Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial

Abstract

Background

New oral anticoagulants may simplify long-term therapy in conditions requiring anticoagulation. Rivaroxaban is a direct factor Xa inhibitor that has been extensively studied and is now approved for the prevention and therapy of a number of thromboembolic conditions.

Objective and methods

This is a multicentre, randomized, open-label, study that will evaluate if Rivaroxaban 20 mg od (or 15 mg od in patients with moderate renal insufficiency) is non-inferior to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and death in high risk (triple positive) patients with antiphospholipid syndrome. Secondary endpoints will assess the incidence of any individual component of the composite end point. An external adjudication committee will evaluate all suspected outcome events. This will be a unique trial, as it will enrol the biggest homogenous cohort of high risk APS individuals.

Conclusion

The methods and the study design should be appropriate to achieve study results that are both scientifically valid and relevant to clinical practice.

Keywords

APS rivaroxaban antiphospholipid syndrome trial warfarin

Introduction

Antiphospholipid syndrome (APS) is an acquired autoimmune disease characterized by thrombosis-related clinical disorders or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL).¹ APS has a high socio-economic burden: it affects young individuals, causing thrombosis in virtually every organ, and leads often to pregnancy loss. Clinical features of APS are commonly encountered in clinical practice, thus the diagnosis of APS is totally based on laboratory findings exploring the presence of antiphospholipid antibodies (Lupus anticoagulant (LA), anti-cardiolipin (aCL) antibodies and anti-ß2-Glycoprotein I (aß2GPI) antibodies).² Patients at highest risk for thrombosis and recurrence are those displaying triple positivity (triple-aPL patients) in the laboratory tests.^3–9 Oral anticoagulant therapy significantly reduces thromboembolic recurrences in thrombotic APS.⁹ The mainstay of anticoagulation therapy in APS are vitamin K antagonists, the management of which is challenging. The narrow therapeutic window makes strict monitoring the key to successful therapy particularly in patients with APS, to avoid treatment failure. In one study,¹⁰ half of the recurrences in APS patients occurred when INR was below therapeutic range. Major bleeding is also a concern among APS patients, with an annual occurrence of 1.5%–2%.^10,11 An oral anticoagulant that requires no monitoring and has a predictable anticoagulant effect would be of great interest, given the characteristics of APS patients. The new oral anticoagulant rivaroxaban, an inhibitor of factor Xa, is at least as effective as warfarin in preventing venous¹² and arterial thromboembolism,^13,14 and displays an even safer profile, significantly reducing cerebral bleeding.¹³ With its once a day administration it improves compliance.

The Trial on Rivaroxaban in Thrombotic Antiphospholipid Syndrome (TRAPS) is a phase III randomized trial (ClinicalTrials.gov Identifier: NCT02157272) which will assess the safety and efficacy of rivaroxaban compared with the usual care.

Study objectives and hypothesis

The primary objective is to demonstrate the non-inferiority of rivaroxaban 20 mg (or 15 mg in cases of moderate renal insufficiency) versus warfarin (INR 2.0–3.0) in the prevention of acute thrombosis (arterial or venous), major bleeding and death in triple aPL-positive APS patients. The secondary and additional objectives are listed in Table 1.

Table 1

Detailed summary of the secondary objectives of the TRAPS trial

Secondary objectives
Any thromboembolic event, such as deep vein thrombosis, pulmonary embolism, intracerebral thrombosis, retinal thrombosis, peripheral- or mesenteric-artery thrombosis, small vessel thrombosis, acute myocardial infarction, stroke/TIA
Major bleeding, defined as: • fatal (causing death), and/or • clinically overt bleeding associated with a fall in hemoglobin level of ≥20 g/L in 24 hours, and/or requiring non-planned transfusion of ≥2 units of packed red blood cells or whole blood • in a critical area or organ, e.g. intracranial bleeding (documented by imaging), retroperitoneal bleeding, intraspinal bleeding, intraocular bleeding causing blindness, pericardial bleeding, joint hemorrhage or need for surgery or angiographic intervention to stop hemorrhage
Minor bleeding, defined as any bleeding event not matching the criteria for major bleeding, with the exclusion of irrelevant bleeding such as conjunctival hemorrhage or small bruising
All-cause mortality
Compliance with treatment (comparing the number of doses remaining in a container with the number of doses that should remain)

