Acute coronary syndromes: Drug treatments

Abstract

Acute myocardial infarction is usually caused by rupture of a pre-existing atherosclerotic lesion in a major coronary artery leading to thrombosis occlusion with transient or permanent ischaemic sequelae. The consequences are strongly related to the site of the lesion, to the degree of obstruction, and to the presence or absence of collateral circulation. In cases of total occlusion and the absence of collaterals, extensive myocardial necrosis occurs with the risk of mechanical and electrical complications. Q waves are frequently seen in the electrocardiographic evolution of this type of myocardial infarction. In the presence of collaterals and a non-occlusive thrombotic process a smaller myocardial infarction may ensue. Q-wave development is usually absent (non-Q wave myocardial infarction). In other cases, ischaemic symptoms may remain without myocardial necrosis: unstable angina pectoris. In many cases, ischaemic symptoms are transient and do not recur: the so called “cooled off” or “stabilised” unstable angina pectoris. Non-Q-wave infarction and unstable angina cannot easily be differentiated at hospital admission and, therefore, are treated in a similiar way. Non-Q wave infarction and unstable angina are called acute coronary syndromes (ACS). The initial approach to patients with ACS is urgent admission to emergency care, where haemodynamic and ECG monitoring is warranted and usually done in the ambulance or emergency department of a hospital. After monitoring and venous access is installed, rapid general and causal treatment is initiated. General treatment consists of pain relief and limitation of myocardial ischaemia. More causal treatment is the institution of antithrombotic therapy. Pain relief can be achieved by nitroglycerin, but is mostly guaranteed with morphine. Anti-ischaemic therapy is aimed at decreasing the ischaemic burden in order to prevent myocardial necrosis. Antithrombotic therapy is given to inhibit clot formation and propagation. In case of suspected total coronary occlusion, for example, in transmural myocardial ischaemia (ST elevation on admission ECG), clot lysis1White HD Van de Werf FJJ Thrombolysis for acute myocardial infarction.Circulation. 1998; 97: 1632-1646Crossref PubMed Scopus (195) Google Scholar or clot destruction2Weaver WD Simes RJ Betriu A et al.Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review.JAMA. 1997; 278: 2093-2098Crossref PubMed Google Scholar is the main goal. In cases of non-transmural myocardial ischaemia, such as in ACS, only drugs that interfere with clot formation and propagation are given as antithrombotic treatment. After these treatments, most patients become free of symptoms. When signs and symptoms of myocardial ischaemia recur, patients usually undergo cardiac catheterisation and subsequent revascularisation, when feasible. Whether a systemic invasive approach is preferable over a selective invasive strategy in patients with ACS, is still a matter of intense debate, which I discuss elsewhere in this supplement. Thus, the general principles of the early pharmacological approach of ACS consist of anti-ischaemic and antithrombotic therapy. Anti-ischaemic treatment of ACS is meant to diminish or abort myocardial ischaemia. Several classes of agents are currently used for this purpose. The most common drug given in the acute treatment of myocardial ischaemia is nitroglycerin. Because of its intense dilating effects on veins and, in higher doses, also on arterioles, preload and afterload of the heart are decreased and, therefore, oxygen demand decreases, which leads to cessation or decrease of myocardial ischaemia. Also, coronary artery dilatation is achieved, but whether this is effective in relieving ischaemia and preventing infarction and death in patients with ACS and fixed coronary artery stenoses is unclear. The agent is also used as a diagnostic tool. For prophylaxis of myocardial ischaemia and the acute treatment of ischaemia in ambulatory patients, buccal nitroglycerin or nitroglycerin mouth spray are used. In ACS, intravenous nitroglycerin is given both as acute treatment and as maintenance infusion. Nitroglycerin dose is usually titrated either on symptoms or on haemodynamic parameters such as heart rate and blood pressure. The major drawback of nitroglycerin therapy is the rapid development of tolerance. Many patients complain of headache during nitroglycerin infusion. Rebound at withdrawal is not seen. Although used in every coronary unit, little is known of the efficacy of nitroglycerin in the prevention of death and (recurrent) myocardial infarction in ACS (table 1). Only trials with myocardial infarction,3Gruppo per lo Studio della Sopravvivenza nell'Infarto MiocardicoGISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-weeks mortality and ventricular function after acute myocardial infarction.Lancet. 1994; 343: 1115-1122PubMed Google Scholar, 4Fourth International Study of Infarct Survival Collaborative GroupISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction.Lancet. 1995; 345: 669-685Crossref PubMed Scopus (1888) Google Scholar and none with unstable angina, exist. Two large trials studied all types of infarction. In ISIS-44Fourth International Study of Infarct Survival Collaborative GroupISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction.Lancet. 1995; 345: 669-685Crossref PubMed Scopus (1888) Google Scholar, separate data are available on patients without ST-segment elevation and without bundle branch block. Their mortality was 5·3% (277 of 5199) for nitrate and 5·5% (285 of 5199) for placebo (relative risk 0·97, p=0·76). The effects of early nitrate treatment on short-term mortality were minimal and do not warrant routine nitrate treatment in ACS. However, this treatment is commonly used everywhere in the world.Table 1Large randomised placebo-controlled studies of anti-ischaemic treatment on early outcome in ACSStudyYearNumber of patientsMortality (%)Relative riskpFollow-up(days)TreatmentControlNitratesGISSI-33Gruppo per lo Studio della Sopravvivenza nell'Infarto MiocardicoGISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-weeks mortality and ventricular function after acute myocardial infarction.Lancet. 1994; 343: 1115-1122PubMed Google Scholar*Nitroglycerin patches,199418 8956·56·90·940·2836ISIS-44Fourth International Study of Infarct Survival Collaborative GroupISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction.Lancet. 1995; 345: 669-685Crossref PubMed Scopus (1888) Google Scholar†Isosorbide dinitrate tablets.199558 0507·37·50·970·3035β-blockersMIAMI6The MIAMI Trial Research GroupMetoprolol in acute myocardial infarction (MIAMI).in: A randomized placebo-controlled international trial. Eur Heart J. 6. 1985: 199-226Google Scholar198555784·34·90·880·2915ISIS-17First International Study of Infarct Survival Collaborative Group(ISIS 1).in: Randomized trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction. Lancet. ii. 1986: 57-65Google Scholar198616·0273·94·60·80·047Calcium-entry blockersMeta-analysis9Held PH Yusuf S Furberg CD Calcium channel blockers in acute myocardial infarction and unstable angina: an overview of randomized trials.BMJ. 1989; 299: 1187-1192Crossref PubMed Scopus (384) Google Scholar198973515·95·21·140·232–42* Nitroglycerin patches,† Isosorbide dinitrate tablets. Open table in a new tab β-adrenoceptor antagonists lower heart rate, blood pressure, and myocardial contractility. Besides hypertension, their main use is in ischaemic heart disease. The earliest studies were aimed at angina. Later, beneficial effects were found in secondary prevention after myocardial infarction.5Yusuf S Peto R Lewis J Collins R Sleight P Beta-blockade during and after myocardial infarction: an overview of the randomized trials.Prog Cardiovasc Dis. 1985; 27: 335-371Summary Full Text PDF PubMed Scopus (2607) Google Scholar Trials in acute myocardial infarction6The MIAMI Trial Research GroupMetoprolol in acute myocardial infarction (MIAMI).in: A randomized placebo-controlled international trial. Eur Heart J. 6. 