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Lipoprotein(a) Blood Levels and Cardiovascular Risk Reduction With Icosapent Ethyl.
Szarek, M, Bhatt, DL, Miller, M, Brinton, EA, Jacobson, TA, Tardif, JC, Ballantyne, CM, Mason, RP, Ketchum, SB, Lira Pineda, A, et al
Journal of the American College of Cardiology. 2024;(16):1529-1539
Abstract
BACKGROUND Elevated lipoprotein(a) (Lp[a]) concentrations are associated with increased cardiovascular event risk even in the presence of well-controlled low-density lipoprotein cholesterol levels, but few treatments are documented to reduce this residual risk. OBJECTIVES The aim of this post hoc analysis of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was to explore the cardiovascular benefit of icosapent ethyl (IPE) across a range of Lp(a) levels. METHODS A total of 8,179 participants receiving statin therapy with established cardiovascular disease or age ≥50 years with diabetes and ≥1 additional risk factor, fasting triglyceride 1.69 to 5.63 mmol/L, and low-density lipoprotein cholesterol 1.06 to 2.59 mmol/L were randomized to receive 2 g twice daily of IPE or matching placebo. Relationships between continuous baseline Lp(a) mass concentration and risk for first and total (first and subsequent) major adverse cardiovascular events (MACE) were analyzed, along with the effects of IPE on first MACE among those with Lp(a) concentrations ≥50 or <50 mg/dL. RESULTS Among 7,026 participants (86% of those randomized) with baseline Lp(a) assessments, the median concentration was 11.6 mg/dL (Q1-Q3: 5.0-37.4 mg/dL). Lp(a) had significant relationships with first and total MACE (P < 0.0001), while event reductions with IPE did not vary across the range of Lp(a) (interaction P > 0.10). IPE significantly reduced first MACE in subgroups with concentrations ≥50 and <50 mg/dL. CONCLUSIONS Baseline Lp(a) concentration was prognostic for MACE among participants with elevated triglyceride levels receiving statin therapy. Importantly, IPE consistently reduced MACE across a range of Lp(a) levels, including among those with clinically relevant elevations.
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Combination of computed tomography angiography with coronary artery calcium score for improved diagnosis of coronary artery disease: a collaborative meta-analysis of stable chest pain patients referred for invasive coronary angiography.
Mohamed, M, Bosserdt, M, Wieske, V, Dubourg, B, Alkadhi, H, Garcia, MJ, Leschka, S, Zimmermann, E, Shabestari, AA, Nørgaard, BL, et al
European radiology. 2024;(4):2426-2436
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Abstract
OBJECTIVES Coronary computed tomography angiography (CCTA) has higher diagnostic accuracy than coronary artery calcium (CAC) score for detecting obstructive coronary artery disease (CAD) in patients with stable chest pain, while the added diagnostic value of combining CCTA with CAC is unknown. We investigated whether combining coronary CCTA with CAC score can improve the diagnosis of obstructive CAD compared with CCTA alone. METHODS A total of 2315 patients (858 women, 37%) aged 61.1 ± 10.2 from 29 original studies were included to build two CAD prediction models based on either CCTA alone or CCTA combined with the CAC score. CAD was defined as at least 50% coronary diameter stenosis on invasive coronary angiography. Models were built by using generalized linear mixed-effects models with a random intercept set for the original study. The two CAD prediction models were compared by the likelihood ratio test, while their diagnostic performance was compared using the area under the receiver-operating-characteristic curve (AUC). Net benefit (benefit of true positive versus harm of false positive) was assessed by decision curve analysis. RESULTS CAD prevalence was 43.5% (1007/2315). Combining CCTA with CAC improved CAD diagnosis compared with CCTA alone (AUC: 87% [95% CI: 86 to 89%] vs. 80% [95% CI: 78 to 82%]; p < 0.001), likelihood ratio test 236.3, df: 1, p < 0.001, showing a higher net benefit across almost all threshold probabilities. CONCLUSION Adding the CAC score to CCTA findings in patients with stable chest pain improves the diagnostic performance in detecting CAD and the net benefit compared with CCTA alone. CLINICAL RELEVANCE STATEMENT CAC scoring CT performed before coronary CTA and included in the diagnostic model can improve obstructive CAD diagnosis, especially when CCTA is non-diagnostic. KEY POINTS • The combination of coronary artery calcium with coronary computed tomography angiography showed significantly higher AUC (87%, 95% confidence interval [CI]: 86 to 89%) for diagnosis of coronary artery disease compared to coronary computed tomography angiography alone (80%, 95% CI: 78 to 82%, p < 0.001). • Diagnostic improvement was mostly seen in patients with non-diagnostic C. • The improvement in diagnostic performance and the net benefit was consistent across age groups, chest pain types, and genders.
