Intracerebral haemorrhage volume, haematoma expansion and 3-month outcomes in patients on antiplatelets. A systematic review and meta-analysis

Abstract

Aims

We assessed the association of prior antiplatelet therapy (APT) at onset of intracerebral haemorrhage (ICH) with haematoma characteristics and outcome.

Methods

We performed a systematic review and meta-analysis of studies comparing ICH outcomes of patients on APT (APT-ICH) with patients not taking APT (non–APT-ICH). Primary outcomes were haematoma volume (mean difference and 95% CI), haematoma expansion (HE), in-hospital 3-month mortality rates and good functional outcome (modified Rankin Scale score 0–2). We provide odds ratios (ORs) from random effects models and subgroup analyses for haematoma expansion and short-term mortality rates.

Results

We included 23 of 1551 studies on 30,949 patients with APT-ICH and 62,018 with non-APT-ICH. Patients on APT were older (Δmean 6.27 years, 95% CI 5.44–7.10), had larger haematoma volume (Δmean 5.74 mL, 95% CI 1.93–9.54), higher short-term mortality rates (OR 1.44, 95% CI 1.14–1.82), 3-month mortality rates (OR 1.58, 95% CI 1.14–2.19) and lower probability of good functional outcome (OR 0.61, 95% CI 0.49–0.77). While there was no difference in HE in the overall analysis (OR 1.32, 95% CI 0.85–2.06), HE occurred more frequently when assessed within 24 h (OR 2.58, 95% CI 1.18–5.67). We found insufficient data for comparison of single versus dual APT-ICH. Heterogeneity was substantial amongst studies.

Discussion

APT is associated with larger baseline haematoma volume, early (<24 h) haematoma expansion, mortality rates and morbidity in patients with ICH. Data on differences in single and dual APT-ICH are scarce and warrant further investigation. New treatment options for APT-ICH are urgently needed.

Introduction

Intracerebral haemorrhage leads to high morbidity and mortality. ¹ Antiplatelet therapy (APT) is highly prevalent in patients with non-traumatic intracerebral haemorrhage (ICH) ² and may be associated with prognostically unfavourable haematoma characteristics and outcome. ³ However, data are mostly based on small, retrospective studies with limited generalisability: while a small recent study observed larger haematoma volume in patients on APT, which, however, was not associated with significantly worse functional outcomes, ⁴ several studies suggest that APT-ICH is associated with more haematoma expansion^5,6 and higher mortality.^7–11 In the last years, new antiplatelet drugs and regimens have been introduced, but knowledge on outcome differences according to prior antiplatelet types (aspirin, clopidogrel, dipyridamole, ² prasugrel, ticagrelor, etc.) and regimens (Single and dual therapy) is scarce.

We conducted a systematic review and meta-analysis to determine whether APT-ICH is associated with larger haematoma volumes, higher risk of haematoma expansion, functional outcome or mortality rates compared to non–APT-ICH. Secondly, we aimed to compare outcomes in patients treated with single versus dual antiplatelet therapy.

Methods

We performed a systematic review and meta-analysis of published studies reporting haematoma characteristics and/or outcome of intracerebral haemorrhage associated with prior APT use compared to controls (no prior APT). This report was prepared with respect to the PRISMA recommendations. ¹² The analysis was performed in 07/2020 according to a pre-planned protocol developed in-house prior to any analysis (see Supplement).

Search strategy

We searched pubmed.gov/MEDLINE for relevant publications on 02.07.2020 (MBG and BS) according to the search strategy which is described in the supplement. We did not include a date restriction into the search strategy.

Eligibility criteria

The eligibility criteria are listed in the study protocol in the supplement. Antiplatelet therapy was defined as medication with aspirin, clopidogrel, ticagrelor, prasugrel, dipyridamole, ticlopidine or cilostazole or as defined by the study group. We only included data from participants in interventional studies for general intensive care measures in ICH patients as well as those in the placebo arms of interventional studies, but not from participants in the interventional arm of interventional studies targeting haematoma or oedema characteristics. Given that anticoagulation itself is associated with poorer ICH outcomes, ¹³ we also excluded studies that included anticoagulated patients (on vitamin K antagonists or direct oral anticoagulants) in one or both of the relevant subgroups.

Screening

MG and BS screened all identified abstracts for eligibility, read full texts of all potentially eligible articles and extracted data on study design and outcomes according to a predefined extraction form between 07/2020 and 09/2020. Discrepancies were resolved in discussion between the two raters or with a third rater (DS).

