Cardiovasc Drugs Ther DOI 10.1007/s10557-016-6682-1

ORIGINAL ARTICLE

Beta-Blockers and Calcium Channel Blockers: First Line Agents Isaac Pascual 1 & Cesar Moris 1 & Pablo Avanzas 1

# Springer Science+Business Media New York 2016

Abstract Beta-blockers and calcium channel blockers (CCB) are milestones in the treatment of stable coronary ischaemic disease. Their main effects are particularly suited for the management of effort-induced angina because of the reduction of oxygen demand they achieve. The clinical benefits of these drugs are highly reproducible and have been shown to improve overall clinical outcomes. Despite the availability of other, and newer antianginal drugs, treatment guidelines continue to recommend the use of beta-blockers and calcium channel blockers as first line therapies.

Keywords Angina . Treatment . Beta receptor . Calcium channel blockers . Beta blockers

Introduction Beta-blockers and calcium channel blockers (CCB) are milestones in the treatment of stable ischaemic heart disease. Their main effects are particularly suited for the management of effort-induced angina because of the reduction of oxygen demand they achieve. The clinical benefits of these drugs are highly reproducible and the association of both drugs improve global clinical outcome. Despite the availability of other and newer antianginal drugs, treatment guidelines continue

* Pablo Avanzas [email protected] 1

Área del Corazón, Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011 Oviedo, Asturias, Spain

recommending the use of beta-blockers and calcium channel blockers as first line therapies.

Beta-Blockers The Beta-adrenergic Receptor β-Adrenergic receptors belong to a group of transmembrane protein receptors called G-protein coupled receptors. The β receptors are composed of 3 parts, an extracellular part (which contains the ligand-binding sites), 7 trans-membrane alpha helical segments, and an intracellular part that is coupled to the G-protein complex [1]. There are at least three types of β receptors: β1, β2 and β3 [2–4]. - β1 adrenoreceptors are found primarily in heart muscle. Activation of these receptors results in increased heart rate, contractility, and atrioventricular (AV) conduction, and decreased AV node refractoriness. β1 Receptors are also located in the kidneys. Their activation inhibits the release of renin from juxtaglomerular cells, and thereby reduces the activity of the renine-angiotensin-aldosterone system. - β2 adrenoreceptors are more prominent in bronchial, peripheral vascular smooth muscle, gastrointestinal tract, uterus and skeletal muscle. Activation of these receptors results in vasodilatation and bronchodilatation. - β3 adrenoreceptors are located in adipose tissue and also in the heart. Their activation may mediate catecholamine induced thermogenesis and may reduce cardiac contractility. β–Blockers competitively bind to G-protein and coupled β-receptors inhibiting the effects of adrenaline and noradrenaline in these receptors. In the cardiac muscle tissue, where β1 receptors are more common, this effect causes a decrease in the c-AMP synthesis and protein-kinase-A activity. It results

Cardiovasc Drugs Ther

in inhibition of the L-type calcium channels, sarcoplasmic reticular calcium/ATPase inhibitory protein and troponin-I, and finally, in negative inotropic and chronotropic effects.

selective β1-antagonist and a β3-agonist, with nitric oxidemediated vasodilatory action [10]. Pharmacokinetics

Pharmacodymamics β-Blockers have different pharmacologic characteristics depending on each individual agent, such as 1) cardio-selectivity, 2) intrinsic sympathomimetic activity, 3) membranestabilising activity and 4) vasodilator activity. β1-Selectivity Cardio-selective β-Blockers are those with predominant β1-adrenoreceptors blocking activity. When used in low doses, β1-selective blocking drugs inhibit cardiac β1-receptors but have less influence on β2-receptors in bronchial and vascular locations. However, given in higher doses the β1-selective agents also block β2-receptors. These selective blockers also allow the vasodilator effect of β 2 adrenoreceptors and thus are relatively safe in patients with peripheral vascular disease. β1-Cardioselective agents are preferred in the treatment of chronic angina [3, 5]. Intrinsic sympathomimetic activity (partial agonist activity) Some β-blockers have intrinsic sympathomimetic activity, also called partial agonist activity. This manifests as a betastimulant effect when background adrenergic activity is low (e.g. during sleep) but β blockade occurs when adrenergic activity is increased (e.g. during exercise). The principal agents with intrinsic sympathomimetic activity are acebutolol, celiprolol, xamoterol, bucindolol, and pindolol. Membrane-stabilising activity The membrane-stabilising activity is a quality that confers anti-arrhythmic and local anaesthetic effects to some βblockers. Carvedilol, metoprolol and propranolol exhibit a class 1 antiarrhythmic effect (blockade of sodium channels), whereas sotalol has a class 3 antiarrhythmic effect (potassiumchannel blockade) [6, 7]. Vasodilator Activity The vasodilator activity is a quality that allows some βblockers to achieve variations in vascular tone by two different mechanisms [8]. Labetalol and carvedilol are β-blocking agents that have antagonistic effects at both α- and βadrenoceptors. Carvedilol, due to its α-blockade activity, has other properties like NO production, enhancement of peripheral microcirculation and free radical scavenging [9]. The second mechanism is a direct vasodilator activity. Nebivolol is a

