Antithrombotic Agents in Coronary Artery Disease

Antithrombotic Agents in Coronary Artery Disease John A. Cairns, MD, Chair; Pierre Theroux, MD; H. Daniel Lewis, Jr., MD; Michael Ezekowitz, MD; Thomas W. Meade, DM; and George C. Sutton, MD

(CHEST 1998; 114:611S-633S) his chapter begins with a section on Pathophysiology, followed by discussion of the clinical syndromes under the major headings of Acute Myocardial Infarction (AMI) , Unstable Angina, Chronic Coronary Artery Disease, and Primary Prevention. In each section, the greatest weight is given to randomized controlled trials (RCTs) and overviews of them. Although the overviews give a broad summary picture, they do not provide the immediacy and more direct relevance of individual, large, well-designed clinical trials with unequivocal results. Details of the major trials provide the reader with a sense of the sorts of patients under study and the potential generalizability of the results to the reader's own patients. This chapter gives greater emphasis to relatively recent evidence, omitting details of individual trials provided in earlier editions of this Consensus Conference. The summaries and recommendations are based on all available evidence whether or not it is discussed in detail in this chapter.

T

PATHOPHYSIOLOGY

Endovascular thrombus formation is a critical factor in the development of AMI, unstable angina, and thrombotic coronary occlusion during coronary angioplasty. Herrick1 is generally credited with the first clinical description of AMI, and his view of the causative role of coronary thrombosis was widely accepted. As a result of many subsequent observations,2-5 the concepts of evolving coronary thrombosis underlying unstable angina and acute occlusive thrombosis producing AMI became firmly established. For a time in the 1960s, the role of coronary thrombosis in the pathogenesis of the acute ischemic syndromes appeared less certain.6 However, eventually a huge body of evidence emerged implicating platelet aggregation, activation of the coagulation system, and eventual coronary thrombosis in the pathophysiology of unstable angina, AMI, and sudden coronary death. More recent work has focused on the plaque characteristics leading to thrombosis and acute ischemic coronary events. There is now a strong rationale and extensive evidence from clinical trials for therapies designed to prevent and limit platelet aggregation and activation of the coagulation cascade, and to lyse or physically disrupt coronary thrombi and to limit their propagation and recurrence in patients with coronary artery disease. Thrombosis most often develops on an underlying atherosclerotic plaque, usually of only mild-to-moderate severity as determined by coronary angiographyJ-9 Recent progression of coronary stenosis is a common feature of Correspondence to: John A. Cairns, MD, Faculty of Medicine, University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3

unstable angina10·u and careful analyses of these stenoses have shown characteristic morphologic features suggestive of plaque disruption, partially lysed thrombus, or both.12·13 The prevalence of thrombosis is highest among those patients who undergo angiography within hours of the most recent episode of chest pain. The angiographic observation of DeWood and colleagues 14 that occlusive coronary thrombosis is an early and important event in >80% of transmural infarcts has been confirmed among thousands of patients undergoing angiography in the early hours of AMI. Angioscopy has confirmed the presence of plaque damage and thrombosis in unstable angina and AMI. 15 Falk16 has shown that patients experiencing sudden death preceded by serial episodes of unstable angina may be found at autopsy to have an occlusive thrombus composed of layers of platelet thrombi at different stages of organization, corresponding to the clinical episodes of ischemia. Platelet emboli distal to the site of the occlusive thrombosis have also been observed.l6 ·17 Davies et all8,19 have reported coronary thrombosis, plaque injury, or both in 95% of sudden death victims. The vulnerable plaque is only moderately stenotic, is relatively soft, and has a central core rich in lipids and a fibrous cap poor in connective tissue and smooth muscle cells, making it pliable and prone to rupture under local rheologic stress conditions, 20 particularly at the junction of the plaque and more normal tissue, the so called "shoulder" region. Increasingly, atherosclerosis is seen as a chronic inflammatory process occurring in response to a variety of injurious influences.21 The unstable plaque shows an exacerbation of this inflammatory process with dense accumulation of monocyte-macrophages, mast cells, lymphocytes, and neutrophils secreting cytokines that mediate the inflammatory process, growth factors associated with cell proliferation, and metalloproteinases that lead to matrix degradation, and eventually plaque erosion and rupture or fissure of the cap. The rupture exposes subendothelial proaggregant and procoagulant substances to the circulating blood. Platelets adhere through surface glycoproteins to von Willebrand factor and collagen. Tissue factor, widely expressed in macrophages and leukocytes within the diseased plaque, forms a complex with circulating factor VIla. This complex triggers the extrinsic and intrinsic pathways of the coagulation cascade leading to factor X activation and the generation of thrombin, a potent platelet agonist. Most of the coagulation process occurs at the platelet surface. Platelet adhesion and stimulation lead to intracellular signaling, an increase in cytoplasmic calcium content, contraction and shape change, and the secretion of active products from the intracytoplasmic granules. The enzymatic liberation of arachadonic acid, and the sequential evolution of prostaglandins results in the synthesis of thromboxane A2 , an extremely potent vasoconstrictor and platelet aggregant. During this process, the platelet membrane surface integrin glycoprotein (GP) Ilblllla receptors undergo a configuration change allowing binding of fibrinogen and other ligands. Unactivated platelets have approximately 50,000 GP lib/Ilia receptors expressed on their surface; an additional 30,000 receptors are exteriorized from the cytoplasmic reticulum on activation. The activated recepCHEST /114/5 / NOVEMBER, 1998 SUPPLEMENT

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tor recognizes the RGD sequence and a dodecapeptide sequence of the fibrinogen molecule. Binding of fibrinogen to the receptor results in platelet linkages, platelet aggregation, and growth of a platelet thrombus . Incorporation of fibrin and RBCs within this thrombus forms a partially or completely occlusive red thrombus . Inappropriate increases in coronary tone, most often in the region of an atherosclerotic plaque, may be an important component of the etiology of many episodes of acute myocardial ischemia. Nitric oxide production is reduced when the endothelium is diseased, resulting in impaired endothelial-dependent vasodilatation. Rarely, coronary spasm may culminate in AMJ.22 Most often, the pathophysiologic sequence appears to be one of atherosclerotic plaque disruption, platelet activation, thrombin generation, and partial or complete thrombotic occlusion 23 with a component of inappropriate vasoconstriction of variable importance. The observation of recurrent formation and disruption of platelet occlusive thrombi at the site of endothelial disruption and stenosis in the canine coronary stenosis model of Folts et al24 and the effects of various interventions thereon 24·25 may be closely representative of the situation in human unstable angina. The causes of the intense inflammatory reaction that leads to plaque degeneration and rupture are unknown. A toxic reaction to substances such as oxidized low-density lipoprotein (LDL) cholesterol or homocysteine, an autoimmune process, or a local or systemic infection are possibilities. Helicobactor pylori, cytomegalovirus, and other herpes viruses have been incriminated in this process; most recent evidence supports a role for Chlamydia pneumoniae by direct infection at the plaque level or a distant infection inducing an immune reaction or crossreactive antibodies and cytokine release. It is unknown whether the infection is an innocent bystander or plays a role in the disease process. Two early pilot studies have suggested that treatment with a macrolide antibiotic could be effective in reducing ischemic outcomes among patients at risk. 26·27 In concert with the clinical course of unstable angina, a variety of markers of activation of platelets and the coagulation system, as well as of inflammation, are found in the plasma or expressed at the surface of platelets and leukocytes. For example, P selectin expressed at the platelet surface mediates platelet leukocyte interaction. Markers of ongoing coagulation present in plasma include fibrinopeptide A, prothrombin fragment 1.2, thrombinantithrombin III complex, and fibrin/fibrinogen degradation products. 28·29 An elevation of the inflammatory marker C-reactive protein predicted impaired prognosis in unstable angina in one study, and in the Physicians' Health Study identified individuals who benefit from aspirin in the primary prevention of myocardial infarction (MI). Unstable angina results from a rapid increase in the severity of coronary stenosis but incomplete occlusion, while acute Q-wave infarction is associated with total occlusion. 23 Non-Q-wave infarction is the consequence of an intermediate degree of obstruction, which is generally subtotal, but may be total with a degree of collateral blood supply or recanalization. Unstable angina is associated with no or minimal myocardial necrosis. There is an 6128

important risk of myocardial necrosis with unstable angina, and of infarct extension with non-Q-wave MI. The risk is increased when the endothelium is not yet healed, maintaining a stimulus to further thrombosis. Tissue factor and clot-bound thrombin are strong thrombogenic stimulus causing ongoing activation of platelets and coagulation factors. Although the endothelium may heal and the plaque may be remodeled, the stenosis has generally progressed from the stable phase and there is a persisting risk of recurrent plaque rupture. The development of irreversible myocardial damage and necrosis worsen immediate and late outcomes. CLINICAL TRIALS IN

MI

Systemic Embolization Systemic embolization after AMI is usually manifested by a stroke. In most cases, the source of the thrombus is the left ventricle (LV) or the left atrium or both.3o A number of clinical studies have focused on the incidence of systemic embolism in patients with AMI, including the particular risk and the association with echocardiographically detected mural thrombosis in anterior MI.3 1-34 The larger studies indicate a risk of stroke between 1% and 3% for all infarctions and between 2% and 6% for patients with anterior MI. In the prethrombolysis era, echocardiographic studies showed that LV thrombus is rare with inferior AMP1·3s but develops in up to 40% of anterior MI, 33 ·35- 37 particularly when there is apical akinesis or dyskinesis.34-36,38 Additional risk factors include extensive infarction, a dilated and dysfunctional LV, acute aneurysm, congestive heart failure (CHF), and atrial fibrillation. Mural thrombi tend to form early after AMI, even during the first 24 h, but may not appear until 1 to 2 weeks. 36·38 A mural thrombus that is protruding into the LV and/or is freely mobile is more likely to embolize. 39 - 41 Most systemic emboli occur within the first few weeks following acute infarction,31·35 although a 13% incidence of systemic embolism throughout a 4-year period among patients with associated poor LV function has been reported.42 A few small nonrandomized studies have documented a reduction by anticoagulants of systemic embolism among AMI patients found to have mural thrombosis.31·34 ·41·43·44 The incidence of stroke was reduced in all three of the large short-term trials of anticoagulation in AMI. 45- 47 Turpie et al48 randomized 221 patients with anterior MI to treatment with high-dose heparin (12,500 U subcutaneously every 12 h) vs low-dose heparin (5,000 U subcutaneously every 12 h). Two dimensional (2D) echocardiography on day 10 demonstrated a reduction in the rate of mural thrombosis from 32 to 11% (p = 0.0004). No patient had received thrombolytic therapy. An overview of four trials among post-AMI patients 44 reveals an odds ratio of 0.32 (95% confidence interval [CI], 0.2 to 0.52) in favor of anticoagulant therapy for the reduction of mural thrombosis. In the postthrombolytic era, Kontny et al 49 evaluated the efficacy and safety of dalteparin in the prevention of arterial thromboembolism after AMI. A total of 776 Fifth ACCP Consensus Conference on Antithrombotic Therapy

