Thrombosis matters nr. 2 2016 beeld abstract 1The Anticoagulation Forum initiated a manuscript providing clinical guidelines for the prevention and treatment of cancer-associated venous thromboembolism (VTE). These clinical guidelines are based on existing guidelines and consensus expert opinions in the absence of guidelines. The following questions are addressed: 1) what is the appropriate workup to search for occult malignancy in patients with idiopathic VTE?; 2) how can high-risk cancer patients be identified for primary thromboprophylaxis?; 3) what is the appropriate immediate and long-term treatment for cancer patients with acute thromboembolism?; 4) what is the appropriate duration of anticoagulation?; 5) what is the appropriate treatment strategy in patients with recurrent VTE on anticoagulation?

1) With regard to the screening for occult cancer, the guidelines recommend a through medical history and physical examination, basic laboratory tests (complete blood counts, metabolic profile and liver function) and chest X-ray. Furthermore, the authors suggest an age- and gender-specific cancer screening for patients without up-to-date cancer screening. Only two studies have directly compared limited and extensive screening. In the only randomized trial included patients with negative limited screening and randomized them to no further screening or additional testing. During the 2 year follow-up period, the extensive screening strategy had a sensitivity of 93%. Moreover, extensive screening had increased detection of the number of cases of early-stage cancer (T1-2) (64 vs. 20%, p=0.047) , and an absolute risk reduction of cancer-related mortality of 1.9%. The other study was a prospective cohort study comparing a limited screening to a more extensive screening strategy including mammography in women and thoracic and abdominal CT. This study failed to show any difference in the number of cancers subsequently diagnosed (5.0 vs. 3.7%) or in overall mortality (8.3 vs. 7.6%) during 2.5 years of follow-up. A decision analysis and a meta-analysis have reported that limited screening combined with a CT abdomen/pelvis had the best yield. These analyses, however, failed to determine the complication rates, cost-effectiveness and difference in morbidity and mortality associated with extensive screening.

2) The authors advice against routine thromboprophylaxis in unselected and low-risk cancer outpatients. Clinical risk factors (primary tumor site, advanced stage and therapeutic interventions), biomarkers or combinations of the two can be used to estimate VTE risk. Also in patients with high bleeding risk routine thromboprophylaxis is not recommended. Outpatient thromboprophylaxis with low-molecular-weight heparins (LMWH) has to be considered in high-risk (Khorana Score ≥3 or advanced pancreas) cancer outpatients receiving chemotherapy and with aspirin or LMWH in patients with myeloma receiving imid-based regimens. Routine inpatient thromboprophylaxis with LMWH or unfractionated heparin in inpatients must be considered in cancer patients hospitalized with an acute medical illness or patients undergoing major surgery. Finally, the authors suggest post-operative thromboprophylaxis with LMWH for up to 4 weeks in patients undergoing major abdominal or pelvic surgery for cancer with high-risk features such as immobility, obesity and history of VTE.

3) The recommended appropriate immediate therapy for patients with active cancer and VTE are LMWH for at least 6 months. Patients with incidentally diagnosed DVT or PE should be treated similarly to patients diagnosed with VTE based on symptoms, i.e. with at least 6 months of LMWH monotherapy, with the exception of isolated subsegmental PE where decisions can be made on a case-by-case basis. Furthermore, the authors suggest that treatment decisions in patients with incidentally diagnosed visceral vein thrombi should be made on a case-by-case basis.

4) According to the guidelines, anticoagulation with LMWH monotherapy should be prescribed for at least 6 months after diagnosis of cancer-associated VTE. After 6 months the need for continuing anticoagulation should be reassessed periodically. In patients with ongoing risk factors, such as metastatic or progressive disease or on ongoing anti-cancer treatment, anticoagulation should be continued beyond 6 months to prevent recurrence. For patients at low risk for recurrence the authors suggest to discontinue anticoagulation after 6 months in the absence of active malignancy and without ongoing or planned anti-cancer therapy.

