TW201249439A - Method for reducing thrombocytopenia and thrombocytopenia-associated mortality - Google Patents

Abstract

Disclosed are methods for reducing the risk of thrombocytopenia-associated mortality and morbidity, and for reducing the risk of becoming thrombocytopenic, in patients whose treatment requires inhibition of platelet aggregation. The methods involve administration of a pharmaceutically acceptable salt of tirofiban.

Description

201249439 VI. INSTRUCTIONS: [Prior Art] Platelet reactivity (ie, activation and agglutination) is critical in the pathogenesis of complications following percutaneous coronary intervention (PCI) and occurs during PCI and immediately after PCI. The degree of platelet inhibition is the key to preventing further ischemic events. These events include reinfarction, revascularization of the target vessel, and other occlusive disease. These events can occur spontaneously or in response to invasive cardiac surgery such as PCI, coronary or peripheral bypass grafts, and heart valve replacement. Many measures have been taken in the past to inhibit platelet aggregation. Inhibitors of intravenous administration of glycoprotein (GP) IIb/IIIa receptor complexes are among these measures. This #inhibitor includes abciximab, tirofiban, and eptifibatide. Such inhibitors should be used concurrently with treatments known to cause unwanted platelet aggregation (e. g., administration of unfractionated heparin). However, it has also been widely observed that there is an inherent risk associated with administration of Ilb/IIIa inhibitors. These risks include large and small amounts of bleeding, and thrombocytosis is a particular concern. In fact, it has been observed that some patients who are protected from reinfarction and even death after PCI may be affected by forks and even death from thrombocytopenia caused by treatment with platelet aggregation inhibitors (mainly gastrointestinal bleeding or cranial Internal bleeding). The severity of platelet-reactive and myocardial damage in patients with ST-segment elevation myocardial infarction (STEMI) (4)! , J ^ various myocardial reperfusion measures (including ST segment recovery after treatment) are strongly related 2,3. In a recent study of abciximab (A) in a primary vascularized patient towel, 156633.doc 201249439, abciximab was used to significantly increase the ST segment fall 4 and also improved mortality at 12 months. Rofeban belongs to the same type as abciximab: anti-gold small (four) 'ie glycoprotein · intestinal depression _. However, tirofiban differs from abciximab in terms of pharmacodynamics and pharmacokinetic profile. Similar to abciximab, tirofiban inhibits platelet activity via glycoprotein and small plate receptor blockade, but unlike abciximab, tirofiban produces competitive and rapid reversible antagonism and does not It inhibits other β3 integrin (such as the glass-linked protein receptor) on the surface of vascular cells, or activates Mad receptor 7 on white blood cells. These have generally been considered important targets to explain the effect of abciximab, especially on the microcirculation in the recorded myocardial infarction environment8. The first direct comparison between abciximab and tirofiban was performed based on the difference in the effect of maintaining at least 5% of abciximab compared to placebo. In this study, abciximab was superior to tirofiban 9 in terms of pre-specified combination indicators. This result was generated by the higher incidence of perioperative myocardial infarction in the tirofiban group, which indicates early insufficient platelet inhibition using a bolus regimen (1 〇 Pg/kg). Subsequent different dose studies have shown that increasing the dose of tirofiban from 1 〇pg/kg to 25 pg/kg provides optimal platelet inhibition 1Q, and several independent pharmacokinetic studies indicate tirofiban Platelet inhibition n·13, which is more consistent than abciximab, can even be produced at increasing doses. To date, three small single-center studies11, I5, and a multicenter randomized study of premature cessation16 have compared high-dose tirofiban with abciximab in 719 patients who underwent PCI; however, None of the researches have sufficient ability to evaluate the comparison between the two drugs. 