate for primary
prevention, it should be offered as soon as
practicable after full risk assessment.
However, the decision to treat should
follow an informed discussion with the
patient about risks and benefits taking
into account additional factors such as
comorbidities and life expectancy.
Patients should be offered information
about their absolute risk of CV disease and
the likely absolute benefits and harms of an
intervention over a 10-year period.
Information should present individualised
risk/benefit scenarios, present the absolute
risk of events numerically, and use
appropriate diagrams and text. 1 NICE
makes particular reference to NPCi, where
there is a patient decision aid on the lipids
floor. More information on the use of patient
decision aids was published in MeReC
Extra 36.7
Before offering
higher intensity
statins, take into
account the
patient’s
preferences
and particular
circumstances,
and the benefits
and risks of
treatment
Patients should usually be prescribed
simvastatin 40mg daily. If simvastatin 40mg
is contraindicated or not tolerated or if there
are potential drug interactions (see MHRA
advice8), patients may be offered a lower
dose or an alternative preparation, such as
pravastatin. Higher intensity statins a
should not be used routinely.1 Fibrates or
anion exchange resins may be considered if
statins are not tolerated but the combination
of an anion exchange resin, fibrate or
nicotinic acid with a statin is not
recommended.1
No target for total or LDL-cholesterol is
recommended. Once a person has been
started on a statin for primary prevention,
repeat lipid measurement is unnecessary.
Clinical judgement and patient preference
should guide the review of drug therapy and
whether to review the lipid profile (see
section below on the reliability of single
cholesterol levels). 1
c
2
What does NICE advise about secondary
prevention of CV diseasec?
Statin therapy is recommended for adults
with established CV disease. As with
primary prevention, the decision to treat
should follow an informed discussion with
the patient about risks and benefits. 1
Fibrates, anion exchange resins or nicotinic
acid may be considered if statins are not
tolerated.1
Patients should usually be prescribed
simvastatin 40mg daily. If simvastatin 40mg
is contraindicated or not tolerated or if there
are potential drug interactions (see MHRA
advice8), patients may be offered a lower
dose or an alternative preparation, such as
pravastatin.1 NICE advises that patients and
prescribers should consider increasing to
simvastatin 80mg if a total cholesterol of
less than 4mmol/L or an LDL-cholesterol of
less than 2mmol/L is not attained. 1
Increasing the dose should be considered
only for patients whose total cholesterol is
greater than 4mmol/L and also whose LDLcholesterol is greater than 2mmol/L. If
either figure is below that level, then
increasing the dose is not recommended
[NICE. Personal communication, November
2008]. Moreover, these figures are intended
to guide treatment. NICE lipid guidance
sets no lipid targets which patients are
expected to achieve.9 Most patients would
not achieve these levels on 80mg
simvastatin daily and modelling suggests
that it is not cost-effective to try to take
more patients to target using higher-cost
statins such as atorvastatin.9 Any decision
to offer simvastatin 80mg should take
into account the patient's informed
preference, comorbidities, multiple drug
therapy, and the benefits and risks of
treatment.1
What does NICE advise about statins in
acute coronary syndrome?
People with acute coronary syndrome
(ACS) should generally be treated with a
higher intensity statin; that is one which
achieves greater lipid lowering than
simvastatin 40mg daily.1 NICE says that
atorvastatin 80mg and simvastatin 80mg
daily are both cost-effective in ACS (but
atorvastatin 80mg is not cost-effective in
stable CV disease).9 The decision to use a
higher intensity statin instead of simvastatin
40mg should take into account the patient’s
particular circumstances and preferences,
as with other patients requiring secondary
prevention.1 It is important to note that no
lipid target is specified in ACS. NICE
does not give guidance on how long
patients with ACS should take a higherintensity statin; that is, at what point after
their ACS event they should be treated in
In people without diabetes or acute coronary syndrome
MeReC Bulletin Volume 19, Number 3
Lipid-modifying treatment
the same way as other secondary
prevention patients, and whether and when
those receiving atorvastatin 80mg should
transfer to simvastatin, and at what dose.
What does NICE advise about statins in
type 2 diabetes?
