Corrochano et al. BMC Cardiovascular Disorders (2020) 20:166 https://doi.org/10.1186/s12872-020-01448-7 RESEARCH ARTICLE Open Access Patient self-management of oral anticoagulation with vitamin K antagonists in everyday practice: clinical outcomes in a single centre cohort after long-term follow- up M. Corrochano1*, B. Jiménez2, J. Millón1, I. Gich3, M. Rambla1, E. Gil1, P. Caparrós1, R. Macho1 and J. C. Souto1 Abstract Background: Patient self-management (PSM) of vitamin K antagonists (VKA) seems a very promising model of care for oral anticoagulation in terms of efficacy and safety. In comparison with other management models of VKA therapy, the number of scientific publications supporting the advantages of PSM is more limited. Currently, most of the scarce information comes from randomized clinical trials. Moreover, a small number of studies have assessed PSM of VKA therapy in real life conditions. Methods: We analyzed clinical outcomes of 927 patients in a single center (6018.6 patient-years of follow-up). Recruitment took place between 2002 and 2017. All patients followed a structured training program, conducted by specialized nurses. Results: Fifty percent of individuals had a mechanical heart valve (MHV), 23% suffered from recurrent venous thromboembolism (VTE) or high-risk thrombophilia, and 13% received VKA therapy because of atrial fibrillation (AF). Median follow-up was 6.5 years (range 0.1–15.97 years), median age was 58.1 years (IQR 48–65.9) and 46.5% were women. The incidence of major complications (either hemorrhagic or thromboembolic) was 1.87% patient-years (pt-ys) with a 95% CI of 1.54–2.27. The incidence of major thromboembolic events was 0.86% pt-ys (95% CI 0.64–1.13) and that of major hemorrhagic events was 1.01% pt-ys (95% CI 0.77–1.31). The incidence of intracranial bleeding was 0.22% pt-ys (95% CI 0.12–0.38). In terms of clinical indication for VKA therapy, the incidence of total major complications was 2.4% pt-ys, 2.0% pt-ys, 0.9% pt-ys and 1.34% pt-ys for MHV, AF, VTE and other (including valvulopathies and myocardiopathies), respectively. Clinical outcomes were worse in patients with multiple comorbidities, previous major complications during conventional VKA therapy, and in older individuals. The percentage of time in therapeutic range (TTR) was available in 861 (93%) patients. Overall, the mean (SD) of TTR was 63.6 ± 13.4%, being higher in men (66.2 ± 13.1%) than women (60.6 ± 13.2%), p < 0.05. (Continued on next page) * Correspondence: mcorrochano@santpau.cat 1 Haemostasis and Thrombosis Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Corrochano et al. BMC Cardiovascular Disorders (2020) 20:166 Page 2 of 13 (Continued from previous page) Conclusions: In terms of clinically relevant outcomes (incidence of major complications and mortality), PSM in real life setting seems to be a very good alternative in properly trained patients. Keywords: Management, Anticoagulation, Vitamin K antagonists, Clinical practice, Complications Background oral anticoagulation with VKA in a single center. This co- Oral anticoagulant therapy (OAT) with vitamin K antago- hort was initiated in 2002, continuing a clinical trial called nists (VKA) has been used for more than 60 years to pre- ACOA [12] that demonstrated the capacity of most vent frequent and serious thromboembolic complications patients to perform self-management of VKA, the great associated with pathological conditions such as cardiac clinical applicability of this model, and the significant re- valve replacement, atrial fibrillation, and venous thrombo- duction of serious complications compared to conven- embolic disease. Inevitably, OAT causes an increased risk tional control. These results were corroborated in meta- of hemorrhagic events in these patients [1]. It is necessary analyses of randomized, controlled studies [3, 13]. The to maintain the anticoagulant effect within margins that present paper aimed at describing the clinical outcomes of are both effective and safe, balancing bleeding and throm- this single center cohort, after a long-term follow-up of botic risk in order to minimize complications. 16 years. The measurement of the anticoagulant effect of the VKA is carried out by the prothrombin time (Quick time) and is Methods expressed by international consensus of the Scientific Soci- Objectives eties as International Normalized Ratio (INR). The optimal The main objective was to determine, in patients under intervals of INR have been defined according to the path- self-management of VKA drugs, the incidence of: ology and indication for OAT. The incidence of serious complications is lower in patients who are within the rec-  Major thromboembolic events (TE): deep vein ommended intervals (INR 2.0–3.5 for the majority of cases). thrombosis, pulmonary embolism, ischemic stroke The Time in Therapeutic Range (TTR) is a parameter that or other arterial thromboembolic events. reflects the percentage of time in which the patient’s INR  Minor but relevant TE (as considered in our study): values were within a desired range [2]. myocardial infarction, transient ischemic attack, Conventionally, INR controls for OAT management are thrombophlebitis or other thromboembolic events. carried out in hospitals and primary care centers, and dos-  Incidence of major hemorrhagic complications: age adjustment is performed by a physician. Nevertheless, grades 3 to 5 according to the BARC scale [14]. other strategies for control such as patient self-testing and  Incidence of clinically relevant, but not major, patient self-management have shown to be equally reliable hemorrhagic complications (grade 2 of the BARC scale). and safe [3]. In patient self-testing (PST), patients perform  Mortality, related or not, to anticoagulant treatment. INR testing by themselves with a point-of-care (POC) in- strument and report results to a physician who will adjust the dose. PST has proven to be comparable to standard Study population and PSM training management in terms of preventing major clinical out- This was a retrospective and unicentric observational comes, and to improve quality of life of patients [4–6]. study (NCT 03532724). We analyzed patients under the Likewise, in patient self-management (PSM), patients per- self-management regime, who were trained and followed- up in the Haemostasis and Thrombosis Unit of the Santa form weekly INR controls by using POC devices but, also, Creu i Sant Pau Hospital between July 2002 and Decem- after a training course, they must be able to adjust the doses ber 2017. In our settings, conventional management of of the drug to stay within their therapeutic range [7]. Few OAT consists of the monthly determination of INR with a population-based studies have collected data in real life setting POC device at a specialized anticoagulation clinic. Dose of this model of care [8–10]. Results showed that the inci- adjustment