JNCI J Natl Cancer Inst (2015) 107(4): djv009 doi:10.1093/jnci/djv009 First published online February 25, 2015 Article
article
Statin Use and Risk for Primary Liver Cancer in the Clinical Practice Research Datalink Katherine A. McGlynn, Katrina Hagberg, Jie Chen, Barry I. Graubard, W. Thomas London, Susan Jick, Vikrant V. Sahasrabuddhe Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (KAM, JC, BIG, VVS); Boston Collaborative Drug Surveillance Program and Boston University School of Public Health, Lexington, MA (KH, SJ); Fox Chase Cancer Center, Philadelphia, PA (WTL); Hepatitis B Foundation, Doylestown, PA (WTL); Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (VVS). Correspondence to: Katherine A. McGlynn, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892 (e-mail: mcglynnk@ mail.nih.gov).
Abstract Background: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely prescribed to reduce cholesterol levels. Studies have suggested that statins are associated with reduced risk for liver cancer, but much of the evidence is from regions of the world with high liver cancer incidence rates. The current study examined the statins– liver cancer relationship in a low-rate region and examined the effects of preexisting liver disease and diabetes on that association.
Results: In total, 1195 persons with primary liver cancer were matched to 4640 control patients. Statin use was associated with a statistically significantly reduced risk for liver cancer (ORadj = 0.55, 95% CI = 0.45 to 0.69), especially among current users (ORadj = 0.53, 95% CI = 0.42 to 0.66). The reduced risk was statistically significant in the presence (ORadj = 0.32, 95% CI = 0.17 to 0.57) and absence of liver disease (ORadj = 0.65, 95% CI = 0.52 to 0.81) and in the presence (ORadj = 0.30, 95% CI = 0.21 to 0.42) and absence of diabetes (ORadj = 0.66, 95% CI = 0.51 to 0.85). Conclusions: In the current study in a low-rate area, statin use was associated with a statistically significantly reduced risk for liver cancer overall. Risk was particularly reduced among persons with liver disease and persons with diabetes, suggesting that statin use may be especially beneficial in persons at elevated risk for liver cancer.
Primary liver cancer is the sixth most commonly occurring cancer in the world and because of a very poor prognosis, the second most frequent cause of cancer mortality (1). In the majority of high-rate liver cancer areas, mainly in Asia and Africa, the most common risk factors are chronic hepatitis B virus (HBV) infection and aflatoxin contamination of foodstuffs. In contrast, in low-rate areas, such as Europe and North America, the
most common risk factors are excessive alcohol consumption, diabetes/obesity, hepatitis C virus (HCV) infection, and nonalcoholic fatty liver disease (NAFLD) (2). Incidence rates have been increasing in many low-rate regions (3), likely because of the increased prevalence of diabetes, obesity, NAFLD and HCV infection (4). Predictions of further increases in incidence (5) underscore the need to identify effective prevention strategies.
Received: October 7, 2014; Revised: November 10, 2014; Accepted: January 7, 2015 Published by Oxford University Press 2015. This work is written by © US Government employee(s) and is in the public domain in the US.
1 of 10
article
Methods: A nested case-control study was conducted within the United Kingdom’s Clinical Practice Research Datalink (CPRD). Persons diagnosed with primary liver cancer between 1988 and 2011 were matched to controls at a four-to-one ratio. Matches stratified on liver disease and on diabetes were also completed. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations of statins with liver cancer were estimated using conditional logistic regression.
2 of 10 | JNCI J Natl Cancer Inst, 2015, Vol. 107, No. 4
Statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co-A) reductase inhibitors) are commonly used cholesterol-lowering medications that have demonstrated effectiveness in the primary and secondary prevention of cardiovascular disease (6). Although statins were initially suspected of increasing the risk of cancer (7), subsequent examination failed to support those concerns (8,9) and raised the possibility that statins could have anticarcinogenic effects (10) related to inhibited angiogenesis, enhanced apoptosis, and metastasis inhibition (11). A potential for liver cancer prevention is particularly indicated, as the liver, the target organ for statins, sequesters the majority of the drug. Promising evidence that statins may decrease risk of liver cancer has been reported in observational studies, many of which were conducted in Taiwan (12–16). The results of studies from areas with low rates of liver cancer, however, have been less consistent (17–22). Furthermore, there has been debate about whether previously reported statins–liver cancer associations are because of biased prescribing patterns (23). Although rare, statin-related hepatotoxicity is not unknown (24), thus there may be a reluctance to prescribe statins to persons with preexisting liver disease. The extent to which prescribing bias has influenced the reported inverse association of statins and liver cancer is unclear. Stratification on liver disease in several studies (13,17) has provided some information on the topic, but more data are needed. More data are also needed on the effect of statins among persons with the most common risk factors, such as diabetes, in low-rate areas. Thus the current study sought to examine, in a low-rate area, the statins–liver cancer relationship overall and among persons with liver disease and diabetes.
