Drug-Induced, Drug-Provoked and Drug-Associated Bradycardia

Drug-Induced, Drug-Provoked and Drug-Associated Bradycardia I.E. OVSYSHCHER Introduction Bradycardia or bradyarrhythmia is present if the heart rate, i.e. ventricular rate, is less than 60 bpm in the setting of sinus rhythm, a variety of atrial rhythms, atrial fibrillation/flutter, junctional, or idioventricular rhythm [1] and advanced atrioventricular (AV) block. Drug-induced bradycardia in adults is frequently observed. This paper will discuss clinically significant and symptomatic bradycardia [1], i.e. bradycardia responsible for the development of syncope, near-syncope, and confusional state, and bradycardia which is accompanied by premature ventricular beats with short long intervals, non-sustained ventricular tachycardia, QT prolongation, low cardiac output, and/or poor left ventricular function (these bradycardias can lead to torsades de pointes and to new onset or deterioration of previous heart failure). Types of Bradycardia Observed in Patients Treated by Drugs Inducing Bradycardia: Definitions Three types of bradycardia maybe observed during therapy with drugs inducing bradycardia: 1. Drug-induced bradycardia. In the heart with normal sinus and AV node and normal infranodal conduction, drug-induced bradycardia may be due to overdosage and toxic effect of medication, or to a synergistic brady effect of several medications. Electrophysiology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel

570 I.E. Ovsyshcher 2. Drug-provoked bradycardia. In the heart with underlying latent disease of the sinus and/or AV node, and/or infranodal conduction system, bradycardia may be due to a trigger effect of even sub-therapeutic doses of drugs inducing bradycardia. This kind of drug-induced bradycardia should be classified as drug-provoked bradycardia. It is important to note that generally drugs inducing bradycardia (β- and calcium channel blockers and most anti-arrhythmic drugs) have no influence on infranodal conduction. 3. Drug-associated bradycardia. In patients with underlying latent disease of the sinus and/or AV node, and/or infranodal conduction, significant bradycardia may be associated with drugs inducing bradycardia but not due to a brady effect of these drugs. Frequently the difference between bradycardia associated with drugs is invisible and the former may be confused with the later. 4. In patients with normal heart therapeutic doses of drugs inducing bradycardia generally cannot cause clinically significant bradycardia, especially due to AV block. This suggestion is logical extension of previous three. All definitions based on level of evidence C. Drugs Inducing Bradycardia Clinically significant bradycardia can be induced by β-blockers, non-dihydropyridine calcium channel antagonists, digitalis, and anti-arrhythmic drugs [1 7]. Other drugs include sympatholytic anti-hypertensives, tedisamil, carbamazepine, cimetidine, anti-depressants, lithium, opioid blockers, and cocaine [3, 8]. This last group has generated relatively little data in the literature. Severe symptomatic bradycardia has been observed after the eating of honey (called mad honey) produced from the nectar of rhododendrons (of the family Ericaceae) [9]. Grayanotoxins extracted from this honey and injected to rats cause severe bradycardia. There are case reports regarding a toxic effect of doxorubicin and antismoking remedy (herbs) leading to symptomatic bradycardia due to heart block [10, 11]. Bradyarrhythmia develops more commonly with amiodarone, sotalol and other β-blockers, propafenone, or flecainide than with procainamide, quinidine, or disopyramide; combined drug therapy increases the risk of significant bradycardia [7, 8, 12]. Advanced age, a history of prior myocardial infarction, decreased systolic performance, and ventricular arrhythmias (i.e. factors strongly associated with sinus node dysfunction and supra- and infranodal conduction disturbances) are independent predictors of brady-

Drug-Induced, Drug-Provoked and Drug-Associated Bradycardia 571 arrhythmic complications of drug therapy [3 8]. An interesting study was published recently regarding high-degree heart block in patients treated with β-blockers and non-dihydropyridine calcium channel antagonists [2]. During AV block, sinus rhythm was 79 ± 17 bpm and troly caused by the drugs was uncommon, being observed in only 8%. The majority of patients presenting with second- or third-degree AV block during therapy with β- or calcium channel blockers will continue to suffer from AV block even after discontinuation of these medications. Importantly, in most of these patients heart block was infranodal, and even when the block resolved after the medication was discontinued, it usually recurred in the absence of drug therapy. In fact, this would be expected because both β- and calcium channel blockers have no effect on infranodal conduction. Thus, it cannot be predicted whether a patient with AV block that appeared during therapy with bradycardia-inducing drugs can expect a benign course after discontinuation of the wrong medication. Moreover, was been emphasised by the authors, in the vast majority of these patients the offending drug cannot be blamed for AV block, but rather plays a bystander role, i.e. in these patients AV block was drug-associated, but not druginduced, and only occasionally was drug-provoked AV block observed (i.e. the drug played a trigger role in AV block initiation). It is very possible that clinically significant and symptomatic drug-induced bradycardia in other patients (without heart block) is also mostly due to underlying sinus and/or AV node disease [1, 6, 8, 12, 13]. In these cases drug-induced bradycardia should be classified as drug-provoked or drug-associated bradycardia. This is of clinical importance because in the 2002 ACC/AHA/NASPE guidelines for pacemaker implantation [14], definitions of various clinical forms of drug-induced bradycardia are missing, and pacemaker implantation is generally considered unnecessary in patients with significant druginduced bradycardia. Is Drug-Induced Bradycardia Evidence of Pro-arrhythmia? Since many of the inducing bradycardia and anti-arrhythmic drugs have a depressant effect on both sinus node automaticity and AV nodal conduction, sinus bradycardia, sinus pauses, sinus arrest, and/or various degrees of supranodal AV block may occur. It is often stated in the literature that bradycardia appearing during treatment by the mentioned groups of drugs is a pro-arrhythmic complication [3 6], a term connoting aggravation of treated arrhythmia or the development of a new tachyarrhythmia [4]. However, drug-induced bradycardia due to either sinus node dysfunction or various degrees of both supra- and infra-nodal AV block appears more common in

572 I.E. Ovsyshcher patients with underlying sinus or/and AV node diseases (usually latent), which frequently occur in patients with structural heart disease [1 6, 12, 13]. Furthermore, true pro-arrhythmic events commonly occur within several days from the start of drug therapy with initially relatively low doses [3 6], whereas bradycardia usually appears after prolonged drug treatment, and only sometimes during a loading process, as with amiodarone [6, 13], especially in the management of malignant ventricular arrhythmia. Thus, characterisation of drug-induced bradycardia as a pro-arrhythmic complication is inaccurate because it represents largely a manifestation of underlying disease of the sinus and/or conduction system or drug overdosage. Of note, bradycardia itself may predispose to bradycardia-dependent pro-arrhythmic tachyarrhythmias. Bradycardia Requiring Permanent Pacing There are no data in the literature regarding the incidence of drug-induced bradycardia in specific cardiac conditions. According to a review of 26 published reports, the incidence of development of drug-induced bradycardia necessitating pacemaker implantation was estimated at 1 15% of patients on a variety of anti-arrhythmic agents used for different indications [1, 7]. In a recent report [13] based on a study of 8770 post-myocardial infarction patients with recent-onset atrial fibrillation, amiodarone use was associated with an increased risk of pacemaker insertion (odds ratio, OR: 2.14, 95% confidence interval, CI). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI). A strong association between prior sinus node dysfunction or conduction disturbances and the need for a permanent pacemaker was also demonstrated. (OR: 3.32, 95% CI). In another report [12] on amiodarone treatment of patients with atrial fibrillation, bradycardia requiring permanent pacing occurred in 1.4% of patients. In a study of patients with atrial fibrillation treated only with sotalol, bradycardia requiring permanent pacing was observed in 2.5% and dose reduction in about 14% of patients [15]. Among 78 patients with a DDDR system implanted for symptomatic bradycardia and paroxysmal or persistent atrial fibrillation, the bradycardia was drug-induced (mostly by amiodarone and sotalol) in 33% [7]. Before pacemaker implantation, the drug dosage had to be reduced or the agent discontinued in these patients, owing to bradycardia despite unsatisfactory rhythm and rate control. After pacemaker implantation, the drug could be used again and was more effective at either the same or an increased dosage [7]. Zeltser et al. [2] recently published a study regarding drug-induced AV

Drug-Induced, Drug-Provoked and Drug-Associated Bradycardia 573 block. They concluded that AV block is commonly related to drugs but is rarely caused by drugs (see above). The incidence of pacemaker implantation for drug-induced bradycardia varies considerably [1, 7]. This variability depends on several factors: drug type, drug combination, and diversity of patient cohorts (patients with normal heart versus patients with sinus and/or AV node dysfunction and conduction disturbances). In addition, the need for pacemaker implantation was decided on the basis of individual clinical judgement rather than published guidelines. Clinical Implications and Conclusions Drug-induced bradycardia is a multifarious and an important but poorly defined clinical problem. Its characterisation as a pro-arrhythmia is unwarranted. Drug-induced bradycardia is common and frequently represents a manifestation of underlying sinus and/or AV node dysfunction and conduction disturbances, i.e. drug-provoked and drug-associated bradycardia. True drug-induced bradycardia is caused by drug overdosage and/or drug toxicity or combination of drugs-inducing bradycardia in inappropriate doses due to their synergistic effect. In patients with symptomatic or clinically significant true drug-induced bradycardia, one must decide whether to stop or reduce the drug therapy or to continue it if there is no acceptable alternative, in which case pacing therapy should be considered. In patients with drugprovoked bradycardia a similar approach should be suggested. In patients with drug-associated bradycardia, especially due to high-degree AV block, pacing implantation should be considered [2]. Frequently, clinical differences between drug-induced, drug-provoked, and drug-associated bradycardias maybe invisible and they may be poorly differentiated. Little is known about when bradycardia discovered in patients treated with offending drugs merely unmasks the presence of clinically important underlying sinus or conduction system disease or both. Little also is known about the natural history and prognosis of patients with drug-induced bradycardia. References 1. Ovsyshcher IE, Barold SS (2004) Drug-induced bradycardia: to pace or not to pace? Pacing Clin Electrophysiol 27:1144 1147 2. Zeltser D, Justo D, Halkin A et al (2004) Drug-induced atrioventricular block: prognosis after discontinuation of the culprit drug. J Am Coll Cardiol 44:105 108 3. Podrid PJ (1995) Aggravation of arrhythmia by antiarrhythmic drugs. In: Podrid PJ, Kowey PR (eds) Cardiac arrhythmia. Mechanisms, diagnosis and management.

574 I.E. Ovsyshcher Williams & Wilkins, Baltimore, pp 507 522 4. Friedman PL, Stevenson WG (1998) Proarrhythmia. Am J Cardiol 82:50N-58N 5. Zipes DP (1987) Proarrhythmic effect of antiarrhythmic drugs. Am J Cardiol 59:26E-31E 6. Hofman R, Leisch F (1995) Symptomatic bradycardia with amiodarone in patients with pre-existing conduction disorders. Wien Klin Wochenschr 107:640 644 7. Israel CW, Ehrlich JR, Barold SS et al (2002) Treatment of tachyarrhythmias with pacing and antiarrhythmic drugs. In: Israel CW, Barold SS (eds) Advances in the treatment of atrial tachyarrhythmias: pacing, cardioversion, and defibrillation. Futura, Armonk, NY, pp 305 323 8. Yusuf S, Camm AJ (2003) Sinus tachyarrhythmias and the specific bradycardia agents: a marriage made in heaven? J Cardiovasc Pharmacol Ther 8:89 105 9. Onat F, Yegen BC, Lawrence R et al (1991) Site of action of grayanotoxins in mad honey in rats. J Appl Toxicol 11(3):199 201 10. Kilickap S, Akgul E, Aksoy S et al (2005) Doxorubicin-induced second degree and complete atrioventricular block. Europace 7:227 230 11. Kolettis TM, Oikonomou G, Novas I et al (2005) Transient complete atrioventricular block associated with herb intake. Europace 7:225 226 12. Hauser TH, Pinto DS, Josephson ME et al (2003) Safety and feasibility of a clinical pathway for the outpatient initiation of antiarrhythmic medications in patients with atrial fibrillation or atrial flutter. Am J Cardiol 91:1437 1441 13. Essebag V, Hadjis T, Platt RW et al (2003) Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction. J Am Coll Cardiol 15:249 254 14. Gregoratos G, Abrams J, Epstein AE et al (2002) ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation 106:2145 2161 15. Chung MK, Schweikert RA, Wilkoff BL et al (1998) Is hospital admission for initiation of antiarrhythmic therapy with sotalol for atrial fibrillation required? J Am Coll Cardiol 32:169 176