Efficacy and safety of single-dose ivermectin in mild-to-moderate COVID-19: the double-blind, randomized, placebo-controlled CORVETTE-01 trial.

Background: To investigate whether ivermectin inhibits SARS-CoV-2 proliferation in patients with mild-to-moderate COVID-19 using time to a negative COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test. Methods: CORVETTE-01 was a double-blind, randomized, placebo-controlled study (August 2020-October 2021) conducted in Japan. Overall, 248 patients diagnosed with COVID-19 using RT-PCR were assessed for eligibility. A single oral dose of ivermectin (200 µg/kg) or placebo was administered under fasting. The primary outcome was time to a negative COVID-19 RT-PCR test result for SARS-CoV-2 nucleic acid, assessed using stratified log-rank test and Cox regression models. Results: Overall, 112 and 109 patients were randomized to ivermectin and placebo, respectively; 106 patients from each group were included in the full analysis set (male [%], mean age: 68.9%, 47.9 years [ivermectin]; 62.3%, 47.5 years [placebo]). No significant difference was observed in the occurrence of negative RT-PCR tests between the groups (hazard ratio, 0.96; 95% confidence interval [CI] 0.70-1.32; p = 0.785). Median (95% CI) time to a negative RT-PCR test was 14.0 (13.0-16.0) and 14.0 (12.0-16.0) days for ivermectin and placebo, respectively; 82.1% and 84% of patients achieved negative RT-PCR tests, respectively. Conclusion: In patients with COVID-19, single-dose ivermectin was ineffective in decreasing the time to a negative RT-PCR test. Clinical Trial Registration: ClinicalTrials.gov, NCT04703205.

Clinical Implication and Optimal Management of Myocardial Bridging: Role of Cardiovascular Imaging.

Myocardial bridging (MB) was historically considered a benign structure as most people with MB are clinically asymptomatic. Recently, however, mounting evidence indicates that MB can cause adverse cardiac events owing to arterial systolic compression/diastolic restriction, atherosclerotic plaque progression upstream from MB, and/or vasospastic angina. In MB patients with refractory angina, the optimal treatment strategy should be determined individually based on versatile anatomic and hemodynamical assessments that often require multidisciplinary diagnostic approaches. The present review summarizes the clinical implication and management of MB, highlighting the role of imaging modalities currently available in this arena.

Autopsy Case Report of Severe COVID-19 Pneumonia at a General Municipal Hospital.

We present the autopsy procedure and findings of severe coronavirus disease 2019 (COVID-19) pneumonia in an 85-year-old man. The patient required intubation immediately after admission for severe COVID-19 pneumonia. He had severe hypoxia that did not improve despite treatment with remdesivir, corticosteroids, and appropriate mechanical ventilation. On day 13, the patient developed sudden hypercapnia. His renal dysfunction subsequently worsened and became associated with hyperkalemia, and he passed away on day 15. An autopsy was performed to clarify the cause of the hypercapnic hypoxia. None of the medical personnel involved in the autopsy developed symptoms of COVID-19. Histologic examination showed various stages of diffuse alveolar damage throughout the lungs, with intra-alveolar hemorrhage in the upper zones. Microscopic examination of the kidneys revealed acute tubular necrosis. There was no significant systemic thrombosis. The autopsy findings were consistent with those typical of COVID-19.

Very late stent thrombosis lacking findings of the typical causes on optical coherence tomography in a patient with SARS-CoV-2.

A 50-year-old male was admitted to our hospital with sudden-onset chest pain. He was a current smoker with severe obesity and diabetes. He had a history of drug-eluting stent (DES) implantation in the left anterior descending artery (LAD) and had continuously taken clopidogrel. Eight days prior to admission, polymerase chain reaction testing confirmed that he was positive for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Emergent coronary angiography revealed total occlusion of previously implanted DES in LAD. Optical coherence tomography (OCT) images demonstrated the presence of large white thrombus within the well-expanded DES with homogenous neointima. There were no findings of malapposed strut, uncovered strut, intimal disruption, or neoatherosclerosis through the stented segment. Subsequent dilation using a drug-coated balloon successfully restored coronary flow in LAD. We experienced a case of very late stent thrombosis without findings of the typical causes on OCT images nor discontinuation of antiplatelet therapy in a patient with SARS-CoV-2. The present case suggests that SARS-CoV-2 infection may induce stent thrombosis irrespective of the presence of known causes and the status of antiplatelet therapy. Learning objectives: The underlying causes of very late stent thrombosis (VLST) include strut malapposition, neoatherosclerosis, uncovered struts and stent underexpansion in addition to inadequate discontinuation of antiplatelet therapy and/or systemic hyper coagulable state. The present case of VLST lacking those factors suggests the enhanced hyper thrombogenicity irrespective of the presence of known causes and the status of antiplatelet therapy in patients with severe acute respiratory syndrome coronavirus type 2.

