12 Antithrombotic therapy for coronary artery disease and valvular heart disease DOUGLAS H. ISRAEL VALENTIN FUSTER JAMES H. C H E S E B R O LINA BADIMON

In the past decade much attention has been focused on the importance of thrombogenesis with respect to the pathophysiology of cardiovascular disease. In this chapter we will review the current role of antithrombotic therapy in coronary artery disease, coronary intervention and in valvular heart disease. We will also outline possible future approaches to the prevention and treatment of thromboembolic disorders.

CORONARY ARTERY DISEASE (Figure 1) It is useful to consider the natural history of coronary atherothrombotic disease in five stages. Stage 1 is characterized by the asymptomatic development of raised fatty streaks. In certain individuals these plaques grow to encroach on the arterial lumen and may eventually result in the clinical syndrome of angina pectoris (stage 2). Stage 3 is defined by sudden and unpredictable plaque disruption, frequently complicated by thrombosis and vasoconstriction that leads to unstable angina, myocardial infarction or ischaemic sudden death. If the thrombus formed in stage 3 persists and becomes organized and incorporated into the plaque, a severely stenotic lesion may result in crescendo exertional angina or stage 4. Finally, in stage 5, extensive left ventricular dysfunction dominates the clinical scenario. As the result of myocardial infarction(s), or severe diffuse coronary disease, left ventricular dysfunction is a major risk factor for systemic thromboembolism and arrhythmic sudden death. In this section we will discuss the pathogenesis of each phase of the atherothrombotic process described above, and the role of antithrombotic therapy in its prevention and treatment.

Stages 1 and 2: the fatty streak and its early progression Stage 1 lesions are asymptomatic raised fatty streaks that consist microscopically of lipid laden macrophages and smooth muscle cells. Pathological Baittibre's Clinical Haematology--

Vol. 3, No. 3. July 1990 ISBN0-702(I--1474-5

705 Copyright© 1990,byBailli~reTindall All rights of reproductionin any formreserved

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]

Coronary Atherosclerotic Disease Coml31icated lesion (Thrombosis)

IPathNogyI Early lesion

Normal

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Myocardial Infarction

I '

Asymptomatic

15

Angina

Unstable Angina SuddenDeath

I I Risk factors

2'0

(LV dysfunction) Sudden death I

4'0

5'o

6b

Age (years)

Figure 1. The five stages of coronary artery disease. Early lesions (stage I) (lower left) are universallyfound but tend to progress to growing lesions capable of producingangina pectoris (stage II) (middle) in patients with risk factors. In some casesplaque disruptionwith thrombosis results in a rapid growth of the plaque (stage III), providingthe pathophysiologicalbasis for the acute coronary syndromes. Such thrombi may undergo atherogenic transformation, further compromising the vessel lumen with worsening angina pectoris (stage IV) (upper right). Finally, extensive ventricular dysfunction dominates the prognosis (stage V) (lower right). Reprinted with permissionfrom the American Collegeof Cardiology(Fuster V et al, Journalof the American Collegeof Cardiology, 5, 1985, 175B-184B). studies from the 1950s and 1960s demonstrated that these lesions arise early in life; fatty streaks were found in the aorta of most children beginning at age 3. Although only a minority of children also had coronary lesions at this age, the incidence of coronary involvement increased progressively up to age 20, when it was nearly always present (Holman et al, 1958; Strong and McGill, 1962). In the extensive International Atherosclerosis Project, investigators examined the aorta and coronary arteries derived from 23 000 autopsy cases from 14 countries and 19 racial groups (McGiil, 1968). This study confirmed that fatty streaks are ubiquitous at an early age, but showed that further evolution into growing fibrous plaques, or stage 2 lesions, differed in incidence and severity among different racial and ethnic groups and with the presence of risk factors for vascular disease.

Haemorrheology and subtle endothelial injury As is true of the growing fibrous plaque, the fatty streak is found most commonly at vessel origins and bifurcations, suggesting that haemorrheological factors, such as shear stress, may play a major role in their early development (Caro et al, 1971). Experimentally, it is possible to demon-

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strate endothelial damage at these sites with no other abnormality of the vessel (Reidy and Boyer, 1977). Shear stress is the force exerted on the vessel wall by the flowing blood within, in the direction of flow, and thus represents a viscous drag that tends to distort or stretch the endothelial monolayer. Important determinants of shear include blood flow velocity, blood viscosity and the luminal diameter of the vessel. The distribution of arterial shear forces is determined by the overall pattern of blood flow; turbulence induced at branch points produces vortices and recirculation zones where markedly elevated shear rates may border areas of abnormally low shear. These physical factors may induce a subtle but chronic injury, resulting in both functional and morphological endothelial aberrations. Increased endothelial turnover stimulated in this fashion may result in the synthesis and release of endothelial derived growth factor(s) capable of stimulating smooth muscle cell chemotaxis and proliferation, even in the absence of gross endothelial disruption. Additionally, it is likely that chronic endothelial damage promotes monocyte and platelet adhesion to the vessel wall, with important consequences to atherogenesis, as discussed below.

Role of the monocyte-macrophage in atherogenesis Recent evidence supports a major role for the monocyte in atherogenesis, particularly in the setting of hypercholesterolaemia. In the hyperlipidaemic monkey, monocyte adherence and penetration of the artery wall may be demonstrated by electron microscopy within 2 weeks of beginning an atherogenic diet (Faggiotto et al, 1984). Within the intima, monocytes are transformed into macrophages which amplify atherogenesis in a number of ways. 1.

2.

Macrophages rapidly take up lipid, becoming transformed into foam cells and increasing substantially the bulk of the lesion. In such cases, protrusion of the lesion into the artery lumen may perturb the local haemorrheology to perpetuate chronic subtle endothelial injury. In addition, recent evidence strongly suggests that, when saturated with lipid, macrophages within the core of a lesion release hydrolytic enzymes that digest the overlying fibrous cap causing rupture of the plaque and an acute coronary syndrome (stage 3). This aspect will be discussed in detail below. Macrophages produce maerophage derived growth factor (MDGF), a mitogen similar or identical to platelet derived growth factor (PDGF), which stimulates chemotaxis of smooth muscle cells from the media towards the intima, where they begin to proliferate. These stimulated smooth muscle cells may also produce similar or identical growth factors contributing to a progressive hyperplastic response. Additionally, the proliferating smooth muscle cells appear phenotypically distinct from those of the media. Unlike medial smooth muscle cells whose function is primarily contractile, hyperplastic intimal smooth muscle cells actively synthesize connective tissue elements of the atherosclerotic plaque (Ross, 1986), perhaps in response to mitogens derived from endothelial

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cells, macrophages or platelets. The transformation of smooth muscle cells into foam cells may also be mediated partly via MDGF/PDGF, which increases smooth muscle cell low-density lipoprotein (LDL) receptor density and lipid uptake. The role of other secretory products of the macrophage in atherogenesis including leukotrienes and interleukin-1 is under investigation and may prove to be significant. . Products of macrophage oxidative metabolism, including oxygen free radicals or oxidatively modified LDL particles, may continuously damage the endothelium overlying atherosclerotic lesions. This could promote atherogenesis by attenuating normal endothelial defence functions and by triggering release of endothelial growth factors. If injury is sufficient to cause gross endothelial disruption, platelets may attach, with consequences described below.

Role of platelets in atherogenesis and thrombogenesis: slow versus fast progression of the atherosclerotic plaque As indicated, not all individuals with fatty streaks show progression to the fibrous plaque that characterizes stage 2. Additionally, for reasons not well understood, mechanisms for and rates of such progression differ in individuals, and appear to be modulated in part by risk factors and genetic determinants. Progression may occur both by a slow mechanism involving progressive intimal hyperplasia partly dependent on platelets (stage 2a), or by a fast mechanism involving recurrent plaque disruption with intermittent thrombosis, followed by organization and healing (stage 2b). If slow progression does indeed occur, it is likely that platelet adhesion and secretion of growth factors contribute to the process. Rapid progression involves not only platelet adhesion, but also platelet aggregation, activation of coagulation and of the endogenous inhibitors of thrombosis. We will discuss each of these mechanisms with respect to basic platelet function and describe possible future implications for antithrombotic therapy.

