Secondary Prevention of Acute Myocardial Infarction with Beta-Blocking Agents and Calcium Antagonists John R. Hampton, DM, DPhil, FRCP
The discovery that /3 blockers possess clinically useful hypotensive, antianginal and antiarrhythmic properties has attracted the interest of clinicians, researchers and the pharmaceutical community alike. In addition, minor differences in a variety of ancillary properties have led to speculation that specific classes of drugs might have advantages over other classes. The enthusiasm that greeted reports from the first small trials, which showed that B blockers reduced the postmyocardial infarction mortality rate, attracted the commercial support necessary to evaluate different @blockers in this clinical setting. The plethora of @blockers that subsequently became available for study led to considerable improvement in both the design and impiementation of large clinical trials. Despite apparent discrepancies in the results of various trials, metaanalysis indicates that most, if not ail, fl blockers reduce postinfarction mortality. However, because meta-analysis cannot recommend a particular drug or specific dose for use in an individual patient, clinical practice must be based on the results of individual trials, not on the conclusions of meta-analysis. The clinical utility of /3 blockers in the secondary prevention of myocardiai infarction, coupled with experimental evidence that calcium antagonists reduce infarct size, led to a series of large studies designed to establish whether calcium antagonists have any effect on reducing mortality in patients with myocardial infarction. Lessons learned from the &?-blocker trials permitted a more rapid evaluation of the efficacy of calcium antagonists in this setting. it is clear that, unlike B blockers, calcium antagonists are not effective in the secondary prevention of myocardial infarction. (Am J Cardiol 1990;66:3C4C)
From the Queen’s Medical Centre, University Hospital, Nottingham, United Kingdom. Address for reprints: J.R. Hampton, DM, DPhil, FRCP, Queen’s Medical Centre, University Hospital, Nottingham NG7 2UH, United Kingdom.
wenty-five years ago, Snow’ reported that treatment with the /I blocker propranolol reduced the mortality rate in patients with acute myocardial infarction. Since then, a plethora of p blockers has appeared on the market, and many trials of different drugs of this type have beenconducted to confirm Snow’s observations.Perhapsbecauseof commercial pressures,P blockers have becomethe most extensively investigated of all drugs, with more patients being included in trials of ,6 blockers than any other type of clinical trial. One clear benefit of the trials of secondaryprevention with ,6blockers has beenconsiderableimprovement in the designand analysis of clinical trials. Snow’strial, e.g.,was far too small to show a statistically significant benefit from active treatment, and results of subsequent small trials were published before the importance of large studies became generally recognized. However, the small studies contributed to an increasedawarenessof different methods of trial analysis. Figure 1 depicts a typical example of an atenolol trial2 that now is clearly seento be much too small, but the style of data presentation that was developed to present the results of such studies3demonstrates 2 important general points. First, it is desirable to know the size and demographic characteristics of the population from which the trial patients were selected. Without this information, the results of a trial may well be “true,” but they may not be applicable to the types of patients seenby clinicians in daily practice. Second,Figure 1 shows the importance of separating the “intention to treat” and the “explicative” or “on treatment” analyses,“Intention to treat” analysis includes all the patients randomized in the trial, whether or not they continued to take the medication to which they were randomized. In the trial shown in Figure 1, the reduction in total mortality associatedwith active treatment was not statistically significant (9% compared with 12% in the placebo group). Among those patients who continued with their allocated treatment, the effect of atenolol was more marked (3% mortality rate with atenolol vs 11% with placebo). Thus, “explicative” analysis suggeststhat the drug may have a beneficial effect. However, Figure 1 also shows that treatment with a p blocker may be harmful: the mortality rate was essentially the same among patients who continued or were withdrawn from placebo therapy (11 and 12%, respectively), but among those withdrawn from atenolol, the mortality rate was 18%. One possibleexplanation for these results is that P-blocking treatment selects those with low and high mortality rates; perhaps patients with severe cardiac diseasewho have a high mortality rate are unable to tolerate therapy with a ,6 blocker.