is performed by a haematologist. dence of complications is lower with PSM than standard care Our cohort of patients under self-management started of VKA treatment. Regarding TTR, results seemed to be at with 194 patients from the ACOA trial [12] who least comparable. In a recent study comparing PSM and dir- remained in PSM after the end of the study. Recruitment ect oral anticoagulants (DOACs), PSM has shown signifi- of patients was not systematic. If patients met the cri- cantly less incidence of thromboembolic complications [11]. teria for enrollment, the decision to include them in the None of these studies contain data from Spanish patients. programme was made by the physician. Physicians prior- In the Hospital de la Santa Creu i Sant Pau we have the itized patients who had had serious complications under largest cohort of Spanish patients in self-management of the conventional control and who could improve their Corrochano et al. BMC Cardiovascular Disorders (2020) 20:166 Page 3 of 13 quality of life with this management strategy. Criteria for disease, atrial fibrillation, chronic obstructive pulmonary enrollment were: patients aged 18 years or older who had disease and others), follow-up period and cause of self- been receiving long-term anticoagulant therapy (for at management termination (death, non-adherence, cognitive least 3 months) under conventional control method. Pa- impairment, voluntary withdrawal, change of treatment, tients with severe physical or mental illness and without a end of anticoagulation indication, displacement, unknown, responsible caregiver were not be included, neither pa- others). In addition, patients who were currently on PSM tients who could not understand the Spanish language. completed a survey on clinical events related to the antic- All patients were required to attend an educational pro- oagulation treatment. gram and pass a final examination. This training course Complications occurring during periods of heparin was similar to that published in 2005 for the ACOA clin- treatment were not considered as related to the anti- ical trial [12]. In brief, the program consisted in two teach- coagulant treatment (for example: bridging therapies or ing lessons of 2 h each, including basic skills on the use of hospital admissions where the anticoagulant regimen a coagulometer, interpretation of INR values and dosing was changed). of VKA drug. Patients had to demonstrate that they could follow the PSM procedures in an adequate form. In Statistical analysis addition, they were requested to demonstrate their skills Baseline characteristics of patients are presented as abso- in a final examination. The lessons were conducted by a lute and relative frequencies [N (%)] for categorical vari- specialized nurse. Disabled patients were accepted to per- ables; and mean and standard deviation (mean ± SD) for form PSM if a caregiver participated in the educational quantitative variables. Person-time was calculated as the program and the examination. All patients used the port- elapsed time between the initiated PSM and the event of able coagulometer CoaguChek S or CoaguChek XS interest or first coming of December 31, 2017: emigra- (Roche Diagnostics, Switzerland) equipped with Coagu- tion, self-management termination by any reason or chek PT-test strips. The requested frequency of INR home death. Clinical endpoints are expressed by incidence testing was once a week. Patients noted every INR result rates and the 95% confidence interval (95% CI), calcu- and corresponding VKA dose in a diary. Since starting the lated as number of events divided by person-time at risk. PSM programme, each patient or caregiver was visited in The time in therapeutical range (TTR) was calculated by scheduled appointments at least once a year by our team the Rosendaal method of lineal interpolation [15]. The of specialized nurses. individual TTR was crudely estimated i.e. without ac- counting for anticoagulation interruption during invasive Data acquisition procedures or bridging therapies. A non-parametric test We performed a comprehensive retrospective search of (Mann-Whitney) was used for comparing the TTR. The clinical information from the following sources: 95% CI of the incidence were also calculated. Analyses were performed by using the Stata (V 15.1) statistics  Medical records from our hospital. We reviewed the software package. follow-up of the Haemostasis and Thrombosis Unit professionals (doctors and nurses) as well as other Results specialities, visits to emergency, and hospitalizations. A total of 1380 patients were initially offered to partici-  Shared clinical records from Catalonia, which pate in the PSM programme, however, 330 (24%) de- collects information regarding assistance of public clined. The remaining 1050 patients were trained for hospitals of Catalonia. This allowed to access PSM, but 30 of them did not pass the final examination. patients’ medical reports since its initiation in 2008. Therefore, 1020 patients were included in the  Information collected in the computerized program programme. Patients over 18 years of age were only in- of public primary care centers in Catalonia, which cluded for analysis. We excluded patients with insuffi- started in 1998 and was generalized in 2005. cient clinical information to evaluate the previously indicated variables, and those who remained less than 1 The following data were obtained: age at start of PSM, month under self-management (Fig. 1). The final cohort gender, anticoagulant treatment indication, date of treat- for analysis included 927 patients. Baseline characteris- ment initiation, drug used, complications prior to the onset tics of the overall population are shown in Table 1. of self-management, complications during conventional The total follow-up was of 6018.6 patient-years (pt-ys), VKA therapy, INR therapeutic range, concomitant use of mean (SD) follow-up was 6.5 ± 4.6 years (range 0.1– antiplatelet drugs, existence of comorbidities (high blood 15.97 years). A total of 431 patients were female (46.5%), pressure, diabetes, gastro duodenal ulcer, cancer, chronic the median age (IQR) at the start of PSM was 58.1 years liver disease, ischemic heart disease, heart failure, periph- (48–65.9). There were 66 patients (7%) managed by a eral vascular disease, chronic renal insufficiency, lipid relative or third person (caregiver). As described before, Corrochano et al. BMC Cardiovascular Disorders (2020) 20:166 Page 4 of 13 Fig. 1 Study flow chart in our center, patients trained for PSM were previously The most used drug was acenocumarol in 833 patients under conventional control. The mean time on conven- (89.9%); in the remaining, warfarin was used (94 pa- tional control before starting PSM was 8.5 ± 7.9 years. tients, 10.1%). A total of 109 (11.8%) patients received, at The main indication for anticoagulation was prosthetic