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Current Medical Research and Opinion
Vol. 12, No. 8, 1991
Atenolol and ischaemic heart disease: an overview
J. M. Cruickshank, D.M.(Oxon.), F.R.C.P.(London), and J. McAinsh,* B.Sc.. M.Sc., Ph.D. Cardiac Department, Whythenshawe Hospital, Manchester; and National Heart Hospital, London, and *Medical Affairs Department, ICI Pharmaceuticals, Imperial Chemical Industries plc. Alderley Park, Macclesfield, England
Curr. Med. Res. Opin., (1991), 12,485.
Received: 9th September 1991
Summary Data generated to date on the use of beta-blockers, especially atenolol, in ischaemic heart disease are reviewed and compared with the results available with the calcium antagonists. Atenolol appears to be effective as an anti-ischaemic agent inpatients with obstructive coronary artery disease when reduction in myocardial oxygen supply (ischaemia not preceded by an increase in heart rate and due presumably to functional coronary stenosis) or increase in demand are the likely causes. Based on current concepts and available data, there is convincing evidence to support the use of atenolol across the spectrum of ischaemic heart disease. In contrast, results with the calcium antagonists have been disappointing and variable. Atenolol, to date, is the only beta-blocker which has been demonstrated to have a life-saving benefit in acute intervention (within 12 hours of onset) in myocardial infarction. This cardioprotective aspect of the drug is likely to be applicable to other areas of ischaemic heart disease, including silent ischaemia. Key words: Atenolol - adrenergic beta receptor blockaders - calcium channel blockers - coronary disease - myocardial infarction - review
Introduction Ischaemic heart disease is the major cause of mortality in Western industrialized countries. It is usually caused by coronary atherosclerosis. The delicate balance of supply and demand of oxygen to the heart is thus disturbed by a relatively fixed coronary stenosis. Spontaneous coronary arterial spasm, which may give rise to variant or Prinmetal’s angina, is very rare. However, dynamic coronary stenosis related to changes in coronary artery tone or platelet aggregability is probably quite commonz5and occurs in the presence of fixed stenosis. Ischaemic episodes peak between 08.00 and 10.00 hours3* when sympathetic drive is maximal.39Interestingly, about 80%of ischaemic episodes occurring over 24 hours are silent in nature.44The silent episodes are accompanied by ischaemic haemodynamic changes4 and are associated with a poor p r o g n ~ s i s . The ’ ~ ~ sum ~~ of silent and painful episodes has been termed the ‘total ischaemic burden’. 485
Atenolol and ischaemic heart disease: an overview
Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
Rationale for beneficial beta-blocker effects upon myocardial ischaemia As predicted by Black in the late 1950s,beta-blockers benefit patients with angina by decreasing the work of the heart. The reduced cardiac work is achieved primarily through a decrease in heart rate and systolic blood pressure but also through a decreased velocity of cardiac contraction. Bradycardia also prolongs coronary diastolic filling time. The vulnerable sub-endocardial blood flow is benefited by internal shunting’ and a reduction in left ventricular end-diastolic pressure during ischaemia. All these changes invariably more than compensate for the potential increased left ventricular wall stresses caused by cardiac enlargement which accompanies bradycardia. Thus, myocardial oxygen consumption is reduced by more than 20%,accompanied by a change from lactate production to extraction3’ and an autoregulatory decrease in coronary blood The betal-receptor is the dominant beta-receptor in the heart. For the uncomplicated patient with ischaemic heart disease, beta-blocker properties other than beta,-blockade therefore are unnecessary.