156633.doc 201249439 There is a need for a treatment regimen that has the desired effect of inhibiting platelet aggregation, but particularly among those who are susceptible to thrombocytopenia, while reducing thrombocytopenia and mortality associated with thrombocytopenia. It has been observed that thrombocytopenia is caused after administration of tirofiban, but it is not significantly higher than the placebo or blank treatment group. It has been widely recognized that tirofiban (GP IIb/ma receptor antagonist) will have a risk profile comparable to other drugs in this category. SUMMARY OF THE INVENTION The present inventors have surprisingly found that a single sputum dose bolus (HDB) tirofiban hydrochloride and subsequent continuous infusion for several hours compared to the effect of abciximab Rofeban hydrochloride causes a significant reduction in the incidence of thrombocytopenia and morbidity and mortality associated with thrombocytopenia. [Examples] Tirofiban hydrochloride (available from AGGRASTAT®) is a non-peptide inhibitor of the platelet GP Ilb/IIIa receptor (the major platelet surface party associated with platelet aggregation). It is chemically described as N-(butylsulfonyl)-indole-[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride or 2-S-(n-butyl) The sulfamoylamino)-3[4-(piperidin-4-yl)butoxyphenyl]propionate salt is described in U.S. Patent No. 5,292,756. Its structure is:

From October 2004 to April 2007, experienced ST-segment elevation myocardial infarction S. 156633.doc 201249439

Phase III open-label cross-country study entitled "Multicentre Evaluation of Single High-Dose Bolus Tirofiban vs Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study" (MULTISTRATEGY) was performed in 745 patients (STEMI). The basic design of the study was detailed earlier. Briefly, patients were randomly assigned to one of four reperfusion intervention strategies using a 2x2 factorial design: abciximab with uncoated scaffold; abcix with sirolimus dissolving scaffold Resistance; HDB tirofiban hydrochloride with uncoated scaffold; or HDB tirofiban hydrochloride with sirolimus-dissolved scaffold. In all four groups, except for the slightly higher prevalence of previous transient ischemic episodes in the tirofiban/uncoated stent group, other patient characteristics were similar. Inclusion criteria were: (1) chest pain for more than 30 minutes, and in two or more adjacent ECG leads, ECG ST segment elevation was 1 mm or greater, or new left bundle branch block, and (2) The symptoms were seen within 12 hours or 12 to 24 hours after the onset of signs of ischemia. Exclusion criteria included administration of fibrinolytic agents over the past 30 days; major surgery within 15 days; and active bleeding or stroke history over the past 6 months. Therapists at each study site then performed open label assignments for study treatment via sealed envelopes after meeting the eligibility criteria and prior to visualization of the coronary vessels via angiography. A non-hierarchical random assignment was achieved using a 1:1:1:1 computer-generated random sequence provided by theoretical statisticians, with 30 blocks. Tirofiban hydrochloride was administered as a single high-dose bolus (25 pg/kg bolus) followed by a continuous infusion (0.15 pg/kg/min for 18 to 24 hours). Such a scheme is described in U.S. Patent No. 6,770,660. Abciximab was administered as a single dose of 156633.doc 201249439 0.25 mg/kg, followed by continuous infusion for 12 hours at p125 pg/kg/min. At the first medical contact, the two drugs were started before the insertion of the arterial sheath. Heparin is administered at 4 to 7 〇 u/kg and the target is at least 200 seconds of activated clotting time. Patients received aspirin (160 to 325 mg or 250 mg intravenously, followed by 80 to 125 mg/day indefinitely) and cl〇pid〇grel (300 mg orally and then 75 mg/d) d, lasting at least 3 months). A 12-lead electrocardiogram was recorded 90 minutes after surgery and 90 minutes after the last balloon inflation in the infarct-related artery. Follow-up is scheduled for the first, fourth and eighth months. Data from all patients with major outcome events were reviewed by an independent adjudication committee whose members were blinded to treatment assignments. The two members will each decide on the event 'and in the case of inconsistency' and obtain the opinion of the third member, and the final decision will be made by negotiation. The committee is also responsible for accumulating changes in the st-segment of the ECG before and after 90 minutes of all clinical events, according to the Academic Research Consortium. ST-segment elevation was measured and accurate to 〇.5 mm by a separate experienced cardiologist who was blinded to treatment assignments 60 ms after point J. In the 217 patients who were randomly selected, the recovery was determined by at least 5% of the st-segment elevation, and the intra-observer consistency was 94·1〇/α (Κ=0·82) (all explained ECG 30) %). Coronary arterial flow was classified by quantitative angiographic analysis using an effective edge detection system (Caas η; Pie Medical, Maastricht, the Netherlands) and according to thrombolytic in the myocardial infarction (TIMI) criteria. An arterial analysis and TIMI grading was performed by an independent cardiologist who did not know about the treatment assignment 156633.doc 201249439. The discrete data is aggregated into frequencies and compared using a likelihood ratio χ2 test or a Fisher exact test. The continuous data is expressed as the mean (sd) or as the median and interquartile range according to its distribution; it is compared using the one-way variance analysis or the Kruskal-Wallis test. For a comparison between the drug groups, a total of 58 patients were required to have a ST-segment elevation drop of at least 5% (which is equivalent to the 50% absolute difference previously observed between abciximab and placebo). 5, and based on previous research results, the absolute difference between the two groups of patients with a significant level of 2·5 ° / ό, and the expected event rate of 85 / 〇 in the control group (relative risk) And 5 series 0_89) achieve greater than 85% efficiency. Using Duncan (1) Can's (1) and Gent's continuity correction χ2, the computer is used to perform a non-inferiority test on the entire patient cohort. This is based on intention-to-treat and compliance principles and is applied to several pre-specified subgroups. Explore the analysis. Cochran-Mantel-Haenszel/inspection was conducted to assess possible relative risk imbalances between different recruitment centers. Compared with abciximab, tirofiban produced a non-inferior recovery from ST-segment elevation after coronary intervention; this result was consistent across different recruitment centers and multiple pre-specified subgroups. Similarly, major adverse cardiovascular events (MACE, determined as a composite event for any cause of death, reinfarction, and clinically induced dry blood regeneration) or bleeding events in tirofiban or abciximab There was no difference between the groups, but compared with the abciximab group, the incidence of sputum, 'non-class, and moderate to moderate or moderate thrombocytopenia was low (probability of clinical relevance) 丨9 . 156633.doc 201249439 For the treatment of high-risk patients, the normalization of ST-segment elevation is crucial. ST-segment regression associated with small infarct size and transmurality is a strong and independent prognostic factor for death or death/MI (death or myocardial infarction), and the internal control of the MULTITRATELY study shows that at least 50% of the lamp segment fall back For the patient, the survival rate without death/MI increased (95% vs 89%, P = 〇.〇23). Regarding the comparison of HDB with tirofiban and abciximab, the primary indicator was the incidence of an increase of 250% in the sacral segment within 9 minutes after percutaneous coronary intervention. The results of the study showed that in the intention-to-treat analysis, abciximab (3 in 2 of 361 patients, 83 6%) and 11][)]5 patients treated with tirofiban (361 patients) There was no significant difference in the percentage of patients who achieved at least 50% ST-segment fallback between 3〇8 and 853%) (the relative risk of tirofiban versus abciximab was 1〇2〇; 97 5% confidence interval It is 〇958 to 1.086; the value of non-inferiority test is <0 001). Compliance analysis yielded similar results (relative risk 1.020; 97.5% confidence interval 〇 959 to 1.086, p-value for non-inferiority test < 〇 〇〇丨). Therefore, this data shows that the use of HDB for rofeban treatment produces a non-inferior ST segment fallback compared to abciximab. (See Figure 1.) Surprisingly, the onset of thrombocytopenia has a significant impact on patient outcomes. As can be seen in Figure 2, patients with clinically under-reported patients (gold plate count <100,000/μ1 [light shade]) are more likely to die after surgery than non-small platelets ( The platelet count is > 丨〇〇, 〇〇〇/μ1 [dark shade] is more than five times higher. Similarly, patients with thrombocytopenia who are dying or have a myocardial infarction after treatment are about 3 times more likely than those with non-grey platelet disease and are only 25 times more likely to have MACE than those with non-platelet hyperactivity.

