Catheter Ablation for VT in Patients With an ICD (CALYPSO)
There are mounting data on the potential negative association between ICD shocks and survival and quality of life. As such, in clinical practice one should try to reduce the risk of ICD shocks in all patients. Although optimal programming may help accomplish that goal, it is not enough in many patients. Therefore, additional therapies are needed that include antiarrhythmic medications and catheter ablation. However, many antiarrhythmic medications have been associated with increased mortality in patients with structural heart disease, many are ineffective at controlling VT, and serious side effects that mandate stopping these medications are common. Catheter ablation is an attractive potential alternative to antiarrhythmic therapy. Although the EHRA/HRS Expert Consensus Statement on Catheter Ablation of Ventricular Arrhythmias recommends that catheter ablation for VT be considered early in the treatment of patients with recurrent VT, data supporting the use of catheter ablation have been derived from relatively small studies that mostly reflect the experience of large academic centers and included many patients who had failed prior antiarrhythmic medications. Importantly, none of the prior trials were powered to examine hard endpoints like survival. These considerations provided the rationale for the CALYPSO pilot study, which was designed to assess the feasibility of a large multicenter clinical trial powered to examine catheter ablation as an early therapy with mortality as a primary endpoint. Unlike prior trials that compared a combination of catheter ablation and an ICD with ICD only, the CALYPSO pilot trial compared catheter ablation with antiarrhythmic medications in ICD patients.
In this study, we found that there are substantial obstacles to enrolling patients in a multicenter randomized clinical trial comparing a strategy of early catheter ablation with a strategy of antiarrhythmic medications. Prior antiarrhythmic medication use was the major reason for ineligibility. This observation reflects the common clinical practice of starting a patient on an antiarrhythmic drug before considering ablation, resulting in a population of patients eligible for ablation with relatively advanced disease whose arrhythmia has already failed antiarrhythmic drugs. It is therefore important to capture patients upstream, i.e., when they first present with appropriate ICD shocks. This could be accomplished by engaging primary electrophysiologists and heart failure specialists practicing in the community who are more likely to provide care for these patients early on and, as such, could refer these patients for enrollment in the trial. Another potential approach is use of central remote monitoring databases to identify potentially eligible patients. To be feasible, several ethical and logistical mandates will have to be addressed. Although an alternative design could be considered in which patients already on an antiarrhythmic medication could still be enrolled if the medication could be switched to amiodarone or if the dose of the medication could be increased, if patients are randomized to the pharmacologic therapy arm, this patient population is being studied by the ongoing Ventricular Tachycardia Ablation Versus Enhanced Drug Therapy (VANISH) trial.
One important observation in our study is that only 18 (8%) patients of the 216 who failed screening did so because of refusal to participate in the trial. This is a notable finding given that patients could have been randomized to a "pill" versus an invasive procedure with known complications, and prior trials comparing a medication with an invasive procedure observed a high rate of patient refusal. Another relevant observation is the low crossover rate from the antiarrhythmic arm to the ablation arm, with only 1 patient out of 14 randomized to antiarrhythmic medication crossing over to catheter ablation 2 months after randomization. However, the short follow-up in this trial may, in part, explain this low crossover rate. However, cross over from the ablation arm to the antiarrhythmic medication arm was higher. Despite introducing catheter ablation early in the course of the disease, 5 out of 11 patients who underwent ablation required an antiarrhythmic drug during follow-up. This was one of the important lessons of our pilot study that will need to be taken into account in designing a larger pivotal trial.
In our study, none of the endpoints were significantly different between the 2 arms. This is in stark contrast with prior trials that compared catheter ablation with antiarrhythmic medications and showed a lower rate of recurrent VT in the catheter ablation arm. Although unlike the prior trials, our study examined ablation as an early therapy, the lack of concordance between the findings of the prior trials and our findings is more likely due to the small sample size and the lack of statistical power to show a difference than to differences in patient populations or study design. However, it is notable that the event rate in our study was relatively high, with 4 out of 27 (15%) patients dying within 6 months of follow-up and 14 out of 27 (52%) patients developing recurrent VT within 6 months of follow-up. This is likely a reflection of the level of morbidity in these patients.
In summary, the CALYPSO pilot randomized clinical trial shows that there are a large number of patients with VT requiring ICD therapy for whom defining the best treatment approach is important. For a large multicenter clinical trial powered to examine hard endpoints to be feasible, the entry criteria especially in relation to prior antiarrhythmic use should be relatively inclusive. More importantly, patients with VT and their physicians should be engaged early on, prior to the progression of the underlying disease and worsening of the VT that could limit therapeutic options and consideration for participation in a randomized trial. Remote monitoring might play a role in identifying potentially eligible patients, and use of central remote monitoring databases should be considered.
Discussion
There are mounting data on the potential negative association between ICD shocks and survival and quality of life. As such, in clinical practice one should try to reduce the risk of ICD shocks in all patients. Although optimal programming may help accomplish that goal, it is not enough in many patients. Therefore, additional therapies are needed that include antiarrhythmic medications and catheter ablation. However, many antiarrhythmic medications have been associated with increased mortality in patients with structural heart disease, many are ineffective at controlling VT, and serious side effects that mandate stopping these medications are common. Catheter ablation is an attractive potential alternative to antiarrhythmic therapy. Although the EHRA/HRS Expert Consensus Statement on Catheter Ablation of Ventricular Arrhythmias recommends that catheter ablation for VT be considered early in the treatment of patients with recurrent VT, data supporting the use of catheter ablation have been derived from relatively small studies that mostly reflect the experience of large academic centers and included many patients who had failed prior antiarrhythmic medications. Importantly, none of the prior trials were powered to examine hard endpoints like survival. These considerations provided the rationale for the CALYPSO pilot study, which was designed to assess the feasibility of a large multicenter clinical trial powered to examine catheter ablation as an early therapy with mortality as a primary endpoint. Unlike prior trials that compared a combination of catheter ablation and an ICD with ICD only, the CALYPSO pilot trial compared catheter ablation with antiarrhythmic medications in ICD patients.
In this study, we found that there are substantial obstacles to enrolling patients in a multicenter randomized clinical trial comparing a strategy of early catheter ablation with a strategy of antiarrhythmic medications. Prior antiarrhythmic medication use was the major reason for ineligibility. This observation reflects the common clinical practice of starting a patient on an antiarrhythmic drug before considering ablation, resulting in a population of patients eligible for ablation with relatively advanced disease whose arrhythmia has already failed antiarrhythmic drugs. It is therefore important to capture patients upstream, i.e., when they first present with appropriate ICD shocks. This could be accomplished by engaging primary electrophysiologists and heart failure specialists practicing in the community who are more likely to provide care for these patients early on and, as such, could refer these patients for enrollment in the trial. Another potential approach is use of central remote monitoring databases to identify potentially eligible patients. To be feasible, several ethical and logistical mandates will have to be addressed. Although an alternative design could be considered in which patients already on an antiarrhythmic medication could still be enrolled if the medication could be switched to amiodarone or if the dose of the medication could be increased, if patients are randomized to the pharmacologic therapy arm, this patient population is being studied by the ongoing Ventricular Tachycardia Ablation Versus Enhanced Drug Therapy (VANISH) trial.
One important observation in our study is that only 18 (8%) patients of the 216 who failed screening did so because of refusal to participate in the trial. This is a notable finding given that patients could have been randomized to a "pill" versus an invasive procedure with known complications, and prior trials comparing a medication with an invasive procedure observed a high rate of patient refusal. Another relevant observation is the low crossover rate from the antiarrhythmic arm to the ablation arm, with only 1 patient out of 14 randomized to antiarrhythmic medication crossing over to catheter ablation 2 months after randomization. However, the short follow-up in this trial may, in part, explain this low crossover rate. However, cross over from the ablation arm to the antiarrhythmic medication arm was higher. Despite introducing catheter ablation early in the course of the disease, 5 out of 11 patients who underwent ablation required an antiarrhythmic drug during follow-up. This was one of the important lessons of our pilot study that will need to be taken into account in designing a larger pivotal trial.
In our study, none of the endpoints were significantly different between the 2 arms. This is in stark contrast with prior trials that compared catheter ablation with antiarrhythmic medications and showed a lower rate of recurrent VT in the catheter ablation arm. Although unlike the prior trials, our study examined ablation as an early therapy, the lack of concordance between the findings of the prior trials and our findings is more likely due to the small sample size and the lack of statistical power to show a difference than to differences in patient populations or study design. However, it is notable that the event rate in our study was relatively high, with 4 out of 27 (15%) patients dying within 6 months of follow-up and 14 out of 27 (52%) patients developing recurrent VT within 6 months of follow-up. This is likely a reflection of the level of morbidity in these patients.
In summary, the CALYPSO pilot randomized clinical trial shows that there are a large number of patients with VT requiring ICD therapy for whom defining the best treatment approach is important. For a large multicenter clinical trial powered to examine hard endpoints to be feasible, the entry criteria especially in relation to prior antiarrhythmic use should be relatively inclusive. More importantly, patients with VT and their physicians should be engaged early on, prior to the progression of the underlying disease and worsening of the VT that could limit therapeutic options and consideration for participation in a randomized trial. Remote monitoring might play a role in identifying potentially eligible patients, and use of central remote monitoring databases should be considered.
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