(Circulation. 2000;102:2385.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Efficacy and Safety of Oral Dofetilide in Converting to and Maintaining Sinus Rhythm in Patients With Chronic Atrial Fibrillation or Atrial Flutter
The Symptomatic Atrial Fibrillation Investigative Research on Dofetilide (SAFIRE-D) Study
From Veterans Affairs Medical Center, Washington, DC (S.S.); James A. Haley Medical Center (R.G.Z.), Tampa, Fla; Cardiology Associates Medical Group of East San Diego, Inc (L.Y.), San Diego, Calif; the Division of Cardiology, University of California–Irvine Medical Center (M.A.B.); the Division of Cardiology, University of California–San Diego Medical Center (G.K.F.); the Division of Cardiology, Presbyterian Hospital of Dallas (M.B.), Dallas, Tex; and Pfizer Inc (C.B.B.), Groton, Conn.
Correspondence to Dr Steven Singh, Veterans Affairs Medical Center, 50 Irving St NW, Room 1E301, Washington, DC 20422. E-mail snsingh{at}erols.com
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Abstract |
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Background—This double-blind, multicenter, placebo-controlled study determined the efficacy and safety of dofetilide in converting atrial fibrillation (AF) or atrial flutter (AFl) to sinus rhythm (SR) and maintaining SR for 1 year.
Methods and Results—Patients with AF or AFl (n=325) were randomized to 125, 250, or 500 µg dofetilide or placebo twice daily. Dosages were adjusted for QTc response and, after 105 patients were enrolled, for calculated creatinine clearance (ClCr). Pharmacological cardioversion rates for 125, 250, and 500 µg dofetilide were 6.1%, 9.8%, and 29.9%, respectively, versus 1.2% for placebo (250 and 500 µg versus placebo; P=0.015 and P<0.001, respectively). Seventy percent of pharmacological cardioversions with dofetilide were achieved in 24 hours and 91% in 36 hours. For the 250 patients who successfully cardioverted pharmacologically or electrically, the probability of remaining in SR at 1 year was 0.40, 0.37, 0.58 for 125, 250, and 500 µg dofetilide, respectively, and 0.25 for placebo (500 µg versus placebo, P=0.001). Two cases of torsade de pointes occurred, 1 on day 2 and the other on day 3 (0.8% of all patients given active drug); 1 sudden cardiac death, classified as proarrhythmic, occurred on day 8 (0.4% of all patients given active drug).
Conclusions—Dofetilide, a new class III antiarrhythmic agent, is moderately effective in cardioverting AF or AFl to SR and significantly effective in maintaining SR for 1 year. In-hospital initiation and dosage adjustment based on QTc and ClCr are necessary to minimize a small but nonnegligible proarrhythmic risk.
Key Words: antiarrhythmia agents • arrhythmia • fibrillation • atrial flutter
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Introduction |
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Atrial fibrillation (AF), one of the most common arrhythmias, is associated with symptomatic impairment and decreased quality of life, and it carries a substantial risk of stroke in patients with risk factors.1 2
Dofetilide, a new class III antiarrhythmic agent, selectively blocks the rapid component of the delayed rectifier potassium channel (IKr) in cardiac cells,3 producing dose-dependent increases in atrial and ventricular refractory periods4 and QT intervals.5 6 The Danish Investigations of Arrhythmia and Mortality on Dofetilide–Congestive Heart Failure (DIAMOND-CHF) showed that dofetilide has no adverse effect on mortality rates in severely ill patients with left ventricular dysfunction and advanced heart failure.7 The Symptomatic Atrial Fibrillation Investigative Research on Dofetilide (SAFIRE-D) study measured the efficacy and safety of dofetilide in the conversion to and the maintenance of sinus rhythm (SR). The study also assessed the effect of SR on symptoms and cardiac function. These data will be presented separately.
