European Heart Journal Advance Access originally published online on January 16, 2007
European Heart Journal 2007 28(4):469-477; doi:10.1093/eurheartj/ehl478
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Adjunctive antiarrhythmic drug therapy in patients with implantable cardioverter defibrillators: a systematic review
1 Epidemiology Unit, Department of Cardiology, Paseo Vall d'Hebron Hospital, Barcelona 119-129, 08035, Spain
2 Department of Cardiology, Dos de Maig Hospital, Barcelona, Spain
3 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
Received 17 October 2006; revised 4 December 2006; accepted 21 December 2006; online publish-ahead-of-print 16 January 2007.
* Corresponding author. Tel: +34 932746177; fax: +34 932746063.E-mail address: nacho_ferreira{at}hotmail.com
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Abstract |
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Aims To assess the efficacy and safety of adjunctive antiarrhythmic drug therapy for preventing implantable cardioverter defibrillator (ICD) therapies.
Methods and results We conducted a systematic literature search to identify all randomized, controlled trials assessing the efficacy of adjunctive antiarrhythmic drug therapy. Trial data were reviewed and extracted independently by two investigators in an unblinded, standardized manner. Eight trials including a total of 1889 patients were analysed. There was heterogeneity in the type of antiarrhythmic used in the treatment arm (amiodarone, sotalol, azimilide, and dofetilide) as well as in the control group (five trials compared with placebo and three trials compared with ß-blocker). The main outcome, risk of shock therapy, was reduced when comparing amiodarone plus ß-blocker with ß-blocker alone (HR 0.27; 95% CI 0.14–0.52) and when comparing sotalol with placebo (HR 0.55; 95% CI 0.4–0.78). The effect was not conclusive when comparing sotalol with other ß-blocker (HR 0.61; 95% CI 0.37–1) and azimilide or dofetilide with placebo (HR 0.78; 95% CI 0.58–1.04 and HR 0.67; 95% CI 0.43–1.04, respectively). Although there were some benefits for secondary outcomes in all antiarrhythmics, the magnitude of the benefit was higher with amiodarone.
Conclusion Amiodarone is the most effective treatment to reduce ICD shock therapies. The benefit of other antiarrhythmics is limited to secondary outcomes.
Key Words: Implantable cardioverter defibrillator (ICD) • Amiodarone • Sotalol • Azimilide • Dofetilide • ß-blocker
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Introduction |
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The implantable cardioverter defibrillator (ICD) has reduced mortality in patients at moderate or high risk for sustained ventricular arrhythmia.1,2 However, the efficacy of ICD depends mainly on its ability to correctly detect the life-threatening arrhythmia, and deliver high-voltage shocks. ICD shocks can be painful, thus reducing the quality of life in patients with ICD,3,4 and shocks, whether appropriate or not, may occur in the first 4 months after the implantation of the ICD up to 10% of patients.5 In addition, ICD shock therapy may lead to premature battery depletion.6
Although modern ICDs incorporate antitachycardia pacing therapy to treat ventricular arrhythmias, the efficacy of the antitachycardia therapy is limited. On the other hand, the possibility of inappropriate shocks when a non-life-threatening tachyarrhythmia, such as supraventricular tachycardia, is incorrectly detected as a ventricular tachycardia increases the rate of ICD shocks. All these drawbacks associated to the use of ICDs raise the question to what extent adjunctive antiarrhythmic drug therapy may be beneficial in this setting to reduce the rate of ICD shocks and therefore improve quality of life.
The aim of the present study is to assess the efficacy and safety of the adjunctive antiarrhythmic drug therapy for preventing ICD therapies.
