Implantable cardioverter-defibrillators (ICDs) are commonly used to prevent sudden cardiac death (SCD), which is often the result of lifethreatening ventricular arrhythmias (VAs), including sustained ventricular tachycardia (VT) and ventricular fibrillation (VF). Over the years, ICDs have proved to be effective in terminating almost all VT or VF episodes.1 In 20% of ICD recipients, atrial fibrillation (AF) is observed.2 AF is the most common arrhythmia, with studies showing its prevalence doubling every decade after 50 years of age, reaching 10% in octogenarians.3-6 AF often co-exists with congestive heart failure, which can compound the difficulty of its treatment. Furthermore, the complex interplay between the two conditions increases the morbidity and mortality associated with each condition.7,8 As a result, a number of ICD patients are likely to be receiving antiarrhythmic drugs (AADs) to treat this underlying arrhythmia. Although beneficial in many ways, the initiation of AADs in these patients may lead to interactions between the pharmacological component and the device that are potentially harmful to the recipient.
Rationale for Adjunctive Antiarrhythmic Drug Therapy in Implantable Cardioverter-Defibrillator Patients
Since ICDs were first introduced, the devices have undergone many technological improvements. ICDs have evolved from being shortlived non-programmable tools for the treatment of VF into sophisticated systems capable of detecting and managing various arrhythmias, including bradycardia, VT and VF. Major improvements have also been made in terms of the diagnosis and management of inappropriate ICD therapy, resulting in decreases in complications and improvements in the quality of life (QoL) of patients. However, despite these developments ICDs continue to generate painful shocks, both appropriately as part of therapy but also inappropriately in the absence of VTs. As many as 20-40% of patients experience inappropriate shocks from their ICDs, which is a cause of anxiety and has a negative impact on QoL.9-11 Several recent studies have addressed the impact of inappropriate shocks. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) II study (n=719) found that one or more inappropriate shocks occurred in 11.5% of participants and this accounted for 31.2% of the total shock episodes.12 In a study by Lin et al.,13 inappropriate shocks were the most common ICD-related complication, occurring in 23% of the 181 enrolled patients, and were most likely to occur in patients with AF. Inappropriate shocks have also been associated with an increased risk of all-cause mortality.12 Therefore, it is critical that the occurrence of these shocks in patients with an ICD is minimised.
Concomitant AAD therapy has been used as a strategy to reduce the number of shocks in ICD patients. AADs not only reduce the frequency of sustained VT and VF appropriately triggering device discharge, but also potentially help to suppress the non-sustained VT arrhythmias that trigger ICD discharges. AADs may also slow the VT rate, therefore enhancing the effectiveness of antitachycardia pacing (ATP) and haemodynamic stability. AADs also decrease the frequency of supraventricular (SV) tachyarrhythmias and/or play a role in controlling the ventricular response during AF and by doing so prevent inappropriate shocks. Finally, AADs are able to blunt exertional sinus tachycardia, which would additionally contribute to the prevention of inappropriate ICD discharge.
An electrical storm constitutes a medical emergency in which three or more VT and/or VF episodes occur within a relatively short time period (24 hours).14-16 In ICD patients, an electrical storm would result in repetitive shocks. Studies indicate that 10-20% of ICD patients experience such episodes (depending on the study duration).14,16,17 Importantly, the occurrence of an electrical storm in ICD patients is a strong independent predictor of adverse outcomes.18 Recently, the investigational novel class III AAD azimilide was found to significantly reduce the risk of recurrent electrical storms in ICD patients, thus providing further insight into the use of AADs in this patient population.19 ICDs effectively detect and terminate adverse arrhythmic events and AADs aim to inhibit the underlying triggers of arrhythmias (thus preventing unnecessary shocks). Therefore, this combination therapy has become widely used in those ICD patients who also present with AF.
Efficacy of Adjunctive Antiarrhythmic Drug Therapy in Patients with Implantable Cardioverter-Defibrillators
Over the past decade, several studies have been performed in order to evaluate the efficacy and safety of different AADs in patients with ICDs.
