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Therapy with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins: No effect on ablation outcome after ablation of atrial fibrillation
Electrophysiology
Therapy with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins: No effect on ablation outcome after ablation of atrial fibrillation ¨ ssinger, MD Bernhard Richter, MD, Michael Derntl, MD, Manfred Marx, MD, Peter Lercher, MD, and Heinz D. Go Vienna, Austria
Background The renin-angiotensin-aldosterone system and inflammation are supposed to play a key role in the pathogenesis of atrial fibrillation (AF). This retrospective clinical study was intended to assess the influence of drugs with antiinflammatory and/or renin-angiotensin-aldosterone system–modulating properties, namely angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs), and statins, on AF-free survival after AF ablation. Methods The study included 234 patients (23-80 years; 71.8% men) with drug-resistant paroxysmal (n = 165) or persistent AF (n = 69) who either underwent a Lasso-guided segmental pulmonary vein isolation (n = 83) or a CARTO-guided left atrial circumferential ablation (n = 151). Treatment with statins (n = 113), ACE-Is, or ARBs (n = 124), or a combination of a statin and an ACE-I or ARB (n = 75) was started N3 months before ablation and was continued during follow-up. Results
After a median follow-up of 12.7 months, 64% of patients with paroxysmal and 45% of patients with persistent AF were free of AF. Statin use (hazard ratio [HR], 1.06; P = .79), ACE-I or ARB use (HR, 1.12; P = .59), and their combined use (statin + ACE-I/ARB; HR, 1.17; P = .54) did not significantly influence ablation outcome as assessed by Cox regression analysis. In addition, after multivariate adjustment for potential confounders, the examined drugs did not significantly affect ablation outcome. Ablation induced an acute up-regulation of C-reactive protein levels (preablation vs 48 hours postablation, 5.9 F 8.1 vs 33.7 F 30 mg/L; P b .001) and other inflammatory markers. The examined drugs did not significantly alter baseline levels or ablation-induced up-regulation of inflammatory markers.
Conclusions The routine use of statins, ACE-Is, or ARBs did not result in an improved outcome of AF ablation. (Am Heart J 2007;153:11329.) The understanding of the pathophysiology of atrial fibrillation (AF) has changed drastically during the last several decades. A significant role of inflammation1,2 and of the renin-angiotensin-aldosterone system (RAAS)2,3 has been postulated both experimentally and clinically. Consequently, drugs with antiinflammatory or RAASmodulating properties attract growing interest as promising treatment modalities for AF. These drugs have been
From the Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria. Submitted June 10, 2006; accepted September 20, 2006. Reprint requests: Bernhard Richter, MD, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Wa ¨ hringer Gu¨rtel 18-20, A-1090 Vienna, Austria. E-mail: [email protected] 0002-8703/$ - see front matter n 2007, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2006.09.006
effective in preventing AF in diverse study populations with AF or at risk of AF.4-15 However, data on effects of drugs with antiinflammatory and RAAS-modulating properties on AF recurrence after radiofrequency (RF) ablation of AF are still lacking. Considering the process of tissue healing16 and reverse remodeling17 during the postablation period, these drugs could have the potential to reduce the substantial recurrence rate after AF ablation. The present study was intended to assess the influence of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs), and statins on AF-free survival after AF ablation.
Methods Subjects In the present study, patients undergoing catheter ablation of either symptomatic, drug-resistant paroxysmal or persistent AF were enrolled. The type of AF was defined according to
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block into PVs indicating total electrical isolation served as procedural end points.
Table I. Baseline characteristics Patients, n Patient age, y Men, n (%) Body mass index, kg/m2 Paroxysmal/Persistent AF, n Applied ablation technique (Lasso/CARTO), n Failed antiarrhythmic drugs (class I or III), n AF history, y Hypercholesterolemia, n (%) Arterial hypertension, n (%) Atherosclerotic cardiovascular disease, n (%) Structural heart disease, n (%) Left ventricular ejection fraction, % Left atrial diameter, mm
234 56.7 F 10.5 168 (71.8) 26.6 F 4.1 165/69 83/151 1.8 F 0.9 6.1 F 4.5 117 (50) 128 (54.7) 33 (14.1) 52 (22.2) 61.3 F 7.4 45 F 7
Continuous data are presented as mean F SD.
generally accepted guidelines.18 Baseline characteristics of the study population are presented in Table I. The study was performed according to the recommendations of the hospital’s ethics committee, and written informed consent was obtained.
Preablation treatment Adequate oral or subcutaneous anticoagulation was given for at least 1 month before the procedure. On admission, medical history, physical examination, 12-lead electrocardiogram, x-ray, transesophageal echocardiogram, and standard laboratory measurements were obtained.
Electrophysiological procedure Patients who were included between May 2002 and April 2004 underwent a Lasso catheter–guided ablation procedure19 (Lasso Catheter, Biosense Webster, Inc, Diamond Bar, CA). Patients included afterward were treated with a CARTO system–guided ablation procedure20 (electroanatomical mapping system CARTO, Biosense Webster, Inc). The procedure was performed with the patient under intravenous sedation using midazolam and fentanyl. Vascular access was obtained through the right and left femoral veins. Two 7-French deflectable catheters (Biosense Webster, Inc) were advanced into the right atrium and positioned at the atrioventricular junction and in the proximal coronary sinus. After transseptal puncture, patients received heparin intravenously aiming to maintain an activated clotting time around 300 seconds.
Lasso-guided procedure After double transseptal puncture, a deflectable, circular venous mapping catheter (Lasso catheter, 12-25 mm) and a temperature-controlled 4-mm-tip quadripolar catheter (Biosense Webster, Inc) were introduced into the left atrium. The Lasso catheter was advanced sequentially into each pulmonary vein (PV) and was used for ostial mapping of PV potentials. Ostial sites with the earliest bipolar activation and/or the most rapid unipolar intrinsic deflection were targeted for ablation. Radiofrequency energy was delivered with a maximum power output of 30 W and an upper temperature limit of 558C. Elimination of all ostial vein potentials and complete entrance
CARTO-guided procedure A temperature-controlled 8-mm-tip quadripolar catheter (Navistar, Biosense Webster, Inc) was advanced into the left atrium and used for mapping and ablation. The electromagnetic mapping system CARTO was used for the generation of a 3-dimensional electroanatomic map of the left atrium. Subsequently, circular ablation lines were placed around the left- and right-sided PVs, followed by an interconnecting roofline and a line from the left circle to the mitral annulus. The encircling lines were created at a distance of about 15 mm from the PV ostia and consisted of consecutive focal lesions. Radiofrequency energy was delivered at a maximum power output of 50 W and an upper temperature limit of 558C for 20 to 40 seconds at each ablation site. The end point of ablation was an 80% reduction in the amplitude of the local bipolar electrogram or a total of 40 seconds of energy delivery.
