Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

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

Efecto de oligofructosa de agave en dietas de gallinas ponedoras en la producción de huevos

ABSTRACT Objective. To determine egg production in laying hens treated with oligofructose from agave. Materials and methods. Eighteen weeks old Hy-line W-36 hens (n = 300) were distributed randomly into 3 treatment groups: no feed supplementation (control) or feed supplementation with 0.1% of 0.2% oligofructose from agave (OFA). Hens were monitored from development until 30 weeks of egg laying. Results. A significant (p<0.05) increase in the percent of egg-laying hens as well as increased in egg weight and egg quality occurred in hens from the OFA treatment groups relative to the control hens. Significantly lower levels (p<0.05) of fecal putrescine were observed in hens from the OFA treatment groups. Conclusions. The oligofructose from agave may be used as an alternative feed additive in laying hens.RESUMEN Objetivo. Determinar la producción de huevos en gallinas tratadas con oligofructosa de agave (OFA). Materiales y métodos. Se utilizaron 300 gallinas de la línea genética Hy-line w-36, de 18 semanas de nacidas, distribuidas aleatoriamente en tres tratamientos con cuatro repeticiones de 25 gallinas cada uno. Los tratamientos consistieron en tres niveles de OFA, 0, 0.1 y 0.2% en alimento. La prueba duró desde las 18 hasta las 30 semanas de postura. Resultados. Se presentó un incremento significativo (p<0.05) en el porcentaje de postura y peso del huevo, así como en índices de calidad del huevo a favor de tratamientos con OFA. Se encontraron valores significativamente (p<0.05) más bajos de putrescina fecal en las gallinas tratadas con OFA. Conclusiones. El uso de la OFA en gallinas ponedoras puede ser una alternativa como aditivo en la alimentación

Frequency of canine degenerative myelopathy SOD1: c.118G>A mutation in 22 dog breeds in Guadalajara, Mexico

Abstract Background: Canine degenerative myelopathy (DM) is a late-onset disease that primarily affects large-breed dogs. The disease involves the spinal cord and produces progressive paresia and, eventually, complete loss of mobility. DM has been related to missense mutation c.118G>A in the SOD1 gene. Objective: To determine the genotypic and genic frequencies of DM in Mexico. Methods: In total, 330 samples from 22 different dog breeds were genotyped using the polymerase chain reaction and restriction fragment length polymorphisms (PCR-RFLP) technique. Results: The mutation was identified in 71 animals from 11 different breeds. Observed genic frequencies were 0.78 for the G allele and 0.14 for the A allele. Genotypic frequencies were 0.79 for the G/G wild-type, 0.14 for the G/A heterozygote, and 0.7 for the A/A homozygote. Conclusion: The genic frequency of this allele is high among the studied populations. A molecular marker program that identifies the DM mutation in breeding dogs should be implemented in order to reduce this frequency.Resumo Antecedentes: A mielopatía degenerativa canina (MD) é uma doença progressiva de apresentação tardia que afeta a medula espinal geralmente de caninos de raças grandes e que produz paresia progressiva e eventualmente a perda completa da mobilidade. Tem sido relacionada com uma mutação pontual por substituição de bases no gen SOD1, recentemente identificado como c.118G>A. Objetivo: Determinar as frequências genotípicas e genéticas para a apresentação de DM no México. Métodos: Genotipagem de 330 amostras de cães de 22 raças por meio da técnica de reação em cadeia da polimerase e polimorfismos no comprimento de fragmentos de restrição (PCR- RFLPs). Resultados: A mutação foi identificada em 71 animais de 11 raças diferentes. As frequências gênicas encontradas foram de 0,78 para o alelo G e de 0,14 para o alelo A. As frequências genotípicas foram de 0,79 para o tipo silvestre G/G, 0,14 para o heterozigoto G/A e 0,7 para o homozigoto A/A. Conclusão: A frequência encontrada para a mutação é alta nas populações estudadas. A implementação de um programa de seleção assistida por marcadores moleculares contra a mutação que causa MDC seria útil para reduzir a sua frequência.Resumen Antecedentes: La mielopatía degenerativa canina (MD) es una enfermedad progresiva de presentación tardía que afecta a la médula espinal, generalmente en caninos de razas grandes, y que produce paresis progresiva y eventual pérdida completa de la movilidad. Se ha relacionado con una mutación puntual por sustitución de bases en el gen SOD1 recientemente identificado como c.118G>A. Objetivo: Determinar las frecuencias genotípicas y génicas para la presentación de DM en México. Métodos: Se genotipificaron 330 muestras de perros de 22 razas mediante la técnica de reacción en cadena de la polimerasa y polimorfismos de longitud de fragmentos de restricción (PCR- RFLPs). Resultados: Se identificó la mutación en 71 animales de 11 razas diferentes. Las frecuencias génicas encontradas fueron de 0,78 para el alelo G y de 0,14 para el alelo A. Las frecuencias genotípicas fueron de 0,79 para el tipo silvestre G/G, 0,14 para el heterocigoto G/A y 0,7 para el homocigoto A/A. Conclusión: La frecuencia encontrada para la mutación es alta en las poblaciones estudiadas. La aplicación de un programa de selección asistida por marcadores moleculares contra la mutación causante de MDC en perros reproductores resultaría útil para reducir su frecuencia

Frequency of canine degenerative myelopathy SOD1:c.118G>A mutation in 22 dog breeds in Guadalajara, Mexico

Abstract Background: Canine degenerative myelopathy (DM) is a late-onset disease that primarily affects large-breed dogs. The disease involves the spinal cord and produces progressive paresia and, eventually, complete loss of mobility. DM has been related to missense mutation c.118G>A in the SOD1 gene. Objective: To determine the genotypic and genic frequencies of DM in Mexico. Methods: In total, 330 samples from 22 different dog breeds were genotyped using the polymerase chain reaction and restriction fragment length polymorphisms (PCR-RFLP) technique. Results: The mutation was identified in 71 animals from 11 different breeds. Observed genic frequencies were 0.78 for the G allele and 0.14 for the A allele. Genotypic frequencies were 0.79 for the G/G wild-type, 0.14 for the G/A heterozygote, and 0.7 for the A/A homozygote. Conclusion: The genic frequency of this allele is high among the studied populations. A molecular marker program that identifies the DM mutation in breeding dogs should be implemented in order to reduce this frequency

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUND Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-highdensity lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS Among patients who had a previous acute coronary syndrome and who were receiving highintensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo

Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol

Background: Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives: In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods: ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions: In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402

Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial

Background: After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4–1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. Methods: ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1–12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65–1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)—defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose—and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402. Findings: At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20–2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25–2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78–2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65–2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, −0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89–1·11). HRs were 0·97 (95% CI 0·87–1·09) for patients with prediabetes and 1·30 (95% CI 0·93–1·81) for those with normoglycaemia (pinteraction=0·11). Interpretation: After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65–1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes. Funding: Sanofi and Regeneron Pharmaceuticals

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

Background: 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. Methods: 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. Results: 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). Conclusions: 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. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUN