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Prostacyclin analog beraprost sodium efficacy in primary glomerular disease or nephrosclerosis: Analysis of the Japanese subgroup in CASSIOPEIR study.
Kurumatani, H, Okada, K, Origasa, H, Fujita, T, Isono, M, Nakamoto, H
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2021;(5):551-564
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Abstract
We conducted a multicenter, randomized, double-blind, placebo-controlled, phase IIb/III study (CASSIOPEIR) using a renal composite endpoint (i.e., doubling of SCr or end-stage renal disease) in seven Asian countries/region. CASSIOPEIR compared TRK-100STP (120 μg and 240 μg) with placebo in patients with non-diabetic CKD patients with primary glomerular disease or nephrosclerosis (n = 892). However, the superiority of TRK-100STP over placebo was not observed. A prior phase II study on which the Phase IIb/III study design was based included only Japanese patients. We therefore evaluated TRK-100STP efficacy and safety in a subgroup of Japanese patients using the CASSIOPEIR dataset. As the timing of treatment initiation is important in CKD, we conducted additional subgroup analyses based on the baseline serum creatinine (SCr) and eGFR. ITT analysis was performed in a Japanese subgroup (n = 339) in which the primary endpoint was the first occurrence of renal composite endpoint. Significant differences were observed for TRK-100STP 240 μg vs. placebo (P = 0.0493; HR 0.69 [95% CI: 0.47, 1.00]), but no significant difference was observed between TRK-100 120 μg and placebo (P = 0.3523; HR 0.85). More prominent improvement was observed with TRK-100STP 240 μg vs. placebo for baseline SCr < 3.0 mg/dL (P = 0.0031; HR 0.43); SCr < 3.5 mg/dL (P = 0.0237, HR 0.59); and eGFR ≥ 10 mL/min/1.73 m2 (P = 0.0339, HR0.67), respectively. No significant changes in urinary albumin/creatinine ratio and blood pressure were observed. TRK-100STP was generally well tolerated and most adverse drug reactions were mild or moderate in severity. In conclusion, in the Japanese subgroup of CASSIOPEIR, TRK-100STP 240 μg/day significantly improved the renal composite endpoint compared with placebo, with greater efficacy in subjects with SCr < 3.5 or eGFR ≥ 10 mL/min/1.73 m2 .
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Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial.
Engelter, ST, Traenka, C, Gensicke, H, Schaedelin, SA, Luft, AR, Simonetti, BG, Fischer, U, Michel, P, Sirimarco, G, Kägi, G, et al
The Lancet. Neurology. 2021;(5):341-350
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BACKGROUND Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines-based on available evidence from mostly observational studies-suggest using aspirin. If proven to be non-inferior to vitamin K antagonists, aspirin might be preferable, due to its ease of use and lower cost. We aimed to test the non-inferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection. METHODS We did a multicentre, randomised, open-label, non-inferiority trial in ten stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalised ratio [INR] 2·0-3·0) for 90 days. Randomisation was computer-generated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major haemorrhage, or death) and MRI outcomes (new ischaemic or haemorrhagic brain lesions) in the per-protocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Non-inferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460. FINDINGS Between Sept 11, 2013, and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI -4 to 21], non-inferiority p=0·55). Thus, non-inferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischaemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial haemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group. INTERPRETATION Our findings did not show that aspirin was non-inferior to vitamin K antagonists in the treatment of cervical artery dissection. FUNDING Swiss National Science Foundation, Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, Academic Society Basel.
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Polypill with or without Aspirin in Persons without Cardiovascular Disease.
Yusuf, S, Joseph, P, Dans, A, Gao, P, Teo, K, Xavier, D, López-Jaramillo, P, Yusoff, K, Santoso, A, Gamra, H, et al
The New England journal of medicine. 2021;(3):216-228
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BACKGROUND A polypill comprising statins, multiple blood-pressure-lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease. METHODS Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly. We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo. For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization. For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed. RESULTS A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo. The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00). The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10). The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the double-placebo group (hazard ratio, 0.69; 95% CI, 0.50 to 0.97). The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups. CONCLUSIONS Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk. (Funded by the Wellcome Trust and others; TIPS-3 ClinicalTrials.gov number, NCT01646437.).
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Risk Factors Control and Early Recurrent Cerebral Infarction in Patients with Symptomatic Intracranial Atherosclerotic Disease.
