Publish in this journal
Journal Information
Vol. 57. Issue 8.
Pages 768-782 (August 2004)
Share
Share
Download PDF
More article options
Vol. 57. Issue 8.
Pages 768-782 (August 2004)
DOI: 10.1016/S1885-5857(06)60311-3
Full text access
Risk Stratification and Prevention of Sudden Death in Patients With Heart Failure
Estratificación del riesgo y prevención de la muerte súbita en pacientes con insuficiencia cardíaca
Visits
...
Julián Villacastína, Ramón Bovera, Nicasio P Castellanoa, Javier Morenoa, Ricardo Moralesa, Arturo García-Espinosaa
a Unidad de Arritmias. Instituto Cardiovascular del Hospital Clínico San Carlos. Madrid. Spain.
Article information
Abstract
Full Text
Bibliography
Download PDF
Statistics
Tables (4)
Fig. 1. Total annual mortality and percentage of sudden death compared with total causes of death in patients with heart failure, according to functional class. NYHA indicates New York Heart Association. Adapted from Uretsky and Sheahan.21
TABLE 1. Randomized Clinical Trials Presenting Results on Secondary Prevention of Sudden Death With Implantable Cardioverter Defibrillator Implantation*
TABLE 2. Principal Randomized Clinical Trials on the Benefit of Antiarrhythmic Drugs in Patients With Heart Failure*
TABLE 3. Randomized Clinical Trials That Offer Results in Primary Prevention of Sudden Death With Implantation of an Implantable Cardioverter Defibrillator*
Show moreShow less
Patients with heart failure can die of progressive refractory heart failure or sudden cardiac death. This article reviews the major clinical predictors of sudden death in patients with heart failure due to left ventricular systolic dysfunction. Although earlier studies have identified many independent univariate predictors of reduced survival in these patients, the positive predictive value of most of them is low. Cardioverter defibrillator implantation has been shown to be the most effective therapy in patients resuscitated after cardiac arrest caused by ventricular fibrillation or poorly tolerated ventricular tachycardia. Low left ventricular ejection fraction, low New York Heart Association functional class, unsustained ventricular tachycardia and inducibility of ventricular arrhythmia in electrophysiological studies may also identify high-risk patients who are candidates for cardioverter defibrillator implantation. The role of amiodarone in preventing sudden death in high-risk patients with heart failure seems to be small. Further studies are needed to improve risk stratification criteria to select patients with heart failure who are candidates for cardioverter defibrillator implantation.
Keywords:
Heart failure
Sudden death
Risk stratification
Los pacientes con insuficiencia cardíaca (IC) pueden fallecer como consecuencia de un fallo progresivo de bomba o de muerte súbita (MS). En este artículo analizaremos los predictores de MS en pacientes con IC secundaria a disfunción sistólica ventricular izquierda. Aunque en los estudios realizados en estos pacientes se han detectado distintos predictores univariados independientes relacionados con la supervivencia, la mayor parte de ellos ha demostrado tener un valor predictivo positivo muy limitado. El desfibrilador implantable ha confirmado ser el tratamiento más eficaz en pacientes resucitados de una parada cardíaca debida a fibrilación ventricular o a una taquicardia ventricular hemodinámicamente mal tolerada. La presencia de una fracción de eyección ventricular izquierda baja, un mal grado funcional, una taquicardia ventricular no sostenida y la inducibilidad de arritmias ventriculares en el estudio electrofisiológico ayudan a identificar a los pacientes candidatos al implante de un desfibrilador. El papel de la amiodarona a la hora de prevenir la MS en pacientes de riesgo elevado con fracaso cardíaco parece pequeño. Se necesitan más estudios que nos ayuden a conseguir una mejor estratificación del riesgo en pacientes con IC, con el fin de reconocer mejor a los candidatos a un desfibrilador implantable.
Palabras clave:
Insuficiencia cardíaca
Muerte súbita
Estratificación del riesgo
Full Text

INTRODUCTION

Earlier chapters in this series have discussed the wide variety of diseases that can lead to heart failure (HF) and underlined the enormous importance of our knowledge of these when establishing adequate diagnosis, prognosis, and treatment for HF. Cardiac death is remarkably common among patients with HF. In Spain, HF is the third cause of cardiovascular death, responsible for 4% of all deaths in men and 8% in women in 2000.1 Data from the Framingham study estimate a 5-year survival of approximately 50% following diagnosis of HF. Current treatment regimens have led to a decrease in this figure, paradoxically, due to the aging of the population, the number of patients with HF has increased considerably.2-7

Patients with HF can die as a consequence of progressive pump failure (defined as death preceded by symptomatic or hemodynamic deterioration of the patients' status) or from sudden death (SD) (defined as death of a previously stable patient within 1 hour of the onset of symptoms).8,9 Sudden cardiac death is defined as natural death due to cardiac causes in the form of sudden loss of consciousness within 1 hour of the onset of acute symptoms; a previous history of cardiopathy may be known but the moment and manner of death are unexpected.10 In this chapter, we will try to learn precisely what can be considered predictors of SD in HF and how SD can be prevented.

Mechanisms of Sudden Death in Patients With Heart Failure

The HF population is heterogeneous which includes patients with preserved systolic function, severe conduction disturbances, severely depressed systolic function but a surprisingly good prognosis, and mildly depressed ventricular contractility that may lead to sudden death or death due to rapid clinical decompensation. The mechanisms that lead to SD in patients with HF are multifactorial and complex.11 They depend to a great degree on the cause of HF: in ischemic etiologies, SD is fundamentally arrhythmic, due to ventricular tachycardia (VT) or ventricular fibrillation (VF) caused by reentry circuits in the infarcted area, acute ischemic episodes, or bradycardias; in non-ischemic etiologies, the percentage of arrhythmic SD seems lower. Published series report 30%-50% of all deaths in patients with HF are classified as SD3 and the most frequent cause is arrhythmic. A small percentage (<2%) are considered due to nonarrhythmic causes (stroke, pulmonary, or systemic embolism, ruptured aortic aneurysm).12 However, one study of SD in patients with implantable cardioverter defibrillators (ICD) showed most terminal events were precipitated by nonarrhythmic causes, simulating SD.13

It is often difficult to distinguish between patients who die suddenly and unexpectedly and those who present terminal arrhythmias in the context of progressive hemodynamic deterioration.14 For example, the AIRE study reported that 45% of SD patients experienced deterioration of HF prior to death.15 In fact, arrhythmia was the cause of death in only 39% of sudden deaths. In patients with HF, one third of deaths are assumed to correspond to SD, another third to SD during episodes of clinical worsening heart failure and the remaining third to pump failure.16

Risk of SD can be determined by the type of cardiopathy, degree of cardiac disease, presence of clinical evidence of acute or chronic pump failure and invasive or noninvasive procedures. However, identifying potential SD patients remains difficult as many are not in the most advanced stages of HF or do not present greater risk of initial arrhythmia. Rather, they belong to the group of patients who are in a better clinical status or who have not yet presented premonitory symptoms or serious arrhythmias (SD incidence is proportionately greater in New York Heart Association [NYHA] functional class II-III patients than in class IV patients) (Figure 1).17-21 Logically, these patients are more likely to die of SD rather than pump failure.

Fig. 1. Total annual mortality and percentage of sudden death compared with total causes of death in patients with heart failure, according to functional class. NYHA indicates New York Heart Association. Adapted from Uretsky and Sheahan.21

Predictors of Sudden Death

Multiple neurohumoral factors and abnormalities in size, form and electrical activation of the heart have been shown to influence the natural history of HF. The role of genetic polymorphisms,22 protein kinase activation,23 Ca-channel conditions,24 and alterations in myocardial protein expression25 in arrhythmic susceptibility and risk of SD in HF are currently being studied.

Risk stratification for arrhythmic events in patients with HF differs substantially depending on whether the underlying cardiopathy is ischemic or non-ischemic. The prognostic significance of noninvasive studies and efficacy of therapeutic measures (drug regimes or devices) can also vary according to etiology. In patients with HF and advanced underlying non-ischemic cardiomyopathy, SD occurrence is distributed uniformly over the 24 hours of the day; by contrast, in patients who present baseline ischemic cardiopathy, SD peaks in the 4 pm to 8 pm interval26.

