Treatment of Chronic Stable Angina Pectoris Richard Gorlin,
htlents with anglna pectorls may be stratMed Into low- or high-risk categories on the bask of cllnkal findim and a careful workup, po&bly Indudhtg nuclear hnagl@ of stress-induced abwntractllepattemsandcornormal perfwkn or onary angkgraphy. High-risk patlents may require revascularlzatlon by angloplesty or bypass surgery, whereas low-risk patientecan be managed medkally. lt ls Important to cons&&r the impact of various anti-kchemk drugs on the myocardlal demand-supply equatlon. A recent study lndkated that the combhmtlon of a f3 blocker plus lsosorblde mononltrate ls more effectlve In lncreasl~ exercise duration than ls eltber the combhmtlon of a f3 blocker and a calcium antagonlst or triple therapy. In patients wtth single-vesseldisease,angloplastyhasbeen shown to be more effective than medkal therapy In relievl~ symptoms, but the hnMence of restenosis and the associated costs are hlgh. Surgery favorably affects mortality in patknts with left main coronary artery disease or 3-vessel disease with left ventrkular impahment. New evledothellal dysfunction may dencesuggeststhat play a more important role In chronk stable anglna pectorls than has been appreciated and that such dysfunction may be treatedwlth nftrates. (Am J Cardiol1992;70:266i31G)
MD
T
he key to therapeutic decision-making in chronic stable angina pectoris is risk stratification (Figure 1). Management begins with identification of factors that may precipitate or exacerbate myocardial ischemia by increasing myocardial oxygen demand, including, but not limited to, obesity, smoking, hypertension, anemia, and thyrotoxicosis. The presence or absence on noninvasivetesting of such signsas ST-T changes at a low level of exercise, inappropriate blood pressureheart rate responses to exercise, large or multiple transient perfusion deficits, or left ventricular (LV) dysfunction helps to distinguish low-risk patients, who should most often receive medical therapy, from high-risk patients, who should undergo coronary angiography. Coronary angiography permits delineation of the subset of patients who are candidates for revascularization by percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting. In the absence of such high-risk angiographic findings as left main coronary artery disease (CAD) or 3-vessel disease (especially with LV dysfunction), a trial of medical therapy is indicated. As shown in the algorithm in Figure 1, if medical treatment fails or is not tolerated, revascularization must be considered; conversely, if the patient becomes symptomatic following revascularization, medical therapy again becomes an option. MEDICAL THERAPY
From the Department of Medicine, The Mount Sinai Medical Center, New York, New York. Dr. Gorlin is currently the Dr. George Baehr Professor of Clinical Medicine and Senior Vice President for Ambulatory Care Programs at The Mount Sinai Medical Center. Address for reprints: Richard Gorlin, MD, Box 1018, the Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, NY 10029. 26G
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
An imbalance between myocardial energy demands and coronary flow will give rise to the metabolic, electrophysiologic, and mechanical aberrations that culminate in ischemia. When selecting a therapeutic intervention for the patient with angina, a key consideration is how that intervention will affect the determinants of demand (cardiac contractility, heart rate, and wall stress) on the one hand and the determinants of supply (perfusion pressure and coronary vascular resistance) on the other. Mechanisms of actlen: Nitrates, p blockers, and calcium antagonists represent the cornerstone of medical therapy for angina pectoris. The nitrates are unique as vasodilators in that they not NOVEMBER 27, 1992
only dilate the arteries and arterioles, but also selectively induce venous dilation. The effects on large arteries are most profound in the coronary vessels, especially at sites of stenosis. Nitrates decrease myocardial oxygen demand primarily by diminishing preload. In addition, nitrates exert mild secondary effects on contractility and heart rate via stimulation of the sympathetic nervous system, concomitant with a fall in blood pressure. Beta blockers act by reducing contractility, heart rate, and blood pressure, particularly in response to any sympathetically modulated stress, and to some extent by redistributing blood flow across the myocardial wall. Calcium antagonists exert a profound vasodilatory effect on both peripheral and coronary resistance vessels and, in the process, reduce afterload. Optim&ing therapy: Successful antianginal therapy depends on objective measurement of drug activity, coupled with selection of a dose, route of administration, and dosing interval that will maximize efficacy and patient convenience and minimize adverse effects and tolerance. With nitrates, for example, measuring the patient’s blood pressure should indicate whether adequate vasodilation has been achieved. However, attention to the dosing interval is particularly important to avoid the development of tolerance.
