Sections

Treatment

Approach Considerations

See also the Guidelines section for recommendations.

The treatment goals for patients with coronary artery atherosclerosis are to relieve symptoms of coronary artery disease (CAD) and to prevent future cardiac events, such as unstable angina, AMI, and death.

The mainstays of pharmacologic therapy of angina include nitrates, beta-blockers, statins, PCSK-9 inhibitors, Ezetimibe, calcium-channel blockers, and ranolazine.^[1]The prevention and treatment of atherosclerosis requires control of the known modifiable risk factors for this disease. This includes therapeutic lifestyle changes and the medical treatment of hypertension, hyperlipidemia, and diabetes mellitus.

Typically, patients with CAD are first seen after they present with a cardiac event. The main focus of their treatment is the index event. The past 4 decades have witnessed tremendous progress in the areas of acute cardiac care, coronary care unit expansion, thrombolytic usage, and PCI. Nevertheless, prevention of cardiac events is likely to have the largest impact on decreasing the burden of atherosclerosis.

High-risk subgroups, in particular, can be targeted for early intervention. Grover and colleagues showed statin therapy in diabetic patients without CAD to be as cost-effective as statin therapy in nondiabetic patients with CAD. Pharmacotherapeutic strategies that affect the risk factor profile, such as the administration of statins for low-density lipoprotein (LDL) reduction or the administration of agents that alter atherosclerotic plaque, are of paramount importance.

Prevention of future cardiac events

Findings from the World Health Organization's Monitor Trends in Cardiovascular Diseases (MONICA) project involving 21 countries showed a 4% fall in CAD death rates. Improvement in the case fatality rate accounted for only one third of the decline; two thirds of the decline resulted from a reduction in the number of events. These findings strongly suggest that the largest impact on decreasing the global burden of atherosclerosis will come from prevention of events.

Fortunately, the natural history of CAD is characterized by early onset and a long dormant phase. This provides an excellent opportunity to intervene in order to reduce the number and severity of cardiovascular events.

Preventive Strategies

The goals of therapy should include arresting atherosclerosis or even reversing its progression. Large, multicenter randomized trials of various pharmacologic modalities have recently achieved great success in the treatment of patients with coronary artery atherosclerosis. In addition, addressing risk factors with lifestyle changes is an integral part of atherosclerosis prevention.

Therapy with lipid-lowering agents should be a component of multiple risk factor intervention and is indicated in primary prevention as an adjunct to diet therapy when the response to a diet restricted in saturated fat and cholesterol has been inadequate. Substantial evidence supports the use of statins in the secondary prevention of CAD, and the efficacy of statins has recently been extended to include primary prevention of CAD in patients with average cholesterol levels.

A separate study found that, compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. However, further investigation is warranted.^[52]

A meta-analysis of nearly 5000 patients found that statins administered before invasive procedures significantly reduced the risk for postprocedural myocardial infarction.^[53]The risk for MI was reduced after percutaneous coronary intervention and noncardiac surgical procedures, but not for coronary artery bypass grafting (CABG). Statins decreased the risk for atrial fibrillation following CABG.

Current guidelines recommend using statin therapy after CABG to keep LDL levels below 100 mg/dL. Results of the Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) trial confirmed that this practice independently associated with improved graft patency, as demonstrated by coronary angiography and saphenous vein graft intravascular ultrasonography. performed 12 months postoperatively. However, LDL reduction to less than 70 mg/dL did not lead to further improvement in graft patency.^[54]

Statin therapy is also safe and can improve liver tests while reducing cardiovascular morbidity in patients with mild- to moderately-abnormal liver test results that may be attributable to nonalcoholic fatty liver disease.^[55]

In the United States, the most commonly used guidelines for cholesterol management are those from the NCEP Adult Treatment Panel (ATP). In high-risk persons, the recommended LDL-C goal is less than 100 mg/dL, but when risk is very high, an LDL-C goal of less than 70 mg/dL is a therapeutic option and a reasonable clinical strategy based on available clinical trial evidence. For moderately high-risk persons (≥2 risk factors and 10-y risk of 10-20%), the recommended LDL-C goal is less than 130 mg/dL, but an LDL-C goal of less than 100 mg/dL is a therapeutic option based on trial evidence.

Newer guidelines on the management of elevated blood cholesterol, released in late 2013 by the American Heart Association/American College of Cardiology (AHA/ACC), no longer specify LDL- and non-HDL-cholesterol targets for the primary and secondary prevention of atherosclerotic cardiovascular disease.^{[56, 57]}The guidelines identify four groups of primary- and secondary-prevention patients in whom efforts should be focused to reduce cardiovascular disease events and recommend appropriate levels of statin therapy for these groups.

