J Thromb Thrombolysis DOI 10.1007/s11239-014-1064-7
Design of the rivaroxaban for heparin-induced thrombocytopenia study Lori-Ann Linkins • Theodore E. Warkentin • Menaka Pai • Sudeep Shivakumar Rizwan A. Manji • Philip S. Wells • Mark A. Crowther
•
Ó Springer Science+Business Media New York 2014
Abstract Rivaroxaban is an ideal potential candidate for treatment of heparin-induced thrombocytopenia (HIT) because it is administered orally by fixed dosing, requires no laboratory monitoring and is effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study evaluating the incidence of new symptomatic venous and arterial thromboembolism in patients with suspected or confirmed HIT who are treated with rivaroxaban. Methodological challenges faced in the design of this study include heterogeneity of the patient population, differences in the baseline risk of thrombosis and bleeding dependent on whether HIT is confirmed or just suspected, and heterogeneity in laboratory confirmation of HIT. The rationale for how these challenges were addressed and the final design of the Rivaroxaban for HIT study is reviewed.
Electronic supplementary material The online version of this article (doi:10.1007/s11239-014-1064-7) contains supplementary material, which is available to authorized users. L.-A. Linkins (&) Department of Medicine, McMaster University, 1280 Main Street West, Juravinski Hospital Site, Rm A3-74, Hamilton, ON L8S 4K1, Canada e-mail: [email protected] T. E. Warkentin M. Pai M. A. Crowther Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada T. E. Warkentin M. Pai M. A. Crowther Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
Keywords Heparin-induced thrombocytopenia Rivaroxaban Study design Clinical trial
Introduction Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction caused by heparin-dependent, platelet-activating IgG antibodies that recognize multimolecular complexes of a cationic ‘‘self’’ protein (platelet factor 4, PF4) when complexed with anionic heparin [1–4].The result of this reaction is platelet activation associated with increased thrombin generation in vivo, which in 50–75 % of patients with serologically-confirmed HIT, is associated with venous and/or arterial thromboembolism [1, 2, 4]. Once HIT is strongly suspected, it is not sufficient simply to discontinue heparin [due to a high thrombotic event rate (TER)] and/or start warfarin (due to the risk of precipitating microthrombosis including venous limb gangrene). To prevent HIT-related thrombotic complications, S. Shivakumar Department of Medicine, Dalhousie University, Halifax, NS, Canada R. A. Manji Cardiac Sciences Program, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada P. S. Wells Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
M. Pai Hamilton Regional Laboratory Medicine Program, McMaster University, Hamilton, ON, Canada
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L.-A. Linkins et al. Table 1 Comparison of anticoagulants in the treatment of HIT Property
Indirect AT-dependent inhibitors (danaparoid, fondaparinux)
Direct thrombin inhibitors (argatroban, bivalirudin, desirudin)
Direct factor Xa inhibitor (rivaroxaban)
Route of administration
Parenteral
Parenteral
Oral
Half-life
Danaparoid: 25h
\2 h
5–9 h
Fondaparinux: 17h Yes
Argatroban: no
Yes
Prophylactic dosing available
a
Bivalirudin: no Desirudin: yes Monitoring
Direct (anti-factor Xa level)
Effect on INR
b
Indirect (PTT): risk for systematic DTI underdosing with underlying coagulopathy (e.g., HIT-associated DIC)
Direct (anti-factor Xa level)b
No significant effect
Increases INR (especially argatroband)
Minimal effecte
Efficacy and safety established for non-HIT indications
Yes
Not established for most non-HIT settings
Yes
Inhibition of clot-bound thrombin or factor Xa
No effect
Inhibition of both free and clot-bound thrombin
Inhibition of both free and clot-bound factor Xa
Cross-reactivity with HIT antibodies
Danaparoid: yesc
No
No
Fondaparinux: yesc Clearance
Renal
Argatroban: hepatobiliary
Renal (66 %)
Bivalirudin: enzymatic (80 %), renal (20 %)
Hepatobiliary (33 %)
Desirudin: renal Antidote available Cost
No $$
No $$$
No $
AT antithrombin, h hours, DIC disseminated intravascular coagulation, DTI direct thrombin inhibitor, PTT partial thromboplastin time, INR international normalized ratio a
Although therapeutic dosing is recommended for HIT, availability of prophylactic-dose regimens increases flexibility when managing potential non-HIT situations (e.g., patients without thrombosis judged to have a low probability of HIT) b Not available at all centres, but anticoagulant monitoring is usually not required c
Considered to be of limited clinical importance
d
Venous limb gangrene during DTI-argatroban warfarin overlap has been reported, a risk that likely is greater with argatroban because it increases the INR and thus poses risk of ‘‘PT (INR) confounding’’
e
Rivaroxaban can be continued long-term without conversion to warfarin; in contrast, parenterally-administered DTIs generally cannot be given in outpatients, thus mandating transition to warfarin—the requirement for DTI—warfarin overlap to begin only after platelet count recovery means that hospitalization is prolonged by at least 5 days compared with simple discharge on continuing oral rivaroxaban
it is appropriate that a non-heparin anticoagulant—usually in therapeutic doses—be started promptly. The initial risk of thrombosis in a patient with serologically-confirmed HIT who does not receive alternative non-heparin anticoagulation is estimated at 5 % per day [4–6]. Unfortunately, the agents approved in many countries for treatment of HIT (e.g. lepirudin, argatroban, danaparoid) are parenteral, costly, and require intensive laboratory coagulation monitoring. Availability can also be a limiting factor (lepirudin, danaparoid). Moreover, even ‘‘simple’’ anticoagulant monitoring—e.g., activated partial thromboplastin time (aPTT)-adjusted dosing of argatroban therapy—can lead to treatment failure; underlying
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abnormalities in the aPTT due to HIT-associated coagulopathy may confound monitoring, resulting in inappropriate dose interruption or reduction [7, 8]. Because of the short half-lives of the approved direct thrombin inhibitors (DTI), inappropriate dose interruption/reduction can quickly lead to subtherapeutic dosing, and failure of therapy. Although the problems of aPTT confounding and short anticoagulant half-life are avoided by fondaparinux, this agent remains ‘‘off-label’’ for the treatment of HIT, is also parenteral, costly, and its clearance is 100 % dependent on renal function [9]. Rivaroxaban, one of the new oral anticoagulants, is an ideal candidate for treatment of HIT for several reasons
Heparin-induced thrombocytopenia study
(Table 1). It is given as a fixed dose, requires no laboratory coagulation monitoring, has a longer half-life than the parenteral DTI (5–9 vs. \1 h), and its efficacy in the treatment of venous and arterial thromboembolism has been established in large randomized controlled trials [10– 13]. Furthermore, unlike fondaparinux and danaparoid, rivaroxaban does not cross-react with HIT antibodies [14, 15] and it is capable of inhibiting clot bound factor Xa [16]. However, designing a clinical trial to evaluate rivaroxaban as a new treatment option for HIT poses a unique set of methodological challenges. In this review, we outline these challenges and discuss how they will be addressed in the Rivaroxaban for HIT study. We will also review the study protocol and expected results.
