Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients.

BACKGROUND: Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. RESULTS: A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels. CONCLUSIONS: Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).

Efficacy and safety of a novel low-dose triple single-pill combination of telmisartan, amlodipine and indapamide, compared with dual combinations for treatment of hypertension: a randomised, double-blind, active-controlled, international clinical trial.

BACKGROUND: Single-pill combinations (SPCs) of three low-dose antihypertensive drugs can improve hypertension control but are not widely available. A key issue for any combination product is the contribution of each component to efficacy and tolerability. This trial compared a new triple SPC called GMRx2, containing telmisartan, amlodipine, and indapamide, with dual combinations of components for efficacy and safety. METHODS: In this international, randomised, double-blind, active-controlled trial, we enrolled adults with hypertension receiving between zero and three antihypertensive drugs, with a screening systolic blood pressure (SBP) ranging from 140-179 mm Hg (on no drugs) to 110-150 mm Hg (on three drugs). Participants were recruited from Australia, the Czech Republic, New Zealand, Poland, Sri Lanka, the UK, and the USA. In a 4-week active run-in, existing medications were switched to GMRx2 half dose (telmisartan 20 mg, amlodipine 2·5 mg, and indapamide 1·25 mg). Participants were then randomly allocated (2:1:1:1) to continued GMRx2 half dose or to each possible dual combination of components at half doses (telmisartan 20 mg with amlodipine 2·5 mg, telmisartan 20 mg with indapamide 1·25 mg, or amlodipine 2·5 mg with indapamide 1·25 mg). At week 6, doses were doubled in all groups, unless there was a clinical contraindication. The primary efficacy outcome was mean change in home SBP from baseline to week 12, and the primary safety outcome was withdrawal of treatment due to an adverse event from baseline to week 12. Secondary efficacy outcomes included differences in clinic and home blood pressure levels and control rates. This study is registered with ClinicalTrials.gov, NCT04518293, and is completed. FINDINGS: The trial was conducted between July 9, 2021 and Sept 1, 2023. We randomly allocated 1385 participants to four groups: 551 to GMRx2, 276 to telmisartan-indapamide, 282 to telmisartan-amlodipine, and 276 to amlodipine-indapamide groups. The mean age was 59 years (SD 11), 712 (51%) participants self-reported as female and 673 (48·6%) male, and the mean clinic blood pressure at the screening visit was 142/85 mm Hg when taking an average of 1·6 blood pressure medications. Following the run-in on GMRx2 half dose, the mean clinic blood pressure level at randomisation was 133/81 mm Hg and the mean home blood pressure level was 129/78 mm Hg. At week 12, the mean home SBP was 126 mm Hg in the GMRx2 group, which was lower than for each of the dual combinations: -2·5 (95% CI -3·7 to -1·3, p<0·0001) versus telmisartan-indapamide, -5·4 (-6·8 to -4·1, p<0·0001) versus telmisartan-amlodipine, and -4·4 (-5·8 to -3·1, p<0·0001) versus amlodipine-indapamide. For the same comparisons, differences in clinic blood pressure at week 12 were 4·3/3·5 mm Hg, 5·6/3·7 mm Hg, and 6·3/4·5 mm Hg (all p<0·001). Clinic blood pressure control rate below 140/90 mm Hg at week 12 was superior with GMRx2 (74%) to with each dual combination (range 53-61%). Withdrawal of treatment due to adverse events occurred in 11 (2%) participants in the GMRx2 group, four (1%) in telmisartan-indapamide, three (1%) in telmisartan-amlodipine, and four (1%) in amlodipine-indapamide, with none of the differences being statistically significant. INTERPRETATION: A novel low-dose SPC product of telmisartan, amlodipine, and indapamide provided clinically meaningful improvements in blood pressure reduction compared with dual combinations and was well tolerated. This SPC provides a new therapeutic option for the management of hypertension and its use could result in a substantial improvement in blood pressure control in clinical practice. FUNDING: George Medicines.

Metabolic dysfunction-associated steatotic liver disease and the heart.