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Effectiveness of icosapent ethyl on first and total cardiovascular events in patients with metabolic syndrome, but without diabetes: REDUCE-IT MetSyn.
Miller, M, Bhatt, DL, Brinton, EA, Jacobson, TA, Steg, PG, Pineda, AL, Ketchum, SB, Doyle, RT, Tardif, JC, Ballantyne, CM
European heart journal open. 2023;(6):oead114
Abstract
AIMS: Metabolic syndrome (MetSyn) is associated with high risk of cardiovascular (CV) events, irrespective of statin therapy. In the overall REDUCE-IT study of statin-treated patients, icosapent ethyl (IPE) reduced the risk of the primary composite endpoint (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization) and the key secondary composite endpoint (CV death, non-fatal myocardial infarction, or non-fatal stroke). METHODS AND RESULTS REDUCE-IT was an international, double-blind trial that randomized 8179 high CV risk statin-treated patients with controlled LDL cholesterol and elevated triglycerides, to IPE 4 g/day or placebo. The current study evaluated the pre-specified patient subgroup with a history of MetSyn, but without diabetes at baseline. Among patients with MetSyn but without diabetes at baseline (n = 2866), the majority (99.8%) of this subgroup was secondary prevention patients. Icosapent ethyl use was associated with a 29% relative risk reduction for the first occurrence of the primary composite endpoint [hazard ratio: 0.71; 95% confidence interval (CI): 0.59-0.84; P < 0.0001, absolute risk reduction (ARR) = 5.9%; number needed to treat = 17] and a 41% reduction in total (first plus subsequent) events [rate ratio: 0.59; (95% CI: 0.48-0.72); P < 0.0001] compared with placebo. The risk for the key secondary composite endpoint was reduced by 20% (P = 0.05) and a 27% reduction in fatal/non-fatal MI (P = 0.03), 47% reduction in urgent/emergent revascularization (P < 0.0001), and 58% reduction in hospitalization for unstable angina (P < 0.0001). Non-statistically significant reductions were observed in cardiac arrest (44%) and sudden cardiac death (34%). CONCLUSION In statin-treated patients with a history of MetSyn, IPE significantly reduced the risk of first and total CV events in REDUCE-IT. The large relative and ARRs observed supports IPE as a potential therapeutic consideration for patients with MetSyn at high CV risk. Registration REDUCE-IT ClinicalTrials.gov number: NCT01492361.
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Supplementation with a β-glucan tablet has no effect on hyperlipidemia: a randomized, placebo-controlled clinical trial.
