AHA Scientific Statement: Guide to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association.

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 21, No. 7Guide to Anticoagulant Therapy: Heparin Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessOtherPDF/EPUBGuide to Anticoagulant Therapy: Heparin A Statement for Healthcare Professionals From the American Heart Association Jack Hirsh, Sonia S. Anand, Jonathan L. Halperin, and Valentin Fuster Jack HirshJack Hirsh Search for more papers by this author , Sonia S. AnandSonia S. Anand Search for more papers by this author , Jonathan L. HalperinJonathan L. Halperin Search for more papers by this author and Valentin FusterValentin Fuster Search for more papers by this author Originally published1 Jul 2001https://doi.org/10.1161/hq0701.093520Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:e9Thrombi are composed of fibrin and blood cells and may form in any part of the cardiovascular system, including veins, arteries, the heart, and the microcirculation. Because the relative proportion of cells and fibrin depends on hemodynamic factors, the proportions differ in arterial and venous thrombi.12 Arterial thrombi form under conditions of high flow and are composed mainly of platelet aggregates bound together by thin fibrin strands.345 In contrast, venous thrombi form in areas of stasis and are predominantly composed of red cells, with a large amount of interspersed fibrin and relatively few platelets. Thrombi that form in regions of slow to moderate flow are composed of a mixture of red cells, platelets, and fibrin and are known as mixed platelet-fibrin thrombi.45 When a platelet-rich arterial thrombus becomes occlusive, stasis occurs, and the thrombus can propagate as a red stasis thrombus. As thrombi age, they undergo progressive structural changes.6 Leukocytes are attracted by chemotactic factors released from aggregated platelets2 or proteolytic fragments of plasma proteins and become incorporated into the thrombi. The aggregated platelets swell and disintegrate and are gradually replaced by fibrin. Eventually, the fibrin clot is digested by fibrinolytic enzymes released from endothelial cells and leukocytes. The complications of thrombosis are caused either by the effects of local obstruction of the vessel, distant embolism of thrombotic material, or, less commonly, consumption of hemostatic elements.Arterial thrombi usually form in regions of disturbed flow and at sites of rupture of an atherosclerotic plaque, which exposes the thrombogenic subendothelium to platelets and coagulation proteins; plaque rupture may also produce further narrowing due to hemorrhage into the plaque.7891011 Nonocclusive thrombi may become incorporated into the vessel wall and can accelerate the growth of atherosclerotic plaques.91213 When flow is slow, the degree of stenosis is severe, or the thrombogenic stimulus is intense, the thrombi may become totally occlusive. Arterial thrombi usually occur in association with preexisting vascular disease, most commonly atherosclerosis; they produce clinical tissue ischemia either by obstructing flow or by embolism into the distal microcirculation. Activation both of blood coagulation and of platelets is important in the pathogenesis of arterial thrombosis. These 2 fundamental mechanisms of thrombogenesis are closely linked in vivo, because thrombin, a key clotting enzyme generated by blood coagulation, is a potent platelet activator, and activated platelets augment the coagulation process. Therefore, both anticoagulants and drugs that suppress platelet function are potentially effective in the prevention and treatment of arterial thrombosis, and evidence from results of clinical trials indicates that both classes of drugs are effective.Venous thrombi usually occur in the lower limbs; although often silent, they can produce acute symptoms due to inflammation of the vessel wall, obstruction of flow, or embolism into the pulmonary circulation. They can produce long-term complications due to venous hypertension by damaging the venous valves. Activation of blood coagulation is the critical mechanism in pathogenesis of venous thromboembolism, whereas platelet activation is less important. Anticoagulants are therefore very effective for prevention and treatment of venous thromboembolism, and drugs that suppress platelet function are of less benefit.Intracardiac thrombi usually form on inflamed or damaged valves, on endocardium adjacent to a region of myocardial infarction (MI), in a dilated or dyskinetic cardiac chamber, or on prosthetic valves. They are usually asymptomatic when confined to the heart but may produce complications due to embolism to the cerebral or systemic circulation. Activation of blood coagulation is more important in the pathogenesis of intracardiac thrombi than platelet activation, although the latter plays a contributory role. Anticoagulants are effective for