7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Pharmacologic therapy in survivors of sudden cardiac arrest : Philip J Podrid, MD, FACC : Scott Manaker, MD, PhD, Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 24, 2021. INTRODUCTION Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden cessation of cardiac activity with hemodynamic collapse, typically due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). The event is referred to as SCA (or aborted SCD) if an intervention (eg, defibrillation, cardioversion, or drug therapy) or spontaneous reversion restores circulation, while the SCD terminology is employed if the patient dies. However, the use of SCD to describe both fatal and nonfatal cardiac arrest often persists by convention. (See "Overview of sudden cardiac arrest and sudden cardiac death", section on 'Definitions'.) The treatment of SCA consists of acute resuscitation using standardized advanced cardiac life- support protocols, followed by therapy to prevent recurrent arrhythmias and SCD. Patients who survive SCA caused by VT/VF not due to a reversible cause generally receive an implantable cardioverter-defibrillator (ICD). Antiarrhythmic drugs are used in select patients as adjunctive therapy, or as primary therapy when an ICD is not indicated or refused by the patient. This approach, endorsed by numerous professional societies, is based on the significant survival benefit of patients receiving an ICD compared with antiarrhythmic drugs alone or no therapy. This topic will review the role of pharmacologic therapy in survivors of SCA, with an emphasis on the role of antiarrhythmic drugs. Issues related to the acute management of SCA, the evaluation of survivors, and the utility of an ICD, arrhythmic surgery, or radiofrequency ablation are discussed separately. (See "Advanced cardiac life support (ACLS) in adults" and "Cardiac https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 1/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate evaluation of the survivor of sudden cardiac arrest" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) INDICATIONS FOR PHARMACOLOGIC THERAPY Nearly all survivors of SCA without a reversible cause should be evaluated for placement of an ICD. Because an ICD treats, but does not prevent, arrhythmias, patients who have arrhythmias with symptoms or device discharges may require adjunctive antiarrhythmic therapy. In addition to ICD therapy for survivors of SCA, there are three main indications for concomitant antiarrhythmic drug therapy [1-3]: To reduce the frequency of ventricular arrhythmias in patients with frequent ICD shocks. In one analysis, the occurrence of frequent ICD shocks was the primary reason for adding an antiarrhythmic drug (64 percent) [3]. To suppress supraventricular arrhythmias that may cause symptoms or interfere with ICD function, potentially resulting in "inappropriate" shocks. "Inappropriate" shocks result from non-life-threatening arrhythmias which meet the programmed parameters for ICD therapy, primarily based upon rate (eg, atrial fibrillation with a rapid ventricular response exceeding the programmed threshold for delivering a shock). "Inappropriate" shocks have been reported in up to 29 percent of ICD patients and can have a substantial impact on the patient s quality of life [4]. These shocks are caused by a variety of arrhythmias including sinus tachycardia, atrial tachycardia, atrial flutter, atrial fibrillation, and nonsustained VT (NSVT) [4,5]. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Inappropriate shocks'.) More sophisticated programming features of current-generation ICDs may allow the device to ignore clinically unimportant and non-life-threatening arrhythmias rather than delivering an unnecessary shock. (See "Implantable cardioverter-defibrillators: Optimal programming".) To reduce the ventricular rate of VT so that it is better tolerated hemodynamically and/or more amenable to termination by anti-tachycardia pacing or low energy cardioversion. CHOICE OF PHARMACOLOGIC THERAPY For patients with an ICD who require adjunctive antiarrhythmic therapy due to ongoing ventricular arrhythmias, we recommend treatment with the combination of amiodarone plus a https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 2/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate beta blocker rather than treatment with amiodarone alone or other antiarrhythmic agents. On occasion, therapy with mexiletine or sotalol may be useful. In general, the class I antiarrhythmic drugs are not used as the majority of patients with SCA have structural heart disease, and these drugs are not recommended in patients with structural heart disease. Pharmacologic therapy, in the form of beta blockers and antiarrhythmic medications, can be helpful in controlling ventricular arrhythmias in survivors of SCA. Virtually all patients who have survived SCA should be considered for beta blocker therapy. However, due to the efficacy of the ICD in treating sustained ventricular tachyarrhythmias and improving mortality, antiarrhythmic drugs are generally reserved for use in select patients as adjunctive therapy, or as primary therapy when an ICD is not indicated or refused by the patient. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Empiric versus guided pharmacologic therapy Empiric pharmacologic therapy for SCA survivors, primarily with beta blockers and/or an antiarrhythmic drug, is an effective approach for survivors of SCA who have refused ICD placement or are not candidates for an ICD. Beta blockers have some efficacy with relatively few side effects, while for most patients amiodarone is the most efficacious antiarrhythmic drug for preventing recurrent ventricular arrhythmias. In the past, the choice of antiarrhythmic drug was guided by objective criteria based upon either noninvasive (ambulatory electrocardiogram [ECG] monitoring) or invasive testing (electrophysiologic studies). An effective drug, identified by either technique, was noted to prevent recurrent arrhythmia and potentially improve survival compared with no therapy or an ineffective drug [6-13]. In current practice, however, when pharmacologic therapy is administered to a patient with or without (because of refusal or noncandidacy for) an ICD, empiric treatment with beta blockers and/or amiodarone is the preferred approach. Other antiarrhythmic drugs (for example mexiletine or sotalol) are considered if there is recurrent arrhythmia despite therapy with amiodarone and/or a beta blocker. Beta blockers Nearly all patients who have survived SCA should receive a beta blocker as part of their therapy. Beta blockers are not generally considered to be adequate monotherapy and should be used in conjunction with an antiarrhythmic drug for most patients resuscitated from SCA due to VT or ventricular fibrillation (VF). However, the associated anti-adrenergic effects of beta blockers may be effective at reducing both arrhythmias and SCA when no specific antiarrhythmic treatment is given. In an analysis from the AVID trial, patients who were discharged from the hospital on a beta blocker had a mortality reduction compared with those patients not receiving a beta blocker [14]. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 3/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Most SCA survivors will have multiple indications for a beta blocker (eg, post-myocardial infarction, heart failure, etc) from which they derive clinical benefit. Beta blockers reduce the incidence of sudden death and total mortality in patients with a recent myocardial infarction and in those with symptomatic heart failure or congenital long QT syndrome. However, even in the absence of any additional indications, beta blockers should be used as part of the medical regimen following SCA due to VT/VF. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Congenital long QT syndrome: Treatment".) Beta blockers can potentiate the effects of class I antiarrhythmic drugs by preventing the effect of sympathetic stimulation on reversing the depressant effect on slowing conduction. They can also potentiate the action of class III antiarrhythmic drugs by preventing the sympathetic effect on shortening repolarization. Antiarrhythmic drugs Among antiarrhythmic medications, amiodarone is the most effective for preventing recurrent ventricular tachyarrhythmias, although mexiletine or sotalol are also efficacious for reducing recurrent ventricular arrhythmias. We prefer empiric therapy with amiodarone for treatment immediately following SCA in patients with recurrent ventricular tachyarrhythmias as well as for those who have refused (or are not candidates for) ICD placement [15]. Following stabilization of the patient, if there are concerns about potential toxicity related to amiodarone, particularly for anticipated long-term use, mexiletine or sotalol may be considered. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Efficacy Several clinical trials and systematic reviews have evaluated the efficacy of antiarrhythmic drugs as adjuvant therapy in ICD patients [5,16-21]. There were significant differences in trial methodologies, which limit direct comparisons. Amiodarone has generally been the most effective antiarrhythmic drug for preventing ventricular arrhythmias (and associated ICD shocks). In one systematic review which included eight randomized trials involving 1889 patients, there was significant heterogeneity among the trials, including variation on the active therapy, control therapy, and outcomes assessed, and the results were divided into those trials that compared class III antiarrhythmic drugs (usually sotalol and amiodarone) with beta blockers, and those trials that compared class III drugs (sotalol, dofetilide, and azimilide) with placebo or no antiarrhythmic therapy [20]. Key findings included: Amiodarone in combination with a beta blocker significantly reduced the incidence of shocks compared with beta blocker alone (hazard ratio [HR] 0.27, 95% CI 0.14-0.52). These results were largely driven by the OPTIC trial. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 4/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Sotalol reduced the incidence of ICD shocks when compared with placebo (HR 0.55, 95% CI 0.4-0.78). There was also a trend toward fewer shocks in patients treated with sotalol versus another beta blocker. Treatment with either azimilide or dofetilide resulted in nonsignificant trends towards reduction in total ICD shocks (generally due to a decrease in supraventricular arrhythmias) compared with placebo. However, the incidence of appropriate ICD therapies (shocks plus antitachycardia pacing) was significantly reduced by azimilide (HR 0.31, 95% CI 0.29-0.34). In a second systematic review of 17 randomized trials involving 5875 patients, patients taking an antiarrhythmic drug had significantly fewer ICD shocks compared with those not on an antiarrhythmic (odds ratio [OR] 0.59, 95% CI 0.36-0.96) [22]. However, the reduction in shocks seen in patients receiving an antiarrhythmic drug was not associated with improved survival (OR 1.07, 95% CI 0.72-1.59). In the OPTIC trial, a multicenter trial that randomized 412 patients with an ICD to treatment with a beta blocker alone, a beta blocker plus amiodarone, or sotalol alone, the rate of any ICD shock at one year was significantly lower with amiodarone plus a beta blocker than with sotalol or a beta blocker alone (10.3 versus 24.3 and 38.5 percent, respectively) [16]. There was a trend toward fewer total ICD shocks in the sotalol group compared with beta blockers alone; however, sotalol had no significant effect compared with a beta blocker alone in reducing the incidence of appropriate shocks or antitachycardia pacing. Another major advantage of amiodarone is a very low frequency of proarrhythmia. Although amiodarone can markedly prolong the QT/QTc interval, torsades de pointes is rare. However, caution is necessary when amiodarone is given with other drugs that can prolong the QT interval or therapy is complicated by hypokalemia or hypomagnesemia. Caution is necessary when combining amiodarone with a beta blocker, as amiodarone also has beta blocking effects and significant bradycardia or AV block may occur. This is not a concern in patients who have an ICD, as there is backup pacing. However, for patients without an ICD or pacemaker this should be considered and patients should be monitored carefully. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Administration When patients are started on an antiarrhythmic drug, they should have a baseline ECG prior to drug initiation and then serial ECGs for the first two to three days, particularly to monitor heart rate and assess for any significant QT/QTc interval prolongation. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 5/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Amiodarone The initial dosing of amiodarone will vary depending on the route (intravenous [IV] or oral) as well as the clinical situation ( table 1): For patients with electrical storm or incessant VT, we recommend IV amiodarone (150 mg IV push, followed by 1 mg/minute IV infusion for six hours, followed by 0.5 mg/minute IV infusion for 18 additional hours) as the initial antiarrhythmic agent. (See "Electrical storm and incessant ventricular tachycardia", section on 'Initial antiarrhythmic medical therapy'.) For patients who have been on IV therapy for more than two weeks, we start maintenance oral amiodarone at a dose of 200 to 400 mg/day. (See "Amiodarone: Clinical uses", section on 'Amiodarone for ventricular arrhythmias'.) For patients who have been on IV therapy for one to two weeks, we start an intermediate maintenance oral amiodarone dose of 400 to 800 mg/day until an adequate loading dose has been achieved, then the dose should be reduced to the usual maintenance dose of 200 mg/day. The recommended IV loading dose is 10 grams or the oral equivalent. As oral amiodarone is approximately 50 percent bioavailable, a total of 20 to 30 grams of oral amiodarone is equivalent to the IV loading dose. For patients who have been on IV therapy for one week or less, we