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Methods |
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Study Design and Patient Population
This double-blind, multicenter, placebo-controlled, dose-ranging study began with an in-hospital conversion phase of 3 days or 5 doses, followed by a 12-month maintenance phase. During the conversion phase, the effects of 3 dosages of dofetilide and placebo on conversion of AF/atrial flutter (AFl) to SR were compared. During the maintenance phase, the times to first relapse to AF/AFl with dofetilide and placebo were compared.
The institutional review board in each study center approved the protocol. After providing informed consent, patients 18 to 85 years of age with AF/AFl for 2 to 26 weeks, confirmed by ECG, were screened. Exclusion criteria are listed below.
Patients were admitted to telemetry for a minimum of 3 days. In patients who received a minimum of 5 doses of study drug without converting pharmacologically, electrical cardioversion was attempted. Converted patients were monitored for an additional 24 hours after conversion and then entered the outpatient maintenance phase. Patients whose SR could not be restored or maintained for 24 hours after conversion were withdrawn from the study. Anticoagulation therapy was initiated before conversion and continued for a minimum of 3 to 4 weeks after SR was established but could be continued throughout the trial, depending on local practice. Patients with contraindications to warfarin therapy were treated according to local practice.
Follow-up clinic visits were scheduled at 2 weeks, 1, 2, and 3 months, and at 3-month intervals thereafter until 1 of the study end points—relapse to AF or AFl for at least 24 hours, as documented by ECG, or maintenance of SR for a full year—was reached. Twelve-month survival data were collected for all randomized patients irrespective of treatment duration.
Exclusion Criteria
Patients with the following characteristics were excluded
from participating in the cardioversion phase of the trial: women of
childbearing potential; inability to tolerate withdrawal from current
antiarrhythmic therapy; syncope of unknown origin in the preceding 6
months; active thyrotoxicosis, AF, or AFl from reversible noncardiac
diseases; uncompensated or rapidly progressive congestive heart
failure; myocardial infarction or unstable angina pectoris within the
preceding month or percutaneous transluminal
coronary angioplasty within the preceding 3 months; heart
surgery in the preceding 2 months; significant sinus node
abnormalities, including sick sinus syndrome, or greater than
first-degree atrioventricular block, unless treated
with a properly functioning pacemaker; ECG intervals exceeding the
following limits in the drug-free state and in the absence of
preexcitation syndrome and bundle-branch block: QRS of >180 ms, QT
interval of >440 ms, or both; in the case of bundle-branch block, the
QT or QTc was not to exceed 500 ms; R-R interval of >3.5 seconds;
ventricular rate of <50 bpm on 12-lead ECG;
systolic blood pressure of <90 mm Hg or
diastolic blood pressure of >110 mm Hg (>105
mm Hg at Canadian centers after the January 1994 protocol amendment);
major hematological, pulmonary, hepatic, or renal disease
(serum creatinine of >221 µmol/L or, after the
April 1994 protocol amendment, calculated ClCr of
<0.3334 mL/s); serum potassium of <4.0 or >5.5 mmol/L and serum
magnesium of <0.75 or >1.25 mmol/L at screening, 1 week before
entry, and immediately before entry into study; concomitant therapy
with other antiarrhythmic agents, verapamil, diltiazem,
diuretics (if serum potassium was out of the specified limits),
antihistamines, tricyclic antidepressants, anticonvulsants or
phenothiazines, digoxin (allowed if the dosage was constant during the
study), cimetidine (after the April 5, 1994, protocol amendment), and
amiodarone (if blood levels of amiodarone >0.3 mg/mL);
history of polymorphic ventricular
tachycardia associated with antiarrhythmic drugs or other
drugs known to prolong the QT interval; history of substance dependency
or abuse; any experimental medication concomitantly or within the 4
weeks of the study; and participation in a previous dofetilide
study.
