Angina Pectoris: A Review of Current and Emerging Therapies

October 1, 2004
John O. Parker, MD

Supplements and Featured Publications, Chronic Angina: Clinical Management and Cost of Care, Volume 10, Issue 11 Suppl

Angina pectoris is a debilitating indication of thepresence of ischemic heart disease that affects millionsof Americans. Although a number of pharmacologictreatments are available, the annual numberof revascularization surgeries continues to rise in theUnited States. Other management strategies, such asspinal cord stimulation, enhanced external counterpulsation,metabolic modulators, and gene therapy,are being explored.

(Am J Manag Care. 2004;10:S332-S338)

Ischemic heart disease is the leadingcause of death in the United States1 andangina pectoris is a common symptom ofthis disease.2,3 "Angina" is used to describeclinical symptoms such as discomfort in thechest, jaw, shoulder, back, or arms that areinduced by physical exertion or emotionalstress and subside with rest or treatmentwith nitroglycerin.4 Some patients do not experiencediscomfort but complain of breathlessnessor tire with activity. These symptomsare the result of underlying myocardialischemia and are sometimes called anginalequivalents.

The American Heart Association (AHA)estimates that 6.8 million Americans sufferfrom angina and that 400 000 new patientspresent with stable angina each year.1Significantly more women have the conditionthan men, both in total numbers and asan age-adjusted percentage.1 Angina limitsnormal daily activities; thus, it has a negativeimpact on quality of life (QOL). It has beenshown that 1 year after coronary revascularization,roughly one third of patients withangina are not able to return to work.5 Notsurprisingly, the societal impact and economiccosts of angina are staggering. In the AmericanCollege of Cardiology (ACC)/AHA 2002Guideline Update for the Management of Patientswith Chronic Stable Angina, Gibbonsand colleagues state, "angina affects manymillions of Americans with associated annualcosts that are measured in tens of billionsof dollars."4

Angina treatment involves a number ofstrategies.4 In general, the first step in anginamanagement includes assessing patientrisk factors, such as smoking, hypertension,dyslipidemia, diabetes mellitus, obesity, andphysical inactivity. While alterations in theserisk factors may improve symptoms andreduce cardiac events, the majority of patientswith chronic stable angina requirespecific antianginal medications. It is recommendedthat beta-adrenergic blocking drugsbe used as first-line therapy for patients withangina because these agents have been shownto have cardioprotective effects.4 Other standardtherapies for chronic angina includecalcium channel blocking agents and organicnitrates,4 but such medical therapy oftendoes not provide adequate symptomatic relief.A number of novel therapies are directedat angina treatment, including new pharmacologicagents, gene therapy, enhanced externalcounterpulsation (EECP), spinal cordstimulation, and innovations in revascularizationtherapy. This article reviews theclassification of angina pectoris and brieflydescribes standard and novel treatmentstrategies for this debilitating health problem.

Understanding Angina. Whereas there hasbeen considerable research regarding angina,the exact mechanism of pain perception inpatients with myocardial ischemia is stillpoorly understood. However, cardiac ischemicdiscomfort may be perceived in the heart,chest wall, arms, and back because of theclose proximity of the spinal nerve receptorsto these areas.6 Chest pain caused bymyocardial ischemia is classified as stable orunstable angina.4 Patients with unstable anginahave a much higher risk of acute cardiacevents than patients with stable angina pectoris.Such risk can be further stratified aslow, moderate, or high, depending on the frequencyand severity of pain and on the presenceof certain electrocardiographicabnormalities. Unstable angina is commonlydescribed based on the way it presents. Thisincludes new onset angina or angina that hasincreased in frequency and severity despitemedical therapy, or angina that occurs at rest(Table 1). Angina is frequently defined usingCanadian Cardiovascular Society (CCS)functional class (Table 2),7 a system that hasbeen used for more than 3 decades. In 2002,a new CCS definition for grade IV angina wassuggested that includes a set of detailed activities,"angina occurs while walking less than1 block…or while walking in the house, ordoing light chores or personal care" ratherthan the previous description: "Inability tocarry on any physical activity without discomfort—anginal symptoms may be presentat rest."8 While other grading systems havebeen defined, the CCS functional classificationhas been the most widely used by cliniciansand investigators.

