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Lipoprotein (a) as a risk factor for ischemic stroke: A meta-analysis
Atherosclerosis 242 (2015) 496e503
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Lipoprotein (a) as a risk factor for ischemic stroke: A meta-analysis Alexander H. Nave a, b, c, *, Kristin S. Lange a, Christopher O. Leonards a, Bob Siegerink a, Wolfram Doehner a, c, Ulf Landmesser c, f, Elisabeth Steinhagen-Thiessen e, Matthias Endres a, b, c, d, Martin Ebinger a, b, c €tsmedizin Berlin, Germany Center for Stroke Research Berlin (CSB), Charit e e Universita €tsmedizin Berlin, Germany Klinik und Hochschulambulanz für Neurologie, Charit e e Universita c German Center for Cardiovascular Research (DZHK), Berlin, Germany d German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany e €tsmedizin Berlin, Germany Department of Geriatrics, Charit e e Universita f €tsmedizin Berlin, Germany Department of Cardiology, Charit e e Universita a
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 March 2015 Received in revised form 11 July 2015 Accepted 13 August 2015 Available online 15 August 2015
Objective: Lipoprotein (a) [Lp(a)] harbors atherogenic potential but its role as a risk factor for ischemic stroke remains controversial. We conducted a meta-analysis to determine the relative strength of the association between Lp(a) and ischemic stroke and identify potential subgroup-specific risk differences. Methods: A systematic search using the MeSH terms “lipoproteins” OR “lipoprotein a” AND “stroke” was performed in PubMed and ScienceDirect for caseecontrol studies from June 2006 and prospective cohort studies from April 2009 until December 20th 2014. Data from eligible papers published before these dates were reviewed and extracted from previous meta-analyses. Studies that assessed the relationship between Lp(a) levels and ischemic stroke and reported generic datadi.e. odds ratio [OR], hazard ratio, or risk ratio [RR]dwere eligible for inclusion. Studies that not distinguish between ischemic and hemorrhagic stroke and transient ischemic attack were excluded. Random effects meta-analyses with mixedeffects meta-regression were performed by pooling adjusted OR or RR. Results: A total of 20 articles comprising 90,904 subjects and 5029 stroke events were eligible for the meta-analysis. Comparing high with low Lp(a) levels, the pooled estimated OR was 1.41 (95% CI, 1.26 e1.57) for caseecontrol studies (n ¼ 11) and the pooled estimated RR was 1.29 (95% CI, 1.06e1.58) for prospective studies (n ¼ 9). Sex-specific differences in RR were inconsistent between caseecontrol and prospective studies. Study populations with a mean age of 55 years had an increased RR compared to older study populations. Reported Lp(a) contrast levels and ischemic stroke subtype significantly contributed to the heterogeneity observed in the analyses. Conclusion: Elevated Lp(a) is an independent risk factor for ischemic stroke and may be especially relevant for young stroke patients. Sex-specific risk differences remain conflicting. Further studies in these subgroups may be warranted. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ischemic stroke Lipoprotein (a) Meta-analysis Systematic review Lipoproteins Risk factor Biomarker
1. Introduction Over 80% of stroke events are ischemic and correlate with traditional cardiovascular risk factorsdnamely, age, male sex, presence of hypertension, diabetes mellitus, atrial fibrillation, and dyslipidemia [1]. However, a large proportion of strokes remain
€tsmedizin Berlin, Hochschulambulanz für * Corresponding author. Universita platz 1, 10117 Berlin, Germany. Neurologie, Charite E-mail address: [email protected] (A.H. Nave). http://dx.doi.org/10.1016/j.atherosclerosis.2015.08.021 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
classified as cryptogenic. In young stroke patients (<55 years), cryptogenic strokes account for almost 40% of all ischemic stroke cases emphasizing the potential importance of other, possibly unknown risk factors especially but not exclusively in this stroke subtype [2,3]. Lipoprotein (a) [Lp(a)] is a low density lipoprotein (LDL)-like particle containing apolipoprotein(a) [apo(a)] and apolipoprotein B100 which are covalently linked by a disulfide bridge bond [4,5]. Lp(a) has been attributed to atherogenic, thrombogenic, vascular inflammatory, and antifibrinolytic potential, and shares structural homology with plasminogen [5,6]. Serum Lp(a) levels are
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genetically determined by an apo(a) size polymorphism encoded in the apolipoprotein(a) gene [5,7]. Lp(a)s role in the underlying pathophysiology of cardiovascular disease (CVD) has been highly investigated and studies have shown that Lp(a) is a causal risk factor for coronary heart disease (CHD) with improved risk prediction [8,9]. One observational study reported that cardiovascular event rates decrease following effective Lp(a) lowering treatment in patients with Lp(a)-hyperlipoproteinemia [10]. Recent reports have found a strong association between Lp(a) and ischemic stroke in children [11,12], but others have failed to show equally homogeneous data in adult stroke patients, making the current literature controversial [13]. Uncertainty regarding the role of Lp(a) in adult ischemic stroke remains, because observed associations vary across populations and limited reports on age and sex-specific Lp(a) associations exist [14,15]. Two previous metaanalyses [16,17] analyzed 1903 ischemic stroke and >4609 all stroke events. However, the latter study did not distinguish between transient ischemic attack (TIA), ischemic or hemorrhagic stroke, and both reviews did not address subtypes of ischemic stroke cases. Since the publication of these papers, evidence has increased. Along with novel potential treatment options for Lp(a) lowering therapy, the high and sustaining interest underscores the relevance of an update on Lp(a) as a risk factor for ischemic stroke and qualifies the attempt to identify subgroups at increased risk. Therefore, this meta-analysis summarizes the current evidence regarding the association of Lp(a) and ischemic stroke and addresses age and sex-specific risk differences of Lp(a). 2. Materials and methods 2.1. Data sources This review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines [18,19]. A systematic literature search of fully accessible studies published in the English language was performed by two independent readers (K.S.L. and A.H.N.) using Medline via PubMed and ScienceDirect using a combination of the MeSH terms “lipoproteins” OR “lipoprotein a” AND “stroke.” Regarding inclusion periods of the latest Lp(a) and ischemic stroke meta-analyses [16,17], we chose the following specific inclusion periods according to study type: prospective cohort studies from April 2009, caseecontrol studies from June 2006, and interventional studies from 1960, to December 20th, 2014. If a study was cited in one of the above mentioned meta-analyses but had been republished with a more complete dataset or longer follow-up period, the latter was included. Reference lists of relevant publications (including review articles) as well as related citations proposed by the databases were hand searched and reviewed for relevance. Further, studies of both previously published metaanalyses [16,17] were screened for eligibility according to the stringent inclusion and exclusion criteria of this meta-analysis. Eligible studies were included in the final meta-analyses. 2.2. Study selection Studies were eligible for inclusion if they 1) examined the relationship between Lp(a) levels and ischemic stroke, diagnosed by computed tomography or magnetic resonance imaging, and clearly distinguished ischemic from hemorrhagic stroke and transient ischemic attack (TIA); 2) reported data from a control group; 3) included subjects aged >18 years; 4) had 50 subjects per group; 5) included either subjects chosen from the general population, subjects with established cardiovascular disease (CHD,
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cerebrovascular or carotid disease, or peripheral artery disease) or with pre-existing hyperlipidemia; 6) reported at least one of the following generic data for cases and controls with respective confidence intervals: odds ratio (OR), hazard ratio (HR), or risk ratio (RR). Studies analyzing distinct patient subgroups, e.g. diabetic patients or patients with renal insufficiency were not included. When several publications reported overlapping subjects, the most extensive, recent publication was included. 2.3. Data extraction and synthesis The following data were extracted from relevant studies: first author's name, year of publication, study name; major inclusion and exclusion criteria for cases and controls or cohort; age and sex; sample size of ischemic stroke and control patients; mean duration of follow-up (for prospective studies); sample storage time; technique of Lp(a) measurement; Lp(a) levels for cases and controls, and Lp(a) baseline values for prospective studies, both converted into mg/dl where possible; the most adjusted risk for ischemic stroke as OR, HR, or RR with 95% CI for high compared to low Lp(a); the defined Lp(a) contrast levels being taken as reported in the contributing studies. We expected Lp(a) to be analyzed as categories (e.g. RR for high vs. low with contrasts being obtained from dichotomous, tertile, quartile, or quintile categorization) as well as continuous (e.g. per unit or per SD increase of Lp(a)). If studies reported multiple and equally adjusted effect sizes for different Lp(a) contrasts, the contrast with the highest risk ratio was used for further analysis. Degrees of statistical adjustments were set as follows: þ ¼ no adjustments; þþ ¼ adjustment for age, sex, smoking, alcohol abuse and conventional cardiovascular risk factors (hypertension, diabetes, dyslipidemia, atrial fibrillation); þþþ ¼ additionally further adjustments (like lipidlowering therapy, socioeconomic status, family history of cardiovascular diseases, or others). 2.4. Statistical analysis Log RRs (prospective cohort studies), log ORs (caseecontrol studies), 95% confidence intervals (95% CI), and prediction intervals for studies that assessed the relationship between Lp(a) and ischemic stroke, defined by the respective study, were calculated using a random effects model a priori as we anticipated heterogeneity to be present. Random effects modeling is better suited for higher degrees of heterogeneity, and prediction intervals help estimate a range for the true treatment effect in a heterogeneous setting (like reference ranges for laboratory values) [20]. Heterogeneity was tested using Cochrane's Q and the I2 statistics [21]. If significant heterogeneity was present for a given analysis (defined as a p < 0.05, or I2>50%), we generated funnel plots and performed mixed effects meta-regression (moderator variables e age, sample size, number of cases, Lp(a) levels, Lp(a) contrast levels, and stroke subtype) to assess potential sources of heterogeneity [22]. Potential publication bias was additionally assessed using Egger's regression test. All meta-analysis procedures were performed using the software package MIX 2.0 Pro [23] and the R version 3.1.1. ‘Metafor’ package [24]. Caseecontrol studies and prospective cohort studies were analyzed separately; nested caseecontrol studies were analyzed together with prospective cohort studies. 3. Results 3.1. Search results The study selection process is displayed in Fig. 1. The computerized literature search in Medline via Pubmed and in ScienceDirect
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Fig. 1. Meta-Analysis Flow Chart. Study selection process flow diagram, adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group statement. MeSH terms: “lipoproteins” OR “lipoprotein a” AND “stroke”. Eligible studies were additionally extracted from previous meta-analyses. Abbreviations: IS, ischemic stroke.
yielded 531 and 515 citations. After reviewing titles, abstracts, and hand searching related citations, 36 potentially relevant articles were identified. Of those, after review of the full-text articles, 24 studies were excluded for the following reasons: being duplicates (n ¼ 7) [25e31]; lack of ischemic stroke-specific data (n ¼ 8) [31e38]; lack of control group (n ¼ 3) [28,39,40]; insufficient statistic data (reporting OR without 95% CI or lacking OR) (n ¼ 2) [29,41]; was included in the meta-analysis of 2006 (n ¼ 1) [30]; or partially overlapping study populations (n ¼ 3) [42e44]. A total of 12 relevant studies published after June 2006 (for caseecontrol studies) and after April 2009 (for prospective studies) comprising 56,961 subjects and 3159 stroke events were identified for qualitative and quantitative analysis: 6 caseecontrol studies [27,45e49], 1 nested caseecontrol study [25], and 5 prospective cohort studies [13,26,50e52]. The meta-analysis of these new studies is depicted in eFigure 1 in the supplement, and eTables 1e2 provide a detailed description of these studies. The aforementioned search criteria yielded only one interventional study [53] which, however, did not address stroke as an outcome parameter. We therefore decided to hand search for relevant interventional studies addressing stroke and Lp(a) treatment and dedicated a separate paragraph in the discussion. 3.2. Merged meta-analyses After adopting the inclusion and exclusion criteria of this study to all relevant studies of the previous meta-analyses [16,17], five caseecontrol studies [54e58], two nested caseecontrol studies [59,60], and one prospective cohort study [61] were additionally
eligible for inclusion in this meta-analysis yielding a total of 20 studies (11 caseecontrol-, 3 nested caseecontrol-, and 6 prospective cohort studies) comprising 90,904 subjects and 5029 ischemic stroke events. Study characteristics of included studies that originate from previous meta-analyses are listed in eTable 3e4 in the supplement. Lp(a) detection methods, time between stroke onset and phlebotomy, sample storage time, and Lp(a) contrast values differed between studies (for details please see eTable 5e6 in the supplement). 3.3. Caseecontrol studies The meta-analysis of 11 caseecontrol studies (2749 cases and 5328 controls) resulted in an increased risk of ischemic stroke with elevated Lp(a) with a pooled adjusted OR of 1.41 (95% CI, 1.26e1.57; prediction interval, 1.07e1.86), as displayed in Fig. 2A. High heterogeneity was present in the analysis (Q ¼ 114.49, p < 0.01, I2 ¼ 89.52%). Funnel plots and Egger's regression intercept of 2.73 (p < 0.01) indicated the presence of potential publication bias in this meta-analysis. Stroke subtypes significantly contributed to heterogeneity assessed by meta-regression; stroke due to large artery atherosclerosis and stroke due to undetermined etiology reported significantly higher ORs (QM ¼ 6.89; p ¼ 0.03; beta ¼ 0.008; se ¼ 0.003). Four studies [47,48,54,56] dichotomized Lp(a) levels at 30 mg/dl (clinical cut-off) or 14 mg/dl, respectively, three studies [27,49,58] compared highest vs. lowest tertile or quartile, respectively, and three studies [45,55,57] reported risk differences for continuous increase in Lp(a), see eTable 6 in the
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Fig. 2. Pooled Analysis of all eligible Studies. Forest plots depicting study sample size with number of ischemic stroke patients (n) and total study participants (N), pooled adjusted risk ratio with 95% confidence interval (95% CI), and p value (P) for all included caseecontrol studies (A) and prospective studies (B) after eligible studies of previous meta-analyses were added. Studies are arranged according to study sample size. Data on subgroups were reported separately. Box sizes represent the individual study weight. aLarge artery atherosclerosis patients; bSmall vessel occlusion patients; cMale patients; dFemale patients.
