Apixaban in Patients With Atrial Fibrillation After Transfemoral Aortic Valve Replacement

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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 9, 2017

Letters to the Editor

MAY 8, 2017:963–70

resuscitated patients with out-of-hospital cardiac

potential for cardiovascular harm warrants pause to

arrest remains a challenge. Despite encouraging

the

and relatively consistent reports from several case

apixaban-based

series and propensity-matched registry data (partic-

Further evidence supporting this concern is found

ularly for patients whose initial electrocardiogram is

in the 12-month analysis of Seeger et al. (1). Early

consistent

with

ST-segment

elevation

clinical

adoption

of

dual

off-label

reduced-dose

antithrombotic

regimens.

myocardial

safety outcomes at 30-day evaluation significantly

infarction), data from large, randomized clinical trials

favored apixaban, primarily driven by acute kidney

do not yet exist.

injury

and

life-threatening

bleeding;

however,

trends were numerically reversed in the 12-month *Joseph P. Ornato, MD

analysis suggesting worse cardiovascular outcomes

*Virginia Commonwealth University Health System

with apixaban treatment.

1250 East Marshall Street, Main Hospital 2nd Floor, Suite 500

This contrast also lends itself to question whether

Richmond, Virginia 23298

parenteral bridging anticoagulation was used in the

E-mail: [email protected]

vitamin K antagonist arm of the trial. It is reasonable

http://dx.doi.org/10.1016/j.jcin.2017.02.006

that with a mean CHA 2DS2-VASc score of 4.9, many

Please note: The author has reported that he has no relationships relevant to the contents of this paper to disclose.

patients in the vitamin K antagonist cohort would have been potential candidates for parenteral anticoagulation surrounding transcatheter aortic valve

Apixaban in Patients With Atrial Fibrillation After Transfemoral Aortic Valve Replacement

replacement procedure and until adequately anticoagulated with phenprocoumon (1,4). Information on the use of bridge therapy would be valuable in proper interpretation of 30-day event rates. Lastly, it seems that current evaluations of combination antithrombotic therapy have been designed to focus on the avoidance of bleeding instead of the

Given the optimal antithrombotic therapy regimen in

prevention of thromboembolic events, despite the

patients

valve

latter being the very reason these therapies are pre-

replacement with concomitant atrial fibrillation re-

scribed. For example, Gibson et al. (5) used an unex-

mains largely undefined, the Seeger et al. (1) 30-day

plained reduced-dose rivaroxaban strategy (15 mg

and 12-month safety and efficacy outcomes with the

once daily) in one arm of the PIONEER AF-PCI (Open-

direct oral anticoagulant apixaban compared with

Label, Randomized, Controlled, Multicenter Study

vitamin K antagonist, phenprocoumon, are an impor-

Exploring Two Treatment Strategies of Rivaroxaban

tant and welcome contribution. Seeger et al. (1) clearly

and a Dose-Adjusted Oral Vitamin K Antagonist

demonstrate the negative outcomes associated with

Treatment Strategy in Subjects with Atrial Fibrillation

atrial fibrillation compared with sinus rhythm, yet the

who Undergo Percutaneous Coronary Intervention)

methodology

anti-

trial. Although this strategy was found to be safe, it

coagulation analysis raises more questions. Because of

provides little confidence on whether it is effective in

the advanced age of the cohort, patients were empiri-

the prevention of thromboembolism because the trial

cally dose-reduced to apixaban 2.5 mg twice daily (1).

was not powered to evaluate efficacy outcomes. It is

Based on criteria for dosage adjustment per the U.S.

critical that future trials evaluating antithrombotic

undergoing

and

transcatheter

interpretation

aortic

of

the

Food and Drug Administration labeling, we estimate

regimens in patients with atrial fibrillation undergo-

that most of the apixaban cohort (>80%) received a

ing transcatheter aortic valve replacement (or percu-

dosage of apixaban less than what they would have

taneous

been prescribed as proven beneficial for stroke and

powered for these efficacy outcomes, particularly if

coronary

intervention)

are

adequately

systemic embolism prevention in atrial fibrillation

using dosing regimens differing from the U.S. Food

(1,2). Forgoing full evidence-based anticoagulation is

and Drug Administration labeling and/or those proven

concerning because the OBRBIT-AF II (Outcomes

beneficial in the pivotal clinical trials (2). If singularly

Registry for Better Informed Treatment of Atrial

unable to power such trials, we hope a multi-

Fibrillation phase II) registry recently suggested an

organization collaborative effort will be considered.

