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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 1 of 6 Uncontrolled if printed 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. Guideline 104FM.2 2 of 6 Uncontrolled if printed 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. Guideline 104FM.2 3 of 6 Uncontrolled if printed 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. Guideline Number 104FM.2 4 of 6 Uncontrolled if printed 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. Guideline Number 104FM.2 5 of 6 Uncontrolled if printed 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 6 of 6 Uncontrolled if printed