Similar Risk Reduction Research Articles

Associations of glycemic status with dynamic disease trajectories of atrial fibrillation and dementia.

Atrial fibrillation (AF) has been associated with elevated dementia risk, while few studies have examined the role of the optimal glycemic status in disease trajectories of AF and dementia. We aim to evaluate associations between glycemic status with disease trajectories of AF and dementia, as well as major dementia subtypes, including Alzheimer's disease and vascular dementia. Population-based cohort study. UK Biobank. A total of 458 368 participants who were free of prevalent dementia and AF at baseline, with complete glycemic status assessment. Based on clinical recommendations, we categorized glycemic status as low-normal (glycated hemoglobin [HbA1c] <5.5 %), normal (HbA1c 5.5 to 5.9 %), pre-diabetes (HbA1c 6.0 to 6.4 %), diabetes with HbA1c<7 %, and diabetes with HbA1c≥7 %. Outcomes including AF, dementia (all-cause and sub-type dementia), and death were ascertained via linkage to external registry databases. A multi-state survival analysis was conducted to evaluate disease trajectories of AF and dementia. Better glycemic status was consistently associated with decreased hazards of trajectories of AF and dementia, including progression from AF to the comorbidity of AF and dementia. Among people with diabetes, those with HbA1c<7 % had a 31 % lower hazard (hazard ratio [HR], 0.69; 95 % confidence intervals [CI], 0.51-0.93) of progression from incident AF to dementia comorbidity, compared to those with HbA1c≥7 %. Similar risk reductions were found in individuals with pre-diabetes, normal HbA1c, and low-normal HbA1c, respectively. Strong dose-response associations were observed, with each 1 % increment in HbA1c related to a 28 % higher hazard of progression from AF to dementia comorbidity (HR,1.28; 95 % CI, 1.19-1.37). The glycemic status was most relevant for associations with disease trajectories of AF and vascular dementia, compared to trajectories of AF and Alzheimer's disease. The better glycemic status was consistently associated with lower hazards of disease trajectories of AF and dementia, including the reduced risk of progression from incident AF to comorbidity of AF and dementia. These findings support the significance of reaching optimal glycemic status to alleviate the huge disease burden of both AF and dementia simultaneously.

Abstract 4124446: Traditional Risk Factors, Cardiovascular Health, and Elevated Lipoprotein(a): The Multi-Ethnic Study of Atherosclerosis

Introduction: One in five individuals have elevated lipoprotein(a) [Lp(a)], an inheritable risk factor that is causally associated with atherosclerotic cardiovascular disease (ASCVD). Whether individuals with elevated Lp(a) derive similar benefit from control of ASCVD risk factors has not been well-studied. Hypothesis: The magnitude of benefit associated with optimal cardiovascular health will be similar across the spectrum of Lp(a). Aim: To assess the association of traditional risk factor burden and Life’s Simple 7 (LS7) score with incident ASCVD across Lp(a) values. Methods: We studied 6,676 participants from the Multi-Ethnic Study of Atherosclerosis who underwent Lp(a) testing and were followed for incident ASCVD events (coronary heart disease and stroke). Elevated Lp(a) was defined as &gt; 50 mg/dL. As defined by the American Heart Association, LS7 metrics included smoking, physical activity, body mass index, diet, total cholesterol, blood pressure, and glucose. Multivariable Cox proportional hazards regression assessed the association of traditional risk factor burden and LS7 score (poor: 0-8, average: 9-10, optimal: 11-14) with incident ASCVD for individuals with and without elevated Lp(a) during a median follow-up of 17.7 years. Results: The mean age was 62.1 years, 53% were women, and 61% were non-white. The median Lp(a) was 17 mg/dL and 20% had Lp(a) &gt; 50 mg/dL. Individuals with Lp(a) &gt; 50 mg/dL had the highest burden of traditional risk factors except cigarette smoking. Compared to those with a poor LS7 score, those with an optimal LS7 score had a lower ASCVD risk that was significant for participants with Lp(a) &lt;50 mg/dL (HR=0.37, 95% CI: 0.25-0.55), but borderline significant for participants with Lp(a) &gt; 50 mg/dL (HR=0.41, 95% CI: 0.16-1.02). Individuals with Lp(a) &gt; 50 mg/dL had the highest absolute event rates across all LS7 categories, and there was no significant interaction between Lp(a) and LS7 score on incident ASCVD (p-interaction=0.64, Figure ). Conclusions: Participants with an optimal LS7 score had similar reduction in ASCVD risk regardless of their Lp(a) burden. These results emphasize the importance of a healthy lifestyle and ASCVD risk factor control among patients with elevated Lp(a).