NICE guidance on type 2 diabetes also
contains
recommendations
on
lipid
modification.4 These are slightly different from
the recommendations for people without
diabetes. People with diabetes aged 40 years
or older should usually be considered for
simvastatin 40mg daily.4 If their CV risk from
non-hyperglycaemia-related factors is low,
their risk should be assessed using the
UKPDS risk engine. Simvastatin 40mg
should be offered if the estimated 10-year
risk of developing CV disease exceeds 20%.4
Simvastatin 40mg should be considered for
people younger than 40 years whose CV risk
profile appears to be particularly poor.4 NICE
advises that the dose should be increased to
simvastatin 80mg daily unless the person’s
total cholesterol is less than 4mmol/L or the
LDL-cholesterol is less than 2mmol/L.4 If
either figure is below that level, then
increasing the dose is not recommended
[NICE. Personal communication, November
2008].
due to side-effects. 13,14 The preliminary
results of the SEARCH study of high dose
simvastatin (which were discussed in a
recent MeReC Stop Press blog15) are in
keeping with these findings. A major
limitation of the studies is that none used
the “gold standard” comparator, simvastatin
40mg daily. These trials are discussed
further on the lipids floor of NPCi.
How reliable is a single cholesterol
measurement?
A recent study has found that the 95%
confidence interval on a single cholesterol
measurement was about ±14% of the
person’s true average cholesterol. 16 In
practical terms, this means that for every
100 people with a single cholesterol
measurement of 5.65mmol/L, we would
expect the true average cholesterol levels
of 95 of them to be in the range from
4.85mmol/L to 6.45mmol/L. Five people in
the 100 will have true average levels
outside this range. This study and its
implications were discussed further in a
MeReC Rapid Review blog. 17 Health
professionals should be wary of adjusting a
patient’s lipid-lowering treatment on the
basis of a single cholesterol measurement.
A single
cholesterol
reading may well
over- or underestimate a
person’s true
level by as much
as 14%
Is there any new evidence for rosuvastatin?
For people with type 2 diabetes who have
established or newly diagnosed CV disease,
or an increased albumin excretion rate,
NICE recommends initiating treatment with
simvastatin 40mg daily. Patients and
prescribers should consider intensifying
treatment with a higher intensity statina or
ezetimibeq to achieve a total cholesterol of
less than 4mmol/L (and an HDL-cholesterol
not exceeding 1.4mmol/L) or an LDLcholesterol of less than 2mmol/L. 4
What evidence is there for “higher
intensity” statinsa?
A large meta-analysis of 14 randomised
controlled trials (RCTs), including 90,056
patients, found that an initial 1mmol/L
reduction in LDL-cholesterol is associated
with about a 20% relative reduction in
major vascular events after one year of
treatment.10 No trials have examined the
use of higher intensity statinsa for primary
prevention. In secondary prevention, no
trials have evaluated the comparative
merits of treating to different target lipid
levels, but some have compared different
doses of statins.11,12,13,14 Some of these have
shown a benefit from higher doses over
lower doses in terms of reducing the risk of
CV events,12,13 but others have not,11,14 and
none has shown a reduction in all-cause
mortality. In the studies in people with
stable CV disease, those taking higher dose
statins were more likely to stop treatment
MeReC Bulletin Volume 19, Number 3
The JUPITER study was the first published
clinical trial to find a beneficial effect of
rosuvastatin on patient-oriented CV outcomes.18
As discussed in a MeReC Rapid Review blog,19
this study compared rosuvastatin 20mg daily
with placebo in people with few elevated CV
risk factors apart from a raised high sensitivity
C-Reactive Protein (hs-CRP). In absolute
terms, for every 1,000 people who took
rosuvastatin 20mg daily for two years, eight
people avoided having an MI or a stroke or
dying from CV causes, but six people
developed physician-reported diabetes who
would not have done so otherwise. Although
JUPITER provides some reassurance about
using rosuvastatin where no other statin is
suitable, it provides no reason to depart from
NICE guidance on choice of statin, the degree
of cholesterol lowering for which to aim, or
which patients to treat.
What is the controversy over ezetimibe q?
Although ezetimibeq lowers LDL-cholesterol
levels, until recently there have been no
published data to say whether or not
ezetimibe q alone or added to a statin
reduces the chance of having a CV event.
