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Thromboembolic disease treatment during cancer therapy


KEY POINTS

  • Active cancer increases the risk of venous thromboembolism (VTE) by four-fold without chemotherapy and seven-fold with chemotherapy

  • The likelihood of developing VTE is highest during the first 3 months after the cancer diagnosis and the majority of thrombotic events occur within the first year

  • Management of cancer-associated VTE is challenging because these patients are at risk of both thrombotic and bleeding events

  • Risk of anticoagulation failure (i.e., VTE recurrence despite anticoagulation) is highest with warfarin at 2.5% per month or 16% at 6 months

  • Low-molecular-weight heparin (LMWH, dalteparin) has been shown to have superior efficacy compared with warfarin with similar major bleeding rates

  • Compared with LMWH (dalteparin), the direct oral anticoagulants (DOACs) have similar (edoxaban) or improved (rivaroxaban, apixaban) efficacy rates. Major bleeding and clinically relevant nonmajor bleeding remain important considerations for DOAC therapy

  • Treatment should continue for as long as the cancer disease process is deemed active, a minimum 6 months

As outlined in Chapter 9 , patients with cancer face an increased risk of venous thromboembolism (VTE), which is attributable to a combination of cancer-specific prothrombotic activity, complications of cancer-directed therapy (e.g., hormonal therapy, chemotherapy, targeted agents or radiotherapy, surgery, or hospital confinement), or the use of chronic indwelling central venous catheters for chemotherapy administration. The risk is highest in the first months to a year after diagnosis ( Fig. 18.1 ). Once diagnosed, the management of VTE in patients with active cancer can be challenging given their increased propensity for both recurrent VTEs as well as major bleeding. The risk of recurrence relates to the persistence of risk factors, at least in part ( Chapter 30 ). An increased risk of anticoagulant-associated major bleeding may result from hepatic dysfunction (primary liver cancer, liver metastasis, hepatic injury owing to chemotherapy), kidney injury, thrombocytopenia, tumor friability, or supratherapeutic international normalized ratio (INR) while on a vitamin K antagonist owing to malnutrition, vomiting, or medication-interactions. Balancing efficacy and safety can be challenging and adds complexity to the treatment of these patients.

FIG 18.1
Cancer Associated Venous Thromboembolism Management.

(From Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med . 2006;166(4):458–464.)

Treatment trials

A number of important treatment trials of cancer-associated VTE have been conducted ( Table 18.1 ). The initial trials compared warfarin with low-molecular- weight heparin (LMWH). The Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) trial remains the landmark cancer VTE treatment trial, which formed the basis for current treatment guidelines and against which all contemporary trials are compared. , Subsequent trials have compared the direct oral anticoagulants (DOACs) with LMWH and will be discussed separately.

TABLE 18.1
Trials for VTE Treatment in Patients With Cancer
TRIAL SIZE DESIGN DRUG COMPARATOR FOLLOW-UP DURATION PRIMARY OUTCOMES
CLOT 672 Randomized, open label Dalteparin 200 IU/kg/day × 30 day then 150 IU/kg/day Dalteparin-coumarin 6 months

  • Dalteparin resulted in lower recurrent VTE rates (9% vs. 17%)

  • Similar major bleeding (6% vs. 4%)

  • Similar mortality (39% vs. 41%)

French Cooperate Group 146 Randomized, open label Enoxaparin 1.5 mg/kg/day Enoxaparin-warfarin 3 months

  • Trial terminated prematurely owing to slow enrollment

  • Similar recurrent VTE and major bleeding composite endpoint (10.5% vs. 21.1%)

  • Similar major bleeding (7% vs. 16%)

  • Similar mortality (11.3% vs. 22.7%)

ONCENOX 122 Randomized, open label Group 1a Enoxaparin 1.0 mg/kg twice daily for 5 days then 1.0 mg/kg once daily
Group 1b Enoxaparin 1.0 mg/kg twice daily for 5 days then 1.5 mg/kg once daily		 Enoxaparin-warfarin 6 months

  • VTE recurrence was similar across three groups: Group 1a (6.9%), Group 1b (6.3%), warfarin (10%)

  • Major bleeding rates were similar: Group 1a (6.5%), Group 1b (11.1%), warfarin (2.9%)

  • Mortality rates were similar: Group 1a (22.6%), Group 1b (41.7%), warfarin (32.4%)

  • Statistical differences between groups were limited by small sample sizes.