Impact of triglyceride levels on plaque characteristics in patients with coronary artery disease.

BACKGROUND: High triglyceride (TG) levels have been demonstrated to be a risk factor for coronary artery disease. This study aimed to clarify the impact of TG levels on the characteristics of coronary plaques. METHODS: A total of 850 consecutive patients who underwent optical coherence tomography (OCT) imaging of the culprit lesion were included. The morphologies of culprit plaques were compared between the higher TG group (nonfasting TG levels ≥150 mg/dL, n = 337) and the lower TG group (nonfasting TG <150 mg/dL, n = 513). RESULTS: The prevalence of lipid-rich plaques (43% vs. 33%, p = 0.005), thin-cap fibroatheromas (TCFAs) (24% vs. 17%, p = 0.015) and macrophages (40% vs. 31%, p = 0.006) was significantly higher in the higher TG group than in the lower TG group. In addition to a high low-density lipoprotein cholesterol (LDL-C) level (≥140 mg/dL), high TGs (≥150 mg/dL) were identified as an independent factor for the presence of TCFAs (odds ratio 1.465, 95% confidence interval 1.004-2.137, p = 0.048). Among patients with lower LDL-C levels (<100 mg/dL), the prevalence of macrophages (38% vs. 26%, p = 0.007) and layered plaques (48% vs. 38%, p = 0.019) was significantly higher in the higher TG group than in the lower TG group. CONCLUSIONS: Higher TG levels were associated with a higher prevalence of TCFAs in culprit coronary lesions. The prevalence of macrophages and layered plaques was more frequently observed in patients with higher TGs than those with lower TGs among patients with LDL-C < 100 mg/dL.

Lower levels of low-density lipoprotein cholesterol are associated with a lower prevalence of thin-cap fibroatheroma in statin-treated patients with coronary artery disease.

BACKGROUND: Reducing low-density lipoprotein cholesterol (LDL-C) levels with statins slows the progression of atherosclerotic plaques and reduces cardiovascular events. The 2019 European Society of Cardiology/European Atherosclerosis Society guidelines recommend absolute LDL-C treatment targets of <100 mg/dL, <70 mg/dL and <55 mg/dL according to coexisting patient risk factors. OBJECTIVE: To clarify the difference in the plaque characteristics of coronary lesions associated with these LDL-C levels in statin-treated patients. METHODS: A total of 685 consecutive statin-treated patients with coronary artery disease (CAD) who underwent optical coherence tomography (OCT) imaging of culprit lesions were enrolled. The characteristics of culprit plaques evaluated by OCT were compared among the high LDL-C group (≥100 mg/dL, n=247), the moderate LDL-C group (70-100 mg/dL, n=289), the low LDL-C group (55-70 mg/dL, n=106) and the very low LDL-C group (<55 mg/dL, n=43). RESULTS: A significant trend toward a lower prevalence of thin-cap fibroatheroma (TCFA) associated with the LDL-C groups was observed (23.1, 18.3, 9.4 and 11.6%, respectively, in each group; p=0.002). A trend toward a lower prevalence of TCFAs associated with the LDL-C groups was also observed among patients with lower hemoglobin A1c (<6.2%; p=0.003). LDL-C <70 mg/dL (the low/very low group) was independently associated with the lack of TCFAs (odds ratio, 0.50; 95% confidence interval, 0.27-0.87, p=0.014). CONCLUSIONS: Lower LDL-C levels were associated with a lower prevalence of TCFAs in culprit plaques among statin-treated patients with CAD.

