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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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Abstract
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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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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Abstract
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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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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Comparison of Ticagrelor Versus Clopidogrel on Cerebrovascular Microembolic Events and Platelet Inhibition during Transcatheter Aortic Valve Implantation.
Vavuranakis, MA, Kalantzis, C, Voudris, V, Kosmas, E, Kalogeras, K, Katsianos, E, Oikonomou, E, Siasos, G, Aznaouridis, K, Toutouzas, K, et al
The American journal of cardiology. 2021;:78-85
Abstract
The impact of the antiplatelet regimen and the extent of associated platelet inhibition on cerebrovascular microembolic events during transcatheter aortic valve implantation (TAVI) are unknown. Our aim was to evaluate the effects of ticagrelor versus clopidogrel and of platelet inhibition on the number of cerebrovascular microembolic events in patients undergoing TAVI. Patients scheduled for TAVI were randomized previous to the procedure to either aspirin and ticagrelor or to aspirin and clopidogrel. Platelet inhibition was expressed in P2Y12 reaction units (PRU) and percentage of inhibition. High intensity transient signals (HITS) were assessed with transcranial Doppler (TCD). Safety outcomes were recorded according to the VARC-2 definitions. Among 90 patients randomized, 6 had an inadequate TCD signal. The total number of procedural HITS was lower in the ticagrelor group (416.5 [324.8, 484.2]) (42 patients) than in the clopidogrel group (723.5 [471.5, 875.0]) (42 patients), p <0.001. After adjusting for the duration of the procedure, diabetes, extra-cardiac arteriopathy, BMI, hypertension, aortic valve calcium content, procedural ACT, and pre-implantation balloon valvuloplasty, patients on ticagrelor had on average 256.8 (95% CI: [-335.7, -176.5]) fewer total procedural HITS than patients on clopidogrel. Platelet inhibition was greater with ticagrelor 26 [10, 74.5] PRU than with clopidogrel 207.5 (120 to 236.2) PRU, p <0.001, and correlated significantly with procedural HITS (r = 0.5, p <0.05). In conclusion, ticagrelor resulted in fewer procedural HITS, compared with clopidogrel, in patients undergoing TAVI, while achieving greater platelet inhibition.
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Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Kasner, SE, Swaminathan, B, Lavados, P, Sharma, M, Muir, K, Veltkamp, R, Ameriso, SF, Endres, M, Lutsep, H, Messé, SR, et al
The Lancet. Neurology. 2018;(12):1053-1060
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BACKGROUND Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. METHODS NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. FINDINGS Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22-1·36), and the risk was similar for those without known PFO (1·06; 0·84-1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51-8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69-4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24-0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. INTERPRETATION Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. FUNDING Bayer and Janssen.
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The Incidence of Myocardial Injury after Loading Doses of Clopidogrel versus Prasugrel in the Candidates for Percutaneous Coronary Intervention: A Randomized Controlled Trial.
Rahmani, R, Jiriaee, L, Jiriaee, Z, Shafiee, A, Zand Parsa, AF
Critical pathways in cardiology. 2018;(2):69-72
Abstract
INTRODUCTION Prevention of myocardial injury is an essential issue in percutaneous coronary intervention (PCI). We compared the incidence of myocardial injury after loading doses of clopidogrel versus prasugrel in the candidates for PCI. METHODS In this randomized-controlled clinical trial, we enrolled 88 stable angina patients, candidate for PCI. Patients received either prasugrel (60 mg orally) (n = 42) or clopidogrel (600 mg orally) (n = 46). Serum levels of creatine phosphokinase muscle-brain type, cardiac troponin I, and high sensitive C-reactive protein were measured at baseline and 6 and 12 hours postprocedural. Primary endpoint was periprocedural myocardial infarction (MI), defined as elevation of cTn values (>5 times) in patients with normal baseline values or a rise of cTn values >20% if the baseline values are elevated. RESULTS Based on the levels of cTnI 6 hours after PCI, 1 patient (2.4%) had MI in the prasugrel group, whereas 4 patients (8.7%) had MI in the clopidogrel group. After 12 hours, 4 patients (9.5%) had MI in the prasugrel group versus 5 patients (10.9%) in the clopidogrel arm. There was no significant difference between the groups regarding the changes in cardiac specific enzyme levels. However, serum levels of cTnI were significantly lower in patients with myocardial injury in the prasugrel arm (P < 0.001). CONCLUSIONS Prasugrel is an effective antiplatelet drug in preventing periprocedural MI.
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Lipid Effects of Icosapent Ethyl in Women with Diabetes Mellitus and Persistent High Triglycerides on Statin Treatment: ANCHOR Trial Subanalysis.
