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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Treatment of angina: a commentary on new therapeutic approaches

Philip A. Poole-Wilson*, Adam Jacques and Alex Lyon

Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK

* Corresponding author. Tel: +44 20 7351 8179; fax: +44 20 7351 8113. E-mail address: p.poole-wilson{at}imperial.ac.uk


   Abstract
Top
 Abstract
Angina and its causes
 Current treatment of angina
 New pharmaceutical approaches
 Long-term outcomes of drugs...
 Conclusion
 References
 
Medical treatment of angina has changed little in recent years, with nitrates, beta-blockers, and calcium antagonists being used to control symptoms and aspirin and statins to improve prognosis. However, data on long-term outcomes with these drugs are scarce, and it is clear that the treatment of angina pectoris with current drugs or with invasive interventions does not resolve the clinical problem of continuing symptoms of angina. Several new agents, with innovative mechanisms of action, are now becoming available, making this an area of considerable medical interest.

Key Words: Angina • Ischaemic heart disease • Drug treatment • Symptoms • Outcomes


   Angina and its causes
Top
 Abstract
 Angina and its causes
Current treatment of angina
 New pharmaceutical approaches
 Long-term outcomes of drugs...
 Conclusion
 References
 
Angina pectoris is a symptom that in appropriate circumstances indicates chest pain arising from the heart. The fundamental cause is often regarded as an imbalance between the supply and demand of the limiting substrate for the heart, namely oxygen. The belief is that such an imbalance is synonymous with the presence of myocardial ischaemia. The definition of ischaemia is surprisingly controversial,1,2 however, and the heart never demands or even has the capability to demand oxygen. A less contentious idea is that an unsteady state exists between the provision of oxygen to the muscle of the heart and the production of adenosine triphosphate (ATP).2 There are rarer causes of angina, such as anaemia, in which the oxygen content of blood is reduced, or aortic stenosis, in which the work of the myocardium is greatly increased. However, the cause is usually an imbalance between the work of the heart muscle, requiring the consumption of ATP, and limitations to blood flow. By far, the most common pathological defect causing reduced coronary blood flow is obstruction due to atheromatous lesions in the coronary arteries. These lesions in the arteries develop in early life,3,4 slowly enlarge, and manifest themselves as angina or a cardiac event in middle to old age.

Angina pectoris was probably recognized many centuries ago,5 but the first clear and elegant description was by Heberden6 in the 18th century. Debate followed as to the exact cause, and the work of many physicians such as Hunter, Black, Fothergil, Jenner, Parry, and Burns established the link of angina to the heart and to abnormalities of the coronary arteries.7 By the end of the 19th century, Osler8 understood angina and the concept of myocardial infarction. It was Obrastzow and Straschenko9 in 1910, and then Herrick,10 who first described myocardial infarction in a patient. More recent work has established the role of the unstable, fissured, or eroded atheromatous plaque in the coronary artery,11–14 thrombosis in the coronary artery leading to myocardial infarction,15,16 and the effects of platelet activation and accumulation on the vessel wall.17–19 Most of these acute abnormalities in the vessel wall lead to acute coronary syndromes or myocardial infarction and carry a poor immediate prognosis. Chronic angina pectoris in contrast is usually a consequence of a fixed obstruction within the coronary artery.

The atheromatous plaque may expand outwards from the lumen of the artery (the Glagov phenomenon), and only late in the progression of atheroma does the lesion reduce the size of the lumen. The extent to which the lumen is occluded by a lesion in the absence of an acute coronary syndrome is a poor guide to the stability of the plaque or the future natural history.20 Most complete coronary occlusion events resulting in ST-elevation myocardial infarction, occur at plaques with <40% stenosis of the vessel lumen, which therefore were not flow-limiting before plaque rupture or erosion. Conversely, plaques causing significant stenosis with flow limitation are often heavily calcified and have a relatively thick fibrous cap, both of which pathological phenomena lead to plaque stability and reduced probability of rupture. In our opinion, this reflects different pathophysiological processes occurring in the coronary artery wall, resulting in the different phenotypic manifestations of coronary artery disease (CAD). As a consequence, many patients with stable angina have a much better prognosis than those with acute coronary syndromes, suggesting that these two phenotypes do not always co-exist. Superimposed statin therapy modifies these risk profiles further, making it more difficult to identify the subgroup of stable angina patients who are most likely to develop acute coronary syndromes.

