This Article Abstract Full Text (PDF) All Versions of this Article: 109/8/990    most recent 01.CIR.0000117090.01718.2Av1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Camm, A. J. Search for Related Content PubMed PubMed Citation Articles by Camm, A. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Attack Related Collections Arrhythmias, clinical electrophysiology, drugs

(Circulation. 2004;109:990-996.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Mortality in Patients After a Recent Myocardial Infarction

A Randomized, Placebo-Controlled Trial of Azimilide Using Heart Rate Variability for Risk Stratification

A. John Camm, MD; Craig M. Pratt, MD; Peter J. Schwartz, MD; Hussein R. Al-Khalidi, PhD; Maria J. Spyt, MD; Michael J. Holroyde, PhD; Roger Karam, MD; Edmund H. Sonnenblick, MD; Jose M.G. Brum, MD, on Behalf of the AzimiLide post Infarct surVival Evaluation (ALIVE) Investigators

From the Department of Cardiology, St George’s Hospital, London, UK (A.J.C.); Baylor College of Medicine, Houston, Tex (C.M.P.); Department of Cardiology, Policlinico S Matteo, IRRCS, and University of Pavia, Italy (P.J.S.); Procter & Gamble Pharmaceuticals Inc, Cincinnati, Ohio (H.R.A., M.J.S., M.J.H., R.K., J.M.G.B.); and Albert Einstein College of Medicine, New York, NY (E.H.S.).

Correspondence to Prof A. John Camm, MD, Department of Cardiology, St George’s Hospital Medical School, Cranmer Terrace, London, SW17 ORE, UK. E-mail jcamm{at}sghms.ac.uk

Received June 2, 2003; de novo received September 24, 2003; accepted November 14, 2003.

	Abstract

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Background— Depressed left ventricular function (LVF) and low heart rate variability (HRV) identify patients at risk of increased mortality after myocardial infarction (MI). Azimilide, a novel class III antiarrhythmic drug, was investigated for its effects on mortality in patients with depressed LVF after recent MI and in a subpopulation of patients with low HRV.

Methods and Results— A total of 3717 post-MI patients with depressed LVF were enrolled in this randomized, placebo-controlled, double-blind study of azimilide 100 mg on all-cause mortality. Placebo patients with low HRV had a significantly higher 1-year mortality than those with high HRV (>20 U; 15% versus 9.5%, P<0.0005) despite nearly identical ejection fractions. No significant differences were observed between the 100-mg azimilide and placebo groups for all-cause mortality in either the "at-risk" patients identified by depressed LVF (12% versus 12%) or the subpopulation of "high-risk" patients identified by low HRV (14% versus 15%) or for total cardiac or arrhythmic mortality. Significantly fewer patients receiving azimilide developed atrial fibrillation than did patients receiving placebo (0.5% versus 1.2%, P<0.04). The incidences of torsade de pointes and severe neutropenia (absolute neutrophil count 500 cells/µL) were slightly higher in the azimilide group than in the placebo group (0.3% versus 0.1% for torsade de pointes and 0.9% versus 0.2% for severe neutropenia).

Conclusions— Azimilide did not improve or worsen the mortality of patients after MI. Low HRV independently identified a subpopulation at high risk of mortality.

Key Words: azimilide • antiarrhythmia agents • trials • heart rate

	Introduction

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Mortality in the first year after myocardial infarction (MI) has been significantly reduced because of the development of a range of interventions and therapies including thrombolysis, coronary angioplasty, aspirin, ß-blockers, ACE inhibitors, and aldosterone antagonists.^1–5 Although the incidence of sudden cardiac death, presumably largely because of ventricular tachyarrhythmia, remains substantial, antiarrhythmic drug therapy has not yet been shown to reduce mortality after MI.^6–8 Failure of antiarrhythmic drugs to reduce sudden cardiac death may be related to limitations of their pharmacological actions or to cardiovascular complications of the therapy. It might also be a result of the inadequate risk stratification, resulting in a study population with a low risk of arrhythmic mortality or a competitive mortality risk from pump failure.⁷ To overcome this problem, it has been proposed that trial designs involving large general populations should be powered to detect significant results in subpopulations most likely to be specifically protected by the intervention.⁹