Relationship Between Sarcopenia and Intensive Blood Pressure Control Efficacy and Safety: A Secondary Analysis of SPRINT.

Sarcopenia and hypertension are independently associated with worse cardiovascular disease (CVD) risk and survival. While individuals with sarcopenia may benefit from intensive blood pressure (BP) control, the increased vulnerability of this population raises concerns for potential harm. This study aimed to evaluate clinical and safety outcomes with intensive (target <120 mm Hg) versus standard (<140 mm Hg) systolic BP targets in older hypertensive adults with sarcopenia compared with nonsarcopenic counterparts in the SPRINT (Systolic Blood Pressure Intervention Trial). Sarcopenia was defined using surrogates of the lowest sex-stratified median of the sarcopenia index (serum creatinine/cystatin C×100) for muscle wasting and gait speed ≤0.8 m/s for muscle weakness. Outcomes included CVD events, all-cause mortality, and serious adverse events. Of 2571 SPRINT participants with sarcopenia index and gait speed data available (aged ≥75 years), 502 (19.5%) met the criteria for sarcopenia, which was associated with higher risks of CVD events (adjusted hazard ratio, 1.49 [95% CI, 1.15-1.94]; P=0.003) and all-cause mortality (adjusted hazard ratio, 1.46 [95% CI, 1.09-1.94]; P=0.010). In participants with sarcopenia, intensive (versus standard) BP control nearly halved the risk of CVD events (adjusted hazard ratio, 0.57 [95% CI, 0.36-0.88]; P=0.012) without increasing serious adverse events. Similar risk reduction was seen for all-cause mortality in participants with sarcopenia (adjusted hazard ratio, 0.66 [95% CI, 0.41-1.08]; P=0.102), but the effect was only significant in those without chronic kidney disease. Older hypertensive adults with sarcopenia randomized to intensive BP control experienced a lower risk of CVD without increased adverse events compared with standard BP control. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Different Patterns of Care and Survival Outcomes in Transplant-Centre Managed Patients with Early-Stage HCC: Real-World Data from an Australian Multi-Centre Cohort Study.

The management of early-stage hepatocellular carcinoma (HCC) is complex, with multiple treatment strategies available. There is a paucity of literature regarding variations in the patterns of care and outcomes between transplant and non-transplant centres. We conducted this real-world multi-centre cohort study in two liver cancer referral centres with an integrated liver transplant program and an additional eight non-transplant HCC referral centres across Australia to identify variation in patterns of care and key survival outcomes. Patients with stage Barcelona Clinic Liver Cancer (BCLC) 0/A HCC, first diagnosed between 1 January 2016 and 31 December 2020, who were managed at a participating site, were included in the study. Patients were excluded if they had a history of prior HCC or if they received upfront liver transplantation. A total of 887 patients were included in the study, with 433 patients managed at a liver cancer centre with a transplant program (LTC) and 454 patients managed at a non-transplant centre (NTC). Management at an LTC did not significantly predict allocation to resection (adjusted OR 0.75, 95% CI 0.50 to 1.11, p = 0.148). However, in those not receiving resection, LTC and NTC patients were systematically managed differently, with LTC patients five times less likely to receive upfront ablation than NTC patients (adjusted OR 0.19, 95% CI 0.13 to 0.28, p < 0.001), even after adjusting for tumour burden, as well as for age, gender, liver disease aetiology, liver disease severity, and medical comorbidities. LTCs exhibited significantly higher proportions of patients undergoing TACE for every tumour burden category, including those with a single tumour measuring 2 cm or less (p < 0.001). Using multivariable Cox proportional hazards analysis, management at a transplant centre was associated with reduced all-cause mortality (adjusted HR 0.71, 95% CI 0.51 to 0.98, p = 0.036), and competing-risk regression analysis, considering liver transplant as a competing event, demonstrated a similar reduction in risk (adjusted HR 0.70, 95% CI 0.50 to 0.99, p = 0.041), suggesting that the reduced risk of death is not fully explained by higher rates of transplantation. Our study highlights systematic differences in HCC care between large volume liver transplant centres and other sites, which has not previously been well-described. Further work is needed to better define the reasons for differences in treatment allocation and to aim to minimise unwarranted treatment variation to maximise patient outcomes across Australia.

