Lipidomic Risk Score to Enhance Cardiovascular Risk Stratification for Primary Prevention.

BACKGROUND: Accurate risk stratification is vital for primary prevention of cardiovascular disease (CVD). However, traditional tools such as the Framingham Risk Score (FRS) may underperform within the diverse intermediate-risk group, which includes individuals requiring distinct management strategies. OBJECTIVES: This study aimed to develop a lipidomic-enhanced risk score (LRS), specifically targeting risk prediction and reclassification within the intermediate group, benchmarked against the FRS. METHODS: The LRS was developed via a machine learning workflow using ridge regression on the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab; n = 10,339). It was externally validated with the Busselton Health Study (n = 4,492), and its predictive utility for coronary artery calcium scoring (CACS)-based outcomes was independently validated in the BioHEART cohort (n = 994). RESULTS: LRS significantly improved discrimination metrics for the intermediate-risk group in both AusDiab and Busselton Health Study cohorts (all P < 0.001), increasing the area under the curve for CVD events by 0.114 (95% CI: 0.1123-0.1157) and 0.077 (95% CI: 0.0755-0.0785), with a net reclassification improvement of 0.36 (95% CI: 0.21-0.51) and 0.33 (95% CI: 0.15-0.49), respectively. For CACS-based outcomes in BioHEART, LRS achieved a significant area under the curve improvement of 0.02 over the FRS (0.76 vs 0.74; P < 1.0 × 10-5). A simplified, clinically applicable version of LRS was also created that had comparable performance to the original LRS. CONCLUSIONS: LRS, augmenting the FRS, presents potential to improve intermediate-risk stratification and to predict atherosclerotic markers using a simple blood test, suitable for clinical application. This could facilitate the triage of individuals for noninvasive imaging such as CACS, fostering precision medicine in CVD prevention and management.

Cancer prevention recommendations: awareness in a Mexican public hospital.

Background: The recommendations of both the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) for the prevention of cancer are important public health tools. These recommendations for the prevention of specific cancers are related to body weight maintenance; physical activity; foods and drinks that promote weight gain; plant foods; foods of animal origin; alcoholic beverages; preservation, processing, and preparation of food; food supplements; and breastfeeding. Methods: This study was a descriptive, cross-sectional, retrospective study. All patients provided written informed consent prior to enrollment in the study. Stratified random sampling was carried out with a convenience sample size of ≥280 participants. The characteristics of the participants were investigated using validated questions. Knowledge about the WCRF/AICR recommendations for the primary prevention of cancer was determined using 14 multiple choice questions validated in this study. Group A included participants who answered that cancer can be prevented and that lifestyle is the main factor related to the onset of cancer; the remaining participants were assigned to Group B. The χ2 test and Mann‒Whitney U test were used to determine differences in the groups. A p-value of ≤0.05 was considered statistically significant. A multiple linear regression analysis with gamma response was performed to assess the knowledge score. Results: A total of 289 participants were included; 168 (58%) participants were in group A, and 121 (42%) participants were in group B. Using a 0 to 14 scale, the median (P25, P75) number of correct answers was 11 (10, 12). There was no evidence of a difference between groups in sex, relationship status, literacy skills, years of education, occupation, monthly income per person, and BMI. Most of the participants reported that they did not consume tobacco (n = 259/289) or alcohol (n = 261/289) in the week prior to completing the survey. Discussion: Most of the participants (58%) considered cancer preventable and agreed that lifestyle factors were the most important factors in cancer development. The results also showed a high level of public awareness of some evidence-based associations between cancer and lifestyle factors, such as tobacco use. Some confusion among the public on other risk factors was also identified: waist circumference, a variable related to excess weight, was not identified as a risk factor for cancer by most of the participants, but the consumption of foods and beverages high in calories was identified as a risk factor by the majority of participants. Awareness of cancer protective and risk factors may lead to positive behavioral changes and eventually reduce the burden of cancer.

Carotid Ultrasound-Based Plaque Score for the Allocation of Aspirin for the Primary Prevention of Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis and the Atherosclerosis Risk in Communities Study.

