Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial.

AIMS: We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: DECLARE-TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: -1.9 to -2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients. CONCLUSIONS: In DECLARE-TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.

Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial.

AIMS: We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding. METHODS AND RESULTS: ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36-2.23 and adj-HR 1.27; 95% CI 1.07-1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02-1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36-0.65; NRI 0.42; 95% CI 0.33-0.51, respectively]. CONCLUSION: Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF.

Effect of evolocumab on acute arterial events across all vascular territories : results from the FOURIER trial.

AIMS: We assessed the impact of the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab on acute arterial events across all vascular territories, including coronary, cerebrovascular, and peripheral vascular beds, in patients with established atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: In the FOURIER trial, 27 564 patients with stable ASCVD on statin therapy were randomly assigned to evolocumab or placebo. Acute arterial events were a composite of acute coronary (coronary heart disease death, myocardial infarction, or urgent coronary revascularization), cerebrovascular (ischaemic stroke, transient ischaemic attack, or urgent cerebral revascularization), or peripheral vascular (acute limb ischaemia, major amputation, or urgent peripheral revascularization) events. Of the 2210 first acute arterial events, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced first acute arterial events by 19% (hazard ratio [HR] 0.81 [95% confidence interval 0.74-0.88]; P < 0.001), with significant individual reductions in acute coronary (HR 0.83 [0.75-0.91]), cerebrovascular (HR 0.77 [0.65-0.92]), and peripheral vascular (HR 0.58 [0.38-0.88]) events. There were 3437 total events (first plus recurrent), with evolocumab reducing total events by 24% (incidence rate ratio 0.76 [0.69-0.85]). The magnitude of reduction in acute arterial events with evolocumab numerically increased over time, with a 16% reduction (HR 0.84 [0.75-0.95]) in the first year followed by a 24% reduction (HR 0.76 [0.67-0.85]) thereafter. CONCLUSION: The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced acute arterial events across all vascular territories with a robust effect over time, indicating a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

Efficacy and Safety of Long-Term Evolocumab Use Among Asian Subjects　- A Subgroup Analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) Trial.

BACKGROUND: There are concerns that Asian patients respond differently to some medications. This study evaluated the efficacy and safety of evolocumab among Asian vs. other subjects in the FOURIER trial, which randomized stable atherosclerosis patients to receive either evolocumab or placebo.Methods and Results:Effects of adding evolocumab vs. placebo to background statin therapy on low-density lipoprotein cholesterol (LDL-C) reductions, cardiovascular outcomes, and adverse events were compared among 27,564 participants with atherosclerotic disease, according to self-reported Asian (n=2,723) vs. other (n=24,841) races followed for a median of 2.2 years in the FOURIER trial. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. At randomization, Asians had slightly lower LDL-C (median 89 [IQR 78-104] mg/dL vs. 92 [80-109] mg/dL; P<0.001) and were much less likely to be on a high-intensity statin (33.3% vs. 73.3%; P<0.001). Evolocumab lowered LDL-C more in Asians than in others (66% vs. 58%; P<0.001). The effect of evolocumab on the primary endpoint was similar in Asians (HR, 0.79; 95% CI, 0.61-1.03) and others (HR, 0.86; 95% CI, 0.79-0.93; P interaction=0.55). There was no excess of serious adverse events with evolocumab among Asians over others. CONCLUSIONS: Use of evolocumab robustly lowers LDL-C and is equally efficacious in lowering the risk of cardiovascular events and safe in Asians as it is in others.

Accuracy of optical frequency domain imaging for evaluation of coronary adventitial vasa vasorum formation after stent implantation in pigs and humans - a validation study - .