B 156633.doc 201249439 More. In 30 days, the ischemic and hemorrhagic outcomes of HDB in the rofeban and abciximab groups (thrombotic lysis (TIMI), massive and small amounts of bleeding in myocardial infarction) were similar (7.2% vs. 7.8%, The corpse = 0.89), just as the incidence of MACE (4.0% vs. 4.3 7%, household = 〇·85). However, it was found that the incidence of severe or moderate oligospermia was significantly higher in patients treated with abciximab compared to those treated with HDB for tirofiban (4.0% vs 0.8%, Ρ =0·004). (See Table 1). Even more strikingly, although the mortality rate of non-platelet patients with HDB for tirofiban or acitretin is actually the same, it becomes platelets after treatment with HDB for tirofiban or abciximab. Significant differences were observed in follow-up studies of mortality data for patients with hypothyroidism. As can be seen in Figure 3, 20 ° /. Patients with abciximab-induced thrombocytopenia died within 8 months, whereas patients with HDB tirofiban-induced thrombocytopenia did not die within the next 8 months. Within 8 months, the incidence of MACE between the HDB tirofiban and abciximab-treated groups was similar (9 9% vs. 12 4〇/〇, household = 〇 3〇) (Table 丨). In the intention-to-treat group, the probability of death/ΜI was 7.5 % in patients treated with abciximab within 8 months after treatment, and *9% in patients treated with HDB for rofeban (Ρ=〇· 5 5). (See Table j and Figure 4) Therefore, the data first showed that the replacement of rofeban treatment surprisingly resulted in a significant reduction in the incidence of severe or moderate thrombocytopenia compared to abciximab treatment. This data additionally shows that the mortality rate of patients with stilbine-induced thrombocytopenia is surprisingly lower than that of abciximab-induced thrombocytopenia patients. 156633.doc 201249439 Table 1 Table 3.30 days and 8 months of clinical results of Kaplanmeier ^mpigj^Meier) evaluation results abciximab plus abciximab fortifixol non-stent drug anti-gaxiban plus Benghazi 1 -1 1 ~ Coated Ramos Coated Ramos uncoated siroli stent Acibutrol drug rack Dissolved stent Dissolved stents Dissolved between mAbs and non-classes (n= 186) Frame (n=186) frame (n=372) P value of the bracket P value (n=372) (n=372) (n=186) (n=186) (n=372) Death 6 (3.2 ) 30 days, number 3 (1.6) 2 (1.1) 2 (1-1) 8 (2.2) 5 (1.3) 0.40 9 (2.4) 4 (1.1) 0.16 reinfarction 5 (2.7) 0 5 (2.7) 5 ( 2.7) 10(2.7) 5(1.3) 0.19 5(1.3) 10(2.7) 0.20 Death or reinfarction 11(5.9) 3(1.6) 7(3.8) 7(3.8) 18(4.8) 10(2.7) 0.12 14 (3.8) 14(3.8) 0.98 Clinically promoted target angiogenesis 5(2.7) 1(0.5) 3(1,6) 5(2.7) 8(2.2) 6(1.6) 0.59 6(1.6) 8(2.2) 0.59 Compound event of death, reinfarction' or angiogenesis 12(6.4) 4(2.2) 7(3.8) 8(4.3) 19(5.1) 12(3.2) 0.20 16(4.3) 15(4.0) 0.85 4 fixed stent blood Plug formation 4(2.2) 1(0.5) 3(1.6) 4(2.2) 7(1.9) 5(1.3) 0.56 5(1.3) 7(1.9) 0.56 Probable stent thrombosis 2(1-1) 1( 0.5) 2(1.1) 0 4(1.1) 1(0.3) 0.18 3(0.8) 2(0.5) 0.65 Determine or likely stent blood formation 6(3.2) 2(1-1) 5(2.7) 4( 2.2) 11(3.0) 6(1-6) 0.22 8(2.2) 9(2.4) 0.81 Safety Analysis 3(1.6) 3(1.6) 5(2.7) 4(2.2) 8(2.2) 7(1.9) 0.79 6 (1.6) 9(2.4) 0.44 Large amount of bleeding Small amount of bleeding 15(8.1) 8(4.3) 11(5.9) 7(3.8) 26(7.0) 15(4.0) 0.09 23(6.2) 18(4.8) 0.40 Red jk ball blood transfusion Unit 1 4 (2.2) 4 (2.2) 9 (4.8) 5 (2.7) 13 (3.5) 9 (2.4) 0.39 8 (2.2) 14 (3.8) 0.20 22 units 4 (2.2) 4 (2.2) 6 (3.2 3(1.6) 10(2.7) 7(1.9) 0.46 8(2.2) 9(2.4) 0.82 Severe thrombocytopenia (<50,000 sprints/mm3) 6(3.2) 3(1.6) 2(1.1) 0 8(2.2) 3(0.8) 