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BMC Medical Research Methodology Jun 2024Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials.
METHODS
We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined.
RESULTS
We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04).
CONCLUSIONS
Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Cholesterol, LDL; Male; Anticholesteremic Agents; Randomized Controlled Trials as Topic; Female; Treatment Outcome; Middle Aged; Hypercholesterolemia; PCSK9 Inhibitors; Aged; Proprotein Convertase 9
PubMed: 38909176
DOI: 10.1186/s12874-024-02260-z -
Journal of Clinical Lipidology May 2024Inclisiran, a small-interfering RNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in clinical trials. Real-world data...
BACKGROUND
Inclisiran, a small-interfering RNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in clinical trials. Real-world data on the potential to attain lipid-goals and reduce treatment gaps is lacking.
OBJECTIVES
To investigate the implementation of inclisiran in real-world clinical setting.
METHODS
Data from a nationwide healthcare organization on patients initiating inclisiran between 3/2022-11/2023. Patients' characteristics, lipid-lowering therapies, post-treatment reduction in low-density lipoprotein cholesterol (LDL-C), and attainment of treatment goals, were evaluated.
RESULTS
Inclisiran was initiated by 503 patients (57 % women; mean age 66±11 years). Cardiovascular disease was present in 54 %, and peak LDL-C levels >190 mg/dL documented in 64 %. Prior exposure to PCSK9 monoclonal antibodies was evident in 28 %. Lipid profile >2 months after filling first prescription, was available in 397 patients (347 with ≥2 injections). In patients treated by inclisiran only (n = 254), median LDL-C reduction from peak levels was 57 % (IQR, 48 %-67 %), and from pre-injection levels 40 % (19 %-54 %). In those with concomitant lipid-lowering therapies (n = 143), median LDL-C reduction from peak levels was 66 % (IQR, 55 %-73 %), and from pre-injection levels 46 % (23 %-59 %). LDL-C < 70 mg/dL was attained by 39 % and LDL-C < 55 mg/dL by 21.9 %. Of those treated with concomitant statin therapy, 38 % attained LDL-C < 55 mg/dL. Overall, 6.5 % discontinued inclisiran therapy after initial injection.
CONCLUSIONS
In real-world practice, inclisiran showed good efficacy in reducing LDL-C with high interindividual variability. However, attainment rates of lipid-goals were suboptimal due to limited use of combination lipid-lowering therapy and high-rates of severe hypercholesterolemia in our patient population cohort.
PubMed: 38908973
DOI: 10.1016/j.jacl.2024.05.003 -
Journal of Clinical Lipidology Apr 2024Cardiovascular (CV) risk scores identify individuals at higher long-term risk of CV events that may benefit from more aggressive preventive interventions.
BACKGROUND
Cardiovascular (CV) risk scores identify individuals at higher long-term risk of CV events that may benefit from more aggressive preventive interventions.
OBJECTIVE
To assess the association of CV-risk categories and criteria with long-term CV events.
METHODS
Observational cohort study between 2000-2019 on patients aged 40-80 years, followed by 14 primary care centers assisted by 1 hospital in Portugal. Follow-up began when electronic health records data allowed for CV-risk classification and dynamic reassessment per 2019 ESC/EAS Guidelines. Inclusion criteria required at least one appointment with a primary care physician within three years before follow-up initiation. We assessed the 10-year adjusted hazard-ratio of combined CV death and non-fatal Atherosclerotic Cardiovascular Disease (ASCVD) hospitalization, across SCORE risk categories and criteria, using Cox proportional hazards models adjusted for sex, age, competing comorbidities, and medication.
RESULTS
The study included 161 681 observations from 87 035 unique patients. During the observation period, 71 787 patients were classified as low/moderate, 51 476 as high and 38 418 as very-high CV-risk categories. In the very-high group, prevalent comorbidities were hypertension (69%), hypercholesterolemia (69%) and type 2 diabetes (61%), and 13% were hospitalized for ASCVD. The adjusted 10-year hazard ratio of the composite of CV death or ASCVD hospitalization was 2.10 (95% CI: 1.91-2.32) for high-risk and 3.56 (95% CI: 3.21-3.96) for very-high-risk patients (low-risk as reference).
