Associations between inflammatory and angiogenic proteomic biomarkers, and cardiovascular events and mortality in relation to kidney function.

Background: The links between chronic kidney disease (CKD) and the high burden of cardiovascular disease remain unclear. We aimed to explore the association between selected inflammatory and angiogenic biomarkers, kidney function and long-term outcome in patients with an acute coronary syndrome (ACS) and to test the hypothesis that CKD status modifies this association. Methods: A total of 1293 ACS patients hospitalized between 2008 and 2015 were followed until 31 December 2017. Plasma was collected on days 1-3 after admission. A total of 13 biomarkers were a priori identified and analysed with two proteomic methods, proximity extension assay or multiple reaction monitoring mass spectrometry. Boxplots and multiple linear regression models were used to study associations between biomarkers and kidney function and adjusted standardized Cox regression with an interaction term for CKD was used to assess whether CKD modified the association between biomarkers and major adverse cardiovascular events and death (MACE+). Results: The concentrations of nine biomarkers-endothelial cell-specific molecule-1 (ESM-1), fibroblast growth factor 23 (FGF-23), fractalkine (CX3CL1), interleukin-1 receptor antagonist (IL-1RA), interleukin-18 (IL-18), monocyte chemotactic protein-1 (MCP-1), placenta growth factor (PlGF), transmembrane immunoglobulin 1 (TIM-1) and vascular endothelial growth factor A (VEGFA)-were inversely associated with kidney function. ESM-1, FGF-23 and TIM-1 showed associations with MACE+. Only FGF23 remained independently associated after adjustment for the other biomarkers (hazard ratio per standard deviation increase 1.34; 95% Bonferroni corrected confidence interval 1.19-1.50). None of the biomarkers showed an interaction with CKD. Conclusions: The concentrations of 9 of the 13 prespecified inflammatory and angiogenic proteomic biomarkers increased when kidney function declined. Only FGF-23 demonstrated an independent association with MACE+, and this association was not modified by CKD status. These findings further support FGF-23 as an independent prognostic marker in ACS patients with and without CKD.

Design and rationale of the myocardial infarction and new treatment with metformin study (MIMET) - Study protocol for a registry-based randomised clinical trial.

AIMS: To investigate if addition of metformin to standard care (life-style advice) reduces the occurrence of cardiovascular events and death after myocardial infarction (MI) in patients with newly detected prediabetes. METHODS: The Myocardial Infarction and new treatment with Metformin study (MIMET) is a large multicentre registry-based randomised clinical trial (R-RCT) within the SWEDEHEART registry platform expected to include 5160 patients with MI and newly detected prediabetes (identified with fasting blood glucose, HbA1c or 2-h glucose on oral glucose tolerance test) at ∼20 study sites in Sweden. Patients 18-80 years, without known diabetes and naïve to glucose lowering therapy, will be randomised 1:1 to open-label metformin therapy plus standard care or standard care alone. OUTCOMES: Patients will be followed for 2 years for the primary outcome new cardiovascular event (first of death, non-fatal MI, hospitalisation for heart failure or non-fatal stroke). Secondary endpoints include individual components of the primary endpoint, diabetes diagnosis, initiation of any glucose lowering therapy, cancer, and treatment safety. Events will be collected from national healthcare registries. CONCLUSIONS: The MIMET study will investigate if metformin is superior to standard care after myocardial infarction in preventing cardiovascular events in patients with prediabetes (Clinicaltrials.gov identifier: NCT05182970; EudraCT No: 2019-001487-30).

Association between high-sensitivity C-reactive protein and coronary atherosclerosis in a general middle-aged population.

