CASE SCIENCE SESSION (CSS)

*Kepaniteraan Klinik Senior/ G1A221068/April 2022

** Pembimbing/ dr. Angga Pramuja, Sp. THT-KL

Pemberian Asam Traneksamat Topical dibandingkan dengan Anterior Nasal

Packing untuk pengobatan epistaksis pada pasien yang memakai obat
antiplatelet : Uji Acak Terkontrol

*Khairi Wilda Prihati, S. Ked

** dr. Angga Pramuja, Sp. THT-KL

KEPANITERAAN KLINIK SENIOR

BAGIAN THT-KL RSUD RADEN MATTAHER
FAKULTAS KEDOKTERAN DAN ILMU KESEHATAN
UNIVERSITAS JAMBI
2022
 HALAMAN PENGESAHAN

Pemberian Asam Traneksamat Topical dibandingkan dengan Anterior Nasal

Packing untuk pengobatan epistaksis pada pasien yang memakai obat
antiplatelet : Uji Acak Terkontrol

Sebagai salah satu tugas kepaniteraan klinik senior

Bagian THT RSUD Raden Mattaher
Fakultas Kedokteran dan Ilmu Kesehatan Universitas
Jambi 2022

Disusun oleh:

Khairi Wilda Prihati, S.Ked

G1A221068

Laporan ini telah diterima dan

dipresentasikan Pada April 2021

PEMBIMBING

dr. Angga Pramuja, Sp. THT-KL

 KATA PENGANTAR

Puji dan syukur penulis panjatkan kepada Tuhan Yang Maha Esa atas
berkat kasih dan karunia-Nya, penulis dapat menyelesaikan Clinical Science
Session ini dengan judul “Pemberian Asam Traneksamat Topical
dibandingkan dengan Anterior Nasal Packing untuk pengobatan epistaksis
pada pasien yang memakai obat antiplatelet : Uji Acak Terkontrol”. Laporan
ini merupakan bagian dari tugas Kepaniteraan Klinik Senior di Bagian Ilmu
Penyakit THT RSUD Raden Mattaher Provinsi Jambi.

Terselesaikannya laporan ini tidak lepas dari bantuan, bimbingan dan

dorongan dari berbagai pihak, oleh karena itu penulis menyampaikan
ucapan terima kasih kepada dr. Angga Pramuja, Sp. THT-KL selaku
pembimbing yang telah memberikan arahan sehingga laporan Clinical
Science Session ini dapat terselesaikan dengan baik dan kepada semua
pihak yang telah membantu dalam penyelesaian Clinical Science Session
ini.
Penulis menyadari bahwa laporan ini masih banyak kekurangannya,
untuk itu saran dan kritik yang bersifat membangun sangat diharapkan oleh
penulis. Semoga kiranya Clinical Science Session ini dapat bermanfaat bagi
kita.

Jambi, April 2021

Penulis
 Pemberian Asam Traneksamat Topical dibandingkan dengan Anterior Nasal
Packing untuk pengobatan epistaksis pada pasien yang memakai obat
antiplatelet : Uji Acak Terkontrol

Reza Zahed, MD, Mohammad Hossain Mousavi Jazayeri, MD, Asieh Naderi, PhD,
Zeinab Naderpour, MD, and Morteza Saeedi, MD

Abstrak
Tujuan : Untuk mengevaluasi keefektifan pemberian injeksi topikal asam
traneksamat dibandingkan dengan obat kemasan nasal anterior untuk pengobatan
epiktaksis pada pasien yang memakai obat antiplatelet (aspirin, clopidogrel, atau
keduanya) yang datang ke unit gawat darurat.
Metode : Sebuah acak, uji klinis kelompok paralel dilakukan di dua UGD. Sebanyak
124 peserta diacak untuk menerima asam traneksamat topikal (500 mg dalam 5 mL)
atau kemasan nasal anterior, masing-masing berjumlah 62 pasien per kelompok. Hasil
utamanya adalah proporsi pasien di setiap kelompok yang perdarahannya berhenti
pada 10 menit. Hasil kedua adalah tingkat perdarahan ulang pada 24 jam dan 1
minggu, lama rawat inap, dan kepuasan pasien.
Hasil : Dalam 10 menit pengobatan, perdarahan dihentikan pada 73% pasien dalam
kelompok TXA, dibandingkan dengan 29% pada kelompok ANP (selisih = 44%,
interval kepercayaan 95%, 26% hingga 57%; p <0,001). Selain itu, perdarahan ulang
dilaporkan pada 10% pasien selama 24 jam pertama di TXA dan ANP masing-masing
kelompok. Pada 1 minggu, 5% pasien dalam kelompok TXA dan 21% pasien dalam
kelompok ANP mengalami perdarahan berulang (p = 0,007). Pasien dalam kelompok
TXA melaporkan skor kepuasan yang lebih tinggi dibandingkan dengan kelompok
ANP. Perdarahan berhenti dari UGD dalam <2 jam dicapai pada 97% pasien dalam
kelompok TXA versus 13% pada ANP kelompok (p < 0,001). Tidak ada efek samping
yang dilaporkan pada kedua kelompok.
Kesimpulan : Dalam populasi penelitian ini, pengobatan epistaksis dengan
menggunakan topikal TXA menghentikan perdarahan lebih cepat, perdarahan ulang
lebih sedikit dalam 1 minggu, dan kepuasan pasien lebih tinggi dibandingkan dengan
ANP.
 Epistaksis adalah keluhan umum dalam unit gawat darurat. Sekitar 60% dari
populasi mengalami epistaksis setidaknya sekali selama hidup mereka dan 6%
memerlukan perhatian medis. Penyebab epistaksis tidak diketahui pada sebagian besar
kasus. Faktor etiologi dapat dibagi menjadi lokal dan penyebab sistemik.. Dari semua
faktor sistemik, penggunaan antikoagulan dan obat antiplatelet tampaknya memiliki
korelasi yang signifikan dengan gejala yang lebih parah dan epiktaksis berulang.

