Abstract
Background
Clinical guidelines indicate that in patients with cancer-associated thrombosis (CAT), anticoagulant treatment should be continued beyond 6 months as long as the cancer is active. We aimed to analyse the safety of low-molecular-weight heparin (LMWH) beyond 12 months in patients with CAT.
Methods
We performed a post hoc analysis of consecutive CAT patients from October 2008 to December 2019. The primary outcome was the rate of clinically relevant bleeding (CRB), and we compared two periods (1–12 vs. 12–24 months). Hazard ratio (HR), competing risk analysis and sensitivity analyses were performed.
Results
Of the 588 patients included, 30.1% (n = 177) received LMWH beyond 12 months. The rate of CRB in the first 12 months compared to the 12–24 month period was 3.2 per 100 patients/month (95% CI 2.5–4.1) vs. 0.9 per 100 patients/month (95% CI 0.4–1.5), (P < 0.0001). The competing risk analysis of CRB comparing both periods showed a lower sub-distribution hazard ratio (SHR) during the period 12–24 months (SHR: 0.5, 95% CI: 0.3–0.8, P < 0.001).
Conclusion
In patients with cancer-associated thrombosis under anticoagulant treatment with LMWH, the rate of clinically relevant bleeding and major bleeding were lower beyond 12 months.
Subject terms: Valvular disease, Cancer
Background
The relationship between venous thromboembolic disease (VTE) and cancer is well-established [1, 2]. In patients with cancer, the presence of VTE has a negative impact on morbidity and mortality, and it is considered the second cause of death after tumour progression [3]. The incidence of VTE in cancer patients varies according to histology, tumour stage and cancer treatment [2].
Anticoagulant treatment of cancer-associated thrombosis (CAT) can be a challenge, balancing treating and preventing bleeding and recurrent VTE [4]. In patients with CAT, clinical practice guidelines recommend anticoagulant treatment for at least 3–6 months [5–8]. However, there is no evidence for the optimal duration of anticoagulant treatment; it is suggested to continue for as long as the cancer is active, or the patient is receiving oncological treatment. On the other hand, due to lack of evidence, the guidelines suggest individualising treatment, by assessing the risk-benefit of anticoagulant treatment and taking into account patient preferences. Several studies have analysed the safety and efficacy of anticoagulant treatment beyond 6 months. The TiCAT (Tinzaparin in Cancer-Associated Thrombosis) study and DALTECAN study (Evaluation of Dalteparin for Long-term [One Year] Treatment of Blood Clots in Subjects With Cancer) were prospective, one-arm, multicentre, open-label studies that analysed, in patients with cancer, the safety of anticoagulant treatment beyond 6 months with tinzaparin and dalteparin, respectively [9, 10]. Similarly, a post hoc analysis of the Hokusai Cancer VTE trial (open-label, multicentre, international) examined the safety and efficacy of treatment with edoxaban and dalteparin beyond 6 months and found a low rate of bleeding and a low rate of recurrent VTE during the 12-month follow-up [11]. Likewise, the post hoc analysis of SELECT-D (multicentre, randomised, open-label study which tested rivaroxaban versus placebo in patients with CAT) was underpowered to detect a statistically significant reduction in recurrent VTE with extended anticoagulation [12].
The evidence generated in recent years on anticoagulant treatment between 6 and 12 months after VTE has shown that the rate of recurrent VTE and bleeding is not continuous over time. For that reason, we aimed to analyse the safety of low-molecular weight heparin (LMWH) beyond 12 months in patients with CAT.
Materials and methods
Study design
We performed a post hoc analysis of consecutive patients evaluated in several prospective studies from October 2008 to December 2019 (2013PI/200, Hispalis study [13]; TiCAT study [9], QCA study [14], 0191-N-14). This post hoc analysis was evaluated and approved by the Ethical Committee of the centre according to Spanish Regulatory Authorities (0511-N-22). The study was conducted in accordance with the principles of the Declaration of Helsinki and International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice and in full conformity with relevant regulations. Documents constituting the master file of the study included documents described in the Good Clinical Practice standard (CPMP/ICH/135/95). In this project, the collection, processing and analysis of all data were carried out anonymously, and only for the purposes of the project. All data were protected in accordance with the European Union Directive 2016/679 of the European Parliament and the European Council, of April 27, 2016, regarding the protection of persons and their personal data.
Patient selection
Adult patients with active cancer and a newly diagnosed incidental or acute symptomatic VTE (deep vein thrombosis [DVT], pulmonary embolism [PE] or unusual VTE) in the Hospital Universitario Virgen del Rocio de Sevilla (Spain) were considered for inclusion. Patients with no possibility of follow-up and those aged under 18 years were excluded.
Active cancer was defined as a diagnosis of cancer (excluding basal cell or squamous cell carcinoma of the skin) within 6 months before enrolment, treatment for cancer within 6 months before enrolment, or documented recurrent or metastatic cancer [6, 8, 15]. All patients had confirmed imaging tests of the thrombotic event by computed tomography, lung scintigraphy, Doppler ultrasonography, or compressive ultrasonography [16–19]. Diagnosis of the tumour required histological confirmation. Major bleeding was assessed according to the following International Society on Thrombosis and Haemostasis (ISTH) criteria: fatal bleeding and/or bleeding in a critical area or organ such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial or intramuscular, organs with compartment syndrome and/or haemorrhage causing a drop in haemoglobin level ≥20 g/L or involving the transfusion ≥two units of whole blood or red blood cells. Likewise, clinically relevant bleeding (CRB) was defined according to the ISTH criteria as any bleeding that required medical intervention by a professional, required hospital admission or face-to-face evaluation [20]. CRB included major bleeding plus clinically relevant non-major bleeding.
Treatment and follow-up
Patients were managed according to the routine clinical practice of attending physicians (there was no standardisation of treatment). Follow-up was updated up until December 31, 2021, and included all oncology clinic visits, VTE consultations and primary care to collect data about clinically relevant bleedings, recurrent VTE, anticoagulant treatment and death. An independent Data Safety Monitoring Committee retrospectively reviewed all safety and efficacy outcomes (clinically relevant bleedings, VTE recurrences and death) (SL-R and MB-H, supervised by LJ-P).
Outcomes
The primary outcome was the rate of CRB under anticoagulant treatment comparing two periods of follow-up: 1–12 months and 12–24 months. Secondary outcomes included: (1) rate of major bleeding under anticoagulant treatment comparing two periods of follow-up (1–12 months and 12–24 months); (2) time to CRB and time to major bleeding; (3) efficacy outcomes: rate of symptomatic, recurrent, proven VTE in the two periods (1–12 months and 12–24 months) and time to recurrent VTE; and (4) sensitivity analyses to investigate the possible heterogeneity of the effects for the following variables: cancer treatment (yes/no), sex (male/female), age (≤65 vs. >65 years), metastases (yes/no), incidental VTE vs. acute symptomatic VTE, VTE location (PE vs. no PE) y Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. >0).
Patients with clinically suspected recurrent VTE were evaluated using the same method as for the initial diagnosis. PE needed to be confirmed by ventilation–perfusion scintigraphy or thorax CT-scan. Recurrent PE was diagnosed if a high-probability lung scan revealed a new area of segmental perfusion defect with ventilation mismatch or if new non-enhancing central filling defects were found on helical computed tomography. Patients with clinically suspected (recurrent) DVT were assessed by compression ultrasonography (or Doppler ultrasonography), and the diagnosis of a new DVT required clear evidence of thrombosis in a previously uninvolved proximal vein segment.
Statistical analyses
Quantitative variables were expressed as (mean ± standard deviation) and the qualitative variables were expressed as numbers and percentages. The primary analysis of safety was performed by comparing CRB rates per month at 1–12 months and at 12–24 months and their 95% confidence interval (CI) using the Clopper–Pearson exact method. The rate was defined as the number of patients with CRB divided by the total number of patients and months at risk of bleeding. We used the Student t test (or Mann–Whitney U test when appropriate) and the χ2 test (or Fisher’s exact test when appropriate) to compare continuous or categorical variables.
