Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation

About 13–26% of all acute ischaemic strokes are related to non-valvular atrial fibrillation, the most common cardiac arrhythmia globally. Deciding when to initiate oral anticoagulation in patients with non-valvular atrial fibrillation is a longstanding, common, and unresolved clinical challenge. Although the risk of early recurrent ischaemic stroke is high in this population, early oral anticoagulation is suspected to increase the risk of potentially harmful intracranial haemorrhage, including haemorrhagic transformation of the infarct. This assumption, and current treatment guidelines, are based on historical, mostly observational data from patients with ischaemic stroke and atrial fibrillation treated with heparins, heparinoids, or vitamin K antagonists (VKAs) to prevent recurrent ischaemic stroke. Randomised controlled trials have subsequently shown that direct oral anticoagulants (DOACs; ie, apixaban, dabigatran, edoxaban, and rivaroxaban) are at least as effective as VKAs in primary and secondary prevention of atrial fibrillation-related ischaemic stroke, with around half the risk of intracranial haemorrhage. However, none of these DOAC trials included patients who had experienced ischaemic stroke recently (within the first few weeks). Clinicians therefore remain uncertain regarding when to commence DOAC administration after acute ischaemic stroke in patients with atrial fibrillation.

Recent developments

Prospective observational studies and two small randomised trials have investigated the risks and benefits of early DOAC-administration initiation (most with a median delay of 3–5 days) in mild-to-moderate atrial fibrillation-associated ischaemic stroke. These studies reported that early DOAC treatment was associated with a low frequency of clinically symptomatic intracranial haemorrhage or surrogate haemorrhagic lesions on MRI scans, whereas later DOAC-administration initiation (ie, >7 days or >14 days after index stroke) was associated with an increased frequency of recurrent ischaemic stroke.

Where next?

Adequately powered randomised controlled trials comparing early to later oral anticoagulation with DOACs in ischaemic stroke associated with atrial fibrillation are justified to confirm the acceptable safety and efficacy of this strategy. Four such randomised controlled trials (collectively planned to include around 9000 participants) are underway, either using single cutoff timepoints for early versus late DOAC-administration initiation, or selecting DOAC-administration timing according to the severity and imaging features of the ischaemic stroke. The results of these trials should help to establish the optimal timing to initiate DOAC administration after recent ischaemic stroke and whether the timing should differ according to stroke severity. Results of these trials are expected from 2021.

Wearable ECG patch improves AF diagnosis in mSToPS

However, he acknowledged that one of the limitations of the study was the low percentage of patients approached who consented. “Only 5.4 percent of patients who received an invitation to participate in mSToPS actually enrolled in the trial.  Thirty-eight percent of those who initially consented to participate never got to wear the patch due to a lack of built-in digital prompting,” Steinhubl said.
“The quality of data collected through the patch is as good as what we see clinically,” said lead investigator Dr Steven Steinhubl from the Scripps Translational Science Institute in La Jolla, California, US. “At 1 year, patients who wore the chest monitor had nearly thrice the likelihood of being diagnosed with AF. A significant proportion of them was started on anticoagulant therapy to lower their stroke risk.” The primary endpoint of the incidence of AF was 6.3 percent (unadjusted odds ratio [OR], 2.8; p<0.0001) in patients monitored using the ECG patch vs 2.3 percent (adjusted OR, 3.0; p<0.0001) in those monitored with routine care at 1 year.
Active monitoring led to a significantly higher rate of initiating anticoagulant therapy (5.4 percent vs 3.4 percent in controls). There was also a small but significant increase in antiarrhythmic therapy (0.8 percent vs 0.3 percent) and pacemaker or implantable cardioverter-defibrillator placement (0.7 percent vs 0 percent) in the active monitoring group. [ACC.18,18-LB-18063] Steinhubl and colleagues sought to determine if participant-generated data available through the ECG patch can better identify AF relative to routine care and facilitate timely anticoagulation. mSToPs included 1,738 Aetna members aged ≥75 years with prior cerebrovascular accident or heart failure, diabetes and hypertension, or obstructive sleep apnoea, who were enrolled through a web-based platform to undergo active monitoring at home with the iRhythm Zio patch that records an ECG continuously. Patients had no known AF but at moderate risk.
They were taught how to apply the patch and made to wear it for an average of 12 days. Each case was matched with two controls of similar age-, sex-, and CHA2DS2-VASc (n=3,476). Data on AF treatment, physician and emergency department visits, blood clot, and stroke events were collected. Patients on ECG patch had significantly more primary care visits vs controls (78.7 percent vs 75 percent) and cardiology outpatient visits (31.6 percent vs 23.6 percent). There was no difference in stroke rate between groups (1.9 percent vs 2.1 percent). Emergency department visits or hospitalizations were also comparable. “We found that remote AF monitoring is a feasible, scalable, and clinically valuable way to screen for AF in an at-risk nationwide population,” said Steinhubl. “Monitoring is associated with greater initiation of guideline-recommended therapies, with increased healthcare utilization at 1 year.”   AF is the most commonly sustained arrhythmia.
For those over the age of 55, there is about a 37 percent lifetime risk of developing AF, he said. “AF is associated with a fivefold increased risk for stroke and a twofold increased risk for mortality. Fortunately, once recognized, therapeutic anticoagulation can decrease the risk for stroke by about 65 percent and mortality by 30 percent.”Further follow-up through 3 years is planned to better understand the clinical impact of ECG patch monitoring in patients at moderate risk of developing AF, he concluded.