Data collection

We extracted continuous data for age, intracerebral haemorrhage, absolute numbers of haematoma expansion, short-term mortality rates, 3-month mortality rates and functional outcome at 3 months. We applied definitions as used in the respective study. If reported separately, intraventricular haemorrhage volume was not considered as part of the haematoma volume. We calculated the absolute number of patients from the relative values (percentages) if studies did not indicate the absolute number.

If available, we extracted the abovementioned parameters for single and dual antiplatelet therapy separately.

Risk of bias

We assessed study quality and risk of bias on a study level using the 8-point scheme suggested by the Cochrane collaboration (see study protocol for assessment criteria). ¹⁴

Statistical analysis

We performed a meta-analysis if the relevant outcome was reported in at least three studies. Within APT-ICH, we compared single with dual antiplatelet therapy according to the same principle. The statistical analysis is described in detail in the protocol in the supplement.

Given that this is an aggregate meta-analysis, we were not able to adjust for possible confounders on a study level. However, we performed post hoc subgroup analyses for in-hospital and 7-/8-day mortality rates as well as for haematoma expansion comparing assessment within 24 h/1 day, within 72 h and other definitions.

Results

Literature search

The literature search identified 1551 studies. After eligibility assessment, we included 23 studies (see flowchart in Figure 1). Study characteristics are described in the Supplemental Table 1.

Figure 1.

Study flowchart.

Creutzfeld et al. analysed patients with APT-ICH according to whether they had received platelet therapy. ¹⁵ Due to the noxious effect of platelet infusion therapy, ¹⁶ we restricted the analysis to the subgroup with APT-ICH that had not received platelet infusions. A multicentre study by Roquer et al. reported data on subgroups of patients with versus without atrial fibrillation (AF). ¹⁷ For this meta-analysis, we only used data from the subgroup without AF to reduce the effect of possible confounders, assuming that risk profiles in patients with and without AF differed.

Amongst 92,923 patients with ICH, 30,896 patients had APT-ICH and 62,027 patients had non–APT-ICH. 16 studies reported on less than 100 patients with APT-ICH.^{4–7,9–11,18–26} Eligibility criteria in eight studies included a time restriction. Five studies included patients who arrived at the hospital up to 24 h after symptom onset,^4,5,7,19,24 one study each included patients who had presented within 6 h after symptom onset, ²⁶ had undergone CT within 12 h after onset ²² or up to 14 days after symptom onset. ²⁷ One study only included patients older than 55 years. ²⁵ None of them applied restrictions regarding baseline haematoma volume or haematoma expansion.

Risk of bias

None of the studies selected patients with APT- and non–APT-ICH from different populations. APT exposure was assessed and described as follows: Three studies used all available information to prospectively assess APT exposure,^17,26,28 and eight studies assessed various aspects of APT (dose, drug type, indication and compliance).^{6,7,18,23–26,29} We considered both approaches reliable, as they take into account various aspects and reduce the probability of false information. Ten retrospective, record-based analyses did not indicate criteria used in record-based assessment and were considered at a moderate risk of bias.^{5,9–11,15,19–22,27} Finally, three studies did not report how they assessed antiplatelet therapy intake.^4,30,31

Most important biases in outcome assessment included large or undefined timespans between symptom onset and imaging for assessment of haematoma volume or haematoma expansion.^{9–11,17,19–23,26,29,31} Given that haematoma growth occurs in the first few hours, ³ it is possible that a potential haematoma expansion was missed and misinterpreted as larger baseline volume in studies with a long delay between symptom onset and first imaging.

Haematoma volume was calculated according to the ABC/2-formula in nine studies,^{4,6,10,11,17,21–23,27} two studies each applied semiautomatic planimetry^20,26 or other, previously published approximation techniques.^9,18 In one study, measurement technique was not further specified. ³¹ Creutzfeld et al. assessed haematoma volumes if all three dimensions were indicated in the medical report instead of measuring the haematoma on imaging. ¹⁵ We consider this as a potential reporting bias. Sprugel et al. reported haematoma volumes for propensity score-matched subgroups only (using the ABC/2 method for round or ellipsoid haematomas and the ABC/3 for irregularly shaped haematomas). ²⁹ Given that case-control settings were excluded from the analysis, we did not include the results of the propensity score-matched analysis into the meta-analysis.