With l3 blockers, a decrease in heart rate is the simplest marker of drug activity. It is interesting to note that, during l3 blockade, cardiac output and heart rate do rise in response to exercise but usually to a level below that achieved without l.3 blockade.’ In patients who experience side effects with l3 blockade, the severity of the reaction must be weighed against the cardioprotective actions of these agents. Since the blood pressure response to calcium antagonists may be muted, recognition of activity can be difficult unless a patient was originally hypertensive or develops orthostatic hypotension. Dosing convenience had been a problem with these agents until recently, when many sustained release preparations became available. Combination therapy: Since some anti-ischemit agents may have complementary modes of action, combination therapy may be useful in relieving ischemia and pain. However, current strategies emphasize that double therapy is often as effective as triple therapy. In a recent double-blind crossover trial by Akhras and Jackson2 patients with stable angina pectoris were randomized to receive atenolol alone, ateno101plus nifedipine, atenolol plus isosorbide mononitrate, or all 3 drugs. The number of angina attacks and consumption of nitroglycerin were
+
q
PTCA CABG
LMCAD, 3VD .-* Decreased LVF
High risk to coronary angiography
Noninvasive i
ETT-Low level of exercise ST-T BP, HR response Large or multiple transient perfusion LVEF, asynergy
controlled -
Other
--)
Symptoms controlled -
+ Coronary angiography
+
Medic& therapy
Risk stratification Clinical ---I
Hypertension post Ml
ä
Success
*
Failure
Low risk to medical therapy
FIGURE l. AlgorRhm for therapwtk deu%om maldng In patlents wRh coronary artery disease. BP = blood pressure; CABQ=coronaryarteybypas,~~m=exerdbetderancete9t;HR=heartrate;LMCAD=leRmelnconnray artery dlseasq LVEF = left ventricular eJectton Ractlon; LVF = left wntrkular f&we; MI = myocardlal Infarctkn; PTCA = percutaneaus translumlnal coronary angloplaw, 3VD = 3-vessel disease. A SYMPOSIUM:
OPTIMIZING
ANTIANGINAL
THERAPY
270
comparable with all 4 regimens. The study’s only significant finding was a longer duration of exercise in patients who received the l3 blocker plus isosorbide mononitrate compared with patients taking the l3blocker alone or with the calcium antagonist. Triple therapy conferred no advantage with regard to either exercise testing or clinical effects. Our approach is to treat stable angina pectoris patients with combination therapy comprising a p blocker and a vasodilator. The l3 blocker is prescribed for its salutary hemodynamic and cardioprotective actions. A nitrate vasodilator is preferable, both for empirical reasons and because the nitrates cause release of nitric oxide, which enhances the impaired coronary vasodilator response seen in the presence of atherosclerosis.
