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Coronary artery disease is a leading cause of death in the United States. Angina is encountered frequently in clinical practice. Effective management of patients with coronary artery disease and stable angina should consist of therapy aimed at symptom control and reduction of adverse clinical outcomes. Therapeutic options for angina include antianginal drugs: nitrates, beta-blockers, calcium channel blockers, ranolazine, and myocardial revascularization. Recent trials have shown that although revascularization is slightly better in controlling symptoms, optimal medical therapy that includes aggressive risk factor modification is equally effective in reducing the risk of future coronary events and death. On the basis of the available data, it seems appropriate to prescribe optimal medical therapy in most patients with coronary artery disease and stable angina, and reserve myocardial revascularization for selected patients with disabling symptoms despite optimal medical therapy., (Published by Elsevier Inc.)

Angina pectoris resulting from myocardial ischemia afflicts half of all patients with coronary heart disease (CHD). Chronic angina remains a major public health burden despite state-of-the-art therapies, and improvement in survival from myocardial infarction and CHD has only increased its prevalence. There is growing experimental and clinical evidence pointing to the anti-ischemic and anti-anginal properties of statins. Some data suggest that the degree of anti-ischemic efficacy of statins may be comparable to the current standard pharmacologic and mechanical strategies. The pleiotropic effects of statins are postulated to be primarily responsible for their anti-ischemic and anti-anginal properties. These include improvement of endothelial function, enhancement of the ischemic vasodilatory response, modulation of inflammation, and protection from ischemia-reperfusion injury. The anti-ischemic effects of statins further strengthen their role as a crucial component of the optimal medical therapy for CHD.

The primary objective of treatment in patients with chronic coronary artery disease (CAD) and stable angina is relief of symptoms and improvement of clinical outcome. The American College of Cardiology/American Heart Association guidelines have emphasized the role of evidence-based therapies. There have been regular updates of the guidelines, with an effort to include the latest data in the recommendations. Since the 2002 guidelines were published, there have been several pivotal studies that have provided strong support for the role of aggressive and optimal medical therapy in improving clinical outcomes in patients with chronic CAD. Recent data from 2 landmark studies have emphasized that optimal medical therapy is as effective as myocardial revascularization with percutaneous coronary intervention or coronary artery bypass grafting in reducing risk of adverse clinical outcomes. The 2009-2010 guidelines will likely incorporate the findings of these studies and accordingly modify the recommendations for treatment of patients with chronic CAD and stable angina.

Ischemic heart disease is the foremost cause of death in the United States and the developed countries. Stable angina is the initial manifestation of ischemic heart disease in one half of the patients and becomes a recurrent symptom in survivors of myocardial infarction (MI) and other forms of acute coronary syndromes (ACS). There are multiple therapeutic modalities currently available for treatment of anginal symptoms in patients with stable CAD. These include anti-anginal drugs and myocardial revascularization procedures such as coronary artery bypass graft surgery (CABGS), percutaneous transluminal coronary angioplasty (PTCA) and percutaneous coronary intervention (PCI). Anti-anginal drug therapy is based on treatment with nitrates, beta blockers, and calcium channel blockers. A newly approved antianginal drug, ranolazine, is undergoing phase III evaluation. Not infrequently, combination therapy is often necessary for adequate symptom control in some patients with stable angina. However, there has not been a systematic evaluation of individual or combination antianginal drug therapy on hard clinical end points in patients with stable angina. Most revascularization trials that have evaluated treatment with CABGS, PTCA, or PCI in patients with chronic CAD and stable angina have not shown significant improvement in survival or decreased incidence of non-fatal MI compared to medical treatment. In the CABGS trials, various post-hoc analyses have identified several smaller subgroups at high-risk in whom CABGS might improve clinical outcomes. However, there are conflicting findings in different reports and these findings are further compromised due to the heterogeneous groups of patients in these trials. Moreover, no prospective randomized controlled trial (RCT) has confirmed an advantage of CABGS, compared to medical treatment, in reduction of hard clinical outcomes in any of the high-risk subgroups. Based on the available data, it appears reasonable to conclude that for most patients (except perhaps in those with presence of left main disease > 50% stenosis) there is no apparent survival benefit of CABGS compared to medical therapy in stable CAD patients with angina. Although these trial have reported better symptom control associated with the revascularization intervention in most patients, this has not been adequately compared using modern medical therapies. Available data from recent studies also suggest treatment with an angiotensin converting enzyme inhibitor (ACEI), a statin and a regular exercise regimen in patients with stable CAD and angina pectoris., (Copyright (c) 2007 Wiley Periodicals, Inc.)

Ambulatory electrocardiographic monitoring was used to assess the anti-ischemic effects of amlodipine in a subset of 56 patients enrolled in a 14-week withdrawal study; amlodipine therapy resulted in a marked decrease in the overall mean number of ischemic events and the average number of transient ischemic episodes (p <0.005). Amlodipine substantially reduced the number of ischemic events among all patients during the single-blind phase, with further significant reductions recorded among patients who remained on amlodipine during double-blind therapy, but the number of ischemic events increased almost to baseline levels in patients switched to placebo during double-blind therapy (p = 0.01 by analysis of variance).

This multicenter, randomized, double-blind, parallel group, placebo lead-in, placebo-controlled study compared the antianginal and anti-ischemic effects of once-daily bedtime dosing of controlled-onset extended-release (COER-24) verapamil to a once-daily morning dosing of amlodipine +/- atenolol in patients with chronic stable angina. A total of 551 patients with exercise-induced myocardial ischemia and evidence of coronary artery disease were randomized to a 4-week, forced-dose titration treatment period with (1) COER-24 verapamil 240 mg titrated to 480 mg at bedtime (n = 173), (2) amlodipine 5 mg titrated to 10 mg/day (n = 149), (3) amlodipine 5 mg (titrated to 10 mg) plus atenolol 50 mg/day in the A.M. (n = 154), or (4) placebo (n = 75). Treadmill exercise tolerance testing (standard Bruce protocol), and 48-hour ambulatory electrocardiographic (Holter) monitoring were performed at the end of placebo lead-in and double-blind treatment. Each active treatment significantly improved symptom-limited exercise duration and time to moderate angina (p < or = 0.01 vs placebo). For patients with baseline ischemia, amlodipine resulted in a statistically significant increase in total duration of ischemic episodes compared with placebo, whereas COER-24 verapamil and amlodipine plus atenolol resulted in statistically significant decreases compared with placebo and amlodipine. Heart rate at onset of ischemic episodes and ST product were also significantly increased with amlodipine (p < 0.05) compared with either COER-24 or amlodipine plus atenolol. COER-24 and amlodipine alone or in combination with atenolol improved exercise capacity in patients with angina pectoris. COER-24 verapamil monotherapy or amlodipine plus atenolol combination therapy were more effective than amlodipine monotherapy in decreasing ambulatory myocardial ischemia, especially during the hours of 6 A.M. to 12 noon.

Myocardial ischemia occurs frequently during daily life and has a circadian pattern similar to that reported for myocardial infarction and sudden death. Because of the increased risk of myocardial ischemia in the morning hours, it has been suggested that the administration of anti-ischemic medication before bedtime may be more effective than the traditional morning dosing. This randomized, double-blind, placebo-controlled, crossover study evaluated the effects of 480-mg/day diltiazem (given either in the A.M. or the P.M.) on myocardial ischemia using ambulatory electrocardiographic monitoring in 68 patients with chronic stable angina and > or = 2 minutes of ischemia per 48 hours. During treatment with diltiazem, the duration and number of myocardial ischemic episodes were reduced by 45% (94 to 52 minutes, p <0.004) and by 40% (4.5 to 2.7 episodes, p <0.003), respectively. The duration and number of myocardial ischemic episodes during daytime (6 A.M. to 6 P.M.) hours were also reduced by 52% (74 to 36 minutes, p <0.002) and by 48% (3.1 to 1.6 episodes, p <0.001), respectively. There was no significant difference between A.M. and P.M. dosing. Morning ischemia (6 A.M. to noon), considered separately from daytime ischemia, was also significantly reduced by both A.M. and P.M. dosing regimens, with no difference between the regimens. The results of this study showed that both A.M. and P.M. dosing of long-acting diltiazem were equally effective in suppressing episodes of ambulatory myocardial ischemia at all times.

Although calcium antagonists form a mainstay of therapy in patients with angina pectoris, the currently available agents have significant limitations. Nifedipine, diltiazem, and verapamil are all high-clearance agents with significant hepatic extraction and rapid clearance, leading to limited and short-lived bioavailability necessitating frequent daily administration. In contrast, amlodipine, a dihydropyridine calcium antagonist, has a long half-life of 35-50 h (compared with 3 to 4 h elimination half-life of diltiazem, verapamil, and nifedipine). After oral doses, the relative bioavailability of amlodipine is high (64%) and absorption is smooth, with peak plasma levels being achieved 6-12 h postdose. Bioavailability is not affected by the consumption of food. In common with other dihydropyridine calcium antagonists, amlodipine is eliminated mainly by metabolism. None of the metabolites of amlodipine has significant calcium antagonist effects in humans. In contrast to verapamil or diltiazem, amlodipine has no effect on sinus or atrioventricular node and little or no effect on the resting heart rate. Amlodipine does not have any appreciable negative inotropic effect with the relevant clinical dose. Other clinical studies have shown amlodipine to be effective when used once-daily in chronic stable angina and vasospastic angina. Comparative studies indicate that the antianginal efficacy of amlodipine is comparable to the beta blocker nadolol and the benzothiazepine calcium antagonist diltiazem. Amlodipine has also been found to provide improved antianginal effects when combined to treatment with beta blockers and/or long-acting nitrates. Treatment with amlodipine either as monotherapy or combined with other antianginal therapy for up to 26 weeks shows that efficacy is maintained, with no evidence of tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

The prognostic significance of ambulatory silent ischemia detected by Holter monitoring during daily life was prospectively evaluated and compared with several exercise test parameters in 86 patients with stable angina and positive exercise tests. Forty-seven patients (group 1) had no evidence of ischemia and 39 (group 2) had 1 or more episodes of silent ischemia during the monitoring period. During mean follow-up of 24 +/- 8 months there were only 2 cardiac deaths (nonsudden) in group 1 (4% mortality) compared with 9 (3 sudden and 6 nonsudden) in group 2 (23% mortality). Kaplan-Meier actuarial analysis revealed worse survival (p less than 0.008) for patients in group 2. The Cox regression analysis of clinical variables, electrocardiographic and exercise parameters, angiographic data and Holter monitoring results revealed silent ischemia during daily life as the most powerful predictor of cardiac mortality (p = 0.003). These results demonstrate that in patients with chronic stable angina and abnormal exercise tests, ambulatory ischemia detected by Holter monitoring provides significant additional prognostic information to that derived from evaluation of exercise test parameters alone.

The anti-ischemic effects of atenolol and nifedipine were compared in a randomized double-blind crossover manner in 24 patients with stable exertional angina and transient silent ischemia during ambulatory electrocardiographic (ECG) monitoring. Both atenolol and nifedipine were effective (p less than 0.005) in reducing the average number and duration of transient ischemic events, but therapy with atenolol was associated with a significantly greater reduction in the mean number (p less than 0.05) and duration (p less than 0.01) of silent ischemic events. Analyses of the silent ischemic activity during the morning hours revealed that only therapy with atenolol produced a significant reduction in the average duration per patient (139 +/- 54 vs. 1,609 +/- 468 s, p less than 0.01) and in the average duration of silent ischemia per event between 6 AM and 12 noon (62 +/- 21 vs. 208 +/- 24 s, p less than 0.005). There were fewer adverse experiences during therapy with atenolol. These results show that although both atenolol and nifedipine are effective in reducing silent ischemic events, treatment with atenolol is associated with significantly greater efficacy, particularly on the morning surge of silent myocardial ischemia.

The predictive value of several exercise test parameters in identifying stable angina patients at risk of silent myocardial ischemia during daily life were examined. A total of 97 patients with coronary artery disease, stable angina and ambulatory electrocardiographic data were evaluated. Of the 86 patients with a positive exercise test, 39 (group 1) had greater than or equal to 1 episodes of ST-segment depression and 47 (group 2) did not develop ST changes during ambulatory electrocardiographic monitoring. Comparison of the exercise test parameters between the 2 groups revealed early onset of ischemia during exercise tests as the single most significant (p less than 0.0005) predictor of ambulatory silent ischemia. The other exercise test parameters showing significant differences between the 2 groups were the peak exercise heart rate (117 +/- 23 vs 126 +/- 20 beats/min, p less than 0.05) and peak systolic blood pressure (160 +/- 27 vs 176 +/- 27 mm Hg, p less than 0.01), both of which were significantly lower in the group 1 patients. These data were used to derive simple mathematical formulas for calculating the risk of ambulatory silent ischemia. These results demonstrate that stable angina patients at risk of silent ischemia during daily life can be accurately identified by evaluation of selected exercise test parameters.

Because of conflicting data and a clear need to establish the relative role of increase in myocardial oxygen demand versus reduction in coronary blood flow in the causation of transient ischemia, the role of heart rate and blood pressure changes immediately preceding and during the transient ischemic events observed during daily life were evaluated in 25 patients with coronary artery disease. Elevations in heart rate before onset of ischemia were observed in 61% of the episodes. Similarly, 73% of the ischemic events were preceded by an increase in arterial pressure. These data provide evidence for a significant role of increased myocardial oxygen demand in the genesis of transient myocardial ischemia.

The prevalence and patterns of silent myocardial ischemia were evaluated in 105 stable angina patients receiving conventional antianginal drug therapy. During 2,520 hours of electrocardiographic monitoring, silent ischemia was detected in 45 (43%) patients. A total of 188 ischemic episodes was observed; 163 (87%) were silent and accounted for a total ischemic duration of 5,771 minutes. There was no difference in the baseline clinical characteristics between the patients with and without ambulatory silent ischemia. However, patients with silent ischemia on ambulatory electrocardiographic monitoring had earlier onset of ischemia during exercise testing. The highest density of silent ischemic events occurred between 6 A.M. and 6 P.M. Comparison of the class or combination of antianginal agents used by the 2 groups revealed no difference. However, in patients with silent ischemia the mean duration per event was shorter for those receiving 2 (p less than 0.05) or more (p = 0.001) antianginal agents compared to those receiving monotherapy. The average duration of silent ischemia per event was significantly less (p less than 0.001) in patients receiving beta blockers. These results demonstrate that silent ischemia during ordinary daily activities occurs frequently despite conventional antianginal drugs prescribed for control of symptoms.

We prospectively examined the prognostic significance of silent myocardial ischemia detected by ambulatory electrocardiogram (ECG) monitoring during daily life in 107 patients with long-term stable angina who were symptomatically controlled on conventional antianginal agents. Forty-six patients (group 1) demonstrated one or more episodes (87% silent) of myocardial ischemia; the remaining 61 patients (group 2) had no ischemic ST segment changes. During the mean follow-up period of 23 +/- 8 months, 11 cardiac deaths (five sudden and six nonsudden) occurred in group 1, and five cardiac deaths (all nonsudden) occurred in group 2. Kaplan-Meier survival analysis between the groups confirmed that patients with silent ischemia (group 1) had worse prognoses during the follow-up period (p = 0.023). Although the higher incidence of hypertension, smoking, hypercholesterolemia, and diabetes in our patients might reflect a more sickly population of stable angina patients, the multivariate Cox's hazard function analysis of these and other variables including Q waves on ECG, exercise parameters, and ambulatory ECG findings revealed presence of silent ischemia during daily life as the most powerful and independent predictor of cardiac mortality (p = 0.01). These data indicate that, in such patients with stable angina, silent myocardial ischemia occurs frequently during treatment with conventional antianginal drugs and identifies a subset of patients who are at high risk of cardiac death.

The most appropriate treatment for a patient with angina pectoris depends on the underlying pathophysiologic process and whether any associated illness is present. Each patient's clinical history must be carefully reviewed so the hemodynamic process responsible for the clinical picture is understood. If symptoms are produced mostly by an increase in myocardial oxygen demand, efforts should be directed toward reducing the demand or improving coronary blood flow to meet the demand. If symptoms appear to occur secondary to vasospasm, treatment should be directed toward relief of spasm with potent vasodilating agents, such as calcium channel blockers. Most patients have a clinical picture consistent with mixed angina and may require combination therapy. Treatment of associated illnesses and the safety of pharmacologic agents used in their presence should be carefully considered. Finally, if treatment is to successfully reduce the incidence of serious cardiac events and prolong life, the goal of therapy should be relief of the total ischemic burden on the heart.