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Journal of Vascular Surgery Dec 2021Acute abdominal aortic occlusion (AAO) is a rare vascular emergency associated with high morbidity and mortality. In the present study, we analyzed the clinical...
BACKGROUND
Acute abdominal aortic occlusion (AAO) is a rare vascular emergency associated with high morbidity and mortality. In the present study, we analyzed the clinical management and outcomes for a consecutive patient series during a 16-year period.
METHODS
We included all patients with an acute AAO and bilateral acute limb ischemia who had been treated between 2004 and 2019. Patients with dissection, aneurysm rupture, or chronic occlusive disease were excluded. The patient characteristics, surgical procedures, and outcomes were extracted retrospectively from a prospective aortic database, electronic patient files, and outpatient examination records. The extent of ischemia was classified according to the TASC II (Inter-Society Consensus for the Management of Peripheral Arterial Disease) section on acute limb ischemia. The primary endpoints were 30-day mortality (safety endpoint) and the combined 6-month amputation and/or death rate (efficacy endpoint). The follow-up outcomes, amputation rates, and 30-day complications were evaluated as secondary endpoints. The patient cohort was divided into four 4-year groups (2004-2007, 2008-2011, 2012-2015, 2016-2019) to assess the outcome changes over time. Statistical analysis included χ tests and univariate and linear regression analyses.
RESULTS
A total of 74 patients (57% male; median age, 64.5 years) with an acute AAO were identified. Arterial thrombosis was the most common etiology (66%). The extent of ischemia was TASC I, IIa, IIb, and III in 7%, 39%, 40%, and 14%, respectively. The patient numbers had increased significantly over time (P = .016). Of the patients, 42% had undergone open transfemoral recanalization (including hybrid procedures), 35% open aortic surgery, 15% extra-anatomic bypass surgery, and 5% (four patients) endovascular therapy alone. The overall 30-day mortality rate was 23%, and the 6-month amputation and/or death rate was 43%. The 30-day mortality rate had declined significantly from 54% for 2004 to 2007 to 10% for 2011 to 2015 (odds ratio [OR], 0.10; 95% confidence interval [CI], 0.001-0.52) and 20% for 2016 to 2019 (OR, 0.21; 95% CI, 0.05-0.90), a statistically nonsignificant trend showing that the relative decline in the use of open aortic procedures was associated with decreased 30-day mortality (P = .06). Univariate analysis indicated that elevated serum lactate on admission (OR, 3.33; 95% CI, 1.06-10.48) and an advanced stage of limb ischemia (OR, 4.33), were strongly associated with an increased 30-day mortality rate. The incidence of severe postoperative systemic complications also indicated a greater incidence of both primary endpoints. The 6-month amputation and/or mortality rates were also affected by the presence of atrial fibrillation (OR, 3.63; 95% CI, 1.34-9.79) and increased patient age (OR, 3.96; 95% CI, 1.49-10.53).
CONCLUSIONS
Acute AAO remains a life-threatening emergency. Immediate transfemoral open or endovascular techniques should be preferred, if technically possible and proper intraoperative imaging is available.
Topics: Acute Disease; Aged; Amputation, Surgical; Aortic Diseases; Arterial Occlusive Diseases; Databases, Factual; Endovascular Procedures; Female; Humans; Ischemia; Limb Salvage; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Vascular Patency; Vascular Surgical Procedures
PubMed: 34182035
DOI: 10.1016/j.jvs.2021.06.021 -
BMC Neurology Oct 2023We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept.
BACKGROUND
We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept.
METHODS
Phase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks. The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables.
RESULTS
The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product.
CONCLUSIONS
Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.
Topics: Humans; Pilot Projects; Biotin; Pharmaceutical Preparations; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Charcot-Marie-Tooth Disease
PubMed: 37899433
DOI: 10.1186/s12883-023-03440-y -
The American Journal of Psychiatry May 2021Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression.
METHODS
Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively.
RESULTS
The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred.
CONCLUSIONS
The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.
