Are transthoracic echocardiographic parameters associated with atrial fibrillation recurrence or stroke? Results from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study.

OBJECTIVES: The purpose of this study was to evaluate the associations of transthoracic echocardiographic parameters with recurrent atrial fibrillation (AF) and/or stroke. BACKGROUND: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, an evaluation of elderly patients with AF at risk for stroke, provided an opportunity to evaluate the implications of echocardiographic parameters in patients with AF. METHODS: Transthoracic echocardiographic measures of mitral regurgitation (MR), left atrial (LA) diameter, and left ventricular (LV) function were evaluated in the AFFIRM rate- and rhythm-control patients who had sinus rhythm resume and had these data available. Risk for recurrent AF or stroke was evaluated with respect to transthoracic echocardiographic measures. RESULTS: Of 2,474 patients studied, 457 had > or =2(+)/4(+) MR, and 726 had a LA diameter >4.5 cm. The LV ejection fraction was abnormal in 543 patients. The cumulative probabilities of at least one AF recurrence/stroke were 46%/1% after 1 year and 84%/5% by the end of the trial (> 5 years), respectively. Multivariate analysis showed that randomization to the rhythm-control arm (hazard ratio [HR] = 0.64; p < 0.0001) and a qualifying episode of AF being the first known episode (HR = 0.70; p < 0.0001) were associated with decreased risk. Duration of qualifying AF episode >48 h (HR = 1.55; p < 0.0001) and LA diameter (p = 0.008) were associated with an increased risk of recurrent AF. Recurrent AF was more likely with larger LA diameters (HR = 1.21, 1.16, and 1.32 for mild, moderate, and severe enlargement, respectively). No transthoracic echocardiographic measures were associated with risk of stroke. CONCLUSIONS: In the AFFIRM study, large transthoracic echocardiographic LA diameters were associated with recurrent AF, but no measured echocardiographic parameter was associated with stroke.

Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.

BACKGROUND: Expectations that reestablishing and maintaining sinus rhythm in patients with atrial fibrillation might improve survival were disproved in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. This report describes the cause-specific modes of death in the AFFIRM treatment groups. METHODS AND RESULTS: All deaths in patients enrolled in AFFIRM underwent blinded review by the AFFIRM Events Committee, and a mode of death was assigned. In AFFIRM, 2033 patients were randomized to a rhythm-control strategy and 2027 patients to a rate-control strategy. During a mean follow-up of 3.5 years, there were 356 deaths in the rhythm-control patients and 310 deaths in the rate-control patients (P=0.07). In the rhythm-control group, 129 patients (9%) died of a cardiac cause, and in the rate-control group, 130 patients (10%) died (P=0.95). Both groups had similar rates of arrhythmic and nonarrhythmic cardiac deaths. The numbers of vascular deaths were similar in the 2 groups: 35 (3%) in the rhythm-control group and 37 (3%) in the rate-control group (P=0.82). There were no differences in the rates of ischemic stroke and central nervous system hemorrhage. In the rhythm-control group, there were 169 noncardiovascular deaths (47.5% of the total number of deaths), whereas in the rate-control arm, there were 113 noncardiovascular deaths (36.5% of the total number of deaths) (P=0.0008). Differences in noncardiovascular death rates were due to pulmonary and cancer-related deaths. CONCLUSIONS: Management of atrial fibrillation with a rhythm-control strategy conferred no advantage over a rate-control strategy in cardiac or vascular mortality and may be associated with an increased noncardiovascular death rate.

Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.

BACKGROUND: The AFFIRM Study showed that treatment of patients with atrial fibrillation and a high risk for stroke or death with a rhythm-control strategy offered no survival advantage over a rate-control strategy in an intention-to-treat analysis. This article reports an "on-treatment" analysis of the relationship of survival to cardiac rhythm and treatment as they changed over time. METHODS AND RESULTS: Modeling techniques were used to determine the relationships among survival, baseline clinical variables, and time-dependent variables. The following baseline variables were significantly associated with an increased risk of death: increasing age, coronary artery disease, congestive heart failure, diabetes, stroke or transient ischemic attack, smoking, left ventricular dysfunction, and mitral regurgitation. Among the time-dependent variables, the presence of sinus rhythm (SR) was associated with a lower risk of death, as was warfarin use. Antiarrhythmic drugs (AADs) were associated with increased mortality only after adjustment for the presence of SR. Consistent with the original intention-to-treat analysis, AADs were no longer associated with mortality when SR was removed from the model. CONCLUSIONS: Warfarin use improves survival. SR is either an important determinant of survival or a marker for other factors associated with survival that were not recorded, determined, or included in the survival model. Currently available AADs are not associated with improved survival, which suggests that any beneficial antiarrhythmic effects of AADs are offset by their adverse effects. If an effective method for maintaining SR with fewer adverse effects were available, it might be beneficial.

