Chronic Ischemic Heart Disease Selection of Treatment Modality

Etiology

The most common cause of chronic ischemia is coronary artery obstruction secondary to atherosclerotic disease. A newly recognized entity, more frequently described in female patients, is endothelial dysfunction or microcirculatory dysregulation, resulting in similar symptoms but without the presence of significant stenosis on angiography. Less common etiologies include coronary vasospasm (Prinzmetal angina) and coronary anomalies which may rarely present with a similar picture.

Epidemiology

It is difficult to ascertain the exact prevalence of stable ischemic heart disease due to the heterogeneity of its patient population and the variable definitions that physicians use. Nonetheless, CAD remains a major public health concern nationally in many regards. An estimated 10 million adults in the United States carry the diagnosis, and despite mortality-reducing therapy, IHD was alone responsible for nearly 380,000 deaths within the United States in 2010. In that approximation, it remains the number one cause of death for male as well as female patients. Furthermore, the increasing survival with the use of modern therapies has produced an aging population where more than 20% of women and 35% of men above the age of 80 have coronary artery disease.

History and Physical

The most classic presentation is with reported angina pectoris (commonly referred to as angina) where patients endorse chest discomfort, often left-sided and substernal, that occurs with exertion or emotion and is relieved with rest or nitroglycerin. The description of the chest discomfort itself can vary from heaviness to pressure, squeezing or tightness. Radiation to the left arm, neck, or jaw is also fairly common. The presence of chest “pain” per se, reproducibility with palpation, variation with respiration, or pinpoint localization by the patient makes ischemia less likely.[7][8][9]

Patients also may present with “angina-equivalent” symptoms where chest discomfort is never quite present, but instead, exertional dyspnea or more atypical symptoms occur during exercise and limit their functionality. Older age, female gender, and diabetes are typical risk factors. In fact, silent ischemia (or silent myocardial infarction) is not a rare occurrence in the latter population.

Temporally, stable angina is differentiated from unstable angina by its chronicity and reproducibility with exertion. Symptoms will typically last for minutes (not seconds or hours) and after a predictable amount of exertion before being relieved with rest. If the stable, chronic nature of angina changes, where it occurs with less exertion, last for a longer duration of time, or becomes more severe, then urgent evaluation for unstable angina needs to be performed.  

Clinically, if all three criteria are met (substernal chest pain, occurring with exertion and emotion, relieved by rest or nitroglycerin), then it is considered typical angina. This definition is meant to imply a high likelihood of ischemic heart disease as the cause of chest discomfort in the right clinical context. Frequently, patients will not fulfill all three criteria and will be further stratified into atypical angina or non-cardiac chest pain, depending on how many criteria they meet and the overall description of their symptoms.

Stable ischemic heart disease also may be completely asymptomatic, and in fact, studies have proven that atherosclerotic disease, the most common precursor to IHD, starts in childhood and develops over decades, during which patients are completely asymptomatic. It is only after the disease reaches a critical proportion, with coronary artery obstruction amounting to at least 50% of the vessel lumen, that symptoms, if any, may develop. During that period, clinicians will need to be proactive in screening patients at intermediate or higher risk in order to start therapy early.[10][11][12]

Evaluation

Primary screening for stable ischemic heart disease starts with identifying risk factors associated with the development of atherosclerosis. Older age, male gender, smoking, hypertension, diabetes mellitus, and hyperlipidemia, as well as family history of premature coronary artery disease (defined as an occurrence in a first-degree relative at the age of less than 55 for males or less than 65 for females), are among the strongest risk factors. Obesity, limited physical activity, psychosocial factors such as stress and depression, as well as co-existing chronic kidney disease or another atherosclerotic cardiovascular disease (ASCVD) such as stroke, or peripheral vascular disease (PVD) are also associated with ischemic heart disease.

The "2010 ACC/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults" recommended the use of global risk scores, such as the Framingham Risk Score (FRS), to risk assess all adults. 

The "2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk” added the pooled cohort ASCVD risk equation as a reliable tool for non-Hispanic African American or non-Hispanic white patients who are 40 to 79 years of age. Both global risk score calculators (as well as several others) rely on similar risk factors known to be associated with IHD as mentioned prior, though certain risk factors like positive family history are difficult to quantify and should be accounted for by the physician for every individual patient.

The ASCVD pooled cohort equation was also used in the “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults” to risk stratify all adults over the age of 21. Patients with known ASCVD, LDL greater than 190mg/dL, diabetes mellitus or 10-year ASCVD calculated risk estimated at greater than 20% are considered high-risk. For this group of patients, high intensity (or maximally tolerated) statin therapy is recommended.