Treatment recommendations include the following :

In patients with atherosclerotic cardiovascular disease, or those with LDL cholesterol levels 190 mg/dL or higher (eg, due to familial hypercholesterolemia), and no contraindications, high-intensity statin therapy should be prescribed to achieve at least a 50% reduction in LDL cholesterol
In patients aged 40 to 75 years of age with diabetes, a moderate-intensity statin that lowers LDL cholesterol by 30% to 49% should be used; in those patients who also have a 10-year risk of atherosclerotic cardiovascular disease exceeding 7.5%, a high-intensity statin is a reasonable choice
In individuals aged 40 to 75 years without cardiovascular disease or diabetes but with a 10-year risk of clinical events >7.5% and an LDL-cholesterol level of 70-189 mg/dL, a moderate- or high-intensity statin should be used

A study applying the 2013 AHA/ACC cholesterol guidelines to data from the 2005–2010 National Health and Nutrition Examination Surveys (NHANES) estimated that an additional 12.8 million US adults would be eligible for statin therapy as compared with treatment based on the NCEP ATP III guidelines.^{[58, 59]}About 10.4 million of these adults would be eligible to receive statins for primary prevention—primarily older people without cardiovascular disease, men more often than women, those with higher blood pressure, and those with lower LDL-C levels.

The 2013 AHA/ACC guidelines also recommend use of a revised calculator to estimate the risk of developing a first atherosclerotic cardiovascular disease (ASCVD) event, which is defined as one of the following, over a 10-year period, in a person who was initially free from ASCVD^[22]:

Nonfatal myocardial infarction
Death from coronary heart disease
Stroke (fatal or nonfatal)

For patients 20-79 years of age who do not have existing clinical ASCVD, the guidelines recommend assessing clinical risk factors every 4-6 years. For patients with low 10-year risk (< 7.5%), the guidelines recommend assessing 30-year or lifetime risk in patients 20-59 years old.

Regardless of the patient’s age, clinicians should communicate risk data to the patient and refer to the AHA/ACC lifestyle guidelines, which cover diet and physical activity. For patients with elevated 10-year risk, clinicians should communicate risk data and refer to the AHA/ACC guidelines on blood cholesterol and obesity.

Treatment of Low HDL levels and High Triglyceride levels in Patients With Diabetes

A combination of low HDL levels and high triglyceride levels is frequently encountered in patients with diabetes and is often referred to as atherogenic dyslipidemia. Many of these patients have metabolic syndrome.

Additional follow-up and analysis of the Veterans Affairs HDL Intervention Trial (VA-HIT) indicated that treatment with gemfibrozil versus placebo resulted in a 32% reduction in major cardiovascular events and a 41% reduction in CHD deaths, in 769 male subjects with diabetes mellitus and CHD who had HDL-C levels of less than 40 mg/dL and LDL-C levels of less than 140 mg/dL.

Interestingly, among 1733 nondiabetic men, increased plasma fasting insulin levels and insulin resistance, as assessed by the homeostasis model assessment for insulin resistance (HOMA-IR; fasting insulin [µU/mL] X fasting glucose [mmol/L]/22.5), were predictive of increased major cardiovascular events and of greater benefit from gemfibrozil treatment.^{[60, 61]}

Somewhat inexplicable was the finding that despite higher plasma triglyceride and lower HDL-C levels in insulin-resistant subjects, these measurements were associated with greater treatment benefit only in those subjects classified as not having insulin resistance by HOMA-IR.

This was the first trial to demonstrate the cardiovascular benefit of treating diabetic and insulin-resistant subjects with low HDL-C levels. Interestingly, the insulin resistance was more predictive of CHD event rate and benefit from gemfibrozil than were HDL-C or triglyceride levels. Because no significant reduction in LDL-C was realized with gemfibrozil therapy, one possibility is that additional CHD benefit would be accrued by adding statins, which have been shown in subgroup analyses of several trials to benefit CHD risk in diabetic patients and in nondiabetic patients with low HDL-C levels.

One caveat is that because of the relatively higher risk of myopathy with combined gemfibrozil-statin treatment and findings that indicate much less risk with statins and fenofibrate, the latter is currently the preferred choice for combined treatment.

ACE Inhibitors to Reduce Blood Pressure

The efficacy of ACE inhibitors on CAD has been examined in blood pressure reduction studies and in studies of subjects with high risk factors for CAD.

ACE inhibitors are effective blood pressure–reducing agents and affect the heart and vasculature through direct and other mechanisms.

ACE inhibitors were not shown to affect plaque in a randomized angiographic regression study, the Quinapril Ischemic Event Trial (QUIET), of 463 subjects with CAD.^[62]

B-mode ultrasonographic studies investigating plaque regression have provided confusing results at best. Although the second Prevention of Atherosclerosis with Ramipril Trial (PART 2) showed no reduction in intima-media thickness at 4-year follow-up in 617 subjects randomized to placebo or ramipril (5-10 mg/d), the Study to Evaluate Carotid Ultrasound Changes with Ramipril and Vitamin E (SECURE) showed a reduction in carotid intima-media thickness proportional to the dose of ramipril (2.5-10 mg/d) in 750 subjects over a 4.5-year follow-up period.^[63]

ACE inhibitors probably affect endothelial function, as well as those of A-II and kinin, to elicit the clinical effects observed in the clinical trials. Tissue binding is variable among the ACE inhibitors, with the highest affinity shown by quinapril, benazepril, and ramipril. In the Trial on Reversing Endothelial Dysfunction (TREND),^[64]which included 105 subjects with CAD (but without CHF or left ventricular dysfunction), the group receiving quinapril at 40 mg/d showed significantly improved response to acetylcholine. ACE inhibitors also increase levels of nitric oxide by increasing its release through a kinin-mediated pathway and through reduction of its breakdown.

