Keywords atrial fibrillation - anticoagulation - stroke prevention - regional differences -
GLORIA-AF
Introduction
Atrial fibrillation (AF) increases the risk of stroke and all-cause mortality.[1 ]
[2 ]
[3 ] Oral anticoagulation (OAC) with vitamin K antagonists (VKAs) such as warfarin reduces
stroke risk by 64% and mortality by 26%, compared with placebo/control, while aspirin
decreases stroke risk by an estimated 19% and has no discernible effect on mortality.[4 ] More recent clinical trials have demonstrated that non-vitamin K antagonist OACs
(NOACs) are at least as effective as warfarin in stroke prevention and may offer greater
safety and convenience.[5 ]
[6 ]
[7 ]
[8 ]
[9 ]
After identification of ‘low-risk’ patients (congestive heart failure, hypertension,
age ≥ 75 years [doubled], diabetes, stroke/transient ischaemic attack (TIA)/thromboembolism
[doubled], vascular disease [prior myocardial infarction, peripheral arterial disease
or aortic plaque], age 65–74 years, sex category [female] [CHA2 DS2 -VASc] score 0 in males, 1 in females) who do not need any antithrombotic therapy,
stroke prevention with OAC should generally be considered in patients with ≥1 stroke
risk factors, given the positive net clinical benefit when balancing reduced stroke
risk against the risk of major bleeding.[10 ] However, substantial geographic differences in use of antithrombotic therapy have
been reported,[11 ]
[12 ]
[13 ] and these differences almost certainly affect thromboembolic and mortality rates.[14 ]
[15 ]
[16 ]
The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial
Fibrillation (GLORIA-AF) is one of the largest ongoing, international AF registries,
which aims to assess safety, effectiveness and utilization patterns of antithrombotic
therapy.[17 ] The primary objective of this article is to explore regional differences in thromboembolic
risk and treatment strategies in 15,092 AF patients from phase II of the registry.
We also examined the magnitude of influence of baseline variables in regard to antithrombotic
treatment choice.
Methods
Study Design
Details of GLORIA-AF study design have been previously published.[17 ] In brief, GLORIA-AF is a prospective registry of patients with newly diagnosed AF
at risk for stroke. The registry consists of three overlapping phases: phase I was
the period before NOAC introduction, phase II began immediately following approval
of the first NOAC in a given country and phase III started once propensity score comparisons
indicated a substantial overlap in the range of the scores for those receiving dabigatran
and those receiving VKA, to facilitate a valid assessment of safety and effectiveness.
This report analyses baseline, cross-sectional data coming from patients enrolled
in phase II of the registry (between November 2011 and December 2014).
Patients and Settings
The registry aims to enrol up to 56,000 AF patients from nearly 50 countries worldwide,
from five geographical regions: (1) Asia, (2) Europe, (3) North America, (4) Latin
America and (5) Africa/Middle East ([Fig. 1 ]). The programme includes up to 2,200 sites in a variety of in- and outpatient settings,
and involves various medical specialties. Inclusion criteria were as follows: adult
patients, new onset (<3 months before study entry, with the exception Latin America,
where it was <4.5 months due to referral patterns) non-valvular AF, and ≥1 risk factor
for stroke as per the CHA2 DS2 VASc score. Main exclusion criteria were as follows: mechanical heart valves or valve
disease requiring surgical valve replacement, history of OAC with VKA less than 60
days for any indication, generally reversible cause of AF, an indication other than
AF for VKA treatment and life expectancy less than 1 year.
Fig. 1 Definition of geographical regions and country participation in Global Registry on
Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF).
Thromboembolic risk was assessed with the use of CHA2 DS2 -VASc score.[18 ] ‘Low-risk’ patients were defined as CHA2 DS2 -VASc = 1 in females (males with CHA2 DS2 -VASc = 0 were not included); ‘moderate-risk’ patients as males with CHA2 DS2 -VASc = 1; and ‘high-risk’ patients as those with CHA2 DS2 -VASc score ≥2. Bleeding risk assessment was based on the HAS-BLED (hypertension,
abnormal renal and liver function, stroke, bleeding, labile INR [international normalized
ratio] values, age ≥ 65 years, drugs or alcohol) score, and high-risk was defined
as HAS-BLED ≥ 3.[19 ]
Data Collection
An Electronic Data Capture System (Cambridge, Massachusetts, United States) was used
to collect and store data as well as to ensure safety and confidentiality. High level
of data integrity is ensured by in-person monitoring, bimonthly calls to all sites
to review data quality, entry and open queries, biweekly updates of follow-up on data
trends (e.g., missing data, termination rates, overdue forms, vital status), regular
visits by audit teams as well as quarterly medical review meetings to assess aggregate
data. Local investigators were instructed in detail regarding system requirements
and functionality as well as encouraged to enrol consecutive eligible AF patients.
All patients entered the study after written, informed consent, and the study complies
with the Declaration of Helsinki.
Statistical Analysis
Baseline data were summarized descriptively. Continuous variables were reported as
median and quartiles. Categorical variables were reported as absolute frequencies
and percentages.
Logistic regression provides odds ratios (OR), which only closely approximate risk
ratios (i.e., relative risks) for rare outcomes (<10%). Because use of OAC and NOAC
was prevalent, we used log-binomial regression to estimate the risk ratios directly.[20 ] From here on and throughout the text, we will use the term ‘probability ratio’ rather
than ‘risk ratio’ as our measure describes drug use rather than adverse outcomes.
Both univariate and multivariable log-binomial regression analyses were conducted
to, respectively, evaluate the crude and adjusted probability ratios (together with
95% confidence intervals [CIs]) of OAC among all eligible patients, and of NOAC treatment
among patients receiving OAC, associated with the variables of clinical relevance:
age, gender, type of AF, categorization of AF, AF cardioversion, hypertension, diabetes
mellitus, previous stroke/TIA, congestive heart failure, coronary artery disease,
myocardial infarction, peripheral artery disease, previous bleeding events, chronic
kidney disease, alcohol abuse, cancer, chronic gastrointestinal disease, CHADS2 score, CHA2 DS2 -VASc score, HAS-BLED score, geographic region, type of site and medical treatment
reimbursement. No variable selection procedure was applied in the multivariable analyses.
The COPY method was used to obtain approximate maximum likelihood estimates where
the log-binomial model does not converge.[21 ] All analyses were performed using SAS statistical software version 9.4 (SAS Institute,
Inc., Cary, North Carolina, United States). Refer to online supplementary materials
for more details on methodology and statistical analysis.
Results
Baseline Data
Baseline characteristics by region are summarized in [Table 1 ]. Patients from Asia were younger, with 28.5% being ≥75 years, compared with Europe
(44.2%) and North America (39.6%). The most prevalent comorbidities were hypertension
(varying from 80.5% in North America to 69.4% in Asia) and hyperlipidaemia (61.3%
in North America, 26.7% in Asia). Diabetes was most common in Africa/Middle East (42.2%)
and less frequent in Asia (20.2%). The proportion of secondary prevention patients
(with prior stroke/TIA), as well as those with coronary artery disease and previous
myocardial infarction, was highest in Africa/Middle East (18.1, 32.5 and 16.6%, respectively).
Congestive heart failure was most common in Latin America (32.4%) and lowest in North
America (19.7%).
Table 1
Baseline characteristics by region
N (%) or median [Q1,Q3]
All
n = 15,092 (100%)
Region 1
Asia, n = 3,071 (20.3%)
Region 2
Europe, n = 7,108 (47.1%)
Region 3
North America, n = 3,403 (22.5%)
Region 4
Latin America, n = 913 (6.0%)
Region 5
Africa/Middle East, n = 597 (4.0%)
Patient characteristics
Age, y, median [Q1,Q3]
71.0 [64–78]
68.0 [60–76]
73.0 [66–79]
71.0 [64–79]
71.0 [62–78]
70.0 [61–76]
Age, ≥75 y
5,907 (39.1)
874 (28.5)
3,144 (44.2)
1,349 (39.6)
354 (38.8)
186 (31.2)
Female gender
6,872 (45.5)
1,337 (43.5)
3,317 (46.7)
1,524 (44.8)
410 (44.9)
284 (47.6)
GFR, mL/min/1.73 m2 , median [Q1,Q3]
75.1 [61–90]
78.7 [65–96]
74.0 [61–88]
74.3 [59–89]
72.5 [59–87]
75.2 [58–92]
No reimbursement for medications
1,076 (7.1)
375 (12.2)
313 (4.4)
103 (3.0)
183 (20.0)
102 (17.1)
Medical history
Hypertension
11,255 (74.6)
2,130 (69.4)
5,217 (73.4)
2,738 (80.5)
690 (75.6)
480 (80.4)
Hyperlipidaemia
6,026 (39.9)
821 (26.7)
2,595 (36.5)
2,085 (61.3)
246 (26.9)
279 (46.7)
Diabetes mellitus
3,487 (23.1)
619 (20.2)
1,510 (21.2)
921 (27.1)
185 (20.3)
252 (42.2)
Previous stroke/TIA
2,147 (14.2)
400 (13.0)
1,107 (15.6)
422 (12.4)
110 (12.0)
108 (18.1)
Congestive heart failure
3,647 (24.2)
837 (27.3)
1,662 (23.4)
671 (19.7)
296 (32.4)
181 (30.3)
Coronary artery disease
3,068 (20.3)
674 (21.9)
1,167 (16.4)
919 (27.0)
114 (12.5)
194 (32.5)
Myocardial infarction
1,600 (10.6)
246 (8.0)
741 (10.4)
418 (12.3)
96 (10.5)
99 (16.6)
Abnormal kidney function[a ]
241 (1.6)
45 (1.5)
89 (1.3)
75 (2.2)
12 (1.3)
20 (3.4)
Type of AF
Paroxysmal
8,052 (53.4)
1,804 (58.7)
3,326 (46.8)
2,240 (65.8)
396 (43.4)
286 (47.9)
Persistent
5,362 (35.5)
1,086 (35.4)
2,763 (38.9)
1,007 (29.6)
316 (34.6)
190 (31.8)
Permanent
1,678 (11.1)
181 (5.9)
1,019 (14.3)
156 (4.6)
201 (22.0)
121 (20.3)
Categorization of AF
Symptomatic
4,263 (28.2)
751 (24.5)
2,258 (31.8)
804 (23.6)
292 (32.0)
158 (26.5)
Minimally symptomatic
6,004 (39.8)
1,460 (47.5)
2,671 (37.6)
1,278 (37.6)
323 (35.4)
272 (45.6)
Asymptomatic
4,825 (32.0)
860 (28.0)
2,179 (30.7)
1,321 (38.8)
298 (32.6)
167 (28.0)
Interventions in AF
AF cardioversion
2,431 (16.1)
331 (10.8)
1,226 (17.2)
646 (19.0)
143 (15.7)
85 (14.2)
AF ablation
161 (1.1)
93 (3.0)
33 (0.5)
26 (0.8)
5 (0.5)
4 (0.7)
CHA2 DS2 -VASc
3.0
3.0
3.0
3.0
3.0
3.0
Low risk (score 1 in women)
332 (2.2)
110 (3.6)
114 (1.6)
83 (2.4)
14 (1.5)
11 (1.8)
Moderate risk (score 1 in men)
1,761 (11.7)
532 (17.3)
684 (9.6)
387 (11.4)
108 (11.8)
50 (8.4)
High risk (score ≥2)
12,999 (86.1)
2,429 (79.1)
6,310 (88.8)
2,933 (86.2)
791 (86.6)
536 (89.8)
HAS-BLED
1.0
1.0
1.0
1.0
1.0
1.0
Low risk (score 0–2)
11,927 (79.0)
2,359 (76.8)
5,538 (77.9)
2,775 (81.5)
772 (84.6)
483 (80.9)
High risk (score ≥3)
1,376 (9.1)
329 (10.7)
575 (8.1)
352 (10.3)
59 (6.5)
61 (10.2)
Missing
1,789 (11.9)
383 (12.5)
995 (14.0)
276 (8.1)
82 (9.0)
53 (8.9)
Physician specialty
Cardiologist
13,863 (91.9)
2,994 (97.5)
6,568 (92.4)
2,872 (84.4)
864 (94.6)
565 (94.6)
GP/geriatrician
359 (2.4)
34 (1.1)
63 (0.9)
229 (6.7)
32 (3.5)
1 (0.2)
Internist
322 (2.1)
12 (0.4)
71 (1.0)
197 (5.8)
17 (1.9)
25 (4.2)
Neurologist
147 (1.0)
7 (0.2)
63 (0.9)
77 (2.3)
0 (0.0)
0 (0.0)
Other
386 (2.6)
24 (0.8)
328 (4.6)
28 (0.8)
0 (0.0)
6 (1.0)
Missing
15 (0.1)
0 (0.0)
15 (0.2)
0 (0.0)
0 (0.0)
0 (0.0)
Type of setting
GP/primary care
968 (6.4)
178 (5.8)
216 (3.0)
496 (14.6)
75 (8.2)
3 (0.5)
Specialist office
4,567 (30.3)
611 (19.9)
1,200 (16.9)
2,290 (67.3)
320 (35.0)
146 (24.5)
Community hospital
3,969 (26.3)
561 (18.3)
2,717 (38.2)
298 (8.8)
251 (27.5)
142 (23.8)
University hospital
5,081 (33.7)
1,659 (54.0)
2,715 (38.2)
265 (7.8)
207 (22.7)
235 (39.4)
Outpatient/anticoagulation clinic
381 (2.5)
62 (2.0)
143 (2.0)
54 (1.6)
51 (5.6)
71 (11.9)
Other
126 (0.8)
0 (0.0)
117 (1.6)
0 (0.0)
9 (1.0)
0 (0.0)
Abbreviations: AF, atrial fibrillation; CHA2 DS2 -VASc, congestive heart failure, hypertension, age ≥75 years (doubled), diabetes,
stroke/transient ischaemic attack/thromboembolism (doubled), vascular disease (prior
myocardial infarction [MI], peripheral arterial disease [PAD] or aortic plaque), age
65 to 74 years, sex category (female); GFR, glomerular filtration rate; GP, general
practitioner; HAS-BLED, hypertension, abnormal renal and liver function, stroke, bleeding,
labile INR (international normalized ratio), age ≥65 years, drugs or alcohol; TIA,
transient ischaemic attack.
a Defined as the presence of chronic dialysis or renal transplantation or serum creatinine
≥200 μmol/L.
