PCSK9 inhibition in patients with and without prior myocardial infarction or ischemic stroke: A pooled analysis of nine randomized-controlled studies of alirocumab

Bruckert, Éric; Kereiakes, Dean J.; Koren, Michael; Louie, Michael J.; Letierce, Alexia; Miller, Kathryn; Cannon, Christopher P.

doi:10.1016/j.jacl.2019.04.005

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…In line with these observations, a recent genome-wide association study suggested that genetic variations at the lipoprotein(a) locus are associated with cardiovascular events during statin therapy, independent of the extent of LDL cholesterol lowering . Interestingly, PCSK9 inhibition by alirocumab has been reported to reduce both LDL cholesterol and lipoprotein(a) levels in patients with a history of ischemic stroke . The safety and potential efficacy of alirocumab for recurrent stroke prevention in patients with intracranial atherosclerosis is currently being tested in an ongoing pilot, double-blind, placebo-controlled RCT .…”

Section: Resultsmentioning

confidence: 99%

New Horizons in Pharmacologic Therapy for Secondary Stroke Prevention

Katsanos

Hart

2020

JAMA Neurol

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ith current guideline-recommended therapies and lifestyle modifications following an ischemic stroke or transient ischemic attack (TIA), there remains a substantial residual lifetime risk of stroke recurrence, incident coronary events, and vascular death. [1][2][3] Even for patients receiving intensive treatment with statins, blood pressure control, and antiplatelet agents after an ischemic stroke or TIA, according to best clinical practices and international recommendations, it is estimated that there is still an annual stroke recurrence risk of 2.5% to 4.0%. 4,5 In addition, the annual incidence rates of vascular death not attributed to stroke and nonfatal myocardial infarction among survivors of stroke are 2.1% and 0.9%, respectively. 6 Hence, there is an important unmet need to further reduce vascular events in patients after stroke and TIA, despite current, guideline-recommended preventive interventions.In this review, we summarize emerging novel pharmacologic approaches that have shown signals of efficacy for stroke prevention from phase II and phase III randomized clinical trials (RCTs). We also provide an overview of drug regimens that have provided promising results in primary stroke prevention and could be considered for further evaluation in future RCTs on secondary stroke prevention. MethodsWe performed a systematic review in MEDLINE for clinical trials or clinical trial protocols in secondary stroke prevention that were published in the last 5 years (January 1, 2015, to March 22, 2020. The keywords used in our database search included ischemic stroke, stroke, transient ischemic attack, cerebral ischemia, cerebrovascular ischemic event, cerebrovascular ischemia, prevention, treatment, and control. All clinical trials and clinical trial protocols published in English were screened for eligibility. One of the authors (A.H.K.) performed a comprehensive search in ClinicalTrials.gov for registered clinical trials in IMPORTANCE Even with currently available therapies and lifestyle modifications following an ischemic stroke, there remains a substantial residual lifetime risk of stroke recurrence and cardiovascular morbidity. This review summarizes emerging novel therapeutic approaches that have demonstrated signals of efficacy for prevention of noncardioembolic stroke from phase II and phase III randomized clinical trials (RCTs) and provides an overview of drug regimens that have had promising results in primary stroke prevention and could be considered for further evaluation.OBSERVATIONS After a minor acute ischemic stroke or transient ischemic attack, patients bear a high cardiovascular risk that is insufficiently addressed by long-term antiplatelet treatment. The potent combination of low-dose rivaroxaban with aspirin as an antithrombotic option for the secondary prevention in patients with clinical atherosclerosis and a history of previous stroke warrants further study. Two international RCTs are currently evaluating the utility of oral factor XI inhibitors combined with antiplatelets for secondary, non...

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Section: Resultsmentioning

confidence: 99%

New Horizons in Pharmacologic Therapy for Secondary Stroke Prevention

Katsanos

Hart

2020

JAMA Neurol

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“…On the other hand, alirocumab added to intensive statin therapy was found to attenuate the risk of type 2 myocardial infarct events (White et al, 2019). Alirocumab may benefit patients who have had an MI and are at very high risk of recurrent CV events since LDL-C target levels can be achieved, regardless of MI or ischemic stroke status (Bruckert et al, 2019). Also, in these high-risk patients that were included in the study, alirocumab was well tolerated with a favorable safety profile [similar treatment-emergent adverse events (TEAEs) were observed among groups], regardless of previous history of MI/ischaemic stroke (Bruckert et al, 2019).…”

Section: Clinical Studies On the Role Of Pcsk9 Inhibition In Myocardimentioning

confidence: 99%

PCSK9 in Myocardial Infarction and Cardioprotection: Importance of Lipid Metabolism and Inflammation

et al. 2020

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Extensive evidence from epidemiologic, genetic, and clinical intervention studies has indisputably shown that elevated low-density lipoprotein cholesterol (LDL-C) concentrations play a central role in the pathophysiology of atherosclerotic cardiovascular disease. Apart from LDL-C, also triglycerides independently modulate cardiovascular risk. Reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma LDL-C, but it is also associated with a reduction in triglyceride levels potentially through modulation of the expression of free fatty acid transporters. Preclinical data indicate that PCSK9 is up-regulated in the ischaemic heart and decreasing PCSK9 expression impacts on infarct size, post infarct inflammation and remodeling as well as cardiac dysfunction following ischaemia/reperfusion. Clinical data support that notion in that PCSK9 inhibition is associated with reductions in the incidence of myocardial infarction, stroke, and coronary revascularization and an improvement of endothelial function in subjects with increased cardiovascular risk. The aim of the current review is to summarize the current knowledge on the importance of free fatty acid metabolism on myocardial ischaemia/reperfusion injury and to provide an update on recent evidence on the role of hyperlipidemia and PCSK9 in myocardial infarction and cardioprotection.

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“…The pathophysiological changes in coronary syndrome share a common pattern: the transformation of coronary atherosclerotic plaques from a stable state to an unstable one, eventually culminating in plaque rupture and thrombosis [ 4 ]. Extensive clinical experience has demonstrated that the perturbation of blood lipid levels [ 5 , 6 ] further exacerbates plaque instability, increasing the cardiac burden and progressively impeding vascular functions due to delayed blood flow metabolism and blockage of ion transport channels.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of PSCK9 Inhibitors on Patients with Acute Coronary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Zhao,

Tong,

Peng

et al. 2024

Rev. Cardiovasc. Med.

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Background: PCSK9 MaB (Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor) may reduce the occurrence of major adverse cardiovascular events (MACEs) in patients diagnosed with acute coronary syndrome (ACS). In this meta-analysis, we conducted a thorough compilation of evidence from established clinical studies to evaluate PCSK9 MaB’s capacity to control blood lipid levels and prevent MACEs in ACS patients. Methods: We conducted searches on Pubmed, Embase, the Cochrane Library, and Web of Science to identify relevant articles. Data from ACS patients were extracted using a standardized format for aggregating data. We calculated the risk ratio (RR) for MACE and assessed changes in blood lipid parameters. All statistical analyses were performed using RevMan. Results: 11 articles representing 5 trials were included in our systematic review and meta-analysis. When compared to a placebo, PCSK9 MaB significantly reduced the risk of MACEs ( = 0%, p = 0.63, RR [95% CI] = 0.88 [0.81, 0.97], p 0.01) and the recurrence rate of ACS ( = 45%, p = 0.18, RR [95% CI] = 0.89 [0.83, 0.95], p 0.01). Additionally, PCSK9 MaB notably reduced low-density lipoprotein cholesterol (LDL-C) levels (SMD [95% CI] = –2.12 [–2.32, –1.92], p 0.01) and Apolipoprotein B (ApoB) levels (SMD [95% CI] = –1.83 [–2.48, –1.18], p 0.01). Importantly, there were no significant differences in adverse reactions between the PCSK9 MaB group and the control group. Conclusions: PCSK9 MaB, whether used as a standalone treatment or in combination with other therapies, can effectively inhibit PCSK9. It substantially lowers key blood lipid parameters, including low-density lipoprotein (LDL), ApoB, and triglycerides, all without giving rise to notable safety concerns.

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PCSK9 inhibition in patients with and without prior myocardial infarction or ischemic stroke: A pooled analysis of nine randomized-controlled studies of alirocumab

Cited by 3 publications

References 44 publications

New Horizons in Pharmacologic Therapy for Secondary Stroke Prevention

New Horizons in Pharmacologic Therapy for Secondary Stroke Prevention

PCSK9 in Myocardial Infarction and Cardioprotection: Importance of Lipid Metabolism and Inflammation

Efficacy and Safety of PSCK9 Inhibitors on Patients with Acute Coronary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

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