Table.

Sex Differences During (A) Acute Phase and (B) Chronic Phase in Bleeding Complications Post-PCI

(A) Authors, year, country	Name of study	Total patients	No. of women (%)	Presentation	Topics	Bleeding outcome	Female sex as an independent risk factor of bleeding	OR or HR [95% CI]
Hochholzer et al (2011) Multi-country29	TRITON-TIMI 38	13,420	25.6	ACS	Prasugrel (60 mg LD, 10 mg/day maintenance dose) vs. clopidogrel (300 mg LD, 75 mg/day maintenance dose)	TIMI major or minor bleeding (instrumented, traumatic and spontaneous) in hospital period and the follow-up period of the trial (6–15 months)	Yes	HR 1.77 [1.22–2.18]* *Majority (73%) of serious bleeding events occurred within the first 3 days
Hess et al (2014) USA†1	TRANSLATE-ACS	6,218	27.5	STEMI or NSTEMI	ADP-receptor inhibitor within the first 12 months after AMI	1-year risk of bleeding according to GUSTO and BARC definitions including patient-reported bleeding not brought to clinical attention	Yes	GUSTO; HR 1.32 [1.06–1.64]* GUSTO moderate or severe; HR 1.63 [1.19–2.24]* *Majority of GUSTO bleeding events observed early after PCI
Mehran et al (2010) Multi-country30	ACUITY + HORIZONS-AMI	17,421	28.7	ACS	Development of a practical risk score to predict the major bleeding	Non-CABG related major bleeding within 30 days	Yes	OR 2.32 [1.98–2.72]
Mehran et al (2020) Multi-country7	LEADERS FREE	2,432	30.3	ACS+CCS	BMS vs. polymer-free, biolimus A9-eluting drug-coated stent with 1-month DAPT	BARC 3 to 5 major bleeding within 30 days and 60 days	Yes	HR 2.22 [1.38–3.62] within 30 days HR 2.22 [1.42–3.47] within 60 days
						Vascular access site major bleeding	Yes	Unadjusted HR 4.65 [1.99–10.87]
Nakamura et al (2018) Japan34	PRASFIT-Practice I	732	23.5	ACS	Low-dose prasugrel (LD/maintenance dose, 20/3.75 mg) vs. standard-dose clopidogrel administration	TIMI major and minor bleeding (64.9±73.8 days)	Yes	NR
Nakamura et al (2019) Japan35	PRASFIT-Practice II	4,155	23.5	ACS+CCS	Low-dose prasugrel (LD/maintenance dose, 20/3.75 mg) vs. standard-dose clopidogrel administration	TIMI major or minor bleeding within 30 days	Yes	HR 3.84 [1.38–10.65]
Numasawa et al (2015) Japan39	JCD	10,220	20.6	ACS+CCS	Examination of sex differences in in-hospital clinical outcomes after PCI	Those requiring blood transfusion, prolonged hospital stay, or showing a decrease in hemoglobin >3.0 g/dL	Yes	OR 1.74 [1.36–2.24]
Numasawa et al (2017) Japan37	Japanese Nationwide Registry	43,239	26.2	NSTE-ACS	Investigation of sex-related differences in patients with NSTE-ACS who underwent PCI	In-hospital bleeding (requiring blood transfusion, including access-site and non-access-site bleeding)	Yes	OR 1.94 [1.35–2.79]
Ohya et al (2018) Japan59	Single-center cohort	992	25	ACS	Very low maintenance dose of prasugrel 2.5 mg in HBR patients vs. low dose 3.5 mg	In-hospital BARC 3 and 5 major bleeding	No	NR
Saito et al (2015) Japan33	PRASFIT Trial	1,802	25.3	ACS+CCS	Low-dose prasugrel (LD/maintenance dose, 20/3.75 mg) vs. standard- dose clopidogrel administration	Periprocedural TIMI major and minor bleeding within 3 days	Yes (ACS)	HR 2.39 [1.19–4.81]
						Periprocedural TIMI major and minor bleeding within 3 days	No (Elective)	NR
Shah et al (2021) Multi-country31	Global meta-analysis of 56 studies	705,098	31	STEMI	Evaluation of sex-based discrepancies in clinical outcomes and identifying primary driving factors	Definition varied by study, generally included bleeding requiring transfusion or repeat procedure	Yes	OR 1.74 [1.56–1.96]
Shoji et al (2020) Japan36	JCD-KiCS registry	1,802	23.1	ACS	Low-dose prasugrel vs. standard-dose clopidogrel administration	TIMI major or minor bleeding within 72 h after PCI	Yes	OR 3.84 [1.05–14.0]