patients were enrolled in a multicenter, randomized, double-blind placebo-controlled trial. Thrombolytic therapy and aspirin were administered to >90% of the patients. In the placebo group, 21.9% of patients had thrombi as compared with 14.2% in the dalteparin group (p = 0.03). The risk of thrombus formation associated with dalteparin was 0.63 (95% CI, 0.43 to 0.92, p = 0.02). Dalteparin was associated with an increased risk of hemorrhage (2.9% vs 0.3% , p = 0.006). Minor hemorrhage was also more common in the dalteparin group (14.8% vs 1.8%, p < 0.001). Thus, dalteparin significantly reduced the formation of LV thrombi but at the price of an increased hemorrhagic risk. The SCAT! group50 evaluated high-dose subcutaneous heparin among AMI patients who received IV streptokinase (SK) but no aspirin. Among patients with first anterior MI, echocardiographic mural thrombus at hospital discharge was decreased from 36.5 to 17.7% (p < 0.01 ). A substudy from GISSI-251 showed only a trend to less frequent mural thrombus vvith a similar subcutaneous heparin regimen to that of the SCATI trial, but with no initial IV bolus and treatment starting at 12 h (22% vs 30% at mean 12 days). There was a trend toward less frequent mural thrombus with SK vs recombinant tissue-type plasminogen activator (rtPA). Studies in the thrombolytic era highlight the link between systemic embolization and atrial fibrillation postMI, and its association with poor LV function.s 2 •53 In the setting of AMI, atrial fibrillation independently predicts the occurrence of stroke (1.8% vs 0.5%, p = 0.0001 ) and is associated with three-vessel disease, flow less than thrombolysis in myocardial infarction (TIMI) grade 3, advanced age, larger MI, and worse Killip class. In addition, mortality rates are significantly higher at 30 days (14.3% vs 6.2%, p = 0.001) and at 1 year (21.5% vs 8.6%, p < 0.0001). Thrombolytic therapy appears to reduce the incidence of atrial fibrillation and by inference, the predisposition to develop a stroke.3° Two retrospective analyses of studies designed primarily to evaluate the effect of angiotensin-converting enzyme (ACE) inhibition of patients with LV dysfunction provided important information \vith regard to the relationship between ejection fraction and stroke and the potential benefit of antithrombotic therapy.54-56 Loh et al54 collected data on 2,231 patients enrolled in the Survival and Ventricular Enlargement (SAVE) study. The incidence of stroke increased as ejection fraction (EF) declined (EF < 28%, stroke rate 8.9%; EF 29 to 35%, stroke rate 7.8%; EF > 35%, stroke rate 4.1%) (relative risk for EF < 28% vs EF > 35%, 1.86, 95% CI 0.15 to 3.04, p = 0.01). The protective effect of anticoagulant therapy was evident in all three subgroups (LVEF < 28%, relative risk (RR) = 0.17; LVEF, 29 to 35%, RR = 0.14; LVEF > 35%, RR = 0.23). Aspirin was also beneficial among patients with LVEF < 28% and 29 to 35%. It appears that one or both of these agents should be considered for patients with LV dysfunction, especially with LVEF<28%. A retrospective analysis of 6, 797 patients from the Studies of Left Ventricular Dysfunction (SOLVD) trial56 of patients with EF < 35% assessed the beneficial roles of warfarin and aspirin. Warfarin was associated with a

reduction of all-cause mortality (adjusted hazard ratio, 0.76; 95% CI, 0.65 to 0.89; p = 0.0006). The incidence of fatal stroke was not influenced by warfarin therapy. Antiplatelet drug use was associated with significant reduction in all-cause mortality (adjusted hazard ratio, 0.8; 95% CI, 0.73 to 0.92; p = 0.0005). The incidence of fatal stroke was not influenced by antiplatelet therapy. Several small studies31·33--16·39·43 consistently showed an increased risk of systemic embolus with the detection of mural thrombus on 2D echo, and an overview« demonstrates a pooled odds ratio of 5.45 (95% CI, 3.02 to 7.83). However, because mural thrombus occurs within 48 h, 56 reliance on detection of 2D echocardiographic evidence of mural thrombosis may be inappropriate. It is generally concluded that if heparin treatment is to reduce embolic risk, it should be initiated as soon as possible following the diagnosis of probable AMI, and it should be maintained until warfarin therapy prolongs the international normalized ratio (INR) to 2 to 3. Evidence of anterior MI should generally be sufficient to prompt the use of heparin. The indication is strengthened in the presence of atrial fibrillation, CHF, dilated LV, acute ventricular aneurysm, or mural thrombus detected on 2D echocardiography. Thrombus is commonly associated with chronic LV aneurysm (48 to 66% in surgical studies). 57.58 However, systemic emboli are infrequent (4 to 5% by preoperative history) . In a retrospective study of 89 patients with LV aneurysm, 20 were treated with anticoagulants for 40 patient-years and 69 were not so treated for 288 patientyears.59 Only one patient who was not receiving anticoagulants had a clinical embolic event, and incidence of 0.35/100 patient-years. On the basis of this study, the presence of a long-term LV aneurysm, even containing thrombus, does not justify anticoagulant therapy.

Venous Thromboembolism There is a high incidence of deep venous thrombosis accompanying AMI, which rises with duration of bed rest, increasing age, and the presence of CHF. The incidence of pulmonary embolism was reduced by almost 50% in the trials of heparin in the preaspirin/fibrinolysis era. 60 - 62 In the trials comparing heparin vs no heparin among patients receiving aspirin and fibrinolytic therapy, the baseline incidence of pulmonary embolism is sharply lower than in earlier trials. It is likely that many changes in management contributed to the decrease, in addition to the beneficial effects of aspirin and fibrinolytic therapy. There is an incremental benefit of heparin, although it is marginal. Although the clinical diagnosis of pulmonary embolism is unreliable as carried out in most trials among patients with AMI, the findings are supplemented by autopsy data63 •64 and by the results of studies using full-dose heparin therapy followed by oral anticoagulants, demonstrating a significant reduction in the incidence of venous thrombosis diagnosed by 1251 fibrinogen leg scanning.65 •66 It is likely that there is underascertainment of pulmonary embolism, suggesting that the absolute reduction with heparin may be greater than is reported in the trials. Several well-designed studies have assessed the efficacy oflow-dose heparin therapy following AMI. The incidence CHEST/114/5/NOVEMBER, 1998 SUPPLEMENT

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of venous thrombosis identified prospectively by radiolabeled fibrinogen scanning or venography was reduced by 69% (p < 0.0001). 61 ·62 Of 668 patients assessed in these trials for the occurrence of pulmonary embolism, there was a reduction in the incidence from 2.4 to 0.9% (p = not significant [NS]). There is no clear difference in the reduction of pulmonary embolism with the low-dose vs high-dose heparin regimens, but there are very few events to be analyzed in the low-dose trials. To our knowledge, there have been no trials of low-dose heparin vs no heparin among patients receiving aspirin and fibrinolytic therapy.

Mortality Trials Anticoagulants: Short-term Trials: Since 1948, there have been >30 reports of the use of anticoagulants in AMI. 60 - 62 However, only three of these trials 45- 47 were of sufficient size to detect a modest but clinically important reduction of mortality (Table 1). One of these studies found a statistically significant reduction of mortality, while the other two found statistically significant reductions in stroke and pulmonary embolism. Design features and outcomes of these trials are detailed in the previous consensus. 67 Overviews of the anticoagulation trials offer greater perspective and reliability for overall interpretation of the evidence from these trials. Chalmers et al 60 reviewed studies of anticoagulants in the management of AMI and identified only 6 (total 3,854 patients) that allocated treatments randomly, including the three large trials of Tables 1 and 2. A pooled analysis yielded a reduction of unweighted mean case fatality rate from 19.6 to 15.4% (risk reduction 21%, p < 0.05). The thromboembolism rate fell from 21.3 to 11.1% (risk reduction, 48%). Hemorrhage was more frequent among those receiving anticoagulants (2.75% vs 8.4%), but there were no hemorrhagic deaths in the randomized trials. Using rigorous overview approaches, Collins et al61,62 summarized the data on early deaths, reinfarction, strokes, pulmonary emboli, and clinically important episodes of bleeding from the 26 unconfounded properly randomized trials of anticoagulant therapy in the acute phase of suspected MI (Table 2). The trials were categorized as those comparing low-dose subcutaneous heparin with no

antithrombotic therapy, high-dose subcutaneous heparin vs no antithrombotic therapy, high-dose IV heparin vs no antithrombotic therapy, and high-dose heparin followed by oral anticoagulant vs no antithrombotic therapy. Using these categories, they separately evaluated those trials in which the comparisons were made among patients also receiving aspirin and those among patients not receiving aspirin. It is clear from this overview that in the absence of aspirin and fibrinolytic therapy, heparin reduces deaths by a statistically significant and clinically important amount (approximately 35 fewer deaths per thousand patients, p = 0.002). The low-dose subcutaneous regimens are probably not effective in reducing death, but there is no clear difference in efficacy among the high-dose regimens. The beneficial effect on mortality is supplemented by reductions of reinfarction (15/1,000, p = 0.08), stroke (10/1 ,000, p = 0.01) , and pulmonary embolus (19/1,000, p = 0.001). The benefits must be balanced against an increase in noncerebral major bleeds of 13/1,000 (p = 0.01), which appeared to be confined to the highdose heparin regimens. Following successful thrombolysis, there is a risk of infarct-related artery reocclusion of 5 to 30% and a rate of reinfarction of about 4% when acetylsalicylic acid (ASA) is not used. 68 The thrombolytic agents may paradoxically lead to platelet activation and the generation of increased amounts of thrombin. 69 Hence, there is a good theoretic rationale for the conjoint use of heparin. In the present era, most patients with suspect AMI will receive aspirin, and a substantial portion will also receive fibrinolytic therapy. Accordingly, the most relevant trials are those comparing heparin vs no heparin among patients receiving aspirin and fibrinolytic therapy. In the Collins et al61,62 overview, within the trials of heparin among patients receiving aspirin, 93% of them also received fibrinolytic therapy. The baseline rates of death, reinfarction, stroke, and pulmonary embolus were markedly less than in the preaspirin!fibrinolysis era. Although the addition of heparin led to a reduction of death (5/1 ,000, p = 0.03), reinfarction (3/1,000, p = 0.04), and pulmonary embolus (11 1,000, p = 0.01) , the benefits were small, and the statistical significance was marginal. The small mortality benefits observed at 7 days in the International Studies of

Table 1-Short-term (In-Hospital) Trials of Anticoagulation in AMI* Mortality Study MRC

45

No. of Patients 1,427

Agent, Dose Heparin~phenindione

Duration of Therapy, d

Therapy. %

Control,%

Relative Risk Reduction, %

p Value

28

16.2

18.2

11

NS

Hospital stay

14.9

21.2

30

<0.005

28

9.6

11.2

14

NS

(INR 1.6-2.1) vs placebo Bronx

Municipal46

VA Cooperative47

1,136

999

Heparin~phenindione

(INR >2-2.5) VS minimal phenindione Heparin~warfarin (INR >2) vs placebo

*MRC =Medical Research Council; VA= Veterans Affairs. 614S

Fifth ACCP Consensus Conference on Antithrombotic Therapy

Table 2-0utcomes of Heparin Therapy in Suspected AMI* Events per 1,000 Patients Heparin in the Presence of Aspirin (93% of Patients Received Thrombolytic Drug)

Heparin in the Absence of Aspirin Outcome

Heparin

No Heparin

Reduction by Heparin

p Value

Heparin

No Heparin

Reduction by Heparin

p Value

Death Reinfarction Stroke Pulmonary embolus Major hemorrhage

114 67 11 20 23

149 82 21 39 11

35 15 10 19 (13)

0.002 0.08 0.01 0.001 0.01

86 30 12 3 10

91 33 11 4 7

5 3 (1) 1 (3)

0.03 0.04 NS 0.01 0.001

*Table constructed from the overview of 26 randomized, unconfounded trials by Collins et al. 61 ·62

Infarct Survival (ISIS-3)7° and GISSI-2 71 ·72 trials (which contributed most of the patients) became less and were no longer statistically significant at 35 days and 6 months of follow-up. Interestingly, the rate of major bleeding was also less than in the preaspirin!fibrinolysis era, and the excess with heparin was less (3/1,000, p = 0.0001 ). Hence the physician is faced with a modest early benefit of heparin of about five fewer deaths, three fewer reinfarctions, and one fewer pulmonary embolus, balanced against three more major bleeds. This suggests that heparin is not indicated for routine use among patients receiving aspirin and fibrinolytic therapy and that careful selection of patients is warranted (see also the chapter "Coronary Thrombolysis" in this supplement, page 634S). Long-term Trials: There were three major randomized controlled trials of long-term oral anticoagulation following AMI, conducted prior to 1980. 73--76 In 1970, an international anticoagulant review group 77 pooled data from nine controlled, long-term anticoagulant trials involving 2,205 men and 282 women. Mortality was reduced by 20% in men given long-term anticoagulant therapy, but the benefit appeared to be restricted to those with prolonged angina or previous infarction on admission to the trial. The 60+ Reinfarction Study78 •79 enrolled patients >60 years who had been receiving oral anticoagulation following transmural MI that had occurred at least 6 months earlier (mean, 6 years) (Table 3). They were randomly allocated double-blind to continue treatment with oral

anticoagulation (INR, 2.7 to 4.5) or matching placebo. Major and minor extracranial hemorrhages were considerably more frequent in the anticoagulant-treated patients, but transfusion was rare and there were no fatal hemorrhages. An efficacy analysis of patients adhering to study therapy showed more marked benefits. The Warfarin Reinfarction Study (WARIS) 80 enrolled patients who had sustained AMI a mean of 27 days previously. They were randomized double-blind to treatment with warfarin (INR, 2.8 to 4.8) or placebo and were advised not to take ASA. There were statistically significant reductions in all-cause mortality, reinfarction, and stroke, and an efficacy analysis revealed more marked benefits. Venous thromboembolism was rare with placebo and did not occur with warfarin. There was one peripheral arterial embolus in each group. There were five intracranial hemorrhages with warfarin treatment, three of them fatal, and there were eight episodes of major extracranial hemorrhage with warfarin treatment, for a combined incidence of major bleeding of 0.6% per year. The Anticoagulation in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) research group 81 enrolled patients who had sustained an AMI within 6 weeks of hospital discharge. They were randomized double-blind to treatment with acenocoumarol (Nicoumalone), phenprocoumon (INR, 2.8 to 4.8), or placebo. There was a favorable trend for reduction of all-cause mortality with statistically significant reductions in reinfarction and stroke. The combined annual incidence