Methodological challenges Heterogeneity in patients: HIT incidence and presentation There is significant heterogeneity in the incidence of HIT according to patient population. Thrombocytopenia, in general, is relatively common, particularly in certain groups such as post cardiac surgery patients and intensive care unit (ICU) patients [17]. Studies have shown that for every one patient who is confirmed to have HIT, 10–20 patients are suspected to have HIT (with a varying degree of clinical suspicion) [18]. The frequency of HIT varies significantly according to the patient type and duration of heparin therapy; HIT occurs in as few as 0.1 % of patients given heparin for \5 days, and as many as 1–5 % of medical and orthopaedic surgical patients, respectively, given unfractionated heparin for at least 10 days [19]. The result is that when we consider all patients with suspected HIT, there is a wide variation in baseline risk for thrombosis and bleeding. Patients with thrombocytopenia due to HIT require high doses of anticoagulant therapy to prevent thrombosis since their thrombotic risk far outweighs their bleeding risk, whereas patients with thrombocytopenia due to other causes should receive low doses (or no anticoagulation at all) as their bleeding risk likely outweighs their thrombotic risk. This heterogeneity of risk poses a clinical challenge, as all patients with a moderate or high clinical suspicion for HIT should receive preventative treatment. A large proportion of this group of patients will not ultimately have HIT, but will still be exposed to high dose anticoagulant therapy while the result of the HIT assay is pending (a process that may take several days). The presentation of HIT is also very heterogeneous. For example, HIT patients may or may not have thrombosis at the time of study entry (HIT vs. HITT), and the types of thrombosis vary widely, ranging from common thrombi involving veins (DVT, PE), to less common thrombi
involving arteries (limb [ cerebral [ coronary), to rare thrombi (e.g., adrenal vein thrombosis leading to hemorrhagic infarction; cerebral vein dural sinus thrombosis). Indeed, the very strong association between HIT and thrombosis (RR = 12.0, 95 % CI 7.0–20.6; P \ 0.0001) [20] means that if a patient with unexpected thrombocytopenia has new thrombosis, it is much more suggestive of HIT than if a patient with thrombocytopenia does not have new thrombosis. The clinical heterogeneity of thrombosis means that while some patients will require urgent surgical interventions (e.g., arterial thromboembolectomy), others may require simple anticoagulation (e.g., DVT, PE). Due to these patient heterogeneity issues, it is difficult to come up with a practical study design to evaluate a new drug for HIT. From a methodological perspective, the ideal HIT study would be a randomized trial comparing rivaroxaban with one of the approved treatments of HIT. However, this study design is also impractical as illustrated by the recently terminated PREVENT–HIT trial. PREVENT-HIT was an open-label randomized controlled trial comparing twice-daily fixed-dose desirudin with argatroban to prevent or treat thrombosis in patients with suspected HIT [21]. The sample size was 120 patients, but the study was terminated after just 16 patients were enrolled over 14 months. The investigators identified issues with patient selection, choice of argatroban as the control group and inadequate research support at clinical centres as major obstacles to the success of their trial [22]. Heterogeneity in laboratory confirmation of HIT Heterogeneity of laboratory tests for HIT also poses a challenge to testing a new drug for HIT. There is currently no standardization of laboratory testing for HIT. A survey of specialized coagulation laboratories in North America identified eight different assays, and wide discrepancies in practice between centres using the same assay [23]. The platelet serotonin-release assay (SRA) is considered a reference standard assay for HIT [24]. The SRA is a functional assay that only detects antibodies of IgG class that recognize the relevant antigen(s) on PF4, and are capable of supporting activation of platelets [25]. The problem with the SRA is that it is only available at a few centres; it requires identification of suitable platelet donors, utilizes a radiolabeled analyte (14C-serotonin), and involves several platelet ‘‘washing’’ steps. This makes the SRA a technically more difficult test when compared with the commercially-available antigen assays. Most centres that have a laboratory test for HIT use some form of antigen assay to detect the presence of HIT antibodies. However, this test has limited utility, as only a small proportion of patients who form HIT antibodies (seroconversion) will develop clinical HIT [26].
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Consequently, a significant proportion of patients diagnosed with HIT based on an antigen assay will thus not truly have HIT (false positives). Over-diagnosis of HIT is a major problem, because it can lead to inappropriate withdrawal of heparin and exposes patients to the complications associated with approved treatments for HIT [27, 28].
Ways to address the methodological challenges To address patient heterogeneity and to accurately reflect the real-world dilemma of waiting for the result of a HIT assay to be reported, the Rivaroxaban for HIT study will enrol patients across the clinical spectrum for suspected or confirmed HIT and will use the same initial dose for patients with and without thrombosis until HIT is excluded. Suspected HIT is defined as clinical suspicion of HIT without laboratory confirmation of the presence of HIT antibodies (i.e., result still pending). Confirmed HIT is defined as clinical suspicion of HIT with presence of HIT antibodies confirmed using a local laboratory assay. The dose of rivaroxaban will not be adjusted for the degree of thrombocytopenia; however, in an attempt to reduce the number of patients with thrombocytopenia due to other causes who receive study drug, only patients with a moderate or high clinical suspicion of HIT will be enrolled in the study (4T’s Score C4 points). A recent meta-analysis showed that the negative predictive value for HIT of a 4T’s Score of 3 points or fewer is 99.8 % [29]. While a randomized trial comparing rivaroxaban with a parenteral agent like argatroban or fondaparinux would be ideal, it is not feasible given that a non-inferiority trial (assuming a new TER of 11 %) would require enrolment of greater than a thousand patients per arm. Consequently, the Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study (NCT01598168). The study is currently recruiting patients within Canada. While rivaroxaban will not be directly compared with argatroban, the goal of the Rivaroxaban for HIT study will be to show that the thromboembolic rate with rivaroxaban is similar to the thromboembolic rate in patients who received argatroban in historical controlled trials. To address the heterogeneity of lab testing for HIT, in the Rivaroxaban for HIT study, the result of the HIT assay routinely used by the individual centres will be used to guide patient management in real time. However blood samples will also be sent to a central laboratory in Hamilton, Ontario, Canada for batch testing with the SRA. This approach will permit analysis of the efficacy of rivaroxaban in patients managed in real-world clinical conditions, while at the same time permitting evaluation of outcomes in two distinct populations—HIT and non-HIT—as determined by the reference standard SRA.
