Vot . 19. No . 2 February 1992 :353-9 IACC
353
Editorial Comment
Epinephrine :, Infusion During Antiarrhythmic Drug Evaluations : Toward a Better Understanding of Drug Activity* JOHN P . DiMARCO, MD, PHD, FACC Chartnrte:vi/fe . Virginia
Serial electrophysiologic testing for the assessment of antiarrhythmic drug therapy has been widely used for >15 years and is the recommended approach in patients with life • threatening arrhythmias. Previous studies have shown that for every drug evaluated to date, patients in whom the agent suppresses induction of ventricular tachycardia have a lower recurrence rate of sustained arrhythmia than do patients in whom an arrhythmia can be induced on the discharge antiarrhythmic regimen . However . arrhythmia recurrences do occur, even in patients whose arrhythmias are suppressed by electropltysiologic criteria, for reasons that may he difficult to discern . Lack of compliance with an often complex drug schedule, changes in the nature or drug sensitivity of the original arrhythmia, development of new and different arrhythmias that may be resistant and transient alterations in neurohumoral or hemodynamic factors must all be considered as possible contributors to drug failure . The present study. In this issue of the Journal, Calkins et al . (1) examine the potential reversibility by catecholamine infesion of the antiarrhythmic effects of two commonly used agents, quinidine and amiodanne, in patients with inducible sustained ventricular tachycardia . After selected baseline measurements (sinus cycle length, QT interval and right ventricular effective refractory period) were obtained, patients received an infusion of epinephrine tfat produced a plasma epinephrine concentration similar to that seen during mild or maximal physical exertion or stress . Similar elect,-ophysiologic measurements during basal conditions and d firing epinephrine infusions were made after oral therapy with quinidine and then amiodarone . The authors (1) report that epinephrine partially or completely reversed the effects of both quinidine and amindarone on sinus cycle length and QT interval. However, decreases in ventricular effective refractory period in response to epinephrine were much smaller
'Falitorials published it Joamaf of the Anne-, College of Cardiology reflect the views of the archers and do not necessa sly represent the views of IACC or the A-500 College of Cardiology. From the Division of Cardiology. Department of internal Medicine . University of Virginia Health Sciences Center . Charlottesville. Virginia . Address for rennet, : John P. DsMarco, MD . PhD, Cardiology Division, Sox 158, University of Virginia Health Silences Center. Chariouesvttle .
VirgiNa 22908 . ©i592 by the
Ameriran Cnttege or Catiotogr
during treatment with amiodarone than those observed in the baseline study or in the presence of quinidine. Even though catecholamine infusions have been reported (2,3) to reverse suppression of ventricular tachycardia induction by many class I antiarrhythmic agents, no such reversal was seen in a small number of patients whose tachycardia became noninducihle during amindarone therapy, Clinical significance. The results of this study are consistent with prior observations. Reversibility of the electricphysiologic effects of class I agents by catecholamine infusions has been previously reported (2 .3) . Amiodarone possesses intrinsic noncompetitive beta-adrenergic blocking activity that appears early during the course of therapy (4) and should be maximal after 9 to 10 days of higl, dose (1,800 mglday) therapy (4,5) . Therefore, antagonism of the effects of epinephrine in amiodarnne-treated patients is not surprising . but can this observation explain an assumed increased efficacy of amiodarone during long-term therapy? Amindarv ne occupies a unique position in the therapy of seriou. ; ventricular arrhythmias for several reasons . Although numerous adverse effects may occur during longterm therapy, amiodarone is surprisingly well tolerated during the early phases of treatment . The drug's unusual pharmacokinetic profile allows once-a-day dosing after loading and lack of patient compliance for even many days after a steady state has been reached entails only a modest risk of loss of efficacy . Because of the long loading period required to achie"e full antiarrhythmic effects, amiodarone is most often used after prior drug failures and, in contrast to the pattern seen with other drugs, patients often continue taking it even if the arrhythmia remains inducible during treatment . No study has directly compared in a controlled fashion arrhythria recurrence during amiodarone treatment versus that during treatment with other drugs . Calkins et al . (1) are correct that some studies have reported 2-year recurrence rate' >3O% in patients with arrhythmias suppressed by antiarrhythmic drugs, but these results were found in early trials and the evaluation protocols used would now be considered prone to error (6) . More recent data (7,8) do not suggest a major drug-specific difference in recurrence rates of arrhythmias controlled by the discharge regimen . With all drugs evaluated by current stimulation protocols, arrhythmia recurrence rates in patients with suppression of induction appear to be < 10% at 2 years. Should we then routinely use catecholamine infusion to aid in the short-term evaluation of antiarrhythmic drugs? T he percent of drug failures in patients whose arrhythmia responds to therapy appears low enough to favor only selected use of catecholamine challenge in routine clinical practice . Current protocols may already be too rigorous, in that many patients treated with a drug that does not suppress ventricular tachycardia induction will remain arrhythmia free during long-term therapy with that agent. Amiodarone may be no different from other drugs in this regard (9). Responses to catecholamine infusion might be helpful in 0735-t09b97/55.00
354
DIMARCO EDITORIAL COMMENT
identifying potential drug failure in these patients if a marker for failure could be identified . It may also be possible to use catecholamine infusions to identify patients with a high potential for proarrhythmia, particularly with drugs such as flecainide or eecainide that have significant use-dependent electrophysiologic effects . Conclusions . The abservations in this study (1) are important, fn addition to reversal of antian hythmic drug activity, beta-adrenergic activity has many potential detrimental effects on arrhythmias, As a group, beta-adrenergic blocking agents have been convincingly shown to decrease mortality in postmyocardial infarction patients and are also effective in preventing myocardial ischemia . The possible addition of a beta-adrenergic blocker to therapy with any antiarrhythmic drug without intensive beta-blocking properties should always be considered .
JACC Vol . 19.N. .2 February 1992353- 4
2. Jazuyen MR, VorWyh . G, Auaall B, McKinnie J . Tchou P. Akhtar M . Isoprorcrenol reversal of antianhythmic effects in patients with inducible sustained vemricular lachyanhylhmias . J Am Coll Cordiol 1989 ;14,705-1 I . 3 . Morady F. Kw Win, wedi,h All, st al Antagonism of quinidine*, electrophysioiogic etems by epinephrine in pouters with ventricular nehyeardie. J Am Cal Cardwl 1988 ;12 .380-9I . 4.'inch-11 LB, Wp,e DG, Gillis AM . Dub Hl . Elenrophannacology of amiodaronr serepy initiation : time course of onset of elecraphysiologic and antia,`gthmlc effects . Circulation 1909:00 .34-42 . 5 . Radish AH,Ch-en R-F,Schmaltz S .MowdyF.Magnitude andtime course of beta-adrenergic antagonism during cral amiodaroro therapy . J Am Coll Candid 1990 :16:1240-5 . 6. Mason JW.Winkle 11A . .lccurecyoftheventnculartachycardiainduction study for predicting long-term efficacy and inefi :asy of antianhythmic drugs. N EngiI Med 1900 :303:1073-7 . 7. Rae AP, Greenspan AM, Spiel ... SR, et d. Ant-rhythmic drug efficacy for ventricular lachyarrhythmias associated with coronary artery disease as assessed by eleclrophysiologic studies . Am I cordial 1985 ;551494-9 .
References
S. Zhu J. Haines DE, Lesman BB, DiMarco JP. Predictors of efficacy of mi+daeone and than nistics of recurrence of arrhythmia in patient, with sustained ventricular tachycardia and coronary artery disease . Circulation 1907 ;76:002-9 .
1 . Can.ins H . Sousa J. El Atassi R . Schmaltz S. Kadish A. Mordy F . Reversal of antianhythmic drug effects by epinephrine: quinidine versus amiodarone .I Am Coll Cardio] 1992 ;19347-52.
9. Fongaras RN, Fiedler BB, Elves 11 . Empirrc amiodarone -its "nieffee . tire'' drug therapy in patients with refractory ventricular lachyarrhylh . mias. PACE 1988:11 :1009-17.
