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Use of enoxaparin for VTE prophylaxis in patients post

neurosurgery Lily Lin

Surgery Rotation October 16th, 2019

Preceptor: Carly Hoffman

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Learning Objectives• List 3 risk factors for VTE in patients post

neurosurgery• List 4 viable alternatives and regimens for VTE

prophylaxis in neurosurgery patients• Determine the appropriate length of time between

surgery and initiation of chemical VTE prophylaxis in select high risk patients

• Select an appropriate regimen and monitoring plan for a patient post neurosurgery for aneurysmal subarachnoid hemorrhage (aSAH)

Patient: TN

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ID 56 y/o F, 70kgCC Headache and confusion HPI Onset of headaches at ~4pm on September 8th, presented to ED

at PM

Medical History Medications Prior to AdmissionType II diabetes mellitus (A1C 7.5 March 2019)

Metformin 250mg po TID

Hypertension Hydrochlorothiazide 25mg po daily Perindopril 8mg po dailyNifedipine ER 90mg po dailyAtenlolol 12.5mg po daily

Dyslipidemia Rosuvastatin 5mg po dailyNKDA, unremarkable social and family Hx

Course in Hospital

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Course in Hospital: • Sept 8: CT in ED showed subarachnoid hemorrhage of left

middle cerebral artery (MCA) aneurysm (aSAH)• Deterioration post CT, intubated

• Sept 8: Repeat CT showed worsening rebleed à external ventricular drain inserted, admitted to Neurosurgery

• Sept 9: Left frontal craniotomy and MCA clipping à ICU• Sept 18: Vasospasm requiring intra-arterial verapamil• Sept 23: Tracheostomy and PEG inserted • Sept 30: Worsening hydrocephalus à ventriculoperitoneal

shunt inserted, step down to NICU

Review of Systems (Oct 4 - POD #23, post-EVD removal day #4)

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Vitals T 37.4, BP 190/87, HR 82 regular, RR 24, O2 Sat 99% (0.28 Trach

Mask)

CNS PEARL, extraocular movements full, face midline, non-verbal, no

pronator drift, no tremor, obeys L hand and L leg with weak R leg,

GCS 7 CVS N S1/S2, no edema, no elevated JVP. ECG Sept 9 QTc 515msRESP Equal air entry bilaterally

Tracheostomy

GI Abdomen soft, non-tender. AST 44, ALT 67, GGT 138, AP 102

Renal SCr 48, CrCl 105, BUN 5.0

Endocrine Gluc checks q6h

Heme WBC 9.5, RBC 3.10, Hgb 93, MCV 95

Lytes/Fluids Na 139, K 3.9, Cl 107, PO4 1.22, Mg 0.84

Review of Systems Continued

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Cultures CSF from EVD (Sept 30): no growth x 4 days

Blood Culture x 2 (Sept 25): no growth x 5 days (final)

Respiratory culture from Trach (Sept 27): no growth

Diagnostics CXR Sept 11: unremarkable

EEG Sept 14: unremarkable

CTA Sept 28: no new hemorrhage, interval progression

of hydrocephalus, no evidence severe vasospasm

Lines/Drains PICC line, PEG tube

Feeds Isosource 1.5, 45 mL/hour (continuous via PEG)

DVT prophylaxis

Sequential compression device

Mobility Not mobilizing

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Medical Problems Medications In HospitalaSAH Nimodipine 60mg po q4h x 21 daysHypertension Hydralazine 10-20 mg IV q15 min PRN

Labetalol 5-10mg IV q10 min PRN (SBP target < 220)

Seizure Prophylaxis Levetiracetam 500mg po BID Diabetes Insulin regular sliding scale Pain Tylenol 325-650g po/ng q4h PRN Constipation Neurosciences Bowel Protocol

DTP’s

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1. Patient is at risk of experiencing complications of hypertension secondary to inadequate therapy and requires reassessment

2. Patient is at risk of experiencing venous thromboembolism secondary to inadequate therapyand requires reassessment

3. Patient is at risk of experiencing adverse effects of levetiracetam secondary to unnecessary therapy and requires reassessment

4. Patient is at risk of experiencing continued uncontrolled blood glucose levels and requires reassessment of therapy

VTE Risk in Neurosurgery Patients• Deep vein thrombosis (DVT) rate as high as 34% -

cause of pulmonary embolism in approx. 36-45% of cases

• Risk factors: duration of surgery, age, coagulopathy, malignancy, altered mental status, prolonged bed rest

• Distinct aSAH risk factors: male sex, black ethnicity• aSAH: highest risk for DVT post rupture is between

days 5 to 9

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J Neurosurg. 2015 October ; 123(4): 891–896. Journal of Clinical Neuroscience 21 (2014) 282–286

Neurosurg Clin N Am 29 (2018) 567–574

Current Guidelines and Practices• Critical Care Guidelines for aSAH (2011)

– Sequential compression devices (SCD’s) upon admission -chemoprophylaxis withheld 24h before and after procedures

– Duration uncertain, may be based on patient mobility

• Chest (2012)– Add pharmacologic to mechanical prophylaxis in high risk patients

• European Society of Anesthesiology (2018)– Delay initiation of UFH or LWMH until at least 24h after surgery (when

there is evidence of hemostasis à post-op CT scan)

– In high risk patients: SCD’s pre-op with addition of LMWH/UFH post-op

– Continue until discharge

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Neurocrit Care (2011) 15:211–240

Chest. 2012 Feb;141(2 Suppl):e227S-e277S.Eur J Anaesthesiol 2018; 35:90–95

Current Guidelines and Practices• Recent meta-analysis (2018) comparing

chemoprophylaxis vs. mechanical prophylaxis or placebo showed significant benefit to chemoprophylaxis (OR 0.51, 95% CI 0.37-0.71, NNT = 11)

• At VGH NSx: start considering chemoprophylaxis after POD #5 – Limiting factors: potential expansion of intracranial hemorrhage

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J Neurosurg. 2018 Oct;129(4):906-915.

Proposed Alternatives1. Dalteparin 5000 units SC daily 2. Enoxparin 40mg SC daily

– Recently replaced DALT for both prophylaxis and treatment of VTE in VCH (PPO’s updated)

– Team reluctant to start ENOX, prefers DALT

3. Heparin 5000 units SC BID– Shown to be as effective as LMWH, used predominantly in

earlier trials

4. Sequential compression devices alone

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Goals of Therapy1. Reduce risk of VTE (DVT/PE) and associated risk of

mortality

2. Prevent hematoma expansion and hemorrhagic events secondary to anticoagulation use

3. Minimize adverse drug reactions secondary toanticoagulation use

4. Facilitate ease of administration withanticoagulation therapy

5. Maintain or improve quality of life

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Clinical Question

P Patients post neurosurgery for aSAH (clipping, coiling, craniotomy)I EnoxaparinC LWMH, UFH or mechanical prophylaxisO Efficacy – Symptomatic, objectively documented VTE (DVT or PE)

Safety – Major bleeding requiring withdrawal of txt (decrease in Hgb level of at least 2g/dL, transfusion of 2 or more units pRBC), fatal bleeding, expansion of hematoma

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In patients post surgery for aSAH, how does enoxaparin compare to other interventions for VTE

prophylaxis relative to efficacy and safety parameters?

Literature Search

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Pubmed (n=89) (((enoxaparin) AND (craniotomy OR neurosurgery OR subarachnoid hemorrhage) AND (dalteparinOR low molecular weight heparin OR heparin)))

OVID EMBASE (n=143) [enoxaparin.mp AND (craniotomy.mp OR neurosurgery.mp OR aneurysmal subarachnoid hemorrhage.mp) AND (dalteparin.mp OR low molecular weight heparin.mp OR unfractionated heparin.mp]

Cochrane RCT (n=7) [enoxaparin.mp AND (craniotomy.mp OR neurosurgery.mp) AND (dalteparin.mp OR low molecular weight heparin.mp OR heparin.mp]

Results specific to PICO

4 Systematic Reviews (1 highlighted above)4 RCT’s (2 highlighted)2 Retrospective analyses (1 highlighted)

Dudley (2010)

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Early Venous Thromboembolic Event Prophylaxis in Traumatic Brain InjuryRetrospective chart review P (n=287) Moderate to severe TBI

Baseline characteristics: mean age 46.5, average GCS score 7.4, 75% M, >50% underwent surgery

I Enoxaparin 30mg BID SC 48-72h post trauma

C Dalteparin 5000 IU SC 48-72h post trauma

O 1. % patients dx with VTE 2. % of patients dx with symptomatic expansion of pre-existing ICH3. Differences between ENOX and DALT

Results: • No significant difference in VTE rates between groups (7% in ENOX, 7.5%

DALT, p=0.868)• 1 patient in ENOX group suffered fatal ICH expansion

Author’s Conclusion: LMWH is safe after ICH stability, no difference in VTE rates between ENOX and DALT

