Journal of Thrombosis and Thrombolysis

, Volume 31, Issue 1, pp 107–112

Venous thromboembolism (VTE) in hospitalized cancer patients: prophylaxis failure or failure to prophylax!

Authors

    • Division of Hematology and Medical Oncology, Department of Internal MedicineKing Hussein Cancer Center
  • Faisal Albadainah
    • Division of Hematology and Medical Oncology, Department of Internal MedicineKing Hussein Cancer Center
  • Shadi Hijjawi
    • Division of Hematology and Medical Oncology, Department of Internal MedicineKing Hussein Cancer Center
  • Asem Mansour
    • Department of RadiologyKing Hussein Cancer Center
  • Imad Treish
    • Department of PharmacyKing Hussein Cancer Center
Article

DOI: 10.1007/s11239-010-0509-x

Cite this article as:
Abdel-Razeq, H., Albadainah, F., Hijjawi, S. et al. J Thromb Thrombolysis (2011) 31: 107. doi:10.1007/s11239-010-0509-x

Abstract

Cancer patients are at higher risk for venous thromboembolism (VTE). Anticoagulants, when used for prophylaxis, had successfully reduced the incidence of VTE in high risk patients. Nevertheless, many registry studies have shown low compliance rate with published prophylaxis guidelines. From January 2004 through June 2008, hospital database was searched for all discharge diagnoses of cancer with deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Prophylaxis rate for the whole group and for subgroups in relation to recent hospitalization, duration of cancer diagnosis and number of other coexisting risk factors were studied. Two hundred patients were identified; majority (91.8%) had advanced-stage cancer at time of VTE diagnosis. In addition to cancer, many patients had multiple coexisting risk factors for VTE with 137 (68.5%) patients had at least three while 71 (35.5%) had four or more. Overall, 111(55.5%) patients developed lower-extremity DVT while 52 (26%) patients developed PE, other sites accounted for 18%. Majority of the patients (72%) had VTE diagnosed within the first 12 months following cancer diagnosis. Almost three quarters of the patients (73.5%) had not received any antecedent prophylaxis. Prophylaxis rate was 23% among patients with ≥3 risk factors and 50% among the highest risk group with ≥5 risk factors. Based on our findings, majority of VTE in cancer patients occurred due to failure to offer prophylaxis, minority were due to prophylaxis failure. Meticulous quality improvement programs should be established to emphasize the importance of implementing more intensive prophylaxis among high-risk cancer patients.

Keywords

CancerHeparinLow molecular weight heparinThromboembolism

Introduction

Deep vein thrombosis (DVT) and pulmonary embolism (PE), collectively known as venous thromboembolism (VTE), are relatively common. Given its silent nature; the incidence, prevalence and mortality rates of VTE are probably under-estimated [1].Though common, VTE is fortunately a preventable disease. The application of suitable prophylactic measure in high risk patients is the best way to decrease VTE and its associated complications. Using unfractionated heparin, the rate of radiologically-detected DVT was reduced by 67%, without significant bleeding complications [2].

Although most patients survive DVT, serious and costly long-term complications may occur; almost one-third of patients will suffer from venous stasis syndrome (postphlebitic syndrome) manifested by painful swelling and recurrent ulcers [3]. On the other hand, PE is associated with substantial morbidity and mortality both tend to be higher among cancer patients [4] and those who survive such event may develop chronic complications like pulmonary hypertension [5]. In a large study, Sørensen et al. examined the survival of patients with cancer and VTE compared to those without VTE matched for many factors including the type and duration of cancer diagnosis; the 1 year survival rate for patients with VTE was 12% compared to 36% in the control group (P < 0.001) [6]. Furthermore, the risk of recurrence after the first VTE is higher in cancer patients compared to those without.

Cancer and its treatment are recognized risk factors for VTE. Some studies have reported a six-fold increased risk of VTE in cancer patients compared to those without [7]. Active cancer accounts for almost 20% of all new VTE events occurring in the community [8]. The risk of VTE varies by cancer type and is especially high among patients with malignant brain tumors, adenocarcinoma of the ovary, pancreas, colon, stomach, lung, prostate, and kidney [9].

Decision on when to offer prophylaxis in cancer patients admitted to medical units is difficult to make. Such patients typically have many risk factors, the interaction of which is difficult to quantify. Furthermore, many patients may have contraindication to VTE prophylaxis which makes the decision more challenging.

In this observational study, we will review all cancer patients who had a confirmed diagnosis of VTE during the study period; we will then study the prophylaxis rate for the whole group and for subgroups of patients in relation the number of other recognized coexisting risk factors for VTE, recent hospitalization and the duration of cancer diagnosis.

