Causes of death in atrial fibrillation: Challenges and opportunities

TR

E N D S I N

C

A R D I O V A S C U L A R

M

E D I C I N E

] (2017) ]]]–]]]

Available online at www.sciencedirect.com

www.elsevier.com/locate/tcm

Causes of death in atrial fibrillation: Challenges and opportunities Antonio Gómez-Outes, MD, PhD, MSca,n, Maria Luisa Suárez-Gea, PharmD, PhDa, and Jose Manuel García-Pinilla, MD, PhDb,c a

Division of Pharmacology and Clinical Drug Evaluation, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Campezo 1, 28022 Madrid, Spain b UGC de Cardiología y Cirugía Cardiovascular, Instituto de Biomedicina de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga, Spain c Centro de Investigación Biomédica en Red-Cardiovascular (CIBER-CV), Instituto de Salud Carlos III, Madrid, Spain

abstra ct Atrial fibrillation (AF) is an age-related arrhythmia associated with several co-morbidities and significant mortality. Most AF patients are in need of anticoagulation due to increased risk of stroke. Despite anticoagulation, AF patients still have a significant risk of death (about 5%/y). Approximately half of deaths in AF are due to heart-related causes (i.e., sudden death, heart failure, and myocardial infarction), one-third of deaths are due to non-vascular causes (i.e., cancer, respiratory diseases, and infections) and the remaining AF patients die from stroke or hemorrhage (about 6% each), or other causes. This review describes current situations related to causes of death in AF, the challenges in the management of AF (e.g., frequent presence of cardiovascular risk factors and co-morbidities, physicians adherence to clinical guidelines and patients adherence to cardiovascular medications in AF) as well as the opportunities for intervention. & 2017 Elsevier Inc. All rights reserved.

Introduction Atrial fibrillation (AF) is the most frequent arrhythmia worldwide [1,2]. The estimated prevalence is approximately 3% in adults, and particularly higher in older persons and in patients with co-morbidities [e.g., hypertension, heart failure (HF), coronary artery disease (CAD), valvular heart disease, obesity, diabetes mellitus (DM), or chronic kidney disease (CKD)] [1]. AF is independently associated with a 1.5- to 2-fold increased risk of all-cause mortality and increased morbidity, such as stroke and HF [1]. Most AF patients are in need of oral anticoagulation (OAC) due to increased risk of stroke. Despite anticoagulation, they still have a significant risk of death (about 5%/y), with stroke

The authors have indicated that there are no conflicts of interest. n Corresponding author. Tel.: þ34 9182 25751; fax: þ34 9182 25161. E-mail address: [email protected] (A. Gómez-Outes). http://dx.doi.org/10.1016/j.tcm.2017.05.002 1050-1738/& 2017 Elsevier Inc. All rights reserved.

accounting for less than 10% of all deaths, while other cardiovascular (CV) deaths (e.g., due to HF and sudden deaths) remain common [3]. In clinical trials and registries in AF, death was the most frequent major adverse clinical event over approximately 2 years of follow-up (NVAF) [3,4], being about 3-fold higher than the rate of stroke and more than 5-fold higher than the rate of major bleeding [4]. Therefore, additional strategies, beyond an appropriate anticoagulation not incurring an excessive risk of major bleeding, are needed to improve outcomes in this elderly population with frequent co-morbidities [3]. This current review will describe current situations related to causes of deaths in AF, the challenges related to the frequent presence of cardiovascular risk factors and co-morbidities in this population, as well as the opportunities for intervention.

2

T

R E N D S I N

C

A R D I O V A S C U L A R

Causes of death in atrial fibrillation The search and development of direct oral anticoagulants (DOACs: dabigatran, rivaroxaban, apixaban, and edoxaban) as alternative to vitamin K antagonists (VKA; i.e., warfarin, acenocoumarol, and others) for stroke prevention in AF has provided the medical community with very useful data from clinical trials [3,5–8] and subsequent post-marketing registries [4,9–13] about current management of AF, patients demographics and clinical outcomes. Table 1 shows a descriptive analysis of pooled data available from contemporary clinical trials that compared the

ME

D I C I N E

] (2017) ]]]–]]]

DOACs and warfarin in AF [3,5–8] versus those in a global registry (GARFIELD-AF, first 2 cohorts) [4]. Clinical trials included a selected “enriched” population at a higher thrombotic and bleeding risk than those from registries, as shown by higher mean values in thromboembolic (CHADS2; CHA2DS2-VASc) and bleeding scores (HAS-BLED) [1], which reflects a higher prevalence of co-morbidities (i.e., HF, hypertension, DM, prior stroke/TIA and renal insufficiency) and a more prolonged course of the disease (i.e., more patients with permanent/persistent AF already anticoagulated with VKA) (Table 1). Comparability is further complicated by the implementation of new thrombotic and bleeding risk scores (i.e., CHA2DS2-VASc and HAS-BLED) [1] as well as changes in the

Table 1 – Pivotal clinical trials with the DOACs versus GARFIELD registry in atrial fibrillation: study and patients characteristics. Characteristics of studies

Meta-analysis DOAC versus warfarin [3]

GARFIELD registry (cohorts 1 and 2) [4]

N Patient-years Period of patients' enrollment (month-year) Study type Antithrombotic treatment Anticoagulation VKA, % Percent TTR, mean (range) DOAC, % APT onlyb, % (range) Anticoagulation plus APTb, % (range) No antithrombotic treatment, % Patients' characteristics Age (years), % (range) 475 years, % (range) Male gender, % Atrial fibrillation type Permanent/persistent, % (range) Paroxysmal, % (range) New (newly diagnosed/new onset) CHADS2 score, mean (range) CHADS2 score Z2, % (range) CHA2DS2-VASc score (mean) CHA2DS2-VASc score Z2 (%) CHA2DS2-VASc score Z3 (%) HAS-BLED score (mean) HAS-BLED score Z3 (%) Heart failure Hypertension Diabetes Prior stroke/TIA, % Prior MI, % (range) CrCl o 50 ml/min History of VKA use (%)

71,683 134,046 December 05–November 10 Meta-analysis of 4 RCTa 100 100 50 62 (55.2–65) 50 0 34 (29–40) 0

