Elevated lipoprotein(a) and coronary risk in acute coronary syndrome patients

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8 January 2024

This observational study in patients with coronary artery disease and elevated lipoprotein(a) [Lp(a)] levels, consistent with the population enrolled in the ongoing Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction [OCEAN(a)]-Outcomes trial, provides valuable insights.

Shiyovich A, Berman AN, Besser SA, et al. Cardiovascular outcomes in patients with coronary artery disease and elevated lipoprotein(a): implications for the OCEAN(a)-outcomes trial population. Eur Heart J Open 2023;3, 1–4.

STUDY SUMMARY

Objective:

To evaluate the association of elevated Lp(a) concentration with cardiovascular outcomes in an observational cohort resembling the OCEAN(a)-Outcomes trial main enrolment criteria.

Study design:

Observational cohort derived from a large retrospective Lp(a) registry (patient inclusion between 2000 and 2019).

Study population:

3,142 patients (median age 61 years, 29% women), with a history of myocardial infarction (MI) or percutaneous coronary intervention (PCI) were included. Patients with severe kidney dysfunction or a malignant neoplasm were excluded.

Primary variable:

The primary outcome was a composite of coronary heart disease (CHD) death, myocardial infarction (MI), or coronary revascularization.

Methods:

Elevated Lp(a) was defined as ≥200 nmol/L, consistent with the OCEAN(a)-Outcomes trial. Kaplan–Meier survival curves were compared using the log-rank tests. Cox proportional hazard regressions were used to assess the association of Lp(a) groups (with or without elevated Lp(a)) on cardiovascular outcome.

Results:

Overall, 12.3% of the cohort had elevated Lp(a) concentration; these patients were more likely to be women (37.6% versus 27.3%) and have hyperlipidaemia compared with those with Lp(a) <200 nmol/L. Over a median follow-up of 12.2 years, the primary composite outcome occurred more frequently in patients with versus those without elevated Lp(a) (46.0% vs. 38.0%, Table 1).

Table 1. Hazard ratio for cardiovascular outcomes associated with Lp(a) ≥ 200 vs. <200 nmol/L. CI confidence interval

Variable	Unadjusted Hazard ratio (95% CI)	p-value
Primary outcome	1.30 (1.09–1.53)	0.003
CHD death	1.40 (1.07–1.83)	0.013
MI	1.41 (1.12–1.78)	0.004
Coronary revascularization	1.40 (1.13–1.72)	0.002

Elevated Lp(a) was still independently associated with the primary outcome after adjustment for age, sex, hypertension, hyperlipidaemia, diabetes mellitus, chronic kidney disease, and smoking (Hazard ratio 1.33, 95%CI 1.12–1.58), p = 0.001).

Author conclusion:

In an observational cohort resembling the main OCEAN(a)-Outcomes Trial enrolment criteria, patients with an Lp(a) ≥200 nmol/L had a higher risk of cardiovascular outcomes.

COMMENT

Extensive evidence supports Lp(a) as a causal risk factor for cardiovascular outcomes, and a contributor to residual cardiovascular risk in high-risk patients (1). Identification and management of elevated Lp(a) concentration, however, suffers from a lack of effective and specific therapies. Novel RNA approaches targeting apolipoprotein(a) [apo(a)] synthesis have been shown to be effective and well tolerated (2-4), although it is still uncertain whether lowering Lp(a) concentration will translate to reduction in cardiovascular outcomes. Trials to address this question are underway; one is the OCEAN(a)-Outcomes trial with olpasiran (5).

The current report aimed to evaluate the association of elevated Lp(a) with cardiovascular outcomes in an observational cohort from a quality Lp(a) registry using the same main inclusion criteria as in the OCEAN(a)-Outcomes trial. The primary outcome was a composite of CHD death, MI, or coronary revascularization. The results of the study show that elevated Lp(a) increases the risk of cardiovascular events in patients already at very high risk who are treated with a statin (90% of the cohort) and other lipid lowering therapy (24.9% of patients with elevated Lp(a) levels versus 14.% in those without). This association persisted after adjustment for multiple confounders. The findings are consistent with other reports that elevated Lp(a) worsens outcome in patients with established cardiovascular disease (1,6).

Despite the retrospective design and potential selection bias, the results of this study support the selection criteria of the OCEAN(a)-Outcomes Trial. Importantly, the results also underline the urgent need to identify and treat elevated Lp(a) levels in this very high-risk patient population.

References

1. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925-46.
2. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244–55.
3. O'Donoghue ML, Rosenson RS, Gencer B, et al; OCEAN(a)-DOSE Trial Investigators. Small interfering RNA to reduce Lipoprotein(a) in cardiovascular disease. N Engl J Med 2022;387:1855-64.
4. Nissen SE, Wolski K, Balog C, et al. Single ascending dose study of a short interfering RNA targeting Lipoprotein(a) production in individuals with elevated plasma Lipoprotein(a) levels. JAMA 2022;327:1679-87.
5. Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction (OCEAN(a)) - Outcomes Trial (ClinicalTrials.gov Identifier: NCT05581303).
6. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019;139:1483–92.

Key words

lipoprotein(a); cardiovascular risk; OCEAN(a)-outcomes trial; registry