Introduction
Pulmonary embolism (PE) is one of the leading causes of cardiovascular mortality and morbidity. It is estimated that it contributes to 100,000 deaths per year [1]. It has a significant mortality rate of 30% if left untreated [2].
Especially affected are patients with active cancer as they have a 4–7-fold increased risk of developing venous thromboembolism (VTE) [3]. Pulmonary embolism is a leading cause of death in this group, second only to the cancer itself [4]. Different types of cancer have different VTE risks: pancreatic cancer, hematological malignancies, lung cancer, gastric cancer, and brain cancer carry the highest risk [5]. Due to the fragility of cancer patients and frequent oligosymptomatic presentation of this condition the diagnosis is challenging [6].
Recurrence and mortality of PE in cancer patients
Populational risk of recurrence after the first episode of VTE is between 5 and 7%, while patients with active cancer are at a higher risk of recurrence [7].
The acute PE mortality rate is significantly higher in cancer patients than noncancer patients (19.6% vs. 3.2%, p < 0.001) [8]. Gussoni et al. reported that the mortality rate in cancer patients during a 3-month follow-up after acute PE was 3% [9].
The mortality rate in the hospital phase of PE can be greatly lowered with the implementation of a pulmonary embolism response team (PERT). The multidisciplinary approach and specialized care those teams provide brought in-hospital mortality rates for both non-cancer and cancer patients to similar levels. Research has also shown that establishing PERT increases access to advanced therapies, while at the same time the number of bleeding complications does not increase in the cancer patient group [10, 11].
Trends in long-term pharmacotherapy of PE in the general population
Current guidelines for PE treatment and diagnosis were established in 2019 by the European Society of Cardiology in collaboration with the European Respiratory Society.
Over the years as medicine progressed, the PE mortality rate decreased. More treatment options became available and new drugs were implemented. This progress is particularly visible in changes in the guidelines between the years 2014 and 2019. Aside from the use of age-specific cut-off levels of D-dimers, detailed recommendations for risk stratification and the possibility of outpatient management, there was a shift in the use of anticoagulants [12]. In 2014 vitamin K antagonists (VKAs) were the gold standard in oral anticoagulation both in acute VTE and in further prevention of recurrence, while direct oral anticoagulants (DOACs) were still being evaluated. The results were promising but not revolutionary. Phase III clinical trials indicated that these agents were non-inferior in terms of efficiency and potentially safer than warfarin [13]. Research showed that compared with VKA-treated patients, critical site major bleeding occurred less frequently in DOAC-treated patients. In particular, there was a significant reduction in intracranial bleeding and in fatal bleeding with DOACs compared with VKAs [14]. Paired with their comparable effectiveness were several advantages over VKAs: they have been shown to have predictable pharmacokinetics and pharmacodynamics, a low potential for drug–drug interactions, and are given at fixed doses without the need for routine coagulation monitoring [15]. Their major disadvantage however is the difficulty in DOAC overdose treatment. Both DOAC and warfarin overdosing can be associated with worse outcomes of major bleeding, stroke/systemic embolism, all-hospitalization and all-cause mortality [16, 17]. In the case of warfarin, diagnosis and treatment are relatively simple, with international normalized ratio (INR) monitoring and intravenous vitamin K readily available [18]. When it comes to DOACs, both are challenging. For rivaroxaban, edoxaban and apixaban their plasma concentrations can be measured using anti-factor Xa chromogenic assays, which reflect drug levels if calibrated. Nevertheless, such tests are infrequently available in emergency situations. For dabigatran a normal diluted thrombin time or ecarin chromogenic or clotting assay can be used, but only normal diluted thrombin time is reliable in high drug concentrations and its availability is limited. A normal prothrombin time (PT) or activated partial thromboplastin time (aPTT) cannot be used to exclude clinically relevant plasma concentrations of any of the DOACs [19]. A qualitative dipstick assay that detects DOACs in the urine is available, but the test has not been validated in patients with bleeding [20]. When a patient presents with uncontrolled or life-threatening bleeding in the course of DOAC overdose, reversal should be considered. Two licensed specific DOAC reversal agents are idarucizumab for reversal of dabigatran and andexanet alfa for reversal of apixaban and rivaroxaban. The drug level for dabigatran that requires reversal according to the recent studies is above 30 ng/ml. It is the same for Xa inhibitors. The concentration below 30 ng/ml is clinically irrelevant for reversal [21]. In terms of clinical usage, idarucizumab is a first line agent for dabigatran reversal and it is available in virtually every major hospital. Andexanet alfa is practically unavailable in Poland, due to its high price and controversial role in current clinical practice. To date it has not been proven superior to prothrombin complex concentrate (PCC), which provides a high possibility of reversal of rivaroxaban and apixaban [21].
Long-term pharmacotherapy of PE in cancer patients
The same change cannot be observed in extended PE treatment in patients with active cancer. It has been proven that the use of low molecular weight heparin (LMWH) over conventional VTE treatment (heparin followed by VKA) is beneficial to the patient. A study from 2003 showed significant reduction in VTE recurrence with LMWH compared with conventional (VKA) treatment without an increase in bleeding complications, making LMWH a leading treatment option for cancer patients [22]. LMWH has predictable pharmacokinetic properties and drug interactions, in contrast to VKA, and it does not depend on gastrointestinal absorption due to subcutaneous administration [23]. LMWH therapy does not require such rigorous monitoring and the therapeutic dosage is weight adjusted, making it well suited for cancer patients, whose weight can be very labile. Furthermore, the multiple conditions affecting cancer patients including malnutrition, vomiting, and liver dysfunction can significantly alter the pharmacokinetics of VKAs while LMWH remains notably less affected. LMWH therapy is flexible with a rapid onset of action and predictable clearance, allowing for frequent interruptions in anticoagulation therapy that may be required in cancer patients due to chemotherapy-induced thrombocytopenia, or prior to surgery or other invasive procedures [22]. In VKA therapy there is a delay of several days between the initiation of treatment and the appearance of a full anticoagulant effect as this depends on the clearance of clotting factors from the plasma, which makes required interruptions challenging [24]. In terms of quality of life, patients tend to prefer LMWH over VKAs. In a qualitative study undertaken to determine whether LMWH was acceptable in 40 palliative care patients, both in the community and inpatient units, the majority had been on warfarin and were switched to LMWH due to difficulties in controlling the INR or resistance to therapy. The majority of those patients preferred a daily injection of LMWH over the frequent INR monitoring required to achieve stable anticoagulation on warfarin. Many reported that the discomfort following injection was short lived and the freedom and simplicity of this therapy increased their quality of life [25].
Subcutaneous administration of LMWH is far from perfect in long-term usage as it lowers patients’ comfort of life, especially in months-long therapy. However, studies show that despite the discomfort of injections LMWH has a positive impact on quality of life and overall health in cancer patients surviving an episode of VTE [26].
DOACs are as effective as VKAs for the treatment of VTE and are associated with less frequent and less severe bleeding [21, 27]. They offer a promising treatment option, combining the lack of rigorous monitoring that was appealing to the patients when taking LMWH with oral administrations of VKA. The treatment is more convenient in patients with cancer, due to their oral administration in fixed-dose regimens and their lower cost compared with LMWH. Similarly to LMWH they can be used in patients with renal impairment, up to the level CrCl = 15 ml/min for some agents, with appropriate dosage adjustment and caution. None of the DOACs is recommended for CrCl < 15 ml/min [28]. When it comes to cancer-related thrombocytopenia they are not recommended if the platelet count is below 50 000/µl [29]. However, the number of cancer patients included in phase III trials of DOACs made up only 3–9% of total patients [28]. A randomized, open-label, non-inferiority trial compared edoxaban with LMWH in the secondary prevention of VTE in 1050 patients with cancer-associated thrombosis [30]. This trial showed that treatment with a fixed once-daily dose of oral edoxaban was non-inferior to dalteparin in the prevention of VTE recurrence or major bleeding over 12 months after randomization. The rate of recurrent VTE was numerically lower with edoxaban than with dalteparin (7.9% and 11.3%), with edoxaban showing a lower rate of recurrent symptomatic deep-vein thrombosis (DVT) (3.6% and 6.7%). The rate of PE was similar in both groups, 5.2% in edoxaban and 5.3% in the dalteparin group. Major bleeding occurred in 6.9% of the patients in the edoxaban arm and 4.0% in the dalteparin arm. The difference was associated mainly with the higher rate of upper gastrointestinal bleeding with edoxaban [28], which is consistent with results of previous studies of DOACs [21]. The increase in upper gastrointestinal major bleeding occurred mainly in patients who had entered the trial with gastrointestinal cancer [30]. A randomized, open-label pilot trial comparing rivaroxaban with dalteparin in 406 patients with VTE and cancer, 58% of whom had metastases, reported similar results [31]. The cumulative VTE recurrence rate at 6 months was 11% for dalteparin and 4% for patients receiving rivaroxaban. The 6-month cumulative rate of major bleeding was 6% for rivaroxaban and 4% for dalteparin. Most major bleeding