Topics: Adult; Anhedonia; Carbamates; Depressive Disorder; Depressive Disorder, Major; Double-Blind Method; Female; Functional Neuroimaging; Humans; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Magnetic Resonance Imaging; Male; Membrane Transport Modulators; Middle Aged; Phenylenediamines; Reward; Ventral Striatum
PubMed: 33653118
DOI: 10.1176/appi.ajp.2020.20050653 -
BMC Cardiovascular Disorders Sep 2022Lactate dehydrogenase (LDH) has been reported in multiple heart diseases. Herein, we explored the prognostic effects of preoperative LDH on adverse outcomes in cardiac...
BACKGROUND
Lactate dehydrogenase (LDH) has been reported in multiple heart diseases. Herein, we explored the prognostic effects of preoperative LDH on adverse outcomes in cardiac surgery patients.
METHODS
Retrospective data analysis was conducted from two large medical databases: Medical Information Mart for Intensive Care (MIMIC) III and MIMIC IV databases. The primary outcome was in-hospital mortality, whereas the secondary outcomes were 1-year mortality, continuous renal replacement therapy, prolonged ventilation, and prolonged length of intensive care unit and hospital stay.
RESULTS
Patients with a primary endpoint had significantly higher levels of LDH (p < 0.001). Multivariate regression analysis presented that elevated LDH was independently correlated with increased risk of primary and secondary endpoints (all p < 0.001). Subgroup analyses showed that high LDH was consistently associated with primary endpoint. Moreover, LDH exhibited the highest area under the curve (0.768) for the prediction of primary endpoint compared to the other indicators, including neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), lactate, and simplified acute physiology score (SAPS) II. The above results were further confirmed in the MIMIC IV dataset.
CONCLUSIONS
Elevated preoperative LDH may be a robust predictor of poor prognosis in cardiac surgery patients, and its predictive ability is superior to NLR, LMR, PLR, lactate, and SAPS II.
Topics: Cardiac Surgical Procedures; Humans; L-Lactate Dehydrogenase; Lactates; Prognosis; Retrospective Studies
PubMed: 36088306
DOI: 10.1186/s12872-022-02848-7 -
Journal of the American College of... Oct 2021REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE.
OBJECTIVES
The purpose of this study was to determine the effects of IPE on investigator-reported events.
METHODS
Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance.
RESULTS
There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints.
CONCLUSIONS
IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).
Topics: Aged; Angina, Unstable; Eicosapentaenoic Acid; Endpoint Determination; Female; Humans; Hypertriglyceridemia; Lipid Regulating Agents; Male; Myocardial Infarction; Myocardial Revascularization; Stroke
PubMed: 34620410
DOI: 10.1016/j.jacc.2021.08.009 -
JACC. Heart Failure Jan 2023Despite hypertrophic cardiomyopathy (HCM) being the most common inherited heart disease and conferring increased risk for heart failure (HF) and sudden cardiac death... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite hypertrophic cardiomyopathy (HCM) being the most common inherited heart disease and conferring increased risk for heart failure (HF) and sudden cardiac death (SCD), risk assessment in HCM patients is still largely unresolved.
OBJECTIVES
This study aims to synthesize and compare the prognostic impact of demographic, clinical, biochemical, and imaging findings in patients with HCM.
METHODS
The authors searched PubMed, Embase, and Cochrane Library for studies published from 1955 to November 2020, and the endpoints were: 1) all-cause death; 2) an arrhythmic endpoint including SCD, sustained ventricular tachycardia, ventricular fibrillation, or aborted SCD; and 3) a composite endpoint including (1) or (2) plus hospitalization for HF or cardiac transplantation. The authors performed a pairwise meta-analysis obtaining the pooled estimate separately for the association between baseline variables and study endpoints. A random-effects network meta-analysis was subsequently used to comparatively assess the prognostic value of outcome associates.
RESULTS
A total of 112 studies with 58,732 HCM patients were included. Among others, increased brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, late gadolinium enhancement (LGE), positive genotype, impaired global longitudinal strain, and presence of apical aneurysm conferred increased risk for the composite endpoint. At network meta-analysis, LGE showed the highest prognostic value for all endpoints and was superior to all other associates except New York Heart Association functional class >class II. A multiparametric imaging-based model was superior in predicting the composite endpoint compared to a prespecified model based on conventional risk factors.
