Physical Activity and Dietary Modifications
Physical activity Regular physical activity and dietary modifications also reduce cardiovascular risk. Physical fitness during middle age is associated with lower long-term cardiovascular mortality66; in addition, self-reported increases in physical activity is associated with reduced all-cause and cardiovascular mortality in elderly men.67 In the Health Professionals Follow-up Study, half an hour or more of brisk walking each day was associated with an 18% relative risk reduction in cardiovascular events; in addition, greater duration and intensity of exercise were associated with greater reductions in risk.68 This study also suggested that weight training was associated with a decreased cardiovascular risk. Although these observational studies are potentially subject to bias, the preponderance of evidence strongly supports recommending regular physical activity to patients.
Patients with chronic stable angina should be encouraged to include moderate aerobic activity in their daily lives.21 Moderate physical activity consists of walking briskly for 30 minutes or more five to seven times a week or the equivalent. Unresolved questions include whether more vigorous physical activity provides greater risk reduction than moderate exercise; whether sustained aerobic exercise of 30 or more minutes is necessary for cardiovascular benefit or whether an accumulation of 30 or more minutes of physical activity during the day is sufficient; and to what extent physical activity provides reductions in risk above and beyond those achieved simply through modification of specific risk factors, such as dyslipidemia, hypertension, and diabetes.
Dietary modification Diet also has the potential to modify multiple coronary risk factors—namely, lipid levels, obesity, insulin resistance, and hypertension. Although trials assessing the effects of dietary modification on stable IHD have not uniformly demonstrated benefit, several trials have shown reductions in cardiac mortality. In the Lyon Diet Heart Study, patients who had had an MI were randomized either to adopt a Mediterranean diet rich in fresh fruits and vegetables, whole grains, olive oil, fish, and relatively little meat or to adopt a prudent Western diet low in saturated fats. At 4 years’ follow-up, patients randomized to the Mediterranean diet enjoyed a 2.5% to 3% per year reduction in cardiac death and nonfatal MI.69 Another trial randomized patients with IHD (about half of whom had a history of MI) either to adopt an Indo-Mediterranean diet rich in fresh fruits, vegetables, legumes, nuts, and whole grains and supplemented with omega-3 fatty acids or to adopt a prudent Indian diet low in saturated fats. Moderate exercise was recommended for all patients. Patients randomized to the Indo-Mediterranean diet had a 7.4% absolute reduction in the risk of MI or cardiac death at 2 years’ follow-up.70 Patients randomized to the intervention diet had significant reductions in daily intake of calories, protein, fat (mostly saturated), cholesterol, and salt; they ingested significantly more complex carbohydrates, fiber, monounsat-urated and polyunsaturated fats, fruits, vegetables, legumes, nuts, and omega-3 polyunsaturated oils.
Other studies demonstrate evidence of the protective benefit of fresh fruits and vegetables. The Nurses’ Health Study and Health Professionals Follow-up Study found that persons in the highest quintile of fruit and vegetable intake had a 20% relative risk reduction for nonfatal MI or cardiac death compared with the lowest quintile.71 A review of diet and IHD concluded that three dietary strategies are effective at reducing the risk of IHD: (1) substituting unsaturated fats (particularly polyunsaturated fats) for saturated fats (e.g., animal fats) and trans-fatty acids (e.g., stick margarine, vegetable shortenings, many commercially prepared baked goods, and deep-fried foods); (2) increasing consumption of omega-3 fatty acids (e.g., oily fish, canola oil, soybean oil, and flaxseed oils); and (3) consuming a diet high in fruits, vegetables, nuts, and whole grains and low in refined grains.72
Medical Therapy to Reduce Cardiovascular Risk
Antiplatelet Agents
Aspirin Acute coronary events commonly result from rupture of an atherosclerotic plaque and subsequent platelet aggregation and thrombosis. Aspirin inhibits cyclooxygenase and the synthesis of prothrombotic platelet thromboxane A2. In studies of more than 3,000 patients with chronic stable angina that compared treatment with aspirin to placebo, the use of aspirin reduced the risk of adverse cardiovascular events by 33% over 6 months.73,74 This reduction in relative risk corresponds to a reduction in absolute risk of approximately 5%. In other words, five cardiovascular events would be prevented for every 100 persons with known cardiovascular disease treated with aspirin for 6 months.73 In the Swedish Angina Pectoris Aspirin Trial, which involved patients with stable angina, the addition of aspirin (75 mg daily) to a regimen of sotalol resulted in a 34% decrease in MI and sudden death75; most of this decrease involved reductions in the incidence of first MI. In the Physician’s Health Study, which involved asymptomatic middle-aged men, the use of aspirin (325 mg every other day) was associated with a decrease in the incidence of MI.76 Doses ranging from 75 to 325 mg daily were found to offer equivalent benefit,77 although the incidence of gastrointestinal toxicity was dose-dependent. All patients with chronic stable angina should be treated with aspirin unless there is a history of documented aspirin allergy or life-threatening gastrointestinal hemorrhage.
