Adenosine as an Antiarrhythmic Agent

Adenosine as an Antiarrhythmic Agent

Adenosine as an Antiarrhythmic Agent Sabrina L. Wilbur, MD and Francis E. Marchlinski, MD Adenosine produces acute inhibition of sinus node and at...

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Adenosine as an Antiarrhythmic Agent Sabrina L. Wilbur,

MD

and Francis E. Marchlinski,

MD

Adenosine produces acute inhibition of sinus node and atrioventricular (AV) nodal function. This profound but short lived electrophysiologic effect makes adenosine a suitable agent for treating supraventricular tachycardias (SVT) that incorporate the sinus node or AV node as part of the arrhythmia circuit, or for unmasking atrial tachyarrhythmias or ventricular pre-excitation. Its antiadrenergic properties also make it an effective agent for use with some unique atrial and ventricular tachycardias. Appropriate dosing and rapid bolusing with intravenous

administration is required. Recognition of infrequent proarrhythmic risks and potential drug interactions with xanthine derivatives and dipyridamole should maximize its safe and effective use. This review will highlight adenosine’s mechanism of action, administration, clinical indications, efficacy, and risks when used in tachyarrhythmic management. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;79(12A):30–37

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and shortened action potential duration.4,5,6 Hyperpolarization of the sinus node and AV nodal cell membranes, much beyond their anticipated resting membrane potential, increases the threshold for triggering a subsequent action potential, thus reducing cell activity. Indirect electrophysiologic effects: In the presence of catecholamine stimulation, adenosine attenuates the slow inward calcium current.7 This phenomenon is mediated by an antagonism of catecholamine-stimulated adenylate cyclase activity, which results in a decrease in intracellular cyclic adenosine monophosphate (AMP) accumulation.8 The deficit in cyclic AMP results in a decrease in the inward calcium current.9 Adenosine has also been shown to decrease the release of norepinephrine from its presynaptic terminal.10 Ventricular myocardial cells do not possess adenosine-mediated potassium channels, and thus adenosine exerts only indirect antiadrenergic action in the ventricle.11,12 In summary, adenosine exerts its potential antiarrhythmic effects by both direct effects on potassium conductance and indirect antiadrenergic actions. The major electrophysiologic effects are on the sinus node, AV node, and atrial tissue, resulting in sinus slowing and arrest, AV nodal conduction slowing and block, and shortening of atrial refractoriness. It is also important to note that after adenosineinduced bradycardia there is usually a period of relative tachycardia. This reaction is most likely the result of a ‘‘rebound’’ increase in sympathetic nerve traffic and plasma catecholamine levels produced by adenosine.13 This effect is usually transient and selflimited but it may play a role in enhancing the occasionally proarrhythmic effects of adenosine (see below).

denosine has proved to be an effective therapeutic agent for the treatment of patients with supraventricular tachycardias (SVT). Its ultra short half-life and the absence of frequent serious side effects make it a front-line agent in arrhythmia management. Since its release at the beginning of the decade, a more complete understanding of its clinical utility and limitations has been defined. This review will summarize and update the reader on the current status of adenosine as an antiarrhythmic agent. After describing important issues related to its mechanism of antiarrhythmic action, the response of adenosine to each type of cardiac arrhythmia will be addressed. Attention will be paid to its limitations as a diagnostic tool for defining the presence of an SVT involving the atrioventricular (AV) node. Important issues related to dosing and method of administration of adenosine, as well as specific concerns with its use in pregnant women and children, will be discussed. We will conclude by detailing the side-effect profile and the uncommon but potential serious proarrhythmic effects of adenosine.

MECHANISM OF ANTIARRHYTHMIC ACTION Adenosine is an endogenous purine nucleoside. Its action on the mammalian heart was first described in 1929 by Drury and Szent-Gyorgyi.1 In 1930, Honey et al2 described its AV nodal blocking properties in the human heart. Cardiac adenosine receptors are located in the coronary arteries, sinoatrial (SA) node, atrial myocytes, and AV node.3 Direct electrophysiologic effects: The predominant antiarrhythmic effects on the SA node, AV node, and atrial myocytes are mediated through direct activation of the adenosine A1 receptor.4 When adenosine binds to this receptor there is an increase in outward potassium current (IK/,ADO,Ach). This increase results in hyperpolarization of the cardiac cell membrane From the Department of Medicine, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania. Address for reprints: Sabrina L. Wilbur, MD, Allegheny University of the Health Sciences, MCP / Hahnemann, 230 North Broad Street, Mail Stop 470, Philadelphia, Pennsylvania 19102.