BACKGROUND: Coronary artery calcium testing using noncontrast cardiac computed tomography is a guideline-indicated test to help refine eligibility for aspirin in primary prevention. However, access to cardiac computed tomography remains limited, with carotid ultrasound used much more often internationally. We sought to update the role of aspirin allocation in primary prevention as a function of subclinical carotid atherosclerosis. METHODS AND RESULTS: The study included 11 379 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) and ARIC (Atherosclerosis Risk in Communities) studies. A harmonized carotid plaque score (range, 0-6) was derived using the number of anatomic sites with plaque from the left and right common, bifurcation, and internal carotid artery on ultrasound. The 5-year number needed to treat and number needed to harm as a function of the carotid plaque score were calculated by applying a 12% relative risk reduction in atherosclerotic cardiovascular disease (ASCVD) events and 42% relative increase in major bleeding events related to aspirin use, respectively. The mean age was 57 years, 57% were women, 23% were Black, and the median 10-year ASCVD risk was 12.8%. The 5-year incidence rates (per 1000 person-years) were 5.5 (4.9-6.2) for ASCVD and 1.8 (1.5-2.2) for major bleeding events. The overall 5-year number needed to treat with aspirin was 306 but was 2-fold lower for individuals with carotid plaque versus those without carotid plaque (212 versus 448). The 5-year number needed to treat was less than the 5-year number needed to harm when the carotid plaque score was ≥2 for individuals with ASCVD risk 5% to 20%, whereas the presence of any carotid plaque demarcated a favorable risk-benefit for individuals with ASCVD risk >20%. CONCLUSIONS: Quantification of subclinical carotid atherosclerosis can help improve the allocation of aspirin therapy.

Lifestyle-Related Risk Factors and Primary Prevention Strategies for Cardiovascular Diseases in a Middle-Income Country: A Scoping Review and Implication for Future Research.

Cardiovascular diseases are the leading cause of death in middle-income countries such as Malaysia. There is a significant gap in knowledge between cardiovascular disease-related risk assessments and interventions in the Malaysian population. In this scoping review, we have determined the status of cardiovascular research in Malaysia by prioritising lifestyle-related risk assessments and interventions. We searched five electronic databases (Ovid MEDLINE, Cochrane Central Register of Controlled Trials, APA PsychINFO, Embase and Scopus) to identify relevant research articles that had been published. The Joanna Briggs Institute and the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews served as a guide for the scoping review. Study selection was made using the Covidence platform, screened, and extracted. Thirty-one studies were included in this review. Studies reviewed reported a significant positive association between physical inactivity, smoking, poor dietary patterns, working hours, clustering of lifestyle risk, and cardiovascular disease risk. Most interventions focused on physical activity and a multimodal lifestyle approach, significantly improving primary and secondary cardiovascular disease-related outcomes. The findings suggest improving lifestyle-related risk assessments and interventions to prevent cardiovascular diseases in this population. It is unclear if these outcomes can translate to higher effectiveness in preventing cardiovascular disease. Nevertheless, intervention using the multifaceted lifestyle approach can improve cardiovascular disease-related outcomes.

Primary prophylaxis with G-CSF for patients with non-round cell soft tissue sarcomas: a systematic review for the Clinical Practice Guidelines for the Use of G-CSF 2022 of the Japan Society of Clinical Oncology.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is an essential supportive agent for chemotherapy-induced severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, "Does primary prophylaxis with G-CSF benefit chemotherapy for non-round cell soft tissue sarcoma (NRC-STS)?" and CQ #2, "Does G-CSF-based intensified chemotherapy improve NRC-STS treatment outcomes?" for the Clinical Practice Guidelines for the Use of G-CSF 2022 of the Japan Society of Clinical Oncology. METHODS: A literature search was performed on the primary prophylactic use of G-CSF for NRC-STSs. Two reviewers assessed the extracted papers and analyzed overall survival, incidence of febrile neutropenia, infection-related mortality, quality of life, and pain. RESULTS: Eighty-one and 154 articles were extracted from the literature search for CQs #1 and #2, respectively. After the first and second screening, one and two articles were included in the final evaluation, respectively. Only some studies have addressed these two clinical questions through a literature review. CONCLUSION: The clinical questions were converted to future research questions because of insufficient available data. The statements were proposed: "The benefit of primary G-CSF prophylaxis is not clear in NRC-STS" and "The benefit of intensified chemotherapy with primary G-CSF prophylaxis is not clear in NRC-STSs." G-CSF is often administered as primary prophylaxis when chemotherapy with severe myelosuppression is administered. However, its effectiveness and safety are yet to be scientifically proven.