Statin therapy decreases cardiovascular events and all-cause mortality in both women and men.^[65]

In addition, ACE inhibitors decrease the plasma levels of type 1 plasminogen activator inhibitor, increase the release of tissue-type plasminogen activator, and favorably affect the fibrinolytic balance, an effect not observed with the angiotensin receptor–blocking agents.

In terms of blood pressure reduction, even though a greater stroke incidence was observed with higher baseline blood pressure in the treatment group in the Captopril Prevention Project (CAPPP), a pooled analysis of 16,161 patients from blood-pressure control trials evaluating ACE inhibitors showed no difference in the cardiovascular outcome risk.^[66]

A possible direct effect of ACE inhibitors on atherosclerosis, independent of blood pressure reduction, was suggested by the Heart Outcomes Prevention Evaluation (HOPE) study,^[67]which included 9297 subjects with history of CAD, stroke, peripheral vascular disease, or diabetes, along with one other CAD risk factor (eg, hypertension, hypercholesterolemia, hypoalphalipoproteinemia, tobacco abuse, microalbuminuria). Subjects were randomized to placebo or ramipril (10 mg/d). At 5-year follow-up, the cardiac death rate was reduced by 25%, nonfatal MI by 20%, need for bypass surgery/PTCA by 16%, and all-cause mortality by 16%. The effects were unrelated to the blood pressure–lowering effect.

Antiplatelet Agents for Acute Coronary Events

Guidelines

The 2007 ACC/AHA guidelines recommend that after an ACS, all patients should receive dual antiplatelet therapy, ideally for 12 months, followed by lifelong aspirin therapy.^[1]The ACCF/ACG/AHA 2010 expert consensus provides a detailed report on reducing the gastrointestinal risks of antiplatelet therapy and nonsteroidal anti-inflammatory drug (NSAID) use.^[68]

The European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) released their focused update on dual antiplatelet therapy (DAPT) in CAD in 2017.^{[69, 70]}Some of their important recommendations are summarized below.

The latest advice in this controversial area advocates a personalized-medicine approach based on ischemic versus bleeding risks, where each treatment and its duration is individualized as much as possible.

DAPT (aspirin plus a P2Y₁₂ inhibitor) reduces the risk of stent thrombosis and/or spontaneous myocardial infarction (MI) in patients following percutaneous coronary intervention (PCI) or an acute coronary syndrome (ACS). The risk of bleeding in patients on DAPT is proportionally related to its duration. The benefits of prolonged DAPT, especially on mortality, depend on the patient's previous cardiovascular history (such as prior ACS/MI vs stable CAD).

For ACS patients, the default DAPT duration should be 12 months, irrespective of the revascularization strategy (medical therapy, PCI, or coronary artery bypass graft [CABG] surgery). Six months of DAPT should be considered in patients at high bleeding risk (PRECISE-DAPT score ≥25). Therapy longer than 12 months may be considered in ACS patients who have tolerated DAPT without a bleeding complication.

The need for a short DAPT regimen should no longer justify the use of bare-metal stents instead of newer-generation drug-eluting stents. DAPT duration should be guided by an assessment of the individual patient's ischemic versus bleeding risks and not by the stent type.

Irrespective of the type of metallic stent implanted, the duration of DAPT in stable CAD patients treated with PCI should be 1 to 6 months depending on the bleeding risk. A longer DAPT duration may be considered in patients whose ischemic risk is greater than the risk of bleeding.

There are insufficient data to recommend DAPT in stable CAD patients treated with CABG.

The addition of DAPT to oral anticoagulation therapy increases the risk of bleeding complications by twofold to threefold. The indication for oral anticoagulation should be reassessed and treatment continued only if there is a compelling indication such as atrial fibrillation, a mechanical heart valve, or recent history of recurrent deep venous thrombosis or pulmonary embolism. The duration of triple therapy (DAPT plus oral anticoagulation) should be limited to 6 months or omitted after hospital discharge, depending on the ischemic and bleeding risks.

Clopidogrel is recommended as the default P2Y₁₂ inhibitor in patients with stable CAD treated with PCI, patients with an indication for oral anticoagulation, and ACS patients in whom ticagrelor or prasugrel are contraindicated. Ticagrelor or prasugrel is recommended for ACS patients unless there are drug-specific contraindications.

The decision on when to initiate a P2Y₁₂ inhibitor depends on both the specific drug and the specific disease (stable CAD vs ACS).

Aspirin no longer in favor

Previously, the risk of myocardial ischemic events in patients with ACS was shown to be reduced by means of platelet inhibition with the use of aspirin. All patients with documented CAD had been recommended to be treated with daily aspirin, unless contraindicated. More recent trials indicate that aspirin has no role in primary prevention of cardiovascular events. Some studies found no effect of aspirin on cardiovascular risk reduction in long-term primary prevention, whereas others demonstrated the risks of aspirin use outweighed its benefits.^{[71, 72, 73, 74]}

