Anticoagulation in Advanced Malignancy: Anticoagulation in Advanced Malignancy Katie Hobson 9th November, 2006


Why anticoagulate?: Why anticoagulate? To treat thromboembolic disease Help symptomatically Prevent (life threatening) complications eg PE To prevent events To improve the survival of our patients


Aims: Aims Common indications for anticoagulation Why cancer patients are at higher risk of thromboembolic disease What the treatment of choice is for thromboembolic disease in cancer patients Factors influencing the acceptability of treatments to patients Should we be anticoagulating all our cancer patients?


Common Indications for Anticoagulation: Common Indications for Anticoagulation


Common Indications for Anticoagulation: Common Indications for Anticoagulation Treatment of venous thrombosis and pulmonary embolism Prophylaxis of venous thrombosis and pulmonary embolism Prophylaxis of thrombosis in patients with central venous catheters DIC Thrombophelbitis migrans Prophylaxis of embolisation in rheumatic heart disease and atrial fibrillation Prophylaxis after insertion of a prosthetic heart valve TIA’s Acute coronary syndromes


Why is this relevant to cancer patients?: Why is this relevant to cancer patients? Clinically apparent thromboembolic disease affects about 15% of all cancer patients 1 2nd leading cause of death for cancer patients 2 Why is this?


Why cancer patients are at higher risk of thromboembolic disease: Why cancer patients are at higher risk of thromboembolic disease


Thrombophilia of Malignancy: Thrombophilia of Malignancy Cancer (and its treatment) can affect all three arms of Virchow’s triad of causation of thromboembolic disease Alteration in blood flow Damage of endothelial cells Production of procoagulants Tumors can directly block neighbouring vessels


Chemotherapy and Thrombosis : Chemotherapy and Thrombosis Chemotherapy itself can increase the risk of thromboembolic disease3 Indwelling central lines create an increased risk for DVT of the ipsilateral upper extremity 5, 6 clots have been venographically documented in 38%-62% of venous access devices Symptomatic rates are lower 15% of patients with UEDVT on USS were found to have a high probability of PE on VQ scan 7


Are any particular groups of cancer patients at risk?: Are any particular groups of cancer patients at risk? The incidence of fatal and nonfatal pulmonary embolism (PE) was evaluated in a series of 578 patients 8 Non cancer patients - PE occurred in 13% and was fatal in 8% In cancer patients – PE occurred in 17% and was fatal in 14% Of these cases of PE 75% occurred in patients with adenocarcinoma 62% occurred in those having tumours of the Pancreas Breast Large bowel Prostate Lung Ovary


What the treatment of choice is for thromboembolic disease in cancer patients: What the treatment of choice is for thromboembolic disease in cancer patients


Should the treatment of thromboembolic disease be any different for cancer patients than it is for non cancer patients?: Should the treatment of thromboembolic disease be any different for cancer patients than it is for non cancer patients? Concerns with cancer patients: Cancer patients who are anticoagulated might have an increased risk of haemorrhage due to Tumour Thrombocytopenia Concurrent coagulation disorders No clear answer Some studies suggests no increased risk 9, 10 Some reports show much higher rates of haemorrhage 11,15 Compared to patients with nonmalignant disease, cancer patients are more likely to have a recurrence on warfarin or after warfarin is stopped 15 20.7% had recurrent VTE who had cancer, v. 6.8% in non-cancer patients


Dilemma: Dilemma When treating a cancer patient with thromboembolic disease there is slightly greater risk of hemorrhage but also a greater risk of recurrent thrombosis In most non moribund cancer patients, anticoagulation for thromboembolic disease is usually begun unless potential contraindications exist


Heparin v. Warfarin: Heparin v. Warfarin Does long-term heparin therapy afford any advantage over warfarin in the treatment of thromboembolic disease in cancer patients?


Heparin v. Warfarin: Heparin v. Warfarin A recent meta-analysis (Iorio et al, 2003) showed a reduction in the rate of recurrence of VTE (odds ratio: 0.66) and major bleeding complications (odds ratio: 0.45) in favour of LMWHs, although this did not reach statistical significance12


The CLOT trial (Comparison of Low-molecular-weight heparin versus Oral anticoagulant Therapy for the prevention of recurrent venous thromboembolism in patients with cancer)13: The CLOT trial (Comparison of Low-molecular-weight heparin versus Oral anticoagulant Therapy for the prevention of recurrent venous thromboembolism in patients with cancer)13 Manufacturer-funded, multicentre, international trial, 2003 Randomised 672 cancer patients (most with metastases) who had acute proximal DVT or PE to 1 of 2 anticoagulation regimens: the low-molecular-weight heparin dalteparin (200 IU/kg subcutaneously, once daily for 5-7 days), followed by oral anticoagulation with warfarin or another coumarin derivative for 6 months (target INR, 2 to 3) only dalteparin for 6 months (200 IU/kg for the first month, about 150 IU/kg for the remaining 5 months) Followed up for 6 months


CLOT: CLOT Conclusion – long term dalteparin was more effective than long-term oral anticoagulation for preventing recurrent DVT or PE in cancer patients, and did not cause excessive bleeding An important question that was not addressed by this study is whether the difference in recurrence between groups translated into a meaningful difference in quality of life


Why is heparin a better anticoagulant than warfarin?: Why is heparin a better anticoagulant than warfarin? Heparin has several antithrombotic mechanisms that warfarin lacks Heparin can Release tissue plasminogen activator and tissue factor pathway inhibitor (TFPI) from endothelial binding sites and increase their circulating levels Since tissue factor is an important stimulus to coagulation in cancer patients, activation of TFPI by heparin causes an antithrombotic effect


What do you do if an anticoagulated patient gets recurrent VTEs?: What do you do if an anticoagulated patient gets recurrent VTEs? Recurrent VTE in cancer patients on anticoagulant therapy is not uncommon - oncology patients are 1.72 times more likely to have recurrent VTE than patients without cancer14 The risk of recurrence appears to be related to the extent of the disease15 2-3x risk of recurrence in patients with more localized cancer 5x risk of recurrence among those with extensive or moderately extensive disease There are no clear clinical data to guide the response to this situation For patients on warfarin there are three choices: continue warfarin at a higher target INR switch to intermittent subcutaneous LWMH put in an IVC filter.


IVC filters: IVC filters No good studies to evaluate the relative safety and efficacy of IVC filter placement versus anticoagulation Studies looking at the use of IVC filters in patients with brain tumours or brain metastases requiring anticoagulation showed 16 The chance of recurrent PE after IVC filter placement is 3%-20% Rate of local thrombotic complication (IVC clot, DVT progression, recurrent DVT, or postphlebitic syndrome) ranges from 5%-57% depending on the series The risk of thromboembolic events in similar patients treated with anticoagulants was 5%-20% The risk of intracerebral hemorrhage was 0%-5% (usually when over anticoagulated) Anticoagulation is a noninvasive, inexpensive, reversible intervention that has the advantage of treating the underlying clotting problem


Are line associated DVTs preventable?: Are line associated DVTs preventable? 1 mg per day of warfarin is a safe and effective prophylaxis against thrombosis in cancer patients with central venous catheters5 Cost effective to treat with 1mg warfarin INR does not need to be checked Anticoagulation of indwelling central lines should be considered in all cancer patients who do not have a specific contraindication Study of 59 cancer patients shows LMWH to have a similar risk:benefit to warfarin and is therefore an alternative17


Primary prophylaxis – should we?: Primary prophylaxis – should we? Shen and Pollak, 1980 8 The incidence of fatal and non fatal pulmonary embolism (PE) was evaluated in a series of 578 hospital patients, to quantify the suspected higher risk in cancer patients of death from massive PE when compared with patients not having cancer PE occurred in 13% and was fatal in 8% of noncancer patients It occurred in 17% and was fatal in 14% (P less than .05) of cancer patients One of every seven hospitalized cancer patients died not of cancer but of PE 60% of all patients who died of massive PE had localized cancer or limited metastatic disease which would have allowed for reasonably long survival in absence of lethal PE Strongly suggest use of prophylactic anticoagulation in hospitalized cancer patients having otherwise good prospects for reasonably long survival


