Appropriate Selection of Substrate Ablation for Persistent Atrial Fibrillation Using Intraprocedural Assessment.

BACKGROUND: It has not been fully elucidated which patients with persistent atrial fibrillation (PerAF) should undergo substrate ablation plus pulmonary vein isolation (PVI). This study aimed to identify PerAF patients who required substrate ablation using intraprocedural assessment of the baseline rhythm and the origin of atrial fibrillation (AF) triggers.Methods and Results: This was a post hoc subanalysis using extended data of the EARNEST-PVI trial, a prospective multicenter randomized trial comparing PVI-alone and PVI-plus (i.e., PVI with added catheter ablation) arms. We divided 492 patients into 4 groups according to baseline rhythm and the location of AF triggers before PVI: Group A (n=22), sinus rhythm with pulmonary vein (PV)-specific AF triggers (defined as reproducible AF initiation from PVs only); Group B (n=211), AF with PV-specific AF triggers; Group C (n=94), sinus rhythm with no PV-specific AF trigger; Group D (n=165), AF with no PV-specific AF trigger. Among the 4 groups, only in Group D (AF at baseline and no PV-specific AF triggers) was arrhythmia-free survival significantly lower in the PVI-alone than PVI-plus arm (P=0.032; hazard ratio 1.68; 95% confidence interval 1.04-2.70). CONCLUSIONS: Patients with sinus rhythm or PV-specific AF triggers did not receive any benefit from substrate ablation, whereas patients with AF and no PV-specific AF trigger benefited from substrate ablation.

Persistent Systemic Inflammation Is Associated With Bleeding Risk in Atrial Fibrillation Patients.

BACKGROUND: This study investigated the impact of systemic inflammation on bleeding risk in non-valvular atrial fibrillation (NVAF) patients treated with direct oral anticoagulants (DOAC).Methods and Results:We conducted a single-center prospective registry of 2,216 NVAF patients treated with DOAC: the DIRECT registry (UMIN000033283). High-sensitivity C-reactive protein (hsCRP) was measured ≤3 months before (pre-DOAC hsCRP) and 6±3 months after initiation of DOAC (post-DOAC hsCRP). Multivariate logistic regression model was used to assess the influence of systemic inflammation and conventional bleeding risk factors on major bleeding according to International Society on Thrombosis and Haemostasis criteria. Based on the findings, we created a new bleeding risk assessment score: the ORBIT-i score, which included post-DOAC hsCRP >0.100 mg/dL and all components of the ORBIT score. A total of 1,848 patients had both pre- and post-DOAC hsCRP data (follow-up duration, 460±388 days). Post-DOAC hsCRP was associated with major bleeding (OR, 2.770; 95% CI: 1.687-4.548, P<0.001). Patients with post-DOAC hsCRP >0.100 mg/dL more frequently had major bleeding than those without (log-rank test, P<0.001). ORBIT-i score had the highest C-index of 0.711 (95% CI, 0.654-0.769) compared with the ORBIT and HAS-BLED scores. CONCLUSIONS: Persistent systemic inflammation was associated with major bleeding risk. ORBIT-i score had a higher discriminative performance compared with the conventional bleeding risk scores.

Difference of neointimal growth patterns in bifurcation lesions among four kinds of drug-eluting stents: an optical coherence tomographic study.

AIM: Neointimal proliferation of bifurcation lesions after implantation of drug-eluting stents (DES) has not been well evaluated. Thus, we compared neointimal proliferation of bifurcation lesions among four DES using optical coherence tomography (OCT). METHODS: 8-month follow-up OCT was performed in 68 bifurcation lesions treated by 15 sirolimus-eluting stents (SES) and 17 paclitaxel-eluting stents (PES) as first-generation DES, and by 17 zotarolimus-eluting stents (ZES) and 19 everolimus-eluting stents (EES) as second-generation DES. Cross-sectional images of the bifurcation lesion using OCT were analyzed every 450 µm. All images were divided into three areas: inner wall of the bifurcation (IB), outer wall of the bifurcation (OB), and ostium of the side branch (SB). We compared the incidence of uncovered struts (IUS) among three areas and the averaged neointimal thickness (NIH) between IB and OB in each stent and also compared these OCT parameters among all DES. RESULTS: There were no significant differences of IUS between IB and OB in second-generation DES, while in first-generation DES, IUS of IB and OB showed significant differences. The IUS of SES in both areas was significantly higher than in the other DES (all P < 0.001). PES had a significantly higher IUS in SB than the others (all P < 0.001). NIH of OB was significantly higher than that of IB in PES, ZES, and EES, but in SES the NIH was similar in the two areas. CONCLUSIONS: OCT revealed different neointimal growth patterns among SES, PES, ZES, and EES in bifurcation lesions.

