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Almanac 2011: Cardiac Arrhythmias and Pacing. The National Society Journals Present Selected Research That has Driven Recent Advances in Clinical Cardiology◊ Department of Cardiology, National Heart Centre Singapore, Duke-NUS Graduate Medical School, Singapore, Singapore Article history:Available online 1 December 2011 ATRIAL FIBRILLATION
group had symptomatic hypotension and renal dysfunction than those in the placebo group. Clinical Trials
Although the main findings from both of these large RCTs were negative, it should be noted that they were secondary prevention In the past 2 years, a number of landmark clinical trials have been studies—that is, patients already had established AF, and also had published which further our understanding and clinical management more advanced stages of disease (over 80% of patients in both studies of patients with atrial fibrillation (AF). Two of the major goals in the had a history of persistent or permanent AF), implying that the sub- treatment of this condition include reducing progression or recur- strate for AF was already well established in both study groups. It rence of the arrhythmia and decreasing the risk of cardiovascular might be argued that blockade of the renin-angiotensin system may events, thereby improving quality of life and decreasing morbidity. be a more effective strategy if performed earlier during the natural Following on from a large body of evidence from preclinical studies, history of the disease or even before AF develops (ie, primary preven- small clinical trials and meta-analyses suggesting that blockade of the tion), since angiotensin-converting enzyme inhibitors and ARBs may renin-angiotensin system has beneficial effects on the pathophysiol- prevent, but not necessarily reverse, the electrical and structural ogy of AF,1 two large multicentre, placebo-controlled, randomised tri- remodelling that leads to the development and progression of the als were conducted to determine the effects of angiotensin II receptor arrhythmia. In support of this, a smaller randomised single-centre study of 62 patients with lone AF, with no history of hypertension or The first of these trials, published in 2009, tested the hypothesis heart disease, presenting to the emergency department reported that that the ARB valsartan could reduce the recurrence of AF in patients patients given ramipril (5 mg/day) had significantly fewer AF relapses with underlying cardiovascular disease, diabetes or left atrial enlarge- during a 3-year follow-up period than patients given placebo.4 ment and a history of documented AF, in addition to established A significant new addition to the pharmacological options availa- treatments.2 A total of 1442 patients were enrolled into the study— ble for treating AF has been the emergence of dronedarone, a mul- 722 assigned to the valsartan group (target dose 320 mg) and 720 to tichannel blocker with similar structural and electrophysiological the placebo group. The investigators found that treatment with val- properties to amiodarone with the main exception being removal of sartan had no significant effect on AF recurrence (AF recurrence 51.4% iodine and the addition of a methane-sulphonyl group.5 These struc- in the valsartan group and 52.1% in the placebo group, P=.73) over a tural changes result in decreased lipophilicity, shortened half-life (to relatively short follow-up period of 1 year. approximately 24 h), reduced tissue accumulation and theoretically The second large ARB randomised controlled trial (RCT) published fewer side effects than associated with amiodarone. this year evaluated whether irbesartan would reduce the risk of car- The ATHENA (A placebo-controlled, double-blind, parallel-arm diovascular events in patients with AF.3 Patients with a history of risk Trial to assess the efficacy of dronedarone 400 mg twice daily for the factors for stroke and a systolic blood pressure of at least 110 mmHg prevention of Hospitalisation or death from any cause in patiENts were randomly assigned to receive either irbesartan (target dose of with Atrial fibrillation/flutter) trial was a ground-breaking study pub- 300 mg once daily) or placebo. Patients for this study were already lished in early 2009 evaluating the effect of dronedarone on cardio- enrolled in one of two other AF trials looking at clopidogrel plus aspi- vascular events in patients with AF.6 In this trial, 4628 patients with rin vs aspirin alone or vs oral anticoagulants. The investigators found AF (paroxysmal or persistent) or atrial flutter who had an additional that irbesartan did not reduce cardiovascular events or hospitalisa- risk factor for death (age ≥70 years, diabetes, history of stroke/tran- tion rates for AF (total of 9016 enrolled with a mean follow-up of 4.1 sient ischaemic attack (TIA), systemic embolism, left atrial diameter years) and that, not surprisingly, more patients in the irbesartan ≥50 mm and ejection fraction (EF) ≤40%) were randomly assigned to receive dronedarone (400 mg twice daily) or placebo. Over a mean follow-up of 21 (5) months, the investigators found that patients in the dronedarone group had significantly lower primary outcome of Reproduced with permission and in agreement with the authors and the editors.
first hospitalisation due to cardiovascular events or death than the As previously published in: Heart. 2011;97:1734-43.
placebo group (734 [32%] vs 917 [39%], respectively, P<.001). Mortal-ity from cardiac arrhythmias was significantly lower in the dronedar- *Corresponding author: Department of Cardiology, National Heart Centre Singapore, 17 Third Hospital Avenue, Singapore 168752, Singapore.
one group, although there was no overall difference in all-cause E-mail address: reginald.liew.k.c@nhcs.com.sg mortality. Interestingly, there was also a small but statistically signifi- 0300-8932/$ - see front matter. Published by Elsevier España, SL. on behalf of the Sociedad Española de Cardiología.
R. Liew / Rev Esp Cardiol Almanac. 2011 cant reduction in acute coronary syndromes in the dronedarone control with β blockers and/or digoxin (target heart rate <80 bpm at group—the exact reason for this remains unclear. Patients taking rest and <110 bpm after walking). The investigators found that resto- dronedarone had higher rates of bradycardia, QT-prolongation, nau- ration of sinus rhythm in patients with AF and heart failure improved sea, diarrhoea, rash and increased serum creatinine than those receiv- quality of life and LV function compared with a strategy of rate con- ing placebo. There were no significant differences in rates of trol (66% in the rhythm control group were in sinus rhythm at 1 year thyroid- and pulmonary-related adverse events between the two and 90% in the rate control group achieved the target heart rate). For groups, although, as acknowledged by the investigators in their dis- patients with AF for whom a rate control strategy has been decided cussion, the follow-up period of 21 months might have been too short upon, the optimal target heart rate has remained controversial. Guide- to detect such adverse effects, which may take more than 2 years to lines have previously recommended strict rate control, although this develop, as is often observed with amiodarone. was not based on clinical evidence. In an attempt to examine this In the original ATHENA trial and also a subsequent post hoc issue, a prospective, multicentre, randomised trial was conducted to analysis,7 there was no evidence of harm in patients with heart failure test the hypothesis that lenient rate control was not inferior to strict or those with a low EF and New York Heart Association (NYHA) class rate control in preventing cardiovascular events in patients with per- II or III symptoms. This contrasts with results from the earlier manent AF.17 The investigators found that of the 614 patients recruited ANDROMEDA (ANtiarrhythmic trial with DROnedarone in Moderate into the study, the frequencies of symptoms and adverse events were to severe congestive heart failure Evaluating morbidity DecreAse) similar between patients assigned to a lenient rate control strategy study, which was terminated early owing to excess mortality in the (resting heart rate <110 bpm) and those assigned to a strict rate con- dronedarone group.8 The reason for this difference may be attributed trol strategy (resting heart rate <80 bpm and heart rate during moder- to the exclusion of patients with NYHA class IV symptoms in the ATH- ate exercise <110 bpm). A lenient-control strategy was easier to ENA study and the fact that the ANDROMEDA study also included achieve as more patients in this group attained their heart rate target patients with a recent exacerbation of heart failure. Nonetheless, in compared with the strict-control group (97.7% vs 67%, P<.001).
view of the results from the ANDROMEDA study, the authors warned Despite some promising results from preclinical experiments and against use of dronedarone in patients with severe heart failure and observational studies in humans,18-20 the potentially beneficial effects left ventricular (LV) dysfunction. This is reflected in the latest Euro- of polyunsaturated fatty acids (PUFA) in AF have not been confirmed pean and American guidelines, which propose that dronedarone can from the results of several prospective randomised trials reported be used as a first-line pharmacological option in patients with symp- recently. The largest and most comprehensive study to date designed tomatic AF, including those with structural heart disease, coronary to examine this subject was a prospective, multicentre, RCT of 663 artery disease, hypertensive heart disease and stable heart failure patients with confirmed paroxysmal (n=542) or persistent (n=121) with NYHA class I or II symptoms, but should not be used in patients AF, with no substantial structural heart disease and in sinus rhythm at with NYHA class III or IV symptoms or recently unstable heart baseline.21 Patients were randomly assigned to take prescription PUFA failure.9,10 A number of post hoc analyses of the ATHENA trial have (8 g/day) or placebo for the first 7 days, followed by PUFA (4 g/day) or been published providing further evidence for several beneficial placebo thereafter for 24 weeks. Despite the assigned treatment being effects of dronedarone. These include a reduction in stroke risk from relatively well tolerated in both groups and plasma levels of eicosap- 1.8% a year to 1.2% a year,11 and favourable effects on rhythm and rate entaenoic and docosahexaenoic acid being significantly higher in the prescription group than in the placebo group at weeks 4 and 24, the Another newly emerging drug that may have a role in the pharma- investigators found no reduction in AF recurrence over 6 months cological cardioversion of AF is the atrial-selective antiarrhythmic between the two groups. Two smaller prospective, placebo-control- drug vernakalant (RSD1235).13 Vernakalant is one of several new led, randomised studies investigating the effects of PUFA in patients agents that have been designed to target atrial-specific ion channels after electrical cardioversion of AF22 and after cardiac surgery23 have and in doing so, theoretically reduce or limit the risk of ventricular failed to demonstrate a beneficial action of PUFA in decreasing the proarrhythmia. In an open-label trial assessing the efficacy of ver- nakalant in the cardioversion of AF, the intravenous agent was found to convert 50.9% of patients with AF (out of a total of 236) to sinus Strategies to Decrease Thromboembolism
rhythm with a median time to conversion of 14 min among respond-ers.14 There were no episodes of ventricular arrhythmias and the drug Important advances have been made in stroke prevention in was relatively well tolerated, apart from 10 patients (4.2%) who had to patients with AF over the past 2 years, which are likely to have a sig- discontinue treatment owing to side effects (most commonly hypo- nificant impact on future clinical management. In the RE-LY study tension). In a more recent small randomised trial of 254 patients with (Randomised Evaluation of Long-term anticoagulation therapY), two recent onset AF (3-48 h duration), vernakalant (10 min infusion of 3 fixed doses (110 mg or 150 mg twice daily) of a new oral direct mg/kg followed by a second 10 min infusion of 2 mg/kg if patient was thrombin inhibitor, dabigatran, were compared with warfarin in over still in AF after a 15 min observation period) was compared with 18 000 patients with AF and at least one additional risk factor for intravenous amiodarone (5 mg/kg over 60 min followed by 50 mg stroke.24 The investigators found that patients taking the 110 mg dose maintenance infusion over 60 min).15 A greater number of patients of dabigatran had similar rates of stroke and systemic embolism to achieved the primary end point of conversion to sinus rhythm within those receiving warfarin, but had lower rates of major haemorrhage, 90 min in the vernakalant group compared with the amiodarone while subjects taking the 150 mg dose had lower rates of stroke and group (60/116 [51.7%] compared with 6/116 [5.2%], P<.0001, respec- systemic embolism, with similar rates of major haemorrhage. Results tively). The median time of cardioversion in the patients receiving from this study were so impressive that dabigatran has since been vernakalant who responded was 11 min and this was associated with incorporated into the latest European and American guidelines on AF a higher rate of symptom relief than with amiodarone. Both drugs as an alternative to warfarin for the prevention of stroke and systemic were well tolerated in this study and there were no cases of ventricu- embolism in patients with paroxysmal and permanent AF.9,25 As 80% of the active drug is excreted by the kidneys, patients with A small randomised study of 61 patients with heart failure and a creatinine clearance of <30 ml/min were excluded from the RE-LY persistent AF contributed additional useful data towards the continu- trial; dabigatran should be used with caution in patients with signifi- ing topic of rate vs rhythm control in patients with heart failure and cant renal impairment. The dose of dabigatran approved by the United AF.16 Patients in this study were randomly assigned to a rhythm con- States Food and Drug Administration in October 2010 was 150 mg trol strategy (oral amiodarone and electrical cardioversion) or rate twice daily in patients with non-valvular AF with a reduced dose of R. Liew / Rev Esp Cardiol Almanac. 