Table of Contents CONTENTS

Section 1: Introduction ACS

The Acute Coronary Syndrome (ACS) that result from disruption or erosion of a plaque comprises of unstable angina, non-Q-wave MI (NQMI) and Qwave MI (QwMI).

Coronary artery disease (CAD) has long been identified as the major cause of death in industrialized nations, and it is becoming the major cause of death in many emerging nations. The term acute coronary syndrome (ACS) refers to a group of distinct clinical entities, whose common etiology is an imbalance between myocardial oxygen supply and requirement (i.e. myocardial ischaemia) distal to the site of a disrupted atheromatous coronary artery plaque   1 . The acute coronary syndrome (ACS) that result from disruption or erosion of a plaque comprises of unstable angina, non-Q-wave myocardial infarction (NQMI) and Q-wave MI (QwMI).

Figure 1. Nomenclature of acute coronary syndromes

Patients with ischaemic discomfort may present with or without ST segment elevation on the electrocardiogram (figure 1)  2 . ST-segment elevation indicates ST-segment elevation myocardial infarction (STEMI), while patients who present without ST-segment elevation are experiencing either unstable angina (UA) or non-STEMI (NSTEMI). The distinction between these two diagnosis is ultimately made on the presence or absence of a cardiac marker (such as creatine kinase myocardial band isoenzymes [CKMB] or troponin) detected in the blood.

Those patients with ST-segment elevation need reperfusion as quickly as possible, while antithrombin and antiplatelet therapy form the cornerstone of therapy in non-ST-segment elevation ACS. Among the patients with ST-segment elevation, approximately one-quarter do not develop Q-waves, whereas in patients with positive cardiac markers but without ST-segment elevation, approximately one-quarter will develop Q-waves.

Since the treatment decisions need to be made long before the final ECG resolution is known, the terms Q-wave MI and non-Q-wave MI have little possible relevance in terms of defining appropriate practice patterns.

Recently, our treatment of acute myocardial infarction (AMI) has significantly improved patient survival. However, patients with non-ST-elevation acute coronary syndromes (ACS) represents a large group that has a correspondingly greater impact on healthcare resources, and it is here that our treatment approaches can still be improvised. Our growing understanding of the pathophysiology of plaque formation and progression, along with thrombogenesis, has suggested new, specific therapeutic approaches. One of the most productive among these is the inhibition of thrombin to interrupt or prevent the development of thrombi, and to inhibit platelets.

Acute Coronary Syndrome: Pathophysiology

Platelets play a key role in the transformation of a stable atherosclerotic plaque to an unstable lesion leading to ACS

Rupture or erosion of an atherosclerotic plaque with superimposed thrombus is by far the most common cause of acute coronary syndrome. Plaque rupture can be precipitated by multiple factors, including high plaque lipid content, local inflammation causing breakdown of the thin shoulder of the plaque, coronary artery constriction at the site of the plaque, local shear stress forces, platelet activation and the status of the coagulation system (i.e., a potentially prothrombotic state), all of which culminate in the formation of platelet rich thrombi at the site of the plaque rupture or erosion and the resultant acute coronary syndrome.

 Platelets play a key role in the transformation of a stable atherosclerotic plaque to an unstable lesion. With rupture or ulceration of an atherosclerotic plaque, the subendothelial matrix (e.g., collagen and tissue factor) is exposed to the circulating blood. The first step is platelet adhesion by means of the platelet glycoprotein IIb/IIIa receptor through its interaction with endothelial von Willebrand factor (figure 2).

 This is followed by platelet activation, which leads to (1) a shape change in the platelet (from a smooth discoid shape to a spiculated form, which increases the  surface area upon which thrombin generation can occur); (2) degranulation of the alpha and dense granules, thereby releasing thromboxane A2 , serotonin, and other platelet aggregatory and chemoattractory agents; and(3) expression of glycoprotein IIb/IIIa receptors on the platelet surface with activation of the receptor so that it can bind fibrinogen. The final step is platelet +aggregation, that is, the formation of the platelet plug. Fibrinogen (or von Willebrand factor) binds to the activated glycoprotein IIb/IIIa receptors of two platelets, thereby creating a growing platelet aggregate.

 

Figure 2. Process of platelet (a) adhesion, (b) activation, and (c) aggregation

Simultaneously with formation of the platelet plug, the plasma  coagulation system is activated. Release of tissue factor appears to be the predominant mechanism of initiating hemostasis during plaque rupture and coronary thrombosis. Ultimately, factor X is activated (to factor Xa), leading to the generation of thrombin, which plays a central role in arterial thrombosis.

Thrombin has several actions: (1) It converts fibrinogen to fibrin in the final common pathway for clot formation(2) It is a powerful stimulus for platelet aggregation and (3) It activates factor XIII, which leads to cross-linking and stabilization of the fibrin clot.

Section 2: ACS - THERAPY

ACS - THERAPY

Aspirin and heparin represent the conventional antithrombotic standard of care, even though they are known to have obvious limitations.

Aspirin and heparin represent the conventional antithrombotic standard of care, even though they are known to have obvious limitations.

Limitations of heparin

Heparin has a variable anticoagulant effect due to its tendency to bind to plasma proteins, requiring frequent monitoring of clotting times and dosage adjustments. Heparin is also associated with the potential of thrombotic rebound upon discontinuation of therapy   3  .

The benefits of adding heparin to aspirin in patients with non - ST segment elevation ACS seems to be rather limited. Activation of GP IIb/IIIa receptors, expression of P-selectin (CD62p) and enhanced platelet aggregation were recently demonstrated despite therapeutic concentrations of heparin in patients with unstable angina 4 .

Limitations of available inhibitors of platelet activation

Platelet aggregation is initiated through several platelet activation pathways which are mobilized once platelets have adhered to damaged vessel wall  5 . Several inhibitors of platelet activation are already available, but each of these blocks only one particular pathway (figure 3).Figure 3. Mechanisms of action of various antiplatelet agents

The unaffected activation pathways are still able to initiate the conformational change in GP IIb-IIIa, therefore platelet aggregation continues.

Aspirin, and agents in development such as thromboxane synthase inhibitors and thromboxane receptor antagonists inhibit the action of  TxA2 but have no effect on the other activation pathways6,7.

 Thienopyridines such as ticlopidine and clopidogrel selectively and irreversibly inhibit ADP-mediated platelet activation but are slow to achieve their effect (3-5 days)   8 and have no effect on other platelet agonists.

In each case, the unaffected activation pathways are still able to initiate the conformational change at GP IIb/IIIa receptors. Platelet aggregation therefore continues, but to a lesser extent.

Glycoprotein IIb/IIIa Receptor5  

The surface of each platelet has about 50,000 GP IIb/IIIa fibrinogen binding sites.

This receptor belongs to the super family of integrin receptor complexes that mediate cell-protein and cell-cell interactions.

Fibrinogen or vWF binds to specific platelet membrane receptors that are located in the GP IIb/IIIa integrin complex.

Figure 4. Processes of Platelet Activation and Aggregation and Inhibition of Platelet Aggregation by Inhibitors of Glycoprotein IIb/IIIa Receptors.

 

All receptors in the integrin superfamily contain an alpha and a beta subunit. Platelet GP IIb/IIIa can recognize both fibrinogen and vWF, as well as some other adhesive

proteins. The GP IIb/IIIa complex is the most abundant receptor on the platelet surface The heterodimeric, ligand-binding GP IIb/IIIa complexes are not normally exposed in their

active forms on the surfaces of quiescent circulating platelets. However, platelet activation converts GP IIb/IIIa into competent receptors by means of specific signal transduction pathways, enabling GP IIb/IIIa to bind to fibrinogen and vWF.

The binding of these adhesive proteins requires that they contain the specific tripeptide sequence Arg-Gly-Asp (RGD). Recognition of fibrinogen and other ligands by the active GP IIb/IIIa complex involves the RGD tripeptide sequence (located at positions 95-97 and 572-574 of each of the two A-alpha chains of fibrinogen). When two activated platelets with functional GP IIb/IIIa receptors each bind the same fibrinogen molecule, a fibrinogen bridge is created between the two platelets (figure 4).

Because the surface of each platelet has about 50,000 GP IIb/IIIa fibrinogen binding sites, numerous activated platelets recruited to the site of vascular injury can rapidly form an occlusive aggregate by means of a dense network of intercellular fibrinogen bridges.

These events of ligand binding to activated platelet membrane GP IIb/IIIa receptors, which mediate the process of platelet aggregation, have served as targets for antiplatelet therapy with GP IIb/IIIa antagonists.

Targeting the common pathway in platelet aggregation

Inhibitors which bind to the GP IIb/ IIIa sites are able to inhibit platelet activation and aggregation to a much greater extent than other platelet inhibitors.

Current ACC/AHA guidelines recommend the use of GP IIb/IIIa inhibitors, in addition to aspirin and heparin, in those patients with continuing ischemia or with other high-riskfeatures

Activation of the platelet receptor, GP IIb/IIIa, which permits the development of fibrinogen links between adjacent platelet is the final common pathway in platelet aggregation 5  (figure 3). Inhibitors which bind to the GP IIb/IIIa sites preventing the interaction with fibrinogen are able to inhibit platelet activation and aggregation to a much greater extent than other platelet inhibitors which block only one of the pathways involved in platelet activation (figure 4).

The key role played by GP IIb/IIIa in platelet aggregation and its importance as a potential target for new antiplatelet agents was first recognised as a resut of studies investigating Glazemann’s thrombasthenia, an inherited deficiency of the functional platelet receptor, GP IIb/IIIa, associated with defective platelet aggregation. Characterization of the receptor revealed it to be a member of the integrin receptor family which is capable of binding several different adhesion molecules. The first GP IIb-IIIa inhibitor to be developed for clinical use was a chimeric monoclonal antibody fragment, abciximab, which was demonstrated to be beneficial in the prevention of thrombotic complications following coronary angioplasty but it cross reacts with other integrin receptors  9 . Since then several synthetic peptides and nonpeptides have been developed which are specific and potent inhibitors of GP IIb/IIIa    5 .

Platelet Gp IIb/IIIa antagonists generally belong to one of the following classes: (1) Monoclonal antibody against Gp IIb/IIIa (2) Peptide (peptidomimetic) antagonists and(3) Nonpeptide (nonpeptidomimetic) antagonists of GP IIb/IIIa.

Three drugs currently available for coronary intervention or acute coronary syndromes represent the prototypes for these groups: Abciximab is a monoclonal antibody, eptifibatide is a peptide antagonist, and Tirofiban is a nonpeptide mimetic. Lamifiban has been evaluated in a clinical trial but did not show a statistically significant benefit; further development of this agent has been suspended. Other GP IIb/IIIa inhibitors include xemilofiban, lotrafiban, and sibrafiban; these drugs are prodrugs of peptidomimetric compounds and are administered orally. Results of clinical trials of these orally administered agents have been disappointing.

Current ACC/AHA guidelines recommend the use of GP IIb/IIIa inhibitors, in addition to aspirin and heparin, in those patients with continuing ischemia or with other high-risk features (e.g., elevated CK-MB, myoglobin, or cardiac troponins) and also in those patients in whom percutaneous coronary intervention (PCI) is planned   2 .

Currently available GP IIb/IIIa inhibitors, Abciximab is a chimeric monoclonal antibody Fab fragment which nonspecifically and irreversibly binds to the GP IIb/IIIa receptor. While, eptifibatide is a cyclic peptide and Tirofiban is a nonpeptide (nonpeptidomimetic), both bind selectively and reversibly to the GP IIb/IIIa receptor. Eptifibatide contains the KGD (Lys-Gly-Asp) sequence of fibrinogen; Tirofiban contains the RGD (Arg-Gly-Asp) sequence of fibrinogen. Cyclic peptides (i.e., eptifibatide) are more resistant to degradation than linear peptides, but still have short half-lives because they are broken down in the body. Tirofiban does not have peptide bonds, which allows for longer survival time in circulation as compared to peptide compounds. Abciximab is an antibody and may be expected to be immunogenic, concern has been raised about repeat administration. Although the mechanism of action of these agents (i.e., inhibition of ligand binding to the receptor) is similar, it should not be assumed that they react at the same site within the receptor or that the consequences of their binding to Gp IIb/IIIa are identical   10  .

Section 3 :TIROFIBAN: A NOVEL PLATELET GP IIb/IIIa ANTAGONIST

TIROFIBAN: A NOVEL PLATELET GP IIb/IIIa ANTAGONIST

Tirofiban is a novel,synthetic,non-peptide(nonpeptidomimetic)and is a highly specific and potent inhibitor of the platelet receptor, GP IIb/IIIa

Tirofiban is a novel, synthetic, non-peptide (nonpeptide-mimetic) and is a highly specific and potent inhibitor of the platelet receptor, GP IIb/IIIa  11 . Unlike GP IIb/IIIa antagonists that are derived from monoclonal antibodies, administration of Tirofiban is not associated with the development of antibodies. Tirofiban can therefore be re-administered to the same patient in any subsequent episodes of acute ischaemic coronary syndrome or during coronary angioplasty intervention. It can also be administered in the emergency setting when a patient’s prior medical history is not known.

Tirofiban hydrochloride monohydrate is chemically described as N- (butylsulfonyl)-O -[4-(4-piperidinyl)butyl]-L-tyrosine monohydrochloride monohydrate.

Its molecular formula is C22H36N2O5S·HCl·H2O. The chemical structure is shown in figure 5.

Figure 5. Structural formula of Tirofiban

TIROFIBAN: PHARMACODYNAMIC PROFILE

1. Inhibition of Platelet Aggregation

Tirofiban HCl inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine diphosphate (ADP) induced platelet aggregation and prolong bleeding time in healthy subjects and patients with coronary artery disease   12  . The time course of inhibition parallels the plasma concentration profile of the drug. Following discontinuation of an infusion of Tirofiban HCl, 0.10 µg/kg/min, ex vivo platelet aggregation returns near to the baseline in approximately 90% of patients with coronary artery disease in 4-8 hours. The addition of heparin to this regimen does not significantly alter the percentage of subjects with >70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, and the number of patients with bleeding times prolonged over >30 minutes.

In patients with unstable angina, a two-staged intravenous infusion regimen of Tirofiban HCl (loading infusion of 0.4 µg/kg/min for 30 minutes followed by 0.1 µg/kg/min for up to 48 hours in the presence of heparin and aspirin), produces approximately 90% inhibition of ex vivo ADP-induced platelet aggregation with a 2.9-fold prolongation of bleeding time during the loading infusion. Inhibition persists over the duration of the maintenance infusion.

2. Effects on Bleeding Times

The effects of intravenous Tirofiban on ADP-induced platelet aggregation in healthy volunteers and patients with acute coronary syndrome were accompanied by increased bleeding times. Median bleeding times in volunteers were prolonged by 1.6- to 4.6-fold (p<0.01 vs baseline) with a 1-hour infusion of Tirofiban 0.05 to 0.4 µg/kg/min and by 1.5- to 5.8-fold with a 4-hour infusion of Tirofiban 0.1 to 0.2 µg/kg/min; these returned to or near baseline within 3 hours after stopping the infusion  13.

Intravenous Tirofiban 0.075 to 0.15 µg/kg/min increased bleeding times to between 10.5 and 19.7 minutes after a 48-hour infusion in patients with unstable angina or non-Q-wave MI  12 . Greater effects on bleeding times were seen in patients receiving Tirofiban with heparin. In high-risk patients undergoing coronary angioplasty, the median bleeding time at 2 hours was increased to > 30 minutes with Tirofiban (0.10 or 0.15 µg/kg/min) plus heparin compare to 11 minutes for patients receiving heparin alone (p≤0.003) and 5 to 6 minutes at baseline 14 .

The 2-fold prolongation of bleeding time associated with Tirofiban (5 µg/kg for 5 minutes then 0.05 µg/kg/min for a total of 6 hours) in 5 Japanese volunteers was not significantly affected by pretreatment with ticlopidine(200 mg/day for 4 days)  15 . However, pretreatment with oral aspirin 650 mg increased the effects of intravenous Tirofiban (0.15 µg/kg/min for 4 hours) on bleeding time in 12 healthy volunteers   16 .

In these individuals, mean bleeding time was extended 4.4-fold from baseline with aspirin plus Tirofiban alone (p<0.001) and 1.8-fold with aspirin alone (p<0.001)   16 .

3. Effects in Models of Coronary Artery Thrombosis

The effects of Tirofiban on coronary artery thrombosis formation have been demonstrated in 2 canine models 17 . Bolus intravenous doses of Tirofiban 300 and 1000 µg/kg completely abolished platelet dependent cyclic flow reductions for 18 and 37 minutes, respectively, in injured stenosed left circumflex coronary arteries of anaesthetized dogs  5 . Furthermore, a 10 µg/kg/min continuous intravenous infusion of Tirofiban delayed or prevented occlusive thrombus formation and reduced thrombus mass in a model of electrically induced left circumflex coronary artery occlusive thrombosis 17 . Intravenous Tirofiban 10 µg/kg/min accelerated reperfusion in this model when administered with heparin and 15 minutes before thrombolytic therapy (alteplase or streptokinase) 17 .

Mechanism of Action

Tirofiban produces approximately 90% inhibition of ADP-induced platelet aggregation

Tirofiban is a competitive inhibitor of glycoprotein (GP) IIb/IIIa preventing the binding of fibrinogen, von Willebrand factor (vWF), and other adhesive ligands to the GP IIb/IIIa receptor on activated platelets. "Integrins ", which are found on virtually all cell types, are a family of adhesion molecules that mediate many physiologic responses. Unlike many of the other integrins, GP IIb/IIIa is platelet specific and is also the most abundant receptor found on activated platelets, with about 50,000 copies/cell. Fibrinogen is the principal ligand to bind to the GP IIb/IIIa receptor. The binding of fibrinogen and, to a lesser extent other ligands such as vWF, to the GP IIb/IIIa receptor results in cross-linking between platelets and is the final common pathway of platelet aggregation, which ultimately leads to thrombus formation. Tirofiban binds to GP IIb/IIIa via an arginine-glycine-aspartic acid (RGD) sequence.

