Statins and atrial fibrillation in patients with left ventricular dysfunction: Insights from the AF-CHF trial

Statins and atrial fibrillation in patients with left ventricular dysfunction: Insights from the AF-CHF trial

Letters to the Editor 575 Statins and atrial fibrillation in patients with left ventricular dysfunction: Insights from the AF-CHF trial☆,☆☆,★ Linda K...

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Letters to the Editor

575

Statins and atrial fibrillation in patients with left ventricular dysfunction: Insights from the AF-CHF trial☆,☆☆,★ Linda Koutbi, Denis Roy, Mario Talajic, Lucie Blondeau, Frédéric Franceschi, Lena Rivard, Laurent Macle, Jason G. Andrade, Peter G. Guerra, Bernard Thibault, Marc Dubuc, Paul Khairy ⁎ Electrophysiology Service, Montreal Heart Institute, Université de Montréal, Montreal, Canada Montreal Heart Institute Coordinating Center, Université de Montréal, Montreal, Canada

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Article history: Received 10 June 2012 Accepted 15 September 2012 Available online 30 September 2012 Keywords: Atrial fibrillation Heart failure Statins Mortality Hospitalization

It has been speculated that statins, by virtue of their pleiotropic antioxidant and anti-inflammatory properties, may protect against new onset atrial fibrillation (AF), decrease the risk of recurrent AF, and delay transition of paroxysmal to permanents forms [1–3]. However, there is a paucity of data regarding the effect of statins on AF in the setting of congestive heart failure (CHF). We, therefore, assessed the impact of statins on overall AF burden and recurrent AF in patients with CHF. The study population consisted of all 1376 patients enrolled in the AF-CHF trial. Inclusion criteria have been previously detailed [4]. In short, patients were required to have a left ventricular ejection fraction b25% or an ejection fraction ≤ 35% with either New York Heart Association functional class II–IV symptoms or a hospitalization for heart failure in the preceding 6 months despite therapy. Patients were required to have had at least one episode of AF with cardioversion or lasting N6 h in the preceding 6 months, or an episode N10 min with a prior history of cardioversion. Patients with persistent AF for N12 months were excluded. The overall AF burden, as previously defined [5], was considered the primary outcome. In short, time intervals between visits were divided into quartiles. “Sinus rhythm” or “atrial fibrillation” was assigned to each time-point for every patient on the basis of electrocardiographic documentation and the investigators' determination of AF occurrence between visits. Time to recurrent AF was assessed in patients randomized to rhythm control. Other secondary outcomes consisted of cardiovascular mortality, all-cause mortality, strokes, hospitalizations (total and cardiovascular), and worsening heart failure. All events were classified by an independent adjudicating committee blinded to the treatment assignment. Continuous normally distributed baseline characteristics between patients with and without statins were compared using independent Student's t tests, and non-normally distributed variables with nonparametric Mann–Whitney tests. Categorical baseline characteristics were compared using chi-square tests. Factors associated with AF

☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ☆☆ Financial support: The AF-CHF trial was funded by the Canadian Institutes of Health Research (CIHR). Dr. Khairy is supported by a Canada Research Chair in Electrophysiology and Adult Congenital Heart Disease. ★ Clinical Trial Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT88597077. ⁎ Corresponding author at: Montreal Heart Institute, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8. Tel.: +1 514 376 3330x3800; fax: +1 514 593 2581. E-mail address: [email protected] (P. Khairy).