events were gastrointestinal; no central nervous system bleeds occurred. Patients with esophageal or gastroesophageal cancer tended to experience more major bleeds with rivaroxaban than with dalteparin. The cumulative rate of clinically relevant non-major bleeding at 6 months was 4% for dalteparin and 13% for rivaroxaban [31]. Although not mentioned in the guidelines due to their late publication, two separate studies regarding apixaban were conducted. Conducted in 2018, the ADAM VTE trial randomized 300 patients with cancer and VTE to receive either apixaban for 6 months or subcutaneous dalteparin [32]. Oral apixaban therapy was associated with very low rates of bleeding and significantly lower VTE recurrence. Major bleeding up to 6 months occurred in none assigned to apixaban and 1.4% assigned to dalteparin. Recurrent VTE occurred in 0.7% in the apixaban group and 6.3% in the dalteparin group [32]. The second trial comparing apixaban to dalteparin was conducted in 2020 on 1155 recruited patients, of whom 97% had active cancer [33]. Patients with basal-cell or squamous-cell carcinoma of the skin, primary brain tumors, intracerebral metastasis, and acute leukemia were excluded. It was a randomized, controlled, investigator-initiated, open-label, noninferiority trial with blinded adjudication of the outcomes. Recurrent VTE occurred in 5.6% of patients from the apixaban group compared with 7.9% from the dalteparin group. Recurrent PE rates were lower in the apixaban arm (3.3% vs. 5.5%). The rates of major bleeding were similar between the two groups: 3.8% and 4% for apixaban and dalteparin, respectively. There was no significant difference between the groups in the rate of gastrointestinal bleeding, which contrasts with the results of previous studies [33]. The aforementioned trials provide evidence for DOAC therapy in patients without gastrointestinal cancer, with an anticipated low risk of bleeding who have no contradiction for oral treatment (Table I) [31–34].
Table I
Comparison of DOAC vs. LMWH trials
| Parameter | Hokusai VTE-Cancer, 2018 [34] | SELECT-D, 2018 [31] | ADAM-VTE, 2020 [32] | Caravaggio, 2020 [33] |
|---|---|---|---|---|
| Trial design | Open-label, noninferiority | Open-label, pilot | Open-label,investigator-initiated | Open-label, controlled, investigator-initiated, noninferiority |
| Number of patients | 942 | 406 | 300 | 1155 |
| Mean age | 64 | 67 | 64 | 67 |
| DOACs | Edoxaban | Rivaroxaban | Apixaban | Apixaban |
| Comparators | Daltepatin | Dalteparin | Dalteparin | Dalteparin |
| Inclusion criteria | Patients with active cancer and acute symptomatic or incidental proximal DVT and/or PE | Patients with active cancer and symptomatic or incidental PE, or symptomatic lower extremity proximal DVT | Patients with activecancer and acuteextremity DVT, PE, splanchnic or cerebralvein thrombosis | Patients with active cancer and acute symptomatic or incidental proximal DVT or PE |
| Cancer types | Gastrointestinal, lung, urogenital, breast, hematological, and gynecological cancer | Solid and hematologic malignancies (other than basal-cell or squamous-cell skin carcinoma) | Solid and hematologic malignancies | Cancers other than basal-cell or squamous-cell carcinoma of the skin, primary brain tumor, intracerebral metastases, or acute leukemia |
| Primary outcome meassurements | The composite of VTE recurrence or major bleeding | VTE recurrence | Episode of majorbleeding | VTE recurrence |
| Primary outcome results | Edoxaban 19.4%; Dalteparin 15.0% (RD = 4.4%; 95% CI: – 4.1 to 12.8%) | Rivaroxaban 4% (95% CI: 2 to 9%); Dalteparin 11% (95% CI: 7 to 16%); (HR = 0.43; 95% CI: 0.19 to 0.99) | Apixaban 0%;Dalteparin 1.4%(p = 0.138) | Apixaban 5.6%; Dalteparin 7.9% (HR = 0.63; 95% CI: 0.37 to 1.07; p < 0.001 for noninferiority) |
Differences within the DOAC group
The 2019 ESC pulmonary embolism guidelines approve of edoxaban and rivaroxaban use in the long-term anticoagulation therapy following an episode of PE, with edoxaban having a higher level of evidence. However, both edoxaban and rivaroxaban are excluded from the use in therapy of patients with gastrointestinal cancer [28]. The 2019 pulmonary embolism treatment guidelines were the first guidelines that put LMWH on par with rivaroxaban and edoxaban. In the newer 2022 ESC cardio-oncology guidelines, edoxaban, rivaroxaban, and apixaban are recommended for the treatment of VTE in cancer patients. Patients with any of the following bleeding risk factors are excluded: unoperated gastrointestinal (GI) or genitourinary malignancies, history of recent bleeding or within 7 days of major surgery, significant thrombocytopenia (platelet count < 50 000/µl), severe renal dysfunction (creatinine clearance (CrCl < 15 ml/min), or GI comorbidities. LMWH should be used in case of unfavorable drug-drug interactions, for patients with inoperable gastrointestinal cancer, severe renal impairment (eGFR < 15 ml/min), gastrointestinal toxicity or other gastrointestinal conditions such as gastric ulcers [29, 35].