any time during PSM, concomitant antiplatelet therapy, mechanical heart valve (MHV) in 465 patients (50.2%): aortic mainly aspirin (93 patients, 10%) and P2Y12 inhibitors (n = 189,40.7%), mitral (n = 138,29.7%), pulmonary (n = 8, (15 patients; 1.6%) and one patient received both. 1.7%), tricuspid (n = 8,1.7%) and double prosthesis (n = 122, Since the year 2010 we have had reliable data on TTR 26.2%). The following most frequent indications were: recur- from 861 (93%) of patients. The overall mean (SD) TTR rent venous thromboembolism (VTE) (213 patients, 23%) was 63.6 ± 13.4%. The TTR in women was lower than and atrial fibrillation (AF) (120 patients, 12.9%). that of men: 60.6 ± 13.2% vs 66.2 ± 13.1% respectively Many patients included for analysis suffered from (p < 0.05). TTR was correlated negatively with the target multi-pathological conditions: 754 (81.3%) had at least INR. It was significantly worse (p < 0.0001) as the INR one comorbidity, and 202 (21.8%) had more than 3. Be- target increased: INR 2.0–3.0 in 563 patients, TTR = fore starting PSM, 163 patients (17.6%) had experienced 68.1 ± 11.3%; INR 2.5–3.5 in 251 patients, TTR = 58.1 ± major complications on conventional control; 113 10.8%, and INR 3.0–4.0 in 13 patients, 45.5 ± 13.0%. In (12.2%) thromboembolic complications and 62 (6.7%) addition, TTR was significantly worse in patients with hemorrhagic ones. Twelve patients had suffered both any major complication (56.0 ± 15.5%) than patients types of major previous complications. (Table 1). without them (64.5 ± 12.9), p < 0.0001. Corrochano et al. BMC Cardiovascular Disorders (2020) 20:166 Page 5 of 13 Table 1 Baseline characteristics of the population included in the study Indication for OAT Overall Atrial fibrillation MHV VTE Cardiopathy Valvulopathies Other Patients N (%) 927 (100) 120 (12.9) 465 (50.2) 213 (23.0) 36 (3.9) 41 (4.4) 52 (5.6) Age (median - IQR) 58.1 [48– 66.3 [58.7–70.9] 60.8 [52.7– 47.6 [38.4– 52.7 [48.2– 62.6 [57.5–68] 48 [39.3– 65.9] 67.1] 56.6] 57.6] 58.7] Female (%) 431 (46.5) 29 (24.2) 234 (50.3) 108 (50.7) 8 (22.2) 30 (73.2) 22 (42.3) Time in traditional control of 8.5 ± 7.9 4.0 ± 4.1 11.4 ± 8.7 5.9 ± 6.1 6.4 ± 5.2 7.5 ± 6.1 5.0 ± 5.5 AVK, before PSM (years ± SD) Previous major complications N (%) Thromboembolic 113 (12.2) 1 (0.8) 86 (18.5) 20 (9.4) 0 (0) 3 (7.3) 3 (5.8) Hemorrhagic 62 (6.7) 5 (4.2) 46 (9.9) 4 (1.9) 0 (0) 1 (2.4) 6 (11.5) Any 163 (17.6) 6 (5.0) 121 (26.0) 24 (11.3) 0 (0) 4 (9.8) 8 (15.4) Comorbidities N (%) Any 754 (81.3) 110 (91.7) 418 (89.9) 115 (54.0) 33 (91.7) 39 (95.1) 39 (75) >3 202 (21.8) 32 (26.7) 129 (27.7) 10 (4.7) 12 (33.3) 11 (26.8) 8 (15.4) High blood pressure 425 (45.9) 81 (67.8) 250 (53.8) 48 (22.7) 17 (47.1) 17 (41.5) 16 (31.7) Diabetes 125 (13.4) 23 (19.1) 76 (16.3) 10 (4.6) 4 (10.5) 10 (24.4) 5 (10.0) Gastro duodenal ulcer 50 (5.4) 10 (8.0) 31 (6.7) 5 (2.5) 2 (5.2) 2 (4.9) 1 (1.7) Cancer 116 (12.5) 24 (19.9) 66 (14.2) 11 (5.3) 4 (10.5) 4 (9.8) 9 (16.7) Chronic liver disease 30 (3.2) 2 (1.6) 23 (5.0) 2 (0.7) 1 (2.6) 1 (2.4) 2 (3.3) Ischemic heart disease 93 (10.1) 22 (18.3) 50 (10.8) 5 (2.5) 8 (23.6) 2 (4.9) 7 (13.3) Heart failure 126 (13.5) 18 (15.1) 86 (18.6) 5 (2.5) 12 (34.0) 5 (12.2) 3 (5.0) Peripheral vascular disease 36 (3.9) 11 (8.8) 20 (4.4) 1 (0.4) 2 (5.2) 0 (0.0) 3 (6.7) Chronic renal insufficiency 114 (12.3) 18 (15.1) 76 (16.3) 6 (2.8) 4 (10.5) 8 (19.5) 6 (11.7) Lipid disease 405 (43.7) 65 (54.2) 237 (50.9) 56 (26.3) 14 (39.3) 22 (53.7) 14 (26.7) Atrial fibrillation 279 (30.1) 8 (6.4) 222 (47.8) 7 (3.2) 18 (49.8) 29 (70.7) 7 (13.3) Chronic obstructive pulmonary 74 (8.0) 21 (17.5) 35 (7.5) 6 (2.8) 6 (15.7) 3 (7.3) 4 (8.3) disease Others 413 (44.6) 56 (47.0) 209 (45.1) 86 (40.5) 16 (44.5) 18 (43.9) 21 (40.0) Complications during follow-up Incidence of complications (major and some relevant, A total of 106 (11.4%) patients had at least one serious such as transitory ischemic attack, TIA) as well as mor- complication during PSM. Three of them suffered both, tality are shown in Table 2. The incidences are displayed one major hemorrhagic and one thrombotic. The overall by relevant co-variables, such as indication for anticoa- incidence of serious complications (thrombotic and gulation, gender, TTR, previous severe complications hemorrhagic) was 1.87% pt-ys (95% CI 1.54–2.27). The under conventional VKA treatment, comorbidities, age incidence of severe hemorrhagic complications was and management of OAT by a caregiver. 1.01% pt-ys (95% CI 0.77–1.31) (n = 59), with an inci- Regarding to indication of anticoagulation, the highest dence of intracranial hemorrhage of 0.22% pt-ys (95% CI incidence of total complications was 2.39% pt-ys in car- 0.12–0.38) (n = 13). The incidence of severe thrombotic riers of MHV (95% CI 1.87–3.01), and the lowest in pa- complications was 0.86% pt-ys (95% CI 0.64–1.13) (n = tients with recurrent VTE (0.89% pt-ys; 95% CI 0.45– 50). Incidence of thromboembolic complications was 1.60). The incidence of major complications was similar slightly higher in MHV, while incidence of major in men and women (1.80% pt-ys and 1.95% pt-ys re- hemorrhagic complications was higher in atrial fibrilla- spectively). Patients with higher TTR had around 4 tion patients (Table 2). times less incidence of complications than patients with A total of 162 patients (17.5%) suffered relevant com- the lower TTR: TTR < 55% the incidence of major com- plications (non-major): hemorrhagic (130 patients, 14%) plications was 3.66% pt-ys (95% CI 2.61–4.98) whilst pa- and thrombotic (46 patients, 5%), or both (14 patients). tients with TTR > 75% had an incidence of 0.77% pt-ys Three patients suffered relevant thrombosis twice. (95% CI 0.33–1.51). Patients who had previous severe Table 2 Severe complications by indication and other relevant variables Any major eventa Thromboembolic Major hemorrhagic Intracranial bleeding Transient ischemic attack Mortality n; numbers per 100 patient-years (95% CI) Overall (n = 927) 106; 1.87 (1.54–2.27) 50; 0.86 (0.64–1.13) 59; 1.01 (0.77–1.31) 13; 0.2 (0.12–0.38) 17; 0.29 (0.17–0.46) 88; 1.46 (1.17–1.80) Indication Atrial fibrillation (n = 120) 14; 2.00 (1.10–3.37) 3; 0.42 (0.09–1.22) 11; 1.57 (0.78–2.81) 6; 0.85 (0.31–1.86) 0 17; 2.34 (1.36–3.75) MHV (n = 465) 71; 2.39 (1.87–3.01) 33; 1.06 (0.73–1.50) 41; 1.32 (0.95–1.79) 5; 0.16 (0.05–0.38) 14; 0.44 (0.24–0.74) 58; 1.79 (1.36–2.32) VTE (n = 213) 11; 0.89 (0.45–1.60) 8; 0.64 (0.28–1.26) 3; 0.24 (0.05–0.69) 0 2; 0.16 (0.02–0.56) 5; 0.38 (0.13–0.91) Corrochano et al. BMC Cardiovascular Disorders Other indication (n = 129) 10; 1.34 (0.64–2.47) 6; 0.78 (0.29–1.71) 4; 0.53 (0.14–1.36) 2; 0.26 (0.03–0.96) 1; 0.13 (0–0.73) 8; 1.04 (0.45–2.05) Male (n = 496) 53; 1.80 (1.35–2.36) 19; 0.62 (0.38–0.97) 35; 1.17 (0.81–1.62) 8; 0.27 (0.11–0.52) 9; 0.29 (0.13–0.55) 51; 1.64 (1.22–2.16) Female (n = 431) 53; 1.95 (1.47–2.56) 31; 1.11 (0.75–1.58) 24; 0.85 (0.55–1.27) 5; 0.18 (0.06–0.41) 8; 0.28 (0.12–0.55) 37; 1.27 (0.89–1.75) TTR < 55% (n = 199)b 40; 3.66 (2.61–4.98) 24; 2.09 (1.34–3.11) 18; 1.54 (0.91–2.43) 2; 0.17 (0.02–0.62) 8; 0.67 (0.29–1.32) 22; 1.78 (1.12–2.70) TTR 55–64% (n = 216) 22; 1.55 (0.97–2.35) 10; 0.68 (0.33–1.25) 12; 0.82 (0.43–1.44) 1; 0.07 (0–0.38) 4; 0.27 (0.07–0.69) 23; 1.53 (0.47–2.24) (2020) 20:166 TTR 65–75% (n = 277) 22; 1.16 (0.73–1.76) 10; 0.52 (0.25–0.95) 12; 0.62 (0.32–1.09) 2; 0.10 (0.01–0.38) 2; 0.10 (0.01–0.37) 17; 0.86 (0.50–1.38) TTR > 75 (n = 169) 8; 0.77 (0.33–1.51) 2; 0.19 (0.02–0.68) 6; 0.57 (0.21–1.24) 4; 0.38 (0.1–0.97) 0 7; 0.65 (0.26–1.34) With previous severe complication 35; 3.70 (2.56–5.12) 17; 1.71 (0.99–2.73) 19; 1.86 (1.12–2.90) 3; 0.29 (0.06–0.86) 9; 0.88 (0.40–1.67) 17; 1.59 (0.93–2.55) (n = 163) Without previous complications 71; 1.51 (1.18–1.91) 33; 0.68 (0.47–0.96) 40; 0.83 (0.60–1.13) 10; 0.21 (0.10–0.38) 8; 0.16 (0.07–0.32) 71; 1.43 (1.12–1.81) (n = 764) > 3 comorbidities (n = 202) 46; 3.36 (2.46–4.48) 19; 1.31 (0.79–2.04) 29; 2.01 (1.35–2.84) 5; 0.35 (0.11–0.81) 5; 0.33 (0.11–0.78) 51; 3.34 (2.44–4.40) ≤ 3 comorbidities (n = 725) 60; 1.40 (1.07–1.81) 31; 0.71 (0.48–1.00) 30; 0.68 (0.46–0.98) 8; 0.18 (0.08–0.36) 12; 0.27 (0.14–0.47) 37; 0.82 (0.58–1.14) Age < 40 (n = 134) 11; 1.25 (0.63–2.24) 6; 0.66 (0.24–1.43) 6; 0.67 (0.25–1.46) 0 0 0 Age 40–59.9 (n = 388) 34; 1.34 (0.93–1.88) 15; 0.58 (0.32–0.96) 20; 0.77 (0.47–1.20) 3; 0.12 (0.02–0.34) 6; 0.23 (0.08–0.50) 31; 1.18 (0.80–1.67) Age 60–75 (n = 359) 50; 2.46 (1.83–3.25) 27; 1.29 (0.85–1.87) 24; 1.12 (0.72–1.67) 3; 0.14 (0.03–0.41) 9; 0.42 (0.19–0.79) 43; 1.95 (1.41–2.63) Age > 75 (n = 46) 11; 5.27 (2.63–9.42) 2; 0.84 (0.10–3.02) 9; 4.27 (1.95–8.1) 7; 3.32 (1.33–6.84) 2; 0.84 (0.10–3.04) 14; 5.82 (3.18–9.75) Patients managed by a third person 15; 3.44 (1.93–5.67) 6; 1.30 (0.48–2.82) 9; 1.89 (0.86–3.59) 6; 1.26 (0.46–2.74) 2; 0.40 (0.05–1.46) 19; 3.77 (2.27–5.84) (n = 66) Patients under strict PSM (n = 861) 91; 1.75 (1.41–2.14) 44; 0.82 (0.60–1.10) 50; 0.93 (0.64–1.23) 7; 0.13 (0.05–0.27) 15; 0.27 (0.15–0.45) 69; 1.25 (0.97–1.58) We have grouped as “other”: cardiopathies, valvulopathies and other indications, because of small number of patients in each category CI confidence interval a Any major event includes thromboembolic and/or haemorrhagic. b TTR was calculated only in 861 patients Page 6 of 13 Corrochano et al. BMC Cardiovascular Disorders (2020) 20:166 Page 7 of 13 complications during conventional control had a higher obtained in our cohort. The incidence of major incidence of major complications during PSM in con- hemorrhagic events was 1.1, 1.6 and 1.0% pt-ys, and trast to those patients with no previous history (3.70% major thrombotic events was 0.4, 0.7, 0.9% pt-ys (Nagler, pt-ys versus 1.51% pt-ys, respectively). Elderly patients Nilsson and our study, respectively; Nilsson did not in- (> 75 years old) had an incidence of major complications clude VTE events). The same happened with the inci- of 5.27% pt-ys, 4 times higher than younger patients (< dence of intracranial bleeding: 0.2, 0.1, 0.2% pt-ys. 40 years old) with an incidence of 1.25% pt-ys. Mortalities reported in the cohorts, related or not to OAT were 1.4, 0.5 and 1.5% pt-ys, respectively. These Type of thrombotic complications incidences (under PSM clinical model) are lower than As mentioned, there were 50 major thrombotic compli- reported from conventional management. Even the cen- cations. Thirty (60%) were cerebrovascular accidents, ters of recognized optimal managing of OAT such as the followed by prosthetic heart valve thrombosis and atrial Swedish clinical network AuriculA report higher inci- thrombosis (n = 11), deep vein thrombosis (n = 8) and dence of complications. Björck et al [16], published re- peripheral arterial embolism (n = 1). sults from around 77,000 patients, corresponding to 217, There were 49 relevant thrombotic complications, in 000 pt-ys, managed in anticoagulation clinics (mean age 46 patients. A total of 17 (35%) were transient ischemic 70) or primary health care centers (mean age 73), associ- attacks (TIA), followed by thrombophlebitis (n = 11), ret- ated with a high standard in quality control (as demon- inal thrombosis (n = 8), acute myocardial infarction (n = strated by TTR over 75%), and with very good clinical 7) and others (n = 6). results in both settings: major bleeding incidence of 2.2% pt-ys, and thromboembolic events (excluding myocardial Type and location of hemorrhagic complications infarction) of 1.7% pt-ys. Of course, any comparison be- There were 59 major hemorrhagic complications. In 11 tween different cohorts and different studies is indirect, cases, the complication was secondary to trauma. and must be done cautiously, especially when indication Thirty-six complications (61%) were of gastrointestinal for anticoagulation, ages or comorbidities are different. origin, of which 4 occurred in patients who received an- We observed a slight increase in the incidence of com- tiplatelet drugs concomitantly. Thirteen patients (22%) plications when patients on PSM had lower TTRs, when had intracranial bleeding, being secondary to a traumatic they had more than three co-morbidities, when they had event in 9 cases. The incidence of intracranial bleeding suffered previous severe complications under conven- was 0.22% pt-ys (95% CI 0.12–0.38). Other complica- tional VKA therapy, or when patients were managed by tions were: retroperitoneal (n = 4), gynecological (n = 3), a caregiver. In this last circumstance, strictly speaking, pulmonary (n = 2) and urinary tract (n = 1) bleeding we cannot consider the model as “patient self- events. management”. Other variable probably associated to There were 130 relevant hemorrhagic complications, worse outcomes is aging, since patients older than 75 ex- 47 (36%) were secondary to a traumatic event, mainly hibited an incidence of total complications 4 times epistaxis (n = 34; 26%), followed by intramuscular bleed- higher than youngest (< 40 years old), mainly due to ing (n = 23; 18%), gastrointestional 15 (11%), Urinary hemorrhagic events (incidences of 4.27% pt-ys vs 0.67% tract 14 (11%), intra-articular 6 (5%), pulmonary 5 (4%), pt-ys). However, any comparison must be done very cau- and other 33 (25%). tiously, since our sample size of older than 75 is very small (46 patients). It is worthy to highlight the very low Mortality incidence of intracranial bleeding of 0.22% pt-ys in our Overall incidence of mortality was 1.46% pt-ys (95% CI cohort, in comparison to reported with different anti- 1.17–1.80) (n = 88). Only 13 deaths were clearly related thrombotic therapies. Recently, Gulati et al [17], re- to VKA treatment; in 7 cases the cause of death was ported the risk of intracranial hemorrhages in users of undetermined. antithrombotic drugs in Norway nationwide. Users of antithrombotic drugs (as a whole) had