17,162 30,829 March 10–June 13 Prospective cohort 78 61 50 55 11 27 15 12

72 (70–73) 38 (31–43) 63 (60–65)

70 38 56

78 (67–83) 23 (17–33) N/A 2.6 (2.1–3.5) 83 (66–100) 4.0 (3–5) 97 (91.2–100) 80 (71–95) 1.9 (1.3–2.5) 31 (10–47) 47 (32–63) 88 (79–94) 31 (23–40) 31 (19–55) 15 (12–17) 19 (17–21) 57 (50–63)

29 25 46 N/A N/A 3.3 86 67 1.5 13 21 78 22 13 9 10 0

APT ¼ antiplatelet therapy; CHADS2 score ¼ congestive heart failure, hypertension, age 4 75, diabetes mellitus, prior Stroke or transient ischemic attack doubled; CHA2DS2-VASc ¼ congestive heart failure, hypertension, age Z75 (doubled), diabetes, stroke (doubled), vascular disease, age 65–74, and sex (female); HAS-BLED: hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile INR, elderly (465 years), drugs/alcohol concomitantly (1 point each); N/A ¼ not available; NVAF ¼ non-valvular atrial fibrillation; RCT ¼ randomized clinical trial; TIA ¼ transient ischemic attack; TTR ¼ time within therapeutic range; VKA ¼ vitamin K antagonist. a Four randomized clinical trials: (1) randomized evaluation of long-term anticoagulation therapy trial (RE-LY); (2) an efficacy and safety study of rivaroxaban with warfarin for the prevention of stroke and non-central nervous system systemic embolism in patients with non-valvular atrial fibrillation (ROCKET AF); (3) apixaban for the prevention of stroke in subjects with atrial fibrillation trial (ARISTOTLE); and (4) effective anticoagulation with factor Xa next generation in atrial fibrillation-thrombolysis in myocardial infarction 48 trial (ENGAGE AF–TIMI 48). b Referred to the use of concomitant aspirin.

T

R E N D S I N

C

A R D I O V A S C U L A R

ME

D I C I N E

3

] (2017) ]]]–]]]

Table 2 – Descriptive analysis of causes of death in clinical trials with DOACs and in the GARFIELD registry, as rate per 1000 patient-years and as percentage of total deaths. Cause of death

Meta-analysis DOAC versus warfarin [3]

GARFIELD Registry (cohorts 1 and 2) [4]

N died N included Patient-years

6206 71,683 134,046

1181 17,162 30829

1) All-cause death 2) Cardiovascular death ● Cardiac death Sudden death/ dysrrhythmia Heart failure Myocardial infarction ● Ischemic stroke/SE ● Hemorrhage (all) ● Other cardiovascular deathc 3) Non-cardiovascular death ● Malignancies ● Infections ● Respiratory ● Trauma/accidental ● Other non-vascular death 4) Undetermined death

Death rate, ‰/y (95% CI)

% of deaths

Death rate, ‰/y (95% CI)

% of deaths

46 29 21 13

100 64 46 28

38 16 9 3

(36–41) (14–17) (8–11)a (2–4)a

100 40 24 8

(5–8) (1–2) (2–3) (2–4) (2–5)

15 3 6 6 6

4 2 2 1 4

(3–5)a (2–3)a (1–3)a (0–1)a,b (3–4)a

11 5 5 2 9

14 (12–16)

30

14 (13–15)

36

11 9 3 1 6

4 (3–4)a 3 (2–3)a 3 (2–4)a N/A 4 (3–4)a

10 7 8 N/A 11

6

9 (8–10)

24

7 1 3 3 3

5 4 2 1 2

(40–53) (22–37) (16–27) (9–17)

(4–6) (2–6) (1––3) (0–1) (1–4)

4 (1–9)

AF ¼ atrial fibrillation; CI ¼ confidence interval; DOAC ¼ direct oral anticoagulant; N/A ¼ not available; SE¼ systemic embolism (other than embolic stroke). a Not calculated in the original publication. Personal calculation using the number of patients who died due to the specific cause of death (numerator) divided by total patient-years of exposure. Poisson (incidence) rate estimate with 95% CI; StatsDirect software version 3.0.193. b Corresponds to “fatal bleedings” in the publication. c Includes CABG, non-coronary atherosclerotic disease, pulmonary embolism, and other unspecified cardiovascular deaths.

classification of AF patterns in clinical practice guidelines [1] after the performance of major contemporary anticoagulation trials, which have been implemented in the registries (i.e., new onset AF). Table 2 shows a descriptive analysis of pooled data of causes of death available from clinical trials [3] and registries [4]. Despite wide differences in methodology and patientʼs profiles, both clinical trials and registries show broadly similar mortality rates and causes of death. Globally, about half of patients with AF died from cardiac-related causes [i.e., sudden cardiac death, HF, myocardial infarction (MI)] and one-third died from noncardiovascular causes (e.g., malignancies, infections, and respiratory diseases), while ischemic stroke and bleeding accounted for a small proportion of deaths (Table 2). The main difference in causes of death between clinical trials and registries seem related to the quality of follow-up and adjudication of causes of death, which seems more accurate in clinical trials than in registries, as suggested by the low proportion of undetermined deaths in clinical trials (only 6%) (Table 2). Global clinical trials and registries have shown regional differences in mortality, stroke, and bleeding in patients with AF, which may be related to differences in patient characteristics, as well as treatment and management options and quality of OAC. In clinical trials, patients enrolled in Asia and Latin America had the highest mortality rates and the lowest quality of anticoagulation with warfarin [14,15]. The RE-LY

Atrial Fibrillation Registry Cohort Study, recruiting 154,000 AF patients in 47 countries over 8 geographical regions, also showed substantial variation in the occurrence of death, stroke, and HF between global regions [13]. The analyses clearly highlighted the importance of economic factors in accounting for differences in all-cause mortality between regions, with the higher mortality rates being observed in China (14%), South America (17%), and Africa (20%), which may reflect the high proportion of patients in these regions with untreated hypertension (around 10%), lowest use of anticoagulation therapy (14–19%) and the lowest time in therapeutic range (33–36%) [13]. Therefore, as the reality of AF disease may differ across regions, the strategies to reduce mortality rates should be tailored to the specific problems found in different healthcare systems (i.e., polypharmacy does not seem to be a major issue in Africa or China, but may be a problem in Europe or in North-Americans with drug coverage).