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EFFECT ON SINUS NODE AND ATRIAL ARRHYTHMIAS For the purpose of this discussion, the response of adenosine will be described for each atrial arrhythmia mechanism (reentrant, triggered, automatic) and site (sinus node reentry). As indicated above, adenosine has both direct and indirect effects on the sinus node and atrial myocytes. The predom-

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FIGURE 1. Adenosine administration unmasking atrial flutter by creating transient high grade AV block.

inant electrophysiologic effect of adenosine is that of hyperpolarization resulting from the activation of the outward potassium current when the A1 receptor is stimulated. In normal atrial myocytes, the net effect of the increased potassium current is to hyperpolarize the cell toward the equilibrium potential of potassium (EK 090 mV).9 The equilibrium potential of potassium is very similar to the normal resting membrane potential of atrial myocytes. Thus, the effect of adenosine-mediated hyperpolarization in this tissue is minimal. However, the shortening of the atrial effective refractory period can facilitate induction of atrial fibrillation (see proarrhythmia). In contrast, the resting membrane potential of the sinus node is approximately 060 mV. Thus, hyperpolarization of the sinus node to 090 mV can result in significant sinus bradycardia or sinus arrest.9,14 Therefore, one would expect that adenosine might be effective in terminating arrhythmias due to sinus node reentry. This has been confirmed in a study by Engelstein et al.15 These investigators demonstrated reproducible termination of sinus node reentry in 6 of 6 patients. In the same study, adenosine had no effect in 13 patients with intra-atrial reentrant tachycardia, including 8 patients with atrial flutter. Adenosine may, however, facilitate the diagnosis of a reentrant atrial tachycardia or atrial flutter by inducing transient AV block during the tachycardia, allowing for better visualization of atrial activity (Figure 1). Uncommonly, atrial tachycardia appears to have a triggered or automatic mechanism. The cellular mechanism for triggered activity is most likely due to an increase in intracellular calcium. As discussed previously, adenosine has been shown to attenuate the slow inward current of calcium in the presence of catecholamine stimulation.7 This is consistent with limited clinical data15 that demonstrate termination of atrial tachycardia due to a suspected triggered mechanism. Response of automatic atrial tachycardia to adenosine has been variable.15,16,17,18,19,20,21 Rate slowing and/or transient termination has been demonstrated (Figure 2). This effect on automatic atrial tachycardia is thought to be mediated via adenosine’s antagonism of catecholamine activity.

longation in AV node conduction, and eventual block if large enough doses are used.22,23 AV nodal reentrant tachycardia (AVNRT) is the most common form of paroxysmal SVT.24 It follows that adenosine would be especially well suited to treat tachycardias involving the AV node. The effectiveness of adenosine has been documented clinically by a number of investigators.23,25,26 The common form of AVNRT uses the ‘‘slow’’ pathway in the anterograde direction and the ‘‘fast’’ pathway retrograde. Adenosine administration during AVNRT most commonly blocks conduction in the anterograde ‘‘slow’’ pathway.26,27 On the surface electrocardiogram, this is often seen as a narrow complex tachycardia that terminates with retrograde atrial activation (often manifesting as a pseudo R* in lead V1, that is not present in the beats following the termination of the tachycardia; Figure 3). The diagnostic utility of adenosine in identifying the mechanism of tachycardia as AVNRT may be limited (Table I). Termination of AV reentrant tachycardia (see below), sinus node reentry, and atrial tachycardias due to triggered activity occur following adenosine therapy. Diagnosis of atrial arrhythmia is suggested by the presence of a P wave followed by a QRS complex that terminates after adenosine administration (a QRS complex is the final event before termination of the tachycardia). However, termination of AVNRT can also occur with block in the retrograde ‘‘fast’’ pathway, with a QRS complex being the final event.26

