Tranexamic acid as a therapeutic option for melasma management: meta-analysis and systematic review of randomized controlled trials

Figures & data

Figure 1. Preferred reporting items for systematic reviews and meta-analysis (PRISMA) flowchart.

Table 1. Characteristics of the included studies.

Last name of the first author	Year of publication	Country	Completed/ participants	Age,y	Interventions	Delivery mode	Duration	Efficacy outcome	Side effects
Kaur	2020	India	40	26–48	Microneedling was done on both sides of the face, followed by 10% TXA solution application on one side of the face and distilled water on the other side of the face.	Topical	8 weeks (2 weekly intervals with a total of 4 sessions)	mMSI	Persistent local erythema (7); Localized pruritus (5); Localized burning (1); Transient hyperpigmentation (2);Dryness (22)
zou	2023	china	120	aged 37.4 + 4.2 (aged 24–51)	control group, treated with 250 mg tranexamic acid given orally twice daily, except during menstruation; group I, treated with broadband light (BBL)  monthly; group II, received intradermal injections of tranexamic acid monthly; and group Ill, treated with BBL with intradermal injection of tranexamic acid monthly.	intradermal injection,oral	1 year and 4 month	MASI	Group 1: transient erythema and pruritus (2), petechiae after the injection (1). Relapsed after treatment: 2 patients in control group, 1 relapse in group I,and there were no relapses in groups Il and Ill.
Gamea	2020	Egypt	40	group A (34–58 years), group B (32–55 years).	Group A (topical tranexamic acid 5% cream twice daily for 12 weeks), group B (received additional intradermal injections of platelet rich plasevery 3 weeks throughout the treatment period)	Topical	12 weeks	MASI	Group A: hyperpigmentation (2). Group B: hyperpigmentation (1); transient erythema (10); pain at sites of injection (12).
Elkamshoushi	2021	Egypt	60	Group A(35.10 ± 8.44), Group B(32.40 ± 8.62), Group C(31.85 ± 8.31)	Group A (treated with oral TXA 250 mg twice daily for three months), group B (treated with TXA similarly combined with topical hydroquinone 4% cream), group C (treated with TXA combined with two sessions of 1064 nm low-fluence Q- switched ND:YAG laser (850–1200 mJ/cm2, 4–5 Hz,spot size 4 mm) spaced 4 weeks apart)	Oral	3 months, 12 month follow up	mMASI	Group A: Gastritis (3). Group B : itching (13), erythema (9). Group C: itching (4); PIH (3).
Behrangi	2022	Iran	40	18–50	40 patients, 20 in each treatment arm, which was done six times with 2-week intervals. Twenty patients were administered localized microinjections (4 mg/ml) of tranexamic acid and O-switched 1064 laser every 2 weeks in one arm, while in the other arm, 20 were given oral tranexamic acid 250 mg three times a day and Q-switched 1064 laser every 2 weeks per visit.	microinjection and oral	1 year  and 10 month	Melasma Area and Severity Index (MASI) and delta E (ΔE)	Microinjection: None (13); GI (1); headache (1); hypo menorrhia (1), pain (4). Oral: None (16); GI (4); headache (0); hypo menorrhia (1); pain (0).
Li	2022	China	36/37	42.6 ± 5.6	patients had their facial halves randomly assigned to receive either 755-nm picosecond laser monotherapy or 755-nm picosecond laser and 2.3 ml TXA combination therapy.	Topical	6 month	hemi-MASI	Laser monotherapy: Irritation (5); Erythema (36); Dryness (36); PIH (7); Scaling (4).  Laser + TTXA combination therapy: Irritation (17); Erythema (36); Dryness (36); PIH (10); Scaling (3).
Basit	2021	Pakistan	60/63	Group A(30.46 ± 6.24), Group B(31.90 ± 4.53)	Group A – oral TXA 250 mg twice daily + triple combination cream once daily at night time, Group B – triple combination cream only once daily at night time	oral	8 weeks	MASI	group A; 3 (nausea, headache, abdominal fullness)
Minni	2020	India	120/180	>18	Group A- 30d kits contain 60 tablets each of (TXA 250 mg + ranitidine 150 mg) Bid + (fluocinolone acetonide 0.01%, tretinoin 0.05% and hydroquinone 2%) Once daily, Group B- 30d placebo kits contain 60 tablets each of (calcium lactate + multivitamin) Bid + FbTC once daily	Oral	24 weeks	mMASI	12 gastrointestinal discomfort, 2 hypomenorrhea, erythema and burning in both groups
Y Qu	2021	China	90/90	24–59	Application of Low-power fractional CO2 laser combined with topical TXA solution	Topical	3 months	MASI	Tx group 12, control group 1 (red swelling, burning,pain) / Tx group 1 (secondary postinflammatory hyperpigmentation)
Badran	2021	Egypt	60/60	31.05 ± 7.57	Group (A) patients received TXA (4 mg/mL) intradermal injections every 2 weeks with, group B received TXA (10 mg/mL) intradermal injections every 2 weeks, group C received TXA cream (10% concentration) twice daily	Intradermal injection, topical	12 weeks	MASI	group A 4,group B 6 (mild pain) / group C 2 (slight irritation)
Karrabi	2020	Iran	54/54	Cysteamine (35.22 ± 6.02) TXA (34.29 ± 7.45)	Cysteamine 5% cream group was instructed to apply the cream on the melasma lesions 30 min before bed for 4 consecutive months. Conversely, 0.05 ml (4 mg/mL) TXA mesotherapy was performed by a physician every 4 weeks until 2 months.	Cysteamine (topical) TXA (intradermal injection)	4 months	mMASI, Dermacatch	(erythema and itching) 20 in cysteamin group and 0 in TXA, (Dryness) 18 in cysteamine group and 17 in TXA, (Burning sensation) 21 in cysteamine group and 0 in TXA group, (irritation) 18 in cysteamine group and 0 in TXA group