CONCLUSIONS
This network meta-analysis supports the development of multiparametric risk prediction algorithms, including advanced imaging markers additively to conventional risk factors, for refined risk stratification in HCM. (Long-term prognosis of hypertrophic cardiomyopathy according to genetic, clinical, biochemical and imaging findings: a systemic review and meta-analysis; CRD42020185219).
Topics: Humans; Cardiomyopathy, Hypertrophic; Contrast Media; Death, Sudden, Cardiac; Demography; Gadolinium; Heart Failure; Network Meta-Analysis; Prognosis; Risk Assessment; Risk Factors
PubMed: 36599547
DOI: 10.1016/j.jchf.2022.08.022 -
ESMO Open Apr 2024Immune checkpoint inhibitors (CPIs) have not been shown to be active in well-differentiated neuroendocrine tumors (NETs), with response rates <5%. Lenvatinib is a...
BACKGROUND
Immune checkpoint inhibitors (CPIs) have not been shown to be active in well-differentiated neuroendocrine tumors (NETs), with response rates <5%. Lenvatinib is a multitargeted tyrosine kinase inhibitor which binds to vascular endothelial growth factor and fibroblast growth factor receptors and has demonstrated efficacy in pancreatic and gastrointestinal NETs [44% and 16% objective radiographic response rate (ORR), respectively]. The combination of antiangiogenic and CPI therapies can be synergistic. We therefore evaluated the combination of lenvatinib and pembrolizumab in well-differentiated gastrointestinal (GI) and thoracic NETs.
PATIENTS AND METHODS
A prospective, phase II trial evaluated patients with advanced GI/thoracic NETs (pancreatic NETs were excluded due to high response rate of lenvatinib monotherapy in this patient population), with evidence of progression within 8 months of study entry and at least two prior lines of systemic therapy. Patients received lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or progression of disease. Primary endpoint was objective response rate, and an interim analysis was planned once 20 patients were enrolled. Four ORRs were required to continue enrollment.
RESULTS
Twenty patients were enrolled on protocol from April 2021 to January 2022 (nine small intestine, five lung, two thymic, two unknown primary, one cecal, one presacral primaries). Two patients (10%) achieved a partial response (atypical lung and small intestinal primaries). Median progression-free survival (PFS) was 8 months (95% confidence interval 5.8-10.2 months). Twelve (60%) patients experienced probably or definitely associated grade 3 adverse events (10 hypertension). Fourteen patients (70%) required dose reductions or discontinued one of the medications. Two patients discontinued treatment before radiographic assessment.
CONCLUSIONS
The combination of pembrolizumab and lenvatinib did not show sufficient response in patients with NETs to warrant continued enrollment on trial.
Topics: Humans; Quinolines; Male; Phenylurea Compounds; Female; Antibodies, Monoclonal, Humanized; Neuroendocrine Tumors; Middle Aged; Aged; Prospective Studies; Adult; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38507897
DOI: 10.1016/j.esmoop.2024.102386 -
Journal of Pain Research 2022Enriched enrollment randomized withdrawal (EERW) pain trials are designed to include only responders with considerable pain relief without unacceptable side effects into... (Review)
Review
Enriched enrollment randomized withdrawal (EERW) pain trials are designed to include only responders with considerable pain relief without unacceptable side effects into the randomized phase. There are no recommendations for primary endpoints in such trials. Our objective was to propose recommendations based on assessment of trial characteristics, endpoints and effect sizes in EERW pain trials. We conducted a systematic review by searching electronic databases up to June 2020 for EERW trials comparing an analgesic with a placebo in adults suffering from chronic pain. A total of 28 trials met our criteria, involving 13662 patients in the open or single-blind phase and 7937 patients in the double-blind phase. As primary endpoint 18 trials used pain intensity measured with the visual analogue scale (VAS) or the 11-point numerical rating scale (NRS); 1 trial used a 4-point NRS. Loss of therapeutic response (LTR) was used in 1 trial and time to LTR was used in 8 trials as primary endpoint. Definitions of time to LTR differed considerably between trials. Only 2 out of 8 trials using time to LTR as primary endpoint reported the percentage of patients experiencing a minimum pain relief of 50%, compared to 14 out of 18 trials using NRS or VAS. Due to the complexity and diversity of time to LTR in EERW pain trials, we propose to use the NRS as primary endpoint with conservative imputation methods, and to use time to LTR as secondary endpoint.