The vast majority of patients were treated by cardiologists (91.9%), with some differences
among regions (97.5% in Asia and 84.4% in North America). In Asia, 54% of patients
were enrolled in university hospitals, while in North America most of the subjects
were recruited in specialist offices (67.3%).
Overall, 79.9% of all patients were prescribed OAC: 32.3% VKA and 47.6% NOACs (dabigatran
31.6%, rivaroxaban 11.4% and apixaban 4.6%), while 12.1% received antiplatelet drugs
(aspirin in 93.1% of cases) and 7.8% received no antithrombotic therapy. Of those
at low bleeding risk, 81.8% were anticoagulated, 9.6% received aspirin, 0.6% other
antithrombotic drugs and 8.1% were not treated. The corresponding proportions for
those at high risk of bleeding (HAS-BLED ≥ 3) were 63.4, 27.6, 3.6 and 5.3%.
Antithrombotic Therapy by Region
The highest OAC rates were observed in Europe (90.1%), followed by Africa/Middle East
(87.4%), Latin America (85.3%) and North America (78.3%), while in Asia it was 55.2%
([Fig. 2A ]). In the subgroup of patients on OACs (n = 12,065; 79.9%), the most prevalent option was NOACs in North America (66.5%), Latin
America (66.0%) and Africa/Middle East (63.6%; [Fig. 2B ]). In Asia, the probability that a patient with AF remained untreated was the highest,
at 19.8%, and in the Africa/Middle East region, it was the lowest, at 1.5%. Antiplatelet
therapy was common in Asia (25.0%) and least prevalent in Europe (6.0%; [Fig. 2A ]).
Fig. 2 Antithrombotic treatments by region, overall (A ) and among oral anticoagulant (OAC) users (B ). Other antithrombotic therapy includes the combination of antithrombotic agents.
Antithrombotic Therapy by Region and Stroke Risk
In Europe, 64.9% of low-risk patients were prescribed OAC and 14.9% antiplatelets.
In North America, the corresponding numbers were 39.8 and 49.4%, respectively, while
in Asia, 28.2 and 32.7%, respectively ([Fig. 3 ]). Among European patients at moderate risk of stroke, 85.1% received OAC, compared
with 79.6% in Latin America and 74.0% in Africa/Middle East. Corresponding proportions
in North America and Asia were 67.7 and 49.4%, respectively. In high-risk patients,
OAC use was highest in Europe (91.1%), followed by Africa/Middle East (89.2%), Latin
America (86.6%), North America (80.8%) and Asia (57.6%).
Fig. 3 Antithrombotic treatment by region and stroke risk.a Other = antiplatelets other than acetylsalicylic acid (ASA) and combination of antithrombotic
agents; Xa inhibitor = rivaroxaban, apixaban. a In Latin America and Africa/Middle East, score = 1 in females is not shown as there
were too low patient numbers to calculate meaningful percentages for comparison.
Antithrombotic Therapy by Region and Country
[Table 2 ] summarizes enrolment rate by regions and countries with their respective antithrombotic
treatment patterns. Europe was the highest recruiting region with 7,108 patients (47.1%)
enrolled, whereas United States was the highest recruiting country (n = 3,007; 19.9%). The greatest heterogeneity in OAC prescription was noted in Asia,
where anticoagulation varied from 21.0% in China to 89.7% in Japan. For Europe, generally
high overall OAC rates were observed in all countries, and with the exception of only
a few high-enrolling countries (>500 patients enrolled, i.e., the Netherlands, Spain,
United Kingdom), NOACs were the more prevalent OAC option.