In 2018, three large trials released their findings regarding the use of aspirin for primary prevention in different patient populations. The A spirin to R educe R isk of I nitial V ascular E vents (ARRIVE) trial (N = 12,546) showed aspirin had no effect on all-cause death or cardiovascular outcome in patients with moderate cardiovascular risk.^[71]The A S tudy of C ardiovascular E vents in D iabetes (ASCEND) (N = 15,480) found a modest benefit in reducing cardiovascular in patients with diabetes, but there was a relatively significant increased risk of major hemorrhage.^[72]The Asp irin in R educing E vents in the E lderly (ASPREE) trial (N = 19,114) revealed that not only did aspirin have no effect on the primary outcome (death, dementia, disability) in elderly patients, but it led to a higher rate of major hemorrhage and the all-cause mortality was actually greater in the group taking aspirin than that of the placebo group.^{[73, 74]}This unexpected finding of higher mortality was primarily atrributed to cancer-related death, which occurred in 3.1% of the aspirin users and in 2.3% of those in the placebo group.^[74]

A 2019 systematic review and meta-analysis of data from 13 trials comprising 164,225 individuals without cardiovascular disease to evaluate the association between aspirin use and cardiovascular and bleeding events found a lower risk of cardiovascular events and a higher risk of major bleeding.^[75]

DAPT trials

Antiplatelet agents help reduce the number of acute coronary events, as demonstrated from the following studies:

Antiplatelet Trialists' Collaboration^[76]
Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial^[77]
Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial^[78]
Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes (TRITON TIMI-38)^[79]

The CAPRIE trial studied the efficacy of clopidogrel (an inhibitor of the P2Y₁₂ adenosine-diphosphate receptor), compared with that of aspirin, on long-term events.^[77]Recurrent cardiovascular events were modestly reduced in patients treated with clopidogrel, in comparison with aspirin.

Extending this, the CURE trial found that regardless of the initial treatment strategy (medical therapy, PCI, or CABG), treatment with the combination of aspirin and clopidogrel was superior to aspirin alone in reducing recurrent events for up to 12 months after hospitalization with ACS. However, in the CHARISMA trial, prolonged dual antiplatelet therapy with aspirin and clopidogrel did not significantly reduce recurrent events in patients with stable cardiovascular disease or in asymptomatic patients at high risk for cardiovascular events.

In the TRITON TIMI-38 trial, prasugrel, a more potent thienopyridine P2Y₁₂ inhibitor, proved more effective than clopidogrel in reducing ischemic events, including stent thrombosis, among patients with ACS who were scheduled for percutaneous coronary intervention. However, the risk of major bleeding, including fatal bleeding, was higher with prasugrel (2.4% versus 1.8% with clopidogrel), although overall mortality did not differ significantly between treatment groups.

Low-dose prasugrel may also be effective in very elderly patients. In a pharmacodynamic and pharmacokinetic study involving 155 patients with stable CAD, investigators found that a 5-mg dose of prasugrel provided adequate platelet inhibition in very elderly patients.^{[80, 81]}The study subjects, who were either aged 45-65 years (mean, 56 y) or older than 75 years (mean, 79 y), were treated for 12 days during each of 3 crossover treatment periods with 1 of 3 regimens: clopidogrel 75 mg, prasugrel 5 mg, or prasugrel 10 mg.

Median maximal platelet aggregation (MPA) response to prasugrel 5 mg in very elderly patients (58%) was noninferior to the 75th percentile of MPA response to prasugrel 10 mg in nonelderly patients (52%).^[81]Antiplatelet effect was significantly lower and high on-treatment platelet reactivity rates significantly higher with prasugrel 5 mg in very elderly patients than with prasugrel 10 mg in nonelderly patients. Prasugrel 5 mg had significantly greater antiplatelet effect than clopidogrel 75 mg in very elderly patients, as did prasugrel 10 mg in nonelderly patients.^[81]

The incidence of bleeding-related adverse events in older patients was similar to that in younger patients.^[81]Bleeding rates were similar with prasugrel 5 mg and clopidogrel 75 mg but were significantly higher with prasugrel 10 mg.

Pharmacologic Treatment of Angina

A number of agents have proven helpful for the treatment of angina. These include beta-blockers, calcium channel blockers, nitrates, and ranolazine (see below).^[1]

Beta-blockers

Beta-blockers inhibit sympathetic stimulation of the heart, reducing heart rate and contractility; this can decrease myocardial oxygen demand and thus prevent or relieve angina in patients with CAD. Since beta-blockers reduce the heart rate–blood pressure product during exercise, the onset of angina or the ischemic threshold during exercise is delayed or avoided. All types of beta-blockers appear to be equally effective in the treatment of exertional angina. The ACC and AHA recommend beta-blockers, unless contraindicated, in all patients with stable angina who have had an ACS or who have left ventricular dysfunction.

Calcium channel blockers

Calcium-channel blockers prevent calcium entry into vascular smooth muscle cells and myocytes, which leads to coronary and peripheral vasodilatation, decreased atrioventricular (AV) conduction, and reduced contractility. In patients with angina, these effects result in decreased coronary vascular resistance and increased coronary blood flow. Calcium blockers also reduce systemic vascular resistance and arterial pressure and provide a negative inotropic effect.

Nitrates

Nitrates are effective in the treatment of acute anginal symptoms. In this situation, they are usually given sublingually. The primary anti-ischemic effect of nitrates is to decrease myocardial oxygen demand by producing systemic vasodilation, although they also cause modest coronary and arteriolar vasodilation, as well as venodilation.

In patients with chronic stable angina, nitrate therapy improves exercise tolerance, time to onset of angina, and ST-segment depression during exercise testing. They are particularly effective in combination with beta-blockers or calcium-channel blockers.