Study design

Overview

This is a multicentre, randomized, controlled, open-label, non-inferiority study. The protocol was reviewed and approved by the Institutional Review Board at each centre. The study is coordinated by a steering management committee. An adjudication committee, whose members are unaware of treatment allocation, reviews all suspected episodes of recurrent thromboembolism, bleeding and death.

Patient population and eligibility

Adult patients with confirmed diagnosis of APS and triple positivity for aPL are eligible for this study. Inclusion and exclusion criteria are listed in Table 2.

Table 2

Inclusion and exclusion criteria

Inclusion criteria	Exclusion criteria
Signed and dated informed consent form	Severe hypersensitivity reaction to rivaroxaban
Male or female of age 18–75	Calculated CLCR <30 mL/min at the screening visit
Triple aPL-positivity^a in the last blood sampling defined as: • aCL IgG/M (≥40 GPL or MPL, medium-to-high titer, and/or greater than the 99th percentile) and • aB2GPI IgG/M (≥40 U, medium-to-high titer, and/or greater than the 99th percentile) and • LA test positive based on the International Society of Thrombosis and Hemostasis Recommendations	Current pregnancy or breast feeding. Pregnancy is highly discouraged in these patients and if programmed patients are excluded from the study. If sexually active, be practicing an effective method of birth control (e.g. intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study
Triple positivity confirmation at the central reference laboratory (Padua Thrombosis Centre)	Concomitant treatment with other anticoagulants, such as unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin, etc.) heparin derivatives (fondaparinux), other oral anticoagulants (dabigatran etexilate, apixaban) in the case they cannot be substituted with the study drugs
History of thrombosis (objectively proven arterial, venous, and/or biopsy proven microthrombosis) With or without pregnancy morbidity according to Miyakis criteria	Patients taking interfering medications: pharmacologic interactions may occur with strong inhibitors of p-glycoprotein and of CYP3A4, e.g. azole-antimycotics, such as ketoconazole, itraconazole, voriconazole, posaconazole, and HIV protease inhibitors; coadministration of rivaroxaban is therefore contraindicated in these cases. Several drugs used in neurological patients, such as phenobarbital, phenytoin, carbamazepine, and St John's wort (hypericum), are p-glycoprotein inducers and should be avoided. Whenever possible, it would be better to use levetiracetam and topiramate as antiepileptic therapy.
	Hemorrhage risk-related criteria • History of or condition associated with increased bleeding risk including, but not limited to: • Major surgical procedure or trauma within 30 days before the randomization visit • Clinically significant gastrointestinal bleeding within six months before the randomization visit • History of intracranial, intraocular, spinal or atraumatic intra-articular bleeding • Chronic hemorrhagic disorder • Known intracranial neoplasm, arteriovenous malformation or aneurysm • Planned invasive procedure with potential for uncontrolled bleeding. • Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg
	Known liver cirrhosis or ALT above three times the upper normal value.

Positivity of aCL and abeta2GPI must be of the same isotype

Stratification and randomization

In each of the participating institutions, after obtaining written informed consent, all potential patients will be screened before enrolment in the study. The screening visit includes patient’s confirmation of triple laboratory positivity for aPL (i.e. positivity for LAC, aCL and B2GPI) and confirmed diagnosis of thrombotic APS. Moreover, a series of laboratory tests are performed during the screening visit. These include complete blood count, renal and liver function and standard coagulation tests. Randomization and study data will be collected and managed using REDCap (Research Electronic Data Capture)¹⁵ electronic data capture tools hosted at the Department of Cardiac Thoracic and Vascular Sciences, Padua University Hospital. Randomization will extend over a two-year period. The investigator will enter the screening information into the web-based management system, which randomly assigns the patient to warfarin or rivaroxaban, with a 1:1 allocation using random block sizes of two, four and six, and stratified on the basis of gender and the presence/absence of previous diagnosis of an autoimmune disease. When in warfarin, patients will be switched to rivaroxaban when INR is below 3.

