Abstract
Aims
Since the introduction of direct oral anticoagulant (DOAC) for atrial fibrillation (AF) therapy, inappropriate and/or underdosing of these drugs has been a major clinical challenge. We evaluated the characteristics of patients with AF treated with inappropriate and low-dose DOACs.
Methods and results
Patients with AF treated with inappropriate and low-dose DOACs from October 2021 to December 2021 were evaluated from the French National Prospective Registry (PAFF). We evaluated 1890 patients with AF receiving DOACs (apixaban 55%, dabigatran 7%, and rivaroxaban 38%). Inappropriate dosing was noted in 18% of the population. Patients with appropriate dosing had less comorbidities: younger age (75 ± 10 vs. 82 ± 8 years old, P < 0.0001), reduced chronic renal failure (26 vs. 61%, P < 0.0001), and lower CHA2DS2VASc and HASBLED scores (3 ± 2 vs. 4 ± 3, P < 0.0001; 2 ±1 vs. 2 ± 2, P < 0.0001), respectively. In multivariate analysis, older age (P < 0.0001) and a higher CHA2DS2VASc score (P = 0.0056) were independently associated with inappropriate DOAC dosing. Among 472 patients (27%) treated with low-dose rivaroxaban or apixaban, 46% were inappropriately underdosed. Patients inappropriately underdosed were younger (82.3 ± 8.4 vs. 85.9 ± 5.9 years, P < 0.0001) with less chronic renal disease (47 vs. 98%, P < 0.0001). However, these patients had higher rates of prior haemorrhagic events (18 vs. 10%, P = 0.01), clopidogrel use (11 vs. 3%, P = 0.0002), and apixaban prescription (74 vs. 50%, P < 0.0001).
Conclusion
Within this large registry, DOACs were associated with inappropriate dosing in 18% of cases. Independent predictors of inappropriate dosing were high CHA2DS2VASc scores and older age. Moreover, 46% of patients treated with low-dose DOACs were inappropriately underdosed and more frequently in patients treated with apixaban.
Keywords: Direct oral anticoagulant, Inappropriate dosing, Atrial fibrillation
Graphical Abstract
Graphical Abstract.
What’s new?
In this large (n = 1890) recent national prospective registry of atrial fibrillation (AF) patients treated with direct oral anticoagulants (DOACs), inappropriate dosing was observed in 18% of cases.
The proportion of patients with AF who underdosed and overdosed with DOACs was 13 and 5%, respectively.
Older age and higher CHA2DS2VASc scores were independent risk factors associated with inappropriate DOAC dosing.
Among patients treated with low-dose DOACs (27% of the registry population), 46% were inappropriately dosed.
Factors associated with inappropriate low dosing were reduced comorbidities and apixaban therapy.
Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia and will affect nearly 18 million people in Europe by 2060.1 The most serious complication of this arrhythmia is stroke and thrombo-embolism, which is risk-stratified using the CHA2DS2VASc score, which forms the basis for oral anticoagulation therapy indication.2,3 Direct oral anticoagulants (DOACs) are the standard anticoagulation therapy for patients with non-valvular AF (NVAF) superseding vitamin K antagonists (VKAs). Currently, three DOACs are available for prescription in France: dabigatran, rivaroxaban, and apixaban.4–6 Importantly, apixaban and rivaroxaban would need dose adjustments according to several factors, including renal function.2,3 Real-world registry data have shown that low-dose DOACs were prescribed in a high proportion of patients with AF (up to 30–40%) compared with those patients recruited into the respective Phase III clinical trials.7,8 Concerns of potential haemorrhagic complications can result in inappropriate underdosing.9,10 The Xantus registry reported that 15% of patients with NVAF were inappropriately underdosed with rivaroxaban.10,11 Indeed, DOAC underdosing can be associated with a higher risk of thrombo-embolic stroke.11,12
Numerous factors have been associated with inappropriate DOAC underdosing, including older age and comorbidities such as concomitant coronary artery disease.13,14
We aimed to evaluate from this recent large French National Prospective Registry the characteristics of patients with NVAF treated with inappropriate and/or underdosed DOACs.
Methods
Study population
Cohort data from October to December 2021 were evaluated from the French National Prospective Registry (PAFF). A national clinical evaluation of the care of patients with NVAF was coordinated by the French College of Cardiology (CNCF). Data collection included baseline characteristics, AF type (paroxysmal, persistent, or permanent), concomitant comorbidities, and associated drug therapies. Data were collected using an electronic record questionnaire completed by 154 nationwide cardiologists.
