The Association of Lipoprotein(a) and Stroke Recurrence: A Systematic Review and Meta-Analysis
Article information
Abstract
Background and Purpose
Lipoprotein(a) [Lp(a)] is a lipoprotein structurally similar to low-density lipoprotein and is considered a genetically determined risk factor for cardiovascular disease. Although Lp(a) has been linked to ischemic stroke, its role in secondary stroke prevention, particularly in stroke recurrence, remains unclear.
Methods
A systematic search of MEDLINE and Scopus databases was conducted to identify randomized controlled trials (RCTs) and observational studies reporting Lp(a) levels in patients with ischemic stroke or transient ischemic attack. The primary outcome was stroke recurrence, and secondary outcomes included poor functional outcome, all-cause mortality, and recurrent vascular events. Pooled odds ratios (ORs) were calculated using a random-effects model.
Results
A total of 12 studies, including one RCT post hoc analysis and 11 observational studies, comprising 17,903 patients (mean age 63 years, 38% female), were included. Elevated Lp(a) levels were significantly associated with increased stroke recurrence (OR: 1.69; 95% confidence interval [CI]: 1.09–2.63; P=0.020) and poor functional outcome (OR: 2.09; 95% CI: 1.40–3.11; P<0.001). No significant associations were found between Lp(a) levels and all-cause mortality (OR: 2.20; 95% CI: 0.89–5.43; P=0.088) or recurrent vascular events (OR: 2.66; 95% CI: 0.95–7.44; P=0.063).
Conclusion
Elevated Lp(a) levels are linked to increased stroke recurrence and poor functional outcome in stroke patients. Lp(a) may represent a novel therapeutic target in secondary stroke prevention in addition to a promising biomarker.
Introduction
Lipoprotein(a) [Lp(a)] is a complex lipoprotein particle structurally similar to low-density lipoprotein cholesterol (LDL-C), distinguished by the presence of apolipoprotein(a), which is covalently bound to apolipoprotein B-100 [1]. Elevated levels of Lp(a) have been recognized as a genetically determined, independent risk factor for cardiovascular disease, including coronary artery disease and ischemic stroke. Its pathophysiological role is thought to arise from both prothrombotic and atherogenic mechanisms, contributing to plaque instability, thrombosis, and vascular inflammation [2].
Previous studies have demonstrated an association between increased Lp(a) levels and adverse cardiovascular outcomes, particularly among patients with coronary artery disease [3,4]. Furthermore, high Lp(a) levels are considered a risk factor for ischemic stroke, particularly in younger individuals and in patients without traditional vascular risk factors [5]. However, the clinical relevance of elevated Lp(a) in secondary stroke prevention, specifically its role in stroke recurrence, remains unclear.
In recent years, there has been growing interest in therapeutics specifically targeting Lp(a) levels. Novel agents, including antisense oligonucleotides and small interfering RNA-based therapies, have shown promising results in significantly reducing plasma Lp(a) concentrations in early-phase clinical trials [6]. These therapies work by selectively inhibiting the hepatic production of apolipoprotein(a), thereby lowering circulating Lp(a) levels by up to 80%–90%. Ongoing large-scale randomized controlled trials (RCTs) are evaluating whether such reductions can translate into improved cardiovascular and cerebrovascular outcomes, potentially establishing Lp(a) as not only a biomarker but also a modifiable risk factor.
In view of the former considerations, we conducted a systematic review and meta-analysis, including all available randomized and observational evidence, evaluating the role of Lp(a) in stroke prognosis and, more specifically, in stroke recurrence among patients with ischemic stroke or transient ischemic attack.
Methods
Standard protocol approvals, registrations, and patient consents
The prespecified protocol for this systematic review and meta-analysis has been registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration ID: CRD42024603931) and adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [7] and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines [8].
Data sources, searches, and study selection
A systematic literature search was conducted to identify eligible studies (RCTs, observational cohort studies, or individual patient data meta-analysis of studies) including adult patients with ischemic stroke or transient ischemic attack for whom Lp(a) levels were measured at baseline. Patients with elevated levels of Lp(a) were compared to those with low levels of Lp(a). Reporting of any of the outcomes of interest as outlined below was required for studies to be considered eligible for inclusion. The literature search was performed independently by three reviewers (LP, KM, MIS). The electronic databases MEDLINE and Scopus were searched, using search strings that included the terms “lipoprotein(a)” and “stroke recurrence.” Studies published in English were considered eligible. Our search spanned from the inception of each database to October 20, 2024.
Studies without a control arm, case series, and case reports were excluded. Commentaries, editorials, and narrative reviews were also discarded. In case of studies with duplicate data, the most recent study, further accounting for the number of included patients and outcome reporting, was retained, while the rest were excluded. All retrieved studies were independently assessed by three reviewers (LP, KM, MIS), resolving any disagreements through discussion with the corresponding author (GT).
