CV risk reduction (HOPE (Heart Outcomes Prevention Evaluation) 1999, ramipril; EUROPA (Euro pean Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Diseas e) 2004, perindopril). ACE-Is have been shown to reduce the risk of CV events in patients w ho are at high risk of events, such as those with established atherosclerotic disease. Choice of agent Not all ACE-Is are licensed for use in all different cardiovascular indi- c ations. It is recommended that a licensed agent, with trial evidence to support its use, is chosen for the indication being managed. Dose \200 For essential hypertension , the dose should be titrated until blood pressure control is achieved, bearing in mind that higher ACE-I doses confer better CV prot ection. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS 99 For other indications, particularly heart failure and for cardioprotection in those with or at risk of cardiovascular disease , the ACE-I MUST be titrated to the target dose or the m aximal tolerated dose if the target dose cannot be achieved (i.e. due to hypotension, renal dysfunction, etc.). Compelling indications for ACE-I use \200 Hypertension : all non-black patients <55years old \200 Heart failure : all patients with any degree of left ventricular systolic function, initiated as soon as possible following diagnosis Post-MI secondary prevention : all patients following an MI, initiated during the inpatient phase of treatment CV risk reduction : all patients with symptomatic or asymptomatic CVD. Contraindications and cautions \200 Contrainidications : aortic/mitral stenosis \200 angioedema (any cause) \200 hypersensitivity to ACE-Is \200 bilateral renal artery stenosis \200 pregnancy. Cautions : hypotension (systolic blood pressure <90 mmHg) \200 Patients on high-dose diuretics (i.e. furosemide > 80 mg daily) \200 Breast-feeding \200 Moderate to severe renal impairment (i.e. creatinine > 150 mol/L or estimated glomerular \201 ltration rate (eGFR)<60 mL/m in/1.73 m 2 ) \200\224 seek specialist advice for initiation. Initiation and target doses of commonly used ACE-Is See Table 2.4. Table 2.4 Indications and doses for commonly used ACE-Is Agent Starting dose Target dose Enalapril 2.5 \200\2235 mg daily 40 mg daily (dose may be divided) Lisinopril 2.5 \200\22310 mg daily depending on indication 35 \200\22380 mg daily Perindopril 2 \200\2234 mg once daily 4 \200\2238 mg daily depending on indication Ramipril 1.25 \200\2232.5 mg daily 10 mg daily (dose may be divided) 100 CHAPTER 2 Drugs for the heart Monitoring \200 Obtain baseline BP and urea and electrolytes (U&Es) before initiation \200 Check BP and U&Es within two weeks of initiation or change of dose, then annually If serum creatinine increases by more than 20 % (or eGFR falls by more than 15 % ) after initiation, stop ACE-I and seek specialist advice. ACE-I dose should only be increased if: \200 systolic blood pressure > 90 mmHg \200 ser um creatinine increases by less than 20 % (or eGFR falls by less than 15 % ) on each dose titration potassium <5.5 mmol/L. Hyperkalaemia : advise low-potassium diet, ensure adequate \202 uid intake Reduce dose if K + > 5.5 mmol/L; withdraw ACE-I if K + > 6 mmol/L. Dealing with adverse effects \200 First-dose hypotension : use a long-acting agent, avoid excessive diuresis prior to initiation. First dose may be given at night before bed to red uce the risk of hypotension and associated falls. Dry cough : may dissipate over time if patient persists with therapy. If troublesome, withd raw agent and re-introduce the same or an alternative ACE-I. Consider an angiotensin recept or blocker (ARB) if cough recurs/persists. Angioedema : a rare but potentially life-threatening adverse effect. ACE-I therapy should be stopped and specialist advice sought before re-initiation. Rash : switch ACE-I and if rash persists consider ARB. Key drug interactions with ACE-Is \200 Ciclosporin : increases risk of