Obat antiplatelet, khususnya aspirin dan clopidogrel, banyak diresepkan untuk

pengobatan atau pencegahan berbagai bentuk penyakit kardiovaskular. Meskipun
tidak ada perbedaan yang signifikan dalam risiko epistaksis pada pasien yang
memakai aspirin atau clopidogrel, manajemen epistaksis lebih sulit pada pasien yang
menggunakan obat antiplatelet.
Anterior nasal packing (ANP), merupakan prosedur yang sering dilakukan
dalam pengelolaan epistaksis, memiliki komplikasi potensial, termasuk
ketidaknyamanan selama penempatan dan perdarahan ulang setelah pelepasan karena
cedera mukosa dan pembentukan sinekia. Dengan demikian, strategi pengobatan yang
lebih optimal diperlukan untuk pengelolaan epistaksis, terutama untuk pasien yang
memakai obat antiplatelet.
Keefektifan penggunaan topikal injeksi bentuk asam traneksamat (TXA) telah
terbukti bermanfaat untuk pengobatan epistaksis anterior idiopatik. Selain itu,
penggunaan topikal TXA dengan oral menghasilkan perdarahan mukosa yang jauh
lebih sedikit. Di dalam penelitian ini, peneliti membandingkan efek TXA topikal
dengan ANP untuk pengobatan epistaksis anterior pada pasien yang minum obat
antiplatelet.

BAHAN DAN METODE

Desain dan Pengaturan Studi
Dilakukan di dua UGD untuk membandingkan keefektifan pengobatan
penggunaan topikal dari bentuk injeksi 10% TXA (500 mg dalam 5 mL) dengan ANP
untuk pengobatan epistaksis pada pasien yang memakai obat-obatan antiplatelet
(aspirin, clopidogrel, atau keduanya). Untuk memastikan pendekatan standar untuk
manajemen epistaksis di dua tempat penelitian, dokter residen pengobatan darurat
PGY2 dan PGY3 berpartisipasi memberikan arahan selama 2 jam tentang ANP dan
pemberian TXA topikal. Rekrutmen pasien dimulai pada Oktober 2015 dan selesai
pada tahun April 2016.
Populasi
Pasien terdaftar di UGD dari dua rumah sakit pendidikan akademik umum di
Universitas Teheran Ilmu Kedokteran, satu dengan 510 pasien rawat inap dan 40.800
kunjungan UGD tahunan dan lainnya dengan 540 pasien rawat inap dan 43.200
kunjungan UGD tahunan. Keduamya memiliki tempat program dalam berbagai
spesialisasi. Rumah bagi 8,7 juta orang, Teheran adalah ibu kota Iran dan merupakan
kota terpadat.
Subjek memenuhi syarat untuk dimasukkan jika mereka datang ke UGD
dengan akut, baru atau berulang, sedang mengalami epistaksis anterior dan saat ini
menggunakan antiplatelet obat-obatan (aspirin, clopidogrel, atau keduanya). Dengan
tidak adanya sistem penilaian yang diterima secara universal untuk tingkat keparahan
epistaksis, kecuali untuk hemoragik herediter telangiectasia, peneliti memasukkan
pasien dengan pendarahan persisten yang membutuhkan perawatan lebih lanjut setelah
20 menit kompresi pada kedua lubang hidung pasien menggunakan ibu jari dan jari
telunjuk. Peneliti mengecualikan pasien yang memiliki epistaksis traumatis, pasien
yang menggunakan obat antikoagulan saat ini, kelainan pendarahan bawaan (termasuk
hemofilia), kelainan trombosit bawaan, normalisasi internasional rasio >1,5, syok,
pembuluh darah yang terlihat, riwayat penyakit ginjal, dan pasien yang tidak setuju.
Institusi komite peninjau etik menyetujui penelitian dan terdaftar di IRCT.Ir
(IRCT201509088872N9). Menulis sepuluh informed consent diperoleh dari semua
pasien sebelum masuk ke persidangan.
Protokol Studi
Pasien yang memenuhi syarat secara acak di masukkan ke salah satu dari
kelompok TXA atau kelompok ANP. Pengolahan penelitian ini menggunakan IBM
SPSS Statistics untuk Windows versi 24 (IBM Corp) untuk menghasilkan alokasi acak
urutan, yang dikelompokkan berdasarkan yang utama. Pengacakan dilakukan dalam
blok dua, empat, dan enam. Pengolahan penelitian dengan mengacak kotak bernomor
urut diisi dengan obat-obatan dan kapas di lokasi yang jauh dari UGD dan tidak dapat
diakses oleh pasien di UGD. Setiap kotak sama dalam ukuran, bentuk, dan berat.
Kotak bernomor diadakan di bagian farmasi dan disampaikan secara berurutan ke
dokter residen yang merawat pasien dengan epistaksis yang terdaftar dalam penelitian.
Kelompok TXA menerima sepotong kapas sepanjang 15 cm yang telah
direndam dalam bentuk injeksi TXA (500 mg dalam 5 mL) dan dimasukkan ke dalam
lubang hidung. Lalu dihapus setelah dokter hadir atau seorang kepala residen
memeriksa orofaring dan kapas yang dibasahi darah untuk memastikan bahwa
perdarahan telah berhenti. Kelompok ANP mendapat kapas yang telah direndam
dalam epinefrin (1:100.000) + lidokain (2%) dimasukkan ke dalam lubang hidung
yang terkena dan dibiarkan selama 10 menit. ANP kemudian dimasukkan dan
beberapa kapas ditutupi dengan salep tetrasiklin. Dibiarkan selama 3 hari sebelum di
hapus. Jika pengobatan yang dialokasikan gagal, peneliti mempertimbangkan ANP
dan kauter (jika diindikasikan) dan kauter saja untuk kelompok TXA dan kelompok
ANP.

Pengukuran
Penilaian untuk perdarahan yang sedang berlangsung dilakukan pada interval
5 menit dan ketika pasien meninggalkan UGD. Penilaian waktunya dimulai setelah
diberikan dengan kapas yang diresapi salep di kelompok ANP dan setelah penyisipan
TXA direndam dalam kelompok TXA. Dokter residen melakukan pengobatan darurat
dan penilaian tindak lanjut melalui telepon atau secara langsung untuk
mendokumentasikan setiap perdarahan ulang atau efek samping pada 24 jam dan 1
minggu. Pengolahan penelitian ini mengevaluasi tingkat kepuasan pada skala
peringkat numerik pada saat keluar dari ugd.