Individual predictors of death among patients with AF In addition to population-level determinants of death among patients with AF, several individual independent predictors of death have been found in post hoc analyses from contemporary AF trials. In RE-LY, baseline independent predictors of overall

4

T

R E N D S I N

C

A R D I O V A S C U L A R

mortality were the presence of HF [89% relative risk increase (RRI)], low-creatinine clearance (r45 ml/min) (88% RRI), intraventricular conduction delay (QRS 4 120 ms) (65% RRI), DM (45% RRI), prior MI (44% RRI) age 470 years (33% RRI), active smoking (27% RRI), compared with patients without these characteristics [16]. In addition, the occurrence of non-fatal major hemorrhage, non-fatal stroke, or non-fatal MI during follow-up were found to be significantly associated with overall mortality (125%, 107%, and 79% RRI versus patients without these non-fatal events, respectively). Looking at cardiac death, the 2 strongest independent predictors were concomitant HF (202% RRI) and prior MI (105% RRI). Of interest, most patients with coronary artery disease (CAD) were not on antiplatelet therapy and around 30% were not on β-blockers and statins. Patients not on statins and βblockers had a significantly higher risk of mortality (25% and 13% RRI) than patients on these therapies [16]. In ROCKET-AF, a similar picture was found regarding the independent predictors of mortality, with HF (51% RRI) and age Z75 years (69% RRI) strongly associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, COPD, peripheral vascular disease, and DM being among the most strongly associated [14]. In ENGAGE-AF TIMI 48 study, the AF pattern was associated with differences in mortality and stroke risk [17]. All-cause mortality was lower with paroxysmal (3.0%/y) compared with persistent (4.4%/y) and permanent AF (4.4%/y). These data suggest that early interventions preventing the progression from paroxysmal to persistent/permanent AF, which occurs in about 15% of patients with paroxysmal AF yearly, could improve patient outcomes [18]. As this progression is generally associated with co-morbidities (i.e., HF, previous stroke or TIA, COPD, and hypertension), leading to structural rather than electrical remodeling, it is essential to identify and treat early these associated risk factors. There are also data available regarding independent predictors of death in contemporary registries and nationwide cohort studies. In the GARFIELD-AF global prospective registry in 17,162 patients [4], most of the variables strongly associated with the risk of death, namely older age, chronic HF, history of bleeding, CKD, DM, smoking, and pattern of AF, were also associated with the risk of stroke, thus suggesting that the overall prognosis of AF is tightly linked to the same risk factors/comorbidities. In the Lorey Valley registry [10], in which 1253 deaths were recorded in 8962 patients with AF, the presence of permanent AF, HF (whether with decreased or with preserved ejection fraction), previous bleeding and renal failure were independently associated with an increase in the risk of allcause mortality (35%, 78%, 42%, and 79%, respectively), while OAC use was independently associated with a lower risk of allcause mortality (28%). Of note, the use of β-blockers was associated with a 25% decrease in all-cause mortality driven by a significant decrease in deaths related to HF. Similar association was found in the Danish cohort study in 205,174 patients, where almost 40,000 had prevalent HF [19]. These results, even after having been adjusted by covariates, may be subject to bias, as for example, patients may not use β-blockers, despite indicated, due to presenting hypotension, low-rate permanent AF, or concomitant diseases (e.g., asthma and COPD), thus selecting a population with a worse prognosis. However, globally considered, and

ME

D I C I N E

] (2017) ]]]–]]]

being entirely consistent across clinical trials, registries and nationwide cohorts, there is a strong suggestion that β-blocker therapy is associated with improved survival in AF and should be implemented in these patients unless contraindicated, while the same applies for OAC in patients at high risk of thromboembolism and statins in patients with AF and history of CAD. An important issue, taking into account that the AF population usually has significant co-morbidities, is the impact of polymedication in all-cause mortality. Two post hoc analyses of ROCKET-AF [20] and ARISTOTLE [21] are available in this respect. In ROCKET-AF, two-thirds had polypharmacy (Z5 medications). In adjusted multivariable Cox models, compared with the use of less than 5 medications, increasing medication use (5–9 medications and Z10 medications, respectively) was associated with higher risk of death (25% and 128% RRI, respectively) and bleeding (16% and 47% RRI, respectively), but not stroke [20]. In ARISTOTLE, each patient used a median of 6 drugs and threequarters of patients had polypharmacy [21]. Compared with the use of r5 medications, increasing medication use (6–8 medications and Z9 medications, respectively) was associated with higher risk of death (41% and 103% RRI, respectively), bleeding (17% and 45% RRI, respectively), and stroke (27% and 54%, respectively). In both studies, despite their lower risk for drug– drug interactions, there was no differential effect (better outcomes) of the DOACs versus warfarin in patients who had polypharmacy compared with those on o5 medications [20,21]. In particular, there was an attenuation of the observed safety benefit of the DOACs with increasing concomitant drugs, which could be due to an increase in gastrointestinal bleeding with coexisting diseases more frequent with increasing numbers of concomitant drugs (e.g., previous gastric ulcers, gastrointestinal surgery, and dyspepsia) or pharmacodynamic drug–drug interactions (e.g., use of aspirin, prednisone, or non-steroidal antiinflammatory drugs), while pharmacokinetic interactions (use of warfarin or apixaban potentiating drugs: CYP3A4, P-glycoprotein inhibitors) did not appear to explain this observed treatment interaction [21]. Increased mortality related to polypharmacy may also be due to the fact that those taking several medications may be sicker than those taking fewer medications. Therefore, drug–drug interactions may be a contributing factor, but not the only reason for increased mortality in these patients.

