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Unmet medical needs and therapeutic opportunities in stable angina

Philippe Gabriel Steg^* and Dominique Himbert

Department of Cardiology, Hôpital Bichat-Claude Bernard
Assistance Publique, Hopitaux de Paris, 46 rue Henri Huchard, 75877 Paris Cedex 18, France

^* Corresponding author. Tel: +33 140258668; fax: +33 140258865. E-mail address: gabriel.steg{at}bch.ap-hop-paris.fr

	Abstract

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 
Stable angina is a frequent problem and it impacts on outcomes and quality of life. The treatment of stable angina includes a wide array of tools, including medical therapy and percutaneous and surgical revascularization. In the past decade, the use of myocardial revascularization techniques has tremendously expanded; new anti-ischaemic therapies have emerged and secondary prevention strategies are ever more effective. However, despite these advances, there remain important unmet medical needs in the treatment of angina pectoris. Many patients are not amenable to revascularization or experience angina despite having had revascularization. In addition, a substantial proportion of patients who are on medical therapy (even including patients with prior revascularization) still experience anginal symptoms. Current medical therapy has shortcomings, mainly related to insufficient efficacy, lack of haemodynamic tolerance and side effects. There is currently little proof of a direct impact of anti-ischaemic therapy on clinical outcomes in the context of stable angina. More studies are needed to explore the impact of anti-anginal therapies on outcomes in the revascularization era. In addition, there is evidence of underuse of effective, evidence-based therapies in patients with coronary artery disease. Efforts are needed to improve physician adherence to prescription guidelines and long-term patient compliance with polytherapy.

Key Words: Angina • Evidence-based medicine • Revascularization

The treatment of stable angina nowadays includes a wide array of tools, including medical therapy and percutaneous and surgical revascularization. The use of myocardial revascularization techniques has tremendously expanded, new anti-ischaemic therapies have emerged, and secondary prevention strategies are ever more effective. Yet, despite these advances, there remain important unmet medical needs in the treatment of patients with angina pectoris.

	Unmet medical needs

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 
Epidemiology
The prevalence of angina pectoris is not well known and most of the available studies are already somewhat old. In an overview,¹ it was estimated that the prevalence of angina ranged from 2 to 5% among men aged 45–54 years and 11 to 20% in men aged 65–74 years. Figures in women of the same age were markedly lower, ranging from 0.5 to 1% and 10 to 14%, respectively. These figures highlight two key features of the epidemiology of angina: at a given age, it is far more prevalent among men than among women (except >85 years old), and its prevalence increases markedly with age after 40 years of age. It is estimated that 2 million people suffer from angina in the United Kingdom.

Recent studies highlight a major change in the epidemiology of the disease in industrialized countries: given the improvement in preventive measures, the continuous increase in the use of revascularization techniques and the improvement in prognosis and survival after acute coronary events, there has been a shift of the disease burden towards older age groups. Given the increasing age of the population in most Western countries, this is therefore likely to result in an increase in the overall prevalence of the disease. Indeed, recent statistics appear to confirm this: a comparison of two British censuses of the prevalence of angina in England and Wales, conducted in 1981–82 and 1991–92, respectively,² demonstrates an overall 60% increase in the prevalence of International Classification of Diseases, 9th revision (ICD-9) code 413, with an almost doubling of the prevalence in patients aged 75 years or more (Figure 1).

View larger version (15K): [in this window] [in a new window]   Figure 1 Prevalence of angina in men in England and Wales in 1981–82 and 1991–92, respectively. From Royal College of General Practitioners, the Office of Population Censuses and Surveys, and the Department of Health.2

 
Angina affects the quality of life in all its dimensions, as demonstrated by a classic analysis from the Randomized Intervention Treatment of Angina (RITA) trial.³ In more than half of the patients, the severity of anginal symptoms seriously limits their everyday activities, often leading to premature retirement.¹ Angina may also occur following an acute coronary event: from the Framingham data, it was classically estimated that approximately half of the patients who survive an acute myocardial infarction suffer from residual angina (although the current relevance of these data in the current more interventional environment is uncertain).

In summary, the epidemiological problem is simple: angina frequently affects the elderly, a growing segment of the population. It is responsible for serious alterations in the quality of life and increased morbidity and mortality and thus is an important public health issue. The unmet medical needs correspond schematically to four clinical scenarios.

