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

Different herbivore responses to two co-occurring chemotypes of the wild crucifer Barbarea vulgaris

Christensen S, Enge S, Munk KR, et al. Different herbivore responses to two co-occurring chemotypes of the wild crucifer Barbarea vulgaris. Arthropod-Plant Interactions. 2019;13(1):19-30.According to coevolution theory, plant chemical defences are continually evolving in response to selection by herbivores. Unique to the Brassicales, a few species in the Barbarea genus produce triterpenoid saponins that are highly deterrent to some specialist insect herbivores. One species, B. vulgaris, has diverged into two chemotypes, the G- and P-type, of which the P-type seems to have lost the saponin-based insect resistance by producing different saponin structures; it also produces different glucosinolates and other potential defence traits. Here, we examined the preference and performance of a larger set of specialist and generalist herbivores on the two plant types, including three generalist mollusc (Arion vulgaris, Deroceras sp., Cepaea sp.) as well as three specialist (Phaedon cochleariae, Athalia rosae, Pieris napi oleraceae) and two generalist (Mamestra brassicae, Myzus persicae) insect herbivores. Five out of six herbivore species preferred leaves of the P-type for feeding, and most of them also survived and/or grew better on the P-type, or preferred it for oviposition. In contrast, larvae of M. brassicae showed no preference and performed equally well on the two plant types; the leaf beetle P. cochleariae preferred the G-type for oviposition, which was, however, not reflecting larval performance. Overall, the defences of the P-type against herbivores seem not to be as effective as those of the G-type, which is surprising given its large geographical distribution, overlapping with that of the G-type in Scandinavia and Finland. This suggests that additional ecological interactions determine the success of the two chemotypes

Changes in the diagnosed incidence of early onset schizophrenia over four decades

Objective: To explore changes in the diagnosed incidence of early onset schizophrenia (EOS) from 1971 to 2010. Method: Examination of incidence rates of schizophrenia in patients under 18 years of age, using a nationwide, population-based, mental health register. Results: The age-standardized incidence rate (IR) of EOS in the period 19712010 was 3.17 (95% CI: 3.16, 3.18) per 100 000 person years in the age group 018 years, and 9.10 (95% CI: 9.00, 9.21) in the age group 1218 years. In the period 19711993, the age-standardized IR of EOS was 1.80 (95% CI: 1.79, 1.82) per 100 000 person years in the age group 018 years, and 5.02 (95% CI: 4.92, 5.11) in the age group 1218 years. In the period 19942010, the age-standardized IR of EOS was 5.15 (95% CI: 5.10, 5.20) per 100 000 person years in the age group 018 years, and 15.73 (95% CI: 15.22, 16.22) in the age group 1218 years. The IR was higher for males than females in the periods 19711993 and 19712010, but in the period 19942010 the IR was higher for females than males. Conclusion: In recent years, the diagnosed incidence of EOS has increased and the usual male excess has disappeared. The changes in IR could be a result of changes in the diagnostic system, increased awareness of early psychosis or a reflection of actual underlying incidence of the disorder