prevention and treatment of intracardiac thrombi, and in patients with prosthetic heart valves, the efficacy of anticoagulants is augmented by drugs that suppress platelet function.Widespread microvascular thrombosis is a complication of disseminated intravascular coagulation or generalized platelet aggregation. Microscopic thrombi can produce tissue ischemia, red cell fragmentation leading to a hemolytic anemia, or hemorrhage due to consumption of platelets and clotting factors. Anticoagulants are effective in selected cases of disseminated intravascular coagulation.Clinical Consequences of ThrombosisIt has been estimated that venous thromboembolism is responsible for more than 300 000 hospital admissions per year in the United States14 and that pulmonary embolism (PE) causes or contributes to death in ≈12% of hospitalized patients and is responsible for 50 000 to 250 000 deaths annually in the United States. The burden of illness produced by venous thromboembolism includes death from PE (either acute or, less commonly, chronic), long-term consequences of the postthrombotic syndrome, the need for hospitalization, complications of anticoagulant therapy, and the psychological impact of a potentially chronic, recurrent illness.Arterial thrombosis is responsible for many of the acute manifestations of atherosclerosis and contributes to the progression of atherosclerosis. The burden of illness from atherosclerosis is enormous. As a generalized pathological process, atherosclerosis affects the arteries supplying blood to the heart, brain, and abdomen or legs, causing acute and chronic myocardial ischemia, including sudden death, MI, unstable angina, stable angina, ischemic cardiomyopathy, chronic arrhythmia, and ischemic cerebrovascular disease (including stroke, transient ischemic attacks, and multi-infarct dementia). In addition, atherosclerosis can cause renovascular hypertension, peripheral arterial disease with resulting intermittent claudication and gangrene, and bowel ischemia, and it can compound the complications of diabetes mellitus and hypertension. Thromboembolism that originates in the heart can cause embolic stroke and peripheral embolism in patients with atrial fibrillation (AF), acute MI, valvular heart disease, and cardiomyopathy.The second version of “A Guide to Anticoagulant Therapy” was published in 1994. Since then, the following important advances have been made: (1) low-molecular-weight heparin (LMWH) preparations have become established anticoagulants for treatment of venous thrombosis and have shown promise for the treatment of patients with acute coronary syndromes; (2) direct thrombin inhibitors have been evaluated in venous thrombosis and acute coronary syndromes; (3) important new information has been published on the optimal dose/intensity for therapeutic anticoagulation with coumarin anticoagulants; and (4) the dosing of heparin for adjunctive therapy in patients with acute coronary syndromes has been reduced because conventional doses cause serious bleeding when combined with thrombolytic therapy or glycoprotein (GP) IIb/IIIa antagonists.Whenever possible, the recommendations in this review of anticoagulant therapy are based on results of well-designed clinical trials. For some indications or clinical subgroups, however, recommendations are of necessity based on less solid evidence and are therefore subject to revision as new information emerges from future studies.Historical HighlightsHeparin was discovered by McLean in 1916.15 More than 20 years later, Brinkhous and associates16 demonstrated that heparin requires a plasma cofactor for its anticoagulant activity; this was named antithrombin III by Abildgaard in 196817 but is now referred to simply as antithrombin (AT). In the 1970s, Rosenberg, Lindahl, and others elucidated the mechanisms responsible for the heparin/AT interaction.181920 It is now known that the active center serine of thrombin and other coagulation enzymes is inhibited by an arginine reactive center on the AT molecule and that heparin binds to lysine sites on AT, producing a conformational change at the arginine reactive center that converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor.18 AT binds covalently to the active serine center of coagulation enzymes; heparin then dissociates from the ternary complex and can be reutilized18 (Figure 1). Subsequently, it was discovered181920 that heparin binds to and potentiates the activity of AT through a unique glucosamine unit18192021 contained within a pentasaccharide sequence,22 the structure of which has been confirmed. A synthetic pentasaccharide has been developed and is undergoing clinical evaluation for prevention and treatment of venous thrombosis.2324Mechanism of Action of HeparinOnly approximately one third of an administered dose of heparin binds to AT, and this fraction is responsible for most of its anticoagulant effect.2526 The remaining two