The role of statin therapy in older adults: best practices and unmet challenges.

INTRODUCTION: Cardiovascular disease (CVD) is associated with significant morbidity, functional decline, and mortality in older adults. The role of statins for primary CVD prevention in older adults remains unclear, largely due to systematic exclusion of these individuals in trials that inform current practice guidelines, leading to conflicting national and international practice recommendations for statin use for primary prevention of CVD in adults aged 75 and older. AREAS COVERED: In this narrative review, we performed a literature review utilizing PubMed, and ultimately focus on seven major national and international guidelines of lipid lowering therapy. Through the lens of two clinical cases, we review physiologic changes in lipid metabolism with aging, discuss the relationship between cholesterol and cardiovascular events in older adults, examine the national and international guidelines and the available evidence informing these guidelines for statin use in primary prevention of CVD in older adults. Finally we review practical clinical considerations for drug monitoring and deprescribing in this population. EXPERT OPINION: Guidelines for the use of statins for primary CVD prevention in older adults is conflicting. Collectively, evidence to date suggests statin therapy may be beneficial for primary CVD prevention in older adults free of life-limiting comorbidities. Randomized controlled trials are currently underway to address current evidence gaps.

One-Year Effects of High-Intensity Statin on Bioactive Lipids: Findings From the JUPITER Trial.

BACKGROUND: Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. This study aimed to investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. METHODS: Using a nontargeted mass spectrometry approach, over 11 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITERdiscovery (n=589) and JUPITERvalidation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate. RESULTS: We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. Concurrently, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an eicosapentaenoic acid-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features. CONCLUSIONS: Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction.

Advancements in risk stratification and management strategies in primary cardiovascular prevention.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for advancements in risk assessment and management strategies. Although significant progress has been made recently, identifying and managing apparently healthy individuals at a higher risk of developing atherosclerosis and those with subclinical atherosclerosis still poses significant challenges. Traditional risk assessment tools have limitations in accurately predicting future events and fail to encompass the complexity of the atherosclerosis trajectory. In this review, we describe novel approaches in biomarkers, genetics, advanced imaging techniques, and artificial intelligence that have emerged to address this gap. Moreover, polygenic risk scores and imaging modalities such as coronary artery calcium scoring, and coronary computed tomography angiography offer promising avenues for enhancing primary cardiovascular risk stratification and personalised intervention strategies. On the other hand, interventions aiming against atherosclerosis development or promoting plaque regression have gained attention in primary ASCVD prevention. Therefore, the potential role of drugs like statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, omega-3 fatty acids, antihypertensive agents, as well as glucose-lowering and anti-inflammatory drugs are also discussed. Since findings regarding the efficacy of these interventions vary, further research is still required to elucidate their mechanisms of action, optimize treatment regimens, and determine their long-term effects on ASCVD outcomes. In conclusion, advancements in strategies addressing atherosclerosis prevention and plaque regression present promising avenues for enhancing primary ASCVD prevention through personalised approaches tailored to individual risk profiles. Nevertheless, ongoing research efforts are imperative to refine these strategies further and maximise their effectiveness in safeguarding cardiovascular health.

Competing risks of monomorphic vs. non-monomorphic ventricular arrhythmias in primary prevention implantable cardioverter-defibrillator recipients: Global Electrical Heterogeneity and Clinical Outcomes (GEHCO) study.

