Net Clinical Outcome Research Articles

Temporal modulation (early escalation and late de-escalation) of antiplatelet therapy in patients undergoing complex high-risk PCI: rationale and design of the TAILORED-CHIP trial.

Despite the use of conventional dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI), the risk of adverse events remains high among patients with increased thrombotic risk. Until recently, the optimal antiplatelet strategy to balance the ischaemic and bleeding risks in patients who are undergoing complex high-risk PCI has been unclear. The TAILored Versus COnventional AntithRombotic StratEgy IntenDed for Complex HIgh-Risk PCI (TAILORED-CHIP) trial is an investigator-initiated, multicentre, prospective randomised trial to evaluate the efficacy and safety of a time-dependent tailored antiplatelet therapy with an early (<6 months post-PCI) escalation (low-dose ticagrelor at 60 mg twice daily plus aspirin) and a late (>6 months post-PCI) de-escalation (clopidogrel monotherapy) in patients undergoing complex high-risk PCI as compared with standard DAPT (clopidogrel plus aspirin for 12 months). Eligible patients had to have at least one high-risk anatomical or procedural feature or clinical characteristic associated with an increased risk of ischaemic or thrombotic events. The primary endpoint was the net clinical outcome, a composite of death from any cause, myocardial infarction, stroke, stent thrombosis, urgent revascularisation, or clinically relevant bleeding (Bleeding Academic Research Consortium type 2, 3, or 5) at 12 months after randomisation. (ClinicalTrials.gov: NCT03465644).

Clinical outcomes in &amp;gt;10,000 Asian vs &amp;gt;61,000 Non-Asian race patients with AF randomized to Warfarin vs DOACs: a patient-level meta-analyses from COMBINE AF

Abstract Background Randomized data comparing clinical outcomes of atrial fibrillation (AF) patients with Asian vs non-Asian races are limited. Methods Using the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database (data from RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48), we performed an individual patient-level meta-analysis to investigate and compare clinical outcomes of AF patients with self-defined Asian and non-Asian races adjusted for baseline characteristics. Standard-dose direct oral anticoagulants (SD DOAC) were defined as dabigatran 150mg bid; rivaroxaban 20mg (15mg) QD, apixaban 5 mg (2.5 mg) bid, or edoxaban 60 mg (30 mg) QD. Low-dose DOACs (DOACs [LD]) were defined as dabigatran 110 mg bid or edoxaban 30 mg (15mg) QD. Results There were 10,212 pts of Asian race and 61,471 non-Asian races in the COMBINE AF database. Compared with non-Asians, Asians were on average 3.2 yrs younger, 20 kg lighter, had worse renal function (mean CrCl 64.9 vs. 77.3 mL/min), and higher rates of prior stroke/transient ischemic attack (37.2% vs 26.6%), P&amp;lt;0.001 for each. The median value of time in therapeutic range of patients randomized to warfarin was lower in Asians than non-Asians (57.7% vs. 66.2%, P&amp;lt;0.001). In the warfarin arm, Asians had a higher adjusted risk of stroke/systemic embolic events (SEE), major bleeding (MB), ICH, GI bleeding (GIB), and net clinical outcome (NCO: stroke/SEE, MB, or death)(Figure; Upper panel). Compared to warfarin, SD DOACs significantly reduced the risks of stroke/SEE, MB, and NCO to a greater degree in Asians than non-Asians (HR stroke/SEE: Asians 0.65 vs Non-Asians 0.86; HR MB: Asians 0.62 vs Non-Asians 0.91; HR NCO: Asians 0.76 vs non-Asians 0.94; Pint &amp;lt;0.02 for each), while SD DOACs increased GIB only in non-Asians (Asian HR 0.92 [0.69-1.23] vs Non-Asians HR 1.41 [1.25-1.58], Pint 0.009; Figure Lower panel). Conclusions The adjusted risks of stroke/SEE and major bleeding with warfarin were higher in Asians compared to non-Asians. The benefits of DOACs over warfarin in preventing stroke/SEE, MB, and net clinical outcomes were significantly greater in Asians than non-Asians.