TIROFIBAN: PHARMACOKINETIC PROFILE

The recommended regimen of 0.4 µg/ kg/min IV for 30 minutes followed by 0.1 µg/kg/min IV thereafter produces a peak Tirofiban plasma concentration that is similar to the steady state concentration during the infusion

Tirofiban is administered intravenously. The recommended regimen of 0.4 µg/kg/min IV for 30 minutes followed by 0.1 µg/kg/min IV thereafter produces a peak Tirofiban plasma concentration that is similar to the steady state concentration during the infusion. Tirofiban is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01-25 µg/mL. In human plasma, the unbound fraction is about 35%. Metabolism of Tirofiban appears to be limited. In patients with coronary artery disease, the plasma clearance of Tirofiban ranges 152-267 mL/min   18  . Plasma clearance is about 19-26% lower in elderly patients (> 65 years) than in younger patients. Plasma clearance is also significantly decreased (> 50%) in patients with a CrCl < 30 mL/min, including patients requiring

hemodialysis18. Mild to moderate hepatic insufficiency does not affect the plasma clearance of Tirofiban. Renal clearance accounts for about 39% of plasma clearance. About 65% of a dose of Tirofiban is excreted in urine and about 25% in faeces, both largely as unchanged drug   18  . The elimination half-life of Tirofiban is approximately 2 hours (range: 1.7-2 hours).

Tirofiban inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine diphosphate (ADP)-induced platelet aggregation and prolong bleeding time. An IV infusion regimen of Tirofiban 0.4 µg/kg/min for 30 min, followed by 0.1 µg/kg/min for up to 48 hours in the presence of heparin and aspirin, produces > 90% inhibition of ex vivo ADP-induced platelet aggregation with a 2.9-fold prolongation of bleeding time during the loading infusion. Platelet inhibition persists over the duration of the maintenance infusion. Following discontinuation of the infusion, ex vivo platelet aggregation returns to near baseline in about 90% of patients within 4-8 hours  18  .

Section 4 :TIROFIBAN CLINICAL TRIALSFigure 6. Trials of Tirofiban in ACS

TIROFIBAN: THERAPEUTIC EFFICACY

There is extensive clinical experience with the intravenous administration of Tirofiban in patients with acute coronary syndrome.

The most potent family of antiplatelet agents are the GPIIb/IIIa receptor  inhibitors. As mentioned, platelet aggregation can be initiated by a number of pathways. However, the final common pathway-irrespective of how it is initiated-involves the binding of the GPIIb/IIIa receptors of adjacent platelets by an interposing fibrinogen molecule. By blocking GPIIb/IIIa receptors, platelet aggregation can be effectively prevented. There is an extensive clinical experience with the intravenous administration of Tirofiban in patients with acute coronary syndrome.

The efficacy of the glycoprotein IIb/IIIa antagonists in the treatment of acute coronary syndromes (unstable angina and non- Q wave MI), MI, and percutaneous coronary interventions has been demonstrated in several multicenter trials (Figure 6).

TIROFIBAN: FOR ISCHEMIC SYNDROMES

PRISM-Tirofiban without heparin significantly reduced the risk of the composite end point at 48 hours by 33% compared with heparin in patients with unstable angina/non-Q-wave MI. PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management)

Two large clinical trials, PRISM 19 and PRISM-PLUS 20  , compared the effects of Tirofiban (alone or with heparin) with those of heparin monotherapy in patients with unstable angina/non-Q-wave MI. PRISM participants began treatment within 24 hours of presenting with unstable angina/non-Q-wave MI, but PRISM-PLUS participants had more severe clinical expression (58% of participants had ST depression compared with 32% in PRISM) and were treated within 12 hours. Tirofiban was administered for a longer period in PRISMPLUS than in PRISM (mean 71.3 vs 45.6 hours); PRISM-PLUS investigators were encouraged to-perform coronary angiography and angioplasty if indicated between 48 and 96 hours after randomization while continuing to administer the study drugs.

PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management)

In the PRISM study, a randomized, parallel, double-blind, active control study, Tirofiban HCl alone (n=1616) was compared to heparin (n=1616) alone as medical management in patients with unstable angina/non-Q-wave myocardial infarction 19  . In this study, the drug was started within 24 hours of the time the patient experienced chest pain. The mean age of the population was 62 years; 32% of the population was female and 25% had non-Q-wave myocardial infarction on presentation. Thirty percent (30%) had no ECG evidence of cardiac ischemia. The primary, prospectively identified endpoint was the composite end point of refractory ischemia, myocardial infraction or death after a 48 hour drug infusion of Tirofiban HCl. The results are shown in Table 1.

Tirofiban without heparin significantly reduced the risk of the composite end point at 48 hours by 33% compared with heparin in patients with unstable angina/non-Q-wave MI. Risk reduction with Tirofiban was no longer significant compared with heparin at 7 or 30 days.

PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management - Patients Limited by Unstable Signs and Symptoms)

PRISM PLUS  There was a 47% risk reduction in myocardial infarction and a 30% risk reduction in refractory ischemia.

PRISM PLUS The  benefit seen at 7 days was maintained over time. At 30 days, the risk of the composite endpoint was reduced by 22% and there was a 30% reduction in the composite of myocardial infarction and death

PRISM PLUS At the end of 6 months the risk of composite endpoint was reduced by 19%

Approximately 90% of patients in the PRISM PLUS study underwent coronary angiography and 30% underwent angioplasty/atherectomy during the first 30 days of the study.

In the multi-center, randomized, parallel, double-blind PRISM-PLUS trial, the use of Tirofiban HCl in combination with heparin (n=773) was compared to heparin alone (n=797) in patients with documented unstable angina/non-Q-wave myocardial infarction within 12 hours of entry to the study and initiation of treatment 20. All patients with unstable angina/non-Q-wave myocardial infarction had cardiac ischemia documented by ECG or had elevated cardiac enzymes. Patients who were medically managed or who subsequently underwent revascularization procedures were studied. The mean age of the population was 63 years; 32% of patients were female and approximately half of the population presented with non-Q-wave myocardial infarction. Exclusions included contraindications to anticoagulation, decompensated

heart failure, platelet count <150,000/mm3, and creatinine >2.5 mg/dl. In this study, patients were randomized to either Tirofiban HCl (30 minute loading infusion of 0.4 µg/kg/min followed by a maintenance infusion of 0.10 g/kg/min) and heparin (bolus of 5000 U followed by an infusion of 1000 U/h titrated to maintain an activated partial thromboplastin time (APTT) of approximately 2 times control), or heparin alone (bolus of 5000 U followed by an infusion of 1000 U/h titrated to maintain an APTT of approximately 2 times control). All patients received concomitant aspirin unless contraindicated. Patients underwent 48 hours of medical stabilization on study drug therapy, and they were to undergo angiography before 96 hours (and, if indicated, angioplasty/atherectomy, while continuing on Tirofiban HCl and heparin for 12-24 hours after the procedure). Some patients went on to coronary artery bypass grafting (CABG) after cessation of drug therapy. Tirofiban HCl and heparin could be continued for up to 108 hours. On an average, patients received Tirofiban HCl for 71.3 hours. A third group of patients was initially randomized to Tirofiban HCl alone (no heparin). This arm was stopped when the group was found, at an interim look, to have greater mortality than the other 2 groups.

The primary endpoint of the study was a composite of refractory ischemia, new myocardial infarction and death at 7 days after initiation of Tirofiban HCl and heparin. At the primary endpoint, there was a 32% risk reduction in the overall composite. The components of the composite were examined separately (they total more than the composite because a patient could have more than one, e.g., by dying after having a new infarction). There was a 47% risk reduction in myocardial infarction and a 30% risk reduction in refractory ischemia. The results are shown in Table 2.

Table 2. PRISM PLUS Outcome Events Among Patients Enrolled

The benefit seen at 7 days was maintained over time. At 30 days, the risk of the composite endpoint was reduced by 22% (p=0.029) and there was a 30% reduction in the composite of myocardial infarction and death (p=0.027). At 6 months, the risk of the composite endpoint was reduced by  19% (p=0.024).

PRISM-PLUS was not designed to provide definitive results in subsets of the overall population. Nonetheless, results were examined for demographic (age, gender, race) subsets and for people who did and did not undergo PTCA, atherectomy, or CABG.

In PRISM-PLUS, there was a consistent treatment effect in patients either greater or less than 65 years old, and in men and women. Too few non-Caucasians were enrolled to make a definite statement about racial differences in treatment effect.

Approximately 90% of patients in the PRISM-PLUS study underwent coronary angiography and 30% underwent angioplasty/atherectomy during the first 30 days of the study. The majority of these patients continued on study drug throughout these procedures. Tirofiban HCl was continued for 12-24 hours (average 15 hours) after angioplasty/atherectomy. The effects of Tirofiban HCl at day 30 did not appear to differ among the sub-populations that did or did not receive PTCA or CABG, both prior to and after the procedure.

A sub-study in PRISM-PLUS of angiograms after 48-96 hours found that there was a significant decrease in the extent of angiographically apparent thrombus in patients treated with Tirofiban HCl in combination with heparin compared to heparin alone   21. In addition, flow in the affected coronary artery was significantly improved.

In the PRISM study, no adverse effect of Tirofiban HCl on mortality at either 7 or 30 days was detected. This result is in conflict with the PRISM-PLUS study, where the arm that included Tirofiban HCl without heparin (n=345) was dropped at an interim analysis by the Data Safety Monitoring Committee due to increased mortality at 7 days. A pooled analysis of the data from these two trials (PRISM and PRISM-PLUS) demonstrated that the effect of Tirofiban HCl alone on mortality (at 7 and 30 days) was comparable to that of heparin alone.

TIROFIBAN IN PERCUTANEOUS CORONARY INTERVENTION

RESTORE Tirofiban is effective in reducing the incidence of acute ischemic complications during PTCA/DCA in patients presenting with an ACS, with extension of these benefits at least into the first week following the intervention.

Two large-scale trials have been conducted using Tirofiban in high-risk patients undergoing PCI: RESTORE  22   and TARGET 23 .

RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis)

The RESTORE study (n=2141) was a randomized, controlled comparison of Tirofiban HCl and placebo, each added to heparin, in patients undergoing PTCA or atherectomy within 72 hours of presentation with unstable angina or acute myocardial infarction    22. The mean age of the population was 59 years; 27% were female. Two-thirds of patients underwent angioplasty for unstable angina and the remainder in association with acute myocardial infarction. Exclusions included anatomy not amenable to angioplasty, contraindications to anticoagulation, platelet count <150,000/mm3, and creatinine >2.0 mg/dl. Tirofiban HCl (with heparin) was initiated immediately prior to the angioplasty/atherectomy at a dose of 10 µg/kg bolus (over 3 minutes) followed by an infusion of 0.15 µg/kg/ min along with a heparin bolus (bolus of 10,000 U, or 150 U/kg for patients <70 kg). The infusion dose of Tirofiban HCl is 50% higher than the dose used in the PRISM-PLUS trial. Tirofiban HCl was administered for a total of 36 hours. In general, heparin was to be discontinued at the conclusion of the angioplasty/atherectomy. Reasons for continued heparin included: imperfect outcome (e.g., large tear, intraluminal filling defect, or residual stenosis >40%), large thrombus load, continuing rest angina through the procedure, abrupt closure or very active artery during

the procedure, or side branch occlusion. The primary endpoint was the composite of all deaths, nonfatal myocardial infarctions, and all repeat revascularization procedures at 30 days. For results see TABLE 3.

The results of the RESTORE trial confirm that Tirofiban is effective in reducing the incidence of acute ischemic complications during PTCA/DCA in patients presenting with an acute coronary syndrome, with extension of these benefits at least into the first week following the intervention. By 30 days, however, the magnitude of the benefit is substantially attenuated and no longer statistically significant.

A sub-study in RESTORE of angiograms after approximately 6 months found that Tirofiban HCl had no significant effect on the extent of coronary artery restenosis following angioplasty 24  .

TARGET (Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial)

TARGETThere was, however, a significantly higher incidence of minor bleeding attributable to abciximab.There was also a significantly greater incidence of thrombocytopenia in the abciximab group.Both agents were equally effective in patients >65 years of age. Abiciximab does not have any additional benefits in diabetic patients

In light of the differing pharmacokinetic and pharmacodynamic properties between Tirofiban and abciximab, the TARGET trial was designed to compare these two agents directly.

The Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial was a double-blind, double -dummy, multinational study conducted to test whether Tirofiban was not inferior to abciximab in patients scheduled to undergo coronary stenting23  . Eligible patients included those undergoing either an elective or urgent procedure but not those in cardiogenic shock or with ECG evidence of an acute ST-segment elevation myocardial infarction. Patients were randomized to receive either Tirofiban (10 µg/kg bolus

followed by a 0.15 µg/kg/min infusion for 18-24 h) with abciximab placebo or abciximab (0.25 mg/kg bolus followed by a 0.125µg/kg/min infusion for12h) with Tirofiban placebo. Randomization was stratified by the presence or absence of diabetes; all patients received 250-500 mg of aspirin and, when possible, a loading dose of 300 mg of clopidogrel. Heparin was administered at the start of the procedure using a weight-based dosing nomogram to achieve an ACT of 250 s.

The primary endpoint was a composite of death, nonfatal MI, or urgent target vessel revascularization within 30 days of the procedure. Prespecified secondary endpoints included the occurrence of a primary endpoint in specific subgroup: diabetics, females, patients (65 yrs of age, patients pretreated with clopidogrel, and patients enrolled in participating U.S. sites.

A total of 5308 patients were enrolled in the trial; 4809 of these patients actually received study drug (2398 in the Tirofiban group and 2411 in the abciximab group) and were included in the analysis. Approximately 75% in each group were men, and 23% in each group were diabetics. Most patients (63%) were enrolled with a diagnosis of an acute coronary syndrome, and almost all (95%) patients in both groups received a coronary stent. A native coronary artery was the target vessel in 95% of cases. Restenotic lesions were treated in 5% of cases in each group.

The primary endpoint occurred in 7.6% of patients in the Tirofiban group compared to 6.0% in the abciximab group. To meet prespecified criteria for noninferiority, the upper bound of the 95% confidence interval  (CI) of the hazard ratio (HR) had to be <1.47. In fact, the upper bound of the one-sided 95% CI was 1.51, failing to meet the criteria necessary to confirm the noninferiority of Tirofiban to abciximab. Once the noninferiority of Tirofiban could not be established, the researchers were then able to assess whether abciximab was superior to Tirofiban. The HR comparing Tirofiban with abciximab showed a statistically significant difference at 1.26 (95% CI = 1.01-1.57, p = 0.038). Most of the benefit was derived from the difference in the nonfatal MI rates between the two drugs (6.9% vs 5.4%, p = 0.04). There was, however, a significantly higher incidence of minor bleeding attributable to abciximab (4.3% vs 2.8%, p = 0.001). There also was a significantly greater incidence of thrombocytopenia in the abciximab group.

Prespecified subgroup analyses revealed that patients who received a stent for the treatment of an acute coronary syndrome obtained greater benefit from abciximab than those patients who received a stent for other reasons. Patients <65 years of age obtained greater benefit with abciximab than with Tirofiban, whereas both agents were equally effective in patients >65 years of age. The presence of diabetes did not result in any difference in efficacy between two agents.

At 6 month the difference between the two agents in the composite endpoint (14.4 vs 13.8, p = NS) was attenuated and, although still favoring abciximab, was no longer statistically significant   25 . A small decrease in the absolute risk reduction from 1.5% at 30 days to 1.4% at 6 month was sufficient to prevent the composite endpoint from reaching statistical significance. Target vessel revascularization also failed to show a statistically significant difference, not only at 30 days but, more importantly, also at 6 months, confirming that the nonspecificity of abciximab for the GPIIb/IIIa integrin does not affect the clinical restenosis rate.

The TARGET trial is the only trial to date that has directly compared two different GPIIb/IIIa inhibitors. Based on the results of this trial, several conclusions can be drawn that can help guide clinical practice. It is safe to say that in patients <65 years of age and particularly in  those presenting with an acute

coronary syndrome and who have a culprit lesion that is amenable to PCI with stenting, abciximab is the preferred agent. Not only is it associated with an improved clinical outcome, but it also provides this benefit without an increase in clinically significant bleeding. Vigilance must be exercised, however, since abciximab is more likely to cause a profound thrombocytopenia (20,000/mm3) than Tirofiban. One recent study cited an incidence of profound thrombocytopenia of approx 0.5%, which correlates well with the 0.3% incidence observed in the TARGET trial. Consequently, early (e.g., 4 h post bolus) and sequential complete blood counts should be performed in all patients treated with abciximab.

The TARGET trial failed to show any difference between the two agents in elderly patients (>65 yr) or those with chronic stable angina who are referred for elective PCI. Multivariate modeling is necessary to understand these subgroup comparisons fully and to identify patients who might derive equal benefit from both agents. The data do not support the theory that  the nonplatelet effects of abciximab influence the clinical restenosis rate. More significant, and most likely reflecting the evolutionary improvements in the procedural aspects of PCI in general, was the observation that the clinical restenosis rate, reflected by the 6-month target vessel revascularization rate, was only approx 8% in both treatment arms   25 .

The main benefit of abciximab is in lowering the incidence of periprocedural myocardial infarctions, as manifested by an asymptomatic elevation in the CK-MB. Although the protective effect of abciximab is greater with larger infarction, in absolute numbers most of the periprocedural myocardial enzyme elevations are of small magnitude, and their clinical significance remains a subject of significant debate. The lack of a significant mortality difference at 6-month and 1 yr follow-up suggests that the increase in the periprocedural MI event rate is not associated with an increase in cardiac death. Longer follow-up will be required to determine whether these infarctions result in progressive LV dysfunction or late sudden cardiac death.

TIROFIBAN Vs ABCIXIMAB IN DIABETIC PATIENTS  UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial (TARGET) 1-year follow-up. 

A sub-study in TARGET, at the time of enrollment, patients were stratified according to diabetes status. As compared with non-diabetic patients, patients with diabetes (n=1117) showed similar 30-day ischemic outcomes, an increased incidence of any target vessel revascularization (TVR) at 6 months (10.3% versus 7.8%; P= 0.008), and a trend toward higher 1-year mortality (2.5% versus 1.6%; P=0.056). Among diabetic patients randomized to Tirofiban (n=560), the incidence of death, myocardial infarction (MI), or urgent TVR at 30 days was 6.2%, and among those randomized to abciximab (n=557) it was 5.4% (hazard ratio [HR] 1.16; P=0.540). At 6 months, the composite of death, MI, or any TVR occurred in 15.7% and in 16.9% of Tirofiban and abciximab patients, respectively (HR 0.93; P=0.610). Any TVR occurred in 9.5% and 11.1%, respectively (HR 0.84; P= 0.366). The 1-year mortality was 2.1% in the Tirofiban group and 2.9% in the abciximab group (HR 0.74; P= 0.436)   25 . This sub-study among diabetic patients undergoing PCI, Tirofiban and abciximab were associated with comparable event rates, including similar rates of 6-month TVR and 1-year mortality. These findings suggest that the non-glycoprotein IIb/IIIa properties of abciximab do not translate into a discernible long-term clinical benefit among diabetic patients.

