Alkaline phosphatase and mortality in stroke patients: a systematic review

Introduction

Stroke is a major cause of death and the leading cause of disability worldwide. Stroke-related complications occur most frequently during the first week after stroke and are associated with higher mortality risk during hospital stay and a longer hospital stay (1). The risk for death is highest in the acute phase of a stroke and then gradually declines. A study from the Danish MONICA project (2) found that the most frequent cause of death in patients with non-fatal strokes was cardiovascular disease, with 32.1% of deaths due to cerebrovascular disease and 22.7% to ischemic heart disease.

Different predictive models for mortality in stroke have been developed (3), but none of them are routinely used in clinical practice. These models include clinical variables, such as age and stroke severity, as predictors of poor outcome and mortality (4). It has been suggested that the addition of blood biomarkers to clinical models might improve their prediction capacity. Over 150 candidate stroke biomarkers have been studied (5). However, there is still a lack of trackable biomarkers capable of predicting the risk and prognosis of stroke, and that may play a role in stroke mortality prevention. Biomarkers could be used to help identify high-risk patients, allowing more aggressive therapeutic strategies targeted at those most likely to benefit. One possible candidate as a diagnostic and prognostic biomarker for stroke is alkaline phosphatase (ALP). This enzyme is responsible for catalyzing the hydrolysis of organic pyrophosphate, an inhibitor of vascular calcification, thus promoting the enhancement of vascular calcification, accelerating the stiffening of vessels, decreasing vascular compliance and consequently promoting atherosclerosis (6). The possible involvement of the serum ALP levels in the risk of cardiac and cerebrovascular diseases as well as in poor outcomes and all-cause mortality after stroke has been under study in recent years.

Given these considerations, we aimed to conduct a systematic review concerning the association between ALP levels and all-cause mortality after stroke and its use as a possible predictor of mortality in this context. We present this article in accordance with the PRISMA reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1627/rc) (7).

Methods

Eligibility criteria

We searched for original studies focused on the impact of ALP levels on overall mortality, in patients who had a past diagnosis of stroke event of any type (ischemic or hemorrhagic) or a transient ischemic attack (TIA).

Articles that only analyzed the incidence of stroke or TIA in the general population (patients without previous stroke events) or that did not present data on mortality were excluded. Case reports, systematic reviews, review articles and studies including animal models were not considered for this study.

No specific limit of time after stroke was defined in which our primary outcome (mortality) had to occur. With this in mind, follow-up time was not considered as an exclusion criterion.

No articles were excluded based on publication date or the language in which the studies were written.

Search strategy

A comprehensive literature search was carried out to identify all reported articles relating the impact of ALP levels on mortality after stroke. This search was conducted on the databases Medline (PubMed) and Web of Science.

The search took place on the 30th of October 2022 in the Web of Science database and on the 31st of October 2022 in the Medline database, using the following query: (“alkaline phosphatase” [MeSH Terms]) OR (“alkaline phosphatase”[All Fields]) AND (“stroke”[MeSH Terms] OR “stroke”[All Fields]).

Additionally, to avoid missing reports, we manually scanned the list of references from the included studies and of the previous review focusing on the relation between ALP and stroke (8).

Selection process

Eligibility was evaluated by four investigators, who independently assured that all the inclusion and exclusion criteria were met. In the screening phase, only the title and the abstract were analyzed. After this process, 22 articles were considered eligible. Full-text critical assessment of the 22 articles followed and 9 articles were included in this systematic review. Divergent opinions regarding the relevance of articles were solved by consensus between the authors.

Data collection process and data item

Data extraction was individually done, by the four above mentioned authors, from the data published in the selected articles, and then compared between the investigators. Any doubtful situation was solved by consensus between the authors.

Study quality assessment

Global article quality assessment was carried out according to the National Heart, Lung and Blood Institute study quality assessment tools (available at https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools) and is presented in Table S1.

Outcome measures

Our primary outcome was the association between the level of ALP and the risk for all-cause mortality, in the period after a stroke event, either ischemic or hemorrhagic, or after a TIA. No statistical analysis was carried out. Arithmetic analysis of the number of deceased patients in studies comparing the highest to the lowest ALP quintiles and in studies comparing the highest to the lowest ALP quartiles was made by retrieving the data from the original reports.

Results

Study selection

In the screening phase, only original observational articles, involving either prospective or retrospective data collection, were included and also a letter to the editor, since it was possible to extract relevant association data from it (9). After applying our inclusion and exclusion criteria, 22 articles were selected for full-text analysis, which was independently performed by four different reviewers. This process is further detailed in Figure 1. The data extracted from the thirteen articles excluded after full-text analysis is exposed in the Table S2.

