Endpoints in Heart Failure Drug Development

Heart failure (HF) is a major health problem worldwide. The development of effective drug and/or device therapy is crucial to mitigate the significant morbidity, mortality and healthcare costs associated with HF. The choice of endpoint in clinical trials has important practical and clinical implications. Outcomes of interest including mortality and HF hospitalisations provide robust evidence for regulatory approval granted there is sufficiency of safety data. At the same time, it is important to recognise that HF patients experience significant impairments in functional capacity and quality of life, underscoring the need to incorporate parameters of symptoms and patient-reported outcomes in clinical trials. In this review, the authors summarise the evolution and definition of cardiovascular endpoints used in clinical trials, discuss approaches to study design to allow the incorporation of mortality, morbidity and functional endpoints and, finally, examine the current challenges and suggest steps for the development of cardiovascular endpoints that are effective, meaningful and meet the needs of all relevant stakeholders, including patients, physicians regulators and sponsors

The ameliorative effects of Averroha carambola on humoral response to sheep erythrocytes in non-treated and cyclophosphamide-immunocompromised mice

AbstractObjectiveTo evaluated immunomodulatory and antioxidant activity of the methanol extract of Averrhoa carambola (A. carambola) leaves in mice.MethodsThe assessment of immunomodulatory activity on specific and non-specific immunity was studied by administration of test extract by oral feeding canula to the test groups. Hemagglutinating antibody (HA) titer, delayed type of hypersensitivity (DTH) response, hematological profile (Hb, WBC, RBC), lipid per oxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) were determined by in vivo experiments.ResultsThe evaluation of immunomodulatory potential of A. carambola (800 and 1 200 mg/kg, p.o.) evoked a dose-dependent increase in antibody titer values and DTH reaction induced by SRBC was also found significant (P<0.001). Also it caused increase in hematological profile, GSH, SOD, CAT activity and significantly decreased LPO levels in cyclophosphamide-induced immunosuppressed mice. Result shows that the extract treated animals showed up regulation of (IL-6 and TNF-α) cytokines.ConclusionsImmunomodulators are being used as an adjuvant in conditions of immunodeficiency in cancer and to a limited extent in acquired immunodeficiency syndrome. The results obtained in this study indicate that A. carambola possesses potential immunomodulatory and antioxidant activity

Healthcare Access Among Individuals of Asian Descent in the U.S.

Introduction. Some groups of Asian Americans, especially Asian Indians, experience higher rates of atherosclerotic cardiovascular disease (ASCVD) compared with other groups in the U.S. Barriers in accessing medical care partly may explain this higher risk as a result of delayed screening for cardiovascular risk factors and timely initiation of preventive treatment. Methods. Cross-sectional data were utilized from the 2006 to 2015 National Health Interview Survey (NHIS). Barriers to accessing medical care included no place to seek medical care when needed, no healthcare coverage, no care due to cost, delayed care due to cost, inability to afford medication, or not seeing a doctor in the past 12 months. Results. The study sample consisted of 18,150 Asian individuals, of whom 20.5% were Asian Indian, 20.5% were Chinese, 23.4% were Filipino, and 35.6% were classified as “Other Asians”. The mean (standard error) age was 43.8 (0.21) years and 53% were women. Among participants with history of hypertension, diabetes mellitus, or ASCVD (prevalence = 25%), Asian Indians were more likely to report delayed care due to cost (2.58 (1.14,5.85)), while Other Asians were more likely to report no care due to cost (2.43 (1.09,5.44)) or delayed care due to cost (2.35 (1.14,4.86)), compared with Chinese. Results among Filipinos were not statistically significant. Conclusions. Among Asians living in the U.S. with cardiovascular risk factors or ASCVD, Asian Indians and Other Asians are more likely to report delayed care or no care due to cost compared with Chinese

Racial disparities in modifiable risk factors and statin usage in Black patients with familial hypercholesterolemia

Background Black men and women are at higher risk for, and suffer greater morbidity and mortality from, atherosclerotic cardiovascular disease (ASCVD) compared with adults of European Ancestry (EA). Black patients with familial hypercholesterolemia are at particularly high risk for ASCVD complications because of lifelong exposure to elevated levels of low-density-lipoprotein cholesterol. Methods and Results This retrospective study analyzed ASCVD prevalence and risk factors in 808 adults with heterozygous familial hypercholesterolemia from 5 US-based lipid clinics, and compared findings in Black versus EA patients. Multivariate logistic regression models were used to determine the strongest predictors of ASCVD as a function of race. No significant difference was noted in the prevalence of ASCVD in Black versus EA patients with familial hypercholesterolemia (39% versus 32%, respectively