Rioux-Labrecque, V, Cossette, M, Rufiange, M, Bilodeau, D, Guertin, MC, Tardif, JC
The American journal of clinical nutrition. 2023;(6):1232-1239
Abstract
BACKGROUND Clinical evidence has suggested that the oat-soluble fiber β-glucan might have lipid-lowering effects. OBJECTIVES The present clinical trial was conducted to evaluate the efficacy and safety of high-medium molecular weight β-glucan on serum low-density lipoprotein (LDL) cholesterol and other lipid subfractions in subjects with hyperlipidemia. METHODS A randomized double-blinded trial was performed to assess the efficacy and safety of β-glucan supplementation in reducing lipid levels. Subjects with LDL cholesterol levels of >3.37 mmol/L when treated or not with a statin were randomly assigned to receive 1 of 3 daily doses of a tableted formulation of β-glucan (1.5, 3, or 6 g) or placebo. The primary efficacy end point was the change from baseline to 12 wk in LDL cholesterol. Secondary end points of lipid subfractions and safety were also assessed. RESULTS A total of 263 subjects were enrolled; 66 subjects were assigned to each of the 3 β-glucan groups, and 65 subjects were assigned to the placebo group. The mean change from baseline to 12 wk in serum LDL cholesterol level was 0.08, 0.11, and -0.04 mmol/L in the 3 β-glucan groups (P = 0.23, 0.18, and 0.72 compared with the placebo group, respectively) and -0.10 mmol/L in the placebo group. The changes in total cholesterol, small LDL cholesterol subclass particle concentration, non-high-density lipoprotein cholesterol, apolipoprotein B, very low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein were also not significant in the β-glucan groups when compared with the placebo group. Gastrointestinal adverse events were reported in 23.4%, 34.8%, and 66.7% of patients in the β-glucan groups and in 36.9% of patients in the placebo group (P < 0.0001 for the overall comparison across the 4 groups). CONCLUSIONS In subjects with LDL cholesterol levels of >3.37 mmol/L, a tablet formulation of β-glucan was not effective in reducing LDL cholesterol concentration or other lipid subfractions when compared with a placebo. This trial was registered at clinicaltrials.gov as NCT03857256.
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Association between coffee or tea consumption and cardiovascular outcomes in patients with stable coronary artery disease: Analysis from the CLARIFY registry.
Abtan, J, Ducrocq, G, Elbez, Y, Ferrari, R, Ford, I, Fox, KM, Tardif, JC, Tendera, M, Danchin, N, Parkhomenko, A, et al
Archives of cardiovascular diseases. 2023;(8-9):382-389
Abstract
BACKGROUND Conflicting data exist on the association between consumption of coffee or tea and cardiovascular outcomes, and few focus on patients with established coronary artery disease. AIM: To describe the association between coffee or tea consumption and cardiovascular outcomes in patients with stable coronary artery disease, using an extensive contemporary international registry, allowing the identification of multiple potential confounders. METHODS The Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease (CLARIFY) registry enrolled in 2009 and 2010 in 45 countries, with a 5-year follow-up. Patients were categorized according to daily consumption of coffee or tea, and were compared with those declaring neither. The primary composite outcome of myocardial infarction, stroke or cardiovascular death was analysed at 5years, as well as all-cause mortality. Sensitivity analyses were performed with a multivariable model. RESULTS A total of 15,459 and 10,029 patients declared coffee or tea consumption, respectively. At 5years, after full adjustment, no association was found between coffee consumption and the primary outcome: hazard ratio 1.04 (95% confidence interval 0.89-1.21) for 1 cup; 0.94 (0.82-1.08) for 2-3 cups; and 1.04 (0.86-1.27) for ≥4 cups (P=0.51). Drinking tea was not associated with a different incidence of the primary outcome before or after adjustment, with fully adjusted hazard ratios of 1.08 (95% confidence interval 0.84-1.38) for 1 cup, 1.12 (0.96-1.31) for 2-3 cups and 0.95 (0.79-1.14) for ≥4 cups (P=0.30). After full adjustment, neither coffee nor tea drinking was associated with all-cause mortality. CONCLUSIONS In outpatients with stable coronary artery disease, there was no association between coffee or tea consumption and ischaemic outcomes or all-cause mortality.
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Potassium reduction with sodium zirconium cyclosilicate in patients with heart failure.