The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing. Physicians who treat patients with MASLD may acknowledge the strong coincidence with cardiometabolic disease, including atherosclerotic cardiovascular disease (asCVD). This raises questions on co-occurrence, causality, and the need for screening and multidisciplinary care for MASLD in patients with asCVD, and vice versa. Here, we review the interrelations of MASLD and heart disease and formulate answers to these matters. Epidemiological studies scoring proxies for atherosclerosis and actual cardiovascular events indicate increased atherosclerosis in patients with MASLD, yet no increased risk of asCVD mortality. MASLD and asCVD share common drivers: obesity, insulin resistance and type 2 diabetes mellitus (T2DM), smoking, hypertension, and sleep apnea syndrome. In addition, Mendelian randomization studies support that MASLD may cause atherosclerosis through mixed hyperlipidemia, while such evidence is lacking for liver-derived procoagulant factors. In the more advanced fibrotic stages, MASLD may contribute to heart failure with preserved ejection fraction by reduced filling of the right ventricle, which may induce fatigue upon exertion, often mentioned by patients with MASLD. Some evidence points to an association between MASLD and cardiac arrhythmias. Regarding treatment and given the strong co-occurrence of MASLD and asCVD, pharmacotherapy in development for advanced stages of MASLD would ideally also reduce cardiovascular events, as has been demonstrated for T2DM treatments. Given the common drivers, potential causal factors and especially given the increased rate of cardiovascular events, comprehensive cardiometabolic risk management is warranted in patients with MASLD, preferably in a multidisciplinary approach.

Cardiovascular and Renal Treatment in Heart Failure Patients With Hyperkalemia or High Risk of Hyperkalemia: Rationale and Design of the CARE-HK in HF Registry.

BACKGROUND: Despite guideline recommendations, many patients with heart failure (HF) do not receive target dosages of renin-angiotensin-aldosterone system inhibitors (RAASis) in clinical practice due, in part, to concerns about hyperkalemia (HK). METHODS AND RESULTS: This noninterventional, multinational, multicenter registry (NCT04864795; 111 sites in Europe and the USA) enrolled 2558 eligible adults with chronic HF (mostly with reduced ejection fraction [HFrEF]). Eligibility criteria included use of angiotensin-converting-enzyme inhibitor/angiotensin-II receptor blocker/angiotensin-receptor-neprilysin inhibitor, being a candidate for or treatment with a mineralocorticoid receptor antagonist, and increased risk of HK (eg, current serum potassium > 5.0 mmol/L), history of HK in the previous 24 months, or estimated glomerular filtration rate < 45 mL/min/1.73 m2). Information on RAASi and other guideline-recommended therapies was collected retrospectively and prospectively (≥ 6 months). Patients were followed according to local clinical practice, without study-specific visits or interventions. The main objectives were to characterize RAASi treatment patterns compared with guideline recommendations, describe RAASi modifications following episodes of HK, and describe RAASi treatment in patients treated with patiromer. Baseline characteristics for the first 1000 patients are presented. CONCLUSIONS: CARE-HK is a multinational prospective HF registry designed to report on the management and outcomes of patients with HF at high risk for HK in routine clinical practice.

The association of obesogenic environments with weight status, blood pressure, and blood lipids: A cross-sectional pooled analysis across five cohorts.

In this observational cross-sectional study, we investigated the relationship between combined obesogenic neighbourhood characteristics and various cardiovascular disease risk factors in adults, including BMI, systolic blood pressure, and blood lipids, as well as the prevalence of overweight/obesity, hypertension, and dyslipidaemia. We conducted a large-scale pooled analysis, comprising data from five Dutch cohort studies (n = 183,871). Neighbourhood obesogenicity was defined according to the Obesogenic Built-environmental CharacterisTics (OBCT) index. The index was calculated for 1000m circular buffers around participants' home addresses. For each cohort, the association between the OBCT index and prevalence of overweight/obesity, hypertension and dyslipidaemia was analysed using robust Poisson regression models. Associations with continuous measures of BMI, systolic blood pressure, LDL-cholesterol, HDL-cholesterol, and triglycerides were analysed using linear regression. All models were adjusted for age, sex, education level and area-level socio-economic status. Cohort-specific estimates were pooled using random-effects meta-analyses. The pooled results show that a 10 point higher OBCT index score was significantly associated with a 0.17 higher BMI (95%CI: 0.10 to 0.24), a 0.01 higher LDL-cholesterol (95% CI: 0.01 to 0.02), a 0.01 lower HDL cholesterol (95% CI: -0.02 to -0.01), and non-significantly associated with a 0.36 mmHg higher systolic blood pressure (95%CI: -0.14 to 0.65). A 10 point higher OBCT index score was also associated with a higher prevalence of overweight/obesity (PR = 1.03; 95% CI: 1.02 to 1.05), obesity (PR = 1.04; 95% CI: 1.01 to 1.08) and hypertension (PR = 1.02; 95% CI: 1.00 to 1.04), but not with dyslipidaemia. This large-scale pooled analysis of five Dutch cohort studies shows that higher neighbourhood obesogenicity, as measured by the OBCT index, was associated with higher BMI, higher prevalence of overweight/obesity, obesity, and hypertension. These findings highlight the importance of considering the obesogenic environment as a potential determinant of cardiovascular health.

