Calcium Channel Blockers (dihydropyridine derivatives ..., Schemes and Mind Maps of Cardiology

Download Calcium Channel Blockers (dihydropyridine derivatives ... and more Schemes and Mind Maps Cardiology in PDF only on Docsity! Medicines Management Programme Preferred Drugs Calcium Channel Blockers (dihydropyridine derivatives) for the treatment of hypertension and stable angina Approved by Prof. Michael Barry, Clinical Lead, MMP. Date Approved 12th September 2016 Version 1.0 i Contents 1. Purpose .............................................................................................................................................. 1 2. Definitions .......................................................................................................................................... 2 3. Classification of calcium channel blockers ........................................................................................ 2 4. Preferred drug .................................................................................................................................... 4 5. Consultation for calcium channel blockers ....................................................................................... 4 6. Selection criteria for calcium channel blocker review...................................................................... 4 6.1 Licensed therapeutic indications ..................................................................................................... 4 6.1.1 Hypertension................................................................................................................................. 5 6.1.1.1 Clinical efficacy in hypertension ................................................................................................. 5 6.1.1.2 Systematic reviews of hypertension ........................................................................................ 14 6.1.1.3 Clinical guidelines for hypertension ......................................................................................... 17 6.1.2 Angina ......................................................................................................................................... 18 6.1.2.1 Clinical efficacy of stable angina............................................................................................... 18 6.1.2.2 Systematic reviews of stable angina ........................................................................................ 21 6.1.2.3 Clinical guidelines for stable angina ......................................................................................... 22 6.2 Patient factors ................................................................................................................................ 24 6.2.1 Dosing and administration .......................................................................................................... 24 6.3 Cautions and contraindications ..................................................................................................... 25 6.4 Adverse drug reactions (ADRs) ...................................................................................................... 25 6.5 Drug interactions ........................................................................................................................... 27 6.6 Cost ................................................................................................................................................. 29 6.7 Prescribing trends in Ireland ......................................................................................................... 30 7. Summary .......................................................................................................................................... 31 8. References ........................................................................................................................................ 32 Bibliography ......................................................................................................................................... 37 Appendix A………………………………………………………………………………………………………………………………………39 1 1. Purpose Calcium channel blockers (CCBs) were initially developed in the 1960s1 and are used in the treatment of various cardiovascular diseases including angina, hypertension and Raynaud’s disease.2 CCBs inhibit the inward-flow of calcium ions causing systemic vasodilation.3 There are three classes of CCBs: dihydropyridine (DHP), phenylalkylamine and benzothiazepine derivatives.4 These classes differ in chemical structure and binding sites resulting in differing cardiac effects.5 The DHP CCBs (e.g. amlodipine) cause reflex activation of the sympathetic nervous system, increasing heart rate and cardiac output. In contrast the phenylalkylamine (verapamil) and benzothiazepine (diltiazem) CCBs cause a modest decrease in heart rate, A-V conduction and cardiac output.6 Verapamil and diltiazem, referred to as rate-limiting CCBs, are often used to treat arrhythmias.7 The differing properties between classes of CCBs means that they cannot be used interchangeably. This document aims to select a preferred DHP CCB, as verapamil and diltizem are rate-limiting CCBs they will not be included in this review. There are six licensed DHP CCBs in Ireland: amlodipine, felodipine, lercanidipine, nifedipine, nilvadipine and nimodipine.8 Nimodipine has a specialist indication in the treatment of aneurysmal subarachnoid haemorrhage, therefore it will not be considered in this review.9 In 2014 expenditure on DHP CCBs on the General Medical Services (GMS) scheme exceeded €16.5 million.10 Expenditure has decreased in recent years due to generic substitution and reference pricing. However the DHP CCBs are still the 17th most expensive class of drug on the GMS scheme, with amlodipine the 9th most commonly prescribed drug.10 The selection by the Medicines Management Programme (MMP) of a preferred CCB, is designed to support prescribers in choosing a medicine of proven safety and efficacy, in the management of patients with hypertension and stable angina. The MMP aims to enhance the quality of prescribing and provide value for money. Prescribers are encouraged to consider the preferred drug when initiating a CCB or when switching from another CCB, when a change in drug treatment is indicated. This guidance is not applicable to all patient populations, it does not include children or patients 2 with hepatic or renal disease, where specialist advice should be sought. The use of CCBs is not recommended during pregnancy unless the clinical benefits outweigh the risk to the foetus.2 2. Definitions  For the purposes of this review the term calcium channel blocker refers to DHP CCBs. Only DHP CCBs, reimbursed and licensed for hypertension and/or stable angina, were reviewed in this document. Where two or more preparations of the same drug are listed (e.g. where there are different manufacturers/suppliers), the least expensive preparation has been selected for the evaluation. Costs are correct as of March 2016.11  The defined daily dose (DDD) is obtained for each drug using the ATC code. This code is a World Health Organisation method for classifying drugs, based on the organ or system on which they act and their therapeutic, pharmacological and chemical properties.12 3. Classification of calcium channel blockers DHP CCBs can be divided into first, second and third generation agents according to their pharmacokinetic and pharmacodynamic properties (table 1).13 Table 1: Classification of dihydropyridine calcium channel blockers.13-20 Drug Classification Nifedipine (immediate-release) First generation Nifedipine long-acting (slow-release or GITS *) Second generation, subclass A Felodipine Second generation, subclass B Nilvadipine Second generation, subclass B Amlodipine Third generation Lercanidipine Third generation * GITS: Gastrointestinal therapeutic system The first generation CCBs (e.g. nifedipine immediate-release) have a rapid onset and short duration of action, therefore multiple daily dosing is required.13,14 These drugs reduce both myocardial contractility and the conduction of electrical impulses to the heart, and also cause reflex tachycardia. These side effects are particularly unwanted when treating patients recovering from an acute MI, or patients with left ventricular dysfunction.13 3 Nifedipine immediate-release should only be used for the treatment of hypertension or chronic stable angina if no other treatment is appropriate due to the dose-dependent increased risk of cardiovascular complications and mortality.14 NICE guidance on hypertension states that only long- acting formulations of nifedipine should be considered for the treatment of hypertension.21 Nifedipine immediate-release will therefore not be considered further in this review. Second generation DHP CCBs were developed in order to improve the pharmacokinetic profile and reduce the unwanted side effects of first generation CCBs, with a longer duration of action and enhanced vascular selectivity.13 There are two subclasses of CCBs in this group, the first (subclass A) comprises the modified release formulations which have an extended duration of action e.g. nifedipine slow-release (SR) or gastrointestinal therapeutic system (GITS).15,16 The second (subclass B) is comprised of chemical entities which have less negative effect on myocardial contractility and heart rate and reduced effect on atrioventricular conduction (e.g. nilvadipine).18 In clinical trials nilvadipine demonstrated a longer duration of action and a vasodilatory effect 5-16 times greater than nifedipine immediate-release.22 However despite these advantages second generation CCBs continue to demonstrate practical problems, such as fluctuations in antihypertensive effect over 24 hours and difficulty with bioavailability in extended release formulations.13 Third generation CCBs interact with specific high affinity binding sites in the calcium channel complex.13 These CCBs do not exhibit the drug-induced autonomic activation which occurs in previous generations of CCBs, causing potentially detrimental effects in patients with left ventricular dysfunction.13 Amlodipine and lercanidipine are examples of third generation CCBs.4 Amlodipine has a gradual onset and prolonged duration of action due to its long plasma half-life (40-50 hours).13 At physiological pH amlodipine is in the ionised state, therefore it combines more slowly with the receptor and binds more firmly to various tissue compartments.4 Lercanidipine is a lipophilic DHP CCB. Lercanidipine accumulates in the lipid bilayer of cell membranes where it is released slowly and gradually, close to the target calcium channels, enabling it to have a long half- life.6 This slow onset of action prevents reflex tachycardia and sympathetic activation. Lercanidipine demonstrates increased vascular selectivity and less of a negative effect on myocardial contractility than other CCBs.6,23 6 Table 3: Calcium channel blocker trials in hypertension included in this review Trial Design Drugs used in trial Findings ACCOMPLISH24 2007 Multi centre, double- blind, RCT, n=11,506 Benazepril- amlodipine vs. benazepril- hydrochlorothiazide Reduction in BP was similar from baseline for both groups. There was a mean reduction in BP of 0.9/1.1mmHg between the groups (p<0.001). Risk of cardiovascular events and death was lower with the benazepril-amlodipine group (absolute risk reduction 2.2%). VALUE 25 2004 Multi centre, double- blind, RCT, n=15,245 Amlodipine vs. valsartan Both groups lowered BP, amlodipine significantly more than valsartan (p<0.001). The composite endpoint of time to first cardiac event did not differ between the treatment groups (p=0.49). The mean patient follow up time was 4.2 years. ASCOT-BPLA26 2005 Multi centre, RCT, n=19,257 Amlodipine +/- perindopril vs. atenolol +/- bendroflumethiazide BP was lower throughout the trial in the amlodipine group. Average difference in BP was 2.7/1.9mmHg (p<0.0001). Primary endpoint of non-fatal MI and fatal CHD was 10% lower in the amlodipine group, but this was not significant. CAMELOT27 2004 Multi centre, double- blind, RCT, n=1,991 Comparison of amlodipine, enalapril or placebo Antihypertensive treatment with either drug significantly lowered BP vs. placebo p<0.001. There was no significant difference in primary endpoint of cardiovascular events between the two treatments (p=0.1). ALLHAT28 2002 Multi centre, double- blind, RCT, n=33,357 Amlodipine vs. chlorthalidone vs. lisinopril Thiazide diuretics were superior in preventing one or more forms of CVD. Five year systolic BP results were significantly higher in amlodipine and lisinopril groups (p<0.001) than chlorthalidone, however diastolic BP was significantly lower in the amlodipine group (p<0.001). Long-term treatment with lercanidipine in patients with mild to moderate hypertension29 1997 Open, multi centre n=355 Lercanidipine Diuretic, ACE or beta- blocker added if needed After 4 weeks lercanidipine caused a significant decrease in BP (p<0.001). Thirty- one (8.7%) patients complained of side effects, 4% of patients withdrew due to side effects. ELYPSE30 2002 Multi centre, open prospective observational study, n=9,059 Lercanidipine Significant reductions in systolic and diastolic BP were observed after one month (p<0.001). 6.5% of patients had an adverse reaction. Most commonly headache (2.9%), oedema (1.2%), flushing (1.1%) and palpitations (0.6%). LEAD31 2003 Multi centre, double- blind, parallel group n=250 Lercanidipine vs. felodipine vs. nifedipine GITS All of the DHPs studied significantly and equally decreased BP after 4 weeks. The number of ADRs was significantly lower in lercanidipine and nifedipine GITS patients compared to felodipine (p<0.05). There was no significant difference in ADRs between lercanidipine and nifedipine GITS. 7 ELLE32 2003 Multi centre, randomised, parallel group comparison trial, n=324 Lercanidipine vs. lacidipine* vs. nifedipine GITS Systolic and diastolic BP was significantly decreased in all three study groups compared to baseline (p<0.01). Incidence of ADRs was lowest in the lercanidipine group (19.4%). Tolerability of long-term treatment with lercanidipine versus amlodipine and lacidipine in elderly hypertensives33 2002 Multi centre, double- blind, parallel study n=828 Lercanidipine vs. amlodipine vs. lacidipine* BP was significantly and equally decreased in all treatment groups (p<0.01). Incidence of oedema was significantly higher in the amlodipine group 19% (p<0.001) compared to lercandipine (9.3%) and lacidipine* (4.3%) groups. Effects of lercanidipine vs. amlodipine in hypertensive patients with cerebral ischemic stroke34 2015 Open label, controlled, randomised, parallel- group study, n=104 Lercanidipine vs. amlodipine BP was significantly decreased in both treatment groups. There was no statistical difference in BP between the two groups. There were less adverse events in the lercanidipine group compared to the amlodipine group (5.7% compared to 19.2%). HOT35 1994 PROBE n=18,790 Felodipine Aspirin Addition of ACE inhibitor, beta-blocker or diuretic if needed to obtain target BP Patients were randomly assigned to one of three target BP groups: ≤90mmHg, ≤85mmHg and ≤80mmHg. Felodipine reduced BP by a similar amount in all 3 target groups. The lowest incidence of cardiovascular events occurred with a mean diastolic BP of 82.6 mmHg. Addition of aspirin reduced the risk of acute MI without increasing the risk of bleeding. STOP-Hypertension-236 1999 PROBE n=6,614 1. Conventional drug group: Atenolol/ metoprolol/pindolol or hydrochlorothiazide plus amiloride 2. ACE inhibitor group: enalapril or lisinopril. 3. CCB group: felodipine or isradipine* BP was lowered by a similar amount in all three therapeutic regimens from baseline values. There was no significant difference between old and new antihypertensive regimens for primary combined endpoint of fatal stroke, fatal MI and other fatal CVD (p=0.89). 