Risk of proarrhythmic events in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: a multivariate analysis.

OBJECTIVES: This study examined the risk of proarrhythmic events in patients receiving antiarrhythmic drugs for treatment of atrial fibrillation (AF) according to present-day safety guidelines. BACKGROUND: Advances in understanding the proarrhythmic risk of antiarrhythmic drugs has led to development of safety guidelines for these agents. Such guidelines were used in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. METHODS: This study was an analysis of the risk of arrhythmic events (arrhythmic death, resuscitated cardiac arrest, sustained ventricular tachycardia (VT), and torsade de pointes VT) in the antiarrhythmic drug arm of the AFFIRM study. Each time an antiarrhythmic drug was begun, it was counted as an exposure to that drug and the risk of an arrhythmic event was calculated. RESULTS: A total of 2,033 patients received 3,030 exposures to antiarrhythmic drugs. Ninety-six arrhythmic events occurred by six years. Patients with a left ventricular ejection fraction <40% had more arrhythmic events. Twelve documented cases of torsade de pointes VT were noted. The incidence of torsade de pointes was 0.6% at five years (95% confidence interval 0.32 to 1.07). CONCLUSIONS: The overall risk of adverse arrhythmic events upon exposure to antiarrhythmic drugs in the AFFIRM study was reasonably low. Strict criteria for the safe use of antiarrhythmic drugs were successful in minimizing proarrhythmic events.

The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation.

OBJECTIVES: We sought to evaluate approaches used to control rate, the effectiveness of rate control, and switches from one drug class to another in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. BACKGROUND: The AFFIRM study showed that atrial fibrillation (AF) can be treated effectively with rate control and anticoagulation, but drug efficacy to control rate remains uncertain. METHODS: Patients (n = 2,027) randomized to rate control in the AFFIRM study were given rate-controlling drugs by their treating physicians. Standardized rate-control efficacy criteria developed a priori included resting heart rate and 6-min walk tests and/or ambulatory electrocardiographic results. RESULTS: Average follow-up was 3.5 +/- 1.3 years. Initial treatment included a beta-adrenergic blocker (beta-blocker) alone in 24%, a calcium channel blocker alone in 17%, digoxin alone in 16%, a beta-blocker and digoxin in 14%, or a calcium channel blocker and digoxin in 14% of patients. Overall rate control was achieved in 70% of patients given beta-blockers as the first drug (with or without digoxin), 54% with calcium channel blockers (with or without digoxin), and 58% with digoxin alone. Adequate overall rate control was achieved in 58% of patients with the first drug or combination. Multivariate analysis revealed an association between first drug class and several clinical variables. There were more changes to beta-blockers than to the other two-drug classes (p < 0.0001). CONCLUSIONS: Rate control in AF is possible in the majority of patients with AF. Beta-blockers were the most effective drugs. To achieve the goal of adequate rate control in all patients, frequent medication changes and drug combinations were needed.

Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: observations from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.

BACKGROUND: Stroke and systemic thromboembolism are serious problems for patients with atrial fibrillation (AF), but their incidence can be substantially reduced by appropriate anticoagulation. Bleeding is the major complication of anticoagulant treatment, and the relative risks for bleeding vs stroke must be considered when starting anticoagulation. METHODS: The AFFIRM trial included patients with AF and at least one risk factor for stroke, randomly assigning them to either a rate-control or rhythm-control strategy. All patients were initially treated with warfarin. The incidence of protocol-defined major and minor bleeding was documented during follow-up. Variables associated with bleeding were determined using a Cox proportional hazards model, using baseline and time-dependent covariates. RESULTS: The 4060 patients in the AFFIRM trial were followed for an average of 3.5 years. Major bleeding occurred in 260 patients, an annual incidence of approximately 2% per year, with no significant difference between the rate-control and rhythm-control groups. Increased age, heart failure, hepatic or renal disease, diabetes, first AF episode, warfarin use, and aspirin use were significantly associated with major bleeding. Minor bleeding was common in both treatment arms, with 738 patients reporting this problem in one or more visits. CONCLUSIONS: Bleeding is a significant problem that complicates management of patients with AF. Risk factors for bleeding can be identified, and knowledge of these risk factors can be used to plan therapy.

Quality of life in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.

OBJECTIVE: The objective of this prespecified substudy of the AFFIRM study, in which no differences in survival or event rates were found in patients with atrial fibrillation (AF) randomized to either rate control or rhythm control, was to test the null hypothesis that quality of life (QoL) is equal with rate- versus rhythm-control treatment strategies in AF. METHODS: Fifty-six (25%) of AFFIRM sites were randomly selected to recruit AFFIRM patients for the QoL substudy. Instruments used in the QoL assessment were (1) Perceived Health; (2) the Cantril Ladder of Life; (3) the Short Form 36 survey; (4) the QoL Index; and (5) the Symptom Checklist: Frequency and Severity. Data were collected at baseline, 2 months, 12 months, and annually; data are reported through 4 years of follow-up. RESULTS: Baseline characteristics of the AFFIRM QoL patients (n = 716) were generally similar to those of the rest of AFFIRM patients. Quality-of-life scores were similar in rate- and rhythm-control assignment groups at all time points. Quality-of-life scores were similar whether the actual rhythm was sinus or AF. Scores increased from baseline to subsequent time points similarly for both groups; these improvements were not additive over time. CONCLUSIONS: Quality of life was comparable between rate- and rhythm-control treatment strategies. In addition, QoL was similar with sinus rhythm versus AF. Attempts to improve QoL by restoring sinus rhythm will usually be unsuccessful.

Clinical factors that influence response to treatment strategies in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.

BACKGROUND: The AFFIRM Study was a randomized multicenter comparison of 2 treatment strategies, rate-control versus rhythm-control, in high-risk patients with atrial fibrillation (AF). The primary outcome of the trial showed no overall difference in survival between strategies. However, there may be important patient subgroups for which there are identifiable differences in outcome with 1 of the 2 strategies. METHODS AND RESULTS: Subgroups that were prespecified for analysis from the main AFFIRM Study were age, sex, coronary artery disease (CAD), hypertension, congestive heart failure (CHF), left ventricular ejection fraction (LVEF), rhythm at randomization, first episode of AF, and duration of the qualifying episode of AF. Baseline characteristics were analyzed for each subgroup. Adjusted hazard ratios for each subgroup and for each stratum were generated using Cox models, and these models were used to determine whether treatment strategy affected overall survival differentially by subgroup. Adjusted survival was worse for patients > or =65 years and for patients with a history of CHF, CAD, or an abnormal LVEF. In the adjusted analyses, the effect of treatment strategy was similar within all of the prespecified subgroups. When each subgroup stratum was analyzed separately, patients > or =65 years and patients without a history of CHF had significantly better outcome with rate-control therapy (each P < .01). CONCLUSIONS: Overall, treatment effect for rate control versus rhythm control was the same within each subgroup. However, certain selected patient categories may have better survival with one particular strategy for management of AF.

Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study.

In the Atrial Fibrillation Follow-up Investigation of Rhythm Management study, preexisting pulmonary disease did not preclude the use of amiodarone. Preexisting pulmonary disease was associated with a higher risk of pulmonary death and had a higher risk of diagnosed amiodarone pulmonary toxicity. However, use of amiodarone in the presence of preexisting pulmonary disease did not increase pulmonary death and all-cause mortality rates. Cautious use of amiodarone to treat atrial fibrillation appears acceptable in elderly patients with atrial fibrillation, even if preexisting pulmonary disease is present.

A comparison of the AVID and DAVID trials of implantable defibrillators.

