Initial RCTs investigating the efficacy of ICIs as anticancer treatment did not report thrombosis as a major adverse event of concern. An initial meta-analysis of these RCTs showed a modest rate of VTE at 2.7% (95% confidence interval [CI] 1.8–4.0) and an arterial thrombosis (ATE) rate of 1.1% (95% CI 0.5–2.1) [13]. Another meta-analysis of RCTs and prospective studies of ICI use in patients with melanoma and non-small cell lung cancer (NSCLC) also reported similar rates (VTE rates: 1.5% in melanoma and 1.9% in NSCLC) [14]. Most recently, an updated meta-analysis showed no significantly increased risk of VTE (odds ratio [OR] 0.99, 95% CI 0.82–1.19) in patients treated with ICIs compared to non-ICI regimens [15]. However, all of these meta-analyses suffered from the possibility of underreporting of thrombosis events in RCTs in the first place. Solinas et al. excluded 40% of the eligible RCTs from analysis as they did not specifically report rates of thrombosis [13]. In addition, in these studies, thrombosis events were reported as adverse events based on the Common Terminology Criteria for Adverse Events (CTCAE) criteria instead of planned outcomes, and adverse events were often only reported if they were over certain percentages. Significant underreporting of thrombosis events had been shown in previous oncology RCTs with focus on efficacy of cancer therapies compared to thromboprophylaxis trials, which requires close attention for data interpretation [16].

Since the approval and wide clinical use of various ICIs, occurrences of venous and/or arterial thromboses are increasingly reported. Table 2 summarized the results of 27 cohort studies reported to date, with the majority being retrospective cohorts from single centers. Most (80–100%) patients had metastatic cancer, with the most common cancers including NSCLC, melanoma, and RCC. All studies included a variety of different ICIs available in clinical care. The incidence of thrombosis differed widely among studies, due to diverse types of underlying malignancies, concurrent cancer therapies (such as chemotherapy), and variable follow-up durations. In general, the incidence of VTE was 5–8% at 6 months and 10–15% at 12 months (Table 2). Overall, the rates reported in these retrospective cohort studies were higher than those reported from RCTs (1–2% in meta-analyses) [13,14], but not considerably higher when considering the 6-month risks of VTE of 9–10% in ambulatory cancer patients with Khorana score of ≥ 2 receiving chemotherapy [17]. However, given the efficacy of ICIs, the exposure of ICIs can be prolonged, and the risks of thrombosis can continue to accumulate. Sheng et al. showed that the thrombosis rate did not plateau until approximately 30 months in patients with metastatic RCC and 36 months in those with metastatic urothelial cancer [18,19]. Therefore, as patients continue ICIs, the risks of thrombosis can continue to increase. This is worth noting as compared to chemotherapy, for which the highest risk of thrombosis is typically seen within the first 6 months.

In addition to retrospective cohort studies, three Danish population cohort studies reported the incidence of thrombosis in patients on ICIs (Table 3) [43,44,45]. It is interesting to note that the rates of thrombosis appear to be numerically lower in the population studies compared to the above-mentioned retrospective studies, with 6-month VTE rate of 2–4% and 4–7% at 12 months. In these population studies, outcomes were identified by ICD10 codes +/− imaging codes (as compared to individual chart review in retrospective studies), which could account for the difference in event rates. In addition, all three studies were from a single country (Danish registry), as compared to various countries from cohort studies (Table 2).

Whether ICI combinations or combined ICI and chemotherapy would be associated with an increased risk of VTE (compared to single ICI or chemotherapy alone) is also an area of debate. Sussman et al. showed that ICI combinations were associated with a higher risk of VTE compared to single agent ICI [46]. A recent meta-analysis also showed that compared to mono-ICI, combined ICIs were associated with an increased risk of VTE and myocardial infarction in those with NSCLC [14]. However, another study showed that combined ICIs were not associated with higher risks [47]. Similarly, some studies showed an increased risk of ICI–chemotherapy combination compared to chemotherapy alone [31,42], while others showed similar rates of thrombosis in patients receiving ICI alone, chemotherapy alone, or combination [22]. Most recently, in the analysis of an oncology database of 2299 patients with stage IV NSCLC, first-line ICI-based regimens were associated with a 26% reduction in the risk of VTE compared to chemotherapy-based regimens, while the risks were comparable between ICI/chemo versus chemotherapy alone [40]. It is worth noting that a fair comparison of the risks of thrombosis associated with combination of chemotherapy and ICIs to ICI alone or chemotherapy alone could be challenging, as the baseline characteristics of these patients commonly differ significantly.

Data on the incidence or arterial thrombosis were even more scant, with rates within 1-2% over a follow-up period of 6 to 17 months (Table 2). A recent meta-analysis showed an increased risk of arterial thrombosis (OR 1.58, 95% CI 1.21–2.06) associated with ICI regimens [15]. In a matched cohort study of 2842 patients, Drobni et al. revealed that there was a three-fold increased risk of cardiovascular events after the start of ICIs compared to other anticancer therapies. The risks were similarly increased when they compared before and after ICI use in the same patients [25]. They also found ICI to be associated with a > three-fold higher rate of progression of total aortic plaque volume, which can be attenuated with concomitant use of corticosteroids or statins [25].

4. Prevention and Treatment of Thrombosis in Patients on Immune Checkpoint Inhibitors