Chronic kidney disease was defined as kidney damage or creatinine clearance (CrCl) < 60 mL/min/1.73 m2 for 3 months or more, irrespective of cause.15 Creatinine clearance was estimated with the Cockcroft–Gault formula.15 Permanent, persistent, and paroxysmal AF, hypertension, and diabetes were defined according to international guidelines.16,17 Antiarrhythmic drugs included all antiarrhythmic types used to treat AF: Class Ic, Class III, and beta-blockers. Ischaemic coronary disease refers to both chronic coronary syndromes and previous acute coronary disease.18 Participants were categorized as appropriately dosed, overdosed, or underdosed. Underdosing and overdosing were, respectively, defined as the administration of a lower or higher DOAC dose than recommended in the European Society of Cardiology guidelines: for dabigatran, 100 mg b.i.d. is indicated for patients with increased bleeding risk, age ≥80 years, or concomitant use of verapamil; for rivaroxaban, 15 mg o.d. is indicated when CrCl is between 15 and 49 mL/min; for apixaban, 2.5 mg b.i.d. is indicated for patients with at least two of three criteria: age ≥80 years, body weight ≤60 kg, and serum creatinine ≥1.5 mg/dL (133 µmol/L).2,3 Factors associated with appropriate DOAC dosing were analysed. Patients treated with dabigatran were excluded, because in France, only the 150 and 110 mg doses are available, and both doses are indicated in patients independent of renal function. This study complied with the Declaration of Helsinki and was approved by the Personal Protection Committee.
Statistical analysis
Continuous variables are expressed as mean ± standard deviation and CHA2DS2VASc and HASBLED scores as median ± interquartile range. Statistical significance was assessed using the unpaired Student’s t-test. Categorical variables, expressed as numbers or percentages, were analysed using the χ2 test or Fisher’s exact test.
Continuous data normality was verified using the Kolmogorov–Smirnov test. A univariate analysis of all variables comparing patients with or without DOAC underdosage was performed. Variables yielding P < 0.05 by univariate analysis and that were not interdependent (i.e. rivaroxaban and apixaban prescription or single parameters included in the CHA2DS2VASc and HASBLED scores) were entered into a multivariate logistic regression analysis that was adjusted according to age and sex. A score of P < 0.05 was considered significant. Statistical analyses were performed using MedCalc software (Belgium).
Results
Baseline characteristics
A total of 1890 patients were included for data analysis (1 patient was excluded due to an incomplete questionnaire).
Baseline characteristics of the study cohort are described in Table 1. The mean age was 76.2 ± 10 years and 60% were males. Previous stroke occurred in 11.4% and coronary artery disease in 14.7% of the cohort. Paroxysmal AF was the most frequent type of AF (42.9%) with persistent and permanent AF recorded in 21.4 and 35.7% of the cohort, respectively. More than half of the cohort (52.7%) were treated with concomitant antiplatelet agents (aspirin 52.7% and clopidogrel 3.6%).
Table 1.
Baseline characteristics of the total population
| N = 1890 | |
|---|---|
| Age (years) | 76.2 ± 10.0 |
| Male sex, n (%) | 1128 (59.7) |
| Comorbidities | |
| Diabetes, n (%) | 452 (23.9) |
| Hypertension, n (%) | 1351 (71.5) |
| Underlying cardiomyopathy, n (%) | 716 (37.9) |
| Chronic kidney disease, n (%) | 583 (31) |
| Hepatic impairment | 17 (0.9) |
| Anaemia <12 g/dL | 138 (7.3) |
| Creatinine (mg/L) | 10.8 ± 3.21 |
| Creatinine clearance (Cockcroft in mL/min) | 65.8 ± 26.0 |
| CHA2DS2VASc score | 3 ± 2 |
| HASBLED score | 2 ± 1 |
| History of ischaemic or haemorrhagic events, n (%) | |
| Stroke | 215 (11.4) |
| Other systemic embolism | 13 (0.7) |
| Peripheral arterial disease | 72 (3.8) |
| Coronary disease | 278 (14.7) |
| Haemorrhagic events | 127 (6.7) |
| Major haemorrhagic events | 23 (1.2) |
| Atrial fibrillation, n (%) | |
| Paroxysmal | 811 (42.9) |
| Persistent | 404 (21.4) |
| Permanent | 675 (35.7) |
| Prescription of DOACs, n (%) | |
| Apixaban 5 mg | 756 (40) |
| Apixaban 2.5 mg | 283 (15) |
| Rivaroxaban 20 mg | 529 (28) |
| Rivaroxaban 15 mg | 189 (10) |
| Dabigatran 150 mg | 76 (4) |
| Dabigatran 110 mg | 57 (3) |
| Echocardiography | |
| LVEF (%) | 59.0 ± 10.1 |
| Medications, n (%) | |
| Clopidogrel | 68 (3.6) |
| Aspirin | 996 (52.7) |
| NSAID | 890 (47.1) |
| Antiarrhythmic drugs | 1750 (92.6) |
DOAC, direct oral anticoagulant; LVEF, left ventricle ejection fraction; NSAID, non-steroid anti-inflammatory drugs.