In relation to their pharmacokinetics, β-blockers can be classified into two categories: lipophilic and hydrophilic. Agents with high lipid solubility have a short half-life (Table 1). They are completely absorbed in the gastrointestinal tract, metabolised by the liver (cytochrome P450 monooxygenase) and readily cross the blood–brain barrier. By contrast, the hydrophilic β blockers have a longer half-life and are incompletely absorbed through the gastrointestinal tract, excreted by kidneys and penetrate the brain less easily (causing less central side-effects). Adverse Events β-blockers are generally well tolerated in patients with stable angina but, like most pharmacological agents, they are not exempt from side effects, which can at times be severe. These effects usually manifest when high doses are used (Table 2). Cardiovascular The adverse cardiovascular effects of β blockade result from their mechanism of action, with decreases in heart rate, contractility, and atrioventricular (AV) node conduction. These effects are seen mainly in patients with impaired sinus node function and some degree of AVnode conduction impairment. The increased peripheral vascular resistance, induced by non-selective agents, can cause or worsen symptoms of peripheral artery disease i.e. claudication [11]. Pulmonary Bronchoconstriction, due to β2 receptor blockade, can be induced by nonselective agents and high doses of cardioselective agents. As a result, many clinicians have assumed that chronic obstructive pulmonary disease (COPD) or asthma is a contraindication to beta blocker therapy. However, β-blockers are safe and effective in patients with mild COPD/asthma who are not taking a β2 adrenergic agonist. Other Adverse Events Central effects (e.g. headache, depression, sleep disturbances, insomnia and vivid dreams), which are less common with hydrophilic drugs, may appear after treatment with β-blockers [12]. Some male patients treated with β-blockers may suffer worsening of erectile dysfunction and loss of libido. β-Blockers may cause a slight increase in body weight and can worsen mild hypoglycemia, hyperglycemia, and hyperlipidemia [13, 14]. Abrupt discontinuation of β-blockers after chronic treatment can lead to rebound symptoms (i.e., hypertension, arrhythmias, exacerbated angina).

Cardiovasc Drugs Ther Table 1

Main characteristics of most common used oral β-blockers

Blockade Medium life (h) Lipid solubility Elimination Range of doses

Metoprolol

Propranolol

Atenolol

Bisoprolol

Carvedilol

Nevibolol

β1 3–7 High Liver Tartate: 50-100 mg/12 h Succinate: 50–400 mg/24 h

β1/β2 4–6, Retard: 8–11 High Liver 40–120 mg/8-12 h Retard: 80–160 mg/24 h

β1 6–9 Low Kidney 50–100 mg/24 h

β1 7–5 Moderate Liver 50 % Kidney 50 % 5–20 mg/24 h

β1/β2/α1 6–10 Moderate Liver 3.125–50 mg/24 h

β1 12–19 Low Liver 5–40 mg

Risk of rebound symptoms is related to upregulation of beta-receptors during chronic treatment. Clinical Efficacy in Chronic Stable Angina The principal aims in the treatment of patients with chronic stable angina are to reduce symptoms, with the consequent improvement of the quality of life, and to prevent adverse events. β-blockers are first line agents in the control of symptoms in patients with chronic stable angina. Angina is the clinical manifestation of myocardial ischaemia, which is due to an imbalance between myocardial metabolic demand and oxygen supply. β-Blockers improve symptoms in patients with angina by the reduction of the ischaemia. The main mechanism whereby β-blockers reduce ischaemia is the reduction of myocardial oxygen demand by lowering heart rate and myocardial wall stress and contractility. β-Blockers produce an overall reduction of the heart rate at rest and during exercise, nodal and atrioventricular conduction, and they also reduce myocardial contractility. These effects result in a decrease of myocardial oxygen demand by counteracting β receptor activity and contribute to a reduction in angina onset. The overall reduction in heart rate increases diastolic time, prolongs the coronary filling time and subendocardial perfusion, and decreases coronary shear stress and wall tension, improving ischemia in stable coronary artery disease patients [15]. β-Blockers reduce blood pressure

