Importantly, these benefits were seen in patients with and without IHD.571,760,761 Studies on multiple polymorphisms in the gene encoding for the beta-adrenergic receptor have variously shown asso- ciations with physiological responses to exercise.774 781 Clin- ical studies with a variety of beta blockers in different patient populations with hypertension have, however, yielded diver- gent results in terms of associations with BP and heart rate,782 785 but it remains to be studied whether this variation is mainly a function of beta-adrenergic receptor genotype and whether genotype influences the clinical outcome of beta- blocker use in patients with SIHD. Beta blockers have been compared with and combined with dihydropyridine calcium channel blockers in controlled clinical trials. The results of the APSIS (Angina Prognosis Study in Stockholm), TIBBS (Total Ischemic Burden Biso- prolol Study), and IMAGE (International Multicenter Angina Exercise) studies showed that a beta blocker was more effective than a calcium channel blocker in control of angina, reduction of cardiovascular events, and need for revascular- ization.786 788 A rationale for combining these agents is a reduction of dihydropyridine-induced tachycardia by beta- blockade. When combined, beta blockers and dihydropyri- dine calcium channel blockers have increased exercise time and shown a trend toward a lower rate of cardiovascular outcomes.788,789 Caution is warranted when a beta blocker is combined with verapamil or diltiazem because of the poten- tial for development of bradycardia, AV block, or excessive fatigue. The combination of a beta blocker with a nitrate could be an additive combination in patients with SIHD. Nitrates increase sympathetic tone, which can lead to reflex tachycardia, which is attenuated by the beta blocker. Beta blockers can increase LV wall tension associated with de- creased heart rate, which is counteracted by the concomitant use of nitroglycerin. Clinical trials have validated this ratio- nale, showing that the combination is more effective in controlling angina than is either monotherapy alone.790,791 Absolute contraindications to beta blockers are severe bradycardia, preexisting high-degree AV block, sick sinus syndrome (without a pacemaker in place), and refractory heart failure. Relative contraindications include bronchospas- tic disease or active PAD (beta blockers without vasodilating properties or selective agents at low doses may be used). Because they can mask symptoms of hypoglycemia, beta blockers should be used with caution in patients with insulin- dependent diabetes mellitus. Abrupt beta-blocker withdrawal should be avoided because heightened beta-receptor density and sensitivity can result in a rebound phenomenon associ- ated with an increased risk for AMI and sudden death. If withdrawal is necessary, beta blockers should be tapered over a 1- to 3-week period, with consideration given to use of sublingual nitroglycerin or substitution with a nondihydro- pyridine calcium channel blocker during the withdrawal period. The principle adverse effects of beta blockers are fatigue, exercise intolerance, lethargy, insomnia, nightmares, and impotence. 4.4.2.3. Renin-Angiotensin-Aldosterone Blocker Therapy Class I 1. ACE inhibitors should be prescribed in all patients with SIHD who also have hypertension, diabetes mellitus, LVEF 40% or less, or CKD, unless contra- indicated.295 298,301 (Level of Evidence: A) 2. ARBs are recommended for patients with SIHD who have hypertension, diabetes mellitus, LV systolic dysfunction, or CKD and have indications for, but are intolerant of, ACE inhibitors.792 794 (Level of Evidence: A) Class IIa 1. Treatment with an ACE inhibitor is reasonable in patients with both SIHD and other vascular dis- ease.795,796 (Level of Evidence: B) 2. It is reasonable to use ARBs in other patients who are ACE inhibitor intolerant.797 (Level of Evidence: C) (Table 15) A substantial body of evidence supports the concept that ACE inhibitors have cardiovascular protective effects, reducing the risks of future ischemic events. ACE inhibitors result in a reduction in angiotensin II with an increase in bradykinin. These changes in the physiological balance between angio- tensin II and bradykinin could contribute to the reductions in LV and vascular hypertrophy, atherosclerosis progression, plaque rupture, and thrombosis; the favorable changes in cardiac hemodynamics; and the improved myocardial oxygen supply/demand that result from treatment with ACE inhibi- tors and ARBs.798 801 Clinical studies have demonstrated significant reductions in the incidence of AMI, UA, and the need for coronary revascularization in patients after MI with LV dysfunction, independent of etiology.559,561,801 The benefits of ACE inhibitors extend to patients with IHD in the absence of LV dysfunction. In patients with Fihn et al Stable Ischemic Heart Disease: Full Text e405 atherosclerotic vascular disease or diabetes mellitus and at least 1 other IHD risk factor, the HOPE (Heart Outcomes Prevention Evaluation) study301 showed that compared with placebo, ramipril significantly decreased the primary composite endpoint of cardiovascular death, AMI, and stroke by 22%.301 MICRO-HOPE (Microalbuminuria, Car- diovascular, and Renal Outcomes), a substudy of HOPE, additionally showed, in middle-aged patients with diabetes mellitus who were at high risk for cardiovascular events, significant reductions in MI by 22%, stroke by 33%, cardiovascular death by 37%, and the combined primary event outcome by 25%.802 Furthermore, the need for revascularization and incidence of worsening angina also were significantly reduced. The EUROPA (European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease) trial provided added support to the HOPE trial results in patients with SIHD without clinical evidence of heart failure.296 In 12 218 patients followed up for a mean of 4.2 years, there was a 20% relative increase in the time to the primary composite endpoint of cardiovascular death, nonfatal MI, or cardiac arrest with perindopril compared with placebo.296 Perindo- pril was further tested in the PEACE (Prevention of Events with Angiotensin-Converting Enzyme Inhibitor) trial, which enrolled 4158 patients with SIHD and normal or slightly reduced LV function (ie, absence of LV wall- motion abnormalities).295 The incidence of the primary endpoint of death from cardiovascular causes, MI, or coronary revascularization was equivalent between perin- dopril and placebo, but the overall rate of cardiovascular events was lower than in the HOPE and EUROPA trials. Equivalent results were seen in HOPE and EUROPA when examined by age, sex, known IHD, LV function, previous MI, hypertension, or diabetes mellitus. In QUIET (Quinapril Ischemic Event Trial), there was also no sig- nificant reduction with quinapril in ischemic events and progression of CAD in coronary angioplasty patients without systolic LV dysfunction (RR: 13%; P0.49), although this finding has been attributed to study design limitations.797 Similarly, the IMAGINE (Ischemia Man- agement With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme) study demonstrated no reduction in clinical outcomes in low-risk patients (LVEF with quinapril after surgical revascularization.803 In a meta-analysis of ACE-inhibitor therapy versus placebo in 31 555 patients from HOPE, EUROPA, PEACE, and QUIET, ACE-inhibitor therapy produced 14% reductions in all-cause mortality and MI (both P0.0004), a 23% reduction in stroke (P0.0004), and a 7% reduction in revascularization procedures (P0.025) compared with Although the cited studies involved a variety of ACE inhibitors that differ with regard to structure, bioavailability, potency, receptor-binding characteristics, tissue distribution, metabolism, and excretion properties, there is little evidence that these differences are associated with therapeutic advan- tages. Because the benefits of ACE inhibitors seem to reflect a class effect, the selection of a particular agent can be based on such factors as availability in local formularies, cost, and tolerability. ACE inhibitors are recommended for all patients with SIHD and hypertension, diabetes mellitus, LV dysfunction (EF 40%), or CKD. Also included in the HOPE301 or EUROPA296 trials were participants who did not have one of these conditions but did have multiple cardiac risk factors, and it seems that they also benefited from use of ACE ARBs also