Clinical Trial Evidence Research Articles

Hemodynamic Support With the Impella 5.5 Acute Mechanical Circulatory Support Device.

The Impella 5.5 is increasingly used as a bridge to recovery or heart replacement therapies despite lack of clinical trial evidence. We report real-world outcomes and hemodynamic effects of 150 consecutive patients from a single, high-volume center. Primary outcome was incidence of recovery, durable left ventricular assist device (LVAD), or heart transplant compared with incidence of death at 90 days. Secondary outcomes included hemodynamic trends and upgrade to veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. The composite endpoint occurred in 59.3% and death in 18.8% of patients (incidence rate ratio: 8.1 [95% confidence interval {CI}: 5.4-12.2], p < 0.001). Decreases in pulmonary artery diastolic pressure (PADP) (p = 0.026), estimated pulmonary effective arterial elastance (Ea) (p < 0.001), and vasoactive-inotropic score (VIS) (p < 0.001) occurred during Impella 5.5 support. Pulmonary artery diastolic pressure correlated with estimated Ea (p < 0.001), suggesting improved right ventricle (RV) afterload with left ventricle (LV) unloading. Veno-arterial extracorporeal membrane oxygenation upgrade occurred in 11.3% of patients who had higher baseline right atrial pressure (RAP) (16.0 [9.0-20.5] vs. 9.0 [7.0-12.0], p = 0.022), PADP (28.5 [25.0-31.0] vs. 23.0 [18.0-28.0], p = 0.011), and lower pulmonary artery pulsatility index (PAPi) (1.45 [0.82-3.45] vs. 2.5 [1.65-3.86], p = 0.029). Upgrade patients had higher repeated measures trends in RAP (p < 0.001) and PADP (p = 0.015). The Impella 5.5 improved hemodynamics and effectively bridged to recovery or heart replacement therapies. Co-existing RV dysfunction can be supported on Impella 5.5 with careful hemodynamic trend monitoring.

Dapagliflozin’s Role in Heart Failure: An Overview of Clinical Trial Evidence

Dapagliflozin’s Role in Heart Failure: An Overview of Clinical Trial Evidence

Longitudinal Assessment of Transfusion Intensity in Patients With JAK Inhibitor—Naive or—Experienced Myelofibrosis Treated With Momelotinib

PurposeAnemia is a cardinal feature of myelofibrosis often managed with red blood cell (RBC) transfusions, which may contribute to negative prognostic, quality-of-life, and healthcare-related economic impacts. The Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib was approved for the treatment of patients with myelofibrosis and anemia based on clinical trial evidence of anemia, spleen, and symptom benefits illustrated using binomial response/nonresponse endpoints. In the present post hoc, descriptive analyses, the impact of momelotinib on RBC transfusion burden over time was further characterized across JAK inhibitor–naive and –experienced patients MethodsAll RBC units transfused were collected during the baseline and 24-week treatment periods, initially in a single-arm phase 2 study as proof-of-concept analysis, and then versus comparators (ruxolitinib, best available therapy [BAT], and danazol) in the phase 3 SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM studies, respectively. ResultsIn the phase 2 study, mean transfusion requirement changed by −1.5 units/28 days, with 85% of patients (35/41) achieving numeric transfusion reduction. Across SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM, mean transfusion requirements decreased with momelotinib (−0.1, −0.36, and −0.86 units/28 days), while mean requirements with ruxolitinib, BAT, and danazol changed by +0.39, 0, and ‒0.28 units/28 days, respectively. Overall, 87% (185/213), 77% (79/103), and 85% (110/130) of patients had improved or stable transfusion intensities with momelotinib versus 54% (117/216), 62% (32/52), and 63% (41/65) with ruxolitinib, BAT, and danazol. ConclusionThese novel time-dependent transfusion burden analyses demonstrate that momelotinib is associated with anemia-related benefits in most patients and greater transfusion burden reduction versus comparators. Trial registrationClinicalTrials.gov identifiers: NCT02515630, NCT01969838, NCT02101268, NCT04173494.

Statistical Non-Significance, Likelihood Ratio, and The Interpretation of Clinical Trial Evidence: Insights from Heart Failure Randomized Trials.

Statistical Non-Significance, Likelihood Ratio, and The Interpretation of Clinical Trial Evidence: Insights from Heart Failure Randomized Trials.

