Acute coronary syndromes: Drug treatments

THE LANCET

Acute coronary syndromes: drug treatments

Freek W A Verheugt Introduction 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. I n 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. N o n - Q wave infarction and unstable angina are called acute coronary syndromes

(ACS). General principles The initial approach to patients with ACS is urgent admission to emergency care, where haemodynamic and E C G 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 lysis~ or clot destruction2 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

Lancet 1999; 353 (suppl II): 2 0 - 2 3 Heartcenter, Department of Cardiology,University Hospital, PO Box 9101, 6500 HB Nijmegen, Netherlands (F W A VerheugtMD) Correspondenceto: Prof Freek W A VerheugL (e-mail: f.verheugt@ca rdio.azn.nl)

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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 therapy Anti-ischaemic treatment of ACS is meant to diminish or abort myocardial ischaemia. Several classes of agents are currently used for this purpose.

Nitrates The most common drug given in tl~e acute treatment of myocardial ischaemia is nitroglycerin. Because of its intense dilating effects on veins and, in higher doses, also on arterioles, preload and aftedoad 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,3'4 and none with unstable angina, exist. Two large trials studied all types of infarction. In ISIS-44, 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.

13-blockers 13-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.~ Trials in acute myocardial infarction6'7 are given in table 1. No large-scale studies in unstable angina and n o n - Q wave infarction are available. B-blockers lower early infarction mortality by 10-15%. Prevention of malignant ventricular arrhythmia, reinfarction, and possibly myocardial rupture 8 are the ACS. 353 • June • 999

THE LANCET Study

Year

Numberof patients Mortality (%) Treatment

Control

Relative risk

p

Follow-up(days)

Nitrates GiSSI-33. ISIS-44¢

1994 1995

18 895 58 050

6.5 7.3

6.9 7.5

0~94 0.97

0.28 0.30

36 35

1985 1986

5578 16 02T

4-3 3.9

4.9 4.6

0.88 0.8

0.29 0.04

15 7

1989

7351

5.9

5.2

1.14

0.23

[~-blockers MIAMI6 ISIS-17

Calcium-entryblockers Meta-analysis9

2-42

Table 1: Large randomised placebo-controlled studies of anti-ischaemic treatment on early outcome in ACS *Nitroglycerin patches, tlsosorbide dinitrate tablets.

mechanisms involved. Major side-effects of [3-blockers in acute myocardial infarction are rare.

Calcium-entry blockers 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 counterproductive9 (table 1). Yet calcium antagonists are still used in many patients with unstable angina and myocardial infarction. Concomitant therapy with [3-blockers may counteract their potentially harmful effect? 8 Thus, the anti-ischaemic component of drug treatment of ACS should be nitroglycerin (pain relief) and [3blockers (reduction of myocardial ischaemia or infarction and cardiac mortality). Monotherapy with calcium antagonists should be avoided. Antithrombotic

therapy

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.

Anticoagulants 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 a P T T 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 effective'~ than antiplatelet therapy alone (aspirin, see below) with an acceptable risk of major bleeding (1.5% v s 0.4% for aspirin alone). A rebound phenomenon is observed after unfractionated heparin is discontinued, against which Study

Year

aspirin is partially effective. '2 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 a P T T monitoring. Furthermore, the agent can be given subcutaneously, which makes use in outpatients possible. Low-molecularweight heparin together with aspirin is much more effective than aspirin alone '3 and is at least as effective as unfractionated heparin 1~-~7(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. ~8 Large clinical trials do not show a significant benefit for hirudin over unfractionated heparin ~9,2° (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.

Thrombolysis Thrombolytic therapy is aimed at plasminogen activation at the site of the thrombotic occlusion during the early hours of acute transmural myocardial infarction. Besides tysis 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. 21

Antiplatelet therapy The most effective treatment strategy in ACS is antiplatelet therapy. Platelet inhibitors affect the aggregative properties of blood platelets. Aspirin inhibits

Number of patients Mortality (%)

Relative risk

p

Follow-up(days)

6.9

0.94

0.06

2-7

3.8

0.37

0.001

6

Treatment

Control

6,5

Unfractlonatedheparin Meta-analysisi l

1994

1353

1996

1506

Low-molecular-weighthepadn FRISC-1~3

Table 2: Large randomised placebo-controlled studies of

ACS • 353 • June • 1999

1-8

anticoagulant

t r e a t m e n t on early outcome in ACS

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THE

LANCET

Study

Year

Number of patients Mortality (%) Treatment

Control

Relative risk

p

Follow-up (days)

Low-molecular-weight heparin FRISC14 ESSENCE15 TIMI-11B16 FRAXISlz

1997 1997 1998 1998

1482 3171 3940 3468

3.9 6.2 5,7 8.8

3.6 7.7 6.8 7-9

1.08 0.80 0.83 1.10

0.33 0.08 0.15 0.46

6 30 14 90

1996 1998

8011 10 141

8,3 3.5

9.1 4-2

0.90 0.83

0.22 0.06

30 7

Hirudin GUSTO-lib19 OASIS-22°

Table 3: Large randomised unfractionated heparin controlled studies of new anticoagulant treatment in ACS

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. 22 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% ~327 (table 4). Since aspirin is inexpensive, it is very costeffective. 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 angina28 (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 Study

Year

Number of patients

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 tiaey show a reduction of myocardial infarction and death up to 25% compared with aspirin and heparin alone29-32 (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 costeffectiveness 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 s a f e t y 33'34.Thus, antithrombotic treatment of ACS consists of aspirin and (low-molecular-weight) heparin. Glycoprotein blockers on top of this may be used in highrisk individuals, especially if they undergo angioplasty. Thrombolytic therapy is not indicated in ACS. Secondary

prevention

After the acute episode, patients are protected against recurrent ischaemic events with continuation of both antiischaemic and antithrombotic treatments ([3-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 admission2TM

Death/(re) MI (%) Treatment

Relative risk

p

Follow-up (days)

Control

Aspirin VA23

Cairns24 ISIS-225. Theroux26 RISC27

1983 1985 1988 1988 1990

1342 555 5409 239 796

6.4 8.6 7.3 3.3 6.5

10.8 17.0 8.2 11.9 17.1

0.59 0.48 0,89 0.29 0.38

0.004 0.001 0.22 0.01 0.001

84 730 35 6 30

1990

682

4-5

6.2

0.72

0.41

30

1998 1998 1998 1994

2282 3232 1915 10948

11.3 5-8 8-7 14.2

11.7 7.1 11-9 15.7

0.97 0.80 0-73 0.90

0-80 0.11 0-03 0.04

30 30 30 30

Ticlopidine Balsano28

Glycoprotein lib/Ilia receptor antagonists PARAGON29t PRISM3°:~ PRISM-PLUS3"tt PURSUIT321"

Table 4: Large randomised placebo-controlled studies of antiplatelet therapy in acute coronary syndrome *Suspected acute myocardial infarction without ST-elevationor bundle branch block. Ml=myocardial infarcLion, tAll on aspirin and unfractionated hepafin. :~AIIpatients on aspirin. Unfractionated heparin as control to glycoprotein blocker.

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ACS • 353 • June • 1999

THE LANCET

Future directions 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. References 1 White H D , Van de Werf FJJ. Thrombolysis for acute myocardial infarction. Circulation 1998; 9 7 : 1 6 3 2 46. 2 WeaverWD, Simes RJ, Betrin A, et al. Comparison of primary coronary angioplasty a n d intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review, ffAMA 1997; 278: 2093 98. 3 G r u p p o per lo Studio della Sopravvivenza nell'Infarto Miocardico. GISSI-3: effects of lisinopriI and transdermal glyceryl trinitrate singly a n d together on 6-weeks mortality and ventricular function after acute myocardial infarction. Lancet 1994; 3 4 3 : 1 1 1 5 - 2 2 . 4 Fourth International Study of Infarct Survival Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captoprit, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet 1995; 345: 669-85. 5 Yusuf 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; 2 7 : 3 3 5 71. 6 T h e M I A M I Trial Research Group. Metoprolol in acute myocardial infarction (MIAMI). A randomized placebo-controlled international trial. EurHeartJ 1985; 6 : 1 9 9 - 2 2 6 . 7 First International Study of Infarct Survival Collaborative Group. (ISIS 1). Randomized trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction. Lancet 1986; ii: 57-65. 8 ISIS-1 (First International Study of Infarct Survival) Collaborative Group. Mechanism for the early mortality reduction produced by beta-blockade started early in acute myocardial infarction: ISIS-1. Lancet 1988; i: 921-23. 9 Held PH,Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview of randomized trials. BMJ 1989; 2 9 9 : 1 1 8 7 4 2 . 10 HINT. 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 Heartff 1986; 5 6 : 4 0 0 13. 11 Oler A, Whooley/VIA, Oler J, G r a d y D. Adding heparin to aspirin

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13 14

15

16 17 18

19

20 21

22

23

24 25

26 27

28

29

30

31

32

33 34 35

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