The breakdown of DOAC prescriptions was as follows (Figure 1 and Table 1): apixaban 55% (40% normal dose, 15% low dose), dabigatran 7% (4% high dose, 3% low dose), and rivaroxaban 38% (28% normal dose, 10% low dose). As shown in Figure 2, apixaban was correctly prescribed in 81% of patients, with inappropriate underdosing in 15% and overdosing in 4% of patients; 85% of patients treated with rivaroxaban received appropriate dosing with 8% of patients inappropriately underdosed and 7% overdosed. The main reasons reported for using low-dose DOACs were major haemorrhage (30%), renal impairment (26%), drug interactions (32%), and patient decision (32%).
Figure 1.
Repartition of DOAC dosage in the study population (n = 1840 patients). DOAC, direct oral anticoagulant.
Figure 2.
Repartition use of appropriate or inappropriate (under or overdosage) rivaroxaban (A) and apixaban (B) dosage.
Characteristics of patients with appropriate or inappropriate direct oral anticoagulant dosing
A total of 1757 patients were included in the analysis of factors associated with appropriate/inappropriate dosing, as 133 patients were treated with dabigatran and therefore excluded. The univariate analysis highlights multiple factors associated with either appropriate or inappropriate DOAC dosing, as shown in Table 2. Patients with appropriate DOAC dosing had reduced comorbidities: younger age (75 ± 10 vs. 82 ± 8 years old, P < 0.0001), less chronic renal failure (26 vs. 61%, P < 0.0001), and lower CHA2DS2VASc and HASBLED scores (3 ± 2 vs. 4 ± 3, P < 0.0001; 2 ± 1 vs. 2 ± 2, P < 0.0001), respectively.
Table 2.
Characteristics of patients with correct DOAC dosage or not (n = 1757)
| Patient characteristics | Appropriate dosage (n = 1441) | Inappropriate dosage (n = 316) | P-value |
|---|---|---|---|
| Age, years | 75 ± 10 | 82 ± 8 | <0.0001 |
| Male gender, n (%) | 879 (61) | 161 (51) | 0.002 |
| Risk factors, n (%) | |||
| Hypertension | 1023 (71) | 234 (74) | 0.28 |
| Diabetes mellitus | 317 (22) | 85 (27) | 0.10 |
| Chronic kidney disease | 375 (26) | 193 (61) | <0.0001 |
| Anaemia <12 g/dL | 101 (7) | 38 (12) | 0.004 |
| Cardiovascular history, n (%) | |||
| Heart failure | 331 (23) | 98 (31) | 0.009 |
| Coronary artery disease | 198 (14) | 75 (24) | <0.0001 |
| Peripheral arterial disease | 42 (3) | 23 (7) | 0.0003 |
| Previous stroke | 147 (10) | 47 (15) | 0.03 |
| Paroxysmal AF | 648 (45) | 118 (37) | 0.01 |
| Persistent AF | 323 (22) | 43 (14) | 0.001 |
| Permanent AF | 456 (32) | 152 (48) | <0.0001 |
| Previous haemorrhagic events, n (%) | |||
| Haemorrhagic events | 78 (5) | 45 (14) | <0.0001 |
| Major haemorrhagic events | 15 (1) | 6 (2) | 0.32 |
| Medications | |||
| Rivaroxaban, n (%) | 609 (42) | 102 (36) | 0.04 |
| Apixaban, n (%) | 832 (58) | 203 (64) | 0.04 |
| Clopidogrel, n (%) | 35 (2) | 29 (9) | <0.0001 |
| Aspirin, n (%) | 736 (51) | 179 (56) | 0.10 |
| NSAID, n (%) | 671 (47) | 147 (47) | 0.98 |
| Antiarrhythmic drugs, n (%) | 1358 (94) | 268 (85) | <0.0001 |
| CHA2DS2VASc score | 3 ± 2 | 4 ± 3 | <0.0001 |
| HASBLED score | 2 ± 1 | 2 ± 2 | <0.0001 |
Bold values correspond to significant differences between the 2 groups, P < 0.05.
