A brief history of sudden cardiac death and its therapy

Pharmacology & Therapeutics 100 (2003) 89 – 99 www.elsevier.com/locate/pharmthera

A brief history of sudden cardiac death and its therapy Michiel J. Janse* Center for Molecular Therapeutics, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, PH7West-318, New York, NY 10032, USA

Abstract At the end of the 19th century, there was both experimental and clinical evidence that coronary artery obstruction causes ventricular fibrillation and sudden death and that fibrillation could be terminated by electric shocks. The dominant figure at that time was McWilliam, who in 1923 complained that ‘‘little attention was given to the new view for many years.’’ This remained so for many decades. It was not until the 1960s that the medical profession became aware of the magnitude of the problem of sudden death and began to install coronary care units where arrhythmias could be monitored and prompt defibrillation could be delivered. This approach was pioneered by Julian in 1961. Milestones that allowed this development were open-chest defibrillation by Beck, closed-chest defibrillation by Zoll, cardiac massage by Kouwenhoven et al., and development of the DC defibrillator by Lown. In 1980, Mirowski et al. implanted the first implantable cardioverter defibrillator (ICD) in a patient. Thereafter, the use of the ICD increased exponentially. Several randomized trials, largely in patients with coronary artery disease and left ventricular dysfunction or in patients with documented lethal arrhythmias, showed beyond doubt that the ICD is superior to antiarrhythmic drug therapy in preventing sudden death, although a number of trials showed no effect. Trials on antiarrhythmic drugs were disappointing. Sodium channel blockers and ‘‘pure’’ potassium channel blockers actually increase mortality, calcium channel blockers have no effect, and, although amiodarone reduces arrhythmic death, it had no effect on total mortality in the 2 largest trials. Only the h-blockers have been proven to reduce the incidence of sudden death, but their effect appears not to be related to the suppression of arrhythmias but rather to the reduction in sinus rate. Drugs that prevent ischemic events, or lessen their impact, such as anticoagulants, statins, angiotensin-converting enzyme inhibitors, and aldosteron antagonists, all reduce the incidence of sudden death. D 2003 Elsevier Inc. All rights reserved. Keywords: Coronary artery disease; Ventricular fibrillation; Reentry; Implantable cardioverter defibrillator; Antiarrhythmic drugs; Randomized prospective clinical trials Abbreviations: ICD, Implantable cardioverter defibrillator.

Contents 1. 2. 3.

Introduction: the awareness of the problem . Mechanisms of lethal arrhythmias . . . . . Therapy and prevention . . . . . . . . . . . 3.1. Electrical shocks . . . . . . . . . . . 3.2. Antiarrhythmic drugs . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

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1. Introduction: the awareness of the problem

* Tel.: 212-305-8754; fax: 212-305-8351. E-mail address: [email protected] (M.J. Janse). 0163-7258/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0163-7258(03)00104-9

Although nowadays almost every grant proposal in the field of cardiac electrophysiology begins by stating that sudden cardiac death is the leading cause of death in the industrialized world, accounting for 300,000 deaths per year

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in the United States alone, and that it is therefore important to fund cardiac electrophysiological studies, it has taken the medical community a long time to become aware of the vastness of the problem of sudden death. Although sudden death is mentioned in the bible, the first studies that linked sudden death to coronary artery obstruction date from the 18th century (for further details, see the books on the history of cardiology by Snellen, 1984; Acierno, 1994; Luederitz, 1995; Bing, 1999). In 1779, John Hunter, an English surgeon and anatomist, and Edward Jenner, famous for the cow pox vaccine, almost simultaneously described extensive ossification and calcification of the coronary arteries in patients with angina pectoris who had died suddenly. (Previously, Heberden had described the syndrome of angina pectoris as a ‘‘sort of indescribable anguish across the breast,’’ syncope, and eventually sudden death but did not relate this syndrome to abnormalities of the coronary arteries (Snellen, 1984).) In 1799, Charles Parry published a book entitled An Inquiry into the Symptoms and Causes of the Syncope Anginosa Commonly Called Angina Pectoris, in which he described in detail autopsies in patients who suffered from angina pectoris and who died suddenly: ‘‘. . .after having examined the more important parts of the heart, without finding anything by means of which I could account either for his sudden death or the symptoms preceding it, I was making a transverse section of the heart pretty near to its base when my knife struck against something so hard and gritty as to notch it. I well remember looking up to the ceiling, which was old and gritty, conceiving that some plaster had fallen down. But upon further scrutiny, the real cause appeared: the coronaries were becoming bony canals’’ (Parry, 1799). Parry thought that the obstructed coronary arteries might ‘‘intercept the blood, which should be the proper support of the muscular fibers of the heart,’’ and he considered that this might diminish the ‘‘energy of the heart’’ by which he meant ‘‘the irritability or excitability.’’ It goes a bit far to conclude that Parry made the link between coronary artery obstruction and ventricular arrhythmias. The first to do so was Erichsen, who in 1840 ligated a coronary artery in a dog heart in the experimental laboratory and noted that this caused the action of the ventricles to cease, with a ‘‘slight tremulous motion alone continuing’’ (Erichsen, 1841 –1842). Experimental studies around the turn of the century confirmed and expanded these findings (Begold, 1867; Cohnheim & Von Schulthess-Rechberg, 1881; Porter, 1894, 1896; Lewis, 1909), and Cohnheim and Von Schulthess-Rechberg (1881) showed that ventricular fibrillation occurred even more often after reperfusion following a short period of coronary artery occlusion than during the ischemic episode itself. Thus, there was firm experimental evidence that both coronary artery obstruction and reperfusion cause ventricular fibrillation and sudden death. However, the clinical importance of these findings was not at all recognized, except by McWilliam. Based on his own experimental studies he wrote in 1889: ‘‘. . .sudden syncope from plug-

ging or obstructing some portion of the coronary system (in patients) is very probably determined or ensured by the occurrence of fibrillar contractions in the ventricles. The cardiac pump is thrown out of gear, and the last of its vital energy is dissipated in a violent and prolonged turmoil of fruitless activity in the ventricular walls’’ (McWilliam, 1889). McWilliam’s ideas were largely ignored by his colleagues for many decades. In the textbook Diseases of the Heart by Sir James Mackenzie, only 3 lines were devoted to ventricular fibrillation in the 76 pages on cardiac arrhythmias (Mackenzie, 1918), and Wenckebach’s monograph on cardiac arrhythmias does not mention ventricular fibrillation at all (Wenckebach, 1904). In the textbook by De Boer (1935), it is stated that ‘‘. . .from that time on (i.e., since the electrocardiograph became widely used in both the clinic and the experimental laboratory [M.J.J.]), fibrillation, and especially atrial fibrillation, became important in the clinic. Because ventricular fibrillation usually results in sudden cardiac death, it is, of course, of much less importance. Besides, ventricular fibrillation occurs much less frequently than atrial fibrillation’’ (translated from Dutch). McWilliam (now spelled MacWilliam) expressed his disappointment in 1923: ‘‘It may be permissible to recall that in the pages of this journal 34 years ago I brought forward a new view as to the causation of sudden death by a previously unrecognized form of failure of the heart’s action in man (e.g., ventricular fibrillation)—a view fundamentally different from those entertained up to that time. Little attention was given to the new view for many years’’ (MacWilliam, 1923). Little attention was given to his views for many decades to come. The reasons that ventricular fibrillation was so neglected probably are that its occurrence in man is difficult to document and that it could not be treated, a view already expressed by Sir Thomas Lewis in 1915: ‘‘Why is fibrillation of the ventricles so uncommon an experience? For a good reason: fibrillation of the ventricles is incompatible with existence. . .If it occurs in man, it is responsible for unexpected and sudden death’’ (Lewis, 1915). Gordon K. Moe wrote in 1984: ‘‘When I went to Western Reserve as a postdoctoral fellow in the laboratory of Carl Wiggers, it was against the advice of one colleague who explained that I would be put to work on ventricular fibrillation; inasmuch that was an invariably fatal catastrophe for which nothing could be done, I would be wasting a year of my scientific career’’ (Moe, 1984). A 1000-page book on myocardial infarction written in 1948 mentions ventricular fibrillation only in a footnote (Wright et al., 1948). Desmond G. Julian recalls how ‘‘In 1956, when I was training under Paul Wood at the National Heart Hospital, I was advised by a professor of medicine in London not to become a cardiologist because all the mitrals had been operated on’’ (Julian, 2001). Only in the 1960s the medical profession began to appreciate that in acute ischemia and in the early phase of myocardial infarction, ventricular fibrillation is a frequent event. Julian (1961) wrote in the Lancet that: ‘‘Cardiac

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arrest due to ventricular fibrillation or asystole is a common mode of death in acute myocardial ischemia and infarction and is responsible for several thousands deaths each year. . .a delay in starting effective cardiac massage of more than 4 min means a very high mortality and morbidity. . .Valuable minutes may be wasted on ineffective procedures such as thumping the chest and injecting adrenaline into the heart. . .There are 2 ways in which this problem of delay could be reduced. Firstly, all medical, nursing, and auxiliary staff should be trained in the techniques of closedchest cardiac massage and mouth-to-mouth breathing. Secondly, patients known to be at risk from ventricular fibrillation or asystole could have their cardiac rhythm constantly monitored. This means that all wards admitting patients with acute myocardial infarction should have a system capable of sounding an alarm at the onset of an important rhythm change and of recording the rhythm automatically on an electrocardiogram’’ (Julian, 1961). Further developments in the 1960s (Day, 1962; Brown et al., 1963; Julian et al., 1964; Lown et al., 1967), as well as the advent of mobile coronary care units recording electrocardiograms from individuals suffering cardiac arrest outside the hospital by Pantridge and Geddes (1967) and Cobb et al. (1980), provided further evidence that ventricular fibrillation was present in many cases. By this time, electrical defibrillation was not only possible but also easy (Lown et al., 1962), and in the next 20 years or so, physicians became aware that, as Lown expressed it in 1979, sudden cardiac death is the major challenge confronting contemporary cardiology (Lown, 1979). In the early studies on the coronary care unit, asystole was often found as the cause of death. It is possible that asystole was the end stage of ventricular

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fibrillation and that a delay in recording the electrocardiogram might have been the cause. Whereas in the setting of acute ischemia, ventricular tachycardia and fibrillation are the causes of cardiac arrest, in patients with severe heart failure, sudden death has been reported to be in about 50% caused by ventricular tachycardia or fibrillation and in the other half by bradyarrhythmias or electromechanical dissociation (Luu et al., 1989; Stevenson et al., 1993). In Sections 2 and 3, I shall concentrate on ventricular fibrillation. As shown in Fig. 1, the risk of sudden death among the population aged 35 years and older is in the order of 1– 2 per 1000 per year. Between the ages of 40 and 65 years, there is a marked increase, with coronary artery disease as the most important cause. In the adolescent and young adult populations, the risk is about 1% of that of the general adult population, and familial diseases play a dominant role (Myerburg & Spooner, 2001).

2. Mechanisms of lethal arrhythmias McWilliam (1887b) suggested for the first time that disturbances in impulse propagation could be responsible for fibrillation: ‘‘Apart from the possibility of rapid spontaneous discharges of energy by the muscular fibers, there seems to be another cause for continued and rapid movement. The peristaltic contraction traveling along such a structure as that of the ventricular wall must reach adjacent bundles at different points in time, and because these bundles are connected with one another by anastomosing branches, the contraction would naturally be propagated from one contracting fiber to another over which the

Fig. 1. Age-related risk of sudden death among general populations (adolescents and young adults, general population older than 35 years) and among adult populations with advanced heart disease. The probable etiologies of a cardiac arrest are dominated by coronary artery disease and cardiomyopathies at age 35 and older and by a diverse group of acquired and inherited disorders in the younger age groups (reproduced with permission from Myerburg & Spooner, 2001).

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contraction wave had already passed. . .Hence, the movement would tend to go on until the excitability of the muscular tissue had been lowered, so that it failed to respond with a rapid series of contractions’’ (McWilliam, 1887a). It is clear that McWilliam envisaged the possibility that myocardial fibers could be reexcited as soon as their refractory period had ended by an irregularly propagating impulse, and he therefore may be considered as a founding father of reentrant excitation. Yet, it was the work of Garrey and Mines, some 30 years later, that firmly established the role of reentry as a mechanism for arrhythmias. Both investigators, working independently, were inspired by the experiments of Mayer, who used an unlikely preparation, namely ring-like structures cut from the muscular tissue of the subumbrella of the jellyfish Scyphomedusa cassiopeia (Mayer, 1906). Mayer was able to induce in these rings by a single stimulus circus movements that continued to circulate along the ring. In the pivotal studies of Garrey and Mines in 1913 and 1914 (Mines, 1913, 1914; Garrey, 1914, 1924), no mechanical or electrographic tracings were presented, only the description of what the author had observed with his own eyes. The important contributions of Garrey include the demonstration that fibrillation is not due to a single, rapidly firing focus and that a minimal tissue mass is required for maintenance of fibrillation (Garrey, 1914). He induced atrial fibrillation by faradic stimulation of the tip of 1 auricular appendix then functionally separated the tip from the fibrillating auricles and found ‘‘as a result of this procedure the appendix came to rest, but the auricles invariably continued their delirium unaltered’’ (Garrey, 1914). When he excised pieces from fibrillating ventricles, he observed that ‘‘. . .any piece cut from any part of the mass of ventricular tissue would cease fibrillating if small enough (e.g., if its surface area was less than 4 cm2)’’ (Garrey, 1914). Garrey also wrote that ‘‘. . .true fibrillation is never made up of a single circuit but ever of shuttling impulses, which make many and various circuits’’ (Garrey, 1924). In his 1913 and 1914 papers, written at the age of 27 and 28 years, Mines, on the basis of his experiments with ring-like preparations of cardiac tissue, formulated the essential characteristics of reentry. (1) For the initiation of reentry, an area of unidirectional block must be present: ‘‘. . .a single stimulus applied to any point in the ring starts a wave in each direction. The waves meet on the opposite side of the ring and die out. However, by the application of several stimuli in succession, it is sometimes possible to start a wave in one direction while the tissue on the other side of the point stimulated is still refractory. Such a wave moves round the ring sufficiently slowly for the refractory period to have passed off in each part of the ring when the wave approaches it. Thus, the wave circulates and may continue to do so’’ (Mines, 1913). (2) Reentry is facilitated by slow conduction and short refractory periods: ‘‘With increasing frequency of stimulation, each wave of excitation in the heart muscle is propagated more slowly but lasts a shorter time at any point in the muscle. The wave of

excitation becomes slower and slower’’ (Mines, 1913). (3) Severance of the reentrant circuit will abolish a reentrant rhythm: ‘‘In a favorable experiment, the vigorous circulating wave, and its instantaneous arrest by section of the ring, is a sight not easily forgotten’’ (Mines, 1914). During a reentrant rhythm, interpolation of extra stimuli may stop the arrhythmia: ‘‘. . .The wave ran all the way round the ring and continued to circulate going around about twice a second. After this had continued for 2 min, extra stimuli were thrown in. After several attempts, the wave was stopped’’ (Mines, 1914). Mines also described what we now call the vulnerable period. He induced ventricular fibrillation by single induction shocks, applied at various times during the cardiac cycle. ‘‘The point of interest is that the stimulus employed would never cause fibrillation unless it was set at a critical instant’’ (Mines, 1914). He showed that a stimulus falling in the refractory period had no effect, ‘‘a stimulus coming a little later set up fibrillation,’’ and a stimulus applied ‘‘later than the critical instant for the production of fibrillation merely induces an extrasystole’’ (Mines, 1914). As described in detail by Acierno (1994), around 1920, a considerable number of people were accidentally electrocuted because more and more electrical devices were installed in households. This eventually prompted electrical companies such as Con Edison to provide grants to university departments to investigate the effects of electrical currents on the heart. This led, among others, to the rediscovery by Wiggers and Wegria of the vulnerable period in 1940 (they coined the name) (Wiggers & Wegria, 1940). In that paper, Mines is not mentioned, but in a later paper by Wiggers, a brief allusion to Mines is made (Wiggers, 1940). Bernard Lown, who in the early 1960s introduced DC defibrillation and cardioversion for atrial fibrillation (Lown et al., 1962; Lown, 1967), wrote recently: ‘‘Ignorance of the history of cardiovascular physiology caused me to waste enormous time in attempting to understand a phenomenon long familiar to physiologists,’’ (Lown, 2002) and then gives full credit to Mines’ discovery. A more detailed description of the contributions of Mayer, Garrey, and Mines can be found in the excellent reviews by Rytand (1966), Rosen (1992), and DeSilva (1997). During the second half of the 20th century, further insight into the mechanism of fibrillation has been obtained initially largely through theoretical analysis and the study of computer models, before it became possible to record simultaneously from multiple sites in fibrillating atria or ventricles. Moe et al., using a computer model, developed the ‘‘multiple wavelet hypothesis’’ (Moe, 1962; Moe et al., 1964). In the model, fibrillation was initiated by a rapid series of impulses and maintained by fractionation of the wave fronts in partially and irregularly excitable tissues, so that independent wavelets occur that course around multiple islets of refractory tissue, which continuously shift their location, causing the pattern of conduction to shift as well. Moe added, ‘‘direct test of this hypothesis is difficult if not impossible in living tissue’’ (Moe, 1962). Allessie et al.

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(1985) tested the multiple wavelet hypothesis by simultaneously recording from 192 electrodes spaced at regular distances of 3 mm on the endocardial surface of right and left atria of isolated canine hearts, perfused through the coronary arteries. Atrial fibrillation was induced by premature stimulation in the presence of acetylcholine (which shortens the atrial refractory period). During maintained fibrillation, the presence of multiple independent wavelets was demonstrated. The width of the wavelets could be as small as a few millimeters, but broad wave fronts propagating uniformly over large segments of the atrial wall were observed as well. Each wavelet existed for a short time only, in the order of a few hundred milliseconds. Extinction of a wavelet could be caused by fusion or collision with another wavelet, by reaching the borders of the atria, or by meeting refractory tissue. New wavelets could be formed by division of a wave at a local area of conduction block or by an offspring of a wave travelling to the other atrium. The major difference between the excitation patterns observed in these experiments and those in the computer model of Moe was that the number of wavelets was much smaller in the canine atria. The critical number of wavelets in both atria to maintain fibrillation was between 3 and 6. Fibrillation has been described as random reentry, in which the functional reentrant circuits change size, shape, and location. There still is debate whether the functional reentrant circuits are of the ‘‘leading circle’’ model or meandering spiral waves. In the ‘‘leading circle’’ concept, the reentrant circuit is the ‘‘smallest possible pathway in which the impulse can continue to circulate. . .in which the stimulating efficacy of the circulating wave front is just enough to excite the tissue ahead, which still is in its relative refractory phase’’ (Allessie et al., 1977). In other words, there is no fully excitable gap, and maintenance of the leading circle is due to repetitive centripetal wavelets that keep the core in a constant state of refractoriness. In spiral wave reentry, there is a curving wave front, which must not only depolarize cells in front of it in the direction of propagation but also where current flows to cells on its sides. A curving wave front may cease altogether when a critical curvature is reached despite the presence of excitable tissue. The essential difference between leading circle and spiral wave reentry is that the core is kept permanently refractory in the former and the core is excitable but not excited in the latter. The slow conduction of a spiral wave is not dependent on conduction in relatively refractory myocardium; therefore, there is an excitable gap (Winfree, 1989; Fast & Kleber, 1997; Athill et al., 1998). Spiral waves have been demonstrated in cardiac tissue (Davidenko et al., 1992; Athill et al., 1998; Gray et al., 1998), but it is yet uncertain whether they occur in ischemic myocardium. Reentry has been shown to underlie ventricular tachycardia and fibrillation in the acute phase of myocardial ischemia, and patterns of activation compatible with the multiple wavelet hypothesis have been described during ischemia-induced fibrillation (Janse et al., 1980; Pogwizd & Corr, 1987). However,

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nonreentrant mechanisms, especially during the ectopic beats that initiated reentry, were demonstrated as well in these studies.

3. Therapy and prevention 3.1. Electrical shocks As described in detail by Acierno (1994), the first successful reversal of apparent death by electroshock took place in 1774 by Squires in the Middlesex Hospital in London. Of course, there is no evidence that the ‘‘apparent death’’ was caused by ventricular fibrillation. Green (1872) had installed a galvanic battery in his operating room and successfully resuscitated 6 of 7 cases of cardiorespiratory arrest due to chloroform anesthesia. In these cases, cardiac arrest was almost certainly caused by ventricular fibrillation, since Levy and Lewis (1911) provided electrocardiographic evidence that cardiac arrest during chloroform anesthesia was due to ventricular fibrillation. McWilliam (1887a, 1887b) had already stressed the clinical importance of abolishing ventricular fibrillation by applying induction shocks directly to the heart, especially when it occurred during anesthesia. Hoffa and Ludwig (1850) were the first to show that electrical currents could induce fibrillation. This was confirmed 49 years later by Prevost and Batelli (1899), who also showed that similar shocks could restore normal sinus rhythm. (More detailed information about the early use of electrical shocks can be found in the books by Snellen (1984), Acierno (1994), Luederitz (1995), and Bing (1999).) Thus, at the turn of the last century, there was both experimental and clinical evidence that ventricular fibrillation could be abolished by electrical shocks. It is perhaps somewhat surprising that it took more than half a century before defibrillation by electrical countershock became common clinical practice. As already mentioned, grants from electricity companies allowed the study of the effects of electrical currents on the heart. One of the important results of such studies was the introduction of defibrillation by countershock and external cardiac massage by Kouwenhoven et al. (Hooker et al., 1933; Kouwenhoven et al., 1960). The studies of Wiggers and Wegria (1940), particularly their rediscovery of the vulnerable period, further expanded our knowledge, and according to Moe (1984), it was on Wiggers’ advice that a defibrillator was installed in the operating room of Claude Beck, the cardiac surgeon: ‘‘One day, Claude, you will save a life.’’ In 1947, Beck defibrillated a patient who developed ventricular fibrillation during chloroform anesthesia by applying a countershock directly to the heart (Beck et al., 1947), thus repeating a feat performed in 1872 by Green. In 1956, Zoll defibrillated patients without opening the chest (Zoll et al., 1956). After Lown had introduced the DC defibrillator in 1962 (Lown et al., 1962), defibrillation became standard therapy in coronary care units.

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An important step was made by Mirowski et al., who in 1970 implanted the first automatic implantable cardioverter defibrillator (ICD) in dogs and in 1980 in humans (Mirowski et al., 1970, 1980). These studies demonstrated that the device was able to recognize ventricular fibrillation and to deliver an appropriate shock. Since then, the number of cardioverter defibrillators implanted in North America and Europe increased exponentially. A useful summary of technical and clinical aspects of ICD therapy is provided by the booklet of Kuck et al. (1996). In recent years, a number of primary and secondary prevention trials using the ICD have been conducted. In the primary prevention trials, patients were included that were thought to be at high risk for developing life-threatening arrhythmias (coronary artery disease, left ventricular dysfunction, and/or spontaneous or induced ventricular arrhythmias), and in the secondary prevention trials, patients had documented spontaneous life-threatening arrhythmias. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT-I) (Moss et al., 1996), patients were enrolled that had a prior myocardial infarction, depressed left ventricular function (left ventricular ejection fraction of 0.35 or less), asymptomatic nonsustained ventricular tachycardia, and inducible sustained ventricular tachycardia at electrophysiological testing. One hundred ninety-six patients were randomized to conventional medical therapy and ICD implantation. In the conventional therapy group, 39 patients died versus 15 in the ICD group. There were some important differences in the treatment of both groups. Thus, in the ICD group, 26% of patients received h-adrenergic blocking agents versus only 8% in the conventional therapy group. For amiodarone, the numbers were 2% and 75%, respectively. In view of the fact that h-blockers have been shown to reduce the incidence of sudden death in post-infarction patients, whereas amiodarone does not reduce all cause mortality in such patients (see Section 3.2), this may have introduced some bias. In the CABG Patch trial, patients with symptomatic coronary artery disease, left ventricular dysfunction (left ventricular ejection fraction 0.35 or less) and positive signal-averaged electrocardiogram and undergoing coronary by-pass surgery were enrolled. After 4 years, the trial was stopped because no difference in all-cause mortality was found between ICD and non-ICD groups, with a negligible chance that a difference would be found if the trial continued (Bigger et al., 1997). One of the criticisms of the CABG trial was that although at the time of the beginning of the study it was believed that a positive signal-averaged electrocardiogram was a good marker for a high risk of ventricular arrhythmias, later evidence questioned this premise (Moss, 2001). Patients eligible for the Multicenter Unsustained Tachycardia Trial (MUSTT) were similar to those of MADIT-I: patients with coronary artery disease, a left ventricular ejection fraction of 0.40 or less, and unsustained ventricular tachycardia. The patients underwent electrophysiological

testing, and when a sustained ventricular tachycardia could be induced, they were randomized into no antiarrhythmic therapy and antiarrhythmic therapy guided by programmed stimulation. If no effective antiarrhythmic drug could be identified, the patients were offered an ICD. The 5-year survival was 75% in the ICD group, 55% in those patients that received antiarrhythmic drug therapy, and 50% in patients receiving no therapy (Buxton et al., 1999). In the most recent trial, MADIT-II (Moss et al., 2002), 1232 patients with a prior myocardial infarction and a left ventricular ejection fraction of 0.30 or less were randomized in a 3:2 fashion to ICD therapy (742 patients) or conventional medical therapy (490 patients). All-cause mortality was the study end point. During an average follow-up of 20 months, mortality rate was 14.2% in the ICD group and 19.8% in the conventional therapy group (95% CI = 0.51– 0.93, P = 0.06). The conclusion of the authors was that ‘‘In patients with a prior myocardial infarction and advanced left ventricular dysfunction, prophylactic implantation of a defibrillator improves survival and should be considered as a recommended therapy.’’ The authors recognized that ‘‘An estimated 3 – 4 million patients have coronary artery disease and advanced left ventricular dysfunction in the United States, and there are f 400,000 new cases annually. If a meaningful number of these patients receive an implantable defibrillator prophylactically, the cost to the health care system would be substantial. We hope that market forces will drive down the cost of this therapy’’ (Moss et al., 2002). Of the secondary prevention trials, only the Antiarrhythmic Versus Implantable Defibrillator (AVID) (The Antiarrhythmics Versus Implantable Defibrillator (AVID) Investigators, 1997) study had sufficient power to detect a significant difference in total mortality between patients receiving ICD therapy or antiarrhythmic drug therapy (amiodarone in over 95% of patients). Eligible patients had either resuscitated ventricular fibrillation or hemodynamically unstable sustained ventricular tachycardia. During a mean follow-up of 18 months, total mortality in the ICD group was 16% versus 24% in the drug group. As in MADIT-I, h-blockers were used more often in the ICD group than in the drug group (42% vs. 17%). Interestingly, patients with ejection fractions lower than 0.35 had more benefit from the ICD than patients with less depressed ventricular function, although the difference was not statistically significant. In the Cardiac Arrest Study Hamburg (CASH), cardiac arrest survivors were randomized into 4 arms (propafenone, an arm that was prematurely stopped because of increased cardiac events, amiodarone, metropolol, and ICD). The study was underpowered to detect significant differences in survival between the groups, although there was a trend towards a lower mortality in the ICD-treated patients (Kuck et al., 2000). In the Canadian Implantable Defibrillator Study (CIDS), there was also a not significant trend towards a lower mortality in the ICD group versus the amiodarone-treated

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group in patients with prior cardiac arrest, hemodynamically unstable ventricular tachycardia, or unexplained syncope (CIDS Investigator et al., 2000). An ongoing trial, SCDHeFT, in which patients with New York Heart Association class II or III heart failure and an ejection fraction of 0.35 or less are include and randomized to 3 arms (placebo, amiodarone, and ICD), is expected to be completed in April 2004. This will be the first ICD trial in which a placebo group is included. By and large, the conclusion from these trials is that ICD therapy in patients at high risk for malignant ventricular arrhythmias improves survival and prevents sudden death in comparison with antiarrhythmic drug therapy, which for the most part involved amiodarone. As already mentioned by the MADIT-II investigators, the costs for prophylactic ICD therapy are considerable. It is noteworthy that in western Europe there are large differences in the number of ICD implantations between different countries, with highest implantation rates in Germany (22 – 24 per million inhabitants) and lowest rates in the United Kingdom, France, and Italy (2 – 6 per million inhabitants) (Euroheart Survey, 2002). Fig. 2 shows the population impact of the ICD trial results. The high-risk group of patients of the completed trials form but a small part of people that die suddenly. 3.2. Antiarrhythmic drugs Antiarrhythmic drugs have been notoriously unsuccessful in the prevention of sudden death. Table 1, which is derived from an overview of 138 trials on antiarrhythmic drugs against ventricular arrhythmias involving a total of 98,000 patients (Teo et al., 1993), shows that sodium

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Table 1 Summary of data on suppression of ventricular arrhythmias 138 Antiarrhythmic drug trials on 98,000 patients 1. Sodium channel blocking drugs (51 trials) 11,712 patients in the treated group: 660 deaths 11,713 patients in the control group: 571 deaths Odds ratio = 1.14; 95% CI = 1.01 – 1.28; P = 0.03 2. h-Adrenergic receptor blocking drugs (55 trials) 26,973 patients in the treated group: 1464 deaths 26,974 patients in the control group: 1727 deaths Odds ratio = 0.81; 95% CI = 0.75 – 0.87; P = 0.00001 3. Calcium channel antagonists (24 trials) 10,154 patients in the treated group: 982 deaths 10,155 patients in the control group: 949 deaths Odds ratio = 1.04; 95% CI = 0.95 – 1.14; P = 0.41 4. Amiodarone (8 trials) 778 patients in the treated group: 77 deaths 779 patients in the control group: 101 deaths Odds ratio = 0.71; 95% CI = 0.51 – 0.97; P = 0.03 Data derived from Teo et al. (1993).

channel blockers actually increase mortality, calcium antagonists have no effect, amiodarone looked promising, and hadrenergic blockers clearly provided benefit. Because sodium channel blockers are effective in suppressing ventricular arrhythmias but increase mortality, whereas h-blockers are not particularly effective in suppressing arrhythmias but are effective in preventing sudden death, it was suggested that ‘‘decreasing heart rate and reducing sympathetic activity may be a more promising approach to the prevention of sudden death than suppression of ambient arrhythmias recorded on Holter monitoring’’ (Teo et al., 1993). Indeed, as shown by Kjekshus (1986), those h-blockers that produced the greatest reduction in sinus rhythm were the most

Fig. 2. Incidence of sudden death and total number of events in the general population and in various subgroups at increasingly high risk. The arrows point to the subgroups that were included in various ICD trials (reproduced with permission from Myerburg & Spooner, 2001).

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effective in preventing sudden death in patients with a myocardial infarction. Another reason why h-blockers reduce mortality in the acute phase of myocardial infarction is that they reduce the incidence of cardiac rupture (ISIS-I Collaborative Group, 1988). Two recent trials, in which the effects of h-blockers were tested in patients with heart failure, showed that bisoprol and metropolol significantly reduced not only the all-cause mortality but also the incidence of sudden death (CIBIS-II Investigators, 1999; MERIT-HF Study Group, 1999). There is no doubt that the only class of antiarrhythmic drugs offering significant protection against sudden death are the h-blockers. Because of the disappointing results of the trials involving sodium channel blockers and of the neutral effects of calcium channel blockers, antiarrhythmic drug trials of the 1990s concentrated on drugs that prolong the action potential and thereby the refractory period, the so-called class III antiarrhythmic drugs. It was believed that prolonging the refractory period would prevent or abolish reentrant arrhythmias by prolonging the wavelength (the product of conduction velocity and refractory period). The ‘‘pure’’ class III drug D-sotalol, with minimal h-blocking effects unlike sotalol, was evaluated in the Survival With Oral D-sotalol (SWORD) trial (Waldo et al., 1996). Patients had a prior myocardial infarction and an ejection fraction of 0.40 or less. The trial was prematurely stopped because of a higher mortality in the treatment group (5.0% vs. 3.1% in the placebo group). Presumed arrhythmic death accounted for the increased mortality. Although the incidence of documented torsade de pointes was low (0.2%), the authors wrote: ‘‘We believe that the higher risk of death with Dsotalol in women than in men suggests that the arrhythmia that caused the adverse effect was torsade de pointes’’ (Waldo et al., 1996). It is known that torsade de pointes occurs more often in women (Lehman et al., 1996), and female rabbits have less IKr than male rabbits (Liu et al., 1998). Thus, an IKr blocker such as D-sotalol can be expected to cause a greater prolongation of action potential duration in females, thereby enhancing the chances for the development of early afterdepolarizations that can initiate torsade de pointes (Haverkamp et al., 2000). Another potassium channel blocker, dofetilide, was tested in the DIAMOND trial (Danish Investigators of Arrhythmias and Mortality on Dofetilide Study Group et al., 1999). The drug was well tolerated but had no significant effect on mortality. Only 3 of 13 randomized controlled trials of amiodarone showed a significant reduction of all-cause mortality in the treated group (Burkart et al., 1990; Doval et al., 1994; Garguichevich et al., 1995). However, all 3 studies suffered from having enrolled only a small number of patients, ranging from 127 to 516. The 2 largest amiodarone trials are the European Myocardial Infarct Amiodarone Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), enrolling 1486 and 1202 patients, respectively (Cairns et al., 1997; Julian et al., 1997). Al-