Methods
article
A nested case-control study was conducted within the Clinical Practice Research Datalink (CPRD) of the United Kingdom (UK). The CPRD is a large, population-based, automated medical records database that contains information on approximately 8.5% of the UK population. The UK National Health Service (NHS) provides universal coverage, therefore no segment of the population is excluded from the CPRD and the age and gender distributions are representative of the general UK population (25). General practitioners (GPs) who contribute to the CPRD provide the data in an anonymous format for research purposes. All GPs have been trained to record demographic data, medical information, details of hospital stays, and deaths. Diagnoses, physical findings, symptoms, and administrative events, such as referrals to specialists, are recorded using Read codes rather than International Classification of Diseases (ICD) codes. Detailed information is available for all medications prescribed. Several studies have examined the validity of the information recorded in the CPRD and indicate that the data are reasonably complete and accurate with regard to clinical illnesses diagnosed either by the GP or a specialist (26,27). Specifically, it has been demonstrated that more than 90% of information from manual medical records gets recorded electronically (26,27) and approximately 95% of all electronically identified primary cancers are confirmed as incident cancers (28). The base population for the current study included all persons between the ages of 10 and 90 years in the CPRD between the years 1988 and 2011. The study
was approved by the National Institutes of Health Human Research Protection Program.
Case Patients and Control Patients The eligibility criteria for case patients were: 1) first-time diagnosis of primary liver cancer (Read codes B150300, B150z00, B152.00), 2) no prior diagnosis of the cancers most likely to metastasize to the liver: lung, stomach, breast, colon, or pancreatic cancer, and 3) no diagnosis of any other cancer (except nonmelanoma skin cancer) in the three years prior to the index date. The index date was defined as the date of liver cancer diagnosis minus one year. All case patients were required to have at least two years of recorded activity in the CPRD prior to the index date. Persons with any code for liver metastases were excluded from the study. Of the 1195 case patients included in the study, the majority (n = 1036, 86.7%) had supporting clinical codes that indicated presence of liver cancer such as diagnostic exams (biopsies), treatment (chemotherapy, radiotherapy, surgery), palliative care, and referrals to specialty care. The minority (n = 159, 13.3%) who had no supporting clinical codes were often persons who died shortly after the liver cancer diagnosis, prior to treatment, or persons whose cancer diagnosis was recorded at the time of death. Control patients were matched to case patients at a fourto-one ratio on age (same year of birth as case), sex, general practice, index date (one year prior to case’s diagnosis date), and number of years in the CPRD prior to the case’s index date. Control patients had to be free of any cancer (except nonmelanoma skin cancer) prior to the index date of the matched case patient and were required to have at least two years of history in the CPRD prior to the case’s index date. Only three eligible control patients could be identified for 140 of the case patients, thus 1055 case patients have four control patients and 130 case patients have only three control patients. Three separate case-control matches were completed for the study. For the full analysis, control patients were matched to all 1195 liver cancer case patients. For the chronic liver disease-matched analysis, control patients with liver disease were matched to the 170 case patients with liver disease, and control patients without liver disease were matched to the 1025 case patients without liver disease. For the diabetes-matched analysis, control patients with diabetes were matched to the 346 case patients with diabetes, and control patients without diabetes were matched to the 849 case patients without diabetes. The inclusion and exclusion criteria were the same across all three matches.
