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104FM.2 LIPID MODIFICATION FOR SECONDARY AND PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE (CVD)
IN ADULT PATIENTS
Table 1: Recommended treatment choices
Condition
Treatment choice
Secondary prevention of CVD
(except in chronic kidney disease (CKD))
1st line:
2nd line:
3rd line:
4th line:
Atorvastatin* 40 to 80 mg daily. Use a lower dose if:
Potential drug interactions
High risk of adverse effects
Patient preference
Simvastatin 40 mg daily if there is intolerance to atorvastatin
Pravastatin 40 mg daily if there is potential for drug interactions
Ezetimibe 10 mg daily only if there is intolerance or contraindications (CIs) to all statins
Target lipid profile: If the starting dose is less than atorvastatin 80 mg daily, the dose should be titrated
depending upon tolerability to achieve an ideal total cholesterol level of <4 mmol/L and LDL <2 mmol/L.
NICE CG 181 recommends a new target of 40% reduction from baseline of non-HDL cholesterol. This
target allows blood tests to be taken without fasting but neither target is currently included in QOF 201516.
For all patients not reaching expected target check adherence.
Secondary prevention of CVD in CKD
GFR <90 and/or albuminuria (G2,A2)**
Atorvastatin 20 mg daily initially
Simvastatin 40 mg is not advised in severe renal impairment (see table 3 below).
Primary prevention of CVD in CKD
GFR <60 and/or albuminuria (G3a,A2)**
Bucks advise step-wise implementation, giving
priority to patients with GFR <45 (G3b,A2)
Increase atorvastatin dose up to 80 mg daily), depending upon tolerability, to achieve the target
lipid profile described above. However, for patients with eGFR <30 ml/min, dose increases should first
be agreed with a renal physician at a routine hospital review.
**NICE CG 182 CKD categories
GFR
2
(mg/min/1.73m )
G2
G3a
G3b
G4
G5
60 - 89
45 - 59
30 - 44
15 - 29
<15
ACR
(albumin/creatinine ratio)
A1 (<3) A2 (3 - 30)
A3 (>30)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
*Unlicensed indication; use is endorsed by NICE
Guideline 104FM.2
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Condition
Treatment choice
Primary prevention of CVD in patients with
10% or greater 10 year CVD risk using
QRISK2 assessment tool
1st line: Simvastatin 40 mg or atorvastatin 20 mg daily
2nd line: Pravastatin 40 mg daily if there is potential for drug interactions
There is a spectrum of views from clinicians and
patients about the practicality of implementing
this recommendation. Bucks advise a step-wise
approach, giving priority to patients with 20% or
greater CVD 10 year risk. All patients offered
statin therapy should have a full discussion on
benefits versus risks and this should be
documented in the notes.
Primary prevention of CVD in:
Type 2 diabetes with a 10% or greater 10
year CVD risk using the QRISK2 assessment
tool
There is no target level for total or LDL cholesterol for primary prevention of CVD and ongoing monitoring of
lipids is not recommended.
1st line:
2ndline:
Simvastatin 40 mg or atorvastatin 20 mg daily
Pravastatin 40 mg daily if there is potential for drug interactions
There is no target level for total or LDL cholesterol for primary prevention of CVD and ongoing monitoring of
lipids is not recommended.
Type 1 diabetes
>40 years OR
disease >10 years OR
established nephropathy OR
other CVD risk factors
Primary prevention of CVD in:
Familial hypercholesterolaemia (FH)
1st line: Atorvastatin 80 mg daily
Aim to achieve a reduction in LDL cholesterol of >50% from baseline. If this is not achieved, check, confirm
adherence and refer to Lipid Clinic for consideration of other treatment options including rosuvastatin.
Any patient with a total untreated cholesterol >7.5 mmol/l and a family history of premature coronary heart
disease (CHD) should be investigated for FH and managed in accordance with NICE CG 71 Familial
Hypercholesterolaemia.
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Table 2: Comparison of LDL cholesterol reduction and costs*
Cost for
28 day
supply*
% LDL cholesterol
reduction expected
Atorvastatin 10 mg tablets
£1.20
37%
Atorvastatin 20 mg tablets
£1.40
43%
Atorvastatin 40 mg tablets
£1.62
49%
Atorvastatin 80 mg tablets
£2.72
55%
Simvastatin 20 mg tablets
£1.01
32%
Simvastatin 40 mg tablets
£1.18
37%
Simvastatin 80 mg tablets
£1.90
42%
Pravastatin 40 mg tablets
£2.05
29%
Ezetimibe 10 mg tablets
£26.31
18%
Rosuvastatin 5 or 10 mg tablets
£18.03
43%
Rosuvastatin 20 mg tablets
£26.02
48%
Rosuvastatin 40 mg tablets
£29.69
53%
Medicine and daily dose
* Prices from drug tariff; March 2015
Table 3: Prescribing of statins and ezetimibe in renal impairment4
Mild
(CrCl 60 - 90
ml/min)
Moderate
(CrCl 10 - 60
ml/min)
Simvastatin
Yes
Yes
40 mg not advised
20 mg with caution
10 mg recommended
Atorvastatin all doses
Yes
Yes
Yes
Rosuvastatin
Yes
Max. dose 20 mg
Contraindicated at any
dose
Pravastatin
Yes
Yes
Yes
Ezetimibe
Yes
Yes
Yes
Drug
Severe
(CrCl <10 ml/min)
Prescribing points
Dose, contraindications and drug interactions




Refer to the SPC for a full list of interactions, contraindications and side effects.