angioplasty. The Veterans Affairs’ Angioplasty Compared to Medicine (ACME) study has just shown that PTCA is somewhat more effective in relieving angina and improving exercise performance in patients who have exercise-induced ischemia and > 70% stenosisof 1 epicardial artery.4 Six months after random assignment to angioplasty or medical therapy, 64% of the patients who underwent angioplasty were free of symptoms,compared with 46% of patients in the medical therapy group (Figure 2). PTCA increased the total duration of exercise by > 2 minutes, whereas medical therapy increased it by only 0.5 minute. Patients in the PTCA group were able to exercise significantly longer without developing angina than were medically treated patients. Moreover, patients who underwent angioplasty experienced 15 fewer angina attacks per month, compared with a decrease REVASCUlARKATlON If medical treatment is ineffective or is not of only 7 attacks per month in the medical therapy tolerated, revascularization by PTCA or bypass group. Myocardial infarction occurred in 5 patients assigned to PTCA and in 3 with medical therapy. grafting must be considered. PTCA was successful in only 80 of the However, Angloplasty: Although angioplasty allows revascularization to be achieved nonsurgically, a major patients. Two of these represent emergency bypass drawback is the high rate of restenosis following surgery, 16 represent repeat PTCA. PTCA also the procedure. Angioplasty is initially successfulin proved to be the more costly of the 2 treatment approximately 87% of patients. Within a year, approaches because of the need for emergency however, nearly a third of these patients will coronary artery bypass surgery and because of the require a second procedure, the success rate of incidence of repeat dilation following restenosis. which is closer to 70%. Thus, the overall outcome Employment status was not altered. Surgery: If an overall reduction in mortality is a is satisfactory in about 80% of patients 1 year after goal of management of coronary artery disease, angioplasty.3 Until recently, it was unclear whether patients then patients must be substratified before an approwith single-vesseldisease and stable angina pecto- priate therapy can be selected. For example, there ris benefited more from medical therapy or from is no doubt that surgery improves survival in
lzl
PTCA
q
Medical therapy nGuGE2.pelceageofpatlentr freeofanglnaeachlnonthaftw translumlnal corana Pw(pTcA)~-~theraw for shgle-vessel comnaty artery dbaseIntheVetemnsAffahs ACME Wal. Nuhers below bars are number of ~atkmts evaluZlbd.Base=basellll& @W-d*-NEnglJMed.‘)
0
105 107 99 104 Base
1
92 92 2
8996 3
81 85
78 78
4
5
96 102 6
Month
280
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
NOVEMBER 27, 1992
patients with left main CAD, where the obstruction jeopardizes virtually the entire left ventricle. It was shown almost 2 decades ago that 42-month survival is nearly 90% in surgically treated patients with left main disease but only 30% in their medically treated counterparts.5 The Coronary Artery Surgery Study (CASS), a randomized trial of 780 patients, demonstrated comparable 5-year survival rates with medical and surgical therapy in patients with stable ischemic heart disease. However, in patients with a subnormal ejection fraction (
htlents with anglna pectorls may be stratMed Into low- or high-risk categories on the bask of cllnkal findim and a careful workup, po&bly Indudhtg nuclear hnagl@ of stress-induced abwntractllepattemsandcornormal perfwkn or onary angkgraphy. High-risk patlents may require revascularlzatlon by angloplesty or bypass surgery, whereas low-risk patientecan be managed medkally. lt ls Important to cons&&r the impact of various anti-kchemk drugs on the myocardlal demand-supply equatlon. A recent study lndkated that the combhmtlon of a f3 blocker plus lsosorblde mononltrate ls more effectlve In lncreasl~ exercise duration than ls eltber the combhmtlon of a f3 blocker and a calcium antagonlst or triple therapy. In patients wtth single-vesseldisease,angloplastyhasbeen shown to be more effective than medkal therapy In relievl~ symptoms, but the hnMence of restenosis and the associated costs are hlgh. Surgery favorably affects mortality in patknts with left main coronary artery disease or 3-vessel disease with left ventrkular impahment. New evledothellal dysfunction may dencesuggeststhat play a more important role In chronk stable anglna pectorls than has been appreciated and that such dysfunction may be treatedwlth nftrates. (Am J Cardiol1992;70:266i31G)
MD
T
he key to therapeutic decision-making in chronic stable angina pectoris is risk stratification (Figure 1). Management begins with identification of factors that may precipitate or exacerbate myocardial ischemia by increasing myocardial oxygen demand, including, but not limited to, obesity, smoking, hypertension, anemia, and thyrotoxicosis. The presence or absence on noninvasivetesting of such signsas ST-T changes at a low level of exercise, inappropriate blood pressureheart rate responses to exercise, large or multiple transient perfusion deficits, or left ventricular (LV) dysfunction helps to distinguish low-risk patients, who should most often receive medical therapy, from high-risk patients, who should undergo coronary angiography. Coronary angiography permits delineation of the subset of patients who are candidates for revascularization by percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting. In the absence of such high-risk angiographic findings as left main coronary artery disease (CAD) or 3-vessel disease (especially with LV dysfunction), a trial of medical therapy is indicated. As shown in the algorithm in Figure 1, if medical treatment fails or is not tolerated, revascularization must be considered; conversely, if the patient becomes symptomatic following revascularization, medical therapy again becomes an option. MEDICAL THERAPY
