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.

Eliciting and prioritising determinants of improved care in multimorbidity: A modified online Delphi study.

Background: Multimorbidity is a major challenge to health and social care systems around the world. There is limited research exploring the wider contextual determinants that are important to improving care for this cohort. In this study, we aimed to elicit and prioritise determinants of improved care in people with multiple conditions. Methods: A three-round online Delphi study was conducted in England with health and social care professionals, data scientists, researchers, people living with multimorbidity and their carers. Results: Our findings suggest a care system which is still predominantly single condition focused. 'Person-centred and holistic care' and 'coordinated and joined up care', were highly rated determinants in relation to improved care for multimorbidity. We further identified a range of non-medical determinants that are important to providing holistic care for this cohort. Conclusions: Further progress towards a holistic and patient-centred model is needed to ensure that care more effectively addresses the complex range of medical and non-medical needs of people living with multimorbidity. This requires a move from a single condition focused biomedical model to a person-based biopsychosocial approach, which has yet to be achieved.

Reducing Premature Coronary Artery Disease in Malaysia by Early Identification of Familial Hypercholesterolemia Using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT): Protocol for a Mixed Methods Evaluation Study.

BACKGROUND: Familial hypercholesterolemia (FH) is predominantly caused by mutations in the 4 FH candidate genes (FHCGs), namely, low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB-100), proprotein convertase subtilisin/kexin type 9 (PCSK9), and the LDL receptor adaptor protein 1 (LDLRAP1). It is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels leading to premature coronary artery disease. FH can be clinically diagnosed using established clinical criteria, namely, Simon Broome (SB) and Dutch Lipid Clinic Criteria (DLCC), and can be identified using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT), a primary care screening tool. OBJECTIVE: This study aims to (1) compare the detection rate of genetically confirmed FH and diagnostic accuracy between the FAMCAT, SB, and DLCC in the Malaysian primary care setting; (2) identify the genetic mutation profiles, including novel variants, in individuals with suspected FH in primary care; (3) explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing in primary care; and (4) evaluate the clinical utility of a web-based FH Identification Tool that includes the FAMCAT, SB, and DLCC in the Malaysian primary care setting. METHODS: This is a mixed methods evaluation study conducted in 11 Ministry of Health primary care clinics located at the central administrative region of Malaysia. In Work stream 1, the diagnostic accuracy study design is used to compare the detection rate and diagnostic accuracy of the FAMCAT, SB, and DLCC against molecular diagnosis as the gold standard. In Work stream 2, the targeted next-generation sequencing of the 4 FHCGs is used to identify the genetic mutation profiles among individuals with suspected FH. In Work stream 3a, a qualitative semistructured interview methodology is used to explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing. Lastly, in Work stream 3b, a qualitative real-time observation of primary care physicians using the "think-aloud" methodology is applied to evaluate the clinical utility of a web-based FH Identification Tool. RESULTS: The recruitment for Work stream 1, and blood sampling and genetic analysis for Work stream 2 were completed in February 2023. Data collection for Work stream 3 was completed in March 2023. Data analysis for Work streams 1, 2, 3a, and 3b is projected to be completed by June 2023, with the results of this study anticipated to be published by December 2023. CONCLUSIONS: This study will provide evidence on which clinical diagnostic criterion is the best to detect FH in the Malaysian primary care setting. The full spectrum of genetic mutations in the FHCGs including novel pathogenic variants will be identified. Patients' perspectives while undergoing genetic testing and the primary care physicians experience in utilizing the web-based tool will be established. These findings will have tremendous impact on the management of patients with FH in primary care and subsequently reduce their risk of premature coronary artery disease. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47911.

Identifying Patients with Bicuspid Aortic Valve Disease in UK Primary Care: A Case-Control Study and Prediction Model.

Bicuspid aortic valve disease (BAV) is the most common congenital heart condition, and early detection can improve outcomes for patients. In this case−control study, patients with a diagnosis of BAV were identified from their electronic primary-care records in the UK's Clinical Practice Research Datalink (CPRD). Each case was propensity-score matched to up to five controls. The clinical features recorded before diagnosis were compared. The proposed clinical features shown to be associated with BAV (p < 0.05) were incorporated into a multivariable regression model. We identified 2898 cases. The prevalence of BAV in the CPRD was 1 in 5181, significantly lower than expected, suggesting that diagnosis and/or recording could be improved. The following biologically plausible clinical features were associated with a subsequent diagnosis of BAV: palpitations (OR: 2.86 (95% CI: 1.60, 3.16)), atrial fibrillation (AF) (OR: 2.25 (95% CI: 1.60, 3.16)) and hypertension (OR: 1.72 (1.48, 2.00)). The best model had an AUC of 0.669 (95% CI: 0.658 to 0.680), a positive predictive value (PPV) of 5.9% (95% CI: 4.0% to 8.7%) and a negative predictive value (NPV) of 99% (95% CI: 99% to 99%) at a population prevalence of 1%. This study indicates that palpitations, hypertension and AF should trigger a clinical suspicion of BAV and assessment via echocardiography. It also demonstrates the potential to develop a prediction model for BAV to stratify patients for echocardiography screening.

