Three-month outcomes in cancer patients with superficial- or deep vein thrombosis in the lower limbs. Results from the RIETE Registry

doi:10.21203/rs.3.rs-1500920/v1

Download PDF

Research Article

Three-month outcomes in cancer patients with superficial- or deep vein thrombosis in the lower limbs. Results from the RIETE Registry

https://doi.org/10.21203/rs.3.rs-1500920/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: The clinical characteristics and outcomes of cancer patients presenting with lower-limb isolated superficial vein thrombosis (SVT) have not been consistently evaluated.

Methods: We used data in the RIETE registry to compare the clinical characteristics and 90-day outcomes in patients with: 1) active cancer and lower-limb SVT; 2) active cancer and lower-limb deep vein thrombosis (DVT); 3) lower-limb SVT without cancer. The primary outcome was the composite of symptomatic subsequent SVT, DVT or pulmonary embolism (PE). Secondary outcomes were major bleeding and death.

Results: From March 2015 to April 2021, there were 110 patients with cancer and SVT, 1,695 with cancer and DVT, and 1,030 with SVT but no cancer. Most patients in all subgroups (93%, 99% and 96%, respectively) received anticoagulants, those with SVT received lower daily doses of low-molecular-weight heparin (114±58, 163±44, and 106±50 IU/kg, respectively). During the first 90 days, 101 patients (3.6%) developed subsequent VTE (PE 47, DVT 41, SVT 13), 72 (2.5%) bled and 282 (9.9%) died. Subsequent 90-day events were respectively: VTE 7.3%, 4.0% and 2.4%; major bleeding 2.7%, 3.9% and 0.3%; mortality 8.2%, 16% and 0.3%. After D90 only one SVT recurrence and one death occurred in SVT cancer patients. On multivariable analysis, cancer was an independent predictor for subsequent VTE (HR=2.04; 95%CI: 1.15-3.62). Initial presentation as SVT or DVT were not associated with a different risk.

Conclusion: The risk for subsequent VTE (including symptomatic SVT, DVT or PE) was similar in cancer patients with isolated SVT than in those with isolated DVT.

Superficial Vein Thrombosis

Deep Venous Thrombosis

Cancer

Anticoagulants

Prognosis

1. Cancer patients with superficial or with deep vein thrombosis have similar (i.e. unexpectedly high) rates of venous thromboembolism recurrences

2. Cancer patients with superficial venous thrombosis have a lower mortality rate than cancer patients with deep vein thrombosis

3. Cancer patients with lower limb superficial vein thrombosis received lower doses of anticoagulants than cancer patients with deep venous thrombosis

4. Most complications of anticoagulant therapy and superficial/deep vein thrombosis recurrences appeared within the first 3 months after SVT diagnosis in cancer patients

The association between cancer and venous thromboembolism (VTE) is known since 1865, when Armand Trousseau reported his own case, and has been widely documented.¹ However, the original report did not refer to a deep venous thrombosis (DVT) but to a superficial vein thrombosis (SVT) that appeared as the first manifestation of a gastric cancer.¹ Isolated SVT is defined by the presence of a blood clot in a superficial vein, without concomitant deep vein thrombosis (DVT) or pulmonary embolism (PE).² The natural history of cancer patients with isolated SVT has not been consistently evaluated since some physicians may consider SVT to be a benign disease despite it is thought to occur at least as often as DVT.^2–3 However, recent reports suggest that cancer patients presenting with isolated SVT are at increased risk to develop DVT or PE,⁴ and that the risk for subsequent DVT or PE may be similar in cancer patients with SVT or DVT.^5,6 These findings have not been consistently evaluated yet.

Current knowledge on the natural history and optimal therapy of cancer patients with isolated SVT is scarce since most studies on this topic included few patients with cancer. Therefore, in the absence of evidence-based recommendations, many cancer patients with isolated SVT are prescribed sub-therapeutic doses of anticoagulants.^6–7 This is why we decided to compare the clinical characteristics, therapeutic strategies and 3-month outcomes of 3 subgroups of patients included in the Registro Informatizado de la Enfermedad TromboEmbolica (RIETE): 1) active cancer and isolated SVT in the lower limbs; 2) active cancer and isolated DVT in the lower limbs; and 3) non-cancer but isolated lower-limb SVT.

Data source

We used the data from the RIETE registry, which prospectively collects information on patients with symptomatic, objectively confirmed acute VTE (ClinicalTrials.gov identifier, NCT02832245). Previous publications have described the design and conduct of the RIETE registry.⁸ All patients (or their relatives) provided written or oral informed consent for participation in the registry, in accordance with the local ethics committee requirements.

Inclusion criteria

At each participating site, the RIETE investigators aimed to enroll consecutive patients with acute VTE confirmed by objective testing. SVT is a variable included in RIETE only since March 2015. SVT was defined as the presence of a confirmed non-compressible venous segment by compression ultrasonography in a superficial vein without concomitant DVT or PE.⁸ Patients presenting with both SVT and DVT were considered as having DVT. Patients with upper limb SVT or DVT or with symptomatic PE or participating in a randomized trial with a blind medication were excluded. SVT cancer patients were managed according to each participating hospital clinical practice because there were no treatment recommendations. All participants were followed up for at least 3 months in the outpatient clinic and beyond the third month in case of participants’ approval.

The following parameters were recorded: age, sex, weight, VTE risk factors (recent surgery or immobility ≥ 4 days, estrogen use, pregnancy or postpartum, prior VTE or SVT, leg varicosities), comorbidities (chronic heart failure, lung disease or renal insufficiency), blood test abnormalities (anemia, leukocytosis, thrombocytopenia, creatinine clearance), concomitant use of corticosteroids or antiplatelet agents, cancer characteristics (time elapsed from diagnosis of cancer to VTE, site of tumor, metastases and anti-tumor therapy), and treatment (drugs, doses, duration).

Study design

We compared the clinical characteristics, treatment strategies and 3-month outcomes in patients with: 1) active cancer and isolated lower limb SVT; 2) active cancer and isolated lower limb DVT; and 3) isolated lower-limb SVT and no cancer. Only symptomatic and objectively confirmed SVT or DVT events were considered. Active cancer was defined as newly diagnosed cancer (< 3 months) or when receiving anti-neoplastic treatment of any type.⁹ The primary outcome was the development of symptomatic, objectively confirmed subsequent VTE events (SVT, DVT or PE) during the first 3 months. Secondary outcomes were major bleeding and all-cause mortality. VTE events were adjudicated by the treating physicians and defined as symptomatic SVT, DVT or PE confirmed on compression ultrasonography, computed tomography angiogram, ventilation/perfusion lung scan or magnetic resonance pulmonary angiography. Bilateral examination for both deep and superficial veins was performed in all patients. DVT was divided into proximal when its upper limit was at or above the popliteal vein and SVT was categorized according to its length (< 5cm, 5-10cm, > 10cm) and to the distance from the saphenofemoral junction. Major bleeding was defined as retroperitoneal, spinal or intracranial bleeding or any overt bleeding requiring transfusion of two units or more of blood, and fatal bleeding as any death occurring within 10 days of a major bleeding in the absence of an alternative cause of death ⁸. Although in RIETE there is not an independent adjudication committee, data quality is regularly monitored for accuracy ⁸.

Statistical analysis

Categorical variables were reported as frequency counts (percentages) and compared using the chi-square test (two-sided) and Fisher´s Exact Test (two-sided). Continuous variables were reported as mean and standard deviation (or median with interquartile range, if not normally distributed), and compared using Student t test. Odds ratios (ORs) and corresponding 95% confidence intervals (CI) were calculated.

We compared the risk for subsequent VTE events during the first 90 days, according to the presence or absence of cancer and initial presentation as SVT or DVT. We used logistic regression models to adjust the risk to a number of potential confounders. Variables previously reported to be clinically relevant or identified on bivariate analyses as predictors of subsequent VTE were included in the multivariate analysis. We included competing risk analysis to evaluate the risk for subsequent VTE, with death being the competing risk. Statistical analyses were conducted with IBM SPSS Statistics (version 25).

From March 2015 to May 2021, there were 110 patients with cancer and SVT, 1,695 with cancer and DVT and 1,030 with SVT and no cancer in the RIETE registry (Table I).

Table I. Clinical characteristics.