Left Atrial Improvement in Patients With Secondary Mitral Regurgitation and Heart Failure: The COAPT Trial

BackgroundFunctional mitral regurgitation induces adverse effects on the left ventricle and the left atrium. Left atrial (LA) dilatation and reduced LA strain are associated with poor outcomes in heart failure (HF). Transcatheter edge-to-edge repair (TEER) of the mitral valve reduces heart failure hospitalization (HFH) and all-cause death in selected HF patients. ObjectivesThe aim of this study was to evaluate the impact of LA strain improvement 6 months after TEER on the outcomes of patients enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. MethodsThe difference in LA strain between baseline and the 6-month follow-up was calculated. Patients with at least a 15% improvement in LA strain were labeled as “LA strain improvers.” All-cause death and HFH were assessed between the 6- and 24-month follow-up. ResultsAmong 347 patients (mean age 71 ± 12 years, 63% male), 106 (30.5%) showed improvement of LA strain at the 6-month follow-up (64 [60.4%] from the TEER + guideline-directed medical therapy [GDMT] group and 42 [39.6%] from the GDMT alone group). An improvement in LA strain was significantly associated with a reduction in the composite of death or HFH between the 6-month and 24-month follow-up, with a similar risk reduction in both treatment arms (Pinteraction = 0.27). In multivariable analyses, LA strain improvement remained independently associated with a lower risk of the primary composite endpoint both as a continuous variable (adjusted HR: 0.94 [95% CI: 0.89-1.00]; P = 0.03) and as a dichotomous variable (adjusted HR: 0.49 [95% CI: 0.27-0.89]; P = 0.02). The best outcomes were observed in patients treated with TEER in whom LA strain improved. ConclusionsIn symptomatic HF patients with severe mitral regurgitation, improved LA strain at the 6-month follow-up is associated with subsequently lower rates of the composite endpoint of all-cause mortality or HFH, both after TEER and GDMT alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079)

Intensive Blood Pressure Lowering in Individuals With Low Diastolic Blood Pressure and Elevated Troponin Levels in SPRINT.

Among individuals with hypertension and low diastolic blood pressure (DBP), the optimal BP target remains controversial due to concerns that BP lowering may reduce coronary perfusion. We determined the impact of intensive BP control among individuals with elevated systolic BP who have low DBP and elevated hs-cTnT (high-sensitivity cardiac troponin T) levels. A total of 8828 participants in SPRINT (Systolic Blood Pressure Intervention Trial) were stratified by baseline DBP. Those with low DBP (<70 mm Hg) were further stratified by elevated hs-cTnT (≥14 ng/L) at baseline. The effects of intensive versus standard BP lowering on a cardiovascular disease composite end point, all-cause death, and 1-year change in hs-cTnT were determined. The combination of low DBP/high hs-cTnT was independently associated with a higher risk for cardiovascular disease and all-cause death, as well as greater 1-year increases in hs-cTnT, compared with DBP ≥70 mm Hg. However, randomization to intensive versus standard BP lowering led to similar reductions in cardiovascular disease risk among individuals with low DBP/high hs-cTnT (hazard ratio [HR], 0.82 [95% CI, 0.57-1.19]), low DBP/low hs-cTnT (HR, 0.48 [95% CI, 0.29-0.79]), and DBP ≥70 mm Hg (HR, 0.73 [95% CI, 0.60-0.89]; P for interaction=0.20). Intensive BP lowering also led to a reduction in all-cause death that was similar across groups (P for interaction=0.57). In this nonprespecified subgroup analysis of SPRINT, individuals with low DBP and elevated hs-cTnT, low DBP and nonelevated hs-cTnT, and DBP ≥70 mm Hg derived similar cardiovascular disease and mortality benefits from intensive BP lowering. These findings warrant confirmation in other studies.

Effectiveness of the SARS-CoV-2 Vaccination in Preventing Severe Disease-Related Outcomes: A Population-Based Study in the Italian Province of Bolzano (South Tyrol).

Objective: To investigate the effectiveness of SARS-CoV2 vaccination in preventing ordinary or intensive care unit (ICU) admissions and deaths among cases registered during a variant transitional pandemic phase in the geographically and culturally unique territory of the Province of Bolzano (South Tyrol), an Italian region with low vaccination coverage. Methods: We collected data from 93,643 patients registered as positive for SARS-CoV-2 by health authorities during the winter of 2021-22. The data were analyzed retrospectively using descriptive statistics and multiple logistic regression. Results: 925 patients were hospitalized (0.99%), 89 (0.10%) were in intensive care, and 194 (0.21%) died. Vaccinated patients had a significantly lower risk of being hospitalized: adjusted Odds Ratio (aOR): 0.39; 95% CI: 0.33-0.46, ICU admission: aOR: 0.16; 95% CI: 0.09-0.29 and death: aOR: 0.41; 95% CI: 0.29-0.58. Similar risk reductions were also observed in booster-vaccinated patients, independent of sex, age, and predominant variant. Furthermore, the median length of stay (LoS) in the ICU was significantly longer for unvaccinated individuals compared to vaccinated subjects (9 vs. 6days; p < 0.003). Conclusion: Primary series vaccination and ongoing campaign booster doses were effective in preventing all severe disease-related outcomes and in reducing ICU Length of Stay, even during a transitional pandemic phase and in a unique territorial context.