Understanding social care need through primary care big data: a rapid scoping review.

BACKGROUND: A more comprehensive understanding and measurement of adult social care need could contribute to efforts to develop more effective, holistic personalised care, particularly for those with multiple long-term conditions (MLTC). Progress in this area faces the challenge of a lack of clarity in the literature relating to how social care need is assessed and coded within variables included in primary care databases. AIM: To explore how social care need is assessed and coded within variables included in primary care databases. DESIGN & SETTING: An exploratory rapid scoping review of peer-reviewed articles and grey literature. METHOD: Articles were screened and extracted onto a charting sheet and findings were summarised descriptively. Articles were included if published in English and related to primary and social care using data from national primary care databases. RESULTS: The search yielded 4010 articles. Twenty-seven were included. Six articles used the term 'social care need', although related terminology was identified including 'need factors', 'social support', and 'social care support'. Articles mainly focused on specific components of social care need, including levels of social care usage or service utilisation and costs incurred to social care, primary care, and other providers in addressing needs. A limited range of database variables were found measuring social care need. CONCLUSION: Further research is needed on how social care need has been defined in a UK context and captured in primary care big databases. There is potential scope to broaden the definition of social care need, which captures social service needs and wider social needs.

Sex disparity in subsequent outcomes in survivors of coronary heart disease.

OBJECTIVE: Evidence on sex differences in outcomes after developing coronary heart disease (CHD) has focused on recurrent CHD, all-cause mortality or revascularisation. We assessed sex disparities in subsequent major adverse cardiovascular events (MACE) in adults surviving their first-time CHD. METHODS: Using a population-based cohort obtained from the Clinical Practice Research Datalink (CPRD GOLD) linked to hospitalisation and death records in the UK, we identified 143 702 adults (aged ≥18 years) between 1 January 1998 and 31 December 2017 with no prior history of MACE. MACE outcome was a composite of recurrent CHD, stroke, peripheral vascular disease, heart failure and cardiovascular-related mortality. Multivariable models (Cox and competing risks regressions) were used to assess differences between sexes. RESULTS: There were 143 702 adults with any incident CHD (either angina, myocardial infarction or coronary revascularisation). Women (n=63 078, 43.9%) were older than men (median age, 73 vs 66 years). First subsequent MACE outcome was observed in 91 706 (63.8%). Women had a significantly lower risk of MACE (hazard ratio (HR), 0.68 (95% CI 0.67 to 0.69); sub-hazard ratio (HRsd), 0.71 (0.70 to 0.72), respectively) and recurrent CHD (n=66 543, 46.3%) (HR, 0.60 (0.59 to 0.61); HRsd, 0.62 (0.61 to 0.63)) when compared with men after incident CHD. However, women had a significantly higher risk of stroke (n=5740, 4.0%) (HR, 1.26 (1.19 to 1.33); HRsd, 1.32 (1.25 to 1.39)), heart failure (n=7905, 5.5%) (HR, 1.09 (1.04 to 1.15); HRsd, 1.13 (1.07 to 1.18)) and all-cause mortality (n=29 503, 20.5%) (HR, 1.05 (1.02 to 1.07); HRsd, 1.11 (1.08 to 1.13)). CONCLUSIONS: After incident CHD, women have lower risk of composite MACE and recurrent CHD outcomes but higher risk of stroke, heart failure, and all-cause mortality compared with men.

Determining propensity for sub-optimal low-density lipoprotein cholesterol response to statins and future risk of cardiovascular disease.