Aspirin alternatives Two thienopyridine derivatives, clo-pidogrel and ticlopidine, inhibit adenosine diphosphate-mediat-ed activation of platelet glycoprotein IIb/IIIa. These agents, particularly clopidogrel, are reasonable alternatives for aspirin-intolerant patients with chronic stable angina. In a randomized, controlled trial of patients with symptomatic vascular disease (including patients with chronic stable angina), clopidogrel was slightly more effective than aspirin in reducing the risk of MI, vascular death, and ischemic stroke.78 Clopidogrel is much more expensive than aspirin; in addition, approximately 200 more patients would need to be treated with clopidogrel than with aspirin for 2 years to prevent one major vascular event.79 There are no studies demonstrating that ticlopidine reduces cardiovascular events in outpatients with chronic stable angina. Ticlopidine can cause cytopenia, and there is a reported rare association with thrombotic thrombocytopenic purpura.
Lipid-Lowering Agents
There are abundant data showing the beneficial effects of lipid-lowering therapy in patients with chronic stable angina. Each 1% reduction in total cholesterol is associated with an approximately 2% reduction in coronary events.80 In the Scandinavian Simvastatin Survival Study, patients with documented is-chemic heart disease (including chronic stable angina) and elevated total cholesterol levels (i.e., levels of 212 to 308 mg/dl) were randomized to receive either a statin or placebo.81 A 30% to 35% reduction in mortality and major coronary events was observed in patients receiving a statin. In the Cholesterol and Recurrent Events Trial, patients with prior MI and somewhat lower cholesterol levels (i.e., mean total cholesterol and LDL cholesterol of 209 mg/dl and 139 mg/dl, respectively) had a 25% relative risk reduction in the composite outcome of fatal or nonfatal MI when treated with a statin.82 In the Heart Protection Study, patients with IHD or conditions that confer a similarly high risk of MI or coronary death (e.g., peripheral vascular disease, cerebrovascular disease, or diabetes) were randomized to receive either simvastatin (40 mg) or placebo, irrespective of baseline LDL level.83 Statin therapy reduced total mortality; the incidence of first MI, coronary death, and stroke; and the use of revascularization procedures among all groups of patients, including those with LDL cholesterol levels of less than 116 mg/dl at entry (3.0 mmol/L). From this study, it may be concluded that all patients with chronic stable angina should be treated with a statin, barring specific allergy. Detailed recommendations for lipid-lowering therapy are provided by the National Cholesterol Education Program Adult Treatment Program III (NCEP ATP III).30
The target for therapy for patients with known IHD, including patients with chronic stable angina, is a serum LDL cholesterol level of less than 100 mg/dl. Patients with diabetes, peripheral vascular disease, and cerebrovascular disease are regarded as having a risk of cardiovascular events equivalent to patients with established IHD; the target for therapy in these patients is an LDL cholesterol level of less than 100 mg/dl, which is the same as in patients with known IHD. For other patients, including patients with possible IHD (e.g., a patient with atypical angina and a nondiagnostic exercise treadmill test) or two or more cardiovascular risk factors, the aggressiveness of lipid-lowering therapy is determined by calculating cardiovascular risk from the Framingham risk calculator30 and the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (http://www.nhlbi.nih.gov/ guidelines/cholesterol/index.htm) [see Figure 2].
