ODYSSEY OUTCOMES Research Articles

Apolipoprotein C3 and risk of cardiovascular events and death in patients on optimized statin treatment after recent acute coronary syndrome.

Apolipoprotein (Apo) C3 has been associated with incident coronary heart disease and major adverse cardiovascular events (MACE). Whether ApoC3 levels predict risk in patients with acute coronary syndrome (ACS) on optimized statin treatment is unknown. ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months' treatment (M4; n=11 176) with alirocumab or placebo in the ODYSSEY OUTCOMES trial. Patients with fasting triglycerides >400 mg/dL were excluded. The association of baseline ApoC3 with risk of MACE or death was assessed in post hoc adjusted Cox regression models and spline analyses adjusted for treatment and ApoB. In adjusted models in the alirocumab group we determined association of ApoC3 change from baseline to M4 with subsequent risk of MACE and death. Median (Q1, Q3) baseline ApoC3 concentration was 85 (65, 113) mg/L. With adjustment for ApoB, baseline ApoC3 showed no clinically meaningful relationship to risk of MACE or death in spline analyses and no association with MACE (P=0.89) or death (P=0.70) in Cox regression analyses. Alirocumab reduced ApoC3 modestly by median -10 (-27, -5) mg/L (P<0.0001) and reduced MACE (10.1% vs 12.1%; P=0.0006) and death (3.5% vs 4.2%; P=0.045) versus placebo. However, the change in ApoC3 on alirocumab did not predict subsequent MACE or death. In patients with recent ACS on optimized statins without severe hypertriglyceridemia, neither baseline ApoC3 (accounting for ApoB) nor ApoC3 change with alirocumab predicted MACE or death. It is uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk.

Risk of Incident Diabetes Related to Lipoprotein(a), LDL Cholesterol, and Their Changes With Alirocumab: Post Hoc Analyses of the ODYSSEY OUTCOMES Randomized Trial.

Previous genetic and clinical analyses have associated lower lipoprotein(a) and LDL cholesterol (LDL-C) with greater risk of new-onset type 2 diabetes (NOD). However, PCSK9 inhibitors such as alirocumab lower both lipoprotein(a) and LDL-C without effect on NOD. In a post hoc analysis of the ODYSSEY OUTCOMES trial (NCT01663402), we examined the joint prediction of NOD by baseline lipoprotein(a), LDL-C, and insulin (or HOMA-insulin resistance [HOMA-IR]) and their changes with alirocumab treatment. Analyses included 8,107 patients with recent acute coronary syndrome on optimized statin therapy, without diabetes at baseline, assigned to alirocumab or placebo with median follow-up 2.4 years. Splines were estimated from logistic regression models. Lower baseline lipoprotein(a) and higher baseline insulin or HOMA-IR independently predicted 782 cases of NOD; baseline LDL-C did not predict NOD. Alirocumab reduced lipoprotein(a) and LDL-C without affecting insulin or NOD risk (odds ratio [OR] vs. placebo 0.998; 95% CI 0.860-1.158). However, in logistic regression, decreased lipoprotein(a) and LDL-C on alirocumab were independent, opposite predictors of NOD. OR for NOD for 25% and 50% lipoprotein(a) reductions on alirocumab were 1.12 (95% CI 1.01-1.23) and 1.24 (1.02-1.52). OR for NOD for 25% and 50% LDL-C reductions on alirocumab were 0.88 (95% CI 0.80-0.97) and 0.77 (0.64-0.94). Baseline lipoprotein(a) was inversely associated with risk of NOD. Alirocumab-induced reductions of lipoprotein(a) and LDL-C were associated with increased and decreased risk of NOD, respectively, without net effect on NOD. Ongoing trials will determine the impact of larger and longer lipoprotein(a) reductions on NOD.

Unveiling Hidden Dangers: Quantitative Analysis of Ischemic Risks in High-Risk Patients with ASCVD and Dyslipidemia.

Cardiovascular disease is one of the foremost causes of morbidity and mortality worldwide, with low-density lipoprotein cholesterol (LDL-C) identified as a significant risk factor for subsequent ischemic events. Elevated LDL-C contributes to vascular injury and fibrosis by upregulating the expression of connective tissue growth factor and collagen IV, which leads to endothelial cell dysfunction that initiates the process of atherosclerotic diseases. Currently, there is an absence of clear, risk-defined criteria to identify patients who are in greater needs for intensive LDL-C reduction, particularly with PCSK9 inhibitors. The data of ischemic risk associated with different patient types are scattered across the sub-analyses of FOURIER and ODYSSEY OUTCOMES trials, as well as trials that analyzed the plaque morphology of high-risk patients. It would be helpful to highlight the use of clinical features and plaque morphology and identify the patient types at higher ischemic risk. This article aims to provide a clear visualization of the ischemic risk associated with various types of patients with atherosclerotic cardiovascular disease (ASCVD) and dyslipidemia, and its implications to improve risk stratification for patients with unveiling hidden dangers.

