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Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

BACKGROUND There are concerns that Asian patients respond differently to some medications. This study evaluated the efficacy and safety of evolocumab among Asian vs. other subjects in the FOURIER trial, which randomized stable atherosclerosis patients to receive either evolocumab or placebo.Methods and Results:Effects of adding evolocumab vs. placebo to background statin therapy on low-density lipoprotein cholesterol (LDL-C) reductions, cardiovascular outcomes, and adverse events were compared among 27,564 participants with atherosclerotic disease, according to self-reported Asian (n=2,723) vs. other (n=24,841) races followed for a median of 2.2 years in the FOURIER trial. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. At randomization, Asians had slightly lower LDL-C (median 89 [IQR 78-104] mg/dL vs. 92 [80-109] mg/dL; P

Background The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density l...

Aims We assessed the impact of the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab on acute arterial events across all vascular territories, including coronary, cerebrovascular, and peripheral vascular beds, in patients with established atherosclerotic cardiovascular disease (ASCVD). Methods and results In the FOURIER trial, 27 564 patients with stable ASCVD on statin therapy were randomly assigned to evolocumab or placebo. Acute arterial events were a composite of acute coronary (coronary heart disease death, myocardial infarction, or urgent coronary revascularization), cerebrovascular (ischaemic stroke, transient ischaemic attack, or urgent cerebral revascularization), or peripheral vascular (acute limb ischaemia, major amputation, or urgent peripheral revascularization) events. Of the 2210 first acute arterial events, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced first acute arterial events by 19% (hazard ratio [HR] 0.81 [95% confidence interval 0.74–0.88]; P Conclusion The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced acute arterial events across all vascular territories with a robust effect over time, indicating a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

Introdution COVID-19 is associated with an increased risk of thrombotic events. However, the contribution of platelet reactivity (PR) to the aetiology of the increased thrombotic risk associated with COVID-19 remains unclear. Our aim was to evaluate PR in stable patients diagnosed with COVID-19 and hospitalized with respiratory symptoms (mainly dyspnoea and dry cough), in comparison with a control group comprised of non-hospitalized healthy controls. Methods Observational, case control study that included patients with confirmed COVID-19 (COVID-19 group, n = 60) and healthy individuals matched by age and sex (control group, n = 60). Multiplate electrode aggregometry (MEA) tests were used to assess PR with adenosine diphosphate (MEA-ADP, low PR defined as

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date. Design COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771). Conclusion In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.

Supplemental Digital Content is available in the text., Background: Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men. Methods: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis–defined major bleeding (safety). Results: In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P

Background: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease. Methods: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. Results: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke ( P trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98–1.36) and 1.24 (95% CI 1.05–1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04–1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81–1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA 2 DS 2 -VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA 2 DS 2 -VASc score of 3. Conclusions: Across a broad spectrum of subjects with cardiometabolic disease, a 32–single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA 2 DS 2 -VASc scores, the GRS identified patients with risk comparable to those with higher CHA 2 DS 2 -VASc scores.

Background: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease. Methods: We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations. Results: A total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles ( P -trend P =0.004) and 2.70-fold (95% CI, 1.81–4.06; P P Conclusions: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.

Background: Patients with elevated triglycerides despite statin therapy have increased risk for ischemic events, including coronary revascularizations. Methods: REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients with elevated triglycerides (135–499 mg/dL), controlled low-density lipoprotein (41–100 mg/dL), and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl 4 g/d or placebo. The primary and key secondary composite end points were significantly reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes. Results: A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58–0.76]; P P P P =0.0005). Conclusions: Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non–low-density lipoprotein–lowering treatment that has been shown to reduce coronary artery bypass grafting in a blinded, randomized trial. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Summary Background The clinical benefit of LDL cholesterol lowering treatment in older patients remains debated. We aimed to summarise the evidence of LDL cholesterol lowering therapies in older patients. Methods In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2015, and Aug 14, 2020, without any language restrictions. We included randomised controlled trials of cardiovascular outcomes of an LDL cholesterol-lowering drug recommended by the 2018 American College of Cardiology and American Heart Association guidelines, with a median follow-up of at least 2 years and data on older patients (aged ≥75 years). We excluded trials that exclusively enrolled participants with heart failure or on dialysis because guidelines do not recommend lipid-lowering therapy in such patients who do not have another indication. We extracted data for older patients using a standardised data form for aggregated study-level data. We meta-analysed the risk ratio (RR) for major vascular events (a composite of cardiovascular death, myocardial infarction or other acute coronary syndrome, stroke, or coronary revascularisation) per 1 mmol/L reduction in LDL cholesterol. Findings Data from six articles were included in the systematic review and meta-analysis, which included 24 trials from the Cholesterol Treatment Trialists' Collaboration meta-analysis plus five individual trials. Among 244 090 patients from 29 trials, 21 492 (8·8%) were aged at least 75 years, of whom 11 750 (54·7%) were from statin trials, 6209 (28·9%) from ezetimibe trials, and 3533 (16·4%) from PCSK9 inhibitor trials. Median follow-up ranged from 2·2 years to 6·0 years. LDL cholesterol lowering significantly reduced the risk of major vascular events (n=3519) in older patients by 26% per 1 mmol/L reduction in LDL cholesterol (RR 0·74 [95% CI 0·61–0·89]; p=0·0019), with no statistically significant difference with the risk reduction in patients younger than 75 years (0·85 [0·78–0·92]; pinteraction=0·37). Among older patients, RRs were not statistically different for statin (0·82 [0·73–0·91]) and non-statin treatment (0·67 [0·47–0·95]; pinteraction=0·64). The benefit of LDL cholesterol lowering in older patients was observed for each component of the composite, including cardiovascular death (0·85 [0·74–0·98]), myocardial infarction (0·80 [0·71–0·90]), stroke (0·73 [0·61–0·87]), and coronary revascularisation (0·80 [0·66–0·96]). Interpretation In patients aged 75 years and older, lipid lowering was as effective in reducing cardiovascular events as it was in patients younger than 75 years. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients. Funding None.