TIROFIBAN: WITH A HIGH BOLUS DOSE DURING PERCUTANEOUS CORONARY INTERVENTION

In the TARGET study, sub-optimal platelet inhibition with Tirofiban was held responsible for the higher incidence of periprocedural CK-MB release compared to abciximab. Since then, a new, higher bolus dose of Tirofiban has been proposed to increase blood concentrations very soon after the start of treatment. The aim of this study was to explore the bleeding risk  and clinical outcome at 30 days in a series of patients undergoing percutaneous coronary intervention (PCI) with the new dosing regimen of Tirofiban (25 µg/kg bolus followed by a 0.15 µg/kg/min infusion for 18 h)27 . A total of 133 consecutive patients underwent a PCI and received a high bolus dose of Tirofiban. Platelet function inhibition was measured using the Ultegra RPFA (Accumetrics) 10 min and 8 and 24 h after the start of therapy in the first 38 cases. The procedural success rate was 98.5%. The mean level of platelet inhibition 10 min after the start of therapy was 94.7 +/- 5.9%. No major bleedings, no need for red blood cell transfusion and no episodes of severe thrombocytopenia were recorded. Groin haematoma was observed in seven patients (5.3%). The cumulative incidence of 30- day major adverse cardiovascular events was 4.6% (five myocardial infarctions and one repeat PTCA for sub-acute stent thrombosis). The results of this study suggest that the use of a high bolus dose of Tirofiban in patients undergoing PCI seems to be safe and not associated with an increased risk of major bleeding. This high bolus dose may help to further reduce the rate of periprocedural adverse events.

Safety of a high bolus dose of tirofiban in patients undergoing coronary stent placement  44.

The use of a high bolus dose of Tirofiban in patients undergoing PCI seems to be safe and not associated with an increased risk of major bleeding.

In patients undergoing coronary stenting, the high bolus dose of tirofiban is safe and not associated with an increased risk of major bleeding or site access complications in comparison with abciximab.

To overcome the suboptimal platelet inhibition induced by tirofiban in the first hour after a percutaneous coronary intervention, a new regimen of 25 µg/kg bolus followed by an 18 hr infusion of 0.15 µg/kg/min has been proposed. The aim of this study was to compare the effects of this high bolus dose of tirofiban with those of abciximab on bleeding risk and 30 day clinical outcome in patients undergoing coronary stenting. We compared two cohorts of patients who underwent coronary stent placement between January 2000 and December 2002. In the first cohort, the only available GP IIb/IIIa receptor inhibitor was abciximab, which was given to 280 (34.9%) out of 802 stented patients; in the second cohort, tirofiban was administered to 274 (38.3%) out of 716 treated patients. The primary endpoints were the proportion of patients with major bleeding and the rate of site access complications; the 30-day incidence of major adverse cardiac events (MACE) was also assessed. After the procedure, the patients were given ticlopidine for 4 weeks and aspirin indefinitely. Major bleeding episodes were observed in four patients receiving abciximab and in none receiving tirofiban (1.4% vs. 0%; P = 0.12); the rates of site access complications were similar (3.6% vs. 3.3%; P = 0.96). The 30-day incidence of MACE was 7.1% in the abciximab group and 5.8% in the tirofiban group (P = 0.65). In patients undergoing coronary stenting, the high bolus dose of tirofiban is safe and not associated with an increased risk of major bleeding or site access complications in comparison with abciximab.

Comparison in Patients Having Primary Coronary Angioplasty of Abciximab Versus Tirofiban on Recovery of Left Ventricular Function    50

In patients treated with primary coronary angioplasty, the use of abciximab improves microvascular perfusion and enhances the recovery of contractile function. This study compared the effects of the new dose regimen of tirofiban (25-µg/kg bolus followed by an 18-hour infusion at 0.15 µg/kg/min) on left ventricular function with those of abciximab in patients who underwent direct angioplasty. One hundred patients who underwent primary coronary angioplasty were randomized to receive a standard dose of abciximab or a large-dose bolus of tirofiban. The primary end point of the study was change in the infarct-zone wall motion score index between the initial and 30-day follow-up echocardiographic studies. The secondary end points were procedural evaluations before and after Thrombolysis In Myocardial Infarction (TIMI) grade flow, TIMI grade myocardial perfusion, and corrected TIMI frame count.

Baseline global and regional ventricular functions were similar in the 2 treatment groups. After the procedure, a TIMI grade 3 flow was obtained in 86% of patients treated with abciximab and 88% of those receiving tirofiban (p =1.0), whereas TIMI grade 3 myocardial perfusion was present in 70% and 76%, respectively (p =0.65); corrected TIMI frame count was 22.5 + 1.9 and 22.1 + 2.5 (p = 0.37). After 30 days, they obtained 87 paired echocardiographic studies. The infarct-zone wall motion score index decreased from 2.20 + 0.3 to 1.99 + 0.2 in the abciximab group and from 2.18 + 0.3 to 1.95 + 0.3 in the tirofiban group (p =0.67). Thus, in patients who had primary coronary angioplasty, abciximab, and the large-dose bolus of tirofiban showed similar effects on the initial angiographic results and 30-day recovery of left ventricular function.

The Additive value of Tirofiban administered with the High-Dose Bolus in the prevention of ischemic complications during high-risk coronary angioplasty: the ADVANCE Trial 48

ADVANCE trial shows, HDB of Tirofiban is safe and significantly reduces the incidence of ischemic / thrombotic complications during high risk PCI

The use of high-dose bolus (HDB) tirofiban in the catheterization laboratory is controversial. In particular, in patients with acute coronary syndromes undergoing PCI, there is no evidence that tirofiban administered in the catheterization laboratory is superior to heparin alone. This finding probably reflects the suboptimal platelet inhibition when tirofiban is employed at RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) regimen. This study was planned to determine the safety and efficacy of high-dose bolus (HDB) tirofiban in high-risk patients undergoing percutaneous coronary intervention (PCI).

A total of 202 patients (mean age 69 +/- 8 years; 137 males [68%]) undergoing high-risk PCI, pretreated with thienopyridines, were consecutively randomized to HDB tirofiban (25 microg/kg/3 min, and infusion of 0.15 microg/kg/min for 24 to 48 h) or placebo immediately before the procedure and then followed for a median time of 185 days range 45 to 324 days) for the occurrence of the primary composite end point of death, myocardial infarction, target vessel revascularization (TVR), and bailout use of glycoprotein (GP)

IIb/IIIa inhibitors. The cumulative incidence of the primary end point was 35% and 20% in placebo and HDB tirofiban groups, respectively (hazard ratio 0.51, 95% confidence interval 0.29 to 0.88; p = 0.01). This difference was mainly due to the reduction of myocardial infarction and bailout use of GP IIb/IIIa inhibitors, with no significant effect on TVR or death. The safety profile did not differ between tirofiban and placebo. The use of tirofiban, when administered at HDB, is safe and significantly reduces the incidence of ischemic/thrombotic complications during high-risk PCI.

PCI IN PATIENTS PRETREATED WITH TIROFIBAN

Two large-scale trials, PRISM-PLUS  20 and TACTICS-TIMI 18 28 , have involved patients presenting with unstable angina or non-ST-elevation MI who were initially treated with Tirofiban and subsequently underwent PCI. A review of these trials will help to define further the role of Tirofiban in the cardiac catheterization laboratory, especially since many patients are referred for coronary angiography and intervention only after having failed aggressive medical therapy with aspirin, heparin, and a GPIIb/IIIa inhibitor such as Tirofiban.

PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management - Patients Limited by Unstable Signs and Symptoms)

PRISM PLUS patients with an acute coronary syndrome who undergo PCI derive particular benefit from pretreatment with Tirofiban in addition to aspirin and heparin.

In the multi-center, randomized, parallel, double-blind PRISM PLUS trial, the use of Tirofiban HCl in combination with heparin (n=773) was compared to heparin alone (n=797) in patients with documented unstable angina/non-Q-wave myocardial infarction within 12 hours of  entry into the study and initiation of treatment. Patients who were medically managed or who subsequently underwent revascularization procedures were studied. The primary endpoint of the study was a composite of refractory ischemia, new myocardial infarction and death at 7 days after initiation of Tirofiban HCl and heparin. At the primary endpoint, there was a 32% risk reduction in the overall composite. The components of the composite were examined separately (they total more than the composite because a patient could have more than one, e.g., by dying after having a new infarction). There was a 47% risk reduction in myocardial infarction and a 30% risk reduction in refractory ischemia.

During the initial hospitalization 90% of patients in the PRISM-PLUS study underwent coronary angiography and 30% underwent angioplasty/atherectomy during the first 30 days of the study. In this subgroup, the 30 days composite endpoint occurred in 8.8% of patients in the Tirofiban plus heparin group and in 15.3% of patients in the heparin-only group, suggesting that patients with an acute coronary syndrome who underwent PCI derive particular benefit from pretreatment with Tirofiban in addition to aspirin and heparin. The results of the PRISM-PLUS study suggest that significant clinical benefit can be anticipated from the early initiation of Tirofiban in patients with early initiation of Tirofiban in patients with acute coronary syndrome. This benefit was evident as early as 48 h into therapy, implying that Tirofiban is effective in patients who are treated medically. These results are consistent with recent meta-analysis of trials of GPIIb/IIIa inhibitors in acute coronary syndrome: an overall 34% reductions in the incidence of death or nonfatal MI was noted during the initial period of medical stabilization prior to PCI.

A reduction in the composite endpoint in PRISM-PLUS was also present at 7 days, 30 days, and 6 month in the combination therapy group. Most of the benefit at these time points was conferred on the subset of patients who underwent PCI. In fact, the incidence of the composite endpoint at 30 days in the group of patients treated with medical management alone, although favoring combination therapy, was not significantly different from that in the heparin-only group (RR = 0.87, 95% CI = 0.6-1.25).

Based on the results of the angiographic substudy, it is evident that the mechanism responsible for the observed clinical benefit is a reduction in the thrombus burden and an improvement in coronary flow. Mechanically, this may also explain why some of the initial comparative trials of early invasive or conservative therapy for patients with acute coronary syndrome, which did not include GPIIb/IIIa inhibitor therapy, demonstrated a worse outcome in the invasive arms. In light of this apparent paradox, the TACTICS-TIMI 18 trial was designed to compare directly an early invasive or conservative treatment strategy in acute coronary syndrome patients treated with Tirofiban combination therapy.

TACTICS-TIMI 18 (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)

TACTICS-TIMI It is possible that suboptimal bolus dosing of Tirofiban contributed to its reduced efficacy in TARGET

TACTICS-TIMI Pretreatment with Tirofiban provides platelet inhibition similar to abciximab and well above the accepted cut off of 80%

The Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI 18) trial randomized 2220 patients with unstable angina or non-ST-elevation MI to early invasive or conservative therapy28. All patients were treated with an aspirin and unfractioned heparin (5000 U bolus followed by a 1000 U/h infusion for 48 h), and Tirofiban was administered as a 0.4 µg/kg/min bolus over 30 min followed by a maintenance infusion of 0.1 µg/kg/min for 48 h or until revascularization, the Tirofiban infusion was continued for at least 12 h after procedure. Patients were eligible for inclusion if they had experienced either a prolonged episode of angina or recurrent episodes at rest or with minimal exertion within the previous 24 h that were associated with ischemic ECG changes, abnormal cardiac enzymes, or prior evidence of documented coronary artery disease. Patients were excluded if they presented with persistent ST-segment elevation, had undergone a PCI or CABG within the previous 6 months, had evidence of severe congestive heart failure or cardiogenic shock, or were felt to be at increased risk of bleeding.

Patients randomized to an early invasive strategy were to undergo diagnostic catheterization between 4 and 48 h after randomization, followed by PCI or CABG as appropriate. Patients randomized to an early conservative therapy underwent invasive procedures only if they failed medical therapy, as defined by the occurrence of any of the following: refractory angina, hemodynamic instability, documented ischemia on routine or nuclear stress testing, rehospitalization for recurrent angina, or new MI. The primary endpoint was the 6-month composite of death, nonfatal MI, and rehospitalization for an acute coronary syndrome.

In the group of patients randomized to an early invasive therapy, diagnostic catheterization was performed in 97%, a median (25th, 75th percentiles) of 22 h (18, 39) after randomization, subsequent revascularization with PCI or CABG was performed in 60% of patients, a median of 25 (19, 46) and 89 (48, 142) hrs after randomization, respectively. Coronary stents were used in 83% of coronary interventions in the invasive group. Tirofiban therapy was administered in 94% of cases.

At 6 months, the primary endpoint had occurred in 15.9% of patients in the invasive group as opposed to 19.4% of patients in the conservative group (OR = 0.78, 95% CI = 0.62-0.97, p = 0.025). This reduction was evident as early as 30 d after randomization  (7.4% vs 10.5%, p = 0.009). The predominant benefit was seen in the reduction of nonfatal MI and rehospitalization for recurrent angina and not in a reduction in mortality.

The many similarities between the patients in the TACTICS trial and those in the TARGET trial allow for several important comparisons. The difference in the incidence of death or nonfatal MI between abciximab and Tirofiban at 30 days in TARGET is no longer evident when the event rate in the abciximab arm in TARGET (5.7%) is compared with the event rate in the invasive arm of TACTICS (4.7%). The fact that the patients in the invasive arm of TACTICS underwent PCI later than those in TARGET suggests several hypotheses that may explain the above observation. It is possible that suboptimal bolus dosing of Tirofiban contributed to its reduced efficacy in TARGET, or that a longer Tirofiban infusion is required prior to PCI in order to passivate the lesion and reduce complications. The preponderance of evidence to date clearly shows that several hours into an infusion of Tirofiban the inhibition of platelet aggregation is similar to that provided by abciximab and well above the accepted cutoff of 80%. Additionally, pretreatment with Tirofiban, which, in PRISM-PLUS, was shown to decrease the thrombus burden and improve coronary flow, may prevent the occurrence of distal microembolization that often results in small myocardial infarctions. Prevention of these periprocedural infarcts is consistent with the observation that the main benefit observed in these trials was in a lower incidence of nonfatal MI.

Early or Late Intervention in unstable Angina (ELISA) pilot study: Tirofiban upstream therapy and acute coronary syndromes.

ELISA Pre-treatment with tirofiban is associated with improved angiographic outcomes and less intial enzyme release, compared to a strategy of immediate angiography without GPIIb/IIIa inhibitor pre-treatment

Only few studies specifically addressed the effect of timing of  angiography and/or pre-treatment with a glycoprotein IIb/IIIa receptor blocker in patients with non-ST elevation acute coronary syndromes (ACS) who undergo invasive treatment. In the Early or Late Intervention in unStable Angina (ELISA) pilot study, 220 patients with non-ST elevation ACS, were randomized to early angiography without tirofiban pre-treatment (Early strategy) or to delayed angiography after 24-48h pre-treatment with tirofiban (Late strategy)  39  . The first 48h after admission, CKMB levels were measured and enzymatic infarct size (LDHQ(48)) was assessed by the area under the LDH release curve. When PCI was performed beyond 48h, CKMB was measured 6 and 12h afterwards. Median time to angiography was 6 (early) and 50 (Late) hours. PCI was performed in 130 patients (59%). In these patients, a patent (TIMI 2 or 3 flow) culprit vessel was more often present in the Late group compared to the Early group (66% vs 82% p=0.05). In patients

with an elevated CKMB (n=96, 44%), LDHQ (48) was significantly lower in patients who underwent angiography after pre-treatment with tirofiban (629+/-503U/L (Early) vs 432+/-441U/L (Late), p=0.02). No difference in clinical outcome between the groups was observed at 30 days follow-up. This pilot study showed that a strategy of delayed angiography with concomitant pre-treatment with tirofiban is associated with improved angiographic outcomes and less initial enzyme release, compared to a strategy of immediate angiography without GP IIb/IIIa inhibitor pre-treatment. The use of an end point parameter, which assess total enzyme release over a give period of time, might be of special value in patients with non-ST elevation ACS, who undergo very early invasive treatment. 

TIROFIBAN IN ACUTE MI EFFECTS OF DIFFERENT THROMBOLYTIC TREATMENT REGIMEN WITH ABCIXIMAB & TIROFIBAN ON PLATELET AGGREGATION & PLATELETLEUCOCYTE INTERACTIONS: A Subgroup Analysis from the GUSTO V & FASTER trials.

GUSTO V & FASTER TRIALS Tirofiban appears to be more effective as compared to abciximab in exerting effects beyond inhibition of GPIIb/IIIa

From The GUSTO V trial (standard rPa vs. reduced dose rPa & abciximab) & the FASTER trial (standard TNK-tPA v/s reduced dose TNK-tPA & Tirofiban), 15 patients were monitored by platelet aggregometry, rapid platelet function assay(RPFA) & flow cytometry(FC). rPA alone (n=5) caused initial increases in platelet aggregation. However platelet aggregation was significantly (p< 0.05) & sufficiently (>80%) inhibited by abciximab/r PA (n=5) & tirofiban/TNK- tpa (n=5). The platelet inhibitory effect of tirofiban/TNK-tPA was more pronounced compared to abciximab/rPA with a significant difference after a-2 h (p<0.05). Tirofiban / TNK-tPA & abciximab/rPA caused decreases in platelet leukocyte aggregates as well as in binding of specific antibodies to platelet vitronectin receptor & P Selectin (p<0.05, respect).

Taken togeteher, GP IIb/IIIa inhibitors overcome platelet activating effect of thrombolytics resulting in sufficient platelet inhibition in this study.

Tirofiban appears to be more effective compared to abciximab to exert effects beyond inhibition of GPIIb/IIIa  38.

Achieved platelet aggregation inhibition after different antiplatelet regimens during percutaneous coronary intervention for ST-segment elevation myocardial infarction 49

Only with high-dose tirofiban, mean periprocedural platelet aggregation inhibition exceeded 80%.

The extent of platelet aggregation inhibition is an independent predictor of major cardiac events after elective PCI. In STEMI patients undergoing PCI, routine dose of antiplatelet agents may be associated with less effective platelet aggregation inhibition. The aim of this study was to evaluate the extent of platelet aggregation inhibition in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), treated with different antiplatelet agents and dosages.