Intravascular ultrasound predictors of long-term outcomes following ABSORB bioresorbable scaffold implantation: A pooled analysis of the ABSORB III and ABSORB Japan trials.

BACKGROUND: The long-term prognostic impact of IVUS findings following Absorb BVS implantation remains uncertain. This study aimed to identify the IVUS predictors of long-term clinical outcomes following ABSORB bioresorbable vascular scaffold (BVS) implantation from the pooled IVUS substudy cohorts of the ABSORB III and Japan trials. METHODS: A total of 298 lesions in 286 patients were enrolled with 2:1 randomization to ABSORB BVS vs. cobalt-chromium everolimus-eluting stents. This sub-analysis included 168 lesions of 160 patients in the Absorb arm whose post-procedural quantitative IVUS were available. The primary endpoint of this analysis was device-oriented composite endpoint (DOCE) of target lesion failure, including cardiac death, target vessel-related myocardial infarction, or ischemia-driven target lesion revascularization. The median follow-up duration was 4.9 [3.1-5.0] years. RESULTS: During follow-up, DOCE occurred in 10.1% of lesions treated with Absorb BVS. Among several post-procedural IVUS indices associated with DOCE, non-uniform device expansion (defined as uniformity index = minimum / maximum device area) (hazard ratio 0.47 per 0.1 increase [95%CI 0.28 to 0.77]; p = 0.003) and residual reference plaque burden (hazard ratio 4.01 per 10% increase [95%CI 1.50 to 10.77]; p = 0.006) were identified as independent predictors of DOCE by Cox multivariable analysis. CONCLUSIONS: Nonuniform device expansion and substantial untreated residual plaque in reference segments were associated with long-term adverse events following BVS implantation. Baseline imaging to identify the appropriate device landing zone and procedural imaging to achieve uniform device expansion if possible (e.g. through post-dilatation) may improve clinical outcomes of BVS implantation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01751906 (ABSORB III); NCT01844284 (ABSORB Japan).

Invasive assessment of myocardial bridging in patients with angina and no obstructive coronary artery disease.

AIMS: Angina and no obstructive coronary artery disease (ANOCA) is common. A potential cause of angina in this patient population is a myocardial bridge (MB). We aimed to study the anatomical and haemodynamic characteristics of an MB in patients with ANOCA. METHODS AND RESULTS: Using intravascular ultrasound (IVUS), we identified 184 MBs in 154 patients. We evaluated MB length, arterial compression, and halo thickness. MB muscle index (MMI) was defined as MB length×halo thickness. Haemodynamic testing of the MB was performed using an intracoronary pressure/Doppler flow wire at rest and during dobutamine stress. We defined an abnormal diastolic fractional flow reserve (dFFR) as ≤0.76 during stress. The median MB length was 22.9 mm, arterial compression 30.9%, and halo thickness 0.5 mm. The median MMI was 12.1. Endothelial and microvascular dysfunction were present in 85.4% and 22.1%, respectively. At peak dobutamine stress, 94.2% of patients had a dFFR ≤0.76 within and/or distal to the MB. MMI was associated with an abnormal dFFR. CONCLUSIONS: In select patients with ANOCA who have an MB by IVUS, the majority have evidence of a haemodynamically significant dFFR during dobutamine stress, suggesting the MB as being a cause of their angina. A comprehensive invasive assessment of such patients during coronary angiography provides important diagnostic information that can guide management.

Achilles tendon thickening is associated with higher incidence of adverse cardiovascular event in patients with coronary artery disease.

Achilles tendon thickening (ATT) is a marker of high risk for coronary artery disease (CAD). However, the association between the presence of ATT and the incidence of cardiovascular events in patients with CAD is unclear. A total of 406 consecutive patients who underwent percutaneous coronary intervention (PCI) and ATT assessment were analyzed. ATT was defined as the Achilles tendon thickness of 9 mm or more on radiography. The incidence of major adverse cardiovascular events (MACE) at 1-year was compared between patients with ATT and those without ATT. MACE included cardiac death, non-fatal myocardial infarction, stroke, target vessel revascularization (TVR), and non-TVR. ATT was found in 67 patients (16.5%). The incidence of cardiac death (3.2 vs. 0.0%, p = 0.001), TVR (12.7 vs. 4.0%, p = 0.005) and MACE (20.6 vs. 9.6%, p = 0.011) was significantly higher in the ATT group than the no ATT group. Patients with ATT had significantly higher incidence of cardiac death (5.6 vs. 0%, p < 0.001) than those without ATT even if they did not meet the diagnostic criteria of familial hypercholesterolemia. A multivariate model demonstrated that ATT was independently associated with the MACE at 1-year (Hazard ratio, 2.09; 95% Confidence Interval, 1.09-4.00, p = 0.026). The presence of ATT was independently associated with 1-year recurrence of cardiovascular events in patients with CAD undergoing PCI. Assessment of ATT might be useful for risk stratification of secondary cardiovascular events.

