TIROFIBAN Solution for infusion Ref.[8520] Active ingredients: Tirofiban

Pharmacotherapeutic group: Blood and blood forming organs – antithrombotic agents – antithrombotic agents – Platelet aggregation inhibitors excl. heparin
ATC-Code: B01AC17

Mechanism of action

Tirofiban hydrochloride (Tirofiban) is a non-peptidal antagonist of the GP IIb/IIIa receptor, an important platelet surface receptor involved in platelet aggregation. Tirofiban prevents fibrinogen from binding to the GP IIb/IIIa receptor, thus blocking platelet aggregation.

Tirofiban leads to inhibition of platelet function, evidenced by its ability to inhibit ex vivo ADP-induced platelet aggregation and to prolong bleeding time (BT). Platelet function returns to baseline within eight hours after discontinuation.

The extent of this inhibition runs parallel to the tirofiban plasma concentration.

Pharmacodynamic effects

In the 0.4 microgram/kg/min infusion regimen of tirofiban, in the presence of unfractionated heparin and ASA, tirofiban produced a more than 70% (median 89%) inhibition of ex vivo ADP-induced platelet aggregation in 93% of the patients, and a prolongation of the bleeding time by a factor of 2.9 during infusion. Inhibition was achieved rapidly with the 30-minute loading infusion and was maintained over the duration of the infusion.

The tirofiban 25 microgram/kg dose bolus regimen (followed by 18-24 hour maintenance infusion of 0.15 microgram/kg/min), in the presence of unfractionated heparin and oral antiplatelet therapy, produced an average ADP-induced inhibition of maximal aggregation 15 to 60 minutes after onset of treatment of 92% to 95% as measured with light transmission aggregometry (LTA).

Clinical efficacy and safety

PRISM-PLUS study

The double-blind, multicentre, controlled PRISM-PLUS study compared the efficacy of tirofiban and unfractionated heparin (n=773) versus unfractionated heparin (n=797) in patients with unstable angina (UA) or acute non-Q-wave myocardial infarction (NQWMI) with prolonged repetitive anginal pain or post-infarction angina, accompanied by new transient or persistent ST-T wave changes or elevated cardiac enzymes.

Patients were randomised to either Tirofiban (30 minute loading infusion of 0.4 microgram/kg/min followed by a maintenance infusion of 0.10 microgram/kg/min) and heparin (bolus of 5,000 units (U) followed by an infusion of 1,000 U/hr titrated to maintain an activated partial thromboplastin time (APTT) of approximately two times control), or heparin alone

All patients received ASA unless contraindicated. Study drug was initiated within 12 hours after the last anginal episode. Patients were treated for 48 hours, after which they underwent angiography and possibly angioplasty/atherectomy, if indicated, while tirofiban was continued. Tirofiban was infused for a mean period of 71.3 hours.

The combined primary study end-point was the occurrence of refractory ischaemia, myocardial infarction or death at seven days after the start of tirofiban hydrochloride.

At 7 days, the primary end-point, there was a 32% risk reduction (RR) (12.9% vs. 17.9%) in the tirofiban hydrochloride group for the combined end-point (p=0.004): this represents approximately 50 events avoided for 1,000 patients treated. After 30 days the RR for the composite end-point of death, MI, refractory ischaemic conditions, or readmissions for UA was 22% (18.5% vs. 22.3%; p=0.029). After six months the relative risk of composite of death, MI, refractory ischaemic conditions, or readmissions for UA was reduced by 19% (27.7% vs. 32.1%; p=0.024).

Regarding the composite of death or MI, at seven days for the tirofiban group there was a 43% RR (4.9% vs. 8.3%; p=0.006); at 30 days the RR was 30% (8.7% vs. 11.9%; p=0.027) and at 6 months the RR was 23% (12.3% vs. 15.3%; p=0.063).

The reduction of MI in patients receiving tirofiban appeared early during treatment (within the first 48 hours) and was maintained through 6 months. In the 30% of patients who underwent angioplasty/atherectomy during initial hospitalisation, there was a 46% RR (8.8% vs. 15.2%) for the primary composite endpoint at 30 days as well as a 43% RR (5.9% vs. 10.2%) for death or MI.