Hasil
Hasil utama adalah proporsi pasien pada setiap kelompok yang perdarahannya
telah berhenti dalam 10 menit. Hasil sekunder adalah: 1) frekuensi kekambuhan
epistaxis pada 24 jam dan 7 hari setelahnya pengobatan, 2) lama rawat inap 3) pasien
kepuasan pada skala peringkat numerik 0–10, dengan skor yang lebih tinggi
menunjukkan kepuasan yang lebih besar.
Analisis Data
Perhitungan ukuran sampel didasarkan pada hasil penelitian sebelumnya
tentang ANP untuk pengobatan epistaksis dimana sekitar 30% pasien mengalami
penghentian perdarahan dalam 10 menit. Peneliti mempertimbangkan perbedaan
penting secara klinis minimum sebesar 25% (yaitu 55% perdarahan berhenti pada 10
menit) diperlukan untuk membuat topikal penggunaan bentuk injeksi TXA lebih
disukai daripada ANP. Peneliti menghitung bahwa ukuran sampel 57 per kelompok
akan memberikan kekuatan 80% untuk mendeteksi perbedaan ini dengan alpha dari
0,05. Peneliti meningkatkan ukuran sampel sebesar 10% di masing-masing kelompok
untuk menjelaskan paada pasien, ukuran sampel akhir yaitu 62 per kelompok.
Analisis statistik dilakukan dengan IBM SPSS Statistik untuk Windows, versi
24 (IBM Corp). Uji chi-square digunakan untuk membandingkan primer dan variabel
sekunder antara dua kelompok. Karena distribusinya yang tidak sesuai, maka Mann-
Whitney U-test digunakan untuk perbandingan tingkat kepuasan dan waktu rata-rata
untuk menghentikan pendarahan antara dua kelompok dan hasilnya dinyatakan
sebagai median dan jangkauan interkuartil (IQR). Interval kepercayaan 95% dari
perbedaan dalam proporsi dihitung menggunakan VassarS tats, kalkulator online yang
dapat diakses di http://vassarstats.net/prop2_ind.html. Perbandingan karakteristik
dasar antara kedua kelompok dilakukan dengan menggunakan uji-t sampel
independen dan uji chi-square untuk variabel kontinu dari masing-masing kategori.
Peneliti menganggap ada hubungan jika kedua variabel nilai p nya <0,05.

HASIL
Karakteristik Subjek
Sebanyak 384 pasien dinilai untuk kelayakan, 260 pasien dikeluarkan, dan 124
subjek (69 laki-laki dan 55 wanita) terdaftar dalam uji klinis acak ini. Sebanyak 124
pasien yang memenuhi syarat diacak dan termasuk dalam analisis yaitu 62 di
kelompok TXA dan 62 di kelompok ANP. Para pasien diikuti selama 7 hari. Dasar
karakteristik masing-masing kelompok ditunjukkan pada Tabel 1. Kecuali untuk
riwayat epistaksis sebelumnya, yang secara signifikan lebih tinggi pada kelompok
TXA, variabel dasar adalah sebanding antara kedua kelompok.
 Gambar 1. Consort flow diagram

Tabel 1. Karakteristik pasien

Anterior Nasal Packing (n=62) Tranexamic Acid (n=62)
Umur 60,7 ± 12,2 58,5 ± 16,1
Jenis kelamin (% pria) 52 60
PLTs x 109/l 302 ± 80 298 ± 83
PT (sec) 12,6 ± 0,9 12,5 ± 1,1
INR 1,07 ± 0,10 1,05 ± 0,08
PTT (sec) 32,7 ± 4,6 31,5 ± 3,8
Riwayat epistaksis (% ya) 21 53
Riwayat pengobatan 82/18 81/19
(ASA/Lainnya)
Hasil utama
Hasil dari setiap pengobatan dirangkum dalam Tabel 2. Pendarahan berhenti
dalam 10 menit di 45 (73%) dari 62 pasien di TXA, dibandingkan dengan 18 (29%)
dari 62 pasien di ANP (perbedaan persen = 44%; 95% CI = 26% sampai 57%; p <
0,001). Waktu rata-rata untuk penghentian perdarahan pada kelompok TXA (10 menit;
IQR = 10-15 menit) secara signifikan lebih rendah dari kelompok ANP (15 menit;
IQR = 10–20 menit; p < 0,001. Perdarahan ulang pada 24 jam didokumentasikan
dalam tiga (5%) dari 62 pasien dalam kelompok TXA dan enam (10%) dari 62 pasien
dalam kelompok ANP (p = 0,299).
Perdarahan ulang pada 1 minggu didokumentasikan dalam tiga (5%) dari 62
pasien dalam kelompok TXA dan 13 (21%) dari 62 pasien dalam kelompok ANP
(perbedaan persen = -16%; 95% CI = –28% hingga –4%; p = 0,007).
Lama rawat inap lebih pendek untuk pasien di kelompok TXA, yaitu 60 orang
(97%) dari 62 pasien dipulangkan dalam waktu 2 jam dibandingkan dengan delapan
(13%) dari 62 pasien di kelompok ANP (perbedaan persen = 84%; 95% CI = 71%
hingga 91%; p < 0,001). Kepuasan pasien secara signifikan lebih besar pada kelompok
TXA (median = 9; IQR = 8–9,25) dibandingkan dengan kelompok ANP (median = 4;
IQR = 3-5; p <0,001). Tidak ada efek samping serius yang terdeteksi selama
penelitian. Tidak ada perbedaan yang signifikan secara statistik pada kejadian
komplikasi (mual/muntah) dan intoleransi pengobatan antara dua kelompok.

Tabel 2. Efek Tranexamid Acid dibandingkan Anterior Nasal Packing pada

keefektifan variabel
ANP TXA Perbedaan Persen (95% Cl) p-value
Waktu 29 73 44 ( 26-57) <0,001
perdarahan
berhenti ≤ 10
min (%)
Waktu 15(10-20) 10(10-15) <0,001
perdarahan
berhenti (min),
median (IQR)
 Waktu 13 97 84 (71-91) <0,001
pengosongan ≤
2 jam (%)
Komplikasi di 5 10 5(-5-15) 0,299
ugd (%)
Perdarahan 10 5 -5(-15-5) 0,299
berulang
dalam 24 jam
(%)
Perdarahan 21 5 -16(28-(-4)) 0,007
berulang
setelah 1
minggu (%)