Cardiovascular Benefit of Statin Use Against Air Pollutant Exposure in Older Adults.

Little is known about the cardiovascular benefit of statin use against ambient air pollution among older adults who are at higher risk of cardiovascular disease (CVD) potentially owing to age-related declines in cardiovascular functions along with other risk factors. This retrospective, population-based cohort study consisted of adults aged 60 years and older free of CVD at baseline identified from the National Health Insurance Service (NHIS) database linked to the National Ambient Air Monitoring Information System (NAMIS) for average daily exposure to PM10 and PM2.5 in 2015 in the major metropolitan areas in the Republic of Korea. Follow-up period began on January 1, 2016 and lasted until December 31, 2021. Cox proportional hazards model was used to evaluate association of cardiovascular benefit with statin use against different levels of air pollutant exposure. Of 1,229,444 participants aged 60 years and older (mean age, 67.4; 37.7% male), 377,076 (30.7%) were identified as statin-users. During 11,963,322 person-years (PY) of follow-up, a total of 86,018 incident stroke events occurred (719.0 events per 100,000 PYs). Compared to statin non-user exposed to high level of PM10 (>50 µg/m3) and PM2.5 (>25 µg/m3), statin users had 20% (adjusted hazard ratio [HR], 0.80; 95% confidence intervals [CI], 0.75 to 0.85) and 17% (adjusted HR, 0.80; 95% CI, 0.80 to 0.86) lower adjusted risk of incident stroke for PM10 and PM2.5, respectively. Similar risk reduction for incident CVD was also found among statin-users exposed to low or moderate level of PM10 (≤50 µg/m3) and PM2.5 (≤25 µg/m3) exposure. Among adults aged 60 years and older with high and low or moderate levels of exposure to PM10 and PM2.5, statin use was associated with a significantly lower risk of stroke.

Association of sodium-glucose cotransporter-2 inhibitors and the risk of retinal vascular occlusion: A real-world retrospective cohort study in Taiwan.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are proposed to alleviate the development of inflammatory eye diseases. However, the association between SGLT2i and retinal vascular occlusion remains unclear. Therefore, this study aims to explore the effects of SGLT2i on the incidence of retinal vascular occlusion. This retrospective cohort study analysed electronic medical records data from the largest multi-institutional database in Taiwan. Individuals who initiated SGLT2is and dipeptidyl peptidase 4 inhibitors (DPP4is) between 2016 and 2019 were included in our analysis. To conduct a homogenous comparison, inverse probability of treatment weighting with propensity scoring was employed. The primary outcome was retinal vascular occlusion, and the secondary outcomes were retinal vascular occlusion-related complications (macular oedema, vitreous haemorrhage, and tractional retinal detachment) and conditions requiring vitreoretinal intervention (intravitreal injection, retinal laser therapy, and vitrectomy). In total, 12,074 SGLT2i users and 39,318 DPP4i users were included. The incidence rate of retinal vascular occlusion in the SGLT2i and DPP4i groups was 1.2 (95% confidence interval [CI], 0.9-1.4) and 1.6 (95% CI, 1.3-1.8) events per 1000 person-years, respectively, which yielded a subdistribution hazard ratio (SHR) of 0.74 (95% CI, 0.55-0.99). Similar risk reductions were observed in the retinal vascular occlusion-related complications (SHR, 0.76; 95% CI, 0.69-0.84) and conditions requiring vitreoretinal intervention (SHR, 0.84; 95% CI, 0.77-0.94). In this multi-institutional study in Taiwan, SGLT2i use was associated with a reduced risk of retinal vascular occlusion. Further prospective studies are required to ascertain this association.

Risk subgroups and intervention effects among infants at high risk for peanut allergy: A model for clinical decision making.