hyperkalaemia \200 Diuretics : enhances hypotensive effect \200 Lithium : increases lithium levels \200 Potassium supplements : increased risk of severe hyperkalaemia. This page intentionally left blank 102 CHAPTER 2 Drugs for the heart Angiotensin receptor blockers (ARBs, also referred to as angiotensin II receptor antagonist s, AIIRAs) (candesartan, irbesartan, losartan, telmisartan, valsartan) Mode of action Angiotensin receptor blockers (ARBs) bind to the angiotensin II recep- tors and therefore block the action of angiotensin II. Angiotensin II is a potent vasoconstricto r and promotes the production of aldosterone, which increases sodium and water retention. A CE-Is therefore lead to vasodilatation and prevent the build up of \202 uid that would re sult from aldosterone release. Unlike ACE-Is the ARBs do not inhibit the break- down of bra dykinin that is responsible for ACE-I-induced cough. Clinical trial data ARBs are supported by fewer clinical trials than ACE-Is, but do have da ta across a range of indications including: \200 Hypertension : numerous clinical studies con \201 rm the blood-pressure- lowering ef \201 cacy of ARBs. Heart failure : con \202 icting data emerged from early studies, but CHARM (Candesartan in Heart Failure \200\224 Assessment of Mortality and Morbidity) con \201 rmed that candesartan reduced the risk of CV mortality or CV hospitalization in patien ts with HF, alone or in addition to ACE-I therapy, and with or without concurrent B -blocke r therapy. (ELITE-II (Evaluation of Losartan in the Elderly, 2000, losartan; ValHeFT (Valsa rtan Heart Failure Trial), 2001, valsartan; CHARM, 2006, candesartan) Post-MI heart failure : valsartan 160 mg bd was non-inferior to captopril in protecting aga inst death and CV event in patients with post MI heart failure (VALIANT (Valsartan in Acute Myocardial Infarction Trial), 2003) * CV risk reduction \200\224 telmisartan 80 mg daily was non-inferior to ramipril 10 mg dail y in protecting against CV events in patients with CV disease (ONTARGET (Ongoing Telmisarta n Alone and in combination with Ramipril, 2008) * . Choice of agent Not all ARBs are licensed for use in all the cardiovascular indications. It is recommended that a licensed agent, with trial evidence to support its use, is chosen fo r the indication being managed. Note: in these and other studies where ACE-Is and ARBs have been combined in one of the tre atment arms, there has been an increase in adverse events (renal dysfunction, symptomatic h ypotension, hyperkalaemia), with no demonstrable improvement in outcomes, with the exceptio n of the CHARM study. Therefore, the use of an ACE-I and ARB in combination should generall y be avoided. ANGIOTENSIN RECEPTOR BLOCKERS 103 Dose \200 For essential hypertension, the dose should be titrated until BP control is achieved For other indications, particularly heart failure and for cardioprotection in those with or at risk of cardiovascular disease, the ARB MUST be titrated to the target dose or the maxi mal tolerated dose if the target dose cannot be achieved (i.e. due to hypotension, renal dy sfunction etc.). Compelling indications for ARB use \200 Hypertension : second line to ACE-I (i.e. ACE-I-i ntolerant patients) for non-black patients aged <55 years Heart failure : second line to ACE-I (i.e. ACE-I-intolerant patients) in all patients with any degree of left ventricular systolic function, initiated as early as possible following diagnosis Candesartan may also be considered in addition to ACE-I for inpatients remaining symptomati c despite optimal ACE treatment, if they are unable to tolerate spironolactone Post-MI heart failure : second line to ACE-I (i.e. ACE-I-intolerant patients); valsartan may be considered for patients with post-MI heart failure CV risk reduction : second line to ACE-I (i.e. ACE-I-intolerant patients); telmisartan may be considered in all patients with symptomatic