We compared 2 studies of implantable cardiac defibrillators (ICDs) to determine the effects of device mode on outcomes. The Antiarrhythmics Versus Implantable Defibrillators (AVID) trial (1993 to 1997) demonstrated improved survival with the ICD compared with antiarrhythmic drug therapy. The Dual-chamber And VVI Implantable Defibrillator (DAVID) trial (2000 to 2002) showed that VVI pacing at 40 beats/min in patients with ICDs reduced the combined end point of death and hospitalization for congestive heart failure compared with DDDR pacing at 70 beats/min. Patients in the AVID trial (631 of 1,016) and the DAVID trial (221 of 506) meeting common inclusion and all exclusion criteria were studied. The major end points were the time to death, and the composite end point of time to death or hospitalization for congestive heart failure. Patients in the AVID and DAVID trials were similar, but more AVID patients had coronary artery disease (p = 0.04), history of myocardial infarction (p = 0.005), and previous ventricular arrhythmias (p = 0.03). DAVID patients underwent more previous revascularization procedures (coronary artery bypass surgery, p = 0.03; percutaneous coronary intervention, p = 0.001), and were more often taking beta-blocking drugs at hospital discharge (p <0.001). The backup VVI ICD groups in both studies had similar outcomes (p = 0.4), even when corrected for the previous demographic differences. The time-to- composite end point was similar in AVID patients treated with antiarrhythmic drugs and DAVID patients treated with DDDR ICDs (p = 0.6). Despite improved pharmacologic therapy and revascularization, outcomes have not improved with backup VVI pacing ICDs. If DDDR ICDs had been used in the AVID trial, benefit from ICDs for patients with serious ventricular arrhythmias could have been missed.

Percent right ventricular pacing predicts outcomes in the DAVID trial.

BACKGROUND: The Dual-Chamber and VVI Implantable Defibrillator (DAVID) trial demonstrated a worse outcome in patients with implantable cardioverter-defibrillators (ICDs) programmed to DDDR at 70 bpm compared with patients who had ICDs programmed to VVI backup pacing at 40 bpm. Pacing was more frequent in the DDDR group. OBJECTIVES: The purpose of this study was to determine whether right ventricular pacing (RV) is an independent predictor of outcome in the DAVID trial. METHODS: We evaluated the relationship of percent RV pacing to the composite endpoint of death or hospitalization for congestive heart failure. Patients who had a 3-month follow-up and who had not yet reached an endpoint were included in the study. Using Cox regression analysis (VVI group N = 195; DDDR group N = 185), we examined multiple factors, including percent RV pacing at 3-month follow-up, that might be associated with adverse outcomes. RESULTS: Percent RV pacing as a continuous variable was correlated with the primary endpoint. As a dichotomous variable, the best separation for predicting endpoints occurred with DDDR RV pacing > 40% vs DDDR RV pacing < or = 40% (P = .025). Patients with DDDR RV pacing < or = 40% had similar or better outcomes to the VVI backup group (P = .07). Correction for baseline variables predictive of the composite outcome in the (nonpaced) VVI group (use of nitrates, increased heart rate, and increased age) did not change the findings for RV pacing (P = .008). In contrast, atrial pacing was not predictive of worse outcomes. CONCLUSION: These results suggest, but do not prove, a causal relationship between frequent RV pacing and adverse outcomes in patients with left ventricular ejection fraction < or = 40%.

Cost-effectiveness of rhythm versus rate control in atrial fibrillation.

BACKGROUND: Atrial fibrillation is the most common type of sustained cardiac arrhythmia, but recent trials have identified no clear advantage of rhythm control over rate control. Consequently, economic factors often play a role in guiding treatment selection. OBJECTIVE: To estimate the cost-effectiveness of rhythm-control versus rate-control strategies for atrial fibrillation in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM). DESIGN: Retrospective economic evaluation. Nonparametric bootstrapping was used to estimate the distribution of incremental costs and effects on the cost-effectiveness plane. DATA SOURCES: Data on survival and use of health care resources were obtained for all 4060 AFFIRM participants. Unit costs were estimated from various U.S. databases. TARGET POPULATION: Patients with atrial fibrillation who were 65 years of age or who had other risk factors for stroke or death, similar to those enrolled in AFFIRM. TIME HORIZON: Mean follow-up of 3.5 years. PERSPECTIVE: Third-party payer. INTERVENTIONS: Management of patients with atrial fibrillation with antiarrhythmic drugs (rhythm control) compared with drugs that control heart rate (rate control). OUTCOME MEASURES: Mean survival, resource use, costs, and cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS: A mean survival gain of 0.08 year (P = 0.10) was observed for rate control. Patients in the rate-control group used fewer resources (hospital days, pacemaker procedures, cardioversions, and short-stay and emergency department visits). Rate control costs 5077 dollars less per person than rhythm control. RESULTS OF SENSITIVITY ANALYSIS: Cost savings ranged from 2189 dollars o 5481 dollars per person. Rhythm control was more costly and less effective than rate control in 95% of the bootstrap replicates over a wide range of cost assumptions. LIMITATIONS: Resource use was limited to key items collected in AFFIRM, and the results are generalizable only to similar patient populations with atrial fibrillation. CONCLUSION: Rate control is a cost-effective approach to the management of atrial fibrillation compared with maintenance of sinus rhythm in patients with atrial fibrillation similar to those enrolled in AFFIRM.