Table 3-Long-term Trials of Anticoagulation Following Ml Study Sixty Plus 78.79 (1980 and 1982) Mortality Reinfarction Stroke WARIS8° (1990) Mortality Reinfarction Stroke ASPECT81 (1994) Mortality Reinfarction Stroke

No. of Patients

Therapy, o/o

Control, o/o

Relative Risk Reduction, o/o

p Value

11.6 6.9 3.1

15.7 15.2 5.2

26 55 40

0.071 0.0005 0.16

15 14 3.3

20 20 7.2

24 55

0.0267 0.0007 0.0015

10 6.7 2.1

11.1 14.2 3.6

10 53 42

878

1,214 34

3,404

CHEST I 114 I 5 I NOVEMBER, 1998 SUPPLEMENT

NS < 0.001 <0.001

6158

of major bleeding was 1.4% per year with oral anticoagulation and 0.4% per year with placebo. Efficacy analysis showed greater risk reductions with anticoagulation. Neri Semeri et al82 evaluated heparin (12,500 U subcutaneously once daily) among 6- to 18-month survivors of Q-wave MI. There was a significant reduction in the rate of reinfarction with favorable trends for the reduction of all-cause and cardiovascular mortality. Efficacy analysis provided stronger evidence for a benefit of heparin. There were no major hemorrhages and no evidence of osteoporosis on bone density measurements.

Antiplatelet Agents Aspirin causes irreversible inhibition of platelet cyclooxygenase, thereby preventing formation of thromboxane A2 , a platelet aggregant and potent vasoconstrictor.83 It has no effect on platelet aggregation induced by other agonists and is therefore a weak platelet inhibitor. Although aspirin possesses many other physiologic effects, none of them has been conclusively associated with the benefit observed in thromboembolic diseases. Aspirin inhibits the constitutive cyclooxygenase 1 that is present in almost all cells involved in general homeostasis. It has no effect on cyclooxygenase 2 induced in endothelial cells and in smooth muscle cells following cytokine and growth factor stimulation. The coronary artery model of Folts et al24 in dogs shows that platelet deposition is reversible with aspirin before an occlusive fibrin thrombus forms, potentially interfering with the thrombotic pathophysiology of the acute syndromes of coronary artery disease. The adverse effects of aspirin are primarily related to bleeding, particularly GI. The latter is less common at the low dosage of 80 to 160 mgld needed to inhibit platelet aggregation. Other nonsteroidal anti-inflammatory drugs reversibly inhibit platelet cyclooxygenase and platelet aggregation, but few clinical trials have been conducted among patients with coronary artery disease. A randomized study of indobufen vs placebo 84 among patients with heart disease and at risk for cardiogenic embolism showed a relative risk reduction of 65% in stroke, transient ischemic attack (TIA), systemic and pulmonary embolism, and fatal MI over a 2 1/2-year follow-up. Indomethacin has been shown to increase myocardial ischemia.ss Various drugs inhibiting thromboxane are A2 synthase or blocking the thromboxane A2 receptor, or both, have been investigated in clinical trials. Although they do not decrease prostacyclin production, they have shown no advantage over aspirin. Sulfinpyrazone, a nonsteroidal anti-inflammatory drug, reversibly inhibits cyclooxygenase, but its exact mechanism of action as a platelet inhibitor remains unclear. 83 It also normalizes shortened platelet survival in patients with prosthetic heart valves, and its benefits appear to be more marked on prosthetic rather than natural surfaces. Adverse effects of sulfinpyrazone include exacerbation of peptic ulcer disease, potentiation of the effects of warfarin, and elevation of uric acid. Dipyridamole's effects appear to be related to an increase in platelet cyclic adenosine monophosphate.83 Its antithrombotic effects are more evident on prosthetic 616S

surfaces. Dipyridamole prolongs shortened platelet survival. In contrast to aspirin, it does not increase the risk of GI bleeding even when combined with warfarin. Ticlopidine is a platelet antiaggregatory agent known to inhibit the formation of arterial thrombi. 83 It is chemically unrelated to the other antiplatelet drugs and its mechanism of action is not completely understood. It inhibits the induction of platelet aggregation by adenosine diphosphate (ADP) and other agonists, prolongs bleeding time, and normalizes shortened platelet survival. It can be associated with diarrhea (which is common), rash, reversible neutropenia (about 1% of cases, sometimes fatal), thrombocytopenia, and liver function abnormalities (rare). Clopidogrel is a thienopyridine, like ticlopidine, which predominantly inhibits platelet activation induced by ADP. The recommended dose achieves the same level of inhibition of ADP-induced platelet activation as ticlopidine. However, it is well tolerated as demonstrated in the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study,86 conducted among > 19,000 patients. The GP IIb/IIIa antagonists occupy the platelet surface integrin GP Ilb!Illa receptors to prevent fibrinogen binding to platelets, platelet to platelet linkages, and platelet aggregation. 87 Their effects are dose related; however, there is usually a steep dose response curve, narrowing the margin between efficacy and risk of bleeding. Abciximab, a monoclonal antibody against the receptor developed by Coller, 87• was the first antagonist available. Peptide and nonpeptide antagonists containing the RGD (or KGD) sequence for fibrinogen binding were subsequently synthetized. Oral active agents are now available and are being investigated in large clinical trials. Abciximab is administered as an IV bolus of 0.25 mglkg followed by an infusion at a rate 10 JJ.g/min for 12 h. This regimen results in >80% receptor occupancy and inhibition of platelet aggregation induced by ADP. The plasma half-life is short, but because the antibody avidity for the receptor is very high, approximately 70% of receptors are still occupied 12 h after drug therapy discontinuation, in association with 50% inhibition of platelet aggregation. The drug can be found on platelets as long as 15 days after its discontinuation. It is not specific for GP IIb!IIIa (a2 j3 3 ) but at therapeutic levels also inhibits the integrin vitronectine receptor (avl3 3 ) that has a role in smooth muscle cell proliferation. Abciximab is immunogenic and has potential for antigenicity. Registry data, however, have shown that it can be safely administered a second time to patients who have received the drug previously. The administration of abciximab in coronary angioplasty trials was initially associated with significant risk of bleeding, but increased experience with the drug, the use of lower doses of heparin, and early discontinuation of heparin therapy before sheath removal have significantly reduced the risk of bleeding. Abciximab is currently approved for high-risk coronary balloon angioplasty; it has been used in bail-out angioplasty procedures and stent implantation with a favorable clinical experience. The drug is now being investigated in AMI as adjunctive treatment to thrombolysis and in unstable angina and non-Q-wave MI. Eptifibatide, a cyclic heptapeptide containing the KGD Fifth ACCP Consensus Conference on Antithrombotic Therapy

sequence for binding to the receptor, and tirofiban, a nonpeptide tyrosine derivative mimicking the RGD sequence for fibrinogen binding, are two highly specific synthetic GP lib/lila antagonists. 87 The two drugs are approved for the medical treatment of patients with unstable angina and non-Q-wave MI as well as for percutaneous coronary interventions in these patients. They have a short half-life of 2 to 3 h with rapid reversal of the inhibition of platelet aggregation, and they are not antigenic. The dose of eptifibatide recommended in the acute coronary syndromes is a 180-j.Lg/kg bolus followed by a 2-j.Lg/kg/min infusion and for coronary angioplasty a 135~J.g/kg bolus followed by 0 . 5-~J.g/kglmin infusion, and for tirofiban, 0.4 ~J.g/kg/min for 30 min followed by an infusion of 0.1 ~J.g/kglmin. Heparin is administered at therapeutic doses with the two drugs. Lamifiban and Kleroal are two nonpeptide IV inhibitors of the receptors currently being investigated in clinical trials. Short-term Trials: In 1979, Elwood and Williams88 reported the results of a randomized, placebo-controlled trial of a single dose of 300 mg of aspirin administered on first contact by general practitioners to patients thought to have MI. Of the 2,530 patients randomly assigned to therapy, results were reported for the 1, 705 patients with confirmed MI. Mortality rate at 28 days was not significantly different between the two groups (19.2% with aspirin, 19.6% with placebo).89 The ISIS-2 pilot study90 was a trial of 619 patients with suspected AMI randomized to treatment with SK 1.5 megaunits (MU) IV over 1 h, or placebo; to aspirin 325 mg on alternate days for 28 days, or placebo; and to heparin, 1,000 Ulh for 48 h or no heparin. Aspirin treatment was associated with a significant decrease in early mortality and a nonsignificant decrease in reinfarction and stroke. Verheught et al91 conducted a randomized trial of 49 patients to evaluate 100 mgld of aspirin vs placebo for 3 months after IV SK therapy for anterior MI. There was a statistically significant reduction in the frequency of left anterior descending coronary artery occlusion among the patients receiving aspirin. This research group also showed in the APRICOT trial 92 that among survivors of thrombolytic therapy for AMI with a patent infarct-related artery at about 48 h, aspirin was more effective than heparin in the prevention of revascularization, recurrent MI, and death, with better maintenance of patency at 3 months. ISIS-293 was a randomized, placebo-controlled, doubleblind trial of short-term therapy with IV SK, oral aspirin, 160 mg daily for 1 month, both, or neither among 17,187 patients with suspect AMI. In addition to the 23% risk reduction in the 5-week vascular mortality among those given SK, there was a 21% reduction among those given aspirin, and a 40% reduction among those given a combination of SK and aspirin, all highly significant. The early reduction in mortality with aspirin persisted when the patients were followed up for a mean of 15 months. Aspirin reduced the risk of nonfatal reinfarction by 49% and nonfatal stroke by 46%. The increased rate of early nonfatal reinfarction noted when SK was used alone is consistent with marked platelet activation after fibrinolytic therapy, and was completely resolved when aspirin was added (3.8% vs 1.3%). Aspirin added to the benefit of SK

therapy in all groups examined. In particular, among patients >70 years, the combination markedly reduced mortality from 23.8 to 15.8% (p < 0.001) without increasing the risk of hemorrhage or stroke. Because of poor prognosis in older patients with AMI, the absolute number of lives saved with aspirin and thrombolytic therapy increases dramatically with age: 2.5 per 100 patients treated <60 years; 7 to 8 per hundred patients treated aged 2=60 years. ISIS-2 showed conclusively that short-term aspirin therapy for AMI decreased mortality and reinfarction, has added benefits to those of SK, and prevents the increase in reinfarction that occurs after thrombolytic therapy. Consequently, aspirin therapy for AMI is not only desirable, but necessary when thrombolytic therapy is used. These benefits were achieved with an aspirin dose of 160 mgld. Although associated with an increased rate of minor bleeding from 1.9 to 2.5%, aspirin therapy was not associated with any significantly increased risk of major bleeding, including hemorrhagic stroke. The benefit of aspirin, in contrast to that of SK, was independent of the time of onset of treatment. However, early administration seems prudent. IMPACT-AMI 94 was a small clinical trial of IV eptifibatide vs placebo in patients with AMI receiving accelerated alteplase, aspirin, and intravenous heparin. The highest eptifibatide dose group from a nonrandomized phase was pooled with randomized patients (n = 51) and compared with placebo (n =55). There was more complete reperfusion (TIMI grade 3 flow), 66% vs 39% for placebo (p = 0.006), and shorter median time to ST-segment recovery (65 vs 116 min for placebo (p = 0.05), without an increase in severe bleeding. However, the randomized phase of the trial with 35 patients receiving eptifibatide and 13 receiving placebo showed a less marked difference: 71% of eptifibatide-treated patients and 62% of placebotreated patients had TIMI grade 3 flow. Pilot angiographic studies have also been performed with lamifiban, eptifibatide, and abciximab in AMI testing the hypothesis that GP lib/Ilia antagonism will improve the success of thrombolysis with possibly increased safety by using lower doses of lytic agents. Long-term Trials: There have been six large, randomized, double-blind trials of aspirin alone following AMI.95-100 Five of them, using doses of 300 to 1,500 mg of aspirin daily, show trends for the reduction of all cause mortality by aspirin, while the Aspirin Myocardial Infarction Study (AMIS) 99 demonstrated a trend against aspirin for mortality, although there was a nonsignificant reduction of recurrent MI. None of these studies recruited sufficient patients to have an 80% chance of demonstrating a 20% reduction in mortality and reinfarction, or in fatal reinfarction at the 0.05 level of significance. In 1994, the Anti platelet Trialists' collaboration updated their meta-analysis to include 145 randomized trials of prolonged antiplatelet therapy vs control in 70,000 highrisk patients with primarily occlusive vascular disease and 30,000 low-risk subjects from the general population.I01 Among the high-risk patients, antiplatelet therapy reduced vascular mortality (odds reduction 18%, SD 3%, 2p < 0.00001), nonfatal MI (odds reduction 35%; SD 4%; CHEST/114/5/NOVEMBER, 1998 SUPPLEMENT