5) On the appropriate treatment strategy in patients with recurrent VTE despite anticoagulation other than LMWH, the authors recommend to transition these patients to therapeutic LMWH, assuming there are no contraindications to LMWH. Cancer patients with symptomatic recurrent VTE on LMWH should continue with LMWH at a higher dose, starting at an increase of approximately 25% of the current dose or resuming the therapeutic weight-adjusted dose if the patient was receiving a non-therapeutic dose at the time of recurrence. The use of an inferior vena cava filter (IVC filter) is not recommended, except in the presence of absolute contraindications to pharmacologic anticoagulation (e.g. active bleeding). If necessary, the authors advice the use of a retrievable filter and a plan to retrieve the filter when appropriate.

VTE is a highly prevalent complication of malignancy and an important cause of morbidity and mortality in cancer patients. In this article, the authors addressed important clinical questions and attempt to provide recommendations for prevention and treatment of cancer-associated VTE based on systematic reviews, meta-analyses and consensus between authors.

Reference

Khorara AA, Carrier M, Garcia DA, et al. Guidance for the prevention and treatment of cancer-associated venous thromboembolism. J Thromb Thrombolysis 2016;41:81-91.


Thrombosis matters nr. 2 2016 beeld abstract 4Results from the CATCH trial showed that treatment with the low-molecular-weight heparin tinzaparin is associated with a lower risk of recurrent venous thromboembolism (VTE) compared to treatment with the vitamin K antagonist warfarin in cancer patients with symptomatic VTE. Moreover, treatment with tinzaparin significantly reduced the rates of clinically relevant non-major bleeding compared to warfarin. In a subanalysis of the CATCH trial the baseline patient-reported health-related quality of life (HRQL) and the impact of having experienced a VTE was described. Data were presented at the International Society For Pharmacoeconomics and Outcomes Research (ISPOR) 18th Annual European Congress.

The CATCH study was a phase III, multinational, randomized, controlled, open-label trial which enrolled 900 patients with active cancer from 32 countries. EQ-5D-3L questionnaire data were collected at baseline and every month for 7 months. The investigators choose to apply the UK preference weight set and explored the baseline data which captured the acute phase of VTE. Exploratory univariate analyses tested the effects of covariates including age, gender, metastatic status, primary tumor site ECOG status, and history of VTE.

At baseline, in the acute stage of the VTE, patients reported poor HRQL (mean EQ-5D score 0.52) compared to EQ-5D estimates reported in the literature for cancer patients. There was no difference between the treatment arms. Women reported significantly worse HRQL than men (0.49 vs. 0.56), while there was no significant difference across age groups. Patients suffering from both symptomatic deep vein thrombosis and symptomatic pulmonary embolism had the worst mean score (0.46). Patients with higher ECOG status reported lower HRQL, whereas similar mean EQ-5D-3L scores were reported for metastatic status and varying scores for different cancer types (brain, breast, lung, hepatobiliary, upper gastrointestinal tract, lower gastrointestinal tract, genitourinary, prostate, gynaecologic, haematological). Patients from Latin America and Asia reported lower scores of HRQL than patients from other regions.

This subanalysis of the CATCH trial showed that cancer-associated VTE has a significant additional impact on the health-related quality of life. Quality of life of women seems to be affected the most by VTE.

Reference

DeWilde S, Lloyd AJ, Holm MV, et al. Quality of life of patient experiencing cancer-associated thrombosis. Value in Health 2015;18:A397-8.


Thrombosis matters nr. 2 2016 beeld abstract 2According to the results of a systematic review, prophylactic dosages of the low-molecular-weight heparins (LMWH) tinzaparin and daltaparin are likely to be safe in patients with renal insufficiency. For these agents, no accumulation was observed and therefore there was no need for a dose reduction. Atiq and colleagues published the results of this comprehensive, systematic literature search including 11 publications conducted on February 17th, 2015. The purpose of this study was to investigate whether prophylactic dosages of LMWH accumulate in patients with renal insufficiency. Therapeutic dosages of most LMWH are known to accumulate in patients with renal insufficiency. As a result, dose reduction is often recommended. For a lower prophylactic dosage of LMWHs that accumulate in therapeutic dosages, dose reduction has been suggested. However, whether these lower prophylactic dosages also accumulate is not yet clear. Accumulation of LMWH due to renal insufficiency leads to an increased risk of bleeding. The pharmacokinetics of different LMWHs vary, therefore, data on accumulation in patients with renal insufficiency cannot be easily converted from one LMWH to the other. Many patients with cancer-associated venous thromboembolism are older patients, who suffer from (severe) renal insufficiency. Especially for these patients in whom the novel oral anticoagulants are contraindicated, it remains important to know whether LMWHs can be prescribed safely.

Of the 11 included publications in this study, 2 were randomized trials and 8 were cohort studies. Dalteparin accumulation was studied in 5 articles, enoxaparin accumulation in 5 studies, tinzaparin, bemiparin, and certoparin in 1 study each. No data for nadroparin were available. In all studies accumulation was defined as an increase in anti-Xa activity after consecutive administration for several days. Only studies in English, with at least 10 patients with renal impairment were included. For dalteparin and tinzaparin, no accumulation in patients with renal insufficiency was observed. Enoxaparin, on the other hand, did lead to accumulation, although not in patients undergoing renal replacement therapy. Bemiparin and certoparin also did show accumulation.

Six studies reported VTEs and bleeding events, although all were underpowered to find significant correlations. Five serious bleeding complications were reported during enoxaparin use, however, anti-Xa activity in these patients was the same as in those without bleeding (p=0.77).

This systematic review shows that prophylactic dosages of dalteparin and tinzaparin did not accumulate in patients with renal insufficiency, while prophylactic dosages of enoxaparin, bemiparin, and certoparin did accumulate. These findings confirm the theory that accumulation depends on the mean molecular weight of LMWHs. The authors conclude that for enoxaparin, bemiparin, and certoparin, the guidelines that recommend dose reduction for prophylactic use in patients with renal insufficiency are evidence based. They recommend a dose reduction for prophylactic use of these LMWHs in patients with CrCl below 30 ml/min. For daltaparin and tinzaparin, prophylactic dosages are likely to be safe in patients with renal insufficiency. Therefore, dose reduction of these LMWHs is not necessary.

Reference

Atiq f, Van den Bemt PM, Leebeek FW, et al. a systematic review on the accumulation of prophylactic dosages of low-molecular-weight heparins (LMWHs) in patients with renal insufficiency. Eur J Clin Pharmacol 2015;71:921-9.


Thrombosis matters nr. 2 2016 beeld abstract 3The addition of a primary prophylactic dose of low-molecular-weight heparin (LMWH) to standard treatment in patients with newly diagnosed lung cancer did not improve overall survival (OS), according to the results of the FRAGMATIC trial. The results of this UK study were recently published in the Journal of Clinical Oncology by Macbeth et al. This is the largest trial to date to examine the effect of LMWH on survival in patients with a single primary malignancy. The investigators found no evidence of a survival benefit from the use of dalteparin for 24 weeks during the initial treatment patients with lung cancer received. Furthermore, there was no evidence of a benefit in metastasis-free survival (MFS) from the use of dalteparin.

Previous evidence suggested that LMWHs might improve survival in cancer patients by preventing venous thromboembolism (VTE) and progression of metastasis. Patients in the FRAGMATIC trail (n=2,202) received standard anticancer treatment with or without dalteparin (s.c. 5,00 IU daily) for a maximum of 24 weeks. Randomization was stratified by intended initial treatment, type of cancer, gender, performance status, presence of metastases, and treatment centre. The primary endpoint was OS, secondary endpoints were, among others, VTE-free survival bleeding, MFS, and toxicity.

The data were analysed after 2,013 of 2,047 deaths intended for the primary analysis. Median follow-up was 23.1 months. Of the patients in the LMWH arm 90% died, in the no-LMWH arm 93% died. The cause of death was lung cancer in 88% of patients. Other causes were deep vein thrombosis (10% in LMWH arm vs. 8.3 in no-LMWH arm), and pulmonary embolism (13.3% vs. 20.8%). A median OS of 9.8 and 10.2 months and 1-year survival rates of 41.3% and 42.5% were observed in the LMWH and no-LMWH arms respectively (difference not significant). A exploratory subgroup analysis revealed no evidence of a benefit of dalteparin over no LMWH in terms of OS in specific subgroups. Median MFS also did not differ significantly between the 2 arms: 9.4 weeks in the LMWH arm vs. 8.9 weeks in the no-LMWH arm.

