Prandoni siteAccording to the results of recent randomized clinical trials, the long-term administration of low molecular-weight heparin (LMWH) is now regarded as the treatment of choice in patients with active cancer. However, in recent years, novel direct oral anticoagulants (DOAC) have emerged to potentially replace conventional treatments for the initial and long-term treatment of venous thromboembolism (VTE). Paolo Prandoni, MD, PhD (University of Padua, Italy) gave his expert opinion on the role of LMWH, DOAC, and vitamin K antagonists in the treatment of VTE in cancer patients.

In most cases the initial treatment of cancer-associated venous thromboembolism (CAT) should be the same as in cancer-free patients. However, long-term treatment of cancer patients is challenging. Cancer patients often require invasive procedures, have an increased risk of infection and may have therapy-related platelet decreases, that increase their bleeding risk. On the other hand, chemotherapy, hormonal agents, invasive procedures and venous catheters not only increase the risk of thrombosis but also create complex clinical situations that make anticoagulation problematic. In addition, cancer patients have a three- to fourfold higher risk of recurrent venous thromboembolism (VTE) during anticoagulant therapy than cancer-free patients.

According to the results of recent randomized clinical trials, low molecular-weight heparin (LMWH) has the potential to provide a more effective antithrombotic regimen in CAT than adjusted doses of vitamin K antagonists (VKA) without increasing the hemorrhagic risk (Lee AY et al, JAMA 2015). Thus, the long-term administration of LMWH is now regarded as the treatment of choice in patients with active cancer.

In recent years, novel direct oral anticoagulants (DOAC) have emerged to potentially replace conventional treatments for the initial and long-term treatment of VTE. DOAC do not interfere with platelets, and as a consequence of their pharmacokinetic and pharmacodynamic properties, they can be administered orally, in fixed doses, without laboratory monitoring. In a recent meta-analysis, pooling data from six studies comparing the DOAC with conventional anticoagulation (VKAs) for the treatment of 1,132 patients with VTE and associated cancer, VTE recurred in 23/595 patients allocated to the novel drugs and in 32/537 allocated to conventional treatment (OR = 0.63; 95% CI, 0.37 - 1.10) (Vedovati MC, et al, Chest 2015). Major bleeding occurred in 19 and 22 patients, respectively (OR = 0.77; 95% CI, 0.41 - 1.44). In another, more comprehensive meta-analysis, the efficacy of the DOAC was found to be significantly higher in the subgroup of patients with cancer without an increase in the bleeding risk (Van Es N, et al, Blood 2014). Although these are encouraging results, the studies had a number of shortcomings. The definition of active cancer was widely different. Moreover, the choice of VKA as comparator was suboptimal, as LMWH and not VKA is the standard of care for CAT. Furthermore, poor nutrition, infection, concomitant medication, vomiting and impaired liver function can cause unpredictable changes in the dose-response of the DOAC,in analogy with that expected with the use of VKA. Although they have fewer drug interactions than VKA, DOAC metabolism is influenced by the CYP3A4 or the P-glycoprotein transport, making potential drug interactions with several chemotherapeutic and even non-cytotoxic agents likely. In addition, DOACs are contraindicated in patients with severe renal failure, and may increase the risk of gastrointestinal bleeding (at least when using dabigatran or rivaroxaban).

Given these results, Prandoni concludes that LMWH is the mainstay of treatment of CAT. The use of LMWH for this indication is, indeed, associated with a benefit-risk profile that is definitely better than that expected with the VKAs. Based on recent findings, whenever deemed necessary, LMWH therapy can be effectively and safely prolonged for 6 additional months. VKA might also have a persistent role in the long-term treatment of CAT, in case the prognosis of patients substantially has improved once the initial course of LMWH successfully has been completed. DOAC cannot be currently recommended on a routine basis for CAT. Although available findings are encouraging, their benefit-risk profile is currently difficult to evaluate. Available studies have substantial limitations, so there is the need for proper future clinical trials in which DOAC and LMWH are compared directly.

