Advances in the Treatment of Chronic Stable Angina

FACULTY:

Nicole K. Brogden, PharmD
PGY1 Pharmacy Resident, University of
Kentucky HealthCare, Lexington, Kentucky

Steven P. Dunn, PharmD, BCPS
Cardiology Clinical Specialist, Department of
Pharmacy Services and Division of
Cardiovascular Medicine, Gill Heart Institute
Adjunct Assistant Professor, University of
Kentucky College of Pharmacy
Lexington, Kentucky

Tracy E. Macaulay, PharmD, BCPS
Cardiology Clinical Specialist, Department of
Pharmacy Services and Division of
Cardiovascular Medicine, Gill Heart Institute
Adjunct Assistant Professor, University of
Kentucky College of Pharmacy
Lexington, Kentucky

FACULTY DISCLOSURE STATEMENTS:

Drs. Brogden, Dunn, and Macaulay have no actual or potential conflicts of interest in relation to this program.
U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous.
Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
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Program No.: 430-000-08-003-H01-P; 430-000-08-003-H01-T
Credits: 2.0 hours (0.20 ceu)

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To review the pathophysiology, clinical presentation, and treatment of chronic stable angina. 

OBJECTIVES:  

After completing this program, participants will be able to:

1. Provide a basic overview of the pathophysiology, diagnosis, and classification of angina.*
2. Evaluate guideline-based management strategies for the treatment of angina.*
3. Discuss the role of beta-blockers, calcium channel blockers, nitrates, and ranolazine in the treatment of angina.*
4. Develop an individualized pharmacotherapy and monitoring plan for the management of chronic stable angina, when given specific patient information.

*Also applies to pharmacy technicians.

Angina is the most frequent symptom of coronary artery disease (CAD), prompting the majority of patients with CAD to seek medical attention.¹ Angina is classically characterized as substernal discomfort, and patients often describe their pain using terms such as “squeezing, suffocating, or pressure-like.”² A diagnosis of chronic stable angina (CSA) includes left anterior chest discomfort that is predictable and reproducible after emotional stress and/or physical activity; the associated anginal symptoms are typically relieved by either sublingual nitroglycerin or cessation of the exacerbating circumstances. Symptoms are typically worse in cold conditions or following meals.^2,3 When a patient presents with chest pain, the initial evaluation should include a detailed history, physical examination, and other appropriate tests in order to determine the patient’s probability of having significant CAD versus acute myocardial infarction (MI).² A detailed history of the pain should be elicited from the patient, including the nature of the pain, precipitating factors, duration, and relief with rest or nitroglycerin.^3,4

A patient presenting with acute onset of angina should also be evaluated for acute coronary syndrome. The following discussion will focus only on the treatment of CSA.

Pathophysiology of Chronic Stable Angina

Symptoms originate from regional myocardial ischemia that arises from inadequate coronary perfusion. This type of angina is typically, although not always, caused by increased myocardial oxygen requirements.^3,4 An increase in myocardial oxygen demand is created during increased activity or stress, leading to a supply-demand mismatch and resulting in ischemia. Progression of atherosclerosis in the coronary arteries can lead to plaque deposition external to the lumen, ultimately intruding into the lumen, causing obstruction, and, therefore, angina (FIGURE 1).⁴

Classification of Angina

Stable angina can be described as classic (typical), atypical, nonanginal, and noncardiac; each type of angina presents with distinct symptoms.^2-4 Classic or typical angina involves three distinct characteristics: 1) substernal chest discomfort or pain that has a characteristic quality and duration, which is 2) brought on by emotional stress or physical activity, and is 3) usually relieved by either rest or nitroglycerin. Atypical angina presents as chest pain that contains two out of the three characteristics of stable angina and is more common in women, elderly patients, and patients with diabetes. Noncardiac angina meets one or none of the characteristics of classic angina, and the differential diagnosis should include gastroesophageal reflux disease (GERD), peptic ulcer disease, mitral valve prolapse, and biliary disease.^2-4

The Canadian Cardiovascular Society (CCS) classification of angina, proposed in 1976, is a widely used mechanism for characterizing angina based on an assessment of disability resulting from the anginal symptoms.^1,4 The classification system is described in TABLE 1. It is important to note that Sangareddi et al demonstrated in 2004 that there is no statistically significant correlation between the CCS angina class and the severity of CAD as determined by coronary angiography.^1,3