Rivaroxaban regimen and rationale

Rivaroxaban is a direct oral factor Xa inhibitor with a high oral bioavailability (≥80%) and predictable pharmacokinetics and pharmacodynamics, that does not require routine coagulation monitoring. It has a fast on–off anticoagulation effect and is associated with few drug–drug or drug–food interactions.¹⁶ Rivaroxaban is approved for the treatment of DVT/PE and secondary prevention of VTE. This approval is backed by the results of the EINSTEIN phase III clinical programme that investigated the use of rivaroxaban as a single-drug approach in contrast to the current dual-drug paradigm of enoxaparin/VKAs.^12,17 In EINSTEIN DVT, not only rivaroxaban was shown to be non-inferior to enoxaparin/VKA, but also was associated with a reduction in major bleeding (EINSTEIN PE) and a significantly improved net clinical benefit. Rivaroxaban is also approved for primary and secondary stroke prevention^13,18 in nonvalvular atrial fibrillation. The ROCKET-AF trial showed non-inferiority to VKA treatment, and there were significantly fewer intracranial bleeds.¹³

Based on these results, rivaroxaban 20 mg once daily was approved for the treatment of all patients with Cockroft–Gault determined creatinine clearance (CrCl) >50 ml/min. For CrCl of 30–50 ml/min rivaroxaban 15 mg should be administered.

Warfarin regimen

Warfarin is the mainstay of therapy for the prevention of thromboembolism (arterial or venous) in APS.¹⁹ The real challenge is to maintain the appropriate anticoagulation intensity. Based on a retrospective study, higher intensity anticoagulation (target INR of 3.5) was initially considered.²⁰ However, two subsequent prospective randomized trials^10,11 have demonstrated that high-intensity was not superior to moderate-intensity anticoagulation (target INR 2.5). Thus, currently APS patients are treated with moderate intensity anticoagulation, and these patients will be included in the TRAPS trial. The initial warfarin dose is determined using the protocol²¹ endorsed by the Italian Federation of Anticoagulation Clinics (FCSA). The subsequent warfarin doses are adjusted to maintain the INR within the range of 2.0–3.0, aiming for a target of 2.5. INR is checked at least every four weeks, or more frequently if needed, at the investigator's discretion.

Duration of study treatment

End of treatment is set after four years from the start of the trial, or when 88 events have occurred. Every effort will be made to avoid loss of follow up to patients. Study treatment may be temporarily stopped if clinically needed, and anticoagulation will be managed according to published guidelines.^16,22 The treatment will be resumed as soon as possible, when deemed clinically appropriate.

In the case of study drug discontinuation, follow-up, including assessment of any clinical event, will be pursued. The reasons for premature discontinuation of investigational products will be recorded. The use of aspirin is allowed according to physician discretion, in both arms.

Primary outcomes

The primary efficacy outcome will be the cumulative incidence of a first thromboembolic event (arterial or venous, confirmed by appropriate imaging studies), major bleeding, or death. The definitions are provided in Table 3.