In patients with HF, developing VT that degenerates into VF is the most frequent cause of SD. Severe bradycardia or electromechanical dissociation (pulmonary embolism, massive acute myocardial infarction [AMI]) is the cause in 5%-33% of cases although the frequency can increase in patients with advanced HF (58%-68% in candidates for transplantation).11 Too little is known of the prognostic factors that identify patients with HF at greater risk of SD, and the variables that predict the initiating mechanism (tachycardias or bradycardias).21,27 The following factors have been found to associate with SD in patients with HF:

Left Ventricular Systolic Function

Left ventricular ejection fraction (LVEF), determined by echocardiography or contrast or radioisotopic ventriculography is an important predictor of long term post-AMI cardiac mortality (represented by SD in a high percentage of patients). Gosselink et al28 analyzed patients with AMI treated with thrombolysis or primary angioplasty and found a mortality rate of 16% at 30±10 months if LVEF was <0.40 versus 2% if LVEF was >0.40. Prognosis is significantly worse when depressed LVEF is accompanied by clinical and radiological signs of congestive heart failure. In patients with LVEF≤0.40 on admission, Nicod et al29 found a 1-year mortality rate of 26% in those with clinical signs and symptoms of HF versus 12% in those without clinical signs and symptoms (P<.01). The same differences occurred if LVEF was 0.41-0.50 or >0.50 (19% vs 6%; P<.01, and 8% vs 3%; P<.02, respectively). Curtis et al30 analyzed the association between ventricular function and mortality in non-hospitalized patients with stable HF. In patients with LVEF ≤45%, they found a linear reduction in mortality as LVEF increased (LVEF <15%, 51.7%; LVEF, 36%-45%, 25.6%; P<.0001); such association persisted in a multivariate analysis. In contrast, mortality was comparable in subgroups with LVEF>45% (LVEF, 46%-55%, 23.3%; LVEF>55%, 23.5%; P=.25). These authors also found progressive deterioration of systolic function associated with greater probability of arrhythmic death (LVEF>55%, 2.8%; LVEF, 46%-55%, 4.2%; LVEF, 26%-35%, 6.3%; LVEF≤15%, 13.9%; P<.01). This was confirmed in other studies such as TRACE31 study. However, it remains controversial and is contradicted by other studies, such as DIAMOND. In patients with LVEF<25% and LVEF, 26%-35%, DIAMOND32 reported that ventricular dysfunction associated with increased overall mortality, but the frequency of arrhythmic cardiac death was similar (≥50%). As mentioned earlier, SD is more likely to occur in patients with NYHA functional class II-III than those with class IV, in whom the principal cause of death is progression of HF.17-21 These findings contrast with results of randomized studies of prevention of SD by ICD implantation in which the device proves more effective in patients with lower EF.33-35 Current thinking is that LVEF is a limited predictor and that often it is impossible to distinguish between patients with high arrhythmic mortality and those with high mortality due to pump failure.

Ventricular function also predicts post-AMI arrhythmic events. In fact, one third of patients with severely depressed LVEF die suddenly and incidence of ventricular tachyarrhythmias is greater.36 The sensitivity, specificity, positive predictive value and negative predictive value of LVEF to detect arrhythmic events are 56%-71%, 74%-83%, 11%-22%, and 96%-98%, respectively37. Given the low positive predictive value, isolated systolic function is insufficient to detect patients at high risk of post-AMI arrhythmia so we must combine this with other diagnostic tests. For example, type B natriuretic peptide has recently been identified as an independent predictor of SD in patients with chronic heart failure.38

Ischemia

Although SD is frequently a result of ventricular arrhythmia, the role of ischemia is often underestimated. Prevalence of acute coronary syndrome and its relationship with SD were examined in the autopsies of 171 patients with HF.39 Among patients with significant coronary heart disease, an acute coronary event was identified in 54% of sudden deaths and 32% of deaths from pump failure, although patients' coronary conditions might have been suspected prior to death. In contrast, an acute coronary syndrome was only found in 5% of SD patients and in 10% of those who died from heart failure among patients without previous coronary heart disease. Over 4 years, the Maastricht Circulatory Arrest Registry40 recorded 492 cases of SD. In 59% of women and 52% of men, SD was the first evidence of heart disease. Among patients with a personal history of heart disease, 77% presented coronary heart disease (66% of whom had suffered at least one previous AMI) and 26% presented HF, with a mean latency period from the first episode of decompensated HF to SD of 4.3 years.

Electrocardiographic Monitoring

Ventricular extrasystoles (VE). Ventricular extrasystoles can be frequent and complex, occurring in 70%-95% of patients with HF.41 Isolated VE have not been show to associate with worse prognosis nor has their pharmacologic suppression been demonstrated to reduce SD.42 Therefore, administration of drugs to diminish VE (blockers or amiodarone) is only recommended in patients who have symptoms caused by arrhythmias or in whom the frequency of VE causes tachycardiomyopathy.43

Nonsustained ventricular tachycardia (NSVT). Bouts of NSVT are found in 50%-80% of patients with HF or cardiomyopathy.41 Data suggest presence of NSVT cannot be considered an independent predictor of SD. The CHF-STAT study analyzed the effect of amiodarone in patients with frequent VE (71% with coronary heart disease) and found an apparent association between NSVT and increased SD. However, in multivariate analysis LVEF and NYHA functional class were independent predictors of mortality, NSVT was not.44 Data from PROMISE41 support these findings. Based on 1080 patients with functional class III-IV, NSVT frequency initially seemed an independent predictor of SD but, a change of statistical model showed it added no new prognostic information when clinical variables such as age, gender, blood pressure, functional class and LVEF were considered.

Accelerated idioventricular rhythm. Accelerated idioventricular rhythm, or slow VT (frequency range, 50-120 beats/min), is present in 8% of patients with HF or cardiomiopathy.45 Treatment is not indicated unless it is highly symptomatic as a relationship with the development of VT or VF has not been demonstrated.

Sustained ventricular tachycardia. Sustained VT is infrequent and occurs in <5% of patients with HF or cardiomyopathy.41 Most have inducible VT in the electrophysiological study (EPS) and remain inducible in spite of the use of antiarrhythmic drugs.46 In contrast to other arrhythmias, sustained VT is a valued predictor of SD.47 Consequently, as with those who survive SD from VT or VF, patients with sustained VT receive ICD implants.48,49

Other electrocardiographic findings. In patients with HF, studies analyzing presence of left bundle branch block,50,51 QRS complex duration (120-150 ms),52 prolonged QTc interval,53 and atrial fibrillation54 find these have no conclusive prognostic value for SD incidence.

Other Noninvasive Tests

Late potentials. Signal-averaged electrocardiograms can predict VT inducibility in patients with non-ischemic cardiomyopathy and NSVT.55 However, both findings are rare and neither negative late potentials nor absence of VT inducibility ensures good prognosis. Consequently, signal-averaged electrocardiograms are not used in clinical decision-making.

Heart rate variability (HRV). HRV is obtained from beat-by-beat measurement and partly reflects the cycle of inspiration (increased vagal activity) and expiration (reduced vagal activity). Reduced HRV correlates with disturbance of the autonomous nervous system balance with a predominance of sympathetic over parasympathetic activity.56 Various studies have shown low HRV to be a powerful predictor of mortality from any cause in patients with previous infarction and in those with dilated cardiomyopathy.57,58 Reduced HRV has also been confirmed as a powerful predictor of VF and SD in patients with ischemic cardiomyopathy.59 A recent study60 analyzed the prognostic value of HRV with controlled respiration for arrhythmic SD in 202 patients with dilated cardiomyopathy and moderate-severe HF. Results showed that low-frequency power (LFP) HRV with controlled respiration ≤11 ms² and presence of ≥83 VE per hour in Holter monitoring were independent predictors of arrhythmic SD (relative risk [RR]=3.0 and RR=3.7, respectively). Although reduced HRV is a powerful predictor of SD independently of other noninvasive risk markers, when considered in isolation its positive predictive value remains quite limited (≥30%). The best prognostic information is offered by the standard deviation of intervals between normal beats (SDNN) and the triangular index, which estimates mean variability. Although cutoff points have been clearly established, on the basis of published studies SDNN<50 ms or a triangular index <15 can be considered to identify patients with severely reduced HRV; SDNN values of 50-100 ms or triangular index values of 15-20 identify those with moderately reduced HRV. The predictive value of HRV alone is modest but can improve significantly when combined with other noninvasive markers. However, the combination of usable noninvasive markers and optimal cutoff points to achieve maximum predictive capacity has yet to be defined. Moreover, HRV has substantial limitations: patients must be in sinus rhythm, interference from VE and its modification for posture, physical activity and respiratory cycle.

Baroreflex sensitivity (BRS). Autonomous nervous system activity can also be studied by evaluating the effect of pharmacologic stimulation of arterial baroreceptors (bradycardia reflected by increased blood pressure with epinephrine) on heart rate. The multicenter ATRAMI study enrolled 1284 patients with recent infarction to compare the possible additional prognostic value of baroreflex sensitivity with HRV. Presence of reduced BRS (slope of linear regression lines R-R vs blood pressure <3 ms/mm Hg) associates with increased risk of global cardiac mortality, independently of HRV. Reduced HRV (SDNN<70 ms) is also associated with greater mortality (RR=2.8 and RR=3.2, respectively)61. Moreover, combining reduced BRS and reduced HRV offers additional prognostic value (RR=8.5). Relative risk for LVEF<0.35 associated with reduced BRS was 8.7 and associated with low HRV, RR was 6.7. The study concluded that examining vagal baroreceptor reflexes in patients with recent infarction adds independent prognostic information on LVEF to that provided by HRV measurement. Principal limitations are the need to measure systolic blood pressure beat-by-beat and the difficulty of defining threshold values for use in clinical practice. Recently, a new measure has been designed to explore BRS. Turbulence of cardiac frequency reflects fluctuation of cardiac cycle duration in sinus rhythm after isolated VE. However, it does not provide adequate risk stratification for ventricular arrhythmia in patients with idiopathic dilated cardiomyopathy.62

T wave alternans (TWA). T wave alternans defines the electrocardiographic profile in which T wave morphology polarity changes from one beat to another indicating heterogeneity in repolarization (electrical vulnerability). Dependant on cardiac frequency, TWA presents maximum predictive capacity in the 100-120 beats/min range, attained through exercise or atrial stimulation. A veraged electrocardiography shows a subtle, invisible T wave variation: T wave microalternans.63 In patients with HF, presence of TWA during exercise predicts arrhythmic events. A study of 107 patients in functional class II-III with LVEF≤45% and no previous history of ventricular arrhythmias evaluated the presence of TWA during exercise. At 14 months, patients with TWA presented more arrhythmic events than those with an indeterminate test or without TWA (21%, 9%, and 0%, respectively).64 In a study that only included patients with dilated non-ischemic cardiomyopathy, TWA also showed a good correlation with presence of ventricular arrhythmias.65 Some authors suggest that patients with non-ischemic dilated cardiomyopathy, LVEF<40%, NYHA functional class II-III, and positive TWA test should be indicated for ICD implant66. In patients with ischemic cardiopathy, presence of TWA shows high sensitivity and specificity to predict presence of inducible arrhythmias during EPS and to detect patients at low risk of arrhythmic events (sensitivity 93%, negative predictive value 98%, positive predictive value 28%).67 T wave alternans can also help identify high-risk patients who fulfill MADIT II criteria.68

Electrophysiological Study

Various studies, generally involving patients with coronary heart disease, have shown the limitations of EPS when used to select antiarrhythmic drug treatment. Although they clearly suppress ventricular arrhythmia inducibility, clinical recurrence of arrhythmias is high. In the ESVEM study of patients with VT or survivors of cardiac arrest with mean LVEF 33%, 1-year arrhythmic recurrence was 20% with sotalol and >20% with other drugs on trial.69 The principal use of EPS is in patients with coronary heart disease and left ventricular dysfunction who also present NSVT. Inducibility of ventricular arrhythmias in these patients identifies them as good candidates for ICD implant, as reported in MADIT I and MUSTT.70,71

The EPS has also been used in relatively small series of patients with idiopathic dilated cardiomyopathy.72-74 Probability of pharmacologically suppressing inducible VT has been seen to vary, with rates <40% in some studies. Although patients in whom inducibility is suppressed generally evolve favorably, some series find that arrhythmias recur in ≤33% of patients.75,76 Moreover, patients who are not inducible are at high risk. Consequently, most patients with non-ischemic cardiomyopathy and sustained VT or VF receive an ICD implant.

The study of new prognostic factors does not cease. One recent report on patients with ICD, most of whom have ischemic cardiopathy, demonstrated that physical and emotional (anger) stress are associated with discharges appropriate to a defibrillator for malignant ventricular arrhythmias.77

Risk Stratification

Preventing arrhythmic SD in patients with HF is one of the greatest challenges in HF treatment today. Arrhythmic risk stratification in patients with HF remains highly complex. Our ability to identify patients with HF at high risk is far from satisfactory. Many studies are small and populations differ from the patients we encounter in daily clinical practice. We need to develop precise, reproducible methods to identify patients at high risk of SD. EPS is expensive, invasive and imperfect, especially in HF with non-ischemic etiologies. On the other hand, studies that evaluate noninvasive tests occasionally differ in the parameters used to measure the same variable and in 20%-30% of patients they are not interpretable due to the presence of atrial fibrillation or other limitations intrinsic to the tests themselves. Moreover, the positive predictive value of these studies is greater in patients with ischemic cardiopathy than in those with idiopathic dilated cardiomyopathy. As shown earlier, the number of prognostic factors is high and we lack adequate knowledge of their interaction. Equally, prognostic significance of the variation in the time when results are obtained from different tests has barely been studied.78 Nor do we know enough about the time and circumstances in which these are of greatest value as the association of these variables with SD may differ in the progressive evolving stages of HF, in relation to concomitant pharmacologic treatment, etc.

Consequently, a complete, individualized approach based on clinical and instrumental data is fundamental in dealing with each patient, as is the integration and use of results from invasive and noninvasive prognostic studies. Only thus will we gain access to adequate prognostic information and be capable of identifying high-risk patients who can benefit from optimal antiarrhythmic drug therapy and/or devices.

Recently published results of the Marburg Cardiomyopathy Study of 343 patients with dilated cardiomyopathy are in accordance with this approach to risk stratification. Patients underwent prospective evaluation of multiple potential predictors of arrhythmic risk including LVEF, left ventricle size, presence of late potentials, NSVT findings in ambulatory monitoring, QT interval dispersion, HRV, BRS, and TWA.79 After 52 months of follow-up, 46 (13%) patients suffered serious arrhythmic events (VT, VF, or SD). In multivariate analysis, only LVEF was independently, statistically associated with arrhythmic risk in patients in sinus rhythm (RR=12.3 for a 10% reduction in LVEF). The combination of LVEF<30% and NSVT increased arrhythmic risk 8.2-fold by comparison with patients with LVEF≥30% without NSVT.

The Marburg results reflect the difficulty of definitively establishing the prognostic role of the multiple variables possibly involved in SD in patients with HF, despite the enormous research effort being employed in the field. Once again, the fundamental importance of classical risk factors such as left ventricular function is reinforced.

Therapeutic Recommendations

Secondary Prevention of SD: Patients Resuscitated After SD or Presenting Sustained VT

An ICD implant is the most frequent treatment of choice in these patients although exceptionally radiofrequency ablation, surgery, or transplant may be used. It is important to know that no antiarrhythmic drug offers sufficient protection in this clinical context and the use of drugs is reserved for patients who reject devices or are not candidates for ICD implantation. This has been demonstrated in 3 randomized studies (CASH, CIDS, and AVID) (Table 1) of ICD efficacy versus antiarrhythmic drugs (amiodarone, beta-blockers, sotalol, or propaphenone) in survivors of cardiac arrest or in patients at high risk of VT, 50% of these with HF.80-82 Metaanalysis of all data found a statistically significant 25% reduction in mortality with ICD compared with amiodarone, due to a 50% reduction in sudden death.83 The absolute reduction in all-cause mortality was 7%, meaning that 15 ICD implants would save 1 life.

Current ACC/AHA/NASPE 2002 recommendations establish the following as class I or IIa indications for ICD implantation as secondary prevention:49

­- Cardiac arrest for VT or VF without transitory, reversible cause (class I, evidence A).

­- Sustained spontaneous VT associated with structural cardiopathy (class I, evidence B).

­- Sustained spontaneous VT in patients without structural cardiopathy that is not subsidiary to other treatments (class I, evidence C).

­- Nonsustained VT in patients with coronary heart disease, previous AMI, ventricular dysfunction, and VT or VF inducible in the EPS that cannot be suppressed by class I antiarrhythmic drugs (class I, evidence A).

In ICD implanted patients, around a quarter of deaths are arrhythmic in origin. These may be due to arrhythmias that are untreatable despite multiple charges or electromechanical dissociation.84

These results show that patients with LVEF≤35% benefit most from ICD implantation and that in those with greater LVEF the benefits are practically inappreciable. These benefits extend to patients with severely depressed LVEF who are more likely to die from pump failure and for whom imperceptible benefits were predicted.88

Only antiarrhythmic drugs (amiodarone or sotalol) can be used in patients with severe ventricular dysfunction. Generally their use is recommended to diminish the number of episodes of VT (in patients with multiple ICD discharges) or treat other arrhythmias such as atrial fibrillation.69,86-90 We cannot forget that these negative effects may also occur in patients: proarrhythmic capacity can increase the number of discharges; slowing of ventricular tachyarrhythmia frequency places this below the threshold for antitachycardia therapy; elevation of defibrillation thresholds, and possible incorrect detection of QRS complex morphology alteration.91 In patients who present multiple ICD discharges, radiofrequency ablation of the VT responsible is also a good option. In these patients, induced tachycardias are very occasionally rapid. However, thanks to new navigation systems that facilitate localization of the circuits without the need for tachycardia, ablation can be successful. On the other hand, bundle branch reentrant VT can be present in ischemic and non-ischemic cardiomyopathy, usually in patients with advanced HF. This is relatively simple to treat by radiofrequency ablation of the branches of the His-Purkinje system.

Ablation of sustained VT by surgery is exceptional and is practically limited to patients with previous AMI associated with left ventricular aneurysm. In contrast, faced with the impossibility of controlling arrhythmia, heart transplants are frequently required.92,93 In these cases, arrhythmic events are due to substantial deterioration of pump function88. Selective ICD implantation has been shown to reduce mortality in patients on heart transplant waiting lists.93,94

Syncope

The AVID study included patients with sustained VT with syncope, whereas CIDS studied patients with syncope of unknown origin in whom the presence of spontaneous sustained or induced VT was later determined.81,82 This aIn a follow-up of almost 500 patients with HF and non-ischemic cardiomyopathy in functional class III or IV, 1-year incidence of SD was much higher in those with unexplained syncope (45% vs 12% in those without syncope).95 Similarly, a 1-3 year follow-up of patients with cardiomyopathy and ICD implant, left ventricular dysfunction and unexplained syncope found produced by VT or VF96,97; this even occurred in patients with negative EPS.98

Current ACC/AHA/NASPE 2002 recommendations establish a class I indication for ICD implantation as secondary prevention of syncope when this is of unknown cause and sustained VT is induced with hemodynamic repercussions in the EPS and drug treatment is inefficient, not tolerated or not desired (evidence B). They do not establish any class IIa indication. To date, there is no proof of the benefit of ICD implantation in patients with syncope and negative EPS, so this therapeutic decision must be taken on an individual basis. Similarly, they establish a class IIb indication, evidence C, in patients with ventricular dysfunction and syncope of indeterminate origin with stable ventricular arrhythmia inducible in the EPS, and in syncope in patients with severe structural cardiopathy in whom invasive and noninvasive tests are negative. They also establish as a class IIb indication, evidence C, ICD implantation for heart transplant waiting list patients and those who present severe symptoms (e.g. syncope) attributable to ventricular tachyarrhythmias.49

Primary Prevention of SD

Antiarrhythmic drugs. The role of antiarrhythmic drugs in preventing SD in patients with cardiomyopathy, HF and asymptomatic arrhythmias (VE or NSVT) seems limited and, usually, counterproductive (due to the proarrhythmic effect and worsening of left ventricular function).32,99 Amiodarone, however, produces limited proarrhythmic activity and can even improve systolic function. It is the only drug to demonstrate positive results in some studies, especially in non-ischemic cardiomyopathy (Table 2).32,100,101 Nevertheless, the SCD-HeFT study seems to show it has no beneficial effect at all in relation to prevention of death,102 as well as carrying the potential risk of its now well known secondary effects.103

Beta-blockers. In several studies (MERIT-HF, metoprolol19; CIBISII, bisoprolol104; COPERNICUS, carvedilol105,106), beta-blockers have been found to improve global survival in patients with HF, partly because they reduce SD. This benefit is maintained even in patients in the worst functional class (NYHA III-IV) and with most severe left ventricular dysfunction (LVEF≤25%).107 The COMET study showed greater chances of survival in patients administered carvedilol versus metoprolol, although these results are controversial as doses administered are not considered equivalent.108

Consequently, assuming beta-blockers are tolerated, they should be administered to patients with HF regardless of functional class.

Angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA-II). It is fully accepted that these drugs prolong survival, prevent decompensation and progression of disease, and improve quality of life in patients with HF. However, their capacity to diminish incidence of arrhythmic SD in these patients is under debate due to contradictory results found in large clinical trials in patients with HF and post-AMI (CONSENSUS; SOLVD; V-HeFT II, enalapril9,109,110; SAVE, captopril111; AIRE, ramipril15; ATLAS, lisinopril112; ELITE II, losartan113; Val-HeFT, valsartan114; CHARM, candesartan115,116). It is generally believed that even though all studies of HF show they prolong survival, their capacity to avoid SD is limited.117,118

Aldosterone antagonists. Spironolactone119 and eplerenone120 have been proven to reduce total mortality and SD in patients with advanced HF.

Implantable cardioverter defibrillator. Most studies that evaluate the efficacy of ICD implantation have enrolled patients with previous AMI and severe left ventricular dysfunction (Table 3). The MADIT I and MUST studies enrolled patients with NSVT, LVEF≤35%-40% and inducible VT in the EPS. In MADIT II, inclusion criteria were less strict, calling only for LVEF≤30%. We cannot forget that MADIT I, MUST, and other studies centered on patients with known ischemic cardiopathy and previous infarction; they did not directly address the problem of ICD use in HF. The first 2 small-scale studies to study the benefit of ICD implantation on survival in patients with idiopathic or non-ischemic cardiomyopathy and severe left ventricular dysfunction (CAT121, AMIOVIRT122) did not find positive results. The role of ICD implants in these patients continues to be debated. Recently, 2 larger studies underline their efficacy:

-­ DEFINITE: 458 patients with non-ischemic dilated cardiomyopathy, LVEF ≤35% and VE or NSVT were enrolled in this study123. Approximately 85% of patients received recommended optimal medical treatment (ACE inhibitors and beta-blockers). Patients were randomized to ICD or drug treatment only. At 2 years, an almost significant trend towards a reduction of total mortality in patients with ICD (8.1% vs 13.8%; P=.06) was found. This difference was statistically significant in patients in functional class III (13% vs 33%). Equally, the authors found a significant reduction in SD in patients with ICD implants, although the number of events was limited.

­- SCD-HeFT trial: this study included 2521 patients with HF in functional class II (70%) and III (30%), with ischemic (52%) and non-ischemic (48%) cardiomyopathy, and with LVEF ≤35%, during a mean 45.5 month follow-up.124 Patients had received optimal drug treatment (ACE inhibitors or ARA-II, 96%; beta-blockers, 69%; spironolactone, 19%). Three treatment groups were established: placebo, amiodarone, and ICD (VVI mode pacing). Total mortality at 3 years by group was ICD 17.1%, treatment with amiodarone 24%, and placebo 22.3%; at 5 years total mortality was 28.9%, 34.1%, and 35.8%, respectively. No differences were found between amiodarone and placebo (RR=1.06 [0.86-1.30]; P=.53), nor for beta-blockers. However, comparison of ICD and placebo showed a clear benefit in total mortality (RR=0.77 [0.62-0.96]; P=.007) with curves beginning to separate after 18 months of follow-up. Analysis of the benefit of ICD by functional class showed this was greater in class II than in class III (RR=0.54 [0.40-0.74] and RR=1.16 [0.84-1.61], respectively). Results also showed a non significant trend towards greater protection in non-ischemic (0.73 [0.50-1.04]) vs ischemic (0.79 [0.60-1.04]) cardiomyopathy. Presence of QRS complex duration ≥120 ms (RR=0.67), treatment with beta-blockers (RR=0.68) and absence of diabetes (RR=0.67) made treatment with ICD significantly more beneficial.

Severely depressed systolic function and NYHA functional class can help select patients with HF at risk of SD. But, if we only take account of these data, the population with HF subsidiary to ICD implantation is enormous. It is more and more obvious that ICDs are the only really efficient means of preventing SD. The problem is that of selecting candidates because ICD implantation is expensive and cannot be routinely offered to all patients as this would have an enormous impact on health care costs. We need to establish the most cost-efficient risk stratification strategy possible. Moreover, ICD implantation is not free from adverse effects, such as inappropriate discharges, problems with the cable or infections.125 Both DDD and VVI mode pacing can increase right ventricular contraction asynchrony and contribute to HF decompensation.35,126,127 Indiscriminate ICD use would entail low-risk patients accepting potential adverse effects without any ultimate benefit.

The ACC/AHA/NASPE 2002 recommendations for ICD implantation do not make express reference to patients with non-ischemic HF. Nor do they establish any class I indication in primary prevention. As class IIa indication, evidence B, we find patients with LVEF ≤30% at ≥1 month post-AMI or 3 months after surgical revascularization.49

Cardiac resynchronization therapy deserves a separate mention.128 More than a third of patients with HF present delayed conduction in the atrioventricular node and His-Purkinje system. This gives rise to a deleterious effect in diastolic and systolic function (asynchrony in ventricular contraction) that can be remedied by a resynchronization device, leading to improved quality of life and functional capacity and lowering rehospitalizations.129 The COMPANION study, unfinished at the time of writing, includes 1520 patients in sinus rhythm, functional class III-IV, with LVEF<35%, left ventricular end-diastolic volume ≥6 cm, PR interval >150 ms and QRS>120 ms. Patients are randomized in three treatment groups: optimal drug treatment, cardiac resynchronization therapy, or ICD with resynchronization. In an interim analysis, ICD with resynchronization presented a 43% relative reduction of mortality due to all causes in comparison with drug treatment.130 As yet, we do not know the capability of cardiac resynchronization therapy to reduce SD in patients with HF, or which subgroup might benefit more, although research suggests therapy might improve some prognostic factors of SD.131

CONCLUSIONS

Risk stratification of SD in patients with HF is currently carried out using classical parameters such as clinical history, NYHA functional class and LVEF in the hope that we can better predict which patients are likely to suffer arrhythmic events.

In patients with HF who have been resuscitated after an SD event or who have suffered sustained VT or unexplained syncope, ICD implantation is the treatment of choice unless counterindicated or a heart transplant is needed. If functional class is poor despite optimal medical treatment, it is advisable to evaluate the use of an ICD capable of ventricular resynchronization. If functional class is acceptable, programmed ventricular stimulation should be avoided if possible using an ICD requiring 40 beat/min or algorhythms to impede stimulation. Antiarrhythmic drugs (amiodarone or sotalol) are only used in patients with ICD to treat arrhythmias such as atrial fibrillation or VT when these are frequent. In the latter case, radiofrequency ablation is a good option.

If NSVT has been determined in patients with HF and ejection fraction ≥40% due to ischemic cause, it is advisable to perform an EPS and consider ICD implantation if ventricular arrhythmias are induced. In patients with HF of any etiology with LVEF≥35% and functional class II-III, as in patients with LVEF≤30% due to ischemic cause, prophylactic ICD implantation can be seriously studied taking into account the risks and situation of each individual patient.

In patients with HF and LVEF>35%, nonsustained ventricular arrhythmia should not be treated as it has not been demonstrated to worsen prognosis because it is not symptomatic. If drug treatment is to be administered, amiodarone, and sotalol are the antiarrhythmic drugs of choice for patients with abnormal LVEF. In patients with HF and preserved LVEF, only symptomatic arrhythmias should be treated and there are no specific counterindications for antiarrhythmic drugs

Initially, risk stratification of arrhythmic death is carried out by determining LVEF and learning whether the cause of the HF is ischemic. To date, other diagnostic tests cannot be considered essential in establishing prognosis in these patients. Finally, we cannot forget that, independently of a good etiologic diagnosis and of the stratification criteria we have analyzed, patients with HF should receive beta blockers, vasodilators, spironolactone and anticoagulation therapy (if required to improve clinical condition or diminish the risk of embolism), assuming the drugs are well tolerated and that there is no counterindication to their use.132,133 All of this, while we wait for new alternative therapies.34

Section Sponsored by Laboratorio Dr Esteve


Correspondence: Dr. J. Villacastín.
Unidad de Arritmias. Hospital Clínico San Carlos. 2.a Norte.
Prof. Martín Lagos, s/n. 28040 Madrid. España.
E-mail: jvillacastin@secardiologia.es

Bibliography
[1]
Rodríguez-Artalejo F, Banegas JR, Guallar-Castillon P..
Epidemiología de la insuficiencia cardíaca..
Rev Esp Cardiol, 57 (2004), pp. 163-70
[2]
MacIntyre K, Capewell S, Stewart S, Chalmers JW, Boyd J, Finlayson A, et al..
Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995..
Circulation, 102 (2000), pp. 1126-31
[3]
Mosterd A, Cost B, Hoes AW, De Bruijne MC, Deckers JW, Hofman A, et al..
The prognosis of heart failure in the general population. The Rotterdam Study..
Eur Heart J, 22 (2001), pp. 1318-27
[4]
Polanczyk CA, Rohde LE, Dec GW, diSalvo T..
Ten-year trends in hospital care for congestive heart failure: improved outcomes and increased use of resources..
Arch Intern Med, 160 (2000), pp. 325-32
[5]
Baker DW, Einstadter D, Thomas C, Cebul RD..
Mortality trends for 23,505 Medicare patients hospitalized with heart failure in Northeast Ohio, 1991 to 1997..
Am Heart J, 146 (2003), pp. 258-64
[6]
Jong P, Vowinckel E, Liu PP, Gong Y, Tu JV..
Prognosis and determinants of survival in patients newly hospitalized for heart failure: a population-based study..
Arch Intern Med, 162 (2002), pp. 1689-94
[7]
Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, et al..
Long-term trends in the incidence of and survival with heart failure..
N Engl J Med, 347 (2002), pp. 1397-402
[8]
Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failur..
The SOLVD Investigators..
N Engl J Med, 325 (1991), pp. 293-302
[9]
The CONSENSUS Trial Study Group..
Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)..
N Engl J Med, 316 (1987), pp. 1429-35
[10]
Myerburg RJ, Castellanos A..
Cardiac arrest and sudden cardiac death. En: Braunwald E, editor. Heart disease: a textbook of cardiovascular medicine. New York: WB Saunders.
Cardiac arrest and sudden cardiac death. En: Braunwald E, editor. Heart disease: a textbook of cardiovascular medicine. New York: WB Saunders, (1997), pp. 742-79
[11]
Luu M, Stevenson WG, Stevenson LW, Baron K, Walden J..
Diverse mechanisms of unexpected cardiac arrest in advanced heart failure..
Circulation, 80 (1989), pp. 1675-80
[12]
Packer M..
Lack of relation between ventricular arrhythmias and sudden death in patients con chronic heart failure..
Circulation, 85 (1992), pp. 50-6
[13]
Pratt CM, Greenway PS, Schoenfeld MH, Bien ML, Reiffel JA..
Exploration of the precision of classifying sudden cardiac death. Implications for the interpretation of clinical trials..
Circulation, 93 (1996), pp. 519-24
[14]
Rodríguez E, Viñolas X..
Causas de muerte súbita. Problemas a la hora de establecer y clasificar los tipos de muerte..
Rev Esp Cardiol, 52 (1999), pp. 1004-14
[15]
Cleland JG, Erhardt L, Murray G, Hall AS, Ball SG, on behalf of the AIRE Study Investigators..
Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators..
Eur Heart J, 18 (1997), pp. 41-51
[16]
Narang R, Cleland JG, Erhardt L, Ball SG, Coats AJ, Cowley AJ, et al..
Mode of death in chronic heart failure. A request and proposition for more accurate classification..
Eur Heart J, 17 (1996), pp. 1390-403
[17]
Gradman A, Deedwania P, Cody R, Massie B, Pitt B, Goldstein S..
Predictors of total mortality and sudden death in mild to moderate heart failure..
J Am Coll Cardiol, 14 (1989), pp. 564-70
[18]
The SOLVD Investigators..
Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure..
N Engl J Med, 325 (1991), pp. 293-302
[19]
MERIT-HF Study Group..
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)..
Lancet, 353 (1999), pp. 2001-7
[20]
Kjekshus J..
Arrhythmias and mortality in congestive heart failure..
Am J Cardiol, 65 (1990), pp. 421-81
[21]
Uretsky BF, Sheahan RG..
Primary prevention of sudden cardiac death in hearth failure: will the solution be shocking?.
J Am Coll Cardiol, 30 (1997), pp. 1589-97
[22]
McNamara DM, Holubkov R, Postava L, Ramani R, Janosko K, Mathier M, et al..
Effect of the Asp298 variant of endotelial nitric oxide sinthase on survival for patients with congestive heart failure..
Circulation, 107 (2003), pp. 1598-602
[23]
Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, et al..
Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase A..
Circ Res, 89 (2001), pp. 997-1004
[24]
Scoote M, Williams AJ..
The cardiac ryanodine receptor (calcium release channel): emerging role in heart failure and arrhythmia pathogenesis..
Cardiovasc Res, 56 (2002), pp. 359-72
[25]
Spragg DD, Leclercq C, Loghmani M, Faris OP, Tunin RS, diSilvestre D, et al..
Regional alterations in protein expression in the desynchronises failing heart..
[26]
Carson PA, O'Connor CM, Miller AB, Anderson S, Belkin R, Neuberg GW, et al..
Circadian rhythm and sudden death in heart failure..
J Am Coll Cardiol, 36 (2000), pp. 541-6
[27]
The implantable cardioverter defibrillator as a
[28]
Gosselink AT, Liem AL, Reiffers S, Zijlstra F..
Prognostic value of predischarge radionuclide ventriculography at rest and exercise after acute myocardial infarction treated with thrombolytic therapy or primary coronary angioplasty. The Zwolle Myocardial Infarction Study Group..
Clin Cardiol, 21 (1998), pp. 254-60
[29]
Nicod P, Gilpin E, Dittrich H, Chappuis F, Ahnve S, Engler R, et al..
Influence on prognosis and morbidity of left ventricular ejection fraction with and without signs of left ventricular failure after acute myocardial infarction..
Am J Cardiol, 61 (1988), pp. 1165-71
[30]
Curtis JP, Sokol SI, Wang Y, Rathore SS, Ko DT, Jadbabaie F, et al..
The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure..
J Am Coll Cardiol, 42 (2003), pp. 736-42
[31]
Kober L, Torp-Pedersen C..
Clinical characteristics and mortality of patients screened for entry in the Trandolapril Cardiac Evaluation (TRACE) study..
Am J Cardiol, 76 (1995), pp. 1-5
[32]
Torp-Pedersen C, Møller M, Block-Thomsen PE, Køber L, Sandøe E, Egstrup K, et al for The Danish Investigations of Arrhyt..
Dofetilide in patients with congestive heart failure and left ventricular dysfunction..
N Engl J Med, 341 (1999), pp. 857-65
[33]
Moss AJ..
Implantable cardioverter defibrillator therapy. The sickest patients benefit most..
Circulation, 101 (2000), pp. 1638-40
[34]
The Antiarrhythmics Versus Implantable Defibrillators (AVID) investigators..
A comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias..
N Engl J Med, 337 (1997), pp. 1576-83
[35]
Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al..
Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction..
N Engl J Med, 346 (2002), pp. 877-83
[36]
Kober L, Torp-Pedersen C, Elming H, Burchardt H..
Use of left ventricular ejection fraction or wall-motion score index in predicting arrhythmic death in patients following an acute myocardial infarction. The TRACE Study Group..
Pacing Clin Electrophysiol, 20 (1997), pp. 2553-9
[37]
de Chillou C, Sadoul N, Bizeau O, Feldmann L, Gazakure E, Ismail M, et al..
Prognostic value of thrombolysis, coronary artery patency, signal-averaged electrocardiography, left ventricular ejection fraction, and Holter electrocardiographic monitoring for life-threatening ventricular arrhythmias after a first acute myocardial infarction..
Am J Cardiol, 80 (1997), pp. 852-8
[38]
Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, et al..
B-type natriuretic peptide predicts sudden death in patients with chronic heart failure..
Circulation, 105 (2002), pp. 2392-7
[39]
Uretsky BF, Thygesen K, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, et al..
Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial..
Circulation, 102 (2000), pp. 611-6
[40]
Gorgels AP, Gijsbers C, Vreede-Swagemakers J, Lousberg A, Wellens HJ..
Out-of-hospital cardiac arrest-the relevance of heart failure. The Maastricht Circulatory Arrest Registry..
Eur Heart J, 24 (2003), pp. 1204-9
[41]
Teerlink JR, Jalaluddin M, Anderson S, Kukin ML, Eichhorn EJ, Francis G, et al..
Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death..
Circulation, 101 (2000), pp. 40-6
[42]
Packer M..
Lack of relation between ventricular arrhythmias and sudden death in patients with chronic heart failure..
Circulation, 85 (1992), pp. 50-6
[43]
Duffee DF, Shen WK, Smith HC..
Suppression of frequent premature ventricular contractions and improvement of left ventricular function in patients with presumed idiopathic dilated cardiomyopathy..
Mayo Clin Proc, 73 (1998), pp. 430-3
[44]
Singh SN, Fisher SG, Carson PE, Fletcher RD and the Department of Veteran Affairs CHF-STAT Investigators..
Prevalence and significance of nonsustained ventricular tachycardia in patients with premature ventricular contractions and heart failure treated with vasodilator therapy..
J Am Coll Cardiol, 32 (1998), pp. 942-7
[45]
Grimm W, Hoffmann J, Menz V, Schmidt C, Muller HH, Maisch B..
Significance of accelerated idioventricular rhythm in idiopathic dilated cardiomyopathy..
Am J Cardiol, 85 (2000), pp. 899-904
[46]
Poll DS, Marchlinski FE, Buxton AE, Doherty JU, Waxman HL, Josephson ME..
Sustained ventricular tachycardia in patients with idiopathic dilated cardiomyopathy: Electrophysiologic testing and lack of response to antiarrhythmic drug therapy..
Circulation, 70 (1984), pp. 451-6
[47]
Chen X, Shenasa M, Borggrefe M, Block M, Hindricks G, Martínez-Rubio A, et al..
Role of programmed ventricular stimulation in patients with idiopathic dilated cardiomyopathy and documented sustained ventricular tachyarrhythmias: Inducibility and prognostic value in 102 patients..
Eur Heart J, 15 (1994), pp. 76-82
[48]
Priori SG, Aliot E, Blomstrom-Lundqvist C, Bossaert L, Breithardt G, Brugada P, et al..
Task force on sudden cardiac death of the European Society of Cardiology..
Eur Heart J, 22 (2001), pp. 1374-450
[49]
ACC/AHA/NASPE 2002 Guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (ACC/AHA/NASPE committee to update the 1998 pacemaker guidelines). Circu
[50]
Baldasseroni S, Opasich C, Gorini M, Lucci D, Marchionni N, Marini M, et al..
Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure..
Am Heart J, 143 (2002), pp. 398-405
[51]
Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN..
QRS duration and mortality in patients with congestive heart failure..
Am Heart J, 143 (2002), pp. 1085-91
[52]
Bode-Schnurbus L, Böcker D, Block M, Gradaus R, Heinecke A, Breithardt G, et al..
QRS duration: a simple marker for predicting cardiac mortality in ICD patients with heart failure..
Heart, 89 (2003), pp. 1157-62
[53]
Vrtovec B, Delgado R, Zewail A, Thomas CD, Richartz BM, Radovancevic B..
Prolonged QTc interval and high B-type natriuretic peptide levels together predict mortality in patients with advanced heart failure..
[54]
Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW..
Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials..
J Am Coll Cardiol, 32 (1998), pp. 695-703
[55]
Turitto G, Ahuja RK, Caref EB, el-Sherif N..
Risk stratification for arrhythmic events in patients with nonischemic dilated cardiomyopathy and nonsustained ventricular tachycardia: Role of programmed ventricular stimulation and the signal-averaged electrocardiogram..
J Am Coll Cardiol, 24 (1994), pp. 1523-8
[56]
Heart rate variability..
Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology..
Eur Heart J, 17 (1996), pp. 354-81
[57]
Fauchier L, Babuty D, Cosnay P, Autret ML, Fauchier JP..
Heart rate variability in idiopathic dilated cardiomyopathy: characteristics and prognostic value..
J Am Coll Cardiol, 30 (1997), pp. 1009-14
[58]
Fauchier L, Babuty D, Cosnay P, Fauchier JP..
Prognostic value of heart rate variability for sudden death and major arrhythmic events in patients with idiopathic dilated cardiomyopathy..
J Am Coll Cardiol, 33 (1999), pp. 1203-7
[59]
Bilchick KC, Fetics B, Djoukeng R, Fisher SG, Fletcher RD, Singh SN, et al..
Prognostic value of heart rate variability in chronic congestive heart failure (Veterans Affairs' Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure)..
Am J Cardiol, 90 (2002), pp. 24-8
[60]
La Rovere MT, Pinna GD, Maestri R, Mortara A, Capomolla S, Febo O, et al..
Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients..
Circulation, 107 (2003), pp. 565-70
[61]
La Rovere MT, Bigger JT.J, Marcus FI, Mortara A, Schwartz PJ..
Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators..
Lancet, 351 (1998), pp. 478-84
[62]
Grimm W, Schmidt G, Maisch B, Sharkova J, Muller HH, Christ M..
Prognostic significance of heart rate turbulence following ventricular premature beats in patients with idiopathic dilated cardiomyopathy..
J Cardiovasc Electrophysiol, 14 (2003), pp. 819-24
[63]
Rosenbaum DS, Jackson LE, Smith JM, Garan H, Ruskin JN, Cohen RJ..
Electrical alternans and vulnerability to ventricular arrhythmias..
N Engl J Med, 330 (1994), pp. 235-41
[64]
Klingenheben T, Zabel M, D'Agostino RB, Cohen RJ, Hohnloser SH..
Predictive value of T-wave alternans for arrhythmic events in patients with congestive heart failure..
Lancet, 356 (2000), pp. 651-2
[65]
Adachi K, Ohnishi Y, Shima T, Yamashiro K, Takei A, Tamura N, et al..
Determinant of microvolt T wave alternans in patients with dilated cardiomyopathy..
J Am Coll Cardiol, 34 (1999), pp. 374-80
[66]
Costantini O, Drabek C, Rosenbaum DS..
Can sudden cardiac death be predicted from the T wave of the ECG? A critical examination of T wave alternans and QT interval dispersion..
Pacing Clin Electrophysiol, 23 (2000), pp. 1407-16
[67]
Ikeda T, Sakata T, Takami M, Kondo N, Tezuka N, Nakae T, et al..
Combined assessment of T-wave alternans and late potentials to predict arrhythmic events after myocardial infarction. A prospective study..
J Am Coll Cardiol, 35 (2000), pp. 722-30
[68]
Hohnloser SH, Ikeda T, Bloomfield DM, Dabbous OH, Cohen RJ..
T-wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation..
Lancet, 362 (2003), pp. 125-6
[69]
Mason JW..
A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators..
N Engl J Med, 329 (1993), pp. 452-8
[70]
Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, et al, for the Multicenter Automatic Defibrillator Implant..
Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia..
N Engl J Med, 335 (1996), pp. 1933-40
[71]
Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G, for the Multicenter Unsustained Tachycardia Trial I..
A randomized study of the prevention of sudden death in patients with coronary artery disease..
N Engl J Med, 341 (1999), pp. 1882-90
[72]
Wilber DJ..
Ventricular tachycardia in patients with heart failure. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology, from cell to bed side. Philadelphia: WB Saunders.
Ventricular tachycardia in patients with heart failure. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology, from cell to bed side. Philadelphia: WB Saunders, (2000), pp. 569-79
[73]
Poll DS, Marchlinski FE, Buxton AE, Josephson ME..
Usefulness of programmed electrical stimulation in idiopathic dilated cardiomyopathy..
Am J Cardiol, 58 (1986), pp. 992-7
[74]
Brembilla-Perrot B, Donetti J, De la Chaise AT, Sadoul N, Aliot E, Juilliere Y..
Diagnostic value of ventricular stimulation in patients with idiopathic dilated cardiomyopathy..
Am Heart J, 121 (1991), pp. 1124-31
[75]
Liem LB, Swerdlow CD..
Value of electropharmacologic testing in idiopathic dilated cardiomyopathy and sustained ventricular tachyarrhythmias..
Am J Cardiol, 62 (1988), pp. 611-6
[76]
Constantin L, Martins JB, Kienzle MG, Brownstein SL, McCue ML, Hopson RC..
Induced sustained ventricular tachycardia in nonischemic dilated cardiomyopathy: dependence on clinical presentation and response to antiarrhythmic agents..
Pacing Clin Electrophysiol, 12 (1989), pp. 776-83
[77]
Lampert R, Joska T, Burg MM, Batsford WP, McPherson CA, Jain D..
Emotional and physical precipitants of ventricular arrhythmia..
Circulation, 106 (2002), pp. 1800-5
[78]
Grigioni F, Barbieri A, Magnani G, Potena L, Coccolo F, Boriani G, et al..
Serial versus isolated assessment of clinical and instrumental parameters in heart failure: prognostic and therapeutic implications..
Am Heart J, 146 (2003), pp. 298-303
[79]
Grimm W, Christ M, Bach J, Muller HH, Maisch B..
Noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy: results of the Marburg Cardiomyopathy Study..
Circulation, 108 (2003), pp. 2883-91
[80]
Kuck KH, Cappato R, Siebels J, Ruppel R, for the CASH Investigators..
Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest. The Cardiac Arrest Study Hamburg (CASH)..
Circulation, 102 (2000), pp. 748-54
[81]
Connolly SJ, Gent M, Roberts RS, Dorian P, Roy D, Sheldon RS, et al..
Canadian Implantable Defibrillator Study (CIDS): A randomized trial of the implantable cardioverter defibrillator against amiodarone..
Circulation, 101 (2000), pp. 1297-302
[82]
A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ven..
The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators..
N Engl J Med, 337 (1997), pp. 1576-83
[83]
Lee DS, Green LD, Liu PP, Dorian P, Newman DM, Grant FC, et al..
Effectiveness of implantable defibrillators for preventing arrhythmic events and death: a meta-analysis..
J Am Coll Cardiol, 41 (2003), pp. 1573-82
[84]
Villacastin J, Almendral J, Arenal A, Albertos J, Ormaetxe J, Peinado R, et al..
Incidence and clinical significance of multiple consecutive appropiate high energy discharges in patients with implantable cardioverter defibrillator..
Circulation, 93 (1996), pp. 753-62
[85]
Relative effectiveness of the implantable cardioverter-defibrillator and antiarrhythmic drugs in patients with varying degrees of left ventricular dysfunction who have survived malignant ventricular arrhythmias. AVID Investigators. Antiarrhythmics Versus Implantable Defibrillators. J Am Coll Cardiol
[86]
Steinberg JS, Martins J, Sadanandan S, Goldner B, Menchavez E, Domanski M, et al, for the AVID Investigators..
Antiarrhythmic drug use in the implantable defibrillator arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study..
Am Heart J, 142 (2001), pp. 520-9
[87]
Pacifico A, Hohnloser SH, Williams JH, Tao B, Saksena S, Henry PD, et al, for the d, l-Sotalol Implantable Cardioverter-D..
Prevention of implantable-defibrillator shocks by pretreatment with sotalol..
N Engl J Med, 340 (1999), pp. 1855-62
[88]
Bansch D, Bocker D, Brunn J, Weber M, Breithardt G, Block M..
Clusters of ventricular tachycardias signify impaired survival in patients with idiopathic dilated cardiomyopathy and implantable cardioverter defibrillators..
J Am Coll Cardiol, 36 (2000), pp. 566-73
[89]
Rankovic V, Karha J, Passman R, Kadish AH, Goldberger JJ..
Predictors of appropriate implantable cardioverter-defibrillator therapy in patients with idiopathic dilated cardiomyopathy..
Am J Cardiol, 89 (2002), pp. 1072-6
[90]
The CASCADE Investigators..
Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE study)..
Am J Cardiol, 72 (1993), pp. 280-7
[91]
Page RL..
Effects of antiarrhythmic medication on implantable cardioverter-defibrillator function..
Am J Cardiol, 85 (2000), pp. 1481-5
[92]
Lorga-Filho A, Geelen P, Vanderheyden M, Malacky T, Primo J, Goethals M, et al..
Early benefit of implantable cardioverter defibrillator therapy in patients waiting for cardiac transplantation..
Pacing Clin Electrophysiol, 21 (1998), pp. 1747-50
[93]
Saba S, Atiga WL, Barrington W, Ganz LI, Kormos RL, MacGowan GA, et al..
Selected patients listed for cardiac transplantation may benefit from defibrillator implantation regardless of an established indication..
J Heart Lung Transplant, 22 (2003), pp. 411-8
[94]
Jeevanandam V, Bielefeld MR, Auteri JS, Sánchez JA, Schenkel FA, Michler RE, et al..
The implantable defibrillator: an electronic bridge to cardiac transplantation..
Circulation, 86 (1992), pp. 276-9
[95]
Middlekauff HR, Stevenson WG, Stevenson LW, Saxon LA..
Syncope in advanced heart failure: High risk of sudden death regardless of the origin of syncope..
J Am Coll Cardiol, 21 (1993), pp. 110-6
[96]
Fonarow GC, Feliciano Z, Boyle NG, Knight L, Woo MA, Moriguchi JD, et al..
Improved survival in patients with nonischemic advanced heart failure and syncope treated with an implantable cardioverter-defibrillator..
Am J Cardiol, 85 (2000), pp. 981-5
[97]
Grimm W, Hoffmann JJ, Muller HH, Maisch B..
Implantable defibrillator event rates in patients with idiopathic dilated cardiomyopathy, nonsustained ventricular tachycardia on Holter and a left ventricular ejection fraction below 30%..
J Am Coll Cardiol, 39 (2002), pp. 780-7
[98]
Knight BP, Goyal R, Pelosi F, Flemming M, Horwood L, Morady F, et al..
Outcome of patients with nonischemic dilated cardiomyopathy and unexplained syncope treated with an implantable defibrillator..
J Am Coll Cardiol, 33 (1999), pp. 1964-70
[99]
Hallstrom A, Pratt CM, Greene HL, Huther M, Gottlieb S, DeMaria A, et al..
Relations between heart failure, ejection fraction, arrhythmia suppression and mortality: analysis of the Cardiac Arrhythmia Suppression Trial..
J Am Coll Cardiol, 25 (1995), pp. 1250-7
[100]
Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R..
Randomised trial of low dose amiodarone in severe congestive heart failure. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardíaca en Argentina (GESICA)..
Lancet, 344 (1994), pp. 493-8
[101]
Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, et al..
Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmias..
N Engl J Med, 333 (1995), pp. 78-82
[102]
Selected Session Coverage on Heart Failure [uted 01/05/2004]. Available from:www.medscape.com/viewarticle/ 471461
[103]
Amiodarone Trials Meta-Analysis Investigators..
Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials..
Lancet, 350 (1997), pp. 1417-24
[104]
CIBIS-II Investigators and Commitees..
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial..
Lancet, 353 (1999), pp. 9-13
[105]
Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al, for the Carvedilol Prospective Randomized Cumulative..
Effect of carvedilol on survival in severe chronic heart failure..
N Engl J Med, 344 (2001), pp. 1651-8
[106]
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al, for the US Carvedilol Heart Failure Study Group..
The effect of carvedilol on morbidity and mortality in patients with chronic heart failure..
N Engl J Med, 334 (1996), pp. 1349-55
[107]
Goldstein S, Fagerberg B, Hjalmarson A, Kjekshus J, Waagstein F, Wedel H, et al..
MERIT-HF Study Group. Metoprolol controlled release/extended release in patients with severe heart failure. Analysis of the experience in the MERIT-HF study..
J Am Coll Cardiol, 38 (2001), pp. 932-8
[108]
Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, et al, Carvedilol Or Metoprolol European Tr..
Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial..
[109]
Pratt CM, Gardner M, Pepine C, Kohn R, Young JB, Greenberg B, et al..
Lack of long-term ventricular arrhythmia reduction by enalapril in heart failure. SOLVD Investigators..
Am J Cardiol, 75 (1995), pp. 1244-9
[110]
Fletcher RD, Cintron GB, Johnson G, Orndorff J, Carson P, Cohn JN..
Enalapril decreases ventricular tachycardia in heart failure: V-HeFT II..
Circulation, 87 (1993), pp. 49-55
[111]
Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, et al..
Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the survival and ventricular enlargement study. The SAVE Investigators..
N Engl J Med, 327 (1992), pp. 669-77
[112]
Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, et al, on behalf of the ATLAS Study Group:..
Circulation, 100 (1999), pp. 2312-8
[113]
Pitt B, Poole-Wilson PA, Segal R, Martínez FA, Dickstein K, Camm AJ, et al..
Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial­the Losartan Heart Failure Survival Study ELITE II..
Lancet, 355 (2000), pp. 1582-7
[114]
Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators..
A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure..
N Engl J Med, 345 (2001), pp. 1667-75
[115]
Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, et al..
Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme..
Lancet, 362 (2003), pp. 759-66
[116]
Barrios V..
Insuficiencia cardíaca con función ventricular deprimida. Estudio CHARM..
Rev Esp Cardiol, 4 (2004), pp. 12-20
[117]
Garg R, Yusuf S..
Overview of randomised trials of angiotensin converting enzyme inhibitors on mortality and morbidity in patients with heart failure..
JAMA, 273 (1995), pp. 1450-6
[118]
González-Juanatey JR, Gómez I..
ARA II en insuficiencia cardíaca..
??D??nde estamos y hacia d??nde vamos? Rev Esp Cardiol, 4 (2004), pp. 3-11
[119]
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Pérez A, et al, for the Randomized Aldactone Evaluation Study Investiga..
The Effect of spironolactone on morbidity and mortality in patients with severe heart failure..
N Engl J Med, 341 (1999), pp. 709-17
[120]
Pitt B, Remme W, Zannad F, Neaton J, Martínez F, Roniker B, et al..
Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction..
N Engl J Med, 348 (2003), pp. 1309-21
[121]
Bansch D, Antz M, Boczor S, Volkmer M, Tebbenjohanns J, Seidl K, et al..
Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT)..
Circulation, 105 (2002), pp. 1453-8
[122]
Strickberger SA, Hummel JD, Bartlett TG, Frumin HI, Schuger CD, Beau SL, et al..
AMIOVIRT Investigators. Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia-AMIOVIRT..
J Am Coll Cardiol, 41 (2003), pp. 1707-12
[123]
Kadish A, Dyler A, Daubert J, Quigg R, Estes M, Anderson K, et al, and the Defibrillators in Nonischemic Cardiomtopathy..
Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy..
N Engl J Med, 350 (2004), pp. 2151-8
[124]
Bardy GH, Lee KL, Mark DB..
The Sudden Cardiac Death in Heart Failure Trial: pilot study [abstract]..
Pacing Clin Electrophysiol, 20 (1997), pp. 1148
[125]
Rosenqvist M, Beyer T, Block M, den Dulk K, Minten J, Lindemans F..
Adverse events with transvenous implantable cardioverter-defibrillators: a prospective multicenter study. European 7219 Jewel ICD investigators..
Circulation, 98 (1998), pp. 663-70
[126]
Saxon LA, Stevenson WG, Middlekauff HR, Stevenson LW..
Increased risk of progressive hemodynamic deterioration in advanced heart failure patients requiring permanent pacemakers..
Am Heart J, 125 (1993), pp. 1306-10
[127]
The DAVID Trial Investigators..
Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator..
JAMA, 288 (2002), pp. 3115-23
[128]
García-Bolao I, Macías A, Alegría E, Berenguel A, Gavira JJ, Azcárate P, et al..
Tratamiento de la insuficiencia cardíaca avanzada mediante estimulación biventricular. Experiencia inicial en una serie de 22 casos consecutivos..
Rev Esp Cardiol, 56 (2003), pp. 245-52
[129]
Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al..
MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure..
N Engl J Med, 346 (2002), pp. 1845-53
[130]
Bristow M, Saxon L, Boehmer J, Krueger S, Kass d, De Marco T, et al, and the Comparison of Medical Therap.y, Pacin.g, and..
Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure..
N Engl J Med, 350 (2004), pp. 2140-50
[131]
Livanis EG, Flevari P, Theodorakis GN, Kolokathis F, Leftheriotis D, Kremastinos DT..
Effect of biventricular pacing on heart rate variability in patients with chronic heart failure..
Eur J Heart Fail, 5 (2003), pp. 175-8
[133]
Muñiz García J, Mosquera Pérez I, Freire Castroseiros E, García Castelo A, Castro-Beiras A..
Uso de anticoagulación al alta hospitalaria en pacientes con insuficiencia cardíaca y fibrilación auricular..
Rev Esp Cardiol, 56 (2003), pp. 880-7
[134]
Herreros González J, Prósper Cardoso F, Alegría Ezquerra E..
Utilización de células madre para la regeneración miocárdica en la insuficiencia cardíaca..
Rev Esp Cardiol, 56 (2003), pp. 935-9
Idiomas
Revista Española de Cardiología (English Edition)

Subscribe to our newsletter

Article options
Tools
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?