Available data suggest a potential benefit for more aggressive lowering of LDL cholesterol. In one study, low-risk patients with stable, mild to moderate angina were randomized to receive either atorvastatin, 80 mg daily, or percutaneous coronary intervention (PCI) followed by usual care (including lipid-lowering treatment). Patients receiving atorvastatin required fewer revascularization procedures or admissions for worsening angina with objective evidence of ischemia (13.4% versus 20.9%).84 Patients in the atorvastatin-treated group reached an average LDL cholesterol level of 77 mg/dl, as compared with 119 mg/dl in the PCI group. A second study compared the effects of intensive lipid-lowering therapy using atorvastatin (80 mg/day) with moderate lipid-lowering therapy using pravastatin (40 mg/day).85 Patients treated with atorvastatin (80 mg/day) achieved an average LDL cholesterol level of 79 mg/dl (2.05 mmol/L) and showed less progression of coronary atherosclerosis than patients treated with pravastatin (40 mg/day), who achieved an average LDL cholesterol level of 110 mg/dl (2.85 mmol/L).
Statin therapy is associated with several important potential adverse reactions. Elevations of liver transaminase levels have been described in patients taking statin drugs, although elevations to levels greater than three times the upper limit of normal (necessitating discontinuance) occur in fewer than 0.3% to 0.5% of patients.86
Rhabdomyolysis from statins is an uncommon dose-related phenomenon that usually occurs within the first few weeks of therapy, but it may occur at any time; rhabdomyolysis resolves after withdrawal of the offending drug. Clinically significant myopathy with 10-fold elevations of creatine kinase (CK) occurs in about 0.5% of patients treated with statins.86 Massive rhab-domyolysis usually occurs only with concomitant use of clofi-brate, niacin, or gemfibrozil. The incidence appears to be higher with drugs that interfere with the cytochrome P-450 system (e.g., simvastatin, lovastatin, and atorvastatin) and lower with less potent agents (e.g., pravastatin and fluvastatin). Predispositions to this adverse effect include certain P-450 polymorphisms (CYP3A4), renal failure, liver disease, hypothryoidism, concomitant medications (e.g, macrolides, azole antifungals, cyclo-sporine, protease inhibitors, selective serotonin reuptake inhibitors, nefazodone, verapamil, diltiazem, and amiodarone), and ingestion of grapefruit juice in quantity.87 Myopathy can also occur without elevation of CK.
Niacin, fibric acid derivatives (e.g., gemfibrozil and clofi-brate), and bile acid sequestrants (e.g., cholestyramine and colestipol) reduce cholesterol an average of 6% to 15%. Niacin raises the HDL cholesterol, lowers the LDL cholesterol, and reduces the level of triglycerides. A meta-analysis of 37 studies suggests that the lipid-lowering effect of these agents is associated with reduced coronary mortality and total mortality.89 In high-risk patients with a low HDL cholesterol level or hyper-triglyceridemia, it is reasonable to consider the use of niacin or a fibric acid derivative, alone or in combination with a statin.90-92 In the Veterans Affairs HDL Intervention Trial (VA-HIT), patients with established IHD and low HDL cholesterol levels who were randomized to receive gemfibrozil experienced a significant reduction in major cardiovascular events and cardiovascular mortality, as compared with patients who received placebo.90 In another study, patients with established IHD and low levels of HDL cholesterol who were randomized to receive simvastatin plus niacin had fewer first cardiovascular events, as compared with patients who received placebo or simvas-tatin alone.91
Ezetimibe represents a new class of agent that inhibits intestinal absorption of cholesterol and produces moderate reductions in LDL cholesterol. Its principal indication at this time, as with the bile-acid sequestrants, is to augment the lipid-lowering efficacy of a statin.93 Ezetimibe is associated with fewer gastroin-stestinal side effects than bile-acid sequestrants. Niacin commonly causes flushing, a side effect that can be mitigated by gradual titration toward a target dose and by pretreatment with aspirin. Extended-release preparations of niacin are associated with less flushing. Niacin modestly increases glucose intolerance and can cause hyperuricemia. As with statins, niacin and fibric acid derivatives are associated with a risk of elevations in transaminase levels, as well as with infrequent hepatitis and rare myositis. Although the manufacturers of these drugs recommend routine laboratory evaluation of liver function, routine monitoring was shown to have a low yield in a primary care practice.94
