concomitant use Statins : plasma concentration of simvastatin, atorvastatin increased by diltiazem/verapamil \200\224 reduce statin dose Sirolimus : plasma levels increased by diltiazem and verapamil \200 Tacrolimus : plasma l evels increased by diltiazem and nifedipine \200 Theophylline : increased plasma levels o f theophylline. This page intentionally left blank 118 CHAPTER 2 Drugs for the heart Lipid-lowering therapies Elevated concentrations of total cholesterol (TC) and low-density lipo- protein cholesterol (LDL-C) increase the risk of an individual developing cardiovascu lar disease. This is further exacerbated by low levels of protec- tive HDL-C (high-density lipoprotein cholesterol) and elevated triglycer- ides. Five main classes of lipid-lowering drug therapies are used: \200 statins \200 \201 brates \200 cholesterol-absorption inhibitors \200 bile acid binders (resins) \200 nicotinic acid derivatives. In terms of lowering cardiovascular risk, the wealth of evidence supports the use of statins in the \201 rst instance. Aims of lipid-lowering therapies The aims of lipid-lowering therapies remain a topic of muc h debate. National and international guidance is summarized overleaf, indicating the curren t disparity in the recommendations. The optimal lipid pro \201 le is: TC <4 mmol/L \200 LDL-C <2.0 mmol/L \200 Triglycerdies <1.7 mmol/L \200 HDL cholester ol (HDL-C): \200 men > 1.0 mmol/L \200 women > 1.2 mmol/L. Lifestyle and blood pressure control alongside lipid lowering The following lifestyle issue s should be addressed alongside consideration of statin therapy: \200 smoking cessation \200 diet (reduce saturated fats, include Mediterranean diet and oily \201 sh twice a we ek, aim for body mass index (BMI) of 19 \200\22325 kg/m 2 , or a minimum of a 10 % reductio n in body weight) alcohol moderation to within safe limits (up to 21 units per week for men and 14 units per week for women) exercise (aim for a total of 30 minutes of moderate-intensity physical activity (e.g. brisk walking) at least 5 \227 a week). Blood pressure control Treat if BP consistently over 140/90 mmHg to achieve a BP of less th an 140/90 mmHg; more aggressive targets apply in patients with chronic kidney disease and d iabetes. LIPID-LOWERING THERAPIES 119 Lipid targets in national and international guidelines NICE (UK) 2008 \200 Primary preven tion : generic statin only, no target lipid levels \200 Secondary prevention : aiming tow ards TC<4 mmol/L and LDL-C<2 mmol/L Type 2I diabetes : treat to achieve TC<4 mmol/L and LDL-C<2 mmol/L \200 ACS : high-intens ity therapy aiming towards TC<4 mmol/L and LDL-C<2 mmol/L. Joint British Societies-2 (UK) 2005 \200 Treat all individuals \200\230at high risk \200 \231: atherosclerotic disease, diabetes, or at high total risk (CVD risk > 20 % over 10 years) Give lifestyle advice, monitor blood lipids, and treat to target: TC<4 mmol/L and LDL-C<2 mmol/L. Examples of drug therapies that can affect the lipid pro \201 le See Table 2.11 . Table 2.11 Drugs that affect the lipid pro \201 le Drug Effect Alcohol Increases HDL-C Beta-blockers Reduce HDL-C Hormones: Androgens: testosterone Increase LDL-C, reduce HDL-C Oestrogens Reduce LDL-C, increase HDL-C Progestins Increases LDL-C, reduce HDL-C Immunosuppresants Ciclosporin Increases LDL-C and HDL-C Tacrolimus Increases LDL-C and HDL-C Steroids \200\224 glucocorticoids Increase HDL-C Thiazide diuretics Increase LDL-C, reduce HDL-C 120 CHAPTER 2 Drugs for the heart Lipid-lowering agents: statins (HMG-CoA reductase inhibitors) (e.g. atorvastatin, pravastat in, rosuvastatin, simvastatin) Statins block the action of the enzyme HMG-CoA reductase, which is responsible for catalyzi ng the conversion of HMG-CoA to mevalonate. As a result, statins lower total cholesterol, L DL-C, apolipoprotein B, very low-density lipoprotein (VLDL), and plasma triglycerides. They also increase serum concentrations of HDL-C. Clinical trial data Consistent and robust clinical trials data support the role of statin t herapy in cardiovascular (CV) risk reduction. \200 Primary prevention : WOSCOPS (West of Scotalnd Coronary Prevention Study, 1995, pravastatin), AFCAPS/TexCAPS (Airforce/ Texas Coronary Atherosclero sis Prevention Study, 1998, lovastatin), CARDS (Collaborative Atorvastatin Diabetes Study, 2004, atorvastatin), JUPITER (Justi \201 cation for the Use of Statins in Primary Preventi on, 2008, rosuvastatin) Secondary prevention : 4S (Scandinavian Simvastatin Survival Study, 1994, simvastatin), CARE (Cholesterol and Recurrent Events, 1996, pravastatin), LIPID (Long -term intervention with Pravastatin in Ischaemic Disease, 2000, pravastatin), HPS (Heart Pr otection Study, 2004, simvastatin), TNT (Treating to New targets, 2005, atorvastatin) \200 ACS: MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering, 2001, atorvas tatin), PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy, 