Catheter Ablation found better than Pharmacological Therapies in atrial fibrillation


Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation.


Catheter ablation of atrial fibrillation is typically performed with uninterrupted anticoagulation with warfarin or interrupted non–vitamin K antagonist oral anticoagulant therapy. Uninterrupted anticoagulation with a non–vitamin K antagonist oral anticoagulant, such as dabigatran, may be safer; however, controlled data are lacking. We investigated the safety of uninterrupted dabigatran versus warfarin in patients undergoing ablation of atrial fibrillation.


In this randomized, open-label, multicenter, controlled trial with blinded adjudicated end-point assessments, we randomly assigned patients scheduled for catheter ablation of paroxysmal or persistent atrial fibrillation to receive either dabigatran (150 mg twice daily) or warfarin (target international normalized ratio, 2.0 to 3.0). Ablation was performed after 4 to 8 weeks of uninterrupted anticoagulation, which was continued during and for 8 weeks after ablation. The primary end point was the incidence of major bleeding events during and up to 8 weeks after ablation; secondary end points included thromboembolic and other bleeding events.

The trial enrolled 704 patients across 104 sites; 635 patients underwent ablation. Baseline characteristics were balanced between treatment groups. The incidence of major bleeding events during and up to 8 weeks after ablation was lower with dabigatran than with warfarin (5 patients [1.6%] vs. 22 patients [6.9%]; absolute risk difference, −5.3 percentage points; 95% confidence interval, −8.4 to −2.2; P<0.001). Dabigatran was associated with fewer periprocedural pericardial tamponades and groin hematomas than warfarin. The two treatment groups had a similar incidence of minor bleeding events. One thromboembolic event occurred in the warfarin group.

In patients undergoing ablation for atrial fibrillation, anticoagulation with uninterrupted dabigatran was associated with fewer bleeding complications than uninterrupted warfarin.


AF Patients Show Frontal Lobe Loss, Not White-Matter Changes

In a study of Framingham Heart Study offspring cohort participants who were in their 60s, MRI scans showed that those with atrial fibrillation (AF) had less frontal brain volume than their peers, independent of other vascular risk factors[1].

The study by Ryan J Piers (Boston University School of Medicine, MA) and colleagues was published online July 11, 2016 in Heart Rhythm.

The frontal lobe of the brain is associated with “visual-spatial executive function skills such as planning, organizing, manipulating, and switching back and forth, [which] impact memory but are not memory per se” and is expected to be affected with vascular brain aging, senior author Dr Rhonda Au (Boston University School of Medicine) told heartwire from Medscape.