PubMed: 35210848
DOI: 10.2147/JPR.S334840 -
Therapeutic Advances in Cardiovascular... 2020The objective of this review is to provide a practical update on endpoint selection for noninferiority (NI) studies in percutaneous coronary intervention studies. (Review)
Review
BACKGROUND
The objective of this review is to provide a practical update on endpoint selection for noninferiority (NI) studies in percutaneous coronary intervention studies.
METHODS
A PubMed search was conducted for predefined terms to explore the use of NI designs and intrapatient comparisons to determine their current importance. Sample size calculations for the most frequently used endpoints with NI hypotheses were done to increase statistical awareness.
RESULTS
Reported NI trials, with the most frequently chosen clinical endpoint of major adverse cardiac events (MACE), had NI margins ranging from 1.66% to 5.00%, resulting in patient populations of 400-1500 per treatment group. Clinical study endpoints comprising of MACE complemented with rates of bleeding complications and stent thrombosis (ST) are suggested to conduct a statistically and clinically meaningful NI trial. Study designs with surrogate endpoints amenable to intrapatient randomizations, are a very attractive option to reduce the number of necessary patients by about half. Comparative clinical endpoint studies with MACE and ST/bleeding rates to study a shortened dual antiplatelet therapy (DAPT) in coronary stent trials are feasible, whereas ST as the sole primary endpoint is not useful.
CONCLUSIONS
Expanded composite clinical endpoints (MACE complemented by ST and bleeding rates and intrapatient randomization for selected surrogate endpoints) may be suitable tools to meet future needs in device approval, recertification and reimbursement.
Topics: Coronary Angiography; Coronary Artery Disease; Coronary Thrombosis; Drug Therapy, Combination; Endpoint Determination; Equivalence Trials as Topic; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Research Design; Risk Factors; Sample Size; Stents; Time Factors; Treatment Outcome
PubMed: 32168991
DOI: 10.1177/1753944720911329 -
Scientific Reports May 2023The purpose of this retrospective, longitudinal study is to evaluate the relationship between MD slope from visual field tests collected over a short period of time...
The purpose of this retrospective, longitudinal study is to evaluate the relationship between MD slope from visual field tests collected over a short period of time (2 years) and the current United States' Food and Drug Administration (FDA) recommended endpoints for visual field outcomes. If this correlation is strong and highly predictive, clinical trials employing MD slopes as primary endpoints could be employed in neuroprotection clinical trials with shorter duration and help expedite the development of novel IOP-independent therapies. Visual field tests of patients with or suspected glaucoma were selected from an academic institution and evaluated based on two functional progression endpoints: (A) five or more locations worsening by at least 7 dB, and (B) at least five test locations based upon the GCP algorithm. A total of 271 (57.6%) and 278 (59.1%) eyes reached Endpoints A and B, respectively during the follow up period. The median (IQR) MD slope of eyes reaching vs. not reaching Endpoint A and B were -1.19 (-2.00 to -0.41) vs. 0.36 (0.00 to 1.00) dB/year and -1.16 (-1.98 to -0.40) vs. 0.41 (0.02 to 1.03) dB/year, respectively (P < 0.001). It was found that eyes experiencing rapid 24-2 visual field MD slopes over a 2-year period were on average tenfold more likely to reach one of the FDA accepted endpoints during or soon after that period.
Topics: Humans; Retrospective Studies; Longitudinal Studies; Neuroprotection; Intraocular Pressure; Vision Disorders; Glaucoma; Visual Field Tests; Disease Progression; Follow-Up Studies
PubMed: 37130950
DOI: 10.1038/s41598-023-34009-x