Gihp-Naco Prospective Registry: Characterization and Care of Major Bleeding in Patients Treated By Direct Oral Anticoagulants

Abstract Introduction: Direct oral anticoagulants, previously new oral anticoagulants (NOACs) had a favorable risk–benefit profile, both for stroke prevention or systemic embolic events in patients with atrial fibrillation (AF), or for venous thromboembolism (VTE) treatment. Although the rate of intracranial hemorrhage is lower, the risk for major bleeding is similar as for warfarin. Only few data are available for the management of major bleeding in clinical practice. The aim of this study is to present preliminary results regarding characterization and care of major bleeding through a French prospective registry. Methods: The GIHP (French Working group on Perioperative hemostasis) – NACO registry is a prospective observatory started in June 2013 in 32 emergency centers in France and Belgium. Only patients treated by NOACs and hospitalized for major bleeding or urgent surgery were registered. Results: In a midterm analysis in June 2014, 339 patients were included, among which 219 for major bleeding. 75 patients were treated by dabigatran (150 mg bid: 81%), and 142 by rivaroxaban (20 mg od: 54%) (2 patients were treated by Apixaban). The mean age was 76.4 +/- 11y, and mean BMI 26.3. Creatinine clearance was lower than 60 ml/min in 65%. Patients were treated for atrial fibrillation (80%) or VTE (20%). Among patients with AF, 67.2% had CHADS2 at 2 or less. 61.6% of patients received concomitantly at least one drug interfering with CYP or Pgp, and 26.9% received another antithrombotic drug at the time of bleeding. Major hemorrhagic sites were gastrointestinal (25%) and intracranial, either spontaneous (20%) or post-trauma (15%). AOD concentrations were determined in 46% of patients. 20% of the patients with major bleeding had a plasma concentration less than 50 ng/ml. As expected, there is no relationship between drug concentrations and standard hemostatic tests such as PT and aPTT. 38.4% of patients received PCC or aPCC, and 25.7% benefited for any additional procedures (surgery, endoscopy, embolization…). 42.2% of bleeding completely stopped after the administration of clotting factors. At 30d of follow up, 9.1% of patients presented a cardiovascular event, and all-cause mortality was 14.2%. Conclusion: This midterm analysis of the GIHP NACO registry shows consistent results with phase III studies, with some particularities compared to clinical trials, especially in the use of PCC. The registry allows the analysis of specific population such as trauma patients and highlights the care of such major hemorrhages. Disclosures Pernod: LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Off Label Use: PCC and aPCC ro reverse effect of antithrombotic drugs. Albaladejo:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Samama:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Sie:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Bosson:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding.

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A Systematic Review of the Efficacy and Safety of Direct Oral Anticoagulants in Atrial Fibrillation Patients with Diabetes Using a Risk Index

Journal of Clinical Medicine ◽

10.3390/jcm10132924 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2924

Author(s):

Domenico Acanfora ◽

Marco Matteo Ciccone ◽

Valentina Carlomagno ◽

Pietro Scicchitano ◽

Chiara Acanfora ◽

...

Keyword(s):

Diabetes Mellitus ◽

Atrial Fibrillation ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Risk Index ◽

Direct Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Efficacy Rate ◽

Cochrane Central Register ◽

Efficacy And Safety

Diabetes mellitus (DM) represents an independent risk factor for chronic AF and is associated with unfavorable outcomes. We aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF), with and without diabetes mellitus (DM), using a new risk index (RI) defined as: RI =Rate of EventsRate of Patients at Risk. In particular, an RI lower than 1 suggests a favorable treatment effect. We searched MEDLINE, MEDLINE In-Process, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials. The risk index (RI) was calculated in terms of efficacy (rate of stroke/systemic embolism (stroke SEE)/rate of patients with and without DM; rate of cardiovascular death/rate of patients with and without DM) and safety (rate of major bleeding/rate of patients with and without DM) outcomes. AF patients with DM (n = 22,057) and 49,596 without DM were considered from pivotal trials. DM doubles the risk index for stroke/SEE, major bleeding (MB), and cardiovascular (CV) death. The RI for stroke/SEE, MB, and CV death was comparable in patients treated with warfarin or DOACs. The lowest RI was in DM patients treated with Rivaroxaban (stroke/SEE, RI = 0.08; CV death, RI = 0.13). The RIs for bleeding were higher in DM patients treated with Dabigatran (RI110 = 0.32; RI150 = 0.40). Our study is the first to use RI to homogenize the efficacy and safety data reported in the DOACs pivotal studies against warfarin in patients with and without DM. Anticoagulation therapy is effective and safe in DM patients. DOACs appear to have a better efficacy and safety profile than warfarin. The use of DOACs is a reasonable alternative to vitamin-K antagonists in AF patients with DM. The RI can be a reasonable tool to help clinicians choose between DOACs or warfarin in the peculiar set of AF patients with DM.

