Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial.

Cannon CP, Cariou B, Blom D, et al.
Eur Heart J. 2015 Feb 16, doi:10.1093/eurheartj/ehv028

Background

The reduction of low-density lipoprotein cholesterol (LDL-C) is the primary target to reduce cardiac events [1-3]. LDL-C reduction with statins lowers the risk of CHD events and all-cause mortality [4]. A substantial proportion of high-risk hypercholesterolaemic patients do not achieve adequate LDL-C reductions, in spite of intensive statin therapy [5,6]. Evidence is needed on new lipid-modifying agents, on top of statin therapy, regarding the event reduction in cardiovascular disease [7]. These therapies include fully human monoclonal antibodies against proprotein convertase subtilisin/
kexin 9 (PCSK9), such as alirocumab and evolocumab. Alirocumab reduces LDL-C concentrations by 40–70% in combination with other lipid-lowering therapies (LLT) or as monotherapy. The COMBO II study compares the efficacy and safety of alirocumab versus the non- statin agent ezetimibe as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia. The COMBO II is an ongoing double-blind, double-dummy, active-controlled, parallel-group, 104-week study that is conducted at 126 sites. Patients (n=720) were randomized to either 75 mg subcutaneous alirocumab every 2weeks (plus oral placebo) or 10 mg daily oral ezetimibe (plus subcutaneous placebo).

Main results

• After 24 weeks, a reduction in LDL-C of 50.6% was seen with alirocumab, and 20.7% with ezetimibe, both in addition to maximum tolerated statin treatment (LS mean difference (SE) vs. ezetimibe: -29.8% (2.3) P <0.0001).
• 77.0% of the patients achieved LDL-C target levels <1.8 mmol/L, compared to 45.6% of the ezetimibe-treated patients (P< 0.0001).
• 18% of patients randomized to alirocumab needed dose adjustment based on their LDL-C levels at week 12.
• The LDL-C decrease achieved with alirocumab was stable during the 52-week follow-up.
• These results were consistent across various patient subgroups.
• Typical statin-related adverse events were equally seen in the treatment arms. Small numerical differences in relevant side effects were observed, like more verified CV events (4.8% vs. 3.7% in alirocumab vs. ezetimibe), more injection-site reactions (2.5% vs. 0.8% with placebo injection), less neurocognitive disorders (0.8 % vs. 1.2%), more often ALT> 3x ULN (1.7% vs. 0.4%) and creatine kinase> 3x ULN (2.8% vs. 2.5%). The alirocumab injections were generally well tolerated and compliance with self-injections was good. 

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Conclusions

Adding alirocumab to a treatment regimen with maximally tolerated statins provided safe and substantial LDL-C reductions and more patients with hypercholesterolaemia can achieve LDL-C goals than by adding ezetimibe. These results are in line with the previous suggestion that maximum LDL-C response to a PCSK9 inhibitor is greater with combination therapy than with monotherapy. The COMBO II study is ongoing and will continue up to 104 weeks follow-up to maximize the available safety data and generate information on the durability of alirocumab lipid-lowering effects [8].

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