Comparison of arrhythmia recurrence in patients presenting with ventricular fibrillation versus ventricular tachycardia in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial.

Because many episodes of ventricular fibrillation (VF) are believed to be triggered by ventricular tachycardia (VT), patients who present with VT or VF are usually grouped together in discussions of natural history and treatment. However, there are significant differences in the clinical profiles of these 2 patient groups, and some studies have suggested differences in their response to therapy. We examined arrhythmias occurring spontaneously in 449 patients assigned to implantable cardioverter-defibrillator (ICD) therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial to determine whether patients who receive an ICD after VT have arrhythmias during follow-up that are different from patients who present with VF. ICD printouts were analyzed both by a committee blinded to the patients' original presenting arrhythmia and by the local investigator. During 31 +/- 14 months of follow-up, 2,673 therapies were reported. Patients who were enrolled in the AVID trial after an episode of VT were more likely to have an episode of VT (73.5% vs 30.1%, p <0.001), and were less likely to have an episode of VF (18.3% vs 28.0%, p = 0.013) than patients enrolled after an episode of VF. Adjustment for differences in ejection fraction, previous infarction, and beta-blocker and antiarrhythmic therapy did not appreciably change the results. Ventricular arrhythmia recurrence during follow-up is different in patients who originally present with VT than in those who originally present with VF. These findings suggest there are important differences in the electrophysiologic characteristics of these 2 patient populations.

Alternative endpoints for mortality in studies of patients with atrial fibrillation: the AFFIRM study experience.

OBJECTIVES: The purpose of this study was to examine possible alternatives for death, particularly hospitalization for cardiovascular reasons (CV hospitalization), as an endpoint in studies of atrial fibrillation (AF) using the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) database. BACKGROUND: AF is associated with increased mortality, but large numbers of patients are needed to demonstrate even a moderate effect of a therapy on mortality. METHODS: AFFIRM studied 4,060 patients with AF, randomized to either rate-control or rhythm-control strategy with death as the primary endpoint. RESULTS: Only CV hospitalization occurred more frequently than death. Like death, CV hospitalization was more frequent in the rhythm-control arm (46% vs 36%, P < .001) overall but not in a cohort that attempted to exclude those CV hospitalizations possibly related to treatment strategy (e.g., cardioversion, 24% vs 27%). In either model there was no interaction of CV hospitalization (analyzed as a time-dependent covariate) with treatment arm (P = .18 and P = .21, respectively). CV hospitalization was highly predictive of death in both treatment arms (P < .001) in either model, but after this event, there was no difference in time to death. A composite endpoint of CV hospitalization combined with death might increase power and reduce the size of trials of therapy for AF in such patients. CONCLUSIONS: In patients with AF such as those in the AFFIRM study, CV hospitalization has many attributes of a surrogate for mortality. More research on CV hospitalization, alone or as part of a composite endpoint, is warranted.

Measuring survival rates from sudden cardiac arrest: the elusive definition.

BACKGROUND: Measuring survival from sudden out-of-hospital cardiac arrest (OOH-CA) is often used as a benchmark of the quality of a community's emergency medical service (EMS) system. The definition of OOH-CA survival rates depends both upon the numerator (surviving cases) and the denominator (all cases). PURPOSE: The purpose of the public access defibrillation (PAD) trial was to measure the impact on survival of adding an automated external defibrillator (AED) to a volunteer response system trained in CPR. This paper reports the definition of OOH-CA developed by the PAD trial investigators, and it evaluates alternative statistical methods used to assess differences in reported "survival." METHODS: Case surveillance was limited to the prospectively determined geographic boundaries of the participating trial units. The numerator in calculating a survival rate should include only those patients who survived an event but who otherwise would have died except for the application of some facet of emergency medical care-in this trial a defibrillatory shock. Among denominators considered were: total population of the study unit, all deaths within the study unit, and documented ventricular fibrillation cardiac arrests. The PAD classification focused upon cases that might have benefited from the early use of an AED, in addition to the likely benefit from early recognition of OOH-CA, early access of EMS, and early cardiopulmonary resuscitation (CPR). Results of this classification system were used to evaluate the impact of the PAD definition on the distribution of cardiac arrest case types between CPR only and CPR + AED units. RESULTS: Potential OOH-CA episodes were classified into one of four groups: definite, probable, uncertain, or not an OOH-CA. About half of cardiac arrests in the PAD units were judged to be definite OOH-CA events and therefore potentially treatable with an AED. However, events that occurred in CPR-only units were less likely to be classified as definite or probable OOH-CA events than those in CPR + AED units (43% versus 55%, odds ratio 0.78, 95% confidence interval 0.57-1.07). The study retained sufficient power to permit a statistical analysis of the alternative hypothesis that the CPR + AED method results in twice as many survivors as a CPR-only approach. The result is critically dependent on the denominator used for calculating survival rates; but the analysis does not require a denominator as the numerators will have identical Poisson distributions (counts for rare events) under the null hypothesis since randomization distributes the risk of cardiac arrest evenly between the two arms. CONCLUSION: Reported OOH-CA rates and survival rates vary widely, depending upon the definitions applied to events. Rigorous assessment of treatments applied to improve survival can be obscured by inappropriate definitions. Large-scale randomized interventions designed to improve survival from OOH-CA can be evaluated based upon the absolute numbers of patients surviving, rather than a change in the proportion surviving.

Conducting research using the emergency exception from informed consent: the Public Access Defibrillation (PAD) Trial experience.

BACKGROUND: The Public Access Defibrillation (PAD) Trial, a prospective, multicenter, randomized clinical trial comparing two prehospital resuscitation strategies, was conducted under the regulations for exception from informed consent (21CFR50.24) in 24 communities in North America. These regulations place additional requirements for human subject protection on investigators and Institutional Review Boards (IRBs), including conducting community consultation (CC) and public disclosure (PD). OBJECTIVE: To describe the IRB approval process at study sites and the number and types of community consultation and public disclosure activities conducted. METHODS: The 24 study sites in the United States and Canada submitted IRB applications, CC and PD plans, and a structured report on IRB process and investigator perceptions to the Clinical Trial Center at the University of Washington. RESULTS: The primary IRBs for all 24 trial sites and a total of 101 IRBs approved the study. The median interval from submission to approval was 108 days (IQR 43-196), and the mean number of revisions was two (range 0-7). Investigators conducted nearly 12,000 activities to achieve CC and PD; activities varied greatly from site to site in both type and quantity. CONCLUSION: The length of time to obtain IRB approval and the extent of community consultation and public disclosure varied greatly among trial sites in meeting the current regulations for conducting emergency research with exception from informed consent. This suggests that more specific guidance may be useful and that determination of effective strategies for community consultation and public disclosure is needed.

Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy.

OBJECTIVES: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) functional status substudy aimed to test the hypothesis that functional status is similar in rate-control and rhythm-control strategies. BACKGROUND: Randomized studies, including the AFFIRM study, have failed to demonstrate survival benefits between rate-control and rhythm-control strategies for atrial fibrillation (AF). However, AF may cause functional capacity or cognitive impairment that might justify maintenance of sinus rhythm. METHODS: Investigators of the AFFIRM study enrolled 4,060 patients with AF who required long-term therapy and who were 65 years of age or older or who had another risk factor for stroke or death. New York Heart Association functional class (NYHA-FC) and Canadian Cardiovascular Society Angina Classification were assessed at initial and each follow-up visit. From 22 randomly chosen functional status substudy sites, 245 participants underwent 6-min walk tests and Mini-Mental State Examination (MMSE) at initial, two-month, and yearly visits. Patients were assigned randomly to rate-controlling drugs, allowing AF to persist, or rhythm-controlling antiarrhythmic drugs, to maintain sinus rhythm. RESULTS: The NYHA-FC worsened with time in both rate-control and rhythm-control groups, with no differences between groups. Presence of AF was associated with worse NYHA-FC (p < 0.0001). No differences were observed in Canadian Cardiovascular Society Angina Classification or MMSE scores. Six-minute walk distance improved over time in both study arms. On average, walk distance was 94 feet greater in the rhythm-control group (adjusted p = 0.049). CONCLUSIONS: Modest improvement in 6-min walk distance was noted in the rhythm-control arm. Presence of AF was associated with worse NYHA-FC. No difference in cognitive function was detected.