Reference

Prandoni P. The treatment of cancer-associated venous thromboembolism in the era of the novel oral anticoagulants. Expert Opin Pharmacother 2015;16(16):2391-4.


Noble siteSimon Noble et al. recently published the results of a feasibility study to inform the design of a randomised controlled trial in which the most clinically effective and cost-effective length of anticoagulation with low-molecular-weight heparin (LMWH) in the treatment of cancer-associated thrombosis should be identified, the so-called ALICAT study. Venous thromboembolism is common in cancer patients and requires anticoagulation with low-molecular-weight heparin (LMWH). Current data recommend LMWH for anticoagulation as far as 6 months, yet guidelines recommend LMWH beyond 6 months in patients who have ongoing or active cancer. This recommendation, based on expertconsensus, is widely practiced but has not been evaluated in a clinical study.

The objectives of the reported feasibility study were threefold:

  • Identification of the most clinically effective and cost-effective length of anticoagulation with LMWH in the treatment of cancer-associated thrombosis (CAT);
  • Identification of practicalities of conducting a full randomised controlled trial (RCT) with regard to recruitment, retention and outcome measurement;
  • Exploring the barriers for progressing to a full RCT.

The ALICAT trial consisted of three components to reach these goals. The first part, a RCT comparing ongoing LMWH treatment for CAT with cessation of LMWH at 6 months’ treatment in patients with locally advanced or metastatic cancer, was several times delayed because of procedural factors and low inclusion. With 5 out of 32 eligible patients that agreed to participate in the RCT, Noble et al. concluded that progession to a full RCT was not feasible. The reason why patients were not consenting for this RCT, asked for in the second part of the trial, was primarily based on past experiences. Patients had a fixed preference for continuing or discontinuing treatment after 6 months of anticoagulation, and a fear of randomisation to their non-preferred option. Focus groups with clinicians revealed that they had fixed views of best management despite the lack of evidence, and they were not willing to recruit to such a study. Patient pathway modelling, the third part of the trial, suggested that there is a broad heterogeneity of practice with respect to CAT management and co-ordination. There was no consensus on ownership on the clinical problem.

Noble et al. conclude that the management of cancer-associated thrombosis beyond 6 months will remain a clinical challenge. Continuing long-term anticoagulation, although not evidence-based, is supported strongly by consensus and clinician experience. As it is unlikely that a phase 3 RCT will successfully recruit, other strategies to obtain relevant data on clinical efficacy and safety, or financial sustainability are necessary.

Reference

Noble SI, Nelson A, Fitzmaurice D, et al. A feasibility study to inform the design of a randomised controlled trial to identify the most clinically effective and cost-effective length of Anticoagulation with Low-Molecular-Weight Heparin In the treatment of Cancer-Associated Thrombosis (ALICAT). Health Technol Assess 2015;19(83):1-94.


item3 siteThe superiority of low molecular weight heparins (LMWH) over warfarin in the extended treatment of cancer-associated thrombosis (CAT) has been demonstrated. Despite the fact that clinical guidelines recommend LMWH as the first-line treatment for CAT, around 30% of patients are prescribed oral anticoagulants, suggesting that treatment decisions are not based on clinical guidelines or efficacy and safety data alone. Whilst poor compliance to anticoagulants is well known, the reasons for this prescribing attitude are not fully understood. Specific to CAT there is a perception that patients prefer an oral anticoagulant over a LMWH. However, it is unknown whether this is a real representation of cancer patients’ view.

Noble and colleagues conducted a study to identify and evaluate the values and preferences of patients with CAT regarding anticoagulant treatment.Two modules were applied: in the qualitative module 9 patients were interviewed about their anticoagulation experiences. Thereafter, in the choice-based conjoint (CBC) module, 100 patients completed a CBC exercise where 15 different scenarios were presented to identify the most important attributes of an anticoagulant (the quantitative module). Those attributes were established in the qualitative module and included: efficacy, risk of minor bleeding, risk of major bleeding, administration form, interference with cancer treatment, frequency of administration, and monitoring through blood tests.

The patient population in the quantitative research (50 patients from Germany and 50 from the UK), was predominantly female, with an average age of 57 years. Nearly half of the patients (41%) had a stage IV cancer. Time from diagnosis of venous thromboembolism (VTE) varied from 1 month prior to the study up to 12 months prior to the study. Almost two third of the patients had been diagnosed with deep vein thrombosis, the other one third with pulmonary embolism.

The main finding of the qualitative research was that patients were most concerned about interactions between the anticoagulant and other medications (particularly the cancer treatment), while they considered the efficacy and safety of the anticoagulant as a prerequisite. In the quantitative module patients most valued an anticoagulant with minimal interference with their cancer treatment (relative importance: 39%). Other values of importance were low thrombosis recurrence rate (24%), and low risk of major bleeding (19%). Preference for oral administration over injection appeared to be of moderate importance (13%). Of low importance to the participating patients were low risk of minor bleeding with 2%, monitoring through blood tests with 2%, and frequency of administration with 1%. The part-worth utility values are important indicators of the effect of the attribute levels on the preference for VTE treatment, and are depicted in the Figure below.

This research gives a valuable insight into patients’ preferences and has several implications for the treatment of CAT. The results suggest that the primacy of CAT patients lies at their cancer and its treatment rather than at the VTE. As such, anticoagulation therapy needs to be managed in close collaboration with the patient’s oncology team. In addition, patients strongly favour efficacy and safety over convenience of anticoagulation administration.

Reference

Noble S, Matzdorff A, Mareveyas A, et al. Assessing patients’ anticoagulation preferences for the treatment of cancer-associated thrombosis using conjoint methodology. Haematologica 2015;100:1486-92.

 

Figure. Effect of attribute levels on preference for VTE treatment: part-worth utilities.

figure1


ash siteEvaluating anticoagulant treatment beyond 6 months in patients with cancer-associated thrombosis

Current guidelines recommend anticoagulation with low molecular weight heparin (LMWH) monotherapy for a minimum of 6 months in the treatment of cancer-associated thrombosis, and long-term anticoagulation for as long as the malignancy is present.1,2 However, treatment recommendations from consensus clinical guidelines are largely based on retrospective reports. In addition, many clinical questions remain unanswered, including optimal duration of anticoagulant therapy. At the 2015 ASH meeting 2 real-world studies on the clinical approach were presented.

 

Update of the EXTEND study

Louzada siteThe first study, by Louzada et al, concerned the EXTEND study that was conducted in Canada.3 Retrospectively, data from adult clinical patients with cancer-associated thrombosis (CAT) who received anticoagulation therapy with LMWH or warfarin for at least 6 months, were collected. The follow-up started at 6 months of anticoagulation and ended at 12 months, at time of a recurrent VTE, or death. The primary outcome measure was VTE recurrence rate and its correlation with anticoagulation strategy after the first 6 months of anticoagulation.

Of the 289 patients who met the inclusion criteria, 284 patients (98%) received LMWH and 4 received warfarin during the first 6 months of anticoagulation therapy. At 6 months of treatment, 73 patients (25%) discontinued therapy. Of the remaining 216 patients, 139 patients (48%) continued on full dose LMWH, 18 patients (6.2%) on prophylactic LMWH, 66 patients (22.8) were switched to warfarin, and 3 (1%) to rivaroxaban.

During the follow-up,77 patients were considered to be in remission of their cancer. Still, 51 of them (66.2) continued on anticoagulation. A recurrent VTE was seen in 18 out of 289 patients (6.2%). Only 2 of them had discontinued anticoagulation. Of 45 patients with incidental pulmonary embolism (PE) at first CAT, 4 patients (10%) presented with a recurrent VTE during follow-up.