Nine studies reported haematoma expansion rates.^{4–6,9–11,19,20,26} In two studies, haematoma expansion was defined as a volume increase by 33% within 24 h after symptom onset.^6,9 One study each assessed any enlargement compared to baseline haematoma volume on the day after admission ¹⁹ or an increase by ≥40% at 24 h compared to baseline haematoma volume. ⁵ Others defined it as a volume increase of ≥12.5 mL or 33% on a follow-up CT within 72 h, ⁴ a volume increase of ≥30% or 6 mL within ≤72 h, ¹⁰ any enlargement compared to baseline haematoma volume within 48 h ²⁰ or on any follow-up imaging. ¹¹ Moussouttas et al. also reported odds ratios (ORs) for the association between HE and APT for various thresholds (>25%, >33% or >50%). ²⁰ For our meta-analysis, we extracted the prevalence of HE >33%. In the CHANT trial, two definitions for haematoma growth within 72 h were used, including haematoma expansion of ≥33%, which we used for this analysis. ²⁶

The most important risk of bias regarding outcome assessment lays in the limited available information on patient performance. While mortality is an unquestionable outcome, assessment of functional outcome status requires precise questioning and can therefore be of limited quality in patients with, for example, aphasia, anosognosia or cognitive impairment.

Several studies assessed mortality rates or functional outcome by combining various sources (patients, next-of-kin, medical reports, family physicians and national mortality registries),^{6,9,18,27,29,31} which we considered of high reliability. Three studies reported outcome assessment was done by certified raters.^10,17,31 One study determined the functional outcome through medical records, ²¹ and the majority of studies did not specify how they assessed mortality and/or functional outcomes.^{4,7,19,27,29,30}

One study excluded patients with missing discharge status, which leads to a potential bias in long-term outcome assessment, ³⁰ and in one study, outcome assessment time points varied between hospitalised and discharged patients. ²⁴

Two of the included studies did not statistically adjust for potential confounders.^21,23 In those with adjusted analyses, one study did not report covariables included in the analysis ²⁵ and seven lacked reporting of univariable associations with relevant covariables.^{5–7,9,27,28,31} Another two studies did not report univariable associations for all covariables in the model.^18,20 And two studies showed incomplete reporting regarding their models and results.^11,32

Age

18 studies reported patients’ ages according to the investigated subgroups. Patients with APT-ICH were significantly older than those with non–APT-ICH (Figure 2(a)).^{4,6,7,9–11,15,17,18,20–22,25–29,31} Two studies reported age means separately for single and dual antiplatelet therapy^24,30 and one study only reported mean age without indicating IQR or SD. ¹⁹ There was no evidence of publication bias as indicated in the funnel plot (Figure 2(b)).

Figure 2.

Age. (a) Forest plot: Age difference between APT- and non-APT-ICH; (b) Funnel plot: Mean difference in the included studies. ICH: intracerebral haemorrhage; APT: antiplatelet therapy.

Haematoma volume

Haematoma volume was 5.74 mL larger in APT-ICH compared to non–APT-ICH in a meta-analysis with 14 studies.^{4,6,9–11,17,18,20–23,26,27,31} In contrast to older studies, the effect of APT on haematoma volume was more pronounced in those published after 2013 (Figure 3(a)). The funnel plot (Figure 3(b)) showed evidence of bias (Egger’s test p = 0.03). Mean haematoma volumes ranged from 13.8 mL ²⁰ to 49.9 mL ²¹ in APT-ICH and from 11.75 mL ⁴ to 37.3 mL ²¹ in non–APT-ICH.

Figure 3.

Haematoma volume and haematoma expansion. (a) Forest plot: mean differences in haematoma volumes in APT-ICH compared to non-APT-ICH; (b) Funnel plot of differences in haematoma volumes between APT- and non-APT-ICH according to the included studies; (c) Forest plot: OR of haematoma expansion in APT-compared to non-APT-ICH. (d) Funnel plot: ORs of haematoma expansion in the included studies. ICH: intracerebral haemorrhage; APT: antiplatelet therapy; OR: odds ratios.

Haematoma expansion

The meta-analysis showed no difference in haematoma expansion.^{4–6,9–11,19,20,26} However, when limited to studies that assessed haematoma expansion within 1 day or 24 h after hospital admission, we found an association of haematoma expansion and APT-ICH with relatively low between-study heterogeneity. Studies that assessed haematoma expansion after 72 h showed a trend towards less haematoma expansion in APT-ICH (Figure 3(c)).We did not observe any differences in more recent studies compared to older studies. There was no evidence of bias for studies reporting on haematoma expansion (Figure 3(d)).

Short-term mortality rates

In the meta-analysis with 12 studies,^{6,7,10,11,15,17,18,20,21,25,28,30} we found that short-term mortality rates were higher in patients with APT-ICH than in those with non–APT-ICH. Nine studies reported overall in-hospital mortality rates, defined as any mortality during hospitalisation,^{6,10,11,15,17,20,25,28,30} one each reported mortality rates at 7, 14 and 28 days (we used 7-day mortality for the analysis), ¹⁸ 8-day mortality rates ⁷ and 7-day and in-hospital mortality rates. ²¹ We performed a sensitivity analysis restricted to in-hospital mortality rates that confirmed these results. There was no difference in mortality rates between APT-ICH and non–APT-ICH when restricted to studies reporting seven- or 8-day mortality rates (Figure 4(a)). There was significant reporting bias towards poorer outcomes (Egger’s test p = 0.03, Figure 4(b)).

Figure 4.

Short-term mortality rates. (a) Forest plot: OR of short-term mortality rates in APT-compared to non-APT-ICH; (b) Funnel plot: ORs of short-term mortality rates in the included studies. ICH: intracerebral haemorrhage; APT: antiplatelet therapy; OR: odds ratios.

Three-month mortality rates

Eight studies reported 3-month mortality rates on a total of 748 APT-ICH and 2834 non–APT-ICH patients.^{4,6,7,9,17,26,27,29} APT-ICH was associated with increased 3-month mortality rates (Figure 5(a)). We observed substantial heterogeneity amongst studies. There was no trend on changes in mortality rates over time. There was no evidence of funnel plot asymmetry (Figure 5(b)). Only one study reported that antiplatelet therapy was stopped within 24 h after ICH, ⁷ while the others did not report their practice.

Figure 5.

3-month mortality rates and functional independence (mRS 0–2). (a) Forest plot: OR of 3-month mortality rates in APT-compared to non-APT-ICH; (b) Funnel plot: ORs of 3-month mortality rates in the included studies; (c) Forest plot: OR of good functional outcome (mRS 0–2) in APT-compared to non-APT-ICH at 3 months. ICH: intracerebral haemorrhage; APT: antiplatelet therapy; OR: odds ratios.

Functional outcome

Patients on APT-ICH had a significantly lower chance of good outcome (mRS 0–2) compared to non–APT-ICH in a meta-analysis with three studies^4,17,29 (Figure 5(c)). We did not investigate heterogeneity or funnel plot symmetry because there were too few studies available.

Six studies found that functional outcome at 3 months was similar or worse in APT-ICH compared to non–APT-ICH.^{4,9,17,24,26,29} Five reported dichotomised modified Rankin Scale (mRS) endpoints^4,17,24,26: Good functional outcome (mRS 0–2) occurred in 35.5%–45.6% of non–APT-ICH patients vs. 22.4–39.2% of APT-ICH patients,^4,17 mRS≤3 in 50% of non–APT-ICH and 47.1% of APT-ICH ²⁶ and mRS 5–6 in 31.2% of non–APT-ICH and 54% of APT-ICH on monotherapy. ²⁴ Sprugel et al. reported no difference in good functional outcomes (mRS 0–2) after propensity score matching. ²⁹ 25% of APT-ICH and 28% of non–APT-ICH had good recovery measured with the Glasgow Outcome Scale. ⁹

Single APT-ICH versus dual APT-ICH

13 of 23 studies reported prevalence of single and dual antiplatelet therapy along with the respective APT combinations.^{4,5,10,11,17,18,22–24,26,27,29,30} They recruited patients from 2001 to 2016 and were published from 2013 to 2018.

Twelve of them provided data on the prevalence of single and dual antiplatelet therapy. In total, 25,453 patients (86.25%) were on single antiplatelet therapy, while 4058 patients (13.75%) were on dual antiplatelet therapy.

