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Macrovascular Residual Risk Studies

21 September 2022
ODYSSEY OUTCOMES: Apolipoprotein B provides incremental information for residual cardiovascular risk
A new analysis from the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial supports using apolipoprotein B (apoB) as a guide to the use of incremental intensive lowering of atherogenic lipoproteins in patients with an acute coronary syndrome (ACS) on statin therapy.
Hagström E, Steg PG, Szarek M, et al. Apolipoprotein B, residual cardiovascular risk after acute coronary syndrome, and effects of alirocumab. Circulation 2022 Jun 30:101161CIRCULATIONAHA121057807. doi: 10.1161/CIRCULATIONAHA.121.057807.
Objective: To investigate the relationships between baseline or achieved levels of apoB and risk of major adverse cardiovascular events (MACE) and to assess whether apoB provides incremental information on residual cardiovascular risk beyond low-density lipoprotein cholesterol (LDL-C), using data from the ODYSSEY OUTCOMES trial.
Study design: ODYSSEY OUTCOMES was a double-blind, randomized, parallel-group, placebo-controlled trial in patients with a recent ACS and elevated atherogenic lipoprotein levels (LDL-C ≥70 mg/dL [1.81 mmol/L], non–high-density lipoprotein cholesterol [HDL-C] ≥100 mg/dL [2.59 mmol/L], or apoB ≥80 mg/dL) despite high-intensity statin therapy. Patients were randomly allocated to treatment with either 75 mg alirocumab or matching placebo subcutaneously every 2 weeks. The trial design incorporated a dose titration design to ensure LDL-C remained within the target range (25-50 mg/dL or 0-64-1.29 mmol/L).
Study population: The trial included 18,924 ACS patients who were followed for a median of 2.8 years.
Primary variable: The primary outcome was MACE, defined as composite of coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischaemic stroke, or hospitalisation for unstable angina.
Methods: Post hoc analysis. Associations between baseline apoB or apoB at 4 months and MACE were assessed using adjusted Cox proportional hazards and propensity score–matched models.
Main results:

Median baseline apoB was 79 mg/dL (interquartile range [IQR] 69–93 mg/dL). In the placebo group, a higher apoB value was associated with an increased risk of MACE (Table 1), and this association persisted even after adjustment for baseline LDL-C. For every 10 mg/dL increase in baseline apoB, there was an 11% higher risk of MACE (1.11, 1.09–1.14; p<0.0001).

Table 1. Association of baseline apoB with risk for MACE in the placebo group


ApoB tertile

Hazard ratio (95% CI)

<75 mg/dL (n=7330)

75 and <90 (n=5874)

≥90 mg/dL (n=5720)



1.24 (1.06–1.45)

1.71 (1.48–1.97)



1.19 (1.02–1.40)

1.64 (1.41–1.90)

* adjustment for demographic and nonlipid clinical variables

At 4 months of treatment, the median apoB level was 39 mg/dL (IQR, 35–53 mg/dL) in the alirocumab group versus 80 mg/dL (IQR, 68–95 mg/dL) in the placebo group (absolute reduction from baseline with alirocumab 36 mg/dL). In the alirocumab group, lower achieved apoB at 4 months was associated with greater relative and absolute reductions in MACE after 4 months (Table 2). This association remained significant after adjustment for achieved levels of LDL-C and non–HDL-C.

In contrast, achieved levels of LDL-C or non–HDL-C were not predictive of MACE after taking achieved apoB into account.


Table 2. Association of achieved apoB with alirocumab treatment and subsequent risk for MACE


Achieved apoB tertile

Reduction in rate of MACE (95% CI),

per 100 patient-years

≤35 mg/dL

>35 to <50 mg/dL

≥50 mg/dL

4.26 (3.78–4.79)

3.09 (2.69–3.54)

2.41 (2.11–2.76

Treatment hazard ratio (95% CI)

0.73 (0.61–0.87)

0.79 (0.66–0.95)

0.99 (0.84–1.17)

Absolute risk reduction, events per 100 patient-years





Authors’ conclusion: In patients with recent ACS and elevated atherogenic lipoproteins, MACE increased across baseline apoB strata. Alirocumab reduced MACE across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACE, even after accounting for achieved LDL-C or non HDL-C, indicating that apoB provides incremental information. Achievement of an apoB level ≤35 mg/dL may reduce lipoprotein-attributable residual risk after ACS.


ApoB levels indicate the atherogenic particle concentration independent of the particle cholesterol or triglycerides content, which may be variable. Supported by extensive evidence, apoB represents the primary marker for assessment of cardiovascular risk attributable to apoB-containing lipoproteins (1,2). This may also have relevance for assessment of residual lipoprotein-related cardiovascular risk among very high risk individuals, such as those with ACS receiving intense statin therapy, as tested in this analysis from ODYSSEY OUTCOMES.

The key findings of this analysis are that irrespective of LDL-C levels on optimised statin therapy, higher on-treatment levels of apoB were associated with an increased risk of MACE. Moreover, the relationship with apoB was stronger than that observed between non-HDL-C and MACE, even after adjustment for achieved LDL-C levels. Thus, apoB may be a preferable marker of residual cardiovascular risk in ACS patients receiving high-intensity statin treatment. This would imply that the number of atherogenic apoB-containing particles is a better predictor of lipoprotein-related residual risk than the combined cholesterol content of those particles, consistent with other reports (3).

The analysis has implications for the management of residual cardiovascular risk in these very high-risk patients. Of those ACS patients meeting the guideline-recommended LDL-C goal (<55 mg/dL or <1.4 mmol/L) on the combination of statin plus alirocumab, less than half (40%) attained an apoB ≤35 mg/dL. Even among patients achieving LDL-C levels <22 mg/dL, nearly one in five (18%) did not achieve apoB levels ≤35 mg/dL. Thus, even with attainment of stringent LDL-C goals, lipoprotein-attributable residual risk persists. Treatment based on apoB goal may be a preferable strategy to reduce lipoprotein-attributable residual risk in ACS patients.

References 1. Sniderman AD, Navar AM, Thanassoulis G. Apolipoprotein B vs low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol as the primary measure of Apolipoprotein B lipoprotein-related risk: the debate Is over. JAMA Cardiol 2022;7:257-8.
2. Behbodikhah J, Ahmed S, Elyasi A, et al. Apolipoprotein B and cardiovascular disease: biomarker and potential therapeutic target. Metabolites 2021;11:690.
3. Marston NA, Giugliano RP, Melloni GEM, et al. Association of Apolipoprotein B-containing lipoproteins and risk of myocardial infarction in individuals with and without atherosclerosis: distinguishing between particle concentration, type, and content. JAMA Cardiol 2022;7:250-6.
Key words residual cardiovascular risk; apolipoprotein B; ODYSSEY OUTCOMES