EFFECT ON WOLFF-PARKINSONWHITE SYNDROME AND AV-RECIPROCATING TACHYCARDIAS Adenosine has been used diagnostically to demonstrate the existence of an accessory pathway. It can TABLE I Response to Adenosine—Supraventricular Tachycardia (SVT) Persistent atrial tachycardia with increased AV nodal block (slows ventricular response)

j Atrial fibrillation j Atrial flutter j Reentrant atrial tachycardia Terminates SVT

EFFECT ON AV NODAL REENTRANT TACHYCARDIA The AV node is richly supplied with adenosine A1 receptors. It has been shown in both animal and human models that adenosine causes a dose-dependent pro-

j AV Nodal Reentry j AV Reentry involving accessory pathway j Sinus node reentry j Automatic atrial tachycardia (transient slowing/termination) j Triggered atrial tachycardia

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FIGURE 2. Adenosine administration during automatic atrial tachycardia. Recordings are continuous. Note tachycardia slowing and transient termination (top panel). Resumption of tachycardia is noted in middle of the second panel. Further acceleration in rate of atrial tachycardia as effect of adenosine resolves.

FIGURE 3. AV nodal reentrant tachycardia terminating with anterograde block in the slow pathway. Note; evidence of a retrograde P wave at the time of termination (arrow).

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FIGURE 4. Adenosine administered during sinus rhythm in patient with history of supraventricular tachycardia. Slowing of the sinus rate allows for demonstration of antegrade conduction over the accessory pathway and suggests AV reentry as the mechanism for SVT.

FIGURE 5. Response of AV reentrant tachycardia to adenosine. Tachycardia terminates (arrow) with retrograde p wave that is distinct from QRS. Block of the reentrant tachycardia is in the AV node.

be administered during sinus rhythm to suppress AV nodal conduction thus allowing anterograde conduction over an accessory pathway to become more clearly manifest. This is especially helpful in diagnosis of a left lateral bypass tract in the presence of an intra-atrial conduction delay. In this clinical situation, the added time it takes for the sinus impulse to cross to the left atrium permits normal or intrinsically rapid AV conduction to mask evidence of an accessory pathway (Figure 4). Similarly, adenosine is often administered at the time of electrophysiologic evaluation in conjunction with ventricular stimulation to better define retrograde accessory pathway existence and localization. AV reciprocating tachycardia (AVRT) characteristically involves a reentrant circuit that includes anterograde conduction through the AV node, and

retrograde, non-decremental conduction over an accessory pathway. Uncommonly, the circuit can be reversed (antidromic AVRT). When given during AVRT, adenosine will terminate the tachycardia by blocking conduction in the AV node26,28,29(Figure 5). Adenosine has been reported to cause a block in the accessory pathway.25,28,30,31,32 This happens in a minority of cases of AVRT and typically will be associated with a decrementally conducting retrograde or an anterograde accessory pathway. Atriofascicular pathways with only unidirectional anterograde conduction appear to be more likely to demonstrate block with adenosine.31 It is not known whether the observed effect represents an indirect antiadrenergic response or whether poorly conducting pathways have an increase in ADO, Ach potassium channels. One must exercise some caution when using aden-

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TABLE II Response to Adenosine—Regular Wide Complex Tachycardia Persistent Atrial Tachycardia With Block in A-V Node

No Effect

Termination

Ventricular tachycardia due to reentry in coronary artery disease or cardiomyopathy

Reentrant SVT involving AV node with BBB*

Atrial flutter with BBB*

VT due to triggered activity or automaticity Sinus node reentry with BBB* Triggered atrial tachycardia with BBB* Automatic atrial tachycardia with BBB* (transient slowing/termination)

Reentrant atrial tachycardia with BBB*

* BBB Å bundle branch block aberration; SVT Å supraventricular tachyarrhythmia.

osine during AVRT. Shortening of the anterograde refractory period of accessory pathways coupled with induction of atrial fibrillation have been reported.33 Antidromic AVRT could also potentially, transiently accelerate and precipitate hemodynamic compromise (see also proarrhythmia).

EFFECT ON VENTRICULAR TACHYCARDIA (VT) Most VTs occur in the setting of long-term coronary artery disease or a diffuse cardiomyopathy. Tachycardias that occur in this setting have a presumed reentrant mechanism. Adenosine has no effect on this type of VT. Although adenosine has no direct effects on ventricular myocytes, it does exert an antiadrenergic effect. VT occurring in the absence of structural heart disease often appears to have a triggered and/or automatic mechanism with initiation of the arrhythmia potentiated by an increase in endogenous or infused catecholamines.11,12,34,35 A number of investigators have demonstrated the ability of adenosine to terminate these ‘‘normal heart VTs.’’34,36 These ‘‘normal heart VTs’’ typically originate from the right ventricular outflow tract and have a left bundle branch QRS configuration with an inferiorly directed frontal plane axis. Caution must be used in interpreting the response of a wide complex tachycardia to adenosine (Tables II and III). Termination of such rhythm with adenosine, as noted above, is neither 100% sensitive nor specific for diagnosing a supraventricular mechanism (Table II). Furthermore, the response can be easily influenced by the dose and mode of adenosine administration. Importantly, standard electrocardiographic criteria have been developed for distinguishing SVT vs VT. Individuals skilled in electrocardiographic interpretation can reliably distinguish SVT vs VT in ú95% of cases. DOSE AND ADMINISTRATION The effective dose of adenosine can vary greatly (Table IV). The drug is rapidly metabolized by erythrocytes and vascular endothelium. Clinical response to adenosine depends not only on the dose but also on the rapidity of the injection, the distance from the heart, the cardiac output, and the balance between adrenergic and vagal tone in individual patients. The half-life of adenosine, determined from in vitro studies in human blood, ranges from 0.6–10 34

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seconds.36 – 38 The clinical effectiveness is usually seen 10–20 seconds after bolus administration and lasts up to 20 seconds. Current package labeling suggests that the initial dose of 6 mg be given by rapid intravenous bolus injection over 1–2 seconds followed by a saline solution flush. If the tachycardia does not terminate within 1–2 minutes, 12 mg should be given as a rapid intravenous bolus. This 12-mg dose may be repeated a second time if required. Increasing the dose to 18 mg may, on occasion, be necessary. Of note, doses as low as 3 mg are often effective if administered through a central vein.39 A starting dose of 3 mg is appropriate if access to a central line is present. Dipyridamole, a blocker of cellular uptake of adenosine, inhibits the metabolism of adenosine in humans. Thus, a reduced dose should be used if adenosine is required. Conversely, methylxanthine compounds such as theophylline and caffeine are competitive inhibitors of the adenosine A1 receptor and can thus block or decrease its action.

MATERNAL AND PEDIATRIC USE Paroxysmal SVT is the most commonly seen sustained arrhythmia in pregnant women.40 Because of its rapid onset but brief duration of action, adenosine may have advantages over other agents—such as verapamil or digoxin—in the acute treatment of SVT after vagal maneuvers have failed. There are only limited data, but it appears that adenosine has no direct effect on the fetus when fetal monitoring is performed during bolus administration.41,42 In contrast, verapamil has been shown to cross the placental barrier43 and may affect fetal cardiovascular activity.44 Additionally, verapamil administration can precipitate prolonged maternal hypotension that could likewise produce untoward fetal hemodynamic effects. Moreover, both digoxin and verapamil have a longer onset of action than adenosine, thereby potentially exposing the fetus to compromised maternal hemodynamics from the arrhythmia for a greater period of time. Thus, our current recommendation would be to consider using adenosine as a first-line agent if other noninvasive measures (i.e., valsalva maneuver, carotid sinus massage, etc.) have failed. Adenosine is also now used as a first-line agent for SVT in the pediatric population.45 – 48 Efficacy rates appear comparable to acute verapamil administration; however, once again it has advantages in

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NONARRHYTHMIC SIDE EFFECTS AND COMPLICATIONS Adenosine has a relatively high frequency of adverse side effects. However, these side effects are usually brief and are not of serious consequence. The most common immediate side effects include flushing, dyspnea, and chest pain or pressure.23,25,26 The flushing results from peripheral vasodilation.23,51 Dyspnea is attributable to carotid body chemoreceptor activation52,53,54 and transient bronchoconstriction55 Although the duration of bronchoconstriction is brief, care should be taken in administering adenosine to patients with reactive airway disease. One case has been reported of bronchospasm in a known asthmatic after bolus injection of adenosine.56 Chest pain can occur in patients with and without coronary artery disease.57,58 The chest pain is most likely due to the presence of adenosine pain receptors located in the heart.57,58 Approximately one-third of patients will indicate that their symptoms are severe. It is advisable to warn patients of anticipated flushing and chest discomfort. Occasionally patients will find symptoms so intolerable that repeated episodes of SVT might be better treated with intravenously administered verapamil.