We analysed the time to the event (CRB, major bleeding or recurrent VTE) using the Kaplan–Meier method (Mantel–Cox Log Rank test). The hazard ratio (HR) and corresponding 95% CI were calculated. The proportion of patients with symptomatic recurrent VTE during the study period was summarised with a 95% CI. A Cox regression with non-parametric proportional hazards adjustment was performed for the sensitivity analysis based on cancer treatment (yes/no), sex (male/female), age (≤65 vs. >65 years), metastases (yes/no), incidental VTE vs. acute symptomatic VTE, VTE location (PE vs. no PE) y Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. >0). Since death can interfere with the occurrence of the event of interest, generating an upward bias in the estimation of the cumulative incidence, a competing risk analysis was performed using the Fine–Gray test. Likewise, the association between risk factors and CRB was evaluated by calculating the sub-distribution of risk ratios with the competing risk approach. A P value <0.05 was considered statistically significant. The IBM SPSS software and R Core Team (2021) software were used. A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. The libraries used were library(survival), library(KMsurv), library(survMisc), library(ggfortify), library(ggplot2), library(gtsummary), library(cmprsk), library (riskRegression), library(prodlim).
Results
Study population
From October 2008 to December 2019, we evaluated 797 patients with cancer and VTE. After excluding 162 who did not receive LMWH and 47 with no follow-up possible, 588 patients were included (Fig. 1). There were no significant differences in patients included vs. lost on follow-up (Supplementary Table 1). The median age was 65 years (p25–p75: 56–74), 52.9% were men (n = 312), adenocarcinoma was the most frequent histology (n = 258, 44.2%), 60.9% had metastases (n = 343) and 69.9% were undergoing cancer treatment at the time of VTE diagnosis (n = 411) (Table 1). The median of anticoagulant treatment was 7.6 months (p25–75: 3.4–14.5 months). The type of LMWH used was: tinzaparin (n = 353, 59.8%), enoxaparin (n = 126, 21.4%), bemiparin (n = 101, 17.1%) and dalteparin (n = 10, 1.7%). One hundred eighty four patients (31.3%, 95% CI 27.6% to 35.2%) died during the first 12 months and 231 (39.3%, 95% CI 35.3% to 43.4%) at 24 months. The median time to death was 5.7 months (p25–75: 2.7–10.4). The patients included in cohort 12–24 months had more DVT plus PE as VTE event presentation (25% vs. 11.7%). In the other epidemiological, clinical characteristics and laboratory parameters, there were no differences in both groups (Table 1).
Fig. 1.
Flow diagram and mean findings of the study.
Table 1.
Baseline characteristics of patients included.
| Baseline characteristics | LMWH (1–12 months) (n = 413) | LMWH (12–24 months) (n = 177) | Total (N = 588) |
|---|---|---|---|
| Gender (male), n (%) | 223 (54%) | 89 (50.3%) | 312 (52.9%) |
| Age (years), (p25–75) | 65 (55–74) | 66 (56–73) | 65 (56–74) |
| Weight (kg), mean ± SD | 72 (10) | 75 (9) | 73 (10) |
| Incidental VTE, n (%) | 119 (28.9%) | 53 (30.1%) | 172 (29.3%) |
| VTE event, n (%) | |||
| DVT at the lower extremity | 151 (36.7%) | 54 (30.7%) | 205 (34.9%) |
| PE alone | 137 (33.3%) | 59 (33.5%) | 196 (33.3%) |
| DVT + PE | 48 (11.7%) | 44 (25%) | 92 (15.6%) |
| DVT at the upper extremity | 41 (10%) | 11 (6.2%) | 52 (8.8%) |
| Unusual DVT | 35 (8.5%) | 8 (4.5%) | 43 (7.3%) |
| Histology (n = 574), n (%) | |||