Table 2
Antithrombotic therapy by region and country
Entire population
All[a ]
15,092 (100)
None
1,182 (7.8)
ASA
1,706 (11.3)
VKA
4,878 (32.3)
NOAC
7,187 (47.6)
Overall OAC
12,065 (79.9)
Other
139 (0.9)
Asia
3,071 (100)
608 (19.8)
727 (23.7)
844 (27.5)
850 (27.7)
1,694 (55.2)
42 (1.4)
China
1,018 (33.1)
431 (42.3)
351 (34.5)
155 (15.2)
59 (5.8)
214 (21.0)
22 (2.2)
Hong Kong
49 (1.6)
3 (6.1)
13 (26.5)
9 (18.4)
24 (49.0)
33 (67.3)
0
Japan
312 (10.2)
27 (8.7)
5 (1.6)
20 (6.4)
260 (83.3)
280 (89.7)
0
Russian Federation
404 (13.2)
2 (0.5)
45 (11.1)
75 (18.6)
282 (69.8)
357 (88.4)
0
Singapore
48 (1.6)
5 (10.4)
5 (10.4)
23 (47.9)
14 (29.2)
37 (77.1)
1 (2.1)
South Korea
997 (32.5)
117 (11.7)
282 (28.3)
541 (54.3)
42 (4.2)
583 (58.5)
15 (1.5)
Taiwan
243 (7.9)
23 (9.5)
26 (10.7)
21 (8.6)
169 (69.5)
190 (78.2)
4 (1.6)
Europe
7,108 (100)
272 (3.8)
373 (5.2)
2,687 (37.8)
3,717 (52.3)
6,404 (90.1)
59 (0.8)
Austria
62 (0.9)
1 (1.6)
0
5 (8.1)
56 (90.3)
61 (98.4)
0
Belgium
38 (0.5)
4 (10.5)
2 (5.3)
3 (8.0)
29 (76.3)
32 (84.2)
0
Bulgaria
303 (4.3)
3 (1.0)
6 (2.0)
61 (20.1)
233 (76.9)
294 (97.0)
0
Croatia
165 (2.3)
11 (6.7)
36 (21.8)
96 (58.2)
22 (13.3)
118 (71.5)
0
Czech Republic
75 (1.1)
7 (9.3)
3 (4.0)
53 (70.7)
12 (16.0)
65 (86.7)
0
Denmark
62 (0.9)
2 (3.2)
0
14 (22.6)
46 (74.2)
60 (96.8)
0
Estonia
45 (0.6)
0
0
17 (37.8)
28 (62.2)
45 (100)
0
France
969 (13.6)
21 (2.2)
22 (2.3)
195 (20.1)
729 (75.2)
924 (95.4)
2 (0.2)
Germany
1,220 (17.2)
39 (3.2)
75 (6.1)
201 (16.5)
899 (73.7)
1,100 (90.2)
6 (0.5)
Greece
270 (3.8)
7 (2.6)
9 (3.3)
113 (41.9)
141 (52.2)
254 (94.1)
0
Republic of Ireland
61 (0.9)
1 (1.6)
5 (8.2)
13 (21.3)
42 (68.9)
55 (90.2)
0
Italy
359 (5.1)
17 (4.7)
14 (3.9)
111 (30.9)
214 (59.6)
325 (90.5)
3 (0.8)
Latvia
60 (0.8)
0
20 (33.3)
6 (10.0)
34 (56.7)
40 (66.7)
0
The Netherlands
528 (7.4)
9 (1.7)
12 (2.3)
317 (60.0)
188 (35.6)
505 (95.6)
2 (0.4)
Norway
77 (1.1)
2 (2.6)
2 (2.6)
16 (20.8)
57 (74.0)
73 (94.8)
0
Poland
75 (1.1)
4 (5.3)
3 (4.0)
9 (12.0)
59 (78.7)
68 (90.7)
0
Portugal
164 (2.3)
5 (3.0)
3 (1.8)
56 (34.1)
100 (61.0)
156 (95.1)
0
Romania
301 (4.2)
1 (0.3)
17 (5.6)
121 (40.2)
152 (50.5)
273 (90.7)
10 (3.3)
Slovenia
68 (1.0)
0
0
2 (2.9)
66 (97.1)
68 (100)
0
Spain
1,155 (16.2)
78 (6.8)
70 (6.1)
725 (62.8)
273 (23.6)
998 (86.4)
9 (0.8)
Sweden
137 (1.9)
0
0
80 (58.4)
57 (41.6)
137 (100)
0
Switzerland
72 (1.0)
1 (1.4)
3 (4.2)
20 (27.8)
47 (65.3)
67 (93.1)
1 (1.4)
United Kingdom
842 (11.8)
59 (7.0)
71 (8.4)
453 (53.8)
233 (27.7)
686 (81.5)
26 (3.1)
North America
3,403 (100.0)
255 (7.5)
455 (13.4)
892 (26.2)
1,774 (52.1)
2,666 (78.3)
27 (0.8)
Canada
396 (11.6)
8 (2.0)
47 (11.7)
101 (25.5)
238 (60.1)
339 (85.6)
2 (0.5)
United States
3,007 (88.4)
247 (8.2)
408 (13.6)
791 (26.3)
1,536 (51.1)
2,327 (77.4)
25 (0.8)
Latin America
913 (100.0)
38 (4.2)
92 (10.1)
265 (29.0)
514 (56.3)
779 (85.3)
4 (0.4)
Argentina
153 (16.8)
4 (2.6)
14 (9.2)
62 (40.5)
73 (47.7)
135 (88.2)
0
Brazil
306 (33.5)
28 (9.2)
42 (13.7)
99 (32.4)
137 (44.8)
236 (77.1)
0
Chile
11 (1.2)
0
1 (9.1)
7 (63.6)
3 (27.2)
10 (90.9)
0
Colombia
134 (14.7)
2 (1.5)
6 (4.5)
29 (21.6)
97 (72.4)
126 (94.0)
0
Ecuador
36 (4.0)
1 (2.8)
5 (13.9)
5 (13.9)
