Thrombosis, cancer and renal insufficiency: low molecular weight ...

Support Care Cancer DOI 10.1007/s00520-012-1590-9

REVIEW ARTICLE

Thrombosis, cancer and renal insufficiency: low molecular weight heparin at the crossroads F. Scotté & J. B. Rey & V. Launay-Vacher

Received: 16 February 2012 / Accepted: 30 August 2012 # Springer-Verlag 2012

Abstract Background Venous thromboembolism (VTE) and renal insufficiency are common in cancer patients. Prompt treatment is necessary to reduce the high rates of VTE-related mortality and morbidity. VTE prophylaxis is underused in cancer patients. We review current recommendations for the treatment and prevention of VTE in cancer patients and discuss low molecular weight heparin (LMWH) use in cases of renal failure. Design This study is a retrospective literature review. Results There are few published recommendations for LMWH use in cancer patients with renal insufficiency. Treatment guidelines largely follow recommendations for other patients with renal failure. Enoxaparin therapy is complicated by the need for regular monitoring of renal function and anti-Xa levels and for dosage adjustment to prevent bleeding. Few data are available to support the systematic use of dalteparin. Tinzaparin is least likely to bioaccumulate in patients with renal failure. Conclusion VTE is the second most common cause of death in cancer patients. Renal insufficiency is present in 50–60 % of cancer patients. Data from renal patients suggest that tinzaparin may be safe and effective for VTE treatment and prevention in cancer patients with renal failure. F. Scotté Department of Medical Oncology, Hôpital Européen Georges Pompidou, Paris, France J. B. Rey Department of Pharmacy, Institut Jean Godinot, Reims, France V. Launay-Vacher (*) Service ICAR, Department of Nephrology, Hôpital Pitié-Salpêtrière, 83, boulevard de l’Hôpital, 75013 Paris, France e-mail: [email protected]

Keywords Cancer . Low molecular weight heparin . Prevention . Renal insufficiency . Kidney disease . Venous thromboembolism

Introduction Venous thromboembolism (VTE) is a frequent cause of mortality and morbidity in patients with malignancy, particularly during prolonged hospitalisation. The incidence of VTE is highest in the first few months after cancer diagnosis, in patients with metastatic disease at the time of diagnosis and after tumour recurrence [1]. VTE may also be treatment-related with risk factors including certain chemotherapy regimens, angiogenesis inhibitors and the presence of indwelling central venous catheters for treatment administration. Catheter-related thrombosis (CRT) may result in clinically overt pulmonary embolism (PE) in 15–25 % of patients [2]. The risk of PE is increased two- to threefold in patients with cancer [3]. VTE is now the second most common cause of death in patients with malignancy after the cancer itself [3, 4]. Prompt recognition and treatment of VTE are therefore required in order to reduce the high levels of VTE-related mortality. Appropriate strategies to prevent VTE are available but are largely underused in cancer patients. Over half of patients with cancer may have renal insufficiency [5, 6] and a high rate of malignancy (~7 %) has also been reported in patients with chronic renal failure [7]. Reduced renal function may result in bioaccumulation of some anti-thrombotic drugs, leading to an increased risk of bleeding. This report reviews the interrelationship between cancer, renal insufficiency and VTE. Current recommendations for the treatment and prevention of VTE in cancer patients are outlined, and the use of low molecular weight heparins

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(LMWHs) in cancer patients with renal insufficiency is discussed.