Table 3

Detailed summary of the primary outcomes of the TRAPS trial

Events included in the primary efficacy outcome
Venous thromboembolism diagnosed by: • Compression ultrasonography or venography in the case of deep vein thrombosis • Spiral tomography, ventilation-perfusion lung scan or pulmonary angiography in case of pulmonary embolism
Cerebral sinus venous thrombosis assessed by computed tomographic scanning, magnetic resonance imaging, or angiography
Retinal thrombosis diagnosed by ophthalmologic examination
Peripheral- or mesenteric-artery thrombosis documented by arteriography or at the surgery table
Small vessel thrombosis evaluated by appropriate imaging study or histopathology in the absence of inflammation in the vessel wall
Acute myocardial infarction diagnosed in the presence of a typical clinical presentation associated to typical electrocardiographic features and elevated cardiac damage markers (CK-MB or Troponins I or T)
Stroke/TIA diagnosed according to standard definitions (TIA is considered for analysis only if cerebral imaging confirmed cerebral ischemia)
Major bleeding is defined as: • Fatal bleeding, causing death • Clinically overt bleeding associated with a fall in hemoglobin level of ≥20 g/L in 24 hours, and/or requiring non-planned transfusion of ≥2 units of packed red blood cells or whole blood • A critical area or organ bleeding, as intracranial bleeding (documented by imaging), retroperitoneal bleeding, intraocular bleeding causing blindness, joint hemorrhage, or need for surgery or angiographic intervention to stop hemorrhage
Minor bleeding defined as any bleeding event not matching the criteria for major bleeding with the exclusion of irrelevant bleeding as conjunctival hemorrhage or small bruising
Vascular death, the causes are obtained from clinical or autopsy reports and/or death certificates

Secondary outcomes

The secondary outcomes are divided into efficacy and safety endpoints. The secondary efficacy endpoint will be any single type of thromboembolic event taken separately and all causes of mortality. The secondary safety outcome will be major bleeding; minor bleeding will also be assessed as a secondary endpoint. The definitions of the outcomes are provided in Table 3.

Assessment of outcomes and follow-up

All patients will have regularly-scheduled hospital visits at one and three months after enrollment, and every six months thereafter. Extra visits will occur in the event of thromboembolic events or major bleeding. Compliance and vital signs will be checked by phone contact every three months until the end of treatment. Hospital visits will check CrCl (every six months), liver function, complete blood count, PT-INR, adverse events, compliance with the treatment and incidence of end-points, and will re-supply medication. The trough determination of anti Xa activity in rivaroxaban group will be performed at steady state in each patient.

Sample size and statistical analysis

The primary analysis was designed to test whether rivaroxaban is non-inferior to warfarin. The non-inferiority margin is set to correspond to the preservation of 50% of the warfarin effect, as adopted in the other rivaroxaban registration trials. The non-inferiority margin is derived from the only observational study considering VKAs versus control in triple positive APS patients.⁹ This study suggests a rate of composite events (thrombosis, major bleeding and death) among APS patients receiving warfarin of approximating 6% per year. On the other hand, the incidence of events in untreated patients is 13%per year. The hazard ratio margin corresponding to preservation of 50% of the warfarin effect is 1.7. To satisfy the non-inferiority hypothesis, the upper bound of the one-sided 95% confidence interval for the hazard ratio of an outcome with rivaroxaban as compared to warfarin must fall below 1.7. A non-inferiority log-rank test with an overall 88 events and sample size of 536 subjects (268 in the reference group and 268 in the treatment group) achieves 80% power at a 0.05 one tail significance level to detect an equivalence hazard ratio of 1.7. The study will last four years, with recruitment limited to the first two years and follow up extended to four years.

Discussion

Most if not all studies in APS patients have included patients with different laboratory profiles, providing cohorts of poor homogeneity.^10,11,20,23 The present trial promises to be the biggest trial assessing a homogenous cohort of APS patients. Triple positive APS patients are at high risk of recurrent thromboembolic events⁹ with a stable aPL pattern.²⁴ Patients with APS receive indefinite anticoagulation based on VKAs. Given the characteristics of APS, patients an alternative to VKAs that is safe, effective and does not require monitoring would be of great benefit.

To this end, rivaroxaban has been approved for the prevention and treatment of DVT and PE, with an excellent efficacy profile. On the other hand it was non-inferior to warfarin in the setting of stroke prevention in non-valvular atrial fibrillation in patients at high thromboembolic risk (CHADSVASc > 3). It was also approved for the secondary prevention of acute coronary syndrome.¹⁴ Under these premises, rivaroxaban should be a suitable agent for the prevention of thrombotic recurrences in APS.

In conclusion, TRAPS will be the biggest randomized controlled trial assessing the efficacy and safety of a novel anticoagulant, rivaroxaban, in the setting of APS. It will include a laboratory homogenous cohort of high-risk APS patients. The results from this study may indicate the standard care and improve our understanding on APS.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Miyakis

Lockshin

Atsumi

. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306.

Pierangeli

de Groot

Dlott

. ‘Criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010. Lupus 2011; 20: 182–190.

Lee

. Does the anti-beta2-glycoprotein I antibody provide additional information in patients with thrombosis? Thromb Res 2003; 111: 29–32.

Pengo

Biasiolo

Pegoraro

Cucchini

Noventa

Iliceto

. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 2005; 93: 1147–1152.

Sailer

Zoghlami

Kurz

. Anti-beta2-glycoprotein I antibodies are associated with pregnancy loss in women with the lupus anticoagulant. Thromb Haemost 2006; 95: 796–801.

Zoghlami-Rintelen

Vormittag

Sailer

. The presence of IgG antibodies against beta2-glycoprotein I predicts the risk of thrombosis in patients with the lupus anticoagulant. J Thromb Haemost 2005; 3: 1160–1165.

Ruffatti

Tonello

Cavazzana

Bagatella

Pengo

. Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy. Thromb Res 2009; 123: 482–287.

Pengo

Ruffatti

Tonello

. Antiphospholipid syndrome: Antibodies to Domain 1 of beta2-glycoprotein 1 correctly classify patients at risk. J Thromb Haemost 2015; 13: 782–787.

Pengo

Ruffatti

Legnani

. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010; 8: 237–242.

10.

Crowther

Ginsberg

Julian

. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. New Engl J Med 2003; 349: 1133–1138.

11.

Finazzi

Marchioli

Brancaccio

. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 2005; 3: 848–853.

12.

Investigators

Bauersachs

Berkowitz

. Oral rivaroxaban for symptomatic venous thromboembolism. New Engl J Med 2010; 363: 2499–2510.

13.

Patel

Mahaffey

Garg

. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 2011; 365: 883–891.

14.

Mega

Braunwald

Wiviott

. Rivaroxaban in patients with a recent acute coronary syndrome. New Engl J Med 2012; 366: 9–19.

15.

Harris

Taylor

Thielke

Payne

Gonzalez

Conde

. Research electronic data capture (REDCap) – a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Informatics 2009; 42: 377–381.

16.

Heidbuchel

Verhamme

Alings

. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094–2106.

17.

Investigators

E-P

Buller

Prins

. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. New Engl J Med 2012; 366: 1287–1297.

18.

Hankey

Patel

Stevens

. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol 2012; 11: 315–322.

19.

Ruiz-Irastorza

Cuadrado

Ruiz-Arruza

. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011; 20: 206–218.

20.

Khamashta

Cuadrado

Mujic

Taub

Hunt

Hughes

. The management of thrombosis in the antiphospholipid-antibody syndrome. New Engl J Med 1995; 332: 993–997.

21.

Pengo

Biasiolo

Pegoraro

. A simple scheme to initiate oral anticoagulant treatment in outpatients with nonrheumatic atrial fibrillation. Am J Cardiol 2001; 88: 1214–1216.

22.

Pengo

Cucchini

Denas

. Standardized low-molecular-weight heparin bridging regimen in outpatients on oral anticoagulants undergoing invasive procedure or surgery: an inception cohort management study. Circulation 2009; 119: 2920–2927.

23.

Levine

Brey

Tilley

. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 2004; 291: 576–584.

24.

Pengo

Ruffatti

Del Ross

. Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile. J Thromb Haemost 2013; 11: 1527–1531.