Medical Care
The main goals of treatment in angina pectoris are to relieve the symptoms, slow the progression of disease, and reduce the possibility of future events, especially MI and premature death.
General measures
Smoking cessation results in a significant reduction of acute adverse effects on the heart and may reverse, or at least slow, atherosclerosis. Strongly encourage patients to quit smoking, and take an active role in helping them to achieve this goal.
Treat risk factors, including hypertension, diabetes mellitus, obesity, and hyperlipidemia.
Several clinical trials have shown that in patients with established coronary artery disease, reduction of low-density lipoprotein (LDL) level with a beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor (ie, statin) is associated with significant reductions in both mortality rate and major cardiac events. [27, 28, 29, 30]
These benefits are present even in patients with mild-to-moderate elevations of LDL cholesterol level.
Trials with cholesterol-lowering agents have confirmed the benefits of the therapeutic LDL lowering in older persons.
Angiographic studies demonstrate that a reduction of the LDL level in patients with coronary artery disease could cause slowing of progression, stabilization, or even regression of coronary artery lesions.
One study demonstrated a significant reduction of symptomatic myocardial ischemia in patients with unstable angina or non–Q-wave infarction with the administration of a statin during the early acute phase.
In a study of 10,001 patients with stable coronary artery disease, an aggressive cholesterol-lowering approach with atorvastatin 80 mg daily (mean cholesterol level of 77 mg/dL) compared to a less-aggressive approach with atorvastatin 10 mg daily (mean cholesterol level of 101 mg/dL) resulted in a 2.2% absolute reduction and a 22% relative reduction in the occurrence of a first major cardiovascular event (defined as death from coronary heart disease; nonfatal, non–procedure-related myocardial infarction; resuscitation from cardiac arrest; or fatal or nonfatal stroke). [31] This occurred with a greater incidence of elevated aminotransferase levels with the aggressive cholesterol-lowering approach (1.2% vs 0.2%, p < 0.001).
Some triglyceride-rich lipoproteins, including partially degraded very LDL levels, are believed to be independent risk factors for coronary artery disease. In daily practice, non-HDL cholesterol level (ie, LDL + very LDL cholesterol [total cholesterol - HDL cholesterol]) is the most readily available measure of the total pool of these atherogenic lipoproteins. Thus, the ATP III has identified non-HDL cholesterol level as a secondary target of therapy in persons with high triglyceride levels (>200 mg/dL). The goal for non-HDL cholesterol level (for persons with serum triglyceride levels >200 mg/dL) is 30 mg/dL higher than the identified LDL cholesterol level goal.
Patients with established coronary disease and low HDL cholesterol levels are at high risk for recurrent events and should be targeted for aggressive nonpharmacological (ie, dietary modification, weight loss, physical exercise) and pharmacological treatment.
Several large epidemiologic studies demonstrated that HDL cholesterol levels are inversely related to cardiovascular risk. Thus, developing pharmaceutical agents to increase the HDL level has been an attractive target for prevention and treatment of CAD. However, several large randomized trials utilizing cholesteryl ester transfer protein (CETP) inhibitors did not show benefit for reducing cardiovascular events in spite of raising HDL levels. Torcetrapib has been one of CETP agents that has been used in large randomized trials. [32, 33]
Investigation of Lipid level management using coronary UltraSound To assess Reduction of Atherosclerosis by CETP inhibition and HDL Elevation (ILLUSTRATE) was a randomized study that looked at the effect of torcetrapib in 1188 patients with CAD who underwent intravascular ultrasonography at baseline. [32] After treatment with atorvastatin to reduce levels of LDL cholesterol to less than 100 mg/dL, patients were randomly assigned to receive atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily.
Intravascular ultrasonography was repeated in 910 of these patients (77%) after 24 months of treatment to evaluate the disease progression. Compared with atorvastatin monotherapy, torcetrapib–atorvastatin therapy was associated with an impressive 61% relative increase in HDL levels and a 20% relative decrease in LDL levels resulting in an LDL to HDL ratio of less than 1.0 in this group of patients. Despite this favorable change in the HDL and LDL levels, among patients who underwent repeat intravascular ultrasonography, the percent atheroma volume between the 2 groups was not different. Torcetrapib did not result in significant decrease in the progression of coronary atherosclerosis, but it was associated with an increase in blood pressure.