Depressed left ventricular (LV) function is associated with increased all-cause mortality after an MI.¹⁰ This increase in mortality is nonspecific, and the predictive value of LV function is relatively low.¹¹ Reduced heart rate variability (HRV), which can be assessed by a variety of techniques, is associated with increased sudden cardiac mortality in patients who have suffered an MI.^12,13 The predictive accuracy of HRV is seen in patients irrespective of the underlying LV function.^12,14,15

Azimilide is an investigational antiarrhythmic drug with a novel molecular structure and mode of action, blocking both the rapid (I_Kr) and slow (I_Ks) components of the delayed rectifier potassium current, leading to prolongation of the myocyte action potential, which is not dependent on heart rate.^16–18 Oral azimilide doses of 75 and 125 mg have been shown to reduce the frequency of ventricular arrhythmias in a clinical study of patients with an implantable cardioverter-defibrillator.¹⁹

The purpose of the present study was to evaluate the effect of azimilide on all-cause and cause-specific mortality in patients with depressed LV function after a recent MI and in a subpopulation of these patients at higher risk, identified by low HRV.

	Methods

Top Abstract Introduction Methods Results Discussion Conclusions References

 
The AzimiLide Post-Infarct SurVival Evaluation (ALIVE) trial was conducted at 483 sites in 26 countries. Institutional Review Board/Ethics Committee approval and written informed consent were obtained before study start.

Patients were included in this study if they were 18 to 80 years old, had had a documented MI within the previous 5 to 21 days, and had an LV ejection fraction (LVEF) of 15% to 35%, determined at least 1 day after the MI.

Patients were excluded if they had a history of torsade de pointes (TdP), unstable angina pectoris or a high-degree heart block, a QTc interval of 450 ms, a resting heart rate <50 bpm, New York Heart Association (NYHA) class IV congestive heart failure, implantable cardioverter-defibrillator, serum potassium concentrations of <4 mEq/L, amiodarone use within 1 month before enrollment, or current use of class I or III antiarrhythmic drugs.

All randomized patients were referred to as the "at-risk" population. A unique feature of this study design was the acquisition of a 24-hour ambulatory ECG recording at baseline from which HRV was analyzed by a central laboratory by the triangular index method previously described by Malik et al.²⁰ The HRV triangular index is a geometric method of quantifying HRV that was used in the ALIVE trial to identify patients at increased mortality risk and was based on data from a previous post-MI trial (the European Myocardial Infarction Amiodarone Trial [EMIAT]). These data provided the dichotomy value used to differentiate between preserved and reduced HRV (20 baseline width units) and the basis for the power calculation for the ALIVE trial.

Although the HRV measurement results were not part of the eligibility requirements, they were used to prospectively stratify the at-risk trial population. Patients with baseline HRV of 20 U were assigned to the "high-risk" cohort. Patients with baseline HRV >20 U are referred to as the "low-risk" group.

Patients were randomly assigned to receive azimilide 75 mg, azimilide 100 mg, or identical placebo. Treatment could be initiated in hospital or out of hospital within 5 to 21 days after MI, at the investigators’ discretion. Because of enrollment difficulties, the azimilide 75 mg arm was discontinued before study completion after enrollment of 336 patients. All patients were followed up to study completion, but only the azimilide 100 mg and placebo arms are presented in this article.

Patients were evaluated at baseline, at 2 weeks, and at months 1, 2, 4, 8, and 12. Standard laboratory tests and 12-lead ECGs were performed. Study drug was discontinued if ECGs revealed a QTc of 525 ms or absolute neutrophil count was <1000/µL.

Statistical Methods
The primary efficacy analysis compared all-cause mortality in patients treated with azimilide 100 mg and placebo at high risk of death. An additional prespecified primary efficacy analysis was all-cause mortality in all randomized patients (at risk). Both analyses were based on longitudinal intention-to-treat observations for 365 days after each patient’s randomization date. Patients who were alive at 365 days were censored at that point; patients with unknown survival status were considered dead the day after the last day they were known to be alive. All statistical testing had a 2-sided, alternative hypothesis, with type I error (=0.0366) allocated to the primary efficacy analysis (all-cause mortality in the high-risk group). An additional proportion of the total type I error (0.0034) was used on 3 planned interim analyses using Lan-DeMets spending function.²¹ The remaining type I error (0.01) supported the alternative primary analysis of all-cause mortality in the at-risk patients. Kaplan-Meier life table estimates of survival and hazard ratios using the Cox proportional hazards model were computed.²²

Statistical assumptions were based on 15% 1-year mortality in the placebo high-risk group and 45% reduction in high-risk azimilide 100 mg patients. High-risk patients were expected to compose 37% of those recruited. On the basis of these statistical assumptions using previous HRV databases, it was determined that to ensure 90% power for the primary efficacy analysis, 1250 high-risk patients (azimilide 100 mg or placebo) should be randomized and followed up for 365 days.

	Results

Top Abstract Introduction Methods Results Discussion Conclusions References

 
The baseline demographic comparison of azimilide 100 mg and placebo patients is presented in Table 1 for both high-risk and at-risk groups. The patient population was primarily male (78%), with a mean LVEF of 29%. More than half of the patients had NYHA II or III congestive heart failure. Several cardiovascular risk factors were more frequent in the high-risk group than in the at-risk group, notably NYHA class III status and diabetes. Concomitant medications at baseline were similar in both treatment groups, with a very high percentage of patients appropriately taking ß-blockers, ACE inhibitors, and aspirin. Therapy was initiated out of hospital in 27% of the patients.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Demographics

Placebo patients in the high-risk group had a significantly higher mortality rate (96/642, 15%) than placebo patients in the low-risk group (100/1048, 9.5%; hazard ratio, 1.64; 95% CI, 1.24 to 2.17; log-rank P=0.0005) (Figure 1).

View larger version (16K): [in this window] [in a new window]   Figure 1. Kaplan-Meier curve of all-cause mortality in placebo patients in high-risk group (HRV 20 U) and low-risk group (HRV >20 U).

Low HRV remained an independent predictor of mortality among placebo patients after control for the following risk factors: age (<65 or 65 years), LVEF (15% to 25% or 26% to 35%), NYHA class (0–I or II–III), sex, diabetes, and ß-blocker use at baseline (hazard ratio, 1.46; 95% CI, 1.10 to 1.94; P=0.009) (Figure 2). However, low HRV did not predict arrhythmic mortality (Table 2).

View larger version (22K): [in this window] [in a new window]   Figure 2. Relative risk of all-cause mortality in subgroups of high-risk and low-risk placebo patients.

View this table: [in this window] [in a new window]   TABLE 2. Causes of Death in At-Risk, Low-Risk, and High-Risk Groups (Numbers of Patients)

Kaplan-Meier survival curves comparing azimilide 100 mg and placebo treatment in the high-risk and at-risk groups are presented in Figure 3. Neither analysis showed a significant difference between azimilide and placebo. The hazard ratio in the high-risk group was 0.95 (95% CI, 0.71 to 1.27; log-rank P=0.74), whereas the hazard ratio in the at-risk group was 1.0 (95% CI, 0.82 to 1.22; log rank P=0.98).

View larger version (15K): [in this window] [in a new window]   Figure 3. Kaplan-Meier curves of all-cause mortality in high-risk group and at-risk group.

The majority of deaths were classified as cardiac deaths, and more than half of these were arrhythmic, with no statistical difference between the treatment groups (Table 2). The vast majority of cardiac deaths classified as arrhythmic had no ECG available, occurred in the outpatient setting, and were unwitnessed. Because more than half of the events, 51% (201/393), occurred in the first 90 days, a 2-piece proportional hazards model was fitted over the periods day 1–90 and day 91–365, and there was no statistical significance between the treatment groups over either period.

The azimilide group showed a median maximal change in QTc (50 ms) that was higher than that of the placebo group (23 ms). Because the therapeutic effects of azimilide (I_Kr and I_Ks blockade) result in QTc prolongation, an exploratory analysis was performed to determine whether the QTc changes in both azimilide and placebo patients who died differed from those in both treatment groups who survived for 1 year. The median maximal increases in QTc for azimilide patients who died (47 ms) or survived (51 ms) were similar, whether all-cause (Figure 4A) or arrhythmic (Figure 4B) mortality was considered. The same was true of placebo patients (23 ms for both patients who died and patients who survived).

