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Aim

The aim of this study is to examine temporal trends in the use oral anticoagulants (OAC) as stroke prophylaxis in patients with atrial fibrillation (AF) and to examine factors associated with OAC initiation.

Methods and results

From Danish nationwide registries, we identified patients diagnosed with AF at Danish hospitals and outpatient clinics between January 2005 and June 2015. OAC initiation was assessed from prescription fills ±180 days from date of AF diagnosis. We identified a total of 108 410 patients with newly diagnosed AF. Before 2010, 40–50% initiated OAC treatment. From 2010, OAC initiation rates increased (P < 0.0001 for trend) and by June 2015, 66.5% of the incident AF patients were initiated on OAC (74.5% increase since December 2009). Increased OAC prescription was especially seen among females and ‘fragile’ patients (age > 75 years and high risk of stroke). The increased OAC initiation was accompanied by introduction and increased uptake of the NOACs. By the end of the study, NOACs accounted for 72.5% of all OACs prescribed in newly diagnosed AF patients. OAC initiation was associated with male gender, age 65–74 years, few comorbidities and increased risk of stroke.

Conclusion

Since 2010, more incident AF patients in Denmark were initiated on OAC therapy with predominant NOAC prescription. The increase was pronounced among females, among patients at high risk of stroke, and among older patients.

Atrial fibrillation , Oral anticoagulation , OAC , VKA , NOAC

Introduction

Protection against stroke and thromboembolism is central to the management of patients with non-valvular atrial fibrillation (AF).1 For decades, vitamin K antagonists (VKA) have been the only available oral anticoagulation (OAC) therapy in patients with AF, reducing the risk of stroke by almost two-thirds.2 The treatment reduces mortality and morbidity,2 but until 2011, significant VKA underuse has been reported among AF patients in western European countries, with treatment rates of <50%.3–6

Since 2010, European guidelines have recommended OAC for all AF patients at moderate or high risk of stroke.7 VKAs have several food and drug interactions and treatment with VKA has a narrow therapeutic range that requires frequent clinical monitoring and dose adjustments. The treatment is associated with an increased risk of bleeding, of which the most serious and disabling is intracranial haemorrhage.2,8 Thus, VKA agents have several drawbacks, likely contributing to a considerable withhold of OAC treatment among AF patients.

Dabigatran, rivaroxaban, and apixaban are the non-vitamin K antagonist oral anticoagulants (NOACs) currently available in Denmark. Clinical trials have shown these agents to be at least non-inferior to VKA with regard to efficacy and safety.9–11 NOACs have fewer drug and food interactions and they do not require frequent clinical monitoring or dose adjustments. Studies have shown trends towards increased NOAC prescribing12 but few contemporary data are available on temporal trends in the proportion of AF patients initiated on OAC treatment.

This study aims to describe temporal nationwide trends in OAC initiation among newly diagnosed AF patients in Denmark; OAC utilization among the entire Danish AF population is also described. Furthermore, factors associated with OAC initiation are examined.

Methods

Data sources

We utilized data from the following Danish national registries: (i) The Danish National Patient Registry contains information regarding all hospitalized patients and outpatients since 1977. Patient contact is recorded in the registry with one primary and, if appropriate, one or more secondary diagnoses, coded according to the International Classification of Diseases (ICD) 8 and 10.13 (ii) The National Prescription Registry contains various information on all prescriptions dispensed in Danish pharmacies since 1995, e.g. date of claimed prescription, number and strength of tablets dispensed. Prescription handouts are coded according to the Anatomical Therapeutic Chemical (ATC) classification system, and Danish legislation requires accurate information and registration from all Danish pharmacies.14,15 (iii) The Civil Registration System is the Danish nationwide civil registry and holds various information including sex, date of birth and death, and vital status.16

All Danish residents are recorded in the registries with a unique personal and permanent registration number that makes it possible to cross-link individual-level data across the different registries.

