CLINICAL NEWS

Research from ASH ’ s online peer-reviewed journal , Blood Advances

Newer direct oral anticoagulants ( DOACs ) offer an effective alternative to warfarin that does not require monitoring , but these agents are often not recommended in patients with cancer because of limited data in this population .

In a study published in Blood Advances , researchers analyzed a large health-care claims database to determine if there is an advantage of DOACs over warfarin for patients with cancer . They found that DOACs were superior to warfarin in preventing the development of incident venous thromboembolism ( VTE ), but rates of bleeding and stroke differed according to the type of anticoagulant .

“ Based on our findings , all of the DOACs appear to be safe , compared with warfarin from the standpoint of rate of severe bleeding ,” wrote lead author Surbhi Shah , MBBS , of the Department of Medicine at the University of Minnesota Medical School in Minneapolis , and co-authors . “ Our data give some reassurance to clinicians that a DOAC may be a reasonable option for patients [ with cancer ] who need anticoagulation for [ whom ] warfarin or low-molecular-weight heparin may not be suitable .”

The researchers used two Truven Health MarketScan databases – the Commercial Claims and Encounters database and the Medicare Supplemental and Coordination of Benefits database – to identify adults with cancer and non-valvular atrial fibrillation ( AF ) who initiated anticoagulation between January 1 , 2010 , and December 31 , 2014 .

Participants were included if they had at least one inpatient or two outpatient claims for non-valvular AF seven to 365 days apart ; at least one prescription for warfarin , rivaroxaban , dabigatran , or apixaban after the first AF claim ; and 90 or more days of continuous enrollment prior to first oral anticoagulant prescription . All patients were also required to be actively receiving cancer treatment when anticoagulation was started ( defined as chemotherapy , radiation therapy , or cancer surgery within 6 months prior to anticoagulation ).

A total of 16,096 people were included and categorized according to the first anticoagulant prescribed after AF diagnosis :

• rivaroxaban ( n = 2,808 ; mean age = 73.8 years )

• dabigatran ( n = 2,189 ; mean age = 74.0 years )

• apixaban ( n = 1,078 ; mean age = 74.9 years )

• warfarin ( n = 10,021 ; mean age = 75.4 years )

Edoxaban was not approved by the U . S . Food and Drug Administration at the start of the study , so it was not included in the analysis .

Patients were allowed to switch between different anticoagulants . To compare effectiveness between the agents , each DOACtreated patient was matched with someone

TABLE 1 . HRs for Safety and Efficacy of Oral Anticoagulants

Severe bleeding 10 551 84 1,744 0.37 ( 0.17-0.79 ) 0.01 Other bleeding 9 538 72 1,699 0.58 ( 0.25-1.31 ) 0.19 VTE * 7 540 218 1,325 0.14 ( 0.07-0.32 ) < 0.0001

* Patients with prevalent VTE were excluded from the analysis . HRs = hazard ratios ; VTE = venous thromboembolism receiving warfarin based on age (± 3 years ), sex , and enrollment date (± 90 days ).

Compared with DOAC users , patients receiving warfarin were slightly older ( mean = 75.4 vs . 74.0 years ) and appeared to have a higher stroke risk ( per CHA 2

DS 2

-VASc score ; mean = 4.6 vs . 4.2 ; p value not provided ). Breast cancer was the most common malignancy , and patients were followed for a mean of 12 months after anticoagulant initiation .

The investigators conducted head-tohead comparisons of severe bleeding risk ( primary endpoint ) and VTE and ischemic stroke risk ( secondary endpoints ) for each DOAC versus warfarin . They reported that all newer agents were associated with a significantly lower risk of VTE ( p < 0.00001 ), but the risks of bleeding varied when the DOACs were compared with warfarin ( see TABLE 1 ). In the rivaroxaban and dabigatran groups ( after mean follow-up of 11 and 16 months , respectively ), rates of severe bleeding were similar to those reported in warfarin users , while apixaban users experienced significantly lower rates of severe bleeding ( p < 0.01 ). Because apixaban was approved in December 2012 , mean follow-up in this cohort was only six months , the authors noted . Rates of ischemic stroke were similar across all types of anticoagulation .

However , patients who received rivaroxaban , dabigatran , or apixaban all had significantly lower rates of VTE , compared with warfarin users ( p < 0.0001 for all ). “ Prevention of VTE was not the primary intent for use of anticoagulation in this population ,

[ but ] all DOACs were associated with 50 to 85 percent reductions in the rate of incident VTE , compared with warfarin in our study population ,” the authors wrote . Better prevention of the development of VTE , they added , “ carries major implications in the morbidity and mortality of [ patients with ] cancer .”

The researchers then conducted a head-to-head comparison of each DOAC ( see TABLE 2 ). Dabigatran was associated with a higher rate of ischemic stroke than rivaroxaban ( p = 0.01 ); this finding , though , was based on just 12 events , the authors noted ( 3 in the rivaroxaban cohort and 9 in the dabigatran cohort ). Dabigatran users appeared to have lower rates of VTE than rivaroxaban users , although this association was not significant . Apixaban users had significantly lower rates of both VTE and severe bleeding , compared with rivaroxaban users ( p < 0.0001 and p < 0.002 , respectively ). Despite limited data on the safety of DOAC use in this patient population , this study shows “ widespread ” use of these agents .

“ Until results of randomized , controlled trials specifically designed to look at the safety and efficacy of DOACs in cancer patients are available , clinicians have to rely on robust observational data ,” the authors concluded . “ If use of DOACs among patients [ with cancer ], as compared with warfarin , does really reduce the rate of incident VTE and / or bleeding events , [ increased ] use of DOACs would have a clinically significant impact on morbidity and mortality of cancer patients .”

The study is limited by its retrospective design , reliance on claims-based data , small number of patients in some cohorts , and limited duration of follow-up . ●

The authors report no financial conflicts .

REFERENCE

Shah S , Norby FL , Datta YH , et al . Comparative effectiveness of direct oral anticoagulants and warfarin in patients with cancer and atrial fibrillation . Blood Advances . 2018 February 13 .

TABLE 2 . Adjusted HRs of Selected Outcomes Comparing DOAC Use

* Patients with prevalent VTE were excluded from the analysis . HRs = hazard ratios ; VTE = venous thromboembolism ; DOAC = direct oral anticoagulants

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