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Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial

Author/s: 
Packer, Douglas L., Mark, Daniel B., Robb, RIchard A., Monahan, Kristi H., Bahnson, Tristram D., Poole, Jessica E., Noseworthy, Peter A., Rosenberg, Yves D., Jeffries, Neal, Mitchell, L. Brent, Flaker, Greg C., Pokushalov, Evgeny, Romanov, ALexander, Bunch, T. Jared, Noelker, Georg, Ardashev, Andrey, Revishvili, Amiran, Wilber, David J., Cappato, Riccardo, Kuck, Karl-Heinz, Hindricks, Gerhard, Davies, D. Wyn, Kowey, Peter R., Naccarelli, Gerald V., Reiffel, James A., Piccini, Jonathan P., Silverstein, Adam P., Al-Khalidi, Hussein R., Lee, Kerry L.

IMPORTANCE:

Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain.

OBJECTIVE:

To determine whether catheter ablation is more effective than conventional medical therapy for improving outcomes in AF.

DESIGN, SETTING, AND PARTICIPANTS:

The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial is an investigator-initiated, open-label, multicenter, randomized trial involving 126 centers in 10 countries. A total of 2204 symptomatic patients with AF aged 65 years and older or younger than 65 years with 1 or more risk factors for stroke were enrolled from November 2009 to April 2016, with follow-up through December 31, 2017.

INTERVENTIONS:

The catheter ablation group (n = 1108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines.

MAIN OUTCOMES AND MEASURES:

The primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Among 13 prespecified secondary end points, 3 are included in this report: all-cause mortality; total mortality or cardiovascular hospitalization; and AF recurrence.

RESULTS:

Of the 2204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio [HR], 0.86 [95% CI, 0.65-1.15]; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 [95% CI, 0.60-1.21]; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 [95% CI, 0.74-0.93]; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 [95% CI, 0.45-0.60]; P < .001).

CONCLUSIONS AND RELEVANCE:

Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial.

Keywords 
symptomatic atrial fib atrial fib cather ablation

Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial

Author/s: 
Mark, Daniel B., Anstrom, Kevin J., Sheng, Shubin, Piccini, Jonathan P., Baloch, Khaula N., Monahan, Kristi H., Daniels, Melanie R., Bahnson, Tristram D., Poole, Jeanne E., Rosenberg, Yves, Lee, Kerry L., Packer, Douglas L.

IMPORTANCE:

Catheter ablation is more effective than drug therapy in restoring sinus rhythm in patients with atrial fibrillation (AF), but its incremental effect on long-term quality of life (QOL) is uncertain.

OBJECTIVE:

To determine whether catheter ablation is more beneficial than conventional drug therapy for improving QOL in patients with AF.

DESIGN, SETTING, AND PARTICIPANTS:

An open-label randomized clinical trial of catheter ablation vs drug therapy in 2204 symptomatic patients with AF older than 65 years or 65 years or younger with at least 1 risk factor for stroke. Patients were enrolled from November 2009 to April 2016 from 126 centers in 10 countries. Follow-up ended in December 2017.

INTERVENTIONS:

Pulmonary vein isolation, with additional ablation procedures at the discretion of the investigators, for the catheter ablation group (n = 1108) and standard rhythm and/or rate-control drugs selected and managed by investigators for the drug therapy group (n = 1096).

MAIN OUTCOMES AND MEASURES:

Prespecified co-primary QOL end points at 12 months, including the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary score (range, 0-100; 0 indicates complete disability and 100 indicates no disability; patient-level clinically important difference, ≥5 points) and the Mayo AF-Specific Symptom Inventory (MAFSI) frequency score (range, 0-40; 0 indicates no symptoms and 40 indicates the most severe symptoms; patient-level clinically important difference, ≤-1.6 points) and severity score (range, 0-30; 0 indicates no symptoms and 30 indicates the most severe symptoms; patient-level clinically important difference, ≤-1.3 points).

RESULTS:

Among 2204 randomized patients (median age, 68 years; 1385 patients [63%] were men, 946 [43%] had paroxysmal AF, and 1256 [57%] had persistent AF), the median follow-up was 48.5 months, and 1968 (89%) completed the trial. The mean AFEQT summary score was more favorable in the catheter ablation group than the drug therapy group at 12 months (86.4 points vs 80.9 points) (adjusted difference, 5.3 points [95% CI, 3.7-6.9]; P < .001). The mean MAFSI frequency score was more favorable for the catheter ablation group than the drug therapy group at 12 months (6.4 points vs 8.1 points) (adjusted difference, -1.7 points [95% CI, -2.3 to -1.2]; P < .001) and the mean MAFSI severity score was more favorable for the catheter ablation group than the drug therapy group at 12 months (5.0 points vs 6.5 points) (adjusted difference, -1.5 points [95% CI, -2.0 to -1.1]; P < .001).

