University of Groningen
Towards prevention of AF progression
Hobbelt, Anne
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Hobbelt, A. (2019). Towards prevention of AF progression. Rijksuniversiteit Groningen.
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Chapter 7
Tailored 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
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.
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.
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.
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 medicine
On 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.
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.
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-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-related complications. 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.
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
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)
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.
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-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)
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