Reduction of non-LDL cholesterol lipid fractions may also reduce cardiovascular risk, particularly in patients who have the metabolic syndrome. Although definitions vary, the metabolic syndrome is a constellation of cardiovascular risk factors, including insulin resistance, obesity, hypertension, and dyslipidemia.95 The dyslipidemia characteristic of the metabolic syndrome consists of elevated triglycerides, a low HDL cholesterol level, and a normal (or near-normal) LDL cholesterol level. Retrospective analysis of the VA-HIT, which studied patients with established coronary disease and low HDL cholesterol levels, suggested that the benefits of treatment with gemfibrozil are most pronounced in patients with insulin resistance (whose fasting plasma insulin levels were comparable to those found in patients with the metabolic syndrome).96 Because patients with the metabolic syndrome have elevated cardiovascular risk despite often having unremarkable LDL cholesterol levels, NCEP ATP III recommends measuring non-HDL cholesterol in patients with elevated triglyceride levels (i.e., triglyceride levels > 200 mg/dl or 2.25 mmol/L) through use of the following formula:
Non-HDL cholesterol = measured total cholesterol – HDL cholesterol
The level of non-HDL cholesterol determined by this formula corresponds to the sum of LDL cholesterol and atherogenic remnant lipoproteins containing apolipoprotein B (very low density lipoprotein cholesterol). Among patients with hypertriglyc-eridemia, the target level for non-HDL cholesterol is less than 130 mg/dl for patients with IHD or IHD equivalent conditions, as well as for patients with two or more cardiovascular risk factors and a 10-year risk of cardiovascular events greater than 20%, as determined by the Framingham risk estimates [see Figure 2].30
In summary, numerous studies demonstrate that patients with IHD benefit from treatment with statins; this includes IHD patients with relatively normal LDL cholesterol levels. The vast majority of patients with chronic stable angina should be treated with a statin. Treatment with niacin or fibric acid derivatives should be considered in patients with a low HDL cholesterol level or an elevated triglyceride level. In view of the consistent benefits of statins across many patient subsets, it would be most reasonable to consider adding niacin or fibric acid derivatives to statin therapy.
Antihypertensive Therapy
Hypertension contributes to cardiovascular risk by increasing myocardial wall stress, oxygen demand, and endothelial injury. Treatment of hypertension in patients with IHD reduces the risk of future cardiovascular events.97 A reduction in systolic blood pressure of 2 mm Hg is associated with a 7% reduction in mortality from IHD.98 By lowering myocardial oxygen demand, treatment of hypertension may also improve anginal symptoms. The therapeutic target for patients with IHD is to maintain blood pressure at levels below 140/90 mm Hg.99
Two groups of patients with hypertension and chronic stable angina warrant particular consideration: patients with specific coexisting chronic conditions (e.g., diabetes, heart failure, or renal insufficiency) and patients with LVH. Guidelines from the Joint National Committee for the Diagnosis, Evaluation, and Treatment of Hypertension (JNC) recommend a lower therapeutic target blood pressure for hypertensive patients who have diabetes, heart failure, or renal insufficiency—namely, a level below 130/85 mm Hg.99 Although no specific target has been promulgated for therapy for hypertension and LVH, the latter is a marker for the severity and chronicity of hypertension and is a risk factor for MI, CHF, and cardiac sudden death.100 Treatment of hypertension results in the regression of LVH; ECG evidence of LVH regression is associated with a significantly reduced risk of cardiovascular events.101 Patients with LVH should therefore be targeted for aggressive antihypertensive therapy.
