Search

Aims Patients with coronary artery disease (CAD) and patients with peripheral artery disease (PAD) are at risk for major adverse cardiovascular events (MACE) and major adverse limb events (MALE). There are limited data regarding dietary patterns and the risk of recurrent MACE and MALE in CAD and PAD patients. We aimed to identify dietary patterns associated with MACE and MALE in patients with CAD and/or PAD. Methods and results We analysed data collected from patients enrolled into the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, in which diet was assessed by a short food frequency questionnaire (FFQ) at baseline. Two dietary pattern scores, the modified Alternate Healthy Eating Index (mAHEI) and Mediterranean Diet Score (mMDS), were calculated. We tested the association between mAHEI and mMDS and the incidence of MACE and/or MALE. The mean mAHEI score was 23.0 ± 7.7 (out of 70) overall and was similar comparing CAD and PAD patients. The incidence of MACE or MALE was 6.3% in the lowest diet quality quartile (as assessed by mAHEI) compared with 4.2% in the highest quartile over 30 months. In the fully adjusted model, the hazard ratio of a low diet quality (Quartile 1) compared with the highest (Quartile 4) for MACE or MALE was 1.27 (95% CI: 1.08–1.49; P = 0.004, Q1 vs. Q4). This excess hazard was primarily driven by higher MACE in both the CAD and PAD cohorts. Conclusions Poor diet quality as assessed by the mAHEI is independently associated with a higher risk of recurrent MACE and MALE in patients with chronic CAD and/or PAD.

Remarkable progress has been made in the pharmacological management of patients with cardiovascular disease, including the frequent use of antithrombotic agents. Nonetheless, bleeding complications remain frequent and potentially life-threatening. Therapeutic interventions relying on prompt antithrombotic drug reversal or removal have been developed to assist clinicians in treating patients with active bleeding or an imminent threat of major bleeding due to urgent surgery or invasive procedures. Early phase studies on these novel strategies have shown promising results using surrogate pharmacodynamic endpoints. However, the benefit of reversing/removing antiplatelet or anticoagulant drugs should always be weighed against the possible prothrombotic effects associated with withdrawal of antithrombotic protection, bleeding, and surgical trauma. Understanding the ischemic-bleeding risk tradeoff of antithrombotic drug reversal and removal strategies in the context of urgent high-risk settings requires dedicated clinical investigations, but challenges in trial design remain, with relevant practical, financial, and ethical implications.

Background: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. Methods: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. Results: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m 2 and 63.8±14.0 g/m 2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was –0.30 g/m 2 (–2.1 to 1.5 g/m 2 ; P =0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20–105 pg/mL) and 55 pg/mL (21–132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were –1.3 mm Hg (–5.2 to 2.6 mm Hg; P =0.52), 0.69 mm Hg (–1.9 to 3.3 mm Hg; P =0.60), and –6.1 pg/mL (–37.0 to 24.8 pg/mL; P =0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. Conclusions: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04461041.

To investigate risk factors and outcomes of cardiogenic shock complicating acute myocardial infarction (AMI-CS) in young patients with AMI.AMI-CS is associated with high morbidity and mortality rates. Data regarding AMI-CS in younger individuals are limited.Consecutive patients with type 1 AMI aged 18-50 years admitted to 2 large tertiary-care academic centers were included, and they were adjudicated as having cardiogenic shock (CS) by physician review of electronic medical records using the Society for Cardiovascular Angiography and Interventions CS classification system. Outcomes included all-cause mortality (ACM), cardiovascular mortality (CVM) and 1-year hospitalization for heart failure (HHF). In addition to using the full population, matching was also used to define a comparator group in the non-CS cohort. Among 2097 patients (mean age 44 ± 5.1 years, 74% white, 19% female), AMI-CS was present in 148 (7%). Independent risk factors of AMI-CS included ST-segment elevation myocardial infarction, left main disease, out-of-hospital cardiac arrest, female sex, peripheral vascular disease, and diabetes. Over median follow-up of 11.2 years, young patients with AMI-CS had a significantly higher risk of ACM (adjusted HR 2.84, 95% CI 1.68-4.81; P0.001), CVM (adjusted HR 4.01, 95% CI 2.17-7.71; P0.001), and 1-year HHF (adjusted HR 5.99, 95% CI 2.04-17.61; P = 0.001) compared with matched non-AMI-CS patients. Over the course of the study, there was an increase in the incidence of AMI-CS among young patients with MI as well as rising mortality rates for patients with both AMI-CS and non-AMI-CS.Of young patients with AMI, 7% developed AMI-CS, which was associated with a significantly elevated risk of mortality and HHF.