Tardif, JC, Rouleau, J, Chertow, GM, Al-Shurbaji, A, Lisovskaja, V, Gustavson, S, Zhao, Y, Bouabdallaoui, N, Desai, AS, Chernyavskiy, A, et al
ESC heart failure. 2023;(2):1066-1076
Abstract
AIMS: Several patients with heart failure and reduced ejection fraction (HFrEF) do not receive renin-angiotensin-aldosterone system (RAAS) inhibitors at the recommended dose or at all, frequently due to actual or feared hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is an orally administered non-absorbed intestinal potassium binder proven to lower serum potassium concentrations. METHODS AND RESULTS PRIORITIZE-HF was an international, multicentre, parallel-group, randomized, double-blind, placebo-controlled study to evaluate the benefits and risks of using SZC to intensify RAAS inhibitor therapy. Patients with symptomatic HFrEF were eligible and randomly assigned to receive SZC 5 g or placebo once daily for 12 weeks. Doses of study medication and RAAS inhibitors were titrated during the treatment period. The primary endpoint was the proportion of patients at 12 weeks in the following categories: (i) any RAAS inhibitor at less than target dose, and no MRA; (ii) any RAAS inhibitor at target dose and no MRA; (ii) MRA at less than target dose; and (iv) MRA at target dose. Due to challenges in participant management related to the COVID-19 pandemic, the study was prematurely terminated with 182 randomized patients. There was no statistically significant difference in the distribution of patients by RAAS inhibitor treatment categories at 3 months (P = 0.43). The proportion of patients at target MRA dose was numerically higher in the SZC group (56.4%) compared with the placebo group (47.0%). Overall, SZC was well tolerated. CONCLUSIONS PRIORITIZE-HF was terminated prematurely due to COVID-19 and did not demonstrate a statistically significant increase in the intensity of RAAS inhibitor therapies with the potassium-reducing agent SZC compared with placebo.
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Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease.
Ottoy, J, Ozzoude, M, Zukotynski, K, Kang, MS, Adamo, S, Scott, C, Ramirez, J, Swardfager, W, Lam, B, Bhan, A, et al
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2023;(6):921-936
Abstract
White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.
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Generalizability of the REDUCE-IT trial to South Asians with cardiovascular disease.
Krishnaraj, A, Bakbak, E, Teoh, H, Bhatt, DL, Quan, A, Puar, P, Lambotharan, B, Kirubaharan, A, Firoz, IN, Meglis, G, et al
Med (New York, N.Y.). 2023;(2):130-138.e1
Abstract
BACKGROUND South Asians (SAs) represent ∼25% of the world's population and account for >50% of global cardiovascular (CV) deaths, yet they continue to be underrepresented in contemporary clinical trials. The REDUCE-IT study demonstrated in a high-risk and predominantly White population that icosapent ethyl (IPE) lowered major adverse cardiovascular events by 25%. We sought to determine the generalizability of these results to a high-risk population of SAs with established CV disease living in Canada. METHODS This was a cross-sectional observational study of 200 statin-treated SAs (≥45 years) with atherosclerotic CV disease (ASCVD) (NCT05271591). SA ethnicity was self-identified as being of Anglo-Indian, Bangladeshi, Bengali, Bhutanese, Goan, Gujarati, Indian, Jatt, Kashmiri, Maharashtrian, Malayali, Nepali, Pakistani, Punjabi, Sindhi, Sinhalese, Sri Lankan, Tamil, Telugu, or other SA. ASCVD was defined as the presence of coronary, carotid, or peripheral atherosclerosis. FINDINGS Mean age of the cohort was 67 years, where 82% were men and 57% had diabetes. The predominant ASCVD phenotype was coronary artery disease (94%). Mean (SD) baseline LDL-C and triglycerides were 1.70 (0.8) mmol/L and 1.42 (1.0) mmol/L, respectively. Three-quarters were on high-intensity statin therapy. According to the Health Canada/Canadian Cardiovascular Society Guidelines and FDA-approved indication, 33% and 25% of the participants were, respectively, eligible for IPE. CONCLUSIONS A large proportion of high-intensity, statin-treated, high-risk patients with ASCVD and of self-reported SA ethnicity are eligible for IPE. These data have important translational implications for SAs who are at a disproportionately higher risk of CV morbidity and mortality. FUNDING This study was funded by an unrestricted grant provided by HLS Therapeutics Inc, Canada.
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Computed tomography angiography versus Agatston score for diagnosis of coronary artery disease in patients with stable chest pain: individual patient data meta-analysis of the international COME-CCT Consortium.
Wieske, V, Walther, M, Dubourg, B, Alkadhi, H, Nørgaard, BL, Meijs, MFL, Diederichsen, ACP, Wan, YL, Mickley, H, Nikolaou, K, et al
European radiology. 2022;(8):5233-5245
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OBJECTIVES There is conflicting evidence about the comparative diagnostic accuracy of the Agatston score versus computed tomography angiography (CTA) in patients with suspected obstructive coronary artery disease (CAD). PURPOSE To determine whether CTA is superior to the Agatston score in the diagnosis of CAD. METHODS In total 2452 patients with stable chest pain and a clinical indication for invasive coronary angiography (ICA) for suspected CAD were included by the Collaborative Meta-analysis of Cardiac CT (COME-CCT) Consortium. An Agatston score of > 400 was considered positive, and obstructive CAD defined as at least 50% coronary diameter stenosis on ICA was used as the reference standard. RESULTS Obstructive CAD was diagnosed in 44.9% of patients (1100/2452). The median Agatston score was 74. Diagnostic accuracy of CTA for the detection of obstructive CAD (81.1%, 95% confidence interval [CI]: 77.5 to 84.1%) was significantly higher than that of the Agatston score (68.8%, 95% CI: 64.2 to 73.1%, p < 0.001). Among patients with an Agatston score of zero, 17% (101/600) had obstructive CAD. Diagnostic accuracy of CTA was not significantly different in patients with low to intermediate (1 to < 100, 100-400) versus moderate to high Agatston scores (401-1000, > 1000). CONCLUSIONS Results in our international cohort show CTA to have significantly higher diagnostic accuracy than the Agatston score in patients with stable chest pain, suspected CAD, and a clinical indication for ICA. Diagnostic performance of CTA is not affected by a higher Agatston score while an Agatston score of zero does not reliably exclude obstructive CAD. KEY POINTS • CTA showed significantly higher diagnostic accuracy (81.1%, 95% confidence interval [CI]: 77.5 to 84.1%) for diagnosis of coronary artery disease when compared to the Agatston score (68.8%, 95% CI: 64.2 to 73.1%, p < 0.001). • Diagnostic performance of CTA was not affected by increased amount of calcium and was not significantly different in patients with low to intermediate (1 to <100, 100-400) versus moderate to high Agatston scores (401-1000, > 1000). • Seventeen percent of patients with an Agatston score of zero showed obstructive coronary artery disease by invasive angiography showing absence of coronary artery calcium cannot reliably exclude coronary artery disease.
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Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction.
Gaba, P, Bhatt, DL, Steg, PG, Miller, M, Brinton, EA, Jacobson, TA, Ketchum, SB, Juliano, RA, Jiao, L, Doyle, RT, et al
Journal of the American College of Cardiology. 2022;(17):1660-1671
Abstract
BACKGROUND REDUCE-IT was a double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in the primary endpoint, including death from cardiovascular (CV) causes. The specific impact of IPE among patients with prior myocardial infarction (MI) was unknown. OBJECTIVES Our goal was to examine the benefit of IPE on ischemic events among patients with prior MI in REDUCE-IT. METHODS We performed post hoc analyses of patients with prior MI. The primary endpoint was CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke. RESULTS A total of 3,693 patients had a history of prior MI. The primary endpoint was reduced from 26.1% to 20.2% with IPE vs placebo; HR: 0.74 (95% CI: 0.65-0.85; P = 0.00001). The key secondary endpoint was reduced from 18.0% to 13.3%; HR: 0.71 (95% CI: 0.61-0.84; P = 0.00006). There was also a significant 35% relative risk reduction in total ischemic events (P = 0.0000001), a 34% reduction in MI (P = 0.00009), a 30% reduction in CV death (P = 0.01), and a 20% lower rate of all-cause mortality (P = 0.054), although there was a slight increase in atrial fibrillation. Sudden cardiac death and cardiac arrest were also significantly reduced by 40% and 56%, respectively. CONCLUSIONS Patients with a history of prior MI in REDUCE-IT treated with IPE demonstrated large and significant relative and absolute risk reductions in ischemic events, including CV death. (A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. [REDUCE-IT]; NCT01492361).