Clinical and Microbiological Features of Asymptomatic SARS-CoV-2 Infection and Mild COVID-19 in Seven Crewmembers of a Cruise Ship.

Objective To describe the clinical features and clinical course of individuals diagnosed with asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or mild coronavirus disease (COVID)-19. Patients The study participants consisted of 7 crewmembers of the passenger cruise-liner, Diamond Princess, who were admitted to our hospital after becoming infected with SARS-CoV-2 aboard the ship. Methods The data on patient background and biochemical test results were obtained from the patients' medical records. All patients had a chest X-ray, and a throat swab and sputum samples were sent for culture on admission. Results The median age of the 7 patients, of whom 4 were male and 3 were female, was 39 years (range: 23-47 years). On admission, none of them had fever, but 4 (57%) had a cough. None of them showed any signs of organ damage on laboratory testing. Chest X-ray showed pneumonia in one individual, which resolved spontaneously, while the other 6 had normal chest X-ray findings. Culture of throat swabs and sputum samples revealed that 4 patients (57%) had bacterial upper respiratory infections (Haemophilus influenzae, Klebsiella pneumoniae, and Staphylococcus aureus). The period from a positive polymerase chain reaction (PCR) test to negative conversion ranged from 5 to 13 days, with a median of 8 days. Conclusion Healthy young adults without risk factors who acquire SARS-CoV-2 infection may have an asymptomatic infection or may experience mild COVID-19. In addition to obesity, an older age, underlying illness, and being overweight can lead to a risk of exacerbation; thus, hospital management for such individuals may be desirable. Culturing respiratory samples may be useful for diagnosing secondary bacterial pneumonia.

Scaffold underexpansion and late lumen loss after bioresorbable scaffold implantation: Insights from ABSORB JAPAN trial.

BACKGROUND: Device underexpansion is associated with late adverse outcomes after bioresorbable vascular scaffold (BVS) implantation. This study, representing official IVUS results of the ABSORB Japan trial, aimed to characterize IVUS findings, focusing specifically on acute device expansion, and to investigate its impact on late lumen loss (LLL) with Absorb-BVS compared with cobalt-chromium everolimus-eluting stents (CoCr-EES). METHODS: ABSORB Japan enrolled 148 patients (2:1 randomization) in the IVUS cohort. Serial IVUS was prescheduled at post-procedure and 3 years. Acute device expansion was evaluated with respect to the degree and uniformity of the implanted device. RESULTS: Overall, Absorb-BVS showed smaller and more nonuniform device expansion at post-procedure, compared with CoCr-EES, which was particularly prominent in small-vessel lesions. In serial analysis, Absorb-BVS showed unique associations of smaller device expansion (r = 0.40, p = 0.001) and more nonuniformity (r = 0.29, p = 0.007) at post-procedure with greater LLL at 3 years, primarily attributable to greater negative remodeling (r = 0.39, p = 0.006). In contrast, acute device expansion showed no relation with subsequent lumen change in CoCr-EES. In Absorb-BVS, ischemic-driven target lesion or vessel revascularization (ID-TLR or ID-TVR) at 3 years occurred more frequently in small- versus large-vessel lesions (12.5% vs. 0%, p = 0.04 for ID-TLR and 15.6% vs. 2.3%, p = 0.08 for ID-TVR). Conversely, Absorb BVS had no target lesion nor vessel failure, even in small-vessel lesions, when adequate device expansion was achieved at post-procedure. CONCLUSIONS: Unlike CoCr-EES, underexpansion was associated with greater negative remodeling and LLL in Absorb-BVS. This may in part account for the poorer outcomes of Absorb-BVS than CoCr-EES when under-expanded.

