tirofiban hydrochloride , commercially available as aggrastat ®, is a nonpeptide inhibitor of the platelet gp iib / iiia receptor , the major platelet surface receptor involved in platelet aggregation . it is chemically described either as n -( butylsulfonyl )- o -[ 4 -( 4 - piperidinyl ) butyl ]- tyrosine monohydrochloride or 2 - s -( n - butylsulfonylamino )- 3 [ 4 -( piperidin - 4 - yl ) butyloxyphenyl ] propionic acid hydrochloride and is described in u . s . pat . no . 5 , 292 , 756 . its structure is : from october 2004 to april 2007 , a phase iii , open - label , multinational study of 745 patients experiencing st - segment elevation myocardial infarction ( stemi ), entitled the 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 conducted . the basic design of the study was detailed earlier . 17 briefly , patients were randomly assigned with the use of a 2 × 2 factorial design to one of four interventional strategies of reperfusion : abciximab with an uncoated stent ; abciximab with a sirolimus - eluting stent ; hdb tirofiban hydrochloride with an uncoated stent ; or hdb tirofiban hydrochloride with a sirolimus - eluting stent . patient characteristics were similar among all four groups except that there was a slightly higher prevalence of prior transient ischemic attacks in the tirofiban / uncoated - stent groups . the inclusion criteria were ( 1 ) chest pain for longer than 30 minutes with an electrocardiographic st - segment elevation of 1 mm or greater in two or more contiguous electrocardiogram leads , or with a new left bundle - branch block , and ( 2 ) admission either within 12 hours of symptom onset or between 12 and 24 hours after onset with evidence of continuing ischemia . the exclusion criteria included administration of fibrinolytics in the previous 30 days , major surgery within 15 days , and active bleeding or previous stroke in the last six months . immediately after eligibility criteria were met and before the visualization of coronary arteries through angiography , the treating physician at each investigational site performed open - label assignments of study treatments via sealed envelopes . randomization was achieved with a 1 : 1 : 1 : 1 computer - generated random sequence supplied by an academic statistician , without stratification , in blocks of 30 . tirofiban hydrochloride was administered in a high - dose bolus ( 25 μg / kg bolus ) followed by a continuous infusion ( 0 . 15 μg / kg / min for 18 - 24 hours ). this type of regimen is described in u . s . pat . no . 6 , 770 , 660 . abciximab was administered in a 0 . 25 mg / kg bolus , followed by 0 . 125 μg / kg / min continuous infusion for 12 hours . the administration of both drugs began at first medical contact , before arterial sheath insertion . heparin was given at 40 to 70 u / kg , targeting an activated clotting time of at least 200 seconds . patients received aspirin ( 160 - 325 mg orally or 250 mg intravenously , followed by 80 - 125 mg / d orally indefinitely ) and clopidogrel ( 300 mg orally and then 75 mg / d for at least three months ). a 12 - lead electrocardiogram was recorded before the procedure and 90 minutes after the last balloon inflation in the infarct - related artery . follow - up visits were scheduled at one , four , and eight months . the data for all patients with primary end - point events were reviewed by an independent adjudication committee whose members were blinded to treatment assignments . events adjudication was performed separately by two members , and in case of disagreement , the opinion of the third member was obtained and the final decision taken by consensus . the committee was also responsible for the adjudication of all clinical events according to the academic research consortium . 18 changes in the st - segment of the electrocardiogram were evaluated cumulatively before and 90 minutes after intervention . st - segment elevation was measured to the nearest 0 . 5 mm at 60 milliseconds after the j point by a single experienced cardiologist who was blinded to treatment assignments . the intraobserver agreement was 94 . 1 % ( k = 0 . 