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Antithrombotic Therapy in Patients With Atrial Fibrillation After Acute Coronary Syndromes or Percutaneous Intervention.
Harskamp, RE, Fanaroff, AC, Lopes, RD, Wojdyla, DM, Goodman, SG, Thomas, LE, Aronson, R, Windecker, S, Mehran, R, Granger, CB, et al
Journal of the American College of Cardiology. 2022;(5):417-427
Abstract
BACKGROUND The use of apixaban instead of vitamin K antagonists (VKA) as well as dropping aspirin results in less bleeding and comparable ischemic events in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention treated with a P2Y12 inhibitor. OBJECTIVES The authors assessed the safety and efficacy of antithrombotic regimens according to HAS-BLED and CHA2DS2-VASc scores in AUGUSTUS (The Open-Label, 2 × 2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention). METHODS In AUGUSTUS, 4,614 patients were randomized in a 2-by-2 factorial design to open-label apixaban or VKA and blinded aspirin or placebo. The primary endpoint was major or clinically relevant nonmajor bleeding over 6 months of follow-up. Cox proportional hazards models were used to assess treatment effects by baseline HAS-BLED (≤2 vs ≥3) and CHA2DS2-VASc (≤2 vs ≥3) scores. RESULTS Of 4,386 (95.1%) patients with calculable scores, 66.8% had HAS-BLED ≥3 and 81.7% had CHA2DS2-VASc ≥3. Bleeding rates were lower with apixaban than VKA irrespective of baseline risk (HR: 0.57; 95% CI: 0.41-0.78 [HAS-BLED ≤2]; HR: 0.72; 95% CI: 0.59-0.88 [HAS-BLED ≥3]; interaction P = 0.23). Aspirin increased bleeding irrespective of baseline risk (HR: 1.86; 95% CI: 1.36-2.56 [HAS-BLED ≤2]; HR: 1.81; 95% CI: 1.47-2.23 [HAS-BLED ≥3]; interaction P = 0.88). Apixaban resulted in a lower risk of death or hospitalization than VKA without a significant interaction with baseline stroke risk (HR: 0.92; 95% CI: 0.67-1.25 [CHA2DS2-VASc ≤2]; HR: 0.82; 95% CI: 0.73-0.94 [CHA2DS2-VASc ≥3]; interaction P = 0.53). CONCLUSIONS Our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for most patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention, irrespective of a patient's baseline bleeding and stroke risk (NCT02415400).
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Efficacy of vonoprazan against bleeding from endoscopic submucosal dissection-induced gastric ulcers under antithrombotic medication: A cross-design synthesis of randomized and observational studies.
Hidaka, Y, Imai, T, Inaba, T, Kagawa, T, Omae, K, Tanaka, S
PloS one. 2021;(12):e0261703
Abstract
Vonoprazan, a potassium-competitive acid blocker, is expected to be superior to proton pump inhibitors (PPIs) in preventing post-endoscopic submucosal dissection (ESD)-induced gastric bleeding. However, the results of randomized controlled trials (RCTs) and observational studies on the efficacy of vonoprazan have been inconsistent. This study aimed to evaluate the effectiveness of vonoprazan in antithrombotic drug users, a population that has been excluded from RCTs. Treatment effects were assessed using cross-design synthesis, which can be adjusted for differences in study design and patient characteristics. We used data from an RCT in Japan (70 patients in the vonoprazan group and 69 in the PPI group) and an observational study (408 patients in the vonoprazan group and 870 in the PPI group). After matching, among the antithrombotic drug users in the observational study, post-ESD bleeding was noted in 8 out of 86 patients in the vonoprazan group and 18 out of 86 patients in the PPI group. After pooling the data from the RCT and observational study, the risk difference for antithrombotic drug users was -14.6% (95% CI: -22.0 to -7.2). CDS analysis suggested that vonoprazan is more effective than PPIs in preventing post-ESD bleeding among patients administered antithrombotic medications.
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Multicenter Randomized Controlled Trial of Vitamin K Antagonist Replacement by Rivaroxaban with or without Vitamin K2 in Hemodialysis Patients with Atrial Fibrillation: the Valkyrie Study.
