Randomized Clinical Trials In Patients Research Articles

Effects of valsartan vs amlodipine and achieved lower blood pressure on the incidence of end-stage kidney disease: The VALUE Trial.

There is a paucity of data investigating the impact of antihypertensive drug classes and blood pressure (BP) treatment targets on the incidence of end-stage kidney disease (ESKD). In patients with high-risk hypertension aged 50-80 years or above, we aimed to, 1) compare effects of valsartan, an angiotensin receptor blocker, with amlodipine, a calcium channel blocker and, 2) assess the effect of achieving systolic BP <135 vs ≥135 mmHg on the ESKD incidence. The VALUE Trial was a multicenter prospective double-blinded randomized clinical trial in patients with essential hypertension and high cardiovascular risk including known coronary disease, left ventricular hypertrophy and previous stroke, in which ESKD was a secondary endpoint defined as progression to kidney transplant and/or dialysis. Patients were randomized to either valsartan or amlodipine, with other anti-hypertensive medications as add-on if needed to reach the systolic BP target of <140 mmHg. Cox proportional hazards ratio (HR) was used to compare different treatment groups and achieved systolic BP <135 with ≥135 mmHg, during 3-6 years of follow-up. 15,245 patients were randomized and followed until 63,631 patient-years with only 90 patients lost to follow-up. The primary outcome, a composite of cardiac morbidity and mortality, was neutral between valsartan and amlodipine. On valsartan 47 patients (0.61 %) and on amlodipine 50 patients (0.66 %) developed ESKD (HR=1.02, 95 % CI 0.68-1.52, p =0.94). Achieved SBP <135 mmHg was strongly related to less ESKD (n =9/5036 patients, 0.2 %) compared with achieved SBP ≥135 mmHg (n =73/8766 patients, 0.8 %) (HR=0.28, CI 0.14-0.58, p <0.001). In hypertensive patients with a high cardiovascular risk, valsartan and amlodipine have a similar impact on the incidence of end-stage kidney disease. Achieving SBP <135 mmHg, averaging 128.8/77.3 mm, is highly efficacious in kidney protection.

The effect of sodium-glucose cotransporter type 2 inhibitors on left ventricular diastolic function: current status and prospects

Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) or gliflozins, are a new class of cardiovascular drugs with a proven clinical efficacy and a beneficial effect on prognosis in patients with heart failure with preserved ejection fraction (HFpEF). Impaired left ventricular (LV) diastolic function (DF) is an important element in the pathogenesis of HFpEF. Experimental studies have found intracellular mechanisms for the so-called diastolic effects in gliflozins. Studies using laboratory models of experimental HFpEF have demonstrated a positive effect of dapagliflozin and empagliflozin on the elastic properties of cardiomyocyte myofilaments, the dynamics of myocardial fibrosis, and intracellular sodium and calcium homeostasis. The significance of anti-inflammatory, antioxidant properties of gliflozins in improving the cardiomyocyte DF has been experimentally established. The effect of SGLT2 inhibitors on LV DF in patients at high risk for cardiovascular diseases and their complications, that has been demonstrated in relatively small clinical studies, is due to primary cardiac and secondary effects. Results of individual studies confirmed the protective (in relation to myocardial relaxation) properties of gliflozins in the conditions of a diastolic stress test. The regression of LV diastolic dysfunction associated with the SGLT2 inhibitor treatment found in small observational studies is important in the context of the significant beneficial effect of empagliflozin and dapagliflozin on the prognosis of cardiovascular diseases that has been demonstrated in large randomized clinical trials in patients with HFpEF.

Aspirin for Metabolic Dysfunction–Associated Steatotic Liver Disease Without Cirrhosis

ImportanceAspirin may reduce severity of metabolic dysfunction–associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown.ObjectiveTo test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD.Design, Setting, and ParticipantsThis 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023.InterventionsParticipants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months.Main Outcomes and MeasuresThe primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified.ResultsAmong 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was −6.6% with aspirin vs 3.6% with placebo (difference, −10.2% [95% CI, −27.7% to −2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (−8.8 vs 30.0 percentage points; mean difference, −38.8 percentage points [95% CI, −66.7 to −10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (−2.7% vs 0.9%; mean difference, −3.7% [95% CI, −6.1% to −1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (−11.7 vs 15.7 percentage points; mean difference, −27.3 percentage points [95% CI, −45.2 to −9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn.Conclusions and RelevanceIn this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT04031729

Investigating the Effectiveness of Melatonin in the Treatment of Critically Ill Patients with COVID-19 Hospitalized in the Intensive Care Unit: A Double-Blind Randomized Clinical Trial.

