A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I

Roth, Eli M.; Moriarty, Patrick M.; Bergeron, Jean; Langslet, Gisle; Manvelian, Garen; Zhao, Jian; Baccara‐Dinet, Marie T.; Rader, Daniel J.

doi:10.1016/j.atherosclerosis.2016.08.043

Cited by 97 publications

(81 citation statements)

References 19 publications

(17 reference statements)

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“…5,10–14,16,17,25 We observed that evolucumab had lower risk of stroke when compared with no PCSK9 inhibitors (RR 0.75, 95% CI 0.62–0.91), and we did not observe any difference in the risk of ischaemic stroke between the alirocumab and no PCSK9 inhibitors (RR 1.71, 95% CI 0.64–5.36) (Figure 3B). No difference was observed in the risk of neurocognitive deficits between evolocumab (RR 1.42, 95% CI 0.74–2.73) and alirocumab (RR 1.04, 95% CI 0.56–1.94) compared with no PCKS9 inhibitors (Figure 4B).…”

Section: Resultsmentioning

confidence: 65%

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

Bajaj

Patel

Kalra

et al. 2017

European Heart Journal - Quality of Care and Clinical Outcomes

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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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Section: Resultsmentioning

confidence: 65%

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

Bajaj

Patel

Kalra

et al. 2017

European Heart Journal - Quality of Care and Clinical Outcomes

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“…A total of 138 study arms from 35 studies were analyzed, comprising 45 539 patients (Table S1). 5, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 Alirocumab was used in 18 studies (28 treatment arms), and evolocumab was used in 17 studies (39 treatment arms; Figure 1); placebo was the most common control used (52 control arms), with ezetimibe used in 17 arms, and standard therapy in 2 arms. Eight studies were of an exclusively FH population, and 5 studies included only patients intolerant to statins.…”

Section: Resultsmentioning

confidence: 99%

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Karatasakis

Danek

Karácsonyi

et al. 2017

JAHA

155

104

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BackgroundWe sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab.Methods and ResultsWe performed a systematic review and meta‐analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45 539 patients (mean follow‐up: 85.5 weeks) were included. Mean age was 61.0±2.8 years, and mean baseline low‐density lipoprotein cholesterol was 106±22 mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64–0.81]; P<0.001), stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67–0.96]; P=0.02), and coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71–0.86]; P<0.001). Overall, no significant change was observed in all‐cause mortality (OR: 0.71 [95% CI, 0.47–1.09]; P=0.12) or cardiovascular mortality (OR: 1.01 [95% CI, 0.85–1.19]; P=0.95). A significant association was observed between higher baseline low‐density lipoprotein cholesterol and benefit in all‐cause mortality (P=0.038). No significant change was observed in neurocognitive adverse events (OR: 1.12 [95% CI, 0.88–1.42]; P=0.37), myalgia (OR: 0.95 [95% CI, 0.75–1.20]; P=0.65), new onset or worsening of preexisting diabetes mellitus (OR: 1.05 [95% CI, 0.95–1.17]; P=0.32), and increase in levels of creatine kinase (OR: 0.84 [95% CI, 0.70–1.01]; P=0.06) or alanine or aspartate aminotransferase (OR: 0.96 [95% CI, 0.82–1.12]; P=0.61).ConclusionsTreatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes. Although no overall benefit was noted in all‐cause or cardiovascular mortality, such benefit may be achievable in patients with higher baseline low‐density lipoprotein cholesterol.

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“…Phase 2 studies indicated that efficacy was not fully maintained over the dosing interval when alirocumab 150 mg Q4W was co-administered with a statin2122, probably because of statin-induced increases in PCSK9 levels leading to increased alirocumab clearance19. However, efficacy was stable with the 150 mg Q2W dose when co-administered with a statin2122, and has also been shown to be relatively stable with a dose of 300 mg Q4W23.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of alirocumab according to background statin type and dose: pooled analysis of 8 ODYSSEY Phase 3 clinical trials

Catapano

Lee

Louie

et al. 2017

Sci Rep

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Low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 monoclonal antibody alirocumab may be affected by background statin dose due to increased PCSK9 levels with higher statin doses. Data from 8 Phase 3 trials conducted with background statin (n = 4629) were pooled by alirocumab dose (75 or 150 mg every 2 weeks) and control (placebo/ezetimibe), and analyzed by background statin type/dose. Overall, 58.4% received high-dose statins (atorvastatin 40–80 mg, rosuvastatin 20–40 mg, simvastatin 80 mg), 28.6% moderate-dose statins (atorvastatin 20–<40 mg, rosuvastatin 10–<20 mg, simvastatin 40–<80 mg), and 12.9% low-dose statins (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <40 mg). Mean baseline PCSK9 levels were higher with high versus moderate and low statin doses (318.5 vs 280.6 ng/mL). Baseline LDL-C levels were similar across pools, regardless of statin intensity. No associations were observed between statin type/dose and LDL-C % change from baseline or % of patients achieving LDL-C goals at Week 24 for alirocumab versus control (interaction P-values non-significant). Incidence of adverse events was similar for alirocumab versus control, except for a higher rate of injection-site reactions with alirocumab. In summary, alirocumab provided consistent LDL-C reductions and was generally well tolerated independent of background statin type/dose.

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A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I

Abstract: Alirocumab 300 mg Q4W is a viable additional treatment option in patients requiring LDL-C-lowering.

Cited by 97 publications

References 19 publications

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

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

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Efficacy of alirocumab according to background statin type and dose: pooled analysis of 8 ODYSSEY Phase 3 clinical trials

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