TY - JOUR
AU - Frost,, Lars
AB - Abstract Aim To explore the potential of small-area variation analysis as a tool for identifying unwarranted variation in oral anticoagulation (OAC) use and clinical outcomes in patients with atrial fibrillation (AF) and thereby identify locations with opportunity for improvement in AF care. Methods and results Based on Danish health care registries, we conducted a nationwide historical cohort study including first-time AF patients with a CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75, diabetes, thromboembolism, vascular disease, age 65–74, and sex category) score ≥ 2 between 2007 and 2014 (n = 94 482). For each administrative region and municipality, we assessed OAC initiation and persistence as well as the risk of ischaemic stroke, haemorrhagic stroke, and other major bleeding, respectively. In addition, potential temporal changes were examined for all outcomes. Initiation of OAC varied among regions from 49.5% to 62.4%. In patients initiating OAC, the proportion of patients still receiving OAC after 1 year varied from 73.9% to 79.3%. Oral anticoagulation use increased in all regions during the study period, particularly after 2010, but regional variation in OAC initiation persisted. Generally, the regions and municipalities with the highest initiation of OAC also had the highest OAC persistence. The risk of ischaemic stroke and other major bleeding was lower in these regions and municipalities. We found no significant difference between regions in risk of haemorrhagic stroke. Conclusion Substantial geographical variation in OAC use and clinical outcomes occurs in Denmark demonstrating the potential of small-area variation analysis as a tool for identifying unwarranted variation in AF care and clinical outcomes. Our findings demonstrate the need for additional initiatives to ensure uniform high-quality care for AF patients. Atrial fibrillation , Oral anticoagulation , Stroke , Small-area analysis , Unwarranted variation Introduction The high and steadily increasing prevalence of atrial fibrillation (AF) requires continuous improvements in AF care in order to meet the growing burden.1,2 Important advances in AF care have indeed been made in recent years. In 2010, the European Society of Cardiology (ESC) published new and highly profiled guidelines.3 Furthermore, the non-vitamin K antagonist (VKA) oral anticoagulants (NOAC) have been introduced,4 and in several health care systems, structured care for AF patients has evolved.5 Quality of care and clinical outcomes for AF patients vary between regions of the world,6–8 whereas little is known about geographical variation within nations.9–11 Furthermore, it is unknown whether the advances in AF care have led to a more homogeneous quality of care. Analyses of small-area variation in use of effective therapies have previously been demonstrated as an effective tool for identifying and characterizing unwarranted variation in health care.12 Analyses of small-area variation may hereby facilitate targeted interventions to change practice and improve patient outcome.12 Therefore, the objective of this study was to explore the potential of small-area variation analysis as a tool for identifying unwarranted variation in oral anticoagulation (OAC) use and clinical outcomes in patients with AF and thereby identify locations with opportunity for improvement in AF care. We examined the extent of inter-regional and inter-municipal unwarranted variation as well as temporal trends in initiation and persistence of OAC and clinical outcomes, including the incidence of ischaemic stroke, haemorrhagic stroke, and other major bleeding. Methods Setting In Denmark, the health care system is tax-supported, built on the principle that all citizens have the right to free and equal health services provided by general practitioners and hospitals and partly reimbursement of expenditures to medication.13 Since 1 January 2007, the administrative structure in Denmark has consisted of 5 regions and 98 municipalities. The regions are responsible for the hospitals and health services provided by private specialists and general practitioners.13 The regions manage these health care facilities in line with regional requests and available facilities.13 The municipalities are responsible for local administration of home nursing, rehabilitation, and other local health services.13 Data sources This historical cohort study was based on the following data sources: The Danish National Patient Registry (DNPR) contains comprehensive information on all somatic and psychiatric patients from Danish hospitals.14 We retrieved data on all somatic diagnoses, examinations, operations, and administrative data including the patient’s municipality of residence at baseline. The Danish National Database of Reimbursed Prescriptions contains data about prescriptions on reimbursed medication filled at a community pharmacy or a hospital-based outpatient pharmacy since 2004.15 The Danish Civil Registration System contains information on gender, date of birth, place of residence, and continuously updated information on vital status.16 We retrieved the most recent update for each patient on vital status and emigration status. Data from the national registries were linked on an individual level by the personal registration number (CPR number), which is used in all Danish public registries enabling linkage between them. Codes for diseases, procedures, and drugs are available in Supplementary material online, Table S4. Study population and patient characteristics We included all patients aged ≥ 40 and < 90 years with a first-time diagnosis of non-valvular AF17 reported from a hospital or an outpatient clinic to the DNPR in the period 1 January 2007 to 31 December 2014. We only included patients with a CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75, diabetes, thromboembolism, vascular disease, age 65–74, and sex category) score ≥ 2, since the ESC 2010 guidelines unambiguously recommended OAC for AF patients with CHA2DS2-VASc ≥ 2.3 For inpatients, we considered the discharge date of the total hospitalization