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Design of Rivaroxaban for HIT study Rivaroxaban Rivaroxaban is an oral, direct (i.e., antithrombin-independent) factor Xa inhibitor. It is an active drug that is well absorbed in the gastrointestinal tract with a bioavailability of about 80 %. Plasma levels peak in about 3 h and its halflife is 5–9 h (elderly 11–13 h) [30]. It has a dual pathway of elimination; one-third of the drug is excreted unchanged by the kidneys, one-third is metabolized in the liver by CYP3A4-dependent and independent pathways and excreted via the feces, and one-third of the inactive metabolites are eliminated by the kidneys [31]. The key advantages of using rivaroxaban for treatment of HIT include ease of administration, absence of a need for laboratory monitoring, lower cost and proven efficacy in the treatment of venous and arterial thromboembolism [10–13]. Furthermore, rivaroxaban can be continued longterm without conversion to warfarin; in contrast, parenterally administered DTI generally cannot be given to outpatients, thus mandating transition to warfarin. The requirement for DTI—warfarin overlap to begin only after platelet count recovery means that hospitalization is prolonged by at least 5 days compared with simple discharge on oral rivaroxaban. Moreover, continuation of rivaroxaban is expected to avoid the increased risk of venous limb gangrene that has been reported during the DTI-warfarin transition period [8, 32]. Potential disadvantages to using rivaroxaban to treat HIT include its partial dependence on renal clearance, potential for interaction with strong inhibitors of both cytochrome P-450 (CYP3A4) and P-glycoprotein, and absence of an antidote. Taken in context, however, danaparoid and fondaparinux are more dependent on renal clearance than rivaroxaban and none of these agents, including argatroban (which undergoes hepatobiliary elimination), has an antidote. Study objectives The primary objective of the study is to determine the incidence of new symptomatic venous and arterial thromboembolism in the combined cohort of patients with suspected and confirmed HIT at 30 days (i.e., evaluation of all enrolled subjects irrespective of whether they ultimately are confirmed as having HIT or not). Secondary objectives include determining the incidence of symptomatic thromboembolism and major bleeding while on-treatment with rivaroxaban, time to platelet recovery, and the incidence of venous and arterial thromboembolism in patients with HIT confirmed by the SRA [25]. The inclusion and exclusion criteria are outlined in Table 2.
Heparin-induced thrombocytopenia study
Study procedures An investigator-completed standardized 4T’s Score [33] and a local laboratory HIT assay will be conducted for all enrolled patients. While awaiting confirmation or exclusion
Table 2 Rivaroxaban for HIT study inclusion and exclusion criteria Inclusion criteria Adult patients with an intermediate or high clinical probability of HIT (4T’s Score C4) at the time of initial evaluation for HIT Exclusion criteria Require ongoing anticoagulant therapy for a mechanical heart valve Severe renal insufficiency (CrCl \ 30 mL/min) Hepatic disease (including Child-Pugh B and C) associated with coagulopathy and a clinically relevant bleeding risk Ongoing requirement for systemic treatment with azoleantimycotics (except fluconazole) or HIV-protease inhibitors or strong CYP3A4 inducers Clinically significant active bleeding or lesions at increased risk of bleeding within the last 6 months Platelet count \80 9 109/L and an ongoing need for antiplatelet therapy (at investigator’s discretion) Nursing women Pregnant or a woman of child-bearing potential not using an adequate birth control method Hypersensitivity to rivaroxaban or to any ingredient in the formulation Patients enrolled in the study within the past 100 days Patients with indwelling epidural catheters unless the catheter can be removed
Fig. 1 Study flow— Rivaroxaban for HIT study
of HIT, patients will receive rivaroxaban 15 mg twicedaily (i.e., the dose used during the acute treatment phase of the EINSTEIN-DVT [12] and EINSTEIN-PE [10] trials). A study flow chart is provided in Fig. 1. Patients who are HIT positive by the local laboratory assay and who do not have acute thrombosis at the time of study enrolment will continue to receive rivaroxaban 15 mg twice-daily until their platelet count reaches recovery [defined as a platelet count C150 9 109/L or to their baseline platelet count (defined as the platelet count on Day 0 of heparin or low-molecular-weight initiation)]. At the time of platelet count recovery, they will be transitioned to a maintenance dose of rivaroxaban 20 mg oncedaily until Study Day 30. HIT positive patients who have acute thrombosis at the time of study enrolment (i.e., HITT) will continue to receive rivaroxaban 15 mg twicedaily for a minimum of 21 days before transitioning to the maintenance dose of 20 mg once-daily (as per the EINSTEIN treatment protocols) [10, 12]. Patients who have HIT excluded by the local laboratory HIT assay will have the study drug discontinued and alternate anticoagulants ordered at the discretion of the most responsible physician. HIT negative patients (per the local laboratory) will receive a phone call at Study Day 30 to inquire about thromboembolic and major bleeding events. HIT positive patients (per the local laboratory) will be reviewed in clinic on Study Day 30 to determine the need for ongoing anticoagulant therapy. Patients who are defined as HIT negative by the local assay, but who meet the criteria for SRA-confirmed HIT, will be labelled as HIT positive.
