Estudio primario

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Lipid Management in Renal Transplant Recipients Using Evolocumab.

Año 2021
Registro de estudios clinicaltrials.gov
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Cardiovascular disease is the leading cause of mortality after renal transplantation, accounting for more than 30% of deaths. Elevated lipid levels (hyperlipidemia) are a frequent finding following transplantation and the immunosuppressive medications play a central role in the development or worsening of hyperlipidemia. In the general population, the correlation between elevated serum cholesterol and increased risk of cardiovascular disease is well established and the reduction in serum LDL cholesterol has proved to significantly reduce both morbidity and mortality.

Statin based drugs are the standard of care in the management of hyperlipidemia. Commonly used statin-based drugs include atorvastatin (Lipitor), fluvastatin (Lescol, Lescol XL), lovastatin (Mevacor, Altoprev), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor), and pitavastatin (Livalo). These drugs have been proven to lower lipid levels as well as cardiovascular risk. However, statin-based drugs also cause a variety of side effects. While the most commonly encountered side effects are toxicity to the liver and muscles, a few others have also been known to cause increased excretion of protein in the urine and kidney failure. These side effects are also more common in a renal transplant recipient due to the simultaneous administration of drugs that prevent rejection. Therefore, there is an emergent need for newer drugs which are both efficient and safe especially in this population PCSK-9 inhibitors (Proprotein Convertase Subtilisin Kinase-9 inhibitors) are a new class of drugs that are highly efficient in lowering lipid levels in the general population. However, an exclusive trial involving kidney transplant recipients is yet to be done. Through this study, we would like to evaluate the safety and tolerability of Evolocumab (trade name: Repatha) which is a PCSK-9 inhibitor developed by Amgen, Inc in renal transplant recipients. The study would involve a total of 120 patients across 3 different hospitals in Boston, Massachusetts.

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Resumen estructurado de revisiones sistemáticas

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PCSK9 inhibitors for cholesterol reduction: evolocumab (Structured abstract)

Año 2015
Autores HAYES , Inc
Revista HAYES, Inc
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Estudio primario

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Effect of Evolocumab on Chronic Total Occlusions (EVOLO-CTO)

Año 2022
Registro de estudios clinicaltrials.gov
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The purpose of this study is to evaluate the effect of proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors added to regular statin therapy on target lesion failure (TLF) and arteriosclerosis progression in patients with chronic total occlusions (CTOs) undergoing successful percutaneous coronary intervention (PCI).

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Revisión sistemática

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Indirect comparison of the efficacy and safety of alirocumab and evolocumab: A systematic review and network meta-analysis

Año 2021
Revista European heart journal. Cardiovascular pharmacotherapy
Enlaces Pubmed , DOI

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Revisión sistemática

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Efficacy and safety of alirocumab and evolocumab: a systematic review and meta-analysis of randomized controlled trials.

Año 2019
Revista European heart journal
Enlaces Pubmed , DOI

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AIMS:

The effect of low-density lipoprotein cholesterol-lowering therapy with alirocumab or evolocumab on individual clinical efficacy and safety endpoints remains unclear. We aimed to evaluate the efficacy and safety of alirocumab and evolocumab in patients with dyslipidaemia or atherosclerotic cardiovascular disease.

METHODS AND RESULTS:

We performed a review of randomized controlled trials (RCTs) comparing treatment with alirocumab or evolocumab vs. placebo or other lipid-lowering therapies up to March 2018. Primary efficacy endpoints were all-cause death, cardiovascular death, myocardial infarction (MI), and stroke. We estimated risk ratios (RR) and 95% confidence intervals (CI) using random effect models. We included 39 RCTs comprising 66 478 patients of whom 35 896 were treated with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors (14 639 with alirocumab and 21 257 with evolocumab) and 30 582 with controls. Mean weighted follow-up time across trials was 2.3 years with an exposure time of 150 617 patient-years. Overall, the effects of PCSK9 inhibition on all-cause death and cardiovascular death were not statistically significant (P = 0.15 and P = 0.34, respectively). Proprotein convertase subtilisin-kexin type 9 inhibitors were associated with lower risk of MI (1.49 vs. 1.93 per 100 patient-year; RR 0.80, 95% CI 0.74-0.86; I2 = 0%; P < 0.0001), ischaemic stroke (0.44 vs. 0.58 per 100 patient-year; RR 0.78, 95% CI 0.67-0.89; I2 = 0%; P = 0.0005), and coronary revascularization (2.16 vs. 2.64 per 100 patient-year; RR 0.83, 95% CI 0.78-0.89; I2 = 0%; P < 0.0001), compared with the control group. Use of these PCSK9 inhibitors was not associated with increased risk of neurocognitive adverse events (P = 0.91), liver enzymes elevations (P = 0.34), rhabdomyolysis (P = 0.58), or new-onset diabetes mellitus (P = 0.97).

