Approximately 6-20% of patients with severe sepsis develop new-onset atrial fibrillation (AF).  Although the risks of chronic AF are well documented, the relationship between new-onset AF in the setting of sepsis and prognosis has not previously been well studied, partly due to the complex nature of this group of patients.

Using a database of patients hospitalised with severe sepsis, Walkey et al. examined the in-hospital stroke and mortality rates of patients developing new-onset AF.  Severe sepsis (n=49,082) was defined according to ICD-9-CM 995.92.  Cases of AF present at admission were excluded.

The authors found that new-onset AF occurred in 5.9% of patients with severe sepsis.  When these patients were compared with severe sepsis patients without new-onset AF, they were noted to have a greater risk of in-hospital stroke (2.6% vs 0.6%; P<0.001) and in-hospital mortality (56% vs 39%; P<0.001).  These findings persisted after sensitivity analysis and adjustment for confounding variables.

Conclusions:

New-onset AF in patients with severe sepsis indicates a group at increased risk of in-hospital stroke and death.

• Walkey AJ, Wiener RS, Ghobrial JM et al.  Incident Stroke and Mortality Assocaited With New-Onset Atrial Fibrillation in Patients Hospitalised With Severe Sepsis.  JAMA 2011.  Doi: 10.1001/jama.2011.1615

While warfarin has served as the oral anticoagulant of choice for decades, its time in widespread clinical use may finally be drawing to a close.  A variety of new agents are in late stage development which hold several advantages: fewer interactions with other drugs, no need for therapeutic drug monitoring, and simpler dosing regimes.

The latest of these warfarin competitors to complete Phase III trials is the factor Xa inhibitor rivaroxaban. In the double-blind, double-dummy ROCKET AF trial, the investigators randomly assigned 14,264 patients with nonvalvular atrial fibrillation – who were at moderate to high risk of stroke – to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin.  Blinding was maintained through encrypted INR monitoring for all participants that allowed for sham adjustment of placebo for those in the rivaroxaban arm.  The primary clinical end-point was stroke or systemic embolism and the principal safety endpoint was a composite of major and non-major clinically relevant bleeding.  The study was powered to demonstrate non-inferiority of rivaroxaban and the median follow-up was 2 years. The primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (HR, 0.79; 95% CI, 0.66 to 0.96; P<0.001 for non-inferiority). In the safety analysis bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (HR, 1.03; 95% CI, 0.96 to 1.11; P=0.44). However, the important end-points of intracranial haemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) demonstrated significant reductions in favour of rivaroxaban therapy.

Conclusions

In patients with atrial fibrillation, the oral factor Xa inhibitor rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism. Rivaroxaban also demonstrated significant reductions in the important safety end-points of intracranial and fatal bleeding.

• Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.  N Engl J Med. 2011 Sep 8;365(10):883-91.

Whilst reducing blood pressure reduces the risk of heart failure and stroke this relationship has thus far not been demonstrated in patients with atrial fibrillation.  This is despite the fact that recent mechanistic work and retrospective analyses have suggested that both ACE inhibitors and ARBs have specific properties that alter atrial mechanical and electrical remodelling and may prevent atrial fibrillation.

To formally test whether these effects translate into clinical gains, in the ACTIVE I study, the authors recruited 9016 patients with permanent or paroxysmal AF at increased risk of stroke, who were randomly assigned to receive the ARB irbesartan at a target dose of 300 mg once daily or double-blind placebo.  ACTIVE I was the sister trial of the ACTIVE W and ACTIVE A trials which compared various combinations of aspirin, clopidogrel and warfarin in the same patients with these stratifications being accounted for in the statistical analysis.  The first co-primary outcome was a composite of stroke, myocardial infarction, or death from vascular causes; the second was this composite plus hospitalization for heart failure.  Patients were followed up for a mean of 4.1 years.  About 60% of patients were already taking an ACE inhibitor at enrolment and these were continued.