PEMBAHASAN
The World Health Organization (WHO) mencantumkan TXA sebagai obat
esensial. Ini adalah obat antifibrinolitik dan turunan sintetis dari asam amino lisin yang
mengurangi konsentrasi plasmin dengan memblokir situs pengikatan lisin
plasminogen, yang pada gilirannya menghambat pengikatan plasminogen ke fibrin
dan kemudian konversi plasminogen menjadi plasmin. Plasmin melalui sistem
komplemen dapat mengganggu fungsi trombosit dan mengurangi adhesi dan agregasi
trombosit.
Beberapa rute pemberian TXA, termasuk oral, intravena, dan topikal telah
dipelajari untuk berbagai jenis perdarahan, termasuk epistaksis. Dalam satu penelitian,
pasien dengan hemoragik herediter telangiectasia yang mengonsumsi TXA oral setiap
hari mengalami penurunan durasi epistaksis yang signifikan setiap bulannya.
dibandingkan dengan mereka yang menggunakan plasebo. TXA topikal juga telah
menunjukkan keberhasilan dalam mencapai hemostasis dan meningkatkan bidang
bedah di sinus endoskopik pembedahan dan telah terbukti mengurangi perdarahan
pasca operasi setelah adenoidektomi.
Sindet-Pedersen menunjukkan bahwa obat kumur dengan 10 mL larutan TXA
berair 5% sangat tinggi untuk kadar obat saliva dan kadar plasma rendah dibandingkan
dengan pemberian oral 1 g obat. Data ini menyarankan bahwa pemberian topikal TXA
dapat bermanfaat dalam menghentikan perdarahan lokal tanpa menghasilkan efek
antifibrinolisis sistemik yang signifikan. Lebih jauh lagi, efek hemostatik topikal dari
TXA telah ditunjukkan dalam pengobatan perdarahan gingiva pada pasien hemofilik
dan pada perdarahan paru dari berbagai etiologi.
Sejauh pengetahuan peneliti, ini adalah yang penelitian pertama yang meneliti
efek TXA untuk pengobatan epistaksis pada pasien yang menggunakan obat
antiplatelet. Peneliti menemukan aplikasi topikal formulasi injeksi TXA lebih efektif
daripada ANP dengan kapas yang diresapi tetrasiklin, dengan 73% dari pasien pada
kelompok sebelumnya perdarahan berhenti dalam waktu 10 menit dibandingkan
dengan 29% pada kelompok yang terakhir.
Selain itu, tingkat perdarahan berulang selama minggu pertama setelah
pengobatan di antara pasien di TXA kelompok secara signifikan lebih rendah daripada
di kelompok ANP. Lama rawat inap menurun secara signifikan di kelompok TXA.
Hal ini sesuai dengan temuan dari penelitian sebelumnya yang meneliti pengobatan
TXA topikal dari epistaksis idiopatik. Dengan demikian, adopsi strategi perawatan ini
dapat meningkatkan kunjungan pasien melalui UGD di pusat-pusat di mana ANP
biasanya digunakan dalam pengobatan epistaksis.
Kepuasan pasien juga lebih besar di kelompok TXA. Perawatan yang lebih
nyaman untuk pasien dan lebih sederhana untuk dilakukan oleh dokter lebih
menyenangkan dan lebih mungkin untuk diintegrasikan ke dalam praktek klinis.
Kesederhanaan dan kenyamanan ini telah dibuktikan dalam pekerjaan kami
sebelumnya dan dari Tibbelin et al dalam studi gel traneksamat untuk pengobatan
epistaksis.
Penggunaan topikal dari bentuk injeksi TXA tampaknya memberikan pilihan
pengobatan yang lebih baik untuk anterior epistaksis dibandingkan dengan ANP pada
pasien yang memakai obat anti platelet. Keuntungan dari pengobatan TXA topikal
yang ditunjukkan pada populasi penelitian kami meliputi: hemostasis lebih cepat, lama
rawat inap lebih pendek, tingkat kekambuhan lebih rendah, dan peningkatan kepuasan
pasien.
KETERBATASAN
Penelitian ini memiliki beberapa keterbatasan. Satu batasan utama adalah
bahwa pasien dengan epistaksis posterior tidak termasuk dalam uji coba ini sehingga
kami tidak dapat mengomentari peran TXA dalam pengelolaan pasien ini. Selain itu,
peneliti tidak mengelompokkan tugas perawatan dengan obat antiplatelet spesifik
yang dikonsumsi pasien jadi peneliti tidak membuat kesimpulan apa pun tentang
manfaat relatif dari pengobatan studi dasar baik agen antiplatelet atau kombinasi dari
agen. Dengan tidak adanya konsensus tentang sistem penilaian keparahan epistaksis,
kecuali untuk pasien dengan telangiectasia hemoragik herediter, peneliti memilih
untuk memasukkan pasien dengan perdarahan persisten setelah 20 menit kompresi
manual kedua lubang hidung. Ada kemungkinan bahwa ada ketidakseimbangan
keparahan epistaksis di antara kelompok-kelompok yang bisa disukai pengobatan
TXA. Namun, hanya ketidakseimbangan yang didokumentasikan di antara perawatan
kelompok adalah proporsi yang lebih tinggi dari pasien dengan riwayat epistaksis pada
kelompok TXA dibandingkan dengan kelompok ANP. Karena riwayat epistaksis
mungkin penanda untuk epistaksis yang lebih parah seperti yang dicatat dalam Skor
Keparahan Epistaksis untuk Perdarahan Herediter Telangiectasia, mungkin saja
temuan kami benar-benar meremehkan efek menguntungkan dari TXA dibandingkan
ke ANP. Akhirnya, meskipun ada secara komersial tersedia spons hidung, tampon,
dan perangkat balon tamponade yang dirancang untuk pengobatan epistaksis, kami
tidak membandingkannya dalam percobaan ini dan sebagainya tidak dapat
mengomentari kemanjuran atau tolerabilitas relatif mereka dibandingkan dengan
TXA.

