Volume
121
Number
3,
Part
Hemodynamics
2
sive technique and observed vasodilati,on not only of small arteries but also of large arteries. Could you extrapolate this observation to explain what is happening in the coronary arteries, because we have found that blood flow also increases? Dr. Frohlich. One thing I have learned about organ circulations is that extrapolations about what hap-
of
vasodilatory
P-blockers
pens in the forearm circulation, the kidney, the splanchnic, coronary, or any other circulation cannot be done. Each organ’s circulation must be measured. In the coronary circulation, even the distribution within the myocardium and the coronary reserve may vary, so I should not want to draw the conclusion you suggest.
Angina, ischemia, and effort tolerance vasodilating ,&blockers
with
@-Blockers are known to suppress exercise-induced ischemia but give rise to such problems as fatigue or dyspnea on effort and also bradycardia. In a series of double-blind, placebo-controlled studies of celiprolol (a cardioselective .B,-blocker with &-agonist and vasodilatory properties) in patients with hypertension and angina and in normal volunteers, it was found that celiprolol did not produce bradycardia when given in combination with verapamil. Celiprolol did reduce exercise-induced ischemia, but there was no reduction in cardiac output at rest or on exercise compared with placebo. Compared with atenolol, celiprolol produced less dyspnea and fatigue at submaximal levels of exercise. It is concluded that celiprolol possesses certain differences, compared with conventional j3-blockers, that may be of direct clinical benefit (AM HEART J 1991;121:1017-20.)
Henry J. Dargie, FRCP,
FESC, S. Grant, MSc, and J. McLenachan,
MRCP
Glasgow, Scotland
In patients with angina, the demonstration of reversible myocardial ischemia imposes a high risk of subsequent cardiac events, including death.l With the development of ambulatory monitoring, knowledge of the pattern of ischemia has improved dramatically, and it is now well established that patients may experience episodes of ischemia but no pain (i.e., “silent ischemia”).2,3 Despite this, the main therapeutic target in clinical practice is still amelioration of chest pain, and although there is also general agreement that suppression of both painful and silent ischemia From the Department of Cardiology, Western Infirmary, and the Department of Physical Education & Sports Science, University of Glasgow. Reprint requests: H.J. Dargie, FRCP, FESC, Department of Cardiology, Western Infirmary, Dumbarton Road, Glasgow Cl1 6NT, United Kingdom. 410126474
is desirable, the long-term effect of this suppression on prognosis is unknown. Ischemia occurs when there is an imbalance between myocardial oxygen demand (which is determined by various factors such as heart rate, blood pressure, and wall tension) and coronary blood flow. Any drug that reduces myocardial oxygen demand is potentially beneficial to a patient with coronary disease. The drugs that are most effective in reducing myocardial oxygen demand are the ,&blockers and nitrates. The probable mechanism of action of calcium antagonists is a combination of coronary and peripheral vasodilation leading to a reduction in myocardial oxygen demand and, in some patients, an increase in coronary flow. Nitrates are also effective in some patients by increasing coronary perfusion.4 The @-blockers are firmly established as being able to
1017
1018
Dargie, Grant, and McLenachan Oxygen consumption (ml/kg per min)
Respiratory exchange
Minute ventilation (Vmin)
60
90
x5
so
80 ‘:‘:, _’ I.:,
40
30
70 65
1
7-o q Placebo **p
:_ .::: .C.’ . :.:s :,. ::. ~:I. 1,s.
t3 Celiprolol
60 n Atenolol
0.01
Fig. 1. Effect of therapy with celiprolol or atenolol compared with placebo on oxygen consumption, respiratory exchange quotient, and minute ventilation in trained athletes undergoing 6 minutes of exercise at 70”;# maximum oxygen consumption.
exercise-induced ischemia, but there remain a number of problems with their use. These include symptoms of fatigue or dyspnea on effort and excessive bradycardia. Drugs such as celiprolol, therefore, that possess a vasodilatory capacity as well as a selective j31-blocking action, have a potentially useful application.
