Platelet transfusion for spontaneous intracerebral hemorrhage with prior antiplatelet: A systematic review and meta-analysis

Abstract

Background:

Recent studies have highlighted the unfavorable prognosis of patients with spontaneous intracerebral hemorrhage (ICH) who have received prior antiplatelet therapy (PAP). Platelet infusion therapy (PIT) is commonly administered to such patients at many medical institutions, but its efficacy remains a subject of debate.

Methods:

To address this uncertainty, we conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library databases for eligible studies published before June 30, 2023. Our primary outcomes of interest were favorable functional outcome and mortality, while secondary outcomes included the incidence of hematoma expansion and adverse events associated with PIT. Meta-analysis was performed using Review Manager 5.3.

Results:

Our analysis included 1 randomized controlled trial (RCT) and 6 retrospective studies, involving a total of 577 patients. Pooled analysis revealed that PIT did not contribute to a better favorable functional outcome at the 3-month follow-up (OR = 0.49, 95% CI 0.27–0.89) among ICH patients with PAP. Furthermore, PIT did not significantly reduce the risk of mortality (OR = 0.79, 95% CI 0.40–1.55) or hematoma expansion (OR = 1.15, 95% CI 0.65–2.01). Notably, no significant differences in serious adverse events were observed between patients who underwent PIT and those who did not.

Conclusions:

Based on the available evidence, there is no indication that PIT can enhance the prognosis of spontaneous ICH patients with prior antiplatelet therapy, although this treatment approach appears to be safe. Therefore, routine recommendation of PIT for ICH patients with prior antiplatelet therapy is not warranted.

1. Introduction

The number of patients with spontaneous intracerebral hemorrhage (ICH) who have previously undergone antiplatelet therapy (PAP) is on the rise. Previous studies have consistently shown that these patients face a higher risk of hematoma volume progression and worse outcomes.^[1–3] Additionally, a study has indicated increased odds of death at 1 month for ICH patients with PAP.^[4] Managing ICH patients with prior antiplatelet therapy presents a critical and challenging task, as there is currently no recommended treatment guideline for this patient group. A systematic review conducted 5 years ago, which included only 3 studies, revealed that platelet infusion therapy (PIT) did not significantly reduce mortality among spontaneous ICH patients with PAP.^[5] In recent years, several newly published studies, including 3 observational studies^[6–8] and 1 randomized trial,^[9] have reported inconsistent or conflicting results regarding the effectiveness of PIT in ICH patients with PAP. Despite these conflicting findings, the administration of platelet transfusions for ICH patients with PAP remains a common practice at many medical institutions. The use of PIT to reverse the effects of antiplatelet agents in ICH patients with previous therapy remains an unresolved issue.

In order to evaluate the safety and efficacy of PIT for ICH patients receiving PAP, we conducted an updated systematic review and meta-analysis.

2. Methods

2.1. Search strategy

The systematic review and meta-analysis were prepared following the preferred reporting items for systematic reviews and meta-analyses (PRISMA).^[10] This study was approved by an ethical review committee of Sichuan Provincial People’s Hospital Review Board. We searched PubMed, EMBASE, and Cochrane Library databases up to 30 June 2023. Our searches were restricted to English language and human studies. Relevant reference lists from published journals were also reviewed for potentially eligible studies. Search terms and keywords were grouped in the following search strategy:

#1 (cerebral OR intracerebral OR brain OR intracranial OR “basal ganglia”) AND (hemorrhage OR hematoma);

#2 “platelet aggregation inhibitors” OR “phosphodiesterase inhibitors” OR “glycoprotein IIb-IIIa inhibitors” OR antiplatelet OR antiplatelet OR aspirin OR dipyridamole OR ticlopidine OR clopidogrel OR cilostazol OR ticagrelor OR prasugrel;

#3 (platelet OR thrombocyte) AND (transfusion OR infusion OR administration OR intravenous OR application);

#4 #1 AND #2 AND #3

2.2. Study selection

Two reviewers (L.Y. and L.M.) initially reviewed the titles and abstracts of the search studies independently to exclude any irrelevant results. Afterward, they examined the full text to identify studies that met the inclusion criteria. In cases where there were disagreements between the reviewers, a consensus was reached through discussion. If necessary, a third reviewer (GYJ) acted as an arbiter to resolve any remaining disputes. The selected studies fulfilled the following criteria: #1 Observational studies or randomized controlled trials (RCT); #2 Studies relating to patients with spontaneous ICH confirmed by brain imaging and had received antiplatelet therapy preceding ICH; #3 Studies involving a comparison between patients who had received platelet transfusion therapy and those without platelet transfusion. Studies were excluded for the following criteria: #1 Studies involving patients with a secondary cause for their intracerebral hemorrhages, such as traumatic ICH, ruptured aneurysm, primary ischemic stroke, arteriovenous malformation, or tumor. #2 Studies focusing on patients with anticoagulant-associated ICH. #3 Studies of case report. #4 Duplicated articles based on the same datasets. #5 Studies from which data could not be extracted.

2.3. Outcome measures

The primary outcomes were favorable functional outcome and mortality (in-hospital or at 3–6 months). Favorable functional outcome was defined as a modified Rankin Scale (mRS) ≤ 3.^[11,12] Secondary outcomes included hematoma expansion and adverse events from platelet transfusion (related complications such as bleeding, infection, thromboembolism, or transfusion reactions, etc.).^[13] Hematoma expansion was defined as an enlargement of intracerebral hemorrhage volume or occurrence of new hemorrhage compared with baseline brain imaging.^[14]

2.4. Data extraction and quality assessment

Data from eligible studies were extracted in standardized forms by 2 independent reviewers (Y.J.P. and L.L.) and cross-checked by a third reviewer (L.Y.). The extracted information included the name of the first author, publication year, study design, sample size, number of patients in each group, baseline Glasgow coma scale (GCS) score, and primary and secondary outcome measures. Any disagreements were resolved through discussion or, if necessary, by a third reviewer (G.Y.J.) serving as an arbiter. The quality assessment of included studies followed the criteria outlined by the Cochrane Collaboration’s tool for RCTs and the Newcastle–Ottawa scale (NOS) system for observational studies.^[15,16] RCTs were assigned a rating of high, low, or unclear risk of bias, while observational studies with NOS scores ≥ 7 were considered of high quality.

2.5. Statistical analysis

We conducted a meta-analysis utilizing odds ratios (ORs) and 95% confidence intervals (95% CIs) under a random effects model. We assessed between-study heterogeneity using the Cochrane I² test. A value of I² = 0 indicated no evidence of heterogeneity, while I² > 50% represented significant heterogeneity.^[17] If adequate data is available, subgroup analyses will be performed to explore differences in study design, antiplatelet agents used, and follow-up time. To evaluate publication bias, we employed funnel plots. All statistical analyses were performed using Review Manager 5.3. Statistical significance was defined as P values < 0.05.

3. Results

3.1. Results of the search

After identifying 969 potentially relevant articles, we excluded duplicates and were left with 803 papers. By screening titles and abstracts, we excluded 765 references for various reasons, including irrelevance, case reports, and review articles. After reading the full texts, we further excluded 31 studies. Among these, 10 did not conform to the eligibility criteria, 7 were irrelevant, 9 had irrelevant outcome data, 2 had incomplete outcome data, 2 were review articles, and 1 was a non-English article. Ultimately, 7 studies^{[6–9,18–20]} were chosen for detailed assessment and meta-analysis. These studies included 6 retrospective studies and 1 randomized controlled trial. The flow diagram of literature screening is shown in Figure 1.

Figure 1.

The flow diagram of literature screening.

3.2. Study characteristics and quality assessment

Ultimately, a total of 7 studies were included, encompassing 577 subjects. Among these studies, aspirin and clopidogrel were commonly used antiplatelet agents. Only 1 RCT, consisting of 190 subjects, met the inclusion criteria. However, it should be noted that there were significant risks of performance bias due to the lack of masking in treatment allocation for both participants and investigators. Regarding the observational studies, 6 were retrospective in nature, with sample sizes ranging from 9 to 121 and a total of 387 subjects. In accordance with the NOS assessment system, 4 retrospective studies were deemed high-quality (NOS ≥ 7), while the remaining 2 studies received a score of 5 (Suzuki et al,^[18] Lam et al^[8]). For a comprehensive summary of the characteristics and quality assessment of the included studies, please refer to Table 1.

Table 1.

Characteristics of included studies.