Ranolazine

Ranolazine is a novel antianginal agent believed to relieve ischemia by reducing myocardial cellular sodium and calcium overload via inhibition of the late sodium current of the cardiac action potential.

In 3 randomized, double-blind trials of patients with chronic angina, ranolazine prolonged exercise duration and reduced symptoms when given as either monotherapy or in combination with other antianginal drugs. When evaluated in patients with non-ST-elevation ACS, ranolazine reduced recurrent ischemia but did not significantly reduce the risk of death or MI at 1 year.

Hormone Therapy Concerns

Hormone therapy has been found to be more risky than beneficial as a means of protecting postmenopausal women against CAD.^[20]The Heart and Estrogen/Progestin Replacement Study follow-up (HERS-II), completed in 2002, reported that after 6.8 years, hormone therapy did not reduce risk of cardiovascular events.^[82]

Similarly, in a study by the Women’s Health Initiative, overall health risks exceeded benefits from the use of combined estrogen and progestin therapy as a means of primary prevention of CAD in healthy, postmenopausal women. Participants in the trial were randomized into hormone therapy (n = 8506) or placebo (n = 8102) groups. The average follow-up period was 5.2 years. All-cause mortality in the study was unaffected by the combination therapy.^[83]

Because of overall increased risk, combined estrogen and progestin therapy should not be initiated or continued for primary prevention of CAD.^[84]

Antibiotic Therapy in Coronary Artery Atherosclerosis

Although inflammation is considered to be a risk factor for the development of atherosclerosis, antibiotic therapy does not appear to have a significant role in secondary prevention of this disorder. Several multicenter trials have evaluated the effect of antibiotic therapy on recurrent cardiac events when used as secondary prevention. The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infarction with Chlamydia (ACADEMIC) trial,^[85]the Azithromycin in Acute Coronary Syndrome (AZACS) study,^[86]the South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA),^[87]the Azithromycin Coronary Events Study (ACES),^[88]and the antibiotic arm of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial^[89]all returned negative results in terms of any significant benefit from antibiotic therapy.

Revascularization Procedures

Revascularization therapies for symptomatic or ischemia-producing atherosclerotic lesions include percutaneous approaches and open heart surgery. For a detailed discussion of these approaches, see Percutaneous Transluminal Coronary Angioplasty and Comparison of Revascularization Procedures in Coronary Artery Disease.

Long-term mortality has been similar after CABG and PCI in most patient subgroups with multivessel CAD; therefore, the choice of treatment typically depends on patient preferences for other outcomes. Exceptions to this are patients with diabetes and those age 65 years or older; Hlatky et al found CABG to be a superior option in these subgroups, because of lower mortality.^[90]

The SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) study determined that in high- and intermediate-risk patients with 3-vessel disease, the rates of revascularization and of major adverse cardiac and cerebrovascular events were significantly higher in patients who had undergone PCI than in those who had undergone CABG.^{[2, 3]}The study also found that PCI and CABG were equally effective in the treatment of low-risk patients with 3-vessel disease and in low- and intermediate-risk patients with left main CAD.

In a more recent study that compared the long-term prognostic value of baseline (ss) and clinical SYNTAX scores (cSS) in 460 Turkish patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease who either underwent CABG (n = 214) or PCI (n = 246), investigators found that ss and cSS had prognostic value in the CABG group but not the PCI group.^[91]Moreover, in the CABG group, cSS appeared to have more discriminative power than SS for long-term adverse effects.

Other revascularization techniques include transmyocardial laser revascularization.

Medical therapy versus PCI revascularization

The COURAGE trial demonstrated that performing PCI in severe lesions reduces angina but does not improve overall outcomes over medical therapy alone in patients with stable CAD. The trial randomized patients with stable CAD, ischemia, and significant stenoses of 70% or more in at least 1 proximal coronary artery to a regimen of optimal medical treatment alone or optimal medical treatment combined with PCI. The primary outcome was death from any cause or non-fatal MI during a follow-up period of between 2.5 and 7 years (median 4.6 years).^[92]

The results of COURAGE showed no evidence of a better outcome for the PCI group than for the group receiving medical treatment alone, for the combined endpoint death, MI and stroke (20.0% PCI group vs 19.5% medical treatment); for admission to hospital for ACS (12.4% vs 11.8%, respectively); or for MI (13.2% vs 12.3%, respectively). Thus, at least among the patients studied in COURAGE, both treatment strategies resulted in similar outcomes for major cardiac complications and deaths. There was a statistically significant advantage for reduction in the prevalence of angina in the PCI group, with respect to freedom from angina. However, by the end of 5 years of follow-up, the difference was no longer significant (74% of the PCI group and 72% of the group receiving medical treatment only were free of angina).

The results of the trial likely resulted from the fact that most of the lesions responsible for later coronary events are nonobstructive. Thus, prophylactic stenting of all identified lesions (the full metal jacket) is impractical and certainly not justified at this time.

In a prospective, natural-history study of coronary atherosclerosis, patients underwent 3-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention.^[93]Major adverse events were related to both recurrence at the site of culprit lesions and to nonculprit lesions.

