HHE 2018 | Page 102

Pending the results of ongoing , randomised controlled trials , NOACs might be considered as an alternative to LMWHs for the treatment of CAT in patients without gastrointestinal or urogenital cancer

HOKUSAI Cancer HOKUSAI Cancer was an open-label , noninferiority trial that randomised 1050 patients with CAT to LMWH for at least five days followed by oral edoxaban 60mg once daily or dalteparin 200IU / kg daily , for one month followed by 150 IU / kg daily during months 2 – 12 . 18 Study drug was given for at least 6 and up to 12 months and all patients were followed for 12 months . The primary outcome was a composite of recurrent VTE or major bleeding during 12 months after randomisation and occurred in 12.8 % of the patients allocated to receive edoxaban and in 13.5 % of those who were randomised to dalteparin ( HR 0.97 ; 95 % CI 0.70−1.36 ). Recurrent VTE occurred in 7.9 % of patients who were receiving edoxaban and in 11.3 % of those allocated to dalteparin ( difference in risk −3.4 %; 95 % CI −7.0−0.2 ). Major bleeding occurred in 6.9 % of the patients in the edoxaban arm and in 4.0 % of patients randomised to receive dalteparin ( difference in risk 2.9 %; 95 % CI 0.1−5.6 ). Most of the difference in major bleeding was related to gastrointestinal and urogenital bleeding and the increase in the risk of major bleeding was especially high in gastrointestinal cancers . The median duration of the assigned treatment was 211 days in the edoxaban group and 184 days in the dalteparin group ( p = 0.01 ); more patients in the dalteparin group stopped trial medication because of inconvenience of dosing . Trial medication was to be continued for at least six months . During this period , the primary outcome of recurrent VTE or major bleeding occurred in 10.5 % and 10.7 % in patients who were receiving edoxaban and dalteparin , respectively ( hazard ratio ( HR ) 1.01 ; 95 % CI 0.69−1.46 ). 18

Select-D Select-D was a prospective , randomised , open label trial comparing dalteparin ( 200IU / kg daily , during the first month , followed by 150IU / kg daily , during months two to six ); and rivaroxaban ( 15mg twice daily for three weeks followed by 20mg once daily , for six months ) in 406 patients with cancer and VTE . The VTE recurrence rate at six months was 11 % ( 95 % CI 7−17 %) for patients on dalteparin and 4 % ( 95 % CI 2−9 %) for patients on rivaroxaban ( HR 0.43 ; 95 % CI 0.19−0.99 ). Major bleeding occurred in 4 % ( 95 % CI 2−8 %) of the patients in the dalteparin and 6 % ( 95 % CI 3−11 %) in the patients allocated to rivaroxaban ( HR 1.83 ;

95 % CI 0.68−4.96 ). Corresponding rates of CRNMB were 4 % ( 95 % CI 2−9 %) and 13 % ( 95 % CI 9−19 %), respectively ( HR 3.76 ; 95 % CI 1.63−8.69 ). 19 There were more clinically relevant non-major bleedings in the rivaroxaban arm ( 13 %; 95 % CI 9−19 %) than in the dalteparin arm ( 2 %; 95 % CI 1−6 %). In total , 5 % ( 95 % CI 3−9 %) of patients in the dalteparin arm had either major or non-major clinically significant bleeding as compared to 17 % ( 95 % CI 12−22 %) of the patients in the rivaroxaban arm . 19 A meta-analysis of these two studies concluded that NOACs are associated with a lower risk of recurrent VTE than LMWH at six months ( RR 0.65 ; 95 % CI 0.42−1.01 ) but are associated with a higher risk of major bleeding ( RR 1.74 ; 95 % CI 1.05−2.88 ) and a higher risk of clinically relevant non-major bleeding than LMWH ( RR 2.31 ; 95 % CI 0.85−6.28 ). 15

The current data regarding the effectiveness of NOACS in patients with CAT remain limited . The comparison with VKA in the Phase III trials is reassuring but the patients included in these studies had less aggressive or less extensive cancer than those included in the LMWH trials . Data from observational cohort studies are limited by the lack of adequate control groups and the lack of blinded adjudication of outcomes , in these studies , a selection bias favouring NOACs cannot be excluded . The lower rate of recurrent VTE with NOACS suggested in these observational cohort studies seems to be confirmed in the two first randomised trials comparing NOACs with LMWH in patients with CAT , although the difference was not significant in either of the two studies . Conversely , an increase in the bleeding risk has been observed in the two trials in the patients who were randomised to receive a NOAC . These results , observed with rivaroxaban and edoxaban , remain to be confirmed for dabigatran and apixaban .

Conclusions Several ongoing randomised controlled trials will probably shed more light on the role of NOACs in patients with CAT . Pending the results of these trials , NOACs might be considered as an alternative to LMWH for the treatment of CAT in patients without gastrointestinal or urogenital cancer and who do not have an increased bleeding risk . NOACs may also be considered as an option in patients who do not tolerate the daily injections of LMWH and in patients who need prolonged anticoagulant treatment after six months of treatment with LMWH .