Alirocumab and chest pain after acute coronary syndrome: An analysis of ODYSSEY OUTCOMES

Patients with recent acute coronary syndrome (ACS) commonly experience chest pain, which affects quality of life even when not due to recurrence of ACS. This post hoc analysis of ODYSSEY OUTCOMES assessed the effect of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, on the incidence of chest pain not due to recurrent ACS. Patients with recent ACS (n = 18,894) and elevated atherogenic lipoprotein levels despite optimized statin therapy were randomized to subcutaneous alirocumab or matching placebo every 2 weeks. Alirocumab dose was adjusted to target low-density lipoprotein cholesterol (LDL-C) 25-50 mg/dL (0.6-1.3 mmol/L) and to avoid consecutive LDL-C <15 mg/dL (0.39 mmol/L). Non-hospitalized chest pain adverse events and chest pain events requiring hospitalization but negatively adjudicated for recurrent ACS were assessed. Chest pain not requiring hospitalization was reported as an adverse event in 1490 patients, including 7.5 % and 8.3 % of alirocumab and placebo groups, respectively. Hospitalization for chest pain negatively adjudicated for recurrent ACS occurred in 952 patients, including 4.8 % and 5.3 % of alirocumab and placebo groups, respectively. Adjusting for baseline covariates, alirocumab use was associated with 8.1 % lower risk of chest pain (either non-hospitalized or hospitalized events) versus placebo (HR: 0.919; 95 % CI: 0.845-0.998; P = 0.046); a landmark analysis at 7 months showed a larger, 11.7 % risk reduction (HR: 0.883; 95 % CI: 0.793-0.984; P = 0.024). Alirocumab use is associated with reduced incidence of chest pain events after ACS, including those not requiring hospitalization and those requiring hospitalization but not adjudicated as recurrent ACS. NCT01663402.

PCSK9 Inhibitors: Focus on Evolocumab and Its Impact on Atherosclerosis Progression.

This paper investigates the therapeutic use of PCSK9 inhibitors, particularly Evolocumab, as monoclonal antibodies for the treatment of atherosclerosis based on recent literature reviews. PCSK9 is an outstanding example of a breakthrough in medical science, with advancements in understanding its biological function driving substantial progress in atherosclerosis treatment. Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of mortality, imposing substantial financial burdens on healthcare systems. Elevated low-density lipoprotein cholesterol (LDL-C), a modifiable risk factor, plays a pivotal role in the development of ASCVD. Emerging treatments such as PCSK9 inhibitors are now being introduced to combat this issue, with the goal of reducing ASCVD risk by directly targeting LDL-C levels. This discovery highlighted the potential of monoclonal antibodies to inhibit PCSK9, thereby enhancing LDL-C receptor activity. This breakthrough led to the development of Alirocumab and Evolocumab inhibitors, which typically reduce LDL-C levels by approximately 50%. This research underscores the importance of PCSK9 inhibitors in treating ASCVD, drawing on evidence from various randomized controlled trials such as FOURIER, ODYSSEY OUTCOMES, and VESALIUS-CV. These trials have also shown that PCSK9 inhibitors are effective and safe for the treatment of several cardiovascular disorders. PCSK9 inhibitors are therefore useful in patients who do not reach their target LDL-C levels when on the highest doses of statins or patients with very high cardiovascular risk who cannot tolerate statins at all.

Abstract 4140115: Comparison of Lipoprotein(a) and Other Apo B Containing Lipoproteins as Predictors of Major Adverse Cardiovascular Events in ODYSSEY OUTCOMES

Background: Lipoprotein(a) [Lp(a)] and other atherogenic lipoproteins each contain one molecule of apolipoprotein B (apoB) per particle. Recent studies have suggested that on a per particle basis, Lp(a) is more strongly associated with major adverse cardiovascular events (MACE) than low density lipoprotein. Hypothesis: In statin-treated patients with recent acute coronary syndrome (ACS), we tested the hypothesis that, on a per particle basis, Lp(a) and its change on treatment with alirocumab (ALI) are more strongly associated with MACE than other [non-Lp(a)] apoB-containing particles. Methods: Molar apolipoprotein(a) [corresponding to Lp(a)] and apo B were measured by mass spectrometry at baseline and month 4 (M4) in a subgroup of 11,957 patients who provided consent for use of stored samples in the ODYSSEY OUTCOMES trial. Non-Lp(a) apoB in nmol/L was calculated as total apo B – Lp(a). Lp(a) and non-Lp(a) apo B at baseline in the placebo group, and absolute changes in their levels on ALI, were related to risk of MACE using proportional hazards models. The latter analysis was adjusted for baseline Lp(a) and non-Lp(a) apo B and stratified by baseline Lp(a) (&lt;125 nmol/L and ≥125 nmol/L). Results: Baseline levels of Lp(a) and non-Lp(a) apoB are shown in the Table . In the placebo group, both baseline Lp(a) and non-Lp(a) apo B independently predicted MACE. At M4 in the ALI group, median Lp(a) change from baseline was -40.9 and -7.0 in those with baseline levels ≥ or &lt;125 nmol/L, respectively. Corresponding median changes in non-Lp(a) apoB were -739 and -776 nmol/L (all P&lt;0.001). In the ALI group with baseline Lp(a)&gt;125 nmol/L, the decrease from baseline in Lp(a), but not the decrease in non-Lp(a) apo B, was significantly related to risk of MACE. Among those with baseline Lp(a)≤125 nmol/L, the decrease from baseline in non-Lp(a) apo B, but not in Lp(a), with ALI was significantly related to risk of MACE. Conclusions: On a per particle basis, baseline Lp(a) and non-Lp(a) apo B both predicted MACE. Among those with high baseline Lp(a), reduction in MACE with ALI was predominantly associated with reduction of Lp(a); among those with lower baseline Lp(a) reduction in MACE with ALI was predominantly associated with reduction in non-Lp(a) apo-B. Lp(a) may be an important target of treatment with ALI in those with elevated levels after ACS.

PCSK9 Inhibitors: The Evolving Future.

PCSK9 inhibitors are a novel class of medications that lower LDL cholesterol (LDL-C) by increasing LDL receptor activity, promoting clearance of LDL-C from the bloodstream. Over the years, PCSK9 inhibitors have been explored as adjunct therapies to statins or as monotherapy in high-risk cardiovascular patients. This review aims to provide an updated perspective on PCSK9 inhibitors, assessing their clinical efficacy, safety, and significance, especially in light of recent clinical trials. The review examines the role of PCSK9 in cholesterol regulation and summarizes the results of major cardiovascular trials, including FOURIER, SPIRE-1, SPIRE-2, and ODYSSEY Outcomes. It also discusses emerging treatments like small interfering RNA (siRNA) therapies and evaluates PCSK9 inhibitor effects on LDL-C and lipoprotein(a) levels. Clinical trials have shown PCSK9 inhibitors reduce LDL-C by up to 60%. In the FOURIER trial, evolocumab reduced LDL-C by 59% and major cardiovascular events by 15%-20%. The SPIRE-2 trial, despite early termination, showed a 21% risk reduction in the primary composite endpoint with bococizumab. The ODYSSEY Outcomes trial reported a 57% LDL-C reduction with alirocumab, alongside a 15% reduction in adverse events. Emerging treatments like Inclisiran offer long-term LDL-C control with fewer doses. PCSK9 inhibitors are generally well-tolerated, with the most common side effect being injection site reactions. PCSK9 inhibitors significantly lower LDL-C and reduce cardiovascular events, offering promising therapies for high-risk patients, including those with familial hypercholesterolemia (FH) and those who cannot tolerate statins. Future research will focus on optimizing these inhibitors, integrating complementary therapies, and exploring gene-editing technologies to improve patient outcomes.

Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events

Abstract Background Lipid lowering therapy is a key cornerstone in secondary prevention of patients with coronary artery disease. However, only a minority of patients with statin therapy reach LDL thresholds as suggested by the ESC. Ezetimibe, bempedoic acic, and proprotein convertase subtilisin/kexin type 9 (PCSK-9) (synthase-) inhibitors allow for the reduction in LDL-cholesterol in addition to statin therapy. Purpose We aimed to perform a meta-analysis of existing trials, evaluating how lipid lowering therapy beyond statins impacts cardiovascular outcome. In specific, we evaluated the potential influence of duration of follow-up on the association with mortality endpoints. Methods We performed a systematic search using the Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies, evaluating the impact of an intensified lipid lowering therapy via ezetimibe, bempedoic acid, Bococizumab, Alirocumab, Evolocumab, Inclisiran in addition to statin therapy compared to statin therapy alone. Manuscript and congress presentations, published until 1st of August 2023, were included. We made our search specific and sensitive using Medical Subject Headings terms and free text and considered studies published in English language. Search terms used were : "Bempedoic Acid" or "Bococizumab" or "Alirocumab" or "Evolocumab" or "Ezetimibe" or "Inclisiran" and "statin" and "cardiovascular events". Results A total of 123,785 patients from 15 randomized controlled trials (IMPROVE-IT, FOURIER, ODYSSEY Outcomes, ODYSSEY LONG TERM, EWTOPIA 75, PACMAN-AMI, RACING, SIPRE I, SPIRE II, OSLER-1 and OSLER-2, CLEAR HARMONY, CLEAR OUTCOMES, CLEAR SERENITY, CLEAR WISDOM) were included. Treatment with ezetimibe or a PCSK-9 inhibitor was associated with a 19% risk reduction in cardiovascular events (OR [95%CI]: 0.81 [0.75; 0.86]). Effect sizes were similar for myocardial infarction (0.81 [0.74; 0.89]) and even more pronounced for ischemic stroke (0.77 [0.70; 0.84]). In contrast, all-cause mortality was not improved by the intensified lipid lowering therapy (0.99 [0.93; 1.04]). Stratifying by follow-up duration of &amp;lt; vs. ≥ 3 years, no improvement in all-cause mortality was observed in both groups (&amp;lt;3 years: 1.04 [0.93; 1.17]; ≥3 years: 0.97 (0.88; 1.06). No relevant heterogeneity and inconsistency between groups was present in all analyses (detailed data not shown). Conclusion Intensified LDL-lowering therapy with ezetimibe, bempedoic acic or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality. A potential survival benefit was also not observed in studies with follow-up duration of ≥ 3 years.

Reassessing pharmacological trials with positive composite outcome driven by reduction in nonfatal myocardial infarction: a systematic review and meta-analysis

Abstract Background Nonfatal myocardial infarction (MI) inadequately predicts cardiovascular and all-cause mortality in contemporary RCTs. The perceived efficacy of new treatments could be overstated if positivity in composite outcome is primarily attributed to reduction in nonfatal MI. Purpose This study seeks to assess pharmacological RCTs with positive results influenced by nonfatal MI reductions and scrutinize the associated clinical guideline recommendations. Methods Pharmacological RCTs focusing on mortality and nonfatal MI published from 2000 to 2023 were searched in PubMed and Web of Science, with subsequent citation tracking in Web of Science and Google Scholar for candidate RCTs referenced in English-language clinical guidelines. Main outcomes included: 1) relative risk reduction in the composite outcome excluding nonfatal MI; 2) relevant guideline recommendations based on the supporting trials. The impact of nonfatal MI on composite outcome was assessed by using the leave-one-out method. Meta-analysis utilized a random effects model. Results After reviewing 19,825 records, we identified 8 RCTs where positive composite outcomes were driven by reductions in non-fatal MI (Figure 1A). These were divided into three therapeutic groups: anti-thrombotic (3 trials), lipid-lowering (3 trials), and anti-inflammatory (2 trials). In guidelines citing these RCTs, lipid-lowering trials (IMPROVE-IT, FOURIER, CLEAR Outcomes; the latter has not been cited yet; a total of 60 recommendations across 17 guidelines; Figure 2) outperformed anti-thrombotic (27 recommendations across 15 guidelines) and anti-inflammatory trials (3 recommendations in 3 guidelines), with significantly higher Class I (45%) and IIa (33.3%) recommendations, and fewer Class IIb (21.7%) recommendations, compared to anti-thrombotic (0%, 22.2%, 66.7%) and anti-inflammatory (0%, 0%, 100%) trials (Figure 1B). In a meta-analysis of all trials on combined intensive lipid-lowering on top of maximally-tolerated statins (the ODYSSEY OUTCOMES, IMPROVE-IT, and FOURIER trials), the exclusion of nonfatal MI data sustained the negative findings (HR 0.94, 95% CI: 0.88 to 1.01). Conclusions Despite the overestimation of efficacy in certain anti-thrombotic, anti-inflammatory, and lipid-lowering RCTs due to the inclusion of nonfatal MI, lipid-lowering trials, particularly those supporting combined intensive therapy with statins, still receive disproportionately favorable guideline recommendations. This underscores the need to reassess the strength of evidence for these trials in guidelines, advocating for a more equitable and evidence-based approach to cardiovascular guideline recommendations.

Relation of apolipoprotein C3 to risk of major adverse cardiovascular events and death after acute coronary syndrome on a background of optimized statin treatment

Abstract Background Apolipoprotein C3 (ApoC3), a component of triglyceride-rich lipoproteins and some low-density lipoprotein and high-density lipoprotein particles, has been shown to predict incident coronary heart disease (CHD) and major adverse cardiovascular events (MACE). However, it is unknown whether ApoC3 predicts risk in patients with acute coronary syndrome (ACS) receiving contemporary therapies including optimized statin treatment, and if any such association is independent of apolipoprotein B (ApoB) levels. Purpose We assessed the association of ApoC3 with first MACE (CHD death, nonfatal myocardial infarction, fatal or nonfatal ischaemic stroke, or hospitalization for unstable angina) and all-cause death in patients with recent ACS treated with high-intensity or maximum-tolerated statin and blinded PCSK9 inhibitor (alirocumab, ALI) or placebo (PBO). Methods ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months (M4; n=11,176) of treatment with ALI or PBO in the ODYSSEY OUTCOMES trial (which had 18,924 total participants). In continuous and spline analyses adjusted for treatment group and ApoB, we assessed the association of baseline ApoC3 with risk of MACE and death. In the ALI group we determined association of change in ApoC3 from baseline to M4 with risk of MACE and death after M4 in a model adjusted for baseline ApoC3 and ApoB, and the change in ApoB from baseline to M4. Results Median (Q1, Q3) baseline ApoC3 concentration was in a normal range [85 (65, 113) mg/L]. Continuous ApoC3 was not related to MACE (p=0.50) or death (p=0.51); spline analysis showed a slight curvilinear association of baseline ApoC3 with risk of MACE and death, but no clinically meaningful relationship (Figure). Findings were similar in the PBO group alone, and without adjustment for ApoB (data not shown). At M4, the median (Q1, Q3) change from baseline in ApoC3 was -10 (-27, -5; p&amp;lt;0.0001) mg/L with ALI and 2 (-14, 18; P = NS) mg/L with PBO. Overall, ALI significantly reduced the incidence of MACE (10.1% vs 12.1%; p=0.0006) and death (3.5% vs 4.2%; p=0.045) compared with PBO among those with available baseline ApoC3. However, the change in ApoC3 on treatment with ALI did not predict the risk of MACE or death after M4. Findings were qualitatively similar without adjustment for ApoB or its change. Conclusion In a cohort with recent ACS receiving optimized statin therapy and with median baseline ApoC3 in a normal range, ApoC3 did not provide clinically meaningful prediction of cardiovascular events or death. A modest reduction of ApoC3 by ALI did not associate with subsequent risk of MACE or death. It remains uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk.

Plasma levels of human growth differentiation factor 15 (GDF-15) and their effect of alirocumab on major adverse cardiovascular events and all-cause death after acute coronary syndrome

Abstract Background Human growth differentiation factor 15 (GDF-15) is a stress response cytokine of the transforming growth factor-β superfamily with roles in health and disease, cell survival and inflammation, and whose elevated plasma levels impair muscle metabolism and cause cachexia. GDF-15 also may play multiple roles in the pathophysiology of cardiovascular disease. Methods The ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab to placebo added to high-intensity or maximum-tolerated statin in patients post-acute coronary syndrome (ACS). We assessed in &amp;gt;11,000 patients for whom biobank samples were available, the relation between GDF-15 levels (Roche Diagnostics) at baseline and at 4 months with risk of major adverse cardiovascular events (MACE; primary endpoint, comprising coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischaemic stroke, unstable angina requiring hospitalization) and all-cause death, with adjustment for age and sex. Results Median GDF-15 (quartile [Q]1, Q3) at baseline was 1022 (755, 1465) pg/mL and was reduced by a placebo-adjusted median of 22 pg/mL with alirocumab (p=0.0009) at month 4. This lowering of GDF-15 by alirocumab may represent the first such report via pharmacotherapy. In the placebo group, baseline GDF-15 was significantly associated with risks of MACE (Figure Panel A) and death (Panel B). Relative risk reduction with alirocumab did not vary according to baseline GDF-15 levels for MACE (Panel C) and death (Panel D). Four-year MACE absolute risk reduction [ARR (95% CI)] with alirocumab at Q1 and Q3 of baseline GDF-15 was 2.0% (0.1%, 3.9%) and 2.6% (0.2%, 5.0%), respectively. Reduction of GDF-15 with alirocumab at month 4 was not associated with subsequent MACE (p=0.46) but was associated with death (p=0.0009), with greater reductions translating to lower risk. Conclusion In patients with recent ACS, GDF-15 is a strong predictor of both MACE and death. Reduction of GDF-15 with alirocumab at month 4 was not associated with subsequent MACE but was associated with death (p=0.0009), with greater ARR reductions translating to lower risk. Figure. Splines for baseline GDF-15 vs risk of MACE (Panel A; spline p&amp;lt;0.0001) or all-cause death (Panel B; spline p&amp;lt;00001) through 4 years in the placebo group; treatment hazard ratio for MACE (Panel C; spline p=0.52) and all-cause death (Panel D; spline p=0.78). All splines reflect adjustment for age and sexFigure

Safety of the PCSK9 inhibitor alirocumab: insights from 47296 patient-years of observation.

The ODYSSEY OUTCOMES trial, comprising over 47000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared with that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection site reactions. Further, the safety of alirocumab compared with placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study

The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. Women were older, had higher baseline low-density lipoprotein cholesterol (LDL-C) levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes. Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).

Association of LDL-cholesterol

Recent intensive low-density lipoprotein cholesterol (LDL-C) lowering trials, including FOURIER, ODYSSEY OUTCOMES, and Treat Stroke to Target (TST) trials, have mostly refuted the concern surrounding statin use, LDL-C lowering, and intracerebral hemorrhage (ICH) risk. However, the results from these trials may not be fully applied to ICH survivors, as the populations studied were mainly patients without prior ICH, in whom the inherent ICH risk is more than 10 times lower than that of ICH survivors. Although available literature on statin use after ICH has demonstrated no excess risk of recurrent ICH, other potential factors that may modify ICH risk, especially hypertension control and ICH etiology, have not generally been considered. Notably, data on LDL-C levels following ICH are lacking. We aim to investigate the association between LDL-C levels and statin use with ICH risk among ICH survivors, and to determine whether the risk differed with patients' characteristics, especially ICH etiology. Follow-up data of consecutive spontaneous ICH survivors enrolled in the University of Hong Kong prospective stroke registry from 2011 to 2019 were retrospectively analyzed. ICH etiology was classified as cerebral amyloid angiopathy (CAA) using the modified Boston criteria or hypertensive arteriopathy, while the mean follow-up LDL-C value was categorized as <1.8 or ⩾1.8 mmol/L. The primary endpoint was recurrent ICH. The association of LDL-C level and statin use with recurrent ICH was determined using multivariable Cox regression. Pre-specified subgroup analyses were performed, including based on ICH etiology and statin prescription. Follow-up blood pressure was included in all the regression models. In 502 ICH survivors (mean age = 64.2 ± 13.5 years, mean follow-up LDL-C = 2.2 ± 0.6 mmol/L, 28% with LDL-C <1.8 mmol/L), 44 had ICH recurrence during a mean follow-up of 5.9 ± 2.8 years. Statin use after ICH was not associated with recurrent ICH (adjusted hazard ratio (AHR) = 1.07, 95% confidence interval (CI) = 0.57-2.00). The risk of ICH recurrence was increased for follow-up LDL-C <1.8 mmol/L (AHR = 1.99, 95% CI = 1.06-3.73). This association was predominantly observed in ICH attributable to CAA (AHR = 2.52, 95% CI = 1.06-5.99) and non-statin users (AHR = 2.91, 95% CI = 1.08-7.86). The association between post-ICH LDL-C <1.8 mmol/L and recurrent ICH was predominantly observed in CAA patients and those with intrinsically low LDL-C (non-statin users). While statins can be safely prescribed in ICH survivors, LDL-C targets should be individualized and caution must be exercised in CAA patients.

Correction to: Long-Term Efficacy, Safety, and Tolerability of Alirocumab in 8242 Patients Eligible for 3 to 5 Years of Placebo-Controlled Observation in the ODYSSEY OUTCOMES Trial.

Correction to: Long-Term Efficacy, Safety, and Tolerability of Alirocumab in 8242 Patients Eligible for 3 to 5 Years of Placebo-Controlled Observation in the ODYSSEY OUTCOMES Trial.

Two of a kind: mass and molar immunoassay-based lipoprotein (a) concentrations are similarly prognostic for MACE risk and predictive of alirocumab benefit in ODYSSEY OUTCOMES

Abstract Background Lipoprotein (a) (Lp(a)) is a risk factor for incident and recurrent ischemic cardiovascular (CV) events and may modify the benefit of PCSK9 inhibitors (PCSK9i). While Lp(a) concentration can be measured in either mass or molar units, to date there has been no direct, large-scale comparison of the relationships of mass vs. molar Lp(a) with CV risk and response to treatment. Purpose Using samples from ODYSSEY OUTCOMES where 18,924 patients with recent acute coronary syndrome were randomized 1:1 to the PCSK9i alirocumab (ALI) or placebo (PBO), baseline mass vs. molar Lp(a) were compared in terms of prognosis for first major adverse CV event (MACE, consisting of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) in the placebo group and associations with ALI risk reduction. Methods Lp(a) mass and molar tests were the Siemens N latex immunonephelometric test and the Roche TinaQuant immunoturbidimetric assay, respectively. Both tests use polyclonal anti-apo(a) antibodies but are designed to be relatively apo(a)-size independent within allowable measurement uncertainty. Absolute risk of MACE at 4 years in the PBO group and treatment risk ratios (RR) by continuous Lp(a) concentrations were estimated by natural cubic splines from Poisson regression models with log follow-up time as an offset and adjustment for baseline LDL-C. For comparative modeling purposes Lp(a) values were transformed into percentiles; due to ties at the lower limits of quantification, minimum percentiles were 8th and 6th for mass and molar, respectively. All analyses were intention-to-treat. Results Baseline mass and molar Lp(a) concentrations, available in 11943 patients, were correlated (r=0.94). ALI MACE reduction in evaluable patients (1324 events; RR [95% CI] = 0.83 [0.74, 0.92]) was similar to the total population (1955 events; RR [95% CI] = 0.85 [0.78, 0.93]). Relationships with risk of MACE in the PBO group were nearly identical for mass (spline p=0.0001) and molar (spline p=0.0002) concentrations (Figure 1). Of note, the confidence boundaries around the splines were nearly superimposable, indicating similar precision of the estimated Lp(a)-associated risk with both measurement techniques. Risk reductions with ALI were similarly related to mass (spline p&amp;lt;0.0001) and molar (spline p&amp;lt;0.0001) concentrations (Figure 2). Conclusion Baseline mass and molar Lp(a) concentrations were similarly prognostic for MACE risk in the PBO group after adjustment for LDL-C. Mass and molar Lp(a) also similarly modified the ALI treatment effect on MACE, with trends towards less treatment benefit at lower concentrations. These results suggest that, at the treatment group level, the prognostic and predictive value of immunoassay-based Lp(a) tests for ischemic CV events in patients with recent acute coronary syndrome is not meaningfully different for the mass or molar concentration essays that were evaluated.Figure 1Figure 2

Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis

OBJECTIVES: Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies—lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes. DESIGN: Genetic and clinical epidemiology, and experimental models. SETTING: Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis. PATIENTS OR SUBJECTS: Nine human cohorts with sepsis (total n = 12,514) were assessed for an association between sepsis mortality and PCSK9 loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in Pseudomonas aeruginosa and Staphylococcus aureus bacteremia sepsis models, and in lipopolysaccharide-induced animal models. INTERVENTIONS: Observational human cohort studies used genetic PCSK9 LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis. MEASUREMENTS AND MAIN RESULTS: Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic PCSK9 LOF was odds ratio = 0.86 (95% CI, 0.67–1.10; p = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32–1.20; p = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival. CONCLUSIONS: PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.

Abstract 13567: Comparison of Change in Lipoprotein(a) Mass and Molar Concentrations by Alirocumab and Risk of Subsequent Cardiovascular Events in ODYSSEY OUTCOMES

Background: Baseline (BL) lipoprotein(a) (Lp(a)) concentration is similarly related to cardiovascular (CV) risk when measured in either mass or molar units by immunoassay (IA). Because of Lp(a) isoform variation in mass, differences may exist between Lp(a) measurement methods in terms of relating change to risk reduction. We determined whether the reduction in major adverse cardiovascular events (MACE) by PCSK9 inhibitor alirocumab (ALI) had a similar relationship to the reduction in Lp(a) concentration as measured by 3 different methods. Methods: Lp(a) was measured by IA-mass (Siemens), IA-molar (Roche), and mass spectrometry (MS)-molar assays at BL and month 4 (M4) in a subgroup of patients in the ODYSSEY OUTCOMES trial which compared PCSK9 inhibitor ALI with placebo in patients with recent acute coronary syndrome. Changes in Lp(a) from BL to M4 were related to subsequent risk of MACE (coronary heart disease (CHD) death, nonfatal myocardial infarction (NFMI), fatal + nonfatal ischemic stroke, or unstable angina hospitalization) in the ALI group. Proportional hazards models were adjusted for BL Lp(a), BL LDL-C and its change from BL to M4, and other patient characteristics. Hazard ratios (HR) were calculated for the median change of each Lp(a) assay. All analyses were by intention-to-treat. Results: Among 5500 patients randomized to ALI with available data from all 3 Lp(a) assays, 443 experienced a subsequent MACE. Changes in Lp(a) IA-mass and MS-molar concentration were significantly related to reduced MACE risk, while change in IA-molar concentration was marginally significant; associations were more evident with CHD death + NFMI ( Figure ). MACE HRs for median change were similar across tests. Conclusion: With caveats of a modest number of MACE for analysis, moderately elevated Lp(a) levels, and intra-patient variability in serial values, 3 Lp(a) assay methods appeared similarly predictive of ALI MACE reduction.

Abstract 13043: LDL-C, Lp(a) and Hs-CRP Each Predict Future Cardiovascular Events After ACS on High-Intensity Statin Therapy. An Analysis of the ODYSSEY OUTCOMES Trial

Background: Atherosclerotic cardiovascular disease (ASCVD) risk has been jointly associated with levels of LDL cholesterol (LDL-C), lipoprotein [Lp](a)] and the inflammatory marker high-sensitivity C reactive protein (hsCRP). It is unclear whether and to what extent each of these biomarkers predict ASCVD risk after acute coronary syndrome (ACS), particularly in the era of intensive LDL-C lowering. Recent analysis of 3 trials in stable ASCVD patients with hypertriglyceridemia suggested that hsCRP may be a stronger predictor for recurrent events than LDL-C; however, only 52% received high-intensity statin. Methods: The ODYSSEY OUTCOMES trial enrolled post-ACS patients not at goal for atherogenic lipoproteins a median of 2.6 months after ACS and on treatment with maximum tolerated (89% high-intensity) atorvastatin or rosuvastatin. Absolute risk of major adverse cardiovascular events (MACE, the primary composite outcome of coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke or unstable angina hospitalization) and all-cause death were analyzed as a function of baseline LDL-C, hs-CRP, and Lp(a) values in patients randomized to the placebo arm via natural cubic splines from Poisson regression models, adjusted for age, sex, diabetes, BMI, current smoking, and the other 2 predictor variables. Results: Among 9149 evaluable patients, median (Q1-Q3) LDL-C, hsCRP, and Lp(a) were 81 (71-97) mg/dL, 1.7 (0.8-3.9) mg/L, and 21.4 (6.6-60.1) mg/dL, respectively. For each parameter, a higher baseline value was associated with a substantial increase in risk of MACE ( Figure , all spline p&lt;0.0001). LDL-C and hsCRP were associated with all-cause death (p&lt;0.0001), but not Lp(a) (p&gt;0.05). Conclusion: In ACS patients receiving intensive statin therapy and not at goal for atherogenic lipoproteins, LDL-C, hs-CRP, and Lp(a) were independent predictors of MACE. LDL-C and hsCRP were independent predictors of all-cause death.

Lipoprotein(a) and the Effect of Alirocumab on Revascularization After Acute Coronary Syndrome.

Many patients require revascularization after index acute coronary syndrome (ACS). Lipoprotein(a) is thought to play a pathogenic role in atherothrombosis. In ODYSSEY OUTCOMES, alirocumab reduced major adverse cardiovascular events after ACS, with greater reduction among those with higher lipoprotein(a) levels. We explored whether risk of revascularization after ACS was modified by the level of lipoprotein(a) and treatment with alirocumab or placebo. In ODYSSEY OUTCOMES alirocumab was compared with placebo in 18,924 patients with ACS and elevated atherogenic lipoprotein levels despite optimized statin treatment. In this post hoc analysis, treatment effects are summarized using competing risks proportional hazard models. A total of 1559 (8.2%) patients had coronary, 204 (1.1%) had limb, and 40 (0.2%) had carotid revascularization. Alirocumab reduced coronary revascularization (2.8 vs 3.2 events per 100 patient-years; hazard ratio [HR], 0.88 [95% confidence interval (CI), 0.80-0.97]; P=0.01) and any revascularization (3.2 vs 3.7 events per 100 patient-years; HR, 0.85 [95% CI, 0.78-0.94]; P= 0.001). Baseline lipoprotein(a) quartile was directly associated with risk of coronary or any revascularization in the placebo arm and inversely related to treatment HRs (all Pfor trend < 0.01). Alirocumab produced the greatest reduction of coronary revascularization in patients with baseline lipoprotein(a) in the top quartile (≥ 59.6 mg/dL; HR, 0.69 [95% CI, 0.57-0.84]), but no apparent reduction in the bottom quartile (HR, 1.00 [95% CI, 0.82-1.22]). Findings were similar for the effect of alirocumab on any revascularization. Alirocumab reduced revascularization rates after ACS. The risk of revascularization and reduction in that risk with alirocumab were greatest in patients with elevated lipoprotein(a) at baseline.