	Cancer and lower-limb SVT	Cancer and lower-limb DVT	Lower-limb SVT, no cancer
Patients, N	110	1,695	1,030
Clinical characteristics,
Male sex	45 (41%)	860 (51%)^*	412 (40%)
Age (mean years ± SD)	67 ± 13	68 ± 13	59 ± 16^‡
Body weight (mean kg ± SD)	76 ± 18	73 ± 15^*	81 ± 17^†
Inpatients	10 (9.3%)	431 (26%)^‡	51 (5.1%)
Initial presentation,
DVT characteristics,
Proximal SVT/DVT	65 (59%)	1,405 (83%)^‡	618 (60%)
SVT characteristics,
Length of SVT < 5 cm	19 (24%)	-	179 (22%)
Length of SVT 5–10 cm	30 (38%)	-	311 (39%)
Length of SVT > 10 cm	29 (37%)	-	311 (39%)
Distance from SF junction < 3 cm	34 (36%)	-	291 (33%)
Distance from SF junction > 3 cm	60 (64%)	-	578 (67%)
SVT on a varicose vein	45 (43%)	-	587 (60%)^†
Additional risk factors for VTE,
Recent surgery	5 (4.5%)	226 (13%)^†	66 (6.4%)
Recent immobility ≥ 4 days	11 (10%)	302 (18%)^*	59 (5.7%)
Estrogen use	11 (10%)	133 (7.8%)	49 (4.8%)^*
Pregnancy or postpartum	0	2 (0.1%)	40 (3.9%)^*
None of the above	83 (75%)	1,074 (63%)^*	820 (80%)
Prior VTE	11 (10%)	192 (11%)	142 (14%)
Prior SVT	16 (15%)	50 (2.9%)^‡	244 (24%)^*
Leg varicosities	49 (45%)	185 (11%)^‡	643 (62%)^‡
Underlying conditions,
Chronic heart failure	5 (4.5%)	55 (3.2%)	14 (1.4%)^*
Chronic lung disease	8 (7.3%)	133 (7.8%)	59 (5.7%)
Recent major bleeding	1 (0.9%)	43 (2.5%)	4 (0.4%)
Anemia	46 (42%)	1,072 (63%)^‡	137 (13%)^‡
Leukocyte count > 11,000/µL	17 (17%)	368 (22%)	87 (9.3%)^*
Platelet count < 100,000/µL	3 (2.9%)	101 (6.0%)	11 (1.2%)
CrCl levels < 60 mL/min	30 (27%)	523 (31%)	114 (11%)^‡
Concomitant drugs,
Corticosteroids	15 (14%)	281 (17%)	44 (4.3%)^‡
Antiplatelets	14 (13%)	213 (13%)	111 (11%)

Comparisons between cancer patients with SVT vs. other subgroups: ^*p < 0.05; ^†p < 0.01; ^‡p < 0.001.

Abbreviations: CrCl, creatinine clearance; DVT, deep vein thrombosis; SD, standard deviation; SF, saphenofemoral; SVT, superficial vein thrombosis; VTE, venous thromboembolism.

Cancer patients with SVT vs. cancer patients with DVT

Compared to cancer patients with DVT, those with SVT were less likely to be men and less likely to have recent immobility or recent surgery, but more likely to have prior SVT or leg varicosities than patients with DVT (Table I). As for the cancer characteristics, patients with SVT were less likely to have metastases at baseline and more likely to have breast or hematologic cancers, but less likely had bladder cancer (Table II). Most patients in both subgroups received anticoagulant therapy (93% vs. 99%), mostly with low-molecular-weight heparin (LMWH) for both initial and long-term therapy. Interestingly, patients with SVT received lower doses of LMWH (for initial- and for long-term therapy) than those with DVT (Table III). Few patients in both subgroups received direct oral anticoagulants or Fondaparinux.

Table II. Cancer characteristics.

	Cancer and lower-limb SVT	Cancer and lower-limb DVT
*Patients, N*	*110*	*1,695*
Time from cancer diagnosis
Mean months (±SD)	32±62	23±44
Median months (IQR)	6 (0-280)	4 (0-26)
Metastases
Yes	48 (44%)	944 (56%)^*
Sites of cancer,
Breast	26 (24%)	202 (12%)^‡
Colorectal	16 (15%)	229 (14%)
Lung	11 (10%)	224 (13%)
Hematologic	18 (16%)	141 (8.3%)^†
Prostate	6 (5.5%)	127 (7.5%)
Uterine	5 (4.5%)	100 (5.9%)
Stomach	6 (5.5%)	60 (3.5%)
Pancreas	4 (3.6%)	107 (6.3%)
Ovary	3 (2.7%)	85 (5.0%)
Carcinoma of unknown origin	3 (2.7%)	21 (1.2%)
Bladder	2 (1.8%)	117 (6.9%)^*
Cerebral	1 (0.9%)	65 (3.8%)
Biliary tract	2 (1.8%)	16 (0.9%)
Melanoma	2 (1.8%)	22 (1.3%)
Other	2 (1.8%)	140 (8.6%)
Therapy for cancer,
Chemotherapy	53 (50%)	805 (52%)
Radiotherapy	15 (14%)	229 (15%)
Immunotherapy	4 (5.3%)	58 (6.7%)
Hormonal therapy	20 (19%)	193 (13%)
None of the above	34 (31%)	635 (37%)

Comparisons between subgroups: *p <0.05; †p <0.01; ‡p <0.001.

