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Philosophy represents a critical examination of the
grounds for fundamental believes and an analysis of the basic concepts employed in the
expression of such believes. This may also be applied to the upraise of medical
innovations and their implementation in clinical practice which are characterised by
phases of euphoria, doubt, reflection, and finally acceptance or rejectance. Such
developments have been very characteristic for the management of supraventricular or
ventricular arrhythmias over the past 25 years. After identification of markers of poor
prognosis after myo-cardial infarction, especially frequent and complex ventricular
arrhythmias1, attempts to prevent sudden cardiac death
with antiarrhythmic drugs were based on the hypothesis that suppression of these
arrhythmias would finally prevent the development of ventricular tachycardia and
ventricular fibrillation. This approach found wide-spread application despite the warning
that no randomised trial had ever shown any benefit. By many, it was even considered
unethical to perform such a randomised controlled clinical trial using an antiarrhythmic
drug versus placebo. Only when the results of the CAST studies2,3
were published showing greater harm of patients on class Ic antiarrhythmic drugs, serious
doubts arose which seem to have opened the box of Pandora. In CAST and Beyond.
Implications of the Cardiac Arrhythmic Suppression Trial, a Task Force of the Working
Group on Arrhythmias of the European Society of Cardiology discussed the implications of
these findings4. Subsequent observations suggested that
also under other circumstances, treatment with class I antiarrhythmic drugs was
detrimental in the presence of poor left ventricular function. The seemingly paradox that
the proportion of sudden death decreases in heart failure with increasing overall
mortality and increasing frequency of ventricular arrhythmias, finally dissociated the
trigger factor from the arrhythmogenic substrate. The Sicilian Gambit Approach to
Antiarrhythmic Drug Actions was an opening move (similar to chess) of a part of a group of
basic and clinical investigators that reconsidered the classification of antiarrhythmic
drugs and proposed that new approaches in our thinking would be necessary5. Analysis and treatment of arrhythmias should include
the elucidation of the probable mechanisms, the critical components and the vulnerable
parameters, the targets, the specific interventions, and the clinical results obtained.
The intention was to move closer to a pathophysiologic approach and a clinical test of
mechanistic appreciation and eventual prediction.
The transient hope that class III antiarrhythmic drugs would hold the test of time was
disappointed by the results of SWORD (Survival With ORal D-sotalol) which evaluated
d-sotalol (devoid of beta blocking effects) in patients with reduced left ventricular
function early or late after myocardial infarction6.
When interim analysis showed a higher mortality of patients on d-sotalol in comparison to
placebo, the trial was stopped. Serious doubts arose on the usefulness of pure class III
antiarrhythmic drugs. Amiodarone, an old antiarrhythmic drug with a variety of actions
beyond class III activity, yielded controversial results in primary prevention studies
with either benefit (GESICA7, EPAMSA8,
BASIS9, PAT10) or
neutral effects (CHF-STAT11, EMIAT12,
CAMIAT13) on overall mortality whereas, for instance,
arrhythmic death was significantly reduced in EMIAT and CAMIAT.
The Sicilian Gambiteers, when meeting again in 1996, deliberated whether new
antiarrhythmic and/or cardioprotective drugs are available, whether there are novel
approaches on the horizon for which arrhythmia drugs are needed, whether there is a prove
of efficacy and safety, and what trials are needed in the future. It was evident that
future research should concentrate on molecular biology and genetics with identification
of the molecular lesion, for instance, ion channel mutations or altered connexin
expression, on congenital arrhythmia variants, on identification of the mechanisms of
remodelling, on assessment of the importance of constitutional and environmental factors,
on the screening of new drugs based on peptide libraries, existing compounds and natural
products, and on the development of target-oriented drugs. However, presently it is still
a long way, when ever achievable, to develop the safe and effective drug that is easy to
take, has no side effects and prolongs life which everybody would desire.
Developments in electrical therapy of arrhythmias have been more successful. For some
arrhythmias like av-node reentrant tachycardia and av-reentry tachycardias incorporating
an accessory pathway, radiofrequency catheter ablation has developed into a very
successful, effective and safe procedure which in many cases has become the treatment of
choice14,15. It has completely replaced antitachycardia
surgery for supraventricular arrhythmias whereas only a small segment of patients is
nowadays operated upon for ventricular tachycardia using map-guided surgery. The area of
management of ventricular tachyarrhythmias has been revolutionised by the implantable
cardioverter defibrillator of which the original concept was developed by Michael Mirowski16. This concept was initially and for some time seriously
challenged by some authorities in the field. ICD-therapy started with enthusiasm on his
side and his co-workers side but with serious doubts in the scientific community but
slowly reached the level of acceptance for daily management of these patients. This is
evidenced by the marked growth in the number of devices implanted worldwide. Retrospective
and case-control analyses comparing patients on ICD therapy with those receiving
antiarrhythmic drugs suggested major benefits of ICD therapy. Only very recently, AVID,
the Antiarrhythmics Versus Implantable Defibrillators trial reported a 38% reduction in
death in the defibrillator group after one year compared to mostly amiodarone and, in a
fewer cases, sotalol therapy17. This secondary
prevention trial was preceded by the results of the primary prevention trial in patients
after myocardial infarction and poor left ventricular function with nonsustained
ventricular tachycardia MADIT, (Multicenter Automatic Defibrillator Implantation Trial)
which also had shown a significant benefit of ICD therapy versus conventional
antiarrhythmic drug therapy18. Astonishingly, the
CABG-Patch trial that randomised patients with poor ventricular function and abnormal
signal-averaged ECGs but no documented sustained tachyarrhythmias intraoperatively to
receive an ICD or no ICD, did find neither a benefit nor harm of ICD therapy19. These controversial results are the basis for an
ongoing discussion on the reasons which might include the effect of accompanying
beta-blocker therapy that was not controlled for in the study design.
The concepts of antiarrhythmic therapy have changed rapidly over the last 25 years
with periods and areas of doubts, but also areas of potential benefit and outlook into a
future which might provide a better understanding of the underlying molecular biological
and genetic mechanisms and may finally lead to even better therapeutic interventions.
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Treatment of
arrhythmias – mechanisms
CAST trial, SWORD trial, GESICA trial, EPAMSA trial, BASIS trial, PAT trial, CHF-STAT
trial, EMIAT trial, CAMIAT trial, class Ic, III drugs, amiodarone, Sicilian Gambit,
molecular biology, gene disease, ICD therapy, AVID trial, MADIT trial, primary prevention,
secondary prevention, CABG-Patch trial, R
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