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Keywords:

  • cancer;
  • cancer-associated thrombosis;
  • low molecular weight heparin;
  • recurrent venous thromboembolism;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of Conflict of Interests
  9. References

Summary. Background: Cancer patients with venous thromboembolism (VTE) are at high risk of recurrent VTE despite standard anticoagulation. To date, very little published literature is available to guide the treatment of cancer patients with recurrent VTE. Objectives: To evaluate the benefit and risk of low molecular weight heparin (LMWH) dose escalation in cancer patients with recurrent VTE. Patients and methods: This was a retrospective cohort study of consecutive cancer outpatients referred for management of a symptomatic, recurrent VTE while receiving an anticoagulant. Confirmed episodes of recurrent VTE were treated with either dose escalation of LMWH in patients already anticoagulated with LMWH, or initiation of therapeutic dose LMWH in patients who were taking a vitamin K antagonist (VKA). All patients were followed for a minimum of 3 months after the index recurrent VTE unless they died during this period. Results: Seventy cancer patients with a recurrent VTE despite ongoing anticoagulation were included. At the time of the recurrence, 67% of patients were receiving LMWH, and 33% were receiving a VKA. A total of six patients [8.6%; 95% confidence interval (CI) 4.0–17.5%] had a second recurrent VTE during the 3-month follow-up period, at an event rate of 9.9 per 100 patient-years (95% CI  2.0–17.8%). Three patients (4.3%; 95% CI  1.5–11.9%), or 4.8 per 100 patient-years (95% CI  0.0–10.3%) of follow-up, had bleeding complications. The median time between the index recurrent VTE to death was 11.4 months (range, 0–83.9 months). Conclusions: Cancer patients with recurrent VTE have a short median survival. Escalating the dose of LMWH can be effective for treating cases that are resistant to standard, weight-adjusted doses of LMWH or a VKA.


Background

  1. Top of page
  2. Abstract
  3. Background
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of Conflict of Interests
  9. References

Patients with cancer have a four-fold increased risk of developing a venous thromboembolism (VTE) relative to the general population [1,2]. They also have a three-fold risk of recurrent VTE and a three-fold to six-fold risk of major bleeding while receiving anticoagulant treatment with a vitamin K antagonist (VKA), as compared with patients without cancer [3–5]. Low molecular weight heparin (LMWH) therapy for 3–6 months is now recommended over VKA as a first-line treatment to reduce the risk of recurrent VTE in patients with active cancer [6,7], on the basis of several randomized controlled trials that compared the relative efficacy and safety of LMWH with VKA therapy [8,9]. In the CLOT trial, a therapeutic dose of dalteparin for the first month followed by a ‘maintenance’ dose of 75–80% of the full therapeutic dose for the next 5 months reduced the relative risk of recurrent VTE in the dalteparin group by 52% [8]. Importantly, differences in bleeding and survival were not observed.

The CLOT study also demonstrated that 9–17% of cancer patients will develop recurrent VTE, despite therapy with LMWH or VKA, over 6 months of follow-up. Furthermore, the overall survival of these patients was reduced: 60% were dead within 1 year after the diagnosis of VTE. To date, very little published literature is available to guide the treatment of cancer patients with recurrent VTE despite standard anticoagulation treatment.

The American College of Chest Physicians previously recommended the insertion of an inferior vena cava (IVC) filter in patients with recurrent VTE while on anticoagulant therapy [10]. However, this recommendation has been withdrawn from the most recent guidelines published in June 2008 [7]. For cancer patients with recurrent VTE, the American Society of Clinical Oncology recommends the use of an alternate anticoagulant regimen (e.g. switch to LMWH if the patient had been receiving a VKA), or the insertion of an IVC filter, as a possible management option [6]. However, these recommendations are based on weak evidence. Indeed, the risk of recurrent deep vein thrombosis (DVT) after IVC filter insertion has been reported to be as high as 32% in patients with cancer, and is associated with significant morbidity and poor quality of life [5,11–14]. These poor outcomes are not unexpected, as filters do not control or dampen the hypercoagulable state in these patients, and may introduce another nidus for thrombus formation.

Dose escalation of LMWH may represent an alternative to IVC filter insertion in cancer patients with recurrent VTE. A retrospective study of 32 patients suggested that LMWH therapy might be effective in the management of recurrent VTE in patients taking a VKA [15]. In that particular study, 63% of patients had a diagnosis of cancer. It is currently unknown whether dose escalation of LMWH would be effective and safe for treating recurrent VTE in cancer patients already on LMWH. One case report has described successful management of recurrent VTE in a patient with cervical cancer using a supratherapeutic dose of LMWH [16].