Opportunities to improve outcomes in atrial fibrillation Participating agents and scope An integrated approach with structured organization of care, multidisciplinary teams and follow-up should be considered in all patients with AF, aiming to improve guidelines adherence and to reduce hospitalizations and mortality [1]. Placing patients in a central role in decision-making should be considered in order to tailor management to patient preferences and improve adherence to long-term therapy [1]. Sustained improvements in CVD risk reduction requires that patients be made aware of their risk factors and unhealthy lifestyle behaviors [22]. Awareness alone is not adequate to change lifestyle behaviors affecting CVD risk. Integral to a collaborative care model for chronic disease is patient

T

R E N D S I N

C

A R D I O V A S C U L A R

empowerment, which is defined as helping patients to develop the inherent capacity to be responsible for oneʼs own life [23]. Employing empowerment in an early phase may be a critical strategy to improve behavior changes to lower risk in individuals vulnerable to CVD [22].

Patient adherence to medications Medication adherence [24] is a cornerstone of management of AF. However, patient adherence to CV medications is suboptimal worldwide and decreases with time, with only about 60% of patients and having an overall good adherence (adherence Z 80%) to CV medications (range: 54% for statins, 59% for antihypertensives, 69% for antidiabetics, and 70% for aspirin) after 3 years [25]. In a comprehensive meta-analysis of 23 studies with half million participants and more than 94,000 mortality events, good adherence to any CVD medication was associated with a 28% decrease in mortality [25]. It was concluded that approximately 9% of all CVD events were indirectly attributable to poor adherence. A recent meta-analysis of controlled trials has shown that the interventions to improve medication adherence among HF patients have significant effects on decreasing the relative risk of mortality by 11% [26]. Factors that significantly influenced adherence levels were low-social status, lowhealth literacy, existence of co-morbid conditions, and polypharmacy. Methods available to improve patient adherence to medications include proper education and counseling, intensified patient care, additional tools (e.g., medications boxes, pill containers, clock alarms to take medication, and calendared blister packages), simplification of drug regimen, regular and pre-specified follow-up visits by physicians, monitoring by pharmacists, financial incentives, collaborative care, lay health mentoring, and direct observation treatment [27,28]. Patients with AF are in particular need for a comprehensive behavioral intervention with educational materials [29]. Simplification of drug regimen, for example, using fixed dose combination medications (polypills) has shown to significantly improve adherence to CV medications, especially among those who are under-treated at baseline [30]. De-prescribing is a suggested intervention to reverse the potential iatrogenic harms of inappropriate polypharmacy. With polypharmacy that is often driven by chronic medical conditions, substantial reductions in the number of drugs are not likely. However, a recent review suggests that patientspecific interventions to de-prescribe potentially inappropriate drugs (e.g., withdrawal of fall-risk-increasing drugs in the elderly) may improve longevity [31]. Therefore, individualized interventions to reduce inappropriate polypharmacy appear safe and feasible.

Physician adherence to clinical practice AF guidelines The treatment goals of AF start with a proper diagnosis through an in-depth examination from a physician of potential underlying causes (Table 3). After a patient is diagnosed with AF, the ideal goals may include rate/rhythm control, anticoagulation to prevent thromboembolism in patients at

ME

D I C I N E

] (2017) ]]]–]]]

5

risk, as well as managing risk factors for stroke, bleeding and co-morbidities [1,2]. The goal of rate/rhythm control therapy of AF is to reduce patient symptoms and preserve cardiac function. Medications like β-blockers and calcium channel blockers slow the heart rate and may help improve AF symptoms, but they do not revert the rhythm abnormality [1,2]. Restoring and maintaining sinus rhythm is an integral part of AF management. Antiarrhythmic drugs approximately double the rate of sinus rhythm compared with placebo. Catheter ablation is generally indicated after failure or intolerance to antiarrhythmic drugs. Hybrid therapy (combining an antiarrhythmic drug with ablation) should be considered based on the different and possibly synergistic effects of these drugs with AF ablation, possibly benefitting patients in whom either treatment alone was previously ineffective [1]. All these interventions have been shown to reduce symptoms and to maintain sinus rhythm in symptomatic AF, but have not demonstrated a reduction in long-term morbidity or mortality [1,2]. Furthermore, the use of some antiarrhythmics has been associated with increased mortality in patients with AF and structural heart disease [1,2]. Flecainide and other potent sodium channel–blocking drugs (e.g., propafenone) should be avoided in patients with AF and ischemic heart disease or left ventricular dysfunction, while dronedarone is contraindicated in patients with permanent AF in whom sinus rhythm is not restored and in patients with HF [1,2]. Amiodarone is usually a second-choice therapy in many patients because of its extracardiac side-effects, but it is still the first choice for rhythm control in patients with AF and HF [1,2]. AF patients may require anticoagulation if they have additional risk factors for stroke and thromboembolism [1,2]. Oral anticoagulation markedly reduces stroke by two-thirds and mortality by one-quarter in these patients [32]. While adherence to AF guidelines is progressively increasing, contemporary registries in AF show that anticoagulation is still frequently not being used according to stroke risk scores and guidelines, with underuse in patients at high risk of stroke (i.e., CHA2DS2VASc score Z 2) and overuse in most patients at truly low risk (i.e., CHA2DS2VASc score ¼ 0 in men and 1 in women) [33]. A recent analysis of the EORP-AF Pilot General Registry in more than 2600 European patients with AF showed that 61% of antithrombotic treatments were adherent to European guidelines for stroke prevention in AF, while 17% of patients were under-treated (no anticoagulated despite being at high risk of stroke) and 22% were overtreated (anticoagulated despite being at low risk of stroke, or received OAC plus antiplatelet therapy despite not having an indication for combination therapy) [34]. All-cause death increased approximately by 52% by undertreatment and 24% by overtreatment [34]. A recent analysis of the ORBIT registry in more than 9500 AF patients recruited in North America has also shown a significant 20% increase in mortality in guideline-eligible patients for OAC who were not anticoagulated compared with those who were appropriately anticoagulated [35]. These contemporary observations emphasize the importance of adherence to the clinical practice guidelines for stroke prevention in AF [1,2]. The choice between the inexpensive VKA when a good TTR can be achieved and the DOAC is a matter of debate, as