Del Brutto, VJ, Liebeskind, DS, Romano, JG, Campo-Bustillo, I, Cotsonis, G, Nizam, A, Prabhakaran, S, ,
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2021;(9):105914
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BACKGROUND The risk of early recurrent cerebral infarction (RCI) is high in patients with symptomatic intracranial atherosclerotic disease (IAD). We sought to determine the relationship between risk factor control and early RCI risk among patients with symptomatic IAD. METHODS We analyzed participants with symptomatic IAD in the multi-center prospective observational MYRIAD study. Risk factor control was assessed at 6-8-week follow-up. Optimal risk factor control was defined by target systolic blood pressure, being non-smoker, target physical activity, and antiplatelet and antilipidemic therapy compliance. Age-adjusted associations were calculated between risk factor control and RCI determined by MRI-evident new infarcts in the territory of the stenotic vessel at 6-8 weeks from the index event. RESULTS Among 82 participants with clinical and brain MRI information available 6-8 weeks after the index event (mean age 63.5 ±12.5 years, 62.2% men), RCI occurred in 21 (25.6%) cases. At 6-8-week follow-up, 37.8% had target systolic blood pressure, 92.7% were non-smokers, 51.2% had target physical activity, and 98.8% and 86.6% were compliant with antiplatelet and antilipidemic therapy, respectively. Optimal risk factor control increased from 4.9% at baseline to 19.5% at 6-8-week follow-up (p=0.01). None of the participants with optimal risk factor control at follow-up had RCI (0% vs. 31.8%, p<0.01). CONCLUSIONS Only one-fifth of MYRIAD participants had optimal risk factor control during early follow-up. Approximately half and two-thirds had physical inactivity and uncontrolled systolic blood pressure, respectively. These risk factors may represent important therapeutic targets to prevent early RCI in patients with symptomatic IAD.
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Details on the effect of very short dual antiplatelet therapy after drug-eluting stent implantation in patients with high bleeding risk: insight from the STOPDAPT-2 trial.
Watanabe, H, Domei, T, Morimoto, T, Natsuaki, M, Shiomi, H, Toyota, T, Ohya, M, Suwa, S, Takagi, K, Nanasato, M, et al
Cardiovascular intervention and therapeutics. 2021;(1):91-103
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Previously we briefly reported the effect of 1-month dual antiplatelet therapy (DAPT) for patients with high bleeding risk (HBR) receiving percutaneous coronary intervention (PCI) in the STOPDAPT-2 trial, but full analysis data have not been available. We conducted post hoc subgroup analysis regarding the effect of very short DAPT for HBR patients in STOPDAPT-2 trial. The primary endpoint was a 1-year composite of cardiovascular (cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) and bleeding (TIMI major/minor bleeding) outcomes. Major secondary endpoints were 1-year cardiovascular composite endpoint and bleeding endpoint. HBR was defined by the academic research consortium (ARC) HBR criteria. Among the 3009 study patients, 1054 (35.0%) were classified as HBR and 1955 (65.0%) were as non-HBR. There were no significant interactions between HBR/non-HBR subgroups and the assigned DAPT group on the primary endpoint (HBR; 3.48% vs. 5.98%, HR 0.57, 95% CI 0.32-1.03, and non-HBR; 1.81% vs. 2.36%, HR 0.78, 95% CI 0.42-1.45; P for interaction = 0.48), the major secondary cardiovascular endpoint (HBR; 3.07% vs. 4.03%, HR 0.77, 95% CI 0.40-1.48, and non-HBR; 1.41% vs. 1.61%, HR 0.89, 95% CI 0.43-1.84; P for interaction = 0.77), and the major secondary bleeding endpoint (HBR; 0.41% vs. 2.71%, HR 0.15, 95% CI 0.03-0.65, and non-HBR; 0.40% vs. 0.85%, HR 0.48, 95% CI 0.14-1.58; P for interaction = 0.22). In conclusion, the effects of 1-month DAPT for the primary and major secondary endpoints were consistent in HBR and non-HBR patients without any significant interactions. The benefit of 1-month DAPT in reducing major bleeding was numerically greater in HBR patients.Clinical trial registration Short and optimal duration of dual antiplatelet therapy after everolimus-eluting cobalt-chromium stent-2 [STOPDAPT-2]; NCT02619760.
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Applicability of the REDUCE-IT trial to the FAST-MI registry. Are the results of randomized trials relevant in routine clinical practice?
