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CLINICAL NEWS

Written in Blood

Rivaroxaban and other direct oral anticoagulants are used as an alternative to warfarin for the prevention of thromboembolism , but data do not support routine use of rivaroxaban for patients with antiphospholipid syndrome ( APS ). In an article published in Blood , investigators examined the safety and efficacy of rivaroxaban in a population of patients with APS who are at high risk of thrombotic events , reporting that the agent showed no benefit , but excess risk , over warfarin .

“ APS is an acquired autoimmune disease characterized by the association of thromboembolic events or pregnancy morbidity [ with ] the presence of antiphospholipid antibodies ,” explained the authors , led by Vittorio Pengo , MD , of the University of Padua in Italy .

This prospective , randomized , phase III trial included 120 adult patients with high-risk , “ triplepositive ” APS , who tested positive for the presence of all three antibodies defining an APS diagnosis ( lupus anticoagulant , anti-cardiolipin , and anti-ß2- glycoprotein I ) and , thus , “ are at highest risk of both a first thrombotic event and of a higher rate of recurrence despite antithrombotic treatment ,” the researchers noted .

Following complete blood count measurements , renal and liver function assessments , and standard coagulation tests at the screening visit , participants with a creatinine clearance ( CrCl ) of > 50 ml / min were randomized to either once-daily rivaroxaban at a dose of 20 mg ( n = 57 ) or warfarin with an international normalized ratio ( INR ) target of 2.5 ( n = 61 ). Patients with a CrCl of 30 to 50 ml / min received once-daily rivaroxaban at a dose of 15 mg ( n = 2 ).

Baseline characteristics were similar between the

TABLE . Efficacy and Safety Outcomes

Composite endpoint

Rivaroxaban N = 59

As-Treated Analysis

Warfarin N = 61

11 ( 19 %) 2 ( 3 %) rivaroxaban and warfarin groups ( median age = 46.5 and 46.1 years ; median platelet counts = 214.9 × 10 9 / L and 209.3 × 10 9 / L , respectively ; ranges not reported ). Eleven patients in the rivaroxaban group ( 19 %) and 14 in the warfarin group ( 23 %) had an arterial thrombotic event prior to enrollment .

Follow-up visits occurred at one month and three months following randomization , and at sixmonth intervals thereafter . The primary outcome was composed of the cumulative incidence of the following :

• thromboembolic adverse events

• major bleeding

• vascular death

Trial enrollment began on November 2 , 2014 , and the study was terminated prematurely because of an excess of events among rivaroxaban-treated patients . At that point , all patients discontinued the study drug and switched to a non-vitamin K antagonist .

The mean follow-up period in the “ as-treated ” cohort ( which excluded 9 rivaroxaban-treated and 3 warfarin-treated patients who discontinued before an endpoint event was recorded ) was 569 days , and 611 days in the entire intention-to-treat ( ITT ) cohort .

Overall , 13 events were reported during followup in the as-treated population , and the composite primary outcome of thromboembolic events , major bleeding , and vascular death occurred in 11 patients in the rivaroxaban group and two patients in the warfarin group . The risk of composite endpoint was

Hazard ratio ( 95 % CI ; p Value )

6.7 ( 1.5-30.5 ; 0.01 )

Rivaroxaban N = 59

Intention-to-Treat Analysis

Warfarin N = 61

13 ( 22 %) 2 ( 3 %) nearly seven times greater in the rivaroxaban group , the authors reported ( hazard ratio [ HR ] = 6.7 ; 95 % CI 1.5-30.5 ; p = 0.01 ).

A similar increased risk of primary outcome was observed in the ITT analysis ( TABLE ). “ Thromboembolic events , all in the arterial circulation , mainly drove the unbalance in the cumulative primary endpoint ,” the authors wrote . “ Thus , rivaroxaban apparently does not protect high-risk patients from arterial events .”

Rivaroxaban also was associated with a greater incidence of other adverse events , including four patients with ischemic stroke ( IS ; 7 %) and three patients with myocardial infarction ( MI ; 5 %). No patients in the warfarin group experienced either IS or MI .

No significant differences were observed between the two groups in the number of major bleeding cases ( 4 vs . 2 , respectively ; HR = 2.5 ; 95 % CI 0.5-13.6 ; p = 0.03 ). In five of six bleeding events , the episode was associated with predisposing factors , including uterine fibroid , anal fissure , Crohn disease , and thrombocytopenia , the researchers noted .

“ Based on our data , and the absence of [ other ] data , rivaroxaban and the other novel oral anticoagulants should not be used in thrombotic high-risk APS patients ,” Dr . Pengo told ASH Clinical News . “ The results of our trial should raise the awareness among health-care personnel about the lack of efficacy of rivaroxaban in [ patients with ] high-risk , triple-positive APS and may be relevant for the other trials testing direct anticoagulants in this setting .” The study ’ s findings are limited by the trial ’ s premature discontinuation , and , the authors noted , these results cannot be translated to people without a “ triple-positive ” APS . “ At present , the one therapeutic strategy in patients with a laboratory profile different from that of this study should be considered

Hazard ratio ( 95 % CI ; p Value )

7.4 ( 1.7-32.9 ; p = 0.008 )

on a case-by-case basis , taking into account the presence of additional risk factors for venous and arterial thrombosis , the nature of venous thromboembolism ( provoked or unprovoked ), and the risk of bleeding ,” they concluded .

The authors reported no conflicts of interest .

REFERENCE

Pengo V , Denas G , Zoppellaro G , et al . Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome . Blood . 2018 July 12 . [ Epub ahead of print ]

PERSPECTIVES

“ Some patients with APS are difficult to manage with warfarin because their lupus inhibitor interferes with INR measurements . This can make warfarin ineffective , increasing the risk of bleeding or thrombosis . In these situations , clinicians consider using direct oral anticoagulants , but we don ’ t have clinical trial results yet that support the use of rivaroxaban or other agents for APS treatment , so informed discussion with patients is needed if this is performed . Given these findings , I would advise an addon , moderate-intensity statin if a direct oral anticoagulant was chosen for patients with non – triple-positive APS who have a 10-year atherosclerotic cardiovascular disease risk of ≥7.5 percent , or an even lower threshold . Hematologists should also consider hydroxychloroquine , an add-on therapy to anticoagulation that is directed at the autoimmune component , as a treatment option for patients with APS .”

Mary Cushman , MD , MSc The University of Vermont Medical Center

Burlington , VT

34 ASH Clinical News September 2018