In modern developed societies, the prevalence of CAD in the whole population is about 6%, and the prevalence of angina is 3%. The prevalence depends critically on age, sex, ethnicity, economic and social factors, and the demographics of the population.


   Current treatment of angina
Top
 Abstract
 Angina and its causes
 Current treatment of angina
New pharmaceutical approaches
 Long-term outcomes of drugs...
 Conclusion
 References
 
Medical treatment
The medical treatment of angina has changed little in the past few years. Nitrates were first described for treatment of the condition by Brunton21 in 1867. Beta-blockers were introduced for treatment in the 1960s, following the development of specific beta-antagonists by James Black. Pronethalol was the first beta-blocker, but because of its side effects it was replaced by propranolol. There has since been a proliferation of beta-blockers with different pharmacological properties such as duration of action, lipid solubility, and cardiac specificity. Beta-blockers have been shown in large trials to have clinical efficacy not only in the treatment of angina but also in hypertension, post-myocardial infarction, and heart failure.

The calcium antagonists were introduced in the 1970s for angina and are presumed to have their major impact by increasing coronary flow as a consequence of dilatation of the coronary vessels. Verapamil and diltiazem also reduce conduction velocity through the atrioventricular node and as negative chronotropes may also reduce myocardial oxygen consumption and increase diastolic perfusion time via this mechanism. Another possibility is that this class of drug diminishes the progression of atherosclerotic lesions. Calcium antagonists are also used for the treatment of hypertension. Several recent trials have demonstrated the long-term safety of these drugs,22 following the suggestion in the 1990s that they might increase mortality from myocardial infarction.

Thus, the current conventional medical treatment of angina pectoris is nitrates, beta-blockers, and calcium antagonists for symptoms and aspirin and statins for prevention. Calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, and blood pressure lowering combinations of drugs may also be used to improve long-term outcomes in selected subsets of patients.

Invasive interventions
Favaloro performed bypass surgery (CABG) in 1967, and in 1979 Gruntzig reported on the first patient treated with percutaneous angioplasty (PCI). The more recent introduction of stents, and subsequently coated stents, has improved the outcome after PCI and diminished the complication of restenosis. Many large clinical trials have sought to demonstrate the benefits of one or other form of revascularization by means of invasive intervention in patients with coronary heart disease presenting as angina pectoris. Unquestionably, these treatments relieve the symptoms of angina. CABG reduces mortality and morbidity in patients with the most severe forms of coronary disease, although the data are now rather old and as medical, anaesthetic, and surgical treatments have advanced, the benefit of CABG for patients with stable angina in contemporary clinical practice is unknown. Currently, CABG is usually recommended only in patients with important obstruction of the left main coronary artery or with extensive obstructive lesions in all three main coronary arteries.

What has not been shown is that mortality or the occurrence of myocardial infarction is reduced by PCI. Two large studies have indicated that CABG may have a small advantage over PCI. PCI is reserved for patients with angina pectoris and atherosclerotic lesions localized to one or two vessels and in whom symptoms remain unacceptable despite best medical treatment. The probable reason is that fatal or non-fatal myocardial infarction is the consequence of erosion or rupture of an atherosclerotic plaque which is not necessarily the lesion that on a simple angiogram appears to be the lesion most hindering blood flow at the time of a coronary angiogram.20 Coronary angiography does not detect unstable plaques or the lesions most likely to be the cause of subsequent cardiac events. Thus, revascularization for most patients with angina is a treatment for symptoms and must compete with medical treatments aimed at the same clinical target and at possible reductions in mortality.

