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

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

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

Importancia del tiempo de suspensión del uso combinado de aspirina y clopidogrel en pacientes sometidos a cirugía de revascularización coronaria

El uso combinado de aspirina y clopidogrel en pacientes con síndromes isquémicos coronarios agudos es la práctica habitual. Lo anterior incrementa el riesgo de sangrado perioperatorio de cirugía de revascularización coronaria (CRC). Este estudio fue diseñado para evaluar el efecto de la terapia antiplaquetaria en la evolución perioperatoria de pacientes sometidos a CRC. Se estudiaron 49 pacientes consecutivos y se compararon dos grupos: grupo A, los que habían suspendido el tratamiento antiplaquetario 6 o más días antes de la cirugía y, grupo B, aquellos que lo recibieron en los últimos 5 días antes de la intervención o no lo suspendieron. Los grupos fueron comparables en sus características demográficas, padecimiento actual, uso pre y postoperatorio de medicamentos, y características de la intervención. Se encontró una tendencia a la mayor frecuencia de complicaciones cardiovasculares postoperatorias (punto final cardiovascular primario) en el grupo que suspendió los antiplaquetarios 6 o más días antes de la cirugía (grupo A 12%, grupo B 8%; p = 0.923). El punto final de sangrado fue significativamente mayor en el grupo B, que continuó el tratamiento antiplaquetario en los 5 días previos a la cirugía (grupo A 4%, grupo B 29%; p = 0.023), al igual que la necesidad de trasfusiones de hemoderivados. Concluimos que la combinación de aspirina y clopidogrel previo a la cirugía de revascularización coronaria se asocia con mayor sangrado y morbilidad; aunque la tendencia parece favorable a los que continuaron con los antiplaquetarios, no hubo diferencia en la evolución cardiovascular

A systematic review and meta-analysis of <it>Toxoplasma gondii</it> infection among the Mexican population

<p>Abstract</p> <p>Background</p> <p>Toxoplasmosis is a disease caused by <it>Toxoplasma gondii</it> and at least one-third of the world’s population has detectable <it>T. gondii</it> antibodies. The seroprevalence of <it>T.gondii</it> ranges from 15% to 50% among the Mexican general population. The aim of this work was to determine the mean prevalence and weighted mean prevalence of <it>T. gondii</it> infection, and to evaluate the epidemiological transition of infection in Mexico.</p> <p>Methods</p> <p>Pub Med, Lilacs, Medline, Latindex, Google Scholar data bases were searched to retrieve reports from 1951 up to 2012 regarding prevalence data, diagnostic tests and risk factors of infection among the adult population. Data collection and criteria eligibility was established in order to determine the crude prevalence (proportion of positive cases) of each study, together with weighted population prevalence according to individual research group categories to limit the bias that may impose the heterogeneous nature of the reports. A Forest Plot chart and linear regression analysis were performed by plotting the prevalence of infection reported from each study over a period of sixty years.</p> <p>Results</p> <p>A total of 132 studies were collected from 41 publications that included 70,123 individuals. The average mean prevalence was 27.97%, and weighted mean prevalence was 19.27%. Comparisons among different risk groups showed that the weighted prevalence was higher in women with miscarriages (36.03%), immunocompromised patients (28.54%), mentally-ill patients (38.52%) and other risk groups (35.13%). <it>Toxoplasma</it> infection among the Mexican population showed a downward trend of 0.1%/year over a period of sixty years that represents a 5.8% reduction in prevalence.</p> <p>Conclusions</p> <p>This analysis showed a downward trend of infection; however, there are individuals at high risk for infection such as immunocompromised patients, mentally-ill patients and pregnant women. Further research is required to provide better prevention strategies, effective diagnostic testing and medical management of patients. Educational efforts are required to avoid the transmission of infection in populations that cannot be controlled by drugs alone.</p