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Three Part Question

In [adult patients presenting with an acute head injury] does [clopidogrel monotherapy as opposed to aspirin monotherapy] [increase the risk of acute intracranial haemorrhage (ICH)?]

Clinical Scenario

A 75 year old man presents to A&E with a closed blunt head injury after a trip and fall on ice. He takes regular clopidogrel following a stroke a few years prior.
He remains well including no signs of skull fracture, GCS 15, no focal neurological deficit, and no loss of consciousness or amnesia experienced.
As per NICE guidelines for adult head injury, you could deduce that no further imaging is required. However, this depends on which medications the clinician considers ‘anticoagulation’ and the department you work in treats clopidogrel (but not aspirin) as such for head injuries and therefore a CT head was performed.
You wonder if there is an increased risk of acute ICH in patients who take clopidogrel as opposed to aspirin monotherapy.

Search Strategy

OVID was used to search EMBASE and MEDLINE on the 9th of April 2025
[ (head injur* or traumatic brain injur* or TBI or brain injur* or intracranial injur*).ti,ab. ] AND
[ (clopidogrel or plavix or (aspirin or acetylsalicylic acid)).mp. OR
antithrombotic agent.ti,ab. ]
limit 5 to (human and english language and (adult <18 to 64 years> or aged <65+ years>))

Search Outcome

This search strategy identified 736 relevant studies from Medline and Embase, majority was able to be excluded from the title and reviewing the abstracts. Further papers were removed which included duplicates, papers which had no full text available (conference abstracts only), and after full text review, papers which did not fully address the question. This left a total of 5 papers

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Rathkjen S, et al 2024 Denmark	325 patients who underwent CT head scans in during a 1 year period between 1.11.2022-31.10.2023 in a Danish hospital. Only patients who met criteria for a ‘medium-risk’ head injury presenting < 24 hours, (GCS 14–15, > 65 years old, and on antiplatelet medication) were included. Aspirin monotherapy (n=132), Clopidogrel monotherapy (n=180), DAPT (n=13)	Retrospective observational	Prevalence of intracranial haemorrhages on CT heads	5.2 % prevalence of ICH on head CT. ICH risk was significantly lower in patients on Clopidogrel compared to aspirin monotherapy (RR 0.33, 95%CI 0.12–0.93).	Decent sample size (325) but wide exclusion criteria (needed to meet criteria for ‘medium-risk’ head injury). Weaker level of evidence – retrospective observational study
			Evaluation of symptomatology, objective findings and comorbidities	For factors e.g. sex, age, patient reported symptoms, objective signs of trauma, hypertension, hypercholesterolemia, no statistically significant associations were recorded. ICH risk was higher in patients with a GCS score of 14 compared to 15 (RR 5.35, 95%CI 2.14–13.47).
Probst M, et al 2020 USA	9070 adult (> 18yo) patients with acute blunt head trauma for whom head CT was ordered between December 2007 and December 2015 across 3 emergency departments in America. Patients taking: > 1 antiplatelet or anticoagulant medication (n=1,323); aspirin monotherapy (n=635); clopidogrel monotherapy (n=109). Exclusion criteria included delayed presentation (> 24 hours after injury), with penetrating trauma, or patients with known intracranial injuries who were transferred to a participating centre	Prospective, observational/ cohort study	Presence of significant intracranial injury (ICI) on neuroimaging (definition excluded isolated linear or basilar skull fractures, single small cerebral contusions, and coincidental or congenital abnormalities).	Aspirin monotherapy = 30/635 (4.7%, 95%CI: 3.3, 6.6%). Relative risk (RR) 1.29 (0.88, 1.87) Clopidogrel monotherapy = 3/109 (2.8%, 95%CI:0.7, 7.0%). RR 0.75 (0.24, 2.3) No Coagulopathy = significant ICI rate 210/5715 (3.7%, 95%CI: 3.2, 4.2%). Therefore no significant difference.	No specific data on patients who presented who did not undergo CT imaging (however 3 month follow up on sample of un-imaged patients suggested rate of missed significant ICI is very low/near zero). No antiplatelet status on those with known intracranial injuries/those who were transferred.
			Need for neurosurgical intervention	Aspirin monotherapy = 9/635 (1.4%, 95%CI: 0.7, 2.5%). RR 0.95 (0.48, 1.88) Clopidogrel monotherapy = 1/109 (0.9%, 95%CI: 0.1, 4.0%). RR 0.62 (0.09, 4.39) No Coagulopathy = 85/5715 (1.5%,95%CI: 1.2, 1.8%) Therefore no significant difference.
			Subgroup analysis (included alertness, age > 65, dangerous mechanism, significant co-morbidity)	No significant difference between clopidogrel and aspirin monotherapy as well as compared to patients with no coagulopathy in terms of prevalence of significant ICI and need for neurosurgical intervention
			Any traumatic injury (including excluded criteria)	No significant difference between aspirin (RR 1.08 (0.82, 1.41)) and clopidogrel (RR 1.14 (0.63, 2.08)) monotherapy.
Pérez de la Blanca I 2023 Spain	Prospectively enrolled consecutive patients aged ≥60 years admitted to the emergency department during 2 periods (October 29, 2010 - May 5, 2013), and November 17, 2017 to June 30, 2020). 2303 patients included with traumatic brain injury < 24 hours and GCS 14-15 and CT head imaging. Aspirin monotherapy n=646 Clopidogrel monotherapy n=97	Prospective cohort	Prevalence of haemorrhagic complications	Bivariate analysis of mild-minimal TBI (mTBI) with antithrombotic drugs and haemorrhagic complications revealed no significant difference for both aspirin and clopidogrel monotherapy: Aspirin = absence of IC n=501; presence of IC n=145. P = 0.424. Odds ratio (OR) 0.916[CI0.737–1.137] Clopidogrel = absence of IC n=81; presence of IC n=16. P = 0.094. OR 0.630[CI0.365–1.087] When the OR was adjusted for age, sex, GCS score, alcohol, malignancy, neurological disease, and diabetes, there was still no significant difference.	Only included patients with mild-minimal TBI and patients > 60 years old
			Prevalence of haemorrhagic progression	Progression was recorded in 24 patients (1%). Was found to be less frequent in aspirin monotherapy (p= 0.009, 0.110[0.015–0.817]), no significant difference with clopidogrel
Alter S et al 2020 USA	327 adult patients who presented to 2 trauma centres in America between 01/01/2016 and 31/12/2017 with blunt head trauma < 24 hours on antiplatelet therapy. Previous use of anticoagulant therapy was an exclusion factor. 128 patients were on aspirin monotherapy; 60 on clopidogrel; 3 on ticagrelor, 0 on prasugrel	Retrospective observational study Level 3, prognostic	Presence of acute intracranial haemorrhage on CT head	Patients on aspirin monotherapy had a higher acute ICH rate compared with patients on P2Y12 inhibitors (48% vs 30%, 18% difference, 95% CI 4 to 33; odds ratio (OR) 2.18, 95% CI 1.15 to 4.13).	Grouped all P2Y12 inhibitors together (including clopidogrel (n=60) and ticagrelor (n=3)). Weaker level of evidence as retrospective observational study. Patients selected from trauma registries – patients who were seen in ED not by the trauma services with head injuries would have been missed. Exclusion criteria also included no antiplatelet therapy in the last 7 days – does not mimic real world scenarios where decisions are based on history taking. No control group i.e. patients not on any antiplatelet medications.
			Presence of delayed intracranial haemorrhage on CT head	3 patients (0.9%) had delayed ICH on repeat CT. 2 patients were on DAPT and the other patient was on clopidogrel monotherapy. These patients compared with no ICH were older, with higher injury severity scores and trended towards lower platelet counts (p<0.05) Numbers too small to make conclusion on antiplatelet effect on delayed ICH.
Sakkas A, et al 2022 Germany	696 patients on antithrombotic medication with mild TBI (mTBI) who were referred to an emergency department of oral and plastic maxillofacial surgery between January 2016 and December 2021 and underwent CT head imaging. mTBI defined by a GCS score ≥ 13, loss of consciousness of < 30 min, and posttraumatic amnesia of < 24 h	Retrospective observational single-centre study	Prevalence of intracranial haemorrhage (ICH) after mTBI.	36 patients (5.1%) had acute traumatic ICH. No association was detected between intracerebral lesions and antithrombotic groups or agents. Positive ICH was seen in 0/14 patients on clopidogrel monotherapy and 30/335 patients on aspirin monotherapy (p = 0.614)	Limited to mild TBI Observational retrospective study design No control group not on antithrombotics. Inhomogeneity of subgroups – small number of patients on clopidogrel monotherapy. No testing of anticoagulation to test adherence to pre injury antithrombotics
			Prevalence of delayed ICH after mTBI	Prevalence of delayed ICH was 0.1%. A control CT was repeated in 5 patients with an initial negative CT (indication= worsening GCS/other neurologic symptoms). 1/5 patients demonstrated delayed ICH

