Heart Failure Risk Assessment Using Biomarkers in Patients With Atrial Fibrillation: Analysis From COMBINE-AF.

BACKGROUND: Heart failure (HF) is common among patients with atrial fibrillation (AF), and accurate risk assessment is clinically important. OBJECTIVES: The goal of this study was to investigate the incremental prognostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and growth differentiation factor (GDF)-15 for HF risk stratification in patients with AF. METHODS: Individual patient data from 3 large randomized trials comparing direct oral anticoagulants (DOACs) with warfarin (ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48], and RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy]) from the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) cohort were pooled; all patients with available biomarkers at baseline were included. The composite endpoint was hospitalization for HF (HHF) or cardiovascular death (CVD), and secondary endpoints were HHF and HF-related death. Cox regression was used, adjusting for clinical factors, and interbiomarker correlation was addressed using weighted quantile sum regression analysis. RESULTS: In 32,041 patients, higher biomarker values were associated with a graded increase in absolute risk for CVD/HHF, HHF, and HF-related death. Adjusting for clinical variables and all biomarkers, NT-proBNP (HR per 1 SD: 1.68; 95% CI: 1.59-1.77), hs-cTnT (HR: 1.39; 95% CI: 1.33-1.44), and GDF-15 (HR: 1.20; 95% CI: 1.15-1.25) were significantly associated with CVD/HHF. The discrimination of the clinical model improved significantly upon addition of the biomarkers (c-index: 0.70 [95% CI: 0.69-0.71] to 0.77 [95% CI: 0.76-0.78]; likelihood ratio test, P < 0.001). Using weighted quantile sum regression analysis, the contribution to risk assessment was similar for NT-proBNP and hs-cTnT for CVD/HHF (38% and 41%, respectively); GDF-15 provided a statistically significant but lesser contribution to risk assessment. Results were similar for HHF and HF-related death, individually, and across key subgroups of patients based on a history of HF, AF pattern, and reduced or preserved left ventricular ejection fraction. CONCLUSIONS: NT-proBNP, hs-cTnT, and GDF-15 contributed significantly and independently to the risk stratification for HF endpoints in patients with AF, with hs-cTnT being as important as NT-proBNP for HF risk stratification. Our findings support a possible future use of these biomarkers to distinguish patients with AF at low or high risk for HF.

Residual Stroke Risk Among Patients With Atrial Fibrillation Prescribed Oral Anticoagulants: A Patient-Level Meta-Analysis From COMBINE AF.

BACKGROUND: Despite oral anticoagulation, patients with atrial fibrillation (AF) remain at risk of ischemic stroke and systemic embolism (SE) events. For patients whose residual risk is sufficiently high, additional therapies might be useful to mitigate stroke risk. METHODS AND RESULTS: Individual patient data from 5 landmark trials testing oral anticoagulation in AF were pooled in A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in AF (COMBINE AF). We calculated the rate of ischemic stroke/SE among oral anticoagulation-treated patients with a CHA2DS2-VASc score≥2, across strata of CHA2DS2-VASc score, stroke history, and AF type, as either paroxysmal or nonparoxysmal. We included 71 794 patients with AF (median age 72 years, interquartile range, 13 years, 61.3% male) randomized to a direct oral anticoagulant or vitamin K antagonist, and followed for a mean of 2.1 (±0.8) years. The median CHA2DS2-VASc score was 4 (interquartile range, 3-5), 18.8% had a prior stroke, and 76.4% had nonparoxysmal AF. The overall rate of stroke/SE was 1.33%/y (95% CI, 1.27-1.39); 1.38%/y (95% CI, 1.31-1.45) for nonparoxysmal AF, and 1.15%/y (95% CI, 1.05-1.27) for paroxysmal AF. The rate of ischemic stroke/SE increased by a rate ratio of 1.36 (95% CI, 1.32-1.41) per 1-point increase in CHA2DS2-VASc, reaching 1.67%/y (95% CI, 1.59-1.75) ≥4 CHA2DS2-VASc points. Patients with both nonparoxysmal AF and CHA2DS2-VASc ≥4 had a stroke/SE rate of 1.75%/y (95% CI, 1.66-1.85). In patients with a prior stroke, the risk was 2.51%/y (95% CI, 2.33-2.71). CONCLUSIONS: AF type, CHA2DS2-VASc score, and stroke history can identify patients with AF, who despite oral anticoagulation have a residual stroke/SE risk of 1.5% to 2.5% per year. Evaluation of additional stroke/SE prevention strategies in high-risk patients is warranted.

