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Chapter 7Tailored treatment strategies: a new approach for modern management of atrial fibrillation

Isabelle C. Van Gelder, Anne H. Hobbelt, Ernaldo G. Marcos, Ulrich Schotten,

Riccardo Cappato, Thorsten Lewalter, Jonas Schwieler, Michiel Rienstra, and

Giuseppe Boriani

Journal of Internal Medicine 2016;279(5):457-66.

92 Chapter 7

absTRaCT

Atrial fibrillation (AF) is not benign. Cardiovascular diseases and risk factors differ im-

portantly amongst patients. Careful phenotyping with the aim to start tailored therapy

may improve outcome and quality of life. Furthermore, structural remodelling plays an

important role in initiation and progression of AF. Therapies that interfere in the remod-

elling processes are promising because they may modify the atrial substrate. However,

success is still limited probably due to variations in the underlying substrate in individual

patients. The most favourable effects of lifestyle changes on success of rhythm control

have been demonstrated in obese patients with AF. Differences in genotype may also play

an important role. Common gene variants have been associated with recurrence of AF after

electrical cardioversion, antiarrhythmic drug therapy and catheter ablation. Therefore,

both phenotyping and genotyping may become useful for patient selection in the future.

Beside the choice of rate or rhythm control, and type of rhythm control, prevention of

complications associated with AF may also differ depending on genotype and phenotype.

Efficacy of stroke prevention has been well established, but bleeding remains a clinically

relevant problem. Risk stratification is still cumbersome, especially in low-risk patients

and in those with a high bleeding risk. The decision whether to start anticoagulation (and

if so which type of anticoagulant) or, alternatively, to implant an occlusion device of the

left atrial appendage may also be improved by genotyping and phenotyping. In this review,

we will summarize new insights into the roles of phenotype and genotype in generating

more tailored treatment strategies in patients with AF and discuss several patient-tailored

treatment options.

Chapter 7 93

inTRoduCTion

Atrial fibrillation (AF) is a cardiovascular epidemic affecting millions of people. AF is a

progressive disease that is associated with significant disease burden and increased cardio-

vascular morbidity and mortality. To improve outcome, it is important to develop safe and

effective treatment strategies tailored to the individual patient.1, 2

So far, predominantly clinical markers of AF progression have been identified, sum-

marized in the HATCH score (i.e. hypertension, age >75 years, thromboembolic event,

pulmonary disease and heart failure).1 However, the HATCH score, such as the CHADS2,

CHA2DS2-VASc and HAS-BLED scores, is fairly indiscriminate and may misclassify many

patients as high risk, whereas their actual risk could remain low for the next decade.3–5

Over the past 20 years, it has become clear that the phenotypes of patients with AF differ

substantially. Translational research has demonstrated that the pathophysiological mecha-

nism and the diversity of molecular alterations leading to AF differ depending on the aeti-

ology of AF. In the last 10 years, there has been a dramatic increase in the understanding of

AF aetiologies and mechanisms as well as new forms of heart disease. Furthermore, many

previously unknown aetiologies of AF have been identified.6 The wide variety of conditions

now known to be associated with AF is shown in Table 1.

Multiple scientific and technical approaches have been and are being developed to iden-

tify the mechanisms through which the various aetiologies lead to AF.7 Currently, we can-

not establish the specific mechanisms for AF in the individual patient. Our goal, however,

is a mechanistic classification for AF that is increasingly moving from an inconceivable

idea to a realistic objective. The believe is that we may be able to classify an individual’s

AF based, at least in part, on mechanistic considerations as well as assess the risk of AF

progression and cardiovascular complications, including stroke, more accurately in the

near future. This may help to determine which therapeutic strategy should be instituted

in individual patients. Therapeutic choices include starting with rate or rhythm control

management, deciding whether to prescribe a particular antiarrhythmic drug and/or atrial

ablation therapy, choosing whether or not to treat with an anticoagulant, and if so which

anticoagulant, and deciding whether or not to implant a left atrial appendage (LAA) occlu-

sion device.