though both trials recruited patients with a recent myocardial infarction, both the entry criteria and the primary end points were different. EMIAT is the only antiarrhythmic drug trial in which presence of ventricular arrhythmias was not an entry criterion. At the time the trial was designed (1989), it was already clear that suppression of arrhythmias did not prevent sudden death and that the most powerful predictor of sudden death was left ventricular dysfunction (Pitt, 1982; Bigger et al., 1984). Thus, EMIAT enrolled patients with a recent myocardial infarction and a left ventricular ejection fraction of 0.40 or less, very similar to the patients recruited in MADIT-II (Moss et al., 2002), and the primary end point was total mortality. In CAMIAT, postmyocardial patients with ventricular arrhythmias were recruited, and the primary end point was arrhythmic death. CAMIAT patients were at lower risk than EMIAT patients, with 1-year mortality in the placebo groups of 6.4% and 8.2%, respectively. Neither trial showed a significant reduction in all-cause mortality, but both reported on a substantial reduction in arrhythmic death and resuscitated cardiac arrest (risk reduction was 35% in EMIAT and 48.8% in CAMIAT). An accompanying editorial highlighted the difficulties in defining and diagnosing arrhythmic death (Gottlieb, 1997). Still, because in both studies the evaluation committees were blinded as to whether the patient was on placebo or amiodarone, one might assume that uncertainties in diagnosing arrhythmic death were equally divided among the 2 groups. A metaanalysis of all amiodarone trials, involving 6500 patients, arrived at the conclusion that prophylactic amiodarone in patients with recent infarction or congestive heart failure reduces the rate of arrhythmic sudden death, resulting in a 13% reduction of all-cause mortality (Amiodarone Trials Meta-Analysis Investigators, 1997). The clinical impact of such a metaanalysis is unclear because patient populations in the various studies are different. In view of the large number of patients required, the results of the metaanalysis are unlikely to be confirmed by a randomized prospective trial. From a practical point of view, it may be noted that amiodarone therapy was discontinued in 41% of patients because of side effects, including thyroid disorders (in the vast majority ‘‘biochemical’’ and not ‘‘clinical’’), neuropathy, lung infiltration, bradycardia, and liver dysfunction. Post hoc analysis of EMIAT and CAMIAT noted a positive interaction between amiodarone and h-blockers (Janse et al., 1998; Boutitie et al., 1999). The reasons for this interaction are not clear. In addition to its h-blocking activity, amiodarone has direct effects on the sinus node reducing sinus rate (Kodama et al., 1997). It may be that the extra reduction in heart rate by combined amiodarone and h-blocker therapy (Janse et al., 1998) is beneficial. It must be emphasized that post hoc analyses of trials can only be hypothesis generating and that prospective studies are needed to corroborate these findings. In summary, antiarrhythmic drug therapy has been very disappointing. Sodium channel blockers and ‘‘pure’’ blockers of potassium channels kill people, calcium antagonists

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have no effect, and amiodarone may suppress arrhythmic death but in the 2 largest trials had no effect on all-cause mortality. As already said, the only antiarrhythmic drugs that are effective in preventing sudden death are the hblockers. One may question the classification of h-blockers as ‘‘antiarrhythmic,’’ because their beneficial effects are not so much related to suppression of arrhythmias but seem largely due to a reduction in heart rate. Drugs that prevent ischemic events or limit their consequences, such as infarct size, as well as drugs that have an effect on remodeling, hypertrophy, and fibrosis, such as anticoagulants, angiotensin-converting enzyme inhibitors, statins, and aldosteron antagonists, have been shown to reduce the incidence of sudden death in patients surviving a myocardial infarction or with heart failure to a far greater extent than antiarrhythmic drugs (Gruppo Italiano per lo Studio della Streptochinasi nel’infarto miocardico (GISSI), 1986; The CONSENSUS Trial Study Group, 1987; ISIS-2 Collaborative Group, 1988; The SOLVD Investigators, 1992; Scandinavian Simvastatin Survival Study Group, 1994; Pitt et al., 1999; Yusuf et al., 2001). Finally, the importance of lifestyle (no smoking, sufficient exercise, a Mediterranean diet, and French paradox) is often forgotten but is a very important element in preventing sudden death (de Lorgeril et al., 2002).

Acknowledgments The author is grateful to Eileen Franey for her careful attention to the preparation of the manuscript.

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