supplement. Four studies reported sex-specific ORs [27,47,48,56]. 3.4. Nested caseecontrol and prospective cohort studies Nine prospective studies with a total of 80,527 participants and 2280 ischemic stroke cases were eligible for the final analysis. The studies differed both in design and study population. Four studies reported a positive association between Lp(a) levels and ischemic stroke risk. The meta-analysis revealed a significantly increased ischemic stroke risk with high Lp(a) levels and a pooled adjusted RR of 1.29 (95% CI, 1.06e1.58, prediction interval, 0.70e2.49), as indicated in Fig. 2B. Funnel plots and Egger's regression intercept of 3.50 (p < 0.01) indicated the presence of potential publication bias in this meta-analysis. High heterogeneity was observed (Q ¼ 44.02; p < 0.01; I2 ¼ 77.28%). Meta-regression revealed that Lp(a) contrast level variation was the main source of heterogeneity. Studies that used categorized Lp(a) contrast levels (i.e. dichotomous, tertile, quartile, or quintile) reported higher RRs, opposed to those studies reporting risk per unit or per standard deviation (SD) increase of Lp(a) (QM ¼ 22.18, p < 0.01; beta ¼ 0.60; se ¼ 0.22). The variation in reported effect sizes according to defined Lp(a) contrast levels of each study are displayed in eFigure 2 in the supplement. Combining the studies of categorized Lp(a) contrast levels and combining the studies with increase per unit change or per SD increase of Lp(a), revealed a substantial difference in the pooled estimated effect sizes with a RR of 1.64 (95% CI ¼ 1.37e1.98) and 0.93 (95% CI ¼ 0.84e1.02), respectively (Fig. 3), and dissolved the observed heterogeneity in total (I2 of 20.44% and 0.00%, respectively).
data in women yielded a lower RR (pooled estimated OR ¼ 1.49; 95% CI ¼ 1.09e2.04; Q ¼ 3.44; p ¼ 0.39; I2 ¼ 12.72%; see eFigure 3A in the supplement). Subgroup analysis of six prospective studies [25,50,51,59,60,62] that reported sex-specific data resulted in a pooled adjusted RR of 1.49 (95% CI ¼ 1.10e2.03; Q ¼ 12.18; p ¼ 0.02; I2 ¼ 67.15%) for women. There was moderate heterogeneity. For men, the pooled adjusted RR was 1.05 (95% CI ¼ 0.80e1.38; Q ¼ 7.76; p ¼ 0.05; I2 ¼ 61.34%). There was not strong evidence for heterogeneity. A higher proportion of studies reporting linear risk calculations were present among males, as depicted in eFigure 2 and 3B in the supplement. 3.5.2. Age Subgroup analysis of caseecontrol studies that investigated stroke populations with a mean age 55 years revealed a pooled estimated OR of 1.94 (95% CI ¼ 0.86e4.40; Q ¼ 8.44, p ¼ 0.04; I2 ¼ 64.46%). Studies that investigated populations with a mean age of >55 years had a pooled estimated OR of 1.37 (95% CI ¼ 1.22e1.53, Fig. 4A) with high study heterogeneity (Q ¼ 100.05; p < 0.01; I2 ¼ 92%). Prospective studies [26,50,51,59,60,62] with a mean population age 55 years followed a similar trend. Pooled analysis showed a higher risk ratio of ischemic stroke with high Lp(a) levels (pooled adjusted RR of 1.36, 95% CI ¼ 1.05e1.76; Q ¼ 31.08; p < 0.01; I2 ¼ 77.48%) compared to studies [13,25,52] with a mean population age >55 years (RR ¼ 1.12; 95% CI ¼ 0.80e1.59; Q ¼ 6.24; p ¼ 0.04; I2 ¼ 67.93%, Fig. 4B). The proportion of studies reporting linear risk calculations did not differ between groups.
3.5. Subgroup analyses
4. Discussion
3.5.1. Sex Three different caseecontrol studies reported data of elevated Lp(a) serum levels of male ischemic stroke patients [27,47,48]. Pooling this data resulted in a significant positive association between high Lp(a) levels and ischemic stroke in men (pooled estimated OR ¼ 2.40; 95% CI ¼ 1.69e3.41; Q ¼ 0.57; p ¼ 0.75; I2 ¼ 0.00%). Pooled analysis of 4 studies [27,47,48,56] that reported
This meta-analysis of 20 studies that met our stringent inclusion criteria reinforces the association of Lp(a) with ischemic stroke after adjustment for several risk factors. The pooled adjusted OR was 1.41 (95% CI, 1.26e1.57) for all included caseecontrol studies. For prospective cohort studies, the pooled adjusted RR was 1.29 (95% CI, 1.06e1.58, Fig. 2). These findings are in accordance with previous findings that have reported that Lp(a) plays a modest role
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Fig. 3. Forest plot of prospective studies grouped by contrast levels. Forest plot illustrating number of cases (n) and overall sample size (N), pooled adjusted risk ratio with 95% confidence interval (95% CI), and p value (P) for all prospective studies grouped by comparable reported Lp(a) contrast levels: categorized contrast levels (dichotomous, tertiles, quartiles, and quintiles, panel A) and more linear relationship (per continuous and per standard deviation increase in Lp(a), respectively, panel B). Data on subgroups were reported separately. Box sizes represent the individual study weight. aMale patients; bFemale patients.
Fig. 4. Pooled Analysis of Studies (55 vs. >55 years of mean age). Forest plots highlighting age-specific risk differences of casecontrol studies (A) and prospective studies (B) reporting a mean age of study participants of 55 years or >55 years, respectively. Depicted are number of ischemic stroke patients (n) and total study participants (N), pooled adjusted risk ratio with 95% confidence interval (95% CI), and p value (P). Data on subgroups were reported separately. Box sizes represent the individual study weight. aMale patients; bFemale patients; cLarge artery atherosclerosis patients; dSmall vessel occlusion patients.
