Use of enoxaparin for VTE prophylaxis in patients post neurosurgery - - PowerPoint PPT Presentation

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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, 70kg CC Headache and confusion HPI Onset of headaches at ~4pm on September 8th, presented to ED at PM Medical History Medications Prior to Admission Type II diabetes mellitus (A1C 7.5 March 2019) Metformin 250mg po TID Hypertension Hydrochlorothiazide 25mg po daily Perindopril 8mg po daily Nifedipine ER 90mg po daily Atenlolol 12.5mg po daily Dyslipidemia Rosuvastatin 5mg po daily NKDA, 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 515ms RESP 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

• f 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 Hospital aSAH Nimodipine 60mg po q4h x 21 days Hypertension 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 therapy and 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

9 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-

• p

– Continue until discharge

10 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

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

Proposed Alternatives

• 1. 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 Therapy

• 1. 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 to

anticoagulation use

• 4. Facilitate ease of administration with

anticoagulation therapy

• 5. Maintain or improve quality of life

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Clinical Question

P Patients post neurosurgery for aSAH (clipping, coiling, craniotomy) I Enoxaparin C LWMH, UFH or mechanical prophylaxis O 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 (dalteparin OR 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 Injury

Retrospective 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 ICH
• 3. 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 aSAH

Randomized, double blind, single centre trial P (n=170) Patients with aneurysmal SAH Baseline characteristics: ~45% M, average age 49 with co-morbidities e.g HTN, smoking I Enoxaparin 40mg SC daily 24-48h post-surgery x 10 days C 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
• utcomes at 3 months
• Bottom line: results could be extrapolated to
• ur patient

Agnelli (1998)

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Enoxaparin plus compression stockings compared with stockings alone in prevention of VTE after elective neurosurgery

Multicentre, randomized, double blind trial P (n=307) Patients undergoing neurosurgery or spinal surgery Baseline characteristics: average age 56, 75% M, 97% tumour resection I Enoxaparin 40mg SC daily + compression stockings (12-24h post surgery) x ≥ 7 days C Compression stockings alone (12-24h post surgery) ≥ 7 days O 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 NS

N 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 tumour resection) 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 TN

Recommendation:

• Initiate enoxaparin 40mg SC daily for VTE prophylaxis

Secondary DTP Recommendations:

• 1. Initiate amlodipine 5mg po daily
• 2. Initiate metformin 500mg bid po
• 3. Initiate levetiracetam wean (250mg BID x 7 days)

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Monitoring - LMWH

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Parameters Frequency Efficacy PE: tachycardia (HR), dyspnea (RR), cough, chest pain DVT: assess leg pain, swelling, warmth Daily by nurse/physician/pharmacist/fa mily 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

• r nosebleeds, bruising

HEME: Platelets (drop by >50%), Hgb (drop by 20g/L) Daily by family, nurse and physician Labs – Baseline SCr, Hgb, platelets qMonday, Wednesday and Friday CT 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

• f VTE or bleed

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References

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

• f 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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