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BRIDGE Trial (2015): Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation

BRIDGE Trial visual abstract

BRIDGE Trial Summary: Douketis JD et al. randomized 1,884 patients on warfarin (INR 2-3 for ≥3m) with AF or A-flutter and CHADS2 Score ≥1 to LMWH: dalteparin (100 IU/kg BID) or placebo. The objective was to assess if bridging anticoagulation reduce rates of arterial thromboembolism compared to no bridging in patients with atrial fibrillation undergoing an invasive procedure. The results showed noninferiority (P=0.01) of the primary outcome (TIA or stroke or arterial embolism) in patients with no bridging as compared with bridging. The authors of the BRIDGE trial concluded that among patients with low- and intermediate-risk atrial fibrillation receiving anticoagulation and undergoing an invasive procedure, periprocedural bridging anticoagulation with LMWH did not reduce the incidence of arterial thromboembolism when compared to no bridging, but did increase the risk of major bleeding.

Source: NEJM

ROCKET-AF: Rivaroxaban vs. warfarin in atrial fibrillation

2011, Rivaroxaban vs. warfarin in atrial fibrillation, NEJM

PROTECT AF Trial: Closure of the LAA versus warfarin therapy in patients with Atrial Fibrillation

PROTECT AF Trial Visual abstract and quick summary poster

We currently lack significant data or clear cut guidelines for closing left atrial appendage in patients with LAA for prevention of stroke. The current ACC/AHA/HRS guidelines recommends anticoagulation in patients with atrial fibrillation and CHA2DS2-VASc >2 (Grade Ia) irrespective of presence or absence of LAA.

The PROTECT AF trial was a randomized non-inferior trial that studied the usefulness of WATCHMAN device in closing LAA and prevention of stroke. The trial did show non-inferiority of the device closure vs warfarin anticoagulation but it was associated with higher side effects which were mostly periprocedural.

Based on this trial, the 2012 Focus European Society of Cardiology Guidelines called for “LAA closure/occlusion/excision” using percutaneous device in patients who are at high stroke risk and have contraindications for long-term oral anticoagulation (Class IIb; Level of Evidence B). The current AHA/ACC/HRS, however, does not include recommendations of LAA closure devices due to lack of enough robust evidence. However, both ESC and AHA/ACC guidelines suggest that surgical excision of the LAA may be considered in patients undergoing cardiac surgery or thoracoscopic atrial fibrillation surgery (Grade IIB)

Sources: Lancet, 2015 ACC/HRS/SCAI LAA Occlusion Device Societal Overview

Risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation

orbit AF substudy visual abstract on use of aspirin versus OAC in patients with atrial fibrillation

Summarized by: Usama bin Nasir, MD

Contribution To Literature:

Atrial fibrillation (AF) was noted to be a risk marker for stroke in the Framingham cohort in 1978. Since then anticoagulation is an important part of managing AF. Use of aspirin in patients with AF is a common practice based on this notion that it might add to prevention of MI or stroke in such patients. The ORBIT-AF study tackled this question by determining the risk factors associated with concomitant use of aspirin and oral anticoagulation (OAC) in patients with AF.

Study Design

The present study was a retrospective review of ORBIT-AF prospective registry that enrolled 7.347 patients with AF on OAC. The ORBIT-AF registry enrolled patients from 174 US sites. Follow up period of this review was of 6 months and the primary outcomes that were studied were: bleeding, hospitalization, CV events, and mortality.

Inclusion Criteria

  • Age ≥ 18 years
  • Atrial fibrillation on EKG

Exclusion Criteria

  • Anticipated life expectancy <6 months
  • Atrial flutter only
  • Patients not taking oral anticoagulant
  • Patients taking antiplatelet therapies other than ASA
  • Transient AF secondary to a reversible condition
  • Current enrollment in a randomized clinical trial of antithrombotic therapy for AF

AF Characterisitcs:

Among 7347 patients, 4804 were on OAC alone and 2543 patients were on both OAC plus aspirin.