T
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER 25,199O
3C
A SYMPOSIUM:
PRIMARY
AND SECONDARY
PREVENTION
Total patient population
Total no. of oatients
i-27
No. of patients in different groups Withdrawn 51
Continued 76 4-b No. of deaths
El
El
I 8%
Mortality
I
p=ns
2
FIGURE 1. Results of a trial2 comparing atenolol 100 mg daiiy with placebo in patients with acute myocardial infarction. Treatment was started immediately (66% within 8 hours).
OF CARDIOVASCULAR
DISEASE
BETA BLOCKERS AND SECONDARY PREVENTION The first P-blocker postinfarction trial that provided all the necessary data to permit different analysesand was also large enough to demonstrate significant results was the Norwegian Multicenter Study on Timolol after Myocardial Infarction4 involving 1,884patients (Fig. 2). This was a classic trial of considerable historical and clinical importance, which clearly demonstrated that therapy with a /3blocker reducespostinfarction mortality. This study was followed by the Beta Blocker Heart Attack Trial (BHAT) of propranolol (Fig. 3) .5The results of this study, which included a cohort of 3,837postinfarction patients, were somewhatlesssatisfactoryin that the outcome of patients withdrawn from treatment was not given. Nevertheless, BHAT demonstrated that a p blocker other than timolol was effective in secondary prevention, suggestingthat reduction in mortality might be a class effect rather than a benefit limited to 1 drug. Furthermore, the patients admitted to the Norwegian and BHAT studies were clearly different, sincethe mortality rates in the placebo groups were 16.2 and 9.8% respectively, suggesting that the benefit of @blocking therapy applies to a wide variety of patients. Detailed analysisof results wasnot routine in the early days of postinfarction trials, although this type of analysis is now common. It is difficult to describe the results of many trials in such detail; thus, the concept of “relative risk reduction” becamewidely accepted.As an example, if the mortality rate in the placebo group of a trial was
Total patient population Total patient population Total no. ot patients
in iriA
I
Total no. of patients in trial
3,837
Propranolol 1,916
Placebo 1,921
No. of patients in different groups Continued 1,456
Continued 1,460
Withdrawn 460
Withdrawn 461
No. of deaths Mortality
10%
11%
16%
No. of deaths
16%
-p
FIGURE 2. Resuits of the Norwegian Mutticenter PostinfarcSon Trial of tiioloL4 Thnolol was administered at a dosage of 10 mg twice daily from 7 to 26 days. Patients were followed for a mean duration of 17 months. The age range was 20 to 75 years.
4c
THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 66
72 hours after the onset of symptoms).
first few hours after admission. Late patients are stable, and only those with an established diagnosis need be included. The 2 groups of patients might well respond differently top blockers, and it has to be acceptedthat the mode of action of these drugs in secondary prevention is not clear and could be different as the illness progresses. Figures 4 and 5 show that ,6 blockers have a more consistent effect in the late trials. When formal statistical techniques of meta-analysis are applied, the drugs appear to be equally efficacious in both early and late settings. However, ISIS-l, becauseof its large size, provides the most compelling evidence for early treatment. Figures 4 and 5 clearly show that the ancillary properties of different P blockers cannot be consideredclinically significant. Both selective (e.g., atenolol and metoprolol) and nonselective (e.g., propranolol) agents have been shown to reduce mortality. Intrinsic sympathomimetic activity has been associatedwith both a beneficial effect on mortality (practolol) and an actual increasein mortality (oxprenolol), and class III antiarrhythmic activity (sotalol) does not appear to confer any particular advantage in terms of preventing mortality. The only conclu-
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER 25,199O
!%
A SYMPOSIUM:
TABLE
PRIMARY
I Calcium
AND SECONDARY
Antagonists
After
Myocardial Mortality
MDPIT = Multicenter Diltiazem tion Reinfarction Israeli Nlfedipine
Postinfarction Trial.