Exposure to Statins For all analyses, statin use was defined as having two or more statin prescriptions recorded prior to the index date of the case patients and control patients. Nonuse was defined as one or no statin prescriptions prior to the index date. Current statin use was defined as use that ended within one year prior to the index date, while past use was defined as use that ended more than one year prior to the index date. Exposure to statins was examined both in relation to number of prescriptions dispensed and in relation to cumulative dose, which was defined as number of pills times the dose per pill.
In addition to analyzing statin exposure as a single entity, specific statins (atorvastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, cerivastatin, and the combination of ezetimibe with simvastatin) were examined individually. Lovastatin, a common statin in other countries, is not marketed in the United Kingdom.
Statistical Analysis Prior to initiating the statistical analysis, the distributions of all covariables were examined to ensure there were no outlying values. For variables with missing values, “unknown” categories were created for the analyses. Interactions between the major matching factors and covariables and statin use were also examined. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression to assess crude and adjusted risk estimates for the relationship of statin use to liver cancer. Wald Chi-square tests were calculated to determine whether trends across categories were statistically significant. Known liver cancer risk factors for which adjustment was made in the analysis included: body mass index (BMI), smoking, alcohol-related disorders, HBV and/or HCV infection, diabetes, and rare metabolic disorders (hemochromatosis, Wilsons Disease, alpha-1 antitrypsin deficiency, porphyrias). As some evidence has suggested that aspirin (29) and antidiabetic medications (30) might be related to liver cancer risk, adjustment was made for those exposures. In addition, adjustment was made for paracetamol use because of a statistically significantly increased risk noted in the univariate analysis. In addition to the full match, the liver disease match, and the diabetes match, two sensitivity analyses were conducted. The first analysis was restricted to case patients with clinical codes for treatment of liver cancer (eg, surgery, chemotherapy, or palliative care) and their matched control patients. The second analysis used an index date of two years prior to the case’s date of diagnosis rather than one year. All statistical tests were two-sided. P values of less than .05 were considered statistically significant.
Results Table 1 displays the characteristics of the 1195 liver cancer case patients and 4640 control patients included in the overall analysis and the univariate analysis of known risk factors. Case patients and control patients were matched on index year, age at index year, sex, and length of enrollment in CPRD prior to index date, thus there were no differences in these factors. Not unexpectedly, case patients were statistically significantly more likely than control patients to be obese (BMI ≥ 30), to be current or ex-smokers, have an alcohol-related condition, be infected with HBV or HCV, have chronic liver disease, use paracetamol, have a rare metabolic disorder, and to have type I or type II diabetes. Table 2 displays the relationship of statin use to liver cancer in the overall analysis. Statin use was associated with a statistically significantly reduced risk (ORadj = 0.55, 95% CI = 0.45 to 0.69) of liver cancer. There was a statistically significant dose-response relationship between risk and cumulative daily dose of statins (P < .001), which was mirrored by the relationship with number of statin prescriptions
(P < .001). When the data were stratified by recency of use, the statistically significant dose-dependent relationship was restricted to current users (ORadj = 0.53, 95% CI = 0.42 to 0.66). Analysis by type of statin found statistically significant inverse associations for the two most commonly prescribed statins, simvastatin (ORadj= 0.57, 95% CI = 0.45 to 0.74) and atorvastatin (ORadj = 0.53, 95% CI = 0.38 to 0.75), as well as for rosuvastatin (ORadj = 0.42, 95% CI = 0.19 to 0.97). The odds ratios for the other statins were of similar magnitude as the ORs for atorvastatin, simvastatin, and rosuvastatin, but did not attain statistical significance. Table 3 displays the relationship of statin use and liver cancer among persons with and without chronic liver disease. Among persons with chronic liver disease, statin use was statistically significantly associated with reduced risk (ORadj= 0.32, 95% CI = 0.17 to 0.57) in a dose-response manner such that risk declined with increasing cumulative daily dose of statins (P < .001). The reduced risk was more evident among current (OR = 0.30, 95% CI = 0.16 to 0.58) than past (OR = 0.38, 95% CI = 0.12 to 1.18) users, although the numbers of past users were small. Among the persons without chronic liver disease, statin use was also statistically significantly associated with reduced liver cancer risk (ORadj = 0.65, 95% CI = 0.52 to 0.81), with risk declining as cumulative dose increased (P < .001). The association was seen among current (OR = 0.62, 95% CI = 0.50 to 0.78) but not among past statin users (OR = 0.92, 95% CI = 0.57 to 1.47). Table 4 displays the relationship of statins and liver cancer among persons with and without diabetes. Among persons with diabetes, statin use was statistically significantly associated with reduced risk (ORadj = 0.30, 95% CI = 0.21 to 0.42), with decreasing risk associated with increasing cumulative dose (P < .001). The association was seen both among current (ORadj = 0.29, 95% CI = 0.21 to 0.41) and past users (OR = 0.45, 95% CI = 0.21 to 0.95). Statin use was also statistically significantly associated with reduced risk among persons without diabetes (OR = 0.66, 95% CI = 0.51 to 0.85), which was evident among current (OR = 0.60, 95%CI 0.46 to 0.79) but not among past users (OR = 1.23, 95% CI = 0.69 to 2.19). The results of the sensitivity analysis restricted to case patients with supporting clinical codes (86.7%) and their control patients did not differ from that in the overall analysis (OR = 0.66, 95% CI = 0.53 to 0.80) (data not shown). Similarly, the sensitivity analysis that was based on an index date of two years prior to the case’s diagnosis date rather than one year resulted in findings very similar to the main analysis (OR = 0.59, 95% CI = 0.48 to 0.72) (data not shown). The interaction analysis of covariables with statin use identified no statistically significant interaction effects.
Discussion In the current study conducted in a low-rate region, statin use was associated with a statistically significantly reduced risk of liver cancer. The relationship was statistically significant in particular among current statin users. The reduced risks between atorvastatin, simvastatin, and rosuvastatin and liver cancer were statistically significant, while the inverse associations of pravastatin, fluvastatin, and cerivastatin did not attain statistical significance. Among persons at elevated risk of liver cancer, persons with liver disease, and persons with diabetes,
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Table 1. Characteristics of case patients and control patients and univariate effects on liver cancer risk, CPRD
Characteristic
article
Index year 1991–1994 1995–1999 2000–2004 2005–2010 Years in CPRD prior to index date Mean ± SD Age at index date, y
article
Statin Use and Risk for Primary Liver Cancer in the Clinical Practice Research Datalink Katherine A. McGlynn, Katrina Hagberg, Jie Chen, Barry I. Graubard, W. Thomas London, Susan Jick, Vikrant V. Sahasrabuddhe Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (KAM, JC, BIG, VVS); Boston Collaborative Drug Surveillance Program and Boston University School of Public Health, Lexington, MA (KH, SJ); Fox Chase Cancer Center, Philadelphia, PA (WTL); Hepatitis B Foundation, Doylestown, PA (WTL); Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (VVS). Correspondence to: Katherine A. McGlynn, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892 (e-mail: mcglynnk@ mail.nih.gov).
Abstract Background: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely prescribed to reduce cholesterol levels. Studies have suggested that statins are associated with reduced risk for liver cancer, but much of the evidence is from regions of the world with high liver cancer incidence rates. The current study examined the statins– liver cancer relationship in a low-rate region and examined the effects of preexisting liver disease and diabetes on that association.
Results: In total, 1195 persons with primary liver cancer were matched to 4640 control patients. Statin use was associated with a statistically significantly reduced risk for liver cancer (ORadj = 0.55, 95% CI = 0.45 to 0.69), especially among current users (ORadj = 0.53, 95% CI = 0.42 to 0.66). The reduced risk was statistically significant in the presence (ORadj = 0.32, 95% CI = 0.17 to 0.57) and absence of liver disease (ORadj = 0.65, 95% CI = 0.52 to 0.81) and in the presence (ORadj = 0.30, 95% CI = 0.21 to 0.42) and absence of diabetes (ORadj = 0.66, 95% CI = 0.51 to 0.85). Conclusions: In the current study in a low-rate area, statin use was associated with a statistically significantly reduced risk for liver cancer overall. Risk was particularly reduced among persons with liver disease and persons with diabetes, suggesting that statin use may be especially beneficial in persons at elevated risk for liver cancer.