Irbesartan reduced blood pressure by a mean of 2.9/1.9 mmHg compared with placebo but this failed to reduce the composite of stroke, MI or vascular death which occurred at a rate of 5.4% per 100 person-years in both groups (HR with irbesartan, 0.99; 95% CI, 0.91 to 1.08; P=0.85).  Similarly there was no difference in the second co-primary outcome which occurred at a rate of 7.3% per 100 person-years among patients receiving irbesartan and 7.7% per 100 person-years among patients receiving placebo (HR, 0.94; 95% CI, 0.87 to 1.02; P=0.12).  In the prespecified secondary outcome of first hospitalization for heart failure irbesartan appeared to show a marginal benefit (HR for irbesartan, 0.86; 95% CI, 0.76 to 0.98;P=0.02) but this came at the increased risk of symptomatic hypotension (127 vs. 64;P<0.001) and renal dysfunction (43 vs. 24;P=0.02) with 4 patients in the irbesartan group requiring dialysis against none in the placebo group.  Finally, there was no benefit from irbesartan in preventing recurrence of AF or hospitalisation for AF.

Conclusions

In this large multi-centre study, irbesartan did not further reduce cardiovascular events in patients with atrial fibrillation or promote maintenance of sinus rhythm when added to conventional therapy.

• ACTIVE I Investigators, Yusuf S, Healey JS, Pogue J, Chrolavicius S, Flather M, Hart RG, Hohnloser SH, Joyner CD, Pfeffer MA, Connolly SJ.   Irbesartan in patients with atrial fibrillation.  N Engl J Med. 2011 Mar 10;364(10):928-38.

For patients with severe systolic heart failure, several randomised trials have shown the ability of implantable cardioverter-defibrillator (ICD) devices to prevent sudden cardiac death.  However, current US guidelines recommend against ICD insertion within 3 months of an initial heart-failure diagnosis, or within forty days of a myocardial infarction.

This retrospective cohort study of cases submitted to the National Cardiovascular Data Registry-ICD Registry between January 1, 2006, and June 30, 2009 looked at data from 111 707 patients.  25145 (22.5%) of patients received non-evidence-based ICD implants.  Patients who received a non-evidence-based ICD had a higher risk of in-hospital death (0.57% vs 0.18%, P<0.001) and any post-procedural complication (3.23% vs 2.41%, P<0.001) than patients who received an ICD appropriately.  Electrophysiologists were less likely to implant an ICD inappropriately than other cardiologists or thoracic surgeons.

Conclusions

Almost a quarter of ICD implants performed in the USA are inappropriate according to current guidelines; in most cases this was due to inappropriate timing of insertion.

• Khatib SM, Hellkamp A, Curtis J, et al. Non-evidence-based ICD implantations in the United States. JAMA 2011; 305:43-49.
• Kadish A and Goldberger J. Selecting patients for ICD implantation: Are clinicians choosing appropriately? JAMA 2011; 305:91-92.

Fish oils, principally omega-3 fatty acids, have previously been investigated as a potential anti-arrhythmic agent for patients suffering from atrial fibrillation. However, the results of several small trials performed to date have been unclear. Therefore this randomised trial was designed to assess the effect of omega-3 fatty acids on patients with paroxysmal or persisting atrial fibrillation without structural heart disease.

Six hundred and sixty-three patients with atrial fibrillation were recruited over a three year period; all were in sinus rhythm at the time of recruitment but were known to have either paroxysmal (n=542) or persistent (n=121) atrial fibrillation. Patients were randomised to either placebo or omega-3 treatment and followed up for 24 weeks. The primary outcome measure was symptomatic recurrence of atrial fibrillation.

At 4 and 24 weeks, both eicosapentaenoic acid and docosahexaenoic acid levels were raised in the treatment group compared to the control group. However, no difference was noted between treatment groups for recurrence of symptomatic AF in the paroxysmal stratum (HR, 1.15; 95% CI 0.90 to 1.46; p=0.26), in the persistent stratum (HR, 1.64; 95% CI 0.92 to 2.92; p=0.09), or both strata combined (HR, 1.22; 95% CI 0.98 to 1.52; p=0.08).

Conclusions

In this randomised study, treatment with omega-3 did not reduce the incidence of paroxysmal atrial fibrillation over a six-month period. Other larger trials examining the effect of fish oils on atrial fibrillation are ongoing.