TABLE III Adenosine for Differential Diagnosis of Wide Complex Tachycardia—Limitations 1. Inadequate dosing or poor administration technique may suggest VT diagnosis when actually is SVT. 2. 5–10% of SVT involving AV node will not terminate with adenosine, suggesting VT. 3. Some VT (automatic/triggered) will terminate with adenosine and suggest diagnosis of SVT. 4. VPDs triggered by adenosine may terminate VT and suggest diagnosis of SVT. 5. Correct diagnosis based on standard ECG criteria without using adenosine (side effects) can be made in ú95% of wide complex tachycardias. SVT Å supraventricular tachyarrhythmia; VPD Å ventricular premature depolarization.

TABLE IV Adenosine Administration j Starting dose: 3–6 mg; increasing to 12–18 mg maximum j Rapid bolus (°1 second) followed by saline flush j Central administration associated with lower effective dose j Should see onset within 20 seconds j Maximum duration of effect Ç20 seconds j Decrease dose or withhold therapy if dipyridamole administered

j Increased dose may be required if theophylline administered

TABLE V Adenosine Versus Verapamil Considerations

Effective for SVT termination (AV node as part of circuit) Ultra-short duration of action Risk of congestive heart failure Vasodilatory collapse (wide complex tachycardia–VT) Cost (wholesale pharmacy cost for average dose)

Adenosine

Verapamil

Yes (ú90%) Yes No

Yes (ú90%) No Yes (low)

No

Yes

///($15)

/($1)

SVT Å supraventricular tachyarrhythmia.

TABLE VI Adenosine—Proarrhythmia 1. Arrhythmia terminationrasystole (due to unmasking underlying sinus node dysfunction/or prolonged adenosine response secondary to concomitant dipyridamole administration) 2. Frequent atrial and ventricular premature depolarizationsrreinitiate SVT 3. Precipitate atrial fibrillation due to shortening of atrial refractory period 4. Accelerate antidromic conduction over accessory pathway with rebound increase in catecholamines 5. Acceleration of atrial flutter after transient slowing due to rebound increase in catecholamines–Greatest risk for atrial flutter with slow atrial rate (õ250 P waves/min) 6. Bradycardia with ventricualr premature depolarizations potentiate ‘‘torsades de pointes’’ in the setting of long QT syndrome or unimorphic VT in patients with appropriate electrophysiology substrate

the acute treatment of SVT because of its rapid onset of action, and more importantly, because of a lower incidence of clinically significant hemodynamic depression attributable to its short duration of action (Table V).49,50

PROARRHYTHMIC COMPLICATIONS Pauses, sinus bradycardia, and transient asystole are often seen after adenosine (Table VI). These arrhythmia events are brief and have no clinical significance, although there are scattered reports of prolonged sinus bradycardia with syncope59 and prolonged asystole.60 In addition, patients with known sick sinus syndrome may be more susceptible to prolonged sinus failure after treatment of their SVT with adenosine. As noted above, extreme caution should also be exercised in giving adenosine to patients taking dipyridamole, as it serves as an adenosine transport blocking agent and can significantly prolong the adenosine effects.61 After bolus administration of adenosine, it is common to see premature atrial and ventricular depolarizations.28 These premature depolarizations can lead to reinitiation of reentrant arrhythmias.25,28,46 As previously discussed there is also a shortening of the atrial action potential that results in decreased atrial refractoriness.62,63 There are several reports of adenosine-induced atrial fibrillation.25,26,64 In most cases atrial fibrillation is self-limiting and without significance. However, atrial fibrillation coupled with a potential acceleration of accessory pathway antidromic conduction can be life threatening. There are several reports of adenosine-induced 1:1 AV conduction during atrial flutter.60,65,66 In general, there is a transient slowing in AV nodal conduction after adenosine bolus administration that can be followed by enhanced AV nodal conduction and a 1:1 ventricular response with adverse hemodynamic consequences. The tachycardia can further stimulate sympathetic activity, thus perpetuating enhanced AV nodal conduction. This has resulted in ventricular rates of up to 280 beats/min and the ne-

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cessity of emergent electrical cardioversion.60 Enhanced AV nodal conduction after adenosine most likely results from secondary increases in sympathetic nerve traffic and plasma catecholamine levels, as shown by Biaggioni et al.13 Finally, there have been reports of adenosineinduced torsades de pointes.67,68 One reported episode of torsades de pointes occurred in the setting of a QT interval of 520 msec and terminated spontaneously after 15 seconds.67 On follow-up electrocardiogram (ECG) several days after the episode the patient continued to demonstrate QT prolongation (QTc 555 msec). The bradycardic event associated with adenosine probably precipitated the arrhythmia event in the setting of QT prolongation. In another event described by Ben-Sorek and Wiesel,69 an 86year-old patient with a narrow complex tachycardia was given a 6-mg bolus of adenosine. This resulted in a 2.2-second pause with nonconducted atrial flutter waves, followed by a junctional escape complex, then by 6 beats of ventricular flutter at 300 beats/min that degenerated into ventricular fibrillation. The ECG pre- and post-resuscitation did not show a prolonged QT interval. It is evident that patients predisposed to ventricular tachyarrhythmias may manifest these sustained arrhythmia events triggered by the pauses and ventricular ectopy that commonly occurs after adenosine administration.

CONCLUSION Adenosine is now a popular agent in the acute management of tachyarrhythmias. The drug is very effective in terminating reentrant tachycardias involving the AV node. The observation that sinus node reentry tachycardia, as well as some atrial and ventricular tachycardias, terminate in response to adenosine administration point out the potential pitfalls of using the drug as a diagnostic tool. Effectiveness of the drug is clearly dependent on appropriate dosing and route of administration. Finally, although the drug rarely produces serious adverse effects, side effects are common. Acute dyspnea, flushing, and chest discomfort are common and patients should be forewarned. Rare but significant proarrhythmic consequences of adenosine administration have been observed. Recognition of their potential, coupled with prompt intervention at the time of their occurrence, should maximize the safe administration of adenosine in patients with arrhythmias.

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DiMarco JP, Sellers TD, Berne RM, West GA, Belardinelli L. Adenosine: electro-physiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation 1983;68:1254–1263. 24. Manolis AS, Estes AM. Supraventricular tachycardia mechanisms and therapy. Arch Intern Med 1987;147:1706–1716. 25. DiMarco JP, Miles W, Akhtar M, Milstein S, Sharma AD, Platia E, McGovern B, Scheinman MM, Govier WC. Adenosine for paroxysmal supraventricular tachycardia: dose ranging and comparison with verapamil. Ann Intern Med 1990;113:104–110. 26. DiMarco JP, Sellers TD, Lerman BB, Greenberg ML, Berne RM, Belardinelli L. Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias. J Am Coll Cardiol 1985;6:417–425. 27. Belhassen B, Glick A, Laniado S. Comparative clinical and electrophysiologic effects on adenosine triphosphate and verapamil on paroxsymal reciprocating junctional tachycardia. Circulation 1988;77:795–805. 28. Rankin AC, Oldroyd KG, Chong E, Rae AP, Cobbe SM. Value and limitations of adenosine in the diagnosis and treatment of narrow and broad complex tachycardias. Br Heart J 1989;62:195–203. 29. Garratt C, Linker N, Griffith M, Ward D, Camm AJ. Comparison of adenosine and verapamil for termination of paroxysmal junctional tachycardia. Am J Cardiol 1989;64:1310–1316. 30. Rinne C, Sharma AD, Klein GJ, Yee R, Szabo T. Comparative effects of adenosine triphosphate on accessory pathway and atrioventricular nodal conduction. Am Heart J 1988;115:1042–1047. 31. Li HG, Morillo CA, Zardini M, Thakur RK, Yee R, Klein GJ. Effect of adenosine or adenosine triphosphate on antidromic tachycardia. J Am Coll Cardiol 1994;24(3):728–731. 32. Fishberger SB, Saul JP, Triedman JK, Epstein MR, Walsh EP. Use of adenosine-sensitive nondecremental accessory pathways in assessing the results of radio-frequency catheter ablation. Am J Cardiol 1995;75:1278–1281. 33. 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