ODYSSEY OUTCOMES: Uncertainty persists about CV benefit at LDL cholesterol <25 mg/dL
This latest analysis from the ODYSSEY OUTCOMES Investigators sought to resolve uncertainty regarding additional cardiovascular benefit at very low LDL cholesterol levels.
Recent guidelines have lowered LDL cholesterol goals in very high-risk patients, to as low as 40 mg/dL (1.0 mmol/L) in patients with recurrent cardiovascular events in the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidaemia guidelines (1). Moreover, according to the ESC/EAS guidelines, the lower the achieved LDL cholesterol value, the better for cardiovascular outcome.
PCSK9 inhibitors have transformed the ability of clinicians to achieve very low LDL cholesterol levels in high-risk patients. However, whether there is additional cardiovascular benefit at these very low LDL cholesterol levels is still uncertain. There is some evidence from statin studies suggesting that there is a lower risk of major adverse cardiovascular events (MACE) at achieved LDL cholesterol levels below 40 mg/dL (2,3), but beyond these levels, there are limited data. Moreover, comparison of cardiovascular benefit at different achieved LDL cholesterol levels may be confounded by other factors including differences in characteristics prognostic for MACE. Consequently, this latest analysis from the ODYSSEY OUTCOMES study sought to overcome these limitations, in a prespecified analysis using propensity score matching to compare patients by tertile of achieved LDL cholesterol with alirocumab versus those in the placebo group with similar baseline characteristics and study medication adherence (4).
Patients allocated to alirocumab were categorized according to measured LDL cholesterol level at month 4 after randomization: >50 mg/dL (n=2197), 25−50 mg/dL (n=3692), or <25 mg/dL (n=3357). The month 4 time point was chosen because it was the nadir for LDL cholesterol levels on alirocumab. Baseline characteristics, incidence rates for MACE, treatment hazard ratio (HR) with 95% confidence interval (CI), and absolute risk reduction (ARR) after month 4 were summarized for each LDL cholesterol category in the alirocumab and placebo groups.
Median LDL cholesterol levels were 99 mg/dL, 88 mg/dL and 79 mg/dL in the >50, 25−50, and <25 mg/dL strata, respectively. Baseline lipoprotein(a)and other nonlipid characteristics also differed between the groups. The >50 mg/dL stratum was younger, had more females and greater use of revascularization procedures for the index acute coronary syndrome (ACS), and the 25−50 mg/dL stratum tended to have less intensive statin therapy and a lower prevalence of diabetes and heart failure. In contrast, the <25 mg/dL stratum was more likely to be on more intensive statin therapy, male sex, and have higher systolic blood pressure and lower prevalence of heart failure. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups.
The effect of alirocumab on risk for MACE was similar for the two lower LDL cholesterol strata. Patients with achieved LDL cholesterol >50 mg/dL had poorer adherence and derived less benefit (Table 1).
Table 1. Hazard ratio and 95% CI for alirocumab versus placebo by month 4 LDL cholesterol level
|LDL cholesterol at month 4 (mg/dL)||Hazard ratio (95% CI)||Absolute risk reduction|
|<25||0.74 (0.62 to 0.89)||0.92|
|25-50||0.74 (0.64 to 0.87)||1.05|
|>50||0.87 (0.73 to 1.04)||0.62|
There were no apparent safety concerns, even at achieved LDL cholesterol levels <15 mg/dL.
In conclusion, this ODYSSEY OUTCOMES analysis supports recent guidelines for lower LDL cholesterol goals in very high-risk patients. However, whether there is further cardiovascular benefit significantly below these goals is still uncertain.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-188. PUBMED https://pubmed.ncbi.nlm.nih.gov/31504418/
- Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014;64:485-494. PUBMED https://pubmed.ncbi.nlm.nih.gov/25082583/
- Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol 2011; 57:1666-1675. PUBMED https://pubmed.ncbi.nlm.nih.gov/21492764/
- Schwartz GG, Steg PG, Bhatt DL et al. Clinical efficacy and safety of alirocumab after acute coronary syndrome according to achieved level of low-density lipoprotein cholesterol: a propensity score-matched analysis of the ODYSSEY OUTCOMES Trial. Circulation 2021; doi: 10.1161/CIRCULATIONAHA.120.049447. Online ahead of print. PUBMED https://pubmed.ncbi.nlm.nih.gov/33438437/