Despite abundant knowledge about the relationship between inflammation and coronary atherosclerosis, it is still unknown whether systemic inflammation measured as high-sensitivity C-reactive protein (hsCRP) is associated with coronary atherosclerosis in a general population. This study aimed to examine the association between hsCRP and coronary computed tomography angiography (CCTA)-detected coronary atherosclerosis in a population-based cohort. Out of 30,154 randomly invited men and women aged 50 to 64 years in the Swedish Cardiopulmonary Bioimage Study (SCAPIS), 25,408 had a technically acceptable CCTA and analysed hsCRP. Coronary atherosclerosis was defined as presence of plaque of any degree in any of 18 coronary segments. HsCRP values were categorised in four groups. Compared with hsCRP below the detection limit, elevated hsCRP (≥ 2.3 mg/L) was weakly associated with any coronary atherosclerosis (OR 1.15, 95% CI 1.07-1.24), coronary diameter stenosis ≥ 50% (OR 1.27, 95% CI 1.09-1.47), ≥ 4 segments involved (OR 1.13, 95% CI 1.01-1.26 ) and severe atherosclerosis (OR 1.33, 95% CI 1.05-1.69) after adjustment for age, sex and traditional risk factors. The associations were attenuated after further adjustment for body mass index (BMI), although elevated hsCRP still associated with noncalcified plaques (OR 1.16, 95% CI 1.02-1.32), proposed to be more vulnerable. In conclusion, the additional value of hsCRP to traditional risk factors in detection of coronary atherosclerosis is low. The association to high-risk noncalcified plaques, although unlikely through a causal pathway, could explain the relationship between hsCRP and clinical coronary events in numerous studies.

Statin Treatment Intensity, Discontinuation, and Long-Term Outcome in Patients With Acute Myocardial Infarction and Impaired Kidney Function.

ABSTRACT: Statin dosage in patients with acute myocardial infarction (AMI) and concomitant kidney dysfunction is a clinical dilemma. We studied discontinuation during the first year after an AMI and long-term outcome in patients receiving high versus low-moderate intensity statin treatment, in relation to kidney function. For the intention-to-treat analysis (ITT-A), we included all patients admitted to Swedish coronary care units for a first AMI between 2005 and 2016 that survived in-hospital, had known creatinine, and initiated statin therapy (N = 112,727). High intensity was initiated in 38.7% and low-moderate in 61.3%. In patients with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 , 25% discontinued treatment the first year; however, the discontinuation rate was similar regardless of the statin intensity. After excluding patients who died, changed therapy, or were nonadherent during the first year, 84,705 remained for the on-treatment analysis (OT-A). Patients were followed for 12.6 (median 5.6) years. In patients with eGFR 30-59 mL/min, high-intensity statin was associated with lower risk for the composite death, reinfarction, or stroke both in ITT-A (hazard ratio [HR] 0.93; 95% confidence interval, 0.87-0.99) and OT-A (HR 0.90; 0.83-0.99); the interaction test for OT-A indicated no heterogeneity for the eGFR < 60 mL/min group ( P = 0.46). Similar associations were seen for all-cause mortality. We confirm that high-intensity statin treatment is associated with improved long-term outcome after AMI in patients with reduced kidney function. Most patients with reduced kidney function initiated on high-intensity statins are persistent after 1 year and equally persistent as patients initiated on low-moderate intensity.

Prognostic importance of biomarkers associated with haemostatic, vascular and endothelial disturbances in acute coronary syndrome patients in relation to kidney function.

