Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer.

BACKGROUND: Growth hormone (GH) resistance is characterized by high GH levels but low levels of insulin-like growth factor-I (IGF-I) and growth hormone binding protein (GHBP) and, for patients with chronic disease, is associated with the development of cachexia. OBJECTIVES: We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. METHODS: We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83% stage III/IV). Patients were grouped by tertile of echocardiographic LVmass/height2 (women, < 50, 50-61, > 61 g/m2; men, < 60, 60-74, > 74 g/m2) and by presence of wasting syndrome with unintentional weight loss (BMI < 24 kg/m2 and weight loss ≥ 5% in the prior 12 months). Repeat echocardiograms were obtained usually within 3-6 months for 85 patients. RESULTS: Patients in the lowest LVmass/height2 tertile had higher plasma GH (median (IQR) for 1st, 2nd, and 3rd tertile women, 1.8 (0.9-4.2), 0.8 (0.2-2.2), 0.5 (0.3-1.6) ng/mL, p = 0.029; men, 2.1 (0.8-3.2), 0.6 (0.1-1.7), 0.7 (0.2-1.9) ng/mL, p = 0.003). Among women, lower LVmass was associated with higher plasma IGF-I (68 (48-116), 72 (48-95), 49 (35-76) ng/mL, p = 0.007), whereas such association did not exist for men. Patients with lower LVmass had lower log IGF-I/GH ratio (women, 1.60 ± 0.09, 2.02 ± 0.09, 1.88 ± 0.09, p = 0.004; men, 1.64 ± 0.09, 2.14 ± 0.11, 2.04 ± 0.11, p = 0.002). GHBP was not associated with LVmass. Patients with wasting syndrome with unintentional weight loss had higher plasma GH and GHBP, lower log IGF-I/GH ratio, and similar IGF-I. Overall, GHBP correlated inversely with log IGF-I/GH ratio (women, r = - 0.591, p < 0.001; men, r = - 0.575, p < 0.001). Additionally, higher baseline IGF-I was associated with a decline in LVmass during follow-up (r = - 0.318, p = 0.003). CONCLUSION: In advanced cancer, reduced LVmass is associated with increased plasma GH and reduced IGF-I/GH ratio, suggesting increasing GH resistance, especially for patients with wasting syndrome with unintentional weight loss. Higher baseline IGF-I was associated with a decrease in relative LVmass during follow-up.

Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort.

AIMS: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. METHODS AND RESULTS: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). CONCLUSION: In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

Intravenous iron and SGLT2 inhibitors in iron-deficient patients with heart failure and reduced ejection fraction.

AIMS: To explore the potential interaction between use of SGLT2 inhibitors and the increase in haemoglobin in patients randomized to intravenous iron or the control group in the IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency) trial. METHODS AND RESULTS: This was a post hoc exploratory analysis of the IRONMAN trial which randomized patients with heart failure, a left ventricular ejection fraction (LVEF) ≤ 45% and iron deficiency (transferrin saturation <20% or ferritin <100 µg/L) to open label intravenous ferric derisomaltose or usual care. Of the 1137 randomized patients, 29 (2.6%) were taking an SGLT2 inhibitor at baseline. The mean (SD) change in haemoglobin from baseline at 4 weeks in those taking an SGLT2 inhibitor at baseline was 1.3 (1.2) g/dL in patients randomized to ferric derisomaltose and 0.1 (0.7) g/dL in the usual care group; between-group difference = 1.0 g/dL (95% CI 0.1, 1.8). The equivalent numbers in the no SGLT2 inhibitor group were 0.6 (0.9) g/dL in those randomized to ferric derisomaltose and 0.1 (0.8) g/dL in the usual care group; between-group difference = 0.4 g/dL (95% CI 0.3, 1.6); interaction P value = 0.10. No patient receiving an SGLT2 inhibitor at baseline developed polycythaemia during follow-up (defined as haemoglobin >16.5 g/dL [men] or >16 g/dL [women]). CONCLUSIONS: In the IRONMAN trial, there was a trend to a greater increase in haemoglobin with ferric derisomaltose in iron-deficient patients taking an SGLT2 inhibitor at baseline, as compared with those not taking one.

Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial.

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

Epidemiology and risk factors for hyperkalaemia in heart failure.