Table 2 Mayor side effects and contraindications of non-selective β-blockers

mainly in relation with their cardiac effects but also to their effect on the activity of the renin-angiotensinealdosterone system. Long-term reductions in blood pressure have been shown in patients with renin forms of hypertension, suggesting the effect on the β1 receptor. Finally, another proposed action of long-term βblockers use is an anti-inflammatory effect. Jenkins et al. documented significant lower levels of Creactive protein in β-blocker treated patients compared to controls [16]. Sir James Black discovered the first β-blocker, propranolol, in 1964 [17]. Earliest clinical trials demonstrating the efficacy and dose dependent effect of propranolol in stable angina included those by Hamer [18] and Warren et al. [19]. Hamer et al. studied the effect of propranolol in 20 patients with angina pectoris by comparing exercise tolerance on a bicycle ergometer before and after intravenous injection of the drug [18]. They observed that the number of patients with severe limiting angina decreased with propranolol injection. The authors concluded that propranolol could be helpful in angina pectoris [18]. The study by Warren et al. included sixty-three propranolol treated patients with stable, severe typical angina pectoris (New York Heart Association functional class III or IV) that were prospectively followed up for 5 to 8 years. They assessed long-term effectiveness and the rate of complications [19]. In this long-term therapy study, propanolol was effective for severe angina pectoris and it did not increase the overall mortality rate, although an increased risk of cardiogenic shock was observed in acute

Mayor side effects

Contraindications

- Fatigue - Mild depression - Sleep disturbances with nightmares - Impotence - Peripheral vasoconstriction - Bronchospasm - Postural hypotension - Blunt hypoglycaemia in diabetes - Block of atrioventricular conduction

- Severe bradycardia - Atrioventricular conduction disorder - Asthma - Chronic obstructive pulmonary disease (caution) - Decompensated heart failure - Cardiogenic shock - Severe peripheral vascular disease - Vasospastic angina

Cardiovasc Drugs Ther

myocardial infarction patients. Hernández-Cañero et al. studied the effect of atenolol in 11 patients with exertion-induced angina in a double-bind trial [20]. The drug significantly reduced heart rate and blood pressure. As a result, ST segment depression was also diminished after treatment. The authors concluded that atenolol was useful in the prevention of angina pectoris, particularly in patients in whom there is associated arterial hypertension. Multiple comparisons were performed between different types of β-blockers in order to evaluate possible differences in their efficacy, however no clear differences have been identified [21–24].

β-Blockers vs Placebo Subsequent clinical trials were performed to evaluate the effect of β-blockers in comparison with placebo, which demonstrated improvement of symptoms, increased threshold of angina onset and the better exercise tolerance. In the 80’s Kaski et al. demonstrated that a single oral dose (25 mg) of carvedilol was effective in preventing the occurrence of exerciseinduced angina in 15 patients with stable exertional angina, positive exercise test responses (greater than or equal to 1 mm of ST depression) and coronary artery disease [25]. One of the most influential trials was the Atenolol Silent Ischaemia Study (ASIST) trial [26]. This was a multicenter, randomized, double-blind, placebo-controlled study of asymptomatic or minimally symptomatic outpatients with daily life silent ischemia due to coronary artery disease. ASIST included 306 outpatients with inducible ischaemia who were randomized to receive atenolol 100 mg/day or placebo. The primary outcome measure was event-free survival at 1 year. Atenolol reduced daily life ischemia and was associated with reduced risk for adverse outcome. β-Blockers have also been tested in patients with stable angina and prior myocardial infarction. The Beta-Blocker Pooling Project was designed to collect and analyse data from the major long-term secondary prevention trials in order to identify subgroups of patients who would most benefit from beta-blocker therapy post-myocardial infarction. [27]. Oneyear all-cause mortality data from nine trials were obtained. Overall, mortality was 24 % lower in the beta-blocker group compared to the placebo group. Trials tested seven different β-blockers, so results were heterogeneous. Subgroups with the highest mortality were patients with a history of previous myocardial infarction, angina pectoris, mechanical or electrical complications, and digitalis usage. These subgroups seemed to benefit particularly from beta-blocker treatment. Lower risk subgroups also appeared to benefit from betablockers, but this benefit was smaller in absolute terms. The Beta-Blocker Pooling Project indicates that high risk MI patients, without contraindications to β-blockers, are the prime

candidates for long-term therapy, but lower risk patients may also receive some benefit [27]. β-Blockers vs Other Antianginal Drugs Major trials comparing β-blockers to CCBs in stable ischemic heart disease include the TIBET [28] and APSIS [29] trials. TIBET was a randomized double-blind parallel group study of atenolol, nifedipine and their combination, which included 682 patients with a diagnosis of chronic stable angina who were not being considered for surgery [28]. The main aim of the trial was to study the relationship between presence or absence of ischaemic events on Holter monitoring and occurrence of a hard endpoint, or combination of hard and soft endpoints. Hard endpoints evaluated were cardiac death, nonfatal myocardial infarction and unstable angina. Soft endpoints included coronary artery bypass surgery, coronary angioplasty and treatment failure. There was ambulatory monitoring before treatment and after 6 weeks of randomized treatment. The study had a prospective follow-up of 2 years. The study showed no association between the presence, frequency or total duration of ischaemic events on Holter monitoring, either on or off treatment, and the main outcome measures. There was a non-significant trend towards a lower rate of hard endpoints (cardiac death, nonfatal myocardial infarction and unstable angina) in the group receiving combination therapy. The APSIS study was a randomized, double-blind, doubledummy trial, designed to study long-term treatment effects of metoprolol or verapamil on combined cardiovascular endpoints and psychological variables in patients with stable angina pectoris [29]. Death and non-fatal cardiovascular events including acute myocardial infarction, incapacitating or unstable angina, cerebrovascular or peripheral vascular events did not significantly differ between both groups. Psychosomatic symptoms and sleep disturbances were significantly improved in both treatment groups, but the magnitudes of change were small and did not differ between treatments. This long-term study indicates that both drugs were well tolerated and that no difference was shown between their effect on mortality, cardiovascular end points and measures of quality of life [29]. Heidenreich et al. conducted a meta-analysis to evaluate which drug was the most effective as the first-line agent for the treatment of stable angina patients [30]. The main objective was to compare the relative efficacy and tolerability of treatment with β-blockers, CCBs and nitrates in patients who had stable angina. There were no significant differences in the rates of cardiac death and myocardial infarction with βblockers compared to CCB treatment (OR, 0.97; 95 % CI 0.67–1.38; p = 0.79). There were fewer episodes of angina per week with β-blockers than with calcium antagonists. The main conclusion was that in randomized trials of patients who

Cardiovasc Drugs Ther

have stable angina, β-blockers provide similar clinical outcomes and were associated with fewer adverse events compared to CCBs. Combination Therapy Real life treatments are often composed of different combinations of several antianginal agents in different scenarios, including patients with or without previous revascularization. Early studies in the 60’s and the 70’s showed a synergistic effect of β-blockers with nitrates, with increase in exercise tolerance and decrease of number of angina attacks [31]. Nowadays, combination therapy with β-blockers and CCBs are often used to control symptoms. A recent meta-analysis also evaluated combinations of several antianginal drugs [32]. Randomised controlled trials comparing the efficacy of antianginal therapies in patients with stable angina refractory to first-line therapy were identified (46 qualifying studies), evaluating 71 treatment comparisons. Exercise tolerance testing data and clinical outcomes were extracted and combined in a series of meta-analyses. The combination of ranolazine added to CCBs or β blockers showed positive outcomes across all outcomes assessed. Other combinations of β blockers, CCBs, long acting nitrates and trimetazidine showed significant benefits for most but not all outcomes. Ivabradine demonstrated benefits for exercise tolerance testing but these were not matched in clinical domains. No qualifying studies were identified for nicorandil in an add-on role [32].