	Medical therapy is insufficient

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 
Because of refractory or disabling angina despite medical therapy, other options must be considered. Usually this will lead to considering revascularization (provided the patient has not already been revascularized). Apart from the issues of safety and tolerability of current anti-anginal agents, the efficacy of anti-anginal therapy often remains insufficient. There are patients who are resistant to anti-anginal therapy and have refractory angina. In the RITA-2 randomized trial, which compared medical therapy with percutaneous transluminal coronary angioplasty (PTCA), more than one-third of the patients initially assigned to medical therapy eventually required revascularization.⁴ Refractory angina is especially frequent among the elderly. In a randomized clinical trial of invasive vs. medical therapy in patients >80 years of age, roughly half of the patients initially assigned to medical therapy eventually underwent revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery because of refractory symptoms, despite being treated with at least two anginal drugs.^5,6 After 4 years of follow-up, revascularization during the first year emerged as a predictor of long-term survival.⁷ Even among young patients, refractory angina is not an uncommon problem. Although figures are lacking to assess its exact magnitude, there is no doubt that there are patients with severe disabling angina and coronary artery disease who are refractory to conventional forms of treatment, even used in combination. A recent European Society of Cardiology (ESC) Joint Study Group report⁸ has reviewed this issue and detailed the potential therapeutic options in patients with refractory angina. These treatments are often largely experimental. Options include (but are not limited to) enhanced external counterpulsation, laser myocardial revascularization, coronary angiogenic therapy, neuromodulation techniques (using transcutaneous electric nerve stimulation and spinal cord stimulation) or even thoracic epidural anaesthesia.

	Angina persists despite revascularization

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 
Revascularization does not always abolish myocardial ischaemia, anginal symptoms, or the need for anti-anginal therapy. One would like to think that after myocardial revascularization, be it surgical or percutaneous, both anginal symptoms and myocardial ischaemia are abolished and that patients are no longer at risk of adverse cardiac events. However, studies demonstrate the opposite even after successful revascularization for stable angina, a condition theoretically rather at low risk of acute events. Myocardial ischaemia often persists after revascularization and in the majority of cases it is silent.⁹ In the RITA-2 trial, PCI improved symptoms early after intervention in comparison with patients assigned to medical therapy. However, in the long term, this difference was attenuated because of symptomatic improvement in the medical therapy group.⁴ Data from the National Heart, Lung, and Blood Institute (NHLBI) Dynamic registry, which enrolled 1755 consecutive PCI patients in 1997 (of whom 26% had angina in the previous 6 weeks), show that 1 year later, event rates were high and higher among patients with more severe angina prior to revascularization.¹⁰ These data also demonstrate that the combined prevalence of angina and events was higher than 18%. Finally, the use of anti-anginal medications was needed in a substantial number of patients (Figure 2), even when they were symptom-free; >60% of the patients were on ß-blockers and roughly one-third of the patients were taking at least one anti-anginal therapy. Even if a fraction of these 60% of patients received ß-blockers, not because of symptoms but as a standard post-myocardial infarction treatment, these figures demonstrate the relatively frequent need for anti-anginal therapy in patients who underwent successful contemporary percutaneous revascularization.¹⁰ In another study using systematic myocardial perfusion assessment following PCI, 19% of patients complained of angina after PCI and 32% had evidence of ischaemia on perfusion imaging.⁹ Silent ischaemia impacted negatively on outcomes, but symptomatic ischaemia was associated with a very high rate (52%) of critical events at follow-up (Figure 3).

View larger version (22K): [in this window] [in a new window]   Figure 2 Use of anti-anginal medications 1 year after successful percutaneous revascularization in the National Heart, Lung, and Blood Institute (NHLBI) Dynamic registry as a function of the presence of anginal symptoms. From Holubkov et al.10

 

View larger version (14K): [in this window] [in a new window]   Figure 3 Impact of use of evidence-based therapies after acute coronary syndromes on adjusted 6-month mortality. Adapted from Mukherjee et al.13

 

