New IV antiplatelets: Do you need two of these drugs on your formulary?
New IV antiplatelets: Do you need two of these drugs on your formulary?
Price, half-life reversion are bottom-line considerations
Since coming to market in 1994, the intravenous antiplatelet ab ciximab (ReoPro, Contocor/Lilly) literally has been in a class by itself for patients admitted with acute coronary syndrome specific to unstable angina or following non-Q-wave myocardial infarction (MI).
But in May 1998, the Food and Drug Administration approved two new IV glycoprotein IIb/IIIa receptor antagonists for the medical management or pre-surgery stabilization of patients with acute coronary syndrome: tirofiban (Aggrastat, Merck) and eptifibatide (Integrilin, Schering-Plough/COR Therapeutics). All three drugs work by attaching to platelet GP IIb/IIIa receptors to prevent fibrinogen from attaching to platelets to form clots.
And all three are being aggressively marketed for a patient population that accounts for 1.3 billion hospital admissions each year, 480,000 of which will undergo some form of coronary surgery, according to the American College of Cardiology in Bethesda, MD.
The drugs' efficacy, safety, administration, side effects, and contraindications are similar, making decisions on which drug to maintain or add to a formulary difficult. Similarities include how they interact with heparin and aspirin, identical rapid onsets, bolus and infusion administrations, general dosing phases and timetables, and the common but manageable complication of site bleeding. And most importantly, all three reduce mortality and help prevent new MIs, refractory ischemia, or repeated surgeries.
"I would say unquestionably a hospital must have at least one in this class," says Nick Chronos, MD, director of research for the Andreas Gruentzig Cardiovascular Center at Emory University Hospital in Atlanta. "It's going to come down to the question of whether you need more than one of them."
Experts note that some subtle differences do exist among the three drugs. For example, the specific labeling for each drug addresses different indications. Because of that, you may want to recommend different drugs based on whether surgery is elective, whether the diagnosis includes acute coronary syndrome, or whether percutaneous transluminal coronary angioplasty (PTCA) or atherectomy is anticipated. You may see an advantage to one over the other for medical management or for use with unresponding patients slated for general percutaneous coronary intervention within 24 hours.
Nevertheless, clinicians interviewed by Drug Utilitization Review did not see enough difference to recommend including more than one of these drugs on your list.
"For example, just because Aggrastat doesn't have identical indications doesn't mean it won't be used for a variety of conditions. Physicians are free to go off-label," says Richard Fry, director of pharmacy affairs at the Academy of Managed Care Pharmacy in Alexandria, VA.
Cost-containment strategies vary
Fry and Chronos agree that other small differences - that Aggrastat alone comes in either a premix or concentrate, for example - are not weighty formulary considerations. Chronos adds that labeling indications simply can reflect a manufacturer's marketing strategy based on clinical trial results.
If the differences between the drugs aren't significant, what about tailoring to patient populations? "That's really difficult," Chronos admits. "If it's a hospital with a predominant ER but not a lot of angioplasty or bypass surgeries, it's probably just as well having Aggrastat, because the reality would be dealing more with unstable angina and medical management. If it's a tertiary referral center without an ER and is receiving patients in more of a cath lab group, then probably ReoPro is best."
Clinically, Aggrastat and Integrilin have half-lives of two hours and 2.5 hours respectively, meaning platelet reaggregation occurs within several hours. Chronos deems this clinical aspect the "most significant" when comparing the two new drugs and ReoPro: "[Platelet reaggregation] is much easier to reverse based on the half-life for Aggrastat and Integrilin. With ReoPro, you must reverse with platelet transfusions. If a patient is expected to go on to bypass, then the others are better."
Fry agrees: "These two drugs are better than ReoPro because you don't have to wait to give an angioplasty based on that platelet reaggregation."
That gets back to Chronos' original point that some hospitals may be better off stocking two of the three agents. "ReoPro is reasonably expensive per patient dose, where Integrilin is the lowest priced, but its efficacy is somewhat lower than ReoPro or Aggrastat," he says. He recommends a ReoPro-Aggrastat formulary combination.
Fry likes the broader approval indications granted to Integrilin, but both say cost is para mount. "Where you've got similar products on the market, [the decision] is probably going to come down to cost considerations," he explains. "The bottom line is, what's the cost per treatment?"
It's a little tricky to predict, but ReoPro, priced at $450 per vial, usually is administered as a bolus and 12-hour infusion totaling three vials, or a $1,350 wholesale cost, according to marketer Lilly. Aggrastat is $350 per 50 mL vial, where a two- to three-day administration can cost between $700 and $1,050, according to Merck. The drug's premixed 500 mL IV bag is priced at $700. (For details on recommended dosing and administration of Aggrastat, see above chart.) Integrilin costs $50.40 at 10 mg/ 10 mL and $157.50 at 75 mg/100 mL, according to Schering-Plough.
Cost-containment strategies or guidelines also can vary. "Specific treatment guidelines for use of these agents are the cost-containment measures," Fry says. "If you restrict them to specific patients, you're going to cut costs. As far as formularies, I think they have to parallel managed care companies' decision-making process. What you may find is a hospital taking a wait-and-see posture like managed care organizations do with many drugs. They may not consider them for another six months until there is some post-marketing experience. If a hospital has gone with ReoPro the last several years and is comfortable with its use, there may not be too much movement or initiative into these other two. Clinical trials are not the real world."
Tirofiban: Unique to PTCA
Nearly 10,000 patients, divided among three separate groups, took part in clinical trials of tirofiban. In PRISM-PLUS (Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms), patients received either tirofiban and heparin or just heparin (with all patients receiving aspirin) for 48 hours before undergoing angiography and angioplasty or atherectomy. Overall average administration was 71 hours, during which time 46% of patients were managed medically, 31% underwent percutaneous coronary intervention (PCI) and 23% had bypass surgery.
The combination of heparin and tirofiban reduced new MI or refractory ischemia by 32% over the first seven days, compared with 17.9% of patients receiving only heparin. Those numbers held up at 30 days and six months.
The tirofiban-only part of PRISM-PLUS was halted due to higher mortality, 4.6% vs. 1.1%, compared with heparin alone after seven days. Again, Aggrastat was approved for use with heparin.
In the separate PRISM study, patients received similar 48-hour administration of tirofiban and aspirin or heparin and aspirin. Forty-eight hours after administration, the frequency of MI, patient death, or refractory ischemia was 5.6% with heparin and aspirin and 3.8% with tirofiban and aspirin, though the numbers equaled out at seven and 30 days.
RESTORE: Tirofiban reduced MI risk
A final study, RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis), compared the drug to placebo in patients undergoing PTCA or atherectomy for acute coronary syndrome or acute MI, a labeled indication unique to Aggrastat as an IV antiplatelet.
With patients already on heparin and aspirin, treatment began at the start of surgery and progressed for 36 hours. Afterward, at two and seven days, patients given tirofiban showed reduced risk of MI, death, or revascularization. However, the numbers began to equalize at 30 days when researchers reported 12.2% of the placebo group and 10.3% of the tirofiban group had one or more events. Still, Aggrastat is approved and labeled for this indication.
The drug's recommended dosage is 0.4 µg/ kg/min for 30 minutes, followed by 0.1 µg/ kg/min, with severely renal insufficient patients recommended for half that dosage. Admin istration is recommended 12 to 24 hours after angioplasty or atherectomy, and throughout angiography.
The drug comes either as a premix of tirofiban 25 mg hydrochloride monohydrate in 500 mL of 0.9% sodium chloride, or as a 250 µg/mL concentrate in 50 mL vials for dilution to the same strength as the premix, of which specific instructions are included in the packaging.
Contraindications include known hypersensitivities, history of diathesis within 30 days, history of intracranial hemorrhage or neoplasm, severe hypertension (>180 mmHg systolic, >110 mmHg diastolic), and acute pericarditis.
Eptifibatide: Broadest indications
Because it is approved for use in either elective or acute PCI, eptifibatide has the broadest indications of the new drugs. Approval followed two large placebo-controlled clinical trials of some 14,000 patients.
In an international trial dubbed PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy), patients received either eptifibatide or placebo for acute coronary syndrome. Of those enrolled, 87% given the drug were managed medically, according to researchers, with 13% undergoing PCI. New MI or mortality within 30 days struck 14.2% given eptifibatide, 15.7% on placebo.
In the drug's IMPACT II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis) study, patients receiving aspirin and heparin were given either placebo or two doses of eptifibatide while undergoing PCI, About 40% of those patients showed acute coronary syndrome. For the study, patients received a bolus dose of 135 µg/kg-initiated PCI, followed by 0.5 or 0.75 µg/kg/min IV infusion, for an overall time of 20 to 24 hours.
Integrilin has varied dosing recommendations, mirroring its broad indications. For patients with acute coronary syndrome, dosing is 180 µg/kg of IV bolus followed by continuous IV infusion at 2 µg/kg/min until discharge or the advent of bypass surgery, capping at 72 hours. (If, instead of bypass, PCI is called for, recommended infusion reduces to 0.5 µg/kg 20 to 24 hours, capping at 96 hours.) (For more information, see table, p. 146, top.)
For patients without acute coronary syndrome undergoing PCI, the recommended dosage changes to 135 µg/kg IV bolus prior to surgery, then 0.5 µg/kg/min for 20 to 24 hours. The drug comes only in solutions of either 20mg/10 mL or 75 mg/100mL. (See table, p. 146, bottom.)
Similar contraindications include known hypersensitivities, history of bleeding diathesis, severe hypertension (>200 systolic, >110 diastolic), history of stroke within 30 days or major surgery within six weeks, platelet count less than 100,000/mm3, or a dependency on renal dialysis.
Abciximab: Adjunct prevention therapy
Abciximab's expanded labeling approval in November 1997 preempted some of the indications its rival drugs are touting. Specifically, that approval allowed use in patients with unstable angina who were not responding to other therapies when PCI was scheduled within 24 hours.
Otherwise, the drug's main indication, since original approval several years ago, remains as an adjunct prevention therapy of cardiac ischemia complications for patients undergoing PCI, including angioplasty, stent placement, and atherectomy.
Recommended dosage for coronary interventions is an IV bolus of 0.25 mg/kg up to an hour before PCI, followed by continuous IV infusion at 0.125 µg/kg/min (with a maximum at 10 µg/ min) for 12 hours.
For its newer indication, recommended dosing is 0.25 mg/kg IV bolus then 10 µg/min IV infusion for 18 to 24 hours, ending one hour after surgery. ReoPro's manufacturer also is pursuing trials in combination with low-dose thrombolytics for acute MI.
[A detailed overview of clinical trials also is available in New England Journal of Medicine 1998; 338:1,488-1,505. For more information, contact Merck & Co. (Aggrastat), (800) 672-6372; Schering-Plough (Integrilin), (800) 526-4099; Centocor (ReoPro), (800) 457-6399; Nick Chronos, (404) 712-4677; Richard Fry, (703) 683-8416.]
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.