From the Department of Medicine, The Mount Sinai Medical Center, New York, New York. Dr. Gorlin is currently the Dr. George Baehr Professor of Clinical Medicine and Senior Vice President for Ambulatory Care Programs at The Mount Sinai Medical Center. Address for reprints: Richard Gorlin, MD, Box 1018, the Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, NY 10029. 26G
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
An imbalance between myocardial energy demands and coronary flow will give rise to the metabolic, electrophysiologic, and mechanical aberrations that culminate in ischemia. When selecting a therapeutic intervention for the patient with angina, a key consideration is how that intervention will affect the determinants of demand (cardiac contractility, heart rate, and wall stress) on the one hand and the determinants of supply (perfusion pressure and coronary vascular resistance) on the other. Mechanisms of actlen: Nitrates, p blockers, and calcium antagonists represent the cornerstone of medical therapy for angina pectoris. The nitrates are unique as vasodilators in that they not NOVEMBER 27, 1992
only dilate the arteries and arterioles, but also selectively induce venous dilation. The effects on large arteries are most profound in the coronary vessels, especially at sites of stenosis. Nitrates decrease myocardial oxygen demand primarily by diminishing preload. In addition, nitrates exert mild secondary effects on contractility and heart rate via stimulation of the sympathetic nervous system, concomitant with a fall in blood pressure. Beta blockers act by reducing contractility, heart rate, and blood pressure, particularly in response to any sympathetically modulated stress, and to some extent by redistributing blood flow across the myocardial wall. Calcium antagonists exert a profound vasodilatory effect on both peripheral and coronary resistance vessels and, in the process, reduce afterload. Optim&ing therapy: Successful antianginal therapy depends on objective measurement of drug activity, coupled with selection of a dose, route of administration, and dosing interval that will maximize efficacy and patient convenience and minimize adverse effects and tolerance. With nitrates, for example, measuring the patient’s blood pressure should indicate whether adequate vasodilation has been achieved. However, attention to the dosing interval is particularly important to avoid the development of tolerance.
With l3 blockers, a decrease in heart rate is the simplest marker of drug activity. It is interesting to note that, during l3 blockade, cardiac output and heart rate do rise in response to exercise but usually to a level below that achieved without l.3 blockade.’ In patients who experience side effects with l3 blockade, the severity of the reaction must be weighed against the cardioprotective actions of these agents. Since the blood pressure response to calcium antagonists may be muted, recognition of activity can be difficult unless a patient was originally hypertensive or develops orthostatic hypotension. Dosing convenience had been a problem with these agents until recently, when many sustained release preparations became available. Combination therapy: Since some anti-ischemit agents may have complementary modes of action, combination therapy may be useful in relieving ischemia and pain. However, current strategies emphasize that double therapy is often as effective as triple therapy. In a recent double-blind crossover trial by Akhras and Jackson2 patients with stable angina pectoris were randomized to receive atenolol alone, ateno101plus nifedipine, atenolol plus isosorbide mononitrate, or all 3 drugs. The number of angina attacks and consumption of nitroglycerin were
+
q
PTCA CABG
LMCAD, 3VD .-* Decreased LVF
High risk to coronary angiography
Noninvasive i
ETT-Low level of exercise ST-T BP, HR response Large or multiple transient perfusion LVEF, asynergy
controlled -
Other
--)
Symptoms controlled -
+ Coronary angiography
+
Medic& therapy
Risk stratification Clinical ---I
Hypertension post Ml
ä
Success
*
Failure
Low risk to medical therapy
FIGURE l. AlgorRhm for therapwtk deu%om maldng In patlents wRh coronary artery disease. BP = blood pressure; CABQ=coronaryarteybypas,~~m=exerdbetderancete9t;HR=heartrate;LMCAD=leRmelnconnray artery dlseasq LVEF = left ventricular eJectton Ractlon; LVF = left wntrkular f&we; MI = myocardlal Infarctkn; PTCA = percutaneaus translumlnal coronary angloplaw, 3VD = 3-vessel disease. A SYMPOSIUM:
OPTIMIZING
ANTIANGINAL
THERAPY
270
comparable with all 4 regimens. The study’s only significant finding was a longer duration of exercise in patients who received the l3 blocker plus isosorbide mononitrate compared with patients taking the l3blocker alone or with the calcium antagonist. Triple therapy conferred no advantage with regard to either exercise testing or clinical effects. Our approach is to treat stable angina pectoris patients with combination therapy comprising a p blocker and a vasodilator. The l3 blocker is prescribed for its salutary hemodynamic and cardioprotective actions. A nitrate vasodilator is preferable, both for empirical reasons and because the nitrates cause release of nitric oxide, which enhances the impaired coronary vasodilator response seen in the presence of atherosclerosis.