Introduction Lipoprotein (a) [Lp(a)] is a risk factor for coronary artery disease (CAD). To the best of our knowledge, this is the first study addressing the relationship between Lp(a) and platelet reactivity in primary and secondary prevention. Methods Lp(a) was evaluated in 396 individuals with (82.3%) and without (17.7%) obstructive CAD. The population was divided into two groups according to Lp(a) concentrations with a cutoff value of 50 mg/dL. The primary objective was to evaluate the association between Lp(a) and adenosine diphosphate (ADP)-induced platelet reactivity using the VerifyNow™ P2Y12 assay. Platelet reactivity was also induced by arachidonic acid and collagen–epinephrine (C-EPI) and assessed by Multiplate™, platelet function analyzer™ 100 (PFA-100), and light transmission aggregometry (LTA) assays. Secondary objectives included the assessment of the primary endpoint in individuals with or without CAD. Results Overall, 294 (74.2%) individuals had Lp(a) 0.05). Finally, multivariable analysis did not show a significant association between ADP-induced platelet reactivity and Lp(a) ≥ 50 mg/dL [adjusted OR = 1.00 [(95% CI 0.99–1.01), P = 0.590]. Conclusion In individuals with or without CAD, Lp(a) ≥ 50 mg/dL was not associated with higher platelet reactivity. Electronic supplementary material The online version of this article (10.1007/s12325-020-01483-y) contains supplementary material, which is available to authorized users.

Background An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial. Objectives The purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Methods Within IMPROVE-IT, 17,708 patients post–acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took ≥1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy. Results In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68). Conclusions Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878), Central Illustration

Guidelines for the management of blood cholesterol were updated in the past year in the United States and Europe, reflecting a more intensive approach to lowering low‐density lipoprotein cholesterol (LDL‐C). The American College of Cardiology/American Heart Association task force on practice guideline released the 2018 guideline on the management of blood cholesterol on behalf of several American societies. Approximately 9 months later, the European Society of Cardiology/European Atherosclerosis Society published their 2019 guideline for the management of dyslipidemias. Both guidelines have similarities for the management of patients with acute coronary syndromes. Both emphasize risk assessment of patients as a main approach to guide therapy; those at higher risk of cardiovascular disease have a greater clinical benefit of LDL‐C reduction by at least 50%. Both guidelines reinforce the indication to lower LDL‐C as an important modifiable risk factor and consider the addition of nonstatin agents, such as ezetimibe and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, in addition to lifestyle counseling and high‐intensity statin for further reduction of LDL‐C levels. However, the guidelines have differences in the concepts of treatment thresholds (≥70 mg/dL in the United States) vs treatment goals (

Background: The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk. Methods: We performed a post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) were then combined in a meta-analysis to assess the class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Last, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab. Results: In FOURIER, the hazard ratio (HR) for VTE with evolocumab was 0.71 (95% CI, 0.50–1.00; P =0.05), with no effect in the 1st year (HR, 0.96 [95% CI, 0.57–1.62]) but a 46% reduction (HR, 0.54 [95% CI, 0.33–0.88]; P =0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR, 0.69 [95% CI, 0.53–0.90]; P =0.007). There was no relation between baseline low-density lipoprotein cholesterol levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline lipoprotein(a) (Lp[a]) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR, 0.52 [95% CI, 0.30–0.89]; P =0.017), whereas, in patients with lower baseline Lp(a) levels, evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk ( P interaction 0.087 for HR; P heterogeneity 0.037 for absolute risk reduction). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction ( P interaction =0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative ( P interaction =0.04) and absolute VTE reduction ( P heterogeneity =0.009) in comparison with those without high genetic risk. Conclusions: PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given the ongoing development of potent Lp(a) inhibitors.

The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk).The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey.FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks.A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score ≥2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (20 mg/dl) compared to the 3,613 patients with LDL-C ≥100 mg/dl (3.8% vs. 4.5%, p = 0.57).The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C 20 mg/dl.

Background Diabetes mellitus is an independent risk factor for stroke and atrial fibrillation. Therefore, the risk/benefit profile of the oral factor Xa inhibitor edoxaban stratified by diabetes is of clinical interest. Methods 21,105 patients enrolled in ENGAGE AF-TIMI 48 were stratified into 2 pre-specified groups: without (N = 13,481) and with diabetes (N = 7,624). Results On average, patients with diabetes were younger, and had a higher body mass index, CHA2DS2-VASc score and baseline endogenous Factor Xa activity. After multivariate adjustments, patients with diabetes had a similar rate of stroke and systemic embolism compared to those without diabetes (adjusted hazard ratio (HRadj) 1.08; 95% confidence interval (CI) 0.94–1.24; p = 0.28). However, the risk of major bleeding was significantly higher in patients with diabetes (HRadj 1.28; 95% CI 1.14–1.44; p 0.05), a finding supported by the preserved edoxaban concentrations and inhibition of Factor Xa regardless of diabetes. The HRs of stroke and systemic embolism in patients receiving the higher-dose edoxaban regimen vs warfarin were 0.93 and 0.84 (p-interaction = 0.54) in those with and without diabetes respectively. The higher-dose edoxaban regimen reduced major bleeding (by 19–21%) and cardiovascular death (by 7–17%) regardless of diabetes (p-interactions = 0.81 and 0.33 respectively). Conclusion Patients with diabetes in ENGAGE AF-TIMI 48 had higher bleeding risk, but after adjustment similar stroke risk, compared to those without diabetes. The higher-dose edoxaban regimen had similar efficacy compared to warfarin, while reducing bleeding and cardiovascular mortality, irrespective of diabetes.

Background: The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established. Methods: We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27–single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years. Results: After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events ( P trend =0.005) and major coronary events ( P trend P =0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 [0.75–0.998], P =0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 [0.55–0.86], P =0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk ( P trend for HR=0.017, ARR P trend =0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk. Conclusion: Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk.

For more than half a century, low-density lipoprotein cholesterol (LDL-C) has been recognized as a major risk factor for incident atherosclerotic cardiovascular disease. The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9) in 2003, which prevents LDL-C receptor recycling, identified a new target for drug intervention. Recently, two large-scale randomized clinical outcomes trials involving fully human anti-PCSK9 monoclonal antibodies tested the hypothesis that targeting this pathway would reduce cardiovascular events. Both the FOURIER (Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) and ODYSSEY OUTCOMES trials met their primary efficacy endpoints, confirming findings reported earlier that major adverse cardiovascular events can be reduced by a further lowering of LDL-C beyond that achieved with statin therapy. In both trials, there were incremental reductions in LDL-C of > 50% from baseline, with no major safety concerns, over the trials’ median follow-up time (2.2 and 2.8 years, respectively). While there were differences in design, lipid management and overall results, key messages from both studies were similar. However, post-publication, additional questions have arisen, especially regarding drug effects over the long-term, including a potential mortality benefit.

