Introduction
Coronary heart disease (CHD), due to atheromatous obstruction of coronary arteries, is the most common form of heart disease. The atheroma forms and accumulates in the wall of the coronary artery (coronary atherosclerosis) beginning at an early age. The disease is thought to be initiated by damage to the endothelium - the inner lining of the vessel wall - as a consequence of a number of so-called risk factors such as smoking, hypertension, diabetes, high cholesterol, the metabolic syndrome, lack of exercise and obesity. Where atheroma accumulates, plaques are formed which intrude into the vessel lumen. Later in life, rupture, fissure or erosion of the plaque initiates many different presentations of heart disease (the coronary syndromes) ranging from myocardial infarction (MI) due to unstable angina or a minor coronary event. If the plaque simply enlarges, then eventually the luminal diameter is decreased so that blood flow to the heart muscle is critically reduced and chronic stable angina pectoris is the clinical consequence.
Of an estimated 57 million deaths worldwide, more than 17 million (31%) are the consequence of cardiovascular disease (CVD).1 Of these CV deaths 43% are attributable to coronary artery disease (CAD) and 32% to stroke. It is often not appreciated that 78% of CV deaths occur in lower or middle income countries and not in the more prosperous countries. Furthermore, these deaths occur at a younger age in less developed countries thus impacting on their economic success. CVD accounts for up to 75% of the cases of overt heart failure in the general population under the age of 75 years.2 Over recent years the number of individuals with CAD has increased steadily and continues to do so. This is an almost inevitable consequence of more patients surviving MI, the ageing population and the increasing prevalence of diabetes, obesity and a lack of physical exercise.3 The four great misconceptions of CHD are that it is a disease of old age, only occurs in men, is a pleasant way to die and is solely the responsibility of individuals. CHD matters.
Unlike the treatment of hypertension and heart failure (HF), there is a relative paucity of definitive information on the impact of drugs used to treat chronic angina pectoris on major clinical outcomes in patients with CHD. The medical management of patients with stable CAD developed initially, and logically, with the use of drugs that were effective in reducing or even abolishing the frequency of anginal symptoms.
In contrast, lifestyle modification and other pharmacologic therapy (treatment of hypertension and high plasma cholesterol) may reduce the incidence of death and MI but there is little or no evidence to suggest these interventions provide immediate symptomatic benefit4 - i.e., the alleviation of angina pectoris. For example, smoking cessation reduces CV mortality and morbidity and improves a patient's ability to exercise, while moderation of excessive alcohol consumption and an increase in physical exercise may also be advantageous;5 however, the major benefit in terms of the symptoms of angina is a consequence of specific medical therapy and/or revascularisation.6
Targeting established risk factors in patients with chronic stable angina, and therefore CHD, is clearly of proven benefit. The efficacy of aspirin in unstable angina, and in acute and post-MI, is well established but the use of aspirin in chronic stable angina is largely founded on the Swedish Angina Pectoris Aspirin Trial (SAPAT).7 In this study although there was a marked reduction of all vascular events, the reduction in all-cause and CV mortality was not significant.
No specific trials with lipid-lowering agents have been conducted exclusively in patients with chronic stable angina. Nonetheless, the accumulated evidence from secondary prevention trials such as 4S,8 Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID)9 and Cholesterol and Recurrent Events trial (CARE)10 and studies performed in high-risk patients, many of whom had a history of chronic stable angina, such as the Heart Protection Study,11 and The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial12, provide compelling evidence of the benefit of statins in reducing CV mortality and morbidity. These data, along with relative benefits of aggressive lowering of low-density lipoprotein (LDL) cholesterol benefits in the AVERT Study13 and more recently the TNT Study,14 provide an evidence base for the treatment of lipid abnormalities in chronic stable angina.
Symptomatic medical treatment of chronic stable angina has largely been based on the use of organic nitrates, beta-blockers and calcium antagonists alone and in combination.
The symptomatic benefits of nitroglycerin have been known for more than 125 years. Organic nitrates are generally well tolerated but their long-term use is limited by the development of tolerance and there is no definitive outcome data of their efficacy in terms of reducing CV mortality and morbidity.
The anti-anginal and anti-ischaemic effects of beta-blockers and their favourable impact on outcome in unstable angina, and in acute and post-MI, have justified their use in chronic stable angina. This is supported by the Atenolol Silent Ischemia Study (ASIST)15 which, although lacking in statistical power, suggested a beneficial effect of atenolol on the prevention of serious CV events in patients with stable angina.
Calcium antagonists are widely used to treat patients with stable angina and are as effective as beta-blockers or nitrates in providing symptomatic benefit. Until very recently the questions as to whether calcium antagonists improve prognosis in stable angina was unanswered and the limited evidence available was based upon comparative studies.
Angiotensin-converting enzyme (ACE) inhibitors provide no symptomatic benefit in chronic stable angina and in the recent large placebo-controlled Quinapril Anti-Ischemia and Symptoms of Angina Reduction (QUASAR) trial16 quinapril did not increase angina-free walking time or reduce exercise-induced or ambulatory ischaemia. One study with ACE inhibitors, which included patients with chronic stable angina, has shown beneficial effects on mortality and morbidity.
Recent Trials of Medical Therapy in Chronic Stable Angina
Over the last five years a series of large clinical trials have reported the effects of different drug therapies on outcome in patients with chronic stable angina. These include:
- International Verapamil-Trandolapril Study (INVEST);
- The Impact Of Nicorandil in Angina (IONA);
- The Heart Outcomes Prevention Evaluation (HOPE);
- The European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA);
- Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE);
- Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT); and
- A Coronary disease Trial Investigating Outcome with Nifedipine (ACTION).
In the INVEST Study,17 over 22,500 patients with hypertension and CAD were randomised to a verapamil-based treatment regimen or an atenolol-based treatment regimen. After a mean follow-up period of 2.7 years no differences were apparent between the groups for the primary end-point (all-cause mortality, non-fatal MI and non-fatal stroke) or any of the other secondary end-points. The study therefore supports the clinical equivalence for CV end-points between the two different strategies and is consistent with studies suggesting equivalent symptomatic benefit and anti-ischaemic effects of beta-blockers and calcium antagonists. The results must be seen in the context of the very limited outcome data with beta-blockers in chronic stable angina.
The IONA study18 was a randomised, double-blind placebo-controlled trial of nicorandil in 5,126 patients with documented CAD and either decreased left ventricular (LV) systolic function, LV hypertrophy, diabetes mellitus or hypertension. After a mean follow-up of 1.6 years there was a significant 17% reduction in the primary end-point (CHD mortality, non-fatal MI or hospitalisation for cardiac chest pain) with nicorandil compared with placebo but no significant reduction in the main secondary end-point (CHD mortality or non-fatal MI). The study included some patients with acute coronary syndrome and for that reason had a higher mortality rate in the placebo group compared with the other trials.
The HOPE study,19 which compared ramipril and placebo over a five year period of follow-up, recruited 9,297 'high-risk' individuals with a history of CAD, stroke or diabetes and at least one other CV risk factor (hypertension, elevated total cholesterol levels, low high-density lipoprotein cholesterol (HDL-C) levels, cigarette smoking or documented microalbuminuria).
There was a significant 22% relative risk reduction in the primary combined end-point of CV death, MI or stroke and in each individual end-point - CV death (26%), MI (20%) and stroke (32%). A small difference blood pressure (3/2mmHg) was apparent between the treatment groups.
EUROPA20 recruited 12,218 patients with documented CAD who were randomised to perindopril or placebo and who were followed-up for 4.2 years. Treatment with perindopril was associated with a significant 20% reduction in the primary combined end-point of CV mortality, MI or cardiac arrest.
In addition, there was a 22% relative risk reduction in non-fatal MI. The benefits appeared to be consistent in all pre-defined subgroups and across the secondary end-points but depended critically on the occurrence of MI, defined using the criteria of the European Society of Cardiology (ESC), which includes troponin-positive chest pain. A statistically significant blood pressure difference of 5/2mmHg was apparent throughout the trial.
The results of the most recently reported trial of an ACE inhibitor in stable CAD contrast with those of HOPE and EUROPA. In the PEACE trial21, 8,290 patients were randomised in a double-blind manner to placebo or trandolapril and were followed-up for a mean period of 4.8 years. Trandolapril did not reduce any of the primary or pre-planned secondary outcomes and overall there were only six fewer CV deaths on trandolapril compared with placebo. The relative blood pressure difference of 3/1.2mmHg achieved during the course of the study was comparable with that of the earlier trials.
The CAMELOT study22 does not really satisfy the criteria of an outcome trial in that the number of patients recruited was small and the follow-up period was relatively short. The trial is of interest in that it directly compared an ACE inhibitor and a calcium antagonist. Patients (n=1,991) with CAD and diastolic blood pressure of less than 100mmHg were randomised to receive amlodipine, enalapril or placebo. At the end of the two-year follow-up period, there was a significant and similar reduction in blood pressure of 6/3mmHg with both amlodipine and enalapril. Patients receiving amlodipine had a significant 31% reduction in the risk of adverse CV events (p=0.003), while the enalapril group had a non-significant risk reduction of 15%.
ACTION23 was the largest ever randomised outcome trial of an anti-anginal drug in patients with symptomatic stable angina. Nifedipine Gastrointestinal Therapeutic System (GITS; a formulation of nifedipine providing a constant concentration of drug over 24 hours or longer) or placebo were added to existing anti-anginal therapy in a double-blind manner in 7,665 patients who where then followed-up for a mean period of 4.9 years. The primary end-point for efficacy (all-cause death, acute MI, refractory angina, new overt heart failure, debilitating stroke and peripheral revascularisation) and primary end-point for safety (all-cause death, acute MI and debilitating stroke) did not differ between the two treatment groups.
With nifedipine GITS the rate of death and any CV event or procedure was significantly less than with placebo. A summary of the findings for selected end-points is shown in Table 1. The 29% reduction in new HF is noteworthy and unexpected; it is unlikely to be solely associated with the 6/3mmHg difference in blood pressure achieved during the trial.
A subgroup analysis of the 52% of ACTION patients who were hypertensive at baseline demonstrated a significant benefit with nifedipine GITS for the primary end-point for efficacy, all CV events, death and any CV event or procedure and vascular events or revascularisation.24
Comparison of Recent Trials
Comparison of different trials (see Table 2) is fraught with difficulty in that entry criteria differ between trials, the definition of end-points and the constituents of composite end-points all substantially differ. The definition of end-points is a special problem in relation to stroke and MI. For example, in ACTION the definition of MI and HF would identify major events, whereas in EUROPA the definition of MI was that of the European Society of Cardiology (ESC), which includes troponin positive chest pain. Debilitating stroke was an end-point in ACTION whereas the other trials included transient ichaemic attacks and minor cerebral events. The effect of the definition of stroke wan shown in the ACTION trial (see Table 1).
The most clinically pertinent comparison is that between the ACE inhibitor and the calcium antagonist trials. In this context it is important to note that of the trials discussed, ACTION was the only one in which there was no change in protocol during the course of the study.
The characteristics of the ACE inhibitor and the calcium antagonist trials shown in Table 3 reveal some important differences between the trials. These are most evident when HOPE is compared with the other studies. Diabetes and peripheral vascular disease at baseline were more common in HOPE, whilst the use of beta-blockers and lipid-lowering drugs was markedly lower. Such discrepancies are also apparent in the annual mortality in the placebo group of the trials (see Table 2).
All of the trials under consideration were statistically powered on the basis of composite end-points and as expected these composite end-points differed between the trials. Similar composite end-points cannot be calculated from the published data. Furthermore, it is impossible to make definitive comparisons of the individual components of the composite end-points due to lack of power. Mortality and CV mortality were common end-points in all of the trials. A comparison of the various trials for these end-points is shown in Figure 1, revealing that only in HOPE was a significant effect on mortality observed. The inadequate power of CAMELOT is apparent.
Therapeutic Implications of Recent Trials
Superficially, the results of PEACE are at odds with those of HOPE and EUROPA. This could be due to the inclusion of patients at high risk in HOPE and the less intensive management of risk factors in both HOPE and EUROPA. In CAMELOT the calcium antagonist proved to be superior to the ACE inhibitor for some end-points. As the overall benefit across the ACE inhibitors trials are relatively modest, it seems reasonable to suggest that their therapeutic use should be based upon the absolute benefit in an individual patient, particularly as these agents provide no symptomatic benefit.
In contrast, the ACTION trial conclusively demonstrates that nifedipine GITS can be used safely for the long-term treatment of CAD patients because, in addition to providing symptomatic benefit, it prolongs CV events and procedure-free survival.
Most patients with CHD should receive aspirin and a statin unless there is good reason not to do so. Patients with chronic angina pectoris should be treated more aggressively and a calcium antagonist added to their treatment because of the benefit in terms of improvement of symptoms, fewer CV procedures and in particular less cardiac surgery. Patients with CHD and hypertension may best be treated with the combination of a calcium antagonist and an ACE inhibitor. This would be supported by the results of the recently reported Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) in hypertensive patients with risk factors for CHD, comparing a treatment regime based on an ACE inhibitor and a calcium antagonist versus a regime combining a diuretic with a beta-blocker. Where a patient is simply at high risk the decision is less certain and a calcium antagonist, an ACE inhibitor or both could reasonably be prescribed.