353
Editorial Comment
Epinephrine :, Infusion During Antiarrhythmic Drug Evaluations : Toward a Better Understanding of Drug Activity* JOHN P . DiMARCO, MD, PHD, FACC Chartnrte:vi/fe . Virginia
Serial electrophysiologic testing for the assessment of antiarrhythmic drug therapy has been widely used for >15 years and is the recommended approach in patients with life • threatening arrhythmias. Previous studies have shown that for every drug evaluated to date, patients in whom the agent suppresses induction of ventricular tachycardia have a lower recurrence rate of sustained arrhythmia than do patients in whom an arrhythmia can be induced on the discharge antiarrhythmic regimen . However . arrhythmia recurrences do occur, even in patients whose arrhythmias are suppressed by electropltysiologic criteria, for reasons that may he difficult to discern . Lack of compliance with an often complex drug schedule, changes in the nature or drug sensitivity of the original arrhythmia, development of new and different arrhythmias that may be resistant and transient alterations in neurohumoral or hemodynamic factors must all be considered as possible contributors to drug failure . The present study. In this issue of the Journal, Calkins et al . (1) examine the potential reversibility by catecholamine infesion of the antiarrhythmic effects of two commonly used agents, quinidine and amiodanne, in patients with inducible sustained ventricular tachycardia . After selected baseline measurements (sinus cycle length, QT interval and right ventricular effective refractory period) were obtained, patients received an infusion of epinephrine tfat produced a plasma epinephrine concentration similar to that seen during mild or maximal physical exertion or stress . Similar elect,-ophysiologic measurements during basal conditions and d firing epinephrine infusions were made after oral therapy with quinidine and then amiodarone . The authors (1) report that epinephrine partially or completely reversed the effects of both quinidine and amindarone on sinus cycle length and QT interval. However, decreases in ventricular effective refractory period in response to epinephrine were much smaller
'Falitorials published it Joamaf of the Anne-, College of Cardiology reflect the views of the archers and do not necessa sly represent the views of IACC or the A-500 College of Cardiology. From the Division of Cardiology. Department of internal Medicine . University of Virginia Health Sciences Center . Charlottesville. Virginia . Address for rennet, : John P. DsMarco, MD . PhD, Cardiology Division, Sox 158, University of Virginia Health Silences Center. Chariouesvttle .
VirgiNa 22908 . ©i592 by the
Ameriran Cnttege or Catiotogr
during treatment with amiodarone than those observed in the baseline study or in the presence of quinidine. Even though catecholamine infusions have been reported (2,3) to reverse suppression of ventricular tachycardia induction by many class I antiarrhythmic agents, no such reversal was seen in a small number of patients whose tachycardia became noninducihle during amindarone therapy, Clinical significance. The results of this study are consistent with prior observations. Reversibility of the electricphysiologic effects of class I agents by catecholamine infusions has been previously reported (2 .3) . Amiodarone possesses intrinsic noncompetitive beta-adrenergic blocking activity that appears early during the course of therapy (4) and should be maximal after 9 to 10 days of higl, dose (1,800 mglday) therapy (4,5) . Therefore, antagonism of the effects of epinephrine in amiodarnne-treated patients is not surprising . but can this observation explain an assumed increased efficacy of amiodarone during long-term therapy? Amindarv ne occupies a unique position in the therapy of seriou. ; ventricular arrhythmias for several reasons . Although numerous adverse effects may occur during longterm therapy, amiodarone is surprisingly well tolerated during the early phases of treatment . The drug's unusual pharmacokinetic profile allows once-a-day dosing after loading and lack of patient compliance for even many days after a steady state has been reached entails only a modest risk of loss of efficacy . Because of the long loading period required to achie"e full antiarrhythmic effects, amiodarone