Based on a safety study, the concomitant administration of tirofiban (30 minute loading dose of [0.4 microgram/kg/min] followed by a maintenance infusion of 0.1 microgram/kg/min for up to 108 hours) with enoxaparin (n=315) was compared to the concomitant administration of tirofiban with unfractionated heparin (n=210) in patients presenting with UA and NQWMI. Patients in the enoxaparin group received a 1.0 milligram/kg subcutaneous injection every 12 hours for a period of at least 24 hours and a maximum duration of 96 hours. Patients randomised to unfractionated heparin received a 5000-unit intravenous bolus followed by a maintenance infusion of 1000 units per hour for at least 24 hours and a maximum duration of 108 hours. The total TIMI bleed rate was 3.5% for the tirofiban/enoxaparin group and 4.8% for the tirofiban/unfractionated heparin group. Although there was a significant difference in the rates of cutaneous bleeds between the two groups (29.2% in the enoxaparin converted to unfractionated heparin group and 15.2% in the unfractionated heparin group), there were no TIMI major bleeds (see section 4.4) in either group. The efficacy of tirofiban in combination with enoxaparin has not been established.

PRISM PLUS trial was conducted at a time when the standard of care of managing acute coronary syndromes was different from that of present times in terms of oral platelet ADP receptor (P2Y12) antagonists use and the routine use of intracoronary stents.

ADVANCE study

The ADVANCE study determined the safety and efficacy of the tirofiban 25 microgram/kg dose bolus regimen as compared with placebo in patients undergoing elective or urgent PCI who exhibit high-risk characteristics including the presence of at least one coronary narrowing 70% and diabetes, need for multi-vessel intervention, or NSTE-ACS. All patients received unfractionated heparin, acetylsalicylic acid (ASA) and a thienopyridine loading dose followed by maintenance therapy. A total of 202 patients were randomised to either tirofiban (25 microgram/kg bolus IV over 3 minutes followed by a continuous IV infusion of 0.15 microgram/kg/minute for 24-48 hours) or Placebo given immediately before PCI.

The primary endpoint was a composite of death, nonfatal MI, urgent target vessel revascularization (uTVR), or thrombotic bailout GP IIb/IIIa inhibitor therapy within a median follow-up of 180 days after the index procedure. The safety endpoints of major and minor bleeding were defined according to the TIMI criteria.

In the intent-to-treat population, the cumulative incidence of the primary end point was 35% and 20% in placebo and tirofiban groups, respectively (hazard ratio [HR] 0.51 [95% confidence interval (CI), 0.29 to 0.88]; p=0.01). As compared with placebo, there was a significant reduction in the composite of death, MI, or uTVR in the tirofiban group (31% vs. 20%, HR, 0.57 95% CI, 0.99–0.33]; p=0.048.

EVEREST study

The randomised open-label EVEREST trial compared the upstream 0.4 microgram/kg/min loading dose regimen initiated in the coronary care unit with the tirofiban 25 microgram/kg dose bolus regimen or abciximab 0.25 milligram/kg initiated 10 minutes prior to PCI. . All patients additionally received ASA and a thienopyridine. The 93 enrolled NSTE-ACS patients underwent angiography and PCI as appropriate, within 24-48 hours of admission.

With respect to the primary endpoints of tissue level perfusion and troponin I release, the results of EVEREST determined significantly lower rates of post-PCI TMPG 0/1 (6.2% vs. 20% vs. 35.5%, respectively; p=0.015), and improved post-PCI MCE score index (0.88 ± 0.18 vs. 0.77 ± 0.32 vs. 0.71 ± 0.30, respectively; p<0.05).

The incidence of post-procedural cardiac Troponin I (cTnI) elevation was significantly reduced in patients treated with the upstream tirofiban regimen compared with PCI 25 microgram/kg dose bolus tirofiban or abciximab (9.4% vs. 30% vs. 38.7%, respectively; p=0.018). The cTnI levels post-PCI were also significantly decreased with the upstream regimen of tirofiban compared with PCI tirofiban (3.8 ± 4.1 vs. 7.2 ± 12; p=0.015) and abciximab (3.8 ± 4.1 vs. 9 ± 13.8; p=0.0002). The comparison between the PCI tirofiban 25 microgram/kg dose bolus and abciximab regimens indicated no significant differences in the rate of TMPG 0/1 post-PCI (20% vs. 35%; p=NS).