Quality control, bias assessment, and data extraction
Two reviewers (LP and KM) independently assessed the quality control and bias assessment among eligible studies employing the revised Cochrane Risk-of-Bias tool (RoB 2) for RCTs [9] and the Risk Of Bias In Non-randomized Studies of Exposures (ROBINS-E) tool for observational studies [10]. Any disagreements were settled by consensus after discussion with the corresponding author (GT). Structured forms, which included trial names, year of publication, period of enrollment, patient sample, patients’ characteristics, and outcomes of interest, were used for data extraction.
Outcomes
The primary outcome of interest was stroke recurrence at follow-up, including ischemic stroke, hemorrhagic stroke, any stroke, or transient ischemic attack, as defined by each study. Poor functional outcome, as defined by each study based on dichotomized modified Rankin Scale (mRS) scores (0–2 vs. 3–6 & 0–1 vs. 2–6), all-cause mortality, and recurrent vascular events at follow-up were evaluated as secondary outcomes of interest.
Statistical analysis
For the pairwise meta-analysis, we calculated the corresponding odds ratios (OR) with 95% confidence intervals (CI) for each dichotomous outcome of interest, for the comparison of outcome events among patients with high Lp(a) levels versus those with low Lp(a) levels. Sensitivity analyses were conducted to address variations in outcome definitions by excluding studies with differing definitions. Furthermore, a subgroup analysis was performed for the primary outcome after stratification according to trial setting and population (i.e., Chinese vs. non-Chinese). Baseline characteristics were described using pooled proportions (after the implementation of the variance-stabilizing double arcsine transformation) for categorical variables and mean values for continuous variables. For studies reporting continuous outcomes in median values and corresponding interquartile ranges, the sample mean and standard deviation were estimated using the quantile estimation method [11]. The random-effects model (DerSimonian and Laird 1986) was used to calculate the pooled estimates [12]. The threshold for statistical significance for the above analyses was set at a two-sided P-value of <0.05. Heterogeneity was assessed with the I2 and Cochran Q statistics. For the qualitative interpretation of heterogeneity, I2 values <25%, between 25%–50%, and >50% were considered to represent low, moderate, and significant heterogeneity, respectively. The significance level for the Q statistic was set at 0.1. The above statistical analyses were performed using the R software version 3.5.0 (package: meta; R Foundation for Statistical Computing, Vienna, Austria) [13].
Data availability statement
All data generated or analyzed during this study are included in this article and its supplementary information files.
Results
Literature search and included studies
The flow diagram for the selection and inclusion of studies in this systematic review is presented in Figure 1. After excluding duplicates, the systematic literature database search yielded a total of 1,028 records. Following the initial screening process, the full texts of 36 records were retrieved. After reading the full-text articles, 24 records were further excluded. Finally, 12 eligible studies (one post hoc analysis of an RCT and 11 observational studies) (Table 1) [14-25] were included in the systematic review and meta-analysis, comprising a total of 17,903 ischemic stroke patients for whom Lp(a) was measured at baseline. Included patients had a mean age of 63 years (Supplementary Figure 1), and 38% were of female sex (Supplementary Figure 2). The majority of the cases presented moderate stroke (mean National Institutes of Health Stroke Scale [NIHSS] score: 7) (Supplementary Figure 3), of which 25% received intravenous thrombolysis and 13% endovascular treatment (Supplementary Figure 4). Twenty-nine percent of the cases were attributed to large-artery atherosclerosis (Supplementary Figure 5), and the mean baseline Lp(a) levels were 34.4 mg/dL (Supplementary Figure 6).
Flowchart of the systematic review.
Characteristics of studies included in the systematic review and meta-analysis
Quality control of included studies
There was no significant bias detected in any of the quality domains assessed for the study of Chemello et al.,16 which was the only post hoc analysis of an RCT included in this systematic review (Supplementary Figure 7). The majority of the observational studies presented a moderate risk of bias (Supplementary Figure 8), mainly due to unblinded outcome measurements and losses to follow-up, with a lesser contribution from selection bias (inclusion of ischemic stroke patients with diabetes or under statin treatment) and reporting bias (incomplete reporting of outcome data). Only two of the observational studies were graded as “low risk of bias” in all domains.
