Sacubitril-valsartan was shown to reduce all-cause mortality by 16% compared to enalapril in ambulatory patients with symptomatic heart failure with reduced ejection fraction (HFrEF). Thus, the development and validation of a risk prediction model for mortality in HFrEF, taking in consideration treatment options, has the potential to improve patient outcomes and allow for a better selection of therapies in HFrEF patients.
The aim is to develop and validate a mortality risk prediction model for HFrEF using real world data.
Electronic medical record data was sourced from Brigham and Women’s Hospital, two-thirds were randomly allocated to a derivation cohort and the other third to a validation cohort.
There were 2417 patients in the derivation cohort and 1033 in the validation cohort. The mortality rate was around 17% in both cohorts. Using the chi-square test, the main effect covariates that did significantly contribute to the model, as determined by a p-value of < 0.05, were included in the multivariable cox proportional model that includes: treatment intervention (ARNi or ACEi/ARBs), age, eGFR<60, prior renal and diabetes diagnosis, prior hospitalization, and current SGLT-2i use.
The Cox regression analysis revealed that ARNi administration has a lower hazard ratio(HR) of 0.755 (95%CI: 0.603–0.946) compared to ACEI/ARBs. Additionally, SGLT-2i showed a lower HR of 0.295 (95%CI: 0.187–0.467), further supporting its effectiveness in having longer time to all-cause mortality in HFrEF patients. The validation cohort showed that the adjusted model discriminated well with a ROCAUC = 0.696 (95%CI,0.65–0.73).
We have developed and validated a mortality risk prediction model based on routinely collected data of HFrEF patients. The model highlighted that ARNi and SGLT-2i had a longer time to all-cause mortality compared to those who didn't receive these treatments. The validation cohort showed that the adjusted model discriminated well between HFrEF patients who died and those who did survive.

INTRODUCTION
There is ongoing debate about the optimal choice of P2Y12 receptor inhibitors for treatment of acute coronary syndrome due to limited direct comparative evidence and concerns about the generalizability of some underpowered analyses. Real-world data provides a valuable source that can potentially validate and complement randomized trial findings in routine clinical practice.



AIMS
To examine whether real-world evidence from this observational database study supports the same guideline recommendations as the randomized controlled trial ISAR-REACT5.

METHODS
This study aimed to emulate ISAR-REACT5 as closely as possible. Propensity score matching on 71 preexposure characteristics was employed to balance confounders. Study protocols were registered before analysis began. The study utilized a German health claims database between 2013-2021. Eligibility criteria were closely adopted from ISAR-REACT5. A total of 17,642 propensity score-matched individuals (n=8,821, each) with acute coronary syndrome and either ticagrelor or prasugrel treatment after hospital discharge were analyzed. Primary outcome was the composite of all-cause mortality, myocardial infarction, or stroke within one year of treatment initiation. Safety outcome was bleeding. Outcomes of this study were compared to ISAR-REACT5 on predefined binary metrics, including regulatory and estimate agreement.



RESULTS
Concordance was quantified in 5 of 6 for regulatory agreement, and 6 of 6 for estimate agreement. The primary composite endpoint occurred in 9.2% of ticagrelor-treated individuals and 7.5% of those treated with prasugrel (HR, 1.24; 95% CI, 1.12-1.37). Safety end point bleeding revealed no significant differences between treatment groups. Subgroup analysis demonstrated superiority for prasugrel in individuals with ST-segment elevation myocardial infarction.



CONCLUSION
This study reiterates the superior effectiveness of prasugrel over ticagrelor in individuals with acute coronary syndrome undergoing invasive strategy in a real-world setting, particularly in those with ST-segment elevation myocardial infarction. It also highlights how carefully-designed observational studies can complement and extend findings from randomized trials, informing clinical decision making.

Introduction: Data suggests that low-dose aspirin may lower the risk of type 2 diabetes in healthy older adults, but its benefits for those with cardiovascular disease (CVD) are uncertain. Moreover, choosing between aspirin and clopidogrel for CVD management is controversial due to their varying effects on cardiovascular and bleeding events.

Aims: To compare the effects of low-dose aspirin versus clopidogrel on the risk of incident type 2 diabetes, cardiovascular events, and bleeding events among patients with CVD.

Methods: We emulated a pragmatic trial to compare aspirin and clopidogrel monotherapy among patients with coronary artery disease, stroke/transient ischaemic attack, or peripheral arterial disease. We used overlap and inverse probability of censoring weight to account for confounding and artificial censoring. We estimated the observational analogues of intention-to-treat (ITT) and per-protocol (PP) effects in hazard ratios (HRs) and eight-year absolute risk (AR) using pooled logistic regression models.

Results: 78,012 and 33,280 patients initiated aspirin or clopidogrel monotherapy after CVDs were included. Aspirin was not associated with a lower risk of diabetes (ITT effect: HR, 1.01; 95%CI, 0.96-1.07; AR, 13.2% vs 13.4%. PP effect: HR, 1.04; 95%CI, 0.96-1.12; AR, 13.5% vs 13.1%) or bleeding events (ITT effect: HR, 1.01; 95%CI, 0.95-1.06; AR, 13.2% vs 12.7%. PP effect: HR, 0.98; 95%CI, 0.91-1.07; AR, 12.6% vs 12.4%), compared with clopidogrel. Aspirin was associated with a higher risk of cardiovascular events than clopidogrel in ITT analysis (HR, 1.06; 95%CI, 1.02-1.11; AR, 21.1% vs 20.0%) but not in PP analysis (HR, 1.03; 95%CI, 0.98-1.09; AR, 17.9% vs 17.8%).

Discussion: Aspirin and clopidogrel have similar risks concerning incident diabetes, acute cardiovascular events, and bleeding events among patients with CVD. The results provide evidence of the real-world comparative effectiveness of the two most commonly used antiplatelet drugs and could guide the choice of antiplatelet therapy for patients without diabetes.

Introduction: Direct oral anticoagulants (DOACs) are commonly co-prescribed with digoxin, but whether there is a drug interaction between them is unclear.
Aims: To investigate potential drug-interactions between DOACs and digoxin.
Methods: We identified DOAC users during 1/1/2011-31/12/2019 using data from Clinical Practice Research Datalink Aurum in cohort design with propensity-score to compare the hazards of effectiveness outcomes (ischaemic stroke, myocardial infarction, venous thromboembolism, cardiovascular mortality, all-cause mortality) and safety outcomes (intracranial bleeding, gastrointestinal bleeding, other bleeding), respectively in DOAC+digoxin users versus DOAC+beta-blockers users. A case-crossover design was conducted to compare odds of exposure to different drug initiation patterns in hazard period versus referent period.
Results: Of 397,459 DOAC users, we identified 25,251 co-prescribed digoxin and 109,779 co-prescribed beta-blockers in cohort study. A lower proportion of DOAC+digoxin users were men (46%) in contrast with that of DOAC+beta-blocker users (53%). No increased risk of pharmacologically predictable DOAC safety outcomes or specific effectiveness outcomes was seen with DOAC+digoxin. A higher risk of all-cause mortality (hazard ratio[HR]:1.35; 99% CI:1.14–1.61) was observed with DOAC+digoxin, versus DOAC+beta-blockers. In the case-crossover study, a 20% higher odds of all-cause mortality was seen with initiating digoxin while taking DOAC (odds ratio[OR]:1.20; 99%CI:1.03–1.39); and a 60% higher odds was also seen with initiating DOAC while taking digoxin (OR:1.59; 99%CI:1.37–1.84).
Discussion/Conclusion: We found no increased risk of bleeding when DOACs are used with digoxin, suggesting combined use does not lead to drug-drug interaction. Future work is recommended to investigate the underlying mechanism of association with all-cause mortality.

Introduction: Oral anticoagulants (OACs) are essential for managing atrial fibrillation (AF) to prevent thrombotic events. However, they are frequently discontinued due to concerns about bleeding, particularly in patients who experience minor bleeding episodes.

Aims: To examine the association between the discontinuation of direct OACs (DOACs) and the incidence of stroke/transient ischemic attack (TIA) among older AF patients who experienced minor bleeding.

Methods: This target trial emulation study used a Japanese governmental claims database (Shizuoka Kokuho Database). Patients aged ≥65 with AF who initiated DOACs between 2013 and 2020 and experienced minor bleeding within 12 months were included. Minor bleeding was defined as outpatient bleeding not leading to hospitalization. We compared treatment assignment in patients who continued vs. discontinued DOACs within 2 months after minor bleeding, with discontinuation defined as a lapse of over 60 days without a prescription refill. Using the clone-censor-weight method, we assessed stroke/TIA events as the primary outcome. A per-protocol analysis was performed, adjusting for selection bias with inverse probability of artificial censoring weights and stabilized weights for death. Weighted pooled logistic models were used, adjusting for baseline covariates, including frailty, linear time, and squared time, with robust standard error estimation. We estimated approximate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Among 2,617 patients who initiated DOACs and experienced minor bleeding, the median age was 79 years (25th–75th percentile: 74–84), and 46% were women. A total of 270 patients discontinued DOACs within 2 months after minor bleeding, while 2,347 continued. Discontinuation was associated with a higher risk of stroke/TIA (adjusted HR [95% CI]: 1.82 [1.10-3.01]).

Discussion/Conclusion: Among contemporary older AF patients who initiated DOACs, discontinuation after minor bleeding was associated with an increased stroke/TIA risk. This finding underscores the importance of carefully considering the continuation of DOACs despite minor bleeding episodes.

Introduction: The utility of fish oil in reducing the risk of cardiovascular disease (CVD) mortality in people with diabetes remains unclear and inconsistent. Till date, no studies have investigated the effect of cardiovascular health (CVH) on the cardioprotective benefits of fish oil supplementation in people with diabetes.
Aims: To investigate the potential modifying effect of CVH level, as assessed using the Life’s Essential 8 (LE8) score, on the association between habitual fish oil supplementation and CVD mortality in people with type 2 diabetes (T2D).
Methods: Participants with T2D in the UK Biobank were included. CVH level was categorized by the mean LE8 score (55 points). Multivariable-adjusted Cox models were used to evaluate the longitudinal association between habitual fish oil supplementation status and CVD mortality. We performed stratified analysis across different CVH levels, and tested potential interaction between fish oil supplementation and CVH level.
Results: The analysis included 19,003 participants (mean age 59.9±6.9 years, 36.1% women), of whom 39.6% were habitual fish oil users. During a median follow-up of 13.7 years, 914 CVD deaths were documented. We found that habitual fish oil supplementation was significantly associated with a lower risk of CVD mortality among participants with better CVH (i.e., LE8 score ≥55 points; hazard ratio [HR]=0.65, 95% confidence interval [CI] 0.50–0.84, P<0.001), but not among those with poorer CVH (i.e., LE8 score <55 points; HR=1.02, 95% CI 0.83–1.25, P=0.867). The interaction between habitual fish oil supplementation and CVH level on CVD mortality was significant (P=0.017).
Conclusions: Only people with a relatively high baseline CVH level may obtain additional cardiovascular benefits from fish oil supplementation. The findings reinforced the great importance of promoting multilateral holistic lifestyle modification and interventions to improve the survival and quality of life of people with diabetes.

Keywords: Fish oil supplement, Life’s Essential 8, cardiovascular health