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Archives of cardiovascular diseases
Volume 111, n° 5
pages 370-379 (mai 2018)
Doi : 10.1016/j.acvd.2017.10.003
Received : 12 April 2017 ;  accepted : 12 October 2017
Clinical research

Initiation and continuation of oral anticoagulant prescriptions for stroke prevention in non-valvular atrial fibrillation: A cohort study in primary care in France
Initiation et suivi des prescriptions d’anticoagulant oral pour la prévention des accidents vasculaires cérébraux dans la fibrillation atriale non valvulaire : une étude de cohorte française en médecine générale

Shuk-Li Collings a, Virginie Vannier-Moreau b, Michelle E. Johnson a, , Gillian Stynes c, Cinira Lefèvre b, Andrew Maguire a, Joelle Asmar d, Geoffray Bizouard d, Didier Duhot e, Frédéric Mouquet f, Laurent Fauchier g
a OXON Epidemiology, Eastside, King's Cross, N1C 4AX London, UK 
b Bristol-Myers Squibb, 92500 Rueil-Malmaison, France 
c Worldwide Health Economics & Outcomes Research, Bristol-Myers Squibb, Uxbridge, Middlesex, UB8 1DH, UK 
d IMS Health Information Solutions, 92773 Boulogne-Billancourt, France 
e Département universitaire de médecine générale, SMBH université Paris 13, 93000 Bobigny, France 
f Ramsay GDS, hôpital privé Le-Bois, 59000 Lille, France 
g Centre hospitalier universitaire Trousseau et université François-Rabelais, 37000 Tours, France 

Corresponding author.

Oral anticoagulants are prescribed in non-valvular atrial fibrillation for stroke prevention; however, little is known about the current management of anticoagulation in France, particularly given the availability of non-vitamin K antagonist oral anticoagulants in recent years.


To describe the characteristics of patients prescribed oral anticoagulants, and assess treatment persistence in French primary care.


We conducted a cohort study of patients with non-valvular atrial fibrillation, who were newly prescribed oral anticoagulants between 1 January 2014 and 31 January 2016, using French primary care data (IMS Longitudinal Patient Database). Adjusting for baseline characteristics, risk of non-persistence (switch or discontinuation) was compared using Cox regression.


Of 4111 patients, 1710 were newly prescribed vitamin K antagonists, 1257 rivaroxaban, 744 apixaban and 400 dabigatran. The median age was 76 years, and 57.5% were male. History of hypertension was the most common co-morbidity (68.1%). Compared with vitamin K antagonists, non-persistence was higher with rivaroxaban (hazard ratio: 1.28; 95% confidence interval: 1.13–1.45) and dabigatran (hazard ratio: 1.42; 95% confidence interval: 1.20–1.69) and similar with apixaban (hazard ratio: 1.12; 95% confidence interval: 0.96–1.32).


Non-persistence (treatment discontinuation or switch) with vitamin K antagonists was lower than with rivaroxaban and dabigatran in French primary care; however, non-persistence with the newest drug, apixaban, was similar to vitamin K antagonists. Larger studies with longer follow-up are needed to support these findings. This study is registered on (NCT02488421).

The full text of this article is available in PDF format.

En France, chez les patients en fibrillation atriale non valvulaire, les données sur la prise en charge par anticoagulants oraux directs sont encore limitées.


Décrire les caractéristiques des patients traités par anticoagulants oraux et évaluer la persistance au traitement, en médecine générale, en France.


Une étude de cohorte (IMS longitudinal patient database ) a été conduite chez des patients en fibrillation atriale non valvulaire, nouvellement traités par anticoagulants oraux, entre le 1er janvier 2014 et le 31 janvier 2016. Après ajustement sur les caractéristiques, le risque de non-persistance (arrêt ou changement de traitement) a été comparé en utilisant un modèle de Cox.