23 (63.9)
28 (77.8)
2 (5.6)
Mexico
220 (24.1)
1 (0.5)
21 (9.5)
47 (21.4)
149 (67.7)
196 (89.1)
2 (0.9)
Peru
44 (4.8)
1 (2.3)
2 (4.5)
15 (34.1)
26 (59.1)
41 (93.2)
0
Venezuela
9 (1.0)
1 (11.1)
1 (11.1)
1 (11.1)
6 (66.7)
7 (77.8)
0
Africa/Middle East
597 (100.0)
9 (1.5)
59 (9.9)
190 (31.8)
332 (55.6)
522 (87.4)
7 (1.2)
Lebanon
243 (40.7)
1 (0.4)
29 (11.9)
62 (25.5)
148 (60.9)
210 (86.4)
3 (1.2)
Saudi Arabia
235 (39.4)
4 (1.7)
8 (3.4)
77 (32.8)
145 (61.7)
222 (94.5)
1 (0.4)
Republic of South Africa
32 (5.4)
2 (6.3)
1 (3.1)
25 (78.1)
3 (9.4)
28 (87.5)
1 (3.1)
United Arab Emirates
87 (14.6)
2 (2.3)
21 (24.1)
26 (29.9)
36 (41.4)
62 (71.3)
2 (2.3)
Abbreviations: ASA, aspirin; NOAC, non-vitamin K antagonists oral anticoagulant; VKA,
vitamin K antagonists; OAC, oral anticoagulant; Other, antiplatelets other than aspirin
and combination of antithrombotic agents.
Note: Data are presented as n (%)—row percentages.
a Data presented in column percentages.
Antithrombotic Therapy by Region and Clinical Setting
In Asia, 80.4% of patients from community hospitals were anticoagulated, compared
with 49.8 and 42.6% of those from university hospitals and specialist offices, respectively
([Fig. 4 ]). NOACs and VKAs were prescribed for 71.1 and 9.3% of patients from community hospitals;
in university hospitals, the corresponding numbers were 11.0 and 38.8%, and in specialist
offices, 21.6 and 20.9%, respectively.
Fig. 4 Antithrombotic treatment by region and setting.a Other = antiplatelets other than acetylsalicylic acid (ASA) and combination of antithrombotic
agents. a In Europe, n = 117 (1.6%) and Latin America n = 9 (1%) patients were included in other types of sites not shown in this graphic.
Overall, physicians from university hospitals prescribed more VKAs (42.7%) and less
NOACs (33.0%). In North America, the highest anticoagulation use was reported by university
hospitals at 83.0% (53.6% NOACs and 29.4% VKAs), compared with 69.8% in community
hospitals and 70.6% in general practices. The highest prevalence of aspirin treatment
or non-treatment was seen not only in Asian specialist offices (55.8%) and university
hospitals (48.5%), but also in American community hospitals (29.5%) and general practices
(29.0%).
Anticoagulation Therapy versus Other Treatment
A log-binomial regression analysis for estimation of probability ratios for the prescription
of anticoagulation therapy (VKA, NOAC) versus other treatment (antiplatelet or no
treatment) is presented in [Supplementary Table S1 ] (online only). In the multivariable analysis, adjusted probability ratios were calculated
for OAC use versus other therapy use.
A lower adjusted probability for OAC treatment prescription compared with other therapy
was found for patients with low and moderate thromboembolic risk by CHA2 DS2 -VASc score (probability 0.63 [95% CI: 0.55–0.71], 0.91 [95% CI: 0.88–0.94], respectively)
and high bleeding risk by HAS-BLED score (0.79 [95% CI: 0.76–0.82]) as well as those
recruited in regions of Asia, North and Latin America (vs. Europe, probability ratios
0.66 [95% CI: 0.64–0.69], 0.91 [95% CI: 0.89–0.93], 0.96 [95% CI: 0.94–0.99], respectively).