Clonal hematopoiesis, cardiovascular events and treatment benefit in 63,700 individuals from five TIMI randomized trials.

Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of cardiovascular (CV) disease in the general population. Currently, it is unclear whether this association is observed in large clinical trial cohorts with a high burden of existing CV disease or whether CV therapies can mitigate CHIP-associated CV risk. To address these questions, we studied 63,700 patients from five randomized trials that tested established therapies for CV disease, including treatments targeting the proteins PCSK9, SGLT2, P2Y12 and FXa. During a median follow-up of 2.5 years, 7,453 patients had at least one CV event (CV death, myocardial infarction (MI), ischemic stroke or coronary revascularization). The adjusted hazard ratio (aHR) for CV events for CHIP+ patients was 1.07 (95% CI: 0.99-1.16, P = 0.08), with consistent risk estimates across each component of CV risk. Significant heterogeneity in the risk of MI was observed, such that CHIP+ patients had a 30% increased risk of first MI (aHR = 1.31 (1.05-1.64), P = 0.02) but no increased risk of recurrent MI (aHR = 0.94 (0.79-1.13), Pint = 0.008), as compared to CHIP- patients. Moreover, no significant heterogeneity in treatment effect between individuals with and without CHIP was observed for any of the therapies studied in the five trials. These results indicate that in clinical trial populations, CHIP is associated with incident but not recurrent coronary events and that the presence of CHIP does not appear to identify patients who will derive greater benefit from commonly used CV therapies.

Dose Reduction of Edoxaban in Patients 80 Years and Older With Atrial Fibrillation: Post Hoc Analysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial.

Importance: In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data. Objective: To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin. Design, Setting, and Participants: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023. Interventions: Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin. Main Outcomes and Measures: Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component. Results: The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03), particularly gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004), with no significant difference in efficacy end points. Findings were supported by analyses of endogenous factor Xa inhibition, a marker of anticoagulant effect, which was comparable between younger patients receiving edoxaban, 60 mg, and older patients receiving edoxaban, 30 mg. In 2406 patients 80 years and older with or without dose-reduction criteria, patients receiving edoxaban, 30 mg, vs warfarin had lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046), whereas rates of stroke or systemic embolism were comparable. Conclusions and Relevance: In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria. Trial Registration: ClinicalTrials.gov Identifier: NCT00781391.

Application of the Win Ratio Method in the ENGAGE AF-TIMI 48 Trial Comparing Edoxaban With Warfarin in Patients With Atrial Fibrillation.

BACKGROUND: Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization. RESULTS: 21 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05-1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05-1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use. CONCLUSIONS: In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.

The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis.

Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits.

Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk.

BACKGROUND: Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. METHODS: In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. RESULTS: A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. CONCLUSIONS: In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.).

Emergent Coronary Thrombectomy for Acute Myocardial Infarction Immediately Following Craniotomy with Tumor Resection.

The management of perioperative acute myocardial infarction (AMI) following oncologic neurosurgery requires balancing competing risks of myocardial ischemia and postoperative bleeding. There are limited human data to establish the safest timing of antiplatelet or anticoagulation therapy following neurosurgical procedures. For patients with malignancy experiencing AMI in the acute postoperative period, staged percutaneous coronary intervention (PCI) with upfront coronary aspiration thrombectomy followed by delayed completion PCI may offer an opportunity for myocardial salvage while minimizing postoperative bleeding risks. CYP2C19 genotyping and platelet aggregation studies can help confirm adequate platelet inhibition once antiplatelet therapy is resumed.

Long-Term Efficacy of Evolocumab in Patients With or Without Multivessel Coronary Disease.