Background Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial. Objectives This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls. Methods Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days. Results In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; pinteraction = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; pinteraction = 0.46). Conclusions When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome; NCT00089895 )

Background Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over Objectives The OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of evolocumab during open-label hypercholesterolemia treatment for up to 5 years. Methods Patients randomized to standard of care (SOC) or evolocumab 420 mg monthly (evolocumab + SOC) for year 1. After year 1, patients could enter the all-evolocumab period and receive evolocumab + SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation. Results A total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received ≥1 evolocumab dose (mean ± SD age 57 ± 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-evolocumab period (year 2 and beyond). Evolocumab + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during evolocumab + SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 evolocumab + SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed. Conclusions The OSLER-1 trial demonstrated consistently excellent LDL-C–lowering efficacy, tolerance, and safety of evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880)

Importance: Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. Objective: To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. Design, Setting, and Participants: This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40430 patients with established atherosclerosis who were receiving statin treatment. Exposures: ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. Main Outcome and Measures: The primary study outcome was incident myocardial infarction (MI). Results: Of the 389529 individuals in the primary prevention group, 224097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P

Background/Introduction ETNA-AF (ETNA) is a multinational, prospective, observational study evaluating the experience with edoxaban in the clinical practice of patients with atrial fibrillation (AF). ENGAGE AF-TIMI 48 was a randomized double-blind trial that tested the clinical benefits of edoxaban versus warfarin. The recommended dose is 60 mg, dose-reduced to 30 mg daily in patients with at least 1 of 3 label-indicated criteria (renal impairment [creatinine clearance: 15–≤50 mL/min], weight ≤60 kg, or concomitant use of potent P-glycoprotein inhibitors). Purpose We assessed whether the effectiveness and safety of edoxaban in clinical practice were consistent with findings from the pivotal randomized clinical trial. Methods We obtained patient-level data from ETNA and ENGAGE AF-TIMI 48. We initially extracted patients from similar geographic regions, and then used propensity-score matching (PSM) to adjust key baseline characteristic differences between studies. The primary effectiveness endpoint was all stroke or systemic embolism (SSE) and mortality; the safety endpoint was major bleeding (MB). We used Cox proportional hazards models to compare event rates for the clinical outcomes between ETNA and ENGAGE AF-TIMI 48. Results 8,615 AF patients with CHADS2 score ≥2 received the 60 mg edoxaban recommended dose (5,462 ETNA; 3,153 ENGAGE AF-TIMI 48). After PSM, key baseline characteristics were well-balanced between the studies: mean age 71.0 years (SD: 9.07); for both ETNA and ENGAGE AF-TIMI 48 median CHA2DS2-VASc score and median HAS-BLED score were 4 and 2. The annualized incidence rate of SSE was 1.65% in ETNA vs 1.53% in ENGAGE AF-TIMI 48 (HR 0.98; 95% CI 0.49, 1.93; p=0.94). ETNA had similar annualized mortality, 2.81%, compared with ENGAGE AF-TIMI 48, 2.34%, (HR 1.49; 95% CI 0.84, 2.63; p=0.17). MB was less frequent in ETNA vs ENGAGE AF-TIMI 48 (1.10% vs 3.56%; HR 0.25; 95% CI 0.14, 0.44; p Conclusions The effectiveness of edoxaban in clinical practice from a large registry was consistent with efficacy findings from the randomized controlled trial. We observed a lower rate of bleeding events in the ETNA observational study compared with the ENGAGE AF-TIMI 48 trial. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Daiichi Sankyo Inc.

Juan Manuel Figueroa,1 Mónica Edith Lombardo,2,3 Ariel Dogliotti,4 Luis Pedro Flynn,5 Robert Giugliano,6 Guido Simonelli,7 Ricardo Valentini,2 Agñel Ramos,8 Pablo Romano,9 Marcelo Marcote,10 Alicia Michelini,11 Alejandro Salvado,12 Emilio Sykora,13 Cecilia Kniz,14 Marcelo Kobelinsky,15 David Manuel Salzberg,16 Diana Jerusalinsky,17 Osvaldo Uchitel18 1Sleep and Respiratory Research Center, Instituto de Ciencia y Tecnología Cesar Milstein, Ciudad Autónoma de Buenos Aires, Argentina; 2Clinical Research Unit, Hospital Universitario CEMIC, Ciudad Autónoma de Buenos Aires, Argentina; 3Scientific Direction, Nobeltri S.R.L, Ciudad Autónoma de Buenos Aires, Argentina; 4Department of Cardiology, Instituto Cardiovascular de Rosario, Rosario, Santa Fe, Argentina; 5Department of Infectology, Sanatorio de Niños de Rosario, Rosario, Santa Fe, Argentina; 6Division of Cardiovascular Medicine, Brigham and Women’s Hospital, and Department of Medicine, Harvard Medical School, Boston, MA, USA; 7Département de Médecine, Université de Montréal and Centre d’études avancées en médecine du sommeil, Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec, Canada; 8Intensive Care Department, Sanatorio Parque de Rosario, Rosario, Santa Fe, Argentina; 9Otolaryngology Department, Clínica y Maternidad Santa Isabel, Ciudad Autónoma de Buenos Aires, Argentina; 10Medical Direction Department, Hospital Interzonal de Agudos Pte. Perón, Avellaneda, Buenos Aires, Argentina; 11Pulmonology Department, Hospital Pediátrico Avelino Castelán, Resistencia, Chaco, Argentina; 12Pulmonology Department, Hospital Británico de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; 13Department of Medicine, Clínica Monte Grande, Monte Grande, Buenos Aires, Argentina; 14Pulmonology Department, Hospital 4 de Junio Dr Ramón Carrillo, Chaco, Argentina; 15Medical Direction, Clínica Modelo De Morón, Morón, Provincia de Buenos Aires, Argentina; 16Department of Family Medicine, Hospital Gral. de Agudos Dr. Teodoro Alvarez, Ciudad Autónoma de Buenos Aires, Argentina; 17Cell Biology and Neurosciences Institute (IBCN), Buenos Aires University–CONICET, Ciudad Autónoma de Buenos Aires, Argentina; 18Institute of Physiology, Molecular Biology and Neurosciences, Buenos Aires University-CONICET, Ciudad Autónoma de Buenos Aires, ArgentinaCorrespondence: Juan Manuel FigueroaInstituto de Ciencia y Tecnología Cesar Milstein, Ciudad Autónoma de Buenos Aires, ArgentinaEmail figuejuan@gmail.comBackground: Iota-Carrageenan (I-C) is a sulfate polysaccharide synthesized by red algae, with demonstrated antiviral activity and clinical efficacy as nasal spray in the treatment of common cold. In vitro, I-C inhibits SARS-CoV-2 infection in cell culture.Research Question: Can a nasal spray with Iota-Carrageenan be useful in the prophylaxis of COVID-19 in health care workers managing patients with COVID-19 disease?Study Design and Methods: This is a pilot pragmatic multicenter, randomized, double-blind, placebo-controlled study assessing the use of a nasal spray containing I-C in the prophylaxis of COVID-19 in hospital personnel dedicated to care of COVID-19 patients. Clinically healthy physicians, nurses, kinesiologists and other health care providers managing patients hospitalized for COVID-19 were assigned in a 1:1 ratio to receive four daily doses of I-C spray or placebo for 21 days. The primary end point was clinical COVID-19, as confirmed by reverse transcriptase polymerase chain reaction testing, over a period of 21 days. The trial is registered at ClinicalTrials.gov (NCT04521322).Results: A total of 394 individuals were randomly assigned to receive I-C or placebo. Both treatment groups had similar baseline characteristics. The incidence of COVID-19 differs significantly between subjects receiving the nasal spray with I-C (2 of 196 [1.0%]) and those receiving placebo (10 of 198 [5.0%]). Relative risk reduction: 79.8% (95% CI 5.3 to 95.4; p=0.03). Absolute risk reduction: 4% (95% CI 0.6 to 7.4).Interpretation: In this pilot study a nasal spray with I-C showed significant efficacy in preventing COVID-19 in health care workers managing patients with COVID-19 disease.Clinical Trials Registration: NCT04521322.Keywords: COVID-19, prophylaxis, nasal, spray, hospital workers