None of the five studies that reported outcomes for single versus dual antiplatelet therapy found a significant difference between subgroups.^{23,24,27,29,30}

Haematoma volumes^23,24,29 and haematoma expansion ²⁴ were similar in single and dual antiplatelet therapy. One study compared patients who were on vitamin K antagonists plus dual antiplatelet therapy (“triple therapy”) to patients who were on vitamin K antagonists plus single antiplatelet therapy and found that patients with triple antithrombotic therapy had larger haematoma volumes. ²⁹ All of the studies reported an insignificant trend towards higher mortality rates^23,27,30 and poorer functional outcomes ²⁴ in dual antiplatelet therapy.

Despite frequent reporting on single versus dual antiplatelet therapy, study designs and reporting were too heterogeneous to allow a meta-analysis on one of the pre-specified outcomes.

Discussion

We performed a systematic review and meta-analysis on the association of pre-stroke antiplatelet therapy with baseline haematoma volume, haematoma expansion and mortality rates in ICH. This study has the following main findings: Firstly, APT-ICH is associated with larger baseline haematoma volume, short-term and 3-month mortality rates as well as poorer functional outcome compared to non–APT-ICH. Secondly, haematoma expansion occurs more often in patients with APT-ICH if assessed within 24 h. Pooled results of all studies are controversial and interpretation should take into account the significant between-study heterogeneity and their observational settings. Thirdly, data on outcomes in dual versus single antiplatelet therapy as well as differences between antiplatelet agents are scarce and warrant further investigation.

This meta-analysis provides an updated and refined overview of the association of APT with relevant ICH outcome predictors (age, haematoma volume and haematoma expansion) as well as standardised outcomes (mortality rates and mRS). While older studies were often small and had heterogeneous results, we have added recent, multicentre studies^17,29–31 which have increased precision and generalisability of this analysis. The reported overall prevalence of 33.3% APT use prior to ICH in these consecutively recruiting studies is slightly higher than previously described. ³² Although this is subject to the recruitment strategies, which were substantially heterogeneous amongst the included studies, it indicates that thorough information on the association of APT with ICH outcomes is of utmost importance for clinicians. This study includes subgroup analyses for short-term mortality rates and haematoma. Given that this analysis is based on aggregate data, we were not able to control for comorbidities, co-medication, ethnic/genetic predisposition or applied treatment strategies and may thus overestimate the impact of APT itself on ICH outcomes due to unmeasured confounders. We also investigated possible changes in outcomes over time, which could have been influenced by newer treatment strategies (e.g. blood pressure control),^33,34 but also newer, more effective APT drugs which are associated with more major bleedings. ³⁵

We restricted our search to published studies in English, leading to a potential selection bias. However, evidence of publication bias or funnel plot asymmetry was only evident for haematoma volumes and short-term mortality rates, and results more likely from a small-study effect than from language restriction. Studies were heterogeneous, but these aspects can be considered equal in both subgroups. Due to heterogeneity and the lack of sufficient information, we could not analyse differences in dual versus single APT or varying effects amongst substance groups.

Haematoma volume was slightly larger in APT-ICH compared to non–APT-ICH, with a tendency towards a more pronounced effect in newer studies.^{4,10,11,17,23} Possible explanations include the use of recently introduced, more efficient antiplatelets.^35,36 However, only one study reported differences in haematoma volumes according to the antiplatelet agent used. ²³ Therefore, this assumption could not be investigated. Measurement imprecision of haematoma volume and methodologic differences in measurements are relevantly contributing to heterogeneity, but affect both APT- and non–APT-ICH subgroups, older and more recent studies. ³⁷ As haematoma volume is a relevant prognostic factor for ICH outcome, ³⁸ the observed difference may be important despite the relatively small increase in haematoma volume in patients with APT.

Haematoma expansion, another relevant prognostic factor, ³⁸ was more frequent in patients with APT-ICH when assessed within 24 h after symptom onset. This finding is in line with previous meta-analyses, which found higher rates of haematoma expansion in APT-ICH.^3,4 Comparably to the primary outcome of a recently published individual patient-level meta-analysis of the CLEAR-III, MISTIE-III and VISTA-ICH cohorts, ³⁹ haematoma expansion did not occur more frequently in APT-ICH when assessed after 72 h. Haematoma expansion occurs mainly in the first 3 h after ICH onset. ³ It is therefore likely that there is a selection bias between studies assessing haematoma expansion within 24 and 72 h. In particular, patients who have died early (and have suffered relevant haematoma expansion) may still have undergone a follow-up imaging within 24 h, but will have died and thus been excluded at 72 h, leading to less pronounced results in studies with a broader time window.^4,10,26 This selection bias likely holds true for randomised controlled trials, as they included only patients who are independent prior to their haemorrhage (e.g. MISTIE-III and CLEAR-III restricted inclusion to patients with prior mRS 0–1 ³⁹ ).

