Number 24, 2004
Angina Pectoris

New developments in the drug treatment of stable angina pectoris

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Pieter A. van Zwieten^1,2, Frans C. Visser^2
1Departments of Pharmacotherapy, Cardiology and Cardiothoracic Surgery, Academic Medical Center, University of Amsterdam, The Netherlands
²Department of Cardiology, Free University Medical Center (VUMC), Amsterdam, The Netherlands
Correspondence: Prof. Dr P.A. van Zwieten, Department of Cardiothoracic Surgery, Academic Medical Center, Room G4-230, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Introduction
Chronic stable angina pectoris has a relatively benign prognosis, with an average annual mortality of 2% to 3% [1,2]. Stable angina pectoris is traditionally treated by drugs, which improve symptoms and quality of life, but drug treatment has not been shown to reduce mortality or the incidence of myocardial infarction [1,2]. Revascularization techniques, such as percutaneous coronary intervention or coronary artery bypass surgery (CABG), have been introduced and were found to enrich the therapeutic management of angina pectoris. Although these procedures offer a more causative approach for the correction of the myocardial ischemia, they are associated with a greater risk than treatment with classical antianginal drugs [1].
Taken together, both drug treatment and revascularization procedures should be considered as a balanced approach in the management of angina pectoris, depending upon the detailed characteristics of the individual patient.
This review deals with the newer approaches in the drug treatment of angina pectoris. Unstable angina pectoris requires a different and more aggressive management, involving both medical and interventional treatment, and is not discussed here.

New approaches concerning classical antianginal agents

Nitrates
Nitroglycerin and isosorbide continue to be the classical nitrates used in the acute management of angina pectoris. In spite of vast investment in research, genuine innovation in this field has not been achieved. Several new galenic preparations of these classical drugs have been introduced, such as sprays, ointments, etc. Some of these new preparations may offer some pharmacokinetic advantages, although such advantages are probably not substantial and not supported by appropriate clinical studies. They have been reviewed by Parker and Parker [3].
It goes without saying that the mode of action of the nitrates, discovered about a decade ago, must be considered to be a highly relevant innovation: in vivo, the nitrates release nitric oxide, which brings about the vasodilator action. The enhanced release of nitric oxide from the drugs is endothelium-independent and therefore persists in conditions of endothelial dysfunction/damage, as in coronary artery disease. Attempts have been made to develop new molecules that also release nitric oxide. Molsidomine is an example of such agents, and the anti-anginal activity of this nitric oxide donor has been demonstrated, although the position of this drug in the management of angina pectoris is not fully established [4].

β-Blockers
Since their introduction in the 1960s, several new β-blockers have been introduced, with the aim of improving their efficacy and tolerability. However, genuine innovation has not really been achieved. Current recommendations are that a selective β-blocker with a sufficiently long duration of action should be used, allowing once-daily administration.
Several β-blockers would fulfill these criteria. In clinical practice, metoprolol, atenolol, or bisoprolol are frequently used for the long-term treatment of angina pectoris [2].
Because a reduction in heart rate is one of the most relevant mechanisms explaining the beneficial effect of β-blockers, those that possess intrinsic sympathomimetic activity (oxprenolol, pindolol) should not be used in the treatment of angina pectoris, as they do not, or barely, reduce heart rate.
A new tendency in the development of β-blockers deserves mention here. On theoretical grounds, it would be desirable to combine β-adrenoceptor blockade with peripheral arterial vasodilatation, to reduce both heart rate and cardiac afterload. Indeed, a few β-blockers with vasodilator activity have been introduced, such as carvedilol, celiprolol, labetalol, and nebivolol. However, the vasodilator component of these agents is much weaker than their β-adrenoceptor antagonistic activity. For this reason, the relevance of the vasodilatation caused by these β-blockers remains uncertain, and does not justify their being preferred agents in the treatment of angina pectoris.

Calcium antagonists
As regards the long-term treatment of angina pectoris, little innovation has occurred in the field of calcium antagonists. For most of the classical calcium antagonists of the various subtypes (verapamil, diltiazem, nifedipine, and related compounds), retarded slow-release preparations have been developed, in order to improve the usually poor pharmacokinetic profile of these agents. Accordingly, the action of these drugs develops more slowly, which has the additional benefit that the problem of reflex tachycardia with dihydropyridine-type calcium antagonists is avoided. In addition, retarded preparations allow once-daily administration [5]. Nifedipine-gastrointestinal therapeutic system (nifedipine-GITS) is an elegant example of a retarded preparation that has the kinetic advantages mentioned above. Genuinely new calcium antagonists aiming at the long-term treatment of angina pectoris have not been introduced in recent years.

Nicorandil
Nicorandil, a nicotinamide ester, displays a dual mechanism of action. The drug opens up ATP-sensitive K⁺ channels, thereby causing dilatation of peripheral and coronary resistant arterioles [6]. In addition, it contains an NO₂-moiety, which dilates systemic veins and epicardial coronary arteries (Figure 1). Accordingly, nicorandil decreases cardiac preload and afterload, and it increases coronary blood flow. Its antianginal activity and safety profile somehow resemble a combination of those of oral nitrates, β-blockers, and calcium antagonists. The ability of nicorandil to relieve symptoms of ischemia is well documented, although its position in regimens for the treatment for angina pectoris remains to be established.