Perinatal exposure to traffic related air pollutants and the risk of infection in the first six months of life: a cohort study from a low-middle income country.

OBJECTIVE: There is limited study from low-and-middle income countries on the effect of perinatal exposure to air pollution and the risk of infection in infant. We assessed the association between perinatal exposure to traffic related air pollution and the risk of infection in infant during their first six months of life. METHODS: A prospective cohort study was performed in Jakarta, March 2016-September 2020 among 298 mother-infant pairs. PM2.5, soot, NOx, and NO2 concentrations were assessed using land use regression models (LUR) at individual level. Repeated interviewer-administered questionnaires were used to obtain data on infection at 1, 2, 4 and 6 months of age. The infections were categorized as upper respiratory tract (runny nose, cough, wheezing or shortness of breath), lower respiratory tract (pneumonia, bronchiolitis) or gastrointestinal tract infection. Logistic regression models adjusted for covariates were used to assess the association between perinatal exposure to air pollution and the risk of infection in the first six months of life. RESULTS: The average concentrations of PM2.5 and NO2 were much higher than the WHO recommended levels. Upper respiratory tract infections (URTI) were much more common in the first six months of life than diagnosed lower respiratory tract or gastro-intestinal infections (35.6%, 3.5% and 5.8% respectively). Perinatal exposure to PM2.5 and soot suggested increase cumulative risk of upper respiratory tract infection (URTI) in the first 6 months of life per IQR increase with adjusted OR of 1.50 (95% CI 0.91; 2.47) and 1.14 (95% CI 0.79; 1.64), respectively. Soot was significantly associated with the risk of URTI at 4-6 months age interval (aOR of 1.45, 95%CI 1.02; 2.09). All air pollutants were also positively associated with lower respiratory tract infection, but all CIs include unity because of relatively small samples. Adjusted odds ratios for gastrointestinal infections were close to unity. CONCLUSION: Our study adds to the evidence that perinatal exposure to fine particles is associated with respiratory tract infection in infants in a low-middle income country.

Physiological Response to the COVID-19 Vaccine: Insights From a Prospective, Randomized, Single-Blinded, Crossover Trial.

BACKGROUND: Rapid development and implementation of vaccines constituted a crucial step in containing the COVID-19 pandemic. A comprehensive understanding of physiological responses to these vaccines is important to build trust in medicine. OBJECTIVE: This study aims to investigate temporal dynamics before and after COVID-19 vaccination in 4 physiological parameters as well as the duration of menstrual cycle phases. METHODS: In a prospective trial, 17,825 adults in the Netherlands wore a medical device on their wrist for up to 9 months. The device recorded their physiological signals and synchronized with a complementary smartphone app. By means of multilevel quadratic regression, we examined changes in wearable-recorded breathing rate, wrist skin temperature, heart rate, heart rate variability, and objectively assessed the duration of menstrual cycle phases in menstruating participants to assess the effects of COVID-19 vaccination. RESULTS: The recorded physiological signals demonstrated short-term increases in breathing rate and heart rate after COVID-19 vaccination followed by a prompt rebound to baseline levels likely reflecting biological mechanisms accompanying the immune response to vaccination. No sex differences were evident in the measured physiological responses. In menstruating participants, we found a 0.8% decrease in the duration of the menstrual phase following vaccination. CONCLUSIONS: The observed short-term changes suggest that COVID-19 vaccines are not associated with long-term biophysical issues. Taken together, our work provides valuable insights into continuous fluctuations of physiological responses to vaccination and highlights the importance of digital solutions in health care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-021-05241-5.