suppress
PATIENT
STUDIES
The mechanism(s) of ischemia seen during ambulatory monitoring remains controversial,5, 6 although recent evidence confirms the importance of an increase in heart rate preceding the ischemic event.’ Even in the same patient, however, the heart rate at the onset of ischemia can vary. P-Blockers seem more effective in suppressing those episodes occurring at higher heart rates whereas vasodilating agents such as the nitrates may be more effective in suppressing episodes occurring at lower heart rates in which a reduction in coronary flow may be more important.8 Combinations of P-blockers and coronary vasodilating agents are, therefore, theoretically attractive and, in the case of calcium antagonists, increased efficacy in reducing the total ischemic burden has been demonstrated.Y
There are important pharmacodynamic reasons why all such combinations are not equally appropriate. For example, the heart rate-limiting calcium antagonists, verapamil and diltiazem, potentially could cause excessive bradycardia and atrioventricular conduction problems in combination with conventional P-blockers. When verapamil was combined with atenolol or celiprolol in a double-blind study in hypertensive patients, the resting heart rates were 56.3 -t 7.3 and 67 + 6.8 beats/min, respectively, indicating that celiprolol may be a more appropriate pblocker to combine with the heart rate-limiting calcium antagonists.lO EXERCISE
STUDIES
In a double-blind crossover study in which atenolol, celiprolol, and placebo were compared, each drug was equally effective in suppressing angina1 episodes. There was, however, no significant improvement in the total exercise capacity of the patients receiving either atenolol or celiprolol, although there was a marked extension of the time to the appearance of 1 mm ST segment depression. Double product at the onset of ischemia was significantly higher with celiprolol as compared with atenolol.ll During this study,
“Ol”nw
121
Number
3,
Part
Etfort angina
2
Dyspnea
Fatigue
60
60
.;~ 270 ‘p < 0.05
“p < 0.01
10 19
Length
of exercise
0
450
90
(s) 0 Placebo
270 Length
q Celiprolol
450 (s)
m Atenolol
Fig. 2. Effect of therapy with celiprolol or atenolol compared with placebo pnea and fatigue in trained athletes undergoing exercise at 70% maximum
cardiac output was also measured using first-pass radionuclide ventriculography. Compared with placebo-treated patients, those given atenolol showed a decrease in cardiac output both at rest and during exercise, whereas patients treated with celiprolol displayed no reduction in cardiac output at rest or during exercise. In order to investigate the effect of celiprolol on exercise capacity, a study was undertaken in which trained athletes were used. The use of athletes meant that their performance on exercise would be reproducible, which was not always the case when cardiac patients were studied. Celiprolol, in common with other ,&blockers, reduced the exercise time and the maximum exercise capacity. Not many people, however, exercise at maximum capacity, and a submaximal level of exercise was chosen-6 minutes at 70 % of the maximum oxygen consumption. During submaximal exercise, the same level of oxygen consumption was reached with celiprolol, atenolol, and placebo. In the case of atenolol, there was an increase in the minute ventilation, whereas with celiprolol there was no such increase when compared with placebo (Fig. 1). In addition to these measurements, the subjects recorded whether or not they felt breathless or fatigued using a visual analog scale. The athletes reported a greater subjective feeling of dyspnea when
of exercise
on subjective feelings of dysoxygen consumption.
receiving atenolol than when receiving celiprolol, particularly at lower levels of exercise. In the subjective assessment of fatigue, there was a greater feeling of fatigue at lower levels of exercise in the atenololtreated rather than the celiprolol-treated subjects (Fig. 2). By contrast, the same observation was not made at higher levels of exercise. This finding may nevertheless have an implication for the treatment of cardiac patients who do not exercise to high levels. CONCLUSIONS
Celiprolol has been shown to possess properties that are different from conventional &blockers and which may be of potential clinical benefit. With the development of flow measurements across individual vessels, it should be possible to determine with greater certainty whether or not a drug has a direct vasodilatory effect on a stenosed artery. This can then be related to the incidence of angina or silent ischemia and, in turn, it may be possible to gain a greater understanding of underlying pathologic processes. At present too little is known about the pathologic mechanisms associated with the subsequent development of unstable angina, myocardial infarction, and sudden death in patients with chronic stable angina and of the effect on these sequelae of agents used for its treatment. Although there have been many
Dar&e,
Grant, and McLenachan
American
studies on the effect of antihypertensive therapy on coronary events, there have been very few investigations on the impact of treatment of angina. Studies such as the TIBET study (Total Ischaemic Burden European Trial) on the impact of silent ischemia during ambulatory monitoring or exercise in patients undergoing symptomatically effective treatment for angina are awaited with interest. REFERENCES
1. Bonow RO, Kent KM, Rosing DR. Exercise-induced ischemia in mildly symptomatic patients with coronary artery disease and preserved left ventricular function. N Engl J Med 1984;311:1339. 2. Selwyn A, Fox K, Eves M, et al. Myocardial ischemia in patients with angina pectoris. Br Med J 1979;2:1594. 3. Lynch P, Dargie HJ, Krikler S, et al. Objective assessment of antianginal therapy: a double-blind comparison of nifedipine, propranolol and their combination. Br Med J 1980;280:184.