Risk of VTE was significantly reduced in the LMWH arm (5.5% compared to 9.7% in the no-LMWh arm; p=0.001). One-year VTE-free survival rates were 94.1% for LMWH vs. 89.5% in the no-LMWH arm (HR 0.57 [95% CI 0.42-0.79], p<0.001). There was no difference between groups in major bleeding events during the study treatment period (1.1% vs. 0.7%), however, a higher incidence of the composite of major and clinically relevant non-major bleeding events was observed in the LMWH arm (5.6% vs. 1.3%). The majority of grade 3/4 adverse events reported in the first 24 weeks could be attributed to the adverse effects of anticancer treatment. No significant difference in adverse events was found between the 2 arms.

The authors conclude that LMWH did not improve OS in patients with lung cancer in this trial. Routine thromboprophylaxis with LMWH is not indicated for these patients, nor probably for the majority of patients with cancer and a similar or lower risk of VTE. These results however, do not rule out a possible survival benefit in specific subgroups. ‘

Reference

Macbeth F, Noble S, Evans J, et al. Randomized phase III trial of standard therapy plus low molecular weight heparin in patients with lung cancer: FRAGMATIC trial. J Clin Oncol 2016;34:488-94.


Cancer patients are at high risk to develop deep vein thrombosis. Thrombosis is life-threatening: around 20% of deaths in cancer patients is due to blood clots, not to tumours. Preventive measures and treatment of thrombosis is of the utmost importance.

The Frontline2 Survey Information Site comprises a survey that will help clinicians to understand patterns of practice and perceptions with regard to cancer-associated thrombosis. The Fundamental Research in Oncology and Thrombosis (Frontline2) is a unique global survey, coordinated by the clinical research team of the Thrombosis Research Institute (TRI), London.

The aim of the survey is to gather the perspectives of oncologists, haematologists, surgeons, radiation oncologists and members of the palliative care team responsible for treating cancer-associated thrombosis, and generate new insights into this important clinical problem. This survey builds upon a previous similar survey (Frontline1) undertaken 15 years ago.
A total 3,891 clinicians participated in the Frontline1 survey. Marked differences were seen in the use of thromboprophylaxis, with over 50% of surgeons reporting that they initiated thromboprophylaxis routinely, while medical oncologists reported using thromboprophylaxis in less than 5% of patients. Low molecular weight heparin (LMWH) was the most favourable method of prophylaxis employed in both surgical and medical patients and was more popular in Europe than in the U.S. Around 20% of responders reported using aspirin for prophylaxis.

The results of the Frontline1 survey demonstrated a need for guidelines to direct clinical practice in line with evidence-based data concerning cancer-associated thrombosis. They also revealed the need for educating oncologists regarding the true risk of VTE associated with certain malignancies and on strategies for prevention and treatment to reduce morbidity and mortality associated with VTE in cancer patients.

The results of the current survey will be very useful in describing the evolution of clinical understanding in this area since 2001 and will be helpful in improving clinical practice and outcome for cancer patients at risk for thrombosis.

The Frontline2 Survey Information Site provides you with:

  • An introduction to the aim of the survey.
  • A word of welcome from the chair of the steering committee, Professor Lord Ajay Kakkar.
  • A survey manual.
  • Free educational materials made available after completing the survey.
  • First-hand access to the results of the survey upon publication after completing the survey.
  • A hyperlink to the publication of Kakkar et al. describing the design and the results of the first survey undertaken in 2001.
  • A hyperlink to the website of the Thrombosis Research Institute with information about thrombosis, the TRI research projects, and more.

 

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Innohep site

 

Enter the weight of your patients and get instantly the correct dose of innohep®

This special app is developed to guide you in dosing of innohep® for VTE or PE prophylaxis and treatment, such as the weight-based dosing of innohep® in patients with or without co-morbidities, including oncology out-patients. The app also provides you with risk-calculations following the medical conditions of your patient. The innohep® app is intended to be used when determining the dose of tinzaparin for patients weighing less than 165 kg. It is released for iPhone and Android.

To download the app click the QR codes below:
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Download the app via QR code or search in the App store for 'inno dosing'. You can use the app only after entering a 4-digit code. To receive this code, mail to This email address is being protected from spambots. You need JavaScript enabled to view it.