Patients were treated with clopidogrel before angiography and randomized to abciximab, tirofiban, high-dose tirofiban, or no glycoprotein (GP) IIb/IIIa inhibitor; GP IIb/IIIa inhibitor bolus, followed by maintenance infusion, was administered after angiography, but before PCI. Platelet aggregation inhibition was assessed before angiography, immediately after PCI, and 1 and 6 h afterwards. The total study population consisted of 112 patients. Platelet aggregation inhibition was variable for individuals and suboptimal for all agents, particularly in the periprocedural period. Only with high-dose tirofiban, mean periprocedural platelet aggregation inhibition exceeded 80%. Angiographic parameters after PCI were not different between the groups. No relationship was found between the level of platelet aggregation and parameters of PCI success (Thrombolysis In Myocardial Infarction frame count and myocardial blush grade), after combining the data from all four groups studied. The results of this study suggest that the platelet aggregation inhibition in STEMI patients undergoing PCI, treated with antiplatelet agents, is variable and suboptimal for all agents and dosages studied. Only with high-dose tirofiban, mean periprocedural platelet aggregation inhibition exceeded 80%.

Ongoing Tirofiban in myocardial Infarction Evaluation (On-Time) Trial: Facilitated Percutaneous Coronary Intervention by Early Initiation of Tirofiban Improving Myocardial Reperfusion Before PCI 40  

ON-TIME Therapy facilitation of primary angioplasty using tirofiban, on top of aspirin and heparin, is an attractive addition to the treatment of patients with acute MI in transit to a medical facility to undergo mechanical reperfusion therapy.

Early initiation with tirofiban resulted in an improvement in reperfusion before PCI.

There may be a delay prior to primary angioplasty among patients identified with acute myocardial infarction in the ambulance or at centers unequipped to perform percutaneous coronary intervention (PCI). The On-Time Trial included 209 ambulance patients and 258 patients from referral centers diagnosed with acute MI who were randomized to receive placebo or 10 ug/kg tirofiban bolus followed by an infusion of 0.15 ug/kg/minute while awaiting angiography (figure 7) 40 . After angiography, those who had initially received placebo then received high-dose tirofiban and those initially receiving tirofiban were given placebo. After PCI, patients were treated with a continuous 24-hour tirofiban infusion. The primary endpoint was TIMI 3 flow at initial angiography and secondary endpoints included other features of the initial angiography. The average time between treatment and angiography was 59 minutes with a range of 11 to 178 minutes. Figure 7: ON-TIME: trial design.

Early initiation with tirofiban resulted in an improvement in reperfusion before PCI. There was better epicardial patency, better myocardial reperfusion, and a significant reduction in thrombus in the coronary vessels. However, TIMI 3 flow was not significantly different between the two treatment groups and was 15% in those having early tirofiban treatment and 19% in those receiving placebo. TIMI 2 and 3 flow combined were significantly better among those treated early with tirofiban as was thrombus score.

The early facilitation of primary angioplasty using tirofiban, on top of aspirin and heparin, is an attractive addition to the treatment of patients with acute MI in transit to a medical facility to undergo mechanical reperfusion therapy.

TIROFIBAN: IMPROVES ANGIOGRAPHIC OUTCOMES IN PATIENTS UNDERGOING PRIMARY ANGIOPLASTY FOR ACUTE MYOCARDIAL INFARCTION

Early administration of Tirofiban improves angiographic outcomes and is safe in patients undergoing primary angioplasty for AMI

Tirofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) pilot trial, a randomized study to evaluate the safety, feasibility and utility of early Tirofiban administration before planned primary angioplasty in patients presenting with acute myocardial infarction  29  . In this study a total of 100 patients presenting with acute myocardial infarction were randomized to either early administration of Tirofiban in the emergency room or later administration in the catheterization laboratory. The primary outcome measures were initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion (“blush”). Thirty-day major adverse cardiac events were also assessed. Angiographic outcomes demonstrated a significant improvement in initial TIMI grade flow, corrected TIMI frame counts, and TIMI grade myocardial perfusion when patients are given Tirofiban in the emergency room before primary angioplasty. The rate of 30-day major adverse cardiac events suggests that early  administration may be beneficial. This pilot study suggests that early administration of Tirofiban improves angiographic outcomes and is safe and feasible in patients undergoing primary angioplasty for acute myocardial infarction.

TIROFIBAN: EFFECTS ON HEMOSTATIC ACTIVATION AND INFLAMMATORY RESPONSE DURING CARDIOPULMONARY BYPASS

The administration of Tirofiban during a cardiopulmonary bypass effectively attenuated activation of biochemical markers of the  hemostatic/inflammatory system

Cardiac surgery involving a cardiopulmonary bypass is associated with the activation of the hemostatic/inflammatory system. This is caused by the contact of blood with large nonendothelial surfaces, operative trauma, the suction and reinfusion of tissue factor enriched y Data Before Cardiopulmonary Bypass

blood from the operation field, and the release of cytokines from the ischemic tissue. In a randomized controlled study, 2 groups of 20 patients who underwent elective CABG were randomized  30 . No patient had coumarin or antiplatelet therapy within 10 days before the surgery. In group 1, anticoagulation was performed using unfractioned heparin alone. In group 2, a 10 µg/kg bolus of Tirofiban was given in addition to the initial bolus of heparin before initiation of the cardiopulmonary bypass.

The laboratory data and the values of the postoperative blood loss are listed in table 5. The administration of Tirofiban during a cardiopulmonary bypass effectively attenuated activation of biochemical markers of the hemostatic/inflammatory system. The present findings may have important implications for the substantial number of patients with acute coronary syndromes who are currently being treated with Tirofiban and require urgent surgery.

TIROFIBAN IN ACUTE MI: ALTEPLASE (50 mg) PLUS TIROFIBAN VS ALTEPLASE (100 MG)

The combination of Tirofiban plus alteplase is feasible in AMI patients and that the increased risk of bleeding is an acceptable risk considering the advantage in terms of the reduction in the extent of an AMI.

A randomized controlled trial, aimed at evaluating the safety and  efficacy of the combination of 50 mg alteplase plus Tirofiban vs 100 mg alteplase in AMI patients 32 . One hundred twenty patients (83 males, 37 females; mean age 54.3 +/- 8 years) were hospitalized for suspected AMI within 6 hours of the onset of symptoms. All patients presented pain and persistent ST-segment elevation, were suitable candidates for thrombolysis (1st episode) and were randomized (double blind) into two groups. Group A (n = 60, 42 males, 18 females) received 50 mg alteplase (15 mg as bolus, followed by an infusion of 35 mg over 60 min) in combination with Tirofiban (0.4 µg/kg/min for 30 min followed by an infusion of 0.1 µg/kg/min for 3 days). Group B (n = 60, 41 males, 19 females) received 100 mg of accelerated-dose alteplase alone. Reperfusion criteria were defined as follows: > 50% reduction in the ST-segment elevation; resolution of chest pain; double  marker of creatine kinase (CK) and CK-MB activity 2 hours after the start of thrombolysis; reperfusion arrhythmias within the first 120 min of thrombolysis. The blood pressure, heart rate and ECG were continuously monitored. The mortality, re-AMI, recurrent angina, major and minor bleeding, and emergency bypass surgery or coronary angioplasty were checked.

The groups were similar with regard to clinical data, risk factors, time elapsed from the onset of symptoms to thrombolytic therapy and AMI localization. Forty-seven patients (78.3%) from group A showed reperfusion (15-60 min) Vs 25 patients (41.7%) from group B (43-105 min after the end of full-thrombolysis, p = 0.01). Group A patients showed an earlier CK peak and lower CK and CK-MB peaks than those in the control group (p = 0.0001, p = 0.011, p = 0.005, respectively). Nine patients (7.5%) died: 6 (10%) in group B and 3 (5%) in group A (p = NS). A non-fatal re-AMI occurred in 8 patients from group A and in 4 patients from group B (p = NS). Recurrent angina occurred in 27 patients (45%) from group A and in 11 (18.3%) from group B (p = 0.037). Twenty-three of these patients underwent urgent coronary angioplasty (17 from group A and 6 from group B) and 3 from group A and 1 from group B underwent urgent coronary artery bypass grafting (p = NS). The frequency of minor bleeding was higher in group A than in group B (56.7 vs 25%, p = 0.033). No major bleeding was observed in the study groups. At the predischarge echocardiogram, the ejection fraction was higher in group A than in group B (50 +/- 9 vs 44 +/- 7%, p = 0.001). The results of this study suggest that the combination of glycoprotein IIb/IIIa inhibitors plus alteplase is feasible in AMI patients and that the increased risk of bleeding is an acceptable risk considering the advantage in terms of the reduction in the extent of an AMI. In addition, this combination can allow one to gain time when it is necessary to perform mechanical revascularization in patients admitted to a hospital without an interventional cardiology laboratory or in those who have to be referred to another hospital for urgent coronary artery bypass grafting.

THE USE OF TIROFIBAN IN AMI-SASTRE TRIAL 45  

Sastre Trial supports the hypothesis that platelets play a key role not only in the atherothrombosis process, but also in the disturbances of microcirculation and tissue perfusion Tirofiban as a conjunctive therapy for lytic and stenting regimens not only

improves TIMI 3 flow rates, but also the TMP 3 rates, which are related to a better clinical outcome without an increase in the risk of major bleeding

There is continued debate as to whether a combined reperfusion regimen with platelet glycoprotein IIb/IIIa inhibitors provides additional benefit in optimal myocardial reperfusion of patients with a ST-elevation acute myocardial infarction (AMI). In addition, the best angiographic method to evaluate optimal myocardial reperfusion is still controversial. Patients (n =144) with a first AMI presenting < 6 hours from onset of symptoms were randomized to receive a conjunctive strategy (n=72) with low-dose alteplase (50 mg) and tirofiban (4 µg/kg/min/30 minute bolus; infusion of 0.1 µg/kg/minute), or tirofiban plus stenting percutaneous coronary intervention (PCI). Control patients (n=72) received standard strategy with either full-dose alteplase (100 mg) or stenting PCI. All patients were submitted to coronary angiographic study at 90 minutes. The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 90 minutes. Secondary end points were TIMI myocardial perfusion (TMP) rates, a composite end point at 30 days (death, reinfarction, refractory ischemia, stroke, heart failure, revascularization procedures, or pulmonary edema), and bleeding or hematologic variables. The rate of TIMI 3 flow at 90 minutes for patients treated with alteplase alone was 42% compared with 64% for those who received low-dose alteplase and tirofiban. Standard stenting PCI achieved 81% of TIMI 3 flow compared with 92% when tirofiban was used. Significantly higher rates of TMP grade 3 were observed when tirofiban was used as the adjunctive treatment in both alteplase (66% vs 47%) and stenting PCI (73% vs 55%). Higher rates of the composite end point were observed in standard regimens compared with conjunctive regimens (hazard ratio 5.8, 95% confidence interval 1.27 to 26.6, p-0.023). Regardless of reperfusion regimen, better outcomes were observed when a combination of TIMI 3 flow and TMP grade 3 was achieved. Beyond TIMI 3 flow rate, the TMP grade was an important determinant. The rates of major bleeding were similar (2.8%) for standard versus conjunctive regimens with tirofiban. Thus, tirofiban as a conjunctive therapy for lytic and stenting regimens not only improves TIMI 3 flow rates, but also the TMP 3 rates, which are related to a better clinical outcome without an increase in the risk of major bleeding. This study supports the hypothesis that platelets play a key role not only in the atherothrombosis process, but also in the disturbances of microcirculation and tissue perfusion.

TIROFIBAN: IN CASE OF UNSUCCESSFUL AND FAILED THROMBOLYSIS IN PATIENTS WITH AMI

The results suggest that in patients with AMI and failed thrombolysis, treatment with Tirofiban, is  feasible. The increase in the risk of bleeding was acceptable. The most important result was that this combination is safe.

In a randomized controlled trial, 84 patients were hospitalized within 4 hours of symptom onset were randomized (single blind) into two groups 33 . Regardless of the group, placebo or GP IIb/IIIa inhibitors were administered to patients who did not present with reperfusion signs (failed thrombolysis) 30 min after starting thrombolysis and 30-60 min after the end of full thrombolysis in patients with pain  recurrence and ST-segment elevation (unsuccessful thrombolysis). Reperfusion was assessed by the creatine kinase peak occurring  within 12 hours, by the observation of rapid ST-segment reduction (50-

70% within 1 hour) in the 12-lead ECG continuous tracing, by the rapid regression of pain and by the development of early ventricular arrhythmias. Group 1 patients (n = 42) received treatment with IV GP IIb/IIIa inhibitors, heparin according to the TIMI 14 trial, and aspirin, during failed thrombolysis or after 30-60 min of effective thrombolysis but with pain recurrence and ST-segment elevation (unsuccessful thrombolysis). Group 2 patients (n = 42) received a full dose of recombinant tissue-type plasminog en activator (rt-PA 100 mg) and placebo either during failed thrombolysis or, after 30 min of effective thrombolysis but with pain recurrence and ST-segment elevation, and standard heparin treatment and aspirin.

In group 1, 39 patients showed rapid reperfusion (4 +/- 3 min); 22 patients received rt-PA 65 mg and 20 patients received rt-PA 100 mg  and subsequent GP IIb/IIIa inhibitor treatment. Coronary angiography, performed after 12-72 hours showed patency of the infarct-related artery in 39 patients whose clinical picture was suggestive of rapid reperfusion during administration of a bolus of GP IIb/IIIa inhibitors. In group 2, no patients showed reperfusion and they were submitted to rescue coronary angioplasty (p < 0.05). Side effects occurred in 3 cases in group 1 and in 2 cases in group 2. Patients receiving GP IIb/IIIa inhibitors showed a reduced incidence of stent treatment (p = NS) and a significant reduction in the occurrence of events (angina) within 30 days of treatment (p = NS). The results of this study suggest that in patients with AMI and failed thrombolysis, treatment with Tirofiban, GP IIb/IIIa receptor inhibitor is feasible. The increase in the risk of bleeding was acceptable. The most important result was that this combination is safe.

 

TIROFIBAN IN COMBINATION WITH LMWH (ENOXAPARIN) IN ACUTE CORONARY SYNDROMES (ACS)

Combination therapy with Tirofiban plus enoxaparin appears safe, relative to therapy with Tirofiban plus UFH.

The Antithrombotic Combination Using Tirofiban and Enoxaparin (ACUTE II study)

In comparison with treatment with unfractionated heparin (UFH) and aspirin (ASA), both tirofiban administered with UFH and ASA, and enoxaparin plus ASA have shown superiority in reducing cardiac ischemic events in patients with unstable angina and non- ST-segment elevation myocardial infarction. Replacing UFH with enoxaparin when tirofiban is administered to patients may offer further therapeutic benefit, but could also increase bleeding. The objective of this study was to provide estimates of the frequency of bleeding complications, as defined by means of the Thrombolysis In Myocardial Infarction (TIMI) group, and collect data on clinical efficacy of the combination of tirofiban with enoxaparin plus ASA. 525 patients with UA/ NSTEMI were treated with tirofiban coadministered with ASA and randomized to receive either UFH (n = 210) or enoxaparin (n = 315). Therapy was administered for 24 to 96 hours. Bleeding incidences were assessed until 24 hours after trial therapy was discontinued; other clinical outcomes were assessed for as long as 30 days. The total bleeding  rate (TIMI major + minor + loss-no-site) for the UFH group versus the enoxaparin group was 4.8% vs 3.5% (odds ratio [OR] 1.4, CI 0.6-3.4). The TIMI major and minor bleeding rates for the UFH versus the enoxaparin groups were 1.0% versus

0.3% (OR 3.0, CI 0.3-33.8) and 4.3% versus 2.5% (OR 1.7, CI 0,7-4.6). There was an increase in nuisance cutaneous and oral bleeds (<50 mL of blood loss) in the enoxaparin group. Death or myocardial infarction occurred with similar frequency in the 2 groups (9.0% vs 9.2%). However, refractory ischemia requiring urgent revascularization and rehospitalization because of unstable angina occurred more frequently in the UFH group (4.3% vs 0.6% and 7.1% vs 1.6%, respectively). Combination therapy with tirofiban plus enoxaparin appears safe, relative to therapy with tirofiban plus UFH.

THE SAFETY AND EFFICACY OF SUBCUTANEOUS  ENOXAPARIN VERSUS INTRAVENOUS UNFRACTIONATED HEPARIN AND TIROFIBAN VERSUS PLACEBO IN THE TREATMENT OF ACUTE ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION PATIENTS INELIGIBLE FOR REPERFUSION (TETAMI)

TETAMI Enoxaparin appears to have a similar safety and efficacy profile to UFH and may be an alternative treatment.

The aims of the Safety and Efficacy of Subcutaneous Enoxaparin Versus Intravenous Unfractionated Heparin and Tirofiban versus Placebo in the Treatment of Acute ST- Segment Elevation Myocardial Infarction patients Ineligible for Reperfusion (TETAMI) study were to demonstrate that enoxaparin was superior to unfractionated heparin (UFH) and that tirofiban was better than placebo in patients with acute ST-segment elevation myocardial infarction (STEMI) who do not receive timely reperfusion  41. An optimal treatment strategy has not been identified for the many STEMI patients ineligible for acute reperfusion. A total of 1224 patients were enrolled in 91 centers in 14 countries between July 1999 and July 2002. Patients with STEMI ineligible for reperfusion were randomized to enoxaparin, enoxaparin plus tirofiban, UFH, or UFH plus tirofiban. All patients received oral aspirin. The primary efficacy end point was the 30 day combined incidence of death, reinfarction, or recurrent angina; the primary analysis was the comparison of the pooled enoxaparin and UFH groups. The incidence of the primary efficacy end point was 15.7% enoxaparin versus 17.3% for UFH (odds ratio 0.89% confidence interval CI = 0.66 to 1.21]) and 16.6% for tirofiban versus 16.4% for placebo (odds ratio 1.02 [95% CI 0.75 to 1.38]). The Thrombolysis In Myocardial Infarction (TIMI) major hemorrhage rate was 1.5% for enoxaparin versus 1.3% for UFH (odds ratio 1.16 [95% CI 0.44 to 3.02]) and 1.8% versus 1% for tirofiban versus placebo (odds ratio 1.82 [95% CI 0.67 to 4.95]). This study did not show that enoxaparin significantly reduced the 30-day incidence of death, reinfarction, and recurrent angina compared with UFH in non-reperfused STEMI patients. However, enoxaparin appears to have a similar safety and  efficacy profile to UFH and may be an alternative treatment. Additional therapy with tirofiban did not appear beneficial.

