Coronary Artery Disease

Stable Angina Pectoris

Diagnosis and Evaluation

Stable angina pectoris is defined as reproducible angina symptoms (chest pain or pressure) of at least 2 months' duration that are precipitated by exertion or emotional stress and have not appreciably worsened. In contrast, unstable angina is defined by new-onset angina or angina occurring at a relatively low level of exertion, occurring at rest, or accelerating in frequency or severity. Unstable angina is associated with increased short-term risk for acute myocardial infarction (MI). As such, the evaluation of patients with angina should include a focused history, eliciting the duration of symptoms, aggravating and relieving factors, and whether symptoms have worsened. Although angina is classically described as tightness, heaviness, or gripping in the chest, it is important to recognize that classic symptoms may be absent, and some demographic groups (women and patients with diabetes mellitus) may have atypical symptoms, including exertional dyspnea.

The physical examination should include an evaluation of the cardiovascular system and a search for findings suggesting conditions that mimic angina, including heart failure, pulmonary hypertension, valvular heart disease (particularly aortic stenosis), and hypertrophic cardiomyopathy. The first step in diagnostic testing is to determine the pretest probability (or likelihood) of coronary artery disease (CAD) (Table 6). Baseline resting electrocardiography (ECG) is required to rule out ongoing ischemia and to guide the choice of stress test (Figure 4). The selection of tests for evaluating chest pain is discussed in Diagnostic Testing in Cardiology. Stress testing is most useful in patients with an intermediate probability of CAD; however, when the pretest probability of CAD is high, testing may provide prognostic information. Other diagnoses should be pursued in patients with normal findings on stress testing. If the stress test yields abnormal results, additional evaluation should be considered.

General Approach to Treatment of Stable Angina Pectoris

All patients with angina should receive guideline-directed medical therapy consisting of risk factor modification, cardioprotective medications, and antianginal medications (Figure 5). Lifestyle modifications, including regular physical activity, weight loss, tobacco cessation, and dietary changes, should be strongly encouraged, and blood pressure control (with a goal of <130/80 mm Hg) and diabetes management should be emphasized. Cardioprotective medications are indicated in patients with CAD to prevent thrombosis and halt further progression of atherosclerotic plaque. Antianginal medications reduce cardiac workload or increase myocardial oxygen delivery, resulting in decreased angina and improved functional capacity.

Cardioprotective Medications

Aspirin reduces the risk for MI and cardiovascular death in patients with stable angina. Guidelines recommend low-dose aspirin (75-162 mg/d) because it is as effective in preventing MI as high-dose aspirin (325 mg/d) and confers a lower bleeding risk. In aspirin-intolerant patients, clopidogrel, a platelet P2Y12 receptor inhibitor, is an acceptable alternative. Neither prasugrel nor ticagrelor has been studied in the context of stable angina, and their role in managing this condition remains to be established.

Lipid-lowering therapy, targeting LDL cholesterol in particular, is indicated to reduce the risk for vascular events and progression of underlying CAD. Statin therapy remains the cornerstone of lipid management for secondary prevention, as it has been shown to reduce the risk for MI, death, and stroke. High-intensity statin therapy (atorvastatin, 40-80 mg/d, or rosuvastatin, 20-40 mg/d) decreases LDL cholesterol levels by 50% or more and is preferred to moderate-intensity therapy in patients with no contraindications to its use. In patients who are intolerant of statins (such as those who develop significant myalgia) or who do not achieve adequate LDL cholesterol reduction with statin therapy, it is reasonable to address LDL cholesterol levels with nonstatin medications, including ezetimibe, bile acid sequestrants, fibrates, and proprotein convertase subtilisin/kexin type 9 inhibitors. Management of statin therapy and nonstatin cholesterol-lowering therapy is discussed in MKSAP 18 General Internal Medicine.

ACE inhibitor therapy is indicated in patients with stable angina if there is concomitant diabetes, chronic kidney disease, left ventricular dysfunction (ejection fraction ≤40%), heart failure, or a history of MI. In these populations, ACE inhibitors have additional benefits that are unrelated to CAD, such as preservation of kidney function and improvement in left ventricular function. Angiotensin receptor blockers (ARBs) may be used as an alternative to ACE inhibitors in these same patient populations.

Chelation therapy involves a series of intravenous infusions of ethylene diamine tetra-acetic acid or similar compounds to bind cations (such as calcium) and increase their excretion from the body. There has been no convincing evidence of any benefit with chelation therapy, and it is not recommended for treatment of CAD.

Antianginal Medications

β-Blockers are recommended as first-line agents in patients with stable angina. β-Blockers simultaneously lower heart rate and blood pressure to reduce myocardial oxygen consumption. All β-blockers are equally efficacious in reducing angina, and dosage should be titrated to achieve a resting heart rate between 55/min and 60/min. The choice of β-blocker may depend on other medical conditions, such as concomitant left ventricular dysfunction, kidney dysfunction, lung disease, and significant hypertension. β-Blockers should be used with caution in patients taking nondihydropyridine calcium channel blockers (verapamil, diltiazem) because of additive negative inotropic and chronotropic actions. Caution should also be exercised with these agents in the setting of significant conduction disease on ECG or left ventricular dysfunction. β1-Selective β-blockers, such as metoprolol, should be used in patients with significant lung disease to avoid worsening respiratory function. Reported side effects include fatigue, lethargy, sleep disturbances, and impotence.

Calcium channel blockers can be useful in patients with symptoms despite β-blocker therapy or in patients intolerant of β-blockers. All calcium channel blockers improve myocardial oxygen delivery by causing coronary vasodilation and reduction in coronary vascular resistance. Additionally, calcium channel blockers can decrease myocardial oxygen consumption through their antihypertensive and negative inotropic effects. The nondihydropyridine calcium channel blockers have negative chronotropic effects and lower heart rate, which can worsen heart failure and increase mortality; therefore, they should not be used in patients with left ventricular dysfunction. Short-acting dihydropyridine formulations, such as short-acting nifedipine, should be avoided because they can paradoxically worsen angina by causing an acute drop in blood pressure, resulting in reflex tachycardia and increased myocardial oxygen demand.

Nitrates cause coronary vasodilation, thereby improving myocardial oxygen delivery. These agents also decrease oxygen consumption by reducing preload, which reduces ventricular wall stress. The beneficial effects may be offset by reflex tachycardia unless β-blockers or calcium channel blockers are used. Short-acting sublingual nitrates should be prescribed to patients with CAD for acute relief of angina. Long-acting nitrates, including isosorbide mononitrate or dinitrate and nitroglycerin patch formulations, provide a constant level of vasodilation throughout the day. A nitrate-free interval of about 12 hours, generally during sleep hours, is needed to avoid development of nitrate tolerance. Side effects include headache, flushing, and hypotension, particularly with rapid-acting formulations. Concomitant use of nitrates and phosphodiesterase 5 inhibitors, such as sildenafil, should be avoided because of the risk for significant hypotension.

Ranolazine decreases angina and modestly increases exercise times in patients with stable angina. However, ranolazine has not been shown to improve other cardiovascular outcomes, including mortality and incidence of myocardial infarction. It inhibits the late sodium current, which in turn reduces sodium-dependent calcium currents, resulting in reduced wall tension and myocardial oxygen consumption. Ranolazine also has a modest QT-prolonging effect, but no proarrhythmic effect has been directly attributed to ranolazine. The QT interval should be monitored carefully when other QT-prolonging drugs are coadministered. The typical dosage is 1000 mg twice daily; however, the dosage should be reduced to 500 mg twice daily in patients receiving moderate inhibitors of cytochrome P-450 3A4 (verapamil, diltiazem). Ranolazine should not be used in patients receiving strong inhibitors of cytochrome P-450 3A4 (clarithromycin, itraconazole, ketoconazole, several HIV medications) because serum levels of ranolazine will significantly increase.

Coronary Revascularization

Decision to Revascularize

Patients with progressive angina symptoms refractory to medical therapy or markedly abnormal stress testing results should be considered for coronary angiography. Before angiography, the risks, benefits, and alternatives to the procedure should be discussed with the patient. It is also important to discuss possible findings and the therapeutic options available after angiography. The goals of revascularization are to improve symptoms of angina and quality of life, prevent future CAD events, and improve survival.

Coronary angiography with fractional flow reserve testing can provide information on the functional significance of angiographically indeterminate lesions (see Diagnostic Testing in Cardiology). Determining the hemodynamic significance of lesions reduces both unnecessary stenting and the need for urgent revascularization. Abnormal fractional flow reserve measures (values <0.80) suggest that a lesion is hemodynamically significant.

Percutaneous Coronary Intervention

Percutaneous coronary intervention (PCI) encompasses several different catheter-based techniques to improve coronary blood flow by relieving coronary obstruction. Initially, PCI was most commonly performed with balloon angioplasty; however, this technique was replaced in the 1990s with bare metal stenting. Currently, most PCI procedures involve drug-eluting stent implantation, which has reduced the risk for in-stent restenosis (the process by which neointimal proliferation within or adjacent to the treated section of coronary artery re-narrows the vessel lumen).

Despite advancements in PCI technology, there is no evidence that PCI is superior to guideline-directed medical therapy in the treatment of stable CAD. Specifically, neither the COURAGE trial of patients with stable angina nor the BARI-2D trial of patients with concomitant CAD and diabetes showed any difference in mortality or incidence of MI between treatment strategies. PCI is indicated for the treatment of patients with medically refractory angina, those who are unable to tolerate optimal medical therapy owing to side effects, or those with high-risk features on noninvasive exercise and imaging tests.

Coronary Artery Bypass Graft Surgery

Coronary artery bypass grafting (CABG) is generally recommended for patients with extensive CAD and in certain subsets of patients for whom studies have shown CABG to be superior to PCI or medical therapy. In patients with multivessel CAD, revascularization with CABG results in decreased recurrence of angina, lower rates of MI, and fewer repeat revascularization procedures compared with PCI. Unlike PCI, CABG improves survival in patients with left main or three-vessel CAD and is recommended to reduce mortality in these high-risk patients. Additionally, CABG has an established role in revascularization of patients with diabetes and in those with left ventricular dysfunction. Long-term (10-year) follow-up of the STICH trial demonstrated a survival advantage with CABG compared with medical therapy alone among patients with multivessel CAD and severe left ventricular dysfunction.

After Revascularization

Patients should continue receiving guideline-directed medical therapy following surgical or percutaneous revascularization, although some antianginal therapies may be reduced or discontinued. Aspirin is recommended indefinitely after revascularization. The addition of a P2Y12 inhibitor to aspirin therapy, known as dual antiplatelet therapy (DAPT), is also indicated; the recommended duration of DAPT depends on many clinical considerations. Clopidogrel is the only antiplatelet drug that has been studied in combination with aspirin after revascularization of patients with stable CAD. The role of newer antiplatelet agents is unclear at this time.

In patients treated with bare metal stent placement, guidelines recommend a minimum of 1 month of DAPT. Studies of the optimal duration of DAPT after drug-eluting stent implantation have suggested safety and benefits with both shorter (6-month) and longer (30-month) treatment courses. Current guidelines recommend treating patients with stable angina with DAPT for at least 6 months after drug-eluting stent placement, with the option to continue therapy for a longer duration in those with a high risk for thrombosis-related complications (such as depressed left ventricular function, saphenous vein graft stenting, and diabetes) and a favorable bleeding profile. Although guidelines define minimum DAPT duration, the optimal duration should be individualized according to the patient's risks for thrombotic and bleeding complications.

In patients undergoing CABG for stable CAD, DAPT for 12 months may be reasonable to improve the patency of vein grafts.

Acute Coronary Syndromes

General Considerations

An acute coronary syndrome (ACS) results from acute or subacute disruption in coronary blood flow. Patients present with acute-onset chest pain or an angina equivalent that occurs without a clear precipitant. Unlike stable angina, which involves a gradual narrowing in the coronary artery, an ACS is caused by acute plaque rupture or erosion, often in sections of the coronary artery with mild or moderate stenosis. The presentation depends on the degree of coronary flow impairment.

ACS is classified as ST-elevation myocardial infarction (STEMI) or non–ST-elevation acute coronary syndrome (NSTE-ACS) based on findings on ECG (Figure 6). The hallmark ECG features of STEMI are ST-segment elevation of 1 mm or more in two or more contiguous limb or chest leads, excepting leads V2 and V3. STEMI is defined as ST-segment elevation of 2 mm or greater in men and 1.5 mm or greater in women in leads V2 and V3. Posterior MI typically manifests as ST-segment depression greater than 2 mm in the anterior leads (V1 through V4), often with ST-segment elevation in the inferior or lateral leads. New left bundle branch block is considered a STEMI equivalent and potentially reflects an acute left anterior descending artery occlusion.

NSTE-ACS is further categorized according to the presence of biomarkers of cardiac injury (troponin T or I) in the serum. Non–ST-elevation myocardial infarction (NSTEMI) is defined as a biomarker-positive presentation that does not meet criteria for STEMI. Unstable angina is characterized by new or worsening angina, with or without ECG changes, and without detectable levels of cardiac injury markers.

The use of troponin assays has resulted in increased diagnosis of NSTEMI. New high-sensitivity troponin assays can detect cardiac injury with even greater sensitivity and earlier in the setting of ACS than previous tests. Their clinical use may expedite risk stratification in patients with chest pain but may increase detection of non-ACS events and consequent downstream testing. Biotin, when taken in exceptionally large dosages exceeding the daily recommended allowance (0.3 mg), may result in a falsely low troponin measurement. Biotin is found in many dietary supplements, and some contain as much as 20 mg to 100 mg. Dietary ingestion of biotin should be assessed and, if excessive, reported to the relevant laboratory, which can confirm whether the troponin assay may be affected.

ST-Elevation Myocardial Infarction

Recognition

The pathogenesis of STEMI typically involves plaque rupture within a coronary artery. The rupture causes platelet adhesion, activation, and aggregation, resulting in a thrombosed coronary artery and acute vessel occlusion. The sudden loss of coronary blood flow leads to transmural ischemia of the myocardium and the ECG manifestation of ST-segment elevation. Because oxygen delivery to the affected artery is acutely and completely obstructed, prompt recognition and initiation of reperfusion therapy are vital (Figure 7).

Although the presentation of STEMI is often dramatic and clear, several diagnoses can mimic STEMI. These disease entities need to be distinguished from STEMI to minimize patient harm. Acute pericarditis presents with acute chest pain, albeit pain with a pleuritic and positional nature, and ST-segment elevation. The ST-segment elevation of pericarditis tends to be diffuse and concave; however, it can be easily misinterpreted for STEMI on ECG (Figure 8). Pericarditis can also be localized and present with regional ST-segment elevation, such as in the inferior leads. Myopericarditis resulting from viral infections or autoimmune conditions can cause cardiac enzyme release, further confusing the clinical picture. A thorough history and physical examination combined with review of the ECG findings may help differentiate the conditions.

Left ventricular hypertrophy–induced ECG changes may also look similar to ST-segment elevation injury currents; however, these changes are typically concave in appearance. Comparison with previous ECG results is helpful in assessing for acute changes.

Aortic dissection can cause ST-segment elevation if the dissection involves the left or right coronary artery. In these cases, the ST-segment elevation is due to transmural myocardial ischemia. Aortic dissection is a surgical emergency and must be recognized early because treatment paradigms are drastically different. Diagnostic clues that help differentiate the two conditions include differential blood pressures in the upper extremities and mediastinal widening on chest radiograph with aortic dissection.

Severe hypercalcemia may result in ST-segment elevation that mimics ACS; however, other findings include a short QT interval and flattened T waves.

Reperfusion

Upon STEMI recognition, reperfusion with thrombolytic agents or primary PCI (PPCI) is necessary. PPCI is the preferred method of reperfusion in most cases.

Thrombolytic Therapy

Thrombolytic therapy is recommended for patients with STEMI when symptom onset is within 12 hours and PPCI is not available within 120 minutes of first medical contact. If symptoms began 12 to 24 hours before presentation and there is evidence of hemodynamic instability or significant myocardium at risk (such as with anterior MI), thrombolytic therapy should be considered. Characteristics of the various thrombolytic agents are presented in Table 7.

In addition to thrombolytic therapy, all patients without a specific contraindication should receive a loading dose of aspirin (162-325 mg) as well as intravenous heparin, enoxaparin, or fondaparinux. Clopidogrel loading has been demonstrated to increase rates of vessel patency and is also recommended in this setting.