2004, pravs tatin vs. atorvastatin), A to Z (2004, simvastatin). Suggested statin choice and dose \200 Primary prevention : initiate a generic statin, simvastatin 40 mg daily (or pravastatin 40 mg daily) UK guidance (NICE) recommends no treatment targets for primary prevention no routine dose escalation is recommended Secondary prevention and diabetes : initiate a generic statin, simvastatin 40 mg daily (or pravastatin 40 mg daily) intensify therapy in patients not achieving targets of TC > 4 mmol/L or LDL-C<2 mmol/L, for example by switching to atorvastatin 40 mg daily or rosuvastatin 10 mg daily, and dose tit rate if necessary ACS : initiate a high-intensity statin such as atorvastatin 80 mg daily \200 Familial hyp erlipidaemia (FH) : initiate a generic statin, simvastatin 40 mg daily \200 switch to a high-intensity statin , such as atorvastatin 40 mg increasing to 80 mg daily, in patients not achieving the required 50 % fall in LDL-C. LIPID-LOWERING AGENTS 121 Average effect of statin therapy on the lipid pro \201 le See Table 2.12 . Table 2.12 Effects of statin therapy on lipid pro \201 les Lipid element Effect of statins TC reduced by 30 % LDL-C reduced by up to 40 % Triglycerides reduced by 20 % HDL-C increased by 6 % Potency of current statins on the UK market (mg to mg basis) Fluvastatin < pravastatin < si mvastatin < atorvastatin < rosuvastatin Water-soluble statins Pravastatin, rosuvastatin Lipid-soluble statins Simvastatin, atorvastatin, \202 uvastatin Contraindications and cautions \200 Contraindications : hypersensitivity to the individual statin \200 Active liver disease (aspartate transamina se (AST) or alanine aminotransferase (ALT) level > 100 iu/L) or unexplained persistent isolated elevations of s erum transaminases pregnancy and lactation \200 consideration should be given to delaying statin therapy or addressing contraceptive needs in women of child-bearing age Cautions : hypothyroidism should be corrected before initiation of a statin \200 patients with a hig h alcohol intake \200 patients with risk factors for myopathy or rhabdomyolysis \200 ac ute porphyria (rosuvastatin is thought to be safe) \200 renal disease \200\224 dose redu ctions may be necessary. Initiation doses and dose ranges See Table 2.13 . 122 CHAPTER 2 Drugs for the heart Table 2.13 Doses for statins Drug Usual initiation dose Dose range Atorvastatin 10 mg daily 10 \200\22380 mg daily (40 mg if switching from simvastatin 40 mg daily) Fluvastatin 20 \200\22340mg daily 20 \200\22380 mg daily Pravastatin Usually 40 mg once at night 10 \200\22340 mg daily 5 \200\22340 mg daily a Rosuvastatin 5 \200\22310 mg daily (max 5 mg in Asian patients) 10 \200\22380 mg daily b Simvastatin Usually 40 mg daily \200\224 but lower dose if drug interactions a 40 mg dose specialist use only. b 80 mg dose recommended by NICE, but rarely used in clin ical practice due to increased risk of myopathy. Simvastatin \200 Lipid-soluble agent; generic available \200 Dose range: 10 \200\22380 mg daily \200 Usual starting dose 40 mg daily; reduce if potential drug interactions or severe renal impairment Increased risk of myopathy at 80 mg dose, so generally avoided in clinical practice in favor of more potent agents First-line choice in most instances, except ACS and FH. Pravastatin \200 Water-soluble agents; generic available \200 Dose range: 10 \200\22340 mg daily \200 Usual starting dose 40 mg daily; limited in terms of potency \200 Partic ularly useful at low doses in patients experiencing statin-related adverse effects with other agents; fewer drug interactions. Fluvastatin \200 Lipid-soluble agent; generic available \200 Dose range: 20 \200\22380 mg daily \200 Usual starting dose 40 mg daily; limited in terms of potency. Atorvastatin \200 Lipid-soluble agent; patented in Europe until 2011 \200 Dose range: 1 0 \200\22380 mg daily \200 Usual starting dose: 20 \200\22340 mg daily unless ACS, where 80 mg daily should be initiated Usually used second-line to simvastatin in secondary prevention and \201 rst-line at high dose in ACS. Rosuvastatin \200 Water-soluble agent; patented in Europe until 2017 \200 Dose range: 5 \200\22340 mg daily (maximum dose of 20 mg in Asian patients) LIPID-LOWERING AGENTS 123 Starting dose: 10 mg daily, except Asians, where a lower starting dose of 5 mg is recommended 40 mg dose recommended only under specialist supervision \200 Fewer drug interactions. Adherence issues \200 50 % of patients stop taking statin therapy within one year of init iation and 75 % within three years. It is essential that patients understand the need for statin therapy to reduce their long-term risk of CV events, and that once initiated statins should be continu ed long term. Care should be taken to address adverse effects should they occur, in order to facilitate ongoing adherence. In patients failing to respond