Renin-Angiotensin-Aldosterone System Inhibitors and Development of Gynecologic Cancers: A 23 Million Individual Population-Based Study.

The chronic receipt of renin-angiotensin-aldosterone system (RAAS) inhibitors including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been assumed to be associated with a significant decrease in overall gynecologic cancer risks. This study aimed to investigate the associations of long-term RAAS inhibitors use with gynecologic cancer risks. A large population-based case-control study was conducted from claim databases of Taiwan's Health and Welfare Data Science Center (2000-2016) and linked with Taiwan Cancer Registry (1979-2016). Each eligible case was matched with four controls using propensity matching score method for age, sex, month, and year of diagnosis. We applied conditional logistic regression with 95% confidence intervals to identify the associations of RAAS inhibitors use with gynecologic cancer risks. The statistical significance threshold was p < 0.05. A total of 97,736 gynecologic cancer cases were identified and matched with 390,944 controls. The adjusted odds ratio for RAAS inhibitors use and overall gynecologic cancer was 0.87 (95% CI: 0.85-0.89). Cervical cancer risk was found to be significantly decreased in the groups aged 20-39 years (aOR: 0.70, 95% CI: 0.58-0.85), 40-64 years (aOR: 0.77, 95% CI: 0.74-0.81), ≥65 years (aOR: 0.87, 95% CI: 0.83-0.91), and overall (aOR: 0.81, 95% CI: 0.79-0.84). Ovarian cancer risk was significantly lower in the groups aged 40-64 years (aOR: 0.76, 95% CI: 0.69-0.82), ≥65 years (aOR: 0.83, 95% CI: 0.75-092), and overall (aOR: 0.79, 95% CI: 0.74-0.84). However, a significantly increased endometrial cancer risk was observed in users aged 20-39 years (aOR: 2.54, 95% CI: 1.79-3.61), 40-64 years (aOR: 1.08, 95% CI: 1.02-1.14), and overall (aOR: 1.06, 95% CI: 1.01-1.11). There were significantly reduced risks of gynecologic cancers with ACEIs users in the groups aged 40-64 years (aOR: 0.88, 95% CI: 0.84-0.91), ≥65 years (aOR: 0.87, 95% CI: 0.83-0.90), and overall (aOR: 0.88, 95% CI: 0.85-0.80), and ARBs users aged 40-64 years (aOR: 0.91, 95% CI: 0.86-0.95). Our case-control study demonstrated that RAAS inhibitors use was associated with a significant decrease in overall gynecologic cancer risks. RAAS inhibitors exposure had lower associations with cervical and ovarian cancer risks, and increased endometrial cancer risk. ACEIs/ARBs use was found to have a preventive effect against gynecologic cancers. Future clinical research is needed to establish causality.

Association between Proton Pump Inhibitor Use and the Risk of Female Cancers: A Nested Case-Control Study of 23 Million Individuals.

Background: Firm conclusions about whether long-term proton pump inhibitor (PPI) drug use impacts female cancer risk remain controversial. Objective: We aimed to investigate the associations between PPI use and female cancer risks. Methods: A nationwide population-based, nested case-control study was conducted within Taiwan's Health and Welfare Data Science Center's databases (2000−2016) and linked to pathologically confirmed cancer data from the Taiwan Cancer Registry (1979−2016). Individuals without any cancer diagnosis during the 17 years of the study served as controls. Case and control patients were matched 1:4 based on age, gender, and visit date. Conditional logistic regression with 95% confidence intervals (CIs) was applied to investigate the association between PPI exposure and female cancer risks by adjusting for potential confounders such as the Charlson comorbidity index and medication usage (metformin, aspirin, and statins). Results: A total of 233,173 female cancer cases were identified, consisting of 135,437 diagnosed with breast cancer, 64,382 with cervical cancer, 19,580 with endometrial cancer, and 13,774 with ovarian cancer. After matching each case with four controls, we included 932,692 control female patients. The number of controls for patients with breast cancer, cervical cancer, endometrial cancer, and ovarian cancer was 541,748, 257,528, 78,320, and 55,096, respectively. The use of PPIs was significantly associated with reduced risk of breast cancer and ovarian cancer in groups aged 20−39 years (adjusted odds ratio (aOR): 0.69, 95%CI: 0.56−0.84; p < 0.001 and aOR: 0.58, 95%CI: 0.34−0.99; p < 0.05, respectively) and 40−64 years (aOR: 0.89, 95%CI: 0.86−0.94; p < 0.0001 and aOR: 0.87, 95%CI: 0.75−0.99; p < 0.05, respectively). PPI exposure was associated with a significant decrease in cervical and endometrial cancer risks in the group aged 40−64 years (with aOR: 0.79, 95%CI: 0.73−0.86; p < 0.0001 and aOR: 0.72, 95%CI: 0.65−0.81; p < 0.0001, respectively). In contrast, in elderly women, PPI use was found to be insignificantly associated with female cancers among users. Conclusions: Our findings, based on real-world big data, can depict a comprehensive overview of PPI usage and female cancer risk. Further clinical studies are needed to elucidate the effects of PPIs on female cancers.