burden were assessed in linear regression models. Candidate variables included baseline demographics, functional class, medical history, type and duration of AF, echocardiographic parameters, QRS duration, serum creatinine level, assigned treatment strategy, and pharmacological therapy. Variables significant at the 0.2 level in univariate analyses were included in an automated backward selection multivariate linear regression model. Survival free of recurrent AF in patients with and without statins randomized to rhythm control was plotted using the Kaplan–Meier method and compared by the by log-rank statistic. All other time-to-event outcomes were studied in the entire AF-CHF study population. Two-tailed P-values b 0.05 were considered statistically significant. The study protocol was approved by each center's institutional review board. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. The authors of this manuscript have certified that they comply with the principles of ethical publishing in the International Journal of Cardiology. A total of 1376 patients, age 67 ± 11 years, 81.7% male, were included and followed for 37 ± 19 months. Overall, 585 (42.5%) patients received statins, whereas 791 (57.5%) did not. Baseline characteristics are summarized in Table 1. The overall proportion of time spent in AF was similar in patients with and without statins [median 39.2% (0%, 100%) versus 37.6% (0%, 100%), P = 0.80]. In those randomized to rhythm control, the total AF burden was a median of 9.6% (0.0%, 46.1%) in statin users compared to 7.2% (0.0%, 48.0%) in the group without statins (P= 0.98). Similarly, in patients randomized to rate control, the overall AF burden was a median of 97.1% (27.4%, 100.0%) versus 96.4% (23.7%, 100.0%) in the groups with and without statins, respectively (P= 0.82). Factors associated with AF burden in univariate and multivariate linear regression analyses are summarized in Table 2. A total of 682 patients, age 66±11 years, were randomized to rhythm control. Actuarial event-free survival curves are portrayed in Fig.1. Factors associated with recurrent AF in univariate and multivariate Cox regression analyses are listed in Table 3. Statin therapy was not associated with a significant reduction in recurrent AF, cardiovascular mortality, allcause death, stroke, cardiovascular hospitalizations, all-cause hospitalizations, or worsening heart failure. Our results are consistent with a recent meta-analysis of 22 trials that found that statins were not associated with a significant reduction in AF [odds ratio 0.95, 95% confidence interval (0.88,1.03), P = 0.24] [6]. To our knowledge, it is the first study to assess the impact of statins on AF burden or recurrent AF in patients with a history of AF and heart failure. In the setting of heart failure, preclinical studies have suggested that statins attenuate atrial electrical and structural remodeling, oxidative stress, and AF promotion in tachycardia-induced and hypertensive cardiomyopathy models [7,8]. The AF-CHF trial provided a unique opportunity to assess the impact of statins on AF burden and recurrent AF in patients with a history of nonpermanent AF and heart failure. Importantly, statin therapy was not randomly allocated. Although attendant biases were thoroughly addressed by adjusting for baseline imbalances and potential confounders, multivariate analyses cannot control for unmeasured variables. Results were, however, unambiguous, with no suggestive protective

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Table 1 Baseline characteristics in all patients and according to whether or not they received statins.

Age, years Male sex, N (%) Body mass index, kg/m2b NYHA class III–IV symptoms, N (%) Persistent atrial fibrillation, N (%) Diabetes, N (%) Hypertension, N (%) Coronary artery disease, N (%) Left ventricular ejection fraction, % QRS duration, ms Prior stroke, N (%) Left atrial diastolic dimension, mm Mitral insufficiency, N (%) Serum sodium, mmol/L Creatinine, μmol/Lb Spironolactone, N (%) Beta-blockers, N (%) ACE inhibitor/ARB, N (%) Digoxin, N (%) Calcium antagonist, N (%) Oral anticoagulant, N (%)

All patients (N = 1376)

Statin therapy (N = 585)

No statin therapy (N = 791)

P-valuea

67 ± 11 1124 (81.7) 27.2 (24.5, 30.7) 431 (31.3) 944 (68.7) 283 (20.6) 656 (47.7) 656 (47.8) 27 ± 6 114 ± 30 124 (9.0) 49 ± 7 438 (33.7) 139 ± 4 105 (88, 125) 616 (44.8) 1085 (78.9) 1315 (95.6) 886 (64.4) 83 (6.0) 1215 (88.3)

68 ± 10 497 (85.0) 27.5 (24.6, 31.2) 200 (34.2) 371 (63.4) 176 (30.1) 313 (53.5) 440 (75.3) 27 ± 6 116 ± 31 66 (11.3) 49 ± 7 207 (38.3) 139 ± 4 107 (90, 133) 242 (41.4) 466 (79.7) 559 (95.6) 360 (61.5) 50 (8.6) 508 (86.8)