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in stroke risk [16,17]. The association becomes particularly evident in (1) studies including younger patients and (2) studies that categorized Lp(a) rather than having analyzed it on a continuous scale (Fig. 3). Both findings are not unexpected. First, moderate risk factors may exhibit higher RRs in the young due to the low absolute risk in this group. Also, because environmental risk factors accumulate with age, the effect of a weaker, genetic risk factor like Lp(a) will also be more pronounced in the young in terms of relative risk. Although the observed difference could be due to chance, these two phenomena possibly explain the different RRs in our age-specific subgroup analysis (Fig. 4). Second, studies that use a categorization of Lp(a) levels are less bound to the constraints of the underlying regression model. In contrast, studies assessing risk per SD or per unit increase in Lp(a) tend to yield lower RR and force a linear association on the scale of the regression model which most likely does not correspond to the true doseeresponse relationship (eFigure 2). We recommend future studies use standardized categorized Lp(a) contrast levels. Comparing results between several studies using various contrasts may also be a limitation of our analysis. Converting eligible prospective studies (i.e. studies that reported risk ratios from tertiles, quartiles, quintiles, or risk per SD increase) to a common unit of exposure (tertiles), as previously introduced by Danesh et al. [63], revealed, as expected, less heterogeneity and a less pronounced risk ratio of 1.32 (95% CI 1.05e1.66, I2 ¼ 37.66%), compared to pooled data of categorized contrasts displayed in Fig. 3. However, not all prospective studies were eligible for this analysis, which has to be considered when interpreting our results. Sex-specific risk differences were inconsistent between caseecontrol and prospective studies and show contradictory results (eFigure 3). Previous large, prospective studies have shown a sexspecific risk difference of high Lp(a) for overall stroke, with an increased risk in men [64,65]. This meta-analysis, however, can only confirm the presumably higher risk of ischemic stroke in men for caseecontrol studies. Analysis of prospective cohort studies did not equally reproduce findings of the caseecontrol studies, which are more susceptible to reverse causation and overestimation of the true relative risk. In fact, the meta-analysis of prospective studies surprisingly indicated the opposite. High Lp(a) clearly seemed to be a risk factor for ischemic stroke in women (eFigure 3B). This finding might be influenced by the higher proportion of studies reporting linear risk calculations that was present among males and the fact that the Women's Health study compared women with very high Lp(a) levels (>44 mg/dl) to women with low levels resulting in strong effect sizes [62]. Hence, the published data on sexdependent risk differences remain unclear. This is particularly true as other factors in the comparison between men and women can obscure the true effect: In contrast to our pooled prospective results for females, Berger et al. prospectively analyzed postmenopausal women and did not find an association between elevated Lp(a) and ischemic stroke. However, approximately 40% of women had received hormonal therapy. This might have contributed to the negative finding which is in line with interventional studies that have shown a significant decrease in Lp(a) by hormonal replacement therapy in postmenopausal women [66]. Further, post-menopausal women in the study had a mean age of ~70 years. Children with high Lp(a) serum levels have more than a fourfold risk of ischemic stroke [11], and more than a tenfold increased risk of recurrent ischemic stroke (children with Lp(a) levels >90th percentile) [12]. Caseecontrol studies have shown that high Lp(a) levels also seem to be a relevant risk factor in young adults [27,58,67,68]. The sifap study [2], which is, so far, the largest study on stroke in the young (18e55 years), emphasized the importance of atherosclerotic pathology in this cohort of stroke survivors. This
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gave rise to the assumption that Lp(a) may play an underlying role. Therefore, we decided to analyze the results of studies reporting data on younger stroke populations (55 years). In general, the studies included within our meta-analyses were heterogeneous with regards to age. Further studies should evaluate the ischemic stroke risk of young adults with high Lp(a) and address the risk of recurrent stroke in young adult stroke survivors with high Lp(a) serum levels. Meta-regression analysis of caseecontrol studies revealed that stroke subtype was a source of heterogeneity. More specifically, large artery atherosclerosis and strokes of undetermined source were significantly associated with higher ORs. In contrast to caseecontrol studies, most prospective studies did not report data regarding stroke subtypes. To elucidate critical patient subgroups susceptible for ischemic stroke at higher Lp(a) serum levels, future prospective studies should provide more information on ischemic stroke subtypes and respective subgroups [68e70]. In particular, prospective cohort studies seldom report patient ethnicities whereas caseecontrol studies have increasingly focused on the racial differences of stroke risk in relation to high Lp(a) levels. However, our subgroup analysis of ethnic-specific risk differences of caseecontrol studies did not reveal that a particular ethnicity was at an increased risk (see eFigure 4). Interventional studies addressing Lp(a) and ischemic stroke are scarce and our systematic literature search only yielded one hit [53]. The authors of the study reported that daily aspirin (150 mg for 4 weeks) decreased Lp(a) levels by >45%. However, the study lacked clinical or control data. Hand searching revealed another study (by Leebmann et al. [10]), which mainly focused on Lp(a) and coronary events as the primary endpoint, but also reported the number of cerebrovascular events as a secondary outcome parameter. In a cohort of 170 patients with Lp(a)hyperlipoproteinemia and the maximum tolerable lipid lowering medication dose, the authors found that lipid apheresis effectively reduced the frequency of cardiovascular and cerebrovascular events over a follow-up period of 2 years. New pharmacological substances, e.g. the anti-sense oligonucleotide of apolipoprotein-B mRNA such as mipomersen or inhibitors of the proprotein convertase subtilisin kexin type 9 (PSCK9) might develop as reasonable candidates for future treatment strategies [71]. If these evolving therapeutic options prove to be effective treatment strategies for high Lp(a) levels, the results of this study should encourage clinicians to determine Lp(a) serum levels in stroke patients more frequently. 4.1. Limitations Our systematic search considered studies from 2006 and 2009 to December 2014 and should therefore be considered an update of previous reviews [16,17]. As we only addressed ischemic stroke, we followed stricter inclusion criteria and therefore not all studies included in previous meta-analyses were eligible for inclusion into our re-assessment. Still, the results are comparable thereby reinforcing the pathological role of Lp(a) in ischemic stroke. As present in the previous analysis by Smolders et al. [17], high levels of heterogeneity are also present in our analysis. However, metaregression identified varying Lp(a) contrast levels and ischemic stroke subtypes as the primary sources of heterogeneity. If studies reported multiple Lp(a) contrasts, the contrast that revealed the highest risk ratio was used for further analyses. Meta-analyzing data with high vs. low contrast irrespective of the categorization will lead to misclassification and result in an underestimation of the true effect that can be expected in a quartile or quintile analysis. Individual patient characteristics differed substantially between studies, making direct comparisons of study results problematic
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[14,72]. A major limitation is the lack of access to individual patient data, as it would have allowed for more standardized analyses in terms of defined Lp(a) contrast levels and adjustments, as well as for the investigation of within-study heterogeneity. The absence of standardized detection methods for Lp(a) limit the comparability of studies because (1) not all studies have used isoform insensitive detection assays and (2) reported storage times of frozen samples varied substantially across studies (see eTable 5). Moreover, the lack of Mendelian randomization studies that have investigated a genetic relationship between Lp(a) and stroke did not allow us to assess a causative role of Lp(a) in ischemic stroke. 4.2. Conclusion In conclusion, our meta-analysis emphasizes the importance of high Lp(a) as an independent but modest risk factor in ischemic stroke. This becomes especially evident in younger stroke populations. Conflicting sex-specific results warrant further studies, preferably using standardized categorized Lp(a) contrast levels. Author contribution Study concept: Nave AH, Lange KS, Ebinger M. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Nave AH, Lange KS. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Nave AH, Leonards CO. Obtained funding: Ebinger M, Endres M. Administrative, technical, or material support: Nave AH, Leonards CO, Ebinger M. Study supervision: Ebinger M. Sources of funding This study was funded by the Federal Ministry of Education and Research through the grant G.2.15 of the Center for Stroke Research Berlin (CSB). Disclosures AHN, KSL, COL, BS, WD, MEn and MEb, have nothing to disclose and no conflicts of interest. EST has received honoraria for presentations, advisory board activities, or data monitoring committee activities from Abbott, Aegerion, Amgen, Astra-Zeneca, BoehringerIngelheim, Bristol-Myers Squibb, Fresenius, Genzyme, a Sanofi company, Kaneka, Merck Sharp & Dohme, Novartis, Roche. Acknowledgments AHN had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. For general support and excellent statistical advice in conducting the systematic review and meta-analysis we thank Dr. Ulrike Grittner from the Center for Stroke Research Berlin and the Department of Biostatistics and Clinical Epidemiology of the . Charite Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.atherosclerosis.2015.08.021.