Applicability of European Society of Cardiology guidelines according to gross national income.

AIMS: To assess the feasibility to comply with the recommended actions of ESC guidelines on general cardiology areas in 102 countries and assess how compliance relates to the country's income level. METHODS AND RESULTS: All recommendations from seven ESC guidelines on general cardiology areas were extracted and labelled on recommended actions. A survey was sent to all 102 ESC national and affiliated cardiac societies (NCSs). Respondents were asked to score recommended actions on their availability in clinical practice on a four-point Likert scale (fully available, mostly/often available, mostly/often unavailable, fully unavailable), and select the top three barriers perceived as being responsible for limiting their national availability. Applicability was assessed overall, per World Bank gross national income (GNI) level, and per guideline.A total of 875 guideline recommendations on general cardiology was extracted. Responses were received from 64 of 102 (62.7%) NCSs. On average, 71·6% [95% confidence interval (CI): 68.6-74.6] of the actions were fully available, 9.9% (95% CI: 8.7-11.1) mostly/often available, 6.7% (95% CI: 5.4-8.0) mostly/often unavailable, and 11·8% (95% CI: 9.5-14.1) fully unavailable. In low-income countries (LICs), substantially more actions were fully unavailable [29·4% (95% CI: 22.6-36.3)] compared with high-income countries [HICs, countries 2.4% (95% CI: 1.2-3.7); P < 0.05]. Nevertheless, a proportion of actions with the lowest availability scores were often fully or mostly unavailable independent of GNIs. Actions were most often not available due to lack of reimbursement and other financial barriers. CONCLUSION: Local implementation of ESC guidelines on general cardiology is high in HICs and low in LICs , being inversely correlated with country gross national incomes.

Artificial intelligence to enhance clinical value across the spectrum of cardiovascular healthcare.

Artificial intelligence (AI) is increasingly being utilized in healthcare. This article provides clinicians and researchers with a step-wise foundation for high-value AI that can be applied to a variety of different data modalities. The aim is to improve the transparency and application of AI methods, with the potential to benefit patients in routine cardiovascular care. Following a clear research hypothesis, an AI-based workflow begins with data selection and pre-processing prior to analysis, with the type of data (structured, semi-structured, or unstructured) determining what type of pre-processing steps and machine-learning algorithms are required. Algorithmic and data validation should be performed to ensure the robustness of the chosen methodology, followed by an objective evaluation of performance. Seven case studies are provided to highlight the wide variety of data modalities and clinical questions that can benefit from modern AI techniques, with a focus on applying them to cardiovascular disease management. Despite the growing use of AI, further education for healthcare workers, researchers, and the public are needed to aid understanding of how AI works and to close the existing gap in knowledge. In addition, issues regarding data access, sharing, and security must be addressed to ensure full engagement by patients and the public. The application of AI within healthcare provides an opportunity for clinicians to deliver a more personalized approach to medical care by accounting for confounders, interactions, and the rising prevalence of multi-morbidity.

The effect of exposure to traffic related air pollutants in pregnancy on birth anthropometry: a cohort study in a heavily polluted low-middle income country.

BACKGROUND: Ambient air pollution has been recognized as one of the most important environmental health threats. Exposure in early life may affect pregnancy outcomes and the health of the offspring. The main objective of our study was to assess the association between prenatal exposure to traffic related air pollutants during pregnancy on birth weight and length. Second, to evaluate the association between prenatal exposure to traffic related air pollutants and the risk of low birth weight (LBW). METHODS: Three hundred forty mother-infant pairs were included in this prospective cohort study performed in Jakarta, March 2016-September 2020. Exposure to outdoor PM2.5, soot, NOx, and NO2 was assessed by land use regression (LUR) models at individual level. Multiple linear regression models were built to evaluate the association between air pollutants with birth weight (BW) and birth length (BL). Logistic regression was used to assess the risk of low birth weight (LBW) associated with all air pollutants. RESULTS: The average PM2.5 concentration was almost eight times higher than the current WHO guideline and the NO2 level was three times higher. Soot and NOx were significantly associated with reduced birth length. Birth length was reduced by - 3.83 mm (95% CI -6.91; - 0.75) for every IQR (0.74 × 10- 5 per m) increase of soot, and reduced by - 2.82 mm (95% CI -5.33;-0.30) for every IQR (4.68 µg/m3) increase of NOx. Outdoor air pollutants were not significantly associated with reduced birth weight nor the risk of LBW. CONCLUSION: Exposure to soot and NOx during pregnancy was associated with reduced birth length. Associations between exposure to all air pollutants with birth weight and the risk of LBW were less convincing.

