TREATMENT OF PATIENTS WITH RISK OF SUDDEN CARDIAC DEATH

Some Pathophysiological Concepts

Dalmo Antonio Ribeiro Moreira M.D, PhD

Head of the Medical Section of Cardiac Arrhythmias and Electrophysiology, Dante Pazzanese
Institute of Cardiology in Sao Paulo, Brazil
Professor in the Department of Human Physiology, Faculty of Medicine Itajubá, Minas Gerais
dalmoantonio@gmail.com

The treatment of patients at risk for sudden death, should be established in a broader
context. Complex ventricular arrhythmias are risk markers and identify the patients
most prone to this catastrophic complication however, its role does not seem to be
predominant in the pathophysiological mechanism that culminates in sudden death. A
fact that supports this assertion is that the abolition of ventricular extrasystoles with
antiarrhythmic therapy did not reduce the sudden mortality as demonstrated in studies
CAST I (NEJM 1989, 321:406-12) and CAST II (NEJM 1992; 327:227-33). In another
study that used amiodarone, type I antiarrhythmic drugs and placebo in treating patients
with a history of ventricular arrhythmia after myocardial infarction, patients who used
amiodarone had improved survival and within this group, the density of ventricular
extrasystoles on 24 hour Holter was similar between those who died and who remained
alive. In other words, it was not the abolition of the ectopic beats that improved the
prognosis, but a likely anti-adrenergic effect and by raising the ventricular fibrillation
threshold effects (class III action).

Another important fact in the concept of risk reduction for sudden death is the use of
non-antiarrhythmic medication. The major class of drugs shown to reduce total
mortality and sudden death in post-infarction and in patients with heart failure, is that of
beta-blockers (Teo KK, et al. JAMA 1993, 270:1589-1595). Other studies have
demonstrated reduced mortality with the use of inhibitors of angiotensin converting
enzyme, angiotensin receptor blockers, statins and aldosterone antagonists (Alberte C,
Zipes DP: JCE 2003, 14 (suppl): S87-S95). It should be noted that these agents are not
antiarrhythmic however, have proven effective as adjuvant therapy in patients at risk.
Thus, one should suspect that the prevention of sudden death is not based on pure and
simple abolition of complex ventricular arrhythmias, something else is involved.

With the advancement in the treatment of heart disease, we observed an increase in the
survival of the population and thus the physician is now treating patients with advanced
age. Currently the mortality due to heart failure is 50% less than 20 years ago. During
this period, there were not news in antiarrhythmic therapy that could modify the natural
history of arrhythmogenic heart diseases which are associated with increased risk of
sudden death. There was an improvement, however, in the approach to coronary artery
disease and heart failure, for example.

One of the greatest advances in the prevention of sudden death was the advent of
automatic cardiac defibrillators (ICD). These devices detect a potentially malignant
arrhythmia and release shocks of varying intensity to restore normal heart rhythm. In
this condition, malignant arrhythmia should be present for the therapeutic effect is
demonstrated. The ICD therefore does not prevent the onset of arrhythmia, but reverses
the ventricular arrhythmia for normal heart rhythm a few seconds after its onset. This
therefore is a form of treatment plan different from that designed for antiarrhythmic
drugs. With drugs, the primary objective is to reduce the likelihood of an arrhythmia
appears, with the ICD the abnormal heart rhythm is normalized. For this reason it is an
important concept that these two forms of treatment should not be competitive, but
complementary, aimed at reducing sudden death.

Several studies over the last two decades compared the efficacy of drug therapy to ICD
in reducing sudden death, both with regard to secondary prevention and for primary
prevention, ie for those who have not had that outcome. In the vast majority of them it
was noted that the drug was less effective and in some cases even more damaging than
the ICD, to cause increased mortality. The poor efficacy and risk of drug therapy are
perhaps the main reason for the increased use of ICD in recent decades. What one see
today is an excessive implant indication, ie more than it should be admitted, and a major
cause of that hype is the difficulty in establishing which patients who will most benefit
from this form of treatment. Unfortunately, most methods of risk stratification,
particularly non-invasive, has low positive predictive value for identifying patients at
risk, as is the electrophysiological study. Thus, one may be sinning by excess indication
of the likely benefit of the ICD in the patient.

To better improve the criteria for ICD indication, a recent publication highlights some
clinical variables that can be employed to better characterize the population that could
benefit from the implant, they are: heart failure with functional class> II, age above 70;
plasma urea> 26 mg%, QRS duration> 120 ms and the presence of atrial fibrillation
(Goldenberg I et al. JACC 2008, 51:288-96). It should be noted that in these criteria the
presence of malignant ventricular arrhythmias is not included. This shows the current
concern for the influence of other factors in the mechanism that culminates in death, in
addition to arrhythmias, which can undoubtedly influence the prognosis.

Use of Amiodarone in the Treatment of Patients with High Risk for Sudden Death

Studies conducted over the past decade (CASCADE, GESICA, CAMIAT, EMIAT, etc.)
highlighted the beneficial effects of amiodarone in reducing arrhythmic mortality in
patients with ventricular arrhythmia. What was not shown however, was the reduction
in overall mortality and this is the main criterion, for the practical point of view, to be
used by clinicians to indicate a specific form of treatment. It is obvious that if the
mortality of arrhythmic cause represented the largest proportion among all causes of
death, there would be a major positive impact on overall mortality, caused by
amiodarone. Two meta-analysis involving 28 randomized clinical trials using
amiodarone to treat patients at risk for sudden death, showed that this drug was
beneficial in reducing overall mortality (from 19% to 25%) and sudden death (up to 30
%) (Slim R et al. Circulation 1997, 96:2823-9; ATMA Investigators. Lancet 1997,
350:1417-24).

What would improve the results from one type of treatment is to identify patients who
would benefit most from it. From a clinical standpoint, it is known fact that the
antiarrhythmic drugs currently available, have no effective antiarrhythmic action in
patients with low ejection fraction or with decompensated heart failure, or even in those
with severe ventricular arrhythmia (ie, those who theoretically would need an
antiarrhythmic drug, are the ones who get the least benefit from it!) (Hohnloser SH et al.
Am Heart J 1987; 114 (1 pt 1) :1-7). For this reason, it is often difficult to interpret
studies that compared the antiarrhythmic efficacy with the implantation of ICD in
reducing sudden death in that class of patients. The SCD-HeFT showed that mortality of
patients with heart failure was lower in the group that received the ICD and the
mortality of those who received amiodarone was similar to the placebo group (Bardy
GH et al. NEJM 2005; 352 :225-37). These results could be expected since a low
ejection fraction would limit the success of drug treatment. Moreover, a sub analysis of
the EMIAT study showed very favorable results of amiodarone with regard to reduction
of sudden death, when patients had lower autonomic disorders assessed by RR interval
variability (Malik M et al. JACC 2000; 35:1263 -75). It is clear therefore that there is
indeed a class of patients who would benefit from the drug treatment. What is needed is
a method or combination of methods to help us in this identification.

Sub-analysis of studies CAMIAT and EMIAT demonstrated the beneficial effects of

amiodarone, when associated with beta-blockers in reducing overall mortality.
Probably, the reduction of the influence of adrenergic factors in patients
hemodynamically decompensated would explain the good results of this combination of
drugs (Bouttie F et al. Circulation 1999, 99:2268-2275). A recent study, which analyzed
data from the VALIANT trial in patients with left ventricular dysfunction after
myocardial infarction, showed that mortality of patients on amiodarone were higher
than those not receiving this agent (Thomas KL et al. Am Heart J 2008, 155:87-93). The
authors argue however that the people who received amiodarone were older, had greater
hemodynamic impairment (worse functional class) and fewer patients were on
concomitant use of beta-blockers.

The overall analysis of these data suggests that amiodarone may be useful in reducing
overall mortality and sudden death in patients at risk, particularly in the pos-infarction
patients with ventricular arrhythmia without heart failure, with ejection fraction> 40%
(condition in which ICD showed no efficacy) or in those patients with dilated
cardiomyopathy. In the latter class of patients, the AMIOVERT study showed that
amiodarone is not less effective than the ICD in reducing mortality (Strickberger AS et
al. 2003:41:1707-12 JACC). Moreover, the combination of amiodarone with beta-
blockers may be indicated for patients with some degree of heart failure with favorable
results. It should be noted however, that there is no randomized prospective study done
so far that might confirm this suggestion. What would limit the use of amiodarone
would be the risk of side effects, which implies the need for suspension of the drug.
With the association with beta-blockers, however, this risk would be lower since lower
doses could be used, thus prolonging the beneficial effects of this drug.

In conclusion, prevention of sudden death is a great challenge for clinicians today. It

should be understood that only the abolition of a malignant ventricular arrhythmia is not
enough to reduce the risk of death. Ventricular dysfunction, autonomic disturbances,
electrolyte and other as yet unknown factors, are involved in destabilization of the
arrhythmogenic substrate that culminates in the emergence of a fatal arrhythmia. It
seems clear that the currently available drugs such as amiodarone and beta-blockers,
and blockers of converting enzyme or angiotensin receptor, spironolactone, and statins
probably should be part of the therapeutic arsenal. Furthermore, it should be improved
the identification of patients likely to benefit from ICD implantation. Although this
prosthesis is undoubtedly important to reduce the risk of sudden death, it should be
noted that it is too expensive for the health system. Increased the lifespan of patients,
according to some studies, is around 2-3 months only, compared to those without ICD;
shocks applied by the generator in addition to causing myocardial damage might worsen
ventricular function, cause severe psychological disorders that compromise the quality
of life (Tung R; 2008:52:1111-21 JACC). Finally it should be noted that there is a class
of patients in which the ICD does not modify the survival rate and amiodarone,
particularly in combination with beta-blockers, can be precisely indicated. Even for
those patients with ICD, the association with drug therapy may reduce de frequency of
shocks by the generator, prolonging the battery life, and improve the patient’s quality of
life.