Secondary prophylaxis - How long should you continue treatment after a VTE?: Secondary prophylaxis - How long should you continue treatment after a VTE? Patients with VTE are usually treated with warfarin for several months after an initial VTE event Insufficient data are available specifically from cancer patients to determine the optimal duration of secondary prophylaxis In the absence of data from clinical trials, the general view is that, following an initial VTE event, thromboprophylactic therapy (with warfarin) should be continued indefinitely in patients with cancer, or certainly for as long as the cancer is active 18, 19


Warfarin – points to consider: Warfarin – points to consider Target INR hard to maintain in cancer patients due to Drug interactions (including paracetamol) Malnutrition Vomiting Liver dysfunction Patients may be having interventions requiring them to come off anti coagulation - shorter half life with LMWH Poor venous access


Risk Factors for Excessive Warfarin Anticoagulation20: Risk Factors for Excessive Warfarin Anticoagulation20 Case control study, warfarin clinic in the USA 289 patients (aged mean 70 years, 50% male) outpatient on warfarin for more than one month with a target INR of 2.0-3.0 Contacted patients by telephone and did a structured interview to identify factors contributing to high or controlled INR Cases: 93 patients (50% male, mean age 70): INR >6.0 (repeated once) (mean INR 8.3) Controls: 196 patients (50% male, mean age 70): randomly selected from the clinic with INR 1.7-3.3 (mean INR 2.4)


Questioned about - : Questioned about - Advanced malignancy Newly-started potentiating medication Warfarin dose more than prescribed Decreased oral intake Acute diarrhoeal illness High vitamin K intake based on 12 point grading scale for foods rich in it 1-2 alcoholic drinks per week Alcoholic drink every other day to 2 per day More than 2 drinks or bingeing 325-2274 mg/week paracetamol (1 to 4 (500 mg) tablets) 2275-4549 mg/week paracetamol (5 to 8 tablets) 4550-9099 mg/week paracetamol (9 to 18 tablets) 9100 or more mg/week paracetamol ( > or = 19 tablets)


Results: Results Patients on warfarin who took more than 2.5 g of paracetamol in the previous week, were at increased risk of having INR >6.0 (NNH = 9) The risk increased as more tablets are taken: 4.5-9.0 g (NNH = 4) 9.0 or more (NNH = 3)


Results: Results Patients were also at increased risk of supratherapeutic INR: with advanced cancer (NNH = 2) who had recently started warfarin potentiating medication (NNH = 4) who took more warfarin than prescribed (NNH = 4) who had decreased oral intake in the last week (NNH = 8) who had an acute diarrhoeal illness in the last week (NNH = 9) Patients appeared to be protected who: had a high vitamin K intake (NNT = 62) had 1/2 to 2 alcoholic drinks a day (NNT = 23)


Factors influencing the acceptability of treatments to patients: Factors influencing the acceptability of treatments to patients


Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study21: Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study21 Current treatment practice with warfarin has a high incidence of complications, including bleeding, poor control and recurrent VTE Long-term low-molecular-weight heparin (LMWH) therapy is safer and more efficacious in this patient group, but there are concerns that daily therapy may have a negative impact on quality of life A qualitative study was carried out to determine whether LMWH was acceptable in palliative care patients, both in the community and in-patient units 40 palliative care patients receiving LMWH for VTE were interviewed (in patients (hospital) and outpatients)


Findings: Findings Participants found LMWH to be an acceptable intervention, allowing them freedom from blood tests and optimism regarding their care It was considered a preferable therapy to warfarin, which had a negative impact on participant's quality of life The findings of this study support the use of LMWH, first line in the treatment of established VTE in the palliative care setting


Themes raised: Themes raised Simplicity Daily injections simpler than INR monitoring Freedom Not having to go to hospital/wait in for the DN for INR check Not worrying about what will be the INR result today Optimism The feeling that something is being done, not been given up on Bruising 11 patients mentioned this as a negative which was still acceptable


Acceptability of low molecular weight heparin thromboprophylaxis for inpatients receiving palliative care: qualitative study22: Acceptability of low molecular weight heparin thromboprophylaxis for inpatients receiving palliative care: qualitative study22 To find out what inpatients with advanced cancer who are receiving palliative care think about the effect of thromoprophylaxis on overall quality of life Qualitative study using audiotaping of semistructured interviews 28 inpatients with advanced metastatic cancer receiving palliative care and low molecular weight heparin


Findings: Findings Patients knew about the risks of venous thromboembolism and the purpose of treatment with heparin All found low molecular weight heparin an acceptable intervention many said that it improved their quality of life by giving them a feeling of safety and reassurance Antiembolic stockings were considered uncomfortable and had a negative impact on quality of life Patients were concerned that because they had advanced disease they might not be eligible for thromboprophylaxis


Should we be anticoagulating all our cancer patients?: Should we be anticoagulating all our cancer patients?


Anticoagulants as Anticancer Therapies: Anticoagulants as Anticancer Therapies In vitro Studies show that warfarin, heparin, fibrinolytics, and even antiplatelet agents inhibit tumor growth and metastasis 23 Thrombin and fibrin have been found to contribute to the adhesion and implantation of tumor cells So antifibrin or antithrombin agents might exert their effects by inhibiting this implantation. Heparin inhibits vascular endothelial growth factor, tissue factor, and platelet-activating factor, each of which may contribute to angiogenesis It has also been hypothesized that fibrin deposits around tumors may offer protection against immune surveillance, so that anticoagulants might aid in immune clearance of small deposits of cancer cells


In vivo: In vivo FAMOUS Trial 24 - Fragmin Advanced Malignancy Outcome Study Studied the ability of LMWH to prolong survival in patients with advanced malignant disease No survival benefit at 1 year 5% increase in survival at 2-3 years in those with a better prognosis at outset CLOT trial 13 – Dalteparin v warfain in the treatment of VTE disease Sub group analysis showed a survival advantage at 1 year in those on LMWH without metastases at start of 6 months treatment Small Cell Lung Cancer Trial 25 Standard chemo v. chemo and LMWH Small survival advantage at 1 year in those on LMWH MALT trial – Malignancy and Low-Molecular-Weight Heparin Therapy26 Patients with solid tumours Given either 6 weeks of LMWH or placebo Small positive survival benefit


Summary: Summary Common indications for anticoagulation Why cancer patients are at higher risk of thromboembolic disease What the treatment of choice is for thromboembolic disease in cancer patients Factors influencing the acceptability of treatments to patients Should we be anticoagulating all our cancer patients?


Good Reviews: Good Reviews Last 4 references are good reviews covering most aspects Leo R. Zacharskia, Paolo Prandonib, Manuel Monreal. Warfarin Versus Low-Molecular-Weight Heparin Therapy in Cancer Patients. The Oncologist, Vol. 10, No. 1, 72-79, January 2005 Anthony Letaia,b, David J. Kuter. Cancer, Coagulation, and Anticoagulation .The Oncologist, Vol. 4, No. 6, 443-449, December 1999 Kakkar AK. Low-molecular-weight heparin and survival in patients with malignant disease. Cancer Control. 2005 Sep;12 Suppl 1:22-30. Review Mousa SA. Role of current and emerging antithrombotics in thrombosis and cancer. Drugs Today (Barc). 2006 May;42(5):331-50. Review.


References: References Green KB, Silverstein RL. Hypercoagulability in cancer. Hematol Oncol Clin North Am 1996;10:499-530 Donati MB. Cancer and thrombosis. Haemostasis 1994;24:128-131 Levine M, Hirsh J, Gent M et al. Double blind randomised trial of very-low-dose warfarin for the prevention of thromboembolism in stage IV breast cancer. Lancet 1994;343:886-889 Rajan R, Gafni A, Levine M et al. Very-low-dose warfarin prophylaxis to prevent thromboembolism in women with metastatic breast cancer receiving chemotherapy: an economic evaluation. J Clin Oncol 1995;13:42-46 Bern MM, Lokich JJ, Wallach S et al. Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Intern Med 1990;112:423-428 Monreal M, Alastrue A, Rull M et al. Upper extremity deep venous thrombosis in cancer patients with venous access devices—prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 1996;75:251-253 Monreal M, Raventos A, Lerma R et al. Pulmonary embolism in patients with upper extremity DVT associated to venous central lines—a prospective study. Thromb Haemost 1994;72:548-550 Shen V, Pollak E. Fatal pulmonary embolism in cancer patients: is heparin prophylaxis justified? South Med J 1980;73:841–843 Bona RD, Sivjee KY, Hickey AD et al. The efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost 1995;74:1055-1058 Bona RD, Hickey AD, Wallace DM. Efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost 1997;78:137-140 Moore FD, Osteen RT, Karp DD et al. Anticoagulants, venous thomboembolis, and the cancer patient. Arch Surg 1981;116:405-407


References: References Iorio A, Guercini F, Pini M. Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants. J Thromb Haemost 2003;1:906–1913. Lee AYY et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003 Jul 10; 349:146-53 Prandoni P, Lensing AWA, Cogo A et al. The long term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7. Prandoni P, Lensing AWA, Piccioli A et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484–3488 Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer 1994;73:493-498 Mismetti P, Mille D, Laporte S et al. Low-molecular-weight heparin (nadroparin) and very low doses of warfarin in the prevention of upper extremity thrombosis in cancer patients with indwelling long-term central venous catheters: a pilot randomized trial. Haematologica 2003;88:67–73.Levine MN. Managing thromboembolic disease in the cancer patient: efficacy and safety of antithrombotic treatment options in patients with cancer. Cancer Treat Rev 2002;28:145–149 Levine MN. Managing thromboembolic disease in the cancer patient: efficacy and safety of antithrombotic treatment options in patients with cancer. Cancer Treat Rev 2002;28:145–149. Lee AY. Treatment of venous thromboembolism in cancer patients. Thromb Res 2001;102:V195–V208 EM Hylek et al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998 279: 657-662.


References: References Noble SI, Findlay IG. Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study. Palliat Med. 2005 Apr;19(3):197-201 Noble SI, Nelson A, Turner C, Findlay IG. Acceptability of low molecular weight heparin thromboprophylaxis for inpatients receiving palliative care: qualitative study. BMJ. 2006 Mar 11;332(7541):577-80. Epub 2006 Feb 3. Hejna M, Radere M, Zielinski CC. Inhibition of metastases by anticoagulants. J Natl Cancer Inst 1999;91:22-36 Kakkar et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004 May 15;22(10):1944-8 Altinbas M, Coskun HS et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost. 2004 Aug;2(8):1266-71 Klerk CP, Smorenburg SM et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005 Apr 1;23(10):2130-5. Epub 2005 Feb 7 Leo R. Zacharskia, Paolo Prandonib, Manuel Monreal. Warfarin Versus Low-Molecular-Weight Heparin Therapy in Cancer Patients. The Oncologist, Vol. 10, No. 1, 72-79, January 2005 Anthony Letaia,b, David J. Kuter. Cancer, Coagulation, and Anticoagulation .The Oncologist, Vol. 4, No. 6, 443-449, December 1999 Kakkar AK. Low-molecular-weight heparin and survival in patients with malignant disease. Cancer Control. 2005 Sep;12 Suppl 1:22-30. Review Mousa SA. Role of current and emerging antithrombotics in thrombosis and cancer. Drugs Today (Barc). 2006 May;42(5):331-50. Review. Johnson MJ, Sproule MW, Paul J. The prevalence and associated variables of deep venous thrombosis in patients with advanced cancer. Clin Oncol (R Coll Radiol). 1999;11(2):105-10.