amlodipine). The phenylalkylamine class of CCBs (e.g. verapamil) mainly acts on cardiac cells, and has negative inotropic and negative chronotropic effects. The benzothiazepine class of CCBs (e.g. diltiazem) combines effects of the previous two classes [34]. Phenylalkylamine and benzothiazepine CCB classes are often classified as Non DHPs. Dihydropyridines DPHs bind to the N-binding site of the calcium channel and their main actions are conducted by blocking calcium channels in a dose-dependent fashion [33, 34]. There are three drug generations. Nifedipine is the key agent of the first generation. Second generation agents are lercanidipine and felodipine and, finally, amlodipine is considered a third generation dihydropyridine (Table 3). DHPs main mechanism of action is due to their selectivity for vascular smooth muscle, resulting in a higher vasodilatory power than other CCBs. These drugs vasodilate coronary arteries, reduce coronary resistance, increase coronary blood flow, and may enhance the development of coronary collaterals [35]. In relation to their vasodilatory effect, DHPs can cause hypotension leading to reflex tachycardia, which can be detrimental for patients with ischemic symptoms because of the increase in myocardial oxygen demand [35, 36]. The side effects of these drugs may include, but are not limited to dizziness, headache, facies rubra, legs and ankle swelling, constipation or gingival overgrowth (Table 4). Non-dihydropyridines

Calcium-Channel Blockers CCBs are a heterogeneous group of drugs used in different cardiovascular disorders such as angina pectoris, hypertension, hypertrophic cardiomyopathy and supraventricular arrhythmias. They were first described in the 1960s by Albrecht Fleckenstein. Mechanism of Action The pharmacological mechanism of action lies in the blockage of calcium flow through calcium channels that are embedded in the membrane of many cells including vascular smooth muscle cells and cardiomyocytes. These drugs induce a common inhibition of the L-type calcium channels but are a heterogenic group of drugs with different binding sites on the calcium channel pores and different selectivity for the Ltype calcium channels in the vasculature and myocardium [32, 33]. Three classes of CCBs have been described with different properties. The class of CCBs known as dihydropyridines (DHPs) mainly affects arterial vascular smooth muscle cells to lower blood pressure by causing vasodilation (e.g.

The non DHPs group is composed by phenilalkylamines and benzothiazepines. Phenylalkylamine CCBs (e. g. verapamil) bind to the V-binding site of the calcium channel and reduce myocardial oxygen demand by their negative inotropic and chronotropic effects. Compared to DHPs, verapamil exhibits minimal vasodilatory effects, therefore causes less reflex tachycardia [6]. Benzothiazepine calcium channel blockers (e.g. diltiazem) belong to the benzothiazepine class of compounds. Diltiazem has actions that fall between DHPs and verapamil. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by DHPs [34]. Clinical Efficacy in Chronic Stable Angina Several studies have demonstrated the effectiveness of CCBs in patients with angina, both classic angina pectoris and the less frequent vasospastic, or variant angina (Prinzmetal’s angina) [37–39]. These drugs do not modify the progression of stable coronary artery disease; however, they prolong the time to the onset of angina during exercise, decrease the

Cardiovasc Drugs Ther Table 3 Classes of CCBs and maximum doses

Dihydropyridines

First generation

Nifedipine (Up to 60 mg/24 h)

Second generation

Lercanidipine (Up to 20 mg/24 h) Felodipine (Up to 10 mg/24 h)

Phenilalkylamines

Third generation Verapamil (Up to 480 mg/24 h)

Benzothiazepines

Diltiazem (Up to 360 mg/24 h)

frequency of episodes of angina, or the use of nitroglycerin [40–42]. Although CCBs are effective as monotherapy for angina, combined treatment with a calcium antagonist, a nitrate, and a beta-blocker can have an additive effect [43]. Dihydropyridines A number of studies have demonstrated the effectiveness of DHPs in the treatment of patients with chronic stable angina. The International Multicenter Angina Exercise (IMAGE) trial was designed to investigate whether combination therapy with metoprolol and nifedipine provides a greater anti-ischemic effect than monotherapy in patients with stable angina pectoris [44]. In this study, both metoprolol and nifedipine increased the mean exercise time to 1-mm ST segment depression; though metoprolol was more effective than nifedipine. In the follow up, the groups randomized to combination therapy had a further increase in time to 1-mm ST segment depression. The ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) trial aimed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris. This randomized study assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine (60 mg once daily) or placebo [45]. The authors observed that the addition of nifedipine to conventional treatment of angina pectoris had no effect on major cardiovascular event-free survival. Nifedipine was found safe and reduced the need for coronary angiography and interventions. Multiple randomized, double-blind, placebo-controlled studies with amlodipine have also shown the effectiveness of this drug in a large number of patients with stable Table 4

