Eli M. Roth

Time course, magnitude, and consistency of platelet inhibition by abciximab, tirofiban, or eptifibatide in patients with unstable angina pectoris undergoing percutaneous coronary intervention

Adjunctive platelet glycoprotein IIb/IIIa blockade during percutaneous coronary intervention (PCI) reduces platelet-mediated adverse ischemic outcomes. Although abciximab, eptifibatide, and tirofiban have received U.S. Food and Drug Administration approval for use, these agents differ in their pharmacodynamic profiles. Each of these agents has been compared in randomized trials with placebo for patients undergoing PCI, but no randomized comparative studies of these agents have been performed. We compared ex vivo platelet function by both standard light transmission aggregometry and rapid platelet function assay during and after administration of abciximab, eptifibatide, or tirofiban in approved dose regimens on a randomized basis at the time of PCI in patients with unstable angina pectoris. A reduced intensity of platelet inhibition by light transmission aggregometry was observed for tirofiban compared with either eptifibatide or abciximab. In addition, the 30-minute bolus strategy used for tirofiban was associated with delayed onset of maximal platelet inhibition relative to the initiation of bolus infusion. Whether the trends in platelet function observed in this study will be translated into differences in clinical outcomes awaits definition by larger scale randomized clinical trials comparing these platelet glycoprotein IIb/IIIa inhibitors.

Efficacy of abciximab induced platelet blockade using a rapid point of care assay.

Anciximab provides potent, but variable degrees of platelet inhibition both during the duration of intravenous administration and at 12 hours following therapy. Platelet function was assessed using the PC-RPFA system in 78 patients scheduled for percutaneous coronary revascularization who were administered the standard abciximab weight-adjusted bolus and 12-hour infusion. The PC-RPFA system is a cartridge-based, semiautomated point-of-care whole-blood assay that incorporates fibrinogen-coated polystyrene beads, buffers, and a modified thrombin receptor activating peptide (Isotrap) in lyophilized form. The instrument detects the agglutination rate between the stimulated platelets and the fibrinogen-coated beads, and provides a quantitative digital display in less than 2 minutes. No differences in the level of platelet inhibition were observed in these abciximab-treated patients by diabetic status, gender, smoking, diagnosis (unstable angina, chronic stable angina, recent myocardial infarction), or abciximab treatment status (first time vs. retreatment). Nocorrelation of the PC-RPFA rate of platelet aggregation with clinical demographic factors was observed, with the exception of baseline hematocrit (r2 = 0.4556). The relationship between the PC-RPFA rate of aggregation and hematocrit reflects light absorbance by erythrocytes and is specific to the PC-RPFA system. The absolute rate of platelet aggregation (slope) reported by the PC-RPFA is correlated with percent aggregation, thus making it potentially possible to predict the level of aggregation without reference to a baseline (pretreatment) measure of platelet function. This correlation was closest for patients having <40% baseline aggregation (r2 = 0.55). Thus, PC-RPFA provides a rapid point-of-care assessment of platelet function that could allow for adjustment of abciximab dosing to achieve targeted levels of platelet inhibition. The utility of this device to optimize therapy with platelet glycoprotein IIb/IIIa inhibitors is currently being evaluated.

ODYSSEY MONO: effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks

ABSTRACT  Alirocumab is a fully human monoclonal antibody to PCSK9. The ODYSSEY MONO study was the first alirocumab Phase III study to test a previously unused dose of 75 mg subcutaneously every 2 weeks in a population on no lipid-lowering therapy. A total of 103 patients were randomly assigned to alirocumab starting at 75 mg subcutaneously every 2 weeks or ezetimibe 10 mg per os every day with alirocumab dose uptitration at 12 weeks based on achieved LDL-cholesterol level at week 8 and followed to week 24. At the week-24 primary end point, the alirocumab intent-to-treat group showed a 47.2% (least square [LS] mean) reduction in LDL-cholesterol compared with a 15.6% (LS mean) reduction with ezetimibe (LS mean difference of 31.6%; p < 0.0001). Safety parameters and adverse events were similar between the two groups.

Antidrug Antibodies in Patients Treated with Alirocumab

In 10 clinical trials involving 4747 patients, among those who received the PCSK9 inhibitor alirocumab, antidrug antibodies developed in 5.1%, although no significant effect was seen on the reduction in LDL cholesterol levels.

Alirocumab for hyperlipidemia: ODYSSEY Phase III clinical trial results and US FDA approval indications

A new class of lipid-lowering drugs, inhibitors of PCSK9 has been generating impressive clinical trial data over the last several years, and alirocumab (Praluent) has become the first to be approved by the US FDA. Alirocumab has been shown to lower low density lipoprotein cholesterol by 45-62% with a safety profile generally comparable to placebo. Alirocumab is a monoclonal antibody to PCSK9 administered subcutaneously and has been evaluated in 16 Phase III clinical trials, the majority of which have been enrolled or completed. This article will be a review of the available Phase III safety and efficacy data of the ODYSSEY studies including a brief description of each of the 16 studies.