Higher serum uric acid and lipoprotein(a) are correlated with coronary spasm.

It has been reported that a major cause of coronary vasospastic angina (VSA) is endothelial dysfunction of the coronary artery. On the other hand, some studies showed that serum uric acid and lipoprotein(a) are correlated with endothelial dysfunction. Thus, we examined whether uric acid and lipoprotein(a), are correlated with VSA. Four hundred forty-one patients with suspected VSA who underwent a coronary angiogram with acetylcholine provocation (ACh test) during an 8-year period were enrolled. We divided them into a VSA group, who showed coronary spasm by the ACh test, and an atypical chest pain (ACP) group, who showed negative ACh test. We compared serum markers between the two groups, including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein (hs-CRP), lipoprotein(a), fibrinogen, total plasminogen activator inhibitor-1, and uric acid. Uric acid, hs-CRP, and lipoprotein(a) were significantly higher in the VSA group than in the ACP group (all P < 0.05) while there were no significant differences in the other parameters. Multivariate analyses identified uric acid and lipoprotein(a) as significant independent markers for VSA. Uric acid and lipoprotein(a) are correlated with VSA, and medical intervention to decrease uric acid and lipoprotein(a) might be effective in controlling VSA.

New approach for rotational dyssynchrony using three-dimensional speckle tracking echocardiography.

Left ventricular (LV) twist can be evaluated using two-dimensional speckle tracking echocardiography (2DSTE) by analyzing difference between apical and basal rotation. However, it is unable to evaluate global rotational dyssynchrony because it cannot assess mid-wall rotation. Recently developed three-dimensional STE (3DSTE) can investigate LV global rotational dyssynchrony. In this study, we investigated the role of torsion on the long-term effects of cardiac resynchronization therapy (CRT) using 3DSTE. We evaluated 43 patients by 3DSTE: 12 CRT responders, 14 CRT nonresponders, and 17 healthy normal controls. Regional torsion and rotation were assessed using 3DSTE across 16 segments during CRT-off (native conduction) and CRT-on. The following parameters were calculated: global peak twist, Δ global peak twist (difference between CRT-on and CRT-off), and torsion delay index. The torsion delay index was considered to be the rotational energy lost by rotational dyssynchrony. Global peak twist did not show significant differences between the responders and nonresponders during CRT-off (4.0 ± 3.4° vs. 2.8 ± 2.3°, P = 0.295), but it significantly improved in responders compared to nonresponders after CRT-on (5.4 ± 3.5° vs. 2.6 ± 2.6°, P = 0.029). The torsion delay index during CRT-off was significantly higher in responders compared to nonresponders and normal controls (18.5 ± 11.3 vs. 8.6 ± 3.8 and 7.8 ± 5.5, P = 0.010 and P = 0.004, respectively). The torsion delay index during CRT-off significantly correlated with the Δ global peak twist (r = 0.503, P = 0.009). Improvement in LV global peak twist, which is one of the mechanisms for the long-term effects of CRT correlated with the torsion delay index during native conduction that can only be calculated by 3DSTE.

Endoscopic view of the vertebra during laser balloon ablation of paroxysmal atrial fibrillation.

Key Clinical Message: Left atrial posterior wall on the vertebra is often difficult to obtain stable tissue contact with ablation-catheter. Laser balloon ablation is effective because the compression from the vertebra can be visualized through endoscopy. Abstract: When performing pulmonary vein isolation (PVI) with radiofrequency, left atrial posterior wall on the vertebra is often difficult to obtain stable tissue contact with ablation-catheter because of the movement of the ablation point. Laser balloon ablation is effective for the achievement of durable PVI in cases with such anatomical characteristics because the compression from the vertebra can be visualized through endoscopy.

Relationship of interleukin-16 with different phenogroups in acute heart failure with preserved ejection fraction.