Effects of atenolol in ischaemic heart disease Atenololt is a betal-adrenoceptor blocking drug with no membrane stabilizing or intrinsic sympathomimetic activities. It has a long record of efficacy and safety in patients with ischaemic heart disease. Stable angina In a study by Majid et atenolol at doses of 100 mg and 200 mg once daily was compared with placebo. The results showed that atenolol increased work done on exercise and caused a smaller reduction in ST-segmentdepression. A few years later, S ~ h w a r t confirmed z~~ these findings and concluded from the 12-month follow-up that atenolol (100 mg once daily) was an effective anti-anginal agent for long-term use because there was no evidence of tachyphylaxis. More recently, Findlay et al. l 2 confirmed that 100 mg atenolol daily was more efficacious than placebo in terms of angina attack rate and glyceryl trinitrate consumption. Additionally, atenolol has been shown to be more effective in treating angina than practol01~~ and pindolol,36 and to have similar efficacy to labetalo12’and propran~lol.’~ Findlay et ~ 1 . showed ’ ~ that there was a trend for atenolol to be more effective than the dihydropyridine calcium antagonist, nifedipine (20 mg 3-times daily). This latter finding has been confirmed in two recent s t ~ d i e s .In ~~ the , ~latter, ~ Shapiro et found that atenolol produced a significant additional reduction compared with nifedipine (10 to 30 mg 3-times daily) in rate-pressure product and a lesser reduction in ST-segment depression. There have been many randomized, double-blind,crossover studies with atenolol in stable angina. An overview of 23 placebo or glyceryl trinitrate controlled studies (Table I) shows that the normal clinical dose of atenolol reduces angina attack t’Tenormin‘. trade mark ICI
486
J. M. Cruickshank and J. McAinsh
rate by 53%,2,7-10.19,24,27,28,34,40-42.45.46,49and nitrate consumption by SOYo.2,7-10.19.24.27. 34,41,42,48 Exercise time to pain and improvement in ST-segment depression averaged 37702.7.8,23 and 40%,2,7,10,1 1,19.20,23.24.27.42respectively.
Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
Table I. Summary of results from 23 crossover studies with atenolol versus placebo or glyceryl trinitrate in 400 stable angina patients: average percentage changes with atenolol Assessment
Change
Anginal attack rate Nitrate consumption Exercise to pain time S-T segment depression
153% J, 50%
T37% 1‘40%
In view of these data, it is not surprising that, in his presentation at the 1989 symposium meeting in San Francisco on “Evolving Concepts in Ischaemic Heart Disease,” Y a m a g ~ c hconcluded i~~ that beta-blockers are the drugs of first choice for exercise-induced angina. Atenolol has been combined with other anti-anginal therapies to produce superior efficacy compared with monotherapy. In particular, atenolol has been combined with nitrates,34 nifedipine,12 felodipine,46 verapamil,26 and molsidomine.6
Mixed angina In mixed angina, a discomfort which occurs at rest and at night as well as with differing levels of exercise, patients have fixed atherosclerotic coronary disease with superimposed dynamic stenosis. In the past, there has been some doubt on the advisability of prescribing a beta-blocker for patients with an element of functional or dynamic stenosis. However, with the probable exception of the very rare Prinzmetal’s angina, clinical evidence supports the view that beta-blockade is a highly effective treatment for these patients. Quyyumi et al.37 compared atenolol (100 mg daily), nifedipine (10 to 20 mg 3-times daily) and isosorbide mononitrate (40 mg twice daily) in a randomized, double-blind, crossover trial in 9 patients with severe mixed angina. The results of this study showed that the duration of exercise to ischaemia during a standardized exercise test was significantly greater with atenolol than with either of the other drugs. Furthermore, there was a greater working capacity with atenolol in 7 of 8 patients compared with isosorbide mononitrate or nifedipine. In addition, atenolol was significantly better than nifedipine or the nitrate in reducing the number and duration of ST-segment changes and, finally, atenolol was more effective than either of the other drugs in reducing pain. The authors concluded, therefore, that beta-receptor blockade, far from being contra-indicated, is in fact of benefit in patients who have severe exertional and nocturnal angina caused by severe coronary artery disease. Further work by Chierchia et aL3 compared atenolol(100mg daily) and placebo in patients with a clinical history of mixed angina (Figure 1).It was of interest that atenolol reduced painful episodes of ischaemia by 69% compared with placebo, 487
Atenolol and ischaemic heart disease: an overview
and painless episodes by 61"h. Furthermore, of the 264 ischaemic episodes recorded during ambulatory monitoring on placebo, 79% were silent.
Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
Figure 1. Incidence of symptomatic and asymptomatic episodes of ischaemia in mixed angina patients on treatment with atenolol ( 100 mg daily) or placebo: number of ischaemic episodes (S-Tsegment depression) in the study by Chierchia et aL3
0Symptomatic
Placebo
A tenolol
Thus, atenolol was more effective at reducing the number of episodes of ischaemia, whether painful or not, that were not preceded by an increase in heart rate, more than those which were preceded by a heart rate increase. This latter finding, although requiring confirmation in other studies, suggests that atenolol may be particularly effective for ischaemic episodes which result from a reduction in oxygen supply (presumably via functional spasm), i.e. no heart rate change, as well as those that result from an increase in oxygen demand, i.e. those in which the heart rate is increased. This unexpected benefit presumably arises due to an increased ischaemic threshold. Silent ischaemia. On the basis that it is ischaemia and not angina that kills, it is important that therapy lessens both silent and overt ischaemia. Under placebo controlled conditions, atenolol (100 mg once daily) has been shown to be highly effective in inhibiting both types of i ~ c h a e m i a . ~ , ' ~ A study by Quyyumi et d3' compared atenolol, nifedipine and isosorbide mononitrate. as previously described. Their results led the investigators to the conclusion that atenolol was the most effective of the three agents in reducing the incidence of silent ischaemia (Figure 2). Together with its proven reduction of painful episodes, these findings indicate that atenolol significantly reduces the total ischaemic burden on the heart. 488
J. M. Cruickshank and J. McAinsh
Figure 2. Comparativeefficacy of atenolol, nifedipine and isosorbide mononitrate in reducing the number of episodes of ischaemia in 9 patients with mixed angina: number of silent and painful episodes. (FromQuyyumi et
Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
7
0Painful
Off treatment
Atenolol
Nifedipine
Isosorbide mononitrate
In a recent study, Mulcahy et investigated whether there is a circadian pattern for the total ischaemic burden and to see if this corresponds with the reported circadian patterns of acute myocardial infarction and sudden death. If so, they then questioned the effect of anti-anginal therapy with either a betablocker - atenolol(lO0 mg once daily), or a calcium antagonist - nifedipine (30 to 60 mg daily) on the circadian distribution of ischaemia. The authors found that the distribution of ischaemic episodes showed a similar circadian variation to that reported for acute myocardial infarction and sudden death. In addition, they showed that nifedipine had little effect on either the frequency or total duration of ischaemic episodes and did not alter the circadian distribution of ischaemic episodes. In contrast, atenolol was associated with a significant reduction in the frequency and total duration of ischaemic episodes throughout the day. It also significantly altered the circadian distribution of ischaemic episodes with elimination of the morning peak; this morning peak being the vulnerable period for sudden death and non-fatal myocardial infarction (Figure 3).
Unstable angina Unstable angina can reflect a changed pattern from stable angina or a condition of recent onset which exacerbates rapidly, occurring at rest, at night as well as at different levels of exercise. Most patients have fixed atherosclerotic coronary disease and many have superimposed dynamic stenosis or clot formation over a ruptured plaque. The disease can exacerbate and acute myocardial infarction develop. This particular disease has also been described as pre-infarct, crescendo, accellerated or progressive angina. The efficacy of atenolol in unstable angina was confirmed in the Oxford/ Wythenshawe study of Yusuf et aL50 The results, based on preservation of the 489
Atenolol and ischaemic heart disease: an overview
Figure 3. Circadian distribution of ischaemia: total duration of ischaemic episodes. (From Mulcahy et nl. 3 2 )
- Off therapy --- On therapy Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
--.-..