Suspected HIT/HITT
Confirmed HIT/HITT
Rivaroxaban 15 mg bid Local HIT Assay
HIT Negative Stop Rivaroxaban
HIT Positive Platelets not recovered Rivaroxaban 15 mg bid
HITT Positive Rivaroxaban 15 mg bid for minimum of 21 days
HIT Positive Rivaroxaban 15 mg bid
HITT Positive Rivaroxaban 15 mg bid for minimum of 21 days Platelet Recovery
Rivaroxaban 20 mg od until Study Day 30
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L.-A. Linkins et al. Fig. 2 Expected findings for the Rivaroxaban for HIT Study. Suspected HIT is defined as clinical suspicion of HIT without laboratory confirmation of the presence of HIT antibodies. Confirmed HIT is defined as clinical suspicion of HIT with presence of HIT antibodies confirmed using a local laboratory assay, a ELISA at majority of centres, TER, thrombotic event rate, b estimated 40 % false positive rate in pts tested with ELISA (in relation to positive SRA status), c serotonin release assay (SRA)
Patients with suspected or confirmed HIT
4T’s Score Moderate or High 4T’s Score
Low 4T’s Score
excluded
200 pts Rivaroxaban started Local HIT Assaya Result
Positive
Negative
25-50 ptsb TER 11% = 3-6 thrombotic events Rivaroxaban continued
150-175 pts TER 5% = 8-10 thrombotic events Rivaroxaban stopped
Overall expected TER 6.5% (both arms combined)
Batch testing at a later date Central HIT Testingc
Central HIT Testingc
HIT POSITIVE 10-30 pts
HIT NEGATIVE 20-40 pts
Outcome measures All venous and arterial events will be confirmed by objective testing as outlined in the ‘‘Online Appendix’’. Bilateral leg ultrasounds at study entry are strongly recommended. Venous or arterial thrombotic events detected on investigations ordered within 24 h of study entry will be captured as baseline events. An interim safety analysis of the proportion of patients with thrombotic and major bleeding events will be performed by an independent Data Monitoring Committee after 100 patients have been enrolled. Due to the nature of the study population, the number of serious adverse events during the study period is expected to be high. Indeed, the mortality of HIT negative patients is expected to be at least as high as HIT positive patients because thrombocytopenia is an adverse prognostic marker for mortality in a number of conditions [27]. Sample size The sample size of 200 patients is based on feasibility. The anticipated TER in the entire study population (with and without confirmed HIT) of 6.5 %. This estimate is derived
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HIT POSITIVE 0 pts
HIT NEGATIVE 150-175 pts
from the combination of an expected TER of 11 % in the HIT positive patients who are treated with rivaroxaban (vs. a background rate of HIT-associated thrombosis in untreated patients of 35–50 %) [4, 5] and an expected TER of 5 % in the HIT negative patients who are treated with rivaroxaban. The expected TER for the HIT positive patients is derived from the argatroban arm of historical controlled trials [34, 35]. The overall rate of new thrombosis in patients given argatroban in these trials was 11.4 % (82/ 722) (95 % CI 9.2–13.9 %) [36]. The argatroban historical controlled trials were selected as the basis for the estimated TER because this group of trials were among the largest in the HIT literature and the study population is similar to the one in the current study (i.e., serological confirmation of HIT was not required for study enrolment). The TER in the HIT negative patients in the proposed study was derived from studies showing the venous and arterial TER despite thromboprophylaxis in cardiac surgery [37, 38], medical patients [39, 40] and intensive care patients [41]. These groups are the most likely to have suspected HIT due to use of heparin and the potential for development of thrombocytopenia for alternate reasons (overall estimate for TER is 5 %).
Heparin-induced thrombocytopenia study
A study sample size of 200 patients with a TER of 6.5 % is expected to yield a 95 % confidence interval of 3.7–10.9 %. The anticipated proportion of patients with SRA-confirmed HIT is 6–15 % (Fig. 2). Limitations of this study design include lack of a prospective comparator arm, a small proportion of patients who will have SRA-confirmed HIT and uncertainty about the efficacy and safety of rivaroxaban in critically ill patients. Strengths of the Rivaroxaban for HIT study include prospective, protocolized enrolment, standardized SRA testing for all study patients, and independent monitoring. Methodologically rigorous data are difficult to generate when investigating rare diseases like HIT. However, the quality of the data obtained from the Rivaroxaban for HIT study will certainly exceed that currently found in the literature for alternative agents such as fondaparinux [19, 42].
Conclusions Rivaroxaban has a number of important advantages over the drugs currently used to treat HIT including fixed dose, oral administration and lower cost. The Rivaroxaban for HIT study is a single-arm prospective cohort study that is evaluating this agent for treatment of patients with suspected or confirmed HIT. Results are expected in 2016. Conflict of interest All authors have contributed to the drafting of this manuscript. The Rivaroxaban for HIT Study is funded by an investigator-initiated study Grant from Bayer Inc. In the past 5 years, Dr. Linkins has received honoraria for presentations from Pfizer. Dr. Warkentin has received lecture honoraria from Pfizer Canada and Instrumentation Laboratories, has provided consulting services to, and/or has received research funding from, GlaxoSmithKline, W. L. Gore, Immucor GTI Diagnostics, and Paringenix, and has provided expert witness testimony relating to HIT. In the last 5 years, Dr. Wells has received honoraria for presentations from Bayer Healthcare, Boehringer Ingelheim, Pfizer and Biomerieiux. He is the recipient of an investigator-initiated research Grant from Bristol Myers Squibb/Pfizer. Dr. Shivakumar has received lecture honoraria from Bayer Inc. Dr. Crowther discloses having sat on advisory boards for Leo Pharma, Pfizer, Bayer, Boehringer Ingelheim, Alexion, CSL Behring, Portola, Viropharm and AKP America; provided expert testimony for Bayer and Merck and has received research funding from Boehringer Ingelheim, Octapharm, Pfizer and Leo Pharma. Dr. Manji and Dr. Pai have no conflict of interest with this study.
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L.-A. Linkins et al. 20. Warkentin TE (2012) HITlights: a career perspective on heparininduced thrombocytopenia. Am J Hematol 87(Suppl 1):S92–S99 21. Boyce SW, Bandyk DF, Bartholomew JR, Frame JN, Rice L (2011) A randomized, open-label pilot study comparing desirudin and argatroban in patients with suspected heparin-induced thrombocytopenia with or without thrombosis: PREVENT-HIT study. Am J Ther 18:14–22 22. Boyce SW (2012) Challenges to the design and execution of controlled clinical studies of anticoagulants in patients with heparin-induced thrombocytopenia: lessons learned. J Thromb Thrombolysis 33:124–128 23. Price EA, Hayward CP, Moffat KA, Moore JC, Warkentin TE, Zehnder JL (2007) Laboratory testing for heparin-induced thrombocytopenia is inconsistent in North America: a survey of North American specialized coagulation laboratories. Thromb Haemost 98:1357–1361 24. Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH (2011) Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost 9:2498–2500 25. Sheridan D, Carter C, Kelton JG (1986) A diagnostic test for heparin-induced thrombocytopenia. Blood 67:27–30 26. Lee DH, Warkentin TE (2007) Frequency of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A (eds) Heparin-induced thrombocytopenia, 4th edn. Informa Healthcare USA, Inc., New York, pp 67–116 27. Lo GK, Sigouin CS, Warkentin TE (2007) What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol 82:1037–1043 28. Cuker A (2011) Heparin-induced thrombocytopenia (HIT) in 2011: an epidemic of overdiagnosis. Thromb Haemost 106:993–994 29. Cuker A, Gimotty PA, Crowther MA, Warkentin TE (2012) Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 120:4160–4167 30. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G (2005) Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 78:412–421 31. Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D (2009) Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 37:1056–1064 32. Smythe MA, Warkentin TE, Stephens JL, Zakalik D, Mattson JC (2002) Venous limb gangrene during overlapping therapy with warfarin and a direct thrombin inhibitor for immune heparininduced thrombocytopenia. Am J Hematol 71:50–52
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33. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A (2006) Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 4:759–765 34. Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG (2001) Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 103:1838–1843 35. Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG (2003) Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 163:1849–1856 36. Warkentin TE, Greinacher A, Koster A, Lincoff AM (2008) Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest physicians evidence-based clinical practice guidelines. Chest 133:340S–380S 37. Bucci C, Geerts WH, Sinclair A, Fremes SE (2011) Comparison of the effectiveness and safety of low-molecular weight heparin versus unfractionated heparin anticoagulation after heart valve surgery. Am J Cardiol 107:591–594 38. Schwann TA, Kistler L, Engoren MC, Habib RH (2010) Incidence and predictors of postoperative deep vein thrombosis in cardiac surgery in the era of aggressive thromboprophylaxis. Ann Thorac Surg 90:760–766 39. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N (1999) A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in medical patients with Enoxaparin Study Group. N Engl J Med 341:793–800 40. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, Turpie AG, Egberts JF, Lensing AW (2006) Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 332:325–329 41. Cook D, Meade M, Guyatt G, Walter S, Heels-Ansdell D, Warkentin TE, Zytaruk N, Crowther M, Geerts W, Cooper DJ, Vallance S, Qushmaq I, Rocha M, Berwanger O, Vlahakis NE (2011) Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 364:1305–1314 42. Warkentin TE, Pai M, Sheppard JI, Schulman S, Spyropoulos AC, Eikelboom JW (2011) Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotoninrelease assay: a 30-month, 16-patient case series. J Thromb Haemost 9:2389–2396
Design of the rivaroxaban for heparin-induced thrombocytopenia study Lori-Ann Linkins • Theodore E. Warkentin • Menaka Pai • Sudeep Shivakumar Rizwan A. Manji • Philip S. Wells • Mark A. Crowther
•
Ó Springer Science+Business Media New York 2014
Abstract Rivaroxaban is an ideal potential candidate for treatment of heparin-induced thrombocytopenia (HIT) because it is administered orally by fixed dosing, requires no laboratory monitoring and is effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study evaluating the incidence of new symptomatic venous and arterial thromboembolism in patients with suspected or confirmed HIT who are treated with rivaroxaban. Methodological challenges faced in the design of this study include heterogeneity of the patient population, differences in the baseline risk of thrombosis and bleeding dependent on whether HIT is confirmed or just suspected, and heterogeneity in laboratory confirmation of HIT. The rationale for how these challenges were addressed and the final design of the Rivaroxaban for HIT study is reviewed.
Electronic supplementary material The online version of this article (doi:10.1007/s11239-014-1064-7) contains supplementary material, which is available to authorized users. L.-A. Linkins (&) Department of Medicine, McMaster University, 1280 Main Street West, Juravinski Hospital Site, Rm A3-74, Hamilton, ON L8S 4K1, Canada e-mail: [email protected] T. E. Warkentin M. Pai M. A. Crowther Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada T. E. Warkentin M. Pai M. A. Crowther Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
Keywords Heparin-induced thrombocytopenia Rivaroxaban Study design Clinical trial
Introduction Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction caused by heparin-dependent, platelet-activating IgG antibodies that recognize multimolecular complexes of a cationic ‘‘self’’ protein (platelet factor 4, PF4) when complexed with anionic heparin [1–4].The result of this reaction is platelet activation associated with increased thrombin generation in vivo, which in 50–75 % of patients with serologically-confirmed HIT, is associated with venous and/or arterial thromboembolism [1, 2, 4]. Once HIT is strongly suspected, it is not sufficient simply to discontinue heparin [due to a high thrombotic event rate (TER)] and/or start warfarin (due to the risk of precipitating microthrombosis including venous limb gangrene). To prevent HIT-related thrombotic complications, S. Shivakumar Department of Medicine, Dalhousie University, Halifax, NS, Canada R. A. Manji Cardiac Sciences Program, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada P. S. Wells Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
M. Pai Hamilton Regional Laboratory Medicine Program, McMaster University, Hamilton, ON, Canada
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L.-A. Linkins et al. Table 1 Comparison of anticoagulants in the treatment of HIT Property
Indirect AT-dependent inhibitors (danaparoid, fondaparinux)
Direct thrombin inhibitors (argatroban, bivalirudin, desirudin)
Direct factor Xa inhibitor (rivaroxaban)
Route of administration
Parenteral
Parenteral
Oral
Half-life
Danaparoid: 25h
\2 h
5–9 h
Fondaparinux: 17h Yes
Argatroban: no
Yes
Prophylactic dosing available
a
Bivalirudin: no Desirudin: yes Monitoring
Direct (anti-factor Xa level)
Effect on INR
b
Indirect (PTT): risk for systematic DTI underdosing with underlying coagulopathy (e.g., HIT-associated DIC)
Direct (anti-factor Xa level)b
No significant effect
Increases INR (especially argatroband)
Minimal effecte
Efficacy and safety established for non-HIT indications
Yes
Not established for most non-HIT settings
Yes
Inhibition of clot-bound thrombin or factor Xa
No effect
Inhibition of both free and clot-bound thrombin
Inhibition of both free and clot-bound factor Xa
Cross-reactivity with HIT antibodies
Danaparoid: yesc
No
No
Fondaparinux: yesc Clearance
Renal
Argatroban: hepatobiliary
Renal (66 %)
Bivalirudin: enzymatic (80 %), renal (20 %)
Hepatobiliary (33 %)
Desirudin: renal Antidote available Cost
No $$
No $$$
No $
AT antithrombin, h hours, DIC disseminated intravascular coagulation, DTI direct thrombin inhibitor, PTT partial thromboplastin time, INR international normalized ratio a