De Vriese, AS, Caluwé, R, Pyfferoen, L, De Bacquer, D, De Boeck, K, Delanote, J, De Surgeloose, D, Van Hoenacker, P, Van Vlem, B, Verbeke, F
Journal of the American Society of Nephrology : JASN. 2020;(1):186-196
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Abstract
BACKGROUND Vitamin K antagonists (VKAs), although commonly used to reduce thromboembolic risk in atrial fibrillation, have been incriminated as probable cause of accelerated vascular calcification (VC) in patients on hemodialysis. Functional vitamin K deficiency may further contribute to their susceptibility for VC. We investigated the effect of vitamin K status on VC progression in 132 patients on hemodialysis with atrial fibrillation treated with VKAs or qualifying for anticoagulation. METHODS Patients were randomized to VKAs with target INR 2-3, rivaroxaban 10 mg daily, or rivaroxaban 10 mg daily plus vitamin K2 2000 µg thrice weekly during 18 months. Systemic dp-ucMGP levels were quantified to assess vascular vitamin K status. Cardiac and thoracic aorta calcium scores and pulse wave velocity were measured to evaluate VC progression. RESULTS Baseline dp-ucMGP was severely elevated in all groups. Initiation or continuation of VKAs further increased dp-ucMGP, whereas levels decreased in the rivaroxaban group and to a larger extent in the rivaroxaban+vitamin K2 group, but remained nevertheless elevated. Changes in coronary artery, thoracic aorta, and cardiac valve calcium scores and pulse wave velocity were not significantly different among the treatment arms. All cause death, stroke, and cardiovascular event rates were similar between the groups. Bleeding outcomes were not significantly different, except for a lower number of life-threatening and major bleeding episodes in the rivaroxaban arms versus the VKA arm. CONCLUSIONS Withdrawal of VKAs and high-dose vitamin K2 improve vitamin K status in patients on hemodialysis, but have no significant favorable effect on VC progression. Severe bleeding complications may be lower with rivaroxaban than with VKAs.
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Safety and efficacy of remote ischemic postconditioning after thrombolysis in patients with stroke.
An, JQ, Cheng, YW, Guo, YC, Wei, M, Gong, MJ, Tang, YL, Yuan, XY, Song, WF, Mu, CY, Zhang, AF, et al
Neurology. 2020;(24):e3355-e3363
Abstract
OBJECTIVE To determine the effect of remote ischemic postconditioning (RIPC) on patients with acute ischemic stroke (AIS) undergoing IV thrombolysis (IVT). METHODS A single-center randomized controlled trial was performed with patients with AIS receiving IVT. Patients in the RIPC group were administered RIPC treatment (after IVT) during hospitalization. The primary endpoint was a score of 0 or 1 on the modified Rankin scale (mRS) at day 90. The safety, tolerability, and neuroprotection biomarkers associated with RIPC were also evaluated. RESULTS We collected data from both the RIPC group (n = 34) and the control group (n = 34). The average duration of hospitalization was 11.2 days. There was no significant difference between 2 groups at admission for the NIH Stroke Scale score (p = 0.364) or occur-to-treatment time (p = 0.889). Favorable recovery (mRS score 0-1) at 3 months was obtained in 71.9% of patients in the RIPC group vs 50.0% in the control group (adjusted odds ratio 9.85, 95% confidence interval 1.54-63.16; p = 0.016). We further found significantly lower plasma S100-β (p = 0.007) and higher vascular endothelial growth factor (p = 0.003) levels in the RIPC group than in the control group. CONCLUSIONS Repeated RIPC combined with IVT can significantly facilitate recovery of nerve function and improve clinical prognosis of patients with AIS. CLINICALTRIALSGOV IDENTIFIER NCT03218293. CLASSIFICATION OF EVIDENCE This study provides Class IV evidence that RIPC after tissue plasminogen activator treatment of AIS significantly increases the proportion of patients with an MRS score of 0 or 1 at 90 days.
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Mediterranean Diet Decreases the Initiation of Use of Vitamin K Epoxide Reductase Inhibitors and Their Associated Cardiovascular Risk: A Randomized Controlled Trial.
Castro-Barquero, S, Ribó-Coll, M, Lassale, C, Tresserra-Rimbau, A, Castañer, O, Pintó, X, Martínez-González, MÁ, Sorlí, JV, Salas-Salvadó, J, Lapetra, J, et al
Nutrients. 2020;(12)
Abstract
Our aim is to assess whether following a Mediterranean Diet (MedDiet) decreases the risk of initiating antithrombotic therapies and the cardiovascular risk associated with its use in older individuals at high cardiovascular risk. We evaluate whether participants of the PREvención con DIeta MEDiterránea (PREDIMED) study allocated to a MedDiet enriched in extra-virgin olive oil or nuts (versus a low-fat control intervention) disclose differences in the risk of initiation of: (1) vitamin K epoxide reductase inhibitors (acenocumarol/warfarin; n = 6772); (2) acetylsalicylic acid as antiplatelet agent (n = 5662); and (3) other antiplatelet drugs (cilostazol/clopidogrel/dipyridamole/ditazol/ticlopidine/triflusal; n = 6768). We also assess whether MedDiet modifies the association between the antithrombotic drug baseline use and incident cardiovascular events. The MedDiet intervention enriched with extra-virgin olive oil decreased the risk of initiating the use of vitamin K epoxide reductase inhibitors relative to control diet (HR: 0.68 [0.46-0.998]). Their use was also more strongly associated with an increased risk of cardiovascular disease in participants not allocated to MedDiet interventions (HRcontrol diet: 4.22 [1.92-9.30], HRMedDiets: 1.71 [0.83-3.52], p-interaction = 0.052). In conclusion, in an older population at high cardiovascular risk, following a MedDiet decreases the initiation of antithrombotic therapies and the risk of suffering major cardiovascular events among users of vitamin K epoxide reductase inhibitors.
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Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial.
Vranckx, P, Valgimigli, M, Eckardt, L, Tijssen, J, Lewalter, T, Gargiulo, G, Batushkin, V, Campo, G, Lysak, Z, Vakaliuk, I, et al
Lancet (London, England). 2019;(10206):1335-1343
Abstract
BACKGROUND We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI). METHODS ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed. FINDINGS From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority). INTERPRETATION In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events. FUNDING Daiichi Sankyo.
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A Pilot Randomized Controlled Trial Testing the Feasibility and Acceptability of a SystemCHANGE Intervention to Improve Medication Adherence in Older Adult Stroke Survivors.
Wessol, JL, Russell, CL, Olds, KE
The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses. 2019;(5):259-265
Abstract
BACKGROUND Adhering to an antithrombotic medication regimen is essential to reducing recurrent stroke in adult stroke survivors. The purpose of this study was to evaluate the feasibility and acceptability of the SystemCHANGE (SC) and attention control (AC) intervention in older adult, nonadherent ischemic stroke patients. METHODS A pilot randomized controlled trial was conducted to determine the feasibility and acceptability of an SC versus AC intervention in older adult, nonadherent stroke survivors in the management of antithrombotic medication. Participants were masked to group assignment. Stroke survivors 50 years or older, taking at least 1 once-a-day antithrombotic medication, were recruited from a Midwest Comprehensive Stroke Center-affiliated neurology office. They were screened electronically using the Medication Event Monitoring System for 2 months to determine baseline medication adherence. Nonadherent stroke survivors (medication adherence < 0.97) were randomized to SC or AC intervention and monitored for 3 months. SC focused on redesigning the interpersonal environmental system and daily routines. The AC group was provided education materials on stroke that consisted of stroke risk factor reduction, stroke facts, rehabilitation, and nutrition with the primary investigator. Participation and intervention experience interviews were evaluated for themes. RESULTS Thirty participants were recruited: median age was 64 years, 46.7% of them were male, and they took an average of 7.77 (SD, 3.191; range, 3-15) prescribed medications. The number of over-the-counter medications taken (excluding aspirin) on a regular basis averaged 1.9 (SD, 0.8; range, 1-4). Two participants were nonadherent and were randomized to the 2 arms. Both participants had positive feedback and were not inconvenienced by their participation in the study. Neither participant voiced concerns about the intervention, survey demands, time requirement, or completing the surveys on the primary investigator's laptop. CONCLUSION The SC and AC intervention protocols were feasible and acceptable to the participants in this study. Additional pilot testing is needed to further evaluate the intervention and its effect on medication adherence in this population.
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Effects of alprostadil combined with calcium dobesilate in patients with diabetic peripheral neuropathy.
Han, K, Liu, C, Shi, X, Rao, X
Neuro endocrinology letters. 2018;(2):143-147
Abstract
OBJECTIVE To observe the clinical curative effects of alprostadil combined with calcium dobesilate in type 2 diabetes patients with peripheral neuropathy. METHODS We randomly divided 120 type 2 diabetes patients with diabetic peripheral neuropathy into two groups. The treatment group was prescribed alprostadil (10 μg, once daily) and oral calcium dobesilate (0.5 g, 3 times daily), and the control group was prescribed alprostadil (10 μg, once daily) for a total treatment duration of 2 weeks. The Michigan Diabetic Neuropathy Score (MDNS) and the Michigan Neuropathy Screening Instrument (MNSI) were used to evaluate differences between the two groups before and after treatment. RESULTS Following 2 weeks of treatment, the total effective rate in the treatment group was significantly better than that of the control group (p<0.05) and the MDNS and MNSI scores in the treatment group were significantly lower than those in the control group (p<0.05 or p<0.01). CONCLUSION Combined alprostadil and calcium dobesilate treatment for type 2 diabetic peripheral neuropathy showed good clinical efficacy and an improved curative effect than single alprostadil treatment.
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Evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST-AF PCI trial.
Vranckx, P, Lewalter, T, Valgimigli, M, Tijssen, JG, Reimitz, PE, Eckardt, L, Lanz, HJ, Zierhut, W, Smolnik, R, Goette, A
American heart journal. 2018;:105-112
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BACKGROUND The optimal antithrombotic treatment after percutaneous coronary intervention (PCI) with stenting in patients with atrial fibrillation (AF) is unknown. In the ENGAGE AF-TIMI 48 trial, edoxaban was noninferior to a vitamin K antagonist (VKA) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF. The effects of edoxaban in combination with single- or dual-antiplatelet therapy in the setting of PCI are unexplored. DESIGN The ENTRUST-AF PCI trial is a multinational, multicenter, randomized, open-label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF. Patients are randomized between 4 hours and 5 days after successful PCI to either an edoxaban-based strategy (experimental arm; 60 mg [or 30 mg according to dose reduction criteria] once daily plus a P2Y12 antagonist [default clopidogrel, 75 mg once daily] for 12 months) or a VKA-based strategy (control arm; VKA plus a P2Y12 antagonist [as above] plus acetylsalicylic acid [100 mg once daily] for 30 days to 12 months). The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis-defined major or clinically relevant nonmajor bleeding. The main efficacy end point is the composite of cardiovascular death, stroke, systemic embolic events, spontaneous myocardial infarction, and definite stent thrombosis. SUMMARY The ENTRUST-AF PCI trial tests the hypothesis that an edoxaban-based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual-antiplatelet therapy in patients with AF in need of oral anticoagulation. The relative risk of ischemic events between groups will be compared.
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Sodium Tanshinone IIA Sulfonate Enhances Effectiveness Rt-PA Treatment in Acute Ischemic Stroke Patients Associated with Ameliorating Blood-Brain Barrier Damage.
Ji, B, Zhou, F, Han, L, Yang, J, Fan, H, Li, S, Li, J, Zhang, X, Wang, X, Chen, X, et al
Translational stroke research. 2017;(4):334-340
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Treatment with sodium tanshinone IIA sulfonate (STS) may ameliorate blood-brain barrier (BBB) damage in acute ischemic stroke patients receiving recombinant tissue plasminogen activator (rt-PA) thrombolysis and improve stroke patients' outcome. This randomized, single-center, placebo-controlled clinical trial investigated the potential effects and underlying mechanisms of STS. Forty-two acute ischemic stroke patients receiving intravenous rt-PA thrombolysis were randomized to intravenous administration either with STS (60 mg/day) (n = 21) or with equivalent volume of saline as a placebo (n = 21) after randomization for 10 days. Clinical outcomes, computer tomography perfusion (CTP) imaging with permeability-surface area product (PS) maps and serum levels of BBB damage biomarkers, were compared between the two groups. The percentage of patients with excellent functional outcome indicated by a 90-day mRS ≤1 was significantly higher in the STS group than in the placebo group (p = 0.028). For patients with CTP imaging (n = 30), PS in the ipsilateral lesion (p = 0.034) and relative PS (p = 0.013) were significantly lower in the STS group than that in placebo. STS-treated patients also had lower levels of matrix metalloproteinase (MMP)-9 (p = 0.036) and claudin-5 (p = 0.026), but higher levels of tissue inhibitor of metalloproteinase (TIMP)-1 (p = 0.040) than those in the placebo group. Post-stroke STS treatment could improve neurologic functional outcomes for acute ischemic stroke patients following rt-PA treatment by reducing BBB leakage and damage, which might be mechanistically associated with MMP-9 inhibition.