The comparison of short-term dual antiplatelet therapy versus standard dual antiplatelet therapy in elderly patients with coronary artery disease who underwent percutaneous coronary intervention

Abstract Introduction Elderly patients are likely to have more underlying risk factors for bleeding and the bleeding risk increases with age although dual anti-platelet therapy (DAPT) is mandatory for patients who underwent percutaneous coronary intervention (PCI) for prevention of ischemic events. Therefore, elderly patients aged 75 or older are included as minor criteria for high bleeding risk, as defined by the Academic Research Consortium for High Bleeding Risk criteria. However, only limited data have been investigated of optimal duration of DAPT for patients aged 75 or older. Purpose The aim of this study is to evaluate optimal DAPT duration for elderly patients aged 75 and older. Methods We selected 1,571 patients aged 75 and older with coronary artery disease (CAD) from the pooled database among the 5 randomized controlled trials related to DAPT duration after PCI. DAPT was consisted of clopidogrel or ticagrelor in addition to aspirin. Short-term DAPT duration was defined as 1 to 3months, and standard DAPT duration was defined as 6 to 12months after PCI. Primary outcomes were net clinical adverse outcomes (NACE), composite of major cardiovascular and cerebrovascular adverse outcomes (MACCE) and TIMI major bleeding at 1 year. The inversed probability of treatment weighting (IPTW) analysis was performed to minimize selection bias effects of pooled database. Results The NACE was not significantly different between the short-term DAPT group (3.9%) and standard DAPT group (7.6%) (HR: 0.69, 95% CI: 0.46-1.04; p=0.076) (Figure A). Moreover, MACCE was not different in both groups. However, the significant reduction of bleeding risk was observed in short-term DAPT group (1.4%) than standard DAPT group (3.4%) (hazard ratio (HR): 0.40, 95% confidential interval (CI): 0.19-0.83; p=0.015) (Figure B). These results were consistent after multivariable Cox regression analysis and IPTW analysis. Conclusions Short-term DAPT duration (1 to 3months) was found to be superior to standard DAPT duration (6 to 12months) in terms of bleeding outcomes without the increased ischemic outcomes in patients aged 75 or older with CAD who underwent PCI.

Switching from warfarin to a DOAC in frail elderly asian patients with atrial fibrillation: a nationwide population-based study

Abstract Background Recently, switching international normalized ratio guided warfarin management to a direct oral anticoagulant (DOAC) was associated with more bleeding complications than maintaining warfarin in frail elderly patients with atrial fibrillation (AF). However, there is a paucity of information on whether these results could be applied to Asian patients with AF, who are known to have relatively low time in therapeutic range (TTR) levels. Purpose To evaluate the safety and effectiveness of switching from warfarin to a DOAC in frail elderly Asian patients with AF. Methods Using a Korean health insurance database, we included patients with AF who were prescribed warfarin between January 2013 and August 2015 without significant bleeding or thromboembolic events during the window period, specifically those aged 75 or older with a Hospital Frailty Risk Score of 5 or more. Those who switched to DOACs during the window period were categorized as the DOAC group and those who continued with warfarin were categorized as the warfarin group. The primary outcome was defined as the composite of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB), and secondary outcomes were defined as thromboembolic events, all-cause death, the composite of MB, CRNMB and ischemic stroke (so-called net clinical outcome [NCO]). The propensity score weighting method was utilized to compare the two groups. Results A total of 12,162 patients were included (8,108 with maintaining warfarin, 4,054 with switching to a DOAC). Baseline characteristics were well-balanced after the inverse probability of treatment weighting (mean age, 80 years; men, 50%; and mean CHA₂DS₂-VASc score, 5.6). Compared with maintaining warfarin, switching to a DOAC was associated with significantly higher risks of the primary outcome (hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.09-1.87, p=0.01), thromboembolic events (1.28, 1.01-1.62, p=0.039), all-cause death (1.38, 1.15-1.66, p&amp;lt;0.001) and the NCO (1.26, 1.01-1.58, p=0.04). (Figure A, Figure B), whereas there was no difference in the risk of intracerebral hemorrhage (0.90, 0.50-1.60, p=0.7157). When comparing each DOAC with maintaining warfarin, switching to rivaroxaban was associated with a higher risk of the composite of MB and CRNMB (1.91, 1.38-2.64, p&amp;lt;0.001) and thromboembolic events (1.40, 1.03-1.91, p=0.034) than maintaining warfarin. Conclusion In line with the non-Asian population, switching to a DOAC was associated with a significantly higher risk of MB or CRNMB, thromboembolic events, all-cause death and NCO compared with maintaining warfarin in frail elderly Asian patients with AF. Therefore, even in Asians, switching to a DOAC should be considered more cautiously in patients who are stably managed on warfarin.

Epidemiological and Prognostic Importance of New-Onset Cancer as a Net Adverse Clinical Outcome after ST-Elevation Myocardial Infarction.

The study assessed the epidemiological frequency and prognostic impact of new-onset cancer as an additional net adverse clinical outcome in patients after ST-elevation myocardial infarction (STEMI), considering its potential clinical significance alongside classical endpoints. This study was designed as a single-center observational study, including 1285 consecutive patients who were diagnosed as STEMI patients as the subject, and the frequency and prognosis of new-onset cancer after STEMI onset were assessed. The incidence of all-cause death, nonfatal myocardial infarction (MI), stroke, and bleeding were analyzed as classical endpoints. Throughout an average of a 1241.4 days observation period, cancers were observed in 7.0% of patients (n = 90), showing development at a constant rate throughout this period (incidence rate, 0.06/1000 person-years). The average duration from STEMI onset to cancer diagnosis was 1371.4 days. Death, MI, or stroke were observed in 21.3%, 4.0%, 6.5%, and 12.8%, giving incidence rates of 0.18, 0.03, 0.06, and 0.11/1000 person-years, respectively. Long-term mortality was higher in patients with newly diagnosed cancer than in patients without cancer (36.7% vs. 20.1%, p < 0.01). Cancer after STEMI should be considered as an additional major adverse clinical event because of its high incidence, constant development, and high mortality in comparison to classical endpoints.

Fluid Management in Critically Ill Children: Single-Center Retrospective Comparison of Trauma and Postoperative Patients, 2020-2022.

Injury and surgery both represent well-defined starting points of a predictable inflammatory response, but the consequent response to IV fluids has not been studied. We aimed to review and compare our single-center fluid management strategies in these two populations. Retrospective cohort study from January 2020 to July 2022. The primary outcome was total IV fluid volume administered. Net fluid balances and select clinical outcomes were also evaluated. Single tertiary academic center and level 1 pediatric trauma center in New York. A dataset of critically ill trauma and surgical patients aged 0-18 years who were admitted to the PICU, 2020-2022. Trauma patients had at least moderate traumatic injuries (Injury Severity Score ≥ 9) and surgical patients had at least a 1-hour operation time. None. We identified 25 trauma and 115 surgical patients. During the first 5 days of hospitalization, we did not identify an association between grouping and total IV fluids administered and fluid balance in the prehospital, emergency department, and operating room ( p = 0.90 and p = 0.79), even when adjusted for weight ( p = 0.96). Time trend graphs of net fluid balance and IV fluid administered illustrated analogous fluid requirement and response with the transition from net positive to net negative fluid balance between 48 and 72 hours. There was an association between total IV fluid and ventilator requirement ( p = 0.003). Critically ill pediatric trauma and postoperative patients seem to have similar fluid management and balance after injury or surgery. In our opinion, these two critically ill populations could be combined in large prospective studies on optimal fluid therapy in critically ill children.

Dose Reduction of Edoxaban in Patients 80 Years and Older With Atrial Fibrillation

In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data. To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin. The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023. Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin. Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component. The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03), particularly gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004), with no significant difference in efficacy end points. Findings were supported by analyses of endogenous factor Xa inhibition, a marker of anticoagulant effect, which was comparable between younger patients receiving edoxaban, 60 mg, and older patients receiving edoxaban, 30 mg. In 2406 patients 80 years and older with or without dose-reduction criteria, patients receiving edoxaban, 30 mg, vs warfarin had lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046), whereas rates of stroke or systemic embolism were comparable. In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria. ClinicalTrials.gov Identifier: NCT00781391.

Efficacy and Safety of Edoxaban in Anticoagulant Therapy Early After Surgical Bioprosthetic Valve Replacement: Rationale and Design of the ENBALV Trial.

Anticoagulant therapy with vitamin K antagonists is recommended within 3 to 6 months after bioprosthetic valve replacement to prevent thromboembolic events. However, data regarding whether direct oral anticoagulants can be an alternative to warfarin in such patients are limited. The purpose of this study is to compare the efficacy and safety of edoxaban versus warfarin within 3 months after bioprosthetic valve replacement. The ENBALV trial is an investigator-initiated, phase 3, randomized, open-label, multicenter study. It involves patients aged 18 to 85 years undergoing bioprosthetic valve replacement at the aortic and/or mitral position. They are randomized 1:1 to receive either edoxaban or warfarin. Administration of edoxaban or warfarin is to be continued for 12 weeks after surgery. The primary outcome is the occurrence rate of stroke or systemic embolism at 12 weeks after surgery. The net clinical outcome is a composite of stroke, systemic embolism, or major bleeding, which is included in the secondary outcomes. The ENBALV trial demonstrates the efficacy and safety of edoxaban compared with warfarin in patients early after bioprosthetic valve replacement, including patients with sinus rhythm, which will bring a significant benefit to patients in clinical practice. Japan Registry of Clinical Trials (jRCT) 2051210209. 30 Mar 2022 https://jrct.niph.go.jp/latest-detail/jRCT2051210209 .

Application of the Win Ratio Method in the ENGAGE AF-TIMI 48 Trial Comparing Edoxaban With Warfarin in Patients With Atrial Fibrillation.

Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events. ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization. 21 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05-1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05-1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use. In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.

Outcomes of on-label reduced-dose edoxaban in octogenarian patients with atrial fibrillation

Abstract Background Non-vitamin K antagonist oral anticoagulants (NOACs) are effective in preventing thromboembolisms and reduce the risk of bleeding compared with warfarin. There are few reports on the outcomes of on-label reduced-dose NOACs. Purpose The aim of this study was to assess the safety and efficacy of on-label reduced-dose edoxaban in octogenarian patients with atrial fibrillation (AF). Methods This study is a multi-center, prospective, non-interventional study to evaluate the safety and efficacy of on-label reduced-dose edoxaban in patients with AF. We evaluated outcomes of major bleeding, stroke or systemic embolism, all-cause death, and composite clinical outcomes. Results A total of 2448 patients (mean age 75.0±8.3 years, 801 [32.7%] males) was included in the present study. 932 patients (38.1%) were octogenarians. Major bleeding events occurred at a rate of 1.69%/yr in octogenarian patients and 0.9%/yr in non-octogenarian patients. The event rate of strokes and systemic embolisms was 1.93%/yr in octogenarian patients and 0.66%/yr in non-octogenarian patients The overall net clinical outcomes occurred at a rate of 5.45%/yr in octogenarian patients and 2.24%/yr in non-octogenarian patients. Conclusions Reduced-dose edoxaban can be used safely in Asian patients with very elderly patients. Older age was associated with a higher risk of ischemic stroke and composite adverse events.

The Net Clinical Outcome of Dual-Pathway Inhibition in Clinical Practice: The "Xarelto plus Acetylsalicylic Acid: Treatment Patterns and Outcomes in Patients with Atherosclerosis" Registry.

Background: In the COMPASS trial, the combination of acetylsalicylic acid (ASA) plus 2.5 mg rivaroxaban twice daily (dual-pathway inhibition, DPI) has been shown to be superior to ASA monotherapy for the reduction in ischemic major adverse cardiovascular events (MACEs, i.e., cardiovascular death, stroke, or myocardial infarction). Methods: The international XATOA registry (Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis) is a prospective post-approval registry that investigates the cardiovascular outcomes of patients taking ASA plus 2.5 mg rivaroxaban. The aim of this pre-specified analysis was to determine the net clinical outcome (NCO), i.e., a combination of MACEs and bleeding events, of DPI in patients from daily clinical practice. Results: Among the 5615 patients, the presence of multiple risk factors resulted in an increase in the total risk of experiencing an NCO event, e.g., from 1.27% (one risk factor) to 2.18% (two risk factors) and 4.07% (three or more risk factors), respectively, with ischemic MACE representing the primary driver of bleeding complications. Conclusions: In the real-world XATOA registry, the annual rate of NCO events was low and numerically similar to those seen in the treatment group in the randomized COMPASS trial.

Prescribing Patterns and Outcomes of Edoxaban in Atrial Fibrillation Patients From Asia - One-Year Data From the Global ETNA-AF Program.

