Medical Management of Angina Pectoris - Circulationcirc.ahajournals.org/content/circulationaha/46/6/1132.full.pdf · Thesuccessful medical managementof a patient with angina pectoris

Medical Management of Angina Pectoris

By R. BRUCE LOGUE, M.D., AND PAUL H. ROBINSON, M.D.

SUMMARYThe successful medical management of a patient with angina pectoris requires careful

attention to many factors including omission of smoking, control of hypertension, andweight reduction for the obese person. Newer knowledge of the importance of theproduct of the systolic blood pressure and the pulse rate in determining the thresholdof angina affords a more meaningful approach to therapy. Each individual must beeducated regarding the factors that aggravate and precipitate his distress so that thesecan be minimized, or prophylactic nitrite therapy can be appropriately applied. Emo-tional stress is of equal importance to effort in the production of angina. The main-stay of treatment is nitroglycerin and sublingual nitrites combined with beta-blockingdrugs. Each drug or combination must be properly readjusted for the individual toassure optimum benefit. Digitalis, diuretics, antiarrhythmic drugs, antihypertensiveagents, and radioiodine may be useful in selected cases.

IN THE MEDICAL management of anginapectoris due to coronary atherosclerosis,

proper identification of the type of ischemicdiscomfort is often helpful. Several types can

be categorized: (1) initial, (2) stable,(3) progressive, and (4) preinfarction. Theinitial onset of angina suggests an acutedynamic change in the coronary arterialcirculation. Rarely in such instances one may

be surprised to find electrocardiographicevidence of myocardial infarction, even

though the duration of distress may have beenonly 5-10 min. When infarction is not sus-

pected, reduction of the myocardial work loadand oxygen consumption by a judicious shortperiod of modified rest may be helpful. On theother hand, a recent progression of previouslystable angina so that it occurs at rest,nocturnally, or with slight exertion may

indicate impending infarction. In such in-stances, the drug therapy, period of rest, andprognostic implications may be quite differentfrom those of initial or stable angina. A historyof this progressive pattern of distress over a

period of days or weeks can be elicited fromone half to two thirds of patients hospitalizedwith acute myocardial infarction.

Although no statistical data are available, itis the authors' experience that many patientstraversing a period of progressive or "prein-

farction" angina rnay revert to their previousstable pattern after an appropriate interludeof rest and tailored modification of theirtherapeutic regimen. During these crescendoperiods, the risk of death from ventricularfibrillation or standstill is increased.

Risk Factors

Risk factors are not only of epidemiologicimportance but also play a limited role in themanagement of the individual patient. Theinfluence of smoking is paramount. Nicotinemobilizes catecholamines and increases myo-

cardial oxygen consumption. It also acts on

the carotid and aortic bodies, causing in-

creased heart rate and blood pressure.1 Thepressure-rate product, an important determi-nant of oxygen consumption, may reach a

level sufficient to produce angina.2 Improve-ment may ensue after smoking is stopped.The control of hypertension by lowering

peripheral resistance and external cardiacwork may produce amelioration of angina. Inpractice, the beneficial effect may not bedramatic. In the authors' experience theomission of smoking is more often accompa-

nied by improvement of angina than thecontrol of hypertension.

Circ12 tion, Volume XLVI, December 1972

From Emory University School of Medicine andEmory University Clinic, Atlanta, Georgia 30322.

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MEDICAL MANAGEMENT OF AP

Weight reduction may reduce the frequencyof angina in some patients, but increasedphysical fitness and a heightened sense ofwell-being seem to be more significant by-products.Lowering the levels of cholesterol and

triglycerides are laudable long-term goals, butlittle influence on angina has been demon-strated. Leren has claimed reduction of theincidence of fatal and nonfatal myocardialinfarction in patients on diets low in saturatedfats and cholesterol.3 The study of the BritishMedical Research Council did not confirmsuch benefits.4Lack of exercise has been cited as a possible

predisposing factor in coronary disease. Exer-cise programs may be accompanied by im-proved physical fitness so that more exercisecan be done without angina. Such improve-ment may result from the reduction of heartrate and/or blood pressure during exercise,known to occur with training. There is nofactual data that the natural history ofcoronary disease is altered, or that thecollateral circulation is enhanced.

