REVIEW ARTICLE
Pharmacologic management of chronic stable angina Deepali Dixit, PharmD, BCPS; Katarzyna Kimborowicz, PharmD, BCPS
A i pectoris Angina i iis most commonly l caused db by a reduction d i in myocardial perfusion secondary to narrowing of coronary arteries. The condition typically is characterized by recurring deep chest pain radiating to the patient’s shoulder, neck, inner arm, or epigastrium. Angina is a common presenting symptom among patients with coronary artery disease. An estimated 10 million Americans have angina and about 500,000 new cases are diagnosed each year.1,2 Chronic stable angina is common in older adults, occurring in about 19% of women ages 70 to 84 years and nearly 25% of women age 85 years and older. About 27% of men age 70 years and older have chronic stable angina.3 Management of chronic stable angina involves cardiovascular risk reduction (including lifestyle modification, antiplatelet therapy, and statins), reduction of angina symptoms with antianginal medications, or coronary revascularization.4,5 In older adults, the goals may be less focused on prolonging survival and more tailored to improving and maintaining quality of life.6 Drugs available to reduce the severity and frequency of angina symptoms include beta-blockers, calcium channel Deepali Dixit is a clinical assistant professor in the Department of Pharmacy Practice and Administration at Rutgers, The State University of New Jersey, in Piscataway, N.J. Katarzyna Kimborowicz is a critical care specialist at Morristown (N.J.) Medical Center. The authors have disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000465223.98395.45 Copyright © 2015 American Academy of Physician Assistants
© DUVAL / BSIP
ABSTRACT Chronic stable angina is a significant problem in older adults. The goal of therapy is to provide symptomatic relief, improve patient quality of life, and prevent subsequent angina or myocardial infarction that could lead to sudden death. The efficacy and safety of drugs such as beta-blockers and calcium channel blockers for managing chronic stable angina in older adults has not been rigorously investigated. Drug selection should be based on physiologic alterations, patient comorbidities, adverse reaction profile, and cost. Keywords: chronic stable angina, older adults, beta-blockers, calcium channel blockers, antianginals, ranolazine
blockers, long-acting nitrates, and a late sodium channel blocker. These agents can be used as monotherapy or in combination. When pharmacotherapy fails to control angina symptoms, revascularization by either percutaneous coronary intervention or coronary artery bypass surgery is considered. Selecting the appropriate antianginal agent for an older patient can be complicated. Older adults are especially vulnerable to adverse drug reactions because of altered pharmacokinetics and pharmacodynamics related to aging and comorbidities. This population also has an increased sensitivity to drug effects; adults who take multiple
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2015 American Academy of Physician Assistants
www.JAAPA.com
REVIEW ARTICLE
Key points Chronic stable angina is a significant problem in older adults. The goal of therapy is to provide symptomatic relief, improve patient quality of life, and prevent subsequent angina or MI that could lead to sudden death. Beta-blockers and calcium channel blockers typically are used to manage chronic stable angina, but their safety and efficacy has not been rigorously investigated in older adults. The selection of which drug to use in an older adult should be based on patient physiologic alterations and comorbidities, and the drug’s adverse reaction profile and cost.
medications are at increased risk for drug-drug interactions.7-9 Prescribers should begin antianginal drugs with low doses and slowly titrate to target doses based on the patient’s clinical response.10,11 BETA-ADRENERGIC BLOCKERS The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend betablockers as first-line therapy for the treatment of chronic stable angina.4 The recommendation is based on the evidence of reduced patient mortality with beta-blockers in patients with systolic heart failure and in patients following myocardial infarction (MI).4,12,13 However, further clinical trials need to be conducted to determine the survival benefit of beta-blockers in patients with chronic stable angina without a prior history of MI or systolic heart failure.13,14 The effects of beta-blockers in the management of chronic stable angina have not been fully investigated in older adults. In most of the clinical trials, the number of older adults enrolled was not specified. Beta-blockers increase exercise tolerance and decrease the frequency and severity of anginal episodes.13 They exert their antianginal effects by reducing heart rate and myocardial contractility, which reduces myocardial oxygen demand. In addition, they increase coronary blood flow during diastole by increasing the diastolic filling period.14,15 All beta-blockers appear to be equally effective in treating chronic stable angina.14 Propranolol was the first nonselective beta-blocker used in patients with chronic stable angina. Small studies have shown that cardioselective beta-blockers (atenolol and metoprolol) are as effective as propranolol in reducing angina attacks and increasing exercise tolerance.16,17 When compared with placebo, atenolol was associated with significantly lower risk (25.3% versus 11.1%, P=0.001) of the composite endpoint of death, MI, aggravation of angina, hospitalization for unstable angina, or a need for revascularization during the 12-month follow-up period (Table 1).18 The results of this study suggest a beneficial effect of atenolol on the preven-
tion of cardiovascular events in patients with chronic stable angina. Beta-blockers generally are well tolerated in patients with chronic stable angina. Select the most appropriate agent based on the patient’s comorbid conditions, and the drug’s adverse reaction profile and cost. The most common adverse reactions include bradycardia, hypotension, depression, fatigue, and sexual dysfunction. Central nervous system adverse reactions such as lethargy, mood changes, sleep disturbances, and depression may occur in certain older adults taking beta-blockers. The dosage should be titrated to a goal resting heart rate of 55 to 60 beats/minute. Use beta-blockers cautiously in older adults with a high risk of symptomatic bradycardia, sick sinus syndrome, atrioventricular block, pulmonary disease, or recurrent hypoglycemia. CALCIUM CHANNEL BLOCKERS Nondihydropyridine (DHP) calcium channel blockers such as verapamil and diltiazem increase myocardial oxygen supply by decreasing heart rate, and are effective as antianginal agents (Table 1).19-24 DHP calcium channel blockers such as amlodipine and felodipine increase myocardial oxygen supply by dilating coronary arteries.24-31 Avoid short-acting DHP calcium channel blockers in patients with chronic stable angina. A meta-analysis suggested that in patients with coronary artery disease, highdose, short-acting nifedipine was associated with increased mortality due to reflex tachycardia.32 Second- and third-generation DHP calcium channel blockers, such as sustained-release nifedipine and amlodipine, are recommended as second-line therapy for patients with chronic stable angina when beta-blockers alone are ineffective or not tolerated; these calcium channel blockers can be used as first-line drugs if beta-blockers are contraindicated.4 A more recent trial also confirmed that sustained-release nifedipine reduced coronary events and patient need for revascularization and hospitalization for chronic stable angina.33 Several observational studies and a meta-analysis have demonstrated that long-acting calcium channel blockers are relatively safe when compared to other antianginal drugs such as beta-blockers.34-36 As with studies of beta-blockers, studies of calcium channel blockers did not indicate the number of older adults enrolled, and the mean age of patients in most of these studies was less than 65 years. In general, calcium channel blockers are considered safe and are well tolerated in older adults.10,11 The decision to use a beta-blocker or calcium channel blockers as a firstline drug depends on the patient’s comorbidities, contraindications, and potential adverse reactions. For example, a patient with systolic heart failure and a history of MI should be prescribed a beta-blocker for chronic stable angina rather than a calcium channel blocker. In contrast, patients with chronic stable angina and hypertension may
www.JAAPA.com
Volume 28 • Number 6 • June 2015
Copyright © 2015 American Academy of Physician Assistants
Pharmacologic management of chronic stable angina TABLE 1. Major
clinical trials on the use of beta-blockers, calcium channel blockers, or a combination in patients with chronic stable angina Primary outcomes
Study
Study type
Number of patients Treatment Study (mean age; number of duration patients ≥65 years)
Pepine and colleagues (ASIST)18
Randomized controlled trial, multicenter, double-blind
306 (64 years; 130 age ≥65 years)
12 months
atenolol 100 mg once daily or placebo
Composite endpoint of death, MI, aggravation of angina, hospitalization for unstable angina: 17 patients (11%) in atenolol group and 39 patients (25%) in placebo group (relative risk 0.44; 95% CI 0.26-0.75, P=0.001)
Ardissino and colleagues (IMAGE)28
Randomized controlled trial, multicenter, double-blind
280 (59 years; not reported)
6 weeks
metoprolol controlled release 200 mg once a day or nifedipine sustained release 20 mg twice a day
Both metoprolol and nifedipine increased time to 1-mm ST-segment depression over baseline; the improvement was greater in the patients receiving metoprolol (P
Pharmacologic management of chronic stable angina Deepali Dixit, PharmD, BCPS; Katarzyna Kimborowicz, PharmD, BCPS
A i pectoris Angina i iis most commonly l caused db by a reduction d i in myocardial perfusion secondary to narrowing of coronary arteries. The condition typically is characterized by recurring deep chest pain radiating to the patient’s shoulder, neck, inner arm, or epigastrium. Angina is a common presenting symptom among patients with coronary artery disease. An estimated 10 million Americans have angina and about 500,000 new cases are diagnosed each year.1,2 Chronic stable angina is common in older adults, occurring in about 19% of women ages 70 to 84 years and nearly 25% of women age 85 years and older. About 27% of men age 70 years and older have chronic stable angina.3 Management of chronic stable angina involves cardiovascular risk reduction (including lifestyle modification, antiplatelet therapy, and statins), reduction of angina symptoms with antianginal medications, or coronary revascularization.4,5 In older adults, the goals may be less focused on prolonging survival and more tailored to improving and maintaining quality of life.6 Drugs available to reduce the severity and frequency of angina symptoms include beta-blockers, calcium channel Deepali Dixit is a clinical assistant professor in the Department of Pharmacy Practice and Administration at Rutgers, The State University of New Jersey, in Piscataway, N.J. Katarzyna Kimborowicz is a critical care specialist at Morristown (N.J.) Medical Center. The authors have disclosed no potential conflicts of interest, financial or otherwise. DOI: 10.1097/01.JAA.0000465223.98395.45 Copyright © 2015 American Academy of Physician Assistants
© DUVAL / BSIP
ABSTRACT Chronic stable angina is a significant problem in older adults. The goal of therapy is to provide symptomatic relief, improve patient quality of life, and prevent subsequent angina or myocardial infarction that could lead to sudden death. The efficacy and safety of drugs such as beta-blockers and calcium channel blockers for managing chronic stable angina in older adults has not been rigorously investigated. Drug selection should be based on physiologic alterations, patient comorbidities, adverse reaction profile, and cost. Keywords: chronic stable angina, older adults, beta-blockers, calcium channel blockers, antianginals, ranolazine
blockers, long-acting nitrates, and a late sodium channel blocker. These agents can be used as monotherapy or in combination. When pharmacotherapy fails to control angina symptoms, revascularization by either percutaneous coronary intervention or coronary artery bypass surgery is considered. Selecting the appropriate antianginal agent for an older patient can be complicated. Older adults are especially vulnerable to adverse drug reactions because of altered pharmacokinetics and pharmacodynamics related to aging and comorbidities. This population also has an increased sensitivity to drug effects; adults who take multiple
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2015 American Academy of Physician Assistants
www.JAAPA.com
REVIEW ARTICLE
Key points Chronic stable angina is a significant problem in older adults. The goal of therapy is to provide symptomatic relief, improve patient quality of life, and prevent subsequent angina or MI that could lead to sudden death. Beta-blockers and calcium channel blockers typically are used to manage chronic stable angina, but their safety and efficacy has not been rigorously investigated in older adults. The selection of which drug to use in an older adult should be based on patient physiologic alterations and comorbidities, and the drug’s adverse reaction profile and cost.
medications are at increased risk for drug-drug interactions.7-9 Prescribers should begin antianginal drugs with low doses and slowly titrate to target doses based on the patient’s clinical response.10,11 BETA-ADRENERGIC BLOCKERS The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend betablockers as first-line therapy for the treatment of chronic stable angina.4 The recommendation is based on the evidence of reduced patient mortality with beta-blockers in patients with systolic heart failure and in patients following myocardial infarction (MI).4,12,13 However, further clinical trials need to be conducted to determine the survival benefit of beta-blockers in patients with chronic stable angina without a prior history of MI or systolic heart failure.13,14 The effects of beta-blockers in the management of chronic stable angina have not been fully investigated in older adults. In most of the clinical trials, the number of older adults enrolled was not specified. Beta-blockers increase exercise tolerance and decrease the frequency and severity of anginal episodes.13 They exert their antianginal effects by reducing heart rate and myocardial contractility, which reduces myocardial oxygen demand. In addition, they increase coronary blood flow during diastole by increasing the diastolic filling period.14,15 All beta-blockers appear to be equally effective in treating chronic stable angina.14 Propranolol was the first nonselective beta-blocker used in patients with chronic stable angina. Small studies have shown that cardioselective beta-blockers (atenolol and metoprolol) are as effective as propranolol in reducing angina attacks and increasing exercise tolerance.16,17 When compared with placebo, atenolol was associated with significantly lower risk (25.3% versus 11.1%, P=0.001) of the composite endpoint of death, MI, aggravation of angina, hospitalization for unstable angina, or a need for revascularization during the 12-month follow-up period (Table 1).18 The results of this study suggest a beneficial effect of atenolol on the preven-
tion of cardiovascular events in patients with chronic stable angina. Beta-blockers generally are well tolerated in patients with chronic stable angina. Select the most appropriate agent based on the patient’s comorbid conditions, and the drug’s adverse reaction profile and cost. The most common adverse reactions include bradycardia, hypotension, depression, fatigue, and sexual dysfunction. Central nervous system adverse reactions such as lethargy, mood changes, sleep disturbances, and depression may occur in certain older adults taking beta-blockers. The dosage should be titrated to a goal resting heart rate of 55 to 60 beats/minute. Use beta-blockers cautiously in older adults with a high risk of symptomatic bradycardia, sick sinus syndrome, atrioventricular block, pulmonary disease, or recurrent hypoglycemia. CALCIUM CHANNEL BLOCKERS Nondihydropyridine (DHP) calcium channel blockers such as verapamil and diltiazem increase myocardial oxygen supply by decreasing heart rate, and are effective as antianginal agents (Table 1).19-24 DHP calcium channel blockers such as amlodipine and felodipine increase myocardial oxygen supply by dilating coronary arteries.24-31 Avoid short-acting DHP calcium channel blockers in patients with chronic stable angina. A meta-analysis suggested that in patients with coronary artery disease, highdose, short-acting nifedipine was associated with increased mortality due to reflex tachycardia.32 Second- and third-generation DHP calcium channel blockers, such as sustained-release nifedipine and amlodipine, are recommended as second-line therapy for patients with chronic stable angina when beta-blockers alone are ineffective or not tolerated; these calcium channel blockers can be used as first-line drugs if beta-blockers are contraindicated.4 A more recent trial also confirmed that sustained-release nifedipine reduced coronary events and patient need for revascularization and hospitalization for chronic stable angina.33 Several observational studies and a meta-analysis have demonstrated that long-acting calcium channel blockers are relatively safe when compared to other antianginal drugs such as beta-blockers.34-36 As with studies of beta-blockers, studies of calcium channel blockers did not indicate the number of older adults enrolled, and the mean age of patients in most of these studies was less than 65 years. In general, calcium channel blockers are considered safe and are well tolerated in older adults.10,11 The decision to use a beta-blocker or calcium channel blockers as a firstline drug depends on the patient’s comorbidities, contraindications, and potential adverse reactions. For example, a patient with systolic heart failure and a history of MI should be prescribed a beta-blocker for chronic stable angina rather than a calcium channel blocker. In contrast, patients with chronic stable angina and hypertension may
www.JAAPA.com
Volume 28 • Number 6 • June 2015
Copyright © 2015 American Academy of Physician Assistants
Pharmacologic management of chronic stable angina TABLE 1. Major
clinical trials on the use of beta-blockers, calcium channel blockers, or a combination in patients with chronic stable angina Primary outcomes
Study
Study type
Number of patients Treatment Study (mean age; number of duration patients ≥65 years)
Pepine and colleagues (ASIST)18
Randomized controlled trial, multicenter, double-blind
306 (64 years; 130 age ≥65 years)
12 months
atenolol 100 mg once daily or placebo
Composite endpoint of death, MI, aggravation of angina, hospitalization for unstable angina: 17 patients (11%) in atenolol group and 39 patients (25%) in placebo group (relative risk 0.44; 95% CI 0.26-0.75, P=0.001)
Ardissino and colleagues (IMAGE)28
Randomized controlled trial, multicenter, double-blind
280 (59 years; not reported)
6 weeks
metoprolol controlled release 200 mg once a day or nifedipine sustained release 20 mg twice a day
Both metoprolol and nifedipine increased time to 1-mm ST-segment depression over baseline; the improvement was greater in the patients receiving metoprolol (P