The Learning Early About Peanut Allergy (LEAP) trial showed that early dietary introduction of peanut reduced the risk of developing peanut allergy by age 60 months in infants at high risk for peanut allergy. In this secondary analysis of LEAP data, we aimed to determine risk subgroups within these infants and estimate their respective intervention effects of early peanut introduction. LEAP raw data were retrieved from ITNTrialShare.org. Conditional random forest was applied to participants in the peanut avoidance arm to select statistically important features for the classification and regression tree (CART) analysis to group infants based on their risk of peanut allergy at 60 months of age. Intervention effects were estimated for each derived risk subgroup using data from both arms. Our main model was generated based on baseline data when the participants were 4-11 months old. Specific IgE measurements were truncated to account for the limit of detection commonly used by laboratories in clinical practice. The model found infants with higher predicted probability of peanut allergy at 60 months of age had a similar relative risk reduction, but a greater absolute risk reduction in peanut allergy with early introduction of peanut, than those with lower probability. The intervention effects were significant across all risk subgroups. Participants with baseline peanut sIgE ≥0.22 kU/L (n = 78) had an absolute risk reduction of 40.4% (95% CI 27.3, 51.9) whereas participants with baseline peanut sIgE<0.22 kU/L and baseline Ara h 2 sIgE <0.10 kU/L (n = 226) had an absolute risk reduction of 6.5% (95% CI 2.6, 11.0). These findings were consistent in sensitivity analyses using alternative models. In this study, risk subgroups were determined among infants from the LEAP trial based on the probability of developing peanut allergy and the intervention effects of early peanut introduction were estimated. This may be relevant for further risk assessment and personalized clinical decision-making.

Adherence to the Diabetes Risk Reduction Diet and Bladder Cancer Risk in the Prostate, Lung, Colorectal, Ovarian (PLCO) Cohort.

This study aimed to explore the relationship between diabetes risk reduction diet (DRRD) and bladder cancer risk in Prostate, Lung, Colorectal, Ovarian (PLCO) cohort. Data from 99,001 participants in the PLCO Cancer Screening Trial were analyzed using Cox proportional hazards regression models to estimate HRs and 95% confidence intervals (CI) for the association between DRRD score and bladder cancer incidence. Subgroup analyses were conducted to assess whether variables such as age, sex, body mass index, cigarette smoking status, and history of diabetes influenced the observed association. The DRRD score was formulated on the basis of nine nutrient intake indicators derived from the Dietary History Questionnaire. During the median follow-up of 11.7 years, 761 new bladder cancer cases were identified. Participants with highest DRRD scores exhibited a reduced risk of bladder cancer compared with those in the lowest quartile (unadjusted analysis, HR, 0.65; 95% CI, 0.53-0.82); multivariable adjusted analysis, HR, 0.79; 95% CI, 0.64-0.98; Ptrend = 0.007). A similar risk reduction was seen solely in transitional cell carcinoma (HR, 0.79; 95% CI, 0.64-0.99; P = 0.007). In addition, the significant negative association between DRRD scores and bladder cancer risk persisted even after excluding participants with unique characteristics. This large prospective population-based study suggests that adherence to a DRRD may contribute to the prevention of bladder cancer. The DRRD could potentially mitigate bladder cancer risk, which warrants further validation in diverse populations.

Changes in Left Ventricular Global Longitudinal Strain in Patients With Heart Failure and Secondary Mitral Regurgitation: The COAPT Trial.

Background Left ventricular (LV) global longitudinal strain (GLS) provides incremental prognostic information over LV ejection fraction in patients with heart failure (HF) and secondary mitral regurgitation. We examined the prognostic impact of LV GLS improvement in this population. Methods and Results The COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial randomized symptomatic patients with HF with severe (3+/4+) mitral regurgitation to transcatheter edge-to-edge repair with the MitraClip device plus maximally tolerated guideline-directed medical therapy (GDMT) versus GDMT alone. LV GLS was measured at baseline and 6-month follow-up. The relationship between the improvement in LV GLS from baseline to 6 months and the composite of all-cause death or HF hospitalization between 6- and 24-month follow-up were assessed. Among 383 patients, 174 (45.4%) had improved LV GLS at 6-month follow-up (83/195 [42.6%] with transcatheter edge-to-edge repair+GDMT and 91/188 [48.4%] with GDMT alone; P=0.25). Improvement in LV GLS was strongly associated with reduced death or HF hospitalization between 6 and 24 months (P<0.009), with similar risk reduction in both treatment arms (Pinteraction=0.40). By multivariable analysis, LV GLS improvement at 6 months was independently associated with a lower risk of death or HF hospitalization (hazard ratio [HR], 0.55 [95% CI, 0.36-0.83]; P=0.009), death (HR, 0.48 [95% CI, 0.29-0.81]; P=0.006), and HF hospitalization (HR, 0.50 [95% CI, 0.31-0.81]; P=0.005) between 6 and 24 months. Conclusions Among patients with HF and severe mitral regurgitation in the COAPT trial, improvement in LV GLS at 6-month follow-up was associated with improved outcomes after both transcatheter edge-to-edge repair and GDMT alone between 6 and 24 months. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01626079.

Reduced risk of mortality among COVID-19 patients with in-hospital selective serotonin reuptake inhibitor administration

Abstract Objectives The anti-inflammatory properties of selective serotonin reuptake inhibitors (SSRI)s, particularly fluvoxamine, have been hypothesized to reduce clinical deterioration in patients with COVID-19 when administered early in the disease course. The objective of this analysis was to examine the effect of maintenance SSRI administration, including variation among different medications, on the outcomes of hospitalized patients with COVID-19. Methods Retrospective analysis of disease progression and mortality risk of over 230,000 patients hospitalized with COVID-19 at facilities associated with a large healthcare system in the United States. Key findings Receipt of SSRIs during the hospital encounter occurred in approximately 10.6% (n = 24,690) of COVID-19 patients. When matched for patient characteristics, disease severity and other treatments, receipt of any SSRI was associated with a 30% reduction in the relative risk of mortality (RR: 0.70, 95% confidence interval [CI]: 0.67–0.73; adjusted P-value &amp;lt;0.001). Similar reductions in the relative risk of mortality were seen with nearly every individual SSRI; for sertraline-treated patients, the most commonly used SSRI in the data set, there was a 29% reduction in the relative risk of mortality (RR: 0.71, 95% CI: 0.66–0.77; adjusted P-value &amp;lt;0.001). Conclusions In total, this retrospective analysis suggests that there is a significant association between SSRI antidepressants and reduced morality among patients hospitalized with COVID-19.

Efficacy of ivabradine in heart failure patients with a high-risk profile (analysis from the SHIFT trial).

Early start and patient profile-oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP)<110mmHg, resting heart rate (RHR)≥75b.p.m., left ventricular ejection fraction (LVEF)≤25%, New York Heart Association (NYHA) Class III/IV, and their combination. The SHIFT trial enrolled 6505 patients (LVEF≤35% and RHR≥70b.p.m.), randomized to ivabradine or placebo on the background of guideline-defined standard care. Compared with placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint (cardiovascular death or HF hospitalization) in patients with SBP<110 and ≥110mmHg [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.74-1.08 vs. HR 0.80, 95% CI 0.72-0.89, P interaction=0.34], LVEF≤25% and >25% (HR 0.85, 95% CI 0.72-1.01 vs. HR 0.80, 95% CI 0.71-0.90, P interaction=0.53), and NYHA III-IV and II (HR 0.83, 95% CI 0.74-0.94 vs. HR 0.81, 95% CI 0.69-0.94, P interaction=0.79). The effect was more pronounced in patients with RHR≥75 compared with <75 (HR 0.76, 95% CI 0.68-0.85 vs. HR 0.97, 95% CI 0.81-0.1.16, P interaction=0.02). When combining these profiling parameters, treatment with ivabradine was also associated with risk reductions comparable with patients with low-risk profiles for the primary endpoint (relative risk reduction 29%), cardiovascular death (11%), HF death (49%), and HF hospitalization (38%; all P values for interaction: 0.40). No safety concerns were observed between study groups. Our analysis shows that RHR reduction with ivabradine is effective and improves clinical outcomes in HF patients across various risk indicators such as low SBP, high RHR, low LVEF, and high NYHA class to a similar extent and without safety concern.

Making Sense of Composite Endpoints in Clinical Research

Multiple drugs currently used in clinical practice have been approved by regulatory agencies based on studies that utilize composite endpoints. Composite endpoints are appealing because they reduce sample size requirements, follow-up periods, and costs. However, interpreting composite endpoints can be challenging, and their misuse is not uncommon. Incorrect interpretation of composite outcomes can lead to misleading conclusions that impact patient care. To correctly interpret composite outcomes, several important questions should be considered. Are the individual components of the composite outcome equally important to patients? Did the more and less important endpoints occur with similar frequency? Do the component endpoints exhibit similar relative risk reductions? If these questions receive affirmative answers, the use and interpretation of the composite endpoint would be appropriate. However, if any component of the composite endpoint fails to satisfy the aforementioned criteria, interpretation can become difficult, necessitating additional steps. Regulatory agencies acknowledge these challenges and have specific considerations when approving drugs based on studies employing composite endpoints. In conclusion, composite endpoints are valuable tools for evaluating the efficacy and net clinical benefit of interventions; however, cautious interpretation is advised.

Biochemical Markers of Bone Fragility in Patients with Diabetes. A Narrative Review by the IOF and the ECTS.