Kesimpulan
Dalam populasi penelitian ini pasien yang memakai antiplatelet obat-obatan
yang datang ke UGD dengan epistaksis, yaitu diacak untuk aplikasi topikal asam
traneksamat menunjukkan penghentian perdarahan yang lebih cepat, lebih sedikit
perdarahan ulang pada 1 minggu, lama rawat inap lebih pendek, dan lebih tinggi
kepuasan pasien dibandingkan mereka yang diobati dengan anterior nasal packing.
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7. Zahed R, Moharamzadeh P, Alizadeharasi S, Ghasemi A, Saeedi M. A new and
rapid method for epistaxis treatment using injectable form of tranexamic acid
topically: a randomized controlled trial. Am J Emerg Med 2013;31:1389–92.
8. Sanchez-Palomino P, Sanchez-Cobo P, Rodriguez-Archilla A, et al. Dental
extraction in patients receiving dual antiplatelet therapy. Med Oral Patol Oral Cirugia
Bucal 2015;20:e616.
9. Solomonov A, Fruchter O, Zuckerman T, Brenner B, Yigla M. Pulmonary
hemorrhage: a novel mode of therapy. Respir Med 2009;103:1196–200.
10. Athanasiadis T, Beule AG, Wormald PJ. Effects of topical antifibrinolytics in
endoscopic sinus surgery: a pilot randomized controlled trial. Am J Rhinol
2007;21:737–42.
11. Jahanshahi J, Hashemian F, Pazira S, et al. Effect of topical tranexamic acid on
bleeding and quality of surgical field during functional endoscopic sinus surgery in
patients with chronic rhinosinusitis: a triple blind randomized clinical trial. PLoS One
2014;9:e104477.
12. Albirmawy OA, Saafan ME, Shehata EM, Basuni AS, Eldaba AA. Topical
application of tranexamic acid after adenoidectomy: a double-blind, prospective,
randomized, controlled study. Int J Pediatr Otorhinolaryngol 2013;77:1139–42.
13. Population and Household by Province and Shahrestan. 2017. Available at:
https://www.amar.org.ir/english/Popu lation-and-Housing-Censuses. Accessed Sep
16, 2017.
14. Selected Results of the 2016 National Population and Housing Census. 2017.
Available at: https://www.amar.org.ir/
Portals/1/census/2016/Iran_Census_2016_Selected_Re sults.pdf. Accessed Sep 16,
2017. 15. Musgrave KM, Powell J. A systematic review of anti-thrombotic therapy in
epistaxis. Rhinology 2016;54:292–391.
16. Kamhieh Y, Fox H. Tranexamic acid in epistaxis: a systematic review. Clin
Otolaryngol 2016;41:771–6.
17. Shi J, Ji H, Ren F, et al. Protective effects of tranexamic acid on clopidogrel before
coronary artery bypass grafting: a multicenter randomized trial. JAMA Surg
2013;148:538–47.
18. Weber CF, Gorlinger K, Byhahn C, et al. Tranexamic acid partially improves
platelet function in patients treated with dual antiplatelet therapy. Eur J Anaesthesiol
2011;28:57–62. 19. Putnam JB, Royston D, Chambers AF, et al. Evaluating the role
of serine protease inhibition in the management of tumor micrometastases. Oncology
(Williston Park) 2003;17:9–30; quiz 31–2.
20. Sindet-Pedersen S, Stenbjerg S, Ingerslev J. Control of gingival hemorrhage in
hemophilic patients by inhibition of fibrinolysis with tranexamic acid. J Periodontal
Res 1988;23:72–4.
21. Shakur H, Elbourne D, Gulmezoglu M, et al. The WOMAN Trial (World Maternal
Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage:
an international randomised, double blind placebo controlled trial. Trials 2010;11:40.
22. Roberts I, Edwards P, Prieto D, et al. Tranexamic acid in bleeding trauma patients:
an exploration of benefits and harms. Trials 2017;18:48.
23. Gaillard S, Dupuis-Girod S, Boutitie F, et al. Tranexamic acid for epistaxis in
hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial
in a rare disease. J Thromb Haemost 2014;12:1494–502.
24. Sindet-Pedersen S. Distribution of tranexamic acid to plasma and saliva after oral
administration and mouth rinsing: a pharmacokinetic study. J Clin Pharmacol
1987;27:1005–8.
25. Tibbelin A, Aust R, Bende M, et al. Effect of local tranexamic acid gel in the
treatment of epistaxis. ORL J Otorhinolaryngol Relat Spec 1995;57:207–9.
CONTINUING MEDICAL EDUCATION IN ACADEMIC EMERGENCY MEDICINE

CME Information: Topical Tranexamic

Acid Compared With Anterior Nasal
Packing for Treatment of Epistaxis in
Patients Taking Antiplatelet Drugs:
Randomized Controlled Trial
CME Editor: Corey Heitz, MD
Authors: Reza Zahed, MD, Mohammad Hossain Mousavi Jazayeri, MD, Asieh Naderi, PhD,
Zeinab Naderpour, MD, and Morteza Saeedi, MD
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ORIGINAL CONTRIBUTION

Topical Tranexamic Acid Compared

With Anterior Nasal Packing for
Treatment of Epistaxis in Patients
Taking Antiplatelet Drugs:
Randomized Controlled Trial
Reza Zahed, MD, Mohammad Hossain Mousavi Jazayeri, MD, Asieh Naderi, PhD,
Zeinab Naderpour, MD, and Morteza Saeedi, MD
A related article appears on page 360.

ABSTRACT
Objective: We evaluated the efficacy of topical application of the injectable form of tranexamic acid (TXA)
compared with anterior nasal packing (ANP) for the treatment of epistaxis in patients taking antiplatelet drugs
(aspirin, clopidogrel, or both) who presented to the emergency department (ED).

Methods: A randomized, parallel-group clinical trial was conducted at two EDs. A total of 124 participants were
randomized to receive topical TXA (500 mg in 5 mL) or ANP, 62 patients per group. The primary outcome was
the proportion of patients in each group whose bleeding had stopped at 10 minutes. Secondary outcomes were
the rebleeding rate at 24 hours and 1 week, ED length of stay (LOS), and patient satisfaction.

Results: Within 10 minutes of treatment, bleeding was stopped in 73% of the patients in the TXA group,
compared with 29% in the ANP group (difference = 44%, 95% confidence interval, 26% to 57%; p < 0.001).
Additionally, rebleeding was reported in 5 and 10% of patients during the first 24 hours in the TXA and the ANP
groups, respectively. At 1 week, 5% of patients in the TXA group and 21% of patients in the ANP group had
experienced recurrent bleeding (p = 0.007). Patients in the TXA group reported higher satisfaction scores (median
[interquartile range {IQR}], 9 [8–9.25]) compared with the ANP group (median [IQR] = 4 [3–5]; p < 0.001).
Discharge from the ED in <2 hours was achieved in 97% of patients in the TXA group versus 13% in the ANP
group (p < 0.001). There were no adverse events reported in either group.

Conclusions: In our study population, epistaxis treatment with topical application of TXA resulted in faster
bleeding cessation, less rebleeding at 1 week, shorter ED LOS, and higher patient satisfaction compared with
ANP.