Two classes of antihypertensives—beta-adrenergic receptor antagonists (i.e., beta blockers) and calcium channel blockers— are also effective antianginal medications. Beta blockers confer mortality benefit in patients after MI102 and are recommended as first-line therapy for most patients with chronic stable angina.32 Calcium channel blockers (e.g., diltiazem, verapamil, and long-acting dihydropyridines) are also effective antihypertensive and antianginal medications. Current ACC/AHA/ACP guidelines recommend beta blockers as first-line antihypertensive therapy in patients with chronic stable angina. Long-acting calcium channel blockers are an acceptable alternative, particularly in patients without a history of MI.102
ACE Inhibitors
Results of the Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that ACE inhibitors reduced MI, stroke, and cardiovascular death in patients at high cardiovascular risk. In this study, patients with a history of IHD, diabetes, stroke, or peripheral vascular disease and at least one additional cardiovascular risk factor (e.g., hypertension, dyslipidemia, cigarette smoking, or microalbuminuria) were randomized to receive either ramipril (10 mg daily) or placebo; patients were followed for an average of 4 years. Total mortality was reduced 1.8% in the ramipril-treated group; in terms of numbers needed to treat (NNT), this means that 56 patients would need to be treated for 4 years to prevent one death. The primary outcome of MI, stroke, or cardiovascular death was reduced by 3.8% (NNT of 26). This study indicated that a broad range of patients at high risk for IHD who had normal left ventricular function obtained an impressive survival benefit from the use of ACE inhibitors. The magnitude of benefit was greater than might have been expected for the small decrement in average blood pressure observed in the study, suggesting a mechanism at work other than reduction in blood pressure.103 In the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), patients with stable coronary disease and no known congestive heart failure or uncontrolled hypertension were randomized to receive either the ACE inhibitor perindopril or place-bo.104 Combined cardiovascular end points were significantly reduced in the perindopril group; in addition, there was a nonsignificant reduction in total mortality. On the basis of the HOPE and EUROPA trials, it can be concluded that most patients with chronic stable angina should be treated with an ACE inhibitor, barring renal insufficiency, hyperkalemia, or an allergy to ACE inhibitors. Angiotensin receptor blockers may offer a similar benefit, but these agents have not been extensively studied in this regard.
Medical Therapy for anginal Symptoms
The major classes of medications for the treatment of angina include beta blockers, calcium channel blockers, and nitroglyc-erin/nitrates. Randomized trials demonstrate that beta blockers and calcium channel blockers are equally effective in relieving angina and improving exercise tolerance.105,106 Current guidelines, however, recommend beta blockers as first-line therapy32,33 because they improve survival and reduce cardiac events in patients who have had a previous acute MI107 and in elderly patients with systolic hypertension108; no similar benefits have been demonstrated for calcium channel blockers or nitrates. In addition, beta blockers improve survival and reduce the risk of stroke and congestive heart failure in patients with hypertension.109 Beta blockers should be considered as initial antianginal therapy in patients with chronic stable angina.
Beta Blockers
Beta blockers decrease heart rate, myocardial contractility, blood pressure, and myocardial oxygen demand by inhibiting cardiac and peripheral beta-adrenergic receptors. Beta blockers delay the onset of angina and increase exercise capacity in patients with exertional angina.110,111 They are titrated to a dose adequate to reduce the resting heart rate to 55 to 60 beats/min. Titration to lower heart rates may be necessary in patients with more severe angina, provided patients do not develop heart block or symptoms of severe bradycardia.
Beta blockers are generally well tolerated by patients with chronic obstructive pulmonary disease; however, they may exacerbate bronchospasm in patients with severe asthma. Beta blockers are well tolerated in patients with diabetes, and in these patients, they can reduce macrovascular events112; theoretically, however, beta blockers can mask the adrenergically mediated symptoms of hypoglycemia insulin (e.g., tachycardia).
Beta blockers are contraindicated in the presence of severe bradycardia, high-degree atrioventricular block, sinus node dysfunction, and uncompensated congestive heart failure. Patients with extensive peripheral vascular disease and claudication may experience worsening of their symptoms. Beta blockers are also contraindicated in the small subset of patients with pure variant or vasospastic angina (i.e., angina occurring in the absence of fixed obstruction of the coronary arteries), in whom beta blockade is unlikely to alleviate symptoms. In these patients, beta blockers may actually worsen angina as a result of unopposed alpha-adrenergic effects. Calcium channel blockers are the preferred first-line agent in this patient group [see Calcium Channel Blockers, below].