A multicentre trial stratified 302 ICD patients based on left ventricular ejection fraction (LVEF). The patients were randomised 1:1 to receive either oral sotalol (160-320mg per day) or comparable doses of placebo in a double-blind fashion.20 The end-points included the time to occurrence of a first shock (for any reason) or death from any cause, the first appropriate shock for VA or death from any cause and the first inappropriate shock for an SV arrhythmia or death from any cause. During the 12-month follow-up, seven deaths occurred in the placebo group versus four in the sotalol group. Treatment with sotalol was associated with a lower risk of all three end-points compared with placebo and a reduction in the mean (± standard deviation [SD]) frequency of shocks due to any cause (1.43±3.53 shocks per year with sotalol versus 3.89±10.65 in the placebo group; p=0.008). The Kaplan-Meier time to event curves for the end-point of first shock for any reason or death from any cause differed significantly between the active treatment groups and placebo (p<0.001 by log-rank test) (see Figure 1). Therefore, sotalol was shown to be effective in reducing the risk of death from any cause while decreasing the number of shocks in ICD patients.
The phase III Shock Inhibition Evaluation with Azimilide (SHIELD) study was a randomised, double-blind, placebo-controlled study designed to determine the effects of daily doses of the investigational AAD azimilide (75 or 125mg) on recurrent symptomatic VTs in ICD patients. The incidence of all appropriate ICD therapies (shocks and ATP to terminate VT) was significantly reduced in patients taking either doses of azimilide (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.30-0.89 and HR 0.38, 95% CI 0.22-0.65 for 75 and 125mg azimilide, respectively). Azimilide also significantly reduced total all-cause shocks plus symptomatic ATP-terminated VT in both dosage groups with relative risk reductions of 57% (HR 0.43, 95% CI 0.26-0.69) and 47% (HR 0.53, 95% CI 0.34-0.83) at the 75 and 125mg doses, respectively. Adverse events were limited in number, and included five patients in the azimilide group experiencing torsade de pointes, although these episodes were efficiently treated by the devices of the patients. By reducing the recurrence of VT or VF terminated by shocks or ATP, azimilide diminished the burden of symptomatic VT.21
The Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) Trial 22 was conducted in 412 ICD patients to compare the relative efficacies of amiodarone plus a β-blocker, sotalol monotherapy or β-blocker monotherapy in the prevention of ICD shocks. Patients who had received an ICD within 21 days for inducible or spontaneously occurring VT or VF were randomly assigned to one of the three treatment groups for one year. The primary outcome was ICD shock for any reason. Shocks occurred in all patients, but amiodarone plus β-blocker or sotalol monotherapy were more effective in reducing the number of shocks relative to β-blocker alone (shocks occurred in 38.5% of patients in the β-blocker group, 24.3% in the sotalol group and 10.3% in the amiodarone plus β-blocker group). Similarly, amiodarone plus β-blocker or sotalol treatment were significantly more effective (p<0.001) in reducing the risk of shock (amiodarone plus β-blocker was more effective than sotalol alone) compared with β-blocker alone. These results suggested that amiodarone plus β-blocker was the most effective strategy for preventing ICD shocks compared with sotalol or β-blocker alone. However, it should be noted that amiodarone plus β-blocker was associated with a higher risk of drug-related adverse effects, such as pulmonary and thyroid events and symptomatic bradycardia.22
A substudy to the Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) trial compared defibrillation thresholds (DFTs) in the three treatment arms.23 DFTs were determined at baseline and again after eight to 12 weeks of treatment in 94 patients (29 treated with β-blocker alone, 30 with sotalol alone and 35 with amiodarone plus β-blocker). Overall, the mean DFT decreased in both the β-blocker and sotalol monotherapy groups while increasing in the amiodarone plus β-blocker group. Although amiodarone plus β-blocker increased defibrillation energy requirements, the absolute change was small and was not considered clinically meaningful for modern ICD systems. Therefore, DFTs should no longer be a concern in therapy and there is no need to perform re-testing on the device.
Of further interest is a study that investigated the effect of different AADs given concomitantly on survival in ICD patients.24 The results from the study suggested that β-blockers had a positive effect on survival in ICD patients, while sotalol and amiodarone had neutral effects. Conversely, digoxin use was associated with a negative effect on survival. Taken together, the above studies describe the overall picture of the potential roles that AADs have in ICD patients in relation to their capacity to reduce the number of appropriate and inappropriate shocks, and to possibly improve overall survival. However, further study is needed to gain a greater understanding of drug-device interactions and the overall effects that AADs may have when administered to ICD patients.