THEMIS is a double-blind, randomized trial of 19,220 patients with diabetes mellitus and stable coronary artery disease (CAD) comparing ticagrelor to placebo, in addition to aspirin. The present study aimed to describe the proportion of patients eligible and reasons for ineligibility for THEMIS within a population of patients with diabetes and CAD included in the Reduction of Atherothrombosis for Continued Health (REACH) registry. The THEMIS eligibility criteria were applied to REACH patients. THEMIS included patients ≥50 years with type 2 diabetes and stable CAD as determined by either a history of previous percutaneous coronary intervention, coronary artery bypass grafting, or documentation of angiographic stenosis of ≥50% of at least one coronary artery. Patients with prior myocardial infarction or stroke were excluded. In REACH, 10,156 patients had stable CAD and diabetes. Of these, 6515 (64.1%) patients had at least one exclusion criteria. From the remaining population, 784 patients did not meet inclusion criteria (7.7%) mainly due to absence of aspirin treatment (7.2%), yielding a 'THEMIS-eligible population' of 2857 patients (28.1% of patients with diabetes and stable CAD). The main reasons for exclusion were a history of myocardial infarction (53.1%), use of oral anticoagulation (14.5%), or history of stroke (12.9%). Among the 4208 patients with diabetes and a previous PCI, 1196 patients (28.4%) were eligible for inclusion in the THEMIS-PCI substudy. In a population of patients with diabetes and stable coronary artery disease, a sizeable proportion appear to be 'THEMIS eligible.' http://www. gov identifier: NCT01991795. The THEMIS trial was funded by AstraZeneca. The REACH registry was sponsored by Sanofi, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan) and is endorsed by the World Heart Federation. Sí

Dietary interventions may best be delivered at supermarkets, which offer convenience, accessibility, full food inventories and, increasingly, in-store registered dietitians, online shopping and delivery services. In collaboration with a large retail supermarket chain, we conducted a multisite supermarket and web-based intervention targeting nutrition trial (no. NCT03895580), randomizing participants (n = 247 (139 women and 108 men)) 2:2:1 to two levels of dietary education (Strategy 1 and Strategy 2) or an enhanced control group that included educational components beyond the routine standard of care. Both Strategies 1 and 2 included individualized, in-person, dietitian-led, purchasing data-guided interventions. Strategy 2 also included online tools for shopping, home delivery, selection of healthier purchases, meal planning and healthy recipes. The primary endpoint was change in dietary approaches to stop hypertension (DASH) score (a measure of adherence to the DASH diet) from baseline to 3 months. The primary endpoint was met because, at 3 months, the DASH score increased by 4.7 more for the combined Strategy 1 and Strategy 2 groups than for the control group (95% confidence interval (CI) (0.9, 8.5), P = 0.02). In a prespecified hierarchical test, at 3 months, DASH score increased by 3.8 more for the Strategy 2 group than for the Strategy 1 group (95% CI (0.8, 6.9), P = 0.01). This trial demonstrates the efficacy of data-guided, supermarket-based, dietary interventions and modern online shopping tools in improving dietary quality in a free-living, community-based population. The trial also demonstrates the opportunity for academic investigators to collaborate with retailers to design and rigorously test comprehensive healthcare interventions.