to statin therapy, compliance issues should be suspected in the \201 rst instance and all efforts made to resolve these before switching to an altern ative statin. Dealing with statin-related adverse effects \200 GI disturbance : advise patient to take with or after food \200\224 ideally with their evening meal rather than last thing at night. Insomnia : try taking the dose earlier in the day, for example with the evening meal or earlier if necessary try an alternative statin if the problem persists Muscle aches and pains : check creatine kinase (CK) to exclude myopathy \200 if no increase in CK, withdraw agent and rechallenge. If problem recurs consider alternative statin Myopathy : muscle pains in the presence of a raised CK > 5 \227 ULN (upper limit of normal ) indicates myopathy. Statin should be withdrawn and CK rechecked. Low doses of less-potent statins may be cautiously reintroduced with careful monitoring under specialist supervisio n. Signi \201 cant statin interactions \200 Anti-arrhythmics : increased risk of myopathy w hen simvastatin given with amiodarone; maximum simvastatin dose = 20 mg Antibacterials : clarithromycin \200\224 increases plasma concentrations of pravastatin and atorvastatin clarithromycin, erythromycin, telithromycin \200\224 increase the risk of myopathy with simvastatin; avoid concurrent use \200 daptomycin \200\224 increased risk of myopathy with statins \200 fusidic acid \200\224 increased risk of myopathy with simv astatin \200 telithromycin \200\224 increased risk of myopathy with atorvastatin; avoid concurrent use Anticoagulants : caution with use of warfarin and other coumarins with atorvastatin, simvastatin, \202 uvastatin, rosuvastatin 124 CHAPTER 2 Drugs for the heart Antifungals : itraconazole, ketoconazole, posaconazole, miconazole \200\224 increased risk of myopathy with simvastatin; avoid concomitant use \200 itraconazole, posaconazole \200\224 increase risk of myopathy with atorvastatin; avoid concomitant use \200 Antivirals : use under specialist supervision on ly \200 Calcium-channel blockers : diltiazem, verapamil \200\224 possible increased in risk of myopathy with simvastatin; dose reduction required diltiazem \200\224 increases plasma concentration of atorvastatin Ciclosporin : increased risk of myopathy with statins; dose reductions required; avoid concomitant use with rosuvastatin \200 Colchicine : increased risk of myo pathy with statins \200 Danazol : possible increase in myopathy with simvastatin \200 F ibrates : avoid concomitant use of statins with gem \201 brozil; increased risk of myopathy when other \201 brates are used with statins Grapefruit juice : plasma concentrations of simvastatin increased \200\224 avoid concomintant use; possible increase in plasma concentrations of atorvastatin with excessive intake Nicotinic acid : increased risk of myopathy with statins. Monitoring See Table 2.14 . LIPID-LOWERING AGENTS 125 Table 2.14 Monitoring of statin therapy Lipid levels Primary prevention : routine monitoring of lipid levels is not recommended, although clinic ians should consider checking lipid levels occasionally throughout treatment to ensure ongo ing adherence to therapy. Total cholesterol (TC) High density lipoprotein (HDL) Secondary prevention : lipid levels should be measured before therapy is initiated; at 12 w eeks following initiation or change of dose; and at 12-monthly intervals thereafter. Low density lipoprotein (LDL) Triglycerides Thyroid function tests (TFTs) Check before initiating statin to exclude hypothyroidism. Liver function tests (LFTs) Baseline liver enzymes should be measured before starting a statin. Liver function (transam inases) should be measured within 3 months of starting treatment and at 12-monthly interval s thereafter. If transaminases > 3xULN) discontinue statin and refer. For lesser increases in transaminases, which remain elevated at 6 months, consider speciali st advice. Creatine kinase (CK) Baseline CK should be measured before starting a statin. CK should then only be measured during treatment when clinically indicated \200\224 i.e. w here there are symptoms of muscle pain or tenderness, muscle weakness, or muscle cramps. Patients should be counseled on initiation of statin to report any usual muscle pain, tende rness, or weakness during treatment. IF MYOSITIS IS PRESENT OR SUSPECTED DISCONTINUE IMMEDIATELY. If muscle soreness occurs: rule out common causes (e.g. exercise), Check TFTs (hypothyroidi sm predisposes to myopathy), Measure CK: \200 if CK elevated > 5xULN stop and seek advice \200 if CK elevated <5xULN \200\223 monitor carefully by repeating CK level in one month \200\223 if remains elevated, reduce dose and recheck CK level in one month \200\223 if still remains elevated consider seeking advice \200\223 if symptoms continue, STOP statin and consult a specialist before re-initiating. Note : Some black African and Caribbean individuals have elevated baseline levels of CK. Th is is not a contraindication to statin therapy. In these patients, after initiation, if the CK > 5x baseline, seek advice. 