6

T

R E N D S I N

C

A R D I O V A S C U L A R

ME

D I C I N E

] (2017) ]]]–]]]

Table 3 – General recommendations for AF management [1,2].a. 1) AF diagnosis and qualification  ECG screening: in subjects at risk, especially stroke survivors and the elderly.  ECG documentation: in all subjects before starting treatment.  Patients’ assessment: clinical evaluation, echocardiography to investigate alterations of cardiac anatomy or function due to underlying cardiovascular conditions (e.g., heart failure, valvular heart disease, hypertension, and coronary artery disease), and assessment of other co-morbidities that may impact the management and/or outcome of AF (e.g., COPD, sleep apnea, dementia, renal and hepatic impairment, diabetes, and thyroid disease).  Individual assessment of thromboembolic and bleeding risk in each patient using validated scores (e.g.: CHA2DS2-VASc and HAS-BLED). 2) General measures  Information and education to empower patients in the support AF management.  Propose lifestyle changes and control of modifiable risk factors to all suitable AF patients to make their management more effective.  Treat underlying cardiovascular conditions adequately (e.g., significant valvular heart disease, heart failure, hypertension, and diabetes). 3) Rate and rhythm control  Measure ventricular rate in all AF patients and use rate control drugs to achieve lenient rate control.  Assess AF-related symptoms (e.g., using the modified EHRA symptoms scale).  Treat symptomatic AF patients by adjustment of rate control therapy and by offering antiarrhythmic drugs, cardioversion, or catheter or surgical ablation.  Select antiarrhythmic drugs based on their safety profile and consider catheter or surgical ablation when antiarrhythmic drugs fail.  No routine genetic testing should be offered to AF patients unless there is suspicion of an inherited cardiac condition.  Rhythm control therapy should NOT be used in asymptomatic AF patients, or in patients with permanent AF.  Cardioversion or catheter ablation should NOT be performed without anticoagulation, unless an atrial thrombus has been ruled out transesophageal echocardiogram. 4) Prevention of thromboembolism and bleeding  Oral anticoagulation is recommended in all AF patients at high risk of stroke,b unless a contraindication exists.  An individualized decision on anticoagulation is recommended in moderate risk of stroke,b balancing the risk of thrombosis and bleeding, with preference for anticoagulation.  No anticoagulation is recommended in AF patients at truly low risk of stroke,b unless anticoagulation is indicated due to other reasons.  Control of all modifiable bleeding risk factors in anticoagulated patients (i.e., modifiable risk factors included in the HAS BLED score): control of hypertension; avoid antiplatelet therapy for AF and non-essential anti-inflammatory drugs; minimize the duration and intensity of antiplatelet and anti-inflammatory drugs if are essential for patient management; treating anemia and eliminating causes for blood loss; maintaining stable INR values in patients on VKAs; moderating alcohol intake; slowing progression of renal and liver disease).  Anticoagulation therapy should be temporarily interrupted in case of severe active bleeding until the underlying cause is resolved.  Anticoagulation must not be permanently discontinued in AF patients at increased risk of stroke unless such a decision is taken by a multidisciplinary team.  Anticoagulation is superior to antiplatelet therapy for stroke prevention in AF.  Dual antiplatelet therapy might be considered in patients with AF in whom oral anticoagulation is considered unsuitable, while antiplatelet monotherapy should be avoided in patients with indications for anticoagulation (i.e., moderate–high risk of stroke).  For patients with AF who have mechanical heart valves, anticoagulation with a VKA, maintaining an INR of at least 2.5, is recommended.

AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ congestive heart failure, hypertension, age Z 75 (doubled), diabetes, stroke (doubled), vascular disease, age 65–74, and sex (female); COPD ¼ chronic obstructive pulmonary disease; ECG ¼ electrocardiogram; EHRA ¼ European Heart Rhythm Association; HAS-BLED ¼ hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile INR, elderly (465 years), drugs/alcohol concomitantly (1 point each); INR ¼ international normalized ratio; VKA ¼ vitamin K antagonists. a Based on the 2016 ESC and 2014 AHA/ACC/HRS guidelines (Refs. [1] and [2]). b The definitions of high, intermediate, and low-risk are not well harmonized across different guidelines, have changed overtime and it is a matter of debate whether female gender alone is a stroke risk factor. The following definitions may be applicable: high risk, for example, 2 or more risk factors [CHA2DS2-VASc score Z 2 (male and females)]; intermediate risk, for example, 1 additional factor [CHA2DS2-VASc score ¼ 1 male]; truly low risk, for example, no additional factors excluding female gender [CHA2DS2-VASc ¼ 0 (male), 1 (female)] (Ref. [1]).

cost-effectiveness of the DOAC is highly dependent upon drug cost and quality of anticoagulation control for warfarin [36]. Treatment with DOACs was associated with a small but significant reduction in all-cause mortality compared with warfarin in AF trials (difference 0.42%/y), which was mainly driven by a reduction in fatal bleedings [37]. In subgroup analyses, a benefit in mortality was shown in centers where control of anticoagulation was suboptimal [as shown by a percent time in therapeutic range (TTR) o 65%] (RRR ¼ 15%; 95% CI: 7–24%), but it was not significant in centers where TTR was 4 65% (RRR ¼ 3%; 95% CI: 9% to 13%) [37]. Therefore, in cases of suboptimal control of VKA therapy despite good adherence, which is a relatively frequent situation (20–40% of patients on VKA, depending on the center

and country) [38], patients should be switched to a DOAC unless contraindication, as a significant benefit in mortality and other major outcomes may be expected [37].