CONCLUSIONS AND RELEVANCE:

Among patients with symptomatic atrial fibrillation, catheter ablation, compared with medical therapy, led to clinically important and significant improvements in quality of life at 12 months. These findings can help guide decisions regarding management of atrial fibrillation.

Keywords 
atrial fib catheter ablation medical therapy QOL

Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding.

Author/s: 
Ray, Wayne A., Chung, Cecilia P., Murray, Katherine T., Smalley, Walter E., Daugherty, James R., Dupont, William D.

IMPORTANCE:

Anticoagulant choice and proton pump inhibitor (PPI) cotherapy could affect the risk of upper gastrointestinal tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment.

OBJECTIVES:

To compare the incidence of hospitalization for upper gastrointestinal tract bleeding in patients using individual anticoagulants with and without PPI cotherapy, and to determine variation according to underlying gastrointestinal bleeding risk.

DESIGN, SETTING, AND PARTICIPANTS:

Retrospective cohort study in Medicare beneficiaries between January 1, 2011, and September 30, 2015.

EXPOSURES:

Apixaban, dabigatran, rivaroxaban, or warfarin with or without PPI cotherapy.

MAIN OUTCOMES AND MEASURES:

Hospitalizations for upper gastrointestinal tract bleeding: adjusted incidence and risk difference (RD) per 10 000 person-years of anticoagulant treatment, incidence rate ratios (IRRs).

RESULTS:

There were 1 643 123 patients with 1 713 183 new episodes of oral anticoagulant treatment included in the cohort (mean [SD] age, 76.4 [2.4] years, 651 427 person-years of follow-up [56.1%] were for women, and the indication was atrial fibrillation for 870 330 person-years [74.9%]). During 754 389 treatment person-years without PPI cotherapy, the adjusted incidence of hospitalization for upper gastrointestinal tract bleeding (n = 7119) was 115 per 10 000 person-years (95% CI, 112-118). The incidence for rivaroxaban (n = 1278) was 144 per 10 000 person-years (95% CI, 136-152), which was significantly greater than the incidence of hospitalizations for apixaban (n = 279; 73 per 10 000 person-years; IRR, 1.97 [95% CI, 1.73-2.25]; RD, 70.9 [95% CI, 59.1-82.7]), dabigatran (n = 629; 120 per 10 000 person-years; IRR, 1.19 [95% CI, 1.08-1.32]; RD, 23.4 [95% CI, 10.6-36.2]), and warfarin (n = 4933; 113 per 10 000 person-years; IRR, 1.27 [95% CI, 1.19-1.35]; RD, 30.4 [95% CI, 20.3-40.6]). The incidence for apixaban was significantly lower than that for dabigatran (IRR, 0.61 [95% CI, 0.52-0.70]; RD, -47.5 [95% CI,-60.6 to -34.3]) and warfarin (IRR, 0.64 [95% CI, 0.57-0.73]; RD, -40.5 [95% CI, -50.0 to -31.0]). When anticoagulant treatment with PPI cotherapy (264 447 person-years; 76 per 10 000 person-years) was compared with treatment without PPI cotherapy, risk of upper gastrointestinal tract bleeding hospitalizations (n = 2245) was lower overall (IRR, 0.66 [95% CI, 0.62-0.69]) and for apixaban (IRR, 0.66 [95% CI, 0.52-0.85]; RD, -24 [95% CI, -38 to -11]), dabigatran (IRR, 0.49 [95% CI, 0.41-0.59]; RD, -61.1 [95% CI, -74.8 to -47.4]), rivaroxaban (IRR, 0.75 [95% CI, 0.68-0.84]; RD, -35.5 [95% CI, -48.6 to -22.4]), and warfarin (IRR, 0.65 [95% CI, 0.62-0.69]; RD, -39.3 [95% CI, -44.5 to -34.2]).

CONCLUSIONS AND RELEVANCE:

Among patients initiating oral anticoagulant treatment, incidence of hospitalization for upper gastrointestinal tract bleeding was the highest in patients prescribed rivaroxaban, and the lowest for patients prescribed apixaban. For each anticoagulant, the incidence of hospitalization for upper gastrointestinal tract bleeding was lower among patients who were receiving PPI cotherapy. These findings may inform assessment of risks and benefits when choosing anticoagulant agents.