Bradycardic agents
Increased heart rate is well known as an important cardiac risk factor and, more specifically, as a determinant challenge for angina pectoris attacks in patients with myocardial ischemia. Conversely, a reduction in heart rate, and in particular, reduction of an increased heart rate, appears to be a useful therapeutic approach. The antianginal actions of β-blockers and of verapamil-type calcium antagonists are well documented, and largely explained by a reduction in heart rate. Efforts to develop specific bradycardic drugs that act through mechanisms other than β-adrenoceptor blockade or L-type calcium antagonism have been in progress for at least two decades. Attempts were made to achieve bradycardic activity by manipulating particular Ca²⁺ or K⁺ channels, or both. However, most of the compounds discovered, such as alinidine, falipamil, and zatebradine, were rejected, for a variety of reasons [9].
Ivabradine is a new heart rate-decreasing agent that selectively inhibits the primary pacemaker I_f current (or funny current) in the sinus node. The I_f current is a mixed Na⁺/K⁺ inward current that is activated by hyperpolarization, thus reducing heart rate at rest and during exercise, in experimental animals and in healthy volunteers [10,11]. Its bradycardic action does not involve β-adrenoceptors or L-type calcium channel blockade. The anti-ischemic activity of this agent was recently demonstrated in patients with stable angina pectoris, who received either ivabradine or placebo in addition to their standard anginal medication [12]. The reduction in heart rate caused by ivabradine appeared to be accompanied by improved exercise tolerance. Withdrawal of ivabradine after treatment for several months caused significant deterioration when the group were compared with patients who continued to receive the drug. The findings of that study indicate that ivabradine could be a valuable alternative to current treatments for angina pectoris [12].

Metabolic therapy
As discussed in the preceding paragraphs, the classical interventions in the management of ischemic heart disease/angina pectoris are aimed at improving the imbalance between myocardial oxygen supply and demand, via hemodynamic procedures. A new approach to treating ischemia/angina pectoris involves improving the efficiency of oxygen utilization by the cardiac tissues.
Several biochemically based approaches to bring about improved oxygen utilization can be envisaged, such as inhibition of tumor necrosis factor (TNF) β activity or its release by appropriate antagonists [13], inhibition of Na⁺/H⁺ exchange by cariporide (HOE 642) and other inhibitors [14,15], and inhibition of fatty acid oxidation and stimulation of glucose oxidation, by trimetazidine and related drugs.
Suppression of the formation or the effects of TNF β has not yet been studied to any significant extent in conditions of ischemic heart disease [13]. The first clinical trial (Guard During Ischemia Against Necrosis) of cariporide in myocardial ischemia provoked by percutaneous coronary intervention or high-risk coronary surgery did not show any protective effect in terms of death or myocardial infarction [14,15].

Trimetazidine
The third of the possible metabolic mechanisms is the only one that, to date, has led to a clinically useful approach to the drug treatment of angina pectoris. Trimetazidine, indeed, appears to be a metabolic agent for the treatment of stable angina pectoris that is largely free of hemodynamic activities. It has repeatedly been discussed and reviewed in Heart and Metabolism (see for example [16]). Here, we will refer only to some of its major pharmacologic and clinical characteristics.

Mode of action
Trimetazidine inhibits mitochondrial long-chain 3-keto acyl coenzyme A thiolase, thus favoring glucose oxidation at the expense of fatty acid oxidation, which is impaired (Figure 2). Trimetazidine can thus be classified as an example of a new class of anti-anginal drugs, the 3-keto acyl coenzyme A thiolase inhibitors.

Clinical effects
The beneficial effects of trimetazidine in the treatment of stable angina pectoris and possible other sequelae of ischemic heart disease have been described in great detail and reviewed several times. We mention here only the most relevant properties of the drug.
Trimetazidine significantly improved symptom-limited exercise in patients with stable angina pectoris when used either as monotherapy or when combined with β-blockers or calcium antagonists. Clinical benefits were also observed in patients with recurrent angina.
Trimetazidine also proved beneficial in patients with angina pectoris with diabetes or congestive heart failure. It is usually well tolerated; in fact better so than nifedipine or propranolol when used as monotherapy in clinical trials with stable angina pectoris. Mild gastrointestinal disorders such as heartburn were the most frequently reported adverse reactions, but their overall incidence was low.
We have mentioned already that trimetazidine is free of hemodynamic activities. It can be combined with classical, ‘hemodynamic’ anti-anginal drugs such as nitrates, β-blockers or calcium antagonists. Furthermore, trimetazidine can be considered a useful alternative to classic hemodynamic agents, even in patients who are resistant to treatment with the aforementioned classical drugs. The clinical characteristics of trimetazidine have been reviewed elsewhere [17–19].

Other metabolic agents
It is very likely that other metabolic drugs for the treatment of ischemic heart disease are in the process of being developed, although very few data have been published to date. Ranolazine showed minimal clinical benefit in patients with coronary artery disease [20].

Conclusion
Major innovations in the pharmacological treatment of stable angina pectoris concern the following categories of drugs: newer calcium antagonists (in particular slow-release preparations); nicorandil, a K⁺ channel opener and nitrate; bradycardiac agents (in particular ivabradine); metabolic drugs, which owe their beneficial effects to improved oxygen utilization. Trimetazidine is the best-known example of the metabolic drugs. It enhances glucose oxidation at the expense of fatty acid oxidation, thus leading to improved preservation of ATP. Trimetazidine is free of hemodynamic actions. Further development of this category of metabolic drugs seems well worthwhile.▪

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REFERENCES

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