From the Department of Emergency Medicine, Imam Khomeini Hospital Complex, Faculty of Medicine (RZ); the Department of Emergency Medi-
cine (MHMJ), the Department of Internal Medicine (ZN), and the Emergency Medicine Research Center, Department of Emergency Medicine (MS),
Shariati Hospital, Faculty of Medicine; and the Eye Research Center, Farabi Eye Hospital (AN), Tehran University of Medical Sciences, Tehran, Iran.
Received July 17, 2017; revision received November 2, 2017; accepted November 5, 2017.
[This article was modified on December 20, 2017, after initial publication to correctly name the Supervising Editor.]
The authors have no relevant financial information or potential conflicts to disclose.
Author contributions: RZ, MHMJ, and MS conceived the study and designed the trial; MS, MHMJ, and ZN supervised the conduct of the trial and
data collection, undertook recruitment of participants, and managed the data; RZ and AN provided statistical advice on study design and analyzed
the data; RZ and AN drafted the article; and all authors contributed substantially to its revision. RZ, AN, and MS had full access to all the study
data and final responsibility for the decision to submit for publication. MS takes responsibility for the paper as a whole.
Supervising Editor: Michael S. Runyon, MD, MPH.
Address for correspondence and reprints: Morteza Saeedi, MD; e-mail: m_saeedi@tums.ac.ir.
ACADEMIC EMERGENCY MEDICINE 2018;25:261–266.

© 2017 by the Society for Academic Emergency Medicine ISSN 1553-2712

doi: 10.1111/acem.13345 261
262 Zahed et al. • TOPICAL TXA FOR EPISTAXIS TREATMENT IN ANTIPLATELET USERS
E pistaxis is a common complaint in the emergency
department (ED).1 About 60% of population
experience epistaxis at least once during their lifetime
and 6% require medical attention.2 The cause of
epistaxis is unknown in the majority of cases. Etio-
logic factors can be divided into local and systemic
causes.3 Of all systemic factors, the use of anticoagu-
lants and antiplatelet drugs appear to have a signifi-
cant correlation with more severe and recurrent
epistaxis.4
Antiplatelet medications, specifically aspirin and
clopidogrel, are widely prescribed for treatment or pre-
ventions of various forms of cardiovascular disease.3
While there is no significant difference in the risk of
epistaxis in patients taking aspirin or clopidogrel,5
epistaxis management is more difficult in patients
taking antiplatelet drugs.4
Anterior nasal packing (ANP), a frequently per-
formed procedure in the management of epistaxis, has
potential complications, including discomfort during
placing and removing the pack and rebleeding follow-
ing removal owing to mucosal injury and synechia for-
mation.6 As such, more optimal treatment strategies
are needed for the management of epistaxis, especially
for patients taking antiplatelet drugs.
The efficacy of topical application of the injectable
form of tranexamic acid (TXA) has been shown bene-
ficial for the treatment of idiopathic anterior epistaxis.7
Additionally, topical use of TXA during oral,8 pul-
monary,9 sinus,10,11 and adenoidectomy12 procedures
results in significantly less mucosal bleeding. In this
study, we compared the effect of topical TXA with
ANP for treatment of anterior epistaxis in patients
taking antiplatelet drugs.
MATERIALS AND METHODS
Study Design and Setting
A randomized, parallel-group clinical trial study was
conducted at two EDs and designed to compare treat-
ment efficacy of topical use of the injectable form of
10% TXA (500 mg in 5 mL) with that of ANP for
treatment of epistaxis in patients taking antiplatelet
drugs (aspirin, clopidogrel, or both). To ensure a stan-
dardized approach to epistaxis management at the two
study sites, PGY2 and PGY3 emergency medicine resi-
dent physicians participated in a 2-hour workshop on
ANP and topical TXA administration. Patient recruit-
ment commenced in October 2015 and finished in
April 2016.
Population
Patients were enrolled in the EDs of the two large gen-
eral academic teaching hospitals of Tehran University
of Medical Sciences, one with 510 beds and 40,800
annual ED visits and the other with 540 beds and
43,200 annual ED visits. Both centers have residency
programs in multiple specialties. Home to 8.7 million
people, Tehran is Iran’s capital and most populous
city.13,14
Subjects were eligible for inclusion if they presented
to the ED with an acute, new or recurrent, ongoing
anterior epistaxis and were currently taking antiplatelet
drugs (aspirin, clopidogrel, or both). In the absence of
a universally accepted grading system for the severity
of epistaxis, save that for hereditary hemorrhagic
telangiectasia, we included patients with persistent
bleeding requiring further treatment after 20 minutes
of compression of both nostrils with the patient’s
thumb and index finger.15 We excluded those with
traumatic epistaxis, current anticoagulant drug use,
inherited bleeding disorders (including hemophilia),
inherited platelet disorders, international normalize
ratio > 1.5, shock, a visible bleeding vessel, a history
of renal disease, and lack of consent. Our institution’s
ethics review committee approved the study and it was
registered at IRCT.Ir (IRCT201509088872N9). Writ-
ten informed consent was obtained from all patients
prior to entry into the trial.
Study Protocol
Eligible patients were randomly allocated to either the
TXA group or the ANP group. Our research nurse
used IBM SPSS Statistics for Windows, version 24
(IBM Corp) to generate the random allocation
sequence, which was stratified by center. Randomiza-
tion was done in blocks of two, four, and six. To
implement the random allocation process, the research
nurse randomized the consecutively numbered boxes
filled with medication and cotton pledgets in a loca-
tion removed from the ED and inaccessible to the ED
personnel. Each box was identical in size, shape, and
weight. The numbered boxes were held in the ED
pharmacy and delivered sequentially to resident physi-
cians treating patients with epistaxis who were enrolled
in the study. Due to differences in the numbers of
pledgets required for ANP compared with topical TXA
and in the consistency, color, and smell of the medica-
tions used for soaking and impregnating the pledgets,
our patients and physicians were not blinded. How-
ever, our analysts were not the same investigators who
ACADEMIC EMERGENCY MEDICINE • March 2018, Vol. 25, No. 3 • www.aemj.org
performed the treatment procedures and they analyzed
the data set blinded to group assignment.
The TXA group received a 15-cm piece of cotton
pledget that had been soaked in the injectable form of
TXA (500 mg in 5 mL) and inserted into the affected
nostril. It was removed after the attending physician or
a chief resident examined the oropharynx and blood-
soaked pledgets to confirm that the bleeding had
stopped. The ANP group received a cotton pledget
that had been soaked in epinephrine (1:100,000) +
lidocaine (2%) inserted into the affected nostril and
left in place for 10 minutes. ANP was subsequently
performed with several cotton pledgets covered with
tetracycline ointment. The packs were left in situ for 3
days before removal. If the allocated treatment failed,
we considered ANP and cautery (if indicated) and cau-
tery alone for the TXA group and the ANP group,
respectively.
Measurements
Assessment for ongoing bleeding was performed at 5-
minute intervals and when the patient left the ED.
The timed assessments began at the completion of
packing with the ointment-impregnated pledgets in the
ANP group and following the insertion of the TXA
soaked pledget in the TXA group. Emergency medi-
cine resident physicians performed follow-up assess-
ments by telephone or in person to document any
rebleeding or adverse events at 24 hours and 1 week.
Our research nurse evaluated satisfaction rate on a
numerical rating scale at the time of ED discharge.
Outcomes
The primary outcome was the proportion of patients
in each group whose bleeding had stopped at 10 min-
utes. Secondary outcomes were: 1) frequency of epis-
taxis recurrence at 24 hours and 7 days after
treatment, 2) ED length of stay (LOS), and 3) patient
satisfaction on a 0–10 numeric rating scale, with a
higher score indicating greater satisfaction.
Data Analysis
Our sample size calculation was based on the results of
a previous study of ANP for the treatment of epistaxis in
which approximately 30% of patients had bleeding ces-
sation in ≤10 min.7 We considered a minimum clini-
cally important difference of 25% (i.e., 55% bleeding
cessation at 10 minutes) necessary to make the topical
use of the injectable form of TXA preferable to ANP.
We calculated that a sample size of 57 per group would
263
give 80% power to detect this difference with an alpha
of 0.05. We increased the sample size by 10% in each
group to account for patients lost to follow-up, giving a
final sample size of 62 per group.
Statistical analyses were performed with IBM SPSS
Statistics for Windows, version 24 (IBM Corp). The
chi-square test was used to compare the primary and
secondary efficacy variables between two groups.
Because of their skewed distribution Mann-Whitney
U-test was used for comparison of satisfaction rate and
median time to stop bleeding between two groups and
results are expressed as median and interquartile range
(IQR). The 95% confidence intervals (CIs) of the dif-
ferences in proportions were calculated using VassarS-
tats, an online calculator accessible at http://vassarsta
ts.net/prop2_ind.html. Baseline characteristic compar-
isons between the two groups were done using the
independent sample t-test and chi-square test for con-
tinuous and categorical variables, respectively. We con-
sidered two-sided p-values < 0.05 to be statistically
significant.
RESULTS
Characteristics of Study Subjects
A total of 384 patients were assessed for eligibility,
260 patients were excluded, and 124 subjects (69 men
and 55 women) were enrolled in this randomized clin-
ical trial (Figure 1). A total of 124 eligible patients
were randomized and included in the intention-to-treat
analysis: 62 in the TXA group and 62 in the ANP
group. The patients were followed for 7 days. Baseline
characteristics of each group are shown in Table 1.
Except for prior epistaxis history, which was signifi-
cantly higher in the TXA group, the baseline variables
were comparable between the two groups.
Main Results
The outcomes of each treatment are summarized in
Table 2. Bleeding stopped within 10 minutes in 45
(73%) of 62 patients in the TXA, compared with 18
(29%) of 62 patients in the ANP (percent difference =
44%; 95% CI = 26% to 57%; p < 0.001). The med-
ian time to bleeding cessation in the TXA group (10
minutes; IQR = 10–15 minutes) was significantly
lower than the ANP group (15 minutes; IQR = 10–
20 minutes; p < 0.001).
Rebleeding at 24 hours was documented in three
(5%) of 62 patients in the TXA group and six (10%)
of 62 patients in the ANP group (p = 0.299).
264 Zahed et al. • TOPICAL TXA FOR EPISTAXIS TREATMENT IN ANTIPLATELET USERS