126 CHAPTER 2 Drugs for the heart Other lipid-lowering agents Fibrates (beza \201 brate, cipro \201 brate, feno \201 brate , gem \201 brozil) Mechanism of action Fibrates act via a number of mechanisms including limiting substrate av ail- ability for triglyceride synthesis in the liver; promoting the effect of lipo- protein lipase resulting in increased LDL clearance; modulation of the LDL receptor/ligand interac tion; and stimulation of reverse cholesterol trans- port. Fibrates lower triglycerides sign i \201 cantly, but also reduce LDL-C and TC levels, while increasing HDL-C. Clinical trial data Limited clinical evidence supports the use of \201 brates to reduce C V events. The most recent study with feno \201 brate in a diabetic population failed to de monstrate a bene \201 t in the primary end-point of coronary events (coro- nary heart dise ase (CHD) death or non-fatal MI), but did show a small but signi \201 cant reduction of 21 % in CV events. Dosing Usual doses are as follows: \200 beza \201 brate : 400 mg once daily (MR prep) \200 cipro \201 brate : 100 mg daily \200 feno \201 brate : 160 mg daily (Supralip p reparation) \200 gem \201 brozil : 600 mg twice daily. Place in therapy The primary effe ct of \201 brates on the lipid pro \201 le is a reduction in trigly- ceride levels. Whil e \201 brates may seem an obvious choice for the treatment of a patient with diabetes whe re raised triglycerides are often a problem, statins remain the \201 rst-line choice even for this group, due to the over- whelming trial evidence of bene \201 t. Combination use of statins plus \201 brates may be considered in patients requiring lipid lowering beyond mono- therapy. However, the combination does increase the risk of myopathy and possibly rh abdomyolysis, and needs careful monitoring. Hypertrilgyceridaemia can be a problem in human immunode \201 ciency virus (HIV) patients taking protease inhibitors and statin \200\223 \201 brate combina- tions may be useful i n this group, under specialist supervision. Adverse effects of \201 brates Key adverse effects include GI disturbances, which are usu ally self-limiting, and myositis. As with statins, drug interactions can be problematic. Pa rticular care should be taken when co-prescribed with warfarin, due to an increased anticoa gulant effect. Impact of non-statin lipid lowering drugs on the lipid pro \201 le See Table 2.15 . OTHER LIPID-LOWERING AGENTS 127 Table 2.15 Impact of non-statin lipid lowering drugs TC LDL-C HDL-C Triglycerides d 15 % d 20 % i 10 \200\22315 % d 40 % Fibrates d 15 % d 20 % i \200\223 3 % d \200\223 8 % Cholesterol-absorption inhibitors d 10 % d 25 % Bile acid sequestrants May increase d \200\223 15 % i \200\223 15 % d \200\223 45 % Nicotinic acid Key drug interactions with \201 brates \200 Antibacterials : increased risk of myopathy with daptomycin \200 Anticoagulants : enhance effect of warfarin and other coumarins \200 Antidiabetic drugs : rosiglitazone levels increased by gem \201 brozil \200\224 consider reducing rosiglitazone dose increased risk of severe hypoglycaemia when gem \201 brozil is given with repaglinide \200 Lipid-lowering drugs : increased risk of cholelithiasis and gall bladder disease when \201 brates are used with ezetimibe \200\224 discontinue if suspected increased risk of myopathy when \201 brates are used with statin \200 avoid concomitant use of gem \201 brozil and statins except under specialist supervision. Cholesterol-absorption inhibitors Currently only ezetimibe is on the market from this class . Mode of action Ezetimibe acts by interfering with the transportation of cholesterol across the brush-border in the GI tract, reducing delivery of intestinal choles- terol to the live r. The primary effect of ezetimibe on the lipid pro \201 le is a signi \201 cant reductio n in LDL, which is accompanied by a small reduction in triglyceride and an increase in HDL levels. Clinical trial data Despite the ef \201 cacy of ezetimibe in lowering LDL-C there remain n o robust CV outcomes data to support this agent. The IMPROVE-IT (Improved Reduction of Outc omes: Vytorin Ef \201 cacy International Trial) data are due to report in 2012/13. Dosing The usual dose of ezetimibe is 10 mg once daily. Place in therapy Ezetimibe is primarily used as an adjunct to statin therapy when statin th erapy alone does not deliver suf \201 cient cholesterol lowering to achieve treatment targ ets. Ezetimibe may also be used as monotherapy in patients who are unable to tolerate stati ns \201 rst line. 128 CHAPTER 2 Drugs for the heart Adverse effects Key adverse effects include GI disturbances, headache, and fatigue. Myalgia can occur