66 ± 12 627 (79.3) 26.9 (24.3, 30.3) 231 (29.2) 573 (72.5) 107 (13.5) 343 (43.4) 216 (27.4) 27 ± 6 112 ± 29 58 (7.3) 49 ± 8 231 (30.4) 140 ± 4 102 (88, 122) 374 (47.3) 619 (78.3) 756 (95.6) 526 (66.5) 33 (4.2) 707 (89.4)

b 0.0001 0.0070 0.0179 0.0487 0.0003 b 0.0001 0.0002 b 0.0001 0.4563 0.0130 0.0114 0.9578 0.0030 0.3486 b 0.0001 0.0292 0.5287 0.9860 0.0575 0.0008 0.1468

NYHA denotes New York Heart Association; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker. a Comparisons between patients with and without statin therapy. b Non-normally distributed continuous variables are summarized by median and interquartile range (25th, 75th percentile).

Table 2 Factors associated with the overall burden of atrial fibrillation over the course of the study.

Univariate analysis Statin therapy Rate versus rhythm control strategy Body mass index, kg/m2 NYHA class III–IV symptoms Persistent versus paroxysmal AF History of AF ≥ 12 months Prior stroke/TIA/intracranial bleed Left atrial diastolic dimension, mm Serum sodium, per mmol/L Digoxin therapy Oral anticoagulation Multivariate analysis Statin therapy Rate versus rhythm control strategy NYHA class III–IV symptoms Persistent versus paroxysmal AF History of AF ≥ 12 months Left atrial diastolic dimension, mm Serum sodium, per mmol/L

Beta-coefficient

Standard error

P-value

− 0.594 41.217 0.724 6.074 23.057 12.742 − 6.883 1.326 1.211 3.229 17.256

2.393 2.075 0.224 2.555 2.489 2.926 4.090 0.171 0.328 2.467 3.671

0.8041 b 0.0001 0.0013 0.0176 b 0.0001 b 0.0001 0.0927 b 0.0001 0.0002 0.1908 b 0.0001

3.109 40.848 5.748 18.137 10.781 2.242 1.015

2.145 2.088 2.286 2.329 2.694 0.144 0.293

0.1474 b 0.0001 0.0120 b 0.0001 b 0.0001 0.0020 0.0005

NYHA denotes New York Heart Association; AF, atrial fibrillation; TIA, transient ischemic attack.

trends. While the data does not permit an analysis of potential moleculespecific effects or dose responses, a meta-analysis of 7 randomized trials of standard versus more intensive statin therapy in 28,964 patients found no evidence that higher doses were associated with a reduction in risk of AF [6]. In conclusion, our analysis of the AF-CHF trial suggests that statins do not reduce the overall AF burden or risk of recurrent AF in patients with heart failure and a history of AF. These results further extend the growing body of literature that casts doubt on any clinically relevant beneficial effect of statins on AF, to the population of patients with heart failure. In the absence of a randomized trial that more definitively addresses this issue, there is no compelling clinical evidence to suggest that statins should be recommended to protect against recurrent AF in patients with heart failure.

Fig. 1. Recurrent atrial fibrillation in patients with and without statins randomized to rhythm control. The adjusted Kaplan–Meier curves plot actuarial survival free from recurrent atrial fibrillation in patients randomized to rhythm control, according to whether or not they received statin therapy.

References [1] Kumagai K, Nakashima H, Saku K. The HMG-CoA reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model. Cardiovasc Res 2004;62:105–11. [2] Shiroshita-Takeshita A, Brundel BJ, Burstein B, et al. Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure. Cardiovasc Res 2007;74:75–84. [3] Shishehbor MH, Brennan ML, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003;108:426–31. [4] Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–77. [5] Talajic M, Khairy P, Levesque S, et al. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. J Am Coll Cardiol 2010;55:1796–802. [6] Rahimi K, Emberson J, McGale P, et al. Effect of statins on atrial fibrillation: collaborative meta-analysis of published and unpublished evidence from randomised controlled trials. BMJ 2011;342:d1250.

Letters to the Editor Table 3 Factors associated with recurrent atrial fibrillation in patients randomized to rhythm control.

Univariate analysis Statin therapy Age, years NYHA class III–IV symptoms Paroxysmal versus persistent AF History of AF ≥ 12 months Prior stroke/TIA/intracranial bleed Left atrial diastolic dimension, mm Coronary artery disease Hypertension Diabetes Serum sodium, mmol/L Serum creatinine, μmol/L Multivariate analysis Statin therapy Paroxysmal versus persistent AF Prior stroke/TIA/intracranial bleed Diabetes Serum sodium, mmol/L

Hazard ratio

95% confidence interval

P-value

1.31 1.02 1.32 0.47 2.21 2.19 1.03 1.30 1.40 1.85 1.07 1.01

0.88, 1.94 1.00, 1.04 0.87, 2.02 0.30, 0.74 1.40, 3.48 1.33, 3.61 1.00, 1.05 0.87, 1.92 0.94, 2.09 1.21, 2.84 1.01, 1.13 1.00, 1.01

0.1784 0.0874 0.1921 0.0009 0.0006 0.0022 0.0705 0.1984 0.0946 0.0049 0.0276 0.0699

1.20 0.49 2.00 1.80 1.08

0.80, 1.82 0.31, 0.76 1.19, 3.34 1.15, 2.81 1.02, 1.14

0.3782 0.0015 0.0085 0.0107 0.0145

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[7] Shiroshita-Takeshita A, Brundel BJ, et al. Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure. Cardiovasc Res 2007;74:75–84. [8] Okazaki H, Minamino T, Wakeno M, et al. Statin prevents structural and electrical atrial remodeling in rat hypertensive heart failure induced by chronic inhibition of NO synthesis. Circulation 2007;116:140.

NYHA denotes New York Heart Association; AF, atrial fibrillation; TIA, transient ischemic attack.

0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.09.033

Hypertension trends in Chinese children in the national surveys, 1993 to 2009 Bo Xi a,⁎, Yajun Liang b, Jie Mi c,⁎⁎ a b c

Department of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan 250012, China School of Public Health, Jining Medical University, Jining 272067, China Department of Epidemiology, Capital Institute of Pediatrics, Beijing 100020, China

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Article history: Received 19 June 2012 Accepted 15 September 2012 Available online 29 September 2012 Keywords: Hypertension Obesity Trends Children

Hypertension, the risk factor for cardiovascular disease, is a major cause of adult morbidity and mortality worldwide [1]. Epidemiological studies have indicated that adult hypertension begins at childhood [2]. Actually, hypertension at childhood is significantly associated with increased risk of end-organ damage ⁎ Correspondence to: B. Xi, Department of Maternal and Child Health Care, School of Public Health, Shandong University, 44 Wen Hua Xi Road, Jinan 250012, China. Tel./fax: + 86 531 88382134. ⁎⁎ Correspondence to: J. Mi, Department of Epidemiology, Capital Institute of Pediatrics, 2 Yabao Road, Beijing 100020, China. Tel.: +86 10 85695591; fax: + 86 10 85632799. E-mail addresses: [email protected] (B. Xi), [email protected] (J. Mi).

including ventricular hypertrophy and increased carotid intima–media thickness [3]. In addition, given the well established association between hypertension and obesity [4], and increased trends in children obesity [5], it is believed that children hypertension has increased in the past decades because of upward trends in obesity. To date, several studies have attempted to investigate whether hypertension increased is in accordance with the obesity trends in children. However, the results have been inconsistent [6–11]. Some studies showed upward blood pressure (BP) trends [6,7], while others indicated downward [8–10] or parallel [11] BP trends. National surveys conducted periodically are necessary to provide updated information for development of effective programs and strategies to prevent and control hypertension [12]. The China Health and Nutrition Survey (CHNS) is a large-scale, national and successive cross-sectional survey that was designed to explore how the health and nutritional status of the Chinese population has been affected by social and economic changes [13]. A multistage, random cluster process was used to draw study sample from nine provinces (Liaoning, Heilongjiang, Jiangsu, Shandong, Henan, Hubei, Hunan, Guangxi and Guizhou). Recently, based on CHNS data, we have reported that both obesity and hypertension increased greatly in Chinese adults during the past decades [14,15]. Although our previous publication indicated that children hypertension increased from 1991 to 2004 in Chinese children [7], the recent trends after 2004 are unclear.