Chemopreventive Effects of Concomitant or Individual Use of Statins, Aspirin, Metformin, and Angiotensin Drugs: A Study Using Claims Data of 23 Million Individuals.

Despite previous studies on statins, aspirin, metformin, and angiotensin-converting-enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs), little has been studied about all their possible combinations for chemoprevention against cancers. This study aimed to comprehensively analyze the composite chemopreventive effects of all the combinations. In this case-control study, health records were retrieved from claims databases of Taiwan's Health and Welfare Data Science Center. Eligible cases were matched at a 1:4 ratio with controls for age and sex. Both cases and controls were categorized into 16 exposure groups based on medication use. A total of 601,733 cancer cases were identified. Cancer risks (denoted by adjusted odds ratio; 99% confidence interval) were found to be significantly decreased: overall risk of all cancers in statin-alone (0.864; 0.843, 0.886), aspirin-alone (0.949; 0.939, 0.958), and ACEIs/ARBs (0.982; 0.978, 0.985) users; prostate (0.924; 0.889, 0.962) and female breast (0.967; 0.936, 1.000) cancers in metformin-alone users; gastrointestinal, lung, and liver cancers in aspirin and/or ACEIs/ARBs users; and liver cancer (0.433; 0.398, 0.471) in statin users. In conclusion, the results found no synergistic effect of multiple use of these agents on cancer prevention. Use of two (statins and aspirin, statins and metformin, statins and ACEIs/ARBs, and aspirin and ACEIS/ARBs) showed chemopreventive effects in some combinations, while the use of four, in general, did not.

Improved diagnosis-medication association mining to reduce pseudo-associations.

BACKGROUND AND OBJECTIVE: Association rule mining has been adopted to medical fields to discover prescribing patterns or relationships among diseases and/or medications; however, it has generated unreasonable associations among these entities. This study aims to identify the real-world profile of disease-medication (DM) associations using the modified mining algorithm and assess its performance in reducing DM pseudo-associations. METHODS: We retrieved data from outpatient records between January 2011 and December 2015 in claims databases maintained by the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan. The association rule mining's lift (Q-value) was adopted to quantify DM associations, referred to as Q1 for the original algorithm and as Q2 for the modified algorithm. One thousand DM pairs with positive Q1-values (Q1+) and negative or no Q2-values (Q2- or Q2∅) were selected as the validation dataset, in which two pharmacists assessed the DM associations. RESULTS: A total of 3,120,449 unique DM pairs were identified, of which there were 333,347 Q1+Q2- pairs and 429,931 Q1+Q2∅ pairs. Q1+Q2- rates were relatively high in ATC classes C (29.91%) and R (30.24%). Classes L (69.91%) and V (52.52%) demonstrated remarkably high Q1+Q2∅ rates. For the 1000 pairs in the validation, 93.7% of the Q1+Q2- or Q1+Q2∅ DM pairs were assessed as pseudo-associations. However, classes M (5.3%), H (4.5%), and B (4.1%) showed the highest rates of plausible associations falsely given Q2- or Q2∅ by the modified algorithm. CONCLUSIONS: The modified algorithm demonstrated high accuracy to identify pseudo-associations regarded as positive associations by the original algorithm and would potentially be applied to improve secondary databases to facilitate research on real-world prescribing patterns and further enhance drug safety.

Risk of cancer in long-term levothyroxine users: Retrospective population-based study.