BACKGROUND: Coronary adventitia harbors a wide variety of components, such as inflammatory cells and vasa vasorum (VV). Adventitial VV initiates the development of coronary artery diseases as an outside-in supply route of inflammation. We have recently demonstrated that drug-eluting stent implantation causes the enhancement of VV formation, with extending to the stent edges in the porcine coronary arteries, and also that optical frequency domain imaging (OFDI) is capable of visualizing VV in humans in vivo. However, it remains to be fully validated whether OFDI enables the precise measurement of VV formation in pigs and humans. METHODS AND RESULTS: In the pig protocol, a total of 6 bare-metal stents and 12 drug-eluting stents were implanted into the coronary arteries, and at 1 month, the stented coronary arteries were imaged by OFDI ex vivo. OFDI data including the measurement of VV area at the stent edge portions were compared with histological data. There was a significant positive correlation between VV area on OFDI and that on histology (R=0.91, P<0.01). In the human protocol, OFDI enabled the measurement of the VV area at the stent edges after coronary stent implantation in vivo. CONCLUSIONS: These results provide the first direct evidence that OFDI enables the precise measurement of the VV area in coronary arteries after stent implantation in pigs and humans.

Mechanisms of Coronary Artery Spasm.

Recent clinical trials have highlighted that percutaneous coronary intervention in patients with stable angina provides limited additional benefits on top of optimal medical therapy. This has led to much more attention being paid to coronary vasomotion abnormalities regardless of obstructive or non-obstructive arterial segments. Coronary vasomotion is regulated by multiple mechanisms that include the endothelium, vascular smooth muscle cells (VSMCs), myocardial metabolic demand, autonomic nervous system and inflammation. Over the years, several animal models have been developed to explore the central mechanism of coronary artery spasm. This review summarises the landmark studies on the mechanisms of coronary vasospasm demonstrating the central role of Rho-kinase as a molecular switch of VSMC hypercontraction and the important role of coronary adventitial inflammation for Rho-kinase upregulation in VSMCs.

Treatment strategies of acute myocardial infarction: updates on revascularization, pharmacological therapy, and beyond.

Owing to recent advances in early reperfusion strategies, pharmacological therapy, standardized care, and the identification of vulnerable patient subsets, the prognosis of acute myocardial infarction has improved. However, there is still considerable room for improvement. This review article summarizes the latest evidence concerning clinical diagnosis and treatment of acute myocardial infarction.

Long-term prognostic significance of history of cancer and atrial fibrillation in coronary artery disease.

Background: Limited data exist on the prognostic significance of a history of cancer and atrial fibrillation (AF) in patients with coronary artery disease (CAD). This study aimed to evaluate the associations among a history of cancer, AF, and long-term prognosis in patients with CAD. Methods: We studied 3,233 patients with CAD (69 ± 11 years; women, 23%) in a multicenter hospital-based cohort study, the CHART-2 and related a history of cancer and AF to cardiovascular outcomes with a median follow-up of 10.8 years. Results: Of the 3,233 patients enrolled, 10.7% and 11.2% had a history of cancer and AF, respectively, while 2.8% had both. Patients with AF and a history of cancer were characterized by older age, male sex, and higher BNP levels. Anticoagulant use with warfarin or direct oral anticoagulants increased from 43% at baseline to 56% at 10 years in patients with CAD with AF and no history of cancer and increased from 49% to 83% in those with both. Patients with CAD with both comorbidities had a higher risk of a composite outcome including stroke, thrombosis, and major bleeding (Hazard Ratio [HRadjusted], 2.26; 1.50-3.40, P < 0.001). Furthermore, patients with both comorbidities had a higher risk of all-cause death (1.55; 95% confidence interval [CI] 1.12-2.12, P = 0.007) including cancer death (2.62; 1.51-4.54, P = 0.001), and new-onset heart failure (HF) requiring hospitalization (2.47; 1.54-3.96, P < 0.001). Conclusions: These results demonstrate that CAD patients with a history of cancer and AF have an increased risk of composite outcomes, including stroke, systemic thrombosis, major bleeding, all-cause death, cancer-related death, and new-onset HF.

Serial assessment of biomarkers and heart failure outcomes in patients with atrial fibrillation.