S. Zaky	2021	Egypt	27/50	31.16 ± 19.16	two groups (25 patients each) of A (topical 4% hydroquinone, nightly application) and B (microneedling + topical 4% TXA, every other week).	Microneedling + topical	8 weeks	MASI	(Post-inflammatory hyper-pigmentation) group A (HQ 4%) (n = 3; 12%),group B (n = 1; 4%) / (erythema)group A (n = 25; 100%),group B (n = 3; 12%).
Meymandi	2020	Iran	60	18–50	tranexamic acid 4%	microneedling plus topical 4% tranexamic acid	monthly for 12 weeks	Mean MASI	Three patients in group B dropped out from the study because of adverse effects
Shihab	2020	Indonesia	60/70	21–64	group A (250 mg of oral tranexamic acid + 4% hydroquinone cream + sunscreen), group B (placebo capsules + hydroquinone 4% cream + sunscreen)	Oral	group A (twice daily for 3 months), group B (twice daily for 3 months) then all additional 3–month follow-up visit on sunscreen alone.	mMASI	group A (One subject complained of changes in the menstrual cycle) group B (first few days of applying the hydro-quinone cream 6% of patient reported erythema and pruritus that resolved with continued application)
Zhao	2019	China	50/237	39.47 ± 6.05	One group using Myjet‐assisted injection of tranexamic acid and the other group receiving vitamin C	Myjet‐assisted transdermal injection	two months	hemi‐MASI score	Two patients reported mild erythema, one patient felt stuffy feeling during the injection process. symptoms generally disappeared after approximately ten minutes. At the two‐month follow‐up point, one case of recurrent melasma was observed; a 48‐year‐old housewife with Fitzpatrick skin type IV and no history of excessive sun exposure.
Tawfic	2019	Cairo	17/19	above 18	There were two groups all patients received full-face low power (12Watts) fractional ablative CO2 laser treatments. One side of the face was randomly received TXA either topically or intradermally.	topically or injected intradermally	Sessions were conducted every 4–6 weeks for five consecutive sessions.	MASI, MI, and erythema index (EI)	post-inflammatory hyperpigmentation, prolonged erythema, acne and milia, contact dermatitis, delayed purpura, HSV reactivation, scarring, and keloid formation. two patients randomized to the topical TXA group discontinued treatment after the first session due to occurrence of post-inflammatory hyper- pigmentation.
Khurana	2018	India	28/30	30–50	tranexamic acid is + sunscreen	one group received, localized microinjections (4 mg/ml) of tranexamic acid monthly in 1 arm, while in the other arm. The other group given oral tranexamic acid 250 mg twice a day.	6 moths	MSAI	in the intralesional group, mild pain and erythema that lasted for 2–3 days and 9.37% had repigmentation of lesions at the end of 6 months. In the oral group, two patients had gastritis and one patient had oligomenorrhea at the end of 3 months. and recurrence with darkening of the lesions
Shin	2012	South Korea	25	28–56, median 48	-Combined group: TXA at a dose of 750 mg per day for 8 weeks amd two rounds with low fluemce QSNY laser therapy at 4 weeks interval; -Laser group: Low fluemce QSNY alone	Oral and laser for combination group; laser only for laser group	8 weeks	MASI scoring, photograph, mexameter, and laser toning	All patients experienced transient erythema after laser. One patient from combination group report medication-associate heartburn, Another one in the same group complained of nausea.
Krishnoji Rao	2022	Turkey	44/48	Topical group 35.59 ± 6.54; TXA group 35.19 ± 7.55	Topical group: triple combination product (hydroquinone 2%, mometasone 0.1%, tretinoin 0.025% once daily for 6 weeks) ; TXA group with intralesional TXA as 5 ml ampoule containing 500 mg of the drug once weekly for 4 weeks	Topical for the first group, and injection for the second group	1 year	Digital photograph, MASI, and DLQI at the end of 6 weeks	Itching and erythema in over application site in topical group
Pradhan	2015	India	64/70	Group A 36 ± 8.932; Group B 35.7 ± 6.258	Group A: Triple combination alone (fluocinolone acetonide 0.01%, tretinoin 0.05%, and hydroquinone 2%) ; Group B: Oral TXA 250 mg twice daily and triple combination	Group A topical combination therapy; Group B oral TXA and topical combination therapy	6 months (from Jan 2013 to June 2013)	MASI, photograph	Erythema and burning in both groups. Hypopigmentation and oligomenorrhoea in group B
Xu	2017	China	22/25	mean age was 38.63 ± 7.11 years	Microneedle (MN) + TXA side vs TXA alone side	Topical TXA with or without MA	5 months (Jan–May 2015)	Visia, MI, EI, TEWL, hydration, skin surface roughness, elasticity	Just 1 patient was found to have dermatographism after MNs treatment; this disappeared after approximately 20 min, so the treatment was not stopped. Of note, this woman had pressure urticaria for the past 3 years.
Li	2020	China	26/30	25 to 52 years with an average of 37.43 ± 6.52	Basic group: Q-switch Nd: YAG 1064 nm Laser treatment only interval of 10 days and a total of 10 treatment; Combined group: Laser with topical TXA 2–4 drops twice a day for 12 weeks	Topical	10 months (Jan to Oct 2018)	MASI	Slight spur-like pain with laser, some had slight erythematous and allergic reaction with symptoms of slight red papulse and wheal

Figure 2. Forest plot showing comparison of MASI score change between post-treatment and pretreatment using tranexamic acid alone.

Figure 3. Forest plot showing the comparison of MASI score change between TA treatment and routine treatment alone.

Figure 4. Forest plot showing comparison of MASI score change between post-treatment and pretreatment using tranexamic acid as adjuvant.

Figure 5. Forest plot showing comparison of mMASI score change between post-treatment and pretreatment using tranexamic acid alone.

Figure 6. Forest plot showing comparison of mMASI score change between post-treatment and pretreatment using tranexamic acid as adjuvant.

Figure 7. Forest plot showing the comparison of mMASI score change between TA treatment and routine treatment alone.

Figure 8. Forest plot showing comparison of MI score change between post-treatment and pretreatment using tranexamic acid as adjuvant.

Figure 9. Forest plot showing the comparison of hemi-MASI score reduction between post- and pre- tranexamic acid treatment.

Table 2. Risk of bias.

	Bias arising from the randomization process (Adequate sequence generation?)	Bias due to deviations from intended interventions (Allocation concealment?)	Bias due to missing outcome data (Incomplete outcome data addressed?)	Bias in measurement of the outcome (Blinding?)	Bias in selection of the reported result (Free of selective reporting?)	Overall RoB
Kaur (2020)	Some concern	Some concern	Some concern	Some concern	low	high
Zou (2023)	Some concern	low	Some concern	low	low	high
Gamea (2020)	Some concern	Some concern	low	Some concern	low	high
Elkamshoushi (2021)	Some concern	Some concern	low	Some concern	low	high
Behrangi (2022)	low	low	low	low	low	low
Li (2022)	low	low	low	low	low	low
Basit (2021)	high	Some concern	high	low	low	high
Minni (2020)	low	low	low	low	low	low
Y Qu (2021)	low	Some concern	low	low	low	Some concerns
Badran (2021)	low	Some concern	low	Some concern	low	High
Karrabi (2020)	low	low	low	low	low	low
S. Zaky (2021)	Low	High	Low	Low	Low	High
Meymandi (2020)	Low	Some concern	Low	Low	Low	Some concerns
Shihab (2020)	Low	Low	Low	Low	Low	Low
Zhao (2019)	Low	Low	Low	Low	Low	Low
Tawfic (2019)	Low	Some concern	Low	Low	Low	Some concern
Khurana (2018)	Low	Some concern	Low	Some concern	Low	High
Shin (2012)	Low	High	Low	Low	Low	High
Krishnoji Rao (2022)	Low	Some concern	Low	Some concern	Low	High
Pradhan (2015)	High	High	Low	High	Some concern	High
Xu (2017)	Some concern	Some concern	Low	Low	Low	High
Li (2020)	Some concern	High	Low	Some concern	Low	High