BACKGROUND: Patients with kidney failure have a high risk for cardiovascular events. We aimed to evaluate the prognostic importance of selected biomarkers related to haemostasis, endothelial function, and vascular regulation in patients with acute coronary syndrome (ACS), and to study whether this association differed in patients with renal dysfunction. METHODS: Plasma was collected in 1370 ACS patients included between 2008 and 2015. Biomarkers were analysed using a Proximity Extension Assay and a Multiple Reaction Monitoring mass spectrometry assay. To reduce multiplicity, biomarkers correlating with eGFR were selected a priori among 36 plasma biomarkers reflecting endothelial and vascular function, and haemostasis. Adjusted Cox regression were used to study their association with the composite outcome of myocardial infarction, ischemic stroke, heart failure or death. Interaction with eGFR strata above or below 60 ml/min/1.73 m2 was tested. RESULTS: Tissue factor, proteinase-activated receptor, soluble urokinase plasminogen activator surface receptor (suPAR), thrombomodulin, adrenomedullin, renin, and angiotensinogen correlated inversely with eGFR and were selected for the Cox regression. Mean follow-up was 5.2 years during which 428 events occurred. Adrenomedullin, suPAR, and renin were independently associated with the composite outcome. Adrenomedullin showed interaction with eGFR strata (p = 0.010) and was associated with increased risk (HR 1.88; CI 1.44-2.45) only in patients with eGFR ≥60 ml/min/ 1.73 m2. CONCLUSIONS: Adrenomedullin, suPAR, and renin were associated with the composite outcome in all. Adrenomedullin, involved in endothelial protection, showed a significant interaction with renal function and outcome, and was associated with the composite outcome only in patients with preserved kidney function.

Prognostic impact of type 1 and type 2 diabetes mellitus in atrial fibrillation and the effect of severe hypoglycaemia: a nationwide cohort study.

AIMS: To compare prognosis between individuals without diabetes, type 1 and type 2 diabetes in a nationwide atrial fibrillation cohort in Sweden and study the significance of severe hypoglycaemia. METHODS: Using data from all-inclusive national registers, 309,611 patients with non-valvular atrial fibrillation were enrolled during 2013-2014. Of these, 2,221 had type 1 and 58,073 had type 2 diabetes. Patients were followed for all-cause mortality until 27 March 2017, and for myocardial infarction, ischaemic stroke and first-ever diagnosis of heart failure or dementia until 31 December 2015. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox and competing risk regression. RESULTS: Using individuals without diabetes as reference (HR = 1), the adjusted HRs in type 1 vs. type 2 diabetes were for mortality 1.87 (CI 1.73-2.02) vs. 1.51 (CI 1.47-1.55), heart failure 1.59 (CI 1.42-1.78) vs. 1.41 (CI 1.34-1.48), myocardial infarction 2.49 (CI 2.17-2.85) vs. 1.70 (CI 1.59-1.81), ischaemic stroke 1.59 (CI 1.35-1.87) vs. 1.31 (CI 1.22-1.40), and dementia 1.46 (CI 1.15-1.85) vs. 1.28 (CI 1.18-1.40). Among individuals with type 2 diabetes, those with previous severe hypoglycaemia had increased risk of mortality (HR 1.26; CI 1.17-1.36) and dementia (HR 1.37; CI 1.08-1.73) compared with those without previous severe hypoglycaemia. CONCLUSION: Presence of diabetes-regardless of type- in atrial fibrillation is associated with an increased risk of premature death, cardiovascular events and dementia. This increase is more pronounced in type 1 than in type 2 diabetes. A history of severe hypoglycaemia is associated with a worsened prognosis in type 2 diabetes.

Impaired fasting glucose: a risk factor for atrial fibrillation and heart failure.

BACKGROUND: Dysglycaemia is associated with overall cardiovascular disease even at prediabetes levels. The aim of this study was to explore the association between glucose levels and future risk of developing atrial fibrillation and heart failure, respectively. METHODS: In this prospective cohort study subjects from the Swedish AMORIS-cohort with fasting glucose from health examinations 1985-1996 without previous cardiovascular disease (N = 294,057) were followed to 31 December 2011 for incident atrial fibrillation or heart failure. Cox proportional hazard models with attained age as timescale and adjustments for sex, cholesterol, triglycerides, and socioeconomic status were used to estimate hazard ratios by glucose categorized groups (normal glucose 3.9-6.0 mmol/L, impaired fasting glucose; 6.1-6.9 mmol/L, undiagnosed diabetes ≥ 7.0 mmol/L, and diagnosed diabetes). RESULTS: During a mean follow-up time of 19.1 years 28,233 individuals developed atrial fibrillation and 25,604 developed heart failure. The HR for atrial fibrillation was 1.19 (95% confidence interval 1.13-1.26) for impaired fasting glucose, 1.23 (1.15-1.32) for undiagnosed diabetes and 1.30 (1.21-1.41) for diagnosed diabetes. Corresponding figures for heart failure were; 1.40 (1.33-1.48), 2.11 (1.99-2.23), 2.22 (2.08-2.36) respectively. In a subset with BMI data (19%), these associations were attenuated and for atrial fibrillation only remained statistically significant among subjects with diagnosed diabetes (HR 1.25; 1.02-1.53). CONCLUSIONS: Fasting glucose at prediabetes levels is associated with development of atrial fibrillation and heart failure. To some extent increased BMI may drive this association.

