Chapter 2 Cardiovascular System

Transcription

1 Chapter 2 page number 1 Chapter 2 Cardiovascular System First line drugs Drugs recommended in both primary and secondary care Second line drugs Alternatives (often in specific conditions) in both primary and secondary care Specialist initiated drugs Secondary care or GP with special interest initiation. Suitable for continuation by primary care. Shared care agreements may be applicable. Secondary care only drugs Drugs only suitable for secondary care use and initiated by appropriate team or specialist. Primary care prescribers should not be asked to prescribe. Management of Heart Failure (1) Offer both angiotensin-converting enzyme (ACE) inhibitors and beta-blockers licensed for heart failure to all patients with heart failure due to left ventricular systolic dysfunction. Use clinical judgement when deciding which drug to start first. Seek specialist advice before offering second-line treatment to patients with heart failure due to left ventricular systolic dysfunction. Second-line treatments for consideration include: - Addition of an aldosterone antagonist licensed for heart failure Spironolactone 1 st line (especially if the patient has moderate to severe heart failure [NYHA class III IV] or has had an MI within the past month), or - Addition of an angiotensin II receptor antagonist (ARB) licensed for heart failure (especially if the patient has mild to moderate heart failure [NYHA class II III]), or - Addition of hydralazine in combination with nitrate (especially if the patient is of African or Caribbean origin and has moderate to severe heart failure [NYHA class III IV]). Digoxin is recommended for worsening or severe heart failure due to left ventricular systolic dysfunction despite firstand second-line treatment for heart failure. Diuretics should be routinely used for the relief of congestive symptoms and fluid retention in patients with heart failure, and titrated (up and down) according to need following the initiation of subsequent heart failure therapies. Amlodipine should be considered for the treatment of co morbid hypertension and/or angina in patients with heart failure, but verapamil, diltiazem or short-acting dihydropyridine agents should be avoided. Management of stable angina This is based on NICE Clinical Guideline CG126 (31) and BNF 64 (32). Patients with stable angina should be offered a beta-blocker or a calcium channel blocker first line. If a beta-blocker or a calcium channel blocker alone fails to control symptoms, a combination of beta-blocker and dihydropyridine calcium channel blocker should be used. If this combination is not appropriate due to intolerance of, or contraindication to, either beta-blocker or dihydropyridine calcium channel blocker, then addition of a long-acting nitrate, nicorandil or ivabradine may be considered, provided drug selection is based on co-morbidities, contraindications, patient preference and drug costs. Because of its cost, ivabradine would usually be considered after isosorbide mononitrate and nicorandil. For those patients in whom both beta-blockers and calcium channel blockers are not tolerated or are contraindicated, monotherapy with long-acting nitrate, nicorandil or ivabradine may be considered. Consider referral to a specialist if two drugs fail to control symptoms. Management of Hypertension (2) Special cases Renal Disease (3) - ACE inhibitors may help prevent deterioration of renal function, unless this is secondary to renal artery stenosis, when these drugs should be avoided. Type 1 diabetes ACE inhibitors and ARBs have additional benefits because of their renoprotective effect. Pregnancy - 1 st line Methyldopa, 2 nd line Nifedipine LA Beta blockers - are no longer preferred as routine initial therapy for hypertension. Combination therapy involving beta blockers and diuretics may induce more new onset diabetes compared with other combinations therapies and therefore should not be a first line option. Generally patients with drug resistant hypertension should be referred to secondary care for further assessment.

2 Chapter 2 page number 2 Treatment of newly diagnosed patients with Hypertension (Based on NICE Clinical Guideline CG127) Black patients are those from African or Caribbean Descent Younger (e.g. < 55yr) and Non-Black Older (e.g. 55yr) or Black patients at any age Step 1 A C Step 2 A + C A + C Step 3 A + C + D Step 4 Resistant Hypertension Add: Doxazosin, spironolactone, other diuretic or Beta blockers Consider seeking specialist advice A: ACE inhibitor (or ARBs if cough or intolerant of ACE inhibitor) C: Calcium Channel Blocker (Dihydropyridine) D: Diuretic (thiazide) Management of Patients Post MI (4) All patients who have had an acute MI should be offered treatment with a combination of the following drugs: ACE (angiotensin-converting enzyme) inhibitor. aspirin. beta-blocker. statin. Clopidogrel, in combination with low-dose aspirin, is recommended for use following an ST-segment elevation MI and in the management of non-st segment-elevation acute coronary syndrome in people who are at moderate to high risk of MI or death. See section 2.9 Antiplatelet drugs for details, including length of treatment Positive Inotropic Drugs Cardiac Glycosides Digoxin Loading dose oral 500 micrograms stat 250 micrograms 6 hours later 250 micrograms 6 hours later Maintenance 125 micrograms (poor renal function) to 250 micrograms daily. Older patients 62.5 micrograms (poor renal function) to 125 micrograms daily Phosphodiesterase Inhibitors Consider checking K +. Only check digoxin level if toxicity or noncompliance suspected. Level should be taken 6-8 hours post dose. Interacts with many drugs, particularly amiodarone, verapamil and diltiazem. The digoxin dose may need reducing or in the case of amiodarone halving, if above 62.5 micrograms daily. See BNF for details. (5) Digoxin Injection if no cardiac monitoring 2 doses of 500 micrograms, each over a minimum of 2 hours in 100ml of normal saline/glucose 5%, 12 hours apart. Emergency loading dose 750 micrograms micrograms as a single dose given as above. Check levels if toxicity suspected particularly if haemodynamic status changed. Digibind injection discussion with Consultant Cardiologist advised. For rescue therapy when supportive measures ineffective or in acute overdose. Three kept as stock in Acute Trust emergency cupboard. Enoximone injection ICU only

