Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. European Cooperative Study Group. Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers. Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP). Results of a randomized multicenter trial by the Italian Cooperative Group for TTP. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. Platelet function during cardiac surgery and cardiopulmonary bypass with low-dose aprotinin. Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Platelet membrane receptor glycoprotein IIb/IIIa antagonism in unstable angina. The Canadian Lamifiban Study. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy.
The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder.
                We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43.
                In the eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of eltrombopag were 26,000, 128,000, and 183,000 per cubic millimeter, respectively; for the placebo group the count was 16,000 per cubic millimeter. By day 15, more than 80% of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count. Bleeding also decreased during treatment in these two groups. The incidence and severity of adverse events were similar in the placebo and eltrombopag groups.
                Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. (ClinicalTrials.gov number, NCT00102739.)
                2007 Massachusetts Medical Society Patients with unstable angina despite intensive medical therapy, ie, refractory angina, are at high risk for developing thrombotic complications: myocardial infarction or coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA). Chimeric 7E3 (c7E3) Fab is an antibody fragment that blocks the platelet glycoprotein (GP) IIb/IIIa receptor and potently inhibits platelet aggregation.
                To evaluate whether potent platelet inhibition could reduce these complications, 60 patients with dynamic ST-T changes and recurrent pain despite intensive medical therapy were randomized to c7E3 Fab or placebo. After initial angiography had demonstrated a culprit lesion suitable for PTCA, placebo or c7E3 Fab was administered as 0.25 mg/kg bolus injection followed by 10 micrograms/min for 18 to 24 hours until 1 hour after completion of second angiography and PTCA. During study drug infusion, ischemia occurred in 9 c7E3 Fab and 16 placebo patients (P = .06). During hospital stay, 12 major events occurred in 7 placebo patients (23%), including 1 death, 4 infarcts, and 7 urgent interventions. In the c7E3 Fab group, only 1 event (an infarct) occurred (3%, P = .03). Angiography showed improved TIMI flow in 4 placebo and 6 c7E3 Fab patients and worsening of flow in 3 placebo patients but in none of the c7E3 Fab patients. Quantitative analysis showed significant improvement of the lesion in the patients treated with c7E3 Fab, which was not observed in the placebo group, although the difference between the two treatment groups was not significant. Measurement of platelet function and bleeding time demonstrated > 90% blockade of GPIIb/IIIa receptors, > 90% reduction of ex vivo platelet aggregation to ADP, and a significantly prolonged bleeding time during c7E3 Fab infusion, without excess bleeding.
                Combined therapy with c7E3 Fab, heparin, and aspirin appears safe. These pilot study results support the concept that effective blockade of the platelet GPIIb/IIIa receptors can reduce myocardial infarction and facilitate PTCA in patients with refractory unstable angina. Platelet products have been proposed as adjuvant therapy for wound healing. We undertook this study to determine the healing effect of topically applied frozen autologous platelets (FAP) on chronic venous ulcers, compared with effect of placebo, and whether use of topical FAP modifies local expression of vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), interleukin 8 (IL-8), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in wound fluid.
                This randomized, placebo-controlled, double-blind trial was carried out in institutional practice, with ambulatory patients with proved chronic venous leg ulcers. In all patients, whole venous blood was drawn for preparation of FAP. FAP or normal saline solution was applied three times per week for up to 12 weeks, together with hydrocolloids and standardized compression bandages. Leg ulcer surface was assessed with numerical pictures. IL-8, VEGF, KGF, and TIMP-1 levels were determined (enzyme-linked immunosorbent assay) in wound fluid after each 4 weeks of treatment.
                Fifteen patients were randomized into two groups with comparable leg ulcer characteristics. Mean percent reduction in ulcer area was 26.2% in the FAP group versus 15.2% in the placebo group (P =.94). One ulcer in each group was completely healed at study end. Levels of TIMP-1 increased significantly during FAP treatment. IL-8 concentration was significantly lower in wound fluid of healing ulcers than in the fluid of nonhealing ulcers, in both FAP and placebo groups. Growth factor levels were not modified with FAP treatment.
                Topical autologous platelets have no significant adjuvant effect on healing of chronic venous leg ulcers and increased wound fluid TIMP-1 concentration. Ulcer healing is associated with a decrease in wound fluid IL-8. Antiplatelet agents are often included in plasma exchange-based regimens for thrombotic thrombocytopenic purpura (TTP) patients; however, the opportuneness of their use in TTP is still controversial. The italian Cooperative Group for TTP carried out a randomized trial to investigate their actual effectiveness, both in acute TTP and as maintenance treatment.
                Seventy-two TTP patients were randomized to receive plasma exchange and steroids with (group B) or without (group A) aspirin and dipyridamole. Treatment efficacy was evaluated after 15 days and salvage treatments were also considered for non-responders. Upon disease remission, the patients already treated with antiplatelet agents received ticlopidine for one year.