Quatre mille cent onze patients ont été inclus : 1710 traités par anti-vitamines K, 1257 par rivaroxaban, 744 par apixaban et 400 par dabigatran. Leur âge médian était de 76 ans et 57,5 % étaient des hommes. Un antécédent d’hypertension était la comorbidité la plus fréquente (68,1 %). En comparaison aux anti-vitamines K, la non-persistance a été plus élevée avec le rivaroxaban (hazard ratio : 1,28 ; intervalle de confiance à 95 % : 1,13–1,45) et le dabigatran (hazard ratio : 1,42 ; intervalle de confiance à 95 % : 1,20–1,69). Pour l’apixaban, la non-persistance était similaire à celle sous anti-vitamines K (hazard ratio : 1,12 ; intervalle de confiance à 95 % : 0,96–1,32).


En médecine générale en France, la non-persistance (arrêt ou changement de traitement) sous anti-vitamines K était plus basse comparée à celle sous rivaroxaban et sous dabigatran. En revanche, sous apixaban, molécule la plus récente, la non-persistance était identique. D’autres études, avec un suivi plus long, sont nécessaires pour confirmer ces résultats. Cette étude est enregistrée sur (NCT02488421).

The full text of this article is available in PDF format.

Keywords : Anticoagulants, Atrial fibrillation, Medication persistence, Primary health care ;

Mots clés : Anticoagulants, Fibrillation atriale, Persistance, Médecine générale

Abbreviations : AF, CI, HR, INR, IQR, LPD, NVAF, NOAC, OAC, VKA


Atrial fibrillation (AF) is the most common sustained heart rhythm disorder, affecting 600,000 to 1 million people in France [1], and over 40 million people worldwide [2]. AF is associated with a five-fold increased risk of stroke compared with those without AF, and one in five strokes are among people with AF [3, 4]. Oral anticoagulant (OAC) therapy is therefore prescribed to patients with AF, to reduce the likelihood of thromboembolic events.

The European Society of Cardiology recommends OACs for those with a high stroke risk (CHA2 DS2 -VASc score>2 among men, >3 among women), and that the non-vitamin K antagonist OACs (NOACs) apixaban, rivaroxaban and dabigatran are preferred over traditional anticoagulation with vitamin K antagonists (VKAs) [5]. For those with a lower stroke risk (CHA2 DS2 -VASc score of 1 among men, 2 among women), OACs may also be considered [5]. While VKAs offer effective stroke prevention [6, 7], their use has been problematic: they have a slow onset of action, multiple drug interactions and necessitate regular monitoring, dose adjustments and dietary restrictions [8]. In recent years, NOACs were developed and approved in France, particularly for non-valvular AF (NVAF). Compared with VKAs, these are simpler to use, at least equivalent in effectiveness [9, 10, 11, 12] and, for apixaban and adjusted-dose dabigatran, have lower rates of bleeding [9, 10, 13].

Little is known about the current use of OACs for stroke prevention in NVAF in France, particularly as apixaban was the latest NOAC to become available for reimbursement for NVAF (December 2013). It is important to understand the characteristics of patients who are prescribed OACs, and their treatment persistence, to establish whether stroke prevention is being maintained. Several studies have highlighted poor persistence with VKAs [14, 15, 16], while other studies have indicated improved persistence among patients prescribed NOACs [17, 18, 19, 20]; however, few studies have examined persistence with individual OACs, including apixaban [19, 21, 22].

This study aims to provide real-world evidence, describing the characteristics of patients with NVAF who are prescribed OACs, and quantifying and comparing the rates of persistence between OACs, using primary care data from the French IMS Longitudinal Patient Database (LPD).


We conducted a cohort study of patients with NVAF who were newly prescribed an OAC (VKA, rivaroxaban, dabigatran or apixaban) in French primary care, using data from the IMS LPD (formerly CSD-LPD), which holds anonymised medical records from 1991 onwards. The IMS LPD covers 1200 primary care physicians and 1.8 million patients – approximately 3% of the population. The database is representative of primary care physicians and the general population, according to age and sex, and the physicians’ geographical location distribution in France [23]. The database contains events recorded during routine care, such as diagnoses (coded and mapped to ICD-10 codes), prescriptions (ATC coding system), measurements and tests. Data are built cumulatively through patient visits; no information is recorded on patient registration, transfer or death, which may lead to incomplete patient medical histories. This study is registered on (identifier NCT02488421).

We identified patients prescribed an OAC between 1 January 2014 and 31 January 2016. The index date was defined as the date of the first OAC prescription in the study period. We included patients with a record of AF and no record of a valvular condition, on or before index date. Patients were aged ≥18 years, with at least 12 months having elapsed since they were first observed in the data. Patients had to be naïve to OAC therapy (i.e. no record of any OAC prescriptions between their first observation date and the index date). In addition to the analysis on the OAC-naïve population, a broader analysis including OAC-experienced patients is described in Appendix A in the Appendix.

Patient characteristics

Patient characteristics were analysed using all data recorded up to, and including, the index date (minimum 12 months of data by design). We described patients’ age, sex, region of residence, time since first record of AF in the data, history of stroke risk factors, baseline stroke risk (CHA2 DS2- VASc score), history of bleeding events, baseline bleeding risk (HAS-BLED score) and concomitant medication use (prescribed on the index date or within 3 months afterwards). For patients prescribed NOACs, we categorised the index date prescription dose in line with recommendations from the Summary of Product Characteristics for NVAF [24, 25, 26]: an ‘adjusted dose’ was defined as a total daily dose of 5mg apixaban, 15mg rivaroxaban and 220mg dabigatran; a ‘standard dose’ was defined as a total daily dose of 10mg apixaban, 20mg rivaroxaban and 300mg dabigatran.

Treatment persistence

Patients prescribed NOAC doses licensed for NVAF and patients prescribed VKAs were included in the persistence analyses. We grouped consecutive prescriptions of the same OAC from index date to the end of follow-up (earliest of end of study period or last observation date) to form treatment lines. We estimated prescription durations (quantity divided by daily dose) to assign prescription end dates. Quantity was available for all prescriptions, and daily dose was available for>95% of prescriptions. If no daily dose was recorded, the observed median duration for each OAC was assigned. Using a method used previously by Azoulay et al. [27], VKA treatment lines were extended by 60 days (median length of observed VKA durations) for every record of an international normalized ratio (INR) test after the index date, to account for possible additional prescriptions or dosage adjustments made outside of primary care. The differential definition of treatment lines between VKAs and other OACs may lead to bias; thus, a sensitivity analysis was conducted where VKA treatment lines were not extended.

If the time between a new prescription and the end of the last prescription was>60 days, and there were >60 days between the end of the treatment line and the end of follow-up, then the treatment line was deemed discontinued. A 60-day gap was shown to be a clinically relevant length of time to obtain a new prescription by Zalesak et al. [20]. A switch was defined if a different OAC was introduced into the regimen or within 60 days following the end of the treatment line; follow-up was censored on the date a different OAC was prescribed.

Patients were persistent if there was no regimen change to the treatment line (discontinuation or switch) during follow-up. Persistence was not assessed for treatment lines with an insufficient amount of follow-up data (≤60 days between index date and end of follow-up).

Statistical analyses

We described the cumulative incidence of non-persistence for each OAC cohort over time since index date. Persistence rates were calculated as 100% minus the cumulative incidence of non-persistence over the entire follow-up period, and at specific time points (3, 6 and 12 months), along with the number of patients at risk and censored. We used Cox regression to compare risk of non-persistence, adjusting for differences in baseline characteristics (using significance-based backward selection to select variables at 5% level) and follow-up time, and reported hazard ratios (HRs) and 95% confidence intervals (CIs). We examined Schoenfeld residuals to assess the proportional hazards assumption. The assumption was satisfied after stratifying on history of congestive heart failure and concomitant parenteral anticoagulant therapy. Analyses were conducted in SAS software, version 9.4 (SAS Institute Inc., Cary, NC, USA).

Sensitivity analyses

Sensitivity analyses were performed where the cumulative incidence of non-persistence was illustrated in the following scenarios:

persistence was redefined using a 30- and 90-day discontinuation gap;
VKA treatment lines were recalculated without the extension for INR records;
analysis was restricted to patients who regularly visited the same physician in the 12 months before the index date (i.e. observed in the data at least once every 3 months), to assess whether non-persistence in the main analysis may have been influenced by patients’ infrequent visits to the same physician.

Patient characteristics

Of 4111 patients with NVAF prescribed an OAC between 1 January 2014 and 31 January 2016, 1710 (41.6%) were prescribed a VKA, 1257 (30.6%) rivaroxaban, 744 (18.1%) apixaban and 400 (9.7%) dabigatran (Table 1). Use of apixaban increased over time, while use of dabigatran diminished; use of rivaroxaban and VKAs remained relatively stable over the study period. By the end of the study period, similar numbers of patients were prescribed apixaban and VKAs. Overall, patients had a median 8.6 years [interquartile range (IQR) 4.8–13.7 years] between their first observation in the data and the index date; this was similar in each OAC cohort.

Overall, a third of patients prescribed a NOAC were prescribed an adjusted dose on the index date (Table 1). The median age at index date was 76 years [IQR: 67–83 years], and there were slightly more men than women (57.5%) (Table 1). There was a high frequency of stroke risk factors, with 68.1% of patients having a history of hypertension, 26.8% vascular disease and 23.9% thromboembolism. Patients prescribed apixaban and VKAs had slightly higher frequencies of stroke risk factors and previous bleeding events. Overall, the mean baseline CHA2 DS2 -VASc score was 3.2±1.5, ranging from 3.0±1.5 with rivaroxaban to 3.5±1.5 with VKAs. Bleeding events before the index date were identified in 13.2% of patients, and were highest among patients prescribed VKAs (14.7%). The baseline HAS-BLED score was 2.6±1.0 in the overall population, with little variation across OAC cohorts.

The characteristics of the larger group of OAC-naïve and OAC-experienced patients are detailed in Table A.1 in the Appendix; stroke risk factors and previous bleeding events were, again, observed slightly more frequently in the apixaban cohort.

Treatment persistence

Of 4111 patients, 3256 had sufficient follow-up (>60 days between the index date and the end of follow-up) to be included in persistence analyses (1400 on VKAs, 953 on rivaroxaban, 575 on apixaban and 328 on dabigatran) (Table 2). Median follow-up was longest with dabigatran (14.5 months [IQR: 8.1–20.0 months]) followed by VKAs (11.9 months [IQR: 6.5–18.0 months]) and rivaroxaban (11.9 months [IQR: 6.8–18.1 months]), and shortest with apixaban (8.8 months [IQR: 4.7–13.1 months]). At 3, 6 and 12 months, we observed the poorest persistence with dabigatran, followed by rivaroxaban and apixaban. Patients prescribed VKAs showed the highest persistence rates throughout (Table 2, Figure 1). For example, at 6 months, persistence rates were 56.6% (95% CI: 50.9–62.0%), 60.0% (95% CI: 56.6–63.2%), 63.0% (95% CI: 58.5–67.2%) and 67.7% (95% CI: 65.0–70.2%) for patients prescribed dabigatran, rivaroxaban, apixaban and VKAs, respectively.

Figure 1

Figure 1. 

Cumulative incidence of non-persistence across oral anticoagulants. VKA: vitamin K antagonist.


In order to compare persistence between OACs, non-persistence was modelled as the event in the time-to-event analysis. After adjusting for differences in characteristics across OACs, compared with VKAs, non-persistence was similar with apixaban (HR: 1.12; 95% CI: 0.96–1.32), but higher with rivaroxaban (HR: 1.28; 95% CI: 1.13–1.45) and dabigatran (HR: 1.42, 95% CI: 1.20–1.69) (Table 3). Compared with apixaban, non-persistence was similar with rivaroxaban (HR: 1.14; 95% CI: 0.97–1.34) and higher with dabigatran (HR: 1.27; 95% CI: 1.04–1.55). Most patients who were non-persistent discontinued therapy (87.7%) instead of switching to a different OAC. Of the small number who did switch, most patients on apixaban or rivaroxaban switched to VKAs (Table 2).

Sensitivity analyses

Differences in non-persistence were attenuated using a 30-day discontinuation gap and amplified with 90-day gap (Figure 2). Without the use of INR records to extend VKA treatment lines, non-persistence with VKAs appeared higher than in the main analysis, and may be similar to rivaroxaban and dabigatran, and thus may also be higher than apixaban (Figure 3). Overall, the cumulative incidence of non-persistence was lower among those who regularly attended the same physician; however, risk differences in non-persistence between OACs appeared to be similar to the main analysis (Figure 4).

Figure 2

Figure 2. 