3 Chapter 2 page number Diuretics Thiazides and related diuretics See 3T s prescribing guidance on management of hypertension and NICE CG127. Please note Bendroflumethiazide remains our first-line formulary choice of thiaizide diuretic, on grounds of affordability. Bendroflumethiazide tablets 2.5mg Doses higher than 2.5mg increase side effects and adverse metabolic effects with no additional anti-hypertensive benefit. (6) Can cause significant erectile dysfunction. (7) Indapamide tablets 2.5mg Chlorothiazide Metolazone tablets Loop Diuretics Furosemide tabs Bumetanide tabs For patients with proven bendroflumethiazide hyponatraemia. Avoid SR preparation (non-formulary) 2.5mg plain tablets are equivalent to 1.5mg SR tablets Paediatric use only. Note: unlicensed preparation, specialist initiation. For use in patients with end- stage heart failure, who have failed to respond to bendroflumethiaizide, prescribed in line with BSH Guidance. Often given on alternate days. Requires very careful monitoring of U&Es. Only available as an unlicensed preparation, and so for consultant initiation and ongoing prescription on hospital outpatient prescription (yellow script) only. 40mg Furosemide is approximately equal to 1mg Bumetanide. Furosemide injection Bumetanide injection Potassium Sparing Diuretics Check potassium 2 weeks after initiation or on dosage change. Monitor closely if on ACE inhibitor or ARBs. Spironolactone Adjunct therapy in heart failure. For use in liver disease, see GI (chapter 1). See MHRA Drug Safety Update Dec 16 for further information and advice on risk of serious adverse effect. Amiloride Used mainly in combination with loop or thiazide diuretics for potassium sparing effect. Dose should not generally exceed 5mg except in specific endocrine conditions. Eplerenone Adjunct in stable patients with Left Ventricular Dysfunction with evidence of heart failure post MI (start therapy within 3-14 days of event). Initiation by consultant cardiologists or endocrinologists only Potassium Sparing Diuretics with other diuretics Co-amilofruse Not generally recommended, as individual components cannot be adjusted independently. Use should be restricted to patients where there is a risk of hypokalaemia or if there are compliance problems. Where more diuresis is required, an extra dose of furosemide should be given rather than doubling the co-amilofruse dose Osmotic diuretics

4 Chapter 2 page number 4 Mannitol injection 2.3. Anti-arrhythmic drugs Supraventricular arrhythmias and Atrial Fibrillation Patients with new or recent onset paroxysmal AF should be referred to the cardiologist for assessment and consideration of cardioversion and/or anticoagulation. Please refer to 3Ts Guidance on QTc interval and drug therapy Acute Management - refer to European/UK Resuscitation Council recommendations. Rank / order of drugs used: - Adenosine injection Supraventricular tachycardia. Contra-indicated in asthmaticscan cause bronchospasm. Plasma levels and cardiovascular effects of adenosine are increased by dipyridamole, avoid concomitant use. See Adenosine SPC. Verapamil injection Co-prescribing of Verapamil and beta-blockers is hazardous and should be avoided due to the risk of hypotension & asystole. (8) Digoxin injection Metoprolol injection Amiodarone injection - Should only be used where facilities for cardiac monitoring, defibrillation and cardiac pacing exist. Flecainide injection discussion with consultant cardiologist advised.

5 Chapter 2 page number 5 Chronic Management Digoxin Verapamil Sotalol Atrial fibrillation or flutter. Contra-indicated in Wolff-Parkinson-White syndrome. Use for patients with hypertension or LVH. Initiate with immediate release preparation tds and convert to Securon SR once stable. Note: Co-prescribing of Verapamil and betablockers may be hazardous and should be avoided due to the risk of hypotension & asystole. (8) Should only be prescribed for prevention of supraventricular arrhythmias including atrial fibrillation. Flecainide Disopyramide Amiodarone Dronedarone Can precipitate prostatic symptoms. Loading regimen followed by once daily maintenance dose. Long half-life necessitating a washout period when changing to another anti-arrhythmic. Many drug interactions, particularly digoxin (see digoxin) and warfarin (please inform anticoagulant clinic when starting and stopping amiodarone). Common side effects include: corneal microdeposits, thyroid dysfunction, pneumonitis, peripheral neuropathy and hepatotoxicity. Chest x-ray should be done before treatment. Patients requiring long-term treatment should have liver function and thyroid function tests performed before treatment, and 6 monthly thereafter. (9) For initiation by Consultant Cardiologist only. See 3Ts Dronedarone SCA. For use in accordance with AGWS Cardiac Network's management of atrial fibrillation pathway. See also NICE TA197, MHRA safety warning and EMA recommendation on restricted use. Propafenone

6 Chapter 2 page number 6 Ventricular arrhythmias Please refer to 3Ts Guidance on QTc interval and drug therapy Acute Management refer to European/UK Resuscitation Council recommendations. Lidocaine (Lignocaine) injection Give Lidocaine as an IV bolus followed by infusion 2 to 4mg per min. Flecainide injection discussion with consultant cardiologist advised. Mexiletine injection (unlicensed medicine) discussion with consultant cardiologist advised. Amiodarone injection - Should only be used where facilities for cardiac monitoring defibrillation and cardiac pacing exist. Chronic Management Amiodarone For prescribing points please refer to notes above. Mexiletine (unlicensed medicine). Seek cardiologist advice before prescribing. 2.4 Beta-adrenoceptor blocking drugs Contra-indicated in asthmatic patients. Remember erectile dysfunction may be problematic. Best avoided in patients at high risk of developing diabetes. For Propranolol, see 3Ts Chapters on Endocrinology (chapter 6) & Migraine prophylaxis (chapter 4). Atenolol tablets Labetalol tabs Metoprolol tabs Beta blockers in heart failure Bisoprolol Carvedilol 4 th line in the management of hypertension. Still used for unstable angina and arrhythmias. (10) Used mainly in pregnancy or if combined alpha and beta blockade desirable. Initiation of beta-blocker post MI. Once stable consider change to Atenolol 25mg od. Seek specialist advice. Dose must be titrated to target doses or maximum tolerated. See BNF for details. (10) Target dose 10mg od. (10) Metoprolol injection Labetalol injection Esmolol injection 2.5 Hypertension and heart failure Vasodilator antihypertensive drugs For unlicensed use of Iloprost, please see Acute Trust guidelines Hydralazine Second line treatment option for management of heart failure in combination with a nitrate, (especially if patient is of African or Caribbean origin and has moderate to severe heart failure). Sodium Nitroprusside strictly Consultant Cardiologist use only Centrally acting anti-hypertensive drugs Clonidine - generally not used for BP control. See CNS (chapter 4) or Gynaecology (chapter 7).

7 Chapter 2 page number 7 Methyldopa Moxonidine Used mainly in pregnancy. Alternative to Doxazosin if diuretics, beta blockers, CCBs and ACE inhibitors fail or are unsuitable Alpha-adrenoceptor blocking drugs Doxazosin Used only if diuretics, beta-blockers, CCBs and ACE inhibitors fail or are unsuitable - (see Management of Hypertension). Phenoxybenzamine injection Phentolamine injection Avoid XL preparations (non-formulary) Start at low dose and titrate up. Phenoxybenzamine

8 Chapter 2 page number Drugs affecting the renin-angiotensin system Angiotensin-converting enzyme inhibitors Titrate upward to target doses for all indications. Monitor urea, potassium and creatinine levels. Some rise in urea, creatinine and potassium is to be expected after initiation of an ACE inhibitor; if an increase is small and asymptomatic no action is necessary. An increase in creatinine of up to 50% above baseline, or 266 micromol/l, whichever is the smaller, is acceptable. An increase in potassium to <5.5 mmol/l is acceptable. (1,11) Please see MHRA Drug Safety Update for increased risk of hyperkalaemia, hypotension and impaired renal function when ACE inhibitors are combined with other classes of renin-angiotensin system blocking agents. See MHRA Drug Safety Update Dec 16 for further information and advice on risk of serious adverse effect. Ramipril (capsules) Hypertension: Initially 1.25 mg once daily, increased at intervals of 1 2 weeks; max dose 10 mg od. Heart failure: Initially 1.25 mg once daily, increased gradually at intervals of 1 2 weeks to max. 10 mg daily if tolerated (doses above 1.25mg in 2 divided doses). Prophylaxis after myocardial infarction: initially 2.5 mg twice daily, increased after 2 days to 5 mg twice daily; maintenance mg twice daily. (13) Lisinopril Hypertension: Initially 10mg od, usual maintenance dose 20mg od, max dose 80mg od. Heart failure: Initially 2.5 mg od, increased gradually at intervals of 2 weeks to max. 35 mg od, if tolerated. Prophylaxis after myocardial infarction: Initially 5mg od, increased after 2 days to 10 mg od, if systolic blood pressure is over 120mmHg Use half the dose if SBP is mmHg. (13) Perindopril erbumine Captopril Enalapril Not for routine use in hypertension. Paediatric use only. Paediatric use only Angiotensin-II receptor antagonists (ARBs) BNF suggests that ARBs should only be used where side effects e.g. cough, are problematic with ACE inhibitors. Titrate upward to target doses for all indications. Please see MHRA Drug Safety Update for increased risk of hyperkalaemia, hypotension and impaired renal function when ARBs are combined with other classes of renin-angiotensin system blocking agents.