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Lipoprotein (a) as a risk factor for ischemic stroke: A meta-analysis Alexander H. Nave a, b, c, *, Kristin S. Lange a, Christopher O. Leonards a, Bob Siegerink a, Wolfram Doehner a, c, Ulf Landmesser c, f, Elisabeth Steinhagen-Thiessen e, Matthias Endres a, b, c, d, Martin Ebinger a, b, c €tsmedizin Berlin, Germany Center for Stroke Research Berlin (CSB), Charit e e Universita €tsmedizin Berlin, Germany Klinik und Hochschulambulanz für Neurologie, Charit e e Universita c German Center for Cardiovascular Research (DZHK), Berlin, Germany d German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany e €tsmedizin Berlin, Germany Department of Geriatrics, Charit e e Universita f €tsmedizin Berlin, Germany Department of Cardiology, Charit e e Universita a
b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 March 2015 Received in revised form 11 July 2015 Accepted 13 August 2015 Available online 15 August 2015
Objective: Lipoprotein (a) [Lp(a)] harbors atherogenic potential but its role as a risk factor for ischemic stroke remains controversial. We conducted a meta-analysis to determine the relative strength of the association between Lp(a) and ischemic stroke and identify potential subgroup-specific risk differences. Methods: A systematic search using the MeSH terms “lipoproteins” OR “lipoprotein a” AND “stroke” was performed in PubMed and ScienceDirect for caseecontrol studies from June 2006 and prospective cohort studies from April 2009 until December 20th 2014. Data from eligible papers published before these dates were reviewed and extracted from previous meta-analyses. Studies that assessed the relationship between Lp(a) levels and ischemic stroke and reported generic datadi.e. odds ratio [OR], hazard ratio, or risk ratio [RR]dwere eligible for inclusion. Studies that not distinguish between ischemic and hemorrhagic stroke and transient ischemic attack were excluded. Random effects meta-analyses with mixedeffects meta-regression were performed by pooling adjusted OR or RR. Results: A total of 20 articles comprising 90,904 subjects and 5029 stroke events were eligible for the meta-analysis. Comparing high with low Lp(a) levels, the pooled estimated OR was 1.41 (95% CI, 1.26 e1.57) for caseecontrol studies (n ¼ 11) and the pooled estimated RR was 1.29 (95% CI, 1.06e1.58) for prospective studies (n ¼ 9). Sex-specific differences in RR were inconsistent between caseecontrol and prospective studies. Study populations with a mean age of 55 years had an increased RR compared to older study populations. Reported Lp(a) contrast levels and ischemic stroke subtype significantly contributed to the heterogeneity observed in the analyses. Conclusion: Elevated Lp(a) is an independent risk factor for ischemic stroke and may be especially relevant for young stroke patients. Sex-specific risk differences remain conflicting. Further studies in these subgroups may be warranted. © 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ischemic stroke Lipoprotein (a) Meta-analysis Systematic review Lipoproteins Risk factor Biomarker
1. Introduction Over 80% of stroke events are ischemic and correlate with traditional cardiovascular risk factorsdnamely, age, male sex, presence of hypertension, diabetes mellitus, atrial fibrillation, and dyslipidemia [1]. However, a large proportion of strokes remain
€tsmedizin Berlin, Hochschulambulanz für * Corresponding author. Universita platz 1, 10117 Berlin, Germany. Neurologie, Charite E-mail address: [email protected] (A.H. Nave). http://dx.doi.org/10.1016/j.atherosclerosis.2015.08.021 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
classified as cryptogenic. In young stroke patients (<55 years), cryptogenic strokes account for almost 40% of all ischemic stroke cases emphasizing the potential importance of other, possibly unknown risk factors especially but not exclusively in this stroke subtype [2,3]. Lipoprotein (a) [Lp(a)] is a low density lipoprotein (LDL)-like particle containing apolipoprotein(a) [apo(a)] and apolipoprotein B100 which are covalently linked by a disulfide bridge bond [4,5]. Lp(a) has been attributed to atherogenic, thrombogenic, vascular inflammatory, and antifibrinolytic potential, and shares structural homology with plasminogen [5,6]. Serum Lp(a) levels are
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genetically determined by an apo(a) size polymorphism encoded in the apolipoprotein(a) gene [5,7]. Lp(a)s role in the underlying pathophysiology of cardiovascular disease (CVD) has been highly investigated and studies have shown that Lp(a) is a causal risk factor for coronary heart disease (CHD) with improved risk prediction [8,9]. One observational study reported that cardiovascular event rates decrease following effective Lp(a) lowering treatment in patients with Lp(a)-hyperlipoproteinemia [10]. Recent reports have found a strong association between Lp(a) and ischemic stroke in children [11,12], but others have failed to show equally homogeneous data in adult stroke patients, making the current literature controversial [13]. Uncertainty regarding the role of Lp(a) in adult ischemic stroke remains, because observed associations vary across populations and limited reports on age and sex-specific Lp(a) associations exist [14,15]. Two previous metaanalyses [16,17] analyzed 1903 ischemic stroke and >4609 all stroke events. However, the latter study did not distinguish between transient ischemic attack (TIA), ischemic or hemorrhagic stroke, and both reviews did not address subtypes of ischemic stroke cases. Since the publication of these papers, evidence has increased. Along with novel potential treatment options for Lp(a) lowering therapy, the high and sustaining interest underscores the relevance of an update on Lp(a) as a risk factor for ischemic stroke and qualifies the attempt to identify subgroups at increased risk. Therefore, this meta-analysis summarizes the current evidence regarding the association of Lp(a) and ischemic stroke and addresses age and sex-specific risk differences of Lp(a). 2. Materials and methods 2.1. Data sources This review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines [18,19]. A systematic literature search of fully accessible studies published in the English language was performed by two independent readers (K.S.L. and A.H.N.) using Medline via PubMed and ScienceDirect using a combination of the MeSH terms “lipoproteins” OR “lipoprotein a” AND “stroke.” Regarding inclusion periods of the latest Lp(a) and ischemic stroke meta-analyses [16,17], we chose the following specific inclusion periods according to study type: prospective cohort studies from April 2009, caseecontrol studies from June 2006, and interventional studies from 1960, to December 20th, 2014. If a study was cited in one of the above mentioned meta-analyses but had been republished with a more complete dataset or longer follow-up period, the latter was included. Reference lists of relevant publications (including review articles) as well as related citations proposed by the databases were hand searched and reviewed for relevance. Further, studies of both previously published metaanalyses [16,17] were screened for eligibility according to the stringent inclusion and exclusion criteria of this meta-analysis. Eligible studies were included in the final meta-analyses. 2.2. Study selection Studies were eligible for inclusion if they 1) examined the relationship between Lp(a) levels and ischemic stroke, diagnosed by computed tomography or magnetic resonance imaging, and clearly distinguished ischemic from hemorrhagic stroke and transient ischemic attack (TIA); 2) reported data from a control group; 3) included subjects aged >18 years; 4) had 50 subjects per group; 5) included either subjects chosen from the general population, subjects with established cardiovascular disease (CHD,