After thrombolytic therapy is administered, the ECG should be monitored at 60 minutes and 90 minutes to confirm at least 50% improvement in maximal ST-segment elevation. One quarter to one third of patients do not achieve reperfusion, particularly if time from symptom onset to receipt of thrombolytic therapy is delayed. Owing to the potential for thrombolytic failure, patients with STEMI treated with thrombolytic therapy should be subsequently transferred to a PCI-capable hospital. Rescue PCI is associated with improved outcomes compared with conservative management in the event of failed reperfusion. Coronary angiography is generally recommended in all patients before discharge, even after successful thrombolysis. Patients with STEMI who present with heart failure or cardiogenic shock, or who develop these complications after thrombolytic therapy, are a particularly high-risk group (mortality rate >50%) and should be immediately transferred to a PCI-capable center.

Although thrombolytic therapy is potentially life-saving, it carries significant risks, primarily related to bleeding. Intracerebral hemorrhage is the most catastrophic complication of thrombolytic therapy and occurs in approximately 1% of patients. Relative and absolute contraindications to thrombolytic therapy are listed in Table 8.

Primary Percutaneous Coronary Intervention

PPCI refers to the process by which an emergency medical provider activates a team of providers to initiate emergent coronary angiography and PCI in patients with STEMI. Ideally, the time from first medical contact until PCI is less than 90 minutes. The amount of myocardial salvage is directly related to ischemic time; therefore, the quicker the artery can be opened, the better the final outcome. Because the rates of achieving vessel patency are higher and more reliable with PPCI than with thrombolysis, PPCI is the preferred method of treating STEMI when the patient presents to a hospital capable of performing PCI or can be transferred from an index hospital to a PCI-capable center quickly (time from first medical contact to PPCI of ≤120 minutes). Once the patient is in the catheterization suite, the initial focus is on quickly restoring flow to the acutely occluded artery. There is ongoing debate as to the timing and potential benefit of PCI of nonculprit vessels.

Patients undergoing PPCI should receive aspirin and heparin before thrombolytic therapy. During the procedure, patients generally receive intravenous heparin (with or without glycoprotein IIb/IIIa blockade) or bivalirudin. Most patients undergo stenting and receive loading doses of additional antiplatelet drugs (P2Y12 inhibitors) (Table 9). Clopidogrel has historically been the most commonly prescribed P2Y12 inhibitor. Compared with clopidogrel, prasugrel is more potent, has a quicker onset of action, and has a lower risk for thrombotic complications; however, prasugrel is also associated with an increased risk for bleeding. Prasugrel should not be used in patients with a history of stroke and those aged 75 years and older, and dosing must be adjusted for those weighing less than 60 kg (132 lb). Ticagrelor, a nonthienopyridine P2Y12 inhibitor, also has greater potency and faster onset of platelet inhibition than clopidogrel. In the PLATO trial of patients with ACS, ticagrelor treatment resulted in significantly lower mortality rates compared with clopidogrel. Ticagrelor causes subjective dyspnea in some patients; this symptom is usually self-limited but occasionally causes drug discontinuation.

Medical Therapy

Medical therapies for the treatment of patients with ACS are summarized in Table 10.

All patients presenting with STEMI should receive aspirin and anticoagulant therapy. Regardless of the selected reperfusion strategy, patients should also be treated with a P2Y12 inhibitor. Clopidogrel is indicated in patients receiving thrombolytic therapy, whereas clopidogrel, prasugrel, and ticagrelor are options for those undergoing PPCI (see Table 9).

β-Blockers decrease myocardial oxygen demand, reduce the incidence of ventricular arrhythmias, and improve long-term survival in patients with STEMI. Current guidelines suggest initiating these drugs within 24 hours of presentation. The COMMIT/CCS-2 trial demonstrated that intravenous metoprolol reduced the early risk for reinfarction and ventricular fibrillation in patients with acute MI but also resulted in a higher rate of cardiogenic shock. β-Blockers should not be given if there is evidence of hypotension, cardiogenic shock, pulmonary congestion, or atrioventricular block. In these cases, β-blockers may be withheld initially and introduced once the patient is stabilized.

ACE inhibitors are indicated in most patients with STEMI and particularly in patients with impaired left ventricular function, heart failure, or anterior wall infarction. ARBs may be used if the patient is intolerant of ACE inhibitors. These agents have shown significant early benefit and should be administered within the first 24 hours of presentation, assuming there are no contraindications.

Eplerenone, an aldosterone antagonist, has proved beneficial in patients with STEMI who have an ejection fraction less than or equal to 40% and either heart failure or diabetes; however, the treatment effects were demonstrated only when eplerenone was initiated within 1 week of presentation. Potassium levels must be carefully monitored, particularly in patients with pre-existing kidney dysfunction and those receiving ACE inhibitors or ARBs.

High-intensity statin therapy is indicated in all patients with STEMI. Cholesterol levels may be transiently lower around the time of MI; however, high-intensity statin therapy should be prescribed regardless.

Intravenous nitroglycerin can be used to treat patients with STEMI and hypertension or heart failure; however, there is no role for the routine use of oral nitrates in the convalescent phase of STEMI. Calcium channel blockers and ranolazine also have no role in treating patients with STEMI.

