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Objectives: This study evaluated the application of a biomarker-based risk score to identify individuals with dysglycemia who are at high risk for incident heart failure (HF) and to inform allocation of effective preventive interventions., Background: Risk stratification tools to identify patients with diabetes and pre-diabetes at highest risk for HF are needed to inform cost-effective allocation of preventive therapies. Whether a biomarker score can meaningfully stratify HF risk is unknown., Methods: Participants free of cardiovascular disease from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], DHS [Dallas Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) were included. An integer-based biomarker score included high-sensitivity cardiac troponin T ≥6 ng/l, N-terminal pro-B-type natriuretic peptide ≥125 pg/ml, high-sensitivity C-reactive protein ≥3 mg/l, and left ventricular hypertrophy by electrocardiography, with 1 point for each abnormal parameter. The 5-year risk of HF was estimated among participants with diabetes and pre-diabetes across biomarker score groups (0 to 4)., Results: The primary analysis included 6,799 participants with dysglycemia (diabetes: 33.2%; pre-diabetes: 66.8%). The biomarker score demonstrated good discrimination and calibration for predicting 5- and 10-year HF risk among pre-diabetes and diabetes cohorts. The 5-year risk of HF among subjects with a biomarker score of ≤1 was low and comparable to participants with euglycemia (0.78%). The 5-year risk for HF increased in a graded fashion with an increasing biomarker score, with the highest risk noted among those with scores of ≥3 (diabetes: 12.0%; pre-diabetes: 7.8%). The estimated number of HF events that could be prevented using a sodium-glucose cotransporter-2 inhibitor per 1,000 treated subjects over 5 years was 11 for all subjects with diabetes and ranged from 4 in the biomarker score zero group to 44 in the biomarker score ≥3 group., Conclusions: Among adults with diabetes and pre-diabetes, a biomarker score can stratify HF risk and inform allocation of HF prevention therapies., Competing Interests: Funding Support and Author Disclosures Dr. Pandey was supported by the Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, and the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01). The ARIC study is conducted as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN2 68201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820 1100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201 100012C). The Dallas Heart Study was funded by a grant from the Donald W. Reynolds Foundation. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (award number UL1TR001105) to the University of Texas Southwestern Medical Center. The Multi-Ethnic Study of Atherosclerosis was supported by the National Heart, Lung, and Blood Institute (R01 HL071739 and contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, and N01-C-95169). Dr. Vaduganathan has been supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541); and has served on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr. Pandey has served on the advisory board of Roche Diagnostics. Dr. Patel was supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant (5T32HL125247-03). Dr. Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on advisory boards for Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck (Diabetes), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca and honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr. de Lemos has received grant support from Roche Diagnostics and Abbott Diagnostics; and has received consulting fees from Roche Diagnostics, Abbott Diagnostics, Ortho Clinical Diagnostics, Siemen’s Health Care Diagnostics, Quidel Cardiovascular, Inc, Novo Nordisk, Amgen, Regeneron, Eli Lilly, and Esperion. Drs. DeFilippi and de Lemos hold a patent pending (U.S. Patent Number: 15/309,754) entitled: “Methods for Assessing Differential Risk for Developing Heart Failure.” Dr. McGuire has received personal fees for trial leadership from GlaxoSmithKline, Janssen, Lexicon, AstraZeneca, CSL Behring, Sanofi, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Eisai Inc., Esperion, and Lilly USA; and has received personal consultancy fees from AstraZeneca, Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Metavant, Applied Therapeutics, Sanofi, and Afimmune. Dr. Everett has received personal consultancy fees from Amarin, Amgen, Gilead, FDA, Merck & Co., National Institute of Diabetes and Digestive and Kidney Diseases, and Roche Diagnostics outside the present work; and has received significant investigator-initiated grant funding from the National Institute of Heart, Lung, and Blood Institute outside the present work. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Canakinumab, a monoclonal antibody targeting interleukin-1β, reduces inflammation and cardiovascular event rates with no effect on lipid concentrations. However, it is uncertain which patient groups benefit the most from treatment and whether reductions in the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) correlate with clinical benefits for individual patients., Methods: The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) used computer-generated codes to randomly allocate 10 061 men and women with a history of myocardial infarction to placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. In a prespecified secondary analysis designed to address the relationship of hsCRP reduction to event reduction in CANTOS, we evaluated the effects of canakinumab on rates of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality according to on-treatment concentrations of hsCRP. We used multivariable modelling to adjust for baseline factors associated with achieved hsCRP and multiple sensitivity analyses to address the magnitude of residual confounding. The median follow-up was 3·7 years. The trial is registered with ClinicalTrials.gov, number NCT01327846., Findings: Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab. However, trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted hazard ratio [HR adj ]=0·75, 95% CI 0·66-0·85, p<0·0001), whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or above (HR adj =0·90, 0·79-1·02, p=0·11). For those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (HR adj =0·69, 95% CI 0·56-0·85, p=0·0004) and all-cause mortality (HR adj =0·69, 0·58-0·81, p<0·0001) were both reduced by 31%, whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. Similar differential effects were found in analyses of the trial prespecified secondary cardiovascular endpoint (which additionally included hospitalisation for unstable angina requiring unplanned revascularisation) and in sensitivity analyses alternatively based on median reductions in hsCRP, on 50% or greater reductions in hsCRP, on the median percent reduction in hsCRP, in dose-specific analyses, and in analyses using a causal inference approach to estimate the effect of treatment among individuals who would achieve a targeted hsCRP concentration., Interpretation: The magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab., Funding: Novartis Pharmaceuticals., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence., Methods: We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose-response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017)., Findings: Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31-0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39-0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18-0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10-0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83-1·06]; p=0·31)., Interpretation: Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required., Funding: Novartis Pharmaceuticals., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: It is somewhat controversial whether caffeine consumption is associated with an increased risk of developing atrial fibrillation (AF)., Objective: We prospectively assessed the relation between caffeine intake and incident AF., Design: A total of 33,638 initially healthy women who participated in the Women's Health Study and who were gt 45 y of age and free of cardiovascular disease and AF at baseline were prospectively followed for incident AF from 1993 to 2 March 2009. All women provided information on caffeine intake via food-frequency questionnaires at baseline and in 2004., Results: During a median follow-up of 14.4 y (interquartile range: 13.8-14.8 y), 945 AF events occurred. Median caffeine intakes across increasing quintiles of caffeine intake were 22, 135, 285, 402, and 656 mg/d, respectively. Age-adjusted incidence rates of AF across increasing quintiles of caffeine intake were 2.15, 1.89, 2.01, 2.24, and 2.04 events, respectively, per 1000 person-years of follow-up. In Cox proportional hazards models updated in 2004 by using time-varying covariates, the corresponding multivariable-adjusted hazard ratios (95% CI) were 1.0, 0.88 (0.72, 1.06), 0.78 (0.64, 0.95), 0.96 (0.79, 1.16), and 0.89 (0.73, 1.09) (P for linear trend: 0.45). None of the individual components of caffeine intake (coffee, tea, cola, and chocolate) were significantly associated with incident AF., Conclusions: In this large cohort of initially healthy women, elevated caffeine consumption was not associated with an increased risk of incident AF. Therefore, our data suggest that elevated caffeine consumption does not contribute to the increasing burden of AF in the population. This trial was registered at clinicaltrials.gov as NCT00000479.

Background: Published reports of a relationship between lipids and incident venous thromboembolism (VTE) are conflicting., Objectives: To clarify the relationship between lipids and VTE risk in healthy women, including potential effect modification by hormone therapy (HT)., Patients/methods: Among 27 081 initially healthy women followed prospectively for incident VTE, we measured a full panel of lipid biomarkers, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides and apolipoproteins A-I (apo A-I) and B(100)., Results: During a median follow-up of 11.4 years, VTE occurred in 355 women. We observed no relationship between any of the lipids and VTE risk. However, when unprovoked VTE was considered separately (n=161), both HDL-C and apo A-I were positively associated with risk. Fully adjusted hazard ratios (HR) and 95% confidence intervals (CI) for extreme tertiles of HDL-C and apo A-I were 1.75 (1.13-2.73) and 1.70 (1.10-2.62), respectively. After stratifying by HT use, this relationship was present only among HT users; the HRs for unprovoked VTE for extreme tertiles of HDL-C and apo A-I were 3.58 (1.69-7.58) and 2.88 (1.29-6.42) among users, but only 0.79 (0.39-1.62) and 0.89 (0.50-1.57) among non-users. The interactions were statistically significant (each Pinteraction<0.05)., Conclusions: We observed little evidence that lipid levels predict risk of incident VTE among non-users of HT. High levels of HDL-C and apo A-I associate with unprovoked VTE risk among HT users. This observation likely reflects prothrombotic effects of HT that are concomitant with HDL-C and apo A-I levels, rather than direct effects of those lipids.

Objective: Elevated levels of interleukin (IL)-18 have been implicated in the development of atherosclerosis in animals. Data in humans are less clear, and data in women are particularly scarce., Methods and Results: In a prospective nested case-control study of initially healthy women, we measured baseline plasma IL-18 levels in 253 participants who subsequently developed cardiovascular disease (CVD) and in 253 healthy age- and smoking-matched controls. IL-18 levels were higher at baseline among those who developed CVD (274.1pg/mL versus 233.8pg/mL, P<0.001), and were associated with future CVD (relative risk (RR) for highest versus lowest quartile 2.53; 95% CI, 1.47-4.35, P<0.001). While that risk was attenuated after adjustment for traditional cardiovascular risk factors (RR 1.60; 95% CI, 0.77-3.34, P=0.13), those with IL-18 levels at or above a threshold of the 90th percentile (442pg/mL) remained at elevated risk after adjustment (RR 2.40; 95% CI, 1.05-5.56, P=0.04). Levels of IL-18 above this threshold modify the fully adjusted risk of future CVD conferred by elevated levels of total cholesterol (P(interaction)=0.02)., Conclusions: In this population of apparently healthy women, IL-18 levels associate with increased risk of cardiovascular disease, but that risk is attenuated in models adjusting for traditional cardiovascular risk factors. Very high levels of IL-18 interact with hypercholesterolemia to alter CVD risk.

Background: The clinical significance of heparin/platelet factor 4 (PF4) antibodies in subjects undergoing cardiac surgery has not been systematically studied. We prospectively investigated whether the presence of heparin/PF4 antibodies would predict clinical thrombosis in this population., Methods: In 299 patients scheduled for cardiac surgery between October 2003 and March 2005, the heparin/PF4 antibodies and platelet count were measured immediately prior to, and 5 days after, surgery. The patients were followed up at 30 days for thrombotic complications., Results: The prevalence of the heparin/PF4 antibodies was 4.3% (13 of 299) prior to surgery and increased more than fivefold to 22.4% (62 of 277) postoperatively (p < 0.0001). Thromboembolic events occurred in 8.8% of patients with negative antibody and in 6.3% of patients with positive antibody (p = 0.77). Of the 62 patients with positive heparin/PF4 antibodies postoperatively, 22 (35.5%) were treated with a nonheparin anticoagulant. There was a trend toward higher rates of thromboembolic events in subjects who were thrombocytopenic compared with those who were not (17.1% and 6.7%, respectively, p = 0.06), regardless of antibody status. Two out of 8 patients (25%) with both thrombocytopenia and a positive antibody (clinical heparin-induced thrombocytopenia [HIT]) suffered a thromboembolic event, compared with 17 of 222 (7.7%) without clinical HIT (p = 0.13)., Conclusions: The high prevalence of antibodies to the heparin/PF4 complex after cardiac surgery and the low rate of thromboembolic complications in this population suggest that the antibody alone does not confer an increased risk of thrombotic complications. Monitoring for thrombocytopenia is recommended.