British Journal of Haematology. Risk factors for cancer-associated venous thromboembolism in outpatient DVT clinics

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1 Risk factors for cancer-associated venous thromboembolism in outpatient DVT clinics Journal: Manuscript ID: BJH R Manuscript Type: Letters Date Submitted by the Author: n/a Complete List of Authors: Rose, Peter; University Hospital Coventry and warwickshire, Haematology McManus, Aidan; MMRx Consulting, Research Arya, Roopen; King's College Hospital, Haematology Scriven, Nicholas; Calderdale Royal Hospital, MAU Farren, Timothy; Barts and The London Hospitals, Haematology Nokes, Timothy; Derriford Hospital, Haematology Bacon, Sue; Scarborough Hospital, Haematology Cooper, Derek; Independent Consultant, Statistics O'Shaughnessy, Denise; Department of Health, Blood Policy Paneesha, Shankara; Birmingham Heartland Hospital, Haematology Key Words: THROMBOSIS, RISK FACTORS, CANCER

2 Page of Risk factors for cancer-associated venous thromboembolism in outpatient DVT clinics Peter Rose, Aidan McManus, Roopen Arya, Nicholas Scriven, Timothy Farren, Tim Nokes, Sue Bacon, Derek Cooper, Denise O'Shaughnessy, Shankaranarayana Paneesha 0 Consultant, Department of Haematology, Warwick Hospital, Warwick, UK; Director, MMRx Consulting, Cheam, Surrey, UK; Consultant, Department of Haematology, King's College Hospital, London, UK; Consultant, Medical Assessment Unit, The Calderdale Royal Hospital, Halifax, UK; Clinical Scientist, Department of Haematology, Barts and The London School of Medicine and Dentistry, London, UK; Consultant, Department of Haematology, Derriford Hospital, Plymouth, UK; Thrombosis Nurse Specialist, North Bristol NHS Trust, Bristol, UK; Statistical Consultant, London, UK; Special Advisor, Blood Policy Unit, Department of Health, London, UK; 0 Consultant Department of Haematology, Heart of England NHS Foundation Trust, Birmingham, UK. Correspondence to: Dr Peter Rose, Department of Haematology, Warwick Hospital, Lakin Road, Warwick CV BW Tel: 0 x 0; Peter.Rose@swh.nhs.uk Funding/Support: The VERITY registry is funded by sanofi-aventis Conflict of interest: Aidan McManus has received consultancy fees from sanofi-aventis

3 Page of Venous thromboembolism (VTE) in cancer patients is increasingly frequent (Khorana et al, 00), is associated with worse survival (Paneesha et al, 00) and its treatment poses particular challenges (Noble, 00), including increased bleeding and recurrence risks. A number of important factors influence thrombotic risk, including site of cancer, presence of metastatic disease and certain chemotherapy and hormonal treatment regimens (Wun and White, 00), but for most types of cancer, there are few data describing the occurrence or relevance of common VTE risk factors and it is not clear to what extent major risk factors such as surgery or previous history of VTE impact the risk already associated with the presence of cancer. This is particularly the case for ambulant cancer patients. While there have been attempts to identify cancer outpatients at high-risk of chemotherapy-associated VTE (Khorana et al, 00), there is a paucity of data on risk factors that might allow identification of those cancer patients most at risk of VTE. In this analysis of patients seen at outpatient DVT clinics, we wished to determine if the incidence of established VTE risk factors differed in patients with VTE according to cancer status (cancer diagnosis vs. no cancer diagnosis). The presence of seven established risk factors for VTE (Arya et al, 00) was compared in cancer and non-cancer patients with confirmed VTE using the χ test with Yates correction. All analyses were conducted using a commercial software package (SPSS version ; SPSS Inc., Chicago, Ill, USA). The risk factors were medical inpatient history or immobilization for more than days within the last weeks, major surgery in the last weeks, hormonal risk (use of hormone-replacement therapy or oral contraceptives; pregnant or post-partum), personal history of VTE, known thrombophilia, intravenous drug abuse and current smoking, as previously described (Arya et al, 00). The data set has been described previously (Paneesha et al, 00). VERITY (VEnous thromboembolism RegIsTrY) is an ongoing prospective registry of patients attending outpatient DVT clinics. A variety of algorithms, mainly based on D-dimer measurement and pre-test probability, are used to exclude VTE. Confirmatory, objective testing is undertaken according to local protocols,

4 Page of usually including ultrasonography or venography for suspected DVT and pulmonary angiography, lung scintigraphy or helical computed tomography for suspected PE. Cancer (current or having received treatment for cancer in the last months) is recorded as one of specific cancer types [bone/sarcoma, breast, central nervous system (CNS), colorectal, endocrine, gynecologic, head/neck, leukemia, lung, lymphoma, melanoma, myeloma, non-melanoma, pancreas, prostate, urological, upper gastrointestinal (GI)] with other. No record is made of metastatic disease, but patients with multiple cancer sites are recorded; no histological description, tumour grade or cancer stage are recorded. In addition, a detailed history of the cancer patients is not recorded, some of whom may have been hospitalized during their care and only briefly used the outpatient service. Of, patients enrolled in VERITY by UK hospitals, 0,0 (.%) had confirmed VTE; (.%) were recorded as having cancer. % of the non-cancer VTE cases were female, compared with % of the cancer VTE patients. Patients with cancer were significantly older than cancer-free VTE cases (. ±. vs.. ±. years; p<0.000) (Paneesha et al, 00). Breast, prostate, colorectal and lung cancer were the most common cancers accounting for.% of the cancerassociated VTE cases (Paneesha et al, 00). Data on the seven established VTE risk factors were available in -% of cases (numbers are shown in Table ). Cancer-associated thrombosis cases were more likely to have experienced a medical inpatient stay/immobilization (.% vs 0.%; χ =.; p<0.00), but less likely to have a history of VTE (.0% vs.%; χ =.; p<0.00), thrombophilia (0.% vs.%; χ =0.; p=0.00), intravenous drug abuse (0.% vs.%; χ =0.; p<0.00) and to smoke (.% vs.%; χ =.; p<0.00) than cancer-free cases; there was no difference in hormonal risk and recent surgery (see Table ). This analysis of an observational registry that enrolled more than 0,000 patients with VTE at outpatient DVT clinics showed that established VTE risk factors previous history of VTE, thrombophilia, IV drug abuse and smoking were less common in patients with cancer-associated VTE. Of the seven risk factors compared, the only risk factor more common in patients with cancer

5 Page 0 of was a medical in-patient stay/immobilization, despite the finding that patients with cancer were significantly older than cancer-free VTE cases. Identification of cancer patients most at risk of VTE is an important clinical goal. Previously, we reported extreme differences in VTE risk associated with different cancer sites in this patient cohort (Paneesha et al, 00). Taken together with our current findings, we suggest that established risk factors for VTE, such as previous thrombosis history, are of less importance than cancer site when assessing the risk of cancer-associated VTE. Our results may be relevant to the design of future studies of risk algorithms for VTE prevention in cancer patients in the outpatient setting.

6 Page of References Arya R, Paneesha S, McManus A, Parsons N, Scriven N, Farren T, Nokes T, Smith H, O'Shaughnessy D, Rose P (00) More on thromboprophylaxis: Quantifying risk for venous thromboembolism. Thrombosis and Haemostasis, 0, -. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH (00) Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer, 0,. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW (00) Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood, :0-0. Noble S. The challenges of managing cancer related venous thromboembolism in the palliative care setting (00) Postgraduate Medicine Journal,, -. Paneesha S, Lokare A, Lester Z, Nokes T, Arya R, Farren T, Scriven N, McManus A, O'Shaughnessy D, Rose P (00) Impact of venous thromboembolism on survival in patients with malignancy. British Journal of Haematology,, -0. Paneesha S, McManus A, Arya R, Scriven N, Farren T, Nokes T, Bacon S, Nieland A, Cooper D, Smith H, O'Shaughnessy D, Rose P. Frequency, demographics and risk (according to tumor type or site) of cancer-associated thrombosis among patients seen at outpatient DVT clinics (00) Thrombosis and Haemostasis, 0, -. Wun T, White RH (00). Venous thromboembolism (VTE) in patients with cancer: epidemiology and risk factors. Cancer Investigations, (Suppl ), -.

7 Page of Table. Statistical analysis of risk factors in VTE patients according to cancer status Risk factor More common in cancer patients No difference More common in non-cancer patients Medical inpatient history/immobilization > days within last weeks weeks risk* history of VTE abuse smoking Patients, N Cancer patients.%.%.%.0% 0.% 0.%.% Non-cancer patients 0.% 0.%.%.%.%.%.% χ *Use of hormone-replacement therapy or oral contraceptives; pregnant or post-partum. Major surgery in last Hormonal Personal Thrombophilia IV drug Current DF p <0.00 <0.0 <0. < <0.00 <0.00