Response to programmed ventricular stimulation and clinical outcome in cardiac arrest survivors receiving randomised assignment to implantable cardioverter defibrillator or antiarrhythmic drug therapy

Riccardo Cappatoa,*, Sigrid Boczorb and Karl-Heinz Kuckb on behalf of the CASH Investigators

a Arrhythmia and Electrophysiology Center, Istituto Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy
b AK S. Georg, Hamburg, Germany

Received October 2, 2003; revised December 10, 2003; accepted January 15, 2004 * Corresponding author. Tel.: +39-2-5277-4450; fax: +39-2-5560-3125
E-mail address: rcappato{at}libero.it

See page 623 for the editorial comment on this article1


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background Using a prospective design which randomly assigned implantable cardioverter defibrillator (ICD) versus antiarrhythmic drugs (AADs), we investigated the usefulness of programmed ventricular stimulation (PVS) for prediction of outcome and therapy effectiveness in cardiac arrest (CA) survivors.

Methods and results We performed baseline PVS in 285 survivors of CA enrolled in the Cardiac Arrest Study Hamburg (CASH) and randomised to ICDs or AADs. Sustained ventricular arrhythmia (VA) was induced in 134 (47.0%) patients. We compared the outcomes of different subgroups based on response to baseline PVS and randomly assigned therapy. Patients were followed for a median of 55 months. The raw death rate was greater among inducible (51.3% [95% CI: 44.9–58.3%]) than non-inducible patients (28.8% [CI: 23.4–36.1%, ]). When challenged in a multivariate model, inducibility still had an independent power for predicting all-cause death (hazard ratio (HR), 1.5 [95% CI, 1.1–2.3], ), but not sudden death (SD) (HR, 1.2 [95% CI, 0.7–3.6], ). Subgroup analysis showed that, when compared to AADs, assignment to ICDs was associated with a lower risk of all-cause death (HR, 0.4 [95% CI, 0.1–0.9], ) in patients with EF<=0.35 and non-inducible arrhythmias, but not in other patient subgroups.

Conclusions In CA survivors, inducibility at baseline PVS is independently associated with an increased risk of all-cause death, but not SD. In addition, response to PVS may help to identify subgroups of patients who could most benefit from ICD.

Key Words: Electrophysiological testing • Cardiac arrest • Implantable defibrillator • Antiarrhythmic therapy


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The widespread use of cardiopulmonary resuscitation and external defibrillation has resulted in an increased number of cardiac arrest (CA) victims being discharged alive after hospitalisation. During follow-up, these patients present a high incidence of arrhythmias and fatal events.1–4 Although the introduction of implantable defibrillators (ICDs) has substantially reduced the risk of sudden death (SD) in CA survivors,5–8 the presence of causes of death other than ventricular arrhythmias (VAs) limit the benefit of this therapy.9 Recent data from randomised trials have suggested that ICDs may improve survival, particularly in subgroups with severely impaired LV function;10,11 these observations call for a more accurate selection of ICD candidates.

Programmed ventricular stimulation (PVS) has long been used to guide therapy in patients with clinically documented VAs.12–17 Interpretation of data in the different studies has been limited because of the different criteria of stimulation, inducibility, and drug efficacy. In addition, the retrospective nature of most such studies has further limited data interpretation and also somewhat discredited PVS in clinical practice.18–22

The Cardiac Arrest Study Hamburg (CASH) was designed to prospectively investigate the efficacy of ICDs in reducing the risk of all-cause death in CA survivors, as compared to antiarrhythmic drug (AAD) therapy.23 The study design also makes it possible to evaluate whether the response to PVS would correlate with the clinical outcome under the treatment strategies selected by randomisation. In this report, we describe the outcome of patients in relation to their response to PVS and we compare death rates from any cause or due to arrhythmia among patients randomly assigned to receive ICDs with death rates among patients randomly assigned to receive drug therapy.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
The entry criteria of CASH have been described in detail elsewhere.23 The study was approved by the institutional review committee of each centre and all subjects gave informed consent. In brief, patients were enrolled in the study if they had a sudden and unexpected collapse with loss of consciousness resulting from a VA requiring cardiopulmonary resuscitation and external cardioversion. Patients were excluded if CA occurred within 72 h of acute myocardial infarction, cardiac surgery, electrolyte abnormalities, or proarrhythmic drug effect. Between March 1986 and March 1996, 346 patients were enrolled in the study and were therefore eligible for PVS.