Change in glycaemic control with structured diabetes self-management education in urban low-resource settings: multicentre randomised trial of effectiveness.

BACKGROUND: In high-resource settings, structured diabetes self-management education is associated with improved outcomes but the evidence from low-resource settings is limited and inconclusive. AIM: To compare, structured diabetes self-management education to usual care, in adults with type 2 diabetes, in low-resource settings. DESIGN: Single-blind randomised parallel comparator controlled multi-centre trial. Adults (> 18 years) with type 2 diabetes from two hospitals in urban Ghana were randomised 1:1 to usual care only, or usual care plus a structured diabetes self-management education program. Randomisation codes were computer-generated, and allotment concealed in opaque numbered envelopes. The intervention effect was assessed with linear mixed models. MAIN OUTCOME: Change in HbA1c after 3-month follow-up. Primary analysis involved all participants. CLINICALTRIAL: gov identifier:NCT04780425, retrospectively registered on 03/03/2021. RESULTS: Recruitment: 22nd until 29th January 2021. We randomised 206 participants (69% female, median age 58 years [IQR: 49-64], baseline HbA1c median 64 mmol/mol [IQR: 45-88 mmol/mol],7.9%[IQR: 6.4-10.2]). Primary outcome data was available for 79 and 80 participants in the intervention and control groups, respectively. Reasons for loss to follow-up were death (n = 1), stroke(n = 1) and unreachable or unavailable (n = 47). A reduction in HbA1c was found in both groups; -9 mmol/mol [95% CI: -13 to -5 mmol/mol], -0·9% [95% CI: -1·2% to -0·51%] in the intervention group and -3 mmol/mol [95% CI -6 to 1 mmol/mol], -0·3% [95% CI: -0·6% to 0.0%] in the control group. The intervention effect was 1 mmol/mol [95%CI:-5 TO 8 p = 0.726]; 0.1% [95% CI: -0.5, 0.7], p = 0·724], adjusted for site, age, and duration of diabetes. No significant harms were observed. CONCLUSION: In low-resource settings, diabetes self-management education might not be associated with glycaemic control. Clinician's expectations from diabetes self-management education must therefore be guarded.

Provision and experience of care among women with hypertension in pregnancy: a multi-center qualitative study in Ghana.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) remain a leading global health problem with complex clinical presentations and potentially grim birth outcomes for both mother and fetus. Improvement in the quality of maternal care provision and positive women's experiences are indispensable measures to reduce maternal and perinatal adverse outcomes. OBJECTIVE: To explore the perspectives and lived experiences of healthcare provision among women with HDP and the associated challenges. METHODS: A multi-center qualitative study using in-depth interviews (IDIs) and focus group discussions (FGDs) was conducted in five major referral hospitals in the Greater Accra Region of Ghana between June 2018 and March 2019. Women between 26 and 34 weeks' gestation with confirmed HDP who received maternity care services were eligible to participate. Thematic content analysis was performed using the inductive analytic framework approach. RESULTS: Fifty IDIs and three FGDs (with 22 participants) were conducted. Most women were between 20 and 30 years, Akans (ethnicity), married/cohabiting, self-employed and secondary school graduates. Women reported mixed (positive and negative) experiences of maternal care. Positive experiences reported include receiving optimal quality of care, satisfaction with care and good counselling and reassurance from the health professionals. Negative experiences of care comprised ineffective provider-client communication, inappropriate attitudes by the health professionals and disrespectful treatment including verbal and physical abuse. Major health system factors influencing women's experiences of care included lack of logistics, substandard professionalism, inefficient national health insurance system and unexplained delays at health facilities. Patient-related factors that influenced provision of care enumerated were financial limitations, chronic psychosocial stress and inadequate awareness about HDP. CONCLUSION: Women with HDP reported both positive and negative experiences of care stemming from the healthcare system, health providers and individual factors. Given the importance of positive women's experiences and respectful maternal care, dedicated multidisciplinary women-centered care is recommended to optimize the care for pregnant women with HDP.