The researchers hypothesized that individuals with AF would also have greater white-matter hyperintensity (seen in cognitive impairment) or accelerated decline in brain volume (seen in dementia), but they did not observe this, she noted. However, the study may have been underpowered and too short, she conceded, because only 73 patients had AF and the MRI scans were done about 6.5 years apart.

Nevertheless, these initial findings are “another piece of data that suggest that AF might not only have effects on the heart but may have effects on the brain as well,” according to Au.

In an accompanying editorial[2], Dr T Jared Bunch (Intermountain Medical Center, Murray, UT) and Victoria Jacobs (Stanford University, Palo Alto, CA) write that the association between AF and frontal lobe atrophy in this study was “modest,” possibly because relatively few individuals had AF.

It is important to continue this line of research because AF is a common cause of stroke, and anticoagulants used to prevent stroke can cause repetitive small intracranial bleeds that can lead to significant brain volume loss and cognitive decline, they note. But improved time in therapeutic range with warfarin, use of novel anticoagulants, and ablation may lower the risk of dementia. Thus, “prospective trials are needed . . . to determine whether choices in treatment and approach [in AF] will lower long-term dementia risk,” Bunch and Jacobs urge.

AF and MRI Brain Scans in Framingham Offspring

Although it is well documented that AF is associated with an increased risk of dementia, it is less well-known whether patients with AF have the type of brain structure changes that are seen in cognitive dysfunction, Piers and colleagues write.
To investigate this, they examined data from 2144 survivors of the Framingham Heart Study Offspring Cohort who participated in examination 7 from 1998 to 2001 and were free of documented stroke, dementia, or neurologic disease when they had a brain MRI from 1999 to 2005.

At baseline, compared with the 2071 participants who did not have AF, the 73 participants with AF were older (70 vs 62 years) and more likely to be male (66% vs 46%), be on antihypertensive therapy (59% vs 29%), and have diabetes (31% vs 9%), prevalent MI (25% vs 3%), or prevalent heart failure (16% vs <1%). They were also less likely to have the APOE4 allele (16% vs 23%), which is linked with brain atrophy, or be a current smoker (6% vs 13%).

In age- and sex-adjusted models, compared with individuals who did not have AF, those with AF had significantly lower total cerebral, frontal lobe, and temporal lobe volumes, but they had similar temporal horn, hippocampal, and white-matter hyperintensity volumes.

After adjustment for vascular risk factors and the presence of the APOE4 allele, AF remained associated with decreased frontal lobe volume (mean decrease of 0.82% of total cranial volume compared with participants without AF; P=0.03), but not with any other brain volume changes.

In the subset of 1533 participants who had a second MRI scan, including 40 participants with AF, having AF was not associated with significantly accelerated changes in the volume of different brain regions or volume of white-matter hyperintensities, after adjustment for multiple variables.

The researchers are continuing to study this cohort, who now have a mean age of 75. “We are about to start examining them again, which will give us a longer follow-up period” and likely more participants will have AF, Au said.

ABC Risk Score Better Predicts Bleeding in Atrial Fibrillation

A biomarker-based model used to assess bleeding risk in atrial fibrillation (AF) patients on anticoagulation outperforms standard bleeding risk scores based on clinical risk factors alone, new research shows[1].

“The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischemic stroke and increase in major bleeding events, and right now, the risk of bleeding in patients on oral anticoagulation is mostly assessed by the HAS-BLED score, which is based on clinical risk factors,” Dr Ziad Hijazi (Uppsala University, Sweden) told heartwire from Medscape in an email.

“However, several biomarkers have now been shown to provide incremental information about the risk of bleeding in patients with atrial fibrillation, so to improve risk assessment, it’s important to include these biomarkers among the candidate variables,” he added.

“And our ABC (age, biomarkers, clinical history) bleeding score showed better discrimination and utility than the HAS-BLED and ORBIT scores concerning major bleeding and intracranial hemorrhages, so it should be useful in decision support regarding oral anticoagulation treatment in patients with atrial fibrillation.”

