Goal-directed therapy in the management of SIHD is focused on (1) prevention of death and MI and (2) reducing symptoms and signs of myocardial ischemia. The intensity of treatment is dictated by the magnitude of risk and the severity of the ischemic burden. The decision to initiate medical, percutaneous, surgical, or hybrid treatment is developed in the context of a patient’s specific clinical, coronary angiographic, and LV functional profiles. Patient values and preferences should also be taken into account.
Aspirin exerts an antithrombotic effect by irreversibly inhibiting cyclooxygenase-1 and the downstream synthesis of platelet thromboxane A2. In the Physicians’ Health Study, aspirin given on alternative days to asymptomatic men was associated with a decreased incidence of MI.88 In the Swedish Angina Pectoris Aspirin Trial, SIHD patients receiving 75 mg of aspirin demonstrated an approximately 33% reduction in MI, sudden death, and vascular events compared with placebo.89 In 2009, the Antithrombotic Trialists’ Collaboration Group published a meta-analysis of 16 randomized placebo-controlled trials evaluating the effect of aspirin on future vascular events (eg, MI, stroke, or vascular death) in approximately 17,000 patients with established CAD.90 Treatment with aspirin significantly decreased the rate of major vascular events, particularly MI (4.3% vs 5.3% per year; rate ratio [RR], 0.69; 95% CI, 0.60-0.80) and stroke (2.08% vs 2.54% per year; RR, 0.81; 95% CI, 0.71-0.92), without inducing a significant increase in the risk of hemorrhagic stroke. Daily use of aspirin (75-162 mg/d) for secondary prevention of MI in both men and women with SIHD is an AHA/ACC Class I recommendation.86 Low-dose aspirin (75 or 81 mg) is recommended for maintenance therapy in combination with P2Y12 inhibitors for patients who undergo PCI.
Clopidogrel is used in combination with aspirin as part of a strategy of dual antiplatelet therapy (DAPT) following PCI in patients with SIHD or ACS (including unstable angina, NSTEMI, and STEMI). The recommended minimal duration of DAPT after PCI with non–first-generation drug-eluting stents (DESs) is 6 months for patients with SIHD and 12 months for patients with ACS, but this remains a “moving target” with the introduction of newer generation stents. Minimal DAPT duration differs for patients treated with bare metal stents (30 days). Based on the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) study, clopidogrel is also provided for up to 1 year in patients with non–ST-segment elevation ACS managed medically.91 Clopidogrel is a Class I recommendation for STEMI patients treated with fibrinolysis or not receiving reperfusion therapy, with an intended 1-year course of treatment.92 Because of their superior efficacy, prasugrel and ticagrelor, two other P2Y12 inhibitors, are preferred over clopidogrel for maintenance therapy (in combination with low-dose aspirin) after PCI for ACS, provided there are no contraindications to their use. Neither prasugrel nor ticagrelor has been studied in the setting of PCI for SIHD, and thus, only clopidogrel is approved for this indication. Prasugrel should not be used in patients with prior stroke or transient ischemic attack and is generally avoided in patients aged over 75 years or of low body weight (< 60 kg) because of a lack of net clinical benefit.
Interest in extended-duration DAPT stems in part from a subgroup analysis of post-MI patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial that demonstrated nearly a 25% reduction in a composite end point of cardiovascular death, MI, and stroke with clopidogrel plus aspirin compared with aspirin alone.93 Several underpowered trials have examined the utility of long-term DAPT in patients after PCI across a spectrum of clinical indications (reviewed in Wang et al94 and Keach et al95). The DES arm of the Dual Antiplatelet Therapy (DAPT)96 study randomized 9961 patients who were clinically stable and without bleeding complications 12 months after PCI (38% for stable angina) to an additional 18 months of aspirin plus a thienopyridine (clopidogrel or prasugrel) or aspirin alone. Prolonged DAPT was associated with a significant reduction in stent thrombosis and MACCE, at the expense of an increased risk of bleeding. The treatment benefit was driven by a reduction in MI related to both stent thrombosis and de novo events in other locations. There was an increased rate of ischemic events over the 3 months after cessation of thienopyridine therapy at completion of the trial. The small absolute increase (0.5%) in total mortality for patients treated with DAPT in this study has not been observed in other studies of DAPT for both cardiac and neurologic indications. The US Food and Drug Administration performed a separate meta-analysis and concluded that there is not an incremental mortality risk with DAPT.
The Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial assessed the effects of DAPT on cardiovascular death, MI, and stroke in patients 1 to 3 years after MI.97 A total of 21,612 post-MI patients were randomized to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, in addition to aspirin. At a median follow-up of 33 months, there were small but significant reductions in the composite primary end point in both ticagrelor arms (HR, 0.85 for ticagrelor 90 mg; 95% CI, 0.75-0.96; P = .008; HR, 0.84 for ticagrelor 60 mg; 95% CI, 0.74-0.95; P = .004) compared to placebo (Fig. 43–3). For every 10,000 patients treated with ticagrelor 90 mg twice daily, 40 primary end points would be prevented at the expense of 41 Thrombolysis in Myocardial Infarction (TIMI) major bleeds; for every 10,000 patients treated with ticagrelor 60 mg twice daily, 42 primary end points would be averted at the expense of 31 TIMI major bleeds. The US Food and Drug Administration has approved the 60-mg ticagrelor dose in combination with aspirin (81 mg) for secondary prevention. Follow-up analyses of the PEGASUS-TIMI 54 trial suggested that the benefit of adding ticagrelor to aspirin for long-term secondary prevention is more marked for post-MI patients continuing on or restarting P2Y12 inhibition after only a brief interruption, especially when compared with patients who have declared themselves stable for 2 or more years after MI and off P2Y12 inhibitor therapy for more than 1 year.98 Data assessing the role of prasugrel under similar clinical circumstances are lacking.
Effect of long-term ticagrelor in patients with prior myocardial infarction. Kaplan-Meier rates of cardiovascular death, myocardial infarction, and stroke through 3 years, according to study group. Study drugs were administered twice daily. The inset shows the same data on an enlarged y axis. Reproduced with permission from Bonaca MP, Bhatt DL, Cohen M: Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015 May 7;372(19):1791-1800.97
Protease-activated receptor (PAR)-1 antagonism with vorapaxar inhibits thrombin-induced activation of platelets. Morrow and colleagues99 tested the effect of vorapaxar on outcomes in a 26,449 patients with SIHD, defined in this study as prior history of MI, ischemic stroke, or peripheral artery disease. At 2 years of follow-up, patients randomized to treatment with vorapaxar 2.5 mg daily had a significant decrease in the risk of cardiovascular death, MI, stroke, or ischemia requiring revascularization compared to placebo (HR, 0.88; 95% CI, 0.82-0.95; P = .001). However, the risk for moderate or severe bleeding was also increased significantly in the treatment arm (HR, 1.66; 95% CI, 1.43-1.93; P < .001), and the study was discontinued early for patients with a history of intracranial hemorrhage. When considering bleeding risk as part of the overall study outcome, there was no difference between groups for the prespecified composite end point of cardiovascular death, MI, stroke, or moderate/severe bleeding (HR, 0.97; 95% CI, 0.90-1.04; P = .40). Decisions regarding long-term DAPT with P2Y12 inhibitors or use of vorapaxar must be individualized, taking into account ischemic risk versus bleeding hazard.
Oral anticoagulant therapy with a vitamin K antagonist such as warfarin is an effective strategy to prevent recurrent MI when the dose is titrated to a target international normalized ratio (INR) of 2.0 to 3.0.100 Hurlen and colleagues101 randomized 3630 post-MI patients to warfarin, aspirin, or combination warfarin plus aspirin for 4 years. Compared with aspirin alone, warfarin or combination warfarin plus aspirin conferred an approximate 19% relative risk reduction for the primary composite end point of death, nonfatal recurrent MI, or stroke. However, warfarin was associated with an elevated rate of major (nonfatal) bleeding complications. Under most circumstances, long-term treatment with aspirin is favored over vitamin K antagonist therapy for the secondary prevention of MI in patients with SIHD, unless an independent indication for warfarin use is present (such as atrial fibrillation).102
Direct oral anticoagulants are used for stroke prevention in patients with atrial fibrillation and elevated CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) scores and for the management of venous thromboembolism. Early studies with dabigatran showed an increased risk with this agent for MI compared with warfarin.103 Low-dose rivaroxaban has been used in combination with DAPT in patients with ACS and is associated with decreased rates of hard clinical end points but with increased bleeding risk.104 Management of patients who require long-term anticoagulation (eg, mechanical valve, atrial fibrillation with CHA2DS2-VASc score > 2) and DAPT after ACS must be individualized to strike the appropriate balance between the risks of stent thrombosis and bleeding. Consideration of bare metal stent use to shorten the duration of DAPT and use of warfarin targeted to a lower therapeutic INR range (2.0-2.5) have been recommended.105 There is limited experience with both direct oral anticoagulants and P2Y12 inhibitors other than clopidogrel in this context. The What Is the Optimal Antiplatelet and Anticoagulation Therapy in Patients With Oral Anticoagulation Trial (WOEST) was an open-label, multicenter, clinical study in Belgium and the Netherlands testing the effect on outcome of clopidogrel alone or combination therapy with clopidogrel plus aspirin in PCI patients on standing anticoagulant therapy with warfarin (n = 573). There was significantly less bleeding in patients assigned to double therapy (warfarin plus clopidogrel) compared to patients assigned to aspirin, clopidogrel, and warfarin (HR, 0.36; 95% CI, 0.26-0.50; P < .0001) without an attendant increase in MI, cardiac death, stroke, or stent thrombosis at 1 year of follow-up.106 Additional studies are in progress.
Previous secondary prevention recommendations emphasized aggressive lipid management to a target LDL cholesterol < 100 mg/dL for all ischemic heart disease patients or < 70 mg/dL if it can be safely achieved in high-risk patients.40 Current guideline recommendations emphasize use of moderate- or high-intensity statin therapy for four patient groups, including those with SIHD. Specifically, in patients aged ≤ 75 years with a history of a prior cardiovascular event, high-intensity statin therapy (eg, rosuvastatin 20-40 mg daily or atorvastatin 40-80 mg daily) is recommended; moderate-intensity statin therapy (eg, rosuvastatin 10-20 mg daily or atorvastatin 20-40 mg daily) is recommended for SIHD patients > 75 years of age. Contraindications to drug therapy, including drug-drug interactions or drug intolerance, should be used to influence dose selection. The Scandinavian Simvastatin Survival Study (4S) demonstrated that treatment with simvastatin in patients with SIHD and a baseline total cholesterol > 210 mg/dL was associated with an approximate 35% reduction in mortality and major coronary event rates.107 In the Cholesterol and Recurrent Events (CARE) study, men and women with previous MI, total cholesterol levels < 240 mg/dL, and LDL cholesterol levels of 115 to 174 mg/dL treated with pravastatin demonstrated a 24% reduction in the risk of future MI compared with placebo.108 LaRosa and colleagues109 tested the hypothesis that high-dose statin therapy is superior to low-dose statin therapy for the secondary prevention of cardiovascular events in patients with SIHD. In the randomized, prospective Treating to New Targets (TNT) trial, 10,001 such patients (enrollment LDL < 130 mg/dL) were randomized to receive 80 or 10 mg of atorvastatin daily over 6 years. Patients treated with 80 mg of atorvastatin achieved a mean LDL cholesterol level of 77 mg/dL versus 101 mg/dL for those allocated to 10 mg of atorvastatin. High-dose atorvastatin therapy was associated with a 22% relative risk reduction for the combined primary end point of death from ischemic heart disease, nonfatal MI, or stroke.109 The lowest optimal level of LDL cholesterol for primary or secondary prevention has not been established.