Short-acting β2-agonist prescription patterns and clinical outcomes in Malaysia: A nationwide cohort of the SABINA III study

Introduction: SABINA III assessed short-acting β2-agonist (SABA) prescription patterns and their association with asthma-related outcomes globally. Herein, we examined SABA prescription and clinical outcomes in the Malaysian cohort of SABINA III. Methods: In this observational, cross-sectional study, patients (≥12 years) were recruited between July and December 2019 from 15 primary and specialty care centres in Malaysia. Prescribed asthma treatments and severe exacerbation history within 12 months prior and asthma symptom control during the study visit were evaluated. Associations of SABA prescription with asthma control and severe exacerbation were analysed using multivariable regression models. Results: Seven hundred thirty-one patients (primary care, n=265 [36.3%]; specialty care, n=466 [63.7%]) were evaluated. The prevalence of SABA over-prescription (≥3 SABA prescriptions/year) was 47.4% (primary care, 47.1%; specialty care, 47.6%), 51.8% and 44.5% among all patients and patients with mild and moderate-to-severe asthma, respectively. Altogether 9.0% (n=66) purchased SABA without a prescription; among them, 43.9% (n=29) purchased ≥3 inhalers. The mean (standard deviation) number of severe asthma exacerbations was 1.38 (2.76), and 19.7% (n=144) and 25.7% (n=188) had uncontrolled and partly controlled symptoms, respectively. Prescriptions of ≥3 SABA inhalers (vs 1–2) were associated with lower odds of at least partly controlled asthma (odds ratio=0.42; 95% confidence interval [CI]=0.27–0.67) and higher odds of having severe exacerbation(s) (odds ratio=2.04; 95% CI=1.44–2.89). Conclusion: The prevalence of SABA over-prescription in Malaysia is high, regardless of the prescriber type, emphasising the need for healthcare providers and policymakers to adopt latest evidence-based recommendations to address this public health concern

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Epidemiology and risk factors for stroke in young individuals: Implications for prevention

Purpose of review: Summarize and examine the epidemiology, etiologies, risk factors, and treatment of stroke among young adults and highlight the importance of early recognition, treatment, and primordial prevention of risk factors that lead to stroke.Recent findings: Incidence of stroke, predominantly ischemic, among young adults has increased over the past two decades. This parallels an increase in traditional risk factors such as hypertension, diabetes, and use of tobacco, and use of illicit substances among young stroke patients. Compared to older patients, there is a much higher proportion of intracerebral and subarachnoid hemorrhage in young adults. The cause of ischemic stroke in young adults is also more diverse compared to older adults with 1/3rd classified as stroke of undetermined etiology due to inadequate effort or time spent on investigating these diverse and rare etiologies. Young premature Atherosclerotic Cardiovascular Disease patients have suboptimal secondary prevention care compared to older patients with lower use of antiplatelets and statin therapy and lower adherence to statins.Summary: Among young patients, time-critical diagnosis and management remain challenging, due to atypical stroke presentations, vast etiologies, statin hesitancy, and provider clinical inertia. Early recognition and aggressive risk profile modification along with primary and secondary prevention therapy optimization are imperative to reduce the burden of stroke among young adults and save potential disability-adjusted life years

Triglycerides and ASCVD risk reduction: Recent insights and future directions

Purpose of review: This review focuses on recent evidence examining the role triglycerides (TG) and triglyceride-enriched lipoproteins (TGRL) play in atherosclerotic cardiovascular disease (ASCVD). It also provides a succinct overview of current and future TG-lowering therapies for ASCVD risk reduction.Recent findings: Epidemiological and Mendelian randomization studies have consistently shown that TGRL are strongly associated with ASCVD. REDUCE-IT demonstrated cardiovascular benefit with icosapent ethyl in high-risk patients with hypertriglyceridemia on statin therapy. Polymorphisms in APOC3 and ANGPTL3 are associated with ASCVD and use of RNA-interfering therapies to target these proteins has shown TG lowering in early phase trials. TG and TGRL are causally associated with ASCVD. Lifestyle modifications and statin therapy can lower TG/TGRL and are considered first-line treatment for hypertriglyceridemia. Icosapent ethyl has been shown to reduce residual ASCVD risk in high-risk patients on maximally tolerated statins. Ongoing clinical trials will better define optimal therapy for patients on statins with residual hypertriglyceridemia