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Prescribing Errors With Direct Oral Anticoagulants and Their Impact on the Risk of Bleeding in Patients With Atrial Fibrillation

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/10742484211019657 ◽

2021 ◽

pp. 107424842110196

Author(s):

Bruria Hirsh Raccah, PharmD, PhD ◽

Yevgeni Erlichman ◽

Arthur Pollak ◽

Ilan Matok ◽

Mordechai Muszkat

Keyword(s):

Atrial Fibrillation ◽

Major Bleeding ◽

Negative Impact ◽

Conditional Logistic Regression ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Drug Dose ◽

Prescribing Errors ◽

Duration Of Treatment ◽

Inappropriate Treatment

Introduction: Anticoagulants are associated with significant harm when used in error, but there are limited data on potential harm of inappropriate treatment with direct oral anticoagulants (DOACs). We conducted a matched case-control study among atrial fibrillation (AF) patients admitting the hospital with a chronic treatment with DOACs, in order to assess factors associated with the risk of major bleeding. Methods: Patient data were documented using hospital’s computerized provider order entry system. Patients identified with major bleeding were defined as cases and were matched with controls based on the duration of treatment with DOACs and number of chronic medications. Appropriateness of prescribing was assessed based on the relevant clinical guidelines. Conditional logistic regression was used to evaluate the potential impact of safety-relevant prescribing errors with DOACs on major bleeding. Results: A total number of 509 eligible admissions were detected during the study period, including 64 cases of major bleeding and 445 controls. The prevalence of prescribing errors with DOACs was 33%. Most prevalent prescribing errors with DOACs were “drug dose too low” (16%) and “non-recommended combination of drugs” (11%). Safety-relevant prescribing errors with DOACs were associated with major bleeding [adjusted odds ratio (aOR) 2.17, 95% confidence interval (CI) 1.14-4.12]. Conclusion: Prescribers should be aware of the potential negative impact of prescribing errors with DOACs and understand the importance of proper prescribing and regular follow-up.

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The Number of Concomitant Drugs and the Safety of Direct Oral Anticoagulants in Routine Care Patients with Atrial Fibrillation

TH Open ◽

10.1055/s-0040-1721499 ◽

2020 ◽

Vol 04 (04) ◽

pp. e417-e426

Author(s):

Carline J. van den Dries ◽

Sander van Doorn ◽

Patrick Souverein ◽

Romin Pajouheshnia ◽

Karel G.M. Moons ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Routine Care ◽

P Value ◽

Risk Of Mortality ◽

Mortality Effect

Abstract Background The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice. Study Design Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0–5, 6–8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA). Results A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87–1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68–0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88–0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use (p-value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed (p-value for interaction <0.01). Conclusion In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients.

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Direct Oral Anticoagulants in Atrial Fibrillation: Practical Considerations and Remaining Issues

Hämostaseologie ◽

10.1055/a-1329-2430 ◽

2021 ◽

Vol 41 (01) ◽

pp. 035-041

Author(s):

Jan Beyer-Westendorf

Keyword(s):

Atrial Fibrillation ◽

Severe Renal Impairment ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Tube Feeding ◽

High Body Mass Index ◽

Short Review ◽

Phase Iii ◽

Phase Iii Trial ◽

Nasogastric Tube Feeding

AbstractPreventing thromboembolic events, while minimizing bleeding risks, remains challenging when managing patients with atrial fibrillation. Despite large and successful trial programs, several clinical concerns remain which commonly relate to fears of over- or underexposure to drugs and unfavorable outcomes. After a short summary of the main phase III trial findings, this short review discusses the evidence and clinical relevance of common clinical concerns (correct direct oral anticoagulant [DOAC] dosing; DOAC in moderate-to-severe renal impairment; and the relevance of fasting, nasogastric tube feeding, or high body mass index) on DOAC plasma levels. Finally, the need for specific DOAC antidotes will be addressed.