COMBINING ENOXAPARIN AND GLYCOPROTEIN IIB/IIIA ANTAGONISTS FOR THE TREATMENT OF ACUTE CORONARY SYNDROMES: THE NATIONAL INVESTIGATORS COLLABORATING ON ENOXAPARIN-3 (NICE-3) STUDY.

NICE-3 Patients undergoing PCI can be safely managed with enoxaparin and a GP IIb/IIIa antagonist, without supplemental use of unfractionated heparin.

In high-risk patients with acute coronary syndromes (ACS), there have been concerns relating to the safety of using low molecular weight heparins (LMWH) in combination with a glycoprotein (GP) IIb/IIIa antagonist, and the continued use of LMWH in patients brought to the cardiac catheterization laboratory for  percutaneous coronary intervention (PCI). The National Investigators Collaborating on Enoxaparin-3 (NICE-3) study was an open-label observational study of  enoxaparin in combination with any 1 of 3 available GP IIb/IIIa antagonists in patients presenting with non- ST-elevation ACS42. The primary end point was the incidence of major bleeding not related to coronary artery bypass graft (CABG) surgery. Data were also recorded on the incidence of death, myocardial infarction (MI), and urgent revascularization for repeat ischemia. A total of 671 patients with validated data were treated with enoxaparin; 628 of these patients also received a GP IIb/IIIa antagonist (tirofiban, n = 229; eptifibatide, n = 272; abciximab, n = 127); 283 of 628 underwent percutaneous coronary intervention (PCI). The 30-day incidence of non-CABG major bleeding was 1.9%, and was not significantly higher than a prespecified historical control rate of 2.0%. Outcome events included death (1.0% at hospital discharge and 1.6% at 30 days), MI (3.5% and 5.1%, respectively), and urgent revascularization (2.7% and 6.8%, respectively). The safety of enoxaparin plus GP IIb/IIIa antagonist was comparable to that of unfractionated heparin plus GP IIb/IIIa antagonist, as reported in other recent major trials. Patients undergoing PCI can be safely managed with enoxaparin and a GP IIb/IIIa antagonist, without supplemental use of unfractionated heparin.

ENOXAPARIN Vs UNFRACTIONATED HEPARIN IN HIGH-RISK PATIENTS WITH NON-ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES MANAGED WITH AN INTENDED EARLY INVASIVE STRATEGY 46

Enoxaparin has demonstrated advantages over unfractionated heparin in low-to moderate-risk patients with non-ST-segment elevation acute coronary syndromes (ACS) treated with a conservative strategy. To compare the outcomes of patients treated with enoxaparin vs unfractionated heparin and to define the role of enoxaparin in patients with non-ST segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach. The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was a prospective, randomized, open-label, multicenter, international trial conducted between August 2001 and December 2003. A total of 10027 high-risk patients with non-ST segment elevation ACS to be treated with an intended early invasive strategy were recruited. Subcutaneous enoxaparin (n=4993) or intravenous unfractionated heparin (n=4985) was to be administered immediately after enrollment and continued until the patient required no further anticoagulation, as judged by the treating physician. Main Outcome Measures the primary efficacy outcome as the composite clinical end-point of all-cause death or nonfatal myocardial infarction during the first 30 days after randomization. The primary safety outcome was major bleeding or stroke. The primary end point occurred in 14.0% (696/4993) of patients assigned to enoxaparin and 14.5% (722/4985) of patients assigned to unfractionated heparin (odds ratio [ORI], 0.96;95% confidence interval [CI], 0.86-1.06). No differences in ischemic events during percutaneous coronary intervention (PCI) were observed between enoxaparin and unfractionated heparin groups,

respectively, including similar rates of abrupt closure (31/2321 [1.3%] vs 40/ 2364 [1.7%]), threatened abrupt closure (25/23211 [1.1%] vs 24/ 2363 [1.0%]), unsuccessful PCI (81/ 2281 [3.6%] vs 79/2328 [3.4%]), or emergency coronary artery bypass graft surgery (6/2323 [0.3%] vs 8/2363 [0.3%]). More bleeding was observed with enoxaparin, with a statistically significant increase in TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs 7.6%, P=.008) but nonsignificant excess in GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs 2.2%, P=.08) and transfusions (17.0% vs 16.0%,P=.16). Enoxaparin was not superior to unfractionated heparin but was noninferior for the treatment of high-risk patients with non-ST- segment elevation ACS. Enoxaparin is a safe and effective alternative to unfractionated heparin and the advantages of convenience should be balanced with the modest excess of major bleeding.

SAFETY AND EFFICACY OF ENOXAPARIN Vs UNFRACTIONATED HEPARIN IN PATIENTS WITH NON-ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES WHO RECEIVE TIROFIBAN AND ASPIRIN: A RANDOMIZED CONTROLLED TRIAL 47  

Enoxaparin or the combination of glycoprotein IIb/IIIa inhibitor tirofiban with unfractionated heparin independently have shown superior efficacy over unfractionated heparin alone in patients with non-ST elevation acute coronary syndromes (ACS). It is not clear if combining enoxaparin with glycoprotein IIb/IIIa inhibitors is as safe or as effective as the current standard combination of unfractionated heparin with glycoprotein IIb/IIIa inhibitors. To assess efficacy and safety of the combination of enoxaparin and tirofiban compared with unfractionated heparin and tirofiban in patients with non-ST elevation ACS. A prospective, international, open-label, randomized, noninferiority trial of 1 mg/kg of enoxaparin every 12 hours (n=2026) compared with weight-adjusted intravenous unfractionated heparin (n=1961) in patients with non-ST-elevation ACS receiving tirofiban and aspirin. Phase A of the A to Z trial was conducted between December 1999 and May 2002. Main Outcome Measures Death, recurrent myocardial infarction, or refractory ischemia at 7 days in the intent-to-treat population with boundaries set for superiority and noninferiority. Safety based on measures of bleeding using the Thrombolysis in Myocardial Infarction (TIMI) classification system. A total of 169 (8.4%) of 2018 patients randomized to enoxaparin experienced death, myocardial infarction, or refractory ischemia at 7 days compared with 184 (9.4%) of 1952 patients randomized to unfractionated heparin (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.71-1.08). This met the prespecified criterion for noninferiority. All components of the composite primary and secondary end points favored enoxaparin except death, which occurred in only 1% of patients (23 for enoxaparin and 17 for unfractionated heparin). Rates for any TIMI grade bleeding were low (3.0% for enoxaparin and 2.2% for unfractionated heparin; P=.13). Using a worst-case approach that combined 2 independent bleeding evaluations, use of enoxaparin was associated with 1 additional TIMI major bleeding episode for each 200 patients treated. In patients receiving tirofiban and aspirin, enoxaparin is a suitable alternative to unfractionated heparin for treatment of non-ST-elevation ACS. The 12% relative and 1% absolute reductions in the primary end point in favour of enoxaparin met criterion for non-inferiority and are consistent with prior trials performed without the use of glycoprotein IIb/IIIa inhibitors.

TIROFIBAN: BENEFITS AND SAFETY AMONG ACUTE CORONARY SYNDROME PATIENTS WITH MILD TO MODERATE RENAL INSUFFICIENCY

Among patients with mild-tomoderate renal insufficiency in PRISM-PLUS, Tirofiban was well tolerated and effective in reducing ischemic acute coronary syndrome complications.

Patients from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial were stratified by creatinine clearance (CrCl) and assessed with respect to treatment assignment to Tirofiban/heparin versus heparin alone for the risk of adverse outcomes and bleeding    34. Patients with severe renal insufficiency (defined as a serum creatinine > or = 2.5  mg/dL) were excluded from PRISM-PLUS as a whole. Patients with the lowest CrCl (< 30 mL/min) were more likely to present with high-risk clinical features. Decreasing renal function was strongly associated with adverse outcome, increasing the risk for ischemic complications at all time points examined (all P < 0.002). Irrespective of CrCl, therapy with Tirofiban reduced the odds of the composite end point of death, myocardial infarction, or refractory ischemia at 48 hours (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.46 to 1.0; P=0.05), 7 days (OR, 0.68; 95% CI, 0.52 to 0.88; P= 0.003), 30 days (OR, 0.78; 95% CI, 0.63 to 0.98; P=0.03), and 6 months (OR, 0.81; 95% CI, 0.68 to 0.98; P=0.03). The risk of myocardial infarction/death was also significantly decreased to a similar magnitude at all time points examined. There was no evidence of treatment-by-CrCl interaction. The presence of declining renal function independently increased the risk for bleeding (OR, 1.57; P < 0.001 for trend across categories), as did therapy with Tirofiban, but no unexpected incremental risk of bleeding due to Tirofiban was observed among lowest CrCl categories. This study suggests that among patients with mild-to-moderate renal insufficiency in PRISM-PLUS, Tirofiban was well tolerated and effective in reducing ischemic acute coronary syndrome complications.

TIROFIBAN: IN UNSTABLE CAROTID DISEASE

Tirofiban has the potential to bridge the ischemic risk in patients with unstable carotid disease & Stroke

Cerebral microembolism of arterial origin has the property of solid emboli, with platelet fibrinogen units as predominant constituent parts in patients with unstable carotid disease. Microembolic signals (MES) as detected by transcranial Doppler ultrasound define an individual stroke risk in patients with carotid artery disease. In this clinical trial Tirofiban was used to study the composition of MES invivo. 24 patients with recent cerebral or retinal embolism of arterial origin and a MES rate >6 per hour on initial transcranial Doppler ultrasonography recording received the GPIIb/IIIa antagonist Tirofiban    35  . With Tirofiban, the MES rate dropped from a median (range) of 38 (9 to 324) to zero in all patients. After cessation of infusion, the inhibitory effect of Tirofiban was reversible, with a significant increase of MES (median 13.5; range, 0 to 35; n=16; P=0.001). 6 patients received overlapping oral antiplatelet agents and remained MES-negative. The results of this study suggest that Tirofiban may have the potential to bridge the ischemic risk in patients with unstable carotid disease.

TIROFIBAN: IN ACUTE STROKE THERAPY

In an open pilot study, the nonpeptide glycoprotein (GP) IIb/IIIa antagonist Tirofiban, a highly effective and selective blocker of platelet aggregation, prevented the transition of ischemic brain tissue into the infarct proper as defined by MRI (perfusion-weighted/T2-weighted) in patients with acute ischemic stroke 36 . The infarct volume (T2 lesion after 1 week) was smaller in treated patients (n = 10) compared with matched control subjects (n = 10; p = 0.029) with similar initial perfusion deficit (TTPmaps). This study suggest that Tirofiban has therapeutic potential in acute stroke therapy.

TIROFIBAN IN PATIENTS WITH PERIPHERAL ARTERIAL OCCLUSIVE DISEASE AND ARTERIAL THROMBOSIS

Tirofiban can be used successfully in patients with peripheral arterial occlusive disease and arterial thrombosis Tirofiban has the potential to bridge the ischemic risk in patients with unstable carotid disease & Stroke

A randomized controlled trial investigated whether the use of Tirofiban has the same favorable effect as the glycoprotein (GP) IIb/IIIa receptor antagonist abciximab and whether lysis times can be shortened and the disease course positively influenced by these substances  37. Sixty patients were randomly assigned to 2 groups. Each group received 5 mg recombinant tissue-type (rt-PA) plasminogen activator by slow intra-arterial injection for 10 minutes followed by 5 mg rt-PA per hour and 500 IU of IV heparin per hour. After randomization 1 group received a bolus of 0.25 mg abciximab per kg body weight followed by 10 mg per minute IV for 12 hours (heparin was reduced to 250 IU/hr). The other group received a bolus of 0.4 µg/kg of Tirofiban as well as postinterventional medication with 0.1 µg/kg/min of Tirofiban for 24  hours. During medication with GP IIb/IIIa inhibitor, the patients received a reduced heparin dosage for 24 hours. After 24 hours both groups received 200 mg aspirin orally and full heparinization controlled on the basis of the partial thromboplastin time. The efficacy criteria analyzed were: rehospitalization events, reintervention events, and amputations within 6 months. Secondary endpoints were changes in the Fontaine stage, the crurobrachial index, the distance to claudication, and the duration of local arterial lysis. No significant differences were found between the abciximab and Tirofiban groups in terms of the rehospitalization, reintervention, or amputation rates, nor were there any group differences in the total number of events. The secondary parameters, such as the crurobrachial index, distance to claudication, and Fontaine stage, also showed no significant differences between the 2 groups within 6 months. Major bleeding events did not occur in either group. With regard to the adverse effect rate, there were no significant differences between the 2 groups. The results of this study suggest that Tirofiban can be used successfully in patients with peripheral arterial occlusive disease and arterial thrombosis.

Section 5 : TIROFIBAN : DOSAGE AND ADMINISTRATION

TIROFIBAN: DOSAGE AND ADMINISTRATION

For the treatment of patients with acute coronary syndrome (unstable angina or non-Q-wave acute myocardial infarction), including patients who are to be managed medically and those undergoing percutaneous coronary intervention (PCI) such as PTCA or atherectomy, in combination with aspirin (unless contraindicated) and heparin :

Intravenous dosage:

Adults: 0.4 µg/kg/minute IV for 30 minutes, and then 0.1 µg/kg /minute IV throughout angiography and for 12-24 hours after angioplasty or atherectomy. During the PRISM-PLUS study, Tirofiban was administered in combination with heparin for 48-108 hours. In the ADVANCE Trial the patients undergoing PCI were started on 25µg/kg IV bolus over 3 min, followed by an infusion of 0.15 µg/kg/min IV for 16-18 hrs. Heparin was administered at a bolus of 70U /kg bolus with additonal boluses to achieve and maintain an ACT > 200 secs.  during the procedure.

Patients with renal impairment:

CrCl < 30 ml/min: Administer one-half the usual rate of infusion (e.g., initially, 0.2 µg/kg/min IV for 30 minutes, followed by 0.05 µg/kg/min IV).

Intermittent hemodialysis:

Dosage recommendations in patients undergoing intermittent hemodialysis have not been established. Tirofiban is removed by hemodialysis; however, plasma clearance of Tirofiban is significantly decreased (> 50%) in patients with a CrCl < 30 mL/min, including patients requiring hemodialysis.

Dosage Protocol for Tirofiban (Aggramed)

Patients of ACS in the Emergency Department Categorized into (A) Troponin Positive,  (B)  Troponin Negative and (C) Patients of Renal Impairment.

(A)Troponin Positive

1. For Management in ICCU

I/V Bolus 0.4 µg/Kg/min over 30 minutes followed by 0.1 µg/Kg/ min continuous infusion for 48 hrs. (Prism19, Prism Plus20, TACTICS- TIMI 18  28 ). 

Heparin to be administered intravenously at a bolus of 5000U followed by an infusion of 1000U/hr to maintain APTT at 50 - 70 secs (Prism  19, Prism Plus  20, TACTICS- TIMI 18  28  , )

2. For PCI

I/V Bolus 25 µg/ Kg/min over 3 minutes followed by 0.15 µg/Kg/min continous infusion. (Danzi.et.al. Protocol  44& ADVANCE Protocol   48 )

Heparin to be administered at a bolus of 70U /kg bolus with additonal boluses to achieve and maintain an ACT > 200 secs during the procedure. Discontinue heparin after the procedure and remove the arterial sheath when ACT < 180 secs (Target Protocol 23 , ADVANCE Protocol 48,)

B)Troponin Negative-

If Troponin test is negative, employ TIMI Risk Score

Each Risk represents one score each

If risk score is more than 4, benefit with Tirofiban dosage of 0.4 µg/kg/min followed by 0.1 µg/kg/min for 48 hrs.

C). Patients of Renal Impairment –

Patients whose creatinine clearance is less than 30 ml/min:

1 For management in  ICCU

I/V Bolus dose of 0.2 µg/Kg/min followed by 0.05 µg/Kg/min for 48 hrs.

2. For PCI

I/V Bolus dose 12.5µg/Kg/min over 3 mins. ,  followed by 0.075  µg/Kg/min continuous infusion.

Section 6 TIROFIBAN: CONTRAINDICATIONS

TIROFIBAN: CONTRAINDICATIONS

Tirofiban is contraindicated in patients with:

 Known hypersensitivity to any component of the product. Active internal bleeding or a history of bleeding diathesis within the previous 30 days. A history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or

aneurysm. A history of thrombocytopenia following prior exposure to Tirofiban HCl. History of stroke within 30 days or any history of hemorrhagic stroke.

Major surgical procedure or severe physical trauma within the previous month.    History, symptoms, or findings suggestive of aortic dissection.

 Severe hypertension (systolic blood pressure >180 mm Hg and/or diastolic blood pressure >110 mm Hg).

 Concomitant use of another parenteral GP IIb/IIIa inhibitor.  Acute pericarditis.

Section 7 TIROFIBAN : DRUG INTERACTIONS

TIROFIBAN: DRUG INTERACTIONS

Tirofiban HCl has been studied on a background of aspirin and heparin.

The use of Tirofiban HCl, in combination with heparin and aspirin, has been associated  with an increase in bleeding compared to heparin and aspirin alone. Caution should be employed when Tirofiban HCl is used with other drugs that affect hemostasis (e.g., warfarin).

In a sub-set of patients (n=762) in the PRISM study, the plasma clearance of Tirofiban in patients receiving one of the following drugs was compared to that in patients not receiving that drug. There were no clinically significant effects of co-administration of these drugs on the plasma clearance of Tirofiban: acebutolol, acetaminophen, alprazolam, amlodipine, aspirin preparations, atenolol, bromazepam, captopril, diazepam, digoxin, diltiazem, docusate sodium, enalapril, furosemide, glyburide, heparin, insulin, isosorbide, lorazepam, lovastatin, metoclopramide, metoprolol, morphine, nifedipine, nitrate preparations, oxazepam, potassium chloride, propranolol, ranitidine, simvastatin, sucralfate and temazepam. Patients who received levothyroxine or omeprazole along with Tirofiban HCl had a higher rate of clearance of Tirofiban HCl. The clinical significance of this is unknown.