Materials and methods

This study was performed at King Hussein Cancer Center, a stand-alone, Joint Commission International (JCI)-accredited comprehensive cancer center. Hospital database was searched for all patients discharged with a diagnosis of DVT and/or PE. Database for a principle diagnosis of DVT or PE among patients within 30 days from hospital discharge was also searched. Additionally, the radiology database was queried for cancer patients undergoing Doppler sonography, ventilation perfusion scan, computerized tomography (CT) of the chest, computerized pulmonary angiography, or venography. To further identify patients with VTE, the pharmacy database was searched for all patients who received pharmacologic treatment with warfarin, therapeutic doses of unfractionated heparin, or low-molecular-weight heparins (LMWH). Patients’ medical records were then reviewed for data collection and confirmation of diagnosis. For each confirmed case of VTE, other recognized coexisting risk factors for VTE were reviewed; such risk factors include recent surgical procedure, immobility, BMI ≥ 25, smoking, previous history of VTE, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), sepsis and hormonal therapy.

Statistical analysis

Descriptive statistical analysis was performed to present patients’ demographic and clinical characteristics, VTE rates and prophylaxis rates. All statistical analysis was carried out using SPSS Software (version 16.0). A P-value <0.05 was considered to be statistically significant, and was measured using Chi-square.

Results

From January 2004 through June 2008, 200 patients; 102 men (51.0%) and 98 women (49%) with VTE were identified. The mean age (±SD) of the whole group was 51.8 (±15.9) years. All patients had active cancer; the most common types of cancer were gastrointestinal (19.5%), lung (11.5%), breast (10.0%), lymphomas (9.0%), and brain tumors (7.0%). The majority of patients had advanced-stage disease at time of VTE diagnosis. Out of 171 stagable patients, 157 (91.8%) patients had stage III, locally-advanced or metastatic stage IV disease, whereas only 14 (8.2%) had stages I or II disease (Table 1). In addition to cancer, majority of patients had other coexisting risk factors for VTE. Forty-six (23.0%) patients had surgery within 3 months, 104 (52.0%) were immobile within 30 days prior to VTE diagnosis, body mass index (BMI) ≥25 was reported in 115 (57.5%), smoking (41.0%), and sepsis (24.0%). Use of hormonal therapy, previous VTE, COPD and CHF were each documented in less than 10.0% of patients (Fig. 1a).
Table 1

Patients characteristics

Variable

N (%)

Gender

 Male

102 (51.0)

 Female

98 (49.0)

Age (year)

 <40

52 (26.0)

 40–60

80 (40.0)

 60–74

53 (26.5)

 >74

15 (7.5)

 Mean (SD)

51.8 (15.9)

Primary cancer

 Gastrointestinal

39 (19.5)

 Lung

23 (11.5)

 Gynecological

21 (10.5)

 Breast

20 (10.0)

 Genitourinary

18 (9.0)

 Lymphoma

18 (9.0)

 Brain

14 (7.0)

 Leukemia

14 (7.0)

 Sarcoma

13 (6.5)

 Others

20 (10.0)

Stage of disease

 I

3 (1.5)

 II

11 (5.5)

 III

23 (11.5)

 IV

116 (58)

 Locally advanced

18 (9.0)

 Unstagable

29 (14.5)

https://static-content.springer.com/image/art%3A10.1007%2Fs11239-010-0509-x/MediaObjects/11239_2010_509_Fig1_HTML.gif
Fig. 1

a Risk factors for venous thromboembolism (VTE). b VTE according to number of risk factors

Most patients had multiple risk factors for venous thrombosis with 137 (68.5%) patients had at least three other predisposing risk factors while 71 (35.5%) had four or more risk factors other than cancer (Fig. 1b).

Pulmonary embolism was diagnosed primarily by spiral chest CT while DVT was diagnosed primarily by venous Doppler ultrasound. Overall, 111 (55.5%) patients had lower-extremity DVT while 52 (26.0%) patients had PE and 15 (7.5%) patients had superior vena cava or internal jugular vein thrombosis; few of them were associated with a central venous catheter. Inferior vena cava thrombosis occurred in 10 cases, other sites accounted for less than 11.0% (Fig. 2). None of the patients who were diagnosed with PE had a prior clinical or radiological diagnosis of DVT. One hundred and thirteen (56.5%) patients had their VTE diagnosed during the initial hospital stay or within 30 days of prior hospitalization, while 87 (43.5%) patients had a primary diagnosis of VTE without history of recent hospitalization.
https://static-content.springer.com/image/art%3A10.1007%2Fs11239-010-0509-x/MediaObjects/11239_2010_509_Fig2_HTML.gif
Fig. 2

Site of venous thromboembolism

Overall prophylaxis rate in this group was low; 147 (73.5%) patients had not received any form of prophylaxis. Among the other 53 (26.5%) patients who received prophylaxis, only 34 (17.0%) were put on LMWH (Enoxaparin at a dose of 40 mg subcutaneously once daily); while 19 others (9.5%) were put on mechanical methods including elastic stockings and intermittent pneumatic compression devices (Table 2). We additionally looked at the prophylaxis rate in relation to number of risk factors patients had within 30 days prior to the diagnosis of VTE. Among patients with ≥3 risk factors, the prophylaxis rate was 23.0%, while it reached 50.0% among the highest risk group with ≥5 risk factors (Fig. 3a). Among the 87 (43.5%) ambulatory patients who developed out-of-hospital VTE, less than 5.0% of them had been on prophylaxis before they developed thrombosis, compared to a prophylaxis rate of 44% (P-value = 0.000) among the group of 113 (56.5%) patients who developed their VTE while in-hospital or within 30-days of hospital discharge (Fig. 3b). Additionally, VTE prophylaxis rate varied in relation to duration of cancer diagnosis (Table 3). Majority of the patients; 144 (72.0%) developed their VTE within the first 12 months following cancer diagnosis; 44 (30.6%) of them were offered prophylaxis compared to a rate of 16.1% among the other 56 (28%) patients who developed VTE beyond one year of cancer diagnosis (P-value = 0.037).
Table 2

Methods of VTE prophylaxis

Method

N (%)

Pharmacological

34 (17.0)

 Unfractionated heparin

0 (0)

 Low-molecular-weight heparins

34 (17.0)

Non-Pharmacological (only)

19 (9.5)

 Pneumatic compression

7 (3.5)

 Elastic stocking

12 (6.0)

Both

3 (1.5)

https://static-content.springer.com/image/art%3A10.1007%2Fs11239-010-0509-x/MediaObjects/11239_2010_509_Fig3_HTML.gif
Fig. 3

a Prophylaxis rate according to number of risk factors. b Prophylaxis rate in relation to recent hospitalization

Table 3

Prophylaxis rate in relation to duration of cancer diagnosis

Duration (months)

Pharmacological prophylaxis (n)

Non-pharmacological prophylaxis (n)

Both methods (n)

Total (n)

Prophylaxis rate (%)

≤12

23

18

3

44

44/144 (30.6)

<3

15

8

1

24

24/88 (27.3)

3–6

1

5

1

7

7/26 (26.9)

6–12

7

5

1

13

13/30 (43.3)

>12

8

1

0

9

9/56 (16.1)

Total

31

19

3

53

53/200 (26.5)

Discussion

VTE prophylaxis in non-surgical patients, even in high risk groups, continued to be underutilized. This underutilization was reported in many registry studies that included heterogenous groups of patients, but none addressed this issue purely in cancer patients. In a national Canadian multi-center survey study, the CURVE study, the medical records of patients in 20 teaching and 8 community hospitals were reviewed to assess the adherence to the established 6th American College of Chest Physicians (ACCP) consensus guidelines for VTE prophylaxis. In this study, 1,894 eligible patients were included; thromboprophylaxis was administered to only 23% of all patients and to 37% of patients who were bedridden for more than 24 h. However, appropriate prophylaxis, as reported, was given to only 16% of such patients. In particular, patients with cancer had a significantly reduced likelihood of receiving prophylaxis (OR = 0.40, 95% CI [0.24, 0.68] [10]). In another trial, The ENDORSE, the prophylaxis rate was 39.5% among a group of 15,487 medically-ill patients judged to be at high risk for VTE and eligible for prophylaxis on the basis of ACCP criteria [11]. Similar findings were also reported in the IMPROVE study [12].

Researchers at Brigham and Women’s Hospital had previously addressed similar question in a heterogeneous group of 384 patients who developed VTE in-hospital or within 30 days of prior hospital discharge. Most of the studied patients were admitted to medical services; with less than one-fourth were admitted to general or orthopedic surgery services. The overall VTE prophylaxis rate among the whole group was 52% [13]. Authors concluded that VTE, in their group of patients, developed secondary to prophylaxis failure rather than omitting prophylaxis. However, VTE prophylaxis rate was not reported in a subgroup of 40.6% of the patients who had a diagnosis of cancer and in 11.7% of patients who were on current chemotherapy. Our findings were different; majority (73.5%) of our cancer patients developed VTE without prior prophylaxis; only 26.5% of the patients with a confirmed diagnosis of VTE had been on prophylaxis, more than one-third of them [19/53 (35.8%)], where put on mechanical methods only which means that minority 34/200 (17.0%) of VTE developed in cancer patients already on prophylaxis.

Many factors may have contributed to low prophylaxis rate in our cancer patients. Fear from bleeding especially in patients undergoing active treatment with chemotherapy which might be complicated by thrombocytopenia might be one of such reasons. While such fear may not represent absolute or even a relative contraindication for using anticoagulants for VTE prophylaxis, nevertheless, we believe that such fear may prevent physicians from prescribing anticoagulant prophylaxis in cancer patients. Fear from bleeding from tumor metastasis in vital structure like the brain may also be a contributing factor. However, such patients can be offered mechanical methods for prophylaxis if anticoagulants deemed contraindicated. We believe that the absence of a suitable risk assessment model is probably the most important factor that contributes to such low prophylaxis rate. Such risk assessment model should take into account the additive or even the synergistic effect of the many other additional risk factors that cancer patients typically have. The confusing and somewhat conflicting published prophylaxis guidelines by many clinical and scientific groups who addressed this issue are adding to the problem; while the ACCP was very conservative and advised prophylaxis for cancer patients who are bedridden with an acute medical illness [14], the national comprehensive cancer network (NCCN) on the other hand suggested a lower threshold for prophylaxis; the most recent updated NCCN guidelines stated “It is the directive of NCCN that all adult, hospitalized patients with cancer receive anticoagulation therapy in the absence of contraindications” [15].

VTE is also common among non-hospitalized ambulatory cancer patients; 87 (43.5%) of our study patients developed VTE without history of prior recent hospitalization, prophylaxis rate in this group of patients was significantly low (<5.0% compared to a prophylaxis rate of 44.0% in the hospitalized group). Current guidelines do not recommend anticoagulant prophylaxis for such ambulatory cancer patients. Several investigators addressed this issue. In one study, Khorana et al. tried to establish a risk assessment model for VTE prophylaxis in ambulatory cancer patients after the initiation of chemotherapy. In this study, the site of the primary tumor, platelet count, leukocyte count, hemoglobin level, use of erythropoiesis stimulating agents (ESA) and BMI were found to be predictive factor for occurrence of VTE [16]. The same issue was addressed by the Vienna Cancer and Thrombosis Study group who reported that elevated plasma P-selectin level predicts VTE in 687 newly diagnosed ambulatory cancer patients. The cumulative probability of VTE after 6 months of follow up was 11.9% in patients with serum P-selectin above and 3.7% in those below the 75th percentile (P = 0.002). Authors postulated that such biomarker could identify ambulatory cancer patients who could benefit from prophylaxis [17]. More recently, the same group reported their experience in utilizing D-Dimer and prothrombin fragments 1 + 2 (F1 + 2), markers that reflect the activation of blood coagulation and fibrinolysis, for prediction of cancer-associated VTE. In this prospective, observational study, D-Dimer and F1 + 2 levels independently predicted the occurrence of VTE in a group of 821 patients with newly diagnosed cancer or progression of disease who did not recently receive active treatment [18]. More work is needed before utilizing such biomarkers in clinical practice.

Decision on when to start prophylaxis in cancer patients will continue to be difficult to make. Formal validated risk assessment model for VTE prophylaxis in such group of patients is highly needed. We recently reported our experience in offering VTE prophylaxis for hospitalized medically-ill cancer patients based on a modified risk assessment model that is under validation by our group [19].

Additionally, meticulous quality improvement programs should be established to emphasize the importance of implementing more intensive prophylaxis guidelines among high-risk cancer patients.

Lastly, our study is not without limitation; given the retrospective nature of the study and despite the methods used, there is still a chance that we may have missed some patients.

In conclusion, majority of VTE in our cancer patients occurred due to failure to offer prophylaxis, minority were due to prophylaxis failure. Meticulous quality improvement programs and projects should be established to emphasize the importance of implementing more intensive prophylaxis among high-risk cancer patients.

Acknowledgment

The authors wish to thank Dr. Luna Zaru, Mr. Ameen Harb, Miss Haifa Al-Ahmad and Mrs. Alice Haddadin for their help in preparing this manuscript.

Conflict of interest

None.

Copyright information

© Springer Science+Business Media, LLC 2010