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cerebrovascular or carotid disease, or peripheral artery disease) or with pre-existing hyperlipidemia; 6) reported at least one of the following generic data for cases and controls with respective confidence intervals: odds ratio (OR), hazard ratio (HR), or risk ratio (RR). Studies analyzing distinct patient subgroups, e.g. diabetic patients or patients with renal insufficiency were not included. When several publications reported overlapping subjects, the most extensive, recent publication was included. 2.3. Data extraction and synthesis The following data were extracted from relevant studies: first author's name, year of publication, study name; major inclusion and exclusion criteria for cases and controls or cohort; age and sex; sample size of ischemic stroke and control patients; mean duration of follow-up (for prospective studies); sample storage time; technique of Lp(a) measurement; Lp(a) levels for cases and controls, and Lp(a) baseline values for prospective studies, both converted into mg/dl where possible; the most adjusted risk for ischemic stroke as OR, HR, or RR with 95% CI for high compared to low Lp(a); the defined Lp(a) contrast levels being taken as reported in the contributing studies. We expected Lp(a) to be analyzed as categories (e.g. RR for high vs. low with contrasts being obtained from dichotomous, tertile, quartile, or quintile categorization) as well as continuous (e.g. per unit or per SD increase of Lp(a)). If studies reported multiple and equally adjusted effect sizes for different Lp(a) contrasts, the contrast with the highest risk ratio was used for further analysis. Degrees of statistical adjustments were set as follows: þ ¼ no adjustments; þþ ¼ adjustment for age, sex, smoking, alcohol abuse and conventional cardiovascular risk factors (hypertension, diabetes, dyslipidemia, atrial fibrillation); þþþ ¼ additionally further adjustments (like lipidlowering therapy, socioeconomic status, family history of cardiovascular diseases, or others). 2.4. Statistical analysis Log RRs (prospective cohort studies), log ORs (caseecontrol studies), 95% confidence intervals (95% CI), and prediction intervals for studies that assessed the relationship between Lp(a) and ischemic stroke, defined by the respective study, were calculated using a random effects model a priori as we anticipated heterogeneity to be present. Random effects modeling is better suited for higher degrees of heterogeneity, and prediction intervals help estimate a range for the true treatment effect in a heterogeneous setting (like reference ranges for laboratory values) [20]. Heterogeneity was tested using Cochrane's Q and the I2 statistics [21]. If significant heterogeneity was present for a given analysis (defined as a p < 0.05, or I2>50%), we generated funnel plots and performed mixed effects meta-regression (moderator variables e age, sample size, number of cases, Lp(a) levels, Lp(a) contrast levels, and stroke subtype) to assess potential sources of heterogeneity [22]. Potential publication bias was additionally assessed using Egger's regression test. All meta-analysis procedures were performed using the software package MIX 2.0 Pro [23] and the R version 3.1.1. ‘Metafor’ package [24]. Caseecontrol studies and prospective cohort studies were analyzed separately; nested caseecontrol studies were analyzed together with prospective cohort studies. 3. Results 3.1. Search results The study selection process is displayed in Fig. 1. The computerized literature search in Medline via Pubmed and in ScienceDirect
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Fig. 1. Meta-Analysis Flow Chart. Study selection process flow diagram, adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group statement. MeSH terms: “lipoproteins” OR “lipoprotein a” AND “stroke”. Eligible studies were additionally extracted from previous meta-analyses. Abbreviations: IS, ischemic stroke.
yielded 531 and 515 citations. After reviewing titles, abstracts, and hand searching related citations, 36 potentially relevant articles were identified. Of those, after review of the full-text articles, 24 studies were excluded for the following reasons: being duplicates (n ¼ 7) [25e31]; lack of ischemic stroke-specific data (n ¼ 8) [31e38]; lack of control group (n ¼ 3) [28,39,40]; insufficient statistic data (reporting OR without 95% CI or lacking OR) (n ¼ 2) [29,41]; was included in the meta-analysis of 2006 (n ¼ 1) [30]; or partially overlapping study populations (n ¼ 3) [42e44]. A total of 12 relevant studies published after June 2006 (for caseecontrol studies) and after April 2009 (for prospective studies) comprising 56,961 subjects and 3159 stroke events were identified for qualitative and quantitative analysis: 6 caseecontrol studies [27,45e49], 1 nested caseecontrol study [25], and 5 prospective cohort studies [13,26,50e52]. The meta-analysis of these new studies is depicted in eFigure 1 in the supplement, and eTables 1e2 provide a detailed description of these studies. The aforementioned search criteria yielded only one interventional study [53] which, however, did not address stroke as an outcome parameter. We therefore decided to hand search for relevant interventional studies addressing stroke and Lp(a) treatment and dedicated a separate paragraph in the discussion. 3.2. Merged meta-analyses After adopting the inclusion and exclusion criteria of this study to all relevant studies of the previous meta-analyses [16,17], five caseecontrol studies [54e58], two nested caseecontrol studies [59,60], and one prospective cohort study [61] were additionally
eligible for inclusion in this meta-analysis yielding a total of 20 studies (11 caseecontrol-, 3 nested caseecontrol-, and 6 prospective cohort studies) comprising 90,904 subjects and 5029 ischemic stroke events. Study characteristics of included studies that originate from previous meta-analyses are listed in eTable 3e4 in the supplement. Lp(a) detection methods, time between stroke onset and phlebotomy, sample storage time, and Lp(a) contrast values differed between studies (for details please see eTable 5e6 in the supplement). 3.3. Caseecontrol studies The meta-analysis of 11 caseecontrol studies (2749 cases and 5328 controls) resulted in an increased risk of ischemic stroke with elevated Lp(a) with a pooled adjusted OR of 1.41 (95% CI, 1.26e1.57; prediction interval, 1.07e1.86), as displayed in Fig. 2A. High heterogeneity was present in the analysis (Q ¼ 114.49, p < 0.01, I2 ¼ 89.52%). Funnel plots and Egger's regression intercept of 2.73 (p < 0.01) indicated the presence of potential publication bias in this meta-analysis. Stroke subtypes significantly contributed to heterogeneity assessed by meta-regression; stroke due to large artery atherosclerosis and stroke due to undetermined etiology reported significantly higher ORs (QM ¼ 6.89; p ¼ 0.03; beta ¼ 0.008; se ¼ 0.003). Four studies [47,48,54,56] dichotomized Lp(a) levels at 30 mg/dl (clinical cut-off) or 14 mg/dl, respectively, three studies [27,49,58] compared highest vs. lowest tertile or quartile, respectively, and three studies [45,55,57] reported risk differences for continuous increase in Lp(a), see eTable 6 in the
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Fig. 2. Pooled Analysis of all eligible Studies. Forest plots depicting study sample size with number of ischemic stroke patients (n) and total study participants (N), pooled adjusted risk ratio with 95% confidence interval (95% CI), and p value (P) for all included caseecontrol studies (A) and prospective studies (B) after eligible studies of previous meta-analyses were added. Studies are arranged according to study sample size. Data on subgroups were reported separately. Box sizes represent the individual study weight. aLarge artery atherosclerosis patients; bSmall vessel occlusion patients; cMale patients; dFemale patients.