Dosing Algorithm
The initial dosage of dofetilide (125, 250, or 500 µg BID) was
determined by randomization. After the first 105 patients had been
enrolled, the protocol was amended to adjust the randomized dosage of
dofetilide for renal function as indicated by each patient’s baseline
calculated creatinine clearance
(ClCr) (Figure 1
).
Patients whose ClCr was <20 mL/min were excluded
from the study. Additionally, if the QTc interval increased by >15%
over baseline, dosage was halved. Dosages could be adjusted only once
for prolongation of QTc intervals, and patients with QT or QTc
intervals that exceeded 550 ms or increased >25% over baseline values
were withdrawn. Treatment comparisons were made with respect to
randomized group, regardless of adjustments or actual dosage
administered.
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Safety Monitoring
Safety was evaluated by physical examination,
cardiopulmonary examination, multiple-lead ECG
analysis, blood tests, and urinalysis. All adverse events and
reactions (observed or volunteered by the patient) were recorded.
Adverse electrophysiological events were
considered separately from other adverse events. Patients who had a
proarrhythmic event were withdrawn from the study and, if appropriate,
followed up until the event subsided.
Statistical Analysis
The Cochran-Mantel-Haenszel test, adjusting for center, was used
to compare the proportion of randomized patients pharmacologically
converting to SR in each dofetilide-treated group with that in the
placebo-treated group. Pharmacological conversion was considered
successful when SR was maintained for a minimum of 24 hours. Time to
conversion was determined by the number of hours from first dose and
displayed graphically by means of the Kaplan-Meier (product-limit)
method. Patients failing to convert were censored at the time of
electrical cardioversion or time of last ECG before
discontinuation.
The maintenance phase analysis included Kaplan-Meier estimates in each treatment group for the probability of maintaining SR for 6, 9, and 12 months after pharmacological or electrical cardioversion. Time in SR was defined as the time from conversion to documented recurrence of AF or AFl lasting >24 hours or last study visit. To examine efficacy of conversion to SR and maintenance of SR, 2 populations were analyzed. In one analysis, which included the intention-to-treat population (all randomized patients), patients whose rhythm could not be converted were considered to have had a relapse at time 0 of the maintenance phase. The other analysis included only patients who were successfully cardioverted, either pharmacologically or electrically, and entered the maintenance phase.
Log-rank tests stratified by center and hazard ratios from the Cox proportional hazards model compared each dofetilide-treated group with the placebo-treated group. The effects of covariates, including age, sex, primary diagnosis, and comorbidity, on the treatment comparisons were assessed by the proportional hazards model analysis.
Twelve-month survival data were presented as raw proportions and analyzed for the combined dofetilide-treated groups versus the placebo-treated group with the Kaplan-Meier method. The hazard ratio with 95% confidence intervals was estimated from the Cox proportional hazards model.
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Results |
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Throughout this section, numbers separated by commas that are enclosed by parentheses refer to data from the 4 randomized treatment groups in the following sequence: 125, 250, and 500 µg BID dofetilide, and placebo.
Patient Characteristics
In total, 325 patients at 37 centers were randomized and
distributed similarly between all groups (Table 1). All randomized patients were
included in the intention-to-treat analyses for both conversion
and maintenance phases. Of these, 250 (60, 61, 61, 68, for
dofetilide 125, 250, and 500 µg BID groups and placebo group,
respectively) patients entered the maintenance phase and were
included in the efficacy analyses for this phase. All patients
were included in the safety analysis. A total of 218 (54, 51,
50, 63) patients reached a study end point or completed 12 months of
follow-up. At baseline, 277 patients (85%) had AF and 48 patients
(15%) had AFl. Eighty-four percent of patients had AF/AFl for 1 or 2
weeks to 26 weeks. Seventy-two percent of the patients were in New York
Heart Association classes II and III. Structural heart disease
(including myocardial infarction, congestive heart failure,
ischemic heart disease, valvular heart disease, and
dilated and obstructive cardiomyopathy) was
present in >50% of patients.
