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Saturday 19 January 2019
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Perspectives for treating cancer-associated thrombosis

It is well known that patients with cancer-associated thrombosis (CAT) have a risk of both venous and arterial thrombotic complications, which exceeds by far that expected in the general population.1 These vascular complications prevail in patients with the most advanced stages of cancer, and are often life-threatening.1 Indeed, pulmonary embolism (PE) is the second most common cause of death in patients with CAT, soon after mortality induced by cancer itself.1 Although venous thromboembolism (VTE) is often triggered by identifiable risk factors (such as surgical operations, central or peripheral venous catheters, chemotherapy or long-standing immobilisation) either alone or in various combinations, VTE complications often arise spontaneously, making it virtually impossible to either predict or prevent their development.2
 

Conventional treatment

When VTE episodes develop in patients with cancer, they are often resistant to conventional treatment. It has, indeed, been shown conclusively that the rate of symptomatic recurrent VTE in CAT while on (even correct) treatment with vitamin K antagonists (VKA) exceeds that expected in patients without cancer by 3–4-times.3 Unfortunately, the rate of major bleeding complications increases as well, making increasing the intensity of VKA therapy unsuitable.3
 

Low-molecular weight heparins

A number of randomised clinical trials, performed in the last ten years, have conclusively demonstrated that the initial and long-term treatment of CAT with therapeutic or slightly sub-therapeutic subcutaneous doses of low-molecular weight heparins (LMWHs) is associated with a statistically significant and clinically relevant reduction in the risk of subsequent symptomatic recurrent VTE over VKA with a comparable risk of major bleeding.1,4–7 Their use, however, leads to a considerable burden for patients and a considerable cost for health care systems. 
 
They are, indeed, much more expensive than both the older and the novel oral anticoagulants, so that in many both European and non-European countries they are not reimbursed beyond the first weeks of therapy. Moreover, they are not free from inconveniences, including heparin-induced thrombocytopenia,8 which makes monitoring of the platelet count at least in the first two weeks mandatory, and the long-term development of osteoporosis and spontaneous fractures.9 Finally, the absolute rate or recurrent symptomatic VTE complications occurring while on LMWH therapy (ranging between 7% and 9% in the available randomised clinical trials) exceeds by far that observed in non-cancer patients (1.5–3%) while on conventional anticoagulant treatment.1,4–7
 
This risk has been reported to persist beyond the first six months of treatment, and has been found to be associated with an increasingly high risk of major bleeding complications.10,11 Interestingly enough, in a prospective cohort study dealing with the six-month observation of approximately 400 consecutive patients with active cancer and a recent episode of VTE who had been given therapeutic doses of LMWH, the cumulative incidence of heparin discontinuation because of either recurrent VTE or major bleeding was approximately 20% of all patients.12 In conclusion, LMWHs have become the treatment of choice for patients with CAT because of an evident superiority over VKA, but the benefit–risk profile of their administration is far from being optimal.  
     

Novel direct oral anticoagulants

Following the demonstration that in subgroups of patients of cancer the novel direct oral anticoagulants (DOAC) possess a favourablebenefit–risk profile in comparison to conventional anticoagulation for the treatment of acute VTE,13 the results of the first two head-to head comparisons between LMWH and DOAC have recently been published.14
 
In an open-label, randomised clinical trial addressing the non-inferiority of edoxaban (a novel inhibitor of factor Xa) compared with LMWH for the treatment of CAT, 1046 patients with active cancer and a recent episode of symptomatic or asymptomatic VTE were given at least five days of parenteral treatment with LMWH or fondaparinux, and were then randomised to receive either subcutaneous dalteparin (200IU/Kg for one month followed by 150IU/Kg) or oral edoxaban (60mg oid, halved in patients with moderate renal failure, low body weight or concomitant treatment with strong inhibitors of P-glycoprotein) for at least six months.14
 
The continuation of the treatment beyond the first six months was left to the discretion of the study operators. The main study outcome was the composite of recurrent symptomatic VTE and major bleeding complications (as assessed by an independent committee unaware of the study arm) occurring within 12 months of recruitment according to an intention-to-treat analysis (thus, irrespective of protocol violations and of drug discontinuation after the first six months). It is worth mentioning that patients randomised to edoxaban had, on average, one more month of anticoagulation compared with patients allocated to dalteparin. 
 
