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Promising News About Antiarrhythmic Drug Therapy
Promising News About Antiarrhythmic Drug Therapy by William A. Check, PhD
Negative trends in drug treatment for cardiac arrhythmias seem to be reversing, according to information released at a recent cardiology meeting.
M
times during the past few adenosine are currently approved years, pharmacologic treatfor their indications; an FDA advient of cardiac arrhythmias sory committee has recommended has seemed to take more steps approving sotalol. New evidence was most abundant backward than forward. In 1989, study coordinators prematurely for sotalol, a beta-blocker with terminated one arm of the Cardiac unique antiarrhythmic properties. Arrhythmia Suppression Trial Sotalol differs from standard beta(CAST), in which patients were blockers in that it prolongs the retreated with the class 1C drugs enfractory period. In a trial reported by Johannes Brachmann, MD, of the cainide and flecainide, because these two drugs increased the rate University of Heidelberg, Germany, of sudden cardiac deaths. Then, as part of its ongoing review of generic versions of proprietary prescription medications, the U.S. Food and Drug Administration (FDA) reconsidered four drugs for treating cardiac arrhythmiasprocainamide HCI, disopyramide phosphate, quinidine sulfate, and quinidine gluconate. In February 1990, FDA downgraded the generic formulation of one of these drugs, disopyramide phosphate, from the "AB" classification (equivalent to the innovator product) to "BX" (inequivalent), considered a prepara- Atrioventricular tion for revoking approval. Node However, at this year's 40th An- Electrical Conduction Systems of the Heart nual Scientific Session of the Amersotalol was compared to five other ican College of Cardiology, the antiarrhythmic drugs in patients trend moved toward positive findwith VTA. During programmed elecings. Favorable information was trical stimulation, sotalol proved to presented about three drugs: sobe the most effective agent for suptalol, which is effective against both pressing VTA (see chart, next page). ventricular tachyarrhythmias Fifty-three patients whose VTA was (VTA) and supraventricular tachysuppressed by sotalol were disarrhythmias (SVT); moricizine, for charged on the drug. During an avlife-threatening VTA; and adenoerage follow-up of 33 months, sudsine, for SVT. Moricizine and
American Pharmacy, Vol. NS31, No.8 August 19911567
den coronary death occurred in three (5.6%) patients. "Such a low death rate in this population is a very favorable result," Brachmann said. He and his colleagues now use sotalol as the drug of first choice in patients with malignant VTA. Sotalol is particularly effective against refractory arrhythmias, reported Andrew C. Rankin, MD, a fellow in cardiology at the Massachusetts General Hospital. In this trial, sotalol was tested in 161 patients with spontaneous VTA. Coronary artery disease was present in 81 % of patients and the mean left ventricular ejection fraction was 40%. Patients had previously failed therapeutic trials with from one to seven drugs. Following electrophysiologic testing, 79 patients were discharged on sotalol. During a followup with a mean of 16 months, arrhythmias occurred in 20 patients. Six patients died, five from sudden cardiac death. Actuarial arrhythmia-free survival in patients taking sotalol after hospital discharge was 88% at six months, 78% at one year, and 65% at two years. Eight patients discontinued therapy due to side effects. Rankin concluded that "in selected patients, sotalol is a well-tolerated antiarrhythmic drug and, when inducible VT or VF is suppressed, it provides effective longterm therapy." For SVT treatment, James L. Cockrell, MD, Chief of Electrophysiology at Letterman Army Medical
27
Center in San Francisco, did a blind clinical trial with sotalol in 23 symptomatic patients. Termination of SVT was seen in six of nine patients receiving low-dose (1.0 mg/kg IV) sotalol and in four of seven treated with a higher dose (1.5 mg/kg). No SVT termination was seen in seven patients on placebo. Patients whose SVT did not terminate on the first injection were advanced to an open-label dose of 1.5 mg/kg sotalol. SVT termination was achieved in seven of 13 with the higher dose. Because sotalol is a beta-blocker, it needs to be used carefully in patients with coexisting VTA and congestive heart failure. Considerable attention was given to the dropping of encainide and flecainide from CAST, which Craig M. Pratt, MD, said was a "disaster." Pratt, who is director of clinical cardiology research at Baylor College of Medicine, pointed out that "moricizine was lost in the fuss about encainide and flecainide." Moricizine is still being tested in the CAST trial for treatment of ventricular arrhythmias. Although mortality data are not out yet, Pratt said that we can at least infer that moricizine is safe, since the trial is continuing. This is particularly impressive since the protocol was changed after applying encainide and flecainide, for example