Treatment of Angina Pectoris. Decreasingthe frequency and severity of anginaimproves QOL for patients with angina. Althoughsmoking cessation, weight control,stress management, moderate exercise, andappropriate management of hypertension,dyslipidemia, and diabetes mellitus mayreduce symptoms and ischemic events,pharmacotherapy with antianginal agents isusually required. Beta-adrenergic blockingagents, calcium channel blocking agents,and short- and long-acting nitrates are thefoundation of medical therapy for patientswith chronic angina.4 Although each has adifferent mechanism of action, these agentshave multiple effects that tend to decreasecardiac workload and, therefore, lower myocardialenergy requirements and/or increasecoronary blood flow or improve its distribution.These effects help lessen the mismatchbetween myocardial oxygen requirementsand oxygen supply. Unfortunately, manypatients require more than 1 drug to controlsymptoms,9 and patients with comorbid conditionsoften require a host of other medicationsas well. Indeed, a variety of agents,including antiplatelet/antithrombotic agents,angiotensin-converting enzyme inhibitors,and lipid-lowering drugs, are important therapeuticadjuncts in the treatment of patientswith chronic angina.4 Ultimately, the potentialfor adverse drug interactions and sideeffects associated with polypharmacy maylimit the ability of a patient with chronic anginato tolerate appropriate medical therapy.

Beta-adrenergic blocking agents are recommendedas first-line therapy in theACC/AHA guidelines.4 These drugs, however,have absolute or relative contraindicationsin patients with asthma, chronic obstructivepulmonary disease, severe peripheral vasculardisease, and in some patients with diabetesmellitus. In such cases, calcium channelblocking agents are often prescribed and certaincalcium channel blockers, such as thedihydropyridines, may be associated withflushing and peripheral edema.4 Diltiazemhas been associated with heart failure inpatients with abnormal left ventricular systolicfunction.10 Sublingual nitroglycerin, eitheras a tablet or spray, is effective in the treatmentof acute episodes of angina and is alsobeneficial for short-term prophylaxis. However,the oral and transdermal organic nitratepreparations, although effective, are associatedwith the development of tolerance whenprescribed in a fashion designed to providetherapeutic effects for 24 hours each day.11 Amore detailed review of the efficacy of drugtherapy for management of chronic angina isavailable in the ACC/AHA guidelines.4 Overall,using traditional therapies to manage painin patients with chronic angina is commonlyassociated with inadequate symptom control,poor tolerance, and limited compliance. Thetreatment shortcomings for patients who sufferfrom chronic angina have resulted in thedevelopment of innovative therapies that arenow being studied.

New Pharmacologic Agents. Metabolicmodulators represent a potential new classof drugs with a novel approach to the treatmentof angina symptoms in the UnitedStates.12,13 In the presence of myocardialischemia, glucose oxidation is a more efficientway of generating energy units adenosinetriphosphate than free fatty acidoxidation.14 Unlike most current classes ofangina therapy, metabolic modulators maybe effective without depending on reductionsin heart rate or blood pressure.13,15

Trimetazidine, a metabolic modulatoravailable outside of the United States, hasdemonstrated anti-ischemic effects in a numberof studies of patients with angina. Thedrug has been shown to increase effort toleranceand to delay the appearance of ischemicsymptoms and electrocardiographic (ECG)changes.12,14,16,17 In addition, patient safetyand tolerance with trimetazidine has beengood.18,19 The efficacy of trimetazidine hasalso been demonstrated in patients with diabetes,who showed improved exercise capacityand duration after 4 weeks of treatment.20Left ventricular dysfunction has improvedduring therapy with trimetazidine.21,22

Gene Therapy. Therapeutic angiogenesisregimens have focused mainly on the administrationof a single growth factor with selectisoforms of the vascular endothelial growthfactor (VEGF) and fibroblast growth factor(FGF). At present, VEGF and FGF have beenthe most extensively studied angiogenicagents.23 Growth factor proteins may begiven directly or through gene-based approachesusing naked plasmid deoxyribonucleicacid or a viral vector that encodes thegene so that it can be taken up by the recipientendothelial cells. These endothelial cellsoffer the potential for persistent expressionof the angiogenic gene.23,24 These agents maybe administered directly to the myocardiumby epicardial, endocardial, or intracoronaryinjection. Some trials have shown beneficialeffects in patients with angina,24 but adequatelypowered, randomized, placebo-controlledclinical studies must be completed toclarify the effectiveness of such therapy.