In this review, we will summarize new insights into the role of phenotype and genotype

in generating more tailored treatment strategies in patients with AF, and discuss several

patient-tailored treatment options.

94 Chapter 7

Table 1. Risk factors associated with atrial fibrillationa

Conventional risk factors

Advancing age

Male sex

Coronary heart disease

Hypertension (above 140/90 mmHg)

Heart failure

Valvular heart disease

Diabetes mellitus

Hyperthyroidism

Others

Less well-established risk factors

Chronic obstructive pulmonary disease

Left atrial dilatation

Atrial conduction delay/PR interval

Left ventricular diastolic dysfunction

Left ventricular hypertrophy

Obesity

Obstructive sleep apnoea syndrome

Genetic factors

Others

Emerging risk factors

Subclinical atherosclerosis

Borderline hypertension (between 120/80 and 140/90 mmHg)

Chronic kidney disease

Subclinical hyperthyroidism

Inflammation

Widened pulse pressure

Excessive endurance exercise

Excessive alcohol intake

Increased height

Increased birth weight

Smoking

Caffeine intake

Ethnicity

Others

a The list is not necessarily exhaustive.Adapted from Wyse et al.14, with permission.

Chapter 7 95

GenoTyPe- and PhenoTyPe-TailoRed af TheRaPy

Structural remodelling plays an important role in the initiation and progression of AF. It

can be caused by risk factors for AF including increasing age, underlying diseases1, 2 and

other factors such as altered metabolism, autonomic changes and genetic and environ-

mental influences (Fig. 1).8 With progressing pathophysiological insights into the mecha-

nisms of AF and increasing awareness of the diversity of molecular alterations leading to

an enhanced susceptibility to and progression of AF, the quest for the diagnostic means to

distinguish between different forms of the arrhythmia has increased considerably over the

past years. One such attempt is based on the observation that AF is a heritable disease. The

lifetime risk of AF is increased by 40% in individuals with a family history of the arrhythmia

(Fig. 2). This percentage may even be higher if AF starts at a young age and no overt struc-

Figure 1. Roadmap from current clinical to personalized cardiovascular medicineOn the left, current practice, using clinical characteristics and risk factors for decision-making, is shown. A better understanding of the molecular disease mechanisms and markers that can identify specific mechanisms in patients, especially in common, chronic and multifactorial cardiovascular diseases such as heart failure and atrial fibrillation, is needed to improve therapies to reverse disease processes and improve outcome in patients. Adapted from Kirchhof et al.,48 with permission.

96 Chapter 7

tural heart disease is present.6, 9 This observation has triggered genomewide association

studies that have so far identified14 common gene variants associated with AF.10–12

The most important common gene variant associated with AF is a polymorphism close to

the gene PITX2 on chromosome 4q25 (rs2200733).10 Fine mapping of chromosome 4q25

revealed that there are four independent variants in this region which are all associated

with an increase in AF risk.13 Depending on the number of AF risk alleles, the relative risk

of AF varies between 0.7 and 3.2 in European populations and from 0.4 to 2.0 in Japanese

populations compared to the respective average risk of AF.13

The exact mechanism underlying the effect of common gene variants on the pathophysi-

ology of AF is currently under investigation. PITX2 is a transcription factor that is involved

in cardiac development and right–left determinism during embryological development.

The expression of PITX2 is far higher in the left atrium than in the right atrium, indicating

a mechanism primarily affecting the left atrium. Other common gene variants may affect

ion channel function, Ca2+ metabolism, metabolic functions and the regulation of the

extracellular matrix.12

Of interest, common gene variants close to PITX2 have been associated with recurrence

of AF after electrical cardioversion, during antiarrhythmic drug therapy, and after catheter

ablation, and thus may be useful in the future for patient selection of rhythm control strate-

gies (patient-tailored therapy).14–17 However, to date, the cohorts investigated have been

Figure 2. Role of family history on risk of atrial fibrillation (AF)There is a 40% increased risk of AF in the case of a family history of AF.Adapted from Lubitz et al.9, with permission.