an incidence of Discussion 0.30% pt-ys, whereas for the different oral anticoagu- There is scarce data on PSM in real world settings. In lants, the incidences were: warfarin 0.55% pt-ys, rivarox- previous similar papers, Nagler et al [8], presented a co- aban 0.51% pt-ys, dabigatran 0.25% pt-ys, and apixaban hort of 1110 patients in Switzerland, with a median age 0.45% pt-ys. Non-users of antithrombotic drugs had an of 54 years, followed-up a median of 4.3 years; and Nils- incidence of 0.08% pt-ys. son et al [9], published outcomes from 2068 patients in In relation to TTR results, in our population of self- Denmark, with a median age of 49 years in women and managed patients we obtained a modest 63.6 ± 13.4%. In 55 in men, followed-up a total of 6900 pt-ys. Incidences our previous clinical trial published in 2005 [12], we ob- of major complications in both studies were similar to served a similar figure. In agreement with Nilsson et al Table 3 Incidence of major complications in different models of anticoagulant therapy in real world in patients with atrial fibrillation (AF) Incidence of major complications (% pt-ys) Author Year Drug N Mean age (years) Total follow-up (pt-ys) Mean follow-up (years) Haemorrhagic Thrombotic Totalc Mortality PSM of VKA Nagler [8] c 2014 VKA 198 64.8 851a 4.3a 1.1 0.1 1.2a 2.5 Grove [11] 2018 VKA 534 63.1 1337 2.5 2.3 0.5 2.8 1.1 Our study 2018 VKA 120 65.3 726 6.0 1.6 0.4 2.0 2.3 Conventional management of VKA in highly specialized centres Wieloch [23] 2011 VKA 2491 74 2043 0.8a 2.6 1.4 4.0 NR a a Sjöegren [24] 2015 VKA 51,229 72.1 143637 2.8 2.2 1.5 3.7 NR Corrochano et al. BMC Cardiovascular Disorders Björck [25] 2016 VKA 40,449 72.5 65,424 1.6a 2.2 1.7 3.9 2.2 a a Esteve-Pastor [26] 2018 VKA 1361 76 8844 NR 2.8 1.5 4.3 6.2 Conventional management of VKA Sorensen [27] 2013 VKA 49,640 73.5 14892a 0.3a 4.3 0.7 5.0a NR (2020) 20:166 Lauffenburger [28] 2015 VKA 43,865 71.4 43865a 1.0 5.2a 3.6a 8.8a NR a a Graham [29] 2015 VKA 67,207 100% > 65 19,382 0.3 4.4 1.4 5.8 3.8 Seeger [30] 2015 VKA 19,189 68.3 6448 0.3 6.2 1.3 7.4a NR a a Larsen [31] 2016 VKA 35,436 72.4 67328 1.9 3.5 2.4 5.9 7.2 Carmo [32]b 2016 VKA 501,019 NR NR NR 5.6 2.8 8.4a 6.1 a a Nielsen [33] 2017 VKA 38,893 71.0 89453 2.3 3.1 2.7 5.8 8.7 Chan [34] 2016 VKA 5251 71 4726a 0.9a 4.3 5.6 9.9 7.1 Li [35] 2017 VKA 38,470 70.9 NR NR 7.5 3.1 10.6a NR Mentias [36] 2018 VKA 101,705 78.4 NR NR 5.3 2.1 7.4a 6.7 a Lee [37] 2018 VKA 12,183 70.7 10,965 0.9 3.6 3.9 7.5 6.6 Gupta [38] 2018 VKA 7607 76.6 5051a NR 4.7 1.9 6.6a NR a Vinogradova [39] 2018 VKA 53,921 74.8 73,939 NR 2.5 1.7 4.2 4.5 Chan [40] 2018 VKA 19,375 71.0 28481a 1.47 3.0 3.3 6.3a 9.1 DOACs Graham [29] 2015 Dabigatran 67,207 100% > 65 18,205 0.3a 4.3 1.1 5.4a 3.3 a a Lauffenburger [28] 2015 Dabigatran 21,070 67.5 21070 1.0 3.2 1.7 4.9 NR Seeger [30] 2015 Dabigatran 19,189 68.7 8059 0.4 4.4 1.0 5.4a NR a a a Larsen [31] 2016 Dabigatran 12,701 67.6 24131 1.9 2.0 1.8 3.8 2.4 Graham [41] 2016 Dabigatran 52,240 100% > 65 15,524 0.3a 3.1 1.0 4.1a 2.2 Page 8 of 13 Table 3 Incidence of major complications in different models of anticoagulant therapy in real world in patients with atrial fibrillation (AF) (Continued) Incidence of major complications (% pt-ys) Author Year Drug N Mean age (years) Total follow-up (pt-ys) Mean follow-up (years) Haemorrhagic Thrombotic Totalc Mortality b Carmo [32] 2016 Dabigatran 210,279 NR NR NR 3.9 1.6 5.5a 3.6 a a a Chan [34] 2016 Dabigatran 5921 75 5329 0.9 2.6 3.7 6.3 2.6 Nielsen [33] 2017 Dabigatran 8875 79.9 20,412 2.3 2.8 2.7 5.5a 9.1 a Mentias [36] 2018 Dabigatran 21,979 75.8 NR NR 3.4 1.5 4.9 2.6 Gupta [38] 2018 Dabigatran 4129 73.0 3061a NR 3.6 1.0 4.6a NR a Vinogradova [39] 2018 Dabigatran 4534 74.7 5083 NR 2.2 1.7 3.9 4.3 Chan [40] 2018 Dabigatran 20,079 75.0 31122a 1.55 2.0 2.7 4.7a 5.0 a a Laliberté [42] 2014 Rivaroxaban 3654 73.3 831 0.23 3.3 4.6 7.9 NR Corrochano et al. BMC Cardiovascular Disorders Camm [43] 2016 Rivaroxaban 6784 71.5 6196a 0.9 2.1 0.8 2.9a 1.9 a a a Larsen [31] 2016 Rivaroxaban 7192 71.8 13664 1.9 3.6 2.3 5.9 6.7 Graham [41] 2016 Rivaroxaban 66,651 100% > 65 20,199 0.3a 4.5 0.8 5.3a 2.5 a a a Chan [34] 2016 Rivaroxaban 3916 76 3524 0.9 3.4 3.1 6.5 3.3 Nielsen [33] 2017 Rivaroxaban 3476 77.9 7994a 2.3 4.0 2.7 6.7a 13.5 (2020) 20:166 a Mentias [36] 2018 Rivaroxaban 23,177 75.7 NR NR 4.7 1.4 6.1 3.1 Gupta [38] 2018 Rivaroxaban 11,284 75.3 8303a NR 4.4 1.3 5.7a NR a Vinogradova [39] 2018 Rivaroxaban 13,597 75.8 12,679 NR 2.6 1.6 4.2 5.5 Chan [40] 2018 Rivaroxaban 27,777 75.0 34443a 1.24 2.1 2.8 4.9a 6.0 Larsen [31] 2016 Apixaban 6349 71.3 5714 0.9 2.7 4.1 6.8 4.8 Nielsen [33] 2017 Apixaban 4400 83.9 4400a 1.0 3.9 4.0 7.9a 14.8 Li [35] 2017 Apixaban 38,470 70.9 NR NR 4.5 2.1 6.6a NR a Gupta [38] 2018 Apixaban 11,284 75.3 7000 NR 2.9 1.0 3.9a NR a Vinogradova [39] 2018 Apixaban 9199 76.5 7511 NR 1.5 1.8 3.3 5.3 Chan [40] 2018 Apixaban 5843 76.0 4440a 0.76 1.5 2.3 3.8a 7.2 a Lee [37] 2018 Edoxaban 4061 70.3 1218 0.3 2.3 3.2 5.5 5.6 Grove [11] 2018 All 2671 63.6 5075 1.9a 2.3 1.6 3.9a 1.4 a Approximated value b Meta-analysis; NR not reported c Total major complications were approximated as the sum of haemorrhagic plus thromboembolic, if not explicitly given in the publication Page 9 of 13 Table 4 Incidence of major complications in different models of anticoagulant therapy in real world in patients with recurrent venous thromboembolism (VTE) Incidence of major complications (% pt-yr) Author Year Drug N Mean age (years) Total follow-up Mean follow-up Haemorrhagic Thrombotic Totalb Mortality (pt-ys) (years) PSM of VKA Nagler [8]b 2014 VKA 451 48.5 1939a 4.3a 0.9 0.5 1.4a 1.1 Larsen [10] 2016 VKA 444 46.6 1953 6.9 0.4 1.3 1.7a 0.5 Corrochano et al. BMC Cardiovascular Disorders Our study 2018 VKA 213 47.5 1288 6.0 0.2 0.6 0.9 0.4 Conventional management of VKA in highly specialized centres Wieloch [23] 2011 VKA 1146 66 802 0.7a 2.6 1.8 4.4a NR a a a Sjöegren [24] 2015 VKA 17,219 65.3 48213 2.8 2.0 1.1 3.1 NR (2020) 20:166 Larsen [10] 2016 VKA 2220 46.8 9569 6.7 0.4 2.2 2.6a 1.1 Conventional management of VKA Ageno [44] 2016 VKA 2149 66.0 1719a 0.8a 2.3 2.6 4.9a 4.1 a a Sindet-Pedersen [45] 2017 VKA 6907 66 3453 0.5 2.1 3.1 5.2 NR Coleman [46] 2017 VKA 32,244 43% > 60 16122a 0.5 1.0 3.5 4.5a NR a a Weycker [47] 2018 VKA 17,878 60 7437 0.4 5.5 7.0 12.5 NR DOACs Ageno [44] 2016 Rivaroxaban 2619 59.0 1833a 0.7a 0.7 1.4 2.1a 0.5 a Sindet-Pedersen [45] 2017 Rivaroxaban 5411 66 2705 0.5 2.3 3.0 5.3a NR a a Coleman [46] 2017 Rivaroxaban 13,609 42% > 60 6804 0.5 0.8 2.8 3.6 NR Berger [48] 2018 Rivaroxaban 3763 57.2 1656a 0.44 1.1 1.4 2.5a NR a a Weycker [47] 2018 Apixaban 17,878 60 7008 0.4 4.2 5.8 10.0 NR The incidences in Ageno et al [44] and Sindet-Pedersen et al [45] were in % patients, not in % pt-ys a Approximated value; NR not reported b Total major complications were approximated as the sum of haemorrhagic