Quantitative analyses
Regarding the overall effect for the primary outcome of interest, increased levels of Lp(a) were associated with stroke recurrence (OR: 1.69; 95% CI: 1.09–2.63; P=0.020; 5 studies; I2=87%; P for Cochran Q<0.01) (Figure 2). A sensitivity analysis was further conducted to ensure homogeneity of stroke recurrence definition, by excluding the study of Chemello et al.16 that had a more inclusive definition for stroke recurrence taking into account not only ischemic stroke, hemorrhagic stroke, or transient ischemic attack, but also cases with carotid revascularization. In the sensitivity analysis, high Lp(a) levels were again significantly associated with stroke recurrence at follow-up (OR: 2.28; 95% CI: 1.23–4.21; P=0.008; 4 studies; I2=84%; P for Cochran Q<0.01) (Supplementary Figure 9). After stratification for trial setting and population, there were no significant subgroup differences for the primary outcome among studies that included Chinese versus non-Chinese patients (P for subgroup differences =0.82) (Supplementary Figure 10).
Forest plot presenting the odds ratio of stroke recurrence among patients with high Lp(a) compared to patients with low Lp(a). Lp(a), lipoprotein(a); IV, inverse variance; CI, confidence interval.
Regarding the secondary outcomes of interest, high Lp(a) levels were associated with increased odds of poor functional outcome at follow-up (OR: 2.09; 95% CI: 1.40–3.11; P<0.001; 5 studies; I2=77%; P for Cochran Q<0.01) (Figure 3). During sensitivity analysis, the study of Chakraborty et al.15 that defined poor functional outcome as mRS scores of 2–6 was excluded to ensure the homogeneity of definition (i.e., the rest of the studies used the dichotomized mRS score of 3–6 to define poor functional outcome). This sensitivity analysis confirmed similar results (OR: 1.96; 95% CI: 1.29–2.97; P=0.002; 4 studies; I2=79%; P for Cochran Q<0.01) (Supplementary Figure 11).
Forest plot presenting the odds ratio of poor functional outcomes among patients with high Lp(a) compared to patients with low Lp(a). Lp(a), lipoprotein(a); IV, inverse variance; CI, confidence interval.
Furthermore, high Lp(a) levels were not associated with mortality (OR: 2.20; 95% CI: 0.89–5.43; P=0.088; 3 studies; I2=66%; P for Cochran Q=0.05) (Figure 4). Finally, there was no association between Lp(a) levels and recurrent vascular events (OR: 2.66; 95% CI: 0.95–7.44; P=0.063; 3 studies; I2=86%; P for Cochran Q<0.01) (Figure 5).
Forest plot presenting the odds ratio of mortality among patients with high Lp(a) compared to patients with low Lp(a). Lp(a), lipoprotein(a); IV, inverse variance; CI, confidence interval.
Forest plot presenting the odds ratio of recurrent vascular events among patients with high Lp(a) compared to patients with low Lp(a). Lp(a), lipoprotein(a); IV, inverse variance; CI, confidence interval.
Discussion
This systematic review and meta-analysis demonstrates that elevated Lp(a) levels are associated with higher odds of recurrent stroke and poor functional outcome among patients with ischemic stroke. However, no significant association was observed between Lp(a) levels and mortality or recurrent vascular events, suggesting that the impact of Lp(a) may be more specific to certain post-stroke outcomes.
The observed association between Lp(a) and stroke recurrence may be attributed to the promotion of both atherogenic and thrombotic processes through the structural similarity of Lp(a) to LDL-C and plasminogen, contributing to plaque formation, vascular inflammation, and impaired fibrinolysis [26,27]. These mechanisms may increase the risk of vascular events, particularly in cerebral arteries. In addition, the strong association of higher Lp(a) levels with large artery atherosclerotic stroke, independent of vascular risk factors, may also partially explain our study findings, since large-artery atherosclerosis is the stroke subtype carrying the highest risk of stroke recurrence [28]. Notably, elevated Lp(a) levels have been linked to large-artery atherosclerosis-associated stroke compared to other subtypes, as previously demonstrated [14]. However, there is insufficient data to explore a potential interaction of large-artery atherosclerosis on the association between Lp(a) and stroke outcomes.
Furthermore, higher Lp(a) levels may lead to greater stroke severity, potentially explaining the association with unfavorable functional outcomes. In fact, a positive correlation between NIHSS and Lp(a) has been shown by previous studies [15,18,22,25]. However, the association of Lp(a) with unfavorable outcomes and mortality persisted even after adjustment for baseline NIHSS [22,25].
Despite its potential clinical relevance, current guidelines offer limited recommendations regarding Lp(a) management. The 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines recommend measuring Lp(a) at least once in individuals at high cardiovascular risk, especially those with a family history of premature cardiovascular disease or recurrent events despite optimal LDL-C-lowering therapy [29]. Similarly, a recent focused update to the 2019 National Lipid Association scientific statement also recognizes Lp(a) as an important biomarker to refine cardiovascular risk assessment [30]. However, no clear guidance exists on the management of elevated Lp(a) levels specifically for secondary stroke prevention.
Traditionally, stroke prevention strategies have focused on reducing LDL-C levels through statin therapy. While LDL-C reduction is essential, our findings highlight the importance of also considering Lp(a) as a potential therapeutic target [16,17]. Nevertheless, it is crucial to recognize that the association between Lp(a) and stroke recurrence, as demonstrated in our meta-analysis, does not imply causation. Ongoing research, including RCTs investigating Lp(a)-targeting therapies (e.g., antisense oligonucleotides and small interfering RNA), may clarify whether lowering Lp(a) may improve long-term outcomes after stroke [31].
The primary strength of this systematic review lies in its comprehensive analysis of all available studies to date that evaluate the association between baseline Lp(a) and stroke outcomes. In total, our meta-analysis encompasses more than 17,000 ischemic stroke patients, offers a broader perspective, and helps contextualize the findings of individual studies. While another systematic review on Lp(a) and stroke has recently been published [32], several limitations restrict the generalizability of its findings, including a narrower focus on only functional outcomes, a smaller sample size, and an overrepresentation of studies conducted in China.
Nonetheless, this study has several limitations that should be acknowledged. First, the vast majority of the included studies were observational, which inherently limits the strength of the evidence due to potential confounding and bias. Second, the observational studies included in this review were found to have moderate risk of bias, primarily due to unblinded outcome assessments and missing data, which could have affected the results. Third, significant heterogeneity was detected in the analysis of all outcomes, likely due to variations in study design, patient populations, and definitions of outcomes. However, in a subgroup analysis stratifying for trial setting and population, there were no differences among studies including Chinese versus non-Chinese patients. Fourth, the present analyses were not adjusted for vascular risk factors, acute reperfusion treatments, and underlying stroke subtypes. However, sensitivity analyses confirmed the robustness of the primary findings, reinforcing the consistency of the results.
Conclusions
In conclusion, while our meta-analysis indicates that elevated Lp(a) levels are associated with stroke recurrence and poor functional outcomes, further research, particularly through well-designed RCTs, is needed to establish causal relationships and guide the development of targeted interventions for Lp(a) management in patients with ischemic stroke.
Supplementary materials
Supplementary materials related to this article can be found online at https://doi.org/10.5853/jos.2024.04623.
Forest plot presenting the mean age (in years) among included patients. IV, inverse variance; CI, confidence interval; SD, standard deviation.
Forest plot presenting the pooled proportion of female sex among included patients. IV, inverse variance; CI, confidence interval.
Forest plot presenting the mean NIHSS score among included patients. IV, inverse variance; CI, confidence interval; SD, standard deviation; NIHSS, National Institutes of Health Stroke Scale.
Forest plot presenting the pooled proportion of patients receiving intravenous thrombolysis (A) and endovascular treatment (B). IV, inverse variance; CI, confidence interval.
Forest plot presenting the pooled proportion of patients with LAA-associated stroke. IV, inverse variance; CI, confidence interval; LAA, large-artery atherosclerosis.
Forest plot presenting the mean baseline lipoprotein(a) levels among included patients. IV, inverse variance; CI, confidence interval.
Traffic light plot (A) and summary plot (B) presenting the quality assessment for the post hoc analysis of a randomized controlled clinical trial using the revised Cochrane Risk-of-Bias tool (RoB 2).
Traffic light plot (A) and summary plot (B) presenting the quality assessment of the included observational studies using the Risk Of Bias In Non-randomized Studies of Exposures (ROBINS-E) tool.
Forest plot presenting the odds ratio of stroke recurrence among patients with high Lp(a) compared to patients with low Lp(a), during sensitivity analysis excluding the study of Chemello et al. [16] IV, inverse variance; CI, confidence interval; Lp(a), lipoprotein(a).
Forest plot presenting the odds ratio of stroke recurrence among patients with high Lp(a) compared to patients with low Lp(a), after stratification according to trial setting and population (i.e., Chinese vs. non-Chinese). IV, inverse variance; CI, confidence interval; Lp(a), lipoprotein(a).
Forest plot presenting the odds ratio of poor functional outcomes among patients with high Lp(a) compared to patients with low Lp(a), during sensitivity analysis excluding the study of Chakraborty et al. [15] IV, inverse variance; CI, confidence interval; Lp(a), lipoprotein(a).
Notes
Funding statement
None
Conflicts of interest
The authors have no financial conflicts of interest.
Author contribution
Conceptualization: GT. Study design: LP, GT. Methodology: LP, KM, MIS, GT. Data collection: LP, KM, MIS, GT. Investigation: LP, KM, MIS, GT. Statistical analysis: LP, GT. Writing—original draft: LP, GT. Writing—review & editing: KM, MIS, AT, SG, VL, DAS, SS, MK, GS. Approval of final manuscript: all authors.