Efficacy patient
of celiprolol
March 1991 Heart Journal
4. Opie LH. In: Opie LH, ed. Drugs for the heart. New York: Grune and Stratton, 1987:l. 5. Quyyumi AA, Mockus L, Wright C, et al. Morphology of ambulatory ST segment changes in patients with varying severity of coronary artery disease. Br Heart J 1985;53:186. 6. Chierchia S, Smith G, Morgan M, et al. Role of heart rate in pathophysiology of chronic stable angina. Lancet 1984;2:1353. 7. McLenachan JM, Weidinger EF, Barry J, et al. Relationship between heart rate and myocardial ischemia during daily life (abstract). Eur Heart J 1989;10:30. 8. McLenachan JM, Weidinger EF, Barry J, et al. Relationships between heart rate, ischemia and drug therapy during daily life in patients with coronary artery disease (abstract). J Am Co11 Cardiol 1990;15:107A. 9. Dargie HJ, Lynch PG, Krikler D, et al. Nifedipine and propranolol: a beneficial drug interaction. Am J Med i98i;71:676. 10. McInnes GT, McLenachan JM, Henderson E, et al. Celiprolol and veranamil in the treatment of essential hypertension. AM HEART J-1988;116:1437. 11. McLenachan JM, Wilson JT, Dargie HJ. Importance of ancillary properties of beta blockers in angina: a study of celiprolol and atenolol. Br Heart J 1988;59:685.
in the elderly
hypertensive
With the rapidly increasing average age of the population of the Western world, care and treatment of the elderly are becoming increasingly important. Cardiovascular diseases are major causes of death and disability in the elderly; hence, identlflcation of cardiovascular risk factors and effective treatment are essential. Evidence indicates that these risk factors in the elderly are similar to those in the young; namely, high blood pressure, hyperliptdemia, glucose intolerance, hyperffbrinogenemia, obesity, and cigarette smoking. The latter two relate to general patient management, whereas the remainder can be significantly influenced by modern drug therapy such as celtprolol. This drug is a third-generation highly selective /3,-adrenoceptor antagonist with &-agonist and vasodilatory activity giving a unique and advantageous pharmacologic profile for antihypertensive therapy with particular benefits for the elderly. The impact of therapy with celiprolol on the cardiovascular risk factors in the elderly hypertensive patient is reviewed. (AM HEART J 1991;121:1020-9.)
S. I-I. Taylor,
MD, PhD, FRCP Leeds, England
The elderly constitute the fastest growing population subgroup in the Western world. A 65year-old person can now be expected to live a further 17 years1 CarFrom ment
the University Department of Cardiovascular of Medical Cardiology, The General Infirmary.
Reprint requests: S. H. Taylor, MD, PhD, Cardiology, The General Infirmary, Leeds 4iW26475
1020
Studies and Depart-
FRCP Department LSl 3EX, United
of Medical Kingdom.
diovascular diseases, particularly stroke and coronary heart disease, are major causes of disability and mortality in the elderly, and account for 75% of deaths beyond the age of 75 years.2 The major underlying pathologic condition is atherosclerosis abetted by high blood pressure, diabetes, and other risk cofactors. Many epidemiologic studies now indicate that cardiovascular risk factors are as applicable in the elderly, at least up to the age of 85 years, as they
121
Number
3,
Part
Hemodynamics
2
sive technique and observed vasodilati,on not only of small arteries but also of large arteries. Could you extrapolate this observation to explain what is happening in the coronary arteries, because we have found that blood flow also increases? Dr. Frohlich. One thing I have learned about organ circulations is that extrapolations about what hap-
of
vasodilatory
P-blockers
pens in the forearm circulation, the kidney, the splanchnic, coronary, or any other circulation cannot be done. Each organ’s circulation must be measured. In the coronary circulation, even the distribution within the myocardium and the coronary reserve may vary, so I should not want to draw the conclusion you suggest.
Angina, ischemia, and effort tolerance vasodilating ,&blockers
with
@-Blockers are known to suppress exercise-induced ischemia but give rise to such problems as fatigue or dyspnea on effort and also bradycardia. In a series of double-blind, placebo-controlled studies of celiprolol (a cardioselective .B,-blocker with &-agonist and vasodilatory properties) in patients with hypertension and angina and in normal volunteers, it was found that celiprolol did not produce bradycardia when given in combination with verapamil. Celiprolol did reduce exercise-induced ischemia, but there was no reduction in cardiac output at rest or on exercise compared with placebo. Compared with atenolol, celiprolol produced less dyspnea and fatigue at submaximal levels of exercise. It is concluded that celiprolol possesses certain differences, compared with conventional j3-blockers, that may be of direct clinical benefit (AM HEART J 1991;121:1017-20.)
Henry J. Dargie, FRCP,
FESC, S. Grant, MSc, and J. McLenachan,
MRCP
Glasgow, Scotland
In patients with angina, the demonstration of reversible myocardial ischemia imposes a high risk of subsequent cardiac events, including death.l With the development of ambulatory monitoring, knowledge of the pattern of ischemia has improved dramatically, and it is now well established that patients may experience episodes of ischemia but no pain (i.e., “silent ischemia”).2,3 Despite this, the main therapeutic target in clinical practice is still amelioration of chest pain, and although there is also general agreement that suppression of both painful and silent ischemia From the Department of Cardiology, Western Infirmary, and the Department of Physical Education & Sports Science, University of Glasgow. Reprint requests: H.J. Dargie, FRCP, FESC, Department of Cardiology, Western Infirmary, Dumbarton Road, Glasgow Cl1 6NT, United Kingdom. 410126474
is desirable, the long-term effect of this suppression on prognosis is unknown. Ischemia occurs when there is an imbalance between myocardial oxygen demand (which is determined by various factors such as heart rate, blood pressure, and wall tension) and coronary blood flow. Any drug that reduces myocardial oxygen demand is potentially beneficial to a patient with coronary disease. The drugs that are most effective in reducing myocardial oxygen demand are the ,&blockers and nitrates. The probable mechanism of action of calcium antagonists is a combination of coronary and peripheral vasodilation leading to a reduction in myocardial oxygen demand and, in some patients, an increase in coronary flow. Nitrates are also effective in some patients by increasing coronary perfusion.4 The @-blockers are firmly established as being able to
1017
1018
Dargie, Grant, and McLenachan Oxygen consumption (ml/kg per min)
Respiratory exchange
Minute ventilation (Vmin)
60
90
x5
so
80 ‘:‘:, _’ I.:,
40
30
70 65
1
7-o q Placebo **p
:_ .::: .C.’ . :.:s :,. ::. ~:I. 1,s.
t3 Celiprolol
60 n Atenolol
0.01
Fig. 1. Effect of therapy with celiprolol or atenolol compared with placebo on oxygen consumption, respiratory exchange quotient, and minute ventilation in trained athletes undergoing 6 minutes of exercise at 70”;# maximum oxygen consumption.
exercise-induced ischemia, but there remain a number of problems with their use. These include symptoms of fatigue or dyspnea on effort and excessive bradycardia. Drugs such as celiprolol, therefore, that possess a vasodilatory capacity as well as a selective j31-blocking action, have a potentially useful application.