plus thromboembolic, if not explicitly given in the publication Page 10 of 13 Corrochano et al. BMC Cardiovascular Disorders (2020) 20:166 Page 11 of 13 [9], we found a better TTR in men that in women. in those indications currently accepted (AF and VTE). Again, our current TTR results call into serious question Again, we must have caution in making conclusions, since the usefulness of evaluating the safety of oral anticoagula- the size of the studies, and the characteristics of the popula- tion by using percentage of in-range INR tests or time tion included may not be always comparable. However, we within target range. The decrease in the risk of complica- want to pay attention in the excellent results reported for tions may be explained by the empowerment of the pa- PSM in different countries and studies. To our knowledge tient [18, 19] and responsibility for making clinical there is only a unique study formally comparing outcomes decisions by themselves. More trained patients, such as of PSM of AVK against DOACs in patients suffering from patients who enter into a PSM regime, are more likely to atrial fibrillation. This is a very recent publication on a na- adhere to the therapy, and hence achieve better results tionwide Danish study by means of a propensity matching from the treatment [20–22]. method [11]. PSM of AVK patients had lower risk of all- The purpose of our study is mainly descriptive, since we cause and ischemic stroke compared to patients under had no comparison group. However, we have collected DOAC treatment, whereas no significant differences were the main clinical outcomes in many publications on differ- seen for major bleeding and mortality. In the current expo- ent models of anticoagulant therapy, in real world condi- nential growth of DOACs’ indication for AF worldwide, the tions to provide better objective (indirect) comparison results of Grove et al [11] along the reported by Nagler between models. The different models and settings con- et al [8] and ours, point out the necessity of designing and sidered are: PSM of VKA therapy, conventional manage- conducting randomized controlled trials comparing PSM of ment of VKA therapy, management of VKA therapy in AVK with DOACs. highly specialized centers, and results from direct oral an- ticoagulants (dabigatran, rivaroxaban, apixaban and edox- Strengths and limitations aban) in everyday clinical practice. Data are summarized Strength of our investigation are the long follow-up and in Tables 3, 4 and 5. We offer main results from different the comprehensive and individualized search of available models of anticoagulant therapy for the three more fre- sources of clinical data, avoiding underestimating com- quent indications: atrial fibrillation [8, 11, 23–43], recur- plications related to anticoagulation (including personal rent venous thromboembolism [8, 10, 23, 24, 44–48] and interview with 79% of the patients). All patients received mechanical heart valves [8, 23, 24, 49–51]. the same training model and technology (POC). In general, incidence of major bleeding, thromboembolic Our study has several limitations. First of all, it is a events, total severe complications and mortality are at least single-center observational study with a retrospective ana- equal and probably better in the reports of PSM than in lysis. Despite the exhaustive search, data on 8% of patients other models, including direct oral anticoagulants (DOACs) was lost and was not available for analysis. We may have Table 5 Incidence of major complications in different models of anticoagulant therapy in real world in patients with mechanical heart valves Incidence of major complications (% pt-ys) Author Year Drug N Mean age Total follow-up Mean follow-up Haemorrhagic Thrombotic Totalb Mortality (years) (pt-ys) (years) PSM of VKA Mair [49] 2012 VKA 160 61.1 1376 8.6 2.2 0.6 2.8a 0.3a b a a Nagler [8] 2014 VKA 356 55.0 1530 4.3 0.4 1.5 1.9 1.0 a Christensen [50] 2016 VKA 615 57.2 2685 7.1 1.1 1.6 2.7 1.1 Our study 2018 VKA 465 58.7 3236 7.0 1.3 1.1 2.4 1.8 Conventional management of VKA in highly specialized centres Wieloch [23] 2011 VKA 597 67 519 0.9a 2.3 2.7 5.0a NR a a a Sjöegren [24] 2015 VKA 6997 66.1 19592 2.8 3.4 1.5 4.9 NR Christensen [50] 2016 VKA 3075 57.0 13,026 6.7 1.4 2.0 3.4 2.5 a Grzymala [51] 2017 VKA 3831 63.3 18,022 4.7 3.1 1.4 4.5 2.4 Conventional management of VKA Mair [49] 2012 VKA 260 66.3 2236 8.6 2.7 1.7 4.4a 1.9a Data from Wieloch et al [23] and Sjöegren et al [24] relates to patients suffering from “heart valve disease”. We assume that the majority of them must be mechanical valves a Approximated value; NR not reported b Total major complications were approximated as the sum of haemorrhagic plus thromboembolic, if not explicitly given in the publication Corrochano et al. BMC Cardiovascular Disorders (2020) 20:166 Page 12 of 13 lost information of patients who received assistance in pri- Ethics approval and consent to participate vate health centers and others that moved out from Cata- The study was carried out following rigorously the international ethical recommendations for medical research in humans. The researchers were lonia. Also, patients who initiated PSM before 2008 (time responsible for ensuring that the study was conducted in accordance with when all clinical information was digitalized in our coun- the standards set out in the Declaration of Helsinki. Before starting the study, try) may have less available information. the Ethical Committee of the Hospital de la Santa Creu i Sant Pau approved the study protocol. There were no specific criteria of selection for patients to participate in the PSM programme. Most of included Consent for publication patients had been under conventional control for a long Not applicable. time and, therefore, had more experience with VKA treatment. Moreover, these patients received additional Competing interests training at the start of PSM, thus this could be a reason The authors report the following general conflicts: JCS has received speaker honoraria or consultancy fees from Roche Diagnostics, Astra Zeneca, Sanofi- of their better outcomes. Aventis, Daiichi-Sankyo and Rovi. Also, financial support to attend scientific congresses from Boehringer Ingelheim, Leo Pharma, Pfizer, Bristol Myers Squibb and Baxter. He was Scientific Director of Monitor Medical and is now Conclusions scientific and clinical advisor in Devicare. MC has received financial support We present clinical outcomes regarding incidence of to attend scientific congresses from Rovi and Novartis. JM has received finan- major complications in a cohort of patients who self- cial support to attend scientific meetings and congresses from Pfizer, Boeh- ringer Ingelheim, Bayer and Rovi. managed their oral anticoagulant treatment with VKA. This is a one-center cohort representing 6019 pt-ys in Author details 1 total which includes different indications for VKA, Haemostasis and Thrombosis Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 2Institut de Recerca. Hospital de la Santa Creu i Sant Pau mainly mechanical heart valves (50% of patients). In (IIB-Sant Pau), Barcelona, Spain. 