play an important role in vascular protection. They bind in a competitive or insurmountable manner to the type 1 angiotensin II receptor, increasing plasma renin activity, plasma renin, and angiotensin I and II concentra- tions. In patients with hypertension or cardiovascular disease, ARBs produce reductions in BP equivalent to those achieved with ACE inhibitors.804 These agents significantly reduce LV mass and stroke incidences compared with beta blockers and improve outcomes in diabetic nephropathy and heart fail- ure.563,565,792,805 A meta-regression analysis of 26 trials com- pared the effects of ACE inhibitors and ARBs on major vascular events by BP effects.804 Treatment with ACE inhib- itor based regimens was associated with a reduction in the risk for stroke (by 19%), IHD (by 16%), and heart failure (by 27%) for each 5 mm Hg reduction in BP; corresponding figures for the reduction in risk for ARBs were 26%, 17%, and 12%, respectively. There were no significant differences between ARB- and ACE inhibitor based regimens in the risk of stroke, IHD, and heart failure for each 5 mm Hg reduction in BP. When these outcomes were assessed at zero BP reduction, the risk reduction for IHD was significantly greater for ACE inhibitors than for ARBs (P0.002). Furthermore, unlike ARBs, ACE inhibitors were associated with a signif- icant additional risk reduction for IHD of 9% (P0.004), without differences seen for stroke or heart failure versus ARBs. It is therefore recommended that ARBs be substituted for ACE inhibitors in patients with SIHD and hypertension who are intolerant of ACE inhibitors.563,565,792,804,805 4.4.2.4. Influenza Vaccination Class I 1. An annual influenza vaccine is recommended for patients with SIHD.806 810 (Level of Evidence: B) In patients with chronic medical conditions such as cardio- vascular disease, influenza contributes to a higher risk for mortality and hospitalization and exacerbates underlying medical conditions. The World Health Organization and the AHA/ACCF recommend annual vaccination with inactivated vaccine (administered intramuscularly) against seasonal in- fluenza to prevent all-cause mortality and morbidity in patients with underlying cardiovascular conditions.806,807 A cohort study in 1340 elderly (ie, 65 years of age) patients with heart failure or IHD showed that annual influenza vaccinations reduced the risk of mortality by 37% during the winter period (January through April), but not the summer period (June through September), resulting in a number needed to treat to prevent 1 death during 1 influenza period of 122 annual vaccinations.808 Further mechanistic and confir- Trandolapril was further tested in the PEACE (Prevention of Events matory studies in heart failure and other cardiovascular disease are needed to confirm these findings. Evidence from 2 prospective randomized clinical studies in patients $65 years of age who were medically stable supports increasing influenza vaccine doses to achieve higher serum antibody titers and potentially improved protection from influenza infection.809,810 This dosing scheme was associated with higher injection site reactions, including pain and myalgias. Currently, it is recommended that patients with SIHD receive an annual influenza vaccination in the standard dose. 4.4.2.5. Additional Therapy to Reduce Risk of MI and Death Class III: No Benefit 1. Estrogen therapy is not recommended in postmeno- pausal women with SIHD with the intent of reducing cardiovascular risk or improving clinical out- comes.811 814 (Level of Evidence: A) 2. Vitamin C, vitamin E, and beta-carotene supplemen- tation are not recommended with the intent of reducing cardiovascular risk or improving clinical outcomes in patients with SIHD.398,527,815 818 (Level of Evidence: A) 3. Treatment of elevated homocysteine with folate or vitamins B6 and B12 is not recommended with the intent of reducing cardiovascular risk or improving clinical outcomes in patients with SIHD.819 822 (Level of Evidence: A) 4. Chelation therapy is not recommended with the intent of improving symptoms or reducing cardio- vascular risk in patients with SIHD.823 826 (Level of Evidence: C) 5. Treatment with garlic, coenzyme Q10, selenium, or chromium is not recommended with the intent of reducing cardiovascular risk or improving clin- ical outcomes in patients with SIHD. (Level of Evidence: C) 4.4.2.5.1. Hormone Replacement Therapy. Numerous obser- vational studies have suggested that estrogen therapy might provide protection against the development of IHD in post- menopausal women.827 829 Beneficial effects of exogenous estrogen include an increase in HDL cholesterol, a decrease in LDL cholesterol, and enhanced endothelial function.830 833 In light of the epidemiological data and evidence of salutary physiological effects, postmenopausal estrogen replacement previously was advocated for the primary and secondary prevention of CAD in women. Clinical trials in women with and without established CAD, however, have failed to con- firm a decrease in cardiovascular events with hormone therapy. In HERS (Heart and Estrogen/progesterone Replace- ment Study), 2763 postmenopausal women with CAD were randomized to therapy with 0.625 mg of conjugated estrogen plus 2.5 mg of medroxy progesterone acetate or placebo and were followed up for an average of 4.4 years. Despite an 11% lower level of LDL cholesterol and a 10% higher level of HDL cholesterol in the hormone therapy group, there was no difference in the composite primary endpoint of MI or IHD death, and an early increase in cardiovascular events was observed.811 In HERS-II, an unblinded follow-up study of HERS, the lack of benefit with estrogen/progestin therapy persisted at an average of 6.8 years.834 A subsequent angio- graphic study demonstrated a nonsignificant worsening of coronary stenoses in patients prescribed estrogen therapy.835 The Women s Health Initiative, a randomized controlled primary prevention trial, also found no evidence that estrogen protects against IHD.812 814 Thus, the weight of current scientific evidence suggests that estrogen/progestin therapy in postmenopausal women does not reduce the risk of vascular events or coronary deaths in secondary prevention. Women who are taking estrogen therapy and who have vascular disease can continue this therapy if it is prescribed for other well-established indications and if no better alternative ther- apies are appropriate, although the FDA recommends use in the lowest dose and shortest duration acceptable. There is, however, no basis for adding or continuing estrogens in postmenopausal women with clinically evident SIHD in an effort to prevent or retard progression of their atherosclerotic disease. 4.4.2.5.2. Vitamin C, Vitamin E, and Beta-Carotene. Epide- miological and population studies have suggested that anti- oxidant vitamins, such as vitamin E, vitamin C, and beta- carotene, could lower cardiovascular risk.836,837 Controlled clinical trials, however, have failed to demonstrate a benefi- cial effect of antioxidant supplements on risk of cardiovas- cular morbidity and mortality.398,527,815 817 A meta-analysis of antioxidant vitamin studies examined 7 trials of vitamin E treatment and 8 trials of beta-carotene treatment with .1000 subjects in each. Most of these studies were performed in patients with CAD or at risk of CAD. Vitamin E had no effect on all-cause mortality or cardiovascular death.838 Beta- carotene led to a small but statistically significant increase in all-cause mortality and cardiovascular death. Thus, existing scientific evidence does not justify routine use of antioxidant supplements for the prevention or treatment of cardiovascular disease. 4.4.2.5.3. Folate and Vitamins B6 and B12. Prospective observational studies have demonstrated that the serum ho- mocysteine level is a strong, independent risk factor for ischemic events.839 841 Homocysteine levels can be lowered with folic acid or B-vitamins. Trials of folate and vitamin B supplementation, however, consistently have failed to dem- onstrate a decrease in cardiovascular morbidity or mortality rates. The VISP (Vitamin Intervention for Stroke Prevention) trial randomized patients with prior nondisabling stroke to varying doses of folic acid, B6, and B12. Despite a reduction in homocysteine that was 2 mmol/L greater in the group allocated to the high dose of supplementation, there were no differences in the incidence of recurrent stroke, IHD, or death.822 Similarly, the HOPE 2 (Heart Outcome in Preven- tion) trial found no benefit of folate and vitamins B6 and B12 in patients with vascular disease or diabetes mellitus.821 The NORVIT (Norwegian Vitamin Trial) examined 3 combina- tions of folate and B vitamins in patients who had an AMI and observed no decrease in the risk of cardiovascular events.820 A meta-analysis of these and 9 other smaller trials also found no reduction in cardiovascular events or mortality with folate supplementation.819 These studies indicate that routine use of folate and B vitamins for the prevention or treatment of cardiovascular disease should not be recommended. 