A similar proportion of patients allocated to the two study arms developed the main study outcome: 67/522 patients (13.8%) randomised to edoxaban and 71/524 (13.5%) allocated to dalteparin. Of interest, symptomatic recurrent VTE developed in 41 patients (7.9%) randomised to edoxaban and in 59 (11.3%) allocated to dalteparin; major bleeding complications developed in 36 (6.9%) and 21 (4.0%), respectively (not significant differences). Interestingly enough, severe bleeding complications (including fatal bleeding, intracranial, retroperitoneal or critical bleeding) developed in similar proportions (12 patients) in each of the two treatment groups. 
 
In addition, most major bleedings that developed in the edoxaban group were gastrointestinal bleedings in patients recruited because of gastrointestinal cancer. Also the rate of clinically symptomatic non-major bleeding was remarkably lower in patients treated with dalteparin (11.1%) than in those receiving edoxaban (14.6%). 
 
In a second smaller clinical trial,  approximately 400 patients with a recent (either symptomatic or asymptomatic) CAT were randomised to receive from the beginning (without an initial parenteral treatment) either subcutaneous dalteparin (same schedule as the Hokusai/K) or oral rivaroxaban (15mg tid for the first three weeks, followed by 20mg oid thereafter) for six months.15
 
The results of the Select/D study are consistent with those observed in the Hokusai/K. While the benefit–risk profile of the two drugs was found to be comparable, compared with dalteparin, rivaroxaban was associated with a remarkable reduction in the rate of symptomatic recurrent VTE (3.9% compared with 8.9%), and a substantial increase in the rate of major (5.4% vs 3.0%) as well as non-major clinically relevant (12.3% vs 3.0%) bleedings. Once again, the rate of severe bleeding was low in each of the study groups; and what accounted for the difference in the rate of major bleedings between edoxaban and dalteparin most was the occurrence of gastrointestinal bleedings in those cancer patients with gastrointestinal cancers who had been allocated to the edoxaban group.
 

Conclusions

According to the findings of the first two head-to-head comparisons between LMWH and the DOACs for the treatment of CAT, the following conclusions can be drawn: 1) the benefit–risk profile of the two drugs categories is comparable. As the novel drugs are less expensive and result in a considerable reduction in the burden and inconveniences for patients compared with LMWHs, their use in place of heparins is fully justified; 2) at least in patients who fulfil the recruitment criteria of the two clinical trials, the novel drugs are likely to be more effective; 3) they are associated with a higher haemorrhagic risk, particularly in patients with gastrointestinal cancer. 
 
In these patients, their use should be discouraged, as well as in patients who have problems with intake and absorption of oral drugs. Anyway, the risk of the most severe bleeding complications does not seem to differ between the two drug categories. In conclusion, an outstanding achievement has been obtained for the treatment of CAT, particularly desirable for patients who may require months or years of anticoagulation. 
 

References

1 Carrier M, Prandoni P. Controversies in the management of cancer-associated thrombosis. Expert Rev Hematol 2017;10:15–22.
2 Prandoni P et al. Cancer and venous thromboembolism. Lancet Oncol 2005;6:401–10.
3 Prandoni P et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484–8.
4 Meyer G et al. Comparison of low molecular weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: A randomized controlled study. Arch Intern Med 2002;162:1729–35.
5 Lee AY et al. Low-molecular weight heparin versus a coumarin for the prevention of venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146–53.
6 Hull RD et al. Long term low-molecular weight heparin versus usual care in proximal vein thrombosis in patients with cancer. Am J Med 2006;119:1062–72.
7 Lee AY et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015;314:677–86.
8 Salter BS et al. Heparin-induced thrombocytopenia: a comprehensive clinical review. J Am Coll Cardiol 2016;67:2519–32.
9 Gajic-Veljanoski O et al. Effects of long-term low-molecular-weight heparin on fractures and bone density in non-pregnant adults: a systematic review with meta-analysis. J Gen Intern Med 2016;31:947–57.
10 Francis CW et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost 2015;13:1028–35.
11 Jara-Palomares L et al. Tinzaparin in cancer associated thrombosis beyond 6months: TiCAT study. Thromb Res 2017;157:90–6.
12 van der Wall SJ et al. Continuation of low-molecular-weight heparin treatment for cancer-related venous thromboembolism: a prospective cohort study in daily clinical practice. J Thromb Haemost 2017;15:74–9.
13 Vedovati MC et al. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest 2015;147:475–83.
14 Raskob GE et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615–24.
15 Young AM et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol 2018; 36:2017–23.

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