During the ICTHIC webinar, “Long-term treatment & DDI implications in the management of CAT,” Dr. Tzu-Fei Wang gave a lecture on drug–drug interactions (DDIs) in cancer patients treated with anticoagulants. Here, we summarize the key messages of his speech. You can also watch Tzu-Fei Wang’s lecture in the video below and the full webinar recording here.
Cancer patients commonly require anticoagulants as they have an increased risk of venous thromboembolism (VTE) and atrial fibrillation. Historically, low-molecular-weight heparin (LMWH) has been the anticoagulation treatment of choice, although warfarin still has a place of use [1-3].
In recent years, direct oral anticoagulants have become the anticoagulant of choice for both treatment and prevention of thrombosis, based on the results of the randomized trials, Hokusai VTE Cancer (NCT02073682), Select-D, Caravaggio (NCT03045406), ADAM-VTE (NCT02585713), Casta-Diva, AVERT and Cassini (NCT02555878) [1-3].
In cancer patients, anticoagulant treatment often comes with concerns about DDIs because of the requirement of many treatments, e.g., anticancer therapy, supportive care drugs, and other comorbidities drugs (such as reduced kidney function).
There are three main types of DDIs: pharmaceutic, pharmacokinetic and pharmacodynamic. The first mechanism refers to when two drugs are directly incompatible; the second occurs when two drugs share some metabolism pathways, causing alterations in drug absorption, distribution, metabolism or excretion. In the third one, a drug enhances its effects in the presence of other drugs .
The prevalence of DDIs is about 30–40% [5-7].
A single-center retrospective observational study in Switzerland analyzed three different cohorts of cancer patients (non-small-cell lung cancer, breast cancer and palliative care unit patients), all with about 100 patients each. Results show that the number of concurrent drugs for each patient is about five to seven, with a risk of DDIs of about 20–30%, considering all the medications, or about 10–20%, considering oral coagulants only .
In addition, the number of comedications was significantly associated with the potential major risk of DDIs: 14% with less than four comedications, 24% with four to seven comedications, 40% with eight to 11 comedications, and 67% more than with 11 comedications .
Potential DDIs were significantly associated with inferior overall survival in breast cancer patients (HR = 1.32, 95% CI: 1.01–1.74, p=0.049) but not in non-small-cell lung cancer or palliative care unit patients .
A prospective study evaluated 95 ambulatory cancer patients for primary thromboprophylaxis with a Khorana score of at least 3 starting chemotherapy. Among the 95 patients, 54 medications determined relevant interactions with at least one anticoagulant, with an average of 3.1 interactions per patient .
In addition, the mean number of potential DDIs per patient with each anticoagulant was 0.96 (range 0–4) with a median of 1. Warfarin was associated with the highest average potential interaction (around 2).
At the 12-month follow-up, 7.5% of VTE events and 12% of bleeding events occurred. Two particular associations of drugs were connected with an increased risk of bleeding: Crizotinib + rivaroxaban or apixaban and proton pump inhibitors + warfarin. In addition, sulfamethoxazole–trimethoprim + warfarin was associated with VTE .
Of note, this study refers to a small cohort, and further investigations are required.
A retrospective study in Brazil analyzed 458 oncology admissions finding that 2% (six admissions) of them were related to DDI, two of which related to anticoagulation .
Another study in a Norwegian hospital analyzed 735 deaths over 2 years and found that 18% of these were due to adverse events from drugs, 4% of which occurred in cancer patients .
To further investigate DDIs in cancer patients, the Ottawa Hospital proposed a single-center retrospective study to evaluate 300 patients with cancer-related thrombosis receiving anticoagulant treatment. The primary outcome will be the percentage of strong or moderate DDIs, while the secondary outcome will be the individual percentage of each interaction by anticoagulant types and tumor types and the association of DDIs with recurrent VTE and bleeding (study in development).
In conclusion, DDI with anticoagulants is commonly cautioned but lacks quality data to guide the best practices.
The current literature is limited and includes mainly case reports or retrospective studies not specific to anticoagulants.
More research is needed to understand the significance of DDI and its associated outcomes.
- Mulder FI, Horváth-Puhó E, van Es N, et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood. 2021;137(14):1959-1969. doi:10.1182/blood.2020007338
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