3
I
100
0
1;k 12 Time (hours)
14
16
I8
’
20
22
Note: Bimodal fits are superimposed on each histogram
ECG R-waves and cardiac enzyme release, showed that, whereas 66% of the 170 patients with threatened infarction who were randomized to control treatmenr progressed to full infarction, only 49% of those randomized to atenolol did so. This was a statistically significant reduction of 26% (p
Current Medical Research and Opinion
Vol. 12, No. 8, 1991
Atenolol and ischaemic heart disease: an overview
J. M. Cruickshank, D.M.(Oxon.), F.R.C.P.(London), and J. McAinsh,* B.Sc.. M.Sc., Ph.D. Cardiac Department, Whythenshawe Hospital, Manchester; and National Heart Hospital, London, and *Medical Affairs Department, ICI Pharmaceuticals, Imperial Chemical Industries plc. Alderley Park, Macclesfield, England
Curr. Med. Res. Opin., (1991), 12,485.
Received: 9th September 1991
Summary Data generated to date on the use of beta-blockers, especially atenolol, in ischaemic heart disease are reviewed and compared with the results available with the calcium antagonists. Atenolol appears to be effective as an anti-ischaemic agent inpatients with obstructive coronary artery disease when reduction in myocardial oxygen supply (ischaemia not preceded by an increase in heart rate and due presumably to functional coronary stenosis) or increase in demand are the likely causes. Based on current concepts and available data, there is convincing evidence to support the use of atenolol across the spectrum of ischaemic heart disease. In contrast, results with the calcium antagonists have been disappointing and variable. Atenolol, to date, is the only beta-blocker which has been demonstrated to have a life-saving benefit in acute intervention (within 12 hours of onset) in myocardial infarction. This cardioprotective aspect of the drug is likely to be applicable to other areas of ischaemic heart disease, including silent ischaemia. Key words: Atenolol - adrenergic beta receptor blockaders - calcium channel blockers - coronary disease - myocardial infarction - review
Introduction Ischaemic heart disease is the major cause of mortality in Western industrialized countries. It is usually caused by coronary atherosclerosis. The delicate balance of supply and demand of oxygen to the heart is thus disturbed by a relatively fixed coronary stenosis. Spontaneous coronary arterial spasm, which may give rise to variant or Prinmetal’s angina, is very rare. However, dynamic coronary stenosis related to changes in coronary artery tone or platelet aggregability is probably quite commonz5and occurs in the presence of fixed stenosis. Ischaemic episodes peak between 08.00 and 10.00 hours3* when sympathetic drive is maximal.39Interestingly, about 80%of ischaemic episodes occurring over 24 hours are silent in nature.44The silent episodes are accompanied by ischaemic haemodynamic changes4 and are associated with a poor p r o g n ~ s i s . The ’ ~ ~ sum ~~ of silent and painful episodes has been termed the ‘total ischaemic burden’. 485
Atenolol and ischaemic heart disease: an overview
Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
Rationale for beneficial beta-blocker effects upon myocardial ischaemia As predicted by Black in the late 1950s,beta-blockers benefit patients with angina by decreasing the work of the heart. The reduced cardiac work is achieved primarily through a decrease in heart rate and systolic blood pressure but also through a decreased velocity of cardiac contraction. Bradycardia also prolongs coronary diastolic filling time. The vulnerable sub-endocardial blood flow is benefited by internal shunting’ and a reduction in left ventricular end-diastolic pressure during ischaemia. All these changes invariably more than compensate for the potential increased left ventricular wall stresses caused by cardiac enlargement which accompanies bradycardia. Thus, myocardial oxygen consumption is reduced by more than 20%,accompanied by a change from lactate production to extraction3’ and an autoregulatory decrease in coronary blood The betal-receptor is the dominant beta-receptor in the heart. For the uncomplicated patient with ischaemic heart disease, beta-blocker properties other than beta,-blockade therefore are unnecessary.