Postablation management and follow-up After ablation, all patients were continuously monitored and received intravenous heparin for 48 hours. Antiarrhythmic drug medication, if present before ablation, and oral anticoagulation were reinitiated and continued for at least 3 months. Patients were discharged 2 days after the procedure. Regular follow-up visits started 6 weeks after ablation and were subsequently conducted in 3-month intervals during the first year and in 3- to 6-month intervals afterward. Regular follow-up visits included a clinical evaluation, a 12-lead surface ECG, and Holter monitoring (24 or 48 hours). In addition, patients were instructed to contact the outpatient clinic whenever they experienced palpitations to document arrhythmias by ECG, Holter, or event monitoring. Successful ablation was defined as no recurrence of AF persisting or developing beyond a period of 2 months after ablation.
Blood sampling and laboratory methods The determination of C-reactive protein (CRP) levels, of the total leukocyte count, and of fibrinogen levels was part of the standardized periablation management and was performed in the hospital’s laboratory. Venous blood samples were collected at admission and on the morning of the second postablation day. The leukocyte count was measured in EDTA blood using a Sysmex XE-2100 Hematology Analyzer (SYSMEX EUROPE GMBH, Hamburg, Germany). Fibrinogen levels were determined in citrate plasma using the method of Clauss (STA-R analyzer, Diagnostica Stago, Asnieres, France). CRP levels were determined in heparinized plasma by the use of a commercially available immunological assay (Roche, Basel, Switzerland). The lower detection limit of the CRP assay was 2 mg/L.
Study design and statistical analyses This clinical study is a retrospective analysis of prospectively collected AF ablation data. The study was powered (80% power; 2-sided a = .05) to detect a risk ratio for AF recurrence of 0.73 or less between patients with and without drug treatment.
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Table II. Antiinflammatory and RAAS-modulating drug treatment Drugs Statins Atorvastatin Simvastatin Pravastatin Fluvastatin Rosuvastatin ACE-Is Ramipril Lisinopril Enalapril Fosinopril ARBs Candesartan Losartan Valsartan Eprosartan ACE-Is or ARBs Statins and ACE-Is or ARBs
n (%) 113 70 23 12 6 2 43 15 13 10 5 84 37 29 15 3 124 75
Table III. Ablation outcome
Dosage (mg/d)
(48.3) 10-80 10-80 10-20 20-80 40 (18.4) 2.5-12.5 15-40 20-40 20-40
Entire study population Lasso Paroxysmal AF Persistent AF CARTO Paroxysmal AF Persistent AF
Patients
Freedom from AF
n
n (%)
234 83 76 7 151 89 62
136 50 48 2 86 57 29
(58.1) (60.2) (63.2) (28.6) (57) (64) (46.8)
(35.9) 4-32 25-100 40-320 600-900 (53) (32.1)
Continuous data are given as mean F SD. Differences in continuous variables were evaluated using paired and unpaired Student t test where appropriate. The m2 test was used to assess differences in AF recurrence rates between different types of statins, ACE-Is, or ARBs. Univariate Cox regression analysis was performed to evaluate the influence of the variables of interest: (1) statin use, (2) ACE-I or ARB (ACE-I/ARB) use, and (3) their combined use (statin and ACE-I/ARB use), as well as of diverse patient characteristics on AF recurrence rates. A multivariate Cox regression model was used to adjust for potential confounders. A value of P b .05 (2-tailed) was considered statistically significant. Statistical analyses were carried out using the statistical software package SPSS 12.0 (SPSS Inc, Chicago, IL).
Results A total of 234 patients with either paroxysmal (n =165) or persistent (n = 69) AF were included in the study. Of these patients, 83 underwent a Lasso-guided ablation procedure, and 151 underwent a CARTO-guided procedure. Additional ablation of the cavotricuspid isthmus was carried out in 37 patients because of a history of isthmus-dependent right atrial flutter. When compared to the CARTO-guided procedure, the Lasso approach had a significantly shorter radiofrequency energy application time (21.9 F 10.6 vs 32.4 F 9.6 minutes; P b .001), a significantly longer fluoroscopic duration (64.1 F 18.4 vs 46.1 F 18 minutes; P b .001), and a significantly longer procedure duration (172.9 F 45.3 vs 141.7 F 42.8 minutes; P b .001).
Treatment with antiinflammatory and RAAS-modulating drugs Table II displays a detailed list of the statins, ACE-Is, and ARBs used in the study population. Of the 234 study
patients, 113 were treated with a statin, and 124 received either an ACE-I or ARB (ACE-I/ARB). Seventy-five patients were treated with a combination of a statin and ACE-I/ARB. Treatment started at least 3 months before ablation and was continued during follow-up. The indications for statin therapy were hypercholesterolemia (n = 113) and/or atherosclerotic cardiovascular disease (n = 24). ACE-I/ARB therapy was given because of arterial hypertension (n = 92), left ventricular hypertrophy (n = 42), atherosclerotic cardiovascular disease (n = 26), and/or left ventricular dysfunction (n = 15).
Ablation outcome After a median follow-up period of 12.7 months (95% confidence interval [CI], 11-14.4 months), 105 (64%) of 165 patients with paroxysmal AF and 31 (45%) of 69 patients with persistent AF were free of AF without (n = 82) or with antiarrhythmic drugs (n = 54) that had previously failed. Table III displays the corresponding data for the entire study population as well as for subgroups. Value of antiinflammatory and RAAS-modulating drugs after AF ablation Statin use (hazard ratio [HR], 1.06; 95% CI, 0.71-1.57; P = .79) (Figure 1, A), ACE-I/ARB use (HR, 1.12; 95% CI, 0.75-1.66; P = .59) (Figure 1, B), and the combined use of statins and ACE-I/ARBs (HR, 1.17; 95% CI, 0.711.94; P = .54) did not significantly influence AF-free survival after AF ablation (Table IV). Of the 136 patients with successful ablation, 65 patients (47.8%) were treated with statins, 70 patients (51.5%) with ACE-I/ ARBs, and 42 patients (30.9%) with a combination of a statin and ACE-I/ARB. Of the 98 patients with failed ablation, 48 (49%) received statins, 54 (55.1%) received ACE-I/ARBs, and 33 (33.7%) received a combination of both. There was no significant difference in AF recurrence rates between the different types of statins ( P = .32), ACE-Is ( P = .68), and ARBs ( P = .45). In addition, after adjustment for potential confounders by multivariate analysis including age, sex, hypercho-
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Figure 1
Table IV. Predictors of AF-free survival in univariate Cox regression analysis
Statins ACE-Is or ARBs Statins and ACE-Is or ARBs AAD use during follow-up Type of AFT Sex Age Body mass index Hypercholesterolemia Arterial hypertension Atherosclerotic cardiovascular disease Structural heart disease Left ventricular ejection fraction Left atrial size Applied ablation technique
HR
95% CI
P
1.06 1.12 1.17 0.81 1.94 0.9 0.99 1 0.97 1.11 0.82 0.93 0.97 1 1.27
0.71-1.57 0.75-1.66 0.71-1.94 0.53-1.24 1.28-2.93 0.57-1.41 0.98-1.01 0.95-1.05 0.65-1.43 0.75-1.66 0.44-1.54 0.57-1.53 0.59-1.6 0.97-1.03 0.83-1.95
.79 .59 .54 .33 .002 .65 .48 .92 .86 .6 .54 .79 .92 .98 .28
AAD, Antiarrhythmic drug use (class I or III). T Paroxysmal versus persistent AF.