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Table 4-Trials of Aspirin vs Oral Anticoagulation Following AMI* All-Cause Mortality Study

No. of Patients

GermanAustrian 97 EPSIM 112

1,303

AFTER 113

1,036

CARS 114

8,803

637

Follow-up, mo

Agents, Dose Phenprocoumon (INR 2.5-5.0) VS ASA 1.5 gld Various oral anticoag vs ASA 1.5 gld Heparin~arfarin (INR 2--2.5) X 3 mo vs ASA 150 mgld Warfarin 1 mg plus ASA 80 mgld vs warfarin 3 mg plus ASA 80 mgld vs ASA 160 mgld

Anticoag, o/o

ASA, RRR/ARR o/o by ASA, o/o

Major Hemorrhage Anticoag, ASA, ARR by o/o o/o ASA,%

p Value

24

12.2

8.5

26/3.7

NS

3.8

2.8

l.O

29

10.3

11.1

-7.8/-0.8

NS

3.2

0.8

2.4

3

8.1

8.9

-9.9/ -0.8

0.65

2.5

l.O

1.5

2.3 (1 mg)

2.3

0

0.11 (log rank)

1.7

1.5

0.2

21/0.6

0.28 (log rank)

2.0

1.5

0.5

14

2.9 (3mg)

*anticoag = anticoagulant; RRR = relative risk reduction; ARR = absolute risk reduction.

2p < 0.00001), nonfatal stroke (odds reduction 31 %; SD 5%; 2p < 0.00001), and vascular events (nonfatal MI, nonfatal stroke, and vascular death) (odds reduction 27%; SD 2%, p < 0.00001 ). The risk reduction for vascular mortality was higher in AMI trials (risk reduction 22%; SD 4%, 2p < 0.00001 ) and unstable angina trials, than in the prior Ml (odds reduction 15%; SD 5%; 2p < 0.005) and cerebral vascular trials (odds reduction 14%; SD 7%; 2p < 0.05). Among about 20,000 patients with AMI, vascular events occurred in 10.6% receiving antiplatelet therapy vs 14.4% on control regimen (odds reduction 29%; SD 4%; 2p < 0.00001) . This represented about 38 vascular events avoided per 1,000 patients treated for 1 month. Among 20,000 patients with a history of MI, events occurred in 13.5% receiving antiplatelet therapy vs 17.1% on control regimen (odds reduction 25%, SD 4%; 2p < 0.00001 ). This represents a 2-year treatment benefit of 36/1,000 patients treated. Among 11,000 patients with prior stroke or TIA, events occurred in 18.4% receiving antiplatelet therapy vs 22.2% on control regimen (odds reduction 22%; SD 4%; 2p < 0.00001) and a 3-year treatment benefit of 38/1,000. The benefit was about 50 events avoided per 1,000 patients for 6 months of treatment among 4,000 patients with unstable angina, and a 1-year benefit of 20/1,000 in 16,000 other high-risk patients (2p < 0.00001). The most widely used antiplatelet regimen in these trials was aspirin. Similar effectiveness was demonstrated

with doses of 500 to 1,500 mg daily, 160 to 325 mg daily, and 75 to 150 mg daily. Other studies have demonstrated less GI side effects with lower dosages.102 The time required to maximal initiation of platelet aggregation at lower doses supports the use of an initial dose of 160 to 325 mg for emergencies.lo3 After aspirin, the most widely studied antiplatelet regimens were aspirin plus dipyridamole, sulfinpyrazone alone, and ticlopidine, all of which showed benefit compared with placebo, but there was no clear evidence of benefit different from that of aspirin. The Anturane Reinfarction Trial Research Group randomized 1,629 patients (86% male) to a regimen of sulfinpyrazone (200 mg qid) or placebo, 25 to 35 days after MI. 104,lOS There was an overall reduction of 32% in cardiac mortality (p = 0.058) and a 43% reduction in sudden death (p = 0.041). The benefits at 24 months were almost entirely due to the 75% reduction in sudden death over the first 6 months of treatment (p = 0.03). The Anturane Reinfarction Italian Study106 randomized 727 patients to a regimen of sulfinpyrazone or placebo. Treatment with sulfinpyrazone for a mean of 19 months did not significantly affect the incidence of total mortality or sudden death, but it did reduce the incidence of reinfarction and of all thromboembolic events. Details of these trials, and the Food and Drug Administration decision not to approve the claims for sulfinpyrazone, 10 7 may be found in the previous Consensus Report. 67 In the Persantine Aspirin Reinfarction Study (PARIS-I)

Table 5-Aspirin in Unstable Angina* All-Cause Mortality Study Lewis et al 119 Cairns et al 120 Theroux et al 121 RISCI 23

No. of Patients

ASA, mgld

Entry Window

Followup

ASA, o/o

Placebo, o/o

RRR, %

1,338 555 479 796

324 1,300 650 75

51 h 8d 24h 72 h

3 mo 24 mo 6d 5d 30 d

1.6 3.0 0 0.25 0.5

3.3 11.7 1.7 0.25 2.0

51 7l 0 75

Cardiac Death or Nonfatal MI p Value

ASA, %

Placebo, o/o

RRR, o/o

p Value

0.054 0.004 NS NS NS

5.0 8.6 3.3 2.5 4.3

10.1 17.0 12.0 5.8 13.4

51 51 72 57 68

0.0005 0.008 0.01 0.033 <0.001

*ASA =aspirin.

6185

Fifth ACCP Consensus Conference on Antithrombotic Therapy

trial, 100 mortality and coronary incidence (coronary death or nonfatal MI) were similar in the two active treatment groups (aspirin plus dipyridamole and aspirin alone), and consistently lower than in the placebo group, but the reductions were not statistically significant. PARIS-2 108 compared a combination of aspirin and dipyridamole with placebo and reported a statistically significant reduction in the composite outcome of coronary death or nonfatal reinfarction. There was no comparison with aspirin alone. These trials provide no evidence for a benefit of a combination of aspirin and dipyridamole over aspirin alone. The Canadian American Ticlopidine Study (CATS)1 09 randomized patients to a regimen of ticlopidine, 250 mg twice daily, or placebo, 1 to 17 weeks after thromboembolic stroke, and patients were followed for up to 3 years. The composite outcome of stroke, MI, or vascular death was significantly reduced by ticlopidine. The Ticlopidine Aspirin Stroke Study (TASS), 110 randomized patients with TIA or minor stroke within the past 3 months to a regimen of ticlopidine, 500 mg daily, or aspirin, 1,300 mg daily, for up to 6 years. The composite of death from any cause or nonfatal stroke was reduced by ticlopidine. Ticlopidine appeared to be as effective in women as in men. The Swedish Ticlopidine Multicentre Study (STIMS) 111 randomized patients with intermittent claudication to a regimen of ticlopidine, 250 mg twice a day, or placebo. The composite of AMI, stroke, or TIA was significantly reduced in an "or treatment" analysis. In these trials, therefore, patients with cerebral vascular disease and patients with peripheral vascular disease had decreased vascular events, including coronary events, while taking ticlopidine. In TASS,U 0 the effectiveness of ticlopidine appeared to be greater than that of aspirin. The use of ticlopidine must be weighed against its greater cost compared with aspirin, and greater incidence of adverse effects and their seriousness. These include rash, diarrhea, and leukopenia or thrombocytopenia, which occurred in 2% of the treated patients in STIMS.l 11 CAPRIE 86 was a randomized clinical trial of clopidogrel (75 mg daily) vs aspirin (325 mg daily) for a mean of 1.91 years among 19,185 patients with recent ischemic stroke, recent Ml, or symptomatic peripheral vascular disease. The composite event rate of ischemic stroke, MI, or vascular death was 5.32% with clopidogrel and 5.83% with

aspirin, a relative risk reduction (RRR) of 8.7% (p = 0.043) in favor of clopidogrel. When outcomes were assessed according to the three clinical subgroups, the following RRRs by clopidogrel were found: stroke (RRR 7.3%, 95% CI -5.7 to 18.7, p = 0.26), MI (RRR -3.7%, 95% CI -22.1 to 12.0, p = 0.66), and peripheral arterial disease (RRR 23.8%, 95% CI 8.9 to 36.2, p = 0.0028). There was slightly more, but minimal incidence of rash and diarrhea in the clopidogrel-treated patients, and slightly more bleeding in the aspirin-treated patients. There was no excess of neutropenia or thrombocytopenia. Antiplatelet therapy is effective in reducing vascular events (nonfatal MI, nonfatal stroke, vascular death) in patients with evidence of atherosclerotic disease (acute MI, unstable angina, history of AMI, stroke, TIA, stable angina, or peripheral vascular disease). Aspirin, 75 to 325 mgld, is as effective as any other regimen, with little risk of adverse events such as GI or intracerebral hemorrhage. Its benefits are seen regardless of age or sex. Aspirin therapy in these high-risk patients reduces vascular events by about one fourth, nonfatal MI by one third, nonfatal stroke by one third, and vascular death by one sixth.

Comparisons of Antiplatelet and Anticoagulant Therapy Oral anticoagulation has been compared directly with aspirin in several trials (Table 4). The German/Austrian trial 97 enrolled 942 patients within 30 to 42 days of AMI to aspirin, placebo, or phenprocoumon. Over a 2-year followup, the aspirin-treated patients had statistically insignificant reductions of all-cause mortality by 26% and of coronary mortality by 46.3% in comparison to phenprocoumon. Aspirin showed a favorable trend in comparison to placebo, but phenprocoumon did not. In the EPSIM trial, 112 1,303 patients were randomized a mean of 11.4 days following AMI to treatment with aspirin or one of several anticoagulants. Over a mean follow-up of 29 months, all-cause mortality was 10.3% with anticoagulation and 11.1% with aspirin. The study was stopped early when it appeared that a statistically significant lower mortality with aspirin would not be found. The AFTER study113 enrolled 1,036 survivors of AMI who had received anistreplase. They were randomized to anticoagulation (IV heparin followed by warfarin or other oral anticoagulant) or aspirin (150 mg daily) and followed

Table 6-Trials of GP llblllla Antagonists in Unstable Angina/Non-Q-wave MI 30-Day Outcomes Death!Ml/Refractory UA*

Death!MI Study

No. of Patients

PRISM 130 PRISM PLUS 131 PURSUIT 132

3,232 1,570 9,461

PARAGON 129

2,282

lib/Ilia,

Control,

Ilb/IIla,

Control,

Regimen

%

%

p Value

%

%

p Value

Tirofiban vs heparin Tirofiban plus heparin vs heparin Eptifibatide plus heparin vs placebo plus heparin Lamifiban low-dose plus heparin vs heparin (and 3 other regimens)

5.8 8.7 14.2

7.1 11.9 15.7

0.11 0.03 0.042

15.9 18.5

17.1 22.3

0.34 0.03

9.0

9.2

NS

*See Table 7 footnote. CHEST I 114 I 5 I NOVEMBER, 1998 SUPPLEMENT

6198

up for the principal outcome of cardiac d eath or recurrent MI by 30 days. The rates of the principal outcome were 11.0% with anticoagulation and 11.2% with aspirin. The trial was stopped early because of declining enrollment rate, and was underpowered to rule out a difference between the two therapies. However, the rate of severe bleeding or stroke was significantly higher with anticoagulation than with aspirin (3.9% vs 1.7%, odds ratio 0.44, 9.5% CI 0.20 to 0.97, p = 0.04). The Coumadin, Aspirin, Reinfarction Study (CARS ) studyll 4 evaluated aspirin 160 mg, vs warfarin 1 mg plus aspirin 80 mg, vs warfarin 3 m g plus aspirin 80 mg. in a randomized double-blind study of 8,803 patients enrolled 3 to 21 days following MI. Dming a m edian follow-up of 14 months, the primary outcome composite of reinfarction, nonfatal ischemic stroke, or cardiovascular death occurred with a rate of 8.6% in the 160-mg aspirin group , 8.8% in the 1-mg warfarin plus 80-mg aspirin group, and 8.4% in the 3-mg warfarin plus 80-mg aspirin group. Major hemorrhage occurred with rates of 0.74% in the aspirin group and 1.4% in the 3-mg warfarin/80-mg aspirin group. Among 3,382 patients assigned to 3 mg warfarin/80 mg aspirin, the INRs were 1.51 at week 1, 1.27 at week 4, and 1.19 at 6 months. The authors concluded that low fixed-dose warfarin (1 or 3 mg) ocmbined with low-dose aspirin (80 mg) did not provide clinical benefit beyond that achievable with 160 mg of aspirin. The results are consistent with the body of literature suggesting that warfarin is effective only at INR ranges b etween 2 and 3.5, at least in the short term. The Thrombosis Prevention Trial (TPT)115 suggests that warfarin at lower INR of approximately 1.5 may be beneficial in primary prevention.

Summary The 2D echocardiographic studies indicate that the risk of systemic embolism is related to the presence of mural thrombus that o ccurs in up to 40% of transmural anterior Ml, but is very uncommon with inferior MI. Patients with extensive LV dysfunction and CHF, a history of previous embolism, and atrial fibrillation are a t particularly high risk. The overviews of the large trials of heparin therapy followed b y oral anticoagulation for approximately 1 month indicated that mortality could be reduced b yabout 20%, while achieving a 50% reduction in the incidence of systemic and venous embolism. Accordingly, there is a strong case among patients with transmural anterior MI, extensive LV dysfunction and CHF, previous embolism, or atrial fibrillation for early full-dose heparin therapy (bolus 75 U/kg IV, initial maintenance 1,000 to 1,200 U!h IV, activated partial thromboplastin time [APTT] 1.5 to 2 times control), that should be sustained throughout the hospital stay or replaced b y subcutaneous heparin (initial dose, 17,500 U every 12 h; APTT 1.5 to 2 times control) or oral warfarin (INR, 2.0 to 3.0). A low-dose subcutaneous heparin regimen (7,500 U bid) may be reserved for patients with non-Q-wave or inferior infarction, who are free of CHF, previous embolism, and atrial fibrillation. Patients with suspect Q-wave MI should generally receive aspirin and fibrinolytic therapy. The evidence 6205

suggests that patients who are to receive rtPA should also receive heparin, as a 7 5-U/kg IV bolus at the time of initiating the rtP A infusion, with an initial maintenance infusion of 1,000 to 1,200 Ulh to maintain APTT at 1.5 to 2 times control. A 48-h infusion is likely to be sufficient if aspirin is being given, and high-dose heparin therapy should be sustained only if there appears to be a high risk of systemic embolism (large anterior MI. CHF, previous systemic embolus, atrial fibrillation ). Otherwise, only lowdose heparin therapy (7,500 U subcutaneously every 12 h) is indicated for prophylaxis against venous thrombosis until the patient is fully ambulatory. By extrapolation from the rtPA data, a similar approach to the use of anticoagulation may be recommended for those patients who have received r eteplase. If the patient has received SK or anistreplase (APSAC), high-dose heparin should be administered only if there appears to be a high risk of systemic embolism. In such patients, the APTT should be evaluated at inte1vals beginning about 4 h after the initiation of thrombolytic therapy, and heparin therapy should be initiated when the APTT falls into the therapeutic range. The appropriate duration of anticoagulant therapy is uncertain . The early large trials of full-dose anticoagulation in patients with AMI required oral anticoagulation for approximately 1 month following AMI. The risk of systemic embolism following MI persists beyond the hospital stay but appears to fall off after 2 to 3 months.31 Studies of the subsequent survival of patients discharged from the hospital alive following AMI indicate that the mortality risk is highest in the first few months following MI, falling to a much lower rate by 1 year. ll 6 •117 Three well-designed clinical trials of long-term oral anticoagulation 78-81 following AMI have shown reductions of death , reinfarction, and stroke with acceptable hemorrhagic risks, although the INR target ranges were higher than is now recommended in most antithrombotic regimens (60 + reinfarction studies 2.7 to 4.5, WARIS and ASPECT, 2.8 to 4.8). The data argue for a p eriod of oral anticoagulation extending somewhat beyond the hospital stay for those patients with transmural anterior MI or extensive LV dysfunction and CHF. The data from recent studies of nonrheumatic atrial fibrillation support permanent anticoagulation for patients with atrial fibrillation following MJ.l 18 Despite the benefits of long-term warfarin therapy for the reduction of vascular events among MI survivors, aspirin will probably continue to be the agent of choice because of its simplicity, low cost, and safety. As yet and to our knowledge, no clinical trials have demonstrated benefit of one agent over the other. When warfarin is considered n ecessary for a patient, specifically for the reduction of the risk of venous or systemic embolism, aspirin need not be given concurrently, and treatment \vith it should be recommended only when the warfarin therapy is discontinued. CLINICAL TRIALS IN UNSTABLE ANGINA

Antithrombotic therapy in unstable angina has evolved at an accelerated pace since the 1995 publication of the Consensus Report.67 Large trials have been completed Fifth ACCP Consensus Conference on Antithrombotic Therapy

with low-molecular-weight heparins, direct thrombin inhibitors, and antagonists of the GP lib/Ilia receptor. The studies with the low-molecular-weight heparins have confirmed the efficacy of heparin, those with the direct thrombin inhibitors have been inconclusive so far, whereas a new class of antithrombotic drugs was introduced in clinical practice with the GP lib/Ilia antagonists.

Antiplatelet Drugs The trials with aspirin have been discussed in detail in the previous Consensus publication and are summarized in Table 5 of this report.l 19 - 123 These trials had demonstrated a significant risk reduction in the rates of total mortality or cardiac death and nonfatal MI with the use of aspirin in unstable angina and non-Q-wave MI. The results were very homogenous between trials despite variations in the dose of aspirin, the time of initiation after the acute clinical episode, and the duration of follow-up. The drug reduced the risk of fatal or nonfatal MI by 71% at 7 days,l 21 ·122 by 60% at 3 months, 119 and by 52% at 2 years.l 20 A randomized, double-blind study of triflusal, an analog of aspirin with somewhat different pharmacokinetic properties, was tested against placebo and no aspirin in 281 patients. A dose of 300 mg tid was used. After 6 months of treatment, triflusal reduced the risk of nonfatal MI by 65.8%, from 12.3 to 4.2% (p = 0.013), of nonfatal infarction or death by 54.4%, from 12.3 to 5.6% (p = 0.048), and of total events including revascularization by 31.6%, from 32.6 to 22.3% (p = 0.054).1 2 3• The magnitude of these gains was similar to that for aspirin. Ticlopidine was also tested in an open-label study of 652 patients with the clinical diagnosis of unstable angina with spontaneous or exercise-induced transient ST segment or T-wave changes.l 24 Ticlopidine, 250 mg bid, plus conventional treatment reduced the rate of vascular death or nonfatal MI by 46.3% from 13.6 to 7.3% (p = 0.009) compared with conventional treatment avoiding the use of aspirin. The life table analyses showed that the gain with ticlopidine appeared after a period of 10 days of treatment, making the treatment less suitable for the acute phase. Clopidogrel has not yet been tested in the acute situations. Four thousand patients with unstable angina were included in the Antiplatelet Trialists' Collaboration metaanalysis101 of patients randomized to antiplatelet therapy or placebo; in these patients, vascular events after 6 months were reduced from 14 to 9% (p < 0.00001). The odds of infarction, stroke, or vascular death were reduced overall by >25%. Trials with abciximab were performed among patients undergoing angioplasty and have included subjects with unstable angina. Of the 2,099 patients enrolled in the EPIC trial,125 489 were enrolled with the diagnosis of unstable angina; the risk of death, MI, or abrupt vessel closure at 30 days was 4.8% with the bolus plus infusion compared to 12.8% with placebo, the risk of death was 1.2% vs 3.2%, and the risk of MI was 1.8% vs 9%.1 26 In the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Ischemia (CAPTURE) trial,127 patients were randomized to placebo or abciximab after the angiographic identification of a culprit coronary lesion suitable for angioplasty.

The procedure was performed within 18 to 20 h and the drug infusion stopped 1 h later. By 30 days, the rate of death, MI, or urgent intervention was reduced with abciximab from 15.9 to 11.3% (p = 0.012). The rate of MI before angioplasty was lower in the abciximab group than in the placebo group, 0.6% vs 2.1 %, p = 0.03). Lamifiban was evaluated in unstable angina in two pilot studies. In the Canadian Lamifiban study,128 365 patients were randomized double-blind to placebo or 1, 2, 4, or 5 tJ-g/min of lamifiban for 72 to 120 h. Concomitant heparin was administered in 28% of patients by physician choice. Lamifiban, all doses combined, reduced the risk of death, nonfatal MI, or the need for an urgent intervention procedure from 8.1 to 3.3%. The rates were 2.5%, 4.9% , 3.3%, and 2.4% with increasing doses . The inhibition of ADP-induced platelet aggregation was 60%, 75%, 100%, and 100%, respectively. The two doses with the best results (1 tJ-g/min and 5 tJ-g/min) were selected for the second trial, the Platelet lib/Ilia Antagonists for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) trial (Table 6).1 29 In this study, 2,282 patients were randomized to placebo, the small dose of lamifiban with and without heparin, and the high dose of lamifiban with or without heparin. The primary end point of death or MI at 30 days occurred at the following rates: heparin alone, 9.2%; low-dose lamifiban plus heparin, 10.3%; low-dose lamifiban plus no heparin, 10.8%; high-dose lamifiban plus heparin, 12.3%; and high-dose lamifiban plus no heparin, 11.6%. The high dose was associated with excess bleeding especially with concomitant heparin. A long-term follow-up in this study at 6 and 12 months showed a reduction in the rate of death or MI with the low dose plus heparin. Tirofiban was investigated in two large trials following the identification in pilot studies of a dose inhibiting platelet aggregation by >80%. The Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM) triaP 30 directly compared tirofiban with heparin in 3,231 patients. The primary composite end point of death, MI, and refractory ischemia measured at the end of a 48-h infusion period was decreased by 36% with tirofiban (p = 0.007). The benefit in the composite end point was not statistically significant at 1 week or 1 month. However, the rate of death was significantly less frequent with tirofiban at 30 days. The Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited By Unstable Signs and Symptoms (PRISM-PLUS) trial 131 randomized a total of 1,915 patients with well-documented unstable angina or non-Q-wave MI to doubleblind administration of tirofiban (0.15 tJ-g/kglmin infusion), heparin alone, or tirofiban (0.1 tJ-g/kglmin) plus heparin. The study drugs were infused for 71 ± 21 h, encompassing 48 h of medical management, subsequent coronary angiography, and coronary angioplasty when indicated. The primary end point was a composite of death, MI, or refractory ischemia within 7 days. The tirofiban alone arm was dropped prematurely for excess mortality at 7 days, 4.6% (n = 345 patients), compared with 1.1% with heparin (350 patients, RR 4.11, 95% CI 1.37 to 12.29). This premature discontinuation precludes CHEST I 114 I 5 I NOVEMBER, 1998 SUPPLEMENT

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any firm conclusion on the benefit of tirofiban without heparin in the population of patients with unstable angina and some risk features. The rates of MI and refractory ischemia were not improved compared with heparin alone, suggesting that the combination of an anticoagulant and a potent antiplatelet therapy provides optimal benefit in acute coronary syndromes, as was documented in trials comparing heparin, aspirin, and the combination. Tirofiban plus heparin, vs heparin, reduced the composite end point from 17.9 to 12.9% (RR 0.68, CI 0.53 to 0.97, p = 0.004) at 7 days, from 22.3 to 18.5% (p = 0.03) at 30 days, and from 32.1 to 27.7% (p = 0.02) at 6 months, and the composite of death or MI from 8.3 to 4.9% (p = 0.006), from 11.9 to 8.7% (p = 0.03), and from 15.3 to 12.3% (p = 0.06), respectively. The composite end point at 48 h, before coronary angioplasty, was reduced from 7.8 to 5.7% (p = 0.08), and the rate of death or MI from 2.6 to 0.9% (p = 0.01). These two end points were significantly reduced at 30 days in the 723 patients treated medically as well as in the patients with an interventional procedure. Major bleeding occurred in 3.0% of heparintreated patients, and 4.0% of combination therapy patients (p = 0.34). The Platelet IIblllla in Unstable Angina Receptor Suppression Using Integrilin (PURSUIT) triaJl 32 has randomized 9,461 patients with unstable angina and non-Qwave MI to eptifibatide or placebo. The results of the trial are not as yet published but were presented. The vast majority of patients in the trial received concomitant heparin. Thirteen percent had a coronary percutaneous intervention during drug infusion and 87% were treated medically. By 30 days, the rate of death or MI was reduced from 15.7 to 14.2%, a statistically significant reduction (p = 0.042). Altogether, these trials show efficacy of GP IIb/IIIa antagonism for the prevention of cardiac events in percutaneous coronary interventions and in unstable angina. The benefits are additive to those of aspirin, and to our knowledge, no trials have evaluated these drugs without aspirin. The data presently available suggest that heparin should also be used concomitantly.

