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

Clinical benefit of evolocumab by severity and extent of coronary Aartery disease: an analysis from FOURIER

Background -The FOURIER trial recently showed that the PCSK9 inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior MI. Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets that derive greater clinical risk reduction with evolocumab. Methods -The 22,351 patients with a prior MI were characterized based on time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events including the primary endpoint (CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary endpoint (CV death, MI or stroke) with evolocumab in these subgroups were compared. Results -A total of 8402 patients (38%) were within 2 years of their most recent MI, 5285 patients (24%) had ≥2 prior MIs, and 5618 patients (25%) had residual multivessel CAD. In a multivariable adjusted model that simultaneously included all three high-risk features as well as other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted HRs for the primary endpoint of 1.37 (1.22-1.53), 1.78 (1.59-1.99) and 1.39 (1.24-1.56), all P<0.001. The relative risk reductions with evolocumab for the primary endpoint tended to be greater in the high-risk subgroups and were 20% (HR 0.80, 0.71-0.91), 18% (HR 0.82, 0.72-0.93), and 21% (HR 0.79, 0.69-0.91) for those with more recent MI, multiple prior MIs, and residual multivessel CAD, whereas they were 5% (HR 0.95, 0.85-1.05), 8% (HR 0.92, 0.84-1.02), and 7% (HR 0.93, 0.85-1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) vs. approximately 1% in the low-risk groups (0.8%, 1.3%, and 1.2%). Conclusions -Patients closer to their most recent MI, with multiple prior MIs or with residual multivessel CAD are at high risk for major vascular events and experience substantial risk reductions with LDL-C lowering with evolocumab. Clinical Trial Registration -URL: https://www.clinicaltrials.gov Unique identifier: NCT01764633

Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: An Analysis from FOURIER.

Background -The FOURIER trial recently showed that the PCSK9 inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior MI. Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets that derive greater clinical risk reduction with evolocumab. Methods -The 22,351 patients with a prior MI were characterized based on time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events including the primary endpoint (CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary endpoint (CV death, MI or stroke) with evolocumab in these subgroups were compared. Results -A total of 8402 patients (38%) were within 2 years of their most recent MI, 5285 patients (24%) had ≥2 prior MIs, and 5618 patients (25%) had residual multivessel CAD. In a multivariable adjusted model that simultaneously included all three high-risk features as well as other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted HRs for the primary endpoint of 1.37 (1.22-1.53), 1.78 (1.59-1.99) and 1.39 (1.24-1.56), all P<0.001. The relative risk reductions with evolocumab for the primary endpoint tended to be greater in the high-risk subgroups and were 20% (HR 0.80, 0.71-0.91), 18% (HR 0.82, 0.72-0.93), and 21% (HR 0.79, 0.69-0.91) for those with more recent MI, multiple prior MIs, and residual multivessel CAD, whereas they were 5% (HR 0.95, 0.85-1.05), 8% (HR 0.92, 0.84-1.02), and 7% (HR 0.93, 0.85-1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) vs. approximately 1% in the low-risk groups (0.8%, 1.3%, and 1.2%). Conclusions -Patients closer to their most recent MI, with multiple prior MIs or with residual multivessel CAD are at high risk for major vascular events and experience substantial risk reductions with LDL-C lowering with evolocumab

Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduced LDL cholesterol and cardiovascular events in the FOURIER trial. In this prespecified analysis of FOURIER, we investigated the efficacy and safety of evolocumab by diabetes status and the effect of evolocumab on glycaemia and risk of developing diabetes. METHODS: FOURIER was a randomised trial of evolocumab (140 mg every 2 weeks or 420 mg once per month) versus placebo in 27 564 patients with atherosclerotic disease who were on statin therapy, followed up for a median of 2·2 years. In this prespecified analysis, we investigated the effect of evolocumab on cardiovascular events by diabetes status at baseline, defined on the basis of patient history, clinical events committee review of medical records, or baseline HbA1c of 6·5% (48 mmol/mol) or greater or fasting plasma glucose (FPG) of 7·0 mmol/L or greater. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularisation. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. We also assessed the effect of evolocumab on glycaemia, and on the risk of new-onset diabetes among patients without diabetes at baseline. HbA1c was measured at baseline then every 24 weeks and FPG was measured at baseline, week 12, week 24, and every 24 weeks thereafter, and potential cases of new-onset diabetes were adjudicated centrally. In a post-hoc analysis, we also investigated the effects on glycaemia and diabetes risk in patients with prediabetes (HbA1c 5·7-6·4% [39-46 mmol/mol] or FPG 5·6-6·9 mmol/L) at baseline. FOURIER is registered with ClinicalTrials.gov, number NCT01764633. FINDINGS: At study baseline, 11 031 patients (40%) had diabetes and 16 533 (60%) did not have diabetes (of whom 10 344 had prediabetes and 6189 had normoglycaemia). Evolocumab significantly reduced cardiovascular outcomes consistently in patients with and without diabetes at baseline. For the primary composite endpoint, the hazard ratios (HRs) were 0·83 (95% CI 0·75-0·93; p=0·0008) for patients with diabetes and 0·87 (0·79-0·96; p=0·0052) for patients without diabetes (pinteraction=0·60). For the key secondary endpoint, the HRs were 0·82 (0·72-0·93; p=0·0021) for those with diabetes and 0·78 (0·69-0·89; p=0·0002) for those without diabetes (pinteraction=0·65). Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR 1·05, 0·94-1·17), including in those with prediabetes (HR 1·00, 0·89-1·13). Levels of HbA1c and FPG were similar between the evolocumab and placebo groups over time in patients with diabetes, prediabetes, or normoglycaemia. Among patients with diabetes at baseline, the proportions of patients with adverse events were 78·5% (4327 of 5513 patients) in the evolocumab group and 78·3% (4307 of 5502 patients) in the placebo group; among patients without diabetes at baseline, the proportions with adverse events were 76·8% (6337 of 8256 patients) in the evolocumab group and 76·8% (6337 of 8254 patients) in the placebo group. INTERPRETATION: PCSK9 inhibition with evolocumab significantly reduced cardiovascular risk in patients with and without diabetes. Evolocumab did not increase the risk of new-onset diabetes, nor did it worsen glycaemia. These data suggest evolocumab use in patients with atherosclerotic disease is efficacious and safe in patients with and without diabetes. FUNDING: Amgen