accepting patients with ejection fractions <40%. Moricizine has thus been used in over 1,000 patients sicker than those initially enrolled. "That makes a fairly strong statement about safety," Pratt said, adding, "We have so little long-term safety data on any antiarrhythmic drug." In addition, Pratt said, moricizine may provide important information about designing safer antiarrhythmic drugs because it has different electrophysiologic properties than encainide and flecainide. "Perhaps," he suggested, "those differences between moricizine and other class Ie drugs explains the safety difference." Adenosine is a natural biological compound, an intracellular messenger that is now being used for terminating SVT. Controlled trials showed that it is at least 92% effective in this context. During a round-table discussion, cardiologists related their experience with adenosine during the year that it had been available. John P. DeMarco, MD, director of the Clinical Physiology Laboratory at the University of Virginia Health Science Center, noted that, with adenosine, "for the first time we've had the chance reversibly and reliably to manipulate the AV [atrioventricular] node. For the first time we can essentially turn the AV
Comparative Efficacy of Six Antiarrhythmic Agents Against Sustained Ventricular Tachyarrhythmias Drug
Sotalol Quinidine Propafenone Mexiletine Procainamide Amiodaronef o
node on and off." This is because adenosine is a natural modulator of AV activity. Most important, says DeMarco, with adenosine one can reliably break conduction through the AV node. "We know that the majority of the time, once you break the arrhythmia it stays broken," DeMarco noted. He believes that the efficacy and safety of adenosine have been proven sufficiently so that it will be widely used in emergency rooms and cardiac care units in community hospitals. Adenosine's safety is due to its very short half-life, said Brian A. McGovern, MD, co-director of the Cardiac Arrhythmias Service at the Massachusetts General Hospital. Because of its short half-life, "adverse effects wouldn't cause a clinical problem," he said. Adenosine is as efficacious for termination of SVT as verapamil, the most widely used agent, McGovern said, but verapamil has more side effects. In a patient in whom safety might be an issue, such as someone with very low blood pressure, McGovern would use adenosine. On the other hand, he noted, verapamil has been used longer and a generic version is available. Michael L. Epstein, MD, agreed that adenosine is now an acceptable alternative to verapamil. Epstein, who is chief of pediatric cardiology at Shands Hospital of the University of Florida, Gainesville, pointed out that adenosine can also be used as a diagnostic agent. It is not always clear from a surface electrocardiogram whether a tachycardia is due to the AV node, especially in the emergency room. Adenosine is specific for the AV node. If mechanisms other than the AV node are operating, adenosine stops AV nodal activity and reveals any remaining pathways, e.g., accessory tracts for atrial flutter. Cardiac arrhythmias of all types represent a constant challenge. The addition of three new agents to treat VTA and/or SVT would help cardiologists to meet that challenge more effectively. William A. Check, PhD, is a medical writer based in Atlanta.
28
American Pharmacy, Vol. NS31, No.8 August 1991/568
Negative trends in drug treatment for cardiac arrhythmias seem to be reversing, according to information released at a recent cardiology meeting.
M
times during the past few adenosine are currently approved years, pharmacologic treatfor their indications; an FDA advient of cardiac arrhythmias sory committee has recommended has seemed to take more steps approving sotalol. New evidence was most abundant backward than forward. In 1989, study coordinators prematurely for sotalol, a beta-blocker with terminated one arm of the Cardiac unique antiarrhythmic properties. Arrhythmia Suppression Trial Sotalol differs from standard beta(CAST), in which patients were blockers in that it prolongs the retreated with the class 1C drugs enfractory period. In a trial reported by Johannes Brachmann, MD, of the cainide and flecainide, because these two drugs increased the rate University of Heidelberg, Germany, of sudden cardiac deaths. Then, as part of its ongoing review of generic versions of proprietary prescription medications, the U.S. Food and Drug Administration (FDA) reconsidered four drugs for treating cardiac arrhythmiasprocainamide HCI, disopyramide phosphate, quinidine sulfate, and quinidine gluconate. In February 1990, FDA downgraded the generic formulation of one of these drugs, disopyramide phosphate, from the "AB" classification (equivalent to the innovator product) to "BX" (inequivalent), considered a prepara- Atrioventricular tion for revoking approval. Node However, at this year's 40th An- Electrical Conduction Systems of the Heart nual Scientific Session of the Amersotalol was compared to five other ican College of Cardiology, the antiarrhythmic drugs in patients trend moved toward positive findwith VTA. During programmed elecings. Favorable information was trical stimulation, sotalol proved to presented about three drugs: sobe the most effective agent for suptalol, which is effective against both pressing VTA (see chart, next page). ventricular tachyarrhythmias Fifty-three patients whose VTA was (VTA) and supraventricular tachysuppressed by sotalol were disarrhythmias (SVT); moricizine, for charged on the drug. During an avlife-threatening VTA; and adenoerage follow-up of 33 months, sudsine, for SVT. Moricizine and
American Pharmacy, Vol. NS31, No.8 August 19911567