| Adenocarcinoma | 185 (45.2%) | 73 (41.7%) | 258 (44.2%) |
| Ductal | 30 (7.3%) | 22 (12.6%) | 52 (8.9%) |
| Epidermoid | 33 (8.1%) | 14 (8%) | 47 (8%) |
| Urothelial | 21 (5.1%) | 10 (5.7%) | 31 (5.3%) |
| Lymphoma | 18 (4.4%) | 11 (6.3%) | 29 (5%) |
| Sarcoma | 13 (3.2%) | 5 (2.9%) | 18 (3.1%) |
| Clear cell | 8 (2%) | 8 (4.6%) | 16 (2.7%) |
| Glioblastoma | 10 (2.4%) | 3 (1.7%) | 13 (2.2%) |
| Leukaemia | 7 (1.7%) | 1 (0.6%) | 8 (1,4%) |
| Multiple myeloma | 5 (1.2%) | 3 (1.7%) | 8 (1.4%) |
| Small cell lung | 5 (1.2%) | 3 (1.7%) | 8 (1.4%) |
| Other | 67 (16.6%) | 19 (11%) | 86 (15%) |
| ECOG performance status, (n = 515), n (%) | |||
| ECOG 0 | 96 (27.3%) | 48 (29.4%) | 144 (28%) |
| ECOG 1 | 175 (49.7%) | 103 (63.2%) | 278 (54%) |
| ECOG 2 | 67 (19%) | 10 (6.1%) | 77 (15%) |
| ECOG 3 | 13 (3.7%) | 2 (1.2%) | 15 (2.9%) |
| ECOG 4 | 1 (0.3%) | 0 (0%) | 1 (0.2%) |
| Cancer type (n = 588), n (%) | |||
| Colorectal | 61 (14.8%) | 29 (16.5%) | 90 (15.3%) |
| Lung | 57 (13.8%) | 28 (15.9%) | 85 (14,5%) |
| Breast | 46 (11.2%) | 26 (14.8%) | 72 (12.2%) |
| Haematologic | 31 (7.5%) | 16 (9.1%) | 47 (8%) |
| Gynaecological | 32 (7.8%) | 8 (4.5%) | 40 (6.8%) |
| Prostate | 27 (6.6%) | 9 (5.1%) | 36 (6.1%) |
| Bladder | 23 (5.6%) | 8 (4.5%) | 31 (5.3%) |
| Renal | 16 (3.9%) | 14 (8%) | 30 (5.1%) |
| Pancreas | 20 (4.9%) | 6 (3.4%) | 26 (4.4%) |
| Cerebral | 13 (3.2%) | 6 (3.4%) | 19 (3.2%) |
| Ear, nose and throat (ENT) | 16 (3.9%) | 5 (2.8%) | 21 (3.6%) |
| Gastric | 5 (1.2%) | 1 (0.6%) | 6 (1%) |
| Other | 65 (15.8%) | 20 (11.4%) | 85 (14.5%) |
| Metastases (n = 588), n (%) | 241 (61.3%) | 102 (60%) | 343 (60.9%) |
| Oncological treatment (n = 588), n (%) | 286 (69.4%) | 125 (71%) | 411 (69.9%) |
| Platinum | 78 (25.7%) | 29 (23.6%) | 107 (25.1%) |
| Monoclonal antibody | 48 (15.8%) | 20 (16.3%) | 68 (15.9%) |
| Tyrosine kinase inhibitors | 17 (5.6%) | 9 (7.3%) | 26 (6.1%) |
| Other chemotherapy | 163 (53.6%) | 79 (64.2%) | 242 (56.7%) |
| Hormonal treatment | 22 (7.2%) | 9 (7.3%) | 31 (7.3%) |
| Radiotherapy up 30 days before VTE (n = 150), n (%) | 5 (6.2%) | 6 (8.7%) | 11 (7.3%) |
| Laboratory parameters at VTE event | |||
| Leucocytes (109/L) (n = 212), mean ± SD | 8.34 (4.77) | 7.12 (2.55) | 7.78 (3.96) |
| Platelet count (109/L) (n = 555), mean ± SD | 250 (119) | 253 (129) | 251 (94) |
| Platelets <100 × 109/L (n = 555), n (%) | 15 (3.9%) | 7 (4.2%) | 22 (4%) |
| Creatinine clearance (mL/min) (n = 399), mean ± SD | 95.4 (35.4) | 91.1 (31.6) | 93.9 (34.4) |
| Creatinine clearance <50 mL/min (n = 399), n (%) | 5 (4.3%) | 12 (12.5%) | 17 (8%) |
SD standard deviation, VTE venous thromboembolism, PE pulmonary embolism, DVT deep venous thrombosis, ECOG Eastern Cooperative Oncology Group.
Primary outcomes
Eighty-two CRBs (13.9%; 95% CI 11.3–17%) were reported at 24 months. The rate of CRB events in the first 12 months compared to the 12–24 months was 3.2 per 100 patients/month (95% CI 2.5–4.1) vs. 0.9 per 100 patients/month (95% CI 0.4–1.5), respectively (P < 0.0001). Median time until CRB was 4.5 months (p25–p75: 1.4–9.2). Seventy-one CRBs occurred during the first 12 months, and 11 in the period 12–24 months. Patients in the 12–24 month group had fewer CRBs than those in the 1–12-month group, with an HR of 0.2 (95% CI 0.1–0.4; P < 0.001) (Fig. 2). Due to the effect that mortality could have on CRB (Fig. 3), we performed competing risk analysis by the Fine–Gray method, with an SHR of 0.5 (95% CI 0.3–0.8). Table 2 shows the locations of clinically relevant bleeding.