thirds has minimal anticoagulant activity at therapeutic concentrations, but at concentrations greater than those usually obtained clinically, both high- and low-affinity heparin catalyze the AT effect of a second plasma protein, heparin cofactor II27 (Table 1).The heparin-AT complex inactivates a number of coagulation enzymes, including thrombin factor (IIa) and factors Xa, IXa, XIa, and XIIa.18 Of these, thrombin and factor Xa are the most responsive to inhibition, and human thrombin is ≈10-fold more sensitive to inhibition by the heparin-AT complex than factor Xa (Figure 2). For inhibition of thrombin, heparin must bind to both the coagulation enzyme and AT, but binding to the enzyme is less important for inhibition of activated factor X (factor Xa; Figure 3).21 Molecules of heparin with fewer than 18 saccharides do not bind simultaneously to thrombin and AT and therefore are unable to catalyze thrombin inhibition. In contrast, very small heparin fragments containing the high-affinity pentasaccharide sequence catalyze inhibition of factor Xa by AT.28293031 By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of factor V and factor VIII.323334Heparin is heterogeneous with respect to molecular size, anticoagulant activity, and pharmacokinetic properties (Table 2). Its molecular weight ranges from 3000 to 30 000 Da, with a mean molecular weight of 15 000 Da (≈45 monosaccharide chains; Figure 4).353637 The anticoagulant activity of heparin is heterogeneous, because only one third of heparin molecules administered to patients have anticoagulant function, and the anticoagulant profile and clearance of heparin are influenced by the chain length of the molecules, with the higher-molecular-weight species cleared from the circulation more rapidly than the lower-molecular-weight species. This differential clearance results in accumulation of the lower-molecular-weight species, which have a lower ratio of AT to anti-factor Xa activity, in vivo. This effect is responsible for differences in the relationship between plasma heparin concentration (measured in anti-factor Xa units) and the activated partial thromboplastin time (aPTT). The lower-molecular-weight species that are retained in vivo are measured by the anti-factor Xa heparin assay, but these have little effect on the aPTT.In vitro, heparin binds to platelets and, depending on the experimental conditions, can either induce or inhibit platelet aggregation.3839 High-molecular-weight heparin fractions with low affinity for AT have a greater effect on platelet function than LMWH fractions with high AT affinity40 (Table 1). Heparin prolongs bleeding time in humans41 and enhances blood loss from the microvasculature in rabbits.424344 The interaction of heparin with platelets42 and endothelial cells43 may contribute to heparin-induced bleeding by a mechanism independent of its anticoagulant effect.44In addition to anticoagulant effects, heparin increases vessel wall permeability,43 suppresses the proliferation of vascular smooth muscle cells,45 and suppresses osteoblast formation and activates osteoclasts, effects that promote bone loss.4647 Of these 3 effects, only the osteopenic effect is relevant clinically, and all 3 are independent of the anticoagulant activity of heparin.48Pharmacology of Unfractionated HeparinThe 2 preferred routes of administration of unfractionated heparin (UFH) are continuous intravenous (IV) infusion and subcutaneous (SC) injection. When the SC route is selected, the initial dose must be sufficient to overcome the lower bioavailability associated with this route of administration.49 If an immediate anticoagulant effect is required, the initial dose should be accompanied by an IV bolus injection, because the anticoagulant effect of SC heparin is delayed for 1 to 2 hours.After entering the bloodstream, heparin binds to a number of plasma proteins (Figure 5), which reduces its anticoagulant activity at low concentrations, thereby contributing to the variability of the anticoagulant response to heparin among patients with thromboembolic disorders50 and to the laboratory phenomenon of heparin resistance.51 Heparin also binds to endothelial cells52 and macrophages, properties that further complicate its pharmacokinetics. Binding of heparin to von Willebrand factor also inhibits von Willebrand factor–dependent platelet function.53Heparin is cleared through a combination of a rapid saturable mechanism and much slower first-order mechanisms545556 (Figure 6). The saturable phase of heparin clearance is attributed to binding to endothelial cell receptors5758 and macrophages,59 where it is depolymerized6061 (Figure 5). The slower, unsaturable mechanism of clearance is largely renal. At therapeutic doses, a considerable proportion of heparin is cleared through the rapid saturable, dose-dependent mechanism (Figure 6). These kinetics make the anticoagulant response to heparin nonlinear at therapeutic