Clinical Trial Evidence of the Gut Microbial Metabolite Butyrate in Hypertension.

Clinical Trial Evidence of the Gut Microbial Metabolite Butyrate in Hypertension.

Long-Term Health Outcomes of Huntington Disease and the Impact of Future Disease-Modifying Treatments: A Decision-Modeling Analysis.

Disease-modifying treatments (DMTs) such as gene therapy are currently under investigation as a potential treatment for Huntington disease (HD). Our objective was to estimate the long-term natural history of HD progression and explore the potential efficacy impacts and value of a hypothetical DMT using a decision-analytic modeling framework. We developed a health state transition model that separately analyzed 40-year-old individuals with prefunctional decline (PFD, HD Integrated Staging System [HD-ISS] stage <3, total functional score [TFC] 13), active functional decline Shoulson and Fahn category 1 (SF1, HD-ISS stage 3, TFC 13-11), and SF2 (HD-ISS stage 3, TFC 10-7). Three-year outcomes from the TRACK-HD longitudinal study were linearly extrapolated to estimate the long-term health outcomes and costs of each population. For PFD individuals, we used the HD-ISS to predict the onset of functional decline. HD costs and quality-adjusted life years (QALYs) were estimated over a lifetime horizon by applying health state-specific costs and utilities derived from a related HD burden-of-illness study. We then estimated the long-term health impacts of hypothetical DMTs that slowed or delayed onset of functional decline. We conducted sensitivity analyses to assess model uncertainties. The expected life years for 40-year-old PFD, SF1, and SF2 populations were 20.46 (95% credible range [CR]: 19.05-22.30), 13.93 (10.82-19.08), and 10.99 (8.28-22.07), respectively. The expected QALYs for PFD, SF1, and SF2 populations were 15.93 (14.91-17.44), 8.29 (6.36-11.79), and 5.79 (4.14-12.91), respectively. The lifetime costs of HD were $508,200 ($310,300 to $803,700) for the PFD population, $1.15 million ($684,500 to $1.89 million) for SF1 individuals, and $1.07 million ($571,700 to $2.26 million) for SF2 individuals. Although hypothetical DMTs led to cost savings in the PFD population by delaying the cost burdens of functional decline, they increased costs in SF1 and SF2 populations by prolonging time spent in expensive progressive HD states. Our novel HD-modeling framework estimates HD progression over a lifetime and the associated costs and QALYs. Our approach can be used for future cost-effectiveness models as positive DMT clinical trial evidence becomes available.

Shanghai consensus on the diagnosis and treatment of gastroesophageal reflux disease in patients undergoing sleeve gastrectomy(2024 edition)

Morbid obesity and its accompanying diseases have become one of the most serious public health problems warranting global effort and bariatric and metabolic surgery is still the most effective method for long-term weight control. Among all bariatric and metabolic procedures, sleeve gastrectomy is currently the most widely used, but it is not a perfect procedure. One of the most serious issues that this surgical procedure faces is the possibility of worsening existing or developing de novo gastroesophageal reflux disease after surgery. Moreover, there is currently a lack of high-level clinical trial evidence on the diagnosis and treatment of gastroesophageal reflux disease in patients undergoing sleeve gastrectomy. Therefore, initiated by four domestic bariatric and metabolic surgery centers, 41 experts with rich experience in bariatric and metabolic surgery and diagnosis and treatment of gastroesophageal reflux disease from China, Japan, and South Korea reached a consensus on the diagnosis and treatment of gastroesophageal reflux disease in sleeve gastrectomy patients using the Delphi method. There are a total of 59 consultation questions in this consensus, of which 44 have reached a consensus. We hope that this consensus can not only serve as a reference for clinical diagnosis and treatment, but also provide more possible directions for future high-quality clinical research.

Lipids, lipid-lowering drugs and lateral epicondylitis of the humerus: a drug-targeted Mendelian randomization study.