Levothyroxine is a widely prescribed medication for the treatment of an underactive thyroid. The relationship between levothyroxine use and cancer risk is largely underdetermined. To investigate the magnitude of the possible association between levothyroxine use and cancer risk, this retrospective case-control study was conducted using Taiwan's Health and Welfare Data Science Center database. Cases were defined as all patients who were aged ≥20 years and had a first-time diagnosis for cancer at any site for the period between 2001 and 2011. Multivariable conditional logistic regression models were used to calculate an adjusted odds ratio (AOR) to reduce potential confounding factors. A total of 601 733 cases and 2 406 932 controls were included in the current study. Levothyroxine users showed a 50% higher risk of cancer at any site (AOR: 1.50, 95% CI: 1.46-1.54; P < .0001) compared with non-users. Significant increased risks were also observed for brain cancer (AOR: 1.90, 95% CI: 1.48-2.44; P < .0001), skin cancer (AOR: 1.42, 95% CI: 1.17-1.72; P < .0001), pancreatic cancer (AOR: 1.27, 95% CI: 1.01-1.60; P = .03), and female breast cancer (AOR: 1.24, 95% CI: 1.15-1.33; P < .0001). Our study results showed that levothyroxine use was significantly associated with an increased risk of cancer, particularly brain, skin, pancreatic, and female breast cancers. Levothyroxine remains a highly effective therapy for hypothyroidism; therefore, physicians should carefully consider levothyroxine therapy and monitor patients' condition to avoid negative outcomes. Additional studies are needed to confirm these findings and to evaluate the potential biological mechanisms.

Development of a Web-Based System for Exploring Cancer Risk With Long-term Use of Drugs: Logistic Regression Approach.

BACKGROUND: Existing epidemiological evidence regarding the association between the long-term use of drugs and cancer risk remains controversial. OBJECTIVE: We aimed to have a comprehensive view of the cancer risk of the long-term use of drugs. METHODS: A nationwide population-based, nested, case-control study was conducted within the National Health Insurance Research Database sample cohort of 1999 to 2013 in Taiwan. We identified cases in adults aged 20 years and older who were receiving treatment for at least two months before the index date. We randomly selected control patients from the patients without a cancer diagnosis during the 15 years (1999-2013) of the study period. Case and control patients were matched 1:4 based on age, sex, and visit date. Conditional logistic regression was used to estimate the association between drug exposure and cancer risk by adjusting potential confounders such as drugs and comorbidities. RESULTS: There were 79,245 cancer cases and 316,980 matched controls included in this study. Of the 45,368 associations, there were 2419, 1302, 662, and 366 associations found statistically significant at a level of P<.05, P<.01, P<.001, and P<.0001, respectively. Benzodiazepine derivatives were associated with an increased risk of brain cancer (adjusted odds ratio [AOR] 1.379, 95% CI 1.138-1.670; P=.001). Statins were associated with a reduced risk of liver cancer (AOR 0.470, 95% CI 0.426-0.517; P<.0001) and gastric cancer (AOR 0.781, 95% CI 0.678-0.900; P<.001). Our web-based system, which collected comprehensive data of associations, contained 2 domains: (1) the drug and cancer association page and (2) the overview page. CONCLUSIONS: Our web-based system provides an overview of comprehensive quantified data of drug-cancer associations. With all the quantified data visualized, the system is expected to facilitate further research on cancer risk and prevention, potentially serving as a stepping-stone to consulting and exploring associations between the long-term use of drugs and cancer risk.

Impact of Safety-Related Regulations on Codeine Use in Children: A Quasi-Experimental Study Using Taiwan's National Health Insurance Research Database.

INTRODUCTION: Safety concerns regarding potential life-threatening adverse events associated with codeine have resulted in policy decisions to restrict its use in pediatrics. However, whether these drug safety communications have had an immediate and strong impact on codeine use remains in question. OBJECTIVE: We aimed to investigate the impact of the two implemented safety-related regulations (label changes and reimbursement regulations) on the use of codeine for upper respiratory infection (URI) or cough. METHODS: A quasi-experimental study was performed using Taiwan's National Health Insurance Research Database. Quarterly data of codeine prescription rates for URI/cough visits were reported, and an interrupted time series design was used to assess the impact of the safety regulations on the uses of codeine among children with URI/cough visits. Multivariable logistic regression models were used to explore patient and provider characteristics associated with the use of codeine. RESULTS: The safety-related regulations were associated with a significant reduction in codeine prescription rates of -4.24% (95% confidence interval [CI] -4.78 to -3.70), and the relative reduction compared with predicted rates based on preregulation projections was 60.4, 56.6, and 53.2% in the first, second, and third year after the regulations began, respectively. In the postregulation period, physicians specializing in otolaryngology (odds ratio [OR] 1.47, 95% CI 1.45-1.49), practicing in district hospitals (OR 6.84, 95% CI 5.82-8.04) or clinics (OR 6.50, 95% CI 5.54-7.62), and practicing in the least urbanized areas (OR 1.60, 95% CI 1.55-1.64) were more likely to prescribe codeine to children than their counterparts. CONCLUSIONS: Our study provides a successful example of how to effectively reduce the codeine prescriptions in children in the 'real-world' settings, and highlights areas where future effort could be made to improve the safety use of codeine. Future research is warranted to explore whether there was a simultaneous decrease in the incidence rates of codeine-related adverse events following the safety-related regulations.