Therapy of acute myocardial infarction
Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich in Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Recently, two monoclonal antibodies have been approved for inhibiting the enzyme paraprotein convertase subtilisin/kexin type 9 (PCSK9). These agents dramatically reduce low-density lipoprotein cholesterol and improve outcomes in selected patients. In a trial of 18,924 patients with ACS in the previous year and low-density cholesterol ≥70 mg/dL (most of whom were already taking statin drugs), alirocumab reduced the composite endpoint of cardiovascular death, MI, stroke, or unstable angina by 15% over a median of 2.8 years of follow-up (118). Patients under age 65 and over age 65 derived similar benefits. In another study of 27,564 patients with chronic atherosclerotic disease, more than 80% of whom had a prior MI, evolocumab also reduced the composite primary endpoint by 15% (absolute rates of 11.3% vs. 9.8%) over a median follow-up of 2.2 years (119). Again, younger and older patient subgroups had similar benefit, although this study excluded patients over age 85. Despite limitations related to subcutaneous administration and high cost, these drugs are an additional therapeutic option for selected patients of all ages with prior MI.
Dyslipidemia
Jahangir Moini, Matthew Adams, Anthony LoGalbo in Complications of Diabetes Mellitus, 2022
PCSK9 monoclonal antibodies are formulated for subcutaneous injection, once to twice per month. They stop proprotein convertase subtilisin/kexin type 9 from attaching to LDL receptors, improving their function. The LDL is lowered by 40%–70%. Trials with alirocumab and evolocumab revealed less cardiovascular events when previous atherosclerotic cardiovascular disease was present. The cholesterol absorption inhibitors, including ezetimibe, inhibit absorption of cholesterol and phytosterol in the intestines. The LDL is usually lowered by ezetimibe by 15%–20%, with small increases in HDL and a slight decrease in total triglycerides. Ezetimibe can be used alone if the patient cannot tolerate statins, or it can be added to statins if the patient is on maximum statin dosage, with LDL remaining chronically elevated. Adverse effects of cholesterol absorption inhibitors are rare.
Familial hypercholesterolemia
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
All medications which lower lipids are contraindicated during pregnancy [107]. A prudent diet for these patients is one low in cholesterol and saturated fat. Oxidative stress contributes to lipid peroxidation and decreases nitric oxide (NO) bioavailability in atherosclerosis. Long-chain (n-3) polyunsaturated fatty acids (PUFA) are easily oxidized and improve endothelial function. In experimental animals, a fish oil-rich diet increased NO production and endothelial NO synthase expression. A fish oil-rich or supplemented diet appears prudent [108]. Double heterozygotes for mutations in LDLR and APOB tend to respond to treatment with statins [3]. Monoclonal antibodies to the PCSK9 convertase have emerged as treatment for even homozygous FH [109]. Two injectable human antibodies, Alirocumab and Evolucumab, have been approved by the FDA. They are capable of reducing LDL cholesterol by 50–70 percent.A cholesterylester transfer protein inhibitor Anacetrapib 100 mg daily added to statin therapy reduced LDL cholesterol by 30 percent [110]. Patients with APOB are responsive to statins [83].
Efficacy and tolerability of alirocumab in Austrian clinical practice – results of the non-interventional PEARL-AT study
Published in Current Medical Research and Opinion, 2020
Deborah R. Leitner, Hermann Toplak, Ludmilla Kedenko, Thomas Steinmaurer, Verena Gräff, Thomas Metzner, Elisabeth M. Schwaiger, Rudolf Prager
Adult patients (≥18 years) on treatment with alirocumab for hypercholesterolemia according to the summary of product characteristics (SmPC) and without contraindications, who did not participate in the ODYSSEY APPRISE study12 could be enrolled in PEARL-AT. According to the SmPC, alirocumab is indicated for adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet, in combination with a statin or statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or, alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated. Alirocumab is also indicated for adults with established atherosclerotic cardiovascular disease to reduce cardiovascular risk by lowering LDL-C levels, in combination with the maximum tolerated dose of a statin with or without other lipid-lowering therapies or, alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated. Contraindications according to the SmPC include hypersensitivity to the active substance or to any of the excipients13.
PCSK9 inhibitors and cardiovascular outcomes
Published in Expert Opinion on Biological Therapy, 2020
Daniel Steffens, Peter Bramlage, Céline Scheeff, Mario Kasner, Adel Hassanein, Julian Friebel, Ursula Rauch-Kröhnert
The lipid-lowering efficacy of alirocumab has been reviewed in detail previously [15,23,31,32]. Alirocumab provides significant and durable LDL-C lowering when administered as monotherapy or in combination with statins (± ezetimibe), in patients with hypercholesterolemia, mixed dyslipidemia or HeFH, and in statin-intolerant patients. The LDL-C lowering effect of alirocumab added to maximally tolerated statins (± other lipid-lowering therapy) has been demonstrated in patients with different degrees of CV risk, and in patients with or without diabetes [33–44]. Alirocumab is generally well tolerated; in clinical trials adverse events reported at a higher rate with alirocumab than with placebo were injection site reactions, pruritus and upper respiratory tract infection [15,45]. A slightly higher rate of neurocognitive events was observed in one of the long-term studies with alirocumab [46]; however, meta-analysis of data from 14 phase 2 or 3 trials of up to 104 weeks’ duration found no significant difference in the incidence of neurocognitive treatment-emergent adverse events between alirocumab and control groups [47]. A placebo-controlled study formally evaluating neurocognitive events during 2 years of alirocumab treatment is underway (clinicaltrials.gov identifier: NCT02957682). Alirocumab did not increase the incidence of new-onset diabetes [48].
Efficacy and safety of PCSK9 monoclonal antibodies: an evidence-based review and update
Published in Journal of Drug Assessment, 2020
Rasha Kaddoura, Bassant Orabi, Amar M. Salam
In two meta-analyses1,79 of RCTs, treatment with PCSK9 inhibitors was not associated with the adverse effects commonly described with statin therapy such as myalgia and elevations in serum aminotransferases or creatine kinase, with overall serious adverse events that were comparable to the control group. The aforementioned meta-analyses did not report the injection site reactions which are the most frequent adverse events with the PCSK9 inhibitors use4. The allergic local injection-site reactions (e.g. itching, redness, swelling) rates were 3.8% in alirocumab group versus 2.1% in placebo (p < .001)99 and 5.9 versus 4.2% over a period of 78 weeks63. Injection-site reactions are usually mild and self-limited99. The reactions rates with evolocumab were 2.1% versus 1.6% in the placebo group98, and there was no increase in hypersensitivity with longer treatment120. Bococizumab caused higher injection-site reactions as compared to placebo (10.4 versus 1.3%, p < .001)104 and 12.7 per 100 person-years in six trials evaluating bococizumab. However, the rates did not increase with longer time121.
Related Knowledge Centers
- Clinical Trial
- Familial Hypercholesterolemia
- Monoclonal Antibody
- Statin
- Cardiovascular Disease
- Atherosclerosis
- Medication
- Hypercholesterolemia
- Low-Density Lipoprotein
- Indication