Fig. 2.
Cumulative incidence of clinically relevant bleeding in period 1–12 months and 12–24 months.
Fig. 3.
Kaplan–Meier curve with cumulative clinically relevant bleeding and death in the period 1–12 months and 12–24 months.
Table 2.
Clinically relevant bleeding locations.
| Cause of bleeding | n | % |
|---|---|---|
| Drop in haemoglobin level ≥20 g/L | 21 | 25.6% |
| Gastrointestinal (GI) bleeding | 11 | 13.4% |
| Epistaxis | 8 | 9.8% |
| Haematuria | 7 | 8.5% |
| Haematoma | 6 | 7.3% |
| Hematoma secondary to function | 6 | 7.3% |
| Haematuria and drop in haemoglobin level ≥20 g/L | 4 | 4.9% |
| Intracranial bleeding | 4 | 4.9% |
| Hematoma and drop in haemoglobin level ≥20 g/L | 3 | 3.7% |
| Intraabdominal bleeding | 3 | 3.7% |
| Haemoptysis | 3 | 3.7% |
| Bleeding related tumour | 1 | 1.2% |
| Haemoptysis, GI bleeding and drop in haemoglobin level ≥20 g/L | 1 | 1.2% |
| Vaginal bleeding | 1 | 1.2% |
| Traumatic bleeding | 1 | 1.2% |
| GI bleeding drop haemoglobin level ≥20 g/L | 1 | 1.2% |
| Haemothorax | 1 | 1.2% |
| Total | 82 | 100% |
Secondary outcomes
In the period 1–12 months, there were 31 major bleeding events (5.3%; 95% CI 3.6–7.4%), and in the period 12–24 months there were 4 major bleeding events (0.7%; 95% CI 0.2–1.7%). The rate of major bleeding in the first 12 months compared to 12–24 months was 1.29 per 100 patients/month (95% CI 0.9–1.8) vs. 0.3 per 100 patients/month (95% CI 0.08–0.8), respectively (P < 0.005). Median time until major bleeding was 4.7 months (p25–p75: 1.4–8.3).
At 24 months, there were 55 recurrent VTE events during anticoagulant treatment (9.4%; 95% CI 7.1–12%). Of these, 34 occurred in the period 1–12 months and 21 in the period 12–24 months. The rate of recurrent VTE events in the first 12 months compared to 12–24 months was 1.54 per 100 patients/month (95% CI 1.07– 2.16) vs. 1.65 per 100 patients/month (95% CI 1.02–2.52, P: 0.81), respectively. Median time until recurrent VTE was 3.9 months (p25–p75: 1.3–7.5). Recurrent VTE locations most frequently were PE (44.8%) and lower limb DVT (32.8%). Median time until death was 5.7 months (p25–p75: 2.7–10.4).
In the period 1–12 months, a subgroup analysis (metastasis, age, incidental thrombosis, ECOG, age and sex) found that variables associated with CRB were incidental VTE and PE location of VTE, with an HR of 1.7 (95% CI 1.0–2.7) and 1.7 (95% CI 1.1–2.8) (Table 3). In the competing risk analysis, incidental VTE remained statistically significant with an SHR of 1.7 (95% CI 1.1–2.8; P: 0.024). In the period 12–24 months, subgroup analysis did not find any variable associated to CRB.
Table 3.
Cox regression with a hazard ratio of clinically relevant bleeding in the period 1–12 months and 12–24 months.
| Variable | Cox Regression in the period 1–12 months HR (95% CI) | P value | Cox Regression in the period 12–24 months HR (95% CI) | P value |
|---|---|---|---|---|
| Metastases | 1 (0.6–1.6) | 0.999 | 3.5 (0.8–16.3) | 0.072 |
| Incidental VTE | 1.7 (1.1–2.7) | 0.041 | 2 (0.6–6.4) | 0.28 |
| Gender (male/female) | 0.9 (0.6–1.5) | 0.73 | 0.8 (0.3–2.8) | 0.773 |
| Age (≤ 65 vs. >65 years) | 0.9 (0.6–1.4) | 0.57 | 1.6 (0.5–5.4) | 0.453 |
| Oncological treatment | 0.9 (0.5–1.4) | 0.565 | 4.9 (0.6–38.5) | 0.062 |
| ECOG performance status (0 vs. >0) | 1.1 (0.6–2.0) | 0.789 | 1.6 (0.4–7.7) | 0.511 |
| VTE location (PE vs. no PE) | 1.7 (1.1–2.8) | 0.024 | 0.7 (0.2–2.4) | 0.597 |
VTE venous thromboembolism, ECOG Eastern Cooperative Oncology Group, PE pulmonary embolism.
