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Impact of Direct Oral Anticoagulant Off-Label Reduced Dose in Combination With Antiplatelet Agents on Clinical Outcome?- Propensity Score-Matching Analysis From the DIRECT Real-World Non-Valvular Atrial Fibrillation Registry.

ABSTRACT: Background: The association between direct oral anticoagulant (DOAC) dose and clinical outcomes when used with antiplatelets still remains to be investigated. Methods?and?Results: We conducted a prospective registry of non-valvular atrial fibrillation (AF) patients with DOAC: the DIRECT registry (n=2,216; follow-up, 407±388 days). We analyzed patients taking standard dose (n=907) and off-label reduced dose (n=338) DOAC in this sub-analysis. These patients were further stratified by add-on antiplatelets. Because DOAC dose was not randomly selected, potential confounding factors were eliminated through a propensity score-matching technique. The primary endpoint was clinically significant bleeding. The secondary endpoint was major adverse cardiovascular events (MACE; composite of all-cause death, all myocardial infarction, and stroke/systemic embolism). In patients with DOAC only/DOAC+antiplatelets, we successfully matched 212/62 patients who received off-label reduced dose DOAC with 212/62 standard dose patients. Off-label DOAC dose reduction did not have a significant impact on bleeding (HR, 1.123; 95% CI: 0.730-1.728, P=0.596) or MACE (HR, 1.107; 95% CI: 0.463-2.648, P=0.819) in patients with DOAC only, whereas in patients with add-on antiplatelets, off-label dose reduction significantly reduced bleeding (HR, 0.429; 95% CI: 0.212-0.868, P=0.019) without increasing MACE (HR, 2.205; 95% CI: 0.424-11.477, P=0.348). Conclusions: Reduced DOAC dose in combination with antiplatelet agents was associated with fewer bleeding complications than standard-dose therapy with no reduction in efficacy.

SUBMITTER: Kobayashi T

PROVIDER: S-EPMC7925311 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Impact of Direct Oral Anticoagulant Off-Label Reduced Dose in Combination With Antiplatelet Agents on Clinical Outcome　- Propensity Score-Matching Analysis From the DIRECT Real-World Non-Valvular Atrial Fibrillation Registry.

Kobayashi Tomoaki T Sotomi Yohei Y Hirata Akio A Sakata Yasushi Y Hirayama Atsushi A Higuchi Yoshiharu Y

Circulation reports 20200407 6

Background: The association between direct oral anticoagulant (DOAC) dose and clinical outcomes when used with antiplatelets still remains to be investigated. Methods and Results: We conducted a prospective registry of non-valvular atrial fibrillation (AF) patients with DOAC: the DIRECT registry (n=2,216; follow-up, 407±388 days). We analyzed patients taking standard dose (n=907) and off-label reduced dose (n=338) DOAC in this sub-analysis. These patients were further ...[more]

PMID: 33693243

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Project description:Background: The use of direct oral anticoagulant (DOAC) off-label doses in atrial fibrillation (AF) patients may result in poor clinical outcomes. However, the true prevalence remains scarce. This study aims at estimating the prevalence of DOAC off-label doses in AF patients. Methods: Databases of MEDLINE, EMBASE, and COCHRANE were searched from inception through February 2020 for real-world studies that reported the off-label definition and prevalence data of AF patients using DOACs. The primacy outcomes were the overall prevalence of DOAC off-label doses and the corresponding underdose and overdose. The random-effects model was used for data synthesis. Variations on individual DOAC and different regions were examined by subgroup analyses. Results: A total of 23 studies involving 162,474 AF patients were finally included. The overall prevalence of DOAC off-label doses was 24% (95% CI, 19-28%), with 18% for dabigatran, 27% for rivaroxaban, 24% for apixaban, and 26% for edoxaban. The prevalence of underdosed DOACs was 20% (95% CI, 16-24%) with significant difference among individual anticoagulants (13% for dabigatran, 22% for rivaroxaban, 22% for apixaban, and 18% for edoxaban; P interaction =0.02). The prevalence of overdosed DOACs was 5% (95% CI, 3-7%), with the lowest prevalence observed in apixaban (2%). Subgroup analyses by regions demonstrated that the prevalence of DOAC off-label doses was higher in Asia (32%) than in North America (14%) and in Europe (22%), with underdose being predominant. Regardless of different regions, the prevalence of overdose was relatively low (4-6%). Conclusion: This study provides an estimation of DOAC off-label doses in the real-world setting. The prevalence rate of DOAC off-label doses in AF patients was relatively high, with underdose being predominant. Clinicians in Asia preferred to prescribe underdose of DOACs to AF patients. More evidence about the appropriateness of DOAC off-label doses in AF patients is urgently needed. Education programs concerning the appropriate prescription of DOACs within the drug labels and accepted guidelines are necessary to DOAC prescribers to ensure the safety and effectiveness of anticoagulation therapy for patients with AF.