Difficulties of Assessment of Drug TherapyAngina is a subjective complaint recognized

by history. Response to treatment is likewisesubjective so that evaluation of any therapy isnotoriously difficult. The many variables andsubtle factors that influence angina oftenprevent accurate assessment of ongoingstudies of response to treatment. The placeboeffect of any therapy for coronary diseasemust always be taken into consideration. Theapproach, interest, and technics of the physi-cian influence the response to any giventherapy.To assess the effectiveness of drugs, they

should be administered so that their maximaleffect is timed to occur when an individual'sangina develops. Thus the patient whodevelops angina on first awakening or onassuming the recumbent position or postpran-dially may not be protected by medicationgiven on an arbitrary schedule such as fourCirculation, Volume XLVI, December 1972

times daily. Such routine dosage has led tocriticism of double-blind studies of one oranother drug. One might conclude that a drugis ineffective because the design of the studywas improper or conversely that an inert drugwas effective.5 A single drug studied mayseem to be ineffective and yet when combinedwith another drug significant improvementmay be noted. Negative results may beobtained with a given dose of a drug, yetbenefit may be obtained with a larger dose.For example, the response to administration ofbeta-blockers is dose related. To quote Russek"it can be seen, therefore, that while uncon-trolled clinical observation has often falselyendowed inert agents with powers which theydo not possess, improperly designed doubleblind studies have frequently divested potentagents of action clearly and consistentlyevident to patient and physician alike."

Objective data such as the electrocardio-graphic response to treadmill exercise and toatrial pacing provide some help in weighingthe effects of short-term drug administration.One should be mindful that pain may occurwithout changes in the electrocardiogram, andthe threshold for pain in a given patient maybe altered by a variety of factors includingemotional state and amount of rest. Long-termstudies professing beneficial therapeuticeffects are suspect because of the greatvariability in the natural history of coronarydisease. Improvements in any parameter maybe independent of treatment.Redwood et al.6 emphasized the pitfalls if

only one level of exercise is used in theevaluation of efficacy of a drug. For example,when the work load is intense and excessive,angina may occur before a drug could beevaluated and, conversely, when the workload is gradually increased resulting in apressure-rate product less than that needed toproduce angina, one might erroneously inferthat a given drug was effective. Loss of anischemic area by infarction may be followedby improvement of angina. At times this maybe the reason for the disappearance of

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ischemic distress in patients following coro-nary artery surgery. It is not always easy forthe clinician to be certain that infarction hasoccurred, since electrocardiographic evidencemay be lacking or there may be T-wavealterations compatible with the inevitablepericarditis incident to incision of the pericar-dium. Electrically silent areas may be presentin the septal, apical, subendocardial, highposterior, or intramural regions. The acquisi-tion of extracardiac causes such as the chest-wall syndrome, hyperventilation syndrome,reflux esophagitis, and postinfarction pericar-ditis may complicate evaluation.

Management of Aggravatingand Precipitating Factors

The education of the patient by thephysician is the most important facet ofmanagement. Time spent in understanding apatient's emotional undergirding, psychophys-iologic responses, behavioral idiosyncracies,motivations, and life style is often morevaluable than that expended in exercisetesting, diet instruction, drug juggling, andstereotyped instruction. Without accurate as-sessment of the nature of the patient'sischemic distress no determination of theefficacy of therapy can be accomplished.Clarification of patterns in some patients mayrequire exercise testing until angina ensues.

The dominant influence on the frequencyand severity of angina is emotional stress. It isfar more important than exercise in producingangina in many patients. A rise in pulse andblood pressure is probably responsible.Examples of sources of tension are: driving inheavy traffic, business reversals, family con-flict, hurrying to make a deadline, jobinsecurity, a lawyer addressing a jury, thesurgeon during an operation, or worry regard-ing well-being of loved ones. The naturalhistory of angina is characterized by episodicvariation in frequency and intensity of symp-toms coincident with periods of increasedemotional stress. Anniversary reactions tosome emotionally charged event such as loss

of a loved one or prior heart attack are notuncommon. Stress incident to holidays orpreparations for graduation or weddings mayinduce ischemic symptoms.

Pain in other organ systems may influencemyocardial oxygen consumption and causeangina. Examples may be cited such asgallbladder distress, abscessed tooth, arthritisof spine, peptic ulcer, pancreatitis, diverticuli-tis, renal colic or infection, ischemic peripheralvascular disease, and diabetic neuropathy.There is not agreement among all observersthat these factors are of importance,7 but longclinical experience attests to their significance.Many patients develop symptoms after void-ing and returning to bed. This is probablyrelated to blood volume shift from theperipheral vascular bed to the heart onassuming the recumbent position. The in-crease in ventricular volume and wall tensionmay offer an explanation for recumbentangina. Parker and associates demonstratedthe subsidence of angina produced by atrialpacing when 300 cc of blood were removed.8Pain returned when blood was reinfused witha constant heart rate. Relief of angina mayoccur with peripheral pooling incident torising to a sitting or standing position.Likewise, it is theoretically possible that thecontraction of blood volume due to chronicdiuretic therapy may explain occasional im-provement of angina in the normotensivepatient. This reduced volume may also limitthe abrupt rise in blood pressure that precipi-tates or results from angina. The product ofthe systolic pressure and pulse rate is onedeterminant of increased oxygen consumption.Prostatic obstruction with straining can aggra-vate symptoms. Pulmonary infection andembolism may precipitate or aggravate an-gina. Occult arrhythmia not appreciated bythe patient is probably not an uncommoncause of pain. While we emphasize theinfluence of chilling and cold on the produc-tion of pain we should not overlook the effectsof heat and humidity.9 Sudden changes inblood volume such as excessive administration

