Recently, concerns have been raised that angiotensin II receptor blockers (ARBs) may be associated with an increased risk for cancer development. However, the relation between ARBs and cancer is still unclear. Therefore, a nationwide population-based study was conducted to investigate the possible influence of ARBs on the occurrence of new cancers in patients with hypertension by using the Taiwan National Health Insurance database. A total of 109,002 patients with newly diagnosed hypertension were identified from a cohort database of 1 million individuals from January 1, 1998, to December 31, 2006. Among them, 40,124 (36.8%) had received ARBs for hypertension. The end point was the development of any type of cancer before the end of 2007. During an average of 5.7 ± 2.6 years of follow-up, a total of 9,067 cases of new cancer occurrence were observed. The log-rank test showed that the occurrence rate of newly diagnosed cancers in the subjects receiving ARBs was significantly lower than those receiving treatment without ARBs (ARBs vs controls 3,082 vs 5,985, p <0.001). After adjusting for age, gender, co-morbidities, and medications for hypertension control, ARB use was found to be independently associated with a decreased risk for cancer occurrence (hazard ratio 0.66, 95% confidence interval 0.63 to 0.68, p <0.001). In conclusion, long-term use of ARBs is associated with a lower incidence of cancer occurrence, thereby suggesting that ARBs may prevent cancer development.
Angiotensin II receptor blockers (ARBs) have been synthesized and available for the treatment of hypertension since the 1990s. Compared to angiotensin-converting enzyme (ACE) inhibitors, they are better tolerated and show similar efficacy in patients after myocardial infarction, stroke, or diabetes. When used in patients who are unable to tolerate ACE inhibitors, ARBs could also reduce cardiovascular mortality and morbidity. Several researchers have postulated that ACE inhibitors and ARBs may have cancer chemopreventive activity. However, Sipahi et al reported that ARBs are associated with a modestly increased risk for new cancer occurrence in a meta-analysis of randomized controlled trials. The relation between ARBs and cancer remains unclear. Therefore, we conducted a nationwide population-based study to investigate the possible influence of ARBs on the occurrence of new cancers in patients with hypertension by using the Taiwan National Health Insurance database.
Methods
The National Health Insurance program in Taiwan has operated since 1995 and enrolls nearly all the inhabitants of Taiwan (21,869,478 beneficiaries among 22,520,776 inhabitants at the end of 2002). Currently, the National Health Insurance Research Database at the National Health Research Institutes in Miaoli, Taiwan, takes charge of the complete National Health Insurance claims database and has published several dozen extracted data sets for researchers. The National Health Research Institutes has released a cohort data set made of 1 million randomly sampled individuals who were alive in 2000 and collected all records on these individuals from 1995 onward. It is 1 of the largest nationwide population-based databases in the world. These random samples have been confirmed by the National Health Research Institutes to be representative of the Taiwanese population. In this cohort data set, each patient’s original identification number has been encrypted to protect privacy. The encrypting procedure is consistent, so the linkage of claims belonging to the same patient is feasible within the data sets.
First, we identified patients who were newly diagnosed with hypertension (International Classification of Diseases, Ninth Revision, Clinical Modification codes 401.xx to 405.xx) from a cohort data set of 1 million individuals sampled from January 1, 1998, to December 31, 2006. Then, we excluded patients who were diagnosed with cancer (140.xx to 239.xx) before the diagnosis of hypertension. We further divided the patients into 2 groups according to the use of ARBs. ARBs were identified and classified by the National Drug Code and the Anatomic Therapeutic Chemical Code, which is an internationally accepted classification system of drugs coordinated by the World Health Organization’s Collaborating Center for Drug Statistics method. ARBs included losartan (C09CA01 and C09DA01), eprosartan (C09CA02 and C09DA02), valsartan (C09CA03, C09DA03, and C09DB01), irbesartan (C09CA04 and C09DA04), tasosartan (C09CA05), candesartan (C09CA06 and C09DA06), telmisartan (C09CA07 and C09DA07), and olmesartan (C09CA08 and C09DA08). Patients had to fill medications each month, and prescription >12 times was defined as prescription for >1 year. The covariate variables included age, gender, and preexisting (in the year before treatment) diabetes mellitus (250.xx), coronary artery disease (410.xx to 414.xx), hyperlipidemia (272.xx), heart failure (428.xx), valvular heart disease (394.xx to 397.xx), ischemic stroke (433.xx to 434.xx, 436, and 437.1), and chronic renal disease (580.xx to 587.xx). The end point of the study included the new occurrence of any type of cancer (the first 2 codes 140.xx to 239.xx) before the end of 2007.