AF, atrial fibrillation; DOAC, direct oral anticoagulant; NSAID, non-steroid anti-inflammatory drugs.
In multivariate analysis, older age (P < 0.0001) and higher CHA2DS2VASc scores (P = 0.0056) were the only two independent factors associated with inappropriate DOAC dosing (Table 3).
Table 3.
Multivariate analysis of factors associated with inappropriate DOAC dosage
| P-value | Odds ratio | 95% CI | |
|---|---|---|---|
| Permanent AF | 0.065 | 1.31 | 0.98–1.74 |
| Male gender, n (%) | 0.79 | 1.04 | 0.78–1.39 |
| Age | <0.0001 | 1.07 | 1.05–1.09 |
| HASBLED score | 0.29 | 1.09 | 0.93–1.28 |
| Apixaban | 0.58 | 1.08 | 0.82–1.43 |
| CHA2DS2VASc score | 0.0056 | 1.17 | 1.05–1.31 |
AF, atrial fibrillation; CI, confidence interval; DOAC, direct oral anticoagulant.
Characteristics of patients with appropriate or inappropriate low-dose direct oral anticoagulant prescriptions
Factors associated with underdosing were additionally explored. As shown in Table 4, we studied 472 patients treated with low-dose rivaroxaban (15 mg o.d.) and low-dose apixaban (2.5 mg b.i.d.). A total of 218 patients (46%) were inappropriately underdosed. Patients with inappropriate low dosing had reduced comorbidities such as younger age (82.3 ± 8.4 vs. 85.9 ± 5.9 years old, P < 0.0001) and a lower prevalence of chronic renal disease (47 vs. 98%, P < 0.0001). However, this subpopulation also had higher rates of prior haemorrhagic events (18 vs. 10%, P = 0.01) and prescription rates of clopidogrel (11 vs. 3%, P = 0.0002). Apixaban prescribing was associated with a higher rate of inappropriate underdosing compared with rivaroxaban (74 vs. 50%, P < 0.0001), whereas rivaroxaban had higher rates of appropriate low-dose prescribing (50 vs. 26%, P < 0.0001). Finally, the proportion of low-dose prescribing among the appropriately dosed patients was 17% (252/1441) compared with 70% (n = 220/316) for patients inappropriately dosed, highlighting the prevalence of inappropriate underdosing.
Table 4.
Characteristics of patients receiving low DOAC dosage with appropriate DOAC dosage or not (n = 472)
| Patient characteristics | Appropriate dosage (n = 254) | Inappropriate dosage (n = 218) | P-value |
|---|---|---|---|
| Age, years | 85.9 ± 5.9 | 82.3 ± 8.4 | <0.0001 |
| Male gender, n (%) | 95 (37) | 117 (54) | 0.0006 |
| Risk factors, n (%) | |||
| Hypertension | 194 (76) | 161 (74) | 0.57 |
| Diabetes mellitus | 50 (19) | 56 (26) | 0.12 |
| Chronic kidney disease | 249 (98) | 102 (47) | <0.0001 |
| Body mass index | 24.6 ± 4.1 | 27.0 ± 4.1 | <0.0001 |
| Anaemia <12 g/dL | 49 (19) | 27 (12) | 0.0496 |
| Cardiovascular history, n (%) | |||
| Heart failure | 97 (38) | 70 (32) | 0.18 |
| Coronary artery disease | 41 (16) | 63 (29) | 0.001 |
| Peripheral arterial disease | 13 (5) | 17 (8) | 0.23 |
| Previous stroke | 41 (16) | 37 (17) | 0.86 |
| Paroxysmal AF | 95 (37) | 78 (36) | 0.83 |
| Persistent AF | 38 (15) | 30 (14) | 0.84 |
| Permanent AF | 121 (48) | 110 (50) | 0.45 |
| Previous haemorrhagic events, n (%) | |||
| Haemorrhagic events | 25 (10) | 39 (18) | 0.01 |
| Major haemorrhagic events | 4 (2) | 5 (2) | 0.57 |
| Medications | |||
| Rivaroxaban, n (%) | 128 (50) | 56 (26) | <0.0001 |
| Apixaban, n (%) | 126 (50) | 162 (74) | <0.0001 |
| Clopidogrel, n (%) | 6 (3) | 23 (11) | 0.0002 |
| Aspirin, n (%) | 151 (59) | 121 (56) | 0.44 |
| NSAID, n (%) | 139 (55) | 93 (43) | 0.14 |
| Antiarrhythmic drugs, n (%) | 238 (94) | 178 (82) | 0.0001 |
| CHA2DS2VASc score | 3 ± 2 | 4 ± 3 | 0.09 |
| HASBLED score | 2 ± 1 | 2 ± 2 | 0.82 |
Bold values correspond to significant differences between the 2 groups, P < 0.05.