Arginase 1 is upregulated at admission in patients with ST-elevation myocardial infarction.

BACKGROUND: The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unresolved. Increased arginase 1 activity leads to reduced nitric oxide (NO) production and increased formation of reactive oxygen species due to uncoupling of the NO-producing enzyme endothelial NO synthase (eNOS). This contributes to endothelial dysfunction, plaque instability and increased susceptibility to ischemia-reperfusion injury in acute myocardial infarction. OBJECTIVE: The purpose of this study was to test the hypothesis that arginase gene and protein expression are upregulated in patients with STEMI. METHODS: Two cohorts of patients with STEMI were included. In the first cohort (n = 51), expression of arginase and NO-synthases as well as arginase 1 protein levels were determined and compared to a healthy control group (n = 45). In a second cohort (n = 68), plasma arginase 1 levels and infarct size were determined using cardiac magnetic resonance imaging. RESULTS: Expression of the gene encoding arginase 1 was significantly elevated at admission and 24-48 h after STEMI but not 3 months post STEMI, in comparison with the control group. Expression of the genes encoding arginase 2 and endothelial NO synthase (NOS3) were unaltered. Arginase 1 protein levels were elevated at admission, 24 h post STEMI and remained elevated for up to 6 months. No significant correlation between plasma arginase 1 protein levels and infarct size was observed. CONCLUSION: The markedly increased gene and protein expression of arginase 1 already at admission indicates a role of arginase 1 in the development of STEMI.

Long-term prognosis in patients with acute myocardial infarction and newly detected glucose abnormalities: predictive value of oral glucose tolerance test and HbA1c.

BACKGROUND: Disturbances of glucose metabolism can be diagnosed by an oral glucose tolerance test (OGTT) and by glycated haemoglobin (HbA1c). The aim of this study was to investigate the association between newly detected disturbances of glucose metabolism and long-term prognosis after acute myocardial infarction (AMI) and to compare the predictive value of an OGTT and HbA1c. METHODS: Patients under the age of 80 years with no known history of diabetes admitted for AMI at the Department of Cardiology, Danderyd University Hospital, Stockholm, Sweden, from January 1st, 2006 until December 31st, 2013, were investigated with an OGTT and a HbA1c before discharge and were classified as having normal glucose tolerance (NGT), prediabetes or diabetes according to American Diabetes Association (ADA) criteria. Using nationwide, all-inclusive registers, patients were followed for the incidence of combined event [CE (first of myocardial infarction, heart failure, ischaemic stroke or mortality)] for a mean follow-up time of 4.8 years. Cox regression analysis was used to calculate Hazard Ratios (HR) and their 95% confidence intervals (CI). RESULTS: Of the 841 patients who were investigated with both an OGTT and a HbA1c, 139 (17%) patients had NGT, 398 (47%) had prediabetes and 304 (36%) had diabetes according to OGTT. The corresponding figures using HbA1c were 320 (38%), 461 (55%) and 60 (7%). Patients with newly discovered diabetes were older and had a higher body mass index compared to those with NGT. OGTT was not predictive for CE. In contrast, prediabetes identified by a HbA1c was associated with an increased risk for CE (HR 1.31; 95% CI 1.05-1.63) compared to normoglycaemia. When comparing the prognostic value of different glucose and HbA1c cut-offs, only a HbA1c ≥ 39 mmol/mol was significantly associated with CE (HR 95% CI; 1.30:1.05-1.61). CONCLUSION: In this single-centre study, in a recent contemporary cohort, we found that around two thirds of the patients admitted with AMI with no known history of diabetes had disturbed glucose metabolism, in accordance with previous studies. HbA1c in the prediabetes range, but not OGTT, added predictive value on the long-term outcome, in a cohort to whom a pathologic OGTT result was communicated with lifestyle advice.