Primary liver cancer is the sixth most commonly occurring cancer in the world and because of a very poor prognosis, the second most frequent cause of cancer mortality (1). In the majority of high-rate liver cancer areas, mainly in Asia and Africa, the most common risk factors are chronic hepatitis B virus (HBV) infection and aflatoxin contamination of foodstuffs. In contrast, in low-rate areas, such as Europe and North America, the
most common risk factors are excessive alcohol consumption, diabetes/obesity, hepatitis C virus (HCV) infection, and nonalcoholic fatty liver disease (NAFLD) (2). Incidence rates have been increasing in many low-rate regions (3), likely because of the increased prevalence of diabetes, obesity, NAFLD and HCV infection (4). Predictions of further increases in incidence (5) underscore the need to identify effective prevention strategies.
Received: October 7, 2014; Revised: November 10, 2014; Accepted: January 7, 2015 Published by Oxford University Press 2015. This work is written by © US Government employee(s) and is in the public domain in the US.
1 of 10
article
Methods: A nested case-control study was conducted within the United Kingdom’s Clinical Practice Research Datalink (CPRD). Persons diagnosed with primary liver cancer between 1988 and 2011 were matched to controls at a four-to-one ratio. Matches stratified on liver disease and on diabetes were also completed. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations of statins with liver cancer were estimated using conditional logistic regression.
2 of 10 | JNCI J Natl Cancer Inst, 2015, Vol. 107, No. 4
Statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co-A) reductase inhibitors) are commonly used cholesterol-lowering medications that have demonstrated effectiveness in the primary and secondary prevention of cardiovascular disease (6). Although statins were initially suspected of increasing the risk of cancer (7), subsequent examination failed to support those concerns (8,9) and raised the possibility that statins could have anticarcinogenic effects (10) related to inhibited angiogenesis, enhanced apoptosis, and metastasis inhibition (11). A potential for liver cancer prevention is particularly indicated, as the liver, the target organ for statins, sequesters the majority of the drug. Promising evidence that statins may decrease risk of liver cancer has been reported in observational studies, many of which were conducted in Taiwan (12–16). The results of studies from areas with low rates of liver cancer, however, have been less consistent (17–22). Furthermore, there has been debate about whether previously reported statins–liver cancer associations are because of biased prescribing patterns (23). Although rare, statin-related hepatotoxicity is not unknown (24), thus there may be a reluctance to prescribe statins to persons with preexisting liver disease. The extent to which prescribing bias has influenced the reported inverse association of statins and liver cancer is unclear. Stratification on liver disease in several studies (13,17) has provided some information on the topic, but more data are needed. More data are also needed on the effect of statins among persons with the most common risk factors, such as diabetes, in low-rate areas. Thus the current study sought to examine, in a low-rate area, the statins–liver cancer relationship overall and among persons with liver disease and diabetes.
Methods
article
A nested case-control study was conducted within the Clinical Practice Research Datalink (CPRD) of the United Kingdom (UK). The CPRD is a large, population-based, automated medical records database that contains information on approximately 8.5% of the UK population. The UK National Health Service (NHS) provides universal coverage, therefore no segment of the population is excluded from the CPRD and the age and gender distributions are representative of the general UK population (25). General practitioners (GPs) who contribute to the CPRD provide the data in an anonymous format for research purposes. All GPs have been trained to record demographic data, medical information, details of hospital stays, and deaths. Diagnoses, physical findings, symptoms, and administrative events, such as referrals to specialists, are recorded using Read codes rather than International Classification of Diseases (ICD) codes. Detailed information is available for all medications prescribed. Several studies have examined the validity of the information recorded in the CPRD and indicate that the data are reasonably complete and accurate with regard to clinical illnesses diagnosed either by the GP or a specialist (26,27). Specifically, it has been demonstrated that more than 90% of information from manual medical records gets recorded electronically (26,27) and approximately 95% of all electronically identified primary cancers are confirmed as incident cancers (28). The base population for the current study included all persons between the ages of 10 and 90 years in the CPRD between the years 1988 and 2011. The study
was approved by the National Institutes of Health Human Research Protection Program.
