Nonsteroidal anti-inflammatory drugs, especially aspirin, are linked to lower risk and better survival of hepatocellular carcinoma: a meta-analysis

Figures & data

Table 1 Characteristics of studies with HCC occurrence risk data

Studies	Study design	Country	NSAIDs	NSAID duration	RR (95%CI)	Controlled variables	Hepatitis virus infection
Coogan et al (2000)^Citation23	Case–control	USA	Salicylates, indoles, propionic acids, fenamates, and/or oxicams	At least 4 days/week for at least 3 months, at least 1 year before admission	Regular use initiated >1 year; 0.9 (0.3–2.9); Nonregular use; 1.6 (0.8–3.1)	Age, sex	NA
Lee et al (2017)^Citation24	Cohort, retrospective	Korea	Aspirin	38.5 months (IQR, 10.4–68.7 months)	0.26 (0.09–0.74)	Cirrhosis	HBV
Oh et al (2017)^Citation25	Retrospective	Korea	Aspirin	NA	0.27 (0.09–0.76) in propensity score-matched pairs; 0.27 (0.10–0.74) in time-varying Cox proportional analyses	Time-varying Cox proportional hazards model; propensity score-matching	NA
Petrick et al (2015)^Citation26	Cohort, prospective	USA	Aspirin, ibuprofen	NA	0.68 (0.57–0.81)	NA	42 (26.6%) were anti-HCV positive and five (3.2%) were HBsAg positive in HCC cases; 10 (2.5%) were anti-HCV positive and three (0.8%) were HBsAg positive in controls
Sahasrabuddhe et al (2012)^Citation16	Cohort, prospective	USA	Aspirin, ibuprofen, naproxen, ketoprofen, piroxicam, sulindac, indomethacin, nambumetone	NA	0.59 (0.45–0.77) for aspirin use; 1.08 (0.84–1.39) for non-aspirin NSAID use	NA	NA
Yang et al (2016)^Citation27	Nested case–control	UK	Aspirin, COX-2 inhibitors, propionic acid derivatives, fenamic acid derivatives, acetic acid derivatives, and enolic acid derivatives	Two or more NSAID prescriptions	1.11 (0.86–1.44) for aspirin use; 1.05 (0.88–1.24) for NSAIDs	Age, sex, general practice, and number of years in the CPRD prior to the case’s index date	HBV and/or HCV infection, 170 (14.2%) in HCC cases and 23 (0.5%) in controls

Abbreviations: CPRD, Clinical Practice Research Datalink; NSAID, nonsteroidal anti-inflammatory drug; COX-2, cyclooxygenase-2; NA, not available; HBV, hepatitis B virus; HCC, hepatocellular carcinoma.

Table 2 Baseline characteristics of studies with HCC survival outcomes

Studies	Study design	Country/area	HCC cases, n	NSAIDs	NSAID duration	Aspirin administration	Treatment regimen	Hepatitis virus infection	Controlled variables	Follow-up
Lee et al (2016)^Citation22	Cohort	Taiwan	9461	Aspirin	≥90 days	100 mg/day	Liver resection	HBV	Propensity score-matching	≥90 days
Li et al (2016)^Citation28	Case–control, retrospective	China	120	Aspirin	≥90 days	100 mg/day	TACE	HBV, n = 110; HCV, n = 5	Age, sex, date of HCC diagnosis, Child-Pugh score	12.0 (1.0–48.0) months
Takami et al (2016)^Citation29	RCT	Japan	232	Meloxicam	NA	None	Hepatic resection and/or microwave ablation	HBV, n = 24; HCV, n = 152	Age, sex, etiology	NA
Wu et al (2012)^Citation30	Cohort	Taiwan	4569	NA	At least 1 day per month on average	NA	Liver resection	HBV	NA	≥90 days
Yeh et al (2015)^Citation31	Cohort, retrospective	Taiwan	15,574	Conventional NSAIDs, aspirin, and COX-2 inhibitors	NA	NA	Liver resection	HBV, n = 8002; HCV, n = 4575	Age, sex, extent of liver resection, comorbidities and drug usage	1.8 (0.8–3.9) years

Abbreviations: HBV, hepatitis B virus; TACE, transarterial chemoembolization; NA, not available; RCT, randomized controlled trial.

Figure 1 Study selection process

Table 3 NOS quality assessment of included studies (case control studies and cohort studies)

Case–control studies		Coogan et al (2000)^Citation23	Yang et al (2016)^Citation27	Li et al (2016)^Citation28
Selection	Is the case definition adequate?	*	*	*
	Representativeness of the cases	*	*	*
	Selection of controls	*	*	*
	Definition of controls	*	*	*
Comparability	Comparability of cases and controls on the basis of the design or analysis	**	**	**
Exposure	Ascertainment of exposure	*	*	*
	Same method of ascertainment for cases and controls	*	*	*
	Non-response rate
NOS scores		8	8	8
Cohort studies		Sahasrabuddhe et al (2012)^Citation16	Lee et al (2017)^Citation24	Petrick et al (2015)^Citation26	Lee et al (2016)^Citation22	Wu et al (2012)^Citation30	Yeh et al (2015)^Citation31
Selection	Representativeness of the exposed cohort
	Selection of the non-exposed cohort	*	*	*	*	*	*
	Ascertainment of exposure	*	*	*	*	*	*
	Demonstration that outcome of interest was not present at start of study	*	*	*	*	*	*
Comparability	Comparability of cohorts on the basis of the design or analysis	*	**	**	**	*	**
Exposure	Assessment of outcome	*	*	*	*	*	*
	Was follow-up long enough for outcomes to occur	*	*	*	*	*	*
	Adequacy of follow-up of cohorts	*	*	*	*	*	*
NOS scores		7	8	8	8	7	8

Notes: A study can be awarded a maximum of one asterisk (*) for each numbered item within the Selection and Exposure categories. A maximum of two asterisks (**) can be given for Comparability.

Abbreviation: NOS, Newcastle–Ottawa scale.

Figure 2 NSAIDs, including aspirin use and HCC risk. The use of NSAIDs, including aspirin and HCC risk (A); publication bias of included studies by Begg’s (B) and Egger’s tests (C); and sensitivity analysis of included studies (D).

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

Figure 3 Subgroup analysis of links between NSAIDs and HCC risk based on NOS scores (A) and study design (B).

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

Figure 4 Aspirin use and HCC risk. Relationship between the use of aspirin and HCC risk (A); publication bias of included studies by Begg’s (B) and Egger’s tests (C); and sensitivity analysis of included studies (D).

Abbreviation: HCC, hepatocellular carcinoma.

Figure 5 Non-aspirin NSAIDs use and HCC risk. Relationship between the use of non-aspirin NSAIDs and HCC risk (A); publication bias of included studies by Begg’s (B) and Egger’s tests (C).

Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; HCC, hepatocellular carcinoma; COX-2, cyclooxygenase-2; PAD, propionic acid derivatives; FAD, fenamic acid derivatives; AAD, acetic acid derivatives; EAD, enolic acid (oxicam) derivatives

Figure 6 Relationship between NSAIDs use and disease-free survival (A) and overall survival (B) in HCC patients.

Abbreviation: HCC, hepatocellular carcinoma.

Figure 7 Two-year (A) and 4-year mortalities (B) of HCC patients who received aspirin treatment.

Abbreviation: HCC, hepatocellular carcinoma.

Figure 8 Bleeding risk of HCC patients who received aspirin treatment.

Abbreviation: HCC, hepatocellular carcinoma.

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