Clinical observations indicate that blood lipids may be risk factors for lateral epicondylitis (LE) of the humerus, and lipid-lowering drugs are also used for the prevention and treatment of tendon diseases, but these lack high-quality clinical trial evidence and remain inconclusive. Mendelian randomization (MR) analyses can overcome biases in traditional observational studies and offer more accurate inference of causal relationships. Therefore, we employed this approach to investigate whether blood lipids are risk factors for LE and if lipid-lowering drugs can prevent it. Genetic variations associated with lipid traits, including low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), were obtained from the UK Biobank and the Global Lipids Genetics Consortium (GLGC). Data on genetic variation in LE were sourced from FinnGen, including 24,061 patients and 275,212 controls. Subsequently, MR analyses were conducted to assess the potential correlation between lipid traits and LE. Additionally, drug-target Mendelian randomization analyses were performed on 10 drug targets relevant to LE. For those drug targets that yielded significant results, further analysis was conducted using colocalization techniques. No correlation was found between three blood lipid traits and LE. Lipoprotein lipase (LPL) enhancement is significantly associated with a decreased risk of LE (OR = 0.76, [95% CI, 0.65-0.90], p = 0.001). The expression of LPL in the blood is associated with LE and shares a single causal variant (12.07%), greatly exceeding the probability of different causal variations (1.93%), with a colocalization probability of 86.2%. The three lipid traits are not risk factors for lateral epicondylitis. LPL is a potential drug target for the prevention and treatment of LE.

Efficacy of Biologics in NSAID-ERD: United Airways From the Nose to the Bronchi

NSAID-exacerbated respiratory disease (NSAID-ERD), the clinical triad of severe chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and respiratory reactions to cyclooxygenase 1 inhibitors, is often challenging to manage, with many patients failing first line therapies for CRSwNP and asthma. There are now six biologic mediations approved for asthma and/or severe CRSwNP: omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab and tezepelumab. With the availability of respiratory biologic treatment for both asthma and CRSwNP, clinicians now have a multitude of additional management options for patients with NSAID-ERD. Herein we will review the currently available clinical trial and real-world evidence for biologic efficacy and safety patients with NSAID-ERD, discuss the mechanisms of biologic therapy specific to NSAID-ERD, and review evidence regarding the use of biologic therapy versus endoscopic sinus surgery therapy for CRSwNP and NSAID-ERD. We will propose a management approach for choosing biologic therapy or endoscopic sinus surgery with aspirin therapy after desensitization for patients with NSAID-ERD.

Ruxolitinib cream

Ruxolitinib cream is licensed for the treatment of non‐segmental vitiligo with facial involvement in adolescents (≥12 years old) and adults. This article summarises its mechanism of action, the clinical trial evidence of efficacy and its place in therapy.

Biosynthesis and Metabolism of ApoB-Containing Lipoproteins.

Recent advances in human genetics, together with a substantial body of epidemiological, preclinical and clinical trial evidence, strongly support a causal relationship between triglyceride-rich lipoproteins (TRLs) and atherosclerotic cardiovascular disease. Consequently, the secretion and metabolism of TRLs have a significant impact on cardiovascular health. This knowledge underscores the importance of understanding the molecular mechanisms and regulation of very-low-density lipoprotein (VLDL) and chylomicron biogenesis. Fortunately, there has been a resurgence of interest in the intracellular assembly, trafficking, degradation, and secretion of VLDL, leading to many ground-breaking molecular insights. Furthermore, the identification of molecular control mechanisms related to triglyceride metabolism has greatly advanced our understanding of the complex metabolism of TRLs. In this review, we explore recent advances in the assembly, secretion, and metabolism of TRLs. We also discuss available treatment strategies for hypertriglyceridemia.

Beyond LDL-C: unravelling the residual atherosclerotic cardiovascular disease risk landscape-focus on hypertriglyceridaemia.

Historically, atherosclerotic cardiovascular disease (ASCVD) risk profile mitigation has had a predominant focus on low density lipoprotein cholesterol (LDL-C). In this narrative review we explore the residual ASCVD risk profile beyond LDL-C with a focus on hypertriglyceridaemia, recent clinical trials of therapeutics targeting hypertriglyceridaemia and novel modalities addressing other residual ASCVD risk factors. Hypertriglyceridaemia remains a significant ASCVD risk despite low LDL-C in statin or proprotein convertase subtilisin/kexin type 9 inhibitor-treated patients. Large population-based observational studies have consistently demonstrated an association between hypertriglyceridaemia with ASCVD. This relationship is complicated by the co-existence of low high-density lipoprotein cholesterol. Despite significantly improving atherogenic dyslipidaemia, the most recent clinical trial outcome has cast doubt on the utility of pharmacologically lowering triglyceride concentrations using fibrates. On the other hand, purified eicosapentaenoic acid (EPA), but not in combination with docosahexaenoic acid (DHA), has produced favourable ASCVD outcomes. The outcome of these trials suggests alternate pathways involved in ASCVD risk modulation. Several other pharmacotherapies have been proposed to address other ASCVD risk factors targeting inflammation, thrombotic and metabolic factors. Hypertriglyceridaemia poses a significant residual ASCVD risk in patients already on LDL-C lowering therapy. Results from pharmacologically lowering triglyceride are conflicting. The role of fibrates and combination of EPA and DHA is under question but there is now convincing evidence of ASCVD risk reduction with pure EPA in a subgroup of patients with hypertriglyceridaemia. Clinical guidelines should be updated in line with recent clinical trials evidence. Novel agents targeting non-conventional ASCVD risks need further evaluation.