Overall (n=7347) OAC Alone (n=4804) OAC+ASA (n=2543)
AF type, %
 New onset 4.0 3.8 4.6
 Paroxysmal 46 45 47
 Persistent 18 18 18
 Long-standing persistent 32 33 30

Primary Outcomes

  • After adjustment for baseline characteristics the primary outcomes for OAC vs OAC + ASA were as follows:
    Risk of major bleeding: HR 1.53 (1.20–1.96), p = 0.0006
    (note, the risk for bleed is almost 1.5 times for OAC + ASA compared to OAC alone)
    All-Cause Hospitalization: HR 1.08 (1.00–1.17), p = 0.06
    Mortality: HR 1.26 (0.98–1.63), p = 0.08

Interpretation:

The present study indicates worse outcomes in terms of major bleeding and also indicates towards higher mortality and hospitalizations but the latter results are not significant.  Based on the real-world National Cardiovascular Data Registry (NCDR) Practice Innovation and Clinical Excellence (PINNACLE) registry more than one-third of 210,380 patients who had CHA2DS2-VASc scores ≥2 were treated with aspirin alone, and not with oral anticoagulants as per ACC/AHA/HRS guidelines. (2) Using OAC is important for prevention of stroke in patients with AF and this has been presented in a number of studies. However, the use of aspirin in addition to OAC in AF has always been questioned. The current study tackled this very question. The results suggest that we should avoid combination therapy in patients who do not have history of CAD. While in patients with history of CAD, using combination therapy outweighs the risks. Note The 2011 ACC/AHA/HRS guidelines recommend using ASA + OAC in patients with history of MI. However, 2014 guidelines have not commented on combination therapy.

References

  1. Wolf PA, et al. “Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The Framingham study.” Neurology.1978;28(10):973-977.
  2. Hsu J.C., Maddox T.M., Kennedy K., et al. (2016) Aspirin instead of oral anticoagulant prescription in atrial fibrillation patients at risk for stroke. J Am Coll Cardiol 67:2913–2923.

Source

PREPIC 2 Trial: Effect of a Retrievable IVC Filter Plus Anticoagulation vs Anticoagulation Alone on Risk of Recurrent Pulmonary Embolism

Source: JAMA

Hokusai VTE Cancer Trial: Edoxaban for Cancer-Associated VTE

edoxaban, hokusai VTE cancer trial visual abstract

Let’s talk methodology…

In this randomized, open-label, non-inferiority trial, the authors analyze a primary composite outcome that includes recurrent VTE and major bleeding in cancer patients taking edoxaban, a factor X inhibitor developed by the study sponsor, Daiichi-Sankyo. They conclude that when compared with LMWH, edoxaban is non-inferior for the aforementioned composite outcome. Because composites occur more often than its components, using composites increase the study efficiency by decreasing the study time and sample size with subsequent costs reduction.

Non-inferiority trials are a useful tool when it is unethical to compare a new drug with placebo because a standard of care is available or because the trial involves serious outcomes such as mortality or in this case recurrence of VTE. Non-inferiority trials are usually confused with equivalence trials but these are different. Equivalence is applied mainly for comparison of generic versus marketed drug preparations to assess for pharmacokinetic differences. Otherwise, equivalence is impossible to be achieved between 2 drugs with different mechanisms of action such as edoxaban and LMWH. A non-inferiority approach may be used when the new treatment – edoxaban – seems to offer advantages such as better compliance, cost or availability over the standard of care – LMWH. Importantly, several considerations need to be accounted for when non-inferiority is part of the study design:

  1. As equivalence cannot be determined, a margin of non-inferiority should be established a-priori. This is defined as an acceptable margin of non-inferiority based on clinical judgment and statistical reasoning and it could be guided by previous trials that compared the control drug (LMWH) with placebo. In this case, the margin was a hazard ratio of 1.5 based on the unmet need for an alternative to parenteral LMWH and the advantages of oral therapy, allowing non-inferiority if the edoxaban population presented the composite outcome at 1.5 times the rate per unit time as the LMWH population or 50% the hazard.
  2. Importantly, the hazard ratio must be interpreted conjointly with time-to-event analysis or Kaplan-Meier curves. In this study, the curves cross for the composite primary outcome indicating non-inferiority, however, when interpretation is performed for each component, edoxaban appears to have less recurrent VTE but more major bleeding events when compared to LMWH. Once these 2 opposing components are combined into a composite, there is a sense of compensation.
  3. Intention-to-treat (ITT) analysis is indicated in superiority trials to preserve randomization – similar characteristics in both groups – avoiding attrition bias, however, including dropouts in non-inferiority trials can lead to bias towards equivalence. For this reason, in non-inferiority trials, it is recommended to perform both ITT and per-protocol analysis and both should demonstrate non-inferiority for it to be concluded. It this study a modified ITT analysis was performed including all patients who underwent randomization and received at least one dose of the assigned drug. These results were confirmed by sensitivity analysis of the primary outcome with a per-protocol approach.

In conclusion, non-inferiority trials should be cautiously executed and interpreted. Further studies with diverse factor X inhibitors are needed to validate these results and physicians must discuss risks and benefits of oral versus subcutaneous anticoagulation in cancer patients for whom quality of life might be the decisive variable.

Daniela Guerrero Vinsard MD.
Internal Medicine Resident at the University of Connecticut Health Center.

Source: NEJM

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