Project description:Patients enrolled into pivotal randomized controlled trials (RCTs) may differ substantially from those treated in a real-world (RW) setting, which may result in a different benefit-risk profile. The aim of the study was to assess the external validity of pivotal RCT findings concerning direct oral anticoagulants (DOACs) for the treatment of nonvalvular atrial fibrillation (NVAF) by comparing patients recruited in RCTs to those treated with DOACs registered in a southern Italian local health unit (LHU) in the years 2013-2017. The Palermo LHU claims database was used to describe the baseline characteristics of incident DOAC users (washout > 1 year) with NVAF compared with those of enrolled patients in DOAC pivotal RCTs. In the RW, DOAC treatment discontinuation was calculated during the follow-up and compared with DOAC treatment discontinuation of enrolled patients in DOAC pivotal RCTs. Rates of effectiveness and safety outcomes during the follow-up were calculated in an unmatched and in a simulated RCT population, by matching individual incidental RW and RCT DOAC users (excluding edoxaban users) on age, sex, and CHADS2 score. Overall, 42,336 and 7092 incident DOAC users with NVAF were identified from pivotal RCTs and from the RW setting, respectively. In RCTs, DOAC use was more common among males (62.6%) compared with an almost equal sex distribution in the RW. RCT patients were younger (mean age ± standard deviation: 70.7 ± 9.2 years) than RW patients (76.0 ± 8.6 years). Compared with RCTs, a higher proportion of RW dabigatran users (30.4% vs. 19.6%) and a lower proportion of RW apixaban (15.9% vs. 25.3%) and rivaroxaban (20.4% vs. 23.7%) users discontinued the treatment during the follow-up (p-value < 0.001). The rate of ischemic stroke was lower in RW high-dose dabigatran users (unmatched/-matched population: 0.40-0.11% per year) than in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) population (0.93% per year). Major bleeding rates were lower in RW users than in RCT users. In conclusion, except for dabigatran, a lower proportion of DOAC discontinuers was observed in the real-world than in pivotal RCT settings. This study provides reassurance to practicing physicians that DOAC use appears to be effective in stroke prevention and is likely safer in RW patients than in RCT enrolled patients. These results may be related to a lower burden of comorbidities despite more advanced age in the RW population compared to the pivotal RCT population.

Dataset Information

Impact of Direct Oral Anticoagulant Off-Label Reduced Dose in Combination With Antiplatelet Agents on Clinical Outcome?- Propensity Score-Matching Analysis From the DIRECT Real-World Non-Valvular Atrial Fibrillation Registry.

Publications

Impact of Direct Oral Anticoagulant Off-Label Reduced Dose in Combination With Antiplatelet Agents on Clinical Outcome　- Propensity Score-Matching Analysis From the DIRECT Real-World Non-Valvular Atrial Fibrillation Registry.

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Dataset Information

Impact of Direct Oral Anticoagulant Off-Label Reduced Dose in Combination With Antiplatelet Agents on Clinical Outcome?- Propensity Score-Matching Analysis From the DIRECT Real-World Non-Valvular Atrial Fibrillation Registry.

Publications

Impact of Direct Oral Anticoagulant Off-Label Reduced Dose in Combination With Antiplatelet Agents on Clinical Outcome - Propensity Score-Matching Analysis From the DIRECT Real-World Non-Valvular Atrial Fibrillation Registry.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Impact of Direct Oral Anticoagulant Off-Label Reduced Dose in Combination With Antiplatelet Agents on Clinical Outcome　- Propensity Score-Matching Analysis From the DIRECT Real-World Non-Valvular Atrial Fibrillation Registry.