The ENHANCE study, in people with familial
hypercholesterolaemia, found no beneficial
effects of ezetimibeq plus simvastatin 80mg
versus simvastatin 80mg plus placebo on
carotid intima-media thickness20 (see the
relevant MeReC Rapid Review blog for
3
Lipid-modifying treatment
Consider the less
well known sideeffects of statins
and report all
suspected
reactions to the
MHRA
more details21) Recently, the SEAS trial in
people with asymptomatic aortic stenosis
found no benefit from simvastatin plus
ezetimibeq versus double placebo on the
risk of major CV events.22 However, SEAS
unexpectedly raised concerns about the
safety of ezetimibeq, because it found a
55% relative increase in the risk of new
cancers in the active treatment group (NNH
= 26 over 52.2 months, P=0.01). An
analysis of interim data from two much
larger ongoing studies of simvastatin plus
ezetimibeq did not find an increased risk of
cancer,23 but there are limitations to this
analysis. 24 A previous very large metaanalysis had shown that statins alone do
not increase the risk of cancer.10 The SEAS
trial and its implications are discussed
further in a recent MeReC Rapid Review
blog.25 All suspected adverse reactions to
ezetimibeq should be reported through the
yellow card scheme.
What about the side-effects of statins?
The most well established side-effects of
statins are their effects on muscle and on
liver enzymes. Although widely believed,
there is no clear evidence from randomised
clinical trials that statins cause myalgia
(muscle pain, tenderness or weakness
without creatine kinase levels greater than
10 times the upper limit of normal [ULN]).26
However, many statin studies included a
run-in period so people who were very
sensitive to statin side-effects may not have
been included in the trial follow-up.
The risk of myopathy (muscle symptoms
with creatine kinase levels >10 times ULN)
is very low at standard doses (typically less
than 1 in 10,000 patient-years) and the risk
of rhabdomyolysis is about a third of that. 26
The risk increases with higher doses, in
patients with certain risk factors such as
renal impairment, and when statins are used
in combination with drugs such as
4
fibrates.8,26,27 In particular, gemfibrozil should
not be used alongside a statin.27 Statins
should be used with caution in those with
risk factors for myopathy or rhabdomyolysis.
The MHRA have also issued specific
warnings and advice regarding drug
interactions, especially but not only with
atorvastatin and simvastatin, 8 and the need
to be particularly cautious in escalating the
dose of rosuvastatin. 28 Myalgia is not
necessarily an indicator of myopathy, but
NICE advises that creatine kinase should be
measured in people who develop muscle
symptoms while taking statins. 1 Routine
monitoring
of
creatine
kinase
in
asymptomatic people is not recommended. 1
Statins currently in use can increase liver
enzymes (especially transaminases) but do
not seem to be hepatotoxic.26 NICE advises
that baseline liver enzymes should be
measured before starting a statin.
Transaminases should be measured within
three months of starting treatment and at 12
months, but not again unless clinically
indicated.1 People who have transaminases
that are raised but are less than three times
the ULN should not be routinely excluded
from statin therapy.1
Less well known side-effects of statins as a
class include depression, sleep disturbances,
memory loss, and sexual dysfunction. Statins
may also very rarely be associated with
interstitial lung disease.29 Patients should be
advised to seek help if they develop
presenting features of interstitial lung disease
such as dyspnoea, non-productive cough, and
deterioration in general health.29 The incidence
of peripheral neuropathy during statin therapy
is similar to that of myopathy.9 NICE advises
that if a person taking a statin develops an
unexplained peripheral neuropathy, the statin
should be discontinued and specialist advice
should be sought.1 Any suspected adverse
drug reactions with statin treatment should be
reported through the yellow card scheme.29
MeReC Bulletin Volume 19, Number 3
Lipid-modifying treatment
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Technology Appraisal Guidance 94. Statins for the prevention
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developing cardiovascular disease or those with established
cardiovascular disease. January 2006
National Institute for Health and Clinical Excellence.
Technology Appraisal Guidance 132. Ezetimibe for the
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hypercholesterolaemia. November 2007
National Institute for Health and Clinical Excellence. Type 2
diabetes: the management of type 2 diabetes (update).