LITE 200 Randomized, open label Tinzaparin 175 IU/kg/day continued for 3 months Unfractionated heparin/warfarin continued for 3 months Treatment: 3 months
Surveillance: 12 months

  • At 3 months, VTE recurrence rates were similar (6% vs. 10%).

  • At 12 months, fewer patients on LMWH had a VTE recurrence (7% vs. 16%)

  • Similar major bleeding (7% vs. 7%)

  • Similar mortality at 3 months (20% vs. 19%) and at 12 months (47% vs. 47%)

CATCH 900 Randomized, open label Tinzaparin 175 IU/kg/day Tinzaparin-warfarin 6 months

  • VTE recurrence was borderline lower in tinzaparin arm (7.2% vs. 10.5%).

  • Symptomatic DVT were less frequent with tinzaparin (2.7% vs. 5.3%).

  • PE rates were similar (4.5% vs. 4.5%).

  • Major bleeding rates were similar (2.7% vs. 2.4%).

  • Similar mortality rates (23.4% vs. 20.6%)

Hokusai VTE Cancer 1050 Randomized, open label LMWH × 5 days then edoxaban 60 mg daily Dalteparin 200 IU/kg/day × 30 days then 150 IU/kg/day 6–12 months

  • Composite of VTE recurrence or major bleeding at 12 months was noninferior (12.8% vs. 13.5%).

  • Recurrent VTE was similar (7.9% vs. 11.3%).

  • Major bleeding was higher for edoxaban arm (6.9% vs. 4.0%).

  • Death rates were similar (39.5% vs. 36.6%).

SELECT-D 406 Randomized, open label Rivaroxaban 15 mg twice daily for 21 days then 20 mg daily Dalteparin 200 IU/kg/day × 30 days then 150 IU/kg/day 6 months

  • Recurrent VTE was lower for rivaroxaban (4% vs. 11%).

  • Major bleeding was similar (6% vs. 4%).

  • Death rates were similar (25% vs. 30%).

ADAM VTE 300 Randomized, open label Apixaban 10 mg twice daily for 7 days then 5 mg twice daily Dalteparin 200 IU/kg/day × 30 days then 150 IU/kg/day 6 months

  • Major bleeding was similar between arms (0% vs. 1.4%).

  • Recurrent VTE was lower for the apixaban arm (0.7% vs. 6.3%).

  • Death rates were similar (16% vs. 11%).

CARAVAGGIO 1155 Randomized, open label Apixaban 10 mg twice daily for 7 days then 5 mg twice daily Dalteparin 200 IU/kg/day × 30 days then 150 IU/kg/day 6 months

  • Recurrent VTE was noninferior for apixaban arm (5.6% vs. 7.9%).

  • Major bleeding was similar between arms (3.8% vs. 4.0%).

  • Death rates were similar (24.3% vs. 26.4%).

Vedovati 595 Meta-analysis of DOAC VTE trials limited to patients with cancer Apixaban (n = 81) Heparin/warfarin 6 months

  • VTE rates were similar (3.7% vs. 6.4%).

  • Major bleeding rates were similar (2.3% vs. 5.0%).

Dabigatran (n = 173)

  • VTE rates were similar (5.7% vs. 7.4%).

  • Major bleeding rates were similar (3.8% vs. 4.6%).

Edoxaban (n = 109)

  • VTE rates were similar (3.7% vs. 7.0%).

  • Major bleeding rates were similar (4.6% vs. 3.0%).

Rivaroxaban (n = 232)

  • VTE rates were similar (2.6% vs. 4.0%).

  • Major bleeding rates were similar (2.6% vs. 4.1%).