                Regarding the treatment of acute phase TTP, similar overall response rates were observed in the two groups (91.4% in group B vs. 75.6% in group A), but lower mortality rates were observed at 15 days in the patients treated with antiplatelet agents; as a matter of fact, 5 patients from arm A died in the first 15 days (13.5%) versus only one in arm B (2.8%). These figures, while not statistically significant, seem to suggest that antiplatelet agents might be useful in preventing deaths in acute TTP; moreover, bleeding did not worsen in antiplatelet agent-treated patients. As for the role of maintenance treatment, our results support the efficacy and safety of one-year ticlopidine therapy since the current relapse rate is significantly higher in non-treated patients; as a matter of fact, 6 patients (21.4%) in the non-ticlopidine group and only 2 (6.25%) in the ticlopidine group relapsed (P = .0182 in favor of maintenance treatment).
                Our results suggest the usefulness of antiplatelet agents in the treatment of acute phase TTP patients. Moreover, one-year ticlopidine maintenance therapy appears to be beneficial in preventing TTP relapses; however, only the completion of an adequate follow-up for all patients will definitively confirm this observation. Most current treatments for chronic immune thrombocytopenic purpura (ITP) act by decreasing platelet destruction. In a phase 1-2 study, we administered a thrombopoiesis-stimulating protein, AMG 531, to patients with ITP.
                In phase 1, 24 patients who had received at least one treatment for ITP were assigned to escalating-dose cohorts of 4 patients each and given two identical doses of AMG 531 (0.2 to 10 microg per kilogram of body weight). In phase 2, 21 patients were randomly assigned to receive six weekly subcutaneous injections of AMG 531 (1, 3, or 6 microg per kilogram) or placebo. The primary objective was to assess the safety of AMG 531; the secondary objective was to evaluate platelet counts during and after treatment.
                No major adverse events that could be attributed directly to AMG 531 occurred during the treatment period; 4 of 41 patients had transient post-treatment worsening of thrombocytopenia. In phase 1, a platelet count that was within the targeted range (50,000 to 450,000 per cubic millimeter) and at least twice the baseline count was achieved in 4 of 12 patients given 3, 6, or 10 mug of AMG 531 per kilogram. Overall, a platelet count of at least 50,000 per cubic millimeter was achieved in 7 of 12 patients, including 3 with counts exceeding 450,000 per cubic millimeter. Increases in the platelet count were dose-dependent; mean peak counts were 163,000, 309,000, and 746,000 per cubic millimeter with 3, 6, and 10 microg of AMG 531 per kilogram [corrected], respectively. In phase 2, the targeted platelet range was achieved in 10 of 16 patients treated with 1 or 3 mug of AMG 531 per kilogram per week for 6 weeks. Mean peak counts were 135,000, 241,000, and 81,000 per cubic millimeter in the groups that received the 1-mug dose, the 3-mug dose, and placebo, respectively.
                AMG 531 caused no major adverse events and increased platelet counts in patients with ITP. (ClinicalTrials.gov number, NCT00111475 [ClinicalTrials.gov].).
                Copyright 2006 Massachusetts Medical Society. To determine whether two low-dose regimens of aprotinin influence platelet function.
                Prospective, randomized, single-blinded trial.
                University teaching hospital performing 600 cardiac operations per year.
                Fifty-nine patients scheduled for cardiac surgery undergoing cardiopulmonary bypass (CPB) of expected duration of 60 minutes or more.
                Patients were randomized into three groups. Group C (control) included 21 patients who did not receive aprotinin. In group A2, 17 patients received 14,286 kallikrein inhibitor units (KIU)/kg (2 mg/kg) of aprotinin before surgery, followed by a continuous infusion of 7,143 KIU/kg/h (1 mg/kg/h) until the end of surgery. In group A4, 19 patients received 28,572 KIU/kg (4 mg/kg) of aprotinin before surgery, followed by the same infusion.
                Postoperative bleeding and transfusion requirements were significantly less in group A4. Changes in platelet number and function were similar in the three groups. Platelet aggregation was assessed in four periods: before CPB (T1), post-CPB (T2), and 2 hours (T3) and 4 hours (T4) after CPB. Platelet aggregation induced by adenosine diphosphate, 1 and 2 micromol/L; ristocetin, 1 mg/mL; and arachadonic acid (AA), 1.4 mmol/L, decreased at T2 (p < 0.001) in all groups, and for the ristocetin and AA groups, remained at less than baseline values at T3 and T4. In five patients from each group, platelet receptors for glycoprotein IIb-IIIa (GPIIb-IIIa) and expression of platelet activation markers, guanosine monophosphate 140 (GMP-140) and lysosomal protein, were measured by flow cytometry before and after CPB. Modifications in the expression of GPIIb-IIIa were always modest and without statistical significance. Platelet activation markers, GMP-140 or lysosomal protein, nearly doubled from baseline to post-CPB only in the A4 group, whereas they remained stable in both other groups (statistically not significant).