AIMS: Interleukin-16 (IL-16) has been reported to mediate left ventricular myocardial fibrosis and stiffening in patients with heart failure with preserved ejection fraction (HFpEF). We sought to elucidate whether IL-16 has a distinct impact on pathophysiology and prognosis across different subphenotypes of acute HFpEF. METHODS AND RESULTS: We analysed 211 patients enrolled in a prospective multicentre registry of acute decompensated HFpEF for whom serum IL-16 levels after stabilization were available (53% female, median age 81 [interquartile range 75-85] years). We divided this sub-cohort into four phenogroups using our established clustering algorithm. The study endpoint was all-cause death. Patients were subclassified into phenogroup 1 ('rhythm trouble' [n = 69]), phenogroup 2 ('ventricular-arterial uncoupling' [n = 49]), phenogroup 3 ('low output and systemic congestion' [n = 41]), and phenogroup 4 ('systemic failure' [n = 52]). After a median follow-up of 640 days, 38 patients had died. Among the four phenogroups, phenogroup 2 had the highest IL-16 level. The IL-16 level showed significant associations with indices of cardiac hypertrophy, diastolic dysfunction, and congestion only in phenogroup 2. Furthermore, the IL-16 level had a significant predictive value for all-cause death only in phenogroup 2 (C-statistic 0.750, 95% confidence interval 0.606-0.863, P = 0.017), while there was no association between the IL-16 level and the endpoint in the other phenogroups. CONCLUSIONS: Our results indicated that the serum IL-16 level had a significant association with indices that reflect the pathophysiology and prognosis of HFpEF in a specific phenogroup in acute HFpEF.

Uplift modeling to identify patients who require extensive catheter ablation procedures among patients with persistent atrial fibrillation.

Identifying patients who would benefit from extensive catheter ablation along with pulmonary vein isolation (PVI) among those with persistent atrial fibrillation (AF) has been a subject of controversy. The objective of this study was to apply uplift modeling, a machine learning method for analyzing individual causal effect, to identify such patients in the EARNEST-PVI trial, a randomized trial in patients with persistent AF. We developed 16 uplift models using different machine learning algorithms, and determined that the best performing model was adaptive boosting using Qini coefficients. The optimal uplift score threshold was 0.0124. Among patients with an uplift score ≥ 0.0124, those who underwent extensive catheter ablation (PVI-plus) showed a significantly lower recurrence rate of AF compared to those who received only PVI (PVI-alone) (HR 0.40; 95% CI 0.19-0.84; P-value = 0.015). In contrast, among patients with an uplift score < 0.0124, recurrence of AF did not significantly differ between PVI-plus and PVI-alone (HR 1.17; 95% CI 0.57-2.39; P-value = 0.661). By employing uplift modeling, we could effectively identify a subset of patients with persistent AF who would benefit from PVI-plus. This model could be valuable in stratifying patients with persistent AF who need extensive catheter ablation before the procedure.

Duration of atrial fibrillation persistence: Implications for recurrence risk after catheter ablation and efficacy of additional substrate ablation.

BACKGROUND: The optimal duration of atrial fibrillation (AF) persistence for predicting poor outcomes after catheter ablation of long-standing AF (LsAF) and the best ablation strategy for these patients remain unclear. OBJECTIVE: We aimed to assess the impact of the duration of AF persistence on outcomes after catheter ablation of AF. METHODS: We analyzed the Efficacy of Pulmonary Vein Isolation Alone in Patients with Persistent Atrial Fibrillation (EARNEST-PVI) trial data comparing pulmonary vein isolation (PVI) alone (PVI-alone) with additional linear ablation or defragmentation (PVI-plus) in persistent AF (PerAF). Patients who received catheter ablation by contact force-sensing catheter were enrolled in the study. In patients with LsAF, the optimal cutoff duration of AF persistence was evaluated. With use of the threshold, patients with LsAF were divided into 2 groups and compared with PerAF <1 year for arrhythmia-free survival after a 3-month blanking period. RESULTS: The optimal cutoff duration was 2.4 years. Of 458 patients, arrhythmia-free survival rates for LsAF 1-2.4 years were comparable to those of PerAF (hazard ratio [HR], 1.01; 95% CI, 0.67-1.52). However, LsAF >2.4 years had a higher recurrence risk than PerAF (HR, 2.22; 95% CI, 1.42-3.47). In LsAF >2.4 years, the PVI-plus strategy showed advantages over the PVI-alone strategy (HR, 0.36; 95% CI, 0.14-0.89). However, the interaction effect between LsAF 1-2.4 years and LsAF >2.4 years did not reach statistical significance (P = .116). CONCLUSION: Whereas LsAF 1-2.4 years has similar outcomes to those of PerAF, LsAF >2.4 years was linked to higher arrhythmia recurrence risks. For LsAF >2.4 years, the PVI-plus strategy showed a potential to be superior to the PVI-alone strategy.