DVT , Deep venous thrombosis; LMWH , Low-molecular-weight heparin; PE , pulmonary embolism; VTE , venous thromboembolism.

Low-molecular-weight heparin compared with warfarin

The CLOT trial randomized 672 patients with active cancer and acute proximal deep vein thrombosis (popliteal or more proximal), pulmonary embolism, or both to receive either LMWH (dalteparin 200 IU/kg/day for 1 month followed by 150 IU/kg/day for 5 months) or dalteparin transitioned to adjusted dose warfarin. Active cancer was defined as cancer diagnosed within 6 months of enrollment, any cancer treatment within the past 6 months, or recurrent or metastatic disease. After a trial duration of 6 months, symptomatic recurrent venous thromboembolism occurred in 9% in the dalteparin group compared with 17% in the warfarin group (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.30 to 0.77; P = .002). No differences were found in major bleeding rates (dalteparin 6% vs. warfarin 4%) or overall mortality (dalteparin 39% vs. warfarin 41%; P = .53). A subsequent post hoc analysis revealed a survival benefit at 12 months among patients with cancer without metastasis receiving dalteparin compared with warfarin (mortality: dalteparin 20% vs. warfarin 36%; HR, 0.50; 95% CI, 0.27 to 0.95; P = .03). The survival benefit was not apparent for those patients with metastatic disease (dalteparin 72% vs. warfarin 69%; HR, 1.1; 95% CI, 0.87 to 1.4; P = .46).

The CATCH trial randomized 900 patients with cancer who had acute symptomatic leg deep venous thrombosis (DVT) or pulmonary embolism (PE) to receive either tinzaparin (175 IU/kg once daily) or tinzaparin transitioned to warfarin for 6 months. The primary composite endpoint was symptomatic DVT recurrence, PE, or incidental VTE. Of the recruited patients, 55% had known metastasis and 42% were receiving active systemic therapy. During the 6 months of treatment, VTE recurrence was similar in the tinzaparin (7.2%) compared with the warfarin group (10.5%; HR, 0.65, P = .07 ). Major bleeding did not differ between treatment groups (tinzaparin 2.7% vs. warfarin 2.4%; HR, 0.89; P = .77). Clinically relevant nonmajor bleeding rates favored tinzaparin therapy (10.9% vs. 15.3%; P = .004). Mortality rates were similar for both treatment arms (tinzaparin 34.7% vs. warfarin 32.2%). The most frequent cause of death was cancer progression. Fatal pulmonary embolism occurred in 3.8% of each group and fatal bleeding in one warfarin treated patient.

Apart from these two trials, a number of smaller negative trials have compared LMWH with warfarin, including a French Cooperate Group, the ONCENOX pilot, and the Long-term Innovations in TreatmEnt (LITE) trial (see Table 18.1 )

Based primarily on the CLOT trial, treatment guidelines had recommended a preference for LMWH, both for initial therapy during the first three months (grade 2B) and for extended therapy beyond three months (grade 2C) regardless of bleeding risk. Anticoagulants are continued until no evidence exists of active malignancy, defined as any evidence of cancer on cross-sectional imaging or any cancer-related treatment (surgery, radiation, or chemotherapy) within the preceding six months.

Low-molecular-weight heparin limitations

Chronic subcutaneous LMWH therapy has several disadvantages. First, these injections may be painful and cause considerable local ecchymoses and hematomas. Second, for individuals without insurance, the cost may be prohibitive, particularly given the extended nature of treatment. Third, thrombocytopenia, which may frequently accompany cancer or cancer treatment, may limit its use. Thrombocytopenia in the setting of heparin therapy may also raise concerns for heparin-induced thrombocytopenia. A history of heparin-induced thrombocytopenia precludes the use of this medication. Fourth, protamine is an imperfect antidote for LMWH therapy if the patient develops major bleeding complications. Fifth, renal impairment, which is not infrequent among patients with cancer, may limit the use of LMWH. For these combined reasons, an alternative anticoagulation therapy for patients with cancer associated VTE would be extremely attractive.

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