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Methods |
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Search strategy
We searched the electronic databases of MEDLINE (1980 to March 2006), and EMBASE (1980 to March 2006), limiting to randomized, controlled trials using a maximally sensitive strategy. We modified a search strategy previously developed by Cochrane Heart Group to locate clinical trials assessing the effectiveness of ICD in primary and secondary prevention.7 Keywords included were: defibrillators, cardioverter, and antiarrhythmia-agents. We did not apply any restriction for ‘antiarrhythmia-agents’, thus including all those antiarrhythmics agents most commonly used (e.g. propafenone, amiodarone, sotalol, other ß-blockers, calcium-channel blockers) as well as other relatively new antiarrhythmics (e.g. azimilide, dofetilide). We also searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, issue 1). The search was complemented by review of abstracts from the meetings of the main professional organizations (American Heart Association, American College of Cardiology, and the European Society of Cardiology) of the last 3 years (2003–06). The reference lists of studies identified were also screened for additional references. Finally, we searched for on-going trials searching the following databases:
- Meta Register of Controlled Trials (mRCT) (http://www.controlled-trials.com)
- US NIH register (http://clinicaltrials.gov)
- Register of the Center for Clinical Trials and Evidence-Based Healthcare (http://trialscentral.org).
We made efforts to locate unpublished studies by contacting experts on the focus. No language restrictions were applied.
Inclusion criteria
The eligibility criteria focused on six domains: (i) Design of the study: randomized, controlled clinical trial with parallel design. Post hoc sub-studies from randomized clinical trials primary designed to compare other types of intervention (e.g. ICD vs. antiarrhythmic drug therapy) were not considered for this review. (ii) Population: patients with ICD for primary or secondary prevention of life-threatening ventricular arrhythmias. (iii) Intervention: antiarrhythmic drug therapy. (iv) Control: placebo or ß-blocker therapy or usual care. Those studies comparing the efficacy of a specific class antiarrhythmic drug with another class of antiarrhythmic drug excepting ß-blockers were not considered for this review. (v) Follow-up: a minimum of 12 months. (vi) Outcomes: at least one of the outcomes pre-specified in the study protocol. We considered as primary efficacy outcome the risk of the first occurrence of ICD shock therapy. We considered as secondary efficacy outcomes risk of the first occurrence of appropriate ICD therapy (shock or ATP), total number of shocks in each group (mean ± SE) at 12 months, risk of the first occurrence of inappropriate ICD shock therapy, risk of death or the first occurrence of ICD shock therapy, and risk of death or the first occurrence of ICD therapy. Finally, we also considered as safety outcomes discontinuation of therapy for any reason and new or worsening heart failure.
Data abstraction and quality assessment
Two reviewers (I.F.-G. and L.D.-S.) independently reviewed the title and abstracts retrieved from the electronic search. We retrieved the full text of all those papers initially selected by any of the reviewers.
Quality assessment and data abstraction were also conducted for the same reviewers. Criteria for quality assessment included: random allocation, allocation concealment, blinding, completeness of follow-up, and intention to treat. All studies were categorized in high quality, moderate quality, or low quality based on explicit criteria about the quality of random allocation, allocation concealment, blinding as well as the degree of completeness of follow-up, and the presence of intention to treat analysis.
Disagreements between reviewers were solved by discussion or by a third reviewer when necessary.
Statistical analysis
Statistical analyses were performed separately for those studies comparing antiarrhythmic drugs therapy vs. ß-blocker therapy and those studies comparing antiarrhytmic drug therapy vs. placebo or usual care.
We employed a random-effect model for those analyses pooling studies with different types of antiarrhythmic drugs, and a fixed-effect model for those analyses combining studies with the same type antiarrhythmic drug.
Since all studies assessed the efficacy of the treatment for most of the outcomes considered using a time-to-survival approach, either by the hazard ratio (HR) or comparing the Kaplan–Meier survival curves for the active and control group by the log-rank test, we used the HR statistic for the quantitative aggregation of the results. One exception was the outcome ‘death or ICD shock therapy’. This outcome was generally not assessed by ‘time-to-survival’ analysis but comparing the proportion of cases between the treatment and control group, thus we used the relative risk (RR) statistic for the quantitative aggregation of this outcome.
For the ‘time-to-survival’ primary and secondary efficacy endpoints, the common HR with 95% CI was estimated using the generic inverse of variance method (Revman 4.1; Cochrane Collaboration). Log HR and VAR(LN HR) were used to estimate the common HR and the 95% CI. According to Parmar et al.,8 two different strategies were employed to estimate the Log HR and the VAR(LN HR) from published studies. In those articles reporting the HR with its 95% CI, log HR was directly calculated from the HR and the VAR(LN HR) was estimated from the upper and lower ends of the HR CI. In those articles only reporting the log-rank P-value, log HR was indirectly estimated from the P-value reported and from the total observed number of events in both treatment and control groups. In this case, the term Oi/4, where Oi is the total observed number of events, is an approximation to the Mantel–Haenszel variance of the HR.