Slow progression (stage 2a). Thus far it has been difficult to study the progression of atherosclerosis in humans. If slow progression occurs, it is likely to be due to chronic endothelial damage stimulating secretion of growth factors from many sources, including adherent platelets. Probably many factors contribute to endothelial damage, which may be functional or ultrastructural. These may include oxidative metabolites of activated macrophages, oxidized LDL, nicotine, or carbon monoxide from tobacco smoke. Hypercholesterolaemia has been suggested to result in an altered cholesterol:phospholipid ratio in the endothelial plasmalemma leading to decreased membrane fluidity. This could sensitize the cell to damage from elevated shear. Even when endothelial structural integrity is maintained, subtle injury may functionally impair its modulation of vasomotor tone and other important defence functions. More severe injury may result in ultrastructural abnormalities or denudation. It is possible to demonstrate such a sequence in experimental animals. In Fagiotto's model of the hypercholesterolaemic pigtail monkey referred to earlier, the fatty streaks noted

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after 12 days of an atherogenic diet continued to enlarge, due to progressive macrophage accumulation and lipid uptake. After 5 months, areas of endothelial discontinuity were noted, resulting in platelet adhesion to the exposed subendothelium. As described below, the platelet-vessel wall interaction that follows results in smooth muscle cell proliferation and connective tissue synthesis. Although more difficult to establish in humans, recent autopsy studies have demonstrated platelet adhesion to endothelium in cases where arteries were examined by electron microscopy within 3 h of death (Vikhert and Rosinova, 1982). In general, the endothelium overlying fatty streaks exhibits pronounced polymorphism. Cell shape may be irregular, with cytoplasmic projections and eccentric, morphologically abnormal nuclei. Frequently there is deviation of the axis of cell orientation relative to the axis of blood flow. Cell junctions are abnormal and platelets are seen attached, anchored in cell gaps and junctions. In some cases, frank endothelial loss and platelet adhesion can be seen. Platelet adhesion (Figure 2) thus results from superficial vessel wall injury. Adherent platelets secrete growth factors from their ot granules, such as

~ectin ain

Figure 2. Scheme of platetet adhesion and aggregation. Platelet glycoprotein Ib binds von Willebrand factor (vWF), helping to mediate platelet adhesion at high shear rates. Glycoprotein IIb/IIIa interacts with vWF, also participating in the process of platelet adhesion. Finally, glycoprotein la serves as a receptor for collagen and may mediate platelet adhesion at lower shear rates. Activation of the platelet membrane by agonists of aggregation unmasks a binding site on glycoprotein lIb/Illa for fibrinogen, vWF, and fibronectin, a process leading to the formation of interplatelet bridges, the final common pathway for platelet aggregation. Reproduced from Hawiger et al (1985) with permission.

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PDGF, with potentially atherogenic functions identical to those of MDGF, as previously described. Other oLgranule components, such as platelet factor 4 and ~-thromboglobulin, are also chemotactic for monocytes and probably smooth muscle cells (Deuel et al, 1981). Platelet adhesion is mediated by the interaction of subendothelial constituents, such as collagen, yon Willebrand Factor (vWF) and fibronectin, with specific platelet membrane glycoprotein receptors. Glycoprotein Ib serves as the receptor for vWF and helps mediate platelet adhesion at arterial shear rates (Hawiger et al, 1985). Glycoprotein complex IIb/IIIa is vital to platelet aggregation by serving as a receptor for fibrinogen and vWF (discussed below), but also participates in platelet adhesion in a complex interaction with vWF, fibronectin and calcium ions. (Nieuwenhuis and Sixma, 1987.) Finally, glycoprotein Ia interacts with subendothelial collagen and may mediate platelet adhesion at lower shear rates (Nieuwenhuis and Sixma, 1987). The above process normally plays an important role in haemostasis and vessel wall repair, as demonstrated by those patients congenitally deficient in platelet glycoprotein Ib who have impaired platelet adhesion and exhibit a serious bleeding diathesis. Despite this protective function, if there is chronic superficial endothelial damage with continuous platelet adhesion and secretion, this could contribute to the gradually progressive intimal hyperplasia of stage 2a. Some evidence for this derives from our finding that pigs with homozygous yon Willebrand disease and defective platelet adhesion are significantly resistant to atherosclerosis (Fuster et al, 1982a), particularly if marked hyperlipidaemia is absent (Fuster and Griggs, 1986). Patients with coronary artery disease and smokers demonstrate decreased platelet survival times, providing further evidence for continuous platelet activation and consumption in vascular disease (Fuster et al, 1981a).

Rapid progression (stage 2b). In some cases the growing atherosclerotic plaque undergoes deeper injury, exposing components of the tunica media. In addition to the process of platelet adhesion described above, deeper arterial injury also triggers platelet aggregation, coagulation, and activation of endogenous inhibitors of thrombosis. When such a process occurs, the resulting thrombus may be occlusive or non-occlusive, and fixed or labile. Fixed thrombi may become organized and incorporated into the lesion, resulting in stenosis progression, but even transient thrombi may accelerate luminal obstruction by rapid release of platelet derived mitogens, as well as changes in the geometry of the lesion induced by the plaque disruption itself. We differentiate stage 2b, in which such rapid progression occurs in a subacute fashion, resulting in gradual progression of stable angina pectoris, from the acute coronary syndromes of stage 3, a spectrum of symptoms including chest pain at rest, evidence of myocardial necrosis or ischaemic sudden death. Platelet aggregation (Figure 3) occurs via interaction of biochemical mediators with specific platelet membrane receptors. Deep arterial injury exposes highly thrombogenic type I and III collagen fibres in the vessel media and releases tissue thromboplastins, resulting in thrombin generation via the extrinsic pathway of coagulation. Platelets exposed to collagen and

711

ANTITHROMBOTICS FOR HEART DISEASE

Activation of membrane receptors (adheson ondogqregation) J ]~,1-. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

"---

TICLOPIOIN£ 7 0

!RAZONE~' e ~e

Figure 3. Activation of membrane receptors leading to platelet adhesion and aggregation, and locus of attack of antithrombotic agents, Reproduced with permission from Verstraete M and Vermylen J (1984) Thrombosis. New York: Pergamon Press,

thrombin in this fashion are strongly stimulated to aggregate and promote arterial thrombosis. In the platelet, the collagen and thrombin-receptor complex activates membrane phospholipase C, resulting in release of phosphatidylinositol and mobilization of intracellular calcium ions. As a result, glycoprotein IIb/IIIa changes conformation and exposes a binding site for fibrinogen, vWF and fibronectin, which link neighbouring platelets, resulting in aggregation (see Figure 2). In addition, the collagen and thrombin-receptor complex also triggers secretion of platelet dense granule constituents, adenosine diphosphate (ADP), serotonin and calcium, and activation of arachidonic acid metabolism, resulting in generation of thromboxane A2 (TxA2). Both ADP and TxA2 amplify the process of platelet aggregation by contributing to exposure of glycoprotein IIb/IIIa sites on neighbouring platelets and recruiting them for the thrombotic process. All the essential cofactors are present in high concentration during thrombosis. ADP is released not only from platelet dense granules but also from haemolysis of red blood cells caused by turbulence in markedly stenotic areas. Fibrinogen is present in large quantities during coagulation, and is also released upon stimulation from platelet c~ granules. Most importantly, collagen is exposed in high local concentrations during plaque rupture, and thrombin is generated during coagulation. Although all of the above mechanisms are important and contribute to platelet aggregation and arterial thrombosis, there is a strong clinical consensus that the extrinsic activators, collagen and thrombin, may be the most important. Thus, although the clinical utility of aspirin is well established, as will be reviewed in detail, it is a relatively weak antiplatelet agent capable of interfering with

