Major differences among the three classes of calcium antagonists

Transcription

1 European Heart Journal (1997) 18 {Supplement A), A56-A70 Major differences among the three classes of calcium antagonists R. Ferrari Chair of Cardiology, University of Brescia; Salvatore Maugeri Foundation, IRCCS, Cardiovascular Pathophysiology Research Center, Gussago, Brescia, Italy The safety of calcium antagonists has recently become a controversial issue among cardiologists. Thus, the role of calcium antagonists in the treatment of myocardial infarction and in secondary cardiovascular prevention is under review. As a consequence, the concept that the words 'calcium antagonists' comprise various drug classes has re-emerged. These differ in basic pharmacological properties, tissue selectivity, pharmacokinetics, and final haemodynamic effect. Obviously, such differences alter their therapeutic effect. Introduction As a class, calcium antagonists are among the most widely used drugs in the treatment of cardiovascular conditions. Regulatory authorities have approved their use in individuals with angina pectoris to relieve chest pain or with hypertension to lower blood pressure. Recently, however, the safety of calcium antagonists has been challenged. A case control study by Psaty et a/.' 1 ' and a new meta-analysis by Furberg et a/.' 21 of 16 randomized secondary-prevention trials with nifedipine initiated a vigorous debate, followed by several editorials in leading medical journals' 3 " 101. However, it is not the intention of this article to further this argument. This dispute has made it very clear that calcium antagonists are not all the same and that significant differences exist between the various subclasses of calcium antagonists' 3 " 101. The concept is not new' u " 13], but despite the abundant existing literature' 14 " 211, is often ignored and disregarded. In this article, some basic pharmacological properties of calcium antagonists relevant to their clinical action are considered briefly. These are then considered in relation to their haemodynamic effects and Correspondence: Prof. Roberto Ferrari, Chair of Cardiology, University of Brescia, Spedali Civili, P.le Spedali Civili, 1, Brescia, Italy. In this article, the major differences among the three classes of calcium antagonists, phenylalkylamines, dihydropyridines and benzothiazepines, are discussed and reviewed. A comparative analysis of available clinical trials focusing on the usefulness of each drug class is provided for the reader's interest. Some particularly relevant pathological conditions are considered: chronic stable angina pectoris, vasospastic angina, unstable angina pectoris with threatened myocardial infarction, myocardial infarction, and congestive heart failure. (Eur Heart J 1997; 18: (Suppl A): A56-A70) Key Words: Calcium antagonists, angina myocardial infarction, congestive heart failure. pectoris, the mechanisms of anti-ischaemic and related secondary preventive action in patients with coronary artery disease. Basic pharmacological properties The bulk of calcium channel antagonists currently approved for clinical use belong to three distinct chemical classes: the phenylalkylamines (e.g. verapamil), the dihydropyridines (e.g. nifedipine), and the benzothiazepines (e.g. diltiazem)' 221. Specific receptor sites for each major class have been identified in the L-type (long-lasting, large capacitance) voltage-dependent calcium channels. Different tissue selectivity for and between each chemical class has also been described' 231. Transient (T-) and long-lasting (L-) type calcium channel In the cardiovascular system there are two major types of calcium channel, the T-type and the L-type channels' 24 ' 251. The N-type and P-type channels are largely found in the nervous system. T-type channels are mainly located in the atria and contribute to the first phase of opening the calcium channel of the sinus atrial node during electrical depolarization. Thus these channels /97/0A S18.00/ The European Society of Cardiology

2 The three classes of calcium antagonists A57 regulate the initiation of the heartbeat and their blockade results in a reduction of heart rate. Dihydropyridines do not interact with T-type channels, whereas verapamil and diltiazem probably do. Whether or not such action is involved in the electrophysiological properties of verapamil and diltiazem is not yet known. In the ventricles, the activity of T-type channels is low, except when left ventricular hypertrophy is present' 261. Interestingly, verapamil is the calcium antagonist of choice in hypertrophic cardiomyopathies, but whether T-type channel blockade plays a role is not yet known. L-type channels are responsible for the later phases of calcium channel opening at less negative voltages. They are mostly represented in the ventricles and effectively contribute to excitation-contraction coupling. Interestingly, calcium antagonists do not really block, but partially reduce calcium channel opening, thereby exerting an intrinsic negative inotropic effect which, in vivo, might be attenuated, masked or even overcome by a sympathetic reflex. Molecular biology of the L-type calcium channel In recent years, major advances have been made in understanding the L-type calcium channel and its interaction with calcium channel antagonists. The data support the view that the L-type calcium channel consists of five subunits termed a\, ai, /?, y and d [27 \ The use of photo-affinity labels in several laboratories showed that the receptors corresponding to each of the three major classes of calcium antagonists are all located on the ai-subunit. This is the largest calcium channel subunit (molecular weight 150 and 170 kda). It contains the calcium channel pores which allow the actual inflow of the calcium ions. The a l-subunit also contains phosphorylation sites. /?-adrenergic stimulation increases intracellular cyclic adenosine monophosphate levels which in turn, via protein kinase A, promote phosphorylation of the ai-subunit, making the channel more likely to be open. Through this and other intracellular phosphorylation processes at the level of the sarcoplasmic reticulum, catecholamines exert their positive chronotropic, dromotropic and inotropic effects. It is important to note that catecholamine-induced activation of the calcium channel occurs at the intracellular level. Cloning of the L-type calcium channel One developement has been the ability to clone the genes for the L-type calcium channel subunits [281. The a\- subunit cloned from several different tissues, including the heart, vascular smooth muscle and brain, is arranged in four repeating hydrophobic motifs (motifs I-IV). Each motif consists of six amino-acidic segments (S1-S6) that are very similar and that span the membrane. As the four motifs are folded in on themselves, each contributes structurally to form one functioning pore through which calcium ions are transported. This is the calcium channel' 291. The function of the other subunits is not yet clarified, although their role is suspected to modulate peak current and gating' 30 ' 311. For instance, the presence of the /?