Modifiable lifestyle risk factors and C-reactive protein in patients with coronary artery disease: Implications for an anti-inflammatory treatment target population.

BACKGROUND: Modifiable lifestyle risk factors (modRF) of coronary artery disease (CAD) are associated with increased inflammation represented by elevated C-reactive protein (CRP) levels. Lifestyle changes may influence the inflammatory burden in patients with CAD, relevantly modifying the target population for emerging anti-inflammatory compounds. AIMS: The aims of this study were to analyse the association of modRF and CRP levels in CAD patients, and to define a potential target population for anti-inflammatory treatment with and without the optimisation of modRF. METHODS: We included all patients with angiographically documented CAD from the observational cohort study INTERCATH. Patients with recent myocardial infarction, malignancy, infectious disease, and pre-existing immunosuppressive medication including a history of solid organ transplantation were excluded. Overweight (body mass index (BMI) ≥ 25 kg/m2), smoking, lack of physical activity (PA; <1.5 h/week), and poor diet (≤12 points of an established Mediterranean diet score (MDS), range 0-28 points) were considered as modRF. CRP was measured by a high-sensitivity assay (hsCRP) at baseline. We performed multivariable linear regressions with log-transformed hsCRP as the dependent variable. Based on these associations, we calculated potential hsCRP levels for each patient, assuming optimisation of the individual modRF. RESULTS: Of 1014 patients, 737 (73%) were male, the mean age was 69 years, and 483 (48%) had an hsCRP ≥ 2 mg/l. ModRF were significantly overrepresented in patients with hsCRP ≥ 2 mg/l compared to patients with an hsCRP < 2 mg/l (BMI ≥ 25 kg/m2: 76% vs 61%; PA < 1.5 h/week: 69% vs 57%; MDS ≤ 12: 46% vs 37%; smoking: 61% vs 54%; p < 0.05 for all). hsCRP increased with the incremental number of modRF present (median hsCRP values for N = 0, 1, 2, 3, and 4 modRF: 1.1, 1.0, 1.6, 2.4, 2.8 mg/l, p < 0.001). Multivariable linear regression adjusting for age, sex, intake of lipid-lowering medication, and diabetes mellitus revealed independent associations between log-transformed hsCRP and all modRF (BMI ≥ 25 kg/m2: exp(ß) = 1.55, p < 0.001; PA < 1.5 h/week: exp(ß) = 1.33, p < 0.001; MDS ≤ 12: exp(ß) = 1.18, p = 0.018; smoking: exp(ß) = 1.18, p = 0.019). Individual recalculation of hsCRP levels assuming optimisation of modRF identified 183 out of 483 (38%) patients with hsCRP ≥ 2 mg/l who could achieve an hsCRP < 2 mg/l via lifestyle changes. CONCLUSION: modRF are strongly and independently associated with CRP levels in patients with CAD. A relevant portion of CAD patients with high inflammatory burden could achieve an hsCRP < 2 mg/l by lifestyle changes alone. This should be considered both in view of the cost and side-effects of pharmacological anti-inflammatory treatment and for the design of future clinical trials in this field.

Target Populations and Treatment Cost for Bempedoic Acid and PCSK9 Inhibitors: A Simulation Study in a Contemporary CAD Cohort.

PURPOSE: The lowered LDL-C treatment goal of the 2019 European Society of Cardiology dyslipidemia guidelines results in a significant increase in the projected need for cost-intensive proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Addition of bempedoic acid (BA) to established oral lipid-lowering medication (LLM) has the potential to enable affordable LDL-C goal attainment, particularly in patients with statin intolerance (SI). The goal of this study was to quantify the target populations for BA and PCSK9 inhibitors as well as the related treatment costs to achieve the LDL-C goal of <55 mg/dL and a ≥50% reduction assuming the addition of BA to LLM. METHODS: This study included 1922 patients with coronary artery disease (CAD) from the contemporary observational cohort study INTERCATH. A Monte Carlo simulation incorporating an algorithm adding sequentially a statin, ezetimibe, optionally BA, and a PCSK9 inhibitor was applied to achieve the LDL-C treatment goal, with consideration of both partial and total SI. Two scenarios were simulated for both a moderate (2% full and 10% partial) and a high (12% full) rate of SI: (1) without BA; and (2) with BA. FINDINGS: Patients' mean age was 69.3 years, and the median baseline LDL-C level was 86.0 mg/dL. The need for a PCSK9 inhibitor would be 41.4% for a moderate rate of SI and 46.1% for a high rate of SI. Addition of BA would: (1) reduce the need for a PCSK9 inhibitor to 25.3% and 29.4%, thus lowering the annual overall treatment cost incurred through PCSK9 inhibitor ± BA per 1 million patients with CAD by 13.3% and 10.5%; (2) lower the cost per prevented event in the entire cohort (-5.0% and -6.3%), although at the price of fewer prevented events (-8.7% and -4.5%); and (3) reduce the cost per prevented event (-6.8% for both rates of SI) while preventing more events (7.6% and 6.9%) in the subpopulation of patients with full SI. IMPLICATIONS: Use of BA is projected to reduce the need for PCSK9 inhibitors as well as the treatment cost for add-on LLM. The subpopulation of patients with full SI might profit particularly.