High blood pressure (hypertension) in pregnancy can have severe complications for both mother and fetus including loss of life. The outcome of pregnancy for women who develop hypertension during pregnancy can be improved by ensuring optimal quality of care. In this study, we explored the opinions and experiences of women whose pregnancies were affected by hypertension concerning the care they received during their recent admission at different hospitals in Ghana and the challenges they faced. In four major referral hospitals in the Greater Accra Region of Ghana, we interviewed the women and had focus group discussions. Women who were pregnant for 26 weeks up to 34 weeks and had hypertension in pregnancy were invited for inclusion in the study.We conducted in-depth interviews with fifty women and three focus group discussions with 22 women. Most women who participated in the study were between 20 and 30 years old, Akans (ethnicity), married/cohabiting, self-employed and secondary school graduates. The women reported both positive and negative experiences of care during their admission at the hospitals. Examples of positive experiences were receiving good quality of care, satisfaction with care, and adequate counselling from the health workers. Examples of negative experiences were poor communication between the providers and affected women, inappropriate attitudes by the healthcare providers, and disrespectful treatment such as verbal and physical abuse. The major factors in the health system that influenced women's experiences of care were lack of logistics, substandard professionalism, inefficient national health insurance system and long delays at health facilities prior to receiving treatment. The individual women's factors that affected the quality of care included financial constraints, psychosocial stress and inadequate knowledge about hypertension during pregnancy.In conclusion, we determined that women with hypertension in pregnancy experience both positive and negative aspects of care and these may be due to challenges associated with the healthcare system, health providers and women themselves. There is the need to ensure optimal quality and respectful maternity care considering the nature of hypertension in pregnancy. These women require dedicated hospital staff with significant  experience to improve the quality of care provided to women with hypertension in pregnancy.

CODE-EHR best practice framework for the use of structured electronic healthcare records in clinical research.

Big data is central to new developments in global clinical science aiming to improve the lives of patients. Technological advances have led to the routine use of structured electronic healthcare records with the potential to address key gaps in clinical evidence. The covid-19 pandemic has demonstrated the potential of big data and related analytics, but also important pitfalls. Verification, validation, and data privacy, as well as the social mandate to undertake research are key challenges. The European Society of Cardiology and the BigData@Heart consortium have brought together a range of international stakeholders, including patient representatives, clinicians, scientists, regulators, journal editors and industry. We propose the CODE-EHR Minimum Standards Framework as a means to improve the design of studies, enhance transparency and develop a roadmap towards more robust and effective utilisation of healthcare data for research purposes.

Structured diabetes self-management education and glycaemic control in low- and middle-income countries: A systematic review.

AIM: To determine the association between structured diabetes self-management education (DSME) and glycaemic control in persons living with diabetes (PLD) in low- and middle-income countries (LMICs). METHODS: PubMed, Embase and Cochrane databases were searched up to June 2020 for intervention studies on the effect of structured DSME on glycaemic control in PLD in LMICs (PROSPERO registration CRD42020164857). The primary outcome was reduction in glycated haemoglobin. Included studies were assessed for risk of bias (RoB) with the Cochrane RoB tool for randomised trials. Findings were summarized in a narrative synthesis. RESULTS: Out of 154 abstracts retrieved and screened for eligibility, nine studies with a total of 1389 participants were included in the review. The structured DSME interventions were culturally tailored and were delivered in-person. They were associated with reductions in glycated haemoglobin in all studies: mean/median reduction ranged between 0.5% and 2.6% relative to baseline. CONCLUSIONS: There is a dearth of literature on the association between structured DSME and glycaemic control among PLD in LMICs. The evidence available suggests that in LMICs; particularly in sub-Saharan Africa, structured DSME is associated with reduction in glycated haemoglobin. We recommend further intervention studies on the effects of structured DSME in LMICs.

Middle cerebral arterial flow redistribution is an indicator for intrauterine fetal compromise in late pregnancy in low-resource settings: A prospective cohort study.

OBJECTIVE: We aimed to determine the prevalence of abnormal umbilical artery (UA), uterine artery (UtA), middle cerebral artery (MCA) and cerebroplacental ratio (CPR) Doppler, and their relationship with adverse perinatal outcomes in women undergoing routine antenatal care in the third trimester. DESIGN: Prospective cohort. SETTING: Kagadi Hospital, Uganda. POPULATION: Non-anomalous singleton pregnancies. METHODS: Women underwent an early dating ultrasound and a third-trimester Doppler scan between 32 and 40 weeks of gestation, from 2018 to 2020. We handled missing data using multiple imputation and analysed the data using descriptive methods and a binary logistic regression model. MAIN OUTCOME MEASURES: Composite adverse perinatal outcome (CAPO), perinatal death and stillbirth. RESULTS: We included 995 women. The mean gestational age at Doppler scan was 36.9 weeks (SD 1.02 weeks) and 88.9% of the women gave birth in a health facility. About 4.4% and 5.6% of the UA pulsatility index (PI) and UtA PI were above the 95th percentile, whereas 16.4% and 10.4% of the MCA PI and CPR were below the fifth percentile, respectively. Low CPR was strongly associated with stillbirth (OR 4.82, 95% CI 1.09-21.30). CPR and MCA PI below the fifth percentile were independently associated with CAPO; the association with MCA PI was stronger in small-for-gestational-age neonates (OR 3.75, 95% CI 1.18-11.88). CONCLUSION: In late gestation, abnormal UA PI was rare. Fetuses with cerebral blood flow redistribution were at increased risk of stillbirth and perinatal complications. Further studies examining the predictive accuracy and effectiveness of antenatal Doppler ultrasound screening in reducing the risk of perinatal deaths in low- and middle-income countries are warranted. TWEETABLE ABSTRACT: Blood flow redistribution to the fetal brain is strongly associated with stillbirths in low-resource settings.

Alcohol consumption in relation to cardiovascular diseases and mortality: a systematic review of Mendelian randomization studies.

The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.

When is it impractical to ask informed consent? A systematic review.

BACKGROUND: Informed consent is one of the cornerstones of biomedical research with human subjects. Research ethics committees may allow for a modification or a waiver of consent when the research has social value, involves minimal risk, and if consent is impractical to obtain. While the conditions of social value and minimal risk have received ample attention in research ethics literature, the impractical condition remains unclear. There seem to be different interpretations of the meaning of impractical within academic literature. To address this lack of clarity, we performed a systematic review on the interpretation of impractical. METHODS: First, we examined international research ethics guidelines on their usage and interpretation of impractical. Next, we used international ethical guidelines to identify synonyms of the term "impractical." Accordingly, PubMed, Embase, and Web of Science were searched for articles that included "informed consent" and "impractical" or one of its synonyms. RESULTS: We found that there were only a few international ethics guidelines that described what could be considered impractical. Out of 2329 identified academic articles, 42 were included. Impractical was used to describe four different conditions: (1) obtaining informed consent becomes too demanding for researchers, (2) obtaining informed consent leads to invalid study outcomes, (3) obtaining informed consent harms the participant, and (4) obtaining informed consent is meaningless for the participant. CONCLUSION: There are conditions that render conventional informed consent truly impractical, such as untraceable participants or harm for participants. At the same time, researchers have a moral responsibility to design an infrastructure in which consent can be obtained, even if they face hardship in obtaining consent. In addition, researchers should seek to minimize harm inflicted upon participants when harm may occur as a result of the consent procedure. Invalidity of research due to consent issues should not be regarded as impractical but as a condition that limits the social value of research. Further research is essential for when a waiver of informed consent based on impractical is also reasonable.

Polygenic risk scores predict diabetes complications and their response to intensive blood pressure and glucose control.

AIMS/HYPOTHESIS: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk. METHODS: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study. RESULTS: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10-21 and p = 9.6 × 10-31, respectively) and a 4.4-fold (p = 6.8 × 10-33) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. CONCLUSIONS/INTERPRETATION: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy.

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients.

BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 µm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 µm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.