Table 1
Canadian Cardiovascular Society Angina Grading Scale
Angina Classification	Accompanying Symptoms
Class I	Normal physical activity (e.g., climbing stairs or walking) does not cause anginal symptoms; angina occurs primarily with strenuous, extended, or rapid physical activity or recreation
Class II	Angina poses a slight limitation on ordinary activity and typically occurs with the following types of activities: Quickly walking or climbing stairs Uphill walking Walking/stair climbing after meals Windy or cold weather Emotional stress Within the first few hours after waking Walking more than two blocks or climbing more than one flight of stairs at a normal pace (under normal conditions)
Class III	Anginal symptoms impose marked limitation on physical activity; angina occurs upon walking one to two blocks or climbing one flight of stairs at a normal pace (under normal conditions)
Class IV	Symptoms of angina may be present at rest; physical activity cannot be carried out without discomfort
Source: Reference 1.

Treatment of Chronic Stable Angina

The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult patients with CSA were updated in 2002, thus providing the most current standards for the medical management of patients with CSA.⁵ The pharmacologic management of patients with CSA is multifaceted but can be classified into two general areas: antianginal/anti-ischemic therapies (i.e., beta-blockers, calcium channel antagonists, and nitrates) and vasculoprotective agents (i.e., lipid-lowering therapies and antiplatelet agents).³ This discussion will focus primarily on the antianginal and anti-ischemic therapies.

In addition to the pharmacologic options and standards of care described by the 2002 ACC/AHA guidelines, ranolazine was approved in January 2006 by the FDA as a novel treatment option for CSA in patients who have not achieved adequate control of angina symptoms with standard therapies.⁶ (These pharmacologic treatments are summarized in TABLE 2.) Nonpharmacologic interventions for CSA, such as percutaneous coronary intervention and lifestyle modifications, remain central to the overall management of the patient and will be discussed as well.

Antianginal and Anti-ischemic Drugs

Beta-blockers: Beta-adrenergic blockers (beta-blockers) produce their antianginal effects primarily through a decrease in myocardial oxygen demand that results from a reduction in heart rate, myocardial contractility, and blood pressure. According to the ACC/AHA 2002 guidelines, beta-blockers are considered to be initial first-line therapy for CSA in all patients without contraindications, including the elderly, those with a history of previous MI, and those who have undergone a previous revascularization.^5,7 Beta-blockers are especially appealing in patients with concurrent cardiovascular risk equivalents, as previous data have demonstrated that beta-blockers are able to decrease the incidence of cardiac events and improve survival in patients who are hypertensive and post-MI.⁸

Despite differing amounts of alpha- and beta-blocking properties, all of the beta-blockers are essentially thought to be equally effective for the treatment of CSA, although not all are FDA approved for this indication.⁷ The beta-blockers exert their antianginal effects in a dose-dependent manner; thus, therapy must be titrated to goal, which is a resting heart rate of 50 to 60 beats per minute (bpm) and an exercise heart rate of less than 100 bpm.⁴

There are several absolute contraindications to beta-blocker therapy, including sick sinus syndrome, severe bradycardia or atrioventricular block, and unstable heart failure (TABLE 2). Relative contraindications to beta-blockers include asthma, peripheral vascular disease, and depression.⁷ General side effects of this class include fatigue, exercise intolerance, brady-cardia, hypotension, altered glucose metabolism, and worsening claudication.^5,7

Calcium Channel Blockers: In general, the calcium channel antagonists (commonly known as calcium channel blockers, or CCBs), are equally effective in the management of stable angina.^9-12 These agents exert their antianginal effects via inhibition of calcium entry into myocardial tissue, resulting in dilation of both systemic and coronary arteries that leads to an increase in coronary blood flow and thus decreases myocardial oxygen consumption.^3,4

The CCBs should be considered first-line therapy in situations when beta-blocker therapy is not indicated, including when patients have absolute contraindications to beta-blockers or are unable to tolerate therapy because of adverse events.⁵ CCBs can also be used as add-on therapy in patients with inadequate control of anginal symptoms on monotherapy with a beta-blocker.⁵ In general, the short-acting dihydropyridine CCBs should not be used for the treatment of angina because of their potential to produce ischemia through rebound activation of the sympathetic nervous system.¹³

Generally, all CCBs cause similar adverse events, including peripheral edema, worsening of heart failure, hypotension, and constipation (TABLE 2). Various CCBs have agent-specific adverse events due to differences in pharmacology (dihydropyridine versus nondihydropyridine), which include excessive reflex tachycardia (e.g., nifedipine) and bradyarrhythmias (e.g., diltiazem and verapamil). Due to differences in the adverse-effect profiles and peripheral and central hemodynamic effects, the initial choice of a calcium channel blocker should be carefully considered.