AF, atrial fibrillation; DOAC, direct oral anticoagulant; NSAID, non-steroid anti-inflammatory drugs.
Discussion
The main findings of this study are: (i) the rate of inappropriate DOAC dosing in patients with AF was still significant at 18% (15% for rivaroxaban and 19% for apixaban), but in the lower range of previously reported studies, (ii) older age and higher CHA2DS2VASc scores were independently associated with inappropriate DOAC dosing; (iii) the rate of low-dose prescribing was 27%, more commonly seen with apixaban than rivaroxaban (61 vs. 39%, P < 0.0001) and 46% of patients with low-dose prescriptions were inappropriately underdosed.
Since DOACs emerged on the market more than a decade ago, prescriptions have progressively increased and have overtaken VKAs. The efficacy and safety of DOACs is dependent on appropriate dosing, and reasons to deviate from the standard dose are different according to the specific drug but predominately based on renal function. Real-world data have shown an initial high rate of low-dose DOAC prescriptions compared with the proportion of patients treated with low-dose DOACs within the Phase III clinical trials.7 It has been suggested that this discrepancy may be attributed to concerns over potential haemorrhagic complications with these newer drugs, with the historical limited availability of antidotes. With increased prescribing guidance and the availability of specific antidotes, low-dose prescribing rate has progressively declined. Staerk et al.19 studied 31 522 patients with AF treated with DOACs, and 32.9% received a low dose, compared with 27% within this study.
However, the pivotal question is whether the low-dose DOAC has been prescribed appropriately. Rates of inappropriate underdosing, causal factors, and the impact of inappropriate DOAC dosing are important clinical questions. In this real-world registry study, the rate of inappropriate dosing with rivaroxaban and apixaban was 18%, similar to the rate of 17.4% reported by Zhang et al.20 in a retrospective analysis of 770 patients with AF.
Apixaban and rivaroxaban are the two most commonly prescribed DOACs in France (around 90% of the market), as edoxaban is not available. In addition, dabigatran 75 mg b.i.d. is not available in France, and the recommended low-dose prescribing (110 mg b.i.d.) for dabigatran is age ≥80 years, concomitant verapamil prescription, or high haemorrhagic risk.2,3 Including dabigatran may have influenced the rate of inappropriate dosage and introduced potential biases in the interpretation of the analysis of associated factors within this study. The rate of inappropriate dosing was relatively high in this registry study (18%), particularly for rivaroxaban (15%). In addition, this rate could have been overestimated for rivaroxaban, because up to 50% of the study population presented with concomitant antiplatelet agents (aspirin and/or clopidogrel). As recommended,2,3,21 a 15 mg o.d. for rivaroxaban is allowed with concomitant antiplatelet agents in the absence of renal failure; thus, the inappropriate low dosing rate of rivaroxaban may be lower (around 5%).
Ruiz Ortiz et al.22 in a prospective Spanish registry of 530 patients with AF observed 32% of patients inappropriately dosed compared with the range of 15–45% in other studies. Several factors may explain such a wide variation such as different population characteristics (age and comorbidities), proportion of dabigatran prescriptions, physician experience, and concerns and variations in the implementation of international guidelines.
Clinical factors associated with inappropriate dosing vary according to studies. Our study highlights that older age and higher CHA2DS2VASc scores are independently associated with inappropriate dosing. In terms of the CHA2DS2VASc score, possible explanations are concerns in avoiding haemorrhagic complications resulting in underdosing or thrombo-embolic risk resulting in overdosing. Consistent with our study, Ferrat et al.23 reported from 1111 patients with AF treated with DOACs that older age, a CHA2DS2VASc score ≥2, and a prescription of apixaban or dabigatran were independently associated with inappropriate DOAC underdosing. Furthermore, Bezabhe et al.24 studied retrospectively 11 251 newly diagnosed patients with AF treated with DOACs. Inappropriate dosing was associated with older age and additional comorbidities such as renal failure. In addition, Godino et al.25 evaluated 760 patients with AF reporting older age, chronic renal failure, history of haemorrhagic event, and the CHA2DS2VASc score were associated with inappropriate dosing. Sugrue et al.26 studied a larger cohort of 8576 patients with AF, highlighting that independent risk factors for inappropriate dosing were: female gender, anaemia, liver failure, and diabetes mellitus. Diemberger et al.27 demonstrated that frailty, evaluated objectively, or by general cardiologist judgement was associated with inappropriate DOAC dosing with edoxaban. These studies emphasize the link between multiple comorbidities and inappropriate dosing with all the available DOACs.
The impact of inappropriate dosing on clinical haemorrhagic and thrombo-embolic events was evaluated in several studies with conflicting results. Steinberg et al., in the Orbit II-AF registry, studied 5738 patients with AF, of whom 12.8% received inappropriate dosing. Interestingly, patients with overdosing had an increased all-cause mortality, whereas underdosed patients had an increased risk of cardiovascular hospitalization. However, no significant increased rates of stroke, transient ischaemic attack, or haemorrhage was noted in inappropriately dosed patients.28 Yao et al. evaluated 14 865 patients with AF treated with DOACs, of whom 12% were underdosed. Patients with inappropriate underdosing with apixaban had a significant five-fold higher risk of stroke, whereas patients with inappropriately underdosed rivaroxaban did not. Furthermore, it was reported that within the potential low-dose DOAC indication cohort (10% of the population), 43% were correctly dosed.29 To extend this analysis, our study has revealed that among the low-dose prescribed patients, 46% had inappropriate low dosing.
Hirsh Raccah et al. observed from 143 patients treated with DOACs that the low-dose prescribing rate was 3 times higher in patients with inappropriate dosing compared with patients treated with the appropriate dose. This observation was reaffirmed within this registry study, as we report a four-fold higher rate (17 vs. 70%).30
Apixaban was more commonly associated with inappropriate low dosing compared with rivaroxaban. This may, in part, be due to the more complex dosing structure for apixaban when compared with the dose reduction recommendations for rivaroxaban. In addition, apixaban may have been prescribed to more patients with multiple comorbidities.
Finally, this registry study reports an unexpected association between age and a lower prevalence of renal dysfunction with inappropriate dosing. It would be expected that younger patients with normal renal function would receive standard doses of DOACs, as the indications for dose reduction are less prevalent in this population. It would therefore follow that a population with lower comorbidities would receive the appropriate standard DOAC dose, findings substantiated in other studies.22,31,32
Limitations
This national French registry is a prospective cohort of patients without a control group or dose randomization to assess more specifically the impact of inappropriate DOAC dosing on AF patient outcomes. In addition, this study was limited in terms of available follow-up data, preventing an analysis of the impact of inappropriate DOAC dosing on clinical outcomes, including thrombo-embolic and/or haemorrhagic events. Patient weight was not specifically analysed, and therefore, it is not possible to determine whether obesity or concerns over body weight may have influenced DOAC dosing.33 As a result of the limitations in the prescribing of dabigatran and edoxaban in France, the findings reported within this study are limited to rivaroxaban and apixaban. Further studies with a more diverse and representative global population including all available DOACs are needed.
Conclusions
In this large prospective national registry, patients with AF treated with DOACs experienced inappropriate dosing in 18% of cases. Independent clinical predictors of inappropriate dosing were older age and higher CHA2DS2VASc scores. Finally, 46% of patients treated with low-dose DOACs were inappropriately underdosed and more frequently observed with apixaban.
Acknowledgements
The authors thank Miss Azrar, Miss Djouadi, and Miss Azouaou for help with data collection.
Contributor Information
Maxime Guenoun, Almaviva Santé, Marseille, France; College National des Cardiologues Français, Paris, France.
Serge Cohen, College National des Cardiologues Français, Paris, France.
Marc Villaceque, Syndicat National des Cardiologues, Paris, France.
Ali Sharareh, College National des Cardiologues Français, Paris, France.
Jerome Schwartz, College National des Cardiologues Français, Paris, France.
Olivier Hoffman, College National des Cardiologues Français, Paris, France.
Jean-Claude Dib, Clinique Ambroise Paré, Neuilly sur Seine, France.
Leon Ouazana, College National des Cardiologues Français, Paris, France.
Serge Assouline, College National des Cardiologues Français, Paris, France.
Eric Parrens, College National des Cardiologues Français, Paris, France; Clinique Tivoli-Ducos, Bordeaux, France.
Thierry Garban, College National des Cardiologues Français, Paris, France.
Vincent Pradeau, College National des Cardiologues Français, Paris, France.
Dominique Guedj-Meynier, College National des Cardiologues Français, Paris, France.
Benoit Lequeux, College National des Cardiologues Français, Paris, France.
Charlotte Cohen, College National des Cardiologues Français, Paris, France.
Philippe Durand, College National des Cardiologues Français, Paris, France; Institut Arnaud Tzanck, Saint Laurent du Var, France.
Francois Dievart, College National des Cardiologues Français, Paris, France.
Tarvinder S Dhanjal, Department of Cardiac Electrophysiology, University of Warwick, Gibbet Hill, Coventry, UK.
Pierre Sabouret, College National des Cardiologues Français, Paris, France; Department of Cardiology, AP-HP, University Hospital Pitie-Salpetriere, Paris, France.
Nicolas Lellouche, Department of Cardiology, AP-HP, University Hospital Henri Mondor, 51, Avenue du Maréchal de Lattre de Tassigny, Creteil 94000, France.
Funding
This study received funding support from Bayer.
Data availability
All data included in the manuscript are available if needed.
References
- 1. Krijthe BP, Kunst A, Benjamin EJ, Lip GHY, Franco OH, Hofman Aet al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013;34:2746–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist Cet al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021;42:373–498. [DOI] [PubMed] [Google Scholar]
- 3. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe Let al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330–93. [DOI] [PubMed] [Google Scholar]
- 4. Connolly SJ, Ezekowitz MD, Yusuf S, EIkelboom J, Oldgren J, Parekh Aet al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. [DOI] [PubMed] [Google Scholar]
- 5. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke Wet al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. [DOI] [PubMed] [Google Scholar]
- 6. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna Met al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. [DOI] [PubMed] [Google Scholar]
- 7. Camm AJ, Amarenco P, Haas S, Hess S, Kirchhof P, Lambelet Met al. Real-world vs. randomized trial outcomes in similar populations of rivaroxaban-treated patients with non-valvular atrial fibrillation in ROCKET AF and XANTUS. Europace 2019;21:421–7. [DOI] [PubMed] [Google Scholar]
- 8. Beyer-Westendorf J, Camm AJ, Fox KAA, Le Heuzey JY, Haas S, Turpie AGGet al. International longitudinal registry of patients with atrial fibrillation and treated with rivaroxaban: RIVaroxaban Evaluation in Real life setting (RIVER). Thromb J 2019;17:7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Yao C, Jones AE, Slager S, Fagerlin A, Witt DM. Exploring clinician perspectives on patients with atrial fibrillation who are not prescribed anticoagulation therapy. PEC Innov 2022;1:100062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Beasley BN, Unger EF, Temple R. Templeanticoagulant options—why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med 2011;364:1788–90. [DOI] [PubMed] [Google Scholar]
- 11. Camm AJ, Amarenco P, Haas S, Hess S, Kirchhof P, Kuhls Set al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016;37:1145–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Camm AJ, Cools F, Virdone S, Bassand JP, Fitzmaurice DA, Arthur Fox KAet al. Mortality in patients with atrial fibrillation receiving nonrecommended doses of direct oral anticoagulants. J Am Coll Cardiol 2020;76:1425–36. [DOI] [PubMed] [Google Scholar]
- 13. Carbone A, Santelli F, Bottino R, Attena E, Mazzone C, Parisi Vet al. Prevalence and clinical predictors of inappropriate direct oral anticoagulant dosage in octagenarians with atrial fibrillation. Eur J Clin Pharmacol 2022;78:879–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Howard M, Lipshutz A, Roess B, Hawes E, Deyo Z, Burkhart JIet al. Identification of risk factors for inappropriate and suboptimal initiation of direct oral anticoagulants. J Thromb Thrombolysis 2017;43:149–56. [DOI] [PubMed] [Google Scholar]
- 15. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert Jet al. Definition and classification of chronic kidney disease: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int 2005;67:2089–100. [DOI] [PubMed] [Google Scholar]
- 16. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier Met al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021–104. [DOI] [PubMed] [Google Scholar]
- 17. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado Vet al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323. [DOI] [PubMed] [Google Scholar]
- 18. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Bretano Cet al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–77. [DOI] [PubMed] [Google Scholar]
- 19. Staerk L, Gerds TA, Lip GYH, Ozenne B, Bonde AN, Lamberts Met al. Standard and reduced doses of dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: a nationwide cohort study. J Intern Med 2018;283:45–55. [DOI] [PubMed] [Google Scholar]
- 20. Zhang ZX, van de Garde EMW, Söhne M, Harmsze AM, van den Broek MPH. Quality of clinical direct oral anticoagulant prescribing and identification of risk factors for inappropriate prescriptions. Br J Clin Pharmacol 2020;86:1567–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose Pet al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423–34. [DOI] [PubMed] [Google Scholar]
- 22. Ruiz Ortiz M, Muñiz J, Raña Míguez P, Roldán I, Marín F, Asunción Esteve-Pastor Met al. Inappropriate doses of direct oral anticoagulants in real-world clinical practice: prevalence and associated factors. A subanalysis of the FANTASIIA Registry. Europace 2018;20:1577–83. [DOI] [PubMed] [Google Scholar]
- 23. Ferrat E, Fabre J, Galletout P, Boutin E, Le Breton J, Renard Vet al. Inappropriate direct oral anticoagulant prescriptions in patients with non-valvular atrial fibrillation: cross-sectional analysis of the French CACAO cohort study in primary care. Br J Gen Pract 2021;71:134–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Bezabhe WM, Bereznicki LR, Radford J, Wimmer BC, Salahudeen MS, Peterson GM. Eight-year trends in direct-acting oral anticoagulant dosing, based on age and kidney function, in patients with atrial fibrillation. J Patient Saf 2022;18:337–41. [DOI] [PubMed] [Google Scholar]
- 25. Godino C, Bodega F, Melillo F, Rubino F, Parlati ALM, Cappelletti Aet al. Inappropriate dose of nonvitamin-K antagonist oral anticoagulants: prevalence and impact on clinical outcome in patients with nonvalvular atrial fibrillation. J Cardiovasc Med 2020;21:751–8. [DOI] [PubMed] [Google Scholar]
- 26. Sugrue A, Sanborn D, Amin M, Farwati M, Sridhar H, Ahmed Aet al. Inappropriate dosing of direct oral anticoagulants in patients with atrial fibrillation. Am J Cardiol 2021;144:52–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Diemberger I, Fumagalli S, Mazzone AM, Bakhai A, Reimitz PE, Pecen Let al. Perceived vs. objective frailty in patients with atrial fibrillation and impact on anticoagulant dosing: an ETNA-AF-Europe sub-analysis. Europace 2022;24:1404–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Steinberg BA, Shrader P, Thomas L, Ansell J, Fonarow GC, Gersh BJet al. Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II Registry. J Am Coll Cardiol 2016;68:2597–604. [DOI] [PubMed] [Google Scholar]
- 29. Yao X, Shah ND, Sangaralingham LR, Gersh BJ, Noseworthy PA. Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol 2017;69:2779–90. [DOI] [PubMed] [Google Scholar]
- 30. Hirsh Raccah B, Rottenstreich A, Zacks N, Matok I, Danenberg HD, Pollak Aet al. Appropriateness of direct oral anticoagulant dosing and its relation to drug levels in atrial fibrillation patients. J Thromb Thrombolysis 2019;47:550–7. [DOI] [PubMed] [Google Scholar]
- 31. Fava JP, Starr KM, Ratz D, Clemente JL. Dosing challenges with direct oral anticoagulants in the elderly: a retrospective analysis. Ther Adv Drug Saf 2018;9:405–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Sato T, Aizawa Y, Fuse K, Fujita S, Ikeda Y, Kitazawa Het al. The comparison of inappropriate-low-doses use among 4 direct oral anticoagulants in patients with atrial fibrillation: from the database of a single-center registry. J Stroke Cerebrovasc Dis 2018;27:3280–8. [DOI] [PubMed] [Google Scholar]
- 33. Malik AH, Yandrapalli S, Shetty S, Aronow WS, Jain D, Frishman WHet al. Impact of weight on the efficacy and safety of direct-acting oral anticoagulants in patients with non-valvular atrial fibrillation: a meta-analysis. Europace 2020;22:361–7. [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
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