0.23 9(2.4) 2(0.5) 0.03 Moderate thrombocytopenia (<100,000 cells/mm3) 2(1.1) 4(2.2) 1(0.5) 0 3(0.8) 4 (1.1) 0.70 6(1.6) 1(0.3) 0.06 8 months, number (%) Compound event of death, reinfarction, or vascular regeneration 30(16.1) 16(8.6) 24(12.9) 13(7.0) 54 (14 .5) 29(7.8) 0.004 46(12.4) 37(9.9) 0.30 Death 8(4.3) 7(3-8) 7(3.8) 4(2.2) 15(4.0) 11(3.0) 0.42 15(4.0) 11 (3.0) 0.42 Reinfarction 9 (4.8) 4 (2.2) 8 (4.3) 8 (4.3) 17 (4.6) 12 (3.2) 0.34 13 (3.5) 16 (4.3) 0.57 Death or reinfarction 16 (8.6) 11 ( 5.9) 12(6.5) 11(5.9) 28(7.5) 22(5.9) 0.37 28(7.5) 22(5.9) 0.55 Clinically promoted blood 21 (11.3 6(3.2) 17(9.1) 6(3.2) 38( 10.2 12(3.2) <0.001 27(7.3) 23(6.2) 0.58 tube regeneration)) Determined stent thrombosis 7(3.8) 3(1-6) 4(2.2) 6(3.2) 11(3.0) 9( 2.4) 0.65 10(2.7) UH2.7) 0.99 Possible stent plug formation 1(0.5) 3(1.6) 3(1-6) 0 4(1.1) 3(0.8) 0.71 4(1.1) 3(0.8) 0.70 Affirmative or Probable Stent Thrombosis 9(4.8) 4(2.2) 6(3.2) 6(3.2) 15(4.0) 10(2.7) 0.31 13(3.5) 12(3.2) 0.85 Affirmative or Probable or Possible Stent Thrombosis 9(4.8) 7(3.8) 8(4.3) 6(3.2) 17(4.6) 13(3.5) 0.45 16(4.3) 14(3.8) 0.71 can be used in any patient who desires or needs to inhibit platelet aggregation or adhesion.治-11· 156633.doc 201249439 already suffering from platelet

To a range of about 30 pg/kg, and subsequent continuous infusion can range from about 0.10 Torr to about 0.20 pg/kg/min for about 6 to about 108 hours. The method of the invention is used during treatment. Such patients may include patients who have been ill, have had thrombocytopenia or are prone to platelet, and the subjects of the present invention are not limited to the administration of tirofiban hydrochloride; any medicine may be used. It can be used as a timofiban salt. Such salts include, but are not limited to, acetate, besylate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, bismuth ethylenediaminetetraacetate, camphor hydrochloride Salt, carbonate, vapor, clavulanate, citrate, dihydrochloride, ethylenediaminetetraacetate, ethyl sulphate, etidinate, ethyl citrate, fumarate, glucoheptane Saccharate, gluconate, glutamate, ethanol oxime p-aminobenzoate, hexyl resorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthalene Formate, moth, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl Nitrate, sulfhydryl sulfate, mucic acid salt, naphthenate, acid salt, oleate, oxalate, dip-naphthate, palmitate, pantothenate, phosphate/diphosphate, Polygalacturonate, salicylate, stearate, acetate, boroline 156633.doc •12- 201249439 salt, tannic acid, tartrate Tea chloro, tosylate, triethylammonium iodide and valerate. References 1. Frossard®, Fuchs I, Leitner JM, et al., Platelet function predicts myocardial damage in patients with acute myocardial infarction. Circulation. 2004; 1 10(1 1): 1392-1397. 2. Campo G, Valgimigli M, Gemmati D et al, Value of platelet reactivity in predicting response to treatment and clinical outcome in patients undergoing primary coronary intervention: insights into the STRATEGY Study. J Am Coll Ca/^o/· 2006; 48 (1 1): 2178-2185 » 3. Huczek Z, Filipiak KJ, Kochman J, et al., Baseline platelet reactivity in acute myocardial infarction with primary angioplasty: influence on myocardial reperfusion, left ventricular performance, and clinical events. Jw Open 2007 ; 154(1): 62-70. 4. Antoniucci D, Migliorini A, Parodi G, et al, Abciximab-supported infarct artery stent implantation for acute myocardial infarction and long-term survival: a prospective, multicenter, randomized trial comparing infarct artery stenting plus abciximab with stenting alone. 2004; 109 (14): 1704-1706.

