Chronic stable angina is the major symptomatic presentation in about 50% of CHD patients.^5,6 There is a growing prevalence of chronic ischemia and angina due to residual coronary artery disease (CAD) after PCI and CABG. Of the 1620 consecutive NHLBI dynamic registry patients who underwent PCI, 26% continued to report angina despite more than one antianginal medication.⁷ In the ARTS trial, patients were randomized to PCI or CABG for symptom relief. Despite optimal revascularization nearly 80% of the patients in the PCI group and 60% in the CABG group continued to experience angina and required antianginal medications.⁴ Thus increased revascularization has led to increasing residual ischemia, and an increasing need for medical therapy.

Patients continue to experience persistent ischemia and angina despite traditional drug therapy. A significant percentage of patients have relative intolerance to full doses of nitrates, CCB and beta-blockers, and despite use of traditional agents, patients reported having two anginal episodes per week on average.³ Combinations of beta-blockers and CCBs have similar depressive effects on blood pressue (BP), heart rate (HR) and AV nodal conduction, thus limiting maximal dosage of each of the medications. Thus improved treatment of recurring ischemia and angina remains an important therapeutic goal.

A disparity between the metabolic demands of the myocardium during exertion (as a consequence of increasing contractility, heart rate and systolic wall stress) and the inability to supply incremental coronary blood flow (CBF) due to narrowed epicardial coronary arteries in the face of increased myocardial oxygen demand is the principal factor in developing angina pectoris in CHD.⁹ Increases in heart rate precipitated by adrenergic stresses, such as physical or emotional stress, sexual activity, or physiologic stresses such as arrhythmias, thyrotoxicosis or infection may precipitate so-called “demand angina”.⁹ CBF is the most important determinant of myocardial oxygen supply. Numerous factors influence the epicardial and subendocardial blood flow. Limitations of CBF may be due to atherosclerosis in either the epicardial or coronary micro-vasculature. In the epicardial coronary arteries, as coronary atherosclerosis progresses, there is progressive plaque deposition in the wall of the artery. As atherosclerosis worsens, the plaque may cause hemodynamic obstruction to CBF and may result in angina.³ Typically, coronary luminal narrowings less than 70% of cross-sectional area may not elicit either spontaneous or exercise-induced angina or ischemia, since the microvasculature (coronary resistance vessels) has the capacity to dilate and increase subendocardial perfusion in response to increasing demand. Such dilation, however, generally becomes maximized when coronary stenoses exceed 70% which, in turn, will trigger either spontaneous or exercise-induced anginal episodes. Symptomatic angina usually occurs about 25 – 30 seconds after onset of the ischemic cascade.¹⁰ Approximately one-half of all stable CAD patients experience episodes of silent myocardial ischemia.

Endothelial dysfunction and coronary vasomotor control are important determinants of myocardial oxygen supply. Impaired smooth muscle relaxation has been suggested as a marker for atherosclerosis. In the WISE study, attenuation of coronary flow reserve was observed with intracoronary adenosine, suggesting impaired vascular smooth muscle relaxation.¹¹ In patients with CAD, there is loss of endothelium-dependent vasodilation and increased sensitivity to catecholamine-induced vasoconstriction.¹² This may become manifest in patients as “variable threshold angina” due to superimposed dynamic obstruction secondary to vasoconstriction of narrowed atherosclerotic vessels.

There is accumulating evidence that implicates coronary microcirculatory dysfunction in CHD patients with angina pectoris, including wide variability in effort tolerance over time, a large scatter or overlap between stenosis severity and coronary flow reserve, and variability in clinical outcomes after initial successful PCI. Approximately 25% of biomarker-positive ACS patients exhibit no flow-limiting stenosis at coronary angiography, but may display plaque fissuring or erosion with microvascular embolization.¹³

Comprehensive management of myocardial ischemia involves antianginal (anti-ischemic) agents and vasculo-protective agents. Antianginal therapies with nitrates, beta-blockers and CCBs are useful for symptom management. Vasculoprotective therapy includes lifestyle changes and pharmacologic therapy with antiplatelet therapy, ACE inhibitors (ACE-I), and statins which, in the aggregate, reduce progression of atherosclerosis, stabilize atherosclerotic plaque, and decrease the risk of thrombosis in patients with chronic stable angina.