JOURNAL OF NEUROTRAUMA 27:2165–2172

Critical Appraisal

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Strengths Uniformed dosing

Limitations • Baseline characteristics unbalanced (more DALT patients severely injured, lower GCS scores)

• CT scans performed only when clinically indicated• Bleeding at other sites not documented • Outcomes of surgical patients not documented • Length of prophylaxis not documented

My conclusion • Not entirely applicable to patient (TBI patients, ? surgery outcomes)

• TBI specific risk factors: higher index severity score, low extremity fracture

• Given high VTE risk in both TBI and aSAH population, warrants extrapolation to our patient

Siironen (2003)

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No effect of enoxaparin on outcome of aSAHRandomized, double blind, single centre trialP (n=170) Patients with aneurysmal SAH

Baseline characteristics: ~45% M, average age 49 with co-morbidities e.gHTN, smoking

I Enoxaparin 40mg SC daily 24-48h post-surgery x 10 daysC Placebo 24-48h post-surgery x 10 days

O GCS and mRS at 3 months

Results: • No significant differences in mRS between groups (p=0.062) • 4/85 patients in placebo group experienced VTE (1 fatal PE at 5 weeks)

vs. 1/85 in ENOX group (at 4 weeks)• 4/85 patients experienced intracranial bleeding in ENOX group – no

treatment required (2 asymptomatic)

Author’s conclusion: No effect on outcome of aSAH, but ENOX could be helpful for VTE prevention in poor-grade patients with prolonged bed rest

J Neurosurg. 2003 Dec;99(6):953-9.

Critical Appraisal

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Strengths Randomized, double-blind, placebo controlled Limitations Primary outcome: prevention of delayed cerebral

ischemia and function outcome My conclusion • Shows efficacy and safety of ENOX in

population of interest• ENOX shown not to worsen functional

outcomes at 3 months • Bottom line: results could be extrapolated to

our patient

Agnelli (1998)

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Enoxaparin plus compression stockings compared with stockings alone in prevention of VTE after elective neurosurgeryMulticentre, randomized, double blind trialP (n=307) Patients undergoing neurosurgery or spinal surgery

Baseline characteristics: average age 56, 75% M, 97% tumour resectionI Enoxaparin 40mg SC daily + compression stockings (12-24h post surgery) x

≥ 7 daysC Compression stockings alone (12-24h post surgery) ≥ 7 daysO Symptomatic, objectively confirmed VTE assessed by bilateral venography

(day 8 +/- 1). Followed-up for 60 days post txt

Results:• VTE in 17% ENOX patients vs 33% of CS patients (RR 0.51, 91% CI 0.33-0.80,

p=0.004). Patients treated for 8.7 +/- 1.3 days• “Clinically overt” thrombotic events: 1% in ENOX, 6% in CS• No difference in major and/or minor bleeding between groups (p=0.18)

Author’s Conclusion: ENOX plus CS > CS alone for VTE prevention after elective NSN Engl J Med 1998; 339:80-85

Critical Appraisal

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Strengths Randomized, double blinded

Limitations Venography not performed in ~20% of patients in each group

My conclusion 97% of surgical procedures involved tumour resection

Potential tumour specific risks: coagulopathy, malignancy, partial resection

Bottom line: high risk in both tumour and aSAH post surgery warrants extrapolation to our patient

J Neurooncol (2018) 136:135–145

Evidence Summary

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ENOX vs. placebo (aSAH post-surgery) Prevention: ENOX > placebo Potentially increased risk of bleeding in ENOX

ENOX + CS vs. CS alone (elective craniotomy, majority tumourresection)

Prevention: ENOX > CS No significant increase in bleeding events

ENOX vs. DALT (TBI, majority requiring surgery)

No significant difference in efficacy or safety

Once daily vs. twice daily dosing: enoxaparin 30mg BID dosing for patients with major orthopedic trauma, orthopedic surgery or spinal cord injury

Evidence Summary Continued

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• Overall, minimal good quality evidence for use of chemoprophylaxis in patients post neurosurgery

• When extrapolating findings from other etiologies of neurosurgery, ENOX shown to be effective in preventing VTE with minimal bleeding risks vs comparators

• Weak evidence shows no difference in efficacy between enoxaparin and dalteparin in the setting of neurosurgery

• Need for more high quality evidence (larger, randomized controlled trials) to compare enoxaparin vs. other interventions

• No set duration of therapy highlighted; patients generally on prophylaxis until discharge

Clinical Studies in the Works

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PROTEST trial Phase III, Double blind RCT (Toronto, CA)Dalteparin 5000 units SC daily x 7 days upon randomization after hospital admission vs. placebo in TBI patients

Alternatives for Our Patient

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Drug Necessary Efficacy Safety Adherence

Enoxaparin 40mg

SC daily

VTE prophylaxis Evidence shows

similar efficacy to

DALT and UFH

Similar bleed

risks to

treatment

alternatives

Once daily

injectable

Dalteparin 5000

units SC daily

Limited evidence

suggests similar

efficacy to ENOX

Similar bleed

risks to

treatment

alternatives

Once daily

injectable

Heparin 5000

units BID SC

Used

predominantly in

early trials

Less predictable

pharmacology

Higher risk of

HIT*

Twice daily

injection

Sequential

compression

devices

Less effective vs.

chemoprophylaxis

Good safety

profile, minimal

bleeding risk

N/A

Therapeutic Plan for TNRecommendation:• Initiate enoxaparin 40mg SC daily for VTE prophylaxis

Secondary DTP Recommendations: 1. Initiate amlodipine 5mg po daily2. Initiate metformin 500mg bid po3. Initiate levetiracetam wean (250mg BID x 7 days)

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Monitoring - LMWH

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Parameters FrequencyEfficacy PE: tachycardia (HR), dyspnea (RR), cough,

chest pain

DVT: assess leg pain, swelling, warmth

Daily by nurse/physician/pharmacist/family at rounds and check ups

Safety CNS: • Change in neurocognitive status (GCS

drop from current baseline (≤ 7), decreased eye and motor response, altered LOC, seizure), severe headache

GI/GU: hematuria, hematemesis, vomiting, melena, CrCl (≥ 30 mL/min)MSK/DERM: prolonged bleeding from cuts or nosebleeds, bruising HEME: Platelets (drop by >50%), Hgb (drop by 20g/L)

Daily by family, nurse and physician

Labs – BaselineSCr, Hgb, platelets qMonday, Wednesday and FridayCT scan if any concerns for ICH

What happened next?• Team decided to initiate dalteparin 5000 units SC

daily for patient • Patient transferred to stepdown unit for gradual

tracheostomy weaning. Stable, no clinical evidence of VTE or bleed

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References1. Shaikhouni A, Baum J, Lonser R. Deep Vein Thrombosis Prophylaxis in the Neurosurgical Patient. Neurosurgery Clinics

of North America. 2018;29(4):567-574.2. Kshettry V, Rosenbaum B, Seicean A, Kelly M, Schiltz N, Weil R. Incidence and risk factors associated with in-hospital

venous thromboembolism after aneurysmal subarachnoid hemorrhage. Journal of Clinical Neuroscience. 2014;21(2):282-286.

3. Liang C, Su K, Liu J, Dogan A, Hinson H. Timing of deep vein thrombosis formation after aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery. 2015;123(4):891-896.

4. Diringer, M. N. et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference. Neurocrit. Care 15, 211–240 (2011).

5. Gould M, Garcia D, Wren S, Karanicolas P, Arcelus J, Heit J et al. Prevention of VTE in Nonorthopedic Surgical Patients. Chest. 2012;141(2):e227S-e277S.

6. Faraoni D, Ferrandis R, Geerts W, Wiles M. European guidelines on perioperative venous thromboembolism prophylaxis. European Journal of Anaesthesiology. 2017;:1.

7. Khan N, Patel P, Sharpe J, Lee S, Sorenson J. Chemical venous thromboembolism prophylaxis in neurosurgical patients: an updated systematic review and meta-analysis. Journal of Neurosurgery. 2018;129(4):906-915.

8. Dudley R, Aziz I, Bonnici A, Saluja R, Lamoureux J, Kalmovitch B et al. Early Venous Thromboembolic Event Prophylaxis in Traumatic Brain Injury with Low-Molecular-Weight Heparin: Risks and Benefits. Journal of Neurotrauma. 2010;27(12):2165-2172.

9. Siironen J, Juvela S, Varis J, Porras M, Poussa K, Ilveskero S et al. No effect of enoxaparin on outcome of aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled clinical trial. Journal of Neurosurgery. 2003;99(6):953-959.

10. Agnelli G, Piovella F, Buoncristiani P, Severi P, Pini M, D'Angelo A et al. Enoxaparin Plus Compression Stockings Compared With Compression Stockings Alone in the Prevention of Venous Thromboembolism After Elective Neurosurgery. Obstetrical & Gynecological Survey. 1998;53(11):681-682.

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