Infarction
(%)
Placebo Nifedipine Trent Study 198612 SPRINT 198813 Verapamil Danish 198414 Diltiazem Non-Q-wave 198615 MDPIT 198816
PREVENTION
Active
6.3 5.7
6.7 5.8
13.9
12.9
3.1 13.5
3.8 13.5
Trial: SPRINT = Secondary
Preven-
sion from meta-analysis of the many trials of secondary prevention is that /3 blockers reduce mortality, an effect probably common to all drugs of this class. CALCIUM ANTAGONISTS AND SECONDARY PREVENTION The utility of the p blockers in reducing mortality, coupled with experimental evidencethat calcium antagonists limit the size of infarct,’ l led to a seriesof large trials to establish whether calcium antagonists have any effect on reducing mortality in patients with myocardial infarction. Experience gained from the P-blocker trials permitted a more rapid evaluation of the efficacy of calcium antagonists. Unlike the /3 blockers, calcium antagonists were not shown to reduce mortality. Table I lists 5 large trials that were carried out with nifedipine (both early’* and later3 administration), verapamil14 and diltiazem.i5J6The results of these trials demonstrate approximately equal mortality rates in patients receiving placebo and active treatment (Table I). The Multicenter Diltiazem Postinfarction Triali enrolled 2,466 patients, of whom approximately 70% had had a Q-wave infarction. In patients with non-Q-wave infarction, diltiazem was reported to reduce reinfarction, but not death.15However, the significance of this result is uncertain because some of the definitions used in the study were inexact, and the observation has not been confirmed by subsetanalysis of the other trials. In conclusion, analysis of the secondary prevention trials with calcium antagonists showsthat there is no preventive role for thesedrugs, although they can be useful in the treatment of angina pectoris. SECONDARY PREVENTION BASED ON THE RESULTS OF CLINICAL TRIALS Meta-analysis of these trials of secondary prevention doesnot provide answersto several therapeutic questions of paramount importance to the clinician. For example, are there subgroups of patients who may benefit more than others? Are all /3blockers equivalent in their effect in secondary prevention? What is the optimal dose? In addition, the P-blocker trials were completed for the most part before the widespread use of aspirin as a secondary prevention agent, and it is not known whether the protective effects of aspirin and the @blockers are additive, 6C
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
OF CARDIOVASCULAR
DISEASE
although theoretically this seemslikely. Similarly, it is not known whether the early useof a 0 blocker increases the protective effect of thrombolytic agents. Early or late treatment? Despite the evidencefrom the ISIS-l9 and MIAMI8 trials that early treatment with an intravenous fl blocker reduces mortality, this treatment modality has not become routine practice in the United Kingdom or in many other European countries. There are probably 2 reasonsfor this. First, both trials included very low-risk patients (placebo group mortality rates in ISIS-l and MIAMI were 4.5 and 4.9%,respectively); becausethe true overall mortality rate of patients admitted to the hospital with suspectedmyocardial infarction is 3 or 4 times higher than this, most clinicians are unsure if the results of the trials really apply to the patients they seein routine practice. Second,the MIAMI trial results only apply to a small proportion of the patients admitted to the participating hospitals (5,784 patients included out of 26,439 admitted), and it is not immediately obvious to a clinician how to selectpatients for treatment in the way that was usedin the trial. Moreover, it is not known how the 16,027patients included in ISIS-I were selected, since no register of excluded patients was kept. Crude calculations suggest that each center was only randomizing 1 or 2 patients per month; thus, somespecial form of selectionmay havebeenoccurring inadvertently. Thus, becauseearly /3-blockingtherapy might be harmful in certain patients, mostclinicians in the United Kingdom do not begin prophylactic treatment until after the acute stage of the infarction. Which patients should be treated? Since the results of clinical trials apply only to patients similar to those who fulfilled the inclusion and exclusion criteria established in the protocol, information is not available about the effect of @blockers on infarct survivors with conditions normally considered to be contraindications for treatment, such as asthma and heart failure. As noted previously, there is a low mortality rate in the placebo groups of many of the secondary prevention trials, but without knowing the fate of patients excludedfrom these trials, it is difficult to be certain of the significance of these figures. The trial of early nifedipine in acute myocardial infarction (Trent study) *2wasthe only large postinfarction study in which a register of excluded patients was maintained and all of thesepatients werefollowed for the duration of the study. The mortality rates in the patients randomized to placebo or nifedipine treatment were 6.3 and 6.7%, respectively, but in the excluded patients, the mortality rate was 18.2%.Therefore,the Trent study applies only to patients at low risk, and it seems likely that the same is true of all the P-blocker trials. Some, but not all, of the P-blocker trials excluded elderly patients. Few trials attempted to define any particular type of patient for inclusion, although the propranolol study by Hansteen et alI0 set out to include only those at high risk. Therefore, attempts to identify special groups of patients who might particularly benefit from or be harmed by @-blockingtherapy depend on subgroup analysesof the published trial, which is always an unreliable process.The problem is that the moresubgroupsthat
25
FIGURE 6. Beta blockers after myocardial infarction: relation between point estimates of relative risk reduction or increase and the placebo mortality rate.