2011 75 mg twice daily for those with mild renal impairment (creatinine neous left atrial appendage (LAA) closure device was compared with clearance of 15-30 ml/min). There are no dosing recommendations warfarin treatment in 707 patients with non-valvular AF. Study par- for patients with a creatinine clearance <15 ml/min or those undergo- ticipants had to have at least one risk factor for stroke (in addition to ing dialysis. In addition to the superiority of dabigatran (150 mg twice AF) and were assigned in a 2:1 ratio to receive the LAA-closure device daily) over warfarin for treatment of stroke and systemic embolism, and subsequent discontinuation of warfarin or warfarin alone (with a another major advantage is that there is no need for international target INR of between 2 and 3). The LAA-closure device was success- normalisation ratio (INR) monitoring. However, disadvantages include fully implanted in 88% of subjects assigned to the intervention group. the lack of a specific antidote (its half-life is 12-17 h) and a slightly After a mean follow-up of 18 (10) months, the primary efficacy event increased risk of non-haemorrhagic side effects, including dyspepsia. rate of stroke (ischaemic or haemorrhagic) was 3 per 100 patient- How this promising new oral anticoagulant drug will be incorporated years (95% confidence interval [95%CI], 1.9 to 4.5) in the intervention into current local practices around the world will require future eval- group and 4.9 per 100 patient-years (95%CI, 2.8 to 7.1) in the control uation and consideration. For example, there may be little to be group. Primary safety events were more common in the intervention gained from switching patients already receiving warfarin and with group than in the control group, and were mainly related to periproc- excellent INR control to dabigatran, while patients with poor INR con- edural complications (pericardial effusion in 4.8%, major bleeding in trol or those who have newly started oral anticoagulation may derive 3.5% and periprocedural ischaemic stroke in 1.1%). This important greater benefit. Local standards of care for anticoagulation control study demonstrates that the Watchman (Atritech, Plymouth, Minne- and follow-up may also be an important consideration, as concluded sota, USA) LAA-closure device may provide an alternative strategy to in a subanalysis of the RE-LY study, in which the investigators found oral anticoagulation for the prevention of stroke in patients at high that sites with poor INR control and greater bleeding from warfarin risk with non-valvular AF and at high thromboembolic risk, although may receive greater benefit from dabigatran 150 mg twice daily.26 the trade-off is an increased risk of periprocedural complications Other substudies following on from the original RE-LY trial have related to device implantation. As with all new interventional proce- shown that the benefits of dabigatran are similar between patients dures, safety of the Watchman LAA-closure device is likely to improve who have never received a vitamin K antagonist (VKA-naive patients) with increased operator experience and familiarity with the new and VKA-experienced patients,27 and that dabigatran can be used as a technology.34 Longer-term follow-up data with an earlier percutane- safe alternative to warfarin in patients requiring cardioversion.28 ous LAA-closure device, PLAATO (Percutaneous Left Atrial Appendage In the ACTIVE A study, the ACTIVE (Atrial Fibrillation Clopidogrel Transcatheter Occlusion) system,35 suggest that such devices can Trial with Irbesartan for prevention of Vascular Events) investigators lower the annualised risk of stroke/TIA compared with the expected evaluated whether the addition of clopidogrel to aspirin would reduce stroke/TIA risk assessed using the CHADS score (3.8% a year and 6.6% the risk of vascular events compared with aspirin alone in patients for a year, respectively), although event rates still remain significant.36 whom a VKA was considered unsuitable.29 The ACTIVE W trial had previously demonstrated that the combination of aspirin and clopi- Epidemiology and Genetics of Atrial Fibrillation
dogrel was inferior to oral anticoagulation for the prevention of vas-cular events in patients with AF at high risk of stroke.30 In the ACTIVE Epidemiological studies have shed further light on the mecha- A study, involving 7554 patients and a median follow-up of 3.6 years, nisms underlying AF and identified new risk factors. Using data from the investigators found that the combination of both antiplatelet the Framingham Heart Study, investigators identified a prolonged PR agents reduced the risk of major vascular events, especially stroke, interval (>200 ms) as a predictor of incident AF, pacemaker implanta- compared with aspirin alone but at the price of increased risk of tion and all-cause mortality in 7575 individuals (mean age 47 years; major haemorrhage. The clinical implications of the ACTIVE A and 54% women).37 This study contradicts the previously held belief that ACTIVE W trials are that oral anticoagulation is better than the com- first-degree heart block is benign38 and raises further questions about bination of aspirin and clopidogrel in stroke prevention in patients the mechanism by which a prolonged PR interval might increase the with AF, but for patients for whom oral anticoagulation is unsuitable, risk of developing AF. In another study using 4764 participants from the combination of antiplatelet agents is better than aspirin alone, the Framingham Heart Study, a new risk score was developed aimed although the risk of major haemorrhage is also greater. This reinforces at predicting an individual’s absolute risk for developing AF.39 Age, the need for appropriate counselling and risk stratification of patients sex, body mass index, systolic blood pressure, treatment for hyper- when deciding upon the most suitable strategy to lower the risk of tension, PR interval, clinically significant cardiac murmur and heart failure were all found to be associated with AF (P<.05, except body Another important randomised controlled clinical trial including mass index P=.08). When incorporated in a risk score, the clinical patients for whom a VKA was not suitable involved the use of new model C statistic was 0.78 (95%CI, 0.76 to 0.80). oral direct and competitive inhibitor of factor Xa, apixaban.31 The In a subsequent study, the same investigators looked at the rela- AVERROES (Apixaban vs acetylsalicylic acid to prevent stroke in tion between a number of plasma biomarkers and incident AF using patients with AF who have are unsuitable for vitamin K antagonist the Framingham cohort and found that B-type natriuretic peptide treatment or for whom this treatment has failed) study involved the (BNP) was a predictor of incident AF and improved risk stratification, random