Background Diabetes and heart failure (HF) promote atrial fibrillation (AF) and are associated with an increased risk of adverse cardiovascular (CV) events in patients with AF. Because of effective anticoagulation options, AF patients are now more likely to develop HF than a stroke or a systemic embolic event. Appropriate risk stratification of patients with AF should therefore not only consider the risk for stroke but also for HF events. Methods Patients with AF admitted to a tertiary academic center between 01/2005 and 07/2019 were identified through a search of electronic health records. The primary outcome of interest was CV death or hospitalization for HF (HHF). We used Cox regression models adjusted for age, sex, estimated glomerular filtration rate, diabetes, HF, body mass index, prior myocardial infarction, hypertension, smoking, C-reactive protein, and LDL-C. To select the most informative variables and overcome the limitations of stepwise regression procedures, we performed a least absolute shrinkage and selection operator logistic regression in a model that incorporated diabetes, HF, NT-proBNP, and the covariates for adjustment in combination with 10-fold cross-validation. Results In total, 7,412 patients (median age 70 years, 39.7% female) were included in the present analysis and followed over a median of 4.6 years. Both diabetes (Adjusted (Adj.) hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.55 to 2.25) and HF (Adj. HR 2.57, 95% CI 2.22 to 2.98) were significantly associated with CV death/HHF after multivariable adjustment. Compared to patients with diabetes, HF patients had a higher risk of HHF but a similar risk of CV and all-cause death. There was a robust relationship between CV death/HHF and NT-proBNP (Adj. HR for 1-unit increase in standardized log-transformed biomarker 1.86, 95% CI 1.67 to 2.07). NT-proBNP showed good discriminatory performance (AUC 0.78, 95% CI 0.77–0.80), and the addition of NT-proBNP to the covariates used for adjustment resulted in a significant AUC improvement (Δ=0.04, P Conclusion These findings suggest that the influence of diabetes and HF expand beyond the risk of stroke and systemic embolic events to CV death/HHF in an unselected AF patient population. NT-proBNP may provide improved risk assessment in AF patients. Funding Acknowledgement Type of funding sources: None. Figure 1. Forest Plot

Background In the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trial, adding the PCSK9 inhibitor evolocumab to statin therapy reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. Although atherosclerotic coronary, cerebrovascular, and peripheral vascular events share a related pathobiology, the effect of aggressive LDL-C lowering with PCSK9 inhibition on the risk of acute arterial events across all three vascular beds is not well-described. Purpose To assess the efficacy of evolocumab on acute arterial events in all vascular territories including coronary, cerebral, and peripheral vascular beds. Methods In the FOURIER trial, patients (n=27,564) with stable atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on a statin were randomly assigned to evolocumab versus placebo and followed for a median of 2.2 years (1.8–2.5). Acute arterial events were defined as a composite of coronary (coronary heart disease [CHD] death, myocardial infarction [MI], or urgent coronary revascularization), cerebrovascular (ischemic stroke, transient ischemic attack [TIA], or urgent cerebral revascularization), or peripheral vascular (acute limb ischemia, major amputation, or urgent peripheral revascularization) events. Cox proportional-hazard models were used to assess the efficacy of evolocumab on these outcomes. Landmark and total event analyses were also done. Results Of the 2,210 first acute arterial events occurring during follow-up, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced the risk of a first acute arterial event by 19% (HR 0.81, 95% CI 0.74–0.88; P Conclusions The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced the risk of acute arterial events across all vascular territories with a robust effect over time. These findings indicate a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The FOURIER trial was supported by Amgen.

Background The 2019 ESC/EAS Dyslipidemia Guidelines recommend an LDL-C goal of Methods FOURIER was a cardiovascular outcomes trial comparing evolocumab vs. placebo in patients with stable ASCVD on optimized statin therapy with a median follow-up of 2.2 years. We performed an exploratory analysis to determine the consistency of CV risk reduction with LDL-C lowering below ∼1 mmol/L (40 mg/dl) with evolocumab. We modeled the achieved LDL-C at 48 weeks in the two treatment arms as well as the percentage of LDL-C difference between the two arms that was due to LDL-C below ∼1 mmol/L (40 mg/dl) as a function of baseline LDL-C. We then modeled the hazard ratio (HR) for the composite of CV death, MI or stroke (per 1 mmol/L reduction in LDL-C) with evolocumab vs. placebo as a function of baseline LDL-C. Results All 27,564 patients from FOURIER were included in this analysis. Patients with lower baseline LDL-C achieved lower LDL-C levels following evolocumab therapy, with achieved LDL-C typically being below 1 mmol/L (40 mg/dl) once the baseline LDL-C was below 2.4 mmol/L (94 mg/dl) and reaching levels approaching 0.5 mmol/L (∼20 mg/dl). Accordingly, the further baseline LDL-C levels were below 2.4 mmol/L (94 mg/dl), the greater the proportion of the difference in achieved LDL-C between the evolocumab and placebo arms was due to LDL-C levels below ∼1 mmol/L (40 mg/dl), reaching nearly 40% of the difference in LDL-C between treatment arms (Upper Panel). Despite this, the clinical benefit of LDL-C lowering was not attenuated (p=0.78) (and even appeared greater), with robust reductions in risk of CV death, MI or stroke even when LDL-C was lowered to nearly 0.5 mmol/L (∼20 mg/dl) and having close to 40% of the LDL-C difference between treatment arms due to LDL-C lowering below ∼1 mmol/L (40 mg/dl) (Lower Panel). Conclusion PCSK9 inhibitors added to statin therapy can achieve LDL-C well below 1 mmol/L (40 mg/dl). There is no evidence for attenuation of the clinical benefit of lowering LDL-C below this threshold. These data support lowering LDL-C to below 1 mmol/L (40 mg/dl) in patients with ASCVD. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health

REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE.The purpose of this study was to determine the effects of IPE on investigator-reported events.Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance.There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints.IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).