Placebo Mortality W)
0 -60 -40 -20 % Relative risk increase
are constructed within which to compare the effects of treatment, the greater the likelihood that an apparently “significant” difference will occur by chance. In general, subgroup analysis should only be used as a means of generating hypothesesthat can be used as a basis for subsequenttrials. In fact, subgroup analysis of the pblocker trials does not identify any patient group that shouldbe treated differently: patients of all agesas well as with all sites of infarction as documented by the electrocardiogram seemedto benefit equally from treatment. Thus, the principal difficulty is to decide whether patients at low or high risk should be treated. Since the prognosisin low-risk patients-the young and those with a first infarction-is good, it may not be useful to treat them, especially in light of the adverse effects that may occur, such as lethargy, muscular aches and pains, cold extremities and impotence.On the other hand, patients at high risk-the elderly, those with multiple previous infarctions and those with poor left ventricular functionmay beharmed by @-blockingtherapy by the induction of heart failure, in addition to the adverse effects of these drugs. Subset analysis of the P-blocker trials in terms of likely risk has also proved unhelpful. In the Norwegian timolol trial,4 the overall relative risk reduction was 36%, whereasin the subgroup with a previous infarction it was 21%. In other subgroupsconsideredto be at high or low risk, the relative risk reductions were 40 and 53%, respectively. Similarly in BHAT,5 the overall risk reduction was 26%,whereasin the subgroupwith a previous infarction it was IX%, and in those who were consideredto be at high or low risk, it was 30 and 27%, respectively. Figure 6 summarizes the relation between the trial resultsand the risk of the patients included by relating the relative risk reduction (or increase)associatedwith active treatment to the placebomortality rate seenin each of the main trials. It has been assumedthat the placebo rate indicates the degreeof risk of the patients included. Al-
0
20 40 60 % Relative risk reduction
though Figure 6 indicates a trend suggestingincreasing benefit from 0 blockers with increasing patient risk, this is far from statistically significant. Thus, a p blocker seems to be indicated for most patients who survive a myocardial infarction, although treatment should be withdrawn immediately in low-risk patients who experiencetroublesome adverse effects. Which beta blocker? Among the late entry trials, both timolo14 and propranololrO have been shown to reduce mortality, although it is likely that all @blockers are effective in secondaryprevention after myocardial infarction. Clearly, practicing clinicians will prefer an agent with proven efficacy and a simple dosageregimen; in the study cited previously, timolol was shown to be effective at dosesof 5 to 10 mg twice daily. CONCLUSIONS
Despite their beneficial effects in angina, calcium antagonists have no preventive effect in patients with myocardial infarction. Meta-analysis of trials of secondary prevention appears to indicate that p blockers are effective in reducing mortality in patients with myocardial infarction, although to date, there are no data to suggest that either high- or low-risk patients in particular will benefit from treatment, nor that the ancillary properties of different drugs in this class are significant in reducing mortality. Therefore, @blockers are generally warranted for most patients who survive a myocardial infarction, although clinical practice and recommendationsregarding a particular drug or dose must be made according to the present condition and past history of each patient. Additional information in this clinical setting will not be available until the relevant clinical trials are conducted. REFERENCES 1. Snow 553,
PJD. Effect of propranolol in myocardial infarction. Lancer 1965;2:551-
2. Wilcox RG, Roland JM, Banks DC, Hampton JR, Mitchell JRA. Randomized trial comparing propranolol with atenolol in immediate treatment of suspected
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER 25,199O
7C
A SYMPOSIUM:
PRIMARY
AND SECONDARY
PREVENTION
OF CARDIOVASCULAR
DISEASE
myocardial infarction. Br Med J 1980;280:885-888. 3. Hampton JR, Presentation and analysis of the results of clinical trials in cardiovascular disease. Br Med J 1981;282:137/-1373. 4. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction, N Engl J Med 1981;304:801-807. 5. &Blocker Heart Attack Study Group. The P-blocker heart attack trial. JAMA 198/;246:2073-2074. 6. Yusuf S, Peto R, Lewis .I, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiouasc Dis 1985
The discovery that /3 blockers possess clinically useful hypotensive, antianginal and antiarrhythmic properties has attracted the interest of clinicians, researchers and the pharmaceutical community alike. In addition, minor differences in a variety of ancillary properties have led to speculation that specific classes of drugs might have advantages over other classes. The enthusiasm that greeted reports from the first small trials, which showed that B blockers reduced the postmyocardial infarction mortality rate, attracted the commercial support necessary to evaluate different @blockers in this clinical setting. The plethora of @blockers that subsequently became available for study led to considerable improvement in both the design and impiementation of large clinical trials. Despite apparent discrepancies in the results of various trials, metaanalysis indicates that most, if not ail, fl blockers reduce postinfarction mortality. However, because meta-analysis cannot recommend a particular drug or specific dose for use in an individual patient, clinical practice must be based on the results of individual trials, not on the conclusions of meta-analysis. The clinical utility of /3 blockers in the secondary prevention of myocardiai infarction, coupled with experimental evidence that calcium antagonists reduce infarct size, led to a series of large studies designed to establish whether calcium antagonists have any effect on reducing mortality in patients with myocardial infarction. Lessons learned from the &?-blocker trials permitted a more rapid evaluation of the efficacy of calcium antagonists in this setting. it is clear that, unlike B blockers, calcium antagonists are not effective in the secondary prevention of myocardial infarction. (Am J Cardiol 1990;66:3C4C)
From the Queen’s Medical Centre, University Hospital, Nottingham, United Kingdom. Address for reprints: J.R. Hampton, DM, DPhil, FRCP, Queen’s Medical Centre, University Hospital, Nottingham NG7 2UH, United Kingdom.
wenty-five years ago, Snow’ reported that treatment with the /I blocker propranolol reduced the mortality rate in patients with acute myocardial infarction. Since then, a plethora of p blockers has appeared on the market, and many trials of different drugs of this type have beenconducted to confirm Snow’s observations.Perhapsbecauseof commercial pressures,P blockers have becomethe most extensively investigated of all drugs, with more patients being included in trials of ,6 blockers than any other type of clinical trial. One clear benefit of the trials of secondaryprevention with ,6blockers has beenconsiderableimprovement in the designand analysis of clinical trials. Snow’strial, e.g.,was far too small to show a statistically significant benefit from active treatment, and results of subsequent small trials were published before the importance of large studies became generally recognized. However, the small studies contributed to an increasedawarenessof different methods of trial analysis. Figure 1 depicts a typical example of an atenolol trial2 that now is clearly seento be much too small, but the style of data presentation that was developed to present the results of such studies3demonstrates 2 important general points. First, it is desirable to know the size and demographic characteristics of the population from which the trial patients were selected. Without this information, the results of a trial may well be “true,” but they may not be applicable to the types of patients seenby clinicians in daily practice. Second,Figure 1 shows the importance of separating the “intention to treat” and the “explicative” or “on treatment” analyses,“Intention to treat” analysis includes all the patients randomized in the trial, whether or not they continued to take the medication to which they were randomized. In the trial shown in Figure 1, the reduction in total mortality associatedwith active treatment was not statistically significant (9% compared with 12% in the placebo group). Among those patients who continued with their allocated treatment, the effect of atenolol was more marked (3% mortality rate with atenolol vs 11% with placebo). Thus, “explicative” analysis suggeststhat the drug may have a beneficial effect. However, Figure 1 also shows that treatment with a p blocker may be harmful: the mortality rate was essentially the same among patients who continued or were withdrawn from placebo therapy (11 and 12%, respectively), but among those withdrawn from atenolol, the mortality rate was 18%. One possibleexplanation for these results is that P-blocking treatment selects those with low and high mortality rates; perhaps patients with severe cardiac diseasewho have a high mortality rate are unable to tolerate therapy with a ,6 blocker.
T
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER 25,199O
3C
A SYMPOSIUM:
PRIMARY
AND SECONDARY
PREVENTION
Total patient population
Total no. of oatients
i-27
No. of patients in different groups Withdrawn 51
Continued 76 4-b No. of deaths
El
El
I 8%
Mortality
I
p=ns
2
FIGURE 1. Results of a trial2 comparing atenolol 100 mg daiiy with placebo in patients with acute myocardial infarction. Treatment was started immediately (66% within 8 hours).
OF CARDIOVASCULAR
DISEASE
BETA BLOCKERS AND SECONDARY PREVENTION The first P-blocker postinfarction trial that provided all the necessary data to permit different analysesand was also large enough to demonstrate significant results was the Norwegian Multicenter Study on Timolol after Myocardial Infarction4 involving 1,884patients (Fig. 2). This was a classic trial of considerable historical and clinical importance, which clearly demonstrated that therapy with a /3blocker reducespostinfarction mortality. This study was followed by the Beta Blocker Heart Attack Trial (BHAT) of propranolol (Fig. 3) .5The results of this study, which included a cohort of 3,837postinfarction patients, were somewhatlesssatisfactoryin that the outcome of patients withdrawn from treatment was not given. Nevertheless, BHAT demonstrated that a p blocker other than timolol was effective in secondary prevention, suggestingthat reduction in mortality might be a class effect rather than a benefit limited to 1 drug. Furthermore, the patients admitted to the Norwegian and BHAT studies were clearly different, sincethe mortality rates in the placebo groups were 16.2 and 9.8% respectively, suggesting that the benefit of @blocking therapy applies to a wide variety of patients. Detailed analysisof results wasnot routine in the early days of postinfarction trials, although this type of analysis is now common. It is difficult to describe the results of many trials in such detail; thus, the concept of “relative risk reduction” becamewidely accepted.As an example, if the mortality rate in the placebo group of a trial was
Total patient population Total patient population Total no. ot patients
in iriA
I
Total no. of patients in trial
3,837
Propranolol 1,916
Placebo 1,921
No. of patients in different groups Continued 1,456
Continued 1,460
Withdrawn 460
Withdrawn 461
No. of deaths Mortality
10%
11%
16%
No. of deaths
16%
-p
FIGURE 2. Resuits of the Norwegian Mutticenter PostinfarcSon Trial of tiioloL4 Thnolol was administered at a dosage of 10 mg twice daily from 7 to 26 days. Patients were followed for a mean duration of 17 months. The age range was 20 to 75 years.
4c
THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 66
72 hours after the onset of symptoms).
first few hours after admission. Late patients are stable, and only those with an established diagnosis need be included. The 2 groups of patients might well respond differently top blockers, and it has to be acceptedthat the mode of action of these drugs in secondary prevention is not clear and could be different as the illness progresses. Figures 4 and 5 show that ,6 blockers have a more consistent effect in the late trials. When formal statistical techniques of meta-analysis are applied, the drugs appear to be equally efficacious in both early and late settings. However, ISIS-l, becauseof its large size, provides the most compelling evidence for early treatment. Figures 4 and 5 clearly show that the ancillary properties of different P blockers cannot be consideredclinically significant. Both selective (e.g., atenolol and metoprolol) and nonselective (e.g., propranolol) agents have been shown to reduce mortality. Intrinsic sympathomimetic activity has been associatedwith both a beneficial effect on mortality (practolol) and an actual increasein mortality (oxprenolol), and class III antiarrhythmic activity (sotalol) does not appear to confer any particular advantage in terms of preventing mortality. The only conclu-
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER 25,199O
!%
A SYMPOSIUM:
TABLE
PRIMARY
I Calcium
AND SECONDARY
Antagonists
After
Myocardial Mortality
MDPIT = Multicenter Diltiazem tion Reinfarction Israeli Nlfedipine
Postinfarction Trial.
Infarction
(%)
Placebo Nifedipine Trent Study 198612 SPRINT 198813 Verapamil Danish 198414 Diltiazem Non-Q-wave 198615 MDPIT 198816
PREVENTION
Active
6.3 5.7
6.7 5.8
13.9
12.9
3.1 13.5
3.8 13.5
Trial: SPRINT = Secondary
Preven-
sion from meta-analysis of the many trials of secondary prevention is that /3 blockers reduce mortality, an effect probably common to all drugs of this class. CALCIUM ANTAGONISTS AND SECONDARY PREVENTION The utility of the p blockers in reducing mortality, coupled with experimental evidencethat calcium antagonists limit the size of infarct,’ l led to a seriesof large trials to establish whether calcium antagonists have any effect on reducing mortality in patients with myocardial infarction. Experience gained from the P-blocker trials permitted a more rapid evaluation of the efficacy of calcium antagonists. Unlike the /3 blockers, calcium antagonists were not shown to reduce mortality. Table I lists 5 large trials that were carried out with nifedipine (both early’* and later3 administration), verapamil14 and diltiazem.i5J6The results of these trials demonstrate approximately equal mortality rates in patients receiving placebo and active treatment (Table I). The Multicenter Diltiazem Postinfarction Triali enrolled 2,466 patients, of whom approximately 70% had had a Q-wave infarction. In patients with non-Q-wave infarction, diltiazem was reported to reduce reinfarction, but not death.15However, the significance of this result is uncertain because some of the definitions used in the study were inexact, and the observation has not been confirmed by subsetanalysis of the other trials. In conclusion, analysis of the secondary prevention trials with calcium antagonists showsthat there is no preventive role for thesedrugs, although they can be useful in the treatment of angina pectoris. SECONDARY PREVENTION BASED ON THE RESULTS OF CLINICAL TRIALS Meta-analysis of these trials of secondary prevention doesnot provide answersto several therapeutic questions of paramount importance to the clinician. For example, are there subgroups of patients who may benefit more than others? Are all /3blockers equivalent in their effect in secondary prevention? What is the optimal dose? In addition, the P-blocker trials were completed for the most part before the widespread use of aspirin as a secondary prevention agent, and it is not known whether the protective effects of aspirin and the @blockers are additive, 6C
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
OF CARDIOVASCULAR
DISEASE
although theoretically this seemslikely. Similarly, it is not known whether the early useof a 0 blocker increases the protective effect of thrombolytic agents. Early or late treatment? Despite the evidencefrom the ISIS-l9 and MIAMI8 trials that early treatment with an intravenous fl blocker reduces mortality, this treatment modality has not become routine practice in the United Kingdom or in many other European countries. There are probably 2 reasonsfor this. First, both trials included very low-risk patients (placebo group mortality rates in ISIS-l and MIAMI were 4.5 and 4.9%,respectively); becausethe true overall mortality rate of patients admitted to the hospital with suspectedmyocardial infarction is 3 or 4 times higher than this, most clinicians are unsure if the results of the trials really apply to the patients they seein routine practice. Second,the MIAMI trial results only apply to a small proportion of the patients admitted to the participating hospitals (5,784 patients included out of 26,439 admitted), and it is not immediately obvious to a clinician how to selectpatients for treatment in the way that was usedin the trial. Moreover, it is not known how the 16,027patients included in ISIS-I were selected, since no register of excluded patients was kept. Crude calculations suggest that each center was only randomizing 1 or 2 patients per month; thus, somespecial form of selectionmay havebeenoccurring inadvertently. Thus, becauseearly /3-blockingtherapy might be harmful in certain patients, mostclinicians in the United Kingdom do not begin prophylactic treatment until after the acute stage of the infarction. Which patients should be treated? Since the results of clinical trials apply only to patients similar to those who fulfilled the inclusion and exclusion criteria established in the protocol, information is not available about the effect of @blockers on infarct survivors with conditions normally considered to be contraindications for treatment, such as asthma and heart failure. As noted previously, there is a low mortality rate in the placebo groups of many of the secondary prevention trials, but without knowing the fate of patients excludedfrom these trials, it is difficult to be certain of the significance of these figures. The trial of early nifedipine in acute myocardial infarction (Trent study) *2wasthe only large postinfarction study in which a register of excluded patients was maintained and all of thesepatients werefollowed for the duration of the study. The mortality rates in the patients randomized to placebo or nifedipine treatment were 6.3 and 6.7%, respectively, but in the excluded patients, the mortality rate was 18.2%.Therefore,the Trent study applies only to patients at low risk, and it seems likely that the same is true of all the P-blocker trials. Some, but not all, of the P-blocker trials excluded elderly patients. Few trials attempted to define any particular type of patient for inclusion, although the propranolol study by Hansteen et alI0 set out to include only those at high risk. Therefore, attempts to identify special groups of patients who might particularly benefit from or be harmed by @-blockingtherapy depend on subgroup analysesof the published trial, which is always an unreliable process.The problem is that the moresubgroupsthat
25
FIGURE 6. Beta blockers after myocardial infarction: relation between point estimates of relative risk reduction or increase and the placebo mortality rate.