In contrast to previous studies that found no difference regarding functional outcome and mortality rates after adjustment for confounding factors,^39,40 we found that short-term, 3-month mortality rates and functional outcomes in APT-ICH were poorer. The funnel plot asymmetry in the short-term mortality rates analysis likely results from the large study size provided by Khan et al. ³⁰

To our knowledge, this is the first meta-analysis that investigates the probability of functional independence (mRS ≤ 2 vs. >2) at a single time point. Definitions of good outcome and assessment time points vary substantially across studies, which is in line with findings of previous studies. ⁴⁰ These aspects highlight the ongoing debate on the definition of clinically relevant functional outcomes and the need for a uniform outcome set to enhance comparability of studies.^41,42

Our study has several limitations: Although we identified a large number of potentially eligible studies, limiting our search to one literature database (MEDLINE) may have led to a certain selection bias. We used aggregate data extracted from original research papers rather than individual patient data. Although we excluded patients on oral anticoagulation therapy, we were not able to account for other confounders (i.e. blood pressure control, do not resuscitate orders). Therefore, we cannot conclude that antiplatelet therapy leads to poorer outcomes, but solely describe the association. Heterogeneity was large among included studies and we therefore urge caution in the interpretation of the results. In particular, certain studies applied selective eligibility criteria regarding age ²⁵ and time between symptom onset to admission,^{4,5,7,19,22,24,26,27} and may therefore be at risk of a certain inclusion bias. Due to a limited number of studies with heterogeneous design, we were not able to perform a meta-analysis of single versus double antiplatelet therapy.

Nevertheless, our study has several strengths: We followed a pre-specified analysis plan using different statistical methods providing robust and consistent results. We included various clinically important outcomes in our analysis. We included a large number of studies from different backgrounds, which allowed subgroup analysis for mortality rates and haematoma expansion according to assessment time points.

The results of our meta-analysis underline the urgent need for targeted treatment options to reduce haematoma expansion and improve outcome in patients with APT-ICH. Firstly, ICH outcomes can be improved by following recent ICH treatment guidelines in the acute setting, in particular adequate blood pressure control and neurosurgical interventions, if necessary, with the aim of reducing haematoma expansion and secondary brain damage due to oedema and neurotoxicity. Given that haematoma expansion occurs within the first 3 h, ³ it is of utmost importance to reduce the delay between symptom onset to hospital admission. Secondly, in analogy to oral anticoagulation, we should aim at reducing the effect of APT to enhance thrombostasis. To date, there exists no direct antagonist for APT, such as this is the case with oral anticoagulants. Therefore, several strategies have been proposed to restitute platelet function: While platelet transfusion has been shown to have a detrimental effect on ICH outcomes, ¹⁶ an ongoing randomised, placebo-controlled trial (NCT03696121) investigates whether desmopressin, a synthetic analogon of vasopressin with high affinity to the V2-receptor (and low affinity to the V1-receptor which is associated with blood pressure increase), could indirectly promote platelet adhesion. Thirdly, further research should also account for etiology and comorbidities (and haematoma location) of APT-associated ICH as relevant factors that might be associated with outcomes. Fourthly, despite the worse outcome in APT-ICH, the overall benefit of APT likely outweighs the risk of ICH complications. APT seems to be safe even in post-ICH patients, ⁴³ but these findings need to be confirmed in additional studies (NCT02966119) .

Conclusion

This meta-analysis confirms that APT-ICH is associated with larger haematoma volume, poorer functional outcome and higher mortality rates in ICH patients. However, the differences between APT- and non–APT-ICH are relatively small if compared to the observed differences between ICH in patients with versus without anticoagulation. ¹³ Although heterogeneity of the presented outcomes precluded a meta-analysis, there seems to be a trend towards poorer outcomes in dual antiplatelet therapy compared to SAPT. Standardised ICH treatment pathways should be implemented as a general measure to improve ICH outcomes. Future studies investigating treatment and secondary prevention in APT-ICH should account for the underlying ICH etiology.

ORCID iDs

Martina B Goeldlin https://orcid.org/0000-0001-5800-116X

Werner Z’Graggen https://orcid.org/0000-0002-5684-4419