4.4.2.5.4. Chelation Therapy. Chelation therapy, which con- sists of a series of intravenous infusions of disodium ethylene diamine tetraacetic acid (EDTA) in combination with other substances, has been promoted as a noninvasive means of Fihn et al Stable Ischemic Heart Disease: Full Text e407 improving blood flow in atherosclerotic vessels. EDTA combines with polyvalent cations, such as calcium ions, to form soluble complexes that can be excreted. Advocates maintain that this process can result in regression of athero- sclerotic plaques and relief of angina and that EDTA reduces oxidative stress in the vascular wall. Anecdotal reports have suggested that EDTA chelation therapy can result in relief of angina in patients with SIHD. In general, however, the efficacy of chelation therapy in athero- sclerotic disease is not supported by clinical trials. Studies in patients with intermittent claudication have failed to demon- strate improvements in exercise measures,823,824 ankle- brachial index,823,824 or digital subtraction angiograms with chelation.825 The only RCT examining the effectiveness of chelation therapy on SIHD826 studied 84 patients with stable angina and a positive treadmill test for ischemia. Those randomized to active therapy received weight-adjusted diso- dium EDTA chelation therapy for 3 hours per treatment, twice weekly for 15 weeks and then once monthly for an additional 3 months. There were no differences between groups in changes in exercise time to ischemia, exercise capacity, or quality-of-life scores. The National Center of Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute have sponsored TACT (Trial to Assess Chelation Therapy),842 an RCT comparing chela- tion to placebo in patients who had experienced an MI. There is insufficient evidence to support chelation therapy for improving symptoms or preventing adverse outcomes in patients with SIHD. Moreover, this therapy is costly and time consuming, can result in harm, and could result in patients failing to pursue proven treatment strategies. 4.4.2.5.5. Garlic, Coenzyme Q10, Selenium, and Chromium. Nu- tritional supplements for the prevention and treatment of cardiovascular disease have grown increasingly popular in the United States. These alternative therapies often are promoted with anecdotal claims of efficacy but have not been studied rigorously. When data are available, they often conflict and consist of results of small, open-label trials. At present, there is no definitive evidence to recommend treat- ment with garlic, coenzyme Q10, selenium, or chromium for improving cardiovascular outcomes in patients with SIHD. 4.4.3. Medical Therapy for Relief of Symptoms 4.4.3.1. Use of Anti-ischemic Medications: Recommendations Class I 1. Beta blockers should be prescribed as initial therapy for relief of symptoms in patients with SIHD.757,765,766 (Level of Evidence: B) 2. Calcium channel blockers or long-acting nitrates should be prescribed for relief of symptoms when beta blockers are contraindicated or cause unaccept- able side effects in patients with SIHD.420,768,769 (Level of Evidence: B) 3. Calcium channel blockers or long-acting nitrates, in combination with beta blockers, should be pre- scribed for relief of symptoms when initial treatment with beta blockers is unsuccessful in patients with SIHD.420 (Level of Evidence: B) 4. Sublingual nitroglycerin or nitroglycerin spray is recommended for immediate relief of angina in patients with SIHD.843 845 (Level of Evidence: B) Class IIa 1. Treatment with a long-acting nondihydropyridine calcium channel blocker (verapamil or diltiazem) instead of a beta blocker as initial therapy for relief of symptoms is reasonable in patients with SIHD.420 (Level of Evidence: B) 2. Ranolazine can be useful when prescribed as a substitute for beta blockers for relief of symptoms in patients with SIHD if initial treatment with beta blockers leads to unacceptable side effects or is ineffective or if initial treatment with beta blockers is contraindicated.846 (Level of Evidence: B) 3. Ranolazine in combination with beta blockers can be useful when prescribed for relief of symptoms when initial treatment with beta blockers is not successful in patients with SIHD.847,848 (Level of Evidence: A) 4.4.3.1.1. Beta Blockers. Beta blockers are recommended as the initial agents to relieve symptoms in most patients with SIHD. Beta blockers reduce myocardial oxygen consumption by reducing heart rate, myocardial contractility, and afterload, with attenuation of cardiovascular remodeling by decreasing LV wall tension with long-term use. The reduction in myo- cardial oxygen demand is directly proportional to the level of adrenergic tonic stimulation. Furthermore, the reduction in heart rate also shifts the cardiac cycle, permitting more diastolic time and greater coronary perfusion, thereby im- proving myocardial oxygen supply. Long-term beta-blocker treatment is well tolerated, has proven benefit in SIHD by reducing ischemic burden and threshold, and improves survival in patients with LV dys- function or history of MI.757,765,766 When prescribed in com- bination with agents that block the renin-angiotensin-aldoste- rone system, beta blockers are the preferred agents for the treatment of angina in patients with LV dysfunction after MI and in patients with heart failure, on the basis of documented improvements in survival and ventricular A meta-analysis of comparison trials between beta block- ers and calcium channel blockers (dihydropyridine and non- dihydropyridine agents) showed negligible differences in the rate of death or MI over relatively brief durations of admin- istration (ie, 6 wk to 6 mo), although patients with heart failure, heart block, or significant pulmonary disease were excluded from the meta-analysis.420 Beta blockers were found to exhibit an advantage with regard to control of angina and withdrawals from therapy due to adverse events, a problem that was most pronounced with nifedipine.420 Calcium chan- nel blockers, however, have not been shown to improve survival after MI, as beta blockers have, but have been shown to offer protection against severe angina and to reduce the risk of reinfarction after MI.849 851 Adherence to beta-blocker therapy can be influenced by the occurrence of adverse effects such as fatigue, lethargy, sexual dysfunction, or sleep disturbances. Although beta blockers have the potential to worsen symptoms in patients with significant depressive illness or PAD, these effects are observed rarely in clinical practice. For patients with severe PAD or those with vasospastic (Prinzmetal s) angina, wors- ening symptoms due to vasoconstriction from unopposed alpha-adrenergic activity can be avoided by using beta blockers with alpha-adrenergic blocking (eg, labetalol or carvedilol) or direct vasodilator (eg, nebivolol) properties. 