Following the premature discontinuation of assignment to propafenone in 1992,24 288 out of 346 enrolled patients completed the study; of these, 99 were assigned to ICDs and 189 to drug treatment (92 to amiodarone and 97 to metoprolol) according to a 1:2 randomisation ratio. Coronary artery disease was diagnosed in 213 (74%) patients, dilated cardiomyopathy in 35 (12%), other heart diseases, including valvular, hypertrophic or congenital, in 12 (4%), and no heart disease in 30 (10%). The ejection fraction (EF) was 0.46±0.18. Eighty patients (27%) were in NYHA class I, 164 (58%) patients in NYHA class II, and 44 (15%) in NYHA class III. Of 31 (11%) patients with no heart disease, none presented with long QT or Brugada syndrome. During hospitalisation following the index event, 57 (20%) patients underwent coronary revascularisation; their clinical characteristics did not differ from those in the remaining patients and they were homogeneously randomised in the two study arms. No repeat evaluation of EF was performed during follow-up to investigate the longitudinal impact of this parameter on the validity of the response to PVS.

Aim of the study
The following parameters were investigated in relation to response to PVS: (1) the general outcome of patients enrolled in the CASH trial; and (2) rates of all-cause death and SD among patients randomly assigned to receive ICDs with the rates among patients randomly assigned to receive drug therapy, depending on whether their baseline EF was 35% or <=35%.

Electrophysiologic studies
In all participating centres, a baseline PVS was performed in the absence of any AA therapy 9±7 days after the index event. Electrical impulses were delivered at twice the diastolic threshold from the right ventricular apex and the right ventricular outflow tract during sinus rhythm and at basic drives of 640, 510 and 440 ms. Up to three ventricular extrabeats following the sinus or basic drive were delivered from each of the two sites. The stimulation was continued until a sustained VA (i.e., 30 s in duration) was induced or the protocol was completed. No pharmacological manoeuvres were attempted during the PVS protocol.

In patients assigned to drug therapy, a second study was performed: drugs were administered up to the steady state (about 5 days) in patients assigned to metoprolol and to a cumulative dose of 10 g in those assigned to amiodarone. Suppression of sustained VAs was defined as inability to induce any sustained VA.

In 52 patients assigned to ICD therapy provided with telemetry option, intervention-related intracardiac electrograms were retrieved from the device during follow up.

Follow-up
The follow-up was 54±34 months (median, 55; range, 24–116 months). The clinical events monitored were all-cause death (primary study endpoint) and sudden death (SD, secondary study endpoint). SD was defined as death within 1 h after the onset of symptoms or an unwitnessed death if the patient had been seen alive and well within the previous 24 h.

Statistical analysis
Continuous data are reported as mean±1 SD, and the distribution of categorical variables is presented as absolute and relative frequency. Comparisons between groups were calculated using the Mann–Whitney -test (for continuous variables) or the Fisher exact test (for categorical variables). Single missing values were treated with the best case replacement. Cumulative survival rates were calculated by the Kaplan–Meier method, with the time to the first event as the outcome variable.25 The significance of the difference between groups was assessed with the log-rank test.26 The cumulative hazard functions were plotted to confirm a proportional distribution over time. The relative risk of co-variates on all-cause death and SD was evaluated by Cox regression analysis models (method: forced entry, all independent variables entered at first step) and expressed as a hazard ratio.27 The contrast method chosen for all regression models was the indicator method and the reference categories were those representing the respective presence of the following risk factors: age55 years, male sex, EF<=35%, NYHA functional class III or IV, smoking, hypertension, diabetes, remote MI, no revascularisation, required use of digitalis or diuretics, sustained VA induced at baseline PVS, and no ICD assignment by randomisation. For sub-analyses, either interaction terms were built up including EF<=35% and non-inducibility or groups were divided by an EF<=35% and inducibility according to an a priori hypothesis. To analyse the influence of risk factors on the survival times, all covariates were first entered in univariate Cox regression and with a -value0.05, based on the significance of the Wald statistic.28 They were then entered in a multiple Cox regression model. All tests for significance were two-tailed and considered as explanatory, so no alpha adjustment had been performed. A -value0.05 was interpreted as significant result. Analysis was carried out with SPSSTM for Windows 11.0–11.5, SPSS Inc. 2001–2003.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Electrophysiologic observations
Baseline
Sustained VA (cycle length, 257±29 ms) was inducible in 134 (47.0%) of 285 patients undergoing baseline PVS: monomorphic VT in 98 (73.1%) and polymorphic VT or VF in 36 (26.9%) patients. In 151 patients (53.0%), no VA was inducible. The distribution of inducible patients was similar in the ICD and drug arms. Non-inducible patients had a lower incidence of coronary artery disease and remote myocardial infarction than inducible patients; they also presented with a significantly higher proportion of EF0.35 (Table 1). The response to PVS by therapy assigned is presented in Table 2.