CONCLUSION:

Proprotein convertase subtilisin-kexin type 9 inhibition with alirocumab or evolocumab was associated with lower risk of MI, stroke, and coronary revascularization, with favourable safety profile.

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Prospective Study of Patients Switched from arilocumab to evolocumab(SWITCH From Arilocumab To Evolocumab study: switch fate Study)

Año 2020
Autores [No se listan los autores]
Registro de estudios UMIN Clinical Trials Registry
Enlaces UMIN-CTR

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INTERVENTION:

Before switching from 75 mg, 150 mg arilocumab to 140 mg, 420 mg evolocumab, and 6 months and 1 year after the switch. Evolocumab 140mg, 420mg continued: at start of intervention, 6 months after intervention, 1 year after intervention

CONDITION:

Hyperlipidemia

PRIMARY OUTCOME:

Lipid profile (TC,TG,HDL‐C, Friedewald LDL‐C,small dense LDL,IDL,Lp(a),LDL oxidation ability,LDL stability,oxidized LDL,3%PAGE,Agarose gel electrophoresis,electronegative LDL),apo protein, apoE phenotype

SECONDARY OUTCOME:

Cr, BUN, Urinal analysis, GOT, GPT, CK, (following in the case of DM), fasting blood glucose, HbA1, hematologic changes such as thrombocytopenia, etc., early‐phase and late‐phase of allergic reaction to PCSK9 inhibitor.

INCLUSION CRITERIA:

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Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism.

Año 2017
Revista Circulation
Enlaces Pubmed , DOI

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BACKGROUND:

Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies.

METHODS:

We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)-apolipoprotein B-100 (apoB), intermediate-density lipoprotein-apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling.

RESULTS:

Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (P<0.001 and P.032, respectively), intermediate-density lipoprotein-apoB (P=0.021 and P=.002, respectively), and LDL-apoB (P<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein-apoB (P=0.043) and LDL-apoB (P<0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (P<0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance.

CONCLUSIONS:

In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials.

CLINICAL TRIAL REGISTRATION:

URL:

http://www.clinicaltrials.gov. Unique identifier: NCT02189837.

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Estudio primario

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Evolocumab Versus LDL Apheresis in Patients With Hypercholesterolemia

Año 2017
Registro de estudios clinicaltrials.gov
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An open-label, prospective phase III study to compare the efficacy and safety of administering evolocumab versus treatment with LDLapheresis in patients with familial hypercholesterolemia and high cardiovascular risk.

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Estudio primario

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Evolocumab In Advanced Chronic Kidney Disease Trial

Año 2021
Autores NYU Langone Health
Registro de estudios clinicaltrials.gov
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110 individuals with stage 4-5 Chronic Kidney Disease (CKD) will be randomized to 1-year of blinded Evolocumab or placebo. Subjects will undergo evaluation of circulating lipids at baseline and end of study. A substudy including 50 subjects will assess myocardial rest and stress positron emission tomography (PET) at baseline and at 1-year.

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Estudio primario

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Cognition After Lowering LDL-Cholesterol With Evolocumab.

Año 2020
Revista Journal of the American College of Cardiology
Enlaces Pubmed , DOI

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BACKGROUND:

The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk).

OBJECTIVES:

The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey.

METHODS:

FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks.

RESULTS:

A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score ≥2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (<20 mg/dl) compared to the 3,613 patients with LDL-C ≥100 mg/dl (3.8% vs. 4.5%, p = 0.57).

CONCLUSIONS:

The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C <20 mg/dl.

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