Keywords 
warfarin apixaban dabigatran rivaroxaban proton pump inhibitor upper gastrointestinal tract anticoagulants atrial fibrillation

Pharmacologic Management of Newly Detected Atrial Fibrillation

Author/s: 
Frost, Jennifer L., Campos-Outcalt, Doug, Hoelting, David, LeFevre, Michael, Lin, Kenneth W., Vaughan, William, Bird, Melanie D.

Purpose
To review the evidence and provide clinical recommendations for the pharmacologic management of atrial fibrillation.
 

Methods
This guideline is based on two systematic reviews of published randomized controlled trials (RCTs) and prospective and retrospective observational studies from 2000 to 2012. An updated literature search was performed to identify new studies from 2012 to December 31, 2015. The target audience for the guideline includes all primary care clinicians, and the target patient population includes adults who have nonvalvular atrial fibrillation that is not due to a reversible cause. This guideline was developed using a modified version of GRADE to evaluate the quality of the evidence and make recommendations based on the balance of benefits and harms.

Keywords 
atrial fibrillation pharmacologic management

Catheter Ablation of Atrial Fibrillation: An Overview for Clinicians

Author/s: 
Nebojša, Marinković, Milan, Lenarczyk, Radoslaw, Tilz, Roland, Potpara, Tatjana S.

Abstract

Catheter ablation (CA) of atrial fibrillation (AF) is currently one of the most commonly performed electrophysiology procedures. Ablation of paroxysmal AF is based on the elimination of triggers by pulmonary vein isolation (PVI), while different strategies for additional AF substrate modification on top of PVI have been proposed for ablation of persistent AF. Nowadays, various technologies for AF ablation are available. The radiofrequency point-by-point ablation navigated by electro-anatomical mapping system and cryo-balloon technology are comparable in terms of the efficacy and safety of the PVI procedure. Long-term success of AF ablation including multiple procedures varies from 50 to 80%. Arrhythmia recurrences commonly occur, mostly due to PV reconnection. The recurrences are particularly common in patients with non-paroxysmal AF, dilated left atrium and the "early recurrence" of AF within the first 2–3 post-procedural months. In addition, this complex procedure can be accompanied by serious complications, such as cardiac tamponade, stroke, atrio-esophageal fistula and PV stenosis. Therefore, CA represents a second-line treatment option after a trial of antiarrhythmic drug(s). Good candidates for the procedure are relatively younger patients with symptomatic and frequent episodes of AF, with no significant structural heart disease and no significant left atrial enlargement. Randomized trials demonstrated the superiority of ablation compared to antiarrhythmic drugs in terms of improving the quality of life and symptoms in AF patients. However, nonrandomized studies reported additional clinical benefits from ablation over drug therapy in selected AF patients, such as the reduction of the mortality and stroke rates and the recovery of tachyarrhythmia-induced cardiomyopathy. Future research should enable the creation of more durable ablative lesions and the selection of the optimal lesion set in each patient according to the degree of atrial remodeling. This could provide better long-term CA success and expand indications for the procedure, especially among the patients with non-paroxysmal AF.

Keywords 
atrial fibrillation catheter ablation interventional cardiology pulmonary vein isolation stroke substrate modification

Stroke Prevention in Patients With Atrial Fibrillation: A Systematic Review Update

Author/s: 
Sanders, D. Gillian, Lowenstern, Angela, Borre, Ethan, Chatterjee, Ranee, Goode, Adam, Sharan, Lauren, Allen LaPointe, Nancy M., Raitz, Giselle, Shah, Bimal, Yapa, Roshini, Davis, J. Kelly, Lallinger, Kathryn, Schmidt, Robyn, Kosinski, Andrzej, Al-Khatib, Sana

Purpose of Review

To update a previous review in patients with atrial fibrillation/atrial flutter (AF) to determine the best assessment tools for predicting risk of stroke and bleeding, as well as the best treatment options to prevent stroke. Current treatments include new antithrombotic strategies, devices, and oral anticoagulants (oral direct thrombin inhibitors, factor Xa inhibitors).

Key Messages

  • CHADS2, CHA2DS2-VASc, and ABC risk scores have the best evidence to support prediction of stroke events.
  • HAS-BLED has the best evidence to support prediction of bleeding risk.
  • Imaging tools for stroke prediction require further evidence.
  • Dabigatran (150 mg dose) is superior to warfarin in preventing stroke or systemic embolism, with no evidence for a difference in major bleeding. There may also be no evidence for a difference in myocardial infarction or all-cause mortality.
  • Apixaban is superior to warfarin in preventing stroke or systemic embolism. Apixaban also has less risk for major bleeding and may also decrease all-cause mortality compared to warfarin.
  • Rivaroxaban may be similar to warfarin in preventing stroke or systemic embolism and in risk of major bleeding. Rivaroxaban is most likely similar to warfarin in the rate of all-cause mortality. However, inconsistent with the randomized controlled trial (RCT) findings, observational studies showed rivaroxaban may better prevent stroke or systemic embolism and may have a higher risk of major bleeding.
  • Edoxaban is most likely similar to warfarin in preventing stroke or systemic embolism and also most likely has less risk for major bleeding and hemorrhagic stroke than warfarin.
  • Further RCTs directly comparing oral anticoagulants, including thrombin inhibitors and individual Xa inhibitors, are needed.

Structured Abstract

Objectives. This review updates previous reviews regarding the optimal risk stratification tools for stroke and bleeding prediction, and treatment options for stroke prevention in patients with atrial fibrillation.

Data sources. We searched PubMed®, Embase®, and the Cochrane Database of Systematic Reviews for relevant English-language comparative studies published from January 1, 2000, to February 14, 2018.

Review methods. Two investigators screened each abstract and full-text article for inclusion, abstracted data, rated quality and applicability, and graded evidence. When possible, random-effects models were used to compute summary estimates of effects.

Results. Our review included 320 articles (185 unique studies). This included 61 studies relevant to predicting thromboembolic risk, 38 relevant to predicting bleeding risk, and 117 relevant to interventions for preventing thromboembolic (TE) events. Data suggest that the CHADS2, CHA2DS2-VASc, and ABC risk scores have the best evidence predicting TE risk (moderate strength of evidence [SOE] for limited prediction ability of each score) and that the HAS-BLED score has the best evidence to predict bleeding risk (moderate SOE).

We found that a thrombin inhibitor (dabigatran 150 mg) was superior to warfarin in preventing stroke (including hemorrhagic) or systemic embolism (relative risk [RR] 0.66; 95% confidence interval [CI] 0.53 to 0.82), with no statistically significant difference in the occurrence of major bleeding (RR 0.93; 95% CI 0.81 to 1.07) (high SOE for both outcomes). The Xa inhibitor apixaban was superior to warfarin in preventing stroke or systemic embolism (hazard ratio [HR] 0.79; 95% CI 0.66 to 0.95; high SOE), major bleeding (HR 0.69; 95% CI 0.60 to 0.80; high SOE), and all-cause mortality (HR 0.89; 95% CI 0.80 to 0.998; low SOE). Apixaban was also superior to aspirin in preventing stroke or systemic embolism (HR 0.45; 95% CI 0.32 to 0.62), with similar risk for major bleeding (HR 1.13; 95% CI 0.74 to 1.75) in patients who are not suitable for warfarin (moderate SOE for both outcomes). The Xa inhibitor edoxaban reduced hemorrhagic stroke and major bleeding compared to warfarin (moderate SOE for both outcomes) but had no evidence of a difference in stroke or systemic embolism (moderate SOE) or myocardial infarction (moderate SOE). The Xa inhibitor rivaroxaban was similar to warfarin in preventing stroke or systemic embolism (HR 0.88, 95% CI 0.74 to 1.03; moderate SOE), with similar rates of major bleeding (low SOE) and death (moderate SOE). Low SOE for major bleeding was due to a trend toward an increase in risk of major bleeding with rivaroxaban seen in observational studies. Comparative effectiveness findings for stroke prevention were limited by the direct comparisons between individual direct oral anticoagulants. Evidence regarding nonpharmacologic interventions was sparse, but left atrial appendage (LAA) closure devices showed a trend toward benefit over warfarin for strokes, major bleeding, and all-cause mortality that did not reach statistical significance. Higher adverse events (excessive bleeding or procedure-related complications) were observed with LAA (low SOE).

Conclusions. Overall, we found that CHADS2, CHA2DS2-VASc, and ABC scores have similar evidence regarding their ability to predict stroke risk in patients with atrial fibrillation, whereas HAS-BLED has the best evidence to predict bleeding risk. Direct oral anticoagulants (specifically apixaban and dabigatran) demonstrate reductions in stroke events and reductions (apixaban) or similar (dabigatran) rates in bleeding events when compared with warfarin, while rivaroxaban was similar in both benefits and harms to warfarin. Edoxaban reduced hemorrhagic stroke and major bleeding compared to warfarin but had no evidence of a difference in other outcomes. More studies are needed directly comparing oral anticoagulants, including thrombin inhibitors and individual Xa inhibitors.

Keywords 
stroke atrial fibrillation atrial flutter
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