It is unclear whether health status and cognitive function assessments can augment traditional coronary artery disease (CAD) and peripheral artery disease (PAD) biomedical risk prediction frameworks. We examined the association between health status and cognitive function and subsequent adverse cardiovascular and limb events in CAD and PAD.Stable CAD and PAD patients from the international, multi-center COMPASS trial completed the visual analogue scale, (VAS) of the EQ-5D-3L to assess overall health status, and the Digit Symbol Substitution test (DSST) to assess cognitive function. Main outcomes were incident development of major adverse cardiovascular events, and the combined endpoint major adverse cardiovascular or limb events. The EQ VAS (per 10 unit increase) and DSST (per 5 unit increase) were added to fully adjusted (medications, demographics, cardiovascular history and risk factors) hierarchical Cox regression models.A total of 23,433 patients were in the CAD cohort and 6,899 in the PAD cohort. Among both the CAD and PAD groups, higher scores on the EQ VAS (CAD: HR = 0.89, 95%CI 0.88-0.89; PAD HR = 0.89, 95%CI 0.88-0.89) and DSST (CAD HR = 0.95, 95%CI 0.94-0.95) (PAD HR = 0.95, 95%CI 0.94-0.95) were associated with a lower risk of a major adverse cardiovascular or limb events. Population attributable risks associated with the lower two quartiles vs. upper quartiles for the EQ-5D and DSST scores were 7% and 16%, respectively in the CAD cohort; and for PAD, at 14% and 18%, respectively.Adding health status and cognitive functioning information to biomedical evaluations can augment cardiovascular risk-stratification in CAD and PAD.In patients with heart and vascular disease, filling out quick standard test that evaluates your health status and completing a 2-minute cognitive test that evaluates aspects such as speed and attention, reveals important information about your future heart and vascular risk. Lower scores on these tests were associated with a higher risk of dying from cardiovascular causes, risk of getting a heart attack, stroke, or amputation, even after controlling for many other known risk factors.These insights may help our understanding of who is at higher risk of future heart and vascular events, and may give us new angles for interventions that may help prevent this risk, such whole person interventions improving physical fitness, mental health, and cognitive functioning.

AIMS: Influenza vaccination is associated with reduced cardiopulmonary morbidity and mortality among patients with heart failure or recent myocardial infarction. The immune response to vaccination frequently results in mild adverse reactions (AR), which leads to vaccine hesitancy. This post hoc analysis explored the association between vaccine-related AR and morbidity and mortality in patients with high-risk cardiovascular disease. METHODS AND RESULTS: The INVESTED trial randomized 5260 patients with recent heart failure hospitalization or acute myocardial infarction to high-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine. We examined the association between vaccine-related AR and adverse clinical outcomes across both treatment groups in propensity-adjusted models. Among 5210 participants with available information on post-vaccination symptoms, 1968 participants (37.8%) experienced a vaccine-related AR. Compared to those without AR, post-vaccination AR, most commonly injection site pain (60.3%), were associated with lower risk for the composite of all-cause death or cardiopulmonary hospitalization (hazard ratio [HR] 0.83 [95% CI, 0.75–0.92], p

Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes.We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age ≥18 years), large (≥500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression (standardised to a definition of a sustained ≥50% decrease in estimated glomerular filtration rate [eGFR] from randomisation, a sustained low eGFR, end-stage kidney disease, or death from kidney failure), acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618.We identified 13 trials involving 90 413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90 409 participants (74 804 [82·7%] participants with diabetes [99% with type 2 diabetes] and 15 605 [17·3%] without diabetes; trial-level mean baseline eGFR range 37-85 mL/min per 1·73 mIn addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.UK Medical Research Council and Kidney Research UK.

Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo. Results: The median age was 68 years, 23% of participants were women, 51% had ST-segment–elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity, with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian versus placebo: hazard ratio, 0.98 [90% CI, 0.71–1.35]). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian 20 and 50 mg versus placebo: hazard ratio, 1.05 [90% CI, 0.69–1.61]). Conclusions: In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients who experienced acute MI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04304534; URL: https://www.clinicaltrialsregister.eu/ctr-search/search ; Unique identifier: 2019-003244-79.

Contrast-associated AKI may result in higher morbidity and mortality. Intravenous fluid administration remains the mainstay for prevention. There is a lack of consensus on the optimal administration strategy. We studied the association of periprocedure fluid administration with contrast-associated AKI, defined as an increase in serum creatinine of at least 25% or 0.5 mg/dl from baseline at 3-5 days after angiography, and 90-day need for dialysis, death, or a 50% increase in serum creatinine.We conducted a secondary analysis of 4671 PRESERVE participants who underwent angiographic procedures. Although fluid type was randomized, strategy of administration was at the discretion of the clinician. We divided the study cohort into quartiles by total fluid volume. We performed multivariable logistic regression, adjusting for clinically important covariates. We tested for the interaction between fluid volume and duration of fluid administration, categorized as6 or ≥6 hours.The mean (SD) age was 70 (8) years, 94% of participants were male, and median (interquartile range) eGFR was 60 (41-60) ml/min per 1.73 mWe found that administration of a total volume of 1000 ml, starting at least 1 hour before contrast injection and continuing postcontrast for a total of 6 hours, is associated with a similar risk of adverse outcomes as larger volumes of intravenous fluids administered for periods6 hours. Mean fluid volumes964 ml may be associated with a higher risk for the primary outcome, although residual confounding cannot be excluded.

The SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial showed the safety but not efficacy of the Symplicity system (Medtronic, Santa Rosa, CA, USA) at 6 months follow-up in patients with treatment-resistant hypertension. This final report presents the 36-month follow-up results.SYMPLICITY HTN-3 was a single-blind, multicentre, sham-controlled, randomised clinical trial, done in 88 centres in the USA. Adults aged 18-80 years, with treatment-resistant hypertension on stable, maximally tolerated doses of three or more drugs including a diuretic, who had a seated office systolic blood pressure of 160 mm Hg or more and 24 h ambulatory systolic blood pressure of 135 mm Hg or more were randomly assigned (2:1) to receive renal artery denervation using the single electrode (Flex) catheter or a sham control. The original primary endpoint was the change in office systolic blood pressure from baseline to 6 months for the renal artery denervation group compared with the sham control group. Patients were unmasked after the primary endpoint assessment at 6 months, at which point eligible patients in the sham control group who met the inclusion criteria (office blood pressure ≥160 mm Hg, 24 h ambulatory systolic blood pressure ≥135 mm Hg, and still prescribed three or more antihypertensive medications) could cross over to receive renal artery denervation. Changes in blood pressure up to 36 months were analysed in patients in the original renal artery denervation group and sham control group, including those who underwent renal artery denervation after 6 months (crossover group) and those who did not (non-crossover group). For comparisons between the renal artery denervation and sham control groups, follow-up blood pressure values were imputed for patients in the crossover group using their most recent pre-crossover masked blood pressure value. We report long-term blood pressure changes in renal artery denervation and sham control groups, and investigate blood pressure control in both groups using time in therapeutic blood pressure range analysis. The primary safety endpoint was the incidence of all-cause mortality, end stage renal disease, significant embolic event, renal artery perforation or dissection requiring intervention, vascular complications, hospitalisation for hypertensive crisis unrelated to non-adherence to medications, or new renal artery stenosis of more than 70% within 6 months. The trial is registered with ClinicalTrials.gov, NCT01418261.From Sep 29, 2011, to May 6, 2013, 1442 patients were screened, of whom 535 (37%; 210 [39%] women and 325 [61%] men; mean age 57·9 years [SD 10·7]) were randomly assigned: 364 (68%) patients received renal artery denervation (mean age 57·9 years [10·4]) and 171 (32%) received the sham control (mean age 56·2 years [11·2]). 36-month follow-up data were available for 219 patients (original renal artery denervation group), 63 patients (crossover group), and 33 patients (non-crossover group). At 36 months, the change in office systolic blood pressure was -26·4 mm Hg (SD 25·9) in the renal artery denervation group and -5·7 mm Hg (24·4) in the sham control group (adjusted treatment difference -22·1 mm Hg [95% CI -27·2 to -17·0]; p≤0·0001). The change in 24 h ambulatory systolic blood pressure at 36 months was -15·6 mm Hg (SD 20·8) in the renal artery denervation group and -0·3 mm Hg (15·1) in the sham control group (adjusted treatment difference -16·5 mm Hg [95% CI -20·5 to -12·5]; p≤0·0001). Without imputation, the renal artery denervation group spent a significantly longer time in therapeutic blood pressure range (ie, better blood pressure control) than patients in the sham control group (18% [SD 25·0] for the renal artery denervation group vs 9% [SD 18·8] for the sham control group; p≤0·0001) despite a similar medication burden, with consistent and significant results with imputation. Rates of adverse events were similar across treatment groups, with no evidence of late-emerging complications from renal artery denervation. The rate of the composite safety endpoint to 48 months, including all-cause death, new-onset end-stage renal disease, significant embolic event resulting in end-organ damage, vascular complication, renal artery re-intervention, and hypertensive emergency was 15% (54 of 352 patients) for the renal artery denervation group, 14% (13 of 96 patients) for the crossover group, and 14% (10 of 69 patients) for the non-crossover group.This final report of the SYMPLICITY HTN-3 trial adds to the totality of evidence supporting the safety of renal artery denervation to 36 months after the procedure. From 12 months to 36 months after the procedure, patients who were originally randomly assigned to receive renal artery denervation had larger reductions in blood pressure and better blood pressure control compared with patients who received sham control.Medtronic.

