Diacerein Versus Chondroitin Sulfate in Treatment of Adult Kashin-Beck Disease: An Intervention Trial in Heilongjiang Province, China

Background: Kashin-Beck disease (KBD) is a special type of osteoarthritis and has disabled and stunted the growth of hundreds of people in China. It also can affect patients' ability to work and live. So, how to conduct effective treatment for adult KBD patients has become a major public health problem in current KBD endemic areas. In this trial, therapeutic effects of diacerein and chondroitin sulfate on adult KBD was to evaluate and compare so that we can screen out more suitable drug. Methods: 308 KBD patients were divided into two groups and received chondroitin sulphate (Group A) and diacerein (Group B) for 24 weeks, respectively. Data were collected at 0 week (baseline), 12 weeks (primary end point) and 24 weeks (secondary end point) to calculate the proportion of patients with effective therapeutic effect and overall improvement rate (primary efficacy parameters), WOMAC pain and stiffness scores (secondary efficacy parameters). Blood sample was collected to measure liver and renal function indexes. All indexes and parameters were analysed with SPSS software and intent-to-treat (ITT) analysis was applied. Results: Two primary efficacy parameters in group B at primary end point were significantly higher than those in group A (P=0.021, P=0.007), but no statistical differences were seen in these two primary efficacy parameters between two groups at secondary end point or between primary and secondary end points in same group (all P>0.05). In both groups, with the prolongation of treatment time, WOMAC pain and stiffness scores decreased significantly (all P<0.001), but no significant differences were seen between primary and secondary end points (all P>0.05). In addition, in both groups, the occurrences of total adverse events were relatively low and no side effect on liver function was seen. Diacerein also had no side effect on renal function. Conclusion: For treatment of adult KBD, both diacerein and chondroitin sulfate were effective, and diacerein might work stronger than chondroitin sulfate. Taking into account both efficacy and safety, the optimal intervention time of diacerein was 12 weeks. Trial registration: The trial was registered complementally on 31/10/2020, and the registration number in the Chinese Clinical Trial Registry is ChiCTR2000039600 (http://www.chictr.org.cn).

A novel endovascular method of atherectomy for calcified common femoral and popliteal disease using the crosser system: Crossbow and Rambow techniques

Objectives This study aims to report the efficacy and safety of new atherectomy methods using the Crosser system for calcified lesions in the common femoral and popliteal artery: the Crosser system supported by bended 0.014 wire (Crossbow) technique and retrograde approach of sheathless Crosser system supported by bended 0.014 wire (Rambow) technique. Materials and Methods This report describes a single-center, retrospective study. A total of 23 patients (mean ± SD age, 73 ± 10 years; 19 men) with symptomatic peripheral artery disease received the Crossbow technique and Rambow technique for treatment of calcified common femoral and popliteal disease; these patients were enrolled between October 2013 and October 2015. The primary efficacy outcome was acute technical success, defined as achievement of residual stenosis < 30% for stenting and < 50% for angioplasty or atherectomy. The primary safety outcome was assessed on the basis of angiographic complications. Results The Crossbow and Rambow techniques were undertaken in 100% and 17% of the patients, respectively. Acute technical success was achieved in 96% of the patients. There were two embolic events. Conclusion Crossbow and Rambow techniques could be effective atherectomy methods of calcified common femoral and popliteal disease. Regarding safety, embolic protection devices may be needed for our atherectomy methods.

Efficacy of chloroquine and hydroxychloroquine for the treatment of hospitalized COVID-19 patients: a meta-analysis

Aims: To evaluate the efficacy and safety of hydroxychloroquine/chloroquine, with or without azithromycin, in treating hospitalized COVID-19 patients. Materials & methods: Data from randomized and observational studies were included in a random-effects meta-analysis. Primary outcomes included time to negative conversion of SARS-CoV-2 tests, length of stay, mortality, incidence of mechanical ventilation, time to normalization of body temperature, incidence of adverse events and incidence of QT prolongations. Results: Fifty-one studies (n = 61,221) were included. Hydroxychloroquine/chloroquine showed no efficacy in all primary efficacy outcomes, but was associated with increased odds of QT prolongations. Conclusion: Due to a lack of efficacy and increased odds of cardiac adverse events, hydroxychloroquine/chloroquine should not be used for treating hospitalized COVID-19 patients.

In search of a gold standard patient-reported outcome measure to use in the evaluation and treatment-decision making in migraine prevention. A real-world evidence study

Background Patient-Reported Outcomes (PROs) have been developed to numerically quantify disability, impact and quality of life. They have been widely used in migraine clinical trials. However, we still do not know which PRO more accurately reflects preventive treatment response from a patient’s perspective or which one may help us with treatment decisions in clinical practice. They have been used to enforce the efficacy results in clinical trials and real-world evidence so far. The aim of this study was to analyze which PROM is (1) better correlated with all primary efficacy endpoints and (2) which one is better associated with treatment continuation with CGRP-mAbs at week-12, which is usually the moment when this decision is made. Methods Patients with migraine who had received 3 administrations of CGRP-mAbs were evaluated in this prospective cohort study. Primary efficacy outcomes considered: a change in migraine days (MMD), headache days (MHD), pain intensity (INT), acute medication days (AMD) and 50% responder rate. The Spearman coefficient (rs) was the measure used for quantify the strength of the correlation between PROMs and treatment efficacy outcomes changes. A stepwise logistic regression identified which PROM was independently associated with treatment continuation at week-12. Results 263 patients completed 12 weeks of treatment. The efficacy outcomes and PROMs scores were statistically significantly reduced at week-12 for all patients. The role function-restrictive (RFR) domain of the Migraine-Specific Quality of Life (MSQ) questionnaire was statistically significantly correlated with all primary efficacy outcomes. Relative changes in MSQ total score (OR[95%]: 0.840[0.619-0.973]; p=0.037) and Patient Global Impression of Change (PGIC) scale (OR[95%]: 15.569[6.254-31.533]; p<0.001) were the PROMs associated with treatment continuation as independent factors at week-12. Conclusions Changes in MSQ questionnaire and PGIC scale at week-12 were the PROMs with higher association with CGRP-mAbs response from a patient’s perspective and medical decision-taking.

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.

Tranexamic acid for intracerebral haemorrhage within 2 hours of onset: protocol of a phase II randomised placebo-controlled double-blind multicentre trial

RationaleHaematoma growth is common early after intracerebral haemorrhage (ICH), and is a key determinant of outcome. Tranexamic acid, a widely available antifibrinolytic agent with an excellent safety profile, may reduce haematoma growth.Methods and designStopping intracerebral haemorrhage with tranexamic acid for hyperacute onset presentation including mobile stroke units (STOP-MSU) is a phase II double-blind, randomised, placebo-controlled, multicentre, international investigator-led clinical trial, conducted within the estimand statistical framework.HypothesisIn patients with spontaneous ICH, treatment with tranexamic acid within 2 hours of onset will reduce haematoma expansion compared with placebo.Sample size estimatesA sample size of 180 patients (90 in each arm) would be required to detect an absolute difference in the primary outcome of 20% (placebo 39% vs treatment 19%) under a two-tailed significance level of 0.05. An adaptive sample size re-estimation based on the outcomes of 144 patients will allow a possible increase to a prespecified maximum of 326 patients.InterventionParticipants will receive 1 g intravenous tranexamic acid over 10 min, followed by 1 g intravenous tranexamic acid over 8 hours; or matching placebo.Primary efficacy measureThe primary efficacy measure is the proportion of patients with haematoma growth by 24±6 hours, defined as either ≥33% relative increase or ≥6 mL absolute increase in haematoma volume between baseline and follow-up CT scan.DiscussionWe describe the rationale and protocol of STOP-MSU, a phase II trial of tranexamic acid in patients with ICH within 2 hours from onset, based in participating mobile stroke units and emergency departments.

FLOT; To Be Treated as a Highly Emetogenic Regimen or a Moderately Emetogenic One? Comparison of the Emetogenic Potential of FLOT versus FOLFOX and TAC Regimens

PurposeThe current study aimed at investigating the efficacy of aprepitant-containing triple antiemetic regimen in FLOT (Fluorouracil+Leucovorin+Oxaliplatin+Docetaxel) recipients as well as the emetogenic potential of FLOT regimen, through comparison of nausea and vomiting rates in a moderately emetogenic chemotherapy, FLOT, and a highly emetogenic chemotherapy recipients.StudyPatients planned to receive one of FLOT, FOLFOX (Fluorouracil+Leucovorin+ Oxaliplatin/moderate-emetic-risk), or TAC (Docetaxel+Doxorubicin+Cyclophosphamide/high-emetic-risk) regimens were recruited. All patients were treated with the same triple antiemetic regimen containing aprepitant.ResultsA total of 165 chemotherapy-naïve patients (52 FLOT recipients) were eligible to enter the study. At the end of day five, “complete response” (primary efficacy endpoint) was achieved by 84.6%, 63.5%, and 61.5% of the FLOT-receiving patients in acute, delayed, and overall phases, respectively. A significant difference was seen among the odds of FLOT recipients and FOLFOX recipients concerning “complete response” achievement in delayed (p=0.014) and overall (p=0.017) phases, “no emesis” in delayed (p=0.018) and overall (p=0.010) phases, also “complete protection” in acute (p=0.023), delayed (p=0.009) and overall (p=0.006) phases; however, the difference between the odds of FLOT recipients and TAC recipients, in relation to achieving these endpoints was insignificant. FLOT group showed significantly faster time-to-antiemetic regimen failure and time-to-first emetic episode in comparison to the FOLFOX group, which was insignificant in comparison to the TAC group.ConclusionAccording to the findings, FLOT has to be considered as a high-emetic-risk regimen. To better management of highly emetogenic regimens, antiemetic guidelines recommend adding olanzapine to aprepitant-containing triple antiemetic regimen besides continuing dexamethasone and olanzapine administration on days 2-4.