Other treatments
Other treatments such as implanted electrical spinal stimulators, transmyocardial laser therapy at the time of CABG, or percutaneous myocardial laser revascularization are used only in patients whose angina cannot be managed in any other way; how much benefit accrues to patients remains controversial. Therapeutic angiogenesis with a protein such as VEGF or the gene for the protein is still largely experimental.

Treatment outcomes
There have been no recent studies of the natural history of angina pectoris. Even before the introduction of invasive intervention techniques, several studies showed that the outcome of patients with angina was not as dismal as often thought and depends on the extent of coronary disease and the function of the left ventricle (Figure 1). Annual mortality in the absence of severe disease and with reasonable left ventricular function ranged between 1 and 3%.23 Large and long-term studies are needed to have any chance of demonstrating a beneficial effect on this endpoint. The recently published ACTION study reported on 7665 patients followed for a mean period of 4.9 years.22,24–26 The analysis of this database has for the first time allowed the creation of a system for risk analysis in patients with stable angina pectoris.24 A surprising finding was how many patients with angina were treated quite satisfactorily with medical treatment and did not go on to have an interventional procedure. About 50% of patients had had procedures before entering the trial, but only 21% had procedures during the trial.26 The relationships between the severity of angina, the number of diseased vessels, and the number of drugs used for treatment were as expected but with more variability than commonly anticipated.26 One reason is that the relation between the extent of obstruction estimated from the coronary angiogram and the impact on blood flow is complex.


Figure 0931
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  		Figure 1 Mortality in medically treated patients with angina. Adapted from Silverman and Grossman. N Eng J Med 1984;310:1712–1717.

 
What has become clear is that the treatment of angina pectoris with current drugs or with invasive interventions does not resolve the clinical problem of continuing symptoms of angina. The number of patients with residual symptoms is substantial, and new drugs to improve symptoms in these patients are urgently needed. Table 1 summarizes the current use of drugs for this condition and Table 2 indicates the modes of action of drugs including the newer drugs that may become available in the near future (Table 3).


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  		Table 1 Drugs in angina and secondary prevention of coronary heart disease
 

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  		Table 2 Mechanisms of action for drugs in angina
 

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  		Table 3 New drugs for the treatment of angina pectoris and mechanisms of action
 

   New pharmaceutical approaches
Top
 Abstract
 Angina and its causes
 Current treatment of angina
 New pharmaceutical approaches
Long-term outcomes of drugs...
 Conclusion
 References
 
In the past few years, new ideas and new drugs have emerged. Although this topic used to be rather dull, it is becoming an area of considerable medical interest as the emphasis of the management of coronary heart disease moves more to prevention of the occurrence or progression of disease rather than treatment of major acute events.

Nicorandil is a drug that has been licensed fairly recently. It is a chimera drug, with the dual actions of increasing the opening probability of ATP-gated K+ channels and having a nitrate-donating moiety. Opening ATP-gated K+ channels relaxes smooth muscle and contributes to coronary vasodilatation, but this drug was initially developed from research demonstrating the importance of these channels in the pathways involved in myocardial preconditioning. Therefore, nicorandil may have a chronic anti-anginal effect through increased myocardial resistance to ischaemia. Nicorandil reduces the symptoms of angina and has been shown to reduce a combined endpoint, including death and non-fatal myocardial infarction, over a period of 21 months in a mixed population of patients with angina pectoris or an acute coronary syndrome.27

Ivabradine is a new drug for the treatment of angina, which is likely to be available to patients within the next year.28 The mode of action is innovative and differs from all other drugs currently available for the treatment of this condition.29 Ivabradine inhibits the If channel in the sinus node and thereby causes bradycardia without any negative inotropic effects. The drug might be regarded as a beta-blocker that lowers heart rate and has no other effects on heart muscle. In man, the immediate mode of action is likely to be an increase in coronary blood flow due to an increase in the diastolic time interval during which blood flows to the myocardium. Several trials have shown that this drug is advantageous to patients because it reduces symptoms of angina.30,31