assignment of 5599 patients with AF (involving 522 centres increasing the C statistic from 0.78 (95%CI, 0.75 to 0.81) to 0.80 (95%CI, in 36 countries) to apixaban (5 mg twice daily) or aspirin (81-324 mg/ day).32 In that study, patients with AF were aged ≥50 years and had to In another community-based population study of older adults have at least one risk factor for stroke in addition to being unable to (n=5445) who participated in the Cardiovascular Health Study (CHS), take a VKA, either because it had already been shown to be unsuitable N-terminal fragment of-BNP (NT-proBNP) was found to predict new- or was deemed to be unsuitable. The investigators found that apixa- onset AF, independently of any other previously described risk fac- ban reduced the risk of stroke or systemic embolism without signifi- tor.41 Similar findings have now been reported in a Finnish cohort.42 cantly increasing the risk of bleeding or intracranial haemorrhage and The potential role of biomarkers may extend beyond predicting inci- also reduced the risk of a first hospitalisation for a cardiovascular dent AF—a recent study reporting that the kinetics of plasma NT- proBNP release in patients presenting acutely with AF provides a Recent studies in the field of new mechanical approaches to stroke potential means of determining its time of onset and the safety of prevention in AF include the PROTECT AF (Watchman Left Atrial cardioversion.43 There therefore appears to be a promising role for Appendage System for Embolic Protection in Patients with AF) study.33 new biomarkers in predicting incident AF, which may help guide cli- In this non-inferiority study, the efficacy and safety of a new percuta- nicians as to which individuals are most at risk of developing AF and R. Liew / Rev Esp Cardiol Almanac. 2011 who may benefit from prophylactic treatments. Other studies looking three patients (3%), and minor complications (arteriovenous [AV] fis- at population data in women have reported body-mass index44 and tula, femoral pseudoaneurysm and asymptomatic pulmonary vein birth weight45 to be associated with incident AF. Furthermore, recent stenosis) occurred in another three patients. The important point to data from 34 722 participants of the Women’s Health Study provided note from this study is that even in experienced hands with a selected evidence that new-onset AF in initially healthy women was inde- AF population (patients who are referred for AF ablation tend to be pendently associated with all-cause and cardiovascular mortality.46 younger and have fewer comorbidities), there is a steady decline in The past 2 years have seen important advances in our understand- arrhythmia-free survival with recurrences seen up to 5 years after ing of the genetics and heredity of AF. Following the landmark discov- ablation, although the majority occur within the first 6-12 months. ery using genome-wide association studies on subjects from European An experienced German centre also recently reported their long- and Chinese descent that two sequence variations on chromosome term follow-up data of catheter ablation in 161 patients (75% male; 4q25 are associated with an increased risk of developing AF,47 two age 59.8 [9.7] years) with symptomatic paroxysmal AF and normal LV new AF susceptibility signals have been identified on the same chro- function.58 They found that 75 patients (46.6%) were in sinus rhythm mosome.48 A meta-analysis of four independent cohorts of European after the initial procedure during a median follow-up period of 4.8 descent (the Framingham Heart Study, Rotterdam Study, Vanderbilt years (0.33 to 5.5 years). A second procedure was performed in 66 and AF Registry and German AF Network) confirmed a significant rela- a third procedure in 12 patients. One patient had an aspiration pneu- tionship between AF and intergenic regions on chromosome 4.49 monia that was successfully treated and two developed a sterile peri- Interestingly, genetic variants in the chromosome 4q25 region also cardial effusion that did not require drainage (no other procedural appear to modulate the risk of AF recurrence after catheter ablation50 complications were noted). There was a low rate of progression to and are associated with the development of AF after cardiac chronic AF during the follow-up period, which was seen in only four surgery.51,52 Whether genetic sequencing of chromosome 4q25 will prove useful in risk stratification for the development of AF after cath- A group from London, United Kingdom, similarly reported their eter ablation or cardiac surgery remains to be determined—at present, long-term results following catheter ablation for AF in 285 patients this remains a distinct and promising possibility. In line with the (75% male; mean age 57 [11] years; 53% paroxysmal AF; 20% with newly emerging genetic data on AF, studies on population-based structural heart disease) undergoing a total of 530 procedures.59 cohorts have also provided evidence for a heredity component. Using During a mean follow-up of 2.7 years (0.2 to 7.4 years), freedom from data from the Framingham Heart Study, investigators found that AF/atrial tachyarrhythmia was 86% for patients with paroxysmal AF familial AF occurred in 1185 (26.8%) and premature familial AF and 68% for those with persistent AF. Complications included three occurred among 351 (7.9%) participants out of 4421 participants strokes/TIAs. Late recurrence was three per 100 years of follow-up (11 971 examinations) during the period 1968-2007.53 The association after >3 years. The investigators also found that targeting complex was not attenuated by adjustment for AF risk factors or reported AF- fractionated atrial electrograms (CFAEs) during the ablation proce- related genetic variants. Racial factors and ancestry also appear to be dure improved outcome in patients with persistent AF. However, this related to the risk of AF. Data from white and African-American sub- was not seen in a randomised study performed by another group in jects enrolled in the CHS and Atherosclerosis Risk in Communities which 119 patients with persistent AF were randomised to additional (ARIC) study suggest that European ancestry is a risk factor for inci- CFAE ablation following pulmonary vein isolation or no additional In summary, the reports on long-term success rates following Catheter Ablation of Atrial Fibrillation
catheter ablation for AF demonstrate that the procedure is effective in a selected group of symptomatic patients with AF, although a significant In a large prospective, multicentre trial involving 19 centres, the proportion require more than one ablation procedure, there are risks of use of catheter ablation was compared with antiarrhythmic drug periprocedural complications and AF recurrence remains a possible treatment.55 A total of 167 patients with paroxysmal AF for whom at problem, even after follow-up periods as long as 5 years. It should be least one antiarrhythmic drug had failed and who had experienced at noted that reported outcomes from the different centres cannot be least three AF episodes in the preceding 6 months were randomised directly compared, since there are differences in patient population (2:1) to undergo catheter ablation or medical treatment. After a 9 (eg, percentage of patients with paroxysmal and permanent AF, patients month follow-up period, the investigators found that catheter abla- with structural heart disease), techniques used (segmental pulmonary tion resulted in a longer time to treatment failure and significantly vein isolation vs wide area circumferential ablation), length of improved quality-of-life scores. Major 30-day treatment-related follow-up and methods used to detect AF recurrence.
adverse events occurred in five of 103 patients (4.9%) treated with A number of studies have been performed to search for new non- catheter ablation and five of 57 patients (8.8%) treated with invasive parameters which may help to predict AF recurrence follow- antiarrhythmic drugs. An improvement in the quality of life was also ing catheter ablation. These factors include renal impairment,61 novel demonstrated in a prospective follow-up study of 502 symptomatic echo parameters such as the atrial electromechanical interval,62 atrial subjects who underwent AF ablation.56 The improvement in quality of fibrosis assessed with echo63 or magnetic resonance imaging (MRI)64 life was sustained at 2 years in patients with and without recurrence of AF, although the change was greatest in patients who remained free from AF and without antiarrhythmic drug treatment.
VENTRICULAR ARRHYTHMIAS AND SUDDEN CARDIAC DEATH
Several well-respected, high-volume centres have recently pub- lished their long-term outcomes following catheter ablation for AF. Ventricular Arrhythmias After Myocardial Infarction
The Bordeaux group reported their 5 year follow-up data on 100 patients (86% male; age 55.7 [9.6] years; 63% paroxysmal AF; 36% To further understand the significance of the occurrence and with structural heart disease).57 Arrhythmia-free survival rates after a timing of ventricular arrhythmias in the context of primary single catheter ablation procedure were 40%, 37% and 29% at 1, 2 and percutaneous coronary intervention (PCI), a secondary analysis of the 5 years, respectively (most recurrences occurred over the first 6 APEX AMI (Assessment of PEXelizumab in Acute Myocardial months). A total of 175 procedures were performed with a median of Infarction) trial was undertaken.66 Of the 5745 patients with two for each patient (51 patients underwent a second procedure and ST-elevation myocardial infarction presenting for primary PCI (across 17 a third). There were no periprocedural deaths, although major 296 hospitals in 17 countries), ventricular tachycardia/ventricular complications (cardiac tamponade requiring drainage) occurred in fibrillation (VT/VF) occurred in 329 (5.7%). Clinical outcomes and R. Liew / Rev Esp Cardiol Almanac. 2011 90-day mortality were found to be worse in those with VT/VF than in Another important area requiring further clarification is the those without. Furthermore, outcomes were worse if the VT/VF optimal timing of ICD insertion among AMI survivors who are deemed occurred late (after the end of cardiac catheterisation) rather than to be at greatest risk of SCD. The landmark DINAMIT study early (before the end of cardiac catheterisation). The occurrence of (Defibrillation IN Acute Myocardial Infarction Trial), which did not ventricular arrhythmias remained associated with a significantly show any mortality benefit from prophylactic ICD insertion in patients increased mortality after adjustment for potential confounders, after AMI if the device was inserted within 40 days of the index although whether they were causally related to a poorer prognosis or event,79 has been used to guide current recommendations on ICD simply a reflection of more severe heart disease is not yet clear. insertion among AMI survivors. A recent secondary analysis of this In the Occluded Artery Trial-Electrophysiological Mechanisms trial confirmed the original findings that the reduction in sudden (OAT-EP) study, PCI to open a persistently occluded infarct-related death in ICD patients was offset by an increase in non-arrhythmic artery after an acute myocardial infarction (AMI) phase was compared deaths, which was greatest in those who received ICD shocks.80 with optimal medical treatment alone to determine which strategy A postmortem study looking at 105 autopsy records of patients reduced markers of vulnerability to ventricular arrhythmias.67 There from the VALIANT (VALsartan In Acute myocardial infarctioN Trial) were no significant differences in heart rate variability, time-domain study who had died suddenly showed that recurrent myocardial signal-averaged ECG, or T-wave variability parameters (all surrogate infarction or cardiac rupture accounted for a high proportion of markers of ventricular instability) between either group at 30 days sudden death in the early period after an AMI, thereby partly and 1 year after the AMI, which is consistent with the lack of clinical explaining the lack of benefit of early ICD insertion on overall benefit from PCI in stable patients after AMI with persistently mortality.81 Arrhythmic death was more likely to occur later on (after occluded infarct-related arteries in the main OAT study. 3 months), which is consistent with the findings of improved survival The CARISMA (Cardiac Arrhythmias and Risk Stratification After among ICD recipients from other major ICD trials in which the devices Myocardial Infarction) trial was designed to investigate the incidence were inserted at a later stage. It should be noted, however, that 20% of and prognostic significance of arrhythmias detected by an sudden deaths in the first month after AMI were presumed arrhythmic implantable cardiac monitor among patients after AMI with as there was no specific postmortem evidence of any additional impaired LV function.68 A total of 297 patients (out of 5969 initially abnormality that might have caused the sudden death. A significant screened) who had had a recent AMI and had reduced LVEF (≤40%) proportion of patients who have an AMI therefore appear to continue received an implantable loop recorder within 11 (5) days of the AMI to die suddenly in the early postinfarction period from cardiac and were followed up every 3 months for an average of 1.9 (0.5) arrhythmias. These patients are not included in current international years. The investigators detected a clinically significant number of guidelines for ICD insertion and remain a group for which more bradyarrhythmias and tachyarrhythmias in these patients (28% research is required. Another group of patients who are not covered new-onset AF, 13% non-sustained VT, 10% high-degree AV block, 7% by current primary prevention ICD guidelines are those with relatively significant sinus bradycardia, 3% sinus arrest, 3% sustained VT and preserved LVEF after an AMI. Although these patients are at lower risk 3% VF). In particular, intermittent high-degree AV block was of SCD than those with poor LVEF, they represent a larger proportion associated with a very high risk of cardiac death. The arrhythmogenic substrate for ventricular arrhythmias following reperfusion therapy Data from a multicentre Japanese study suggest that in the era of for AMI was investigated in a study of 36 AMI survivors referred primary PCI there is a low incidence of SCD among AMI survivors for catheter ablation of VT (13 [9] years after the AMI).69 Of these, (overall mortality was 13.1% and SCD 1.2% over an average follow-up 14 patients had early reperfusion during AMI, while 22 were non- period of 4.2 years among 4122 patients).82 The risk was highest for reperfused. The investigators found, using detailed electroanatomical those with poor LVEF (<30%), although the absolute number at risk mapping, that scar size and pattern were different between VT was greatest in those with relatively preserved LVEF (>40%).
patients with and without reperfusion during AMI, with early The Intermediate Risk Stratification Improves Survival (IRIS) trial reperfusion and less confluent electroanatomical scar being published in 20 09 further tested the hypothesis that early implantation of an ICD soon after an AMI could improve survival compared with optimal medical treatment. 83 This was a randomised, Risk Stratification for Sudden Cardiac Death and Implantable
prospective, multicentre trial which enrolled 898 patients, 5-31 days Cardioverter Defibrillators
after their AMI, who met the following clinical criteria: LVEF ≤40% and a heart rate ≥90 bpm on the first available ECG or non-sustained VT A continuing area of active research in ventricular arrhythmias (≥150 bpm) during Holter monitoring. The main difference between and sudden cardiac death (SCD) is in improved methods of risk this study and DINAMIT was a contemporary patient population (70% stratification and selection of appropriate implantable cardioverter had undergone PCI and the majority were receiving optimal long- defibrillator (ICD) recipients.70 A numb er of non-invasive term medication) and additional non-invasive criteria to identify a cardiovascular tests have recently been evaluated among patients population at potentially higher risk. However, the investigators did with an increased risk of SCD (eg, AMI survivors and patients with not find that ICD therapy reduced overall mortality after a mean coronary artery disease and cardiomyopathies) with promising follow-up of 37 months. Consistent with the findings from DINAMIT, results. These include T-wave alternans,71,72 single-photon emission the reduced incidence of SCD among ICD recipients in the IRIS study computed tomography myocardial perfusion imaging,73 sympathetic was offset by an increased incidence of non-SCD.
nerve imaging with 123-iodine metaiodobenzylguanidine74 and late-gadolinium enhancement on cardiac MRI.75 In addition, plasma Catheter Ablation of Ventricular Arrhythmias
biomarkers, such as serum collagen levels, which reflect extracellular matrix alterations that may play a part in the generation of the The VTACH (Ventricular Tachycardia Ablation in Coronary Heart arrhythmogenic substrate,76 may have a future role in risk disease) study, involving 16 centres in four European countries, stratification. Genetic markers may also be relevant, as suggested by assessed the potential benefit of catheter ablation of VT before ICD the observation from a combined population of 19 295 black and implantation in patients with a history of VT, myocardial infarction white adults from the ARIC Study and the CHS that sequence and LVEF ≤50%.84 Patients (n=110) were randomly allocated to receive variations in the nitric oxide synthase 1 adaptor protein (NOS1AP) catheter ablation and an ICD or an ICD alone and followed-up for a were associated with baseline QT interval and the risk of SCD in white mean period of 22.5 (9) months. The investigators found that prophy- (but not black) United States adults.77,78 lactic VT ablation before ICD implantation prolonged the time to VT R. Liew / Rev Esp Cardiol Almanac. 2011 recurrence from 5.9 months (IQR 0.8-26.7) in the ICD only group to ure and that there was no significant difference in mortality between 18.6 months (lower quartile 2.4 months; upper quartile could not be the two groups (which was 3% annually). Furthermore, the study determined) in the ablation and ICD group. Complications related to failed to show that NYHA class I patients fulfilling the enrolment cri- the ablation procedure occurred in two patients. This study is in accordance with an earlier prospective randomised study of In RAFT (Resynchronisation-defibrillation for Ambulatory heart 128 patients, which demonstrated that prophylactic catheter ablation Failure Trial), CRT-D was compared with ICD alone in patients with of the ventricular arrhythmogenic substrate reduced the incidence of NYHA class II or III heart failure, LVEF ≤30%, intrinsic QRS duration ICD therapy in patients with a history of myocardial infarction and ≥120 ms or a paced QRS duration of ≥200 ms.94 The investigators previous ventricular arrhythmias.85 It should be noted that VT abla- found that over a mean period of 40 months, the primary outcome tion was performed in experienced centres in both these trials and (all-cause mortality or heart failure hospitalisation) occurred in fewer that there was no significant effect of catheter ablation on overall patients in the CRT-D group (33.2% compared with 40.3% in the ICD mortality. Whether VT ablation should routinely be performed before group, P<.001). Unlike MADIT-CRT, RAFT demonstrated that CRT-D ICD insertion for secondary prevention of SCD in stable patients with significantly reduced overall mortality and cardiovascular mortality previous myocardial infarction remains to be determined.
compared with ICD alone, although more adverse device-related There has been an increase in the number of publications on epi- events were also seen in the CRT-D group. Possible reasons for mor- cardial ablation for VT over the past few years in view of the realisa- tality benefit seen in RAFT, but not MADIT-CRT, are that RAFT included tion that not all VTs can be successfully eliminated by an patients with more advanced disease (and a higher proportion with endocardial-only approach.86,87 In a retrospective study of 156 epicar- ischaemic heart disease) and follow-up was longer and more com- dial ablations for VT (out of a total of 913 VT ablations) in three terti- ary centres evaluating the safety and mid-term complications of A number of subanalyses of MADIT-CRT have since been con- epicardial VT ablation, the risk of major acute (epicardial bleeding, ducted to provide further information on the findings. One subanaly- coronary stenosis) and delayed (pericardial inflammatory reaction, sis demonstrated that women experienced significantly greater delayed tamponade, coronary occlusion) complications related to reductions in all-cause mortality and heart failure than men, which epicardial access was found to be 5% and 2%, respectively.88 Therefore, was accompanied by greater echo evidence of reverse cardiac remod- although this technique can be effective in some cases, especially elling.95 Another subanalysis looking specifically at the echo parame- where endocardial ablation has failed, it is associated with significant ters and performance between the two groups found that CRT morbidity and should only be performed in centres experienced with significantly improved cardiac size and performance compared with the ICD-only strategy, which probably accounted for the outcomes The prognostic significance of frequent premature ventricular benefit in the CRT-D group.96 Other studies have also provided addi- contractions (PVCs) and the effect of catheter ablation of these ectop- tional echo evidence that CRT in mild heart failure (NYHA class I/II) ics has received further attention recently. In a study of 239 asympto- results in major structural and functional reverse remodelling which matic patients with structurally normal hearts and frequent PVCs may prevent disease progression.97,98 The PACE (Pacing to Avoid Car- (>1000/day) from the right or LV outflow tract, a significant negative diac Enlargement) study explored whether biventricular pacing was correlation between PVC prevalence and δLVEF and positive correla- better than RV apical pacing in preventing adverse cardiac remodel- tion with δLV diastolic diameter was observed over a 5.6 (1.7)-year ling in patients with bradycardia and normal ventricular function at period.89 In addition to PVC burden, other factors such as longer PVC baseline.99 In this small randomised study of 177 patients followed up duration, presence of non-sustained VT, multiform PVCs and right over a 12-month period, the investigators found that the mean LVEF ventricular (RV) PVCs may be associated with a decline in LV was significantly lower in the RV-pacing group than in the biventricu- function.90,91 Although it is well known that catheter ablation of fre- lar-pacing group (54.8 [9.1]% vs 62.2 [7]%, P<.001), with an absolute quent PVCs can improve and restore LV function in some patients, the difference of 7.4% points. However, the beneficial effects of biven- potential benefits of ablation in patients with normal LV function tricular pacing on echo parameters in this group of patients were not have been less well studied. A prospective study of 49 patients with accompanied by any clinical benefit.
frequent PVCs and normal baseline LVEF demonstrated that catheter Other important and continuing areas of investigation in the field ablation can improve the subtle LV dysfunction-detected pre-ablation of CRT include how best to select candidates who are most likely to using speckle tracking imaging analysis.92 However, unanswered respond to CRT and how to optimise response. Parameters that have questions remain, including benefits of catheter ablation on hard end recently been studied to improve patient selection include QRS mor- points (especially mortality) and when ablation should be performed phology in MADIT-CRT (left bundle branch block [LBBB], rather than (degree of PVC burden, LV function, after a trial of antiarrhythmic non-LBBB, patterns appears to be the predominant morphology—that is, related to response),100 baseline LV radial dyssynchrony, discordant LV lead position, and myocardial scar in the region of the LV pacing CARDIAC RESYNCHRONISATION THERAPY AND PACING
lead,101 and pre-pacing systolic dyssynchrony measured by tissue Doppler imaging velocity.102 Consistent with existing knowledge, LV Two pivotal cardiac resynchronisation therapy (CRT) clinical trials lead positioning has been reconfirmed to be important in MADIT-CRT have been published in the past 2 years that potentially expand the patients103 and patients with non-ischaemic dilated cardiomyopa- indications for CRT in patients with heart failure to those in NYHA thy.104 The prospective, randomised SMART-AV (SmartDelay deter- class I and II symptoms. MADIT-CRT (Multicenter Automatic Defibril- mined AV optimisation: a comparison with other AV delay methods lator Implantation Trial-CRT) compared the use of ICD alone with used in CRT) study compared three different methods of AV optimisa- CRT-D (CRT with a defibrillator component) in patients with asymp- tion (fixed empirical AV delay of 120 ms, echo-optimised AV delay, or tomatic or mildly symptomatic heart failure symptoms (NYHA class I AV optimisation with an ECG-based algorithm) in 980 patients with a or II), LVEF ≤30% and QRS duration of ≥130 ms.93 During an average CRT device to determine if any method was superior.105 The study follow-up of 2.4 years, fewer patients in the CRT-D group experienced found that neither echo- or ECG-based AV optimisation was better the primary composite end point (all-cause mortality and heart fail- than a fixed AV delay of 120 ms and therefore concluded that the rou- ure) compared with the ICD group (17.2% compared with 25.3%, tine use of AV optimisation techniques was not indicated. However, respectively, P=.001). Although these results appear impressive at first the data did not exclude the possibility that AV optimisation might glance, closer examination of the data reveals that the main superior- have a role in selected patients who do not respond to CRT with ity of CRT-D was in reducing the rate of hospitalisation for heart fail- R. Liew / Rev Esp Cardiol Almanac. 