Patients are further stratified into those with intermediate-risk if their ASCVD risk is calculated at 7.5% to 20%, or borderline if their ASCVD risk is 5% to 7.5%. For this group, it is advised to initiate a discussion with the patients regarding their individual risk factors before making a decision to start statin therapy. Further risk stratification using coronary artery calcium (CAC) score could also be helpful. In general, patients with CAC score more than 100, or higher than 75th percentile for their age-matched cohorts are considered at higher risk. Other risk enhancers include hs-CRP of at least 2.0 mg/L, ABI < 0.9 and elevated Lp(a) or apoB levels.

The newer 2017 guidelines also rely on global risk calculators such as the Reynold Risk Score or the MESA (Multi-Ethnic Atherosclerosis Study), but add an LDL-C target instead of an intensity-based approach to statin therapy and/or lipid management strategy. Amidst all of these sequential guidelines, what remains constant is an emphasis on screening for higher risk patients and beginning therapy with lifestyle modification as well as lipid-lowering agents (statins being the cornerstone) while patients are still asymptomatic.

For patients known or suspected to have stable ischemic heart disease, initial evaluation should begin with a thorough history and physical examination, along with a baseline ECG to look for signs of ischemia or previous infarction. Stress testing, as well as an assessment of functional capacity is often necessary, particularly if the patients have active symptoms or evidence of ischemia such as ST changes on ECG. All patients diagnosed with stable ischemic heart disease should have an echocardiogram to assess for ventricular dysfunction because it directly affects management. This is especially true if it shows reduced LVEF. It may also show regional wall motion abnormalities suggestive of ischemia or an old infarction within a specific coronary artery territory. Laboratory tests such as a lipid panel, HbA1c, and renal function are routinely obtained as well. Troponin enzyme levels, brain natriuretic peptide (BNP) or NT-proBNP are not necessary for the diagnosis but may be useful in the right clinical setting.

After the clinical history and non-invasive testing are used to define patient risk, the decision to pursue invasive testing can be made. This is done through cardiac catheterization, where a coronary angiogram can define coronary anatomy with the aim of identifying flow-limiting atherosclerotic lesions. However, the indications to perform such a procedure largely depend on whether or not the information obtained is likely to affect management. While a coronary angiogram may occasionally be used to diagnose IHD in a patient with an atypical clinical presentation or indeterminate stress test results, it is often not done for purely diagnostic reasons. The primary benefit for the majority of patients is in providing another layer of risk-stratification that can direct revascularization-eligible patients towards that route, where they may receive primary cutaneous intervention (PCI) or be referred for coronary artery bypass graft (CABG) surgery.

In that respect, the 2014 ACC/AHA focused update for the diagnosis and management of stable ischemic heart disease guidelines recommend coronary angiography in patients with high-risk of severe IHD (as determined by the clinical setting and stress test results) who are amenable to revascularization (Class IIA recommendation) or patients with refractory ischemic symptoms despite goal-directed medical therapy (Class I recommendation). It is also reasonable to perform in patients with suspected stable ischemic heart disease, where diagnostic tests, including stress test results, are indeterminate.

Coronary angiography is not recommended to assess risk in asymptomatic patients or those at low-risk according to clinical criteria prior to noninvasive stress testing. It also is not recommended in patients with preserved LV function (ejection fraction greater than 50%) and low risk on non-invasive testing. Higher risk patients should also not undergo angiography if they are not candidates for revascularization because of comorbidities or individual preference since it exposes them to the risks of the procedure without affecting future management or improving outcomes.

Treatment / Management

The goals of treatment are to limit atherosclerotic disease progression, prevent or reduce complications including death, and to near-completely eliminate ischemic symptoms with the aim of improving quality of life, and restoring functional capacity. In order to achieve that, three aspects must be addressed: (1) risk-modification, (2) guideline-directed medical therapy (GDMT), and (3) revascularization.

Risk modification begins with individualized life-style changes such as dietary modification, weight reduction, smoking cessation, and frequent exercise. It is also reasonable to counsel patients to avoid stressors and develop coping mechanisms for depression and anxiety where applicable. Education regarding medication adherence and careful self-monitoring also is vital. Importantly, much attention should be directed towards optimizing hypertension, diabetes, and dyslipidemia management since they can directly affect stable ischemic heart disease outcomes, and increase risk of future events.