Although therapeutic dosing is recommended for HIT, availability of prophylactic-dose regimens increases flexibility when managing potential non-HIT situations (e.g., patients without thrombosis judged to have a low probability of HIT) b Not available at all centres, but anticoagulant monitoring is usually not required c
Considered to be of limited clinical importance
d
Venous limb gangrene during DTI-argatroban warfarin overlap has been reported, a risk that likely is greater with argatroban because it increases the INR and thus poses risk of ‘‘PT (INR) confounding’’
e
Rivaroxaban can be continued long-term without conversion to warfarin; in contrast, parenterally-administered DTIs generally cannot be given in outpatients, thus mandating transition to warfarin—the requirement for DTI—warfarin overlap to begin only after platelet count recovery means that hospitalization is prolonged by at least 5 days compared with simple discharge on continuing oral rivaroxaban
it is appropriate that a non-heparin anticoagulant—usually in therapeutic doses—be started promptly. The initial risk of thrombosis in a patient with serologically-confirmed HIT who does not receive alternative non-heparin anticoagulation is estimated at 5 % per day [4–6]. Unfortunately, the agents approved in many countries for treatment of HIT (e.g. lepirudin, argatroban, danaparoid) are parenteral, costly, and require intensive laboratory coagulation monitoring. Availability can also be a limiting factor (lepirudin, danaparoid). Moreover, even ‘‘simple’’ anticoagulant monitoring—e.g., activated partial thromboplastin time (aPTT)-adjusted dosing of argatroban therapy—can lead to treatment failure; underlying
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abnormalities in the aPTT due to HIT-associated coagulopathy may confound monitoring, resulting in inappropriate dose interruption or reduction [7, 8]. Because of the short half-lives of the approved direct thrombin inhibitors (DTI), inappropriate dose interruption/reduction can quickly lead to subtherapeutic dosing, and failure of therapy. Although the problems of aPTT confounding and short anticoagulant half-life are avoided by fondaparinux, this agent remains ‘‘off-label’’ for the treatment of HIT, is also parenteral, costly, and its clearance is 100 % dependent on renal function [9]. Rivaroxaban, one of the new oral anticoagulants, is an ideal candidate for treatment of HIT for several reasons
Heparin-induced thrombocytopenia study
(Table 1). It is given as a fixed dose, requires no laboratory coagulation monitoring, has a longer half-life than the parenteral DTI (5–9 vs. \1 h), and its efficacy in the treatment of venous and arterial thromboembolism has been established in large randomized controlled trials [10– 13]. Furthermore, unlike fondaparinux and danaparoid, rivaroxaban does not cross-react with HIT antibodies [14, 15] and it is capable of inhibiting clot bound factor Xa [16]. However, designing a clinical trial to evaluate rivaroxaban as a new treatment option for HIT poses a unique set of methodological challenges. In this review, we outline these challenges and discuss how they will be addressed in the Rivaroxaban for HIT study. We will also review the study protocol and expected results.
Methodological challenges Heterogeneity in patients: HIT incidence and presentation There is significant heterogeneity in the incidence of HIT according to patient population. Thrombocytopenia, in general, is relatively common, particularly in certain groups such as post cardiac surgery patients and intensive care unit (ICU) patients [17]. Studies have shown that for every one patient who is confirmed to have HIT, 10–20 patients are suspected to have HIT (with a varying degree of clinical suspicion) [18]. The frequency of HIT varies significantly according to the patient type and duration of heparin therapy; HIT occurs in as few as 0.1 % of patients given heparin for \5 days, and as many as 1–5 % of medical and orthopaedic surgical patients, respectively, given unfractionated heparin for at least 10 days [19]. The result is that when we consider all patients with suspected HIT, there is a wide variation in baseline risk for thrombosis and bleeding. Patients with thrombocytopenia due to HIT require high doses of anticoagulant therapy to prevent thrombosis since their thrombotic risk far outweighs their bleeding risk, whereas patients with thrombocytopenia due to other causes should receive low doses (or no anticoagulation at all) as their bleeding risk likely outweighs their thrombotic risk. This heterogeneity of risk poses a clinical challenge, as all patients with a moderate or high clinical suspicion for HIT should receive preventative treatment. A large proportion of this group of patients will not ultimately have HIT, but will still be exposed to high dose anticoagulant therapy while the result of the HIT assay is pending (a process that may take several days). The presentation of HIT is also very heterogeneous. For example, HIT patients may or may not have thrombosis at the time of study entry (HIT vs. HITT), and the types of thrombosis vary widely, ranging from common thrombi involving veins (DVT, PE), to less common thrombi
involving arteries (limb [ cerebral [ coronary), to rare thrombi (e.g., adrenal vein thrombosis leading to hemorrhagic infarction; cerebral vein dural sinus thrombosis). Indeed, the very strong association between HIT and thrombosis (RR = 12.0, 95 % CI 7.0–20.6; P \ 0.0001) [20] means that if a patient with unexpected thrombocytopenia has new thrombosis, it is much more suggestive of HIT than if a patient with thrombocytopenia does not have new thrombosis. The clinical heterogeneity of thrombosis means that while some patients will require urgent surgical interventions (e.g., arterial thromboembolectomy), others may require simple anticoagulation (e.g., DVT, PE). Due to these patient heterogeneity issues, it is difficult to come up with a practical study design to evaluate a new drug for HIT. From a methodological perspective, the ideal HIT study would be a randomized trial comparing rivaroxaban with one of the approved treatments of HIT. However, this study design is also impractical as illustrated by the recently terminated PREVENT–HIT trial. PREVENT-HIT was an open-label randomized controlled trial comparing twice-daily fixed-dose desirudin with argatroban to prevent or treat thrombosis in patients with suspected HIT [21]. The sample size was 120 patients, but the study was terminated after just 16 patients were enrolled over 14 months. The investigators identified issues with patient selection, choice of argatroban as the control group and inadequate research support at clinical centres as major obstacles to the success of their trial [22]. Heterogeneity in laboratory confirmation of HIT Heterogeneity of laboratory tests for HIT also poses a challenge to testing a new drug for HIT. There is currently no standardization of laboratory testing for HIT. A survey of specialized coagulation laboratories in North America identified eight different assays, and wide discrepancies in practice between centres using the same assay [23]. The platelet serotonin-release assay (SRA) is considered a reference standard assay for HIT [24]. The SRA is a functional assay that only detects antibodies of IgG class that recognize the relevant antigen(s) on PF4, and are capable of supporting activation of platelets [25]. The problem with the SRA is that it is only available at a few centres; it requires identification of suitable platelet donors, utilizes a radiolabeled analyte (14C-serotonin), and involves several platelet ‘‘washing’’ steps. This makes the SRA a technically more difficult test when compared with the commercially-available antigen assays. Most centres that have a laboratory test for HIT use some form of antigen assay to detect the presence of HIT antibodies. However, this test has limited utility, as only a small proportion of patients who form HIT antibodies (seroconversion) will develop clinical HIT [26].
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Consequently, a significant proportion of patients diagnosed with HIT based on an antigen assay will thus not truly have HIT (false positives). Over-diagnosis of HIT is a major problem, because it can lead to inappropriate withdrawal of heparin and exposes patients to the complications associated with approved treatments for HIT [27, 28].