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Efficacy of Conversion and Maintenance of SR
Dofetilide restored SR in a dose-dependent manner (Table 2). Significantly more patients treated
with 250 and 500 µg dofetilide than placebo-treated patients
converted to SR (P=0.015 and P<0.001,
respectively). Of the patients who converted pharmacologically, 70%
did so within 24 hours and 91% within 36 hours (Figure 2). Analysis of pharmacological
conversion by primary diagnosis for the 500 µg BID dofetilide group
showed a 21.6% rate for the AF subgroup and 66.7% for the AFl
subgroup. However, both of these subgroups were highly statistically
significant with respect to the conversion rate for placebo.
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Electrical cardioversion was attempted for patients who did not
cardiovert pharmacologically. The rate of successful conversion,
defined as maintenance of SR for 24 hours, with either study
drug or electrical cardioversion was similar in all treatment groups
(Table 2
).
Dofetilide showed a dose-response relation in maintaining SR. The
probabilities of maintaining SR at 12 months in patients who converted
and entered the maintenance phase were 40%, 37%, and 58% for
the dofetilide groups and 25% for placebo (Table 3 and Figure 3). The log-rank test revealed a
significant difference between the 500 µg BID dofetilide and placebo
groups (P=0.001).
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The median time to relapse was also analyzed. In the placebo-treated group, the median time to relapse to AF was 27 days, whereas a dose-response relation of 31, 179, and >365 days was obtained for the dofetilide-treated groups.
Analysis of the probability of achieving and maintaining SR for
all randomized (intention-to-treat) patients showed a dose-response
pattern similar to that of the maintenance group, except that
all 4 groups’ probabilities were 
20% lower. This reflects the
addition of classifying patients who failed initially to convert to SR
as having relapsed at the onset of the maintenance period. The
log-rank test demonstrated a significant difference between the 500
µg BID dofetilide and placebo groups (P=0.008).
In the examination of the effects of baseline covariates by the Cox proportional hazards model, the only significant factor other than treatment group was primary diagnosis (AF or AFl). In a model including terms for treatment, center, and primary diagnosis, the effect of primary diagnosis was highly significant (P=0.0004), indicating that patients with AFl maintained SR better than patients with AF. The correction for the baseline imbalance of fewer patients with AFl in the 250 µg group apparently provides a more consistent dose response with respect to separation of the efficacy of the 125 and 250 µg dofetilide groups.
The effect of the dosing algorithm on maintenance of SR was examined. Of the 77 patients in the 500 µg group, 37 (48%) had their dosage adjusted, 20 for reduced ClCr and 17 for >15% change from baseline in QT or QTc. Efficacy in those patients was maintained.
Effect of Dofetilide on Mortality Rates
Although this study was not designed to provide robust
statistical evidence of the benefits of conversion and
maintenance of SR with respect to all-cause mortality, survival
was similar among all 4 groups. By 12 months, 2.5% of
dofetilide-treated patients and 3.5% of placebo-treated patients had
died (2, 2, 2, 3 in each group, respectively). The mortality hazard
ratio (dofetilide/placebo) was 0.70 (range, 0.17 to 2.78).
Adverse Events
Eleven patients were withdrawn because of adverse events
potentially related to treatment. Prolongation of QT or QTc interval
accounted for 10 of the withdrawals (2, 2, 5, 1); 7 occurred during the
first 3 days. One sudden death occurred. Dosages were adjusted in 79
(33%) patients treated with dofetilide for either
ClCr or prolonged QT or QTc.
The incidence of serious adverse events was comparable in all 4 groups. Serious adverse events potentially related to treatment were reported in 7 patients (2.9%) in the dofetilide-treated groups and in 2 patients (2.3%) in the placebo-treated group. There was no evidence of a dose-response relation for serious adverse events, with 2, 2, and 3 events occurring in patients receiving 125 µg, 250 µg, and 500 µg dofetilide, respectively.