-subunit enhances the number of drug-receptor sites ten-fold [311. Binding sites for calcium antagonists From the clinical perspective, perhaps the most important issue is the modulation of the channel by drug binding. Although the binding sites for all the three classes of calcium antagonists are located on the a\- subunit, each class has its own particular binding site. For nifedipine and all dihydropyridines this is probably on the extracellular loop of the S6 segments. The site is present on three of the four transmembrane-spanning motifs (I, III and IV) [321. Relevant to the clinic is the fact that the dihydropyridine binding site is located on the external portion of the calcium channel and extends into the channel pore on the S6 side f33]. Amlodipine, a long-acting and long-lasting dihydropyridine-based calcium antagonist seems to have rather different binding characteristics Diltiazem's binding site on the al-subunit 1341 is possibly located on the S6 segment, but not in the extracellular loop. The site is probably allosterically linked to the dihydropyridines' site as diltiazem promotes the binding of dihydropyridines In contrast, verapamil inhibits the binding of dihydropyridines and has its own separate binding site' 361. The region labelled by phenylalkylamines is localized on a 42 amino acid segment that encompasses part of the S6 segment in motif IV and an adjacent short sequence in the intracellular tail of the ai-subunit [30]. Thus, the binding site for phenylalkylamines does not line the pore directly, as the S6 segments of motif IV surround the poreling structural elements. Relevant to their clinical action is the fact that phenylalkylamines block the calcium channel from the intracellular side' 301. To understand the clinical effects of calcium antagonists, a general but useful observation is that calcium channels consist of four S5-S6 segments from the four motifs of the ai-subunit. However, none of the calcium antagonists binds to all four segments, leaving the possibility of some calcium entry. Therefore when used clinically they do not cause total arrest of excitation-contraction coupling or complete inhibition of the sinus node. Clinical relevance of the specific binding sites A dihydropyridine receptor has been identified in various tissues, including cardiac and smooth muscles. Interestingly, this receptor can also be activated by

3 A58 R. Ferrari dihydropyridine-based structures, such as Bay K 8644, or modulated (activated and then inhibited, for example) by different dihydropyridine molecules' 37 ' 381. Thus, in the isolated heart, compounds such as nitrendipine or nicardipine at a low dosage increase inotropism, whereas at higher dosage they exhibit a negative inotropic action A similar pattern has not been confirmed for the phenylalkylamines or benzothiazepines, suggesting modulation of the binding site which does not follow classic receptor pharmacology. The presence of a well-defined receptor for dihydropyridine has strongly influenced the development of several derivatives of this class of drug. All the new compounds have been tested and differentiated, at least at the pharmacological level, for potency and selectivity of action in addition to the optimal duration of the therapeutic effect' 401. This is not the case for the derivatives of the phenylalkylamines. Like gallopamil, anipamil and tiapamil differ from the prototype verapamil as regards the intrinsic mechanism of action rather than in the realm of potency or selectivity, the latter not being prerequisites in their synthesis. As their binding site is probably intracellular, the intracellular effects seem to be important. Thus, gallopamil and anipamil (but not verapamil) have the capacity to reduce mitochondrial calcium transport' 39 ' 41 " 431 or to modulate sarcoplasmic reticulum Ca 2+ uptake and release' 44 ' 451. At present, derivatives of diltiazem for clinical use are not available, because of the difficulty in altering the molecular structure of diltiazem without losing the calcium antagonist properties. Dihydropyridines block the calcium channel at the extracellular level and have greater vascular selectivity than the other classes of calcium antagonist. They are selective for the L-type calcium channel and have little, if any, effect on nodal issue. When used clinically, as a result of vigorous peripheral vasodilation, they tend reflexly to increase heart rate and often contractility, as catecholamines activate the calcium channel intracellularly, on a different site from that blocked by dihydropyridines. The same does not occur with verapamil; this causes less sympathetic activation and exerts intracellular blockade of the calcium channel. Thus, the differing molecular structure and the variation in binding sites explain the profound differences between phenylalkylamines and dihydropyridines. The clinical similarities between verapamil and diltiazem, however, cannot be simply predicted by the different site of action on the calcium channel. Tissue selectivity Tissue-selectivity, on the one hand, is considered one of the most beneficial properties of calcium antagonists as it diminishes the likelihood of undesirable side-effects. On the other hand, it can be a disadvantage, causing adaptive reactions. In general, the skeletal muscle, the bronchial, tracheal, and intestinal smooth muscle and neuronal tissue are relatively insensitive to calcium antagonists. The non-specificity for skeletal muscle is an important property of these drugs as it allows maintenance of posture. Skeletal muscle fatigue is not a side-effect of calcium antagonist therapy as it is for the /?