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View from the Nosebleed Section: The Role of Tranexamic Acid in the Management of

Epistaxis

Rajeev Shah, PharmDRajeev.Shah@rwjbh.org

PGY-1 Pharmacy ResidentRobert Wood Johnson University Hospital Somerset

RWJBarnabas Health

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Disclosures

I, Rajeev Shah, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

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Objectives

• Summarize the evidence for use of tranexamic acid in epistaxis

• List dosing and administration regimens for the use of tranexamic acid

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PATIENT CASE

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Patient Case

• TG is an 89 year old female admitted to the ED for severe epistaxis

• Nosebleed started the morning of admission

• Hospitalized previously within past year for epistaxis– Recently seen in ED for epistaxis 2 days ago;

treated with topical tranexamic acid nasal packing

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Medications Prior to Admission

• Alprazolam 0.25 mg PO HS• Duloxetine 60 mg PO daily• Docusate 100 mg PO BID• Fentanyl Patch 50 mcg q72h• Levothyroxine 50 mcg PO daily• Lubiprostone 24 mcg PO BID

with meals • Magnesium oxide 400 mg PO

daily• Metoprolol tartrate 50 mg PO

BID

• Oxycodone 5 mg PO q4h PRN• Pantoprazole 40 mg PO daily• Paroxetine 30 mg PO daily• PEG Powder 17 g PO daily• Ramipril 5 mg PO daily • Senna 8.8 mg PO daily• Torsemide 20 mg PO daily

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Relevant Examination Findings

• Allergies: meperidine (reaction unknown)• ENT Exam: epistaxis in left nare• Blood Pressure: 208/103 mm Hg• Heart Rate: 92 bpm• Respiratory Rate: 24 bpm• Temperature: 96.8 F⁰

6.72 2059.8

33.8

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EPISTAXISBackground, Etiology, and Treatment

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Background

• Bleeding from the nostril, nasal cavity or nasopharynx

• About 60% of the population experiences epistaxis

• Over 90% of nosebleeds occur in anterior nasal cavity

• About 5-10% occur in the posterior nasal cavity

Suh JD, Garg R. Epistaxis (nosebleeds). American Rhinologic Society. Available from: http://care.american-rhinologic.org/epistaxis

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Etiology

Suh JD, Garg R. Epistaxis (nosebleeds). American Rhinologic Society. Available from: http://care.american-rhinologic.org/epistaxisKucik CJ, Clenney T. Management of epistaxis. Am Fam Physician. 2005 Jan 15;71(2):305-311

Local Causes• Trauma• Mucosal irritation• Septal abnormalities• Inflammation• Tumors• Dry mucosa

System Causes• Medications• Blood disorders• Arteriosclerosis• Hereditary

hemorrhagic telangiectasia

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Treatment Options

Suh JD, Garg R. Epistaxis (nosebleeds). American Rhinologic Society. Available from: http://care.american-rhinologic.org/epistaxisKucik CJ, Clenney T. Management of epistaxis. Am Fam Physician. 2005 Jan 15;71(2):305-311

Prevention• Petrolatum• Humidifiers• Proper nasal spray technique

Non-pharmacological • Direct pressure• Anterior or posterior nasal packing• Angiographic embolization• Direct surgical ligation or clipping

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Pharmacologic Treatment Options

Suh JD, Garg R. Epistaxis (nosebleeds). American Rhinologic Society. Available from: http://care.american-rhinologic.org/epistaxisKucik CJ, Clenney T. Management of epistaxis. Am Fam Physician. 2005 Jan 15;71(2):305-311

Topical

• Nasal Decongestants• Epinephrine/Lidocaine• Topical Antibiotics• Xeroform• Tranexamic Acid?

Systemic

• Anticoagulant Reversal Agents• 4 Factor Prothrombin

Complex Concentrate• Fresh Frozen Plasma

• Tranexamic Acid?

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TRANEXAMIC ACIDBackground, Mechanism of Action, Contraindications, Adverse Reactions and Dosing

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Background

• Discovered in 1962 by Utako Okamoto and is on the WHO list of essential medications

• Lysine analog that forms a reversible complex that displaces plasminogen from fibrin, resulting in inhibition of fibrinolysis

• Formulations:– Intravenous solution (1,000 mg/10 mL)– Oral tablets (650 mg)

Tranexamic Acid. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed December 12, 2016.Watts G. Utako Okamoto. Lancet. 2016;387:2286.

