Refractory Angina



Refractory Angina


Anbukarasi Maran

Katrina A. E. L. Bidwell

Valerian Fernandes



INTRODUCTION

Angina pectoris is the symptom complex resulting from mismatch in myocardial oxygen supply and demand. Most commonly, this imbalance occurs in the setting of compromised blood flow to the myocardium as a result of progressive atherosclerotic disease of the coronary arteries. There are several definitions for refractory angina (RA); generally, criteria that must be met include the following:



  • Objective evidence of ischemia demonstrated by exercise treadmill testing, stress imaging, or invasive coronary testing such as fractional flow reserve measurement


  • Persistent angina despite conventional medical therapy1

The European Society of Cardiology (ESC) Joint Study Group further stipulates that RA is a chronic (>3 months), persistent, painful condition characterized by the presence of angina caused by coronary insufficiency in the presence of coronary artery disease (CAD) that cannot be controlled by a combination of medical therapy, angioplasty/percutaneous interventions, and coronary bypass surgery. Although the presence of reversible myocardial ischemia must be clinically established to be the root cause, the pain experienced may arise or persist with or without this ischemia.2


Prevalence

The subset of patients with advanced CAD who develop RA represent a substantive and growing population. The exact prevalence and incidence of RA are unknown because of the heterogeneity of patients labeled with a diagnosis of RA. It is estimated that there are 600,000 to 1.8 million patients with RA in the United States, with 50,000 to 100,000 new cases diagnosed per year.3,4 The Canadian Community Health Survey suggests that approximately 500,000 Canadians are living with RA and 30,000 to 50,000 new cases are diagnosed in Europe annually.2,5 Many case series did not include patients with nonobstructive CAD or possible microvascular angina.6,7

The patient population with RA experiences an impaired quality of life with high utilization of health care resources in the form of recurrent emergency room visits, hospitalizations, repeated stress tests, and, frequently, repeated invasive procedures such as cardiac catheterization. The Joint Study Group estimates that the incidence of RA is from 5% to 10% of patients undergoing cardiac catheterization.2 In the United Kingdom, evaluation and management of RA accounts for 1.3% of the total National Health Service expenditure, which is around £669,000,000 annually ($865,241,115 in US dollars). In 2008, an Ontario-based study quoted an annualized cost of Canadian dollars of $19,209 per patient.5 Not uncommonly, these patients also leave the work force secondary to their poor quality of life and limited functional status and subsequently go on disability. Subsequently there is also increased psychological stress and increased levels of depression in this population. Patients are not infrequently labeled being “palliative,” “end-stage,” having no options or are overlooked by their health care providers, adding yet another layer of stress. One of the most robust prospective studies on RA described a mortality rate of 3.9% at 1 year and 28.4% at 9 years, which is comparable to survival seen in chronic stable CAD.8 Thus, patients with RA have a long life expectancy coupled with a poor quality of life. The incidence and prevalence of RA will continue to rise as the general population continues to age and the condition is increasingly recognized in clinical practice.


PATHOGENESIS

Deficient myocardial blood flow can occur in the presence of flow-limiting atherosclerotic CAD; however, processes that affect the microvasculature can also be responsible, as can spontaneous coronary artery dissection, infection, vasculitis, and metabolic and genetic diseases. Owing to the infrequency with which some of these are seen, they pose a challenge both from a diagnostic and management standpoint. Delay in diagnosis, possible lack of treatment options for the inciting disease, and absence of targets for revascularization can result in what is ultimately labeled as RA.

The role of coronary microcirculation in the development of anginal symptoms is increasingly recognized. In contrast to the epicardial vessels in which flow is limited by stenosis from obstruction, microvascular impairment stems from abnormal function or remodeling. Abnormal remodeling can occur because of the following6,9:



  • Medial hypertrophy or intimal proliferation of small arterioles


  • Small vessel compression


  • Obstruction in the setting of hypertrophic cardiomyopathy


  • Microvasculopathy


  • Microemboli


  • Inflammatory disease


  • Idiopathic disease


Pathophysiologic mechanisms of microvascular dysfunction include endothelial dysfunction, decreased coronary perfusion pressure across a stenosis or diffuse epicardial narrowing, increased intercapillary oxygen perfusion distances as a result of hypertrophy, microvasculopathy or microemboli, and differential hyperemic responses of subendocardium versus subepicardium.6 Microvascular dysfunction can occur both with and without CAD and in the presence or absence of traditional risk factors for CAD.10

In patients with CAD, microvascular dysfunction is highly prevalent, being found in anywhere from 39% to 60% of patients with both obstructive and nonobstructive disease; and in 20% or more of patients with CAD, microvascular dysfunction can cause anginal symptoms and occasionally ischemic changes on electrocardiogram. The pain episodes are not rapidly relieved after cessation of activity or sublingual nitroglycerine. Focal, scattered ischemia throughout the myocardium is felt to be caused by prearteriolar dysfunction, and the presence of such defects might explain the paradox of angina and ST-segment depression or elevation in the absence of wall-motion changes.