Patients with heart failure (HF), particularly those with impaired renal function receiving renin-angiotensin-aldosterone system inhibitors (RAASis), are at risk of hyperkalaemia; when hyperkalaemia is severe, this can have serious clinical consequences. The incidence, prevalence, and risk factors for hyperkalaemia reported in randomized trials of RAASis may not reflect clinical practice due to exclusion of patients with elevated serum potassium (sK+ ) or severe renal impairment: information on patients managed in routine clinical care is important to understanding the actual burden of hyperkalaemia. This paper reviews the available clinical epidemiology data on hyperkalaemia in HF and considers areas requiring further research. Observational studies published since 2017 that focused on hyperkalaemia, included patients with HF, and had ≥1000 participants were considered. Hyperkalaemia occurrence in HF varied widely from 7% to 39% depending on the setting, HF severity, follow-up length, and concomitant medications. Rates were lowest in patients with newly diagnosed HF and highest in patients with greater disease severity; comorbidities, such as chronic kidney disease and diabetes, and RAASi use, reflected commonly identified risk factors for hyperkalaemia in patients with HF. Hyperkalaemia was most often mild; however, from the limited data available, persistence of mild hyperkalaemia was associated with an increased risk of mortality and major adverse cardiovascular events. There were also limited data available on the progression of hyperkalaemia. Recurrence was common, occurring in one-quarter to two-fifths of hyperkalaemia cases. Despite HF guidelines recommending close monitoring of sK+ , 55-93% of patients did not receive appropriate testing before or after initiation of RAASi or in follow-up to moderate/severe hyperkalaemia detection. Many of the observational studies were retrospective and from a single country. There is a need for international, prospective, longitudinal, observational studies, such as the CARE-HK in HF study (NCT04864795), to understand hyperkalaemia's prevalence, incidence, and severity; to identify and characterize cases that persist, progress, and recur; to highlight the importance of sK+ monitoring when using RAASi; and to assess the impact of newer HF therapies and potassium binders in clinical practice. Data from both clinical trials and observational studies with adjustments for confounding variables will be needed to assess the contribution of hyperkalaemia to clinical outcomes.

Relationship between sex, body size, and cardiac resynchronization therapy benefit: A patient-level meta-analysis of randomized controlled trials.

BACKGROUND: Women might benefit more than men from cardiac resynchronization therapy (CRT) and do so at shorter QRS durations. OBJECTIVE: This meta-analysis was performed to determine whether sex-based differences in CRT effects are better accounted for by height, body surface area (BSA), or left ventricular end-diastolic dimension (LVEDD). METHODS: We analyzed patient-level data from CRT trials (MIRACLE, MIRACLE ICD, MIRACLE ICD II, REVERSE, RAFT, COMPANION, and MADIT-CRT) using bayesian hierarchical Weibull regression models. Relationships between QRS duration and CRT effects were examined overall and in sex-stratified cohorts; additional analyses indexed QRS duration by height, BSA, or LVEDD. End points were heart failure hospitalization (HFH) or death and all-cause mortality. RESULTS: Compared with men (n = 5628), women (n = 1439) were shorter (1.62 [interquartile range, 1.57-1.65] m vs 1.75 [1.70-1.80] m; P < .001), with smaller BSAs (1.76 [1.62-1.90] m2 vs 2.02 [1.89-2.16] m2; P < .001). In adjusted sex-stratified analyses, the reduction in HFH or death was greater for women (hazard ratio, 0.54; credible interval, 0.42-0.70) than for men (hazard ratio, 0.77; credible interval, 0.66-0.89; Pinteraction = .009); results were similar for all-cause mortality even after adjustment for height, BSA, and LVEDD. Sex-specific differences were observed only in nonischemic cardiomyopathy. The effect of CRT on HFH or death was observed at a shorter QRS duration for women (126 ms) than for men (145 ms). Indexing QRS duration by height, BSA, or LVEDD attenuated sex-specific QRS duration thresholds for the effects of CRT on HFH or death but not on mortality. CONCLUSION: Although body size partially explains sex-specific QRS duration thresholds for CRT benefit, it is not associated with the magnitude of CRT benefit. Indexing QRS duration for body size might improve selection of patients for CRT, particularly with a "borderline" QRS duration. GOV REGISTRATION: NCT00271154, NCT00251251, NCT00267098, NCT00180271.

Iron deficiency and supplementation in heart failure.

Non-anaemic iron deficiency (NAID) is a strategic target in cardiovascular medicine because of its association with a range of adverse effects in various conditions. Endeavours to tackle NAID in heart failure have yielded mixed results, exposing knowledge gaps in how best to define 'iron deficiency' and the handling of iron therapies by the body. To address these gaps, we harness the latest understanding of the mechanisms of iron homeostasis outside the erythron and integrate clinical and preclinical lines of evidence. The emerging picture is that current definitions of iron deficiency do not assimilate the multiple influences at play in patients with heart failure and, consequently, fail to identify those with a truly unmet need for iron. Additionally, current iron supplementation therapies benefit only certain patients with heart failure, reflecting differences in the nature of the unmet need for iron and the modifying effects of anaemia and inflammation on the handling of iron therapies by the body. Building on these insights, we identify untapped opportunities in the management of NAID, including the refinement of current approaches and the development of novel strategies. Lessons learned from NAID in cardiovascular disease could ultimately translate into benefits for patients with other chronic conditions such as chronic kidney disease, chronic obstructive pulmonary disease and cancer.

Medicines optimization prior to discharge in patients admitted to hospital with heart failure.

AIMS: Approximately half of patients with heart failure and a reduced ejection fraction (HeFREF) are discharged from hospital on triple therapy [angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs)]. We investigated what proportion of patients are on optimal doses prior to discharge and how many might be eligible for initiation of sacubitril-valsartan or sodium-glucose co-transporter-2 inhibitors (SGLT2Is). METHODS AND RESULTS: Between 2012 and 2017, 1277 patients admitted with suspected heart failure were enrolled at a single hospital serving a local community around Kingston upon Hull, UK. Eligibility for sacubitril-valsartan or SGLT2I was based on entry criteria for the PIONEER-HF, DAPA-HF, and EMPEROR-Reduced trials. Four hundred fifty-five patients had HeFREF with complete data on renal function, heart rate, and systolic blood pressure (SBP) prior to discharge. Eighty-three per cent of patients were taking an ACE-I or ARB, 85% a BB, and 63% an MRA at discharge. More than 60% of patients were eligible for sacubitril-valsartan and >70% for SGLT2I. Among those not already receiving a prescription, 37%, 28%, and 49% were eligible to start ACE-I or ARB, BB, and MRA, respectively. Low SBP (≤105 mmHg) was the most frequent explanation for failure to initiate or up-titrate therapy. CONCLUSIONS: Most patients admitted for heart failure are eligible for initiation of life-prolonging medications prior to discharge. A hospital admission may be a common missed opportunity to improve treatment for patients with HeFREF.

2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.

Document Reviewers: Rudolf A. de Boer (CPG Review Co-ordinator) (Netherlands), P. Christian Schulze (CPG Review Co-ordinator) (Germany), Elena Arbelo (Spain), Jozef Bartunek (Belgium), Johann Bauersachs (Germany), Michael A. Borger (Germany), Sergio Buccheri (Sweden), Elisabetta Cerbai (Italy), Erwan Donal (France), Frank Edelmann (Germany), Gloria Färber (Germany), Bettina Heidecker (Germany), Borja Ibanez (Spain), Stefan James (Sweden), Lars Køber (Denmark), Konstantinos C. Koskinas (Switzerland), Josep Masip (Spain), John William McEvoy (Ireland), Robert Mentz (United States of America), Borislava Mihaylova (United Kingdom), Jacob Eifer Møller (Denmark), Wilfried Mullens (Belgium), Lis Neubeck (United Kingdom), Jens Cosedis Nielsen (Denmark), Agnes A. Pasquet (Belgium), Piotr Ponikowski (Poland), Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Bianca Rocca (Italy), Xavier Rossello (Spain), Leyla Elif Sade (United States of America/Türkiye), Hannah Schaubroeck (Belgium), Elena Tessitore (Switzerland), Mariya Tokmakova (Bulgaria), Peter van der Meer (Netherlands), Isabelle C. Van Gelder (Netherlands), Mattias Van Heetvelde (Belgium), Christiaan Vrints (Belgium), Matthias Wilhelm (Switzerland), Adam Witkowski (Poland), and Katja Zeppenfeld (Netherlands) All experts involved in the development of this Focused Update have submitted declarations of interest. These have been compiled in a report and simultaneously published in a supplementary document to the Focused Update. The report is also available on the ESC website www.escardio.org/guidelines See the European Heart Journal online for supplementary documents that include evidence tables.

Impact of vasodilators on diuretic response in patients with congestive heart failure: A mechanistic trial of cimlanod (BMS-986231).

AIM: To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide. METHODS AND RESULTS: In this randomized, double-blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 µg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT-proBNP at baseline was 1487 (interquartile range: 847-2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post-furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion. CONCLUSIONS: For patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload.

Phenotyping patients with ischaemic heart disease at risk of developing heart failure: an analysis of the HOMAGE trial.

AIMS: We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI). METHODS AND RESULTS: HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow-up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between-group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase-7 (MMP-7), galectin-4 (GAL4), plasminogen activator inhibitor 1 (PAI-1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP-7, neurotrophin-3 (NT3), pulmonary surfactant-associated protein D (PSPD), and lower plasma tumour necrosis factor-related activation-induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months. CONCLUSIONS: In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes.

Evaluation of the stopping angiotensin converting enzyme inhibitor compared to angiotensin receptor blocker (STOP ACEi trial) in advanced and progressive chronic kidney disease.

In the STOP-ACEi trial, the outcome was similar whether or not renin-angiotensin system inhibitors (RASi) were discontinued. We now investigate whether the effect of withdrawing angiotensin converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARBs) differed. In this open label trial patients with estimated glomerular filtration rates (eGFR) under 30ml/min per 1.73 m2 and progressive chronic kidney disease (CKD) were randomized to stop or continue RASi. The primary outcome was eGFR at three years. The composite of kidney failure, over 50% fall in eGFR, or kidney replacement therapy (KRT) was also assessed. Of patients randomized, 99 stopped and 123 patients continued ACEi while 104 stopped and 77 continued ARB at baseline. At three years, the eGFR was similar whether or not patients were withdrawn from ACEi or from ARB. Kidney failure or initiation of KRT occurred in 65% of those stopping and 54% continuing ACEi (hazard ratio if stopped, 1.52; 95% Confidence Interval, 1.07 to 2.16) and in 60% on an ARB regardless of randomized group (hazard ratio if stopped, 1.23; 0.83 to 1.81). Kidney failure/Initiation of KRT with over 50% decline in eGFR occurred in 71% of those stopping and 59% continuing ACEi (relative risk if stopped, 1.19; 95% CI, 1.00 to 1.41) and in 65% stopping and 69% continuing ARB (relative risk if stopped, 0.96; 0.79 to 1.16). Thus, neither discontinuing ACEi nor ARB slowed the rate of decline in eGFR. Although discontinuation of ACEi appeared to have more unfavorable effects on kidney outcomes than stopping ARB, the trial was neither designed nor powered to show differences between agents.

Hospital admissions in the last year of life of patients with heart failure.

AIM: To explore the frequency, causes, and pattern of hospitalisation for patients with chronic heart failure (HF) in the 12 months preceding death. We also investigated cause of death. METHODS: Patients referred to a secondary care HF clinic were routinely consented for follow-up between 2001 and 2020 and classified into three phenotypes: (i) HF with reduced ejection fraction (HFrEF), (ii) HF with preserved ejection fraction (HFpEF) with plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) 125-399 ng L-1, and (iii) HFpEF with NT-proBNP ≥400 ng L-1. Hospital admissions in the last year of life were classified as: HF, other cardiovascular (CV), or non-cardiovascular (non-CV). The cause of death was systematically adjudicated. RESULTS: A total of 4925 patients (38% women; median age at death 81 [75-87] years) had 9127 hospitalisations in the last year of life. The median number of hospitalisations was 2 (1-3) and total days spent in hospital was 12 (2-25). Out of the total, 83% of patients had ≥1 hospitalisation but only 20% had ≥1 HF hospitalisation; 24% had ≥1 CV hospitalisation; 70% had ≥1 non-CV hospitalisation. Heart failure hospitalisations were most common in patients with HFrEF, but in all groups, at least two thirds of admissions were for non-CV causes. There were 788 (16%) deaths due to progressive HF, of which 74% occurred in hospital. CONCLUSION: For patients with chronic HF in the last year of life, most hospitalisations were for non-CV causes regardless of HF phenotype. Most patients had no HF hospitalisations in their last year of life. Most deaths were from causes other than progressive HF.

Multiple Cardiac Biomarkers to Improve Prediction of Cardiovascular Events: Findings from the Generation Scotland Scottish Family Health Study.

BACKGROUND: Many studies have investigated whether single cardiac biomarkers improve cardiovascular risk prediction for primary prevention but whether a combined approach could further improve risk prediction is unclear. We aimed to test a sex-specific, combined cardiac biomarker approach for cardiovascular risk prediction. METHODS: In the Generation Scotland Scottish Family Health Study, N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor-15 (GDF-15), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and C-reactive protein (CRP) were measured in stored serum using automated immunoassays. Sex-specific Cox models that included SCORE2 risk factors evaluated addition of single and combined biomarkers for prediction of major adverse cardiovascular events (MACE). Combined biomarker models were compared to a baseline model that included SCORE2 risk factors. RESULTS: The study population comprised 18 383 individuals (58.9% women, median age of 48 years [25th-75th percentile, 35-58 years]). During the median follow up of 11.6 (25th-75th percentile, 10.8-13.0) years, MACE occurred in 942 (5.1%) individuals. The greatest increase in discrimination with addition of individual biomarkers to the base model was for women GDF-15 and for men NT-proBNP (change in c-index: + 0.010 for women and +0.005 for men). For women, combined biomarker models that included GDF-15 and NT-proBNP (+0.012) or GDF-15 and cTnI (+0.013), but not CRP or cTnT, further improved discrimination. For men, combined biomarker models that included NT-proBNP and GDF-15 (+0.007), NT-proBNP and cTnI (+0.006), or NT-proBNP and CRP (+0.008), but not cTnT, further improved discrimination. CONCLUSIONS: A combined biomarker approach, particularly the use of GDF-15, NT-proBNP and cTnI, further refined cardiovascular risk estimates.