Study patients

Incident AF patients

From 1 January 2005 to 30 June 2015, we identified all patients with a first-time primary diagnosis of AF (see Supplementary material online, Appendix, for ICD diagnosis codes). The AF diagnosis has previously been validated in the Danish National Patient Registry with a positive predictive value of 99% among hospitalized patients.17 We excluded patients <30 years and >100 years, patients with valvular heart disease, patients who had undergone hip or knee arthroplasty surgery within eight weeks of AF diagnosis, and patients with venous thromboembolism within 6 months of AF diagnosis.

As a supplementary analysis, we identified patients with AF as either primary or secondary diagnosis in order to examine differences in OAC initiation related to ‘type of diagnosis’.

Prevalent AF patients

The entire (prevalent) Danish AF population was identified each month since January 2005. The prevalent AF population was defined as the cumulative incidence of incident AF patients since 1974 with dead and migrated patients excluded. Only patients with AF as primary diagnosis were included.

OAC treatment among study patients

OAC initiation was assessed from prescription fills ± 180 days from date of AF diagnosis. Most patients were diagnosed with AF at a hospital with subsequent OAC initiation. However, some patients were diagnosed by their general practitioner, and started on OAC treatment before the first hospital contact and thereby registration of the AF diagnosis. OAC utilization among the prevalent AF patients at a given month was defined from OAC prescription fills within 180 days before the particular month.

In Denmark, dabigatran was introduced to the market 22 August 2011, rivaroxaban 6 February 2012, and apixaban 10 December 2012. Edoxaban was introduced in Denmark 2016, and thus, is not part of this analysis.

Comorbidities and concomitant pharmacotherapy

Concomitant pharmacotherapy was determined from prescription fills 180 days before inclusion date. Comorbidities were identified from previous hospital admissions with ICD 10 diagnosis codes up to 10 years before inclusion date (see Supplementary material online, Appendix).

Hypertension was defined from related prescription fills and alcohol abuse was defined from related prescription fills and ICD-10 diagnosis codes (see Supplementary material online, Appendix, for definition). The estimated risk of stroke (CHA2DS2-VASc score [congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, history of stroke/transient ischemic attack/systemic thromboembolism, vascular disease, age 65–74 years, and female gender]) and bleeding (HAS-BLED [hypertension, abnormal renal/liver function, history of stroke, history of bleeding, labile International Normalized Ratio (left out due to missing data), age > 65 years, and drug consumption with antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse]) was calculated similar to previous studies.5,12

Statistical analysis

Comparisons of baseline characteristics were performed using the Kruskal–Wallis test for continuous variables and for categorical variables the χ2 test was used. The Cochran–Armitage trend test was used to examine temporal trends in OAC initiation and utilization over time.

Multiple logistic regression was used to estimate odds ratios of being initiated on OAC therapy according to different patient related factors. The first analysis was adjusted for sex, age group, time period, and comorbidities and a test for interaction with time was done (Figure 4). The second analysis contained patients stratified by their calculated CHA2DS2-VASC scores (Figure 6). A P value <0.05 was considered statistical significant.

Data management and statistical analyses were performed using SAS software (SAS version 9.4, SAS Institute, Cary, NC, USA). Figures were created in R (R version 3.2.2, R Foundation for Statistical Computing).

Ethics

Retrospective registry-based studies do not require approval from the Research Ethics Committee System. The Danish Data Protection Agency had approved use of data for this study (ref. no: 2007-58-0015/GEH-2014-012 I-Suite no: 02720).

Results

In total, 108,410 patients were included in the study population; 52.4% of the patients initiated OAC treatment in relation to the AF diagnosis (38.1% initiated VKA and 14.3% initiated NOAC). Selection of the study cohort is depicted in Figure 1.
Selection process of the incident AF patients.
Figure 1

Selection process of the incident AF patients.