supplement. Four studies reported sex-specific ORs [27,47,48,56]. 3.4. Nested caseecontrol and prospective cohort studies Nine prospective studies with a total of 80,527 participants and 2280 ischemic stroke cases were eligible for the final analysis. The studies differed both in design and study population. Four studies reported a positive association between Lp(a) levels and ischemic stroke risk. The meta-analysis revealed a significantly increased ischemic stroke risk with high Lp(a) levels and a pooled adjusted RR of 1.29 (95% CI, 1.06e1.58, prediction interval, 0.70e2.49), as indicated in Fig. 2B. Funnel plots and Egger's regression intercept of 3.50 (p < 0.01) indicated the presence of potential publication bias in this meta-analysis. High heterogeneity was observed (Q ¼ 44.02; p < 0.01; I2 ¼ 77.28%). Meta-regression revealed that Lp(a) contrast level variation was the main source of heterogeneity. Studies that used categorized Lp(a) contrast levels (i.e. dichotomous, tertile, quartile, or quintile) reported higher RRs, opposed to those studies reporting risk per unit or per standard deviation (SD) increase of Lp(a) (QM ¼ 22.18, p < 0.01; beta ¼ 0.60; se ¼ 0.22). The variation in reported effect sizes according to defined Lp(a) contrast levels of each study are displayed in eFigure 2 in the supplement. Combining the studies of categorized Lp(a) contrast levels and combining the studies with increase per unit change or per SD increase of Lp(a), revealed a substantial difference in the pooled estimated effect sizes with a RR of 1.64 (95% CI ¼ 1.37e1.98) and 0.93 (95% CI ¼ 0.84e1.02), respectively (Fig. 3), and dissolved the observed heterogeneity in total (I2 of 20.44% and 0.00%, respectively).
data in women yielded a lower RR (pooled estimated OR ¼ 1.49; 95% CI ¼ 1.09e2.04; Q ¼ 3.44; p ¼ 0.39; I2 ¼ 12.72%; see eFigure 3A in the supplement). Subgroup analysis of six prospective studies [25,50,51,59,60,62] that reported sex-specific data resulted in a pooled adjusted RR of 1.49 (95% CI ¼ 1.10e2.03; Q ¼ 12.18; p ¼ 0.02; I2 ¼ 67.15%) for women. There was moderate heterogeneity. For men, the pooled adjusted RR was 1.05 (95% CI ¼ 0.80e1.38; Q ¼ 7.76; p ¼ 0.05; I2 ¼ 61.34%). There was not strong evidence for heterogeneity. A higher proportion of studies reporting linear risk calculations were present among males, as depicted in eFigure 2 and 3B in the supplement. 3.5.2. Age Subgroup analysis of caseecontrol studies that investigated stroke populations with a mean age 55 years revealed a pooled estimated OR of 1.94 (95% CI ¼ 0.86e4.40; Q ¼ 8.44, p ¼ 0.04; I2 ¼ 64.46%). Studies that investigated populations with a mean age of >55 years had a pooled estimated OR of 1.37 (95% CI ¼ 1.22e1.53, Fig. 4A) with high study heterogeneity (Q ¼ 100.05; p < 0.01; I2 ¼ 92%). Prospective studies [26,50,51,59,60,62] with a mean population age 55 years followed a similar trend. Pooled analysis showed a higher risk ratio of ischemic stroke with high Lp(a) levels (pooled adjusted RR of 1.36, 95% CI ¼ 1.05e1.76; Q ¼ 31.08; p < 0.01; I2 ¼ 77.48%) compared to studies [13,25,52] with a mean population age >55 years (RR ¼ 1.12; 95% CI ¼ 0.80e1.59; Q ¼ 6.24; p ¼ 0.04; I2 ¼ 67.93%, Fig. 4B). The proportion of studies reporting linear risk calculations did not differ between groups.
3.5. Subgroup analyses
4. Discussion
3.5.1. Sex Three different caseecontrol studies reported data of elevated Lp(a) serum levels of male ischemic stroke patients [27,47,48]. Pooling this data resulted in a significant positive association between high Lp(a) levels and ischemic stroke in men (pooled estimated OR ¼ 2.40; 95% CI ¼ 1.69e3.41; Q ¼ 0.57; p ¼ 0.75; I2 ¼ 0.00%). Pooled analysis of 4 studies [27,47,48,56] that reported
This meta-analysis of 20 studies that met our stringent inclusion criteria reinforces the association of Lp(a) with ischemic stroke after adjustment for several risk factors. The pooled adjusted OR was 1.41 (95% CI, 1.26e1.57) for all included caseecontrol studies. For prospective cohort studies, the pooled adjusted RR was 1.29 (95% CI, 1.06e1.58, Fig. 2). These findings are in accordance with previous findings that have reported that Lp(a) plays a modest role
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Fig. 3. Forest plot of prospective studies grouped by contrast levels. Forest plot illustrating number of cases (n) and overall sample size (N), pooled adjusted risk ratio with 95% confidence interval (95% CI), and p value (P) for all prospective studies grouped by comparable reported Lp(a) contrast levels: categorized contrast levels (dichotomous, tertiles, quartiles, and quintiles, panel A) and more linear relationship (per continuous and per standard deviation increase in Lp(a), respectively, panel B). Data on subgroups were reported separately. Box sizes represent the individual study weight. aMale patients; bFemale patients.
Fig. 4. Pooled Analysis of Studies (55 vs. >55 years of mean age). Forest plots highlighting age-specific risk differences of casecontrol studies (A) and prospective studies (B) reporting a mean age of study participants of 55 years or >55 years, respectively. Depicted are number of ischemic stroke patients (n) and total study participants (N), pooled adjusted risk ratio with 95% confidence interval (95% CI), and p value (P). Data on subgroups were reported separately. Box sizes represent the individual study weight. aMale patients; bFemale patients; cLarge artery atherosclerosis patients; dSmall vessel occlusion patients.
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in stroke risk [16,17]. The association becomes particularly evident in (1) studies including younger patients and (2) studies that categorized Lp(a) rather than having analyzed it on a continuous scale (Fig. 3). Both findings are not unexpected. First, moderate risk factors may exhibit higher RRs in the young due to the low absolute risk in this group. Also, because environmental risk factors accumulate with age, the effect of a weaker, genetic risk factor like Lp(a) will also be more pronounced in the young in terms of relative risk. Although the observed difference could be due to chance, these two phenomena possibly explain the different RRs in our age-specific subgroup analysis (Fig. 4). Second, studies that use a categorization of Lp(a) levels are less bound to the constraints of the underlying regression model. In contrast, studies assessing risk per SD or per unit increase in Lp(a) tend to yield lower RR and force a linear association on the scale of the regression model which most likely does not correspond to the true doseeresponse relationship (eFigure 2). We recommend future studies use standardized categorized Lp(a) contrast levels. Comparing results between several studies using various contrasts may also be a limitation of our analysis. Converting eligible prospective studies (i.e. studies that reported risk ratios from tertiles, quartiles, quintiles, or risk per SD increase) to a common unit of exposure (tertiles), as previously introduced by Danesh et al. [63], revealed, as expected, less heterogeneity and a less pronounced risk ratio of 1.32 (95% CI 1.05e1.66, I2 ¼ 37.66%), compared to pooled data of categorized contrasts displayed in Fig. 3. However, not all prospective studies were eligible for this analysis, which has to be considered when interpreting our results. Sex-specific risk differences were inconsistent between caseecontrol and prospective studies and show contradictory results (eFigure 3). Previous large, prospective studies have shown a sexspecific risk difference of high Lp(a) for overall stroke, with an increased risk in men [64,65]. This meta-analysis, however, can only confirm the presumably higher risk of ischemic stroke in men for caseecontrol studies. Analysis of prospective cohort studies did not equally reproduce findings of the caseecontrol studies, which are more susceptible to reverse causation and overestimation of the true relative risk. In fact, the meta-analysis of prospective studies surprisingly indicated the opposite. High Lp(a) clearly seemed to be a risk factor for ischemic stroke in women (eFigure 3B). This finding might be influenced by the higher proportion of studies reporting linear risk calculations that was present among males and the fact that the Women's Health study compared women with very high Lp(a) levels (>44 mg/dl) to women with low levels resulting in strong effect sizes [62]. Hence, the published data on sexdependent risk differences remain unclear. This is particularly true as other factors in the comparison between men and women can obscure the true effect: In contrast to our pooled prospective results for females, Berger et al. prospectively analyzed postmenopausal women and did not find an association between elevated Lp(a) and ischemic stroke. However, approximately 40% of women had received hormonal therapy. This might have contributed to the negative finding which is in line with interventional studies that have shown a significant decrease in Lp(a) by hormonal replacement therapy in postmenopausal women [66]. Further, post-menopausal women in the study had a mean age of ~70 years. Children with high Lp(a) serum levels have more than a fourfold risk of ischemic stroke [11], and more than a tenfold increased risk of recurrent ischemic stroke (children with Lp(a) levels >90th percentile) [12]. Caseecontrol studies have shown that high Lp(a) levels also seem to be a relevant risk factor in young adults [27,58,67,68]. The sifap study [2], which is, so far, the largest study on stroke in the young (18e55 years), emphasized the importance of atherosclerotic pathology in this cohort of stroke survivors. This
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gave rise to the assumption that Lp(a) may play an underlying role. Therefore, we decided to analyze the results of studies reporting data on younger stroke populations (55 years). In general, the studies included within our meta-analyses were heterogeneous with regards to age. Further studies should evaluate the ischemic stroke risk of young adults with high Lp(a) and address the risk of recurrent stroke in young adult stroke survivors with high Lp(a) serum levels. Meta-regression analysis of caseecontrol studies revealed that stroke subtype was a source of heterogeneity. More specifically, large artery atherosclerosis and strokes of undetermined source were significantly associated with higher ORs. In contrast to caseecontrol studies, most prospective studies did not report data regarding stroke subtypes. To elucidate critical patient subgroups susceptible for ischemic stroke at higher Lp(a) serum levels, future prospective studies should provide more information on ischemic stroke subtypes and respective subgroups [68e70]. In particular, prospective cohort studies seldom report patient ethnicities whereas caseecontrol studies have increasingly focused on the racial differences of stroke risk in relation to high Lp(a) levels. However, our subgroup analysis of ethnic-specific risk differences of caseecontrol studies did not reveal that a particular ethnicity was at an increased risk (see eFigure 4). Interventional studies addressing Lp(a) and ischemic stroke are scarce and our systematic literature search only yielded one hit [53]. The authors of the study reported that daily aspirin (150 mg for 4 weeks) decreased Lp(a) levels by >45%. However, the study lacked clinical or control data. Hand searching revealed another study (by Leebmann et al. [10]), which mainly focused on Lp(a) and coronary events as the primary endpoint, but also reported the number of cerebrovascular events as a secondary outcome parameter. In a cohort of 170 patients with Lp(a)hyperlipoproteinemia and the maximum tolerable lipid lowering medication dose, the authors found that lipid apheresis effectively reduced the frequency of cardiovascular and cerebrovascular events over a follow-up period of 2 years. New pharmacological substances, e.g. the anti-sense oligonucleotide of apolipoprotein-B mRNA such as mipomersen or inhibitors of the proprotein convertase subtilisin kexin type 9 (PSCK9) might develop as reasonable candidates for future treatment strategies [71]. If these evolving therapeutic options prove to be effective treatment strategies for high Lp(a) levels, the results of this study should encourage clinicians to determine Lp(a) serum levels in stroke patients more frequently. 4.1. Limitations Our systematic search considered studies from 2006 and 2009 to December 2014 and should therefore be considered an update of previous reviews [16,17]. As we only addressed ischemic stroke, we followed stricter inclusion criteria and therefore not all studies included in previous meta-analyses were eligible for inclusion into our re-assessment. Still, the results are comparable thereby reinforcing the pathological role of Lp(a) in ischemic stroke. As present in the previous analysis by Smolders et al. [17], high levels of heterogeneity are also present in our analysis. However, metaregression identified varying Lp(a) contrast levels and ischemic stroke subtypes as the primary sources of heterogeneity. If studies reported multiple Lp(a) contrasts, the contrast that revealed the highest risk ratio was used for further analyses. Meta-analyzing data with high vs. low contrast irrespective of the categorization will lead to misclassification and result in an underestimation of the true effect that can be expected in a quartile or quintile analysis. Individual patient characteristics differed substantially between studies, making direct comparisons of study results problematic
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[14,72]. A major limitation is the lack of access to individual patient data, as it would have allowed for more standardized analyses in terms of defined Lp(a) contrast levels and adjustments, as well as for the investigation of within-study heterogeneity. The absence of standardized detection methods for Lp(a) limit the comparability of studies because (1) not all studies have used isoform insensitive detection assays and (2) reported storage times of frozen samples varied substantially across studies (see eTable 5). Moreover, the lack of Mendelian randomization studies that have investigated a genetic relationship between Lp(a) and stroke did not allow us to assess a causative role of Lp(a) in ischemic stroke. 4.2. Conclusion In conclusion, our meta-analysis emphasizes the importance of high Lp(a) as an independent but modest risk factor in ischemic stroke. This becomes especially evident in younger stroke populations. Conflicting sex-specific results warrant further studies, preferably using standardized categorized Lp(a) contrast levels. Author contribution Study concept: Nave AH, Lange KS, Ebinger M. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Nave AH, Lange KS. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Nave AH, Leonards CO. Obtained funding: Ebinger M, Endres M. Administrative, technical, or material support: Nave AH, Leonards CO, Ebinger M. Study supervision: Ebinger M. Sources of funding This study was funded by the Federal Ministry of Education and Research through the grant G.2.15 of the Center for Stroke Research Berlin (CSB). Disclosures AHN, KSL, COL, BS, WD, MEn and MEb, have nothing to disclose and no conflicts of interest. EST has received honoraria for presentations, advisory board activities, or data monitoring committee activities from Abbott, Aegerion, Amgen, Astra-Zeneca, BoehringerIngelheim, Bristol-Myers Squibb, Fresenius, Genzyme, a Sanofi company, Kaneka, Merck Sharp & Dohme, Novartis, Roche. Acknowledgments AHN had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. For general support and excellent statistical advice in conducting the systematic review and meta-analysis we thank Dr. Ulrike Grittner from the Center for Stroke Research Berlin and the Department of Biostatistics and Clinical Epidemiology of the . Charite Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.atherosclerosis.2015.08.021.
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