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only the TxA2-dependent pathway of platelet activation (Figure 3), and its effectiveness is thus limited in the setting of an overwhelming thrombogenic stimulus. For this reason, future therapies may be geared toward inhibition of thrombin-induced platelet aggregation, or towards development of agents which inhibit multiple pathways of platelet activation. Activation of coagulation plays an important role in the thrombotic response to deep arterial injury. Subendothelial collagen stimulates platelet activation and, simultaneously, the intrinsic pathway of coagulation. Tissue thromboplastins are released from a ruptured plaque and activate the extrinsic pathway. Mutually interdependent, coagulation and platelet activation stimulate and amplify each other in three ways. (1) Phospholipid of the platelet membrane acts as a catalytic surface to accelerate the activation of factors Xa and thrombin in association with factors VIII and V, respectively. Thrombin thus generated enhances further platelet activation. (2) Formation and cross-linking of fibrin is essential to stabilize the platelet thrombus against arterial shear forces. (3) Platelets secrete clotting factors V and fibrinogen. Because of the vital importance of coagulation to arterial thrombosis, a future approach to therapy may be to combine anticoagulant therapy with low dose aspirin, but the safety of this approach with respect to haemorrhagic side-effects will need to be clearly demonstrated. Endogenous inhibitors of thrombosis contribute to the non-thrombogenicity of normal endothelium and prevent uncontrolled intravascular coagulation. The most important inhibitors of thrombosis include prostacyclin, the fibrinolyticsystem, the protein S/protein C system and antithrombin III. Each of these mechanisms depends upon intact endothelium to function optimally. Thus endothelial injury and dysfunction contribute importantly to both atherogenesis and thrombogenesis. Defects in protein S, protein C, fibrinolysis and antithrombin Ill have all been linked to recurrent thrombosis (Egeberg, 1965; Wohi et al, 1979; Comp and Esmon; 1984; Griffin et al, 1981).

Antithrombotic therapy for coronary disease: stages 1 and 2 No currently available platelet inhibitor prevents platelet adhesion and secretion of trophic factors that trigger intimal hyperplasia. Thus, antithrombotic therapy in its present form does not have a role in preventing initiation of atherosclerosis or its slow progression (stages 1 and 2a). Because slow progression depends upon continuous endothelial injury and platelet activation, both stimulated in part by risk factors, we advise risk factor modification as primary therapy in these patients, as well as in all other patients with coronary disease. Because rapid progression of coronary stenosis due to intermittent thrombosis appears to occur randomly in the protracted course of coronary disease, there is a rationale for the prophylactic use of aspirin in patients with stable angina pectoris for the prevention of rapid subacute progression (stage 2b), or of the acute coronary syndromes (stage 3). Clinical studies are currently testing this hypothesis and results will soon be available upon which to formulate well founded recommendations. Indirect evidence of the benefit of aspirin in patients with stable angina derives from

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the Canadian Multicenter Trial of aspirin and sulphinpyrazone in unstable angina, in which the benefit of aspirin in preventing myocardial infarction persisted after the patients' acute symptoms stabilized. Similarly, in studies of peripheral vascular disease, patients treated with aspirin, or aspirin plus dipyridamole, for 2-4 years demonstrated significantly fewer occlusions compared to placebo matched controls, reflecting the important role of thrombosis in lesion progression (Schoop et al, 1983; Hess et al, 1985). Stage 3: acute coronary syndromes

A large body of evidence implicates plaque disruption complicated by thrombosis as the pathophysiological link between the acute coronary syndromes of unstable angina, myocardial infarction and ischaemic sudden death. Commonly, plaque rupture or fissuring occurs in fatty lesions that have become weakened as a result of hydrolytic enzyme release from macrophages and are unable to withstand haemodynamic stresses due to vasotonicity, changes in pressure and flow due to exertion, or even the chronic pulsatile vibration due to the cardiac cycle. In most cases, plaque rupture or fissuring elicits a thrombotic response due to exposure of collagen and tissue thromboplastins as previously described. The clinical syndrome resulting from plaque disruption and thrombosis is determined by the depth of injury to the artery wall; this, in turn, determines the degree and persistence of thrombus formation, and its ability to overwhelm endogenous antithrombotic defences. Elevated shear rates also contribute to thrombosis by increasing platelet delivery to the blood vessel wall. In our laboratory we have examined the relationship between shear rate and platelet deposition using a perfusion chamber utilizing different blood vessel substrates while varying the shear rate, as might occur naturally with different degrees of stenosis (Badimon et al, 1986). We approximate mild injury by utilizing strips of de-endothelialized aorta. At low shear rates characteristic of large arteries and veins, only a single layer of platelets adhered to the vessel wall. At shear rates characteristic of small and medium sized arteries with stenotic lesions, platelets deposit rapidly up to 10-20 rain but are thereafter dislodged or embolized by the flowing blood. Thus, mild injury to the vessel wall may lead to thrombi that are labile, resulting in intermittent arterial occlusion, and may help to explain.the occurrence of episodic rest pain in unstable angina. When deep vessel wall injury is mimicked by using collagen in the perfusion chamber, rapid platelet deposition ensues, but thrombi remain fixed; a situation that may be clinically relevant in the setting of Q wave myocardial infarction. When Q wave myocardial infarction occurs, another thrombotic event, left ventricular mural thrombosis and systemic embolization, may complicate the clinical course. Finally, in the context of the acute coronary syndromes we will consider the role of antithrombotic therapy in the prevention of rethrombosis following thrombolysis.

1. Unstable angina (Figure 4) Patients with angiographic evidence of coronary artery disease and stable

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anginal syndromes who develop unstable angina are known to demonstrate progression of coronary stenosis if a second arteriogram is performed, in contrast to patients whose symptoms remained stable (Ambrose et al, 1986). Angiographically, the 'culprit' lesion is frequently eccentric with irregular edges and a narrow neck (Ambrose et al, 1985). Angioscopic study has demonstrated that these complicated lesions responsible for development of unstable angina may or may not be complicated by thrombosis. Plaque rupture alone may alter lesion geometry, increasing luminal obstruction sufficiently to accelerate a previously stable anginal pattern. Increasing evidence points to intermittent thrombosis superimposed on plaque rupture to explain transient episodes of chest pain at rest (see above). Such transient thromboses have been documented angioscopically (C. T. Sherman et al, 1986), and pathologically (Falk, 1985). In addition, chest pain at rest has been temporally related to increases in serum and urine fibrinopeptide A and platelet thromboxane metabolites (Fitzgerald et al, 1986; Theroux et al, 1987). Vasoconstriction may contribute to chest pain at rest, either as a result of endothelial dysfunction, or of release of thromboxane, serotonin or P D G F by aggregating platelets. Our current hypothesis of unstable angina is

Figure 4. Coronary arteriograms and accompanying schematic diagrams of the left anterior descending arteries in two patients with complex eccentric plaques, the end result of plaque rupture and thrombosis. The arrows point to the lesions depicted in the schematic representation of the angiogram. Both patients had unstable angina. LCA, left coronary artery; RAO, right anterior oblique; LAO, left anterior oblique. From Ambrose et al (1985); reprinted with permission from the American College of Cardiology.

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therefore as follows: a non-obstructive or mildly obstructive lesion undergoes relatively minor disruption, increasing the degree of stenosis and reducing the threshold for exertional ischaemia. Superimposed thrombosis may occur, resulting in intermittent arterial occlusion, but the thrombus is labile due to the mild nature of the inciting plaque disruption. Vasoconstriction or transient increases in myocardial oxygen demand may further contribute to rest angina.

