Highlights
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DOAC treatment in patients with atrial fibrillation is performed with two doses (standard and reduced) selected according to recommended criteria.
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The MAS trial demonstrated that the use of either dose, especially the reduced dose, did not prevent too low or too high DOAC blood levels in some patients because of the very high interpatient DOAC variability.
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In this sub-analysis of the MAS study, we evaluated whether the use of the age-adjusted Charlson Comorbidity Index would have led to significant differences in DOAC dosing compared with the standard criteria.
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We did not observe a potential benefit of using the Charlson index.
Abstract
Background
Frailty influences the effectiveness and safety of anticoagulant therapy in patients with atrial fibrillation (AF). The age-weighted Charlson comorbidity index may offer a valuable tool to assess the risk of adverse events in AF patients treated with direct oral anticoagulants (DOACs). This sub-analysis of MAS trial data aimed to assess whether using the Charlson index, instead of the standard criteria, would have led to different dosing and improved adverse event occurrence during treatment.
Methods
The MAS study looked for a relationship between DOAC levels assessed at baseline and adverse events during follow-up. The study is described in detail elsewhere.
Results
Among the 1,657 patients studied, 832 (50.2 %) had a relatively low Charlson index (up to 6, general median class), of whom 132 (15.9 %) were treated with reduced doses. Conversely, among the 825 patients with a high Charlson index (≥7), 257 (31.1 %) received standard doses. A weak but statistically significant positive correlation (r = 0.1413, p < 0.0001 by ANOVA) was observed between increasing Charlson classes and DOAC levels standardized to allow comparability among drug results. However, no significant differences were found in the incidence or number of adverse events during follow-up, or in other parameters, between patients with low and high Charlson’s scores.
Conclusions
Utilizing the Charlson index would have led to notable differences in DOAC dosing compared to standard criteria. However, we found no evidence that its use would have improved the prediction of adverse events in AF patients enrolled in the MAS study.
Introduction
Atrial fibrillation (AF), the most common cardiac arrhythmia, is a significant risk factor for stroke, with an incidence about five times higher than in those without AF. The prevalence of AF increases with age, affecting approximately 9 % of individuals over 80 years old. Aging itself is also a risk factor for stroke, highlighting the importance of chronic anticoagulant therapy for stroke prevention in elderly patients with AF. However, anticoagulation carries an inherent risk of bleeding, which is particularly pronounced in older adults.
In the past decade, a new class of anticoagulants, known as direct oral anticoagulants (DOACs), has been introduced. Clinical trials and meta-analyses , have demonstrated the efficacy and safety of DOACs in preventing strokes in patients with non-valvular AF. Compared to warfarin, DOACs have shown lower rates of stroke and systemic embolism, similar rates of major bleeding, and a reduced risk of intracranial hemorrhage, even among elderly and frail populations. , These benefits, along with their ease of use, have made DOACs the most widely prescribed drugs to prevent thromboembolism in non-valvular AF patients. However, the risk of thrombotic and bleeding events persists in patients receiving DOACs.
DOACs are typically administered at standard or reduced doses, without adjustment based on DOAC concentration measurements. Reduced doses are often prescribed to mitigate the risk of bleeding in patients with advanced age, comorbidities, low body weight, or impaired renal function. However, recent findings from the MAS trial indicate that reduced dosing may not always achieve these goals. Thrombotic complications were notably associated with very low DOAC activity levels at baseline, while high DOAC levels at baseline, despite reduced dosing, were linked to an increased incidence of bleeding events, particularly during the first three months of therapy. These results suggest that, given the considerable variability in individual DOAC activity levels, , reduced doses alone may not ensure appropriate DOAC activity levels for all patients.
This sub-analysis of the MAS data explores whether using the Charlson age-weighted comorbidity index, originally developed to classify prognostic comorbidity in longitudinal studies to assess the overall characteristics of the patient population, could have influenced the decision to use reduced or standard DOAC doses, as well as the outcomes observed in the MAS study.
Material and methods
The observational, prospective cohort, multicenter Measure and See study (MAS, NCT03803579) examined patients with AF who started treatment with a DOAC (apixaban, dabigatran, edoxaban, or rivaroxaban). The study was promoted and funded by the “Arianna Anticoagulazione” Foundation (Bologna, Italy) and conducted in Anticoagulation Clinics affiliated with the Italian Federation of Anticoagulation Centers (FCSA). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Independent review board approval was obtained prior to all study-related activity from the Ethics Committee (EC) of the coordinating center (Cremona) (approval number 14725; 02/05/2018) and from the ECs of all the other participant centers. The promoter of the study provided the measures to safeguard the subject’s privacy and the protection of personal data according to the EU GDPR 2016/679 and Italian law.