The risk of fragility fractures is increased in both type 1 and type 2 diabetes. Numerous biochemical markers reflecting bone and/or glucose metabolism have been evaluated in this context. This review summarizes current data on biochemical markers in relation to bone fragility and fracture risk in diabetes. Literature review by a group of experts from the International Osteoporosis Foundation (IOF) and European Calcified Tissue Society (ECTS) focusing on biochemical markers, diabetes, diabetes treatments and bone in adults. Although bone resorption and bone formation markers are low and poorly predictive of fracture risk in diabetes, osteoporosis drugs seem to change bone turnover markers in diabetics similarly to non-diabetics, with similar reductions in fracture risk. Several other biochemical markers related to bone and glucose metabolism have been correlated with BMD and/or fracture risk in diabetes, including osteocyte-related markers such as sclerostin, HbA1c and advanced glycation end products (AGEs), inflammatory markers and adipokines, as well as IGF-1 and calciotropic hormones. Several biochemical markers and hormonal levels related to bone and/or glucose metabolism have been associated with skeletal parameters in diabetes. Currently, only HbA1c levels seem to provide a reliable estimate of fracture risk, while bone turnover markers could be used to monitor the effects of anti-osteoporosis therapy.

Effect of intratrial mean 25(OH)D concentration on diabetes risk, by race and weight: an ancillary analysis in the D2d study

BackgroundHigher serum 25-hydroxyvitamin D [25(OH)D] is associated with lower type 2 diabetes risk. 25(OH)D varies due to skin pigmentation and weight. ObjectivesThis analysis aims to determine whether the effect of vitamin D differs among people of color and those with overweight/obesity (who have higher diabetes risk) compared with individuals who are White or have normal weight. MethodsThe D2d study is a randomized clinical trial in people with prediabetes that tested the effects of daily vitamin D3 4000 IU vs. placebo on diabetes risk (median followup 2.5 y). We compared baseline and intratrial mean 25(OH)D concentrations, defined as the mean of all available annual 25(OH)D values, among groups defined by self-reported race and body mass index (BMI). We used Cox proportional hazards models to assess the associations between intratrial mean 25(OH)D and diabetes risk by race- and BMI-based groups. ResultsAsian (n=130), Black (n=616), and White (n=1616) participants were included. Both baseline and intratrial mean 25(OH)D concentrations differed significantly by race groups (both P < 0.001) and were lower in Asian and Black vs. White participants, and in those with higher vs. lower BMI adjusted for race (both P < 0.001). Compared with those with lower concentrations, Black and White participants with intratrial mean 25(OH)D ≥ 40 ng/mL had significantly reduced diabetes risk [HR (95% CI): Black: 0.51 (0.29, 0.92); White: 0.42 (0.30, 0.60)] and with a similar reduction in diabetes risk among Asian participants: 0.39 (0.14, 1.11). Compared with those with lower concentrations, participants with baseline BMI < 40 kg/m2 who achieved intratrial mean 25(OH)D concentrations ≥ 40 ng/mL had a significantly reduced diabetes risk. There was no statistically significant interaction between intratrial 25(OH)D and race or between intratrial 25(OH)D and BMI on diabetes risk. ConclusionsAmong people with prediabetes, particularly for Black and White race groups and those with BMI < 40 kg/m2, the optimal 25(OH)D concentration may be ≥ 40 ng/mL to optimize diabetes-prevention efforts.This trial was registered at clinicaltrials.gov as NCT01942694.

Abstract P603: Diet Quality Scores Measured With Standard and Modified Component Weights Are Associated With Mortality Risk in the Multiethnic Cohort

Introduction: The Dietary Patterns Methods Project reported higher scores of four selected dietary indices were all inversely associated with mortality risk. Diet quality components are generally weighted equally but previous meta-analyses and NHANES analyses suggest some may be more integral for mortality risk reduction. Thus, we examined if modified weight (vs. standard) Healthy Eating Index (HEI)-2015 scores were differently associated with all-cause and cardiovascular (CVD) mortality risks. Hypothesis: High modified weight (vs. standard) HEI-2015 scores will be associated with stronger mortality risk reduction. Methods: Data from adults (n=156,863) enrolled in the Multiethnic Cohort (MEC) Study recruited between 1993-96 from Hawaii and California with vital status and dietary data were analyzed. Baseline diet quality was assessed with the HEI-2015 using a food frequency questionnaire. Standard component weights of 5 or 10 points on 9 adequacy and 4 moderation components were reweighted creating two modified HEI scores, the Key Facets HEI with equally weighted fruits, vegetables, whole grains, and plant proteins and the Machine Learning (ML)-weighted HEI, calculated using weights reflecting relative component contributions to mortality risk from a prior analysis of NHANES III adults using LASSO models. All 3 HEI scores were assigned to deciles; sex-stratified, adjusted Cox models evaluated associations of HEI deciles with all-cause and CVD mortality risk. Results: Participants represented 5 ethnic groups (24% White, 16% African American, 23% Latino, 29% Japanese American, and 7% Native Hawaiian), and 55.3% were women. The mean age was 59.1 years, mean BMI was 26.4 kg/m 2 , and 27.3% were college graduates. For men and women, high scores (≥90th, vs. &lt;10th percentile) on all HEIs were significantly associated (p&lt;0.05) with 10% to 24% reduced all-cause and CVD mortality risks. Conclusions: Similar mortality risk reductions were observed for standard and modified weight diet quality scores in this sample.