Melatonin, a tryptophan product, has anti-inflammatory and virucidal effects. A study evaluated whether melatonin is more effective than placebo in critically ill COVID-19 patients. The present study used a double-blind, randomized clinical trial in patients with COVID-19 hospitalized in the intensive care unit of Rasool Akram Hospital, Tehran. Iran. Melatonin 10 mg and placebo were given to the patients at night before bed. Patients were randomly divided into 2 groups. The first group was given melatonin with a therapeutic dose of 10 mg daily, and the second group was given a placebo with the same dose of 10 mg daily. Patients received melatonin or placebo for 7 days.The chi-square or Fisher exact test was used to compare qualitative variables. The study analyzed the mean of the variables under investigation by conducting a 2-factor repeated measures analysis of variance at 3 different time intervals in those administered medication or placebo. The study analyzed 44 melatonin patients and 42 placebo groups. The mean intensive care unit (ICU) hospitalization days were 11.23 ± 4.73 days in the melatonin group and 11.90 ± 6.52 days in the placebo group (P = 0.582). The mean days of hospitalization in the melatonin group were 19.70 ± 8.77 days and 21.48 ± 10.85 days in the placebo group (P = 0.407). The mean oxygen saturation before and after discharge from ICU in the melatonin group was 81 ± 6.73%, 91.02 ± 1.17%, and in the placebo group, 83.36 ± 8.27%, 91.21 ± 1.26, respectively (P = 0.467 and P = 0.150). Melatonin can significantly reduce inflammation and oxidative stress markers in patients, making it a promising therapeutic option for COVID-19 patients. Further research is needed to determine the optimal treatment dosage and duration. Nonetheless, these results offer a promising avenue for future research and clinical practice.

Conditional Risks of Biochemical Failure and Prostate Cancer–Specific Death in Patients Undergoing External Beam Radiotherapy

As patients achieve years of survival after treatment for prostate cancer, the risk of biochemical failure (BF) or prostate cancer-specific death (PCSD) may evolve over time, with clinical relevance to both patients and clinicians. To determine conditional BF-free survival, PSCD, and overall survival estimates for patients with low- or intermediate-risk prostate cancer enrolled in the Radiation Therapy Oncology Group (RTOG) 0126 and RTOG 0415 clinical trials. A secondary objective was to determine whether prognostic factors at diagnosis remain relevant at later points in follow-up. A pooled secondary analysis of patients treated with external-beam radiotherapy alone and enrolled in the prospective randomized clinical trials RTOG 0126 and RTOG 0415 was performed. Patients included for analysis were enrolled between March 2002 and December 2009 with a median follow-up of 6.9 years. Overall survival was calculated using the Kaplan-Meier method at various survivorship time points. Cumulative incidence was used to calculate BF rates using the Phoenix definition, as well as PCSD. Risk factors such as Gleason score, tumor (T) stage, prostate-specific antigen level, and the equivalent dose in 2 Gy fractions of prescribed dose were analyzed at different time points using multivariable Cox proportional hazards modeling. Data were analyzed from November 2021 to February 2023. Conditional risks of BF and PCSD after completion of external-beam radiotherapy. A total of 2591 patients (median [IQR] age, 69 [63-73] years) were included in the study with a mean (range) PSA level of 7.1 (4.7-8.9) ng/mL, 1334 patients (51.5%) with a Gleason score 6 disease, and 1706 patients (65.8%) with T1 disease. Rates of BF from time of treatment were 1.63% (95% CI, 1.20%-2.18%) at 1 year, 7.04% (95% CI, 6.09%-8.08%) at 3 years, 12.54% (95% CI, 11.28%-13.88%) at 5 years, and 22.32% (95% CI, 20.46%-24.24%) at 8 years. For patients surviving 1, 3, and 5 years without BF, the rates of BF in the next 5 years were 14.20% (95% CI, 12.80%-15.66%), 17.19% (95% CI, 15.34%-19.14%), and 18.85% (95% CI, 16.21%-21.64%), respectively. At the initial time point, the rate of PCSD in the next 5 years was 0.66% (95% CI, 0.39%-1.04%). For patients who achieved 1, 3, 5, and 8 years of survivorship, the rates of PCSD in the next 5 years were 1.16% (95% CI, 0.77-1.67) at 1 year, 2.42% (95% CI, 1.74%-3.27%) at 3 years, 2.88% (95% CI, 2.01%-3.99%) at 5 years, and 3.49% (95% CI, 0.98%-8.73%) at 8 years. In this secondary analysis of 2 randomized clinical trials of patients undergoing external beam radiotherapy for prostate cancer, the conditional risks of BF and death from prostate cancer increased with time for patients with low- and intermediate-risk prostate cancer treated with radiotherapy alone. These results could inform optimal trial design and may be helpful information for patients evaluated in follow-up. ClinicalTrials.gov Identifier: NCT00033631; NCT00331773.

Pathological macroscopic evaluation of breast density versus mammographic breast density in breast cancer conserving surgery

Correlation between imaging and anatomopathological breast density has been superficially explored and is heterogeneous in current medical literature. It is possible that mammographic and pathological findings are divergent. The aim of this study is to evaluate the association between breast density classified by mammography and breast density of pathological macroscopic examination in specimens of breast cancer conservative surgeries. Post-hoc, exploratory analysis of a prospective randomized clinical trial of patients with breast cancer candidates for breast conservative surgery. Breast mammographic density (MD) was analyzed according to ACR BI-RADS® criteria, and pathologic macroscopic evaluation of breast density (PMBD) was estimated by visually calculating the ratio between stromal and fatty tissue. From 412 patients, MD was A in 291 (70,6%), B in 80 (19,4%) B, C in 35 (8,5%), and D in 6 (1,5%). Ninety-nine percent (201/203) of patients classified as A+B in MD were correspondently classified in PMBD. Conversely, only 18.7% (39/209) of patients with MD C+D were classified correspondently in PMBD (p < 0.001). Binary logistic regression showed age (OR 1.06, 1.01–1.12 95% CI, p 0.013) and nulliparity (OR 0.39, 0.17–0.96 95% CI, p 0.039) as predictors of A+B PMBD. ConclusionMammographic and pathologic macroscopic breast density showed no association in our study for breast C or D in breast image. The fatty breast was associated with older patients and the nulliparity decreases the chance of fatty breasts nearby 60%.

Phase 1 study of oral selective estrogen receptor degrader (SERD) amcenestrant (SAR439859), in Japanese women with ER-positive and HER2-negative advanced breast cancer (AMEERA-2)

BackgroundThis AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.MethodsIn this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed.ResultsNo DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported.ConclusionsAmcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer.Trial registrationClinical trial registration NCT03816839.

Efficacy and safety of intracoronary epinephrine for the management of the no-reflow phenomenon following percutaneous coronary interventions: a systematic-review study.

Currently, no pharmacological or device-based intervention has been fully proven to reverse the no-reflow phenomenon. To assess the efficacy and safety of intracoronary (IC) epinephrine in the management of no-reflow phenomenon following percutaneous coronary intervention (PCI), either as first-line treatment or after the failure of conventional agents. Systematic review. PubMed and Scopus databases were systematically searched up to 28 May 2022, with additional manual search on the Google Scholar and review of the reference lists of the relevant studies to identify all published studies. Cohort studies, case series, and interventional studies written in English which evaluated the efficacy and safety of IC epinephrine in patients with no-flow phenomenon were included in our review. Six of the 646 articles identified in the initial search met our inclusion criteria. IC epinephrine was used either as a first-line treatment [two randomized clinical trials (RCTs)] or after the failure of conventional agents (two cohort studies and two case series) for restoring the coronary flow, mainly after primary PCI. As first-line therapy, IC epinephrine successfully restored coronary flow in over 90% of patients in both RCTs, which significantly outperformed IC adenosine (78%) but lagged behind combination of verapamil and tirofiban (100%) in this regard. In the refractory no-flow phenomenon, successful reperfusion [thrombolysis in myocardial infarction (TIMI) flow grade = 3] was achieved in three out of four patients after the administration of IC epinephrine based on the results from both case series. Their findings were confirmed by a recent cohort study that further compared IC epinephrine with IC adenosine and found significant differences between them in terms of efficacy [% TIMI flow grade 3: (69.1% versus 52.7%, respectively; p value = 0.04)] and 1-year major adverse cardiac event (MACE) outcomes (11.3% versus 26.7%, respectively; p value ⩽ 0.01). Overall, malignant ventricular arrhythmias were reported in none of the patients treated with IC epinephrine. Results from available evidence suggest that IC epinephrine might be an effective and safe agent in managing the no-reflow phenomenon.

