The role of the renin–angiotensin system blocking in the management of atrial fibrillation

Figures & data

Table 1.  Causes of atrial fibrillation.

Cardiac	Non-cardiac
Valvular disorders	Thyrotoxicosis
Left ventricular hypertrophy	Pulmonary embolism
Heart failure	Rare mutations in a series of ion channels
Coronary artery disease	Sepsis
Congenital heart disease	Pneumonia
Sick sinus syndrome
Pericarditis
Myocarditis
Hypertension

Figure 1.  Renin–angiotensin system.

Table 2.  Actions of aldosterone.

(1) Regulation of K^+ homeostasis

(2) NaCl retention which helps to prevent arterial hypotension35 by retaining blood volume

(3) Non-geonomic actions which recent evidence suggests maybe attributable to the classical mineralocorticoid receptors36

(4) Improvement of endothelial cell dysfunction and a reduction in vascular smooth muscle cells and myocyte remodeling. This contributes to improved vascular compliance, which in turn reduces the development of left ventricular dysfunction and end-organ damage30

Table 3.  Summary of clinical trials.

First author/study, year published (reference number)	Population	Number of patients	Drug used	Control drug	Mean follow-up	Finding	p-value
Left ventricular dysfunction
Pedersen (TRACE), 1999	LVD secondary to MI	1577	Trandolapril	Placebo	2–4 years	Reduced new onset AF 5.3 vs. 2.8% RR 0.55; 95% CI 0.33–0.91	<0.05
Vermes (SOLVD), 2003	LVD, CHF	374	Enalapril	Placebo	3.3 years	Reduced new onset AF 24 vs. 5.45% RR 0.30; 95% CI 0.15–0.58	<0.0001
Maggioni (Val-HeFT), 2005	LVD	4395	Valsartan	Placebo	23 months	Reduced new onset AF 7.95 vs. 5.12% RR 0.70; 95% CI 0.57–0.87	<0.0002
Ducharme (CHARM), 2006	LVD, CHF, PLVF	6379	Candesartan	Placebo	37.7 months	Reduced new onset AF 6.15 vs. 5.55% RR 0.822; 95% CI 0.662–0.998	0.048
Hypertension
L'Allier, 2004	HTN, retrospective study of a cohort of 10,926 patients	10926	ACE inhibitors	CCB	4.5 years	Reduced new onset AF 22.1 vs. 19.4% RR 0.95; 95% CI 0.74–0.97	0.018
Wachtell (LIFE), 2005	HTN, LVH	8815	Losartan	Atenolol	4.9 years	Reduced new onset AF 10.1 vs. 6.8% RR 0.67; 95% CI 0.56–0.84	<0.001
Hansson (CAPP), 1999	HTN	10,985	Captopril	β-blockers and/or diuretics	6.1 years	No difference in new onset AF RR 0.87%; 95% CI 0.68–1.11	NS
Hansson (STOP-H2), 1999	HTN	6614	Enalapril or CCBs	β-blockers and/or diuretics	5.0 years	No difference in new onset AF between the three groups RR 1.10; 95% CI 0.93–130	NS
Julius (VALUE), 2004	HTN	15313	Valsartan	Amlodipine	4.2 years	No difference in new onset AF RR 1.19; 95% CI 0.96–1.47	NS
Heckbert, 2009	HTN	2322	Varied in study	Nil	NS	Reduced episodes of new onset AF. adjusted OR 0.63, 95% CI 0.44–0.91	NS
Yamashita T, (J-RHYTHM II), 2010	HTN	318	Candesatran	Amlodipine	1 year	No difference in new onset AF 3.8 ± 5.0 in the ARB group vs. 4.8 ± 6.3 in the CCB group	NS
ONTARGET investigators, 2008	HTN	25620	Ramipril or temlisartan		56 months	No difference in new onset AF 16.5 vs. 16.7%; RR 1.01; 95% CI 0.94–1.09	NS
Yusuf (Transcend), 2008	HTN, intolerant to ACE-i	5926	Temlisartan	Placebo	56 months	No difference in primary events. 15.7 vs. 17.0%, HR 0.92, 95% CI 0.81–1.05	0.216
Post-MI and CABG
Pizetti (GISSI), 2001 (25)	Post-MI	17,749	Lisinopril or lisinopril and nitrates	Nitrates	42 days	No significant reduction in new onset AF RR 0.93; 95% CI 0.84–1.03	NS
Mathew 2004 (26)	Post-CABG	4657	ACE inhibitors	No ACE inhibitors	NS	Postoperative withdrawal of ACE inhibitor increased risk of AF OR 1.69; 95% CI 1.38–2.08 Reduced risk of AF with pre and Postoperative administration of ACE Inhibitors OR 0.62; 95% CI 0.48–0.79	0.001 <0.001
Mathew	Undergoing CABG	4657 (626 given ACE-I)	ACE-I	–	NS	Reduced incidence of new onset AF. CI (0.62 (0.48–0.79)	<0.001
Recurrence of AF
Van den Burg, 1995	Post electrical CV, CHF	30	Lisinopril	Placebo	84 days	Sinus rhythm maintained in 71% in the lisinopril vs. 36% in the placebo group	NS
Madrid, 2002	AF, post pharmacological and electrical CV	154	Irbesartan and amiodarone	Amiodarone	254 days	More patients in the Irbesartan group remained in SR 84.79 vs. 63.16%. This remained statistically significant on multivariate analysis RR 0.19; 95% CI 0.04–0.86	0.031
Ueng, 2003	Post electrical CV	125	Enalapril and amiodarone	Amiodarone	270 days	More patients in the enalapril group remained in SR 74.3 vs. 57.3% HR 0.60; 95% CI 0.25–0.91*	0.021
Yin, 2006	Paroxysmal AF	177	Losartan and amiodarone, perindopril and amiodarone	Amiodarone	2 years	Significant reduction in recurrence of AF in losartan and amiodarone (19%) (RR 0.46; 95% CI 0.17–0.75) and perindopril and amiodarone (24%) groups (RR 0.58; 95% CI 0.20–0.78) vs. 41% in the amiodarone	0.006 0.008
Murray, 2004	AF	732	ACE inhibitors or ARBs	No ACE inhibitors or ARBs	3.5 years	No difference in AF recurrence HR 0.91; 95% CI 0.77–1.09	NS
Van Noord, 2005	AF	107	ACE inhibitors treatment before start of the present episode of AF	No ACE inhibitors	1 month	Pre-treatment with ACE inhibitors improved acute success of ECV. Recurrence at 1 month was similar RR 0.98; 95% CI 0.75–1.66	0.04 NS
Richter, 2006	AF	234	Statins, ACE inhibitors or ARBs. Statins plus an ACE inhibitor or ARBs.	NA	12.7 months	No difference in AF recurrence after ablation	NS
Aenn, 2004	AF	196	ACE inhibitors/ARBs	NA	2.2 years	ACE inhibitors/ARBs pre-treatment reduced risk of post ablation AF RR 0.55; 95% CI 0.31–0.97	0.04
CAPRAF	AF prior to ECV	124	Candesartan	Placebo	29 days	No difference in recurrence of AF
Fogari, 2008	HTN and DM and AF	296	Valsartan	Atenolol	1 year	Fewer recurrences of AF 20.3 vs. 34.1%	<0.01
Fogari, 2008	HTN	369	Valsartan or ramipril	Amlopine	1 year	Fewer recurrences in AF with trial drugs. 16.1 vs. 27.9 vs. 47.4%	<0.01

ACEI, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; AF, atrial fibrillation; CABG, coronary artery bypass graft; CHARM, Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity program; CAPP, Captopril Prevention Project; CCBs, calcium channel blockers; CHF, congestive heart failure; EC, electrical cardioversion; GISSI, The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardio trial; HTN, hypertension; LVD, left ventricular dysfunction; LIFE, Losartan Intervention for End Point Reduction in Hypertension trial; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; n/a, not available; NS, not significant; PLVF, preserved left ventricular function; MI, myocardial infarction; SOLVD, Study of Left Ventricular Dysfunction trial; STOP-H2, Swedish Trial in Old Patients with Hypertension-2 study; TRACE, Trandolapril Cardiac Evaluation Study; Val-HeFT, Valsartan Heart Failure Trial; VALUE, Valsartan Antihypertensive Long-term Use Evaluation.

*Subgroup of patients with left atrial size >40 mm

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