AIMS: Cardiac functional and structural remodelling in patients with atrial fibrillation (AF) contributes to development of heart failure (HF) as their major cardiovascular comorbidity. Circulating biomarkers may reflect these cardiac alterations. METHODS AND RESULTS: ENGAGE AF-TIMI 48 was a randomized trial of edoxaban versus warfarin in 21 105 patients with AF. We performed a nested biomarker study, analysing high-sensitivity troponin T (hsTnT, n = 8705), N-terminal pro-B-type natriuretic peptide (NT-proBNP, n = 8765), and growth differentiation factor-15 (GDF-15, n = 8705) at baseline and 12 months. Of the biomarker cohort, 5207 had a history of HF, among whom 3996 had known ejection fraction (EF): 926 with reduced EF (HFrEF; ≤40%), 1043 with mildly reduced EF (HFmrEF; 40-49%), and 2027 with preserved EF (HFpEF; ≥50%). Elevated baseline hsTnT, NT-proBNP, and GDF-15 were associated with higher risk of hospitalization for HF (HHF) or HF death overall and in subpopulations defined by HF history and EF (p < 0.001 for each). These associations of outcome with each biomarker were consistent regardless of a history of HF or EF (p-interaction >0.05 for each). Patients who had an increase in or had persistently elevated values in any of the three biomarkers over 12 months were at higher risk for HHF or HF death in the overall population (p < 0.001 for each biomarker and category). CONCLUSION: Serial measurement of hsTnT, NT-proBNP, and GDF-15 revealed that higher baseline values, and increasing or persistently elevated values over 1 year are associated with higher risk of HF outcomes in patients with AF regardless of HF history or HF phenotype based on EF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov unique identifier NCT00781391.

Effect of Evolocumab in Patients With Prior Percutaneous Coronary Intervention.

BACKGROUND: Patients with prior percutaneous coronary intervention (PCI) are at high residual risk for multiple types of coronary events within and beyond the stented lesion. This risk might be mitigated by more intensive LDL-C (low-density lipoprotein cholesterol)-lowering beyond just with statin therapy. METHODS: FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27 564 patients with stable atherosclerotic disease on statin to the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab or placebo with a median follow-up of 2.2 years. The end points of interest were major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, stroke, unstable angina or coronary revascularization), and major coronary events (a composite of coronary heart death, myocardial infarction, or coronary revascularization). We compared the risk of MACE and the magnitude of relative and absolute risk reductions with evolocumab in patients with and without prior PCI. RESULTS: Seventeen thousand seventy-three patients had prior PCI. In the placebo arm, those with prior PCI had higher rates of MACE (13.2% versus 8.3%; hazard ratio [HR]adj 1.61 [95% CI, 1.42-1.84]; P<0.0001) and major coronary events (11.5% versus 6.0%; HRadj, 1.72 [95% CI, 1.49-1.99]; P<0.0001). Relative risk reductions with evolocumab were similar in patients with and without prior PCI (MACE: HR, 0.84 [0.77-0.91] versus HR, 0.88 [0.77-1.01]; Pinteraction 0.51; major coronary events: HR, 0.82 [0.75-0.90] versus HR, 0.88 [0.75-1.04]; Pinteraction 0.42). Absolute risk reductions for MACE were 2.0% versus 0.9% (Pinteraction 0.14) and for major coronary events 2.0% versus 0.7% (Pinteraction 0.045). In those with prior PCI, the effect of evolocumab on coronary revascularization (HR, 0.76 [0.69-0.85]) was directionally consistent across types of revascularization procedures: coronary artery bypass grafting (HR, 0.71 [0.54-0.94]); any PCI (HR, 0.77 [0.69-0.86]); PCI for de novo lesions (HR, 0.76 [0.66-0.88]); and PCI for stent failure or graft lesions (HR, 0.76 [0.63-0.91]). CONCLUSIONS: Evolocumab reduces the risk of MACE in patients with prior PCI including the risk of coronary revascularization, with directionally consistent effects across several types of revascularization procedures, including coronary artery bypass grafting and PCI for stent or graft failure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Efficacy and Safety of Dapagliflozin According to Background Use of Cardiovascular Medications in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Importance: Dapagliflozin was shown to reduce the cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. However, data are limited on the relationship of the effect and safety with the concurrent use of CV medications in patients with type 2 diabetes. Objective: To assess whether the cardiorenal efficacy and safety of dapagliflozin were consistent with and without background use of CV medications commonly used for heart failure (HF) and kidney disease in patients with type 2 diabetes. Design, Setting, and Participants: This study is a prespecified secondary analysis of DECLARE-TIMI 58, which was a randomized trial of dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and either atherosclerotic disease or multiple risk factors for CV disease. Patients were stratified by baseline use of the following CV medications: angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARBs), ß-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs). The study was conducted from May 2013 to September 2018, and data were evaluated for this analysis from February 2021 to May 2022. Interventions: Dapagliflozin or placebo. Main Outcomes and Measures: The outcomes of interest were the composite of CV death or hospitalization for HF (HHF), HHF alone, and a kidney-specific composite outcome (persistent ≥40% decrease in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney-related death). Results: Among 17 160 patients, 13 950 (81%) used ACEI/ARBs, 9030 (53%) used ß-blockers, 6205 (36%) used diuretics, and 762 (4%) used MRAs at baseline. Changes in blood pressure and eGFR at 48 months with dapagliflozin compared with placebo did not differ regardless of concurrent therapy (placebo-corrected change, -1.6 mm Hg [95% CI, -4.2 to 1.0] to -2.6 mm Hg [95% CI, -3.3 to -2.9]; P > .05 for each interaction). Dapagliflozin consistently reduced the risk of CV death/HHF, HHF alone, and the kidney-specific composite outcome regardless of background use of selected medications (hazard ratio [HR] range: HR, 0.50; 95% CI, 0.39-0.63; to HR, 0.82; 95% CI, 0.72-0.95; P > .05 for each interaction). In patients receiving ACEI/ARBs + ß-blockers + diuretics (n = 4243), dapagliflozin reduced the risk of CV death/HHF and of the kidney-specific outcome by 24% (HR, 0.76; 95% CI, 0.62-0.93) and 38% (HR, 0.62; 95% CI, 0.44-0.87), respectively. There were no significant treatment interactions with the concomitant CV medications for adverse events of volume depletion, acute kidney injury, or hyperkalemia (range: HR, 0.12; 95% CI, 0.02-0.99; to HR, 1.04; 95% CI, 0.83-1.32; P > .05 for each interaction). Conclusions and Relevance: Dapagliflozin consistently reduced the risk of CV and kidney outcomes irrespective of background use of various CV medications without any treatment interaction for key safety events. These data show the clinical benefit and safety of dapagliflozin in a broad range of patients with type 2 diabetes regardless of background therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.

Biomarker Prediction of Complex Coronary Revascularization Procedures in the FOURIER Trial.

BACKGROUND: Biomarkers are known to predict major adverse cardiovascular events. However, the association of biomarkers with complex coronary revascularization procedures or high-risk coronary anatomy at the time of revascularization is not understood. OBJECTIVES: We examined the associations between baseline biomarkers and major coronary events (MCE) and complex revascularization procedures. METHODS: FOURIER was a randomized trial of the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab vs placebo in 27,564 patients with stable atherosclerosis. We analyzed adjusted associations among the biomarkers, MCE (coronary death, myocardial infarction, or revascularization), and complex revascularization (coronary artery bypass graft or complex percutaneous coronary intervention) using a multimarker score with 1 point assigned for each elevated biomarker (high-sensitivity C-reactive protein ≥2 mg/L; N-terminal pro-B-type natriuretic peptide ≥450 pg/mL; high-sensitivity troponin I ≥6 ng/L; growth-differentiation factor-15 ≥1,800 pg/mL). RESULTS: When patients were grouped by the number of elevated biomarkers (0 biomarkers, n = 6,444; 1-2 biomarkers, n = 12,439; ≥3 biomarkers, n = 2,761), there was a significant graded association between biomarker score and the risk of MCE (intermediate score: HRadj: 1.57 [95% CI: 1.38-1.78]; high score: HRadj: 2.90 [95% CI: 2.47-3.40]), and for complex revascularization (intermediate: HRadj: 1.33 [95% CI: 1.06-1.67]; high score: HRadj: 2.07 [95% CI: 1.52-2.83]) and its components (Ptrend <0.05 for each). The number of elevated biomarkers also correlated with the presence of left main disease, multivessel disease, or chronic total occlusion at the time of revascularization (P < 0.05 for each). CONCLUSIONS: A biomarker-based strategy identifies stable patients at risk for coronary events, including coronary artery bypass graft surgery and complex percutaneous coronary intervention, and predicts high-risk coronary anatomy at the time of revascularization. These findings provide insight into the relationships between cardiovascular biomarkers, coronary anatomical complexity, and incident clinical events. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633).

Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT.

BACKGROUND: The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL despite maximally tolerated statin. OBJECTIVES: The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70 mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS). METHODS: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125 mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke. RESULTS: Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20 mg/dL). The effect of ezetimibe/simvastatin vs placebo/simvastatin on primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dL (HR: 0.92 [95% CI: 0.80-1.05]), 70-<100 mg/dL (HR: 0.93 [95% CI: 0.87-1.01]), or 100-125 mg/dL (HR: 0.94 [95% CI: 0.86-1.03]; P interaction = 0.95). Normalized relative risk reductions per 1-mmol/L difference in achieved LDL-C at 4 months between treatment arms were 21% in patients with baseline LDL-C of 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL (P interaction = 0.91). No significant treatment interactions by baseline LDL-C were present for safety endpoints. CONCLUSIONS: Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C <70 mg/dL. (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878).

Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization.

OBJECTIVES: This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization. BACKGROUND: PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall. METHODS: FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG). RESULTS: In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p < 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p < 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p < 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p < 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years). CONCLUSIONS: Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

Co-existence of carotid artery disease, renal artery stenosis, and lower extremity peripheral arterial disease in patients with coronary artery disease.

In atherosclerosis, carotid artery stenosis (CAS), renal artery stenosis (RAS), lower extremity peripheral arterial disease (PAD), and coronary artery disease (CAD) are common pathologic lesions; their interrelationship is, however, unclear. We studied concomitant multiple atherosclerotic lesions in patients with CAD to understand their prevalence and relations. A cross-sectional analysis was performed on data from consecutive patients who underwent nonemergent coronary angiography. Simultaneous carotid and renal artery Doppler studies and ankle-brachial systolic pressure measurements were reviewed to diagnose concomitant lesions and their severity. The study included 1,734 patients (aged 71 ± 9 years; 70% men), with prevalences of CAS, RAS, lower extremity PAD, and CAD of 6%, 7%, 13%, and 72%, respectively. In patients with CAD (n = 1,253), the prevalences of CAS, RAS, and lower extremity PAD were 7%, 9%, and 16%, respectively; 24% CAD patients had ≥1 additional atherosclerotic lesion. Significant interactions among the prevalences of these lesions were found. In addition, the extent of CAD and the prevalences of CAS, RAS, and lower extremity PAD were significantly correlated. Multivariate analysis supported these relationships. In conclusion, the prevalences of CAS, RAS, lower extremity PAD, and CAD were strongly interrelated in the study population; CAD severity was related to that of other atherosclerotic lesions. Additional systematic screening of other concomitant atherosclerotic lesions is recommended, especially in CAD patients having multivessel disease, left main disease, and/or already diagnosed with other concomitant atherosclerotic lesions.