-blockers. Non-selectivity for skeletal muscle At first glance, the insensitivity of skeletal muscle to calcium antagonists seems paradoxical because Ca 2+ current, calcium antagonist-sensitive channels and specific calcium-antagonist binding sites are all present. There are two possible explanations: (a) muscle contraction is triggered by a sudden increase in cytosolic, intracellular, Ca 2+, not by an inward flux of extracellular Ca 2+ ; (b) skeletal muscle L-type Ca 2+ channels are not identical to those of cardiac or smooth muscle. Indeed, recent studies have shown that differences exist between these channels. Skeletal muscle Ca 2+ channels cluster in the clefts of the transverse tubules, whereas in cardiac and smooth muscle they are distributed along the entire cell surface' 461. Patch-clamp studies have shown that skeletal, although not cardiac, L-type Ca 2+ channels are activated at strong negative potential, have small-slope conductance (indicative of a relatively small ion-carrying capacity) and are relatively insensitive to calcium antagonists. Thus, whereas nanomolar concentrations of the dihydropyridine-based antagonists are needed to produce a 50% block in cardiac L-type channels, micromolar concentrations are needed for skeletal muscle' 471. Ca 2+ The lack of sensitivity is possibly a consequence of the relatively large number of binding sites that exist in skeletal muscle since a higher dosage would be needed to saturate these sites. It follows that the high concentrations required to produce a significant 'block' of the skeletal muscle channels cannot be achieved in practice because they would cause either profound vasodilatation or cardiac arrest. Low selectivity for tracheal, bronchial and neuronal tissues Equally, the insensitivity of tracheal and bronchial smooth muscle, compared with vascular smooth muscle, can be explained in terms of: (a) the relative importance of 'receptor-activated', as opposed to 'voltagecontrolled' calcium channels in facilitating Ca 2+ ions entry, and (b) the relative importance of the extracellularly derived, as opposed to the intracellularly released, activator Ca 2+ ' 4849 '. Calcium antagonists have almost no effect on neuronal tissue. This is because the Ca 2+ channels located in the dendrites are important for transmitter release and are mainly N-type channels' 501. Neuronal tissue does contain some L-type Ca 2+ channels, but mostly in the 'resting state', which is insensitive to

4 The three classes of calcium antagonists A59 calcium antagonists 15 ' 1. The fact that calcium antagonists have little or no effect on neuronal tissue is of clinical importance, since it explains, for example, why these drugs do not disturb reflex control mechanisms and why mental depression does not appear as a side-effect as it does with some of the /?-blockers. Selectivity for pacemaker and atrioventricular nodal cell Verapamil and diltiazem, but not dihydropyridines, have prominent effects on nodal tissues. This may be partly explained by a possible action of verapamil, at least on the channel. The differing binding sites may also play a role. Ionized drugs, such as verapamil and diltiazem, will gain access to their internal binding site by the channel lumen only when the channel is open. Repetitive depolarizations occur in the rapid firing atrioventricular nodal tissue and in the myocardium, therefore facilitating the binding of these drugs. For this reason they have been described as possessing 'use-dependence' [521. This probably explains why verapamil and diltiazem slow atrioventricular conduction, whereas the dihydropyridines do not. In addition, calcium antagonists interact preferentially with different 'voltage-dependent states' of the channel. Verapamil and diltiazem have a use-dependent or, better, a frequency-dependent effect. The more frequently the calcium channel opens, the better the penetration to the binding site. This explains their effect on nodal tissue in paroxysmal supraventricular tachycardia. Myocardial versus vascular selectivity Clear differences between the three classes of calcium antagonists exist in the ratio of potency on vascular smooth muscle compared with that in the myocardium. Nifedipine is at least 10 times more vascular- than myocardial-selective than are verapamil and diltiazem. Nisoldipine and felodipine are at least 1000 times more selective than nifedipine In general, vascular selectivity is considered a desirable quality, as it permits coronary and peripheral dilatation in the absence of significant myocardial depression. This concept, however, has not proved correct, at least in the treatment of angina pectoris and myocardial infarction or for secondary prevention against ischaemic heart disease. Here, calcium antagonists that effectively reduce heart rate and inotropism, in analogy with /?-blockers, have been more successful than dihydropyridines, as discussed in detail later. The major disadvantage for high vascular selectivity is that it may be counterproductive. A reflex-adrenergic discharge with consequent tachycardia and positive inotropism increases oxygen demand. Phenylalkylamines and benzothiazepines present a different picture because, although selective for the cardiovascular system, they are approximately equipotent for the myocardium, the atrioventricular conducting tissue and the vasculature. Within the vascular system they are not specific for any particular site. Therefore their action is not merely the result of vasodilatation but rather of modulation of several different muscular tissues. The general absence of 'use-dependence' and the presence of'voltage-sensitivity' of dihydropyridine binding explains their vascular selectivity. The preferential selectivity within the different dihydropyridine derivatives for specific vascular beds is more difficult to explain. The chemical profile of the drug and the lipid composition of the cell membrane may play an important role. Dihydropyridines reach their receptors either directly in the external surface of the membrane or by way of the plasma lipid. The lipid profile of a particular vascular bed and the precise chemical structure of the dihydropyridine-based antagonist will determine how much of the antagonist reaches the receptor. In addition, different regions of the vascular system operate at different transmembrane-resting potentials and this may affect the binding activity of dihydropyridines. Finally, the nature of the stimulus that triggers the contractile response may be important. In some vascular beds, the depolarization-induced increase in cytosolic Ca 2+ may predominate. In others extrinsic factors, including the presence of histamine, serotonin, noradrenaline or other effectors, may provoke a rise in cytosolic Ca 2+ that overwhelms those caused by membrane depolarization. Dihydropyridines are expected to block only the rise in calcium due to depolarization. When considered all together, these factors could ensure greater accessibility of a specific drug for its receptor in a particular type of smooth muscle, thus increasing receptor binding and selectivity. Pharmacokinetics Aside from the newer dihydropyridines, all three drug groups have similar pharmacokinetic properties. All demonstrate a low and variable bioavailability, high first-pass metabolism, rapid onset of action, high protein binding, short elimination half-life, and metabolism compared to inactive or less active metabolites. Amlodipine is a newer dihydropyridine with a very different pharmacokinetic profile. It is water soluble and photostable, and has, like bepridil and nitrendipine, a long half-life (35-50 h). It is absorbed slowly but absolute bioavailability is high, and it is extensively metabolized in the liver. The long half-life is associated with a prolonged (>24 h) duration of pharmacodynamic action' 54 '. The absolute bioavailability can vary consid- erably between individuals, as do clearance and plasma concentration. Liver impairment is the main systemic condition which may alter the pharmacokinetic profile. The pharmacokinetic profile of nifedipine and nicardipine, with rapid onset of action and short half-life