82 ) in identifying the recovery by at least 50 % of st - segment elevation in 217 randomly selected patients ( 30 % of all interpretable electrocardiograms ). quantitative angiographic analyses were performed with a validated edge - detection system ( caas ii ; pie medical , maastricht , the netherlands ), and coronary flow was classified according to thrombolysis in myocardial infarction ( timi ) criteria . angiographic analyses and timi grading were performed by one independent cardiologist who was blinded to treatment assignments . discrete data were summarized as frequencies , and comparisons were made with the likelihood - ratio χ 2 test or fisher exact test . continuous data were expressed as mean ( sd ) or median and interquartile range according to their distribution ; comparisons were made with a one - way analysis of variance or the kruskal - wallis test . with respect to comparison between drug groups , a total of 580 patients was required for greater than 85 % power in detecting a 9 % absolute difference , 0 . 89 in terms of relative risk , between groups in the proportion of patients who attained at least 50 % resolution of st - segment elevation , which corresponds to the 50 % previously observed absolute difference between abciximab and placebo , 5 with a two - sided 2 . 5 % significance level and an 85 % expected event rate in the control group based on previous findings . 5 the noninferiority test was computed with the continuity - corrected χ 2 of dunnett and gent on the entire patient cohort . this was based on both intention - to - treat and per - protocol principles and was applied to an exploratory analysis across several prespecified subgroups . the cochran - mantel - haenszel χ 2 test was performed to evaluate possible imbalances of the relative risk among different recruiting centers . tirofiban yielded noninferior recovery from st - segment elevation after coronary intervention in comparison with abciximab ; this result was consistent across different recruiting centers and multiple prespecified subgroups . similarly , the rate of major adverse cardiovascular events ( mace , identified as the composite of death from any cause , reinfarction , and clinically - driven target - vessel revascularization ) or bleeding events did not differ between the tirofiban or abciximab groups , but the incidence of severe or moderate thrombocytopenia was lower in the tirofiban group compared with the abciximab group , a finding of potential clinical relevance . 19 normalization of st - segment elevation is crucial for managing high - risk patients . st - segment resolution , correlated to small infarct size and transmurality , is a strong and independent prognostic factor for death or death / mi ( death or myocardial infarction ), and internal controls from the multistrategy study showed an increase in death / mi - free survival ( 95 % versus 89 %, p = 0 . 023 ) for patients achieving st - segment resolution of at least 50 %. with respect to the comparison of hdb tirofiban and abciximab , the primary endpoint was the incidence of ≧ 50 % resolution in st - segment elevation within 90 minutes following percutaneous coronary intervention . the results of the study showed no significant difference in the percentage of patients achieving at least 50 % st - segment resolution between the abciximab ( 302 out of 361 patients , 83 . 6 %) and the hdb - tirofiban - treated patients ( 308 out of 361 patients , 85 . 3 %) in the intention - to - treat analysis ( relative risk for tirofiban vs . abciximab , 1 . 020 ; 97 . 5 % confidence interval , 0 . 958 - 1 . 086 ; p value & lt ; 0 . 001 for noninferiority ). the per - protocol analysis yielded similar results ( relative risk , 1 . 020 ; 97 . 5 % confidence interval , 0 . 959 - 1 . 086 ; p & lt ; 0 . 001 for noninferiority ). the data thus showed that treatment with hdb tirofiban led to noninferior st - segment resolution compared with abciximab . ( see fig1 .) surprisingly , the onset of thrombocytopenia had a significant effect on patient outcome . as can be seen in fig2 , patients with clinical thrombocytopenia ( a platelet count of & lt ; 100 , 000 / μl [ lighter shading ]) were greater than five times more likely to die following the procedure than nonthrombocytopenic patients ( platelet count of & gt ; 100 , 000 / μl [ darker shading ]). similarly , thrombocytopenic patients were approximately three and one - half times more likely to die or have a myocardial infarction and greater than two and one - half times more likely to suffer a mace following treatment than nonthrombocytopenic patients . at 30 days , ischemic and hemorrhagic outcomes ( thrombolysis in myocardial infarction ) ( timi ), major and minor bleeding ) were similar in the hdb - tirofiban and abciximab groups ( 7 . 