Cost-effectiveness of Laparoscopic vs Open Gastrectomy for Gastric Cancer

Laparoscopic gastrectomy is rapidly being adopted worldwide as an alternative to open gastrectomy to treat gastric cancer. However, laparoscopic gastrectomy might be more expensive as a result of longer operating times and more expensive surgical materials. To date, the cost-effectiveness of both procedures has not been prospectively evaluated in a randomized clinical trial. To evaluate the cost-effectiveness of laparoscopic compared with open gastrectomy. In this multicenter randomized clinical trial of patients undergoing total or distal gastrectomy in 10 Dutch tertiary referral centers, cost-effectiveness data were collected alongside a multicenter randomized clinical trial on laparoscopic vs open gastrectomy for resectable gastric adenocarcinoma (cT1-4aN0-3bM0). A modified societal perspective and 1-year time horizon were used. Costs were calculated on the individual patient level by using hospital registry data and medical consumption and productivity loss questionnaires. The unit costs of laparoscopic and open gastrectomy were calculated bottom-up. Quality-adjusted life-years (QALYs) were calculated with the EuroQol 5-dimension questionnaire, in which a value of 0 indicates death and 1 indicates perfect health. Missing questionnaire data were imputed with multiple imputation. Bootstrapping was performed to estimate the uncertainty surrounding the cost-effectiveness. The study was conducted from March 17, 2015, to August 20, 2018. Data analyses were performed between September 1, 2020, and November 17, 2021. Laparoscopic vs open gastrectomy. Evaluations in this cost-effectiveness analysis included total costs and QALYs. Between 2015 and 2018, 227 patients were included. Mean (SD) age was 67.5 (11.7) years, and 140 were male (61.7%). Unit costs for initial surgery were calculated to be €8124 (US $8087) for laparoscopic total gastrectomy, €7353 (US $7320) for laparoscopic distal gastrectomy, €6584 (US $6554) for open total gastrectomy, and €5893 (US $5866) for open distal gastrectomy. Mean total costs after 1-year follow-up were €26 084 (US $25 965) in the laparoscopic group and €25 332 (US $25 216) in the open group (difference, €752 [US $749; 3.0%]). Mean (SD) QALY contributions during 1 year were 0.665 (0.298) in the laparoscopic group and 0.686 (0.288) in the open group (difference, -0.021). Bootstrapping showed that these differences between treatment groups were relatively small compared with the uncertainty of the analysis. Although the laparoscopic gastrectomy itself was more expensive, after 1-year follow-up, results suggest that differences in both total costs and effectiveness were limited between laparoscopic and open gastrectomy. These results support centers' choosing, based on their own preference, whether to (de)implement laparoscopic gastrectomy as an alternative to open gastrectomy.

Structural Valve Deterioration After Self-Expanding Transcatheter or Surgical Aortic Valve Implantation in Patients at Intermediate or High Risk

The frequency and clinical importance of structural valve deterioration (SVD) in patients undergoing self-expanding transcatheter aortic valve implantation (TAVI) or surgery is poorly understood. To evaluate the 5-year incidence, clinical outcomes, and predictors of hemodynamic SVD in patients undergoing self-expanding TAVI or surgery. This post hoc analysis pooled data from the CoreValve US High Risk Pivotal (n = 615) and SURTAVI (n = 1484) randomized clinical trials (RCTs); it was supplemented by the CoreValve Extreme Risk Pivotal trial (n = 485) and CoreValve Continued Access Study (n = 2178). Patients with severe aortic valve stenosis deemed to be at intermediate or increased risk of 30-day surgical mortality were included. Data were collected from December 2010 to June 2016, and data were analyzed from December 2021 to October 2022. Patients were randomized to self-expanding TAVI or surgery in the RCTs or underwent self-expanding TAVI for clinical indications in the nonrandomized studies. The primary end point was the incidence of SVD through 5 years (from the RCTs). Factors associated with SVD and its association with clinical outcomes were evaluated for the pooled RCT and non-RCT population. SVD was defined as (1) an increase in mean gradient of 10 mm Hg or greater from discharge or at 30 days to last echocardiography with a final mean gradient of 20 mm Hg or greater or (2) new-onset moderate or severe intraprosthetic aortic regurgitation or an increase of 1 grade or more. Of 4762 included patients, 2605 (54.7%) were male, and the mean (SD) age was 82.1 (7.4) years. A total of 2099 RCT patients, including 1128 who received TAVI and 971 who received surgery, and 2663 non-RCT patients who received TAVI were included. The cumulative incidence of SVD treating death as a competing risk was lower in patients undergoing TAVI than surgery (TAVI, 2.20%; surgery, 4.38%; hazard ratio [HR], 0.46; 95% CI, 0.27-0.78; P = .004). This lower risk was most pronounced in patients with smaller annuli (23 mm diameter or smaller; TAVI, 1.32%; surgery, 5.84%; HR, 0.21; 95% CI, 0.06-0.73; P = .02). SVD was associated with increased 5-year all-cause mortality (HR, 2.03; 95% CI, 1.46-2.82; P < .001), cardiovascular mortality (HR, 1.86; 95% CI, 1.20-2.90; P = .006), and valve disease or worsening heart failure hospitalizations (HR, 2.17; 95% CI, 1.23-3.84; P = .008). Predictors of SVD were developed from multivariate analysis. This study found a lower rate of SVD in patients undergoing self-expanding TAVI vs surgery at 5 years. Doppler echocardiography was a valuable tool to detect SVD, which was associated with worse clinical outcomes. ClinicalTrials.gov Identifiers: NCT01240902, NCT01586910, and NCT01531374.

