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Abstract

  1. Top of page
  2. Abstract
  3. Sotalol in Heart Failure Patients
  4. Conclusions
  5. Acknowledgments
  6. References

The number of heart failure patients with implantable cardioverter-defibrillators is rising. Common issues encountered in this population are high defibrillation thresholds and inappropriate shocks. In order to resolve these problems, the addition of a class III antiarrhythmic such as sotalol is often considered. Given the emerging issue of polypharmacy and medication compliance in the heart failure population, the question of the efficacy of sotalol in reducing inappropriate shocks, defibrillation thresholds, and its ability to replace conventional β-blockers is often raised. Current literature review suggests that sotalol is a useful adjunct to the contemporary heart failure regimen. It has the ability to reduce inappropriate shocks and defibrillation thresholds, but appears not to fully reproduce the pleiotropic beneficial effects of the β-blockers more commonly employed for their mortality/remodeling benefits in heart failure patients.

In recent years, evidence-based therapy of heart failure has seen dramatic advances. Due to landmark trials such as the Comparison of Medical, Pacing, and Defibrillation Therapies in Heart Failure (COMPANION) trial, the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), and the Multicenter Automated Defibrillator Implantation Trial (MADIT), the standard of care has been expanded to include not only pharmacologic therapy, but also device therapy via implantable cardioverter-defibrillators (ICDs) with and without biventricular pacemakers. The US Food and Drug Administration reports that between 1990 and 2002, 415,780 ICDs were implanted in the United States.1 Among the challenges one faces in treating heart failure patients with ICDs are high defibrillation thresholds (DFTs) and inappropriate shocks. In this select population, the addition of an agent such as sotalol is often considered as a method of managing these issues.

Sotalol is somewhat unique in that it displays non selective β-adrenergic receptor antagonism and also has electrophysiologic properties of cardiac action potential prolongation via inhibition of the delayed potassium rectifier current (Ik). The racemic (d,l-sotalol) oral formulation is currently available in the United States. The l-isomer accounts for virtually all of the β-blocker effects, while the d- and l-isomers both contribute to its antiarrhythmic properties. Sotalol hydrochloride is a hydrophilic compound that has 90% to 100% bioavailability. It undergoes no significant first-pass metabolism and 80% to 90% is eliminated unchanged by the kidneys.2

Sotalol in Heart Failure Patients

  1. Top of page
  2. Abstract
  3. Sotalol in Heart Failure Patients
  4. Conclusions
  5. Acknowledgments
  6. References

The fact that sotalol does have β-blocking activity raises an interesting question. There is a select population of congestive heart failure patients who have an ICD, are on a β-blocker with proven mortality benefits such as metoprolol succinate,3 bisoprolol,4 or carvedilol,5 and have an indication for sotalol. Is sotalol an acceptable replacement for standard β-blocker in these patients? Alternatively, what is the impact of adding sotalol to a contemporary heart failure regimen?

Ischemic Cardiomyopathy.  One of the initial studies investigating the clinical benefits of sotalol in the heart failure population was the Effect of d-Sotalol on Mortality in Patients With Left Ventricular Dysfunction After Recent and Remote Myocardial Infarction (SWORD) trial. In this study, d-sotalol, the isomer of sotalol with pure potassium-channel blocking activity and no β-blocker activity was tested against placebo. The study population consisted of patients with ejection fractions (EFs) of 40% or less, and symptomatic heart failure after remote myocardial infarction (>42 days) or a recent myocardial infarction (6–42 days). The trial was terminated early due to excess mortality in the d-sotalol group (5.0% vs 3.1%, relative risk 1.65 [95% confidence interval {CI}, 1.15–2.36]; P=.006).6

The mechanism of increased mortality in the SWORD trial is unclear. There was no definitive evidence for a proarrhythmic effect.7

Inappropriate Shocks.  One problem not uncommonly encountered in the treatment of patients with heart failure and ICDs is inappropriate shocks. In fact, the majority of patients with single chamber ICDs will have discharges at follow-up, and up to 30% of those will be inappropriate shocks due to supraventricular tachyarrhythmias.8

There are 2 studies commonly quoted as evidence of the ability of sotalol to reduce inappropriate shocks. Pacifico and colleagues9 published a trial of 151 patients in 1999 with ICDs. The goal of the study was to show that sotalol could prevent inappropriate shocks in ICD patients. In this randomized, placebo controlled study, patients were followed for 12 months. Sotalol reduced the risk of the primary endpoint of death or first shock for any reason by 48% (P<.001). More specifically, it reduced the risk of appropriate shocks by 44% (P=.007) and the risk of inappropriate shocks by 64% (P=.004).9