The study was published in the June 4, 2016 issue of the Lancet.

Strongest Biomarkers

Hijazi and colleagues selected what they felt were the strongest biomarkers available to assess bleeding risk in AF for their new model. These included growth-differentiating factor-15 (GDF-15), a marker of oxidative stress; cardiac troponin measured with high-sensitivity assays (cTnT-hs), a marker of myocardial injury; cystatin C or estimated glomerular filtration rate (eGFR) for renal function, and hemoglobin or hematocrit, both markers of anemia.

They also included clinical risk factors along with N-terminal pro-B-type natriuretic peptide (NT-proBNP), a stroke risk biomarker.

First, the novel risk score was validated in a large cohort of patients involved in the Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial that randomized patients to apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) or warfarin. Biomarker data were available for 14,537 ARISTOLE participants. Major bleeding occurred in 662.
Using the new ABC bleeding risk score, Hijazi and colleagues found that the strongest predictors of major bleeding among ARISTOLE participants were GDF-15, hemoglobin, cTnT-hs, age, and history of a prior bleed.

These five variables were subsequently included in their revised ABC bleeding risk-prediction model and its ability to predict major bleeding was compared with that of the HAS-BLED score and newer ORBIT score.

The ABC bleeding risk score showed a c-index of 0.68, Hijazi reported. A c-index of 1.0 implies perfect discrimination between events and nonevents while a c-index of 0.5 is poor and corresponds to flipping a coin.

The HAS-BLED achieved a c-index of 0.61 and the ORBIT a c-index of 0.65. The difference between the ABC bleeding risk score was significant for both the HAS-BLED (P<0.001) and ORBIT (P=0.0008) scores.

“The ABC bleeding score performed equally well in patients treated with warfarin or apixaban, without any significant interaction with the effects of the randomized treatment,” investigators observed.

External Validation

Hijazi and colleagues then went on to externally validate their findings based on biomarker data in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), in which AF patients were randomized to dabigatran (Pradaxa, Boehringer Ingelheim) or warfarin. Biomarker samples were available for 8468 patients, and 463 major bleeding events were observed.

Again, the novel ABC bleeding risk score achieved a higher c-index than the two comparator scores at 0.71 vs 0.62 for the HAS-BLED and 0.68 for the ORBIT ( P<0.0001 and P=0.0016, respectively).

“The ABC bleeding score also outperformed the HAS-BLED and ORBIT scores concerning the predictive value of intracranial hemorrhages,” Hijazi noted (c-index 0.66 vs 0.58 and 0.60, respectively).

“Importantly, the results from the external validation confirmed that the ABC bleeding risk score provided a better risk prediction than the other risk scores in the comparison,” he added.

The novel biomarker-based bleeding risk score also discriminated bleeding risk well in different AF subgroups and was able to accurately identify bleeding risk even among patients with low HAS-BLED and ORBIT scores.

Asked whether the ABC bleeding risk score is ready for “prime-time,” senior author Dr Lars Wallentin (Uppsala University) noted that troponin is already widely available in large parts of the world and Roche expects to launch GDF-15 as a novel biomarker in June 2016.

“Most clinicians are used to nomograms, electronic calculators, or digital apps in everyday practice—for example, to calculate creatinine clearance, GRACE scores, and so forth,” Wallentin added. “So availability will probably not be a problem, especially considering the advantage of the ABC bleeding score, which improves risk prediction [of major bleeding in AF patients].”

Several Merits

Commenting to heartwire on the study, Dr Paulus Kirchhof (University of Birmingham, UK) said clinical scoring systems have been used to identify patients at high risk of bleeding, but they often overlap with scoring systems for ischemic strokes. Almost all patients at high risk of bleeding on anticoagulation are also at high risk of stroke without anticoagulation. In most patients, this does not matter as the risk of stroke without anticoagulation is much higher than the risk of bleeding with anticoagulation.

