Abstract
Background:
Visceral adiposity is a risk factor for colorectal adenomas, and aspirin is an established chemopreventive agent. Evidence from clinical trials suggests the effectiveness of aspirin at preventing cardiovascular disease and cancer may require higher doses for higher body weight.
Methods:
Body mass index, body surface area, fat-free mass, and fat mass were calculated from baseline height and weight in 1,121 participants of the Aspirin/Folate Polyp Prevention Study, a double-blind, placebo-controlled, 3×2 factorial randomized clinical trial of low-dose (81 mg/d) or high-dose (325 mg/d) aspirin and/or 1 mg/d folic acid to prevent metachronous colorectal adenomas. Participants were treated during a surveillance colonoscopy interval of approximately 3 years. Risk ratios (RR) with 95% confidence intervals (CI) for any colorectal neoplasia and high-risk adenoma (HRA, advanced or ≥3 adenomas) were estimated from log-linear regression.
Results:
We did not find evidence to suggest aspirin dose-response differed by body composition measurements including weight alone. Among those weighing ≥80 kg, treatment effects for low-dose aspirin (RR for colorectal neoplasia, 0.75; CI, 0.60–0.94; RR for HRA, 0.52; CI, 0.31–0.86) and high-dose aspirin (RR for colorectal neoplasia, 0.88; CI, 0.72–1.08; RR for HRA, 0.68; CI, 0.43–1.09) were not meaningfully different than for those weighing 70–79 kg or <70 kg.
Conclusions:
Measurements of body composition calculated from height and weight did not modify aspirin treatment effects for colorectal adenoma prevention.
Impact:
Aspirin dosing strategies accounting for body weight suggested in previous trials of colorectal cancer may not apply to adenomas.
Keywords: aspirin, body weight, body mass index, body surface area, colorectal adenoma, fat-free mass
Introduction
The United States Preventive Services Task Force recommends low-dose (81 mg/d) aspirin for the primary prevention of colorectal cancer (CRC) for those 50–69 years old with 10-year risk of cardiovascular disease ≥10%, and advocates more research on dosing strategies (1). In randomized clinical trials (RCTs), aspirin reduces metachronous colorectal adenoma risk by approximately 20% (2). A meta-analysis of RCTs found body weight modified the association between aspirin dose and CRC risk: 75–100 mg/d aspirin reduced risk among those weighing <70 kg, and ≥325 mg/d among those weighing <80 kg (3). We assessed aspirin treatment effects according to height, weight, and body composition measurements predicted from height and weight, in the Aspirin/Folate Polyp Prevention Study (AFPPS), a double-blind placebo-controlled RCT of 81 or 325 mg/d aspirin for the prevention of metachronous adenomas (4).
Materials and Methods
AFPPS is 3×2 factorial RCT comparing 81 and 325 mg/d aspirin to placebo and 1 mg/d of folic acid to placebo (4). Participants recruited from nine clinical centers between 1994–1998 were 21–80 years old and recently diagnosed with ≥1 colorectal adenoma. Aspirin treatment ended at a 3-year follow-up colonoscopy. We evaluated the incidence of any colorectal neoplasia ≥1 year following randomization determined by a standardized pathology review, including conventional adenomas, sessile serrated adenomas/polyps (SSA/P), or CRC. High-risk adenoma (HRA) findings were defined as ≥1 advanced adenoma (tubulovillous/villous adenomas, ≥1 cm in diameter, with high-grade dysplasia, or CRC) or ≥3 adenomas, without considering SSA/P.
Body mass index (BMI), body surface area (BSA) (5), and fat-free mass (FFM) (6) were calculated from self-reported baseline height and weight. Fat mass (FM) was calculated as weight minus FFM. Risk ratios (RR) with 95% confidence intervals (CIs) were estimated from log-linear regression with robust standard errors, adjusting for age, sex, center, and treatment assignment. Heterogeneity of RRs for aspirin according to body composition was tested using 2-df Wald tests for interactions with each dose vs placebo in intention-to-treat analyses. Secondary analyses were stratified by sex using different categories for body composition variables when appropriate. Two-sided P≤0.05 was considered statistically significant.
