Connell3In a recently published paper by O’Connell et al in the Journal of the National Comprehensive Cancer Network, the available data on the management of incidental VTE (IVTE) and PE events (IPE) are summarized and discussed. A growing number of retrospective and case-controlled reports have described the prevalence, prognostic implications and treatment options for so called incidentally discovered VTE events and have reported similar clinical outcomes for patients with incidental and symptomatic VTE. Because most reported patients with incidental VTE have been treated in a manner similar to those with symptomatic events, the present recommendations, except in rare circumstances, support the use of standard anticoagulation in the management of incidental deep vein thrombosis and pulmonary embolism.

The current knowledge of the incidence, demographics and outcome of cancer-related VTE is generally based on reported symptomatic events. However, the unsuspected finding of PE, DVT, or intra-abdominal thrombosis in the splanchnic or visceral veins is not uncommon on routine staging CT scans of chest, abdomen and pelvis. Unfortunately, clinical trials involving patients undergoing cancer treatments have not consistently distinguished between incidental and symptomatic or suspected VTE, and therefore limited prospective data are available on patients with incidental VTE. Thus, no high-grade recommendations can be made regarding their treatment. Although the data may be flawed by the inclusion of various cancer types, stages and treatment modalities known to impact survival, the general conclusion of nearly all published studies is that no significant difference in clinical outcome exists between patients with incidental versus symptomatic DVT and PE. The American College of Chest Physicians (ACCP) guidelines currently provide a grade 2B recommendation for the treatment of incidental PE and incidental DVT with anticoagulation. Most surveyed physicians self-report the use of anticoagulation to treat patients with cancer and incidental VTE. ASCO guidelines suggest that the appropriate treatment of incidental PE, identified proximal to the subsegmental pulmonary, is not different from the standard treatment recommendation for cancer-associated VTE. Despite the limitations presented by the paucity of prospective treatment trials involving the management of patients with cancer who have IDVT and IPE more proximal than the subsegmental pulmonary arteries, the weight of evidence strongly suggests that these patients have a clinical outcome similar to that of symptomatic patients. These patients frequently have symptoms that are likely PE-related but overlooked or misattributed to other factors. Therefore, several expert advisory groups have favored treating patients with IDVT and IPE similarly to patients with symptomatic DVT and PE, i.e. with extended use of LMWH.

However, in order to have more definite data, cancer clinical trials should report the incidental identification of VTE, including location, biomarkers and treatment outcomes separately from suspected VTE.

Reference

O’Connell C, et al. Approach to the management of incidental venous thromboembolic events in patients with cancer. J Natl Compr Canc Netw 2014;12:1557-60.


 

BSTH2

Venous thromboembolism (VTE) is one of the leading causes of death in patients with malignancy after cancer itself. As such, prompt recognition and adequate treatment of VTE are essential in order to reduce the risk of VTE-related mortality. During the 22nd Annual Meeting of the Belgian Society on Thrombosis and Haemostasis (BSTH), LEO Pharma hosted a satellite symposium discussing the optimal thrombosis treatment in cancer patients.

In a first lecture, Prof. Ismail Elalamy(Head of the Haematology Department at CHU Paris Hospital Tenon, France) elaborated on the intimate relationship between cancer and thrombosis and discussed the pivotal role of low-molecular-weight-heparins (LMWH) in VTE management. In a second presentation, Dr. Simon Noble(Clinical reader in palliative medicine, Cardiff University Wales, UK) focused on the challenges clinicians are facing when treating cancer patients for VTE in daily practice.

 

LMWH and cancer: present, future and beyond

There is a mutual relationship between cancer and thrombosis: cancer predisposes to thrombosis, and the evolution of the oncological process is linked to this acquired hypercoagulable state. The risk of venous thrombo-embolic disease is significantly increased in cancer patients (Relative Risk 3 to 6).1 Metastatic disease further increases this risk, and this effect is even more pronounced during chemotherapy or radiotherapy.2 Thrombin generation, as a result of a cascade of activated coagulant proteases, plays a key role in the evolution of cancer. Thrombin induces fibrin formation, creating tumour cell lodges, known to promote tumour cell survival and metastatic colony formation.3,4 Thrombin activates the protease-activated receptor 1 (PAR1), contributing to tumour cell growth, invasion and angiogenesis.