Comment(s)

The literature comparing the risk of acute intracranial haemorrhage on clopidogrel versus aspirin monotherapy is limited and heterogeneous, consisting mainly of retrospective studies in which answering this question was not the primary aim of the studies. Given nature of question being asked, designing a RCT would not be feasible as it would neither be ethical nor practical. There is no clear evidence that across these studies that clopidogrel as opposed to aspirin monotherapy is associated with an increased likelihood of acute intracranial haemorrhage. This review did not look into the risk of acute haemorrhage in patients taking anticoagulants as opposed to antiplatelets - it is important to note that anticoagulants are already considered established risk factors for acute ICH in head trauma, as are listed in the NICE CT head guidelines as indications for imaging. Further targeted literature searches would be needed to confirm the strength and consistency of this association in the evidence base.

Clinical Bottom Line

No evidence that clopidogrel monotherapy poses a greater risk of acute intracranial bleed as opposed to aspirin monotherapy in patients presenting with acute head injury.

References

1. Rathkjen S, et al Scandinavian Neurotrauma Guidelines: Frequency of intracranial hemorrhage in patients over 65 years old and on anti-platelet medication European Journal of Radiology 2024. Article Number: 111778
2. Probst M, et al Prevalence of Intracranial Injury in Adult Patients With Blunt Head Trauma With and Without Anticoagulant or Antiplatelet Use Annals of Emergency Medicine 75(3) (pp 354-364), 2020.
3. Pérez de la Blanca I Antithrombotic and risk of hemorrhagic complications in over-60-year-olds after mild-minimal traumatic brain injury Brain Injury 37(12-14) (pp 1355-1361), 2023
4. Alter S et al Analysis of traumatic intracranial hemorrhage and delayed traumatic intracranial hemorrhage in patients with isolated head injury on anticoagulation and antiplatelet therapy. Journal of Neurosciences in Rural Practice 14(4) (pp 686-691), 2023.
5. Sakkas A, et al Impact of antithrombotic therapy on acute and delayed intracranial haemorrhage and evaluation of the need of short-term hospitalisation based on CT findings after mild traumatic brain injury European journal of trauma and emergency surgery 50(1) (pp 157-172), 2024.