or asymptomatic CVD. Contraindications and cautions \200 Contraindications : hypersensitivity to ARBs \200 pregnancy \200 breast-feeding Cautions : bilateral renal artery stenosis \200 aortic or mitral valve stenosis \200 hypertrophic cardiomyopathy \200 prior angioedema of any cause \200 hypotension (systolic blood pres sure <90 mmHg) \200 patients on high-dose diuretics (i.e. furosemide > 80 mg daily) \200 moderate to severe renal impairment (i.e. creatinine > 150 mol/L or eGFR<60 mL/min/1.73 m 2 ) \200\224 seek specialist advice for initiation. Initiation and target doses of commonly used ARBs See Table 2.5 . 104 CHAPTER 2 Drugs for the heart Table 2.5 Indications and doses for commonly used ARBs Agent Starting dose Target dose Candesartan: Hypertension 8 mg daily 8 \200\22332 mg daily Heart failure 4 mg daily Aim for 32 mg daily if tolerated Irbesartan 75 \200\223150 mg daily Up to 300 mg daily Losartan 50 mg daily 50 \200\223100 mg daily Telmisartan 40 mg daily Up to 80 mg daily Valsartan: Hypertension 80 mg daily Up to 320 mg daily Post-MI heart failure 20 mg twice daily Aim for160 mg twice daily if tolerated Monitoring \200 Obtain baseline BP and U&Es before initiation \200 Check BP and U&Es wi thin two weeks of initiation or change of dose, then annually If serum creatinine increases by more than 20 % (or eGFR falls by more than 15 % ) after initiation, stop ARB and seek specialist advice ARB dose should only be increased if: \200 systolic blood pressure > 90 mmHg \200 serum creatinine increases by less than 20 % (or eGFR falls by less than 15 % ) on each dose titration potassium is <5.5 mmol/L. Hyperkalaemia : advise low-potassium diet, ensure adequate \202 uid intake. Reduce dose if K + > 5.5 mmol/L; withdraw ARB if K + > 6 mmol/L. Adverse effects of ARBs \200 Symptomatic hypotension : rare but may occur, particularly i f there is intravascular volume depletion. Avoid excessive diuretic doses. \200 Angioedem a : has been reported rarely with ARBs. Particular caution should be taken when initiating an ARB in a patient with a history of angioedema of any cause. Key ARB drug interactions \200 Ciclosporin : increases risk of hyperkalaemia \200 Diure tics : enhance hypotensive effect \200 Lithium : increases lithium levels \200 Potassiu m supplements : increased risk of severe hyperkalaemia. This page intentionally left blank 106 CHAPTER 2 Drugs for the heart Aldosterone antagonists (eplerenone, spironolactone) Mode of action The aldosterone antagonists are steroids that are structurally similar to al dosterone, a hormone that binds to mineralocorticoid receptors to promote sodium and water retention. Aldosterone increases blood pres- sure, promotes magnesium and potassium loss, p otentiates the effects of the sympathetic nervous system, impairs the function of barorecep tors and endothelial function, and stimulates vascular \201 brosis. The aldosterone antagonists competitively bind to the aldosterone receptor to reduce sodium reabsorption and potassium excretion at the distal tubule and antagonize the effects of al dosterone listed above. Clinical evidence The landmark trial RALES (Randomized Aldactone Evaluation Study, 1999), s ecured the place of spironolactone in the management of severe heart failure (NYHA (New Yor k Heart Association) class IV or class III with recent class IV exacerbation; ejection frac tion (EF)<35 % ), by dem- onstrating a 30 % reduction in mortality and a 35 % reduction in hospitali- zations for heart failure, compared to placebo. In the EPHESUS (2003) study, epl erenone, initiated in patients with post-MI left ventricular dys- function (EF<40 % ) withi n 3 \200\22314 days of the acute event, demonstrated a 15 % reduction in the risk of death over the course of one year. Place in therapy Heart failure : initially licensed at high doses (100 \200\223400 mg daily) to augment the effects of other diuretics in the treatment of congestive heart failure, spironolactone is now primarily used at low doses (25 \200\22350 mg daily) in patients with moderate to sever e heart failure, as an adjunct to optimal ACE-I and B -blocker therapy for its prognostic b ene \201 ts. Eplerenone may be considered as an alternative to spironolactone, under speci alist super- vision, for patients with severe left ventricular systolic dysfunction, where spironolactone is indicated but has not been tolerated, usually due to the development of g ynaecomastia. This is an unlicensed use. Post-MI heart failure : In line with NICE post-MI secondary prevention guid- ance, eplereno ne should be prescribed within 3 \200\22314 days of MI, preferably after initiation of ACE- I therapy, for patients with symptoms and/or signs of heart failure and left ventricular se ptal defect (LVSD) with an EF (cid:100) 40 % . Hypertension : Spironolactone is also indica ted as an option at step 4 of the NICE/BHS (British Hypertension Society) hypertension trea tment algorithm. ALDOSTERONE ANTAGONISTS 107 Compelling indications for aldosterone antagonists \200 Chronic heart failure : spironola ctone \200\224 as an adjunct to standard therapy (ACE-I, B -blocker plus diuretic) at low doses in patients with moderate to severe heart failure. Eplerenone may be considered as an alternative in patients unable to tolerate spironolactone \201 rst line (unlicensed) \200 Post-MI heart failure : eplerenone \200\224 in patients with signs and symptoms of h eart failure and reduced left ventricular systolic dysfunction. Start within 3 \200\22314 d ays of the event Hypertension : consider fourth line in patients with hypertension resistant to standard therapies (i.e. ACE-I, calcium-channel blocker, and thiazide diuretic ). Contraindications and cautions \200 Contraindications : hypersensitivity to spironolacton e or eplerenone, serum K + > 5.0 mmol/L at initiation, moderate to severe renal insuf \201 ciency, anuria, severe hepatic insuf \201 ciency Cautions : hepatic impairment (monitor electrolytes closely), renal impairment (avoid if eGFR<50 mL/min, monitor electrolytes closely), pregnancy and lactation , elderly. Target doses of commonly used aldosterone antagonists See Table 2.6 . Table 2.6 Doses for commonly used aldosterone antagonists Agent Starting dose Target dose Spironolactone 50 mg daily a Heart failure 25 mg daily 25 \200\223200 mg daily Hypertension 100 mg daily 50 mg daily a Eplerenone 25 mg daily Lower doses may be used in the event of hyperkalaemia (i.e. spironolactone 12.5 mg daily or 25 mg on alternate days). See Table 2.7 . Table 2.7 Recommended dose adjustments based on potassium levels Serum K + (mmol/L) Action Dose adjustment <5.0 Increase dose 25 mg every other day to 25 mg daily 25 mg daily to 50 mg daily 5.0 \200\2235.4 Maintain dose No dose adjustment 5.5 \200\2235.9 Decrease dose 50 mg daily to 25 mg daily 25 mg daily to 25 mg every other day 25 mg every other day to withhold drug (cid:116) 6.0 Withhold drug Following withdrawal due to hyperkalaemia, restart at a dose of 25 mg every other day if K + <5.0 mmol/L. 108 CHAPTER 2 Drugs for the heart Dosing \200 Chronic heart failure : spironolactone is usually initiated at a dose of 25 m g daily, increasing to 50 mg daily after 4 \200\2236 weeks if the patient remains symptomat ic. Dose reduction to 12.5 mg daily or 25 mg on alternate days may be required in the event of renal decline, hyperkalaemia, or hypotension. Post-MI heart failure : eplerenone should be initiated within 3 \200\22314 days of the acut e event at a dose of 25 mg daily, increasing to 50 mg daily after 4 weeks. Doses of both spironolactone and eplerenone may need to be adjusted according to renal function and potassium levels. Monitoring \200 Check baseline blood chemistry and blood pressure. \200 Check blood che mistry within a week (e.g. serum creatinine, urea, potassium, sodium) of starting therapy or dose adjustment and again after a month of therap y or dose adjustment. Monitoring is recommended at least 3 monthly thereafter. Adverse effects of aldosterone antagonists \200 Hyperkalaemia : this is common. Patients should be advised to avoid foods that are high in potassium \200\224 bananas, tomatoes, ci trus fruit, Lo-Salt. Dose reduction, and in some cases drug withdrawal, may be necessary. Renal dysfunction : renal decline is common following initiation of spironolactone or epler enone, particularly if already treated with ACE-I and diuretics. Careful control of \202 uid balance is essential. Dose reduction, and in some cases drug withdrawal, may be require d. \200 Gynaecomastia : some patients may tolerate minor swelling and discomfort; however , this frequently requires withdrawal of spironolactone. Eplerenone, free of effects on the progesterone receptor, may be considered as an alternative, although this is unlicensed in chronic heart failure. Gastrointestinal : diarrhea, constipation, nausea, vomiting, and abdominal discomfort have been reported. Menstrual irregularities. \200 Rashes. ALDOSTERONE ANTAGONISTS 109 Drug interactions with aldosterone antagonists \200 ACE-Is and ARBs : increased risk of s evere hyperkalaemia with aldosterone antagonists Alpha-blockers : enhanced hypotensive effect \200 Antiarrhythmic drugs : plasma levels of eplerenone increased by amiodarone \200\224 reduce eplerenone dose Antibacterial drugs : plasma levels of eplerenone increased by clarithromycin and telithrom ycin \200\224 avoid concurrent use Antidepressants : plasma levels of eplerenone reduced by St Johns Wort \200\224 avoid concurrent use Anti-epileptic drugs : plasma levels of eplerenone reduced by carbamazepine and phenytoin \200\224 avoid concurrent use Antifungal drugs : plasma levels of eplerenone increased by itraconazole and ketoconazole Antiviral drugs : plasma levels of eplerenone increased by nel \201 navir and ritonavir \200\224 avoid concomitant use; also by saquinavir \200\224 reduce eplerenone dose Cardiac glycosides : spironolactone may increase plasma levels of digoxin \200 Ciclospori n : increased risk of hyperkalaemia \200 Lithium : increased lithium levels with associat ed increased risk of toxicity Potassium salts : increased risk of hyperkalaemia \200 Tacrolimus : increased risk of hyp erkalaemia. 110 CHAPTER 2 Drugs for the heart Beta-adrenoceptor blockers ( B -blockers) (e.g. atenolol, bisoprolol, metoprolol, nebivolol) Mode of action Beta-blockers block the action of noradrenaline at B -adrenceptors, which ar e located in the myocardium, throughout the circulatory system and elsewhere. As a result, B -blockers inhibit sympathetic stimulation of heart rate and myocardial contractility. Bet a-blockers slow the \201 ring of the pacemaker cells in the sino-atrial node and hence ar e negatively chronotropic, and also affect the conduction through the atrioventricular (AV) node. Thus they also have anti-ischaemic and anti-arrhythmic effects. Beta-blockers lower blood pressure, although the exact mechanism for this effect is unclear. It is postulated t hat reducing circulating renin levels or lowering sympathetic tone may be responsible. Clinical trial data \200 Angina : IMAGE (International Multicenter Angina Exercise, metop rolol, 1992), APSIS (Angina Prognosis Study in Stockholm, metoprolol, 1996), TIBET (Total I schaemic Burden European Trial, atenolol, 1996), ASIST (Atenolol Silent Ischaemia Study, at enolol, 1994) Post-MI secondary prevention : BHAT (Beta-blockers Heart Attack Trial, propranolol 1983), N orwegian Muticentre Study Group (timolol, 1981) Heart failure : CIBIS II (Cardiac Insuf \201 ciency Bisoprolol Study, bisoprolol), COPERNICUS (carvedilol), CAPRICORN (Carvedilol Prospective randomized Cumulati ve Survival, carvedilol), MERIT-HF (Metoprolol CR/XL Randomized Intervention trial in Conge stive Heart failure, metoprolol), SENIORS (Study of the Effect of Nebivolol Interventions o n Outcomes and rehospitalization in Seniors with heart Failure, nebivolol) Atrial \201 brillation : limited data but summarized in NICE guideline CG36 Atrial Fibrillation (2006) Hypertension : meta-analyzes have concluded that B -blockers do not confer the same stroke protection as other antihypertensive drugs, for the same degree of BP lowering. Beta-blocke rs are now no longer recommended early in the treatment of hypertension, unless there is an other compelling indication to use them, i.e. post-MI, heart failure, or angina (NICE 2006) . Choice of agent This should take into account the indication, the clinical trial data, and the properties of the individual B -blockers. Key properties include: duration of action \200\224 longer-acting agents are preferred \200 water or lipid solub ility, which will in \202 uence adverse effects \200 cardioselectivity. See \200\230Com pelling indications for beta-blockers \200\231, b p.111. BETA-ADRENOCEPTOR BLOCKERS (B-BLOCKERS) 111 Dose Optimal B -blockade is often described as control of resting heart rate to between 50 and 60 bpm. Usual starting and target doses of B -blockers are listed in Table 2.8 . \200 For patient s with borderline bradycardia, heart failure, or hypotension, on multiple antihypertensive therapy, or who are elderly, lower starting doses may be considered. To ensure optimal cardioprotective effects, aim to titrate to the maximum tolerated dose. Compelling indications for beta-blockers \200 Heart failure : all patients with symptomat ic heart failure and LVSD, initiated as early as possible following diagnosis in stable patients \200\224 only bisopr olol, carvedilol and nebivolol are licensed in the UK Post-MI secondary prevention : all patients following an MI, initiated during the inpatient phase of treatment Angina : \201 rst line for all patients with angina \200\224 aim to control resting heart rate to 50 \200\22360 bpm Atrial \201 brillation : \201 rst line for patients in whom a rate-control strategy is appropriate. Contraindications and cautions \200 Contraindications : asthma or history of bronchospasm * \200 second- or third-degree heart block \200 sever e peripheral vascular disease \200 patients on verapamil. Cautions: chronic obstructive pulmonary disease (if evidence of a reversible component) uncontrolled heart failure \200 sick sinus syndrome \200 patients on diltiazem \200 h ypotension or bradycardia <60 bpm \200 peripheral vascular disease \200 pregnancy and b reast feeding. Initiation and target doses of commonly used beta-blockers See Table 2.8 and Table 2.9. Beta-blocker may be considered in heart failure under specialist supervision. 112 CHAPTER 2 Drugs for the heart Table 2.8 Doses for commonly used B -blockers Starting dose a Target dose b Agent Atenolol 25 \200\22350 mg daily 50 \200\223100 mg daily Bisoprolol 10 mg daily 10 \200\22320 mg daily Bisoprolol in heart failure 1.25 mg daily Increase slowly over 10 \200\22312 weeks aiming for 10 mg daily Carvedilol 12.5 mg daily 50 mg daily Carvedilol in heart failure 3.125 mg twice daily Increase slowly over 10 \200\22312 weeks aiming for 25 mg twice daily Metoprolol 25 mg twice daily 50 \200\223100 mg two to three times daily Monitoring \200 Obtain baseline BP and pulse before initiation and after dose changes. \200 In the absence of side-effects review within 4 weeks and consider dose titration. Lethargy and/or impotence are not necessarily indications for drug withdrawal. Side-effects are frequently distressing but may wear off over time. Patient concerns should be addresse d; however, they should be strongly encouraged to persevere with therapy in view of the car diac bene \201 ts. If medication discontinuation proves necessary, withdraw B -blocker slowly to avoid re \202 ex tachycardia. Table 2.9 Characteristics of commonly prescribed B -blockers Agent Half-life (h) Lipid solubility Cardioselectivity Atenolol 7 \200\223 + Bisoprolol 11 + + + Carvedilol 6 + \200\223 Metoprolol 5 + + Nebivolol 10 + + + + + + + Adverse effects of beta-blockers \200 Bradycardia (HR<50bpm): consider dose reduction, ex clude heart block. Symptomatic hypotension : consider dose reduction, exclude heart block. \200 Bronchospasm : review need for B -blocker and consider alternative drug class. If compelling indication, use a cardioselective B -blocker with extreme caution and under specialist supervision. Fatigue : may dissipate during therapy. BETA-ADRENOCEPTOR BLOCKERS (B-BLOCKERS) 113 Cold extremities : protect \201 ngers and toes with gloves/socks in cold weather. Sleep disturbances : consider a water-soluble agent. Key drug interactions with beta-blockers \200 Alpha-blockers : enhanced hypotensive effec t \200 Anti-arrhythmics : amiodarone \200\224 increased risk of myocardial depression, AV block and bradycardia \202 ecainide \200\224 increased risk of myocardial depression and bradycardia \200 li docaine \200\224 increased risk of toxicity with propranolol \200 propafenone \200\224 increased plasma concentration of metoprolol and propranolol \200 Antidepressants : citalopram, escitalopram, paroxetine \200\224 increased metoprolol plasma concentration enhanced hypotensive effect with monoamine oxidase inhibitors (MAOIs) Antimalarials : me \202 oquine \200\224 increased risk of bradycardia \200 Calcium-chan nel blockers : enhanced hypotensive effect \200 diltiazem \200\224 risk of AV block, bradycardia \200 verapamil \200\224 severe hypotension and heart failure \200 Ciclsporin : increased pla sma concentration with carvedilol \200 Clonidine : increased risk of withdrawal hypertens ion \200 Diuretics : enhanced hypotensive effect \200 Sympathomimetics : adrenaline, do butamine: \200\224 increased risk of severe hypertension and bradycardia with non-cardiose lective B -blockers Note: Sotalol, a B -blocker with class III anti-arrhythmic effects, has a number of speci \201 c interactions, which should be checked before prescribing. 114 CHAPTER 2 Drugs for the heart Calcium-channel blockers (CCBs) (e.g. dihydropyridine (DHP) type: amlodipine, felodipine, l acidipine, nifed- ipine; non-dihydropyridine (non-DHP) type: diltiazem and verapamil) Mode of action CCBs inhibit the inward movement of calcium ions through the slow channels l ocated in the cells of the myocardium, the His \200\223Purkinje system, and in vascular smo oth muscle. The DHP-type CCBs have more af \201 nity for the vascular smooth muscle, resul ting in peripheral vasodilatation, reduced blood pressure, and reduced afterload, while the non-DHP type have more effect on the myocardial cells and conduction system, resulting in negative inotropy, myocardial depression, and AV conduction delay. Clinical trial data Hypertension: multiple studies demonstrate a signi \201 cant reduction in mor- tality and morbidity, which are summarized in NICE CG34: Hypertension (2006). Angina: reduce frequency and severity of angina episodes. As effective as B -blockers in pr otecting against effort-induced angina (APSIS, (verapamil, 1996)/TIBET (nifedipine, 1996). No end-point outcome data (mortality/ morbidity) in stable or unstable angina, although ver apamil and diltiazem are supported by studies indicating a reduction in events in post-MI p atients. Atrial \201 brillation: verapamil, diltiazem \200\224 multiple small studies demonstrate ef \201 cacy in controlling heart rate at rest and during exercise, summarized in NICE CG 36 Atrial Fibrillation (2006). Choice of agent DHP CCBs are usually used for the management of hypertension and as an addi tion to B -blocker to improve angina control. Non-DHP agents are chosen for the rate-contro l properties in angina, where B -blockers are contraindicated or not tolerated, and for the management of arrhyth- mias, particularly AF. Care should be taken when prescribing, to choose the correct dose and formulation, particul arly for diltiazem and nifedipine, with numerous dosing schedules depending on brand. Dose Usually the dose is titrated against response, aiming for adequate BP control in hyper tension or a resting heart rate between 50 and 60 bpm in angina management. The starting do ses and usual dose ranges of commonly prescribed CCBs are summarized in Table 2.10 . Compelling indications for CCBs \200 Angina : \201 rst line in patients where B -blockers are contraindicated or not tolerated \200 \224 rate-controlling effects of diltiazem and verapamil may confer an advantage here may also be used in combination with B -blockers (not verapamil), nitrates, nicorandil, or ivabradine (not diltiazem, verapamil) CALCIUM-CHANNEL BLOCKERS (CCBs) 115 Hypertension : \201 rst line for older patients ( > 55 years) and black patients \200 A trial \201 brillation : verapamil may considered for rate control where \201 rst- line options have failed, or are contraindicated or not tolerated. Contraindications and cautions \200 Contraindications : cardiogenic shock, advanced aortic stenosis, within one month of acute MI (AMI), unstable angina or acute coronary syndrome (ACS) \200 diltiazem, verapami l \200\224 AV block, severe bradycardia, left ventricular failure, sick sinus syndrome, an d Wolff \200\223Parkinson \200\223White syndrome Cautions : worsening heart failure. Initiation and dose range for CCBs See Table 2.10 . Table 2.10 Doses for CCBs Agent Starting dose Dose range Amlodipine 5 mg daily 5 \200\22310 mg daily Diltiazem Dose depends on formulation and brand Felodipine 5 mg daily 5 \200\22320 mg daily Lacidipine 2 mg daily 2 \200\2236 mg daily Nifedipine 20 \200\22330 mg daily (LA preparation) 30 \200\22390 mg daily (LA preparation) Verapamil 120 mg daily (LA preparation) 240 \200\223480 mg daily (La preparation) CCB adverse effects \200 Bradycardia (HR<50 bpm): (non-DHP only) consider dose reduction, exclude heart block. Symptomatic hypotension : consider dose reduction. \200 Flushing: dissipates over time \200\224 encourage patient to persist with therapy. GI disturbance : may make constipation worse \200 Ankle oedema : often dose related, cons ider dose reduction or combine with ACE-I or ARB Gingival hyperplasia : withdraw CCB and consider alternatives. Monitoring CCBs \200 Obtain baseline BP and pulse before initiation and after dose change s \200 In the absence of side-effects review within 4 weeks and consider dose titration. Headache and \202 ushing are common in the \201 rst week or two of treatment and usually resove over time. Simple analgesics can be used to control headache i f necessary. The patient should be reassured and encouraged to continue with therapy. Ankle swelling is common, especially with the DHP-type CCB at higher doses (i.e. after incr easing from amlodipine 5 mg to 10 mg daily), and may limit the maximum dose. 116 CHAPTER 2 Drugs for the heart Key drug interactions with CCBs \200 Alpha-blockers : enhanced hypotensive effect \200 Anesthetics : enhanced hypotensive effect \200 Anti-arrhythmics : non-DHP type: increased risk of bradycardia, myocardial depression with amiodarone and risk of asystole when verapamil given with \202 ecainde/disopyramide Anti-epileptics : variable effects on plasma levels \200\224 consult product literature \200 Antifungals \200 Antivirals \200 Barbiturates : effect of CCB reduced \200 Beta-blockers : enhanced hypotensive effect \200 diltiazem \200\224 risk of AV block, bradycardia \200 verapamil \200\224 severe hypotension and heart failure Digoxin : verapamil increases digoxin levels, with increased risk of AV block/bradycardia Ciclosporin : variable effects on plasma levels \200\224 consult product literature \200 Ivabradine : plasma levels increased by diltiazem, verapamil \200\224 avoid 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