Guideline-directed medical therapy (GDMT) itself can be split into two categories. The first includes therapies that slow down the atherosclerotic disease, decrease future events of myocardial infarction, and longitudinally decrease mortality. They include anti-platelet agents, beta blockers, renin-angiotensin-aldosterone blockers and lipid-lowering drugs. The second category directly addresses symptoms, and attempts to eliminate angina (or angina-equivalent symptoms) through use of nitrates, beta blockers, calcium channel blockers, and novel therapies. We will discuss the former category of GDMT first, then go through available anti-anginal therapies, and lastly address revascularization.

Medical Therapy to Prevent Myocardial Infarction and Death

Antiplatelet therapy is recommended for secondary prevention in patients with stable ischemic heart disease. The most commonly used agent is aspirin, which irreversibly acetylates platelet cyclooxygenase, and limits thromboxane A2 production thereby decreasing platelet aggregation. Studies have shown that aspirin use following acute coronary syndrome can decrease mortality, and improve outcomes in several trials such as CLARITY-TIMI (which studied patients post-fibrinolysis), and CURRENT OASIS which compared high-dose to low-dose therapy. Consequently, guidelines recommend aspirin 81 to 162 mg daily indefinitely to all patients who can tolerate it.

Controversy remains regarding the use of aspirin for primary prevention in patients at variable risk of coronary CAD. Major recent trials have shown no significant reduction in cardiovascular events, often with an increased risk of bleeding. The ARRIVE trial identified patients at moderate risk who received aspirin for primary prevention, and demonstrated no reduction in the primary outcomes of CV death, MI, unstable angina, stroke or transient ischemic attack. Furthermore, there was an increase in gastrointestinal bleeding (HR = 2.11, CI 95%, 1.36 - 3.28). Similar findings were found in the ASCEND trial, which studied diabetic patients, and the ASPREE trial which followed more than 19,000 patients at least 65 years of age, who were free from CVD or dementia. These findings may suggest that aspirin should not be routinely prescribed for the sole purpose of primary prevention, and that a careful risk-benefit assessment - as pertains to cardiovascular outcomes versus bleeding - needs to be performed before initiation of life-time therapy.

A relative contraindication exists for patients with an NSAIDs allergy and the Samter triad (asthma, nasal polyps, and aspirin sensitivity). In those circumstances, clopidogrel 75 mg daily, which works through irreversibly inhibiting P2Y12 receptors and has demonstrated favorable outcomes in the CAPRIE trial as compared to aspirin, can be used instead. Newer anti-platelet agents such as ticagrelor and prasugrel are not currently recommended for the treatment of stable ischemic heart disease unless patients have had a recent acute coronary event, due to unacceptably elevated risk of bleeding as compared to more traditional therapy in this cohort.

Beta blockers are the only anti-anginal drugs known to prevent infarction and impact mortality in ischemic cardiomyopathy as demonstrated in multiple studies. This is particularly true for patients with reduced LVEF, where trials such as CIBIS II and MERIT-HF showed improved survival. The CAPRICORN trial also studied patients with ischemic cardiomyopathy post myocardial infarction with LVEF less than 35% and showed similar outcomes. Subsequently, current guidelines recommend beta blocker use for at least 3 years after a myocardial infarction and indefinitely for all patients with LVEF of less than 40%, and heart failure symptoms.

The selective use of renin-angiotensin-aldosterone inhibitors is also recommended, and the strongest evidence exists for patients with reduced LVEF as well as those with high risk features. The 1992 survival and ventricular enlargement trial (SAVE), for example, demonstrated decreased mortality with use of captopril in patients with asymptomatic reduced LVEF after an acute myocardial infarction. While the more recent HOPE trial showed improved outcomes with the use of ramipril in patients with established CAD or known atherosclerotic risk factors. However, this is not universal to all patients with stable ischemic heart disease since several studies were unable to demonstrate the same benefits in lower risk populations. As it currently stands, ACE inhibitors are recommended for stable ischemic heart disease patients with reduced LVEF less than 40% and those with high-risk features such as hypertension, diabetes and chronic kidney disease. Angiotensin-receptor blockers (ARBs) also can be used for similar indications in ACE intolerant patients.

Mineralocorticoid antagonists also were studied post myocardial infarction in the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival) trial, where patients with LVEF less than 40% were started on eplerenone and showed decreased cardiovascular mortality. Per current guidelines, spironolactone or eplerenone are recommended in the subset of patients with reduced LVEF after acute myocardial infarction if they have heart failure or DM.