3Clinical Epidemiology Department, Hospital terms of clinically relevant outcomes, such as the global de la Santa Creu i Sant Pau, Barcelona, Spain. incidence of major complications and mortality by any Received: 18 February 2019 Accepted: 26 March 2020 cause, PSM in real life setting seems to be a very good alternative in properly trained patients. References Abbreviations 1. Duxbury BM, Poller L. The oral anticoagulant saga: past, present, and future. PSM: Patient self-management; VKA: Vitamin K antagonists; MHV: Mechanical Clin Appl Thromb Hemost. 2001;7(4):269–75. heart valve; VTE: Recurrent venous thromboembolism; AF: Atrial fibrillation; 2. Ansell J, et al. Pharmacology and management of the vitamin K antagonists: TTR: Time in therapeutic range; OAT: Oral anticoagulant therapy; American College of Chest Physicians Evidence-Based Clinical Practice INR: International normalized ratio; TE: Thromboembolic events; Guidelines (8th edition). Chest. 2008;133(6 Suppl):160S–98S. TIA: Transitory ischemic attack; DOACs: Direct oral anticoagulants 3. Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: systematic review and Acknowledgements meta-analysis. Lancet. 2006;367(9508):404–11. This project was partly funded by a non-restricted grant from Roche Diag- 4. Gadisseur A, Breukink-Engbers W, van der Meer F, van den Besselaar A, Sturk nostics, Spain. No one else than the authors have been involved in the de- A, Rosendaal F. Comparison of the quality of oral anticoagulant therapy sign, data analysis, data interpretation or preparation of this manuscript. through patient self-management and management by specialized anticoagulation clinics in the Netherlands. Arch Intern Med. 2003;163(21): Declarations 2639. 5. Gardiner C, Williams K, Mackie I, Machin S, Cohen H. Patient self-testing is a – All authors of the manuscript have read and agreed to its content and reliable and acceptable alternative to laboratory INR monitoring. Br J are accountable for all aspects of the accuracy and integrity of the Haematol. 2005;128(2):242–7. manuscript. 6. Matchar D, Jacobson A, Dolor R, Edson R, Uyeda L, Phibbs C, et al. Effect of – The article is original, has not already been published in a journal, and home testing of international normalized ratio on clinical events. N Engl J is not currently under consideration by another journal. Med. 2010;363(17):1608–20. – I agree to the terms of the BioMed Central Copyright and License 7. Jennings I, Kitchen D, Keeling D, Fitzmaurice D, Heneghan C. Patient self- Agreement, and Open Data policy testing and self-management of oral anticoagulation with vitamin K antagonists: guidance from the British Committee for Standards in Haematology. Br J Haematol. 2014;167(5):600–7. Authors’ contributions 8. Nagler M, Bachmann LM, Schmid P, Raddatz Müller P, Wuillemin WA. All authors contributed substantially to the conception and design of the Patient self-management of oral anticoagulation with vitamin K antagonists study, data analyses and interpretation. JCS, MC, BJ and JM were the primary in everyday practice: efficacy and safety in a nationwide long-term contributors to the design of the study. MR, EG, RM and PC teached, prospective cohort study. PLoS One. 2014;9(4):e95761. followed-up the patients over the years, and interviewed them for data ac- 9. Nilsson H, Grove EL, Larsen TB, Nielsen PB, Skjøth F, Maegaard M. Sex quisition. IG and MC were the main persons responsible for statistical ana- differences in treatment quality of self-managed Oral anticoagulant therapy: lyses. MC and JCS drafted the manuscript, which was critically revised and 6,900 patient-years of follow-up. PLoS One. 2014;9(11):e113627. approved for submission by all authors. 10. Larsen TB, Skjøth F, Grove EL, Nielsen PB, Christensen TD. Effectiveness of self-managed oral anticoagulant therapy in patients with recurrent venous Funding thromboembolism. A propensity-matched cohort study. Thromb Haemost. This research was not supported by funding. 2016;116(3):524–9. 11. Grove EL, Skjøth F, Nielsen PB, Christensen TD, Larsen TB. Effectiveness and Availability of data and materials safety of self-managed oral anticoagulant therapy compared with direct The datasets used and/or analysed during the current study are available oral anticoagulants in patients with atrial fibrillation. Sci Rep. 2018;8(1): from the corresponding author on reasonable request. 15805. Corrochano et al. BMC Cardiovascular Disorders (2020) 20:166 Page 13 of 13 12. Menéndez-Jándula B, Souto JC, Oliver A, Montserrat I, Quintana M, Gich I, anticoagulants and warfarin in patients with atrial fibrillation: propensity et al. Comparing self-management of oral anticoagulant therapy with clinic weighted nationwide cohort study. BMJ. 2017;356:j510. management: a randomized trial. Ann Intern Med. 2005;142(1):1–10. 34. Chan YH, Kuo CT, Yeh YH, Chang SH, Wu LS, Lee HF, et al. Thromboembolic, 13. Heneghan C, Ward A, Perera R, Bankhead C, Fuller A, Stevens R, et al. Self- bleeding, and mortality risks of rivaroxaban and Dabigatran in Asians with monitoring of oral anticoagulation: systematic review and meta-analysis of Nonvalvular atrial fibrillation. J Am Coll Cardiol. 2016;68(13):1389–401. individual patient data. Lancet. 2012;379(9813):322–34. 35. Li XS, Deitelzweig S, Keshishian A, Hamilton M, Horblyuk R, Gupta K, et al. 14. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Effectiveness and safety of apixaban versus warfarin in non-valvular atrial Standardized bleeding definitions for cardiovascular clinical trials: a fibrillation patients in “real-world” clinical practice. A propensity-matched consensus report from the bleeding academic research consortium. analysis of 76,940 patients. Thromb Haemost. 2017;117(6):1072–82. Circulation. 2011;123(23):2736–47. 36. Mentias A, Shantha G, Chaudhury P, Vaughan Sarrazin MS. Assessment of 15. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to outcomes of treatment with Oral anticoagulants in patients with atrial determine the optimal intensity of oral anticoagulant therapy. Thromb fibrillation and multiple chronic conditions: a comparative effectiveness Haemost. 1993;69(3):236–9. analysis. JAMA Netw Open. 2018;1(5):e182870. 16. Björck F, Sandén P, Renlund H, Svensson PJ, Själander A. Warfarin treatment 37. Lee SR, Choi EK, Han KD, Jung JH, Oh S, Lip GYH. Edoxaban in Asian quality is consistently high in both anticoagulation clinics and primary care patients with atrial fibrillation: effectiveness and safety. J Am Coll Cardiol. setting in Sweden. Thromb Res. 2015;136(2):216–20. 2018;72(8):838–53. 