Accuracy of a novel stress echocardiography pattern for myocardial bridging in patients with angina and no obstructive coronary artery disease - A retrospective and prospective cohort study.

BACKGROUND: Myocardial bridge (MB) may cause angina in patients with no obstructive coronary artery disease (CAD). We previously reported a novel stress echocardiography (SE) pattern of focal septal buckling with apical sparing in the end-systolic to early-diastolic phase that is associated with the presence of an MB. We evaluated the diagnostic accuracy of this pattern, and prospectively validated our results. METHODS: The retrospective cohort included 158 patients with angina who underwent both SE and coronary CT angiography (CCTA). The validation cohort included 37 patients who underwent CCTA in the emergency department for angina, and prospectively underwent SE. CCTA was used as a reference standard for the presence/absence of an MB, and also confirmed no obstructive CAD. RESULTS: In the retrospective cohort, an MB was present in 107 (67.7%). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 91.6%, 70.6%, 86.7% and 80%, respectively. On logistic regression, focal septal buckling and Duke treadmill score were associated with an MB. In the validation cohort, an MB was present in 31 (84%). The sensitivity, specificity PPV and NPV were 90.3%, 83.3%, 96.5% and 62.5%, respectively. On logistic regression, focal septal buckling was associated with an MB. CONCLUSION: Presence of focal septal buckling with apical sparing on SE is an accurate predictor of an MB in patients with angina and no obstructive CAD. This pattern can reliably be used to screen patients who may benefit from advanced non-invasive/invasive testing for an MB as a cause of their angina.

Age- and Gender-Related Differences in Coronary Lesion Plaque Composition on Optical Coherence Tomography.

BACKGROUND: The pathophysiology and chronological course of atherosclerosis seems to be different between men and women due to biological differences, and age and gender differences in plaque composition of coronary lesions remain to be elucidated.Methods and Results:A total of 860 consecutive patients with a median age of 69 years (IQR, 60-78 years) who underwent optical coherence tomography (OCT) of culprit lesions was included. The composition of culprit plaque on OCT was compared between female (n=171) and male (n=689) subjects in younger (<70 years old) and elderly (≥70 years old) patients. In elderly patients, the prevalence of thin-cap fibroatheroma (TCFA) was significantly higher in women than in men (30.6 vs. 15.2%, P<0.001). In younger patients, the prevalence of large calcification was significantly higher in women than in men (60.0 vs. 32.8%, P<0.001). The prevalence of other vulnerable plaque characteristics (i.e., macrophages, microchannels, and spotty calcification), was similar between women and men. Elderly women had a significantly higher prevalence of TCFA (OR, 2.13; 95% CI: 1.33-3.44, P=0.002) than other patients. CONCLUSIONS: Women had a higher prevalence of TCFA and of large calcification than men in patients ≥70 and <70 years old, respectively. This may facilitate the understanding of gender differences in the pathogenesis of coronary atherosclerosis, and the tailoring of therapy and of prevention according to age and gender.

Vascular response and intrastent thrombus in the early phase after drug-eluting versus bare-metal stent implantation in patients with ST-segment elevation myocardial infarction: An observational, single-center study.