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of fluid or contraction of intravascular spacedue to blood loss may increase angina.Correction or control of linked disorders maybring overall improvement. The patient withstable angina may develop a preinfarctionpattern in the presence of significant anemiaand revert to a stable condition when redblood cell volume is restored to normal.Angina due to coronary atherosclerosis mayimprove dramatically when significant associ-ated valve disease such as aortic stenosis orinsufficiency is corrected surgically.The patient should be taught to identify

and avoid precipitating factors as far aspossible. A list of common factors follows:

1. Emotional tension (anger, excitement).2. Walking up an incline.3. Sudden effort.4. Heavy lifting.5. Hurrying (planes, trains, busses, etc).6. Exercise after meals.7. Intercourse.8. High altitude.9. Hypoglycemia.

10. Isometric exercise such as lifting, raisinga window, sweeping, work involving use ofhands overhead.

11. Epinephrine or other sympathomimeticamines.

12. Dental work.13. Chilling by cold wind.14. Iced drinks or ice cream.15. Hot weather and high humidity.16. Excitement incident to television or

sports.17. Funerals, reunions.18. Foreign travel.19. Mowing a lawn.20. Shovelling snow.Precipitating or aggravating factors may

cause catastrophic change in the naturalhistory of coronary disease by inducingpreinfarction angina or acute myocardialinfarction. Patients should be instructed tonotify their physician when there is an abruptchange in the character and duration of pain.For example, when stable angina of 5-minCirculation, Volume XLVI, December 1972

duration is replaced by distress lasting %-1hour, prompt hospitalization and surveillancein a coronary care unit may be indicated.Unless this advice is followed, it may turn outthat the physician is the greatest barrier tosolving the problem of sudden death due tocoronary disease.

Nitroglycerin

Nitroglycerin is the mainstay in the treat-ment of angina, yet it is shocking to findworthless long-acting preparations prescribedwhen the patient has never received nitrogly-cerin. Nitroglycerin acts to reduce myocardialischemia in a local area of the myocardium,even though the total coronary blood flowmay remain unaltered. This improved distri-bution of blood flow and oxygenation may bedue to an effect on collateral channels. It iswell accepted that nitroglycerin dilates majorcoronary arteries but it is probable thatdilation of small collaterals in a local area is ofgreater importance in producing relief.10-13This can be demonstrated by recordingoxygen potentials using platinum electrodesplaced in both the endocardium and epicar-dium. The administration of nitroglycerinim,proves the ratio of endocardial to epicardialflow suggesting improved blood flow to theendocardium.'4 By contrast, dipyridamoleincreases total coronary blood flow which isconfined largely to the epicardium. It isineffective in the treatment of angina. Manystudies indicate that benefit accrues from theother effects of nitroglycerin that reduceoxygen consumption:'15-18 ( 1 ) reduction inarterial blood pressure with decrease in theafterload of the heart, (2) reduction invenous tone with reduced preload, (3) reduc-tion in ventricular volume, (4) reduction inleft ventricular end-diastolic pressure, (5) re-duction in wall tension, (6) decrease in therate of rise of left ventricular pressure,(7) decrease in ejection time, and (8) rever-sal of ischemic bulges. Detry and Bruce havedemonstrated that maximal total-body oxygenconsumption could be reached without angina

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in some patients pretreated with nitroglycer-in.19 Nitroglycerin may delay and reduce thedegree of ischemic S-T depression producedby exercise.

Nitroglycerin should be used initially insmall dose such as 0.15 mg to avoid headache.The "nitrite effect" must be explained to thepatient so that he may better accept the drug.The dose is adjusted to avoid headache but, ifheadache accompanies full therapeutic effect,analgesics may be added. Unfortunately,headache from an excessive dose may preventa patient from taking nitroglycerin subse-quently. The supply of nitroglycerin should bereplenished periodically to assure potency. Ifthe tablets do not produce burning of thetongue or the characteristic sensation offullness in the head they must be replaced. Aswith the chronic use of many drugs, tachyphy-laxis may occur, and the dosage may need tobe increased. An effective dose must bedetermined individually and reevaluated afterprolonged use. Care should be taken to avoidsignificant postural hypotension, particularlyin the elderly where this is more common. Theblood pressure should be taken in therecumbent and upright position after initialuse of the drug. Nitrite syncope may occurafter multiple doses taken at short intervals,particularly if the patient is standing. Thisphenomenon may be confused with acutemyocardial infarction. Nitroglycerin should beused prophylactically before known precipitat-ing events. It should be taken promptly whendiscomfort occurs and repeated twice at 5-minintervals if there is no relief. Nitroglycerin istaken not for pain alone, but for whateversymptoms characterize the patient's myocar-dial ischemia. Thus, it may be administeredfor heaviness, pressure, burning, indigestion,tightness, constriction, breathlessness, aching,or expanding sensation, whether it be in theepigastrium, chest, jaw, throat, shoulder, back,or arms. Paradoxic worsening of angina due toan inordinate drop in mean aortic pressureand coronary filling may rarely occur. Excep-tionally, this phenomenon may be observed in