Background: This study reports prescribing patterns and the 1-year effectiveness and safety of edoxaban in an Asian cohort of Edoxaban Treatment in routiNe clinical prActice (ETNA)-Atrial Fibrillation (AF) patients. Methods and Results: The Global ETNA-AF program integrates prospective, observational, noninterventional regional studies, collecting data on characteristics and clinical outcomes of patients with AF receiving edoxaban for stroke prevention. Baseline characteristics, medical history, and 1-year clinical event rates were assessed in patients from South Korea, Taiwan, Hong Kong, and Thailand. Clinically relevant events assessed at 12 months included all-cause death, cardiovascular death, ischemic and hemorrhagic stroke, systemic embolic events (SEEs), bleeding, and net clinical outcome (NCO). Overall, 3,359 patients treated with edoxaban 60 or 30 mg once daily completed 1-year follow-up; 70.9% of patients received recommended dosing according to local labels. Baseline mean±standard deviation age was 71.7±9.6 years, CHA2DS2-VASc score was 3.1±1.5, and modified HAS-BLED score was 2.3±1.1. Mean age and sex were similar across countries/regions. The 1-year event rate for all-cause death was 1.8%; major bleeding, 1.3%; ischemic stroke, 1.1%; cardiovascular mortality, 0.7%; hemorrhagic stroke, 0.3%; SEEs, 0%; and NCO, 4.1%; with differences observed between countries/regions and dosing groups. Conclusions: Most Asian patients with AF were prescribed recommended edoxaban dosing in routine care settings. At 1-year follow-up, this analysis supports the effectiveness and safety of edoxaban in these patients.

Efficacy and Safety of Non-Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation.

The efficacy and safety of non-vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain. We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m2 (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m2. Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m2, and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HRadj], 0.80 [95% CI, 0.73-0.88]; P<0.001), with a generally consistent effect across BMI (Ptrend across HRs, 0.48). NOACs also reduced major bleeding overall (HRadj, 0.88 [95% CI, 0.82-0.94]; P<0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [Ptrend], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HRadj, 0.91 [95% CI, 0.87-0.95]; P<0.001; death, HRadj, 0.91 [95% CI, 0.86-0.97]; P=0.003), these benefits were attenuated at higher BMI (Ptrend, 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW. The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW.

Clinical outcomes and anticoagulation therapy in elderly non-valvular atrial fibrillation and heart failure patients.

Atrial fibrillation (AF) and heart failure (HF) often coexist. Older age is strongly associated with stroke, HF, and mortality. The association between coexistence of HF and a risk of clinical outcomes and the effectiveness of anticoagulation therapy including direct oral anticoagulants (DOACs) in elderly patients with AF and HF have not been investigated. We aimed to evaluate 2years of outcomes and to elucidate the efficacy of DOACs or warfarin in elderly AF patients in the All Nippon AF In the Elderly (ANAFIE) Registry with and without a history of HF. The ANAFIE Registry is a multicentre, prospective observational study following elderly non-valvular AF patients aged ≥75years for 2years. Hazard ratios (HRs) were calculated based on the presence or absence of an HF diagnosis and DOAC or warfarin use at enrolment. Among 32275 eligible patients, 12116 (37.5%) had been diagnosed with HF. Patients with HF had significantly higher rates of HF hospitalization or cardiovascular death (HR 1.94, P<0.001), cardiovascular events (HR 1.59, P<0.001), cardiovascular death (HR 1.49, P<0.001), all-cause death (HR 1.32, P<0.001), and net clinical outcome including stroke/systemic embolism, major bleeding, and all-cause death (HR 1.23, P<0.001), compared with those without HF; however, HRs for stroke/systemic embolism (HR 0.96, P=0.56) and major bleeding (HR 1.14, P=0.13) were similar. DOAC use was associated with a low risk of stroke/systemic embolism (HR 0.86, P=0.19 in HF; HR 0.79, P=0.016 in non-HF; P for interaction=0.56), major bleeding (HR 0.71, P=0.008 in HF; HR 0.75, P=0.016 in non-HF; P for interaction=0.74), HF hospitalization or cardiovascular death (HR 0.81, P<0.001 in HF; HR 0.78, P<0.001 in non-HF; P for interaction=0.26), cardiovascular events (HR 0.83, P<0.001 in HF; HR 0.82, P=0.001 in non-HF; P for interaction=0.65), cardiovascular death (HR 0.84, P=0.12 in HF; HR 0.75, P=0.035 in non-HF; P for interaction=0.18), all-cause death (HR 0.89, P=0.082 in HF; HR 0.80, P=0.001 in non-HF; P for interaction=0.091), and net clinical outcome (HR 0.88, P=0.019 in HF; HR 0.81, P<0.001 in non-HF; P for interaction=0.21) compared with warfarin, irrespective of the presence or absence of HF. Analysis using the propensity score matching method showed similar associations. Non-valvular AF patients aged ≥75years with a history of HF had higher risks of cardiovascular events and mortality. DOACs were favourable to warfarin regardless of the coexistence of HF. These results might encourage the use of DOACs in elderly patients with non-valvular AF with or without HF.