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Table 1 Characteristics of the subgroups defined by the results of baseline PVS

 

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Table 2 Response to baseline PVS and drug testing according to group assignment

 
After drug load
Of the patients assigned to drug therapy, 166 (88.3%) underwent drug testing. Ten patients, of which 5 were assigned to metoprolol and 5 to amiodarone, refused a second study, whereas deterioration of clinical conditions prevented a second study in another 12, of whom 5 were assigned to metoprolol and 7 to amiodarone.

In patients undergoing both studies, the daily maintenance doses of amiodarone and metoprolol during the loading period were 924±134 and 85±73 mg, respectively. Seventy-four out of 166 patients (44.6%) were inducible at baseline PVS; of them, 39 (52.7%) remained inducible and 35 (47.3%) became non-inducible. Ninety-two out of 166 patients (55.4%) were non-inducible at baseline PVS; of them, 72 (78.3%) remained non-inducible, whereas 20 (21.7%) became inducible under drug treatment. A similar response to drug testing was observed in patients assigned to amiodarone and metoprolol (Table 2). Drug treatment also resulted in a similar prolongation of the baseline ventricular effective refractory period in amiodarone (from 251±32 to 274±40 ms, ) and metoprolol patients (from 241±26 to 276±36 ms, ).

Response to programmed ventricular stimulation and clinical outcome
One hundred twenty patients (41.6%) died during follow-up. Death occurred in 70 inducible and 50 non-inducible patients; 32 (45.7%) and 18 episodes (36.0%) were due to SD in the two groups, respectively. The raw death rates were higher among inducible (51.3% [CI: 44.9–58.3%]) than non-inducible patients (28.8% [CI: 23.4–36.1%, ]) (Fig. 1). Similarly, SD rates were significantly higher among inducible (26.9% [CI: 19.9–34.7%]) than non-inducible patients (13.8% [CI: 9.4–18.8%, ]) (Fig. 1).



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Fig. 1 Kaplan–Meier estimates of the rates of survival free of all-cause death (left panel) and SD (right panel) in patients with inducible and non-inducible sustained VAs. Patients are divided according to response to baseline PVS (two lines above) and assignment by randomisation (three lines below).

 
At univariate analysis, inducibility during baseline PVS was a predictor of both all-cause death and SD (Table 3) regardless of whether the inducible arrhythmia was VT or VF. Other predictors were: for all-cause death, age over 55 years, EF<=0.35, and a history of remote myocardial infarction; for SD, inducibility at baseline PVS and assignment to ICD by randomisation. When challenged in a multivariate analysis model, inducibility at baseline PVS and NYHA functional class III or IV portended significant power to predict all-cause death. For SD, a NYHA functional class III or IV and assignment to ICD by randomisation maintained an independent power.