patients with severe aortic stenosis or hyper-trophic subaortic stenosis.

Long-Acting Nitrites

Long-acting nitrites remain controversial,and studies of their benefits give conflictingresults.5 20 15 The duration of action claimedby pharmaceutical houses has been disputed.Many of the timed-release preparation ap-pear to act selectively on the cerebral ratherthan the coronary circulation, producingheadache without significant improvement ofangina. Countless patients are taking expen-sive and ineffective drugs. It may be trying forthe physician to decide when therapy isindicated, what dosage is required, and whichdrug is effective. Should drugs be prescribedfor the patient with only occasional angina?Does such therapy offer any beneficial effectwhere recurrent arrhythmia or myocardialfailure is present? Is it possible to forestallprolonged pain and thereby reduce theprobability of finite muscle necrosis? Theanswers are not available.On one hand, the clinician may satisfy

himself that a drug is effective, yet its actionin terms of reduction of the triple product ofpulse rate, systolic blood pressure, and ejec-tion time may be negligible. Thus Goldstein etal. claimed that isosorbide sublingually maybe shown to be no more effective thannitroglycerin.24 They found that 21 of 24patients exercised longer without developingangina 10 min after receiving 5 mg isosorbidedinitrate sublingually. Benefit was present at 1hour in the minority, and no persistent effectwas apparent at 2 hours. Aronow andChesluk23 claimed isosorbide was no moreeffective than placebo but Bunn and Chre-mos21 concluded that its action was moreprolonged than that of nitroglycerin and therewas less S-T depression with exercise at theend of 3% and 1 hour. Russek noted that 5 mgsublingual isosorbide was effective up to 2hours. Oral preparations of isosorbide in adose of 10 mg four times daily have notproduced worthwhile benefits,26 but studies

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using larger doses more frequently have notbeen reported. Despite this evidence, isosor-bide 10-20 mg four times daily, is widely used.Russek reported that pentaerythritol tetrani-trate, 20-40 mg, produced less benefit withdelayed onset of 1-1Us hours, but some effectwas present up to 4 hours. The sustained-action preparations were ineffective. Erythri-tyl tetranitrate in a 10-mg chewable form mayproduce an effect within 5 min that is claimedto last several hours. There are no precisestudies of the effect of this drug.

Sublingual isosorbide, 2.5-5.0 mg, is usefulprior to meals or intercourse or anesthesia,and an effect may be obtained for 1 hour. Thedosage must be carefully titrated and gradu-ated to avoid headache and to insure optimumeffect. In selected patients, it may be helpfulwhen given orally as often as every 1-2 hours.The major side effects of nitrites are headacheand symptoms due to postural hypotension.The use of long-acting nitrites does not impairthe tolerance or effectiveness of nitroglycer-in.23 Synergistic effect has been noted whenisosorbide dinitrite has been used in conjunc-tion with beta-blocking agents.2' 2528 Thedecrease in pulse rate, prolongation of systole,and increase in ventricular volume are coun-teracted partially by nitrite effects of increasein pulse rate, decrease in systolic timeintervals, and decrease in ventricular volumeand end-diastolic pressure.

Nitroglycerin ointment is helpful, especiallyin preventing nocturnal angina. The 2%ointment is applied over an area 2-5 cm indiameter on the forearm at bedtime. Occa-sionally, reapplication may be needed after4-6 hours.

