Drug-drug interactions (DDIs) between anticoagulants (AC) and anticancer therapies present a significant concern in the care of patients with cancer-associated thrombosis (CAT), with uncertain clinical implications [1].
During the ICTHIC webinar titled “The prevalence of relevant drug-drug interactions and associated outcomes,” Dr. Tzu-Fei Wang discussed the problem of drug-drug interactions and their impact on patients with cardiovascular disease. Here, we summarize the main points from her speech. You can watch Tzu-Fei Wang’s lecture in the video below and the full webinar video here.
Cancer therapies and anticoagulation
Cancer patients are known to have a 12-fold increased risk of venous thromboembolism (VTE), and with cancer therapies, this risk further rises to 23-fold, along with an increased risk of atrial fibrillation (AF). For this reason, the use of anticoagulants is very common [2].
In general, DDIs account for 20-30% of adverse drug reactions and occur more frequently in cancer patients due to their advanced age, polypharmacy, or impairment of kidney and liver function, which can affect the metabolism of drugs [1].
Historically, low molecular weight heparins (LMWH) have been the anticoagulant of choice, but in recent years, direct oral anticoagulants (DOACs) have become the preferred agent for both treatment and prevention of VTE in cancer patients [1].
Now we know that DOACs are substrates of two main metabolism pathways: CYP3A4 and P-gp transporter. The concurrent use of either inhibitors or inducers of these pathways (e.g., tyrosine kinase inhibitors) with DOAC could potentially affect the efficacy and safety of DOACs, while some anticancer therapies are associated with an increased risk of bleeding by itself given their antiplatelet properties (e.g., Ibrutinib, Imatinib, etc.) [1].
Considering potential DDIs with anticoagulants, there are two main types: pharmacokinetic (PK), resulting from the use of drugs that share the same metabolic pathway (e.g., DOACs and CYP3A4 inhibitors/inducers), and pharmacodynamic (PD), where the effect of one drug is enhanced by another drug (e.g., anticoagulants and antiplatelet) [3].
Limited literature on the prevalence and clinical relevance of DDIs
Despite the concerns and potential importance, looking at the literature on the prevalence of DDIs in cancer patients, it turns out there is actually very limited evidence and data. In a small prospective study focused on the evaluation of potential DDIs in ambulatory cancer patients referred for consideration of prophylactic anticoagulation, potential anticoagulant-drug interactions were assessed using the drug reference database Lexicomp. This allowed for a comprehensive review of all concurrent medications with different anticoagulants. The mean number of potential DDIs per patient was 0.96 for each anticoagulant [4].
However, current literature predominantly focuses on the theoretical potential of DDIs and doesn’t effectively address their clinical relevance [1].
A retrospective single-center cohort study
Due to data limitations, Dr. Tzu-Fei Wang’s group conducted a retrospective cohort study to identify the prevalence of anticoagulant-relevant DDIs in the cancer population. Patients with cancer-associated thrombosis who started anticoagulation before December 2020 at the Ottawa Hospital Thrombosis Unit were eligible if they were concurrently receiving any cancer treatments or supportive care therapies. The patients were followed for 6 months or until death if it occurred before the 6-month follow-up period [1].
The study included the evaluation of VTE recurrences as an efficacy outcome, while the safety outcome was major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) by the International Society on Thrombosis and Haemostasis (ISTH) criteria [1, 5].
Standard data were collected, including patient demographics, cancer characteristics, anticoagulant use, all concomitant medications, and safety and efficacy outcomes. Then, the patients were divided into two groups: DDI vs non-DDI. To define the groups, the Lexicomp database was used to define five different categories of DDI risk. Among these, the following three categories are thought to have clinical relevance affecting anticoagulant efficacy and safety:
- Category C, a close monitoring plan is needed;
- Category D, more significant, consider therapy modification;
- Category X, the risks outweigh the benefits, and the combination should be avoided [1].
The main results
The total cohort included 267 patients: 111 (41.6%) in the DDI group (with AC), with the remaining in the non-DDI group. Considering all medications combined (not limited to AC), 95.5% of the patients in the total cohort had drug interactions in category C and above [1]. Comparing the baseline characteristics collected in the two groups, the DDI group highlighted a slight increase in the number of co-medications per patient. Furthermore, patients who initiated treatment with DOAC were more likely to belong to the DDI group, whereas the use of LMWH was associated with patients assigned to the non-DDI group [1]. The majority of DDIs belonged to category C risk, only 10% to category D, and none to category X.
The list of most common interacting drugs with either LMWH or DOAC revealed that antiplatelet agents and antidepressants were the majority, with only 1.5% related to anticancer therapy. Regarding DOACs, CYP/P-gp inhibitors or inducers also represent additional important interacting drugs [1].
The 6-month incidence of recurrent VTE in the whole cohort was 8.2% (95% CI 5.3%-11.9%), and that of combined MB and CRNMB was 6.7% (95% CI 4.2%-10.2%). Comparing the outcomes of the two groups (DDI vs no DDI groups), the cumulative incidences and time-to-event analysis didn’t show statistically significant differences in terms of VTE recurrence, MB, and CRNMB rates [1].
Conclusion
While DDIs with anticoagulants are commonly cautioned in cancer patients, limited high-quality data are available to guide best practices. This is due to limited current literature, primarily related to in-vitro PK data, with unclear clinical implications. Furthermore, each individual medication or anticancer therapy may have different interaction risks.
Despite the potential limitations of the present study, associated with the single-center (with thrombosis expertise) retrospective study design and the modest sample size, a high incidence of DDIs with AC has been found in the study population (41.6%), and, in contrast to previous literature, DDIs were correlated with clinically relevant outcomes in this study.
The majority of interactions were not attributable to anticancer therapy but to other co-medications, such as antiplatelets and antidepressants. The use of DOACs has revealed a higher incidence of DDIs compared to LMWH, but PD interactions with LMWH remain frequent and should not be overlooked.
Finally, this study highlights the importance of correlating the clinical outcomes of DDIs with theoretical PK/PD concerns. Further research is required to develop optimal management and monitoring strategies for drug combinations that may result in relevant clinical outcomes.
In this context, personalized cancer care should consider both anticancer therapies and anticoagulation when deemed appropriate.
Watch Tzu-Fei Wang’s lecture:
References
- Wang TF, Hill M, Mallick R, et al. The prevalence of relevant drug-drug interactions and associated clinical outcomes in patients with cancer-associated thrombosis on concurrent anticoagulation and anticancer or supportive care therapies. Thromb Res. 2023;231:128-134.
- I. Mulder, E. Horvath-Puho, N. van Es, H.W.M. van Laarhoven, L. Pedersen, F. Moik, C. Ay, H.R. Buller, H.T. Sorensen, Venous thromboembolism in cancer patients: a population-based cohort study, Blood 137 (14) (2021) 1959–1969
- Beijnen JH, Schellens JH. Drug interactions in oncology. Lancet Oncol. 2004;5(8):489-496.
- Ng HK, Rogala BG, Ades S, et al. Prospective evaluation of drug-drug interactions in ambulatory cancer patients initiated on prophylactic anticoagulation. J Oncol Pharm Pract. 2020;26(7):1637-1642.
- Kaatz S, Ahmad D, Spyropoulos AC, Schulman S; Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(11):2119-2126.