Non–Vitamin K Antagonist versus Vitamin K Antagonist
A log-binomial regression analysis for estimation of probability ratios for the prescription
of NOAC versus VKA is presented in [Supplementary Table S2 ] (online only). In the multivariable analysis, adjusted probability ratios were calculated
for NOAC (compared with VKA use).
Patients recruited at specialist office, community hospital and other health care
settings, compared with university hospitals, had a higher adjusted probability for
NOAC versus VKA prescription, probability ratios 1.53 (95% CI: 1.46–1.60), 1.46 (95%
CI: 1.39–1.53), 1.52 (95% CI: 1.43–1.60), respectively. In contrast, patients with
persistent AF (vs. paroxysmal AF, probability ratio 0.93 [95% CI: 0.90–0.96]), diabetes
mellitus (probability ratio 0.92 [95% CI: 0.88–0.96]), prior myocardial infarction
(probability ratio 0.85 [95% CI: 0.80–0.91]) and chronic kidney disease (probability
ratio 0.92 [95% CI: 0.89–0.96]) had a lower probability for NOAC use, compared with
VKA.
Discussion
The principal findings of this analysis are as follows: (1) despite a relatively high
global OAC use, substantial inter-regional differences are evident, with OAC use being
highest in Europe (90.1%) and lowest in Asia (55.2%); (2) among OAC users, NOACs have
replaced VKAs as the more prevalent option in all regions, with the highest uptakes
in North America (66.5%) and lowest in Asia (50.2%); (3) intra-regional differences
in antithrombotic therapy use are apparent; and (4) AF guideline adherence requires
improvement, as nearly half of low-risk patients are over-treated, while every sixth
high-risk patient (8.8% in Europe, 18.9% in North America and 42.4% in Asia) is under-treated
with OAC.
There may be several potential reasons for substantial heterogeneity in OAC use by
regions in this analysis, such as apparent differences in baseline characteristics,
associated comorbid disease, thromboembolic and bleeding risk, type of AF or enrolling
site, physicians' specialty, AF guidelines or health care system and reimbursement
in a given country.[11 ]
[12 ]
[13 ]
[22 ]
[23 ]
[24 ] While some previous reports have shown that there are regions with lower OAC uptake,
particularly in Asia, we found that the uptake within regions varies considerably
by country, health care setting and type of anticoagulation (VKA vs. NOACs).[25 ]
[26 ]
[27 ]
Prior studies have reported several issues limiting optimal anticoagulation, such
as fear of bleeding complications or poor quality of INR control.[27 ]
[28 ]
[29 ] Our study shows that NOACs are a more prevalent treatment option than VKAs in all
study regions, and in 33 out of 44 participating countries. Even more importantly,
higher anticoagulation rates were observed in those regions and countries where NOACs
were the main anticoagulants. This was evident in Africa/Middle East and Latin America,
which as regions was found to be associated with higher use of NOACs (vs. VKAs) compared
with Europe, and reported even higher anticoagulation uptake than North America. Interestingly,
in Africa/Middle East and Latin America, there was no reimbursement for medications
in 14 to 26%, while self-pay for medications was only reported in approximately 3
to 4% in North America and Europe.
Despite having the highest NOAC uptake among OAC users, overall anticoagulation use
in North America was relatively low. This pattern may be partially explained by American
AF guidelines, which in contrast to the European and Asia Pacific guidelines offer
OAC, aspirin or even no AF stroke prophylaxis in patients with CHA2 DS2 -VASc score of 1, while OAC is recommended in those with the score ≥2.[30 ]
[31 ]
[32 ] When compared with other regions of GLORIA-AF registry, the proportion of participating
cardiologists in North America was lowest. Indeed, lower prescription rates have been
reported by registries where broader spectrum of physician specialties were included.[24 ] In addition, the incidence of paroxysmal AF (as compared with other AF patterns)
was also highest in North America and in the present analysis, was associated with
lower OAC prescription. Other studies have also reported less OAC use in patients
with paroxysmal AF, although current guidelines recommend anticoagulation regardless
of AF pattern.[30 ]
[33 ]
The highest overall OAC use was reported in Europe, with generally NOACs being more
frequently prescribed than VKAs. However in some countries, including high-enrolling
ones (i.e., the Netherlands, Spain and United Kingdom), VKAs were more frequently
prescribed than NOACs. Western European countries generally provide good quantity
and quality of anticoagulation and more guideline-adherent OAC use compared with other
European and non-European countries.[16 ]
[34 ]
[35 ] Regardless of OAC type (whether with an NOAC or VKA), being treated for AF in Europe
was associated with higher likelihood of being anticoagulated (vs. antiplatelet or
no therapy), compared with North and Latin America or Asia.