To reduce the risk of intolerance, titration up to atorvastatin 80 mg daily is recommended.
All statins are contraindicated in active liver disease, pregnancy and breastfeeding.
Prescribing in renal impairment is described in table 3 above.
Statin intolerance
 Titrate to maximum tolerated dose, OR
 Change to an alternative product.
Ezetimibe
 Has less CVD outcome data compared to statins. It is therefore reserved for intolerance,
contraindications or where drug interactions with all statins limit their usefulness.
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Rosuvastatin
 Rosuvastatin which has not been initiated by the Lipid Clinic, where intolerance or inefficacy
has not been demonstrated with atorvastatin, should be switched to an appropriate dose of
atorvastatin (rosuvastatin 10 mg is equivalent to atorvastatin 20 mg).
 If the indication is familial hypercholesterolaemia, and atorvastatin 80 mg daily has been tried
but not tolerated or is ineffective, then rosuvastatin may be initiated by the Lipid Clinic and
continued by the GP.
Fibrates
Are not recommended by NICE CG 181, July 2014, for primary prevention, secondary prevention,
CKD, type 1 or type 2 diabetes.
Interactions
 Due to increased risk of myopathy, simvastatin is contraindicated or requires dose reduction
when used with several classes of interacting medicines (see table 4).
 All statins interact with fibrates and this combination poses a higher risk of rhabdomyolysis.
 Several drugs interact with both simvastatin and atorvastatin, but not with pravastatin. They
include amiodarone, antifungals (itraconazole, posaconazole, ketaconazole, voriconazole,
fluconazole), combined oral contraceptives, digoxin, diltiazem, erythromycin and
clarithromycin (use with caution with pravastatin), telaprevir, ticagrelor, verapamil, several
HIV medicines (e.g. indinavir, nelfinavir, itonavir, saquinavir), St John’s Wort (with caution).
Table 4:
Simvastatin drug interactions associated with increased risk of myopathy/rhabdomyolysis
Interacting agents
Prescribing recommendations
Ciclosporin
Clarithromycin
Danazol
Erythromycin
Gemfibrozil
HIV protease inhibitors (e.g. nelfinavir)
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Telithromycin
Contraindicated with simvastatin
Other fibrates (except fenofibrate)
Do not exceed 10 mg simvastatin daily
Amiodarone
Amlodipine
Diltiazem
Ranolazine
Verapamil
Do not exceed 20 mg simvastatin daily
Fusidic acid
Patients
should
be
closely
monitored.
Temporary suspension of simvastatin treatment
may be considered.
Grapefruit juice
Avoid grapefruit juice when taking simvastatin
Ticagrelor
Do not exceed 40 mg simvastatin daily
General points
Lifestyle advice
All patients prescribed statins should be given lifestyle advice on modifications which might reduce
their CV risk, including advice on diet, exercise, alcohol and smoking.
Compliance
Check compliance at every review, especially if lipid results have not improved as expected.
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Table 5: Monitoring requirements
Blood tests
required
Monitoring required before initiating a statin
Lipid profile
Total cholesterol:
HDL, LDL and
triglycerides
For secondary prevention, as a statin is indicated
irrespectively, only one reading is necessary ideally pretreatment as baseline reference.
Liver function tests
(LFTs)
Before therapy (transaminases AST/ALT + bilirubin). Do
not initiate statin if AST/ALT are ≥3 x upper limit normal
(ULN).
For primary prevention, HDL and total cholesterol are only
needed for initial screening of CVD risk.
If total
cholesterol >7, a repeat fasting lipid profile is indicated to
assess type of dyslipidaemia.1
Statins may be safely initiated if ALT or AST <3 x ULN.
(Patients with LFTs that are elevated but <3 x ULN
should not be excluded from statin therapy.)
Monitoring required after initiating a statin
At 4 - 12 weeks after initiation or following change in
statin/statin dose increase for all secondary prevention and/or
for familial hypercholesterolaemia.
Then monitor at every 12 - 15 months.
There is NO need for annual monitoring cholesterol if for
primary prevention. Only consider random cholesterol level
every 1 - 3 years if for reasons of compliance, patient
acceptance, etc.2
LFTs should be measured within 3 months after starting or
changing treatment and then at 12 months, but NOT again unless
clinically indicated, e.g. signs/symptoms of hepatotoxicity or
patient on other concomitant drug associated with possible
hepatoxicity.3
If LFTs are abnormal after initiating statin treatment:
If AST/ALT <3 x ULN, continue statin and repeat LFTs within 4 - 6 weeks to exclude further increases in LFTs. No
additional monitoring is required if AST/ALT are stable and remain at <3 x ULN.