doses, with both the intensity and duration of effect rising disproportionately with increasing dose. Thus, the apparent biological half-life of heparin increases from ≈30 minutes after an IV bolus of 25 U/kg to 60 minutes with an IV bolus of 100 U/kg and 150 minutes with a bolus of 400 U/kg.545556The plasma recovery of heparin is reduced62 when the drug is administered by SC injection in low doses (eg, 5000 U/12 h) or moderate doses of 12 500 U every 12 hours63 or 15 000 U every 12 hours.49 However, at high therapeutic doses (>35 000 U/24 hours), plasma recovery is almost complete.64 The difference between the bioavailability of heparin administered by SC or IV injection was demonstrated strikingly in a study of patients with venous thrombosis49 randomized to receive either 15 000 U of heparin every 12 hours by SC injection or 30 000 U by continuous IV infusion; both regimens were preceded by an IV bolus dose of 5000 U. Therapeutic heparin levels and aPTT ratios were achieved at 24 hours in only 37% of patients given SC heparin compared with 71% of those given the same total dose by continuous IV infusion.Dose-Response Relationships and Laboratory MonitoringThe risk of heparin-associated bleeding increases with dose6566 and with concomitant thrombolytic67686970 or abciximab7172 therapy. The risk of bleeding is also increased by recent surgery, trauma, invasive procedures, or concomitant hemostatic defects.73 Randomized trials show a relationship between the dose of heparin administered and both its efficacy496374 and its safety.7172 Because the anticoagulant response to heparin varies among patients with thromboembolic disorders,75767778 it is standard practice to adjust the dose of heparin and monitor its effect, usually by measurement of the aPTT. This test is sensitive to the inhibitory effects of heparin on thrombin, factor Xa, and factor IXa. Because there is a relationship between heparin dose and both anticoagulant effect and antithrombotic efficacy, it follows that there should be a relationship between anticoagulant effect and antithrombotic efficacy.In the past, we were secure in the contention that a strong relationship existed between the ex vivo effect of heparin on the aPTT and its clinical effectiveness, but several lines of evidence have challenged the strength of such a relationship. First, the initial findings supporting a tight relationship between the effect of heparin on aPTT and its clinical efficacy were based on retrospective subgroup analysis of cohort studies and are therefore subject to potential bias49637576777879 (Table 3). Second, the results of a randomized trial80 and 2 recent meta-analyses of contemporary cohort studies8182 call into question the value of the aPTT as a useful predictor of heparin efficacy in patients with venous thrombosis. Third, no direct relationship between aPTT and efficacy was observed in the subgroup analysis of the GUSTO-I study (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries) in patients with acute MI who were treated with thrombolytic therapy followed by heparin.83 Fourth, even if the aPTT results were predictive of clinical efficacy, the value of this test would be limited by the fact that commercial aPTT reagents vary considerably in responsiveness to heparin.84 Although standardization can be achieved by calibration against plasma heparin concentration (the therapeutic range is 0.2 to 0.4 U/mL based on protamine titration or 0.3 to 0.7 U/mL based on anti-factor Xa chromogenic assay), this is beyond the scope of many clinical laboratories. Heparin monitoring is likely to become less problematic in the future as LMWH replaces UFH for most indications.85Despite its limitations for monitoring heparin, aPTT remains the most convenient and most frequently used method for monitoring the anticoagulant response. aPTT should be measured ≈6 hours after the bolus dose of heparin, and the continuous IV dose should be adjusted according to the result. Various heparin dose-adjustment nomograms have been developed86 (Tables 4 and 5), but none are applicable to all aPTT reagents,84 and the therapeutic range must be adapted to the responsiveness of the reagent used. In addition, the dosage regimen should be modified when heparin is combined with thrombolytic therapy87 or platelet GP IIb/IIIa antagonists.72 When heparin is given by SC injection in a dose of 35 000 U/24 hours in 2 divided doses,64 the anticoagulant effect is delayed ≈1 hour, and peak plasma levels occur after ≈3 hours.Limitations of HeparinThe limitations of heparin are based on its pharmacokinetic, biophysical, and nonanticoagulant biological properties.88 All are caused by the AT-independent, charge-dependent binding properties of heparin to proteins and surfaces. Pharmacokinetic limitations are caused by AT-independent binding of heparin to plasma proteins,89 proteins released from platelets,90 and possibly endothelial cells, resulting