Abbreviations: SVT, superficial vein thrombosis; DVT, deep vein thrombosis; SD, standard deviation; IQR, inter-quartile range

Table III. Treatment strategies.

	Cancer and lower-limb SVT	Cancer and lower-limb DVT	Lower-limb SVT, no cancer
*Patients, N*	*110*	*1,695*	*1,030*
Duration of anticoagulant therapy,
Mean days (±SD)	125±155	201±213^‡	125±171
Median days (IQR)	95 (48-145)	128 (86-240)	89 (47-124)
Initial therapy, N
Low-molecular-weight heparin	97 (88%)	1,532 (90%)	721 (70%)^‡
Mean daily doses (IU/kg/day)	114±58	163±44^‡	106±50 559 (78%)^*
LMWH doses <150 IU/kg/day	66 (68%)	519 (34%)^‡	106±50 559 (78%)^*
Fondaparinux	5 (4.5%)	33 (1.9%)	203 (20%)^‡
Daily doses <7.5 mg/daily	4 (3.6%)	1 (0.1%)^‡	144 (14%)^‡
Rivaroxaban	3 (2.7%)	28 (1.7%)	41 (4.0%)
Apixaban	1 (0.9%)	9 (0.5%)	22 (2.2%)
DOACs at lower-than recommended doses	2 (1.8%)	4 (0.2%)^*	12 (1.2%)
Thrombolytic drugs	0	0	1 (0.10%)
Inferior vena cava filter	5 (4.5%)	115 (6.8%)	0
Mechanical thrombolysis	0	9 (0.6%)	3 (0.4%)
No initial therapy	0	12 (0.7%)	15 (1.5%)
Long-term therapy, N
Low-molecular-weight heparin	80 (73%)	1,213 (72%)	441 (43%)^‡
Mean daily doses (IU/kg/day)	118±60	152±41^‡	97±41^† 384 (87%)^‡
LMWH doses <150 IU/kg/day	52 (65%)	549 (45%)^‡	97±41^† 384 (87%)^‡
Fondaparinux	6 (5.5%)	27 (1.6%)^*	175 (17%)^‡
Daily doses <7.5 mg/daily	3 (2.7%)	1 (0.1%)^‡	132 (13%)^‡
Vitamin K antagonists	6 (5.5%)	177 (10%)	138 (13%)^*
DOACs	5 (5%)	159 (9.4%)	145 (14%)
DOACs at lower-than recommended doses	2 (1.8%)	15 (0.9%)^‡	14 (1.4%)
No long-term therapy	8 (7.3%)	20 (1.2%)^‡	95 (9.2%)

Comparisons between cancer patients with SVT vs. other subgroups: ^*p <0.05; ^†p <0.01; ^‡p <0.001.

Abbreviations: DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; IQR, inter-quartile range; IU, international units; SD, standard deviation; SVT, superficial vein thrombosis; LMWH, low-molecular-weight heparins.

During the first 90 days, 76 patients (4.2%) developed subsequent VTE events (PE 41, DVT 33, SVT 2), 69 (3.8%) suffered major bleeding and 279 (15.5%) died (Table IV). Of these, 4 patients died of PE and 13 died of bleeding. There were no significant differences in the rates of subsequent VTE events (OR: 1.82; 95%CI: 0.75-3.91) or major bleeding (OR: 0.69; 95%CI: 0.17-2.00), but the mortality rate was half in cancer patients with SVT than in those with DVT (OR: 0.47; 95%CI: 0.22-0.91).

Table IV. Outcomes.

	SVT with cancer		DVT with cancer		SVT without cancer
	*Day 1-90* N 110	*Day 1-180* *N 110*	*Day 1-90* *N 1,695*	*Day 1-180* *N 1,695*	*Day 1-90* *N 1,030*	*Day 1-180* *N 1,030*
SVT recurrences	1 (0.9%)	2 (1.8%)	1 (0.1%)	2 (0.1%)^*	11 (1.1%)	14 (1.4%)
DVT recurrences	4 (3.6%)	4 (3.6%)	29 (1.7%)	43 (2.5%)	8 (0.8%)^*	9 (0.9%)^*
PE recurrences	3 (2.7%)	3 (2.7%)	38 (2.2%)	43 (2.5%)	6 (0.6%)^*	6 (0.6%)^*
VTE recurrences	7 (6.4%)	7 (6.4%)	61 (3.6%)	76 (4.5%)	14 (1.4%)^†	15 (1.5%)^†
Major bleeding	3 (2.7%)	3 (2.7%)	66 (3.9%)	81 (4.8%)	3 (0.3%)^*	3 (0.3%)^*
Overall death	9 (8.2%)	10 (9.1%)	270 (16%)^*	359 (21%)^†	3 (0.3%)^‡	3 (0.3%)^‡
Fatal PE	1 (0.9%)	1 (0.9%)	3 (0.2%)	3 (0.2%)	2 (0.2%)	2 (0.2%)
Fatal bleeding	0	0	13 (0.8%)	14 (0.8%)	0	0

Comparisons between cancer patients with SVT vs. other subgroups: ^*p <0.05; ^†p <0.01; ^‡p <0.001.