BACKGROUND AND OBJECTIVES: Second-generation drug-eluting stents (G2-DES) are associated with a lower rate of acute and subacute stent thrombosis compared with bare-metal stent (BMS) in the setting of ST-segment elevation myocardial infarction (STEMI). In this study, our aim was to compare the vascular response and thrombus burden between G2-DES and BMS in early-phase STEMI. METHODS: Between May 2010 and August 2014, a total of 41 STEMI patients treated by either G2-DES (n = 26; everolimus-eluting stent [EES]: n = 15, zotarolimus-eluting stent [ZES]: n = 11) or BMS (n = 15) and, with multivessel disease requiring additional percutaneous coronary intervention (PCI), were prospectively enrolled. Optical coherence tomography (OCT) imaging was performed at 1 month after stent implantation. RESULTS: Baseline clinical characteristics, except for age (61.5 ± 9.3 vs 69.3 ± 9.8, P = 0.01, t test), were comparable between patients with drug-eluting stent (DES) and BMS. The incidence of residual thrombus after the stent implantation for STEMI was comparable between DES and BMS (7.7% vs 6.7%, P = 0.88, χ 2 test). At 1 month, thrombus burden, defined as the mean thrombus area divided by the mean lumen area, was significantly smaller with DES than with BMS (median interquartile range (IQR), 1.2 (0.0, 1.0) vs 1.2 (0.0, 2.2), P = 0.04, Mann-Whitney U test), despite a similar percentage of malapposed (median (IQR), 6.2 (2.4, 9.0) vs 2.6 (0.0, 5.8)%, P = 0.07, Mann-Whitney U test) or uncovered struts (median (IQR), 6.8 (1.8, 13.1) vs 6.14 (2.8, 18.5)%, P = 0.45, Mann-Whitney U test). No significant difference in thrombus burden was observed between EES and ZES. CONCLUSIONS: Thrombus burden was significantly smaller with DES than with BMS at 1-month follow-up in STEMI cases, although the percentage of malapposed or uncovered struts was similar between the groups. This may partly explain the lower rate of acute and subacute stent thrombosis in G2-DES that has previously been reported in the literature.

Lower Level of Low Density Lipoprotein Cholesterol is Associated with a Higher Increase in the Fractional Flow Reserve in Patients with Fixed-dose Rosuvastatin.

AIM: Fractional flow reserve (FFR) reflects on the diffuse atherosclerosis per coronary artery. It is unknown whether the statin therapy affects long term FFR after stenting. The aim of this study was to evaluate the long term FFR after stent implantation in patients who are intaking fixed-dose rosuvastatin. METHODS: A total of 22 patients with stable angina pectoris were enrolled. The values of FFR were measured before, immediately after, and 18 months after (follow-up day) the implantation of everolimus eluting stent (EES; Promus ElementTM or Promus Element PlusTM). A fixed dose of rosuvastatin at 5 mg/day was administrated to all patients. RESULTS: Of the 22 patients, 2 were excluded because of adverse effect of rosuvastatin and in-stent total occlusion after EES implantation. Overall, the values of FFR immediately after and 18 months after EES implantation did not show significant change (from 0.90±0.05 to 0.88±0.06, p=0.16). However, there was a significant negative correlation between low density lipoprotein (LDL) cholesterol level at follow-up day and changes in the value of FFR (p=0.01, r =－0.74). There was an increase in the FFR value after stenting in 8 out of 9 patients with LDL cholesterol level below 75 mg/dl (area under the curve 0.92, p=0.0005). CONCLUSIONS: LDL cholesterol level was associated with the change in the FFR value in patients following stent implantation. Lower LDL cholesterol tended to improve in the long-term FFR, underscoring the importance of lowering LDL cholesterol to prevent the progression of coronary atherosclerosis.

Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation.

In recent years, direct oral anticoagulants (DOACs) of dabigatran, rivaroxaban, apixaban, edoxaban, which are all alternatives to warfarin, have been released. The use of DOACs is becoming more widespread in the clinical management of thrombotic stroke risk in patients with atrial fibrillation (AF). In large-scale clinical trials of each drug, DOACs were reported to inhibit intracranial hemorrhage, stroke, and death compared to warfarin. Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). OC is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification in the vessel wall. GAS6 prevents the apoptosis of vascular smooth muscle cells. Therefore, decrease of blood vitamin K levels may cause osteoporosis, vascular calcification, and the inhibition of vessels angiogenesis. This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. We studied 21 consecutive patients with persistent or chronic AF, who were treated with warfarin at least for 12 months. Warfarin administration was changed to rivaroxaban (10 or 15 mg/day) in all patients. Osteopontin (OPN), bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were measured. Pulse wave velocity (PWV) and augmentation index (AI) were also measured as atherosclerosis assessments. All measurements were done before and six months after the rivaroxaban treatment. There was a significant increase in serum level of BAP compared to baseline (12.5 ± 4.6 to 13.4 ± 4.1 U/L, P < 0.01). In contrast, there was a significant decrease in the serum level of ucOC (9.5 ± 5.0 to 2.7 ± 1.3 ng/ml, P < 0.01). Also, in the ucOC levels, there was a significant negative correlation between baseline values and baseline to 6-months changes in high ucOC group (r = -0.97, P < 0.01). The atherosclerosis- and osteoporosis-related biomarker, serum level of OPN were significantly decreased compared to baseline (268.3 ± 46.8 to 253.4 ± 47.1 ng/ml, P < 0.01). AI and PWV were significantly decreased after 6 months of treatment with rivaroxaban (33.9 ± 18.4 to 24.7 ± 18.4%, P = 0.04; 1638.8 ± 223.0 to 1613.0 ± 250.1 m/s, P = 0.03, respectively). Switching to rivaroxaban from warfarin in patients with atrial fibrillation was associated with an increase of bone formation markers and a decrease of bone resorption markers, and also improvements of PWV and AI.