Mean difference with 95% CI using the random-effect model or the fixed-effect model where appropriate was estimated for continuous efficacy outcomes.
RR with 95% CI using the random-effect model or the fixed-effect model where appropriate was computed for binary safety outcomes and for the efficacy outcome ‘death or ICD shock therapy’.
Heterogeneity between studies was tested by means of the 
2 and I2 statistics (Revman 4.1).We performed several sensitivity analyses in order to investigate several sources of heterogeneity. Two sources of heterogeneity were anticipated before performing the analysis: heterogeneity related to the intervention, such as the specific type of antiarrhythmic drug, and heterogeneity related to the rate of ß-blocker therapy adjunctive to other types of antiarrhythmics.
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Results |
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The electronic search yielded 892 citations (Pubmed 260, Embase 492, and Cochrane Central 130). After reading the titles and abstracts, 21 references were selected; Kappa agreement 0.78 (95% CI: 0.72–0.84). After reading full text, 13 studies did not meet the inclusion criteria: six were experimental studies, which did not include any of the clinical outcomes of interest; three studies used Class I antiarrhythmics as a control group; two studies were post hoc studies from another randomized clinical trial; one study was an observational study; one study was a randomized clinical trial but using a factorial design and only including nine patients meeting the inclusion criteria.
The review of the databases from the meetings of professional organizations led to find another study9 published only in abstract format. Although contact with the author did not provide additional information to properly assess the general quality of the study, we finally decided to include it in the quantitative aggregation, since the abstract contained enough information concerning the patients, interventions, and outcomes.
We localized, from Pubmed and the Meta Register of Controlled Trials database, three ongoing clinical trials meeting the inclusion criteria. Contact of experts in the field did not reveal additional studies.
Description of the studies
All studies, including a total of 1889 patients, assessed the efficacy and safety of Class III antiarrhythmics. Three studies compared the efficacy of Class III antiarrhythmics with ß-blockers (582 patients): two of them compared sotalol with metoprolol10,11 and one of them compared sotalol and amiodarone with metoprolol, bisoprolol, or carvedilol.6 Five studies compared Class III antiarrhythmics with placebo or usual care (1372 patients), specifically sotalol (n = 2),12,13 azimilide (n = 2),14,15 and dofetilide (n = 1).9
Appendices 1 and 2 summarize the main characteristics concerning the design, patients included, intervention performed, and outcomes considered. In general, the global arrhythmic risk according to the inclusion criteria was similar across studies. However, there was an important heterogeneity in the type of outcomes considered. Three studies did not include the primary outcome ‘risk of recurrence of ICD shock (whether appropriate or not)’ and only considered the appropriate therapies.10,11,13 Three out of five studies that compared antiarrhythmics with placebo reported the rate of the use of ß-blockers. There was an important heterogeneity that ranged between 28% in Pacifico's study to 77% in the SHIELD study.
Most of patients included in the overall studies had history of myocardial infarction (65–80%) and were male (83–95%). The concomitant therapy with other drugs with potential antiarrhythmic effect, such as digoxin, was reported in three studies.12,14,15 Only the OPTIC and SHIELD studies pre-specified a standardized ICD programming. Five studies pre-specified a follow-up time of 12 months,6,9,12,14,15 whereas the remaining three did not pre-specified a follow-up time frame.10,11,13
Methodological quality
Attending to the individual criteria and the available information, reviewers evaluated the global quality of the included studies as high in three of them and low to moderate in the remaining five (Kappa agreement 0.82).
Only three of eight studies reported the method of randomization.6,12,15 In all cases it was adequate, using computer-generated random codes. Two of them12,15 stratified by ejection fraction.
Only two studies reported the method for allocation concealment,6,15 both cases using a call to an automatic computer-based system (interactive voice-response system).
Four studies were reported to be double blinded.9,12,14,15 Five studies reported that the investigators who assessed the appropriateness of the therapy were blinded.6,9,12,14,15 Four studies were open label.6,10,11,13
All but one9 study provided detailed information concerning the loss of follow-up.
