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Review Article

Arterial hypertension and atrial fibrillation: Selectingantihypertensive therapy

Jirı Widimsky

Hypertension Center, Department of Medicine III, General University Hospital, Prague, Czech Republic

a r t i c l e i n f o

Article history:

Received 10 August 2012

Accepted 15 August 2012

Available online 17 August 2012

Keywords:

Hypertension

Atrial fibrillation

Antihypertensive therapy

nt matter & 2012 The Cze.1016/j.crvasa.2012.08.004

jwidi@lf1.cuni.cz

a b s t r a c t

Arterial hypertension is the most common cardiovascular disease. Atrial fibrillation in

hypertension has frequent occurrence, which increases with age. While the mechanism

underlying the development of atrial fibrillation is complex, hypertension is considered one

of the main pathogenic factors resulting in this arrhythmia. Hypertension is also the key

risk factor for stroke, with the risk markedly increasing in the presence of atrial fibrillation.

In addition, hypertension is a major factor when stratifying the risk of thromboembolism in

atrial fibrillation.

Antihypertensive therapy reduces not only the risk for stroke but also the risk for atrial

fibrillation.

Based on current evidence (mostly retrospective data), some classes of antihypertensive

agents seem to be more effective than others in preventing recent-onset atrial fibrillation.

This paper discusses various options of antihypertensive strategy in hypertensive patients

with atrial fibrillation. Anticoagulation and antiarrhythmic therapy make an integral part of

AF management.

& 2012 The Czech Society of Cardiology. Published by Elsevier Urban & Partner Sp. z o.o. All

rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e249

2. Atrial fibrillation and antihypertensive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e249

2.1. Renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors and angiotensin

receptor blockers) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e249

2.1.1. Results of meta-analyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e249

2.1.2. Results of individual studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e250

2.2. Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e250

2.3. Calcium-channel blockers (CCBs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e250

2.4. Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e250

2.5. Aldosterone antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e250

2.6. Combination antihypertensive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e251

ch Society of Cardiology. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

c o r e t v a s a 5 4 ( 2 0 1 2 ) e 2 4 8 – e 2 5 2 e249

3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e251

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e251

1. Introduction

Arterial hypertension is the most common cardiovascular

(CV) disease with a high prevalence (20–50%) in the adult

population of industrialized nations [1–3]. Together with

smoking, diabetes, dyslipidemia, and obesity (primarily

abdominal), arterial hypertension is also one of the major

risk factors for stroke, coronary heart disease (CHD), and

peripheral arterial disease. Meta-analyses of population-

based studies have consistently documented an association

between cerebrovascular and CV morbidity and mortality on

the one hand, and blood pressure (BP) levels on the other.

Atrial fibrillation (AF) is the most common arrhythmia whose

occurrence rises steeply with increasing age and is estimated

to be somewhere at 1–2% in the general population. Interest-

ingly, the prevalence of hypertension in studies designed to

investigate various aspects of AF is reported to be 50–90% [4].

Hypertension constitutes one of the leading risk factors when

calculating the annual risk for stroke (CHA2DS2-VASc score).

Left ventricular hypertrophy (LVH) and dilatation have been

shown to be independent risk factors for AF.

Because of the very frequent co-incidence of hypertension

and AF in hypertensive patients, the Task Force ‘‘Hyperten-

sion, arrhythmia, and atrial fibrillation’’ of the European

Society of Hypertension (ESH) decided to develop a position

paper summarizing current concepts of diagnostic, preven-

tive, and therapeutic approaches in hypertension associated

with AF [4]. Our brief paper discusses issues related to

selection of antihypertensive agents in patients with AF

based primarily on the ESH document [4].

2. Atrial fibrillation and antihypertensivetherapy

Given the high risk for CV events, and stroke in particular, in

hypertensive patients with AF, achieving normal BP levels is a

most important consideration. Adequate BP control in AF

patients is critical also because of the frequent concomitant

chronic anticoagulation therapy instituted in an effort to

reduce the risk for intracerebral and extracerebral hemor-

rhage with decreasing BP levels.

While antihypertensive agents reduce the risk for AF primar-

ily by decreasing BP per se, there may be other mechanisms

associated with individual classes of antihypertensives such as

Table 1 – Treatment of hypertension in AF according to ESH (R

1. The ultimate goal of treatment in hypertensive patients with AF i

2. Renin-angiotensin-aldosterone system blockers reduce the risk fo

high-risk patients, particularly in those with left ventricular dysfu

effects have been documented in post hoc analyses

3. Beta-blockers are effective in heart rate control and, perhaps, also i

their use in preventing recent-onset AF

4. There is a lack of data for the other classes of antihypertensive d

LVH or remodeling, an effect on sympathetic nervous activity,

and so on.

Given the scanty evidence from prospective clinical trials,

our choice of antihypertensive therapy can only be based on

data from secondary analyses of large randomized trial and

several meta-analyses. To date, the largest body of data has

been obtained for renin-angiotensin system (RAS) blockers

(see below).