There were 7 proarrhythmic events, 3 of which were considered treatment related and 4 secondary to other illnesses. Two of the treatment-related events were torsade de pointes. One of these occurred in a 66-year-old white woman randomized to treatment with 250 µg BID dofetilide. After 1 dose, her dosage was reduced to 125 µg BID because of QT interval prolongation. On day 2, after 3 dofetilide doses, torsade de pointes developed, which degenerated to ventricular fibrillation. She was successfully defibrillated. The other patient, a 38-year-old white man with a history of dilated cardiomyopathy and heart failure, randomized to treatment with 500 µg BID, had torsade de pointes and ventricular fibrillation on day 3 after 5 doses. He underwent electrical defibrillation that subsequently produced AF with frequent ventricular ectopy. Magnesium was infused, and the event resolved. Both of these patients had calculated ClCr of >60 mL/min.
The third treatment-related proarrhythmic event occurred in a 69-year-old black man in the 500 µg dofetilide group who died on day 8 of treatment; the death was unwitnessed and presumed to be a sudden cardiac death.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study showed that oral dofetilide is moderately effective in converting AF and AFl to SR. The conversion rate for those randomized to treatment with 500 µg BID dofetilide was 30%. The 10% pharmacological conversion rate for patients randomized to 250 µg BID is similar to the 12% conversion rate of DIAMOND-CHF, in which 250 µg BID was the maximum dose evaluated in patients with AF.7 In patients given 500 µg dofetilide in the current study, 70% of the pharmacological conversions occurred within 24 hours and 91% within 36 hours. This suggests that electrical cardioversion should be considered if the patient does not convert within 24 to 36 hours of the start of dofetilide therapy.
Preventing recurrence of AF during antiarrhythmic therapy
should not be the only measure of drug success. Rather, the frequency
of recurrence may be a more appropriate measure of
efficacy.8 Without drug therapy, AF recurs in 75% of
patients within 1 year after conversion.9
Prophylactic drug therapy has been shown to decrease the
probability of recurrence of AF to 50%.9 This
finding was strongly reinforced by our results, in which a randomized
dosage of 500 µg BID dofetilide was significantly more effective than
placebo (58% versus 25%) at maintaining SR for 1 year. In addition,
analysis of the median time to relapse of AF for the 500 µg
BID dofetilide group was >365 days, compared with 27 days observed in
the placebo group. Although maintenance of SR for 1 year was
higher (80%) in the DIAMOND-CHF study, most of these patients
(88%) were pharmacologically converted on dofetilide and thus would be
more likely to maintain SR on continued dofetilide
therapy.7 The results of both of these trials, however,
indicate that dofetilide favorably affects the time to
recurrence of AF.
The dose adjustment for renal function attempted to provide equivalent serum concentrations in patients with different degrees of renal function within each randomized-dosage group. The dosing algorithm also allowed dose adjustment for QT/QTc prolongation. Efficacy was maintained in both dosage-adjusted and dosage-unadjusted subgroups.
Implications for Therapy of AF
The goal of antiarrhythmic therapy should be either to reduce
symptoms or to improve mortality or both. The treatment should not be
worse than the disease itself.10 Unfortunately, currently
available drug therapies to prevent or convert AF have adverse
effects11 12 or may increase mortality rates or worsen
heart failure.13
In this study, 3 (1.2%) proarrhythmic events were considered to be related to dofetilide. In the DIAMOND-CHF7 study, the incidence of torsade de pointes was substantially reduced by adjusting the dose for renal function. The DIAMOND-CHF7 study of patients with ventricular dysfunction and congestive heart failure showed that treatment with dofetilide does not increase mortality when it is initiated in the hospital with dosage determined on the basis of renal function and QTc response to therapy.
The low incidence of proarrhythmia and sudden death in the current study along with its neutral effect on mortality in DIAMOND-CHF7 suggest that when initiated in a monitored setting and dosed according to renal function and QT response to therapy, dofetilide is a safe therapy for conversion of AF or AFl and subsequent maintenance of SR.
Highly symptomatic AF or AFl of >1 week’s duration should
benefit from dofetilide as primary therapy provided that (1) patients
have a ClCr 
20 mL/min; (2) starting doses 500,
250, and 125 µg BID are used for ClCr >60, 40
to 60, and 20 to <40 mL/min; (3) dosing is halved if corrected QT
increases >15% versus baseline or is >500 ms (550 ms if
ventricular conduction abnormalities exist) 2 to 3 hours
after the first dose. Because of the small nonnegligible risk of
proarrhythmia, dofetilide should be initiated in the hospital
with continuous ECG monitoring.
Conclusions
Dofetilide, a new class III antiarrhythmic agent, is
moderately effective in cardioverting AF or AFl to SR and significantly
effective in maintaining SR for 1 year once patients are
pharmacologically or electrically converted. In-hospital initiation and
dosage adjustment based on QTc and ClCr are
necessary to minimize a small but nonnegligible risk of proarrhythmic
or sudden death. Withdrawal from treatment during maintenance
of SR is low. Dofetilide should be considered an important new
treatment option for patients with AF or AFl.
Appendix
In addition to the authors, the following Dofetilide Atrial
Fibrillation Investigators also participated in the study: Jeffrey
Anderson, MD, LDS Hospital, Salt Lake City, Utah; John Atwood, MD,
Department of Veterans Affairs Medical Center,
Cardiology Medical Service, Palo Alto, Calif; Lawrence
Baruch, MD, Veterans Affairs Medical Center, Bronx, NY; Rajinder
Bhalla, MD, Saint John Hospital, Nassau Bay, Tex; Benoit Coutu, MD,
Hopital Notre Dame, Montreal, Quebec, Canada; Mark Eaton, MD, David
Grant United States Air Force Medical Center, Travis Air Force Base,
Calif; Kenneth Ellenbogen, MD, Virginia Commonwealth University,
Medical College of Virginia Hospitals, Richmond, Va; Jack Farahi, MD,
Daniel Freeman Memorial Hospital, Inglewood, Calif; Anne Gillis, MD,
Foothills Hospital, Calgary, Alberta, Canada; Michael Giudici, MD,
Saint Lukes Regional Heart Center, and Cardiovascular
Medicine PC, Davenport, Iowa; Frank Gold, MD, Illinois Heart Institute,
and Proctor Hospital, and Methodist Medical Center, Peoria, Ill; Robert
Harizi, MD, Fallon Medical Center, Worcester, Mass; Gaetan Houde, MD,
Hopital De L’Enfant, Jesus Departement D’Electrophysiolgie, Quebec,
Canada; Ronald Karlsberg, MD, Brotman Medical Center, Culver City,
Calif; Jeffrey Kluger, MD, Hartford Hospital, Hartford, Conn; William
Kou, MD, Veterans Affairs Medical Center, Ann Arbor, Mich; Robert
Leman, MD, Medical University of South Carolina, Charleston; Ronald
McCowan, MD, Charleston Area Medical Center, Charleston, WV; Claude
Nadeau, MD, Jesus Departement D’Electrophysiologie, Quebec, Canada;
David Navratil, MD, Nevada Heart Care, and Nevada Research
Consultants, and University Medical Center of Southern Nevada,
Las Vegas; Padraig O’Neill, MD, Sutter Memorial Hospital, and Mercy
General Hospital, Sacramento, Calif; Antonio Pacifico, MD, The
Methodist Hospital, Houston, Tex; Marc Platt, MD, Torrance Memorial
Medical Center, Torrance, Calif; Peter Pool, MD, Antone F. Salel, MD, a
Medical Corporation, and North County Cardiology
Research Laboratory, Encinitas, Calif; Guylaine Pruneau, MD, Center
Hospitalier De La Region De L’Amiante, Quebec, Canada; Kodangudi
Ramanathan, MD, Veterans Affairs Medical Center, and University of
Tennessee, Memphis; Philip Sager, MD, Wadsworth Veterans Affairs
Medical Center, Los Angeles, Calif; Sanjeev Saksena, MD, Eastern Heart
Institute, Passaic General Hospital, Passaic, NJ; Antone Salel, MD,
Antone F. Salel, MD, a Medical Corporation, Encinitas, Calif; Jeffrey
Shanes, MD, Gottlieb Memorial Hospital, Melrose Park, Ill; Udipi
Shettigar, MD, Bay Pines Veterans Affairs Medical Center, Bay Pines,
Fla; Nicholas Stamato, MD, Cardiology Associates PC,
Johnson City, NY; Vilma Torres, MD, Loma Linda University Medical
Center, and International Heart Institute, Loma Linda, Calif; Dennis
Unks, MD, Keesler Medical Center, Keesler Air Force Base, Biloxi, Miss;
Michael Weber, MD, Department of Veterans Affairs Medical Center, Long
Beach, Calif; Jule Wetherbee, MD, Saint Lukes Medical Center,
Milwaukee, Wis; Bruce Wilkoff, MD, The Cleveland Clinic Foundation,
Cleveland, Ohio; and David Wyse, MD, Foothills Hospital, Calgary, and
the University of Calgary Medical Clinic, North Calgary, Alberta,
Canada.
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Acknowledgments |
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This study was supported by a grant from Pfizer Inc.
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Footnotes |
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1 Other members of the Dofetilide Atrial Fibrillation Investigators are listed in the Appendix.
Received February 21, 2000; revision received June 13, 2000; accepted June 15, 2000.
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V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]
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 V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]
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V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): 700 - 752. [Full Text] [PDF]
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Authors/Task Force Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation executive summary: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Eur. Heart J., August 2, 2006; 27(16): 1979 - 2030. [Full Text] [PDF]
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 C. Lafuente-Lafuente, S. Mouly, M. A. Longas-Tejero, I. Mahe, and J.-F. Bergmann Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med, April 10, 2006; 166(7): 719 - 728. [Abstract] [Full Text] [PDF]
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B. S. Nagra, G. S. Ledley, and B. K. Kantharia Marked QT Prolongation and Torsades de Pointes Secondary to Acute Ischemia in an Elderly Man Taking Dofetilide for Atrial Fibrillation: A Cautionary Tale Journal of Cardiovascular Pharmacology and Therapeutics, July 1, 2005; 10(3): 191 - 195. [Abstract] [PDF]
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 M. Duytschaever, Y. Blaauw, and M. Allessie Consequences of atrial electrical remodeling for the anti-arrhythmic action of class IC and class III drugs Cardiovasc Res, July 1, 2005; 67(1): 69 - 76. [Abstract] [Full Text] [PDF]
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A. Grom, T. S. Faber, M. Brunner, C. Bode, and M. Zehender Delayed adaptation of ventricular repolarization after sudden changes in heart rate due to conversion of atrial fibrillation. A potential risk factor for proarrhythmia? Europace, January 1, 2005; 7(2): 113 - 121. [Abstract] [Full Text] [PDF]
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 C. A. Palin, R. Kailasam, and C. W. Hogue Jr Atrial Fibrillation After Cardiac Surgery: Pathophysiology and Treatment Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2004; 8(3): 175 - 183. [Abstract] [PDF]
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 A. V Guanzon and M. A Crouch Phase IV Trial Evaluating the Effectiveness and Safety of Dofetilide Ann. Pharmacother., July 1, 2004; 38(7): 1142 - 1147. [Abstract] [Full Text] [PDF]
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P. Chandra, T. S. Rosen, Z.-H. Yeom, K. Lee, H.-Y. Kim, P. Danilo Jr, and M. R. Rosen Evaluation of KCB-328, a new IKr blocking antiarrhythmic agent in pacing induced canine atrial fibrillation Europace, January 1, 2004; 6(5): 384 - 391. [Abstract] [Full Text] [PDF]
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 R. L. McNamara, L. J. Tamariz, J. B. Segal, and E. B. Bass Management of Atrial Fibrillation: Review of the Evidence for the Role of Pharmacologic Therapy, Electrical Cardioversion, and Echocardiography Ann Intern Med, December 16, 2003; 139(12): 1018 - 1033. [Abstract] [Full Text] [PDF]
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 C.J. Boos, J. Carlsson, and R.S. More Rate or rhythm control in persistent atrial fibrillation? QJM, December 1, 2003; 96(12): 881 - 892. [Abstract] [Full Text] [PDF]
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Committee Members, C. Blomstrom-Lundqvist, M. M. Scheinman, E. M. Aliot, J. S. Alpert, H. Calkins, A. J. Camm, W. B. Campbell, D. E. Haines, K. H. Kuck, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias --executive summary: a report of the American college of cardiology/American heart association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) Developed in Collaboration with NASPE-Heart Rhythm Society J. Am. Coll. Cardiol., October 15, 2003; 42(8): 1493 - 1531. [Full Text] [PDF]
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C. Blomstrom-Lundqvist, M. M. Scheinman, E. M. Aliot, J. S. Alpert, H. Calkins, A. J. Camm, W. B. Campbell, D. E. Haines, K. H. Kuck, B. B. Lerman, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Supraventricular Arrhythmias*--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias) Circulation, October 14, 2003; 108(15): 1871 - 1909. [Full Text] [PDF]
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Committee Members, C. Blomstrom-Lundqvist, M. M Scheinman, E. M Aliot, J. S Alpert, H. Calkins, A.J. Camm, W.B. Campbell, D. E Haines, K. H Kuck, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias--executive summary: A Report of the American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines(Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias)Developed in collaboration with NASPE-Heart Rhythm Society Eur. Heart J., October 2, 2003; 24(20): 1857 - 1897. [Full Text] [PDF]
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 A. Capucci and D. Aschieri Antiarrhythmic drug therapy: what is certain and what is to come Eur. Heart J. Suppl., September 1, 2003; 5(suppl_H): H8 - H18. [Abstract] [PDF]
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P. Touboul, J. Brugada, A. Capucci, H. J.G.M. Crijns, N. Edvardsson, and S. H. Hohnloser Dronedarone for prevention of atrial fibrillation: A dose-ranging study Eur. Heart J., August 2, 2003; 24(16): 1481 - 1487. [Abstract] [Full Text] [PDF]
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R. L. Page, T. W. Tilsch, S. J. Connolly, D. J. Schnell, S. R. Marcello, W. E. Wilkinson, E. L.C. Pritchett, and for the Azimilide Supraventricular Arrhythmia Prog Asymptomatic or "Silent" Atrial Fibrillation: Frequency in Untreated Patients and Patients Receiving Azimilide Circulation, March 4, 2003; 107(8): 1141 - 1145. [Abstract] [Full Text] [PDF]
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 R. H. Falk Management of Atrial Fibrillation -- Radical Reform or Modest Modification? N. Engl. J. Med., December 5, 2002; 347(23): 1883 - 1884. [Full Text] [PDF]
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 G Nichol, F McAlister, B Pham, A Laupacis, B Shea, M Green, A Tang, and G Wells Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation Heart, June 1, 2002; 87(6): 535 - 543. [Abstract] [Full Text] [PDF]
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F. G. Cosio and E. Delpon New Antiarrhythmic Drugs for Atrial Flutter and Atrial Fibrillation: A Conceptual Breakthrough at Last? Circulation, January 22, 2002; 105(3): 276 - 278. [Full Text] [PDF]
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