Increased myocardial oxygen demand can be triggered by increase in physical, emotional, or metabolic activities; the mechanisms that lead to myocardial supply/demand mismatch and the pathways that link the myocardial and neural axes to result in the subjective experience of angina are complex. The relationship between angina and inadequate myocardial oxygen supply encompasses the spectrum of (1) classic angina in the presence of ischemia; (2) lack of symptoms in the setting of myocardial ischemia/infarction or “silent” ischemia; and (3) anginal symptoms in the absence of objective findings of ischemia, mediated in some cases by unobserved subendocardial ischemia and in other cases by aberrant pain mechanisms. The spectrum of presentations illustrates the intricate interplay of coronary circulation on the micro- and macro-level myocyte metabolism, and nociception. The subjectivity of the experience of angina is also reflected in the variety of manifestations from patients and the significant symptomatic improvement observed when RA is treated with placebo.11

The patient with RA experiences a cyclic relationship between myocardial hypoxia and the neuropathophysiology of persistent pain.12 In the presence of noxious stimuli (such as ischemia), bradykinin, adenosine, lactate, and potassium are released into the coronary sinus.13,14 These substances stimulate the polymodal afferent cardiac sensory neurons. Calcitonin gene-related peptide and substance P are also synthesized and augment adenosine-provoked pain. These noxious inputs enter the upper thoracic spinal cord and synapse with the second-order sensory neurons in the dorsal horn. This information is amplified and ascends via multiple pathways including Lissauer tract, the spinothalamic tract, and spinoamygdaloid and spinohypothalamic pathways to cortical and subcortical areas of the brain with somatic receptive fields in the chest and arm. The parietal cortex and anterior cingulate cortex cognitively apprise these stimuli as threatening, in turn causing activation of the bilateral prefrontal cortex and limbic system and producing an impending sense of doom, anxiety, and further pain15,16,17,18 (Algorithm 8.1). Modulation of the neural pathways by which the subjective experience of pain is elaborated and amplified has provided an additional therapeutic target in the treatment of patients with RA.







MANAGEMENT OF THE PATIENT WITH REFRACTORY ANGINA


Medical Approach

The approach to patients begins with the assumption that optimization of traditional risk factors for CAD and other significant comorbidities have been performed. If not, the patient does not meet criteria for RA; furthermore, addressing poorly controlled comorbidities such as uncontrolled hypertension, severe anemia, or heart failure generally produces the symptomatic relief sought by the patient.19 Ideally, other lifestyle interventions such as initiation of an exercise program and tobacco cessation will already have been made, and, if not, provide another opportunity for improvement. When seeing
a patient in consultation for RA, a detailed history should be obtained, with attention to what symptoms the patient experiences, in what settings, how those symptoms have changed over time, what limitations they experience because of their symptoms, and the effect on their quality of life. A detailed family history for relevant inherited disorders (such as hypertrophic cardiomyopathy and Fabry disease) and less obvious entities that can rarely present initially with angina (such as sickle cell disease) should be obtained. A careful physical examination can suggest suboptimally controlled comorbid conditions that the patient may not identify. Routine laboratory assessment includes complete metabolic panel (including liver function testing), complete blood count, lipid panel, and glycosylated hemoglobin to rule out or assess any comorbid or contributing diseases as well as evaluate the suitability of certain medications.

Gastrointestinal disease is a frequent comorbid condition in the evaluation and treatment of RA. Entities such as gastroesophageal reflux disease, hiatal hernia, presbyesophagus, esophageal dysmotility and spasm, gallbladder disease, and biliary dysfunction are frequently convincing mimics of angina, and are seen frequently in the patient population with known coronary disease or risk factors. Further confounding the clinical picture is the fact that many of these smooth muscle pains may be relieved by nitroglycerine. A careful clinical history may help differentiate these symptoms from angina, particularly in patients who have continued symptoms despite complete revascularization.








Conventional therapy for chronic stable angina due to CAD includes aspirin, statin, beta-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors or aldosterone receptor blockers (ARBs). Calcium channel blockers and nitrates are mainstays for coronary vasospasm. In the setting of microvascular dysfunction, the data is less robust concerning appropriate therapy. Moderate-quality evidence suggests that ACE inhibitors and ranolazine may improve quality of life. Beta-blockers, calcium channel blockers, and statins each have been shown to produce significant improvements in anginal frequency and ischemia based on lower quality evidence.20

When patients are on maximum dose or maximally tolerated conventional therapy and still symptomatic, second-line therapies can be considered. Ivabradine, nicorandil, trimetazidine, long-acting nitrates, and ranolazine are considered second-line therapies in the treatment of RA in the ESC guidelines. Nicorandil and trimetazidine are not yet available in the United States.21 In the context of microvascular disease, ivabradine and trimetazidine each failed to improve symptoms or objective measures of ischemia.20 Narcotic analgesics can be considered in a very select group of patients; however, they should be used rarely. See Table 8.1 for a summary of first- and second-line antianginal medications.

Patients who have continued symptoms on second-line therapies for RA should be considered for repeat angiography. Where available, cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET) can be
used in the evaluation of coronary flow reserve and myocardial viability. Other invasive studies for angiographically normal coronaries are discussed later. Most of the time, patients are not candidates for revascularization for multiple reasons2:






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May 8, 2022 | Posted by in CARDIOLOGY | Comments Off on Refractory Angina

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