4.4.3.1.2. Calcium Channel Blockers. If adverse effects or contraindications limit the use of beta blockers, calcium channel blockers are recommended for relief of anginal symptoms. These agents noncompetitively limit calcium ion influx through voltage-dependent L-type calcium channels, resulting in negative inotropic effects, cardiac pacemaker depression, slowing conduction, and smooth muscle relax- ation. There are 3 classes of calcium channel blockers: the dihydropyridines (eg, nifedipine) and 2 types of nondihydro- pyridines, the phenylalkylamines (eg, verapamil) and the benzothiazepines (eg, diltiazem). All classes improve myo- cardial oxygen supply by decreasing coronary vascular resis- tance and augmenting epicardial conduit vessel and systemic arterial blood flow. Myocardial demand is decreased by a reduction in myocardial contractility, systemic vascular resis- tance, and arterial pressure. However, the phenylalkylamines and, to a lesser extent, the benzothiazepines also depress cardiac pacemaker rate and slow conduction. This depressant effect can cause sinus bradycardia or can worsen preexisting conduction defects, leading to heart block. Myocardial con- tractile depression also is a common feature, although the degree is variable according to drug class. As a result of these pharmacological properties, the calcium channel blockers are effective anti-ischemic drugs, but their use must be All classes of calcium channel blockers reduce anginal episodes, increase exercise duration, and reduce use of sublingual nitroglycerin in patients with effort-induced an- gina.854 856 Because all 3 classes also reduce the frequency of Prinzmetal s variant angina, they are the drugs of choice, along with nitrates, used alone or in combination.857 859 Because the 3 classes seem to be equally efficacious in treating angina, the choice of a particular agent should be based on potential drug interactions and adverse events. The dihydropyridine class is preferred over other calcium channel blockers in patients with cardiac conduction defects such as sick sinus syndrome, sinus bradycardia, or significant AV conduction disturbances. Dihydropyridines should be used with caution in patients with severe aortic valve stenosis. Short-acting dihydropyridines in patients with fixed lesions can exacerbate angina, possibly by excessive lowering of arterial pressure with reflex tachycardia, and therefore should be avoided. Short-acting nifedipine seems to increase mortal- ity in patients with hypertension,860 but there is currently no evidence that these concerns apply to extended-release prep- arations.861,862 Because of their effects on contractility, none of the calcium channel blockers are recommended for routine treatment of patients with current or prior symptoms of heart failure and a reduced LVEF.21 Many drug interactions associated with calcium channel blockers occur because of rapid absorption or low bioavail- ability due to high first-pass metabolism by the cytochrome P450 (ie, CYP3A4) system. These pharmacokinetic properties result in high intraindividual and interindividual variability, necessitating dosage adjustment. These drugs should be used with caution when combined with cyclosporine, carbamaz- epine, lithium carbonate, amiodarone, or digoxin (ie, 50% to 70% increase in digoxin concentrations in first week of therapy). Combining verapamil or diltiazem with beta block- ers generally should be avoided because of potentially pro- found adverse effects on AV nodal conduction, heart rate, or cardiac contractility. Overall, calcium channel blockers, particularly diltiazem, are well tolerated. The major adverse effects of dihydropyr- idines are related to vasodilation and systemic hypotension, including headache, dizziness, palpitations, and flushing. Many patients experience peripheral edema because of ex- cessive arterial vasodilation unmatched to venous dilation. Verapamil can cause constipation that can be severe, partic- ularly in the elderly. 4.4.3.1.3. Nitrates. Nitrates are effective in the treatment of all forms of angina. They relax vascular smooth muscle in the systemic arteries, inclusive of the coronary arteries, and veins (predominant effect at lower doses) in patients with SIHD. Short-term continuous nitroglycerin delivery by the intrave- nous or transdermal route for only 2 to 4 hours protects the endothelium from experimental ischemia in healthy volun- teers and reduces ischemia during coronary angioplasty and physical exercise in IHD patients.863 865 Oxygen free radical release seems to be associated with these protective out- comes. Nitroglycerin causes dilation of the artery wall not affected by plaque, but independent of an intact endothelium, leading to reduced resistance across the obstructed lumen.866 Furthermore, nitroglycerin contributes to coronary blood flow redistribution, by augmenting collateral flow and lowering ventricular diastolic pressure, from areas of normal perfusion to ischemic zones.867 Preload is reduced, leading to reduc- tions in myocardial wall tension and myocardial oxygen demand, although this effect is offset by increased heart rate and myocardial contractile state due to reflex sympathetic activity. Nitroglycerin also has demonstrated antithrombotic and antiplatelet effects.868,869 Long-term nitrate therapy, however, could offset the beneficial short-term ischemic preconditioning effects. Long- term nitroglycerin therapy is associated with endothelial dysfunction via accumulation of the same oxygen free radi- cals that seem to be beneficial in short-term administra- tion.870,871 The oxygen free radical accumulation increases arterial sensitivity to vasoconstrictors such as angiotensin II, which can be counteracted by concomitant treatment with an ACE inhibitor or hydralazine.872 875 Importantly, these phys- iological changes are independent of dose or the presence or absence of a nitrate-free interval and can result in a decrease in the anginal threshold during the nitrate-free interval.876 Further research to better understand the balance between the long-term benefits and safety concerns of these compounds is warranted in patients with SIHD. Despite these physiological observations, nitrates improve exercise tolerance, time to ST-segment depression, and time to onset of angina in patients with SIHD, albeit in small patient studies conducted for relatively short periods.876 878 Comparisons of nitrates to beta blockers or calcium channel blockers have not shown significant differences with regard to weekly anginal episodes, time to ST-segment depression, total exercise time, or sublingual nitroglycerin use.420 With- drawal for adverse effects was also not statistically different between the drug classes. All patients with SIHD should be prescribed sublingual nitroglycerin tablets or nitroglycerin spray for immediate relief of angina. Most patients respond within 5 minutes of taking 1 to 2 sublingual dose(s) of 0.3 to 0.6 mg. Nitroglyc- erin spray is available in a 0.4-mg metered-dose canister that dispenses 200 doses. The tablets should be placed under the tongue and not swallowed. If the spray is used, it should be applied to the tongue and not swallowed or inhaled. If additional doses are necessary, they should be taken at 5-minute intervals, for a maximum dose of #1.2 mg within 15 minutes. During this timeframe, if relief does not occur, Fihn et al Stable Ischemic Heart Disease: Full Text e409 the patient should seek immediate medical attention. These products are also effective for prevention of effort-induced angina when administered 5 to 10 minutes before activity, with relief lasting approximately 30 to 40 minutes. The tablets must be kept in the manufacturer s bottle (loss of potency can occur in a few hours if out of the bottle) and should be stored in a cool, dry place but should not be refrigerated. The tablets should not be used 6 to 12 months after opening the bottle. Patients usually are able to detect when tablets have lost potency by the absence of a burning sensation beneath the tongue. Nitroglycerin ointment also may be used for short-term relief of angina. Applied to the chest in doses of 0.5 to 2.0 inches, with a delay in relief of 30 minutes, this preparation can be effective for 4 to 6 hours. Absorption can be increased by rotating the application sites, covering the paste with plastic, or not applying the ointment continuously (ie, maintenance of a nitrate-free interval).879 881 All short-acting nitrate preparations can cause hypotension, sometimes severe, and headaches that limit adherence to these agents. Patients should be counseled about these ad- verse effects and advised to seek medical treatment if syncope or resistant chest pain occurs. The ointment can cause permanent discoloration of clothing. Long-acting nitrate preparations (eg, nitroglycerin, isosor- bide dinitrate, isosorbide-5-mononitrate) are recommended for treatment of angina when initial therapy with a beta blocker or nondihydropyridine calcium channel blocker is contraindicated or poorly tolerated or when additional ther- apy to control angina is necessary. Isosorbide dinitrate undergoes rapid high first-pass metabolism, resulting in low bioavailability. However, substantial interpatient variability exists in the metabolic enzyme systems responsible for isosorbide dinitrate conversion. Isosorbide mononitrate, the active metabolite