Case Patients and Control Patients The eligibility criteria for case patients were: 1) first-time diagnosis of primary liver cancer (Read codes B150300, B150z00, B152.00), 2) no prior diagnosis of the cancers most likely to metastasize to the liver: lung, stomach, breast, colon, or pancreatic cancer, and 3) no diagnosis of any other cancer (except nonmelanoma skin cancer) in the three years prior to the index date. The index date was defined as the date of liver cancer diagnosis minus one year. All case patients were required to have at least two years of recorded activity in the CPRD prior to the index date. Persons with any code for liver metastases were excluded from the study. Of the 1195 case patients included in the study, the majority (n = 1036, 86.7%) had supporting clinical codes that indicated presence of liver cancer such as diagnostic exams (biopsies), treatment (chemotherapy, radiotherapy, surgery), palliative care, and referrals to specialty care. The minority (n = 159, 13.3%) who had no supporting clinical codes were often persons who died shortly after the liver cancer diagnosis, prior to treatment, or persons whose cancer diagnosis was recorded at the time of death. Control patients were matched to case patients at a fourto-one ratio on age (same year of birth as case), sex, general practice, index date (one year prior to case’s diagnosis date), and number of years in the CPRD prior to the case’s index date. Control patients had to be free of any cancer (except nonmelanoma skin cancer) prior to the index date of the matched case patient and were required to have at least two years of history in the CPRD prior to the case’s index date. Only three eligible control patients could be identified for 140 of the case patients, thus 1055 case patients have four control patients and 130 case patients have only three control patients. Three separate case-control matches were completed for the study. For the full analysis, control patients were matched to all 1195 liver cancer case patients. For the chronic liver disease-matched analysis, control patients with liver disease were matched to the 170 case patients with liver disease, and control patients without liver disease were matched to the 1025 case patients without liver disease. For the diabetes-matched analysis, control patients with diabetes were matched to the 346 case patients with diabetes, and control patients without diabetes were matched to the 849 case patients without diabetes. The inclusion and exclusion criteria were the same across all three matches.
Exposure to Statins For all analyses, statin use was defined as having two or more statin prescriptions recorded prior to the index date of the case patients and control patients. Nonuse was defined as one or no statin prescriptions prior to the index date. Current statin use was defined as use that ended within one year prior to the index date, while past use was defined as use that ended more than one year prior to the index date. Exposure to statins was examined both in relation to number of prescriptions dispensed and in relation to cumulative dose, which was defined as number of pills times the dose per pill.
In addition to analyzing statin exposure as a single entity, specific statins (atorvastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, cerivastatin, and the combination of ezetimibe with simvastatin) were examined individually. Lovastatin, a common statin in other countries, is not marketed in the United Kingdom.
Statistical Analysis Prior to initiating the statistical analysis, the distributions of all covariables were examined to ensure there were no outlying values. For variables with missing values, “unknown” categories were created for the analyses. Interactions between the major matching factors and covariables and statin use were also examined. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression to assess crude and adjusted risk estimates for the relationship of statin use to liver cancer. Wald Chi-square tests were calculated to determine whether trends across categories were statistically significant. Known liver cancer risk factors for which adjustment was made in the analysis included: body mass index (BMI), smoking, alcohol-related disorders, HBV and/or HCV infection, diabetes, and rare metabolic disorders (hemochromatosis, Wilsons Disease, alpha-1 antitrypsin deficiency, porphyrias). As some evidence has suggested that aspirin (29) and antidiabetic medications (30) might be related to liver cancer risk, adjustment was made for those exposures. In addition, adjustment was made for paracetamol use because of a statistically significantly increased risk noted in the univariate analysis. In addition to the full match, the liver disease match, and the diabetes match, two sensitivity analyses were conducted. The first analysis was restricted to case patients with clinical codes for treatment of liver cancer (eg, surgery, chemotherapy, or palliative care) and their matched control patients. The second analysis used an index date of two years prior to the case’s date of diagnosis rather than one year. All statistical tests were two-sided. P values of less than .05 were considered statistically significant.