Effects of atenolol in ischaemic heart disease Atenololt is a betal-adrenoceptor blocking drug with no membrane stabilizing or intrinsic sympathomimetic activities. It has a long record of efficacy and safety in patients with ischaemic heart disease. Stable angina In a study by Majid et atenolol at doses of 100 mg and 200 mg once daily was compared with placebo. The results showed that atenolol increased work done on exercise and caused a smaller reduction in ST-segmentdepression. A few years later, S ~ h w a r t confirmed z~~ these findings and concluded from the 12-month follow-up that atenolol (100 mg once daily) was an effective anti-anginal agent for long-term use because there was no evidence of tachyphylaxis. More recently, Findlay et al. l 2 confirmed that 100 mg atenolol daily was more efficacious than placebo in terms of angina attack rate and glyceryl trinitrate consumption. Additionally, atenolol has been shown to be more effective in treating angina than practol01~~ and pindolol,36 and to have similar efficacy to labetalo12’and propran~lol.’~ Findlay et ~ 1 . showed ’ ~ that there was a trend for atenolol to be more effective than the dihydropyridine calcium antagonist, nifedipine (20 mg 3-times daily). This latter finding has been confirmed in two recent s t ~ d i e s .In ~~ the , ~latter, ~ Shapiro et found that atenolol produced a significant additional reduction compared with nifedipine (10 to 30 mg 3-times daily) in rate-pressure product and a lesser reduction in ST-segment depression. There have been many randomized, double-blind,crossover studies with atenolol in stable angina. An overview of 23 placebo or glyceryl trinitrate controlled studies (Table I) shows that the normal clinical dose of atenolol reduces angina attack t’Tenormin‘. trade mark ICI
486
J. M. Cruickshank and J. McAinsh
rate by 53%,2,7-10.19,24,27,28,34,40-42.45.46,49and nitrate consumption by SOYo.2,7-10.19.24.27. 34,41,42,48 Exercise time to pain and improvement in ST-segment depression averaged 37702.7.8,23 and 40%,2,7,10,1 1,19.20,23.24.27.42respectively.
Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
Table I. Summary of results from 23 crossover studies with atenolol versus placebo or glyceryl trinitrate in 400 stable angina patients: average percentage changes with atenolol Assessment
Change
Anginal attack rate Nitrate consumption Exercise to pain time S-T segment depression
153% J, 50%
T37% 1‘40%
In view of these data, it is not surprising that, in his presentation at the 1989 symposium meeting in San Francisco on “Evolving Concepts in Ischaemic Heart Disease,” Y a m a g ~ c hconcluded i~~ that beta-blockers are the drugs of first choice for exercise-induced angina. Atenolol has been combined with other anti-anginal therapies to produce superior efficacy compared with monotherapy. In particular, atenolol has been combined with nitrates,34 nifedipine,12 felodipine,46 verapamil,26 and molsidomine.6
Mixed angina In mixed angina, a discomfort which occurs at rest and at night as well as with differing levels of exercise, patients have fixed atherosclerotic coronary disease with superimposed dynamic stenosis. In the past, there has been some doubt on the advisability of prescribing a beta-blocker for patients with an element of functional or dynamic stenosis. However, with the probable exception of the very rare Prinzmetal’s angina, clinical evidence supports the view that beta-blockade is a highly effective treatment for these patients. Quyyumi et al.37 compared atenolol (100 mg daily), nifedipine (10 to 20 mg 3-times daily) and isosorbide mononitrate (40 mg twice daily) in a randomized, double-blind, crossover trial in 9 patients with severe mixed angina. The results of this study showed that the duration of exercise to ischaemia during a standardized exercise test was significantly greater with atenolol than with either of the other drugs. Furthermore, there was a greater working capacity with atenolol in 7 of 8 patients compared with isosorbide mononitrate or nifedipine. In addition, atenolol was significantly better than nifedipine or the nitrate in reducing the number and duration of ST-segment changes and, finally, atenolol was more effective than either of the other drugs in reducing pain. The authors concluded, therefore, that beta-receptor blockade, far from being contra-indicated, is in fact of benefit in patients who have severe exertional and nocturnal angina caused by severe coronary artery disease. Further work by Chierchia et aL3 compared atenolol(100mg daily) and placebo in patients with a clinical history of mixed angina (Figure 1).It was of interest that atenolol reduced painful episodes of ischaemia by 69% compared with placebo, 487
Atenolol and ischaemic heart disease: an overview
and painless episodes by 61"h. Furthermore, of the 264 ischaemic episodes recorded during ambulatory monitoring on placebo, 79% were silent.
Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
Figure 1. Incidence of symptomatic and asymptomatic episodes of ischaemia in mixed angina patients on treatment with atenolol ( 100 mg daily) or placebo: number of ischaemic episodes (S-Tsegment depression) in the study by Chierchia et aL3
0Symptomatic
Placebo
A tenolol
Thus, atenolol was more effective at reducing the number of episodes of ischaemia, whether painful or not, that were not preceded by an increase in heart rate, more than those which were preceded by a heart rate increase. This latter finding, although requiring confirmation in other studies, suggests that atenolol may be particularly effective for ischaemic episodes which result from a reduction in oxygen supply (presumably via functional spasm), i.e. no heart rate change, as well as those that result from an increase in oxygen demand, i.e. those in which the heart rate is increased. This unexpected benefit presumably arises due to an increased ischaemic threshold. Silent ischaemia. On the basis that it is ischaemia and not angina that kills, it is important that therapy lessens both silent and overt ischaemia. Under placebo controlled conditions, atenolol (100 mg once daily) has been shown to be highly effective in inhibiting both types of i ~ c h a e m i a . ~ , ' ~ A study by Quyyumi et d3' compared atenolol, nifedipine and isosorbide mononitrate. as previously described. Their results led the investigators to the conclusion that atenolol was the most effective of the three agents in reducing the incidence of silent ischaemia (Figure 2). Together with its proven reduction of painful episodes, these findings indicate that atenolol significantly reduces the total ischaemic burden on the heart. 488
J. M. Cruickshank and J. McAinsh
Figure 2. Comparativeefficacy of atenolol, nifedipine and isosorbide mononitrate in reducing the number of episodes of ischaemia in 9 patients with mixed angina: number of silent and painful episodes. (FromQuyyumi et
Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
7
0Painful
Off treatment
Atenolol
Nifedipine
Isosorbide mononitrate
In a recent study, Mulcahy et investigated whether there is a circadian pattern for the total ischaemic burden and to see if this corresponds with the reported circadian patterns of acute myocardial infarction and sudden death. If so, they then questioned the effect of anti-anginal therapy with either a betablocker - atenolol(lO0 mg once daily), or a calcium antagonist - nifedipine (30 to 60 mg daily) on the circadian distribution of ischaemia. The authors found that the distribution of ischaemic episodes showed a similar circadian variation to that reported for acute myocardial infarction and sudden death. In addition, they showed that nifedipine had little effect on either the frequency or total duration of ischaemic episodes and did not alter the circadian distribution of ischaemic episodes. In contrast, atenolol was associated with a significant reduction in the frequency and total duration of ischaemic episodes throughout the day. It also significantly altered the circadian distribution of ischaemic episodes with elimination of the morning peak; this morning peak being the vulnerable period for sudden death and non-fatal myocardial infarction (Figure 3).
Unstable angina Unstable angina can reflect a changed pattern from stable angina or a condition of recent onset which exacerbates rapidly, occurring at rest, at night as well as at different levels of exercise. Most patients have fixed atherosclerotic coronary disease and many have superimposed dynamic stenosis or clot formation over a ruptured plaque. The disease can exacerbate and acute myocardial infarction develop. This particular disease has also been described as pre-infarct, crescendo, accellerated or progressive angina. The efficacy of atenolol in unstable angina was confirmed in the Oxford/ Wythenshawe study of Yusuf et aL50 The results, based on preservation of the 489
Atenolol and ischaemic heart disease: an overview
Figure 3. Circadian distribution of ischaemia: total duration of ischaemic episodes. (From Mulcahy et nl. 3 2 )
- Off therapy --- On therapy Curr Med Res Opin Downloaded from informahealthcare.com by CDL-UC Davis on 12/27/14 For personal use only.
--.-..
3
I
100
0
1;k 12 Time (hours)
14
16
I8
’
20
22
Note: Bimodal fits are superimposed on each histogram
ECG R-waves and cardiac enzyme release, showed that, whereas 66% of the 170 patients with threatened infarction who were randomized to control treatmenr progressed to full infarction, only 49% of those randomized to atenolol did so. This was a statistically significant reduction of 26% (p