Amlodipine (Up to 10 mg/24 h)

exercise-induced angina pectoris. Amlodipine decreased the number of angina attacks, reduced the consumption of nitroglycerin and increased exercise capacity [46]. The Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study investigated the effect of enalapril and amlodipine on cardiovascular events in patients with coronary artery disease and normal blood pressure. This randomized controlled trial demonstrated a significant reduction of cardiovascular events after 24 months follow up in patients treated with amlodipine [47]. In the same study, amlodipine also showed evidence of slowing of atherosclerosis progression, assessed by intracoronary ultrasound. Non Dihydropyridines The earliest double-blind, placebo-controlled trials demonstrated that verapamil (360–480 mg/day) reduces the number of angina attacks, increases exercise duration and decreases the consumption of nitroglycerin tablets in patients with chronic stable angina. Verapamil has been shown to be safe and an effective alternative to β-blockers. Compared to propranolol [48] and metoprolol [29], it has demonstrated equal efficacy in preventing anginal attacks and in prolonging exercise duration. The International Verapamil-Trandolapril Study (INVEST) study compared mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy (including verapamil) or a non–calcium antagonist strategy (including atenolol). The authors concluded that both strategies were clinically effective, without differences [49, 50]. Outcome studies comparing diltiazem and verapamil are currently not available.

Mayor side effects, contraindications and drug interactions of CCB

Calcium channel blocker

Major side effects

Contraindications

Drug interactions

DHPs

- Reflex Tachycardia - Headache - Fatigue - Flushing - Ankle swelling - Bradycardia - Cardiac conduction defect - Low ejection fraction - Gingival hyperplasia - Constipation

- Severe aortic stenosis - Cardiogenic shock - Obstructive cardiomiopathy

- CYP3A4 substrates

- Heart rhythm disorder - Sick sinus syndrome - Congestive heart failure - Low blood pressure

- CYP3A4 substrates - Cardiodepressant (such as β-blockers and flecainide)

Non DHPs

DHPs Dihydropyridines, Non DHPs Non Dihydropyridines

Cardiovasc Drugs Ther

Several randomized trials have shown the clinical efficacy of diltiazem in patients with chronic stable angina. Hossack et al. [51] compared the drug with placebo in patients with exercise-induced angina. Patients treated with diltiazem increased exercise performance, time to onset of angina and time to appearance of 1 mm S-T segment depression. Strauss et al. [52] evaluated the efficacy of diltiazem versus placebo with respect to rate of attacks of angina, nitroglycerin consumption and duration of treadmill exercise, showing similar results in favour of diltiazem. Due to its favorable side-effect profile, diltiazem has advantages, compared with verapamil, in the treatment of exercise induced angina pectoris. As mentioned above, diltiazem combines the properties of verapamil and DHPs (i.e. negative inotropic effect and peripheral vasodilation). Diltiazem should not be used in combination with a ß-blocker, and is also not recommended in patients with coronary artery disease and impaired left ventricular function [34].

Combination Therapy of Calcium Channel Blockers with Beta Blockers Controlled, double-blind clinical trials have demonstrated that combinations of a CCB and a ß-blocker result in improved symptomatic benefit compared with either drug class alone. In a recent meta-analysis by Belsey et al., the safety and efficacy of this association was broadly confirmed, across a range of commonly assessed exercise and clinical outcomes [32]. Verapamil and diltiazem in combination with a ß-blocker appear to have the greatest therapeutic efficacy, but also the highest frequency of harmful adverse cardiac effects [53], therefore these combinations are not recommended [7]. The combination of nifedipine and a ß-blocker is generally safer, but less efficacious than the combination of a ß-blocker and other CCBs [54]. The IMAGE study, as previously described [44], compared long-acting preparations of nifedipine and metoprolol, given alone or in combination. Patients received monotherapy for 6 weeks and combination therapy for another 4 weeks. The mean increase in exercise time to 1-mm ST segment depression increased from 37 seconds to 107 seconds with the addition of a second drug, vs. 49 seconds with placebo added. However, the anti-ischemic effect from the combination was primarily due to improvement in patients who had not responded to monotherapy rather than an additive effect of the two drugs. A true additive effect was seen in a minority of patients (14 % in whom nifedipine was added to metoprolol, and 24 % in whom metoprolol was added to nifedipine). Dunselman et al. [55] evaluated the efficacy of adding amlodipine to atenolol in 147 patients with angina and positive bicycle exercise tests despite optimal beta blockade (heart rate at rest