Risk for Myocardial Infarction Following 5-Fluorouracil Treatment in Patients With Gastrointestinal Cancer: A Nationwide Registry-Based Study

Abstract

Background: Myocardial infarction is a cardiac adverse event associated with 5-fluorouracil (5-FU). There are limited data on the incidence, risk, and prognosis of 5-FU-associated myocardial infarction.

Objectives: The aim of this study was to examine the risk for myocardial infarction in patients with gastrointestinal (GI) cancer treated with 5-FU compared with age- and sex-matched population control subjects without cancer (1:2 ratio).

Methods: Patients with GI cancer treated with 5-FU between 2004 and 2016 were identified within the Danish National Patient Registry. Prevalent ischemic heart disease in both groups was excluded. Cumulative incidences were calculated, and multivariable regression and competing risk analyses were performed.

Results: A total of 30,870 patients were included in the final analysis, of whom 10,290 had GI cancer and were treated with 5-FU and 20,580 were population control subjects without cancer. Differences in comorbid conditions and select antianginal medications were nonsignificant (P > 0.05 for all). The 6-month cumulative incidence of myocardial infarction was significantly higher for 5-FU patients at 0.7% (95% CI: 0.5%-0.9%) versus 0.3% (95% CI: 0.3%-0.4%) in population control subjects, with a competing risk for death of 12.1% versus 0.6%. The 1-year cumulative incidence of myocardial infarction for 5-FU patients was 0.9% (95% CI: 0.7%-1.0%) versus 0.6% (95% CI: 0.5%-0.7%) among population control subjects, with a competing risk for death of 26.5% versus 1.4%. When accounting for competing risks, the corresponding subdistribution hazard ratios suggested an increased risk for myocardial infarction in 5-FU patients, compared with control subjects, at both 6 months (hazard ratio: 2.10; 95% CI: 1.50-2.95; P < 0.001) and 12 months (hazard ratio: 1.39; 95% CI: 1.05-1.84; P = 0.022).

Conclusions: Despite a statistically significantly higher 6- and 12-month risk for myocardial infarction among 5-FU patients compared with population control subjects, the absolute risk for myocardial infarction was low, and the clinical significance of these differences appears to be limited in the context of the significant competing risk for death in this population.

Keywords: 5-FU, 5-fluorouracil; 5-fluorouracil; GI, gastrointestinal; IQR, Interquartile range; MI, myocardial infarction; cardiotoxicity; gastrointestinal cancer; myocardial infarction.

Graphical abstract

Central Illustration

Risk for Myocardial Infarction Comparison of 5-fluorouracil (5-FU)–treated patients with gastrointestinal cancer (red) and control group (blue). The 6-month cumulative incidence of myocardial infarction was significantly higher for 5-FU-treated patients at 0.7% compared with 0.3% among population control subjects (P < 0.001). The corresponding 1-year cumulative incidences were 0.9% and 0.6% for 5-FU-treated patients and population control subjects (P = 0.051).

Figure 1

Mortality Risk Comparison of 5-fluorouracil (5-FU)–treated patients with gastrointestinal cancer (red) and control group (blue). Six-month competing risk for death was 12.1% versus 0.6%. The corresponding 1-year competing risk for death was 26.5% versus 1.4%.

Figure 2

Risk for Myocardial Infarction in Different Groups Comparison of 5-fluorouracil (5-FU)–treated patients with gastrointestinal (GI) cancer without ischemic heart disease (IHD) (red), 5-FU-treated patients with GI cancer with pre-existing IHD (black), and control group (blue). The 6-month and 1-year cumulative incidence of myocardial infarction was significantly higher for 5-FU-treated patients with pre-existing IHD compared with the other 2 groups.