OBJECTIVE In patients with moderate to severe albuminuric kidney disease, sodium–glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to RESULTS Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38–0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001). CONCLUSIONS Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease.

Risk prediction following ST-Elevation Myocardial Infarction (STEMI) in resource limited countries is critical to identify patients at an increased risk of mortality who might benefit from intensive management.North India ST-Elevation Myocardial Infarction (NORIN-STEMI) is an ongoing registry that has prospectively enrolled 3,635 STEMI patients. Of these, 3191 patients with first STEMI were included. Patients were divided into two groups: development (n=2668) and validation (unseen) dataset (n=523). Various ML strategies were used to train and tune the model based on validation dataset results that included 31 clinical characteristics. These models were compared in sensitivity, specificity, F1-score, receiver operating characteristic area under the curve (AUC), and overall accuracy to predict mortality at 30 days. ML model decision making was analyzed using the Shapley Additive exPlanations (ShAP) summary plot.At 30 days, the mortality was 7.7%. On the validation dataset, Extra Tree ML model had the best predictive ability with sensitivity: 85%, AUC: 79.7%, and Accuracy: 75%. ShAP interpretable summary plot determined delay in time to revascularization, baseline cardiogenic shock, left ventricular ejection fraction30%, age, serum creatinine, heart failure on presentation, female sex, and moderate-severe mitral regurgitation to be major predictors of all-cause mortality at 30 days (P0.001 for all).ML models lead to an improved mortality prediction following STEMI. ShAP summary plot for the interpretability of the AI model helps to understand the model's decision in identifying high-risk individuals who may benefit from intensified follow-up and close monitoring.

Low dose enteric-coated aspirin (EC-ASA) is routinely used for secondary cardiovascular event prevention. However, absorption of EC tablets is poor, which can result in subtherapeutic antiplatelet effects. Phospholipid-aspirin liquid filled capsules (PL-ASA) are a novel FDA-approved immediate-release formulation designed to reduce gastrointestinal (GI) injury by limiting direct contact with the stomach lining. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of PL-ASA versus EC-ASA at a low dose. This randomized, open-label, crossover study assessed PK and PD following a single 81-mg dose of PL-ASA versus EC-ASA under fasting conditions in 36 volunteers without cardiovascular disease between 18 and 75 years of age. Volunteers were randomly assigned 1:1 to either PL-ASA then EC-ASA or vice versa with a minimum 14-day washout. Assessments included PK parameters for acetylsalicylic acid and salicylic acid, platelet aggregation in response to arachidonic acid (AA), and serum thromboxane B2 (TxB2) assessments over 24 h. PL-ASA was rapidly absorbed. PL-ASA reached Tmax 3 h earlier (1.01 vs. 4.00 h, p max (720 vs. 368 ng/mL, p 0-t: 601 vs. 416 h*ng/mL, p = 0.0013) compared with EC-ASA. Within 1 h of dosing, PL-ASA achieved significantly lower residual platelet aggregation, which persisted for the full 24 h (median AA-LTA was 47% with PL-ASA vs. 80.5% with EC-ASA; p = 0.0022 at hour-24). Treatment with PL-ASA also resulted in significantly lower serum TxB2 concentrations at each time point compared with EC-ASA (all p-values Clinical Trial Registration ClinicalTrials.gov identifier: NCT04811625.

OBJECTIVE To investigate trends, optimal levels for cardiometabolic risk factors, and multifactorial risk control in diabetic nephropathy and end-stage kidney disease (ESKD) in patients with diabetes and matched control subjects. RESEARCH DESIGN AND METHODS This study included 701,622 patients with diabetes from the Swedish National Diabetes Register and 2,738,137 control subjects. Trends were analyzed with standardized incidence rates. Cox regression was used to assess excess risk, optimal risk factor levels, and risk according to the number of risk factors, in diabetes. RESULTS ESKD incidence among patients with and without diabetes initially declined until 2007 and increased thereafter, whereas diabetic nephropathy decreased throughout follow-up. In patients with diabetes, baseline values for glycated hemoglobin, systolic blood pressure (SBP), triglycerides, and BMI were associated with outcomes. Hazard ratio (HR) for ESKD for patients with type 2 diabetes who had all included risk factors at target was 1.60 (95% CI 1.49–1.71) compared with control subjects and for patients with type 1 diabetes 6.10 (95% CI 4.69–7.93). Risk for outcomes increased in a stepwise fashion for each risk factor not at target. Excess risk for ESKD in type 2 diabetes showed a HR of 2.32 (95% CI 2.30–2.35) and in type 1 diabetes 10.92 (95% CI 10.15–11.75), compared with control. CONCLUSIONS Incidence of diabetic nephropathy has declined substantially, whereas ESKD incidence has increased. Traditional and modifiable risk factors below target levels were associated with lower risks for outcomes, particularly notable for the causal risk factors of SBP and HbA1c, with potential implications for care.

