abstr 1Experiencing recurrent venous thromboembolism (rVTE) or bleeding has a significant negative impact on the health-related quality of life (HRQL). This conclusion was drawn based on an analysis of the health-related quality of life (HRQL) data from patients in the CATCH trial. Noble et al. recently presented these data during the annual meeting of ESMO. The CATCH trial is a randomised trial comparing the efficacy in preventing rVTE of tinzaparin versus warfarin in 900 patients with active cancer and acute VTE from 32 countries. EQ-5D-3L data from a total of 883 patients in the trial were analysed to assess the impact of rVTE and bleeding events on HRQL.

The EQ-5D-3L scores ranged from 1.0 (full health) to 0 (dead) and down to -0.594. The analyses was designed to correct for effects of covariates such as age, gender, metastatic status, primary site of cancer, ECOG performance status, and history of VTE. The specific impact of a rVTE or bleeding event was reflected when it occurred within around two weeks from a planned data collection point.

The investigators collected 183 HRQL assessments during follow-up. A total of 76 rVTE events and 141 bleeding events occurred during this period. The estimated HRQL scores are listed in the Table below.

  Number of events Mean EQ-5D 95% CI
No event 4.525 0.64 0.62-0.67
Non-fatal DVT 36 0.61 0.52-0.68
Non-fatal PE 3 0.62 0.48-0.73
Fatal PE 16 0.46 0.27-0.60
Recurrent VTE 55 0.57 0.49-0.64
Major bleeding 15 0.59 0.46-0.69
Non-major bleeding 113 0.62 0.57-0.67
DVT=deep vein thrombosis, PE=pulmonary embolism, VTE=venous thromboembolism.

Table. Estimated health-related quality of life scores.

The authors conclude that experiencing a rVTE or bleeding events significantly worsens the HRQL. The data allow the investigators to quantify the burden for patients with cancer-associated thrombosis as well as the value of secondary VTE prevention. A limitation of the study was the fact that not all events could be captured in the planned HRQL assessments. Detecting VTE related HRQL signals against the background of other influences on HRQL measurement proved to be challenging when analysing the data. Future work possibly using qualitative measures could be helpful in understanding how and why patients’ HRQL is affected.

Reference

Noble S, Lloyd AJ, Dewilde S, et al. The impact of cancer-associated thrombosis and treatment related bleedings on patients' quality of life. Ann Oncol 2016;27 (Suppl 6)


abstr 3The results from a population-based study confirmed the long-term risk of venous thromboembolism (VTE) in breast cancer patients and identified a comprehensive set of clinical risk predictors that may facilitate future risk stratification and prevention efforts. Specifically within the first year of diagnosis, breast cancer patients are at highest risk of VTE events. An older age at the time of diagnosis, a body mass index ≥25 kg/m2, a history of VTE, a tumour size >40 mm, progesterone receptor (PR)-negative disease, comorbidities, more than 4 affected lymph nodes, and chemo- and endocrine therapy were all independent predictors of VTE in breast cancer patients.

Breast cancer patients have a 3- to 4-fold increased risk of developing VTE compared to women without cancer. The long-term consequences of VTE in terms of morbidity and quality of life are substantial, especially for non-metastatic patients who have a rather good prognosis. Moreover, breast cancer has a very high incidence and thus contributes to a large number of cancer-associated VTE events. Insight into the time-dependent etiology of VTE in breast cancer patients, as well as having tools for risk stratification is of great importance for the timing of preventive strategies, including early detection and short-time prophylaxis covering periods of highest risk.

A Swedish population-based study included 8,338 patients with primary invasive breast cancer diagnosed between 2001 and 2008 in the Stockholm-Gotland region. Patients were free of distant metastasis at the time of diagnosis. Follow-up was complete until December 2012. The VTE incidence in this population was compared to the VTE incidence among 39,013 age-matched reference individuals from the general population. From the Stockholm Breast Cancer Registry the following variables were extracted: tumour size, histological grade, estrogen receptor (ER)/PR status, number of affected lymph nodes, type of surgery, radiotherapy, and receipt of chemo- and endocrine therapy. The aim of the study was to assess the risk and predictors of VTE in breast cancer patients by time since diagnosis.

The mean age at the time of diagnosis of breast cancer was 57.1 years. A total of 426 breast cancer patients experienced a VTE event during a median follow-up of 7.2 years. The 1-, 2-, and 5-year cumulative incidences of VTE in the breast cancer cohort were 2.0%, 2.5%, and 4.0%, respectively. The corresponding cumulative incidences of VTE in the age-matched cohort were considerably lower; 0.3%, 0.5%, and 1.1%, respectively. For the breast cancer cohort, the VTE rates were 7.9 per 1,000 person-years, compared to 2.4 per 1,000 person-years for the age-matched reference individuals. Overall, breast cancer patients experienced a 3-fold increased risk of VTE compared to the age-matched controls (HR 3.28 [95% CI 2.87-3.74].