usually start with a full oral amiodarone loading dose of 400 to 1200 mg/day (typically in two or three divided doses). This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 mg/day. Sotalol In contrast to amiodarone, sotalol is not universally available in IV form. Bradycardic and proarrhythmic events (especially due to QT/QTc prolongation) can occur after the initiation of sotalol therapy and with each upward dosing adjustment. As a result, sotalol should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment. We start sotalol at a dose of 80 mg twice daily, with dose adjustments at three-day intervals once steady-state plasma concentrations have been achieved and the QT interval has been reviewed on a surface ECG. Patients with renal insufficiency require a modification of the dosing interval. (See "Clinical uses of sotalol", section on 'Dosing'.) Mexiletine Mexiletine, which is a lidocaine-like antiarrhythmic drug, is only available for oral use. It is often used with or without amiodarone for treating patients with an ICD who have ventricular arrhythmias that are of concern. The usual dose is 200 to 400 mg three times daily. Treatment of breakthrough arrhythmias Patients who have recurrent, or breakthrough, arrhythmias resulting in repeat ICD shocks or sudden cardiac arrest in spite of therapy with a https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 6/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate beta blocker and/or antiarrhythmic drug represent a significant clinical challenge. As with the occurrence of any ventricular arrhythmia, any identifiable reversible causes (eg, myocardial ischemia, electrolyte disturbances) should be corrected. In the absence of any reversible causes, we approach treatment in the following way: For patients who are taking only a beta blocker, we add an antiarrhythmic drug, ideally amiodarone. For patients who are taking only an antiarrhythmic drug, we add a beta blocker. For patients who are taking both a beta blocker and an antiarrhythmic drug, treatment options include upward titration of either or both existing drugs or the discontinuation of the current antiarrhythmic drug in favor of an alternative antiarrhythmic drug. We prefer to first increase the dose of the beta blocker and the current antiarrhythmic drug to the maximum recommended dose (or maximum tolerated dose if side effects arise). If this approach is ineffective and the patient continues to have recurrent ventricular arrhythmias and shocks, we would consider stopping the current antiarrhythmic drug and initiating treatment with another agent. Another important option for patients with recurrent arrhythmia despite amiodarone and beta blocker is the addition of a class I antiarrhythmic agent ( table 2) that does not alter the QT/QTc interval (ie, mexiletine or propafenone). For patients with recurrent ventricular tachyarrhythmia despite the use of multiple antiarrhythmic drugs, cardiac ablation is often the next step in management. Further details on the treatment of refractory VT can be found elsewhere. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.) IMPACT ON ICD THERAPIES The primary goal of using blockers and/or antiarrhythmic drugs in patients with an ICD is to minimize the frequency of recurrent ventricular arrhythmias, thereby decreasing the likelihood of the patient receiving additional ICD shocks. Beyond reducing the likelihood of ICD shocks, however, antiarrhythmic drug therapy may impact the efficacy of ICD therapies by potentially increasing defibrillation thresholds beyond the device s capability to defibrillate or by slowing the ventricular rates of any recurrent sustained tachyarrhythmias below the device s threshold for arrhythmia detection. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 7/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Alterations in DFTs Any antiarrhythmic drug can potentially alter the defibrillation threshold (DFT), although the effect has been most pronounced with amiodarone and its major metabolite desethylamiodarone, which increase the DFT in a dose-dependent fashion [23-25]. DFT testing has historically been performed at the time of ICD implantation, although the routine necessity for this evaluation with the current generation of ICDs has been questioned. However, repeat DFT testing may be warranted after the initiation of amiodarone if there is concern about rising DFT thresholds (as may occur in certain clinical situations, including atrial fibrillation, hypertension, and left ventricular hypertrophy). In the report on the efficacy of routine ICD testing discussed above, 71 patients had an ICD test due to the initiation or dose-adjustment of an antiarrhythmic drug (primarily