Maximum Tolerated Statin Therapy Research Articles

Effect of alirocumab on coronary plaque stratified by atherothrombotic risks

Abstract Background Previous clinical studies have shown that high-risk subgroups including patients with major atherosclerotic cardiovascular disease (ASCVD) events and multiple atherothrombotic risk factors derive enhanced cardiovascular benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. To date, the effect of alirocumab on coronary plaque regression stratified by the number of atherothrombotic risk factors remains unknown. Purpose To investigate the utility of atherothrombotic risk stratification to identify patients with acute myocardial infarction (AMI) who have the greatest potential for benefit on plaque regression as assessed by intracoronary imaging from the addition of alirocumab to high-intensity statin therapy. Methods This was a substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Intravascular ultrasound (IVUS) was serially performed in non-infarct-related coronary arteries at baseline and after 52 weeks. Atherothrombotic risk factors defined in the 2018 ACC/AHA cholesterol guidelines include myocardial infarction, ischemic stroke, peripheral artery disease, age ≥65 years, familial hypercholesterolemia, coronary revascularization, diabetes, hypertension, chronic kidney disease, current smoking, LDL-C ≥100 mg/dL despite maximum tolerated statin therapy, and history of heart failure. The key endpoint was the change in IVUS-derived percent atheroma volume (PAV) from baseline to 52 weeks. Results A total of 263 patients available for serial IVUS data were analyzed for the current study. The most prevalent atherothrombotic risk factors were current smoking (49%), hypertension (43%), and age ≥65 years (24%). Patients were divided into 3 groups according to the number of risk factors (0 risk factor: n=52, 1 risk factor: n=101, ≥2 risk factors: n=100). Patients with risk factors had greater PAV at baseline compared with those with 0 risk factor (39.0% vs. 42.6% vs. 42.8%, P=0.008). The addition of Alirocumab to high-intensity statin therapy demonstrated a significant reduction in PAV among patients with 0 risk factor (-2.66% vs. -1.02%, P=0.009) and those with 1 risk factor (-2.36% vs. -0.76%, P<0.001) (Figure 1). In contrast, patients with ≥2 risk factors had no significant PAV reduction by alirocumab (-1.72% vs. -1.12%, P=0.076, P for interaction=0.009). Conclusions Among AMI patients with no or 1 atherothrombotic risk factor, the addition of alirocumab to high-intensity statin therapy demonstrated greater coronary plaque regression. Patients with fewer risk factors thus appear to be more susceptible for atheroma regression.Change in PAV stratified by risk factors

Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects

BackgroundMechanistic studies suggest that proprotein convertase subtilisin/kexin type 9 inhibitors can modulate inflammation. MethodsDouble-blind, placebo-controlled trial randomized 41 ASCVD subjects with type 2 diabetes with microalbuminuria and LDL-C level >70 mg/dL on maximum tolerated statin therapy received subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were change in circulating immune cell transcriptional response, lipoproteins and blood viscosity at 2 weeks and 12 weeks. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population. ResultsAll 41 randomized subjects completed the 2-week visit. Six subjects did not receive study medication consistently after the 2-week visit due to COVID-19 pandemic suspension of research activities. The groups were well-matched with respect to age, comorbidities, baseline LDL-C, white blood cell counts, and markers of systemic inflammation. Evolocumab reduced LDL-C by −68.8% (p < 0.0001) and −52.8% (p < 0.0001) at 2 and 12 weeks, respectively. There were no differences in blood viscosity at baseline nor at 2 and 12 weeks. RNA-seq was performed on peripheral blood mononuclear cells with and without TLR4 stimulation ("Stress" transcriptomics). "Stress" transcriptomics unmasked immune cell phenotypic differences between evolocumab and placebo groups at 2 and 12 weeks. ConclusionsThis trial is the first to demonstrate that PCSK9 mAB with evolocumab can modulate circulating immune cell properties and highlights the importance of "stress" profiling of circulating immune cells that more clearly define immune contributions to ASCVD.

Effect of proprotein convertase subtilisin/kexin type 9 inhibition on cancer events: A pooled, post hoc, competing risk analysis of alirocumab clinical trials.

Assess the risk of new and worsening cancer events among participants who received the lipid-lowering therapy alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor. Pooled post hoc analysis. Six phase 3 or phase 4 placebo-controlled randomised trials with alirocumab. A total of 24,070 patients from the safety population with complete dosing data (alirocumab, n = 12,533; placebo, n = 11,537). Alirocumab 75 mg, alirocumab 150 mg, alirocumab 75 mg increasing to 150 mg if low-density lipoprotein cholesterol <50 mg/dL not achieved, or placebo, all every 2 weeks. All participants received background high-intensity or maximum-tolerated statin therapy. The first new or worsening incident cancer events were assessed during the treatment-emergent adverse event period. Four outcomes were evaluated: any-neoplasm, malignant neoplasms, broad definition of hormone-sensitive cancers, and stricter definition of hormone-sensitive cancers. Sub-distribution hazard ratios and 95% confidence intervals (CIs) were estimated using a competing risk framework, with death as a competing risk. Considering both treatment arms in aggregate, 969 (4.03%), 779 (3.24%), 178 (0.74%) and 167 (0.69%) patients developed any neoplasm, malignant neoplasms, broad definition of hormone-sensitive cancer and strict definition of hormone-sensitive cancer events, respectively. There was no significant difference in the risk of having any neoplasm in the alirocumab versus the placebo group (sub-distribution hazards ratio [95% CI], 0.93 [0.82-1.1]; p = 0.28). A nominally lower risk of having any neoplasms with alirocumab was observed among subjects aged ≥64 years (sub-distribution hazards ratio 0.83; 95% CI, 0.70-0.99). Intensive low-density lipoprotein cholesterol lowering with a proprotein convertase subtilisin/kexin type 9 inhibitor combined with statin does not appear to increase the risk of new or worsening cancer events.

ANMCO Position paper: Inclisiran: an innovative therapeutic approach for the clinical management of hypercholesterolemia

Research focused on lipid-lowering treatments has led to the development of new therapeutic options aimed at cardiovascular risk reduction. Gene silencing represents one of the most innovative approaches to reduce low-density lipoprotein cholesterol (LDL-C). Inclisiran is a small interfering RNA that inhibits proprotein convertase subtilisin/kexin type 9 synthesis and promotes LDL-C clearance by enhancing LDL-C receptor expression on hepatocyte cell surface. Several clinical studies have demonstrated inclisiran efficacy in terms of LDL-C reduction (~50%) with a dosage regimen of 300 mg administered twice a year after the first two doses administered at time 0 and after 90 days. Inclisiran use has recently been approved by the European and American drug regulatory agencies as a therapeutic option in addition to the maximum tolerated statin therapy in adults with primary hypercholesterolemia or mixed dyslipidemia who need further LDL-C reduction.

Transiently achieved very low LDL-cholesterol levels by statin and alirocumab after acute coronary syndrome are associated with cardiovascular risk reduction: the ODYSSEY OUTCOMES trial.

Long-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus PCSK9 inhibitor. In 18,924 patients post-acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score-matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median 8.3 months from randomization, after a median 6.0 months with LDL-C < 0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C versus 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047). A short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years. ClinicalTrials.gov NCT01663402.

Abstract 10470: Projected Lifetime Benefits of Alirocumab in Patients After Acute Coronary Syndrome

Introduction: In the ODYSSEY OUTCOMES trial, alirocumab improved cardiovascular outcomes and reduced death after acute coronary syndrome (ACS). Median follow-up was 2.8 yrs (range 2-5). The effects of alirocumab on long-term survival are unknown. Objective: To calculate projected life span and potential survival gains with alirocumab vs placebo after ACS using validated nonparametric age-based methods. Methods: In ODYSSEY OUTCOMES (NCT01663402), 18,924 patients with recent ACS and elevated atherogenic lipoproteins despite high-intensity or maximum-tolerated statin therapy were randomized to alirocumab or placebo. All-cause death was a secondary trial outcome. Age-based estimates of projected survival and event-free (all-cause death, nonfatal myocardial infarction, nonfatal ischemic stroke) survival were calculated. In each treatment arm at every year of age, lifespan was estimated from area under the survival curve, to a maximum of 85 yrs. Differences in areas under the survival curves provide an estimate of the benefit of alirocumab on survival. Results: Mean (SD) baseline age was 58.5 (9.3) yrs. Mean survival benefits with alirocumab vs placebo ranged from 0.03 to 1.62 yrs, decreasing with age and becoming neutral at age 80-85 yrs. For example, at age 40, estimated survival was another 37.5 yrs with alirocumab and 35.9 yrs with placebo (difference 1.62 yrs [95% CI, 0.30-2.94]; P =0.016). At age 60, it was 20.5 vs 19.6 yrs (difference 0.88 [95% CI, 0.16-1.61]; P =0.017); at age 75 it was 8.8 vs 8.3 (difference 0.57 [0.09-1.05]; P =0.019); and at age 80, it was 4.5 vs 4.5 years (difference 0.03 [-0.28 to 0.35]; P =0.83). Mean event-free survival benefit similarly ranged from 1.85 to 0.0 yrs. Conclusions: Modeling suggests that long-term treatment with alirocumab may result in a meaningful increase in survival among patients less than 80 yrs of age. This analysis may facilitate shared decision-making with patients. Funding: Sanofi, Regeneron Pharmaceuticals

Alirocumab reduces total coronary plaque burden in patients with familial hypercholesterolaemia and no previous clinical atherosclerotic disease

Abstract Background It is well known that statins, ezetimibe and other lipid lowering treatments such as Evolocumab (PCSK9-Inhibitor) reduce cardiovascular events by decreasing LDL-cholesterol (LDL-C) levels and slowing the progression of coronary atherosclerosis. Nevertheless, cardiovascular (CV) risk remains. Alirocumab, a PCSK9 inhibitor has demonstrated a reduction in cardiovascular events but its relationship with coronary atherosclerosis reduction has not been adequately demonstrated. Purpose The ARCHITECT trial sought to determine whether Alirocumab 150 mg/2 weeks is able to stop or reverse coronary atherosclerosis progression, by assessing coronary plaque burden (CPB) by serial multidetector computed tomography (MDCT). Methods A total of 104 patients with molecularly characterized heterozygous familial hypercholesterolaemia (FH) without clinical cardiovascular disease were enrolled in this trial. Patients had to have CPB &amp;gt;30% as documented by MDCT, be on maximum tolerated statin therapy with or without ezetimibe and LDL-C &amp;gt;100 mg/dL. Patients underwent a MDCT at enrollment and after 18-month treatment with alirocumab and they were analyzed by means of QAngio CT (Medis medical imaging system, the Netherlans). The pre-specified primary endpoint was change in CPB. Results Median age was 53.3 (46.2–59.4) years (54, 51.9% woman). Median LDL-cholesterol was 138.9 mg/dL. There was a significant reduction in the primary endpoint as Alirocumab reduced CPB from 34.6 (32.9–36.8)% to 30.4 (27.4–33.4)%. Significant reductions in LDL-C (67%) and atherosclerotic plaque volume were also found. Plaque regression as estimated by CPB was found in 91 (87.5%) patients. Main resuts may be found in figure 1. Conclusions Alirocumab demonstrated significant regression of CPB on MDCT over 18 months. ARCHITECT provides crucial mechanistic clues on coronary plaque behavior under the use of Alirocumab and its results could link and explain ODYSSEY-OUTCOMES results. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi

Achievement of ESC/EAS LDL-C treatment goals after an acute coronary syndrome with statin and alirocumab.

European guidelines set low-density lipoprotein cholesterol (LDL-C) treatment goals &lt;1.4 mmol/L after acute coronary syndrome (ACS), and &lt;1.0 mmol/L for patients with recurrent cardiovascular events ≤2 years. Many ACS patients do not achieve these goals on statin alone. We examined actual goal achievement with alirocumab and projected achievement with ezetimibe, either added to optimized statin therapy. The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18 924 patients with recent ACS and hyperlipidaemia despite high-intensity or maximum-tolerated statin therapy. This subanalysis comprised 17 589 patients with LDL-C ≥1.4 mmol/L at baseline who did not receive ezetimibe treatment. High-intensity statin treatment was used in 88.8%. Median (interquartile range) baseline LDL-C was 2.3 (1.9-2.7) mmol/L. With alirocumab, 94.6% of patients achieved LDL-C &lt;1.4 mmol/L at ≥1 post-baseline measurement vs. 17.3% with placebo. Among 2236 patients with a previous cardiovascular event within 2 years (before the qualifying ACS), 85.2% vs. 3.5%, respectively, achieved LDL-C &lt;1.0 mmol/L. Among patients not treated with ezetimibe, we projected that its use would have achieved LDL-C &lt;1.4 and &lt;1.0 mmol/L in 10.6 and 0%, respectively, at baseline (assuming 18 ± 3% reduction of LDL-C). Among patients with recent ACS and LDL-C ≥1.4 mmol/L despite optimized statin therapy, the addition of alirocumab allowed 94.6% to achieve the 2019 European guideline LDL-C goal &lt;1.4 mmol/L, and 85.2% of those with recurrent cardiovascular events to achieve &lt;1.0 mmol/L. In contrast, the addition of ezetimibe to optimized statin therapy was projected to achieve LDL-C &lt;1.4 mmol/L in only 10.6% of patients at baseline.

Effect of Alirocumab on Incidence of Atrial Fibrillation After Acute Coronary Syndromes: Insights from the ODYSSEY OUTCOMES Trial

BackgroundUsing data from the ODYSSEY OUTCOMES trial (NCT01663402), we sought to identify factors associated with the development of incident atrial fibrillation in patients with recent acute coronary syndrome without prior atrial fibrillation and to determine whether alirocumab treatment influenced risk of incident atrial fibrillation. MethodsODYSSEY OUTCOMES compared alirocumab treatment with placebo in 18,924 patients with recent acute coronary syndrome and dyslipidemia despite high-intensity or maximum-tolerated statin therapy. The primary outcome of major adverse cardiovascular events (MACE) comprised death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization. Patients were classified as having previous atrial fibrillation (present prior to or at randomization) or no previous atrial fibrillation. A multivariable model was used to determine factors associated with incident atrial fibrillation. ResultsAmong 18,262 participants without prior atrial fibrillation at baseline, 499 (2.7%) had incident atrial fibrillation during follow-up. Older age, history of heart failure or myocardial infarction, and higher body mass index were significantly associated with incident atrial fibrillation. Treatment with alirocumab or placebo did not influence the cumulative incidence of atrial fibrillation (hazard ratio 0.91; 95% confidence interval, 0.77-1.09). Patients with vs without a history of atrial fibrillation had a higher incidence of MACE (8.8 vs 3.7 events per 100 patient-years), without significant interaction between atrial fibrillation and randomized treatment on risk of MACE (Pinteraction = .78). ConclusionsWhile alirocumab did not modify risk of incident atrial fibrillation after acute coronary syndrome, it did reduce the risk of MACE, regardless of prior atrial fibrillation history. History of atrial fibrillation is an independent predictor of recurrent cardiovascular events after acute coronary syndrome.

The therapeutic management of South African dyslipidaemic patients at very high cardiovascular risk (CARDIO TRACK): a cross-sectional study.

Dyslipidaemia is a major modifiable risk factor for atherosclerotic cardiovascular disease. At the time the study was conducted, guidelines recommended a low-density lipoprotein cholesterol (LDL-C) target of less than 1.8 mmol/l and a reduction of at least 50% if the baseline LDL-C was between 1.8 and 3.5 mmol/l in patients with either very high cardiovascular risk or established atherosclerosis. In South Africa, there is a paucity of data on attainment of LDL-C goal in patients with very high cardiovascular risk who are on maximum tolerated statin with or without ezetimibe. The aim was to assess the percentage of very high cardiovascular risk South African patients with dyslipidaemia not reaching an LDL-C goal of less than 1.8 mmol/l, despite maximum tolerated statin with or without ezetimibe. This was a multi-centre, observational, cross-sectional study conducted at 15 private healthcare sector sites and one public sector site. Adults (> 18 years) with very high cardiovascular risk of familial hypercholesterolaemia receiving stable, maximum-tolerated statin therapy for at least four weeks prior to their latest lipid profile were enrolled into the study, and electronic case report forms were completed after written informed consent was provided. LDL-C goal attainment was modelled, first assuming an increase in the statin dose to the registered maximum, followed by the addition of ezetimibe or a PCSK9-inhibitor. In total, 507 patients were screened, of whom 492 were eligible for study participation. One patient was excluded from the analysis because of a missing LDL-C value. Most participants were male (male 329, 67%; female 162, 33%). Most patients were either obese (223, 46.0%) or overweight (176, 36.3%). Hypertension and diabetes mellitus were frequent co-morbidities and were found in 381 (77.6%) and 316 (64.4%) patients, respectively. Eighty (16.3%) patients reported current smoking. Only 68 (13.8%) patients were taking ezetimibe in addition to a statin. Reasons for not using ezetimibe included no requirement for ezetimibe in the opinion of the treating physician (229, 48.7%), cost (149, 31.7%), Physician's choice (39, 8.3%), or other (53, 11.3%). Only 161 (32.8%) of the patients attained their goal LDL-C level. In our modelling analysis, increasing the statin dose to the registered maximum and adding ezetimibe brought an additional 34.5% of patients to goal, while adding a PCSK9-inhibitor, irrespective of any other changes to lipid-lowering therapy brought over 90% of not-at-goal patients to goal. Most study participants were not at LDL-C goal despite maximum-tolerated statin, highlighting the need for treatment intensification in this high-risk population. Although intensifying treatment by adding a PCSK9-inhibitor brought more patients to goal, the initial addition of ezetimibe would be more reasonable, given the cost of PCSK9-inhibitors.

Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial

BackgroundCholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain. ObjectivesThis study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy. MethodsA cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non–high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl. ResultsAcross the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses. ConclusionsIn patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402)

Homozygous familial hypercholesterolemia in a young woman with dual gene mutations of low-density lipoprotein receptor and proprotein convertase subtilisin/kexin type 9

A 28-year-old woman with a rare combination of homozygous LDLR and heterozygous PCSK9 mutations had a phenotype consistent with homozygous familial hypercholesterolemia. She reported a clinical history of coronary and extracoronary atherosclerosis treated with 3 coronary stenting procedures, one coronary bypass, and aortic and mitral valve replacements. Because the patient refused lipoprotein apheresis, lipid-lowering therapy with statins, ezetimibe, and evolocumab was started. The desired low-density lipoprotein cholesterol target was not achieved. Dose-escalated lomitapide therapy (up to 30 mg/d) was added, enabling achievement of low-density lipoprotein cholesterol levels of 45 mg/dL during 24 months' follow-up. During this period, no cardiovascular events or clinical evidence of side effects occurred. In this case, lomitapide has been used in combination with maximum-tolerated statin therapy to successfully treat a patient with a rare combination of mutations in both LDLR and PCSK9 genes.

P5329Montreal score and coronary artery calcification in the prediction of cardiovascular event in patients with familial hypercholesterolemia

Abstract Introduction Familial hypercholesterolemia (FH) is characterized by elevated levels of LDL-C and early cardiovascular disease (CVD). However, the risk of CVD in HF is variable. The Montreal score was designed to stratify cardiovascular risk in the FH population. Coronary calcium score (CAC) is a tool that can be used to optimize CVD risk assessment in FH. Purpose The objective of this study is to evaluate whether CAC is superior to the Montreal score in cardiovascular risk discrimination in FH. Methods We Included 206 patients with molecular diagnosis of FH (36.4% men, mean age 45±14 years, mean baseline LDL-C: 269±70 mg/dL). All patients underwent CAC and were treated with maximum tolerated statin therapy. We evaluated cardiovascular risk factors and calculated Montreal score as prior publication. Cox regression analysis was performed to test the association of CAC with the incidence of cardiovascular events. CAC was transformed into LogCAC + 1 to optimize the distribution of the CAC as previously described. Area under the ROC curve was calculated for Montreal score and CAC. Results Patients were followed by a median of 3.7 years (interquartile range: 2.7 to 6.8 years). Mean Montreal score was 22±8, median of 22. CAC was positive in 105 individuals (51%) and 15 CVD events (7.2%) had occurred. Montreal score above the median was associated with CAC (OR: 8.36, 95% CI: 4.47–15.62, p&lt;0.001), and there was a gradient of increase in the Montreal score with CAC increase (mean Montreal score for CAC = 0, CAC 1–100, CAC&gt;100: 17±7, 23±7, 30±4, p&lt;0.001). Univariate analysis showed that the following variables were associated with CVD occurrence: male gender, family history of early coronary disease, corneal arcus, HDL-c (protective), logCAC + 1 and Montreal score. Multivariate analysis was performed: model 1 with Montreal score and logCAC + 1, only logCAC + 1 was associated with the occurrence of CVD (RR: 3.886; 95% CI: 2.112–7.148, p&lt;0.001). Model 2 with family history of early coronary disease, corneal arcus, logCAC + 1 and Montreal score, only the latter was not associated with the occurrence of CVD. CAC presents greater area under the ROC curve for CVD event discrimination compared to the Montreal score: 0.839 versus 0.685, p=0.0074. Conclusion The Montreal score is associated with CAC in FH, however CAC is superior than this clinical score in predicting the occurrence of CVD in FH.

Risk Categorization Using New American College of Cardiology/American Heart Association Guidelines for Cholesterol Management and Its Relation to Alirocumab Treatment Following Acute Coronary Syndromes.

The 2018 US cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with low-density lipoprotein cholesterol ≥70 mg/dL or non-high-density lipoprotein cholesterol ≥100 mg/dL despite maximum tolerated statin therapy. Such patients are considered at very high risk (VHR) based on a history of >1 major atherosclerotic cardiovascular disease (ASCVD) event or a single ASCVD event and multiple high-risk conditions. We investigated the association of US guideline-defined risk categories with the occurrence of ischemic events after acute coronary syndrome and reduction of those events by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor. In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), patients with recent acute coronary syndrome and residual dyslipidemia despite optimal statin therapy were randomly assigned to alirocumab or placebo. The primary trial outcome (major adverse cardiovascular events, ie, coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) was examined according to American College of Cardiology/American Heart Association risk category. Of 18 924 participants followed for a median of 2.8 years, 11 935 (63.1%) were classified as VHR: 4450 (37.3%) had multiple prior ASCVD events and 7485 (62.7%) had 1 major ASCVD event and multiple high-risk conditions. Major adverse cardiovascular events occurred in 14.4% of placebo-treated patients at VHR versus 5.6% of those not at VHR. In the VHR category, major adverse cardiovascular events occurred in 20.4% with multiple prior ASCVD events versus 10.7% with 1 ASCVD event and multiple high-risk conditions. Alirocumab was associated with consistent relative risk reductions in both risk categories (hazard ratio=0.84 for VHR; hazard ratio=0.86 for not VHR; Pinteraction=0.820) and by stratification within the VHR group (hazard ratio=0.86 for multiple prior ASCVD events; hazard ratio=0.82 for 1 major ASCVD event and multiple high-risk conditions; Pinteraction=0.672). The absolute risk reduction for major adverse cardiovascular events with alirocumab was numerically greater (but not statistically different) in the VHR group versus those not at VHR (2.1% versus 0.8%; Pinteraction=0.095) and among patients at VHR with multiple prior ASCVD events versus a single prior ASCVD event (2.4% versus 1.8%; Pinteraction=0.661). The US guideline criteria identify patients with recent acute coronary syndrome and dyslipidemia who are at VHR for recurrent ischemic events and who may derive a larger absolute benefit from treatment with alirocumab. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.

Bempedoic Acid a Small Molecule Drug Process and Synthesis, Innovation And /Or Advantages, Development Status And /Or Regulatory Status

The current standard of care for patients with hypercholesterolaemia is primarily statins which can reduce LDL-C. However, some patients, particularly those with heterozygous familial hypercholesterolaemia, coronary heart disease (CHD), CHD-risk equivalents, and other clinical manifestations of atherosclerotic cardiovascular disease [1] (ASCVD), require additional LDL cholesterol lowering on top of what can be achieved with maximum tolerated statin therapy.

Treatment effect of alirocumab according to age group, smoking status, and hypertension: Pooled analysis from 10 randomized ODYSSEY studies

Age, smoking, hypercholesterolemia, and hypertension are major risk factors for atherosclerotic cardiovascular disease. We examined whether the effects of alirocumab on low-density lipoprotein cholesterol (LDL-C) differed according to age, hypertension, or smoking status. Data were pooled from 10 Phase 3 ODYSSEY randomized trials (24-104weeks' duration) in 4983 people with heterozygous familial hypercholesterolemia (FH) or non-familial hypercholesterolemia (3188 on alirocumab, 1795 on control [620 on ezetimibe and 1175 on placebo]). Most participants received concomitant maximum tolerated statin therapy. In 8 trials, the alirocumab dose was increased from 75mg every 2weeks (Q2W) to 150mg Q2W at Week 12 if predefined risk-based LDL-C goals were not achieved at Week 8 (≥70mg/dL in very high cardiovascular risk; ≥100mg/dL in moderate or high cardiovascular risk). Two trials compared alirocumab 150mg Q2W vs placebo. The efficacy and safety of alirocumab were assessed post hoc in subgroups stratified by age (<65, ≥65 to <75, ≥75years) and baseline hypertension or smoking status. Alirocumab reduced LDL-C by 23.7% (75/150mg vs ezetimibe+statin) to 65.4% (150mg vs placebo+statin) from baseline to Week 24 vs control. Subgroup analyses confirmed no significant interactions in response to alirocumab between age group, hypertension, or smoking status. Overall rates of treatment-emergent adverse events were similar between alirocumab and control groups. In this pooled analysis from 10 trials, alirocumab led to substantial LDL-C reductions vs control in every age group and regardless of hypertension or smoking status. Alirocumab was well tolerated in all subgroups.

Proprotein convertase subtilisin/kexin type 9 in kidney disease.

Chronic kidney disease (CKD) is associated with a substantially increased risk for the development of atherosclerotic cardiovascular (CV) disease. Accordingly, CV mortality is increased even in the earliest stages of CKD. In the general population and in CKD patients, high plasma levels of low-density lipoprotein cholesterol (LDL-C) are crucially involved in the initiation and progression of atherosclerotic vascular lesions. Lowering LDL-C by use of statins and/or ezetimibe represents the gold standard of lipid-lowering therapy, with a great body of evidence from several large clinical trials. Statin therapy reduces CV events in patients with normal and impaired kidney function alike, while the evidence for patients on maintenance haemodialysis is weaker. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease represents a novel lipid-lowering tool. Currently the monoclonal antibodies evolocumab and alirocumab are the approved PCSK9 inhibitors. Despite maximum-tolerated statin therapy, they efficiently further reduce LDL-C plasma levels without any major adverse effects. Moreover, in large clinical outcome trials, both antibodies have been proven to lower CV events. Notably, the LDL-lowering capacity was independent of baseline kidney function and also efficient in patients with moderate CKD. However, patients with severely impaired kidney function, that is, the population at the highest CV risk, have been excluded from those trials. The relevance of the LDL-independent effects of PCSK9 inhibitors, such as lowering lipoprotein(a) or ameliorating dyslipidaemia in patients with nephrotic syndrome, has to be determined. Therefore further specific studies assessing the effects and outcomes of PCSK9-inhibiting treatment in CKD patients are warranted.

Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial.

It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.

Recent Insights into Pharmacologic Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) affects nearly 30 million Americans and carries an increased risk of macrovascular complications of myocardial infarction, stroke, and cardiovascular death. While aggressive cardiovascular risk factor reduction has long been advocated in patients with diabetes, clinical trials have only recently demonstrated that such reductions result in improved outcomes. This review discusses recent evidence for risk reduction strategies and therapies with a focus on the management of glycemia, dyslipidemia, and hypertension. Although the degree to which aggressive glycated hemoglobin reduction decreases the risk of macrovascular outcomes remains unclear, the use of specific agents, such as the newer sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, may reduce cardiovascular events in patients with diabetes, irrespective of glycated hemoglobin reduction. Statins have been the mainstay of dyslipidemia management, with recent guidelines recommending statin use in all patients aged 40-75years with diabetes. There is an emerging role for the recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in diabetes, as these agents further reduce serum cholesterol and clinical cardiovascular events beyond the maximum tolerated statin therapy. Lastly, most evidence suggests that aggressive blood pressure lowering in diabetic patients with hypertension reduces macrovascular events. Recent studies have re-affirmed a goal blood pressure of 140/90, and a lower pressure is likely prudent in most patients with diabetes. Specifically, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may reduce cardiovascular risk in patients with diabetes beyond their blood pressure-lowering effect. In conclusion, there is a growing literature which shows that the risk of cardiovascular outcomes can be reduced in most patients with diabetes, as outlined in this review.

Role of Non-Statins, LDL-C Thresholds, and Special Population Considerations: A Look at the Updated 2016 ACC Consensus Committee Recommendations.

The 2013 ACC/AHA Cholesterol guidelines was a major paradigm shift in the management and treatment of dyslipidemia. The new guidelines outlined "statin benefit groups," highlighted weighing the benefit versus risks of statin therapy ("net benefit"), and discussed the importance of shared decision making between patients and providers in primary prevention. While there was widespread agreement on the main groups benefiting from statin therapy, there was significant controversy regarding LDL-C goals and thresholds, the role of non-statin therapy, and the use of statins in specific populations. The goal of this review is to understand the rationale for the updated 2016 ACC Expert Consensus on Non-Statins and to contrast it with the 2015 NLA Recommendations on the Management of Dyslipidemia. The findings of the ACC Expert Consensus Panel were largely influenced by the results of several new clinical trials using non-statin therapy in combination with moderate to high intensity statin therapy. The IMPROVE-IT trial demonstrated that ezetimibe on top of statin therapy lowered ASCVD risk in patients with acute coronary syndromes whose LDL was driven below the previous LDL-C target of <70mg/dL. In addition, preliminary data assessing the safety of evolocumab and alirocumab on top of statin therapy suggested possible large reductions in ASCVD risk in post hoc analysis. Both the 2016 ACC Consensus Recommendations and the 2015 NLA Recommendations emphasize the importance of maximally tolerated statin therapy, the use of adjunctive non-statin LDL lowering therapy, and the use of LDL-C goals and thresholds to guide intensification of LDL lowering therapy. Although there are some important differences between the ACC Consensus and NLA recommendations in terms of treatment of special populations (i.e., CHF) and on the use of non-HDL-C goals and thresholds, both guidelines support a role for ezetimibe, bile acid sequestrants, and PCSK-9 inhibitors in patients on maximum tolerated statin therapy. The recent positive results of the FOURIER trial gives additional support to the non-statin recommendations of both the ACC and NLA.