Another important finding relates to health care clinical settings. Overall physicians
from university hospitals prescribed anticoagulation less frequently than those from
other health care settings, and preferred VKAs over NOACs. Potential reasons for such
differences in treatment patterns by setting may be multifactorial and may include
more common and complex invasive procedures being performed or higher number of patients
with comorbid disease and contraindications to OAC being enrolled by university hospitals.
Nonetheless, a growing body of evidence suggests that OAC should be neither interrupted
nor bridged during various invasive procedures, including AF ablation, as this does
not lower the risk of bleeding complications but brings increased risk of thromboembolism.[36 ]
[37 ]
[38 ]
Geographic differences may also play a role. For example, OAC prescription in Asian
university hospitals was nearly twofold lower than in community hospitals or specialist
offices, whereas in other regions a more homogenous distribution of OAC by setting
(regardless of anticoagulant type) was observed. Such heterogeneity in anticoagulation
rates between community and university hospitals in Asia may reside in more evident
between-country differences in national health care systems compared with other geographic
regions. In addition, country- and site-specific OAC prescription patterns and predominantly
enrolling sites may play a role. Indeed, for example, 1 in 5 patients in China versus
9 in 10 in Japan were prescribed OAC. A marked difference in NOAC versus VKA prescription
was also noted, with overall higher OAC use in those Asian countries where NOAC was
the main anticoagulant.
In Europe, nearly two-thirds of low-risk patients were anticoagulated, while many
patients with ≥2 stroke risk factors are not treated as such.[39 ]
[40 ] Also, aspirin is commonly prescribed to low-risk patients and those at high risk
of bleeding, being prescribed in 10.0% of subjects at high thromboembolic risk. Stroke
prevention with aspirin monotherapy is neither effective nor safe, and majority of
AF guidelines do not recommend its use.[30 ]
[32 ]
[41 ] Such non-compliance with guidelines has been reported by previous registries, which
observed improved outcomes in patients who were treated in line with AF guidelines.[14 ]
[16 ]
Limitations and Strengths
GLORIA-AF is not a population-based programme, which limits patient representativeness.
Particularly, relatively low number of patients has been enrolled from Latin America
and Africa/Middle East. Patients could enter the study only after signing an informed
consent, which might have resulted in higher anticoagulation rates compared with general
AF population. Inclusion of patients with new onset AF and once NOACs were on offer
in given countries could result in higher OAC rates compared with registries which
enroll AF ‘all-comers’. As countries with various health care systems, drug reimbursement
policy, predominantly enrolling sites, AF guidelines and different OAC prescribing
patterns have been grouped within one geographic region, a bias resulting from a direct
comparison of antithrombotic treatment among such defined regions cannot be excluded.
Because a considerable number of countries did not enrol enough patients to allow
meaningful country-specific data, country (as a variable) was not incorporated into
the multivariable analysis. Higher use of dabigatran versus other NOACs should not
be surprising as this report covers specifically the period that started once the
first NOAC (predominately dabigatran) became available in a given country.[17 ]
[42 ]
Nevertheless, despite not being representative for the general AF population, GLORIA-AF
is as much representative as other AF registries in the field, what is also reflected
by inclusion/exclusion criteria. Global reach, broad country, site and physician inclusion,
high-quality control measures along with unique study design with phase II commencing
data collection immediately following first NOAC launch in given countries are evident
strengths of GLORIA-AF. Consequently, this report provides an up-to-date global, regional
(continental) and local (including country and health care setting) overview of contemporary
antithrombotic treatment patterns for stroke prevention in newly diagnosed AF.
Conclusion
Substantial inter- and intra-regional differences in ATT for stroke prevention in
AF are evident, as summarized in [Fig. 5 ]. While guideline-adherent ATT can be further improved, NOACs are the main contributor
to high OAC use worldwide.
Fig. 5 Summary infographic showing substantial inter- and intra-regional differences in
antithrombotic therapy for stroke prevention in AF (atrial fibrillation).
What is known about this topic?
What does this paper add?
In this global registry of 15,092 patients newly diagnosed with non-valvular AF at
risk for stroke, oral anticoagulation (OAC) use was 79.9%, being highest in Europe
(90.1%), followed by Africa/Middle East (87.4%), Latin America (85.3%), North America
(78.3%) and Asia (55.2%).
Among OAC users, vitamin K antagonists (VKAs) have been replaced by non-VKA OACs (NOACs)
as the more prevalent OAC option in all regions, with highest use in North America
(66.5%) and lowest use in Asia (50.2%).
Globally, 76.5% of low-risk patients were prescribed ATT (46.1% OAC), whereas 17.7%
high-risk patients were not anticoagulated (Europe 8.8%, North America 18.9% and Asia
42.4%).
Substantial inter- and intra-regional differences in ATT for stroke prevention in
AF are evident.