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Mechanism of Action

Plasminogen Plasmin Fibrin Fibrinolysis

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Pharmacokinetics of Tranexamic Acid

• PK: – Absorption: 45% bioavailability– Distribution: Vd = 9-12 L

– Elimination: 95% unchanged in the urine• T1/2: 2-11 hours

Tranexamic Acid. Lexi-Drugs. Lexicomp. Tranexamic Acid. Drug Facts and Comparisons. Facts & Comparisons eAnswers. Cyklokapron (R) [package insert]. New York, NY: Pfizer Inc; 2016

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Topical Dosing for Epistaxis

• Epistaxis topical administration:– 15 cm cotton pledget soaked in 500 mg/5 mL IV

tranexamic acid solution and applied until arrest of bleeding

Shakur H, Roberts I, Bautista R, et al. Lancet. 2010 Jul 3;376(9734):23-32.

Zahed R, Moharamzadeh P, Alizadeharasi S, et al. Am J Emerg Med. 2013 Sep;31(9):1389-92.

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Topical Administration of Tranexamic Acid

Parameter Trial Design

Methods Prospective, randomized, single center, parallel group clinical trial

Enrollment 216 total patients randomized; 107 to topical tranexamic acid and 109 to conventional treatment

Excluded: epistaxis following major trauma, posterior epistaxis, known history of bleeding disorder, INR > 1.5, shock and visible bleeding vessel

Interventions Treatment Group: pledget soaked in 500 mg/5 mL solution of tranexamic acid inserted in to the nostril

Control Group: pledget soaked in epinephrine (1:100,00) with lidocaine (2%) for 10 minutes

Zahed R, Moharamzadeh P, Alizadeharasi S, et al. Am J Emerg Med. 2013 Sep;31(9):1389-92.

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Efficacy of Topical Tranexamic AcidLido/Epi TXA Odds Ratio

(95% CI)P-value

Primary Outcome:

Bleeding Stop Time < 10 min (%)

31.2 71 2.28 (1.68-3.09)

< 0.001

Secondary Outcomes:

Re-bleeding in 24 hours (%)

12.8 4.7 0.36 (0.14-0.98)

0.034

Re-bleeding in 1 week (%)

11 2.8 0.26 (0.07-0.88)

0.018

Patient Satisfaction Score (Mean) + (SD)

4.4 + 1.8 8.5 + 1.7 - < 0.001

Zahed R, Moharamzadeh P, Alizadeharasi S, et al. Am J Emerg Med. 2013 Sep;31(9):1389-92.

Key: Lido/Epi: lidocaine with epinephrine, TXA: tranexamic acid, CI: Confidence Interval

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Systemic Dosing for Epistaxis• No literature for systemic tranexamic acid use in epistaxis

• Data can be extrapolated from trauma studies due to acceptable safety

• Epistaxis IV administration*:– 1 g in 100 mL NS IVPB over 10 minutes – Followed by 1 g over 8 hours if refractory

• Max rate 100 mg/minute• May be diluted in 50 to 250 mL NS or D5W

*Extrapolated from trauma data

Shakur H, Roberts I, Bautista R, et al. Lancet. 2010 Jul 3;376(9734):23-32.

Zahed R, Moharamzadeh P, Alizadeharasi S, et al. Am J Emerg Med. 2013 Sep;31(9):1389-92.

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Systemic Administration of Tranexamic Acid

Trial Parameter Trial Design

Methods Randomized, double-blind, multi-centered, placebo controlled trial

Inclusion Adult TRAUMA patients with significant hemorrhage (SBP < 90 mm Hg or HR > 110 bpm) or at high risk of hemorrhage within 8 hours

Enrollment Total 20,211 patients randomized to tranexamic acid or placebo10,096 given tranexamic acid and 10,115 given placebo

Interventions Treatment Group: tranexamic acid 1 g over 10 min followed by 1 g over 8 hours

Control Group: matching infusion with normal saline

Outcomes Primary: death in hospital within 4 weeksShakur H, Roberts I, Bautista R, et al. Lancet. 2010 Jul 3;376(9734):23-32. Roberts I, Shakur H, Afolabi A, et al. Lancet. 2011 Mar 26;377(9771):1096-101.