“However, in a few patients at extreme bleeding risk and at relatively low risk for stroke, there may be a need to seek treatment options that reduce the risk of bleeding on anticoagulation such as an approved, reduced dose of a novel oral anticoagulant or even left atrial appendage occlusion or removal,” he noted in an email. “In such conditions, it seems very reasonable to measure blood biomarkers such as GDF-15 or creatinine clearance, high-sensitive troponin, or brain natriuretic peptide,” but only when difficult decisions regarding oral anticoagulation are made by a multidisciplinary team involving neurologists and cardiologists.

Cryoballoon Ablation is Noninferior to Radiofrequency Ablation

Cryoballoon ablation was found to be noninferior to radiofrequency ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation, and there is no significant difference between the two procedures in regard to patient safety, according to late-breaking clinical trial research presented as part of ACC.16 in Chicago and simultaneously published in The New England Journal of Medicine.

The FIRE AND ICE trial, conducted by Karl-Heinz Kuck, MD, FACC, et al, is the largest randomized trial of its kind, and included participants from 16 centers in eight European countries. “The FIRE AND ICE trial demonstrated that the cryoballoon, a newer, easier-to-use ablation catheter, worked as well as the established technology, which ultimately means that more patients can be treated for atrial fibrillation without having [to go to a] specialized cardiac center,” said Kuck. “In addition, there was, in general, a low risk of procedural complications in both groups, demonstrating that catheter ablation has become much safer over the years.”

The authors wanted to compare the effectiveness of point-by-point mode applied radiofrequency ablation to that of cryoballoon ablation applied in a single step mode, a newer and less complex technique. The primary efficacy endpoint of the trial was time to first documented recurrence of AF/atrial tachycardia/atrial flutter, prescription of antiarrhythmic drugs or repeat ablation.

The multicenter, randomized, noninferior open-label trial analyzed data gathered from patients ranging from 18 to 75 years old, with symptomatic paroxysmal AF and prior antiarrhythmic drug failure. After exclusions for previous left atrial (LA) ablation, percutaneous coronary intervention or myocardial infarction within three months of enrollment, and other clinical issues, 693 patients undergoing pulmonary vein isolation were randomly assigned in a 1:1 ratio; 352 underwent radiofrequency ablation and 341 underwent cryoballoon ablation.

In-office visits were scheduled at three, six, and 12 months and every six months after. The primary efficacy endpoint occurred in 138 patients in the cryoballoon group and in 143 patients in the radiofrequency group. A pre-specified superiority test performed for the primary efficacy endpoint did not indicate a significant difference between the treatment groups. The most common treatment-related serious adverse events were groin site complication and atrial flutter or atrial tachycardia.

The authors did see significant procedural differences between the two groups. Radiofrequency ablation required less fluoroscopy time (17 vs. 22 minutes). Procedure time was shorter in the cryoballoon group, (124 minutes vs. 141 minutes). LA dwell time in the cryoballoon group was shorter as well (92 vs. 109 minutes). A favorable safety profile was observed in both groups.

“The procedure time was interesting because there are more cost pressures on the health care system for more efficient tools that keep procedures short and predictable,” Kuck said.

According to Kuck, the findings could help inform future medical guidelines on the use of different catheter ablation techniques for treating atrial fibrillation. One limitation of the study is that it did not investigate ablation for treating patients with more advanced stages of atrial fibrillation. A separate trial would be needed to assess the ablation techniques’effectiveness and safety for that patient population, he said.

– See more at: http://www.acc.org/latest-in-cardiology/articles/2016/03/23/18/25/mon-8am-fire-and-ice-effective-afib-ablation-acc-2016?wt.mc_id=twitter#sthash.M0E66Z4X.dpuf

Rate-Control Treatment and Mortality in Atrial Fibrillation



This abstract is available on the publisher’s site.

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More Digoxin Cautions: Use in AF, Heart Failure Raises Mortality in Meta-analysis

Digoxin use was linked with a 29% increased risk of mortality in more than 235,000 patients with atrial fibrillation (AF) and with a 14% increased risk of death in more than 91,000 patients with congestive heart failure (CHF) during an average follow-up of 2.5 years, researchers report[1].

These findings by Dr Mate Vamos (JW Goethe University, Frankfurt, Germany) and colleagues, based on data from 19 contemporary studies of digoxin, were published online May 4, 2015 in the European Heart Journal.

Even though digoxin has been used for 200 years, only one study, the Digitalis Investigation Group (DIG) study in AF, which dates from the 1990s, was a randomized controlled trial. Therefore, according to the authors, until proper contemporary randomized trials with dose-adjusted digoxin are conducted, the drug “should be used with great caution (including monitoring plasma levels), particularly when administered for rate control in AF,” the authors urge.

Indeed, a key take-away message for clinicians is “better think twice before prescribing digoxin,” senior author Dr Stefan H Hohnloser (JW Goethe University) told heartwire from Medscape. There are good alternatives such as beta-blockers for rate control in AF, and therapy for congestive HF has “dramatically changed . . . compared with the time when the DIG trial was conducted,” he added.

“Until proper randomized controlled trials are completed, digoxin should be used with great caution (including monitoring plasma levels), particularly when administered for rate control in AF,” Vamos and colleagues stress. However, “patients should not stop their digoxin on their own but rather should consult with their cardiologists,” Hohnloser cautioned.

How Safe Is Digoxin?

Digoxin slows conduction in the AV node during rest, which is why it is used in AF for rate control, and it is a positive inotropic drug, which is why it is used in CHF, Hohnloser explained. However, it can cause arrhythmias (both brady- and tachyrhythmias), it interacts with other medications, it has a narrow therapeutic window, and it may cause direct toxicity if overdosed, he added
Current European Society of Cardiology and US guidelines recommend considering digoxin in certain patients with HF or AF, but “in essence, these recommendations reflect the highly unsatisfactory data basis on which to judge the supposed benefits of digoxin,” Vamos and colleagues write.

Recent studies suggested that digoxin may increase the risk of death.

To investigate this, Vamos and colleagues identified studies of digoxin published since 1993, comprising 326,426 patients: nine studies in patients with AF, seven in patients with CHF, and three in patients with both conditions.

In follow-up ranging from 0.83 to 4.7 years, digoxin use was associated with an increased risk of all-cause mortality.

Risk for All-Cause Mortality, Patients Receiving vs Not Receiving Digoxin*

Reason for digoxin HR (95% CI) P
AF 1.29 (1.21–1.39) <0.01
HF 1.14 (1.06–1.22) <0.01
AF or HF 1.21 (1.07–1.38) <0.01
AF=atrial fibrillation
HF=heart failure
*After controlling for multiple confounders
“Looking at recent [novel oral anticoagulant] NOAC trials, for example, digoxin is used in approximately 20% to 30% of AF patients, [and it probably] is used less commonly in CHF patients in sinus rhythm,” Hohnloser said.

When digoxin is used, to maximize patient safety, it is important to monitor patient’s serum digoxin levels and be aware of harmful drug-drug interactions of digoxin with antiarrhythmic drugs such as amiodarone or dronedarone, according to Hohnloser. He prescribes digoxin “only very occasionally if I feel that I have no other option.”

Oral Anticoagulant Prescription in Patients With Atrial Fibrillation and a Low Risk of Thromboembolism

In patients with atrial fibrillation (AF) who are at risk for thromboembolism, anticoagulation therapy with warfarin or the newer novel anticoagulants reduces morbidity and mortality.1,2 Because oral anticoagulant use carries a risk of bleeding, the drugs are not recommended in patients with AF who are at a particularly low risk for stroke. Specifically, previous AF guidelines recommend against the use of oral anticoagulation in patients younger than 60 years without heart disease or other known risk factors for thromboembolism,3and more recently updated guidelines do not recommend the use of oral anticoagulation in patients with AF without any established risk factor for stroke.4 We sought to examine the prevalence of oral anticoagulant prescription that does not adhere to the guidelines in young and healthy patients with AF who were at the lowest risk for thromboembolism, as well as the clinical predictors of this practice.

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