Background: Trimethoprim-sulfamethoxazole (TMP-SMX) may inhibit the drug efflux transporter P-glycoprotein (P-gp) expressed on the proximal tubule of the kidney and thereby increase digoxin serum concentration
Objectives: To characterize the risk of digoxin toxicity in older adults taking digoxin following co-prescription of TMP-SMX compared with co-prescription of amoxicillin.
Methods: We conducted a retrospective population-based cohort study in Ontario, Canada (2002-2020) using linked healthcare data. Participants comprised 47 961 older adults taking digoxin (58% women; median age 80 years [interquartile range 74-86]) who were newly treated with TMP-SMX (n=10 273) compared with those newly treated with amoxicillin (n=37 688). We compared the co-prescription of TMP-SMX vs. amoxicillin in older adults who were concurrently taking digoxin. The primary outcome was a hospital encounter (i.e., hospital admission or emergency department visit) with digoxin toxicity within 30 days of the antibiotic prescription. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. The number needed to harm (NNH) was calculated as 1/RD.
Results: A hospital encounter with digoxin toxicity occurred in 49/10 273 (0.48%) patients treated with TMP-SMX versus 32/37 688 (0.14%) in those treated with amoxicillin (weighted RR, 5.71 [95% CI, 3.19 to 10.24]; weighted RD, 0.39% [95% CI, 0.25% to 0.53%]; NNH 256 [95% CI, 233 to 400]).
Conclusions: In older adults taking digoxin, the 30-day risk of a hospital encounter with digoxin toxicity was nearly 6 times higher in those co-prescribed TMP-SMX versus amoxicillin, although the absolute risk difference was low (0.4%). If TMP-SMX must be co-prescribed with digoxin (if the benefit is believed to outweigh the risk), digoxin should be dose-reduced as described in the product monograph.