A 2018 systematic review found that supplemental oxygen in the setting of normal oxygen saturation increases mortality in patients with acute myocardial infarction (see MKSAP 18 Pulmonary and Critical Care Medicine). An international guideline strongly recommends that oxygen therapy not be initiated for patients with an acute myocardial infarction and an oxygen saturation as measured by pulse oximetry (SpO2) of 93% or higher and weakly recommends withholding oxygen therapy for an SpO2 of 90% or higher. For patients receiving oxygen therapy, the SpO2 should be maintained at 96% or lower. The 2017 European Society of Cardiology guidelines for the management of acute STEMI recommend oxygen therapy for an arterial oxygen saturation (SaO2) less than 90% or arterial PO2 less than 60 mm Hg (<7.98 kPa), and oxygen is not recommended for an SaO2 higher than 90%. An upper SaO2 limit is not provided. The American Heart Association recommends oxygen therapy for an oxygen saturation less than 90% or in the presence of heart failure or dyspnea without providing an upper oxygen saturation limit.

Complications of STEMI

Arrhythmias commonly occur in the peri-infarct setting. Atrial fibrillation, which affects up to 10% to 20% of patients with STEMI, complicates management and may cause hemodynamic instability. Ventricular tachycardia and fibrillation may also occur during MI or after reperfusion. Repetitive and sustained bouts of postinfarct ventricular arrhythmias may warrant consultation with an electrophysiologist, as predischarge implantable cardioverter-defibrillator therapy has a role in treating late arrhythmias complicating STEMI. Routine suppression of ventricular ectopy with antiarrhythmic agents is generally not recommended and is associated with increased risk for ventricular arrhythmias. In particular, accelerated idioventricular rhythm, which commonly arises after reperfusion, is generally benign and transient, requiring no treatment. Atrioventricular blocks, including Wenckebach and complete heart block, may occur after inferior MIs. Temporary transvenous pacemakers are sometimes necessary, but permanent pacing is rarely required. Benign forms of vagally mediated heart block must be differentiated from Mobitz type 2 second-degree atrioventricular block, which is more frequently observed with anterior infarction and damage to the conduction system. Mobitz type 2 block may progress to complete heart block and necessitates permanent pacing.

Cardiogenic shock is a common complication of STEMI. It typically results from a large anterior MI due to severely reduced left ventricular systolic function and carries a mortality rate of 50% to 80%. Patients with cardiogenic shock, particularly those younger than 75 years, have a higher rate of survival if they receive emergent revascularization. In these cases, an intra-aortic balloon pump (IABP) or left ventricular assist device may be implanted temporarily, although limited data support their benefits in cardiogenic shock. Once the patient is stabilized, weening the patient from mechanical and inotropic support and gentle uptitration of afterload-reducing agents, such as captopril, can be attempted. β-Blockers should be avoided initially and can be introduced once the patient is stabilized. Diuretics should be used to treat pulmonary vascular congestion.

Approximately 10% to 20% of cases of anterior STEMI are complicated by left ventricular apical thrombus. Although not supported by rigorous studies, anticoagulation with warfarin is generally recommended for at least 3 months to reduce the risk for systemic embolization.

Rates of mechanical complications after STEMI, including left ventricular free wall rupture, right ventricular infarction, ventricular septal defect (VSD), and acute mitral regurgitation, are low; however, clinicians must be able to recognize these complications, given their highly morbid nature. Free wall rupture produces sudden-onset chest pain or syncope with rapid progression to pulseless electrical activity. It is more common in older adults, women, patients with anterior MI, those receiving anti-inflammatory agents, and patients with a significant delay in receiving reperfusion therapy (>12 hours). Surgery should be considered, but mortality rates, even among those who survive to the operating room, are very high.

Right ventricular infarction, typically indicated by ST-segment elevation in right-sided ECG leads (V1 and V4R), can complicate right coronary artery occlusion. It presents with hypotension, elevated jugular venous pressure, and an absence of findings on lung auscultation. Right ventricle pump dysfunction causes inadequate filling of the left ventricle, resulting in shock. Treatments include volume resuscitation and positive inotropes (dobutamine or dopamine) to bridge the right ventricle to recovery, which generally takes 2 to 3 days. Nitrates are contraindicated because they may worsen hypotension by reducing preload.

Acquired VSD from septal wall rupture may complicate inferior or anterior STEMI. With inferior STEMI, the VSD tends to be located in the inferior basal septum, whereas anterior STEMI generally leads to an apical VSD. VSDs typically occur within 3 to 5 days of STEMI presentation. Patients present with worsening heart failure and shock, and a harsh holosystolic murmur may be heard at the left lower sternal border. The diagnosis is confirmed with echocardiography. Although initial management may include afterload reduction with medical therapy and IABP support, the mortality rate in patients with medically treated postinfarct VSDs approaches 100%. Surgical closure should be considered; however, the mortality rate in surgical series is still high (approximately 50%). Patch closure can be very difficult owing to the necrotic tissue and inability to find viable myocardium to suture and patch. Percutaneous closure with a VSD occluder device is possible but often unsuccessful because of the nature of the defect, and residual shunting around the device is common.

Acute severe mitral regurgitation may occur as a result of papillary muscle rupture. Most often, the posteromedial papillary muscle ruptures with right coronary artery occlusion. This complication tends to occur several days after STEMI. Afterload reduction and IABP placement may be tried, but urgent surgical intervention is usually necessary. Acute severe mitral regurgitation may also result from left ventricular dysfunction and is often related to an inferior MI with restriction of the posterior mitral leaflet, termed functional ischemic mitral regurgitation. Ischemic mitral regurgitation is treated with revascularization and medical therapy.

Non–ST-Elevation Acute Coronary Syndromes

NSTE-ACS is a common presentation of CAD. The chest pain associated with an NSTE-ACS is generally acute, is new in onset, and often occurs with rest or minimal exertion. The pathogenesis is plaque rupture within a coronary artery and transient or incomplete occlusion of the vessel. NSTEMI is differentiated from unstable angina by the presence of elevated serum cardiac biomarkers at the time of evaluation.