Kaplan-Meier plot of the probability of freedom from recurrent AF in patients after radiofrequency ablation. A, With and without statin use. B, With and without ACE-I/ARB use. P values are derived from univariate Cox regression analysis.
lesterolemia, arterial hypertension, atherosclerotic cardiovascular disease, left ventricular ejection fraction, type of AF, antiarrhythmic drug treatment during followup, statins, and ACE-I/ARBs, the examined drugs did not significantly predict ablation outcome. Among all examined covariates, only the type of AF (paroxysmal vs persistent AF) was a significant univariate (HR, 1.94; 95% CI, 1.28-2.93; P = .002) (Table IV) and multivariate (HR, 1.97; 95% CI, 1.28-3.05; P = .002) predictor of ablation outcome.
Subgroup analyses None of the examined antiinflammatory or RAASmodulating drugs have the potential to significantly influence AF recurrence rates in the paroxysmal AF group or in the persistent AF group. In detail, in the paroxysmal AF group, the hazards of developing recurrent AF were 0.89 for statin use (95% CI, 0.53-1.47; P = .64), 1.02 for ACE-I/ARB use (95% CI, 0.62-1.7; P = .93), and 1.01 for the combined use of statins and ACE-I/ARBs (95% CI, 0.54-1.88; P = .97). The corresponding hazards in the persistent AF group were 1.18 for statin use (95% CI, 0.62-2.27; P = .62), 1.17 for ACE-I/ARB use (95% CI, 0.61-2.24; P = .64), and 1.22 for their combined use (95% CI, 0.52-2.88; P = .65). The examined drugs significantly affected ablation outcome in neither the subgroup of patients undergoing a Lasso-guided procedure nor the subgroup of patients undergoing a CARTO-guided procedure. In detail, in the Lasso-group, the hazards of developing recurrent AF were 0.8 for statin use (95% CI, 0.38-1.67; P = .55), 1.27 for ACE-I/ARB use (95% CI, 0.64-2.52; P = .5), and 1.17 for their combined use (95% CI, 0.48-2.81; P = .73). The corresponding hazards in the CARTO group were 1.13 for statin use (95% CI, 0.7-1.82; P = .63), 1.03 for ACE-I/ARB use (95% CI, 0.63-1.68; P = .91), and 1.09 for their combined use (95% CI, 0.59-2.03; P = .78). Inflammatory markers and ablation Ablation induced an acute up-regulation of CRP levels (preablation vs 48 hours postablation, 5.9 F 8.1 vs 33.7 F 30 mg/L; P b .001), leukocyte counts (5.84 F 1.66 109/L vs 6.59 F 1.73 109/L; P b .001), and fibrinogen levels (355.5 F 87 vs 443 F 76.2 mg/dL; P b .001). Statin use was not associated with signifi-
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cantly lower baseline CRP levels (statin vs no statin, 5.4 F 4.8 vs 6.3 F 10.3 mg/L; P = .48), leukocyte counts (6.03 F 1.57 109/L vs 5.66 F 1.73 109/L; P = .12), or fibrinogen levels (365.5 F 84.8 vs 345.9 F 85.9 mg/dL; P = .12) and did not significantly attenuate the ablation-induced up-regulation of the examined inflammatory markers. Similarly, ACE-I/ARB use did not significantly affect the baseline levels of inflammatory markers or the ablation-induced inflammatory response (data not shown).
Discussion The results of the present study demonstrate that the routine use of statins and ACE-I/ARBs as single drug treatment or as combination therapy does not significantly improve outcome of AF ablation. This holds true not only for the entire study population but also for the subgroups of patients with paroxysmal and persistent AF and for patients undergoing a Lasso-guided or a CARTOguided ablation approach. To the best of our knowledge, the present study is the first to evaluate the possible effects of the previously mentioned drugs on AF ablation outcome. Anne et al21 retrospectively examined the effects of ACE-Is and ARBs on the occurrence of AF in patients undergoing ablation of isthmus-dependent right atrial flutter and postulated a preventive effect of the assessed drugs on subsequent AF occurrence. Apart from this study, protective effects of ACE-Is, ARBs, and statins on the occurrence of AF have been observed in diverse nonablation cohorts. In detail, statins were considered effective in preventing AF after electrical cardioversion,9 after cardiac surgery,12 in patients with coronary artery disease,8 and in patients with left ventricular dysfunction.7 ACE-Is or ARBs exerted a protective effect against AF in patients with left ventricular dysfunction,5,6 in hypertensive patients with left ventricular hypertrophy,13 in patients with paroxysmal AF,14 in patients with myocardial infarction complicated by left ventricular dysfunction,15 and after cardiac surgery11 and electrical cardioversion.10 The search for new treatment modalities for the periand postablation management is driven by the substantial recurrence rate of AF ablation22 and the relative inefficacy of the currently available pharmacotherapy.23,24 The new agents are supposed to target key processes of the pathogenesis of AF, namely inflammation and angiotensin-mediated effects. Regarding inflammation, mounting evidence links increased CRP levels not only to already existing AF but also to the risk to develop future AF.1,2 As shown in the present study, ablation induces an acute inflammatory up-regulation reflected by an increase of CRP and fibrinogen levels and of the leukocyte count. The observed inflammatory response is consistent with previous histopathologic information on ablation-in-
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duced inflammatory activation16 and is supposed to contribute to the phenomenon of early AF recurrence.25 Correspondingly, in patients undergoing cardiopulmonary bypass surgery, the peak incidence of postoperative arrhythmia on the second to third postoperative day coincides with the CRP peak.26 Although it is not yet known whether inflammation acts as initiator or is just a consequence of AF, there is evidence that CRP-lowering therapies could prevent AF.14 Statins as well as ACE-Is and ARBs have the potential to modulate inflammatory pathways1,2 and could therefore reduce the susceptibility to AF after ablation in general and attenuate the acute inflammatory response in the early postablation period in particular. In the present study, however, none of the examined drugs significantly affected the acute upregulation of inflammatory markers during the early postablation period. Apart from inflammation, activation of the RAAS, which is commonly observed in AF patients, is supposed to constitute a key mechanism in the pathogenesis of AF.1,2 Up-regulation of the RAAS and consequently generation of angiotensin II promote atrial fibrosis and contribute to the structural and electrical remodeling of the atria by various actions.2,3 Elevated angiotensin II levels could particularly be harmful in the postablation period because extensive structural changes take place during this time span. These changes include processes of tissue healing and scar formation in the areas of RF lesions16 and reverse remodeling17 comprising reduction of left atrial size. RAAS inhibition by ACE-Is or ARBs has been shown to beneficially influence ventricular remodeling after myocardial infarction, which is another model of myocardial necrosis.27 With regard to AF, expected beneficial actions of RAAS inhibition include hemodynamic changes leading to lower intra-atrial pressure and wall stress,3 reduction of atrial fibrosis,3 modulation of refractoriness,1,2 stabilization of electrolyte concentrations,1 as well as modulation of sympathetic tone2 and ion channel function.2,3 Nevertheless, in the present study, neither statins nor ACE-I/ARBs had the potential to improve ablation outcome. A possible explanation might be the preserved left ventricular function in the examined cohort. In recent meta-analyses about beneficial effects of ACE-Is and ARBs on AF,4,28 AF prevention was greatest in patients with left ventricular dysfunction and was not constantly observed in patients with normal left ventricular function. Therefore, it cannot be excluded that performing the same study in patients with impaired left ventricular function might lead to different results. In addition, previous studies on AF prevention by antiinflammatory and RAAS-modulating drugs were predominantly conducted in populations at risk of AF and rarely in populations with already existing AF. The present study cohort, however, consists of patients with a long history of drug refractory AF and thus constitutes
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a collective with a rather advanced stage of the disease. The inefficacy of the examined drugs in these very patients might indicate that the treatment with the examined drugs is rather a domain of the early phase of AF development. Moreover, it has to be mentioned that only a small proportion of patients were treated with the highest recommended dosage of the examined drugs in the present study. Most patients received intermediate dosages. It is therefore open whether the use of the maximum dosage would have yielded significant results. However, in numerous previous studies on AF prevention, significant results have been observed with predominantly moderate doses of the examined agents.5,9,10,15 In addition, the median follow-up of 12.7 months might have been too short for beneficial changes to become observable. A follow-up period of several years might be necessary to show the effects of the respective drugs on ablation outcome because lengthy processes such as fibrosis and atrial remodeling are involved, and ablation itself might generate an overwhelming inflammatory reaction that could require months to overcome. Comparably, left ventricular hypertrophy, which constitutes another chronic myocardial alteration, has been shown to continuously regress under treatment with losartan over a period of several years.29 Contrary to this hypothesis, antiinflammatory and RAAS-modulating drugs have been effective in preventing AF after electrical cardioversion even after pretreatment of only several weeks.10 Despite a growing body of evidence to support a protective role of drugs with antiinflammatory or RAASmodulating properties, it should not be overlooked that there are also numerous studies that could not find a preventive effect on AF occurrence at all.30-33 These conflicting data may in part be related to profound differences in study populations such as differences in AF history and predisposing diseases. Furthermore, there was a great variance in study protocols that could contribute to controversial results. Among others, the sample size, follow-up duration, duration of drug application, and method to assess occurrence of AF varied widely. Moreover, a wide range of different substances have been examined. Especially in the case of statins, this could account for inconsistent results because the antiinflammatory properties and therefore maybe the AF preventing potential might vary among the available substances.34 Furthermore, it should not be overlooked that previous data are mainly derived from retrospective studies5,8,9,15,21 and might in part be biased because no multivariate adjustment for confounders has been performed. In addition, the conflicting results may also be indicative that the respective drugs might not be useful in all conditions associated with AF. Their beneficial
effects might be restricted to certain inflammatory or hemodynamic states that have not yet been identified. A better understanding of the pathogenesis of AF together with an improved knowledge on the ongoing inflammatory processes possibly by determination of serological inflammatory markers might be helpful to select the suitable candidates for a treatment with the respective drugs. At the moment, it remains open whether AF patients with a certain amount of atrial fibrosis and remodeling or maybe with certain predisposing or causal comorbidities such as left ventricular dysfunction4,28 or hypertrophy28 are more appropriate for the treatment with the respective drugs than others.
Limitations The study was a retrospective analysis of prospectively gathered data and hence is subject to the limitations inherent in any retrospective study. Medical treatment was not randomly assigned. Therefore, further evaluation by randomized, prospective trials is needed to finally answer the question whether antiinflammatory and RAAS-modulating drugs are useful after ablation. A possible limitation of this study is that AF-free followup included a proportion of patients continued on previously ineffective antiarrhythmic drugs reflecting a rather conservative strategy of withdrawal of antiarrhythmic drugs after ablation in our center. However, also after statistical adjustment for the covariate antiarrhythmic drug use during follow-up, the examined agents did not influence ablation outcome. Although systematic attempts to identify asymptomatic recurrence of AF were undertaken, as described in the Methods section, asymptomatic episodes of AF may have been missed. Conclusions The routine use of statins and ACE-I/ARBs as single drug treatment or as combination therapy did not significantly improve outcome of AF ablation. However, there is a rationale for large randomized, placebocontrolled prospective studies investigating this issue. We express our gratitude to Faustina Oberst for her great support.
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5. Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circulation 2003;107:2926 - 31. 6. Ducharme A, Swedberg K, Pfeffer MA, et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J 2006;151:985 - 91. 7. Hanna IR, Heeke B, Bush H, et al. Lipid-lowering drug use is associated with reduced prevalence of atrial fibrillation in patients with left ventricular systolic dysfunction. Heart Rhythm 2006;3:881 - 6. 8. Young-Xu Y, Jabbour S, Goldberg R, et al. Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. Am J Cardiol 2003;92:1379 - 83. 9. Siu CW, Lau CP, Tse HF. Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion. Am J Cardiol 2003;92:1343 - 5. 10. Ueng KC, Tsai TP, Yu WC, et al. Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation. Results of a prospective and controlled study. Eur Heart J 2003;24:2090 - 8. 11. Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 2004;291:1720 - 9. 12. Marin F, Pascual DA, Roldan V, et al. Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting. Am J Cardiol 2006;97:55 - 60. 13. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol 2005;45:712 - 9. 14. Dernellis J, Panaretou M. Effect of C-reactive protein reduction on paroxysmal atrial fibrillation. Am Heart J 2005;150:1064. 15. Pedersen OD, Bagger H, Kober L, et al. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999;100:376 - 80. 16. Tanno K, Kobayashi Y, Kurano K, et al. Histopathology of canine hearts subjected to catheter ablation using radiofrequency energy. Jpn Circ J 1994;58:123 - 35. 17. Reant P, Lafitte S, Jais P, et al. Reverse remodeling of the left cardiac chambers after catheter ablation after 1 year in a series of patients with isolated atrial fibrillation. Circulation 2005;112:2896 - 903. 18. Levy S, Camm AJ, Saksena S, et al. International consensus on nomenclature and classification of atrial fibrillation; a collaborative project of the Working Group on Arrhythmias and the Working Group on Cardiac Pacing of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Europace 2003;5:119 - 22. 19. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659 - 66.
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20. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004;109:327 - 34. 21. Anne W, Willems R, Van der Merwe N, et al. Atrial fibrillation after radiofrequency ablation of atrial flutter: preventive effect of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics. Heart 2004;90:1025 - 30. 22. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 2005;111:1100 - 5. 23. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825 - 33. 24. Levy S. Pharmacologic management of atrial fibrillation: current therapeutic strategies. Am Heart J 2001;141:S15 - S21. 25. Oral H, Knight BP, Ozaydin M, et al. Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation. J Am Coll Cardiol 2002;40:100 - 4. 26. Bruins P, te Velthuis H, Yazdanbakhsh AP, et al. Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia. Circulation 1997;96:3542 - 8. 27. Lopez-Sendon J, Swedberg K, McMurray J, et al. Expert consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease. The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 2004;25:1454 - 70. 28. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol 2005;45:1832 - 9. 29. Devereux RB, Dahlof B, Gerdts E, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation 2004;110:1456 - 62. 30. Schwartz GG, Olsson AG, Chaitman B, et al. Effect of intensive statin treatment on the occurrence of atrial fibrillation after acute coronary syndrome: an analysis of the MIRACL Trial (Abstract). Circulation 2004;110:740. 31. Tveit A, Grundtvig M, Gundersen T, et al. Analysis of pravastatin to prevent recurrence of atrial fibrillation after electrical cardioversion. Am J Cardiol 2004;93:780 - 2. 32. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensinconverting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353:611 - 6. 33. Murray KT, Rottman JN, Arbogast PG, et al. Inhibition of angiotensin II signaling and recurrence of atrial fibrillation in AFFIRM. Heart Rhythm 2004;1:669 - 75. 34. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20 - 8.
Therapy with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins: No effect on ablation outcome after ablation of atrial fibrillation ¨ ssinger, MD Bernhard Richter, MD, Michael Derntl, MD, Manfred Marx, MD, Peter Lercher, MD, and Heinz D. Go Vienna, Austria
Background The renin-angiotensin-aldosterone system and inflammation are supposed to play a key role in the pathogenesis of atrial fibrillation (AF). This retrospective clinical study was intended to assess the influence of drugs with antiinflammatory and/or renin-angiotensin-aldosterone system–modulating properties, namely angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs), and statins, on AF-free survival after AF ablation. Methods The study included 234 patients (23-80 years; 71.8% men) with drug-resistant paroxysmal (n = 165) or persistent AF (n = 69) who either underwent a Lasso-guided segmental pulmonary vein isolation (n = 83) or a CARTO-guided left atrial circumferential ablation (n = 151). Treatment with statins (n = 113), ACE-Is, or ARBs (n = 124), or a combination of a statin and an ACE-I or ARB (n = 75) was started N3 months before ablation and was continued during follow-up. Results
After a median follow-up of 12.7 months, 64% of patients with paroxysmal and 45% of patients with persistent AF were free of AF. Statin use (hazard ratio [HR], 1.06; P = .79), ACE-I or ARB use (HR, 1.12; P = .59), and their combined use (statin + ACE-I/ARB; HR, 1.17; P = .54) did not significantly influence ablation outcome as assessed by Cox regression analysis. In addition, after multivariate adjustment for potential confounders, the examined drugs did not significantly affect ablation outcome. Ablation induced an acute up-regulation of C-reactive protein levels (preablation vs 48 hours postablation, 5.9 F 8.1 vs 33.7 F 30 mg/L; P b .001) and other inflammatory markers. The examined drugs did not significantly alter baseline levels or ablation-induced up-regulation of inflammatory markers.
Conclusions The routine use of statins, ACE-Is, or ARBs did not result in an improved outcome of AF ablation. (Am Heart J 2007;153:11329.) The understanding of the pathophysiology of atrial fibrillation (AF) has changed drastically during the last several decades. A significant role of inflammation1,2 and of the renin-angiotensin-aldosterone system (RAAS)2,3 has been postulated both experimentally and clinically. Consequently, drugs with antiinflammatory or RAASmodulating properties attract growing interest as promising treatment modalities for AF. These drugs have been
From the Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria. Submitted June 10, 2006; accepted September 20, 2006. Reprint requests: Bernhard Richter, MD, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Wa ¨ hringer Gu¨rtel 18-20, A-1090 Vienna, Austria. E-mail: [email protected] 0002-8703/$ - see front matter n 2007, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2006.09.006
effective in preventing AF in diverse study populations with AF or at risk of AF.4-15 However, data on effects of drugs with antiinflammatory and RAAS-modulating properties on AF recurrence after radiofrequency (RF) ablation of AF are still lacking. Considering the process of tissue healing16 and reverse remodeling17 during the postablation period, these drugs could have the potential to reduce the substantial recurrence rate after AF ablation. The present study was intended to assess the influence of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs), and statins on AF-free survival after AF ablation.
Methods Subjects In the present study, patients undergoing catheter ablation of either symptomatic, drug-resistant paroxysmal or persistent AF were enrolled. The type of AF was defined according to
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block into PVs indicating total electrical isolation served as procedural end points.
Table I. Baseline characteristics Patients, n Patient age, y Men, n (%) Body mass index, kg/m2 Paroxysmal/Persistent AF, n Applied ablation technique (Lasso/CARTO), n Failed antiarrhythmic drugs (class I or III), n AF history, y Hypercholesterolemia, n (%) Arterial hypertension, n (%) Atherosclerotic cardiovascular disease, n (%) Structural heart disease, n (%) Left ventricular ejection fraction, % Left atrial diameter, mm
234 56.7 F 10.5 168 (71.8) 26.6 F 4.1 165/69 83/151 1.8 F 0.9 6.1 F 4.5 117 (50) 128 (54.7) 33 (14.1) 52 (22.2) 61.3 F 7.4 45 F 7
Continuous data are presented as mean F SD.
generally accepted guidelines.18 Baseline characteristics of the study population are presented in Table I. The study was performed according to the recommendations of the hospital’s ethics committee, and written informed consent was obtained.
Preablation treatment Adequate oral or subcutaneous anticoagulation was given for at least 1 month before the procedure. On admission, medical history, physical examination, 12-lead electrocardiogram, x-ray, transesophageal echocardiogram, and standard laboratory measurements were obtained.
Electrophysiological procedure Patients who were included between May 2002 and April 2004 underwent a Lasso catheter–guided ablation procedure19 (Lasso Catheter, Biosense Webster, Inc, Diamond Bar, CA). Patients included afterward were treated with a CARTO system–guided ablation procedure20 (electroanatomical mapping system CARTO, Biosense Webster, Inc). The procedure was performed with the patient under intravenous sedation using midazolam and fentanyl. Vascular access was obtained through the right and left femoral veins. Two 7-French deflectable catheters (Biosense Webster, Inc) were advanced into the right atrium and positioned at the atrioventricular junction and in the proximal coronary sinus. After transseptal puncture, patients received heparin intravenously aiming to maintain an activated clotting time around 300 seconds.