Consistent with previous reports, the incidence of VTE was highest in the first 6 to 12 months after diagnosis (HR 8.62 [6.56-11.33], and 4.46 [3.52-5.66], respectively). Thereafter, the risk was on average 2-fold higher compared to the incidence among age-matched controls and remained constant for many years (HR at 2, 5, and 7 years: 2.01 [1.50-2.70], 2.19 [1.80-2.67], and 2.26 [1.70-2.99], respectively). The overall and relative risk of deep vein thrombosis and pulmonary thrombosis were assessed in separate analyses, which resulted in similar HRs. Analysis of the HRs for VTE by patient, tumour, and treatment characteristics showed that an older age, being overweighed, pre-existing VTE, comorbid disease, tumour size >40 mm, PR-negative status, more than 4 affected lymph nodes, and receipt for chemo- and endocrine therapy were associated with an increased VTE risk in breast cancer patients. The impact of most predictors was constant over time, except for chemotherapy, comorbid disease, and PR-negative status. Both comorbid conditions and PR-negative tumours were associated with late-onset VTE. Chemotherapy, on the other hand, was associated with events occurring within the first year after diagnosis. In line with data from randomised clinical trials, the effect of chemotherapy was limited to the active treatment period.

This population-based cohort study demonstrated that breast cancer patients are at highest risk of VTE within the first year of diagnosis. After two years the VTE risk remains 2-fold higher compared to the general population. The investigators identified an extensive set of clinical risk predictors of VTE in breast cancer patients. Some predictors had a temporal association, providing insight into the time-dependent etiology of VTE.

Reference

Brand JS, Hedayati E, Bhoo-Pathy N, et al. Time-dependent risk and predictors of venous thromboembolism in breast cancer patients: a population-based cohort study. Cancer 201 Oct 11 [Epub ahead of print].


longkanker 200 200The results of a meta-analysis of six randomised trials indicated that the administration of heparin as primary thromboprophylaxis for lung cancer patients without an indication for anticoagulants is associated with a significant survival benefit compared to the control arm. This benefit was particularly large for patients with limited-stage small cell lung cancer (SCLC). Moreover, the prophylactic use of heparin led to a significant reduction in thromboembolic events, while no significant increase in bleeding, major bleeding and thrombocytopenia was observed.

Besides its antithrombotic properties in cancer-associated thrombosis, heparin exhibits a potential antitumor effect. The preclinical and clinical evidence for the antitumor properties of low-molecular-weight heparin (LMWH) have been studied and reviewed extensively, suggesting that LMWH decreased mortality in cancer patients. However, the exact effect of LMWH on cancer survival and the anticancer mechanism still need to be elucidated. Several studies have evaluated the effect of heparin on survival of lung cancer patients, as well as the safety profile of heparin in these patients. Yu and colleagues have conducted a systematic literature search for relevant randomised controlled trials that compared the addition of low-molecular weight heparin (LMWH) or unfractionated heparin (UFH) to standard chemotherapy in lung cancer patients without an indication for anticoagulants. LMWH or UFH had to be given for at least four weeks without interruption to ensure an adequate amount of therapeutic time. The primary endpoint was survival. Other outcomes were symptomatic deep vein thrombosis, symptomatic pulmonary embolism, all reported thromboembolic events, and adverse events including major bleeding, minor bleeding and thrombocytopenia.

A total of six studies with 753 patients in the heparin group and 640 patients in the control group were included for the meta-analysis. In one study the intervention was UFH, in the other five LMWH was used. Four studies reported survival outcomes. Across all studies, heparin had a clear effect on survival in lung cancer patients (HR 0.71 [95% CI 0.60-0.84], I2=42.0%). Among the subgroup of patients with SCLC, the HR was 0.72 [95% CI 0.59-0.87] (I2=47.4%). The survival benefit of heparin was most obvious in the subgroup of patients with limited-stage SCLC (HR 0.57 [95% CI 0.43-0.77]).

There was a significant difference in thromboembolic events between the patients who received heparin (19 events among 529 patients) and the patients in the control group (34 events in 404 patients; RR 0.46 [95% CI 0.27-0.80], I2=0%). Based on four studies, bleeding occurred in 42 of 534 patients (7.9%) in the heparin group compared to 25 of 413 patients (6.1%) in the control group. In the fixed-effects model, heparin use did not increase bleeding (RR 1.53 [95% CI 0.96-2.45], I2=6.2%) or major bleeding complications (RR 1.43 [95% CI 0.59-3.45], I2=0%). Moreover, the incidence of thrombocytopenia was not significant different between the two groups. In the three studies that reported thrombocytopenia, 78 of 335 (23.3%) patients in the heparin group, and 95 of 332 (28.6%) patients in the control group experienced thrombocytopenia (RR 0.86 [95% CI 0.66-1.12], I2=13.7%).

This retrospective meta-analysis showed that administration of heparin as primary thromboprophylaxis in lung cancer patients without an indication for anticoagulants improves survival. A significant survival benefit for heparin over no anticoagulants (control group) was seen, particularly in patients with limited-stage SCLC. In the heparin group, a significant reduction in thromboembolic events was observed compared to the control group. The risk for bleeding, major bleeding, and thrombocytopenia was not significantly increased in heparin-treated patients compared with the control group.