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; SVT, superficial vein thrombosis; VTE, venous thromboembolism.

Cancer patients with SVT vs. non-cancer patients with SVT

Compared to non-cancer patients with SVT, those with cancer were older and less likely to have prior SVT or leg varicosities, but more likely to have chronic heart failure, anemia, renal insufficiency or to receive corticosteroids at baseline (Table I). Most patients in both subgroups (93% vs. 99%) received anticoagulant therapy, most of them with LMWH for both initial and for long-term therapy (Table III). Patients without cancer received similar daily doses of LMWH than those with cancer, but the proportion of patients receiving Fondaparinux was much higher in patients without cancer than in those with cancer (20% vs. 4.5%).

During the first 90 days, 33 patients (1.8%) developed subsequent VTE events (PE 9, DVT 12, SVT 12), 6 (0.5%) suffered major bleeding and 12 (1.0%) died (Table IV). Of these, 3 patients died of PE and none died of bleeding. Patients with cancer had a much higher rate of subsequent VTE events (OR: 4.92; 95%CI: 1.82-12.4), major bleeding (OR: 9.56; 95%CI: 1.63-56.2) or death (OR: 30.3; 95%CI: 8.41-141) than those with SVT but without cancer.

In patients with SVT, almost all the events occurred within the first three months, except one SVT recurrence and one death in cancer patients and 3 SVT recurrences and 1 DVT, in non-cancer patients.

VTE recurrence among the whole population

On multivariable analysis, patients aged < 65 years (hazard ratio [HR]: 2.04; 95CI: 1.27-3.33), with active cancer (HR: 2.04; 95CI: 1.15-3.62), leukocytosis (HR: 1.75; 95CI: 1.10-2.77) or with creatinine clearance levels ≥ 60 mL/min were at increased risk for subsequent VTE events (Table V). Initial presentation as DVT or SVT was not associated with a different risk for subsequent VTE events.

Table V. Uni- and multivariable analysis for VTE recurrences.

	Univariable analysis	Logistic Regression	Competing risk analysis
Clinical characteristics,
Age <65 years	2.27 (1.45- 3.45)^†	2.08 (1.28-3.33)^†	2.04 (1.27-3.33)^†
Male sex	1.35 (0.90-2.03)	-	-
Proximal DVT	0.79 (0.51-1.21)	-	-
Risk factors,
Unprovoked VTE	Ref.	Ref.	Ref.
Cancer	1.80 (1.06-3.04)^*	2.30 (1.29-4.10)^†	2.04 (1.15-3.62)^*
Transient risk factors	1.54 (0.63-3.73)	-	-
Prior VTE,
Prior DVT or PE	1.05 (0.56-1.94)	-	-
Prior SVT	1.07 (0.56-2.03)	-	-
Leg varicosities	0.66 (0.41-1.08)	-	-
Underlying conditions,
Chronic heart failure	1.68 (0.60-4.69)	-	-
Chronic lung disease	1.58 (0.81-3.09)	-	-
Recent major bleeding	0.61 (0.08-4.47)	-	-
Anemia	0.87 (0.58-1.32)	-	-
WBC >11,000/µL	1.93 (1.21-3.07)^†	1.73 (1.07-2.78)^*	1.75 (1.10-2.77)^*
PlC <100,000/µL	1.04 (0.38-2.89)	-	-
CrCl levels ≥60 mL/min	2.70 (1.39-5.26)^†	2.33 (1.16-4.76)^*	2.27 (1.10-4.55)^*
Concomitant drugs,
Corticosteroids	0.96 (0.51-1.82)	-	-
Antiplatelets	1.07 (0.58-1.98)	-	-
Full dose anticoagulation	1.14 (0.75-1.72)	-	-

^*p <0.05; ^†p <0.01; ^‡p <0.001.

