The study population consisted of 1303 cases with HCC diagnosed between January 1, 2001, and December 31, 2002, and 5212 controls without HCC matched on age, sex, and incidence density (ratio, 1:4). Mean age was 72 years. Most subjects (99%) were men, and 13% were African Americans. As expected from incidence density sampling and matching, cases and controls had no significant differences in age and duration between entry and index dates (). The case group had significantly higher proportions of liver disease, HCV treatment and HBV treatment; however both were quiet low. The case group had slightly lower proportions of patients with filled prescriptions for aspirin and ACE inhibitor.
Demographic Factors and Filled Prescription Data in Cases with HCC and HCC-free Matched Controls
During a mean exposure period of 2.4 years that preceded index dates for cases and controls, approximately 49% had a recorded filled statin prescription, 4% had nonstatin cholesterol-lowering drugs, and 9% had triglyceride-lowering drugs. In cases and controls, 41.6% of whom had had a prescription filled for at least 6 months, 32.3% had it filled for at least 12 months, and 22.7% had it filled for at least 18 months. The mean overall duration of any given statin prescription was 578.2 days (SD=334.4). Liver disease recorded as early as January 1, 1997, or within 4–6 years prior to the index date, was recorded in a larger population of cases (67.4%) than controls (8.7%).
The propensity score (to use statins) was generated from the model that contained coronary artery disease, myocardial ischemia, liver disease, obesity, and diabetic nephropathy as covariates, and was categorized into three equal tertiles: low (found in 12.6% of the study population), medium (39.1%), and high propensity (48.3%). A propensity score categorical variable (high propensity vs. other) was used a covariate in all the final models examining the statin-HCC associations. Further, the statin-HCC models were conducted as a sensitivity analysis in a group limited to patients with high propensity score.
We found high accuracy for our definitions of case-control as well as statin prescriptions. After reviewing a sample of medical records at the MEDVAMC, we found all 95 controls were correctly classified as not having HCC. All 57 patients who had filled prescription statins recorded in administrative records were correctly identified, and 65 patients classified as having had no statin prescriptions during CYs 1999–2002 in administrative data were also correctly identified (100% positive predictive value and 100% negative predictive value for administrative data). Of cases identified as HCC in the VA Medicare dataset, 89% were correctly identified as HCC by chart reviews. The underlying etiology in HCC cases was HCV (23%), alcoholic liver disease only (23%), fatty liver disease (38%), while there was no mention of risk factors or cirrhosis in 15%.
The proportions of patients with filled statin (or simvastatin) prescriptions were significantly lower among cases than controls (). The difference was mainly in the proportions of patients receiving more than 3 fills/refills, which was significantly lower in cases than that in controls (18.2% vs. 43.5%). Among those with at least one statin prescription, controls had an average of 9.9 (SD 7.1) fills/refills as compared to 9.4 (6.9) in cases. On the hand, there were no significant differences between cases and controls in the proportions of patients with filled prescriptions for triglyceride lowering and non-statin cholesterol reducing medications.
Having filled prescriptions for any statin was associated with a reduced risk of HCC in the primary analyses as well as in analyses stratified by the presence of known liver disease of any kind prior to HCC (). These significant associations were observed in unadjusted conditional logistic regression models and were also present but attenuated in the models adjusted for HCV, ALD, cirrhosis, alcoholism, race, HCV treatment, apirin/NSAID, ACE inhibitor, and propensity score. The relative odds of HCC were reduced in all groups (values ranged between .46 and .79). The lowest relative risk for all patients (adjusted and unadjusted) as well as for patients without liver disease (unadjusted) occurred when the duration of filled prescriptions was at least 18 months. When the analysis excludes statin prescriptions recorded within the one year preceding HCC diagnosis, the associations between statins and HCC were less strong.
Relative Risk for HCC Associated with Use of Any Statin in Cases with HCC and Controls without HCC: Results of Conditional Logistic Regression Models
Running the same analysis using simvastatin alone produced similar reductions in relative risk of HCC (relative risk values varied between 0.45 and 0.72) (). As with the analyses that used any statin, the reduced relative risk values in the adjusted population were less than those in the unadjusted population. In both analyses ( and ) but especially those for simvastatin, there was a trend toward lower OR (i.e., more risk reduction) with having >3 filled prescription than with 1–3 prescriptions as compared with no statins.
Relative risk for HCC Associated with Having Filled Prescriptions of Simvastatin in Cases with HCC and Controls without HCC
In an analysis restricted to patients with cirrhosis (data not shown), risk estimates for statins were of similar magnitude to those observed in the primary analysis. However, due to the small number of subjects (367 cases and only 86 controls), there was no statistical significance. In another analysis restricted to patients in the highest tertile for propensity score to use statins, risk estimates for statins also persisted in direction and significance; for example, the OR associated with having 1 to 3 filled statin prescriptions was 0.63 (0.33–1.18) and that of using more 3 filled statin prescriptions was 0.67 (0.49–0.93).
When the duration of prescription filling was divided into mutually exclusive periods, the reduced relative risk values for any statin or for simvastatin persisted (). There was a weak trend toward duration response relationship between statin and HCC risk. For any statin or for simvastatin alone, the association between the statin and HCC was weakest with the shortest duration of filled prescriptions. For example, for any statin the 0.59 relative risk at <6 months was the highest value of the periods measured; however, there was no significant or consistent trend of reduction with longer duration (0.40, 0.57, 0.42, 0.39) for 6–12, 12–18, 18–24, or >24 months, respectively.
Relative risk for HCC Associated with the Effect of Cumulative Duration and Dose Duration of any Filled Statin Prescription Examined in Mutually Exclusive Periods.
When exposure to simvastatin was measured in quartiles of dose duration, the lowest dose duration produced weaker associations with HCC than higher dose duration. Some of the associations with the lowest dose duration were not significant in the analyses stratified by liver disease status. Likewise, the magnitude of inverse association with HCC was least for the quartile with the lowest dose and duration (OR, 0.52; CI = 0.41–0.65) than the higher quartiles; however, there was no discernible trend in the OR values of the second, third, and fourth quartiles that followed (0.49, 0.41, and 0.44, respectively).
Finally, we determined if the observed associations were unique to statins as compared to other lipid lowering medications. In the analyses shown in , there were no significant associations between HCC and either triglyceride or non statins cholesterol lowering drugs.
Relative risk for HCC Associated with Having Filled Prescriptions of Nonstatin Cholesterol–lowering Medications in Cases with HCC and Controls without HCC