Table 1 lists the main recommendations of the European

Society of Hypertension for the hypertensive patient with AF.

2.1. Renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors and angiotensin receptorblockers)

2.1.1. Results of meta-analysesAs the effect of antihypertensive therapy with RAS blockers

has been assessed in a number of meta-analyses, only the

largest ones are reviewed in the present paper. The main

complication when interpreting results of most studies

included into meta-analyses is that the overwhelming major-

ity of the trials have not been primarily designed to assess

the effect of various CV drug treatments on the risk for AF.

In their meta-analysis of 11 randomized controlled clinical

trials, Healay et al. [5] noted that RAS inhibitors significantly

reduce the relative risk (RR) for recent-onset AF by 28%

(15–40%); however, the benefit had been seen only in

patients with systolic dysfunction or those with LVH. In

another meta-analysis [6], use of angiotensin-converting

enzyme inhibitors (ACEIs) or angiotensin receptor blockers

(sartans, ARBs) was associated with an average 49% (35–72%)

relative reduction in the risk for recent-onset AF, a 53%

(24–92%) decrease in the incidence of failed electrical cardi-

oversion of AF, and with a 61% (20–75%) decrease in the

incidence of recurrent AF after electrical cardioversion.

In yet another meta-analysis by Schneider et al. [7], RAS

inhibition reduced the risk for AF by 32% (0.22–0.43;

po0.00001), with similar effects of ACEIs and ARBs. In

primary prevention, RAS inhibition was the most effective

option in patients with LVH and/or heart failure. In secondary

prevention, RAS inhibition decreased the probability of recur-

rent AF in cardioversion-treated patients by 45% (0.34–0.89;

po0.01) and in those receiving pharmacotherapy by 63%

(0.27–0.49; po0.00001).

ef. [4]).

s reduction of BP per se

r recent-onset AF. However, this effect has been shown mainly in

nction, LVH, and in myocardial infarction survivors. Most beneficial

n maintaining sinus rhythm. There is inadequate evidence regarding

rugs

c o r e t v a s a 5 4 ( 2 0 1 2 ) e 2 4 8 – e 2 5 2e250

2.1.2. Results of individual studiesIn the Valsartan Antihypertensive Long-term Use Evaluation

(VALUE) trial, use of valsartan (compared with amlodipine)

was associated with a 16% decrease (po0.0455) in the inci-

dence of at least once documented episode of recent-onset

AF, and decreased the incidence of persistent AF by 32%

(po0.0046) [8]. A similar benefit of sartans in decreasing the

incidence of recent-onset AF was documented in pre-

specified analysis of data from the Losartan Intervention

For Endpoint reduction in hypertension (LIFE) trial comparing

the incidence of recent-onset AF in losartan-treated patients

and those treated with the beta-blocker atenolol [9]. In the

ONgoing Telmisartan Alone and in combination with Rami-

pril Global Endpoint Trial (ONTARGET) [10], the incidence

of recent-onset AF was only slightly lower in the group

of patients receiving a sartan (telmisartan) than in those treated

with an ACEI (ramipril) suggesting there is no difference—in

this respect—between the two types of RAS inhibition.

No significant differences in modulating the risk for devel-

oping AF between the RAS inhibitors and placebo were

observed in the TRANSCEND (Telmisartan Randomised

AssessmeNt Study in ACE-INtolerant Subjects with Cardio-

vascular Disease), PROFESS (Prevention Regimen For Effec-

tively avoiding Second Strokes), and HOPE (Heart Outcomes

Prevention Evaluation) trials [11,12].

The recently published double-blind, placebo-controlled

Candesartan in the Prevention of Relapsing Atrial Fibrillation

(CAPRAF) trial did not demonstrate any benefit of candesar-

tan therapy in maintaining sinus rhythm after cardioversion

in patients not treated with antiarrhythmics [13]. Similar

conclusions were reported by the largest secondary preven-

tion GISSI-AF (Gruppo Italiano per lo Studio della Sopravvi-

venza nell’Insufficienza cardiaca atrial fibrillation) trial

involving 1442 patients with CV risk factors (primarily hyper-

tension, in 85%) and paroxysmal or persistent AF after a

recent cardioversion [14]. At one year, no effect on time to the

first recurrent episode of AF as the primary endpoint was

observed after the addition of valsartan to optimal pharma-

cotherapy (including antiarrhythmics). Likewise, no differ-

ences were seen in the numbers of patients experiencing

more than one recurrent episode of AF (26.9% vs. 27.9%)

compared with placebo [14].

Although the outcomes of individual trials and meta-

analyses assessing the effects of RAS blockers on AF preven-

tion are inconsistent, current ESH guidelines do prefer these

classes of antihypertensives for long-term use in this indica-

tion. The effect of RAS blockers seems to be the most marked

in individuals at high CV risk. For example, in the TRAndo-

lapril Cardiac Evaluation (TRACE) trial, long-term trandolapril

use in patients with heart failure resulted in a 55% reduction

of the risk for AF compared with placebo [15].

The beneficial effects of RAS blockers on reducing the risk

for AF can be partly explained by prevention of atrial

remodeling and reversal of LVH [9,16].