Aims To compare the effectiveness and safety of clopidogrel, ticagrelor, and prasugrel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). Methods and results Nationwide, registry-based study of STEMI patients treated with primary PCI (2011–17) and subsequently with aspirin and a P2Y12 inhibitor. The effectiveness outcome was major adverse cardiovascular events (MACE) defined as a composite of recurrent myocardial infarction, repeat revascularization, stroke, or cardiovascular death at 12 months. The safety outcome was bleeding requiring hospitalization at 12 months. Multivariable logistic regression with average treatment effect modeling was used to calculate absolute and relative risks for outcomes standardized to the distributions of demographic characteristics of all included subjects. We included 10 832 patients; 1 697 were treated with clopidogrel, 7 508 with ticagrelor, and 1,627 with prasugrel. Median ages were 66, 63, and 59 years (P Conclusion Ticagrelor and prasugrel were associated with lower risks of MACE after STEMI than clopidogrel, and ticagrelor was associated with a marginal reduction compared with prasugrel. The risk of bleeding was lower with ticagrelor compared with clopidogrel, but did not significantly differ between ticagrelor and prasugrel.

AimsTo describe clinical characteristics and outcomes for those with STEMI and reduced left ventricular ejection fraction (LVEF) in low-income and middle-income countries (LMICs).Methods and resultsAdults presenting with STEMI to two government-owned tertiary care centres in Delhi, India were prospectively enrolled in the North India ST-elevation myocardial infarction (NORIN-STEMI) registry. LVEF was evaluated at presentation and clinical characteristics were compared across LVEF categories. Overall, 3597 patients were included, of whom 468 (13%) had LVEF >50%, 1482 (41%) had mildly reduced LVEF (40-49%), 1357 (38%) had moderately reduced LVEF (30-39%), and 290 (8%) had severely reduced LVEF (24h, prior MI, and hyperlipidaemia were associated with decreasing LVEF category. Although most patients with reduced LVEF were discharged on appropriate guideline-directed therapies, adherence at 1year was low (ACE inhibitor/ARB 91% to 41%, beta blocker 98% to 78%, aldosterone receptor antagonist 69% to 6%). After multivariable adjustment, a Cox regression model showed moderately reduced LVEF (HR 1.77, 95% CI 1.20, 2.60) and severely reduced LVEF (HR 3.63, 95% CI 2.41, 5.48) were associated with increased risk of all-cause mortality compared with LVEF ≥50%.ConclusionsOn presentation for STEMI, almost 90% of NORIN-STEMI participants had at least mildly reduced LVEF and almost half had LVEF

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID-19 pandemic, cases of DKA have also been reported in cases of COVID-19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of serious illness and suggest they are not recommended for routine in-hospital use. However, recent data suggest potential beneficial effects of SGLT2 inhibitors in the setting of acute illness with COVID-19 with no increase in adverse events and low rates of DKA, which were non-severe. Given the low rates of DKA in cardiovascular outcome trials and in hospitalized patients with type 2 diabetes, the potential for SGLT2 inhibitors not being re-initiated following discharge and their cardiovascular and kidney benefits, we believe the practice of routine 'sick day' guidance should be re-examined based on current evidence with a call for further research in this area. Furthermore, high-quality trials of initiation of SGLT2 inhibitors in people admitted to hospital with cardiovascular disease or kidney disease, and trials of continuation of SGLT2 inhibitors in people, with careful monitoring of DKA should be conducted. These should be further supplemented with large observational studies.