Ranolazine is another drug with a novel mechanism of action, which may come to the market in the next year. This drug has had a long history. Previously, the drug was believed to act by modifying the use of substrate in the ischaemic myocardium, switching substrate use from lipids to glucose.32,33 Recent work has suggested a completely different mode of action.34,35 Ranolazine inhibits the slow sodium channel in ventricular heart muscle. An increase in sodium cytosolic concentration is thereby prevented, sodium/calcium exchange is reduced, and calcium accumulation is prevented. The diastolic calcium concentration in the cytosol is lessened. A role for sodium/hydrogen/calcium exchange in myocardial ischaemia was first proposed by Lazdunski.36 Such an effect is likely to prevent the alterations of diastolic function that occur early in myocardial ischaemia and particularly in clinical situations such as angina on exercise and the acute coronary syndromes. Recent clinical trials have shown benefit in that symptoms are reduced.37–39


   Long-term outcomes of drugs used in the treatment of angina pectoris
Top
 Abstract
 Angina and its causes
 Current treatment of angina
 New pharmaceutical approaches
 Long-term outcomes of drugs...
Conclusion
 References
 
The availability of these new drugs to the physician will increase the options in the medical management of patients with angina. A further consideration, however, is whether these drugs have any impact for either benefit or harm in the long-term. There is no information on the long-term outcome with most drugs used to treat angina. The evidence for the use of beta-blockers comes from studies on patients with different medical conditions such as heart failure and post-myocardial infarction. The only long-term study in angina pectoris is the ACTION study, which followed 7665 patients for a period of almost 5 years.22 That study showed calcium antagonists to be effective in reducing cardiovascular procedures but not to have an impact on mortality or the combined endpoint of death, stroke, or myocardial infarction. The safety endpoint was met. Several other trials in hypertension have confirmed the safe use of calcium antagonists in the long-term.

There is evidence relating to ACE inhibitors in slightly different groups of patients, namely those at high risk of coronary heart disease (HOPE study with ramipril40) and those with coronary heart disease and/or previous myocardial infarction.41,42 These studies do provide a basis for believing that in certain groups of patients, probably those at highest risk, ACE inhibitors may prevent adverse cardiovascular outcomes. Whether these results can be applied to patients with angina is a matter of judgement because no trial in this group of patients has been reported; ACE inhibitors are not effective in the reduction of the symptoms of angina, and much of their benefit is attributable to the lowering of blood pressure. There were important differences in the baseline characteristics of the patients admitted to these trials (Tables 4 and 5). The annual mortality does provide an indication of the type of patient included in these trials and the degree of risk. Where the annual mortality is low and approaching that in the normal population, the treatment may be worse than the disease.


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  		Table 4 Comparison of patients in recent coronary heart disease trials
 

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  		Table 5 Mortality studies in chronic stable angina, coronary heart disease, or high-risk patients
 
Other treatments have been shown to be effective in the prevention of events in patients with coronary heart disease, notably, the statins43 and aspirin.44 Most of the data on aspirin comes from studies in patients with acute coronary syndromes. Only one study has reported on the effect of aspirin in a group of patients with chronic angina pectoris.45


   Conclusion
Top
 Abstract
 Angina and its causes
 Current treatment of angina
 New pharmaceutical approaches
 Long-term outcomes of drugs...
 Conclusion
References
 
The availability of new drugs with which to treat patients with angina provides a new opportunity and challenge to the cardiovascular physician. We will have to learn exactly how to use these drugs, in which patients they are beneficial, and in what circumstances they should be prescribed. There are many patients whose lives may be enhanced by the careful use of these innovative drugs. Eventually, it will be necessary to have evidence of the impact on long-term outcomes.

Conflict of interest: P.A.P.-W. was the Chair of the Steering Committee of the ACTION trial. He has been a consultant adviser to Menarini, Servier and CV Therapeutics.


   References
Top
 Abstract
 Angina and its causes
 Current treatment of angina
 New pharmaceutical approaches
 Long-term outcomes of drugs...
 Conclusion
 References
 

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