Author (year)	Study design	Sample size	PAA	PIT, n (%)	Without PIT, n (%)	Outcomes (course)	Quality assessment
Baharoglu et al (2016)	RCT	190	Aspirin Clopidogrel Carbasalate dipyridamole	97 (51.1)	93 (48.9)	1. mortality (3 mo) 2. mRS ≤ 3 (3 mo) 3. hematoma expansion 4. complication from transfusion	High risks of bias in blinding: participants and investigators were not blinded.
Arnone et al (2018)	Retrospective study	62	Aspirin Clopidogrel	31 (50.0)	31 (50.0)	1. mortality (in hospital) 2. mRS ≤ 3 (on discharge) 3. hematoma expansion 4. complication from transfusion	NOS score = 8
Lam et al (2018)	Retrospective study	9	Aspirin Clopidogrel	6 (66.7)	3 (33.3)	1. mortality (in hospital) 2. hematoma expansion	NOS score = 5
Engel-Haber et al (2015)	Retrospective study	63	Aspirin	39 (61.9)	24 (38.1)	1. hematoma expansion	NOS score = 7
Suzuki et al (2014)	Retrospective study	66	Aspirin Clopidogrel Ticlopidine Cilostazol Sarpogrelate dipyridamole	6 (9.1)	60 (90.9)	1. mortality (in hospital)	NOS score = 5
Ducruet et al (2010)	retrospective study	66	Aspirin Clopidogrel	35 (53.0)	31 (47.0)	1. mortality (in hospital) 2. hematoma expansion	NOS score = 8
Creutzfeldt et al (2009)	Retrospective study	121	Aspirin Clopidogrel Dipyridamole	53 (43.8)	68 (56.2)	1. mortality (in hospital) 2. mRS ≤ 3 (on discharge)	NOS score = 8

NOS = Newcastle-Ottawa scale, PAA = prior antiplatelet agents, PIT = platelet infusion therapy, Without PIT = without platelet infusion therapy, and treated patients were treated according to the national guideline for the management of ICH.

3.3. Outcomes and meta-analysis

3.3.1. Favorable functional outcome (mRS ≤ 3).

A combined analysis of 2 retrospective studies^[7,20] revealed no significant association between PIT and functional outcome in patients with spontaneous ICH and PAP (OR = 1.57, 95% CI 0.82–3.03). Moreover, a randomized controlled trial (Baharoglu et al^[9]) demonstrated a clear trend indicating that PIT increased the risk of poor functional outcomes during a 3-month follow-up in patients with spontaneous ICH and PAP (OR = 0.49, 95% CI 0.27–0.89; as shown in Fig. 2).

Figure 2.

Favorable functional outcome (mRS ≤ 3) between platelet infusion vs without infusion groups in intracerebral hemorrhage patients with prior antiplatelet.

3.3.2. Mortality.

Mortality was examined in 6 out of the 7 studies. Among these 6 studies, 1 RCT (Baharoglu et al^[9]) reported mortality (OR = 1.50, 95% CI 0.77–2.94) within a 3-month period, while 5 retrospective studies evaluated in-hospital mortality (OR = 0.55, 95% CI 0.29–1.05). None of the studies indicated a significant association between PIT and mortality. The pooled analysis revealed that PIT did not reduce the risk of mortality in patients with ICH and PAP (OR = 0.79, 95% CI 0.40–1.55). There was low heterogeneity among these studies (P = .20, I² = 31%; as shown in Fig. 3).

Figure 3.

Mortality between platelet infusion vs without infusion groups in intracerebral hemorrhage patients with prior antiplatelet.

3.3.3. Hematoma expansion.

Five of the studies, 4 retrospective studies and 1 RCT, evaluated the enlargement of hematoma volume during the hospitalization period. Pooled analysis showed that PIT did not decrease the risk of hematoma expansion in patients with ICH on PAP (OR = 1.15, 95% CI 0.65–2.01). Heterogeneity was low between these studies (P = .77, I² = 0; Fig. 4).

Figure 4.

Hematoma expansion between platelet infusion vs without infusion groups in intracerebral hemorrhage patients with prior antiplatelet.

3.3.4. Complications from platelet transfusion.

Complications arising from platelet transfusion, such as bleeding, infection, thromboembolism, or transfusion reactions, were documented in 2 out of the 7 studies. Arnone et al^[7] found no adverse reactions associated with platelet transfusion in patients with ICH. Additionally, Baharoglu et al^[9] reported no significant differences in serious adverse events between the platelet infusion and no platelet infusion groups. Although 4 cases of thromboembolism and 1 case of minor transfusion reaction were observed in the platelet infusion group, the no infusion group reported only 1 case of thromboembolism.

3.3.5. Publication bias.

By visual inspection, the funnel plot of mortality was approximately symmetrical, suggesting the absence of significant publication bias (Fig. 5).

Figure 5.

The funnel plot of mortality for intracerebral hemorrhage patients with prior antiplatelet.

4. Discussion

This comprehensive analysis of 7 studies, which included 577 patients with ICH and PAP, indicates that PIT did not show significant improvement in functional outcome (mRS ≤ 3). It also did not decrease the risk of mortality or hematoma expansion among ICH patients with PAP. However, these findings, though limited, do suggest that PIT is a safe treatment option for spontaneous ICH patients with PAP.