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Table 3 Predictors of all-cause death and sudden death in the general population

 
When the combined influence of PVS and EF was investigated, arrhythmia inducibility was still associated with a significantly higher all-cause death rate in patients with an EF0.35, but not in patients with an EF<=0.35 (Table 4). Similarly, inducibility accounted for a significantly higher SD rate in patients with an EF0.35, but not in patients with an EF<=0.35 (Table 4). Among patients with an EF<=0.35, assignment to ICD was associated with a significantly lower incidence of all-cause death (reduction vs AA drugs, 46.1% [CI: 29.7–64.8%]) and SD (no SD in the ICD arm vs 36.8% [CI: 11.8–61.8%] in the drug arm) in non-inducible patients. In contrast, no differences in all-cause death and SD were observed between the ICD and the drug arm in patients with EF<=0.35 and inducible arrhythmia or in patients with EF0.35 regardless of their response to baseline PVS (Table 5).


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Table 4 Influence of inducibility at baseline PVS on all-cause death and SD, as predicted in subgroups with EF0.35 or EF<=0.35

 

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Table 5 Influence of ICD assignment on all-cause death and sudden death, as predicted in subgroups with EF0.35 and inducibility, EF<=0.35 and inducibility, EF0.35 and non-inducibility, and EF<=0.35 and non-inducibility

 
Analysis of telemetry data in the ICD arm was available from November 1991 and included 52 (53.6%) out of 97 patients undergoing baseline PVS stimulation. Of these patients, 20 (38.5%) had inducible VT, 5 (9.6%) had inducible VF, and 27 (51.9%) did not have an inducible VA. During follow up, 30 patients (57.6%) experienced 197 arrhythmic events (range per patient, 1–29 events). The sensitivity, specificity, and positive and negative accuracy of PVS were 42.8%, 50.0%, 52.2%, and 40.7%, respectively, for the prediction of recorded VA; 55.0%, 74.5%, 44.0%, and 82.0%, respectively, for the prediction of recorded VT; and 28.6%, 92.7%, 33.3%, and 91.1%, respectively, for the prediction of recorded VF.

Response to drug testing and clinical outcome
Suppressability of an inducible VA by amiodarone or metoprolol was not associated with a better outcome than non-suppressability (Fig. 2). Similarly, no differences in clinical outcome were observed among non-inducible patients at baseline PVS, regardless of their response at the second study.



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Fig. 2 Kaplan–Meier estimates of the rates of survival free of all-cause death in subgroups with arrhythmia inducibility at baseline PVS depending on suppressability or not during second PVS.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The results of this study indicate that among CA survivors receiving ICD or amiodarone or metoprolol therapy, inducibility of a sustained VA at baseline PVS is independently associated with an increased risk of all-cause death, but not SD over long-term follow-up. The inability of PVS to independently predict SD is substantiated by the observations that: (1) differences in SD according to PVS response were only detectable in subgroups with EF0.35; and, (2) the only subgroup showing a more benefit from ICD as compared to AADs was represented by patients with EF<=0.35 and non-inducibility at baseline PVS. The latter observation suggests that SD secondary to a VA in CA survivors with low EF is more likely to occur among non-inducible than inducible patients. The current results also indicate that the risk of all-cause death predicted by inducibility at baseline PVS in CA survivors does not appear to be dependent on the type of arrhythmia induced, whether VT of VF, and tends to persist over a median follow-up of nearly 4.5 years.

The observation that inducibility at baseline PVS independently predicts all-cause death over long-term follow-up is new when applied to CA survivors. A similar observation has been shown in studies investigating other patient categories, such as those with remote myocardial infarction, poor LV function, and unsustained VT,29 although in those studies the risk among inducible patients for CA and SD exceeded the risk for all-cause death.

In the present study, arrhythmia inducibility did not prove to be an independent predictor of SD. One possible explanation for this finding is that the number of patients is not large enough to achieve statistical significance. Another explanation may be that assignment to ICD therapy in about one third of the patients might have influenced the interpretation regarding the predictive power of arrhythmia inducibility at baseline PVS; in particular, ICD might have prevented SD more often in inducible than non-inducible patients. However, two observations make this possibility unlikely: (1) the very low sensitivity and specificity of inducibility in predicting future appropriate therapy in screened ICD recipients; (2) the presence in one patient subgroup of a predictable benefit of ICD over amiodarone or metoprolol based on non-inducibility rather than inducibility.