period as baseline (Day 0) to ensure that the index hospitalization was ended. For outpatients, the date of AF diagnosis was baseline. We excluded patients with observation time ≤ 0 days from baseline, discharge date later than 31 December 2014, or invalid municipality. We estimated a modified HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalised ratio (INR), elderly, drugs or alcohol) score without labile INR, since data on INR were not available. We obtained diagnosis and operation codes reported in a window of 10 years before baseline and a 1-year time window before baseline for prescription history. Outcomes We defined initiation of OAC as filling at least one prescription of any OAC within 90 days after baseline. We further specified the type of the first filled prescription within 90 days after baseline as either VKA or NOAC. Additionally, we identified OAC initiation in combination with antiplatelet (AP) treatment as filling at least one prescription of any OAC and at least one prescription of AP within 90 days after baseline. The measure of persistence was assessed only in patients who had filled a prescription of OAC within 90 days after baseline and were still alive and not emigrated at Day 365. Persistence was defined as filling at least one prescription of OAC from Day 365 and 90 days forward, i.e. Day 365–455 after baseline. For clinical outcomes, we measured the cumulative incidence of ischaemic stroke, haemorrhagic stroke, and other major bleeding 1 year after baseline. Intracranial bleeding was investigated as a supplementary analysis. Further definition and codes are available in Supplementary material online, Table S4. Statistical methods We used the pseudo-values approach to estimate the cumulative incidence function at a fixed time point with death considered a competing event.18–20 We first estimated the cumulative incidence of any OAC prescription redemption after 90 days and clarified whether this first filled prescription after baseline was a prescription of VKA or NOAC. We further estimated the cumulative incidence of both OAC and AP prescription redemption within 90 days. The outcome of OAC persistence was estimated for all patients who had filled a prescription of any OAC within 90 days after baseline and were still alive and not emigrated at Day 365. For these patients, we estimated the cumulative incidence of OAC prescription redemption from Day 365 and 90 days forward, i.e. Day 365–455 after baseline. For the clinical outcomes, we estimated the cumulative incidence after 1 year. For the clinical outcomes by region, we used the Aalen Johansen estimator to plot cumulative incidence functions, considering death as a competing event, and used time since baseline as underlying time scale. To examine temporal development for all outcomes, we estimated the cumulative incidence for each calendar year for regions and each 2-year interval for municipalities. To compare AF care across regions and municipalities, we analysed the pseudo-values for each outcome in generalized linear models and thereby estimated relative risks (RRs) and risk differences (RDs) between regions and between municipalities. We used the Capital Region and Copenhagen as reference region and municipality, respectively. For the two treatment outcomes, we exclusively calculated unadjusted estimates, since all patients had a CHA2DS2-VASc ≥ 2 and therefore by definition an indication for OAC treatment. For the clinical outcomes, we adjusted for age (linearly) and sex in model 1. In model 2 for ischaemic stroke, we further adjusted for the components of CHA2DS2-VASc, statins, AP drugs, and non-steroidal anti-inflammatory drug. In model 2 for the bleeding outcomes beyond age and sex, we further adjusted for the components of the modified HAS-BLED. For each clinical outcome, we used the fully adjusted RD from the best presenting region to estimate the number of events that potentially could have been prevented assuming that the differences found represent a causal effect (calculations in Supplementary material online, Tables S1–3). To examine the correlation between OAC initiation and the other outcomes, for regions and municipalities, we plotted the cumulative incidence of OAC initiation against the cumulative incidence of OAC persistence and against the fully adjusted RDs of the clinical outcomes. We also plotted linear fit prediction plots based on the municipality-specific estimates weighted according to population size. We tested the null hypotheses of no difference between administrative areas with likelihood ratio tests. For all estimates, we used 95% confidence intervals (CI) to illustrate statistical precision. All analyses were performed using STATA version 14.1, College Station, TX, USA. Ethics The study was approved by The Danish Data Protection Agency (1-16-02-356-15). In Denmark, registry based studies do not require approval from an Ethics Committee. Results Patient characteristics A total of 94 482 patients fulfilled the inclusion criteria (see Supplementary material online, Figure S1 for flow chart). Of these, 47 213 (50.0%) initiated OAC therapy within 90 days, were still alive and not emigrated after 1 year and hence eligible for the analyses of persistence (Supplementary material online, Figure S1). Table 1 presents patient characteristics at baseline according to region. The study population had a median age of 76 years (interquartile range 69–82) and 51.5% were women. Previous stroke and bleeding were most prevalent in the Capital Region (17.1% and 16.2%, respectively) and least prevalent in Region North (12.4% and 12.6%, respectively), but CHA2DS2-VASc and HAS-BLED scores did not vary substantially between the regions. Table 1 Baseline characteristics of atrial fibrillation patients with CHA2DS2-VASc score ≥2 by region Characteristics Total North Central South Capital Zealand Overall, % (n) 100.0 (94 482) 10.8 (10 221) 21.7 (20 503) 22.1 (20 886) 28.4 (26 847) 17.0 (16 025) Women, % (n) 51.5 (48 618) 50.7 (5180) 50.5 (10 566) 50.6 (10 566) 53.8 (14 440) 50.4 (8070) Age, median (IQR), years 