The clinical efficacy of the inhibitors of the renin-angiotensin-aldosterone system (RAAS) as an upstream therapy for atrial fibrillation (AF) prevention is controversial. No study has itemized so far the role of RAAS inhibitors in AF prevention after atrial flutter (AFL) ablation. This trial aims to investigate the effect of ramipril compared with placebo on AF occurrence in patients hospitalized for AFL ablation without structural heart disease. The Prevention of Atrial Fibrillation by Inhibition Conversion Enzyme (ICE) After Radiofrequency Ablation of Atrial Flutter (PREFACE) trial was a prospective, multicenter, randomized, double-blind, double-dummy trial depicting the AF occurrence during a 12-month follow-up as the primary end point. A total of 198 patients hospitalized for AFL ablation were enrolled in the trial and randomized to placebo or ramipril 5 mg/day. Patients were followed up during 1 year after AFL ablation using 1-week Holter electrocardiogram at 3, 6, 9, and 12 months. The intention-to-treat population encompassed 97 patients in the ramipril group and 101 patients in the placebo group. The primary end point, such as AF occurrence during the 1-year follow-up, was not different between the 2 groups (p = 0.96). Secondary end points, including the occurrence of supraventricular arrhythmia (p = 0.50), heart failure, stroke, and death, were not different between the 2 groups. Safety outcome parameters, including serious adverse events leading to treatment disruption (p = 0.10), hypotension, impairment of renal function, and elevated serum potassium level, also were not different between the 2 groups. In conclusion, RAAS inhibition using ramipril does not reduce AF occurrence in patients facing AFL ablation during the 1-year follow-up.
Atrial fibrillation (AF) occurrence is very common in patients with a history of atrial flutter (AFL) ablation. Over 35% of these patients experience recorded AF after a 3-year follow-up. The interrelation between AF and AFL seems to be explained by a common atrial substrate. The persistence of atrial cardiomyopathy after AFL ablation could explain the high, long-term incidence of AF. The inhibitors of the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers, seem to prevent atrial remodeling, in particular, by reducing atrial fibrosis. RAAS inhibition reduces AF occurrence in patients with structural heart disease and hypertension, but randomized clinical trials failed to prove a significant role of RAAS inhibitors on AF prevention in patients without structural heart disease. Recent guidelines suggest the use of RAAS inhibitors as an upstream therapy in patients with AF, but robust data are still lacking. In addition, no study has characterized so far the role of the inhibition of RAAS on AF occurrence after AFL ablation. This study aims to evaluate the role of ramipril, an angiotensin-converting enzyme inhibitor, on AF medium-term prevention after AFL ablation based on a randomized clinical trial.
The PREFACE study was a French, multicenter, prospective, randomized, double-blind, double-dummy, parallel-group, placebo-controlled trial comparing ramipril with placebo in patients with a first episode of AFL or recurrence of AFL. The trial was sponsored by the University Hospital of Saint-Étienne and was supported by a grant from the French Ministry of Health (PHRC Programme Hospitalier de Recherche Clinique National 2006). The trial was approved by the national authorities and ethics committee and was conducted in accordance with the Declaration of Helsinki. This study is registered with ClinicalTrials.gov (NCT00736294).
Consecutive patients aged 18 years or older who had an ablation of a cavotricuspid-dependent AFL within the previous 3 days (based on the radiofrequency of the cavotricuspid isthmus and the bidirectional line of the block) were eligible. Patients were excluded if they had any contraindication to ramipril, a serum potassium concentration >5 mmol/L, a severe chronic kidney disease (stage 4 and 5), a history of significant AF (i.e., AF with prescription of antiarrhythmic drug and/or antithrombotic agent), an indication for therapy with a RAAS inhibitor and no possibility of medication withdrawal, heart failure with left ventricular (LV) ejection fraction <40%, and were women who were pregnant or breast-feeding. All the participants provided written informed consent.
Patients with an AF history were enrolled in the trial only in case of paroxysmal AF, with rare and brief episodes of AF without any prescription of antiarrhythmic drugs.
Patients were centrally randomized in a 1:1 ratio to receive either ramipril 5 mg/day or placebo for 12 months using a central computerized Internet-based system (ClinInfo SA Lyon, France). Using a computer algorithm, a statistician from the Clinical Investigation Center of Saint-Étienne (CIC 1408) generated the assignment list in randomly permuted blocks of 2, 3, 4, or 6. Randomization was stratified according to the center and the presence or absence of an AF history before AFL ablation. The selection of patients was made after hospitalization for AFL ablation 3 days before randomization. After written informed consent had been obtained, patients were randomly assigned to receive 1 tablet of ramipril 5 mg/day or an identical-looking placebo. All patients were followed up for 12 months. Face-to-face visits were scheduled at 3, 6, 9, and 12 months after randomization. During the follow-up visits, the adherence of patients to treatment and their tolerance were assessed. Systematic clinical, biologic, and electrophysiologic examination was managed as follows: systematic clinical examination, blood pressure measurement, assessment of a 7-day electrocardiogram (ECG) Holter recording, creatinine clearance, and potassium serum concentration. According to clinical and biologic tolerance related to the treatment administration, the dosage was appropriately adjusted, either reduced/terminated or increased to 10 mg/day. In case of severe hypotension defined by systolic blood pressure lower than 95 mm Hg, symptomatic hypotension, angioedema, serum potassium concentration more than 5 mmol/L, and a severe chronic kidney disease, study medication was stopped. All the patients were followed up as planned in the protocol, that is, until the follow-up visit at 12 months, even if the treatment was stopped before the end of the study.
