This study had three major findings: First, despite no differences in age, sex, body weight, or renal function, patients with asymptomatic PE had better vital signs and lower severity with a lower level of RV dysfunction but a higher prevalence of proximal DVT than patients with symptomatic PE. Patients with asymptomatic DVT were older and often female with lower body weight and renal function, but had a higher prevalence of distal DVT relative to those with symptomatic DVT. In both groups, active cancer and recent surgery were more prevalent in asymptomatic patients than in symptomatic patients. Second, regarding rivaroxaban treatment, asymptomatic PE patients mostly had an intensive rivaroxaban treatment with a modestly shorter treatment duration than symptomatic PE patients. In contrast, asymptomatic DVT patients more often received an off-label reduced dose of rivaroxaban treatment with a significantly shorter treatment duration than symptomatic DVT patients. Third, in the PE and DVT groups, there were no differences in the incidences of recurrence or aggravation of symptomatic VTE, major bleeding, or clinically relevant events between the asymptomatic and symptomatic groups.
Characteristics and clinical outcomes of patients with asymptomatic PE
We first clarified the difference in patient characteristics between asymptomatic and symptomatic PE patients who received rivaroxaban treatment in Japan. No differences were observed in age, female sex, body weight, or renal function between the asymptomatic and symptomatic PE groups, but asymptomatic PE patients were at a lower risk of PE, which was reflected by better vital signs, less frequent massive PEs, and lower RV dysfunction assessed by the RV/LV diameter ratio. Unexpected and incidentally detected PE is found in 3.3–5.0% of cancer patients and 1–2% of all thoracic CT scans [7, 18, 19]. Our data indicated that the rate of active cancer in the asymptomatic group was 27%, which was higher than that in the symptomatic PE group. Of all incidentally discovered PEs, 11% to 27% are said to be confined to subsegmental vessels [9, 10, 20]. In this study, we did not have any data regarding the segmental or subsegmental PE. However, approximately 80% of the asymptomatic PE patients had non-massive PE, suggesting that some patients had subsegmental PE. The effects of treating incidental PE by direct oral anticoagulants (DOAC) have not yet been evaluated in large prospective studies. There are some real-world data supporting the treatment of incidentally detected PE in patients with known VTE risk factors such as cancer because these patients have been reported to have high rates of recurrent VTE and mortality [10], especially those who had not received anticoagulation therapy [11]. Unfortunately, Japanese guidelines have not stated a treatment strategy for particular patients with asymptomatic PE and concomitant cancer or those without cancer thus far [2]. Nonetheless, the 2019 European Society of Cardiology guidelines recommend that patients with incidentally detected PE and concomitant cancer should be managed similarly to those with symptomatic PE, also stating that no firm data exist [21], as similarly recommended by the American Society of Clinical Oncology (informal consensus, moderate strength recommendations) [22]. The higher proportion of proximal DVT and active cancer in the asymptomatic PE group in this study may be a consequence of the physicians’ motivation to prescribe rivaroxaban treatment to improve the prognosis even in such asymptomatic PE patients. From another aspect, asymptomatic PE can also lead to pulmonary hypertension. In recent years, the prevalence of CTEPH after symptomatic acute PE treatment has been reported to be 3.8–5.4% [23, 24]. Theoretically, asymptomatic PE patients might be underdiagnosed and thus not receive anticoagulant therapy, leading to an increased risk of developing CTEPH. In fact, the prognosis of incidentally discovered PE and symptomatic PE is similar [25].
Due to this trend, the American College of Chest Physicians (Grade 2B) recommends treating patients with incidentally discovered PE and symptomatic PE similarly to those with symptomatic VTE [26]. Therefore, in the real-world setting, physicians might have decided to administer the initial on-label dose of rivaroxaban (30 mg) in most asymptomatic PE patients. However, the dose might have been reduced in some patients at low-VTE risk, such as subsegmental PE. Our study also showed equivalent incidences of recurrent VTE, major bleeding, and a composite outcome between asymptomatic and symptomatic PE patients under rivaroxaban treatment. Major bleeding events were numerically, and minor bleeding events significantly, lower in the asymptomatic than the symptomatic PE group. None of the asymptomatic PE patients had fatal bleeding. This provides support for an evaluation that the benefit of improved prognosis outweighs the risk of bleeding burden from rivaroxaban treatment, even in most asymptomatic PE patients.
