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Sudden cardiac death is a major cause of death in the
western hemisphere. The majority of patients who present with sudden cardiac death have
organic heart disease, mainly chronic coronary artery disease manifested by previous
myocardial infarction and left ventricular dysfunction.
There are a variety of potential causes of sudden cardiac death. Malignant ventricular
arrhythmias, ie primary ventricular fibrillation and sustained ventricular tachycardia
account for most sudden cardiac deaths (at least 75-80%), although the exact proportion
depends on the underlying organic heart disease. In order to prevent sudden cardiac death,
we need to prevent malignant ventricular arrhythmias, however appropriate treatment for
the prevention of sudden cardiac death remain an unresolved issue.
With development of newer therapeutic modalities, therapeutic strategies are changing
rapidly and relative roles of antiarrhythmic drug therapy and non pharmacologic therapy
are evolving rapidly. Many different strategies for primary and secondary prevention of
malignant ventricular arrhythmias have been developed and have been undergoing evolution.
Particularly, antiarrhythmic drug therapy and implantable cardioverter defibrillator, two
commonly used therapeutic modalities, are undergoing a dramatic evolution. Now it is well
recognized the difficulty in assessing the impact of new therapies without the advantage
of well designed, prospective, randomized studies. Any small amount of progress toward a
clinical solution to the problem of sudden cardiac death has been the product of
prospective, randomized trials.
Recent experiences in cardiovascular trials showed that desired and anticipated
therapeutic benefits are sometimes not confirmed when tested with prospective randomised
trials. The key benefit of randomisation is the elimination of the potential for bias in
patient selection that cannot be only large but cannot be effectively controlled in any
other way. While randomisation of patients is only one of many factors required to yield
reliable information in evaluating therapies studies, studies are inherently unreliable
without it. The real problem is that we need randomised trials, not case series.
Moreover, methods of assessing long term survival benefit from these therapies are
also evolving. As recommended by NASPE, total mortality should be used as an end-point for
efficacy of antiarrhythmic therapy. Other end-points, such as sudden cardiac death can be
used for the purpose of specific studies; however they should not replace total mortality
as the primary end-point.
The bulk of randomised, placebo-controlled data has been collected in patients only
suspected to be at risk for malignant ventricular arrhythmias, but in whom malignant
ventricular arrhythmias not yet occurred. Therefore it seems appropriate to primarily
discuss the issue of primary prevention and then to review the small number of studies
were ß-blockers as well as amiodarone were included as individual treatment in patients
with documented malignant ventricular arrhythmias.
As regards antiarrhythmic drug therapy for primary prevention of malignant ventricular
arrhythmias, the results of multiple, prospective, randomised trials and meta-analytic
studies have more clearly delineated the risk and benefit of antiarrhythmic drug therapy.
A recent overview1 of antiarrhythmic drug trials on
high-risk patients for the primary prevention of sudden cardiac death have demonstrated
that there is no evidence that class I antiarrhythmic drugs are beneficial and the data
suggest an increased risk of death when used prophylactically after myocardial infarction.
Conversely, pooled data from the major b-blockers trials
and meta-analytic review of multiple, randomised, controlled trials, involving over 20 000
patients, that evaluated b-blockers1
indicate a trend toward improvement in overall survival, although limitation in study size
precludes analysis of cause-specific mortality.
Furthermore, experience accumulated from several large trials2
strongly suggests that b-blockers should be used for the
management of chronic congestive heart failure. However to confirm the improvement in
survival recently reported with carvedilol, further prospective trials using different b-blockers, are warranted.
It is surprising that despite many years of b-blockers
usage, the mechanisms of late mortality benefit post-myocardial infarction have still not
yet established. The benefits of b-blockers are likely due to
multiple effects, including relief of ischemia, prevention of cardiac rupture, reduction
of heart rate and maintenance of favourable autonomic balance. It is important to
underline that the favourable effects of b-blockers are not
tightly linked to the suppression of ventricular antiarrhythmic, since b-blockers
suppress arrhythmias only at modest extents. Therefore, although b-blockers
do not act directly on ventricular arrhythmias, they have nevertheless a substantial
effect by continuously modulating the arrhythmogenic influences on the substrate.
The beneficial effects of b-blockers are extremely
convincing and conclusively demonstrated. Although this clear evidence has led several
national consensus committees to strongly recommend the use of b-blockers
in eligible patients after myocardial infarction, these drugs are substantially underused3-4. There are many reasons why physicians continue to
omit such agent from patient's regimen. These reasons may include mistaken belief that b-blockers are harmful or less beneficial for patients with left
ventricular dysfunction and exaggerated concerns regarding adverse effects on quality of
life. b-blockers are also uncritically avoided in elderly
patients although such an attitude is unfound. Moreover extensive marketing of the newer
Ca-antagonist may also have contributed to clinicians negative attitude toward b-blockers (although the apparent frequent substitution of
Ca-antagonist for b-blockers following myocardial infarction is
associated with an increased mortality risk). It is important to note that 27% of the
patients in the CAST trial were given b-blockers as concomitant
therapy to the blind medication (and this percentage confirms that the b-blockers
are underused). Patients receiving b-blockers therapy were
found to have significantly better survival (apparently 1/3 less mortality) than patients
treated without b-blockers. The use of class I antiarrhythmic
drugs did not cause a higher mortality when compared with placebo in contrast to findings
when class I was given without concomitant b-blockers. It thus
seems that the use of b-blockers that revealed to be
significant independently related to a decreased risk of sudden cardiac death, prevents
the proarrhythmic effects of class I drugs. This is in agreement with a number of
observation1 showing that there is a reversal of
antiarrhythmic effects of class I antiarrhythmic drugs in the presence of cathecolamines.
There has been a clear increasing use of b-blockers in
primary prevention in patients with myocardial infarction3.
Quite likely intensive participation in large randomised clinical trials may have
contributed to the attention to the treatment prescribed. This trend probably indicates a
generalised acceptance of the results of randomised trials in clinical practice, as well
as lessening in the fear often associated with the use of b-blockers.
However, in spite of the significant increase in the use of b-blockers
in high-risk patients, still too many physicians seem more reluctant to the use of b-blockers in clinical practice than is justified by the available
evidence. Thus too many patients are still denied the advantage of such treatment, even
among patients presenting specific clinical indication. Today less than half of patients
whom could benefit from this treatment is treated like this.
Amiodarone is a unique antiarrhythmic drug originally as class III agent which also
exerts class I, II and IV effects, with several antiarrhythmic action an unusual
pharmacokinetics1. On the other hand, a direct evidence
of deleterious effects of pure class III drugs in the absence of b-blocking effects was
forthcoming in the Survival With ORal D-sotalol (SWORD6)
trial in post-myocardial infarction patients with reduced ejection fraction.
A number of randomised placebo-controlled trials have been done to evaluate the impact
of amiodarone in total mortality in patients at high risk for malignant ventricular
arrhythmias and sudden cardiac death. These trials have included two overlapping high-risk
populations: survival of myo-cardial infarction and patients with chronic congestive heart
failure. In GESICA7, a placebo-controlled, prospective,
randomised trials of amiodarone in patients with severe congestive heart failure, the
study population was stratified according to the present of non sustained ventricular
tachycardia. Patient treated with amiodarone had a risk reduction of total mortality of
28%. Furthermore, amiodarone was associated with significantly lower rate of sudden
cardiac death and death from progressive congestive heart failure. In CHF-STAT8, a placebo controlled randomised trial that examined the
effect of amiodarone on total mortality in patients with congestive heart failure and 10
or more premature ventricular beats, amiodarone had no effect on total mortality at two
years. Anyway there was a trend in favour of amiodarone among patients with idiopathic
cardiomyopathy. The use of amiodarone in small post-myocardial infarction trials was
encouraging but nor entirely consistent1. The need for
larger trials was strong. However, the recent published results of the two largest
amiodarone trials9,10, have raised much controversy and
have not resolved the therapeutic dilemma regarding the use of amiodarone in
post-myocardial infarction patients. Both CAMIAT9 and
EMIAT10 trials reported substantial statistically
significant reduction in risk of sudden cardiac death (48 and 35% respectively), but both
trials failed to detect significant differences in total or cardiac mortality between the
amiodarone and placebo groups.
It is important to note, as outlined by Yap and Camm11,
that both CAMIAT and EMIAT showed that there was an important synergistic interaction
between amiodarone and b-blockers in reduction of total
mortality. In EMIAT there were fewer cardiac deaths among amiodarone treated patients who
were receiving concomitant b-blockers (45% of patients) than
among those who were not. Similarly, of those patients who received b-blockers
there was a substantial reduction in total cardiac mortality among those who were also
given amiodarone. In CAMIAT the reduction in sudden cardiac death among amiodarone treated
patients was even greater in those patients (60%) also taking b-blockers
than in those who were not (relative risk reduction 87%). This finding suggests that the
benefit of amiodarone is likely to be additive to that of b-blockers.
The mechanism of protection is unknown, however this reviews the possibility of a greater
potential benefit of using a combination therapy with b-blockers
and amiodarone in reduction of sudden cardiac death and total mortality among
post-myocardial infarction patients. Obviously, since previous large-scale trials and
meta-analysis have showed that b-blockers improve survival
after myocardial infarction and also reduce sudden cardiac death and total mortality,
hence any antiarrhythmic drug must confer additional benefit if it is to be of clinical
value. A randomised-controlled trial will be useful to explore the potential of
combination of b-blockers and amiodarone.
Both CAMIAT and EMIAT represented the largest trials to date examining the
prophylactic use of amiodarone in post-myocardial infarction patients; however neither
these trials had sufficient power to detect modest but important reduction in total
mortality. Therefore the principal investigators of all relevant amiodarone related trials
in survivors of myocardial infarction or congestive heart failure patients have
collaborated to carry out a systematic meta-analysis to obtain a more precise estimation
of the effects of amiodarone on sudden cardiac death and total mortality. This
meta-analysis12 has shown that amiodarone reduces the
risk of sudden cardiac death, but has little or no effect on non-arrhythmic death. Effect
on total mortality is statistically significant with a risk reduction of 13%. Since the
relative risk reduction is similar among different type of patients, the greatest absolute
benefit will occur among those whose risk of sudden cardiac death is highest (patients
with congestive heart failure or left ventricular dysfunction). Thus, prophylactic
amiodarone would be a reasonable treatment in patients at particularly high risk. The
rates of adverse effect experiences due to amiodarone that resulted in early permanent
discontinuation of drug were low and mainly serious side effects were few. No cases of
torsade de pointes were observed, in striking contrast to the finding in the other class
III trials.
Critical in the evaluation of the potential prophylactic antiarrhythmic therapy is the
definition of the best contemporary antiarrhythmic therapy. For example, recently
concluded MADIT trial12 regarding the prophylactic use
of implantable cardioverter defibrillator, enrolled patients with previous myocardial
infarction, low ejection fraction, non-sustained ventricular tachycardia and inducible not
suppressible ventricular tachycardia during programmed ventricular stimulation.
"Conventional therapy" was compared with implantable cardioverter defibrillator.
The result showed marked reduction in mortality (54%) with implantable cardioverter
defibrillator therapy. However, although 74% of the patients assigned to receive
"conventional therapy" were taking amiodarone, less than 15% of the patients in
the "conventional therapy" group were received b-blockers
(versus 27% of patients in the implantable cardioverter defibrillator group confirming the
underuse of these drugs!). The underuse of b-blockers may be,
in part, attributable to the fact that 79% of conventionally treated patients were treated
with amiodarone, with the erroneously assumption that this drug provided equivalent
protection to b-blockers. As stated by Friedman14 the real question, that cannot be answered by MADIT, is
whether implantable cardioverter defibrillator offers any survival benefit over
"truly conventional therapy". "Conventional therapy" is the therapy
that is known to be beneficial and that in absence of contraindication should be given to
everyone. In patients with previous myocardial infarction such therapies should include
ß-blockers, eventually in combination with amiodarone as suggested by the results of
EMIAT and CAMIAT.
It is mandatory an optimal use of effective conventional therapy to avoid important
limitation of the recently reported trials. The additional planned trials of prophylactic
implantable cardioverter defibrillator therapy (SCD in heart failure trial and MADIT II)15 comparing the device with the best conventional therapy
have to consider this point.