Chapter 7 97

small, and the exact contribution of common gene variants and the independent associa-

tion of these variants to the onset and recurrence of AF remain to be established.

Convincing evidence of differential responsiveness of AF therapy in patients with com-

mon gene variants associated with AF is currently lacking; therefore, it has not yet been

possible to establish a genotype-tailored approach to AF. For this reason, genetic testing

targeted to common gene variants is currently not recommended in the general AF popu-

lation.18 More research is needed to determine whether a personalized decision-making

approach targeting the pathophysiological drivers underlying AF can fulfil the promise to

improve treatment outcomes and minimize adverse events.

RaTe and RhyThm ConTRol TailoRed To The PhenoTyPe

Symptom reduction and prevention of severe complications are the main targets of AF

treatment. These therapeutic goals need to be pursued in parallel. Prevention of AF-related

complications relies on antithrombotic therapy, control of ventricular rate and adequate

therapy of concomitant cardiovascular diseases (cardiovascular risk management). These

therapies may already alleviate symptoms, but symptom relief may require additional

rhythm control therapy by cardioversion, antiarrhythmic drug therapy or ablation therapy

(Fig. 3). Although rhythm control strategies including AF ablation techniques are continu-

ally improving, the success of rhythm control is limited. In terms of cardiovascular outcome,

no benefit has been shown for rhythm control strategies over approaches in which AF is

accepted.19, 20 In fact, anticoagulant treatment is currently the only therapy that has been

shown to improve the prognosis of patients with AF.21 Although underlying heart disease

may be a more important determinant of prognosis than rhythm control22, results of the

rate versus rhythm control trials may have been influenced by failure of pharmacological

rhythm control strategies. In addition, patients included in these trials had relatively long

histories of AF. Therefore, there is a considerable need to search for early AF treatment,

with therapies that significantly improve the current treatment and prognosis of patients

with AF in a cost-effective way.23

Therapies that interfere early in the structural remodelling process are promising and

are increasingly being used, in part for cardiovascular risk management. The term ‘up-

stream therapy’ refers to the use of non-antiarrhythmic drugs that may modify the atrial

substrate or target specific mechanisms of AF to prevent the occurrence or recurrence

of the arrhythmia. Such agents include renin–angiotensin–aldosterone system (RAAS)

modulators, statins, N-3 polyunsaturated fatty acids and glucocorticoids. Interventions to

promote a better lifestyle including physical activity, weight reduction and a healthy diet

could also be considered as upstream therapies.24–28 The key targets of upstream therapy

are structural changes in the atria, such as fibrosis, hypertrophy, inflammation and oxida-

98 Chapter 7

tive stress, but direct and indirect effects on atrial ion channels, gap junctions and calcium

handling are also applied. As a consequence of these effects, upstream therapies may be

more effective in maintaining sinus rhythm than conventional rhythm control therapies.

Regrettably, however, at present the beneficial effect of upstream therapy instituted as

secondary prevention seems limited24, 25, even in patients with paroxysmal AF as included

in the Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) study.29 In

the ANTIPAF trial, 430 patients with paroxysmal AF were randomly assigned to 40 mg olm-

esartan daily or placebo and were followed using daily transtelephonic electrocardiogram

recordings. After 1 year, the primary end-point (AF burden) was not significantly different

between groups (Fig. 4). The lack of beneficial outcome may be related to the late start of

upstream therapies at the moment when the structural remodelling had already occurred

or, alternatively, may be due to a wide range of phenotypes amongst patients included in

the majority of studies. Favourable effects of lifestyle changes on the success of rhythm

control have been demonstrated in a selected group of patients, namely obese patients

with AF.26–28 In a randomized control trial, 150 obese symptomatic patients with AF were

randomly assigned to either weight management including physical activity and counsel-

Figure 3. ‘Natural’ time course of atrial fibrillation (AF)The dark blue boxes show a typical sequence of periods in AF against a background of sinus rhythm and illus-trate the progression of AF from silent and undiagnosed to paroxysmal and chronic forms (at times symptom-atic). The upper bars indicate therapeutic measures that could be pursued. Lighter blue boxes indicate thera-pies that have proven effects on ‘hard outcomes’ in AF, such as stroke or acute heart failure. Red boxes indicate therapies that are currently used for symptom relief, but may in the future contribute to reduce AF-relatedcomplications. Rate control (grey box) is valuable for symptom relief and may improve cardiovascular out-comes. Adapted from The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC)49, with permission.

Chapter 7 99

ling or general lifestyle advice, both in combination with aggressive cardiovascular risk

management.26 In addition to a significant reduction in body mass index, AF symptoms

and AF burden were significantly reduced in the patients assigned to aggressive weight

management. A subsequent study conducted by the same investigators, the long-term ef-

fect of goal-directed weight management in an atrial fibrillation cohort: a 5-year follow-up

(LEGACY) study, showed that progressive weight loss was associated with a reduction in

AF burden and symptoms in obese patients with symptomatic AF and, in addition and of

particular interest, weight loss had a beneficial effect on cardiac structure.28 Left atrial vol-

ume corrected for body surface area decreased significantly suggesting reversal of the atrial

remodelling process. Therefore, at present, obese patients with AF represent a phenotype

that may deserve patient-tailored therapy including lifestyle management and strategies

for weight loss.

In the routine versus aggressive upstream rhythm control for prevention of early atrial

fibrillation in moderate heart failure (RACE 3) trial, we investigate whether the combi-

nation of RAAS modulators, statins and cardiac rehabilitation interventions to promote

a better lifestyle (including physical activity, weight reduction and a healthy diet) would

reduce progression of the arrhythmia in patients with persistent AF.30

Of interest is the role of the patient’s genotype. As mentioned above, common gene vari-

ants close to PITX2 are associated with recurrent AF and thus may be useful for selection

of patients for rhythm control strategies in future.14–17, 31 However, subsequent studies are

warranted to establish the role of genotype in patient-tailored therapy.

Figure 4. Distribution of the primary study end-point [atrial fibrillation (AF) burden] by study group (olmes-artan versus placebo)This mirror histogram shows the AF burden in the two groups (P = 0.770). Adapted from Goette et al.29, with permission.

100 Chapter 7

ChRoniC kidney disease and af

Several comorbidities may importantly affect therapeutic approaches in patients with AF,

both for rate and rhythm control and for initiation of oral anticoagulant drugs (OAC).

The prevalence of chronic kidney disease (CKD), defined as a glomerular filtration rate

(GFR) < 60 mL min-1/1.73m2 for > 3 months, is more than 10% in the adult population

and reaches 47% in individuals older than 70 years, and there is a clear temporal trend

towards increasing prevalence according to data from the USA.32, 33 Most of the increase in

the prevalence of CKD can be explained by the increasing prevalence of hypertension and

diabetes in the population. The presence of CKD is associated with an increased risk of

subsequently developing AF and vice versa.34 In patients on dialysis the prevalence of AF is

high, with estimates ranging from 7% to 27%, and increasing with age.35 The prevalence of

AF in the predialysis stages of CKD appears to be in the range of 4–21%.35 CKD is currently

classified in different stages, on the basis of GFR, as shown in Table 2.35 Amongst patients

with GFR < 60 mL min-1/1.73m2, incident AF was found to be associated with an increased

risk of evolution to end-stage renal disease, the most advanced stage of CKD, indicating

that AF can accelerate CKD progression.35 Various factors may explain the increased risk

of AF in CKD, including electrolyte imbalances (acute or chronic), increased dispersion

of repolarization, myocardial fibrosis, left ventricular hypertrophy and dysfunction, au-

tonomic imbalance, endothelial dysfunction, inflammatory processes, oxidative stress,

acidosis, uraemia and haemodynamic instability during haemodialysis.35 Patients with

AF and CKD are at high risk of stroke and thromboembolism, as well as major bleeding,

thus creating a therapeutic dilemma related to the risk–benefit ratio of oral anticoagulants,

which becomes extremely challenging in the setting of renal-replacement therapy, whether

this is dialysis or renal transplantation.36 It is noteworthy that recent observational data

suggest that anticoagulation could be associated with a slowing of CKD progression in

patients with AF and CKD.35 All the currently available non-vitamin K antagonist OACs

(NOACs) have a degree of renal excretion and should not be used in the case of severe renal

impairment (creatinine clearance < 25–30 mL min-1), a setting in which warfarin remains

Table 2. Staging of chronic kidney disease according to GFR

GFR category GFR (mL/min/1.73 m2) Stage of renal function

G1 ≥90 Normal or high

G2 60–89 Mildly decreased

G3a 45–59 Mildly to moderately decreased

G3b 30–44 Moderately to severely decreased

G4 15–29 Severely decreased

G5 <15 Kidney failure (includes ESRD)

ESRD, end-stage renal disease; GFR, glomerular filtration rate.

Chapter 7 101

the anticoagulant of choice [35]. Thus, CKD patients represent a phenotype warranting

special care and patient-tailored therapy.

Role of noaCs foR PaTienT-TailoRed TheRaPy

The explore the efficacy and safety of once-daily oral rivaroxaban for the prevention of

cardiovascular events in patients with nonvalvular atrial fibrillation scheduled for cardio-

version (X-VeRT) study is the first randomized controlled trial to explore the efficacy and

safety of a NOAC (rivaroxaban 20 mg once daily) compared with warfarin for prevention

of cardiovascular events in patients with AF scheduled for cardioversion.37 A total of 1504

patients were randomly assigned to rivaroxaban (20 mg once daily; 15 mg if creatinine

clearance was between 30 and 49 mL min-1) or dose-adjusted vitamin K antagonists (VKAs).

Investigators selected either an early (target period of 1–5 days after randomization) or de-

layed (3–8 weeks) cardioversion strategy. The primary efficacy outcome was the composite

of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction and car-

diovascular death. The primary safety outcome was major bleeding. The primary efficacy

outcome occurred in five (two strokes) of 978 patients (0.5%) in the rivaroxaban group

and in five (two strokes) of 492 patients (1.0%) in the VKA group [risk ratio 0.50; 95%

confidence interval (CI) 0.15–1.73]. In the rivaroxaban group, four patients experienced

primary efficacy events following early cardioversion (0.7%) and one following delayed

cardioversion (0.2%). In the VKA group, primary efficacy events occurred in three patients

(1.1%) following early cardioversion and in two (0.9%) following delayed cardioversion.

Major bleeding occurred in six patients (0.6%) in the rivaroxaban group and four patients

(0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21–2.67). Therefore, in line with data

from nonrandomized trials of cardioversion with dabigatran38 and apixaban39,NOACs

appear to be an effective and safe alternative to a VKA. Of interest, in the delayed group, as-

signment to rivaroxaban was associated with a significantly shorter time to cardioversion

(median 22 days vs. 30 days, P < 0.001). The reason for the shorter time to cardioversion

with rivaroxaban was that within the scheduled target period a significantly larger propor-

tion of rivaroxaban patients (77%) could be cardioverted compared to patients assigned

to a VKA (36%, P < 0.001). The primary reason for not performing cardioversion as first

scheduled was inadequate anticoagulation. Only one patient who received rivaroxaban did

not achieve adequate anticoagulation (indicated by drug compliance <80%), compared

with 95 patients receiving a VKA (indicated by weekly INRs outside the range of 2.0–3.0

for three consecutive weeks before cardioversion). Therefore, NOACs may allow earlier

cardioversion in patients in a rhythm control strategy, preventing unnecessary progression

of the remodelling process while awaiting cardioversion.

102 Chapter 7

PaTienT-TailoRed anTiCoaGulaTion in af: The Role of lefT aTRial

aPPendaGe (laa) deviCes

The LAA occlusion device may have an important influence on patient-tailored therapy.

Stroke risk depends on the patients’ phenotype and is at present assessed using the

CHA2DS2-VASc score.40 The efficacy of stroke prevention with (N)OACs in these patients

has been well established.41–43 However, associated bleeding risks may offset the thera-

peutic benefits. Despite improvements achieved by NOACs, bleeding, and in particular

gastrointestinal bleeding, remains a clinically relevant problem. Percutaneous occlusion

of the LAA may be considered as an alternative stroke prevention therapy in AF patients

with a high bleeding risk.44, 45 The percutaneous closure of the left atrial appendage for

prevention of stroke in patients with atrial fibrillation (PROTECT-AF) study is the first

randomized controlled trial that assessed the efficacy and safety of percutaneous closure

of the LAA for prevention of stroke compared to warfarin treatment. A total of 707 adult

patients with nonvalvular AF and a CHADS2 score of ≥1 were randomly assigned in a 2:1

manner to percutaneous closure of the LAA and subsequent discontinuation of warfarin or

to warfarin treatment. Efficacy was assessed as a primary composite end-point consisting

of stroke, cardiovascular death and systemic embolism in an intention-to-treat analysis.

This randomized controlled trial showed that the efficacy of percutaneous LAA occlusion

was noninferior to that of chronic warfarin therapy.46 At a follow-up of 45 months, LAA

occlusion was shown to be noninferior and superior to warfarin for stroke, peripheral

embolism and cardiovascular or unexplained death (composed annual event rates 2.3%

vs. 3.8%).47 In addition, LAA occlusion was superior in preventing all-cause mortality,

cardiovascular mortality and haemorrhagic stroke.

Figure 5 shows an algorithm for stroke prevention in AF including the role of the LAA

occlusion device. It is recommended that an LAA occlusion device should not be used when

extra-LAA sites are relevant for possible thrombus formation, for example atrial walls in

rheumatic heart disease or extra-atrial foci such as an aortic plaque or a left ventricular

thrombus in the case of impaired left ventricular function. Further, it should be recognized

that at present an LAA occlusion device is not a simple alternative to (N)OAC treatment

because limited data from prospective randomized trials are available and procedural

complications may occur. Therefore, compliant patients eligible for (N)OACs with an

acceptable bleeding risk during long-term treatment should receive (N) OAC treatment.

At present, an LAA occlusion device can be considered in the case of absolute (N)OAC

contraindication, such as an untreatable source of intracranial or intraspinal bleeding or

severe gastrointestinal or urogenital bleeding, in patients at high risk of stroke. Another

important potential group of patients who may benefit are those with severe side effects

under VKA therapy and contraindications for a NOAC, such as patients with severe CKD.

An LAA occlusion device may also be considered in patients with a relative OAC contra-

Chapter 7 103

indication such as a high risk of bleeding (e.g. due to haemodialysis, recurrent falls with

injuries and significant bleeding, recurrent need for triple therapy in severe coronary artery

disease and a high HASBLED score) and in patients unwilling or unable to undergo long-

term (N)OAC treatment.

ConClusion

Careful phenotyping of patients with AF and tailoring of AF treatment according to the

individual characteristics of a specific patient is a way to improve the management of this

complex arrhythmia. Such a strategy should include the choice between rate or rhythm

control, the choice of a particular antiarrhythmic drug and/or atrial ablation therapy,

antithrombotic prophylaxis (with a VKA or NOAC or, in selected cases, with an LAA oc-

clusion device), as well as management of comorbidities (e.g. CKD, as discussed above).

A further step towards more tailored treatment strategies involves analysing the role of the

genotype. More research is needed to determine whether a personalized decision-making

approach targeting a genotype-tailored approach to AF can fulfil the promise to improve

treatment outcomes and minimize adverse events.

Figure 5. Patient-tailored algorithm for stroke prevention in atrial fibrillation (AF)Adapted from Meier et al.45, with permission.

104 Chapter 7

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