Traditionally, PVS has been identified as a predictor of future sudden arrhythmic events and the majority of studies addressing the role of PVS in CA survivors have focused on the usefulness of this method in guiding the selection of AADs for the prevention of future arrhythmic events15–17,19–20,22. Oppositely, the data from the present study suggest that inducibility at baseline PVS identifies patients at higher risk of all-cause death but does not predict the type of death, whether cardiac or SD. A number of factors in previous studies may account for differences in comparison with the present study, including the following: all-cause death and SD were rarely investigated independently, and never using a multivariate model for risk prediction12–22,30–34; patients usually presented with poorer LV function and a lower proportion with EF0.35 than in CASH; finally, drugs other than those investigated in CASH may have unfavourably affected clinical outcome. The inability to predict future SD by inducibility of sustained VAs observed in the present study may also explain, at least in part, the contradictory data regarding the role of serial drug testing in previous reports.18,21,30–32,35,36

Another original finding of the present study is that differences in all-cause death between inducible and non-inducible patients were significantly more evident in subgroups with an EF0.35 than in those with an EF<=0.35. In addition to a possible change in the predictive power of PVS in relation to changes of LV function, this difference may also be attributed to the larger expected benefit from ICD in CA survivors with poorer LV function.37,38 In this study, such a possibility is supported by the observation that patients with EF<=0.35 and non-inducibility of a sustained VA presented a significantly larger survival rate if assigned to ICD than to AADs. In contrast, assignment to ICD did not improve survival in subgroups with EF<=0.35 and inducibility of a sustained VA, or in patients with EF0.35. The possibility that non-inducible patients with low EF have a higher risk of SD than inducible patients has also been suggested by data observed in other patient categories (i.e., with coronary artery disease and EF<=0.30), in which non-inducible patients presented a significantly larger incidence of VF recorded by ICD telemetry during follow-up than inducible patients.39

Patients with amiodarone- or metoprolol-related suppression of an inducible VA at baseline PVS did not show a lower incidence of death from any cause or SD than patients without arrhythmia suppression, regardless of their EF. This coincides with previous reports on prospective studies in similar populations.22,40 In patients assigned to AADs, no differences were observed between amiodarone and metoprolol with regard to protection against SD and death from any cause. This finding suggests that the two drugs have a similar interaction with the myocardial substrate of CA survivors, and is substantiated by the observation that they both show a similar degree of prolongation on ventricular refractoriness. The changes produced by metoprolol on ventricular refractoriness are an original finding and suggest that oral treatment with this drug results in different effects as compared to intravenous infusion. The homogeneous distribution of patients assigned to metoprolol and amiodarone within the drug arm who did not undergo a second PVS is unlikely to have affected the interpretation of serial drug testing in relation to outcome.

This study is based on subgroup analysis and several issues require comment. First, the relatively small numbers of patients in the different groups limit the value of comparison. Second, the absence of control of co-interventions makes it possible that other effects are present between undetected parameters and those in the analysis. Third, the correlations proposed between the response to PVS and the outcome only apply to patients receiving the same therapies as in this study. Fourth, these are results from a single study and can be influenced by the biases inherent to single studies and retrospective analysis of this sort. In particular, the relatively low inducibility rate in this study as compared to other studies in CA survivors may reflect the relatively high mean EF in CASH. As a result, the present data on the role of PVS as a risk stratifier in CA survivors require confirmation. However, if confirmed, these findings may have relevant implications for the provision of more cost-effective therapies to CA survivors.

In conclusion, the results of baseline PVS indicate that inducibility is associated with an increased risk of all-cause death, but not SD in CA survivors receiving state-of-the-art therapy, and their value tends to be confirmed during long term follow-up. In addition, the present data indicate that ICD treatment may be most effective in sub-groups of patients with low EF and non-inducibility at baseline PVS. Future prospective trials may be required to test the hypotheses generated by the present observations.