Initial findings of impact of strut width on stent coverage and apposition of sirolimus-eluting stents assessed by optical coherence tomography.

OBJECTIVES: We investigate the influence of stent design on stent coverage at 6-9 months after sirolimus eluting stent (SES) implantation using optical coherence tomography (OCT). BACKGROUND: Although some reports suggest that stent design may correlate with stent coverage of stent struts, there were few detailed data whether stent design impact on stent coverage in the same drug-eluting stent. METHODS: A total of 21 SESs (15 patients), who had implanted 2.5, 2.75, and 3.0 mm stents, underwent OCT at 6-9 months after stent implantation. SES is constructed by two different strut width-components; narrow strut width parts (59 µm) and wide strut width parts (115 µm). Thus, we divided stent struts of SESs into two groups: narrow strut width parts (narrow group) and wide ones (wide group). We compared the incidence of incomplete apposed struts, uncovered struts, and neointimal hyperplasia (NIH) thickness between the two groups. RESULTS: We could detect 2,948 struts (narrow group consisted of 1,132 struts and wide group consisted of 1,816 struts). Incidence of uncovered struts in the narrow group was significantly lower than in the wide group (30.2% vs. 40.8%, P < 0.001), and NIH thickness in the narrow group was significantly greater than in the wide group (127.5 ± 93.4 µm vs. 118.6 ± 81.4 µm, P = 0.03). CONCLUSIONS: Stent design, especially strut width, affects stent coverage of SES. The narrow strut may avoid the absence of stent coverage in SES, which correlates with stent thrombosis.

Peripartum Cardiomyopathy with the Cardiac Function Restored by Cabergoline.

Peripartum cardiomyopathy (PPCM) is a left ventricular systolic dysfunction associated with heart failure (HF) in late-term pregnancy or peripartum. A 29-year-old pregnant woman with no history of cardiac disease noted lower extremity edema around 34 weeks' gestation with significant weight gain. She delivered twins via caesarean section, and the edema regressed postpartum. On postpartum day 4, however, she experienced difficulty breathing at night and was diagnosed with HF owing to PPCM. HF treatment along with cabergoline was initiated. With low prolactin blood levels, her symptoms and cardiac function improved over time. This case demonstrated the usefulness of anti-prolactin therapy with cabergoline in PPCM.

Erratum to "Twice- or once-daily dosing of direct oral anticoagulants and gastrointestinal bleeding in patient with atrial fibrillation" [Am. Heart J. Plus: Cardiol. Res. Pract. Volume 22, October 2022, 100203].

[This corrects the article DOI: 10.1016/j.ahjo.2022.100203.].

Long-Term Impact of Additional Ablation After Pulmonary Vein Isolation: Results From EARNEST-PVI Trial.