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Baseline characteristics

Patient characteristics according to OAC initiation at time of AF diagnosis are shown in Table 1. About 52.1% of the non-initiators were male compared with 58.4% of the OAC initiators. The median age (inter quartile range [IQR]) was slightly higher among non-initiators (72 years [61–82]) compared with the OAC initiators (71 years [64–78]) (P < 0.01) and non-initiators were more frequently either <65 years or ≥75 years. No major difference was seen in the estimated risk of stroke and bleeding (mean CHA2DS2-VASc and mean HAS-BLED score). Females were overall older than men at time of AF diagnosis (median age [IQR]: 75 years [66–83] and 68 years [60–77], respectively). Baseline characteristics according to choice of OAC are shown in the supplementary material (see Supplementary material online, Table S1).

Table 1
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Patient characteristics for incident AF patients according to baseline OAC initiation

VariableNo OAC initiationOAC initiationP value
Patient characteristics
 Number of patients (%)51 590 (47.6)56 820 (52.4)
 Male sex (%)26 864 (52.1)33 206 (58.4)<0.001
 Age, median [IQR]72.0 [61.0–82.0]71.00 [64.0–78.0]<0.001
 Age groups (%)<0.001
  <65 years17 120 (33.2)15 291 (26.9)
  65–74 years12 027 (23.3)20 044 (35.3)
  ≥75 years22 443 (43.5)21 485 (37.8)
 CHA2DS2-VASc, mean (SD)2.56 (1.76)2.53 (1.55)0.001
 CHA2DS2-VASc, groups (%)<0.001
  CHA2DS2-VASc = 07115 (13.8)5609 (9.9)
  CHA2DS2-VASc = 19245 (17.9)9781 (17.2)
  CHA2DS2-VASc ≥ 235 230 (68.3)41 430 (72.9)
 HAS-BLED, mean (SD)1.83 (1.27)1.90 (1.16)<0.001
Comorbidities (%)
 Stroke5887 (11.4)6050 (10.6)<0.001
 Myocardial infarction4157 (8.1)3526 (6.2)<0.001
 Ischaemic heart disease11 506 (22.3)10 061 (17.7)<0.001
 Peripheral artery disease2138 (4.1)1554 (2.7)<0.001
 Heart failure8320 (16.1)8182 (14.4)<0.001
 Chronic kidney disease2620 (5.1)3 (3.2)<0.001
 Abnormal liver function895 (1.7)562 (1.0)<0.001
 Bleeding7166 (13.9)5224 (9.2)<0.001
 Hypertension19 357 (37.5)25 608 (45.1)<0.001
 Diabetes mellitus5010 (9.7)6155 (10.8)<0.001
 Alcohol abuse2128 (4.1)1323 (2.3)<0.001