LMWHs are a heterogeneous group of heparin polysaccharides obtained by fractionation of the natural mastocyte-extracted heparin, thereby exerting their anticoagulant activity largely through the mandatory pentasaccharide-binding domain interaction with antithrombin. This enhances the inhibitory effect of antithrombin on activated factor X, thrombin and activated factor IX and XII, to a variable extent for each factor according to the different chain molecular weight.5 LMWHs also act on regulation through the stimulation of the release of endothelial tissue factor pathway inhibitor (TFPI), and also in part through inhibition of factor VIIa, again according to the structural characteristics and the molecular weight of the LMWH.5 For example, TFPI release was reported to be in the order of magnitude of 7000 ng/mL/2.105 cells with tinzaparin (Molecular Weight 6500 Da) and in the range of 4000 ng/mL/2.105 cells with enoxaparin (4200 Da) or nadroparin (4500 Da).6 Unfractionated or natural heparin has an effect of equal intensity on factor Xa and on thrombin (FIIa). Tinzaparin and dalteparin have the highest molecular weights of the available LMWHs and therefore the longest polysaccharide chains. This gives them an anticoagulant profile closer to natural heparin, including a more pronounced anti-IIa effect. As such, tinzaparin is most similar to unfractionated heparin in terms of inhibiting thrombin activity.7

Based on the results of clinical trials comparing LMWHs with vitamin K antagonists, or unfractionated heparin, most international guidelines (ACCP, ASCO, ESMO) recommend the use of LMWHs as an initial treatment in case of a VTE event in cancer patients.8-10 In addition to their effect on the VTE incidence, professor Elalamy illustrated that LMWHs may also be associated with an improved survival in cancer patients. This effect on survival seemed to be most pronounced in patients with a good prognosis.11-14 Similarly, studies in myeloma suggest that LMWHs may have an anti-myeloma effect. In fact, a meta-analysis of 3 randomized studies comparing melphelan-prednisone-thalidomide (MPT) with MPT in combination with a LMWH, demonstrated a significantly longer overall survival in the combination arm (31 vs. 31 months; p= 0.046).15

In summary, cancer induces a prothrombotic state and this thrombotic process is closely linked to tumour proliferation in cancer patients. LMWHs are currently the first-line and long-term treatment of choice in these patients. Professor Elalamy concluded that dissemination and implementation of good clinical practice for VTE management, the second cause of death in cancer patients, is a major public health priority. Moreover, he underlined that preventing thrombosis in cancer patients is not only a medical necessity, but also an economical opportunity. In a personal communication, professor Elalamy stated that he recently conducted a study in patients with breast and prostate cancer, two tumour types with a relatively low risk of VTE, revealing that adequate VTE prevention could save up to 5 million Euro over 2 years. When extrapolating these finding to more aggressive tumour types, savings in medical expenses could rise to an impressive 300 million Euro per year.

 

Management of cancer associated thrombosis when the evidence is lacking, a real world experience

In the second lecture of the symposium, Dr. Simon Noble focused on the practical challenges physicians are facing when treating cancer patients for VTE. As already mentioned by professor Elalamy, several randomized studies demonstrated that LMWHs are superior to vitamin K antagonists in preventing VTE recurrence in cancer patients.14,16,17 These data formed the basis for the general recommendation that LMWHs should be the first-line treatment of choice in treating cancer patients for VTE. These international guidelines cover patients with metastatic disease, a performance status of 0-2, an estimated prognosis of more than 3 months, a platelet count above 75.000/mm2, a body weight above 40 kg, without active bleeding and an adequate renal function. However, many patients seen in daily clinical practice do not comply with these criteria. For example, treating a patient with active bleeding, recurrent thrombosis, renal impairment, or a low platelet count can be challenging. In this respect, the scientific subcommittee on hemostasis and malignancy of the ISTH recently bundled the limited data on the management of challenging cases of patients with cancer-associated thrombosis.18 To illustrate the challenges physicians can be confronted with, Dr. Noble discussed several real-life cases.

A first case described a 62-year old lady with pancreatic cancer and liver metastases who was treated with full dose LMWH for VTE, which was reduced to 75% of the dose later on. The symptoms initially improved but after some time, progressive symptoms were observed despite full anticoagulation. A repeated Doppler analysis showed propagation of the thrombus. In such a case, Dr. Noble first ensures that the patient is on the full dose and then checks the anti Xa level to aim for a level between 0.8 and 1.1 U/ml. Guidelines recommend to increase the LMWH dose by 20% until a symptomatic response is seen. In some patients, with highly resistant thrombosis, twice daily dosing can be considered. Subtherapeutic treatment is often a problem in heavier patients. Especially in these cases, a dose increase can be of use.

A second case described a 58-year old man with metastatic melanoma and extensive vascular cutaneous lesions, extensive DVT and breathlessness. His breathlessness and leg swelling improved with LMWHs, but as a result of the LMWH therapy, he started bleeding from his cancer lesions. In dealing with such a patient, one should try to balance the advantages of treating the DVT symptoms and the risk of bleeding. Dr. Noble underlined that it is essential to involve the patient in the treatment choices: what does the patient experiences to be most troublesome, the bleeding, or the breathlessness? In the case at hand, topical adrenaline in the dressings of the cutaneous lesions and a prophylactic dose of LMWH twice daily was able to control the symptoms.

A third case Dr. Noble presented concerned a 76-year old male with advanced myeloma who was renally impaired with a platelet count of 51,000 platelets/mm2 who developed acute DVT and symptomatic PE. With respect to LMWH use in patients with thrombocytopenia, experience is accumulating and cases have been described where LMWHs were safely used in patients with a platelet count as low as 25,000 platelets/mm3. The renal impairment on the other hand needs more attention. First of all, the anti Xa level needs to be determined to avoid bio-accumulation of the LMWH. Secondly, the choice of LMWH is important. It has been demonstrated that heavier chain LMWHs (e.g. tinzaparin) do not bio-accumulate in case of renal impairment and therefore, tinzaparin should be the LMWH of choice in patients with renal impairment (creatine clearance between 60 and 20 ml/min), according to Dr. Noble.

Dr. Noble concluded his lecture by mentioning the use of the new oral anticoagulants (NOACs) in cancer patients. Many physicians tend to prefer oral therapies as they feel that these treatments are less troublesome for the patient. However, data on the use of these NOACs in the cancer setting are limited and far from convincing, according to Dr. Noble. A pooled subgroup analysis of the cancer patients in the EINSTEIN-DVT and the EINSTEIN-PE study comparing the NOAC rivaroxaban with enoxaparin and a vitamin K antagonist (VKA) did demonstrate a reduced incidence of VTE recurrence in the rivaroxaban arm (N=354) as compared to the enoxaparin-VKA arm (N=301) (5% vs. 7%). However, Dr. Noble argued that the patient population in this analysis was not well balanced between both treatment arms. In fact, the rivaroxaban arm contained less metastatic patients as compared to the enoxaparin-VKA arm (19% vs. 26%) and included less patients receiving chemotherapy (20% vs. 25%).19 These imbalances on itself can be responsible for the difference in VTE recurrence risk seen in this study, according to Dr. Noble, and as such, these data do not support the use of NOACs in cancer patients.

In summary, for the majority of patients, the management of cancer-associated thrombosis is straightforward. However, the situation of a proportion of patients will not be in line with the characteristics of patient populations in published studies.In these patients, VTE management needs to consider pharmacology, pathophysiology and the patients’ wishes. Overall, LMWHs currently form the cornerstone of VTE management in cancer patients, concluded Dr. Noble.

References

  1. Pruemer J et al. Am J Health Syst Pharm 2005;62(22 Suppl 5):S4–S6.
  2. Lyman G. Cancer 2011;117:1334–1349.
  3. Tsopanoglou et al. Eur Cytokine Netw 2009;20(4):171-9.
  4. Rickles F. Pathophysiol Haemost Thromb 2006;35(1-2):103-10.
  5. Fareed J et al. Clin Appl Thromb Hemost 2008;14(4):385-92.
  6. Mousa S. Methods Mol Biol 2010;663:109-32.
  7. Gerotziafas G et al. J Thromb Haemost 2007;5(5):955-62.
  8. Kearon C et al. Chest 2012;141(2 Suppl.):e419S-e494S.
  9. Lyman G et al. J Clin Oncol 2013;31(17): 2189-204.
  10. Mandala M et al. Ann Oncol 2011;22(Suppl. 6): vi85-vi92.
  11. Kakkar A et al. J Clin Oncol. 2004;22(10):1944-8.
  12. Altinbas M, et al. J Thromb Haemost. 2004;2(8):1266-71.
  13. Klerk CP, et al. J Clin Oncol. 2005;23(10):2130-5.
  14. Lee AY, et al. N Engl J Med. 2003;349(2):146-53.
  15. Beksac M et al. Presented at ASH 2013; Abstract 3970.
  16. Meyer G et al. Arch Intern Med 2002;162(15):1729-35.
  17. Hull R et al. Am J med 2006;119(12):1062-72.
  18. Carrier M et al. J Thromb Haemost 2014;11:1760-5.
  19. Prins M et al. Thromb J 2013;11(1):11-21.

 

Elalamy-350 Noble1a-350

 


 

Elalamy

Venous thromboembolism (VTE) is a frequent cause of mortality and morbidity in patients with malignancy. Thrombosis is one of the leading causes of death in patients with malignancy after cancer itself. As such, prompt recognition and treatment of VTE are required in order to reduce the risk of VTE-related mortality. A recently published paper in the Journal for Blood Disorders and Transfusion reviews the interrelationship between cancer, renal insufficiency and VTE. The working group behind this review article concluded that low molecular weight heparins (LMWHs) decrease the risk of recurrent venous thrombosis in cancer patients without increasing major bleeding complications. LMWHs are therefore recommended as first line antithrombotic treatment in cancer patients with a clear clinical benefit. In patients with renal dysfunction, who are both at increased risk of bleeding and of thrombotic complications, preference should be given to unfractionated heparin or a LMWH with a mean molecular weight such as tinzaparin, having less risk of plasma accumulation and offering the possibility to maintain full therapeutic dose.

The BIRMA trial reported a 64% prevalence of renal dysfunction (Glomerular Filtration Rate [GFR] lower than 90 mL/min) in Belgian cancer patients. On the other hand, the same study showed that many anticancer treatment combinations used had also potentially nephrotoxic effects. This fact together with the mainly renal elimination of most drugs implies that even a GFR of 90 mL/min should be considered with caution, as nephrotoxicity of chemotherapeutic agents tends to increase with decreasing renal function. These agents may even accelerate the spiral of renal damage and consequently increase the risk of LMWH accumulation with a concomitant increase of bleeding risk.

There is a well-established correlation between LMWH molecular weight and its excretion. The higher the weight, the more the LMWH is excreted through the reticulo-endothelial system, and not through the kidney route. Data have shown that only tinzaparin has an unchanged apparent half-life when renal function declines as far as to 20 mL/min. Other LMWHs, such as enoxaparin or dalteparin do show a degree of drug accumulation as their apparent half-life increases with lower renal filtration, especially in case of standard therapeutic dosing..

Reference

Elalamy I, Canon J-L., Bols A, et al. Thrombo-embolic events in cancer patients with impaired renal function. J Blood Disorders Transf 2014;5(4).

Elalamy article JBD


 

App1-300

CoaguleXThe App CoaguleX contains all the major anticoagulant drugs in use and keeps you updated on the latest recommendations of the perioperative use of anticoagulants. Information is constantly updated with extensive scientific review, consistent with the latest recommendations of Societies of Anesthesiology and Perioperative Medicine worldwide. This app contains information for each drug on:

  • the active principle
  • trade/commercial names
  • duration of the suspension and resumption of use
  • half-life time
  • class
  • mechanism of action
  • monitoring
  • recommendations of ASRA (American Society of Regional Anesthesia and Pain Medicine) and ESRA (European Society of Regional Anaesthesia & Pain Therapy).

Following drugs are presented in the App: apixaban, argatroban, acetylsalicylic acid, bivalirudin, cilostazol, clopidogrel, dabigatran, dalteparin, desirudin, dipyridamole, drotrecogin, enoxaparin, eptifibatide, fondaparinux, heparin, herbals, lepirudin, NSAIDs, prasugrel, reteplase, rivaroxaban, streptokinase, tenecteplase, ticagrelor, ticlopidine, tinzaparin, tirofiban, urokinase, and warfarin.

Available for iPhone, iPad, iPod Touch in the App Store and for Android in the Play Store. Released September 4, 2014 by vandFald Inc.


 

Noble1-350

Take home messages:

  1. The PELICAN study assesses the patients’ experience of living with cancer associated thrombosis
  2. Patients regard cancer associated thrombosis as more disturbing than their cancer itself
  3. Comprehensive patient education on cancer associated thrombosis is lacking