Ticagrelor vs. Clopidogrel After Complex Percutaneous Coronary Intervention in Patients With Stable Coronary Artery Disease

Background: Patients undergoing complex percutaneous coronary intervention (PCI) have an increased risk of cardiovascular events. Whether potent antiplatelet therapy after complex PCI improves outcomes in patients with stable coronary artery disease (SCAD) remains unclear.Objectives: To assess the efficacy and safety of ticagrelor vs. clopidogrel in patients with SCAD undergoing complex PCI.Methods: Patients with a diagnosis of SCAD and undergoing PCI during January 2016 to December 2018 were selected from an institutional registry. The primary efficacy endpoint was major adverse cardiac events (MACE) within 12 months after PCI. The primary safety endpoint was major bleeding.Results: Among 15,459 patients with SCAD included in this analysis, complex PCI was performed in 6,335 (41.0%) patients. Of patients undergoing complex PCI, 1,123 patients (17.7%) were treated with ticagrelor. The primary efficacy outcome after complex PCI occurred in 8.6% of patients in the ticagrelor group and 11.2% in the clopidogrel group. Compared with clopidogrel, ticagrelor decreased the risk of MACE in patients undergoing complex PCI [adjusted hazard ratio (HR): 0.764; 95% confidence interval (CI): 0.615 to 0.949; p = 0.015], but not in non-complex PCI (p for interaction = 0.001). There was no significant difference in incidence of major bleeding between patients treated with ticagrelor and clopidogrel (p = 0.221), while ticagrelor was associated with an increased risk of minor bleeding (adjusted HR: 3.099; 95% CI: 2.049 to 4.687; p &lt; 0.001).Conclusion: In patients with SCAD and undergoing complex PCI, ticagrelor could substantially reduce the risk of adverse cardiovascular outcomes without increasing the risk of major bleeding compared with clopidogrel.

Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: comparison of 40 mg o.d. vs 40 mg b.i.d. The X-COVID19 Randomized Clinical Trial

It is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID-19 patients hospitalized in general wards. This is a multicentre, open-label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. vs 40 mg o.d. enoxaparin in COVID-19 patients, between April 30, 2020 and April 25, 2021. Primary efficacy outcome was in-hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6.5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (Sto arrivando! 6.5, 95% CI, 1.5-11.6). Absence of concomitant DVT and imaging characteristics suggest that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically non-significant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. In conclusion, no DVT developed in COVID-19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events.

Registration, publication, and outcome reporting among pivotal clinical trials that supported FDA approval of high-risk cardiovascular devices before and after FDAAA

Background Selective registration, publication, and outcome reporting of clinical trials distort the primary clinical evidence that is available to patients and clinicians regarding the safety and efficacy of US Food and Drug Administration (FDA)-approved medical devices. The purpose of this study is to compare registration, publication, and outcome reporting among pivotal clinical trials that supported FDA approval of high-risk (class III) cardiovascular devices before and after the FDA Amendment Act (FDAAA) was enacted in 2007. Methods Using publicly available data from ClinicalTrials.gov, FDA summaries, and PubMed, we determined registration, publication, and reporting of findings for all pivotal clinical studies supporting FDA approval of new high-risk cardiovascular devices between 2005 and 2020, before and after FDAAA. For published studies, we compared both the primary efficacy outcome with the FDA’s Premarket Approval (PMA) primary efficacy outcome and the published interpretation of findings with the FDA reviewer’s interpretation (positive, equivocal, or negative). Results Between 2005 and 2020, the FDA approved 156 high-risk cardiovascular devices on the basis of 165 pivotal trials, 48 (29%) of which were categorized as pre-FDAAA and 117 (71%) as post-FDAAA. Post-FDAAA, pivotal clinical trials were more likely to be registered (115 of 117 (98%) vs 24 of 48 (50%); p < 0.001), to report results (98 of 117 (87%) vs 7 of 48 (15%); p < 0.001) on ClinicalTrials.gov, and to be published (100 or 117 (85%) vs 28 of 48 (58%); p < 0.001) in peer-reviewed literature when compared to pre-FDAAA. Among published trials, rates of concordant primary efficacy outcome reporting were not significantly different between pre-FDAAA trials and post-FDAAA trials (24 of 28 (86%) vs 96 of 100 (96%); p = 0.07), nor were rates of concordant trial interpretation (27 of 28 (96%) vs 93 of 100 (93%); p = 0.44). Conclusions FDAAA was associated with increased registration, result reporting, and publication for trials supporting FDA approval of high-risk medical devices. Among published trials, rates of accurate primary efficacy outcome reporting and trial interpretation were high and no different post-FDAAA.