Rivaroxaban vs Vitamin K Antagonist in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease

BackgroundTreatment with vitamin K antagonists (VKAs) has been linked to worsening of kidney function in patients with atrial fibrillation (AF). ObjectivesXARENO (Factor XA-inhibition in RENal patients with non-valvular atrial fibrillation Observational registry; NCT02663076) is a prospective observational study comparing adverse kidney outcomes in patients with AF and advanced chronic kidney disease receiving rivaroxaban or VKA. MethodsPatients with AF and an estimated glomerular filtration rate (eGFR) of 15 to 49 mL/min/1.73 m2 were included. Blinded adjudicated outcome analysis evaluated adverse kidney outcomes (a composite of eGFR decline to <15 mL/min/1.73 m2, need for chronic kidney replacement therapy, or development of acute kidney injury). A composite net clinical benefit outcome (stroke or systemic embolism, major bleeding, myocardial infarction, acute coronary syndrome, or cardiovascular death) was also analyzed. HRs with 95% CIs were calculated using propensity score overlap weighting Cox regression. ResultsThere were 1,455 patients (764 rivaroxaban; 691 VKA; mean age 78 years; 44% females). The mean eGFR was 37.1 ± 9.0 in those receiving rivaroxaban and 36.4 ± 10.1 mL/min/1.73 m2 in those receiving VKA. After a median follow-up of 2.1 years, rivaroxaban was associated with less adverse kidney outcomes (HR: 0.62; 95% CI: 0.43-0.88) and all-cause death (HR: 0.76, 95% CI: 0.59-0.98). No significant differences were observed in net clinical benefit. ConclusionsIn patients with AF and advanced chronic kidney disease, those receiving rivaroxaban had less adverse kidney events and lower all-cause mortality compared to those receiving VKA, supporting the use of rivaroxaban in this high-risk group of patients.

De-escalation from ticagrelor to clopidogrel in patients with acute myocardial infarction: the TALOS-AMI HBR substudy.

The benefits of de-escalation of P2Y12 inhibition after percutaneous coronary intervention (PCI) may differ by high bleeding risk (HBR) status. We investigated the efficacy and safety of de-escalation from ticagrelor to clopidogrel after PCI by HBR status. This is a non-prespecified post hoc analysis of the TicAgrelor Versus CLOpidogrel in Stabilized Patients with Acute Myocardial Infarction (TALOS-AMI) trial. Net adverse clinical events (a composite of cardiovascular death, myocardial infarction, stroke, or Bleeding Academic Research Consortium [BARC] bleeding type 2, 3, or 5) at 1 year post-PCI were compared between the de-escalation (clopidogrel plus aspirin) and the active control (ticagrelor plus aspirin) groups by HBR status, as defined by the modification of the Academic Research Consortium (ARC) criteria. A total of 2,625 patients in the TALOS-AMI trial were analysed. Of these, 589 (22.4%) met the modified ARC-HBR criteria. The de-escalation group had lower primary endpoint rates than the control group in both HBR (hazard ratio [HR] 0.47, 95% confidence interval [CI]: 0.26-0.84) and non-HBR (HR 0.59, 95% CI: 0.41-0.84) patients. There were no differences in treatment effect for the primary endpoint regardless of HBR status (p for interaction=0.904). BARC bleeding type 3 or 5 was less common in the de-escalation than the control group among HBR patients only (HR 0.24, 95% CI: 0.07-0.84). In stabilised acute myocardial infarction patients, unguided de-escalation from ticagrelor to clopidogrel was associated with a lower rate of net adverse clinical outcomes irrespective of HBR status. The effect of de-escalation of P2Y12 inhibition on reducing haemorrhagic events was greater in patients with HBR.