1985: 199-226Google Scholar, 7First International Study of Infarct Survival Collaborative Group(ISIS 1).in: Randomized trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction. Lancet. ii. 1986: 57-65Google Scholar are given in table 1. No large-scale studies in unstable angina and non-Q wave infarction are available. β;-blockers lower early infarction mortality by 10–15%. Prevention of malignant ventricular arrhythmia, reinfarction, and possibly myocardial rupture8ISIS-1 (First International Study of Infarct Survival) Collaborative GroupMechanism for the early mortality reduction produced by beta-blockade started early in acute myocardial infarction: ISIS-1.Lancet. 1988; i: 921-923Google Scholar are the mechanisms involved. Major side-effects of β-blockers in acute myocardial infarction are rare. Calcium antagonists also lower blood pressure and myocardial contractility, but in general do not affect heart rate, the most important determinant of myocardial oxygen consumption. These agents have an anti-ischaemic effect in stable coronary artery disease. In ACS, their effect is neutral or even counterproductive9Held PH Yusuf S Furberg CD Calcium channel blockers in acute myocardial infarction and unstable angina: an overview of randomized trials.BMJ. 1989; 299: 1187-1192Crossref PubMed Scopus (384) Google Scholar (table 1). Yet calcium antagonists are still used in many patients with unstable angina and myocardial infarction. Concomitant therapy with β-blockers may counteract their potentially harmful effect.10HINT Early treatment of unstable angina in the coronary care unit: a randomised, double blind, placebo controlled comparison of recurrent ischaemia in patient treated with nifedipine or metoprolol or both.Br Heart J. 1986; 56: 400-413Crossref PubMed Scopus (266) Google Scholar Thus, the anti-ischaemic component of drug treatment of ACS should be nitroglycerin (pain relief) and β- blockers (reduction of myocardial ischaemia or infarction and cardiac mortality). Monotherapy with calcium antagonists should be avoided. Antithrombotic therapy for ACS potentially consists of anticoagulants (heparin, hirudin, coumadin), thrombolytics, and antiplatetet therapy, and is aimed at inhibition of clot formation and propagation and at lysis. The anticoagulant used most in ACS is heparin. Heparin exerts its antithrombotic effect through its stimulating effect of antithrombin-III. Therefore, it is an indirect thrombin inhibitor. Hirudin is a direct thrombin inhibitor and does not need antithrombin-III for its effects. Intravenous heparin rapidly decreases thrombin activity in plasma, but it has a large variability in dose response within and between individuals. The effect of heparin is usually measured by the prolongation of the activated partial thromboplastin time (aPTT). The therapeutic range is thought to be an aPTT of 60–90 s. Unfractionated heparin has been tested in ACS in six randomised controlled trials of moderate size (table 2) and found to be marginally more effective11Oler A Whooley MA Oler J Grady D Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis.JAMA. 1996; 276: 811-815Crossref PubMed Google Scholar than antiplatelet therapy alone (aspirin, see below) with an acceptable risk of major bleeding (1·5% vs 0·4% for aspirin alone). A rebound phenomenon is observed after unfractionated heparin is discontinued, against which aspirin is partially effective.12Theroux P Waters D Lam J Juneau M McCans J Reactivation of unstable angina after the discontinuation of heparin.N Engl J Med. 1992; 327: 141-145Crossref PubMed Scopus (443) Google Scholar Low-molecular-weight heparin consists of the smaller molecules of the compounds of which heparin is a mixture. The pharmacological response (anti-Xa activity) is more predictable and does not need aPTT monitoring. Furthermore, the agent can be given subcutaneously, which makes use in outpatients possible. Low-molecular-weight heparin together with aspirin is much more effective than aspirin alone13FRISC Study GroupLow-molecular-weight heparin during instability in coronary artery disease.Lancet. 1996; 347: 561-568Crossref PubMed Scopus (646) Google Scholar and is at least as effective as unfractionated heparin14Klein W Buckwald A Hillis SE et al.Comparison of low molecular weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease.in: Fragmen in unstable coronary artery disease study (FRIC). Circulation. 96. 1997: 61-68Google Scholar, 15Cohen M Demers C Gurfinkel EP et al.A comparison of low-molecular weight heparin with unfractionated heparin for unstable coronary artery disease.N Engl J Med. 1997; 337: 447-452Crossref PubMed Scopus (1398) Google Scholar, 16Antman EA The TIMI-11B study.in: Presented 20th Congress of the European Society of Cardiology, Vienna August, 1998Google Scholar, 17Leizorovicz A The FRAXIS study Presented 20th Congress of the European Society of Cardiology, Vienna August, 1998Google Scholar (table 2). Through its ease of administration and lack of need for monitoring it has become the preferred anticoagulant treatment in ACS. Hirudin has also a predictable dose response. A rebound is also possible with hirudin.18Serruys PW Herrman JP Simon R et al.A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty.N Engl J Med. 1995; 333: 757-763Crossref PubMed Scopus (406) Google Scholar Large clinical trials do not show a significant benefit for hirudin over unfractionated heparin19GUSTO-IIb InvestigatorsA comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes.N Engl J Med. 1996; 335: 775-782Crossref PubMed Scopus (816) Google Scholar, 20Yusuf S The OASIS-2 study.in: Presented 20th Congress of the European Society of Cardiology, Vienna August, 1998Google Scholar (table 3). Because it is expensive, hirudin is not a useful anticoagulant in ACS. Oral anticoagulants indirectly inhibit thrombin activity by inhibition of the formation of several clotting factors, one of which is prothrombin. These agents are not commonly used in ACS, since evidence of efficacy from large trials is not available.Table 2Large randomised placebo-controlled studies of anticoagulant treatment on early outcome in ACSStudyYearNumber of patientsMortality (%)Relative riskpFollow-up(days)TreatmentControlUnfractionated heparinMeta-analysisi11Oler A Whooley MA Oler J Grady D Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis.JAMA. 1996; 276: 811-815Crossref PubMed Google Scholar199413536·56·90·940·062–7Low-molecular-weight heparinFRISC-113FRISC Study GroupLow-molecular-weight heparin during instability in coronary artery disease.Lancet. 1996; 347: 561-568Crossref PubMed Scopus (646) Google Scholar199615061·83·80·370·0016 Open table in a new tab Table 3Large randomised unfractionated heparin controlled studies of new anticoagulant treatment in ACSStudyYearNumber of patientsMortality (%)Relative riskpFollow-up (days)TreatmentControlLow-molecular-weight heparinFRISC14Klein W Buckwald A Hillis SE et al.Comparison of low molecular weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease.in: Fragmen in unstable coronary artery disease study (FRIC). Circulation. 96. 1997: 61-68Google Scholar199714823·93·61·080·336ESSENCE15Cohen M Demers C Gurfinkel EP et al.A comparison of low-molecular weight heparin with unfractionated heparin for unstable coronary artery disease.N Engl J Med. 1997; 337: 447-452Crossref PubMed Scopus (1398) Google Scholar199731716·27·70·800·0830TIMI-11B16Antman EA The TIMI-11B study.in: Presented 20th Congress of the European Society of Cardiology, Vienna August, 1998Google Scholar199839405·76·80·830·1514FRAXIS17Leizorovicz A The FRAXIS study Presented 20th Congress of the European Society of Cardiology, Vienna August, 1998Google Scholar199834688·87·91·100·4690HirudinGUSTO-IIb19GUSTO-IIb InvestigatorsA comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes.N Engl J Med. 1996; 335: 775-782Crossref PubMed Scopus (816) Google Scholar199680118·39·10·900·2230OASIS-220Yusuf S The OASIS-2 study.in: Presented 20th Congress of the European Society of Cardiology, Vienna August, 1998Google Scholar199810 1413·54·20·830·067 Open table in a new tab Thrombolytic therapy is aimed at plasminogen activation at the site of the thrombotic occlusion during the early hours of acute transmural myocardial infarction. Besides lysis of fibrinogen, plasmin also splits several important clotting factors such as prothrombin. When prothrombin is split, thrombin generation occurs and this has strong procoagulant effects. Although the procoagulant effect of thrombolysis can be diminished by concomitant heparin therapy, the nature of heparin therapy with its unpredictable efficacy and risk of bleeding makes complete abolistion of the procoagulant effect of thrombolytic therapy unsure. Since only a few patients with ACS have a total thrombotic coronary occlusion, reperfusion therapy is not indicated and may even be harmful through its procoagulant effect. In several trials of thrombolytic therapy in ACS, bleeding and thrombotic complications have made this therapy unpopular.21TIMI-IIIB InvestigatorsEffects of tissue plasminogen activator and a comparison of early invasive and consecutive strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI-IIIB trial.Circulation. 1994; 89: 1545-1556Crossref PubMed Scopus (976) Google Scholar The most effective treatment strategy in ACS is antiplatelet therapy. Platelet inhibitors affect the aggregative properties of blood platelets. Aspirin inhibits the activity of cyclo-oxygenase in all body cells. Since platelets do not have a nucleus, cyclo-oxygenase cannot be formed after the platelets have been in contact with aspirin and the platelets are not able to produce thromboxane A2, the proaggregatory platelet-specific prostaglandin, during its lifespan (median 8 days), while the other body cells rapidly increase production of cyclo-oxygenase after contact with aspirin. There is no tolerance with aspirin and there is no rebound effect observed in patients who are on chronic aspirin therapy.22Pedersen AK Fitzgerald GA Dose-related kinetics of aspirin Presystemic acetylation of platelet cyclooxygenasc.N Engl J Med. 1984; 311: 1206-1211Crossref PubMed Scopus (453) Google Scholar Spontaneous life-threatening bleeding with aspirin is rare. Five important trials performed in the 1970s and the 1980s of patients with ACS showed a reduction of myocardial infarction and death of up to 70%23Lewis IID Davis JW Archibald DG et al.Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina.N Engl J Med. 1983; 309: 396-403Crossref PubMed Scopus (1371) Google Scholar, 24Cairns JA Gent M Singer J et al.Aspirin, sulfinpyrazone, or both in unstable angina.N Engl J Med. 1985; 313: 1369-1375Crossref PubMed Scopus (885) Google Scholar, 25ISIS-2 (Second International Study in Infarct Survival) Collaborative GroupRandomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.Lancet. 1988; ii: 349-360Google Scholar, 26Theroux P Ouimet H McCans J et al.Aspirin, heparin, or both to treat acute unstable angina.N Engl J Med. 1988; 319: 1105-1111Crossref PubMed Scopus (1125) Google Scholar, 27The RISC GroupRisk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.Lancet. 1990; 336: 827-830Summary PubMed Scopus (897) Google Scholar (table 4). Since aspirin is inexpensive, it is very cost-effective.Table 4Large randomised placebo-controlled studies of antiplatelet therapy in acute coronary syndromeStudyYearNumber of patientsDeath/(re) MI (%)Relative riskpFollow-up (days)TreatmentControlAspirinVA23Lewis IID Davis JW Archibald DG et al.Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina.N Engl J Med. 1983; 309: 396-403Crossref PubMed Scopus (1371) Google Scholar198313426·410·80·590·00484Cairns24Cairns JA Gent M Singer J et al.Aspirin, sulfinpyrazone, or both in unstable angina.N Engl J Med. 1985; 313: 1369-1375Crossref PubMed Scopus (885) Google Scholar19855558·617·00·480·001730ISIS-225ISIS-2 (Second International Study in Infarct Survival) Collaborative GroupRandomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.Lancet. 1988; ii: 349-360Google Scholar*Suspected acute myocardial infarction without ST-elevationor bundle branch block. MI=myocardial infarction.198854097·38·20·890·2235Theroux26Theroux P Ouimet H McCans J et al.Aspirin, heparin, or both to treat acute unstable angina.N Engl J Med. 1988; 319: 1105-1111Crossref PubMed Scopus (1125) Google Scholar19882393·311·90·290·016RISC27The RISC GroupRisk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.Lancet. 1990; 336: 827-830Summary PubMed Scopus (897) Google Scholar19907966·517·10·380·00130TiclopidineBalsano28Balsano F Rizzon P Violi F et al.Antiplatelet treatment with ticlopidine in unstable angina.in: A controlled multicenter clinical trial. Circulation. 82. 1990: 17-26Google Scholar19906824·56·20·720·4130Glycoprotein IIb/IIa receptor antagonistsPARAGON29PARAGON InvestigatorsInternational, randomized, controlled trial of lamifiban (a glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina.Circulation. 1998; 97: 2386-2395Crossref PubMed Scopus (439) Google Scholar†All on aspirin and unfractionated heparin.1998228211·311·70·970·8030PRISM30PRISM Study InvestigatorsA comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina.N Engl J Med. 1998; 338: 1498-1505Crossref PubMed Scopus (987) Google Scholar‡All patients on aspirin. Unfractionated heparin as control to glycoprotein blocker.199832325·87·10·800·1130PRISM-PLUS31PRISM-PLUS Study InvestigatorsInhibition of platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q wave myocardial infarction.N Engl J Med. 1998; 338: 1488-14973Crossref PubMed Scopus (1635) Google Scholar†All on aspirin and unfractionated heparin.199819158·711·90·730·0330PURSUIT32PURSUIT InvestigatorsInhibition of platelet glycoprotein IIb/IIIa with eptifibaride in patients with acute coroanry sydromes.N Engl J Med. 1998; 339: 436-443Crossref PubMed Scopus (1693) Google Scholar†All on aspirin and unfractionated heparin.19941094814·215·70·900·0430* Suspected acute myocardial infarction without ST-elevationor bundle branch block. MI=myocardial infarction.† All on aspirin and unfractionated heparin.‡ All patients on aspirin. Unfractionated heparin as control to glycoprotein blocker. Open table in a new tab The second-generation platelet inhibitors are the thienopyridines, ticlopidine and clopidogrel. Ticlopidine inhibits the ADP receptor on the platelet surface and does not interfere with the cyclo-oxygenase pathway inhibition by aspirin. Ticlopidine prolongs bleeding time beyond that of aspirin. Contrary to aspirin, the effect of ticlopidine takes several days to develop and also takes several days to disappear after discontinuation of ticlopidine. Ticlopidine is indicated in patients who have undergone coronary stenting and there has been one large study of ticlopidine in unstable angina28Balsano F Rizzon P Violi F et al.Antiplatelet treatment with ticlopidine in unstable angina.in: A controlled multicenter clinical trial. Circulation. 82. 1990: 17-26Google Scholar (table 4). A rebound effect of ticlopidine has not been observed. Because of the sometimes severe haematological and dermatological side-effects of ticlopidine, the agent will be replaced by clopidogrel in the near fututre. The third-generation platelet inhibitors are the glycoprotein IIb/IIIa-receptor antagonists. These inhibitors specifically inhibit the fibrinogen receptor on the platelet, which is the instrument of the final common pathway of platelet aggregation. Both monoclonal antibodies (abciximab) and non-antibody compounds (tirofiban, eptifibatide, and lamifiban) may achieve this inhibition. The agents increase bleeding time. The monoclonal antibody achieves an irreversible binding to the receptor and the non-antibody compounds a competitive one. After discontinuation of these intravenous drugs, the effects on platelets disappear within hours. These inhibitors are indicated in interventional cardiology. In ACS they show a reduction of myocardial infarction and death up to 25% compared with aspirin and heparin alone29PARAGON InvestigatorsInternational, randomized, controlled trial of lamifiban (a glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina.Circulation. 1998; 97: 2386-2395Crossref PubMed Scopus (439) Google Scholar, 30PRISM Study InvestigatorsA comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina.N Engl J Med. 1998; 338: 1498-1505Crossref PubMed Scopus (987) Google Scholar, 31PRISM-PLUS Study InvestigatorsInhibition of platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q wave myocardial infarction.N Engl J Med. 1998; 338: 1488-14973Crossref PubMed Scopus (1635) Google Scholar, 32PURSUIT InvestigatorsInhibition of platelet glycoprotein IIb/IIIa with eptifibaride in patients with acute coroanry sydromes.N Engl J Med. 1998; 339: 436-443Crossref PubMed Scopus (1693) Google Scholar (table 4). Their beneficial effects are seen in patients undergoing coronary interventions and in those without interventions. The rate of severe bleeding with these drugs is acceptable. The agents are expensive (up to US$1000 per treatment), which is prohibitive for routine use, and their cost-effectiveness over aspirin and heparin is not yet established. Oral glycoprotein IIb/IIIa blockers have a longer plasma half-life. Xemilofiban and lefradafiban have been recently tested in ACS, but the preliminary results are disappointing with regard to efficacy and safety33Cannon CP OPUSTIMI-16 study.in: Presented 48th Annual Scientific Session American College of Cardiology, New Orleans March, 1999Google Scholar, 34Wilcox RG The FROST study.in: Presented 48th Annual Scientific Session American College of Cardiology, New Orleans March, 1999Google Scholar. Thus, antithrombotic treatment of ACS consists of aspirin and (low-molecular-weight) heparin. Glycoprotein blockers on top of this may be used in high-risk individuals, especially if they undergo angioplasty. Thrombolytic therapy is not indicated in ACS. After the acute episode, patients are protected against recurrent ischaemic events with continuation of both anti-ischaemic and antithrombotic treatments (β-blockade with or without nitrates and aspirin). Lifelong aspirin is usually advised, but anti-ischaemic drugs may be discontinued, when ischaemia provocation tests are negative during outpatient clinic visits. Other preventive measures include smoking cessation and lowering of plasma cholesterol by statin therapy, irrespective of blood lipid concentrations at hospital admission.35Scandinavian Simvastatin Survival GroupRandomised trial of cholesterol lowering in 4444 patients with coronary heart disease: Scandinavian Simvastatin Survival Study.Lancet. 1994; 344 (AS): 1383-1389PubMed Google Scholar, 36Sacks FM Pfeffer MA Moye LA et al.The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.in: Cholesterol And Recurrent Events (CARE) Trial investigators. N Engl J Med. 1996: 335Google Scholar The new antithrombotic agents, low-molecular-weight heparin, and the glycoprotein IIb/IIIa receptor antagonists, although effective separately, have not been tested in combination. They may have a synergistic effect, but may also increase bleeding. Randomised trials are currently underway to address this issue. One of the problems of the current and future studies is the sharp increase in routine early interventional procedures, which may obscure the benefit of new drugs or drug combinations and may exaggerate their risk of bleeding. The field of pharmacological treatment of ACS is dynamic. Currently, the effect of clopidogrel plus aspirin versus aspirin alone is being tested in a megatrial (CURE study), as are abciximab (GUSTO-4), the oral glycoprotein IIb/IIIa receptor antagonist sibrafiban (SYMPHONY trials), and warfarin (OASIS-2 and ASPECT-2). New anticoagulants include pentasaccharides and oral Xa antagonists, both of which will shortly undergo testing in randomised clinical trials. Early treatment of acute coronary syndrome is increasingly focused on pacitication of the ruptured atheromatous coronary plaque. Early high-dose statin therapy may achieve this goal and these agents are currently being tested in large randomised trials in the early days of ACS. Other candidate agents that may improve endothelial function in ACS are folic acid and inhibitors of angiotensin-converting enzyme, none of which have so far been tested in large randomised studies in patients with unstable coronary artery disease.