Enhanced External Counterpulsation.EECP is another novel treatment for patientswith ischemic heart disease who havechronic angina and are unresponsive toother therapies. EECP is carried out byencircling the legs with compression devices,inflating them during diastole to 300 mm Hg,and deflating them during systole.25 Thisunloads the left ventricle during ventricularsystole, and this augmentation of pressure isthought to improve coronary blood flow duringdiastole. In the only published randomizedclinical trial of EECP,25 which involved139 patients with class II to III angina, thecontrol group was treated by compressingthe lower extremities at 75 mm Hg, and theexperimental group was treated by compressingthe lower extremities at 300 mm Hg.While clinical symptoms and treadmill exercisetimes improved and a variable effect onmyocardial perfusion imaging studies wasreported, the absence of proper blindingduring this study makes the results uncertain.The mechanisms thought to beresponsible for the improvement of symptomsinclude enhancement of endothelialfunction, promotion of collateral flow, improvementin ventricular function, andperipheral effects similar to those seen withphysical exercise.26 For EECP to be effective,patients require daily in-clinic treatments overseveral weeks, which is a schedule that mightbe difficult for many patients to maintain.

Spinal Cord Stimulation. Spinal cordstimulation, another proposed method forpain relief in patients with angina, involvesplacing a stimulating electrode in the dorsalepidural space at the C7-T1 level. Althoughthe mechanism of action is complex and notfully elucidated, it has been proposed thatspinal cord stimulation exerts beneficialeffects by decreasing pain and sympathetictone, yielding reductions in myocardial oxygenconsumption and improved myocardialmicrocirculatory blood flow.27 Early resultswith implanted spinal cord stimulators indicateimprovements in exercise duration,time to angina, and perceived QOL.28 Inanother trial, anginal symptoms decreasedeven after discontinuation of therapy, perhapsindicating a long-term, primary analgesiceffect of this treatment.29

Revascularization Strategies. Revascularizationstrategies have expanded to includenew techniques for coronary artery bypassgrafting (CABG) and percutaneous coronaryintervention (PCI). Another approach istransmyocardial revascularization (TMR).

CABG

. The standard CABG procedurerevolutionized treatment of coronary arterydisease (CAD) in the 1960s and incorporatesmidline sternotomy with cardiopulmonarybypass. While traditional CABG proceduresare still in use, off-pump CABG has beenshown to reduce operative morbidity, operativemortality, and length of hospital staycompared with on-pump CABG.30 Morerecently, minimally invasive bypass techniquesthat use a small, anterior thoracotomyhave been developed as well. Althoughthe saphenous vein was the vessel of choicefor graft repair during the first 2 decades ofCABG surgery, long-term survival was shownto be consistently higher when the internalmammary artery was used.31 Since the late1980s, arterial grafts from the internal mammary,gastroepiploic, inferior epigastric, andradial arteries have all been used for arterialrevascularization. Whether the CABG benefitsof increased QOL and decreased anginafrequency persist long term remains unclearbecause data from some studies suggest thatthese benefits subside over time.32,33

PCI

. Advances in PCI technology havehad a significant impact on the way coronaryand vascular diseases are treated. Theintroduction of percutaneous transluminalcoronary angioplasty by Gruentzig34 in thelate 1970s revolutionized the treatment ofCAD, even though outcomes were limited byrestenosis, dissection, and acute vessel closure.Later, coronary stents were shown to besuperior to balloon angioplasty,35,36 and eachyear they are being used more often thanangioplasty alone. At present, there is a widerange of stents, with the latest designs offeringdrug-eluting coatings with antiproliferativeagents, such as sirolimus and paclitaxel.In addition, stents that incorporate syntheticcoverings have been introduced to treat avariety of lesions, including saphenous veingrafts. A recent study, however, indicated nobenefit of the covered stent over a conventionalstent with respect to acute results,restenosis, or clinical event rates.37 Forpatients with angina seeking symptom relief,the long-term benefits associated with PCIand CABG remain to be determined.32,38,39

TMR

. TMR involves the use of laser energyto create a series of transmural endomyocardialchannels. There are 2 types ofprocedures in use. The first, TMR, is performedsurgically using an epicardial approach,and, the second, percutaneousmyocardial revascularization, employs anendocardial approach. Both procedures havebeen associated with a reduction in anginasymptoms, improved exercise tolerance, andenhanced QOL, although sham-controlledtrials do indicate evidence of a placebo effectwith these therapies.40 The basis for improvementsreported with TMR remainsunclear. The initial hypothesis was that thechannels provided additional blood flow tothe myocardium, but this no longer appearsto be the case. It has also been suggestedthat clinical improvement may be secondaryto angiogenesis or to myocardial denervation.41