den coronary death occurred in three (5.6%) patients. "Such a low death rate in this population is a very favorable result," Brachmann said. He and his colleagues now use sotalol as the drug of first choice in patients with malignant VTA. Sotalol is particularly effective against refractory arrhythmias, reported Andrew C. Rankin, MD, a fellow in cardiology at the Massachusetts General Hospital. In this trial, sotalol was tested in 161 patients with spontaneous VTA. Coronary artery disease was present in 81 % of patients and the mean left ventricular ejection fraction was 40%. Patients had previously failed therapeutic trials with from one to seven drugs. Following electrophysiologic testing, 79 patients were discharged on sotalol. During a followup with a mean of 16 months, arrhythmias occurred in 20 patients. Six patients died, five from sudden cardiac death. Actuarial arrhythmia-free survival in patients taking sotalol after hospital discharge was 88% at six months, 78% at one year, and 65% at two years. Eight patients discontinued therapy due to side effects. Rankin concluded that "in selected patients, sotalol is a well-tolerated antiarrhythmic drug and, when inducible VT or VF is suppressed, it provides effective longterm therapy." For SVT treatment, James L. Cockrell, MD, Chief of Electrophysiology at Letterman Army Medical
27
Center in San Francisco, did a blind clinical trial with sotalol in 23 symptomatic patients. Termination of SVT was seen in six of nine patients receiving low-dose (1.0 mg/kg IV) sotalol and in four of seven treated with a higher dose (1.5 mg/kg). No SVT termination was seen in seven patients on placebo. Patients whose SVT did not terminate on the first injection were advanced to an open-label dose of 1.5 mg/kg sotalol. SVT termination was achieved in seven of 13 with the higher dose. Because sotalol is a beta-blocker, it needs to be used carefully in patients with coexisting VTA and congestive heart failure. Considerable attention was given to the dropping of encainide and flecainide from CAST, which Craig M. Pratt, MD, said was a "disaster." Pratt, who is director of clinical cardiology research at Baylor College of Medicine, pointed out that "moricizine was lost in the fuss about encainide and flecainide." Moricizine is still being tested in the CAST trial for treatment of ventricular arrhythmias. Although mortality data are not out yet, Pratt said that we can at least infer that moricizine is safe, since the trial is continuing. This is particularly impressive since the protocol was changed after applying encainide and flecainide, for example
accepting patients with ejection fractions <40%. Moricizine has thus been used in over 1,000 patients sicker than those initially enrolled. "That makes a fairly strong statement about safety," Pratt said, adding, "We have so little long-term safety data on any antiarrhythmic drug." In addition, Pratt said, moricizine may provide important information about designing safer antiarrhythmic drugs because it has different electrophysiologic properties than encainide and flecainide. "Perhaps," he suggested, "those differences between moricizine and other class Ie drugs explains the safety difference." Adenosine is a natural biological compound, an intracellular messenger that is now being used for terminating SVT. Controlled trials showed that it is at least 92% effective in this context. During a round-table discussion, cardiologists related their experience with adenosine during the year that it had been available. John P. DeMarco, MD, director of the Clinical Physiology Laboratory at the University of Virginia Health Science Center, noted that, with adenosine, "for the first time we've had the chance reversibly and reliably to manipulate the AV [atrioventricular] node. For the first time we can essentially turn the AV
Comparative Efficacy of Six Antiarrhythmic Agents Against Sustained Ventricular Tachyarrhythmias Drug
Sotalol Quinidine Propafenone Mexiletine Procainamide Amiodaronef o
node on and off." This is because adenosine is a natural modulator of AV activity. Most important, says DeMarco, with adenosine one can reliably break conduction through the AV node. "We know that the majority of the time, once you break the arrhythmia it stays broken," DeMarco noted. He believes that the efficacy and safety of adenosine have been proven sufficiently so that it will be widely used in emergency rooms and cardiac care units in community hospitals. Adenosine's safety is due to its very short half-life, said Brian A. McGovern, MD, co-director of the Cardiac Arrhythmias Service at the Massachusetts General Hospital. Because of its short half-life, "adverse effects wouldn't cause a clinical problem," he said. Adenosine is as efficacious for termination of SVT as verapamil, the most widely used agent, McGovern said, but verapamil has more side effects. In a patient in whom safety might be an issue, such as someone with very low blood pressure, McGovern would use adenosine. On the other hand, he noted, verapamil has been used longer and a generic version is available. Michael L. Epstein, MD, agreed that adenosine is now an acceptable alternative to verapamil. Epstein, who is chief of pediatric cardiology at Shands Hospital of the University of Florida, Gainesville, pointed out that adenosine can also be used as a diagnostic agent. It is not always clear from a surface electrocardiogram whether a tachycardia is due to the AV node, especially in the emergency room. Adenosine is specific for the AV node. If mechanisms other than the AV node are operating, adenosine stops AV nodal activity and reveals any remaining pathways, e.g., accessory tracts for atrial flutter. Cardiac arrhythmias of all types represent a constant challenge. The addition of three new agents to treat VTA and/or SVT would help cardiologists to meet that challenge more effectively. William A. Check, PhD, is a medical writer based in Atlanta.
28
American Pharmacy, Vol. NS31, No.8 August 1991/568