Lasso-guided procedure After double transseptal puncture, a deflectable, circular venous mapping catheter (Lasso catheter, 12-25 mm) and a temperature-controlled 4-mm-tip quadripolar catheter (Biosense Webster, Inc) were introduced into the left atrium. The Lasso catheter was advanced sequentially into each pulmonary vein (PV) and was used for ostial mapping of PV potentials. Ostial sites with the earliest bipolar activation and/or the most rapid unipolar intrinsic deflection were targeted for ablation. Radiofrequency energy was delivered with a maximum power output of 30 W and an upper temperature limit of 558C. Elimination of all ostial vein potentials and complete entrance
CARTO-guided procedure A temperature-controlled 8-mm-tip quadripolar catheter (Navistar, Biosense Webster, Inc) was advanced into the left atrium and used for mapping and ablation. The electromagnetic mapping system CARTO was used for the generation of a 3-dimensional electroanatomic map of the left atrium. Subsequently, circular ablation lines were placed around the left- and right-sided PVs, followed by an interconnecting roofline and a line from the left circle to the mitral annulus. The encircling lines were created at a distance of about 15 mm from the PV ostia and consisted of consecutive focal lesions. Radiofrequency energy was delivered at a maximum power output of 50 W and an upper temperature limit of 558C for 20 to 40 seconds at each ablation site. The end point of ablation was an 80% reduction in the amplitude of the local bipolar electrogram or a total of 40 seconds of energy delivery.
Postablation management and follow-up After ablation, all patients were continuously monitored and received intravenous heparin for 48 hours. Antiarrhythmic drug medication, if present before ablation, and oral anticoagulation were reinitiated and continued for at least 3 months. Patients were discharged 2 days after the procedure. Regular follow-up visits started 6 weeks after ablation and were subsequently conducted in 3-month intervals during the first year and in 3- to 6-month intervals afterward. Regular follow-up visits included a clinical evaluation, a 12-lead surface ECG, and Holter monitoring (24 or 48 hours). In addition, patients were instructed to contact the outpatient clinic whenever they experienced palpitations to document arrhythmias by ECG, Holter, or event monitoring. Successful ablation was defined as no recurrence of AF persisting or developing beyond a period of 2 months after ablation.
Blood sampling and laboratory methods The determination of C-reactive protein (CRP) levels, of the total leukocyte count, and of fibrinogen levels was part of the standardized periablation management and was performed in the hospital’s laboratory. Venous blood samples were collected at admission and on the morning of the second postablation day. The leukocyte count was measured in EDTA blood using a Sysmex XE-2100 Hematology Analyzer (SYSMEX EUROPE GMBH, Hamburg, Germany). Fibrinogen levels were determined in citrate plasma using the method of Clauss (STA-R analyzer, Diagnostica Stago, Asnieres, France). CRP levels were determined in heparinized plasma by the use of a commercially available immunological assay (Roche, Basel, Switzerland). The lower detection limit of the CRP assay was 2 mg/L.
Study design and statistical analyses This clinical study is a retrospective analysis of prospectively collected AF ablation data. The study was powered (80% power; 2-sided a = .05) to detect a risk ratio for AF recurrence of 0.73 or less between patients with and without drug treatment.
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Table II. Antiinflammatory and RAAS-modulating drug treatment Drugs Statins Atorvastatin Simvastatin Pravastatin Fluvastatin Rosuvastatin ACE-Is Ramipril Lisinopril Enalapril Fosinopril ARBs Candesartan Losartan Valsartan Eprosartan ACE-Is or ARBs Statins and ACE-Is or ARBs
n (%) 113 70 23 12 6 2 43 15 13 10 5 84 37 29 15 3 124 75
Table III. Ablation outcome
Dosage (mg/d)
(48.3) 10-80 10-80 10-20 20-80 40 (18.4) 2.5-12.5 15-40 20-40 20-40
Entire study population Lasso Paroxysmal AF Persistent AF CARTO Paroxysmal AF Persistent AF
Patients
Freedom from AF
n
n (%)
234 83 76 7 151 89 62
136 50 48 2 86 57 29
(58.1) (60.2) (63.2) (28.6) (57) (64) (46.8)
(35.9) 4-32 25-100 40-320 600-900 (53) (32.1)
Continuous data are given as mean F SD. Differences in continuous variables were evaluated using paired and unpaired Student t test where appropriate. The m2 test was used to assess differences in AF recurrence rates between different types of statins, ACE-Is, or ARBs. Univariate Cox regression analysis was performed to evaluate the influence of the variables of interest: (1) statin use, (2) ACE-I or ARB (ACE-I/ARB) use, and (3) their combined use (statin and ACE-I/ARB use), as well as of diverse patient characteristics on AF recurrence rates. A multivariate Cox regression model was used to adjust for potential confounders. A value of P b .05 (2-tailed) was considered statistically significant. Statistical analyses were carried out using the statistical software package SPSS 12.0 (SPSS Inc, Chicago, IL).
Results A total of 234 patients with either paroxysmal (n =165) or persistent (n = 69) AF were included in the study. Of these patients, 83 underwent a Lasso-guided ablation procedure, and 151 underwent a CARTO-guided procedure. Additional ablation of the cavotricuspid isthmus was carried out in 37 patients because of a history of isthmus-dependent right atrial flutter. When compared to the CARTO-guided procedure, the Lasso approach had a significantly shorter radiofrequency energy application time (21.9 F 10.6 vs 32.4 F 9.6 minutes; P b .001), a significantly longer fluoroscopic duration (64.1 F 18.4 vs 46.1 F 18 minutes; P b .001), and a significantly longer procedure duration (172.9 F 45.3 vs 141.7 F 42.8 minutes; P b .001).
Treatment with antiinflammatory and RAAS-modulating drugs Table II displays a detailed list of the statins, ACE-Is, and ARBs used in the study population. Of the 234 study
patients, 113 were treated with a statin, and 124 received either an ACE-I or ARB (ACE-I/ARB). Seventy-five patients were treated with a combination of a statin and ACE-I/ARB. Treatment started at least 3 months before ablation and was continued during follow-up. The indications for statin therapy were hypercholesterolemia (n = 113) and/or atherosclerotic cardiovascular disease (n = 24). ACE-I/ARB therapy was given because of arterial hypertension (n = 92), left ventricular hypertrophy (n = 42), atherosclerotic cardiovascular disease (n = 26), and/or left ventricular dysfunction (n = 15).
Ablation outcome After a median follow-up period of 12.7 months (95% confidence interval [CI], 11-14.4 months), 105 (64%) of 165 patients with paroxysmal AF and 31 (45%) of 69 patients with persistent AF were free of AF without (n = 82) or with antiarrhythmic drugs (n = 54) that had previously failed. Table III displays the corresponding data for the entire study population as well as for subgroups. Value of antiinflammatory and RAAS-modulating drugs after AF ablation Statin use (hazard ratio [HR], 1.06; 95% CI, 0.71-1.57; P = .79) (Figure 1, A), ACE-I/ARB use (HR, 1.12; 95% CI, 0.75-1.66; P = .59) (Figure 1, B), and the combined use of statins and ACE-I/ARBs (HR, 1.17; 95% CI, 0.711.94; P = .54) did not significantly influence AF-free survival after AF ablation (Table IV). Of the 136 patients with successful ablation, 65 patients (47.8%) were treated with statins, 70 patients (51.5%) with ACE-I/ ARBs, and 42 patients (30.9%) with a combination of a statin and ACE-I/ARB. Of the 98 patients with failed ablation, 48 (49%) received statins, 54 (55.1%) received ACE-I/ARBs, and 33 (33.7%) received a combination of both. There was no significant difference in AF recurrence rates between the different types of statins ( P = .32), ACE-Is ( P = .68), and ARBs ( P = .45). In addition, after adjustment for potential confounders by multivariate analysis including age, sex, hypercho-
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Figure 1
Table IV. Predictors of AF-free survival in univariate Cox regression analysis
Statins ACE-Is or ARBs Statins and ACE-Is or ARBs AAD use during follow-up Type of AFT Sex Age Body mass index Hypercholesterolemia Arterial hypertension Atherosclerotic cardiovascular disease Structural heart disease Left ventricular ejection fraction Left atrial size Applied ablation technique
HR
95% CI
P
1.06 1.12 1.17 0.81 1.94 0.9 0.99 1 0.97 1.11 0.82 0.93 0.97 1 1.27
0.71-1.57 0.75-1.66 0.71-1.94 0.53-1.24 1.28-2.93 0.57-1.41 0.98-1.01 0.95-1.05 0.65-1.43 0.75-1.66 0.44-1.54 0.57-1.53 0.59-1.6 0.97-1.03 0.83-1.95
.79 .59 .54 .33 .002 .65 .48 .92 .86 .6 .54 .79 .92 .98 .28
AAD, Antiarrhythmic drug use (class I or III). T Paroxysmal versus persistent AF.
Kaplan-Meier plot of the probability of freedom from recurrent AF in patients after radiofrequency ablation. A, With and without statin use. B, With and without ACE-I/ARB use. P values are derived from univariate Cox regression analysis.
lesterolemia, arterial hypertension, atherosclerotic cardiovascular disease, left ventricular ejection fraction, type of AF, antiarrhythmic drug treatment during followup, statins, and ACE-I/ARBs, the examined drugs did not significantly predict ablation outcome. Among all examined covariates, only the type of AF (paroxysmal vs persistent AF) was a significant univariate (HR, 1.94; 95% CI, 1.28-2.93; P = .002) (Table IV) and multivariate (HR, 1.97; 95% CI, 1.28-3.05; P = .002) predictor of ablation outcome.
Subgroup analyses None of the examined antiinflammatory or RAASmodulating drugs have the potential to significantly influence AF recurrence rates in the paroxysmal AF group or in the persistent AF group. In detail, in the paroxysmal AF group, the hazards of developing recurrent AF were 0.89 for statin use (95% CI, 0.53-1.47; P = .64), 1.02 for ACE-I/ARB use (95% CI, 0.62-1.7; P = .93), and 1.01 for the combined use of statins and ACE-I/ARBs (95% CI, 0.54-1.88; P = .97). The corresponding hazards in the persistent AF group were 1.18 for statin use (95% CI, 0.62-2.27; P = .62), 1.17 for ACE-I/ARB use (95% CI, 0.61-2.24; P = .64), and 1.22 for their combined use (95% CI, 0.52-2.88; P = .65). The examined drugs significantly affected ablation outcome in neither the subgroup of patients undergoing a Lasso-guided procedure nor the subgroup of patients undergoing a CARTO-guided procedure. In detail, in the Lasso-group, the hazards of developing recurrent AF were 0.8 for statin use (95% CI, 0.38-1.67; P = .55), 1.27 for ACE-I/ARB use (95% CI, 0.64-2.52; P = .5), and 1.17 for their combined use (95% CI, 0.48-2.81; P = .73). The corresponding hazards in the CARTO group were 1.13 for statin use (95% CI, 0.7-1.82; P = .63), 1.03 for ACE-I/ARB use (95% CI, 0.63-1.68; P = .91), and 1.09 for their combined use (95% CI, 0.59-2.03; P = .78). Inflammatory markers and ablation Ablation induced an acute up-regulation of CRP levels (preablation vs 48 hours postablation, 5.9 F 8.1 vs 33.7 F 30 mg/L; P b .001), leukocyte counts (5.84 F 1.66 109/L vs 6.59 F 1.73 109/L; P b .001), and fibrinogen levels (355.5 F 87 vs 443 F 76.2 mg/dL; P b .001). Statin use was not associated with signifi-
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cantly lower baseline CRP levels (statin vs no statin, 5.4 F 4.8 vs 6.3 F 10.3 mg/L; P = .48), leukocyte counts (6.03 F 1.57 109/L vs 5.66 F 1.73 109/L; P = .12), or fibrinogen levels (365.5 F 84.8 vs 345.9 F 85.9 mg/dL; P = .12) and did not significantly attenuate the ablation-induced up-regulation of the examined inflammatory markers. Similarly, ACE-I/ARB use did not significantly affect the baseline levels of inflammatory markers or the ablation-induced inflammatory response (data not shown).