during therapy \200\224 check CK to exclude myopathy. Hypersensitivity reaction s including rash, angioedema, and anaphylaxis have been reported. Drug interactions Although drug interaction are uncommon with ezetimibe, there is an increa sed risk of rhabdomyolysis when ezetimibe and statins are combined. Key interactions are as follows: Ciclosporin : plasma concentrations of both drugs may be increased \200 Lipid-lowering dr ugs : increased risk of myopathy and rhabodomyolysis when added to statins. Bile acid sequestrants (resins) (colestyramine, colestipol, and colesevelam) Mode of action Bile acid sequestrants reduce the enterohepatic circulation of cholesterol b y preventing reabsorption from the gut. The fall in intestinal reabsorp- tion increases LDL receptor activity in the liver, resulting in increased clearance of LDL from the plasma. T he primary effect of bile acid seques- trants is therefore a reduction in LDL cholesterol l evels, but the drugs can increase triglyceride levels, exacerbating hypertriglyceridaemia. Clinical trial data Cholestyramine showed a trend towards reduced mortality and non- fatal MI in the LRC-CPPT (Lipids Research Clinics Coronary Primary Prevention Trial, 1984); howev er, there are few other robust outcomes data to support this class. Colesevelam was launche d in the UK in 2007 and may generate further CV outcomes data. Dosing Usual dosing is as follows: \200 colestyramine : initially 4 g daily (max 36 g dai ly) in one to four divided doses. Each 4 g sachet must be mixed with at least 150 mL water colestipol : initially 5 g daily (max 30 g daily) in one or two divided doses. Each 5 g sachet must be mixed with at least 100 mL water colesevelam : monotherapy \200\224 3.75 mg daily in one or two divided doses \200 with statin \200 \224 2.5 \200\2233.75 mg daily in one or two divided doses Place in therapy Bile acid binders are limited in clinical practice by poor tolerability, d rug interactions, and an adverse effect on triglyceride levels. Colesevelam, shows some pro mise in terms of improved ef \201 cacy and tolerability, although the possibility of drug interactions remains, and a negative impact on triglyceride levels has been established. Adverse effects of bile acid sequestrants Key adverse effects are GI, including constipatio n and diarrhea, nausea and vomiting, and bloating. OTHER LIPID-LOWERING AGENTS 129 Key drug interactions with bile acid sequestrants \200 Anticoagulants : cholestryamine ma y increase or reduce the ef \201 cacy of warfarin and other coumarins. Bile acid sequestrants may affect the absorption of other drug therapies, including digoxin, thyroid hormones, fat-soluble vitamins (A, D, and K), and thi azide diuretics. As a result, other drug therapies should be taken at least 1 hour before or 4 hours after b ile acid sequestrants, to reduce possible interference with absorption. Nicotinic acid Mode of action The exact mechanism of action by which nicotinic acid lowers cholesterol is unclear, but it is postulated that it disrupts the synthesis of triglyceride s in the liver by blocking the enzyme DGAT-2, while also increasing the clearance of ApoA1. Nicotinic acid therefore primarily reduces triglyceride levels, with a moderate reduction in LDL-C, accompanied by a substantial increase in HDL. Clinical trial data Fifteen-year follow-up of the Coronary Drug Project (1986) indicated th at nicotinic acid signi \201 cantly reduced non-fatal MI and CHD death by a relative 14 % . Place in therapy Limited outcomes data place nicotinic acid as an adjunct to statin therapy or as an alternative in patients unable to tolerate statins. Nicotinic acid may be particu larly useful for patients with small dense LDL particles, high triglycerides and low HDL, a pattern frequently seen in patients with dia- betes. However, as a molecule, nicotinic aci d is poorly tolerated with a high incidence of facial \202 ushing, which results in frequ ent treatment dis- continuation. As a result, nicotinic acid has failed to deliver the outc omes demonstrated in the Coronary Drug Project in wider clinical practice. Dosing \200 Nicotinic acid : Niaspan MR (modi \201 ed release) prep \200\224 375 mg MR for one week, then 500 mg at night for one week, then 750 mg at night for one week then 1 g at night for one week. Increase by 500 mg at intervals of 4 weeks, to a maximum of 2 g daily. Adverse effects of nicotinic acid Common adverse effects include GI disturbance (nausea, vo miting diar- rhoea, dyspepsia, abdominal pain), \202 ushing, and rash. Tredaptive (nic otinic acid plus laropiprant) Tredaptive , a combination of nicotinic acid and an anti- \202 ushing agent, laropiprant, was launched in 2009. Laropiprant, a prostaglandin inhibit or, suppresses prostaglandin-mediated \202 ushing associated with nicotinic acid, without affecting its lipid-lowering ef \201 cacy. It is hoped that Tredaptive will enhance ad herence to therapy through improved tolerability. However, \202 ushing is still reported in approximately 12 % of patients on Tredaptive . 130 CHAPTER 2 Drugs for the heart The impact of Tredaptive on CV end-points is being assessed in HPS- THRIVE (Heart Protec tion Study: Treatment of HDL to Reduce the Incidence of Vascular Events), due to report in 2012. Strategies to minimize \202 ushing with nicotinic acid \200 Start at a low dose and inc rease slowly in line with the dose titration schedule. Delay dose increases if necessary in patients experiencing signi \201 cant \202 ushing. Avoid drinking alcohol and hot drinks at the same time as taking the dose of nicotinic acid, as these will exacerbate the \202 ushing side-effects. \200 Con sider the use of aspirin or a non-steroidal anti-in \202 ammatory drug (NSAID), which can reduce the severity of \202 ushing experienced \200\224 a single dose of aspirin 600 mg or ibuprofen 400 mg half an hour before taking the nicotinic acid dose is recommended. Key drug interactions with nicotinic acid \200 Lipid-lowering drugs: increased risk of my opathy when nicotinic acid is combined with statins. Tredaptive dose \200 The usual dose of Tredaptive is one MR tablet (1 g nicotinic acid/20 mg laropiprant) increasing to two tablets (2 g/40 mg) at four weeks. This page intentionally left blank 132 CHAPTER 2 Drugs for the heart Nitrates (glyceryl trinitrate (GTN), isosorbide mononitrate, isosorbide dinitrate) Mode of action Nitrates have powerful vasodilatory and venodilatory effects to improve coro nary blood \202 ow while reducing preload and afterload. Myocardial workload is therefore reduced, resulting in a reduction in myocardial oxygen demand. Nitrates protect against ex ercise-induced ischaemia by preventing coronary spasm and coronary arterial vasoconstrictio n induced by exercise. Clinical evidence Nitrates have been shown to reduce the frequency and severity of angina a ttacks if taken chronically at appropriate doses. Single dose of nitrates of between 15 mg and 120 mg have been shown to protect against effort- induced angina for up to 8 hours. Hig her doses may be required to reduce angina frequency \200\224 one study using a longer-act ing nitrate showed that only doses of 120 \200\223240 mg once daily had a signi \201 cant effect on effort- induced chest pain. Place in therapy Sublingual GTN is used for the rapid symptomatic relief of angina, either for the relief of acute chest pain or prophylactically to prevent the devel- opment of pred ictable exertional chest pain. Oral nitrates should be considered as adjunctive therapy in the prophylaxis of anginal ches t pain. Nitrates may be added to B -blocker, calcium-channel blocker, or nicorandil therapy to improve symptom control. Oral nitrates are generally not suitable as monotherapy, due to the problem of \200\230nit rate tolerance \200\231 (requiring a nitrate-free period) and the potential to precipitate re \202 ex tachycardia. Intravenous nitrates are used for the management of severe acute chest pain that is unrespo nsive to sublingual nitrates, and may be used to control blood pressure in acute situations . Compelling indications for nitrates \200 Angina : rapid symptomatic relief of angina and for prophylactic use to prevent the development of p redictable exertional chest pain \200 background anti-anginal therapy is indicated in all patients to prevent recurrence of chest pain, except those with very minimal and predictable symptoms t hat are manageable with sublingual nitrates alone. The BNF ( British National Formulary ) r ecommends initiation of anti-anginal therapy where attacks occur more than twice per week. Contraindications and cautions \200 Contraindications : nitrate hypersensitivity, aortic stenosis, hypotensive and hypovolaemic conditions, hypertrophic constrictive myopathy, card iac tamponade, constrictive pericarditis, mitral stenosis, marked NITRATES 133 anemia, head trauma, cerebral hemorrhage. Concurrent sildenafenil (Viagra ) therapy Cautions : hypothyroidism, closed-angle glaucoma. Initiation and dose range for nitrates See Table 2.16 . Table 2.16 Doses for nitrates Agent Dose GTN Tablets/spray: one tablet/spray (300 \200\2231000 mcg) under the tongue, repeat every 5 \200\22310 minutes. If chest pain does not resolve within 20 minutes, urgent medical advice should be sought Infusion: 10 \200\223200 mcg/min titrated to control chest pain. Maintain systolic blood pr essure above 100 mmHg Isosorbide mononitrate Short-acting: 20 \200\22340 mg twice daily is commonly prescribed but may be subtherapeutic Long-acting formulations: 60 \200\223120 mg daily Isosorbide dinitrate Short-acting: 20 \200\22360 mg twice daily Adverse effects of nitrates \200 Hypotension : patients should be advised to sit down bef ore taking sublingual nitrates. Signi \201 cant