Calcium Channel Blockers
Calcium channel blockers reduce smooth muscle tone and cause coronary and peripheral vasodilatation, improving coronary blood flow and reducing peripheral vascular resistance. Calcium channel blockers can be used as monotherapy in the treatment of chronic stable angina, although combinations of beta blockers and calcium channel blockers relieve angina more effectively than either agent alone. Combination therapy with a beta blocker may blunt the reflex tachycardia that can occur with dihydropyridine calcium channel antagonists. All calcium channel blockers exert some negative inotropic effect, although this effect is typically most significant clinically with the nondihy-dropyridine agents verapamil and diltiazem. Calcium channel blockers are contraindicated in the presence of decompensated congestive heart failure, although the vasoselective dihydropyri-dine agents amlodipine and felodipine are tolerated in patients with clinically stable LV dysfunction.113 Verapamil and diltiazem have a pronounced effect on heart rate and conduction; they should be used with caution in combination with beta blockers because of the increased risk of heart block associated with the combined use of these agents. Constipation and peripheral edema are common side effects of calcium channel blockers.
Nitrates and Nitroglycerin
Nitrates and nitroglycerin dilate coronary arteries and their collateral vessels, directly improve myocardial perfusion, diminish afterload, and increase venous capacitance. These agents exert antianginal effects by improving coronary blood flow and by reducing myocardial oxygen demand. Long-acting nitrate preparations, in tablet or patch form, reduce the severity and frequency of angina and improve exercise tolerance; however, they often induce a reflexive increase in sympathetic tone and increase heart rate. Therefore, long-acting nitrates are often used in combination with beta blockers or calcium channel blockers. Short-acting nitroglycerin tablets or spray is appropriate for the immediate relief of exercise-induced or rest angina. They may also prevent angina when taken several minutes before exertion sufficient to cause angina.
Nitroglycerin and nitrates should not be used within 24 hours of taking sildenafil (Viagra) or other phosphodiesterase inhibitors used in the treatment of erectile dysfunction, because of the potential for life-threatening hypotension.114 It is important to discuss this interaction with patients taking nitrates or sildenafil. Nitroglycerin and nitrates are relatively contraindicated in patients with severe aortic stenosis or hypertrophic obstructive car-diomyopathy because of an increased risk of syncope resulting from diminished cardiac output. Continued use of long-acting nitrates results in tachyphylaxis; the mechanism of this is unclear. An adequate nitrate-free period (8 to 12 hours each day) is necessary to minimize this effect. Headaches are common and often limit nitroglycerin and nitrate therapy; with continued use, headaches will diminish in up to 80% of patients. Hypotension may occur, particularly in hypovolemic patients.
In general, patients who are found to be at low or moderate risk for cardiovascular complications during risk stratification should be treated aggressively with medical therapy. Medical therapy should not be considered to have failed until the patient has been treated with full therapeutic doses of a beta blocker, a calcium channel blocker, and a long-acting nitrate and continues to experience angina or develops unacceptable adverse effects.
Patients With Diabetes Mellitus
IHD therapy for patients with diabetes merits special consideration. Cardiovascular events are the leading cause of death in patients with diabetes, and this patient group is at particularly high risk for MI. Middle-aged persons with diabetes and no history of MI have a risk of MI and cardiac death equivalent to that of non-diabetic patients with a history of MI.115 A substudy of the Heart Protection Study demonstrated that treatment with statins reduced major coronary and major vascular events, even among diabetic patients without a prior diagnosis of ischemic heart disease and among diabetic patients with LDL cholesterol levels lower than 116 mg/dl (3 mmol/L).116 Treatment with statins resulted in a relative risk reduction for major coronary events (nonfatal MI and coronary death [27%]), stroke (25%), and first revascularization procedures (17%). A HOPE substudy demonstrated the benefits of ACE inhibitors in patients with diabetes and one or more cardiovascular risk factors.117 Treatment with an ACE inhibitor resulted in a 25% reduction in MI, stroke, or cardiovascular death. Total mortality was reduced 24%; progression to overt nephropathy was reduced by 24%. In the United Kingdom Prospective Diabetes Study, beta blockers were found to be equivalent to ACE inhibitors in reducing the risk of macrovascu-lar complications.112 Another study found that cardiovascular events were more common in patients with type 2 diabetes melli-tus and hypertension who were randomized to receive a dihy-dropyridine calcium channel blocker, as compared with patients who received an ACE inhibitor.118 It remains uncertain whether to attribute this result to a higher risk of cardiovascular events among the group taking the calcium channel blocker amlodipine or to a reduced risk of cardiovascular events among the group taking the ACE inhibitor fosinopril. Nevertheless, most experts consider calcium channel blockers to be third-line agents for patients with diabetes and hypertension. Results of the Hypertension Optimal Treatment (HOT) study support aggressive blood pressure reduction in patients with diabetes; the target blood pressure for these patients is 135/80 mm Hg or lower.119
Although it remains uncertain when to initiate antiplatelet therapy in diabetic patients, it is reasonable to treat diabetic patients who have any additional cardiovascular risk factor with aspirin or an equivalent antiplatelet therapy.120 The American Diabetes Association and the NCEP recommend a target LDL cholesterol level of 100 mg/dl (2.59 mmol/L) or lower.31,121
Revascularization
Techniques for revascularization include PCI, using catheter-based methods with or without placement of intracoronary stents, and CABG. For most patients with angina, survival with optimal medical therapy is equivalent to that resulting from revascularization; in addition, CABG results in excellent symptom relief. For a select few patients with chronic stable angina, revascularization is associated with improved survival, as compared with that achieved with medical therapy.122 Among 2,649 patients with left main coronary stenoses or multivessel coronary artery disease and reduced LV systolic function, those who were treated with CABG in randomized trials had an absolute mortality at 5 years that was more than 5% lower than that of patients assigned to medical management (10.2% versus 15.8%).123 This benefit persisted at 10 years’ follow-up. There is much weaker evidence to suggest that patients with proximal stenoses of the left anterior descending coronary artery and normal LV function also experience lower mortality with CABG. One randomized trial showed no difference in mortality among patients assigned to CABG, PCI, or medical management.124 In two trials comparing CABG with PCI, survival was equivalent; however, the patients who underwent surgery had fewer symptoms and required fewer antianginal medications and subsequent revas-cularization procedures.125,126 Initial costs and short-term (procedure-related) mortality were higher in patients who underwent CABG. Most of the patients enrolled had two-vessel CAD and normal LV systolic function. In one study, survival was improved in patients with diabetes who underwent CABG, as compared with patients who underwent PCI.125
Randomized trials comparing PCI with medical management in patients with one- or two-vessel CAD and normal LV systolic function have demonstrated equivalent survival.127,128 Relief of symptoms was generally greater with PCI than that seen with medical therapy, although PCI was associated with an increased risk of procedure-related MI and death127,128 and substantially greater cost.129
On the basis of a limited number of randomized trials, it appears that only the subgroup of patients with severe coronary disease (defined as two- or three-vessel disease) and impaired LV function can confidently expect improved average survival after revascularization and that improvement is seen only with CABG. Thus, evaluation for revascularization is generally recommended for patients who are at moderate or high risk of death and who are willing to undergo a revascularization procedure.32 Patients meeting these criteria who are found to have either extensive areas of ischemia on noninvasive testing or reduced LV systolic function should then be considered candidates for angiography. It should be recognized, however, that the results of currently available studies comparing PCI, CABG, and medical therapy do not reflect recent advancements in all three forms of treatment. For example, restenosis rates with PCI using stents, drug-eluting stents, and platelet inhibitors are lower than previously reported rates with angioplasty techniques.
In general, medical therapy is preferred in patients who are determined through risk stratification by noninvasive testing to be at low risk for death. There is no evidence that revascular-ization improves survival in such patients. For this reason, currently available evidence suggests that many revasculariza-tion procedures conducted in the United States may not be warranted.
Complications
Chronic stable angina, as the name suggests, is a long-standing stable or progressive condition caused, in most instances, by atherosclerotic narrowing of the coronary vessels. Coronary atherosclerosis, however, is a risk factor for acute coronary syndromes, including MI and sudden cardiac death. Much of the diagnostic evaluation of patients with chronic stable angina is undertaken to determine the intermediate-term risk of acute coronary events. Much of the treatment of patients with chronic stable angina is intended to reduce the risk of acute coronary complications, principally MI and sudden cardiac death. Another major complication of chronic stable angina is CHF. Major causes of CHF include MI and hypertension—common conditions in patients with IHD.130 Finally, patients with IHD are at risk for other vascular diseases, namely stroke and peripheral vascular disease.