angioplasty. The Veterans Affairs’ Angioplasty Compared to Medicine (ACME) study has just shown that PTCA is somewhat more effective in relieving angina and improving exercise performance in patients who have exercise-induced ischemia and > 70% stenosisof 1 epicardial artery.4 Six months after random assignment to angioplasty or medical therapy, 64% of the patients who underwent angioplasty were free of symptoms,compared with 46% of patients in the medical therapy group (Figure 2). PTCA increased the total duration of exercise by > 2 minutes, whereas medical therapy increased it by only 0.5 minute. Patients in the PTCA group were able to exercise significantly longer without developing angina than were medically treated patients. Moreover, patients who underwent angioplasty experienced 15 fewer angina attacks per month, compared with a decrease REVASCUlARKATlON If medical treatment is ineffective or is not of only 7 attacks per month in the medical therapy tolerated, revascularization by PTCA or bypass group. Myocardial infarction occurred in 5 patients assigned to PTCA and in 3 with medical therapy. grafting must be considered. PTCA was successful in only 80 of the However, Angloplasty: Although angioplasty allows revascularization to be achieved nonsurgically, a major patients. Two of these represent emergency bypass drawback is the high rate of restenosis following surgery, 16 represent repeat PTCA. PTCA also the procedure. Angioplasty is initially successfulin proved to be the more costly of the 2 treatment approximately 87% of patients. Within a year, approaches because of the need for emergency however, nearly a third of these patients will coronary artery bypass surgery and because of the require a second procedure, the success rate of incidence of repeat dilation following restenosis. which is closer to 70%. Thus, the overall outcome Employment status was not altered. Surgery: If an overall reduction in mortality is a is satisfactory in about 80% of patients 1 year after goal of management of coronary artery disease, angioplasty.3 Until recently, it was unclear whether patients then patients must be substratified before an approwith single-vesseldisease and stable angina pecto- priate therapy can be selected. For example, there ris benefited more from medical therapy or from is no doubt that surgery improves survival in
lzl
PTCA
q
Medical therapy nGuGE2.pelceageofpatlentr freeofanglnaeachlnonthaftw translumlnal corana Pw(pTcA)~-~theraw for shgle-vessel comnaty artery dbaseIntheVetemnsAffahs ACME Wal. Nuhers below bars are number of ~atkmts evaluZlbd.Base=basellll& @W-d*-NEnglJMed.‘)
0
105 107 99 104 Base
1
92 92 2
8996 3
81 85
78 78
4
5
96 102 6
Month
280
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70
NOVEMBER 27, 1992
patients with left main CAD, where the obstruction jeopardizes virtually the entire left ventricle. It was shown almost 2 decades ago that 42-month survival is nearly 90% in surgically treated patients with left main disease but only 30% in their medically treated counterparts.5 The Coronary Artery Surgery Study (CASS), a randomized trial of 780 patients, demonstrated comparable 5-year survival rates with medical and surgical therapy in patients with stable ischemic heart disease. However, in patients with a subnormal ejection fraction (