Ferrières, J, Bataille, V, Puymirat, E, Schiele, F, Simon, T, Danchin, N, ,
Clinical cardiology. 2020;(11):1260-1265
Abstract
BACKGROUND The reduction of cardiovascular events with icosapent ethyl-intervention trial (REDUCE-IT) trial revealed robust atherosclerotic cardiovascular risk reduction with a strategy comprising high-dose omega-3 icosapent ethyl vs placebo in statin-treated patients with elevated triglycerides and controlled low-density lipoprotein cholesterol (LDL-C). HYPOTHESIS Are the results of the REDUCE-IT trial applicable to the French registry on acute ST-elevation and non-ST-elevation myocardial infarction (FAST-MI) population? METHODS Data were extracted from the FAST-MI 2010 and 2015 registries. We applied the REDUCE-IT enrolment criteria (triglycerides 150-500 mg/dL and LDL-C 40-100 mg/dL on statins) to the FAST-MI population in patients aged ≥45 years who had detailed lipid values postacute hospitalization, focusing on their clinical profile and cardiovascular prognosis. RESULTS Of the 3789 FAST-MI patients with a full lipid profile (median 11.1 [IQR 7.6-17.4] months after hospitalization for myocardial infarction), 472 (12.5%; 95% CI 11.4-13.5) met the eligibility criteria for REDUCE-IT (REDUCE-IT-like group). The cardiovascular event rate (all-cause death, nonfatal myocardial infarction, nonfatal stroke) was 36.7 (95% CI 27.8-48.6) per 1000 person-years for the REDUCE-IT-like group, which compares with the 36.9 (95% CI 26.1-51.5) per 1000 person-years (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) reported in the REDUCE-IT trial. The residual cardiovascular risk related to elevated triglycerides in the REDUCE-IT-like group was similar to the risk in the REDUCE-IT trial. CONCLUSIONS If the results of REDUCE-IT are applied to patients hospitalized for a myocardial infarction in France, 12.5% of these patients could benefit from a strategy of high-dose omega-3 icosapent ethyl on top of contemporary therapy including statins to improve their clinical outcomes.
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One-year clinical outcomes of patients with versus without acute coronary syndrome with 3-month duration of dual antiplatelet therapy after everolimus-eluting stent implantation.
Natsuaki, M, Morimoto, T, Yamamoto, E, Watanabe, H, Furukawa, Y, Abe, M, Nakao, K, Ishikawa, T, Kawai, K, Yunoki, K, et al
PloS one. 2020;(3):e0227612
Abstract
There has been no previous prospective study evaluating 3-month dual antiplatelet therapy (DAPT) after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation in patients with acute coronary syndrome (ACS). The STOPDAPT trial is a prospective multi-center single-arm study evaluating 3-month DAPT duration in all-comer population after CoCr-EES implantation. Among 1525 study patients enrolled from 58 Japanese centers, the present study compared the 1-year clinical outcomes between ACS patients (N = 487) and stable coronary artery disease (CAD) patients (N = 1038). In the ACS group, 228 patients (47%) had unstable angina and 259 patients (53%) had myocardial infarction. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, definite stent thrombosis (ST) and TIMI major/minor bleeding. Thienopyridine was discontinued within 4-month in 455 patients (94.0%) in the ACS group and 977 patients (94.3%) in the stable CAD group. Cumulative 1-year incidence of and the adjusted risk for the primary endpoint were not significantly different between the ACS and stable CAD groups (2.3% vs. 3.0%, P = 0.42, and HR 0.94, 95%CI 0.44-1.87, P = 0.87). In the 3-month landmark analysis, cumulative incidence of the primary endpoint was also not significantly different between the ACS and stable CAD groups (1.3% vs. 2.4%, P = 0.16). There was no definite/probable ST through 1-year in both groups. In the propensity matched analysis, the cumulative 1-year incidence of the primary endpoint were similar between the ACS and stable CAD groups (2.3% versus 2.1%, P = 0.82). In conclusion, stopping DAPT at 3 months after CoCr-EES implantation in patients with ACS including 47% of unstable angina was as safe as that in patients with stable CAD.
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Secondary prevention of coronary heart disease in elderly population of Turkey: A subgroup analysis of ELDERTURK study.
Kilic, S, Sümerkan, MÇ, Emren, V, Bekar, L, Cersit, S, Tunc, E, Gök, G, Altuntas, E, Canpolat, U, Sinan, UY, et al
Cardiology journal. 2019;(1):13-19
Abstract
BACKGROUND Secondary prevention plays an important role after acute coronary event due to high risk of adverse events in elderly. In present study we aimed to evaluate the lifestyle, management of risk factors and medical treatment for secondary protection in elderly patients with known coronary heart disease (CHD). METHODS ELDERTURK is a non-interventional, multi-centered, observational study, which included total of 5694 elderly patients ( > 65 years) from 50 centers in Turkey. In this study elderly patients from the ELDERTURK population with known CHD were evaluated for cardiovascular risk factors, comor- bidities and medication usage. RESULTS A total of 2976 (52.3% of study) out of 5694 patients included in the ELDERTURK study were evaluated. All had known CHD with a mean age of 73.4 ± 6.2 years and 60.3% were male. 13.0% of patients were smokers, 42.4% were overweight and 21.1% were obese. Only 23.6% of patients reported to do regular exercise, 73.4% had history of hypertension, 47.4% had dyslipidemia and 33.9% had diabetes mellitus. The rate of patients with systolic blood pressure > 140 mmHg were 31.1% and only 13.9% of patients had a recommended ≤ 70 mg/dL level of low-density lipoprotein cholesterol. Anti- platelet, statin, beta-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker usage was limited to 27.3%. CONCLUSIONS The ELDERTURK study shows that many patients with CHD have a high prevalence of modifiable risk factors and unhealthy lifestyle. Apart from this, many patients are not receiving thera- peutic intervention and as a consequence most were not achieving the recommended goals.