Figure 1 Flowchart showing literature search method.

The process of article selection was finalized with a total number of nine articles selected for the purpose of the present study (10-18) (Figure 1). The complete set of studies is presented in Table 1.

Study characteristics

Stroke was defined by the World Health Organization (WHO) clinical criteria (19) in five of the nine articles (10,11,13,14,16), as rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death with no apparent cause other than of vascular origin. Five studies (13-16,18) confirmed the clinical diagnosis through brain imaging [computed tomography (CT) or magnetic resonance imaging (MRI) scan]. Not all articles studied populations with the same type of stroke. Three studies (14,16,17) focused on mortality purely after ischemic stroke, two (11,13) purely after hemorrhagic stroke and four (10,12,15,18) after either hemorrhagic or ischemic stroke. Regarding the studies that considered patients who suffered a hemorrhagic stroke, three studies excluded hemorrhagic strokes caused by subarachnoid hemorrhage (SAH) (10,12,13), while the other two (15,18) included both SAH and spontaneous intracerebral hemorrhage as hemorrhagic strokes. From those that focused solely on ischemic stroke, two (15,18) also included TIA, whilst Zhong et al. (14) excluded patients diagnosed with TIA. Liu et al. (16) specifically evaluated patients with minor ischemic stroke, defined as a National Institutes of Health Stroke Scale (NIHSS) score at admission lower or equal to 3. Two articles (10,17) detailed the aetiology of the ischemic stroke events according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria (20). Still concerning the seven ischemic stroke focused articles (Table 1), not all apply the same criteria regarding the inclusion of patients who underwent thrombolytic treatment. Ryu et al. (10) included 159 patients (7.8%) that had been submitted to thrombolytic treatment. Zhong et al. (14) included 70 patients (2.4%) who have received thrombolytic therapy, but also conducted a sensitivity analysis excluding these patients. Nezu et al. (17) excluded all patients that underwent either intravenous thrombolysis or endovascular treatment. The remaining four ischemic stroke focused articles, during their population selection process, do not conduct any type of restriction regarding thrombolytic therapy.

An acceptable period of time, after onset of stroke symptoms and until admission, was defined for each study, except for Liu et al. (16) in which the only criteria for enrollment was a NIHSS lower or equal to 3 at admission. The time of onset of the stroke was defined as the time in which the patient or observer first became aware of the symptoms. One article (12) considered patients eligible for enrollment if they were admitted within 2 weeks from symptom onset, six articles (10,13-15,17,18) within 7 days and one article (11) within 3 days. It is thus expected that the levels of ALP at admission of some patients might not accurately reflect the levels at stroke onset. For this reason, Zhong et al. (14) restricted their analysis to patients with time from onset to admission inferior to 2 days and their findings remained unaltered.

Of the nine included articles, three were retrospective analyses (13,15,17) and six were prospective studies (10-12,14,16,18). All the studies were published between 2010 and 2022.

China contributed with most of the studies (n=5). The remaining studies were conducted in Korea (n=1), Japan (n=1), and in India (n=2). The sample size included in the studies varied from 60 to 16,367 patients.

Available demographics and comorbidities data were extracted and are presented in Table 2.

Since liver disease might affect ALP levels, five studies (10-13,15) excluded patients with established liver disease. Additionally, as alcohol consumption, even in small amounts, can cause derangement in liver function, Pratibha et al. (12) defined alcohol consumption within the previous 3 months as an exclusion criterion. In contrast, six articles (13-18) included data on alcohol consumption, and it ranged from 9.6% (14) to 29.7% of patients (17) (Table 3).

Synthesis of results

As depicted on Table 1, the nine studies included in this review defined mortality after stroke as one of their outcomes. Nevertheless, not all studies have the same follow-up period, allowing for mortality to be accounted, as an outcome, at different time intervals post stroke occurrence. Ryu et al. (10) followed their enrolled patients for a maximum period of 2.5 years, three studies (12,15,16) for 1 year, two studies (17,18) for 3 months, one study (13) for 90 days, one study (11) for 30 days and one study (14) only for the hospitalization period of each patient, a mean of 10.0 (8.0–14.0) days of hospital stay.

Elevated serum ALP correlated significantly and independently with all-cause mortality in all the studies included in our systematic review, even after data adjustment for potential confounding variables (Table 1), and specifically with vascular death, defined as death caused by stroke, myocardial infarction, heart failure, pulmonary embolism, cardiac arrhythmia, or other definite vascular causes, in two studies (10,12).

The studies comparing the highest to the lowest ALP quintiles (10,12,15) showed an aggregate value of 1.8 times greater risk of mortality for the former, when compared to the latter. The studies comparing the highest to the lowest ALP quartiles for which data were available (13,18) showed an aggregate value of 2.4 times greater risk of mortality for the former, when compared to the latter.

All of the nine studies included in this systematic review estimated, at admission, the severity of neurologic impairment using either the NIHSS or the Glasgow Coma Scale (GCS), as shown in Table 4. Seven of the nine studies (10,13-18) conducted data adjustment for the NIHSS or GCS score at admission. This covariate was selected to integrate multivariable adjusted models since stroke severity has been associated with mortality after stroke and ALP levels (21,22). ALP remained independently associated with mortality after adjustment for admission NIHSS or GCS score and this association was not weakened.

From the six above mentioned studies that included data on alcohol consumption, all included this variable in their multivariable models. Zong et al. (15) even conducted a stratified analysis by alcohol consumption that showed that the effects of ALP on mortality were not changed by alcohol consumption.

Data concerning other main prognostic findings, besides mortality, were available for six studies (12,13,15-18) (Table 5). Elevated ALP levels were significantly associated with increased risk of adverse stroke outcomes, except for two studies (16,18).

Risk of bias in the included studies

Five studies (10,14,15,17,18) excluded patients due to lack of serum ALP concentration values (selection bias), limiting the generalizability of the findings.

As demonstrated in Table 3, three articles (10,11,15) excluded liver disease through self-reported questionnaires, which may lead to reporting bias. Additionally, Zong et al. (15) did not exclude patients with obstructive biliary disease for lack of biliary levels data registration and Nezu et al. (17) did not evaluate detailed information on liver diseases that affect serum ALP levels. However, Nezu et al. (17) conducted multivariable analysis for both daily alcohol intake and other liver enzymes, adjusting for these influences.

Discussion

In the present report, the association of ALP levels and mortality after stroke was under review.

ALP is a key regulator of the phosphate/pyrophosphate ratio (23), by catalyzing the hydrolysis of organic pyrophosphate, which plays a role in vascular calcification (23). Increased ALP levels have been proposed to accelerate this process therefore decreasing vascular compliance, which in turn results in vascular aging.

Therefore, serum ALP has been progressively accepted as a marker of vascular calcification and, consequently, might constitute a risk factor for ischemic stroke. Also, through the above-mentioned vascular aging, these weakened vessels might be more prone to rupture potentially increasing the risk of hemorrhagic stroke too. Indeed, elevated ALP levels have been demonstrated to be associated with stroke recurrence and other cardiovascular diseases—both known causes of post-stroke mortality.

Plausible mechanisms through which ALP detrimentally affects survival post-stroke may thus include increased vascular calcification, an association with other cardiovascular diseases, an association with liver disease, and changes in cholesterol metabolism (24).

Concerning the risk of post-stroke mortality over time, Brønnum-Hansen et al. (2) demonstrated that 72% survived their first stroke by 27 days and 41% died after 1 year. The risk of death between 4 weeks and 12 months after the first stroke was 18.1%. After the first year, the annual risk for death was approximately 10% and remained almost constant.

The 28-day mortality of intracerebral haemorrhage has been shown to be considerably higher than that of ischaemic stroke. We analyzed data concerning the two main types of stroke and also ischemic stroke subtypes. From the four studies (10,12,15,18) that included both ischemic and hemorrhagic stroke, only Ryu et al. (10) compared the association of ALP levels and all-cause mortality after an ischemic versus hemorrhagic stroke, showing that this association was significant irrespective of stroke subtypes, although it has a greater impact on haemorrhagic stroke (ischemic stroke hazard ratio 2.51 versus hemorrhagic stroke hazard ratio 5.79). Guo et al. (18) concluded that Kaplan-Meier curves of 3-month cumulative rates of all-cause mortality differ significantly in different stroke subtypes, demonstrating that spontaneous intracerebral hemorrhage and subarachnoid hemorrhage might have higher mortality rates than TIA and ischemic stroke, providing a new direction for investigating the association of ALP levels and different stroke types.

A biomarker providing strong prognostic indications could help identify high-risk patients that could benefit from different therapeutic approaches. Accordingly, an ideal stroke biomarker should be capable of predicting stroke prognosis and facilitating therapeutic stratification and monitoring (5), for example by indicating risk of hemorrhagic transformation after stroke or after tissue type plasminogen activator treatment (rt-PA). In fact, Zhu et al. (25) already demonstrated that higher serum ALP levels were independently associated with a poor outcome in patients after intravenous thrombolysis.