Antithrombotic therapy for unstable angina The efficacy of antithrombotic therapy in unstable angina has been conclusively demonstrated for both aspirin and heparin. The Veterans' Administration Cooperative Study randomized 1266 men with unstable angina to receive buffered aspirin (as Alka Seltzer, 324 rag/day) or placebo for 12 weeks. The incidence of death and acute myocardial infarction was reduced 51% over the 12-week treatment period and, importantly, the benefits persisted over a 1-year follow-up. Significantly, at the dosage employed there was no excess of gastrointestinal side-effects as compared with the placebo group (Lewis et al, 1983). The Canadian Multicenter Trial randomized 555 patients, including 27% females, to receive aspirin (1300 mg/day), sulphinpyrazone (800 rag/day), both, or placebo. At the end of 2 years, the combined incidence of death and non-fatal myocardial infarction was decreased by 50%. Sulphinpyrazone was not of benefit alone, and did not add to the effectiveness of aspirin when the two drugs were combined. The greater dose of aspirin utilized in this trial did not result in greater risk reduction for coronary events than in the Veterans' Administration Cooperative Trial, but did lead to a significantly greater incidence of gastric side-effects (Cairns et al, 1985). Intravenous heparin has also been shown to be beneficial in unstable angina. In a group of patients randomized to receive heparin, atenolol, both or placebo, there was an 80% reduction in combined death or myocardial infarction over 8 days (Telford et al, 1981). The recently published Montreal Heart Institute Trial compared the relative efficacy of intravenous heparin, aspirin or both versus placebo in 479 patients with unstable angina. Over the 6-day trial period, aspirin decreased the myocardial infarction rate by 72% compared with 89% for heparin (Theroux et al, 1988). Although the greater efficacy of heparin was not statistically significant, one may advocate the use of heparin during hospitalization for acute unstable angina to avoid aspirin related bleeding in the event that coronary artery bypass is required. The combination of heparin and aspirin did not appear better than either alone, but did lead to more bleeding complications. In view of the major importance of both platelets and the coagulation system to the pathogenesis of the acute coronary syndromes, the combination of anticoagulants with lower dose aspirin (80 mg/day) is currently being tested.

2. Non-Q wave myocardial infarction Non-Q wave myocardial infarction represents an intermediate stage in the

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spectrum of the acute coronary syndromes. In 25% of patients the infarct related artery is totally occluded but the vascular territory is partly protected by collateral flow (DeWood et al, 1986). However, the majority of such patients have a patent infarct related artery at angiography, but demonstrate a lesion with morphology similar to that described for unstable angina (Ambrose et al, 1988), suggesting that plaque disruption is common to both syndromes. The presence of ST elevation and early peaking creatine phosphokinase washout kinetics suggest that coronary thrombosis and early spontaneous thrombolysis play an important aetiological role in non-Q wave infarction (Timmis et al, 1987). Thus, we postulate that non-Q wave infarction involves a greater degree of plaque disruption than unstable angina, with longer persistence of thrombus, but not so long as to cause Q wave infarction. The incidence of recurrent myocardial infarction and sudden death in survivors of non-Q wave infarction is similar to that of unstable angina, suggesting that a similar antithrombotic strategy may be of benefit. Although data to support this hypothesis are scarce, administration of aspirin and dipyridamole to patients with non-Q wave infarcts resulted in a 53% reduction in subsequent coronary events in the PARIS II Trial (Klimt et al, 1986).

3. Q Wave myocardial infarction Angiographic studies of Q wave infarction show that between 50 and 75 % of patients have occlusive thrombi superimposed on mild to moderately stenotic lesions (Brown et al, 1986). In these cases it would appear that the inciting event is rupture into the atherosclerotic plaque which is deeper than in the other acute coronary syndromes. This results in a well anchored thrombus that may produce chronic total coronary occlusion, or may eventually undergo fibrinolysis but in either case persists at least several hours, a time frame sufficient to allow transmural necrosis in the absence of adequate collateral support. Roughly 25% of patients with Q wave infarction demonstrate thrombotic occlusion of a severely stenotic lesion, perhaps more a reflection of stasis than of anatomical plaque disruption.

Antithrombotic therapy for myocardial infarction: primary prevention Because, as discussed, a large proportion of Q wave infarctions occur due to plaque rupture superimposed on non-obstructive (and therefore asymptomatic) lesions, a certain percentage of patients present with Q wave infarction as the first manifestation of ischaemic heart disease. Thus, a rationale exists for the use of prophylactic antithrombotic therapy in the primary prevention of these events. Recently, data concerning the role of aspirin in the primary prevention of myocardial infarction have become available from two large studies. The Physicians' Health Study randomized 22071 healthy physicians to receive aspirin 325mg every other day, or placebo. After nearly 5 years of follow-up, the trial was terminated due to a 47% reduction in fatal and non-fatal myocardial infarction. In spite of this, total cardiovascular mortality was unchanged due to small increases in other

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vascular mortality, including sudden death, and moderate to severe or fatal haemorrhagic stroke (Physicians' Health Study, 1988). Another recent trial of more than 5000 British physicians, randomized to receive 500 mg aspirin daily or placebo, failed to demonstrate a significant reduction in myocardial infarction but, disturbingly, also disclosed a trend toward increased stroke in aspirin treated individuals (Peto et al, 1988). Although provocative, it would seem the results of the Physicians' Health Study require further analysis and confirmation before the administration of prophylactic aspirin should be advised for apparently healthy subjects. Although the lack of excess gastrointestinal side-effects demonstrate the apparent safety of aspirin at this dosage, the effects of long-term inhibition of prostaglandin metabolism throughout the body are unknown. At present, it would appear advisable to prescribe aspirin for primary prevention of myocardial infarction only to those individuals with significant risk factors for coronary disease, perhaps excluding those with severe hypertension.

Antithrombotic therapy for myocardial infarction: secondary prevention The goal of antithrombotic therapy in unstable angina and non-Q wave myocardial infarction is to prevent coronary occlusive events leading to Q wave infarction and ischaemic sudden death. The favourable results with aspirin in these settings are due to the high frequency of thrombotic events in the natural history of these syndromes. Once Q wave infarction has occurred, the rationale for antithrombotic therapy is to prevent rethrombosis in the same coronary artery after spontaneous clot lysis, or in a distant coronary artery, leading in either case to progressive left ventricular dysfunction. We consider antithrombotic therapy for secondary prevention of myocardial infarction in three phases.

(a) Hospital phase and first month postinfarction. Many of the deaths occurring within the first month of myocardial infarction may be attributed to rethrombosis, thus antithrombotic therapy may be expected to exert a protective effect during this period. The strongest evidence for this is derived from the ISIS-2 study (ISIS-2, 1988), in which over 17000 patients with clinically suspected infarction were randomized to receive aspirin (160 mg/day), intravenous streptokinase, both, or placebo. By 5 weeks of follow-up, mortality in the group treated with aspirin alone was decreased 23% compared to placebo, a reduction similar to that obtained with streptokinase alone (25%). The rate of reinfarction with aspirin was decreased nearly 50%. The use of anticoagulants in the early postinfarction period, though popular in the 1950s and 1960s, fell into disfavour when several large trials failed to demonstrate statistically significant benefits, despite a trend toward improved outcome (Medical Research Council, 1969; Drapkin et al, 1973; Veterans' Administration Cooperative Trial, 1973). When results from all such trials were pooled, there was a 21% reduction in mortality in patients receiving anticoagulants postinfarction compared with controls (Chalmers et al, 1977).

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(b) First2 years postinfarction. Many deaths occurring during this time frame occur due to left ventricular dysfunction and ventricular arrhythmia. These non-thrombotic events are consequences of the initial infarction and thus represent a non-specific endpoint for antithrombotic therapy, whereas new thrombotic events are relatively less frequent (low sensitivity). In order to avoid this sort of dilutional effect, trials of antithrombotic therapy during this period must include large numbers of patients to detect significant benefits of treatment (Table 1). A recent meta-analysis of the several large randomized placebo controlled trials of platelet inhibitors for secondary prevention of myocardial infarction showed a 31% decrease in recurrent non-fatal myocardial infarction, 13% reduction in mortality and 42% decrease in non-fatal stroke (Antiplatelet Trialists' Collaboration, 1988). In this regard, aspirin is the most thoroughly studied, convenient and inexpensive drug to use and appears safe at a dose of 325 mg daily. The addition of dipyridamole does not appear to confer additional benefit beyond that of aspirin alone, and results with sulphinpyrazone have been inconsistent. Anticoagulants seem to have similar protective effects: results from the International Anticoagulant Review Group (1970) found an overall 21% reduction in mortality when the results from all adequately designed randomized trials were combined.