5 A60 R. Ferrari are believed to be responsible for the greater reported incidence of adverse effects. These agents reduce blood pressure primarily via arteriolar vasodilation and the antihypertensive effect is closely correlated with plasma concentration. Rapidly absorbed preparations such as nifedipine capsules produce a rapid drop in blood pressure, which in turn provokes a reflex increase in sympathetic nervous activity associated with a reflex tachycardia and prominence of the vasodilatory adverse effects. Sustained release (nifedipine S/R) or long-acting agents (e.g. amlodipine) exert a more consistent antihypertensive effect of slower onset, with lower baroreceptor reflex stimulation and fewer side effects as a consequence' 551. The available drug preparation of verapamil is a racemic mixture of dextro (d)- and levo (l)-verapamil. The 1-isomer, which is around ten times more potent as a dromotropic and inotropic agent than the d-form, is preferentially metabolised (stereoselective first pass metabolism), so that after oral administration there is a lower ratio of the more active form when compared to i.v. plasma level response. Haemodynamic effects The final haemodynamic effect of a calcium antagonist administered in vivo in man will depend on: (1) the relative tissue selectivity at the therapeutic concentration, (2) the potency and velocity of action at therapeutic concentration (which, in turn, depends on pharmacokinetics), (3) the interaction between all the different effects, and (4) the pharmacokinetics. We have carried out a systematic evaluation of the acute haemodynamic effect of the prototypes of the three major families of calcium antagonists in coronary artery disease patients' 56^58 '. Nifedipine was injected at 15 ug. kg~ ' in 22 patients; verapamil at 0-1 mg. kg"' as a bolus, followed by chronic infusion of 005 mg. kg" '. min" ' for 3 min in 14 patients and diltiazem at 250 ug. kg~ ' in 12 patients. These dosages are supposed to cause similar effects on systemic vascular resistance. Before the acute administration of the calcium antagonist, there were no major differences regarding the haemodynamic indices among the three groups selected for having normal myocardial systolic function in the presence of diastolic dysfunction' '. All calcium antagonists reduced afterload parameters. The percentage of reduction in systemic vascular resistance and mean aortic pressure was more pronounced after nifedipine than after verapamil or diltiazem. In the nifedipine group, these changes were associated with a 30% increase in heart rate. Minimal or no change in heart rate was present in the verapamil and diltiazem groups. Increases in left ventricular ejection fraction, cardiac output and stroke volume index are observed in all groups, corresponding to the degree of load reduction. Effects of intrinsic contractility and relaxation Nifedipine significantly increased all contractile indices (left ventricular dp/dt max, Vce max, Vmax), while verapamil and diltiazem reduced intrinsic contractility. Left ventricular diastolic function was clearly improved by the calcium antagonists, since constant T, negative dp/dt and protodiastolic pressure were all reduced. The reduction was statistically significant only after infusion of verapamil and diltiazem. The ischaemia-induced alterations in diastolic tone during ischaemia have been explained in terms of reduced adenosine triphosphate available for dissociation of actin and myosin and for calcium extrusion against the various cellular and intracellular concentration gradients, leading to increased cytosolic calcium concentration' 591. Diastole is therefore an energyrequiring process. Experimentally, all calcium antagonists exert protection against the ischaemia-induced alterations of diastolic function' 60 ' 6 ' 1. The mechanism of protection relies on a reduction in the rate of adenosine triphosphate consumption which is strictly correlated with the reduction of influx of calcium through the slow calcium channels during the early stage of ischaemia. Accordingly, if administered late during ischaemia or reperfusion, when the myocytes are already depleted of adenosine triphosphate, the beneficial effect on diastolic function is absent' 62 " 641. Diastolic improvement by calcium antagonists in man There are several explanations for the improved diastolic performance in coronary artery disease patients modulated by verapamil and diltiazem. They may reduce the extent of chronic myocardial ischaemia by acting directly on the smooth muscle of the coronary arteries to increase coronary flow, either via the natural vessels or collaterals or both. Such a mechanism would be beneficial, notably in those patients whose blood flow is limited by vasoconstriction rather than by fixed stenosis. The same mechanism should also be operating after nifedipine. Alternatively, verapamil and diltiazem may improve the relaxation phase by a reduction in the afterload. This would cause a reduction in left ventricular loading coupled with a reduction in oxygen consumption. Both processes will decrease the myocytes' demand for adenosine triphosphate (ATP), thereby leaving more ATP available for calcium extrusion. However, it is very unlikely as nifedipine and dihydropyridine derivatives lead to a more pronounced reduction in systemic vascular resistance and afterload. Finally, the direct effect of calcium antagonists in reducing myocardial contractility would be expected to diminish oxygen consumption and therefore to improve adenosine triphosphate content within the myocardium. This possibility can be attributed only to verapamil and