Results
Overall, 1,121 participants underwent randomization. Baseline characteristics by treatment assignment were previously reported, along with summaries of excellent compliance and avoidance of non-protocol non-steroidal anti-inflammatory drugs (NSAIDs) (4). Among 712 men and 409 women, mean (SD) height was 1.8 (0.1) m and 1.6 (0.1) m, respectively. The mean weight was 87.5 (14.6) kg and 71.9 (14.3) kg, respectively. A total of 1,084 participants (97%) completed the follow-up colonoscopy; among these, 470 (43%) had incident colorectal neoplasia, including 140 (13%) with HRA.
For each body composition measurement, risk of colorectal neoplasia and HRA increased comparing the highest to lowest category (Table 1). No statistically significant treatment effect modification was found (Table 2). Treatment effects for low-dose aspirin did not differ according to whether participants weighed <70 kg or ≥70 kg. High-dose aspirin did not, in general, result in statistically significant treatment effects, and there was no evidence to suggest greater risk reduction in those weighing <80 kg compared to ≥80 kg. Sex-specific effects were of similar magnitudes as overall sex-adjusted effects, but estimates were less precise (Supplementary Tables 1–4).
Table 1.
Main effect of body composition measurements for risk of any colorectal neoplasia and high-risk adenoma in the Aspirin/Folate Polyp Prevention Study.
| Colorectal neoplasia | HRA | |||||
|---|---|---|---|---|---|---|
| Baseline measurement | Total | No. with endpoint (%) | RRa (95% CI) | No. with endpoint (%) | RRa (95% CI) | |
| Height, m | ||||||
| <1.70 | 407 | 161 (40) | 1 (Ref) | 41 (10) | 1 (Ref) | |
| 1.70–1.79 | 371 | 159 (43) | 0.96 (0.77, 1.20) | 48 (13) | 0.84 (0.52, 1.38) | |
| ≥1.80 | 304 | 149 (49) | 1.12 (0.88, 1.42) | 51 (17) | 1.17 (0.69, 1.97) | |
| Weight, kg | ||||||
| <70 | 245 | 87 (36) | 1 (Ref) | 20 (8) | 1 (Ref) | |
| 70–79 | 271 | 112 (41) | 1.12 (0.87, 1.44) | 39 (14) | 1.39 (0.78, 2.46) | |
| ≥80 | 568 | 271 (48) | 1.25 (0.99, 1.59) | 81 (14) | 1.42 (0.80, 2.54) | |
| BMI, kg/m2 | ||||||
| <25 | 333 | 124 (37) | 1 (Ref) | 32 (10) | 1 (Ref) | |
| 25–29 | 507 | 229 (45) | 1.14 (0.95, 1.36) | 74 (15) | 1.35 (0.91, 2.03) | |
| ≥30 | 242 | 116 (48) | 1.23 (1.02, 1.50) | 34 (14) | 1.45 (0.92, 2.27) | |
| BSAb, m2 | ||||||
| <1.90 | 441 | 162 (37) | 1 (Ref) | 43 (10) | 1 (Ref) | |
| 1.90–1.99 | 204 | 91 (45) | 1.15 (0.92, 1.44) | 30 (15) | 1.16 (0.70, 1.94) | |
| ≥2.00 | 437 | 216 (49) | 1.29 (1.05, 1.57) | 67 (15) | 1.30 (0.84, 1.99) | |
| FFMc, kg | ||||||
| <55 | 439 | 170 (39) | 1 (Ref) | 38 (9) | 1 (Ref) | |
| 55–59 | 146 | 65 (45) | 0.96 (0.68, 1.34) | 24 (16) | 1.08 (0.51, 2.26) | |
| ≥60 | 497 | 234 (47) | 1.02 (0.75, 1.39) | 78 (16) | 1.23 (0.61, 2.48) | |
| FMd, kg | ||||||
| <25 | 621 | 265 (43) | 1 (Ref) | 80 (13) | 1 (Ref) | |
| 25–29 | 199 | 89 (45) | 1.13 (0.94, 1.35) | 27 (14) | 1.33 (0.89, 1.98) | |
| ≥30 | 262 | 115 (44) | 1.08 (0.90, 1.29) | 33 (13) | 1.21 (0.82, 1.77) | |
Abbreviations: BSA, body surface area; BMI, body mass index; CI, confidence interval; FFM, fat-free mass; FM, fat mass; HRA, high-risk adenoma; RR, risk ratio.
Note: Two participants were missing height, and thus excluded from the calculations of BMI, BSA, FFM, and FM.
RR adjusted for age, sex, clinical center, aspirin assignment, and folic acid assignment. Endpoints were contrasted to those without colorectal neoplasia.
Calculated using the method of DuBois and DuBois (5).
Calculated using the method of Janmahasatian et al. (6).
Weight minus FFM.
Table 2.
Aspirin treatment effect for risk of any colorectal neoplasia and high-risk adenoma according to body composition measurements in the Aspirin/Folate Polyp Prevention Study.
| Colorectal neoplasia | HRA | ||||
|---|---|---|---|---|---|
| Baseline measurement | 81 mg/d aspirin vs placebo RRa (95% CI) | 325 mg/d aspirin vs placebo RRa (95% CI) | 81 mg/d aspirin vs placebo RRa (95% CI) | 325 mg/d aspirin vs placebo RRa (95% CI) | |
| Height, m | |||||
| <1.70 | 0.69 (0.50, 0.96) | 1.00 (0.76, 1.31) | 0.51 (0.24, 1.08) | 0.83 (0.41, 1.67) | |
| 1.70–1.79 | 1.00 (0.72, 1.38) | 1.13 (0.83, 1.53) | 0.48 (0.21, 1.07) | 1.00 (0.55, 1.82) | |
| ≥1.80 | 0.72 (0.54, 0.95) | 0.83 (0.63, 1.08) | 0.53 (0.29, 0.96) | 0.73 (0.42, 1.28) | |
| P-interaction | 0.21 | 0.31 | 0.98 | 0.75 | |
| Weight, kg | |||||
| <70 | 0.82 (0.52, 1.29) | 0.96 (0.63, 1.47) | 0.81 (0.27, 2.50) | 1.09 (0.37, 3.17) | |
| 70–79 | 0.87 (0.59, 1.26) | 1.19 (0.85, 1.65) | 0.38 (0.16, 0.91) | 1.11 (0.62, 1.99) | |
| ≥80 | 0.75 (0.60, 0.94) | 0.88 (0.72, 1.08) | 0.52 (0.31, 0.86) | 0.68 (0.43, 1.09) | |
| P-interaction | 0.79 | 0.33 | 0.58 | 0.40 | |
| BMI, kg/m2 | |||||
| <25 | 0.78 (0.55, 1.12) | 1.03 (0.74, 1.42) | 0.73 (0.32, 1.71) | 1.16 (0.55, 2.47) | |
| 25–29 | 0.84 (0.66, 1.07) | 0.94 (0.74, 1.18) | 0.53 (0.30, 0.94) | 0.93 (0.58, 1.50) | |
| ≥30 | 0.67 (0.47, 0.96) | 0.92 (0.69, 1.22) | 0.35 (0.16, 0.77) | 0.46 (0.22, 0.98) | |
| P-interaction | 0.75 | 0.86 | 0.45 | 0.19 | |
| BSAb, m2 | |||||
| <1.90 | 0.85 (0.62, 1.18) | 1.06 (0.79, 1.43) | 0.50 (0.24, 1.07) | 0.93 (0.49, 1.75) | |
| 1.90–1.99 | 0.80 (0.53, 1.22) | 1.11 (0.78, 1.58) | 0.44 (0.15, 1.31) | 1.28 (0.60, 2.75) | |
| ≥2.00 | 0.73 (0.57, 0.92) | 0.84 (0.67, 1.04) | 0.52 (0.31, 0.89) | 0.63 (0.38, 1.03) | |
| P-interaction | 0.73 | 0.29 | 0.96 | 0.28 | |
| FFMc, kg | |||||
| <55 | 0.80 (0.59, 1.09) | 0.97 (0.73, 1.28) | 0.36 (0.15, 0.85) | 0.69 (0.35, 1.37) | |
| 55–59 | 1.01 (0.61, 1.67) | 1.35 (0.85, 2.14) | 0.90 (0.29, 2.85) | 2.04 (0.77, 5.36) | |
| ≥60 | 0.72 (0.57, 0.91) | 0.87 (0.71, 1.08) | 0.52 (0.32, 0.87) | 0.72 (0.45, 1.14) | |
| P-interaction | 0.47 | 0.24 | 0.44 | 0.14 | |
| FMd, kg | |||||
| <25 | 0.82 (0.65, 1.04) | 1.02 (0.83, 1.26) | 0.64 (0.36, 1.11) | 1.08 (0.68, 1.71) | |
| 25–29 | 0.71 (0.49, 1.05) | 0.85 (0.59, 1.21) | 0.40 (0.16, 1.00) | 0.77 (0.37, 1.63) | |
| ≥30 | 0.74 (0.51, 1.07) | 0.92 (0.66, 1.27) | 0.38 (0.17, 0.83) | 0.44 (0.19, 1.03) | |
| P-interaction | 0.78 | 0.64 | 0.49 | 0.19 | |
Abbreviations: BSA, body surface area; BMI, body mass index; CI, confidence interval; FFM, fat-free mass; FM, fat mass; HRA, high-risk adenoma; RR, risk ratio.
Note: Two participants were missing height, and thus excluded from the calculations of BMI, BSA, FFM, and FM.