A. Cumulative incidence of non-persistence across oral anticoagulants in sensitivity analyses, using a discontinuation gap of 30 days. B. Cumulative incidence of non-persistence across oral anticoagulants in sensitivity analyses, using a discontinuation gap of 90 days. VKA: vitamin K antagonist.


Figure 3

Figure 3. 

Cumulative incidence of non-persistence across oral anticoagulants in a sensitivity analysis when international normalised ratio records are not used to estimate vitamin K antagonist (VKA) treatment.


Figure 4

Figure 4. 

Cumulative incidence of non-persistence across oral anticoagulants in a sensitivity analysis among patients who regularly visited the same physician in the 12 months before the index date. VKA: vitamin K antagonist.



To our knowledge, this is the first study to present real-world evidence regarding the current management of OACs in NVAF, including the most recently approved OAC – apixaban – in France. The study describes the profiles of patients prescribed different OACs, and how continuation of therapy varies between OACs in French primary care. The generalisability of our results is limited to this setting; however, we expect many patients to be managed by their primary care physician, and such data therefore provide valuable information on drug therapy. We acknowledge that there may be incomplete therapy information if patients are prescribed by a specialist or a primary care physician outside of those contributing to this database.

History of stroke risk factors and previous bleeds were slightly more prevalent in patients prescribed apixaban and VKAs, although the differences were small. This could indicate that primary care physicians favour apixaban and VKAs over rivaroxaban and dabigatran for certain patient groups. Concerns over bleeding risks with dabigatran were raised in 2011 [28]; physicians and patients may, subsequently, be wary of dabigatran if the patient has a history of bleeds. Alternatively, physicians may consider that apixaban and VKAs provide improved efficacy in preventing stroke for those with a history of stroke risk factors, despite rivaroxaban and dabigatran also demonstrating lower rates of stroke compared with VKAs in clinical trials. The differences in patient characteristics observed in this study highlight the potential for channelling bias, which should be borne in mind in future studies of OAC use.

A third of patients prescribed NOACs were initiated on an adjusted dose. Although NOACs have been developed with a single dose for most patients, adjusted doses are recommended in certain patients (e.g. those with kidney disease). In our study, it was not possible to examine whether patients were prescribed on-label NOAC doses because of incomplete laboratory data.

While nearly 60% of patients were prescribed a NOAC in the study period, physicians may follow guidelines from either the European Society of Cardiology (where NOACs are preferred over VKAs) [5] or the Haute Autorité de Santé (where NOACs should be second “intention” to VKAs) [29]. As it is not possible to know about a patient's OAC exposure with a physician outside of the IMS LPD network, it is difficult to assess which guidelines are being adhered to.

The persistence rates, ranging from 42.6% (95% CI: 36.7–48.4%) with dabigatran to 56.4% (95% CI: 53.4–59.3%) with VKAs at 12 months, were markedly lower than in other studies [18, 20, 21, 30]. In a similar study we conducted in the UK, rates ranged from 66.7% with dabigatran to 82.8% with apixaban [19]. Differences in persistence between studies may be expected when comparing with different countries and healthcare systems. For example, in the UK, there are anticoagulation clinics for VKA monitoring, which may improve a patient's likelihood of persistence with a VKA compared with in countries without such provisions. Moreover, in France, patients might have consulted a specialist without referral from primary care, which could mean a higher rate of consultation with the cardiologist in France, leading to lower observed persistence in primary care.