Concomitant medication (%)
 Acetylsalicylic acid16 978 (32.9)20 316 (35.8)<0.001
 Dipyridamole1400 (2.7)1894 (3.3)<0.001
 ADPa receptor inhibitors2637 (5.1)3157 (5.6)<0.001
 NSAIDb7691 (14.9)9203 (16.2)<0.001
 Non-loop-diuretics15 412 (29.9)19 654 (34.6)<0.001
 Loop-diuretics11 897 (23.1)9760 (17.2)<0.001
 Beta-blockers17 478 (33.9)22 088 (38.9)<0.001
 Calcium channel blockers10 778 (20.9)15 126 (26.6)<0.001
 RAS-inhibitorsc17 695 (34.3)17 025 (41.2)<0.001
 Digoxin5812 (11.3)4055 (9.8)<0.001
 Amiodarone778 (1.5)483 (1.2)<0.001
VariableNo OAC initiationOAC initiationP value
Patient characteristics
 Number of patients (%)51 590 (47.6)56 820 (52.4)
 Male sex (%)26 864 (52.1)33 206 (58.4)<0.001
 Age, median [IQR]72.0 [61.0–82.0]71.00 [64.0–78.0]<0.001
 Age groups (%)<0.001
  <65 years17 120 (33.2)15 291 (26.9)
  65–74 years12 027 (23.3)20 044 (35.3)
  ≥75 years22 443 (43.5)21 485 (37.8)
 CHA2DS2-VASc, mean (SD)2.56 (1.76)2.53 (1.55)0.001
 CHA2DS2-VASc, groups (%)<0.001
  CHA2DS2-VASc = 07115 (13.8)5609 (9.9)
  CHA2DS2-VASc = 19245 (17.9)9781 (17.2)
  CHA2DS2-VASc ≥ 235 230 (68.3)41 430 (72.9)
 HAS-BLED, mean (SD)1.83 (1.27)1.90 (1.16)<0.001
Comorbidities (%)
 Stroke5887 (11.4)6050 (10.6)<0.001
 Myocardial infarction4157 (8.1)3526 (6.2)<0.001
 Ischaemic heart disease11 506 (22.3)10 061 (17.7)<0.001
 Peripheral artery disease2138 (4.1)1554 (2.7)<0.001
 Heart failure8320 (16.1)8182 (14.4)<0.001
 Chronic kidney disease2620 (5.1)3 (3.2)<0.001
 Abnormal liver function895 (1.7)562 (1.0)<0.001
 Bleeding7166 (13.9)5224 (9.2)<0.001
 Hypertension19 357 (37.5)25 608 (45.1)<0.001
 Diabetes mellitus5010 (9.7)6155 (10.8)<0.001
 Alcohol abuse2128 (4.1)1323 (2.3)<0.001
Concomitant medication (%)
 Acetylsalicylic acid16 978 (32.9)20 316 (35.8)<0.001
 Dipyridamole1400 (2.7)1894 (3.3)<0.001
 ADPa receptor inhibitors2637 (5.1)3157 (5.6)<0.001
 NSAIDb7691 (14.9)9203 (16.2)<0.001
 Non-loop-diuretics15 412 (29.9)19 654 (34.6)<0.001
 Loop-diuretics11 897 (23.1)9760 (17.2)<0.001
 Beta-blockers17 478 (33.9)22 088 (38.9)<0.001
 Calcium channel blockers10 778 (20.9)15 126 (26.6)<0.001
 RAS-inhibitorsc17 695 (34.3)17 025 (41.2)<0.001
 Digoxin5812 (11.3)4055 (9.8)<0.001
 Amiodarone778 (1.5)483 (1.2)<0.001
a