ICH has been reported to occur more frequently in patients with PAP, and it is possible that the higher rate of in-hospital death is associated with PAP.^[21] PIT has been suggested as a potential treatment to reverse antiplatelet effects in ICH patients with PAP, with the aim of improving prognosis by reducing the risk of hematoma expansion. However, a previous systematic review conducted 5 years ago, which included only 3 studies involving spontaneous ICH patients with PAP who received PIT, did not find a significant reduction in in-hospital mortality. Additionally, there was no evidence regarding the impact of PIT on long-term functional outcomes of ICH patients with PAP. Consequently, according to guideline recommendations (Class IIb; Level of Evidence C), the effectiveness of platelet infusion in ICH patients with PAP remained uncertain.^[22] Our updated meta-analysis, which included 3 more recent cohort studies and 1 RCT, indicates that PIT does not have any effect on favorable outcomes, hematoma expansion, or adverse events in spontaneous ICH patients with PAP. Consistent with the previous systematic review, PIT did not result in a significant decrease in mortality for spontaneous ICH patients with PAP.

Favorable functional outcome, defined as a mRS score ≤ 3, was not only a crucial indicator of the effectiveness of PIT, but it was also the primary outcome assessed in this study. Previous research suggested that PIT was associated with a higher mRS at 3 months follow-up,^[9] while other studies suggested no such association.^[7,20] However, our pooled analysis demonstrated that PIT did not lead to a significant difference in favorable functional outcome. It should be noted that the follow-up time and available data on transfusion time were inconsistent across studies, highlighting the need for high-quality research to provide a definitive conclusion.

Early hematoma expansion is a well-known factor that contributes to cerebral edema, increased intracranial pressure, early neurological deterioration, and poor overall outcomes.^[23] However, in the studies included in our analysis, there was no uniform timing of platelet transfusion, and related data on this timing were not available. Additionally, the included studies did not demonstrate a decreased risk of hematoma expansion, which could potentially be attributed to a delayed timing of platelet transfusion.

There were notable methodological limitations in the studies included in this research. Firstly, the retrospective studies published by Lam et al^[8] and Suzuki et al^[18] had small sample sizes, which could introduce a potential sample selection bias. Secondly, the RCT excluded severely impaired patients (GCS < 8) and patients undergoing neurological surgery, making the utility of platelet transfusion in these specific patients with ICH uncertain. Furthermore, there was a high risk of performance bias, as both patients and investigators were aware of the treatment allocation. Finally, it is important to note that the majority of patients in these studies were taking aspirin, so the findings may not be applicable to patients taking other antiplatelet medications.

Several limitations of our meta-analysis should be acknowledged. Firstly, we restricted our search to published articles written in English, which may introduce a potential publication bias. Secondly, the inclusion of only one RCT in our study warrants caution in interpreting the results. Thirdly, a review of the literature included in this study did not provide specific data on the specific time from antiplatelet use to the occurrence of spontaneous ICH. The ideal time for platelet transfusion, particularly in relation to the time of antiplatelet use, remains to be determined. Finally, it is possible that differences in the effectiveness of PIT may be observed in patients with different disease states, anticoagulant therapies, and gender differences. future RCTs may provide more comprehensive insights into the effectiveness of PIT in different patient populations and help inform clinical decision-making in this area.

Whether platelet transfusion can be used as an adjuvant treatment for ICH with PAP needs to be further evaluated. The main implication of this study was that the future high quality research of PIT should focus more on ICH with different timing of PIT (ultra-early treatment) and should include more severely ill patients.

Further evaluation is required to determine whether platelet transfusion can be utilized as an adjuvant treatment for ICH with PAP. The key implication of this study highlights the necessity for future high-quality research on platelet transfusion, specifically focusing on the different timing of platelet transfusion (such as ultra-early treatment) in ICH cases. Additionally, including a larger proportion of severely ill patients would contribute to a more comprehensive understanding of the potential benefits of platelet transfusion in these scenarios.

5. Conclusions

There is currently insufficient evidence to support the use of PIT as a means to improve the prognosis of patients with spontaneous ICH and PAP. While the treatment regimen may be considered safe, it is not recommended to routinely administer PIT for ICH patients with PAP based on the available data. Further research is needed to determine the efficacy and potential benefits of PIT in this specific population.

Author contributions

Conceptualization: Jie Yang.

Data curation: Lei Liu, Yapeng Lin.

Formal analysis: Jie Yang.

Funding acquisition: Jie Yang.

Investigation: Yan Lin, Yong Liu, Lei Liu, Lili Zhang, Yapeng Lin.

Methodology: Yan Lin, Yong Liu.

Software: Lei Liu, Lili Zhang, Yapeng Lin.

Writing – original draft: Yan Lin, Yong Liu.

Writing – review & editing: Jianping Yu, Jie Yang.