Discussion

Although there are many therapies availableto treat angina and many more beingstudied, finding an effective solution thatrelieves symptoms and improves QOL maybe difficult in some cases. Although a medicalmanagement approach is preferable,many patients remain symptomatic whentaking traditional antianginal agents, evenwhen multiple agents are taken. Failure ofmedical management in patients withrefractory angina has led to the introductionof more invasive treatments such as CABGand PCI, although some reports seem toindicate that these invasive procedures areoften considered before medical therapy hasbeen given an adequate trial.42

Surgical and percutaneous interventionsare costly, and many patients have comorbidconditions that put them at high risk for suchprocedures. Data from the latest HealthcareCost and Utilization Project indicate that themean charge for a CABG procedure is$60 853 and $28 558 for PCI.1 Despite concernsabout long-term results, the number ofpercutaneous interventions in the UnitedStates has increased dramatically in the past20 years. In 2001, an estimated 571 000 PCIprocedures were performed, representing a266% increase over the number of proceduresperformed in 1987.1

Although CABG and PCI may improveangina in some patients, studies have shownthat within 1 year of a CABG procedure,approximately 10% to 26%5,43-45 of patientshave recurrent pain and many requireantianginal medications.5,44,45 Similar resultshave been seen with PCI—29% to 34%5,44,45 ofpatients had their angina recur within 1 year,and the majority of patients were still takingantianginal medications.44,45 Fewer than 30%of patients in a 5-year multicenter studywere working 5 years after coronary revascularizationand, at that time, more than20% of patients rated their health as poor orfair.5 The results of the Clinical OutcomesUtilizing Revascularization and AggressiveDrug Evaluation (COURAGE) trial, in whichaggressive medical therapy is being comparedwith aggressive medical therapy plusPCI, are expected to help delineate the usefulnessof revascularization in patients withangina.46

Conclusion

Angina is a serious, debilitating healthproblem that signals the presence of CADand may foreshadow myocardial infarctionor stroke. While there have been considerableadvances in medical management, surgicaland percutaneous revascularizationstrategies, many patients remain symptomaticat substantial personal and societalcost. Given the inadequacy of current medicalmanagement and the expense and disappointinglong-term efficacy associatedwith surgical and percutaneous revascularization,further study of new treatments iswarranted.

Heart Disease andStroke Statistics—2004 Update

1. American Heart Association. . Dallas, Tex: AmericanHeart Association; 2003.

Mayo Clin Proc.

2. Elveback LR, Connolly DC, Melton LJ 3rd. Coronaryheart disease in residents of Rochester, Minnesota VII.Incidence, 1950-1982. 1986;61:896-900.

Am J Cardiol

3. Kannel WB, Feinleib M. Natural history of anginapectoris in the Framingham study. Prognosis and survival.. 1972;29:154-163.

4. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA2002 guideline update for the management of patientswith chronic stable angina: a report of the AmericanCollege of Cardiology/American Heart Association TaskForce on Practice Guidelines 2002. Available at:www.acc.org/clinical/guidelines/stable/stable.pdf.Accessed April 7, 2004.

JAMA.

5. Five-year clinical and functional outcome comparingbypass surgery and angioplasty in patients with multivesselcoronary disease. A multicenter randomized trial.Writing Group for the Bypass AngioplastyRevascularization Investigation (BARI) Investigators. 1997;277:715-721.

Heart Disease.A Textbook of Cardiovascular Medicine.

6. Braunwald E, Zipes DP, Libby P, eds. 6th ed.Philadelphia, Pa: WB Saunders Co. 2001.

Circulation.

7. Campeau L. Letter: grading of angina pectoris. 1976;54:522-523.

Can JCardiol.

8. Campeau L. The Canadian Cardiovascular Societygrading of angina pectoris revisited 30 years later. 2002;18:371-379.

Am J Cardiol.

9. Pepine CJ, Abrams J, Marks RG, Morris JJ, Scheidt SS,Handberg E. Characteristics of a contemporary populationwith angina pectoris. TIDES Investigators. 1994;74:226-231.

