Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study

Background - The PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low-density lipoprotein-cholesterol (LDL-C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin-associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone. Methods and Results - Patients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL-C target levels were not met. The primary efficacy endpoint was LDL-C percentage change from baseline to W24. Mean baseline LDL-C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n= 59), 154.5 mg/dL (alirocumab 75 mg Q2W, n= 116), and 158.5 mg/dL (placebo, n= 58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least-squares mean LDL-C changes from baseline to W24 were -51.7% and -53.5%, respectively (placebo [+ 4.7%]; both groups P< 0.0001 versus placebo). In total, 63.9% and 70.3% of alirocumab-treated patients achieved their LDL-C targets at W24. Treatment-emergent adverse events occurred in 77.6% (alirocumab 150 mg Q4W), 73.0% (alirocumab 75 mg Q2W), and 63.8% (placebo) of patients, with injection-site reactions among the most common treatment-emergent adverse events. Conclusions - Alirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL-C

Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses

BACKGROUND: Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: Changes in PCSK9, alirocumab, and low-density lipoprotein cholesterol (LDL-C) levels were assessed after treatment with alirocumab at doses of 75 or 150 mg every 2 weeks (Q2W). METHODS: Data were analyzed from 4 phase 3 trials (MONO; COMBO II; FH I; LONG TERM); all but MONO enrolled patients on statins. Three trials evaluated alirocumab 75 mg Q2W, with possible dose increase to 150 mg Q2W at week 12 based on week 8 LDL-C; LONG TERM studied alirocumab 150 mg Q2W. RESULTS: Patients on background statin therapy had higher mean baseline free PCSK9 concentrations vs patients not on statin. After alirocumab administration, increased alirocumab concentrations were associated with dramatic reductions in circulating free PCSK9, resulting in significant LDL-C reductions and a corresponding increase in inactive PCSK9:alirocumab complex. Alirocumab dose increase was associated with a further lowering of PCSK9 and LDL-C. Patients with higher baseline LDL-C levels (>160 mg/dL) were more likely to have their dose increased. LDL-C reductions with alirocumab were consistent between patients with baseline PCSK9 levels above or below the median when the dose increase strategy was used. When started as alirocumab 150 mg Q2W, patients with PCSK9 levels above vs below the median had a greater LDL-C reduction. CONCLUSIONS: Alirocumab-induced changes in PCSK9 and LDL-C levels were consistent with the known physiologic relationship between PCSK9, LDL receptor, and LDL-C levels, as well as statin-induced increases in PCSK9 production. (C) 2019 National Lipid Association. Published by Elsevier Inc.Peer reviewe

Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events : The ODYSSEY OUTCOMES Trial

The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS

Dairy calves' personality traits predict social proximity and response to an emotional challenge

Abstract The assessment of individual traits requires that tests are reliable (i.e. consistency over time) and externally valid, meaning that they predict future responses in similar contexts (i.e. convergent validity) but do not predict responses to unrelated situations (i.e. discriminant validity). The aim of this study was to determine if dairy calf personality traits (Fearfulness, Sociability and Pessimism), derived from behaviours expressed in standardized tests, predict individuals’ responses in related situations. The first experiment tested if the trait ‘Sociability’ was related to the expression of social behaviour in the home-pen, with calves assigned individual proximity scores (based on proximity to other calves) while they were in their home-pen at approximately 113 and 118 d of age. The second experiment aimed at exploring whether traits ‘Fearfulness’ and ‘Pessimism’ were related to the calves’ emotional response to transportation. All calves were subjected to two 10-min transportation challenges done on two consecutive days. Emotional response was assessed using the maximum eye temperature (measured using infrared thermography) and the number of vocalizations emitted. Social proximity scores (Experiment 1), vocalizations emitted and maximum eye temperature after loading (Experiment 2) were consistent over time. In addition, the results showed good convergent validity with calves scoring higher in Sociability also having higher proximity scores in the home-pen, and animals scoring higher in Fearfulness and Pessimism showing a more intense emotional response to transportation. The results also showed good discriminant validity, as neither Fearfulness nor Pessimism were associated with the expression of social behaviours (Experiment 1) and Sociability was not associated with the animal’s emotional response to transportation (Experiment 2). We conclude that the methodology used to measure personality traits shows good reliability and external validity

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Organic Dairy Cattle: Do European Union Regulations Promote Animal Welfare?

Animal welfare is an emerging concept in EU law; with the advent of specific regulations intending to protect animals. The approach taken by European lawmakers is to provide “minimum standards” for conventional farming; argued by some as failing to adequately protect animals. In contrast, the EU organic farming regulations aim to “establish a sustainable management system for agriculture” and promote “high animal welfare standards”. The first aim of this review was to identify key areas where there are clear improvements in quality of life for dairy cattle housed under the EU organic regulations when compared to the conventional EU regulations. Using the available scientific evidence, our second aim was to identify areas where the organic regulations fail to provide clear guidance in their pursuit to promote high standards of dairy cattle welfare. The greater emphasis placed on natural living conditions, the ban of some (but unfortunately not all) physical mutilations combined with clearer recommendations regarding housing conditions potentially position the organic dairy industry to achieve high standards of welfare. However, improvements in some sections are needed given that the regulations are often conveyed using vague language, provide exceptions or remain silent on some aspects. This review provides a critical reflection of some of these key areas related to on-farm aspects. To a lesser extent, post farm gate aspects are also discussedLand and Food Systems, Faculty ofNon UBCReviewedFacultyResearche

Individual Variability in Response to Social Stress in Dairy Heifers

Regrouping is associated with increased aggression, and disruption of time-budgets. Individuals vary in how well they cope with social stress. Our objective was to describe individual differences in agonistic behavior in dairy heifers after regrouping, and determine how time-budget and behavioral synchronization were affected by these coping strategies. A total of 30 heifers were individually regrouped at 5-months of age into stable groups of 12 unfamiliar animals. For 24 h, agonistic behaviors initiated and received by the regrouped heifer were continuously recorded, and standing, resting and feeding time and synchronization were sampled every 5 min. Scores of engagement in agonistic interactions and avoidance of interactions were calculated for each regrouped heifer. Linear mixed effects models were used to assess whether these two response types were related, and how variation in these responses related to activity and synchronization. Engaged heifers displayed lower avoidance and spent more time feeding. Avoidant heifers spent less time feeding and resting, and were less synchronized while feeding. We conclude that dairy heifers differ in social coping strategy when regrouped through different levels of engagement and avoidance, and that these differences affected their time-budget and behavioral synchronization.Land and Food Systems, Faculty ofReviewedFacult

Postpartum Stressors Cause a Reduction in Mechanical Brush Use in Dairy Cows

Dairy cows are often subjected to multiple post-partum stressors but how these stressors impact cows’ affective states remain poorly understood. Negative affective states are often associated with reduced expression of low-resilience behaviors, so we explored whether cows would reduce their use of a brush after calving. Before calving, cows were offered the opportunity to use a mechanical brush once a week for 10 min. In Experiment 1, we explored whether cows reduced their use of a mechanical brush after parturition (compared to prepartum values) when subjected to the myriad of stressors typically experienced by cows at this time. In Experiment 2, we assessed the effect of cow–calf separation. Results from Experiment 1 showed that cows displayed a reduced brush use following parturition compared to the week before calving. In Experiment 2, we showed that cows given more time to bond with their calf, and who were separated more recently from their calf, showed a more pronounced reduction in brush use. Cows provided part-time contact with their calf for 29 days also reduced their brush use when they were permanently separated from their calf on day 30 after calving. These results suggest that cows experienced anhedonia and point to new directions for research on dairy cow affective states.Land and Food Systems, Faculty ofReviewedFacult

Pessimistic dairy calves are more vulnerable to pain-induced anhedonia.

Pain induces deficits in appreciation of rewards (i.e. anhedonia) and variation in response to pain may be partly explained by individual differences in general expectations (i.e. optimism). Dairy calves are routinely subjected to painful procedures such as hot-iron disbudding. We tested if female Holstein calves (n = 17) display signs of anhedonia (as evidenced by reduced consumption of a sweet solution) after hot-iron disbudding (performed under general and local anesthesia), and whether individual differences in optimism explain the variation in this response. Individual variation in optimism was measured using responses to two judgment bias tests (performed when calves were 25 d old), and anhedonia was measured by comparing consumption of a sweet solution before and after hot-iron disbudding. We found that intake of the sweet solution declined (by mean ± SD: 48.4 ± 44.3%) on the day after disbudding, and that more pessimistic calves were more affected. Sweet solution consumption did not return to baseline for the duration of the study (i.e. 5 days). Calves reduced their intake of a sweet solution after hot-iron disbudding, consistent with pain-induced anhedonia, and more pessimistic calves showed stronger evidence of anhedonia, suggesting that they were more affected by the procedure. However, our results cannot rule out the possibility that calf responses were driven by anorexia