SummaryBackgroundIota-Carrageenan (I-C) is a sulfate polysaccharide synthesized by red algae, with demonstrated antiviral activity and clinical efficacy as nasal spray in the treatment of common cold. In vitro, I-C inhibits SARS-CoV-2 infection in cell culture.MethodsThis is a pragmatic multicenter, randomized, double-blind, placebo-controlled trial assessing the use of a nasal spray containing I-C in the prophylaxis of COVID-19 in hospital personnel dedicated to care of COVID-19 patients.Clinically healthy physicians, nurses, kinesiologists and others medical providers were assigned in a 1:1 ratio to receive four daily doses of I-C spray or placebo for 21 days.The primary end point was clinical COVID-19, as confirmed by reverse-transcriptase–polymerase-chain-reaction testing, over a period of 21 days. The trial is registered at ClinicalTrials.gov (NCT04521322).FindingsA total of 394 individuals were randomly assigned to receive I-C or placebo. Both treatment groups had similar baseline characteristics.The incidence of COVID19 was significantly lower in the I-C group compared to placebo (1·0% vs 5·0%) (Odds Ratio 0·19 (95% confidence interval 0·05 to 0·77; p= 0·03). Workday loss in placebo group compared to I-Cc were 1.6% days / person (95% ci, 1.0 to 2.2); p There were no differences in the incidence of adverse events across the two groups (17·3% in the I-C group and 15·2% in the placebo group, p= 0·5).InterpretationI-C showed significant efficacy in preventing SARS-Cov-2 infection in hospital personnel dedicated to care patients with COVID-19 disease.Research in contextEvidence before this studyWe searched PubMed for research articles published up to February 14, 2021, with no language restrictions, using the terms “SARS-CoV-2” or “COVID-19”, “prevention”, “clinical trial”, and “prophylaxis”. Except for studies on vaccines we only found three peer-reviewed publications available on the efficacy of Hydroxycholoquine to prevent COVID-19 disease in individuals at risk of exposure. Hydroxychloroquine did not prevent COVID-19 used as pre or postexposure prophylaxis. We also did not find results from clinical trials on the efficacy of carrageenan in the prevention or treatment of cOVID-19.Added value of this studyWe report the clinical efficacy of a nasal spray with Iota-Carrageenan for the prevention of COVID-19 disease in a randomised, double-blind, placebo-controlled, multicentre study in República Argentina, including 394 participants.Implications of all the available evidenceA simple intervention such as the administration of a nasal spray with Iota-Carrageenan, in addition to hand hygiene, use of personal protective equipment and social distancing, could provide additional protection until vaccines can be administered to the majority of the population.

Hypertension is a risk factor for both stroke and bleeding in patients with atrial fibrillation. Data are sparse regarding the interaction between blood pressure and the efficacy and safety of direct oral anticoagulants. In the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48), 19,679 patients with atrial fibrillation and hypertension were categorized according to average systolic blood pressure (SBP) and diastolic blood pressure (DBP). The primary efficacy and safety end points were the time to the first stroke or systemic embolic event and the time to the first International Society of Thrombosis and Hemostasis major bleeding event, respectively. Risk was calculated using Cox proportional hazards models based on average SBP and DBP and adjusting for 18 clinical characteristics. The efficacy and safety of a higher dose edoxaban regimen (60/30 mg) versus warfarin were evaluated with stratification by average SBP and DBP. Stroke/systemic embolic event occurred significantly more frequently in patients with elevated average SBP (hazard ratio, 2.01; 95% CI, 1.50–2.70 for SBP ≥150 mm Hg relative to 130–139 mm Hg) or DBP (hazard ratio, 2.36; 95% CI, 1.76–3.16 for DBP ≥90 mm Hg relative to 75–P interaction =0.55) and DBP ( P interaction =0.44) compared with warfarin. The higher dose edoxaban regimen reduced the risk of major bleeding events, including intracranial hemorrhage, without modification by average SBP ( P interaction =0.29). The relative safety of edoxaban was most pronounced in patients with elevated DBP ( P interaction =0.007). The efficacy and safety of edoxaban were consistent across the full range of SBP, while the superior safety of edoxaban was most pronounced among patients with elevated DBP.

Background Addition of ezetimibe to statin therapy reduces the risk of recurrent cardiovascular (CV) events in patients with prior acute coronary syndrome (ACS). The role of biomarkers in identifying subsets of patients who may derive greater clinical benefit with ezetimibe is unknown. Objectives This study sought to evaluate the role of established CV biomarkers in assessing likely benefit with ezetimibe added to statin therapy in post-ACS patients. Methods In a pre-specified nested analysis within a randomized, double-blind trial of ezetimibe/simvastatin versus placebo/simvastatin (IMPROVE-IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), high-sensitivity troponin T, N-terminal pro–B-type natriuretic peptide, growth-differentiation factor-15, and high-sensitivity C-reactive protein was measured in 7,195 patients stabilized (1 month post-randomization) after ACS. A multimarker approach based on biomarker values was used to examine the risk of recurrent CV events and clinical benefit with ezetimibe. Results Elevated levels of each biomarker were independently associated with higher risks of CV death/myocardial infarction/stroke and CV death/heart failure (ptrend Conclusions A biomarker-based strategy identifies a gradient of risk among patients post-ACS, offering the potential to identify higher-risk patients with a correspondingly high absolute benefit from the addition of ezetimibe to statin therapy.

Background Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents. Objectives This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease. Methods ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration. Results Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj: 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups. Conclusions Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.

Andexanet alfa, a recombinant modified human "decoy" factor Xa (FXa) protein, is the first and only available antidote approved by the Food and Drug Administration to manage life-threatening or uncontrolled bleeding associated with the anti-Xa agents. It binds to direct and indirect anti-Xa oral anticoagulants with high specificity to reverse their inhibitory effects and restore the activity of FXa. Andexanet alfa is administered via two different dosing regimens, standard and high dose, based on the specific FXa inhibitor, dose, and time since the patient's last dose of FXa inhibitor. The approval for andexanet alfa is supported by data from two phase 3 studies (ANNEXA-A, ANNEXA-R) and preliminary data from the phase 3b/4 ANNEXA-4 trial. The first study found that andexanet alfa rapidly reduced anti-Xa activity by 92%-94% in healthy volunteers taking apixaban or rivaroxaban. The ANNEXA-4 study found that the median anti-Xa activity decreased by 89%-93% in patients with major bleeding taking apixaban or rivaroxaban. However, thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up in ANNEXA-4. Additionally, only 40% of patients had restarted anticoagulation and, in this group, the rate of thrombotic events was 12%. Four patients had a thrombotic event within 3 days after andexanet alfa treatment. The wholesale acquisition cost of the standard dose regimen is $24,750, and the high-dose regimen is $49,500. The estimated annual drug budget of treating 10-100 patients ranges from $248K to $495M. Effective October 1, 2018, Medicare will provide an add-on payment for andexanet alfa of up to $14,063 per qualifying case to Inpatient Prospective Payment System-participating acute care hospitals. In this formulary review for a health system's pharmacy and therapeutics committee, andexanet alfa clinical trials and medication package insert were summarized and, after consulting with clinical experts from our institutions, practical recommendations for use were generated to ensure appropriate and safe use of this agent.

Recent reports have suggested that aspirin effect might be influenced by bodyweight, with decreased efficacy in heavier individuals. We investigated the influence of bodyweight on aspirin pharmacodynamics in two independent datasets of patients taking non-enteric coated aspirin 100 mg QD for coronary artery disease (CAD). In the first dataset, 368 patients had their platelet aggregation assessed using VerifyNow Aspirin and measured in Aspirin Reaction Units (ARU). In the second dataset, 70 patients had serum thromboxane B2 (TXB2) dosage assessed by an ELISA assay and measured in pg/mL. Platelet aggregation was independently associated with bodyweight, with 8.41 (95% CI 1.86–14.97; adjusted p-value = 0.012) increase in ARU for every 10 kg. Furthermore, the rate of non-response to aspirin (defined as ARU ≥ 550) was significantly associated with increased bodyweight (adjusted p-value = 0.007), with OR = 1.23 (95% CI 1.06–1.42) for every 10 kg. Similar results were found considering body mass index (in kg/m2), with 15.5 (95% CI 5.0 to 25.9; adjusted p-value = 0.004) increase in ARU for every 10 kg and non-response OR = 1.43 (95% CI 1.13 to 1.81, adjusted p-value = 0.003) for every 5 kg/m2. Moreover, serum TXB2 was higher in patients weighting more than 70 kg (222.6 ± 62.9 versus 194.9 ± 61.9 pg/mL; adjusted p-value = 0.018). In two different datasets of patients with CAD on non-enteric coated aspirin 100 mg QD, increased bodyweight was independently associated with impaired response to aspirin.

Patients with active cancer are at an increased risk of arterial and venous thromboembolism (VTE) and bleeding events. Historically, in patients with cancer, low molecular weight heparins h...

Background: Numerous scales exist for the classification of major bleeding events. Limited data compare the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. Here, we analyze bleeding outcomes according to the ISTH (International Society on Thrombosis and Hemostasis), TIMI (Thrombolysis in Myocardial Infarction), GUSTO (Global Usage of Strategies to Open Occluded Arteries), and BARC (Bleeding Academic Research Consortium) bleeding scales in the ENGAGE AF (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation)–TIMI 48 trial (NCT00781391) of edoxaban versus warfarin. Methods: A total of 21 105 patients with atrial fibrillation at risk for stroke (CHADS 2 score ≥2) were enrolled in the ENGAGE AF-TIMI 48 trial comparing warfarin with a higher- (60/30 mg daily) or lower- (30/15 mg daily) dose edoxaban regimen. Median follow-up was 2.8 years. Bleeding events occurring among on-treatment patients were examined. Annualized event rates were calculated by the ISTH, TIMI, GUSTO, and BARC scales and compared across treatment arms. Cox proportional hazards for a first bleeding event of each type were calculated for higher-dose edoxaban regimen vs warfarin and lower-dose edoxaban regimen versus warfarin. Results: A total of 10 311 bleeding events were reported. In a comparison of the most severe events in each scale, ISTH major bleeding was the most common (n=1289), followed by TIMI major (n=548), GUSTO severe/life-threatening (n=347), and BARC 3c+5 (n=276) bleeding. Lower bleeding risk with edoxaban compared with warfarin was seen regardless of bleeding scale (higher-dose edoxaban regimen range: hazard ratio [HR], 0.47 [95% CI, 0.35–0.62] for BARC 3c+5 versus HR, 0.80 [95% CI, 0.71–0.91] for ISTH major; lower-dose edoxaban regimen range: HR, 0.32 [95% CI, 0.23–0.45] for BARC 3c+5 versus HR, 0.47 [95% CI, 0.41–0.55] for ISTH major). Furthermore, a gradient of more pronounced risk reduction with edoxaban was observed with greater severity of first bleeding event (higher-dose edoxaban regimen: HR, 0.47 [95% CI, 0.35–0.62] for BARC 3c+5 bleeds versus HR, 0.86 [95% CI, 0.81–0.91] for any BARC bleed; lower-dose edoxaban regimen: HR, 0.32 [95% CI, 0.23–0.45] for BARC 3c+5 bleeds versus HR, 0.68 [95% CI, 0.63–0.72] for any BARC bleed). The direction of this trend was consistent for both gastrointestinal bleeding and nongastrointestinal bleeding. Conclusions: Among patients with atrial fibrillation at risk for stroke, there was a >4-fold difference in the frequency of the most severe bleeding events across commonly used bleeding scales. Furthermore, the relative safety of edoxaban compared with warfarin tended to increase with greater severity of bleeding. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Polyvascular disease and type 2 diabetes are each associated with increased cardiovascular risk, but whether these risks are additive is unknown. In this exploratory analysis of a randomised trial, we explored the long-term cardiovascular risk associated with polyvascular disease, type 2 diabetes, and their combination in patients with acute coronary syndrome, and assessed the effect of ezetimibe given on top of statin therapy in patients with these concomitant conditions.IMPROVE-IT was a multicentre, double-blind, randomised, placebo-controlled trial assessing the effect of ezetimibe added to statin therapy after acute coronary syndrome. Recruitment was from Oct 26, 2005, to July 8, 2010, and the trial was done at 1158 sites in 39 countries. 18 144 patients aged 50 years and older who had been stabilised after an acute coronary syndrome were randomly assigned to 40 mg per day simvastatin plus either 10 mg per day ezetimibe or matched placebo, for a median duration of 6 years. In this post-hoc exploratory analysis, we assessed the prespecified endpoints of the trial, including the primary composite endpoint (cardiovascular death, a major coronary event [non-fatal myocardial infarction, documented unstable angina requiring hospital admission, or coronary revascularisation occurring at least 30 days after randomisation], or stroke [ischaemic or haemorrhagic]) by concomitant polyvascular disease at baseline (peripheral artery disease or previous stroke or transient ischaemic attack) and stratified by concomitant type 2 diabetes. Efficacy analyses were done according to intention to treat and event rates. IMPROVE-IT is registered with ClinicalTrials.gov, number NCT00202878.1005 patients (6%) had peripheral artery disease and 1071 (6%) had stroke or transient ischaemic attack at baseline. Of these, 388 (39%) and 409 (38%) also had concomitant type 2 diabetes, respectively. At 7 years, patients with either polyvascular disease or type 2 diabetes had similar rates of the primary endpoint (39·8% and 39·9%, respectively), which were higher than patients without polyvascular disease or diabetes (29·6%). Polyvascular disease with concomitant type 2 diabetes was associated with further heightened risk (60·0% 7-year Kaplan-Meier rate, adjusted hazard ratio versus those with polyvascular disease 1·60, 95% CI 1·38-1·85; p0·0001). Ezetimibe reduced cardiovascular risk consistently across groups with greater numerical absolute risk reductions in the highest-risk subgroups.In patients with coronary artery disease, concomitant polyvascular disease or type 2 diabetes are associated with increased long-term cardiovascular risk. The combination of polyvascular disease and diabetes is additive, resulting in very high risk. The benefit of ezetimibe is consistent in patients with and without polyvascular disease and type 2 diabetes; however, by nature of their higher risk patients with one, or especially both, of these diseases might derive the greatest absolute benefits.Merck.