suppress
PATIENT
STUDIES
The mechanism(s) of ischemia seen during ambulatory monitoring remains controversial,5, 6 although recent evidence confirms the importance of an increase in heart rate preceding the ischemic event.’ Even in the same patient, however, the heart rate at the onset of ischemia can vary. P-Blockers seem more effective in suppressing those episodes occurring at higher heart rates whereas vasodilating agents such as the nitrates may be more effective in suppressing episodes occurring at lower heart rates in which a reduction in coronary flow may be more important.8 Combinations of P-blockers and coronary vasodilating agents are, therefore, theoretically attractive and, in the case of calcium antagonists, increased efficacy in reducing the total ischemic burden has been demonstrated.Y
There are important pharmacodynamic reasons why all such combinations are not equally appropriate. For example, the heart rate-limiting calcium antagonists, verapamil and diltiazem, potentially could cause excessive bradycardia and atrioventricular conduction problems in combination with conventional P-blockers. When verapamil was combined with atenolol or celiprolol in a double-blind study in hypertensive patients, the resting heart rates were 56.3 -t 7.3 and 67 + 6.8 beats/min, respectively, indicating that celiprolol may be a more appropriate pblocker to combine with the heart rate-limiting calcium antagonists.lO EXERCISE
STUDIES
In a double-blind crossover study in which atenolol, celiprolol, and placebo were compared, each drug was equally effective in suppressing angina1 episodes. There was, however, no significant improvement in the total exercise capacity of the patients receiving either atenolol or celiprolol, although there was a marked extension of the time to the appearance of 1 mm ST segment depression. Double product at the onset of ischemia was significantly higher with celiprolol as compared with atenolol.ll During this study,
“Ol”nw
121
Number
3,
Part
Etfort angina
2
Dyspnea
Fatigue
60
60
.;~ 270 ‘p < 0.05
“p < 0.01
10 19
Length
of exercise
0
450
90
(s) 0 Placebo
270 Length
q Celiprolol
450 (s)
m Atenolol
Fig. 2. Effect of therapy with celiprolol or atenolol compared with placebo pnea and fatigue in trained athletes undergoing exercise at 70% maximum
cardiac output was also measured using first-pass radionuclide ventriculography. Compared with placebo-treated patients, those given atenolol showed a decrease in cardiac output both at rest and during exercise, whereas patients treated with celiprolol displayed no reduction in cardiac output at rest or during exercise. In order to investigate the effect of celiprolol on exercise capacity, a study was undertaken in which trained athletes were used. The use of athletes meant that their performance on exercise would be reproducible, which was not always the case when cardiac patients were studied. Celiprolol, in common with other ,&blockers, reduced the exercise time and the maximum exercise capacity. Not many people, however, exercise at maximum capacity, and a submaximal level of exercise was chosen-6 minutes at 70 % of the maximum oxygen consumption. During submaximal exercise, the same level of oxygen consumption was reached with celiprolol, atenolol, and placebo. In the case of atenolol, there was an increase in the minute ventilation, whereas with celiprolol there was no such increase when compared with placebo (Fig. 1). In addition to these measurements, the subjects recorded whether or not they felt breathless or fatigued using a visual analog scale. The athletes reported a greater subjective feeling of dyspnea when
of exercise
on subjective feelings of dysoxygen consumption.
receiving atenolol than when receiving celiprolol, particularly at lower levels of exercise. In the subjective assessment of fatigue, there was a greater feeling of fatigue at lower levels of exercise in the atenololtreated rather than the celiprolol-treated subjects (Fig. 2). By contrast, the same observation was not made at higher levels of exercise. This finding may nevertheless have an implication for the treatment of cardiac patients who do not exercise to high levels. CONCLUSIONS
Celiprolol has been shown to possess properties that are different from conventional &blockers and which may be of potential clinical benefit. With the development of flow measurements across individual vessels, it should be possible to determine with greater certainty whether or not a drug has a direct vasodilatory effect on a stenosed artery. This can then be related to the incidence of angina or silent ischemia and, in turn, it may be possible to gain a greater understanding of underlying pathologic processes. At present too little is known about the pathologic mechanisms associated with the subsequent development of unstable angina, myocardial infarction, and sudden death in patients with chronic stable angina and of the effect on these sequelae of agents used for its treatment. Although there have been many
Dar&e,
Grant, and McLenachan
American
studies on the effect of antihypertensive therapy on coronary events, there have been very few investigations on the impact of treatment of angina. Studies such as the TIBET study (Total Ischaemic Burden European Trial) on the impact of silent ischemia during ambulatory monitoring or exercise in patients undergoing symptomatically effective treatment for angina are awaited with interest. REFERENCES
1. Bonow RO, Kent KM, Rosing DR. Exercise-induced ischemia in mildly symptomatic patients with coronary artery disease and preserved left ventricular function. N Engl J Med 1984;311:1339. 2. Selwyn A, Fox K, Eves M, et al. Myocardial ischemia in patients with angina pectoris. Br Med J 1979;2:1594. 3. Lynch P, Dargie HJ, Krikler S, et al. Objective assessment of antianginal therapy: a double-blind comparison of nifedipine, propranolol and their combination. Br Med J 1980;280:184.
Efficacy patient
of celiprolol
March 1991 Heart Journal
4. Opie LH. In: Opie LH, ed. Drugs for the heart. New York: Grune and Stratton, 1987:l. 5. Quyyumi AA, Mockus L, Wright C, et al. Morphology of ambulatory ST segment changes in patients with varying severity of coronary artery disease. Br Heart J 1985;53:186. 6. Chierchia S, Smith G, Morgan M, et al. Role of heart rate in pathophysiology of chronic stable angina. Lancet 1984;2:1353. 7. McLenachan JM, Weidinger EF, Barry J, et al. Relationship between heart rate and myocardial ischemia during daily life (abstract). Eur Heart J 1989;10:30. 8. McLenachan JM, Weidinger EF, Barry J, et al. Relationships between heart rate, ischemia and drug therapy during daily life in patients with coronary artery disease (abstract). J Am Co11 Cardiol 1990;15:107A. 9. Dargie HJ, Lynch PG, Krikler D, et al. Nifedipine and propranolol: a beneficial drug interaction. Am J Med i98i;71:676. 10. McInnes GT, McLenachan JM, Henderson E, et al. Celiprolol and veranamil in the treatment of essential hypertension. AM HEART J-1988;116:1437. 11. McLenachan JM, Wilson JT, Dargie HJ. Importance of ancillary properties of beta blockers in angina: a study of celiprolol and atenolol. Br Heart J 1988;59:685.
in the elderly
hypertensive
With the rapidly increasing average age of the population of the Western world, care and treatment of the elderly are becoming increasingly important. Cardiovascular diseases are major causes of death and disability in the elderly; hence, identlflcation of cardiovascular risk factors and effective treatment are essential. Evidence indicates that these risk factors in the elderly are similar to those in the young; namely, high blood pressure, hyperliptdemia, glucose intolerance, hyperffbrinogenemia, obesity, and cigarette smoking. The latter two relate to general patient management, whereas the remainder can be significantly influenced by modern drug therapy such as celtprolol. This drug is a third-generation highly selective /3,-adrenoceptor antagonist with &-agonist and vasodilatory activity giving a unique and advantageous pharmacologic profile for antihypertensive therapy with particular benefits for the elderly. The impact of therapy with celiprolol on the cardiovascular risk factors in the elderly hypertensive patient is reviewed. (AM HEART J 1991;121:1020-9.)
S. I-I. Taylor,
MD, PhD, FRCP Leeds, England
The elderly constitute the fastest growing population subgroup in the Western world. A 65year-old person can now be expected to live a further 17 years1 CarFrom ment
the University Department of Cardiovascular of Medical Cardiology, The General Infirmary.
Reprint requests: S. H. Taylor, MD, PhD, Cardiology, The General Infirmary, Leeds 4iW26475
1020
Studies and Depart-
FRCP Department LSl 3EX, United
of Medical Kingdom.
diovascular diseases, particularly stroke and coronary heart disease, are major causes of disability and mortality in the elderly, and account for 75% of deaths beyond the age of 75 years.2 The major underlying pathologic condition is atherosclerosis abetted by high blood pressure, diabetes, and other risk cofactors. Many epidemiologic studies now indicate that cardiovascular risk factors are as applicable in the elderly, at least up to the age of 85 years, as they