Discussion The results of the present study demonstrate that the routine use of statins and ACE-I/ARBs as single drug treatment or as combination therapy does not significantly improve outcome of AF ablation. This holds true not only for the entire study population but also for the subgroups of patients with paroxysmal and persistent AF and for patients undergoing a Lasso-guided or a CARTOguided ablation approach. To the best of our knowledge, the present study is the first to evaluate the possible effects of the previously mentioned drugs on AF ablation outcome. Anne et al21 retrospectively examined the effects of ACE-Is and ARBs on the occurrence of AF in patients undergoing ablation of isthmus-dependent right atrial flutter and postulated a preventive effect of the assessed drugs on subsequent AF occurrence. Apart from this study, protective effects of ACE-Is, ARBs, and statins on the occurrence of AF have been observed in diverse nonablation cohorts. In detail, statins were considered effective in preventing AF after electrical cardioversion,9 after cardiac surgery,12 in patients with coronary artery disease,8 and in patients with left ventricular dysfunction.7 ACE-Is or ARBs exerted a protective effect against AF in patients with left ventricular dysfunction,5,6 in hypertensive patients with left ventricular hypertrophy,13 in patients with paroxysmal AF,14 in patients with myocardial infarction complicated by left ventricular dysfunction,15 and after cardiac surgery11 and electrical cardioversion.10 The search for new treatment modalities for the periand postablation management is driven by the substantial recurrence rate of AF ablation22 and the relative inefficacy of the currently available pharmacotherapy.23,24 The new agents are supposed to target key processes of the pathogenesis of AF, namely inflammation and angiotensin-mediated effects. Regarding inflammation, mounting evidence links increased CRP levels not only to already existing AF but also to the risk to develop future AF.1,2 As shown in the present study, ablation induces an acute inflammatory up-regulation reflected by an increase of CRP and fibrinogen levels and of the leukocyte count. The observed inflammatory response is consistent with previous histopathologic information on ablation-in-
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duced inflammatory activation16 and is supposed to contribute to the phenomenon of early AF recurrence.25 Correspondingly, in patients undergoing cardiopulmonary bypass surgery, the peak incidence of postoperative arrhythmia on the second to third postoperative day coincides with the CRP peak.26 Although it is not yet known whether inflammation acts as initiator or is just a consequence of AF, there is evidence that CRP-lowering therapies could prevent AF.14 Statins as well as ACE-Is and ARBs have the potential to modulate inflammatory pathways1,2 and could therefore reduce the susceptibility to AF after ablation in general and attenuate the acute inflammatory response in the early postablation period in particular. In the present study, however, none of the examined drugs significantly affected the acute upregulation of inflammatory markers during the early postablation period. Apart from inflammation, activation of the RAAS, which is commonly observed in AF patients, is supposed to constitute a key mechanism in the pathogenesis of AF.1,2 Up-regulation of the RAAS and consequently generation of angiotensin II promote atrial fibrosis and contribute to the structural and electrical remodeling of the atria by various actions.2,3 Elevated angiotensin II levels could particularly be harmful in the postablation period because extensive structural changes take place during this time span. These changes include processes of tissue healing and scar formation in the areas of RF lesions16 and reverse remodeling17 comprising reduction of left atrial size. RAAS inhibition by ACE-Is or ARBs has been shown to beneficially influence ventricular remodeling after myocardial infarction, which is another model of myocardial necrosis.27 With regard to AF, expected beneficial actions of RAAS inhibition include hemodynamic changes leading to lower intra-atrial pressure and wall stress,3 reduction of atrial fibrosis,3 modulation of refractoriness,1,2 stabilization of electrolyte concentrations,1 as well as modulation of sympathetic tone2 and ion channel function.2,3 Nevertheless, in the present study, neither statins nor ACE-I/ARBs had the potential to improve ablation outcome. A possible explanation might be the preserved left ventricular function in the examined cohort. In recent meta-analyses about beneficial effects of ACE-Is and ARBs on AF,4,28 AF prevention was greatest in patients with left ventricular dysfunction and was not constantly observed in patients with normal left ventricular function. Therefore, it cannot be excluded that performing the same study in patients with impaired left ventricular function might lead to different results. In addition, previous studies on AF prevention by antiinflammatory and RAAS-modulating drugs were predominantly conducted in populations at risk of AF and rarely in populations with already existing AF. The present study cohort, however, consists of patients with a long history of drug refractory AF and thus constitutes
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a collective with a rather advanced stage of the disease. The inefficacy of the examined drugs in these very patients might indicate that the treatment with the examined drugs is rather a domain of the early phase of AF development. Moreover, it has to be mentioned that only a small proportion of patients were treated with the highest recommended dosage of the examined drugs in the present study. Most patients received intermediate dosages. It is therefore open whether the use of the maximum dosage would have yielded significant results. However, in numerous previous studies on AF prevention, significant results have been observed with predominantly moderate doses of the examined agents.5,9,10,15 In addition, the median follow-up of 12.7 months might have been too short for beneficial changes to become observable. A follow-up period of several years might be necessary to show the effects of the respective drugs on ablation outcome because lengthy processes such as fibrosis and atrial remodeling are involved, and ablation itself might generate an overwhelming inflammatory reaction that could require months to overcome. Comparably, left ventricular hypertrophy, which constitutes another chronic myocardial alteration, has been shown to continuously regress under treatment with losartan over a period of several years.29 Contrary to this hypothesis, antiinflammatory and RAAS-modulating drugs have been effective in preventing AF after electrical cardioversion even after pretreatment of only several weeks.10 Despite a growing body of evidence to support a protective role of drugs with antiinflammatory or RAASmodulating properties, it should not be overlooked that there are also numerous studies that could not find a preventive effect on AF occurrence at all.30-33 These conflicting data may in part be related to profound differences in study populations such as differences in AF history and predisposing diseases. Furthermore, there was a great variance in study protocols that could contribute to controversial results. Among others, the sample size, follow-up duration, duration of drug application, and method to assess occurrence of AF varied widely. Moreover, a wide range of different substances have been examined. Especially in the case of statins, this could account for inconsistent results because the antiinflammatory properties and therefore maybe the AF preventing potential might vary among the available substances.34 Furthermore, it should not be overlooked that previous data are mainly derived from retrospective studies5,8,9,15,21 and might in part be biased because no multivariate adjustment for confounders has been performed. In addition, the conflicting results may also be indicative that the respective drugs might not be useful in all conditions associated with AF. Their beneficial
effects might be restricted to certain inflammatory or hemodynamic states that have not yet been identified. A better understanding of the pathogenesis of AF together with an improved knowledge on the ongoing inflammatory processes possibly by determination of serological inflammatory markers might be helpful to select the suitable candidates for a treatment with the respective drugs. At the moment, it remains open whether AF patients with a certain amount of atrial fibrosis and remodeling or maybe with certain predisposing or causal comorbidities such as left ventricular dysfunction4,28 or hypertrophy28 are more appropriate for the treatment with the respective drugs than others.
Limitations The study was a retrospective analysis of prospectively gathered data and hence is subject to the limitations inherent in any retrospective study. Medical treatment was not randomly assigned. Therefore, further evaluation by randomized, prospective trials is needed to finally answer the question whether antiinflammatory and RAAS-modulating drugs are useful after ablation. A possible limitation of this study is that AF-free followup included a proportion of patients continued on previously ineffective antiarrhythmic drugs reflecting a rather conservative strategy of withdrawal of antiarrhythmic drugs after ablation in our center. However, also after statistical adjustment for the covariate antiarrhythmic drug use during follow-up, the examined agents did not influence ablation outcome. Although systematic attempts to identify asymptomatic recurrence of AF were undertaken, as described in the Methods section, asymptomatic episodes of AF may have been missed. Conclusions The routine use of statins and ACE-I/ARBs as single drug treatment or as combination therapy did not significantly improve outcome of AF ablation. However, there is a rationale for large randomized, placebocontrolled prospective studies investigating this issue. We express our gratitude to Faustina Oberst for her great support.
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