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EDITORIAL

NEJM

Volume 347:1019-1022 September 26, 2002 Number 13

Despite encouraging trends over the past three decades, coronary heart disease remains the leading cause of death in the United States and other industrialized countries. Recent data from the National Center for Health Statistics and the National Heart, Lung, and Blood Institute¹ emphasize the full dimensions of this health problem, revealing that nearly 13 million Americans have coronary heart disease and that 7.5 million have had a myocardial infarction. Because there are 1.1 million myocardial infarctions in the United States alone each year and because 450,000 of them represent recurrent infarctions, which carry an inherently greater risk of death and disability than first events, the importance of secondary-prevention strategies that can be widely implemented is unparalleled in health care.

In this issue of the Journal,² the potential role of oral anticoagulant therapy as secondary prevention is highlighted in the Warfarin, Aspirin, Reinfarction Study (WARIS II), reported by Hurlen et al. In this open-label study, patients hospitalized in 20 Norwegian centers for acute myocardial infarction were randomly assigned to long-term treatment with either warfarin (at a dose targeted to achieve an international normalized ratio [INR] of 2.8 to 4.2), 160 mg of aspirin daily, or 75 mg of aspirin daily plus warfarin (INR, 2.0 to 2.5). The primary outcome � a composite of death, nonfatal reinfarction, or thromboembolic stroke � occurred in 20.0 percent of the patients in the aspirin-only group, 16.7 percent of those in the warfarin-only group, and 15.0 percent of those in the combination-therapy group. The overall risk reduction was 29 percent in the combination-therapy group (P=0.001 for the comparison with the aspirin-only group) and 19 percent in the warfarin-only group (P=0.03). The incidence of nonfatal major hemorrhage among the patients receiving warfarin (either alone or in combination) was three to four times that among the patients receiving aspirin alone.

Does the hypothesis that oral anticoagulant therapy may be effective for secondary prevention after myocardial infarction have a sound scientific basis? Angioscopic studies have documented residual thrombosis and soft (vulnerable) plaques in the majority of patients for several months after myocardial infarction,³ with coexisting evidence of thrombin generation. Thrombin that is incorporated into plasma fibrin clots, and its subsequent binding to purified fibrin, is saturable and reversible. Thrombin activity, determined by in situ zymography, is approximately 4.5 IU per gram (wet weight) of thrombus.⁴ Although there is firm evidence that thrombin is the primary procoagulant enzyme in both physiologic hemostasis and pathologic thrombosis, its mechanism of generation and regulatory functions represent critical considerations in the development of effective therapies for cardiovascular thrombotic disorders.⁵

A cell-based model of vascular thrombosis,⁶ which fosters a functional, physiologic view of complex biochemical events on cell surfaces, identifies tissue factor�bearing cells (monocytes and endothelial cells) as the initiating sites of coagulation (Figure 1). The complexing of tissue factor with factor VIIa (from plasma) leads to thrombin generation, which in turn activates platelets by way of protease-activated receptors. The final phase takes place on platelet surfaces after the assembly of tenase complex (factor VIIIa and tissue factor�factor VIIa complex) and prothrombinase complex (factors Va and Xa, calcium, and phospholipid).

View larger version (53K): [in this window] [in a new window]   Figure 1. A Cell-Based Paradigm of Arterial Thrombosis. Arterial thrombosis, though traditionally viewed as a platelet-dependent process, occurs on a variety of other cell surfaces, including the surfaces of activated endothelial cells and monocytes, which are tissue factor (TF)�bearing cells. Inflammatory cytokines (tumor necrosis factor [TNF-] and interleukin-1) impair surface fibrinolysis by the provoked release of thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen-activator inhibitor type 1 (PAI-1). Oral anticoagulants potentially interrupt several prothrombotic, inflammatory, and regulatory processes.