The need for PCSK9 inhibitors and associated treatment costs according to the 2019 ESC dyslipidaemia guidelines vs. the risk-based allocation algorithm of the 2017 ESC consensus statement: a simulation study in a contemporary CAD cohort.

BACKGROUND: The recently updated European Society of Cardiology (ESC) dyslipidaemia guidelines recommend a lower low-density lipoprotein cholesterol (LDL-C) goal of <55 mg/dL for patients with atherosclerotic cardiovascular disease (ASCVD), with a concomitant Class IA upgrade for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients not reaching their LDL-C goal under conventional lipid-lowering therapy. AIMS: We aim to quantify the need for PCSK9i and the related costs to achieve the revised LDL-C goal in ASCVD patients compared to former ESC recommendations, in particular the risk-based 2017 ESC consensus update. METHODS AND RESULTS: We included patients with ASCVD from an observational cohort study ongoing since 2015. A Monte Carlo simulation incorporating a treatment algorithm adding sequentially a statin, ezetimibe, and a PCSK9i was applied with consideration of partial and total statin intolerance. The need for PCSK9i was calculated for three different ESC recommendations (2019 guidelines, 2016 guidelines, 2017 consensus update). Preventable events and treatment costs due to PCSK9i were calculated for a range of annual event rates from 2% to 8% and annual treatment costs of ca. 6050 €. We included 1780 patients (mean age 69.5 years). Median LDL-C at baseline was 85.0 mg/dL, with 61% of patients taking lipid-lowering medication. The need for PCSK9i was simulated to be 42.0% (ESC 2019), 31.9% (ESC 2016), and 5.0% (ESC 2017). The LDL-C goals were achieved in 97.9%, 99.1%, and 60.9% of patients, respectively. Annual treatment cost for PCSK9i per 1 000 000 ASCVD patients would be 2.54 billion € (ESC 2019) compared to 0.30 billion € (ESC 2017). Costs per prevented event due to PCSK9i initiation differed widely, e.g. 887 000 € for an event rate of 3% and a treatment goal of <55 mg/dL compared to 205 000 € for an event rate of 7% and risk-based use of PCSK9i. CONCLUSION: The revised LDL-C treatment goals increase the projected need for PCSK9i with a substantial increase in associated treatment cost. An allocation strategy based on residual LDL-C and clinical or angiographic risk factors leads to a more tailored target population for PCSK9i with a reasonable benefit/cost ratio.

Association of high-sensitivity troponin T and I with the severity of stable coronary artery disease in patients with chronic kidney disease.

BACKGROUND AND AIMS: Cardiac troponin blood levels are frequently elevated in patients with impaired renal function. Their predictive value for the severity of stable coronary artery disease (CAD) remains unclear in these cases. Therefore, we aimed to evaluate the blood levels of high-sensitivity troponin T and I (hsTnT/I) and their association with the severity of stable CAD in patients with chronic kidney disease. METHODS: Overall, 2209 patients with suspected stable CAD undergoing invasive coronary angiography were included in an ongoing prospective cohort study. We identified 595 patients with impaired renal function defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Coronary morphology was assessed by the number of affected major coronary vessels (CAD classification), SYNTAX, and Gensini scores. hsTnT/I blood levels were measured by three latest-generation assays (Roche Diagnostics Elecsys, Abbott ARCHITECT STAT, and Singulex Clarity). Ordinal logistic regression for the severity of CAD adjusted by classical cardiovascular risk factors and eGFR were performed with each troponin assay as an independent variable. RESULTS: Mean age was 72.9 ± 9.8 years (33.6% female). Median eGFR was 47.5 ml/min/1.73 m2 (interquartile range [IQR] 34.9, 54.1). For the association of Roche-hsTnT, Abbott-hsTnI, and Singulex-hsTnI with the CAD classification, odds ratios per standard deviation (OR) were 1.27 (95% confidence interval [CI] 1.07-1.51), 1.21 (CI 1.02-1.44), and 1.24 (CI 1.04-1.47), respectively. The associations for the investigated assays with SYNTAX and Gensini scores, respectively, were OR 1.40, CI 1.11-1.78 and OR 1.24, CI 1.01-1.51 (Roche-hsTnT), OR 1.42, CI 1.12-1.78 and OR 1.25, CI 1.02-1.52 (Abbott-hsTnI), OR 1.38, CI 1.09-1.74 and OR 1.25, CI 1.02-1.53 (Singulex-hsTnI). CONCLUSIONS: In patients with impaired renal function, blood levels of hsTnT/I were significantly associated with the severity of stable CAD. These findings may help clinicians guide further diagnostic assessment.