Reference

Yu Y, Lv Q, Zhang B, et al. Adjuvant therapy with heparin in patients with lung cancer without indication for anticoagulants: a systematic review of the literature with meta-analysis. J Can res ther 2016;12:37-42.


abstr 4In spite of clinical practice guidelines recommending the long-term use of low-molecular-weight heparins (LMWH) as the standard of care for cancer-associated thrombosis (CAT), there is a clear and consistent LMWH underprescription. The authors of a literature review concluded that only approximately 50% of patients with CAT are managed according to the established guideline recommendations. Patient profiles and comorbidities are factors influencing compliance with treatment guidelines.

The recommended management of patients with CAT consists of treatment with LMWH. The optimal duration of treatment is still under debate. Current data support anticoagulation therapy up to six months in patients with active cancer and VTE. Few data are available regarding adherence to the clinical practice guidelines. Mahé et al. aimed to assess the actual implementation of the guidelines in CAT management, based on follow-up data from studies published in the scientific literature. A total of 14 studies with CAT patients receiving anticoagulation therapy for at least three months were included in the review (Table).

Study Design CAT patients (n) Long-term LMWH (%)
RIETE registry (Trujillo-Santos, 2010) registry 4,709 53%
SWIVTER (Spirk, 2011) prospective 315 34%
Delate, 2012 retrospective 1,089 25%
CARMEN (Sevestre, 2014) prospective 500 59%
RECOVERY (Kahn, 2012) prospective 74 43%
Kakkar, 2003 survey 3,891 37%
Siragusa, 2005 prospective 207 49%
Wittkowsky, 2006 prospective 100 19%
Belhadj-Chaidi, 2013 retrospective 145 44%
Rahme, 2013 retrospective 2,070 43%
Kaatz, 2014 retrospective 329 40%
Noble, 2015 prospective 100 70%
Matzdorff, 2015 prospective 76 67%
Mahé, 2016 retrospective 204 63%

Table. Proportion of CAT patients receiving long-term treatment with LMWH (studies included in the literature review).

The number of patients was highly variable across studies (Table). A clear and consistent underprescription was observed in older studies as less than 50% of CAT patients received long-term LMWH. The proportion of patients treated with LMWH tended to increase after the publication of clinical practice guidelines for the management of CAT in 2008. A recent report from the RIETE registry up to December 2013 has shown that 66% of the patients receive long-term LMWH for the treatment of CAT. Overall, a trend towards an increase in the long-term use of LMWH in CAT patients is observed, suggesting a positive impact of the treatment guidelines on physician’s clinical practice.

The actual prescription of long-term LMWH treatment does not necessarily imply adherence to treatment guidelines. In a recent retrospective, observational study from Mahé et al in a cohort of 204 patients 63% received long-term LMWH for at least three months, but the treatment adhered to guidelines in only 31% of patients, mainly because of the prescription of an anticoagulant other than LWMH in the absence of renal insufficiency, the prescription of an anticoagulant other than VKA (45%), and inappropriate dosing (46%). In specific circumstances, non-adherence to guidelines is justified by several factors such as safety, costs, or geography. However, this only accounts for approximately one third of the cases of non-adherence to guidelines.

Reference

Mahé I, Chidiac j, Helfer H, et al. Factors influencing adherence to clinical guidelines in the management of cancer-associated thrombosis. J Thromb Haemost 2016;14:1-7.


App 1 schermThe Management of Anticoagulation in the Peri-Procedural Period (MAPPP) tool has been developed to assist in determining the safest and most appropriate management of anticoagulation in the peri-procedural period based on the most current guidelines. This app is intended for use by physicians, pharmacists and other clinical providers as an evidence-based resource.

Surgery and invasive medical interventions increase the risk of bleeding, while withholding anticoagulants increases the risk of thrombosis due to the underlying condition(s) for which anticoagulation was originally prescribed. This requires adequate evaluation of procedure-related bleeding risk and underlying risk of thrombosis, as well as educated decision making from the clinical team regarding the decision to interrupt oral anticoagulation for a medical procedure and, if interrupted, whether to ‘bridge’ anticoagulation with injectable anticoagulants, such as low molecular weight heparin (LMWH) in warfarin treated patients. The app provides detailed guidance for drug dosing and laboratory monitoring in the peri-procedural period.

 


Logo world thrombosis day

 

 

 

 

Increase global awareness of venous thrombosis

In 2014, World Thrombosis Day (WTD) was initiated to raise global awareness for venous thrombosis. WTD is to be held every year since. Public awareness is without doubt of great importance. All effort to increase public awareness are therefore noteworthy, and it is important to measure the impact of awareness days. For this purpose, the use of internet based data seems promising. A Dutch research team used Google Trends data to assess the impact of WTD on internet searches on venous thrombosis. Their findings showed that in the years 2014 and 2015 WTD was associated with an increase in digital information seeking on venous thrombosis worldwide.

Reference

Scheres, Lijfering WM, Middeldorp S, et al. Influence of World Thrombosis Day on digital information seeking on venous thrombosis: a Google Trends study. J Thromb Haemost 2016 Oct 13 [Epub ahead of print].