Atherosclerotic cardiovascular disease (ASCVD) is highly prevalent and a major contributor to morbidity and mortality worldwide. Elevated blood cholesterol is a key driver of risk for atherosclerotic events, and patients with established ASCVD comprise a specific high-risk population in which low-density lipoprotein cholesterol (LDL-C) lowering therapy is strongly endorsed by multiple guidelines. An increasing number of medications across several pharmacologic classes are available today in clinical practice. Therefore, guidance on the appropriate use of these interventions is necessary for cost-effective solutions to managing residual atherothrombotic risk. In this review we summarize the key evidence supporting LDL-C lowering as described in the most recent 2018 multi-society Blood Cholesterol Guidelines, and provide a framework for optimizing LDL-C lowering therapy in secondary prevention populations.

Background: Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug or withdraw consent once enrolled in a clinical trial is unknown. Methods: Eleven phase 3/4 TIMI (Thrombolysis in Myocardial Infarction) trials were included (135 879 men and 51 812 women [28%]). The association between sex and premature study drug discontinuation and withdrawal of consent were examined by multivariable logistic regression after adjusting for potential confounders in each individual trial and combining the individual point estimates in random effects models. Results: After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation (adjusted odds ratio [OR adj ], 1.22 [95% CI, 1.16–1.28]; P adj , 1.20 [95% CI, 1.13–1.27]) and active therapy arms (OR adj , 1.23 [95% CI, 1.17–1.30)]; there was some evidence for regional heterogeneity ( P interaction P =0.60). Women were also more likely to withdraw consent compared with men (OR adj , 1.26 [95% CI, 1.17–1.36]; P Conclusions: Women were more likely than men to prematurely discontinue study drug and withdraw consent across cardiovascular outcome trials. Premature study drug discontinuation was not explained by baseline differences by sex or a higher proportion of adverse events. Future trials should better capture reasons for drug discontinuation and withdrawal of consent to understand barriers to continued study drug use and clinical trial participation, particularly among women.

Introduction The efficacy and safety of the oral factor Xa inhibitor edoxaban compared to warfarin stratified by CHA2DS2VASc scores have not been described. Methods The ENGAGE AF-TIMI 48 trial randomized patients with atrial fibrillation to once-daily edoxaban or warfarin. We classified patients based on CHA2DS2VASc score and compared pharmacokinetics (edoxaban concentration), pharmacodynamics (anti-factor Xa [FXa] with edoxaban, time-in-therapeutic range for warfarin), efficacy (stroke or systemic embolism [SSE]), safety (major bleeding [MB], intracranial hemorrhage), and cardiovascular mortality, for the approved edoxaban regimen vs warfarin. Results The distribution CHA2DS2VASc score were:≤3, N = 4159 (29.6%); 4, N = 4066 (28.9%); 5, N = 3165 (22.5%); and ≥6, N = 2681 (19.1%). Increasing rates of SSE (1.05 to 2.99%/year) and MB (2.27 to 4.66%/year) were observed in the warfarin arm as the CHA2DS2VASc score increased. The hazard ratios per unit increase of CHA2DS2VASc score were 1.29 (1.21-1.38) and 1.26 (1.17-1.36) for SSE, and 1.20 (1.13-1.27) and 1.19 (1.12-1.27) for MB, with warfarin and edoxaban, respectively. Time-in-therapeutic range in warfarin-treated patients was similar and high (median 68%-69%) across CHA2DS2VASc scores, whereas edoxaban trough concentration, exogenous anti-FXa activity and %inhibition of endogenous FXa were higher at increasing CHA2DS2VASc scores. Edoxaban reduced SSE, MB, intracranial hemorrhage, and cardiovascular mortality vs warfarin to a similar degree across the range of CHA2DS2VASc scores (P-int = 0.90, 0.96, 0.21, and 0.37, respectively). Because of higher event rates the number of events prevented with edoxaban tended to be greater in patients with higher CHA2DS2VASc scores. Conclusion The benefit and safety of edoxaban versus warfarin is maintained across CHA2DS2VASc scores. While the relative risk reductions remain similar, edoxaban provides incrementally larger absolute reductions in outcomes over warfarin in patients with higher CHA2DS2VASc scores.

