New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients

Figures & data

Table 1 Principal pharmacokinetic properties of rivaroxaban, apixaban, and dabigatran

	Bioavailability	Elimination	Onset of anticoagulation after the first dose	Duration of anticoagulation after the last dose	ttPeak	Peak	Elimination half-life
Rivaroxaban	90%	66% renal 28% intestinal/fecal hepatic	Within 30 minutes	24 hours	2–4 hours	50–500 ng/mL	7–11 hours Young: 5–9 hours Elderly: 9–13 hours
Apixaban	50%–60%	30% renal 50% intestinal	Within 30 minutes	24–36 hours	1–3 hours	40–120 ng/mL	8–12 hours when administered twice daily 12–15 when administered once daily
Dabigatran	7%	80% renal (40% in active form and 40% in the form of metabolites) 20% biliary	Within 30 minutes	12 hours	2 hours	200–400 ng/mL	9–13 hours after a single dose 12–17 hours after multiple doses

Abbreviation: ttPeak, time to Peak.

Table 2 Main drug interactions and contraindications of the new antithrombotic agents

	Drug interactions	Contraindications
Rivaroxaban	Increase of active concentration in plasma Inhibitors of CYP3A4 cytochrome subunit • Azoles (antifungal drugs): ketoconazole, itraconazole, voriconazole, posaconazole, except fluconazole • Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor: citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, zimelidine • HIV protease inhibitors (ie, ritonavir)	Cautious administration if creatinine clearance is 15–30 mL/min. Absolute contraindication if creatinine clearance is <15 mL/min. Avoid using rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy. Co-administration with ketoconazole.
Apixaban	Inhibitors of P-glycoprotein • Diltiazem, rifampicin amiodarone, quinidine, macrolides (clarithromycin, erythromycin, and azithromycin), phenytoin, ranolazine, phenobarbital, dronedarone, felodipine, St John’s wort, cyclosporine, lapatinib, nilotinib, sunitinib, imatinib, tamoxifen, taxol Decrease of active concentration in plasma Inducers of CYP3A4 • Dexamethasone • Inducers of P-glycoprotein • Dexamethasone, doxorubicin, vinblastine, verapamil	Cautious administration if creatinine clearance is 15–30 mL/min. Absolute contraindication if creatinine clearance is <15 mL/min. Possibly safe in patients with liver impairment as no hepatic metabolism but caution is advised. Co-administration with ketoconazole, itraconazole, lopinavir/ritonavir, indinavir/ritonavir, and conivaptan. Avoid concomitant use of rivaroxaban and apixaban with drugs that are combined P-glycoprotein and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, and St John’s wort).
Dabigatran	Inhibitors of P-glycoprotein rifampicin amiodarone, quinidine, clarithromycin, verapamil, macrolides (clarithromycin), phenytoin, phenobarbital, St John’s wort Minor interactions with atorvastatin	Lower dose if creatinine clearance is 15–30 mL/min. Contraindication if creatinine clearance <30 mL/min.

Abbreviation: min, minute.

Table 3 Efficacy and safety of new antithrombotic agents in thromboprophylaxis in acutely ill medical patients – focus on subgroups with cancer

Randomized controlled trial	Experimental design	n	Subgroup of cancer patients	Primary efficacy endpoint in total population	Primary efficacy endpoint in cancer subgroup	Primary safety endpoint in total population	Primary safety endpoint in cancer
MAGELLAN^Citation25,Citation26	VTE prophylaxis in acutely ill medical patients. Rivaroxaban 10 mg ×35 days versus enoxaparin 4,000 anti-Xa IU od sc for 10 days followed by placebo until day 35. Routine ultrasonography of the legs on day 10 and day 35.	Rivaroxaban =3,977 Enoxaparin/placebo =4,001	Rivaroxaban =7% Enoxaparin/placebo =7%	In 10 days Rivaroxaban =2.7% Enoxaparin =2.7% P=0.0025 for non-inferiority In 35 days Rivaroxaban =4.4% Enoxaparin/placebo =5.7% P=0.02 for superiority 77% RRR	In 35 days Rivaroxaban =9.9% Enoxaparin =7.4% P=0.074	In 10 days Rivaroxaban =3.4% Enoxaparin =1.5% P<0.05 In 10–35 days Rivaroxaban =1.9% Enoxaparin/placebo =0.6% P<0.05	In 35 days Rivaroxaban =5.4% Enoxaparin =1.7%
ADOPT^Citation27	VTE prophylaxis in acutely ill medical patients. Apixaban 2.5 mg twice-daily for 35 days versus enoxaparin 4,000 anti-Xa IU od sc for 6–14 days followed by placebo until day 35. Routine compression ultrasound examination was performed at the time of discharge and at day 30.	Apixaban =2,211 Enoxaparin =2,211	History of cancer Apixaban =9.6% Enoxaparin =9.8% Active cancer Apixaban =3.5% Enoxaparin =3% Remote cancer Apixaban =6.1% Enoxaparin =6.8%	Apixaban =2.7% Enoxaparin =3% P=0.44	The results of the primary efficacy outcome were consistent in the prespecified subgroup of cancer patients	Apixaban =0.47% Enoxaparin =0.19% P=0.04	The authors did not mention any significant difference in the rate of primary safety endpoint in the subgroup of patients with cancer

Abbreviations: IU, international units; FXa, activated factor Xa; od, once daily; RRR, relative risk ratio; sc, subcutaneously; VTE, venous thromboembolism.

Table 4 Efficacy and safety of NOACs in the treatment of VTE in patients with active cancer

Randomized controlled trial	Experimental design	n	Subgroup of patients with active cancer	Primary efficacy endpoint in total population	Primary efficacy endpoint in cancer subgroup	Primary safety endpoint in total population	Primary safety endpoint in cancer
EINSTEIN acute DVT^Citation29	Treatment of symptomatic DVT Rivaroxaban 15 mg bid ×3 weeks and then 20 mg od versus enoxaparin 1 mg/kg bid sc/VKA for 6 months. Total duration of treatment 3, 6, or 12 months.	Rivaroxaban =1,731 Enoxaparin/VKA =1,718	Rivaroxaban =6.8% Enoxaparin/VKA =5.2%	Rivaroxaban =2.1% Enoxaparin/VKA =3% P>0.05	Rivaroxaban =3.4% Enoxaparin/VKA =5.6% P>0.05	Rivaroxaban =8.1% Enoxaparin/VKA =8.1% P>0.05	Rivaroxaban =14.4% Enoxaparin/VKA =15.9% P>0.05
EINSTEIN DVT extension^Citation29	Rivaroxaban 20 mg od versus placebo. Duration more than 6 months after completing the first phase of treatment.	Rivaroxaban =602 Placebo =594	Rivaroxaban =4.5% Placebo =4.4%	Rivaroxaban =1.3% Placebo =7.1%	Rivaroxaban =2.1% Enoxaparin/VKA =1.8% P>0.05	Rivaroxaban =0.7% Placebo =0% (P=0.11)	Rivaroxaban =12.3% Enoxaparin/VKA =9.3% P>0.05
EINSTEIN-PE^Citation30	Treatment of symptomatic PE Rivaroxaban 15 mg bid ×3 weeks and then 20 mg od versus enoxaparin 1 mg/kg bid sc/VKA for 6 months. Total duration of treatment 3, 6, or 12 months.	Rivaroxaban =2,419 Enoxaparin/VKA =2,413	Rivaroxaban =4.7% Enoxaparin/VKA =4.5%	Rivaroxaban =2.1% Enoxaparin/VKA =1.8% P=0.003 for a one-sided non-inferiority margin of 2.0 and P=0.57 for superiority	No difference on efficacy outcome is reported for the subgroup of cancer patients as compared with the total population	Rivaroxaban =10.3% Enoxaparin/VKA =11.4%	No difference on efficacy outcome is mentioned for the subgroup of cancer patients as compared with the total population
AMPLIFY^Citation32	Treatment of symptomatic VTE. Apixaban 10 mg bid for 7 days and then 5 mg bid for 6 months versus enoxaparin 1 mg/kg bid sc/VKA for 6 months.	Apixaban =2,609 Enoxaparin/VKA =2,635	Apixaban =2.5% Enoxaparin/VKA =2.5%	Apixaban =2.3% Enoxaparin/VKA =2.7% P>0.05	No data	Apixaban =4.3% Enoxaparin/VKA =9.7% P<0.001	No data
AMPLIFY-extension^Citation33	Secondary prevention of recurrent VTE after having completed the first phase of treatment. Apixaban 2.5 mg bid; apixaban 5 mg bid versus placebo. Duration of treatment =12 months.	Placebo =829 2.5 mg apixaban =840 5 mg apixaban =813	Placebo =2.2% 2.5 mg apixaban =1.8% 5 mg apixaban =1.1%	Placebo =8.8% 2.5 mg apixaban =1.7% 5 mg apixaban =1.7% P<0.001 for both comparisons	No data	Major bleeding Placebo =0.5% 2.5 mg apixaban =0.2% 5 mg apixaban =0.1% Clinically relevant non-major bleeding Placebo =2.3% 2.5 mg apixaban =3% 5 mg apixaban =4.2%	No data
RE-COVER^Citation34	Treatment of symptomatic acute proximal DVT or PE, in patients who were initially given parenteral anticoagulant therapy. Dabigatran 150 mg bid versus dose-adjusted warfarin INR 2–3. Duration of treatment 6 months.	Dabigatran =1,274 Warfarin =1,265	Dabigatran =5% Warfarin =4.5%	Dabigatran =2.4% Warfarin =2.1% P<0.001 for non-inferiority	No data	Total population Dabigatran =1.6% Warfarin =1.9% Discontinuation of treatment Dabigatran =9% Warfarin =6.8% P=0.05
RE-COVER II^Citation35	Replica study to confirm the results of RE-COVER	Dabigatran =1,279 Warfarin =1,289			Dabigatran =2.4% Warfarin =2.2%	Dabigatran = 14.5% major or clinically relevant bleeding events warfarin = 13.2% major or clinically relevant bleeding events P>0.05	ACS events were less than 1% in the trial, with more cases in the dabigatran treatment group than those treated with warfarin.

Abbreviations: ACS, acute coronary syndrome; bid,twice daily; DVT, deep vein thrombosis; INR, international normalized ratio; NOAC, new orally active anticoagulant; od, once daily; PE, pulmonary embolism; sc, subcutaneously; VKA, vitamin K antagonists; VTE, venous thromboembolism.

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