ODYSSEY Outcomes: Cardiovascular outcomes with alirocumab after acute coronary syndrome

Reported from the ACC Scientific Sessions 2018 (ACC.18) in Orlando, United States

Patients with ACS experience adverse events despite guideline recommended care. This reiterates the need for additional therapy to address this problem in addition to standard care. Alirocumab in ODYSSEY Outcomes, the first trial conducted exclusively in ACS patients, provides promise with 15% reduction in MACE events.

Why is this trial important?

Despite all the advances in cardiovascular medicine, we continue to see high rates of recurrent cardiovascular events among patients following an index event particularly in the setting of an acute coronary syndrome with cardiovascular mortality up to 15% in the first 5 years post event. Several studies have now been conducted or underway to see if these events can be reduced further. ODYSSEY Outcomes is one such randomised controlled trial.

The aim of this study was to evaluate if reduction in LDL-C with subcutaneous administration of PCSK9 inhibitor (a human monoclonal antibody) alirocumab (bi-weekly injection 75-150 mg) compared with matching placebo on top of maximum tolerated approved doses of atorvastatin or rosuvastatin fulfilling 1 of the criteria: LDL-C >/=70mg/dL, non HDL-C >/=100 mg/dL or apolipoprotein cholesterol >/=80mg/dL will reduce the occurrence of a composite of coronary heart disease death, non-fatal MI, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalisation (MACCE) in patients aged 40 years and over who had ACS 4-52 weeks prior to randomisation. Patients with LDL-C less than 70mg/dL were excluded. The study duration was 64 months. In total 18,924 patients (n=9462 alirocumab, n=9462) were recruited with median follow-up of 2.8 years from 57 countries.

What were the results?

Median age was 58 years in both groups and all other baseline data were matched between the 2 groups. 49% of patients had NSTEMI, 35% STEMI, unstable angina 17%, revascularisation for index event occurred in 72% of patients. Median LDL-C level was 87 mg/dL. High dose atorvastatin or rosuvastatin was used in 89% of patients. At 1 year with alirocumab there was 61% reduction in LDL-C.

ODYSSEY Outcomes demonstrated an absolute reduction of 1.6% in the composite primary outcome with alirocumab compared with placebo (Hazard Ratio 0.85, 95% CI 0.78-0.93, P=0.0003). There were no differences on the adverse reactions between the 2 groups other than minor problems at the injection site in the Alirocumab group. The primary efficacy MACE reduction was primarily driven by non-fatal MI (HR 0.86, 95%CI 0.77-0.96; p=0.006), ischemic stroke (HR 0.73, 95%CI 0.57-0.93; p=0.01) and unstable angina (HR 0.61, 95%CI 0.41-0.92; p=0.02).

Importantly in the secondary outcome efficacy analysis, there was a 15% reduction (absolute risk reduction of 0.6%) in the all-cause death with alirocumab (HR 0.85, 0.73-0.98; p=0.026), 12 % reduction in ischemia driven revascularisation (p=0.009). Interestingly the patients that benefitted the most were those that had LDL-C levels >/=100mg/dL with 24% (ARR 3.4%) reduction in the primary efficacy endpoint and 29% reduction (ARR 1.7%) in all-cause death in this group. This group also had significant reduction in CHD death (28%), CV death (31%). The investigators concluded that alirocumab compared with placebo reduced MACE, MI and ischemic stroke. It was associated with lower rate of all-cause death. It was safe and well tolerated over the duration of the trial. It is important to note the main differences in the Fourier Outcomes trial and Odyssey Outcomes trial are as follows: Fourier consisted of stable atherosclerosis patients with Odyssey consisting of ACS patients with >3year F/U and on maximum statin therapy.

My take on ODYSSEY Outcomes

Patients with ACS experience adverse events despite guideline recommended care. This reiterates the need for additional therapy to address this problem in addition to standard care. Alirocumab in ODYSSEY Outcomes, first trial conducted exclusively in ACS patients provides promise with 15% reduction in MACE events. This benefit was particularly noted in those patients with high LDL-C >/=100mg/dL. The challenges associated with translating this into practice will be the high costs of the drug (2015- $14,300/year) which may not be affordable in many countries and the need for sub-cutaneous injections. However, given repeat events and the resulting repeat hospitalisations also lead to excess healthcare cost, whether identifying at risk patients up front and initiating therapy will make this drug cost effective needs to be carefully evaluated!

PCRonline cardio poll results

Prior to the release of the results at ACC.18, we asked our website audience which results they were expecting - view the ODYSSEY Outcomes poll results here.

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