BACKGROUND: In FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), during a median follow-up of 2.2 years, risk reduction for major adverse cardiovascular event with evolocumab was greater in patients with multivessel disease (MVD). The FOURIER Open-Label Extension (FOURIER-OLE) provides an additional median follow-up of 5 years. OBJECTIVES: The purpose of this study was to assess the long-term benefit of evolocumab in patients with and without MVD. METHODS: FOURIER randomized 27,564 patients to evolocumab vs placebo; 6,635 entered FOURIER-OLE. Patients with coronary artery disease were categorized based on the presence of MVD (≥40% stenosis in ≥2 large vessels). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary endpoint was cardiovascular death, myocardial infarction, or stroke. RESULTS: Of 23,656 patients in FOURIER with coronary artery disease, 25.4% had MVD; 5,887 patients continued into FOURIER-OLE. The risk reduction with initial allocation to evolocumab tended to be greater in patients with MVD than in those without: 23% (HR: 0.77 [95% CI: 0.68-0.87]) vs 11% (HR: 0.89 [95% CI: 0.82-0.96]) for the primary and 31% (HR: 0.69 [95% CI: 0.59-0.81]) vs 15% (HR: 0.85 [95% CI: 0.77-0.94]) for the key secondary endpoints (Pinteraction = 0.062 and Pinteraction = 0.031, respectively). The magnitude of benefit tended to grow during the first several years, reaching 37% to 38% reductions in risk in patients with MVD and 23% to 28% reductions in risk in patients without MVD. CONCLUSIONS: Evolocumab reduced the rate of major adverse cardiovascular event in patients with and without MVD. The benefit tended to occur earlier and was larger in patients with MVD. However, the magnitude grew over time in both groups. These data support early initiation of intensive low-density lipoprotein cholesterol lowering both in patients with and without MVD.

Lipoprotein(a), C-Reactive Protein, and Cardiovascular Risk in Primary and Secondary Prevention Populations.

Importance: Elevated lipoprotein(a) (Lp[a]) is a putative causal risk factor for atherosclerotic cardiovascular disease (ASCVD). There are conflicting data as to whether Lp(a) may increase cardiovascular risk only in the presence of concomitant inflammation. Objective: To investigate whether Lp(a) is associated with cardiovascular risk independent of high-sensitivity C-reactive protein (hs-CRP) in both primary and secondary prevention populations. Design, Setting, and Participants: This cohort study uses data from 3 distinct cohorts, 1 population-based cohort and 2 randomized clinical trials. Participants included individuals from the UK Biobank (data from 2006-2010) without prevalent ASCVD, participants in the FOURIER (TIMI 59) trial (data from 2013-2017) who had baseline Lp(a) and hs-CRP data, and participants in the SAVOR-TIMI 53 trial (data from 2010-2013) who had prevalent ASCVD and baseline values for Lp(a) and hs-CRP. The data analysis took place from November 2022 to November 2023. Exposure: Baseline plasma Lp(a), considered either as a continuous variable or dichotomized at 125 nmol/L. Main Outcomes and Measures: Risk of major adverse cardiovascular events (MACE) (composite of cardiovascular death, myocardial infarction [MI], or ischemic stroke), the individual MACE components, and peripheral artery disease (PAD). Results: Among 357 220 individuals in the UK Biobank without prevalent ASCVD, 232 699 (65%) had low hs-CRP (<2 mg/L), and 124 521 (35%) had high hs-CRP (≥2 mg/L) values. In a Cox proportional hazard model adjusted for ASCVD risk factors, higher Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP value for MACE (hs-CRP ≥2 mg/L: hazard ratio [HR] per 50-nmol/L higher Lp[a], 1.05; 95% CI, 1.04-1.07; P < .001; for hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.04-1.07; P < .001; P = .80 for interaction), as well as MI, ischemic stroke, and PAD individually. Among 34 020 individuals in the FOURIER and SAVOR trials with baseline cardiometabolic disease, there were 17 643 (52%) with low and 16 377 (48%) with high baseline hs-CRP values. In Cox proportional hazard models using aggregated data from FOURIER and SAVOR, higher baseline Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP for MACE (hs-CRP ≥2 mg/L: HR per 50-nmol/L higher Lp[a], 1.02; 95% CI, 1.00-1.05; P = .04; hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.02-1.08; P < .001; P = .16 for interaction), MI, and PAD. Conclusions and Relevance: In this study, higher levels of Lp(a) were associated with MACE, MI, and PAD in both primary and secondary prevention populations regardless of baseline hs-CRP value.

Novel Polygenic Risk Score and Established Clinical Risk Factors for Risk Estimation of Aortic Stenosis.

Importance: Polygenic risk scores (PRSs) have proven to be as strong as or stronger than established clinical risk factors for many cardiovascular phenotypes. Whether this is true for aortic stenosis remains unknown. Objective: To develop a novel aortic stenosis PRS and compare its aortic stenosis risk estimation to established clinical risk factors. Design, Setting, and Participants: This was a longitudinal cohort study using data from the Million Veteran Program (MVP; 2011-2020), UK Biobank (2006-2010), and 6 Thrombolysis in Myocardial Infarction (TIMI) trials, including DECLARE-TIMI 58 (2013-2018), FOURIER (TIMI 59; 2013-2017), PEGASUS-TIMI 54 (2010-2014), SAVOR-TIMI 53 (2010-2013), SOLID-TIMI 52 (2009-2014), and ENGAGE AF-TIMI 48 (2008-2013), which were a mix of population-based and randomized clinical trials. Individuals from UK Biobank and the MVP meeting a previously validated case/control definition for aortic stenosis were included. All individuals from TIMI trials were included unless they had a documented preexisting aortic valve replacement. Analysis took place from January 2022 to December 2023. Exposures: PRS for aortic stenosis (developed using data from MVP and validated in UK Biobank) and other previously validated cardiovascular PRSs, defined either as a continuous variable or as low (bottom 20%), intermediate, and high (top 20%), and clinical risk factors. Main Outcomes: Aortic stenosis (defined using International Classification of Diseases or Current Procedural Terminology codes in UK Biobank and MVP or safety event data in the TIMI trials). Results: The median (IQR) age in MVP was 67 (57-73) years, and 135 140 of 147 104 participants (92%) were male. The median (IQR) age in the TIMI trials was 66 (54-78) years, and 45 524 of 59 866 participants (71%) were male. The best aortic stenosis PRS incorporated 5 170 041 single-nucleotide variants and was associated with aortic stenosis in both the MVP testing sample (odds ratio, 1.41; 95% CI, 1.37-1.45 per 1 SD PRS; P = 4.6 × 10-116) and TIMI trials (hazard ratio, 1.44; 95% CI, 1.27-1.62 per 1 SD PRS; P = 3.2 × 10-9). Among genetic and clinical risk factors, the aortic stenosis PRS performed comparably to most risk factors besides age, and within a given age range, the combination of clinical and genetic risk factors was additive, providing a 3- to 4-fold increased gradient of risk of aortic stenosis. However, the addition of the aortic stenosis PRS to a model including clinical risk factors only improved risk discrimination of aortic stenosis by 0.01 to 0.02 (C index in MVP: 0.78 with clinical risk factors, 0.79 with risk factors and aortic stenosis PRS; C index in TIMI: 0.71 with clinical risk factors, 0.73 with risk factors and aortic stenosis PRS). Conclusions: This study developed and validated 1 of the first aortic stenosis PRSs. While aortic stenosis genetic risk was independent from clinical risk factors and performed comparably to all other risk factors besides age, genetic risk resulted in only a small improvement in overall aortic stenosis risk discrimination beyond age and clinical risk factors. This work sets the stage for further development of an aortic stenosis PRS.

Efficacy and Safety of Non-Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation.

BACKGROUND: The efficacy and safety of non-vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain. METHODS: We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m2 (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m2. RESULTS: Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m2, and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HRadj], 0.80 [95% CI, 0.73-0.88]; P<0.001), with a generally consistent effect across BMI (Ptrend across HRs, 0.48). NOACs also reduced major bleeding overall (HRadj, 0.88 [95% CI, 0.82-0.94]; P<0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [Ptrend], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HRadj, 0.91 [95% CI, 0.87-0.95]; P<0.001; death, HRadj, 0.91 [95% CI, 0.86-0.97]; P=0.003), these benefits were attenuated at higher BMI (Ptrend, 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW. CONCLUSIONS: The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW.

Rationale and design of the effect of evolocumab in patients at high cardiovascular risk without prior myocardial infarction or stroke (VESALIUS-CV) trial.

BACKGROUND: The reduction of low-density lipoprotein cholesterol (LDL-C) with evolocumab, a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9i), reduces the risk of major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD) with a prior MI, prior stroke, or symptomatic peripheral artery disease, with no offsetting safety concerns. The effect of evolocumab on CV outcomes in lower risk patients without a history of MI or stroke has not been explored. STUDY DESIGN: VESALIUS-CV is a randomized, double-blind, placebo-controlled, global clinical trial designed to evaluate the effect of evolocumab on the risk of major cardiovascular events in patients at high cardiovascular risk but without a prior ischemic event. The study population consists of 12,301 patients with atherosclerosis or high-risk diabetes mellitus without a prior MI or stroke; an LDL-C ≥ 90 mg/dL, or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 120 mg/dL, or apolipoprotein B ≥ 80 mg/dL; and treated with optimized lipid-lowering therapy. Patients were randomized in a 1:1 ratio to evolocumab 140 mg subcutaneously every 2 weeks or matching placebo. The primary efficacy objective is to assess whether evolocumab reduces the risk of the dual primary composite endpoints of coronary heart disease (CHD) death, myocardial infarction (MI), or ischemic stroke (triple primary endpoint) and of CHD death, MI, ischemic stroke, or ischemia-driven arterial revascularization (quadruple primary endpoint). Recruitment began in June 2019 and completed in November 2021. The trial is planned to continue until at least 751 patients experience an adjudicated triple endpoint, at least 1254 experience an adjudicated quadruple endpoint, and the median follow-up is ≥4.5 years. CONCLUSION: VESALIUS-CV will determine whether the addition of evolocumab to optimized lipid-lowering therapy reduces cardiovascular events in patients at high cardiovascular risk without a prior MI or stroke. TRIAL REGISTRATION: NCT03872401.

Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association.

The objective of this scientific statement is to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive low-density lipoprotein cholesterol lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke. The writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize existing evidence and to identify gaps in current knowledge. Although some retrospective, case control, and prospective longitudinal studies suggest that statins and low-density lipoprotein cholesterol lowering are associated with cognitive impairment or dementia, the preponderance of observational studies and data from randomized trials do not support this conclusion. The risk of a hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is nonsignificant, and achieving very low levels of low-density lipoprotein cholesterol does not increase that risk. Data reflecting the risk of hemorrhagic stroke with lipid-lowering treatment among patients with a history of hemorrhagic stroke are not robust and require additional focused study.

Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition: A Narrative Review.

Importance: Adenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss. Observations: While numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed. Conclusions and relevance: ACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.

Evaluation of Large-Scale Proteomics for Prediction of Cardiovascular Events.

Importance: Whether protein risk scores derived from a single plasma sample could be useful for risk assessment for atherosclerotic cardiovascular disease (ASCVD), in conjunction with clinical risk factors and polygenic risk scores, is uncertain. Objective: To develop protein risk scores for ASCVD risk prediction and compare them to clinical risk factors and polygenic risk scores in primary and secondary event populations. Design, Setting, and Participants: The primary analysis was a retrospective study of primary events among 13 540 individuals in Iceland (aged 40-75 years) with proteomics data and no history of major ASCVD events at recruitment (study duration, August 23, 2000 until October 26, 2006; follow-up through 2018). We also analyzed a secondary event population from a randomized, double-blind lipid-lowering clinical trial (2013-2016), consisting of individuals with stable ASCVD receiving statin therapy and for whom proteomic data were available for 6791 individuals. Exposures: Protein risk scores (based on 4963 plasma protein levels and developed in a training set in the primary event population); polygenic risk scores for coronary artery disease and stroke; and clinical risk factors that included age, sex, statin use, hypertension treatment, type 2 diabetes, body mass index, and smoking status at the time of plasma sampling. Main Outcomes and Measures: Outcomes were composites of myocardial infarction, stroke, and coronary heart disease death or cardiovascular death. Performance was evaluated using Cox survival models and measures of discrimination and reclassification that accounted for the competing risk of non-ASCVD death. Results: In the primary event population test set (4018 individuals [59.0% women]; 465 events; median follow-up, 15.8 years), the protein risk score had a hazard ratio (HR) of 1.93 per SD (95% CI, 1.75 to 2.13). Addition of protein risk score and polygenic risk scores significantly increased the C index when added to a clinical risk factor model (C index change, 0.022 [95% CI, 0.007 to 0.038]). Addition of the protein risk score alone to a clinical risk factor model also led to a significantly increased C index (difference, 0.014 [95% CI, 0.002 to 0.028]). Among White individuals in the secondary event population (6307 participants; 432 events; median follow-up, 2.2 years), the protein risk score had an HR of 1.62 per SD (95% CI, 1.48 to 1.79) and significantly increased C index when added to a clinical risk factor model (C index change, 0.026 [95% CI, 0.011 to 0.042]). The protein risk score was significantly associated with major adverse cardiovascular events among individuals of African and Asian ancestries in the secondary event population. Conclusions and Relevance: A protein risk score was significantly associated with ASCVD events in primary and secondary event populations. When added to clinical risk factors, the protein risk score and polygenic risk score both provided statistically significant but modest improvement in discrimination.