hypotension and syncope can occasionally result. Headache : occurs due to cerebral vasodilatation. Can be reduced by spitting out the sublin gual tablet after resolution of chest pain (sprays cannot be dealed with in this way). Simp le analgesics (preferably paracetamol based) may be used. Dosing With short-acting nitrate formulations, dosing should be asymmetric (also referred t o as eccentric) to allow for a nitrate-free period within each 24 hours. An interval of sev en hours should be left between doses where a twice-daily regimen is prescribed (i.e. 8 am and 3 pm \200\224 nitrate levels will then fall overnight to reduce the risk of the patien ts developing nitrate tolerance. Slow-release formulations release nitrate slowly over a period of 15 \200\22320 hours, allo wing for a nitrate-free period within each 24 hours. These should not be prescribed twice d aily for prophylaxis against angina, as nitrate levels will remain raised throughout the 24 -hour period and ef \201 cacy will be signi \201 cantly reduced. With the longer-acting f ormulations, doses of 120 \200\223240 mg have been shown to signi \201 cantly reduce the f requency of angina attacks. 134 CHAPTER 2 Drugs for the heart Monitoring nitrates Little speci \201 c monitoring is required for patients taking nitrate s, other than ensuring BP is maintained, with a systolic BP of > 100 mmHg. The patient shou ld be advised on managing nitrate-induced headaches and counseled carefully on asymmetric d osings if appropriate. Key nitrate drug interactions \200 Anticoagulants : infusion of GTN reduces the anticoagu lant effect of heparins. Sildena \201 l, tadala \201 l, vardena \201 l : hypotensive effects of nitrates are signi \201 cantly enhanced; avoid concomitant use. This page intentionally left blank 136 CHAPTER 2 Drugs for the heart Potassium-channel activators (nicorandil) Mode of action Nicorandil is a potassium-channel activator with a nitrate-like action. Open ing of the potassium channel leads to arterial vasodilatation and reduced afterload, while the nitrate effect leads to venous dilatation and a reduced preload. Clinical evidence IONA (Impact of Nicorandil in Angina, 2002): this was designed to deter- mine if nicorandil could reduce the frequency of coronary events in patients with chronic s table angina and standard anti-anginal treatment at high risk of cardiovascular events. The study reported a modest reduction in the composite primary end-point of coronary heart dis ease death, non- fatal MI, or unplanned hospital admission for cardiac chest pain (15.5 % p lacebo vs. 13.1 % nicorandil ( P = 0.014)). Place in therapy Nicorandil is licensed for the prevention and long-term treatment of chron ic stable angina and also for reducing the risk of acute coronary syndromes in patients wit h chronic stable angina and at least one of the following risk factors: previous MI or CABG , or CHD on angiography or a positive exercise test together with LVH on ECG, left ventricu lar dys- function, age (cid:116) 65 years, diabetes mellitus, hypertension, or documented v ascular disease. It is most frequently used as an adjunct to \201 rst-line anti-anginal t herapies to provide additional symptomatic relief. Dosing A dose of 10 mg twice daily is recommended initially, reduced to 5 mg twice daily in patients who are predisposed to headaches. The dose should be increased gradually accordin g to clinical response, to a maximum of 30 mg twice daily. Monitoring nicorandil \200 Blood pressure should be monitored at intervals during therapy . \200 The drug dose should be adjusted to optimize symptomatic relief of angina episodes. Compelling indications for nicorandil \200 Angina : as an adjunct or alternative to \201 rst-line anti-anginal therapies to prevent angina episodes. POTASSIUM-CHANNEL ACTIVATORS 137 Contraindications and cautions \200 Contraindications : cardiogenic shock, left ventricul ar failure with low \201 lling pressures and hypotension, hypersensitivity to nicorandil, pregnancy and breast-feeding Cautions : depleted blood volume, low systolic blood pressure, acute pulmonary oedema, or acute MI with acute left ventricular failure and low \201 lling pres sures patients should be advised not to drive or operate machinery until it is established that their performance is not impaired. Adverse effects of nicorandil \200 Headache : occurs commonly, especially in the early ph ase of treatment; consider a lower starting dose Dizziness and hypotension : especially at higher doses \200 Peripheral vasodilation leadi ng to \202 ushing : occurs commonly \200 Ulceration : GI ulceration, skin ulceration, a nd ulcers of the mucosal membranes have been reported These tend to be refractory to treatm ent and most only respond to withdrawal of nicorandil treatment Angioedema : occurs uncommonly. Key drug interactions with nicorandil \200 Antihypertensives : enhanced hypotensive effec t with the addition of nicorandil Oral corticosteroids : increase of gastric erosions when used in combination with nicorandil; avoid concomitant use Sildena \201 l, tadala \201 l, vardena \201 l : due to the risk of severe hypotension, the concomitant use of nicorandil and phosphodiesterase 5 inhibitors (e.g. sildena \201 l, tadala \201 l, vardena \201 l) is contraindicated. 138 CHAPTER 2 Drugs for the heart Ivabradine Mode of action Treatment with ivabradine causes as dose-dependent reduction in h eart rate by selective and speci \201 c inhibition of the cardiac pacemaker I f current (k nown as the funny channel) that controls spontaneous depolarization in the sinus node and h ence regulates heart rate. The usual effect is a 10 bpm reduction in heart rate whether at rest or during exercise. The fall in heart rate leads to a reduction in cardiac workload an d myocardial oxygen consumption. Clinical evidence Clinical studies have shown ivabradine to be as effective as B -blockers in the prevention and treatment of angina. The BEAUTIFUL (Morbidity \200\223 Mortality Eval uation of Ivabradine in Patients with CAD and Left Ventricular Systolic Dysfunction) study investigated the role of heart-rate control with ivabradine on top of background therapy, i ncluding B -blockers in the majority in patients with CHD and left ventricular failure. Iva bradine failed to demonstrate an impact on the primary end-point, a composite of cardiovasc ular death, hospitalization for acute MI, or hospitaliza- tion for new-onset or worsening h eart failure. However, the study did con \201 rm the safety of the combination of ivabradi ne and B -blockers. The SHIFT (Systolic Heart Failure Treatment with I f Inhibitor Ivabradi ne Trial) showed reduction of hospitalization and cardiovascular mortality in heart failure patients. Place in therapy Ivabradine was initially licensed for the symptomatic treatment of chronic stable angina in patients unable to tolerate, or with a contraindication to, the use of B -blockers; following the publication of the BEAUTIFUL study, the license has been extended to include use in combination with B -blockers in patients who are inadequately controlled with an optimal B -blocker dose and whose heart rate is > 60 bpm. In clinical practice, iva bradine is often used in patients that cannot tolerate either B -blockers or rate-controlli ng calcium-channel blockers on the basis of cost. Dosing \200 Initiation : ivabradine is usually initiated at a dose of 5 mg twice daily. \200 After 3 \200\2234 weeks it may be increased to 7.5 mg twice daily if required for gre ater symptom control. If the patient is elderly or 5 mg twice daily is not tolerated, the d ose can be reduced to 2.5 mg twice daily. Monitoring ivabradine \200 Obtain baseline BP and pulse before initiation and after each change in dose. In the absence of adverse effects, review within 4 weeks and consider increasing the dose if required for better symptom control. IVABRADINE 139 Compelling indications for ivabradine \200 Angina : as an adjunct or alternative to \201 rst-line anti-anginal therapies to prevent angina episodes. Contraindications and cautions \200 Contraindications : sick sinus syndrome, bradycardia (resting heart rate <60 bpm), cardiogenic shock and acute MI, within 4 weeks of CVA, sino-a trial block and third-degree AV block, congenital QT syndrome, pacemaker-dependent patients , unstable angina, pregnancy, and breast-feeding Cautions : pre-existing cardiac arrhythmias, concurrent heart-rate- lowering agents, mild h eart failure (NYHA class I \200\223II), moderate to severe heart failure (NYHA class III \200\223IV \200\224 SHIFT study), post-CVA, retinitis pigmentosa, hypotension (avoid if BP <90/50 mmHg), hepatic insuf \201 ciency (avoid if severe), severe renal insuf \201 ciency (CrCl (creatinine clearance) <15 mL/min). Adverse effects of ivabradine \200 Visual symptoms : most commonly reported adverse effec t. Luminous phenomena occurred in 15 % of patients, and therefore new patients should be wa rned about this potential transient side-effect. The possible occurrence of such luminous p henomena should be taken into account when driving or using machines in situations where su dden variations in light intensity may occur, especially when driving at night. Blurred vis ion has also been reported Cardiac conduction effects : bradycardia, AV 1st-degree block, ventricular extrasystoles can occur during therapy Headache : generally during the early treatment phase \200 Dizziness : possibly related t o bradycardia \200 GI disturbances : nausea, vomiting, diarrhea. Key drug interactions with ivabradine \200 Antihypertensives : enhanced hypotensive effec t with the addition of nicorandil Oral coricosteroids : increase of gastric erosions when used in combination with nicorandil; avoid concomitant use