Brinton, EA, Ballantyne, CM, Guyton, JR, Philip, S, Doyle, RT, Juliano, RA, Mosca, L
Journal of women's health (2002). 2018;(9):1170-1176
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BACKGROUND High triglycerides (TG) and diabetes mellitus type 2 (DM2) are stronger predictors of cardiovascular disease (CVD) in women than in men, but few randomized, controlled clinical trials have investigated lipid-lowering interventions in women and none have reported results specifically in women with high TG and DM2. Icosapent ethyl (Vascepa) is pure prescription eicosapentaenoic acid (EPA) ethyl ester approved at 4 g/day as an adjunct to diet to reduce TG ≥500 mg/dL. METHODS The 12-week ANCHOR trial randomized 702 statin-treated patients (73% with DM; 39% women) at increased CVD risk with TG 200-499 mg/dL despite controlled low-density lipoprotein cholesterol (LDL-C; 40-99 mg/dL) to receive icosapent ethyl 2 g/day, 4 g/day, or placebo. This post hoc analysis included 146 women with DM2 (97% white, mean age 62 years) randomized to icosapent ethyl 4 g/day (n = 74) or placebo (n = 72). RESULTS Icosapent ethyl significantly reduced TG (-21.5%; p < 0.0001) without increasing LDL-C and lowered other potentially atherogenic lipid/lipoprotein, apolipoprotein, and inflammatory parameters versus placebo. Icosapent ethyl increased EPA levels in plasma (+639%; p < 0.0001; n = 49) and red blood cells (+599%; p < 0.0001; n = 47) versus placebo. Safety and tolerability of icosapent ethyl were generally similar to placebo. CONCLUSION In women with DM2 at high CVD risk with persistently high TG on statins, icosapent ethyl 4 g/day reduced potentially atherogenic parameters with safety and tolerability comparable to placebo. Potential CVD benefits of icosapent ethyl are being tested in ∼8000 men and women at high CVD risk with high TG on statins in the ongoing Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial (REDUCE-IT) cardiovascular (CV) outcome trial.
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A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions.
Werner, GS, Martin-Yuste, V, Hildick-Smith, D, Boudou, N, Sianos, G, Gelev, V, Rumoroso, JR, Erglis, A, Christiansen, EH, Escaned, J, et al
European heart journal. 2018;(26):2484-2493
Abstract
AIMS: The clinical value of percutaneous coronary intervention (PCI) for chronic coronary total occlusions (CTOs) is not established by randomized trials. This study should compare the benefit of PCI vs. optimal medical therapy (OMT) on the health status in patients with at least one CTO. METHOD AND RESULTS Three hundred and ninety-six patients were enrolled in a prospective randomized, multicentre, open-label, and controlled clinical trial to compare the treatment by PCI with OMT with a 2:1 randomization ratio. The primary endpoint was the change in health status assessed by the Seattle angina questionnaire (SAQ) between baseline and 12 months follow-up. Fifty-two percent of patients have multi-vessel disease in whom all significant non-occlusive lesions were treated before randomization. An intention-to-treat analysis was performed including 13.4% failed procedures in the PCI group and 7.3% cross-overs in the OMT group. At 12 months, a greater improvement of SAQ subscales was observed with PCI as compared with OMT for angina frequency [5.23, 95% confidence interval (CI) 1.75; 8.71; P = 0.003], and quality of life (6.62, 95% CI 1.78-11.46; P = 0.007), reaching the prespecified significance level of 0.01 for the primary endpoint. Physical limitation (P = 0.02) was also improved in the PCI group. Complete freedom from angina was more frequent with PCI 71.6% than OMT 57.8% (P = 0.008). There was no periprocedural death or myocardial infarction. At 12 months, major adverse cardiac events were comparable between the two groups. CONCLUSION Percutaneous coronary intervention leads to a significant improvement of the health status in patients with stable angina and a CTO as compared with OMT alone. TRIAL REGISTRATION NCT01760083.
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Cost-effectiveness of a fixed dose combination (polypill) in secondary prevention of cardiovascular diseases in India: Within-trial cost-effectiveness analysis of the UMPIRE trial.
Singh, K, Crossan, C, Laba, TL, Roy, A, Hayes, A, Salam, A, Jan, S, Lord, J, Tandon, N, Rodgers, A, et al
International journal of cardiology. 2018;:71-78
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BACKGROUND The Use of Multidrug Pill In Reducing cardiovascular Events (UMPIRE) trial, showed that access to a cardiovascular polypill (aspirin, statin and two blood pressure lowering drugs) significantly improved adherence, lowered systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDLc) in patients with or at high risk of cardiovascular disease (CVD). We aimed to analyze the within-trial cost-effectiveness of the polypill strategy versus usual care in India. METHODS Relative effectiveness and costs of polypill versus usual care groups in UMPIRE were estimated from the health sector perspective. Only direct medical costs were considered. The effectiveness of the polypill was reported as a percentage increase in adherence and mean reductions in SBP, and LDL-c, over the 15-month trial period. Healthcare resource utilization and costs were collected for each patient during the trial. Polypill price was constructed using a range of scenarios: $0.06-$0.94/day. The cost-effectiveness of the polypill was measured as the additional cost for 10% increase in adherence, and per unit reduction in SBP and LDL-c. RESULTS Overall, the mean cost per patient was significantly lower with the polypill strategy (-$203 per person, (95% CI: -286, -119, p < 0.01). In scenario analyses that varied polypill price assumptions, incremental cost-effectiveness ratios for a polypill strategy ranged between cost-saving to $75 per 10% increase in adherence for polypill price of $0.94 per day. CONCLUSIONS The polypill strategy was cost-saving compared to usual care among patients with or at high risk of CVD in India.