Non-pharmacological measures Lifestyle changes and control of modifiable risk factors (e.g., making healthful nutrition choices, getting adequate exercise, cessation of smoking and heavy drinking, managing stress levels, and getting adequate quantity and quality of sleep) should be proposed to all suitable AF patients to make their AF management more effective (Table 3) [1,2]. Diet is a powerful determinant of CV health. Reductions in CV events can be seen after changes in diet at the population

T

R E N D S I N

C

A R D I O V A S C U L A R

level [39,40], which may be of special relevance in patients at high-CVD risk [41]. It is likely that the benefits of a healthy diet may extend to primary prevention of AF [42], but this assumption deserves further investigation. Regular moderate physical activity, particularly leisure-time activity and walking, are associated with reduced incident AF [43]. Tobacco is a common risk factor for CVD and cancer, and strategies to promote smoking cessation and to reduce tobacco consumption may have a synergistic beneficial effect in patients with AF [44]. High-alcohol consumption (43 drinks per day) is associated with approximately 47% RRI of AF compared with no drinking, and it is also associated with increased risk of fatal arrhythmias, dilated cardiomyopathy, and hemorrhagic stroke [39]. Multicomponent strategies to promote cessation of smoking and drinking are best [39].

Management of co-morbidities HF is present in half of the AF population and accounts for 15% of all deaths in AF [3]. On the other hand, patients with AF and HF have a higher risk of death, stroke and venous thromboembolism than AF patients without HF, which has been attributed to a hypercoagulable state [45]. AF and HF share common risk factors and pathophysiologic processes such as hypertension, DM, CAD, and valvular heart disease, which often occur together [46]. Patients with HF presenting with AF have to be examined for HF characterization and identification of potentially correctable causes and precipitating factors, as this may determine management strategy and outcome [47]. Once an accurate diagnosis has been established, patients should receive evidence-based medications [e.g., angiotensin-converting enzyme inhibitors (ACEIs), βblockers, mineralocorticoid receptor antagonists (MRAs), and diuretics]. Even in the context of controlled clinical trials in AF, a significant proportion of HF patients are not on optimal evidence-based therapies for HF, as shown by the 30% of HF patients that were not on β-blockers and the 20% of HF patients that were not on ARB/ACE inhibitors in the RE-LY study [16]. A recent retrospective study using a European health insurance database (n 4 85,000 HF subjects) has found that patients who received a therapy with ACEIs and βblockers according to clinical practice guidelines (60% of all subjects) had a 55% lower relative risk of mortality than the 40% of patients who were not on these therapies [48]. Hypertension is present in around 80–90% of patients with AF [3,4]. Blood pressure control is particularly important, since antihypertensive treatment prevents both stroke and HF, which are frequent complications in AF. Most patients show a high-ventricular rate when in AF. In these patients, βblockers and non-dihydropyridine calcium antagonists are treatments of choice [49]. ACEIs and angiotensin receptor blockers (and β-blockers and MRAs if systolic dysfunction is present) should be considered as antihypertensive agents for prevention in patients at risk of new or recurrent AF [50]. Approximately 20–30% of the AF population has concomitant DM [3,4]. People with DM are on average at double the risk of CVD. Lifestyle management to aid weight control by sustainable dietary changes and increased physical activity levels should be central in the management of patients with DM. Intensive management of hyperglycemia reduces the risk of microvascular

ME

D I C I N E

] (2017) ]]]–]]]

7

complications and, to a lesser extent, the risk of CVD. However, targets should be relaxed in the elderly, frail, those with longduration DM and those with existing CVD [39].

Summary of challenges and opportunities for improving survival in AF Table 4 summarizes common deficiencies in AF management, which are basically related to non-healthy lifestyles, suboptimal physiciansʼ adherence to guidelines and patientsʼ adherence to essential medications in the management of AF, HF, ACS, and hypertension. A multifaceted collaborative approach is needed in AF, with interventions at the population and individual level. Primary prevention of AF is of critical importance. The promotion of healthy lifestyle (i.e., diet, exercise, avoid smoking, and heavy drinking) has to be applied in all AF patients in order to control modifiable risk factors that have an impact on CV and non-CV mortality, given that both types of death are quantitatively and qualitatively important in AF. At the individual level, anticoagulation in patients at risk, as well as treatment of associated risk factors like hypertension, HF and DM, coupled with rate/rhythm control strategies, appear to be the cornerstone for improving survival in patients with AF. Anticoagulation has consistently shown to reduce the risk and mortality associated to ischemic stroke in patients at high risk of stroke. It is essential to promote the adherence to already available clinical practice guidelines in the management of AF (e.g., anticoagulation and rate/rhythm control) and other guidelines related to the treatment of comorbidities (i.e., hypertension, HF, and DM) as well as patientsʼ adherence to medications.

Future research Future strategies for reversing the growing epidemic of AF will come from basic science and genetic, epidemiological, and clinical studies [2]. Fields for future research in AF may include the investigation of emerging risk factors for developing the disease, as well as the use of diverse approaches for investigation, like personalized medicine and big data. There are emerging risk factors for AF (e.g., subclinical hyperthyroidism, obesity, CKD, obstructive sleep apnea, heavy alcohol use, and even high-level endurance training), which have received much less attention than the traditional ones (age, hypertension, HF, DM, etc.) [50]. Further research is needed to ascertain whether interventions to reduce these emerging risk factors may result in better outcomes. The clinical management of AF is already personalized with respect to the decisions to undergo cardioversion or ablation, or antiarrhythmic drug therapy depending on patient symptoms and preference, or to receive anticoagulation according to validated risk prediction scores based on clinical characteristics [1,2]. However, despite nuanced clinical judgments, AF recurrence, progression to persistent AF, and response to treatment are largely unpredictable [51]. Envisioned future management algorithms for AF may involve the improvement in the taxonomy of AF in order to

8

T

R E N D S I N

C

A R D I O V A S C U L A R

ME

D I C I N E

] (2017) ]]]–]]]

Table 4 – Summary of common problems detected in the AF population/management and the potential impact in mortality risk. Problem detected

Patient population

Potential RRI (%)

References

Tobacco and alcohol use, salt intake, obesity, hypertension, and diabetes No β-blocker use Polypharmacy No anticoagulation

AF, global

20–25a

[45]

AF, global AF, global AF at moderate or high thromboembolic risk AF, global AF, anticoagulated with VKA AF and concomitant HF AF and concomitant HF AF and hypertension AF and history of ACS

13b 25–45b 20–52b

[16] [20,21] [34,35]

24b 15b

[34] [37]

55b 11b 29b 27–45b

[50] [26] [25] [16,25]