European Society of Cardiology Guidelines

The European Society of Cardiology (ESC) released updated guidelines on the management of stable coronary artery disease (CAD).^{[94, 95]}These guidelines note that microvascular angina and vasospasm are more common as causes of angina than previously believed, and they increase reliance on pretest probabilities (PTP) for stable CAD as well as discuss a larger role for modern imaging modalities (eg, cardiac magnetic resonance [CMR] imaging and coronary computed-tomography angiography [CCTA]).

Highlights of the 2013 ESC guidelines include the following^{[94, 95]}:

PTP for a CAD diagnosis uses more contemporary data than those used in the Diamond and Forrester Chest Pain Prediction Rule: For example, in patients with suspected CAD using the 2013 criteria, if the PTP is < 15%, investigate other possible causes and consider a diagnosis of functional coronary disease; if the PTP is intermediate (eg, 15%-85%), send the patient for noninvasive testing; if the PTP is high (eg, >85%), a diagnosis of CAD is established, and patient risk stratification should follow
In stable CAD, the functional impact of coronary lesions relative to their angiographic severity has a larger role than previously in determining the role of PCI
In patients with severe symptoms or clinical characteristics suggestive of high-risk coronary anatomy: Initiate guideline-directed medical therapy
For noncomplex coronary disease: Consider medical therapy first; in the presence of complex coronary lesions or if the patient has many comorbidities, CABG is preferred over PCI; however, if the patient prefers PCI, use drug-eluting stents
In patients within the lower range of intermediate PTP for stable CAD (in whom good image quality can be obtained): Consider CCTA as an alternative to stress-imaging techniques (1) to exclude stable CAD and (2) after an inconclusive exercise electrocardiogram (ECG) or stress imaging test or those in whom stress testing is contraindicated
On first contact in every person with chest pain: Obtain a resting echocardiogram
In patients with a clinically important left main coronary artery stenosis: If there is only 1-vessel involvement, use PCI for ostial or mid-shaft lesions but also include a heart team discussion to decide on PCI or CABG for lesions at a distal bifurcation; for multivessel involvement, use the SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) score (eg, if ≤22, the team should discuss, but if ≥23, CABG should be chosen)
Second-line anti-anginal agents include ranolazine, nicorandil, and ivabradine (not approved for angina in the United States)

However, the following three studies are not recommended^{[94, 95]}:

Coronary calcium scoring on CT imaging in asymptomatic patients
Screening for CAD with CCTA in asymptomatic patients
Stenosis quantification with CCTA in patients with a high likelihood of calcifications

In collaboration with the European Association for the Study of Diabetes (EASD), the ESC also developed guidelines on diabetes, prediabetes, and cardiovascular diseases; these guidelines place emphasis on the following^{[94, 96]}:

Patient-centered care
Less aggressive approach to glycemic control for the elderly and patients with "long-standing diabetes with autonomic neuropathy”
A “simplified diagnostics” algorithm in which glycosylated hemoglobin or fasting plasma glucose studies have priority in the workup, but the oral glucose-tolerance test is reserved for "cases of uncertainty”
CABG as the preferred/first revascularization choice, rather than PCI

Diet

High intakes of red or processed meat were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality in a study by Sinha et al. The baseline population was a cohort of half a million people aged 50-71 years from the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study.^[97]

A meta-analysis by Ferdowsian and Barnard suggested that plant-based diets are effective in lowering plasma cholesterol concentrations. In a review of 4 types of plant-based diets studied in 27 trials, a vegetarian or vegan diet combined with nuts, soy, and/or fiber demonstrated the greatest effects (up to 35% reduction in plasma LDL-C, followed by vegan and ovolactovegetarian diets. Diets that included small amounts of lean meat demonstrated less dramatic reductions in levels of total cholesterol and LDL.^[98]

The ATP III recommended a multifaceted lifestyle approach to reduce the risk for CHD. This is the approach of therapeutic lifestyle changes (TLCs), and its essential features are as follows:

Reduced intake of saturated fats (< 7% of total energy intake) and cholesterol (< 200 mg/d)
Therapeutic options for enhancing LDL lowering, such as plant stanols/sterols (2 g/d) and increased viscous (soluble) fiber intake (10-25 g/d)
Weight reduction
Increased physical activity

To initiate TLCs, intake of saturated fats and cholesterol is first reduced to lower LDL-C levels. To improve overall health, the ATP III TLC diet generally contains the recommendations embodied in the Dietary Guidelines for Americans, 2000. One exception is that total fat is allowed to range from 25-35% of total energy intake, provided saturated fats and trans fatty acids are kept low. A higher intake of total fat, mostly in the form of unsaturated fat, can help to reduce triglyceride levels and to raise HDL-C levels in persons with the metabolic syndrome.

In accordance with the Dietary Guidelines, moderate physical activity is encouraged. After 6 weeks, the LDL response is determined; if the LDL-C goal has not been achieved, other therapeutic options for LDL lowering, such as plant stanol/sterols and viscous fiber, can be added.

After maximum reduction of LDL-C levels with dietary therapy, emphasis shifts to management of the metabolic syndrome and associated lipid risk factors. Most persons with these latter abnormalities are overweight or obese and sedentary.

Weight therapy for patients who are overweight or obese enhances LDL lowering and provides other health benefits, including modification of other lipid and nonlipid risk factors. Assistance in the treatment of these patients is provided by the Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults from the NHLBI Obesity Education Initiative (1998). Additional risk reduction can be achieved by simultaneously increasing physical activity.