AIMS: Ablation of monomorphic ventricular tachycardia (MMVT) has been shown to reduce shock frequency and improve survival. We aimed to compare cause-specific risk factors for MMVT and polymorphic ventricular tachycardia (PVT)/ventricular fibrillation (VF) and to develop predictive models. METHODS AND RESULTS: The multicentre retrospective cohort study included 2668 patients (age 63.1 ± 13.0 years; 23% female; 78% white; 43% non-ischaemic cardiomyopathy; left ventricular ejection fraction 28.2 ± 11.1%). Cox models were adjusted for demographic characteristics, heart failure severity and treatment, device programming, and electrocardiogram metrics. Global electrical heterogeneity was measured by spatial QRS-T angle (QRSTa), spatial ventricular gradient elevation (SVGel), azimuth, magnitude (SVGmag), and sum absolute QRST integral (SAIQRST). We compared the out-of-sample performance of the lasso and elastic net for Cox proportional hazards and the Fine-Gray competing risk model. During a median follow-up of 4 years, 359 patients experienced their first sustained MMVT with appropriate implantable cardioverter-defibrillator (ICD) therapy, and 129 patients had their first PVT/VF with appropriate ICD shock. The risk of MMVT was associated with wider QRSTa [hazard ratio (HR) 1.16; 95% confidence interval (CI) 1.01-1.34], larger SVGel (HR 1.17; 95% CI 1.05-1.30), and smaller SVGmag (HR 0.74; 95% CI 0.63-0.86) and SAIQRST (HR 0.84; 95% CI 0.71-0.99). The best-performing 3-year competing risk Fine-Gray model for MMVT [time-dependent area under the receiver operating characteristic curve (ROC(t)AUC) 0.728; 95% CI 0.668-0.788] identified high-risk (> 50%) patients with 75% sensitivity and 65% specificity, and PVT/VF prediction model had ROC(t)AUC 0.915 (95% CI 0.868-0.962), both satisfactory calibration. CONCLUSION: We developed and validated models to predict the competing risks of MMVT or PVT/VF that could inform procedural planning and future randomized controlled trials of prophylactic ventricular tachycardia ablation. CLINICAL TRIAL REGISTRATION: URL:www.clinicaltrials.gov Unique identifier:NCT03210883.

Inclusion of Rurality and Social Determinants of Health in Documents for the Primary Prevention of Type 2 Diabetes: A Systematic Review.

Purpose: The type 2 diabetes (T2D) burden is disproportionately concentrated in low- and middle-income economies, particularly among rural populations. The purpose of the systematic review was to evaluate the inclusion of rurality and social determinants of health (SDOH) in documents for T2D primary prevention. Methods: This systematic review is reported following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We searched 19 databases, from 2017-2023, for documents on rurality and T2D primary prevention. Furthermore, we searched online for documents from the 216 World Bank economies, categorized by high, upper-middle, lower-middle, and low income status. We extracted data on rurality and the ten World Health Organization SDOH. Two authors independently screened documents and extracted data. Findings: Based on 3318 documents (19 databases and online search), we selected 15 documents for data extraction. The 15 documents applied to 32 economies; 12 of 15 documents were from nongovernment sources, none was from low-income economies, and 10 of 15 documents did not define or describe rurality. Among the SDOH, income and social protection (SDOH 1) and social inclusion and nondiscrimination (SDOH 8) were mentioned in documents for 25 of 29 high-income economies, while food insecurity (SDOH 5) and housing, basic amenities, and the environment (SDOH 6) were mentioned in documents for 1 of 2 lower-middle-income economies. For U.S. documents, none of the authors was from institutions in noncore (most rural) counties. Conclusions: Overall, documents on T2D primary prevention had sparse inclusion of rurality and SDOH, with additional disparity based on economic status. Inclusion of rurality and/or SDOH may improve T2D primary prevention in rural populations.

Interactions between antiepileptic drugs and direct oral anticoagulants for primary and secondary stroke prevention.

INTRODUCTION: Direct oral anticoagulants (DOAC) are the guideline-recommended therapy for prevention of stroke in atrial fibrillation (AF) and venous thromboembolism. Since approximately 10% of patients using antiepileptic drugs (AED) also receive DOAC, aim of this review is to summarize data about drug-drug interactions (DDI) of DOAC with AED by using data from PubMed until December 2023. AREAS COVERED: Of 49 AED, only 16 have been investigated regarding DDI with DOAC by case reports or observational studies. No increased risk for stroke was reported only for topiramate, zonisamide, pregabalin, and gabapentin, whereas for the remaining 12 AED conflicting results regarding the risk for stroke and bleeding were found. Further 16 AED have the potential for pharmacodynamic or pharmacokinetic DDI, but no data regarding DOAC are available. For the remaining 17 AED it is unknown if they have DDI with DOAC. EXPERT OPINION: Knowledge about pharmacokinetic and pharmacodynamic DDI of AED and DOAC is limited and frequently restricted to in vitro and in vivo findings. Since no data about DDI with DOAC are available for 67% of AED and an increasing number of patients have a combined medication of DOAC and AED, there is an urgent need for research on this topic.

Implementation of a Pharmacist-Driven Aspirin Deprescribing Protocol Among Older Veterans in a Primary Care Setting.

Background Recent cardiovascular guideline updates recommend against the use of aspirin for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in older people. However, aspirin use remains common in this population. Objective To implement and evaluate the benefit of a pharmacist-driven aspirin deprescribing protocol compared with primary care provider (PCP) education-only in a primary care setting. Methods This prospective, cohort project targeted deprescribing for patients prescribed aspirin for primary prevention of ASCVD. Patients were included if they received primary care services at the Milwaukee Veterans Health Administration Medical Center (VHA) and were 70 years of age or older. Criteria for exclusion were aspirin obtained outside the VHA system, aspirin prescribed for a non-ASCVD-related condition, and/or a history of ASCVD. Active deprescribing by pharmacists and PCP education took place in the intervention group with PCP education only in the standard-of-care group. The primary outcome was the proportion of patients who had aspirin deprescribed in each group. Secondary outcomes included patient acceptability of the intervention and barriers to implementation. Results A total of 520 patients were prescribed aspirin in the intervention group versus 417 in the education-only group. Sixty-five patients met intervention criteria and were contacted for aspirin deprescribing. The pharmacist-led active deprescribing group led to a higher rate of aspirin deprescriptions versus the education-only group (54% vs 18%; P = 0.0001) for patients who met criteria. Conclusion A pharmacist-led aspirin deprescribing protocol within a primary care setting significantly decreased the number of aspirin prescriptions compared with PCP education only.

Pharmacist-Led Deprescribing of Aspirin in Older People in an Outpatient Setting.

Background In 2019, the American College of Cardiology and American Heart Association updated their joint guidelines stating low-dose aspirin should not be used on a routine basis for primary prevention of atherosclerotic cardiovascular disease (ASCVD) among people older than 70 years of age because of increased bleeding risk.1 In addition to these updated guidelines, a statement released by the US Preventive Services Task Force in April 2022 recommends against the initiation of low-dose aspirin for primary prevention of cardiovascular disease in people 60 years of age or older.² Despite these updated recommendations, aspirin continues to be a common medication older patients take, providing an opportunity for a clinical pharmacist deprescribing intervention. Objective To identify the role of a pharmacist-led aspirin deprescribing intervention within a safety-net health system in the outpatient setting. Methods This project included patients 70 years of age and older who had aspirin listed as an active medication without documented ASCVD. This project assessed aspirin deprescribing rates, time spent on pharmacist outreach, and reasons for patient and/or provider refusal to discontinue aspirin. Results One hundred thirty-one eligible patients were contacted. Of those, 78 (60%) patients discontinued aspirin after speaking with the pharmacist, and 8 patients discontinued aspirin after a clinical pharmacist recommendation to the patient's primary care provider (PCP). The median time spent on outreach was approximately eight minutes. Of the 6 patients who consented to the project but declined to discontinue aspirin therapy based on pharmacist intervention, 5 preferred to discuss the issue with their PCP, while 1 patient was told by an outside provider to take aspirin. Conclusion Results indicate the successful impact a clinical pharmacist may have in deprescribing aspirin in a high-risk population. These data may also suggest that an active and intentional approach to deprescribing is likely to be more effective than a written recommendation to providers.

Primary and secondary prevention of cervical cancer among Italian AFAB transgender people.