BACKGROUND: Variability in low-density lipoprotein cholesterol (LDL-C) response to statins is underappreciated. We characterised patients by their statin response (SR), baseline risk of cardiovascular disease (CVD) and 10-year CVD outcomes. METHODS AND RESULTS: A multivariable model was developed using 183,213 United Kingdom (UK) patients without CVD to predict probability of sub-optimal SR, defined by guidelines as <40% reduction in LDL-C. We externally validated the model in a Hong Kong (HK) cohort (n = 170,904). Patients were stratified into four groups by predicted SR and 10-year CVD risk score: [SR1] optimal SR & low risk; [SR2] sub-optimal SR & low risk; [SR3] optimal SR & high risk; [SR4] sub-optimal SR & high risk; and 10-year hazard ratios (HR) determined for first major adverse cardiovascular event (MACE). Our SR model included 12 characteristics, with an area under the curve of 0.70 (95% confidence interval [CI] 0.70-0.71; UK) and 0.68 (95% CI 0.67-0.68; HK). HRs for MACE in predicted sub-optimal SR with low CVD risk groups (SR2 to SR1) were 1.39 (95% CI 1.35-1.43, p<0.001; UK) and 1.14 (95% CI 1.11-1.17, p<0.001; HK). In both cohorts, patients with predicted sub-optimal SR with high CVD risk (SR4 to SR3) had elevated risk of MACE (UK HR 1.36, 95% CI 1.32-1.40, p<0.001: HK HR 1.25, 95% CI 1.21-1.28, p<0.001). CONCLUSIONS: Patients with sub-optimal response to statins experienced significantly more MACE, regardless of baseline CVD risk. To enhance cholesterol management for primary prevention, statin response should be considered alongside risk assessment.

Case-finding and genetic testing for familial hypercholesterolaemia in primary care.

OBJECTIVE: Familial hypercholesterolaemia (FH) is a common inherited disorder that remains mostly undetected in the general population. Through FH case-finding and direct access to genetic testing in primary care, this intervention study described the genetic and lipid profile of patients found at increased risk of FH and the outcomes in those with positive genetic test results. METHODS: In 14 Central England general practices, a novel case-finding tool (Familial Hypercholetserolaemia Case Ascertainment Tool, FAMCAT1) was applied to the electronic health records of 86 219 patients with cholesterol readings (44.5% of total practices' population), identifying 3375 at increased risk of FH. Of these, a cohort of 336 consenting to completing Family History Questionnaire and detailed review of their clinical data, were offered FH genetic testing in primary care. RESULTS: Genetic testing was completed by 283 patients, newly identifying 16 with genetically confirmed FH and 10 with variants of unknown significance. All 26 (9%) were recommended for referral and 19 attended specialist assessment. In a further 153 (54%) patients, the test suggested polygenic hypercholesterolaemia who were managed in primary care. Total cholesterol and low-density lipoprotein-cholesterol levels were higher in those patients with FH-causing variants than those with other genetic test results (p=0.010 and p=0.002). CONCLUSION: Electronic case-finding and genetic testing in primary care could improve identification of FH; and the better targeting of patients for specialist assessment. A significant proportion of patients identified at risk of FH are likely to have polygenic hypercholesterolaemia. There needs to be a clearer management plan for these individuals in primary care. TRIAL REGISTRATION NUMBER: NCT03934320.

Lipid levels and major adverse cardiovascular events in patients initiated on statins for primary prevention: an international population-based cohort study protocol.

BACKGROUND: Clinical guidelines recommend specific targets for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) for primary prevention of cardiovascular disease (CVD). Furthermore, individual variability in lipid response to statin therapy requires assessment of the association in diverse populations. AIM: To assess whether lower concentrations of LDL-C and non-HDL-C are associated with a reduced risk of major adverse cardiovascular events (MACE) in primary prevention of CVD. DESIGN & SETTING: An international, new-user, cohort study will be undertaken. It will use data from three electronic health record databases from three global regions: Clinical Practice Research Datalink, UK; PREDICT-CVD, New Zealand (NZ); and the Clinical Data and Analysis Reporting System, Hong Kong (HK). METHOD: New statin users without a history of atherosclerotic CVD, heart failure, or chronic kidney disease, with baseline and follow-up lipid levels will be eligible for inclusion. Patients will be classified according to LDL-C (<1.4, 1.4-1.7, 1.8-2.5, and ≥2.6 mmol/l) and non-HDL-C (<2.2, 2.2-2.5, 2.6-3.3, and ≥3.4 mmol/l) concentrations 24 months after initiating statin therapy. The primary outcome of interest is MACE, defined as the first occurrence of coronary heart disease, stroke, or cardiovascular death. Secondary outcomes include all-cause mortality and the individual components of MACE. Sensitivity analyses will be conducted using lipid levels at 3 and 12 months after starting statin therapy. CONCLUSION: Results will inform clinicians about the benefits of achieving guideline recommended concentrations of LDL-C for primary prevention of CVD.

Nasal fentanyl alone plus buccal midazolam: an open-label, randomised, controlled feasibility study in the dying.