Anticoagulants and Aspirin-Heparin Combination Therapy Trials with heparin have been of small sample size but have consistently shown a benefit except for an openlabeled study of 285 patients by Holdright et al; 133 the trial, however, had an unusually high event rate and considered MI present before randomization as an end point event confounding the real rate of new events. The first modem randomized, double-blind, controlled trial of heparin was published in 1981 by Telford and Wilson. 134 A total of 400 patients were randomized to heparin, atenolol, heparin plus atenolol, or placebo. An 80% reduction of the incidence of MI was reported by 7 days with heparin compared with no heparin. Subsequently, in 1986, Williams et al 135 published the results of a small trial of 102 patients randomized at hospital admission to treatment with heparin for 48 h followed by warfarin for 6 months. Entering all events in the analysis, the risk reduction was 6228

65% with treatment (p < 0.05). The trial from Montreal has reintroduced heparin as standard treatment of unstable angina (Table 7).1 21 ·122 The incidence of fatal and nonfatal MI was reduced from 7.5 to 1.2% (risk reduction 85%, p = 0.007), and of recurrent refractory ischemia from 19.7 to 9.6% (risk reduction 51%, p = 0.02). These risk reductions were greater than the risk reductions with aspirin alone, and the combination of aspirin with heparin, although adding no benefit during the infusion of heparin, permitted maintenance of benefit by preventing recurrence of ischemic events following the discontinuation of heparin therapy.l 36 The RISC study of 945 men also compared aspirin, heparin, both, or placebo. 123 Heparin therapy was initiated relatively late, after 24 h, and used at relatively low dose with no titration. Heparin was not associated with a benefit in the study, but the combination of aspirin and of heparin resulted in a significant risk reduction in death and MI at 5 days. A small randomized double-blind study of 57 patients allocated to warfarin (INR, 2 to 2.5) or placebo in addition to aspirin using repeated coronary angiography reported less progression after 10 weeks in the culprit lesion with warfarin (Coumadin) (4% of patients vs 33%) and more regression (19% vs 9%).13 7 Another study of limited size, the ATACS trial, randomized 214 patients with unstable angina and non-Q-wave MI not previously taking aspirin, to aspirin alone, 162.5 mg, or the combination of aspirin, 162.5 mg plus heparin titrated to APTT, followed by warfarin (INR 2 to 2.5).1 38 At 14 days, there was a significant reduction in the combined end point of death, MI, and recurrent ischemia in the combination group vs aspirin alone (10.5% vs 27%; p = 0.004). The survival curves diverged mainly during the first few days of treatment. A meta-analysis by the authors of the three studies comparing combination therapy with aspirin alone showed a 56% reduction in the incidence of the hard end points of fatal and nonfatal MI with the combination therapy. 138 A more recent metaanalysis of trials comparing combination heparin plus aspirin vs aspirin alone also supported a significant risk reduction of 33% with the combination. 139 The Organization to Assess Strategies for Ischemic Syndromes (OASIS) pilot study of hirudin vs heparin also compared a fixeddose regimen of 3 mg of warfarin in 309 patients, or a moderate dose titrated to an INR of 2 to 2.5 in 197 patients, for 6 months after the acute phase.l 40 Aspirin was recommended for all patients. The low-intensity fixed dose of warfarin had no benefit; moderate-intensity warfarin reduced the risk of death, MI, or refractory angina by 58% (p = 0.08), and the need for rehospitalization for unstable angina by 58% (p = 0.03). The low-molecular-weight heparins 14 1 present distinct advantages over unfractionated heparin. They can be administered subcutaneously once or twice a day, with no need for monitoring. They bind plasma proteins and endothelial cells less avidly than unfractionated heparin resulting in a more predictable degree of anticoagulation. They also stimulate platelets less and are less often associated with heparin-induced thrombocytopenia. These advantages have been well demonstrated in venous disease, and are now emerging in unstable angina (Table 8). Fifth ACCP Consensus Conference on Antithrombotic Therapy

A small randomized, open-labeled pilot study from Argentina 142 of 219 patients compared the combination of aspirin plus nadroparin calcium with aspirin alone and with the combination of unfractioned heparin plus aspirin; event rates during hospitalization were, respectively, 0%, 9.6%, and 5.7%, and of nonfatal MI, 0%, 6%, and 9.5%. Three larger randomized studies have recently been completed. The Fragmin during Instability in Coronary Artery Disease (FRISC) 143 compared dalteparin (120 U/kg) plus aspirin administered for 35 to 45 days with placebo plus aspirin in 1,506 patients. The rate of death and MI was reduced at 6 days from 4.8 to 1.8% (risk ratio 0.37, CI 0.20 to 0.68, p = 0.001) and the need for revascularization from 1.2 to 0.4%. Although an excess of events was observed with the dose reduction to once daily after 6 days, significant benefit was still present after 40 days. No differences were found in death, new MI, or revascularization procedures after 4 to 5 months. The Fragmin in Coronary Artery Disease (FRIC) 144 study compared dalteparin (120 mglkg 12-hourly) with standard heparin in 1,482 patients and showed no statistically significant differences between the two drug regimens: death or MI at day 6 had occurred in 9.3% of dalteparin-treated patients and 7.8% of standard heparin-treated patients (NS). Patients were then treated double-blind from day 6 to 45 with dalteparin (7,500 IU once daily) or placebo. No statistically significant differences were observed between the two groups, but mortality was higher in dalteparintreated patients, 1.5% vs 0.4% (95% CI 0.09 to 0.99, p = 0.057). The larger Enoxaparin in Unstable Angina and Non-Q-Wave Myocardial Infarction (ESSENCE) triali 45 showed significantly better results with the low-molecularweight heparin than with standard heparin. In this doubleblind placebo-controlled study, 3,171 patients were randomized to enoxaparin at doses of 1 mglkg subcutaneously twice a day or continuous IV unfractionated heparin for a minimum of 48 h and a maximum of 8 days. The primary composite end point of death, MI, or recurrent angina at 14 days was reduced from 19.8 to 16.6% (p = 0.019); at 48 h it was reduced from 7.4 to 6.2% (p = 0.176), and at 30 days from 23.3 to 19.8% (p = 0.016). The need for a revascularization procedure was reduced at 30 days from 32.2 to 27.0% (p = 0.001). The 30-day incidence of major bleeding complications was 6.5% with enoxaparin and 7.0% with unfractionated heparin, but the incidence of bleeding overall was significantly higher with enoxaparin, 18.4% vs 14.2%, p = 0.001, primarily because of ecchymoses at injection sites. Alarge TIMI trial is now ongoing with enoxaparin. The documentation of equivalence between low- and standard-molecular-weight heparins would be helpful because low-molecular-weight heparins can be administered subcutaneously with no monitoring required and because they cause fewer adverse effects. All low-molecular-weight heparins are not the same with regard to inhibition of factor X vs factor II; accordingly the results obtained with various agents may differ. Clinical Trials of Direct Thrombin Inhibitors: The direct thrombin inhibitors are potent anticoagulants providing predictable inhibition of thrombin, in the absence of the need for a cofactor and of known physiologic inhibitors.l 45 • Hirudin, the prototype, inhibits the catalytic

and anion-binding sites of thrombin; inogatran and efegatran are small peptides and argatroban is an arginine derivative active at the catalytic sites of thrombin; hirulog is a 20 amino acid peptide inhibiting the two active sites. Large trials have been performed with hirudin and with hirulog in coronary angioplasty, with hirudin and argatroban as adjunctive therapy to thrombolysis in AMI, and with hirudin and efegatran in unstable angina. These trials, in general, have shown drug efficacy during the infusion, but have failed to document a sustained benefit. Two trials with hirudin were also interrupted prematurely based on an excess bleeding with infusion doses of hirudin of 0.2 mglkglh. 14 6 ·147 The dose subsequently was reduced to 0.1-mglkg bolus and 0.1-mglkglh infusion. In Global Use of Strategies to Open Occluded Arteries (GUST0)-2B, 148 the primary end point of death or nonfatal MI at 30 days occurred in 8.9% of patients with hirudin and 9.8% with heparin (p = 0.06). In the 4,131 patients with ST segment elevation, end points were reached in, respectively, 9.9% and 11.3% of patients (p = 0.13) and in the 8,011 patients without ST segment elevation, in 8.3% and 9.1% (p = 0.2).164 The benefit of hirudin during the first 24 h was, however, striking, a 1.3% event rate vs 2.1% with heparin, a risk reduction of 36% (p = 0.001) and at 48 h, 2.3% vs 3.1% (risk reduction 25%, p = 0.001 ). Other trials of moderate sample size with synthetic direct thrombin inhibitors also had failed to show a clear trend to benefit with the intervention.149 The OASIS pilot study140 has tested a small dose of r-hirudin of 0.2-mglkg bolus and 0.1-mglkglh infusion, and a moderate dose of 0.4-mglh bolus and 0.15-mglkglh infusion vs heparin in 909 patients with unstable angina or suspected AMI without STsegment elevation. At 7 days, 6.5% of patients in the heparin group, 4.4% in the low-dose group, and 3.0% in the medium-dose group suffered cardiovascular death, new MI, or refractory angina (p = 0.047 heparin vs medium-dose hirudin). The proportions with cardiovascular death, new MI, or refractory or severe angina were 15.6%, 12.5%, and 9.4%, respectively (p = 0.02 for heparin vs medium dose). The rates of new MI were 4.9%, 2.6%, and 1.9%, respectively (p = 0.046 heparin vs medium dose). Minor bleeding rates were more frequent with hirudin, but there was no excess major bleeding. Alarge phase III trial of 10,000 patients is ongoing to confirm the potential benefit of the moderate dose. PRIMARY PREVENTION

There have been three large trials of ASA administration to men free of a history of previous major vascular events (MI or stroke) (Table 9).ll5 •150 ·151 The Physicians' Health Study150 was a double-blind, placebo-controlled, randomized trial designed to test two primary prevention hypotheses in a population of physicians free of Ml, stroke, TIA, cancer, and current liver or renal disease, peptic ulcer, or gout. It was postulated that ASA might decrease mortality from cardiovascular disease and 13-carotene might decrease cancer incidence. There were 22,071 male US physicians, aged 40 to 80 years, randomly allocated to low-dose ASA (as Bufferin, Bristol Myers products, 325 mg every other day) or placebo, plus CHEST I 114 I 5 I NOVEMBER, 1998 SUPPLEMENT

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Table 1-Aspirin vs Aspirin Plus Heparin in Unstable Angina Cardiac Death or Nonfatal MI No. of Patients

ASA, mgld

RISC 123

796

75

Theroux et all21,122 ATACS 138 Overview138

479 214

650 162.5

Study

Entry Window, h

Heparin Bolus q6h

72

Bolus, infusion Bolus, infusion

24 48

13-carotene (50 mg every other day), or placebo according to a 2 X 2 factorial design. The ASA component was terminated in 1998 at the recommendation of the Data and Safety Monitoring Board (DSMB) because of a clear reduction of MI, a low likelihood of detecting a benefit of ASA on cardiovascular mortality before the year 2000, and the high prevalence of ASA use among participants following the occurrence of a nonfatal vascular event. The principal outcome of cardiovascular death occurred at a rate of only 15% of that expected for a general population of white men with the same age distribution over a similar period, and was not different between ASA (0.23% per year) and placebo (0.24% per year). Total death was also not different (ASA 0.4% per year, placebo 0.42% per year). There was a striking reduction in the rates of MI with ASA (0.26% per year) vs placebo (0.44% per year, risk reduction 44%; p < 0.00001). The observed overall stroke rate was higher with aspirin (0.22% per year) vs placebo (0.18% per year, p = 0.15). The rate of hemorrhagic stroke was higher with aspirin (0.04% per year) vs placebo (0.02% per year, p = 0.06). The combined outcome of "important vascular events" (nonfatal MI, nonfatal stroke, and death from a cardiovascular cause) was significantly reduced in the ASA group (0.56% per year) vs placebo (0.68% per year, relative risk reduction 18%; p = 0.01). The British Doctors' Study151 was an open-label, randomly allocated trial of ASA, 500 mg daily, vs aspirin

ASA,

ASA!Heparin,

RRR,

Follow-up, d

%

%

%

p Value

5 30 6 5

3.7 4.8 3.3 8.3

1.4 3.8 1.6 3.8

62 21 52 54 56

NS NS NS NS < 0.05

avoidance (2:1 ratio of ASA vs avoidance), conducted among British male physicians who had no history of stroke, definite MI, or peptic ulcer. There were 5,139 male physicians recruited and followed for up to 6 years. Vascular death rates, including sudden death from unknown cause, and peptic ulcer and gastric hemorrhage, were less frequent with ASA (0.79% per year) vs no ASA (0.84% per year, relative risk reduction 6%; p = NS). Total mortality was somewhat less with ASA (1.44% per year) vs no ASA (1.6% per year, p = NS ). There was only a trend toward reduced confirmed MI (ASA, 0.9% per year; no ASA, 0.93% per year; relative risk reduction, 3%; p = NS ). Although there were significantly fewer confirmed TIAs in the ASA group (ASA, 0.16% per year; no ASA, 0.28% per year; 2p < 0.05), there were more confirmed strokes in the ASA group (ASA, 0.32% per year, no ASA, 0.29% per year; p = NS) , and considerably more disabling strokes in the ASA group (ASA, 0.19% per year; no ASA, 0.07% per year; risk ratio 2.58; 2p < 0.05). An overview of the two trials confirms a reduced frequency of nonfatal AMI by ASA (risk reduction 32%; p < 0.0001), although there appears to be heterogeneity of the observations (p = 0.035). 152 The composite outcome of "any vascular event" is significantly reduced (relative risk reduction 13%; p < 0.05), and there is a trend toward increased nonfatal stroke with aspirin (risk increase 18%;

Table 8-Trials of Low-Molecular-Weight Heparin in Unstable Angina!Non-Q-wave MI* Death/MI Study LMWH vs no Heparin Gurfinkel et al 142 FRISC1 43 LMWHvs UF Heparin Gurfinkel et ali42 FRJCI44 ESSENCE' 4s *LMWH

6248

=

LMWH

Nadroparin vs control X 5-7 d Dalteparin vs placebo X 40 d

Nadroparin vs UF heparin X 5-7 d Dalteparin vs UF heparin X 6 d Dalteparin vs placebo 6-45 d Enoxaparin vs UF heparin X 2.6 days

low-molecular-weight heparin; UF

=

No. of Patients

LMWH,

Control,

Follow-up

%

%

141 1,506 1,493

In-hospital 6d 40 d

0 1.8 8.0

9.5 4.8 10.7

138

In-hospital

0

6d 6-45d 14 d 30 d

3.9 4.3 4.9 6.2

1,482 1,132 3,171

unfractionated; UA

=

Death!MI!Refractory UA LMWH,

Control,

p Value

%

%

p Value

0.01 0.001 0,07

22 2.2 20.5

59 5.7 25.7

0.0001 <0.001 0.011

6.0

0.5

22

63

0.0001

3.6 4.7 6.1 7.7

0.80 0.76 0.13 0.08

9.3 12.3 16.6 19.8

7.6 12.3 19.8 23.3

0.33 NS 0.019 0.02

unstable angina. Fifth ACCP Consensus Conference on Antithrombotic Therapy

Table 9-Primary Prevention of Coronary Disease With Aspirin and Warfarin: Rates per 1,000 Subjects per Year Physicians' Health Study~so

Thrombosis Prevention Triall!S

British Doctors' StudyiSI

Wvs W/ASA VS ASA vs Placebo Placebo Placebo Placebo

Outcome

ASA

Placebo

Reduction

ASA

Place bo

Reduction

ASA

w

W/ASA

Total Fatal Nonfatal IHD Total Fatal Nonfatal Stroke Total Fatal Nonfatal Hemorrhagic Thrombotic All-cause mortality

2.55 0.18 2.36

4.40 0.48 3.90

l.9t 0.3i l.5i

8.98 4.73 4.25

9.29 4.96 4.33

0.3 0.2 0.1

8.5 2.7 5.8

9.4 1.5 8.0

7.8 2.0 5.8

12.1 3.1 9.0

3.6* 0.4 3.2*

2.7 1.6* 1.0

4.4t

10.2 4.4 5.8

10.3 2.4 8.0

8.7 3.0 5.8

13.3 4.2 9.0

3.0 (0.2) 3.2*

2.9 1.9*

1.1

4.5t 1.3 3.3*

2.2 0.2 2.0 0.3 1.9 13.6

2.7 0.6 2.1 0.5 2.2 11.4

3.6 1.5 2.1 l.l 2.5 12.4

3.2 0.1 3.1 0.2 3.0 13.1

l.O (0.1 )

0.5 (0.5) 1.0 (0.3) 0.8 1.7

(0.4} (l.4}t l.O (0.9 )* 0.5 0.7

MI

2.18 0.16 2.02 0.42 1.67 3.97

1.79 0.11 1.68 0.22 1.50 4.15

(0.4) (0.05 ) (0.34} (0.2) (0.17} 0.2

4.8 1.6 3.2 0.69 4.15 14.4

4.07 1.27 2.8 0.63 3.49 16.0

(0.7) (0.3 ) (0.4) (0.06} (0.66} 1.6

1.1 (0.1 ) l.l (0.5 )

1.1 3.2*

*p::; 0.05. tp ::; 0.01. ip ::; 0.001.

p = NS). There is no statistically significant reduction in total cardiovascular death or all-cause mortality in the overview. The TPT115 was similar to the two previous trials in recruiting men who had not so far experienced major, clinically manifest episodes of ischemic heart disease (IHD) but differed in selecting those at increased risk. TPT recruited 5,499 men aged between 45 and 69 years at entry through 108 general practices in the United Kingdom. Those considered eligible fell in the top 20% of a risk score distribution based on smoking, family history, body mass index BP, serum cholesterol, plasma fibrinogen, and factor VII activity, each weighted according to their associations with IHD in the first Northwick Park Heart Study.l53 Of those eligible, 52% entered the trial. The two regimens evaluated were low-intensity oral anticoagulation to an INR of about 1.5 with warfarin and a controlledrelease 75-mg formulation of aspirin. The design was factorial , the four treatment groups thus established being active warfarin and active aspirin (WA), active warfarin and placebo aspirin (W) , placebo warfarin and active aspirin (A), and placebo warfarin and placebo aspirin (P). The mean warfarin dose required was 4.1 mg daily (range, 0.5 to 12.5 mg). There were 410 events of IHD (142 fatal, 268 nonfatal). The main effect of warfarin (ie, comparing WA and W vs A and P) was a reduction in all IHD events of 21% (p = 0.02) chiefly due to a 39% reduction in fatal events (p = 0.003) so that warfarin reduced the death rate from all causes by 17% (p = 0.04). The main effect of aspirin (WA and A vs Wand P) was a reduction in all IHD of 20%, almost entirely due to a 32% reduction (p = 0.004) in nonfatal events. In the individual treatment groups, the absolute reductions in all IHD due to absolute reductions of IHD events compared with placebo, were warfarin 2.6, aspirin 2.3, and warfarin/aspirin 4 per 1,000 person-years. Neither W nor A alone affected the incidence of all stroke, although W A increased hemorrhagic strokes (p = 0.009). Of the 10 hem-

orrhagic strokes that occurred, 7 were in the WA group and the mean systolic BP of these men at trial entry was 158 mm Hg compared with 146 in those experiencing other strokes and 135 in those who did not have strokes. Major noncerebral bleeding episodes were about twice as frequent in the active treatment groups as in the double placebo group (P) but the differences were not significant and there was no significant difference in frequency among the three active treatment groups (WA, W, and A). Less serious bleeding occurred more frequently in the WA than in the other groups. ASA therapy consistently reduces ischemic cardiac events in all three trials, although the effect appears to be most marked for nonfatal MI. Although there were trends to increased total stroke and hemorrhagic stroke with ASA in the first t\vo trials, there was a trend toward less total stroke with ASA in the third trial. There is a consistent failure in these three trials to show a reduction in all-cause mortality by ASA. In the US Physicians' Trial, 150 the risk of MI among men aged 40 to 49 years was only 0.1% per year (1/yr/1,000 men), whereas among men aged 60 to 69 years, the rate of MI was 0.82% per year (8.2/yr/1,000 men). Among the older men, the absolute risk reduction with ASA was about 4.4 infarcts per year per 1,000 men treated. Similarly, the absolute benefits were greater among men with diabetes mellitus, systolic or diastolic hypertension, cigarette smoking, and lack of exercise. In the TPT,us patients enrolled were at substantially increased risk of cardiovascular events, the event rates in the placebo group were substantially higher than in the US Physicians' Trial, and the absolute benefits of ASA were greater. Although even among the higher-risk patients there is no evidence for a reduction of all-cause mortality, the reduction of (mainly nonfatal) ischemic cardiac and ischemic cerebrovascular events probably outweighs the risk of hemorrhagic stroke, other bleeding, and GI side effects, and may CHEST I 114 I 5 I NOVEMBER, 1998 SUPPLEMENT

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justifY the prophylactic use of aspirin among men with no history of AMI, stroke, or TIA. Warfarin appears to have similar efficacy to ASA for the prevention of all ischemic heart disease outcomes, but it is particularly effective in reducing fatal events, resulting in a statistically signiflcant reduction in all-cause mortality (relative risk reduction 17%, p = 0.04). A combination of warfarin and aspirin was particularly effective in reducing ischemic cardiac events. Although hemorrhagic stroke was increased by the warfarin/aspirin combination, this risk can probably be minimized by careful BP monitoring and effective antihypertensive therapy. Compared with placebo, the risk of noncerebral major bleeding was increased to a similar degree by aspirin, warfarin, and a combination. It would be reasonable to consider aspirin or warfarin for prophylactic therapy in male patients who are at increased risk of cardiovascular events but do not have an increased risk of cerebrovascular or other hemorrhage with these agents. A combination of warfarin and aspirin might be reserved for those individuals at particularly high risk of ischemic events. The primary prevention trials of aspirin have not included women. The only available data are from a large prospective cohort study of 28,678 US registered nurses aged 34 to 65 years, free of diagnoses of coronary artery disease, stroke, and cancer at baseline.154 Among women taking one to six aspirins per week, the age-adjusted relative risk of a first MI was 0.68 (p = 0.005). This benefit was confined to women 2:50 years (relative risk 0.61; p = 0.002). There were trends toward less cardiovascular death (RR 0.89; p = 0.56) and important vascular events (RR 0.85; p = 0.12), but there was no difference for stroke (RR 0.99). No benefits were observed among women taking more than six aspirins per week. As in any cohort trial, there are concerns that unanticipated and undocumented confounders may bias the conclusions. Such factors might explain the failure to observe benefit among the women taking more than six aspirins per week, although a beta error might also be possible. Overall, the findings support those of aspirin trials in men. New data should come from the Women's Health Study. 1ss In other settings of vascular disease, there are trials that indicate that women benefit from aspirin therapy when the underlying problem is unstable angina120 or AMJ.93 However, the lower age-matched risk of cardiac events for women compared with men suggests that absolute benefits at a given age are likely to be less among women. CHRONIC CORONARY ARTERY DISEASE

Of the 22,071 male physicians without a history of MI, stroke, or transient cerebral ischemia enrolled in the Physician's Health Study, 333 had a history of exertional angina.l 56 During 60.2 months of follow-up, those randomly assigned to receive aspirin had a 70% relative risk reduction for MI compared with those assigned to placebo (p = 0.003) . Controlling for other cardiovascular risk factors, the relative risk reduction was 87% (p < 0.001). The Swedish Angina Pectoris Trial (SAPAT) Group 157 described 2,035 patients with stable angina randomly assigned to receive aspirin, 75 mg daily, or placebo for a median of 15 months. All patients received sotalol for 6268

control of angina. There was a 34% reduction of the primary outcome of MI and sudden death (CI, 24 to 49%; p = 0.003). Other vascular events and mortality were reduced by 22 to 32%. This was a secondary prevention study with angina serving as a marker for coronary artery disease, just as do prior MI, stroke, or TIA.