Section 8 TIROFIBAN: ADVERSE EFFECT PROFILE

TIROFIBAN: ADVERSE EFFECT PROFILE

Tirofiban was generally well tolerated in clinical trials in patients with acute coronary syndromes. Bleeding, secondary to drug-induced platelet dysfunction, is the most common adverse event associated with use of Tirofiban. Major bleeding associated with Tirofiban has included intracranial bleeding, cardiac tamponade, retroperitoneal bleeding, hemopericardium and pulmonary (alveolar) hemorrhage or a severe decrease in haemoglobin (Hb) of > 5 g/dl. Minor bleeding events include spontaneous gross hematuria, spontaneous hematemesis, observed blood loss with a Hb decrease of more than 3 g/dl, or a decrease in Hb of at least 4 g/dl without an identified bleeding site. In the PRISM-PLUS study, major bleeding occurred in 1.4% of patients (n=1570) treated with Tirofiban plus heparin and in 0.8% of patients in the heparin control group; minor bleeding occurred in 10.5% and 8% of patients, respectively.[495] In the RESTORE study, major bleeding occurred in 2.2% of patients (n=2141) in the Tirofiban group and 1.6% of patients in the placebo group; minor bleeding occurred in 12% and 6.3% of patients, respectively (all patients received heparin during the PCI procedure).[503] The incidence of intracranial bleeding in the RESTORE study was 0.1% for Tirofiban in combination with heparin and 0.3% for the heparin control group; there were no reports of intracranial bleeding in the PRISM-PLUS study. In the PRISM-PLUS and RESTORE studies, the incidence of retroperitoneal bleeding was similar for the treatment and placebo

groups, 0.6% and 0.3%, respectively. Major GI bleeding and genitourinary bleeding for Tirofiban in combination with heparin was 0.1-0.2% and 0-0.1%, respectively.

In controlled clinical trials, the incidence of non-bleeding adverse events in Tirofiban-treated patients that occurred at an incidence of >1% and numerically higher than control, regardless of drug relationship, included edema (2%), pelvic pain (6%), hypotension associated with a vasovagal reaction (2%), sinus bradycardia (4%), coronary artery dissection (5%), leg pain (3%), dizziness (3%), and diaphoresis (2%). Other non-bleeding side effects (considered at least possibly related to Tirofiban therapy) reported in >1% of patients were nausea/vomiting, fever, and headache; these side effects were reported at a similar rate in the heparin control group.

Section 9 CONCLUSIONS

CONCLUSIONS

Tirofiban is a synthetic, non-peptide (nonpeptide-mimetic) and a specific antagonist of the GPIIb/IIIa receptor with unique pharmacological properties that distinguishes it from the other agents in its class that have been approved recently. A wealth of evidence from well-designed, large-scale trials now exists confirming that therapy with Tirofiban reduces the incidence of adverse cardiac events in acute coronary syndrome patients treated medically as well as in patients undergoing PCI directly. In both groups, the observed benefits include a reduction in the combined incidence of death or MI as well as a reduction in the incidence of refractory ischemia or need for urgent repeat revascularization. Furthermore, it is evident that in patients with acute coronary syndrome who are initially treated medically, the ones who derive the greatest benefit are those who subsequently proceed to cardiac catheterization and coronary intervention.

Clinical studies have shown that intravenous Tirofiban has an acceptable tolerability profile in patients with acute coronary syndromes. As with other antiplatelet agents, the beneficial effects of Tirofiban are accompanied by an increase in bleeding times and, therefore, an increased risk of bleeding complications. The rate of major bleeding associated with Tirofiban alone was not significantly different from that with heparin. Importantly, dose finding trials showed that median bleeding times returned to near normal 3 hours after cessation of an intravenous infusion of Tirofiban.

Thus in a nutshell, the glycoprotein IIb/IIIa receptor antagonist Tirofiban has an acceptable tolerability profile and reduces the short term and longer term risk of ischaemic complications in patients with unstable angina/non-Q-wave MI. The benefits of Tirofiban was also apparent when it was administered during revascularisation procedures. Besides, Tirofiban is a promising candidate for the management of acute ischemic stroke and peripheral arterial disease.

Tirofiban Dosage & Administration Summary : 

Dosage Charts: Dosage In Unstable Angina and NSTEMI   and  Dosage With High Dose Bolus

Dose for Medical Management of ACS :

 0.4 µg/Kg/ IV bolus over 30 min followed by 0.1 µg/ Kg / min for 48-72 hrs (Prism 19 , Prism Plus  20  , TACTICS- TIMI 18  28   ,)

Dose for PCI :  

IV Bolus 25 µg/Kg/min for 3 minutes followed by 0.15 µg/ Kg / min continuous infusion. (Danzi.et.al. Protocol   44 & ADVANCE Protocol  48)

For patients with CrCL < 30 ml/min, decrease infusion and maintenance rates by 50%

Anticoagulation along with Tirofiban (Heparin or Enoxaparin):

1. Unfractionated Heparin

1. For Management in ICCU

 Heparin to be administered intravenously at a bolus of 5000U followed by an infusion of 1000U/hr to maintain APTT at 50-70 secs. (Prism    19 , Prism Plus 20 , TACTICS- TIMI 1828  ,)

2. For PCI

Heparin to be administered at a bolus of 70U /kg bolus with additional boluses to achieve and maintain an ACT > 200 secs. during the procedure. Discontinue heparin after the procedure and remove the arterial sheath when ACT < 180 secs. (Target Protocol  23, ADVANCE Protocol  48 ,)

2. Enoxaparin

a. Give 1 mg/kg subcutaneously every 12 hours. (NICE-3   43 )

Management of Tirofiban with Cardiac Catheterization/Intervention

Percutaneous coronary intervention

1. Test the ACT before proceeding with the intervention

2. Give Enoxaparin Subcutaneously in dosage of 1mg/kg aiming for target ACT of 200-30 seconds.

3. Test the ACT after Enoxaparin dose to ensure ACT is in target range.

4. With Enoxaparin, perform PCI within 2-8 hour after first dose of Enoxaparin. If PCI is performed after 8 hr of Enoxaparin give IV Enoxaprin (0.2-0.3mg/kg)

5. Monitor ACT every 90 minutes during procedure

Management of the patient post-procedure

1. Do not place patient on immediate post-procedural IV heparin.

2. Remove sheaths when ACT < 150 seconds or 8 hrs after the last dose of enoxaparin with manual compression & sooner with closure devices while still on tirofiban

3. Only if necessary, restart IV heparin or S/C enoxaparin 4 hours after sheath removal.

4. Continue tirofiban for at least 18-24 hours after the procedure.

5. Continue aspirin (clopidogrel if coronary stenting is done)

Management of a Patient Receiving Tirofiban if a Major Bleeding Complication Occurs

1. Immediately discontinue tirofiban. Perform platelet transfusions (10- pack initially) as required to control bleeding. Consider dialysis in the first 4 hours after discontinuing tirofiban if clinically needed.

2. Immediately discontinue heparin or enoxaparin. Administer protamine as required to control bleeding.

Management of a Patient on Tirofiban in case of Cardiac Surgery

(Duration of platelet inhibition is 4-8 hours)

1. Discontinue tirofiban 3-6 hours prior to surgery or as close to that time as possible.

2. Perform platelet transfusions only as required to control bleeding after surgery.

3. Consider dialysis if < 4 hrs since discontinuing tirofiban.

Management of a Post-Tirofiban Thrombocytopenia

For platelet count > 100,000:

Do not alter treatment

For platelet count 40,000-100,000:

Redraw stat platelet count in a citrate preserved tube. If similar count of < 100,000, immediately discontinue tirofiban.

Perform platelet transfusions only as required to control bleeding Repeat platelet count every 12 hours until > 100,000. For platelet count < 40,000 Immediately discontinue tirofiban. Perform platelet transfusion as required to control bleeding or consider administering to

maintain platelet count of > 40,000. Repeat platelet count every 12 hours until the count is > 100,000. Consider stopping heparin.

Section 10 BIBLIOGRAPHY

BIBLIOGRAPHY:

1. Fuster V, Badimon L, Badimon JJ et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-250.

2. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. Updated March 17, 2002. Available at http://www.acc.org/clinical/guidelines/unstable/update/pdf/UA_update.pdf

3. Theroux P, Waters D, Lam J et al. Reactivation of unstable angina after discontinuation of heparin. N Engl J Med 1992; 327: 141-145.

4. Xiao Z, Theroux P. Platelet activation with unfractioned heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998; 97: 251-256.

5. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. NEngl J Med 1995; 332: 1553-1559.

6. Stein B, Fuster V, Israel DH et al. Platelet inhibitor agents in cardiovascular disease: an update. J Am Coll Cardiol 14: 813-836

7. Verstraete M, Zoldhelyi P. Novel antithrombotic drugs in development. Drugs 49: 856-884.

8. Schror K. Antiplatelet drugs-a comparative review. Drugs 30: 7-28.

9. The EPILOG Investigators. Effect of platelet glycoprotein IIb/IIIa receptor inhibitor, abciximab, with lower heparin dosages on ischemic complications of percutaneous coronary revascularisation. N Engl J Med 1997; 336: 1689-1696.

10. Ferguson JJ, Lau TK. New antipatelet agents for acute coronary syndromes. Am Heart J 1998; 135: S194-200.

11. McClellan KJ, Goa KL. Tirofiban: A review of its use in Acute Coronary Syndromes. Drugs 1998; 56: 1067-1080.

12. Theroux P, White H, David D, et al. A heparin-controlled study of MK-383 in unstable angina. Circulation 1994; 90:231.

13. Barrett JS, Murphy G, et al. Pharmacokinetics and pharmacodynamics of MK-383, a selective nonpeptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men. Clin Pharmacol Ther 1994; 56: 377-88.

14. Kereiakes DJ, Kleiman NS, et al. Randomized double-blind, placebo-controlled dose-ranging study of Tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty. J Am Coll Cardiol 1996; 27: 536-42.

15. Umermura K, Kondo K, Ikeda Y, et al. Enhancement by ticlopidine of the inhibitory effect on in vitro platelet aggregation of the glycoprotein IIb/IIIa inhibitor Tirofiban. Thromb Haemost 1997; 78: 1381-4.

16. Peerlinck K, Arnout J, et al. Combined effect of aspirin and MK 383 (L-700,462), a selective GPIIb/IIIa  antagonist, in healthy volunteers. Thromb Haemost 1993; 69: 560.

17. Lynch JJ, Cook JJ, Sitko GR, et al. Nonpeptide glycoprotein IIb/IIIa inhibitors. 5. Antithrombotic effects of MK-0383. J Pharmacol Exp Ther 1995; 272: 20-32.

18. Merck and Co. Inc. Aggrastat (Tirofiban hydrochloride) prescribing information. West Point, USA, 1998.

19. The PRISM Study Investigators. A comparison of aspirin plus Tirofiban with aspirin plus heparin for unstable angina. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. N Engl J Med. 1998 May 21; 338(21):1498-505.

20. The PRISM-PLUS Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with Tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISMPLUS) Study Investigators. N Engl J Med. 1998 May 21; 338(21):1488-97.

21. Zhao XQ, Theroux P, Snapinn SM, Sax FL. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with Tirofiban in unstable angina or non-Q-wave myocardial infarction.

Angiographic results from the PRISM-PLUS trial (Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). PRISM-PLUS Investigators. Circulation. 1999 Oct 12; 100(15):1609-15.

22. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with Tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis. Circulation. 1997 Sep 2; 96(5):1445-53.

23. Topol EJ, Moliterno DJ, Herrmann HC, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, Tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. TARGET Investigators. Do Tirofiban and ReoPro Give Similar Efficacy Trial. N Engl J Med. 2001 Jun 21; 344(25):1888-94.

24. Gibson CM, Goel M, Cohen DJ, et al. Six-month angiographic and clinical follow-up of patients prospectively randomized to receive either Tirofiban or placebo during angioplasty in the RESTORE trial. Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis. J Am Coll Cardiol. 1998 Jul; 32(1):28-34.

25. Moliterno DJ, Yakubov SJ, DiBattiste PM, et al. Outcomes at 6 months for the direct comparison of Tirofiban and abciximab during percutaneous coronary revascularisation with stent placement: the TARGET follow-up study. Lancet. 2002 Aug 3; 360(9330):355-60.

26. Roffi M, Moliterno DJ, Meier B, et al. Impact of different platelet glycoprotein IIb/IIIa receptor inhibitors among diabetic patients undergoing percutaneous coronary intervention: : Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial (TARGET) 1-year follow-up. Circulation. 2002 Jun 11; 105(23):2730-6.

27. Danzi GB, Capuano C, Sesana M, Baglini R. Preliminary experience with a high bolus dose of Tirofiban during percutaneous coronary intervention. Curr Med Res Opin. 2003; 19(1):28-33. 28. The TACTICS-TIMI18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor Tirofiban. N Engl J Med. 2001 Jun 21; 344(25):1879-87.

29. Lee DP, Herity NA, Hiatt BL, et al. Adjunctive platelet glycoprotein IIb/IIIa receptor inhibition with Tirofiban before primary angioplasty improves angiographic outcomes: results of the Tirofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) pilot trial. Circulation. 2003 Mar 25; 107(11):1497-501.

30. Koster A, Chew DP, Kuebler W, et al. Effects of Tirofiban on hemostatic activation and inflammatory response during cardiopulmonary bypass. Am J Cardiol. 2003 Feb 1; 91(3):346-7.

31. Cohen M, Theroux P, Borzak S, et al. Randomized double-blind safety study of enoxaparin versus unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes treated with Tirofiban and aspirin: the ACUTE II study. The Antithrombotic Combination Using Tirofiban and Enoxaparin. Am Heart J. 2002 Sep; 144(3):470-7.

32. Sarullo FM, Pasquale PD, D’Alfonso G, et al. Safety and efficacy of thrombolysis with alteplase (50 mg) plus Tirofiban versus alteplase (100 mg) alone in acute myocardial infarction: preliminary findings. Ital Heart J. 2001 Aug; 2(8):605-11.

33. Di Pasquale P, Sarullo FM, Cannizzaro S, et al. Increased reperfusion by glycoprotein IIb/IIIa receptor antagonist administration in case of unsuccessful and failed thrombolysis in patients with acute myocardial infarction: a pilot study. Ital Heart J. 2001 Oct; 2(10):751-6.

34. Januzzi JL Jr, Snapinn SM, DiBattiste PM, Jang IK, Theroux P. Benefits and safety of Tirofiban among acute coronary syndrome patients with mild to moderate renal insufficiency: results from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial. Circulation. 2002 May 21; 105(20):2361-6.

35. Junghans U, Siebler M. Cerebral microembolism is blocked by Tirofiban, a selective nonpeptide platelet glycoprotein IIb/IIIa receptor antagonist. Circulation. 2003 Jun 3; 107(21):2717-21.

36. Junghans U, Seitz RJ, Ritzl A, et al. Ischemic brain tissue salvaged from infarction by the GP IIb/IIIa platelet antagonist Tirofiban. Neurology. 2002 Feb 12; 58(3):474-6.

37. Schweizer J, Kirch W, Koch R, Muller A, Hellner G, Forkmann L. Use of abciximab and Tirofiban in patients with peripheral arterial occlusive disease and arterial thrombosis. Angiology. 2003 Mar-Apr; 54(2):155-61.56

38. BaSci UB, Moser M,Peter K, Kuecherer HF, et al. Effects of Different Thrombolytic Treatment Regimen with Abciximab and Tirofiban on Platelet Aggregation and Platelet-Leukocyte Interactions: A Subgroup Analysis from the GUSTO V and FASTER Trials. Journal of Thrombosis and Thrombolysis 14(3), 197- 203, 2002.

39. Van ‘t Hof AW, de Vries ST et al. A comparison of two invasive strategies in patients with non- ST elevation acute coronary syndromes: results of the Early or the Intervention in unStable Angina (ELISA) pilot study. 2b/3a upstream therapy and acute coronary syndromes. Eur Heart J. 2003 Aug;24(15):1401-5

40. Menko Jan de Boer. Late-Breaking Clinical Ttials and Trial Updates: Novel Therapies for Acute Myocardial Infarction. ACC s Annual Scientific session 2004.

41. Cohen M, Theroux P et al. Randomized double-blind safety study of enoxaparin versus unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes treated with tirofiban and aspirin: the ACUTE II study. The Antithrombotic Combination Using Tirofiban and Enoxaparin. Am Heart J.2002 Sep;144(3):470-7

42. Cohen M, Gensini GF et al. The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST- segment elevation myocardial infarction patients ineligible for reperfusion (TETAMI): a randomized trial. J Am coll Cardiol. 2003 Oct 15;42(8):1348-56.

43. Ferguson JJ, Antman EM et al. Combining enoxaparin and glycoprotein IIb/IIIa antagonists for the treatment of acute coronary syndromes: final results of the National Investigators Collaborating on Enoxaparin-3 (NICE-3) study. Am heart J. 2003 Oct;146(4):628-34

44. Danzi GB, Capuano C et al. Safety of a high boius dose of tirofiban in patients undergoing coronary stent placement. Catheter Vardiovasc Interv. 2004 Feb;61(2):179-84.

45. Martinez-Rios MA et al. Comparison of Reperfusion Regimens

with or without Tirofiban in ST-Elevation Acute Myocardial Infarction, AM J. Cardiol 2004:93:280-287.

46. Ferguson JJ, Califf RM et al. Enoxaparin vs Unfractionated heparin in High-Risk Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Managed With an Intended Early Invasive Strategy. JAMA 2004; 292:45-54.

47. James A. De Lemos JA, White HD et al. Safety and Efficacy of Enoxaparin vs Unfractionated Heparin in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Who Receive Tirofiban and Aspirin. JAMA 2004; 292:55-64

48. Valgimigli M, Percoco G et al. The additive value of tirofiban administered with the high-dose bolus in the prevention of ischemic complications during high-risk coronary angioplasty: the (ADVANCE) Trial. J Am Coll Cardiol. 2004 Jul 7;44(1):14-9.

49. Ernst NM, Suryapranata H 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 Sep 15;44(6):1187-93.

50. Danzi GB, Sesana M et al. Comparison in Patients Having Primary Coronary A ngioplasty of Abciximab Versus Tirofiban on Recovery of Left Ventricular Function. Am J Cardiol 2004 July 1; 94:35–39

Dosage Charts UA / NSTEMI

Dosage Chart With High Dose Bolus

NOKLOTulceration) , skin rash and pruritis. Other reported side

effects include chest pain, accidental injury, influenzalikesymptoms, headache, dizziness, arthralgia and

back pain.DOSAGE AND ADMINISTRATION :

The recommended dose of Noklot is 75 mg once dailywith or without food. No dosage adjustment is necessary

for elderly patients or patients with renal disease.OVERDOSAGE :

One case of deliberate overdosage with clopidogrel hasbeen reported. A 34-year-old woman took a single

1,050-mg dose of clopidogrel (equivalent to 14 standard75 mg tablets). There were no associated adverseevents. No special therapy was instituted, and she

recovered without sequelae.However, based on biological plausibility, platelet

transfusion may be appropriate to reverse thepharmacological effects of clopidogrel if quick reversal

is required.PRESENTATION :

Pack of 10’sKEEP IN A COOL DRY PLACE

PROTECT FROM LIGHTMarketed by : Zydus Medica

(A Division ofCadila Healthcare Limited)

Manufactured by :Cadila Healthcare Limited.