If AST/ALT >3 x ULN, discontinue statin and recheck LFTs within 4 - 6 weeks to ensure values returning to normal. If LFTs
normalise, consider switching statin and recheck LFTs at further 4 - 6 weeks, then again at 3 months.
STOP statin if AST/ALTs continue to be ≥3 x ULN and consider specialist opinion.
Creatine kinase
(CK)
also known as
creatine
phosphokinase
(CPK)
Serum CK does not need to be routinely monitored prior Check CK only in symptomatic patients with signs or symptoms of
to initiation of a statin.
myalgia or muscle tenderness.4
Rule out other causes for symptoms or CK elevation.
It should only be considered pre-treatment in patients with
If CK >5 x ULN stop statin, check renal function and repeat CK
pre-disposing factors for muscle toxicity, including a
within 2 - 4 weeks . Consider expert opinion for further advice.
personal or familial history of myopathy.
If CK <5 x ULN temporarily stop statin and repeat CK in 1 month.
If normalised consider use alternative statin and monitor.5
Renal function –
Creatinine (Cr)
U&Es including Cr if not undertaken within last 6 - 12 months - see table 3 above for prescribing guidance in renal impairment.
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Monitoring table 5 - comments
1. The 95% confidence interval of a single cholesterol reading is ± 14% due to analytical variability
and week to week biological variation around a stable average. Ref. Annals Int Med 2008: 148
656-61.
2. A 20% relative reduction in CVD risk is achieved by being on statins alone irrespective of
absolute cholesterol levels in primary prevention patients.
3. There is no evidence to support the need for long term monitoring of liver function in people
taking statins (for more than 12 months). The recommendation to repeat LFTs within 3 months is
based on individual SPCs of the drugs and in accordance with the expert consensus of the NICE
Guidance Development Group (2008). The recommendations to repeat LFTs after a dose
increase is also based on expert opinion, NICE Guideline 67, 2010 (revised).
4. Incidence of myopathy is a dose-related side effect of statins and more likely to occur when coprescribed with other agents likely to be myotoxic or known to interact with statins. Risk of
myopathy following treatment with statins is increased with concurrent administration of
ciclosporin, fibrates, macrolide antibiotics, niacin or azole antifungals.
5. Myalgia in the absence of raised CK is not a reason to stop statin unless patient finds symptoms
intolerable. Risk of myositis associated with CK >5 x ULN and risk of rhabdomyolysis associated
with CK >10 x ULN.
References
1. NICE 2014: Lipid Modification. Cardiovascular risk assessment and the modification of blood
lipids for the primary and secondary prevention of cardiovascular disease[ Clinical Guideline
181], London: NICE.
2. NICE 2007: Ezetimibe for the treatment of primary (heterozygous-familial and non-familial)
hypercholesterolaemia. [Technology Appraisal 132], London: NICE
3. NICE 2008: Identification and management of familial hypercholesterolaemia. [Clinical
Guideline 71], London: NICE.
4. Ashley Caroline, Aileen Currie. The Renal Drug Handbook 3rd edition.
5. MHRA and CHM Drug safety update volume 6, issue 1 (1s), August 2012.
6. Joint Formulary Committee. British National Formulary (online) London: BMJ group and
Pharmaceutical Press http://www.medicinescomplete.com [Accessed on 16/2/14].
7. NICE 2014: Chronic Kidney Disease. Early identification and management of chronic kidney
disease in adults in primary and secondary care. [Clinical Guideline 182], London: NICE.
Title of Guideline
Guideline Number
Version
Effective Date
Review Date
Original Version Published
Approvals:
Formulary Management Group
Clinical Guidelines Subgroup
Area Prescribing Committee
Author/s
Lipid modification for the secondary and primary prevention of
cardiovascular disease in adult patients
104FM
2
June 2015
June 2018
November 2009
th
25 February 2015
th
16 April 2015
rd
3 June 2015
Maire Stapleton, Formulary Manager, BHT
Sarah Crotty, Interface Pharmacist, AV & Chiltern CCG
Jane Butterworth, Head of Medicines Management AV & Chiltern CCG
Piers Clifford, Consultant Cardiologist, BHT
Chris Wathen, Consultant Chest Physician, BHT
Stuart Logan,Aylesbury Vale GP Exec Clinical Lead for Chronic
Diseases, Medicines Management and End of Life Care
Stephen Stamp, GP, Aylesbury Vale CCG
Raj Bajwa, Chiltern CCG Director for Long Term Conditions, End of Life
Care and Prescribing
Maria Smith Senior Pharmaceutical Adviser, AV/Chiltern CCGs
SDU(s)/Department(s) responsible
Cardiology
for updating the guideline
Pharmacy
th
Uploaded to Intranet
9 June 2015
Buckinghamshire Healthcare NHS Trust/Aylesbury Vale and Chiltern Clinical Commissioning Groups
Guideline Number 104FM.2
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