Assessed for eligibility Excluded (n = 260)

No antiplatelet drug use (n = 135)

Enrollment
(n = 384)
No consent (n = 92)
Warfarin use (n = 15)
Trauma (n = 10)
Renal failure (n = 5)
Randomized Thrombocytopenia (n = 3)
(n = 124)

Allocation
Allocated to ANP (n = 62) Allocated to TXA (n = 62)
Received intervention (n = 62) Received intervention (n = 62)
Follow-up

Lost to follow-up (n = 0) Lost to follow-up (n = 0)

Analysis

Analyzed (n = 62) Analyzed (n = 62)

Figure 1. CONSORT flow diagram. ANP = anterior nasal packing; TXA = tranexamic acid.

Table 1 ED LOS was shorter for patients in the TXA

Patient Characteristics group, with 60 (97%) of 62 patients discharged within
Anterior Nasal Tranexamic 2 hours compared with eight (13%) of 62 patients in
Packing (n = 62) Acid (n = 62)
the ANP group (percent difference = 84%; 95% CI =
Age (y) 60.7  12.2 58.5  16.1
71% to 91%; p < 0.001). Patient satisfaction was sig-
Sex (% male) 52 60
nificantly greater in the TXA group (median = 9;
PLTs 9109/l 302  80 298  83
PT (sec) 12.6  0.9 12.5  1.1
IQR = 8–9.25) compared with the ANP group
INR 1.07  0.10 1.05  0.08 (median = 4; IQR = 3–5; p < 0.001).
PTT (sec) 32.7  4.6 31.5  3.8 No serious adverse events were detected during the
History of epistaxis (% yes) 21 53 study. There was no statistically significant difference
History of drugs (%) 82/18 81/19 in the incidence of complications (nausea/vomiting
(ASA/others)
and treatment intolerance) between two groups.
ASA = acetylsalicylic acid; INR = international normalized ratio;
PLTs = platelets; PT = prothrombin time; PTT = partial thrombo-
plastin time.
DISCUSSION
The World Health Organization lists TXA as an
Rebleeding at 1 week was documented in three (5%) of essential medication.16 It is an antifibrinolytic drug
62 patients in the TXA group and 13 (21%) of 62 and a synthetic derivative of the amino acid lysine that
patients in the ANP group (percent difference = –16%; reduces plasmin concentration by blocking the lysine-
95% CI = –28% to –4%; p = 0.007). binding sites of plasminogen, which in turn inhibits

Table 2
Effects of Tranexamic Acid Compared With Anterior Nasal Packing on Efficacy Variables

Anterior Nasal Packing Tranexamic Acid Percent Difference (95% CI) p-value
Bleeding stop time ≤ 10 min (%) 29 73 44 (26 to 57) <0.001
Bleeding stop time (min), median [IQR] 15 [10–20] 10 [10–15] <0.001
Discharge time ≤ 2 h (%) 13 97 84 (71 to 91) <0.001
Complications in the ED (%) 5 10 5 (–5 to 15) 0.299
Rebleeding in the first 24 h (%) 10 5 –5 (–15 to 5) 0.299
Rebleeding from procedure until 1 week (%) 21 5 –16 (–28 to –4) 0.007
ACADEMIC EMERGENCY MEDICINE • March 2018, Vol. 25, No. 3 • www.aemj.org
the binding of plasminogen to fibrin and then
conversion of plasminogen to plasmin.17 Plasmin via
the complement system may interfere with platelet
function18 and reduce platelet adhesion and aggrega-
tion.19
Multiple routes of TXA administration, including
oral, intravenous, and topically have been studied for
various types of bleeding, including epistaxis.7,8,20–22
In one study, patients with hereditary hemorrhagic
telangiectasia who took daily oral TXA had a signifi-
cant decrease in the duration of epistaxis each month
compared with those taking placebo.23 Topical TXA
has also demonstrated success in achieving hemostasis
and improving the surgical field in endoscopic sinus
surgery10 and has been shown to decrease postopera-
tive hemorrhage after adenoidectomy.12
Sindet-Pedersen24 showed that mouth rinse with 10
mL of a 5% aqueous TXA solution achieved very high
salivary drug levels and low plasma levels compared
with oral administration of 1 g of the drug. These data
suggest that topical administration of TXA can be ben-
eficial in arresting local hemorrhage without producing
significant systemic antifibrinolysis effects. Further-
more, the topical hemostatic effect of TXA has been
shown in the treatment of gingival bleeding in hemo-
philic patients20 and in pulmonary hemorrhage from
various etiologies.9
To the best of our knowledge, this is the first
trial investigating the effects of TXA for treatment of
epistaxis in patients taking antiplatelet drugs. We
found the topical application of the injectable formu-
lation of TXA to be more effective than ANP with
tetracycline-impregnated pledgets, with 73% of
patients in the former group achieving bleeding ces-
sation within 10 minutes compared with 29% in
the latter group.
Moreover, the rate of recurrent bleeding during the
first week after treatment among patients in the TXA
group was significantly lower than in the ANP group.
ED LOS was significantly decreased in the TXA
group. This is consistent with findings from a prior
study by our group that examined topical TXA treat-
ment of idiopathic epistaxis.7 As such, adoption of
this treatment strategy may improve patient flow
through the ED at centers where ANP is commonly
employed in the treatment of epistaxis.
Patient satisfaction was also greater in the TXA
group. Treatments that are more comfortable for
patients and simpler for physicians to perform are
more pleasant and more likely to be integrated into
265
clinical practice. This simplicity and convenience has
been demonstrated in our prior work7 and that of
Tibbelin et al.25 in a study of tranexamic gel for the
treatment of epistaxis.
Topical use of the injectable form of TXA seems
to provide a better treatment option for anterior
epistaxis compared with ANP in patients taking anti-
platelet drugs. The advantages of topical TXA treat-
ment demonstrated in our study population include
quicker hemostasis, shorter ED LOS, lower recur-
rence rate, and increased patient satisfaction. The
technique is also relatively simple and is easy to
teach and learn.
LIMITATIONS
This study has several limitations. One key limitation
is that patients with posterior epistaxis were not
included in this trial and so we cannot comment on
the role of TXA in the management of these
patients. Another limitation is that the physicians
and patients were not blinded to treatment allocation.
Moreover, we did not stratify treatment assignment
by the specific antiplatelet drug the patient was taking
and so we cannot make any conclusions about the
relative benefit of the study treatment on the basis of
either antiplatelet agent or a combination of the
agents. Also, in the absence of consensus on an epis-
taxis severity grading system, save that for patients
with hereditary hemorrhagic telangiectasia, we chose
to include those patients with persistent bleeding after
20 minutes of manual compression of both nostrils.
While we feel that this is reasonable, clinically rele-
vant population, it is possible that there was an
imbalance of epistaxis severity among the groups that
could have favored the TXA treatment. However, the
only imbalance documented among the treatment
groups was a higher proportion of patients with a
history of epistaxis in the TXA group compared with
the ANP group. Since a history of epistaxis may be a
marker for more severe epistaxis (as noted in the
Epistaxis Severity Score for Hereditary Hemorrhagic
Telangiectasia) it is possible our findings may actually
underestimate the beneficial effects of TXA compared
to ANP. Finally, although there are commercially
available nasal sponges, tampons, and balloon tam-
ponade devices that are designed for epistaxis treat-
ment, we did not compare them in this trial and so
cannot comment on their relative efficacy or tolerabil-
ity as compared with TXA.
266 Zahed et al. • TOPICAL TXA FOR EPISTAXIS TREATMENT IN ANTIPLATELET USERS

CONCLUSION patients with chronic rhinosinusitis: a triple blind random-

ized clinical trial. PLoS One 2014;9:e104477.
In our study population of patients taking antiplatelet 12. Albirmawy OA, Saafan ME, Shehata EM, Basuni AS, Eldaba
drugs who presented to the ED with epistaxis, those AA. Topical application of tranexamic acid after adenoidec-
randomized to topical application of tranexamic acid tomy: a double-blind, prospective, randomized, controlled
demonstrated faster bleeding cessation, less rebleeding study. Int J Pediatr Otorhinolaryngol 2013;77:1139–42.
at 1week, shorter ED length of stay, and higher 13. Population and Household by Province and Shahrestan.
patient satisfaction than those treated with anterior 2017. Available at: https://www.amar.org.ir/english/Popu
nasal packing. lation-and-Housing-Censuses. Accessed Sep 16, 2017.
14. Selected Results of the 2016 National Population and Hous-
ing Census. 2017. Available at: https://www.amar.org.ir/
References Portals/1/census/2016/Iran_Census_2016_Selected_Re
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