Table 1. Randomized trials of platelet inhibitors after myocardial infarction in the secondary prevention of vascular events. Dosage (mg/day)

No. of patients

1000 990 225

4524 3128

Aspirin

972

2026

MRC-II 4

Aspirin + dipyridamole Aspirin

972 225 900

1682

CDP 5

Aspirin

972

1529

MRC-I 6

Aspirin

300

1239

GARS 7

Aspirin

1500

626

Trial

Drug

AMIS 1 PARIS-II 2

Aspirin Aspirin + dipyridamole

PARIS 3

Results of therapy No benefit Decreased reinfarction; trend toward lower total and coronary mortality Trend toward reduced total and coronary mortality Trend toward reduced total and coronary mortality Trend toward reduced total and coronary mortality Trend toward reduced total and cardiovascular mortality Trend toward reduced total death Trend toward reduced coronary death and myocardial infarction

AMIS=Aspirin Myocardial Infarction Study. PARIS-11=Second Persantine-Aspirin Reinfarction Study. PARIS-I = First Persantine-Aspirin Reinfarction Study. 1 Aspirin Myocardial Infarction Study Research Group, 1980. 2 Klimt et al, 1986. 3 Persantine-Aspirin Reinfarction Study Research Group, 1980. 4 Elwond and Sweetnam, 1979. 5 Coronary Drug Project Research Group, 1976. 6 Elwood et al, 1974. v Breddin et al, 1980,

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FOR HEART DISEASE

719

(c) Beyond the first 2 years postinfarction. Recurrent ischaemia due to coronary disease again strongly determines the prognosis during this time as those patients with severely impaired left ventricular function and malignant arrhythmia frequently die during the early postinfarction period. The late postinfarction period thus represents a specific model for deaths related to thrombosis. The Sixty-Plus Reinfarction Study Research Group (1980) in fact showed a significant decrease in recurrent infarction and total mortality in patients over 60 years of age in whom anticoagulants were continued after 5-6 years of therapy, compared with those in whom anticoagulants were discontinued. The role of aspirin in this time period is presently being examined. Antithrombotic therapy for myocardial infarction: prevention of left ventricular mural thrombosis and systemic embolization Large Q wave myocardial infarctions involving the anterior walt and apex may result in left ventricular mural thrombosis and systemic embolization due to the coexistence of endocardial damage, stasis of blood flow and the hypercoagulable state observed after myocardial infarction. Using pooled data from echocardiographic studies, left ventricular thrombi are found in about 4% of inferior infarctions and 20-40% of anterior infarcts. Extensive anterior infarctions may be associated with mural thrombosis in up to 60% of cases. The incidence of systemic emboli appears to be approximately 10% of the incidence of mural thrombosis and generally complicates the clinical course in 2-3% of all patients with myocardial infarction (Meltzer et al, 1986), although clinically silent emboli may be found in a higher percentage of patients at autopsy. The embolic risk decreases dramatically after the first 2-3 months to about 0.35 events per 100 patients years, in the absence of severe diffuse left ventricular dysfunction. Immediate anticoagulation after hospital admission is effective in reducing the incidence of mural thrombosis detected echocardiographically, an effect that apparently requires full dose anticoagulation and correlates with the activated partial thromboplastin time and plasma heparin levels (Turpie et al, 1989). Immediate anticoagulation reduces the incidence of cerebral emboli (Medical Research Council, 1969; Veterans' Administration Cooperative Clinical Trial, 1973; Asinger et al, 1981) but Coumadin (warfarin) begun after echocardiographic detection of thrombus did not favourably affect the incidence of embolization (Visser et al, 1983). Thus, we favour anticoagulating patients with large anterior infarctions with full dose heparin without waiting for the demonstration of mural thrombus by echocardiography.

Antithrombotic therapy for myocardial infarction: prevention of rethrombosis following thrombolysis The incidence of rethrombosis after initially successful coronary thrombolysis varies between 5 and 20% (Sherry, 1987). Major risk factors for rethrombosis include altered haemorrheology due to residual stenosis and the persistence of a potent thrombogenic stimulus due to the inciting plaque

720

D. H . I S R A E L ET AL

rupture and residual unlysed thrombus. Rethrombosis is more common when residual stenosis exceeds 75% (Gash et al, 1986) or luminal cross-sectional area is less than 0.4 mm 2 (Harrison et al, 1984). We believe residual stenosis enhances rethrombosis partly by the promoting effect of elevated wall shear rates on platelet deposition. The residual stenosis is itself caused in part by residual thrombus. Recent experimental evidence from our laboratory suggests that residual thrombus is among the most powerful stimuli known to promote further thrombosis (Badimon et al, 1987). Using stripped tunica media (a model of deep arterial injury) in an ex vivo perfusion chamber containing an eccentric stenosis of variable severity, we measured deposition of [Zlqn]-labelled platelets over time. With an 80% stenosis (high shear), platelet deposition proceeded rapidly for 30 min and then dropped abruptly; this was likely to be due to spontaneous partial thrombolysis with disaggregation of platelets. Immediately following this, platelets redeposited at a rate even higher than that initially observed. With ongoing perfusion, this cycle of thrombosis, lysis and rethrombosis is repeated. Thus, in acute coronary syndromes, including the post-thrombolysis setting, it would appear that multiple cycles of thrombotic occlusion and spontaneous thrombolysis may occur, with vasoconstriction also acting to promote intermittent coronary occlusion (Hackett et al, 1987). Evidence for the favourable effect of platelet inhibitors on decreasing post-thrombolysis rethrombosis may be derived from ISIS-2. As indicated earlier, both aspirin and streptokinase alone decreased 5-week mortality by 23-25%, a combination of the two drugs resulted in a 42% decline in vascular deaths at 5 weeks. It is likely that the beneficial effect of aspirin is due to prevention of rethrombosis after spontaneous or streptokinaseinduced thrombolysis. Convincing evidence of a protective role for heparin in the postthrombolysis setting has been more difficult to obtain. In experimental animals, heparin has been shown to decrease platelet deposition in a dose dependent manner in the postangioplasty setting, another model of deep arterial injury (Heras et al, 1988). For this reason, while awaiting the results of the large GISSI-2 and ISIS-3 trials, both of which will test the use of heparin post-thrombolysis, we recommend the use of high dose intravenous heparin to maintain the activated partial thromboplastin time to × 2-2.5 control, with concomitant aspirin, 80 mg daily. If revascularization is not required during the acute hospitalization, patients may be discharged on aspirin therapy, 325 mg daily. Future antithrombotic approaches to prevention of post-thrombolysis reocclusion may evolve as a result of our greater understanding of the biochemistry of ptatelet adhesion and aggregation (see Figure 2). Experimental evidence shows that the combination of tissue plasminogen activator (tPA) with a monoclonal antibody directed against platelet glycoprotein IIb/IIIa resulted in a shorter interval between treatment and restoration of vessel patency, and prevention of reocclusion (Gold et al, 1988). We have found similar preliminary results: treatment with an antibody raised against porcine vWF resulted in an 81% reduction in platelet deposition, compared with a 30% decrease seen with aspirin therapy, when heparinized blood was

ANTITHROMBOTICS FOR HEART DISEASE

721

exposed to type I collagen at high shear rates in a perfusion chamber (Badimon et al, 1988). Peptide blockers to thrombin-induced platelet activation are currently being tested with promising preliminary results. Such approaches will need to be extensively tested with respect to safety before they can be applied to human thrombolysis, but they demonstrate a potential benefit of inhibiting alternative pathways of platelet activation relevant to the pathogenesis of the acute coronary syndromes, other than the TxA2 pathway (see Figure 3). Stages 4 and 5: atherosclerotic coronary occlusion and left ventricular dysfunction

Progression of advanced coronary stenosis to chronic total occlusion (stage 4) may have deleterious effects on patient outcome for a number of reasons. Progression of the primary arterial supply to total occlusion may accelerate exertional ischaemia, provoke unstable angina, or result in myocardial infarction, depending on the adequacy of collateral flow. Similarly, total coronary occlusion may promote ischaemia at a distance if the occluded artery was itself a collateral donor to other vascular territories. Finally, recent evidence suggests that, even when acute coronary occlusion leads to Q wave infarction, failure of the artery to recanalize (either spontaneously or due to pharmacological thrombolysis) may promote infarct extension, left ventricular dilatation and left ventricular dysfunction resulting from ischaemic damage (stage 5). The pathogenesis of total chronic coronary occlusion requires further study. Probably it occurs most commonly when an occlusive thrombus formed during an acute coronary syndrome undergoes organization and atherogenic transformation, rather than undergoing natural lysis. It is currently unknown whether stage 4 might occur by slow chronic progression of atherosclerosis in the absence of an intervening thrombotic occlusive event. Once severe diffuse left ventricular dysfunction occurs, intracavitary mural thrombi are frequently found. One echocardiographic study detected left ventricular thrombi in 36% of cases of dilated cardiomyopathy (Stratton and Resnick, 1987). The incidence of thrombi was similar whether the aetiotogy was ischaemic or idiopathic, as was the 11% incidence of clinical embolization (Gottdiener et al, 1983).

Antithrombotic therapy for stages 4 and 5 There are few data to determine the efficacy of platelet inhibitors in advanced stages of coronary disease in preventing further ischaemic complications. Furthermore, there is no prospective randomized trial of anticoagulation for the prevention of thromboembolism in patients with severe left ventricular dysfunction due to ischaemic damage. In the Mayo Clinic study of idiopathic dilated cardiomyopathy, there was a moderately high frequency of embolic events (3.5% per year), occurring in 14% of patients in sinus rhythm and 33% of patients in atrial fibrillation. Patients receiving anticoagulants had no emboli in 101 patient-years of follow-up (Fuster et al, 1981b). Therefore, pending further study, we recommend long-term

722

D . H . I S R A E L ET A L

Coumadin therapy to maintain the prothrombin time, using a typical North American commercial thromboplastin with an international sensitivity index (ISI) of 2.2, at x 1.5-2.0 control values (INR = 3.0-4.5) in patients with coronary artery disease and severe left ventricular dysfunction. This indication is even stronger in the presence of atrial fibrillation. Summary of recommendations: antithrombotic therapy for coronary artery disease 1.

Aspirin at a dose of 325 rag/day is recommended for patients with unstable angina, and should be continued indefinitely thereafter. High dose anticoagulation with intravenous heparin has been shown to be effective during the acute hospital phase of unstable angina and may be used instead of aspirin. Patients at particularly high risk may benefit from a combination of high dose intravenous heparin and low dose aspirin (80 mg/d). Ongoing trials are evaluating the safety and efficacy of this combination. 2. The use of aspirin for patients with chronic stable angina to prevent acute coronary syndromes or subacute thrombotic progression (stage lib) is theoretically beneficial and may be recommended, based on the low toxicity of 325 mg of aspirin, but should be reevaluated when the results of ongoing trials are available. 3. The use of aspirin 325 mg/daily is advised in the early and late postinfarction periods, based on its protective effects against reinfarction, stroke and total mortality. The use of oral anticoagulants may provide similar benefits but is not recommended because of the greater risk of haemorrhage and need for costly and inconvenient laboratory monitoring of therapy. 4. In the post-thrombolysis setting, pending further data, we recommend the use of high dose intravenous heparin, 100 units/kg bolus, followed by 1000 units/h, adjusted to maintain the activated partial thromboplastin time to x 2.0-2.5 control, in combination with aspirin at a dose of 80 mg/day. This regimen may continue for 3-5 days, at which time the heparin may be discontinued and the aspirin dose increased to 325 mg/ day. 5. To prevent left ventricular mural thrombosis and systemic thromboemboli, patients presenting with large anterior or extensive inferoapical Q wave myocardial infarction should receive full immediate systemic heparin therapy to maintain the activated partial thromboplastin time at 1.5-2.0 times control values. Oral anticoagulation with Coumadin should be begun simultaneously, aimed at prolonging the prothrombin time to x 1.5-2.0 control (INR = 3.0-4.5). Coumadin may be discontinued after 3 months unless chronic therapy is indicated by another risk factor for thromboembolism such as cardiac failure, atrial fibrillation or extensive left ventricular dysfunction. Patients with chronic left ventricular aneurysm, but otherwise preserved left ventricular function, do not require Coumadin beyond the first 3 months following myocardial infarction.

723

ANTITHROMBOTICS FOR HEART DISEASE

6.

7.

For the prevention of systemic thromboembolism, patients with chronic left ventricular dysfunction secondary to extensive coronary disease and myocardial infarction should receive long-term oral anticoagulation and Coumadin (warfarin) to maintain the prothrombin to × 1.5-2.0 control values (INR = 3.0--4.5). The use of aspirin for primary prevention of myocardial infarction requires further study. Currently it is recommended only for individuals with multiple risk factors for coronary disease, perhaps excluding those with severe hypertension, due to the risk of intracranial haemorrhage.

A

8 20"

ALL TYPES OF GRAFTS Occlusion rates ~; 1 month after operation 22%

31t 20 i

2%

7/32...9

10% 35/336 m

6% 26/lm0 7/123 i---1

t5.

* p < 0.05

New occlusion rates after 1 month 27% ~' -~ 20

~1

~)

14%

2 9% 2 4

16%

1

1

25/94

6

~ 10o

Occlusionrates late after operation 50"1 [E3 Treated 40-~ I Placebo 23% 30d 11% 76/336 20-t 35/329 m 10~ ~ • Per distal anastomosis

20% 2~/193

42% 51/120 RN

I

Per patient

I

5"

0

A1

[li A3

A/D

C 100-

Day 10

Day t80

Day 360

9080s~ 70605040p < 0.05 p < 0,05 p < 0.05 Tielopidine [777~Placebo

Figure 5, Occlusion rates in three major placebo-controlled trials of platelet inhibitors in saphenous vein bypass grafting. A The Mayo Clinic trial of aspirin and dipyridamole versus placebo, B The Veterans' Administration Cooperative Trial: P, placebo; A1, aspirin 325 mg once daily; A3. aspirin 325mg three times daily; A/D, aspirin 325mg once daily plus dipyridamole 75 mg three times daily; S, sulphinpyrazone 267 mg three times daily. C Trial of Limet et al (1987) using ticlopidine 250 mg twice daily or placebo, Reproduced with permission from the New England Journal of Medicine, the American Heart Association and the CV Mosby Company,

724

D.H.

I S R A E L ET A L

Pathophysiology Despite the striking success of coronary artery bypass grafting in alleviating symptoms and prolonging life in some patients, saphenous vein graft disease still represents a formidable problem, resulting in occlusion of up to 10-15% of grafts within 1 month of surgery and up to 50% of grafts within 10 years. Vein graft occlusion in the early postoperative period is generally thrombotic, whereas late occlusion, occurring after the first postoperative month, occurs as a result of intimal hyperplasia and atherosclerosis complicated intermittently and unpredictably by superimposed episodic thrombosis. The pathogenesis of vein graft disease begins with intraoperative trauma to the saphenous vein that occurs with harvesting, surgical manipulation and suturing. Saphenous endothelial damage is reflected biochemically by impaired prostacyclin synthesis (Angelini et al, 1987), decreased fibrinolytic activity (Malone et al, 1978) and impaired endothelial dependent relaxation noted after harvesting. Lack of prior adaptation to arterial shear forces may result in further endothelial trauma and increases susceptibility to immediate platelet deposition, which may be visualized angioscopically at the distal anastomosis. Trauma to platelets induced by the cardiopulmonary bypass machine may result in activation and increased tendency to deposit in the susceptible vein grafts. In some cases, mural thrombosis may occlude the graft in the early postoperative period. When this does not occur, platelet deposition and secretion of trophic factors results in intimal hyperplasia that is histologically evident by the first postoperative month (Unni et al, 1974). Intimal hyperplasia may be complicated by episodic superimposed thrombosis. Although these late thrombotic events are unpredictable, risk factors may include low blood flow in the graft, and the presence of severe diffuse disease in the distal grafted coronary artery. After the first postoperative year, progressive atherosclerosis and its thrombotic complications become the principal pathophysiological factors in subsequent vein graft occlusive events.

Antithrombotic therapy for saphenous vein graft disease Platelet Inhibitors. Because of the importance of thrombosis in saphenous vein graft disease, we designed a randomized trial to test the hypothesis that platelet inhibitor therapy could significantly reduce this complication. Experimental evidence suggested that preoperative dipyridamole decreased intraoperative platelet activation, maintained the platelet count during cardiopulmonary bypass but, unlike aspirin, did not increase operative blood loss. Thus, in our trial (Figure 5), therapy with dipyridamole (100 mg/q.i.d.) was begun 2 days preoperatively, and aspirin was begun at a dose of 325 mg per nasogastric tube 7h postoperatively. Thereafter, patients received aspirin 325mg/daily and dipyridamole 75mg/t.i.d. Early angiography performed a median of 8 days postoperatively showed an overall patency rate of 96% in the treated group versus 85% in the placebo group. This significant treatment benefit was noted in over 50 subgroups, including those at high risk for graft occlusion, as determined by graft blood flow and distal coronary

ANTITHROMBOTICS FOR HEART DISEASE

725

diameter (Chesebro et al, 1982). Late angiography at a median of 1 year postoperatively was performed in 84% of study patients. Of patients with individual grafts patent up to 1 month after surgery, there appeared to be no difference in vein graft diameter for the entire length and for the proximal and distal 2 cm, suggesting that platelet inhibitor therapy did not prevent intimal hyperplasia in the grafts. The percentage of new, late occlusions, however, was reduced from 14% in the placebo group to 9% in the treated group; thus, platelet inhibitor therapy significantly decreased the incidence of late thrombosis complicating intimal hyperplasia (Chesebro et al, 1984). The preoperative administration of dipyridamole is safe, since bleeding did not differ between placebo and treated groups. However, discontinuation of platelet inhibitors because of headache or gastrointestinal symptoms was necessary in only 6% of treated patients versus 2% of placebo treated controls. A large number of studies now convincingly demonstrate the importance of beginning platelet inhibitor therapy in the perioperative period, preferably before, but definitely no later than 48 h following surgery (Table 2). Therapy begun later than 2 days postoperatively does not significantly improve early graft patency. The recently reported Veterans' Administration Cooperative Study (Goldman et al, 1988) (Figure 5) adds important information on the dose of aspirin and the use of dipyridamole and sulphinpyrazone. Five different treatment regimens were tested: aspirin 325 mg/daily, aspirin 325 mg/t.i.d., aspirin 325 mg/day plus dipyridamole 75 mg/t.i.d., sulphinpyrazone 267 mg/ t.i.d., and placebo. Aspirin was begun 12h preoperatively, all other therapies were begun 48 h before surgery. All aspirin treated groups had significantly greater early graft patency (92-93.5%) versus placebo controls (85%). Aspirin given once daily was as effective as aspirin given three times a day. The addition of dipyridamole was not of additional benefit to the use of one daily dose of aspirin, and sulphinpyrazone did not significantly improve graft patency, despite a beneficial trend. The preoperative use of aspirin was associated with greater perioperative bleeding, increased transfusion requirements, and higher rates of reoperation to control bleeding. A recent randomized placebo-controlled trial of ticlopidine 250 mg twice daily in patients undergoing coronary artery bypass showed a significantly decreased incidence of graft occlusion at 10, 180 and 360 days postoperatively (Figure 5). Because of its potent effects on platelets, ticlopidine was begun on the second postoperative day (Limet et al, 1987).

Anticoagulants. Although recent studies have highlighted the role of platelets in the pathogenesis of saphenous vein graft disease, the coagulation system plays an important role in vein graft thrombosis. In one trial, dipyridamole and subcutaneous heparin were given for 1 week after surgery and oral anticoagulants were introduced on the seventh postoperative day. After 2 months, only 67% of controls had all grafts patent, versus 81% in patients on anticoagulants. Anticoagulated patients had 90% of all grafts patent versus 84% in controls, but the benefit of anticoagulants was only seen in grafts with low flow, a condition predisposing to fibrin deposition (Gohlke et al, 1981). In two other studies, oral anticoagulation begun on the

Baur et al (1982) Lorenz et al (1984) Mayer et al (1981) Cheseboro et al (1984)

* Denotes statistically significant treatment effect.

Limet et al (1987)

Goldman et al (1988)

Brown et al (1985)

Brooks et al (1985)

McEnany et al (1980) Sharma et al (1985)

Pantley et al (1979)

Rajah et al (1985)

Cheseboro et al (1982)

Dose of platelet inhibitor (mg)

Sulphinpyrazone 800 Aspirin 100 Aspirin 1300 Dipyridamole 400 Aspirin 325 Dipyridamole 225 Aspirin 975 Aspirin 990 Dipyridamole 225 Aspirin 975 Dipyridamole 225 Aspirin 600 Aspirin 975 Dipyridamole 225 Aspirin 990 Dipyridamole 225 Aspirin 975 Aspirin 975 + Dipyridamole 225 Aspirin 325 Aspirin 975 Aspirin 325 + Dipyridamole 225 Sulfinpyrazone 801 Ticlopidine 500

Study reference

- 12 h - 12 h - 12 h - 2 - 2 2

2-3

10 days 180 days 360 days

60 days

12 months

11-14 months

1-47 months t2 months

3-4 3-5 2-3

6 months

4-7.5 months

93.5* 92.3* 91.9" 90.2 92.9* 85* 84,1"

85 86.6 76 73.9

88* 86*

89

80 83

82

92*

96* 89*

96* 90* 92*

Treated (%)

85 85 85

79 79

87

73 80

82

75

85 75

8 days median 11-18 months

Control (%) 90 68 78

Follow-up

Patency rate of grafts

7-14 days 4 months 3-6 months

3

1 1 1 - 2 1 1 1 - 1

Day started

Table 2. Antiplatelet therapy in coronary artery bypass graft surgery.

ANTITHROMBOTICS FOR HEART DISEASE

727

third postoperative day was ineffective in decreasing early graft occlusion. Even if effective, use of anticoagulants is unlikely to be widely endorsed because of their inconvenience, greater risk of haemorrhage and requirement for costly monitoring. However, clinical trials of combined anticoagulants and low dose aspirin may be justified for patients with high risk of graft closure, such as those with diseased distal vessels and low graft flow.

Summary of recommendations: antithrombotic therapy for saphenous vein bypass graft disease 1.

Platelet inhibitor therapy is required for the prevention of early thrombotic graft occlusion. In view of the increased blood loss due to preoperative aspirin, we advise the use of dipyridamole 100 mg/q.i.d., beginning 48 h preoperatively, and the postoperative administration of aspirin 325 rag/daily at the earliest possible time. Aspirin should be continued indefinitely, but dipyridamole may be discontinued postoperatively. 2. Preliminary results with the use of ticlopidine appear promising, but its role in saphenous vein bypass grafting will need to be clarified in further clinical trials. 3. The use of internal mammary artery grafting, particularly to the left anterior descending system, is advised whenever possible because of its outstanding long-term patency and favourable effects on survival. 4. Risk factor modification is strongly advised for all patients undergoing coronary artery bypass, both to minimize atherosclerosis in the grafts as well as progression of native coronary disease. POSTANGIOPLASTY OCCLUSION AND RESTENOSIS Pathophysio/ogy In the past decade percutaneous transluminal coronary angioplasty (PTCA) has emerged as an alternative to coronary bypass in some groups of patients. Successful PTCA appears to require splitting and fracture of the plaque, and medial distortion and expansion of the external diameter of the artery. Angiography immediately following PTCA shows angiographic features of intimal disruption including intimal flaps, intraluminal haziness and dissection. The clinical outcome following PTCA depends on the response of the haemostatic system to the injury as well as the haemodynamic results of the procedure itself. Experimentally, following superficial injury to the intima, the subendothelium is covered by a carpet of adherent platelets (Steele et al, 1985). Following more severe injury, exposure of medial collagen types I and III stimulates both platelet activation and coagulation as previously described. Thrombin generation rapidly ensues, providing a strong stimulus to further platelet deposition. As seen in the pig and rabbit models of PTCA, platelet deposition occurs in all cases, but frank thrombus formation, which

728

D . H . I S R A E L ET A L

may lead to acute occlusion, occurs only if injury is more severe. Even without macroscopic thrombosis, platelet deposition results in release of platelet derived mitogens which contribute to smooth muscle cell proliferation and synthesis of collagen. These pathophysiological processes may also result from balloon-induced endothelial injury and direct trauma to smooth muscle cells. The flow characteristics of blood in the vessel undergoing angioplasty are also vital in determining the haemostatic response. As indicated, there is a substantially greater degree of platelet deposition on severely injured vessels in the setting of elevated shear rates as evidenced by significant residual stenosis. Thus, two events caused by PTCA predispose to platelet deposition and thrombosis: deep arterial injury with exposure of collagen, and presence of residual stenosis with increased local wall shear rates. Vasoconstriction may also result in elevated shear rates by decreasing luminal diameter, and so may also enhance platelet deposition. Recent data show that vasoconstriction frequently accompanies PTCA and may occur as the result of the release of vasoactive substances by adherent platelets, or the loss of endothelial dependent relaxation. Other factors may alter flow characteristics and so stimulate platelet deposition and thrombosis. For example, a large intimal flap may disturb flow in such a way as to promote acute occlusion. These theoretical constructs appear to be supported by human data. Acute occlusion within 24h of PTCA occurs in approximately 3% of patients, particularly those with dissections and large intimal flaps. Restenosis remains the major weakness of PTCA, occurring in 25-30% of cases. Clinical predictors of restenosis include recent onset of angina and crescendo or unstable angina, perhaps because of the frequent occurrence of recent plaque ruptures and thrombosis in these cases. An important procedural variable associated with restenosis is a high postangioplasty trans-stenotic gradient associated with high wall shear rates (Guiteras et al, 1987).

Antithrombotic therapy for postangioplasty occlusion and restenosis Studies of antithrombotic therapy in the porcine angioplasty model with standard dose heparin have shown that macroscopic mural thrombosis occurs in 80-90% of deeply injured arteries, but this number can be decreased to 30-35% using aspirin ( l m g k g - 1 day- 1 ), aspirin (20mgkg- 1 day- 1 ) plus dipyridamole (2.5 m g k g - 1 day- 1), intravenous ibuprofen, and anagrelide (Steele et al, 1984). Recently we have shown that higher dose heparin alone significantly decreased mural thrombosis in deeply injured arteria! segments, from 100% when the total heparin dose was less than 3.1 units kg- 1min- 1, to 25% with heparin doses exceeding this amount (Heras et al, 1988). Preliminary results with hirudin, a peptide inhibitor of thrombin induced platelet activation, have been extremely promising in decreasing platelet deposition following PTCA (Heras et al, 1989). Finally, experimental work is underway to test the efficacy of antibodies to platelet-adhesive glycoproteins and vWF for the prevention of the platelet-vessel wall interaction during and after PTCA.

ANTITHROMBOTICS FOR HEART DISEASE

729

Clinical studies in humans now demonstrate that platelet inhibitor agents significantly reduce the risk of acute thrombotic occlusion and Q wave myocardial infarction in heparinized patients during PTCA. This has been shown for aspirin and dipyridamole (Barnathan et al, 1987), as well as ticlopidine (White et al, 1987). Despite these positive results, studies of antithrombotic therapy have yielded disappointing results in the context of combating restenosis. Studies involving the use of aspirin, with or without dipyridamole, Coumadin, ticlopidine and steroids have failed to demonstrate a preventive effect on restenosis. Probably this is a reflection of the failure of these drugs to inhibit the platelet-vessel wall interaction, an important promoter for the subsequent smooth muscle proliferative response. Studies of to-3 fatty acids have yielded inconsistent results. Three studies have found a significant decrease in restenosis in fish oil treated patients (Slack et al, 1987; Dehmer et al, 1988; Milner et al, 1988), an effect not detected in two other studies (Grigg et al, 1987; Reis et al, 1988). Recent experimental evidence appears to suggest that fish oils may act to decrease synthesis of P D G F activity by endothelial cells (Fox and DiCorleto, 1988), while augmenting endothelial dependent relaxation, independent of their well recognized platelet inhibitory effects. None the less, it remains to be clarified whether these in vitro effects will translate to reproducible clinical benefit in decreasing postangioplasty restenosis, and the routine use of fish oils for this purpose cannot be recommended at present. Similarly, heparin is known to suppress smooth cell proliferation in animal models but the use of heparin beyond the first 24-48 h following PTCA has not yet been tested in humans.

Summary of recommendations: antithrombotic therapy for postangioplasty occlusion and restenosis 1.

The use of aspirin 325 mg daily is advised, beginning at least 1 day prior to PTCA, and including a dose I h before the procedure in order to inhibit TxA2 synthesis from platelets released from the bone marrow since the preceding dose. Aspirin should be continued indefinitely following PTCA. 2. All patients should receive a heparin bolus of 100 units/kg at the beginning of the procedure, followed by an infusion of 15 units k g - l h - l ; this should continue until the next day when the arterial sheath may be removed. If thrombus is noted on the angiogram following PTCA, or if a large intimal flap has been created, the heparin infusion may be continued for 48 h. 3. If vasospasm is noted to contribute to a reduction in luminal diameter, the use of oral or intravenous nitrates should be strongly considered to improve blood flow and diminish shear dependent platelet deposition. 4. There is a need for better therapies to decrease the problem of restenosis. Future approaches may include potent inhibition of the platelet-vessel wall interaction, or development of strategies to decrease smooth muscle proliferation and connective tissue synthesis.

730

D.H.

I S R A E L ET AL

VALVULAR HEART DISEASE

In the setting of valvular heart disease, thrombosis tends to occur within the atrium. Although incompletely understood, stasis probably plays an important aetiological role, particularly when atrial fibrillation results in the loss of atrial mechanical activity. Although such thrombi are largely composed of fibrin, there is a substantial platelet component as well. Mitral stenosis and incompetence

For patients with valvular heart disease, the greatest risk of thromboembolism occurs in isolated mitral stenosis, or combined mitral stenosis and incompetence. Thrombi form in the enlarged left atrium, and also in the left atrial appendage. The incidence of embolism can be as high as 5% per year, and 75% involve the cerebral circulation. Before oral anticoagulants were used, thromboembolism accounted for 16-19% of the mortality in mitral stenosis, and embolism was the presenting symptom in up to 10% of cases. Isolated mitral incompetence carries a smaller risk of systemic emboli, but the risk increases with the severity of regurgitation. For those patients with combined mitral stenosis and incompetence, emboli may complicate the clinical course in as many as 14-18% (Coulshed et al, 1970). Overall, in our study with 10-year follow-up, there were 2.9 events per 100 patient-years (Fuster et al, in press). The most important determinant of thromboembolic risk in mitral stenosis or incompetence is atrial fibrillation, which increases risk by a factor of between 6 and 18. Left atrial enlargement increases the risk of atrial fibrillation but, by itself, may not be a risk factor for emboli. Most emboli occur shortly after the onset of atrial fibrillation (one-third within a month, and two-thirds within a year) (Szekely, 1964); thus, it is appropriate to anticipate its onset by serial echocardiographic measurements of left atrial dimensions and to begin prophylactic oral anticoagulation before the dysrhythmia occurs. Emboli tend to recur particularly within 6 months, an outcome associated with substantial mortality. There has never been a randomized primary prevention trial of oral anticoagulants in mitral valve disease; however, a number of studies demonstrate their efficacy in prevention of recurrent emboli (Wook and Conn, 1954; Szekely, 1964; Adams et al, 1974).

Antithrombotic therapy for mitral stenosis and incompetence Patients with mitral stenosis, mitral incompetence or mixed lesions in atrial fibrillation are at great risk for thromboemboli. Anticoagulation with Coumadin is strongly advised to prolong the prothrombin time to × 1.5-2.0 control (INR=3-4.5). Patients in sinus rhythm with marked left atrial dilatation of > 5 0 m m by M-mode echocardiography should be prophylactically anticoagulated in an attempt to lower the high incidence of embolism immediately after the onset of atrial fibrillation. All patients with a previous embolus require anticoagulation, as do patients with globally

ANTITHROMBOTICS FOR HEART DISEASE

731

impaired left ventricular systolic function (ejection fraction