Table 1 Risk factors for venous thromboembolism (VTE) in cancer patients Risk factors for VTE

Thrombosis and cancer Prevalence VTE, as defined by deep vein thrombosis (DVT), CRT or PE, is a frequent cause of mortality and morbidity in cancer patients and is a common complication of chemotherapy. In two comprehensive analyses of first-time VTE, 18 % of cases overall were attributed to cancer [8, 9]. In patients with malignancy, the risk of thromboembolic events has increased significantly over the past 10–15 years [10] and is up to seven times higher than in patients without cancer [11, 12]. The overall prevalence of VTE in cancer patients has been reported to range from 4 [10] to 20 % [13], although some subgroups of cancer patients have a higher risk than others. Tumours associated with the highest risk of VTE include mucin-secreting adenocarcinomas of the stomach, tumours of the ovary, pancreas, brain, kidney and lung and haematological malignancies such as myeloma, nonHodgkin’s lymphoma and Hodgkin’s disease [10, 13]. The risk of recurrent VTE and all-cause mortality has been reported to be three times higher in patients with VTE and concurrent malignancy than in VTE patients without cancer [4]. VTE is now the second most common cause of death in these patients after cancer progression itself [3, 4]. The epidemiology of VTE in cancer patients has been studied closely and various tumour-, patient- and treatmentrelated risk factors have been identified (Table 1). The risk of developing VTE is highest during prolonged hospitalisation and after tumour recurrence [1]. The presence of metastatic disease at the time of diagnosis is associated with a high risk of VTE and is the strongest predictor of VTErelated mortality [1]. The incidence of CRT, defined as a mural thrombosis extending from the catheter into the vessel lumen and leading to total or partial catheter occlusion with or without clinical symptoms, has also increased in cancer patients due to the increased use of central venous catheters for the administration of intravenous chemotherapy and other supportive therapies [3]. Depending on the study, the incidence of CRT has been reported to be around 4–5 % (range 0– 28 %) for symptomatic events, 30 % (range 27–66 %) for asymptomatic events detected by venography and 15–20 % for events detected by ultrasound echography [2]. CRT may result in clinically overt PE in 15–25 % of patients, although the incidence of autopsy-proven PE has been reported to be as high as 50 % [2]. The incidence of VTE is highest in the first few months after the diagnosis of cancer [12] and after disease

Tumour related Metastatic disease at the time of diagnosis Fast growing, biologically aggressive tumours Primary site of cancer (gastrointestinal tract, brain, lung, gynaecological, renal, haematological) Increased hypercoagulability due to tumour production of procoagulant proteins or inflammatory cytokines Compromised venous blood flow due to tumour mass Patient related Older age Prolonged immobilisation Increased number of chronic medical co-morbid conditions Prior history of VTE Pre-chemotherapy platelet count ≥350×109/l, leukocyte count >11×109/l, body mass index >35 kg/m2 in ambulatory patients Asian/Pacific Islander descent (lower incidence) Treatment related Recent major surgery—post-operative VTE Current hospitalisation Long-term central venous catheters Some types of chemotherapy/hormone therapy and angiogenesis inhibitors Erythropoiesis-stimulating agents Red blood cell and platelet transfusions

References

[1, 12, 20] [12] [16] [59]

[59] [16] [59] [12, 60] [16] [20]

[12] [3, 59] [16] [2, 3, 59] [11, 59, 61] [16, 20] [62]

recurrence [1]. Cancer has been shown to double the risk of post-operative DVT and to triple the risk of PE [3]. Recommendations A number of national and international working groups, set up under the auspices of the American College of Chest Physicians (ACCP) [14, 15], American Society of Clinical Oncology (ASCO) [16], National Comprehensive Cancer Network (NCCP) [17, 18], Italian Medical Oncology Society (AIOM) [19], European Society of Medical Oncology (ESMO) [20] and the French ‘Institut National du Cancer’ (INCa) [3, 21, 22], have published recommendations for the treatment and prevention of cancer-associated VTE. These recommendations are based on a critical analysis of wellconducted, randomised, clinical trials and meta-analyses published in the literature. Curative treatment The published recommendations for the treatment of cancerassociated VTE are summarised in Table 2.