2011 The potentially deleterious effects of chronic RV pacing on cardiac rs16847548 and rs10494366) were genotyped to assess the effect of function were re-examined in 103 patients with isolated congenital AV variant alleles on QTc and on the incidence of cardiac events.117 The block. Long-term pacing was not found to be associated with the investigators found that variant alleles tagged by SNPs rs4657139 and development of heart failure or deterioration of ventricular function in rs16847548 were associated with an average QTc prolongation of patients who were negative for antinuclear antibody, although patients 7 ms and 8 ms, respectively, whereas rs4657139 and rs10494366 were who tested positive for the antibody were more likely to develop heart associated with an increased incidence of cardiac events. Furthermore, failure.106 Pacing in hypertrophic cardiomyopathy was also recently the rs10494366 minor allele was an independent prognostic marker re-examined in a single-centre study, which found some evidence of among patients with QTc <500 ms, but not in the entire cohort. These benefit from dual chamber pacing in patients with hypertrophic two studies demonstrate that genetic testing for variants in the NOS1AP cardiomyopathy with NYHA III-IV symptoms, rest gradients of and tagged SNPs may be clinically useful for risk stratification of >50 mmHg and who were refractory to other drugs, after follow-up patients with congenital LQTS and potentially guide the choice of periods of up to 10 years.107 Another group of patients in whom the role of pacing has remained controversial are those with carotid sinus The FINGER (France, Italy, Netherlands, GERmany) registry, one of hypersensitivity (CSH) with syncope. In a double-blind, placebo- the largest series on patients with Brugada syndrome (BrS) so far, controlled, crossover study, 34 patients (aged >55 years) with CSH and involved 1029 consecutive individuals (745 men; 72%) with BrS (with more than three unexplained falls in the preceding 6 months were a spontaneous or drug-induced type I ECG) who were followed up for a randomised to receive a dual-chamber pacemaker with rate-drop median period of 31.9 months.118 The cardiac event rate per year was response programming which was switched on or off.108 The 7.7% in patients with aborted SCD, 1.9% in patients with syncope and investigators found that the pacing intervention had no effect on the 0.5% in asymptomatic patients. This study provides important number of falls and concluded that the role of pacing for this group of information that the event rate among asymptomatic patients with a patients remains controversial. A similar conclusion was reached in a Brugada ECG (which comprised 64% of subjects in the registry) is low. multicentre study of 141 patients (mean age 78 years) with In addition, symptoms and a spontaneous type 1 ECG were predictors of arrhythmic events, whereas gender, familial history of SCD, inducibility of VTs during an EP study and the presence of an SCN5A INHERITED ARRHYTHMOGENIC DISEASES
mutation were not predictive of arrhythmic events. In an interesting mechanistic study of BrS, in vivo high-density Major advances have been made in our understanding of the basic mapping using non-contact mapping array was performed in the mechanisms, genetics and clinical features of the inherited arrhyth- right ventricle of 18 patients with BrS and 20 controls.119 The mogenic diseases (IADs) over the past 2 years. Since these cannot all investigators identified marked regional endocardial conduction be covered in this short overview, only some of the major studies with delay and heterogeneities in repolarisation in patients with BrS and important implications for general cardiologists will be mentioned. proposed that the slow-conduction zones may have a role in the The rapid expansion in our knowledge of the genetic basis of the IADs initiation and maintenance of ventricular arrhythmias. and rise in commercially available clinical genetic services has In line with these findings, an outstanding study was subsequently brought with it an additional dimension to how we manage these performed in which nine symptomatic patients with BrS who had conditions. The reader is referred to a number of useful recently pub- recurrent VF episodes underwent endocardial and epicardial mapping lished reviews that examine these issues in more detail.110-112 of the right ventricle. Ablation at unique abnormal low voltage sites SCD without morphological evidence of heart disease accounted for (clustering exclusively in the anterior aspect of the RV outflow tract 23% of cases in a recent pathological study of United Kingdom athletes.113 [RVOT] epicardium) rendered VT/VF non-inducible in seven of the Potential causes of unexplained cardiac arrest were systematically nine patients, with no recurrence of ventricular arrhythmias in all evaluated in a prospective study involving 63 patients in nine centres patients over a follow-up period of 20 (6) months. Interestingly, across Canada.114 The tests, which included cardiac MRI, signal-averaged normalisation of the Brugada ECG pattern was seen in eight patients ECG, exercise testing, drug challenge and selective electrophysiology (EP) after ablation. This important proof-of-concept study lends further testing, resulted in a specific diagnosis (IAD, early repolarisation, support to the notion that the underlying EP mechanism in patients coronary spasm and myocarditis) in 35 patients (56%). The remaining with BrS is delayed depolarisation in the RVOT (specifically over the 28 patients were considered to have idiopathic VF. Subsequent genetic anterior epicardial region) and demonstrates for the first time that testing performed in 19 patients found evidence of causative mutations substrate modification may be an effective strategy in patients with in nine (47%) of these. Family screening of 64 family members of the symptomatic BrS with recurrent VF episodes.
nine patients with causative mutations led to the discovery of mutations Flecainide has recently emerged as a promising new treatment for in 15 individuals (23%), who were subsequently treated. This study catecholaminergic polymorphic ventricular tachycardia (CPVT). In a provides evidence that targeted genetic testing may play a part in helping mouse model of CPVT, flecainide was found to prevent arrhythmias to diagnose genetically mediated arrhythmia syndromes, which may by inhibiting cardiac ryanodine receptor-mediated calcium release.120 result in successful family screening.
In the same publication, flecainide also completely prevented CPVT in An important study that investigated the presence of genetic factors two patients who had remained highly symptomatic with conven- or modifiers that could partly explain the phenomenon of incomplete tional drug treatment. In a clinical study of 33 patients who had penetrance seen in congenital long QT syndrome (LQTS) identified the received flecainide because of exercised-induced ventricular arrhyth- NOS1AP as one such candidate.115 This protein was chosen on the basis mias despite conventional treatment, flecainide was found to either of previous studies that showed an association between genetic partially or completely reduce the arrhythmias in 76% of cases.121 variants of NOS1AP and small quantitative increases in the QT interval and an increased risk of death in a general population.77,116 In the study CONFLICTS OF INTEREST
involving a South African LQTS population (500 subjects, 205 mutation carriers), NOS1AP variants were found to be significantly associated with the occurrence of symptoms, clinical severity (including cardiac arrest and SCD) and a greater likelihood of having a QT interval in the REFERENCES
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