The national recommendations regarding lipid-lowering therapy have generated much controversy in the past several years, but an agreement exists regarding the need for all patients to be on statin therapy if tolerated. The “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults” recommended an intensity-based approach, where all patients with established ASCVD (including SIHD) should be on high-intensity statin therapy, or the highest-intensity therapy tolerated, regardless of LDL target. Newer publications advocate a risk-assessment algorithm, where individual patient risk is assessed, and most patients with stable ischemic heart disease are targeted for an LDL less than 70 (or less than 55 for patients with the highest risk). The “2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk” also advocates the selective use of PCSK9 inhibitors, ezetimibe, bile acid sequestrants, nicotinic acid, and fibrates for patients who are intolerant of or have an inadequate response to statin therapy.

Currently, patients with very high ASCVD risk (those with recurrent events, or one ASCVD event in addition to multiple risk factors) are recommended to maintain an LDL level < 70. If patient are unable to achieve their LDL target goal, then Ezetimibe should be added. If goal target is still not achieved, or if patients are intolerant to statin therapy, then PCSK inhibitors should be initiated.

Medical Therapy for Relief of Symptoms

Beta blockers are considered first-line agents, as they are the only anti-anginal medication proven to impact survival. Past the initiation of beta-blocker therapy, the treatment strategy requires escalation of administered dosage or addition of second-line agents until complete or near-complete symptom relief is achieved. If medical therapy fails due to medication intolerance or intractable pain, then revascularization is pursued.

Nitrates are potent vasodilators and cause a combination of venodilation (decreasing preload), arterioral dilation (decreasing afterload), as well as coronary dilation. It is the decreased preload and ventricular wall stress, with resultant decreased oxygen demand that primarily mediates its anti-anginal effects, however. Nitrates are available in sublingual form, which bypasses the first-pass effect and can be used acutely, while more sustained oral or transdermal formulations may be added to beta-blocker therapy for prolonged anti-anginal effect. This requires that a nitrate-free interval of at least 10 to 12 hours be maintained, usually overnight, to prevent tachyphylaxis and diminishing effect.

Calcium channel blockers (CCB) are considered second-line therapy and can be used to augment beta-blocker therapy or as a substitute in patients who are intolerant to them. They are only recommended for uncontrolled ischemic symptoms since they do not affect long-term survival or reduce mortality. Nondihydropyridine CCB agents, such as verapamil and diltiazem, should be used with caution when combined with beta blockers, since that may cause combined negative inotropic and chronotropic effect, with severe hypotension and/or atrioventricular block. This is especially true in patients with reduced systolic function or baseline conduction impairment. Therefore, dihydropyridine agents such as amlodipine are more commonly used in this setting.

Ranolazine, a sodium-channel blocker, is a newer medication that may be used if all the former agents are unsuccessful in controlling chest pain. It may be used in combination with beta-blockers and CCBs. Rarely, alternative therapies such as enhanced external counterpulsation (EECP) or spinal stimulation may be utilized. However, the majority of patients that fail medical therapy would qualify for revascularization, if feasible, to improve symptoms.

Revascularization

In stable ischemic heart disease, there are two main aims of revascularization. The first is to improve symptoms and would require that angina be present despite optimal GDMT in a patient with favorable coronary anatomy for revascularization. The second aim is to improve survival, which is reliant on the presence of high risk anatomy often in the setting of high-risk clinical features. In that regard, revascularization is indicated in left-main (or left-main equivalent) disease, three-vessel disease, or two-vessel disease, including proximal left anterior descending (LAD) coronary artery stenosis. Similar recommendations do not apply to single-vessel disease or two-vessel disease not including the proximal LAD in the absence of refractory symptoms.

While both CABG and primary cutaneous intervention (PCI) are reasonable for the intent of revascularization; the presence of complex anatomy, LV dysfunction, diabetes mellitus, anticipated low-surgical risk and/or high PCI procedural risk are indications to choose CABG over PCI. The literature evidence showing improved survival has also traditionally favored CABG, particularly where left internal mammary grafts were used to bypass proximal LAD stenosis. Clinically, less complex coronary anatomy in association with ischemic symptoms is often treated with PCI to achieve symptom relief. Several studies, including the landmark COURAGE and BARI 2D trials, failed to show mortality benefit in the latter population however.  Despite benefits of symptom relief, no evidence to date has shown survival benefit for revascularization in single-vessel disease, not including the proximal LAD.

Differential Diagnosis

• Acute pericarditis

• Angina pectoris

• Atherosclerosis

• Coronary artery vasospasm

• Dilated cardiomyopathy

• Familial hypercholesterolemia

• Giant cell arteritis

• Hypertension

• Hypertensive heart disease

• Kawasaki disease