scholarly journals Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis

Stroke ◽  
2020 ◽  
Vol 51 (5) ◽  
pp. 1546-1554 ◽  
Author(s):  
Robert P. Giugliano ◽  
Terje R. Pedersen ◽  
Jeffrey L. Saver ◽  
Peter S. Sever ◽  
Anthony C. Keech ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Arterial Disease ◽  
Hazard Ratio ◽  
Proprotein Convertase ◽  
Vascular Events ◽  
Unique Identifier ◽  
Double Blind ◽  
History Of

Background and Purpose— The PCSK9 (proprotein convertase subtilisin-kexin type 9) monoclonal antibody evolocumab lowered LDL (low-density lipoprotein) cholesterol by 59% to 0.8 (0.5–1.2) mmol/L and significantly reduced major vascular events in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Herein, we report the results of a prespecified analysis of cerebrovascular events in the overall trial population and in patients stratified by prior stroke. Methods— FOURIER was a randomized, double-blind trial comparing evolocumab versus placebo in patients with established atherosclerosis, additional risk factors, and LDL cholesterol levels ≥1.8 (or non-HDL [high-density lipoprotein] ≥2.6 mmol/L) on statin therapy. The median follow-up was 2.2 years. We analyzed the efficacy of evolocumab to reduce overall stroke and stroke subtypes, as well as the primary cardiovascular composite end point by subgroups according to a history of stroke. Results— Among the 27 564 patients, 469 (1.7%) experienced a total of 503 strokes of which 421 (84%) were ischemic. Prior ischemic stroke, diabetes mellitus, elevated CRP (C-reactive protein), history of heart failure, older age, nonwhite race, peripheral arterial disease, and renal insufficiency were independent predictors of stroke. Evolocumab significantly reduced all stroke (1.5% versus 1.9%; hazard ratio, 0.79 [95% CI, 0.66–0.95]; P =0.01) and ischemic stroke (1.2% versus 1.6%; hazard ratio, 0.75 [95% CI, 0.62–0.92]; P =0.005), with no difference in hemorrhagic stroke (0.21% versus 0.18%; hazard ratio, 1.16 [95% CI, 0.68–1.98]; P =0.59). These findings were consistent across subgroups, including among the 5337 patients (19%) with prior ischemic stroke in whom the hazard ratios (95% CIs) were 0.85 (0.72–1.00) for the cardiovascular composite, 0.90 (0.68–1.19) for all stroke, and 0.92 (0.68–1.25) for ischemic stroke ( P interactions, 0.91, 0.22, and 0.09, respectively, compared with patients without a prior ischemic stroke). Conclusions— Inhibition of PCSK9 with evolocumab added to statin in patients with established atherosclerosis reduced ischemic stroke and cardiovascular events in the total population and in key subgroups, including those with prior ischemic stroke. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.

scholarly journals The history of proprotein convertase subtilisin kexin-9 inhibitors and their role in the treatment of cardiovascular disease

2020 ◽  
Vol 11 ◽  
pp. 204062232092456
Author(s):  
Eun Ji Kim ◽  
Anthony S. Wierzbicki
Keyword(s):  
Cardiovascular Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Epidemiological Studies ◽  
Lipid Lowering ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Activating Mutations ◽  
History Of ◽  
New Guidelines

A consensus has formed based on epidemiological studies and clinical trials that intervention to reduce low density lipoprotein cholesterol (LDL-C) will reduce cardiovascular disease (CVD) events. This has progressively reduced the thresholds for intervention and targets for treatment. Whist statins are sufficient for many people in primary prevention, they only partially achieve the newer targets of secondary prevention for established CVD. Increasing use of statins has highlighted that 1–2% cannot tolerate these drugs. Other cholesterol-lowering drugs such as ezetimibe add to the benefits of statins but have limited efficacy. The discovery of activating mutations in proprotein convertase subtilisin kexin-9 (PCSK9) as a cause of familial hypercholesterolaemia while inactivating mutations lower LDL-C led to the idea to develop PCSK9 inhibitors as drugs. This article reviews the history of lipid-lowering therapies, the discovery of PCSK9 and the development of PCSK9 inhibitors. It reviews the key trials of the current antibody-based drugs and how these have influenced new guidelines. It also reviews the controversy caused by their cost and the increasing application of health economics to determine the optimum strategy for implementation of novel therapeutic pathways and surveys other options for targeting PCSK9 as well as other LDL-C lowering compounds in late development.