Risk Stratification

Many treatment options are available for patients with NSTE-ACS, and risk stratification tools can be used to aid in diagnostic and therapeutic decision making. The two most commonly used risk scores are the TIMI and GRACE risk models. The simpler of the two models, the TIMI risk score, predicts 14-day death, recurrent MI, and urgent revascularization rates (Table 11). The GRACE risk score (available at www.gracescore.org) is more complex, requiring a nomogram to calculate. It incorporates physical examination findings (heart rate, blood pressure, Killip class), clinical features (age, cardiac arrest at admission), electrocardiographic findings (ST-segment deviation), and biomarker variables (creatinine levels, elevated cardiac enzymes) to predict in-house and postdischarge death and MI risk. These scoring systems are useful in determining which patients may benefit most from more aggressive strategies, such as anticoagulation or an early invasive approach (Figure 9). An elevated troponin level is itself a powerful predictor of outcomes and identifies patients who will benefit from aggressive medical and invasive strategies (coronary angiography).

Medical Therapy

Medical therapies for patients with NSTE-ACS are similar to those for other ACS presentations; however, some unique features in this patient population are highly relevant to the treatment of this condition. Notably, thrombolytic therapy is not beneficial in patients with NSTE-ACS and is not recommended. Medical therapies for the treatment of NSTE-ACS are summarized in Table 10.

Antiplatelet Medications

Aspirin (162-325 mg) should be administered at presentation to all patients with definite or likely NSTE-ACS, followed by a daily dose of 81 to 162 mg. Early clopidogrel loading has been recommended in patients with NSTEMI; however, the optimal timing for loading of other oral antiplatelet agents is unclear. Prasugrel loading before coronary angiography is not beneficial. Clopidogrel or ticagrelor therapy is recommended for 1 year after NSTE-ACS presentation, regardless of the treatment strategy. Prasugrel is indicated only in patients treated with PCI. Evidence supports continuing DAPT beyond 1 year in patients at high risk for recurrent vascular events (such as those with depressed left ventricular function, saphenous vein graft stenting, or diabetes) in whom the benefit exceeds the bleeding risk.

The use of intravenous glycoprotein IIb/IIIa inhibitors (eptifibatide, tirofiban) has decreased over the past decade. Although these drugs had been shown to improve outcomes in patients with NSTE-ACS (particularly higher-risk and troponin-positive patients), subsequent study demonstrated no benefit of upstream glycoprotein IIb/IIIa blockade and an increased risk for bleeding. These agents are generally reserved for use during PCI; however, given the advent of quicker-acting and more potent oral antiplatelet agents, administration of glycoprotein IIb/IIIa inhibitors in the setting of PCI has also significantly declined.

Anticoagulant Medications

Patients with definite NSTE-ACS should undergo anticoagulation. Intravenous unfractionated heparin and subcutaneous enoxaparin are most commonly used. Intravenous heparin is preferred in patients with kidney dysfunction because enoxaparin and similar agents are partially cleared by the kidneys. For patients proceeding to the catheterization laboratory, anticoagulant therapy should be provided until revascularization with PCI or CABG. In medically treated patients, anticoagulation is recommended for at least 48 hours and is generally continued until discharge.

Antianginal Medications

β-Blockers should be administered within 24 hours of NSTE-ACS because these agents reduce ventricular arrhythmias and long-term mortality. β-Blockers are not appropriate for patients with evidence of heart failure or shock at presentation. Likewise, these agents should not be given to patients with bradycardia, heart block, or a PR interval greater than 240 ms on ECG.

Calcium channel blockers are recommended for patients with NSTE-ACS intolerant of β-blocker therapy or in patients with angina symptoms despite therapy with nitrates and β-blockers. The nondihydropyridine calcium channel blockers reduce heart rate, blood pressure, and cardiac contractility, thereby reducing myocardial oxygen demand. However, because of these hemodynamic effects, use of these agents is also contraindicated in the setting of shock, pulmonary edema, or significant conduction disease. Importantly, short-acting dihydropyridine calcium channel blockers are contraindicated, owing to their ability to acutely lower the blood pressure and raise the heart rate.

Nitrates are primarily used to manage angina symptoms in patients with NSTE-ACS. Sublingual nitrates should be administered at presentation to relieve chest pain. For patients with persistent chest pain despite β-blockade, intravenous nitroglycerin can alleviate symptoms, particularly in those with hypertension. Patients receiving nitroglycerin infusions for a prolonged time will often require increased doses due to the development of nitrate tolerance. Nitrates should be avoided in patients who have had recent exposure (within 24-48 hours) to phosphodiesterase type 5 inhibitors such as sildenafil.

Patients with chest pain refractory to antianginal medications should be evaluated for noncardiac causes of chest pain and biomarker elevation, as well as for the possibility of severe underlying CAD or electrocardiographically silent coronary thrombosis.

Lipid-Lowering Medications

Statin therapy reduces mortality and adverse clinical event rates after ACS. High-intensity statin therapy is recommended because it improves outcomes compared with lower-intensity treatment. Initiating statins in the inpatient setting is associated with greater medication adherence. Furthermore, statin preloading before PCI has been associated with lower rates of periprocedural MI.

Invasive Versus Ischemia-Guided Treatment

Immediate invasive treatment (within 2 hours) is recommended for patients with NSTE-ACS who have hemodynamic instability, refractory chest pain, heart failure, or ventricular arrhythmias. In patients with an elevated clinical risk score, significant ST-segment deviation, or elevated cardiac biomarkers, cardiac catheterization is usually performed within 24 hours of presentation. The type of revascularization procedure (PCI or CABG) depends on the results of angiography.

An invasive strategy improves the composite clinical endpoint of death, recurrent MI, and repeat hospitalization compared with an ischemia-guided approach in high-risk and troponin-positive patients with NSTE-ACS. An invasive strategy is the favored approach, with the exception of patients with extensive noncardiac comorbid conditions (such as cancer), in whom the clinical benefits of revascularization may be lower, and patients with acute chest pain unlikely to be related to CAD.

With an ischemia-guided treatment strategy, patients undergo noninvasive stress testing before hospital discharge; cardiac catheterization is reserved for patients with active or intermittent ischemia, including those with angina despite medical therapy or evidence of ischemia on stress testing, and patients at very high clinical risk based on risk score. The ischemia-guided approach is appropriate for low-risk patients (TIMI score <2 or GRACE score <109).

Acute Coronary Syndromes Not Associated with Obstructive Coronary Disease

Elevations in cardiac enzymes, particularly cardiac troponins, coupled with ECG changes provide excellent diagnostic discrimination for ACS. However, some patients with chest pain, elevated cardiac troponin levels, and characteristic ST-segment elevation on ECG have myocardial infarction in the absence of obstructive coronary artery disease (MINOCA). Other related syndromes may mimic MINOCA but do not involve frank infarction. Regardless of whether there is irreversible myocardial injury, treatment of these conditions with thrombolytic agents and revascularization in the absence of occlusive coronary disease and plaque rupture is not beneficial or recommended.

Patients with accelerated hypertension, significant left ventricular hypertrophy, and cardiomyopathies may present with chest pain and elevated cardiac troponin levels caused by elevated left ventricular filling pressures or wall tension rather than plaque rupture and true myocardial infarction. The ECG findings are often abnormal in these patients. Patients with supraventricular tachycardias, which may also dramatically increase the rate-pressure product, often present with chest pain, ST-segment depressions, and elevated cardiac enzyme levels, even if no CAD is present.

Coronary vasospasm is sudden constriction of a coronary artery. It may occur spontaneously or follow use of illicit substances (methamphetamines, cocaine) or prescription drugs (5-fluorouracil, bromocriptine). ECG abnormalities may be nonspecific or mimic STEMI patterns. Coronary vasospasm is a diagnosis of exclusion. Unless the patient has a history of vasospasm, patients often undergo coronary angiography, which may reveal normal findings or slowed coronary flow resulting from microvascular dysfunction. Provocative testing can be performed but is not usually indicated. Patients suspected of having vasospasm (or the related microvascular dysfunction) are usually treated empirically with nitrates and/or calcium channel blockers.

Takotsubo cardiomyopathy, alternatively termed stress cardiomyopathy or apical ballooning syndrome, is a relatively uncommon form of ACS (see Heart Failure). Patients present with acute chest pain, ECG changes (often ST-segment elevations), and elevated cardiac enzyme levels. Takotsubo cardiomyopathy most commonly occurs in women, and there is often, but not always, an antecedent psychological or physical stressor. Patients may initially be diagnosed with STEMI but found to have no significant coronary stenosis at the time of cardiac catheterization. Systolic apical ballooning and notable sparing of the base of the heart on echocardiography or ventriculography are characteristic of this syndrome.

Cardiac syndrome X is a poorly defined condition characterized by anginal chest pain in the presence of angiographically normal coronary arteries or insignificant CAD (<50% stenosis). Cardiac syndrome X is a frequent cause of chest pain syndromes in women, and patients often present without traditional risk factors for CAD. Several hypotheses have been proposed to explain the pathogenesis of this syndrome. One of the most accepted centers on microvascular dysfunction as the cause. Patients may be treated with β-blockers, calcium channel blockers, and nitrates.

Patients with chronic inflammatory muscle diseases or neuromuscular diseases may have elevated levels of cardiac troponin T due to expression of this enzyme in skeletal muscle. The cardiac troponin I level is normal in these cases, which can be helpful in differentiating ACS from these other entities.

Care After an Acute Coronary Syndrome

All patients with ACS should continue aspirin, preferably 81 mg/d, indefinitely. DAPT is recommended for at least 1 year (see Table 10). There is some evidence for extending DAPT beyond 1 year in stented and medically treated patients; however, the decision to prolong therapy should be individualized, with the risk for bleeding weighed against the risk for thrombosis.

Statin therapy should continue indefinitely. Patients with a history of multiple major atherosclerotic cardiovascular disease (ASCVD) events or one major ASCVD event and multiple high-risk conditions are judged to be at very high risk for recurrent ASCVD events. These patients may benefit from the addition of nonstatin drug therapy to maximally tolerated statin therapy. (See MKSAP 18 General Internal Medicine for a discussion on the combined use of statin and nonstatin drugs in selected higher-risk and very-high-risk patients.) Patients younger than 50 years with STEMI have a nearly 10% risk for probable or definite familial hypercholesterolemia, and screening for familial hypercholesterolemia should be considered in this population.

β-Blockade and ACE inhibitor therapy should also be continued indefinitely in patients with left ventricular dysfunction; continuation of these medications is reasonable in patients with normal left ventricular function. Guidelines recommend avoiding NSAIDs if possible, owing to the increased cardiovascular risk associated with these drugs.

Patients should be referred for cardiac rehabilitation, a medically observed exercise program, which reduces mortality while improving functional capacity and risk factor profiles. Patients at low risk (aged ≤75 years with symptoms less than New York Heart Association functional class III to IV, a normal ejection fraction, and no arrhythmia) who prefer home-based cardiac rehabilitation with remote coaching and indirect exercise supervision will benefit as well.