Outcomes
A. Class III antiarrhythmic drug therapy vs. ß-blocker therapy
The outcomes of Class III antiarrhythmic drug therapy vs. ß-blocker therapy (Table 1) are as follows.
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Risk of the first occurrence of ICD shock therapy (primary outcome)
Data were available from only one study.6 The overall effect was beneficial for the treatment group (HR 0.42; 95% CI 0.19–0.93; P = 0.03) but the test of heterogeneity was statistically significant (P = 0.05; I2 = 73%), indicating a possible class effect of the type of antiarrhythmic therapy. In fact, the treatment was clearly beneficial for amiodarone therapy (HR 0.27; 95% CI 0.14–0.52; P = < 0.001), whereas it was not conclusive for sotalol therapy (HR 0.61; 95% CI 0.37–1.01; P = 0.05).
Risk of recurrence of appropriate ICD shock therapy
Data were available from three studies. The analysis including the overall studies shows an enormous heterogeneity between studies (P = 0.0003; I2 = 84.8%) (Figure 1), therefore suggesting a marked class effect of the type of Class III antiarrhythmic therapy. Whereas the HR for amiodarone therapy was clearly beneficial for the treatment arm (HR 0.30; 95% CI 0.14–0.66; P = 0.003), the analysis including only sotalol studies shown absence of beneficial effect of sotalol therapy (HR 1.21; 95% CI 0.47–3.09; P = 0.69). However, the analysis combining sotalol studies also shows a high heterogeneity between studies (P = 0.005; I2 = 81.3%), probably due to the effect favouring the control arm in Seidl's study (HR 3.3; 95% CI 1.56–7.25). In fact, there was no heterogeneity in the analysis including only Kettering's study and the OPTIC study (P = 0.53), which shows a non-significant trend to a beneficial effect with sotalol therapy over other ß-blocker therapy without Class III antiarrhythmic effect (HR 0.74; 95% CI 0.47–1.17).
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Risk of recurrence of appropriate ICD therapies (shocks and ATP)
Data were available from two studies.6,11 The global analysis including the two different types of Class III antiarrhythmic therapies (amiodarone and sotalol) shows large heterogeneity between studies (P = 0.006; I2 = 80.4%). There was a clear benefit with amiodarone therapy (HR 0.3; 95% CI 0.17–0.53; P < 0.0001), whereas the effect of sotalol on the risk of recurrence of appropriate ICD shock or ATP therapy was non-conclusive (HR 0.67; 95% CI 0.63–1.21; P = 0.41).
Rate of shocks per year (mean ± SE) at 12 months
Data were available only from one study.6 There was a marked reduction in the rate of shocks per year in both types of Class III antiarrhythmic therapies, with a global mean reduction of 3.6 (95% CI 1.7–5.5) of shocks per patient-year.
Risk of recurrence of inappropriate ICD shock therapies
Only the OPTIC study reported the rate of inappropriate ICD shock therapies. There was a global trend to reduce the global risk of inappropriate ICD shock therapies (HR 0.4; 95% CI 0.15–1.07; P = 0.07) with the benefit mostly concentrated in the amiodarone group (HR 0.22; 95% CI 0.07–0.67) and an absence of conclusive benefit in the sotalol group (HR 0.6; 95% CI 0.3–1.2).
Discontinuation of therapy for any reason
Three studies assessed the outcome.6,10,11 There was a global increased risk for discontinuation of the therapy in those patients treated with Class III antiarrhythmic drugs compared with those patients treated with ß-blocker alone (RR 2.57; 95% CI 1.32–5; P = 0.006) (Figure 2).
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New or worsening heart failure
Data were available from two studies.6,10 There was a global not statistically significant trend to an increased risk of new onset or worsening heart failure with Class III antiarrhythmic drugs (RR 1.44; 95% CI 0.84–2.46; P = 0.18).
B. Class III antiarrhythmic drug therapy vs. placebo or non-antiarrhythmic therapy
The outcomes of Class III antiarrhythmic drug therapy vs. placebo or non-antiarrhythmic therapy (Table 2) are as follows.
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Risk of the first occurrence of ICD shock therapy (primary outcome)
Data were available from three studies.9,12,15 The pooled analysis shows a reduction of the risk of all causes of ICD shock therapy (HR 0.67; 95% CI 0.55–0.82; P = 0.0001). No statistically significant heterogeneity was present (P = 0.49; I2 = 0) (Figure 3).
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Risk of recurrence of appropriate ICD shock therapy
Three studies assessed this outcome.9,12,13 The pooled analysis shows a benefit in favour of Class III antiarrhythmic drugs (HR 0.58; 95% CI 0.43–0.79; P = 0.0004) without significant heterogeneity (P = 0.57; I2 = 0) (Figure 4).
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Risk of recurrence of appropriate ICD therapies (shocks and ATP)
Data were available from four studies.9,13–15 The pooled analysis shows a benefit (HR 0.4; 95% CI 0.32-0.49; P < 0.00001) but with large heterogeneity (P < 0.00001; I2 = 83.4%). The subgroup analysis shows a significant difference in favour of azimilide (HR 0.31; 95% CI 0.29–0.34; P < 0.00001) and sotalol (HR 0.48; 95% CI 0.25–0.9) but there was no benefit associated to dofetilide therapy (HR 1; 95% CI 0.67–1.5) (Figure 5).
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Rate of shocks per year (mean ± SE) at 12 months
Only Pacifico's trial assessed this outcome. It found a reduction in the mean of shocks at 1 year of follow-up of 2.46 (95% CI 0.67–4.25; P = 0.007).
Risk of recurrence of inappropriate ICD shock therapies
This outcome was not statistically assessed in any study. Pacifico's trial reported six patients in the sotalol group and five patients in the placebo group who received an inappropriate first shock. The SHIELD trial reported all inappropriate ICD therapies (shock or ATP). A total of 50 patients in the azimilide 75 mg group, 42 patients in the azimilide 125 mg group, and 57 patients in the placebo group received at least an inappropriate ICD therapy.
Risk of death or the first occurrence of ICD shock therapy
Data were available from two studies12,15 (unpublished results). The analysis combining both studies shows a not statistically significant risk reduction (RR 0.81; 95% CI 0.65–1.01) but also an important heterogeneity between studies (P = 0.05; I2 = 67.7%). The analysis based on the type of antiarrhythmic shows a 39% RR reduction in the sotalol group (RR 0.61; 95% CI 0.46–0.81; P = 0.0007) and an absence of significant benefit with azimilide therapy (RR 0.91; 95% CI 0.79–1.03; P = 0.14) (Figure 6).
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Discontinuation of therapy for any reason
Three studies reported this outcome in detail.12,14,15 The pooled analysis did not show a significant difference between the active and placebo groups in the risk of discontinuation of therapy (RR 0.95; 95% CI 0.83–1.09; P = 0.43).
New or worsening heart failure
Data were available from two studies.12,15 The pooled analysis shows an important heterogeneity between studies (P = 0.05; I2 = 67.6%). Those patients treated with sotalol developed heart failure more frequently than patients in the placebo group (RR 1.5; 95% CI 0.79–2.84) although the difference was not statistically significant. By contrast, in the SHIELD study, there were no significant differences between the treatment and control arms (RR 0.8; 95% CI 0.45–1.4).
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Discussion |
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In the clinical daily practice, adjunctive antiarrhythmic might be administered to between 49 and 69% of patients who have an ICD.16,17 However, the selection of the most appropriate drug may be a challenge since their use is not exempt of risks. Adjunctive antiarrhythmic drug therapy can interfere with ICD function18 and, in addition, the possibility of both proarrhythmic effects and serious side effects may lead to the discontinuation of the treatment in roughly 20% of patients.6 For these reasons, we aimed to review the data existing in the literature in this setting using a systematic approach to assess the benefits and harms associated to antiarrhythmic drugs. Unfortunately, the differences in design detected among studies make the global quantitative assessment of the efficacy of antiarrhythmic drugs challenging.
We only found clinical trials assessing the effect of Class III antiarrhythmics drugs. Of these, three studies compared Class III antiarrhythmics with ß-blocker therapy, whereas the other five used placebo or non-antiarrhythmic therapy as control arm. Since a certain antiarrhythmic effect of the ß-blocker therapy cannot be ruled out, we decided to perform the quantitative analysis separately for these two kinds of comparisons in order to minimize the differences in the rates of patients with ß-blocker therapy across studies. If there was a positive effect of the ß-blocker therapy, those studies with the lowest rate of ß-blocker therapy in the control arm may overestimate the benefit of the Class III antiarrhythmics. This could explain the impressive benefit of the sotalol therapy observed in Pacifico's study (regarding the risk of recurrence of appropriate ICD shock therapy), in which only 28% of the patients in the placebo arm received ß-blockers, and the absence of benefit of this therapy in the other three studies that compared sotalol with ß-blockers, in which almost 100% of the patients in the control arm received ß-blockers.6,10,11
We found a great heterogeneity among studies regarding the endpoints used to test the efficacy of therapy considered. The primary endpoint that we prespecified in our protocol (risk of recurrence of ICD shock therapies, whether appropriate or not) was only used in four studies, thus complicating the assessment of the efficacy of the therapy. We believe that this outcome is the most appropriate to assess the benefit of the therapy, since the quality of life of the patients with ICD depends on the number of discharges delivered by the device, whether appropriate or not. Unfortunately, most of early studies were aimed to assess outcomes related to the efficacy of antiarrhythmics to decrease the rate of ventricular arrhythmias, which is not necessarily linked with the rate of ICD shock therapies. In fact, a specific antiarrhythmic drug may be very effective to prevent ventricular arrhythmias but it may otherwise provoke supraventricular arrhythmias or even interfere with ICD function, thus leading to an increase in the rate of inappropriate ICD shock discharges.
One of the main findings of our overview is that it seems to be an important class effect inherent to the specific type of antiarrhythmic. For the primary outcome (recurrence of ICD shock), data suggest a benefit of amiodarone when compared with ß-blocker (only supported by one study), a benefit of sotalol when compared with placebo (only supported by one study), an absence of benefit of sotalol when compared with other types of ß-blockers, and a non-conclusive benefit of azimilide when compared with placebo. However, the benefit of sotalol when compared with placebo comes from Pacifico's study, whose external validity is rather questionable, since the rate of patients taking ß-blocker in this study was very low (<30%). Finally, all the information available from dofetilide comes from a single small-size study only published in abstract, thus any conclusion about the efficacy of this drug may be misleading.
We found important differences in quality across studies. Although all of them were randomized clinical trials, the quality could be judged as high only in three of them, whereas the other five were of poor quality. Therefore, although we did not analyse the interaction between the quality of the study and the magnitude of the therapy, the estimation of the effect when pooling the results of studies with large differences in quality should be cautiously interpreted, since an unpredictable bias cannot be ruled out.
In summary, amiodarone is effective in reducing the risk of ICD shock therapies, whereas the efficacy of other antiarrhythmics on this outcome is non-conclusive. However, data also suggest a poor tolerability and a non-conclusive increased risk of developing heart failure with amiodarone, thus it cannot be routinely recommended. There is also a definitive benefit with amiodarone to reduce the risk of appropriate shock and antitachycardia pacing therapies, whereas the impact of other Class III antiarrhythmics on these outcomes is less important, specially when ß-blocker therapy is used as a control group.
Further clinical trials are needed to both assess if the benefit of amiodarone to prevent ICD shocks balances the associated side effects, and to establish the magnitude of the benefit of the other Class III antiarrhythmics on the primary outcome. Future randomized clinical trials should consider the same outcomes to assess the efficacy of this therapy. Given the implications for the quality of life, ICD shock therapies (whether appropriate or not) should be used as primary outcome.
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Acknowledgements |
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We are very grateful to Dr. Paul Dorian for sharing some unpublished data. We are very grateful to Dr. Pablo Alonso for his insightful comments in the critical review of the manuscript. I.F.-G. is funded by Carlos III Spanish Institute of Health Research Fellowship Award (FIS).
Conflict of interest: none declared.
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References |
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 J. B. Johansen, S. S. Pedersen, H. Spindler, K. Andersen, J. C. Nielsen, and P. T. Mortensen Symptomatic heart failure is the most important clinical correlate of impaired quality of life, anxiety, and depression in implantable cardioverter-defibrillator patients: a single-centre, cross-sectional study in 610 patients Europace, May 1, 2008; 10(5): 545 - 551. [Abstract] [Full Text] [PDF]
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