This study is one of the few involving sotalol that included information on concomitant use of β-blockers, and provides information on EF while also examining the effect of sotalol on ICD discharges. This study stratified the patients according to left ventricular EF (LVEF) (≤30% or >30%) and began with an initial dose of sotalol 120 mg twice daily. Investigators were allowed to adjust to a minimum dose of 80 mg and a maximum of 160 mg twice daily. Thirty-four percent of both the sotalol and placebo groups had LVEF ≤30%. Baseline characteristics for New York Heart Association (NYHA) Heart Failure class were also given, with 40% and 36% of placebo and sotalol groups falling into NYHA class II, respectively; and 4% and 7% recorded in NYHA class III. After the initiation of the study, 28% and 27% of the placebo and sotalol groups were using concomitant β-blocker therapy, respectively. At the conclusion of the study, β-blockers were being used in 37% of placebo patients and 23% of sotalol patients, for the only significant difference in concomitant medication therapy (P=.01), including calcium channel blockers, digoxin, diuretics, and angiotensin-converting enzyme inhibitors. Reasons for the significant decline in β-blocker therapy within the sotalol group were not noted. However, the author does comment that the use of β-blockers had no significant effect on the primary endpoint of risk of death or delivery of first shock for any reason. With regard to EF, there was also no significant difference in the relative risk of reaching the primary endpoint between the two groups (EF ≤30% or >30%; P=.45).9

Kuhlkamp and colleagues10 published a similar study looking at the ability of sotalol to prevent recurrence of ventricular tachycardia (VT), ventricular fibrillation (VF) and sudden cardiac death. Ninety-three patients with inducible VT/VF who had undergone electrophysiologic testing on sotalol and remained inducible were implanted with ICDs and then randomized to oral sotalol or no antiarrhythmic therapy. The EF was 35% to 38%±18% to 19% in this group. At follow-up, 30% of the ICD/sotalol group, as opposed to 51% of the ICD-only group, had recurrence of VT or VF. A total of 36.2% (32.6%) of the ICD/sotalol group and 53.2% of the ICD-only group reached the primary end point of VT, VF, or sudden death (P=.023). The baseline characteristics included no significant difference between groups with respect to NYHA functional class I to III or LVEF.

Both studies effectively demonstrated that d,l-sotalol can significantly decrease ICD discharges and the occurrence of VT/VF in ICD patients, and demonstrated how this agent may be beneficial in addition to a standard heart failure regimen.

Adding support to this data is the recently published Optimal Pharmacological Therapy in Implantable Cardioverter Defibrillator Patients trial (OPTIC).11 This trial looked at the use of sotalol vs β-blocker vs amiodarone plus β-blocker for the prevention of ICD shocks. The hypothesis was that treatment with either sotalol alone or amiodarone plus β-blocker would prove superior to therapy with β-blocker alone. This was a multicenter randomized controlled trial that enrolled 412 patients who had received an ICD within 21 days for spontaneous VT or VF. β-Blockers tested included metoprolol, bisoprolol, and carvedilol. Patients with NYHA class IV symptoms were excluded. The treatment groups were well-matched with respect to NYHA class II or greater symptoms, and had a mean EF of 34%.

At 1 year of follow-up, both the sotalol and amiodarone plus β-blocker treatment groups showed a significant reduction in risk of shock when compared to β-blocker alone (hazard ratio [HR], 0.44; 95% CI, 0.28–0.68; P<.001). When the active treatment groups were examined independently in comparison to β-blocker alone, the amiodarone plus β-blocker group fared best in terms of risk of ICD shock in comparison to β-blocker alone (HR, 0.27; 95% CI, 0.14–0.52; P<.001). The sotalol group showed a reduction in risk of ICD shock that was not significant (HR, 0.61; 95% CI, 0.37–1.01; log-rank P=.055) in comparison to β-blocker.11 This lends support to the theory that sotalol may have some qualities in common with the β-blockers considered central to contemporary heart failure therapy.

In fact, Ferreira-Gonzalez and colleagues12 recently published a systematic review of the literature on adjunctive antiarrhythmic drug therapy in patients with ICDs. The primary inclusion criteria were: randomized controlled trials of parallel design, patients with ICDs for primary or secondary prevention of ventricular arrhythmias, and antiarrhythmic therapy vs placebo or β-blocker or usual care. Five of the studies reviewed compared sotalol with placebo or β-blocker. The authors postulated that β-blockers themselves may have some antiarrhythmic effects, and that in some of the studies, the variable percentages of patients on β-blockers may have confounded the results. Of note, in the Pacifico study, only 28% of the group randomized to placebo received β-blockers, which may have influenced the results in favor of sotalol.9

This question of whether the β-blockers exhibit a class effect regarding cardioprotection has been addressed in the past by Hjalmarson.13 Reduction of blood pressure, supraventricular arrhythmias, and a decrease in the severity of angina pectoris are all widely regarded as class effects. In terms of post-infarction mortality and sudden cardiac death, there is evidence that sotalol in particular may be inferior to other β-blockers. It is proposed that the differential effects of sotalol in comparison to other β-blockers may be attributed to its hydrophilicity or greater class III antiarrhythmic effects.13

Another proposed strategy for reduction of inappropriate shocks from ICDs is the utilization of dual-chamber systems, as opposed to single-chamber ICDs, to take advantage of the atrial lead to improve rhythm discrimination. The efficacy of this method is somewhat controversial, with literature both supporting and disputing dual-chamber systems’ superiority to single-chamber systems regarding significant reduction of inappropriate shocks.14,15 Studies are ongoing. Of the studies discussed above in our review, OPTIC involved patients with dual-chamber ICDs only.11 The details regarding the types of ICDs used in the Pacifico study were not available.9 In the Kuhlkamp study, which was performed between 1988 and 1995, it was noted that several different device types were implanted due to the rapidly evolving technology at that time, including a minority of epicardial lead systems.10 The effect of sotalol on inappropriate shocks in dual- vs single-chamber systems is unclear due to the sparse data available, and remains an issue to be investigated in future trials.

When considering the effects of the combination of sotalol plus β-blocker in patients with ICDs, the potential for symptomatic bradycardia or hypotension should be taken into account. Iatrogenic bradycardia, in patients not pacer dependent, may result in the intrinsic sinus rate being reduced to below the base pacing rate of the ICD, which could induce right ventricular pacing unless programming allowances are made. This potentially could result in right ventricular pacing for long periods of time, which induces ventricular dyssynchrony. This is why ICD manufacturers have developed devices to reduce right ventricular pacing in patients with at least some AV nodal conduction. The deleterious effects of excessive right ventricular pacing vs right ventricular backup pacing only in patients with dual-chamber devices and ICD indications were made apparent in trials such as The Dual Chamber and VVI Implantable Defibrillator (DAVID) trial.16 Of the studies reviewed here, in the Pacifico study, bradycardia led to discontinuation of therapy in 2 patients (2 of 151) in the sotalol group. This makes symptomatic bradycardia or hypotension unlikely to be the cause of the decline in β-blocker therapy in the sotalol group.9 In the OPTIC study, there was a significantly higher incidence of symptomatic bradycardia among those patients randomized to amiodarone and β-blocker (8 of 140, 6.4%, P=.009) relative to sotalol or β-blocker. The sotalol group experienced symptomatic bradycardia at only 1.5% (2 of 134).11 In the Kuhlkamp study, symptomatic bradycardia or hypotension was a primary endpoint. Sotalol was withdrawn or the dose reduced in a total of 8 of 53 (15%) patients in the sotalol group for hemodynamic intolerance. In the ICD/sotalol group, hemodynamic intolerance resulted in withdrawal or dose reductions in a total of 4 of 46 (8.7%) patients.10

Though this is a relatively small sample size, it appears that only a small proportion of patients on sotalol experience hemodynamic intolerance to a degree that requires discontinuation of the drug, and it is possible that dose adjustment of the sotalol or β-blocker may provide some resolution.

Effect on the DFT.  The DFT may be influenced by many factors, including pharmacologic therapy with commonly used agents such as amiodarone17 and carvedilol,18 which are known to increase the threshold. Sotalol, by contrast, has the useful property of lowering the DFT. In a small study of 48 patients receiving ICDs, 25 received sotalol at 160–320 mg/d orally (mean dose 171±58 mg). Twenty-three of these patients were included in a non-randomized control group with no significant differences in clinical characteristics. Of those, 18 received amiodarone, 2 received β-blockers, and 3 were not given any drugs. The mean EF was 37%±15%. VF was induced and defibrillation was attempted with monophasic shocks at 15, 10, 7, 4, 3, and 2 J (joules) to establish the lowest successful defibrillation energy. There were 21 patients in the sotalol group in which LSE could be calculated. This group showed a decrease in the required energy for defibrillation of 5.9±3.4 J. In the control group of 23 patients, the lowest energy requirement for defibrillation was 16±10 J (P<.01).19

When compared to other antiarrhythmics, class III agents including d,l-sotalol, amiodarone, and dofetilide have been shown to have better safety profiles in patients with left ventricular dysfunction than class I agents.20 The 2006 Heart Failure Society of America guidelines take the position that in heart failure patients, class III agents may decrease the frequency of ventricular arrhythmias but may also carry an increased risk of adverse events without significant benefit.21 The evidence presented above suggests that sotalol has the benefit of decreasing DFTs, inappropriate shocks, and VT/VF, but does not exhibit a mortality benefit in this population.

Conclusions

  1. Top of page
  2. Abstract
  3. Sotalol in Heart Failure Patients
  4. Conclusions
  5. Acknowledgments
  6. References

There is a lack of clinical trials that address the question of the role and possible beneficial/deleterious effects of sotalol in the heart failure population with ICDs. In this group of patients, the current data suggest that it would be more appropriate to add sotalol to any heart failure regimen already containing a β-blocker as opposed to replacing one of these more established agents. A definitive answer to the question would require, at the very least, a noninferiority randomized controlled trial in heart failure patients with ICDs with the primary endpoints of mortality and improvement in NYHA class or EF, testing metoprolol succinate, bisoprolol, or carvedilol vs sotalol in combination with one of these drugs. Such trials have the potential to not only expand the therapeutic indications for sotalol, but also to complement and improve the growing repertoire of contemporary heart failure therapy.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Sotalol in Heart Failure Patients
  4. Conclusions
  5. Acknowledgments
  6. References

Acknowledgments:  We would like to acknowledge David Nabert, MD, for reviewing the manuscript.

References

  1. Top of page
  2. Abstract
  3. Sotalol in Heart Failure Patients
  4. Conclusions
  5. Acknowledgments
  6. References
  • 1
    Mauro AMP. Pacemaker and ICD generator malfunctions: rates, trends and implications—questions and answers. Available at Updated; http://www.fda.gov/cdrh/ocd/icd/qa.html. Accessed on September 9, 2005.
  • 2
    Teva Pharmaceuticals. Sotalol [package insert]. Sellersville, PA: Teva Pharmaceuticals; 2004.
  • 3
    Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA. 2000;283:12951302.
  • 4
    CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999; 353(9146): 914.
  • 5
    Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure. Circulation. 2002;106:21942199.
  • 6
    Waldo A, Camm A, DeRuyter H, et al. Effect of d-sotalol on mortality in patient with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet. 1996;348:712.
  • 7
    Pratt CM, Camm AJ, Cooper W, et al. Mortality in the Survival With Oral D-Sotalol (Sword) trial: why did patients die? Am J Cardiol. 1998;81(7):869876.
  • 8
    Nanthakumar K, Dorian P, Paquett M, et al. Is inappropriate implantable defibrillator shock therapy predictable? J Interv Card Electrophysiol. 2003;8:215220.
  • 9
    Pacifico A, Hohnloser S, Williams J, et al. Prevention of implantable defibrillator shocks by treatment with sotalol. N Engl J Med. 1999;340:18551862.
  • 10
    Kuhlkamp V, Mewis C, Mermi J, et al. Suppression of sustained ventricular tachyarrhythmias: a comparison of d,l-sotalol with no antiarrhythmic drug treatment. J Am Coll Cardiol. 1999;33:4652.
  • 11
    Connolly S, Dorian P, Roberts R, et al. Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) Investigators. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA. 2006;295:165171.
  • 12
    Ferreira-Gonzalez I, Dos-Subira L, Guyatt G. Adjunctive antiarrhythmic drug therapy in patients with implantable cardioverter defibrillators: a systematic review. Eur Heart J. 2007;28:469477.
  • 13
    Hjalmarson A. Cardioprotection with beta-adrenoceptor blockers. Does lipophilicity matter? Basic Res Cardiol. 2000;95(Suppl 1):I41I45.
  • 14
    Gehi AK, Mehta D, Gomes JA. Evaluation and management of patients after implantable cardioverter-defibrillator shock. JAMA. 2006;296(23):28392847.
  • 15
    Anselme F, Mletzko R, Bowes R, et al. Prevention of inappropriate shocks in ICD recipients: a review of 10,000 tachycardia episodes. Pacing Clin Electrophysiol. 2007;30(suppl 1):S128S133.
  • 16
    Wilkoff BL, Dual Chamber and VVI Implantable Defibrillator trial investigators. The Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial: rationale, design, results, clinical implications, and lessons for future trials. Card Electrrophysiol Rev. 2003;7:468472.
  • 17
    Nielsen TD, Hamdan MH, Kowal RC, et al. Effect of acute amiodarone loading on energy requirements for biphasic ventricular defibrillation. Am J Cardiol. 2001;88:446448.
  • 18
    Melichercik J, Goepfrich M, Briedenbach T, et al. Rise of defibrillation energy requirement under carvedilol therapy. Pacing Clin Electrophysiol. 2001;24(9 pt 1):14171419.
  • 19
    Dorian P, Newman D. Effect of sotalol on ventricular fibrillation and defibrillation in humans. Am J Cardiol. 1993;72:72A79A.
  • 20
    Sager P. New advances in class III antiarrhythmic drug therapy. Curr Opin Cardiol. 2000;15:4153.
  • 21
    Adams KF, Lindenfeld J, Arnold JM, et al. HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2006;12:e1e119.