Practice Update: Cardiology

AHA 2016 27

Reconstituted apolipoprotein A-I CSL112 enhances cholesterol efflux after acute MI The reconstituted, infusible, plasma-derived apolipoprotein A-I has been shown to enhance cholesterol efflux after acute myocardial infarction, with no significant alterations in liver or kidney function or other safety concerns reports the Apo-I Event Reducing in Ischaemic Syndromes I (AEGIS-I) trial. M ichael Gibson, MS, MD, of Beth Israel Deaconess Medical Center, Boston, all four infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%.

The novel finding that low- molecular-weight heparin acutely modified the endothelial function of pregnant women at high risk of preeclampsia supports the rationale tomount an adequately powered trial to determine the effectiveness of low-molecular-weight heparin for prevention of early-onset preeclampsia inwomen at highest risk. assessments. High-risk women were then randomised to low- molecular-weight heparin or saline placebo (30 mg IV bolus and 1 mg/kg subcutaneous dose, respectively). Cardiovascular function was assessed 1 and 3 h post randomisation. In vitro endothelial effects of patient serum and exogenous low-molecular-weight heparin on human umbilical venous endothelial cells were determined. High-risk women demonstrated reduced cardiac output and a high-resistance haemodynamic profile with impaired radial artery flow-mediated dilation versus controls. Low-molecular- weight heparin increased flow-mediated dilation in high-risk women 3-h following randomisation versus baseline and increased plasma levels of placental growth factor, soluble fms-like tyrosine kinase-1, and myeloperoxidase. Serum from high-risk women impaired endothelial cell angiogenesis and increased placental growth factor-1 and -2 transcription versus serum from low-risk controls. Coexposure of high-risk serum with low-molecular-weight heparin improved the in vitro angiogenic response such that it was equivalent to that of low-risk serum and promoted placental growth factor secretion. Dr Kingdom concluded that in vivo and in vitro findings demonstrated that pregnant women at high-risk of preeclampsia demonstrate significant cardiovascular abnormalities versus low-risk women at 24 weeks of gestation. The study provided the first human documentation that low-molecular-weight heparin acutely modifies the endothelial function and circulating angiogenic proteins of pregnant women at high- risk of preeclampsia. In parallel, in vitro endothelial function was also influenced by low-molecular-weight heparin, with significant angiogenic responses and effects on placental growth factor secretion. Placental growth factor may help mediate endothelial function in pregnant women. The novel finding that low-molecular-weight heparin acutely modified the endothelial function of pregnant women at high risk of preeclampsia supports the rationale to mount an adequately powered trial to determine the effectiveness of low-molecular-weight heparin for prevention of early- onset preeclampsia in women at highest risk. Early-onset preeclampsia can be predicted with reasonable accuracy by the second trimester with multiparameter screening, providing an opportunity to initiate preventative therapies prior to the onset of clinical symptoms.

assachusetts, explained that human or recombinant apolipo- protein A-I has been shown to increase high-density lipoprotein – mediated cholesterol efflux capacity and to regress atheroscle- rotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apolipoproteinA-I that has been studied in normal subjects or those with stable coro- nary artery disease. AEGIS-I was a multicentre, randomised, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomised 1:1:1 to CSL112 (2 g apolipoprotein A-I per dose) and high-dose CSL112 (6 g apolipoprotein A-I per dose), or placebo for four consecutive weekly infusions. Coprimary safety endpoints were the occurrence of either a hepatic safety event (an increase in alanine transaminasemore than three times the upper limit of normal or an increase in total bilirubinmore than twice the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement of renal replacement therapy). A total of 1258 patients were randomised, and 91.2% received

Similarly, the difference in incidence rates of an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol- defined noninferiority margin of 5%. CSL112 was associated with increases in apolipoprotein A-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. With regard to the secondary efficacy endpoint, the risk for the composite of major adverse cardiovascular events among the groups was similar. Dr Gibson concluded that among patients with acute myocardial infarction, four weekly infusions of CSL112 were shown to be feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial.

DECEMBER 2016