OBJECTIVE: Currently, available data on preventive measures for Human Papillomavirus (HPV) infection and cervical cancer in the transgender assigned female at birth (AFAB) community are extremely limited. Our aim was to analyze adherence to primary and secondary cervical cancer prevention screening programs among transgender AFAB people attending our gender clinic. METHODS: Transgender AFAB people attending our center were recruited. Anamnestic data were collected for each person through completion of a medical history form and medical records. Variables recorded included previous HPV vaccination, adherence to regional screening programs (Pap smear or HPV DNA test), subject age, duration of current or prior gender-affirming hormone therapy (GAHT) and whether gender affirmation surgery (GAS) with hysterectomy had been performed. Open questions regarding reasons for not undergoing screening tests were also included. RESULTS: In this cross-sectional study, 263 AFAB transgender people were included, with a mean age of 30.6 ± 10.5 years. GAS with hysterectomy had been performed on 37.6 % of these people. Of our participants, 71.7 % who were born after 1998 (the first cohort to receive HPV vaccination invitations in Italy) had been vaccinated for HPV. Seventy-four-point-nine percent of participants who were still eligible for cervical screening had never undergone Pap smear or HPV DNA testing, whereas those who had undergone at least one cervical screening had done so on average 4.2 ± 4.5 years ago. CONCLUSION: HPV vaccination prevalence in the AFAB transgender population born after 1998 is in line with the Italian AFAB general population. However, adherence to cervical cancer screening programs in the transgender AFAB population appears to be lower in comparison to the cisgender population. Further efforts are required from the medical community to enhance AFAB transgender people's adherence to HPV vaccination and to cervical screening.

New York Heart Association functional class and implantable cardioverter-defibrillator in non-ischaemic heart failure with reduced ejection fraction: Extended follow-up of the DANISH trial.

AIMS: Current guidelines recommend implantable cardioverter-defibrillator (ICD) therapy in patients with heart failure, a left ventricular ejection fraction of ≤35%, and New York Heart Association (NYHA) class II-III. However, the evidence regarding the benefit of primary prevention ICD is less consistent in patients with NYHA class III. We investigated the long-term effects of primary prevention ICD implantation according to NYHA class in an extended follow-up study of the DANISH trial. METHODS AND RESULTS: The DANISH trial randomized 1116 patients with non-ischaemic heart failure with reduced ejection fraction (HFrEF) to ICD implantation or usual care. Outcomes were analysed according to NYHA class at baseline (NYHA class II and III/IV). The primary outcome was all-cause mortality. Of the 1116 patients randomized in the DANISH trial, 597 (53.5%) were in NYHA class II at baseline, 505 (45.3%) in NYHA class III, and 14 (1.3%) in NYHA class IV. During a median follow-up of 9.5 years, NYHA class III/IV, compared with NYHA class II, were associated with a greater long-term rate of all-cause mortality (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.20-1.93) and cardiovascular death (HR 1.95 [1.47-2.60]). ICD implantation, compared with usual care, did not reduce the long-term rate of all-cause mortality (all participants: HR 0.89 [95% CI 0.74-1.08]; NYHA class II: HR 0.85 [0.64-1.13]; NYHA class III/IV: HR 0.89 [0.69-1.14]; pinteraction = 0.78) or cardiovascular death (all participants: HR 0.87 [95% CI 0.70-1.09]; NYHA class II: HR 0.78 [0.54-1.12]; NYHA class III/IV: HR 0.89 [0.67-1.19]; pinteraction = 0.58), irrespective of NYHA class. Similarly, NYHA class did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (all participants: HR 0.60 [95% CI 0.40-0.92]; NYHA class II: HR 0.73 [0.40-1.36]; NYHA class III/IV: HR 0.52 [0.29-0.94]; pinteraction = 0.39). CONCLUSIONS: In patients with non-ischaemic HFrEF, ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce sudden cardiovascular death, regardless of baseline NYHA class. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00542945.

Effects of primary or secondary prevention with vitamin A supplementation on clinically important outcomes: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

OBJECTIVES: This systematic review with meta-analyses of randomised trials evaluated the preventive effects of vitamin A supplements versus placebo or no intervention on clinically important outcomes, in people of any age. METHODS: We searched different electronic databases and other resources for randomised clinical trials that had compared vitamin A supplements versus placebo or no intervention (last search 16 April 2024). We used Cochrane methodology. We used the random-effects model to calculate risk ratios (RRs), with 95% CIs. We analysed individually and cluster randomised trials separately. Our primary outcomes were mortality, adverse events and quality of life. We assessed risks of bias in the trials and used Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) to assess the certainty of the evidence. RESULTS: We included 120 randomised trials (1 671 672 participants); 105 trials allocated individuals and 15 allocated clusters. 92 trials included children (78 individually; 14 cluster randomised) and 28 adults (27 individually; 1 cluster randomised). 14/105 individually randomised trials (13%) and none of the cluster randomised trials were at overall low risk of bias. Vitamin A did not reduce mortality in individually randomised trials (RR 0.99, 95% CI 0.93 to 1.05; I²=32%; p=0.19; 105 trials; moderate certainty), and this effect was not affected by the risk of bias. In individually randomised trials, vitamin A had no effect on mortality in children (RR 0.96, 95% CI 0.88 to 1.04; I²=24%; p=0.28; 78 trials, 178 094 participants) nor in adults (RR 1.04, 95% CI 0.97 to 1.13; I²=24%; p=0.27; 27 trials, 61 880 participants). Vitamin A reduced mortality in the cluster randomised trials (0.84, 95% CI 0.76 to 0.93; I²=66%; p=0.0008; 15 trials, 14 in children and 1 in adults; 364 343 participants; very low certainty). No trial reported serious adverse events or quality of life. Vitamin A slightly increased bulging fontanelle of neonates and infants. We are uncertain whether vitamin A influences blindness under the conditions examined. CONCLUSIONS: Based on moderate certainty of evidence, vitamin A had no effect on mortality in the individually randomised trials. Very low certainty evidence obtained from cluster randomised trials suggested a beneficial effect of vitamin A on mortality. If preventive vitamin A programmes are to be continued, supporting evidence should come from randomised trials allocating individuals and assessing patient-meaningful outcomes. PROSPERO REGISTRATION NUMBER: CRD42018104347.

Lack of Prognostic Value of T-Wave Alternans for Implantable Cardioverter-Defibrillator Benefit in Primary Prevention.

BACKGROUND: New methods to identify patients who benefit from a primary prophylactic implantable cardioverter-defibrillator (ICD) are needed. T-wave alternans (TWA) has been shown to associate with arrhythmogenesis of the heart and sudden cardiac death. We hypothesized that TWA might be associated with benefit from ICD implantation in primary prevention. METHODS AND RESULTS: In the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter-Defibrillators) study, we prospectively enrolled 2327 candidates for primary prophylactic ICD. A 24-hour Holter monitor reading was taken from all recruited patients at enrollment. TWA was assessed from Holter monitoring using the modified moving average method. Study outcomes were all-cause death, appropriate shock, and survival benefit. TWA was assessed both as a contiguous variable and as a dichotomized variable with cutoff points <47 µV and <60 µV. The final cohort included 1734 valid T-wave alternans samples, 1211 patients with ICD, and 523 control patients with conservative treatment, with a mean follow-up time of 2.3 years. TWA ≥60 µV was a predicter for a higher all-cause death in patients with an ICD on the basis of a univariate Cox regression model (hazard ratio, 1.484 [95% CI, 1.024-2.151]; P=0.0374; concordance statistic, 0.51). In multivariable models, TWA was not prognostic of death or appropriate shocks in patients with an ICD. In addition, TWA was not prognostic of death in control patients. In a propensity score-adjusted Cox regression model, TWA was not a predictor of ICD benefit. CONCLUSIONS: T-wave alternans is poorly prognostic in patients with a primary prophylactic ICD. Although it may be prognostic of life-threatening arrhythmias and sudden cardiac death in several patient populations, it does not seem to be useful in assessing benefit from ICD therapy in primary prevention among patients with an ejection fraction of ≤35%.