Implantable cardioverter-defibrillators (ICDs) are now the standard of care in primary and secondary prevention of malignant arrhythmias, however with their increasing use it has been noted that ICD therapies – both appropriate and inappropriate – are associated with an increased risk of death and worsening of heart failure. The recent Multicenter Automatic Defibrillator Implantation Trial to Reduce Inappropriate Therapy (MADIT-RIT) found that for primary prevention, prolonging the arrhythmia detection interval or setting a high cut-off rate reduced inappropriate therapies.

The purpose of the ADVANCE III (Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III) trial was to assess whether increasing the number of detection intervals was beneficial in any type of ICD with the capability of delivering antitachycardia pacing (ATP) during capacitor charge, in this case among patients with both primary and secondary indications for an ICD implant. Specifically the trial looked at whether using 30 of 40 intervals to detect ventricular arrythmias, as opposed to standard detection with 18 of 24 intervals, could reduce ATP and shock delivery during spontaneous fast VT episodes.

1902 primary and secondary prevention patients with ischaemic and nonischaemic indications for first ICD implantation were enrolled, and randomised in a single-blind fashion to programming with long- (30 of 40) or standard-detection (18 of 24) intervals. The main outcome measure was the total number of ATPs and shocks delivered for all episodes; inappropriate shocks, mortality, and syncopal rates were secondary outcomes.

Over a median follow-up of 12 months, patients in the long-detection group had 346 delivered therapies compared to 557 in the standard-detection group (P<.001). The long- vs. standard-detection group also had fewer ATPs (23 per 100 person-years vs. 37 per 100 person-years; P<.001), fewer shocks (19 vs. 30; P=.06), and a reduction in the first occurrence of inappropriate shocks. However, mortality (P=.50) and arrhythmic syncope rates (P=.22) did not differ significantly between groups.

Conclusions:

Among patients undergoing first ICD implantation, the use of long- vs standard-detection intervals resulted in lower rates of ATP and shocks. This programming strategy may therefore be a useful alternative approach for ICD recipients.

• Gasparini M, Proclemer A, Klersy C et al. Effect of Long-Detection Interval vs Standard-Detection Interval for Implantable Cardioverter-Defibrillators on Antitachycardia Pacing and Shock Delivery. The ADVANCE III Randomized Clinical Trial. JAMA 2013;309:1903-1911.

Intrauterine fetal death occurs in approximately 1 in every 160 pregnancies; postmortem evaluation often fails to find an underlying cause.  The objective of this paper was to determine the spectrum and prevalence of mutations in the three most common Long QT syndrome (LQTS) susceptible genes in a cohort of cases of unexplained intrauterine death.

Retrospective post-mortem genetic testing was carried out on 91 unexplained intrauterine fetal deaths collected between 2006 and 2012.  Publically available exome databases were assessed for the general population frequency of identified genetic variants.  Mutations analysis was performed by liquid chromatography and DNA sequencing.  Functional analysis of novel mutations was performed using heterologous expression and patch-clamp recording.

The three LQTS missense mutations (KCNQ1,p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W) were discovered in three intrauterine fetal deaths.  Both KV7.1-A283T (16-week male) and KV7.1- R397W (16-week female) mutations were associated with marked KV7.1 loss-of- function consistent with in utero LQTS type 1, while the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. Furthermore, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants that conferred in vitro electrophysiological characteristics consistent with potentially pro-arrhythmic phenotypes.

Conclusions:

This analysis found that 3 of 91 unexplained intrauterine deaths were associated with missense LQTS mutations, and genetic variants leading to dysfunctional LQTS-associated ion channels were found in 8 cases.  Although preliminary, these results may provide insights into possible mechanisms of stillbirth.

• Crotti L, Tester DJ, White WM et al.  Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death.  JAMA. 2013;309(14):1473-1482

The implantable cardioverter-defibrillator (ICD) has consistently demonstrated benefit in reducing sudden cardiac death in patients at high risk of ventricular arrhythmias, but inappropriate ICD activations are a common occurrence with potential adverse effects on patient well-being and increased costs for health services. Strategies to reduce the frequency of inappropriate device activation without reducing efficacy in life-threatening situations would therefore be highly beneficial.

In the multi-centre MADIT-RIT trial, 1500 patients with a primary-prevention ICD implant were randomly assigned to a series of pre-specified programming configurations with the primary objective to determine whether high-rate therapy (with initiation at a heart rate of ≥200 beats per minute) or delayed therapy (with a 60-second delay at 170 to 199 beats per minute, a 12-second delay at 200 to 249 beats per minute, and a 2.5-second delay at ≥250 beats per minute) was associated with a decrease in occurrence of inappropriate antitachycardia pacing or shocks. Secondary end-points included death from any cause and the first episode of syncope. The results strongly favoured the novel programming algorithms. During an average follow-up of 1.4 years, high-rate and delayed therapy were associated with reductions in a first inappropriate therapy (HR with high-rate vs. conventional, 0.21; 95% CI, 0.13 to 0.34; P<0.001; HR with delayed vs. conventional, 0.24; 95% CI, 0.15 to 0.40; P<0.001) and an impressive reduction in all-cause mortality (HR with high-rate vs. conventional, 0.45; 95% CI, 0.24 to 0.85; P=0.01; HR with delayed vs. conventional, 0.56; 95% CI, 0.30 to 1.02; P=0.06). There was no difference in rates of syncope between any of the groups.

Conclusion

In this large randomised study, programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher – or with a prolonged delay in therapy at 170 beats per minute or higher – was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up, with no evidence of adverse effects.

• Moss AJ, Schuger C, Beck CA, Brown MW, Cannom DS, Daubert JP, Estes NA 3rd, Greenberg H, Hall WJ, Huang DT, Kautzner J, Klein H, McNitt S, Olshansky B, Shoda M, Wilber D and Zareba W. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med. 2012 Dec 13;367(24):2275-83.

The decision to anticoagulate a patient with atrial fibrillation involves a balance between the risks of thromboembolism against those of haemorrhage, with both risks imperfectly predicted by even the best stratification scoring systems.  Although warfarin reduces the risk of stroke in patients with atrial fibrillation, its use remains limited by several limitations.  Apixaban is a novel direct factor Xa inhibitor, previously found to be superior to warfarin at prevention of stroke or systemic embolism in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.

Lopes et al. attempted to determine how the results of anticoagulation with apixiban differed depending on the patients’ baseline risk of ischaemic events (CHADS2 & CHA2DS2-VASc) and bleeding (HAS-BLED) and found that apixaban consistently outperformed warfarin in terms of reducing the risk of clinical events (stroke, bleeding, and mortality) irrespective of CHADS2, CHA2DS2-VASc or HAS-BLED score.  In addition, Apixaban also appeared to be even more effective in reducing the risk of intracranial bleeding in patients with higher HAS-BLED scores. In individuals with HAS-BLED scores of >3, apixaban reduced the risk of intracranial bleeding 78% compared with warfarin, whereas the risk of intracranial bleeding was reduced 34% compared with warfarin in patients with HAS-BLED scores of 0 to 1.

Although apixaban is one of a number of novel oral anticoagulants that have been shown to have a clinical advantage over warfarin, it is the only one that has been shown to be associated with a reduction of both thromboembolism and haemorrhage, in addition to a reduction in all-cause mortality. This secondary analysis adds weight to the benefits of apixaban over warfarin in patients requiring anticoagulation for atrial fibrillation and reduction in intracranial bleeds in those with the highest risk of bleeding may provide physicians with an safer alternative therapy in these patients.

Conclusions:

Apixaban has benefits over warfarin that are consistent across the spectrum of stroke and bleeding risk, suggesting that the CHADS2,CHA2DS2VASc, and HAS-BLED scores may be less relevant for patients taking apixaban than they are for patients taking warfarin.

• Lopes RD, Al-Khatib SM, Wallentin L, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and bleeding in atrial fibrillation: a secondary analysis of a randomized controlled trial. Lancet 2012; DOI:10.1016/S0140-6736(12)60986-6.

Both clinical and experimental evidence have suggested an anti-arrhythmic effect of long-chain n-3 polyunsaturated fatty acids (n-3-PUFAs) in fish oil.  However, the effect of n-3-PUFAs on atrial arrhythmias such as postoperative atrial fibrillation (AF) remain uncertain.  The Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) trial was designed to test whether perioperative n-3-PUFA supplementation could reduce postoperative AF.

 1516 patients scheduled for cardiac surgery in 28 centres in the United States, Italy, and Argentina were enrolled between August 20120 and June 2012.  Patients were randomised to receive fish oil or placebo, with preoperative loading of 10g over 3 to 5 days, followed postoperatively by 2g per day until hospital discharge or postoperative day first, whichever was sooner.  Patients not in sinus rhythm at the outset were excluded.  The main outcome measure was the occurrence of postoperative AF lasting longer than thirty seconds.