CONCLUSION
Our study reinforces the prognostic relevance of CV-risk stratification for long-term prediction of CV death and ASCVD hospitalization in an unselected cohort, independently of sex, age, competing comorbidities and medication.
PubMed: 38908967
DOI: 10.1016/j.jacl.2024.04.002 -
BMJ Open Jun 2024In trials, subgroup analyses are used to examine whether treatment effects differ by important patient characteristics. However, which subgroups are most commonly... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
In trials, subgroup analyses are used to examine whether treatment effects differ by important patient characteristics. However, which subgroups are most commonly reported has not been comprehensively described.
DESIGN AND SETTINGS
Using a set of trials identified from the US clinical trials register (ClinicalTrials.gov), we describe every reported subgroup for a range of conditions and drug classes.
METHODS
We obtained trial characteristics from ClinicalTrials.gov via the Aggregate Analysis of ClinicalTrials.gov database. We subsequently obtained all corresponding PubMed-indexed papers and screened these for subgroup reporting. Tables and text for reported subgroups were extracted and standardised using Medical Subject Headings and WHO Anatomical Therapeutic Chemical codes. Via logistic and Poisson regression models we identified independent predictors of result reporting (any vs none) and subgroup reporting (any vs none and counts). We then summarised subgroup reporting by index condition and presented all subgroups for all trials via a web-based interactive heatmap (https://ihwph-hehta.shinyapps.io/subgroup_reporting_app/).
RESULTS
Among 2235 eligible trials, 23% (524 trials) reported subgroups. Follow-up time (OR, 95%CI: 1.13, 1.04-1.24), enrolment (per 10-fold increment, 3.48, 2.25-5.47), trial starting year (1.07, 1.03-1.11) and specific index conditions (eg, hypercholesterolaemia, hypertension, taking asthma as the reference, OR ranged from 0.15 to 10.44), predicted reporting, sponsoring source and number of arms did not. Results were similar on modelling any result reporting (except number of arms, 1.42, 1.15-1.74) and the total number of subgroups. Age (51%), gender (45%), racial group (28%) were the most frequently reported subgroups. Characteristics related to the index condition (severity/duration/types etc) were frequently reported (eg, 69% of myocardial infarction trials reported on its severity/duration/types). However, reporting on comorbidity/frailty (five trials) and mental health (four trials) was rare.
CONCLUSION
Other than age, sex, race ethnicity or geographic location and characteristics related to the index condition, information on variation in treatment effects is sparse.
PROSPERO REGISTRATION NUMBER
CRD42018048202.
Topics: Humans; Chronic Disease; Clinical Trials as Topic; Epidemiologic Studies; Research Design
PubMed: 38908852
DOI: 10.1136/bmjopen-2023-081315 -
Cardiovascular Drugs and Therapy Jun 2024Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density... (Review)
Review
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the modulation of lipid metabolism as a critical negative regulator of hepatic low-density lipoprotein receptor (LDLR) levels and circulating low-density lipoprotein (LDL) clearance. Numerous gain-of-function (GOF) mutations in PCSK9 have been identified as causing familial hypercholesterolemia (FH) by reducing LDLR levels, and loss-of-function (LOF) mutations associated with a hypercholesterolemia phenotype protective against atherosclerosis. PCSK9 represents an example of successful translational research resulting in the identification of PCSK9 as a major drug target for a lipid-lowering therapy. To explore the genetic constitution of PCSK9 and its biologic role, in this review, we summarize the current evidence of clinically significant PCSK9 genetic variants involved in lipid metabolism as well as emphasize the importance of PCSK9 inhibition for the improvement of cardiovascular outcomes by conducting a meta-analysis of the available data on the incidence of cardiovascular disease events.
PubMed: 38907775
DOI: 10.1007/s10557-024-07599-5 -
Journal of Neurology, Neurosurgery, and... Jun 2024The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy...
BACKGROUND
The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy alcohol consumption and CIS with subgroup analyses stratified by sex and age.
METHODS
Altogether, 540 patients aged 18-49 years (median age 41; 47.2% women) with a recent CIS and 540 sex-matched and age-matched stroke-free controls were included. Heavy alcohol consumption was defined as >7 (women) and >14 (men) units per week or at least an average of two times per month ≥5 (women) and ≥7 (men) units per instance (binge drinking). A conditional logistic regression adjusting for age, sex, education, hypertension, cardiovascular diseases, diabetes, hypercholesterolaemia, current smoking, obesity, diet and physical inactivity was used to assess the independent association between alcohol consumption and CIS.
RESULTS
Patients were twice as more often heavy alcohol users compared with controls (13.7% vs 6.7%, p<0.001), were more likely to have hypertension and they were more often current smokers, overweight and physically inactive. In the entire study population, heavy alcohol consumption was independently associated with CIS (adjusted OR 2.11; 95% CI 1.22 to 3.63). In sex-specific analysis, heavy alcohol consumption was associated with CIS in men (2.72; 95% CI 1.25 to 5.92), but not in women (1.56; 95% CI 0.71 to 3.41). When exploring the association with binge drinking alone, a significant association was shown in the entire cohort (2.43; 95% CI 1.31 to 4.53) and in men (3.36; 95% CI 1.44 to 7.84), but not in women.
CONCLUSIONS
Heavy alcohol consumption, particularly binge drinking, appears to be an independent risk factor in young men with CIS.
PubMed: 38906694
DOI: 10.1136/jnnp-2024-333759 -
Advances in Food and Nutrition Research 2024Nowadays, the growing knowledge about the high nutritional value and potential functionality of hempseeds, the edible fruits of the Cannabis sativa L. plant, has sparked... (Review)
Review
Nowadays, the growing knowledge about the high nutritional value and potential functionality of hempseeds, the edible fruits of the Cannabis sativa L. plant, has sparked a surge in interest in exploring the worthwhile attributes of hempseed proteins and peptides. This trend aligns with the increasing popularity of hemp-based food, assuming a vital role in the global food chain. This chapter targets the nutritional and chemical composition of hempseed in terms of short- and medium-chain bioactive peptides. The analytical approaches for their characterization and multifunctional properties are summarized in detail. Moreover, the processing, functionality, and application of various hempseed protein products are discussed. In the final part of the chapter-for evaluating their propensity to be transported by intestinal cells-the transepithelial transport of peptides within hempseed protein hydrolysate is highlighted.
Topics: Cannabis; Seeds; Plant Proteins; Peptides; Humans; Nutritive Value
PubMed: 38906589
DOI: 10.1016/bs.afnr.2024.01.002 -
Journal of Medicinal Food Jun 2024Iron supplementation is a common method for alleviating symptoms of iron deficiency, but excessive iron intake may lead to systemic copper deficiencies and...
Iron supplementation is a common method for alleviating symptoms of iron deficiency, but excessive iron intake may lead to systemic copper deficiencies and hypercholesterolemia. In our study, we explored the intricate relationship between dietary iron and copper levels and their impact on cholesterol metabolism. Using a rat model, we conducted dietary interventions with varying iron and copper concentrations and analyzed hepatic transcriptomes. High iron intake coupled with low copper intake induced hypercholesterolemia and altered the expression of genes associated with cholesterol and lipid metabolism, thereby, exacerbating cardiovascular disease risks. Conversely, copper supplementation mitigated these hepatic gene expression alterations, suggesting that dietary copper plays a role in cholesterol regulation. Transcriptomic analysis revealed significant upregulation of genes involved in cholesterol synthesis and antioxidative pathways in response to high iron intake, while genes involved in cholesterol elimination were downregulated. Furthermore, high iron consumption was associated with cellular apoptosis and the activation of cholesterol synthesis. Our findings underscore the importance of balanced iron and copper intake in cholesterol homeostasis and highlight the potential of copper supplementation for mitigating iron-induced hypercholesterolemia.
PubMed: 38905120
DOI: 10.1089/jmf.2024.k.0139 -
Journal of Vascular Surgery Jun 2024Type B intramural hematoma (IMH) is often managed medically, yet may progress to dissection, aneurysmal dilation, or rupture. The aim of this study was to report the...