Discussion
Our study of unselected patients with cancer and VTE demonstrated the safety of LMWH beyond 12 months in patients with CAT, with a rate of clinically relevant bleeding and major bleeding in the period 12–24 months significantly lower than in the period 1–12 months. There were no differences in rates of recurrent VTE in the two periods. In the period 1–12 months, incidental VTE was associated with a higher rate of clinically relevant bleeding. These findings showed the safety of low-molecular weight heparin beyond 12 months, with a non-continuous risk of clinically relevant bleeding along time.
Clinical characteristics of the patients included in this study were similar to other cohorts published [10, 21]. The presence of metastases was similar in our cohort (60.9%) to other studies such as the DALTECAN study (62%) [10] and to the dalteparin arm of CLOT study (64%) [21]. On the other hand, the Hokusai VTE Cancer study included a lower percentage of metastases (41.3%) [11]. The TICAT and DALTECAN studies observed a trend towards a lower rate of major bleeding when comparing 1–6 versus 7–12 months [9, 10]. In the TICAT study, there was a rate of major bleeding during the first 6 months of 2.8% and a rate of 2.1% in the period 7–12 months [9]. In the DALTECAN study, the rate of major bleeding during the first 6 months was 7.8%, and in the period 7–12 months, it was 2.4% [10]. Our primary outcome was CRB, which allowed us to obtain enough statistical power to find differences that may have clinical relevance for patients with CAT. The rate of major bleeding was lower in the period 12–24 months. Regarding the incidence of recurrent VTE, our study showed similar results to the CLOT study [21]. It could be thought that the lower number of clinically relevant bleedings in the period 12–24 months can be justified by a reduction of the intensity of anticoagulant treatment (intermediate dose of LMWH), but in our study patients received anticoagulant treatment at full doses.
The sensitivity analysis has made it possible to evaluate the influence of different variables on the presence of CRB both in the first and second years of treatment with LMWH. In the period 12–24 months, we found no differences in CRB in any of the variables analysed. However, we found that incidental VTE was associated with an increased risk of CRB in the first year of LMWH treatment. These findings are similar to those found by Caiano et al. [22] These investigators conducted a systematic review and meta-analysis to evaluate the outcomes in patients with cancer, and incidental VTE compared to those with symptomatic VTE and found that the risk of bleeding beyond 6 months was numerically higher in patients with incidental VTE (relative risk [RR] 1.47, 95% CI 0.99–2.2).
We do not know the reason for the higher risk of bleeding in patients with incidental VTE. One of the hypotheses postulated is about differences in the clinical characteristics of patients with incidental VTE versus symptomatic VTE [22]. In the Hokusai VTE Cancer trial [11], there was a lower percentage of haematologic cancer, a higher percentage of gastrointestinal cancer, and a higher percentage of metastases in the group of patients with incidental VTE. In our work, we considered the presence of metastases in the sensitivity analysis, and we did not find an association with CRB, neither in the period 1–12 months nor in the period 12–24 months. In 2019, one of the most relevant studies on patients with incidental PE was published [23]. This international, prospective study of unselected patients with incidental PE included 695 patients. The authors found a 12-month cumulative incidence of recurrent VTE of 6%, with no differences in patients with subsegmental or more proximal PE. The cumulative incidence of bleeding beyond 12 months was 5.7%.
Anticoagulant treatment in CAT patients is a challenge for clinicians; it is a dilemma to maintain, or not, anticoagulant treatment beyond 6–12 months. Although we assumed that the risk of bleeding and recurrent VTE is not constant over time, we only had evidence up to the first year of anticoagulant treatment [9–12]. The knowledge of the risk of bleeding over time will help inform future decisions. Several studies have focused on the safety and efficacy of anticoagulant treatments in the 6–12-month period, and have concluded that anticoagulant treatment is safe in this period. Data about long-term anticoagulant treatment beyond 12 months are scarce. The API-CAT trial (APIxaban Cancer Associated Thrombosis, NCT03692065) will provide data. The objective of this trial is to determine whether a low-dose regimen of apixaban (2.5 mg bid) is non-inferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent venous thromboembolism (VTE) in patients with active cancer and VTE who have completed at least 6 months of anticoagulant therapy.