It is the direct involvement of coagulation proteases in thrombotic, inflammatory, and cellular regulatory processes that provides a scientific underpinning to the consideration of anticoagulant agents in secondary prevention. The four hydroxycoumarin compounds used currently in clinical practice � warfarin, phenprocoumon, acenocoumarol, and dicumarol � inhibit the vitamin K�dependent, post-translational carboxylation of coagulation factors II, VII, IX, and X (which is required for calcium-mediated binding of these factors to the negatively charged phospholipids found in platelets and injured endothelial cells). The ability to inhibit thrombin generation offers considerable appeal; however, inhibition of one or more specific coagulation proteases may also prove beneficial. Tissue factor requires a cofactor, factor VIIa from plasma, to fulfill its enzymatic capabilities. Factor Xa, a vital component of prothrombinase-mediated conversion of prothrombin to thrombin, induces the expression of tissue factor from endothelial cells, smooth-muscle cells, and macrophages; increases endothelial-cell expression of E-selectin, intercellular adhesion molecule 1, and vascular-cell adhesion molecule 1, with subsequent leukocyte adhesion; and stimulates the synthesis and release of interleukin-6, interleukin-8, and monocyte chemotactic protein 1.⁹ Thus, our knowledge of atherosclerosis, inflammation, and thrombosis firmly supports a hypothesis designed to test oral anticoagulant therapy for the secondary prevention of cardiovascular events after myocardial infarction.

The evolution of oral anticoagulant agents for the management of acute coronary syndromes has taken a circuitous path, although much insight has been achieved along the way. In WARIS I,¹⁰ patients with myocardial infarction received either warfarin (INR, 2.8 to 4.8) or placebo. With warfarin, the incidence of major hemorrhage was twice that with placebo, but mortality and the rate of reinfarction were reduced by 24 percent and 34 percent, respectively. Interest in oral anticoagulant therapy then waned during the 1990s because two large-scale trials, the Coumadin Aspirin Reinfarction Study (CARS) (median INR, 1.3)¹¹ and the Combination Hemotherapy and Mortality Prevention (CHAMP) study (median INR, 1.8)¹² found no reduction in mortality, in the rate of reinfarction, or in the rate of stroke with warfarin (alone or in combination with aspirin) as compared with aspirin monotherapy.

The favorable results observed in WARIS I, coupled with the disappointing findings of CARS and CHAMP, not only established the need for a definitive trial of anticoagulant therapy in acute coronary syndromes but also raised the important possibility of a "threshold" level of anticoagulation for benefit (as previously observed in venous thromboembolic disorders and atrial fibrillation). Indeed, WARIS II,² the recently published Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis 2 study,¹³ and the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis 2 trial¹⁴ support a target level of anticoagulation approaching an INR of 3.0 (range, 2.5 to 3.5) for anticoagulation monotherapy and of 2.5 (range, 2.0 to 3.0) for combination therapy with aspirin. Thus, the available data, based on nearly 20,000 patients participating in randomized clinical trials, are strong and show that oral anticoagulants, when given in adequate doses, reduce the rates of reinfarction and thromboembolic stroke but at the cost of increased rates of hemorrhagic events.

Maximizing the benefit associated with oral anticoagulant therapy while minimizing the risk is a key consideration in management strategies designed to achieve and maintain a target level of inhibition. Because coumarin compounds have complex pharmacokinetic and pharmacodynamic properties and are among the most challenging drugs to regulate, coordinated anticoagulation clinics may be the preferred means to provide safe and effective care. Accumulating data show a 50 percent reduction in the rate of thromboembolism, major hemorrhage, and emergency medical visits with the use of this strategy; the use of portable, point-of-care coagulation monitors, by allowing frequent testing, may improve outcomes further.¹⁵ Even under ideal circumstances, the complexities of coumarin therapy create real obstacles for clinicians and their patients. In WARIS II, the INR in approximately one third of the patients receiving warfarin alone was below the target range; one third discontinued warfarin treatment at some point during the 80-month study period; 5 to 7 percent were withdrawn from treatment because of hemorrhagic complications; and 2 to 3 percent were deemed noncompliant. The exclusion of patients 75 years of age or older undoubtedly reduced the warfarin-associated risk of hemorrhage.