View larger version (19K): [in this window] [in a new window]   Figure 4. Comparison of maximal change from baseline QTc in patients who died and patients who survived. Horizontal row inside box represents median maximal change.

The relative risk of mortality for prespecified subgroups in the at-risk group is summarized in Figure 5. Although there was no significant difference in mortality between azimilide 100 mg and placebo for any subgroup, there was a trend toward improved survival in patients receiving azimilide without ß-adrenergic blocking drugs (P=0.06). These results were similar in the high-risk group (not shown). In addition, no difference was seen in all-cause mortality between the at-risk patients who received azimilide 75 mg (n=336) and the placebo patients who were randomized at the same time (n=336) (hazard ratio, 0.76; 95% CI, 0.48 to 1.20; log-rank P=0.24).

View larger version (25K): [in this window] [in a new window]   Figure 5. Relative risk of all-cause mortality in prespecified subgroups of patients.

Patient compliance in the placebo and azimilide 100 mg groups was similar (94%). Withdrawal because of excessive QTc prolongation (>525 ms) occurred more frequently in azimilide 100 mg patients (3.7%) than in placebo patients (0.2%) and accounted for a higher rate of study drug discontinuation among azimilide 100 mg patients (19%) compared with placebo patients (15%). Withdrawals because of adverse events were similar in both groups (7.1% in the azimilide group versus 6.6% in the placebo group). Frequent reasons for discontinuation included ventricular tachycardia, which was similar in both groups, and rash, which tended to be more common in azimilide patients (0.5%, versus 0.2% in placebo patients; P=NS). Overall, the number of serious adverse events was similar among azimilide and placebo patients (38% for both groups) (Table 3).

View this table: [in this window] [in a new window]   TABLE 3. Serious Adverse Events Occurring in 2% or More of the Study Population

With the exception of new or worsening heart failure, serious cardiovascular events occurred at a similar rate in both treatment groups (28% for azimilide and 31% for placebo). Fewer azimilide patients reported new or worsening heart failure than placebo patients (6% versus 8%, respectively; P=0.026). Significantly fewer patients who took azimilide developed atrial fibrillation documented by ECG than did patients who took placebo (0.5% versus 1.2%, P<0.04). TdP occurred more frequently in patients taking azimilide (0.3%) than in patients taking placebo (0.1%). Severe neutropenia occurred in 15 azimilide patients (0.9%) and 4 placebo patients (0.2%).

	Discussion

Top Abstract Introduction Methods Results Discussion Conclusions References

 
In this study, long-term treatment with azimilide 100 mg did not reduce or increase chances of survival and had a 1-year all-cause mortality rate similar to that of placebo in both high-risk and at-risk populations. In addition to azimilide, several other potassium channel blockers (class III antiarrhythmic drugs), including sotalol, amiodarone, and dofetilide, have been shown to have no effect on all-cause mortality in patients after MI.^23–25

The ALIVE results, together with those of previous trials, suggest that antiarrhythmic drug trials in this patient population may no longer be appropriate until new antiarrhythmic strategies are developed. However, such mortality trials have been used to establish the overall safety of antiarrhythmic drugs for the purposes of registration. At present, the best target populations for antiarrhythmic drug therapy and drug development may be patients with atrial fibrillation or patients with an implantable cardioverter-defibrillator. These 2 populations are the current focus of azimilide development, and the results seen in the ALIVE trial support the safety of azimilide in these patients. As shown in pervious studies, the occurrence of atrial fibrillation was significantly reduced in those patients assigned to treatment with azimilide.^19,26

TdP, a recognized complication of antiarrhythmic therapy, occurred more frequently among patients taking azimilide 100 mg (0.3%) than among placebo patients (0.1%) but was generally lower than in other recent studies with class III antiarrhythmic agents. A TdP rate of 3.1% in patients with a history of MI has been reported among patients taking sotalol.²⁷ In the DIAMOND-MI trial, in which continuous 3-day in-hospital ECG monitoring was used, a TdP rate of 0.94% was reported among patients taking dofetilide.²⁸ Severe neutropenia was also more frequent in azimilide 100 mg patients than placebo patients.