Patient population
Patients older than 18 years, with non-valvular AF, who had initiated a DOAC treatment within one month, and had given their signed informed consent, were included in the study between 27 August 2018 and 10 November 2022. They agreed to have blood sampling and a follow-up for one-year after sampling. Patients with other indications for anticoagulant therapy or with indication for electrical cardioversion were excluded from the study. The prescription of the DOAC drug and dose was left to the discretion of the treating physicians.
The anonymity of included patients was obtained by an identifying personal code given to each patient by the participant centers. The code was used to collect clinical information, identify plasma samples, and record the results of DOAC level measurements. Data were gathered in a specific electronic database located at a section of Aruba cloud, rented by the “Arianna Anticoagulazione” Foundation, which guaranteed storage, backup, and maintenance of the database. The collected information included: patient code, date of birth, gender, type and dose of DOAC used, weight, body mass index, kidney function [estimated by creatinine clearance (CrCl) according to the Cockroft-Gault formula], liver function, diabetes, CHA 2 DS 2 VASc and HAS-BLED scores, previous stroke/TIA, other comorbidities, and concomitant medications. The Charlson weighted comorbidity index score, combining both age and comorbidity, was also calculated in all patients; the items included in the index are shown in Table 1 .
| Weight for diseases | Conditions |
|---|---|
| 1 | Myocardial infarct |
| Congestive heart failure | |
| Peripheral vascular disease | |
| Cerebrovascular disease | |
| Dementia | |
| Chronic pulmonary disease | |
| Connective tissue disease | |
| Ulcer disease | |
| Mild liver disease | |
| Diabetes | |
| 2 | Hemiplegia |
| Moderate or severe renal disease | |
| Diabetes with end organ damage | |
| Any tumor | |
| Leukemia | |
| Lymphoma | |
| 3 | Moderate or severe liver disease |
| 6 | Metastatic solid tumor |
| AIDS |
Blood sampling and DOAC measurement
Venous blood was sampled in all patients within the first 2-4 weeks of initiation of treatment (steady state), immediately before the subsequent intake of the drug (at trough). The collection of an additional blood sample on the same day, 2 hours after the last drug intake (at peak) was left to the decision of participating centers. The present report analyzes only DOAC level results assessed at trough. As described in detail elsewhere, blood samples were centrifuged and plasma aliquots were frozen and at first locally stored; plasma aliquots were then centralized and – finally – DOAC activity was measured in all the aliquots in only one laboratory [in the coordinating center (Cremona)].
The results of measured C-trough DOAC activity levels, identified with the patient identity code, were transmitted to the central database repository, and kept blind to patients, participating centers and attending physicians until the end of follow-up.
Follow-up and outcomes
All thromboembolic and bleeding complications, death, and other events were recorded during the 12-month follow-up. Thromboembolic complications included: objectively documented ischemic cerebral vascular events [stroke or transient ischemic attack (TIA)], systemic emboli, acute venous thromboembolism (VTE), acute myocardial infarction (AMI), and thrombotic and cardiovascular deaths. Bleeding outcomes were the major bleeding (MB), defined as to the International Society for Thrombosis and Haemostasis, and clinically relevant non-major bleeding (CRNMB). An independent adjudication committee, that was unaware of patient name, the results of DOAC measurements, and the enrolling center, assessed all the adverse events.
The CHA 2 DS 2 VASc risk stratification scheme to predict stroke and thromboembolism was calculated; while the HAS-BLED and the DOAC-Score were calculated to predict the risk of bleeding.
Statistical analysis
Descriptive analysis was performed. Continuous variables are expressed as median and range. Categorical variables are expressed as frequencies and percentages. ANOVA was used for analysis of variance.
To make comparable the results of the different DOAC drugs, the absolute DOAC plasma activity values were standardized by subtracting from the original values the mean value of all results of each DOAC drug divided by the standard deviation. Standardized values represent the distance of each value from the drug mean distribution and may be therefore pooled to evaluate the drug activity levels, irrespective of the DOAC type and administration (OD or BID).
Patients were censored at the end of the study, after the occurrence of a qualifying clinical event, when the initial anticoagulant treatment was stopped or modified, when they moved to another clinical center or were lost to follow-up.
The incidence of thrombotic and bleeding events occurring during follow-up was calculated in patients treated with reduced or standard dose, whose standardized values were stratified in three increasing classes (≤ – 0.50, representing the lowest, between -0.49 and 0.50, the middle, and > 0.50, the highest DOAC levels).