 

Patients with a hematologic malignancy or lung cancer are at higher risk of VTE recurrence

The only potential independent predictor for VTE recurrence was tumour site. Patients with a hematologic malignancy or lung cancer were at higher risk of VTE recurrence (OR [95%CI]: 3.62 [1.356-9.67], p=0.0102). The relative risk of VTE recurrence in patients with ongoing active malignancy did not significantly differ from that of patients considered to be in remission (0.79 [95%CI 0.316-1.99], p=0.625). Prophylactic LMWH, oral anticoagulant, no anticoagulant, cancer stage, residual VTE, gender, and age were not predictors of VTE recurrence.

This study confirmed that patients with CAT have an ongoing high risk for recurrent VTE, although this risk seems to be lower than the risk in the first 6 months of anticoagulation therapy, which historically ranges between 9 and 17%. The EXTEND study was not able to accurately identify potential predictors of VTE recurrence, apart from tumour site. The study, however, demonstrated that patients with incidental PE have a significant higher risk of recurrence and, as such, should receive standard anticoagulant therapy.3

 

Patient persistence on anticoagulant treatment for CAT

khorana siteThe objective of the second study was to evaluate current treatment patterns and patient persistence on anticoagulant treatment for CAT. Therefore, Khorana et al. identified 2,941 newly diagnosed cancer patients who developed VTE after their first cancer diagnosis and received anticoagulation in an ambulatory care setting. Depending on the first anticoagulant agent they received, patients were categorized into one of the following cohorts: LMWH (N=735; 25%), LMWH/warfarin (N=550; 18.7%), warfarin N=853; 29%), and rivaroxaban N=709; 24.1%). Mean age and gender were well balanced between treatment cohorts, as well as diagnosis for deep venous thrombosis (DVT) (55%), PE (27%), and DVT/PE (18%). Around 90% of patients had solid tumours. Patients with treatment for cancers associated with very high VTE risk (e.g. stomach, pancreas, and brain) ranged from 15% in LMWH to 6% in rivaroxaban cohorts, while patients with cancers associated with high VTE risk (e.g. lung, lymphoma, gynaecologic, bladder, testicular, and renal) ranged from 39% in LMWH to 30% in warfarin and LMWH/warfarin cohorts.

The median treatment duration in the LMWH, LMWH/warfarin, warfarin, and rivaroxaban cohort was 3.29, 7.76, 8.12, and 7.92 months, respectively. Kaplan-Meier estimates of persistence to initial treatment were 37%, 60%, 62%, and 61% at 6 months, and 21%, 37%, 34%, and 36% at 12 months for the LMWH, LMWH/warfarin, warfarin, and rivaroxaban cohorts, respectively. Patients on warfarin, LMWH/warfarin, and rivaroxaban were significantly more likely to remain on their initial therapy compared to patients on LMWH (HRs [95%CI]: 0.38 [0.32-0.45], 0.40 [0.34-0.46], and 0.42 [0.36-0.50], respectively. As such, the proportion of patients that switched to another anticoagulation treatment was highest in the LMWH cohort (22.9%) as compared to the LMWH/warfarin (8.9%), warfarin (7.3%), and rivaroxaban (4.7%) cohorts.

 

References

  1. Mandalà M, Falanga A, Roila F, et al. ESMO Guidelines Working Group Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011;22(suppl 6):vi85-92.
  2. Kearon C, Akl EA, Comerota AJ, et al. American College of Chest Physicians Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 suppl):419S-94.
  3. Louzada ML, Al-Ani F, Kovacs MJ, et al. Evaluating the need for anticoagulation beyond 6 months for patients with cancer-associated venous thromboembolism (VTE): a retrospect of real life (EXTEND study – updated results). Presented at ASH 2015, Abstract #2320.
  4. Khorana AA, McCrea K, Milentijevic D, et al. Current practice patterns and patient persistence on anticoagulant treatments for cancer-associated thrombosis. Presented at ASH 2015, Abstract #626.

Innohep site

 

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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.

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