Background An optimal strategy for left atrial ablation in addition to pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF) has not been determined. Methods and Results We conducted an extended follow-up of the multicenter randomized controlled EARNEST-PVI (Efficacy of Pulmonary Vein Isolation Alone in Patients With Persistent Atrial Fibrillation) trial, which compared 12-month rhythm outcomes in patients with persistent AF between patients randomized to a PVI-alone strategy (n=248) or PVI-plus strategy (n=248; PVI followed by left atrial additional ablation, including linear ablation or ablation targeting areas with complex fractionated electrograms). The present study extended the follow-up period to 3 years after enrollment. Outcomes were compared not only between randomly allocated groups but also between on-treatment groups categorized by actually created ablation lesions. Recurrence rate of AF or atrial tachycardia (AT) was lower in the randomly allocated to PVI-plus group than the PVI-alone group (29.0% versus 37.5%, P=0.036). On-treatment analysis revealed that patients with PVI+linear ablation (n=205) demonstrated a lower AF/AT recurrence rate than those with PVI only (26.3% versus 37.8%, P=0.007). In contrast, patients with PVI+complex fractionated electrograms ablation (n=37) had an AF/AT recurrence rate comparable to that of patients with PVI only (40.5% versus 37.8%, P=0.76). At second ablation in 126 patients with AF/AT recurrence, ATs excluding common atrial flutter were more frequent in patients with PVI+linear ablation than in those with PVI only (32.6% versus 5.7%, P<0.0001). Conclusions Left atrial ablation in addition to PVI was efficacious during 3-year follow-up. Linear ablation was superior to other ablation strategies but may increase iatrogenic ATs. Registration URL: http://www.umin.ac.jp/ctr/index-j.htm; Unique identifier: UMIN000019449.

Registry for Evaluating Healthy Life Expectancy and Long-Term Outcomes after Catheter Ablation of Atrial Fibrillation in the Very Elderly (REHEALTH AF) study: rationale and design of a prospective, multicentre, observational, comparative study.

INTRODUCTION: Data are lacking on the extent to which patients with non-valvular atrial fibrillation (AF) who are aged ≥80 years benefit from ablation treatment. The question pertains especially to patients' postablation quality of life (QoL) and long-term clinical outcomes. METHODS AND ANALYSIS: We are initiating a prospective, registry-based, multicentre observational study that will include patients aged ≥80 years with non-valvular AF who choose to undergo treatment by catheter ablation and, for comparison, such patients who do not choose to undergo ablation (either according to their physician's advice or their own preference). Study subjects are to be enrolled from 52 participant hospitals and three clinics located throughout Japan from 1 June 2022 to 31 December 2023, and each will be followed up for 1 year. The planned sample size is 660, comprising 220 ablation group patients and 440 non-ablation group patients. The primary endpoint will be the composite incidence of stroke/transient ischaemic attack (TIA) or systemic embolism (SE), another cardiovascular event, major bleeding and/or death from any cause. Other clinical events such as postablation AF recurrence, a fall or bone fracture will be recorded. We will collect standard clinical background information plus each patient's Clinical Frailty Scale score, AF-related symptoms, QoL (Five-Level Version of EQ-5D) scores, Mini-Mental State Examination (optional) score and laboratory test results, including measures of nutritional status, on entry into the study and 1 year later, and serial changes in symptoms and QoL will also be secondary endpoints. Propensity score matching will be performed to account for covariates that could affect study results. ETHICS AND DISSEMINATION: The study conforms to the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies issued by the Ministry of Health, Labour and Welfare, Japan. Results of the study will be published in one or more peer-reviewed journals. TRIAL REGISTRATION NUMBER: UMIN000047023.

Bidirectional endovascular treatment for chronic total occlusive lesions of the femoropopliteal arterial segment using a hand-carried ultrasound device and a retrograde microcatheter.

BACKGROUND: Although endovascular therapy for complex lesions in the lower limbs has frequently achieved successful recanalization by improvement of techniques and devices, chronic total occlusion in the femoropopliteal arterial segment still remains a challenge for treatment by endovascular therapy. We investigated the efficacy and safety of endovascular therapy for chronic total occlusion in the femoropopliteal arterial segment guided by a hand-carried ultrasound (HCUS) device and supported by a retrograde microcatheter. METHODS: We attempted endovascular therapy for chronic total occlusion lesions in the femoropopliteal arterial segment using a protocol involving a dual-access procedure using the HCUS device and a retrograde 2.7F microcatheter from January 2008 to June 2010. We evaluated the success rate, complications, and clinical outcomes, including the ankle-brachial index (ABI) and primary and secondary patency. RESULTS: Success was achieved in 18 of 19 patients (95%), without major complications (only two small hematomas). The HCUS device was useful in reducing the personnel and space requirements, radiation exposure, and the required amount of contrast agent. The retrograde flexible 2.7F microcatheter was also useful in achieving successful recanalization and contributed to reducing puncture-related complications. The ABI was significantly improved, from 0.56 ± 0.12 to 0.81 ± 0.11 at 1 year (P < .01) and this effect remained stable. Primary and secondary patency was 63% and 89%, respectively, at 3 years. CONCLUSIONS: HCUS-guided and retrograde 2.7F microcatheter-supported endovascular therapy for chronic total occlusion lesions of the femoropopliteal arterial segment can achieve a favorable clinical outcome without major complications.