in the variable anticoagulant response to heparin and the phenomenon of heparin resistance.80 AT-independent binding to macrophages and endothelial cells also results in a dose-dependent mechanism of heparin clearance.The biophysical limitations occur because the heparin-AT complex is unable to inactivate factor Xa in the prothrombinase complex and thrombin bound to fibrin or to subendothelial surfaces. The biological limitations of heparin include osteopenia and heparin-induced thrombocytopenia (HIT). Osteopenia is caused as a result of binding of heparin to osteoblasts,46 which then release factors that activate osteoclasts, whereas HIT results from heparin binding to platelet factor 4 (PF4), forming an epitope to which the HIT antibody binds.9192 The pharmacokinetic and nonanticoagulant biological limitations of heparin are less evident with LMWH,93 whereas the limited ability of the heparin-AT complex to inactivate fibrin-bound thrombin and factor Xa is overcome by several new classes of AT-independent thrombin and factor Xa inhibitors.94Platelets, fibrin, vascular surfaces, and plasma proteins modify the anticoagulant effect of heparin. Platelets limit the anticoagulant effect of heparin by protecting surface factor Xa from inhibition by the heparin-AT complex9596 and by secreting PF4, a heparin-neutralizing protein.97 Fibrin limits the anticoagulant effect of heparin by protecting fibrin-bound thrombin from inhibition by heparin AT.98 Heparin binds to fibrin and bridges between fibrin and the heparin binding site on thrombin. As a result, heparin increases the affinity of thrombin for fibrin, and by occupying the heparin binding site on thrombin, it protects fibrin-bound thrombin from inactivation by the heparin-AT complex.99100 Thrombin also binds to subendothelial matrix proteins, where it is protected from inhibition by heparin.101 These observations explain why heparin is less effective than the AT-independent thrombin and factor Xa inhibitors94 for preventing thrombosis at sites of deep arterial injury in experimental animals102103 and may explain why hirudin is more effective than heparin in patients with unstable angina or non–Q-wave MI.104Clinical Use of HeparinHeparin is effective for the prevention and treatment of venous thrombosis and PE, for prevention of mural thrombosis after MI, and for treatment of patients with unstable angina and MI. Although heparin is used to prevent acute thrombosis after coronary thrombolysis, recent reports question the benefits of heparin in this setting when patients are also treated with aspirin (see below).In patients with venous thromboembolism or unstable angina, the dose of heparin is usually adjusted to maintain aPTT at an intensity equivalent to a heparin level of 0.2 to 0.4 U/mL as measured by protamine titration or an anti-factor Xa level of 0.30 to 0.7 U/mL. For many aPTT reagents, this is equivalent to a ratio (patient/control aPTT) of 1.5 to 2.5. The recommended therapeutic range4979 is based on evidence from animal studies105 and supported by subgroup analysis of prospective cohort studies involving treatment of deep vein thrombosis (DVT),49 prevention of mural thrombosis after MI,63 and prevention of recurrent ischemia after coronary thrombolysis.7576 Recommended heparin regimens for venous and arterial thrombosis are summarized in Table 6.Treatment of Venous ThromboembolismUse of heparin for the treatment of venous thrombosis and PE is based on results of randomized studies.106107 The effectiveness and safety of heparin administered by continuous IV infusion have been compared with intermittent IV injection in 6 studies108109110111112113 and with high-dose SC heparin in 6 studies.64114115116117118 It is difficult to determine the optimal route of heparin administration because different doses were used in these studies, most of the studies were small and underpowered, and different criteria were used to assess efficacy and safety. Nevertheless, the results indicate that heparin is safe and effective when appropriate doses are given. Thus, in a recent pooled analysis of 11 clinical trials in which ≈15 000 patients were treated with either heparin (administered as an initial bolus of 5000 U followed by 30 000 to 35 000 U/24 hours with aPTT monitoring) or SC LMWH,119 the mean incidence of recurrent venous thromboembolism among patients assigned heparin was 5.4%. The rate of major bleeding was 1.9%, fatal recurrent venous thromboembolism occurred in 0.7%, and bleeding was fatal in 0.2% of heparin-treated patients. The initial dose of heparin is particularly critical when heparin is administered by SC injection, because an adequate anticoagulant response is not achieved in the first 24 hours unless a high starting dose is used (17 500 U SC).64Audits of heparin monitoring practices indicate that dosage adjustments are frequently inadequate, and dosing practices can be improved by use of a