Background The effects of anticoagulants at extremes of body weight (BW) are not well described. The aim of this study was to analyze the pharmacokinetics/pharmacodynamics and clinical outcomes in patients randomized to warfarin, higher dose edoxaban (HDER), and lower dose edoxaban (LDER) regimens at extremes of BW in ENGAGE AF-TIMI 48.Methods and Results We analyzed three BW groups: low BW (LBW: 95th percentile, ≥120 kg, N = 1,093). In the warfarin arm, LBW patients had higher rates of stroke/systemic embolism (SSE: 6.5 vs. 4.7 in MBW vs. 1.6% in HBW, P trend Conclusion Patients with LBW in ENGAGE AF-TIMI 48 had in general a more fragile clinical status and poorer international normalized ratio control. The pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across extremes of BW, resulting in similar efficacy compared with warfarin, while major or clinically relevant non-MB and net outcomes were most favorable with edoxaban as compared to warfarin in LBW patients.

Introduction: Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for first ischemic stroke after accounting for traditional risk factors in four clinical trials across the spectrum of cardiometabolic disease. Methods: Subjects who had consented for genetic testing, were of European ancestry, and had no prior history of stroke from the SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. A recently validated GRS composed of 36 SNPs associated with ischemic stroke was calculated in each patient. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for age, sex, ancestry, hypertension, hyperlipidemia, smoking, diabetes mellitus, atrial fibrillation, coronary artery disease, and congestive heart failure. Results: In 23,089 subjects across the four trials, a total of 313 ischemic strokes occurred over a median follow-up of 3 years. Those with higher genetic risk were at significantly increased risk for ischemic stroke with an adjusted HR per 1-SD GRS of 1.12 (1.004-1.25; p=0.043). Individuals in the top 10% of genetic risk had a 42% greater hazard for ischemic stroke than those in the lower 90% of genetic risk (adjusted HR 1.42 [1.03-1.97]; p=0.034). The magnitude of risk conferred by high genetic risk was similar or greater than the risk provided by well-established clinical risk factors (Figure). Conclusions: Across four large clinical trials of subjects with cardiometabolic disease, a 36-SNP GRS was a strong, independent predictor of first ischemic stroke. The risk of stroke was particularly high in patients in the top 10% of genetic risk.

Introduction: Among patients with atherosclerotic cardiovascular disease (ASCVD), those with history of PCI represent an important population for potential high risk for cardiovascular (CV) events. We examined the clinical efficacy of the PCSK9 inibitor evolocumab in patients with prior PCI. Methods: FOURIER randomized 27,564 patients with ASCVD on statin therapy to evolocumab or placebo with a median follow-up of 2.2 yrs. The primary end point (PEP) was the composite of CV death, MI, stroke, unstable angina, or coronary revascularization; major coronary events were the composite of coronary death, MI, or coronary revascularization. The risk of events in patients with and without a history of PCI were compared in the placebo arm. The clinical benefit of evolocumab vs. placebo was compared using a Cox proportional hazards model. Results: 17,073 (62%) patients had prior PCI at baseline. Among patients in the placebo arm, those with prior PCI (N=8563) had a 1.6x higher rate of the PEP (16.8 vs 10.7%; adjusted HR 1.61; 95% CI 1.42-1.84 P Conclusions: In a contemporary cohort with ASCVD on statin therapy, patients with prior PCI were at heightened risk for coronary events. Evolocumab was highly effective in this group, reducing major coronary events by 18% with a NNT at 3 years of only 36.

Introduction: Patients with loss of function (LoF) mutations of the LDL receptor gene (LDLR) have lifelong elevations in LDL-C. We investigated their risk of cardiovascular (CV) events compared with patients with intact LDLR function. Methods: We performed a prospective genetic cohort analysis from the FOURIER trial including all 14,297 patients who consented for genetic testing, passed QC, and were of European ancestry. All patients had established ASCVD and were on moderate or high intensity statin therapy. Whole exome sequencing was performed and LoF mutations in LDLR were identified using LOFTEE, a tool for detecting protein-truncating variants. Polygenic risk for CAD was also calculated for each patient using a previously validated 27-SNP genetic risk score, with high and low risk defined as above and below the median. The primary endpoint was a composite of CV death, myocardial infarction, stroke, unstable angina, or coronary revascularization. Results: There were 111 (0.8%) patients identified with an LDLR LoF mutation, representing an approximately 4-fold enrichment compared to the general population. These patients had mean baseline LDL-C levels 62 mg/dl higher than those without an identified LDLR LoF mutation (160 vs. 98 mg/dl, pFigure, a ). When polygenic risk for CAD was combined with LDLR mutation status there was a significant gradient of risk identified (p-trend=0.001). Patients without a monogenic LDLR mutation or high polygenic risk had a 2.5-year KM event rate of 8.6%; those with either one had a 10.0-12.9% event rate; those with both had a 17.1% event rate ( Figure, b ). Conclusion: ASCVD patients with LDLR LoF mutations have persistently elevated LDL-C and increased CV risk despite intensive statin therapy. The combination of a monogenic LDLR mutation with high polygenic risk for CAD appears additive in this secondary prevention cohort.

Introduction: The clinical benefit from LDL-C lowering therapy in the elderly remains debated. Aim: To synthesize the efficacy of lowering LDL-C in patients aged ≥75 years in the light of most recently published data. Methods: Medline database was searched for the most recent evidence (2015-2020). The key inclusion criterion was a randomized controlled cardiovascular outcome trial testing an LDL-C lowering therapy with data available in patients aged ≥75 years at randomization. For efficacy, we meta-analyzed the risk ratio (RR) of major vascular events (a composite of cardiovascular (CV) death, myocardial infarction, stroke or coronary revascularization) per 1-mmol/L reduction in LDL-C. Results: Among 244,090 patients from 29 trials, 21,492 (8.8%) were elderly; 11,750 from statin trials, 6209 from ezetimibe trials, and 3533 from PCSK9 inhibitor trials. Median follow-up ranged from 2.2-6.0 years. LDL-C lowering therapy significantly reduced major vascular events (n=3519) in the elderly by 26% per 1-mmol/L LDL-C reduction (RR 0.74 [0.61-0.89], P=0.002), which was at least as good as the magnitude of effect seen in the non-elderly patients (RR 0.85 [0.78-0.92]; P interaction =0.24). Amongst the elderly, the RR was similar for statin (0.81 [0.70-0.94]) and non-statin therapy (0.67 [0.47-0.95]; P interaction =0.60). The benefit of LDL-C lowering in the elderly was observed for each component of the composite, including CV death (RR 0.85 [0.73-0.996], P=0.045), myocardial infraction (RR 0.80 [0.70-0.92], P=0.001), stroke (RR 0.71 [0.58-0.87], P=0.001) and coronary revascularization (RR 0.78 [0.63-0.96], P=0.017). Conclusion: In patients 75 years and older, lipid-lowering therapy is as effective in reducing CV events as it is in younger adults. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin therapy, in the elderly.