The ALIVE trial differs from previous antiarrhythmic drug mortality trials in patients surviving MI. For the first time, low HRV was studied prospectively to assess its predictive power and was used, in addition to depressed LV function, to identify the target high-risk population. The combination of low HRV and depressed LVEF was selected to identify the high-risk group in ALIVE. The additive value of using HRV along with LVEF is exemplified by the observation that the mean LVEF in placebo patients with low and high HRV were similar (28.8% versus 29.7%, respectively), yet the placebo patients characterized by low HRV had a 64% higher mortality rate than placebo patients with a similar EF and high HRV. This HRV effect among placebo patients was significant even after all relevant covariates were considered.

The 15% 1-year placebo mortality rate in the ALIVE high-risk patient population compares favorably with the EMIAT trial evaluating amiodarone (13.7% mortality at 21 months) and the DIAMOND trial evaluating dofetilide (23% mortality at 12 months).^24,28 The EMIAT trial included patients with a higher LVEF than the ALIVE trial (40% in the EMIAT trial and 35% in the ALIVE trial), resulting in the lower mortality rate seen in EMIAT.²⁴ Patients in the DIAMOND trial had an LVEF similar to those in ALIVE, but DIAMOND enrollment was restricted to hospitalized patients, many of whom were very sick.

	Conclusions

Top Abstract Introduction Methods Results Discussion Conclusions References

 
In summary, low HRV independently predicts significantly higher mortality in post-MI patients with depressed LV function. Azimilide, a potent class III antiarrhythmic drug that is currently under active investigation for the treatment of atrial fibrillation and for patients with an implantable cardioverter-defibrillator, did not improve or worsen the mortality of post-MI patients. The results of ALIVE provide important safety data relating to azimilide in patients with congestive heart failure and/or ischemic heart disease.

	Acknowledgments

 
This work was supported by grants from the Health Care Research Center, Procter & Gamble Pharmaceuticals Inc, Cincinnati, Ohio. We would like to thank the 489 clinical investigators who provided and cared for study patients.

	Footnotes

 
The following authors were consultants and members of the ALIVE Steering Committee: Drs Camm, Pratt, Schwartz, and Sonnenblick. In addition, the following authors are Procter & Gamble employees: Drs Al-Khalidi, Spyt, Holroyde, Karam, and Brum.

Guest Editor for this article was William S. Weintraub, MD, Emory University School of Medicine, Atlanta, Ga.

	References

Top Abstract Introduction Methods Results Discussion Conclusions References

 

1. Arora RB. Role of aldosterone in myocardial infarction. Ann N Y Acad Sci. 1965; 118: 539–554.[CrossRef][Medline] [Order article via Infotrieve]
   
2. Elwood PC, Sweetnam PM. Aspirin and secondary mortality after myocardial infarction. Lancet. 1979; 2: 1313–1315.[CrossRef][Medline] [Order article via Infotrieve]
   
3. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with evidence of heart failure. Lancet. 1993; 342: 821–828.[Medline] [Order article via Infotrieve]
   
4. Berger PB, Holmes DR Jr, Stebbins AL, et al. Impact of an aggressive invasive catheterization and revascularization strategy on mortality in patients with cardiogenic shock in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial. Circulation. 1997; 96: 122–127.[Abstract/Free Full Text]
   
5. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998; 339: 489–497.[Abstract/Free Full Text]
   
6. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991; 324: 781–788.[Abstract]
   
7. Pratt CM, Waldo AL, Camm AJ. Can antiarrhythmic drugs survive survival trials? Am J Cardiol. 1998; 81: 24D–34D.[CrossRef][Medline] [Order article via Infotrieve]
   
8. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol Lancet. 1996; 348: 7–12.[CrossRef][Medline] [Order article via Infotrieve]
   
9. The search for novel antiarrhythmic strategies: Sicilian Gambit. Eur Heart J. 1998; 19: 1178–1196.[Free Full Text]
   
10. Bigger JT, Fleiss JL, Kleiger R, et al. The relationship among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation. 1984; 69: 250–258.[Abstract/Free Full Text]
    
11. Odemuyiwa O, Poloniecki J, Malik M, et al. Temporal influences on the prediction of postinfarction mortality by heart rate variability: a comparison with the left ventricular ejection fraction. Br Heart J. 1994; 71: 521–527.[Abstract/Free Full Text]
    
12. Hartikainen JE, Malik M, Staunton A, et al. Distinction between arrhythmic and nonarrhythmic death after acute myocardial infarction based on heart rate variability, signal-averaged electrocardiogram, ventricular arrhythmias and left ventricular and ejection fraction. J Am Coll Cardiol. 1996; 28: 296–304.[Abstract]
    
13. LaRovere MT, Pinna GD, Hohnloser SH, et al. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation. 2001; 103: 2072–2077.[Abstract/Free Full Text]
    
14. Malik M, Camm AJ, Janse MJ, et al. Depressed heart rate variability identifies post infarction patients who might benefit from prophylactic treatment with amiodarone: a substudy of EMIAT (the European Myocardial Infarct Amiodarone Trial). J Am Coll Cardiol. 2000; 35: 1263–1275.[Abstract/Free Full Text]
    
15. Bilchick KC, Fetics B, Djoukeng R, et al. Prognostic value of heart rate variability in chronic congestive heart failure (Veterans Affairs’ Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure). Am J Cardiol. 2002; 90: 24–28.[CrossRef][Medline] [Order article via Infotrieve]
    
16. Davies MP, Freeman LC, Kass RS. Dual actions of the novel class III antiarrhythmic drug (NE-10064) on delayed potassium channel currents in the guinea pig ventricular sinoatrial node cells. J Pharmacol Exp Ther. 1996; 276: 1149–1154.[Abstract/Free Full Text]
    
17. Salata JJ, Brooks RR. Pharmacology of azimilide dihydrochloride (NE-10064) a class III antiarrhythmic agent. Cardiovasc Drug Rev. 1997; 15: 137–156.[CrossRef]
    
18. Karam R, Marcello S, Brooks RR, et al. Azimilide dihydrochloride, a novel antiarrhythmic agent. Am J Cardiol. 1998; 81: 40D–46D.[CrossRef][Medline] [Order article via Infotrieve]
    
19. Singer I, Al-Khalidi H, Niazi I, et al. Azimilide decreases recurrent ventricular arrhythmias in patients with implantable cardioverter defibrillators. J Am Coll Cardiol. 2004; 43: 39–43.[Abstract/Free Full Text]
    
20. Malik M, Cripps T, Farrell T, et al. Long-term spectral analysis of heart rate variability: an algorithm based on segmental frequency distributions of beat-to-beat intervals. Int J Biomed Comput. 1989; 24: 89–110.[CrossRef][Medline] [Order article via Infotrieve]
    
21. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983; 70: 649–653.
    
22. Collett D. Modelling Survival Data in Medical Research. London, UK: Chapman & Hall; 1994.
    
23. Cairns JA, Connolly SJ, Roberts R, et al. Randomized trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarization. CAMIAT. Lancet. 1997; 349: 675–682.[CrossRef][Medline] [Order article via Infotrieve]
    
24. Julian DG, Camm AJ, Frangin G, et al. Randomized trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction. EMIAT. Lancet. 1997; 349: 667–674.[CrossRef][Medline] [Order article via Infotrieve]
    
25. Yap YG, Camm AJ. Lessons from antiarrhythmic trials involving class III antiarrhythmic drugs. Am J Cardiol. 1999; 84: 83R–89R.[CrossRef][Medline] [Order article via Infotrieve]
    
26. Connolly SJ, Schnell DJ, Page RL, et al. Dose-response relations of azimilide in the management of symptomatic, recurrent, atrial fibrillation. Am J Cardiol. 2001; 88: 974–979.[CrossRef][Medline] [Order article via Infotrieve]
    
27. Lehmann MH, Hardy S, Archibald D, et al. Sex differences in risk of torsade de pointes with d,l-sotalol. Circulation. 1996; 94: 2534–2541.
    
28. Kober L, Bloch Thomsen PE, Moller M, et al. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomized trial. Lancet. 2000; 356: 2052–2058.[CrossRef][Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				I. Savelieva and J. Camm Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches Europace, June 1, 2008; 10(6): 647 - 665. [Abstract] [Full Text] [PDF]

				A. H. Glassman, J. T. Bigger, M. Gaffney, and L. T. Van Zyl Heart Rate Variability in Acute Coronary Syndrome Patients With Major Depression: Influence of Sertraline and Mood Improvement Arch Gen Psychiatry, September 1, 2007; 64(9): 1025 - 1031. [Abstract] [Full Text] [PDF]

				K. Fox, J. S. Borer, A. J. Camm, N. Danchin, R. Ferrari, J. L. Lopez Sendon, P. G. Steg, J.-C. Tardif, L. Tavazzi, M. Tendera, et al. Resting Heart Rate in Cardiovascular Disease J. Am. Coll. Cardiol., August 28, 2007; 50(9): 823 - 830. [Abstract] [Full Text] [PDF]

				O. A. Centurion The Open Artery Hypothesis: Beneficial Effects and Long-term Prognostic Importance of Patency of the Infarct-Related Coronary Artery Angiology, February 1, 2007; 58(1): 34 - 44. [Abstract] [PDF]

				Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]

				F. Lombardi, M. Borggrefe, W. Ruzyllo, B. Luderitz, and for the A-COMET-II Investigators Azimilide vs. placebo and sotalol for persistent atrial fibrillation: the A-COMET-II (Azimilide-CardiOversion MaintEnance Trial-II) trial Eur. Heart J., September 2, 2006; 27(18): 2224 - 2231. [Abstract] [Full Text] [PDF]

				Writing Committee 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: full text: 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 Europace, September 1, 2006; 8(9): 651 - 745. [Full Text] [PDF]

				Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]

				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]

				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]

				C. M. Pratt, H. R. Al-Khalidi, J. M. Brum, M. J. Holroyde, P. J. Schwartz, S. R. Marcello, M. Borggrefe, P. Dorian, A. J. Camm, and on behalf of the Azimilide Trials Investigators Cumulative Experience of Azimilide-Associated Torsades de Pointes Ventricular Tachycardia in the 19 Clinical Studies Comprising the Azimilide Database J. Am. Coll. Cardiol., August 1, 2006; 48(3): 471 - 477. [Abstract] [Full Text] [PDF]

				C. Falcone, M. P. Buzzi, C. Klersy, and P. J. Schwartz Rapid Heart Rate Increase at Onset of Exercise Predicts Adverse Cardiac Events in Patients With Coronary Artery Disease Circulation, September 27, 2005; 112(13): 1959 - 1964. [Abstract] [Full Text] [PDF]

				P. Dorian, M. Borggrefe, H. R. Al-Khalidi, S. H. Hohnloser, J. M. Brum, D. S. Tatla, J. Brachmann, R. J. Myerburg, D. S. Cannom, M. van der Laan, et al. Placebo-Controlled, Randomized Clinical Trial of Azimilide for Prevention of Ventricular Tachyarrhythmias in Patients With an Implantable Cardioverter Defibrillator Circulation, December 14, 2004; 110(24): 3646 - 3654. [Abstract] [Full Text] [PDF]

				S. H. Hohnloser, K. H. Kuck, P. Dorian, R. S. Roberts, J. R. Hampton, R. Hatala, E. Fain, M. Gent, S. J. Connolly, and the DINAMIT Investigators Prophylactic Use of an Implantable Cardioverter-Defibrillator after Acute Myocardial Infarction N. Engl. J. Med., December 9, 2004; 351(24): 2481 - 2488. [Abstract] [Full Text] [PDF]

				I. Savelieva and A. John Camm Atrial fibrillation and heart failure: natural history and pharmacological treatment Europace, January 1, 2003; 5(s1): S5 - S19. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 109/8/990    most recent 01.CIR.0000117090.01718.2Av1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Camm, A. J. Search for Related Content PubMed PubMed Citation Articles by Camm, A. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Attack Related Collections Arrhythmias, clinical electrophysiology, drugs