5. Antoniucci D, Rodriguez A, Hempel A, et al, A s 156633.doc -13- 201249439 randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction. J Co// Carc/io/· 2003; 42 (11)·· 1879-1885. 6. Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. 1999; 353(9148): 227-231 ° 7. Lele M, Sajid M, Wajih N, Stouffer GA. Eptifibatide and 7E3, but not tirofiban, Inhibit alpha(v) beta(3) integrin-mediated binding of smooth muscle cells to thrombospondin and prothrombin. 2001; 104(5): 582-587 0 8. Reininger AJ, Agneskirchner J, Bode PA, Spannagl M, Wurzinger LJ. c7E3 Fab inhibits low shear flow modulated platelet adhesion to endothelium and surface-absorbed fibrinogen by blocking platelet GP lib/ Ilia as well as endothelial vitronectin receptor: results from patients with acute myocardial infarction and healthy controls. ZTzro/w厶2000; 83(2 ): 217-223 o 9. Topol EJ, Moliterno DJ, Herrmann HC et al, Comparison of two platelet glycoprotein Ilb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N five g/ /Med. 2001; 344(25): 1888-1894 〇10. Schneider DJ, Herrmann HC, Lakkis N, etc. Increased concentrations of tirofiban in blood and their correlation with inhibition of platelet aggregation after 156633.doc •14· 201249439 greater bolus doses of tirofiban. Am J Cardiol. 2003; 91(3): 334-336 « 11. Valgimigli M, Percoco G, Malagutti P et al, Tirofiban and sirolimus-eluting stent vs abciximab and bare-metal stent for acute myocardial infarction: a random-ized trial. «/U. 2005; 293(17): 2109-2117. 12. Danzi GB 'Capuano C ' Sesana M ' Mauri L ' Sozzi FB. Variability in extent of platelet function inhibition after administration of optimal dose of glycoprotein Ilb/IIIa receptor blockers in patients undergoing a high-risk percutaneous coronary intervention. Am J Cardiol 2006; 97(4): 489-493 ° 13. Ernst NM, Suryapranata H, Miedema K et al, Achieved platelet aggregation inhibition after different antiplatelet regimens during percutaneous coronary intervention for ST-segment elevation myocardial infarction, «/dw Co/ / Cardb/. 2004; 44(6): 1 187-1 193. 14. Bolognese L, Falsini G, Liistro F et al, Randomized comparison of upstream tirofiban versus downstream high bolus dose tirofiban or abciximab on tissue-level perfusion and troponin release in high-risk acute coronary syndromes treated with percutaneous coronary interventions: the EVEREST trial Dm Co// 2006; 47(3): 522-528. 15. Danzi GB, Sesana M, Capuano C, Mauri L, Berra s 156633.doc -15- 201249439

Centurini P, Baglini R. Comparison in patients having primary coronary angioplasty of abciximab versus tirofiban on recovery of left ventricular function. Am J Cardiol, 2004; 94(1): 35-39 ° 16. TENACITY trial officially halted; Guilford seeks partner or Buyer for tirofiban. Http://www.theheart.org /view Article, do ?primary Key=5 16083&from=/searchLayout.d 〇· Accessed January 9, 2008 o 17. Valgimigli M, Bolognese L, Anselmi M, et al., Two- By-two factorial comparison of high-bolus-dose tirofiban followed by standard infusion versus abciximab and sirolimus-eluting versus bare-metal stent implantation in patients with acute myocardial infarction: design and rationale for the MULTI-STRATEGY trial. Am Heart J. 2007 154(1): 39-45 ° 18. Cutlip DE, Windecker S, Mehran R, et al, Clinical end points in coronary stent trials: a case for standardized definitions. 2007; 115(17): 2344-2351 ° 19. Merlini PA, Rossi M, Menozzi A et al, Thrombocytopenia caused by abciximab or tirofiban and its association with clinical outcome in patients undergoing coronary stenting. 2004; 109(18): 2203-2206. Schematic Description Figure 1 shows the non-inferiority analysis of tirofiban relative to abciximab. The 156633.doc -16- 201249439 analysis is based on the comparison of the effectiveness of the main indicators. The primary indicator is defined as achieving at least 50% fall/recovery from ST-segment elevation in a 12-lead ECG 90 minutes after intervention. Figure 2 shows a comparison of the results of a treated myocardial infarction patient within 8 months, depending on whether the patient becomes a platelet that is a side effect of treatment (light shades versus dark shades). Comparison of death, death, or myocardial infarction for any cause, and major adverse cardiac events (defined as a composite event for any cause of death, reinfarction, and clinically-promoted target angiogenesis within the first 8 months) Probability. Figure 3 shows a comparison of the probability of death in patients treated with HDB for tirofiban or abciximab within 8 months of treatment, depending on whether the patient has (light shades) or not (dark shade) thrombocytopenia. Figure 4 shows a comparison of the probability of a clinical event (death or reinfarction) experienced in patients undergoing myocardial infarction treated with HDB tirofiban or abciximab within 8 months of treatment [Simplified illustration] Figure 1 shows Tero Non-inferiority analysis of tirofiban compared to abciximab. Figure 2 shows the effect of thrombocytopenia on patient outcomes in patients undergoing primary PCI surgery. Figure 3 shows the results of a comparison of the effects of thrombocytopenia on mortality in patients treated with HDB for tirofiban or abciximab. Figure 4 shows a comparison of the likelihood that a patient will experience a clinical event (death or myocardial infarction) within 8 months of treatment with HDB for tirofiban or abciximab. 156633.doc

Claims (1)

201249439 VII. Application for Patent Park: 1. A tir〇fiban salt, which is used as a thrombocytopenia-related mortality or morbidity for patients with conditions that require inhibition of platelet aggregation therapy. The risk or the risk of becoming a risk of thrombocytopenia. 2. The tirofiban salt of claim 1, wherein the tirofiban salt is tirofiban hydrochloride. 3. If the request item! or 2 is tirofiban salt, the patient has had too few platelets, pre-existing platelets or pre-existing platelet deficiency or is normal in this regard. 4. The tirofiban salt used as a drug in claim (4), wherein the tirofiban is administered intravenously in a single high dose bolus followed by continuous infusion over time. 5. The tirofiban salt for use as a medicament according to claim 3, wherein the tirofiban is administered intravenously in a single high dose bolus followed by continuous infusion over time. 6. The tirofiban salt for use as a medicament according to claim 4, wherein the single high dose bolus is about 25 g and the continuous infusion is about _g/min for about 18 to 24 hours. As for the drug used in the item 5, "7^* Ding 03⁄4 is about 25 Hg/kg and the continuous infusion is about 15 to 24 hours. Used to reduce the need for thrombocytosis. 8. Use of a tirofiban salt for the treatment of patients with conditions to inhibit platelet aggregation. 156633.doc 201249439 Risk of mortality or morbidity or becoming platelets The drug. < Risk 9· The use of claim 8 wherein the tirofiban salt system, tirofiban hydrochloride 0 10 female ^ luxury card _ ts . ^ the use of item 8 or 9, wherein The patient has had too few platelets, the first month is too little gray plate or susceptible to thrombocytopenia or is normal in this regard. 156633.doc