Impact of oral anticoagulants in frail atrial fibrillation patients: a report from an observational registry of european patients

Abstract Background The last years showed a substantial increase of interest about the clinical issue of frailty among patients with cardiovascular diseases. Impact of frailty in atrial fibrillation (AF) has been examined in terms of management, quality of life and increased risk of outcomes; nonetheless, the impact of treatment with oral anticoagulants (OAC) remains suboptimally understood. Purpose To analyse the impact of OAC in a cohort of frail AF patients. Methods We used data from a European-wide prospective observational AF registry. Frailty was evaluated with a 40-items frailty index (FI) built according to the cumulative deficit method proposed by Rockwood and Mitnitski. OAC treatment was evaluated at baseline. A net clinical outcome (NCO) of all-cause death, major adverse cardiovascular outcomes, and major bleeding, as well as the single components were the study outcomes. Results Among 10,172 patients available for this analysis, 2,171 (21.3%) were frail. AF frail patients had a mean (SD) age of 71.7 (9.8) years and were 1,073 (49.4%) females. Overall, 1,801 (83.0%) were treated with OAC, of which 1,232 (68.4%) prescribed with vitamin K antagonist (VKA) and 569 (31.6%) prescribed with non-vitamin K antagonist oral anticoagulants (NOACs). Over a mean (SD) follow-up time of 1.56 (0.74) years there were 571 (26.3%) NCO events. Frail patients prescribed with OAC had a lower rate of NCO compared to those not prescribed (27.1% vs. 44.6%, p&amp;lt;0.001). After adjustments, use of OAC was associated with lower risk of NCO and all the other secondary outcomes (Table 1). Regarding the type of OAC, patients prescribed with NOACs reported a lower rate of NCO compared to those prescribed with VKAs (22.7% vs. 29.1%). After adjustments, use of NOACs was associated with a lower risk of NCO and all the other secondary outcomes, except for major bleeding (Table 1). When comparing patients with FI &amp;lt;80th percentile with those with FI ≥80th percentile, adjusted analysis showed that in the FI &amp;lt;80th group the use of OAC was consistently associated with lower risk of all outcomes (except for major bleeding), with a non-statistically significant trend seen in those with FI ≥80th percentile treated with OAC (Table 1). Conclusions In frail AF patients, use of OAC was associated with a lower risk of outcomes, as well as the use of NOACs compared with VKAs. In patients with a very high frailty burden the benefits of OAC may be attenuated.

Comparative analysis of oral anticoagulation therapy in Asian patients with atrial fibrillation and end-stage renal disease: a nationwide population-based cohort study

Abstract Background The efficacy and safety of direct oral anticoagulants (DOACs) in patients with end-stage renal disease (ESRD) on dialysis is unclear. Although the RENAL-AF trial (Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation), a prematurely stopped randomized controlled trial, has been recently reported, the risks of clinical outcomes comparing DOAC and warfarin in pateints with AF and ESRD is still inconclusive. Purpose To analyze comparative effectiveness and safety of oral anticoagulant therapy including warfarin, rivaroxaban, apixaban, and edoxaban in Asian patients with AF and ESRD Methods Using a Korean nationwide claims database, anticoagulated patients with AF and ESRD between 2014 and 2020 were included. The occurrence of ischemic stroke, major bleeding, all-cause death, and the net clinical outcome (NCO, the composite of all clinical outcomes) were evaluated. We firstly compared between pooled DOAC and warfarin, and also compared each DOAC (rivaroxaban, apixaban, and edoxaban) to warfarin. Inverse probability of treatment weighting using propensity scores were used to balance difference in baseline characteristics of each group. Results A total of 5503 patients were included (3484 with warfarin, 407 with rivaroxaban, 1273 with apixaban, and 339 with edoxaban). During a median 1.4-year (interquartile ranges 0.5-3.0 years) of follow-up, 345, 376, 2321, and 2617 of ischemic stroke, major bleeding, all-cause death, and the NCO were occurred (incidence rate, 3.44, 3.77, 22.11, and 27.35 per 100 person-years, respectively). to warfarin, DOAC was associated with significantly lower risks of major bleeding (hazard ratio, 95% confidence interval: 1.159, 0.929-1.440, p=0.187), all-cause death (0.667, 0.520-0.847, p&amp;lt;0.001), and NCO (0.816, 0.748-0.889, p&amp;lt;0.001), with a comparable risk of ischemic stroke (1.159, 0.299-1.440, p=0.001) (Figure A). For the comparison between each DOAC and warfarin (Figure B), apixaban showed a comparable risk of ischemic stroke with warfarin, however, rivaroxaban and edoxaban were associated with a higher risk of ischemic stroke than warfarin. Among 3 DOACs, only apixaban associated with a lower risk of major bleeding than warfarin (0.600, 0.434-0.812, p=0.001). All DOACs were associated with a lower risk of all-cause death than warfarin. Overall, apixaban and rivaroxaban showed a significantly lower risk of NCO than warfarin (0.799, 0.719-0.887, p&amp;lt;0.001 for apixaban vs. warfarin; 0.842, 0.732-0.963, p=0.013 for rivaroxaban vs. warfarin). The results were consistent in a competing risk analysis. Conclusion In this large-scale observational cohort study, DOAC might be associated with a lower NCO than warfarin in Asians patients with AF and ESRD on dialysis. In line with current guidelines, apixaban and rivaroxaban could be a reasonable choice to achieve better net clinical benefit than warfarin in patients with AF and ESRD who are needed anticoagulation therapy.