6 The three classes of calcium antagonists A61 diltiazem, because nifedipine increases myocardial contractility. Thus, the different behaviour of verapamil, diltiazem and nifedipine on myocardial contractility may account for the more pronounced improvement in the left ventricular filling phase induced by these calcium antagonists. The dihydropyridines paradox The positive inotropic and chronotropic effect of nifedipine may be viewed as a paradox since in vitro nifedipine has a potent negative inotropic action. This probably results from reflex stimulation of the sympathetic system. When given acutely, nifedipine causes a rapid and abrupt drop of peripheral resistance with the threat of hypotension. This is due to the high selectivity for smooth muscle cell, to the rapid access to the dihydropyridine receptor located in the external portion of the cellular membrane and to nifedipine's pharmacokinetics. This in turn results in a sympathetic response which counteracts the potential negative inotropic action of nifedipine at the myocardial level, as previously discussed. Catecholamines improve the slow calcium current of the sarcolemma via a cyclic AMP-mediated phosphorylation of the slow calcium channel' 651. This process takes place in the cytosol on the inner surface of the sarcolemma. Nifedipine inhibits the slow calcium channel on the external surface of the sarcolemma. It is not surprising therefore that in vivo catecholamines can completely overcome the intrinsic negative effect of nifedipine. As a result, left ventricular contractility and heart rate in man are indirectly enhanced after nifedipine administration. To test this concept, we studied the acute effects of intravenous nifedipine (15ug.kg~') on haemodynamics and left ventricular function of coronary artery disease patients without previous /^-blockade but after 5 days' acebutolol (9mg.kg"', daily) The effect of nifedipine on the smooth muscle was evident regardless of treatment with acebutolol. It provoked a reduction in systemic arterial resistance with an increase in cardiac output and heart rate. The effect of nifedipine on intrinsic myocardial contractility was quite different and depended on the presence of /?-adrenergic blockade. Left ventricular dp/dt max, Vce max and Vmax were increased after infusion of nifedipine in patients not receiving the /?-blocker, whereas the same variables were all significantly depressed by nifedipine in patients receiving acebutolol. This suggests that nifedipine possesses an intrinsic direct negative inotropic effect on the myocardium and that it is necessary to block the compensatory reflexes to unmask this effect. A similar conclusion was also drawn in studies in which nifedipine was administered to isolated heart muscle' 62 ' or as an intracoronary administration to humans' 67 ' 681. It is worthwhile to note that the strong sympathetic reflex which we have documented is a consequence of the intravenous administration of the drug. Similar data have been confirmed by other investigators using the same route of administration' Both the positive inotropic effect in the absence of /^-blockade and the negative inotropism of the combination of nifedipine with /?-blockers are significantly less pronounced when using sublingual or oral formulations' 71 " 731. In addition, the recently developed lipophilic dihydropyridine derivatives and the new slow-release formulation of nifedipine cause a very modest sympathetic reflex. Effect of calcium antagonists in chronic stable angina pectoris Since the whole issue was brilliantly surveyed by Lionel Opie' 741, the results of two well-conducted trials, the Total Ischaemic Burden European Trial (TIBET) and the Angina Prognosis Study in Stockholm (APSIS), have become available' 75 " 781. Results from earlier studies The therapeutic goal in angina pectoris is to relieve symptoms and to improve quality of life and prognosis. It seems difficult to decrease the already low mortality further in patients with mild to moderate angina under pharmacological treatment. Nevertheless, it is mandatory that alternative therapies, besides relieving symptoms and improving quality of life, do not increase morbidity and mortality. In general, comparative data delineate different mechanisms for the anti-anginal effect of verapamil, diltiazem and nifedipine. The final anti-anginal effects of these three agents are similar in most studies, but there is preliminary evidence that nifedipine and dihydropyridines are less effective than verapamil and diltiazem. New controlled trials are required to clarify the issue. Compared with /^-blockade, nifedipine proved worst in three out of five studies' 79 " 841, verapamil best in four out of six studies' 85 " 901 and diltiazem equal' 84 ' 91 " 941. Nifedipine probably did worse than the other calcium antagonists because it causes trachycardia and increases contractility. Since concern was obviously raised by the recent challenge on the safety of calcium antagonists' 1 " 101, the results from the TIBET and APSIS studies are most timely and fundamental in this respect. Data from TIBET and APSIS studies In the TIBET study, atenolol, nifedipine SR and their combination were administered to patients with chronic stable angina pectoris. In all, 682 patients with an established diagnosis of mild to moderate angina pectoris were recruited to a randomized, double-blind, parallel-group study. The /?-blocker atenolol was given

7 A62 R. Ferrari in a dosage of 100 mg daily and nifedipine SR in a dose of 40 mg daily. The same dosages were used in the combined atenolol and nifedipine group. The two drugs and their combination were equally effective in significantly reducing all markers of reversible myocardial ischaemia during exercise testing and ambulatory electrocardiographic monitoring. During an average follow-up period of 2 years (range 1-3 years) there was no statistically significant difference in 'hard' end-points defined as cardiac death, non-fatal myocardial infarction and unstable angina pectoris. The APSIS is a mono-centre randomized doubleblind study which recruited 809 patients with stable angina pectoris. They were treated with either metoprolol 200 mg daily or verapamil 240 mg twice daily. During a median follow-up period of 3-4 years (range months) there were no differences in fatal or non-fatal cardiovascular events (non-fatal myocardial infarctions, incapacitating or unstable angina pectoris and cerebrovascular or peripheral vascular events). Cardiovascular mortality was 47% in both groups. Nonfatal cardio vascular events occurred in 26-1 and 24-3% of metoprolol- and verapamil-treated patients, respectively. Quality of life did not change on either drug. Thus both studies, although using different drugs, basically reached the same conclusion: treatment with a /?-blocker or a calcium channel blocker is equally effective as regards symptomatic relief. Furthermore, there was no evidence that calcium antagonists are harmful in patients with established ischaemic heart disease. Both drug types, two different /?-blockers and two different calcium antagonists, produced the same outcome as regards mortality and serious cardiovascular morbidity. It should be emphasized, considering the size of the patient populations, that the power in APSIS is higher than that in TIBET. The safety issue regarding treatment with calcium antagonists in patients with stable angina pectoris is therefore possibly better documented for verapamil than nifedipine. Both the TIBET and APSIS studies raise the question whether drugs improve prognosis in patients with moderately severe angina pectoris. To this end, a study comparing the outcome of revascularization with bypass surgery or angioplasty and drug treatment should be performed. As mortality is low anyhow, approaching 1-2% per year, it seems unlikely that invasive or surgical procedures would be superior to medical treatment. It also seems that although drugs of various types do not differ in efficacy, they may differ as regards tolerability, as demonstrated in TIBET. Therefore, measures other than efficacy must be carefully evaluated in future trials of pharmacological treatment of angina pectoris. Vasospastic angina The main mechanism responsible for vasospastic angina is spasm of the large coronary arteries' 95 " 971. Therapy with all the three classes of calcium antagonists is highly effective in this disorder confirming the ability of these drugs to prevent and resolve smooth muscle contraction of the large coronary arteries' 98 " The various agents seem to be approximately equally effective, but strict double-blind comparisons are not available. Unstable angina pectoris with threatened infarction The heterogeneous nature of the pathophysiology of unstable angina demands a complex therapeutic approach. The four critical factors in the mechanism of unstable angina are the atherosclerotic plaque, a partial thrombus, the platelets and coronary vasospasm. Central to the pathophysiology is that prolonged pain and left ventricular failure often present in 'true' unstable angina lead to catecholamine release with consequences such as tachycardia and metabolically-based increase in myocardial oxygen demand' 107 ' It has been shown by several authors, in both randomized and double-blind studies, that calcium antagonists reduce the symptoms and signs of ischaemia in unstable angina 1108 " 110], although the results of larger randomized studies on the effects on development of myocardial infarction and death produced different data according to the class of drug employed. Dihydropyridines in unstable angina pectoris The largest trial on nifedipine for unstable angina was stopped early because of a trend towards more non-fatal infarctions in a subgroup receiving nifedipine as monotherapy' 105 ' 1 " 1. This was not observed when nifedipine was combined with metoprolol However, the combination nifedipine-metoprolol was not better than metoprolol alone. These reservations about the use of nifedipine are supported by isolated case reports of adverse responses to the drug 1 " 2 "" 41. Diltiazem and verapamil for unstable angina pectoris In patients admitted to the coronary care unit for prolonged chest pain and true unstable angina, diltiazem (360 mg daily) was as effective as propranolol (240 mg daily) 1101 ', but verapamil (480 mg daily) was slightly better than propranolol It should be stressed that the overall number of patients enrolled is rather small and no data exist comparing these agents with nifedipine. It is nonetheless clear that the use of verapamil or diltiazem is preferable to nifedipine if calcium antagonist monotherapy is desirable to treat unstable angina. More studies are available for /?-blockers which, for this reason, remain the drug of choice, although, when compared, produce the same (if not poorer) results as

8 The three classes of calcium antagonists A63 verapamil and diltiazem. To sum up, it is clear that: (1) when ischaemia approaches myocardial infarction, clear differences in outcome exist between the different classes of calcium antagonists, and (2) there is the need for further comparative studies assessing the benefits of verapamil and diltiazem and comparing these two classes of calcium antagonists with /?-blockers. Myocardial infarction From the recent randomized trials of myocardial infarction treatment we now have a large database of information on the subsequent risk of sudden death. This shows that after the initial 48 h the survival curves flatten out over the first week. The risk is greatest early, but is still substantial over the first year. Thereafter there is a much more stable mortality rate, but in the first few years post myocardial infarction, this annual mortality is still about 4-5% many times greater than in the age-matched population who have not experienced a myocardial infarction. This risk is greatest in those who are older. The 5-week mortality of patients who have had the benefit of thrombolysis plus aspirin is still about 20% in those over the age of 80 years. Such patients are often excluded from randomized trials, but since the incidence of myocardial infarction increases strikingly with age, the majority of patients hospitalized with acute myocardial infarction are elderly. Thus, there is a clear need for a greater choice of therapy after myocardial infarction. This statement is based on the following data: (a) a history of prior myocardial infarction identifies that individual as a person at high risk of subsequent mortality and morbidity; (b) this mortality and morbidity can be substantially reduced by treatment, as evidenced by a number of well-designed, large, randomized, controlled trials; (c) at present the most important drugs to reduce morbidity and mortality comprise aspirin, ^-receptor blocking agents, (propranolol, timolol and metoprolol), and some but not all antiarrhythmic drugs. Nitrates, commonly used for symptoms of angina, are less well proven for mortality benefit. ACE inhibitors are particularly useful for patients with impaired left ventricular function 1 " 5 "" 91 and (d) not all patients can be treated with these drugs because of individual patient factors which contraindicate their use. This is particularly true for /?-blocking agents, where the presence of asthma or bronchitis-related bronchospasm is a major contraindication; another major contraindication is the presence of peripheral vascular disease in the form of intermittent claudication. Since bronchitis, peripheral vascular disease and coronary disease are all powerfully related to smoking, they are all commonly associated in the same patients. /?-blocker therapy also poses some problems for diabetic patients, particularly for insulin-treated patients, since they may experience difficulty in recognizing the signs of hypoglycaemia. ^-blockade is a problem for patients who need a high level of physical activity, either for their work or for sport. These considerations, together with other side effects, such as cold extremities and fatigue due to lowered cardiac output, add to the number of patients who are unable to tolerate betablockade. For these reasons the proportion of patients receiving /^-blocking drugs prophylactically post myocardial infarction is variable, but rarely exceeds more than 30-35% and is often nearer to 10-20%. It varies widely and possibly illogically between countries. Calcium antagonists could be an alternative Twenty-three randomized controlled studies of calcium antagonists are available. In 17 of these studies, treatment was started within a few hours after onset of symptoms and continued short-term; in two trials treatment was started early and continued long-term; in four trials treatment was begun some days to weeks after infarction and continued for 1 to 5 years. About patients were studied in total; the number of patients per trial varied from about 20 to Nifedipine was evaluated in 10 trials in a total of 9700 patients; diltiazem in four trials in a total of 3100 patients and verapamil in four trials in a total of 4500 patients. It should be stressed that all these studies are rather old and were conducted in a pre-thrombolytic era. When taken together, a rather negative picture emerges' 120 " A more careful examination clearly indicates that the final outcome strictly depends on the agent utilized. Nifedipine shows no benefit or excess mortality, diltiazem shows promise, and verapamil reduces mortality. It follows that meta-analysis cannot be applied to all calcium antagonists, as these drugs, despite sharing a common name, are not the same and the prevalence of one or another type would inevitably bias the results of the meta-analysis. Effects of nifedipine in myocardial infarction Nifedipine was administered at doses ranging from 30 to 120 mg 1 ' 22 " 130 '. In no study were mortality, reinfarction, infarct size or enzyme release altered by the nifedipine therapy. In the study by Muller et a/. 1 ' 3 ' 1, nifedipine was associated with a significant increase in death rate during the 6 months of treatment (7-5 vs 2-5% with placebo), a finding confirmed elsewhere' All these studies were conducted with shortacting nifedipine. When pooled together with the addition of a few more trials not addressing the issue of acute myocardial infarction, it appears that there is an increased risk of death among patients taking high doses (>50mg daily) of short-acting nifedipine' 21. The metaanalysis has been criticized and the debate is beyond the aim of this article. It is nevertheless clear that short-term nifedipine does not exert benefit; it may even be harmful, and therefore should not be used.

9 A64 R. Ferrari Effects of diltiazem in myocardial infarction Diltiazem was given at doses ranging from 120 to 360 mg. The short-term trial by Gibson et a/. [133) has produced some encouraging results. The study differs in two significant aspects from earlier trials with verapamil or nifedipine. Firstly, a particular subset of patients was used, those with non Q-wave infarction. Secondly, the treatment was initiated h after infarction. The trial extended over only 14 days and used reinfarction as its end point. Whilst mortality was unchanged, the rate of re-infarctions was reduced, reaching a conventional level of significance (/ > <005) on a onetailed test but not on a two-tailed test. In the long-term multicentre diltiazem post-infarction trial, 9% of 296 patients treated, compared with 15% of 338 controls, developed a re-infarction or suffered a cardiac death at the end of one year's treatment 1 ' 341. This is important in that it shows that in this particular subset of patients who are at high risk for recurrent infarction, prophylactic therapy with diltiazem can slow or prevent the progression of damage caused by inadequate perfusion. In the case of non Q-wave infarction, calcium antagonists are given to cells that have not yet died, but are probably threatened by severe ischaemia. Furthermore, in the multicentre diltiazem post-infarction trial, it was suggested that there was significant bidirectional interaction as regards mortality' A favourable but non-significant trend was observed in patients without pulmonary congestion, but in patients with pulmonary congestion there was a significant adverse effect. As stated by the authors, these analyses should be cautiously interpreted because they have not yet been verified in a prospective study. These results clearly indicate that in complex conditions like myocardial infarction the choice of calcium antagonist and of patients to treat is of great importance. Effects of verapamil Interestingly, the first calcium antagonist trial in myocardial infarction was with verapamil Verapamil was given at doses ranging from 320 to 360 mg. It involved 717 patients in the treated group and 719 in the placebo group, with therapy starting about 4 h after the onset of severe chest pain and continuing for 180 days. On the basis of the data obtained over 180 days of treatment, verapamil failed to reduce the incidence of mortality. Similar negative data were obtained in two more studies At first sight, the results, particularly of the Danish multicentre trial, are discouraging. However, if the trial data are examined carefully, an interesting pattern of response emerges. During the first week of treatment the incidence of death was higher in the verapamil- than in the placebo-treated group. Death was due to cardiac failure, cardiogenic shock and atrioventricular block. If the data that relate only to the days treatment period are considered, then both mortality and re-infarction rate were significantly reduced. The study, therefore, shows that verapamil therapy may actually increase the death rate if the drug is administered during the first hours of a myocardial infarction (when ischaemic damage has already occurred), but for those patients who survive and who are maintained on therapy, the risk of re-infarction is reduced and some kind of cardioprotection occurs. These retrospective analyses of the data were the major reason for the decision to conduct a late intervention study, the Danish verapamil infarction trial II (1990), the purpose of which was to examine whether treatment with verapamil from the second week after acute myocardial infarction and continuing for 12 to 18 months might reduce total mortality and major events compared with placebo. Eight hundred and seventyeight patients took verapamil 360 mg a day and 897 had a placebo. In the treated group there was a significant reduction in mortality and re-infarction rate' This positive effect might be related to a reduction in myocardial ischaemia as there was a lower prevalence of angina pectoris in the verapamil group compared with placebo. This in turn is probably related to the significantly lower heart rate and blood pressure resulting from verapamil therapy 1 ' 4014 ' 1. The subgroup analysis of the second Danish trial (planned prior to termination of the follow-up) has demonstrated that patients without heart failure in the coronary care unit had a significantly better prognosis than patients with heart failure. The effect of verapamil in patients without heart failure corresponds to the findings of the multicentre diltiazem post infarction trial (1988) but, contrary to diltiazem, verapamil had no harmful effect in patients with heart failure. Interestingly, in patients without heart failure the reduction in hazard ratio of 20 to 26% for the verapamil-treated group corresponds to the effect of /?-blockers. Regrettably, no clinical studies are available for other derivatives of verapamil, such as gallopamil or anipamil which, at least from experimental data, should be very promising. Congestive heart failure In theory, calcium antagonists should be a useful treatment for chronic congestive heart failure because of the combination of vasodilating and anti-ischaemic properties and because coronary artery disease is by far the most common cause of heart failure' 142 ' 143 '. Furthermore, in several experimental models of heart failure, calcium antagonists have been beneficial. When taken together, these encouraging experimental findings coupled with the known clinical properties of calcium antagonists gave rise to the expectation that these drugs would have a useful role in congestive heart failure. Two properties of calcium antagonists have always caused concern with regard to their potential efficacy in congestive heart failure: (1) depression of myocardial contractility (a negative inotropic effect) and (2) activation of neurohormonal systems, notably the

10 The three classes of calcium antagonists A65 sympathetic and renin-angiotensin systems, leading to reflex tachycardia and fluid retention. However, other negative inotropic agents may paradoxically be useful in congestive heart failure. /?-blockers for instance also interfere, albeit indirectly, with the delivery of calcium to contractile proteins' 1441 and are associated with adverse haemodynamic and clinical effects after short-term treatment in patients with congestive heart failure' Long-term treatment with carefully titrated /?-blockers may actually improve the clinical status of patients' 146 " 149]. /?-blockers have also been shown to reduce mortality in patients with congestive heart failure after myocardial infarction" 5015 ". Despite these concerns, calcium antagonists are widely used in patients with left ventricular dysfunction. In the Studies of Left Ventricular Dysfunction Trial (SOLVD)" 521, over 30% of 2500 patients with treated congestive heart failure and an ejection fraction <35% were receiving calcium antagonists in addition to digitalis and diuretics. This is surprising since congestive heart failure is not a formal indication for the use of a calcium antagonist. An indication for use might have been coronary artery disease, but /?-blockers were used in only 5-10% of patients. Dihydropyridines in congestive heart failure There are studies, although ambiguous, showing haemodynamic improvement after nifedipine administration in patients with impaired ventricular function' 153 " In contrast, the first controlled trial on the subject showed unequivocally that nifedipine exerts deleterious effects' Studies with newer dihydropyridines, which are thought to be more selective for smooth muscle, have produced similar results' 160 " Felodipine and amlodipine are the only dihydropyridines that produced encouraging data' 165 " Amlodipine, for instance, improved clinical symptoms and exercise tolerance in patients with congestive heart failure and decreased neurohormonal activation. Based on these promising results a large-scale trial has been conducted (Prospective Randomized Amlodipine Survival Evaluation Trial, PRAISE) in 1153 patients randomized to amlodipine 5-10 mg. day ~' or to placebo. These patients had congestive heart failure (80% NYHA III), with an average ejection fraction of 21%. There was no significant effect on risk ratio for cardiovascular events and death. Surprisingly, subgroup analysis for ischaemic/non-ischaemic aetiology of congestive heart failure revealed that the benefit of amlodipine was seen only in patients with congestive heart failure of non-ischaemic cardiomyopathy in whom the relative risks for cardiovascular events and death were 69% (/><0034) and 55% (/ > <0001), respectively' 168 '. A similar trial performed with felodipine (vasodilator heart trial, V-HeFT III) found the drug to be neither helpful nor harmful when given to patients with congestive heart failure under stable therapy with enalapril, digoxin and diuretics' In recent years there has been a re-emergence of interest in the entity of diastolic heart failure. Diastolic heart failure is often assumed to be present when the ejection fraction at rest is normal, but the patient has a reduced exercise capacity, which is believed to be the consequence of heart failure. However, diastolic dysfunction, particularly on exercise, is commonly associated with systolic dysfunction in most patients with heart failure, so that whether systolic or diastolic function relates to exercise capacity is unknown. Impaired left ventricular diastolic filling is found in most patients with coronary artery disease' Calcium antagonists have been shown to improve indices of diastolic function in these patients' Patients who do not have dilated ventricles and who have nearnormal ejection fraction measurements often have an impaired functional capacity. The DEFIANT I study was designed to determine whether nisoldipine (coatcore, 20 mg daily) could alter diastolic filling parameters assessed by Doppler and two-dimensional echocardiography. The trial was a multicentre, double-blind, placebo-controlled trial lasting 4 weeks in 135 patients. The results suggest that a slow release preparation of nisoldipine improved echocardiographic indices of diastolic function and exercise capacity in patients with impaired ventricular function but no overt heart failure after a myocardial infarction' Verapamil and diltiazem in congestive heart failure In patients with ventricular dysfunction and ejection fraction below 35%, a full dose of verapamil has been shown to cause marked haemodynamic and clinical deterioration' 174 '. Some investigators reported a shortterm benefit even in this group of patients, presumably related to the vasodilator properties of the drug: after prolonged therapy at least 50% of patients showed clinical deterioration' 175 '. Other studies reported a worsening of heart failure when verapamil is used in the management of angina pectoris and hypertension' 176 ' It should be noted that unlike /?-blockers no studies are available on the effects of dose titration of verapamil. There are almost no data on diltiazem. Conclusion Unquestionably, calcium antagonists do differ, and these differences matter for their clinical efficacy. In ischaemic heart disease calcium antagonists that are non-selective for the smooth muscle are advantageous. This work was supported by the target project G179038C FATMA of the National Council of Research (CNR), Rome, Italy. The authors thank Roberta Bonetti for the secretarial assistance in preparing the manuscript and Alessandro Colizzi for editing the text.

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