of the dinitrate formulation, is 100% bio- available. Nitroglycerin also can be delivered through sili- cone gel or polymer matrix release patch systems. The rate of release varies between these systems, necessitating individu- alization of dosing. With all formulations, titration of dose is important to gain adequate anginal control with the lowest possible dose to limit the occurrence of headaches, avoid nitrate tolerance, and facilitate long-term adherence. The effectiveness of all of these formulations seems to be roughly equivalent despite differences in the preparation and dosing schedules.843,882 With all of them, it is necessary to maintain a daily nitrate-free interval of 10 to 14 hours to avoid development of nitrate tolerance.843 Nitrate tolerance does not develop with the sublingual route of administration. Use of long-acting nitrates also does not result in tolerance to the use of sublingual products. Nitrates are relatively well tolerated if a titration schedule is used at initiation and with discontinuation. The most common side effects are headache, flushing, and hypotension. Patients should be instructed to remain seated when taking rapid-acting nitrate products as a safety precaution to avoid syncope from vasodilation. Tolerance to the headaches could develop after a few weeks of continuing the medication. Prophylactic analgesics can be helpful until headache toler- ance develops. Methemoglobinemia is a rare adverse effect, usually seen only with large doses. Nitrates are relatively contraindicated in hypertrophic obstructive cardiomyopathy because of the potential to increase the outflow tract obstruc- tion and mitral regurgitant flow. They should be avoided in patients with severe aortic valvular stenosis. Coadministra- tion of the phosphodiesterase inhibitors sildenafil, tadala- fil, or vardenafil with long-acting nitrates should be strictly avoided within 24 hours of nitrate administration because of the risk of profound hypotension (eg, 25 mm Hg drop in systolic BP). Patients should be advised not to take phosphodiesterase inhibitors within 24 hours of long- acting nitrates, and nitrates should not be taken for 24 hours after use of sildenafil or 48 hours after tadalafil; a suitable time interval after vardenafil has not been deter- mined. Patients should be made aware of the possibility of intensification of their angina if nitrates are discontinued abruptly. This effect could be reduced by concomitant administration of other antianginals or by tapering of the long-acting nitrate dosage. 4.4.3.1.4. Ranolazine. Ranolazine inhibits the late inward sodium current, indirectly reducing the sodium-dependent calcium current during ischemic conditions and leading to improvement in ventricular diastolic tension and oxygen consumption. Minimal changes in mean heart rate (,2 beats per minute) and systolic BP (,3 mm Hg) occur in controlled studies. At maximal exercise, the rate pressure product is not increased, independent of age, or in the presence of diabetes mellitus, reactive airway disease, or heart failure.883 Ranola- zine is currently indicated for the treatment of chronic angina and may be used in combination with beta blockers, nitrates, dihydropyridine calcium channel blockers, ACE inhibitors, ARBs, and antiplatelet and lipid-lowering therapy. It should be prescribed only in low doses in combination with verap- amil or diltiazem, as described later. The lack of an effect on BP and heart rate makes ranolazine an attractive alternative in patients with bradycardia or low BP. Although ranolazine has been well studied in SIHD, the agent was not administered in the COURAGE (Clinical Outcomes Utilizing Revasculariza- tion and Aggressive Drug Evaluation) study,366 and further clinical evaluation is needed, especially of ranolazine as an element of intensive interventions for multiple risk factors. The ranolazine extended-release preparation reduces the frequency of angina, improves exercise performance, and delays the development of exercise-induced angina and ST- segment depression.847,884 In one study, ranolazine reduced weekly anginal frequency by 36% and nitroglycerin use by 43% in comparison with placebo.848 Other studies indicated that among patients with ACS, ranolazine did not reduce the incidence of MI or death885 but did reduce recurrent ischemia in the postinfarction period.886 In patients with preexisting angina, it was superior to placebo in improving patients angina and quality of life.887 Ranolazine could exert a beneficial effect on glycemic control and has demonstrated consistent reductions in HbA1c in patients with diabetes Ranolazine blocks the delayed rectifier potassium current and prolongs the QTc interval in a dose-related manner, resulting in a mean increase in QTc of approximately 6 msec at maximal recommended dosing. Currently, there is limited experience with concomitant administration of ranolazine and other drugs that prolong the QT interval, including Class IA and III antiarrhythmics and certain antipsychotics (thiorida- zine and ziprasidone). In 3162 patients with ACS, there was no increased risk of proarrhythmia or sudden death. In this study, there was a significantly lower incidence of arrhyth- mias, including ventricular tachycardia, bradycardia, su- praventricular tachycardia, and new atrial fibrillation, in patients treated with ranolazine (80%) versus placebo Ranolazine does not require dose adjustment for age, sex, New York Heart Association class I IV heart failure, or diabetes mellitus. Plasma concentrations of ranolazine are increased by up to 50% in patients with Stage 4 CKD (creatinine clearance ,30 mL/min).892 The drug is contrain- dicated in patients with clinically significant hepatic impair- ment because of increased plasma concentrations and QT prolongation. In general, dosing in the elderly should start at the low end of the dosing range.883 Ranolazine is contraindicated in combination with potent inhibitors of the CYP3A4 pathway, including ketoconazole (3.2-fold increase in ranolazine plasma levels) and other azole antifungals, macrolide antibiotics, HIV (human immunodefi- ciency virus) protease inhibitors, grapefruit products or juice, diltiazem (1.8- to 2.3-fold increase in ranolazine plasma levels), itraconazole, clarithromycin, and certain HIV protease inhibi- tors. When administered with moderate inhibitors of CYP3A such as diltiazem, verapamil, aprepitant, erythromycin, flucona- zole, or grapefruit juice, the dose of ranolazine should be limited to 500 mg twice daily because of an approximately 2-fold increase in ranolazine plasma levels. No dose adjustment is required in patients treated with cimetidine or paroxetine. Co- administration of ranolazine (1000 mg twice daily) with simva- statin increases the plasma concentration of simvastatin and its active metabolite 2-fold. Digoxin plasma concentrations are increased 1.5-fold, but this interaction might not be clinically relevant with lower digoxin dosing (0.125 mg daily). Coadmin- istration of ranolazine with drugs that inhibit CYP2D6, with the exceptions of tricyclic antidepressants and some antipsychotics, does not require dosage adjustment. Ranolazine is well tolerated; the major adverse effects are constipation, nausea, dizziness, and headache. The incidence of syncope is ,1%. 4.4.3.1.5. Antianginal Agents Not Currently Available in the United States 4.4.3.1.5.1. Nicorandil. Nicorandil is a nicotinamide ester with a dual mechanism of action. It activates adenosine triphosphate sensitive potassium channels and promotes sys- temic venous and coronary vasodilation through a nitrate moiety.893 This dual action increases coronary blood flow, with reductions in afterload, preload, and oxidative injury.893 The agent does not exhibit effects on contractility or conduc- tion.894,895 The antianginal efficacy and safety of nicorandil are similar to those of oral nitrates, beta blockers, and calcium channel blockers.893,896,897 In a prospective, randomized, study of 5126 patients with chronic stable angina, the addition of nicorandil to standard therapy was found to produce a 17% RR reduction in the composite endpoint of IHD death, nonfatal MI, or unplanned hospital admission for cardiac chest pain.898 There was, however, no difference between nicorandil and placebo with regard to death from IHD or nonfatal MI.894 Tolerance can develop with long-term dos- ing.899 Common side effects include flushing; palpitation; weakness; headache; ulceration of the mouth, perianal, ileal, and peristomal areas; nausea; and vomiting. The agent is not currently available in the United States. 4.4.3.1.5.2. Ivabradine. Ivabradine is a specific inhibitor of the If current of pacemaker cells in the sinoatrial node at concentrations that do not inhibit other cardiac currents.900 This action results in heart rate reduction, prolonging diastole and thereby improving myocardial oxygen balance. Ivabra- dine has no effect on BP, myocardial contractility, or intra- cardiac conduction parameters.901 903 Ivabradine improves exercise capacity and reduces anginal frequency in compar- ison to atenolol among patients with chronic stable an- gina.904,905 In 5479 patients with IHD and LV systolic dysfunction, however, ivabradine added to standard treatment had no effect, when compared with placebo, on the composite endpoint of cardiovascular death, admission to the hospital for AMI, and admission to the hospital for new-onset or worsening heart failure.906 The most common adverse event, reported in 14.5% of patients, is phosphenes, described as a transient enhanced brightness in a limited area of the visual field that typically occurs within the first 2 months of treatment. Most of these luminous visual-field disturbances (77%) resolve without discontinuing treatment. The drug is approved in Europe (not currently available in the United States) for the symptomatic treatment of chronic stable angina in patients with normal sinus rhythm with a contrain- dication or intolerance to beta blockers. 4.4.3.1.5.3. Trimetazidine. Trimetazidine seems to improve cellular tolerance to ischemia by inhibiting fatty acid metab- olism and secondarily by stimulating glucose metabolism, although the exact anti-ischemic mechanisms are un- known.907 In patients with chronic stable angina, this agent increases coronary flow reserve, delaying the onset of ische- mia associated with exercise and reducing the number of weekly angina episodes and weekly nitroglycerin consump- tion.908,909 The anti-ischemic effects are not associated with changes in heart rate or systolic BP. Few data exist on the effect of trimetazidine on cardiovascular endpoints, mortality, or quality of life. The most frequently reported adverse events are gastrointestinal disorders, but the incidence is low. The agent is not available in the United States but is available in Europe and reportedly in .80 countries worldwide. 4.4.4. Alternative Therapies for Relief of Symptoms in Patients With Refractory Angina: Recommendations Class IIb 1. Enhanced external counterpulsation (EECP) may be considered for relief of refractory angina in patients with SIHD.910 (Level of Evidence: B) 2. Spinal cord stimulation may be considered for relief of refractory angina in patients with SIHD.911,912 (Level of Evidence: C) 3. Transmyocardial revascularization (TMR) may be considered for relief of refractory angina in patients with SIHD.913 915 (Level of Evidence: B) Class III: No Benefit 1. Acupuncture should not be used for the purpose of improving symptoms or reducing cardiovascular risk in patients with SIHD.916,917 (Level of Evidence: C) TMR has been used as either a percutaneous or a surgical procedure concomitant with CABG or as sole therapy in patients with angina refractory to medical therapy,913 915,918 although the mechanism by which it might be efficacious is unknown.919,920 Early studies of the percutaneous approach demonstrated no therapeutic benefit, and it was promptly abandoned.921 When used as sole therapy by a surgical approach, TMR is reserved for the patient with incapacitat- ing, medically refractory angina and no other feasible thera- Fihn et al Stable Ischemic Heart Disease: Full Text e411 peutic options. Proposed mechanisms of action include stim- ulation of microcirculation, creation of myocardial scarring, and denervation of ischemic myocardium.922 Various energy sources have been used, including carbon dioxide XeCl excimer and holmium:YAG lasers.923 925 There is no con- vincing evidence that one energy source is superior to the others. TMR also has been combined with cardiac denerva- tion by thoracic sympathectomy.926 Numerous single-center and a few multicenter randomized trials have been published that compare TMR with medical therapy for relief of refractory angina.927 930 Most have shown better angina relief with TMR but no survival benefit. The exception is a single multicenter trial that shows a survival benefit as well as better relief of angina at 5 years.931 A 5-year follow-up of a multicenter, prospectively random- ized trial reported not only sustained angina relief but also improved survival in CCS Class IV angina, and patients with no additional options for therapy who were randomized to sole-therapy TMR.931 A meta-analysis of 7 RCTs involving 1053 patients evaluated the effect of TMR on survival and angina relief.932 The conclusion was that at 1 year, TMR improved angina class but not survival when used as the sole procedural intervention compared with medical therapy alone. A number of other series also have reported sustained angina relief and improved quality of life in randomized patients receiving TMR at 3 to 5 years after treatment (Section 5.10 for additional information on TMR in revascularization). A growing number of patients with SIHD have refractory angina, defined as multivessel CAD with ischemia and symptoms that cannot be controlled with medical therapy or surgical or percutaneous revascularization. The prevalence of this syndrome is not well established, but data from registries suggest that about 10% of patients referred for angiography for symptomatic SIHD have coronary anatomy that is not amenable to revascularization.933 935 Other nonpharmacologi- cal therapies may be considered in these patients in an effort to improve quality of life. 4.4.4.1. Enhanced External Counterpulsation EECP is a technique that uses inflatable cuffs wrapped around the lower extremities to increase venous return and augment diastolic BP. The cuffs are inflated sequentially from the calves to the thigh muscles during diastole and are deflated instantaneously during systole. The resultant diastol- ic augmentation increases coronary perfusion pressure, and the systolic cuff depression decreases peripheral resistance. Treatment is associated with improved LV diastolic filling and improved endothelial function936 938; other putative mechanisms for improvement in symptoms include recruit- ment of collaterals, release of proangiogenic cytokines, and a peripheral training effect. A treatment course typically con- sists of 35 hour-long treatment sessions, given 5 days a week. Contraindications include decompensated heart failure, se- vere PAD, and severe aortic regurgitation. The efficacy of EECP in treating stable angina pectoris has been evaluated in a single RCT and several observational registry studies. In MUST-EECP (Multicenter Study of En- hanced External Counterpulsation), 139 patients with angina, documented CAD, and evidence of ischemia on exercise testing were randomized to 35 hours of active counterpulsa- tion or to inactive counterpulsation.910 Time to $1-mm ST-segment depression increased significantly in patients treated with active counterpulsation (from 337618 s to 379618 s) compared with placebo (from 326621 s to 330620 s; P50.01), although there was no difference be- tween the groups in exercise duration. More active counter- pulsation patients experienced a decrease in anginal episodes. Of patients receiving EECP, 55% reported adverse events, including leg and back pain and skin abrasions, compared with 26% in the control group, with approximately half of these events categorized as device related. In a meta-analysis of 13 observational studies that tracked 949 patients, anginal class as categorized by the CCS classi- fication was improved by $1 class in 86% (95% CI: 82% to 90%).939 The EECP Consortium reported results in 2289 consecutive patients undergoing EECP therapy at 84 partic- ipating centers, including a subgroup of 175 patients from 7 centers who underwent radionuclide perfusion stress tests before and after therapy.940 Treatment was associated with improved perfusion images and increased exercise duration. Similarly, the International EECP Registry reported improve- ment of $1 angina class in 81% of patients immediately after the last treatment.941 In general, existing data, largely from uncontrolled studies, suggest a benefit from EECP in patients with angina refrac- tory to other therapy. Additional data from well-designed RCTs are needed to better define the role of this therapeutic strategy in patients with SIHD.942 4.4.4.2. Spinal Cord Stimulation Spinal cord stimulation at the T1 to T2 level has been advocated as a therapeutic option for patients with angina pectoris that is refractory to medical therapy and coronary revascularization. The stimulation lead is inserted into the epidural space and is connected to a pulse generator im- planted subcutaneously. A paresthetic stimulus is delivered in a continuous, cyclic, or intermittent manner. The mechanisms by which spinal cord stimulation leads to reduced angina are not well established. Although inhibition of pain transmission plays a role, some studies suggest that spinal cord stimulation also might reduce myocardial ischemia.943 945 The efficacy of spinal cord stimulation has been evaluated in several observational and cohort studies. The Prospective Italian Registry described outcomes in 104 patients with severe angina refractory to medical therapy over an average of 13 months after initiation of spinal cord stimulation.946 A .50% reduction in anginal symptoms was observed in 73% of patients. CCS class improved by $1 class in 80% and by $2 classes in 42% of patients. Similarly, in a cohort of 51 patients with refractory CCS Class III or IV angina, spinal cord stimulation was associated with a significant reduction in anginal episodes in 88% of subjects at 24 months of follow-up.947 There were no significant complications of therapy in either series. The published RCTs of spinal cord stimulation were small. One study tested the efficacy of spinal cord stimulation in 13 patients with chronic, intractable angina compared with 12 controls over 6 weeks.912 Patients with spinal cord stimulation demonstrated greater exercise duration and time to angina during treadmill testing and fewer bouts of angina and fewer episodes of ST depression on ambulatory echocardiographic monitoring. A subsequent trial com- pared spinal cord stimulation to CABG.911 Subjects included 104 patients with severe angina who would not be expected to derive survival benefit from revascularization, were at increased risk of surgical complications, and were unsuitable for PCI. Patients in both groups had significant symptom relief. Those assigned to bypass surgery had greater increases in exercise capacity and less ST depression on treadmill testing than did those treated with spinal cord stimulation. Mortality and cardiovascular morbidity rates were lower in the spinal cord stimulation group. In summary, studies of spinal cord stimulation suggest that this technique might have some use as a method to relieve angina in patients with symptoms that are refractory to standard medical therapy and revascularization. There is a paucity of data on the mechanisms and long-term risks and benefits of this therapeutic approach, however. Acupuncture is used by some practitioners for the relief of acute and chronic pain. The efficacy of acupuncture in the treatment of angina pectoris has not been studied rigorously, however. In part this is due to the difficulty of blinding both patients and healthcare providers. Twenty-six patients with severe angina resistant to standard medical therapy were studied in one of the first randomized trials comparing acupuncture and sham acupuncture.917 There was no differ- ence between groups in the frequency of angina or use of nitroglycerin, although patients treated with acupuncture achieved a higher pressure rate product on exercise testing. A subsequent study by the same investigators in patients with less severe ischemia failed to show a difference in either exercise variables or subjective measures between acupunc- ture and placebo patients.916 In contrast, a decrease in anginal episodes and an increase in the workload required to induce ischemia were observed with acupuncture in a crossover study of 21 patients with stable angina. The control condition in this trial was a pill placebo, however, so neither subjects nor investigators were blinded.948 In summary, acupuncture has not been studied sufficiently to warrant recommendation as a treatment option for relief of symptoms in patients with SIHD. 5. CAD Revascularization Recommendations and text in this section are the result of extensive collaborative discussions between the PCI and CABG writing committees, as well as key members of the SIHD and UA/NSTEMI writing committees. Certain issues, such as older versus more contemporary studies, primary analyses versus subgroup analyses, and prospective versus post hoc analyses, have been carefully weighed in designating COR and LOE; they are addressed in the appropriate corre- sponding text. The goals of revascularization for patients with CAD are to 1) improve survival and 2) relieve symptoms. Revascularization recommendations in this section are based predominantly on studies of patients with symptomatic SIHD and should be interpreted in this context. As discussed later in this section, recommendations on the type of revascularization are, in general, applicable to patients with UA/NSTEMI. In some cases (eg, unprotected left main CAD), specific recommendations are made for patients with UA/NSTEMI or STEMI. Historically, most studies of revascularization have been based on and reported according to angiographic criteria. Most studies have defined a significant stenosis as $70% diameter narrowing; therefore, for revascularization decisions and recommendations in this section, a significant stenosis has been defined as $70% diameter narrowing ($50% for left main CAD). Physiological criteria, such as an assessment of FFR, have been used in deciding when revascularization is indicated. Thus, for recommendations about revascularization in this section, coronary stenoses with FFR #0.80 can also be considered to be significant. As noted, the revascularization recommendations have been formulated to address issues related to 1) improved survival and/or 2) improved symptoms. When one method of revascularization is preferred over the other for improved survival, this consideration, in general, takes precedence over improved symptoms. When options for revascularization are discussed with the patient, he or she should understand when the procedure is being performed in an attempt to improve symptoms, survival, or both. Although some results from the SYNTAX (Synergy be- tween Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) study are best characterized as subgroup analyses and hypothesis generating, SYNTAX nonetheless represents the latest and most comprehensive comparison of PCI and CABG.949,950 Therefore, the results of SYNTAX have been considered appropriately when formulating our revascularization recommendations. Although the limitations of using the SYNTAX score for certain revascularization recommendations are recognized, the SYNTAX score is a reasonable surrogate for the extent of CAD and its complex- ity and serves as important information that should be considered when making revascularization decisions. Recom- mendations that refer to SYNTAX scores use them as surrogates for the extent and complexity of CAD. Revascularization recommendations to improve survival and symptoms are provided in the following text and are summarized in Tables 18 and 19. References to studies comparing revascularization with medical therapy are pre- sented when available for each anatomic subgroup. When such studies have been completed only for CABG, RCTs or cohort studies comparing CABG with PCI are presented, but the LOE for PCI is downgraded. See Online Data Supplements 3 and 4 for additional data regarding the survival and symptomatic benefits with CABG or PCI for different anatomic subsets. 5.1. Heart Team Approach to Revascularization Decisions: Recommendations Class I 1. A Heart Team approach to revascularization is recommended in patients with unprotected left main or complex CAD.950 952 (Level of Evidence: C) Fihn et al Stable Ischemic Heart Disease: Full Text e413 Table 18. Revascularization to Improve Survival Compared With Medical Therapy Anatomic Setting COR LOE References UPLM or complex CAD CABG and PCI I Heart Team approach recommended C (950 952) CABG and PCI IIa Calculation of STS and SYNTAX scores B (949, 950, 953 957) UPLM* PCI IIa For SIHD when both of the following are present: Anatomic conditions associated with a low risk of PCI procedural complications and a high likelihood of good long-term outcome (eg, a low SYNTAX score of #22, ostial or trunk left main CAD) Clinical characteristics that predict a significantly increased risk of adverse surgical outcomes (eg, STS-predicted risk of operative IIa For UA/NSTEMI if not a CABG candidate B (949, 968 971, 976 979, 981) IIa For STEMI when distal coronary flow is TIMI flow grade ,3 and PCI can be performed more rapidly and safely than CABG IIb For SIHD when both of the following are present: Anatomic conditions associated with a low to intermediate risk of PCI procedural complications and an intermediate to high likelihood of good long-term outcome (eg, low-intermediate SYNTAX score of ,33, bifurcation left main CAD) Clinical characteristics that predict an increased risk of adverse surgical outcomes (eg, moderate severe COPD, disability from prior stroke, or prior cardiac surgery; STS-predicted operative mortality III: Harm For SIHD in patients (versus performing CABG) with unfavorable anatomy for PCI and who are good candidates for CABG 3-vessel disease with or without proximal LAD artery disease* IIa It is reasonable to choose CABG over PCI in patients with complex 3-vessel CAD (eg, SYNTAX score .22) who are good candidates for CABG 2-vessel disease with proximal LAD artery disease* 2-vessel disease without proximal LAD artery disease* CABG IIa With extensive ischemia B (327, 990 992) IIb Of uncertain benefit without extensive ischemia C (987) 1-vessel proximal LAD artery disease CABG IIa With LIMA for long-term benefit B (412, 987, 993, 994) 1-vessel disease without proximal LAD artery involvement LV dysfunction PCI Insufficient data N/A (Continued) Class IIa 1. Calculation of the STS and SYNTAX scores is reasonable in patients with unprotected left main and complex CAD.949,950,953 957 (Level of Evidence: B) One protocol used in RCTs950 952,958 often involves a multi- disciplinary approach referred to as the Heart Team. Com- posed of an interventional cardiologist and a cardiac surgeon, the Heart Team 1) reviews the patient s medical condition and coronary anatomy, 2) determines that PCI and/or CABG are technically feasible and reasonable, and 3) discusses revascularization options with the patient before a treatment strategy is selected. Support for using a Heart Team approach comes from reports that patients with complex CAD referred specifically for PCI or CABG in concurrent trial registries have lower mortality rates than those randomly assigned to PCI or CABG in controlled trials.951,952 The SIHD, PCI, and CABG guideline writing committees endorse a Heart Team approach in patients with unprotected left main CAD and/or complex CAD in whom the optimal revascularization strategy is not straightforward. A collabor- ative assessment of revascularization options, or the decision to treat with GDMT without revascularization, involving an interventional cardiologist, a cardiac surgeon, and (often) the patient s general cardiologist, followed by discussion with the patient about treatment options, is optimal. Particularly in patients with SIHD and unprotected left main and/or complex CAD for whom a revascularization strategy is not straight- forward, an approach has been endorsed that involves termi- nating the procedure after diagnostic coronary angiography is completed; this allows a thorough discussion and affords both the interventional cardiologist and cardiac surgeon the opportunity to discuss revascularization options with the patient. Because the STS score and the SYNTAX score Table 18. Continued Anatomic Setting COR LOE References Survivors of sudden cardiac death with presumed ischemia- mediated VT PCI I C (1003) No anatomic or physiological criteria for revascularization *In patients with multivessel disease who also have diabetes mellitus, it is reasonable to choose CABG (with LIMA) over PCI30,991,1005 1011 (Class IIa; LOE: B). CABG indicates coronary artery bypass graft; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; COR, class of recommendation; EF, ejection fraction; LAD, left anterior descending; LIMA, left internal mammary artery; LOE, level of evidence; LV, left ventricular; N/A, not available; PCI, percutaneous coronary intervention; SIHD, stable ischemic heart disease; STEMI, ST-elevation myocardial infarction; STS, Society of Thoracic Surgeons; SYNTAX, Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery; TIMI, Thrombolysis In Myocardial Infarction; UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction; UPLM, unprotected left main disease; and VT, ventricular tachycardia. Table 19. Revascularization to Improve Symptoms With Significant Anatomic (>50% Left Main or >70% Non Left Main CAD) or Physiological (FFR <0.80) Coronary Artery Stenoses Clinical Setting COR LOE References $1 significant stenoses amenable to revascularization and unacceptable angina despite GDMT $1 significant stenoses and unacceptable angina in whom GDMT cannot be implemented because of medication contraindications, adverse effects, or patient preferences IIa CABG C N/A IIa PCI C N/A Previous CABG with $1 significant stenoses associated with ischemia and unacceptable angina despite GDMT IIa PCI C (1021 1024) IIb CABG C (1025) Complex 3-vessel CAD (eg, SYNTAX score .22) with or without involvement of the proximal LAD artery and a good candidate for CABG IIa CABG preferred over PCI B (980, 987 989) Viable ischemic myocardium that is perfused by coronary arteries that are not amenable to grafting IIb TMR as an adjunct to CABG B (923, 927, 929, 1026, No anatomic or physiological criteria for revascularization III: Harm CABG C N/A III: Harm PCI C N/A CABG indicates coronary artery bypass graft; CAD, coronary artery disease; COR, class of recommendation; FFR, fractional flow reserve; GDMT, guideline-directed medical therapy; LOE, level of evidence; N/A, not available; PCI, percutaneous coronary intervention; SYNTAX, Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery; and TMR, transmyocardial revascularization. Fihn et al Stable Ischemic Heart Disease: Full Text e415 have been shown to predict adverse outcomes in patients undergoing CABG and PCI, respectively, calculation of these scores is often useful in making revascularization 5.2. Revascularization to Improve Survival: Recommendations Left Main CAD Revascularization Class I 1. CABG to improve survival is recommended for patients with significant (>50% diameter stenosis) left main coronary artery stenosis.73,381,412,959 962 (Level of Evidence: B) Class IIa 1. PCI to improve survival is reasonable as an alterna- tive to CABG in selected stable patients with signif- icant (>50% diameter stenosis) unprotected left main CAD with: 1) anatomic conditions associated with a low risk of PCI procedural complications and a high likelihood of good long-term outcome (eg, a low SYNTAX score [<22], ostial or trunk left main CAD); and 2) clinical characteristics that predict a significantly increased risk of adverse surgical out- comes (eg, STS-predicted risk of operative mortality >5%).949,953,955,958,963 979 (Level of Evidence: B) 2. PCI to improve survival is reasonable in patients with UA/NSTEMI when an unprotected left main coronary artery is the culprit lesion and the patient is not a candidate for CABG.949,968 971,976 979,981 (Level of Evidence: B) 3. PCI to improve survival is reasonable in patients with acute STEMI when an unprotected left main coronary artery is the culprit lesion, distal coronary flow is less than TIMI (Thrombolysis In Myocardial Infarction) grade 3, and PCI can be performed more rapidly and safely than CABG.965,982,983 (Level of Evidence: C) Class IIb 1. PCI to improve survival may be reasonable as an alternative to CABG in selected stable patients with significant (>50% diameter stenosis) unprotected left main CAD with: a) anatomic conditions associ- ated with a low to intermediate risk of PCI proce- dural complications and an intermediate to high likelihood of good long-term outcome (eg, low intermediate SYNTAX score of <33, bifurcation left main CAD); and b) clinical characteristics that predict an increased risk of adverse surgical out- comes (eg, moderate severe chronic obstructive pul- monary disease, disability from previous stroke, or previous cardiac surgery; STS-predicted risk of operative mortality >2%).949,953,955,958,963 979,984 (Level of Evidence: B) Class III: Harm 1. 