To further evaluate the benefit and risk of LMWH dose escalation in cancer patients with recurrent VTE, we performed a retrospective study in two large thrombosis clinics.

Patients and methods

  1. Top of page
  2. Abstract
  3. Background
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of Conflict of Interests
  9. References

Patient population

A retrospective cohort study of consecutive cancer outpatients referred for management of a symptomatic, recurrent VTE while receiving an anticoagulant was conducted at the Ottawa Hospital Thrombosis Unit, Ottawa, ON (July 2004 to June 2008; n = 31) and the Henderson Hospital Outpatient Thrombosis Unit, Hamilton, ON (April 2003 to June 2007; n = 39). Patients were included if they had: (i) documented active malignancy; (ii) objectively proven first episode of VTE [proximal lower extremity DVT, upper extremity DVT or pulmonary embolism (PE)]; and (iii) objectively documented recurrent VTE (either new or extended proximal lower extremity DVT, upper extremity DVT, or PE) while taking systemic anticoagulation medication (LMWH or a VKA). Only cases with symptomatic VTE were included. Research ethics board approval was obtained for the study.

Data collection

The following variables were prespecified prior to data collection: (i) patient demographics; (ii) management of the initial VTE; (iii) cancer history (site and stage); (iv) dates of diagnosis of the initial and recurrent episodes of VTE; (v) radiologic evidence of the location/extent of the initial and recurrent VTE; (vi) dose of LMWH (therapeutic, maintenance, low dose) or International Normalized Ratio (INR) (therapeutic or subtherapeutic) at the time of the index recurrent VTE; (vii) management of the index recurrent VTE; (viii) further recurrent VTE or bleeding within 3 months after the index recurrence; and (ix) death (date and cause). Other information relevant to recurrent VTE or bleeding events, such as withholding of anticoagulation treatment for surgery, was also recorded.

For this study, a therapeutic dose of LMWH was defined as dalteparin 200 units kg−1 once daily, tinzaparin 175 units kg−1 once daily, or enoxaparin 1 mg kg−1 twice daily or 1.5 mg kg−1 once daily. The maintenance dose of LMWH was defined as 75–80% of the full therapeutic dose. Low dose was defined as any dose less than 75% of the full therapeutic dose. The therapeutic anticoagulation for VKA was defined as an INR greater than or equal to 2.0. Subtherapeutic INR was defined as less than 2.0.

Data were extracted independently by two investigators at each site. Disagreements on information were resolved by consensus or retrieving further information from other medical records.

Management

The management of recurrent VTE was consistent at both thrombosis units. All objectively confirmed episodes of recurrent VTE were treated with either dose escalation of LMWH in patients already anticoagulated with LMWH or initiation of a therapeutic dose of LMWH in patients who were taking a VKA. Patients on a therapeutic dose of LMWH at the time of the recurrent VTE were managed by increasing the weight-adjusted dose by 20–25% for at least 4 weeks. Patients on a maintenance dose were treated by increasing the LMWH to a therapeutic dose for 6–12 weeks. Patients on low-dose LMWH were managed by increasing the LMWH to a therapeutic dose for 1 month, and using a maintenance dose thereafter. Similarly, patients on a VKA (therapeutic or subtherapeutic) were treated with a therapeutic dose of LMWH for 1 month, followed by a maintenance dose. Anti-factor Xa measurements at the time of the index recurrent VTE or after dose escalation were not routinely performed.

Outcome assessment and follow-up

All patients were followed for a minimum of 3 months after the index recurrent VTE, unless they died during this period. The primary outcome measure was the incidence of a second, symptomatic recurrent VTE diagnosed over a 3-month follow-up period after the first (index) recurrent VTE. Initial proximal lower extremity DVT was defined a non-compressible segment on compression leg vein ultrasound imaging in the popliteal vein or a more proximal leg vein. Initial upper extremity DVT was defined as a non-compressible segment on compression ultrasound in the brachial or internal jugular deep veins, or absent flow in the subclavian vein. Initial PE was defined as a high-probability ventilation/perfusion (V/Q) lung scan or a segmental or larger pulmonary artery filling defect on spiral computed tomography (sCT) scan. Recurrent DVT was defined as a new non-compressible site or proximal extension from a previous measurement. Recurrent PE was defined as a new mismatched segmental or greater perfusion defect on V/Q scan or a new intraluminal filling defect in a segmental or larger pulmonary artery on sCT scan.

Secondary outcome measures included minor and major bleeding over the 3-month period after the index recurrent VTE (regardless of the status of anticoagulation at the time of the bleed), and overall and VTE-related death. Major bleeding events were defined as: (i) fatal bleeding; (ii) symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome; and (iii) bleeding causing a fall in hemoglobin level of 20 g L−1 or more, or leading to transfusion of two or more units of whole blood or red cells [17]. Date of last follow-up and date of death (if available in the clinic chart) were recorded. VTE-related death was defined as a fatal PE confirmed on autopsy or as an unexplained sudden death [18].

Analyses

A descriptive summary of the baseline characteristics of the cohort is provided. We reported the proportions, with 95% confidence intervals (CIs), of patients with a second or more episodes of recurrent VTE and major bleeding during the 3-month follow-up period. The corresponding event rates were calculated on the basis of 100 patient-years of follow-up. A Kaplan–Meier survival curve was constructed to estimate the time to the index recurrent VTE from the initial diagnosis, and a separate curve was plotted to estimate overall survival following the index recurrent VTE. Patients were censored after the last known date of follow-up or death. The median time between the initial and index recurrent VTE, and the median time between the index recurrent VTE and death, were determined.

Results

  1. Top of page
  2. Abstract
  3. Background
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of Conflict of Interests
  9. References

Seventy cancer patients with a recurrent VTE despite ongoing anticoagulation are included in this report. The study participants’ characteristics are summarized in Table 1. The median age was 60 years (range, 27–84 years). Thirty-eight (54%) were female. Forty-four patients (63%) had metastatic cancer at the time of their initial VTE. The most common type of cancer was lung carcinoma. At the time of the initial VTE, 39 patients (56%) had a proximal lower extremity DVT, 12 (17%) had an upper extremity DVT (five cases were catheter-related), 14 (20%) had a PE, and five (7%) had both a leg DVT and a PE.

Table 1.   Baseline characteristics
  LMWH (N = 47) (n, %)Vitamin K antagonist (N = 23) (n, %)Study population (N = 70) (n, %; 95% CI)
  1. CI, confidence interval; DVT, deep vein thrombosis; GI, gastrointestinal; GU, genitourinary; LMWH, low molecular weight heparin; NA, not applicable; PE, pulmonary embolism; VTE, venous thromboembolism.

Female25 (53.2)13 (56.5)38 (54.3; 42.7–65.5)
Age, years (median; range)58 (27–83)64 (49–90)60 (27–90)
Cancer location
 Lung15 (31.9)6 (26.1)21 (30.0; 20.5–41.6)
 Colon9 (19.2)1 (4.3)10 (14.3; 8.0–24.4)
 Breast3 (6.3)2 (8.6)5 (7.1; 3.2–15.7)
 GI10 (21.3)2 (8.6)12 (17.1; 10.1–27.7)
 GU1 (2.1)3 (13.0)4 (5.7; 2.3–13.8)
 Gynecological2 (4.3)3 (13.0)5 (7.1; 3.2–15.7)
 Hematological4 (8.5)2 (8.6)6 (8.6; 4.1–17.5)
 Other3 (6.3)4 (17.4)7 (10.0; 5.0–19.3)
Cancer stage
 Non-metastatic18 (38.3)6 (26.1)24 (34.3; 24.2–46.0)
 Metastatic28 (59.6)16 (69.6)44 (62.9; 51.1–73.2)
 NA1 (2.1)1 (4.3)2 (2.9; 0.9–9.8)
Initial VTE
 Lower extremity DVT24 (51.1)15 (65.2)39 (55.7; 44.0–66.8)
 Upper extremity DVT9 (19.2)3 (13.0)12 (17.1; 10.1–27.7)
 Catheter-related5 (10.6)05 (7.1; 3.2–15.7)
 PE11 (23.4)3 (13.0)14 (20.0; 12.3–30.9)
 DVT and PE3 (6.3)2 (8.6)5 (7.1; 3.2–15.7)
Anticoagulation at time of recurrence(n, %; 95% CI)(n, %; 95% CI) 
 LMWH
  Therapeutic dose15 (21.4; 13.5–32.4)NA 
  Maintenance dose24 (34.3; 24.2–46.0)NA 
  Low dose8 (11.4; 6.0–21.0)NA 
 Vitamin K antagonists
  TherapeuticNA11 (15.7; 9.1–26.0) 
  SubtherapeuticNA8 (11.4; 6.0–21.0) 
  UnknownNA4 (5.7; 2.3–13.8) 

At the time of the symptomatic index recurrence, 47 (67%) patients were on LMWH, and 23 (33%) were on VKAs. Of the 47 patients on LMWH, 15 (32%), 24 (51%) and eight (17%) were on therapeutic, maintenance and low doses, respectively. Eleven (48%) and seven (30%) of the 23 patients on VKAs had a therapeutic (≥ 2) and subtherapeutic INR, respectively, whereas five (22%) patients did not have a documented INR result at the time of the recurrent VTE event.

Of the 70 index recurrent VTEs, 40 (57%) involved the lower extremity, 13 (19%) occurred in an upper extremity (five were catheter-related), and 15 (21%) presented as PE. Two (3%) patients had a recurrent VTE in the IVC. Table 2 summarizes the location and extent of the index recurrences. It is of note that 67% of the recurrent VTEs developed at a new site (e.g. the initial episode was a right leg DVT, and the recurrent episode presented as a PE). The median time between the initial VTE to recurrence (index episode) was 3.5 months (range, 0.3–193 months) (Fig. 1). A total of 20 patients (29%) had the index recurrent VTE less than 4 weeks following the initial diagnosis.

Table 2.   Recurrent venous thromboembolism events
 Study population (N = 70)
  1. CI, confidence interval; DVT, deep vein thrombosis; PE, pulmonary embolism; IVC, inferior vena cava.

Recurrent lower extremity DVT (n, %; 95% CI)40 (57.4; 45.4–68.1)
 Ipsilateral13 (18.6; 11.2–29.3)
 Ipsilateral and new upper extremity DVT1 (1.4; 0.3–7.6)
 Contralateral12 (17.1; 10.1–27.7)
 Bilateral3 (4.3; 1.6–11.9)
 New DVT11 (15.7; 9.1–26.0)
Recurrent upper extremity DVT (n, %; 95% CI)13 (18.6; 11.2–29.3)
 Ipsilateral3 (4.3; 1.6–11.9)
 Contralateral1 (1.4; 0.3–7.6)
 New upper extremity DVT9 (12.9; 7.0–22.7)
Recurrent PE (n, %; 95% CI)15 (21.4; 13.5–32.4)
 Recurrent PE7 (10.0; 5.0–19.3)
 New PE8 (11.4; 6.0–21.0)
Other (IVC thrombus) (n, %; 95% CI)2 (2.9; 0.9–9.8)
image

Figure 1.  Time to index recurrent venous thromboembolism (VTE) after initial diagnosis of VTE.

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All 70 objectively confirmed episodes of recurrent VTE were treated with either dose escalation of LMWH in patients already anticoagulated with LMWH or initiation of therapeutic-dose LMWH in patients who were taking a VKA. Three patients also had an IVC filter inserted. Overall, 55 patients were treated with a therapeutic dose of LMWH, and 15 patients received 120% of a therapeutic dose of LMWH for the index recurrent VTE.

A total of six patients (8.6%; 95% CI  4.0–17.5%) had a second recurrent VTE during the 3-month follow-up period, at an event rate of 9.9 per 100 patient-years (95% CI 2.0–17.8%). The median time between the index and second recurrent VTE was 1.9 months (range, 0.6–3.0 months). Three patients (50%) had their second recurrence while on therapeutic doses of LMWH, and the other three were on 120% of a therapeutic dose of LMWH. All were treated by increasing the weight-adjusted dose by 20–25% for at least 4 weeks, and one patient had an IVC filter inserted as well. None of these patients had any further recurrent thrombotic event during the 3-month follow-up period. Of these six patients with a second recurrence, five (83%) had metastatic disease and four (67%) had an underlying diagnosis of lung carcinoma.

Only three patients (4.3%; 95% CI  1.5–11.9%), or 4.8 per 100 patient-years (95% CI  0.0–10.3%) of follow-up, had bleeding complications after their index recurrent VTE. One patient with a malignant brain tumor had an intracranial bleed after the LMWH was increased to a therapeutic dose. Two patients (2.9%; 95% CI  0.9–9.8%) had a minor bleeding episode while receiving therapeutic LMWH.

At the time of the last follow-up, a total of 36 patients were dead. None of the deaths were related to the recurrent VTE or bleeding. The median time between the index recurrent VTE to death was 11.4 months (range, 0–83.9 months) (Fig. 2). The median survival was only 4.3 months (range, 0.9–4.9 months) after a second recurrence (data not shown).

image

Figure 2.  Kaplan–Meier survival curve after index recurrent venous thromboembolism (VTE).

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Discussion

  1. Top of page
  2. Abstract
  3. Background
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of Conflict of Interests
  9. References

This is the largest report on the management and outcomes of cancer patients following a recurrent episode of VTE while they were being treated with an anticoagulant. Our retrospective cohort study demonstrates that recurrent VTE in cancer patients can be effectively and safely managed by escalating the dose of LMWH or switching to LMWH from warfarin. Although the exact dosing of LMWH for the recurrent VTE differed (depending on the anticoagulant regimen at the time of the recurrence), escalating the dose of LMWH resulted in a second recurrent VTE rate of 8.6% (95% CI  4.0–17.5%), and it was well tolerated, with few bleeding complications. The high rate of response to dose escalation suggests that recurrent VTE in cancer patients might be a consequence of ‘resistance’ to standard doses of LMWH, and that higher doses are needed. This is in contrast to a true failure of LMWH anticoagulation, whereby dose escalation is not successful and other therapeutic options would be required to suppress the hypercoagulable state. The heightened hypercoagulable state in these patients is also indirectly reflected by the short time to recurrence: 29% of the index recurrences occurred within the first 4 weeks of treatment. We can only speculate on the mechanism of anticoagulant resistance. Given that the majority of patients responded to a higher dose of LMWH, it is likely that these patients did not achieve therapeutic levels with standard, weight-adjusted doses of LMWH. Whether this is due to lower bioavailability from increased non-specific binding of LMWH to plasma proteins or cells, enhanced renal clearance, or perhaps a large clot burden, is unknown. We were unable to explore these hypotheses, because of the retrospective design of the study and the lack of anti-FXa levels at the time of the recurrence.

Our study also shows that the median survival of patients with recurrent VTE, especially following a second recurrent VTE, is very poor in cancer patients. Previous studies have demonstrated that cancer patients who develop a VTE have a shorter life expectancy than matched cohorts without thrombotic complications [19–21]. The short median survival of 11.4 months after a recurrent VTE in our study is consistent with a previously published report of a small cohort of cancer patients with recurrent VTE [22]. It is unknown whether the early deaths are due to undiagnosed fatal PE or aggressive malignancies, which may have contributed to the anticoagulant resistance or failure. This should be taken into consideration when managing cancer patients with recurrent VTE.

There are limitations of our study. First, this is a retrospective cohort study, and the results may be subject to bias, incomplete information, or misdiagnosis. We tried to minimize selection bias by including all consecutive patients assessed at the two different thrombosis units. Charts of all patients with a diagnosis of cancer were fully reviewed by two reviewers independently, to identify patients with recurrent VTE on anticoagulants, and only patients with objectively diagnosed, symptomatic events were included. Second, a control group of cancer patients without a recent VTE were not available for comparison to evaluate the impact on survival or risk factors for recurrent VTE. Third, anti-FXa measurements were not routinely performed at the time of the index recurrent VTE. This is difficult to do in practice, as patients do not present at a time when peak or trough levels can be taken. Also, previous studies have shown a poor correlation between anti-FXa levels and clinical outcome [23,24]. Fourth, the total numbers of second recurrent VTEs and bleeding events were small. Larger studies are needed to provide more reliable estimates of the risk of recurrent VTE, bleeding and overall survival after dose escalation with LMWH.

Conclusion

  1. Top of page
  2. Abstract
  3. Background
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of Conflict of Interests
  9. References

Cancer patients with recurrent VTE have a poor prognosis. Although the evidence is limited, our study suggests that escalating the dose of LMWH can be effective for treating cases that are resistant to standard, weight-adjusted doses of LMWH or a VKA. Prospective trials are required to assess the effectiveness and safety of this management option and to identify those who are at highest risk of anticoagulant resistance.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Background
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of Conflict of Interests
  9. References

The authors state that they have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Patients and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of Conflict of Interests
  9. References
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