Managing Unstable Angina in High-Risk Patients (Part I)

Derek P. Chew, MBBS and David J. Moliterno, MD
Derek P. Chew, MBBS and David J. Moliterno, MD
Platelets are now widely acknowledged as pivotal in the development of arterial thrombosis and its resultant acute ischemic coronary syndromes (ACS), including unstable angina (UA), non-Q wave myocardial infarction (NQWMI), ST-segment elevation acute myocardial infarction (AMI) and the acute ischemic complications of percutaneous coronary intervention (PCI).1 Injury to the endothelium of a coronary artery generally results in platelet adhesion, followed by platelet activation and aggregation. Platelet aggregation, in turn, causes thrombus formation. The extent of occlusion of the coronary artery by a thrombus generally determines the clinical presentation of ACS — whether as UA, NQWMI or Q-wave MI.2 Recognition of the compositional and pathophysiological differences between arterial and venous thrombi has contributed to recent advances in the management of ACS. Arterial thrombi are composed primarily of platelets with little fibrin and few erythrocytes (“white” thrombi), whereas venous thrombi are composed primarily of erythrocytes in a fibrin mesh (“red” thrombi). However, the distinction between these two types of thrombi is not absolute since the composition of thrombi is in a constant state of flux that is determined by the stage of thrombus formation. Thrombi that occur in coronary arteries of patients with stent thrombosis and UA are primarily “white” thrombi, whereas the more complete occlusions found in patients with AMI are more likely to be composed of “red” thrombi. This difference in the composition of thrombi may offer a partial explanation as to why fibrinolytic agents are effective as first-line treatment in patients with AMI but of no benefit in patients with UA or NQWMI.3 Platelet activation is mediated by multiple agonists and can occur via several different pathways. However, regardless of the agonist that stimulates platelet activation, a key component leading to formation of platelet-rich thrombi is the expression and activation of glycoprotein (GP) IIb/IIIa on the surface, enabling the binding of fibrinogen and other adhesive proteins to platelet receptor glycoprotein IIb/IIIa on multiple platelets.1,2,4,5 Consequently, research has focused on discovering antagonists of this receptor that could completely inhibit platelet aggregation and thereby reduce the morbidity and mortality associated with ACS.2 Risk Stratification in ACS Patients with ACS are heterogeneous with respect to the severity and prognosis of their underlying disease. Early risk stratification allows for more appropriate decisions for admission and therapeutic triage of patients, and is essential in the selection of the most beneficial and cost-effective approach for the individual patient.6 Patient prognosis can be correlated with the Braunwald classification of UA, and an association between the severity of pain (Class III or C) and in-hospital event rates has been observed. The electrocardiogram (ECG) remains the gold standard for early diagnosis of AMI. However, in patients with UA, ECG results can be inconclusive. In patients presenting acutely with chest pain, approximately 40% will have a normal ECG, 26% will have inverted T-waves, and approximately 20% will have ST-segment depression.7 In recognition of the sweeping changes that have occurred in the practice of coronary angiography and intervention since the 1994 publication of the Agency for Health Care Policy and Research (AHCPR) guidelines, the American College of Cardiology (ACC) and American Heart Association (AHA) have recently revised guidelines for the care of ACS. With the increased utilization of coronary stenting and improvements in adjunctive pharmacology over the past 5 years, the relationship between specific AHA/ACC lesion morphology classifications and clinical outcomes has been obscured; the current task force committee has therefore recommended a change from the prior classification of lesion morphology toward a “low-risk, high-risk” patient-based classification.8 Multivariate analyses have shown age, history of significant documented coronary stenosis, significant ST-segment deviation, rest angina and elevation in serum cardiac-specific markers to be important risk predictors among patients presenting with non-ST segment elevation ACS. Serum cardiac troponin T and I levels are directly related to adverse patient outcomes and can provide prognostic information that is distinct from and additive to findings of elevated creatinine kinase-MB (CK-MB) (Figure 1).9 Furthermore, they are more sensitive than CK-MB.7 The development of rapid assays for the detection of serum markers of myocardial necrosis, such as troponin T and I, represents an exciting and useful advance. The presence of either elevated troponin T or I has been shown to be predictive of adverse clinical outcomes (death, MI, or need for revascularization).10 A direct, quantitative relationship between serum troponin level and the risk of subsequent ischemic events has been demonstrated10 in large, randomized, controlled clinical trials, including Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-IIa,11 GUSTO-III,12 Thrombolysis in Myocardial Infarction (TIMI)11a13 and Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC)-II studies.14 C-reactive protein levels, a nonspecific marker of inflammation, also provide additional information for risk stratification of patients with UA and NQWMI.8,10 In addition, other potentially useful markers such as brain (B-Type) natriuretic peptide are emerging.15 Patients with non-ST elevation ACS should be risk-stratified to permit selective application of more aggressive catheter-based therapeutic strategies. Risk can be assessed at the bedside on the basis of presenting symptom complex (Braunwald class of angina), the 12-lead ECG, serum biochemical markers and physical examination. Patients should be considered at particularly high risk if they show signs of left ventricular decompensation, hypertension or ischemic mitral valve dysfunction during episodes of angina. Characterization of anginal symptoms by Braunwald classification can help define risk for subsequent in-hospital death, MI or survival to 30 days. Similarly, the presence and magnitude of electrocardiographic ST-segment depression on the 12-lead ECG has been correlated with in-hospital and 30-day death rates.10 Traditional Management Strategies for ACS The primary goals of therapy in the treatment of ACS are stabilization of an evolving coronary arterial thrombosis, restoration of coronary artery patency, alleviation of chest pain symptoms and prevention of AMI and sudden death. The two primary management strategies to achieve these goals are treatment with medical management (conservative strategy) and interventional therapies such as PCI (aggressive strategy). Pharmacologic therapies recommended for the ACS patient usually include oral aspirin and intravenous heparin.3 Thrombus formation has long been known to be inhibited to a degree by aspirin and several other therapeutic agents. Heparin and aspirin are therapeutically useful in a variety of acute ischemic coronary syndromes, but neither has all the characteristics considered desirable in an ideal antithrombotic agent. Aspirin inhibits cyclooxygenase, thereby preventing the production of thromboxane A2, but leaves open all the other agonist pathways — notably thrombin and adenosine diphosphate (ADP) — that lead to platelet activation. Although all platelet activation agonists utilize this pathway, most of them can also activate the glycoprotein IIb/IIIa receptor even if the cyclooxygenase pathway is blocked. Consequently, although aspirin is cost-effective, it is not a potent platelet antagonist because it leaves numerous alternative routes available for platelet activation.3,16 Heparin is routinely used in the treatment of ACS to limit further stimulation of platelet aggregation by thrombin and stabilization of the thrombus by fibrin. However, its effectiveness is reduced by several factors, most notably its inability to inhibit clot-bound thrombin. Heparin indirectly inhibits thrombin-mediated thrombosis, and is therefore dependent on antithrombin levels. Also, heparin has been associated with higher rates of hemorrhagic stroke when administered at high doses in patients receiving thrombolytic therapy; it also may activate platelets or cause thrombocytopenia and ischemic or hemorrhagic complications.3,17–21 Other pharmacologic therapies used in the management of UA/NQWMI include intravenous nitroglycerin and beta-blockers. Nitroglycerin is often used to alleviate the pain associated with cardiac ischemia because it dilates the coronary arteries and reduces cardiac preload.22 Beta-blockers are often used in the management of UA to slow the heart rate and reduce myocardial oxygen demand.22,23 Lipid-lowering agents are known to reduce long-term mortality in patients with stable coronary disease or significant risk factors.24 Data from the GUSTO-IIb and Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trials were used to compare all-cause mortality among patients with acute coronary syndromes who were discharged on lipid-lowering agents (n = 3,653) with those who were not (n = 17,156).24 Lipid-lowering therapy was associated with a lower rate of death at 30 days (0.5% versus 1.0%, respectively; p = 0.001) and at 6 months (1.7% versus 3.5% respectively; p 24 After adjustment for the propensity to be prescribed lipid-lowering agents and other potential confounders, prescription of a lipid-lowering agent at discharge remained associated with a reduced risk of death at 6 months (p = 0.023). Prescription of a lipid-lowering drug at hospital discharge was thus independently associated with reduced short-term mortality among patients after an ACS.24 Table 1 describes available therapies for treating patients with unstable angina.17–20,22,23,25–55 Conservative and Invasive Management Strategies Two different treatment strategies are employed in the management of patients with unstable angina and NQWMI.22 In the “early conservative” strategy, coronary angiography is reserved for those patients with evidence of recurrent ischemia (angina at rest or with minimal activity, dynamic ST-segment changes) or a strongly positive stress test despite maximal medical therapy.22 The conservative approach spares the use of invasive procedures along with their associated risks and costs.22 In the “early invasive” strategy, patients who do not have clinically obvious contraindications to coronary revascularization are recommended for coronary angiography and, if possible, angiographically directed revascularization.22 The invasive approach can identify those 10–15% of patients who have no significant coronary stenoses as well as the approximately 20% of patients with 3-vessel disease with left ventricular (LV) dysfunction or left main coronary artery disease. Early PCI also offers the potential of reducing the risk for subsequent hospitalization and the need for multiple drug regimens to manage angina.22 Rationale for GP IIb/IIIa Inhibition in Unstable Angina Many patients with vascular disease who are treated with older antithrombotics or drugs such as aspirin can still develop thrombi that can result in ischemic complications. This and other shortcomings of conventional therapeutic approaches stimulated research aimed at developing more effective and safer platelet inhibitors.16 While initial studies demonstrated success with these agents, the role of upstream initiation required clarification.56 Risk stratification is useful in triaging patients to early angiography (with PCI as indicated and feasible) or further observation and subsequent provocative stress testing. Data from the C7E3 Fab Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment (CAPTURE), PURSUIT and Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) studies have shown that “upstream” initiation of treatment with platelet GP IIb/IIIa inhibitors (abciximab for 18–24 hours and eptifibatide for 48–96 hours, respectively) before angiography or PCI can reduce the pre-procedural incidence of death or MI.10,57–59 Based on experience gained at the Ohio Heart Health Center at the Christ Hospital in Cincinnati, Ohio, rapid triage of high-risk patients to early coronary angiography and PCI in conjunction with abciximab can be combined with early hospital discharge to achieve excellent clinical outcomes in a very cost-effective manner.10 The integration of more expensive technologies (stent, abciximab) that improve clinical outcomes into an expedited patient care pathway with abbreviated hospital length of stay can effectively offset cost increments of technology and reduce the net cost of care.10 Clinical Trials of GP IIb/IIIa Inhibitors in UA/NQWMI The primary causes of acute complications following PCI are abrupt or threatened vessel closure and distal vessel embolization with microvascular obstruction. Balloon dilation can cause endothelial denudation, produce cracks and tears in the arterial wall and expose thrombogenic subendothelial material.60 Ulcerated atherosclerotic plaques are particularly thrombogenic.60 Although the deployment of coronary stents may improve procedural success rates and reduce major complications [coronary dissection, abrupt vessel closure, urgent coronary artery bypass grafting (CABG)], compared with standard balloon angioplasty in patients with UA, stents do not effectively treat the underlying increase in platelet activation, and non-ST segment elevation ACS remains a significant hazard for the development of adverse clinical events even following coronary stent deployment.10 The long-term results of the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) study have shown that GP IIb/IIIa blockade with abciximab during PCI in patients with ACS is associated with sustained clinical benefits at 3 years following therapy.61 Questions remain as to what extent this benefit is GP IIb/IIIa inhibitor “class-specific” or abciximab-specific.10 EPIC. The first phase-III trial of abciximab enrolled 2,099 patients who were at high risk for peri-procedural ischemic complications of percutaneous transluminal coronary angioplasty (PTCA) or directional coronary atherectomy (DCA). Patients were classified as high risk if they had UA and/or recent NQWMI, acute Q-wave myocardial infarction (QWMI) within 12 hours of symptom onset, or other clinical and coronary morphologic characteristics predictive of acute ischemic complications. In a double-blind design, patients were randomized to receive either abciximab bolus (0.25 mg/kg bolus plus placebo infusion for 12 hours), abciximab bolus plus infusion (0.25 mg/kg bolus plus 10 µg/min infusion for 12 hours) or placebo (placebo bolus plus placebo infusion for 12 hours). All patients also received aspirin plus a non-weight-adjusted, standard-dose heparin (10,000–12,000 U) regimen before intervention, and a heparin infusion was continued following the angioplasty procedure. The primary composite endpoint was the occurrence of death, MI or need for urgent coronary intervention at 30 days. Follow-up evaluations were subsequently conducted at 6 months and 3 years post-treatment.62 Patients in the abciximab bolus plus abciximab infusion group showed a relative reduction of 33% in composite endpoint event rates within the first 48 hours (placebo 9.9%, abciximab 6.6%; p = 0.025).63 This treatment benefit was sustained for the 30-day composite endpoint with a 35% risk reduction (RR) in event rates (placebo 12.8%, abciximab 8.3%; p = 0.008).62 At 6 months, the RR in the composite endpoint was 30% (placebo 17.6%, abciximab 12.3%; p = 0.006), and at 3 years the RR in the composite endpoint was 20% (placebo 24.4%, abciximab 19.6%; p = 0.027).63 The beneficial effect of treatment with abciximab bolus plus infusion in these high-risk patients was consistent in all patient subgroups. In contrast, treatment with abciximab bolus plus placebo infusion produced only a 10% reduction in the primary endpoint at 30 days (placebo 12.8%, abciximab 11.5%; p = 0.43).62 Evaluation of the subset of 489 patients with UA enrolled in the EPIC trial revealed an even greater therapeutic benefit of treatment with abciximab bolus plus infusion compared with placebo. At 30 days, the composite endpoint event rates of death, MI or urgent revascularization was reduced by 62% for patients receiving the abciximab bolus plus 12-hour infusion (12.8% placebo versus 4.8% abciximab; p = 0.012), which was attributed primarily to a reduction in the incidences of death (3.2% placebo versus 1.2% abciximab; p = 0.164) and MI (9.0% placebo versus 1.8% abciximab; p = 0.004). At 6 months, the event rates for death and MI were further reduced in patients with UA who were treated with abciximab bolus plus 12-hour infusion (6.6% placebo versus 1.8% abciximab; p = 0.018 and 11.1% placebo versus 2.4% abciximab, p = 0.002, respectively).61 CAPTURE. CAPTURE was a randomized, double-blind, placebo-controlled, multicenter trial that recruited 1,265 patients from 69 centers in 12 countries. The objective of this trial was to evaluate the effects of abciximab on the acute ischemic complications associated with PTCA when administered to patients with documented refractory unstable angina 18–24 hours before and 1 hour after the procedure. CAPTURE enrolled only those patients with refractory UA after management with acetylsalicylic acid, aspirin (ASA), nitrates, and heparin, and only those who had angiographic evidence of eligibility for PTCA. After catheterization and determination of eligibility for PTCA, patients were randomized to receive either abciximab as a weight-adjusted 0.25 mg/kg bolus, followed by continuous infusion of 10 µg/min, or placebo.57 The primary endpoint was the composite incidence of death (any cause), MI or urgent intervention (PTCA, CABG, stent placement or intra-aortic balloon pump) at 30 days. Secondary endpoints included major components of the primary endpoint and non-urgent interventions. CAPTURE was conducted entirely in European centers and may not be representative of United States practice patterns for the management of UA because patients were considered to be refractory only after 48 hours of treatment with antianginal and antithrombotic agents. CAPTURE also employed a dosing regimen in which treatment was started within 2 hours of randomization and continued during the 18–24 hours before angioplasty and for only 1 hour after completion of the procedure.57 The primary composite endpoint at 30 days was reduced from 15.9% in the 635 placebo recipients to 11.3% in the 630 patients in the abciximab arm (p = 0.012). This effect was primarily accounted for by a reduction in the rate of MI from 2.1% to 0.6% prior to PTCA (p = 0.029) and from 5.5% to 2.6% during PTCA (p = 0.009). Infarction rates were low in both groups from day 2 to day 30. A slight, not statistically significant reduction in death was observed, from 1.3% for the placebo group to 1.0% for the treated group (p = NS). A non-statistically significant reduction in urgent interventions from 10.9% to 7.8% (p = 0.054) was also seen. Of the secondary efficacy endpoints, only the incidence of MI at 30 days was significantly lower among patients administered abciximab than among those administered placebo (8.2% to 4.1%, respectively; p = 0.002). At 6 months, death or MI occurred in 10.9% of the placebo patients and 9.0% of patients treated with abciximab, but these differences were not statistically significant.57 Continued on next page
1. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995;332:1553–1559. 2. Phillips DR, Scarborough RM. Clinical pharmacology of eptifibatide. Am J Cardiol 1997;80(Suppl 4A):11B–20B. 3. Topol EJ. Targeted approaches to thrombus inhibition — An end to the shotgun approach. Clin Cardiol 1997;20(Suppl I):I-22–I-26. 4. Coller BS. Platelets and thrombolytic therapy. N Engl J Med 1990;322:33–42. 5. Phillips DR, Charo IF, Parise LV, et al. The platelet membrane glycoprotein IIb-IIIa complex. Blood 1988;71:831–843. 6. Heeschen C, Goldmann BU, Terres W, et al. Cardiovascular risk and therapeutic benefit of coronary interventions for patients with unstable angina according to the troponin T status. Eur Heart J 2000;21:1159–1166. 7. Hamm CW. Risk stratifying acute coronary syndromes: Gradient of risk and benefit. Am Heart J 1999;138:S6–S11. 8. Kereiakes DJ. ACC/AHA PTCA guidelines. Presented at the American College of Cardiology 49th Annual Scientific Session; Anaheim, California. March 15, 2000. Available at http://www.medscape.com/medscape/cno/2000/acc/story.cfm?story_id=1112. Accessed March 6, 2001. 9. Hamm CW, Goldmann BU, Heeschen C, et al. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med 1997;337:1648–1653. 10. Kereiakes DJ, McDonald M, Broderick T, et al. Platelet glycoprotein IIb/IIIa receptor blockers: An appropriate-use model for expediting care in acute coronary syndromes. Am Heart J 2000;139:S53–S60. 11. Newby LK, Christenson RH, Ohman M, et al. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes. Circulation 1998;98:1853–1589. 12. Ohman EM, Armstrong PW, White HD, et al. Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction. Am J Cardiol 1999;84:1281–1286. 13. Antman EM, Sacks DB, Rifai N, et al. Time to positivity of a rapid bedside assay for cardiac-specific troponin T predict prognosis in acute coronary syndromes: A thrombolysis in myocardial infarction (TIMI) 11A substudy. J Am Coll Cardiol 1998;31:326–330. 14. Lindahl B, Diderholm E, Lagerqvist B, et al. Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: A FRISC II substudy. J Am Coll Cardiol 2001;38:979–986. 15. De Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014–1021. 16. Lefkovits J, Topol EJ. The clinical role of platelet glycoprotein IIb/IIIa receptor inhibitors in ischemic heart disease. Cleveland Clin J Med 1996;63:181–189. 17. Hirsh J. Heparin. N Engl J Med 1991;324:1565–1574. 18. Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med 1995;333:764–769. 19. Gurfinkel EP, Manos EJ, Mejail RL, et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol 1995;26:313–318. 20. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: A randomised trial. Lancet 1999;353:429–438. 21. Frangos SG, Chen AH, Sumpio B. Vascular drugs in the new millennium. J Am Coll Surg 2000;191:76–92. 22. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36:970–1062. 23. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease, II: Unstable angina, heart failure, primary prevention with aspirin, and risk factor modification. JAMA 1988;260:2259–2263. 24. Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: An observational study. Lancet 2001;357:1063–1068. 25. Busman WD, Passek D, Sciden W, et al. Reduction of CK and CK-MB indexes of infarct size by intravenous nitroglycerin. Circulation 1981;63:615–622. 26. Jugdutt BI, Warnica JW. Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion, and complications: Effect of timing, dosage and infarct location. Circulation 1988;78:906–919. 27. Yusef S, Collins R, MacMahon S, Peto R. Effect of intravenous nitrates on mortality in acute myocardial infarction: An overview of the randomised trials. Lancet 1988:1088–1092. 28. Armstrong PW. Stable ischemic syndromes. In: Topol EJ (ed). Textbook of Cardiovascular Medicine. Philadelphia, Pennsylvania: Lippincott-Raven, 1998: pp. 333–364. 29. Lubsen J, Tijssen JG. Efficacy of nifedipine and metoprolol in the early treatment of unstable angina in the coronary care unit: Findings from the Holland Interuniversity Nifedipine/Metoprolol Trial (HINT). Am J Cardiol 1987;60:18A–25A. 30. Pepine CJ, Faich G, Makuch R. Verapamil use in patients with cardiovascular disease: An overview of randomized trials. Clin Cardiol 1998;21:633–641. 31. The Danish Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Eur Heart J 1984;5:516–528. 32. Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest 1978;61:314–319. 33. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets, I: Acetylation of a particulate fraction protein. J Clin Invest 1975;56:624–632. 34. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol 1971;231:232–235. 35. Buchanan MR, Dejana E, Cazenave JP, et al. Differences in inhibition of PGI2 production by aspirin in rabbit artery and vein segments. Thromb Res 1980;20:447–460. 36. Jaffe EA, Weksler BB. Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin. J Clin Invest 1979;63:532–535. 37. Schror K. The basic pharmacology of ticlopidine and clopidogrel. Platelets 1993;4:252–261. 38. Balsano F, Rizzon P, Violi F, et al. Antiplatelet treatment with ticlopidine in unstable angina: A controlled multicenter clinical trial. The Studio della Ticlopidina nell’Angina Instabile Group. Circulation 1990;82:17–26. 39. CAPRIE Steering Committee. A randomised, blinded trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet 1996;348:1329–1349. 40. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. 41. Telford AM, Wilson C. Trial of heparin versus atenolol in prevention of myocardial infarction in intermediate coronary syndrome. Lancet 1981;1:1225–1228. 42. Williams DO, Kirby MG, McPherson K, et al. Anticoagulant treatment of unstable angina. Br J Clin Pract 1986;40:114–116.