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Three Part Question

In [a patient with acute myocardial ischaemia] is [a low molecular weight heparin better than a platelet glycoprotein IIb/IIIa complex inhibitor] at [reducing morbidity and mortality]?

Clinical Scenario

A 45 year old man attends the Emergency department with 30 minutes of chest pain. An ECG shows ST segment depression in the inferior leads. You wonder whether he should be treated with low molecular weight heparin or a glycoprotein IIa/IIIb complex inhibitor.

Search Strategy

Medline 1966-10/99 using the OVID interface.
[{exp angina, unstable OR unstable angina.mp OR exp myocardial ischemia OR myocardial ischemia$.mp OR myocardial ischaemia.mp} AND ({exp heparin OR exp heparin, low-molecular-weight OR heparin$.mp OR LMWH$.mp} AND {exp platelet aggregation inhibitors OR exp platelet glycoprotein gpiib-iiia complex OR tirofiban$.mp})] AND maximally sensitive RCT filter LIMIT to human AND english.

Search Outcome

324 papers found of which 318 irrelevant or of insufficient quality for inclusion. The six remaining papers, which refer to five studies, are shown in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Gurfinkel EP et al 1996 Argentina	219 patients with unstable angina Aspirin alone vs aspirin and heparin vs aspirin and low-molecular-weight heparin	Double-blind PRCT	Major end points (recurrent angina, myocardial infarction, urgent revascularisation, major bleeding, death)	Recurrent angina, myocardial infarction, and urgent revascularisation were significantly less frequent in the LMWH group. Major bleeding only occurred in the unfractionated heparin group
			Minor end points (silent myocardial ischemia, minor bleeding)	Silent myocardial ischemia was significantly less frequent in the LMWH group. Minor bleeding was significantly more frequent in the unfractionated heparin group.
Cohen M et al (2 & 3) 1997 and 1998 USA	3171 patients with angina at rest or non-Q-wave myocardial infarction enoxaparin vs unfractionated heparin	Double-blind PRCT	Composite end point (recurrent angina, myocardial infarction, death)	No difference at 48h. Significantly better (16.6% vs 19.8%) in enoxaparin group at 14 days. Difference continues at 30 days.
PRISM study investigators 1998	3232 with unstable angina, myocardial ischemia, raised CK-MB or history of significant IHD. All on aspirin Unfractionated heparin or tirofiban	Double-blind PRCT	Composite end point (refractory ischemia, myocardial infarction, death)	Significantly better (2.3% vs 3.6%) in tirofiban group at 48h. No difference at 14 and 30 days, although mortality was lower in tirofiban group at this time. No difference in mortality at 6 months
PRISM-PLUS study investigators 1998	1915 patients with unstable angina, myocardial ischemia or raised CK-MB. All on aspirin Unfractionated heparin or tirofiban or unfractionated heparin and tirofiban	Double-blind PRCT	Composite end point (refractory ischemia, myocardial infarction, death)	Significantly worse mortality in tirofiban alone group at 7 days (4.6% vs 1.1% for heparin alone). Significantly lower composite end point occurrence in tirofiban plus heparin group at 7 (12.9% vs 17.9%) and 30 days.	Tirofiban alone group stopped prematurely
The PARAGON investigators 1998	2282 patients with non-ST-elevation acute coronary syndromes. All on aspirin High or low dose tirofiban with or without unfractionated heparin vs heparin alone	Double-blind PRCT	Composite end point (non-lethal myocardial infarction or death)	No differences at 30 days. Significantly lower composite end point occurrence at 6 months for low dose lamifiban and heparin.

Comment(s)

There is no trial that directly compares LMWHs with platelet glycoprotein IIb/IIIa complex inhibitors. Both treatments appear to be better than no treatment. The evidence that enoxaparin is better than unfractionated heparin is compelling (for unstable angina ORs 0.81 [0.68-0.96]), while that for tirofiban is less so. Even more work is required in this area.

Clinical Bottom Line

All patients with unstable angina should receive LMWHs in preference to unfractionated heparin. The case for the use of platelet glycoprotein IIb/IIIa complex inhibitors in preference to LMWHs has not been established.

References

1. Gurfinkel EP, Manos EJ, Mejail RI et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol 1995;26(2):313-8.
2. Cohen M, Demers C, Gurfinkel EP et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety of subcutaneous enoxaparin in non-Q-wave coronary events study group. N Engl J Med 1997;337(7):447-52.
3. Cohen M, Demers C, Gurfinkel EP et al. Low-molecular-weight heparins in non-ST-segment elevation ischemia: the ESSENCE trial. Efficacy and Safety of subcutaneous Enoxaparin versus intravenous unfractionated heparin, in non-Q-wave coronary Am J Cardiol 1998;82(5B):19L-24L.
4. PRISM study investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338(21):1498-505.
5. PRISM-PLUS study investigators. Inhibition of platelet glycoprotein IIb/IIIa receptor with Tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998;338(21):1488-97.
6. The PARAGON investigators. International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina. Circulation 1998;97(24):2386-95.