Catheter-Directed Thrombolysis vs Anticoagulation in Patients With Acute Intermediate-High–risk Pulmonary Embolism

The optimal treatment of intermediate-high-risk pulmonary embolism (PE) remains unknown. To assess the effect of conventional catheter-directed thrombolysis (cCDT) plus anticoagulation vs anticoagulation monotherapy in improving echocardiographic measures of right ventricle (RV) to left ventricle (LV) ratio in acute intermediate-high-risk PE. The Catheter-Directed Thrombolysis vs Anticoagulation in Patients with Acute Intermediate-High-Risk Pulmonary Embolism (CANARY) trial was an open-label, randomized clinical trial of patients with intermediate-high-risk PE, conducted in 2 large cardiovascular centers in Tehran, Iran, between December 22, 2018, through February 2, 2020. Patients were randomly assigned to cCDT (alteplase, 0.5 mg/catheter/h for 24 hours) plus heparin vs anticoagulation monotherapy. The proportion of patients with a 3-month echocardiographic RV/LV ratio greater than 0.9, assessed by a core laboratory, was the primary outcome. The proportion of patients with an RV/LV ratio greater than 0.9 at 72 hours after randomization and the 3-month all-cause mortality were among secondary outcomes. Major bleeding (Bleeding Academic Research Consortium type 3 or 5) was the main safety outcome. A clinical events committee, masked to the treatment assignment, adjudicated clinical outcomes. The study was prematurely stopped due to the COVID-19 pandemic after recruiting 94 patients (mean [SD] age, 58.4 [2.5] years; 27 women [29%]), of whom 85 patients completed the 3-month echocardiographic follow-up. Overall, 2 of 46 patients (4.3%) in the cCDT group and 5 of 39 patients (12.8%) in the anticoagulation monotherapy group met the primary outcome (odds ratio [OR], 0.31; 95% CI, 0.06-1.69; P = .24). The median (IQR) 3-month RV/LV ratio was significantly lower with cCDT (0.7 [0.6-0.7]) than with anticoagulation (0.8 [0.7-0.9); P = .01). An RV/LV ratio greater than 0.9 at 72 hours after randomization was observed in fewer patients treated with cCDT (13 of 48 [27.0%]) than anticoagulation (24 of 46 [52.1%]; OR, 0.34; 95% CI, 0.14-0.80; P = .01). Fewer patients assigned to cCDT experienced a 3-month composite of death or RV/LV greater than 0.9 (2 of 48 [4.3%] vs 8 of 46 [17.3%]; OR, 0.20; 95% CI, 0.04-1.03; P = .048). One case of nonfatal major gastrointestinal bleeding occurred in the cCDT group. This prematurely terminated randomized clinical trial of patients with intermediate-high-risk PE was hypothesis-generating for improvement in some efficacy outcomes and acceptable rate of major bleeding for cCDT compared with anticoagulation monotherapy and provided support for a definitive clinical outcomes trial. ClinicalTrials.gov Identifier: NCT05172115.

Brief, intensive group-based cognitive therapy integrated in cardiac rehabilitation reduces psychological distress in cardiac patients with anxiety and depression a randomized controlled

Abstract Background/Introduction Patients with coronary artery disease (CAD) and valvular heart disease (VHD) often suffer from psychological distress, which in turn leads to impaired quality of life, delayed return to work, and increased morbidity and mortality. European guidelines emphasize recognition and intervention, but evidence-based treatment options are limited and perceived as costly. Manageable interventions addressing psychological distress in cardiac patients are needed. Purpose To develop an efficient and cost-effective model for cardiac patients to reduce psychological distress. Methods A multi-center randomized clinical trial in patients with newly diagnosed CAD and/or surgically treated VHD, part of the workforce and concomitant psychological distress (defined as Hospital Anxiety and Depression scale (HADS) Anxiety ≥8 or Depression ≥8). The patients were randomized to five sessions of group-based cognitive-behavioral therapy plus cardiac rehabilitation (Intervention, I) or cardiac rehabilitation alone (Control, C). Furthermore, 41 cardiac patients (male gender 85.4%, age 57±6.4 years) without psychological distress (background, B) participated as reference group to follow the natural course. The primary outcome was a total HADS score at three months. Secondary outcomes were return to work, adherence to CR (participation in &amp;gt;80% of planned training sessions), adherence to lifestyle interventions for CVD risk factor goals, HeartQoL (is a disease-specific questionnaire that measures cardiac quality of life), and cardiovascular readmissions after 12 months. Results 148 patients were included, 67% men, mean age 54±7.5 years and median HADS score at baseline 15 (IQR 10–19) (Table 1). At 3 months HADS score improved significantly more in the intervention group (p&amp;lt;0.001) and this difference persisted at 6 months (p&amp;lt;0.001, Figure). Similar results were seen for HADS anxiety and HADS depression (Figure 1). HeartQol also improved more in the intervention group. 78% had returned to work at 6 months in the intervention group versus 67% in the control (p=0.11). There were no differences in other secondary outcomes Conclusion Brief cognitive-behavioral therapy provided by cardiac nurses to patients with CAD/VHD and a high HADS score significantly reduced psychological distress and quality of life. The program is simple and can be integrated with existing CR programs at low costs. Larger trials are needed to confirm the effect of the program on retaining cardiac patients in the workforce. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The trial is fonded by TrygFonden

Effect of Dimethyl Fumarate vs Interferon β-1a in Patients With Pediatric-Onset Multiple Sclerosis

With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS). To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS. The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021. Patients were randomized to DMF or IFNβ-1a. The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group. Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a. This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated. ClinicalTrials.gov Identifier: NCT02283853.

Death without Previous Hospital Readmission in Patients with Heart Failure with Reduced Ejection Fraction-A New Endpoint from Old Clinical Trials.

Background: Most of the drugs approved and registered for use in heart failure (HF) therapy were examined in randomized clinical trials (RCTs) with the primary composite endpoint of death or hospital readmission. This study aimed to analyze the rates of the newly calculated event: death without prior hospital readmission, in HFrEF patients in large RCTs to show that the newly defined endpoint probably delivers additional data on the structure of the composite endpoint and helps to interpret the results of interventional studies. Methods: This study included RCTs on therapeutic interventions in HF patients. A literature search was performed, and 31 trials in which death without hospital admission could be calculated were included in the analyses. The death without a prior hospital admission endpoint was calculated as the difference between the composite endpoint rate (death or hospital readmission) and the readmission rate. The differences in the new endpoint between the study groups were calculated. Result: The death rates without prior hospital admission were lower in the intervention groups in five trials. In the SENIORS study, significant differences were found in the primary (composite) and death without previous hospital admission endpoints. In the ACCLAIM, VEST, and GISSI-HF STATIN trials, death without previous hospital admission was the only endpoint with a significant difference between the study groups. Moreover, the new endpoint rates were higher in the intervention group in the latter two studies. Conclusions: The new endpoint describing patients who died without prior hospital admission might be useful in previous and future interventional studies to provide additional data on the structure of the composite endpoint. Some therapies might reduce death without previous hospital admission rates, which could be beneficial, even without a reduction in overall long-term mortality.

Effects of Dexamethasone and Pentoxifylline on Mania-like and Depression-like Behaviors in Rats.

Several studies support the notion that inflammation plays a role in the pathophysiology and treatment approaches of psychiatric illnesses, particularly mood disorders. Congruently, classic anti-inflammatory drugs were found efficacious in randomized clinical trials of patients with mood disorders. Moreover, accumulating data indicate that psychotropic drugs exhibit some anti-inflammatory effects. This study was undertaken to examine the efficacy of dexamethasone (a potent corticosteroid) and pentoxifylline (a methylxanthine drug with proven anti-tumor necrosis factor-α inhibitory activity) in behavioral models in rats, which were treated intraperitoneally with either dexamethasone or pentoxifylline for two weeks and then subjected to a battery of behavioral tests. Treatment with pentoxifylline, but not dexamethasone, was associated with antidepressant-like and anti-manic-like effects. The beneficial behavioral effects of pentoxifylline were accompanied by a prominent reduction in pro-inflammatory mediator levels in the brain. For the first time, the current work proves the efficacy of pentoxifylline against both mania-like and depressive-like behaviors. These results suggest that pentoxifylline may be a promising therapeutic intervention for patients with mood disorders. Taking into account the excellent tolerability profile of pentoxifylline in humans, it is warranted to conduct randomized clinical trials to investigate its therapeutic efficacy in patients with psychiatric disorders.