8 Lercanidipine hydrochloride versus felodipine sustained- release for mild-to-moderate hypertension: a multi-centre, randomised clinical trial37 2015 Multi centre, RCT, open-label, parallel group, n=281 Lercanidipine vs. felodipine There was a significant decrease in BP compared to baseline for lercanidipine and felodipine (p<0.0001). There was no significant difference between groups for BP lowering. ADRs were 26.6% in the lercanidipine group and 25.3% in the felodipine group. INSIGHT38 2000 Prospective, RCT, double-blind trial n=6,321 Nifedipine GITS vs. co-amilozide After titration BP remained close to 138/82mmHg in both groups. Primary endpoints were cardiovascular death, MI, heart failure or stroke. There was no significant difference in primary endpoints between Nifedipine GITS and co- amilozide. There were 8% more withdrawals in the nifedipine group from peripheral oedema (p<0.0001), however serious adverse events were more frequent in the co-amilozide group. Treatment of mild-to- moderate hypertension with CCBs: comparison of nifedipine GITS with amlodipine39 Multi centre, parallel group, double-blind RCT n=155 Nifedipine GITS vs. amlodipine The primary criterion for assessing efficacy between drugs was mean diastolic BP. Both groups reduced BP (p<0.001). There was no significant difference in BP lowering between the 2 groups. The incidence of adverse effects was 7.9% in the nifedipine group and 10.1% in the amlodipine group. Comparison of the efficacy of nilvadipine and nitrendipine on circadian blood pressure40 1992 Double-blind, placebo controlled trial, n=183 Nilvadipine vs. nitrendipine* Nilvadipine was significantly better at lowering systolic and diastolic BP than placebo and slightly better than nitrendipine. Nilvadipine had a more sustained duration of action than nitrendipine and less side effects. Peripheral oedema incidence was 29% with nitrendipine and 5% with nilvadipine. Effects of nilvadipine and amlodipine in patients with mild/moderate essential hypertension41 2005 Double-blind, parallel group, RCT, n=168 Nilvadipine vs. amlodipine There was no significant difference between BP lowering in the two treatment groups (p=0.22). There was also no significant difference in ADRs between groups. Lower limb oedema was the most frequent event leading to study withdrawal. CCB: Calcium channel blocker; ACE: Angiotensin converting enzyme; ARB: Angiotensin-II receptor blocker; RCT: Randomised controlled trial; PROBE: Prospective, randomised, open with blinded endpoint evaluation. * Not licensed in Ireland 11 to three months. At the end of this observational study 64% of patients had achieved a diastolic BP <90mmHg. Adverse events occurred in 6.5% of patients. These included headache (2.9%), ankle oedema (1.2%), flushing (1.1%) and palpitations (0.6%). The low numbers of patient with adverse effects showed lercanidipine had good tolerability in clinical practice.30  The LEAD study in 2003 (n=250) compared the effects of lercanidipine, felodipine and nifedipine GITS, on BP and heart rate, in patients with mild to moderate hypertension. BP decreased significantly and equally in all treatment groups (p<0.01). Adverse events were significantly lower in patients treated with nifedipine and lercanidipine than felodipine (p<0.05). Overall lercanidipine had the best tolerability profile with a lower incidence of withdrawals from ankle oedema (0.9%), compared to nifedipine GITS (3.8%) and felodipine (4.5%).31  The 2003 ELLE study (n=324) compared the effects of lercanidipine, lacidipine (not licensed in Ireland) and nifedipine GITS on BP and heart rate in elderly hypertensive patients (≥65 years). BP was found to be significantly decreased in all treatment groups (p<0.01). Lercanidipine was found to be equivalent to nifedipine and better than lacidipine at lowering BP. Adverse events were lowest in the lercanidipine group (19.4%), compared to lacidipine (27.1%) and nifedipine GITS (28.4%).32  Tolerability of lercanidipine compared to amlodipine and lacidipine was assessed in a 2002 study of elderly hypertensive patients (n=828). While all the drugs had similar antihypertensive effect, the incidence of peripheral oedema in the amlodipine group (19%) was significantly higher compared to the lercanidipine (9.3%) and lacidipine (4.3%) groups (p<0.001).33  In 2015 a study of 104 hypertensive patients with cerebral ischaemic stroke compared amlodipine with lercanidipine. There was no statistical difference between the two groups in terms of BP reduction. The lercanidipine group was found to have less adverse events than the amlodipine group (5.7% compared to 19.2%, p=0.03). This trial stated that larger studies were required to verify the results.34 12 Felodipine Felodipine has been less extensively studied than other DHP CCBs such as amlodipine. Two of the most significant trials are the Hypertension Optimal Treatment trial and the STOP-2-Hypertension-2 trial.  The 1994 Hypertension Optimal Treatment (HOT) trial involved 18,790 patients in 26 countries with hypertension (defined as diastolic BP between 100-115 mmHg). Each patient was randomly assigned to one of three groups, each with a different target diastolic BP. Results showed that taking felodipine daily, reduced BP in all 3 treatment groups. The lowest incidence of cardiovascular events occurred with a diastolic BP of 82.6 mmHg.35  The 1999 STOP-2-Hypertension-2 trial investigated 6,614 elderly patients (aged 70-84 years) with hypertension. Each patient was randomly assigned to one of three treatment groups: conventional antihypertensives (beta-blockers or diuretics), CCBs or ACE inhibitors. There was a similar decrease in BP with each treatment group from baseline values. There was no significant difference between older and newer antihypertensive drugs in the primary combined endpoint of prevention of cardiovascular mortality or major events (p=0.89).36  A 2015 a trial (n=281) which compared lercanidipine with felodipine sustained release, for the treatment of mild to moderate hypertension demonstrated that there was a significant difference in BP lowering with each drug from baseline. The mean systolic BP decreased by 18mmHg in the lercanidipine group and 19mmHg in the felodipine group (p<0.001).37 There was no significant difference in BP lowering effect between groups. Incidence of adverse events was similar between groups, 26.6% for the lercanidipine group and 25.3% for the felodipine group (p=0.892).37 Nifedipine long-acting The BP lowering efficacy of nifedipine GITS has been demonstrated in the LEAD and ELLE studies, as previously discussed in the lercanidipine section.31,32  The 2000 INSIGHT trial (n=6,321) was a large scale multi-centre trial across Europe and Israel involving patients aged 55-80 years with hypertension and one other cardiovascular risk factor. Patients were randomly assigned to either nifedipine GITS or co-amilozide (amiloride and 13 hydrochlorothiazide). Following titration, BP in both groups remained close to 138/82mmHg for the duration of the trial. There was no difference in the primary endpoints of cardiovascular death, myocardial infarction (MI), heart failure or stroke between treatment groups (p=0.35). Nifedipine patients had 8% more withdrawals due to peripheral oedema (p<0.0001), but co-amilozide patients had more serious side effects e.g. metabolic disorders.38  Nifedipine GITS was compared with amlodipine in a multi centre RCT (n=155), both drugs were found to significantly reduce BP.39 Comparison between groups found a similar reduction in mean diastolic BP. This was the primary criterion for assessing efficacy. The incidence of adverse events was low, 7.9% in the amlodipine group and 10.1% in the nifedipine group. Most of the adverse effects were headache, dizziness and vertigo.39 Nilvadipine Nilvadipine has been less extensively studied than other DHP CCBs such as amlodipine and lercanidipine.  A 1992 trial (n=183) comparing nilvadipine and nitrendipine (not licensed in Ireland) to placebo, found that nilvadipine lowered BP significantly better than placebo and slightly more effectively than nitrendipine. Nilvadipine also had a longer duration of effect due to its half-life of 20 hours, compared to 12 hours for nitrendipine. Common side effects included headache, flushing, palpitations and peripheral oedema.40  A 2005 double-blind prospective RCT comparing nilvadipine to amlodipine (n=168) found that there was no significant difference in BP lowering between the treatment groups (p=0.22). There was also no significant difference in ADRs between the groups (p=0.24).41 Lower limb oedema accounted for 20% of the ADRs reported in nilvadipine patients and 29.3% in amlodipine patients.41 16 over a 24 hour period and significantly more than placebo for systolic and diastolic BP (p<0.00001).46 Evidence of tolerability of calcium channel blockers The tolerability of lercanidipine compared to other CCBs was assessed by Makarounas-Kirchmann et al. (2009), in a meta-analysis conducted on eight RCTs (n=2,034).43 Results showed that lercanidipine did not differ statistically from the other CCBs in BP lowering efficacy. However there was a difference in tolerability between the DHPs.43 Compared to the first generation DHPs, lercanidipine was associated with a reduced relative risk (0.44) of peripheral oedema and a reduced relative risk (0.24) of patients withdrawing from treatment, because of peripheral oedema.43 There was no significant difference in tolerability between lercanidipine and the second generation CCBs.43 Peripheral oedema is the commonest side effect reported in DHPs and can contribute to poor adherence to therapy.33,43 A meta-analysis by Makani et al. (2011) evaluated the incidence and withdrawal rate due to peripheral oedema with CCBs.42 One hundred and six studies with 99,469 participants were included in the analysis. Trials compared CCBs with placebo and other antihypertensive therapies. Results found that there was a significant increase in withdrawal rates due to peripheral oedema with CCBs compared to placebo (p<0.0001). The risk of peripheral oedema with lipophilic DHPs (e.g. lercanidipine) was 57% lower than traditional DHPs (RR 0.43, p<0.0001). The incidence of peripheral oedema with DHPs was 12.3% compared to 3.1% with non DHPs (p<0.0001).42 A systematic review on the treatment of hypertension stated that the five main classes of antihypertensives i.e. ACE inhibitors, ARBs, diuretics, beta-blockers and CCBs all reduce BP by a similar amount.47 However the tolerability profile of these classes may differ significantly. Third generation CCBs induce less peripheral oedema in hypertensive patients than second generation CCBs.47 Calcium channel blockers have similar efficacy in terms of blood pressure lowering effects. Calcium channel blockers differ in tolerability profiles. 17 6.1.1.3 Clinical guidelines for hypertension In the absence of clinical guidelines specific to Ireland, international guidelines for hypertension from the UK, Europe and America were reviewed, to establish if a particular CCB was preferred within the class. The results are shown in table 6. Table 6: Review of clinical guidelines for hypertension Review Body Guideline Year Recommendations Preferred CCB American College of Cardiology/America n Heart Association (ACC/AHA)49 An effective approach to high BP control 2014 HTN Stage 1: BP systolic 140-159 or diastolic 90-99. Lifestyle modifications and consider adding a thiazide. HTN Stage 2: BP systolic >160 or diastolic >100. Lifestyle modification &  thiazide and ACE inhibitor, ARB or CCB  or ACE inhibitor and CCB Not specified European Society of Cardiology and European Society of Hypertension (ESC/ESH)50 Guidelines for the management of arterial HTN 2013 CCB, diuretics, beta blockers, ACE inhibitors and ARBs are all suitable for initiation and maintenance of antihypertensive treatment. Not specified National Institute for Health and Care Excellence (NICE) and the British Hypertension Society21 HTN in adults- diagnosis and management 2011 CCB is used step 1 in management of HTN for >55yrs or black African/Caribbean of any age. CCB can be used second line in combination with an ACE or ARB. Use once daily dosing. Prescribe generically. Not specified Scottish Intercollegiate Guideline Network (SIGN)51 Guideline number 97- Risk estimation and the prevention of CVD 2007 CCBs are as effective as the other classes of antihypertensive agents. CCBs and thiazide diuretics are most clinically and cost effective choice in the majority of cases. Not specified CCB: Calcium channel blocker; ACE: Angiotensin converting enzyme; ARB: Angiotensin-II receptor blocker; HTN: Hypertension These guidelines all recommend that CCBs are used for the treatment of hypertension.21,49-51 However there are differences between guidelines in relation to the stage that these drugs are introduced in the hypertension treatment algorithm. The jointly issued guidance from the American College of Cardiology and the American Heart Foundation recommends that CCBs are used in the management of stage 2 hypertension.49 None of the guidelines differentiate between individual calcium channel blockers, assuming a class effect. The joint guidance issued by the European Society of Cardiology and the European Society of Hypertension, states that they are all equally suitable for initiation and maintenance of antihypertensive treatment.50 18 Northern Ireland has recently published a regional formulary to promote safe, clinically effective and cost effective prescribing of medicines.52 This formulary recommends amlodipine as first choice CCB in the treatment of hypertension.52 Other NHS trusts in the UK have also selected amlodipine as the first choice of calcium channel blocker, such as NHS Lothian, County Durham and Darlington NHS trust and the Dorset Cardiology working group on hypertension.53-55 6.1.2 Angina 6.1.2.1 Clinical efficacy of stable angina A literature search was carried out to identify the main clinical trials of CCBs used to treat stable angina. The following databases were used: EMBASE (1947-2016), MEDLINE (1946-2016) and CINAHL (1937-2016). Trials examined are outlined in table 7, this list is not exhaustive but represents a number of the most significant trials of CCBs for stable angina. Lercanidipine and nilvadipine are not currently licensed to treat stable angina in Ireland (see table 2).18,20 The majority of direct drug comparisons in stable angina trials involve calcium channel blockers with beta blockers.56 AMLODIPINE is among the calcium channel blockers recommended for treating hypertension in a number of international clinical guidelines. AMLODIPINE is the recommended calcium channel blocker in a number of NHS regional formularies. 21 Felodipine There are fewer trials to provide evidence of efficacy of felodipine in the treatment of stable angina. A small early trial by Metcalfe et al. (1989) showed that felodipine had antianginal effects, however the significance of this effect was found to reduce at 4 weeks treatment.63 The larger TRAFFIC trial (1999) demonstrated that felodipine was an effective antianginal drug.65 It was found to be significantly better than metoprolol when used as monotherapy (p=0.03), and also significantly better in combination with metoprolol compared to metoprolol monotherapy (p=0.04).65 6.1.2.2 Systematic reviews of stable angina Relevant meta-analyses and reviews for the treatment of stable angina with CCBs were also considered in the review process. A selection of relevant studies are included in table 8 below: Table 8: Meta-analyses and reviews of CCBs in stable angina Meta-analysis/Review Year Reviewed drugs Conclusions Treatment of stable angina66 2007 Beta blockers CCBs Nitrates Symptoms of chronic stable angina can usually be managed with optimum doses of CCB, beta blocker or long-acting nitrate, alone or in combination Current status of safety and efficacy of CCBs in cardiovascular diseases: A critical analysis 100 studies67 2000 CCBs Evidence based on RCTs suggest equivalent safety of CCBs (other than short-acting nifedipine) and beta blockers in stable angina Meta-analysis of trials comparing beta blockers, CCBs, and nitrates for stable angina 90 studies56 1999 Beta blockers CCBs Long-acting nitrates RCTs of stable angina show that beta blockers provide similar clinical outcomes and fewer adverse effects than CCBs CCB: Calcium channel blocker The most significant meta-analysis of CCBs was carried out by Heidenreich et al. (1999).56 This analysed 90 studies, comparing the relative tolerability and efficacy of all classes of CCBs with beta blockers and nitrates in the treatment of stable angina. There was no significant difference found with angina episodes, nitroglycerin use and exercise time between CCBs and beta blockers.56 When DHP CCBs were compared to beta blockers separately there were fewer adverse events (odds ratio, 0.63) and angina episodes per week (odds ratio, 0.61) with beta blockers than CCBs.56 In this meta- analysis