Results Table 1 displays the characteristics of the 1195 liver cancer case patients and 4640 control patients included in the overall analysis and the univariate analysis of known risk factors. Case patients and control patients were matched on index year, age at index year, sex, and length of enrollment in CPRD prior to index date, thus there were no differences in these factors. Not unexpectedly, case patients were statistically significantly more likely than control patients to be obese (BMI ≥ 30), to be current or ex-smokers, have an alcohol-related condition, be infected with HBV or HCV, have chronic liver disease, use paracetamol, have a rare metabolic disorder, and to have type I or type II diabetes. Table 2 displays the relationship of statin use to liver cancer in the overall analysis. Statin use was associated with a statistically significantly reduced risk (ORadj = 0.55, 95% CI = 0.45 to 0.69) of liver cancer. There was a statistically significant dose-response relationship between risk and cumulative daily dose of statins (P < .001), which was mirrored by the relationship with number of statin prescriptions
(P < .001). When the data were stratified by recency of use, the statistically significant dose-dependent relationship was restricted to current users (ORadj = 0.53, 95% CI = 0.42 to 0.66). Analysis by type of statin found statistically significant inverse associations for the two most commonly prescribed statins, simvastatin (ORadj= 0.57, 95% CI = 0.45 to 0.74) and atorvastatin (ORadj = 0.53, 95% CI = 0.38 to 0.75), as well as for rosuvastatin (ORadj = 0.42, 95% CI = 0.19 to 0.97). The odds ratios for the other statins were of similar magnitude as the ORs for atorvastatin, simvastatin, and rosuvastatin, but did not attain statistical significance. Table 3 displays the relationship of statin use and liver cancer among persons with and without chronic liver disease. Among persons with chronic liver disease, statin use was statistically significantly associated with reduced risk (ORadj= 0.32, 95% CI = 0.17 to 0.57) in a dose-response manner such that risk declined with increasing cumulative daily dose of statins (P < .001). The reduced risk was more evident among current (OR = 0.30, 95% CI = 0.16 to 0.58) than past (OR = 0.38, 95% CI = 0.12 to 1.18) users, although the numbers of past users were small. Among the persons without chronic liver disease, statin use was also statistically significantly associated with reduced liver cancer risk (ORadj = 0.65, 95% CI = 0.52 to 0.81), with risk declining as cumulative dose increased (P < .001). The association was seen among current (OR = 0.62, 95% CI = 0.50 to 0.78) but not among past statin users (OR = 0.92, 95% CI = 0.57 to 1.47). Table 4 displays the relationship of statins and liver cancer among persons with and without diabetes. Among persons with diabetes, statin use was statistically significantly associated with reduced risk (ORadj = 0.30, 95% CI = 0.21 to 0.42), with decreasing risk associated with increasing cumulative dose (P < .001). The association was seen both among current (ORadj = 0.29, 95% CI = 0.21 to 0.41) and past users (OR = 0.45, 95% CI = 0.21 to 0.95). Statin use was also statistically significantly associated with reduced risk among persons without diabetes (OR = 0.66, 95% CI = 0.51 to 0.85), which was evident among current (OR = 0.60, 95%CI 0.46 to 0.79) but not among past users (OR = 1.23, 95% CI = 0.69 to 2.19). The results of the sensitivity analysis restricted to case patients with supporting clinical codes (86.7%) and their control patients did not differ from that in the overall analysis (OR = 0.66, 95% CI = 0.53 to 0.80) (data not shown). Similarly, the sensitivity analysis that was based on an index date of two years prior to the case’s diagnosis date rather than one year resulted in findings very similar to the main analysis (OR = 0.59, 95% CI = 0.48 to 0.72) (data not shown). The interaction analysis of covariables with statin use identified no statistically significant interaction effects.
Discussion In the current study conducted in a low-rate region, statin use was associated with a statistically significantly reduced risk of liver cancer. The relationship was statistically significant in particular among current statin users. The reduced risks between atorvastatin, simvastatin, and rosuvastatin and liver cancer were statistically significant, while the inverse associations of pravastatin, fluvastatin, and cerivastatin did not attain statistical significance. Among persons at elevated risk of liver cancer, persons with liver disease, and persons with diabetes,
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McGlynn et al. | 3 of 10
4 of 10 | JNCI J Natl Cancer Inst, 2015, Vol. 107, No. 4
Table 1. Characteristics of case patients and control patients and univariate effects on liver cancer risk, CPRD
Characteristic
article
Index year 1991–1994 1995–1999 2000–2004 2005–2010 Years in CPRD prior to index date Mean ± SD Age at index date, y