Safety and cardiometabolic efficacy of novel antidiabetic drugs

ABSTRACT Introduction There are three major drug classes discussed in this review: dipeptidyl dipeptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAS), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. A literature review of the landmark cardiovascular outcome trials from 2008 to 2021 was conducted. Areas covered The cumulative data shown in this review suggest that in patients with Type 2 Diabetes (T2D), SGLT2 inhibitors and GLP-1 RAS may reduce cardiovascular (CV) risk. Specifically, in the heart failure (HF) population, SGLT2 inhibitors have shown a reduction in hospitalizations in some randomized controlled trials (RCTs). DPP4 inhibitors have not shown a similar reduction in CV risk and even exhibited an increase in hospitalizations for HF in one RCT. It is important to note that the DPP4 inhibitors did not demonstrate an increase in major CV events, with the exception of the increase in HF hospitalizations in the SAVOR TIMI 53 trial. Expert Opinion Future avenues of research to explore include the use of novel antidiabetic agents to reduce post-myocardial infarction (MI) CV risk and arrhythmias independent of their use as diabetic agents.

Reduced dose direct oral anticoagulants compared with warfarin with high time in therapeutic range in nonvalvular atrial fibrillation

Direct oral anticoagulants (DOACs) used in nonvalvular atrial fibrillation (NVAF) are dose-reduced in elderly and patients with impaired renal function. Only reduced dose dabigatran is concluded as having similar stroke risk reduction and lower risk of major bleeding than warfarin in the pivotal studies. In clinical practice, reduced dose is prescribed more often than expected making this an important issue. The objective of this study was to compare effectiveness and safety between reduced dose DOACs and high TTR warfarin treatment (TTR ≥ 70%) in NVAF. A Swedish anticoagulation registry was used in identifying eligible patients from July 2011 to December 2017. The study cohort consisted of 40,564 patients with newly initiated DOAC (apixaban, dabigatran, or rivaroxaban) (11,083 patients) or warfarin treatment (29,481 patients) after exclusion of 374,135 patients due to not being warfarin or DOAC naïve, not being prescribed reduced dose, having previous mechanical heart valve (MHV), or being under 18 years old. The median durations of follow up were 365, 419, 432 and 473 days for apixaban, dabigatran, rivaroxaban and warfarin, respectively. Warfarin TTR identified from Auricula was 70.0%. Endpoints (stroke and major bleeding) and baseline characteristics were collected from hospital administrative registers using ICD-10 codes. Cohorts were compared using weighted adjusted Cox regression after full optimal matching based on propensity scores. DOACs are associated with lower risk of major bleeding (HR with 95% CI) 0.85 (0.78–0.93), intracranial bleeding HR 0.64 (0.51–0.80), hemorrhagic stroke HR 0.68 (0.50–0.92), gastrointestinal bleeding HR 0.81 (0.69–0.96) and all-cause stroke HR 0.87 (0.76–0.99), than warfarin. Apixaban and dabigatran are associated with lower risk of major bleeding, HR 0.70 (0.63–0.78) and HR 0.80 (0.69–0.94), and rivaroxaban is associated with lower risk of ischemic stroke, HR 0.73 (0.59–0.96), with higher major bleeding risk, HR 1.31 (1.15–1.48), compared to warfarin. Apixaban is associated with higher all-cause mortality compared to warfarin, HR 1.12 (1.03–1.21). DOACs are associated with lower risk of major bleeding and all-cause stroke, than high quality warfarin treatment, with exception of rivaroxaban that carried higher risk of major bleeding and lower risk of stroke or systemic embolism. In this large observational registry-based NVAF cohort, DOACs are preferred treatment in patients with indication for DOAC dose reduction, even in a high TTR setting.