Lifestyle changes

Intensive multifactorial risk reduction has been shown to reduce the rate of coronary luminal narrowing and decrease hospitalizations for cardiac events.¹⁴ Patients with chronic stable angina who are receiving medical therapy should be encouraged to exercise as tolerated by their symptoms. Regular exercise may promote “ischemic preconditioning” and provide protection during recurring bouts of ischemia. A trial comparing PCI with graded, regular aerobic exercise in patients with single-vessel CAD showed that 20 minutes of daily exercise was associated with improved maximal myocardial O ₂ uptake, lower costs, and fewer rehospitalizations for angina pectoris as compared with PCI during a 1-year follow-up.¹⁵ All patients should be encouraged to enroll in a comprehensive cardiac rehabilitation program. A diet low in saturated fat, and with appropriate restriction of excessive carbohydrate consumption (especially in patients with diabetes mellitus (DM) or insulin resistance) is encouraged.⁵ Epidemiologic studies have also consistently demonstrated the benefits associated with modest alcohol intake, which may reduce progression of CAD and lower the likelihood of developing coronary events.⁵ Vigorous efforts at smoking cessation and weight control should be encouraged in all patients.⁵ In patients with DM, strict control of blood sugar (with a target HbA1C less than 7%) and control of blood pressure (target less than 120 – 130/80 mmHg) may reduce the rate of secondary events.⁵

Adjunctive pharmacologic therapy

Antiplatelet agents

Aspirin and clopidogrel are the common antiplatelet agents that have been used in the secondary prevention of cardiovascular disease. In high-risk patients with CHD, the use of aspirin was associated with a significantly reduced risk of non-fatal MI, non-fatal stroke and vascular death by 22%.¹⁶ In patients with chronic stable angina, use of aspirin was associated with significant reduction in proinflammatory markers and high-sensitivity C-reactive protein (hs-CRP) levels.¹⁷ Long-term aspirin at a dose of 81 – 325 mg is recommended in all patients with stable angina who do not exhibit aspirin allergy or evidence of aspirin resistance,⁵ in which cases clopidogrel may be substituted. The use of clopidogrel alone was slightly superior to aspirin, and associated with 8.7% relative reduction in vascular death, ischemic stroke and myocardial infarction in the large CAPRIE study.¹⁸

Dual antiplatelet therapy has been well studied in patients with acute coronary syndrome (ACS) and those undergoing PCI. In the CHARISMA trial,¹⁹ over 15000 patients with clinically evident cardiovascular disease or multiple risk factors were randomized to receive clopido-grel (75mg) with low-dose aspirin (75–162mg daily) or placebo plus low-dose aspirin. The combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the composite primary end-point of MI, stroke or death from cardiovascular causes among patients with stable CHD or multiple cardiovascular risk factors. There was a strong suggestion of benefit in patients with established vascular disease and symptomatic atherothrombosis (prespecified secondary endpoint), but alternatively, a suggestion of harm in asymptomatic patients with multiple risk factors and no demonstrable heart or vascular disease.

ACE inhibitors

The role of ACE-I in patients with left ventricular dysfunction has been well documented.^20–22 ACE-I improve survival in patients with symptomatic and asymptomatic heart failure, improve heart function after MI, and have provided renal protection in patients with renal insufficiency, especially diabetics. The use of ACE-I is a Class I, Level A recommendation in stable angina patients with diabetes, previous MI and those with evidence of left ventricular systolic dysfunction, generally defined as an ejection fraction <40%.⁵ Treatment with quinapril improved endothelial function in patients who did not have severe hyperlipidemia or heart failure.²³ The Heart Outcomes Prevention and Evaluation (HOPE) trial showed that ramipril reduced cardiovascular death, MI and stroke in patients with vascular disease in the absence of heart failure.²² However, the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial showed that in patients with stable heart disease and preserved left ventricular function receiving standard therapy, trandolapril did not add any incremental mortality benefit.²⁴

Controversy exists over the best ACE-I to use in patients with CAD. Tissue-specific agents such as quinapril, ramipril, perindopril and trandolapril may have high lipophilicity and better ACE binding capability. It is postulated that these tissue-specific ACE-I are able to penetrate the endothelial wall better and achieve better degrees of ACE inhibition that may impede atherogenesis, although this remains an unsettled question clinically. In patients who are unable to tolerate ACE-I, angiotensin receptor-blocking agents (ARBs) may be used. ARBs have been shown to be as effective as ACE-I in high-risk patients.^25–27

Statins

Multiple randomized controlled trials of both primary and secondary prevention have convincingly demonstrated the clinical benefit of statins in reducing death, MI and stroke. The role of statins in patients with cardiovascular disease continues to evolve, with more and more aggressive efforts to lower low-density lipoprotein (LDL) cholesterol to levels <70mg/d (1.82mmol/L) in high-risk CHD patients (those who are post-MI, ACS patients, diabetics, and those with prior stroke or peripheral arterial disease). Epidemiologic studies have shown a consistent and positive relationship between LDL cholesterol and the risk of coronary heart disease.²⁸ Statins have emerged as the most widely prescribed medication for lowering LDL cholesterol. The reduction in LDL cholesterol with statins ranges from 30% to 60%. The benefits of statins may at least partly be explained by the reduction in LDL cholesterol. Statins generally do not cause a significant increase in high-density lipoprotein (HDL) cholesterol or a reduction in serum tri-glyceride levels, with the possible exception of rosuvastatin. They have been shown to promote plaque stabilization in ACS patients,²⁹ improve endothelial dysfunction, and elicit regression of atherosclerotic plaques.³⁰ The anti-inflammatory effects of statins are reflected in the reduction seen in C-reactive protein levels.³¹ These benefits have translated clinically into significant reductions in total mortality, rates of fatal and non-fatal MI, stroke, and the need for myocardial revascularization procedures in patients with stable CAD.^32,33 Lipid reduction with statins has been shown to reduce the progression of atherosclerosis not only in native vessels, but also in graft vessels after CABG surgery.³⁴ Intensive lowering of lipids (LDL <70mg/dL) as compared to moderate lipid reduction (LDL <100mg/dL) has been demonstrated to result in less progression of atheroma burden in the coronary arteries.³⁵ Trials of lower LDL cholesterol levels in patients with stable CAD and angina have demonstrated the benefits of statins and the need to lower the targets for LDL cholesterol for secondary prevention. These trials form the basis of the NCEP guidelines for LDL cholesterol to less than 100 mg/dL in high-risk patients and less than 70 mg/dL for very high-risk patients (e.g. diabetes).³⁶ Higher doses of statins may increase the incidence of adverse effects. Intensive lipid lowering with 80 mg of atorvastatin daily is associated with greater incidence of elevated serum aminotransferases as compared to 10 mg of atorvastatin daily.³⁷ The risk of muscle injury is increased with higher doses of statins as well as with the concomitant use of fibrates, which may be used in CAD patients with mixed dyslipidemia (high LDL-C and triglyc-eride levels).

The role of HDL-C is being increasingly recognized because of the strong inverse relationship between low levels of HDL-C and the risk of developing cardiac events. There are abundant epidemiologic data to support the observation that a low HDL-C level is a strong, independent predictor of CHD risk, with levels less than 35 mg/dL associated with an eightfold higher risk than HDL-C levels above 65mg/dL.³⁸ Raising the level of HDL-C has been shown to reduce coronary event rates in primary and secondary prevention. Based on growing clinical evidence, patients should be treated to achieve HDL-C of 40 mg/dL in men and 50 mg/dL in women.³⁹ Combination therapy with a statin and extended-release niacin may offer the best strategy for controling mixed dyslipidemia characterized by increased LDL-C and reduced HDL-C levels, and may optimize cardiovascular rate reduction in patients with CHD.^40,41

Inhibition of cholesterol absorption

Ezetimibe is the first member of a class of agents that inhibits the absorption of cholesterol from the intestine.^42,43 Ezetimibe co-administered with statins produces inhibition of both cholesterol synthesis and intestinal cholesterol absorption, resulting in complementary effects that lower LDL-C.^44,45 Co-administration of ezetimibe with a statin results in approximately a 18 – 24% greater reduction of LDL-C, beyond the LDL-C reduction attributable to the statin alone.^46,47 Accordingly, the percentage of patients who can reach their risk-appropriate NCEP goal is considerably higher when ezetimibe is added to LDL-C-reducing therapy, especially statins.^42,47

Recent data have shown that ezetimibe also leads to significantly greater reductions in CRP in combination with statins; in one study, reductions on CRP ranged from 26% to 44% across background simvastatin doses of 10 – 80 mg as compared with 4 – 20% reductions with simvastatin alone at the same doses. Thus, with both greater LDL-C and CRP reductions, the percentage of patients who reach LDL-C < 70 mg/dL in conjunction with CRP <2mg/dL¹⁷ is nearly doubled when ezetimibe is added. In the recent Vytorin Versus Atorvastatin (VYVA) trial, the combination ezeti-mibe/simvastatin approximately doubled the rates of achieving this degree of lowering of LDL-C and CRP across the approved dose ranges.⁴⁴ This promises to be an important component of combination dyslipidemic therapy, although definitive clinical outcomes data are presently lacking until the ongoing IMPROVE-IT Trial is completed and published.

Anti-ischemic/antianginal therapy

Beta-blockers