Beta-BlockersBeta-blockers exemplified by propranolol

act to decrease myocardial oxygen consump-tion. At the same time there is a negativeinotropic effect with decrease in the force ofmyocardial contraction. The effects of propran-olol may be summarized as follows:29, 30

(1) decrease in myocardial contractility;(2) decrease in pulse rate; (3) mild decreaseCirculation, Volume XLVI, December 1972

in blood pressure; (4) decrease in rate of riseof pressure in the left ventricle; (5) increasein ventricular volume; (6) increase in leftventricular end-diastolic pressure; (7) reduc-tion in stroke output; (8) lengthening of sys-tolic ejection; and (9) quinidinelike effect.The preponderant effect of propranolol is

the reduction of oxygen consumption throughhemodynamic changes. An additional factormay be an effect on oxygen delivery to themyocardium. Propranolol may increase coro-nary vascular resistance, largely through de-creased myocardial oxygen demand, but alsoby vasoconstriction of coronary resistancevessels. In some instances the A-V oxygendifference is increased.30 Studies in dogsindicate that, while coronary blood flow tonormal myocardium is reduced, blood flow toregional areas of ischemia may remain un-changed.2' There are divergent effects ondeterminants of myocardial oxygen consump-tion. Rarely, propranolol decreases exercisecapacity and increases oxygen consumptionvia a disproportionate increase in left ventricu-lar volume and ejection time.0 Thus, the drugis contraindicated in the patient with conges-tive heart failure and should be used withgreat caution in the presence of ventriculardysfunction. Rarely, left ventricular failuremay be precipitated in the absence of clinicalevidence of dysfunction (fig. 1). In themajority of patients, however, there is evi-dence of improved exercise tolerance andreduction of electrocardiographic changes ofischemia.32-38 Not all studies have reportedbeneficial effects in angina. This may be dueto difference in patient selection, dosage,protocol, and associated medication.39 Scrivas-tava et al. could show no statistical evidenceof benefit in a double-blind study using 30-60mg propranolol daily.39 Using a larger dosageof 30 mg three times daily Kellan found 13 of19 patients had fewer attacks and 14 requiredless nitroglycerin as compared to placebo.38Long-term studies of 65 patients on 160-400mg propranolol daily resulted in 37-50% reduc-tion of anginal attacks and nitroglycerin

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Figure 1

(Left) C. H., age 51 years. Interstitial pulmonary edema in patient with preinfaretion anginathat developed while receiving digitalis and 120 mg propranolol daily over a period of 1week. (Right) Clearing 4 days later afterdiuretics.

requirements. Eight of 65 patients diedsuddenly, 9% developed left ventricular failure,and two developed asthma. There was anaverage decrease of 18% in the resting pulserate.411The dose required to produce an effect has

varied widely, but evidence suggests there is adose relationi. Prichard and Gillam in adouble-blind study of 16 patients notedmaximum benlefit with an average dose of 417mg (range 80-1280).4l Progressive decrease inbenefit was noted as the dose was reduced toone half, one fourth, and one eighth. The one-eighth dose was still superior to placebo. Somestudies indicate no improvement with lessthani 160 mg daily.40 whereas 40 mg daily maybe beneficial when combined with nitritessuch as isosorbide dinitrate. Mizagala et al.reported that propranolol produiced suistainedimprovement in 13 of 15 patients with acutecoronary insufficiency refractory to all medicaltreatmenit.42 Papazogloui noted benefit in six ofseveni cases of preinfaretion angina that wererefractory after 2 weeks' treatment withdrugs.43 The dose ranged from 80 to 160 mg.

omission of propralonol and administration of

Our experience with preinfaretion angina hasbeeni less impressive, however.When instituting propranolol therapy, one

should begin with small amounts of the drugsuch as 10 mg three to four times daily andgradually increase the dose to tolerance oruntil clinical benefit ensues. The side effectsthat may be encountered are: (1) feeling offatigue; (2) headache; (3) diarrhea;(4) nausea; (5) bradycardia; (6) posturalhypotension; and (7) bronchospasm.Many prefer to digitalize patients on

propranolol to counteract the decrease in forceof myocardial contraction. The combination ofdigitalis and propranolol may limit the dosebecause of bradycardia. A rule of thumb is tochoose the dose that will decrease the restingpulse rate 20 beats or to a rate no less than 55beats/min. Ordinarily, there is only a slightdecrease in blood pressure but posturalhypotension is not uncommon, particularlywhen propranolol is administered in conjunc-tion with other drugs such as nitrites, diure-tics, Rauwolfia derivatives, or tranquilizers.Extra care is needed in the elderly patient


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with basilar-vertebral arteriosclerosis in whompostural hypotension may occur in the ab-sence of drug therapy. Propranolol should beomitted 96 hours prior to anesthesia andsurgery, in order to lessen the possibility ofrefractory cardiac arrest.Newer beta-blocking agents that lack myo-

cardial depressant effects are being studied.These agents slow the pulse rate and decreasethe blood pressure but lack the anestheticproperties of propranolol. Practolol, sotalol,and oxyprenolol have been reported to givecomparable beneficial effects in the treatmentof angina.40 48 Sowton et al. repo.rted that thetotal work performance before the develop-ment of angina increased 40% on a daily doseof 400 mg practolol.49 The heart rate at whichangina occurred was approximately 15% lower.These drugs, unlike propranolol, do notincrease airway resistance or produce bron-chospasm.