Ezetimibe enhances and stabilizes anticoagulant effect of warfarin.

Ezetimibe reduces plasma levels of low-density lipoprotein cholesterol by inhibiting Niemann-Pick C1-like protein 1 (NPC1L1). A recent study demonstrated that NPC1L1 plays an important role in absorption of fat-soluble vitamins including vitamin K. We evaluated whether the add-on treatment of ezetimibe affects anticoagulation in patients taking warfarin. Between October 2007 and March 2015, the administration of ezetimibe was started to a total of 101 outpatients who were already on oral anticoagulation with warfarin. We retrospectively analyzed blood lipid levels, prothrombin time international normalized ratio (PT-INR) and time in therapeutic INR range (TTR). Seventy-one patients (70 %) showed increase in PT-INR after ezetimibe treatment (1.96 ± 0.45 to 2.20 ± 0.61, p < 0.001). It was necessary to reduce the warfarin dose in 9 of 101 patients for clinical indication. There was a significant positive correlation between change in PT-INR and statin usage at baseline (p = 0.03). The mean value of changes in PT-INR of patients with taking statin was significantly larger than that of patients without taking statin (0.34 ± 0.54 vs. 0.06 ± 0.36, p = 0.03). There was an increase in the TTR (52 ± 26 to 61 ± 23 %, p < 0.0001) and a decrease in the frequency to change the dose of warfarin after the ezetimibe treatment [45 times of 735 examination days (6 %) to 20 times of 695 examination days (3 %), p = 0.02]. Our data suggest possible drug interaction between warfarin and ezetimibe. Ezetimibe may increase and stabilize the anticoagulant effect of warfarin, especially in patients taking statins.

Duodenal stenting followed by systemic chemotherapy for patients with pancreatic cancer and gastric outlet obstruction.

OBJECTIVES: Endoscopic duodenal stenting has recently been proposed as a substitute for surgical gastrojejunostomy for the treatment of gastric outlet obstruction. We aimed to evaluate the efficacy and safety of duodenal stenting followed by systemic chemotherapy for patients with advanced pancreatic cancer with gastric outlet obstruction. METHODS: This was a single-center, retrospective cohort study, conducted at an academic medical center, of 71 patients with advanced pancreatic cancer and gastric outlet obstruction (mean age: 67.6 years; range: 31-92 years) who underwent duodenal stenting with or without subsequent chemotherapy. Overall survival, duration of oral intake of foods, the rate of introduction of chemotherapy, progression-free survival, and adverse events were evaluated. RESULTS: Stent placement was technically successful in 69 (97%) patients. Thirty-six (51%) patients were treated with chemotherapy: 17 with gemcitabine alone, 15 with S-1 alone, 3 with FOLFIRINOX, and 1 with paclitaxel. Median progression-free survival and overall survival after chemotherapy were 2.6 months (95% confidence interval: 1.3-3.9 months) and 4.7 months (95% confidence interval: 2.6-6.8 months), respectively. Cases of grade 3 anemia were frequently observed during chemotherapies following duodenal stenting (32%). Tumor stage, performance status, neutrophil-to-lymphocyte ratio, and introduction of chemotherapy were independent prognostic factors for survival (hazard ratios of 3.73, 2.21, 2.69, and 1.85 with p-values of <0.001, 0.010, <0.001, and 0.045, respectively). CONCLUSIONS: The findings of this study suggest that endoscopic duodenal stenting is an advantageous treatment in advanced pancreatic cancer patients with gastric outlet obstruction regarding its safety and smooth conduction of subsequent chemotherapies.