2.2. Beta-blockers

Beta-blockers are effective in heart rate control. In heart

failure patients, use of beta-blockers helps maintain sinus

rhythm [17].

In the LIFE trial, therapy based on the ARB losartan proved

to be superior to beta-blocker therapy with atenolol in

reducing the risk for recent-onset AF or its recurrence.

However, it is difficult to draw any authoritative conclusions

based on the results of trials comparing two or more regi-

mens of active antihypertensive therapy as it is not clear

whether the observed effects indicate an adverse effect of

one of the regimens or a beneficial effect of the other. The

United Kingdom-based General Practice Research Database

trial including records of an approx. 5 million patients

showed ACEIs, ARBs, and beta-blockers to be superior to

calcium-channel blockers in reducing the risk for AF [18].

Putative modes of action of beta-blockers in this context may

include prevention of adverse remodeling and ischemia or a

decrease in sympathetic tone.

2.3. Calcium-channel blockers (CCBs)

Calcium-channel blockers are a heterogeneous class of drugs

with antihypertensive properties. Non-dihydropyridines such

as diltiazem, and particularly verapamil, lead to delayed

ventricular response to AF. As a result, verapamil may be

effective in heart rate control in AF. As demonstrated by De

Simone et al. [19], verapamil in combination with propafe-

none may significantly decrease the incidence of recurrent AF

as compared with propafenone alone. In another study

involving patients with permanent AF following electrical

cardioversion, verapamil without additional antiarrhythmic

therapy failed to provide a clear benefit [20]. By contrast, long-

term verapamil use in patients with recurrent paroxysms of

AF resulted in a significant decrease in the incidence

of episodes of this arrhythmia [21]. An advantage of verapa-

mil in hypertension and AF, unlike dihydropyridine CCBs,

may be its potential inhibitory effect on sympathetic nervous

activity [22].

By contrast, in the VALUE trial, dihydropyridine CCBs

(amlodipine) were shown to be inferior to valsartan in

preventing AF [8]. Compared with verapamil, dihydropyridine

CCBs thus seem to be less effective in preventing AF.

Retrospective data not distinguishing between dihydropyr-

idine CCBs and verapamil from the US national integrated

database of medical care and pharmaceutical services showed

a lower incidence of recent-onset AF in ACEI-treated patients

as compared with CCB-treated ones [23].

2.4. Diuretics

The ability of diuretics to prevent AF in hypertension has not

been assessed in detail to date. Given the risk of hypokale-

mia, utmost caution should be exercised during chronic

antihypertensive therapy based on potassium-non-sparing

diuretics such as thiazides, chlorthalidone, and indapamide

[4], combined with plasma potassium monitoring.

2.5. Aldosterone antagonists

The risk of patients with primary hyperaldosteronism for

developing AF is 12 times that of patients with essential

hypertension [24]. As a result, it is appropriate to consider

this relatively frequent form of secondary hypertension in

c o r e t v a s a 5 4 ( 2 0 1 2 ) e 2 4 8 – e 2 5 2 e251

individuals with moderate-to-severe hypertension who

develop AF, particularly in the presence of kalemia below

4.0 mmol/l. The mechanism of the increased risk for AF in

primary aldosteronism seems to be complex with several

contributing factors such as hypokalemia, severe hyperten-

sion or LVH. Patients with AF have been reported to have

increased aldosterone levels [4]. Several trials with spirono-

lactone and eplerenone are currently underway.

2.6. Combination antihypertensive therapy

Combination therapy in hypertension should be used in at

least 70% of individuals with high BP levels. Quite surpris-

ingly, no data are available in this respect.

Potentially appropriate combinations in hypertension and

AF include those of an ACE inhibitor/ARBþa CCB (particularly

a non-dihydropyridine type/verapamil) or an ACE inhibitor/

ARBþa beta-blocker. Use of the latter dual combination may

be questioned given the lower additive antihypertensive

effect of the RAS blocker and beta-blocker combination.

A potentially useful combination in heart failure patients

may be that of an ACE inhibitor/ARBþa diuretic and/or an

ACE inhibitor/ARBþbeta-blocker.

3. Conclusion

There is no doubt patients with arterial hypertension are at

increased risk for developing AF. Drug-based strategies in AF

in hypertension should include not only antihypertensive but

also antiarrhythmic and anticoagulant agents. The main

classes of antihypertensives may seem to differ in modulat-

ing the risk for AF. Compared with other antihypertensive

classes, use of ACE inhibitors, angiotensin receptor blockers,

and beta-blockers seems to be more effective in preventing

AF, particularly in high-risk populations (with CHD, chronic

heart failure, left ventricular hypertension, and in myocardial

infarction survivors). Among the other antihypertensives,

verapamil is a potentially suitable alternative. Angiotensin-

converting enzyme inhibitors/ARBs plus CCBs (particularly

non-dihydropyridine type-verapamil) or ACEIs/ARBs and

diuretics may be useful options for combination antihyper-

tensive therapy in AF.

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