Mechanical thrombectomy has become the standard of care for acute ischemic stroke due to large vessel occlusions. However, up to 29% of all mechanical thrombectomies fail (26). Recently, acute intracranial stenting has been reported to be a highly promising bailout strategy for these thrombectomy cases with predictably poor outcomes (27-29). Park et al. (30) has already demonstrated that high levels of total ALP activity predicted coronary stent thrombosis. In the future, it would be interesting to study ALP levels as a possible predictor of intracranial stent thrombosis.

In the future, it would be interesting to define the timeline of influence of ALP levels in mortality post-stroke. Indeed, as time passes by, since stroke onset, the risk of mortality and the corresponding promoting causes vary. Regarding post-stroke mortality causes over time, Viitanen et al. (31) showed that the dominant causes of death were cerebrovascular disease (90%) in the first week and later than 3 months after stroke, cardiac disease, mainly myocardial infarction dominated.

When attempts are made to reduce mortality after stroke, there seems to be a considerable potential for prevention and early treatment of complications, such as cardiac disorders. Mortality rate due to all cardiovascular diseases in stroke populations is almost four times higher than that in the general population (8). Myocardial infarction is one of the leading causes of death during long-term follow-up in patients with an ischemic stroke, since it shares common risk factors with coronary artery disease (32). Liu et al. (33) found that higher serum ALP levels, even within the normal range, were significantly and linearly associated with higher risks of cardiovascular disease in both men and women, without previous stroke. Moreover, their analyses showed that each per unit increment in natural log-transformed ALP levels was independently associated with 31%, 61%, and 206% greater risks of acute coronary syndrome, ischemic stroke and hemorrhagic stroke, respectively, in men. This review has demonstrated that the elevation of ALP levels is consistently associated to increased mortality after stroke, however it is not known if it represents short-term or long-term mortality and, consequently, the specific cause of death that lies behind it.

It is possible that the underlying cause of the higher mortality 3 months after stroke is the higher risk of cardiovascular disease, which these patients have, since cardiovascular disease starts to dominate as the main post-stroke mortality cause.

The regulation of ALP is already a potential novel treatment strategy that might reduce vascular calcification and improve cardiovascular outcomes (34). The mechanisms suggested are mainly two: inhibition of ALP activity and the modulation of its expression. A novel direct ALP inhibitor, SBI-425, effectively inhibits vascular calcification in animal models at doses that do not alter bone mineralization. Interestingly, two phase II trials showed that apabetalone (a novel bromo-domain and extra-terminal motif inhibitor RVX-208) administration reduced circulating levels of ALP, which was associated with a marked reduction of major cardiovascular events (34,35).

Limitations

The limitations for the present report include the heterogeneity in the studies characteristics, namely concerning the types of stroke under study and length of follow-up. A further limitation is that the reviewed studies come predominantly from Asia.

In the nine studies reviewed, measurement of ALP was carried out exclusively at admission. Since no serial measurements of serum ALP were conducted, the association between ALP changes during hospitalization and all-cause mortality could not be examined. Likewise, Guo et al. (18) stated that because the study was only focused on the association of serum ALP levels within 24 h of admission and the 3-month outcome, the potential influence of changes in ALP levels after discharge was not analyzed. Besides Guo et al., two other authors (10,14) presented this fact as a possible limitation. Ryu et al. (10) states that changes of serum ALP levels during the acute period of stroke have not yet been understood, and therefore, it is possible that an acute phase reaction accompanying stroke or in-hospital complications may be behind the elevation of ALP levels. Additionally, since ALP was only measured in the acute stroke period, they were unable to rule out post-stroke cholestasis that can, although rarely, lead to death after stroke.

Two authors (10,12) identified the time interval until death as a possible limitation. On one hand, due to the previously mentioned possible acute phase reaction accompanying stroke, Ryu et al. (10) conducted a subsequent analysis excluding early mortality (inferior to 1 month), but no variations concerning the association between ALP and mortality after stroke were verified. On the other hand, Pratibha et al. (12) suggested that a longer follow up time would have yielded much more information regarding long term mortality.

Conclusions

ALP was demonstrated to be a promising biological marker for improving the predictive ability for stroke outcomes (17). Serum ALP measurement requires a routinely available blood test, which is simple, low-cost, and standardized, and our review indicates that it may be a potential test to predict stroke outcomes, namely mortality.

In conclusion, measuring ALP levels may provide a cost-effective prognostic indicator of stroke-related mortality (17). A finding that warrants further investigation in future primary studies that follow standardized methodologies.

Acknowledgments

This systematic review was carried out in the context of a master’s thesis in the Integrated Cycle of Studies for the Master’s Degree in Medicine of the Faculty of Medicine of the University of Porto.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-23-1627/rc

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-23-1627/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1627/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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