Outcome measures

The three primary outcomes of interest were dichotomous measures of diagnosis of hypertension, diabetes, and/or hyperlipidemia in the first year following CRC diagnosis (or anchor date for matched noncancer controls). The three secondary outcomes of interest were time-varying binary indicators from CVD-related chronic disease control based on clinical practice guidelines that covered the study period: blood pressure (for nondiabetic patients <150/90 mm Hg, for diabetic patients <140/90 mm Hg),24 diabetes (A1c <7% vs ≥7%),25 and hyperlipidemia [low-density lipoprotein (LDL) <100 mg/dL vs ≥100 mg/dL].26 Chronic disease control outcomes were collected from EHR data measured in outpatient clinics over the year following the anchor date; diabetes diagnosis in the pre-period was used to define the blood pressure threshold. If an individual had multiple measurements of an outcome per day, the average measurement for the day was used.

Statistical analysis


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We used logistic regression to assess associations between CRC survivors’ and matched noncancer controls prevalence of hypertension, diabetes, and hyperlipidemia diagnoses. Odds of control of BP, A1c, and LDL were estimated using a generalized linear mixed model for each outcome, with an individual-level random intercept to account for correlation among multiple measures per person. The model included an indicator for whether a patient was a CRC survivor vs a matched noncancer control, continuous time from anchor date, and their interaction. Statistical analyses were conducted using SAS Enterprise Guide 7.1 and SAS 9.4 (SAS Institute Inc., Cary, NC) with a priori two-sided statistical significance level set at 0.05.

Additional analyses

We conducted a sensitivity analysis, using stratified age as an interaction term, examining whether the associations found varied by categorical age group. Given the differences in hypertension control, we conducted a post-hoc analysis to evaluate differences in polypharmacy and antihypertensive medication-taking behaviors. We report the overall number of oral cardiovascular medications patients were prescribed. To assess adherence to antihypertensive medications, we calculated Medication Possession Ratio (MPR), a pharmacy refill-based measure of medication adherence, for patients prescribed metoprolol tartrate in the outpatient setting in the year following the anchor date.27,28 Due to the MPR not being normally distributed, a difference in MPR between cases and controls was checked using the Wilcoxon Rank Sum test, a nonparametric test.

RESULTS

Patient sample

We identified 15,218 CRC survivors who were diagnosed during the study period. After applying exclusion criteria (eg, stage IV, diagnosed outside of study time frame), 9,758 CRC survivors and 29,066 matched noncancer control patients were included in the analytic sample (Figure 1).

Patient characteristics

Baseline characteristics for CRC survivors and matched noncancer control patients, including presence of CVD risk factors, are presented in Table 1. Most cases were white (79.3%), males (97.7%). Patients were commonly married (48.9%), overweight (BMI 25.0–29.9; 29.7%), or obese (BMI ≥30; 32.5%). Most patients received VA health care without a copay (78.9%) because of either low annual income (44.3%) or military service-related disability (34.6%).

Among CRC cases, the mean age at diagnosis was 67.0 years. A larger proportion of CRC cases died within three years of the anchor date compared to the noncancer control patients (22.83 vs 9.22%, respectively).

Presence of CVD-related chronic conditions among CRC survivors

At baseline, 69.4% of CRC survivors were diagnosed with hypertension, 36.7% with diabetes, and 52.2% with hyperlipidemia. In the post-period, approximately 7% of cases and 11% of controls had newly diagnosed hypertension; 6% and 24% of cases and controls, respectively, had newly diagnosed hyperlipidemia; and 5% and 4% of cases and controls, respectively, had newly diagnosed diabetes. In the year following the anchor date, compared to matched noncancer control patients (Table 2), CRC survivors had 57% higher odds of being diagnosed with hypertension (OR=1.57, 95% CI=1.49–1.64). This includes all diagnoses of hypertension in the sample (ie, not limited to new diagnosis). Also, at 1 year post-anchor date, we identified no difference between CRC survivors and controls regarding diabetes diagnoses (OR=0.97, 95% CI=0.93–1.02). Compared to matched noncancer control patients, CRC survivors had half the odds of being diagnosed with hyperlipidemia (OR=0.50, 95% CI=0.48–0.52).

CVD-related chronic condition control

Twelve months post-anchor date (Table 3), CRC cases experienced 7% higher odds of good blood pressure control (OR=1.07, 95% CI 1.02–1.13) and 12% lower odds of LDL control (OR=0.88, 95% CI 0.81–0.94) compared to matched noncancer controls. There was no significant difference between CRC cases and matched controls in odds of A1c control at 12 months.

Sensitivity analysis for age stratification

There was minor variation by age group, but the magnitude and direction of the associations were consistent (Table 4). We also report age-stratified analysis with regard to CVD risk factor control (Table 5).


Polypharmacy and differences in medication adherence

Regarding polypharmacy, CRC survivors and matched noncancer controls were prescribed similar numbers of overall oral medications (CRC cases, mean =4.21, SD 3.70; matched noncancer controls, mean 4.13, SD 3.67). Based on pharmacy refill data, adherence was significantly lower among CRC survivors compared with matched noncancer controls (mean MPR 85% and 93%, respectively, p<0.001).

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