In an observational study at the Mayo Clinic, comparing apixaban to rivaroxaban and enoxaparin, there was no significant difference in the rate of recurrence or major bleeding among patients from different treatment groups. Rivaroxaban therapy was associated with a higher rate of clinically relevant non-major bleeding. The Mayo clinic study is the first study reporting a difference in mortality rates in high-risk cancer patients based on anticoagulant assignment with rivaroxaban showing lower mortality compared to apixaban and enoxaparin [36].
Another Mayo clinic study focused on bleeding in patients with gastrointestinal cancer treated with apixaban, rivaroxaban, or enoxaparin. In luminal GI cancer apixaban had a higher rate of major bleeding compared with enoxaparin and compared with patients with non-GI cancer treated with apixaban. However, previous reports that patients with GI cancer treated with rivaroxaban have an increased risk of bleeding were not substantiated. The aforementioned higher rate of clinically relevant non-major bleeding was also observed in this study both in patients with GI cancer and in patients with non-GI cancer [37].
There was also a retrospective study utilizing U.S. electronic health record (EHR) data from January 2013 to December 2020 comparing apixaban and rivaroxaban. It included adults diagnosed with active cancer, excluding esophageal, gastric, unresected colorectal, bladder, noncerebral central nervous system cancers and leukemia, who experienced VTE and received a therapeutic VTE dose of rivaroxaban or apixaban. Similar effectiveness and safety were reported for treatment of cancer-associated VTE through 6 months with both drugs [38]. Rivaroxaban and apixaban were the only anticoagulants from the DOAC group that were compared in cancer-associated VTE. As of this date, dabigatran has not been specifically studied in a randomized trial in patients with cancer-associated VTE.
Patterns of anticoagulant utilization
Currently the pharmacological anticoagulant agents most frequently used for cancer-associated VTE are LMWH and DOACs, with LMWH being the first choice for initial anticoagulation treatment, as shown in a real-world analysis, from September 2018 to January 2020 [39]. In the retrospective cohort study utilizing data from January 1, 2015, to May 31, 2018, the results were similar. LMWH and unfractionated heparin (UFH) were the most common initial treatments (35.2 and 27.4%, respectively) with DOACs being used in 9.6% of the cases. DOACs were the most common initial post-discharge outpatient option. Within 3 months after discharge, DOACs were most frequently used in the outpatient setting (40.3%), followed by LMWH (18.0%) and warfarin (10.7%); nearly one-third of patients (30.5%) had no outpatient anticoagulants. Persistence and adherence in outpatients appeared higher in patients using DOACs or warfarin versus LMWH or UFH [40]. Furthermore, a comparative effectiveness study from 2023, which included 5100 patients, reported a general preference for DOAC therapy use, with nearly twice as many patients receiving this class of medication compared with other classes [41].
Conclusions
The treatment of cancer-associated thrombosis presents several challenges, including increased risks of bleeding and recurrent VTE. Both VKAs and DOACs were proven to be an effective treatment option in cancer-associated PE [28], with DOACs having a lower risk of bleeding and better results than LMWH. The DOACs provide an improved therapeutic option for many patients, while having fewer limitations and drug-drug interactions. VKAs, while less effective, still should be considered as a valid alternative, due to their high persistence and adherence rates compared to LMWH and UFH. Overall, assessment of patient- and cancer-related variables, and patient preference, are key to choosing an anticoagulant regimen.