The Challenge of Inappropriate Medical Therapy in Patients with Implantable Cardioverter-Defibrillators
AADs are often beneficial in ICDs patients, but adjunctive AAD therapy may also have deleterious effects (see Table 1). For example, 30-40% of patients in the SHock Inhibition Evaluation with Azimilide (SHIELD) study experienced side effects.21 First, AADs can be pro-arrhythmic in nature; therefore, they may actually increase the use of the device. Additionally, AADs may slow the VT rate (below the low cut-off rate for detection) and prolong the QRS duration (QRSd) – a change that can prevent the device from recognising an arrhythmia. Some AADs may increase the DFT and the pacing threshold, which would also result in a loss of efficacy. However, as previously mentioned, these changes in DFT are small and are not considered clinically meaningful with modern ICD systems that deliver bi-phasic shocks.
Sotalol and amiodarone are among the most common AADs in use today in ICD patients. However, the associated side-effect profiles of these two agents significantly limit their use in many ICD patients. For instance, sotalol must be used sparingly in patients already receiving β-blocker therapy as it also has significant β-blocking activity. Moreover, sotalol cannot be used to treat patients who are unable to tolerate β-blockers.25,26 Excessive β-adrenergic blockade may cause hypotension, potentially leading to haemodynamic complications in patients with heart failure.27 This limitation becomes a major problem as most patients with ICDs are already receiving some form of β-blocking treatment. Although amiodarone has proved effective in reducing the risk of all-cause shock,22 it is well-known for its side-effect profile that dramatically limit its use on a long-term basis.27
Hybrid Therapies – Role of Catheter Ablation
In recent years, there has been an expansion in the use of catheter ablation as an option for the treatment of AF. As the technique has evolved, it has become an important alternative for controlling recurrent VTs. However, in the case of inappropriate shocks due to SV arrhythmia, the respective roles of AADs and catheter ablation have yet to be determined.
Ablation is often combined with ICD therapy and/or AADs for scarrelated VTs associated with structural heart disease.28 Studies have shown a potential positive effect of ablation on the clinical status of ICD patients.29,30 A recent randomised trial evaluated the effects of prophylactic substrate-based catheter ablation in patients with a history of myocardial infarction who received ICDs for the secondary prevention of sudden death. The trial demonstrated that ablation was associated with a reduced number of painful shocks delivered to ICD patients. While ablation did not provide any survival benefit over ICD alone, the reduction in shocks was associated with improvements in anxiety levels and overall QOL.31 Catheter ablation has also been shown to be effective in the short-term treatment of electrical storms and may improve cardiac mortality when performed in conjunction with long-term drug therapy.32
In light of the difficulties that can be encountered with AAD treatment as an adjunct to ICD, several important matters arise in terms of the use of this combination therapy, and the respective roles of AADs and catheter ablation in ICD patients were discussed at the third Cardiac Rhythm/Electrophysiology And Targeted Education (CREATE) Annual Advisory Meeting in 2008. The following discussion reflects the debates and consensus on these important topics.
Inappropriate Shocks Due to Supraventricular Arrhythmias – What Is the Role of Catheter Ablation and Adjunctive Antiarrhythmic Drugs?
AADs have the potential to cause proarrhythmic effects, and classic induced class IC (or amiodarone) flutters may create both diagnostic and therapeutic problems, often leading to inappropriate therapies in ICD patients. Therefore, physicians must ensure they are correctly identifying this side effect and treat appropriately, either by stopping the drug or by performing a cavotricuspid isthmus catheter ablation.