9 Chapter 2 page number 9 Losartan Hypertension, diabetic nephropathy in type 2 diabetes mellitus: Initially 50 mg od, if necessary increased after several weeks to 100 mg once daily. Initially 25 mg daily, if elderly over 75 years, or if volume depleted. Chronic heart failure: Initially, 12.5 mg once daily, increased at weekly intervals to 150 mg once daily if tolerated. (13) Candesartan Hypertension: initially 8 mg (hepatic impairment 2 mg, renal impairment or intravascular volume depletion 4 mg) once daily, increased if necessary at intervals of 4 weeks to max. 32 mg once daily; usual maintenance dose 8 mg once daily. Heart failure: initially 4 mg once daily, increased at intervals of at least 2 weeks to target dose of 32 mg once daily or to max. tolerated dose. (13) Sacubitril valsartan For initiation and titration by community heart failure service or secondary care Cardiology specialist, in line with NICE TA388. See Swindon CCG s Sacubitril Valsartan Prescribing Guidance and Wiltshire CCG s Sacubitril Valsartan Prescribing Guidance for further information. 2.6 Nitrates, calcium channel blockers, and potassium activators Nitrates Please note that patients with stable angina should be offered a beta-blocker or calcium channel blocker ahead of longacting nitrates or nicorandil, as per NICE CG126. Glyceryl Trinitrate Spray Isosorbide Mononitrate (conventional release & slow release 60mg tablets) Conventional formulations should not usually be given more than twice daily unless small doses are used. Dosing times should allow for nitrate free period. (e.g and 14.00). SR preparations are designed for ONCE daily dosing Calcium-channel blockers, and dihydropyridine calcium channel blockers Glyceryl Trinitrate infusion Glyceryl Trinitrate patches Nutrition team only.

10 Chapter 2 page number 10 Amlodipine Nimodipine Lercanidipine Nifedipine For patients intolerant of Amlodipine. For hypertension in pregnancy and management of Raynauds syndrome only. Contra-indicated within one month of MI. See SPC. Caution with beta-blockers including topical ophthalmic preparations can cause severe hypotension and heart failure. Different versions of modified-release nifedipine preparations may not have the same clinical effect. Prescribers should specify the brand to be dispensed. Diltiazem Verapamil Once daily prep = Slozem MR available as 120mg, 180mg, 240mg, 300mg. Twice daily prep = Angitil SR available as 90mg, 120mg, 180mg. Note: Co-prescribing of Verapamil and beta-blockers may be hazardous and should be avoided due to the risk of hypotension & asystole. (8) Other antianginal drugs See NICE CG126

11 Chapter 2 page number 11 Nicorandil Ivabradine See management of stable angina for details of place in local treatment pathway. See MHRA Drug Safety Update Jan 16 for further safety information and advice. For treatment of chronic stable angina: as a second antianginal drug in patients with a contraindication to, or intolerance of, either betablocker or dihydropyridine calcium channel blocker in whom adding a long-acting nitrate or nicorandil as a second agent would be inappropriate or as monotherapy in patients for whom betablockers, calcium channel blockers, long-acting nitrates and nicorandil are contraindicated or not tolerated. See Management of Stable Angina for details of place in local treatment pathway. Please see MHRA Drug Safety Update for information on risk of bradycardia. Ivabradine For treatment of chronic heart failure in patients: with New York Heart Association (NYHA) class II to IV stable chronic heart failure with systolic dysfunction and who are in sinus rhythm with a heart rate of 75 beats per minute (bpm) or more and who are given ivabradine in combination with standard therapy including beta-blocker therapy, angiotensin-converting enzyme (ACE) inhibitors and aldosterone antagonists, or when beta-blocker therapy is contraindicated or not tolerated and with a left ventricular ejection fraction of 35% or less. Only to be initiated after 4 weeks of stabilisation on optimised standard therapy with ACE inhibitors, betablockers and aldosterone antagonists. See NICE TA267 for further information. Please note prescribing responsibility will ONLY transfer to primary care once the dose of ivabradine has been stabilised. All subsequent dose titration and monitoring will remain the responsibility of the secondary care specialist, in line with NICE TA 267. Please see MHRA Drug Safety Update for information on risk of bradycardia. Ranolazine For initiation only by specialists in the treatment of chronic stable angina Ranolazine is recommended as add on therapy for the treatment of patients with chronic stable angina who are inadequately controlled on, intolerant of, or have contraindications to first line anti-anginal therapies, nitrates and/or nicorandil, and third-line ivabradine, where no revascularisation options are available to the patient. Once patients have experienced a satisfactory response (reviewed by cardiologist after 3 months), prescribing may be transferred to primary care Peripheral vasodilators and related drugs Older preparations are not recommended due to limited evidence as to effectiveness

12 Chapter 2 page number 12 Naftidrofuryl Oxalate Cilostazol 2.7 Sympathomimetics Inotropic sympathomimetics Existing patients only. See MHRA Drug Safety Update (April 2013) for information on the risk of cardiovascular and bleeding events Vasoconstrictor sympathomimetics Adrenaline Emergency use. (Epinephrine) EpiPen See MHRA Drug Safety Update Aug 2017 for information on the importance of carrying two auto-injectors at all times. Adrenaline (Epinephrine) injection Dopamine infusion For paediatric use only. Dobutamine infusion Isoprenaline Dopexamine - For pre-operative optimisation of selected patients on ICU only, on consultant request. Noradrenaline (Norepinephrine) injection Metaraminol injection Ephedrine injection Midodrine tablets 2.5mg and 5mg For initiation by Cardiology & DOME consultants only Cardiopulmonary resuscitation See European/UK Resuscitation Council recommendations. 2.8 Anticoagulants and protamine Parenteral anticoagulants Dalteparin See VTE policy for dosing details. Fondaparinux Heparin Flush 10units/ml. For VTE if Dalteparin unsuitable. To maintain patency of central venous catheters as per GWH Line Insertion Service protocol. Dalteparin for prophylaxis or treatment of VTE in pregnancy. Fondaparinux - for acute coronary syndrome (ACS). See also the GWH Suspected Acute Cardiac Chest Pain Protocol. Heparin Flush 100units/ml To maintain patency of central venous catheters as per GWH Line Insertion Service protocol. Lepirudin - prescribe only on recommendation of consultant haematologist. Bivalirudin prescribe only on recommendation of consultant cardiologist. Used in PCI instead of a glycoprotein IIb/IIIa inhibitor. Epoprostenol

13 Chapter 2 page number Oral anticoagulants (OACs) see prescribing notes Great Western Hospital NHS Trust Anticoagulation Service monitors patients requiring warfarin in the Acute Trust and many patients within Swindon and the surrounding area. Please access the anticoagulation hospital intranet pages for Trust protocols/ loading regimes/extent of service. Over or under anticoagulated patients within the Acute Trust or Primary Care should be referred to the Anticoagulation Service or the on-call haematologist. Asymptomatic over anticoagulated patients (INR>8) may need oral Vitamin K see below. Underanticoagulated patients may need heparinisation. Supply of Coagucheck strips for home INR testing on prescription generally it is appropriate to supply the strips if the home testing machine purchase has been discussed with GP and/or the anticoagulant service and agreed as appropriate. In addition, the patient should have undergone a period of training and assessment undertaken by either the Anticoagulant Service or their GP Practice. Reversal of warfarin or phenindione Vitamin K is very well absorbed orally. When partial correction is required, it may be necessary to give intravenous vitamin K or alternatively give the intravenous preparation orally. In patients with major bleeding, reversal with intravenous vitamin K is preferable. A dose of either 5 or 10 mg is recommended. (14) Vitamin K will usually lower the INR within 12 to 24 hours. Repeat doses may be needed after 24 hours if the INR is still too high. For medication data, see chapter Warfarin Patients with time in therapeutic range (TTR) > 65% should only be switched to a DOAC if there is a clear clinical reason to do so. See MHRA Drug Safety Update July 2016 for information and advice on risk of calciphylaxis. Phenindione Warfarin allergy only. Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation When choosing between warfarin, apixaban, rivaroxaban, edoxaban and dabigatran for stroke prevention in non-valvular AF, prescribers should also take into account the patient's HAS-BLED score, renal function, liver function, concomitant medicines, etc. See 3Ts Guidance on AF- Choosing the correct oral anticoagulant for your AF patient, AF - New Oral Anticoagulant Decision Aid and FAQs for further information. Warfarin See MHRA Drug Safety Update July 2016 for information and advice on risk of calciphylaxis Please see MHRA Drug Safety Update (October 2013) for information on risk of serious haemorrhage with apixaban, rivaroxaban and dabigatran. See also Anticoagulant Service intranet site for GWH protocols on hospital management of overdose, haemorrhage and emergency surgery in patients on apixaban, rivaroxaban and dabigatran. Please note existing warfarin patients with time in therapeutic range (TTR) > 65% should only be switched to a DOAC if there is a clear clinical reason to do so.

14 Chapter 2 page number 14 Apixiban For primary or secondary prevention of stroke & systemic embolism in patients with non-valvular atrial fibrillation (AF) in accordance with NICE TA275. See 3Ts Guidance on AF -Apixaban Prescribing Criteria for more information. Rivaroxaban For primary or secondary prevention of stroke & systemic embolism in patients with non-valvular atrial fibrillation (AF) in accordance with NICE TA256. See 3Ts Guidance on AF -Rivaroxaban Prescribing Criteria for more information. Dabigatran For primary or secondary prevention of stroke & systemic embolism in patients with non-valvular atrial fibrillation (AF) in accordance with NICE TA249 See 3Ts Guidance on AF -Dabigatran Prescribing Criteria for more information. Edoxaban For prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation (AF), in accordance with NICE TA355. See 3Ts Guidance on AF -Edoxaban Prescribing Criteria for more information. Treatment and prevention of DVT and PE When choosing between warfarin, rivaroxaban, dabigatran, apixaban and edoxaban for treatment or prevention of DVT & PE, prescribers should also take into account the patient's bleeding risk, renal function, liver function, concomitant medicines, etc. See 3Ts Guidance onvte - DOACs for DVT & PE and FAQs for further information. See also Anticoagulant Service intranet site for GWH protocols on hospital management of overdose, haemorrhage and emergency surgery in patients on rivaroxaban, dabigatran, apixaban and edoxaban. Warfarin See MHRA Drug Safety Update July 2016 for information and advice on risk of calciphylaxis Rivaroxaban First-line choice of New Oral Anticoagulant (NOAC) for the treatment of deep vein thrombosis and pulmonary embolism and the prevention of recurrent deep vein thrombosis in accordance with NICE TA261. Please note Dabigatran (as per NICE TA327), Apixaban (as per NICE TA341) and Edoxaban (as per NICE TA354) are available as options for patients unable to take Rivaroxaban but ONLY on the advice of the Anticoagulant team. VTE prophylaxis following extended orthopaedic surgery See GWH Thromboprophylaxis in Adults Policy. See also Anticoagulant Service intranet site for GWH protocols on hospital management of overdose, haemorrhage and emergency surgery in patients on dabigatran, rivaroxaban and apixaban.

15 Chapter 2 page number 15 Dabigatran For the primary prevention of venous thromboembolic events (VTE) in adults who have undergone elective total hip replacement or total knee replacement surgery in accordance with NICE TA157. See MHRA Safety Update (July 2012) and MHRA safety update (January 2013). See MHRA Drug Safety Update for information on the risk of thrombosis and haemorrhage in patients with prosthetic heart values. If dabigatran is inappropriate for a patient, apixaban or rivaroxaban are available as options on the advice of a consultant haematologist. Acute Coronary Syndrome When considering rivaroxaban for prevention of adverse outcomes after acute management of Acute Coronary Syndrome, prescribers should also take into account the patient's bleeding risk, renal function, liver function, concomitant medicines, etc. See 3Ts Guidance on ACS - New Oral Anticoagulants in ACS for further information. See also Anticoagulant Service intranet site for GWH protocols on hospital management of overdose, haemorrhage and emergency surgery in patients on rivaroxaban. Rivaroxaban Protamine sulfate For the prevention of adverse outcomes after acute management of Acute Coronary Syndrome, in accordance with NICE TA335. Protamine sulfate 2.9 Antiplatelet drugs See 3Ts Prescribing Guidance for Oral Antiplatelet Drugs for local practice. Treat GI disturbances symptomatically and consider gastro protection. Consider use of lansoprazole 15-30mg od with low dose aspirin in those with indigestion or who are at risk from GI bleeding. (4) Clopidogrel is a suitable alternative to Aspirin, (or Aspirin plus dipyridamole MR post stroke), when aspirin is contraindicated or genuinely NOT tolerated. NICE defines Aspirin intolerance as a proven hypersensitivity to Aspirin or a history of SEVERE indigestion caused by LOW dose Aspirin.

16 Chapter 2 page number 16 Aspirin Dipyridamole SR See 3Ts Prescribing Guidance for Oral Antiplatelet Drugs for local practice. Recommended dose: 75mg daily. Post- CABG: 300mg daily for 12months then 75mg daily. Post- stroke: 300mg daily in the immediate post event period then switch to clopidogrel 75mg daily. AF: 75mg -300mg daily. Discontinue if patient requires anti-coagulation. (17) E.C Aspirin is non formulary, as there is no advantage to E.C. preparation and therapeutic levels may not be obtained. (18,19) For people who have had a transient ischaemic attack or ischaemic stroke, modified-release dipyridamole plus aspirin is only recommended as a treatment option if clopidogrel is unsuitable, not tolerated or otherwise contraindicated. For people who have had a transient ischaemic attack or ischaemic stroke and have a contraindication or intolerance to both clopidogrel and aspirin, modified-release dipyridamole alone is recommended as a treatment option. See 3Ts Prescribing Guidance for Oral Antiplatelet Drugs for local practice. Refer to NICE TA210 for background information. (30) Tirofiban Injection as per NICE guidance in Acute Coronary Syndrome. Abciximab (ReoPro) used in percutaneous coronary intervention, consultant cardiologists only.

17 Chapter 2 page number 17 Clopidogrel For use in suspected Acute Coronary Syndrome see Hospital Trust Protocol. Amber for this indication Co-prescribe with aspirin for the following: - Non ST Elevation Acute Coronary Syndrome - 12 months therapy. (20) ST Elevation Acute Coronary Syndrome 28 days therapy (21, 22). While awaiting urgent angiography. Angioplasty with or without CABG until procedure then as outlined below: Non-drug eluting stent: Stop 28 days post-stent. Drug eluting stent: Length of course depends on stent inserted. Patient/GP will be advised. The course will be of at least 12 months duration (26). Discontinue if there is no evidence of major vessel disease. See 3Ts Prescribing Guidance for Oral Antiplatelet Drugs for local practice. Please also see Sanofi safety letter (August 2013) Clopidogrel Clopidogrel monotherapy is recommended as an option to prevent occlusive vascular events for: People who have had an ischaemic stroke. People who have had a transient ischaemic attack (TIA). People with peripheral arterial disease, as a treatment option. For people with multivascular disease, as a treatment option. People who have had a myocardial infarction, only when treatment with aspirin is contraindicated or not tolerated. See 3Ts Prescribing Guidance for Oral Antiplatelet Drugs for local practice. Refer to NICE TA210 for background information. For Clopidogrel and PPI's drug interaction - see MHRA Drug Safety Update Vol3 Issue 9 April Concomitant use of Clopidogrel with either Omeprazole or Esomprazole should be discouraged. Formulary choice in this situation is Lansoprazole. Refer to Formulary Working Group statement on use of generic Clopidogrel. Please also see Sanofi safety letter (August 2013)

18 Chapter 2 page number 18 Prasugrel For initiation by Consultant Cardiologist only. Prasugrel, in combination with aspirin, is available for the prevention of atherothrombotic events in people with acute coronary syndromes where: immediate primary percutaneous coronary intervention for ST segment-elevation myocardial infarction is necessary and the patient is 75 or under with no history of cerebrovascular disease or stent thrombosis has occurred during clopidogrel treatment or the patient has demonstrated intolerance to clopidogrel See 3Ts Prescribing Guidance for Oral Antiplatelet Drugs for local practice. See NICE TA182 for further information. See also MHRA Safety Update - May 2011 and January Ticagrelor For initiation by Consultant Cardiologist only. Ticagrelor in combination with low-dose aspirin is available for the prevention of atherothrombotic events in adults with acute coronary syndromes (ACS) i.e. those: with ST-segment-elevation myocardial infarction (STEMI) defined as ST elevation or new left bundle branch block on electrocardiogram that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or with non-st-segment-elevation myocardial infarction (NSTEMI) or admitted to hospital with unstable angina in line with NICE TA236 and NICETA 420.