High Platelet Count in Platelet-Rich Plasma Reduces Measured Platelet Inhibition by Abciximab but not Tirofiban nor Eptifibatide Glycoprotein IIb/IIIa Receptor Antagonists

We evaluated the differential effect of platelet count in platelet-rich plasma (PRP) on the level of ex vivo inhibition of platelet aggregation provided by abciximab, eptifibatide, and tirofiban as part of a randomized, comparative trial of these agents on platelet function in patients with unstable angina pectoris undergoing percutaneous coronary intervention. Platelet count <350 K/µL in PRP reduced measured platelet inhibition by abciximab, but not eptifibatide nor tirofiban. This observation suggests the need for standardized, uniform platelet counts in PRP during future comparisons of the degree of platelet inhibition by these agents.

Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

Abstract Background. Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is in Phase III development for the treatment of hypercholesterolemia. In Phase II studies, 150 mg every 2 weeks (Q2W) was the highest Q2W dose studied, and it is currently the highest Q2W dose under development. To better assess the safety and efficacy of this dose, data across three Phase II studies were pooled. Methods. We analyzed data from three double-blind, randomized, placebo-controlled Phase II studies of 8 or 12 weeks’ duration. In the current analysis, 77 patients were randomized to the control group and 108 were randomized to alirocumab 150 mg Q2W administered via a single 1 mL subcutaneous injection. Results. Adverse events (AEs) occurred in 58.3% of alirocumab patients compared with 54.5% of placebo-controlled patients. The most common AE was mild, transient injection-site reactions. No signal for muscle symptoms such as myalgia and no cases of neurocognitive effects were reported or observed. One alirocumab patient, also receiving atorvastatin 80 mg/day, had an increase in aspartate transaminase 3 to 5 times the upper limit of normal. Alirocumab 150 mg Q2W reduced low-density lipoprotein cholesterol (LDL-C) from baseline by 68.4% compared with 10.5% for the control group. More than 90% of patients achieved an LDL-C target of < 70 mg/dL with alirocumab versus 8% with control. Marked reductions in other atherogenic lipids and modest increases in high-density lipoprotein cholesterol were also observed. Conclusion. At the highest Q2W dose under development (150 mg), alirocumab appears well tolerated and produces robust LDL-C reductions. These data suggest that alirocumab 150 mg Q2W is an appropriate dose for further evaluation in Phase III trials.

Effects of Evolocumab on Vitamin E and Steroid Hormone LevelsNovelty and Significance

Rationale: Vitamin E transport and steroidogenesis are closely associated with low-density lipoproteins (LDLs) metabolism, and evolocumab can lower LDL cholesterol (LDL-C) to low levels. Objective: To determine the effects of evolocumab on vitamin E and steroid hormone levels. Methods and Results: After titration of background lipid-lowering therapy per cardiovascular risk, 901 patients with an LDL-C ≥2.0 mmol/L were randomized to 52 weeks of monthly, subcutaneous evolocumab, or placebo. Vitamin E, cortisol, adrenocorticotropic hormone, and gonadal hormones were analyzed at baseline and week 52. In a substudy (n=100), vitamin E levels were also measured in serum, LDL, high-density lipoprotein, and red blood cell membranes at baseline and week 52. Absolute vitamin E decreased in evolocumab-treated patients from baseline to week 52 by 16% but increased by 19% when normalized for cholesterol. In the substudy, vitamin E level changes from baseline to week 52 mirrored the changes in the lipid fraction, and red blood cell membrane vitamin E levels did not change. Cortisol in evolocumab-treated patients increased slightly from baseline to week 52, but adrenocorticotropic hormone and the cortisol:adrenocorticotropic hormone ratio did not change. No patient had a cortisol:adrenocorticotropic hormone ratio <3.0 (nmol/pmol). Among evolocumab-treated patients, gonadal hormones did not change from baseline to week 52. Vitamin E and steroid changes were consistent across subgroups by minimum postbaseline LDL-C <0.4 and <0.6 mmol/L. Conclusions: As expected, vitamin E levels changed similarly to lipids among patients treated for 52 weeks with evolocumab. No adverse effects were observed in steroid or gonadal hormones, even at very low LDL-C levels. Clinical Trial Registration: URL: . Unique identifier: [NCT01516879][1]. # Novelty and Significance {#article-title-56} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01516879&atom=%2Fcircresaha%2F117%2F8%2F731.atomRATIONALE Vitamin E transport and steroidogenesis are closely associated with low-density lipoproteins (LDLs) metabolism, and evolocumab can lower LDL cholesterol (LDL-C) to low levels. OBJECTIVE To determine the effects of evolocumab on vitamin E and steroid hormone levels. METHODS AND RESULTS After titration of background lipid-lowering therapy per cardiovascular risk, 901 patients with an LDL-C ≥2.0 mmol/L were randomized to 52 weeks of monthly, subcutaneous evolocumab, or placebo. Vitamin E, cortisol, adrenocorticotropic hormone, and gonadal hormones were analyzed at baseline and week 52. In a substudy (n=100), vitamin E levels were also measured in serum, LDL, high-density lipoprotein, and red blood cell membranes at baseline and week 52. Absolute vitamin E decreased in evolocumab-treated patients from baseline to week 52 by 16% but increased by 19% when normalized for cholesterol. In the substudy, vitamin E level changes from baseline to week 52 mirrored the changes in the lipid fraction, and red blood cell membrane vitamin E levels did not change. Cortisol in evolocumab-treated patients increased slightly from baseline to week 52, but adrenocorticotropic hormone and the cortisol:adrenocorticotropic hormone ratio did not change. No patient had a cortisol:adrenocorticotropic hormone ratio <3.0 (nmol/pmol). Among evolocumab-treated patients, gonadal hormones did not change from baseline to week 52. Vitamin E and steroid changes were consistent across subgroups by minimum postbaseline LDL-C <0.4 and <0.6 mmol/L. CONCLUSIONS As expected, vitamin E levels changed similarly to lipids among patients treated for 52 weeks with evolocumab. No adverse effects were observed in steroid or gonadal hormones, even at very low LDL-C levels. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01516879.