Overtreatmentc Poor control of VKA therapy (TTR o 65%) in need for switching to DOACs Poor physician adherence to HF guidelinesd Poor patient adherence to prescribed HF medications Poor patient adherence to antihypertensives No statin use or poor patient adherence to statin treatment

ACS ¼ acute coronary syndrome; AF ¼ atrial fibrillation; DOACs ¼ direct oral anticoagulants; HF ¼ heart failure; TTR ¼ time within therapeutic range; RRI ¼ relative risk increase; VKA ¼ vitamin K antagonists. a With a combined target at the population level: 30–50% relative reduction in prevalence of tobacco use, 10% reduction in per-person alcohol consumption, 30% reduction in mean population intake of salt, halting the rise in the prevalence of obesity, 25% relative reduction in the prevalence of raised blood pressure, halting the rise in the prevalence of diabetes. b Relative risk increase in comparison with the patient population without the detected problem (i.e., well treated, adherent, and DOAC use). c Combined anticoagulation plus antiplatelet therapy (only recommended in high-risk patients after an ACS and no longer than 1 year) and/or anticoagulation in low-risk patients despite not being indicated. d No use of β-blockers and/or angiotensin-converting enzyme inhibitors in accordance to guidelines in 40% of cases.

facilitate a personalized approach in which therapy is tailored to an individualʼs unique clinical, histopathologic and genetic profile, as well as to molecular determinants of disease and response to drugs [51,52]. Further investigations may enable the design of therapeutic strategies tailored to these individualʼs determinants of the disease, which will have to be tested in clinical trials to ascertain whether they may reduce morbidity and mortality associated with AF. The use of “big data” has a huge potential in cardiology research and clinical cardiology [53]. In the last decade, there has been an exponential growth in health data in cardiology, including AF, from sources such as wearable and implantable devices, smartphones, and real-time sensors. System capacities for data acquisition, storage, and processing have become more affordable. The proper application of these techniques is seen as a novel approach to answering clinical questions that may have been previously very difficult to address with traditional clinical trials and/or registries (e.g., CVD risk prediction, precision medicine using genomic information, and clinical decision support through machine-learning algorithms). The era of big data is still in its beginnings, but it is likely that it will help to design new strategies for reducing mortality associated with heart diseases, including AF.

Multifaceted collaborative approach is needed in AF, with interventions at the population and individual level. Primary prevention of AF is of critical importance. The promotion of healthy lifestyle has to be applied in all AF patients in order to control modifiable risk factors that have an impact on CV and non-CV mortality, given that both types of death are quantitatively and qualitatively important in AF. At the individual level, anticoagulation in patients at risk, as well as treatment of associated risk factors and co-morbidities appear to be the cornerstone for improving survival in patients with AF. There is a need for further improvement in physiciansʼ adherence to clinical practice guidelines as well as in the patientsʼ adherence to medications, as they are still suboptimal and may be associated with an increased mortality risk in AF. Fields for future research in AF include the investigation of emerging risk factors for developing the disease, as well as the use of diverse approaches for investigation, like personalized medicine and big data, which may help to explore strategies to further reduce mortality and morbidity associated with AF.

Acknowledgments Conclusion AF is an age-related arrhythmia associated with several comorbidities and significant mortality. Approximately half of deaths in AF are due to heart-related causes (i.e., sudden death, HF, and MI); one-third of deaths are due to nonvascular causes (i.e., cancer, respiratory diseases, and infections) and the remaining AF patients die from stroke or hemorrhage (about 6% each), or other causes.

The contents of this study are solely the responsibility of the authors and do not necessarily represent the official view of their institutions or any other party.

re fe r en ces

[1]

Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the management of atrial

T

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

R E N D S I N

C

A R D I O V A S C U L A R

fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014(64):e1–76. Gómez-Outes A, Lagunar-Ruíz J, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol 2016;68:2508–21. Bassand JP, Accetta G, Camm AJ, Cools F, Fitzmaurice DA, Fox KA, et al. Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF. Eur Heart J 2016;37:2882–9. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. Mazurek M, Huisman MV, Lip GY. Registries in atrial fibrillation: from trials to real-life clinical practice. Am J Med 2017;130:135–45. Fauchier L, Villejoubert O, Clementy N, Bernard A, Pierre B, Angoulvant D, et al. Causes of death and influencing factors in patients with atrial fibrillation. Am J Med 2016;129:1278–87. Huisman MV, Ma CS, Diener HC, Dubner SJ, Halperin JL, Rothman KJ, et al. Antithrombotic therapy use in patients with atrial fibrillation before the era of non-vitamin K antagonist oral anticoagulants: the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) Phase I cohort. Europace 2016;18:1308–18. Lip GYH, Laroche C, Boriani G, Dan GA, Santini M, Kalarus Z, et al. Regional differences in presentation and treatment of patients with atrial fibrillation in Europe: a report from the EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace 2015;17:194–206. Healey JS, Oldgren J, Ezekowitz M, Zhu J, Pais P, Wang J, et al. Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study. Lancet 2016;388:1161–9. Pokorney SD, Piccini JP, Stevens SR, Patel MR, Pieper KS, Halperin JL, et al. Cause of death and predictors of all-cause mortality in anticoagulated patients with nonvalvular atrial fibrillation: data from ROCKET AF. J Am Heart Assoc 2016;4: e002197. Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E. Direct oral anticoagulants for stroke prevention in patients with atrial fibrillation: meta-analysis by geographic region with a focus on European patients. Br J Clin Pharmacol 2016;82:633–44. Marijon E, Le Heuzey JY, Connolly S, Yang S, Pogue J, Brueckmann M, et al. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulant therapy study. Circulation 2013;128:2192–201. Link MS, Giugliano RP, Ruff CT, Scirica BM, Huikuri H, Oto A, et al. Stroke and mortality risk in patients with various patterns of atrial fibrillation: results from the ENGAGE AF-

ME

D I C I N E

[18]

[19]

[20]

[21]

[22]

[23] [24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

] (2017) ]]]–]]]