 233 (30.7%) of patients assigned to placebo developed postoperative AF compared to 227 (30.0%) assigned to n-3 PUFAs (P=.74).  The number of postoperative AF episodes also did not differ between the placebo and PUFA groups, nor did the incidence of AF that was sustained, symptomatic, or treated (P=.70).  However, supplementation with n-3 PUFAs was generally well tolerated, and there was no suggestion of increased bleeding or serious adverse events.

Conclusions:

 This trial found no evidence that preoperative supplementation with n-3 PUFAs, compared with placebo, could reduce the risk of postoperative AF in patients undergoing cardiac surgery.

•  Mozaffarian D, Marchioli R, Macchia A et al.  Fish Oil and Postoperative Atrial Fibrillation.  The Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Randomized Trial.  JAMA 2012;308(19):2001-2011.

Atrial fibrillation is the commonest cardiac arrhythmia. While a number of established drug therapies are often successful in achieving satisfactory control, more recently radiofrequency catheter ablation has emerged as an effective therapy for patients with paroxysmal AF.  However, the place of catheter ablation remains unclear with limited data comparing ablation with antiarrhythmic drug therapy as first-line treatment in patients.

In the MANTRA-PAF trial 294 patients (mean age 55) with new onset paroxysmal atrial fibrillation and no history of antiarrhythmic drug use were randomly assigned to an initial strategy of either catheter ablation (146 patients) or therapy with class IC or class III antiarrhythmic agents (148 patients). Follow-up was by 7-day Holter-monitoring at 3, 6, 12, 18, and 24 months. The primary end points were the cumulative and per-visit burden of atrial fibrillation (i.e., percentage of time in atrial fibrillation). During follow-up there was no significant difference between ablation and drug-therapy in cumulative AF burden (90th percentile of arrhythmia burden, 13% and 19%, respectively; P=0.10) or the burden at 3, 6, 12, or 18 months. At 24 months, the burden of atrial fibrillation was significantly lower in the ablation group (90th percentile, 9% vs. 18%; P=0.007), and more patients in the ablation group were free from any AF (85% vs. 71%, P=0.004) and from symptomatic AF (93% vs. 84%, P=0.01). However, this slight improvement came at the price of one death in the ablation group due to a procedure-related stroke and there were also three cases of cardiac tamponade.
Conclusions:

In this study there is no significant difference between catheter ablation and antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation. In view of the potential for significant complications with catheter ablation, current practice of using drug therapy as first line treatment appears justified.

• Cosedis Nielsen J, Johannessen A, Raatikainen P, Hindricks G, Walfridsson H, Kongstad O, Pehrson S, Englund A, Hartikainen J, Mortensen LS, Hansen PS. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med. 2012 Oct 25;367(17):1587-95.

The goal of antiarrhythmic therapy following cardioversion for atrial fibrillation (AF) is to prevent further recurrences for as long as possible.  However, it is known that the atrial action potential normalises after 2-4 weeks of sinus rhythm, suggesting that drugs may not be essential in the long-term.  The goal of this study was to investigate whether short-term antiarrhythmic treatment following cardioversion for AF was non-inferior to long-term treatment.

In this prospective, randomised trial, patients at 44 centres in Germany were randomly assigned to either no antiarrhythmic treatment, treatment with 200-300mg of flecainide per day for 4 weeks, or flecainide treatment for six months.   The primary endpoint measure was the time to persistent atrial fibrillation or death, the former being assessed in a core laboratory who were masked as to the patient’s treatment group.

Overall the primary outcome occurred in 46% of patients receiving short-term treatment versus 39% of patients receiving long-term treatment; the difference between the two groups in the mean percentage of patients who did not have persistent AF was 7.9%, which did not reach the specified non-inferiority margin (p=0.2081).  A post-hoc analysis of all patients who had not reached the primary endpoint in the first month found long-term treatment to be superior to short-term treatment (p=0.0001).

Conclusion:

Although antiarrhythmic short-term treatment with flecainide after cardioversion for AF was not non-inferior to long-term treatment, this study shows that short-term treatment can be considered for AF patients who are at increased risk for adverse drug effects or other complications.

• Kirchhof P, Andresen D, Bosch R et al.  Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial.  Lancet 2012; doi:10.1016/S0140-6736(12)60570-4.

Patients with atrial fibrillation (AF) have a risk of stroke that is five times greater than that of the general population.  Moreover, it has previously been described that women with atrial fibrillation have a higher annual rate of stroke than men (3% vs. 1.6%).    The reasons for this remain unclear, although previous studies have suggested that women may be treated with warfarin less frequently than men.  Therefore the aim of this study was to compare the utilisation patterns of warfarin and the risk of subsequent stroke between older men and women with AF.

In this retrospective cohort study of patients with AF in Quebec, Canada, the authors investigated the risk of stroke in patients admitted to hospital with AF between 1998 and 2007.  Administrative data were linked with prescription drug claims databases.

47.2% of the cohort of 39,398 patients were male.  The authors noted that at the time of admission with AF, women tended to be older and had a higher CHADS₂ score than men (1.99 vs. 1.74; P<0.001).  At 30 days after discharge, more women than men (60.6% vs 58.2%) had filled a warfarin prescription, a finding that was confirmed following adjusted analysis.  Despite good compliance with warfarin treatment in both sexes, the crude stoke incidence was higher in women than in men (2.02 per 100 person-years vs. 1.61 per 100 person-years; P<0.001), and that this difference was largely driven by the population of patients aged 75 years or older.  Multivariable regression analysis confirmed that women had a higher risk of stroke than men (adjusted HR, 1.14; P<0.001), even after adjustment for baseline comorbid conditions, the components of the CHADS₂ score, and warfarin treatment.

Conclusions:

In this retrospective study, women admitted to hospital with AF were at a higher risk of stroke than men, regardless of warfarin use.

• Tsadok MA, Jackevicius CA, Rahme E et al.  Sex Differences in Stroke Risk Among Older Patients With Recent Diagnosed Atrial Fibrillation.  JAMA 2012;307:1952-1958.

The number of electronic cardiac devices, including pacemakers and cardioverter-defibrillators, being implanted each year is increasing.  As a result, there has been a 210% increase in the incidence of device infection between 1993 and 2008 in the United States.  Cardiac device infective endocarditis (CDIE) is significant in that it is associated with a higher mortality rate than device infection without endocarditis.

Athan et al. examined prospective data from the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS), collected from 61 centers in 28 countries over a six year period.  All patients were hospitalised adults with definite endocarditis as defined by the modified Duke endocarditis criteria.  The authors examined in-hospital and 1-year mortality.

CDIE was diagnosed in 6.4% of patients with definite infective endocarditis.  CDIE generally occurred in older patients (median age, 71.2 years), was caused by staphylococci (66.6% of patients), and was associated with contact with health care services (45.8%).  37.3% of patients also had co-existing valve involvement (especially the tricuspid valve).  In-hospital and one-year mortality rates were 14.7% and 23.2%, respectively.  Removal of the device was associated with an increased chance of survival at one year (hazard ratio 0.42 when compared to patients who did not undergo device removal).

Conclusion:

Patients with cardiac device infective endocarditis have high rates of mortality and concomitant valve infection.  Early device removal is indicated to improve survival at one year.

• Athan E, Chu VH, Tattevin P et al.  Clinical Characteristics and Outcome of Infective Endocarditis Involving Implantable Cardiac Devices.  JAMA 2012;307:1727-1735.

Approximately 25% of all strokes are of unknown cause, and it has long been hypothesised that short subclinical episodes of atrial fibrillation (AF) may be an important common etiologic factor.  While several studies have attempted to detect episodes of subclinical AF, most have been hampered by the infrequency of such episodes and the unlikelihood of picking them up even with monitoring over a period of days or weeks.  In the US around 400,000 pacemakers are inserted each year, many of which are able to detect and record episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. In this study Healy et al. evaluated whether subclinical episodes of AF detected by these devices were associated with an increased risk of ischemic stroke.

Recruiting 2580 individuals, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted, patients were monitored for 3 months to detect subclinical AF (episodes of atrial rate >190 bpm for more than 6 minutes) and were followed for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. By 3 months, subclinical AF had been detected in 261 patients (10.1%). Subclinical AF was associated with an increased risk of clinical AF (HR, 5.56; 95% CI, 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (HR, 2.49; 95% CI, 1.28 to 4.85; P=0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical AF detected by 3 months, and none had had clinical atrial fibrillation by 3 months.  Overall, the population attributable risk of stroke or systemic embolism associated with subclinical AF was 13% with subclinical AF remaining predictive even after adjustment for other predictors of stroke (HR, 2.50; 95% CI, 1.28 to 4.89; P=0.008).

Conclusions

Subclinical AF occurred frequently in patients in this study and was associated with a significantly increased risk of ischemic stroke or systemic embolism. .

• Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C, Morillo CA, Carlson M, Themeles E, Kaufman ES, Hohnloser SH; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012 Jan 12;366(2):120-9.