19 Chapter 2 page number Fibrinolytic drugs Streptokinase injection (SK) For intrapleural fibrinolysis in patients with empyema, resistant to tube drainage, where surgery is not immediately possible due to patient co-morbidities, feasibility of transfer or other clinical / logistical reasons. Not for routine use for intrapleural fibrinolysis in all patients with pleural infection. See BTS Guidelines for further information. For initiation by Respiratory / ITU Consultants only. Tenecteplase (TNK) For treatment of acute MI. See NICE TA52 for further information. See GWH Suspected Acute Cardiac Chest Pain Protocol. For second line treatment of acute PE in cardiovascularly unstable patients requiring more timely fibrinolysis than alteplase (unlicensed indication). Alteplase infusion For treatment of acute ischaemic stroke in adults if: treatment is started as early as possible within 4.5 hours of onset of stroke symptoms, and intracranial haemorrhage has been excluded by appropriate imaging techniques. See NICE TA 264 and NICE CG68 for further information. For arterial re-perfusion and first-line treatment of acute PE in patients with a significant risk of PE-related mortality or morbidity Antifibrinolytic drugs and haemostatics Tranexamic acid Now available OTC. tablets Urokinase injection For use in unblocking central lines only. Only to be administered by, under supervision of, or after appropriate training from Clinical Nurse Specialists from GWH Central Line Insertion Service. Tranexamic acid injection Drotrecogin Alfa prescribe in accordance with NICE guidance (25)

20 Chapter 2 page number Lipid regulating drugs See prescribing guidance below and 3Ts Lipid Modification guideline. Primary Prevention All adults who have a 20% or greater 10-year risk of developing CV disease should be considered for statin therapy, despite lifestyle intervention. The decision to treat should follow an informed discussion with the patient about risks and benefits, taking into account additional factors such as co-morbidities and life expectancy. A target for total LDL cholesterol is not recommended for patients who are treated with a statin for primary prevention. Simvastatin 40mg ON is the 1 st line statin for PRIMARY prevention. If simvastatin 40mg is contraindicated or not tolerated or if there are potential drug interactions, patients may be offered a lower dose or an alternative preparation, such as Pravastatin 10-40mg ON. (26) Secondary prevention All People with diabetes aged 40 years or older should usually be considered for simvastatin 40mg ON. Simvastatin 40mg should be considered for people with diabetes younger than 40 years in those patients with a high cardiovascular risk. The decision to treat should follow an informed discussion with the patient about risks and benefits, taking into account additional factors such as co-morbidities and life expectancy. Consider increasing the dose of simvastatin to 80mg ON if the person s total cholesterol is not less than 4mmol/L or the LDL-cholesterol is not less than 2mmol/L after 3 months. For type 2 diabetics with an increased albumin excretion or newly diagnosed CVD, consider escalation of treatment to a more effective statin (e.g. atorvastatin 40-80mg). (26) Acute Coronary Syndrome People with acute coronary syndrome (ACS) should generally be treated with a higher intensity statin (a statin which achieves greater lipid lowering than simvastatin 40mg daily). Simvastatin 80mg is the 1 st line statin for ACS patients. Atorvastatin 80mg may be considered for patients intolerant of or unsuitable for simvastatin 80mg. There are no lipid targets specified for patients with ACS. Although there is no guidance on how long patients with ACS should take higher-intensity statins, patients on high dose statins should be routinely reviewed by their G.P after 3 months of treatment. The recommendations for secondary prevention should be followed thereafter. *Please note the MHRA has published a Drug Safety Update in May 2010 regarding the safety of simvastatin 80mg. It states that There is an increased risk of myopathy associated with high-dose (80 mg) simvastatin. The 80-mg dose should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks Statins See 3Ts Lipid Modification Guideline for further information and advice. HIV protease inhibitors strongly increase exposure to statins; Consult HIV consultant or pharmacist before initiating statin in patients taking antiretrovirals. If patient is prescribed a short term course of a macrolide antibiotic, omit statin until end of course. See 3Ts lipid modification guideline for details on statin interactions. See MHRA safety alert on interactions with fusidic acid. Simvastatin Do not co-prescribe with amiodarone or verapamil. Prescribe Atorvastatin as alternative. Concomitant prescribing with diltiazem - max dose 20mg Simvastatin. (29) See SPC. Note: Statin Guidelines above suggest use of Atorvastatin 10mg as alternative. Refer to 3Ts Simvastatin Interactions letter for information on interaction with Amlodipine, etc. Pravastatin Atorvastatin Rosuvastatin Alternative to Simvastatin in primary and secondary prevention of CVD. Alternative to Simvastatin in secondary prevention of CVD. Alternative to Simvastatin for management of patients with ACS. Restricted use for high risk patients intolerant of Simvastatin, Atorvastatin and Pravastatin. In management of familial hyperlipidaemia Atorvastatin remains 1 st line in this condition. Recheck TC (& ALT) after 3 months aiming for a reduction in TC by 25%. If not achieved, first of all check medicines adherence before swapping the patient onto an alternative treatment or referring to a specialist.