9

TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Circ Arrhythm Electrophysiol 2017. http: //dx.doi.org/10.1161/CIRCEP.116.004267. de Vos CB, Pisters R, Nieuwlaat R, Prins MH, Tieleman RG, et al. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol 2010;55:725–31. Nielsen PB, Larsen TB, Gorst-Rasmussen A, Skjøth F, Lip GY. β-blockers in atrial fibrillation patients with or without heart failure: association with mortality in a nationwide cohort study. Circ Heart Fail 2016;9:e002597. Piccini JP, Hellkamp AS, Washam JB, Becker RC, Breithardt G, Berkowitz SD, et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation 2016;133:352–60. Jaspers-Focks J, Brouwer MA, Wojdyla DM, Thomas L, Lopes RD, Washam JB, et al. Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial. Br Med J 2016;353:i2868. Kashani M, Eliasson AH, Walizer EM, Fuller CE, Engler RJ, Villines TC, et al. Early empowerment strategies boost selfefficacy to improve cardiovascular health behaviors. Glob J Health Sci 2016;8:55119. Funnell MM, Anderson RM. Patient empowerment: a look back, a look ahead. Diabetes Education 2003;29:454–8. Vrijens B, De Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T, et al. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol 2012;73:691–705. Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J 2013;34:2940–8. Ruppar TM, Cooper PS, Mehr DR, Delgado JM, Dunbar-Jacob JM. Medication adherence interventions improve heart failure mortality and readmission rates: systematic review and meta-analysis of controlled trials. J Am Heart Assoc 2016. http://dx.doi.org/10.1161/JAHA.115.002606. Santo K, Kirkendall S, Laba TL, Thakkar J, Webster R, Chalmers J, et al. Interventions to improve medication adherence in coronary disease patients: a systematic review and meta-analysis of randomised controlled trials. Eur J Prev Cardiol 2016;23:1065–76. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. Authors’ response: from monitoring to vigilance about patient adherence to new oral anticoagulants. Europace 2014;16:149–50. Clarkesmith DE, Pattison HM, Lane DA. Educational and behavioural interventions for anticoagulant therapy in patients with atrial fibrillation. Cochrane Database Syst Rev 2013;6:CD008600. Webster R, Patel A, Selak V, Billot L, Bots ML, Brown A, et al. Effectiveness of fixed dose combination medication (‘polypills’) compared with usual care in patients with cardiovascular disease or at high risk: a prospective, individual patient data meta-analysis of 3140 patients in six countries. Int J Cardiol 2016;205:147–56. Page AT, Clifford RM, Potter K, Schwartz D, Etherton-Beer CD. The feasibility and effect of deprescribing in older adults on mortality and health: a systematic review and meta-analysis. Br J Clin Pharmacol 2016;82:583–623. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. Camm AJ, Accetta G, Ambrosio G, Atar D, Bassand JP, Berge E, et al. Evolving antithrombotic treatment patterns for

10

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

T

R E N D S I N

C

A R D I O V A S C U L A R

patients with newly diagnosed atrial fibrillation. Heart 2017;103:307–14. Lip GY, Laroche C, Popescu MI, Rasmussen LH, Vitali-Serdoz L, Dan GA, et al. Improved outcomes with European Society of Cardiology guideline-adherent antithrombotic treatment in high-risk patients with atrial fibrillation: a report from the EORP-AF General Pilot Registry. Europace 2015;17:1777–86. Hess PL, Kim S, Fonarow GC, Thomas L, Singer DE, Freeman JV, et al. Absence of oral anticoagulation and subsequent outcomes among outpatients with atrial fibrillation. Am J Med 2017;130:449–56. You JH. Novel oral anticoagulants versus warfarin therapy at various levels of anticoagulation control in atrial fibrillation - a cost-effectiveness analysis. J Gen Intern Med 2014; 29:438–46. Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis of subgroups. Thrombosis 2013;2013:640723. Le Heuzey JY, Ammentorp B, Darius H, De Caterina R, Schilling RJ, Schmitt J, et al. Differences among western European countries in anticoagulation management of atrial fibrillation. Data from the PREFER IN AF registry. Thromb Haemost 2014;111:833–41. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–81. Tong TY, Wareham NJ, Khaw KT, Imamura F, Forouhi NG. Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study. BMC Med 2016;14:135. Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–90. Martínez-González MÁ, Toledo E, Arós F, Fiol M, Corella D, Salas-Salvadó J, et al. Extravirgin olive oil consumption

ME

D I C I N E

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50] [51]

[52]

[53]

] (2017) ]]]–]]]

reduces risk of atrial fibrillation: the PREDIMED (Prevención con Dieta Mediterránea) trial. Circulation 2014;130:18–26. Mozaffarian D, Furberg CD, Psaty BM, Siscovick D. Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study. Circulation 2008;118:800–7. Kontis V, Mathers CD, Rehm J, Stevens GA, Shield KD, Bonita R, et al. Contribution of six risk factors to achieving the 25  25 non-communicable disease mortality reduction target: a modelling study. Lancet 2014;384:427–37. Thomas I, EncisoSilva J, Schlueter M, Greenberg B. Anticoagulation therapy and NOACs in heart failure. Handb Exp Pharmacol 2017. http://dxdoi.org/10.1007/164_2016_126. Pulignano G, Del Sindaco D, Tinti MD, Tolone S, Minardi G, Lax A, et al. Atrial fibrillation management in older heart failure patients: a complex clinical problem. Heart Int 2016;11:e41–9. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. Neubauer S, Schilling T, Zeidler J, Lange A, Engel S, Linder R, et al. Impact of guideline adherence on mortality in treatment of left heart failure. Herz 2016;41:614–24. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34:2159–219. Khaji A, Kowey PR. Update on atrial fibrillation. Trends Cardiovasc Med 2017;27:14–25. Zakeri R, Van Wagoner DR, Calkins H, Wong T, Ross HM, Heist EK, et al. The burden of proof: the current state of atrial fibrillation prevention and treatment trials. Heart Rhythm 2017;14:763–82. Goette A, Kalman JM, Aguinaga L, Akar J, Cabrera JA, Chen SA, et al. EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterisation, and clinical implication. J Arrhythm 2016;32:247–78. Kim J. Big data, health informatics, and the future of cardiovascular medicine. J Am Coll Cardiol 2017;69:899–902.