At all stages of dietary therapy, physicians are encouraged to refer patients to registered dietitians or other qualified nutritionists for medical nutrition therapy, which is the term for the nutritional intervention and guidance provided by a nutrition professional.

Moderate alcohol intake (20 g/day or less) in men is associated with a reduced incidence of coronary heart disease events.^[99]The mechanism(s) of this benefit is not well understood. Although alcohol may have cardiovascular benefits in women,^[100]even moderate intake of alcohol in women has been associated with a significantly increased risk for breast cancer.^[101]Heavy alcohol intake is associated with an increased incidence of coronary heart disease events, as well as with cardiomyopathy, arrhythmia, and other adverse health effects and obviously should be discouraged.

Physical activity

Lack of physical activity is a major modifiable risk factor for CHD. A sedentary lifestyle augments the lipid and nonlipid risk factors of the metabolic syndrome. Inactivity may enhance risk by impairing cardiovascular fitness and coronary blood flow. Regular physical activity reduces very low-density lipoprotein (VLDL) levels, raises HDL-C levels, and, in some persons, lowers LDL levels. It can also lower blood pressure, reduce insulin resistance, and favorably influence cardiovascular function.

Most health benefits occur with at least 150 minutes a week of moderate-intensity physical activity, such as brisk walking. Additional benefits occur with more physical activity.^[86]

The ATP III therefore recommends that regular physical activity become a routine component in the management of high serum cholesterol levels. The evidence base for this recommendation is contained in the US Surgeon General's Report on Physical Activity.

Additional Therapies for Atherosclerosis

Partial ileal bypass is a surgical procedure that uses shortening of the ileum to lower circulating cholesterol levels. It has been used since the 1960s for the treatment of hyperlipidemia. Chelation therapy, using intravenous ethylenediaminetetraacetic acid and/or hydrogen peroxide, is a controversial treatment for atherosclerosis. Plethysmography/extracorporeal counterpulsation may reduce angina and improve exercise tolerance in patients with CAD, possibly by improving vascular endothelial function.

Stable Coronary Artery Disease after Intervention

Patients presenting with stable angina or ischemia after physiologic testing and who have undergone revascularization therapy, either in the form of PCI or CABG, benefit from adjuvant pharmacologic therapy and aggressive risk reduction. In post-PCI patients, adjuvant pharmacologic therapy, such as administration of intravenous glycoprotein IIb/IIIa inhibitors (eg, eptifibatide, abciximab), oral aspirin, clopidogrel, or ticlopidine, significantly reduces adverse cardiovascular outcomes. Consultation with a cardiac rehabilitation team is recommended for assistance with aggressive risk reduction, which comprises smoking cessation, weight management, physical exercise, and lipid control.

Consultations

Consultation with the following may be indicated:

Cardiologists
Cardiovascular surgeons
Lipidologists
Nutritionists and dietitians
Cardiac rehabilitation team
Radiologists

Consultation with a cardiac rehabilitation team for assistance with smoking cessation, weight management, physical exercise, and lipid control is recommended.

Guidelines

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Media Gallery

Coronary Artery Atherosclerosis. Stress test, part 1. Resting electrocardiogram showing normal baseline ST segments. (See the image below for part 2.)
Coronary Artery Atherosclerosis. Stress test, part 2. Stress electrocardiogram showing significant ST-segment depression. (See the image above for part 1.)
Coronary Artery Atherosclerosis. Stress nuclear imaging showing anterior, apical, and septal wall perfusion defects during stress, which are reversible as observed on the rest images. These defects strongly suggest the presence of significant stenosis in the left anterior descending coronary artery.
Coronary Artery Atherosclerosis. Cardiac catheterization and coronary angiography in the left panel shows severe left anterior descending coronary artery stenosis. This lesion was treated with stent placement in the left anterior descending coronary artery, as observed in the right panel.
Coronary Artery Atherosclerosis. The illustrations depict vulnerable plaque and the mechanism of plaque rupture.
Coronary Artery Atherosclerosis. Positive and negative arterial remodeling are illustrated.
Coronary Artery Atherosclerosis. Low power, hematoxylin and eosin (H&E) stain of an atheromatous plaque of the coronary artery. The wall is thickened, and no internal or external elastic lamina is seen. There is a thick fibrous cap containing some neovascularization in the lower left of the image.
Coronary Artery Atherosclerosis. Low power, hematoxylin and eosin (H&E) stain of an atheromatous plaque of the coronary artery. There is marked luminal narrowing. The fibrous cap on the left contains a central lipid core containing macrophages and cholesterol clefts (lower center). Calcification (dark purple) is seen on the right.
Coronary Artery Atherosclerosis. This image is from a patient with an acute anterolateral myocardial infarction who developed cardiogenic shock. Coronary angiography images showed severe stenosis of the left anterior descending coronary artery, which was dilated by percutaneous transluminal coronary angioplasty.