Simonsson et al (2019) Sweden32	SWEDEHEART registry	97,597	35.1	ACS	Development and validation of a new in-hospital bleeding risk score	In-hospital non-CABG major bleeding defined as fatal, intracranial or bleeding requiring blood transfusion or surgery (including endoscopic and vascular intervention)	Yes	NR
Venetsanos et al (2017)†2 Multi-country	ATLANTIC trial	1,862	20	STEMI	Prehospital vs. in-hospital administration of 180 mg ticagrelor	TIMI or BARC bleeding at 30 days	No	TIMI major; HR 1.28 [0.47–3.48] BARC type 3–5; HR 1.45 [0.72–2.91]
Widimsky et al (2015) Multi-country28	ACCOAST	4,033	27.5	NSTEMI	(A) 30 mg prasugrel LD followed by CAG with an additional 30 mg prasugrel at the time of PCI or (B) placebo LD followed by 60 mg prasugrel at the time of PCI	TIMI major bleeding through 7 days	Yes	HR 2.57 [1.32–5.00]
(B) Authors, year, country	Name of study	Total patients	No. of women (%)	Presentation	Topics	Bleeding outcome	Female sex as an independent risk factor of bleeding
Baber et al (2016) USA and Europe50	PARIS (External validation of each score was performed in the ADAPT-DES registry)	4,190	25.5	ACS+CCS	Development of risk scores of major bleeding	BARC 2 or 5 bleeding within 2 years	No
Chichareon et al (2020) Multi-country45	GLOBAL LEADERS	15,968	23.3	ACS+CCS	1-month DAPT+23-month ticagrelor monotherapy vs. 12-month DAPT+12-month aspirin monotherapy after PCI	BARC 3 or 5 bleeding at 1 year and 2 years	No
Généreux et al (2015) USA and Europe55	ADAPT-DES	8,582	25.9	ACS+CCS	Incidence, predictors, and prognostic impact of post- discharge bleeding after PCI with DES	TIMI major or minor bleed; GUSTO severe or moderate bleed; ACUITY major bleed at (<30 days), late (30 days to <1 year), or very late (1–2 years)	No
Grodecki et al (2018) Multi-country47	BleeMACS	13,727	23	ACS	Post-discharge bleeding among patients on DAPT after ACS	In-hospital bleeding defined as any TIMI major or minor bleeding, or any GUSTO moderate or severe bleeding, or any BARC 3 bleeding	No
Hess et al (2014)†1 US	TRANSLATE-ACS	6,218	27.5	STEMI or NSTEMI	ADP-receptor inhibitor within the first 12 months after AMI	1-year risk of bleeding according to GUSTO and BARC definitions including patient-reported bleeding not brought to clinical attention	Yes BARC 1; IRR 1.42 [1.26–1.70] BARC 2; IRR 1.72 [1.36–2.14] No BARC ≥3: IRR 1.14 [0.75–1.75]
Husted et al (2014) Multi-country51	PLATO	18,624	28.3	ACS	Ticagrelor vs. clopidogrel	Non-CABG-related study criteria major bleeding at 7 days, 7–240 days, after day 240	No
Kodaira et al (2021) Japan8	JCD-KiCS registry	2,494	22	ACS	Investigation of the differences between sexes for long-term bleeding complication requiring readmission in East Asia	Any bleeding event requiring readmission during 2-year follow-up	Yes HR 1.826–1.895 [1.107–3.093]
Lee et al (2018) Multi-country43	CURE, COMMIT, CLARITY-TIMI 28, TRITON-TIMI 38, PLATO, CHANCE, TRILOGY ACS, SPS3 and SOCRATES	109,570	30	ACS	Newer P2Y12 inhibitors (ticagrelor and prasugrel) vs. clopidogrel	Defined by the individual studies that used either TIMI or GUSTO, or trial specific criteria	No
Lee et al (2014) Korea53	DES LATE	5,045	30.7	ACS+CCS	12-month DAPT after DES implantation followed by aspirin monotherapy vs. further 24-month DAPT	TIMI major bleeding through 48 months	No
Lee et al (2018) Korea52	KAMIR-NIH	13,104	24.1	AMI	12-month DAPT after DES implantation with aspirin and clopidogrel (75 mg/day), ticagrelor (90 mg twice daily) or prasugrel (10 mg/day)	TIMI major and minor bleeding at 1 year after PCI	No
Matteau et al (2015) Multi-country56	PROTECT + PROTECT US	9,410	27	ACS+CCS	Predictor of bleeding and ischemic events beyond 1 year	GUSTO moderate/severe bleeding (median follow-up duration was 4.1 years)	No