Abbreviations: VTE, venous thromboembolism, DVT, deep vein thrombosis; PE, pulmonary embolism; SVT, superficial vein thrombosis; WBC, white blood cell count; PlC, platelet count; CrCl, creatinine clearance; Ref., reference.

Data on SVT in cancer patients is limited. Our study confirms the high rate of subsequent DVT events in cancer patients with SVT but shows above all that cancer patients with SVT have a longer survival than those with DVT and that almost all venous thrombotic and bleeding events occur within the first three months of treatment in cancer patients with SVT. Moreover, our data reveal that the risk for subsequent VTE events (including symptomatic SVT, DVT or PE) during the first 3 months of therapy in cancer patients with isolated SVT is similar to the risk in cancer patients with DVT. This is important since many clinicians do not consider SVT as a potentially fatal disease in patients with cancer.³ This may also explain why one in every three patients with SVT in our cohort was prescribed sub-therapeutic doses of anticoagulants (particularly with LMWH) for initial and for long term therapy. Interestingly, three of the six patients who died of PE in our cohort had initially presented with isolated SVT. Thus, our findings suggest that isolated lower-limb SVT should not be underestimated, particularly in patients with cancer. Of note, the rate of SVT recurrence, DVT, bleeding and death is the same at three and six months in cancer patients with SVT. The lower rate of subsequent VTE in non-cancer patients with isolated SVT than in those with cancer is likely explained by the influence of cancer on the risk for VTE, as shown in the multivariable analysis with an increased risk in patients with cancer. We also found a lower mortality rate in cancer patients with SVT than in cancer patients with DVT. This may likely be explained because those with SVT were less likely to have metastatic cancer, as also reported in the OPTIMEV study.⁶

Most randomized trials of SVT therapy did not include patients with cancer,^10-16 or only a few patients.^17-19 The lack of specific data leads to the inconsistency of the current recommendations for treatment of patients with isolated SVT: different doses (from prophylactic to therapeutic doses) and different durations (from 6 weeks to 6 months).^20-21 ESVS guidelines suggest high-risk patients, such as patients with active cancer, would be candidates for full anticoagulation for 3 months.²² Since we found that: 1) in cancer patients with isolated SVT almost all thrombotic and all bleeding events occurred within the first three months; and 2) that those aged <65 years, with leukocytosis or normal renal function were at increased risk for subsequent VTE events, our findings may help to design randomized studies comparing different doses and durations of anticoagulants aimed to try to reduce the risk for these complications.

In the literature, the risk of extension of an isolated SVT into the deep venous system is not negligible in patients with cancer. Cancer was associated with a higher risk to develop subsequent DVT or PE in a retrospective study on 411 patients with isolated SVT.⁴ In the French retrospective series, 13 of 94 (14%) cancer patients with isolated SVT developed subsequent DVT.⁷ In the OPTIMEV series, the rate of subsequent DVT or PE events was also similar between cancer patients with isolated SVT or DVT.⁶ It is important to highlight that the risk to develop subsequent DVT or PE in our cohort was independent of the distance from the saphenofemoral junction and of receiving lower than recommended doses of anticoagulants.

Unexpectedly, less than 5% of cancer patients and SVT and 20% of non-cancer patients with SVT were prescribed Fondaparinux in our cohort, many of them at lower than recommended doses. Fondaparinux is the only drug approved by the European Medicines Agency for the treatment of patients with isolated SVT. Unfortunately, our cohort has not been designed to compare the effectiveness and safety of the different anticoagulants used for SVT therapy.

Finally, we found isolated SVT to be less frequently diagnosed than DVT in patients with cancer. In the literature, the incidence of SVT in cancer patients is the same as that of DVT in a literature review,³ but lower in other studies.^4,5,12,23 Since the POST study revealed that one in every 4 cancer patients with SVT may also have concomitant DVT,²³ the low frequency of cancer patients with isolated SVT in our cohort may have been due to its higher risk for concomitant DVT.

Our study has some limitations. First, Riete is an observational registry and cannot be used to compare therapeutic strategies; RIETE is hypothesis generating and may help only to identify gaps where well-designed randomized trials should be performed. Second, the length of SVT and its proximity to the sapheno-femoral junction was not available in some patients (32 and 11 missing data). Third, the lower proportion of patients with SVT than DVT in cancer patients may reflect under-reporting of SVT due to an underestimation of the severity of this disease. Forth, our patient sample may not be representative of the cancer population as most oncologists are not involved in the RIETE registry. Nevertheless, our cohort is the larger cohort of patients on this topic and brings data that could help to better treat isolated SVT in cancer patients. Finally, the treatment of our patients was quite variable: from LMWH to VKAs or DOACs, and the different treatments could have influenced the outcomes in addition to SVT or DVT.