Sarkhej-Bavla N.H. No. 8 A,Moraiya, Tal : Sanand,

Dist : Ahmedabad 382 210For the use of a Registered Medical Practitioner or a

Hospital or a Laboratory onlyClopidogrel Bisulphate Tablets

Noklot TabletsCOMPOSITION :

Each film coated tablet contains :Clopidogrel bisulphate equivalent to

Clopidogrel 75 mgDESCRIPTION :

Clopidogrel bisulfate is an inhibitor of ADP-inducedplatelet aggregation acting by direct inhibition of

adenosine diphosphate (ADP) binding to its receptorand of the subsequent ADP-mediated activation of theglycoprotein GPIIb/IIIa complex. Chemically it is methyl

(+)-(S)--(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5 (4H)-acetate sulfate (1:1). The empirical

formula of clopidogrel bisulfate isC16H16ClNO2S.H2SO4 and its molecular weight is

419.9.CLINICAL PHARMACOLOGY :

Clopidogrel selectively inhibits the binding of adenosinediphosphate (ADP) to its platelet receptor and the

subsequent ADP-mediated activation of the glycoproteinGPIIb/IIIa complex, thereby inhibiting platelet

aggregation. Biotransformation of clopidogrel isnecessary to produce inhibition of platelet aggregation,but an active metabolite responsible for the activity of

the drug has not been isolated. Clopidogrel also inhibitsplatelet aggregation induced by agonists other than ADP

by blocking the amplification of platelet activation byreleased ADP. Clopidogrel does not inhibit

phosphodiesterase activity. Clopidogrel acts byirreversibly modifying the platelet ADP receptor.

Consequently, platelets exposed to clopidogrel areaffected for the remainder of their lifespan.

Dose dependent inhibition of platelet aggregation canbe seen 2 hours after single oral doses of clopidogrel.Repeated doses of 75 mg clopidogrel per day inhibit

ADP-induced platelet aggregation on the first day, andinhibition reaches steady state between Day 3 and Day7. At steady state, the average inhibition level observedwith a dose of 75 mg clopidogrel per day was between40% and 60%. Platelet aggregation and bleeding time

Noklot-PL-301gradually return to baseline values after treatment is

discontinued, generally in about 5 days.PHARMACOKINETICS :

Clopidogrel is rapidly absorbed after oral administrationof repeated doses of 75 mg clopidogrel (base), with

peak plasma levels (approx 3 mg/L) of the maincirculating metabolite occurring approximately 1 hour

after dosing. Clopidogrel is extensively metabolized bythe liver. The main circulating metabolite is thecarboxylic acid derivative, and both the parent

compound and the carboxylic acid derivative have noeffect on platelet aggregation. Clopidogrel and the maincirculating metabolite bind reversibly in vitro to human

plasma proteins (98% and 94%, respectively). Followingan oral dose of 14C-labeled clopidogrel in humans,approximately 50% was excreted in the urine andapproximately 46% in the feces in the 5 days after

dosing. The elimination half-life of the main circulatingmetabolite was 8 hours after single and repeated

administration. Administration of clopidogrel with mealsdid not significantly modify the bioavailability of

clopidogrel as assessed by the pharmacokinetics of themain circulating metabolite.

INDICATIONS :Noklot is indicated for the reduction of atherosclerotic

events (myocardial infarction, stroke, and vasculardeath) in patients with atherosclerosis documented by

recent stroke, recent myocardial infarction, orestablished peripheral arterial disease.

CONTRAINDICATIONS :The use of Noklot is contraindicated in the following

conditions :1) Hypersensitivity to Clopidogrel or any

component of the product.2) Active pathological bleeding such as peptic ulcer

or intracranial hemorrhage.PRECAUTIONS AND WARNINGS :

As with other anti-platelet agents, Noklot should be usedwith caution in patients who may be at risk of increased

bleeding from trauma, surgery, or other pathologicalconditions. If a patient is to undergo elective surgeryand an antiplatelet effect is not desired, clopidogrel

should be discontinued 7 days prior to surgery.Clopidogrel should be used with caution in patients whohave lesions with a propensity to bleed (such as ulcers).

Drugs that might induce such lesions such as aspirinand other nonsteroidal anti-inflammatory drugs

[NSAIDs] should be used with caution in patients takingclopidogrel.

Experience is limited in patients with severe hepaticdisease, who may have bleeding diatheses. Clopidogrel

should be used with caution in this population.Safety and effectiveness of the drug in paediatric

population has not been established. Clopidogrel shouldbe used in pregnant and lactating mothers only if clearly

needed.DRUG INTERACTIONS :

Concomitant use of Noklot with aspirin, other NSAIDs,heparin and warfarin should be undertaken with cautionfor the fear of causing increasing bleeding. No clinically

significant pharmacodynamic interactions wereobserved when clopidogrel was co-administered with

atenolol, nifedipine, digoxin or theophylline. Thepharmacodynamic activity of clopidogrel was also not

significantly influenced by the co-administration ofphenobarbital, cimetidine or estrogen.

Clopidogrel may interfere with the metabolism ofphenytoin, tamoxifen, tolbutamide, warfarin, torsemide,fluvastatin, and many non-steroidal anti-inflammatoryagents, but there are no data with which to predict the

magnitude of these interactions. Caution should be usedwhen any of these drugs is coadministered with Noklot.

In addition to the above specific interaction studies,patients entered into CAPRIE received a variety of

concomitant medications including diuretics, betablockingagents, angiotensin converting enzyme

inhibitors, calcium antagonists, cholesterol loweringagents, coronary vasodilators, antidiabetic agents,

antiepileptic agents and hormone replacement therapy

without evidence of clinically significant adverseinteractions.

ADVERSE EFFECTS :The overall tolerability of clopidogrel is similar to that of

aspirin regardless of age, gender and race. The clinicallyimportant adverse events reported with the drug include

the following : hemorrhagic (GI, intracranial) ;neutropenia/agranulocytosis, GIT (abdominal pain,

dyspepsia, gastritis, constipation, diarrhoea and

ZYNICORName of Company

Rhône-Poulenc Rorer SUMMARYName of Product OF PRODUCT PL 00012/0229-30Ikorel Tablets 10mg and 20mg CHARACTERISTICS

Name of Active IngredientNicorandil Page 1 of 3

e:\software-development\java-webapps\resinapps\mediweb\products\zynicor\nikorandil.docThis document was printed on 24/06/2004

ZYNICOR (Nicorandil Tablets)CLINICAL PARTICULARSTherapeutic IndicationsZynicor tablets are indicated for the prevention and long term treatment of chronic stableangina pectoris.Posology and Method of AdministrationRoute of administration: oral.Adults: The recommended starting dose is 10mg nicorandil twice daily, although 5mgtwice daily may be employed in patients particularly susceptible to headache.Subsequently the dosage should be titrated upward depending on the clinical response.The usual therapeutic dosage is in the range 10 to 20mg nicorandil twice daily, althoughup to 30mg twice daily may be employed if necessary.Elderly: There is no special requirement for dosage reduction in elderly patients. Aswith all medicines, the lowest effective dosage should be used.Children: A paediatric dosage has not been established and use of nicorandil is notrecommended.ContraindicationsZynicor is contraindicated in patients with cardiogenic shock, left ventricular failure withlow filling pressures and in hypotension. It is also contraindicated in patients who havedemonstrated an idiosyncratic response or hypersensitivity to nicorandil. Due to the riskof severe hypotension, the concomitant use of Zynicor and sildenafil is contraindicated.Special Warnings and Special Precautions for UseThe use of nicorandil should be avoided in patients with depleted blood volume, lowsystolic blood pressure, acute pulmonary oedema or acute myocardial infarction with

acute left ventricular failure and low filling pressures.Therapeutic doses of nicorandil may lower the blood pressure of hypertensive patientsand therefore nicorandil, as with other antianginal agents, should be used with care whenprescribed with antihypertensive drugs.Alternative therapy should be considered if persistent aphtosis or severe mouth ulcerationoccurs.Name of CompanyRhône-Poulenc Rorer SUMMARYName of Product OF PRODUCT PL 00012/0229-30Ikorel Tablets 10mg and 20mg CHARACTERISTICSName of Active IngredientNicorandil Page 2 of 3e:\software-development\java-webapps\resinapps\mediweb\products\zynicor\nikorandil.docThis document was printed on 24/06/2004Interaction with Other Medicaments and Other Forms of InteractionNo pharmacological or pharmacokinetic interactions have been observed in humans oranimals with beta-blockers, digoxin, rifampicin, cimetidine, nicoumalone, a calciumantagonist or a combination of digoxin and frusemide. Nevertheless, there is thepossibility that nicorandil may potentiate the hypotensive effects of other vasodilators,tricyclic antidepressants or alcohol.As the hypotensive effects of nitrates or nitric oxide donors are potentiated by sildenafil,the concomitant use of Zynicor l and sildenafil is contraindicated.Pregnancy and LactationPregnancy: Animal studies have not revealed any harmful effect of nicorandil on thefoetus although there is no experience in humans. It should not be used in pregnantpatients unless there is no safer alternative.Lactation: As it is not known whether nicorandil is excreted in human milk,breastfeeding should be avoided by lactating patients who require therapy.Effects on Ability to Drive and Use MachinesPatients should be warned not to drive or operate machinery until it is established thattheir performance is unimpaired by nicorandil.Undesirable EffectsThe most frequent effect to be anticipated is headache, usually of a transitory nature,especially when treatment is initiated.Cutaneous vasodilation with flushing is less frequent. Nausea, vomiting dizziness and afeeling of weakness have been reported occasionally. Myalgia and different types of rashhave been reported rarely.There have been very rare reports of angioedema and hepatic function abnormalities.Hypotension may occur at high therapeutic doses. An increase in heart rate may occur athigh doses.Rare cases of persistent aphtosis or mouth ulcers which were occasionally severe havebeen reported. These resolved following treatment discontinuation.OverdoseAcute overdosage is likely to be associated with peripheral vasodilation, decreased bloodpressure and reflex tachycardia. Cardiac function should be monitored and generalsupportive measures employed. If necessary, circulating plasma volume should beName of Company

Rhône-Poulenc Rorer SUMMARYName of Product OF PRODUCT PL 00012/0229-30Ikorel Tablets 10mg and 20mg CHARACTERISTICSName of Active IngredientNicorandil Page 3 of 3e:\software-development\java-webapps\resinapps\mediweb\products\zynicor\nikorandil.docThis document was printed on 24/06/2004increased by infusion of suitable fluid. In life-threatening situations, administration ofvasopressors should be considered. There is no experience of massive overdosage inhumans, although the LD50 in dogs is in the range 62.5 to 125 mg/kg and in rodents it isin the order of 1200 mg/kg.PHARMACOLOGICAL PROPERTIESPharmacodynamic PropertiesNicorandil provides a dual mode of action leading to relaxation of vascular smoothmuscle. A potassium channel opening action provides arterial vasodilation, thusreducing afterload, while the nitrate component promotes venous relaxation and areduction in preload. Nicorandil has a direct effect on coronary arteries without leadingto a steal phenomenon. The overall action improves blood flow to post-stenotic regionsand the oxygen balance in the myocardium.Pharmacokinetic PropertiesNicorandil is well absorbed with no significant first-pass metabolism. Maximumplasma concentrations are achieved in 30 to 60 minutes and are directly related to thedosage. Metabolism is mainly by denitration of the molecule into the nicotinamidepathway with less than 20% of an administered dose being excreted in the urine. Themain phase of elimination has a half-life of about 1 hour. Nicorandil is only slightlybound to plasma proteins.No clinically relevant modifications in the pharmacokinetic profile have been seen in theelderly or in patients with liver disease or chronic renal failure.

ZYROVA TABLETS( Rosuvastatin calcium)DESCRIPTIONRosuvastatin is a synthetic lipid-lowering agent. Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzesthe conversion of HMG-CoA to mevalonate, an early and rate-limiting step incholesterol biosynthesis.Rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt. The empirical formula for Rosuvastatin calcium is(C22H27FN3O6S)2Ca. Rosuvastatin calcium is a white amorphous powder that issparingly soluble in water and methanol, and slightly soluble in ethanol.Rosuvastatin is a hydrophilic compound with a partition coefficient (octanol/water)of 0.13 at pH of 7.0.CLINICAL PHARMACOLOGY

Cholesterol and TG synthesized in the liver are incorporated into VLDL and secreted intothe circulation for delivery to peripheral tissues. TG are removed by the action of lipases,and in a series of steps, the modified VLDL is transformed first into IDL and then intocholesterol-rich LDL. IDL and LDL are removed from the circulation mainly byhigh affinity ApoB/E receptors, which are expressed to the greatest extent on liver cells.HDL is hypothesized to participate in the reverse transport of cholesterol from tissuesback to the liver.Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL,and remnants, can also promote atherosclerosis. Elevated plasma triglycerides arefrequently found with low HDL-C levels and small LDL particles, as well as inassociation with non-lipid metabolic risk factors for coronary heart disease (CHD). Assuch, total plasma TG has not consistently been shown to be an independent risk factorfor CHD. Furthermore, the independent effect of raising HDL or lowering TG on the riskof coronary and cardiovascular morbidity and mortality has not been determined.Mechanism of Action: Rosuvastatin is a selective and competitive inhibitor of HMGCoAreductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutarylcoenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, andin vitro studies in cultured animal and human cells have shown Rosuvastatin tohave a high uptake into, and selectivity for, action in the liver, the target organfor cholesterol lowering. In in vivo and in vitro studies, Rosuvastatin produces itslipid-modifying effects in two ways. First, it increases the number of hepatic LDLreceptors on the cell-surface to enhance uptake and catabolism of LDL. Second,Rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number ofVLDL and LDL particles. Rosuvastatin reduces total cholesterol (total-C), LDL-C,ApoB, and nonHDL-C (total cholesterol minus HDL-C) in patients withhomozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial formsof hypercholesterolemia, and mixed dyslipidemia. Rosuvastatin also reduces TG andproduces increases in HDL-C. Rosuvastatin reduces total-C, LDL-C, VLDLcholesterol(VLDL-C), ApoB, nonHDL-C and TG, and increases HDL-C in patientswith isolated hypertriglyceridemia. The effect of Rosuvastatin on cardiovascularmorbidity and mortality has not been determined.Pharmacokinetics and Drug MetabolismAbsorption: In clinical pharmacology studies in man, peak plasma concentrations ofRosuvastatin were reached 3 to 5 hours following oral dosing. Both peak concentration(Cmax) and area under the plasma concentration-time curve (AUC) increased inapproximate proportion to Rosuvastatin dose. The absolute bioavailability ofRosuvastatin is approximately 20%. Administration of Rosuvastatin with fooddecreased the rate of drug absorption by 20% as assessed by Cmax, but there was noeffect on the extent of absorption as assessed by AUC. Plasma concentrations ofRosuvastatin do not differ following evening or morning drug administration.Significant LDL-C reductions are seen when Rosuvastatin is given with or without food,and regardless of the time of day of drug administration.Distribution: Mean volume of distribution at steady-state of Rosuvastatin isapproximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostlyalbumin. This binding is reversible and independent of plasma concentrations.Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a

radiolabeled dose is recovered as metabolite. The major metabolite is N-esmethylRosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro studieshave demonstrated that N-desmethyl Rosuvastatin has approximately one-sixth toone-half the HMG-CoA reductase inhibitory activity of Rosuvastatin. Overall, greaterthan 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for byRosuvastatin.Excretion: Following oral administration, Rosuvastatin and its metabolites areprimarily excreted in the feces (90%). The elimination half-life (t1/2) of Rosuvastatin isapproximately 19 hours. After an intravenous dose, approximately 28% of total bodyclearance was via the renal route, and 72% by the hepatic route.INDICATIONS AND USAGERosuvastatin is indicated:1. as an adjunct to diet to reduce elevated total-C, LDL-C, ApoB, nonHDL-C, and TGlevels and to increase HDL-C in patients with primary hypercholesterolemia(heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type IIaand IIb);2. as an adjunct to diet for the treatment of patients with elevated serum TGlevels (Fredrickson Type IV);3. to reduce LDL-C, total-C, and ApoB in patients with homozygous familialhypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDLapheresis) or if such treatments are unavailable.CONTRAINDICATIONSRosuvastatin is contraindicated in patients with a known hypersensitivity to anycomponent of this product. Rosuvastatin is contraindicated in patients with activeliver disease or with unexplained persistent elevations of serum transaminases.WARNINGSHMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have beenassociated with biochemical abnormalities of liver function.It is recommended that liver function tests be performed before and at 12 weeksfollowing both the initiation of therapy and any elevation of dose, and periodically (e.g.,semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months oftreatment with Rosuvastatin. Patients who develop increased transaminase levelsshould be monitored until the abnormalities have resolved. Should an increase inALT or AST of >3 times ULN persist, reduction of dose or withdrawal of Rosuvastatinis recommended.ADVERSE REACTIONSRosuvastatin is generally well tolerated. Adverse reactions have usually been mildand transient. In clinical studies of 10,275 patients, 3.7% were discontinued due toadverse experiences attributable to Rosuvastatin. The most frequent adverse eventsthought to be related to Rosuvastatin were myalgia, constipation, asthenia, abdominalpain, and nausea.OVERDOSAGEThere is no specific treatment in the event of overdose. In the event of overdose, thepatient should be treated symptomatically and supportive measures instituted asrequired. Hemodialysis does not significantly enhance clearance of Rosuvastatin.DOSAGE AND ADMINISTRATION

The patient should be placed on a standard cholesterol-lowering diet before receivingRosuvastatin and should continue on this diet during treatment. Rosuvastatin can beadministeredas a single dose at any time of day, with or without food.The dose range for Rosuvastatin is 5 to 40 mg once daily. Therapy with Rosuvastatinshould beindividualized according to goal of therapy and response. The usual recommendedstarting dose of Rosuvastatin is 10 mg once daily. Initiation of therapy with 5 mgonce daily may be considered for patients requiring less aggressive LDL-C reductions orwho have predisposing factors for myopathy. For patients with markedhypercholesterolemia (LDL-C > 190 mg/dL) and aggressive lipid targets, a 20-mgstarting dose may be considered. The 40-mg dose of Rosuvastatin should be reserved forthosepatients who have not achieved goal LDL-C at 20 mg.STORAGEStore at controlled room temperature, 20-25ºC (68-77ºF). Protect from moisture