Acute Myopericarditis After the Third Vaccination of BNT162b2 in a Middle-Aged Man.

Messenger ribonucleic acid (mRNA) vaccines against coronavirus disease 2019 (COVID-19) are highly effective in preventing and decreasing disease severity, but the duration of the effect is attenuated over time and repeated vaccination is required. A 41-year-old Japanese male presented to our hospital with chest pain three days after receiving the third dose of the BNT162b2 mRNA vaccine. After various examinations, such as endomyocardial biopsy and viral polymerase chain reaction (PCR) testing of endomyocardial biopsy tissue, we made the diagnosis of acute myopericarditis associated with booster vaccination. Here, we report a rare case of myopericarditis after booster mRNA vaccination.

Cardiac involvement of diffuse large B-cell lymphoma presenting as various arrythmias.

Symptomatic cardiac involvement of malignant lymphoma is rare. Silent invasion of malignant lymphoma makes it difficult to diagnose it in the early phase of clinical course. We describe a case with cardiac involvement of diffuse large B-cell lymphoma presenting various types of arrythmias that were not diagnosed until autopsy.

Comparison of Low-Dose Direct Oral Anticoagulants for Patients <80 Versus ≥80 Years of Age With Atrial Fibrillation.

Evidence on the efficacy and safety of low-dose direct oral anticoagulant (DOAC) in older patients with nonvalvular atrial fibrillation is still scarce. We conducted a single-center prospective registry of patients with nonvalvular atrial fibrillation treated with DOACs: the DIRECT registry (n = 2,216; follow-up, 407 ± 388 days, UMIN000033283). The whole population was divided into 2 groups: the older group (age ≥80 years, n = 548) versus the younger group (age <80 years, n = 1,668). Primary safety and efficacy end points were major bleeding according to the International Society on Thrombosis and Haemostasis criteria, and stroke or systemic embolism (SSE), respectively. Effects of known risk factors and low-dose DOAC on major bleeding and SSE were assessed using a multivariable Cox proportional hazards model. In the older group, low-dose DOAC was associated with lower bleeding events (hazard ratio 0.279, 95% confidence interval 0.087 to 0.892, p = 0.031) but was not associated with increased SSE (p = 0.894). In the younger group, low-dose DOAC was neither associated with risk of major bleeding nor SSE (both p >0.05). In conclusion, in older patients, low-dose DOAC was associated with reduced risk of major bleeding without compromising its efficacy.

Twice- or once-daily dosing of direct oral anticoagulants and gastrointestinal bleeding in patient with atrial fibrillation.

Aims: Direct oral anticoagulant (DOAC) is widely used for the prevention of embolic stroke in non-valvular atrial fibrillation (NVAF) patients. However, the gastrointestinal bleeding risk in several DOAC regimens was higher than warfarin, especially in once-daily regimens. Methods and results: We conducted a single-center prospective registry of patients with NVAF treated with DOACs: the DIRECT registry (N = 2216; follow-up duration 650 [IQR 103-1574] days, UMIN000033283). All patients were divided into 2 groups: the twice-daily (BID) regimen group (dabigatran and apixaban) versus the once-daily (QD) regimen group (rivaroxaban and edoxaban). Out of 2216 patients, we successfully matched 904 patients in the QD group and 904 patients in the BID group using propensity score. The primary endpoint was gastrointestinal bleeding defined as any bleeding in the gastrointestinal tract that was identified through medical records regardless of bleeding site or severity. The BID group showed a significantly lower gastrointestinal bleeding rate than the QD group (3.5/100 person-year vs. 6.2/100 person-year, log-rank P < 0.0001). The secondary endpoints were all death, stroke, major bleeding, and any bleeding. The rate of major bleeding was significantly lower in patients with BID regimen group (log-rank P = 0.040). In contrast, all death, stroke, and any bleeding did not differ between both groups (log-rank P = 0.280, 0.520 and 0.066, respectively). Conclusions: The BID regimen as compared with the QD regimen was associated with reduced risk of gastrointestinal bleeding.