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Table. Four Statin Benefit Groups and Major Recommendations

Table. Four Statin Benefit Groups and Major Recommendations

	Group	Recommendation
1.	Age ≥21 years with clinical ASCVD (including history of or current acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, PAD presurmed to be of atherosclerotic origin)	1.For patients age >75 years, high-intenstiy statin(or moderate-intensity statinif not candidate for high-intensity due to safety concerns) 2. For patients age >75 years, moderate-intensity statin
2.	Adults aged ≥21 years with LDL-C ≥190 mg/dl (not due to modifiable	1. High-intensity statin therapy to achieve ≥50% reduction in LDL-C statin (or moderate-intenstiy if not a candidate for high-intensity statin due to safety concerns) 2. May consider combining statin and non-statin therapy to further reduce LDL-C 3. Cascade screeing of close biologic relatives should be performed to identify others with the disease who would benefit from treatment.
3.	Adults aged 40-75 years without ASCVD but with diabetes and with LDL-C 70-189 mg/dL	1. Moderate-intensity statin 2. If 10-year ASCVD risk ≥7.5%, consider high-intensity statin.
4.	Adults aged 40-75 years without ASCVD or diabetes, and with LDL-C 70-189 mg/dL and an estimated 10 year risk for ASCVD of ≥7.5%	1. Estimate 10-year ASCVD risk using Pooled Cohort Equations a. if ≥7.5%, moderate- or high-intensity statin; b. If ≥to < 7.5%, consider moderate-intensity statin. 2. If selected individuals with 10-year ASCVD risk < 5%, or age < 40 or > 75 years, individualize decisions based on presence of other high-risk features. 3. Before initiation of statin therapy for primary prevention, it is reasonable for clinicians and patients to engage in a discussion that considers the potential for ASCVD risk-reduction benefits and for adverse effects and drug-drug interactions, as well as patient preferences for treatment.
ASCVD = atherosclerotic cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; PAD = peripheral artery disease; TIA = transient ischemic attack.

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Author

Sandy N Shah, DO, MBA, FACC, FACP, FACOI Cardiologist

Sandy N Shah, DO, MBA, FACC, FACP, FACOI is a member of the following medical societies: American College of Cardiology, American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Osteopathic Association, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Yasmine S Ali, MD, MSCI, FACC, FACP Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine; President, LastSky Writing, LLC

Yasmine S Ali, MD, MSCI, FACC, FACP is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, American Medical Writers Association, National Lipid Association, Tennessee Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: LastSky Writing;Philips Healthcare;M Health;Verywell Health; MedStudy;WellnessVerge;Prose Media; AKH, Inc.; LearnRoll, LLC; Eradigm; RxCe.com; M3 USA; M3 EU; Future US Inc.; Edanz Group; ChesterPA511<br/>Serve(d) as a speaker or a member of a speakers bureau for: RxCe.com.

Additional Contributors

F Brian Boudi, MD, FACP Clinical Associate Professor, University of Arizona College of Medicine (Phoenix Campus); Fellow, Sarver Heart Center, University of Arizona College of Medicine; Regional Faculty, American Heart Association; Adjunct Assistant Professor of Medicine, Mid-Western University; Staff Physician, Site Director for Clinical Rotations Emergency Medicine, Phoenix Veterans Administration Health Care System

F Brian Boudi, MD, FACP is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American College of Physicians, American Society of Echocardiography, Arizona Medical Association, Association of Program Directors in Internal Medicine, American College of Healthcare Executives, American Society of Nuclear Cardiology

Disclosure: Nothing to disclose.

Chowdhury H Ahsan, MD, PhD, MRCP, FSCAI Clinical Professor of Medicine, Director of Cardiac Catheterization and Intervention, Marlon Cardiac Catheterization Laboratory, Director of Cardiovascular Research, University Medical Center, University of Nevada School of Medicine

Chowdhury H Ahsan, MD, PhD, MRCP, FSCAI is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, Society for Cardiovascular Angiography and Interventions, American Stroke Association

Disclosure: Received consulting fee from sanofi for consulting; Received honoraria from astra zeneca for speaking and teaching; Received honoraria from BI for speaking and teaching.

Acknowledgements

Steven J Compton, MD, FACC, FACP Director of Cardiac Electrophysiology, Alaska Heart Institute, Providence and Alaska Regional Hospitals

Steven J Compton, MD, FACC, FACP is a member of the following medical societies: Alaska State Medical Association, American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Heart Rhythm Society

Disclosure: Nothing to disclose.

John A McPherson, MD, FACC, FAHA, FSCAI Associate Professor of Medicine, Division of Cardiovascular Medicine, Director of Cardiovascular Intensive Care Unit, Vanderbilt Heart and Vascular Institute

John A McPherson, MD, FACC, FAHA, FSCAI is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American Heart Association, Society for Cardiac Angiography and Interventions, Society of Critical Care Medicine, and Tennessee Medical Association

Disclosure: CardioDx Consulting fee Consulting; Gilead Consulting fee Consulting; Abbott Vascular Corp. Consulting fee Consulting

James L Orford, MBChB

Disclosure: Nothing to disclose.

Andrew P Selwyn, MD, MA, FACC, FRCP

Disclosure: Nothing to disclose.

George A Stouffer III, MD Henry A Foscue Distinguished Professor of Medicine and Cardiology, Director of Interventional Cardiology, Cardiac Catheterization Laboratory, Chief of Clinical Cardiology, Division of Cardiology, University of North Carolina Medical Center

George A Stouffer III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Physicians, American Heart Association, Phi Beta Kappa, and Society for Cardiac Angiography and Interventions

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Coronary Artery Atherosclerosis Treatment & Management