The effects of nonsteroidal anti-inflammatory drugs in the incident and recurrent risk of hepatocellular carcinoma: a meta-analysis

Figures & data

Figure 1 Flow chart of search strategy and study selection.

Abbreviation: CI, confidence interval.

Table 1 Baseline characteristics for studies included in meta-analysis

Study	Area	Design	Study period	Follow-up (years)	Information source	Drug type	Definition of user	Median age	Total size	Cases size	Adjusted variables	NOS
HCC incidence
Coogan et al^Citation19	America	CC	1977–1998	–	Questionnaire	NSAIDs	Regular use ≥1 y	50–70	5,833	51	Age, sex, interview year, center, race, religion, smoking, family education, drinking	7
Chiu et al^Citation20	Taiwan	CC	1996–2008	NR	Database	Aspirin, NSAIDs	≥1 prescriptiona	66.08/65.92	1,166	1,166	None	6
Jacobs et al^Citation21	America	Cohort	1992–2008	Up to 16	Questionnaire	Aspirin	Regular use	60	58,848/41,291	70/48	Age, sex, race, education, smoking, BMI, physical activity, heart disease, stroke	8
Sahasrabuddhe et al^Citation22	America	Cohort	1995–2008	17	Questionnaire	Aspirin, non-aspirin NSAIDs	Any use	62.8	260,555/39,949	199/51	Age, sex, race, BMI, smoking, drinking, diabetes	8
Petrick et al^Citation23	America	Cohort	1985–2010	11.9	Questionnaire	Aspirin, non-aspirin NSAIDs	Any use	≥40	477,470/606,663	315/364	Age, sex, race, cohort, BMI, smoking, drinking, diabetes	8
Yang et al^Citation24	UK	CC	1988–2011	NR	Database	Aspirin, non-aspirin NSAIDs	≥2 prescriptions	67.2/67.0	4,640	1,195	BMI, smoking, alcohol disorders, HBV, HCV, diabetes, other NSAIDs, antidiabetic medications, statins	7
Kim et al^Citation25	Korea	Nested CC	2002–2013	NR	Database	Aspirin	Any use	≥40	1,374	229	None	7
HCC recurrence
Wu et al^Citation26	Taiwan	Cohort	2003–2010	2.23	Database	NSAIDs	Any use	54.5	2,452/2,117	939/932	Age, sex, resection extent, liver cirrhosis, diabetes, use of statins, metformin	9
Yeh et al^Citation27	Taiwan	Cohort	1997–2010	2.9	Database	Aspirin, non-aspirin NSAIDs	Any use	58.3	9,811/5,763	7,229	Age, sex, HBV, HCV, cirrhosis, diabetes, hypertension, stains, metformin	8
Takami et al^Citation28	Japan	CC	2008–2011	NR	Database	Non-aspirin NSAIDs	15 mg daily	69.5/70.7	111/113	62/64	None	7
Lee et al^Citation29	Taiwan	Cohort	1997–2011	3.5 4.3	Database	Aspirin, non-aspirin NSAIDs	Any use	62.3/62.2	442/1,786 728/1,482	215/906 404/717	Age, sex, liver cirrhosis, diabetes, coronary artery disease, cerebral vascular accidents, peptic ulcers, and use of nucleoside analogs, statins, metformin	9
HCC mortality
Jacobs et al^Citation21	America	Cohort	1992–2008	Up to 16	Questionnaire	Aspirin	Regular use	60	58,848/41,291	70/48	Age, sex, race, education, smoking, BMI, physical activity, heart disease, stroke	8
Li et al^Citation30	China	Cohort	2008–2013	2.1	Database	Aspirin	Full dose use	67.2/66.0	92	46	Age, gender, total bilirubin and GGT levels, PLT, cirrhosis, tumor size and number, tumor vascular invasion, treatment	8

Note:

a One or more NSAIDs prescription(s) recorded from the database or questionnaire.

Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; HCC, hepatocellular carcinoma; CC, case-control; RCT, randomized clinical trial; NR, not reported; BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; NOS, Newcastle–Ottawa Scale; GGT, gamma-glutamyl transferase; PLT, platelet count.

Figure 2 Forest plots of meta-analysis on the use of NSAIDs and risk of HCC incidence (A) and recurrence (B), stratified according to the categories of NSAIDs.

Note: Weights are from random-effects analysis.
Abbreviations: HCC, hepatocellular carcinoma; NSAIDs, nonsteroidal anti-inflammatory drugs; HR, hazard ratio; CI, confidence interval.

Table 2 Subgroup analysis and meta-regression analysis for studies that assessed the preventive effect of NSAIDs use in HCC incident risk