Mehran et al (2020) Multi-country7	LEADERS FREE	2,432	30	ACS+CCS	BMS vs. polymer-free, biolimus A9-eluting drug-coated stent with 1-month DAPT	Major bleeding (BARC 3–5) and major or minor bleeding (BARC 2–5) through 780 days	No
Nakamura et al (2019) Japan38	PRASFIT-Practice II	4,155	23.5	ACS+CCS	Low-dose prasugrel (LD/maintenance dose, 20/3.75 mg) vs. standard- dose clopidogrel administration	TIMI major or minor bleeding within 1 year (after 31 days)	No
Natsuaki et al (2018) Japan40	CREDO-Kyoto registry cohort 2 vs. RESET and NEXT	9,447	25	ACS+CCS	Development of CREDO-Kyoto thrombotic and bleeding risk scores	GUSTO moderate or severe bleeding through 3 years excluding in-hospital bleeding	No
Sawaya et al (2017) Multi-country48	EXCELLENT, OPTIMIZE, PRODIGY, RESET, SECURITY and ITALIC PLUS	11,473	30	ACS+CCS	Short vs. long-term DAPT after DES implantation	TIMI bleeding in 4 trials, the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE) criteria and BARC bleeding at 1 year	No
Schreuder et al (2020) Multi-country49	DISPERSE-2, PLATO, PRASFIT-ACS, TRILOGY ACS and TRITON-TIMI 38	43,990	29.6	ACS	DAPT with potent P2Y12 inhibitor vs. clopidogrel after PCI	Major bleeding (TIMI criteria 1, BARC 2, 3, and 5 or GUSTO bleeding criteria 1) and minor bleeding (TIMI criteria 2) with a median follow-up time of 1.06 years	No
Spirito et al (2021) Switzerland42	Bern PCI Registry	16,821	26	ACS+CCS	Assessment of the performance of ARC-HBR criteria separately in women and men	1. Composite of BARC 3 or 5, further stratified into non- access-site and access-site related bleeding at 1 year 2. BARC 2, 3 or 5 bleeding, TIMI and GUSTO bleeding	No (overall) Nearly Yes (access site by TFI; HR 1.99 [0.96–4.11] P=0.063) No (access site by TRI)
Yu et al (2016)†3 USA and Europe	PARIS	5,018	25.5	ACS+CCS	Investigation of the patterns and impact of DAPT cessation in women and men	BARC >3 within 2 years	Yes HR 1.39 [1.02–1.89] P=0.04* *Hb value and renal function data were missing and not adjusted
Vogel et al (2021) Multi-country54	TWILIGHT	9,006	23.9	ACS+CCS	Ticagrelor with vs. without aspirin from the 3rd month after PCI	Primary; BARC 2, 3, or 5 bleeding at 1 year Secondary; BARC 3 or 5 bleeding, TIMI major bleeding, GUSTO moderate, severe, or life-threatening bleeding or major bleeding as defined by ISTH at 1 year	No
Xanthopoulou et al (2017)†4 Greece	GRAPE Registry	2,047	17.6	ACS	1-year DAPT after PCI	Every type of BARC bleeding at 1 year	No (BARC 2–5) Yes (BARC 1; HR 1.58 [1.27–1.96])

Data derived from meta-analyses, randomized clinical trials, and registries with focus on sex differences. Studies are presented in alphabetical order of author.^†1–4 Citation details are provided in Supplementary Appendix 2. ACS, acute coronary syndrome; ADP, adenine diphosphate; AMI, acute myocardial infarction; ARC-HBR, The Academic Research Consortium for High Bleeding Risk; BARC, Bleeding Academic Research Consortium; BMS, bare metal stent; CABG, coronary artery bypass graft; CAG, coronary angiography; CCS, chronic coronary syndrome; CI, confidence interval; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; Hb, hemoglobin; HR, hazard ratio; IRR, incidence rate ratio; ISTH, International Society of Thrombosis or Hemostasis; LD, loading dose; NR, not recorded; NSTE-ACS, non-ST-elevation-acute coronary syndrome; NSTEMI, non-ST-elevation myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; REPLACE, Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events; STEMI, ST-elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction; TRI, transradial intervention.