LOSACAR A

For the use of a Registered Medical Practitioner or aHospital or a Laboratory only.Losartan Potassium &Hydrochlorothiazide TabletsLosacar - H TabletsCOMPOSITION :Each film coated tablet of Losacar - H contains :Losartan potassium 50 mgHydrochlorothiazide I.P. 12.5 mgDESCRIPTION :Losacar-H is a fixed dose combination of anangiotensin II receptor (type AT1) antagonist, losartanpotassium, and a diuretic, hydrochlorothiazide. Losartanpotassium, a non-peptide molecule, is chemically describedas 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol mono-potassiumsalt. Its empirical formula is C22H22ClKN6O, and itsmolecular weight is 461.01. On the other hand, hydrochlorothiazideis 6-chloro-3,4-dihydro-2H-1,24-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empiricalformula is C7H8ClN3O4S2 and its molecular weightis 297.74.MECHANISM OF ACTION :Losartan and its principal active metabolite block thevasoconstrictor and aldosterone secreting effects ofangiotensin II by selectively blocking the binding ofangiotensin II to the AT1 receptor found in many

tissues, (e.g., vascular smooth muscle, adrenal glandetc.). In vitro binding studies indicate that losartan is areversible competitive inhibitor of the AT1 receptor. Theactive metabolite is 10 to 40 times more potent by weightthan losartan and appears to be a reversible, non-competitiveinhibitor of the AT1 receptor.Hydrochlorothiazide is a thiazide diuretic. Thiazidesaffect the renal tubular mechanisms of electrolytereabsorption, directly increasing excretion ofsodium and chloride in approximately equivalentcontrolled with losartan monotherapy may be switchedto Losacar-H (losartan potassium 50mg/ hydrochlorothiazide12.5mg) once daily. If blood pressure remainsuncontrolled after about 3 weeks of therapy, the dosemay be increased to two tablets once daily.OVERDOSAGE :Limited data are available in regard to overdosage inhumans. The most likely manifestations of overdosagewould be hypotension and tachycardia ; bradycardiacould occur from parasympathetic (vagal) stimulation.If symptomatic hypotension should occur, supportivetreatment should be instituted. Neither losartan nor itsactive metabolite can be removed by hemodialysis.The most common signs and symptoms observed withthiazide overdosage are those caused by electrolytedepletion (hypokalemia, hypochloremia, hyponatremia)and dehydration resulting from excessive diuresis.The degree of hydrochlorothiazide that is removed byhemodialysis has not been established.PRESENTATION : Pack of 10’sKEEP IN A COOL DRY PLACEPROTECT FROM LIGHTLosacar-H PL1-801Marketed by : Zydus Medica(A Division of Cadila Healthcare Limited.)Manufactured by :Cadila Healthcare Limited.Sarkhej–Bavla N.H. No. 8 A, Moraiya,Tal : Sanand, Dist : Ahmedabad 382 210

controlled with losartan monotherapy may be switchedhemodialysis has not been established.PRESENTATION : Pack of 10’sKEEP IN A COOL DRY PLACEPROTECT FROM LIGHT

TrichekFor the use of a Registered Medical Practitioner or a Hospital or a Laboratory onlyFENOFIBRATE CAPSULESCOMPOSITION:Each capsule containsFenofibrate (micronised) 200mgDESCRIPTION:TRICHEK Capsules contain micronised fenofibrate, a fibric acid derivative, which is a lipidregulating drug with actions on plasma lipids similar to those of bezafibrate. The chemical namefor fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.The empirical formula is C20H21O4Cl and the molecular weight is 360.83.MECHANISM OF ACTION:Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol,LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) intreated patients. In addition, treatment with fenofibrate results in increases in high densitylipoprotein (HDL) and apoproteins apoAI and apoAII.The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenicmice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferatoractivated receptor _ (PPAR_). Through this mechanism, fenofibrate increases lipolysis andelimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducingproduction of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall intriglycerides produces an alteration in the size and composition of LDL from small, denseparticles (which are thought to be atherogenic due to their susceptibility to oxidation), to largebuoyant particles. These larger particles have a greater affinity for cholesterol receptors and arecatabolized rapidly. Activation of PPAR_ also induces an increase in the synthesis ofapoproteins A-I, A-II and HDL-cholesterol.Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals byincreasing the urinary excretion of uric acid.PHARMACOKINETICS:Fenofibrate is readily absorbed from the gastro-intestinal tract when taken with food; absorptionis substantially reduced if fenofibrate is administered after an overnight fast. It is rapidlyhydrolysed to its active metabolite fenofibric acid which is extensively bound to plasma albumin.The plasma elimination half-life is about 20 hours. Fenofibrate acid is excreted predominantly inthe urine, mainly as the glucuronide conjugate, but also as a reduced form of fenofibric acid andits glucuronide.INDICATIONS:TRICHEK Capsules are indicated in the treatment of types IIa, IIb, III, IV and V hyperlipidemiaresistant to dietary therapy alone.CONTRAINDICATIONS:TRICHEK Capsules are contraindicated in patients who exhibit hypersensitivity to fenofibrate.They are also contraindicated in patients with hepatic or severe renal dysfunction, includingprimary biliary cirrhosis, and patients with unexplained persistent liver function abnormality.TRICHEK Capsules are also contraindicated in patients with pre-existing gallbladder disease.PRECAUTIONS AND WARNINGS:Laboratory studies should be done to ascertain that the lipid levels are consistently abnormalbefore instituting TRICHEK therapy. Every attempt should be made to control serum lipids withappropriate diet, exercise, weight loss in obese patients, and control of any medical problems

such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities.Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens)should be discontinued or changes if possible prior to consideration of triglyceride-lowering drugtherapy. Periodic determination of serum lipids should be obtained during initial therapy in orderto establish the lowest effective dose of TRICHEK. Therapy should be withdrawn in patientswho do not have an adequate response after two months of treatment with the maximumrecommended dose of 200 mg per day.Fenofibrate has been associated with increases in serum transaminases [AST (SGOT) or ALT(SGPT)]. The incidence of increases in transaminase related to fenofibrate therapy appear to bedose related. Regular periodic monitoring of liver function, including serum ALT (SGPT) shouldbe performed for the duration of therapy with TRICHEK, and therapy discontinued if enzymelevels persist above three times the normal limit.Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile,leading to cholelithiasis. TRICHEK therapy should be discontinued if gallstones are found.Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. Thisoccurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, adirect drug effect, or a secondary phenomenon mediated through biliary tract stone or sludgeformation with obstruction of the common bile duct.Acute hypersensitivity reactions including severe skin rashes requiring patient hospitalizationand treatment with steroids have occurred very rarely during treatment with fenofibrate,including rare spontaneous reports of Stevens-Johnson syndrome, and toxic epidermalnecrolysis.Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observedin patients following initiation of fenofibrate therapy. However, these levels stabilize during longterm administration. Extremely rare spontaneous reports of thrombocytopenia andagranulocytosis have been received. Periodic blood counts are recommended during the first 12months of TRICHEK administration.The use of fibrate alone, including fenofibrate, may occasionally be associated with myopathy.Treatment with drugs of the fibrate class has been associated on rare occasions withrhabdomyolysis, usually in patients with impaired renal function. Myopathy should beconsidered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or markedelevations of creatinine phosphokinase levels. Patients should be advised to report promptlyunexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise orfever. CPK levels should be assessed in patients reporting these symptoms, and TRICHEKtherapy should be discontinued if markedly elevated CPK levels occur or myopathy isdiagnosed.USAGE IN PREGNANCY, LACTATION & CHILDREN:Fenofibrate has been shown to be embryocidal and teratogenic in rats. There are no adequateand well-controlled studies in pregnant women. TRICHEK should be used during pregnancyonly if the potential benefit justifies the potential risk to the fetus. TRICHEK should not be usedin nursing mothers. Because of the potential for tumorigenicity seen in animal studies, adecision should be made whether to discontinue nursing or to discontinue the drug. Safety andefficacy of the drug in pediatric patients has not been established.DRUG INTERACTIONS:Caution should be exercised when coumarin anticoagulants are given in conjunction withTRICHEK. The dosage of the anticoagulants should be reduced to maintain the prothrombintime/INR at the desired level to prevent bleeding complications. Frequent prothrombin time/INRdeterminations are advisable until it has been definitely determined that the prothrombintime/INR has stabilised.The combined use of TRICHEK and HMG-CoA reductase inhibitors should be avoided unless

the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drugcombination.Since bile acid sequestrants may bind other drugs given concurrently, patients should takeTRICHEK at least 1 hour before or 4-6 hours after a bile acid binding resin to avoid impeding itsabsorption.Because cyclosporine can produce nephrotoxicity with decreases in creatinine clearance andrises in serum creatinine, and because renal excretion is the primary elimination route of fibratedrugs including fenofibrate, there is a risk that an interaction will lead to deterioration. Thebenefits and risks of using TRICHEK with immunosuppressants and other potentiallynephrotoxic agents should be carefully considered, and the lowest effective dose employed.ADVERSE REACTIONS:The most common adverse effects in both long- and short-term studies of fenofibrate have beengastro-intestinal disturbances, occurring in about 3 to 5% of patients. These include abnormalliver function tests, diarrhea, nausea and constipation. Other reported adverse effects includedermatological, musculoskeletal, and neurological disorders.DOSAGE AND ADMINISTRATION:Patients should be placed on an appropriate lipid-lowering diet before receiving TRICHEK, andshould continue this diet during treatment with the drug. TRICHEK should be given with meals,thereby optimizing the bioavailability of the medication.For the treatment of adult patients with primary hypercholesterolemia, hypertriglyceridemia ormixed hyperlipidemia, the usual recommended dose of TRICHEK is 200 mg per day.Treatment with fenofibrate should be initiated at a lower dose in the elderly and in patientshaving impaired renal function, and increased only after evaluation of the effects on renalfunction and lipid levels at this dose.Lipid levels should be monitored periodically and consideration should be given to reducing thedosage of TRICHEK if lipid levels fall significantly below the targeted range.OVERDOSAGE:There is no specific treatment for overdose with fenofibrate. General supportive care of thepatient is indicated, including monitoring of vital signs and observation of clinical status, shouldan overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesisor gastric lavage; usual precautions should be observed to maintain the airway. Becausefenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.PRESENTATIONS:200mg CapsulesSTORAGE:Store at 15-30oC.Protect from moisture.MANUFACTURED & MARKETED BY:

ZYTANIXFor the use of a Registered Medical Practitioner or a Hospital or a Laboratory onlyMETOLAZONE TABLETS USPCOMPOSITION:Each uncoated tablet contains:Metolazone USP 2.5 mgEach uncoated tablet contains:Metolazone USP 5 mg

Each uncoated tablet contains:Metolazone USP 10 mgDESCRIPTION:ZYTANIX Tablets USP contain metolazone which is a diuretic / saluretic / antihypertensive drugof the quinazoline class. It has the molecular formula C16H16CIN3O3S, the chemical name 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide, and amolecular weight of 365.83.MECHANISM OF ACTION:Metolazone is a quinazoline diuretic, with properties generally similar to the thiazide diureticseven though it does not contain a thiazide ring system. The actions of metolazone result frominterference with the renal tubular mechanism of electrolyte reabsorption. Metolazone actsprimarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in theproximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalentamounts. The increased delivery of sodium to the distal tubular exchange site results inincreased potassium excretion. Metolazone does not inhibit carbonic anhydrase. The diureticpotency of metolazone at maximum therapeutic dosage is approximately equal to thiazidediuretics. However, unlike thiazides, metolazone may produces diuresis in patients withglomerular filtration rates below 20 mL/min. When metolazone tablets are given, diuresis andsaluresis usually begin within one hour and may for 24 hours or more. A single daily dose isrecommended. Metolazone and furosemide administered concurrently have produced markeddiuresis in some patients where edema or ascites was refractory to treatment with maximumrecommended doses of these or other diuretics administered alone.PHARMACOKINETICS:Metolazone is slowly and incompletely absorbed form the gastro-intestinal tract. An average ofabout 65% of the administered dose has been reported to be absorbed following an oral dose inhealthy subjects, and an average of about 40% in patients with cardiac disease. About 95% ofthe drug is bound in the circulation; about 50 to 70% to the red blood cells and between 15 and33% to plasma proteins. The half-life has been reported to be 8 to 10 hours in whole blood and4 to 5 hours in plasma. About 70 to 80% of the amount of metolazone absorbed is excreted inthe urine, of which 80 to 95% is excreted unchanged. The remainder is excreted in the bile andsome enterohepatic circulation has been reported. Metolazone crosses the placental barrier andis excreted in breast milk.INDICATIONS:ZYTANIX Tablets are indicated for the treatment of hypertension, alone or in combination withother antihypertensive drugs of a different class, and for the treatment of salt and waterretention including edema accompanying congestive heart failure and renal diseases, includingthe nephrotic syndrome and states of diminished renal function.CONTRAINDICATIONS:ZYTANIX Tablets are contraindicated in patients with anuria, hepatic coma or precoma and inpatients with known allergy or hypersensitivity to metolazone.USAGE IN PREGNANCY & LACTATION:There are no adequate and well-controlled studies with metolazone in pregnant women. Itcrosses the placental barrier and appears in cord blood and may expose the fetus to certainhazards. ZYTANIX Tablets should therefore be used during pregnancy only if clearly needed.Since metolazone appears in breast milk and because of the potential for serious adversereactions in nursing infants from metolazone, a decision should be made whether to discontinuenursing or to discontinue the drug taking into account the importance of the drug to the mother.PRECAUTIONS AND WARNINGS:All patients receiving therapy with ZYTANIX Tablets should have serum electrolytemeasurement done at appropriate intervals and be observed for clinical signs of fluid and/or

electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, hypokalemia,hypomagnesemia and hypecalcemia. Rarely, the rapid onset of severe hyponatremia and/orhypokalemia has been reported following initial doses of thiazide and non-thiazide diuretics.When symptoms consistent with severe electrolyte imbalance appear rapidly, the drug shouldbe discontinued and supportive measures should be initiated immediately.Metolazone may raise blood glucose concentrations possibly causing hyperglycemia andglycosuria in patients with diabetes or latent diabetes. Metolazone also causes an increase inserum uric acid and can occasionally precipitate gouty attacks even in patients without a priorhistory of them.Azotemia, presumably prerenal azotemia, may be precipitated during the administration ofmetolazone. If azotemia and oliguria worsen during treatment of patients with severe renaldisease, the drug should be discontinued. Caution should be used when administeringZYTANIX Tablets to patients with severely impaired renal function. As most of the drug isexcreted by the renal route, accumulation may occur.Cross allergy may occur when metolazone is given to patients known to be allergic tosulfonamide-derived drugs, thiazides, or quinethazone. Sensitivity reactions (e.g. angioedema,bronchospasm) may occur with or without a history of allergy or bronchial asthma and mayoccur with the first dose of the drug.DRUG INTERACTIONS:Diuretics: Furosemide and other loop diuretics given concomitantly with metolazone can causeunusually large or prolonged losses of fluid and electrolytes.Other Antihypertensives: When ZYTANIX Tablets are used with other antihypertensive drugs,care must be taken, especially during initial therapy. Dosage adjustments of otherantihypertensives may be necessary.Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiatedby the volume contraction that may be associated with metolazone therapy.Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of themyocardium to digitalis. Serious arrhythmias can result.Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and waterretention.Lithium: Serum lithium levels may increase.Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effectsof curariform drugs (such as tubocurarine) – the most serious effect would be respiratorydepression which could proceed to apnea. Accordingly, it may be advisable to discontinueZYTANIX Tablets three days before elective surgery.Salicylates and Other Non-Steoridal Anti-Inflammatory Drugs: May decrease theantihypertensive effects of metolazone tablets.Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, butthis diminution is not sufficient to preclude effectiveness of the pressor agent for therapeuticuse.Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect thehypoprothrombinemic response to anticoagulants, dosage adjustments may be necessary.ADVERSE REACTIONS:Metolazone is usually well tolerated, and most reported adverse reactions have been mild andtransient. The following adverse events have been reported with metolazone therapy:Cardiovascular: Chest pain/discomfort, orthostatic hypotension, excessive volume depletion,hemoconcentration, venous thrombosis, palpitations.Central and Peripheral Nervous System: Syncope, neuropathy, vertigo, paresthesias,dizziness/light-headedness, drowsiness, fatigue, weakness, restlessness, headache.Dermatologic/Hypersensitivity: Toxic epidermal necrolysis, Steven-Johnson syndrome,

necrotizing angiitis (cutaneous vasculitis), purpura, dermatitis (photosensitivity), urticaria, skinrashes.Gastrointestinal: Hepatitis, intrahepatic cholestatic jaundice, pancreatitis, vomiting, nausea,epigastric distress, diarrhea, constipation, anorexia, abdominal bloating.Hematologic: Aplastic/hypoplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.Metabolic: Hypokalemia, hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis,hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine,hypophosphatemia, hypomagnesemia, hypercalcemia.Musculoskeletal: Joint pain, acute gouty attacks, muscle cramps or spasm.Other: Transient blurred vision, chills, dry mouth.OVERDOSAGE:There is no specific antidote available but immediate evacuation of stomach contents isadvised. Dialysis is not likely to be effective. Care should be taken when evacuating the gastriccontents to prevent aspiration, especially in the stuporous or comatose patient. Supportivemeasures should be initiated as required to maintain hydration, electrolyte balance, respiration,and cardiovascular and renal function.DOSAGE AND ADMINISTRATION:Effective dosage of metolazone should be individualized according to indication and patientresponse. A single daily dose is recommended. Therapy with metolazone should be titrated togain an initial therapeutic response and to determine the minimal dose possible to maintain thedesired therapeutic response.The usual initial recommended dose of ZYTANIX Tablets in the various indications is as follows:Mild to moderate essential hypertension: 2.5 to 5 mg once daily.Edema of cardiac failure: 5 to 20 mg once daily.Edema of renal disease: 5 to 20 mg once daily.Doses should be adjusted to at appropriate intervals to achieve maximum therapeutic effect.When the desired therapeutic effect has been obtained, it may be advisable to reduce the doseif possible.PRESENTATION:2.5mg, 5mg & 10mg Tablets.STORAGE:Store at 25oC; excursions permitted to 15oC-30oC.Protect from light.MANUFACTURED & MARKETED BY: