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Three Part Question

In a patient with a [head injury], does concurrent [treatment with clopidogrel] [increase morbidity and mortality]?

Clinical Scenario

A 78-year old male presents to the Emergency Department in a coma two days after a minor head injury. You note he is taking clopidogrel for treatment of his ischaemic heart disease. CT scan shows a large sub-dural haematoma. You wonder whether the clopidogrel has contributed to the development of this haematoma?

Search Strategy

Medline: 1950 – 2007 April week 1
[(brain injury.mp. or exp Brain Injuries/) OR (craniocerebral trauma.mp. or exp Craniocerebral Trauma/) OR (head injur$.mp.)] AND [(antithromb$.mp.exp Platelet Aggregation Inhibitors/ or clopidogrel.mp.) OR (platelet aggregation inhibitor$.mp.)] limit to (humans and english language)
EMBASE: [cranio-cerebral trauma OR head injury] AND [clopidogrel OR antithrombocytic agent] LIMIT to humans

Search Outcome

Medline yielded 113 papers,EMBASE 58. 4 were relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Jones et al. 2006 USA	43 injured patients, over the age of 50, documented to be taking clopidogrel (P), matched to controls (C) with similar mechanisms of injury, age, sex and ISS. 25 head injuries in group P (9 SDH/EDH) and 21 head injuries in group C (10 SDH/EDH)	Retrospective chart review	Death	3/9 (33%) in P vs. 4/10 (40%) in C, NS	Small numbers Retrospective review Not isolated minor head injury: patients reported were classed as having major head injuries.
			Need for surgery	6/9 (66%) in P vs. 2/10 (20%), p=0.055
			Blood/platelet transfusion	11 in P vs. 3 in C, p<0.015
			Rebleed	5/9 (55%) vs. 1/10 (10%), p=0.005
			ICU stay	5.8 days for P vs. 5.3 days for C, NS
			Hospital stay	11 days for P vs. 10.5 days for C, NS
Ohm et al. 2005 USA	90 patients, 50 years or older, taking anti-platelet agents with a traumatic intra-cranial haemorrhage matched to 89 control patients with similar ISS, GCS, age and sex not taking anti-platelet agents.	Retrospective chart review	Mortality	21/90 (23%) study gp vs.8/89 (8.9%) controls, p=0.016.	Retrospective review. Different anti-platelet agents used. Co-morbidity rates were different in the 2 groups. 71% of study gp had 3 or more co-morbidities vs. 35% in the control gp (p<0.001). Small numbers.
			Need for surgery	21/90 (23%) vs. 17/89 (19%), NS
			Blood transfusion	20/90 (22%) vs. 13/89 (15%), p=0.262
			Platelet transfusion	24/90(27%) vs. 5/89 (6%), p=0.001
			FFP transfusion	13/90 (14%) vs. 3/89 (3%), p=0.009
Mina et al. 2002 USA	37 patients admitted with intracerebral injury and on anticoagulants (including clopidogrel) and 37 matched controls.	Retrospective analysis	Death	14/37 (38%) vs. 3/37 (8%) in controls, p=0.006	Retrospective study. Only 2 patients were on clopidogrel.
Rozzelle et al. 1995 USA	Patients aged 65 years or over admitted with a subdural haematoma.	Retrospective cohort	Risk factor for death (logistic regression)	Anti-thrombotic medication use was not associated with hospital mortality.	30% had no documented trauma. Only 31 patients were on anti-platelet treatment.

Comment(s)

The clinical impression is that concomitant with the increase in the number of patients taking clopidogrel, there is a rise in the number of patients on clopidogrel presenting with significant intra-cranial haemorrhage after minor head injury. Whether clopidogrel contributes to the development of the intra-cranial haemorrhage is unclear and there is currently very little evidence addressing this subject. This is perhaps not surprising considering that clopidogrel is a relatively new drug and even with older established anticoagulant and anti-thrombotic drugs such as warfarin and aspirin, there is continued debate about the quality and quantity of evidence delineating their exact role in the development of intra-cranial haemorrhage following head injury.

Clinical Bottom Line

There is insufficient evidence to firmly state that clopidogrel worsens outcomes in patients with minor head injury.

References

1. Jones K, Sharp C, Mangram A, Dunn EL. The Effects of Preinjury Clopidogrel Use On Older Trauma Patients with Head Injuries. American Journal of Surgery 2006;192:743-745
2. Ohm C, Mina A, Howells G, Bair H, Bendick P. Effects of Antiplatelet Agents On Outcomes for Elderly Patients With Traumatic Intracranial Hemorrhage. Journal of Trauma 2005;58:518-522
3. Mina AA. Knipfer JF. Park DY. Bair HA. Howells GA. Bendick PJ. Intracranial complications of preinjury anticoagulation in trauma patients with head injury. Journal of Trauma-Injury Infection & Critical Care. 2002, 53(4):668-72.
4. Rozzelle CJ. Wofford JL. Branch CL. Predictors of hospital mortality in older patients with subdural hematoma. Journal of the American Geriatrics Society. 1995, 43(3):240-4.