Background: The role of diabetes in the development of valvular heart disease, and, in particular, the relation with risk factor control, has not been extensively studied. Methods: We included 715 143 patients with diabetes registered in the Swedish National Diabetes Register and compared them with 2 732 333 matched controls randomly selected from the general population. First, trends were analyzed with incidence rates and Cox regression, which was also used to assess diabetes as a risk factor compared with controls, and, second, separately in patients with diabetes according to the presence of 5 risk factors. Results: The incidence of valvular outcomes is increasing among patients with diabetes and the general population. In type 2 diabetes, systolic blood pressure, body mass index, and renal function were associated with valvular lesions. Hazard ratios for patients with type 2 diabetes who had nearly all risk factors within target ranges, compared with controls, were as follows: aortic stenosis 1.34 (95% CI, 1.31–1.38), aortic regurgitation 0.67 (95% CI, 0.64–0.70), mitral stenosis 1.95 (95% CI, 1.76–2.20), and mitral regurgitation 0.82 (95% CI, 0.79–0.85). Hazard ratios for patients with type 1 diabetes and nearly optimal risk factor control were as follows: aortic stenosis 2.01 (95% CI, 1.58–2.56), aortic regurgitation 0.63 (95% CI, 0.43–0.94), and mitral stenosis 3.47 (95% CI, 1.37–8.84). Excess risk in patients with type 2 diabetes for stenotic lesions showed hazard ratios for aortic stenosis 1.62 (95% CI, 1.59–1.65), mitral stenosis 2.28 (95% CI, 2.08–2.50), and excess risk in patients with type 1 diabetes showed hazard ratios of 2.59 (95% CI, 2.21–3.05) and 11.43 (95% CI, 6.18–21.15), respectively. Risk for aortic and mitral regurgitation was lower in type 2 diabetes: 0.81 (95% CI, 0.78–0.84) and 0.95 (95% CI, 0.92–0.98), respectively. Conclusions: Individuals with type 1 and 2 diabetes have greater risk for stenotic lesions, whereas risk for valvular regurgitation was lower in patients with type 2 diabetes. Patients with well-controlled cardiovascular risk factors continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control.

Background: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl—Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk. Methods: Serum levels of interleukin-1β, interleukin-6, high-sensitivity C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured at baseline, at 12 months, at 24 months, and at the end-of-study visit among REDUCE-IT participants with triglyceride levels ≥ 135 mg/dL and Results: At baseline, median levels of each biomarker were similar in the 2 treatment groups. The levels of biomarkers associated with atherosclerosis increased over time among those allocated to mineral oil treatment; in this group at 12 months, the median percent increases from baseline were 1.5% for homocysteine, 2.2% for lipoprotein(a), 10.9% for oxidized low-density lipoprotein cholesterol, 16.2% for interleukin-6, 18.5% for lipoprotein-associated phospholipase A2, 21.9% for high-sensitivity C-reactive protein, and 28.9% for interleukin-1β (all P values P values ≤0.007). These data are consistent with previous REDUCE-IT results in which the median percent change for low-density lipoprotein cholesterol at 12 months was −1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator. Conclusions: Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil. The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Background Data on Device-related Thrombus (DRT) after left atrial appendage closure (LAAC) remain scarce. This study aimed to investigate risk factors for DRT from centers reporting to the EUROC-DRT registry. Methods We included 537 patients (112 with DRT and 425 without DRT) who had undergone LAAC between 12/2008 and 04/2019. Baseline and implantation characteristics, anti-thrombotic treatment and clinical outcomes were compared between both groups in uni- and multivariate analyses. Additional propensity-score matching (PSM) was conducted to focus on the role of implantation characteristics. Results Patients with DRT showed higher rates of previous stroke/transient ischemic attack (TIA) (49.1% vs. 34.7%, p < 0.01), spontaneous echocardiographic contrast (SEC) (44.9% vs. 27.7%, p < 0.01) and lower left atrial appendage (LAA) peak emptying velocity (35.4 +/- 18.5 vs. 42.4 +/- 18.0 cm/s, p= 0.02). Occluders implanted in DRT patients were larger (25.5 +/- 3.8 vs. 24.6 +/- 3.5 mm, p =0.03) and implanted deeper in the LAA (mean depth: 7.6 +/- 4.7 vs. 5.7 +/- 4.7 mm, p

REDUCE-IT was a multinational, double-blind trial that randomized 8179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. IPE was associated with a substantial reduction in the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. Since the original publication of the trial, there have been a myriad of additional analyses confirming the benefit of IPE in various patient groups. Our objectives in this review are to summarize the key findings of the REDUCE-IT trial and its subsequent analyses as well as to call for the reevaluation and expansion of current guidelines to incorporate IPE as a therapy for patients at elevated cardiovascular risk with mild or moderate hypertriglyceridemia.

Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin–angiotensin–aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium–glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease.