Randomised controlled trial to investigate optimal antithrombotic therapy in patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention: a study protocol of the OPTIMA-AF trial

IntroductionThe optimal antithrombotic strategy for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) is uncertain. For patients with non-AF, many trials are now evaluating short 1-month dual antiplatelet therapy. In patients with AF undergoing PCI, in contrast, short dual therapy (P2Y12 inhibitor +direct oral anticoagulant (DOAC)) has not yet been evaluated.Methods and analysisThe OPTIMA-AF trial (OPTIMAl antiplatelet therapy in combination with direct oral anticoagulants in patients with non-valvular Atrial Fibrillation undergoing percutaneous coronary intervention with everolimus-eluting stent) is an investigator-initiated, open-label, nationwide, multicentre, prospective, randomised controlled trial. The primary objective is to compare the efficacy and safety of short dual therapy (1-month DOAC +P2Y12 inhibitor followed by DOAC monotherapy) against long dual therapy (12-month DOAC +P2Y12 inhibitor followed by DOAC monotherapy) in the treatment of AF subjects undergoing PCI. The primary efficacy endpoint is a composite of death or thromboembolic events (myocardial infarction, definite stent thrombosis, stroke or systemic embolism) at 365 days; and the primary safety endpoint is bleeding (International Society on Thrombosis and Haemostasis major or clinically relevant non-major bleeding) at 365 days. This trial is intended to show the non-inferiority of short dual therapy versus long dual therapy in terms of the primary efficacy endpoint and show superiority in terms of the primary safety endpoint. A total of 1090 subjects will be randomised in a 1:1 ratio at approximately 60 sites.Ethics and disseminationThis study received approval from the Certified Review Board of Osaka University (a certified research ethics committee by the Japanese Clinical Research Act). The findings will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberJapan Registry of Clinical Trials: jRCTs051190053; Pre-results.

Outcomes after ticagrelor versus clopidogrel treatment in end-stage renal disease patients with acute myocardial infarction: a nationwide cohort study

Clinical outcomes are unknown after ticagrelor treatment in patients with end-stage renal disease (ESRD) who are diagnosed with acute myocardial infarction (AMI). ESRD patients who were on hemodialysis and received dual antiplatelet therapy (DAPT) for AMI between July 2013 and December 2016 were identified in Taiwan's National Health Insurance Research Database. Using stabilized inverse probability of treatment weighting, patients receiving aspirin plus ticagrelor (n = 530) were compared with those receiving aspirin plus clopidogrel (n = 2462) for the primary efficacy endpoint, a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke, and bleeding, defined according to the Bleeding Academic Research Consortium. Study outcomes were compared between the two groups using Cox proportional hazards model or competing risk model for the hazard ratio or subdistribution hazard ratio (SHR). During 9 months of follow-up, ticagrelor was comparable to clopidogrel with respect to the risks of primary efficacy endpoint [11.69 vs. 9.28/100 patient-months; SHR, 1.16; 95% confidence interval (CI) 0.97–1.4] and bleeding (5.55 vs. 4.36/100 patient-months; SHR 1.14; 95% CI 0.88–1.47). In conclusion, among hemodialysis patients receiving DAPT for AMI, ticagrelor was comparable to clopidogrel with regard to the composite efficacy endpoint and bleeding.

Efficacy and Safety of a Hyaluronic Acid–Containing Cream in the Treatment of Chronic, Venous, or Mixed-Origin Leg Ulcers: A Prospective, Multicenter Randomized Controlled Trial

Introduction. Topical applications of hyaluronic acid (HA)–containing formulations, based on the complex and vital role of HA in all stages of the wound-healing process, are routinely used with standard therapy to promote faster healing of chronic wounds. However, evidence to guide clinical decisions on the use of topical HA in the healing of vascular leg ulcers is limited. Objective. This study compared the efficacy and safety of topical application of a hyaluronic acid cream vs a neutral comparator (identical cream without HA) in treating subjects with chronic leg ulcers of vascular origin. Materials and Methods. This was a prospective, multicenter double-blind randomized controlled trial. One hundred sixty-eight subjects with chronic leg ulcers of venous or mixed (venous and arterial) origin were randomized to receive either topical applications of 0.2% HA cream or neutral comparator cream for a maximum of 20 weeks. The primary efficacy endpoint was complete ulcer healing (100% reepithelialization of the wound area centrally assessed at 20 weeks or before and confirmed 3 weeks later). In both groups, topical treatment was associated with standard therapy (ulcer cleansing and optimized compression). Results. The proportion of subjects with centrally assessed complete healing of the target ulcer that was confirmed 3 weeks later (primary efficacy endpoint) was substantially higher in the HA cream group (31.3%) than in the neutral cream group (14.8%; P =.009). Results in the full analysis, per protocol, and as assessed by the investigator were consistent with primary results. No significant difference in treatment effect was observed when subjects were stratified according to baseline ulcer size (≤20 cm2 or >20 cm2) regardless of topical treatment. Safety and tolerability were comparable between treatments. Conclusions. Treatment of subjects with chronic leg ulcers of venous or mixed origin with HA cream is safe, well tolerated, and results in a higher rate of healing than a neutral comparator cream.

Prospective application of a risks-adjusted antithrombotic protocol in elderly patients treated with the last generation of everolimus-eluting stents. The SIERRA-75 (EPIC-05) registry

Background Elderly patients show a higher incidence of ischemic and bleeding events after PCI. Purpose We sought to investigate clinical outcomes in elderly patients revascularized with last generation everolimus-eluting stent (EES) treated with antithrombotic strategies guided by bleeding and ischemic risks. Methods Prospective multicenter registry including patients over 75 years revascularized with EES and subsequent antithrombotic therapy guided according to a protocol based on clinical presentation, PCI complexity and the PRECISE DAPT score. The primary safety endpoint was a composite of cardiac death, myocardial infarction and definitive/probable stent thrombosis and the primary efficacy endpoint was TLR. An historical matched group of patients treated with current drug eluting stents other than EES was used as control. Results Finally, 1,064 patients were included, 80.8±4.2 years, 36.6% women, 72% ACS and 53.6% complex PCI. Primary safety endpoint was met in 6.2% and primary efficacy endpoint in 1.5%. Bleeding BARC 2–5 was reported in 7.8% and definite or probable stent thrombosis in 1.3%. The multivariable adjusted model showed no significant association of the prescribed short/long therapies with any endpoint. No stent thrombosis were reported in the subgroup with shorter DAPT duration. As compared to control group, bleeding BARC 2–5 was significantly lower in SIERRA-75 group (7.4% vs 10.2%, p=0.04) as well as the composite of MACE and bleeding (14.3% vs 18.5%, p=0.02). Conclusions In elderly population the use of last generation EES along with a predefined risks-adjusted antithrombotic regimen seems to be associated with an improved prognosis in terms of ischemic and bleeding outcomes. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Abbott Laboratories

Initial Results after the Implementation of an Edge-To-Edge Transcatheter Tricuspid Valve Repair Program

Transcatheter tricuspid valve repair (TTVr) has emerged as an alternative for the treatment of severe tricuspid regurgitation (TR). We report our initial experience with an edge-to-edge TTVr system in a high-volume institution. Methods: We included consecutive patients who underwent edge-to-edge TTVr systems. The primary efficacy endpoint was a reduction in the TR of at least one grade. The primary safety endpoint was procedure-related clinical serious adverse events. Results: A total of 28 patients underwent TTVr with edge-to-edge systems. All patients presented with at least severe TR with a high impact on quality of life (82% of patients in NYHA class ≥ III). The Triclip system was the most used device (89%). The primary efficacy endpoint was met in all patients. Only one patient experienced a procedural complication (femoral pseudoaneurysm). At three-month follow-up, 83% of patients were in NYHA I or II (18% baseline vs. 83% 3 months follow-up; p < 0.001). Echocardiography follow-up showed residual TR ≤ 2 in 79% of patients (paired p < 0.001). At the maximum follow-up (median follow up = 372 days), no patients had died. Conclusions: Edge-to-edge TTVr systems seem to represent a very valid alternative to prevent morbidity and mortality associated with TR as depicted by the favorable efficacy and safety.

Early Covid-19 Treatment With SARS-CoV-2 Neutralizing Antibody Sotrovimab

Background: Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization and death in older patients and those with underlying comorbidities. Sotrovimab is a pan-sarbecovirus monoclonal antibody designed to treat such high-risk patients early in the course of disease, thereby preventing Covid-19 progression. Methods: In this ongoing, multicenter, double-blind, phase 3 trial, nonhospitalized patients with symptomatic Covid-19 and at least one risk factor for disease progression were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was the proportion of patients with Covid-19 progression, defined as hospitalization longer than 24 hours or death, through day 29. Results: In this preplanned interim analysis, which included an intent-to-treat population of 583 patients (sotrovimab, 291; placebo, 292), the primary efficacy endpoint was met. The risk of Covid-19 progression was significantly reduced by 85% (97.24% confidence interval, 44% to 96%; P = 0.002) with a total of three (1%) patients progressing to the primary endpoint in the sotrovimab group versus 21 (7%) patients in the placebo group. All five patients admitted to intensive care, including one who died by day 29, received placebo. Safety was assessed in 868 patients (sotrovimab, 430; placebo, 438). Adverse events were reported by 17% and 19% of patients receiving sotrovimab and placebo, respectively; serious adverse events were less common with sotrovimab (2%) versus placebo (6%). Conclusion: Sotrovimab reduced progression of Covid-19 in patients with mild/moderate disease, was well tolerated, and no safety signals were identified. Funded by Vir Biotechnology, Inc. and GlaxoSmithKline; ClinicalTrials.gov NCT04545060

Efficacy and safety of nivolumab and trabectedin in pretreated patients with advanced soft tissue sarcomas (STS): Preliminary results of a phase II trial of the German Interdisciplinary Sarcoma Group (GISG-15, NitraSarc) for the non-L sarcoma cohort.

11545 Background: Single-agent PD-1 inhibitors have modest activity in the treatment of most STS. Potential strategies to increase efficacy include combination therapies targeting the tumor microenvironment. Considering that apart from direct growth inhibition and death of malignant cells, trabectedin (Tr) also induces macrophage depletion and/or different immunologic effects, suggesting a possible synergistic effect of combined Tr plus anti-PD-1 treatment. We therefore aimed to evaluate the efficacy and safety of combined Tr and nivolumab (Ni) as a second-line treatment in STS. Methods: The prospective, explorative, two group, non-randomized phase II NiTraSarc trial enrolled pretreated patients (pt) with advanced STS (Group A: lipo- or leiomyosarcomas, Group B: non-L-sarcomas). Pt were initially treated with 3 cycles of Tr 1.5 mg/m2, followed by the combination of Tr 1.5 mg/m2 + Ni 240 mg (“late combination cohort” (LCC)) for up to 16 cycles. After positive results of a preplanned interim analysis, pt received the combination therapy starting with cycle 2 (“early combination cohort” (ECC)). 92 pt were recruited to the trial (55 in Group A, 37 in Group B). Primary efficacy endpoint is progression-free survival rate after 6 months (PFSR6) according to RECIST v.1.1. This is a first analysis of the primary efficacy endpoint in Group B based on a modified intention-to-treat (mITT) population of evaluable 36 pt: 23 and 13 pt from the LCC and ECC, respectively. Results: The most common Group B subtypes comprised undifferentiated pleomorphic/not otherwise specified sarcoma (UPS/NOS, 13pt) and fibromyxoid sarcoma (FMS, 6pt). After a median follow-up of 5 months (m) PFSR6 was 13.9% for all pt, 8.7% in LCC and 23.1% in ECC. Median duration of disease stabilization (DoDS) was 4m in all pt, the LCC and the ECC. Two pt had a partial response (PR), 10 had disease stabilization (SD), while 13 pt progressed, and 11 had missing data. By subtype: PR- UPS/NOS=2 (DoDS 12.7m/12.5m). SD: UPS/NOS=3, epithelioid=2, synovial=2, FMS=1, fibrosarcoma=1, other=1. All 36 pt experienced at least one adverse event (AE) reaching a total of 579 AEs, 141 (24.4%) of which were considered to be grade ≥3 treatment-related AEs. The main grade ≥3 AEs were: leukopenia (47.2% of pt), neutropenia (41.7% of pt), thrombocytopenia (33.3% of pt), increased ALT (30.6% of pt), and anemia (27.8% of pt). Conclusions: Tr+Ni was well tolerated and showed activity in at least some patients with non-L-sarcomas (mostly UPS/NOS) especially in the ECC. Analyses of the collected data, including PD-L1 expression profile, with the goal to establish whether Tr+Ni should be further pursued in these patients, are ongoing. ClinicalTrials.gov Identifier: NCT03590210; EudraCT: 2017-001083-38. Clinical trial information: NCT03590210.