Support Care Cancer Table 2 Summary of published recommendations/guidelines for the treatment of venous thromboembolism in cancer patients Recommended treatment

Guidelines

Treatment of DVT and PE VTE—acute LMWH, UFH or fondaparinux VTE—long-term

Vena cava filter

LMWH for 3–6 months, then LMWH or VKA indefinitely or until cancer is resolved LMWH for at least 6 months LMWH or VKA for 3–6 months (DVT) or 6–12 months (PE); indefinite anticoagulation if active cancer or persistent risk factors Failure, VTE relapse or contraindications to anticoagulants

Cerebral tumour

Same anticoagulation except for central nervous system bleed, risk of bleed, recent cerebral surgery or platelets 3 months

Thrombolytic therapy

Catheter removal

NCCN, ASCO, AIOM, [3, 15–17, 19, 20] ESCO, INCa, ACCP, SOR AIOM, ACCP, SOR [3, 15, 19] ASCO NCCN

[16] [17]

NCCN, ACSO, AIOM, ACCP, SOR, ESCO NCCN, ASCO, SOR

[3, 15–17, 19, 20] [3, 16, 17]

NCCN, SOR, INCa AIOM, ESCO SOR, NCCN

[3, 17] [19, 20] [3, 17, 20]

NCCN

[17]

ACCP SOR NCCP ACCP

[15] [3] [17] [15]

While catheter is in place, cancer is active and anti-cancer SOR therapy is continued; 6 weeks after catheter removal if no active cancer or anti-cancer treatment Catheter-directed thrombolytic therapy for massive DVT, in NCCN, ACCP, SOR patients with poorly tolerated vena cava syndrome and in patients with no risk of bleeding and severe symptoms of recent onset If symptoms or clot persist, if catheter unnecessary or not functional, NCCN, ACCP, SOR if unfavourable clinical evolution under anticoagulation, if distal catheter tip not in correct position, infected thrombophlebitis

The use of unfractionated heparin (UFH) is complicated by the need for continuous intravenous infusion and a high rate of heparin-induced thrombocytopenia [23] and serious bleeding when compared to LMWH [23]. In contrast, LMWH has a more predictable anticoagulant response than UFH, with the advantage that a fixed body-weight adjusted dose can be administered subcutaneously by medical staff or the patient him/herself, without the need for laboratory monitoring. A head-to-head comparison of clinical trials in which different LMWHs were administered once (o.d.) versus twice daily (b.i.d.) for the initial treatment of VTE showed that once daily treatment can be as safe and effective as twice daily administration and is more convenient to the patient [24]. LMWH is therefore recommended as first-line treatment and, as can be seen below, also for long-term treatment of acute VTE (Table 2). Low tolerance of daily subcutaneous (SC) injections may be major constraints to LMWH therapy

References

[3]

[3, 15, 17]

[3, 15, 17]

in some patients. However, in a study of 40 palliative care patients, LMWH was preferred to treatment with a vitamin K antagonist (VKA; warfarin) as it required less biological surveillance and therapeutic adaptation [25]. Long-term LMWH is an acceptable intervention that has a positive impact on the quality-of-life of cancer patients, allowing them freedom from blood tests and optimal care [25]. The recommended minimum duration of LMWH treatment after VTE is 3 months, with an optimal duration of 6 months or longer if cancer persists. The recommended doses and protocols for the various LMWHs are summarised in Tables 3 and 4. Alternatively, UFH can be administered by intravenous infusion of a 80 IU/kg bolus followed by a continuous infusion of 18 IU/kg/h, adjusted to obtain an activated partial thromboplastin time prolongation of 1.5–2.5 times the basal value [16]. Prolonged antithromboembolic treatment is indicated for symptomatic VTE and for the prevention of relapses in cancer patients.

Support Care Cancer Table 3 Summary of clinical product guidelines for LMWHs derived from the RxList internet drug index [63, 64] Treatment of acute VTE

Tinzaparin

Enoxaparin

Nadroparin

Dalteparin

Available forms

Multi-dose vial 2.0 ml/40,000 IU

10,000 IU/ml Single-dose prefilled syringes 0.3 ml/3,000 IU 0.4 ml/4,000 IU Graduated prefilled syringes 0.6 ml/6,000 IU 0.8 ml/8,000 IU 1.0 ml/10,000 IU

Single-dose prefilled syringes 0.2 ml/1,900 IU 0.3 ml/2,850 IU 0.4 ml/3,800 IU 0.6 ml/5,700 IU 0.8 ml/7,600 IU 1.0 ml/9,500 IU

Single-dose prefilled syringes 0.2 ml/2,500 IU 0.2 ml/5,000 IU 0.3 ml/7,500 IU 0.4 ml/10,000 IU0.5 ml/12 500 IU 0.6 ml/15,000 IU 0.72 ml/18,000 IU

Dosage

175 IU/kg o.d.

Indications Duration of treatment

DVT + PE At least 6 days

Multi-dose vial 3.0 ml/30,000 IU 15,000 IU/ml 0.8 ml/12,000 IU 1.0 ml/15,000 IU 1 mg/kg b.i.d. or 1.5 mg/kg o.d.

86 IU/kg b.i.d. or 171 IU/kg o.d.

DVT ± PE angina At least 5 days (average 7 days)

DVT angina At least 7 days

However, currently only dalteparin has marketing authorisation for use a specific prolonged treatment indication in cancer patients. Dalteparin should be given at a dose of 200 IU/kg o.d. during the first month following the VTE and at a dose of 150 IU/kg o.d. from the second to the sixth month following VTE for the prevention of relapse (Tables 3 and 4). In the case of confirmed VTE occurring in a patient with cancer, LMWH is also recommended as follow-on to initial treatment (Grade A). The following LMWH doses have been validated and recommended in the Standards, Options and Recommendations of INCa (Table 4) [21]: dalteparin 200 IU/kg o.d. for 1 month followed by 150 IU/kg o.d.; tinzaparin 175 IU/kg o.d. and enoxaparin 150 IU/kg o.d. If anticoagulant treatment fails or is contraindicated, a vena cava filter should be inserted (Table 4). The recommendations for the treatment of CRT in cancer patients are shown in Tables 2 and 4. If the catheter is functional, well placed and shows no sign of infection, it may be left in place and anticoagulant treatment implemented. There is no consensus regarding when anticoagulant treatment should be started if the catheter is removed. Thrombolytics may be considered for massive DVT and PE, and in the case of poor clinical tolerance (vena cava syndrome). Preventive treatment Although VTE is a preventable event, prophylactic strategies remain largely underused in medical and surgical

Single-dose ampule 1.0 ml/10,000 IU Multi-dose vial 3.8 ml/95,000 IU 9.5 ml/95,000 IU 100 IU/kg b.i.d. or 200 mg/kg o.d. month 1 150 IU/kg o.d. months 2–6 DVT angina 6 months (extended treatment)

cancer patients despite the high levels of VTE-related morbidity and mortality [26, 27]. A recent multinational cross-sectional survey (ENDORSE study) of over 68,000 patients showed that only 37 % of medical patients with active malignancy and a high risk of VTE were receiving appropriate ACCP-recommended prophylaxis [28]. Similarly, only 50 % of cancer patients in the RIETE registry were receiving longterm LMWH prophylaxis [29]. Alarmingly, in the SWIVTER study of clinical predictors of the use of prophylaxis prior to the onset of acute VTE in hospitalised patients, cancer was not predictive of prophylaxis use (OR01.06 [95%CI, 0.89–1.25]) [30]. Recommendations for the use of VTE prophylaxis in specific groups of cancer patients have been published and are summarised in Table 5. The suggested drug regimens and use of mechanical devices for the prevention of VTE are shown in Tables 3, 4 and 5. Advice for routine practice Clinicians should be aware of the increased risk of lifethreatening VTE in patients with malignancy and should aim to identify high-risk patients at the start of hospitalisation. Appropriate VTE prophylaxis should be administered systematically to all at risk patient populations according to published recommendations (Tables 3, 4, 5 and 6) [27].

Support Care Cancer Table 4 SORa recommendations for the treatment and prevention of venous thromboembolism and catheter-related thrombosis in cancer patients with and without renal insufficiency [21, 22, 65, 66] Treatment of DVT

Standards 1. Initial treatment (until day 10): LMWH at therapeutic doses for at least 3 months (but all drugs approved for this indication—LMWH, UFH, pentasaccharides, danaparoid—may be used) 2. After 10 days, LMWH at therapeutic (dalteparin 200 IU/kg o.d. for the first month then 150 IU/kg o.d., tinzaparin 175 IU/kg o.d., enoxaparin 150 IU/kg o.d.) doses should be given for 3–6 months 3. Treatment should be continued after 6 months if cancer persists or is being treated. If the VTE is a first event, and in the absence of active cancer, stop treatment at 6 months 4. If the patient has severe renal impairment, treat with UFH followed by VKA (as early as the first day if possible) for 3 months 5. In the presence of absolute contraindication to anticoagulant treatment or VTE recurrence despite optimal treatment, a vena cava filter should be considered. Continue anticoagulant treatment if the vena cava filter is inserted for VTE recurrence. If the filter is inserted for a contraindication, anticoagulants should be stopped and reinstated when the contraindication has been removed 6. In cancer patients with severe PE, the indications and uses of thrombolytic drugs are the same as in non-cancer patients 7. In cancer patients with intracranial malignancies, the indications and uses of VTE treatments are the same as those in cancer patients with non-intracranial malignancies Options

Catheter-related thrombosis

1. If LMWH administration for 3 months is refused or impossible, short-term use of LMWH followed by VKA for at least 3 months may be proposed 2. LMWH should be administered for 3–6 months. The dosage regimen administered in the second 3 months should be the same as that in the first 3 months 3. If the event is a first VTE event secondary to a transient risk factor, anticoagulant treatment can be discontinued after 6 months if the cancer is not active or is not treated 4. After the first 6 months, anticoagulant treatment should be continued if the cancer is active or is being treated. The choice between LMWH and VKA depends on their benefit–risk ratio and acceptability 5. If a vena cava filter is considered, the use of a retrievable (or optional) filter may be discussed Standards 1. The distal tip of the central venous catheter (CVC) should be placed at the junction between the superior vena cava and right atrium 2. Primary prevention of CVC-related thrombosis with anticoagulant drugs is not recommended 3. The catheter should be maintained if it is mandatory, well-placed, functional and non-infected, with a favourable clinical outcome. Anticoagulant treatment should be maintained as long as the catheter is present 4. If the catheter is removed, there is no standard approach in terms of the interval between removal and initiation of anticoagulant treatment Options 1. If insertion of a new catheter is necessary, the status of the superior vena cava network should be assessed by a scan or by Doppler ultrasonography 2. If prolonged LMWH treatment is refused or impossible, short-term use of LMWH followed by VKA may be proposed 3. In the event of poor clinical tolerance (vena cava syndrome), and in the absence of contraindications, thrombolytic drugs may be considered 4. There are no reliable data on the optimal duration of anticoagulant treatment after catheter removal

a

These recommendations were produced by a multidisciplinary working party set up by the French National Federation of Cancer Centres (Fédération Nationale des Centres de Lutte Contre le Cancer) led by the French National Cancer Institute (Institut National du Cancer). A literature review was carried out of studies published between 1999 and 2007 using the MEDLINE database, and the recommendations were classified as Standards or Options

In patients who develop VTE, anticoagulant therapy with LMWH should be administered for at least the first 3– 6 months and longer term if cancer persists. In the case of

contraindication to LMWH or VTE relapse, VKA should be prescribed or a vena cava filter inserted until the cancer is resolved and the risk of VTE has diminished.

Support Care Cancer Table 5 Summary of recommendations for the prevention of venous thromboembolism in specific groups of cancer patients Patient group

Systematic prophylaxis

Guideline

Ambulatory patients receiving systemic chemotherapy/ hormone therapy Patients with central venous catheters Hospitalised medical patients

Not recommended Exception Myeloma patients receiving thalidomide or lenalidomide plus chemotherapy or dexamethasone Not recommended Prophylaxis recommended in the absence of bleeding or other contraindications Prophylaxis recommended for bedridden patients with acute medical complication Prolonged prophylaxis is recommended in cancer patients undergoing major surgery and/or neurosurgery if no contraindications Prophylaxis recommended in patients undergoing laparotomy, laparoscopy or thoracotomy for >30 min Prophylaxis should be continued for at least 4 weeks after surgery/hospital discharge in high-risk patients (abdominal or pelvic surgery, residual/advanced disease, obese patients, previous history of VTE, anaesthesia time >2 h, age >60 years, bed rest >4 days)

ASCO, AIOM, ACCP [14, 16, 19] ASCO [16]

Prophylaxis during surgery

Prophylaxis after hospital discharge

Reference

AIOM, NCCN, ACCP [14, 18, 19] ASCO, NCCN [16, 18] AIOM, ACCP

[14, 19]

ASCO, AIOM, NCCN, [14, 16, 18–20] ACCP, ESMO ASCO

[16]

ASCO, AIOM, NCCN, [14, 16, 18, 19] ACCP

SOR guidelines do not mention prophylaxis in these groups of cancer patients

Renal insufficiency and cancer Prevalence and impact on survival Patients with chronic renal failure (CRF) have a greater risk of developing malignancies than the general population [31–33], particularly lymphomas and carcinomas of the kidney, liver, prostate and uterus [7, 34]. Over a 20-year study period, Cengiz reported various organ tumours in 6.7 % of hospitalised patients with CRF [7]. Many risk factors for malignancy have been identified in these patients including the development of acquired cystic kidney disease, the use of cytotoxic

drugs such as cyclophosphamide [34] and the immunosuppressive effects of uraemia, particularly on cellular immunity [35]. Abnormal renal function is also a common complication in patients with malignancy [6]. When assessed by creatinine clearance (CrCl; Cockcroft-Gault formula) or glomerular filtration rate (GFR; abbreviated ‘modification of diet in renal disease’ formula (aMDRD)), Launay-Vacher et al., on behalf of the Renal Insufficiency and Anticancer Medications (IRMA) study group, reported abnormal renal function or renal insufficiency in 50–60 % of patients with solid tumours [5], including the commonest tumours, of the lung [36], breast [37] and prostate [38]. Risk factors for the

Table 6 Recommended regimens for venous thromboembolism prophylaxis in cancer patients Type of prophylaxis

Recommended regimen

Prophylaxis for DVT and PE Pharmacological LMWH or UFH if laparotomy, laparoscopy or thoracotomy >30 min LMWH, UFH or fondaparinux LMWH, UFH (3 days) or fondaparinux in high-risk patients with major surgery for cancer or acutely ill medical patients with cancer LMWH for medical and neurosurgery patients. For general surgery patients: high-dose LMWH or UFH Mechanical devices Use recommended if contraindications to pharmacological prevention (active bleeding) Intermittent pneumatic venous compression devices and/or compression stockings recommended for inpatients with known or suspected cancer Prophylaxis for CRT Pharmacological Not recommended Mechanical

Ensure correct positioning of the central venous catheter at the junction between the superior vena cava and right atrium in a specialised unit

Guideline

Reference

ASCO ASCO, NCCN ACCP, ESCO

[12] [12, 14] [11, 60]

AIOM

[15]

ASCO, ACCP, ESMO NCCN

[11, 12, 60]

NCCN, ASCO, AIOM, ACCP, SOR SOR

[12, 17, 20–23]

[14]

[17, 18]

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development of acute renal failure (ARF) in cancer patients have been described by Darmon et al. [39]. Renal insufficiency has been linked to increased mortality in patients with various types of tumours. In a retrospective, multicentre study of 4,267 cancer patients followed up for 2 years, Launay-Vacher et al. reported a significant reduction in overall survival and length of survival of patients with renal insufficiency when all types of patient and tumour type were analysed (p