amiodarone or sotalol), and the ICD failed to defibrillate only two patients [26]. The role of ICD testing after the initiation of antiarrhythmic therapy was more directly assessed in a substudy of the OPTIC trial, in which 94 patients underwent serial ICD testing to determine the impact of each of three drug regimens (beta blockers, amiodarone plus a beta blocker, and sotalol) on DFTs [27]. At a mean follow-up of 60 days after drug initiation, the mean DFT decreased from baseline in the patients assigned to beta blockers or sotalol (8.8 to 7.1 and 8.1 to 7.2 joules, respectively), while among patients taking amiodarone there was a nonsignificant increase in the mean DFT from 8.5 to 9.8 joules. Given the relatively small number of patients in each arm of this study, the small mean increase in DFT does not preclude the possibility that there may be a larger increase in some patients. Thus, the necessity for ICD testing after the initiation of antiarrhythmic drugs, primarily amiodarone, remains uncertain. Programming changes for VT detection In patients receiving chronic antiarrhythmic drug therapy, the rate of recurrent VT is often slower than the rate seen during the index arrhythmia. Thus, it is common practice to lower the VT detection rate when initiating antiarrhythmic drug therapy; the specific detection threshold rate is determined by the characteristics of the patient s prior events. However, reducing the VT detection rate can have both positive and negative consequences for the patient: If the VT detection rate is reduced and the ICD therapy program includes antitachycardia pacing (ATP), episodes of slow VT may be terminated with ATP before the patient is aware of the event. If the detection rate is set too low, the ICD will not treat the arrhythmia unless it accelerates above the detection rate or progresses to ventricular fibrillation (VF). Thus, some patients who have their detection threshold rate decreased may not receive ICD treatments during episodes of slow VT and may have symptomatic VT (eg, syncope, palpitations, chest pain, dyspnea, or even SCA). https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 8/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Close follow-up with remote device interrogation can help determine whether new VT detection settings are appropriate. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Basic and advanced cardiac life support in adults".) SUMMARY AND RECOMMENDATIONS Because of the survival benefit associated with an implantable cardioverter-defibrillator (ICD) compared with antiarrhythmic therapy alone, most survivors of sudden cardiac arrest (SCA) due to ventricular tachycardia (VT) or ventricular fibrillation (VF) not associated with a reversible cause should receive an ICD. Antiarrhythmic drugs can be considered as the primary therapy when an ICD is not indicated or refused by the patient. (See 'Indications for pharmacologic therapy' above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Nearly all patients who have survived SCA should receive a beta blocker as part of their therapy, which may also provide additional antiarrhythmic benefits. (See 'Empiric versus guided pharmacologic therapy' above.) Because an ICD does not prevent arrhythmias, patients who have arrhythmias (ventricular or supraventricular) with symptoms or device discharges may require adjunctive antiarrhythmic therapy or consideration of catheter ablation. The three main indications for concomitant antiarrhythmic drug therapy are (see 'Indications for pharmacologic therapy' above): To reduce the frequency of ventricular arrhythmias in patients with frequent ICD shocks. To suppress other arrhythmias that cause symptoms or interfere with ICD function (eg, causing "inappropriate" shocks). To reduce the ventricular rate of VT so that it is better tolerated hemodynamically and more amenable to termination by anti-tachycardia pacing or low-energy cardioversion. https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 9/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate For patients with an ICD who require adjunctive antiarrhythmic therapy due to ongoing arrhythmias, we recommend treatment with the combination of amiodarone plus a beta blocker rather than treatment with amiodarone alone or other antiarrhythmic agents (Grade 1B). This approach is especially preferred in patients with significant left ventricular dysfunction who require adjunctive antiarrhythmic therapy, since amiodarone does not exacerbate heart failure and is less proarrhythmic than other agents. (See 'Choice of pharmacologic therapy' above.) Antiarrhythmic drug therapy may impact the efficacy of ICD therapies by potentially increasing defibrillation thresholds beyond the device s capability to defibrillate or by slowing the ventricular rates of any recurrent sustained tachyarrhythmias below the device s threshold for arrhythmia detection.(See 'Impact on ICD therapies' above.) ACKNOWLEDGMENT The UpToDate editorial staff thanks Jie Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Knilans TK, Prystowsky EN. Antiarrhythmic drug therapy in the management of cardiac arrest survivors. Circulation 1992; 85:I118. 2. Manz M, Jung W, L deritz B. Interactions between drugs and devices: experimental and clinical studies. Am Heart J 1994; 127:978. 3. Steinberg JS, Martins J, Sadanandan S, et al. Antiarrhythmic drug use in the implantable defibrillator arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study. Am Heart J 2001; 142:520. 4. Nanthakumar K, Paquette M, Newman D, et al. Inappropriate therapy from atrial fibrillation and sinus tachycardia in automated implantable cardioverter defibrillators. Am Heart J 2000; 139:797. 5. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. N Engl J Med 1999; 340:1855. 6. Kim SG. The management of patients with life-threatening ventricular tachyarrhythmias: https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 10/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate programmed stimulation or Holter monitoring (either or both)? Circulation 1987; 76:1. 7. Wilber DJ, Garan H, Finkelstein D, et al. Out-of-hospital cardiac arrest. Use of electrophysiologic testing in the prediction of long-term outcome. N Engl J Med 1988; 318:19. 8. Graboys TB, Lown B, Podrid PJ, DeSilva R. Long-term survival of patients with malignant ventricular arrhythmia treated with antiarrhythmic drugs. Am J Cardiol 1982; 50:437. 9. Lampert S, Lown B, Graboys TB, et al. Determinants of survival in patients with malignant ventricular arrhythmia associated with coronary artery disease. Am J Cardiol 1988; 61:791. 10. Vlay SC, Kallman CH, Reid PR. Prognostic assessment of survivors of ventricular tachycardia and ventricular fibrillation with ambulatory monitoring. Am J Cardiol 1984; 54:87. 11. Mason JW. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med 1993; 329:445. 12. Mason JW. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med 1993; 329:452. 13. Swerdlow CD, Winkle RA, Mason JW. Determinants of survival in patients with ventricular tachyarrhythmias. N Engl J Med 1983; 308:1436. 14. Exner DV, Reiffel JA, Epstein AE, et al. Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol 1999; 34:325. 15. Weinberg BA, Miles WM, Klein LS, et al. Five-year follow-up of 589 patients treated with amiodarone. Am Heart J 1993; 125:109. 16. Connolly SJ, Dorian P, Roberts RS, et al. 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; 295:165. 17. Dorian P, Borggrefe M, Al-Khalidi HR, et al. Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator. Circulation 2004; 110:3646. 18. Singer I, Al-Khalidi H, Niazi I, et al. Azimilide decreases recurrent ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators. J Am Coll Cardiol 2004; 43:39. 19. K hlkamp 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; https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 11/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate 33:46. 20. Ferreira-Gonz lez I, Dos-Subir L, Guyatt GH. Adjunctive antiarrhythmic drug therapy in patients with implantable cardioverter defibrillators: a systematic review. Eur Heart J 2007; 28:469. 21. Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE Study). The CASCADE Investigators. Am J Cardiol 1993; 72:280. 22. Ha AH, Ham I, Nair GM, et al. Implantable cardioverter-defibrillator shock prevention does not reduce mortality: a systemic review. Heart Rhythm 2012; 9:2068. 23. Zhou L, Chen BP, Kluger J, et al. Effects of amiodarone and its active metabolite desethylamiodarone on the ventricular defibrillation threshold. J Am Coll Cardiol 1998; 31:1672. 24. Pelosi F Jr, Oral H, Kim MH, et al. Effect of chronic amiodarone therapy on defibrillation energy requirements in humans. J Cardiovasc Electrophysiol 2000; 11:736. 25. Nielsen TD, Hamdan MH, Kowal RC, et al. Effect of acute amiodarone loading on energy requirements for biphasic ventricular defibrillation. Am J Cardiol 2001; 88:446. 26. Brunn J, B cker D, Weber M, et al. Is there a need for routine testing of ICD defibrillation capacity? Results from more than 1000 studies. Eur Heart J 2000; 21:162. 