It is also important to consider complications of conditions that predispose patients to IHD. For example, diabetes is a major risk factor for IHD and is often complicated by peripheral vascular disease, renal insufficiency, neuropathy, and retinopathy. In addition to increasing the risk of IHD, cigarette smoking confers a significant risk of chronic pulmonary disease, cancer, and peripheral vascular disease.
Follow-up
Patients with chronic stable angina should be regularly followed in a primary care setting. There is little evidence to recommend a particular frequency of follow-up visits, although ACC/AHA/ACP guidelines suggest regular visits at 4- to 12-month intervals for patients with chronic stable angina.21 The expert panel recommends addressing the following questions at each visit21:
• Has there been a change in the level of activity since the last
visit?
• Have anginal symptoms increased in severity or frequency?
• Is current therapy well tolerated?
• Has the patient been successful at modifying cardiac risk factors?
• Has the patient developed new or worsening comorbid illnesses that may have an impact on the patient’s angina?
It is important to inquire about changes in anginal symptoms or activity levels to identify patients who require increased intensity of antianginal therapy or further risk stratification. For example, it would be reasonable to repeat noninvasive testing in a patient with stable class II angina who developed new class III anginal symptoms since the last clinic visit. Similarly, in a patient with new symptoms of CHF, it would be appropriate to perform echocardiography and consider referral for coronary angiogra-phy; multiple-vessel CAD with reduced left ventricular function would be an indication for CABG.
Medical therapy should be reviewed at each visit to assess adherence to recommended therapy, knowledge about doses and indications, and potential side effects. In addition, it is worth considering whether recent evidence for benefit from new therapies or new indications for existing therapies support a modification of IHD management. Patients with chronic stable angina should be encouraged to quit smoking, to eat a prudent diet, and to regularly engage in moderate exercise. Successful adoption of these interventions is challenging, but repeated encouragement from a personal physician enhances success.131
Vital signs (i.e., heart rate, blood pressure, and weight) should be regularly followed. The physical examination is focused on the heart, lungs, and vasculature. Findings of particular note include signs of CHF, new or changing heart murmurs, arrhythmias, or evidence of carotid or peripheral vascular disease.
Laboratory assessment should include periodic measurements of fasting lipid levels. Regular measurements of liver transami-nase and CK levels are not recommended in the absence of symptoms. Other laboratory testing is indicated by comorbid conditions or changes in the patient’s history and physical examination.
There is no evidence showing that regular ECG studies are helpful in the management of patients with chronic stable angina in the absence of changes in history or physical examination. ECGs are indicated when new medications are introduced that may affect cardiac conduction. Changes in anginal or syncopal symptoms and findings suggestive of dysrhythmia or conduction abnormalities should also prompt a repeat ECG.
There is little evidence to guide the use of repeat stress testing in patients with chronic stable angina. Recommendations for follow-up stress testing vary according to initial assessments of a patient’s cardiovascular risk.21 For example, patients with class II angina whose exercise treadmill test places them at low risk have an annual risk of mortality of less than 1%; these patients do not require follow-up stress testing for a period of 3 to 4 years in the absence of new and concerning symptoms or signs. Similarly, patients who underwent PCI more than 6 months earlier and who have minimal residual stenosis are unlikely to benefit from regular stress testing. It is not known whether patients at intermediate or high cardiovascular risk benefit from periodic stress testing.
Follow-up noninvasive tests are selected according to the approach outlined (see above). When possible, the same form of stress (exercise or pharmacologic) and testing (ECG or imaging) should be repeated, because this permits the most valid comparison with the original study.21
Patients should be referred to a cardiologist when appropriate for consideration of revascularization. Candidates for referral include patients with valvular disorders that require repair, patients with angina that is refractory to maximal medical therapy, and patients with comorbidities that complicate therapy.