Stitziel and colleagues in collaboration with the Myocardial Infarction Genetics Consortium Investigators sequenced exons of the NPC1L1 protein in a large cohort of patients with coronary heart disease and in normal controls and reported that carriers of inactivating mutations had LDL cholesterol levels that were 12 mg/dL lower than in noncarriers (P = .04). Carrier status was associated with a relative reduction in risk for coronary heart disease events of 53% (OR, 0.47; 95% CI, 0.25-0.87; P = .008).110 These findings coincided with clinical trial data from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) suggesting that simvastatin (40 mg daily) in combination with ezetimibe (10 mg daily), which targets the NPC1L1 gene, was more effective than simvastatin alone for decreasing LDL levels and cardiovascular events at 6 years after ACS.111 Alirocumab and evolocumab are monoclonal antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9), which degrades hepatic LDL receptors. These therapies have been approved for the treatment of patients who are heterozygous for familial hypercholesterolemia and in patients with clinical atherosclerotic disease who require additional LDL cholesterol lowering or are unable to tolerate guideline-recommended doses of statins plus ezetimibe.
β-Adrenergic Receptor Antagonists
β-Adrenergic receptor antagonists (when administered orally) are associated with increased short- and long-term survival rates in post-MI patients.112,113,114 The use of these agents in the acute phase of MI has been influenced by the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) results.115 Numerous long-term trials of β-adrenergic receptor antagonists attest to their efficacy for secondary prevention of recurrent MI and cardiac death, but to date, no trial has tested whether β-blockers reduce mortality in patients with SIHD, years after or without antecedent MI. In general, their effectiveness is relatively greater among higher risk patients, particularly among those with reduced EF, HF, or ventricular arrhythmias. In lower risk patients, however, β-adrenergic receptor antagonists are recommended only for up to 3 years after uncomplicated MI without other relative indications (eg, atrial fibrillation, reduced EF). In patients with SIHD and HF, treatment should be restricted to the use of carvedilol, long-acting metoprolol, or bisoprolol, agents shown to reduce adverse outcomes in this population.116,117,118 On a physiologic level, β-adrenergic receptor antagonists favorably influence myocardial oxygen supply-demand balance by reducing heart rate, myocardial contractility, systemic arterial pressure, and LV wall stress. The reduction in heart rate may also allow for enhanced CBF as a result of longer diastolic filling times, and anginal frequency and nitroglycerin use are decreased.119
The therapeutic benefit of β-adrenergic receptor antagonists appears to be a class effect with the exception of agents that express intrinsic sympathomimetic activity. In patients with severe angina (ie, CCS class III/IV), full drug efficacy depends largely on dose titration to achieve a heart rate ≤ 60 bpm at rest or ≤ 75 bpm with exertion (or ≤ 75% of the heart rate at which angina occurs). Ambulatory monitoring may be necessary to ensure that severe bradycardia (ie, ≤ 40 bpm) or advanced atrioventricular (AV) block does not occur.
Recent registry data affirm earlier findings that the benefit of β-adrenergic receptor antagonists is observed principally in the post-MI period. Observational data from the Reduction of Atherothrombosis for Continued Health (REACH) registry, for example, demonstrated that among a total cohort of 44,708 patients, rates for the composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke did not differ relative to β-adrenergic receptor antagonist use in patients with CAD without prior MI, with remote history of MI, or with only risk factors for CAD.120 The initiation of β-adrenergic receptor antagonists following MI and continuing for 3 years is a Class I indication in patients with normal LV function. Use of β-adrenergic receptor antagonists is also a Class I indication in patients with LV systolic dysfunction and HF or prior MI, unless contraindicated.121
Fatigue, lethargy, insomnia, nightmares, worsening claudication, and impotence are potential adverse effects and may adversely affect medication adherence. Absolute contraindications to the use of β-adrenergic receptor antagonists include severe bradycardia (heart rate < 60 bpm at rest), preexisting AV block (PR interval > 0.24 seconds, second- or third-degree AV block), sick sinus syndrome, or acutely decompensated HF. Asthma, severe depression, brittle diabetes, and peripheral vascular disease are relative contraindications that require cautious use, but β-adrenergic receptor antagonists may be an important part of medical management strategies in patients with these disorders and as a rule tend to be underused in patients with chronic obstructive pulmonary disease in particular.
β-Adrenergic receptor antagonists are frequently used in combination with other antianginal medications for maximum benefit and symptom control. Adding a β-adrenergic receptor antagonist to nitrates, for example, appears more effective in controlling anginal symptoms than monotherapy with either agent alone.122 Similar observations have been made with combination calcium channel blockers (CCBs); long-acting dihydropyridine derivatives are preferred to avoid excessive bradycardia in this setting.86,122
CCBs decrease vascular smooth muscle cell and cardiac myocyte transmembrane calcium flux. They induce vasodilatation of epicardial coronary arteries to improve CBF and attenuate vasospastic and exertional angina. CCBs also improve angina by lowering systemic vascular resistance and mean arterial blood pressure to decrease LV afterload, thereby decreasing myocardial oxygen demand. The negative inotropic effects of these agents also favorably influences myocardial oxygen supply-demand balance, but may affect cardiac function adversely in patients with significantly impaired LV function. In patients with normal LV systolic function, CCBs may result in increased myocardial contractility as a compensatory response to lowered systemic vascular resistance.
Antianginal efficacy with CCBs is comparable to that obtained with β-adrenergic receptor antagonists.42 However, the efficacy of CCB monotherapy for reducing MI or cardiac death in patients with SIHD has not been demonstrated convincingly. The primary indications for CCB therapy include blood pressure or heart rate control and alleviation of anginal symptoms after optimization of β-adrenergic receptor, nitrate, and angiotensin-converting enzyme inhibitor therapy.
Renin-Angiotensin-Aldosterone System Inhibitors
Several randomized controlled trials in support of long-term angiotensin-converting enzyme (ACE) inhibition for the reduction of cardiovascular death, recurrent MI, and stroke in intermediate- and high-risk patients with SIHD have been reported. The Heart Outcomes Prevention Evaluation (HOPE) study tested the efficacy of ramipril (10 mg/d) on cardiovascular outcomes in a large cohort of patients with CAD, stroke, peripheral vascular disease, or diabetes plus at least one other cardiovascular risk factor.123 Patients with comorbid HF were excluded, and participants were not known to a have a decreased LVEF. Compared with placebo, ramipril therapy resulted in a significant reduction in the rate of death from cardiovascular causes, MI, stroke over 5 years (14.0% vs 17.8%; RR, 0.78; 95% CI, 0.70-0.86). ACE inhibitor therapy also reduced incident diabetes. In the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), a trial that enrolled patients with chronic CAD and relatively lower risk profiles, perindopril therapy was associated with a directionally similar reduction in cardiovascular disease outcomes.124 The consequences of adding perindopril to standing β-adrenergic receptor antagonist therapy were analyzed in a retrospective analysis of the EUROPA trial. This subgroup study showed that combination therapy reduced the relative risk of the primary end point of cardiovascular death, nonfatal MI, or resuscitated cardiac arrest by 24% compared with placebo plus β-adrenergic receptor antagonist therapy (HR, 0.76; 95% CI, 0.64-0.91; P = .02).125 The salutary effects of ACE inhibitors were not as firmly established among lower risk patients enrolled in the Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy (PEACE) trial, especially among patients with normal LV function, optimal lipid profiles, and prior revascularization.126 ACE inhibitors are a Class I recommendation for all SIHD patients with LV dysfunction (EF < 0.40), hypertension, diabetes, or chronic kidney disease and a Class IIa recommendation for patients with both SIHD and other vascular disease.126 Angiotensin receptor blockers (ARBs) are an appropriate alternative for patients who cannot tolerate ACE inhibitors.121,127 They should not be used in combination with ACE inhibitors. The mineralocorticoid receptor antagonists spironolactone and eplerenone have been demonstrated to be beneficial for patients with both advanced (NYHA Class III/IV and EF < 0.35) and lesser degrees of HF.128,129,130 Initiation of eplerenone, in addition to the use of β-adrenergic receptor antagonist and ACE inhibitor therapy, is a class I recommendation for treatment of patients after MI with reduced EF (< 0.40), HF, or diabetes.131 Use of these agents must be considered in the context of renal function and potassium homeostasis. Indications for the use of combination sacubitril/valsartan, in preference to an ACE inhibitor or ARB, are reviewed in Chap. 70.