2 % vs . 7 . 8 %, p = 0 . 89 ), as was the incidence of mace ( 4 . 0 % vs . 4 . 37 %, p = 0 . 85 ). however , the incidence of severe or moderate thrombocytopenia was found to be significantly greater in patients treated with abciximab compared with those treated with hdb tirofiban ( 4 . 0 % vs . 0 . 8 %, p = 0 . 004 ). ( see table 1 .) even more striking , while the mortality rates of nonthrombocytopenic patients treated with hdb tirofiban or abciximab were virtually identical , a remarkable difference was seen in the follow - up study of the data in the mortality rate for patients who became thrombocytopenic following treatment with hdb tirofiban or abciximab . as can be seen in fig3 % of the patients with abciximab - induced thrombocytopenia died within eight months , whereas none of the patients with hdb - tirofiban - induced thrombocytopenia died in the following eight - month period . at eight months , the incidence of mace was found to be similar between the hdb - tirofiban and abciximab treatment groups ( 9 . 9 % vs . 12 . 4 %, p = 0 . 30 ) ( table 1 ). in the intent - to - treat population , the probability of death / mi within eight months after treatment was 7 . 5 % for patients treated with abciximab versus 5 . 9 % for patients treated with hdb tirofiban ( p = 0 . 55 ). ( see table 1 and fig4 .) thus , the data show in the first place that hdb - tirofiban treatment surprisingly results in significantly diminished incidence of severe or moderate thrombocytopenia compared to abciximab treatment . the data further show a surprising reduction in mortality of patients with hdb - tirofiban - induced thrombocytopenia vs . abciximab - induced thrombocytopenia . the methods of the present invention can be employed during the treatment of any patients for whom inhibition of platelet aggregation or adhesion is desired or required . such patients can include patients who are already thrombocytopenic , are prethrombocytopenic or predisposed to thrombocytopenia , or are normal in this regard . the treatments to which the patients are being subjected may be , but are not confined to , arterial grafts , carotid endaterectomy and other cardiovascular procedures wherein manipulation of arteries or organs , and / or the interaction of platelets with artificial surfaces , leads to platelet aggregation and potential formation of thrombi and thromboemboli . the practice of the invention is not limited to the preferred administration regimen described earlier herein ; any suitable hdb / continuous - infusion regimen may be employed . for example , the hdb may be in the range of about 20 to about 30 μg / kg and the subsequent continuous infusion may be in the range of about 0 . 10 to about 0 . 20 μg / kg / min for a period of about 6 to about 108 hours . the practice of the invention is not limited to the administration of the hydrochloride salt of tirofiban ; any pharmaceutically acceptable tirofiban salt may be employed . such salts include , but are not limited to , acetate , benzenesulfonate , benzoate , bicarbonate , bisulfate , bitartrate , borate , bromide , calcium edetate , camsylate , carbonate , chloride , clavulanate , citrate , dihydrochloride , edetate , edisylate , estolate , esylate , fumarate , gluceptate , gluconate , glutamate , glycollylarsanilate , hexylresorcinate , hydrabamine , hydrobromide , hydrochloride , hydroxynapthoate , iodide , isothionate , lactate , lactobionate , laurate , malate , maleate , mandelate , mesylate , methylbromide , methyinitrate , methylsulfate , mucate , napsylate , nitrate , oleate , oxalate , pamoate , palmitate , panthothenate , phosphate / diphosphate , polygalacturonate , salicylate , stearate , subacetate , succinate , tannate , tartrate , teoclate , tosylate , triethiodide and valerate . 1 . frossard m , fuchs i , leitner j m , et al . platelet function predicts myocardial damage in patients with acute myocardial infarction . circulation . 2004 ; 110 ( 11 ): 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 cardiol . 2006 ; 48 ( 11 ): 2178 - 2185 . 3 . huczek z , filipiak k j , kochman j , et al . baseline platelet reactivity in acute myocardial infarction treated with primary angioplasty : influence on myocardial reperfusion , left ventricular performance , and clinical events . am heart j . 