Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Tirofiban plus heparin was more effective than heparin alone for unstable angina and non-Q-wave MI

ACP J Club. 1998 Nov-Dec; 129:62. doi:10.7326/ACPJC-1998-129-3-062


Source Citation

The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med. 1998 May 21;338:1488-97. [PubMed ID: 9599103]


Abstract

Question

In patients with unstable angina or non-Q-wave myocardial infarction (MI), can tirofiban prevent acute ischemic events?

Design

6-month randomized, double-blind, placebo-controlled trial.

Setting

72 hospitals in 14 countries.

Patients

1915 patients (mean age 63 y, 68% men, 85% white) who had prolonged or repetitive episodes of angina at rest or with minimal exercise in the previous 12 hours, with cardiac enzyme or electrocardiographic changes. Exclusion criteria were ST-segment elevation for > 20 minutes; recent thrombolysis, stroke, coronary angioplasty, or bypass surgery; angina caused by identifiable factors; history of platelet disorder or thrombocytopenia; active bleeding or high risk for bleeding; or high serum creatinine levels or low platelet counts.

Intervention

All patients received aspirin, 325 mg/d, and adjusted full-dose heparin. Patients were allocated to tirofiban (0.4 µg/kg per min for 30 min, then 0.1 µg/kg per min) (n = 773) or placebo (n = 797). Coronary angiography and angioplasty were done as needed after ≥ 48 hours. A treatment arm of tirofiban alone was stopped early because of excess mortality.

Main outcome measure

Composite measure of all-cause mortality, new MI, refractory ischemia, and rehospitalization for unstable angina.

Main results

Analysis was by intention to treat. At 7 days, patients who received tirofiban had a lower rate of the composite end point (P = 0.004), ischemia (P = 0.02), MI (P = 0.006), and MI or death (P = 0.006) than those who received placebo (Table). The composite end point benefit for tirofiban continued at 1 month (P = 0.03) and 6 months (P = 0.02). The groups did not differ for death (1.9% vs 1.9%, P = 0.99) or major bleeding incidents (4.0% for tirofiban vs 3.0% for placebo, P = 0.34).

Conclusion

Patients with unstable angina or non-Q-wave MI who received tirofiban plus heparin had lower rates of a composite measure of death, MI, refractory ischemia, and rehospitalization than those who received heparin alone.

Source of funding: Not stated.

For correspondence: Dr. P. Théroux, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec H1T 1C8, Canada. FAX 514-376-1076.


Table. Tirofiban vs placebo for unstable angina and non-Q-wave MI at 7 days*

Outcomes Tirofiban Placebo RRR (95% CI) NNT (CI)
Composite† 12.9% 17.9% 27.9% (8.8 to 43.0) 20 (12 to 70)
Ischemia 9.3% 12.7% 26.5% (2.3 to 44.7) 30 (15 to 381)
MI 3.9% 7.0% 44.8% (15.2 to 64.1) 32 (18 to 109)
MI or death 4.9% 8.3% 40.6% (12.9 to 59.6) 30 (17 to 109)

*MI=myocardial infarction. Other abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.
†Composite death, MI, refractory ischemia, or rehospitalization for unstable angina.


Commentary

Inhibiting platelet aggregation on a disrupted coronary artery plaque is a major goal in treating patients with unstable angina or non-Q-wave MI. Antiplatelet agents now include cyclo-oxygenase inhibitors (aspirin), adenosine diphosphate-receptor inhibitors (ticlopidine and clopidogrel), and glycoprotein (GP) IIb/IIIa receptor inhibitors (abciximab, eptifibatide, and tirofiban).

The PRISM-PLUS study involved high-risk patients (angina within 12 h, 90% with ST-T wave changes, and 45% with elevated cardiac enzymes) who were later referred for interventional procedures (90% cardiac catheterization and 54% revascularization) and showed a sustained reduction in adverse events when tirofiban was added to aspirin and heparin. These results contrast with the PRISM study in which lower-risk patients (angina within 24 h, 75% with ST-T wave changes, and 25% with elevated cardiac enzymes) who were treated with fewer procedures (62% cardiac catheterization and 39% revascularization) did not show a sustained treatment benefit when aspirin plus tirofiban was compared with aspirin plus heparin (1). Therefore, tirofiban with concomitant heparin therapy is more likely to be useful in high-risk patients.

The use of composite measures in recent trials obscures the source of treatment benefit. Although tirofiban lowered the composite rate of death, MI, refractory ischemia, and rehospitalization, the benefit was only in rates of MI and ischemia. This is also true for the other GP IIb/IIIa inhibitors and contrasts with the reduced mortality seen with fibrinolytic agents in acute MI. Unlike the fibrinolytic agents, GP IIb/IIIa inhibitors do not substantially increase the risk for intracerebral hemorrhage.

The cost of tirofiban ranges from $350 to $3000 depending on patient weight and treatment duration. Further studies are needed to show whether GP IIb/IIIa inhibitors will be cost-effective by either decreasing interventional procedures or by facilitating early stenting and decreased length of stay (24 to 48 h).

Eric R. Bates, MD
University of MichiganAnn Arbor, Michigan, USA

Eric R. Bates, MD
University of Michigan
Ann Arbor, Michigan, USA


Reference

1. 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;338:1498-505. [PubMed ID: 9599104]