Anticoagulation in Atrial Fibrillation

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 69, NO. 7, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2016.11.062

EDITORIAL COMMENT

Anticoagulation in Atrial Fibrillation Is the Paradigm Really Shifting?* Prakash Deedwania, MD,a Tushar Acharya, MDb

A

trial fibrillation (AF) is the most common

some instances superior anticoagulation compared

arrhythmia encountered in clinical practice.

with VKA without the need for constant monitoring.

Patients with AF, especially those with multi-

It is hoped that due to their significant ease of

ple comorbid conditions and high CHA2DS2 -VASc

administration, NOAC will expand the scope of anti-

(Congestive heart failure, Hypertension, Age $75

coagulation in AF by enrolling those patients that are

years, Diabetes mellitus, previous Stroke, Vascular

ineligible, intolerant, or unwilling to use VKA as well

disease, Age 65 to 74 years, Sex category) score, are at

as those that are already on VKA therapy but who are

an increased risk of developing cardioembolic stroke.

undertreated

Vitamin K antagonists (VKA), primarily warfarin,

normalized ratio levels. Thus, increasing prescription

have traditionally been used in these patients to

of NOAC should lead to decrease in the number of

reduce the risk of stroke and subsequent morbidity

untreated patients as well as those on VKA.

due

and mortality (1). However, prescribing physicians

to

fluctuating

international

SEE PAGE 777

and patients using VKA are well aware of its many limitations, such as delayed onset of action, narrow ther-

The GLORIA AF (Global Registry on Long-Term Oral

apeutic window, numerous drug-drug and drug-food

Antithrombotic Treatment in Patients With Atrial

interactions, and the need for frequent and regular

Fibrillation) phase 2 registry published in this issue of

monitoring. Even in the monitored setting of random-

the Journal gives us some insight regarding the use of

ized trials, anticoagulation with VKA has been unreli-

NOAC in clinical practice (4). This registry describes

able. The ROCKET AF (Rivaroxaban Once Daily Oral

oral anticoagulant (OAC) treatment patterns in newly

Direct Factor Xa Inhibition Compared with Vitamin K

diagnosed AF patients from around the world. The

Antagonism for Prevention of Stroke and Embolism

investigators report 79.9% overall compliance with

Trial in Atrial Fibrillation) trial reported the VKA arm

OAC therapy (47.6% on NOAC and 32.3% on VKA) in

to be within the therapeutic range of the international

15,641 AF patients enrolled between 2011 and 2014.

normalized ratio only 55% of the time (2). These multi-

Those with Class I indication for anticoagulation

ple impediments have led to significant underutiliza-

(CHA 2DS2-VASc score $2) are reported to receive some

tion of VKA therapy (3), thereby exposing patients to

form of OAC 82.2% of the time. The phase 2 registry

risk of thromboembolic complications.

compares these trends to the pre-NOAC phase 1 reg-

The

availability

of

novel

oral

anticoagulants

istry and concludes that NOAC have now taken over

(NOAC) has changed this paradigm. NOAC are espe-

VKA as the more frequently prescribed OAC in most

cially appealing because they provide reliable and in

geographical locations. Given the many advantages of NOAC, these findings are not surprising. With growing

*Editorials published in the Journal of the American College of Cardiology

confidence among prescribers and patients, the pro-

reflect the views of the authors and do not necessarily represent the

portion of patients on NOAC should almost certainly

views of JACC or the American College of Cardiology.

increase further.

Division of Cardiology, Department of Internal Medicine,

Perhaps the more important and disturbing finding

University of California, San Francisco, Fresno, California; and the

is that nearly 20% of AF patients are not on appro-

b

priate stroke preventive therapy. Even accounting for

From the

a

Advanced Cardiovascular Imaging Laboratory, Cardiovascular and

Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Both authors have reported

high bleeding risk in some patients that could poten-

that they have no relationships relevant to the contents of this paper to

tially prevent OAC prescription (9.1% had a HAS-

disclose. P.K. Shah, MD, served as Guest Editor for this paper.

BLED [Hypertension, Abnormal renal/liver function;

Deedwania and Acharya

JACC VOL. 69, NO. 7, 2017 FEBRUARY 21, 2017:786–8

Anticoagulation in Atrial Fibrillation

Stroke, Bleeding, Labile international normalized ra-

paroxysmal AF (26.5%) (5). However, EORP-AF used

tio, Elderly (age >65 years), previous Drug, alcohol, or

the category of “first diagnosed AF” comprising

medication usage] score $ 3), still at least 10% of the

another 30.3% of their total AF patients. The Euro-

eligible patients are either on no therapy or inferior

pean Society of Cardiology AF guidelines have used

therapies such as aspirin. Some readers that take the

this category to describe AF that has not been diag-

“glass half-full” point-of-view may be encouraged by

nosed before, irrespective of duration (10). Without

the findings of the GLORIA-AF phase 2 registry and

this category, which is not part of the American

argue that 80% coverage is a marked improvement

College of Cardiology/American Heart Association

from what has been reported so far. And herein comes

AF guidelines (11), most of the newly diagnosed AF

the word of caution in interpreting these results: the

patients are lumped together as “paroxysmal” as seen

reported high percentage of OAC use is not consistent

in the GLORIA-AF phase 2 registry. It is important to

across the board. In fact, unlike GLORIA-AF and

note that EORP-AF registry enrolled patients with AF

EORP-AF (EURObservational Research Programme for

within the past year and may also under-represent

Atrial Fibrillation) registries (5), which show 80% OAC

long-standing AF patients.

usage, other contemporary registries have shown OAC

Second, GLORIA-AF phase 2 registry was launched

prescription to be more in the 50% range, even after

at the time of dabigatran approval and enrolled 15

the availability of NOAC. The GARFIELD-AF (Global

more patients at many more sites than phase 1 did. It

Anticoagulant Registry in the Field) registry, another

is possible that clinical sites participating in the

ongoing observational study has reported 60.8% OAC

clinical trials were more amenable to prescribing the

use in 17,162 new AF patients from 30 countries (6).

newly marketed NOAC and participated in dispro-

The PINNACLE (Practice Innovation and Clinical

portionately greater numbers in this registry. Such

Excellence) registry reported 44.9% OAC used among

over-representation, if present, would artificially

429,417 patients seen in U.S.-based clinical practices

elevate the number of patients receiving NOAC for

(7). Veterans Administration records show a 43.1%

stroke prevention.

OAC (warfarin or dabigatran) use for new onset AF (8).

Third, to describe treatment patterns in a registry, it

Have the prescription patterns really changed as

is paramount to enroll consecutive patients. Consec-

dramatically as suggested by GLORIA-AF? This ap-

utive data collection avoids potential selection bias of

pears unlikely. Hospital discharge data from 1.6

enrolling patients that receive the desired therapy.

million admissions in 812 U.S. hospitals was recently

Though the participating sites were trained to enroll

presented at the American Heart Association’s 2016

consecutive patients, they did not use screening logs

scientific session (9). It showed a dismal 46% OAC

to ascertain this. Thus, over-representation of pa-

prescription in new onset AF patients, compared with

tients on desired treatment within a participant site

the 78.3% reported from North America in GLORIA-AF

cannot be reliably excluded.

phase 2.

Furthermore, there are some indications within the

These variations suggest important methodological

registry that are concerning. For example, sites from

differences between these studies. They also highlight

Africa are reported to have an 87.4% compliance rate

the inherent problems with interpreting data from

with OAC prescription (compared with 78.3% in North

registries that may not be entirely representative of

America) with only 1.5% of eligible patients not on

the general population. GLORIA-AF has important

any therapy (7.5% in North America). This incongru-

limitations that limit generalizability. Although some

ently superior compliance with an expensive therapy

of these have been mentioned by Huismann et al. (4),

in a low-resource setting suggests selection bias and

there is need for further elaboration.

requires further explanation.

First, this is an incident AF registry that enrolled

Also, the direct comparison of OAC therapy trends

patients with AF within 3 months of initial presenta-

between phases 1 and 2 should be avoided. There was

tion. This cohort is not representative of most AF

minimal, if any, overlap between patient populations

patients in the general population or routine clinical

represented in phase 1 and phase 2 studies. Whereas

practice and as such these findings may not be

the current phase 2 registry (4) reports data predom-

generalizable

AF.

inantly from Europe (47.1%) and North America

Patients with paroxysmal AF (53%) appear to be over-

(22.5%), 67.1% of the patients enrolled in the phase 1

represented in the GLORIA-AF registry with persis-

cohort were from China (12). In fact, no centers from

tent (35.5%) and permanent AF (11.1%) accounting

North America were represented in the phase 1

for a minority. The EORP-AF registry reported some-

cohort. Thus, any comparison of OAC use between the

what similar proportions of persistent (26%) and

2 phases may represent geographical rather than

permanent AF (17.3%), but a lower percentage of

temporal variation.

for

those

with

long-standing

787

788

Deedwania and Acharya

JACC VOL. 69, NO. 7, 2017 FEBRUARY 21, 2017:786–8

Anticoagulation in Atrial Fibrillation

Despite the limitations cited, the results from

those at high risk of stroke receive appropriate

this registry are important as they advance our

guideline-directed anticoagulant therapy. Perhaps,

knowledge

in this situation, it is appropriate to remind our-

regarding

the

emerging

prescription

trends of OAC. The findings of this study, however,

selves that “an ounce of prevention is worth a

cannot be applied to populations other than those

pound of cure.”

enrolled in the registry. Let us not be lulled into a false sense of security. More representative data

ADDRESS

are needed to get realistic estimates of where we

Deedwania, Division of Cardiology, Department of

FOR

CORRESPONDENCE:

stand in terms of OAC use for stroke prevention in

Internal Medicine, University of California-San Fran-

AF. Meanwhile, from the information we have, it is

cisco, Fresno, Division of Cardiology Academic Offices,

apparent that much ground needs to be covered

2335 East Kashian Lane, Suite 460, Fresno, Califor-

before all eligible patients with AF, especially

nia 93701. E-mail: [email protected].

Dr. Prakash

REFERENCES 1. Hart RG, Pearce LA, Aguilar MI. Meta-analysis:

(EORP-AF) Pilot General Registry. Europace

10. Kirchhof P, Benussi S, Kotecha D, et al. 2016

antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67.

2014;16:308–19.

ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016;18:1609–78.

2. Patel MR, Mahaffey KW, Garg J, et al., for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. 3. Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med 2010; 123:638–45.e4. 4. Huisman MV, Rothman KJ, Paquette M, et al., for the GLORIA-AF Investigators. The changing landscape for stroke prevention in AF: findings from the GLORIA-AF registry phase 2. J Am Coll Cardiol 2017;69:777–85. 5. Lip GY, Laroche C, Dan GA, et al. A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation

6. Bassand JP, Accetta G, Camm AJ, et al., for the GARFIELD-AF Investigators. Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF. Eur Heart J 2016;37:2882–9. 7. Hsu JC, Maddox TM, Kennedy KF, et al. Oral anticoagulant therapy prescription in patients with atrial fibrillation across the spectrum of stroke risk: insights from the NCDR PINNACLE registry. JAMA Cardiol 2016;1:55–62. 8. Buck J, Kaboli P, Gage BF, Cram P, Vaughan Sarrazin MS. Trends in antithrombotic therapy for atrial fibrillation: data from the Veterans Health Administration Health System. Am Heart J 2016; 179:186–91. 9. Priedt R. Many atrial fibrillation patients missing out on blood thinners. HealthDay News, November 16, 2016. Available at: https:// consumer.healthday.com/cardiovascular-healthinformation-20/atrial-fibrillation-959/many-atrialfibrillation-patients-missing-out-on-blood-thinners716879.html. Accessed November 17, 2016.

11. January CT, Wann L, Alpert JS, et al. 2014 AHA/ ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1–76. 12. Huisman MV, Ma SM, Diener HC, et al. Antithrombotic therapy use in patients with atrial fibrillation before the era of non-vitamin K antagonist oral anticoagulants: the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) Phase I cohort. Europace 2016;18:1308–18.

KEY WORDS atrial fibrillation, novel oral anticoagulant agents, registry data, stroke prevention