Proguanil and atovaquone use is associated with lower colorectal cancer risk: a nationwide cohort study

Data sources

The present nationwide cohort study was approved on February 6, 2013, by the Regional Ethical Review Board in Lund (Dnr 2012/795 and later amendments), Sweden. By linkages to the Swedish Multi-generation Register and the Swedish Cancer Registry, we identified all adults who have 1 or more first-degree relatives (parents or siblings) diagnosed with CRC by using the 10th International Classification of Diseases codes C18, C19, and C20 (n=477,582). The Swedish Multi-generation Register consists of data from more than 12 million individuals with information available on their biological parents as well as their siblings of the index persons [14]. It has been used in many previous analyses about the familial risk of various cancer. The Swedish Cancer Registry, which is based on compulsory reports from clinical doctors and pathologists/cytologists, has close to 100% complete coverage of the entire Swedish population.

Assessment of proguanil/atovaquone use

By linkage to the Swedish Prescribed Drug Register, we further retrieved information on prescriptions of proguanil/atovaquone among people with a family history of CRC according to Anatomical Therapeutic Chemical Classification (ATC) code P01BB51. The Swedish Prescribed Drug Register was created on 1 July 2005 and includes data on all prescribed drugs dispensed at pharmacies covering the entire Swedish population with lower than 0.3% missing data [15]. Each record includes the date of dispensation, ATC code, and defined daily dose (DDD), which is defined as the assumed average maintenance dose per day for a drug for its main indication in adults. We adopted a new-user study design with a washout period of a half year to exclude prevalent proguanil/atovaquone users. The entry date was set as 1 January 2006; thus, individuals prescribed proguanil/atovaquone before January 2006 were excluded (n=591).

For each proguanil/atovaquone user, up to 10 comparisons who did not receive a prescription of proguanil/atovaquone and had not experienced CRC on the date of the first prescription of the corresponding individual (index date) were randomly selected based on sex and age at index (Fig. 1 for the flowchart of the study design). In Sweden, proguanil/atovaquone was prescribed for three consecutive days when it was used to treat malaria. However, it should be initiated 24 to 48 h before arrival in the malaria-endemic area and continued throughout the stay when it was prescribed as prophylaxis. For those individuals who had multiple prescriptions, the use of proguanil/atovaquone was intermittent. The most common DDD for each prescription was 6 (45.8%) or 3 (33.1%).

Fig. 1figure 1

Flow chart of participants involved in this national cohort study

Assessment of outcome

By linkage to the Swedish Cancer Registry, we could identify patients diagnosed with colon or rectal cancer between 1 January 2006 and 31 December 2018 using ICD codes C18, C19, and C20. The Swedish Cancer Registry contains data on the TNM staging system, including the size of the tumor (T), nodal status (N), and presence of metastatic disease (M). By combining the T, N, and M categories, we can determine the stage at diagnosis of CRC, ranging from stage I (the least advanced) to stage IV (the most advanced) as follows: stage I (T1 or T2, N0, M0), stage II (T3 or T4, N0, M0), stage III (any T, N1 or N2, M0), and stage IV (any M1) [16]. By further linkage to the Cause of Death Register, we could identify individuals who had died during the follow-up period, and they were censored during the analyses.

Participants were followed from the date of the first dispensation of proguanil/atovaquone or the index date in the corresponding comparisons and ended at (i) the first date of CRC diagnosis, (ii) the date of death from any cause, and (iii) the end of this study (31 December 2018) whichever came first. To minimize reverse causation, patients with a follow-up time of fewer than 3 months were not included in the study.

Assessment of covariates

By retrieving data from the National Patient Register and Statistics Sweden’s Total Population Register, we extracted information on potential confounding factors, including age, sex (male or female), birth country (Sweden or others), the highest education level (1–9, 10–11, ≥12 years) [15], history of inflammatory bowel disease (IBD, including Crohn’s disease or ulcerative colitis, yes/no), history of colonoscopy (yes/no), obesity (identified from the National Patient Register using ICD-10 code “E66”, yes/no), chronic obstructive pulmonary disease (COPD, yes/no) as a proxy for smoking, prescription of other medication (statin and statin, yes/no), and Charlson Comorbidity Index score (CCI, 0, 1, 2, ≥3). As comorbidity is an important factor affecting the health condition and risk of cancer, we calculated the CCI based on a total of 17 categories [17]. As there is no national recommendation for the screening of CRC in Sweden, the use of colonoscopy might reflect individuals’ healthy behaviors [18], which might affect our results, we thus included a history of colonoscopy as a confounding factor in our multiple regression models. Individuals with missing values of any variables mentioned above were excluded from the present study.

The Swedish personal identification number was used to link different registers and was then replaced with serial numbers by Statistics Sweden to ensure pseudonymity.

Statistical analysis

Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of CRC associated with proguanil/atovaquone use. The final multivariable model adjusted for age, sex, birth country, highest education level, history of IBD, colonoscopy, obesity, COPD, use of aspirin, and use of statin. In addition, we calculated the cumulative defined daily doses (cDDDs) of proguanil/atovaquone as the sum of DDDs for all prescriptions during the follow-up period using records from the Swedish Prescribed Drug Register. We then performed a dose-response analysis by modeling cDDD as three tertiles and tested for the trend by entering the median value of the cDDD for each tertile in the regression model. We then evaluated the effect of the duration of proguanil/atovaquone administration. The duration was calculated from the date of the first prescription to the end date of the last prescription. We categorized the proguanil/atovaquone use durations into three groups (<1 week, 1 week to 1 year, ≥1 year). Moreover, we evaluated the association of proguanil/atovaquone use with the risk of the specific site of cancer (colon, rectum) and specific stage of cancer (stage I or II, stage III or IV). We also stratified the analyses based on age and sex to evaluate the interactive effects of proguanil/atovaquone on the risk of CRC.

We further conducted several sensitivity analyses to explore the possibility of chance findings. First, in consideration of biological latency and avoiding reverse causation, we performed a sensitivity analysis lagging the exposure to proguanil/atovaquone for 1 year after the first prescription. Second, we excluded the individuals who had been diagnosed with benign colorectal tumors. Third, we investigated the association of quinine use with CRC risk to evaluate the potential indication bias from proguanil/atovaquone use based on the fact that quinine is also a widely prescribed medication for malaria prophylaxis in Sweden. Fourth, to increase confidence in the reported association, we examined the subsequent risk of accidents, which was used as a negative outcome control. In addition, considering that data were collected concerning a long time interval of 12 years in which the diagnosis and treatment of CRC have changed, we did a stratified analysis by dividing the individuals into two groups according to their index date (group 1: from Jan 1, 2006, to Dec 31, 2011; group 2: from Jan 1, 2012, to Sep 30, 2018), to explore whether there was a difference between the two time period.

All analyses were conducted using SAS, version 9.4 (SAS Institute, Cary, NC).

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