In comparisons of non-persistence with VKAs, apixaban was similar and rivaroxaban and dabigatran were higher. This is supported by one study from Sweden [21]; however, several studies found non-persistence was higher with VKAs [19, 20, 30, 31] compared with other NOACs. In comparison with apixaban, non-persistence was similar with rivaroxaban, but higher with dabigatran. Higher non-persistence with dabigatran than apixaban has been observed consistently in several studies [19, 21, 31, 32]. A recent study from Denmark also identified higher non-persistence with dabigatran (and VKAs) compared with apixaban, and similar persistence between rivaroxaban and apixaban [22]. Reasons for non-persistence were not examined in this study; however, bleeding side effects of OACs is a major concern, and a common reason for non-persistence [17, 33]. NOACs have demonstrated lower rates of bleeding compared with VKAs in clinical trials and observational studies [9, 12, 13, 34, 35], and two recent studies have indicated a lower bleeding risk with apixaban over other NOACs [22, 36]. The higher persistence with VKAs observed in our study could result, in part, from our approach, which extended VKA treatment lines to account for VKAs prescribed outside of primary care. This may have overestimated VKA exposure, leading to higher persistence rates. Other reasons for differences in non-persistence between OACs include whether patients are prescribed an adjusted dose (e.g. those on an adjusted NOAC dose could potentially be at lower bleeding risk and demonstrate higher persistence than those on a standard dose), as well as differences in the length of time each NOAC had been available, which could lead to differences in patient or physician preferences. There are also situations where a discontinuation or switch is appropriate, such as severe renal impairment or if a patient has undergone cardioversion. Overall, this study highlights that there is a large proportion of patients who cease OAC treatment, despite an elevated risk of stroke. Further research is needed to investigate reasons for non-persistence, and whether it is appropriate, as well as the comparative safety and effectiveness of OAC treatments. In addition, future real-world studies with larger populations and longer follow-up periods could assess changes in non-persistence over calendar time, given that guidelines, clinical practice and physician and patient education have changed over the last few years.

Real-world studies of persistence vary by study design, which contributes to the variation in observed persistence rates (e.g. differing lengths of time between prescriptions, which define discontinuation, and differing approaches to handling missing prescribing information). Differences in methods and assumptions can hinder the ability to compare studies, and can be perceived as limitations; however, they are necessary, given the differing nature of the data in each study, and can still be internally valid and plausible.

Real-world primary care data is, however, a key strength of this study, removing the influence of study environment on patient persistence, and capturing a large proportion of people with NVAF in France. In this database, prescribing data are detailed, reducing the assumptions needed to estimate persistence, and a broad spectrum of medical information is available. This database is also representative of physicians and the general population by age and sex, and for physicians, geographical location [23]. Physicians are selected among all physicians using the same patient management software, thus there can be no differential influence on physician behaviour through the software. However, there are limitations to using this database: for example, information on time in therapeutic range of VKA was not calculable, as INR test result values are limited and information on patient adherence to NOAC therapy was unavailable. Further limitations to using routinely collected data exist, including the absence of prescribing information outside of primary care and potential differences in how physicians code, and residual confounding is likely to be present as a result of unknown and unmeasured factors. No information on death or patient transfers was recorded; follow-up was based on last observed visit, which could underestimate follow-up time and length of persistence. A further drawback of the database is the potential for incompleteness of prescribing data if physicians frequently choose to leave the database.


This study is the first to describe the use of currently available OACs, including the most recently introduced drug, apixaban, in the routine care of patients with NVAF in France. NOACs were more commonly prescribed than VKAs, and there may be differences in patients prescribed different OACs. Patients prescribed VKAs were more persistent than those prescribed rivaroxaban and dabigatran, whereas persistence with apixaban was similar to VKAs. This study had a limited amount of follow-up available, and the results would benefit from further real-world studies with larger populations and longer follow-up periods to validate the findings and examine longer-term persistence. In addition to this, safety outcomes and other potential reasons for non-persistence should be investigated.

Sources of funding

This study was funded by Bristol-Myers Squibb and Pfizer.

Disclosure of interest

S.-L.C., M.E.J. and A.M. Employed by the company OXON Epidemiology Ltd. Paid consultants to the companies Bristol-Myers Squibb and Pfizer in connection with conducting this study, and with the development of this manuscript.

V.V.-M., G.S. and C.L. Employed by the company Bristol-Myers Squibb.

J.A. and G.B. Employed by the company IMS Health. Paid consultants to the companies Bristol-Myers Squibb and Pfizer in connection with conducting this study.

D.D., F.M. and L.F. Paid consultants to the companies Bristol-Myers Squibb and Pfizer in connection with providing clinical advice to this study.


S.-L.C., M.E.J., C.L., A.M., V.V.-M. and G.S. participated in the study design. J. A. and G. B. performed the statistical analyses. All authors contributed to the interpretation of results. S.-L.C. and M.E.J. drafted the manuscript. All authors contributed to further drafts and approved the final manuscript.

Appendix A. Supplementary material

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