21 Chapter 2 page number Other Lipid regulating drugs Colestyramine Should only be used for lipid lowering in powder exceptional circumstances and be initiated by a consultant. See link for use in bile salt absorption Fenofibrate Bezafibrate Ezetimibe NICE state that fibrates should not routinely, alone or in combination, be prescribed to prevent cardiovascular disease, although they may be helpful in lowering LDL-C in patients with familial hypercholesterolaemia where statins or ezetimibe are not appropriate. Fibrates should only be prescribed on the advice of a specialist. NICE state that fibrates should not routinely, alone or in combination, be prescribed to prevent cardiovascular disease, although they may be helpful in lowering LDL-C in patients with familial hypercholesterolaemia where statins or ezetimibe are not appropriate. Fibrates should only be prescribed on the advice of a specialist. See NICE TA385. Ezetimibe may then be an option for high risk patients who are intolerant to 3 statins. People with primary hypercholesterolaemia should be considered for ezetimibe, in line with latest NICE TA, where statins are either contraindicated or have not been tolerated (as above). Please note that Ezetimibe is not licensed for the primary or secondary prevention of cardiovascular events Monoclonal Antibodies Alirocumab For treatment of non-familial primary hypercholesterolaemia and mixed dyslipidaemia, in line with NICE TA393, by Consultant Cardiologists ONLY. Please note patients with familial primary hypercholesterolaemia MUST be referred to tertiary centre in Oxford for assessment & prescription. Evolocumab For treatment of non-familial primary hypercholesterolaemia and mixed dyslipidaemia, in line with NICE TA394, by Consultant Cardiologists ONLY Local Sclerosants Please note patients with familial primary hypercholesterolaemia MUST be referred to tertiary centre in Oxford for assessment & prescription. Ethanolamine injection Sodium Tetradecyl Sulfate injection

22 Chapter 2 page number 22 NHS Swindon, NHS Wiltshire and Great Western Hospital NHS Foundation Trust in collaboration with Avon & Wilts Mental Healthcare Partnership Trust. References 1. NICE Clinical Guideline CG108: Management of chronic heart failure in adults in primary and secondary care. August NICE Clinical Guideline CG127: Hypertension: August Anon; Lowering Blood Pressure in particular patient groups, DTB 2001;Vol 3. p NICE clinical guideline 48 secondary prevention Secondary prevention in primary and secondary care for patients following a myocardial infarction. Issue date: May BNF 59, March Cardiac Glycosides BNF 59, March Thiazides and related diuretics Dukes M.N.G., Aronson J.K. Meylers Side Effects of Drugs. Fifteenth Edition. August BNF 59, March Calcium Channel Blockers BNF 59, March Drugs for arrhythmias BNF 59, March Beta Adrenoceptor blocking drugs M K Davies, C R Gibbs, G Y H Lip. ABC of heart failure Management: diuretics, ACE inhibitors, and nitrates BNF 59, March Drugs affecting the Renin-angiotensin System IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet 2002; 359: British Society for Haematlogy Guidelines on oral anticoagulation (warfarin): Third edition 2005 update. 15. Combining aspirin with antithrombotic agents BMJ.2006;333: th Oct NICE Clinical Guideline 68: Diagnosis and initial management of stroke and Transient Ischaemic Attack (TIA). July NICE Clinical Guideline 36: The management of Atrial Fibrillation. June Kelly J et al, Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product, Lancet 1996; 348: Lauer S. Aspirin for Primary Prevention of Coronary Events. NEJM 2002, 346: Technology Appraisal 80: Clopidogrel in the treatment of non-st-segment-elevation acute coronary syndrome. NICE July MeReC Extra: Clopidogrel following STEMI:we now have CLARITY (issue 17) plus CLARITY TIMI 28: New England Journal of Medicine 2005:352:p COMMIT Study: The Lancet; Nov 5th 11 th : V366: p Drug Eluting Stent Thrombosis Royal Infirmary 3 rd October NICE Technology Appraisal Guidance 182 Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. 25. NICE Technology Appraisal 84: Sepsis(Severe) (drotrecogin) September Lipid modification Cardiovascular risk assessment and the modification of blood lipids for primary and secondary prevention of cardiovascular disease. NICE Clinical Guideline CG67 May 2008 (reissued March 2010) IDEAL Investigators Total Cardiovascular Disease Burden: Comparing Intensive With Moderate Statin Therapy: Insights From the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) Trial. J. Am. Coll. Cardiol. 2009;54; MTRAC: Verdict and summary Atorvastatin 80mg daily. Sept MHRA/CSM Bulletin. Current Problems in Pharmacovigilance: Statins and Cytochrome P450 interactions. Volume 30 P1-2, October NICE technology appraisal guidance 210. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events Review of NICE technology appraisal guidance 90. Issue date: December NICE CG BNF 64, September 2012