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Efficacy in NSTE-ACS

Two large-scale clinical studies established the efficacy of Aggrastat® in the treatment of patients with NSTE-ACS (unstable angina/non-ST elevation MI). The two studies examined Aggrastat® alone and added to heparin, prior to and after percutaneous coronary revascularization (if indicated) (PRISM-PLUS) and in comparison to heparin in a similar population (PRISM).

Aggrastat Pharmacy Clinical Studies

Primary Outcomes at 7 days in PRISM-PLUS

Endpoint Aggrastat®
Heparin
(n=773)
Heparin
(n=797)
Risk®
Reduction
p-value
Death, new MI, and refractory ischemia at 7 days 12.9% 17.9% 32% 0.004
Death 1.9% 1.9%
MI 3.9% 7.0% 47% 0.006
Refractory Ischemia 9.3% 12.7% 30% 0.023

In the double-blind PRISM-PLUS trial, 1570 patients with NSTE-ACS within 12 hours of entry into the study were randomized to Aggrastat® (30 minute initial infusion of 0.4 mcg/kg/min followed by a maintenance infusion of 0.10 mcg/kg/min) in combination with heparin (5,000 U followed by an infusion of 1,000 U/h titrated to maintain an APTT of approximately 2 times control) or to heparin alone. All patients received concomitant aspirin unless contraindicated. Patients who were medically managed or who 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-ST elevation myocardial infarction. On average, patients received Aggrastat® for 71 hours.

The primary endpoint of the study was a composite of refractory ischemia, new MI and death within 7 days. There was a 32% risk reduction in the overall composite primary endpoint. The components of the composite were examined separately and the results are shown in the table (above). Note that the sum of the individual components may be greater than the composite (if a patient experiences multiple component events only one event counts towards the composite).

In 2013, the FDA approved the Aggrastat® High-Dose Bolus regimen (25 mcg/kg over 3 minutes, followed by 0.15 mcg/kg/min). The High-Dose Bolus Regimen is the recommended dosing for Aggrastat® for the reduction of thrombotic cardiovascular events in patients with non-ST elevated acute coronary syndrome (NSTE-ACS).

High-Dose Bolus plus Short Infusion Aggrastat® regimen: SAVI-PCI

The Shortened Aggrastat® Versus Integrilin in Percutaneous Coronary Intervention (SAVI-PCI) Trial was a U.S.-based, multicenter, randomized, open-label, non-inferiority trial conducted at 13 sites.

SAVI-PCI compared clinical outcomes at 48 hours post-PCI (or hospital discharge, whichever came first) after treatment with short duration Aggrastat® or two different longer-infusion regimens of Aggrastat® or Integrilin® in patients undergoing PCI for elective or NSTE-ACS indications. Clinical outcomes (death, periprocedural myonecrosis, uTVR) and major bleeding (REPLACE-2) were reported.

In patients undergoing elective PCI or PCI for NSTE-ACS, short infusion Aggrastat® demonstrated non-inferior reduction in combined ischemic/bleeding endpoint at 48 hours or discharge*

SAVI-PCI Primary Efficacy Endpoint

Variable,n (%)Aggrastat®
Short infusion
n=209
Aggrastat®
Long infusion
n=124
Integrilin®
Long infusion
n=202
Primary outcome†69 (34.2%)48 (39.0%)60 (30.9%)
PPM†69 (34.2%)45 (36.6%)60 (30.9%)
Death0 (0.0%)0 (0.0%);1 (0.5%)
uTVR1 (0.5%)1 (0.8%)0 (0.0%)
REPLACE-2 major
bleeding
0 (0.0%)4 (3.2%)1 (0.5%)

uTVR=Urgent Target Vessel Revascularization; PPM=Periprocedural Myonecrosis

†To be included in the primary composite endpoint analysis, a patient must have had the pre-PCI troponin local laboratory measurement and at least one troponin local laboratory measurement within 48 hours following PCI or hospital discharge, whichever came first. 16 patients without these measurements were excluded from the primary outcome and PPM endpoint analyses (n=519); Aggrastat® short infusion (n=202), Aggrastat® long infusion (n=123), Integrilin® long infusion (n=194).

Risk Difference (95% Confidence Interval)Aggrastat Pharmacy Risk Difference

Non-inferiority of the risk difference in the primary composite endpoint between groups. All comparisons between groups fulfilled the specified non-inferiority margin of 19.1%. Risk difference is shown as the risk of the composite endpoint in the left group minus the right group.

SAVI-PCI was open-label and clinical endpoints were not adjudicated. The Aggrastat® long infusion arm was added after enrollment of 159 patients and there may have been differences in practice compared to the beginning of enrollment. Event rates in SAVI-PCI were lower than originally anticipated, reducing the overall power of the study.

Secondary endpoint analysis using varying definitions of periprocedural myonecrosis (PPM)

Frequency of Events(%)

Aggrastat Pharmacy Secondary PPM

PPM=Periprocedural Myonecrosis; ULN=Upper Limit of Normal

PPM in the primary endpoint was defined as a troponin ≥3 times the ULN and ≥20% than baseline and occurred in 33.5% of the overall study population. Rates of greater PPM elevations in the overall study population (all of which also required a ≥20% increase over baseline) were also evaluated. All comparisons between groups were non-significant (p>0.05) unless otherwise noted. P-value is the overall p-value from the logistic regression model

Aggrastat Pharmacy Study Design
SAVI-PCI Study Design
Purpose Compare high-dose bolus plus a shortened infusion of Aggrastat® (tirofiban hydrochloride) vs label-dosing of Integrilin® (eptifibatide).
Primary endpoint Composite endpoint of death, PPM, uTVR, or major bleeding at 48 hours or hospital discharge, whichever came first.
Secondary endpoint
  • Individual components of death (any-cause), urgent target revascularization (repeat PCI or any CABG procedure after the index PCI on a non-selective basis in the target vessel because of recurrent myocardial ischemia) or non-CABG related major bleeding as quantified according to REPLACE-2 major bleeding criteria.
  • Individual components of PPM (defined as ≥3 times, ≥10 times, ≥20 times or ≥50 times the upper limit of normal troponin and at least 20% or greater than the baseline troponin value).
Key inclusion criteria Patients >18 years old scheduled to undergo PCI with an FDA, approved or cleared device.
Key exclusion criteria Primary PCI for STEMI as index procedure, prior STEMI within 48 hours before randomization, prior PCI within 30 days before randomization, planned staged PCI within the subsequent 24 hours after index PCI, use of abciximab within 7 days before randomization, use of tirofiban or eptifibatide within 12 hours before randomization, use of low-molecular weight heparin within 12 hours before randomization; use of bivalirudin within 12 hours before randomization.
Patient population
  • N=535
  • Patients undergoing PCI for either elective indications or for NSTE-ACS in one or more native coronary target lesions.
Protocol
  • Patients were randomized to receive either:
    • Aggrastat® 25 mcg/kg bolus + 0.15 mcg/kg/min infusion for the duration of the PCI procedure plus 1-2 hours post-PCI; or
    • Integrilin® two boluses of 180 mcg/kg given 10 minutes apart
      followed by a 2.0 mcg/kg/min infusion for 12-18 hours post-PCI;
      or
    • Aggrastat® 25 mcg/kg bolus followed by a 0.15 mcg/kg/min
      infusion for 12-18 hours post-PCI.
  • In patients with renal insufficiency, dosage adjustment was made as
    labeled.1,2
  • All patients received UFH 50 U/kg and administered DAPT including
    ASA 81-325 mg QD and an oral P2Y12 antagonist per local practice
    and physician discretion

PPM=Periprocedural Myonecrosis; uTVR=Urgent Target Vessel Revascularization; PCI=Percutaneous Coronary Intervention; CABG=Coronary Artery Bypass Graft; REPLACE-2=Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events STEMI=ST-Elevation Myocardial Infarction; NSTE-ACS=Non-ST Elevation-Acute Coronary Syndrome; UFH=Unfractionated Heparin; DAPT=Dual Antiplatelet Therapy; ASA=Aspirin.

SAVI-PCI was open-label and clinical endpoints were not adjudicated. The Aggrastat long infusion arm was added after enrollment of 159 patients and there may have been differences in practice compared to the beginning of enrollment. Event rates in SAVI-PCI were lower than originally anticipated, reducing the overall power of the study.

Disclaimers: The study was funded by Medicure Pharma and designed by an executive steering committee with non-binding input from Medicure. The statistical analysis plan and analyses were completed by JSS Medical research (Montreal, QC, Canada).

References:

  1. Aggrastat® (tirofiban hydrochloride) Prescribing Information. 2020
  2. Integrilin® (eptifibatide) Prescribing Information. 2013
Important Safety Information

Indication:

Aggrastat® is indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS).

Contraindications:

  • Known hypersensitivity to any component of Aggrastat®.
  • History of thrombocytopenia with prior exposure to Aggrastat®.
  • Active internal bleeding, or history of bleeding diathesis, major surgical procedure or severe physical trauma within the previous month.

Warnings and Precautions:

  • Aggrastat® can cause serious bleeding. Most bleeding associated with Aggrastat® occurs at the arterial access site for cardiac catheterization. Minimize the use of traumatic or potentially traumatic procedures such as arterial and venous punctures, intramuscular injections, nasotracheal intubation, etc. Concomitant use of fibrinolytics, anticoagulants and antiplatelet drugs increases the risk of bleeding. If bleeding cannot be controlled, discontinue Aggrastat®.
  • Thrombocytopenia: discontinue Aggrastat® and heparin.

Adverse Reactions:

  • Bleeding is the most commonly reported adverse reaction.

For additional information, refer to the full Prescribing Information.

You are encouraged to report negative side effects of prescription drugs to the FDA.

Visit www.FDA.gov/medwatch
or call 1-800-FDA-1088.