Cardiovascular Disease Prevention

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Osborne Gregory
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Summary Guidelines May 2009 Cardiovascular Disease Prevention ISBN 0 902238 70 1 Primary prevention Smoking cessation Improve diet and physical activity BP control < 140/90mmHg 15% CHD risk = 20% CVD

stent/cabg Statin Acute coronary syndrome Treat with higher intensity statin any of the following: Simvastatin 80mg Atorvastatin 80mg Beta blocker + aspirin 75mg + ACE inhibitors + Clopidogrel after

1 Summary Guidelines May 2009 Cardiovascular Disease Prevention ISBN Primary prevention Smoking cessation Improve diet and physical activity BP control < 140/90mmHg 15% CHD risk = 20% CVD risk Simvastatin 40mg Secondary Prevention Smoking cessation Improve diet and physical activity Optimal BP control < 130/80mmHg Optimal total cholesterol < 4mmols/l OR LDL < 2mmols/l MI, ACS, Angina, stent/cabg Statin Acute coronary syndrome Treat with higher intensity statin any of the following: Simvastatin 80mg Atorvastatin 80mg Beta blocker + aspirin 75mg + ACE inhibitors + Clopidogrel after ACS/stent Stroke/TIA, PAD Statin Aspirin + dipyridamole 200mg bd Type 2 Diabetes Age > 40 yrs + Statin Stable CHD/angina, stroke, TIA, diabetes or peripheral arterial disease Simvastatin 40mg Cholesterol 4mmols/l or LDL cholesterol 2mmols/l Simvastatin 80mg BP control < 140/80mmHg

2 2 Cardiovascular Disease Introduction This guidance summarises up to date evidence on the management of people at increased risk of cardiovascular disease. We have been asked by many clinicians to put recent changes to recommendations in a single document. We have tried to make this consistent with NICE guidance. In a world of competing guidelines and commercial pressure there are inevitably some grey areas. We have tried to highlight those areas where there is greatest consensus. We have used NICE guidance on lipid modification, myocardial infarction, Type 2 diabetes, obesity, familial hypercholesterolaemia, hypertension and east London and NICE guidance on chronic kidney disease. This guideline represents NICE guidance and more recent evidence on best practice for cardiovascular disease and promotes the most effective and cost-efficient use of resources. See CEG The NHS Health Check - Reducing heart disease, stroke, diabetes and chronic kidney disease GUIDANCE 2009 for details of risk estimation. Lipid modification and CVD risk Type 2 diabetes Obesity Familial hypercholesterolaemia Hypertension CKD guidance The report was compiled by Dr John Robson and the Clinical Effectiveness Group, QMUL (j.robson@qmul.ac.uk ). Further copies or information can be obtained from: Clinical Effectiveness Group (CEG) Centre for Health Sciences Institute of Health Sciences Education Barts and The London School of Medicine and Dentistry Abernethy Building 2 Newark Street London E1 2AT Tel: CEG website:

3 Cardiovascular Disease 3 Choice of Statin Primary prevention For people with a CVD risk of 20% or more in 10 years treat with simvastatin 40mg. Simvastatin 40mg if CVD risk 20% Most people over 75 years are 20% CVD risk and should be considered for treatment in their social and clinical context. Before treatment check Fasting total and HDL cholesterol, LDL cholesterol and triglycerides. Current recommendations advise starting rosuvastatin at 10mg. South Asians and people over 70 years should start at 5mg. The dose of atorvastatin 80mg may be lowered where there is increased risk of adverse events, intolerance or drug interaction. Stable CHD/angina, stroke, TIA, diabetes or peripheral arterial disease Simvastatin 40mg Cholesterol still 4mmols/l or LDL cholesterol 2mmols/l Simvastatin 80mg Fasting blood glucose, egfr and LFTs. Check thyroid function where disease is suspected. Check LFTs within 6 months and at a year but not again if within acceptable limits (>2x upper limit of normal (ULN) and reconsider treatment if 3x ULN). It is not necessary to routinely measure cholesterol for primary prevention. Where simvastatin is not tolerated consider simvastatin 10mg or 20mg or pravastatin. Secondary prevention Acute coronary syndrome Treat with higher intensity statin any of the following: Simvastatin 80mg Atorvastatin 80mg There is trial evidence of reduction in cardiovascular events after ACS with both simvastatin 80mg and atorvastatin 80mg. Both are considered cost effective by NICE which recommended intitation with simvastatin on the basis of cost rather than clinical effectiveness. Rosuvastatin 20mg now has a single randomised trial in people at increased risk but without established CVD. This reduced CVD events by 50% and total deaths by 20% (Jupiter NEJM 2008). A trial in heart failure showed no benefit (Lancet 2008). The cost of simvastatin 80mg has reduced considerably and is not much more expensive than two 40mg tablets, so that a single 80mg tablet may improve compliance. The NICE guidance found that atorvastatin 80mg was not cost effective in stable CHD at its current price and did not recommend its routine use in stable secondary prevention. LDL lowering STELLAR trial Before treatment check Fasting total and HDL cholesterol, LDL cholesterol and triglycerides. Fasting blood glucose, egfr and LFTs. Thyroid function if secondary cause of dyslipidaemia suspected. LFTs within 6 months and a year but not again if within acceptable limits (>2x upper limit of normal and reconsider treatment if 3x ULN). Cholesterol annually. LDL lowering Outocome trials Cost/month Simvastain 40mg 40% 30% HPS 1.42 Simvastain 80mg 46% no placebo trial 4.84 Atorvastatin 80mg 51% 40% SPARCL Rosuvastatin 20mg 52% 50% JUPITER 26.02