INTRODUCTION: Many patients want to stay at home to die. They invariably become unable to take oral medication during their terminal phase. Symptoms are usually controlled by subcutaneous medications. There have been no studies on nasal fentanyl (NF) or buccal midazolam (BM) to control symptoms in the dying. OBJECTIVE: To establish how best to conduct a definitive, randomised controlled trial (RCT) to determine whether NF and BM administered by families, for patients dying at home, lead to faster and better symptom control and fewer community nursing visits than standard breakthrough medication by healthcare professionals. METHODS: This open-label mixed-method feasibility RCT compared the efficacy of NF and BM by family members to standard breakthrough medication by nurses for the terminally ill in a specialist palliative care unit. Partway through the study, a third observational arm was introduced where BM alone was used. The primary outcomes were whether recruitment and randomisation were possible, assessment of withdrawal and drop-out, and whether the methods were acceptable and appropriate. RESULTS: Administration of NF and BM was acceptable to patients and families. Both were well tolerated. We were unable to obtain quality of life data consistently but did get time period data for dose-controlled symptoms. CONCLUSIONS: Study participation in a hospice population of the dying was acceptable. The results will help guide future community study planning. TRIAL REGISTRATION NUMBER: NCT02009306.

Predicting fracture risk in patients with chronic obstructive pulmonary disease: a UK-based population-based cohort study.

OBJECTIVE: To assess the incidence of hip fracture and all major osteoporotic fractures (MOF) in patients with chronic obstructive pulmonary disease (COPD) compared with non-COPD patients and to evaluate the use and performance of fracture risk prediction tools in patients with COPD. To assess the prevalence and incidence of osteoporosis. DESIGN: Population-based cohort study. SETTING: UK General Practice health records from The Health Improvement Network database. PARTICIPANTS: Patients with an incident COPD diagnosis from 2004 to 2015 and non-COPD patients matched by age, sex and general practice were studied. OUTCOMES: Incidence of fracture (hip alone and all MOF); accuracy of fracture risk prediction tools in COPD; and prevalence and incidence of coded osteoporosis. METHODS: Cox proportional hazards models were used to assess the incidence rates of osteoporosis, hip fracture and MOF (hip, proximal humerus, forearm and clinical vertebral fractures). The discriminatory accuracies (area under the receiver operating characteristic [ROC] curve) of fracture risk prediction tools (FRAX and QFracture) in COPD were assessed. RESULTS: Patients with COPD (n=80 874) were at an increased risk of fracture (both hip alone and all MOF) compared with non-COPD patients (n=308 999), but this was largely mediated through oral corticosteroid use, body mass index and smoking. Retrospectively calculated ROC values for MOF in COPD were as follows: FRAX: 71.4% (95% CI 70.6% to 72.2%), QFracture: 61.4% (95% CI 60.5% to 62.3%) and for hip fracture alone, both 76.1% (95% CI 74.9% to 77.2%). Prevalence of coded osteoporosis was greater for patients (5.7%) compared with non-COPD patients (3.9%), p<0.001. The incidence of osteoporosis was increased in patients with COPD (n=73 084) compared with non-COPD patients (n=264 544) (adjusted hazard ratio, 1.13, 95% CI 1.05 to 1.22). CONCLUSION: Patients with COPD are at an increased risk of fractures and osteoporosis. Despite this, there is no systematic assessment of fracture risk in clinical practice. Fracture risk tools identify those at high risk of fracture in patients with COPD.

Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease.

OBJECTIVE: To assess low-density lipoprotein cholesterol (LDL-C) response in patients after initiation of statins, and future risk of cardiovascular disease (CVD). METHODS: Prospective cohort study of 165 411 primary care patients, from the UK Clinical Practice Research Datalink, who were free of CVD before statin initiation, and had at least one pre-treatment LDL-C within 12 months before, and one post-treatment LDL-C within 24 months after, statin initiation. Based on current national guidelines, <40% reduction in baseline LDL-C within 24 months was classified as a sub-optimal statin response. Cox proportional regression and competing-risks survival regression models were used to determine adjusted hazard ratios (HRs) and sub-HRs for incident CVD outcomes for LDL-C response to statins. RESULTS: 84 609 (51.2%) patients had a sub-optimal LDL-C response to initiated statin therapy within 24 months. During 1 077 299 person-years of follow-up (median follow-up 6.2 years), there were 22 798 CVD events (12 142 in sub-optimal responders and 10 656 in optimal responders). In sub-optimal responders, compared with optimal responders, the HR for incident CVD was 1.17 (95% CI 1.13 to 1.20) and 1.22 (95% CI 1.19 to 1.25) after adjusting for age and baseline untreated LDL-C. Considering competing risks resulted in lower but similar sub-HRs for both unadjusted (1.13, 95% CI 1.10 to 1.16) and adjusted (1.19, 95% CI 1.16 to 1.23) cumulative incidence function of CVD. CONCLUSIONS: Optimal lowering of LDL-C is not achieved within 2 years in over half of patients in the general population initiated on statin therapy, and these patients will experience significantly increased risk of future CVD.