Adenosine diphosphate.

b

Nonsteroidal anti-inflammatory drugs.

c

Renin–Angiotensin system.

Table 1
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Patient characteristics for incident AF patients according to baseline OAC initiation

VariableNo OAC initiationOAC initiationP value
Patient characteristics
 Number of patients (%)51 590 (47.6)56 820 (52.4)
 Male sex (%)26 864 (52.1)33 206 (58.4)<0.001
 Age, median [IQR]72.0 [61.0–82.0]71.00 [64.0–78.0]<0.001
 Age groups (%)<0.001
  <65 years17 120 (33.2)15 291 (26.9)
  65–74 years12 027 (23.3)20 044 (35.3)
  ≥75 years22 443 (43.5)21 485 (37.8)
 CHA2DS2-VASc, mean (SD)2.56 (1.76)2.53 (1.55)0.001
 CHA2DS2-VASc, groups (%)<0.001
  CHA2DS2-VASc = 07115 (13.8)5609 (9.9)
  CHA2DS2-VASc = 19245 (17.9)9781 (17.2)
  CHA2DS2-VASc ≥ 235 230 (68.3)41 430 (72.9)
 HAS-BLED, mean (SD)1.83 (1.27)1.90 (1.16)<0.001
Comorbidities (%)
 Stroke5887 (11.4)6050 (10.6)<0.001
 Myocardial infarction4157 (8.1)3526 (6.2)<0.001
 Ischaemic heart disease11 506 (22.3)10 061 (17.7)<0.001
 Peripheral artery disease2138 (4.1)1554 (2.7)<0.001
 Heart failure8320 (16.1)8182 (14.4)<0.001
 Chronic kidney disease2620 (5.1)3 (3.2)<0.001
 Abnormal liver function895 (1.7)562 (1.0)<0.001
 Bleeding7166 (13.9)5224 (9.2)<0.001
 Hypertension19 357 (37.5)25 608 (45.1)<0.001
 Diabetes mellitus5010 (9.7)6155 (10.8)<0.001
 Alcohol abuse2128 (4.1)1323 (2.3)<0.001
Concomitant medication (%)
 Acetylsalicylic acid16 978 (32.9)20 316 (35.8)<0.001
 Dipyridamole1400 (2.7)1894 (3.3)<0.001
 ADPa receptor inhibitors2637 (5.1)3157 (5.6)<0.001
 NSAIDb7691 (14.9)9203 (16.2)<0.001
 Non-loop-diuretics15 412 (29.9)19 654 (34.6)<0.001
 Loop-diuretics11 897 (23.1)9760 (17.2)<0.001
 Beta-blockers17 478 (33.9)22 088 (38.9)<0.001
 Calcium channel blockers10 778 (20.9)15 126 (26.6)<0.001
 RAS-inhibitorsc17 695 (34.3)17 025 (41.2)<0.001
 Digoxin5812 (11.3)4055 (9.8)<0.001
 Amiodarone778 (1.5)483 (1.2)<0.001
VariableNo OAC initiationOAC initiationP value
Patient characteristics
 Number of patients (%)51 590 (47.6)56 820 (52.4)
 Male sex (%)26 864 (52.1)33 206 (58.4)<0.001
 Age, median [IQR]72.0 [61.0–82.0]71.00 [64.0–78.0]<0.001
 Age groups (%)<0.001
  <65 years17 120 (33.2)15 291 (26.9)
  65–74 years12 027 (23.3)20 044 (35.3)
  ≥75 years22 443 (43.5)21 485 (37.8)
 CHA2DS2-VASc, mean (SD)2.56 (1.76)2.53 (1.55)0.001
 CHA2DS2-VASc, groups (%)<0.001
  CHA2DS2-VASc = 07115 (13.8)5609 (9.9)
  CHA2DS2-VASc = 19245 (17.9)9781 (17.2)
  CHA2DS2-VASc ≥ 235 230 (68.3)41 430 (72.9)
 HAS-BLED, mean (SD)1.83 (1.27)1.90 (1.16)<0.001
Comorbidities (%)
 Stroke5887 (11.4)6050 (10.6)<0.001
 Myocardial infarction4157 (8.1)3526 (6.2)<0.001
 Ischaemic heart disease11 506 (22.3)10 061 (17.7)<0.001
 Peripheral artery disease2138 (4.1)1554 (2.7)<0.001
 Heart failure8320 (16.1)8182 (14.4)<0.001
 Chronic kidney disease2620 (5.1)3 (3.2)<0.001
 Abnormal liver function895 (1.7)562 (1.0)<0.001
 Bleeding7166 (13.9)5224 (9.2)<0.001
 Hypertension19 357 (37.5)25 608 (45.1)<0.001
 Diabetes mellitus5010 (9.7)6155 (10.8)<0.001
 Alcohol abuse2128 (4.1)1323 (2.3)<0.001
Concomitant medication (%)
 Acetylsalicylic acid16 978 (32.9)20 316 (35.8)<0.001
 Dipyridamole1400 (2.7)1894 (3.3)<0.001
 ADPa receptor inhibitors2637 (5.1)3157 (5.6)<0.001
 NSAIDb7691 (14.9)9203 (16.2)<0.001
 Non-loop-diuretics15 412 (29.9)19 654 (34.6)<0.001
 Loop-diuretics11 897 (23.1)9760 (17.2)<0.001
 Beta-blockers17 478 (33.9)22 088 (38.9)<0.001
 Calcium channel blockers10 778 (20.9)15 126 (26.6)<0.001
 RAS-inhibitorsc17 695 (34.3)17 025 (41.2)<0.001
 Digoxin5812 (11.3)4055 (9.8)<0.001
 Amiodarone778 (1.5)483 (1.2)<0.001
a

Adenosine diphosphate.

b

Nonsteroidal anti-inflammatory drugs.

c

Renin–Angiotensin system.

Temporal trends in OAC prescription among the incident and prevalent AF patients

OAC initiation rates among the incident AF patients decreased from 46.3% in January 2005 to 38.1% in December 2009 (P < 0.0001 for trend). From 2010, more patients were initiated on OAC therapy (P < 0.0001 for trend) and by June 2015, 66.5% of the incident AF patients initiated treatment with an OAC (74.5% increase since December 2009) (Figure 2, red curve). When we considered incident patients eligible for OAC treatment (men with a CHA2DS2-VASc score ≥ 1 and women with a CHA2DS2-VASc score ≥ 2), only a few extra percent initiated treatment compared to the total AF population (69.6% in June 2015). When we excluded patients with comorbidities which would likely lessen the likelihood of OAC initiation (alcohol abuse, bleeding and vascular disease), the OAC initiation rates only increased slightly (68.6% in June 2015).
Temporal trends in OAC initiation and overall utilization. The red curve illustrates OAC initiation among the incident AF patients. The blue curve illustrates OAC utilization among the prevalent AF patients.
Figure 2

Temporal trends in OAC initiation and overall utilization. The red curve illustrates OAC initiation among the incident AF patients. The blue curve illustrates OAC utilization among the prevalent AF patients.

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From 2011, more prevalent AF patients were treated with an OAC (P < 0.0001 for trend); 47.0% utilized OAC in January 2011 and by June 2015, 63.2% of the prevalent AF population was treated with an OAC (Figure 2, blue curve).

Trends in choice of OAC

Figure 3 illustrates trends in choice of OAC (VKA or NOAC) among newly diagnosed AF patients. From 2011, a decreasing proportion of the newly diagnosed AF patients was initiated on VKA (P< 0.0001 for trend). This decrease in VKA initiation was followed by a rapid increase in NOAC initiation (P < 0.0001 for trend) and by June 2015, 48.3% initiated treatment with a NOAC (72.6% of the OAC initiators were prescribed NOAC).
Temporal trends in overall OAC initiation, initiation with VKA, and initiation with NOAC.
Figure 3

Temporal trends in overall OAC initiation, initiation with VKA, and initiation with NOAC.

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Factors associated with OAC initiation

Figure 4 displays factors associated with OAC initiation before and after 2010. Male gender was associated with more OAC initiation in both periods. However, as depicted in, see Supplementary material online, FiguresS7 and S9, from 2010, the difference in gender-specific initiation rates decreased and, in the first 6 months of 2015, an equal fraction of men and women were initiated on OAC. In a sub-analysis, the difference in gender-related odds ratios associated with OAC initiation likewise decreased from 2011.
Odds ratios associated with OAC initiation versus no OAC initiation before and after 2010, according to gender, age, calendar year and co-morbidity. *Significant change in OR from <2010 to ≥2010.
Figure 4

Odds ratios associated with OAC initiation versus no OAC initiation before and after 2010, according to gender, age, calendar year and co-morbidity. *Significant change in OR from <2010 to ≥2010.

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The odds of OAC initiation were the highest among 65–74 year old patients. From 2010, patients ≥75 years of age were more likely to be initiated on OAC compared with patients <65 years old. Figure 5 illustrates the temporal trends in OAC initiation according to age. All age groups experienced increasing initiation rates from 2010, more pronounced in patients ≥75 years of age.
OAC initiation according to age at time of AF diagnosis.
Figure 5

OAC initiation according to age at time of AF diagnosis.

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Hypertension was associated with OAC initiation whereas vascular disease, previous bleeding, and alcohol abuse was associated with absence of treatment in both periods. From 2010, heart failure was associated with the absence of treatment. From <2010 to ≥ 2010, the OR for OAC initiation significantly increased in patients aged 65–74 and >75 years, and in patients with hypertension or vascular disease whereas the OR for males and patients with heart failure decreased.

In, see Supplementary material online, Figure S9, we used segmented linear regression to find ‘breakpoints’ and obtain the relations in the intervals. We examined age, gender, CHA2DS2-VASc groups, and co-morbidities, and, for all factors, we found increased OAC initiation around 2010.