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Anticoagulation Challenges in Hematogeriatrics: Effectiveness and Safety of Direct Oral Anticoagulants Vs Vitamin k Antagonist in Elderly with Atrial Fibrillation

Blood ◽

10.1182/blood-2019-125150 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1162-1162

Author(s):

Desirée Campoy ◽

Gonzalo Artaza ◽

César A Velasquez ◽

Tania Canals ◽

Erik A Johansson ◽

...

Keyword(s):

Atrial Fibrillation ◽

Elderly Patients ◽

Vitamin K ◽

Major Bleeding ◽

Frail Elderly ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Systemic Embolism ◽

Bleeding Events

BACKGROUND Direct oral anticoagulants (DOAC) are increasingly used in patients with Non Valvular Atrial Fibrillation (NVAF) for stroke prevention. However, Follow-Up (FU) and dosing these agents in the elderly can be challenging due to different factors, such as chronic kidney disease, frailty, falls, multifactorial anemia and concomitant polypharmacy. These factors in elderly patients predisposes to both thromboembolic and bleeding events once atrial fibrillation occurs. Therefore, balancing risks and benefits of antithrombotic strategies in older populations is crucial. Despite recent increases in DOAC use in NVAF, there are still limited data regarding DOACs effectiveness and safety in frail elderly patients. AIM To assess the effectiveness and safety according to DOAC or Vitamin K Antagonist (VKA) in a cohort of elderly patients with NVAF. METHODS From April 2016 to April 2019, we consecutively included NVAF elderly patients (≥80 years-old) treated with DOAC or VKA in a prospective multicenter registry. Demographic, laboratory, frailty risk stratification and antithrombotic therapy data were collected. Patients had a minimum FU of 6 months. VKA patients had a standard FU through digital international normalized ratio (INR) control and the efficacy of therapy was determined by the time in therapeutic range (TTR) values from the preceding 6 months of treatment using Rosendaal's method. FU in DOAC patients was performed through structured and integral assessment following the Tromboc@t Working Group recommendations for management in patients receiving DOAC (Olivera et al, Med Clin 2018). Key practical management aspects are listed in the flow chart (Figure 1). Clinical Frailty Scale (CFS score) was assigned to each patient at the beginning and during the FU; patients were classified into three categories: non-frail (CFS 1-4), mild-to-moderately frail (CFS 5-6), and severely frail (CFS 7-9). RESULTS From a total of 1040 NVAF patients, 690 (63.5%) were treated with DOAC (61 dabigatran, 95 rivaroxaban, 254 edoxaban and 280 apixaban) and 350 with VKA. In the VKA group, the mean TTR was 52.8%. Demographic characteristics and CFS score are summarized in table 1. Kaplan-Meier analysis (median FU: 16.5 months) showed a significantly high incidence of stroke/systemic embolism among VKA patients vs DOAC patients (4.2 vs 0.5 events per 100 patient-years, p<0.001). Major bleeding in the DOAC group was significantly infrequent compared with VKA group (2.2 vs 8.9 events, p=0.001). In the DOAC group, 90% (n=20/22) of the major bleedings were gastrointestinal [16 rivaroxaban and 4 edoxaban]. However, in the VKA group 64% (n = 20/31) were gastrointestinal, 25.8% (n= 8/31) intracranial and 9.7% (n = 3/31) urogenital bleedings. We identified 365 very elderly patients (aged ≥ 90 years) of which 270 (39.1%) were DOAC patients and 95 (27.1%) VKA patients. In this subgroup of patients, after a multivariate regression analysis, the stroke/systemic embolism incidence was similar in both treatment groups regardless of the age, but major bleeding decreased significantly in DOAC group (adjusted HR 0.247, 95% CI 0.091-0.664). CONCLUSIONS Our data indicate that DOACs can be a good therapeutic option for stroke/systemic embolism prevention in frail elderly patients, showing low rates of stroke as well as bleeding events when a structured and integral FU is applied to anticoagulated patients. Further investigations are necessary to analyze the impact in the quality of life and net clinical benefit of anticoagulant therapy when a FU program is applied in elderly patients. Disclosures Sierra: Novartis: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria.

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Safety and timing of resuming dabigatran after major gastrointestinal bleeding reversed by idarucizumab

SAGE Open Medical Case Reports ◽

10.1177/2050313x17753336 ◽

2018 ◽

Vol 6 ◽

pp. 2050313X1775333 ◽

Cited By ~ 1

Author(s):

Gian Galeazzo Riario Sforza ◽

Francesco Gentile ◽

Fabio Stock ◽

Francesco Caggiano ◽

Enrica Chiocca ◽

...

Keyword(s):

Atrial Fibrillation ◽

Case Report ◽

Major Bleeding ◽

Acute Treatment ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Oral Vitamin ◽

Bleeding Events ◽

Massive Rectal Bleeding

The recent introduction of direct oral anticoagulants, including rivaroxaban, dabigatran, apixaban, and edoxaban, for the acute treatment and secondary prevention of venous thromboembolism and in atrial fibrillation has been shown to provide greater clinical benefit than oral vitamin K antagonists. However, direct oral anticoagulants are associated with adverse events, the most common being major bleeding; such events require the reversal of the anticoagulant effects by specific agents. In this case report, we describe an 87-year-old female with atrial fibrillation treated with dabigatran who had massive rectal bleeding. Idarucizumab 5 g (2 × 2.5 g/50 mL) was successfully used to reverse dabigatran effect; subsequent to this, treatment with dabigatran was resumed, and there were no further bleeding events. This suggests that dabigatran can be safely restarted after major bleeding, but this outcome needs to be confirmed in studies involving larger groups of patients.

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Impact of weight on the efficacy and safety of direct-acting oral anticoagulants in patients with non-valvular atrial fibrillation: a meta-analysis

EP Europace ◽

10.1093/europace/euz361 ◽

2020 ◽

Vol 22 (3) ◽

pp. 361-367 ◽

Cited By ~ 3

Author(s):

Aaqib H Malik ◽

Srikanth Yandrapalli ◽

Suchith Shetty ◽

Wilbert S Aronow ◽

Diwakar Jain ◽

...

Keyword(s):

Atrial Fibrillation ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Outcome Data ◽

Phase Iii ◽

Safety And Efficacy ◽

Low Bmi ◽

Direct Acting ◽

The Impact ◽

Direct Acting Oral Anticoagulants

Abstract Aims This study sought to determine the impact of weight and body mass index (BMI) on the safety and efficacy of direct-acting oral anticoagulants (DOACs) compared with warfarin in patients with non-valvular atrial fibrillation. Methods and results A systematic literature search was employed in PubMed, Embase, and Cochrane clinical trials with no language or date restrictions. Randomized trials or their substudies were assessed for relevant outcome data for efficacy that included stroke or systemic embolization (SSE), and safety including major bleeding and all-cause mortality. Binary outcome data and odds ratios from the relevant articles were used to calculate the pooled relative risk. For SSE, the data from the four Phase III trials showed that DOACs are better or similarly effective with low BMI 0.73 (0.56–0.97), normal BMI 0.72 (0.58–0.91), overweight 0.87 (0.76–0.99), and obese 0.87 (0.76–1.00). The risk of major bleeding was also better or similar with DOACs in all BMI subgroups with low BMI 0.62 (0.37–1.05), normal BMI 0.72 (0.58–0.90), overweight 0.83 (0.71–0.96), and obese 0.91 (0.81–1.03). There was no impact on mortality in all the subgroups. In a meta-regression analysis, the effect size advantage of DOACs compared with warfarin in terms of safety and efficacy gradually attenuated with increasing weight. Conclusion Our findings suggest that a weight-based dosage adjustment may be necessary to achieve optimal benefits of DOACs for thromboembolic prevention in these patients with non-valvular atrial fibrillation. Further dedicated trials are needed to confirm these findings. PROSPERO 2019 CRD42019140693. Available from: https://www.crd.york.ac.uk/prospero/display_record.php? ID=CRD42019140693.

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Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and cancer a meta-analysis

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-020-02304-3 ◽

2020 ◽

Cited By ~ 2

Author(s):

Marco Valerio Mariani ◽

Michele Magnocavallo ◽

Martina Straito ◽

Agostino Piro ◽

Paolo Severino ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Major Bleeding ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Significant Risk ◽

Bleeding Complications ◽

Efficacy And Safety

Abstract Background Direct oral anticoagulants (DOACs) are recommended as first-line anticoagulants in patients with atrial fibrillation (AF). However, in patients with cancer and AF the efficacy and safety of DOACs are not well established. Objective We performed a meta-analysis comparing available data regarding the efficacy and safety of DOACs vs vitamin K antagonists (VKAs) in cancer patients with non-valvular AF. Methods An online search of Pubmed and EMBASE libraries (from inception to May, 1 2020) was performed, in addition to manual screening. Nine studies were considered eligible for the meta-analysis involving 46,424 DOACs users and 182,797 VKA users. Results The use of DOACs was associated with reduced risks of systemic embolism or any stroke (RR 0.65; 95% CI 0.52–0.81; p 0.001), ischemic stroke (RR 0.84; 95% CI 0.74–0.95; p 0.007) and hemorrhagic stroke (RR 0.61; 95% CI 0.52–0.71; p 0.00001) as compared to VKA group. DOAC use was associated with significantly reduced risks of major bleeding (RR 0.68; 95% CI 0.50–0.92; p 0.01) and intracranial or gastrointestinal bleeding (RR 0.64; 95% CI 0.47–0.88; p 0.006). Compared to VKA, DOACs provided a non-statistically significant risk reduction of the outcomes major bleeding or non-major clinically relevant bleeding (RR 0.94; 95% CI 0.78–1.13; p 0.50) and any bleeding (RR 0.91; 95% CI 0.78–1.06; p 0.24). Conclusions In comparison to VKA, DOACs were associated with a significant reduction of the rates of thromboembolic events and major bleeding complications in patients with AF and cancer. Further studies are needed to confirm our results.

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Direct Oral Anticoagulants in Atrial Fibrillation Patients With Concomitant Hyperthyroidism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa050 ◽

2020 ◽

Vol 105 (9) ◽

pp. 2893-2904

Author(s):

Yi-Hsin Chan ◽

Lung-Sheng Wu ◽

Lai-Chu See ◽

Jia-Rou Liu ◽

Shang-Hung Chang ◽

...

Keyword(s):

Atrial Fibrillation ◽

Major Bleeding ◽

Lower Risk ◽

Randomized Clinical Trials ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Study Groups ◽

Research Database ◽

Nonvalvular Atrial Fibrillation ◽

Asian Patients

Abstract Objective Patients with hyperthyroidism were excluded from the randomized clinical trials of direct oral anticoagulants (DOACs) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). Methods We performed a nationwide retrospective cohort study using data from the Taiwan National Health Insurance Research Database. We enrolled 3213 and 1181 NVAF patients with hyperthyroidism who were taking DOACs and warfarin, respectively, from June 1, 2012 to December 31, 2017. We also enrolled 53 591 and 16 564 NVAF patients without hyperthyroidism, taking DOACs and warfarin, respectively. We used propensity score stabilized weights (PSSWs) to balance covariates across the study groups. We also used 1:4 matching on both taking DOACs, with (n = 3213) and without hyperthyroidism (n = 12 852); and both taking warfarin, with (n = 1181) and without hyperthyroidism (n = 4724). Results After PSSW, DOAC had a comparable risk of ischemic stroke/systemic embolism (IS/SE) and a lower risk of major bleeding (hazard ratio [HR] 0.65; 95% confidential interval [CI], 0.44–0.96; P = 0.0295) than warfarin among patients with hyperthyroidism. There were comparable risks of IS/SE and major bleeding between those patients with and without hyperthyroidism. However, among patients taking warfarin, those with hyperthyroidism had a lower risk of IS/SE than those without hyperthyroidism (HR 0.61; 95% CI, 0.43–0.86; P = 0.0050). Conclusion Among NVAF Asian patients with concomitant hyperthyroidism, DOACs may be an effective and safer alternative to warfarin. Thromboprophylaxis with DOACs may be considered for such patients, and it is important to validate this finding in further prospective study.

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Do the Safety and Efficacy Outcomes Reported in the Clinical Trials of Direct Oral Anticoagulants (DOAC) Translate to the Real-World?

Blood ◽

10.1182/blood.v126.23.2335.2335 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2335-2335

Author(s):

Shammim Haji ◽

Jignesh P Patel ◽

Vivian Auyeung ◽

Lara N Roberts ◽

Julia Czuprynska ◽

...

Keyword(s):

Clinical Trials ◽

Major Bleeding ◽

Real World ◽

Research Funding ◽

Oral Anticoagulants ◽

Phase Iii ◽

World Population ◽

Safety And Efficacy ◽

The Real ◽

Pooled Data

Abstract Do the safety and efficacy outcomes reported in the clinical trials of direct oral anticoagulants (DOAC) translate to the 'real-world'? Background: A number of DOACs are now available for clinicians to prescribe in clinical practice. Whilst the results from large clinical trials demonstrate that these agents are as effective as vitamin K antagonists, there is some concern that the patients studied in the trials were not representative of patients, clinicians encounter in everyday practice. The aim of our study was to compare the real-world clinic population commenced on a DOAC to that from the clinical trials for these agents, in order to assess potential differences in safety and efficacy. Patients and methods: A retrospective observational cohort study was undertaken. Patients who were initiated on a DOAC (apixaban, dabigatran and rivaroxaban) at a large teaching hospital in South East London between 1st August 2012 and 31st July 2014 were identified through pharmacy issue data with those followed-up for a minimum of 6 months included. Baseline demographic data, rates of stroke/VTE and rates of major/non-major clinically relevant (NMCR) (ISTH definition) bleeding were assessed and compared to pooled data reported from the corresponding Phase III trials. Differences between groups were compared using t-tests or chi-squared tests. Results: During the review period, 748 patients were initiated on a DOAC, 365 for atrial fibrillation (AF) and 383 for venous thromboembolism (VTE). In terms of demographic differences, the real-world AF population comprised more females, were significantly older, had poorer renal function and a lower body weight. In contrast, the real-world VTE population typically had a higher body weight and poorer renal function, compared to the trial population, (table 1). Efficacy of DOACs was found to be similar across both the VTE and AF populations. With respect to safety, the real-world AF population experienced similar rates of major bleeding and a significantly lower rate of NMCR bleeding compared to the trial populations. In contrast, the real-world VTE population experienced a significantly higher rate of major bleeding, particularly gastrointestinal bleeding. Although the rate of NMCR bleeding was similar, there was a significantly higher rate of urogenital bleeding in the real-world VTE population, specifically heavy menstrual bleeding in women. Conclusions: The efficacy outcomes of DOAC use in a real-world AF and VTE population are consistent with the Phase III trials, despite some significant differences in baseline characteristics. However, a significantly increased rate of major bleeding was observed in the real-world VTE population, which requires further investigation. Table 1. Baseline demographic characteristics, efficacy and safety outcomes in the real-world population versus the trial population Atrial Fibrillation Venous Thromboembolism Trial population+N=28,342 Real-world population Trial population++ Real-world population N=365 N=8,716 N=383 Baseline Demographics, mean (SD) unless otherwise specified Age, years 72 (9.6) 76.8 * (12.1) 56.9 (14.2) 55.6 (18.7) Female (%) 10451 (36.9) 215 * (58.9) 3753 (43.1) 184 (48.0) Weight, kg 82.7 (19.5) 77.3 * (22.6) 84.9 (19.6) 88.2 * (23.0) Creatinine clearance, mL/min 69 (26.7) 58.1 * (26.9) 105.8 (40.7) 91.1 * (37.6) Concomitant aspirin therapy 10341 (36.5) 49 * (13.4) - 0 (0) Previous VKA use (%) 15711 (55.4) 193 (52.9) - 85 (22.2) Efficacy (%) All-cause mortality 1695 (6.0) 37 * (9.1) 160 (1.8) 10 (2.5) Stroke 676 (2.4) 8 (2.0) - 1 (0.3) VTE 39 (0.1) 1 (0.2) 192 (2.2) 7 (1.8) Safety (%) Major Bleeding 1419 (5.0) 17 (4.2) 79 (0.9) 15 * (3.8) Intracranial 170 (0.6) 1 (0.2) 6 (0.1) 2 * (0.5) Gastrointestinal 644 (2.3) 8 (2.0) 8 (0.1) 8 * (2.0) Non-major Clinically relevant (NMCR) bleeding 4824 (17.0) 30 * (7.4) 540 (6.2) 26 (6.6) Gastrointestinal - 9 (2.2) 53 (4.2) 10 (2.5) Urogenital 296 (4.2) 16 (3.9) 100 (2.5) 38 * (9.6) +Pooled data from ARISTOTLE, RE-LY and ROCKET-AF trials ++Pooled data from AMPLIFY, RE-COVER and EINSTEIN-PE/DVT trials *p<0.05 Disclosures Patel: Bayer plc: Research Funding. Auyeung:Bayer PLC: Research Funding. Arya:Bayer plc: Research Funding.

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