Characteristics and clinical outcomes of patients with asymptomatic DVT
Our study found that distal DVT accounted for 73.9% of asymptomatic DVT patients, which was a higher rate than that in symptomatic DVT patients. Asymptomatic DVT patients had a higher incidence of recent surgery and trauma. These results suggest that DVT was incidentally detected after general or orthopedic surgery in most asymptomatic DVT patients. Asymptomatic distal DVT that was detected by postoperative screening has increased in recent years [12]. Regarding VTE recurrence, asymptomatic distal DVT is considered even less risky than symptomatic peripheral DVT [13]. In a prospective blinded study, the incidence of PE in untreated distal DVT patients was as low as 1.6% [27]. Distal DVT has fewer PE recurrences than proximal DVT [28]. A double-blind, randomized controlled study of low-molecular-weight heparin treatment of symptomatic distal DVT showed no benefit from anticoagulation in preventing worsening DVT or symptomatic PE (3% vs. 5%; P = 0.54) and only increased hemorrhagic complications (4% vs. 0 %; P = 0.0255) [29]. Therefore, there is no evidence supporting the benefit of recent anticoagulant therapy, such as heparin or warfarin, in asymptomatic DVT or distal DVT. This study shed light on the potential for DOAC treatment in asymptomatic DVT patients in that the annual incidence of recurrent VTE in the asymptomatic DVT group did not differ from that in the symptomatic DVT group under rivaroxaban treatment (1.7 vs. 3.1 events per 100 patient-year; P = 0.21).
The annual recurrent VTE incidence was similar even to that of symptomatic Japanese and global VTE patients who had been treated with rivaroxaban in the J-EINSTEIN-PE/DVT [30] (1.8%) and EINSTEIN-PE/DVT [31, 32] (1.8%) studies, respectively.
Additionally, the incidence of major bleeding in the asymptomatic DVT group was not different from that in the symptomatic DVT group (5.2 vs. 3.0 events per 100 patient-year; P = 0.45), but this incidence was modestly higher compared with the annual rates reported in the J-EINSTEIN-PE/DVT (0.0%) and EINSTEIN-PE/DVT (1.1%), respectively. Therefore, the risks and benefits should be carefully considered when initiating rivaroxaban in asymptomatic DVT patients, especially in patients with a high risk of bleeding from cancer. Major bleeding events in this study were mostly due to concomitant active cancer (67%, 4 of a total of 6 patients suffering from major bleeding, Table 4). A retrospective observational study of Japanese VTE patients treated with DOACs [33] has also stated that bleeding events due to active cancer complications should be considered more important than VTE-related events in patients with active cancer complicated with VTE. Therefore, in the real-world setting of this study, it is speculated that the asymptomatic compared with the symptomatic DVT group was more often administered off-label underdosed rivaroxaban by physicians, with a shorter treatment duration, possibly due to the high bleeding and low VTE risk in this group that was older and had a higher female sex ratio, lower body weight and CrCL, and a higher proportion of distal DVT and active cancer.
Clinical implications
Our data may provide a basis for using rivaroxaban to treat and prevent the recurrence of VTE in asymptomatic PE (with or without DVT) and DVT-only patients. Patients with asymptomatic PE displayed the patient characteristics of those with incidentally detected PE as reported previously; i.e., the PE severity involved mostly low-risk non-massive and occasionally sub-massive PE, but the concomitant cancer rate was high. Despite use of intensive rivaroxaban treatment in the asymptomatic PE group, clinically relevant events, including VTE recurrence and mortality, were similar to those in the symptomatic PE group. In addition, major bleeding and fatal bleeding events were low. Our data suggest that intensive rivaroxaban treatment can be an option for prophylaxis of VTE and VTE-related complications, even in asymptomatic PE patients with or without concomitant cancer, as recommended previously for incidental PE patients [21, 22, 26].
The asymptomatic DVT group also had a higher rate of cancer incidence, similar to the PE group, and concomitant active cancer was one of the risks for clinically relevant events, mostly driven by cancer-related death rather than bleeding or VTE-related death in both the PE and DVT groups. Our study strongly recommends that concomitant active cancer should be carefully managed in both the PE and DVT-only groups. Notably, the asymptomatic DVT group had a higher risk of bleeding (related to older age, female sex, lower body weight, and lower renal function) and more distal DVT than the asymptomatic PE group. Due to this patient background, asymptomatic DVT patients more often initially received an off-label underdose rivaroxaban with a shorter treatment duration than did the symptomatic DVT and the symptomatic/asymptomatic PE group. Recurrent VTE was lowest in this group (1.7 events per patient-year), however, major bleeding events were highest in the asymptomatic DVT group among the four groups (5.2 vs. 3.0 events per patient-year for symptomatic DVT, 1.9 for asymptomatic PE, and 2.7 for symptomatic PE, respectively). Therefore, whether to initiate rivaroxaban should be carefully judged while considering the risks and benefits for asymptomatic DVT patients. Once physicians decide to initiate rivaroxaban, an underdosed rivaroxaban with a treatment duration adjustment based on careful monitoring of the bleeding and VTE risks may be a choice in such patients [34].
Limitations
This study has some limitations. First, the sample size was relatively small, and the number of clinical events was also limited because it included only Japanese patients. Second, selection bias occurred. Patients enrolled in this study received rivaroxaban at the discretion of their physicians, and the absence from the study of patients who were diagnosed with VTE but did not receive anticoagulation must be considered. Thus, selection bias in enrolling patients must be carefully considered when interpreting the results of this study. Finally, information regarding the patients enrolled was lacking. In particular, the lack of information on the detailed location of thrombi in pulmonary emboli and the clinical stage of patients with malignant tumors may have led to inadequate analyses.