Nitrates: Nitrates provide an exogenous source of the endogenous endothelium-independent vasodilator nitric oxide. It is well known that in the presence of atherosclerosis there is impaired production of nitric oxide; thus, nitrates can be given to improve symptoms of angina by reducing both myocardial ischemia and improving coronary blood flow. Once converted to nitric oxide inside the vessel wall, the enzyme guanylate cyclase is stimulated to produce cyclic guanosine monophosphate (cGMP). This results in a decrease in calcium in the vascular myocyte, causing vasodilation. Nitrates are better vasodilators of veins than of arteriole; therefore, dose-limiting blood pressure-lowering effects occur, but generally only at higher doses or with combination therapy.

There are many different nitrate preparations, most of which are FDA approved for the treatment of angina (TABLE 2). The most commonly utilized agent is sublingual nitroglycerin, which has an elimination half-life of only a few minutes and is the treatment of choice to halt acute anginal episodes. The instability of nitroglycerin tablets makes nitroglycerin spray an attractive alternative for more active individuals or those with chronically dry mouth. In vivo, nitroglycerin is extrahepatically converted rapidly to longer-acting dinitrates, which are biologically active.¹⁴ However, when isosorbide dinitrate is administered orally, it must be converted by the liver into active mononitrates. Isosorbide dinitrate given sublingually has an antianginal effect lasting about one hour and, when ingested, will last up to six hours. The longest-acting oral preparation is the biologically active formulation isosorbide mononitrate, which is also available in a sustained-release (SR) preparation.

Unlike beta-blockers, nitrates have not demonstrated the ability to reduce MIs or death. However, studies have shown increased exercise duration with isosorbide mononitrate 120 to 240 mg daily and isosorbide dinitrate 15 to 120 mg administered several times a day.^15,16 Nitrates are also ideal when used in combination with beta-blockers, which may prevent the nitrate adverse effect of reflex tachycardia.¹⁷ When used in combination with calcium channel blockers, hypotension may be more profound, but this combination has also demonstrated positive effects on exercise tolerance. Other important interactions causing profound hypotension include concomitant use of phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil), a combination that should be avoided for up to 24 hours after administration of sildenafil or vardenafil, and 48 hours after long-acting tadalafil.¹⁸

However, there is a potentially beneficial drug interaction with hydralazine, which lessens nitrate tolerance by decreasing nitric oxide degradation.¹⁹ Nitrate tolerance was first noticed by Brunton and published in the Lancet in 1867.²⁰ Tachyphylaxis is the primary reason for therapy failure with longer-acting preparations, but it can be circumvented by providing a 10-to 12-hour nitrate-free interval or by concurrent administration with hydralazine.²¹ With so many options for administration, nitrates are ideal to treat angina in patients without compelling indications for previously discussed classes or as adjunct therapy.

Ranolazine

On January 1, 2006, the FDA approved ranolazine as a new treatment option for patients with CSA. Its mechanism of action remains unknown, although the antianginal effects are produced without any significant changes in hemodynamic properties such as heart rate and blood pressure.⁶

Despite some uncertainty regarding the exact mechanism of action, ranolazine is thought to exert its effects by altering the production of adenosine triphosphate (ATP) away from oxidation of fatty acids, thus favoring the more oxygen-efficient oxidation of carbohydrates.²² During myocardial ischemia, the levels of fatty acids rise suddenly, thus promoting their uptake and oxidation in the myocardial tissue.²² The phosphorylation of ATP during the oxidation of fatty acids requires more oxygen than carbohydrate oxidation, ultimately leading to an inefficient use of the available oxygen supply. A shift in metabolism from fatty acid to carbohydrate oxidation theoretically promotes more efficient use of oxygen and would potentially lessen ischemia.^22,23 In addition, ranolazine has been shown to inhibit the late phase of the inward sodium current during repolarization of cardiac tissue, which may also reduce myocardial ischemia and control symptoms of angina.²⁴ Fatty acid metabolism by myocytes also produces potentially harmful byproducts, thereby suggesting a potential role for ranolazine in reducing harmful cardiac events.

Ranolazine undergoes significant metabolism in the liver and gut, with a half-life of approximately seven hours.⁶ Nearly 75% of the drug is excreted in the urine, while the remainder is excreted via feces. Ranolazine is currently contraindicated in patients with preexisting long QT syndrome (irregular electrical activity of the heart that places patients at risk for ventricular arrhythmias) or in those receiving QT-prolonging drugs. Ranolazine is also contraindicated in patients receiving concurrent therapy with CYP3A inhibitors (including diltiazem) and in patients with severe hepatic impairment. No cases of torsades de pointes (a rare form of ventricular tachycardia) have been reported to date.⁶

Ranolazine is available as an SR oral tablet that can be taken with or without regard to meals (TABLE 2). Therapy is initiated at 500 mg bid and titrated up to 1,000 mg bid, based on clinical symptoms (maximum dose is 1,000 mg bid). In general, concurrent therapy with other antianginal treatments is well tolerated.⁶

To date, four major trials have been published describing the efficacy and safety of ranolazine: the Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) trial,²² the Combination Assessment of Ranolazine in Stable Angina (CARISA) trial,²³ the Efficacy of Ranolazine in Chronic Angina (ERICA) trial,²⁵ and the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial.²⁴ A brief description of each of these trials is included in the following paragraphs.

Table 2
Pharmacologic Treatments for Chronic Stable Angina
Drug Class	Mechanism of Action	Place in Therapy	Specific Agents (Dosing)	Side Effects	Contraindications
Beta- blockers	Decreased myocardial oxygen demand, resulting from a reduction in heart rate, myocardial contractility, and blood pressure	First-line in all patients without contraindi- cations	Atenolol: 25-200 mg qd Metoprolol tartrate: 100-450 mg/day in 2 to 3 divided doses Propranolol: 80-320 mg/day in divided doses (2 to 4 times/day); Long-acting formulation: 80-320 mg qd	Bradycardia, hypotension, glucose intolerance, fatigue, exercise intolerance, worsening claudication	Absolute: severe bradycardia, sick sinus syndrome, AV block, unstable heart failure Relative: asthma, depression, peripheral vascular disease
Calcium channel blockers	Dilation of systemic and coronary arteries, leading to an increase in coronary blood flow and decreasing myocardial oxygen consumption	First-line in patients with contraindi- cations to beta-blockers and in patients with unacceptable adverse events or inadequate symptom control on monotherapy with beta-blockers	Amlodipine: 5-10 mg/day (5 mg/day in elderly patients) Diltiazem: ER capsule: 120-180 mg qd (max dose 480 mg/day); ER tablet: 180-360 mg/day; IR tablet: 180-360 mg/day in divided doses Felodipine: 2.5-10 mg qd Nifedipine: IR capsule: 10-30 mg tid; SR tablet: 30-60 mg qd Verapamil: 240-480 mg/day in 3 to 4 divided doses (40 mg tid in elderly patients and those with small frames)	Bradycardia, hypotension, constipation, worsening of heart failure, peripheral edema, agent- specific events, prolongation of QT-interval (bepridil), AV-block (verapamil, diltiazem), excessive heart rate elevation (nifedipine)	DHP: hypersensitivity Non-DHP: acute MI with pulmonary congestion, Wolf Parkinson-White syndrome, AV block, hypersensitivity, symptomatic hypotension, sick sinus syndrome, cardiogenic shock, heart failure (verapamil)
Nitrates	Vasodilation of peripheral veins and arteries, thus decreasing myocardial oxygen demand through a reductionin preload	Treatment of angina in patients without compelling indications for other antianginal therapies, or as adjunct therapy	Isosorbide dinitrate: Oral (IR): 5-40 mg 4 times/day; Oral (SR): 40 mg every 8-12 h; Sublingual: 2.5-5 mg every 5-10 min (max 3 doses in 15-30 min), can also be used as prophylaxis 15 min prior to activities that provoke angina Isosorbide mononitrate: Regular tablet: 5-20 mg bid, with at least 12 h separating doses; ER tablet: initiate therapy at 30-60 mg as a single dose in the morning, then titrate upward every 3 days as needed to max daily single dose of 240 mg Translingual spray: 0.4 mg/spray, q5 min (max 3 doses in 15 min)	Headache, dizziness, hypotension	Hypersensitivity to nitrates, concurrent use of PDEs (sildenafil, tadalafil, vardenafil), increased intracranial pressure, symptomatic hypotension
Ranolazine	Mechanism of action not clear; possible shift in the production of ATP away from oxidation of fatty acids, thus favoring the more oxygen-efficient oxidation of carbohydrates	Combination therapy with amlodipine, nitrates, or beta-blockers in patients not well controlled with monotherapy on these agents	Initiate at 500 mg bid; titrate up to max dose of 1,000 mg bid	Dizziness, headache, constipation, nausea	Severe hepatic dys- function, concurrent use of QT-interval-prolonging agents or preexisting QT interval prolongation at baseline, concurrent therapy with CYP3A
AV: atrioventricular; ER: extended-release; max: maximum; IR: immediate-release: SR: sustained-release; DHP: dihydropyridine; MI: myocardial infarction; PDEs: phosphodiesterase inhibitors; ATP: adenosine triphosphate. Source: References 3, 6.

MARISA: The MARISA trial was the first placebo-controlled trial to examine ranolazine SR as monotherapy in patients with chronic angina. All subjects had at least a three-month history of exertional angina that was responsive to beta-blockers, CCBs, and/or long-acting nitrates. The primary end point of the trial was total exercise duration at trough of ranolazine plasma concentrations. The authors concluded that doses of 500 to 1,500 mg of ranolazine improved exercise performance significantly and delayed or prevented the ECG evidence and symptoms of myocardial ischemia (during exercise tests of patients with CSA). These effects occurred with minimal or no effects on heart rate and blood pressure.²²

CARISA: The CARISA trial was a double-blind, three-group parallel trial designed to assess the antianginal and anti-ischemic effects of ranolazine in patients with anginal symptoms despite standard treatment with atenolol, diltiazem, or amlodipine. The primary end point of the trial was to compare the effects of placebo versus ranolazine with regard to exercise duration when ranolazine levels were at a trough (i.e., 12 hours after administration of the dose). Subjects discontinued all antianginal drugs except those required for background therapy (atenolol, amlodipine, or diltiazem), and the subjects were randomized to receive ranolazine or placebo. The trial met the primary end point, as the duration of exercise in those patients taking ranolazine was increased over placebo.²³

ERICA: The ERICA trial was a prospective, randomized, double-blind trial of patients experiencing three or more anginal attacks per week despite maximal therapy with amlodipine. Frequency of angina episodes during the six-week treatment period was the primary end point; efficacy was assessed by the consumption of nitroglycerin per week and the Seattle Angina Questionnaire. The results of the trial displayed a significant reduction in the frequency of angina episodes and consumption of nitroglycerin in the ranolazine group. Patients who experienced more frequent angina displayed a more profound treatment effect.²⁵

MERLIN-TIMI 36: The MERLIN-TIMI 36 trial was a randomized, controlled trial of hospitalized patients with non-ST elevation acute coronary syndrome. The primary objective of the study was to evaluate the effect of ranolazine (compared to placebo) on the composite of recurrent ischemic events or cardiovascular death; ECG measurements were used to assess the incidence of clinically significant arrhythmias. The results of the MERLIN-TIMI 36 trial failed to meet the primary end point. However, ranolazine did demonstrate non-significant decrease in the incidence of sudden cardiac death when compared to placebo. Of note, treatment with ranolazine also appeared to have some antiar-rhythmic properties, reducing events seen on ambulatory monitoring. While these results demonstrate that ranolazine does not reduce clinical events, they do suggest that ranolazine appears to be safe and effective when used as long-term antianginal therapy, and that it may have some antiarrhythmic effects. Further studies are required to examine the future of ranolazine as an antiarrhythmic agent.²⁴

Nonpharmacologic Management

Although aggressive medical management and invasive intervention are indicated to treat CSA, significant lifestyle modifications should also be encouraged to avoid MI and worsening of disease. Many such interventions revolve around controlling known risk factors for cardiovascular disease and include smoking cessation, increasing physical activity, and involvement in a weight-management program to reduce obesity. Beyond these basic lifestyle modifications, several nonpharmacologic strategies aimed at the improvement of angina symptoms are available, including exercise training, surgical revascularization, enhanced external counterpulsation (EECP), and surgical laser transmyocardial revascularization (TMR).