This work has several strengths. Until now, we had no evidence of the safety of anticoagulant treatment beyond one year, and this work provides evidence that can inform clinicians about stopping or continuing anticoagulant treatment. Second, the analysis by subgroups made it possible to elucidate the possible effect of confounding variables. Third, regardless of the number of patients included in the study, another aspect that gives value to this work is that the patients included came from prospective real-world studies and not from clinical trials where there may be a selection bias, and for that reason our results are more generalisable, which provides external validity.
This study has limitations that are important to consider. One of the main limitations of this work is that it is a post hoc study, and there is no control arm to compare the results, although this aspect is solved in part with the comparison in two periods (1–12 versus 12–24 months). The fact that the study included a high percentage of patients with metastasis could bias the results due to high mortality, but we solved this by performing subgroup analyses and competing for risk analyses. Another limitation relates to the analysis of recurrent VTE for the efficacy outcome. In our case, there was no active search for recurrent VTE, which may have underestimated the incidence, and similarly, in patients in whom death was attributed to cancer progression, there could have been recurrent VTE, but in the patient with cancer in an advanced situation, a necropsy is not usually performed, which may have also underestimated the recurrent VTE. Third, this study only included patients under treatment with LMWH. Although LMWH is one of the classic anticoagulant treatments, direct oral anticoagulants (DOACs) are also an option to treat patients with CAT. We cannot extrapolate the data obtained with LMWH to DOACs, since, although the use of either drug is globally recommended, another series of factors must be taken into account when deciding to prescribe one drug or another (i.e., patients with a high risk of bleeding, nausea, vomiting, gastrointestinal tumour, patient preferences, reimbursement policy in each country). Fourth, we provided the clinical characteristics and laboratory parameters of the two cohorts of patients at the moment of the VTE event. Unfortunately, information at the moment of the outcome was not collected and probably may be also relevant.
Conclusions
In patients with cancer-associated thrombosis under anticoagulant treatment with LMWH, rates of clinically relevant bleeding and major bleeding were lower beyond 12 months. These data increase knowledge of the long-term safety of LMWH.
Supplementary information
Acknowledgements
We would like to thank Henry Antonio Andrade Ruiz, from the Methodological and Statistical Support Unit, for his support and contribution to the statistical analysis.
Author contributions
Conception and design: MB-H, SL-R, SM-R and LJ-P. Data analysis and interpretation: MB-H, SL-R, SM-R and LJ-P. Synthesis of the results: all authors. Manuscript writing: SL-R and LJ-P. Manuscripts review and edits. Final approval of manuscript: all authors. Accountable for all aspects of the work: all authors.
Funding
This project was supported by LEO Pharma Research Foundation.
Data availability
The datasets generated and/or analysed during this study are available from the corresponding author on reasonable request.
Competing interests
LJ-P reports personal fees from Bayer Hispania, Actelion, Rovi, Pfizer, Menarini, and Leo Pharma, outside the submitted work. ROC reports grant support from Leo Pharma and Bayer Healthcare, and fees for serving on advisory boards and giving lectures from Leo Pharma, Rovi, Bayer Healthcare, MSD and Actelion. There are no other competing interests.
Ethics approval and consent to participate
This post hoc analysis was evaluated and approved by the Ethical Committee of the centre according to Spanish Regulatory Authorities (0511-N-22). This study was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice and in full conformity with relevant regulations. Documents constituting the master file of the study included all the documents established in good clinical practice (CPMP/ICH/135/95). In this project, the collection, process and analysis of all data were anonymously carried out, and only for the purposes of the project. All data were protected in accordance with the European Union directive 2016/679 of the European Parliament and the European Council, of April 27, 2016, regarding the protection of persons and their personal data.
Consent to publish
No publication consent is required for this specific study. This post hoc analysis was evaluated and approved by the Ethical Committee of the centre according to Spanish Regulatory Authorities (0511-N-22). Original prospective studies required informed consent.
Footnotes
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Supplementary information
The online version contains supplementary material available at 10.1038/s41416-022-02007-x.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analysed during this study are available from the corresponding author on reasonable request.