Figure 6 illustrates the likelihood of being initiated on OAC according to the individual CHA2DS2-VASc scores stratified into three sub periods. Patients with a CHA2DS2-VASc score = 2 had the highest likelihood of being initiated on OAC in all sub-periods. From January 2005 to June 2008, CHA2DS2-VASc scores ≥ 5 were associated with lower odds of OAC initiation when compared with a CHA2DS2-VASc score = 0. During our study period, however, the odds increased and from June 2012, no CHA2DS2-VASc scores were associated with significant lower odds of OAC initiation when compared with CHA2DS2-VASc = 0. The odds of being initiated on OAC for all CHA2DS2-VASc scores increased over time. Similar results were found for the HAS-BLED score (see Supplementary material online, FigureS8).
Odds ratios associated with OAC initiation versus no OAC initiation according to CHA2DS2-VASc scores stratified by time.
Figure 6

Odds ratios associated with OAC initiation versus no OAC initiation according to CHA2DS2-VASc scores stratified by time.

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Difference in type of diagnosis

The overall pattern of OAC initiation and AF incidence among patients with either primary or secondary AF was similar to that of AF as primary diagnosis alone (see Supplementary material online, Figure S2). However, patients with AF as either primary or secondary diagnosis were 18.4% less frequently initiated on OAC treatment throughout the study period.

Discussion

The main purpose of this nationwide study was to investigate temporal trends in OAC initiation among incident AF patients and furthermore to investigate factors associated with OAC initiation. Our principal findings were as follows: (i) since 2010, more incident AF patients were initiated on OAC treatment; by June 2015, 66.5% of the incident AF patients initiated OAC therapy; (ii) NOACs have replaced VKA as the OAC of choice in AF and by June 2015, NOACs accounted for 72.6% of all OACs prescribed in incident AF; (iii) In particular, male sex, a CHA2DS2-VASc score = 2, and a patient age of 65–74 years were factors associated with initiation of OAC treatment.

Previous OAC underuse among AF patients

Before 2010, <50% of the incident and prevalent AF patients in Denmark were prescribed OAC. Increased AF incidence and a constant number of patients initiated on OAC even caused a slight decrease in the initiation rates. Several other studies have demonstrated similar low rates of OAC use.3–6 Before 2006, OAC treatment was reserved patients at high risk of stroke and acetylsalicylic acid was widely used in patients at low and moderate risk.18 Thus, the low-treatment rates do not necessarily reflect deviation from temporal guidelines on AF management, but rather another consensus on the use of OAC treatment.

Increased use of OAC in patients with AF

Several studies have stressed the beneficial effects of VKA treatment in patients with AF. In a meta-analysis, VKA treatment reduced the risk of ischemic stroke by 67% and reduced the risk of all-cause mortality by 26% with only a slight increase in the risk of intracranial hemorrhage.2

The ACC/AHA/ESC 2006 guidelines for the management of patients with AF introduced different risk stratification schemes (e.g. the CHADS2 score) and recommended VKA for patients with two or more moderate risk factors.18 In August 2010, ESC guidelines on AF management included the use of the CHA2DS2-VASc score and recommended OAC for all AF patients at moderate to high risk of stroke (i.e. CHA2DS2-VASc score ≥ 1)7; in the 2012 updated guidelines, acetylsalicylic acid was no longer recommended as stroke prophylaxis in low-risk AF patients, unless they refused or were ineligible for any type of OAC.19 Increased awareness, physicians becoming more familiar with the CHADS2 and CHA2DS2-VASc score, and more specific guidelines on AF management are possible explanations of the increased OAC use seen in our study since 2010/11. Reasons for the improvement in OAC initiation rates may also be explained by better monitoring of INR in anticoagulation clinics and better infrastructure of care processes.

In addition, the increased OAC initiation and utilization were likely influenced by the introduction and availability of the NOACs. Large clinical trials9–11 have shown relative efficacy, safety, and convenience of the NOACs compared with VKA, and these novel alternatives to VKA have likely contributed to increased OAC prescriptions.