Effects of Evolocumab on Vitamin E and Steroid Hormone LevelsNovelty and Significance: Results From the 52-Week, Phase 3, Double-Blind, Randomized, Placebo-Controlled DESCARTES Study

Rationale: Vitamin E transport and steroidogenesis are closely associated with low-density lipoproteins (LDLs) metabolism, and evolocumab can lower LDL cholesterol (LDL-C) to low levels. Objective: To determine the effects of evolocumab on vitamin E and steroid hormone levels. Methods and Results: After titration of background lipid-lowering therapy per cardiovascular risk, 901 patients with an LDL-C ≥2.0 mmol/L were randomized to 52 weeks of monthly, subcutaneous evolocumab, or placebo. Vitamin E, cortisol, adrenocorticotropic hormone, and gonadal hormones were analyzed at baseline and week 52. In a substudy (n=100), vitamin E levels were also measured in serum, LDL, high-density lipoprotein, and red blood cell membranes at baseline and week 52. Absolute vitamin E decreased in evolocumab-treated patients from baseline to week 52 by 16% but increased by 19% when normalized for cholesterol. In the substudy, vitamin E level changes from baseline to week 52 mirrored the changes in the lipid fraction, and red blood cell membrane vitamin E levels did not change. Cortisol in evolocumab-treated patients increased slightly from baseline to week 52, but adrenocorticotropic hormone and the cortisol:adrenocorticotropic hormone ratio did not change. No patient had a cortisol:adrenocorticotropic hormone ratio <3.0 (nmol/pmol). Among evolocumab-treated patients, gonadal hormones did not change from baseline to week 52. Vitamin E and steroid changes were consistent across subgroups by minimum postbaseline LDL-C <0.4 and <0.6 mmol/L. Conclusions: As expected, vitamin E levels changed similarly to lipids among patients treated for 52 weeks with evolocumab. No adverse effects were observed in steroid or gonadal hormones, even at very low LDL-C levels. Clinical Trial Registration: URL: . Unique identifier: [NCT01516879][1]. # Novelty and Significance {#article-title-56} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01516879&atom=%2Fcircresaha%2F117%2F8%2F731.atomRATIONALE Vitamin E transport and steroidogenesis are closely associated with low-density lipoproteins (LDLs) metabolism, and evolocumab can lower LDL cholesterol (LDL-C) to low levels. OBJECTIVE To determine the effects of evolocumab on vitamin E and steroid hormone levels. METHODS AND RESULTS After titration of background lipid-lowering therapy per cardiovascular risk, 901 patients with an LDL-C ≥2.0 mmol/L were randomized to 52 weeks of monthly, subcutaneous evolocumab, or placebo. Vitamin E, cortisol, adrenocorticotropic hormone, and gonadal hormones were analyzed at baseline and week 52. In a substudy (n=100), vitamin E levels were also measured in serum, LDL, high-density lipoprotein, and red blood cell membranes at baseline and week 52. Absolute vitamin E decreased in evolocumab-treated patients from baseline to week 52 by 16% but increased by 19% when normalized for cholesterol. In the substudy, vitamin E level changes from baseline to week 52 mirrored the changes in the lipid fraction, and red blood cell membrane vitamin E levels did not change. Cortisol in evolocumab-treated patients increased slightly from baseline to week 52, but adrenocorticotropic hormone and the cortisol:adrenocorticotropic hormone ratio did not change. No patient had a cortisol:adrenocorticotropic hormone ratio <3.0 (nmol/pmol). Among evolocumab-treated patients, gonadal hormones did not change from baseline to week 52. Vitamin E and steroid changes were consistent across subgroups by minimum postbaseline LDL-C <0.4 and <0.6 mmol/L. CONCLUSIONS As expected, vitamin E levels changed similarly to lipids among patients treated for 52 weeks with evolocumab. No adverse effects were observed in steroid or gonadal hormones, even at very low LDL-C levels. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01516879.