increased risk of cardiovascular hospitalization in patients receiving less than full anticoagulation as recommended by U.S. Food and Drug Administration labeling (3). Although these data are subject to confounding and require further confirmation, the

*Brandon E. Cave, PharmD Augustus R. Hough, PharmD David Parra, PharmD Robert S. Rosenstein, MD

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 9, 2017

Letters to the Editor

MAY 8, 2017:963–70

*West Palm Beach VA Medical Center

12-month mortality among the apixaban-treated

Department of Cardiology

patients, which however did not reach statistical

7305 North Military Trail

significance and is not attributable to thromboem-

West Palm Beach, Florida 33410

bolic events, because cardiovascular mortality was

E-mail: [email protected]

similar, at 6.2% for apixaban and 6.0% for VKA.

http://dx.doi.org/10.1016/j.jcin.2017.02.010

Of note, in the adjusted analysis of the retrospective

Published by Elsevier on behalf of the American College of Cardiology Foundation Please note: All authors have reported that they have no relationships relevant to the contents of this paper to disclose.

ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) trial, there was no difference

regarding

the

occurrence

of

stroke,

bleeding, or hospitalization between patients with labeled dosed and underdosed treatment. In addi-

REFERENCES

tion, the impact of anticoagulation dosage on reho-

1. Seeger J, Gonska B, Rodewald C, Rottbauer W, Wöhrle J. Apixaban in patients with atrial fibrillation after transfemoral aortic valve replacement. J Am Coll Cardiol Intv 2017;10:66–74. 2. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. 3. Steinberg BA, Shrader P, Thomas L, et al. Off-label dosing of non-vitamin k antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II Registry. J Am Coll Cardiol 2016;68:2597–604. 4. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141 Suppl 2: e326S–50S. 5. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375: 2423–34.

spitalization is questionable, especially as reasons for rehospitalization were not further differentiated and cannot be attributed to the anticoagulation dosage. Bridging therapy is another important point. There was no post-procedural bridging with use of a VKA in the present study that could have been a possible confounder regarding bleeding events. Indications for bridging therapy have been redefined in the American College of Cardiology’s 2017 guidelines (3). According to these guidelines, only one patient in the VKA group who experienced a stroke would have been recommended for bridging therapy because of high risk for thromboembolic events. So far, published randomized trials have shown higher rates of

REPLY: Apixaban in Patients With

bleeding events with bridging therapy without

Atrial Fibrillation After Transfemoral

reducing ischemic events in patients with low to

Aortic Valve Replacement

intermediate CHA 2DS2-VASc scores (3). However, data on patients with nonvalvular atrial fibrillation or data

We thank Dr. Cave and colleagues for their letter

on patients with anticoagulation for atrial fibrillation

regarding our recent publication on apixaban in pa-

after percutaneous coronary intervention should not

tients with atrial fibrillation after transfemoral aortic

be transferred to an older population undergoing

valve replacement (TAVR) (1), which addresses

TAVR. Apixaban was as safe as a VKA in preventing

some important considerations. In a TAVR popula-

thromboembolic

tion at high risk for thromboembolic and bleeding

fibrillation after TAVR, at a lower rate of bleeding

events, dose adjustment is a critical point. Généreux

events. However, this was a single-center experience,

et al. (2) clearly demonstrated that late bleeding

and further confirmation is needed in ongoing larger

events were associated with a 3.9-fold increased risk

randomized controlled trials.

events

in

patients

with

atrial

for 1-year mortality. Thus, in contrast to Cave and colleagues, especially in the high-risk TAVR population, balanced

the not

anticoagulation only

to

regimen

prevent

must

be

thromboembolic

Julia Seeger, MD Wolfgang Rottbauer, MD *Jochen Wöhrle, MD

events but also to guarantee low bleeding rates. The

*Department of Internal Medicine II

rate of life-threatening bleeding was significantly

University of Ulm

reduced in the apixaban group within 30 days of

Albert-Einstein-Allee 23

follow-up at a similar rate of disabling and nondis-

89081 Ulm

abling stroke compared with a vitamin K antagonist

Germany

(VKA) (1). Landmark analysis after 30 days demon-

E-mail: [email protected]

strated no late catch-up phenomenon for the occur-

http://dx.doi.org/10.1016/j.jcin.2017.02.034

rence of all strokes over 12 months in the apixaban group (1). There was a numerically higher rate of

Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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