Alprenolol produces a dose-dependent de-crease in pulse rate and systolic blood pressurewhen patients with angina are exercised.Sealey et al. noted a 24-31% delay in onset ofangina and a 25% increase of total work withdecrease in degree of S-T depression afteralprenolol.47

Perhexiline maleate is a new antianginaldrug that in animal experiments producescoronary, systemic, and pulmonary vasodila-tion. It reduces left ventricular work anddecreases myocardial oxygen consumption.Slowing of the cardiac rate and reduction ofthe pressure-rate index occurs.50 It has aquinidinelike action and prolongs depolariza-tion and repolarization. Its effect is not alteredby vagotomy, atropine, or sotalol.51 Limitedhuman experience has given favorable re-sponse.52

Diuretics

Diuretic therapy is theoretically beneficialin: (1) ventricular dysfunction or failure,(2) hypertension, (3) limiting peak rise ofsystolic pressure in the normotensive, and(4) producing mild contraction of bloodvolume. Diuretic therapy may be used inconjunction with digitalis when borderline or


overt congestive heart failure is suspected ofinitiating or exacerbating angina pectoris.Maintenance therapy must be tailored to eachpatient. Potassium chloride supplementation isusually necessary but serum levels should bechecked and special care taken with patientswho have renal insufficiency. The addition ofspironolactone or triamterene to reduce potas-sium loss may be helpful. Potassium chlorideand spironolactone should not be adminis-tered in conjunction since severe, perhapslethal, hyperkalemia could result.

DigitalisVentricular dysfunction is common during

angina, and the pulmonary wedge pressuremay or may not be elevated during anattack.53 Digitalis has been used with conflict-ing results. The majority of studies indicate nobenefit in angina, even though there may beimprovement of the ventricular performance.Most of the studies have been carried out overa period of 1-2 hours, using limited amounts ofglycosides intravenously. There are no data onthe effects on angina by optimal digitalizationover weeks or months. Clinical impressions ofbenefit cannot be substantiated, particularlysince nitrites and beta-blockers may be used inconjunction with digitalis. Some authors haveexpressed the fear that digitalis would aggra-vate angina,56 but in practice this must be arare occurrence.

Digitalis increases the force of myocardialcontractions with subsequent rise in oxygenconsumption. In many patients with angina,the left ventricular volume and end-diastolicpressure may be reduced along with adecrease in the rate of rise of left ventricularpressure. The net effects of this improvedmyocardial performance may be reduction ofoxygen consumption and lessening of angina.On the other hand, there may be an increasedrate of rise of left ventricular pressure thatoffsets the decreased left ventricular volumeand end-diastolic pressure causing angina at alower level of exercise. We have observedimprovement in occasional patients withcomplaint of easy fatigability in the absenceof clinical evidence of ventricular dysfunction

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following digitalization. It would seem rea-sonable to try digitalis when there is evidenceof ventricular dysfunction manifested by thefollowing: (1) S4; (2) S3 gallop; (3) pulsusalternans; (4) reverse split of second soundnot due to complete left bundle-branch block;(5) ischemic bulge; (6) well-marked mitralregurgitation due to papillary muscle dusfunc-tion; and (7) venous hypertension or intersti-tial edema in the chest X-ray.

Nocturnal angina has been a conventionalindication for digitalization. A trial of the drugis warranted for angina decubitus or progres-sive angina. Frequently ventricular prematurebeats may impair coronary perfusion. Thesemay subside following digitalis administration,even in the absence of clinical evidence ofventricular dysfunction or failure. Digitaliza-tion may be helpful when there is a history ofparoxysmal atrial tachycardia, atrial fibrilla-tion, or atrial flutter.

Antiarrhythmic DrugsUncommonly there are patients whose

angina results from one or more of a variety ofarrhythmias. Most such patients are unawareof their cardiac irregularity, regardless of itsorigin. Documentation of this cause-and-effectrelationship is difficult. Therapy is usuallydictated by clinical inference and/or byelectrocardiographic clues. All types of ar-rhythmias are more common in the setting of:(1) acute injury of myocardial cells, whichmay be occult without change in the electro-cardiogram or enzymes; (2) severe ventricu-lar dysfunction from prior infarction; (3) sig-nificant mitral regurgitation due to papillarymuscle dysfunction; (4) ventricular aneu-rysm; (5) sinus bradyeardia or second- andthird-degree A-V block due to disease of thesinus and A-V nodes or to drugs such asdigitalis and propranolol; and (6) potassiumdepletion due to diuretic drugs such as thoseused in the treatment of hypertension.

In 'some instances, angina probably resultsfrom inadequate coronary perfusion secondaryto reduced stroke volume coincident withfrequent premature beats or tachyarrhythmia.In others, bradyarrhythmias are responsible.

Resting and exercise electrocardiograms ormonitoring over a period of hours with aportable monitor recorder may help in identi-fying the rhythm disturbance.When angina is associated with frequent

ventricular premature beats or ventriculartachycardia, propranolol, quinidine, procain-amide, or rarely diphenylhydantoin, individ-ually or in combination, may be successful inreducing or eliminating the episodes ofrhythm-induced angina.Where paroxysmal atrial tachycardia has

been documented or is strongly suspectedclinically by the patient's evaluation of therhythm's classically abrupt inception andcessation, quinidine, digoxin, or propranololalone or in combination is usually adequate.These drugs are equally useful in paroxysmalnodal tachycardia or paroxysmal atrial fibrilla-tion. When paroxysmal supraventricular ar-rhythmia and angina are associated with theWolff-Parkinson-White syndrome, propranololhas been found to be effective. Whenbradyarrhythmias are responsible for angina,propranolol and digitalis are contraindicatedbecause of their bradyeardiac effects. Paren-teral atropine or methylscopolamine bromidemay be helpful in the short-term managementof bradyarrhythmia but temporary or perma-nent pacing may be required.

Sedatives, Tranquilizers,and Antidepressants

In those patients whose angina is adverselyaffected by emotional stress, tension, depres-sion, worry, hyperreactivity, and agitation, thejudicial use of sedatives, tranquilizers, orantidepressants may be indicated. However,close patient-physician relationship with pro-perly tailored education of the patient regard-ing the nature of his disease cannot bereplaced by hastily written prescriptions formedications that temporarily alleviate con-cern, allay anxiety, or lift his mood. Concertedeffort must be made by the physician toidentify the role of emotional factors in thepatient's anginal pattern. Eliciting a history ofprecipitating events and contributory mentalstresses can be obtained from the patient but


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quite often are more accurately assessed byconsulting the spouse or reliable familymembers and friends.

It is not unusual to find an individual whocan mow his lawn, trim hedges, or hoe hisgarden without angina, yet develops classicalpain when talking about business problems,his adolescent's hostility, or while watchingwrestling on television. Some will developsymptoms when they merely think aboutsexual intercourse. In such individuals cate-chol release results in an increased bloodpressure and pulse sufficient to exceed theanginal threshold. In 23 healthy medicalstudents studied by Hickam et al.57 theanxiety before an examination produced epi-nephrinelike increased oxygen consumption.

In those individuals whose emotional re-sponses must be curbed to control their angina,mild tranquilizers such as diazepam, 2 or 5 mgthree or four times a day, or phenobarbital,15-30 mg three or four times a day, may suf-fice. Often a short-acting barbiturate such assodium amytal, 30-60 mg every 4 hours, isadequate.

Nocturnal angina may not be the earlymanifestation of congestive heart failure butthe product of an exciting or disturbingdream. Not infrequently patients relate dreamcontent that has produced angina. Studies ofthese individuals during sleep have shownthat rapid eye movements occur first followedby some elevation in the blood pressure andincrease in the pulse rate with subsequent S-Tdepression in the ECG, as the patients awakenwith angina. Barbiturates in this setting,especially in older individuals, have not beenfound to reduce significantly the incidence ofdreaming. Diazepam, 5 or 10 mg, may bebetter tolerated by the older individual andmay be tried in this situation.

Depression with or without agitation mayproduce angina. A trial of antidepressant drugsis warranted. Due caution should be takenwhen nortriptyline hydrochloride (Aventyl),thioridazine (Mellaril), and amitriptylinehydrochloride (Elavil) are used since theyraise the heart rate and blood pressure withworsening of angina. In addition, thioridazineCirculation, Volume XLVI, December 1972

has been known to produce a variety ofarrhythmias.

ExerciseIn patients with angina a properly

designed -exercise program not only reducesthe frequency and severity of attacks ofischemic discomfort,58-61 but also increasestheir work capacity and sense of well-being.Redwood6 has demonstrated that the exerciseprotocol for evaluation of any particularprogram of training must be carefully con-trolled. The training carried out in a properlyequipped laboratory has been shown to be ofsignificant benefit. Such exercise is usuallyaccomplished on a bicycle ergometer withgraded increase in work loads. A characteristicprotocol involves two training periods a dayfor 5 days a week. If the bicycle ergometer isused, the work load is begun at 20 w andincreased by 20 w every 3 min until anginaoccurs.58 Obviously this type of program is notpractical for the mass of patients encountereddaily in the physician's office, but often asatisfactory substitute can be found in agraduated walking program. The usual patientsubmitted to such an exercise schedule hasmild-to-moderate stable angina. He may bereceiving both propranolol and isosorbidedinitrate, as well as nitroglycerin, but ordinari-ly is not digitalized. Although some authorsadvise prophylactic isosorbide dinitrate ornitroglycerin, these are not usually necessary.If possible, walking should be done on levelground when the temperature is between 55and 75°F. Extremes of temperature will oftenprecipitate angina,5 thwarting the walker andoccasionally permanently discouraging him.Beginning at a slow pace for 3-5 min duringeach exercise period, the patient should beinstructed to increase both his speed anddistance until he can walk a mile in 15-20 minafter 4-6 weeks of training. There may becomplaints that: (1) there are no sidewalks;(2) the ground is too uneven; or (3) it's toohilly. However, there are few who can't driveto a nearby shopping center, many of whichhave large air-conditioned malls permittingdaily strolls under all weather conditions. If

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the patient finds walking inconvenient, anexercycle or treadmill may be purchased orrented for home use. It is foolhardy toprescribe an exercise program for the patientwho develops angina with slight exertion.Many patients are made miserable by suchunwarranted and misdirected advice. Further-more, it is probably unwise to recommendthat the patient "walk through" angina sincethe risk of ventricular fibrillation is surelyenhanced. The presence of ventricular prema-ture beats following exercise is not uncommonin normal people as well as those withcoronary heart disease. On the other hand,when they occur close to the T wave or insalvos and when short runs of ventriculartachycardia occur exercise should be prohibit-ed.The mechanism by which exercise improves

angina is unknown. Studies have demonstrat-ed that benefit is not correlated withincreased coronary collaterals62 nor with sig-nificant change in cholesterol or blood pres-sure63 or cardiac output.60 However, physicalworking capacity is improved and seems to berelated to increased stroke volume and de-creased tension-time index for a given load.60Training apparently enhances circulatory effi-ciency.60' 64 For a given work load, total-bodyoxygen consumption has been shown to bereduced by 57%.58 There is a decrease in theproduct of the blood pressure and pulse rate.In some patients, there may be, in addition, anincrease in oxygen delivery.

Because of the significant role of theemotional and psychological state of thepatient with angina, his reassurance in realiz-ing that he not only can exercise but also isable to reduce the frequency and severity ofhis ischemic episodes is of immeasurablebenefit.

AnticoagulantsAnticoagulation offers no benefit in the

management of stable angina. Some feel thatit may be useful in the treatment of preinfarc-tion angina, with the hope of forestallinginfarction. It should be recalled that onlyapproximately 50% of patients dying with

transmural infarction have demonstrablethrombi in the coronary arteries and thesemay develop subsequent to onset of infarc-tion.65 A trial of anticoagulant therapy iswarranted when there is clinical suspicion ofpulmonary embolism with or without docu-mentation.

Radioactive IodineMyxedema induced by radioactive iodine

decreases oxygen consumption and may sharp-ly reduce the frequency of angina.66' 67 Thistherapy is applicable to those with disablingangina not controlled by medical measuresand who are not suitable candidates forsaphenous vein bypass grafts. It should beconfined to those willing to accept the sideeffects of hypothyroidism. These includeweight gain, puffiness of face and abdomen,dry skin, sensitivity to cold, constipation,muscle aching, and some slowing of thephysical and mental processes. The lattersymptoms need not be marked if thyroidreplacement therapy is titrated carefully.Unfortunately, the low level of metabolismrequired for benefit often limits replacementtherapy. An increase of as little as 4 gr ofthyroid extract or 5-10 ,g of L-triiodothyroninemay bring a return of angina to its previousfrequency and severity. Many patients areable to carry on satisfactorily in their occupa-tion after thyroid ablation. However, hypothy-roidism is more acceptable to the older, re-tired person. It generally requires 2-3 monthsbefore benefit is obtained. One cannot useconventional studies such as 131I uptake todetermine dosage since there is a lag betweenthe development of symptoms and depressionof function tests. Skill and judgment arerequired to find the optimal level of control ofangina without side effects. Thyroiditis maydevelop within several weeks of 131I adminis-tration. At this time the release of increasedamounts of thyroxin may aggravate angina.Prompt recognition of the syndrome with theinstitution of prednisone, 40-60 mg daily, andpropranolol, 10-20 mg four times a day, for 1-2weeks will minimize symptoms. Thyroiditis ismore common when large doses are required


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because of low 131J uptake. The uptakebythegland can be increased by administration of40-60 mg methimazole (Tapazole) daily for 1week before uptake studies are repeated andthe therapeutic dose calculated. An average

dose of 7 mCi delivered to the gland willgenerally produce a satisfactory degree ofhypothyroidism. Supplemental dosage after3-4 months may be required on rare occasions.

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R. BRUCE LOGUE and PAUL H. ROBINSONMedical Management of Angina Pectoris

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1972 American Heart Association, Inc. All rights reserved.

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