Placebo Mortality W)
0 -60 -40 -20 % Relative risk increase
are constructed within which to compare the effects of treatment, the greater the likelihood that an apparently “significant” difference will occur by chance. In general, subgroup analysis should only be used as a means of generating hypothesesthat can be used as a basis for subsequenttrials. In fact, subgroup analysis of the pblocker trials does not identify any patient group that shouldbe treated differently: patients of all agesas well as with all sites of infarction as documented by the electrocardiogram seemedto benefit equally from treatment. Thus, the principal difficulty is to decide whether patients at low or high risk should be treated. Since the prognosisin low-risk patients-the young and those with a first infarction-is good, it may not be useful to treat them, especially in light of the adverse effects that may occur, such as lethargy, muscular aches and pains, cold extremities and impotence.On the other hand, patients at high risk-the elderly, those with multiple previous infarctions and those with poor left ventricular functionmay beharmed by @-blockingtherapy by the induction of heart failure, in addition to the adverse effects of these drugs. Subset analysis of the P-blocker trials in terms of likely risk has also proved unhelpful. In the Norwegian timolol trial,4 the overall relative risk reduction was 36%, whereasin the subgroup with a previous infarction it was 21%. In other subgroupsconsideredto be at high or low risk, the relative risk reductions were 40 and 53%, respectively. Similarly in BHAT,5 the overall risk reduction was 26%,whereasin the subgroupwith a previous infarction it was IX%, and in those who were consideredto be at high or low risk, it was 30 and 27%, respectively. Figure 6 summarizes the relation between the trial resultsand the risk of the patients included by relating the relative risk reduction (or increase)associatedwith active treatment to the placebomortality rate seenin each of the main trials. It has been assumedthat the placebo rate indicates the degreeof risk of the patients included. Al-
0
20 40 60 % Relative risk reduction
though Figure 6 indicates a trend suggestingincreasing benefit from 0 blockers with increasing patient risk, this is far from statistically significant. Thus, a p blocker seems to be indicated for most patients who survive a myocardial infarction, although treatment should be withdrawn immediately in low-risk patients who experiencetroublesome adverse effects. Which beta blocker? Among the late entry trials, both timolo14 and propranololrO have been shown to reduce mortality, although it is likely that all @blockers are effective in secondaryprevention after myocardial infarction. Clearly, practicing clinicians will prefer an agent with proven efficacy and a simple dosageregimen; in the study cited previously, timolol was shown to be effective at dosesof 5 to 10 mg twice daily. CONCLUSIONS
Despite their beneficial effects in angina, calcium antagonists have no preventive effect in patients with myocardial infarction. Meta-analysis of trials of secondary prevention appears to indicate that p blockers are effective in reducing mortality in patients with myocardial infarction, although to date, there are no data to suggest that either high- or low-risk patients in particular will benefit from treatment, nor that the ancillary properties of different drugs in this class are significant in reducing mortality. Therefore, @blockers are generally warranted for most patients who survive a myocardial infarction, although clinical practice and recommendationsregarding a particular drug or dose must be made according to the present condition and past history of each patient. Additional information in this clinical setting will not be available until the relevant clinical trials are conducted. REFERENCES 1. Snow 553,
PJD. Effect of propranolol in myocardial infarction. Lancer 1965;2:551-
2. Wilcox RG, Roland JM, Banks DC, Hampton JR, Mitchell JRA. Randomized trial comparing propranolol with atenolol in immediate treatment of suspected
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myocardial infarction. Br Med J 1980;280:885-888. 3. Hampton JR, Presentation and analysis of the results of clinical trials in cardiovascular disease. Br Med J 1981;282:137/-1373. 4. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction, N Engl J Med 1981;304:801-807. 5. &Blocker Heart Attack Study Group. The P-blocker heart attack trial. JAMA 198/;246:2073-2074. 6. Yusuf S, Peto R, Lewis .I, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiouasc Dis 1985