Effect of Ultrasonography-Guided Corticosteroid Injection vs Placebo Added to Exercise Therapy for Achilles Tendinopathy

Corticosteroid injections and exercise therapy are commonly used to treat chronic midportion Achilles tendinopathy, but the evidence for this combination is limited. To investigate the effect of corticosteroid injection and exercise therapy compared with placebo injection and exercise therapy for patients with Achilles tendinopathy. This was a participant-blinded, physician-blinded, and assessor-blinded randomized clinical trial of patients with Achilles tendinopathy verified by ultrasonography. Assessment of pain and function were conducted at baseline and at 1, 2, 3, 6, 12, and 24 months. Patients were recruited from a university medical clinic and a private rheumatology clinic in Denmark between April 2016 and September 2018. Data analysis was performed from June to September 2021. Corticosteroid injection and placebo injection were performed with ultrasonography guidance. Exercise therapy was based on previous trials and consisted of 3 exercises done every second day. The primary outcome was the Victorian Institute of Sports Assessment-Achilles (VISA-A) score (range, 1-100, with 100 representing no symptoms) at 6 months. Secondary outcomes included pain measured using a 100-mm Visual Analog Scale for morning pain and pain during exercise (with higher scores indicating worse pain), global assessment (Likert scale), and tendon thickness. A total of 100 patients were included, with 52 randomized to placebo (mean age, 46 years [95% CI, 44-48 years]; 32 men [62%]) and 48 randomized to corticosteroid injection (mean age, 47 years [95% CI, 45-49 years]; 28 men [58%]). Patients in the 2 groups had similar height (mean [SD], 177 [8] cm), weight (mean [SD], 79 [12] kg), and VISA-A score (mean [SD], 46 [18]) at baseline. The group receiving exercise therapy combined with corticosteroid injections had a 17.7-point (95% CI, 8.4-27.0 points; P < .001) larger improvement in VISA-A score compared with patients receiving exercise therapy combined with placebo injections at 6 months. No severe adverse events were observed in either group, and there was no deterioration in the long term (2-year follow-up). Corticosteroid injections combined with exercise therapy were associated with better outcomes in the treatment of Achilles tendinopathy compared with placebo injections and exercise therapy. A combination of exercise therapy and corticosteroid injection should be considered in the management of long-standing Achilles tendinopathy. ClinicalTrials.gov Identifier: NCT02580630.

Reduced psychological distress three months after intensive group-based cognitive therapy in cardiac patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): TrygFondenHelseFonden Background/Introduction Patients with coronary artery disease (CAD) and valvular heart disease (VHD) often suffer from psychological distress, which in turn leads to impaired quality of life, delayed return to work and increased morbidity and mortality. Manageable interventions addressing psychological distress in cardiac patients are needed. Purpose To develop an efficient and cost-effective model for cardiac patients to reduce psychological distress. Methods A multi-centre, prospective, randomized clinical trial in patients with newly diagnosed CAD and/or surgically treated VHD and concomitant psychological distress defined as Hospital Anxiety and Depression (HADS A(Anxiety) or D(Depression) ≥8) and part of the work force. The patients were randomized to either usual out-patient cardiac rehabilitation (CR) comprising an 8-week multidisciplinary program or usual care supplemented by five group-based cognitive therapy sessions performed by trained CR nurses. The primary outcome was total HADS score at three months. Results We included 147 patients with HADS score &amp;gt;=8; mean age was 55, 74% were male and 92% had CAD (Table 1). At three months, total HADS score improved by 8 (CI: 8.0-10.7) in the intervention versus 3,9 (CI: 11.8-15.4) in the usual care group (p for difference &amp;lt;0.001). Both subscales, anxiety and depression improved significantly more in the intervention group (Figure 1). Conclusion Brief cognitive behavioral therapy provided by cardiac nurses to patients with a high HADS score significantly reduced psychological destress after 3 months when compared to usual care. Baseline demographic and clinical characteristics Table 1 SD: Standard deviation, IQR: Interquartile range, CAD: Coronary artery disease, PCI Percutaneous Coronary intervention, CABG: coronary artery bypass graft, LVEF: Left ventricular ejection fraction

Single-Dose Dexamethasone Is Not Inferior to 2 Doses in Mild to Moderate Pediatric Asthma Exacerbations in the Emergency Department.

The purpose of this study was to compare the efficacy of a single dose of dexamethasone to 2 doses of dexamethasone in treating mild to moderate asthma exacerbations in pediatric patients. We anticipated that there would not be a difference in the rate of return visits to the emergency department (ED), urgent care, or primary care physician for continued asthma symptoms. This was a prospective, randomized, single-center, unblinded, parallel-group randomized clinical trial of patients 2 to 20 years old presenting to a pediatric ED with mild to moderate asthma exacerbations. The patients were randomized to receive 1 or 2 doses of dexamethasone (0.6 mg/kg per dose, maximum of 16 mg). Telephone follow-up interviews were performed on the sixth day after ED visit. The primary outcome measures were return visits to either primary care physician or ED for continued asthma symptoms. Secondary outcomes were days of symptoms, missed school days, and adverse effects. Of the 318 children initially enrolled, 308 patients met the enrollment criteria. These patients were randomized into 2 groups. There were 116 patients in group 1 and 116 patients in group 2. There was no significant difference between groups regarding return visits (group 1, 12.1%; group 2, 10.3%; odds ratio [OR], 0.892 [95% confidence interval {CI}, 0.377-2.110]), days to symptom resolution (group 1, 2.4; group 2, 2.5; OR, 0.974 [95% 95% CI, 0.838-1.132]), missed school days (group 1, 47%; group 2, 51%; OR, 1.114 [95% CI, 0.613-2.023]), or vomiting (group 1, 8.6%; group 2, 3.4%; OR, 2.424 [95% CI, 0.637-9.228]). In this single-center, unblinded randomized trial of children and adolescents with mild to moderate acute exacerbations of asthma, there was no difference in the rate of return visits for continued or worsened symptoms between patients randomized to 1 or 2 doses of dexamethasone.