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) Incidence year, % (n)  2007 10.7 (10 124) 12.0 (1231) 10.8 (2210) 11.2 (2332) 10.3 (2767) 9.9 (1584)  2008 11.1 (10 451) 11.0 (1126) 11.0 (2252) 10.9 (2270) 11.1 (2973) 11.4 (1830)  2009 11.4 (10 767) 11.6 (1187) 10.8 (2213) 11.3 (2354) 12.2 (3264) 10.9 (1749)  2010 12.1 (11 460) 12.1 (1239) 11.8 (2425) 12.0 (2496) 12.5 (3361) 12.1 (1939)  2011 12.7 (11 986) 12.1 (1239) 13.1 (2694) 12.6 (2626) 12.8 (3437) 12.4 (1990)  2012 13.5 (12 792) 13.2 (1349) 14.4 (2959) 13.2 (2753) 12.9 (3468) 14.1 (2263)  2013 14.2 (13 381) 13.7 (1400) 13.8 (2833) 14.9 (3120) 13.7 (3689) 14.6 (2339)  2014 14.3 (13 521) 14.2 (1450) 14.2 (2917) 14.1 (2935) 14.5 (3888) 14.6 (2331) Comorbiditya, % (n)  Abnormal liver function 1.5 (1401) 1.1 (114) 1.3 (262) 1.3 (274) 1.9 (497) 1.6 (254)  Abnormal renal function 6.2 (5830) 5.3 (538) 6.8 (1395) 6.1 (1267) 6.1 (1642) 6.2 (988)  Alcohol related disease 3.4 (3220) 2.3 (235) 2.7 (552) 2.8 (589) 4.8 (1296) 3.4 (548)  Bleeding 14.7 (13 923) 12.6 (1286) 14.3 (2931) 14.5 (3025) 16.2 (4339) 14.6 (2342)  Congestive heart failure 12.8 (12 051) 10.9 (1116) 12.9 (2652) 12.9 (2694) 12.6 (3392) 13.7 (2197)  Diabetes mellitus 18.8 (17 786) 18.3 (1874) 18.0 (3686) 18.7 (3901) 19.3 (5171) 19.7 (3154)  Hypertension 72.3 (68 313) 75.3 (7696) 73.9 (15157) 73.3 (15 302) 69.3 (18 595) 72.2 (11 563)  Thromboembolism 18.6 (17 582) 16.1 (1644) 18.3 (3751) 18.0 (3758) 20.3 (5437) 18.7 (2992)   Ischaemic stroke 14.6 (13 770) 11.8 (1201) 14.0 (2870) 13.8 (2882) 16.5 (4416) 15.0 (2401)   Systemic embolism 0.9 (830) 0.8 (79) 0.8 (164) 0.7 (153) 1.1 (286) 0.9 (148)   Transient ischaemic attack 5.4 (5113) 5.4 (552) 5.6 (1137) 5.4 (1119) 5.8 (1543) 4.8 (762)  Stroke 15.2 (14 343) 12.4 (1262) 14.6 (2988) 14.4 (2999) 17.1 (4584) 15.7 (2510)  Vascular disease 21.8 (20 554) 20.5 (2094) 23.8 (4871) 21.5 (4491) 20.4 (5468) 22.7 (3630)   Acute myocardial infarction 11.3 (10 664) 10.2 (1042) 11.9 (2441) 10.3 (2153) 11.5 (3083) 12.1 (1945)   Coronary procedure 13.1 (12 371) 14.0 (1426) 15.8 (3231) 12.6 (2631) 11.2 (3008) 13.0 (2075)   Peripheral artery disease 6.2 (5818) 4.7 (483) 5.8 (1188) 7.1 (1474) 5.8 (1563) 6.9 (1110) Concomitant medicationb, % (n)  Antiplatelet drugs 52.0 (49 130) 52.3 (5350) 56.2 (11 513) 52.3 (10 917) 49.3 (13 239) 50.6 (8111)  NSAID 26.3 (24 836) 26.8 (2734) 24.3 (4978) 26.4 (5513) 26.1 (7005) 28.7 (4606)  Statins 42.3 (39 979) 44.1 (4510) 44.7 (9157) 43.2 (9014) 40.4 (10 845) 40.3 (6453) CHA2DS2-VASc, mean ± SD 3.6 ± 1.4 3.5 ± 1.3 3.6 ± 1.4 3.6 ± 1.4 3.6 ± 1.4 3.6 ± 1.4 HAS-BLEDc, mean ± SD 2.6 ± 1.0 2.6 ± 1.0 2.7 ± 1.0 2.6 ± 1.0 2.6 ± 1.1 2.6 ± 1.0 HAS-BLEDc, % (n)  0 0.6 (573) 0.5 (55) 0.6 (117) 0.5 (108) 0.7 (198) 0.6 (95)  1 13.3 (12 586) 12.7 (1293) 12.7 (2608) 13.0 (2723) 14.3 (3833) 13.3 (2129)  2 30.6 (28 950) 32.3 (3298) 29.9 (6135) 30.6 (6393) 30.6 (8206) 30.7 (4918)  ≥3 55.4 (52 373) 54.5 (5575) 56.8 (11 643) 55.8 (11 662) 54.4 (14 610) 55.4 (8883) Characteristics Total North Central South Capital Zealand Overall, % (n) 100.0 (94 482) 10.8 (10 221) 21.7 (20 503) 22.1 (20 886) 28.4 (26 847) 17.0 (16 025) Women, % (n) 51.5 (48 618) 50.7 (5180) 50.5 (10 566) 50.6 (10 566) 53.8 (14 440) 50.4 (8070) Age, median (IQR), years 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) Incidence year, % (n)  2007 10.7 (10 124) 12.0 (1231) 10.8 (2210) 11.2 (2332) 10.3 (2767) 9.9 (1584)  2008 11.1 (10 451) 11.0 (1126) 11.0 (2252) 10.9 (2270) 11.1 (2973) 11.4 (1830)  2009 11.4 (10 767) 11.6 (1187) 10.8 (2213) 11.3 (2354) 12.2 (3264) 10.9 (1749)  2010 12.1 (11 460) 12.1 (1239) 11.8 (2425) 12.0 (2496) 12.5 (3361) 12.1 (1939)  2011 12.7 (11 986) 12.1 (1239) 13.1 (2694) 12.6 (2626) 12.8 (3437) 12.4 (1990)  2012 13.5 (12 792) 13.2 (1349) 14.4 (2959) 13.2 (2753) 12.9 (3468) 14.1 (2263)  2013 14.2 (13 381) 13.7 (1400) 13.8 (2833) 14.9 (3120) 13.7 (3689) 14.6 (2339)  2014 14.3 (13 521) 14.2 (1450) 14.2 (2917) 14.1 (2935) 14.5 (3888) 14.6 (2331) Comorbiditya, % (n)  Abnormal liver function 1.5 (1401) 1.1 (114) 1.3 (262) 1.3 (274) 1.9 (497) 1.6 (254)  Abnormal renal function 6.2 (5830) 5.3 (538) 6.8 (1395) 6.1 (1267) 6.1 (1642) 6.2 (988)  Alcohol related disease 3.4 (3220) 2.3 (235) 2.7 (552) 2.8 (589) 4.8 (1296) 3.4 (548)  Bleeding 14.7 (13 923) 12.6 (1286) 14.3 (2931) 14.5 (3025) 16.2 (4339) 14.6 (2342)  Congestive heart failure 12.8 (12 051) 10.9 (1116) 12.9 (2652) 12.9 (2694) 12.6 (3392) 13.7 (2197)  Diabetes mellitus 18.8 (17 786) 18.3 (1874) 18.0 (3686) 18.7 (3901) 19.3 (5171) 19.7 (3154)  Hypertension 72.3 (68 313) 75.3 (7696) 73.9 (15157) 73.3 (15 302) 69.3 (18 595) 72.2 (11 563)  Thromboembolism 18.6 (17 582) 16.1 (1644) 18.3 (3751) 18.0 (3758) 20.3 (5437) 18.7 (2992)   Ischaemic stroke 14.6 (13 770) 11.8 (1201) 14.0 (2870) 13.8 (2882) 16.5 (4416) 15.0 (2401)   Systemic embolism 0.9 (830) 0.8 (79) 0.8 (164) 0.7 (153) 1.1 (286) 0.9 (148)   Transient ischaemic attack 5.4 (5113) 5.4 (552) 5.6 (1137) 5.4 (1119) 5.8 (1543) 4.8 (762)  Stroke 15.2 (14 343) 12.4 (1262) 14.6 (2988) 14.4 (2999) 17.1 (4584) 15.7 (2510)  Vascular disease 21.8 (20 554) 20.5 (2094) 23.8 (4871) 21.5 (4491) 20.4 (5468) 22.7 (3630)   Acute myocardial infarction 11.3 (10 664) 10.2 (1042) 11.9 (2441) 10.3 (2153) 11.5 (3083) 12.1 (1945)   Coronary procedure 13.1 (12 371) 14.0 (1426) 15.8 (3231) 12.6 (2631) 11.2 (3008) 13.0 (2075)   Peripheral artery disease 6.2 (5818) 4.7 (483) 5.8 (1188) 7.1 (1474) 5.8 (1563) 6.9 (1110) Concomitant medicationb, % (n)  Antiplatelet drugs 52.0 (49 130) 52.3 (5350) 56.2 (11 513) 52.3 (10 917) 49.3 (13 239) 50.6 (8111)  NSAID 26.3 (24 836) 26.8 (2734) 24.3 (4978) 26.4 (5513) 26.1 (7005) 28.7 (4606)  Statins 42.3 (39 979) 44.1 (4510) 44.7 (9157) 43.2 (9014) 40.4 (10 845) 40.3 (6453) CHA2DS2-VASc, mean ± SD 3.6 ± 1.4 3.5 ± 1.3 3.6 ± 1.4 3.6 ± 1.4 3.6 ± 1.4 3.6 ± 1.4 HAS-BLEDc, mean ± SD 2.6 ± 1.0 2.6 ± 1.0 2.7 ± 1.0 2.6 ± 1.0 2.6 ± 1.1 2.6 ± 1.0 HAS-BLEDc, % (n)  0 0.6 (573) 0.5 (55) 0.6 (117) 0.5 (108) 0.7 (198) 0.6 (95)  1 13.3 (12 586) 12.7 (1293) 12.7 (2608) 13.0 (2723) 14.3 (3833) 13.3 (2129)  2 30.6 (28 950) 32.3 (3298) 29.9 (6135) 30.6 (6393) 30.6 (8206) 30.7 (4918)  ≥3 55.4 (52 373) 54.5 (5575) 56.8 (11 643) 55.8 (11 662) 54.4 (14 610) 55.4 (8883) IQR, interquartile range; NSAID, non-steroidal anti-inflammatory drug; SD, standard deviation. a Comorbidity within a 10-year time window before baseline. b Concomitant medical therapy within 1 year before baseline. c Modified HAS-BLED-score without labile international normalized ratio. Table 1 Baseline characteristics of atrial fibrillation patients with CHA2DS2-VASc score ≥2 by region Characteristics Total North Central South Capital Zealand Overall, % (n) 100.0 (94 482) 10.8 (10 221) 21.7 (20 503) 22.1 (20 886) 28.4 (26 847) 17.0 (16 025) Women, % (n) 51.5 (48 618) 50.7 (5180) 50.5 (10 566) 50.6 (10 566) 53.8 (14 440) 50.4 (8070) Age, median (IQR), years 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) Incidence year, % (n)  2007 10.7 (10 124) 12.0 (1231) 10.8 (2210) 11.2 (2332) 10.3 (2767) 9.9 (1584)  2008 11.1 (10 451) 11.0 (1126) 11.0 (2252) 10.9 (2270) 11.1 (2973) 11.4 (1830)  2009 11.4 (10 767) 11.6 (1187) 10.8 (2213) 11.3 (2354) 12.2 (3264) 10.9 (1749)  2010 12.1 (11 460) 12.1 (1239) 11.8 (2425) 12.0 (2496) 12.5 (3361) 12.1 (1939)  2011 12.7 (11 986) 12.1 (1239) 13.1 (2694) 12.6 (2626) 12.8 (3437) 12.4 (1990)  2012 13.5 (12 792) 13.2 (1349) 14.4 (2959) 13.2 (2753) 12.9 (3468) 14.1 (2263)  2013 14.2 (13 381) 13.7 (1400) 13.8 (2833) 14.9 (3120) 13.7 (3689) 14.6 (2339)  2014 14.3 (13 521) 14.2 (1450) 14.2 (2917) 14.1 (2935) 14.5 (3888) 14.6 (2331) Comorbiditya, % (n)  Abnormal liver function 1.5 (1401) 1.1 (114) 1.3 (262) 1.3 (274) 1.9 (497) 1.6 (254)  Abnormal renal function 6.2 (5830) 5.3 (538) 6.8 (1395) 6.1 (1267) 6.1 (1642) 6.2 (988)  Alcohol related disease 3.4 (3220) 2.3 (235) 2.7 (552) 2.8 (589) 4.8 (1296) 3.4 (548)  Bleeding 14.7 (13 923) 12.6 (1286) 14.3 (2931) 14.5 (3025) 16.2 (4339) 14.6 (2342)  Congestive heart failure 12.8 (12 051) 10.9 (1116) 12.9 (2652) 12.9 (2694) 12.6 (3392) 13.7 (2197)  Diabetes mellitus 18.8 (17 786) 18.3 (1874) 18.0 (3686) 18.7 (3901) 19.3 (5171) 19.7 (3154)  Hypertension 72.3 (68 313) 75.3 (7696) 73.9 (15157) 73.3 (15 302) 69.3 (18 595) 72.2 (11 563)  Thromboembolism 18.6 (17 582) 16.1 (1644) 18.3 (3751) 18.0 (3758) 20.3 (5437) 18.7 (2992)   Ischaemic stroke 14.6 (13 770) 11.8 (1201) 14.0 (2870) 13.8 (2882) 16.5 (4416) 15.0 (2401)   Systemic embolism 0.9 (830) 0.8 (79) 0.8 (164) 0.7 (153) 1.1 (286) 0.9 (148)   Transient ischaemic attack 5.4 (5113) 5.4 (552) 5.6 (1137) 5.4 (1119) 5.8 (1543) 4.8 (762)  Stroke 15.2 (14 343) 12.4 (1262) 14.6 (2988) 14.4 (2999) 17.1 (4584) 15.7 (2510)  Vascular disease 21.8 (20 554) 20.5 (2094) 23.8 (4871) 21.5 (4491) 20.4 (5468) 22.7 (3630)   Acute myocardial infarction 11.3 (10 664) 10.2 (1042) 11.9 (2441) 10.3 (2153) 11.5 (3083) 12.1 (1945)   Coronary procedure 13.1 (12 371) 14.0 (1426) 15.8 (3231) 12.6 (2631) 11.2 (3008) 13.0 (2075)   Peripheral artery disease 6.2 (5818) 4.7 (483) 5.8 (1188) 7.1 (1474) 5.8 (1563) 6.9 (1110) Concomitant medicationb, % (n)  Antiplatelet drugs 52.0 (49 130) 52.3 (5350) 56.2 (11 513) 52.3 (10 917) 49.3 (13 239) 50.6 (8111)  NSAID 26.3 (24 836) 26.8 (2734) 24.3 (4978) 26.4 (5513) 26.1 (7005) 28.7 (4606)  Statins 42.3 (39 979) 44.1 (4510) 44.7 (9157) 43.2 (9014) 40.4 (10 845) 40.3 (6453) CHA2DS2-VASc, mean ± SD 3.6 ± 1.4 3.5 ± 1.3 3.6 ± 1.4 3.6 ± 1.4 3.6 ± 1.4 3.6 ± 1.4 HAS-BLEDc, mean ± SD 2.6 ± 1.0 2.6 ± 1.0 2.7 ± 1.0 2.6 ± 1.0 2.6 ± 1.1 2.6 ± 1.0 HAS-BLEDc, % (n)  0 0.6 (573) 0.5 (55) 0.6 (117) 0.5 (108) 0.7 (198) 0.6 (95)  1 13.3 (12 586) 12.7 (1293) 12.7 (2608) 13.0 (2723) 14.3 (3833) 13.3 (2129)  2 30.6 (28 950) 32.3 (3298) 29.9 (6135) 30.6 (6393) 30.6 (8206) 30.7 (4918)  ≥3 55.4 (52 373) 54.5 (5575) 56.8 (11 643) 55.8 (11 662) 54.4 (14 610) 55.4 (8883) Characteristics Total North Central South Capital Zealand Overall, % (n) 100.0 (94 482) 10.8 (10 221) 21.7 (20 503) 22.1 (20 886) 28.4 (26 847) 17.0 (16 025) Women, % (n) 51.5 (48 618) 50.7 (5180) 50.5 (10 566) 50.6 (10 566) 53.8 (14 440) 50.4 (8070) Age, median (IQR), years 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) 76 (69–82) Incidence year, % (n)  2007 10.7 (10 124) 12.0 (1231) 10.8 (2210) 11.2 (2332) 10.3 (2767) 9.9 (1584)  2008 11.1 (10 451) 11.0 (1126) 11.0 (2252) 10.9 (2270) 11.1 (2973) 11.4 (1830)  2009 11.4 (10 767) 11.6 (1187) 10.8 (2213) 11.3 (2354) 12.2 (3264) 10.9 (1749)  2010 12.1 (11 460) 12.1 (1239) 11.8 (2425) 12.0 (2496) 12.5 (3361) 12.1 (1939)  2011 12.7 (11 986) 12.1 (1239) 13.1 (2694) 12.6 (2626) 12.8 (3437) 12.4 (1990)  2012 13.5 (12 792) 13.2 (1349) 14.4 (2959) 13.2 (2753) 12.9 (3468) 14.1 (2263)  2013 14.2 (13 381) 13.7 (1400) 13.8 (2833) 14.9 (3120) 13.7 (3689) 14.6 (2339)  2014 14.3 (13 521) 14.2 (1450) 14.2 (2917) 14.1 (2935) 14.5 (3888) 14.6 (2331) Comorbiditya, % (n)  Abnormal liver function 1.5 (1401) 1.1 (114) 1.3 (262) 1.3 (274) 1.9 (497) 1.6 (254)  Abnormal renal function 6.2 (5830) 5.3 (538) 6.8 (1395) 6.1 (1267) 6.1 (1642) 6.2 (988)  Alcohol related disease 3.4 (3220) 2.3 (235) 2.7 (552) 2.8 (589) 4.8 (1296) 3.4 (548)  Bleeding 14.7 (13 923) 12.6 (1286) 14.3 (2931) 14.5 (3025) 16.2 (4339) 14.6 (2342)  Congestive heart failure 12.8 (12 051) 10.9 (1116) 12.9 (2652) 12.9 (2694) 12.6 (3392) 13.7 (2197)  Diabetes mellitus 18.8 (17 786) 18.3 (1874) 18.0 (3686) 18.7 (3901) 19.3 (5171) 19.7 (3154)  Hypertension 72.3 (68 313) 75.3 (7696) 73.9 (15157) 73.3 (15 302) 69.3 (18 595) 72.2 (11 563)  Thromboembolism 18.6 (17 582) 16.1 (1644) 18.3 (3751) 18.0 (3758) 20.3 (5437) 18.7 (2992)   Ischaemic stroke 14.6 (13 770) 11.8 (1201) 14.0 (2870) 13.8 (2882) 16.5 (4416) 15.0 (2401)   Systemic embolism 0.9 (830) 0.8 (79) 0.8 (164) 0.7 (153) 1.1 (286) 0.9 (148)   Transient ischaemic attack 5.4 (5113) 5.4 (552) 5.6 (1137) 5.4 (1119) 5.8 (1543) 4.8 (762)  Stroke 15.2 (14 343) 12.4 (1262) 14.6 (2988) 14.4 (2999) 17.1 (4584) 15.7 (2510)  Vascular disease 21.8 (20 554) 20.5 (2094) 23.8 (4871) 21.5 (4491) 20.4 (5468) 22.7 (3630)   Acute myocardial infarction 11.3 (10 664) 10.2 (1042) 11.9 (2441) 10.3 (2153) 11.5 (3083) 12.1 (1945)   Coronary procedure 13.1 (12 371) 14.0 (1426) 15.8 (3231) 12.6 (2631) 11.2 (3008) 13.0 (2075)   Peripheral artery disease 6.2 (5818) 4.7 (483) 5.8 (1188) 7.1 (1474) 5.8 (1563) 6.9 (1110) Concomitant medicationb, % (n)  Antiplatelet drugs 52.0 (49 130) 52.3 (5350) 56.2 (11 513) 52.3 (10 917) 49.3 (13 239) 50.6 (8111)  NSAID 26.3 (24 836) 26.8 (2734) 24.3 (4978) 26.4 (5513) 26.1 (7005) 28.7 (4606)  Statins 42.3 (39 979) 44.1 (4510) 44.7 (9157) 43.2 (9014) 40.4 (10 845) 40.3 (6453) CHA2DS2-VASc, mean ± SD 3.6 ± 1.4 3.5 ± 1.3 3.6 ± 1.4 3.6 ± 1.4 3.6 ± 1.4 3.6 ± 1.4 HAS-BLEDc, mean ± SD 2.6 ± 1.0 2.6 ± 1.0 2.7 ± 1.0 2.6 ± 1.0 2.6 ± 1.1 2.6 ± 1.0 HAS-BLEDc, % (n)  0 0.6 (573) 0.5 (55) 0.6 (117) 0.5 (108) 0.7 (198) 0.6 (95)  1 13.3 (12 586) 12.7 (1293) 12.7 (2608) 13.0 (2723) 14.3 (3833) 13.3 (2129)  2 30.6 (28 950) 32.3 (3298) 29.9 (6135) 30.6 (6393) 30.6 (8206) 30.7 (4918)  ≥3 55.4 (52 373) 54.5 (5575) 56.8 (11 643) 55.8 (11 662) 54.4 (14 610) 55.4 (8883) IQR, interquartile range; NSAID, non-steroidal anti-inflammatory drug; SD, standard deviation. a Comorbidity within a 10-year time window before baseline. b Concomitant medical therapy within 1 year before baseline. c Modified HAS-BLED-score without labile international normalized ratio. Initiation and persistence of oral anticoagulation treatment Table 2 presents the results of OAC initiation and persistence for the total population and by region. In the period 2007–2014, overall 54.4% (95% CI 54.1–54.7%) of patients with a CHA2DS2-VASc score ≥ 2 filled a prescription of OAC within 90 days after baseline (Table 2). In patients who initiated OAC therapy within 90 days, overall persistence was 76.5% (95% CI 76.1–76.9%) (Table 2). Table 2 Initiation and persistence of oral anticoagulation treatment by region % (95% CI) Total North Central South Capital Zealand Any OAC initiationa 54.4 (54.1–54.7) 62.4 (61.5–63.4) 57.0 (56.3–57.6) 57.0 (56.3–57.7) 49.5 (48.9–50.1) 50.9 (50.1–51.7)  VKAb 40.4 (40.1–40.7) 47.1 (46.1–48.0) 43.1 (42.4–43.8) 43.3 (42.6–44.0) 33.9 (33.3–34.5) 39.8 (39.0–40.6)  NOACb 14.0 (13.8–14.2) 15.4 (14.7–16.1) 13.8 (13.4–14.3) 13.7 (13.2–14.2) 15.6 (15.2–16.0) 11.1 (10.6–11.6) OAC initiation + APc 16.4 (16.1–16.7) 18.0 (17.1–18.9) 19.2 (18.5–19.9) 18.1 (17.4–18.7) 13.4 (12.9–13.9) 15.3 (14.6–15.9) OAC persistenced 76.5 (76.1–76.9) 79.3 (78.2–80.3) 76.2 (75.4–77.0) 78.4 (77.6–79.2) 73.9 (73.1–74.7) 76.3 (75.3–77.2) % (95% CI) Total North Central South Capital Zealand Any OAC initiationa 54.4 (54.1–54.7) 62.4 (61.5–63.4) 57.0 (56.3–57.6) 57.0 (56.3–57.7) 49.5 (48.9–50.1) 50.9 (50.1–51.7)  VKAb 40.4 (40.1–40.7) 47.1 (46.1–48.0) 43.1 (42.4–43.8) 43.3 (42.6–44.0) 33.9 (33.3–34.5) 39.8 (39.0–40.6)  NOACb 14.0 (13.8–14.2) 15.4 (14.7–16.1) 13.8 (13.4–14.3) 13.7 (13.2–14.2) 15.6 (15.2–16.0) 11.1 (10.6–11.6) OAC initiation + APc 16.4 (16.1–16.7) 18.0 (17.1–18.9) 19.2 (18.5–19.9) 18.1 (17.4–18.7) 13.4 (12.9–13.9) 15.3 (14.6–15.9) OAC persistenced 76.5 (76.1–76.9) 79.3 (78.2–80.3) 76.2 (75.4–77.0) 78.4 (77.6–79.2) 73.9 (73.1–74.7) 76.3 (75.3–77.2) CI, confidence interval; OAC, oral anticoagulation; VKA, vitamin K antagonists; NOAC, non-vitamin K antagonist oral anticoagulants; AP, antiplatelets. a Cumulative incidence of any filled OAC prescription after 90 days with death considered a competing event. b Indicates the type of the first filled OAC prescription within 90 days. c Cumulative incidence of both OAC and AP prescription within 90 days. Death is considered a competing event. d Cumulative incidence of any filled OAC prescription from Day 365 and 90 days forward, i.e. Day 365–455 after baseline, in patients who had filled a prescription of OAC within 90 days after baseline and who were still alive at Day 365. Table 2 Initiation and persistence of oral anticoagulation treatment by region % (95% CI) Total North Central South Capital Zealand Any OAC initiationa 54.4 (54.1–54.7) 62.4 (61.5–63.4) 57.0 (56.3–57.6) 57.0 (56.3–57.7) 49.5 (48.9–50.1) 50.9 (50.1–51.7)  VKAb 40.4 (40.1–40.7) 47.1 (46.1–48.0) 43.1 (42.4–43.8) 43.3 (42.6–44.0) 33.9 (33.3–34.5) 39.8 (39.0–40.6)  NOACb 14.0 (13.8–14.2) 15.4 (14.7–16.1) 13.8 (13.4–14.3) 13.7 (13.2–14.2) 15.6 (15.2–16.0) 11.1 (10.6–11.6) OAC initiation + APc 16.4 (16.1–16.7) 18.0 (17.1–18.9) 19.2 (18.5–19.9) 18.1 (17.4–18.7) 13.4 (12.9–13.9) 15.3 (14.6–15.9) OAC persistenced 76.5 (76.1–76.9) 79.3 (78.2–80.3) 76.2 (75.4–77.0) 78.4 (77.6–79.2) 73.9 (73.1–74.7) 76.3 (75.3–77.2) % (95% CI) Total North Central South Capital Zealand Any OAC initiationa 54.4 (54.1–54.7) 62.4 (61.5–63.4) 57.0 (56.3–57.6) 57.0 (56.3–57.7) 49.5 (48.9–50.1) 50.9 (50.1–51.7)  VKAb 40.4 (40.1–40.7) 47.1 (46.1–48.0) 43.1 (42.4–43.8) 43.3 (42.6–44.0) 33.9 (33.3–34.5) 39.8 (39.0–40.6)  NOACb 14.0 (13.8–14.2) 15.4 (14.7–16.1) 13.8 (13.4–14.3) 13.7 (13.2–14.2) 15.6 (15.2–16.0) 11.1 (10.6–11.6) OAC initiation + APc 16.4 (16.1–16.7) 18.0 (17.1–18.9) 19.2 (18.5–19.9) 18.1 (17.4–18.7) 13.4 (12.9–13.9) 15.3 (14.6–15.9) OAC persistenced 76.5 (76.1–76.9) 79.3 (78.2–80.3) 76.2 (75.4–77.0) 78.4 (77.6–79.2) 73.9 (73.1–74.7) 76.3 (75.3–77.2) CI, confidence interval; OAC, oral anticoagulation; VKA, vitamin K antagonists; NOAC, non-vitamin K antagonist oral anticoagulants; AP, antiplatelets. a Cumulative incidence of any filled OAC prescription after 90 days with death considered a competing event. b Indicates the type of the first filled OAC prescription within 90 days. c Cumulative incidence of both OAC and AP prescription within 90 days. Death is considered a competing event. d Cumulative incidence of any filled OAC prescription from Day 365 and 90 days forward, i.e. Day 365–455 after baseline, in patients who had filled a prescription of OAC within 90 days after baseline and who were still alive at Day 365. Figure 1 presents cumulative incidence of OAC initiation (A + B) and persistence (C + D) in 5% intervals for regions (A + C) and municipalities (B + D). Region North was the region with most patients both initiating OAC (Figure 1A and Table 2) and persistent to OAC after 1 year (Figure 1C and Table 2). Compared to the Capital Region, the RR of OAC initiation and persistence in Region North was 1.26 (95% CI 1.24–1.29) and 1.07 (95% CI 1.05–1.09), respectively (Supplementary material online, Figure S2). This corresponded to a RD of 13.0% (95% CI 11.8–14.1%) for OAC initiation and 5.3% (95% CI 4.0–6.7%) for OAC persistence (Supplementary material online, Figure S2). Figure 1 Open in new tabDownload slide Cumulative incidence of oral anticoagulation initiation and persistence. Cumulative incidence of oral anticoagulation initiation after 90 days (A + B) and persistence from Day 365 and 90 days forward (C + D) for regions (A + C) and municipalities (B + D), with death considered a competing event. Figure 1 Open in new tabDownload slide Cumulative incidence of oral anticoagulation initiation and persistence. Cumulative incidence of oral anticoagulation initiation after 90 days (A + B) and persistence from Day 365 and 90 days forward (C + D) for regions (A + C) and municipalities (B + D), with death considered a competing event. In the 98 municipalities, OAC initiation ranged from 45.1% (95% CI 43.9–46.3%) to 68.4% (95% CI 65.9–70.8%) (Figure 1B) and OAC persistence ranged from 66.1% (95% CI 60.7–71.5%) to 86.4% (95% CI 82.3–90.5%) (Figure 1D). The variation between municipalities is presented in Figure 2. In the municipalities with the highest proportion of patients initiating and persistent to OAC, the RR compared to Copenhagen was 1.52 (95% CI 1.45–1.59) for OAC initiation (Figure 2A) and 1.19 (95% CI 1.12–1.27) for persistence (Figure 2B). This corresponded to a RD of 23.2% (95% CI 20.3–26.1%) for OAC initiation (Supplementary material online, Figure S3A) and 13.7% (95% CI 8.4–19.1%) for OAC persistence (Supplementary material online, Figure S3B). Figure 2 Open in new tabDownload slide Relative risk of oral anticoagulation initiation and persistence. Fully adjusted relative risk of oral anticoagulation initiation (A) and persistence after 1 year (B) for municipalities. Copenhagen is the reference municipality (red). Figure 2 Open in new tabDownload slide Relative risk of oral anticoagulation initiation and persistence. Fully adjusted relative risk of oral anticoagulation initiation (A) and persistence after 1 year (B) for municipalities. Copenhagen is the reference municipality (red). Regions and municipalities with higher cumulative incidence of OAC initiation tended to have higher cumulative incidence of OAC persistence (Figure 3A). Figure 3 Open in new tabDownload slide Oral anticoagulation persistence and clinical outcomes plotted against oral anticoagulation initiation. The cumulative incidence of oral anticoagulation initiation plotted against cumulative incidence of oral anticoagulation persistence (A), fully adjusted risk difference (RD) of ischaemic stroke (B) and fully adjusted risk difference of other major bleeding (C) for region and municipalities. Death is considered a competing event. For risk difference the references are the Capital Region and Copenhagen for municipalities. Fitted values are for municipalities. Figure 3 Open in new tabDownload slide Oral anticoagulation persistence and clinical outcomes plotted against oral anticoagulation initiation. The cumulative incidence of oral anticoagulation initiation plotted against cumulative incidence of oral anticoagulation persistence (A), fully adjusted risk difference (RD) of ischaemic stroke (B) and fully adjusted risk difference of other major bleeding (C) for region and municipalities. Death is considered a competing event. For risk difference the references are the Capital Region and Copenhagen for municipalities. Fitted values are for municipalities. Figure 4 depicts change over time in cumulative incidence of OAC initiation (A) and persistence (B) for each region. There was an increase in cumulative incidence of both treatment outcomes in all regions from 2011 to 2014, but variation remained for OAC initiation. Please see Supplementary material online, Figures S4 and S5, for change over time for the two treatment outcomes by municipality. Figure 4 Open in new tabDownload slide Temporal development in oral anticoagulation initiation and persistence. Annual cumulative incidence of oral anticoagulation initiation (A) and persistence after 1 year (B) for regions, with death considered a competing event. Figure 4 Open in new tabDownload slide Temporal development in oral anticoagulation initiation and persistence. Annual cumulative incidence of oral anticoagulation initiation (A) and persistence after 1 year (B) for regions, with death considered a competing event. Clinical outcomes One year after baseline, the overall cumulative incidences were 2.3% (95% CI 2.2–2.4%) for ischaemic stroke, 0.4% (95% CI 0.4–0.4%) for haemorrhagic stroke, and 4.0% (95% CI 3.8–4.1%) for other major bleeding. The cumulative incidences of the clinical outcomes are presented for regions (Figure 5) and for municipalities (Figure 6). Region North had the lowest unadjusted risk of all clinical outcomes. Supplementary material online, Figure S6, presents change over time in the clinical outcomes. Figure 7 presents RR between regions of the clinical outcomes with the Capital Region as reference. After adjustment for potential confounders, the RR between regions remained significantly different for ischaemic stroke (P < 0.001) and other major bleeding (P = 0.004). Region North was the region with lowest fully adjusted RR of ischaemic stroke [0.72 (95% CI 0.61–0.85)]. The fully adjusted RR of other major bleeding was also low [0.88 (95% CI 0.79–0.98)] in Region North but even lower in Region South [0.86 (95% CI 0.79–0.93)]. Risk differences for the clinical outcomes are presented in Supplementary material online, Figure S7, for regions. For municipalities, fully adjusted RDs are presented in Supplementary material online, Figure S8, for ischaemic stroke and other major bleeding. Figure 5 Open in new tabDownload slide Cumulative incidence of the clinical outcomes by region. Cumulative incidence functions of the clinical outcomes for regions, with death considered a competing event. Figure 5 Open in new tabDownload slide Cumulative incidence of the clinical outcomes by region. Cumulative incidence functions of the clinical outcomes for regions, with death considered a competing event. Figure 6 Open in new tabDownload slide Cumulative incidence of the clinical outcomes by municipality. Cumulative incidence of the clinical outcomes after 1 year for municipalities, with death considered a competing event. Figure 6 Open in new tabDownload slide Cumulative incidence of the clinical outcomes by municipality. Cumulative incidence of the clinical outcomes after 1 year for municipalities, with death considered a competing event. Figure 7 Open in new tabDownload slide Relative risk of the clinical outcomes. Relative risk of the clinical outcomes within 1 year after baseline. Death is considered a competing event. The capital region is the reference region. Figure 7 Open in new tabDownload slide Relative risk of the clinical outcomes. Relative risk of the clinical outcomes within 1 year after baseline. Death is considered a competing event. The capital region is the reference region. When applying the fully adjusted RD from the best presenting region on the entire country, 464 ischaemic strokes (21.4%), 63 haemorrhagic strokes (17.0%), and 312 other major bleedings (8.3%) could potentially have been prevented assuming a causal effect (Supplementary material online, Tables S1–3). Regions and municipalities with higher cumulative incidence of OAC initiation tended to have a lower risk of both ischaemic stroke (Figure 3B) and other major bleeding (Figure 3C). The results of the supplementary analyses of intracranial bleeding did not differ distinctly from the analyses of haemorrhagic stroke and are not presented. Discussion In this nationwide cohort study, we found substantial variation between administrative regions and municipalities in Denmark in OAC initiation, persistence, and clinical outcomes for AF patients. In general, the regions and municipalities with the highest initiation of OAC also had the highest OAC persistence. The risk of ischaemic stroke and other major bleeding was lower in these regions and municipalities. Within 1 year after baseline, one out of five ischaemic strokes could potentially have been prevented assuming that the differences found represent a causal effect. Both OAC initiation and persistence increased substantially during the study period, particularly after 2010. However, geographical variation in OAC initiation remained, and a substantial proportion of patients were still not treated with OAC in 2014. The fact that some regions and municipalities were superior in all outcomes suggests that quality of care for patients with AF truly varies between administrative units. Even though Denmark has a universal and fairly uniform health care system, differences in health care delivery between administrative units appear to impose inequalities in AF care resulting in many potentially preventable strokes. Attitude and attention towards AF patients may in general vary between administrative units, and there is concern that the responsibility for OAC initiation, at least in some areas, is in no man’s land between primary and secondary health care. To overcome some obstacles, structured care for AF patients has evolved. In a Dutch randomized trial, structured nurse-led AF clinics were superior to usual care with respect to guideline adherence, cardiovascular hospitalizations, and cardiovascular mortality.5 Also in a Danish context, structured AF services are found effective.21 The establishment of AF clinics started off in the western part of Denmark and the AF clinics therefore might have been unevenly distributed in the administrative units in Denmark. A possible explanation for the increase in OAC use after 2010 is the publication of the ESC guidelines in 2010, which were considered to demonstrate broader indications for OAC and were more explicit and clear compared to previous guidelines.3 This treatment approach has remained in subsequent updates of the guidelines.3,22,23 Another possible contributing factor is the introduction of NOAC. In Denmark, dabigatran was introduced in August 2011, rivaroxaban in February 2012, and apixaban in December 2012. Non-vitamin K antagonist oral anticoagulants can be administered at predetermined doses and have limited food and drug interactions; therefore, NOAC overcome some of the limitations of warfarin.4 Strengths and limitations The registries used in this study cover the entire Danish population making data particularly suitable for research by unambiguous linkage through the CPR number. Hence, our study population comprises a national cohort of AF patients. Data in the Danish national registries are prospectively collected and validated in numerous validation studies.14,24–27 The Danish Civil Registration System has virtually complete coverage of all people living in Denmark with an overall loss to follow-up of only 0.3% between 1968 and 2014.27 Further, several control mechanisms ensure data accuracy including mandatory registration and several checking mechanisms.27 All codes for identifying diagnoses in DNPR have been carefully reviewed in validation studies,14,24–26 and definitions of both outcome and confounders are carefully selected to achieve high validity of data. Conditions such as uncomplicated diabetes and hypertension are incompletely registered in DNPR because these relatively mild conditions are often treated by the general practitioner and thus not registered at the hospital.14 For these conditions, we included medication in the definition as suggested by Hvidberg et al.28 The use of the Diagnosis-Related Group system may for some diseases influence coding practice.14 Consequently, we defined the outcome of ischaemic stroke as either a diagnosis of ischaemic stroke or unspecified stroke as a primary diagnosis alone or as a secondary diagnosis together with a primary diagnosis of rehabilitation. The inclusion of rehabilitation in the definition of stroke is recommended by the Danish Stroke Registry.29 The Danish National Database of Reimbursed Prescriptions is an administrative database containing data on reimbursed medication. Therefore, non-reimbursed medication will lack completeness in the database. However, nearly all the ATC-groups used in this study has a completeness in the database of above 95%.15 No study of the validity of the Danish National Database of Reimbursed Prescriptions exists. However, due to the administrative nature of the database and computerized registration and accounting systems in the pharmacies, data entry errors and data loss are unlikely.15 Despite the above limitations, there is no indication that these limitations could have produced the geographical variation found in this study. Please see Supplementary material online, Table S4, for all definitions of exposure, outcomes, and confounders as well as references for the validity of the definitions. There are no nationwide registry data available on INR levels, time in therapeutic interval, body weight, and creatinine. Hence, we were not able to examine the optimal dose of VKA and NOACs. During the study period, different guidelines have been published with different recommendations for OAC treatment.3,22 Our study population was patients with a CHA2DS2-VASc score ≥ 2, since clinical guideline recommendations in most of the study period recommended OAC for this target group.3 Hence, we have included patients diagnosed before 2010 who might have been considered a lower thrombo-embolic risk level at baseline. This could potentially have resulted in an underestimated guideline-adherence regarding OAC treatment. However, the analyses of temporal development showed that even in the recent years not enough patients were treated with OAC. In the analyses of the clinical outcomes, we adjusted for potential confounders. The noticeable unexplained variation between regions and between municipalities in the risk of ischaemic stroke and other major bleedings suggests that considerations other than the measured clinical patient characteristics may be of great importance. A study by Healey et al.6 from 2016 on differences between 47 countries in the occurrence of death and stroke in AF patients also found regional variation in outcomes unexplained by clinical variables. We did not have access to all potential confounding factors including socioeconomic factors and patient preferences. Healey et al.6 found great importance of economic factors on the risk of all-cause mortality. This confirms the appropriateness of not including mortality as a quality of care measure due to high risk of uncontrolled residual confounding.30 Implications of findings The substantial differences found in a fairly uniform health care system as the Danish suggest that identifying unwarranted variation in AF care could also be essential in other countries. Future studies are also required to address questions of unwarranted variation for other quality of care measures, subgroups of AF patients, and reasons for the unwarranted variation. Our findings regarding OAC suggest that continuous focus on initiation and persistence of treatment is needed, especially in the regions where many patients are still left without treatment. A nationwide initiative has recently been launched in Denmark in order to improve compliance with AF guidelines in clinical practice by establishing a nationwide clinical quality database, which will systematically monitor and audit a set of process and outcome performance measures including initiation and persistence of OAC therapy. The results will be audited nationally and regionally and subsequently made publicly available. The overall aim is to improve and standardize the quality of care across the country by setting targets for good clinical practice and support the sharing of experience between hospitals, practicing cardiologists, and general practitioners on how best to organize AF care locally. The international, cluster-randomized controlled trial IMPACT-AF from 2017 found that a multifaceted intervention involving education of AF patients and health care providers, and regular monitoring and feedback, significantly increased the OAC use in the intervention group.31 The principles of IMPACT-AF are also seen as cornerstones in the Danish initiative. Conclusion Substantial variation between administrative regions and municipalities in OAC use and clinical outcomes in AF patients occurs in Denmark. In general, the regions and municipalities with the highest initiation of OAC also had the highest OAC persistence and a lower risk of ischaemic stroke and other major bleeding. Initiation and persistence of OAC treatment increased in all regions during the study period, particularly after 2010, but considerable regional variation in OAC initiation persisted even after the publication of ESC’s 2010 guidelines and the introduction of NOACs. Variation in the risk of ischaemic stroke and other major bleeding was unexplained by patient characteristics. Our findings demonstrate the potential of small-area variation analysis as a tool for identifying unwarranted variation in AF care and clinical outcomes and demonstrate the need for initiatives to ensure uniform high-quality care for AF patients. Supplementary material Supplementary material is available at European Heart Journal – Quality of Care and Clinical Outcomes online. Acknowledgements Technical support was provided by Steffen Somer, Somer Consulting, Risskov, Denmark and Jakob Hjort, Department of Clinical Medicine, Aarhus University, Denmark. Funding Regional Hospital Central Jutland Research Foundation; Aarhus University Research Foundation; Helga and Peter Korning’s Foundation; and Raimond and Dagmar Ringgård-Bohns Foundation. 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A multifaceted intervention to improve treatment with oral anticoagulants in atrial fibrillation (IMPACT-AF): an international, cluster-randomised trial . Lancet 2017 ; 390 : 1737 – 1746 . WorldCat Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
TI - Inequality in oral anticoagulation use and clinical outcomes in atrial fibrillation: a Danish nationwide perspective
JF - European Heart Journal - Quality of Care and Clinical Outcomes
DO - 10.1093/ehjqcco/qcy011
DA - 2018-07-01
UR - https://www.deepdyve.com/lp/oxford-university-press/inequality-in-oral-anticoagulation-use-and-clinical-outcomes-in-atrial-lRNTI00aX7
SP - 189
VL - 4
IS - 3
DP - DeepDyve
ER -