▶ Kowey PR, Reiffel JA, Ellenbogen KA, et al. Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation. A randomized controlled trial.JAMA 2010;304:2363–72.

Guidelines for the treatment of atrial fibrillation (AF) suggest that, where rate control is the preferred management stratey, a resting heart rate of less than 80 bpm and an exercise heart rate of less than 110 bpm should be targeted.  These values are based on the belief that lower heart rates will result in fewer symptoms, are likely to be associated with better cardiovascular function because of longer diastolic filling times and more satisfactory hemodynamics, and are associated with a lower risk of tachycardia-related cardiomyopathy.  While these assumptions may be supported by some epidemiological and echocardiographic data, there is no prospective evidence to guide clinicians and in the RACE (RAte Control Efficacy) II trial the authors set out to explore this question.
In this prospective, multi-centre study, 614 patients with permanent atrial fibrillation were recruited and randomly assigned to either a strict rate control strategy (resting heart rate <80 bpm and heart rate during moderate exercise <110 bpm) or a lenient strategy (resting heart rate <110 beats per minute).  Decisions on therapy were left to individual physicians, but there were high rates of beta-blocker and calcium antagonist use in both groups with individuals in the strict control group generally on higher doses to achieve targets.  The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events after a follow up of at least 2 years and a maximum of 3.
The results showed no benefit from the strict strategy with the incidence of the primary outcome of 14.9% versus 12.9% in the lenient-control group (90% CI, −7.6 to 3.5; P<0.001 for the prespecified noninferiority margin).  The frequencies of the components of the primary outcome were similar in the two groups and symptoms and adverse events were also similar.  Moreover, patients in the lenient-control group met the heart-rate targets with fewer total visits reducing resource use and clinic time.
Whilst there are limitations to the study, including recruitment of a relatively young and fit AF population, a preponderance of men (while women are known to have a greater symptom burden) and also a limited follow-up that may not be able to detect the long term benefits of a strict rate control strategy, this is the first work of its kind to examine an important question in clinical cardiology.

Conclusions:
In this randomised controlled trial, an aggressive rate control regime (resting heart rate <80 bpm) in patients with atrial fibrillation appeared to have no benefits over a more lenient one (resting heart rate <110bpm).

•    Lenient versus strict rate control in patients with atrial fibrillation. Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM, Hillege HL, Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA, Van Veldhuisen DJ and Van den Berg MP for the RACE II Investigators N Engl J Med. 2010 Apr 15;362(15):1363-73.

Although Implantable Cardioverter-Defibrillators (ICDs) are an established treatment for the prevention of death from ventricular arrhythmia, they require transvenous lead implantation and thus their insertion is prone to complications.  If cardiac pacing is not also required, then potentially transvenous electrodes can be avoided altogether.  The authors report the results of a novel subcutaneous ICD system designed to avoid the need for electrodes within or on the heart.
The authors initially conducted two short-term clinical trials to find a suitable device.  Four subcutaneous ICD configurations were tested in 78 patients and subsequently the best configuration was tested in an additional 49 additional patients to determine the optimal subcutaneous defibrillation threshold.  Following this, the long-term use of subcutaneous ICDs were tested in a pilot study involving initially 6, then 55, patients.
A parasternal electrode and a left lateral thoracic pulse generator were found to constitute the optimal device, and this configuration was found to be as effective as a transvenous ICD for terminating ventricular fibrillation; however, a significantly higher mean energy requirement was needed (36.6J vs 11.1J).  For those patients who received a permanent subcutaneous ICD, ventricular fibrillation was successfully detected in 100% of 137 episodes; after a mean of 10 months the device had successfully detected and treated all 12 episodes of spontaneous sustained ventricular tachycardia.

Conclusions:
In preliminary proof-of-concept studies, an entirely subcutaneous ICD device successfully detected and converted ventricular fibrillation and tachycardia.  Larger scale clinical trials are now indicated.

•    Bardy GH, Smith WM, Hood MA, Crozier IG, Melton IC, Jordaens L, et al. An entirely subcutaneous implantable cardioverter-defibrillator. N Engl J Med 2010, May 12.
Journals scanned
American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Lancet; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax

Reviewers
Dr Alistair C Lindsay, Dr Hussain Contractor