nifedipine accounted for 79% of all the DHPs analysed therefore it is difficult to demonstrate if the increase in adverse events is a class effect.56 The meta-analysis concluded that 22 as beta blockers were better tolerated than CCBs, they should be considered first line in stable angina.56 A critical analysis of the safety and efficacy of all CCBs in cardiovascular diseases by Opie at al. (2000) showed that there was a lack of large RCTs comparing CCBs to beta blockers in stable angina.67 From the evidence available from RCTs, beta blockers and CCBs are thought to have equivalent safety and efficacy in stable angina.67 The review concluded that more RCTs with open label follow up and prospective observational studies are required on CCB safety.67 A review of the treatment of stable angina by Ben-Dor and Battler (2007) stated that the three major classes of anti-ischaemia drugs: CCBs, beta blockers and nitrates; have been shown to decrease the frequency of angina and prolong the duration of exercise before the onset of angina.66 Head-to-head comparative trials have failed to demonstrate greater antianginal efficacy for any one class of drugs over another. No observed differences have been found between rates of cardiac death or MI between beta blockers and CCBs.66 6.1.2.3 Clinical guidelines for stable angina International guidelines for stable angina from the UK, Europe and America were reviewed, to establish if a particular CCB was preferred within the class. International guidelines included rate- limiting CCBs (verapamil and diltiazem), which are beyond the scope of this document. The results are shown in table 9. Calcium channel blockers reviewed have similar efficacy in treating stable angina. Calcium channel blockers and/or beta blockers can be used to treat stable angina. 23 Table 9: Review of clinical guidelines for stable angina Review Body Guideline Year Recommendations Preferred CCB European Society of Cardiology (ESC)68 Guidelines on the management of stable coronary artery disease 2013 First line: CCB or beta blocker to control heart rate and symptoms Not specified National Institute for Health and Care Excellence (NICE)69 Stable angina management (CG126) 2011 First line: CCB or beta blocker Not specified Scottish Intercollegiate Guideline Network (SIGN)70 Guideline number 96- Management of stable angina 2007 First line: Beta blocker Add CCB to beta blocker if symptom control not achieved. Use rate-limiting CCB (verapamil or diltiazem), long acting nitrate or nicorandil if intolerant to beta blocker. DHP CCB if added to beta blocker. Amlodipine or felodipine if coexisting heart failure. American college of cardiology/ American heart association (ACC/AHA)71 Guidelines for the management of patients with chronic stable angina 2002 (updated 2007) Beta-blocker should be used, substitute with a CCB if contraindicated or add in CCB. Not specified The ESC and NICE guidelines recommend that either a beta blocker or CCB could be used first line in the treatment of stable angina.68,69 The SIGN and joint ACC/AHA guidelines both recommend that a beta blocker is used first line and a CCB added if symptom control is not achieved.70,71 These guidelines also recommend that if there is intolerance to a beta blocker it can be substituted with a CCB.70,71 The SIGN guideline states that rate-limiting CCBs (verapamil or diltiazem) can be used alone as an alternative to a beta blocker, however if a CCB is added to a beta blocker then the DHP CCBs are more suitable.70 There is no specific CCB chosen by the ESC, NICE or the ACC/AHA guidelines.68,69,71 Amlodipine and felodipine are the most appropriate CCBs for addition to beta blocker therapy in heart failure.70 The Northern Irish formulary and the NHS Lothian formulary recommend amlodipine for patients with angina, who are already taking a beta blocker and diltiazem for patients who cannot tolerate a beta blocker.52,53 Calcium channel blockers or beta blockers are recommended for the treatment of stable angina in international clinical guidelines. Amlodipine is the CCB of choice if added to a beta blocker to treat stable angina. 26 oedema (13.6%), headache (5.8%), flushing (3.9%) and rash (2%).77 Switching these patients to lercanidipine showed significant reductions in these adverse effects (p<0.001).77 Table 13: Common/very common adverse drug reactions of calcium channel blockers15-20 Adverse Drug Reaction Amlodipine Nifedipine Felodipine Nilvadipine Lercanidipine Dizziness   Flushing    Headache     Peripheral Oedema     Vasodilation  Palpitations  Dyspnoea  GI Disturbance, altered bowel habit  Constipation  Malaise  Visual disturbance  Muscle cramps  Fatigue/asthenia  Somnolence   common adverse-effect;  very common adverse-effect Peripheral oedema Oedema is an accumulation of fluid in the interstitial space which occurs as the capillary filtration exceeds the limits of lymphatic drainage.78 Peripheral oedema refers to fluid accumulation in a limb or limbs, most commonly lower.79 There are many different causes of peripheral oedema such as: allergic reaction, cardiac disease, cellulitis, DVT and lymphedema.78 Peripheral oedema is also an adverse effect of certain medications including CCBs.78 The exact mechanism that causes peripheral oedema in DHP CCBs is unclear, it is not linked to systemic retention of fluid and does not respond to diuretics.6 It is thought to be due to an increase in intracapillary hydrostatic pressure which causes an increase in fluid filtration from the