Comparison of baseline characteristics and outcomes of on-label full dose (20mg) and off-label reduced dose (15mg) rivaroxaban in patients with atrial fibrillation in Asian elderly patients

Abstract Introduction In ROCKET-AF trial, rivaroxaban 20mg was on label dose and dose reduction criteria for rivaroxaban is creatinine clearance (CrCl) less than 50ml/min. Some Asian countries using reduced doses label compared with other global regions according to the J-ROCKET trial. Purpose The aim of this study was to assess the patients characteristic and outcomes of on-label full dose rivaroxaban and off-label reduced dose rivaroxaban in Asian elderly patients. Methods This study is a multi-center, prospective, non-interventional observational study to evaluate the efficacy and safety of rivaroxaban in atrial fibrillation patients older than 65 years old with or without renal impairment. Results A total of 1098 patients (mean age 72.8±5.8 years, 691[62.9%] males) was included and 265 patients received on label full does (20mg) rivaroxaban and 560 patients received off label reduced dose (15mg) rivaroxaban. Off label group showed older, more female patients, lower body weight, impaired CrCl and higher CHADS-VASc score. There showed no significant differences between two groups in major and minor bleeding, stroke and net-clinical outcomes. Conclusions Physicians prefer to prescribe off-label reduced dose rivaroxaban in patients with older and frail patients in Asia real world practice. There showed no differences in outcomes in these patients. Off label 15mg of rivaroxaban might be consider in specific populations.

Abstract 14204: Efficacy and Safety of Low-Dose Edoxaban According to Body Weight in Very Elderly Patients With Atrial Fibrillation: A Sub-Analysis of the ELDERCARE-AF Trial

Background: The ELDERCARE-AF trial showed that low-dose edoxaban is beneficial in elderly patients with non-valvular atrial fibrillation (AF) who are considered ineligible candidates for standard oral anticoagulants (OACs) due to high bleeding risk, but it was not known whether this is the case in low-body-weight patients. Methods: This was a prespecified sub-analysis, by body weight (≤45 and &gt;45 kg), of the ELDERCARE-AF trial, a randomized, placebo-controlled trial comparing low-dose edoxaban (15 mg once daily) with placebo. All patients were of Japanese ethnicity and considered ineligible for standard doses of OACs. The primary efficacy endpoint was stroke or systemic embolism (SSE). The key secondary endpoints were all-cause mortality and net clinical outcome. The primary safety endpoint was major bleeding according to the definition of the International Society on Thrombosis and Hemostasis. Results: Of the 984 patients, 374 patients (38.0%) were in the ≤45 kg group and 610 (62.0%) patients were in the &gt;45 kg group. The SSE was lower with edoxaban than with placebo in both weight groups (≤45 kg group: hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.16-0.80; &gt;45 kg group: HR 0.31, 95% CI 0.13-0.73; interaction P 0.82). Both all-cause mortality and net clinical outcome were higher in the ≤45 kg group, with no significant difference between treatment groups. Major bleeding was numerically higher with edoxaban than with placebo (≤45 kg group: HR 3.05, 95% CI 0.84-11.11; &gt;45 kg group: HR 1.40, 95% CI 0.56-3.48), with no interaction with body weight (interaction P 0.33). Similar results were obtained in the exploratory analysis of patients divided into four quartiles of body weight (&gt;57.9, &gt;49.0 to ≤57.9, &gt;42.0 to ≤49.0, and ≤42.0 kg). Conclusions: The benefit of edoxaban 15 mg was consistent in elderly AF patients with low body weight, provided clinicians remain vigilant about the risk of major bleeding.