Organic nitrates (eg, nitroglycerin, isosorbide dinitrate) are nitric oxide donors that activate soluble guanylyl cyclase in vascular smooth muscle cells to increase intracellular cyclic guanosine monophosphate and induce blood vessel relaxation. These medications treat ischemia by (1) inducing venodilation of capacitance vessels to decrease preload, thus decreasing LV wall stress and myocardial oxygen demand; (2) dilating epicardial coronary arteries to improve CBF; and (3) recruiting coronary collaterals. In patients with CAD, use of nitrates is associated with lower angina frequency and increased time to ischemic ECG findings on treadmill testing.86 Nitroglycerin also expresses antithrombotic properties, predominately via attenuation of platelet aggregation. Monotherapy with nitrates does not influence survival or decrease cardiovascular death rates in SIHD patients.
Tachyphylaxis to organic nitrate use is common in clinical practice, although the precise mechanisms remain unclear. Pentaerithrityl tetranitrate (PETN) has been shown in preclinical studies to exert properties that delay nitrate tolerance. However, a randomized, controlled study of 655 patients demonstrated that PETN did not affect exercise duration significantly compared to placebo in patients with SIHD. There was a signal of possible benefit in a prespecified subgroup of patients with low exercise tolerance at baseline.132 Nevertheless, in the absence of available nitrate derivatives for which drug tolerance is not a concern, integrating a nitrate-free interval (8-12 hours) or longer drug holidays has been suggested (ie, intermittent drug cessation for 2- to 3-day periods). Co-administration of nitrates with sildenafil greatly increases the risk of potentially life-threatening hypotension because both agents increase cyclic guanosine monophosphate bioactivity to potentiate vasodilatation.133
Ranolazine is a selective inhibitor of late sodium influx into myocytes, which in turn leads to decreased myocardial contractility.134 Early clinical trials established that ranolazine monotherapy is effective in improving exercise tolerance in patients with SIHD.135 In the prospective, randomized, placebo-controlled Combination Assessment of Ranolazine in Stable Angina (CARISA) trial, ranolazine (750-1000 mg twice daily) in combination with standard doses of atenolol, amlodipine, or diltiazem, significantly increased time to onset of angina and exercise performance compared with placebo.136 Additionally, ranolazine significantly reduced the frequency of angina and nitroglycerin requirements during the 12-week period following randomization. Findings from a meta-analysis of seven randomized controlled trials (including CARISA) comparing ranolazine with placebo or usual care support a benefit with ranolazine on exercise tolerance and angina frequency.137 Adverse effects include dizziness and constipation; discontinuation rates in large trials have been approximately 1%.138 Although rare, QT interval prolongation has been seen with ranolazine therapy but not yet linked to clinically important arrhythmias. Drug interactions may be important, however, and the use of ranolazine is not recommended in patients receiving nondihydropyridine CCBs, quinolones, or azole antifungal medications, among others. Ranolazine is best reserved for patients with persistent symptoms despite maximal medical therapy or for patients unable to tolerate other antianginal therapies because of adverse effects.