The primary outcome of the trial was the diagnosis of an episode of AF of more than 1 minute assessed by either ECG or 7-day ECG Holter up to 12 months. Secondary outcomes were supraventricular tachyarrhythmia excluding AF (i.e., atrial tachycardia, atypical AFL, or recurrence of cavotricuspid isthmus-dependent AFL), major cardiovascular event (death or thromboembolic event or hospitalization for heart failure), and adverse events caused by ramipril administration and leading to discontinuation of the treatment (symptomatic or severe hypotension, worsening of renal function defined by chronic kidney disease stage 3 and 4, elevated serum potassium more than 5 mmol/L, angioedema, and cough).
Based on previous studies, we assumed with placebo a rate of 30% of AF at 1 year after AFL ablation. Assuming a reduction by 40% of AF at 1 year with ramipril administration, a sample size of 195 patients per group had an 80% power to detect a difference between the groups (two-sided 5% level of significance). Because of the lack of recruitment, the study was prematurely stopped after the inclusion of 198 patients. All analyses were performed using the intention-to-treat population, that is, all randomized patients. Patients who were lost to follow-up were censored at the time of their last follow-up assessment. Time-to-event outcomes were estimated by the Kaplan-Meier method, and between-groups comparisons were performed using the log-rank test. The hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated. If any baseline characteristics was differently distributed between the 2 groups (differences being evaluated in clinical terms), the comparisons were adjusted on the variables concerned using a Cox proportional hazards regression model. Regarding the safety outcome, that is, serious or nonserious adverse event, the differences between the 2 groups of treatment were evaluated by the Fisher’s exact test. The relative risks (RRs) and corresponding 95% CIs were calculated. Statistical analyses were performed using the SAS software, version 9.4 SAS Institute Inc., Cary, USA.
From July 8, 2008 to January 21, 2014, a total of 198 patients underwent randomization at 7 centers in France. A total of 97 patients were randomly assigned to receive ramipril and 101 to receive placebo ( Figure 1 ). Of these, 75 of 97 patients (77.3%) in the ramipril group and 70 of 101 patients (69.3%) in the placebo group attended the 12-month visit. In both groups, the most common reason for dropping out was the refusal of patients to continue the follow-up process. Baseline characteristics were well balanced between the 2 groups except that more patients with a history of coronary artery disease were assigned to receive ramipril ( Table 1 ). Briefly, randomized patients were 67 years old, mainly men (79.8%), overweight (26.7%), had a history of hypertension (45.5%) or AF (24.7%), and had a normal renal function (creatinine clearance ≥90 ml/min, 34.0%). Regarding cardiac function, the studied population did not face LV dysfunction and had a mild left atrial dilation. Patients were included during hospitalization for a persistent (78.3%) or counterclockwise (91.4%) AFL ablation, and 8.1% of the patients were included because of a recurrent AFL.
| Variable | Ramipril(N = 97) | Placebo(N = 101) |
|---|---|---|
| Median age (interquartile range)-(years) | 67 (61-74) | 67 (60-73) |
| Men | 73 (75.3%) | 85 (84.2%) |
| Median body mass index (IQR)-(kg/m 2 ) | 27.1 (24.2-31.0) | 26.4 (23.7-29.0) |
| ≥30 | 30 (31.3%) | 22 (22.2%) |
| Medical conditions | ||
| Diabetes mellitus | 13 (13.4%) | 23 (22.8%) |
| Arterial hypertension | 44 (45.4%) | 46 (45.5%) |
| Smoker | 48 (53.9%) | 52 (59.1%) |
| Valvular heart disease | 11 (11.3%) | 8 (7.9%) |
| History of coronary artery disease | 16 (16.5%) | 7 (6.9%) |
| History of atrial fibrillation | 25 (25.8%) | 24 (23.8%) |
| History of heart failure | 14 (14.4%) | 13 (12.9%) |
| Characteristics of the AFL | ||
| Counterclockwise | 91 (93.8%) | 90 (89.1%) |
| Persistent | 71 (73.2%) | 84 (83.2%) |
| Paroxysmal | 26 (26.8%) | 17 (16.8%) |
| Recurrent AFL | 7 (7.2%) | 9 (8.9%) |
| Laboratory tests | ||
| Median systolic blood pressure (IQR)-(mm Hg) | 127 (120-140) | 130 (120-138) |
| Median diastolic blood pressure (IQR)-(mm Hg) | 76 (67-83) | 77 (70-82) |
| Creatinine clearance (ml/min) | ||
| <30 | 1 (1.0%) | 1 (1.0%) |
| 30 to 60 | 18 (18.8%) | 22 (22.4%) |
| 60 to 90 | 46 (47.9%) | 40 (40.8%) |
| ≥90 | 31 (32.3%) | 35 (35.7%) |
| Median serum potassium level (IQR)-(mmol/L) | 4.2 (4.0-4.5%) | 4.3 (4.0-4.5%) |
| Echocardiographic features | ||
| Significant mitral regurgitation , † | 19 (44.2%) | 16 (31.4%) |
| Median left ventricular ejection fraction (IQR)-(%) | 60 (50-65) | 60 (55-65) |
| Median left atrial diameter (IQR)-(mm) | 41 (36-46) | 40 (35-48) |
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