Management of Coronary Artery Disease in Special Populations

Women

Clinical Presentation

Women usually develop ischemic heart disease at an older age than men and more commonly present with stable CAD than an ACS. In women with typical angina symptoms, nonobstructive coronary stenoses are present on coronary angiography in more than 50% of cases, and microvascular dysfunction (endothelium-dependent or endothelium-independent) is thought to be a predominant cause of symptoms in these patients. In women with acute MI, the predominant symptom is chest pain or pressure; however, women can often have atypical symptoms, such as fatigue, dyspnea, nausea, or abdominal symptoms.

Several unique manifestations of cardiovascular disease, including spontaneous coronary artery dissection, takotsubo cardiomyopathy, and coronary vasospasm, occur primarily in women. Spontaneous coronary artery dissection is a common cause of chest pain among younger women who present with ACS. In many cases, spontaneous coronary artery dissection occurs in the peripartum period and is thought to be caused by hormonal changes, although the true cause is unknown. Given the preponderance of young women with this condition, minimizing radiation exposure and avoiding invasive angiography are recommended. This can typically be achieved with the use of supportive care with or without CT angiography. In severe cases, vessel occlusion causes STEMI and necessitates emergent revascularization.

Evaluation and Treatment

Noninvasive stress testing for the evaluation of CAD symptoms has a lower sensitivity and specificity in women than in men, and ST-segment deviation has a lower reported accuracy in women. Therefore, stress testing with imaging provides better accuracy in women (see Diagnostic Testing in Cardiology). Despite these differences, the same guideline recommendations apply to both women and men.

Reports from observational studies and substudies of randomized controlled trials suggest that women have worse outcomes after STEMI presentation. The cause of these worse outcomes is thought to be delays in recognition of CAD and longer overall ischemic time. Complication rates are also reported to be higher in women who undergo reperfusion therapy for STEMI. The COURAGE trial demonstrated that among patients with stable angina treated with revascularization, women had lower rates of overall mortality and nonfatal MI but a higher rate of complications compared with men. Overall, treatment guidelines do not differ for men and women.

Diabetes Mellitus

Risk and Evaluation

Diabetes has been proposed as a CAD equivalent because age-adjusted risk for CAD events is twoto threefold higher in patients with diabetes. Cardiovascular morbidity and mortality are also significantly higher in this population, especially in patients with type 2 diabetes. Much of the risk has been attributed to the higher incidence of known cardiovascular risk factors; however, evidence suggests that underlying vascular dysfunction may play an important role.

Patients with diabetes may present with atypical cardiac symptoms, such as dyspnea or nausea, requiring a high index of suspicion for CAD during their evaluation. The diagnostic accuracy of noninvasive stress testing in symptomatic patients with diabetes is similar to that in patients without diabetes. Although traditional risk factors for CAD should be aggressively managed in patients with diabetes, screening for CAD in asymptomatic persons is controversial, and routine stress testing is not recommended.

Medical Therapy and Secondary Prevention

Medical therapy for patients with diabetes and CAD includes aggressive risk factor reduction, glucose control, and antianginal therapy. The American College of Cardiology/American Heart Association recommend antihypertensive treatment with a target blood pressure below 130/80 mm Hg in patients with diabetes. The American Diabetes Association (ADA) notes that a blood pressure target of less than 130/80 mm Hg may be appropriate for patients with either existing ASCVD or a 10-year ASCVD risk of 15% or greater if it can be safely obtained. For patients at lower ASCVD risk, a blood pressure target of less than 140/90 mm Hg is recommended. ACE inhibitors and ARBs are preferred in the setting of hypertension because of their kidney-protective effects. High-intensity statin therapy is indicated in most patients with diabetes and CAD.

Aspirin is recommended for secondary prevention in all patients with diabetes and CAD.

Tight glycemic control reduces microvascular complications; however, it does not reduce the risk for MI. The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes has been shown to reduce rates of acute MI, stroke, and cardiovascular death. For patients with type 2 diabetes and clinical ASCVD, SGLT2 inhibitors may reduce hospitalization for heart failure. These benefits seem to be unrelated to their glucose-lowering effects. Based on strong evidence, the ADA recommends introducing an SGLT2 inhibitor or a GLP-1 receptor agonist with demonstrated cardiovascular disease benefit as part of a glycemic control regimen in patients with type 2 diabetes and clinical ASCVD. If the patient is already taking metformin combined with another therapeutic agent or agents and not taking an SGLT2 inhibitor or GLP-1 receptor agonist, the ADA recommends considering switching to one of these agents.

Initial studies suggested thiazolidinediones, specifically rosiglitazone, were associated with an elevated risk for cardiovascular events, although a subsequent clinical trial demonstrated no elevated risk for MI or death. Consequently, the FDA has removed the restriction on rosiglitazone use in patients with type 2 diabetes and CAD. Metformin does not have any cardiovascular effects, but caution should be exercised in patients undergoing coronary angiography, patients who have had an MI, and patients with heart failure because of concern for potentially fatal lactic acidosis.

Invasive Treatment

The choice of revascularization strategy (PCI or CABG) in patients with diabetes is based on many factors, including the severity and extent of CAD, comorbid conditions, and degree of atherosclerotic narrowing of small, distal vessels. Mortality rates are similar between the two procedures; however, CABG is generally preferred because it is associated with lower rates of repeat revascularization. In patients who undergo PCI, drug-eluting stent placement is recommended to reduce the occurrence of target vessel revascularization because of higher rates of restenosis in patients with diabetes.