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 . circulation . 2004 ; 109 ( 14 ): 1704 - 1706 . 5 . antoniucci d , rodriguez a , hempel a , et al . a randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction . j am coll cardiol . 2003 ; 42 ( 11 ): 1879 - 1885 . 6 . topol e j , byzova t v , plow e f . platelet gpiib - iiia blockers . lancet . 1999 ; 353 ( 9148 ): 227 - 231 . 7 . lele m , sajid m , wajih n , stouffer g a . eptifibatide and 7e3 , but not tirofiban , inhibit alpha ( v ) beta ( 3 ) integrin - mediated binding of smooth muscle cells to thrombospondin and prothrombin . circulation . 2001 ; 104 ( 5 ): 582 - 587 . 8 . reininger a j , agneskirchner j , bode p a , spannagl m , wurzinger l j . c7e3 fab inhibits low shear flow modulated platelet adhesion to endothelium and surface - absorbed fibrinogen by blocking platelet gp iib / iiia as well as endothelial vitronectin receptor : results from patients with acute myocardial infarction and healthy controls . thromb haemost . 2000 ; 83 ( 2 ): 217 - 223 . 9 . topol e j , moliterno d j , herrmann h c , et al . comparison of two platelet glycoprotein iib / iiia inhibitors , tirofiban and abciximab , for the prevention of ischemic events with percutaneous coronary revascularization . n engl j . med . 2001 ; 344 ( 25 ): 1888 - 1894 . 10 . schneider d j , herrmann h c , lakkis n , et al . increased concentrations of tirofiban in blood and their correlation with inhibition of platelet aggregation after 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 randomized trial . jama . 2005 ; 293 ( 17 ): 2109 - 2117 . 12 . danzi g b , capuano c , sesana m , mauri l , sozzi f b . variability in extent of platelet function inhibition after administration of optimal dose of glycoprotein iib / iiia receptor blockers in patients undergoing a high - risk percutaneous coronary intervention . am j . cardiol . 2006 ; 97 ( 4 ): 489 - 493 . 13 . ernst n m , suryapranata h , miedema k , et al . achieved platelet aggregation inhibition after different antiplatelet regimens during percutaneous coronary intervention for st - segment elevation myocardial infarction . j am coll cardiol . 2004 ; 44 ( 6 ): 1187 - 1193 . 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 . j am coll cardiol . 2006 ; 47 ( 3 ): 522 - 528 . 15 . danzi g b , sesana m , capuano c , mauri l , berra 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 / viewarticle . do ? primarykey = 516083 & amp ; from =/ searchlayout . do . accessed jan . 9 , 2008 . 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 d e , windecker s , mehran r , et al . clinical end points in coronary stent trials : a case for standardized definitions . circulation . 2007 ; 115 ( 17 ): 2344 - 2351 . 19 . merlini p a , rossi m , menozzi a , et al . thrombocytopenia caused by abciximab or tirofiban and its association with clinical outcome in patients undergoing coronary stenting . circulation . 2004 ; 109 ( 18 ): 2203 - 2206 . fig1 : a noninferiority analysis of tirofiban with respect to abciximab is shown . the analysis is based on comparison of effectiveness in achieving the primary end point , defined as attainment of at least 50 % resolution of / recovery from st - segment elevation in a 12 - lead electrocardiogram 90 minutes after intervention . fig2 : a comparison is shown of the outcome within eight months for patients treated for myocardial infarction depending on whether or not they become thrombocytopenic ( lighter shading vs . darker shading ) as a side effect of the treatment . compared are the chances for death from any cause ; for death or another myocardial infarction ; and for occurrence of a major adverse cardiovascular event ( defined as the composite of death from any cause , reinfarction , and clinically - driven target - vessel revascularization within the first eight months ). fig3 : a comparison is shown of the chances of mortality within eight months of treatment in myocardial - infarction patients treated either with hdb tirofiban or abciximab and depending on whether the patients were thrombocytopenic ( lighter shading ) or not ( darker shading ). fig4 : a comparison is shown of the probability of experiencing a clinical event ( death or reinfarction ) within eight months of treatment of myocardial - infarction patients treated either with hdb tirofiban or abciximab .
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 .