4 4 Cardiovascular Disease Type 2 diabetes NICE guidance recommends simvastatin 40mg and increasing dose to simvastatin 80mg when serum cholesterol remains above 4mmols/l or LDL 2mmols/l. Adverse events with high dose statins There are more adverse effects from high dose statins. Adverse events are dose related and more common with Fibrates Diltiazem Switching statins Switching from high cost atorvastatin 10mg and 20mg to simvastatin 40mg has proved to be easy, acceptable and effective. Atorvastatin is six times the cost of simvastatin. Whilst this will be generally appropriate there will be some patients and their clinicians who would prefer not to change their medication in this way. Simvastatin 40mg reduces LDL cholesterol slightly more than atorvastatin 10mg and slightly less than atorvastatin 20mg. However, simvastatin increases HDL cholesterol more than atorvastatin - an effect more marked at higher doses. Verapamil Amiodarone Ciclosporin Erythromycin People taking atorvastatin 10mg or 20mg should be switched to simvastatin 40mg. Antifungal agents Antiviral treatment Grapefruit juice should be avoided. Statins are contraindicated in pregnancy. Starting or changing statin dose may alter anticoagulant control which should be checked. Muscle pain should be investigated with creatine kinase (CK) measurement. Myalgia is muscle discomfort not associated with CK rises and is not in itself an indication to stop treatment. Myopathy/myositis is associated with muscle damage typically with increase in CK 10x ULN. In symptomatic patients rises of CK >3x ULN should prompt treatment review. Statins may also cause peripheral neuropathy. Simvastatin and atorvastatin There is one systematic review that suggests that at standard doses atorvastatin is associated with more adverse events than simvastatin. However this was not shown by two other reviews. There is no evidence to suggest simvastatin at higher dose is any more or less likely than atorvastatin to cause adverse events or is less tolerated. Rosuvastatin 20mg was not associated with any excess of adverse events in the Jupiter trial (NEJM 2008). Abnormal lipids and familial hypercholesterolaemia Consider further investigation or referral where Serum cholesterol >8mmols/l Serum triglycerides >10mmols/l Suspected familial hypercholesterolaemia Positive family history of premature coronary heart disease (a heart attack or angina in a parent or brother or sister under age 60 years, or a grandparent, aunt or uncle under 50 years) and where total cholesterol is 7.5mmols/l should be investigated or referred to confirm familial hypercholesterolaemia. Cardiac rehabilitation Post ACS patients should receive a program of cardiac rehabilitation and assessment by a specialist to consider revascularisation.