In the United States, percutaneous coronary intervention and stenting are performed in 15 to 20 percent of patients who have myocardial infarction with ST-segment elevation, and an additional 20 to 40 percent undergo percutaneous coronary intervention within the subsequent six weeks. The proportion of patients who have myocardial infarction without ST-segment elevation and who undergo percutaneous coronary intervention is even higher. Histologic examination reveals platelets and leukocytes clustered around the stent struts, and electron microscopy identifies fibrinogen, prothrombin, thrombin, and tissue factor on the outer surface of the platelet monolayer. Therapies designed primarily to inhibit platelet activation and aggregation take existing pathobiologic processes into consideration and are preferred to anticoagulant therapy in this setting.

The contribution of WARIS II to our current knowledge base is multidimensional. First, targeted inhibition of one or more coagulation proteases (and, potentially, of their proinflammatory or cell-regulatory properties) represents an important physiological concept in arterial thrombosis. Second, a threshold level of inhibition is required for benefit. Third, close monitoring and meticulous dose adjustment are absolute prerequisites for safe and effective treatment. Fourth, oral anticoagulant agents with more predictable pharmacokinetic and pharmacodynamic properties than coumarin compounds and with a broader therapeutic index should be developed.

Although it is likely that antiplatelet therapy will remain the standard of care in many countries for secondary prevention after myocardial infarction, the findings of WARIS II must not be overlooked. Oral anticoagulant therapy should be strongly considered for patients at risk for thromboembolic events, those with thrombophilia involving the arterial system (e.g., the antiphospholipid syndrome), and � pending further investigation of combination antiplatelet therapy in acute coronary syndromes associated with ST-segment elevation � patients with possible aspirin resistance. Advances in pharmacogenomics will ultimately permit patient-specific antithrombotic therapy for patients with acute coronary syndromes and other thrombotic disorders.

Richard C. Becker, M.D.
University of Massachusetts Medical School
Worcester, MA 01605

Editor's note: Dr. Becker receives research support from the National Heart, Lung, and Blood Institute, Daiichi Pharmaceuticals, and Merck, and he has received speaking fees from Aventis.

References

1. Morbidity & mortality: 2002 chart book on cardiovascular, lung, and blood diseases. Bethesda, Md.: National Heart, Lung, and Blood Institute, May 2002.
2. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002;347:969-974. [Abstract/Full Text]
3. Ueda Y, Asakura M, Yamaguchi O, Hirayama A, Hori M, Kodama K. The healing process of infarct-related plaques: insights from 18 months of serial angioscopic follow-up. J Am Coll Cardiol 2002;38:1916-1922. [ISI]
4. Mutch NJ, Robbie LA, Booth NA. Human thrombi contain an abundance of active thrombin. Thromb Haemost 2001;86:1028-1034. [ISI][Medline]
5. Nelken NA, Soifer SJ, O'Keefe J, Vu TK, Charo IF, Coughlin SR. Thrombin receptor expression in normal and atherosclerotic human arteries. J Clin Invest 1992;90:1614-1621. [ISI][Medline]
6. Hoffman M, Monroes DM III. A cell-based model of hemostasis. Thromb Haemost 2001;85:958-965. [ISI][Medline]
7. McEver RP. Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb Haemost 2001;86:746-756. [ISI][Medline]
8. Goel MS, Diamond SL. Neutrophil enhancement of fibrin deposition under flow through platelet-dependent and -independent mechanisms. Arterioscler Thromb Vasc Biol 2001;21:2093-2098. [Abstract/Full Text]
9. Senden NH, Jeunhomme TM, Heemskerk JW, et al. Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. J Immunol 1998;161:4318-4324. [Abstract/Full Text]
10. Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990;323:147-152. [Abstract]
11. Coumadin Aspirin Reinfarction Study (CARS) Investigators. Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 1997;350:389-396. [ISI][Medline]
12. Fiore L, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi P. Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation 2002;105:557-563. [Abstract/Full Text]
13. van Es RF, Jonker JJ, Verheugt FWA, et al. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002;360:109-113. [ISI][Medline]
14. Brouwer MA, van den Bergh PJPC, Aengevaeren WRM, et al. Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis (APRICOT)-2 trial. Circulation 2002;106:659-665. [Abstract/Full Text]
15. Burken MI, Whyte JJ. Home international normalized ratio monitoring: where evidence-based medicine is exemplified in the Medicare coverage process. J Thromb Thrombolysis 2002;13:5-7. [ISI][Medline]