Circulation.

10. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S.Diltiazem increases late-onset congestive heart failure inpostinfarction patients with early reduction in ejectionfraction. The Adverse Experience Committee; and theMulticenter Diltiazem Postinfarction Research Group. 1991;83:52-60.

N Engl J Med.

11. Parker JD, Parker JO. Nitrate therapy for stableangina pectoris. 1998;338:520-531.

Br J Clin Pharmacol.

12. Detry JM, Sellier P, Pennaforte S, Cokkinos D,Dargie H, Mathes P. Trimetazidine: a new concept inthe treatment of angina. Comparison with propranolol inpatients with stable angina. Trimetazidine EuropeanMulticenter Study Group. 1994;37:279-288.

JAMA.

13. Chaitman BR, Pepine CJ, Parker JO, et al. Effects ofranolazine with atenolol, amlodipine, or diltiazem onexercise tolerance and angina frequency in patients withsevere chronic angina: a randomized, controlled trial. 2004;291:309-316.

Fundam Clin Pharmacol.

14. Stanley WC, Marzilli M. Metabolic therapy in thetreatment of ischaemic heart disease: the pharmacology oftrimetazidine. 2003;17:133-145.

J Am Coll Cardiol.

15. Chaitman BR, Skettino SL, Parker JO, et al.Anti-ischemic effects and long-term survival duringranolazine monotherapy in severe chronic angina. 2004;43:1375-1382.

Eur J Clin Pharmacol.

16. Sellier P, Audouin P, Payen B, Corona P, Duong TC,Ourbak P. Acute effects of trimetazidine evaluated byexercise testing. 1987;33:205-207.

Eur Heart J.

17. Detry JM. Clinical features of an antianginal drug inangina pectoris. 1993;14:18-24.

Cardiovasc Drugs Ther.

18. Monpere C, Brochier M, Demange J, Ducloux G,Warin JF. Combination of trimetazidine with nifedipinein effort angina. 1990;4:824-825.

Curr Ther Res.

19. Michaelides AP, Vyssoulis GP, Bonoris PE, et al.Beneficial effects of trimetazidine on men with stableangina under beta-blocker treatment. 1989;46:565-576.

Cardiovasc Drugs Ther.

20. Szwed H, Pachocki R, Domnzal-Bochenska M. Theantiischaemic effects and tolerability of trimetazidine incoronary diabetic patients. A substudy from TRIMPOL-1. 1999;13:217-222.

Eur Heart J.

21. Brottier A, Barat JL, Combe C, Boussens B, Bonnet J,Bricaud H. Therapeutic value of a cardioprotectiveagent in patients with severe ischaemic cardiomyopathy. 1990;11:207-212.

Eur Heart J.

22. Belardinelli R, Purcaro A. Effects of trimetazidine onthe contractile response of chronically dysfunctionalmyocardium to low-dose dobutamine in ischaemic cardiomyopathy. 2001;22:2164-2170.

Ann Thorac Surg.

23. Sellke FW, Ruel M. Vascular growth factors andangiogenesis in cardiac surgery. 2003;75:S685-S690.

Am JCardiol.

24. Grines C, Rubanyi GM, Kleiman NS, Marrott P,Watkins MW. Angiogenic gene therapy with adenovirus5 fibroblast growth factor-4 (Ad5FGF-4): a new optionfor the treatment of coronary artery disease. 2003;92(9B):24N-31N.

J Am Coll Cardiol.

25. Arora RR, Chou TM, Jain D, et al. The multicenterstudy of enhanced external counterpulsation (MUSTEECP):effect of EECP on exercise-induced myocardialischemia and anginal episodes. 1999;33:1833-1840.

J Am Coll Cardiol.

26. Bonetti PO, Holmes DR Jr, Lerman A, Barsness GW.Enhanced external counterpulsation for ischemic heartdisease: what's behind the curtain? 2003;41:1918-1925.

Clin Cardiol.

27. Latif OA, Nedeljkovic SS, Stevenson LW. Spinalcord stimulation for chronic intractable angina pectoris:a unified theory on its mechanism. 2001;24:533-541.

Am Heart J.

28. Hautvast RW, DeJongste MJ, Staal MJ, van Gilst WH,Lie KI. Spinal cord stimulation in chronic intractableangina pectoris: a randomized, controlled efficacy study. 1998;136:1114-1120.