	Revascularization is impossible

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 
There is a temptation to think that given the tremendous advances in percutaneous and surgical myocardial revascularization, the issue of chronic stable angina is dwindling. This is in fact far from true. Given the increasing lifespan of patients with established coronary artery disease, they will often experience acute coronary events, revascularization, and stable angina, although at different times. Often, angina persists despite revascularization or after it has already been performed and the issue is that of attempting further revascularization. There are a host of reasons why revascularization may not be attempted.⁸ In fact, a Swedish survey of patients referred for angiography because of severe angina pectoris in 1994–95 found that 6 to 9% of patients referred for revascularization were rejected despite severe symptoms.⁸

	Medical therapy is poorly tolerated

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 
Almost all current anti-anginal agents have frequent and sometimes severe side effects, most of which are related to their haemodynamic impact. Even side effects that are considered relatively mild (e.g. headaches with nitrates or leg oedema with calcium blockers), although certainly not life-threatening, are common reasons for treatment discontinuation. The problem of side effects is even bigger given the frequency of use of ‘combination therapy’ with several anti-ischaemic agents to prevent or control ischaemic symptoms. In that case, side effects such as hypotension, leg oedema, negative inotropy, or low heart rate become much more frequent. These issues are typically more frequent among the elderly group of patients, in whom maintaining long-term intensive medical therapy is often a challenge, leading fairly often to eventual revascularization.⁷

There are also patient subsets in whom anti-anginal therapy is more difficult: a good example is patients with angina pectoris and congestive heart failure who are a difficult group to treat. Though their prognosis is far more severe than patients with angina of the same age, treatment options are often limited in this group. In the context of acute heart failure, it is impossible to institute ß-blockers or other negative inotropic anti-anginal agents, and it is usually necessary to discontinue them if they were previously prescribed. Therefore, in that context, nitrates and nitrate-like agents are often the only anti-ischaemic therapy that can be used. In fact, despite the overall frank clinical benefit of ß-blockers in chronic heart failure, patients with angina and congestive heart failure remain undertreated with ß-blockers.¹¹

	Therapeutic opportunities

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 
Need for more evidence of improved clinical outcomes with anti-anginal therapy
Because the extent and severity of ischaemia have a direct link to prognosis in patients with coronary artery disease, it might be hoped that anti-ischaemic agents would be helpful for improving prognosis. However, very few trials have suggested or demonstrated a potential clinical benefit on ‘hard outcomes’ such as death or myocardial infarction, solely from anti-anginal agents, in the context of stable angina, largely because of the lack of placebo-controlled trials.¹² There is, thus, a dire need for more trials in appropriate, and particularly in older, high-risk patient populations to test and demonstrate that outcomes really can be improved with anti-anginal agents. In this respect, the landmark Trial of Invasive versus Medical therapy in Elderly patients with chronic symptomatic coronary artery disease (TIME) set an example that needs to be followed in investigating this difficult but increasingly frequent issue.^5,6

Better implementation of evidence-based therapies
There is clear evidence from the recent literature that despite having effective and proven therapies available, these are not always used in ‘real-life’ situations. Studies have shown that ‘undertreatment’ with evidence-based therapies is associated with worse outcomes. Specifically, patients with coronary artery disease clearly benefit from therapy using the ‘fab four’ combination of anti-platelet agents, ß-blockers, statins, and aspirin, and recently, increased mortality has been linked to underprescription of this combination in patients with acute coronary syndromes¹³ (Figure 3). This has prompted efforts to improve adherence to guidelines¹⁴ and use of evidence-based therapies. Although efforts are already underway in the field of acute coronary artery disease, much remains to be done in patients with stable angina. The recent publication of the Euro Heart Survey on stable angina provides a description of pharmacological and revascularization strategies used in Europe.¹⁵ It showed a shortfall in the use of evidence-based therapies such as the fab four with use of aspirin in 78%, statins in 48%, ß-blockers in 67%, and angiotensin-converting enzyme (ACE) inhibitors in 37% of the patients overall. Also, although almost half of the newly diagnosed patients underwent revascularization, this appeared driven neither by symptoms nor by risk assessment, but mainly by national rates of angiography and the availability of invasive facilities.¹⁵

Treatment of angina pectoris
The goals of treatment are to improve prognosis (i.e. prolong life expectancy) by preventing death and/or myocardial infarction and by improving quality of life by treating and preventing the symptoms related to ischaemia.^16,17 Some of the therapies designed to relieve myocardial ischaemia may be expected to impact on the risk of death and myocardial infarction.

Treatments that prevent death or myocardial infarction
Most of these treatments do not have a direct anti-ischaemic effect, with the exception of ß-blockers. There are essentially four categories of such therapies: ß-blockers, anti-platelet agents, statins, and ACE-Inhibitors.

ß-Blockers
ß-Blockers represent the cornerstone of anti-ischaemic therapy for stable effort angina (in patients with pure rest angina related to coronary spasm with angiographically normal coronary arteries, ß-blockers are ineffective and may in fact exacerbate symptoms by resulting in unopposed -receptor activation). However, the benefit of ß-blockers may well extend beyond their ability to control anginal symptoms. The survival benefit of ß-blockers in secondary prevention after myocardial infarction¹⁸ suggests that they might be effective in preventing recurrent episodes of instability and myocardial infarction. In addition, considering the role of the sympathetic nervous system in the triggering or facilitation of severe ventricular tachyarrhythmias and sudden death, ß-blockers may also be beneficial to patients with stable angina by preventing ventricular arrhythmias or sudden death. However, no trial has unequivocally established that ß-blockers prevent infarction or sudden death in chronic stable angina without previous infarction.

Anti-platelet agents
Anti-platelet agents have proven efficacy in preventing cardiac events and death in all forms of coronary heart disease: unstable angina and acute myocardial infarction, but also stable angina. A collaborative analysis of trials of anti-platelet agents showed a 22 per 1000 absolute reduction in the risk of adverse vascular events for 2 years of treatment in patients with stable angina.¹⁶ Thus, aspirin is widely recommended for patients with all forms of ischaemic heart disease, including patients with stable angina, in the absence of contraindications. In patients who are intolerant or allergic to aspirin, thienopyridines, and specifically clopidogrel, may be an alternative therapy. When aspirin is absolutely necessary (e.g. for patients who do not have prolonged access to clopidogrel or when the patient has received a stent), desensitization to aspirin can be performed.¹⁹ Although there are no data available regarding the specific group of patients with stable angina, the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial suggests that in a secondary prevention trial of cardiovascular disease²⁰ clopidogrel is at least as effective as aspirin. The future of anti-platelet therapy in stable angina patients may lie in long-term dual oral anti-platelet therapy, as is currently being investigated in the Clopidogrel for high Atherothrombotic Risk and Ischaemic Stabilization, Management, and Avoidance (CHARISMA) trial,²¹ performed in high-risk patients, comparing combined clopidogrel and aspirin with aspirin, in the hope of an improved prevention of cardiovascular events, without increases in the risk of severe bleeding.

Statins
There is solid evidence for a reduction in cardiovascular events with statin therapy in patients with elevated cholesterol. The Heart Protection Study demonstrated that treatment with 40 mg of simvastatin was associated with a reduction in all-cause mortality in patients at high risk of cardiovascular events, including patients with ‘normal’ lipid levels and with a substantial reduction (odds ratio, 0.76) in the risk of any vascular event in patients with all forms of coronary heart disease. More recently, the Treating to New Targets randomized trial demonstrated that intensive lipid-lowering therapy with a high dose of atorvastatin, to lower low-density lipoprotein (LDL) cholesterol levels below 1 g/L (mean 0.77 g/L) in patients with stable angina, was associated with significant clinical benefit, compared with a group treated with a lower dose (10 mg of atorvastatin), which reached the ‘conventional’ target of 1 g/L LDL. Specifically, major cardiovascular events were reduced from 10.9 to 8.7% over the course of 4.9 years, a 2.2% absolute and a 22% relative risk reduction.²² Therefore, aggressive lipid-lowering treatment should be initiated in patients with established coronary artery disease such as stable angina¹⁷ and probably target LDL cholesterol levels below 0.70 g/L.²³

ACE-Inhibitors
ACE-Inhibitors are of proven efficacy for treating hypertension and heart failure. The Heart Outcomes Prevention Evaluation (HOPE) trial²⁴ established its benefits in 9297 patients at high risk of cardiovascular events, defined as age 55 years, with evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure. In that trial, total mortality was reduced by 16% from 12.2 to 10.4% (P=0.006), and the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke was reduced from 17.8 to 14.0% (P<0.005). This was strongly suggestive of benefits beyond treatment of hypertension or heart failure. The EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease²⁵ (EUROPA) was established to test the ability of perindopril 8 mg to reduce cardiovascular death, nonfatal myocardial infarction, and cardiac arrest in patients with stable coronary artery disease and without heart failure or uncontrolled hypertension, on top of standard preventive therapy. After 4.2 years of follow-up, patients randomly assigned to perindopril 8 mg had a lower rate of cardiovascular death, myocardial infarction, or cardiac arrest than patients randomized to placebo (8.0 vs. 9.9%; P=0.0003). This was associated with a consistent benefit on secondary endpoints, notably the combined endpoint of total mortality, nonfatal myocardial infarction, unstable angina, and cardiac arrest (14.8 vs. 17.1%; P=0.0009), as perindopril 8 mg reduced risk of nonfatal myocardial infarction by 22% (P=0.001) and hospitalization for heart failure by 39% (P=0.002). EUROPA confirms and extends the results seen in the HOPE trial. In aggregate, these two trials strongly suggest that all patients with coronary artery disease should receive perindopril 8 mg or ramipril 10 mg daily. In a recent study, the Prevention of Events with Angiotensin-Converting Enzyme inhibition (PEACE) trial did not find any benefit of 4 mg of trandolapril in a similar risk population when compared with the EUROPA trial.²⁶ A meta-analysis of the HOPE, PEACE, and EUROPA data shows significant reduction in mortality (by 14%; P<0.001), re-infarction, and stroke. This confirms the clear benefits of ACE inhibition in patients with vascular disease and no left ventricular dysfunction.²⁷ Another meta-analysis of the seven clinical trials of ACE-Inhibitors in this indication also found a clinical benefit of this therapy with a 14% relative reduction in overall mortality and an 18% reduction in the incidence of myocardial infarction (N. Danchin, personal communication).

Medical therapy to relieve ischaemia and symptoms
There are various classes of agents available to control or prevent myocardial ischaemia and anginal symptoms in patients with coronary artery disease, including ß-blockers, calcium channel blockers, nitrates, and nitrate-like agents (e.g. molsidomine), metabolic agents (e.g. trimetazidine or ranolazine), and potassium channel blockers (e.g. nicorandil). It is generally estimated that these agents have a similar efficacy on angina (judged from the number of angina attacks or the use of rapid-acting nitrates) or on ischaemia (judged from the duration of exercise on a stress test). However, most of these agents have not been proved to reduce morbidity/mortality in patients with angina, largely because of the small number of trials performed and because of the low background rate of events in patients with stable coronary artery disease.

Calcium blockers
As a class, calcium antagonists appear very similar to ß-blockers in relieving anginal symptoms in chronic stable angina.¹⁷ These agents have been shown to be very effective in reducing angina in patients with vasospastic angina. However, their impact on patient outcomes has been the subject of intense debate: some,²⁸ but not all, analyses of retrospective case–control studies in hypertensive patients have shown increased risks of myocardial infarction with calcium antagonists, mostly with immediate or short-acting dihydropyridines. The 2002 American College of Cardiology (ACC)/American Heart Association (AHA) updated guidelines for the management of chronic stable angina have indicated that relatively short-acting dihydropyridine calcium antagonists have the potential to enhance the risk of adverse cardiac events and should be avoided, whereas long-acting calcium antagonists, including slow-release and long-acting dihydropyridines and nondihydropyridines, are effective in relieving symptoms and should be used in combination with ß-blockers if they are not sufficient or as a substitute when they are contraindicated or have unacceptable side effects.¹⁷ Recently, A Coronary disease Trial Investigating Outcome with Nifedipine GITS (ACTION) compared the long-acting GITS (gastrointestinal therapeutic system) formulation of nifedipine with placebo.²⁹ This is in contrast to previous studies that have used short-acting formulations of nifedipine. Just under 8000 patients were followed for a mean of 4.9 years—half of whom were treated with nifedipine GITS and half with placebo. The primary endpoint was major cardiovascular event-free survival, defined as time to occurrence of the first of the following events: death from any cause, acute myocardial infarction, refractory angina, new overt heart failure, debilitating stroke, and peripheral revascularization. Mortality was 1.64 per 100 patient-years among patients allocated to nifedipine compared with 1.53 in those allocated to placebo (P=0.41). Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo (P=0.54). The difference was mainly attributable to a reduction in the soft endpoint of ‘need for coronary angiography and interventions’ in patients assigned to nifedipine, despite an increase in peripheral revascularization. Despite significant reduction in systolic and diastolic blood pressures, nifedipine had no effect on the rate of myocardial infarction. Considering that this study compares nifedipine with placebo, these data do not make a compelling case for adding nifedipine to the treatment of patients. They suggest that long-acting nifedipine is probably safe in the context of stable angina, but conversely does not have a benefit in terms of reduction of ‘hard’ endpoints.

Nitrates
Nitrates are highly effective in relieving anginal symptoms, for which short-acting sublingual spray or tablet preparations are mostly used. In addition, transdermal or oral long-acting nitrates also prevent ischaemic episodes and anginal recurrences. Despite their unequivocal efficacy in treating or preventing anginal attacks, there is no fruitful study performed to demonstrate the benefit of nitrates on clinical outcomes in stable angina. Thus, at present, this class of agents is mostly indicated for symptom relief and prevention, alone or in addition to ß-blockers or calcium blockers.

Nicorandil
Nicorandil is a potassium channel activator that has haemodynamic effects similar to those of nitrates and appears effective in the treatment of stable angina. In addition to its anti-ischaemic properties, this agent may have cardioprotective effects related to mimicking the myocardial preconditioning effect. The Impact Of Nicorandil in Angina (IONA) trial³⁰ has demonstrated that, in patients with stable angina, nicorandil was associated with a reduction in the combined endpoint of coronary heart disease death, nonfatal myocardial infarction, or unplanned hospitalization for cardiac chest pain after a mean follow-up of 1.6 years (15.5 vs. 13.1% in the placebo and nicorandil groups, respectively; P=0.014). The trial did not demonstrate a reduction in mortality or combined mortality and nonfatal myocardial infarction.

Metabolic agents
Trimetazidine, the first 3-ketoacyl coenzyme A thiolase (KAT) inhibitor, has been shown, in several double-blind randomized trials, to improve exercise capacity and anginal symptoms.^31–34 These symptomatic benefits are equivalent to those of propranolol³⁵ or nifedipine³⁶ and additive with diltiazem³⁷ or metoprolol.³⁸ Another agent is ranolazine, not yet available, which has been shown to be effective in improving symptoms in patients with chronic stable angina, notably in the recent Combination Assessment of Ranolazine In Stable Angina (CARISA) placebo-controlled randomized trial.^39,40 However, for both of these agents, no reduction in adverse cardiovascular events (such as cardiovascular death or myocardial infarction) has yet been demonstrated, but studies are ongoing.

Ivabradine
Ivabradine, a selective and specific inhibitor of the sinus node I_f current, is a new anti-ischaemic and anti-anginal agent, which acts through a pure heart rate reduction, without interaction with global cardiac function. It is described in detail in other articles in this supplement.

	An important emerging opportunity: the role of physical training

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 
Rehabilitation has traditionally been viewed as a therapy to help recovery of patients following severe acute myocardial infarction and/or CABG. More recently, evidence has accumulated that exercise training is useful for patients with angina pectoris. This is true not only for patients who are not candidates for revascularization but also for eligible patients. The symptomatic benefits appear to stem not only from reduction in the heart rate and/or rate pressure product at submaximal workloads, but also possibly from improved endothelial function⁴¹ or even increased circulating progenitor cells.⁴² More recently, a spectacular randomized clinical trial demonstrated that, compared with PCI, a 12-month programme of regular physical exercise in selected patients with stable coronary artery disease resulted in superior event-free survival and exercise capacity at lower costs, notably owing to reduced rehospitalizations and repeat revascularizations.⁴³ These results justify moving towards a more widespread use of physical training in patients with stable angina, as this represents a cost-effective, safe, and effective therapy.

Improved secondary prevention
Apart from the use of anti-anginal agents, evidence-based therapies also encompass other areas such as secondary prevention and lifestyle interventions. Clearly, more needs to be done to address the issue of continued smoking in patients with coronary artery disease and the growing problems of obesity and the metabolic syndrome, harbingers of future trouble for these patients.

Therapeutic opportunities: the ten commandments of stable angina (Table 1)

1. Identify and treat precipitating factors,⁴⁴ such as anaemia, uncontrolled hypertension, tachyarrythmias, uncontrolled congestive heart failure, and so on.
   
2. Initiate diet and lifestyle changes, to control risk factors, improve diet, and encourage physical activity.⁴⁵ This is particularly important in view of the fact that the majority of patients with established coronary artery disease have abnormal glucose regulation.⁴⁶
   
3. Initiate anti-anginal therapy, tailored to the patient symptoms, starting with one category, usually ß-blockers. If symptoms persist, consider adding another class of anti-anginals. The choice between classes is largely driven by the coexistence of associated diseases such as hypertension, diabetes, heart failure, hypercholesterolaemia, and COPD.
   
4. Ensure prescription of proper effective evidence-based pharmacological secondary prevention. This is mostly centred around the concept of the fab four quartet of medications of anti-platelet therapy (usually using low-dose aspirin), ß-blockers, statins, and ACE-Inhibitors. There is evidence, at least in patients who have experienced acute coronary syndromes, that the continued use of the fab four quartet of drug categories is linked to improved outcomes.^13,47,48
   
5. Ensure that sublingual nitroglycerin has been prescribed and its use explained to the patient for both relief of anginal symptoms as well as for prophylaxis in the case of planned exertion in patients with debilitating angina.
   
6. Re-evaluate the patient clinically and noninvasively for symptoms and for objective evidence of ischaemia, as well as the severity and extent of ischaemia, in order to avoid ‘missing the train’ of revascularization, if appropriate.
   
7. Consider coronary angiography with a view to revascularization in patients who have severe symptoms or evidence of severe ischaemia on noninvasive testing, or patients in whom occupation or lifestyle require a more aggressive approach (particularly in young patients).
   
8. Consider the symptomatic and prognostic benefits of physical training, and, if applicable, enrol the patient in an exercise programme.
   
9. Education of the patient with respect to the need for lifelong therapies, the proper use of preventive and curative anti-ischaemic treatments, and the need for long-term compliance is an essential component of therapeutic success. Most studies of compliance with treatment in chronic cardiovascular disease show disappointingly low rates of long-term compliance, related in part to the side effects of treatment, to their cost, and to the burden of preventive treatment in patients who may have few symptoms or be asymptomatic. Enrolment in a disease-management programme may provide opportunities to improve long-term patient adherence to therapy.
   
10. Educate the patients about the steps to take in the event of recurrent symptoms, including the pathway for seeking urgent medical help.
    

View this table: [in this window] [in a new window]   Table 1 The ‘ten commandments’ of the management of stable angina

 

	Conclusion

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 
In conclusion, stable angina is a frequent problem and it impacts on outcomes and the quality of life. Many patients are not amenable to revascularization or experience angina despite having had one or several revascularizations. In addition, a substantial proportion of patients who are on medical therapy (even including patients with prior revascularization) still experience anginal symptoms. Current medical therapy has shortcomings, mainly related to insufficient efficacy, lack of haemodynamic tolerance, and side effects. There is currently little proof of a direct impact of anti-ischaemic therapy on clinical outcomes in the context of stable angina. More studies are needed to explore the impact of anti-anginal therapies on outcomes in the revascularization era, as well as to improve physician adherence to prescription guidelines and long-term patient compliance.

	References

Top Abstract Unmet medical needs Medical therapy is insufficient Angina persists despite... Revascularization is impossible Medical therapy is poorly... Therapeutic opportunities An important emerging... Conclusion References

 

1. Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J 1997;18:394–413.[Free Full Text]
2. Royal College of General Practitioners, the Office of Population Censuses and Surveys, and the Department of Health. Morbidity Statistics from General Practice, Fourth National Study, 1991–1992. London: Her Majesty's Stationery Office; 1995.
3. Pocock S, Henderson R, Seed P et al. Quality of life, employment status, and anginal symptoms after coronary angioplasty or bypass surgery. 3-year follow-up in the Randomized Intervention Treatment of Angina (RITA) Trial. Circulation 1996;94:135–142.[Abstract/Free Full Text]
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