Ways to address the methodological challenges To address patient heterogeneity and to accurately reflect the real-world dilemma of waiting for the result of a HIT assay to be reported, the Rivaroxaban for HIT study will enrol patients across the clinical spectrum for suspected or confirmed HIT and will use the same initial dose for patients with and without thrombosis until HIT is excluded. Suspected HIT is defined as clinical suspicion of HIT without laboratory confirmation of the presence of HIT antibodies (i.e., result still pending). Confirmed HIT is defined as clinical suspicion of HIT with presence of HIT antibodies confirmed using a local laboratory assay. The dose of rivaroxaban will not be adjusted for the degree of thrombocytopenia; however, in an attempt to reduce the number of patients with thrombocytopenia due to other causes who receive study drug, only patients with a moderate or high clinical suspicion of HIT will be enrolled in the study (4T’s Score C4 points). A recent meta-analysis showed that the negative predictive value for HIT of a 4T’s Score of 3 points or fewer is 99.8 % [29]. While a randomized trial comparing rivaroxaban with a parenteral agent like argatroban or fondaparinux would be ideal, it is not feasible given that a non-inferiority trial (assuming a new TER of 11 %) would require enrolment of greater than a thousand patients per arm. Consequently, the Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study (NCT01598168). The study is currently recruiting patients within Canada. While rivaroxaban will not be directly compared with argatroban, the goal of the Rivaroxaban for HIT study will be to show that the thromboembolic rate with rivaroxaban is similar to the thromboembolic rate in patients who received argatroban in historical controlled trials. To address the heterogeneity of lab testing for HIT, in the Rivaroxaban for HIT study, the result of the HIT assay routinely used by the individual centres will be used to guide patient management in real time. However blood samples will also be sent to a central laboratory in Hamilton, Ontario, Canada for batch testing with the SRA. This approach will permit analysis of the efficacy of rivaroxaban in patients managed in real-world clinical conditions, while at the same time permitting evaluation of outcomes in two distinct populations—HIT and non-HIT—as determined by the reference standard SRA.
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Design of Rivaroxaban for HIT study Rivaroxaban Rivaroxaban is an oral, direct (i.e., antithrombin-independent) factor Xa inhibitor. It is an active drug that is well absorbed in the gastrointestinal tract with a bioavailability of about 80 %. Plasma levels peak in about 3 h and its halflife is 5–9 h (elderly 11–13 h) [30]. It has a dual pathway of elimination; one-third of the drug is excreted unchanged by the kidneys, one-third is metabolized in the liver by CYP3A4-dependent and independent pathways and excreted via the feces, and one-third of the inactive metabolites are eliminated by the kidneys [31]. The key advantages of using rivaroxaban for treatment of HIT include ease of administration, absence of a need for laboratory monitoring, lower cost and proven efficacy in the treatment of venous and arterial thromboembolism [10–13]. Furthermore, rivaroxaban can be continued longterm without conversion to warfarin; in contrast, parenterally administered DTI generally cannot be given to outpatients, thus mandating transition to warfarin. The requirement for DTI—warfarin overlap to begin only after platelet count recovery means that hospitalization is prolonged by at least 5 days compared with simple discharge on oral rivaroxaban. Moreover, continuation of rivaroxaban is expected to avoid the increased risk of venous limb gangrene that has been reported during the DTI-warfarin transition period [8, 32]. Potential disadvantages to using rivaroxaban to treat HIT include its partial dependence on renal clearance, potential for interaction with strong inhibitors of both cytochrome P-450 (CYP3A4) and P-glycoprotein, and absence of an antidote. Taken in context, however, danaparoid and fondaparinux are more dependent on renal clearance than rivaroxaban and none of these agents, including argatroban (which undergoes hepatobiliary elimination), has an antidote. Study objectives The primary objective of the study is to determine the incidence of new symptomatic venous and arterial thromboembolism in the combined cohort of patients with suspected and confirmed HIT at 30 days (i.e., evaluation of all enrolled subjects irrespective of whether they ultimately are confirmed as having HIT or not). Secondary objectives include determining the incidence of symptomatic thromboembolism and major bleeding while on-treatment with rivaroxaban, time to platelet recovery, and the incidence of venous and arterial thromboembolism in patients with HIT confirmed by the SRA [25]. The inclusion and exclusion criteria are outlined in Table 2.
Heparin-induced thrombocytopenia study
Study procedures An investigator-completed standardized 4T’s Score [33] and a local laboratory HIT assay will be conducted for all enrolled patients. While awaiting confirmation or exclusion
Table 2 Rivaroxaban for HIT study inclusion and exclusion criteria Inclusion criteria Adult patients with an intermediate or high clinical probability of HIT (4T’s Score C4) at the time of initial evaluation for HIT Exclusion criteria Require ongoing anticoagulant therapy for a mechanical heart valve Severe renal insufficiency (CrCl \ 30 mL/min) Hepatic disease (including Child-Pugh B and C) associated with coagulopathy and a clinically relevant bleeding risk Ongoing requirement for systemic treatment with azoleantimycotics (except fluconazole) or HIV-protease inhibitors or strong CYP3A4 inducers Clinically significant active bleeding or lesions at increased risk of bleeding within the last 6 months Platelet count \80 9 109/L and an ongoing need for antiplatelet therapy (at investigator’s discretion) Nursing women Pregnant or a woman of child-bearing potential not using an adequate birth control method Hypersensitivity to rivaroxaban or to any ingredient in the formulation Patients enrolled in the study within the past 100 days Patients with indwelling epidural catheters unless the catheter can be removed
Fig. 1 Study flow— Rivaroxaban for HIT study
of HIT, patients will receive rivaroxaban 15 mg twicedaily (i.e., the dose used during the acute treatment phase of the EINSTEIN-DVT [12] and EINSTEIN-PE [10] trials). A study flow chart is provided in Fig. 1. Patients who are HIT positive by the local laboratory assay and who do not have acute thrombosis at the time of study enrolment will continue to receive rivaroxaban 15 mg twice-daily until their platelet count reaches recovery [defined as a platelet count C150 9 109/L or to their baseline platelet count (defined as the platelet count on Day 0 of heparin or low-molecular-weight initiation)]. At the time of platelet count recovery, they will be transitioned to a maintenance dose of rivaroxaban 20 mg oncedaily until Study Day 30. HIT positive patients who have acute thrombosis at the time of study enrolment (i.e., HITT) will continue to receive rivaroxaban 15 mg twicedaily for a minimum of 21 days before transitioning to the maintenance dose of 20 mg once-daily (as per the EINSTEIN treatment protocols) [10, 12]. Patients who have HIT excluded by the local laboratory HIT assay will have the study drug discontinued and alternate anticoagulants ordered at the discretion of the most responsible physician. HIT negative patients (per the local laboratory) will receive a phone call at Study Day 30 to inquire about thromboembolic and major bleeding events. HIT positive patients (per the local laboratory) will be reviewed in clinic on Study Day 30 to determine the need for ongoing anticoagulant therapy. Patients who are defined as HIT negative by the local assay, but who meet the criteria for SRA-confirmed HIT, will be labelled as HIT positive.