Glucagon-like peptide-1 receptor agonists and the risk of cardiovascular events in diabetes patients surviving an acute myocardial infarction.

AIMS: Trial evidence indicates that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may reduce the risk of cardiovascular (CV) events in patients with diabetes and myocardial infarction (MI). We aimed to expand this observation to routine care settings. METHODS AND RESULTS: Prospective observational study including all patients with diabetes surviving an MI and registered in the nationwide SWEDEHEART registry during 2010-17. Multivariable Cox regression analyses were used to estimate the association between GLP-1 RAs use and the study outcome, which was a composite of stroke, heart failure, Re-infarction, or CV death. Covariates included demographics, comorbidities, presentation at admission, and use of secondary CV prevention therapies. In total, 17 868 patients with diabetes were discharged alive after a first event of MI. Their median age was 71 years, 36% were women and their median estimated glomerular filtration rate was 75 mL/min/1.73m2. Of those, 365 (2%) were using GLP-1 RAs. During median 3 years of follow-up, 7005 patients experienced the primary composite outcome. Compared with standard of diabetes care, use of GLP-1 RAs was associated with a lower event risk [adjusted hazard ratio (HR) 0.72; 95% confidence interval (CI): 0.56-0.92], mainly attributed to a lower rate of re-infarction and stroke. Results were similar after propensity score matching or when compared with users of sulfonylurea. There was no suggestion of heterogeneity across subgroups of age, sex, chronic kidney disease, and STEMI. CONCLUSION: GLP-1 RAs use, compared with standard of diabetes care, was associated with lower risk for major CV events in healthcare-managed survivors of an MI.

Low-density lipoprotein-cholesterol target attainment according to the 2011 and 2016 ESC/EAS dyslipidaemia guidelines in patients with a recent myocardial infarction: nationwide cohort study, 2013-17.

AIMS: To assess low-density lipoprotein cholesterol (LDL-C) treatment target attainment among myocardial infarction (MI) patients according to the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) dyslipidaemia guidelines from 2011 (LDL-C < 1.8 mmol/L or ≥50% LDL-C reduction) and 2016 (LDL-C < 1.8 mmol/L and ≥50% LDL-C reduction). METHODS AND RESULTS: Using nationwide registers, we identified 44 890 patients aged 21-74 admitted for MI, 2013-17. We included those attending follow-up visits at 6-10 weeks (n = 25 466) and 12-14 months (n = 17 117) after the event. Most patients received high-intensity statin monotherapy [84.3% (6-10 weeks) and 69.0% (12-14 months)] or statins with ezetimibe (2.7% and 10.2%). The proportion of patients attaining the 2011 LDL-C target was 63.8% (6-10 weeks) and 63.5% (12-14 months). The corresponding numbers for the 2016 LDL-C target were 31.6% (6-10 weeks) and 31.5% (12-14 months). At the 6- to 10-week follow-up, 37% of those not attaining the 2011 LDL-C target and 48% of those not attaining the 2016 target had an LDL-C level that was ≥0.5 mmol/L from the target. When comparing LDL-C measurements performed before vs. after the release of the 2016 guidelines, attainment of the 2016 LDL-C target increased from 30.2% to 35.0% (6-10 weeks) and from 27.6% to 37.6% (12-14 months). CONCLUSION: In a nationwide register, one out of three patients with a recent MI had not attained the LDL-C target of the 2011 ESC/EAS guidelines and two out of three patients had not attained the LDL-C target of the 2016 guidelines.