simple and effective weight-adjusted dosage regimen.74 There is evidence that a 5-day course of heparin is as effective as a 10-day course120121 (Table 7). The short-course regimen has obvious appeal, reducing hospital stay and the risk of HIT. Although the shorter course of treatment can be recommended for most patients with venous thromboembolism, this may not be appropriate in cases of extensive iliofemoral vein thrombosis or major PE, because such patients were underrepresented in these studies.120121Prophylaxis of Venous ThromboembolismHeparin in a fixed low dose of 5000 U SC every 8 or 12 hours is an effective and safe form of prophylaxis in medical and surgical patients at risk of venous thromboembolism. Low-dose heparin reduces the risk of venous thrombosis and fatal PE by 60% to 70%.122123 Among general surgical patients, the incidence of fatal PE was reduced from 0.7% in controls to 0.2% in one study (P<0.001)120 and from 0.8% to 0.3% (P<0.001) in a larger analysis that included orthopedic surgical patients.123 There was also a small but statistically significant decrease in mortality from 3.3% to 2.4% with low-dose heparin prophylaxis (P<0.02).123 The use of low-dose heparin is associated with a small excess incidence of wound hematoma122123124 and a minimal, statistically insignificant increase in major bleeding but no increase in fatal bleeding. Low-dose heparin also effectively prevents venous thromboembolism in patients with MI and in those with other serious medical disorders,125 and it reduced in-hospital mortality by 31% (P<0.05) in a study of 1358 general medical patients aged >40 years.126 Although low-dose heparin is also effective in reducing DVT after hip surgery,123 the incidence of thrombosis remains substantial (20% to 30%) and can be reduced further with either adjusted low-dose heparin127 or fixed-dose LMWH.93 Moderate-dose warfarin is effective in patients undergoing major orthopedic surgical procedures,128129 but direct comparisons of low-dose heparin and warfarin have not been performed in major orthopedic surgery.Coronary Artery DiseaseCoronary thrombosis is important in the pathogenesis of unstable angina, acute MI, and sudden cardiac death. It is also important in the pathogenesis of reinfarction and death in patients with acute MI treated with thrombolytic agents or percutaneous transluminal coronary angioplasty. In most patients, heparin ameliorates the thrombotic manifestations of acute coronary syndromes, but it is no longer used as the sole antithrombotic drug in these settings. Today, heparin is always used in combination with aspirin in potentially eligible patient groups with acute myocardial ischemia,130 in those receiving thrombolytic therapy for evolving MI, in those treated with platelet GP IIb/IIIa antagonists for unstable angina,131132 and in those undergoing high-risk coronary angioplasty.7172132 When combined with aspirin,130133 thrombolytic agents, or GP IIb/IIIa antagonists, however, heparin in full doses increases the risk of bleeding, and the dose is usually reduced in these settings.72Unstable Angina and Non–Q-Wave MIHeparin has been evaluated in a number of randomized, double-blind, placebo-controlled clinical trials for the short-term treatment of unstable angina or non–Q-wave MI.134135136137 When given alone to patients with unstable angina, heparin is effective in preventing acute MI and recurrent angina,135136137 and when used in combination with aspirin, the results of a meta-analysis of 6 small trials suggest that the combination also reduces short-term rates of cardiovascular death and MI by ≈30% over those achieved with aspirin alone.134Theroux et al135 compared the relative efficacy and safety of heparin, aspirin, and their combination in 479 patients with unstable angina. Heparin was administered as an initial 5000-U IV bolus, followed by IV infusion of 1000 U/h, adjusted to maintain the aPTT at 1.5 to 2.0 times the control value. Treatment was initiated within 24 hours after the onset of chest pain and continued for ≈6 days. The incidence of MI during the acute period was 11.9% in the placebo group and was reduced to 3.3% in the aspirin groups (P=0.012), 0.8% in the heparin group (P<0.0001), and 1.6% in the group given the combination of aspirin and heparin (P=0.001). The incidence of refractory angina (22.9% in the placebo group) was significantly reduced to 8.5% (P=0.002) in the heparin group and 10.7% in the heparin-plus-aspirin group (P=0.11) but was 16.5% in the aspirin group. In a second study,138 these investigators compared the efficacy and safety of heparin and aspirin. This was a continuation of the previous study in which the placebo and combination groups were discontinued and an additional 245 patients were randomized to receive either continuous IV heparin or oral aspirin twice daily during the in-hospital phase (≈6 days). Fatal or nonfatal MI occurred during the acute period i