Sodium-glucose cotransporter 2 inhibitors reduce the risk of incident type 2 diabetes in people with heart failure without diabetes: An analysis of real-world, cohort data.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is), used as a glucose-lowering therapy in people with type 2 diabetes (T2D), have significant cardiorenal benefits, reducing hospitalization for heart failure (HF) and cardiovascular mortality in patients with and without T2D. Recent clinical trial evidence suggests their potential utility in preventing incident T2D among the high-risk HF populations. Therefore, we aimed to assess whether this finding was reproducible in a real-world setting. We performed a retrospective cohort analysis of 484 643 patients with HF, without baseline diabetes, prescribed either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers with/without SGLT2is (treatment, n = 42 018; reference, n = 442 625) across 95 global health care organizations, using a large real-world ecosystem. Propensity score matching balanced arms 1:1 for confounders (n = 39 168 each arm). Subgroup analysis further evaluated the impact on patients with prediabetes and the efficacy of dapagliflozin/empagliflozin, specifically, on incident T2D and secondary outcomes, including all-cause mortality, acute pulmonary oedema and hospitalization. Treatment with SGLT2is significantly reduced incident T2D {hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.63, 0.75]} in patients with HF. The analysis of patients with prediabetes found that SGLT2is further reduced incident T2D [HR 0.62 (95% CI 0.45, 0.80)]. The magnitude of reduction in incident T2D was higher in patients prescribed dapagliflozin [HR 0.47 (95% CI 0.39, 0.56)] versus empagliflozin [HR 0.81 (95% CI 0.70, 0.93)]. Treatment with SGLT2is in patients with HF was associated with a reduced risk of incident T2D, most strikingly in people with prediabetes.

Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

The attitudes, knowledge and confidence of healthcare professionals about cannabis-based products

BackgroundUse of cannabis-based products is becoming more frequent, and it is important that healthcare professionals are informed and confident about them when making evidence-based decisions about their use. This study aimed to gain an international perspective on the attitudes, knowledge, and confidence of healthcare professionals about cannabis-based products.MethodsAn online questionnaire regarding these products was completed by 1580 healthcare professionals (neurologists, psychiatrists, general practitioners, pharmacists and nurses) from 16 countries across Asia, Europe, Oceania, South America, and the Middle East.ResultsRespondents expressed a high level of interest in cannabis-based products (median score 9 out of 10) and reported that they felt knowledgeable about them (median score 6 out of 7). They reported a high level of confidence when providing patients with information on cannabis-based products, returning median scores of 6 and 5 out of 7 for their legality and regulations, and their benefits and risks, respectively. Despite this, healthcare professionals sought further information on cannabis-based products across areas including legality, neurobiology, and scientific evidence. Finally, 59% (n = 930) of respondents considered robust clinical trial evidence as the most important factor to ensure patient safety in the context of these products. Few nominally significant differences emerged between healthcare professionals from different specialities or regions.ConclusionIn conclusion, this large survey of attitudes held by healthcare professionals towards cannabis-based products revealed a high level of interest and a demand for more information. Limitations of this study include potential sample bias and limited external validity.

Clinical trial evidence supporting FDA approval of novel orphan drugs between 2017 and 2023

Characterization analysis of 87 pivotal clinical trials for 72 novel orphan drugs (76 orphan indications) approved by the FDA from 2017 to 2023 revealed that the clinical trial evidence supporting FDA orphan drug approvals often lacked high-quality designs, which frequently did not incorporate randomization, blinding, placebo or no treatment control, or clinical endpoint-driven methodologies. Additionally, regulatory flexibility was observed in the quantity of clinical trial evidence required, which included choices such as a single trial plus confirmatory evidence, one large multicenter trial or at least two trials. Furthermore, the overall strength of the clinical trial evidence exhibited variations across different orphan drugs and indications, influenced by features such as the therapeutic area and whether the orphan drug was granted accelerated approvals.