As regards the use of antiarrhythmic drugs as secondary prevention of malignant
ventricular arrhythmias and sudden cardiac death, the results of observational,
retrospective and non-controlled studies1 have
suggested the efficacy of empirical ß-blockers in patients with malignant ventricular
arrhythmias, even if refractory to conventional treatment and more favourable results when
combined with other antiarrhythmic drugs, mainly amiodarone. Similarly, non controlled and
non randomised studies1 suggested a significant
reduction in sudden cardiac death in patients treated with amiodarone. The results of few
randomised clinical trials16-18 have changed our
paradigm with respect to the preferred approach to antiarrhythmic drug therapy. The
results of these trials have shown a superiority of the drug-specific responses over
technique-specific responses. The technique of programmed ventricular stimulation (or
Holter monitoring) has not been validated against an independent and inherently valid
control. No controlled studies have been conducted to address whether better outcomes of
patients treated with programmed ventricular stimulation-guided therapy are the results of
drug therapy or if programmed ventricular stimulation simply identified patient with
favourable outcome. No defined degree of suppression of ambient arrhythmias has provided
an index to predict a favourable impact on mortality due to malignant ventricular
arrhythmias. Briefly, the results of these trials have shown that class I antiarrhythmic
drugs, even guided by Holter monitoring or programmed ventricular stimulation are inferior
to therapy with empirical amiodarone (as in CASCADE16)
or therapy with empirical metoprolol (as in the study conducted by Steinback17) or therapy with sotalol guided by Holter monitoring
(as in ESVEM study18).
It is interesting to know that in a subsequent analysis of ESVEM19
the survival benefit of sotalol relative to class I drugs was apparent only in patients
not treated with b-blockers; survival was similar in
sotalol-treated patients and those treated with b-blockers in
addition to class I drugs.
These data essentially limit the choice of antiarrhythmic drugs to b-blockers
and amiodarone.
The role of amiodarone and b-blockers in patients with
malignant ventricular arrhythmias needs to be re-evaluated, especially with availability
of implantable cardioverter defibrillator. Obviously no trial will be able to assess the
absolute benefit of active therapy in this population since each trial has a positive
control group. In fact ethical considerations preclude clinical trials to evaluate how
much active therapy improves survivals compared to no therapy.
Three large prospective, controlled, randomised trials (CASH, CIDS and AVID15) have been developed in order to evaluate the efficacy
of the best medical therapy (b-blockers or amiodarone) in
comparison to implantable cardioverter defibrillator in patients with malignant
ventricular arrhythmias. The recently stopped AVID trial20
found marked reduction in the risk of death with implantable cardioverter defibrillator
(27%) at two years in comparison to amiodarone treated patients. However only 16% at the
entry and 10% at the time of last follow-up of the medically treated patients were taking b-blockers versus 42 and 39% respectively of the implantable
cardioverter defibrillator group. Therefore like in MADIT there is an underuse of b-blockers in conventionally treated patient and significantly
greater use of b-blockers in implantable cardioverter
defibrillator patients. Many physicians may have felt that the addition of b-blockers to amiodarone was not necessary or may aggravate
brady-arrhythmias. Although subgroup analysis suggests that this treatment imbalance has
no important effect on outcome, it is hard to ignore, as suggested by Myerburg21, the possibility that some of the apparent benefit of
implantable cardioverter defibrillator may have in fact be due to b-blockers.
On the other hand preliminary results from the CASH have shown no significant difference
in the incidence of sudden cardiac death and total mortality between patients treated with
metoprolol, amiodarone or implantable cardioverter defibrillator. In conclusion,
implantable cardioverter defibrillator is superior to amiodarone for increasing overall
survival, however is probably uncorrected to select amiodarone as representing the best
available antiarrhythmic therapy, as stated in AVID. The best contemporary antiarrhythmic
medical therapy is probably the combination of b-blockers and
amiodarone. In the future, if combination of b-blockers and
amiodarone will be proved as effective as implantable cardioverter defibrillator in the
control of malignant ventricular arrhythmias, it would be ethical to compare newer
antiarrhythmic drugs versus b-blockers plus amiodarone.
Alternatively a newer antiarrhythmic drug may be evaluated against placebo in
controlled trials utilizing implantable cardioverter defibrillator in the both treatment
limbs.
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