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Meta-Analysis
. 2018 Apr 1;4(2):132-141.
doi: 10.1093/ehjqcco/qcx037.

Neurological effects of proprotein convertase subtilisin/kexin type 9 inhibitors: direct comparisons

Navkaranbir S Bajaj  1   2 , Nirav Patel  2 , Rajat Kalra  3 , Amier Ahmad  4 , Anand Venkatraman  5 , Garima Arora  2 , Pankaj Arora  2   6
Affiliations
Meta-Analysis

Neurological effects of proprotein convertase subtilisin/kexin type 9 inhibitors: direct comparisons

Navkaranbir S Bajaj et al. Eur Heart J Qual Care Clin Outcomes. .

Abstract

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably alter the lipid profile. We sought to examine the rates of ischaemic stroke and neurocognitive deficits in patients treated with and without PCSK9 inhibitors.

Methods and results: Randomized controlled trials (RCTs) reporting rates of ischaemic stroke and neurocognitive deficits in patients using PCSK9 inhibitors were identified. Standard meta-analysis techniques were used to compare these outcomes among patients treated with and without PCSK9 inhibitors and the two US Food and Drug Administration-approved PCSK9 inhibitors, evolocumab and alirocumab. The results were presented in terms of risk ratio (RR) with 95% confidence intervals (CIs). Sixteen RCTs with 39 104 patients were included. Evolocumab was used in six RCTs with 33 450 patients, whereas alirocumab was used in 10 RCTs with 5654 patients. We observed a significantly lower risk of ischaemic stroke among those treated with PCSK9 inhibitors (RR 0.77, 95% CI 0.64-0.93) when compared with those without. We did not observe any difference in the risk of neurocognitive deficits between the aforementioned groups (RR 1.11, 95% CI 0.93-1.32). The lower stroke risk in the PCSK9 inhibitors group was driven by evolocumab studies. We observed no difference in the risk of neurocognitive deficits among evolocumab and alirocumab when compared with no PCSK9 inhibitors group.

Conclusion: Treatment with PCSK9 inhibitors significantly lowers the risk of ischaemic stroke, without any increased risk of neurocognitive deficits. PCSK9 inhibitors are neuroprotective due to the decrease in ischaemic-mediated neurovascular events and should be considered cognitively innocuous medications.

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Figures

Figure 1
Figure 1
Randomized controlled trials on PCSK9 inhibitors. Black diamond represents studies lacking desired outcomes; blue diamond represents studies using non-US-FDA-approved PCSK9 inhibitors; green diamond represents studies with overlapping population with OSLER 1 study; and maroon diamond represents studies with overlapping population with OSLER 2 study.
Figure 2
Figure 2
Flow diagram for study selection.
Figure 3
Figure 3
(A) Forest plot comparing the incidence of ischaemic stroke between PCSK9 inhibitor and the no PCSK9 inhibitor groups. (B) Forest plot comparing the incidence of ischaemic stroke between PCSK9 inhibitor and the no PCSK9 inhibitor groups in subgroups. The blue diamond is the point estimate representing the 95% confidence interval. The red dotted lines represent the random effects generated overall estimate. Data are presented with risk ratios and 95% confidence intervals. RR: risk ratio, PCSK9: proprotein convertase subtilisin/kexin type 9.
Figure 4
Figure 4
(A) Forest plot comparing the incidence of neurocognitive deficits between PCSK9 inhibitor and the no PCSK9 inhibitor groups. (B) Forest plot comparing the incidence of neurocognitive deficits between PCSK9 inhibitor and the no PCSK9 inhibitor groups in subgroups. The blue diamond is the point estimate representing the 95% confidence interval. The red dotted lines represent the random effects generated overall estimate. Data are presented with risk ratios and 95% confidence intervals. RR: risk ratio, PCSK9: proprotein convertase subtilisin/kexin type 9.
Figure 5
Figure 5
The funnel plot of studies reporting ischaemic stroke (A) and neurocognitive deficits (B). The solid line represents the summary effect line. The dashed lines represent the expected 95% confidence interval around summary estimate. The dark blue circles represent individual studies.
Figure 6
Figure 6
Meta-regression analysis showing the relationship between incidence of stroke (A) and neurocognitive deficits (B) with duration in weeks. Blue hollow circles represents individual study. Solid red line represents trend line.
Figure 7
Figure 7
Meta-regression analysis showing the relationship between incidence of stroke with baseline (A) and 12 weeks (B) LDL-C levels. Blue hollow circles represents individual study. Solid red line represents trend line.
Figure 8
Figure 8
Meta-regression analysis showing the relationship between incidence of neurocognitive deficits with baseline (A) and 12 weeks (B) LDL-C levels. Blue hollow circles represent individual study. Solid red line represents trend line.
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