27. Hohnloser SH, Dorian P, Roberts R, et al. Effect of amiodarone and sotalol on ventricular defibrillation threshold: the optimal pharmacological therapy in cardioverter defibrillator patients (OPTIC) trial. Circulation 2006; 114:104. Topic 972 Version 27.0 https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 12/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate GRAPHICS Amiodarone dosing in adults by indication Indications Loading dose Maintenance dose Atrial arrhythmias Prevention of recurrent PAF Total loading dose: 6 to 10 grams Lowest effective dose, usually 100 to 200 mg orally once per day Pharmacologic cardioversion of PAF Outpatient: Given as 400 to 600 mg orally per day in divided doses with meals Maximum 200 mg orally per day Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals Pretreatment before elective cardioversion or Total loading dose: 6 to 10 grams orally over 2 to 6 Lowest effective dose, usually 100 to 200 mg orally catheter ablation of AF weeks once per day Given as 400 to 1200 mg Maximum 400 mg orally per orally per day in divided doses day in most circumstances Restoration and maintenance of NSR in critically ill patients with AF Total IV loading dose: 1050 mg Given as 150 mg IV bolus over 10 to 30 minutes, followed by continuous IV infusion at 1 mg per minute for 6 hours, then 0.5 mg per Ventricular rate control in critically ill patients with AF and rapid ventricular response minute for 18 hours* IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy If amiodarone will be used chronically: Following IV infusion, give 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams; consider overlapping IV and oral amiodarone for 24 to 48 hours https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 13/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Ventricular arrhythmias Primary and secondary prevention of SCD in patients with LV dysfunction who are not candidates for or refuse ICD implantation Total oral loading dose: 6 to 10 grams Maximum 400 mg orally per day in most circumstances Outpatient: 400 to 600 mg orally per day in divided doses with meal Lowest effective dose, ideally 200 mg or less orally once per day or in divided doses Inpatient: 400 to 1200 mg orally per day in divided doses with meals for 1 to 2 weeks Prevention of ventricular arrhythmias in patients Total loading dose: 6 to 10 grams Maximum 400 mg orally per day in most circumstances with ICDs to decrease risk of shocks Outpatient: Given as 400 to 600 mg orally per day in Lowest effective dose, ideally 200 mg or less orally per day divided doses with meals Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals until desired dose is achieved Cardiac arrest associated with VF or pulseless VT 300 mg IV or IO rapid bolus with a repeat dose of 150 mg as indicated Upon return of spontaneous circulation follow with an infusion of 1 mg per minute for 6 hours and then 0.5 mg per minute for 18 hours* Electrical (VT) storm and incessant VT in hemodynamically stable Total IV loading dose: 1050 mg If amiodarone is used chronically: Lowest effective dose, ideally 200 mg or less 150 mg IV bolus over 10 minutes, followed by continuous IV infusion at 1 mg per minute for 6 hours, patients orally per day; maximum 400 mg orally per day in most circumstances then 0.5 mg per minute for 18 hours IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 14/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Additional 150 mg boluses may be given if VT storm recurs If amiodarone will be used chronically: Following IV infusion 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams. Consider overlapping IV and oral amiodarone for 24-48 hours PAF: paroxysmal atrial fibrillation; AF: atrial fibrillation; NSR: normal sinus rhythm; IV: intravenous; SCD: sudden cardiac death; LV: left ventricular; ICD: implantable cardioverter-defibrillator; VF: ventricular fibrillation; VT: ventricular tachycardia; IO: intraosseous. When administered to critically ill patients with atrial fibrillation and rapid ventricular response, repeated 150 mg boluses can be given over 10 to 30 minutes if needed, but no more than six to eight additional boluses should be administered in any 24-hour period. Typically, patients are given 1 or 2 doses of oral amiodarone prior to discontinuation of the IV infusion. Graphic 117524 Version 5.0 https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 15/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 16/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/pharmacologic-therapy-in-survivors-of-sudden-cardiac-arrest/print 17/18 7/6/23, 1:41 PM Pharmacologic therapy in survivors of sudden cardiac arrest - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Scott Manaker, MD, PhD Other Financial Interest: Expert witness in workers' compensation and in medical negligence matters [General pulmonary and critical care medicine]; National Board for Respiratory Care [Director]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. 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