Ups and downs in PCSK9 inhibition in the cardiovascular arena: a review.

PURPOSE OF REVIEW: This article reviews PCSK9 inhibitors (PCSK9i) with a focus on clinically relevant studies published in the last 18 months. RECENT FINDINGS: Prespecified subgroup evaluations, secondary analyses, and open-label extension studies from the two landmark trials, FOURIER and ODYSSEY Outcomes, have provided new data on the safety and efficacy of the monoclonal PCSK9 antibodies evolocumab and alirocumab. Recent studies of PCSK9i early in ACS and post percutaneous coronary intervention have explored early effects on biomarkers and plaque morphology with various imaging modalities. Two large outcome trials with PCSK9i in lower risk patients without prior myocardial infarction or stroke are ongoing and could expand the eligible population for these potent therapies. Additionally, novel methods to inhibit PCSK9 using oral administration, vaccination, and gene therapy are in various stages of clinical development. SUMMARY: PCSK9i represent a potent class of lipid-lowering therapies that are well tolerated and effective in a wide group of patients with high-risk atherosclerotic cardiovascular disease. Ongoing studies of PCSK9i in patients at lower risk and with acute myocardial infarction have the potential to broaden their indication. Alternative methods of PCSK9i are being evaluated and could provide easier and less expensive options for this important class of medication.

Assessment of Atherothrombotic Risk in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Risk of atherothrombotic events is not uniform in patients with type 2 diabetes mellitus (T2DM). Tailored risk assessment may help guide selection of pharmacotherapies for cardiovascular primary and secondary prevention. OBJECTIVES: The purpose of this study was to develop a risk model for atherothrombosis in patients with T2DM. METHODS: We developed and validated a risk model for myocardial infarction (MI) or ischemic stroke (IS) in a pooled cohort of 42,181 patients with T2DM from 4 TIMI (Thrombolysis In Myocardial Infarction) clinical trial cohorts. Candidate variables were assessed with multivariable Cox regression, and independent variables (P < 0.05) were retained in the final model. Discrimination and calibration were assessed. Treatment interactions with dapagliflozin (sodium-glucose cotransporter-2 inhibitor) and evolocumab (proprotein convertase subtilisin/kexin type 9 inhibitor) were explored in the DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis In Myocardial Infarction 58) and FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trials, respectively. RESULTS: Sixteen variables were independent predictors of MI or IS. The model identified a >8-fold gradient of MI or IS rates between the top vs bottom risk quintiles in the validation cohort (3-year Kaplan-Meier rate: 14.9% vs 1.4%; P < 0.0001). C-indexes were 0.704 and 0.706 in the derivation and validation cohorts, respectively. The model was well-calibrated in both primary and secondary prevention. Absolute reduction in the rates of MI or IS tended to be greater in patients with higher baseline predicted risk for both dapagliflozin (absolute risk reduction: 2.1% vs 0.2%) and evolocumab (absolute risk reduction: 3.2% vs 1.0%). CONCLUSIONS: We developed and validated a risk score for atherothrombotic events, leveraging 16 routinely assessed clinical variables in patients with T2DM. The score has the potential to improve risk assessment and inform clinical decision-making.