Search

Objectives: The objective of this study is to report the dose response in ODYSSEY phase 3 clinical trials of proprotein convertase subtilisin kexin type 9 inhibition with alirocumab in patients not at prespecified lipid goals who received a per-protocol dose increase from 75 every 2 weeks (Q2W) to 150 mg Q2W. Methods: Patients (n=2181) receiving statins were enrolled in six phase 3 randomized, double-blind, double-dummy trials (24–104 weeks): alirocumab versus placebo or ezetimibe 10 mg/day. The 75 mg subcutaneous Q2W dose was increased to 150 mg at week 12 if week 8 LDL cholesterol (LDL-C) was greater than or equal to 70 mg/dl (>100 mg/dl in OPTIONS studies for patients without previous coronary heart disease, but with other risk factors). LDL-C percentage reductions from baseline (on-treatment data, n=1291) were compared at week 12 versus week 24. Results: Most patients (n=951; 73.7%) with 75 mg Q2W dose plus background statin achieved LDL-C less than 70 or less than 100 mg/dl at week 8. In 340 (26.3%) patients, alirocumab dose was increased to 150 mg Q2W at week 12, and 60.9% of these patients achieved LDL-C goals at week 24, with an additional 14.2% reduction in LDL-C from week 12 to week 24. Adverse event rates were comparable in patients with versus without a dose increase (72.4 vs. 71.8% in placebo-controlled trials; 67.0 vs. 67.6% in ezetimibe-controlled trials). Conclusion: Most patients achieved LDL-C goals with alirocumab 75 mg Q2W plus statins. Of those (26.3%) receiving a dose increase, 60.9% achieved LDL-C goals at week 24 with an additional 14.2% reduction in LDL-C.

Background: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein–mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. Methods: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times 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 for renal replacement therapy). Results: A total of 1258 patients were randomized, and 91.2% received all 4 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%. Similarly, the difference in incidence rates for 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 apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. Conclusions: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are 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. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.

Until recently, patients with heterozygous familial hypercholesterolemia (HeFH) were considered the best subjects for the assessment of changes in carotid intima-media thickness (cIMT) in randomized intervention trials. Our aims were to investigate whether contemporary statin-treated HeFH patients still show accelerated cIMT increase and to assess the impact of statin treatment, before and after random assignment, on atherosclerosis progression.We retrospectively evaluated cIMT change, and prior statin treatment and postbaseline LDL-C change as predictors of cIMT change, in 1513 HeFH patients who were randomly assigned to the statin arms of the early ASAP and more recent RADIANCE 1, CAPTIVATE, and ENHANCE studies. In the 3 recent studies combined, mean cIMT increased at only 33% of the rate of the simvastatin-treated patients in the ASAP study (0.014 mm/2 years [95% confidence interval, -0.0003-0.028] versus 0.041 mm/2 years [95% confidence interval, 0.020-0.061]; P<0.05). Patients whose statin therapy could be intensified, as evidenced by an LDL-C decrease after the initiation of on-trial statin therapy, showed cIMT decrease in the first 6 to 12 months and a much lower cIMT increase measured over the full 2 years. In line with this, previously statin-naive HeFH patients showed a lower overall cIMT increase.Over the years, intensification of statin therapy in HeFH patients has resulted in an impressive decrease in carotid atherosclerosis progression. In studies that assess other antiatherosclerotic modalities, statin therapy may still induce rapid changes in cIMT. For future cIMT studies, our analyses suggest that patient populations other than intensively pretreated HeFH patients should be selected and that the statin regimen should not be changed on study initiation. [ABSTRACT FROM AUTHOR]

The article investigates whether prolactin levels are associated with the occurrence of coronary artery disease (CAD). The method involves a nested case control study among healthy individuals aged 45 to 79 who developed fatal or non fatal CAD. Results suggest that elevated systemic prolactin levels do not predict CAD in the general population although prolactin receptors were found in human atherosclerotic plaques that may indicate a role for prolactin in atherosclerotic plaque development.