vascular to the interstitial compartment.33 Theories to explain the less frequent occurrence of peripheral oedema with the third generation lipophilic CCBs include; that there is less sympathetic activation and therefore less difference between arteriolar and venular dilation, or that there is less effect on vascular permeability and therefore fluid extravastation.5,31,33 Although peripheral oedema is not life-threatening it can cause distress to the patient and lead to decreased compliance.76 The incidence of peripheral oedema with the DHP CCBs has been 27 investigated in a meta-analysis of one hundred and six studies by Makani et al. (2011).42 This analysis found that the incidence of peripheral oedema was significantly higher (12.3%, p<0.00001) with DHPs, than non DHP CCBs (3.1%).42 Only 2.4% of patients on DHP CCBs withdrew from treatment due to this ADR.42 Patients who experience ADRs but are well controlled with a DHP CCB, may benefit from changing to a lipophilic DHP CCB, such as lercanidipine.5 6.5 Drug interactions The DHP CCBs exhibit a class effect as substrates for the cytochrome P450 isoenzyme CYP3A4. Concomitant use of CCBs and drugs which induce or inhibit this isoenzyme should either be avoided, or the drug taken with caution and appropriate monitoring.2 Examples of common drugs which induce or inhibit CYP3A4 are listed in table 14.80 Drugs which are enzyme inhibitors have the potential to reduce the metabolism of CCBs, causing accumulation in the body. Conversely drugs which act as enzyme inducers have the potential to increase metabolism of CCBs, reducing levels of the drug in the body.80 Table 14: Drugs which are known to induce or inhibit CYP3A480* Inhibitors Inducers Cimetidine Carbamazepine Clarithromycin Phenobarbital Diltiazem Rifampicin Erythromycin Phenytoin Fluconazole St Johns Wort Itraconazole Ketoconazole Ritonavir Verapamil Grapefruit Juice *this list is not exhaustive and is intended to serve as an example only The DHP CCBs also exhibit drug interactions which are not related to cytochrome P450. The most significant are summarised, a complete list of CCB drug interactions is available in the individual SmPCs and in the British National Formulary (BNF).2, 15-20 Peripheral oedema is an adverse effect of dihydropyridine calcium channel blockers, it does not respond to diuretics. Lercanidipine may be used as an alternative in patients with this adverse-effect. 28 Beta-blockers: There is an enhanced hypotensive effect when CCBs are given with beta-blockers, therefore care should be taken when they are used together. Nifedipine may cause severe hypotension and heart failure when administered with a beta-blocker, this combination should be avoided.2,15,16 Alpha-blockers: There is an enhanced hypotensive effect when CCBs are administered with alpha- blockers. These drugs should only be used together with caution.2 Aminophylline/theophylline: CCBs may increase the plasma concentration of aminophylline and theophylline. Patients should be monitored for signs of aminophylline/theophylline toxicity including headache, nausea and tremor and the dose adjusted accordingly.2, 15-20 Tacrolimus: The concentration of tacrolimus is increased with amlodipine, felodipine and nifedipine, there is limited evidence with nilvadipine but it is predicted to act similarly. Tacrolimus blood levels should be monitored and the dose adjusted as required.2, 77 Ciclosporin: The levels of ciclosporin should be monitored when co-administered with CCBs. Nilvadipine can cause an increase in ciclosporin levels, conversely the concentration of nifedipine can be increased when administered with ciclosporin.15,16,18 When lercanidipine is co-administered with ciclosporin the levels of both drugs can be increased, this combination should be avoided.20 Simvastatin: There is an increased risk of myopathy when high dose simvastatin is co-administered with amlodipine. When amlodipine 10mg was administered with simvastatin 80mg there was a 77% increase in simvastatin levels. Therefore it is advised that amlodipine patients are limited to a dose of 20mg simvastatin.19 In clinical practice simvastatin 80mg is only recommended in patients with severe hypercholesterolemia and high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks.81 Digoxin: Levels of digoxin should be monitored when administered with lercanidipine, nifedipine and nilvadipine, due to the potential increase in plasma concentration of digoxin.15,16,18,20 31 7. Summary AMLODIPINE is the preferred calcium channel blocker for the treatment of hypertension and stable angina under MMP guidance.  Amlodipine is licensed to treat both hypertension and stable angina  Amlodipine has similar efficacy to other CCBs in terms of reducing blood pressure and treating stable angina  Amlodipine is among CCBs recommended to treat hypertension in international guidelines  CCBs or beta blockers are recommended first line to treat stable angina in international clinical guidelines  Amlodipine is the CCB of choice for hypertension in NHS regional formularies  Amlodipine is the CCB of choice, in addition to a beta blocker, for stable angina in NHS regional formularies  Amlodipine has once daily dosing  Amlodipine has the lowest acquisition cost  Amlodipine currently holds 63% of the market share in Ireland  Lercanidipine may be used as an alternative in patients who develop the adverse drug reaction of peripheral oedema 32 8. References 1. Dolphin A. 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