Frequency of symptomatic atrial fibrillation in patients enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.

INTRODUCTION: The frequency of symptomatic paroxysmal atrial fibrillation (AF) may identify subsets with different characteristics. Because the approach to AF now is so varied, ranging from drug therapy to surgery and catheter ablation, the frequency of AF may have important therapeutic implications if the frequency identifies subsets with distinguishing features. METHODS AND RESULTS: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study is evaluating patients with AF who are at high risk for stroke. We evaluated the clinical characteristics of the patients in the AFFIRM Study in an attempt to identify features that might distinguish patients with infrequent and frequent AF occurrences. Patients were divided into five groups, based upon the historic frequency of occurrence of AF at the time the patients were enrolled in the study. Although statistically significant differences were present among the groups, no important differences were noted in clinical or echocardiographic characteristics that could differentiate patients with frequent episodes of AF from other patients in the AFFIRM population. CONCLUSION: In a large population of patients with AF at high risk for stroke, individual historic and echocardiographic characteristics failed to distinguish patients based on the frequency of AF. Those with frequent and infrequent AF were similar. Although AF frequency has been suggested as a marker of a focal etiology in young populations with little overt heart disease, it does not seem to be a distinguishing characteristic in older populations at high risk for stroke.

Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial.

CONTEXT: Implantable cardioverter defibrillator (ICD) therapy with backup ventricular pacing increases survival in patients with life-threatening ventricular arrhythmias. Most currently implanted ICD devices provide dual-chamber pacing therapy. The most common comorbid cause for mortality in this population is congestive heart failure. OBJECTIVE: To determine the efficacy of dual-chamber pacing compared with backup ventricular pacing in patients with standard indications for ICD implantation but without indications for antibradycardia pacing. DESIGN: The Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial, a single-blind, parallel-group, randomized clinical trial. SETTING AND PARTICIPANTS: A total of 506 patients with indications for ICD therapy were enrolled between October 2000 and September 2002 at 37 US centers. All patients had a left ventricular ejection fraction (LVEF) of 40% or less, no indication for antibradycardia pacemaker therapy, and no persistent atrial arrhythmias. INTERVENTIONS: All patients had an ICD with dual-chamber, rate-responsive pacing capability implanted. Patients were randomly assigned to have the ICDs programmed to ventricular backup pacing at 40/min (VVI-40; n = 256) or dual-chamber rate-responsive pacing at 70/min (DDDR-70; n = 250). Maximal tolerated medical therapy for left ventricular dysfunction, including angiotensin-converting enzyme inhibitors and beta-blockers, was prescribed to all patients. MAIN OUTCOME MEASURE: Composite end point of time to death or first hospitalization for congestive heart failure. RESULTS: One-year survival free of the composite end point was 83.9% for patients treated with VVI-40 compared with 73.3% for patients treated with DDDR-70 (relative hazard, 1.61; 95% confidence interval [CI], 1.06-2.44). The components of the composite end point, mortality of 6.5% for VVI-40 vs 10.1% for DDDR-70 (relative hazard, 1.61; 95% CI, 0.84-3.09) and hospitalization for congestive heart failure of 13.3% for VVI-40 vs 22.6% for DDDR-70 (relative hazard, 1.54; 95% CI, 0.97-2.46), also trended in favor of VVI-40 programming. CONCLUSION: For patients with standard indications for ICD therapy, no indication for cardiac pacing, and an LVEF of 40% or less, dual-chamber pacing offers no clinical advantage over ventricular backup pacing and may be detrimental by increasing the combined end point of death or hospitalization for heart failure.