Adverse Effects of Low-Dose Methotrexate from the CIRT Trial

Jack Cush, MD

Feb 18, 2020 4:27 pm

Low-dose methotrexate (LD-MTX) was studied in high risk cardiac patients in the cardiac intervention trial (CIRT), but was prematurely ended for not showing a change in cardiovascular event rates. Nonetheless this trial studied the safety and adverse event rates of LD-MTX and those results are reported in the current issue of Annals of Internal Medicine.

This prospective randomized controll trial enrolled adults with known cardiovascular disease and diabetes or metabolic syndrome to receive either placebo or LD-MTX (≤20 mg/wk) or placebo and all received folic acid, 1 mg/d, 6 days per week.

Overall, 6158 patients were enrolled and 4786 randomly assigned to a treatment group with a median follow-up of 23 months and a median dosage 15 mg/wk. There were more males (81%) and the patients were older (65.7 years) than those who usually receive MTX therapy (e.g., rheumatoid arthritis patients).

The following adverse events were increased in the LD-MTX patients (compared to placebo)

Overall adverse events - hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25])
Gastrointestinal - HR 1.91 [CI, 1.75 to 2.10]
Pulmonary - HR 1.52 [CI, 1.16 to 1.98]
Infectious - HR 1.15 [CI, 1.01 to 1.30]
Hematologic - HR 1.15 [CI, 1.07 to 1.23]
Skin cancer - HR 2.05 [CI, 1.28 to 3.28] (Other cancers were not increased)
Renal AEs were reduced in the LD-MTX group - HR, 0.85 [CI, 0.78 to 0.93].

Specific AEs

MTX pneumonitis: thought to be a rare event, was seen in 6 patients on MTX vs. 1 on PBO (HR, 6.94 [CI, 0.85 to 56.0], exact test P = 0.044); These cases in the LD-MTX group occurred between 2 and 27 months after randomization.
Pneumonia: was not increased with MTX therapy (HR 1.28; 0.89-1.83)
Risk of leukopenia (HR, 1.46 [CI, 1.19 to 1.80]) and anemia (HR, 1.36 [CI, 1.22 to 1.52]) were increased; not thrombocytopenia. Pancytopenia was rare.
Skin cancers (HR 2.0) - including basal-cell, squamous cell and melanoma
Cirrhosis: there were 5 cases on MTX but none on PBO; none of the cirrhosis patients used alcohol but all were diabetic, and 3 of the 5 had repeated LFT abnormal labs (in >5/9 tests)

Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased.

Adverse Effects of Low-Dose Methotrexate: A Randomized Trial