In conclusion, our study reveals that cancer patients with SVT have a lower mortality but the same risk for subsequent VTE events than cancer patients with DVT. The risk in non-cancer patients with isolated SVT seems to be lower, but this may be due to the influence of cancer given the results of the multivariable analysis. Most complications of anticoagulation therapy and most SVT/DVT recurrences developed within the first 3 months after SVT diagnosis in cancer patients.

Authors contributions: Philippe DEBOURDEAU, Laurent BERTOLETTI and Manuel MONREAL conceived the study idea, collected the data, analyzed the data, wrote the manuscript and approved the final version of the manuscript.

Carme FONT, Juan José LÓPEZ-NÚÑEZ, Covadonga GÓMEZ-CUERVO, Isabelle MAHÉ, Remedios OTERO, Ángeles BLANCO-MOLINA and Patricia LÓPEZ-MIGUEL collected the data, analyzed the data, reviewed and contributed to the manuscript and approved the final version of the manuscript.

Funding: the RIETE registry s supported by SANOFI, LEO PHARMA and ROVI

Trousseau A (1865). Phlegmasia Alba Dolens. Clinique Médicale de l’Hôtel Dieu de Paris. 2nd edn, vol 3. Paris: JB Baillère; p 659–612.
Evans NS, Ratchford EV (2018). Superficial vein thrombosis. Vasc Med 23(2):187–189.
Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC (2013). Epidemiology of cancer-associated venous thrombosis. Blood 122(10):1712–1723.
Barco S, Pomero F, Di Minno MND, Tamborini Permunian E, Malato A, Pasca S, Barillari G, Fenoglio L, Siragusa S, Di Minno G, Ageno W, Dentali F (2017). Clinical course of patients with symptomatic isolated superficial vein thrombosis: the ICARO follow-up study. J Thromb Haemost 15(11):2176–2183.
Galanaud JP, Sevestre MA, Pernod G, Genty C, Richaud C, Rolland C, Weber L, Kahn SR, Quéré I, Bosson JL; OPTIMEV-SFMV Investigators (2017). Long-term risk of venous thromboembolism recurrence after isolated superficial vein thrombosis. J Thromb Haemost 15(6):1123–1131.
Galanaud JP, Blaise S, Sevestre MA, Terrisse H, Pernod G, Gaillard C, Genty C, Monreal M, Rabah Y, Kahn SR, Quéré I, Bosson JL; OPTIMEV-SFMV investigators (2018). Long-term outcomes of isolated superficial vein thrombosis in patients with active cancer. Thromb Res 171:179–186.
Ghenassia-Fouillet L, Morel A, Frappé P, Le Hello C, Lerche V, Sevestre MA, Bertoletti L (2021). Management of superficial venous thrombosis in unevaluated situations: Cancer, severe renal impairment, pregnancy and post-partum. Phlebology 36(6):464–472
Bikdeli B, Jimenez D, Hawkins M Ortíz S, Prandoni P, Brenner B, Decousus H, Masoudi FA, Trujillo-Santos J, Krumholz HM, Monreal M; RIETE Investigators (2018). Rationale, Design and Methodology of the Computerized Registry of Patients with Venous Thromboembolism (RIETE). Thromb Haemost 118:214–224.
NICE Guidance. Quality statement 7: Treatment of people with active cancer.https://www.nice.org.uk/guidance/qs29/chapter/Quality-statement-7-Treatment-of-people-with-active-cancer
Decousus H, Prandoni P, Mismetti P Bauersachs RM, Boda Z, Brenner B, Laporte S, Matyas L, Middeldorp S, Sokurenko G, Leizorovicz A; CALISTO Study Group (2010). Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med 363(13):1222–1232.
Cosmi B, Filippini M, Tonti D, Avruscio G, Ghirarduzzi A, Bucherini E, Camporese G, Imberti D, Palareti G; STEFLUX Investigators (2012). A randomized double-blind study of low-molecular-weight heparin (parnaparin) for superficial vein thrombosis: STEFLUX (Superficial ThromboEmbolism and Fluxum). J Thromb Haemost 10(6):1026–1035.
Belcaro G, Nicolaides AN, Errichi BM, Cesarone MR, De Sanctis MT, Incandela L, Venniker R (1999). Superficial thrombophlebitis of the legs: a randomized, controlled, follow-up study. Angiology 50(7):523–529.
Marchiori A, Verlato F, Sabbion P, Camporese G, Rosso F, Mosena L, Andreozzi GM, Prandoni P (2002). High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study. Haematologica 87(5):523–527
Rathbun SW, Aston CE, Whitsett TL. A randomized trial of dalteparin compared with ibuprofen for the treatment of superficial thrombophlebitis. J Thromb Haemost. 2012;10(5):833–839.
Lozano FS, Almazan A (2003). Low-molecular-weight heparin versus saphenofemoral disconnection for the treatment of above-knee greater saphenous thrombophlebitis: a prospective study. Vasc Endovascular Surg 37(6):415–420.
Spirkoska A, Jezovnik MK, Poredos P (2015). Time course and the recanalization rate of superficial vein thrombosis treated with low- molecular-weight heparin. Angiology 66(4):381–386.
Superficial Thrombophlebitis Treated By Enoxaparin Study Group (2003). A pilot randomized double-blind comparison of a low-molecular-weight heparin, a nonsteroidal anti-inflammatory agent, and placebo in the treatment of superficial vein thrombosis. Arch Intern Med 163(14):1657–1663.
Beyer-Westendorf J, Schellong SM, Gerlach H, Rabe E, Weitz JI, Jersemann K, Sahin K, Bauersachs R; SURPRISE investigators (2017). Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial. Lancet Haematol 4(3):e105-e113.
The Vesalio Investigators Group (2005). High vs. low doses of low-molecular-weight heparin for the treatment of superficial vein thrombosis of the legs: a double-blind, randomized trial. J Thromb Haemost 3(6):1152–1157.
NCCN. https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf
Mahé I, Meyer G, Girard P, Bertoletti L, Laporte S, Couturaud F, Mismetti P, Sanchez O, pour le groupe de travail Recommandations de bonne pratique pour la prise en charge de la MVTE (2021). Traitement de la maladie veineuse thromboembolique au cours du cancer. Mise à jour mars 2021. Rev Mal Respir 38(4):427–437.
Kakkos SK, Gohel M, Baekgaard N Bauersachs R, Bellmunt-Montoya S, Black SA, Ten Cate-Hoek AJ, Elalamy I, Enzmann FK, Geroulakos G, Gottsäter A, Hunt BJ, Mansilha A, Nicolaides AN, Sandset PM, Stansby G, Esvs Guidelines Committee, de Borst GJ, Bastos Gonçalves F, Chakfé N, Hinchliffe R, Kolh P, Koncar I, Lindholt JS, Tulamo R, Twine CP, Vermassen F, Wanhainen A, Document Reviewers, De Maeseneer MG, Comerota AJ, Gloviczki P, Kruip MJHA, Monreal M, Prandoni P, Vega de Ceniga M (2021). Editor's Choice. Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg 61(1):9–82.
Decousus H, Quéré I, Presles E, Becker F, Barrellier MT, Chanut M, Gillet JL, Guenneguez H, Leandri C, Mismetti P, Pichot O, Leizorovicz A; POST (Prospective Observational Superficial Thrombophlebitis) Study Group (2010). Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med 152(4):218–224.

Competing interest reported. Dr. DEBOURDEAU reports personal fees and non-financial support from BAYER, personal fees and non-financial support from LEO-PHARMA, personal fees and non-financial support from PFIZER, outside the submitted work Dr. BERTOLETTI reports personal fees and non-financial support from ASPEN, personal fees and non-financial support from ACTELION, grants, personal fees and non-financial support from BAYER, personal fees and nonfinancial support from BMS/PFIZER, personal fees and non-financial support from LEO-PHARMA, grants, personal fees and non-financial support from MSD, outside the submitted work. Dr. FONT has nothing to disclose. Dr. LÓPEZ-NÚÑEZ reports personal fees from BMS, personal fees from Rovi, personal fees from Bayer, personal fees from Sanofi, other COI from Pfizer, personal fees from Bayer, outside the submitted work Dr. GÓMEZ-CUERVO reports other COI from Sanofi-Aventis, from Leo Pharma, outside the submitted work Dr. MAHÉ reports grants, personal fees and non-financial support from BMS Pfizer, grants, personal fees and non-financial support from Leo Pharma, personal fees and non-financial support from Bayer, outside the submitted work Dr. LÓPEZ-MIGUEL, Dr. ADARRAGA, Dr. OTERO have nothing to disclose. Dr. MONREAL reports grants from Sanofi, grants from Leo, grants from Rovi, during the conduct of the study

RIETERegistry.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

Three-month outcomes in cancer patients with superficial- or deep vein thrombosis in the lower limbs. Results from the RIETE Registry

Status:

Version 1

Abstract

Key Points

Introduction

Methods

Data source

Inclusion criteria

Study design

Statistical analysis

Results

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1