On the other hand, managing inappropriate ICD therapy due to AF is slightly more complicated. At this point, if the ICD has not been properly programmed to avoid inappropriate shocks, it should first be re-programmed. The physician must also ensure that the underlying disease is treated fully and appropriately. Pharmacological treatment of these patients with rate-control drugs and/or AADs should be individualised. In some patients, atrioventricular (AV) node ablation may provide greater control of the ventricular rate and may have a beneficial effect, especially in cardiac resynchronisation therapy, to achieve 100% left ventricular pacing in patients with long-lasting AF refractory to conventional medical treatment that is unresponsive to external cardioversion. There are data suggesting that in patients with congestive heart failure (CHF) and New York Heart Association (NYHA) functional class III-IV with co-existing AF, catheter ablation for atrial fibrillation may restore sinus rhythm without the use of drugs. Furthermore, AF catheter ablation is associated with improvements in both LVEF and the clinical status of these patients.29,33 It has been suggested that to achieve the best haemodynamic outcome treatment guidelines should direct physicians to attempt estoration of sinus rhythm before considering ICD insertion. However, data tosupport this approach are limited in the CHF population. AF ablation should be considered when arrhythmia is symptomatic or produces inappropriate ICD therapies despite optimal medical therapy. When inappropriate ICD therapy occurs due to AV nodal re-entry tachycardia, atrial tachycardia or atrial flutter, the patient should undergo ablation to prevent these shocks.
When sinus tachycardia is the cause of inappropriate ICD therapies, ablation should not be performed. Instead, drugs that can slow the sinus rate should be chosen, such as β-blockers and calcium antagonists. Ivabradine is not yet approved for this indication but may be a future consideration.
Should Adjunctive Antiarrhythmic Drug Treatment Be Stopped After Device Implantation?
For patients who are already being treated with AADs to prevent SV arrhythmias before device implantation there is no rationale for discontinuation of pharmacotherapy. Accordingly, it is recommended that AAD treatment should continue after implantation. If the index arrhythmia is a VT/VF storm, AAD therapy should definitely be continued, as withdrawal may increase the risk of storm recurrence resulting in a poor psychological impact on the patient and an increased risk of death. If pharmacotherapy needs to be discontinued for any reason, it should be carried out very carefully and as slowly as possible.
In all other ICD patients, there is no need for systematic AAD treatment. Often these patients are already being treated by pharmacotherapy, which should be stopped on device implantation if the arrhythmia does not require immediate control. Any treatment, including AADs, should be avoided as much as possible and only the clinical history during follow-up will eventually guide addition of AAD therapy.
Should the Devices Be Tested (Antitachycardia Pacing Parameters, Shock Threshold) in the Context of Drug Treatment?
This matter continues to be greatly debated among experts. There have been some anecdotal data suggesting that when there is a drug dose change all cardiac/shock parameters should be tested. However, this weak evidence was collected with older, uniphasic devices. Currently, newer ICDs deliver bi-phasic shock and there are little to no data available based on these systems. However, as previously mentioned, the changes observed with AADs on the DFT are small and do not appear to be clinically meaningful with modern bi-phasic ICD systems.
The vast majority of physicians believe it is important to perform efficacy testing with at least one shock during implantation, although currently there is no established consensus. If a problem is detected during testing, a further test of the ICD should be performed when a new drug is introduced in follow-up to ensure that an acceptable safety margin is still present. Similarly, with certain specific inherited cardiac syndromes, such as Brugada syndrome, testing should be performed to confirm the safety margin when a change is made to the treatment regimen during follow-up, as the patient may have an extremely high DFT.
Is There a Place for the Development of New Drugs to Reduce Multiple Appropriate Therapies?
The number of ICD implantations is expected to increase, which will lead to an expected concomitant increase in the number of ICD patients using AADs to minimise discharges. Shocks, whether appropriate or inappropriate, are associated with a lower QOL and subsequent increased mortality providing a strong rationale for preventative management.12 Therefore, there remains a definite need for safer and more effective drugs for the chronic management of these patients, who are usually in poor cardiac condition.
For acute management of a VT storm the situation is slightly different. This is a challenging situation for which all treatment options need careful consideration, including the combination of existing AADs. Ablation is used more frequently in this context, in an attempt to avoid multiple tachycardia recurrences. Currently, patient numbers are insufficient to justify the development of a new drug for use solely in an acute setting; however, this is an open indication for an existing drug.
Summary and Conclusion
Patients with ICDs often receive adjunctive therapy with AADs to treat their underlying arrhythmia, but also to limit the number of appropriate and inappropriate shocks that can potentially increase the risk of mortality. Combination therapy has been shown to be effective in reducing both the number of shocks and all-cause mortality. However, combination therapy as a treatment strategy may also result in negative cardiac and non-cardiac secondary effects for the patient, including potential impairment of the tachycardic recognition capabilities of the ICD. In order to provide patients with optimal therapy, careful consideration of drug-device interactions must take place.