Clinical Guideline 66. May 2008
National Institute for Health and Clinical Excellence.
Identification
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hypercholesterolaemia. Clinical Guideline 71. August 2008
National Prescribing Centre. Assessing and communicating
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Bulletin
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14. Pedersen T J, Faergeman O, Kastelein J, et al. High-dose
atorvastatin vs usual-dose simvastatin for secondary
prevention after myocardial infarction: the IDEAL study: a
randomized controlled trial. JAMA 2005;294:2437-45
15. National Prescribing Centre. Is lower cholesterol better? – the
SEARCH continues. MeReC Stop Press Blog 238. November
18th 2008
16. Glasziou P, Irwig L, Heritier S, et al. Monitoring cholesterol
levels: measurement error or true change? Ann Intern Med
2008;148:656-61
17. National Prescribing Centre. Cholesterol measurements in
the first few years of statin treatment may mislead. MeReC
Rapid Review Blog 165. August 8th 2008
18. Ridker P, Danielson E, Fonseca F, et al. Rosuvastatin to
prevent vascular events in men and women with elevated Creactive protein. New Engl J Med 2008;359:2195-207 (the
JUPITER study)
19. National Prescribing Centre. Higher dose rosuvastatin in
lower risk patients.
MeReC Rapid Review Blog 236.
November 12th 2008
20. Kastelein J, Akdim F, Stroes E, et al. Simvastatin with or
without ezetimibe in familial hypercholesterolemia. New Engl
J Med 2008;358:1431-43 (the ENHANCE study)
21. National Prescribing Centre. What does ENHANCE tell us
about the place in therapy of ezetimibeq? MeReC Rapid
Review Blog 97. April 16th 2008
7.
National Prescribing Centre. Using patient decision aids.
MeReC Extra 2008; No. 36
8.
MHRA and CHM. Statins: interactions, and updated advice for
atorvastatin. Drug Safety Update, January 2008;1(6):2-4
9.
National Collaborating Centre for Primary Care and the Royal
College of General Practitioners. Lipid Modification.
Cardiovascular risk assessment: the modification of blood
lipids for the primary and secondary prevention of
cardiovascular disease. Full Guideline. May 2008
23. Peto R, Emberson J, Landray M, et al. Analyses of cancer
data from three ezetimibe trials. N Engl J Med
2008;359:1357-1366
10. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy
and safety of cholesterol-lowering treatment: prospective
meta-analysis of data from 90 056 participants in 14
randomised trials of statins. Lancet 2005;366:1267-78
25. National Prescribing Centre. SEAS and ezetimibe q: no
benefits on CV endpoints, questions raised over cancer risk.
MeReC Rapid Review Blog 199. September 15th 2008
11. de Lemos J, Blazing M, Wiviott S, et al. Early intensive vs a
delayed conservative simvastatin strategy in patients with
acute coronary syndromes: phase Z of the A to Z Trial. JAMA
2004;292:1307-16
12. Cannon CP, Braunwald E, McCabe C, et al. Intensive versus
moderate lipid lowering with statins after acute coronary
syndromes. New Engl J Med 2004;350:1495-1504 (the
PROVE-IT study)
13. LaRosa J, Grundy S, Waters D, et al Intensive lipid lowering
with atorvastatin in patients with stable coronary disease.
New Engl J Med 352:1425-35 (the TNT study)
22. Rossebø A, Pedersen T, Boman K, et al for the SEAS
Investigators. Intensive lipid lowering with simvastatin and
ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56
24. Fleming T. Identifying and addressing safety signals in clinical
trials. New Engl J Med 2008;359:1400-02
26. Armitage J. Safety of statins in clinical practice Lancet
2007;370:1781-90
27. MHRA and CHM. Fibrates: new prescribing advice. Drug
Safety Update, November 2007;1(4):2-3
28. MHRA and CHM. Rosuvastatin (Crestor): introduction of 5 mg
starting dose Current Problems in Pharmacovigilance May
2006;31:4
29. MHRA and CHM. Statins: class effects identified. Drug Safety
Update, February 2008;1(7):2-4
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MeReC Bulletin Volume 19, Number 3
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