On-TIME 2 study

The On-TIME 2 trial was a multi-centre, prospective, randomised, controlled clinical trial which was designed to assess the effect of early upfront Tirofiban administration using the 25 microgram/kg dose bolus regimen in patients with STEMI planned for primary PCI. All patients received ASA, a 600 mg loading dose of clopidogrel, and unfractionated heparin. The use of bail-out Tirofiban was allowed according to pre- specified criteria. The study was accomplished in two phases: a pilot, open label phase (n=414) followed by a larger double-blind phase (n=984). A pooled analysis of data from both phases was pre-specified to evaluate the effect of the 25 microgram/kg dose bolus regimen compared to control as measured by a primary endpoint defined as the 30-day MACE rate (death, recurrent MI and uTVR).

In this pooled analysis, MACE at 30 days was significantly reduced by early upfront initiation of Tirofiban compared to control (5.8% vs. 8.6%; p=0.043). In addition, there was a strong trend toward a significant decrease in mortality with Tirofiban with respect to all-cause death (2.2% in the Tirofiban arm vs. 4.1% in the control arm; p=0.051). This mortality benefit was mainly due to a reduction of cardiac death (2.1% vs. 3.6%; p=0.086). At 1-year follow-up (the secondary endpoint), the mortality difference was maintained (3.7% vs. 5.8%; p=0.078 for all-cause mortality and 2.5% vs. 4.4% for cardiac mortality; p=0.061).

Patients who underwent primary PCI (86% of study population of pooled analysis) demonstrated a significant reduction in mortality both at 30 days (1.0% in the Tirofiban group vs. 3.9% in the control group; p=0.001) and at 1 year (2.4% for Tirofiban vs. 5.5% for control; p=0.007).

MULTISTRATEGY study

The MULTISTRATEGY study was an open-label, 2X2 factorial, multinational trial which compared the Tirofiban (n=372) with abciximab (n=372) when used in conjunction with either a sirolimus-eluting (SES) or bare metal stent (BMS), in patients with STEMI. Either Tirofiban (bolus of 25 microgram/kg, followed by an infusion at 0.15 microgram/kg/min continued for 18 to 24 hours) or abciximab (bolus of 0.25 mg/kg, followed by a 12-hour infusion at 0.125 microgram/kg/min) was initiated before arterial sheath insertion during the angiography. All patients received unfractionated heparin, ASA and clopidogrel.

The primary endpoint for the drug comparison was cumulative ST-segment resolution expressed as the proportion of patients who achieve at least 50% recovery within 90 minutes after the last balloon inflation and tested the hypothesis that Tirofiban is noninferior to abciximab with respect to this endpoint.

In the intention-to-treat population, the percentage of patients with at least 50% recovery from ST-segment elevation was not significantly different between Tirofiban (85.3%) and abciximab (83.6%), demonstrating the non-inferiority of Tirofiban to abciximab (RR for Tirofiban vs. abciximab, 1.020; 97.5% CI, 0.958-1.086; p<0.001 for non-inferiority).

At 30 days, the rates of major adverse cardiac events (MACE) were similar for abciximab and Tirofiban (4.3% vs. 4.0%, respectively; p=0.85) with these results maintained at 8 months (12.4% vs. 9.9%, respectively; p=0.30).

In On-TIME 2 and MULTISTRATEGY, patients were treated with dual oral antiplatelet therapy consisting of ASA and high-dose clopidogrel. The efficacy of tirofiban in combination with either prasugrel or ticagrelor has not been established in randomised controlled trials.

Meta-analysis of Randomised Trials of Tirofiban 25 microgram/kg Dose Bolus Regimen

The results of a meta-analysis evaluating the efficacy of the Tirofiban 25 microgram/kg dose bolus regimen versus abciximab (including 2213 ACS patients, across the ACS spectrum, with both NSTEMI and STEMI patients) did not reveal any significant difference in the OR for death or MI at 30 days between the two agents (OR, 0.87 [0.56-1.35]; p=0.54). Similarly, there were no significant differences in 30- day mortality between tirofiban and abciximab (OR, 0.73 [0.36-1.47]; p=0.38).

Additionally, at the longest follow-up, death or MI was not significantly different between tirofiban and abciximab (OR, 0.84 [0.59-1.21]; p=0.35).

TARGET study

In one study using a 10 microgram/kg bolus followed by a 0.15 microgram/kg/min infusion of tirofiban, tirofiban failed to demonstrate noninferiority to abciximab: the incidence of the composite primary endpoint (death, MI, or uTVR at 30 days) showed that abciximab was significantly more effective on clinically relevant endpoints, with 7.6% in the tirofiban and 6.0% in the abciximab group (p=0.038), which was mainly due to a significant increase in the incidence of MI at 30 days (respectively 6.9% vs. 5.4%; p=0.04).