Diabetes, metformin and glucose lowering therapies after myocardial infarction: Insights from the SWEDEHEART registry.

OBJECTIVE: To explore real-life use of glucose lowering drugs and prognosis after acute myocardial infarction (AMI) with a special focus on metformin. METHODS: Patients (n = 70270) admitted for AMI 2012-2017 were stratified by diabetes status and glucose lowering treatment and followed for mortality and MACE+ (AMI, heart failure (HF), stroke, mortality) until end of 2017 (mean follow-up time 3.4 ± 1.4 years) through linkage with national registries and SWEDEHEART. Hazard ratios (HR) were calculated in adjusted Cox proportional hazard regression models. RESULTS: Mean age was 68 ± 11 years and 70% were male. Of patients with diabetes (n = 16356; 23%), a majority had at least one glucose lowering drug (81%) of whom 51% had metformin (24% monotherapy), 43% insulin and a minority any SGLT2i/GLP-1 RA (5%). Adjusted HR for patients with versus without diabetes was 1.31 (95% CI 1.27-1.36) for MACE+ and 1.48 (1.41-1.56) for mortality. Adjusted HR for MACE+ for diabetes patients on metformin was 0.92 (0.85-0.997), p = 0.042 compared to diet treated diabetes. CONCLUSION: Diabetes still implies a high complication risk after AMI. Metformin and insulin were the most common treatment used in almost half of the diabetes population. Furthermore, patients treated with metformin had a lower cardiovascular risk after AMI and needs to be confirmed in prospective controlled trials.

Preoperative disturbances of glucose metabolism and mortality after coronary artery bypass grafting.

BACKGROUND: Disturbances of glucose metabolism are important risk factors for coronary artery disease and are associated with an increased mortality risk. The aim was to investigate the association between preoperative disturbances of glucose metabolism and long-term all-cause mortality after coronary artery bypass grafting (CABG). METHODS: Patients undergoing a first isolated CABG in 2005-2013 were included. All patients without previously known diabetes underwent an oral glucose tolerance test (OGTT) before surgery. They were categorised as having normal glucose tolerance (NGT), pre-diabetes (impaired glucose tolerance and/or impaired fasting glucose) or newly discovered diabetes. Data were collected from nationwide healthcare registers. Cox regression was used to calculate adjusted HR with 95% CI for death in patients with pre-diabetes and diabetes, using NGT as reference. RESULTS: In total, 497 patients aged 40-86 years were included. According to OGTT, 170 (34%) patients had NGT, 219 (44%) patients with pre-diabetes and 108 (22%) patients had newly discovered diabetes. Baseline characteristics were similar between the groups except for slightly higher age among patients with newly discovered diabetes. There were 133 (27%) deaths during a mean follow-up time of 10 years. The cumulative 10-year survival was 77% (69%-83%), 83% (77%-87%) and 71% (61%-79%) in patients with NGT, pre-diabetes and newly discovered diabetes, respectively. There was no significant difference in all-cause mortality between the groups after multivariable adjustment. CONCLUSION: In this study, patients with pre-diabetes or newly discovered diabetes prior to CABG had similar long-term survival compared with patients with NGT.

Application of the 2019 ESC/EAS dyslipidaemia guidelines to nationwide data of patients with a recent myocardial infarction: a simulation study.