Data were analyzed with the use of Prism software (Version 10.3.1, GraphPad Software Incorporated, San Diego, CA) and SPSS software (version 26 SPSS Inc., IBM, Armonk, NY), and R (version 4.3.1, R Foundation for Statistical Computing, Vienna). Raw data and scripts used for analysis are available upon request to the Authors at osf.io ( https://osf.io , Center for Open Science, Charlottesville, VA).
Results
Charlson index results and use of reduced or standard DOAC doses
The demographic and clinical characteristics of all AF patients studied and those treated with reduced or standard DOAC doses are detailed in Table 2 . Table 2 also includes information on BMI and body weight of patients, data that are not included in the Charlson index. Compared to patients on standard doses, those on reduced doses were significantly older, more frequently had body weight ≤ 60 Kg and severe/moderate renal insufficiency or heart failure, and had higher CHA2DS2-VASc, HAS-BLED and DOAC scores. The median and distribution of Charlson index results in patients on reduced or standard dose are shown in Fig. 1 . Patients with relatively low Charlson index (up to 6, which was the general median class) were 832 (50.2 % of the 1,657 patients studied), of whom 700 were actually treated with standard doses and 132 received reduced doses. Conversely, of the 825 patients in classes ≥ 7, 568 were treated with reduced doses and 257 with standard doses. Among the 140 patients who received a reduced dose considered inappropriate, 95 (67.8 %) had a Charlson index ≥ 7; vice versa, 213 (24.2 %) of those who received a standard dose considered appropriate had a high index (≥ 7) ( Table 3 ).
| All patients n = 1657 | Those receiving reduced doses n = 700 | Those receiving standard doses n = 957 | P Reduced vs standard dose | |
|---|---|---|---|---|
| Age ≤ 50 years n (%) 51-60 61-70 71-80 > 80 | 7 (0.4) 36 (2.2) 237 (14.3) 636 (38.4) 741 (44.7) | 0 3 (0.4) 33 (4.7) 165 (23.6) 499 (71.3) | 7 (0.7) 33 (3.4) 204 (21.3) 471 (49.2) 242 (25.3) | * * * * * |
| Diabetes, n (%) | 367 (22.1) | 153 (21.9) | 214 (22.4) | |
| Cerebrovascular disease, n (%) | 183 (11.0) | 81 (11.6) | 102 (10.7) | |
| Myocardial infarction, n (%) | 279 (16.8) | 133 (19.0) | 146 (15.3) | |
| Congestive heart failure, n (%) | 317 (19.1) | 185 (26.4) | 132 (13.8) | * |
| Peripheral vascular disease, n (%) | 57 (3.4) | 25 (3.6) | 32 (3.3) | |
| Chronic pulmonary disease, n (%) | 205 (12.4) | 104 (14.9) | 101 (10.6) | |
| Dementia, n (%) | 52 (3.1) | 27 (3.9) | 25 (2.6) | |
| Moderate or severe renal disease, n (%) | 858 (51.8) | 588 (84.0) | 270 (28.2) | * |
| Any cancer, n (%) | 55 (3.3) | 30 (4.3) | 25 (2.6) | |
| Moderate or severe liver disease, n (%) | 9 (0.5) | 1 (0.1) | 8 (0.8) | |
| Charlson comorbidity index, median (min-max) | 6 (1-14) | 7 (2-13) | 5 (1-14) | * |
| Charlson comorbidity index, n (%) ≤ 4 5-6 7 ≥ 8 | 377 (22.8) 455 (27.4) 372 (22.4) 453 (27.4) | 30 (4.3) 102 (14.6) 236 (33.7) 332 (47.4) | 347 (36.3) 353 (36.9) 136 (14.2) 121 (12.6) | * * * * |
| Polytherapy ≥3, n (%) | 1196 (72.2) | 553 (79.0) | 643 (67.2) | * |
| BMI median (min-max) | 26.2 (14.9-68.1) | 24.9 (14.9-47.8) | 27.2 (16.9-68.1) | * |
| Body weight, n. ≤ 60 Kg (%) | 309 (18.6) | 245 (35.0) | 64 (6.7) | * |
| CHA 2 DS 2 VASc score, median (min-max) | 4 (0-8) | 5 (0-7) | 4 (0-8) | * |
| CHA 2 DS 2 VASc score ≥4, n (%) | 1072 (64.7) | 578 (82.6) | 494 (51.6) | * |
| HAS-BLED in all patients, median (min-max) | 3 (0-6) | 3 (0-6) | 2 (0-5) | * |
| HAS-BLED score ≥3, n (%) | 996 (60.1) | 581 (83.0) | 415 (43.4) | * |
| DOAC-Score, median (min-max) | 7 (0-10) | 7 (0-10) | 6 (0-10) | * |
| DOAC-Score, ≥7, n (%) | 860 (51.9) | 545 (77.9) | 315 (32.9) | * |
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