Clinical results after arthroscopic reconstruction of the posterolateral corner of the knee: A prospective randomized trial comparing two different surgical techniques

IntroductionArthroscopic reconstruction techniques of the posterolateral corner (PLC) of the knee have been developed in recent years. Reconstruction techniques for higher-grade PLC injuries have not yet been validated in clinical studies. This study aimed to compare clinical outcomes of two different techniques and to present results of the first prospective randomized clinical trial of patients to undergo these novel procedures.Materials and methods19 patients with Fanelli Type B posterolateral corner injuries and additional posterior cruciate ligament ruptures were included in this prospective study. They were randomly assigned to one of two novel arthroscopic reconstruction techniques, based on open surgeries developed by Arciero (group A) and LaPrade (group B). Follow-up was conducted at 6 and 12 months postoperatively and included clinical examinations for lateral, rotational and posterior stability, range of motion and subjective clinical outcome scores (IKDC Subjective Score, Lysholm Score, Tegner Activity Scale and Numeric Rating Scale for pain).ResultsAt 6 and 12 months postoperative, all patients in both groups presented stable to varus, external rotational and posterior forces, there were no significant differences between the two groups. At 12-month follow-up, group A patients showed significantly higher maximum flexion angles (134.17° ± 3.76° vs. 126.60° ± 4.22°; p = 0.021) compared to patients of group B. Duration of surgery was significantly longer in Group B patients than in group A (121.88 ± 11.63 vs. 165.00 ± 35.65 min; p = 0.003). Posterior drawer (side-to-side difference) remained more reduced in group A (2.50 ± 0.69 mm vs. 3.27 ± 0.92 mm; p = 0.184). Subjective patient outcome scores showed no significant differences between groups (Lysholm Score 83.33 ± 7.79 vs. 86.40 ± 9.21; p = 0.621).ConclusionsThis study indicates sufficient restoration of posterolateral rotational instability, varus instability and posterior drawer after arthroscopic posterolateral corner reconstruction without neurovascular complications.Increased postoperative range of motion and a shorter and less invasive surgical procedure could favor the arthroscopic reconstruction technique according to Arciero over LaPrade’s technique in future treatment considerations.

No obesity paradox in patients with community-acquired pneumonia \u2013 secondary analysis of a randomized controlled trial

BackgroundObesity is associated with an increased risk for several chronic conditions and mortality. However, there are data in support of beneficial outcome in acute medical conditions such as community-acquired pneumonia (CAP), termed “obesity paradox”. The aim of this study was to test the association of BMI with clinical outcomes in a large randomized clinical trial of patients hospitalized with CAP.Design and MethodsIn total, 773 patients hospitalized with CAP were included in this study. Patients were stratified into four groups according to their baseline BMI (underweight <18.5, normal weight 18.5–25, overweight 25–30, and obese >30 kg/m2). The primary endpoint was time to clinical stability (TTCS). Secondary endpoints included 30-day mortality, ICU admission rate, CAP complications, and duration of antibiotic treatment.ResultsBMI and TTCS had a U-shaped association with shortest TTCS among patients at an overweight BMI of 28 kg/m2. In patients with obesity, there was a trend towards reduced hazards to reach clinical stability when compared to patients with normal weight (HR 0.82; 95%CI, 0.67–1.02; p = 0.07). In underweight BMI group TTCS was prolonged by 1 day (HR 0.63; 95%CI, 0.45–0.89; p = 0.008). There was no difference in mortality or ICU admission rates between BMI groups (p > 0.05). While in the underweight BMI group the total duration of antibiotic treatment was prolonged by 2.5 days (95%CI, 0.88–4.20, p = 0.003), there was no difference in patients with obesity.ConclusionsThe overweight BMI group had shortest time to clinical stability. While underweight patients face adverse clinical outcomes, there is neither beneficial, nor adverse outcome in patients with obesity hospitalized for CAP.ClinicalTrials.gov (registration no. NCT00973154).