scholarly journals The Role of Lipid-Lowering Treatment in the Secondary Prevention of Ischemic Stroke

Diseases ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 3
Author(s):  
Alexandra Tsankof ◽  
Konstantinos Tziomalos
Keyword(s):  
Ischemic Stroke ◽  
Secondary Prevention ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Pcsk9 Inhibitors ◽  
Stroke Treatment ◽  
Icosapent Ethyl ◽  
History Of ◽  
Coronary Events

Dyslipidemia is a major modifiable risk factor for ischemic stroke. Treatment with statins reduces the incidence of recurrent ischemic stroke and also reduces coronary events in patients with a history of ischemic stroke. Therefore, statins represent an important component of secondary prevention of ischemic stroke. In patients who do not achieve low-density lipoprotein cholesterol (LDL-C) targets despite treatment with the maximal tolerated dose of a potent statin, ezetimibe should be added to their lipid-lowering treatment and also appears to reduce the risk of cardiovascular events. Selected patients who do not achieve LDL-C targets despite statin/ezetimibe combination are candidates for receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Finally, it appears that adding icosapent ethyl might also reduce cardiovascular morbidity in patients who have achieved LDL-C targets but have persistently elevated triglyceride levels.

Abstract 13130: Efficacy and Safety of Bempedoic Acid by Sex: Pooled Analyses From Phase 3 Trials

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anne C Goldberg ◽  
Maciej Banach ◽  
Alberico L Catapano ◽  
P Barton Duell ◽  
Lawrence A Leiter ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherosclerotic Cardiovascular Disease ◽  
Efficacy And Safety ◽  
Atp Citrate Lyase ◽  
Statin Intolerance ◽  
Phase 3 ◽  
Double Blind ◽  
Citrate Lyase ◽  
History Of

Introduction: Bempedoic acid (BA), an ATP-citrate lyase inhibitor, lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. Objective: To report efficacy and safety of BA by sex in patients with elevated LDL-C. Methods: Data were pooled from 4 phase 3 randomized (2:1), double-blind studies investigating oral BA (180 mg once daily) vs placebo for 12 weeks to 52 weeks in adults receiving maximally tolerated statins who required additional LDL-C lowering, analyzed by sex. The primary efficacy endpoint was % change in LDL-C from baseline to week 12. Results were analyzed in cohorts with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (“ASCVD/HeFH on statins pool”, n=3009) or history of statin intolerance (“statin intolerant pool”, n=614). Safety assessments included treatment-emergent adverse events (TEAEs). Results: Of all participants, 34.3% were women. Significant LDL-C lowering from baseline with BA vs placebo was demonstrated in both pools and sexes ( P < 0.001; Table 1 ), with greater lowering in women vs men in the ASCVD/HeFH on statins pool ( P = 0.04). Rates of TEAEs were similar across groups ( Table 2 ). Rates of common TEAEs were similar in both pools and sexes, except urinary tract infection (men: BA, 2.8%; placebo, 3.0%; women: BA, 8.0%; placebo, 10.3%) and pain in extremity (men: BA, 2.5%; placebo, 1.2%; women: BA, 4.2%; placebo, 2.9%), which occurred more frequently in women. Conclusion: BA lowered LDL-C significantly in both women and men, with greater effect in women vs men in both pools, and a safety profile generally comparable to placebo in both sexes.

Intracranial Hemorrhage in the TST Trial

Stroke ◽  
2021 ◽  
Author(s):  
Pierre Amarenco ◽  
Jong S. Kim ◽  
Julien Labreuche ◽  
Hugo Charles ◽  
Maurice Giroud ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Intracranial Hemorrhage ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Uncontrolled Hypertension ◽  
Unique Identifier ◽  
Coronary Artery Atherosclerosis ◽  
Increase Risk ◽  
Ischemic Attack

Background and Purpose: Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH. Methods: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of <70 mg/dL or 100±10 mg/dL, using statin or ezetimibe. Results: Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38–4.04] and 2.32/1000 patient-years [95% CI, 1.61–3.03], respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01–6.31], P =0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00–5.62], P =0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH. Conclusions: Targeting an LDL cholesterol of <70 mg/dL compared with 100±10 mg/dL in patients with atherosclerotic ischemic stroke nonsignificantly increased the risk of ICH. Incident ICHs were not associated with low LDL cholesterol. Uncontrolled hypertension and anticoagulant therapy were associated with ICH which has important clinical implications. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875; EUDRACT identifier: 2009-A01280-57.

scholarly journals Antihypertensives and Statin Therapy for Primary Stroke Prevention

Stroke ◽  
2021 ◽  
Author(s):  
Jackie Bosch ◽  
Eva M. Lonn ◽  
Gilles R. Dagenais ◽  
Peggy Gao ◽  
Patricio Lopez-Jaramillo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Ischemic Stroke ◽  
Cardiovascular Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Blood Pressure Lowering ◽  
Stroke Subtype ◽  
Unique Identifier ◽  
Pressure Lowering

Background and Purpose: The HOPE-3 trial (Heart Outcomes Prevention Evaluation–3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups. Methods: Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed. Results: Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59–1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55–1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34–1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41–2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52–0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37–0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59–2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57–2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36–0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23–0.72]). Conclusions: Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00468923.

4943Remnant cholesterol increases the risk for recurrent vascular events independent of LDL-cholesterol in patients with clinical manifest vascular disease

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
B E Heidemann ◽  
C Koopal ◽  
M L Bots ◽  
F W Asselbergs ◽  
J Westerink ◽  
...  
Keyword(s):  
Vascular Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Composite Endpoint ◽  
Arterial Disease ◽  
Chylomicron Remnant ◽  
Vascular Events ◽  
All Cause Mortality ◽  
Remnant Cholesterol

Abstract Background For many years, low density lipoprotein cholesterol (LDL-C) is recognized as an important risk factor for the development of atherosclerosis and cardiovascular disease. However, even with normal LDL-C levels there is a residual risk for cardiovascular disease and mortality. Previous research in patients with ischemic heart disease, diabetes mellitus type 2 (T2DM) and in the general population has shown that this residual risk could be explained by elevated plasma levels of very low density lipoprotein- (VLDL) and chylomicron-remnant cholesterol. Purpose We evaluated the relation between plasma levels of VLDL- and chylomicron-remnant cholesterol and recurrent vascular disease and all-cause mortality in a cohort of patients with clinical manifest arterial disease. Methods Prospective cohort study in 8057 patients with manifest arterial disease from the UCC-SMART study. Patients with triglyceride levels >9 mmol/L or known homozygote Apo E2 genotype were excluded. Cox proportional hazard models were used to evaluate the effect of fasting VLDL- and chylomicron-remnant cholesterol (calculated by total cholesterol - high density lipoprotein cholesterol (HDL-C) - LDL-C) on occurence of myocardial infarction (MI), stroke, vascular death, a composite endpoint (i.e. MI, stroke, vascular death) and all-cause mortality. Models were adjusted for LDL-C, current smoking, waist circumference, creatinine and systolic blood pressure. Effect modification of HDL-C and T2DM on the relation between remnant cholesterol and vascular endpoints was evaluated. Results Patients mean age was 60.0±10.3 years, 74% were male, 4894 (61%) had a prior history of coronary artery disease (CAD), 2445 (30%) of stroke and 1990 (25%) patients had peripheral arterial disease (PAD) or aneurysm abdominal aorta (AAA). There were 1544 vascular events and 1792 deaths during a median follow up of 8.2 (interquartile range (IQR) 4.5–12.2) years and a total follow up of 68699 person-years. For every 1 mmol/L increase in remnant cholesterol, risk for recurrent vascular events was increased in patients with manifest vascular disease (HR 1.17; 95% CI 1.05–1.31 for the composite endpoint (figure 1)). There was no effect for all-cause mortality in this population. Furthermore, there was no significant effect modification of HDL-C and the presence of T2DM on the relation between remnant cholesterol and vascular endpoints. Figure 1 Conclusion In patients with clinically manifest arterial disease plasma remnant cholesterol confers an increased risk for recurrent vascular events, independent of traditional risk factors such as LDL-C levels.

scholarly journals Proatherogenic Oxidized Low-Density Lipoprotein/β2-Glycoprotein I Complexes in Arterial and Venous Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Jeffrey S. Berger ◽  
Caron B. Rockman ◽  
Kirk E. Guyer ◽  
Luis R. Lopez
Keyword(s):  
Carotid Artery ◽  
Carotid Artery Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Arterial Disease ◽  
Adverse Outcomes ◽  
Venous Disease ◽  
Glycoprotein I ◽  
History Of ◽  
Artery Disease

OxLDL/β2GPI complexes have been implicated in the initiation and progression of atherosclerosis and associated with disease severity and adverse outcomes. We investigate the significance of anti-oxLDL/β2GPI antibodies and oxLDL/β2GPI complexes in patients with arterial and idiopathic venous disease. A cohort of 61 arterial disease patients, 32 idiopathic venous disease patients, and 53 healthy controls was studied. Because statins influence oxLDL/β2GPI, these complexes were analyzed on subjects not taking statins. Arterial and venous groups expressed higher levels of IgG anti-oxLDL/β2GPI antibodies than controls without any other significant clinical association. OxLDL/β2GPI complexes were significantly elevated in arterial (0.69 U/mL,P=0.004) and venous disease (0.54 U/mL,P=0.025) than controls (0.39 U/mL). Among arterial diseases, oxLDL/β2GPI was 0.85 U/mL for carotid artery disease, 0.72 U/mL for peripheral artery disease, and 0.52 U/mL for abdominal aortic aneurysm. There was a significant association with male gender, age, hypertension, and history of thrombosis. Subjects with oxLDL/β2GPI above the median (0.25 U/mL) were more likely to have arterial (OR 4.5,P=0.004) or venous disease (OR 4.1,P=0.008). Multivariate regression indicated that males (P=0.021), high cholesterol (P=0.011), and carotid disease (P=0.023) were significant predictors of oxLDL/β2GPI. The coexistence of oxLDL/β2GPI in arterial and venous disease may suggest a common oxidative mechanism that independently predicts carotid artery disease.

Dihomo-γ-Linolenic Acid in Patients with Atherosclerosis: Effects on Platelet Aggregation, Plasma Lipids and Low-Density Lipoprotein-Induced Inhibition of Prostacyclin Generation

1984 ◽  
Vol 51 (02) ◽  
pp. 186-188 ◽  
Author(s):  
A Szczeklik ◽  
R J Gryglewski ◽  
K Sladek ◽  
E Kostka-Trąbka ◽  
A Żmuda
Keyword(s):  
Linolenic Acid ◽  
Plasma Lipids ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Thromboxane A2 ◽  
Low Density ◽  
Red Cell ◽  
Double Blind ◽  
Daily Dose ◽  
Antithrombotic Effects

SummaryDihomo-γ-linolenic acid (DHLA), a precursor of monoenoic anti-aggregatory prostaglandins (PGE1, PGD2), was administered for 4 weeks in a daily dose of 1.0 g into 33 patients with atherosclerosis on a basis of a double-blind trial. Comparison of treatment and placebo groups revealed elevation of DHLA in red cell lipids in DHLA-treated subjects. No differences, however, between the two groups could be observed in platelet aggregability, thromboxane A2 generation by platelets, serum cholesterol, PGE1 and PGE2 levels, and in inhibitory activity of low-density lipoproteins against prostacyclin synthetizing system in arteries. The dietary supplementation used did not lead to distinct antithrombotic effects.

Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis

2019 ◽  
Vol 20 (10) ◽  
pp. 1029-1040 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Structure And Function ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Proprotein Convertase ◽  
Novel Target ◽  
New Treatments ◽  
And Function

Background:One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy.Methods:We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis.Results:New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis.Conclusion:PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

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