Vitamin D therapy in chronic kidney disease: a critical appraisal of clinical trial evidence.

In people with chronic kidney disease (CKD), the physiology of vitamin D is altered and leads to abnormalities in bone and mineral metabolism which contribute to CKD mineral and bone disorder (CKD-MBD). Observational studies show an association between vitamin D deficiency and increased risk of mortality, cardiovascular disease and fracture in CKD. Although vitamin D therapy is widely prescribed in people with CKD, clinical trials to date have failed to demonstrate a clear benefit of either nutritional vitamin D supplementation or active vitamin D therapy in improving clinical outcomes in CKD. This review provides an updated critical analysis of recent trial evidence on vitamin D therapy in people with CKD.

Identification of novel genetic loci associated with major depressive disorder and the hippocampus in a European population using the condFDR method

To identify additional loci associated with depression and the hippocampus (HIP) through genome-wide association study. The depression-related genome-wide association study (GWAS) meta summary data was downloaded from the official website of the Psychiatric Genomics Consortium, which had involved 170 756 cases and 329 443 controls. The left and right hippocampal volume GWAS data sets were downloaded from the UK Biobank, which involved 33 224 participants. The conditional false discovery rate (condFDR) was used to identify novel genetic loci for depression and left and right hippocampal volumes, and a conjunctional false discovery rate (conjFDR) was used to evaluate the enrichment of pleiotropic loci between depression and left and right hippocampal volumes. Respectively, 7, 13, and 12 new loci have been associated with depression, left hippocampal volume and right hippocampal volume, with a significant threshold of condFDR < 0.01. A site of rs1267073 locus was found to be shared by the depression and right hippocampal volume with a threshold of conjFDR < 0.01. Above findings have provided more insights into the genetic mechanisms underlying the volume of hippocampus and the risk for depression. The results may also provide evidence for future clinical trials for treating depression.

Diagnosis and initial treatment of transplant-eligible high-risk myeloma patients: A British Society for Haematology/UK Myeloma Society Good Practice Paper.

This Good Practice Paper provides recommendations for the diagnosis and initial management of transplant-eligible high-risk myeloma patients. It describes recent updates to the genetic diagnostics of high-risk myeloma and provides recommendations for treatment on the basis of recent prospective clinical trial evidence.

Cost-Effectiveness of Vedolizumab as a First-Line Advanced Therapy Versus Adalimumab Treatment Sequences for Ulcerative Colitis in Italy.

Today, there are many treatment options available for the management of ulcerative colitis, creating challenges in selecting the most efficacious and cost-effective treatment sequences. Treatments in the anti-tumor necrosis factor alpha (TNFα) therapeutic class, as well as vedolizumab, are widely used and endorsed as first-line options according to treatment guidelines. The aim of this study was to compare treatment sequences involving vedolizumab and the anti-TNFα treatment adalimumab in terms of cost-effectiveness in the treatment of moderately to severely active ulcerative colitis in Italy. A cost-effectiveness model comparing treatment sequences within the Italian National Health Service in terms of costs and quality-adjusted life years (QALYs) with a lifetime horizon was developed. The analysis focused on the relative positioning of vedolizumab and adalimumab, leveraging the results of the landmark head-to-head VARSITY clinical trial as key inputs. The robustness of the results was investigated through a range of sensitivity and scenario analyses. The strategy of vedolizumab as a first-line advanced therapy followed by adalimumab was associated with higher costs and health benefits compared with first-line adalimumab followed by vedolizumab. The incremental cost-effectiveness ratio was €16,146/QALY, which was found to be robust to changes to inputs associated with areas of high uncertainty. This economic evaluation estimated a 94% probability that vedolizumab as a first-line advanced therapy is cost-effective at a threshold of €33,004/QALY when compared with first-line adalimumab sequences. Using clinical trial evidence to inform the efficacy of second-line treatments estimated that the effectiveness of anti-TNFα treatments is not substantially reduced by vedolizumab exposure.