17. Gulati S, Solheim O, Carlsen SM, Øie LR, Jensberg H, Gulati AM, et al. Risk of 38. Gupta K, Trocio J, Keshishian A, Zhang Q, Dina O, Mardekian J, et al. Real- intracranial hemorrhage (RICH) in users of oral antithrombotic drugs: world comparative effectiveness, safety, and health care costs of Oral Nationwide Pharmacoepidemiological study. PLoS One. 2018;13(8): anticoagulants in Nonvalvular atrial fibrillation patients in the U.S. e0202575. Department of Defense population. J Manag Care Spec Pharm. 2018;24(11): 18. Ansell JE. Empowering patients to monitor and manage oral 1116–27. anticoagulation therapy. JAMA. 1999;281(2):182–3. 39. Vinogradova Y, Coupland C, Hill T, Hippisley-Cox J. Risks and benefits of 19. Piso B, Jimenz-Boj E, Krinninger B, Watzke HH. The quality of oral direct oral anticoagulants versus warfarin in a real world setting: cohort anticoagulation before, during and after a period of patient self- study in primary care. BMJ. 2018;362:k2505. management. Thromb Res. 2002;106(2):101–4. 40. Chan YH, See LC, Tu HT, Yeh YH, Chang SH, Wu LS, et al. Efficacy and safety 20. Latham CE. Is there data to support the concept that educated, of Apixaban, Dabigatran, rivaroxaban, and warfarin in Asians with empowered patients have better outcomes? J Am Soc Nephrol. 1998;9(12 nonvalvular atrial fibrillation. J Am Heart Assoc. 2018;7(8):e008150. Suppl):S141–4. 41. Graham DJ, Reichman ME, Wernecke M, Hsueh YH, Izem R, Southworth MR, 21. Goldman DP, Smith JP. Can patient self-management help explain the SES et al. Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries health gradient? Proc Natl Acad Sci U S A. 2002;99(16):10929–34. treated with Dabigatran or rivaroxaban for nonvalvular atrial fibrillation. 22. Piette JD, Russell EG. Education and home glucose monitoring. In: Gerstein JAMA Intern Med. 2016;176(11):1662–71. HC, Hayne RB, editors. Evidence-based Diabetes Care. 1ª Ed. London: Decker 42. Laliberté F, Cloutier M, Nelson WW, Coleman CI, Pilon D, Olson WH, et al. Inc. 2001; p.207–51. Real-world comparative effectiveness and safety of rivaroxaban and warfarin 23. Wieloch M, Själander A, Frykman V, Rosenqvist M, Eriksson N, Svensson PJ. in nonvalvular atrial fibrillation patients. Curr Med Res Opin. 2014;30(7): Anticoagulation control in Sweden: reports of time in therapeutic range, 1317–25. major bleeding, and thrombo-embolic complications from the national 43. Camm AJ, Amarenco P, Haas S, Hess S, Kirchhof P, Kuhls S, et al. XANTUS: a quality registry AuriculA. Eur Heart J. 2011;32(18):2282–9. real-world, prospective, observational study of patients treated with 24. Sjögren V, Grzymala-Lubanski B, Renlund H, Friberg L, Lip GY, Svensson PJ, rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J. 2016; et al. Safety and efficacy of well managed warfarin. A report from the 37(14):1145–53. Swedish quality register Auricula. Thromb Haemost. 2015;113(6):1370–7. 44. Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, et al. 25. Björck F, Renlund H, Lip GY, Wester P, Svensson PJ, Själander A. Outcomes Safety and effectiveness of oral rivaroxaban versus standard anticoagulation in a warfarin-treated population with atrial fibrillation. JAMA Cardiol. 2016; for the treatment of symptomatic deep-vein thrombosis (XALIA): an 1(2):172–80. international, prospective, non-interventional study. Lancet Haematol. 2016; 3(1):e12–21. 26. Esteve-Pastor MA, Rivera-Caravaca JM, Roldán V, Orenes-Piñero E, Romiti GF, 45. Sindet-Pedersen C, Langtved Pallisgaard J, Staerk L, Gerds TA, Fosbøl EL, Romanazzi I, et al. Estimated effectiveness and safety of nonvitamin K Torp-Pedersen C, et al. Comparative safety and effectiveness of rivaroxaban antagonist oral anticoagulants compared with optimally acenocoumarol versus VKAs in patients with venous thromboembolism. A Danish anticoagulated "real-world" in patients with atrial fibrillation. Am J Cardiol. nationwide registry-based study. Thromb Haemost. 2017;117(6):1182–91. 2018;122(5):785–92. 46. Coleman CI, Bunz TJ, Turpie AGG. Effectiveness and safety of rivaroxaban 27. Sørensen R, Gislason G, Torp-Pedersen C, Olesen JB, Fosbøl EL, Hvidtfeldt versus warfarin for treatment and prevention of recurrence of venous MW, et al. Dabigatran use in Danish atrial fibrillation patients in 2011: a thromboembolism. Thromb Haemost. 2017;117(10):1841–7. nationwide study. BMJ Open. 2013;3(5):e002758. 47. Weycker D, Li X, Wygant GD, Lee T, Hamilton M, Luo X, et al. Effectiveness and 28. Lauffenburger JC, Farley JF, Gehi AK, Rhoney DH, Brookhart MA, Fang G. safety of apixaban versus warfarin as outpatient treatment of venous Effectiveness and safety of dabigatran and warfarin in real-world US patient thromboembolism in U.S. clinical practice. Thromb Haemost. 2018;118(11):1951–61. with non-valvular atrial fibrillation: a retrospective cohort study. J Am Heart 48. Berger JS, Seheult R, Laliberté F, Crivera C, Lejeune D, Xiao Y, et al. Clinical Assoc. 2015;4(4):e001798. outcomes of prolonged anticoagulation with rivaroxaban after unprovoked 29. Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, venous thromboembolism. Res Pract Thromb Haemost. 2017;2(1):58–68. Levenson M, et al. Cardiovascular, bleeding, and mortality risks in elderly 49. Mair H, Sachweh J, Sodian R, Brenner P, Schmoeckel M, Schmitz C, et al. Medicare patients treated with dabigatran or warfarin for nonvalvular atrial Long-term self-management of anticoagulation therapy after mechanical fibrillation. Circulation. 2015;131(2):157–64. heart valve replacement in outside trial conditions. Interact Cardiovasc 30. Seeger JD, Bykov K, Bartels DB, Huybrechts K, Zint K, Schneeweiss S. Safety Thorac Surg. 2012;14(3):253–7. and effectiveness of dabigatran and warfarin in routine care of patients with 50. Christensen TD, Skjøth F, Nielsen PB, Maegaard M, Grove EL, Larsen TB. Self- atrial fibrillation. Thromb Haemost. 2015;114(6):1277–89. management of anticoagulant therapy in mechanical heart valve patients: a 31. Larsen TB, Skjøth F, Nielsen PT, Kjældgaard JT, Lip G. Comparative matched cohort study. Ann Thorac Surg. 2016;101(4):1494–9. effectiveness and safety of non-vitamin K antagonist oral anticoagulants 51. Grzymala-Lubanski B, Svensson PJ, Renlund H, Jeppsson A, Själander A. and warfarin in patients with atrial fibrillation: propensity weighted Warfarin treatment quality and prognosis in patients with mechanical heart nationwide cohort study. BMJ. 2016;353:i3189. valve prosthesis. Heart. 2017;103(3):198–203. 32. Carmo J, Moscoso Costa F, Ferreira J, Mendes M. Dabigatran in real-world atrial fibrillation. Meta-analysis of observational comparison studies with vitamin K antagonists. Thromb Haemost. 2016;116(4):754–63. Publisher’s Note 33. Nielsen PB, Skjøth F, Søgaard M, Kjældgaard JN, Lip G, Larsen TB. Springer Nature remains neutral with regard to jurisdictional claims in Effectiveness and safety of reduced dose non-vitamin K antagonist oral published maps and institutional affiliations.