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Safety and efficacy of heparin during dialysis in the context of systemic anticoagulant and antiplatelet medications.
Brunelli, SM, Cohen, DE, Marlowe, G, Liu, D, Njord, L, Van Wyck, D, Aronoff, G
Journal of nephrology. 2019;(3):453-460
Abstract
Heparin is widely used to prevent coagulation during hemodialysis. Although systemic anticoagulants and antiplatelet agents are commonly prescribed in the hemodialysis population, the safety and efficacy of heparin in the presence of these medications is unclear. This retrospective cohort study considered adult hemodialysis patients treated in the United States (August 2015-July 2017). For each month, patients were ascribed a three-part exposure status (heparin use, anticoagulant use, antiplatelet agent use) based on electronic health records. Outcomes included anemia measures, peri-treatment bleeding and clotting, and hospitalization for gastrointestinal (GI) bleeding. Within systemic medication exposure categories, associations of heparin use were examined using adjusted generalized linear, negative binomial, or Poisson models. Across all systemic medication exposures, heparin use was associated with lower erythropoiesis stimulating agent (ESA) dose, higher hemoglobin levels, and lower monthly intravenous (IV) iron dose; lower rates of clotting during treatment and hospitalization for GI bleeding; and similar rates of peri-treatment bleeding. Associations with respect to ESA, IV iron, hemoglobin, and clotting were approximately twofold more potent in the absence of a systemic anticoagulant; the presence of an antiplatelet agent had little impact. Neither medication type influenced associations between heparin use and peri-treatment or GI bleeding. These results suggest that heparin use is safe and effective in the presence and absence of systemic anticoagulants and antiplatelet agents. Clinical judgment must be applied to assess bleeding risk in individual patients; however, the decision to withhold heparin should not solely be based upon the concurrent use of anticoagulant or antiplatet agents.
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Antithrombotic treatments in patients with acute ischemic stroke and non-valvular atrial fibrillation before introduction of non-vitamin K antagonist oral anticoagulants into practice in Korea.
Bae, HJ, Heo, JH, Jung, KH, Lee, YS, Hong, KS, Seo, WK, Koo, J, Cha, JK, Lee, MJ, Seo, BJ, et al
PloS one. 2018;(11):e0202803
Abstract
BACKGROUND This study aimed to describe patterns of long-term antithrombotic use in acute ischemic stroke (AIS) patients with non-valvular atrial fibrillation (NVAF) in Korea and their impacts on clinical events before introduction of non-vitamin K antagonist oral anticoagulants (NOAC) into practice in 2015. METHODS Patients with NVAF who were admitted due to the AIS and discharged no later than 2008 were enrolled retrospectively. Data were collected at 11 time points during the first 3 years of follow-up. The primary outcome event was a composite of stroke recurrence, major bleeding, and death. Vitamin K antagonist (VKA) users were categorized into a well-controlled INR group and a poorly-controlled INR group (modified TTR ≥47.0% vs <47.0%). RESULTS Of 1,350 patients enrolled in this study, 95% were on antithrombotic medications at discharge. The rate of VKA usage decreased over time (77% and 40% at discharge and 3 years, respectively). The cumulative event rates of the primary outcome differed by treatment patterns. Among the 10 most frequent treatment types, the highest outcome rate was observed in patients who started with VKA-only therapy but discontinued VKAs during follow-up without restarting (70.2%); this was followed by those starting with antiplatelet-only therapy and stopping it without restart (66.7%). Among VKA users, the 3-year cumulative primary outcome rates were higher in the poorly-controlled INR group than the well-controlled INR group (24.5% vs 15.7%; p = 0.015). CONCLUSION Our study revealed that, in pre-NOAC era, there was a wide spectrum of long-term antithrombotic use. The incidence of the composite outcome also varied by patterns of antithrombotic use.