New Clinical Trials Evaluate High-Dose AGGRASTAT(R) in High-Risk Patients
This is an old study but a quote from Eric Topol is important to explain the study that basically killed the sales of this drug when Merck owned it in the US.
Eric Topol, M.D. of the Cleveland Clinic Heart Center explains, "This study provides further support for doing a repeat large-scale trial testing tirofiban versus abciximab, since so much data now suggest the bolus dose we used (for tirofiban) in TARGET was inappropriately low." In the Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial (TARGET) trial, tirofiban was given at 10 mcg/kg bolus followed by a 0.15 mcg/kg/min infusion for 18 to 24 hours.
Merck used the wrong dose in the target trial. Here are the results.
TARGET
In the first study to compare the effects of 2 platelet glycoprotein IIb/IIIa inhibitors, researchers compared tirofiban (Aggrastat) to abciximab (ReoPro), said Eric Topol, MD, chairman of cardiology at the Cleveland Clinic Foundation. The trial included 4812 patients at 149 hospitals in 18 countries throughout North America, Europe, and Australia who were scheduled for an interventional procedure including a stent.
In the study, 2398 patients were assigned to tirofiban and 2414 to abciximab. The end point at 30 days was death, myocardial infarction, or urgent target vessel revascularization. In the tirofiban group, 7.55% of patients reached one of the end point situations. In the abciximab group, 6.01% of patients reached the end point. Dr Topol said the difference was 26% favoring abciximab—a statistically significant finding. The study concluded that the preferred agent for coronary stenting was abciximab at the 30-day end point. In a released statement, Rick Sax, MD, senior director of clinical research at Merck Research Laboratories said, "Merck remains firm in its commitment to the use of Aggrastat when it is indicated in patients presenting to the hospital with acute coronary syndromes, including patients who subsequently go on to have an angioplasty procedure. The benefits of Aggrastat in improving outcomes in these patients were firmly established in the PRISM-PLUS study." Merck sponsored the TARGET trial.
BALTIMORE, July 29 /PRNewswire-FirstCall/ -- Guilford Pharmaceuticals,
Inc. (Nasdaq: GLFD) today announced the publication of two new clinical trials
of AGGRASTAT(R) that evaluated the safety and efficacy of high-dose
AGGRASTAT(R) Injection (tirofiban hydrochloride) in patients undergoing
primary coronary angioplasty for ST segment elevation myocardial infarction
(STEMI) and high-risk coronary angioplasty. These trials used a new dosing
regimen of AGGRASTAT(R)
(25 mcg/kg bolus over 3 minutes followed by infusion at 0.15 mcg/kg/min for
18 hours) and compared this regimen to abciximab (ReoPro(R)) or placebo.
AGGRASTAT(R), in combination with heparin and aspirin, is indicated for
the treatment of acute coronary syndrome (ACS) including patients who are to
be managed medically and those undergoing PTCA or atherectomy.
Results from the first trial known as ADVANCE, published in the Journal of
the American College of Cardiology(1) yielded a significantly reduced primary
composite end point (death, nonfatal MI, urgent TVR, and bailout GP IIb/IIIa
inhibitor therapy during follow-up) with heparin plus tirofiban over heparin
plus placebo [20% vs. 35%, respectively (hazard ratio 0.51, 95% confidence
interval 0.29 to 0.88; p = 0.01)]. This double-blind, placebo-controlled,
randomized trial included 202 high-risk patients undergoing percutaneous
coronary intervention (PCI).(2) In this trial, 98% of patients underwent
stenting. Any stent type approved by a regulatory agency could be implanted.
All patients were pretreated with aspirin (160 to 325 mg orally) and
thienopyridine (ticlopidine 500 mg as a loading dose and then 250 mg twice
daily or clopidogrel 300 mg orally as a loading dose and then 75mg/day at
least 48 or 6 hours before the procedure).
Investigators conclude that high-dose bolus tirofiban plus heparin was
safe and effective in this study. Minor bleeding was observed in both the
tirofiban and placebo arms; the difference between the two was not
statistically significant (p=0.19). There was no severe thrombocytopenia in
either treatment, and one patient in each treatment arm had mild
thrombocytopenia.
"These data suggest that high-dose tirofiban can reduce the frequency of
major adverse cardiovascular events in high-risk patients undergoing PCI,"
says Matthew Meldorf, M.D., Senior Director, Medical Affairs of Guilford
Pharmaceuticals. "We are encouraged by these data and are evaluating our
options for pursuing additional large-scale trials to confirm these results."
Findings from a randomized study of 100 patients, published in the
American Journal of Cardiology(3) suggest high-dose bolus tirofiban may be as
effective as abciximab for 30-day recovery of left ventricular function (as
the primary endpoint) in patients undergoing primary coronary angioplasty for
STEMI [mean baseline LV ejection fraction - 47 plus or minus 7%, increased to
55 plus or minus 9% similarly in both groups (p = 0.001)]. In the trial, 97%
of patients underwent stenting. Thrombolysis In Myocardial Infarction (TIMI)
grade flow (a secondary endpoint) was 0 in approximately 80% of patients prior
to the procedure. After the procedure, final TIMI 3 grade flow was achieved
in 88% of tirofiban patients vs. 86% of abciximab patients, respectively
(p = 1.0).
Investigators conclude that abciximab and tirofiban affected both initial
angiographic outcomes and 30-day recovery of LV function following primary
coronary angioplasty. With no major bleeding or severe thrombocytopenia and
no need for red blood cell transfusions, researchers say the study provides
important information about the safety of high-dose bolus tirofiban. More
abciximab-treated patients than tirofiban-treated patients [8% vs. 4%,
respectively] experienced minor bleeding, but this difference was not
significant (p=0.71). The 30-day incidence of major adverse cardiovascular
events was also greater, but not significantly so, in the abciximab group when
compared to the tirofiban group [6% vs. 4% (p = 0.74)].
Eric Topol, M.D. of the Cleveland Clinic Heart Center explains, "This
study provides further support for doing a repeat large-scale trial testing
tirofiban versus abciximab, since so much data now suggest the bolus dose we
used (for tirofiban) in TARGET was inappropriately low." In the Do Tirofiban
and ReoPro Give Similar Efficacy Outcomes Trial (TARGET) trial, tirofiban
was given at 10 mcg/kg bolus followed by a 0.15 mcg/kg/min infusion for 18 to
24 hours.
Important Information About AGGRASTAT(R) Injection
AGGRASTAT(R) was approved by the Food and Drug Administration (FDA) on
May 14, 1998. AGGRASTAT(R), in combination with heparin, and aspirin, if not
contraindicated, is indicated for the treatment of ACS including patients who
are to be managed medically and those undergoing PTCA or atherectomy. In this
setting, AGGRASTAT(R), has been shown to decrease the rate of a combined
endpoint of death, new myocardial infarction or refractory ischemia/repeat
cardiac procedure. In most patients, AGGRASTAT(R) should be administered
intravenously, at an initial rate of 0.4 mcg/kg/min for 30 minutes and then
continued at 0.1 mcg/kg/min. For complete information, please refer to the
product's prescribing information.
AGGRASTAT(R) (tirofiban hydrochloride) 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; or a
history of intracranial hemorrhage, intracranial neoplasm, arteriovenous
malformation, or aneurysm. Other contraindications to AGGRASTAT(R) include: a
history of thrombocytopenia following prior exposure to AGGRASTAT(R); history
of stroke within 30 days or any history of hemorrhagic stroke; major surgical
procedure or severe physical trauma within the previous month; or history,
symptoms, or findings suggestive of aortic dissection. AGGRASTAT(R) is
also contraindicated in patients with: severe hypertension (systolic blood
pressure >180 mmHg and/or diastolic blood pressure >110 mmHg); concomitant use
of another parenteral GP IIb/IIIa inhibitor; or acute pericarditis.
Bleeding is the most common complication encountered during therapy with
AGGRASTAT(R). Administration of AGGRASTAT(R) is associated with an increase
in bleeding events classified as both major and minor bleeding events, by
criteria developed by the Thrombolysis In Myocardial Infarction Study group
(TIMI). Most major bleeding associated with AGGRASTAT(R) occurs at the
arterial access site for cardiac catheterization. Fatal bleedings have been
reported. AGGRASTAT(R) should be used with caution in patients with platelet
count <150,000/mm3, in patients with hemorrhagic retinopathy, and in chronic
hemodialysis patients. Because AGGRASTAT(R) inhibits platelet aggregation,
caution should be employed when it is used with other drugs that affect
hemostasis. The safety of AGGRASTAT(R) when used in combination with
thrombolytic agents has not been established. During therapy with
AGGRASTAT(R), patients should be monitored for potential bleeding. When
bleeding cannot be controlled with pressure, infusion of AGGRASTAT(R) and
heparin should be discontinued.
The following additional adverse reactions have been reported in post-
marketing experience: Bleeding: intracranial bleeding, retroperitoneal
bleeding, hemopericardium, and pulmonary (alveolar) hemorrhage. Fatal
bleedings have been reported; Body as a whole: acute and/or severe decreases
in platelet counts which may be associated with chills, low grade fever, or
bleeding complications; Hypersensitivity: rash and/or hives.