Suspected HIT/HITT
Confirmed HIT/HITT
Rivaroxaban 15 mg bid Local HIT Assay
HIT Negative Stop Rivaroxaban
HIT Positive Platelets not recovered Rivaroxaban 15 mg bid
HITT Positive Rivaroxaban 15 mg bid for minimum of 21 days
HIT Positive Rivaroxaban 15 mg bid
HITT Positive Rivaroxaban 15 mg bid for minimum of 21 days Platelet Recovery
Rivaroxaban 20 mg od until Study Day 30
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L.-A. Linkins et al. Fig. 2 Expected findings for the Rivaroxaban for HIT Study. Suspected HIT is defined as clinical suspicion of HIT without laboratory confirmation of the presence of HIT antibodies. Confirmed HIT is defined as clinical suspicion of HIT with presence of HIT antibodies confirmed using a local laboratory assay, a ELISA at majority of centres, TER, thrombotic event rate, b estimated 40 % false positive rate in pts tested with ELISA (in relation to positive SRA status), c serotonin release assay (SRA)
Patients with suspected or confirmed HIT
4T’s Score Moderate or High 4T’s Score
Low 4T’s Score
excluded
200 pts Rivaroxaban started Local HIT Assaya Result
Positive
Negative
25-50 ptsb TER 11% = 3-6 thrombotic events Rivaroxaban continued
150-175 pts TER 5% = 8-10 thrombotic events Rivaroxaban stopped
Overall expected TER 6.5% (both arms combined)
Batch testing at a later date Central HIT Testingc
Central HIT Testingc
HIT POSITIVE 10-30 pts
HIT NEGATIVE 20-40 pts
Outcome measures All venous and arterial events will be confirmed by objective testing as outlined in the ‘‘Online Appendix’’. Bilateral leg ultrasounds at study entry are strongly recommended. Venous or arterial thrombotic events detected on investigations ordered within 24 h of study entry will be captured as baseline events. An interim safety analysis of the proportion of patients with thrombotic and major bleeding events will be performed by an independent Data Monitoring Committee after 100 patients have been enrolled. Due to the nature of the study population, the number of serious adverse events during the study period is expected to be high. Indeed, the mortality of HIT negative patients is expected to be at least as high as HIT positive patients because thrombocytopenia is an adverse prognostic marker for mortality in a number of conditions [27]. Sample size The sample size of 200 patients is based on feasibility. The anticipated TER in the entire study population (with and without confirmed HIT) of 6.5 %. This estimate is derived
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HIT POSITIVE 0 pts
HIT NEGATIVE 150-175 pts
from the combination of an expected TER of 11 % in the HIT positive patients who are treated with rivaroxaban (vs. a background rate of HIT-associated thrombosis in untreated patients of 35–50 %) [4, 5] and an expected TER of 5 % in the HIT negative patients who are treated with rivaroxaban. The expected TER for the HIT positive patients is derived from the argatroban arm of historical controlled trials [34, 35]. The overall rate of new thrombosis in patients given argatroban in these trials was 11.4 % (82/ 722) (95 % CI 9.2–13.9 %) [36]. The argatroban historical controlled trials were selected as the basis for the estimated TER because this group of trials were among the largest in the HIT literature and the study population is similar to the one in the current study (i.e., serological confirmation of HIT was not required for study enrolment). The TER in the HIT negative patients in the proposed study was derived from studies showing the venous and arterial TER despite thromboprophylaxis in cardiac surgery [37, 38], medical patients [39, 40] and intensive care patients [41]. These groups are the most likely to have suspected HIT due to use of heparin and the potential for development of thrombocytopenia for alternate reasons (overall estimate for TER is 5 %).
Heparin-induced thrombocytopenia study
A study sample size of 200 patients with a TER of 6.5 % is expected to yield a 95 % confidence interval of 3.7–10.9 %. The anticipated proportion of patients with SRA-confirmed HIT is 6–15 % (Fig. 2). Limitations of this study design include lack of a prospective comparator arm, a small proportion of patients who will have SRA-confirmed HIT and uncertainty about the efficacy and safety of rivaroxaban in critically ill patients. Strengths of the Rivaroxaban for HIT study include prospective, protocolized enrolment, standardized SRA testing for all study patients, and independent monitoring. Methodologically rigorous data are difficult to generate when investigating rare diseases like HIT. However, the quality of the data obtained from the Rivaroxaban for HIT study will certainly exceed that currently found in the literature for alternative agents such as fondaparinux [19, 42].
Conclusions Rivaroxaban has a number of important advantages over the drugs currently used to treat HIT including fixed dose, oral administration and lower cost. The Rivaroxaban for HIT study is a single-arm prospective cohort study that is evaluating this agent for treatment of patients with suspected or confirmed HIT. Results are expected in 2016. Conflict of interest All authors have contributed to the drafting of this manuscript. The Rivaroxaban for HIT Study is funded by an investigator-initiated study Grant from Bayer Inc. In the past 5 years, Dr. Linkins has received honoraria for presentations from Pfizer. Dr. Warkentin has received lecture honoraria from Pfizer Canada and Instrumentation Laboratories, has provided consulting services to, and/or has received research funding from, GlaxoSmithKline, W. L. Gore, Immucor GTI Diagnostics, and Paringenix, and has provided expert witness testimony relating to HIT. In the last 5 years, Dr. Wells has received honoraria for presentations from Bayer Healthcare, Boehringer Ingelheim, Pfizer and Biomerieiux. He is the recipient of an investigator-initiated research Grant from Bristol Myers Squibb/Pfizer. Dr. Shivakumar has received lecture honoraria from Bayer Inc. Dr. Crowther discloses having sat on advisory boards for Leo Pharma, Pfizer, Bayer, Boehringer Ingelheim, Alexion, CSL Behring, Portola, Viropharm and AKP America; provided expert testimony for Bayer and Merck and has received research funding from Boehringer Ingelheim, Octapharm, Pfizer and Leo Pharma. Dr. Manji and Dr. Pai have no conflict of interest with this study.
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