AIMS: To estimate the proportion of patients with a recent myocardial infarction (MI) who would be eligible for additional lipid-lowering therapy according to the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidaemias, and to simulate the effects of expanded lipid-lowering therapy on attainment of the low-density lipoprotein cholesterol (LDL-C) target as recommended by the guidelines. METHODS AND RESULTS: Using the nationwide SWEDEHEART register, we included 25 466 patients who had attended a follow-up visit 6-10 weeks after an MI event, 2013-17. While most patients (86.6%) were receiving high-intensity statins, 82.9% of the patients would be eligible for expanded lipid-lowering therapy, as they had not attained the target of an LDL-C level of <1.4 mmol and a ≥50% LDL-C level reduction. When maximized use of high-intensity statins followed by add-on therapy with ezetimibe was simulated using a Monte Carlo model, the LDL-C target was reached in 19.9% using high-intensity statin monotherapy and in another 28.5% with high-intensity statins and ezetimibe, while 50.7% would still be eligible for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. When use of alirocumab or evolocumab was simulated in those who were eligible for PCSK9 inhibitors, around 90% of all patients attained the LDL-C target. CONCLUSION: Our study suggests that, even with maximized use of high-intensity statins and ezetimibe, around half of patients with MI would be eligible for treatment with PCSK9 inhibitors according to the 2019 ESC/EAS guidelines. Considering the current cost of PCSK9 inhibitors, the financial implications of the new guidelines may be substantial.

Comparing a novel equation for calculating low-density lipoprotein cholesterol with the Friedewald equation: A VOYAGER analysis.

Treating elevated low-density lipoprotein cholesterol (LDL-C) to risk-stratified target levels is recommended in several guidelines. Thus, accurate estimation of LDL-C is required. LDL-C is typically calculated using the Friedewald equation: (total cholesterol) - (non-high-density lipoprotein cholesterol [non-HDL-C]) - (triglycerides [TGs]/5). As the equation uses a fixed value equal to 5 as a divisor for TGs, it does not account for inter-individual variability, often resulting in underestimation of risk and potentially undertreatment. It is specifically inapplicable in patients with fasting triglycerides ≥400 mg/dL. A novel method of LDL-C calculation was derived and validated by Martin et al.: (non-HDL-C) - (triglycerides/adjustable factor). This equation uses an adjustable factor, the median TG:very-low-density lipoprotein cholesterol ratio in strata defined by levels of TG and non-HDLC, as divisor for TGs, and the adjustable factor ranging from 3 to 12 has been shown to provide more accurate estimates of LDL-C compared with the Friedewald equation using a direct assay as the gold standard. We used 70,209 baseline and on-treatment lipid values from the VOYAGER meta-analysis database to determine the difference in calculated LDL-C values using the Friedewald and novel equations. In patients with TGs <400 mg/dL, LDL-C values calculated using the novel equation were plotted against those calculated using the Friedewald equation. The novel equation generally resulted in LDL-C values greater than the Friedewald calculation, with differences increasing with decreasing LDL-C levels; 23% of individuals who reached a LDL-C target of 70 mg/dL with the Friedewald equation did not achieve this target when the novel equation was used to calculate LDL-C; these figures were 8% and 2% for <100 mg/dL and < 130 mg/dL targets, respectively. In patients with triglycerides ≥400 mg/dL, in whom the Friedewald equation is not valid, lipid values calculated using the novel equation were compared with those obtained by ß-quantification. Values calculated with the novel equation did not appear to be closely related with those calculated by ß-quantification in these patients. In conclusion, the novel equation provides a higher estimation of exact LDL-C values than the Friedewald equation, particularly in patients with low LDL-C levels, which may result in undertreatment of some patients whose LDL-C was calculated using the Friedewald method. However, neither may be suitable for patients with TG ≥400 mg/dL.

Modeling Statin-Induced Reductions of Cardiovascular Events in Primary Prevention: A VOYAGER Meta-Analysis.

OBJECTIVE: We used individual patient data from the VOYAGER database to estimate cardiovascular (CV) risk reduction with commonly used high-intensity statins. METHODS: In patients with known atherosclerotic CV disease (ASCVD) treated with high-intensity statin therapy (n = 6,735), the predicted risk reduction was estimated using the Cholesterol Treatment Trialists' Collaboration meta-analysis, which determined risk reduction per 38.7 mg/dL statin-mediated reduction in low-density lipoprotein cholesterol. RESULTS: The greatest reductions in risk were seen in major vascular events (estimated rate ratios ranged from 0.55 with rosuvastatin [RSV] 40 mg to 0.60 with atorvastatin [ATV] 40 mg) and coronary heart disease death (estimated rate ratios ranged from 0.58 with RSV 40 mg to 0.64 with ATV 40 mg). CONCLUSIONS: Our results show that, in individuals without clinical ASCVD, statin therapy has the potential to reduce the frequency of CV events.

High overall cardiovascular risk and mortality in patients with atrial fibrillation and diabetes: A nationwide report.

AIM: To describe nationwide complication patterns in patients with atrial fibrillation and diabetes mellitus. METHODS: All ( n = 326,832) patients in Sweden with non-valvular atrial fibrillation during 2006-2012 were identified, and information on events, comorbidities and pharmacological therapy was extracted using nationwide mandatory registers. Patients were followed until 31 December 2013 and the mean follow-up time was 3.7 years (0.9-8 years). RESULTS: Diabetes was present in 17.7%. The most frequent events in those with and without diabetes were mortality (48.8% vs 36.4%; p < 0.001), heart failure (21.4% vs 13.1%; p < 0.001), ischaemic stroke (8.2% vs 6.8%; p < 0.001), myocardial infarction (7.3% vs 4.3%; p < 0.001) and any bleeding (6.3% vs 5.2%; p < 0.001), respectively. Diabetes predicted mortality (hazard ratio = 1.28; 95% confidence interval = 1.25-1.31), combined event (first of mortality, heart failure, ischaemic stroke or myocardial infarction; hazard ratio = 1.22; 95% confidence interval = 1.20-1.25), single events and bleeding (hazard ratio = 1.12; 95% confidence interval = 1.06-1.19). The standardised mortality ratio for patients with atrial fibrillation and diabetes compared to the general population was 2.06 (95% confidence interval = 2.00-2.12) and for patients with atrial fibrillation without diabetes was 1.33 (95% confidence interval = 1.31-1.35). CONCLUSION: In this real-world setting, patients with atrial fibrillation and diabetes have a high cardiovascular risk, with mortality and heart failure rates exceeding those for stroke.

Effects of age, gender and statin dose on lipid levels: Results from the VOYAGER meta-analysis database.

BACKGROUND AND AIMS: The effectiveness of statins in the treatment of dyslipidaemia and reduction of cardiovascular risk is well established. However, the association of statin-mediated lipid effects with age and gender is unclear. This study aimed to determine whether age and gender are associated with statin-mediated changes in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and non-HDL-C. METHODS: Individual patient data (n = 32,258) were obtained from VOYAGER. Least-squares mean percentage change from baseline in LDL-C, non-HDL-C and HDL-C with atorvastatin 10-80 mg, rosuvastatin 5-40 mg or simvastatin 10-80 mg was estimated in women aged <70 years, women aged ≥70 years, men aged <70 years and men aged ≥70 years. RESULTS: All statins and doses gave significant dose-dependent reductions in LDL-C and non-HDL-C, and increases in HDL-C, in all four patient groups. A 2.1% greater reduction in LDL-C was observed in women, compared with men (p < 0.0001). Patients aged ≥70 years experienced a 2.7% greater reduction in LDL-C compared with younger patients (p < 0.0001). Similar results were also observed for statin-mediated changes in non-HDL-C. Men experienced a significantly greater increase in HDL-C than women, and patients aged ≥70 years achieved a significantly greater increase than younger patients (both p = 0.001). CONCLUSIONS: While statins improve the lipid profile in all gender and age groups analysed, the improvements are greater in women than in men and in those aged ≥70 years compared with those aged <70 years.