is most often used after prior drug failures and, in contrast to the pattern seen with other drugs, patients often continue taking it even if the arrhythmia remains inducible during treatment . No study has directly compared in a controlled fashion arrhythria recurrence during amiodarone treatment versus that during treatment with other drugs . Calkins et al . (1) are correct that some studies have reported 2-year recurrence rate' >3O% in patients with arrhythmias suppressed by antiarrhythmic drugs, but these results were found in early trials and the evaluation protocols used would now be considered prone to error (6) . More recent data (7,8) do not suggest a major drug-specific difference in recurrence rates of arrhythmias controlled by the discharge regimen . With all drugs evaluated by current stimulation protocols, arrhythmia recurrence rates in patients with suppression of induction appear to be < 10% at 2 years. Should we then routinely use catecholamine infusion to aid in the short-term evaluation of antiarrhythmic drugs? T he percent of drug failures in patients whose arrhythmia responds to therapy appears low enough to favor only selected use of catecholamine challenge in routine clinical practice . Current protocols may already be too rigorous, in that many patients treated with a drug that does not suppress ventricular tachycardia induction will remain arrhythmia free during long-term therapy with that agent. Amiodarone may be no different from other drugs in this regard (9). Responses to catecholamine infusion might be helpful in 0735-t09b97/55.00
354
DIMARCO EDITORIAL COMMENT
identifying potential drug failure in these patients if a marker for failure could be identified . It may also be possible to use catecholamine infusions to identify patients with a high potential for proarrhythmia, particularly with drugs such as flecainide or eecainide that have significant use-dependent electrophysiologic effects . Conclusions . The abservations in this study (1) are important, fn addition to reversal of antian hythmic drug activity, beta-adrenergic activity has many potential detrimental effects on arrhythmias, As a group, beta-adrenergic blocking agents have been convincingly shown to decrease mortality in postmyocardial infarction patients and are also effective in preventing myocardial ischemia . The possible addition of a beta-adrenergic blocker to therapy with any antiarrhythmic drug without intensive beta-blocking properties should always be considered .
JACC Vol . 19.N. .2 February 1992353- 4
2. Jazuyen MR, VorWyh . G, Auaall B, McKinnie J . Tchou P. Akhtar M . Isoprorcrenol reversal of antianhythmic effects in patients with inducible sustained vemricular lachyanhylhmias . J Am Coll Cordiol 1989 ;14,705-1 I . 3 . Morady F. Kw Win, wedi,h All, st al Antagonism of quinidine*, electrophysioiogic etems by epinephrine in pouters with ventricular nehyeardie. J Am Cal Cardwl 1988 ;12 .380-9I . 4.'inch-11 LB, Wp,e DG, Gillis AM . Dub Hl . Elenrophannacology of amiodaronr serepy initiation : time course of onset of elecraphysiologic and antia,`gthmlc effects . Circulation 1909:00 .34-42 . 5 . Radish AH,Ch-en R-F,Schmaltz S .MowdyF.Magnitude andtime course of beta-adrenergic antagonism during cral amiodaroro therapy . J Am Coll Candid 1990 :16:1240-5 . 6. Mason JW.Winkle 11A . .lccurecyoftheventnculartachycardiainduction study for predicting long-term efficacy and inefi :asy of antianhythmic drugs. N EngiI Med 1900 :303:1073-7 . 7. Rae AP, Greenspan AM, Spiel ... SR, et d. Ant-rhythmic drug efficacy for ventricular lachyarrhythmias associated with coronary artery disease as assessed by eleclrophysiologic studies . Am I cordial 1985 ;551494-9 .
References
S. Zhu J. Haines DE, Lesman BB, DiMarco JP. Predictors of efficacy of mi+daeone and than nistics of recurrence of arrhythmia in patient, with sustained ventricular tachycardia and coronary artery disease . Circulation 1907 ;76:002-9 .
1 . Can.ins H . Sousa J. El Atassi R . Schmaltz S. Kadish A. Mordy F . Reversal of antianhythmic drug effects by epinephrine: quinidine versus amiodarone .I Am Coll Cardio] 1992 ;19347-52.
9. Fongaras RN, Fiedler BB, Elves 11 . Empirrc amiodarone -its "nieffee . tire'' drug therapy in patients with refractory ventricular lachyarrhylh . mias. PACE 1988:11 :1009-17.
