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Prof. Steen Dalby Kristensen,
Prof. Raffaele De Caterina,
Prof. Kurt Huber,
The prognosis of patients with acute coronary syndromes is highly dependent on an immediate and correct diagnosis. The diagnostic strategy aims for prompt classification into acute ST-elevation myocardial infarction (STEMI) and non-STEMI/unstable angina. STEMI patients should undergo primary angioplasty or, if this is not feasible, receive fibrinolytic therapy as soon as possible (1,2). NSTEMI/unstable angina pectoris patients usually undergo cardiac catherisation within a few days.
Which kind of concomitant anti-thrombotic therapy should be started immediately in STEMI and non-STEMI/unstable angina patients in order to improve their outcome?
STEMI patients should be given aspirin. Although controlled trials are lacking, it seems logical to start aspirin therapy as soon as possible.
Although low-dose (75-100 mg) aspirin administered daily is as effective as higher doses are - and are therefore chronically recommendend by Guidelines - a higher dose is likely to be better because it insures a rapid and complete block of cyclooxygenase-1. For this purpose 300-500 mg is likely to be optimal.
The drug can be given orally in a soluble form or it can be chewed, but it may also be given intravenously.
This strategy should be conducted both in patients treated with primary angioplasty or fibrinolytics. The initial bolus dose should be followed by 75-150 mg orally life-long.
Clopidogrel is being tested in on-going studies in STEMI patients. In patients undergoing primary PCI we suggest that 300 mg of clopidogrel be given immediately, because most (approximately 90%) of these patients will receive an intracoronary stent. A study with an increased loading dose of clopidogrel (600 mg) is currently being performed (BRAVE-3). If fibrinolysis is used, there is currently no evidence that the patients will benefit from clopidogrel. However, the CLARITY TIMI-28 trial, which has been recently finished, has addressed this question. Data can be expected at the ACC meeting in 2005.
Should STEMI patients receive unfractionated heparin or low-molecular heparin as soon as the diagnosis is made?
In patients undergoing primary PCI, unfractionated heparin is used during the intervention. With this strategy, therapy can be started immediately after the diagnosis is made with a bolus of 70-150 IU/kg administered intravenously. However, this range of doses depends on whether the patients receives additional abciximab or not.
If the patient receives abciximab, the lowest dose of heparin should be used, yet the use of low molecular weight heparins is presently undergoing testing. Abciximab, on the other hand, is now used in most patients undergoing primary PCI and there is some evidence that immediate therapy with abciximab, in the ambulance pre-hospitally or in the emergency room at the latest, might be beneficial if the patient is going for primary angioplasty (ACE-trial, ADMIRAL trial, ReoPro-BRIDGIN trial) (4). Other GP IIb/IIIa-receptor antagonist might have similar efficacy but they are less intensively tested (eptifibatid, ONTIME trial; tirofiban, INTAMI trial).
If a strategy with fibrinolysis with alteplase, tenecteplase or reteplase is used, concomitant therapy with unfractionated heparin or low-molecular weight heparin (enoxaparin and dalteparin are the only one to have been investigated) is given at the time fibrinolytic therapy is started. There is some caveat to using full doses of low molecular weight heparin as adjunctive therapy to fibrinolysis in patients older than 75 years of age because of higher bleeding complications (ASSENT-3 PLUS trial). The important question is whether a reduced dosage of enoxaparin is similarly effective and safe as unfractionated heparin in the elderly patient. This is currently being investigated (ExTRACT TIMI 25 trial).
NSTEMI/unstable angina pectoris patients should be treated with aspirin as soon as the diagnosis is suspected (same dose-regimen as above). When the diagnosis is verified, low-molecular weight heparin therapy with enoxaparin or dalteparin should be initiated. Clopidogrel therapy should also be started as this stage with a 300 mg oral bolus followed by 75 mg daily (4,5,6). Again the use of high-dose clopidogrel (600 mg loading dose) is currently being tested (ISAR REACT-2 trial). The use of tirofiban or eptifibatide at this stage could be used prior to coronary catherisation as “upstream” treatment.
The use of anti-thrombotic therapy in acute coronary syndromes is an evolving area. Upcoming trials will also tell us whether clopidogrel should be given at a higher initial dose and whether the use of pentasaccharides or direct thrombin inhibitors given orally or intravenously will further improve prognosis in these patients.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Van de Werf F, Ardissino D, Betriu A, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal 2003 24, 28-66. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12559937
2. Kristensen SD, Andersen HR, Thuesen L et al. Should patients with acute ST elevation myocardial infarction be transferred for primary PCI? Heart 2004: 90; 1358-136. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15486148
3. Topol EJ, Neumann FJ, Montalescot G. A preferred reperfusion strategy for acute myocardial infarction. JACC Vol. 42, 11, 2003: 1886-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14662246 4. The CURE investigators. Effects of Clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N.Engl.J.Med. 2001;345:494-502. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11519503 5. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK et al. Effects of pretreatment with clopidogrel and aspirin followed by long- term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-33. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11520521 6. Steinhubl SR, Berger PE, Mann JT III et al. Early and sustained dual oral anti-platelet therapy following percutaneous coronary stenting – a randomized, controlled trial. JAMA 2002; 288: 2411-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12435254