5 Cardiovascular Disease 5 Ezetimibe The routine use of ezetimibe cannot be recommended on the present evidence. Since the NICE HTA reported optimistically in 2007 on the possible benefits of ezetimibe, new evidence (NELM 2008) on ezetimibe is of concern. Two new ezetimibe trials are the only ones to have reported cardiovascular outcomes. The combination of ezetimibe with simvastatin did not improve the primary outcome in either trial. Furthermore there was a significant unexpected increase in cancer deaths, but not new cancer cases. This finding was still present when preliminary results of two ongoing trials assessing ezetimibe were examined. These results could be due to chance and trials are continuing. Clinicians should note that there is no current evidence to support the routine addition of ezetimibe to a statin and there are also concerns about possible unexpected harm. The main trial is expected to report in Ezetimibe is an option in statin intolerant patients. Aspirin and Secondary Prevention Aspirin 75mg (soluble not enteric coated) is recommended at all ages for both men and women after MI, Stable Angina, Stroke/TIA, Peripheral Vascular Disease. Clear net benefit in terms of reduced cardiovascular events, results from its use in these very high risk groups. Where there is gastric intolerance, treat with an antacid or H2 antagonist. A low dose proton-pump inhibitor may be required. Clopidogrel 75mg is as likely to cause gastrointestinal bleeding as aspirin and should not be used as a substitute in people with dyspepsia or at increased risk of bleeding. It is indicated only for people with proven allergy to aspirin causing persistent or severe rash or wheeze or as specifically indicated (see later). Avoid Cox -2 inhibitors and use lowest effective dose for shortest duration of naproxen or ibuprofen. Stroke and TIA If raised, reduce blood pressure optimally to below 130/80mmHg. Treat confirmed ischaemic stroke or TIA with aspirin 75mg together with dipyridamole M/R 200mg bd. Dipyridamole can cause headache in which case consider reducing dose or monotherapy with aspirin. In patients with atrial fibrillation warfarin is treatment of choice. In haemorrhagic stroke no antithrombotic is advised and use a statin only if some other indication applies. Aspirin and Primary Prevention Routine use of aspirin cannot be recommended for primary prevention including people with diabetes. (NB The recommendation to use aspirin in people after MI, stroke or PVD still stands). The evidence base for the benefit of aspirin in primary prevention has been substantially reassessed in the light of recent trials of aspirin in people with type 1 or 2 diabetes and peripheral vascular disease. These people were at high risk of a vascular event (equivalent to a 30% CVD risk in 10 years) but showed no improvement in the primary endpoints - either CVD mortality or major events. (Belch et al BMJ 2008;337: ). There have now been seven major trials of aspirin for primary prevention, all of which have been negative for the primary endpoint and none has shown a reduction in CVD mortality even in subanalysis of higher risk groups. There is no evidence of benefit in women and the benefits in people over 70 years of age may be offset by increased risk of bleeding (Nelson et al BMJ 2005; 330:1306). In some studies there was a reduction in the risk of non-fatal MI but not of stroke and these benefits may be attenuated in people with raised blood pressure. On the basis of the current evidence, low dose aspirin cannot be routinely recommended in people with diabetes, cannot be recommended in women and cannot be recommended in people over age 70 years. There may be a reduction of one-third in non-fatal MI in men with BP <150/90. The absolute benefits are likely to be greatest in men at high risk. Aspirin 75mg may be considered in men under 70 years without diabetes who are at high CVD risk (30% or more 10yr CVD risk) but in whom blood pressure is below 150/90mmHg - in whom it may reduce non-fatal MI by one-third but has not been shown to improve mortality. NICE guidance 2009 on aspirin in diabetes was completed before the two main trials (Belch BMJ 2008; Ogawa JAMA 2008) reported no benefit of aspirin. Some clinicians may prefer to follow NICE guidance.

6 6 Cardiovascular Disease Clopidogrel Clopidogrel 75mg should be used together with aspirin 75mg for one year only. Following acute coronary syndrome.* After stent insertion (Bare metal stents for one month only). *Local policy applies to both NSTEMI and STEMI Survivors at 1 year are likely to be at lower risk and clopidogrel may be stopped. Continuing treatment with clopidogrel places the patient at increased risk of bleeding and is only warranted where the risks of thrombosis and infarction are very high and outweigh the risks of bleeding. The risk of bleeding with clopidogrel is at least as great as with aspirin. Clopidogrel should not be substituted for aspirin in people with dyspepsia/ulcer symptoms. It is safer to use aspirin plus a proton pump inhibitor than clopidogrel. Other drugs ACE inhibitors after ACS, MI and in patients with angina. Beta blockers for people with coronary heart disease, MI, ACS, angina. Blood pressure management Primary prevention treatment threshold 160/100mmHg or more 140/90mmHg or more when 20% CVD risk (15% CHD) Target <140/90mmHg Audit target <150/90mmHg Secondary prevention treatment threshold CVD, diabetes or renal disease: 140/90mmHg or more Target* < 130/80mmHg Audit target <140/90mmHg Renal disease < 130/80mmHg * Joint British guidance 2006 recommends an optimal target of 130/80 mmhg for both secondary (including diabetes) and primary prevention. The audit targets agree with NICE. Clinical assessment History: Including angina or claudication, breathlessness. Discuss compliance with treatment. Review other exacerbating drugs: NSAIDs raise BP by around 5mmHg; oral contraceptives or oral steroids. Clinical review: exclude end-organ damage or secondary CVD. Urinalysis: protein or blood should instigate renal investigation. Anti-hypertensive drugs Many patients will require two or three drugs to lower their blood pressure if they start at a systolic pressure over 155mmHg. NICE Guidance Hypertension advises First choice therapy 55 years or older, or Black patients of any age Either a low cost calcium channel blocker (CCB) or a thiazide diuretic. Under 55 years ACE inhibitor (or ARB if not tolerated). Second choice. Add an ACE inhibitor. Under 55 years Add CCB or thiazide to ACE. Third choice. combine all three drugs. Thiazide diuretic, ACE inhibitor, CCB. Fourth choice. Any of the following drugs may be appropriate: Beta-blockers, alpha-blockers or further diuretic therapy. Where blood pressure is controlled with a beta-blocker there is neither an urgent need nor an absolute need to replace it with an alternative agent. Where people are on a beta-blocker and blood pressure is not controlled, the drug should be withdrawn by step-wise reductions in dose with the addition of the preferred drugs above. People on beta-blockers post MI, to reduce angina or for heart failure should not have their medication changed. Beta-blockers may be appropriate in younger women who may get pregnant or people in whom ACE inhibitors are contraindicated/not tolerated. In this circumstance a CCB and not a thiazide is preferred.

7 Cardiovascular Disease 7 Common side effects Common side effects Less common side effects Thiazide Gout ACE inhibitor Cough (1 in 5) Renal impairment may improve Foetal abnormality Avoid in pregnancy Calcium channel blocker Ankle oedema Beta blockers Asthma, heart block Angiotensin Renal impairment receptor blocker Alpha-blockers Urinary incontinence Heart failure in women Detailed dosing People under 55 years should start on an ACE to which would be added either or both CCB and thiazide. By way of illustration, an ideal dosing schedule is given for people over 55 years, stepping up if the target 140/90 mmhg is not achieved using the mean of at least two and preferably more readings at monthly reviews. Step 1 Start either bendroflumethiazide 2.5mg daily or amlodipine 5mg (generic) daily. If amlodipine is not tolerated consider issuing pill cutter and restarting at 2.5mg. Step 2 Check U&Es (results from within last 6/12 acceptable). Initiate with lisinopril 2.5-5mg daily or other low cost ACE and if tolerated increase to 5mg and 10mg at weekly intervals if BP not controlled. (NSAID should be avoided in patients on ACE inhibitors and ACE should not be used in pregnancy). Recheck U&Es at 1-4 weeks repeating bloods after every dose increase. Lisinopril may be increased to 20mg daily and to 40mg daily if tolerated (or equivalent low cost ACE inhibitor). Check U&Es annually or after each dose increase. If ACE inhibitors not tolerated start angiotensin receptor blocker (lower dose in the elderly or renally impaired). Recheck U&Es at 1 to 4 weeks and repeat after each dose change. If BP not controlled increase incrementally to recommended maximum dose. Step 3 Add thiazide or CCB if not already on them. Increase to amlodipine 10mg daily if BP still not at target. Step 4 If not already on beta-blocker: Add atenolol 50mg or metoprolol 50mg or other generic beta blocker (unless frail elderly or <50kg then 25mg daily). If BP not controlled within 4 weeks increase to 100mg (especially if heart rate remains above 60bpm, and check compliance). Alternatively consider an alpha blocker. If not already on an alpha-blocker, add doxazosin 4mg daily. If BP not controlled within 4 weeks increase to 8mg od. Spironolactone and moxonidine are used as antihypertensives where other drugs have failed to control blood pressure or are not tolerated. Failure to control risk factors 1. Review concomitant drugs NSAID, oral contraceptives, oral steroids, compliance and alcohol. 2. Consider secondary causes renal (MSU protein and blood), endocrine. Refer or fully investigate all hypertension under age 30yrs. 3. Consider other treatment options or specialist advice or referral. Most people have a decreasing benefit with each added drug. The risks of polypharmacy, particularly in the very old or frail with co-morbidities, need to be weighed against the relatively small benefits of additional drugs where patients are already taking 4 or more drugs. Electrolytes are of concern in the frail elderly on multiple drugs and on spironolactone. 7

8 8 Cardiovascular Disease Life Style Health Education for Primary & Secondary Prevention Stopping smoking is the single most important change that can be achieved to reduce coronary heart disease Smoking Smokers should be offered smoking cessation support including nicotine replacement, bupropion or varenicline combined with individual or group support. People who have not stopped after local cessation programmes should be considered for referral to more intensive programmes if they are available. Physical activity People should aim to substantially exceed the minimum of 30 minutes five times a week. Further increases in activity lead to increased benefit and should be encouraged. Walking some of the way to work, shopping and school drops should be encouraged. Graded increases in physical activity should be an integral part of treatment plans and lifestyle change. Diet Overall dietary change is recommended to reduce risk of cardiovascular disease. This includes a reduction in salt; reduction in saturated fat intake and use of unsaturated oils and margarines; at least five portions of fruit and vegetables each day and consumption of 2-3 portions of oily fish per week. The greater the change in diet the greater the benefit. A major change in diet, particularly for those with existing cardiovascular disease is likely to be beneficial. A diet low in saturated fat Be aware of hidden saturated fats e.g. pies, pastries, croissants, mince, biscuits, cakes, samosas and coconut. Also limit 'takeaway' or 'processed foods' e.g. burgers, chips, fried chicken, crisps, chocolate, pilau or fried rice. Choose low fat dairy products e.g. skimmed or semi skimmed milk, low fat cottage cheese and low fat yoghurt. Avoid full fat hard cheeses. Use rapeseed, sunflower, corn or olive oil. Measure oil used in cooking. Choose margarines high in monoand poly- unsaturated fat rather than butter. Cooking methods: use steam, poach, microwave, grill or casserole instead of frying. Encouraging fruit and vegetables At least 5 portions of fruit and vegetables are recommended each day. This can include fresh, frozen, dried, tinned or a glass of fruit juice. A portion is approximately a 'handful' (80g) e.g. apple, orange, 3 dried apricots, 1tbsp raisins, ½ grapefruit, slice of melon. These foods are high in antioxidants. There is no evidence that antioxidant vitamin supplements reduce heart disease. A 'Mediterranean' type diet high in fruit, vegetables, wholegrain cereals and low in saturated fat has been shown to reduce cardiovascular risk. Salt reduction Salt should not be added at the table and foods high in salt should be limited. Other foods for consideration for individuals with CHD include: Oats, beans, pulses (black-eyed peas, lentils, baked beans or dahl). They are high in soluble fibre and help reduce cholesterol levels. Plant sterol or stanol products e.g. Benecol and Flora Pro-Active. These may help reduce cholesterol (but have not been shown to reduce mortality) and large amounts need to be consumed, which may cause problems if individuals are trying to lose weight. They are also expensive and once the products are stopped, the benefits stop. Post myocardial infarction. Fish oils ( g omega- 3 fat per day), either as fish or as fish oil supplements. Obesity A reduction in calories is necessary for weight reduction. Local guidelines and referral criteria should be considered e.g. whether to refer to a local Dietitian or other community activities. Group activities may help some individuals deal with improving dietary change. An increase in physical activity further reduces the likelihood of diabetes or cardiovascular events. It also increases calories used and increases muscle mass. NICE provide guidance on treating obesity with Orlistat and Sibutramine. This guidance should be consulted before prescribing, together with any other local guidelines. Reduce fat in meat e.g. remove skin or visible fat and choose smaller portions.

Younger adults with a family history of premature artherosclerotic disease should have their cardiovascular risk factors measured.

Younger adults with a family history of premature artherosclerotic disease should have their cardiovascular risk factors measured. Appendix 2A - Guidance on Management of Hypertension Measurement of blood pressure All adults from 40 years should have blood pressure measured as part of opportunistic cardiovascular risk assessment.