OBJECTIVE
Type B intramural hematoma (IMH) is often managed medically, yet may progress to dissection, aneurysmal dilation, or rupture. The aim of this study was to report the natural history of medically managed Type B IMH, and factors associated with progression.
METHODS
We reviewed patients with medically managed Type B IMH between January 1995 to December 2022 at a single center. Any patients with immediate surgical or endovascular intervention were excluded. Demographic profiles, comorbidities, imaging, and follow-up details were reviewed. Patients were divided into two groups: Group 1 had isolated IMH, and Group 2 had IMH along with aneurysm or dissection at the time of presentation. On follow-up, progression was defined as degeneration to aneurysm/dissection or increase in the thickness of IMH in Group 1. In Group 2, progression was an increase in the size of aneurysm or development of new dissection.
RESULTS
Of 104 patients with Type B IMH during the study period, 92 were medically managed. The median age was 77 years, and 45 (48.9%) were females. Comorbidities included hypertension (83.7%), hypercholesterolemia (44.6%), and active smoking (47.8%). Mean Society for Vascular Surger comorbidity score was 6.3. Mean IMH thickness and aortic diameter at presentation were 8.9 mm and 38.3 mm, respectively. Median follow-up was 55 months. Overall survival at 1 year and 5 years was 85.8% and 61.9%, respectively. During follow-up, 19 patients (20.7%) required intervention, more common in Group 2 (Group 1, 8/66; 12.3% vs Group 2, 11/26; 42.3%; P = .001). This resulted in higher freedom from intervention in Group 1 at 1 year (93.5% vs 62.7%) and 5 years (87.5% vs 51.1%; P < .001). Indication for intervention was dissection (n = 4), aneurysm (n = 12), and progression of IMH (n = 3). In Group 1, progression was seen in 25 (37.9%), three (4.5%) remained stable, 29 (43.9%) had complete resolution of IMH, and nine patients were lost to follow-up. In Group 2, 11 patients (42.3%) had progression, seven (26.9%) remained stable, and eight were lost to follow-up. IMH thickness at presentation >7.2 mm is associated with both increased odds of progression (odds ratio, 3.3; 95% confidence interval, 1.2-11.1; P = .03) and intervention (odds ratio, 5.5; 95% confidence interval, 1.3-36.9; P = .03) during the follow-up.
CONCLUSIONS
Although many patients with Type B IMH managed medically stabilize or regress, progression or need for intervention can occur in up to 40% of cases. This is associated with the presence of aneurysm, dissection, and IMH thickness. Long-term follow-up is mandatory as late interventions occur, particularly for higher risk patients.
PubMed: 38904581
DOI: 10.1016/j.jvs.2024.04.069 -
Frontiers in Pharmacology 2024Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish...
BACKGROUND
Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish the safety profile of lorlatinib based on the Food and Drug Administration Adverse Event Reporting System (FAERS).
METHODS
Reports from the FAERS between 2019 and 2023 were collected to conduct the disproportionality analysis. Reporting odds ratio (ROR) was employed to detect the potential adverse events (AEs) related to lorlatinib. The clinical characteristics, age and gender differences, time to onset of AEs were also investigated.
RESULTS
A total of 2,941 AE reports were found to be associated with lorlatinib among the 8,818,870 AE reports obtained from the FAERS database. 167 lorlatinib-related AE signals were identified. The frequently reported AEs including hypercholesterolemia, oedema, and cognitive disorder were in line with those observed in clinical trials and drug instruction. However, AEs such as interstitial lung disease and AV block indicated in the drug label require further evaluation. More attention should be paid to the new potential unexpected AEs including pulmonary arterial hypertension and radiation necrosis. Furthermore, we examined the specific high-risk AEs of different ages and genders. In addition, majority of AEs occurred within the first 2 months after lorlatinib initiation with a median onset time of 51 days.
CONCLUSION
Our study provides valuable insight into the post-marketing safety profile of lorlatinib, which can potentially benefit the rational and safe administration of lorlatinib in the clinic. Further prospective studies are needed to validate the associations between lorlatinib and the identified AEs.
PubMed: 38903993
DOI: 10.3389/fphar.2024.1385036