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Relative Risk (95%) CI of Death with Tranexamic Acid

Sample Size All Cause Mortality

Bleeding Death

Non-bleeding Death

Overall 20,127 0.91 (0.85-0.97)

0.85 (0.76-0.96)

0.94 (0.86-1.02)

Time to tx (h)

< 1 7,451 0.87 (0.76-0.97)

0.68 (0.57-0.82)

1.04 (0.89-1.21)

> 1-3 6,033 0.87 (0.77-0.97)

0.79 (0.64-0.97)

0.91 (0.78-1.02)

> 3 6,634 1.00(0.90-1.13)

1.44 (1.12-1.84)

0.89 (0.78-1.02)

Shakur H, Roberts I, Bautista R, et al. Lancet. 2010 Jul 3;376(9734):23-32. Roberts I, Shakur H, Afolabi A, et al. Lancet. 2011 Mar 26;377(9771):1096-101.

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Contraindications

• Relative Contraindications for IV Administration:– Renal impairment defined as SCr >1.5 mg/dL or

CrCl <50 mL/min– Ischemic heart disease– History of thromboembolic or vascular disease– Disseminated intravascular coagulation– History of seizures

Cyklokapron (R) [package insert]. New York, NY: Pfizer Inc; 2016

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Contraindications

• Contraindications for IV Administration (consider topical administration):– Acquired defective color vision – Subarachnoid hemorrhage – DVT or PE within 12 months of surgery– History of DVT or PE being treated with

anticoagulation– Known congenital thrombophilia– Cardiac stent, MI or ischemic stroke within 1 year

Cyklokapron (R) [package insert]. New York, NY: Pfizer Inc; 2016

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Adverse Reactions

• Topical Adverse Reactions– Nausea– Vomiting

• Systemic Adverse Reactions– Hypotension – Blurred vision– Convulsions– Thromboembolic events

Cyklokapron (R) [package insert]. New York, NY: Pfizer Inc; 2016Zahed R, Moharamzadeh P, Alizadeharasi S, et al. Am J Emerg Med. 2013 Sep;31(9):1389-92.

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Patient Case

• Left nare hemostasis with 7.5 cm Rhinorocket repacking

• Tranexamic acid 1 g IVPB in 50 mL NS over 30 min– Patient failed previous nasal packing from prior admission

• Observed for 3 hours; no bleeding/discharge

• No readmission for epistaxis

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Summary and Conclusions

• Consider IV tranexamic acid in severe epistaxis when topical administration is inadequate or structural abnormalities prevent nasal packing

• Decreased bleeding, blood transfusions and hospital length of stay with low risk of thromboembolic events

• Dose: 1 g IVPB over 10 minutes– Extrapolated from trauma literature

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• Which of the following is appropriate first line therapy for patients that present with epistaxis?a) Topical therapy with oxymetazoline followed by

nasal packing with tranexamic acid soaked gauzeb) 4 Factor Activated Prothrombin Complex

Concentrate 25 units/kg IVc) Tranexamic acid 45 mg/kg IVPB over 10 minutes

Question 1

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• A patient presents to the ED with severe epistaxis refractory to topical therapies and has structural abnormalities within the nasal cavity. What therapy would be appropriate for this indication? a) Xeroform Nasal Packingb) Tranexamic acid 1 g IVPB over 10 minutes c) Tranexamic acid 2 g IVPB over 1 hour

Question 2

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References

1. Suh JD, Garg R. Epistaxis (nosebleeds). American Rhinologic Society. Available from: http://care.american-rhinologic.org/epistaxis

2. Kucik CJ, Clenney T. Management of epistaxis. Am Fam Physician. 2005 Jan 15;71(2):305-3113. Tranexamic Acid. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at:

http://online.lexi.com. Accessed December 12, 2016..4. Tranexamic Acid. Drug Facts and Comparisons. Facts & Comparisons eAnswers. Wolters Kluwer

Health, Inc. Riverwoods, IL. Available at: http://online.factsandcomparisons.com. Accessed December 12, 2016.

5. Cyklokapron (R) [package insert]. New York, NY: Pfizer Inc; 20166. Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events,

and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32.

7. Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011 Mar 26;377(9771):1096-101.

8. Zahed R, Moharamzadeh P, Alizadeharasi S, et al. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomised controlled trial. Am J Emerg Med. 2013 Sep;31(9):1389-92.

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View from the Nosebleed Section: The Role of Tranexamic Acid in the Management of

Epistaxis

Rajeev Shah, PharmDRajeev.Shah@rwjbh.org

PGY-1 Pharmacy ResidentRobert Wood Johnson University Hospital Somerset

RWJBarnabas Health