Cardiology.

29. Norrsell H, Pilhall M, Eliasson T, Mannheimer C.Effects of spinal cord stimulation and coronary arterybypass grafting on myocardial ischemia and heart ratevariability: further results from the ESBY study. 2000;94:12-18.

Ann Thorac Surg.

30. Reston JT, Tregear SJ, Turkelson CM. Meta-analysisof short-term and mid-term outcomes following off-pumpcoronary artery bypass grafting. 2003;76:1510-1515.

N Engl J Med.

31. Loop FD, Lytle BW, Cosgrove DM, et al. Influenceof the internal mammary artery graft on 10-year survivaland other cardiac events. 1986;314:1-6.

N Engl J Med.

32. Serruys PW, Unger F, Sousa JE, et al. Comparisonof coronary-artery bypass surgery and stenting for thetreatment of multivessel disease. 2001;344:1117-1124.

Eur Heart J.

33. van Domburg RT, Foley DP, Breeman A,van Herwerden LA, Serruys PW. Coronary arterybypass graft surgery and percutaneous transluminalcoronary angioplasty. Twenty-year clinical outcome. 2002;23:543-549.

Circulation.

34. Gruentzig AR, Myler RK, Hanna EH, et al. Coronarytransluminal angioplasty. 1977;55-56(suppl III):III-84.

N Engl JMed.

35. Fischman DL, Leon MB, Baim DS, et al. A randomizedcomparison of coronary-stent placement and balloonangioplasty in the treatment of coronary arterydisease. Stent Restenosis Study Investigators. 1994;331:496-501.

N Engl J Med.

36. Serruys P, de Jaegere P, Kiemeneji F, et al. A comparisonof balloon expandable-stent implantation withballoon angioplasty in patients with coronary arterydisease. Benestent Study Group. 1994;331:489-495.

J Am Coll Cardiol.

37. Schachinger V, Hamm CW, Munzel T, et al. A randomizedtrial of polytetrafluoroethylene-membrane-coveredstents compared with conventional stents inaortocoronary saphenous vein grafts. 2003;42:1360-1369.

Am Heart J.

38. Holubkov R, Laskey WK, Haviland A, et al. Angina1 year after percutaneous coronary intervention: a reportfrom the NHLBI Dynamic Registry. 2002;144:826-833.

J Am Coll Cardiol.

39. Henderson RA, Pocock SJ, Clayton TC, et al. Seven-yearoutcome in the RITA-2 trial: coronary angioplastyversus medical therapy. 2003;42:1161-1170.

J Am Coll Cardiol.

40. Saririan M, Eisenberg MJ. Myocardial laser revascularizationfor the treatment of end-stage coronary arterydisease. 2003;41:173-183.

Ann Thorac Surg.

41. Huikeshoven M, Beek JF, van der Sloot J, Tukkie R,van der Meulen J, van Gemert MJ. 35 years of experimentalresearch in transmyocardial revascularization:what have we learned? 2002;74:956-970.

Clin Cardiol.

42. Samuels BA, Diamond GA, Mahrer PR, Denton TA.Intensity of antianginal therapy in patients referred forcoronary angiography: a comparison of fee-for-serviceand health maintenance organization therapeutic strategies. 2000;23:165-170.

J Am Coll Cardiol.

43. Cameron AA, Davis KB, Rogers WJ. Recurrence ofangina after coronary artery bypass surgery: predictorsand prognosis (CASS Registry). Coronary Artery SurgeryStudy. 1995;26:895-899.

N EnglJ Med.

44. Hamm CW, Reimers J, Ischinger T, Rupprecht HJ,Berger J, Bleifeld W. A randomized study of coronaryangioplasty compared with bypass surgery in patientswith symptomatic multivessel coronary disease. GermanAngioplasty Bypass Surgery Investigation (GABI). 1994;331:1037-1043.

Lancet.

45. The SoS Investigators. Coronary artery bypass surgeryversus percutaneous coronary intervention withstent implantation in patients with multivessel coronaryartery disease (the Stent or Surgery trial): a randomisedcontrolled trial. 2002;360:965-970.

46. Department of Veterans Affairs CooperativeStudies Program #424. Clinical Outcomes UtilizingRevascularization and Aggressive Drug Evaluation(COURAGE). Available at: http://www.couragetrial.gov.Accessed February 2, 2004.