Covariates	Subgroup	No of studies	HR (95% CI)		Heterogeneity		Subgrouped		Meta-regression
			Random-effects model	Fixed-effects model	P-value	I^2	Q value	P-value	Crude P-value	Adjusted P-value
Overall		11	0.81 (0.69–0.94)	0.83 (0.77–0.90)	0.001	66.6
NSAIDs categories	Aspirin	5	0.77 (0.58–1.02)	0.78 (0.69–0.89)	0.001	77.8	3.52	0.172	0.647	–
	Non-aspirin	3	0.81 (0.70–0.94)	0.81 (0.70–0.94)	0.696	0
	All NSAIDs	3	0.84 (0.56–1.28)	0.94 (0.81–1.09)	0.022	73.9
Information source	Database	5	0.93 (0.79–1.09)	0.92 (0.84–1.02)	0.046	58.8	14.57	<0.001	0.025	1.000
	Questionnaire	6	0.66 (0.56–0.78)	0.66 (0.57–0.76)	0.343	11.3
Publication year	Before 2013	6	0.76 (0.63–0.93)	0.77 (0.68–0.87)	0.081	49.0	2.89	0.089	0.505	–
	After 2013	5	0.85 (0.66–1.10)	0.89 (0.80–0.99)	0.002	76.8
Region	Asia	3	0.82 (0.71–0.94)	0.81 (0.71–0.93)	0.344	6.30	0.17	0.685	0.829	–
	America/Europe	8	0.79 (0.63–1.00)	0.84 (0.76–0.93)	<0.001	74.6
Design	Cohort	5	0.66 (0.55–0.79)	0.65 (0.56–0.76)	0.255	24.9	14.87	<0.001	0.023	0.731
	Others	6	0.93 (0.80–1.08)	0.92 (0.84–1.02)	0.084	48.5
Adjusted confounders	No	3	0.82 (0.71–0.94)	0.81 (0.71–0.93)	0.344	6.30	0.17	0.685	0.829	–
	Yes	8	0.79 (0.63–1.00)	0.84 (0.76–0.93)	<0.001	74.6

Note: Bold values indicate statistical significance (P<0.05).

Abbreviations: HCC, hepatocellular carcinoma; NSAIDs, nonsteroidal anti-inflammatory drugs; HR, hazard ratio; CI, confidence interval.

Figure 3 Begg’s funnel plots and Egger’s funnel plots of studies that assessed the effects of NSAIDs use in risk of HCC incidence (A, B) and recurrence (C, D).

Abbreviations: HCC, hepatocellular carcinoma; NSAIDs, nonsteroidal anti-inflammatory drugs; HR, hazard ratio.

Figure S1 Galbraith’s plot of studies that assessed the preventive effect of NSAIDs use in risk of HCC incidence.

Notes: ^*Aspirin; ^#non-aspirin NSAIDs; ^&all NSAIDs.

Abbreviations: HCC, hepatocellular carcinoma; NSAIDs, nonsteroidal anti-inflammatory drugs.

Figure S2 Forest plots of the meta-analysis on the association between NSAIDs and risk of HCC incidence after removal of the outliers of the heterogeneity.

Note: Weights are from random-effects analysis.

Abbreviations: HCC, hepatocellular carcinoma; NSAIDs, nonsteroidal anti-inflammatory drugs; HR, hazard ratio; CI, confidence interval.

Figure S3 Influence analysis of studies that assessed the effects of NSAIDs use in the risk of HCC incidence (A) and recurrence (B).

Abbreviations: HCC, hepatocellular carcinoma; NSAIDs, nonsteroidal anti-inflammatory drugs; CI, confidence interval.

CooganPFRosenbergLPalmerJRNonsteroidal anti-inflammatory drugs and risk of digestive cancers at sites other than the large bowelCancer Epidemiol Biomarkers Prev20009111912310667472

 PubMed Web of Science ®Google Scholar

ChiuHFHoSCChenCCYangCYStatin use and the risk of liver cancer: a population-based case-control studyAm J Gastroenterol2011106589489821157439

 PubMed Web of Science ®Google Scholar

JacobsEJNewtonCCGapsturSMThunMJDaily aspirin use and cancer mortality in a large US cohortJ Natl Cancer Inst2012104161208121722888140

 PubMed Web of Science ®Google Scholar

SahasrabuddheVVGunjaMZGraubardBINonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinomaJ Natl Cancer Inst2012104231808181423197492

 PubMedGoogle Scholar

PetrickJLSahasrabuddheVVChanATNSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the liver cancer pooling projectCancer Prev Res (Phila)20158121156116226391917

 PubMed Web of Science ®Google Scholar

YangBPetrickJLChenJAssociations of NSAID and paracetamol use with risk of primary liver cancer in the Clinical Practice Research DatalinkCancer Epidemiol20164310511127420633

 PubMed Web of Science ®Google Scholar

KimGJangSYHanEEffect of statin on hepatocellular carcinoma in patients with type 2 diabetes: a nationwide nested case-control studyInt J Cancer2017140479880627861855

 PubMed Web of Science ®Google Scholar

WuCYChenYJHoHJAssociation between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resectionJAMA2012308181906191423162861

 PubMed Web of Science ®Google Scholar

YehCCLinJTJengLBNonsteroidal anti-inflammatory drugs are associated with reduced risk of early hepatocellular carcinoma recurrence after curative liver resection: a nationwide cohort studyAnn Surg2015261352152624950265

 PubMed Web of Science ®Google Scholar

TakamiYEguchiSTateishiMA randomised controlled trial of meloxicam, a Cox-2 inhibitor, to prevent hepatocellular carcinoma recurrence after initial curative treatmentHepatol Int201610579980626846471

 PubMed Web of Science ®Google Scholar

LeePCYehCMHuYWAntiplatelet therapy is associated with a better prognosis for patients with hepatitis B virus-related hepatocellular carcinoma after liver resectionAnn Surg Oncol201623Suppl 587488327541812

 PubMedGoogle Scholar

LiJHWangYXieXYAspirin in combination with TACE in treatment of unresectable HCC: a matched-pairs analysisAm J Cancer Res2016692109211627725915

 PubMed Web of Science ®Google Scholar