Exercise training or cardiac rehabilitation has shown remarkable efficacy in increasing exercise tolerance,^26,27 with more limited data showing improvement in symptomatology.^26,28 Several studies have also shown decreases in objective measures of ischemia, such as ST-segment depression and myocardial perfusion imaging.^26,28

While there are only limited data linking exercise programs to improvement in disease progression and patho-physiology, exercise programs likely benefit the patient, and many practitioners believe that these programs also entitle the patient to an improved sense of well-being. In addition, exercise has been positively associated with improved control of known cardiovascular risk factors such as hypertension, hyperlipidemia, and diabetes, and thus should be enthusiastically recommended to all patients with CSA.

Two well-established forms of coronary revascularization exist—coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). Coronary bypass surgery involves a median sternotomy and surgical grafting of the coronary arteries, whereas PCI is primarily performed via balloon angioplasty and coronary stent placement.

For the most part, PCI has emerged as the nonpharmacologic treatment of choice for CSA due to its relative simplicity and decreased recovery time for the patient when compared to CABG. However, CABG is still preferred for patients with difficult coronary anatomy, as well as for those with high-risk features such as multivessel coronary disease, left main disease, or decreased left ventricular ejection fraction.⁵ PCI is also not completely without long-term complications, as coronary stent restenosis and now stent thrombosis with drug-eluting stents have been problematic to manage. PCI has been compared to CABG in multiple studies, the results of which have been mixed and serve to define which subgroups of patients should receive one therapy over the other.^24,25 It should also be noted that PCI has recently been shown not to offer a survival advantage to patients receiving the procedure when compared with aggressive medical management.²⁹ However, many patients crossed over into the PCI group by the end of the follow-up period, implying more frequent treatment failure with patients receiving aggressive medical therapy. While the long-term impact of this study and its effect on consensus-based guidelines remains to be seen, it seems reasonable that PCI could be deferred or omitted if a patient responds to aggressive antianginal medication therapy.

Several alternative nonpharmacologic methods for relieving angina are also recommended by ACC/AHA guidelines, although primarily for refractory disease.⁵ EECP is a technique using cuffs to compress a patient’s lower extremities during diastole, thereby forcing vascular counterpulsation and increasing coronary artery blood flow. This procedure has been evaluated in a placebo-controlled trial in which patients were randomized to receive EECP (35 hours) versus inactive EECP over a four- to seven-week period. The results of the study demonstrated that EECP reduced angina frequency and increased exercise time when compared with placebo.³⁰ EECP has also been analyzed in the International EECP Patient Registry in comparison with patients undergoing surgical revascularization (i.e., PCI or CABG), showing decreased frequency of angina, MI, and hospitalizations at six months.³¹

TMR is an advanced surgical technique for patients with refractory angina. It can be performed percutaneously or via surgical creation of transmural endomyocardial channels designed to improve myocardial circulation. In general, these techniques have been shown to offer short-term relief of angina symptoms, but few data exist describing long-term outcomes of the procedures.^32,33

Conclusion

According to the ACC/AHA updated guidelines for the management of adult patients with CSA, the central treatments continue to include beta-blockers, calcium channel blockers, and nitrates. However, since the release of these guidelines in 2002, ranolazine has received FDA approval as another potential treatment option in patients not receiving adequate control of anginal symptoms on standard therapy, although it is not currently considered a first-line treatment option.

Several factors should be considered when selecting therapy for a patient newly diagnosed with stable angina, including other comorbid conditions, concurrent medication use, and the cost of therapy. Ranolazine is currently only available as a brand name product; therefore, monotherapy may be significantly more expensive than combination therapy with generic options from the other therapeutic classes (i.e., beta-blockers, calcium channel blockers, and nitrates). In terms of improvement of anginal symptomatology, few data purport superiority of one medication over another. However, given the fact that angina suggests active CAD and increased risk of MI, beta-blockers should be considered the monotherapeutic treatment of choice. Other agents may be considered in lieu of, or in combination with, beta-blockers, but offer no survival advantage.

Nonpharmacologic therapies remain a cornerstone in the treatment of CSA. While PCI is likely the overall treatment of choice for uncomplicated coronary disease, there is no survival benefit offered to patients receiving the procedure. Advanced therapies are available for refractory disease, but few long-term data exist. Overall, aggressive pharmacotherapeutic management of the patient with CSA remains critically important for first-line stabilization of CAD.

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