Argatroban anticoagulation, compared with historical control subjects, improves clinical outcomes in patients who have heparin-induced thrombocytopenia, without increasing bleeding risk.
Argatroban therapy, compared with historical control, improves outcomes, particularly new thrombosis and death due to thrombosis, in patients with heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome associated with thrombosis. Alternative anticoagulation to heparin is needed for HIT patients during percutaneous coronary intervention (PCI). We evaluated argatroban, a direct thrombin inhibitor, for anticoagulation in this setting. Ninety-one HIT patients underwent 112 PCIs while on intravenous argatroban (25 microg/kg/min [350 microg/kg initial bolus], adjusted to achieve an activated clotting time of 300-450 sec). Primary efficacy endpoints were subjective assessments of the satisfactory outcome of the procedure and adequate anticoagulation during PCI. Among patients undergoing initial PCIs with argatroban (n = 91), 94.5% had a satisfactory outcome of the procedure and 97.8% achieved adequate anticoagulation. Death (zero patients), myocardial infarction (four patients), or revascularization (four patients) at 24 hr after PCI occurred in seven (7.7%) patients overall. One patient (1.1%) experienced periprocedural major bleeding. For patients who had subsequent hospitalizations (mean separation of 150 days) for repeat PCI using argatroban anticoagulation (n = 21), there were no unsatisfactory outcomes. Overall, outcomes were comparable with those historically reported for heparin. Argatroban therefore is a reasonable anticoagulant option in this setting, where current options are limited.
The di-substituted piperazines, GBR12909 (1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-[3- phenylpropyl]piperazine) and GBR12935 (1-[2-(diphenyl-methoxy)-ethyl]-4-(3-phenylpropyl)piperazine), are potent and selective (20-to 100-fold) inhibitors of [3H]dopamine reuptake, relative to [3H]5-HT and [3H]norepinephrine uptake. The GBR12935 analog, 1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)homopiperazine (LR1111), was synthesized as part of a systematic structure-activity study of analogs of GBR12935 and GBR12909. LR1111 differs from GBR12935 by the addition of a methylene group into the piperazine ring to yield a compound with a seven-member homopiperazine ring. The IC50 values for LR1111 at the dopamine, norepinephrine, and serotonin transporters were 7.2 nM, 34,072 nM, and greater than 20,000 nM, respectively, whereas the IC50 values of GBR12935 were 3.7 nM, 289 nM, and 1261 nM for these same transporters. This demonstrates that the addition of a single methylene group in the piperazine ring results in a compound with similar affinity but significantly higher selectivity for the dopamine transporter. LR1111 increased motoric activity in rats after intravenous administration. These indicate that LR1111 is a potent and highly selective inhibitor of the dopamine transporter.
on Behalf of the Study Investigators* Background-Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET A receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET A receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. Methods and Results-This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21Ϯ1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure Ն15 mm Hg and a cardiac index Յ2.5 L ⅐ min Ϫ1 ⅐ m Ϫ2 were randomized to 1 of 3 doses (1.5, 3.0, or 6.0 mg/kg) of sitaxsentan or placebo as an intravenous infusion over 15 minutes. Hemodynamic responses were assessed by catheterization of the right side of the heart for 6 hours. Sitaxsentan decreased pulmonary artery systolic pressure, pulmonary vascular resistance, mean pulmonary artery pressure, and right atrial pressure (PՅ0.001, 0.003, 0.017, and 0.031, respectively) but had no effect on heart rate, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, or systemic vascular resistance. Plasma ET-1 levels were elevated at baseline and decreased with sitaxsentan. Conclusions-In patients with moderate to severe heart failure receiving conventional therapy, acute ET A receptor blockade caused selective pulmonary vasodilation associated with a reduction in plasma ET-1. Sitaxsentan may be of value in the treatment of patients with pulmonary hypertension secondary to chronic heart failure. (Circulation.
Argatroban in combination with glycoprotein IIb/IIIa inhibition appears to provide adequate anticoagulation and be well tolerated with an acceptable bleeding risk for patients undergoing percutaneous coronary intervention. Additional studies are warranted.
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