Rating Atherosclerotic Disease change by Imaging with A New Cholesteryl-Ester-transfer protein inhibitor (RADIANCE) 2, a trial reported in 2007, looked into the effect of torcetrapib on carotid atherosclerosis progression in patients with mixed dyslipidaemia. [33] Although similar to the ILLUSTRATE trial, torcetrapib also substantially raised HDL levels and lowered LDL levels in this study; it did not affect the progression of carotid atherosclerosis. Similar to the ILLUSTRATE trial, torcetrapib also significantly increased systolic blood pressure.
Investigation of Lipid level management to Understand its iMpact IN ATherosclerotic Events (ILLUMINATE), an international phase 3 study of 15,000 patients, was terminated early because it had already recorded 82 deaths in the patients taking torcetrapib-atorvastatin compared with 51 deaths in patients taking atorvastatin alone. In addition, the rates of MI, revascularization, angina, and heart failure were higher in the torcetrapib-atorvastatin arm.
Due to the similar failure of multiple clinical trials focused on HDL raising, current expert thinking about HDL is that it is to be regarded as a marker of risk rather than as a target of therapy.
Other approaches to cardiac risk factor reduction should also be used in combination with the above. Exercise training results in improvement of symptoms, an increase in the threshold of ischemia, and improvement of patients' sense of well-being. However, before enrolling a patient in an exercise-training program, perform an exercise tolerance test to establish the safety of such a program.
Enteric-coated aspirin at a dose of 81 mg per day should be advised for all patients with stable angina who have no contraindications to its use. [34, 35] In patients in whom aspirin cannot be used because of allergy or gastrointestinal complications, consider clopidogrel. [36]
Although early observational studies suggested a cardiovascular protective effect with the use of hormone replacement therapy, recent large randomized trials failed to demonstrate any benefit with hormone replacement therapy in the primary or secondary prevention of cardiovascular disease. [37]
In fact, these studies even demonstrated an increased risk of coronary artery disease and stroke in patients on hormone replacement therapy.
The Women's Health Initiative study demonstrated that the use of hormone replacement therapy for 1 year in 10,000 healthy postmenopausal women is associated with 7 more instances of coronary artery disease, 8 more strokes, 8 more pulmonary emboli, 8 more invasive breast cancers, 5 fewer hip fractures, and 6 fewer colorectal cancers.
Based on these data, the risks and benefits of hormone replacement therapy must be assessed on an individual basis for each patient.
Sublingual nitroglycerin has been the mainstay of treatment for angina pectoris. Sublingual nitroglycerin can be used for acute relief of angina and prophylactically before activities that may precipitate angina. No evidence indicates that long-acting nitrates improve survival in patients with coronary artery disease. [38]
Beta-blockers are also used for symptomatic relief of angina and prevention of ischemic events. They work by reducing myocardial oxygen demand and by decreasing the heart rate and myocardial contractility. Beta-blockers have been shown to reduce the rates of mortality and morbidity following acute MI. [39] A post hoc analysis from the ADDITIONS (prActical Daily efficacy anD safety of Procoralan In combinaTION with betablockerS) trial demonstrated metoprolol in combination with ivabradine for treatment of patients with stable angina was safe and effective. [40] The investigators reported a reduction in heart rate by 19.7 +/- 11.2 bpm, with an 8-fold decrease in weekly angina attacks and nitrate use, accompanied by improvement in quality of life. [40]
Long-acting heart rate–slowing calcium channel blockers can be used to control anginal symptoms in patients with a contraindication to beta-blockers and in those in whom symptomatic relief of angina cannot be achieved with the use of beta-blockers, nitrates, or both. Avoid short-acting dihydropyridine calcium channel blockers because they have been shown to increase the risk of adverse cardiac events.
Anginal symptoms in patients with Prinzmetal angina can be treated with calcium channel blockers with or without nitrates. In one study, supplemental vitamin E added to a calcium channel blocker significantly reduced anginal symptoms among such patients. [41]
In patients with syndrome X and hypertension, ACE inhibitors may normalize thallium perfusion defects and increase exercise capacity. [42]
A study by Losordo et al proposes injections of autologous CD34+ cells (105 cells/kg) for patients with refractory angina. Patients who received this experienced significant improvements in angina frequency and exercise tolerance. [2]
Diet and activity
A diet low in saturated fat and dietary cholesterol is the mainstay of the Step I and Step II diet from the American Heart Association.
The level of activity that aggravates anginal symptoms is different for each patient. However, most patients with stable angina can avoid symptoms during daily activities simply by reducing the speed of activity.
Surgical Care
Revascularization therapy (ie, coronary revascularization) can be considered in patients with left main artery stenosis greater than 50%, 2- or 3-vessel disease and LV dysfunction (ejection fraction, < 45%), poor prognostic signs during noninvasive studies, or severe symptoms despite maximum medical therapy. The 2 main coronary revascularization procedures are percutaneous transluminal coronary angioplasty, with or without coronary stenting, and coronary artery bypass grafting (CABG).
Patients with 1- or 2-vessel disease and normal LV function who have anatomically suitable lesions are candidates for percutaneous transluminal coronary angioplasty and coronary stenting. Restenosis is the major complication, with symptomatic restenosis occurring in 20-25% of patients. Restenosis mostly occurs during the first 6 months after the procedure and can be managed by repeat angioplasty. Several trials have demonstrated that the use of drug-eluting stents (eg, sirolimus-eluting stents, paclitaxel-coated stents) can remarkably reduce the rate of in-stent restenosis. With the introduction of these drug-coated stents, patients with multivessel coronary artery disease are more frequently treated with percutaneous revascularization as opposed to the surgical revascularization. [43, 44] More recently, some concerns have arisen that instead of improving the long-term prognosis, drug-eluting stents might actually worsen it. In addition, stent thrombosis is a major concern with the useofdrug-eluting stents.
A meta-analysis of individual data on 4,958 patients enrolled in 14 randomized trials comparing sirolimus-eluting stents with bare-metal stents looked at the long-term effect of these stents. [44] The mean follow-up interval was 12.1-58.9 months. The primary end point was death from any cause. The secondary end points were stent thrombosis, the composite end point of death or myocardial infarction, and the composite of death, MI, or a revascularization.
The overall risk of death and the combined risk of death or MI were not significantly different for patients receiving sirolimus-eluting stents versus bare-metal stents. A sustained reduction in the need for revascularization occurred after the use of sirolimus-eluting stents compared with bare-metal stents. The overall risk of stent thrombosis with sirolimus-eluting stents was not significantly higher than bare-metal stents. However, evidence showed an increase in the risk of stent thrombosis associated with sirolimus-eluting stents after the first year.
Patients with single-vessel disease and normal ventricular function treated with percutaneous transluminal coronary angioplasty show improved exercise tolerance and fewer episodes of angina compared with those who receive medical treatment. However, no difference in the frequency of MI or death has been shown between these two groups.
The Clinical Outcomes Utilizing Revascularization and AGgressive Drug Evaluation (COURAGE) trial looked at the benefits of PCI as an initial management strategy in patients with stable CAD. This trial was a randomized and involved 2287 patients who had objective evidence of myocardial ischemia and significant CAD. [45] Of these, 1149 patients were randomized to undergo PCI with optimal medical therapy (PCI group) and 1138 were to receive optimal medical therapy alone (medical-therapy group). They were observed for 2.5-7 years (median, 4.6 y). During the follow-up, no difference was reported in the primary outcome of death from any cause and nonfatal MI between the PCI group and the medical-therapy group. In addition, no significant differences were noted between the 2 groups in the secondary end points of the composite of death, MI, and stroke; hospitalization for acute coronary syndrome; or MI.
A 2012 study was prematurely halted after it showed a significant benefit in its primary endpoint (a composite of death, myocardial infarction, or urgent revascularization) in patients with stable coronary disease who underwent fractional flow reserve (FFR)-guided PCI plus the best available medical therapy (PCI group) compared to those who received only the best available medical therapy alone (medical-therapy group). In this study, patients in whom at least one stenosis was functionally significant (FFR, ≤0.80) were randomly assigned to FFR-guided PCI plus the best available medical therapy or the best available medical therapy alone while patients in whom all stenosis had an FFR > 0.80 received the best available medical therapy. The significant difference in primary endpoint was driven by a lower rate of urgent revascularization in the FFR-guided PCI patients (1.6%) than in the medical-therapy alone patients (11.1%; hazard ratio, 0.13; 95% CI, 0.06 to 0.30; P< 0.001).
Significantly fewer urgent revascularizations were triggered by a myocardial infarction or evidence of ischemia on electrocardiography in the FFR-guided PCI group. The authors conclude that in patients with stable coronary artery disease and functionally significant stenosis, FFR-guided PCI plus the best available medical therapy reduces the need for urgent revascularization compared with the best available medical therapy alone. In patients without ischemia, the outcome is favorable with the best available medical therapy alone. These results suggest a significant role for use of FFR in patients with stable coronary artery disease to select those who might benefit from PCI. [46]
Patients with significant left main coronary artery disease, 2- or 3-vessel disease and LV dysfunction, diabetes mellitus, or lesions anatomically unsuitable for percutaneous transluminal coronary angioplasty have better results with coronary artery bypass grafting. The overall operative mortality rate for coronary artery bypass grafting is approximately 1.3%. The rate of graft patency 10 years after surgery is less than 50% for vein grafting, although more than 90% of grafts using internal mammary arteries are patent at 10 years. In recent years, interest has increased regarding surgery without cardiopulmonary bypass (ie, off-pump) in an attempt to avoid the morbidity associated with cardiopulmonary bypass. A recent randomized study demonstrated that off-pump coronary surgery was as safe as on-pump surgery and caused less myocardial damage. However, the graft-patency rate was lower at 3 months in the off-pump group than in the on-pump group.
Laser transmyocardial revascularization
Laser transmyocardial revascularization has been used as an experimental therapy for the treatment of severe, chronic, stable angina refractory to medical or other therapies. [5] This technique has been performed with either an epicardial surgical technique or by a percutaneous approach. In both approaches, a series of transmural endomyocardial channels are created to improve myocardial perfusion. The surgical transmyocardial revascularization technique has been associated with symptomatic relief for end-stage chronic angina in the short term. However, no published data address the long-term efficacy of surgical transmyocardial revascularization. Nonetheless, this technique appears to provide at least symptomatic relief for end-stage chronic angina in the short term. [47]
Human CD34+ stem cells
A subgroup of patients with coronary artery disease experiences angina that is not amenable to revascularization and is refractory to medical therapy. Some studies have indicated that human CD34+ stem cells induce neovascularization in ischemic myocardium enhancing perfusion and function.
The feasibility and safety of this treatment was tested in a recent phase I/IIa double-blind, randomized controlled trial of 24 patients (19 men and 5 women aged 48-84 y) with Canadian Cardiovascular Society class 3 or 4 angina who were undergoing optimal medical treatment and who were not candidates for mechanical revascularization. [48] Patients received granulocyte colony-stimulating factor 5 microg x kg(-1) x d(-1) for 5 days with leukapheresis on the fifth day.
Electromechanical mapping was performed to identify ischemic but viable regions of myocardium for injection of cells in the active treatment group versus saline injection in the placebo group. The total dose of cells was divided in 10 intramyocardial and transendocardial injections. There was no incidence of myocardial infarction, elevation of cardiac enzymes, perforation, or pericardial effusion. Also, there was no incidence of ventricular tachycardia or ventricular fibrillation during the administration of granulocyte colony-stimulating factor or intramyocardial injections.
Serious adverse events were evenly distributed between the therapy and the control groups. A trend was demonstrated in frequency of angina, nitroglycerine usage, exercise time, and Canadian Cardiovascular Society class that favored CD34+ cell-treated patients versus control subjects given saline injections. Based on the results of this study a larger phase IIb study is currently under way to further evaluate this novel therapy.
Increased coronary sinus pressure
Increased coronary sinus pressure has been suggested to reduce myocardial ischemia by redistribution of blood from nonischemic to ischemic areas. The Coronary Sinus Reducer is a percutaneous implantable device designed to establish coronary sinus narrowing and to elevate coronary sinus pressure.
In a 2007 study, the safety and feasibility of the Coronary Sinus Reducer was evaluated in 15 patients with coronary artery disease and refractory angina who were not candidates for revascularization. [49] All procedures were completed successfully and no procedure-related adverse events occurred during the periprocedural and the follow-up periods. Angina score improved in 12 of 14 patients. Also, the extent and severity of myocardial ischemia measured by dobutamine echocardiography and by thallium single-photon emission computed tomography was reduced significantly (p = 0.004 [n = 13] and p = 0.042 [n = 10], respectively). This study demonstrated that the implantable Coronary Sinus Reducers may be a feasible and safe treatment for patients with refractory angina. Further large clinical studies are needed before the use of these devices become an accepted treatment.
Prevention
Coronary atherosclerosis is the main preventable cause of mortality in the United States. A rigorous effort to address correctable risk factors is the mainstay of preventive cardiovascular medicine.
Smoking cessation is the single most effective preventive intervention to reduce coronary atherosclerosis prevalence. It has been associated with a coronary artery disease reduction of 7-47% in primary prevention settings.
Aggressive treatment of diabetes mellitus, hypertension, LV hypertrophy, hyperlipidemia, and obesity has an important role in the prevention of coronary artery disease.
The most important recent development in coronary atherosclerosis risk modification is the introduction of inhibitors of beta-hydroxy-beta-methylglutaryl coenzyme A reductase. Reductions of total and LDL cholesterol levels by 25% and 35%, respectively, can achieve a similar reduction in rates of total and coronary mortality, MI, and need for coronary revascularization.