Selective serotonin reuptake inhibitors for debilitating vasovagal syncope: looking for copper and finding gold

Funding Acknowledgements Type of funding sources: None. Background Despite its benign course, recurrent and unpredictable vasovagal syncope (VVS) may be disabling. Even though a non-pharmacological approach is generally regarded as first-line, a variety of drugs might also be of use. In this respect, the clinical value of selective serotonin reuptake inhibitors (SSRIs) is still a matter of debate. Purpose To perform a meta-analysis aimed at evaluating the extent to which SSRIs might reduce VVS recurrences in susceptible patients. Methods We systematically searched MEDLINE, Embase, Web of Science, Cochrane Library and Google Scholar for prospective studies, addressing the effect of SSRIs on the recurrence rate of VVS in predisposed patients, published up until December 31st, 2020. In order to be included in the quantitative analysis, studies were required to encompass a positive head-up tilt table (HUTT) test for VVS diagnosis and a minimum patient follow-up of 6 months. The primary endpoint was recurrent spontaneous VVS, whereas secondary endpoints included the efficacy outcome of HUTT test-induced VVS and the safety outcome of drug discontinuation for adverse effects. Randomized controlled trials (RCTs) and studies including the most represented SSRI drug were further investigated separately, with respect to the primary endpoint. Study-specific odds ratios (ORs) were pooled using traditional meta-analytic techniques, under a random-effects model. Results 3 RCTs (2 placebo-controlled and 1 both placebo- and active-controlled) and 1 non-randomized prospective study, encompassing 222 and 127 patients, respectively, were regarded as eligible for quantitative evaluation. Patient follow-up ranged between 6 and 24 months. 131 patients were allocated to the SSRI arm, which featured fluoxetine as the most represented element (97 cases). The absolute number of events for each outcome may be reported as follows: primary efficacy endpoint, 57; secondary efficacy endpoint, 68 (only 2 RCTs reporting); secondary safety endpoint, 4 (only 2 RCTs reporting). In the main analysis, SSRIs were not found to significantly reduce VVS recurrence rate (OR 0.48, 95% CI 0.13-1.81, P 0.28, i2 74%). This null result was, however, single-handedly driven by the only non-randomized study included (OR 4.5, 95% CI 0.85-23.8). Likewise, fluoxetine was not able to significantly reduce the primary efficacy endpoint (OR 0.7, 95% CI 0.12-4.12, P 0.7, i2 78%), while SSRIs only numerically cut HUTT test-induced VVS events (OR 0.66, 95% CI 0.24-1.84, P 0.43, i2 59%). Nevertheless, when only RCTs are considered, SSRIs exerted a meaningful reduction in VVS recurrence rate, with no heterogeneity (OR 0.25, 95% CI 0.12-0.5, P 0.0001, i2 0%). In addition, drug discontinuation for safety reasons was rare and comparable between the SSRI and the placebo arms (OR 1.51, 95% CI 0.21-10.74, P 0.59, i2 0%). Conclusion SSRIs do represent one more safe pharmacological option to reduce syncope recurrences in patients with otherwise refractory VVS. Abstract Figure.

Cardiac Catheterizations in Patients With Prior Coronary Bypass Surgery: Impact of Access Strategy on Short-Term Safety and Long-Term Efficacy Outcomes

Little data are available on access strategy outcomes for cardiac catheterizations in patients with prior coronary artery bypass graft surgery (CABG). We investigated the effect of transradial access (TRA) and transfemoral access (TFA) on short-term major vascular complications (MVC) and long-term major adverse cardiovascular events (MACE). In this single-center, retrospective cohort study, 1084 patients met our inclusion criteria (TRA = 469; TFA = 615). The cumulative incidence for the primary safety endpoint MVC at 30 days (a composite of major bleeding, retroperitoneal hematoma, dissection, pseudoaneurysm, and arteriovenous fistula) was lower with TRA (0.7% vs 3.0%, P < .01) and this difference remained significant after propensity score adjustment (odds ratio: 0.24; 95% CI, 0.07-0.83; P = .024). The cumulative incidence for the primary efficacy endpoint MACE at 36 months (a composite of all-cause mortality, myocardial infarction, stroke, and urgent target vessel revascularization) was 28.6% with TRA and 27.6% with TFA, respectively. Kaplan-Meier curves showed no difference for the primary efficacy endpoint ( P = .65). Contrast use (mL) was significantly lower with TRA (130 [100-180] vs 150 [100-213], P < .01). In conclusion, in patients with prior CABG, TRA was associated with significantly fewer short-term MVC and contrast use, but not with a difference in long-term MACE, compared with TFA.