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in a Different Vein

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

DOACs Versus Warfarin in Patients With Cancer and Atrial Fibrillation

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
Number of Events Person-Years Number of Events
Person-Years Rivaroxaban user ( n = 2,808 )
Matched warfarin user ( n = 5,673 )
HR ( 95 % CI )
p Value
Ischemic stroke
16
2,277
59
5,279
0.74 ( 0.40-1.39 )
0.35
Severe bleeding
68
2,245
181
5,207
1.09 ( 0.79-1.50 )
0.59
Other bleeding
50
2,213
177
5,031
0.79 ( 0.55-1.13 )
0.20
VTE *
124
2,046
472
3,903
0.51 ( 0.41-0.63 )
< 0.0001
Dabigatran user ( n = 2,189 )
Matched warfarin user ( n = 8,339 )
Ischemic stroke
26
3,310
127
10,878
0.89 ( 0.56-1.42 )
0.63
Severe bleeding
70
3,273
329
10,706
0.96 ( 0.72-1.27 )
0.75
Other bleeding
40
3,236
306
10,376
0.58 ( 0.41-0.84 )
0.003
VTE *
49
3,199
743
8,206
0.28 ( 0.21-0.38 )
< 0.0001
Apixaban user ( n = 1,078 )
Matched warfarin user ( n = 2,775 )
Ischemic stroke
4
550
18
1,773
0.71 ( 0.19-2.60 )
0.60
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
HR ( 95 % CI )
p Value
Dabigatran user ( n = 859 ) vs .
matched rivaroxaban user ( n = 922 )
Ischemic stroke
7.61 ( 1.52-38.12 )
0.01
Severe bleeding
1.07 ( 0.50-2.32 )
0.86
Other bleeding
0.81 ( 0.32-2.06 )
0.65
VTE *
0.47 ( 0.21-1.04 )
0.06
Apixaban user ( n = 1,126 ) vs .
matched rivaroxaban user ( n = 2,016 )
Ischemic stroke
0.52 ( 0.13-2.17 )
0.37
Severe bleeding
0.29 ( 0.13-0.65 )
0.002
Other bleeding
0.64 ( 0.28-1.49 )
0.30
VTE *
0.23 ( 0.12-0.47 )
< 0.0001
* Patients with prevalent VTE were excluded from the analysis . HRs = hazard ratios ; VTE = venous thromboembolism ; DOAC = direct oral anticoagulants
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CLINICAL NEWS in a Different Vein Research from ASH’s online peer-reviewed journal, Blood Advances DOACs Versus Warfarin in Patients With Cancer and Atrial Fibrillation Newer direct oral anticoagulants (DOACs) offer an effective alternative to warfarin that does not require monitoring, but these agents are often not recommended in pa- tients 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 pa- tients with cancer. They found that DOACs were superior to warfarin in preventing the development of incident venous thrombo- embolism (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. TABLE 1. 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 anti- coagulant 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 effec- tiveness between the agents, each DOAC- treated patient was matched with someone 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 malig- nancy, and patients were followed for a mean of 12 months after anticoagulant initiation. The investigators conducted head-to- head 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 sig- nificantly 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 bleed- ing were similar to those reported in warfa- rin 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 riva- roxaban, dabigatran, or apixaban all had significantly lower rates of VTE, compared with warfarin users (p<0.0001 for all). “Pre- vention of VTE was not the primary intent for use of anticoagulation in this population, HRs for Safety and Efficacy of Oral Anticoagulants Number of Events Person-Years Rivaroxaban user (n=2,808) Number of Events Person-Years Matched warfarin user (n=5,673) HR (95% CI) p Value Ischemic stroke 16 2,277 59 5,279 0.74 (0.40-1.39) 0.35 Severe bleeding 68 2,245 181 5,207 1.09 (0.79-1.50) 0.59 Other bleeding 50 2,213 177 5,031 0.79 (0.55-1.13) 0.20 VTE* 124 2,046 Dabigatran user (n=2,189) 472 3,903 0.51 (0.41-0.63) <0.0001 Matched warfarin user (n=8,339) 26 3,310 127 10,878 0.89 (0.56-1.42) 0.63 Severe bleeding 70 3,273 329 10,706 0.96 (0.72-1.27) 0.75 Other bleeding 40 3,236 306 10,376 0.58 (0.41-0.84) 0.003 VTE* 49 3,199 743 8,206 0.28 (0.21-0.38) <0.0001 Apixaban user (n=1,078) 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. Adjusted HRs of Selected Outcomes Comparing DOAC Use TABLE 2. HR (95% CI) p Value Dabigatran user (n=859) vs. matched rivaroxaban user (n=922) Ischemic stroke Ischemic stroke [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 preven- tion 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). 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