Other studies support our findings. Kirchhof et al.20 examined the management of patients with AF in seven European countries after the release of the 2010 ESC guidelines (during 2012). According to their results, >80% received OAC in this period. Lip et al.21 found similar results with ∼80% receiving OAC in a cohort of AF patients between February 2012 and March 2013. Both studies included in- and outpatients followed by a cardiologist, and this may be the reason for the higher treatment rates observed since specialists are more likely to prescribe OAC.22

The most recent 2016 ESC guidelines for the management of AF recommend using the CHA2DS2-VASc score in order to identify truly low-risk AF patients with no benefit of OAC treatment. Furthermore, NOACs are now recommended over VKA in eligible patients.23

Factors associated with OAC initiation

After adjustment for age and comorbidities, females were less likely to be initiated on OAC compared with men. This is surprising since females are at increased risk of stroke5,24 and possibly derive the greatest benefit from OAC treatment.25,26 Other studies have found similar results,4,27 but reasons behind OAC underuse in women is not well examined. Our results suggest, however, that gender differences in terms of OAC initiation has been minimized in recent years (see Supplementary material online, Figure S7) and this might be associated with the introduction of the CHA2DS2-VASc score where female gender counts as a risk factor.

Nelson et al. found better INR control among men compared with women,28 but clinicians decision on OAC initiation are most likely not influenced by this knowledge. Females were older than men when diagnosed with AF, which presumably contributed to fewer women initiated on OAC (especially before 2010). Other factors associated with reduced OAC initiation (bleeding, alcohol abuse and vascular disease) were predominant among males.

We found a distinctive increase in OAC initiation among ‘fragile’ patients who were previously undertreated. Older age have previously been associated with less OAC initiation4,27 and before 2010, this was also found in our study. From 2010, however, OAC initiation rates increased substantially among patients ≥75 years and exceeded the initiation rates in patients <65 years.

The odds of being initiated on OAC for all CHA2DS2-VASc scores increased over time and at study end no CHA2DS2-VASc score was associated with less OAC initiation when compared with low-risk patients. OAC initiation was most likely in patients with a CHA2DS2-VASc score =2 which was also found by Lip et al.21

Strengths and limitations

The main limitation of the study is inherited in the observational nature of the design. The Danish registries lack relevant information on left ventricle ejection fraction, labile INR, body mass index, smoking, and alcohol consumption. Thus, specific information on indications or contraindications in the clinical decision for initiating or withholding OAC treatment is not available in the registries. Finally, temporal trends observed in this study do not necessarily reflect the patterns in other countries or ethnicities.

The quality of data in the Danish registries, however, allowed us to identify the entire cohort of patients diagnosed with AF at Danish hospitals and outpatient clinics from January 2005 to June 2015. We chose to include only patients with AF as primary diagnosis. In the incident population, AF as primary or secondary diagnosis led to an 18.4% lower initiation rate during the 10½ year study period.

Conclusion

Since 2010, more incident AF patients were initiated on OAC therapy with predominant NOAC prescription. By June 2015, 66.5% initiated therapy (a 74.5% increase since December 2009). Among patients eligible for OAC treatment, 69.6% initiated treatment in June 2015. The increase was pronounced among females, among patients at high risk of stroke, and among older patients. Male gender, age >65 years, and high risk of stroke were factors associated with initiation of OAC treatment.

Supplementary material

Supplementary material is available at European Heart Journal online.

Funding

This work was supported by an unrestricted grant from Bristol-Myers Squibb.

Conflict of interest: K.G., E.L.F., A.G., and J.B.O. have received funding for research from BMS. L.S. and G.G. have received funding from BI. E.L.F. and J.B.O. have received funding from the Lundbeck Foundation. E.L.F. has received funding from Janssen pharmaceuticals. J.B.O. has received speaker fees from BMS, BI, and Bayer. G.Y.H.L. has been speaker- and served as a consultant for Bayer, BMS/Pfizer, Medtronic, BI, Microlife, and Daiichi-Sankyo. G.Y.H.L has served as consultant for Biotronik and speaker for Roche. G.G. have received funding from Pfizer, AstraZeneca, and Bayer and declares ownership of stock in Lundbeck A/S, NovoNordisk A/S, and ALK Abello pharmaceuticals.

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