RR from interaction between body composition measurement and aspirin assignment, adjusted for age, sex, clinical center, and folic acid assignment. Endpoints were contrasted to those without colorectal neoplasia.
Calculated using the method of DuBois and DuBois (5).
Calculated using the method of Janmahasatian et al. (6).
Weight minus FFM.
Discussion
Our findings did not show the dose-response pattern by weight identified by Rothwell et al. (3). We found low-dose aspirin reduced risk of colorectal neoplasia and HRA by 25% and 48%, respectively, among those weighing ≥80 kg, findings not meaningfully different from those weighing <70 kg. No effect modification was observed for other measurements of body composition.
Overall, AFPPS identified a statistically significant 19% reduced risk of adenomas for low-dose aspirin relative to placebo, and a non-significant 4% reduced risk for high-dose aspirin (4). A previous analysis from AFPPS reported treatment effects according to BMI, considering conventional and advanced adenomas as endpoints, but did not evaluate weight alone or other measurements of adoposity (7).
Abdominal visceral adiposity is a known risk factor for colorectal adenomas (8), but measurement requires medical imaging. We calculated FFM and FM using validated prediction equations trained on data from dual-energy x-ray absorptiometry and bioelectrical impedance analysis (6). FFM is often regarded as equivalent to lean body mass (LBM), although the former excludes lipids in the central nervous system, bone marrow, and cell membranes (accounting for ~4% difference between FFM and LBM) (6). We also calculated classical BSA, as it remains in use to dose some chemotherapies.
AFPPS had excellent follow-up and compliance, avoidance of non-protocol NSAIDs, standardized pathology, and evaluation of 2 different aspirin doses by design. Predictions from height and weight may be subject to error, but the randomized design helped balance any inaccuracies by treatment assignment. Weight-based aspirin dosing aims to maximize bioavailability while minimizing side-effects such as bleeding (3), but data from AFPPS does not support the effectiveness of this approach for preventing metachronous colorectal adenomas.
Supplementary Material
Acknowledgments
On behalf of the Polyp Prevention Study Group, the authors express their appreciation to the study participants, investigators, and staff. The authors thank Dr. Gail McKeown-Eyssen for comments on the manuscript. Study tablets were provided by Wyeth (Madison, NJ). This research was funded by the National Cancer Institute at the National Institutes of Health (R01CA059005 to J. A. Baron), and the National Institute of General Medical Sciences at the National Institutes of Health (P20GM104416 to M. N. Passarelli).
Footnotes
http://ClinicalTrials.gov Identifier: NCT00272324
Disclosure of Potential Conflicts of Interest
Together with the Trustees of Dartmouth College, J. A. Baron holds a use patent, not licensed, for the chemopreventive use of aspirin for colorectal cancer.
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