Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review

Bruggen, Folkert H. van; Nijhuis, G B J; Zuidema, Sytse U.; Luijendijk, Hendrika J.

doi:10.1080/17512433.2020.1787832

Cited by 22 publications

(17 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a meta-analysis that included 14 studies on alirocumab, the overall rate of neurocognitive events was low, similar to patients receiving a placebo [ 82 ]. These findings were also validated by multiple meta-analyses [ 65 , 70 , 71 , 83 , 84 ]. Furthermore, a low LDL-C level induced by PCSK-9 inhibitors did not increase the rate of cognitive performance [ 66 ].…”

Section: Pcsk-9 Inhibitors and Adverse Reactionssupporting

confidence: 53%

Recent Advances on the Roles of PCSK-9 Inhibitors in the Management of Acute Ischemic Stroke Patients

Iluţ

Pirlog

Pîrlog

et al. 2022

IJMS

View full text Add to dashboard Cite

Acute ischemic stroke (AIS) represents an important cause of disability and death. Since only a minor percentage of patients with AIS are eligible for acute therapy, the management of risk factors is mandatory. An important risk factor of AIS is hyperlipemia. The current guidelines recommend a strict correction of it. Statins are recommended as the first-line treatment, while proprotein convertase subtilin/kexin type 9 (PCSK-9) inhibitors are administered as a second or even third option when the goal for a low-density lipoprotein cholesterol (LDL-C) level is not achieved. PCSK-9 inhibitors effectively decrease the LDL-C levels through the inhibition of PCSK-9-LDL-receptor complex formation. The in-depth understanding of the PCSK-9 protein mechanism in the metabolism of LDL-C led to the development of effective targeted approaches. Furthermore, a better understanding of the LDL-C metabolic pathway led to the development of newer approaches, which increased the therapeutic options. This article aims to offer an overview of the PCSK-9 inhibitors and their mechanism in reducing the LDL-C levels. Moreover, we will present the main indications of the current guidelines for patients with hyperlipemia and for those who have suffered an acute ischemic stroke, as well as the importance of LDL-C reduction in decreasing the rate of a recurrence.

show abstract

Section: Pcsk-9 Inhibitors and Adverse Reactionssupporting

confidence: 53%

Recent Advances on the Roles of PCSK-9 Inhibitors in the Management of Acute Ischemic Stroke Patients

Iluţ

Pirlog

Pîrlog

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…It was 4.8% for evolocumab and 4.3% for placebo in participants with >2.5 years of followup. A possible problem with all-cause mortality had already been shown in the preceding lipid-lowering trials: the pooled odds ratio was 1.18 (95% CI 0.46-3.02) [15].…”

Section: Increased Rate Of All-cause Mortalitymentioning

confidence: 89%

Evolocumab’s Long-Term Mortality Risk Unclear Due to Shortened Follow-Up of FOURIER

Bruggen

Luijendijk

2021

Am J Cardiovasc Drugs

View full text Add to dashboard Cite

The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 inhibition in Subjects with Elevated Risk) trial was conducted to study cardiovascular outcomes of treatment with evolocumab. The trial was terminated after a median follow-up of 2.2 years instead of the planned 3.6 years. We question this decision. According to the investigators, the event rate was 50% higher than expected. However, the accrued number of key secondary events (1829) was only 12% higher than the targeted number (1630). Also, around one-third of the events consisted of non-atherosclerotic myocardial infarctions, hemorrhagic strokes, and cardiovascular deaths unrelated to myocardial infarction or stroke. Moreover, halfway through the trial, the sample size changed from 22,500 to 27,500, even though the accrual of the targeted number of events was on track. Finally, the rate of all-cause mortality had started to diverge in favor of placebo after 2 years of follow-up. It was 4.8% for evolocumab and 4.3% for placebo in participants with > 2.5 years of follow-up. A long-term follow-up would have yielded more events and thus more power to evaluate the effect of evolocumab on all-cause mortality. We conclude that adaptive designs carry a recognized risk of false-positive efficacy results, but the risk of false-negative safety results is underappreciated.

show abstract

“…[ 161 ]. Additionally, meta-analyses and reviews of numerous randomized clinical trials did not reveal higher frequency in neurological disorders (including neurocognitive ones) with the use of PCSK9 inhibitors compared to the control groups [ 162 , 163 , 164 , 165 ].…”

Section: Pcsk9 and Central Nervous System (Cns)mentioning

confidence: 99%

Insight into the Evolving Role of PCSK9

et al. 2022

View full text Add to dashboard Cite

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.

show abstract

Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review

Cited by 22 publications

References 62 publications

Recent Advances on the Roles of PCSK-9 Inhibitors in the Management of Acute Ischemic Stroke Patients

Recent Advances on the Roles of PCSK-9 Inhibitors in the Management of Acute Ischemic Stroke Patients

Evolocumab’s Long-Term Mortality Risk Unclear Due to Shortened Follow-Up of FOURIER

Insight into the Evolving Role of PCSK9

Contact Info

Product

Resources

About