Microsoft SQL Server (Microsoft Corporation, Redmond, Washington) was used for data management and computing. Statistical analysis was performed using SPSS version 15.0 (SPSS, Inc., Chicago, Illinois). All data are expressed as the frequency (percentage) or mean ± SD. Parametric continuous data between the different groups of patients were compared using unpaired Student’s t tests. Categorical data between the different groups were compared using chi-square test and Yates’ correction or Fisher’s exact test as appropriate. Survival analysis was assessed using Kaplan-Meier analysis, with significance based on the log-rank test. Survival time was calculated from the date of hypertension diagnosis to the date of new cancer diagnosis. Multiple regression analysis was carried out using Cox proportional-hazards regression analysis. Statistical significance was inferred at a 2-sided p value of <0.05.
Results
A total of 109,002 patients were enrolled in the study, including 40,124 patients in the ARB group and 68,878 patients in the control group ( Figure 1 ). Hypertensive patients with ARB treatment were older, were more often women, more frequently had diabetes mellitus and chronic renal disease, less frequently had ischemic stroke, and were taking more concomitant medications than patients without ARB use ( Table 1 ). During an average of 5.7 ± 2.6 years of follow-up, a total of 9,067 cases (8.35%) of new cancer occurrence were observed. The log-rank test showed that the occurrence rate of cancers in the subjects receiving ARBs was significantly lower in than those without ARBs (p <0.001). Figure 2 exhibits the results of a Kaplan-Meier analysis. After adjusting for age, gender, co-morbidities, and medications for hypertension control, ARB use was found to be independently associated with a decreased risk for cancer occurrence (hazard ratio 0.66, 95% confidence interval 0.63 to 0.68, p <0.001), and the benefits were noted among different subgroups of patients ( Figure 3 ) and different ARBs ( Table 2 ). To our interest, the benefit of ARBs in cancer prevention correlated with the duration of treatment, and greater benefit was observed in patients receiving ARBs for >1 year (hazard ratio 0.50, 95% confidence interval 0.46 to 0.53, p <0.001; Figure 3 , Table 2 ). Furthermore, the beneficial effect of ARBs in cancer development was observed in all types of cancers ( Figure 4 ).
| Variable | ARB Treatment | ||
|---|---|---|---|
| Yes (n = 40,124) | No (n = 68,878) | p Value | |
| Age (years) | 59.32 ± 12.73 | 57.95 ± 13.97 | <0.001 |
| Men | 20,322 (50.6%) | 35,913 (52.1%) | <0.001 |
| Diabetes mellitus | 3,432 (8.6%) | 4,535 (6.6%) | <0.001 |
| Coronary artery disease | 1,095 (2.7%) | 1,991 (2.9%) | 0.121 |
| Hyperlipidemia | 1,463 (3.6%) | 2,643 (3.8%) | 0.110 |
| Heart failure | 212 (0.5%) | 336 (0.5%) | 0.361 |
| Valvular heart disease | 43 (0.1%) | 73 (0.1%) | 0.954 |
| Ischemic stroke | 343 (0.9%) | 697 (1%) | 0.010 |
| Chronic renal disease | 465 (1.16%) | 569 (0.83%) | <0.001 |
| Other antihypertensive agents | |||
| ACE inhibitors | 7,086 (17.7%) | 8,330 (12.1%) | <0.001 |
| β blockers | 10,317 (25.7%) | 15,364 (22.3%) | <0.001 |
| Calcium channel blocker | 12,752 (31.8%) | 15,819 (23%) | <0.001 |
| Thiazide | 3,071 (7.7%) | 3,538 (5.1%) | <0.001 |
| Mean number of antihypertensive agents | 1.83 ± 1.00 | 0.63 ± 0.87 | <0.001 |
| Variable | Unadjusted HR | 95% CI | p Value | Adjusted HR | 95% CI | p Value |
|---|---|---|---|---|---|---|
| Overall | 0.69 | (0.66–0.72) | <0.001 | 0.66 | (0.63–0.68) | <0.001 |
| Duration (years) | ||||||
| <1 | 0.84 | (0.79–0.88) | <0.001 | 0.79 | (0.75–0.83) | <0.001 |
| ≥1 | 0.52 | (0.49–0.56) | <0.001 | 0.50 | (0.46–0.53) | <0.001 |
| Type of ARB | ||||||
| Losartan | 0.73 | (0.68–0.78) | <0.001 | 0.77 | (0.72–0.82) | <0.001 |
| Valsartan | 0.65 | (0.61–0.69) | <0.001 | 0.68 | (0.64–0.72) | <0.001 |
| Irbesartan | 0.62 | (0.56–0.68) | <0.001 | 0.63 | (0.58–0.70) | <0.001 |
| Candesartan | 0.50 | (0.40–0.63) | <0.001 | 0.52 | (0.41–0.65) | <0.001 |
| Telmisartan | 0.58 | (0.48–0.69) | <0.001 | 0.58 | (0.49–0.69) | <0.001 |
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