Venous thromboembolism (VTE) in hospitalized cancer patients: prophylaxis failure or failure to prophylax!
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- Abdel-Razeq, H., Albadainah, F., Hijjawi, S. et al. J Thromb Thrombolysis (2011) 31: 107. doi:10.1007/s11239-010-0509-x
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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.
KeywordsCancerHeparinLow molecular weight heparinThromboembolism
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 .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 .
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 . On the other hand, PE is associated with substantial morbidity and mortality both tend to be higher among cancer patients  and those who survive such event may develop chronic complications like pulmonary hypertension . 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) . 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 . Active cancer accounts for almost 20% of all new VTE events occurring in the community . 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 .
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.
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.
Stage of disease
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).
Methods of VTE prophylaxis
Prophylaxis rate in relation to duration of cancer diagnosis
Pharmacological prophylaxis (n)
Non-pharmacological prophylaxis (n)
Both methods (n)
Prophylaxis rate (%)
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] ). 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 . Similar findings were also reported in the IMPROVE study .
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% . 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 , 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” .
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 . 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 . 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 . 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 .
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.
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