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
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Abstract |
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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: 44.958.3%]) than non-inducible patients (28.8% [CI: 23.436.1%, ]). When challenged in a multivariate model, inducibility still had an independent power for predicting all-cause death (hazard ratio (HR), 1.5 [95% CI, 1.12.3],
), but not sudden death (SD) (HR, 1.2 [95% CI, 0.73.6],
). 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, 0.10.9],
) 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
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Introduction |
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Programmed ventricular stimulation (PVS) has long been used to guide therapy in patients with clinically documented VAs.1217 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.1822
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.
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Methods |
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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, 24116 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 MannWhitney -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 KaplanMeier 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: age
55 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
-value
0.05, 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
-value
0.05 was interpreted as significant result. Analysis was carried out with SPSSTM for Windows 11.011.5, SPSS Inc. 20012003.
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Results |
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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: 44.958.3%]) than non-inducible patients (28.8% [CI: 23.436.1%, ]) (Fig. 1). Similarly, SD rates were significantly higher among inducible (26.9% [CI: 19.934.7%]) than non-inducible patients (13.8% [CI: 9.418.8%,
]) (Fig. 1).
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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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Discussion |
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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 events1517,1920,22. 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 prediction1222,3034; 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.18,21,3032,35,36
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 EF
0.35. 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.
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Footnotes |
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References |
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