a report by

Udho T h a d a n i

Professor of Medicine, Division of Cardiology, Oklahoma University Health Sciences Center (OUHSC)

Management o f S tab le Ang ina – Drugs , S tent s andDev i ces for Coronar y Bypass Surger y

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Udho Thadani was appointedEmeritus Professor of Medicine inthe Division of Cardiology,Oklahoma University Health SciencesCenter (OUHSC) in 2001, prior towhich he was Professor of Medicinefrom 1983 to 2001. He has alsobeen Consultant Cardiologist at theOklahoma University Medical Centerand Oklahoma City Department ofVeterans’ Affairs Medical Center(VAMC) since 1980. ProfessorThadani was Associate Professor ofMedicine, OUHSC, from 1980 to1983; Assistant Professor ofMedicine, Queen’s University,Ontario, from 1978 to 1980;Registrar and Research Fellow atQueen’s University, Ontario, andLeeds University, England, from1969 to 1978; House Physician andIntern at Kingston General Hospital,Hull, England, and All IndiaInstitute of Medical Sciences (AIIMS)New Delhi, India, from 1965 to1969. He is the recipient of severalawards, most recently the James FHammersten Award for PatientCare, Research and Education,VAMC, in 2003 and Provost’s SeniorFaculty Research Award, OUHSC, in1995. He was a member of theCardio Renal Advisory Committee ofthe US Food and DrugAdministration (FDA) from 1995 to1999 and is a Fellow of the RoyalSociety of Medicine, London; RoyalCollege of Physicians and Surgeonsof Canada; American College ofCardiology (ACC); and the AmericanHeart Association (AHA). ProfessorThadani is a Member of theCanadian Cardiovascular Society(CCS), American Society ofHypertension (ASH) and HeartFailure Society of America (HFSA).

Stable angina pectoris is a common disorder; itsprevalence increases with age. Patients with stableangina pectoris experience a pressure or a chokingsensation in the chest and adjacent areas or shortnessof breath (angina equivalent) associated with physicalor emotional stress. Most patients with stable anginapectoris have severe obstructive atheroscleroticlesions of complex morphology in one or morecoronary arteries and multiple non-obstructivelesions. Obstructive lesions limit the increase of bloodflow that is required during periods of increasedmyocardial oxygen demand, such as exercise.

The endothelium overlying the lesions is dysfunctionaland is responsible for paradoxical constriction of thestenotic site during exercise, resulting in furtherreduction of blood flow distal to the lesion. Theresultant imbalance between myocardial oxygen supplyand demand produces reversible myocardial ischaemiaand its clinical consequences, such as anginal painand/or shortness of breath. Non-obstructive lesions arelipid-rich and soft in consistency and the endotheliumoverlying these lesions is prone to fissuring anddisruption. The exact mechanism of plaque-endothelial surface disruption remains elusive. Severalmechanisms, including an active inflammatory process,have been implicated. The fissured endotheliumexposes the atheromatous material inside the vessel wallto the circulating blood. This results in plateletaggregation and deposition, which may be followed byadditional intraluminal thrombosis. The clinicalpresentation may remain silent or manifest as acutecoronary syndrome (myocardial infarction (MI),unstable angina) or sudden ischaemic death.

The annual death rate of patients with stable anginais 1.6% to 3.2%. The most important determinant ofprognosis is underlying left-ventricular systolicfunction at rest, co-morbid conditions and theseverity and extent of coronary artery disease.

T r e a tmen t G o a l s

Treatment goals are:

• abolition or reduction of the frequency of anginaattacks;

• prolongation of angina-free walking duration;

• abolition or reduction of other consequences ofreversible myocardial ischaemia, such as dyspneadue to transient elevation of left-ventricularsystolic and diastolic pressure; and

• prevention or reduction of serious adverseoutcomes (MI, unstable angina and ischaemicsudden death) due to plaque-endothelial surfacedisruption.

The treatment must be applicable to a large segmentof the population of stable angina. Pharmacologicaltherapy should be devoid of intolerable adverseeffects and drug interactions. Newer therapy shouldbe either superior to or as effective as already proventherapy and should show additional beneficial effectswhen used in addition to currently proven andeffective treatment of stable angina pectoris.

Currently available anti-anginal drugs (long-actingnitrates, beta-blockers and calcium channel blockers)and revascularisation procedures alleviate or preventanginal symptoms but have not been shown toimprove survival or reduce the incidence of MI inpatients with stable angina pectoris. On the other hand,the strategies that reduce the incidence of adverseoutcomes have little anti-anginal effect. Therefore,treatment of stable angina must include the use of anti-anginal drugs and/or revascularisation procedures plusstrategies that reduce adverse clinical outcomes.

T r e a tmen t A imed a t D e c r e a s i n g t h eF r e q u e n c y a n d S e v e r i t y o f A n g i n a lS ymp t oms a n d Myo c a r d i a l I s c h a em i a

Several strategies are available to achieve the goal ofdecreasing the frequency and severity of anginalsymptoms and myocardial ischaemia. Anti-anginaldrugs (nitrates, beta-blockers and calcium channelblockers) are usually the first option. Revascularisationprocedures, percutaneous balloon dilation of thecoronary artery (PTCA), with or without stentplacement, are being used increasingly, especially in theUS, and coronary bypass surgery is now being offeredonly to selected patients with stable angina pectoris.

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D r u g s

Nitrates are nitric oxide donors and predominantlyreduce myocardial oxygen demand by reducingvenous return. These agents also dilate stenoticcoronary lesions and increase sub-endocardial bloodflow to the ischaemic areas. Sublingual nitroglycerinis very effective and prolongs exercise tolerance inpatients with stable angina pectoris. Long-acting andsustained-release formulations of nitrates, althoughused widely, do not provide 24-hour anti-anginalprophylaxis due to development of tolerance. Basedon the published data, it can be concluded that noneof the nitrate preparations or regimens providecontinuous 24-hour anti-anginal prophylaxis. Manypatients are unable to tolerate intermittent therapywith nitrates due to nitrate-induced headaches.

Beta-blockers reduce myocardial oxygen demand byreducing heart rate, myocardial contractility andexercise-induced increase in systolic blood pressure.Beta-blockers also increase coronary blood flow byincreasing the diastolic filling period. These agentsare the most effective anti-ischaemic agents andreduce exercise and ambulatory ischaemia to agreater extent than other anti-anginal drugs. Bothnon-selective and cardio-selective agents have beenshown to improve exercise performance and reduceexercise-induced ischaemia in patients with stableangina pectoris.

Beta-blockers improve survival and reducehospitalisation in patients with reduced left-ventricular function. However, there are no studiesof beta-blockers on survival in patients with stableangina pectoris and normal left-ventricularfunction. Some patients are unable to tolerate beta-blockers due to excessive decrease in heart rate orfatigue, or due to concomitant diseases such assevere chronic obstructive pulmonary disease,bronchial asthma and severe peripheral vasculardisease with resting limb ischaemia.

Calcium channel blockers act mainly by vasodilatingthe coronary arteries and by reducing peripheralvascular resistance. Non-dihydropyridine agents,verapamil and diltiazem, depress sinoatrial and atrio-ventricular node activity and also reduce myocardialoxygen demand. Long-acting dihydropyridine agentsthat are widely used to treat patients with stable anginaprimarily reduce myocardial oxygen demand by theirpredominant arterial dilating effects.

Recent studies with long-acting dihydropyridineand non-dihydropyridine groups of calciumchannel blockers have shown that these agents arerelatively safe and effective in patients with stableangina and preserved left-ventricular function.Calcium channel blockers should be avoided in

patients with stable angina who have systolic left-ventricular dysfunction.

When used in adequate doses, all three classes of anti-anginal drugs, i.e. long-acting nitrates, beta-blockersand calcium channel blockers, have been shown toincrease angina-free walking duration and totalexercise time and to reduce angina frequency duringdaily activities. The combination of two agents fromdifferent classes (beta-blocker plus a long-actingnitrate or a calcium channel blocker, especially adihydropyridine agent) may be more effective thanmonotherapy. However, triple therapy is notnecessarily superior to treatment with two agents ofdifferent classes.

None of the three classes of anti-anginal drugs hasbeen shown to reduce the frequency of seriousadverse outcomes in patients with stable angina, theexception being patients with stable angina who haveexperienced a recent MI or who have reduced left-ventricular function; beta-blockers improve survivalin these patients.

Nicorandil is a nitro-vasodilator with potassiumchannel-opening properties. Improvement in exercisetolerance has been reported in some studies, but not all.On the other hand, in patients with coronary arterydisease, nicorandil was shown to reduce the incidenceof serious adverse outcomes compared with placebo.

The metabolic agents trimetazidine (available insome countries) and ranolazine (not available as yet)are effective anti-anginal and anti-ischaemic agentsand hold promise as they are devoid of circulatingand haemodynamic effects.

De v i c e s a n d C o r o n a r y B y p a s s S u r g e r y

Revascularisation procedures increase coronary bloodflow and have no effect on myocardial oxygendemand. Several studies have shown that PTCA, withor without stent placement, relieves anginal episodes inthe majority of patients and increases angina-freewalking time. However, the restenosis rate (20% to30%) and recurrence of symptoms has remained amajor problem especially in patients with diabetesmellitus. Drug-coated stents (sirolimus-eluting stents,paclitaxel-eluting stents) have reduced the rates ofrestenosis significantly. However, acute thrombosis ofthe stent still remains an issue. The majority of patientswho undergo balloon dilation of the coronary arterywith or without stent placement are currentlymaintained on anti-anginal drug therapy.

Compared with medical therapy (anti-anginal drugs)percutaneous coronary interventions do not reducemortality or the incidence of MI in patients withstable angina pectoris. In a randomised study, in

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patients with proximal left-anterior coronary arterydisease, PTCA did not reduce the incidence of deathor MI compared with medical therapy.

Coronary artery bypass surgery utilises venous orarterial conduits and increases the blood flow to theareas distal to the significant stenotic lesions. Theprocedure is effective in patients with graftable vesselsand abolishes or reduces angina frequency in 70% to80% of patients. Angina-free exercise duration alsoincreases following surgery. In unblinded, parallel-design, randomised studies, coronary bypass surgeryreduced neither the incidence of death nor thefrequency of MI compared with medical therapy.Subgroup, post hoc analysis showed that patients withsevere narrowing of the left main coronary artery andthose with poor left-ventricular function andmultivessel coronary artery disease (MVD) had bettersurvival rates after surgery compared with medicaltreatment. Recent trials have compared coronarybypass surgery to PTCA with or without stentplacement. Both strategies are equally effective inrelieving angina although the need for a repeatpercutaneous procedure or bypass surgery is greater inpatients who have undergone a percutaneousrevascularisation procedure. Currently, bypass surgeryis indicated in diabetic patients with MVD.

Many of the patients who have undergone bypasssurgery experience recurrence of symptoms overtime due to progressive atherosclerotic occlusion ofthe venous conduits. This usually manifests itself 10to 15 years after surgery and, in many of thesepatients, native coronary arteries are not suitablefor a repeat revascularisation procedure due todisease progression.

Given the evidence that neither percutaneousinterventions nor coronary artery bypass surgeryimproves survival or reduces serious adverseoutcomes compared with medical therapy, it ispreferable to try medical therapy first and considerpercutaneous intervention or bypass surgery ifmedical therapy has failed.

Enhanced external counterpulsation (EECP)improves exercise performance with reduction inmyocardial ischaemia in patients with stable anginapectoris. However, reported trials are rather smalland, at present, EECP is reserved for patients who donot respond to conventional anti-anginal therapy andare not candidates for a revascularisation procedure.

At present, direct laser revascularisation proceduresare only being used in patients who are notcandidates for a revascularisation procedure and arerefractory to medical therapy. Percutaneoustransmyocardial revascularisation is not superior to asham procedure in patients with stable angina.

Spinal cord stimulation and transcutaneous nervestimulation are reserved for those patients who are notcandidates for a revascularisation procedures andremain very symptomatic despite optimal drug therapy.

Anti-anginal drugs, PTCA with or without stents,bypass surgery and other devices do not improvesurvival or reduce the incidence of MI in patientswith stable angina. The following strategies are,therefore, needed to improve outcome.

T r e a tmen t A imed a t R e d u c i n g A d v e r s e O u t c ome s

Smoking cessation reduces the risk of coronary arterydisease mortality by 50% after one year. After five to10 years, the coronary mortality rate in ex-smokersmatches that of non-smokers. Stopping smoking mayincrease exercise performance in patients with stableangina pectoris.

Aspirin reduces the incidence of death and acute MIin patients with stable angina pectoris. Therefore, allpatients with stable angina pectoris should be treatedwith daily aspirin (81mg to 320mg), provided theydo not have a history of allergic reaction to aspirinand do not experience intolerable gastrointestinalside effects.

There is no data to indicate that newer antiplateletagents – clopidogrel and ticlopidine – are superiorto aspirin in patients with stable angina pectoris.Large-scale trials comparing aspirin withclopidogrel in patients with stable angina pectorisare lacking.

Lipid lowering therapy, especially with statins,reduces coronary morbidity and mortality in patientswith established coronary artery disease. In a smallstudy, aggressive lowering of low-density lipoproteincholesterol with atorvastatin plus anti-anginal therapywas superior to percutaneous interventions plus anti-anginal therapy in patients with stable anginapectoris. Gemfibrozil reduced the incidence ofserious adverse outcome in male patients with stableangina and low high-density lipoprotein levels(<35mg per dl) in the Veterans’ Administration LowHigh-density Lipoprotein Cholesterol InterventionTrial (VA-HIT).

Available data supports the aggressive treatment oflipid abnormalities in addition to daily use ofaspirin and smoking cessation in patients withstable angina pectoris. ■

This article is continued, with graphics, tables andreferences, in the Reference Section on the BBL websitesupporting this business briefing (www.bbriefings.com/cdps/cditem.cfm?NID=886).122

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