Thrombotic end point for assessing argatroban therapy for heparin-induced thrombocytopenia: learning from secondary analyses of prospective studies

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder for which relatively scarcely any alternative anticoagulants have undergone prospective evaluation as therapeutic agents. Accordingly, individual seeks to learn as a great deal of as possible from those studies that have been performed. In this issue of CHEST (see page 1407) Lewis and colleagues (1) report a secondary analysis of the prospective cohort studies (23) of argatroban that l to regulatory approval of this direct thrombin inhibitor (DTI) for the treatment of HIT with or without thrombosis. Should we pay attention to secondary analyses of prospective studies? Yes

HIT has a track record for revealing important information from further analyses of prospective trials. For example, for the DTI lepirudin a secondary analysis (4) of three prospective studies set a major bleeding rate of 174% which varied from 108 to 330% depending upon whether the patient's serum creatinine horizontal was < 90 [micro]mol/L or > 90 [micro]mol/L, respectively. Based upon these (and other) data, the authors proposeed that the standard lepirudin dosing regimen (a bolus of 04 mg/kg then 015 mg/kg/h) should be revised downward (to 010 mg/kg/h without a bolus infusion). Other investigators (5) have independently conclud that the approved lepirudin dosing regimen is too high.

Another example: a randomized controll trial compared unfractionated heparin with low-molecular-weight heparin for thromboprophylaxis after hip replacement surgery (6) Data upon the daily platelet counts were bring togethered prospectively, but HIT ascertainment was initiated alone after completion of the clinical trial. Nevertheless, the conclusions of this secondary analysis (that the risk of HIT is greatly reduc by dint of therapy with low-molecular-weight heparin in orthopedic surgery patients (6)) has been confirmed. (7)

In their fresh study, Lewis and colleagues (1) combined data from three prospective cohort studies, Arg-911, Arg-915, plus its extension phase, Arg-915X, for a total of 697 patients who received argatroban for the treatment of clinically suspected HIT. Patients were classified at baseline into clusters depending on whether they had HIT without thrombosis (n = 321) or HIT-associated thrombosis (n = 376) A novel approach was to analyze as their primary extreme point point a thrombotic composite comprising death to be paid to thrombosis, amputation secondary to HIT-associated thrombosis, or novel thrombosis within 37 days of baseline (maximum, individual event per patient). This extreme point point addresses the limitations of the previous composite extreme point point (as required by the US nourishment and Drug Administration) of all-cause mortality, limb amputation, or novel thrombosis, in which enrollment of patients with life-threatening comorbidities and advanced limb ischemia could have compromised the detection of autithrombotic efficacy. (8)

What can we learn from this fresh analysis? First, using the novel extremity point, the antithrombotic effect of argatroban did appear to be greater (ie, lower hazard ratios) than that estimated from the previous studies. The hazard ratios using the thrombotic composite ranged from 033 (HIT) to 039 (HIT-associated thrombosis), whereas the corresponding values for the composite extreme point point in the Arg-911 and Arg-915 trials ranged from 060 to 064 (HIT) and from 056 to 057 (HIT-associated thrombosis).

next to the first limb amputation rates did not differ between argatroban-treated patients and historical sway subjects. Although disappointing, this finding should be viewed in its historical adjoining matter Guidelines for managing DTI-warfarin overlap did not exist when these trials were performed (1995 to 1998) It is now recognized that DTI-warfarin cotherapy must be carefully managed to minimize the potential for warfarin-associated microvascular thrombosis, including venous limb gangrene. (89) For example, warfarin therapy should be postpon until the platelet enumerate has substantially resolved, should be administered solitary in low initial doses, and should be overlapped for at least 5 days with the DTI. (8) The clinician also emergencys to be aware that therapy with argatroban lengthens the international normalized ratio (10) and that the international normalized ratio increases further during DTI-warfarin cotherapy, (11) in like manner that an incorrect conclusion is not reached that a patient has prematurely attained therapeutic anticoagulation with warfarin therapy. Further, initiating treatment with a novel anticoagulant within a clinical trial words immediately preceding [i]or[/i] following faces inherent delays, including the time to transfer patients to inquiry sites and obtaining informed assent not to mention the "learning curve" required for the optimal use of an experimental agent. These factors can jeopardize the salvage of a harshly ischemic limb. Thus, a more accurate assessment of the expansion to which limb loss might be averted by dint of therapy with argatroban (or any other therapy) awaits data from postapproval studies.

Third, the research provides insights into the potential risk factors for HIT-associated thrombosis. single interesting finding was that women had a higher oftenness of HIT-associated thrombosis. Does this throw back a truly greater risk of thrombosis in women with HIT, or rather that female bring under rules were more likely to have actually had HIT in this study? Given that women may be at greater risk of HIT than men (12) and that patients were listed in the study based upon a clinical suspicion of HIT rather than a positive trial result for HIT antibodies, either interpretation is plausible.