                The two regimens of aprotinin, both considered low dosage, did not exert a protective effect on platelet function. Neither dose produced changes in platelet GPIIb-IIIa or platelet activation markers. However, bleeding and transfusion needs were decreased. Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period.
                We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months' duration who had baseline platelet counts lower than 30,000 per μL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (≤ 15,000 per μL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50,000-400,000 per μL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331.
                Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8·2, 99% CI 3·59-18·73; p<0·0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0·016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0·001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag-treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients (vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (<1%) patient treated with eltrombopag.
                Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatment.
                GlaxoSmithKline.
                Copyright © 2011 Elsevier Ltd. All rights reserved. Ligand binding to the platelet membrane receptor glycoprotein (GP) IIb/IIIa, the final and obligatory step to platelet aggregation, can now be inhibited by pharmacological agents. This study was designed to evaluate the potential of lamifiban, a novel nonpeptide antagonist of GP IIb/IIIa, for the management of unstable angina.
                In a prospective, dose-ranging, double-blind study, 365 patients with unstable angina were randomized to an infusion of 1, 2, 4, or 5 micrograms/min of lamifiban or of placebo. Treatment was administered for 72 to 120 hours. Outcome events were measured during the infusion period and after 1 month. Concomitant aspirin was administered to all patients and heparin to 28% of patients. Lamifiban, all doses combined, reduced the risk of death, nonfatal myocardial infarction, or the need for an urgent revascularization during the infusion period from 8.1% to 3.3% (P = .04). The rates were 2.5%, 4.9%, 3.3%, and 2.4% with increasing doses. At 1 month, death or nonfatal infarction occurred in 8.1% of patients with placebo and in 2.5% of patients with the two high doses (P = .03). The highest dose of lamifiban additionally prevented the need for an urgent intervention. Lamifiban dose-dependently inhibited platelet aggregation. Bleeding times were significantly prolonged with platelet inhibition of > 80%. Major (but neither life-threatening nor intracranial) bleedings occurred in 0.8% of patients with placebo and 2.9% with lamifiban.
                The nonpeptide GP IIb/IIIa antagonist lamifiban protected patients with unstable angina from severe ischemic events during a 3- to 5-day infusion and reduced the incidence of death and infarction at 1 month, suggesting considerable promise for this new therapeutic approach. Aggregation of platelets is the pathophysiologic basis of the acute coronary syndromes. Eptifibatide, a synthetic cyclic heptapeptide, is a selective high-affinity inhibitor of the platelet glycoprotein IIb/IIIa receptor, which is involved in platelet aggregation. We tested the hypothesis that inhibition of platelet aggregation with eptifibatide would have an incremental benefit beyond that of heparin and aspirin in reducing the frequency of adverse outcomes in patients with acute coronary syndromes who did not have persistent ST-segment elevation.
                Patients who had presented with ischemic chest pain within the previous 24 hours and who had either electrocardiographic changes indicative of ischemia (but not persistent ST-segment elevation) or high serum concentrations of creatine kinase MB isoenzymes were enrolled in the study. They were randomly assigned, in a double-blind manner, to receive a bolus and infusion of either eptifibatide or placebo, in addition to standard therapy, for up to 72 hours (or up to 96 hours, if coronary intervention was performed near the end of the 72-hour period). The primary end point was a composite of death and nonfatal myocardial infarction occurring up to 30 days after the index event.
                A total of 10,948 patients were enrolled between November 1995 and January 1997. As compared with the placebo group, the eptifibatide group had a 1.5 percent absolute reduction in the incidence of the primary end point (14.2 percent, vs. 15.7 percent in the placebo group; P=0.04). The benefit was apparent by 96 hours and persisted through 30 days. The effect was consistent in most major subgroups except for women (odds ratios for death or nonfatal myocardial infarction, 0.8 [95 percent confidence interval, 0.7 to 0.9] in men, and 1.1 [0.9 to 1.31 in women). Bleeding was more common in the eptifibatide group, although there was no increase in the incidence of hemorrhagic stroke.
                Inhibition of platelet aggregation with eptifibatide reduced the incidence of the composite end point of death or nonfatal myocardial infarction in patients with acute coronary syndromes who did not have persistent ST-segment elevation.
There was currently no evidence to support that TPO receptor agonists are effective in chronic ITP. Compared to placebo or SOC, despite significantly increased platelet response, there was no evidence to demonstrate that TPO receptor agonists did improve significant bleeding events in chronic ITP. The effect on overall survival awaits further analysis. Although long-term studies are lacking, current data demonstrated adverse effects of TPO receptor agonists were similar to that of placebo and SOC.