    Footnotes
 
1 doi:10.1016/j.ehj.2004.02.029. Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Liberthson RR, Nagel EL, Hirschman JC et al. Prehospital ventricular defibrillation. Prognosis and follow-up course. N. Engl. J. Med. 1974;291:317–321.[Medline]
  2. Baum RS, Alvarez H III, Cobb LA. Survival after resuscitation from out-of-hospital ventricular fibrillation. Circulation. 1974;50:1231–1235.[Medline]
  3. Eisenberg MS, Hallstrom A, Bergner L. Long-term survival after out-of-hospital cardiac arrest. N. Engl. J. Med. 1982;306:1340–1343.[Medline]
  4. Myerburg RJ, Kessler KM, Estes D et al. Long-term survival after pre-hospital cardiac arrest: analysis of outcome during an 8 year study. Circulation. 1984;70:538–546.[Abstract]
  5. Winkle RA, Mead RH, Ruder MA et al. Long-term outcome with the automatic implantable cardioverter-defibrillator. J. Am. Coll. Cardiol. 1989;13:1353–1361.[Medline]
  6. Fogoros RN, Elson JJ, Bonnet CA et al. Efficacy of the automatic implantable cardioverter-defibrillator in prolonging survival in patients with severe underlying cardiac disease. J. Am. Coll. Cardiol. 1990;16:381–386.[Medline]
  7. Newman D, Sauve MJ, Herre J et al. Survival after implantation of the cardioverter defibrillator. Am. J. Cardiol. 1992;69:899–903.[Medline]
  8. Bardy GH, Hofer B, Johnson G et al. Implantable transvenous cardioverter-defibrillators. Circulation. 1993;87:1152–1168.[Abstract]
  9. Luu M, Stevenson WG, Stevenson LW et al. Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation. 1989;80:1675–1680.[Abstract]
  10. Domanski MJ, Sakseena S, Epstein AE et al. for the AVID Investigators 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. J Am Coll Cardiol 1999;34:1090–1095.
  11. Sheldon R, Connolly S, Krahn A et al. on behalf of the CIDS Investigators, Identification of patients most likely to benefit from implantable cardioverter-defibrillator therapy, The Canadian Implantable Defibrillator Study. Circulation. 2000;101:1660–1664.[Abstract/Free Full Text]
  12. Wellens HJ. Value and limitations of programmed electrical stimulation of the heart in the study and treatment of tachycardias. Circulation. 1978;57:845–853.[Abstract]
  13. Wellens HJ, Brugada P, Stevenson WG. Programmed electrical stimulation of the heart in patients with life-threatening ventricular arrhythmias: What is the significance of induced arrhythmias and what is the correct simulation protocol? Circulation. 1985;72:1–7.[Medline]
  14. Josephson ME, Horowitz LN. Electrophysiologic approach to therapy of recurrent sustained ventricular tachycardia. Am. J. Cardiol. 1979;43:631–642.[CrossRef][Medline]
  15. Mason JW, Winkle RA. Accuracy of the ventricular tachycardia-induction study for predicting long-term efficacy and inefficacy of antiarrhythmic drugs. N. Engl. J. Med. 1980;303:1073–1077.[Abstract]
  16. Morady F, DiCarlo L, Winston S et al. Clinical features and prognosis of patients with out-of-hospital cardiac arrest and a normal electrophysiologic study. J. Am. Coll. Cardiol. 1984;4:39–44.[Medline]
  17. Schoenfeld MH, McGovern B, Garan H, Kelly E, Grant G, Ruskin JN. Determinants of the outcome of electrophysiologic study in patients with ventricular arrhythmias. J. Am. Coll. Cardiol. 1985;6:298–306.[Medline]
  18. Wellens HJ, Dovendans P, Smeets J et al. Arrhythmia risk: Electrophysiological studies and monophasic action potentials. Pacing Clin. Electrophysiol. 1997;20:2560–2565.[Medline]
  19. Poole JE, Mathisen TL, Kudenchuck PJ et al. Long-term outcome in patients who survive out of hospital ventricular fibrillation and undergo electrophysiologic studies: Evaluation by electrophysiologic subgroups. J. Am. Coll. Cardiol. 1990;16:657–665.[Medline]
  20. Fogoros RN, Elson JJ, Bonnet CA et al. Long-term outcome of survivors of cardiac arrest whose therapy is guided by electrophysiologic testing. J. Am. Coll. Cardiol. 1992;19:780–788.[Medline]
  21. Mason JW, for the Electrophysiologic Study Versus Electrocardiographic Monitoring Investigator. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic drug efficacy for ventricular tachyarrhythmias. N. Engl. J. Med. 1993;329:445–451.[Abstract/Free Full Text]
  22. The CASCADE investigators. Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (The CASCADE study). Am. J. Cardiol. 1993;72:280–287.[Medline]
  23. Kuck KH, Cappato R, Siebels J et al., for the CASH investigators. A randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation 2000;102;748–54.
  24. Siebels J, Cappato R, Rüppel R et al., the CASH Investigators. ICD versus drugs in cardiac arrest survivors: preliminary results of the cardiac arrest study Hamburg. PACE 1993;16:552–8.
  25. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 1958;53:457–481.
  26. Lee ET. Statistical methods for survival data analysis. 2nd ed. New York: John Wiley & Sons; 1992. .
  27. Cox DR. Regression models and life-tables. J. R. Stat. Soc. [B]. 1972;34:187–220.
  28. Marubini E, Valsecchi MG. Analysing survival data from clinical trials and observational studies. 2nd ed. New York: John Wiley & Sons; 1995. .
  29. Buxton AE, Lee KL, DiCarlo L et al, for the Multicenter Unsustained Tachycardia Trial Investigators. Electrophysiologic testing to identify patients with coronary artery disease who are at risk for sudden death. N. Engl. J. Med. 2000;342:1937–1945.[Abstract/Free Full Text]
  30. Ruskin JN, DiMarco JP, Garan H. Out-of-hospital cardiac arrest: electrophysiologic observations and selection of long-term antiarrhythmic therapy. N. Engl. J. Med. 1980;303:607–613.[Abstract]
  31. Wilber DJ, Garan H, Finkelstein D et al. Out-of-hospital cardiac arrest. Use of electrophysiologic testing in the prediction of long-term outcome. N. Engl. J. Med. 1988;318:19–24.[Abstract]
  32. Skale BT, Miles WM, Heger JJ et al. Survivors of cardiac arrest: prevention of recurrence by drug therapy as predicted by electrophysiologic testing or electrocardiographic monitoring. Am. J. Cardiol. 1986;57:113–119.[Medline]
  33. The Antiarrhythmic 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. 1997;337:1576–1583.[Abstract/Free Full Text]
  34. Connolly SJ, Gent M, Roberts RS et al. Canadian Implantable Defibrillator Study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation. 2000;101:1297–1302.[Abstract/Free Full Text]
  35. Mitchell LB, Duff HJ, Manyari DE et al. A randomized clinical trial of the noninvasive and invasive approaches to drug therapy of ventricular tachycardia. N. Engl. J. Med. 1987;317:1681–1687.[Abstract]
  36. Rodriguez LM, Sternich EB, Smeets JL et al. Induction of ventricular fibrillation predicts sudden death in patients treated with amiodarone because of ventricular tachyarrhythmias after myocardial infarction. Heart. 1996;75:23–28.[Abstract]
  37. Sheldon R, O`Brien BJ, Blackhouse G et al. Effect of clinical risk stratification on cost-effectiveness of the implantable cardioverter defibrillator study: The Canadian implantable cardioverter-defibrillator. Circulation. 2001;104:1622–1626.[Abstract/Free Full Text]
  38. Connolly SJ, Hallstrom AP, Cappato R et al. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. Eur. Heart J. 2000;21:2071–2078.[Abstract/Free Full Text]
  39. Moss AJ, on behalf of the MADIT-II investigators. Substudies from the Multicenter Automatic Implantable Defibrillator II (MADIT II) Trial. Invited (oral) Presentation at the 23rd Annual Scientific Session of NASPE, May 8–11, 2002, San Diego, CA.
  40. Steinbeck G, Andresen D, Bach P et al. A comparison of electrophysiologically guided antiarrhythmic drug therapy with beta-blocker therapy in patients with symptomatic, sustained ventricular tachyarrhythmias. N. Engl. J. Med. 1992;327:987–992 Erratum in: N. Engl. Med. 1993;328:71.[Abstract]

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