Anticoagulants in acute coronary syndromes

Anticoagulants in Acute Coronary Syndromes Alexander G. G. Turpie,

MD

Antithrombotic and antiplatelet agents, particularly unfractionated heparin and aspirin, are longstanding therapeutic mainstays for acute coronary syndromes such as unstable angina and non–Q-wave myocardial infarction (MI). Early studies demonstrated that aspirin reduces the risk of mortality or nonfatal MI by 50 –70% in patients presenting with unstable angina or non–Q-wave MI. Added to aspirin, heparin regimens further diminish the incidence of these myocardial ischemic events in the acute setting. Three major clinical studies demonstrated that such enhanced risk reductions can be achieved without significant increases in bleeding complications. The low-molecular-weight (LMW) heparin, dalteparin, proved superior to placebo but not unfractionated heparin in diminishing the incidence of (1) death or MI; (2) death, MI, or recurrence of angina; or (3) frequency of revascularization procedures. On the other hand, another LMW heparin, enoxaparin, did reduce these events at 14 and 30 days, as well as 1 year after treatment. The principal biophysical limitation of heparins, however, is that they cannot inactivate clot-bound thrombin, which probably contributes to morbidity and

mortality in acute coronary syndromes. The natural leech-derived polypeptide hirudin and its derivatives (e.g., lepirudin) inactivate both fibrin-bound and free thrombin. Lepirudin has been approved in certain countries for the treatment of heparin-induced thrombocytopenia and is now being evaluated in the clinical management of acute myocardial ischemic syndromes. The well-documented pathophysiologic foundation for acute coronary syndromes is partial or intermittent thrombotic occlusion of a coronary artery as the result of atherosclerosis. Although a stable atherosclerotic plaque may not be clinically problematic, plaque rupture, which occurs under a variety of stimuli, touches off a cascade of enzymatic and cellular responses that frequently culminate in thrombotic occlusion. In the coronary circulation, such an occlusion may cause transmural MI, unstable angina, or non–Q-wave MI. Because the pathogenetic mechanisms of atherosclerosis with thrombotic complications have been elucidated, this knowledge can be translated into a rational clinical approach using antithrombotic therapies. 䊚1999 by Excerpta Medica, Inc. Am J Cardiol 1999;84:2M– 6M

he first intervention in diminishing acute coronary syndromes is a preventive strategy to avoid vasT cular injury. Thrombogenesis is frequently precipi-

tients should also receive intravenous unfractionated heparin to prolong the activated partial thromboplastin time (aPTT) to therapeutic levels (1.5–2.5 ⫻ control) for 3– 4 days. For those who are aspirin intolerant, the ACCP recommended the platelet inhibitor ticlopidine (250 mg, twice daily), or warfarin for those in whom either aspirin or ticlopidine is contraindicated. At the recent fifth conference of the ACCP,2 low-molecularweight (LMW) heparins were introduced as therapeutic alternatives to intravenous unfractionated heparin. Aspirin: Well-designed placebo-controlled studies3– 6 conducted between 1983 and 1993 demonstrated that aspirin statistically significantly diminished the risk of mortality or nonfatal myocardial infarction (MI) from 50% to ⬎70% in patients presenting with unstable angina or non–Q-wave MI (Table I). Before the use of aspirin in this setting, about 15 of every 100 patients with unstable angina either died or had an MI, whereas after its advent, this proportion was reduced to about 6 or 7 per 100. Unfractionated heparin: Generation of thrombin is well established as a pivotal step in the pathogenesis of coronary thrombosis. Thrombin converts fibrinogen to fibrin. Once fibrin forms, thrombin attaches to its surface and amplifies its own generation 3–500-fold through activation of factors V and VIII. Thrombin is, of course, one of the most potent physiologic activators of platelet function; thus, much of the pharmaceutical focus has been directed toward inhibiting thrombin. The prototype anticoagulant is unfractionated hep-

tated by vascular endothelial injury, which exposes thrombogenic subendothelial proteins (e.g., collagen) and may contribute to erosion in plaque stability and, ultimately, plaque fissure or rupture. Although the prevalence of acute coronary syndromes has been decreased by reducing cardiovascular risk factors such as hypercholesterolemia, cigarette smoking, and hypertension, these syndromes remain the most common causes of cardiac morbidity and mortality. The second point of attack is to attenuate platelet adhesion and aggregation. Third, antithrombotic agents may be effective by inhibiting thrombin generation and subsequent fibrin formation. Finally, fibrinolytic agents (e.g., tissue-type plasminogen activator, streptokinase) have found clinical utility in promoting plasmin generation (Figure 1).

THERAPEUTIC ALTERNATIVES Upon review of the existing evidence on the use of antithrombotic agents in the management of unstable angina, the American College of Chest Physicians (ACCP)1 recommended that patients who present with this complaint should receive aspirin (160 –325 mg/ day) indefinitely. According to the ACCP, most paFrom McMaster University, Hamilton, Ontario, Canada. Address for reprints: Alexander G. G. Turpie, MD, HHSC-General Division 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2.

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©1999 by Excerpta Medica, Inc. All rights reserved.

0002-9149/99/$20.00 PII S0002-9149(99)00490-7

FIGURE 1. Schematic representation of broad avenues of attack in acute coronary thrombotic syndromes.

TABLE I Reduction in the Incidence of Fatal or Nonfatal Myocardial Infarction in 4 Placebo-Controlled Aspirin Studies

Study 3

Lewis et al Cairns et al4 The´roux et al5 RISC group6

Placebo Incidence (%)

Aspirin Incidence (%)

Reduction (%)

p Value

10.1 17.0 12.0 13.4

5.0 8.6 3.3 4.3

51 57 72 68

0.0005 0.008 0.012 ⬍0.0001

Reproduced with permission from Chest.2

arin, which has been available for approximately 50 years. Heparin mediates thrombin inhibition, in part by inducing a conformational change in antithrombin III at the arginine-reactive center and consequently enhancing thrombin inhibitory activity by about 1,000fold.7 The´roux et al8 at the Montreal Heart Institute conducted a randomized, double-blind study on the use of unfractionated heparin or aspirin to prevent MI in 484 patients with acute unstable angina. Aspirin was administered at a dosage of 325 mg twice daily, whereas heparin was infused as a 5,000-IU bolus, after which the dosage was titrated to maintain aPTT at 1.5–2.5 ⫻ control values. Treatment was instituted upon hospitalization (8.3 ⫾ 7.8 hours after the last episode of pain), and outcomes were assessed at 5.7 ⫾ 3.3 days. The advantage of heparin over aspirin in the acute phase was clearly demonstrated in this trial. Only 2 (0.8%) of 240 patients allocated to unfractionated heparin had an MI, compared with 9 (3.7%) of 244 patients in the aspirin arm (p ⫽ 0.035); risk reduction was thus 78%. Kaplan-Meier hazard plots from a similar study8 demonstrated that patients with unstable angina on maximal antianginal therapy had about a 30% risk of developing an ischemic heart problem. This risk was reduced by approximately 50% with aspirin and 75% with heparin. Discontinuation of heparin at 4 to 5 days led to a sharp increase in the risk of ischemic outcomes. This trend was interpreted as either “anticoagulant rebound,” or “ongoing thrombin generation,” or a combination of these 2 factors. These adverse phenomena were attenuated if patients were maintained and continued on aspirin. Initial concerns that such a combination of an antiplatelet and anticoagulant agent might lead to bleeding diatheses were diminished principally by 3 clinical studies by the Montreal Heart Institute,5 the Research Group on Instability in Coronary Artery Disease (RISC),6 and the Antithrombotic Therapy in

Acute Coronary Syndromes (ATACS) group.9 In these investigations, the risk of death or MI on combination aspirin– heparin was reduced by 56% compared with aspirin alone, and there was no significant increase in risk of clinically significant bleeding.9 Although combination therapy with heparin and aspirin proved effective in reducing the number of fatalities or MIs experienced by unstable angina patients from 15/100 to about 3/100, the clinical benefits accruing using unfractionated heparin were observed chiefly in the acute setting, with some subsequent loss of cardioprotective effect thereafter. Longer term prevention of myocardial ischemic events represents an ongoing challenge in the evolution of antithrombotic treatment. In addition, the use of unfractionated heparin is constrained by certain pharmacokinetic and pharmacologic limitations. Because of these difficulties, 3 new varieties of antithrombotic therapies have been developed: LMW heparins, hirudin, and derivatives of this leech protein. LMW heparins: First introduced for the prevention of thrombosis and venous thromboembolism (for which they have revolutionized clinical management), LMW heparins are attractive therapeutic alternatives because they can be administered subcutaneously, at a fixed dose, and with little attendant need for monitoring aPTT or activated coagulation time. These benefits result from distinct pharmacodynamic and pharmacokinetic advantages of LMW heparins over unfractionated heparin. LMW heparins (e.g., dalteparin, enoxaparin) and nadroparin are now being evaluated in unstable angina and non–Q-wave MI, and the largely favorable findings strongly support their clinical utility in these settings. Dalteparin: In the Fragmin During Instability in Coronary Artery Disease (FRISC) trial,10 a randomized, double-blind, placebo-controlled study involving

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FIGURE 2. Cardiac events in dalteparin and placebo groups in acute care. (Adapted with permission from Lancet.10)

TABLE II Primary Endpoints During Acute-Phase (6 Days) Treatment with Dalteparin Placebo (n ⫽ 757) Death or MI Death, MI, or revascularization Death, MI, revascularization, or heparin

Dalteparin (n ⫽ 741)

Risk Ratio

p Value

36 (4.8%) 43 (5.7%)

13 (1.8%) 16 (2.2%)

0.37 0.38

0.001 ⬍0.001

78 (10.3%)

40 (5.4%)

0.52

⬍0.001

MI ⫽ myocardial infarction. Reproduced with permission from Lancet.10

1,506 patients with unstable angina or non–Q-wave MI, dalteparin was administered at an initial dosage of 120 IU/kg twice daily for the first 6 days, after which patients received 7,500 IU for the next 35– 45 days. Concomitant medications included aspirin (75 mg/ day) and ␤-adrenergic blockers. At 6 days, the LMW heparin-aspirin combination significantly diminished the rates of (1) death or MI; (2) death, MI, or revascularization; and (3) death, MI, revascularization, or the need for intravenous heparin. These reductions ranged from 48 – 63% (Table II). Kaplan–Meier plots of selected findings are shown in Figure 2. On the other hand, at 40 days the dalteparinaspirin regimen reduced the hard endpoints of death or MI nonsignificantly, by 25% (p ⫽ 0.07). The foregoing findings left unanswered the pivotal question of whether LMW heparins are superior to unfractionated heparin in attenuating acute coronary thrombotic syndromes. The Fragmin in Unstable Coronary Artery Disease (FRIC) study by Klein et al11 addressed this matter. A randomized trial, the FRIC study, involving 1,482 patients with either unstable angina or non–Q-wave MI compared open-label acute treatment with the LMW heparin dalteparin (120 IU/kg twice daily) with dose-adjusted intravenous heparin infusions for 6 days; from this juncture to 45 days, patients received either subcutaneous dalteparin 7,500 IU/day or placebo. All patients also received aspirin (75–165 mg/day). Dalteparin was not shown to be different from intravenous unfractionated heparin in terms of the incidences of death or MI; death, MI, or recurrence of 4M THE AMERICAN JOURNAL OF CARDIOLOGY姞

angina in the acute phase; or frequencies of revascularization procedures. On the other hand, the LMW heparin was clearly easier to administer than intravenous heparin, with subcutaneous injections and no necessary monitoring of coagulant function. Rates of bleeding complications were similar to those on unfractionated heparin. A principal objective of this trial was to determine if continuing the LMW heparin at a low dose once per day for ⬎1 month would prevent these adverse coronary events. However, compared with the placebo–aspirin combination, the dalteparin– aspirin regimen did not diminish the foregoing endpoints. Enoxaparin: The LMW heparin enoxaparin proved more effective than intravenous unfractionated heparin in attenuating myocardial ischemic sequelae on the basis of findings from the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events (ESSENCE) trial.12 In this multicenter, randomized, double-blind, placebo-controlled study, 3,171 patients with either angina at rest or non–Qwave MI were treated with either enoxaparin (1 mg/kg twice daily) subcutaneously or therapeutic doses of continuous intravenous unfractionated heparin for 48 hours to 8 days. In addition, all patients received aspirin (100 –325 mg/day). Table III shows that enoxaparin substantially improved the incidence of the triple endpoint of death, MI, or recurrent angina compared with unfractionated heparin. Second, this protective benefit was sustained at both 14 and 30 days. On the other hand, although the incidence of the hard double endpoint (death or

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TABLE III Incidences of Triple Endpoints on Unfractionated Heparin (UFH) or Enoxaparin Treatment Group Time Point

Endpoint

48 Hours

Composite Death MI Recurrent angina Composite Death MI Recurrent angina Composite Death MI Recurrent angina

14 Days

30 Days

UFH (n ⫽ 1,564)

Enoxaparin (n ⫽ 1,607)

115 7 14 99 309 36 70 243 364 57 81 281

99 8 11 83 266 36 51 207 318 47 62 252

(7.4%) (0.4%) (0.9%) (6.3%) (19.8%) (2.3%) (4.5%) (15.5%) (23.3%) (3.6%) (5.2%) (18.0%)

(6.2%) (0.5%) (0.7%) (5.2%) (16.6%) (2.2%) (3.2%) (12.9%) (19.8%) (2.9%) (3.9%) (15.7%)

Risk Reduction

p Value

6.2 ⫺11.2 23.5 18.4 16.2 2.7 29.1 17.1 15.0 19.8 25.5 12.7

0.18 0.83 0.50 0.16 0.02 0.92 0.06 0.03 0.02 0.25 0.08 0.08

MI ⫽ myocardial infarction. Reproduced with permission from N Engl J Med.12

FIGURE 3. Structure of lepirudin, a hirudin derivative. Cys ⴝ cysteine; Leu ⴝ leucine; Lys ⴝ lysine; Tyr ⴝ tyrosine; Val ⴝ valine.

MI) was reduced on enoxaparin, the difference from unfractionated heparin did not reach statistical significance. Follow-up data demonstrated that the 30-day reduction in the triple endpoint was maintained at 1 year, at which the decrease (vs unfractionated heparin) in the incidence of the hard endpoint of death or MI was virtually identical to that at 30 days.13 Although the incidence of minor bleeding was significantly higher (p ⬍0.001) on enoxaparin (11.9%) compared with unfractionated heparin (7.2%), the proportions of patients with major bleeds or stroke were similar. A recent study, Thrombolysis in Myocardial Infarction (TIMI)-11B, confirmed the superiority of enoxaparin over heparin in the management of unstable angina and non–Q-wave MI.14 Hirudin and derivatives: LMW heparins are constrained by biophysical properties similar to their progenitor, unfractionated heparin. First and foremost, they cannot inactivate fibrin-bound thrombin, which is

particularly problematic in that patients often have ongoing ischemic outcomes because thrombin generation persists within the thrombus. Second, neither unfractionated heparin nor LMW heparins can inactivate thrombin bound to the subendothelial matrix. Finally, both types of heparin bind nonspecifically and variably to fibronectin, vitronectin, von Willebrand factor, histidine-rich glycoproteins, and platelet factor 4. To overcome these limitations, investigators have studied the properties of an antithrombotic agent derived from the saliva of the medicinal leech (Hirudo medicinalis): hirudin. This single-chain, 65-amino acid polypeptide has been produced by recombinant technology, and derivatives such as lepirudin, hirugen, and hirulog have also been developed. The chief biophysical advantage of the hirudin category of direct thrombin inhibitors is their ability to inhibit clot-bound thrombin. There are 4 receptors on the surface of thrombin: a substrate-recognition site, a

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catalytic center, a fibrin-binding site, and a heparinbinding site. The heparin-binding locus lies in proximity to the fibrin-binding site. When thrombin binds to fibrin, it renders the heparin-binding site inaccessible to the heparin-antithrombin III complex. Therefore, heparins are unable to inhibit fibrin-bound thrombin. On the other hand, direct thrombin inhibitors such as hirudin, lepirudin, hirugen, and hirulog do not require access to heparin-binding sites and thus can effectively inhibit clot-bound thrombin. An array of hirudin derivatives has been developed through genetic engineering and synthesis. Depicted in Figure 3 is the structure of lepirudin, which has been tested in a number of experimental in vivo models and has been demonstrated to be an effective antithrombotic agent. It has been approved for human use in several countries for patients in need of ongoing antithrombotic therapy who cannot tolerate unfractionated heparin because of heparin-induced thrombocytopenia. Lepirudin has also been evaluated in rigorous clinical trials involving acute coronary syndromes, and the findings of these studies constitute a major aspect of this supplement. 1. Cairns JA, Lewis HD Jr, Meade TW, Sutton GC, The´roux P. Antithrombotic

agents in coronary artery disease. Chest 1995;108(suppl 4):380S– 400S. 2. Cairns JA, The´roux P, Lewis HD Jr, Ezekowitz M, Meade TW, Sutton GC.

Antithrombotic agents in coronary artery disease. Chest 1998;114:611S– 633S. 3. Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty

JE III, Schnaper HW, LeWinter MM, Linares E, Pouget JM, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med 1983;309:396 – 403. 4. Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky

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G, Kostuk WJ, Melendez LJ, Myers MG, et al. Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial. N Engl J Med 1985;313:1369 –1375. 5. The´roux P, Waters D, Qiu S, McCans J, de Guise P, Juneau M. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina. Circulation 1993;88:2045–2048. 6. The RISC Group. Risk 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– 830. 7. Rosenberg RD. The heparin-antithrombin system: a natural anticoagulant mechanism. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 2nd ed. Philadelphia: JB Lippincott, 1987:1373–1392. 8. The´roux P, Oimet H, McCans J, Latour J-G, Joly P, Levy G, Pelletier E, Juneau M, Stasiak J, de Guise P, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988;319:1105–1111. 9. Cohen M, Adams PC, Parry G, Xiong J, Chamberlain D, Wieczorek I, Fox KAA, Chesebro JH, Strain J, Keller C, et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users: primary end points analysis from the ATACS trial. Circulation 1994;89:81– 88. 10. Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996;347:561–568. 11. Klein W, Buchwald A, Hillis SE, Monrad S, Sanz G, Turpie GG, van der Meer J, Olaisson E, Undeland S, Ludwig K, for the FRIC Investigators. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: Fragmin in Unstable Coronary Artery Disease (FRIC). Circulation 1997;96:61– 68. 12. Cohen M, Demers C, Gurfinkel EP, Turpie AGG, Fromell CJ, Goodman S, Langer A, Califf R, Fox KAA, Premmereur J, Bigonzi F, for the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997; 337:447– 452. 13. Goodman S, Langer A, Demers C, Turpie A, Bigonzi F, Radley D, Le louer V, Gosset F, Fromell G, Cohen M, for the ESSENCE Group. One-year follow-up of the ESSENCE trial (enoxaparin vs heparin in unstable angina/non-Q-wave myocardial infarction): sustained clinical benefit. Can J Cardiol 1998;14(suppl F):122F. (Abstr.) 14. Antman E, McCabe C, Gurfinkel E, Premmereur J, Bernink PJLM, Turpie AGG. Enoxaparin for the acute and chronic management of unstable angina/nonQ-wave myocardial infarction: results of TIMI 11B. Circulation 1998;98.

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