RECOMMENDATIONS

Acute Myocardial Infarction Anticoagulation: It is strongly recommended that all patients with AMI be considered for anticoagulant therapy. When thrombolytic therapy has been administered It is recommended that all patients who have received rtPA or reteplase should receive heparin according to the following regimen: (a) about 75 Ulkg N bolus at initiation of rtPA infusion or first rPA bolus, initial maintenance 1,000 to 1,200 U!h N , APTf 1.5 to 2 times control, maintained for 48 h; (b) maintenance of the APTf at 1.5 to 2 times control beyond 48 h should be undertaken only in the presence of determinants of high risk of systemic or venous thromboembolism (anterior Q-wave infarction, severe LV dysfunction, CHF, history of systemic or pulmonary embolus, 2D echo evidence of mural thrombosis, atrial fibrillation). In such cases, theN regimen may be sustained, or consideration may be given to subcutaneous administration (initial dose approximately 17,500 U every 12 h, to maintain APIT at 1.5 to 2 times control), or to conversion to warfarin therapy (target INR 2.5 [range, 2.0 to 3.0]). Grade A2-based on 2 RCTs 70- 72 and an overview61,62 showing marginal benefit of heparin, and expert interpretation of angiographic patency studies.5 7 It is recommended that all patients who have received SK or APSAC should receive N heparin only in the presence of determinants of high risk of systemic or venous thromboembolism (anterior AMI, CHF, previous embolus, atrial fibrillation), and then according to the following regimen: (a) measure APTf when the indication emerges but not <4 h after beginning SK or APSAC infusion; If more than two times control, repeat APTf as appropriate, and commence infusion of heparin when APTf less than two times control and maintain APTf at 1.5 to 2 times control as long as the risk of thromboembolism is considered to be high; (b) after 48 h, consideration may be given to subcutaneous administration (initial dose approximately 17,500 U every 12 h to maintain APTf at 1.5 to 2 times control), or for conversion to warfarin therapy (target INR 2.5 [range, 2.0 to 3.0]). Grade A2-based on two RCTs 70 - 72 and an overview61·62 showing marginal benefit of heparin, and one RCT showing no difference between N and subcutaneous heparin with SKJ58

When no thrombolytic therapy has been given It is strongly recommended that patients at increased risk for systemic or pulmonary embolism because of anterior Q-wave infarction, severe LV dysfunction, CHF, history of

Fifth ACCP Consensus conference on Antithrombotic Therapy

systemic or pulmonary embolism, 2D echo evidence of mural thrombosis, or atrial fibrillation, receive heparin (about 75 Ulkg bolus IV, initial maintenance 1,000 to 1,200 U/h IV, AYIT 1.5 to 2 times control), followed by warfarin (target INR 2.5 [range, 2.0 to 3.0]) for up to 3 months. Warfarin therapy should be maintained for atrial fibrillation (target INR 2.5 [range, 2.0 to 3.0]). Grade A2-based on individual RCTs in the prethrombolytic era,4 5- 47 an overview,61 ·62 and evidence from echocardiographic studies reporting markedly increased frequency of mural thrombosis in anterior vs inferior MJ3I,32,34,44 and three RCTs of long-term anticoagulation_78- 8l The recommendation for patients with atrial fibrillation is further supported by six RCTs and an overview,ll8 It is strongly recommended that every patient with AMI receive not less than low-dose heparin therapy (7,500 U subcutaneously every 12 h) until ambulatory, unless there is a specific c:ontraindication. Grade B2-based on results of two RCTs65·66 using heparin 15,000 U/d subcutaneously, and demonstrating reduced calf vein thrombosis, an overview,61,62 and evidence from echocardiographic trials.31,32,34 Antiplatelet Therapy

1. It is strongly recommended that all patients with AMI receive nonenteric-coated aspirin, 160 to 325 mg (two to four children's tablets, or one half to one adult tablet) to chew and swallow as soon as possible after the clinical impression of evolving AMI is formed, and whether or not thrombolytic therapy is to be given. The dose should be repeated daily by mouth indefinitely. Grade A1-based on results of one RCT for the initial month 93 and an overview of aspirin trials following AMI101 for ongoing use. The enteric-coated form will result in fewer gastric side effects in long-term therapy. If the patient is to receive heparin, aspirin should be given conjointly. However, if warfarin tl1erapy is commenced, the aspirin tl1erapy should be discontinued until the plarmed course of warfarin is complete. Aspirin therapy should then be restarted and maintained indefmitely. It is recommended that aspirin not be given concurrently with warfarin except in situations of very high embolic risk or previous failure of either therapy alone. Grade A2 for heparin/aspirin based on an overview. 61 ,62 Grade C2 for warfarin/aspirin based on expert opinion. 2. When embolic risk is low, aspirin is recommended for long-term therapy in preference to warfarin because of its simplicity, safety, and low cost. Long-term warfarin therapy is recommended in clinical settings of increased embolic risk (duration 1 to 3 months following AMI, or AMI complicated by severe LV dysfunction, CHF, previous emboli, or 2D echocardiographic evidence of mural thrombosis; duration indefinite witl1 atrial fibrillation. Grade C2-for these choices, based on expert extrapolation from an overview of antiplatelet agents101 showing marked benefit of aspirin over placebo and RCTs of longterm oral anticoagulation78 - 81 ·118 showing benefit of oral anticoagulation over control therapy. Trials of aspirin vs oral anticoagulation have not been helpful in permitting the

recommendation of one agent over the other. Patients who have contraindications to aspirin should be considered for long-term therapy with clopidogrel. Grade A1~one trial demonstrating a modest benefit of clopidogrel over aspirin.86 A further alternative for patients who have contraindications to aspirin is warfarin (INR 2.0 to 3.0). The increased complexity, risk, and cost of such therapy are concerns. Grade A2- based on three RCTsJ8-81 Some patients with recurrent ischemic episodes following AMI may benefit from a combination of warfarin and aspirin. Treatment with low-dose aspirin (80 mg) and low-intensity warfarin (target INR about 2) is advised. Grade C2-based on expert opinion. Sulfinpyrazone is not recommended for survivors of AMI. Grade B2-two level II trials10s.ws suggest a benefit of sulfinpyrazone, but the recommendation against it is made because the evidence for benefit of aspirin, a less expensive agent with a simpler dose regimen, and more extensive evidence supporting its efficacy. Dipyridamole (either alone or in combination with aspirin) is not recommended for survivors of AMI. Grade B1-based on two level II studies, one showing no difference between a combination of dipyridamole and aspirin vs aspirin alone 100 and the other showing a trend favoring the combination of dipyridamole and aspirin over placebo.los Unstable Angina Antiplatelet Agents: It is strongly recommended that patients witl1 unstable angina should be treated with aspirin (160 to 325 mgld) commencing as soon as possible after the clinical impression of unstable angina is fonned and continued indefinitely. Grade A1-based on four RCTsll9-121,123 and an overview.l01 Alternatives: It is recommended that patients with wlstable angina, who have aspirin allergy, be considered for therapy witl1 ticlopidine (250 mg bid). Triflusal may be another alternative to aspirin in countries where the drug is available. Grade A2-based on the results of only one RCT for toclopidine124 and one RCT for triflusal,l23a Clopidogrel may be considered as an alternative to ticlopidine, because of fewer serious side effects and its similar benefit to ASA post-MI, but to our knowledge, there is no reported RCT of its use in the setting of unstable angina. It is recommended that patients with unstable angina, who have contraindications to ASA, ticlopidine, and clopidogrel receive heparin, followed by warfarin (INR 2.0 to 3.0) for a period of several months. Grade C2-based on nonrandomized studiesl30 -133 and on expert opinion. The use of sulfinpyrazone is not recommended for patients with unstable angina. Grade A1-based on the negative results of one RCTJ 20 Anticoagulants: It is strongly recommended that patients hospitalized with unstable angina should, in addition to

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aspirin, commence IV heparin therapy (about 75 U!kg IV bolus, initial maintenance 1,250 U/h IV, AYIT 1.5 to 2 times control). The heparin therapy should be maintained for at least 48 h, or until the unstable pain pattern resolves with the present or more definitive therapy. Grade A1 (three level I trials and an oveJView121- 123·138). Alternatives: Low-molecular-weight heparins (specifically enoxaparin and dalteparin) may be substituted for unfractionated heparin, with similar efficacy. Potential advantages of low-molecular-weight heparin include ease of administration and lower incidence of heparin-induced thombocytopenia, but the cost in relation to unfractionated heparin is not yet clear. Grade A2-two RCfs against no heparin showing benefit, 142,143 one RCf showing equivalence to unfractionated heparin, 144 and two RCTs showing benefit over unfractionated heparin. 142·145 IV lib/lila receptor inhibitors should be considered for patients hospitalized with unstable angina of sufficient severity to warrant coronary care unit admission. Those patients whose angina is particularly unstable or resistant to treatment should be considered for this type of medical therapy, as well as for percutaneous transluminal coronary angioplasty. Grade A2-based on two RCfs of tirofiban,I30.1 31 one of eptifibatide, 132 and two of abciximab (with angioplasty) .126· 127

Chronic Coronary Artery Disease 1. It is recommended that all patients with stable angina receive oral aspirin (160 to 325 myd) indefinitely. Grade A1-based on the results of one RCTI57 and the analysis of a subgroup of patients with stable angina from a large RCf.l 50·156 2. It is recommended that all patients with clinical or laboratory evidence of coronary artery disease receive oral aspirin (160 to 325 myd indefinitely). Grade C2-based on expert advice derived from the results of RCfs, 150·157 analysis of a subgroup of patients with stable angina, 156 and the Antiplatelet Trialists' OveJView. 101 Primary Prevention

1. The routine use of aspirin for primary prevention of coronary artery disease outcomes in individuals free of a history of AMI, stroke, or transient cerebral ischemic attack, and <50 years, is not recommended. Grade B2-based on a subgroup analysis of a large RCT,150 indicating very low risk among patients <50 years, and overall an increased rate of duodenal ulcer, bleeding, and transfusion and a trend toward more hemorrhagic stroke among those receiving aspirin. 2. For individuals free of prior MI, stroke, or transient cerebral ischemic attack but with increasing levels of risk, there are data available for the efficacy of aspirin, warfarin, and the combination. Because of the increased complexity and costs of treatment with warfarin, and the greater likelihood of cerebral hemorrhage with the combination of aspirin and warfarin, the following recommendations are made for individuals at increasing risk of cardiovascular events. (a) It is recommended that aspirin (80 to 325 myd) be considered for individuals >50 years who have at least one 6288

major risk factor for coronary artery disease and who are free of contraindications to aspirin. Grade A2 for men- based on the results of a large RCTI50 indicating reduced MI and important vascular events overall. In that trial, the absolute benefits increased with advancing age, and with the presence of diabetes mellitus, systolic or diastolic hypertension, cigarette smoking, and a lack of exercise, though not with increasing cholesterol. 150 Based also on a recent trial of men at high risk of ischelnic cardiac events. 115 Grade C2 for women- based on the results of a large prospective cohort study154 indicating reduced MI. In that study, the absolute benefits increased with age >50 years, cigarette smoking, hypertension, diabetes mellitus, high cholesterol levels, and history of parental infarction. (b) It is recommended that low-intensity warfarin therapy (INR target 1.5) be considered as an alternate to aspirin for men at high risk of cardiovascular events in the prevention of those events and reduction in all-cause mortality. Grade A2-based on the results of one large RCT.l15 (c) It is recommended that a combination of low-dose aspirin (75 to 80 myd) and low-intensity warfarin (INR target 1.5) be considered as an alternate to aspirin or warfarin alone for men at very high risk of cardiovascular events for the prevention of these events and reduction in all-cause mortality. Grade A2-based on the results of one large RCf.U5

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