Unstable angina: pathophysiological concepts and therapeutic options

International Elsevier

1

Journal of Cardiologv, 24 (1989) l-7

IJC 00886

Review

Unstable angina: pathophysiological concepts and therapeutic options Paul Broadhurst Cardiology Department

and Edward

B. Raftery

and Division of Clinical Sciences, Northwick Ptirk Hospital and Clinical Research Centre, Harrow, Middlesex, U.K. (Received 6 January 1989; accepted 30 January 1989)

Key words: Unstable angina; Pathophysiology;

Therapeutics

Introduction Patients with unstable angina are at increased risk of myocardial infarction or sudden death, [l-5] compared to those with chronic stable angina [6]. Recognition of this fact has produced an aggressive management policy, including hospitalisation, intensive medical therapy, early coronary angiography and revascularisation or angioplasty. Both the medical and the surgical policies probably reduce the risks of subsequent events [7] but not everyone feels that such an aggressive policy is justified [8]. The existence of controversy is not surprising when one considers the heterogeneous nature of the condition. A major cardiological textbook [9] includes the following subgroups in its definition: first, those with angina of recent origin (< 60 days); second, those with angina of increasing frequency and intensity (so called crescendo angina); and, third, those with prolonged rest pain, poorly responsive to nitrates but in the absence of myocardial necrosis (acute coronary insufficiency). It is possible that the widely differing treatments dispensed by physicians result from poor under-

Correspondence to: Dr. E.B. Raftery, Dept. of Cardiology, Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ, U.K. 0167-5273/89/$03.50

standing of the pathophysiology of the condition. Recent advances have produced a more rational basis for therapeutic decision-making. It must be recognized that most of this work was derived from patients with angina so severe as to require hospitalization, and, therefore, may not be applicable to the out-patient with newly diagnosed angina, even though technically “unstable”. It is the purpose of this review to highlight these recent advances, and to describe how they influence the therapeutic options available to the clinician.

Pathophysiology Myocardial ischaemia is precipitated by an imbalance between oxygen supply and demand. In patients with chronic stable angina, this occurs at a relatively fixed and, for the patient at least, usually predictable workload. Nevertheless, dayto-day variations in such workloads do occur [lo] and are probably related to subtle changes in either coronary vasomotor tone altering myocardial oxygen supply or left ventricular volume altering myocardial oxygen demand. Ischaemia occurring in unstable angina was previously thought to be due to an increase in oxygen demand in the presence of critical stenoses which limit supply [ll]. Although such a mechanism may, on occasions, be responsible [12], there is overwhelming evidence that a primary reduction in coronary

0 1989 Elsevier Science Publishers B.V. (Biomedical Division)

arterial flow relative to myocardial demand is of greater importance. This suggests that platelet aggregation, thrombus formation and possibly coronary arterial spasm (related to an ulcerated or fissured atheromatous plaque) may be the cause. If the reduction enough,

myocardial

Much reduction angina

in coronary ischaemia

of the work in coronary

is attributable

blood

flow is severe

at rest will result.

demonstrating blood flow to Chierchia

a primary in unstable

and colleagues

[13]. In a series of elegant experiments, they showed that a reduction in oxygen saturation within the coronary sinus preceded the onset of myocardial ischaemia at rest. In the absence of any increase in cardiac work to explain such a phenomenon, they suggested that a reduction in coronary blood flow was responsible. Although their patients were atypical (in that they all had a positive response to ergonovine administration, and, thus, probable coronary arterial spasm as the cause of their ischaemia), an increase in myocardial oxygen demand relative to supply was clearly

thrombus probably undergoes endogenous fibrinolysis and reendothelialization, or else becomes incorporated into the re-modelled plaque. Angiograms obtained after an episode of unstable angina have shown progression cases, stable

of the stenosis

in 75% of

compared with films obtained during the phase of the disease. In contrast, progres-

sion over a similar

time scale is seen in only one

third of patients with stable angina [18,19]. Coronary angioscopy is a recently developed technique which enables investigators to view intra-luminal anatomy through a fine fibre-optic endoscope introduced during by-pass surgery. Although the number of patients studied in this way is small, the results corroborate the plaque rupture/thrombosis theory of unstable angina. Sherman et al. [20] found no “complicated” (ruptured) atheromatous plaques or overlying thrombi in the 17 “offending” arteries in 10 patients with stable angina but observed them in all of the “offending” arteries of 10 patients with unstable angina. Other researchers have adopted a haemotologi-

not the only mechanism precipitating myocardial ischaemia. Other workers have corroborated their

cal or biochemical approach. Fitzgerald et al. [21] demonstrated a close temporal relationship be-

findings

tween platelet

by showing

a lack

of increase

in heart

rate and blood pressure (major determinants of myocardial oxygen demand) immediately preceding ischaemia at rest [14]. Evidence that disruption

of an atheromatous

plaque is the initiating pathological stable angina comes from several

lesion in unsources. Am-

brose and colleagues [15], examined magnified coronary angiographic frames and identified a specific morphologic lesion in 71% of the arteries presumed to be producing the angina in patients with unstable angina. Similar lesions were present in only 16% of the arteries of patients with stable angina. These appearances were eccentric stenoses in the form of a convex intraluminal obstruction with a narrow neck. Postmortem studies suggested that such appearances frequently represent a ruptured atheromatous plaque and associated thrombus [16]. Similar findings have been noted at postmortem angiography in patients dying suddenly after an episode of unstable angina. Further analysis has revealed intraluminal thrombosis anchored to an ulcerated atheromatous plaque [17]. In patients whose condition stab&es, the overlying

activation

and recurrent

episodes

of

chest pain in patients with unstable angina. They measured the urinary and plasma metabolites of thromboxane A, and prostacyclin. The former is an arachidonic acid metabolite secreted by activated platelets, promoting their aggregation as well as the vasoconstriction of large and medium vessels. Prostacyclin is produced by vascular endothelium and has physiological properties opposing those of thromboxane A,. These investigators showed that 84% of episodes of chest pain in their patients were associated with an increase in the synthesis of thromboxane and prostacyclin. De Caterina et al. [22] measured plasma beta-thromboglobulin and platelet factor 4 (specific proteins secreted by activated platelets) in normal subjects and those with coronary arterial disease, including a subgroup with frequent angina at rest. They found significant elevations in the group of patients with frequent angina at rest compared with the normal controls and those patients with quiescent coronary arterial disease. In addition, they used a sampling technique that overcame some of the problems experienced with earlier

3

studies, notably by excluding samples contaminated with artefactual platelet activation. Kruskai et al. [23] addressed the problem by measuring the serum concentrations of specific fibrin degradation products in patients with angina at rest, and comparing the results with those in healthy controls, patients with myocardial infarction, and those with non-cardiac chest pain. Patients with unstable angina and myocardial infarction had significantly elevated levels compared with the other groups. Finally, Theroux et al. [24] demonstrated significantly elevated levels of fibrinopeptide A (a sensitive marker of thrombin generation) in patients with unstable angina compared with a group with stable angina. These various studies [21-241 suggest that activation of platelets and formation of fibrin may be the result of, rather than the cause of unstable angina. Taken in conjunction with the work described earlier, however, they are more consistent with the view that platelet aggregation and thrombus formation produces the reduction in coronary blood flow that appears to be the direct cause of myocardial ischaemia at rest. This evidence is opposed to the earlier view that ischaemia at rest was due to coronary arterial spasm. But the two concepts are not incompatible. It is known that platelets can secrete a wide range of vasoactive compounds, such as serotonin, and platelet-activating substances. They generally cause vasodilatation but in the presence of damaged endothelium, (such as at the site of a rupture plaque) they may cause vasoconstriction, thus further reducing coronary arterial flow. The explanation for this is not clear but current work suggests that endothelial derived relaxing factor may be deficient at such sites and that it is this component which usually prevents the vasoconstricting effects of these factors derived from platelets [25]. Plaques rupture, platelets aggregate and clots form. But why doesn’t the lumen totally occlude and infarction ensue? Recent work by Badimon and colleagues [26] has produced a rheological explanation based on an experimental model. They identified the shear rate (the difference in flow velocity between the centre of the vessel and its wall) as being influential on both the number of

platelets adherent to artificially injured endothelium and how long they remain at such a site. At high shear rates in medium sized stenotic arteries, and in the presence of mild vessel wall injury, platelets aggregate for only some lo-20 minutes before being dislodged by the flow of blood. In contrast, with deeper injury of the vessel wall, platelet deposition is greater at both low and high shear rates and remains more firmly adherent. The scene is then set for further aggregation, formation of clot and, possibly, luminal obstruction. Although this model relies on artificially injured (but otherwise normal) endothelium, it may be that platelets behave in a similar fashion when aggregating over a ruptured atheromatous plaque. It is tempting to suggest that unstable angina with transient coronary arterial occlusion may be due to aggregation of platelets over mild or superficial plaque injury with subsequent dislodgement. In contrast, myocardial infarction could represent occlusive thrombosis in response to a deeper insult. In summary then, unstable angina appears to be a dynamic process predominantly involving a reduction in coronary blood flow. This appears to be due to rupture of an atherosclerotic plaque, often with superimposed thrombosis. Coronary arterial calibre may be further reduced by the release of vasoconstricting substances from platelets. Blood flow reduction, however, is not critical nor prolonged enough to produce myocardial necrosis.

Therapeutic options As we now have a clearer understanding of the pathophysiology of unstable angina, decisions concerning treatment may be made on a more rational basis. As a primary reduction in coronary blood flow is often the precipitant of the condition, the therapeutic options available are either to reverse this process or to reduce myocardial demand for oxygen. Medical therapy should have both aims. Myocardial demand for oxygen is primarily determined by the heart rate, systolic wall tension (in the absence of outflow tract obstruction, this is proportional to systemic systolic pressure) and myocardial contractility. Beta-

4

blockers (and, to a lesser extent, the calcium antagonists verapamil and diltiazem) exert a favourable negative effect on all of these parameters. Indeed, there are many placebo-controlled studies demonstrating their ability to reduce the frequency of ischaemic episodes in unstable angina [27]. Furthermore, calcium antagonists maximise coronary blood flow and are, therefore, especially useful where a vasospastic element is suspected as causative of the reduction in coronary blood flow. Nitrates decrease systolic wall tension by reducing pre- and after-load and, like calcium antagonists, maximise coronary blood flow by reversing any vasoconstriction present. Although these therapies are effective in reducing the frequency of angina1 episodes, they are unlikely to have any beneficial effect on the causative arterial lesion. Their effects in terms of reduction in mortality have (not surprisingly) been disappointing. Three studies assessing the effects of anticoagulants (heparin) and platelet inhibition (aspirin) have shown more convincing benefit using end points of myocardial infarction and death. This would be expected if platelet aggregation and thrombosis played a major role in the causation of the syndrome. Telford and Wilson [28], in a study of 214 patients with unstable angina randomised to placebo, intravenous heparin, oral atenolol or a combination of both, demonstrated an infarction or death rate of 17% in those not receiving heparin and in only 3% receiving it. Defects of the studies included the large number (186) of patients incorrectly recruited, and, possibly, the inclusion of a group with non-Q wave infarction. In addition, the benefits beyond 8 weeks were not assessed. These results are still impressive but we wonder if they could have been improved further by greater attention to the quality of anticoagulation (clotting indices were not routinely measured and heparin was given in intravenous boluses). Lewis et al. [29] in their large multicentric study of 1266 men with unstable angina demonstrated a 10% myocardial infarction or death rate in those random&d to placebo and 5% in those receiving 324 mg of aspirin daily. The observation period was only 12 weeks but Cairns et al. [30] in a similar study, demonstrated a similar reduction in

coronary events maintained over 2 years. The dosage of aspirin was higher (325 mg four times daily) but clearly aspirin (and probably, heparin) reduce the myocardial infarction and death rate in this syndrome. Aspirin and heparin act to prevent aggregation of platelets and formation of thrombus but have little ability to lyse formed thrombi. The use of fibrinolytic agents would seem a logical extension to their proven benefit in acute myocardial infarction. An early study was that of Lawrence et al. [31] who conducted a single blind trial of intravenous streptokinase plus warfarin versus placebo infusion plus warfarin. Forty patients were enrolled and within a six-month period of followup, 8 cases out of 20 treated with warfarin alone experienced a cardiovascular event (four myocardial infarction and four sudden deaths). Only one sudden death occurred in the 20 treated with streptokinase. This difference was considered to be statistically significant (P < 0.02). Other studies have been limited to addressing the ability of fibrinolytic agents to dissolve intracoronary thrombi or reduce the frequency of myocardial ischaemia. Table 1 summarises these studies, the results of which are clearly disparate. Rentrop et al. [32] and Ambrose et al. [35] were able to show little benefit with intracoronary streptokinase in 41 patients whereas Gotoh et al. [12] found symptomatic benefit and improvement in the patency of the artery presumed responsible for the ischaemic events in 20 of 21 patients given intracoronary urokinase. How can such widely differing results be explained? These studies employed different fibrinolytic agents in different dosages given after different time periods from the last episode of chest pain. The latter point is particularly important, as intracoronary thrombi may become organised and consequently resistant to dissolution with such drugs. All that one can conclude from these studies is that some patients may benefit from thrombolysis. Which patients, and the dose of thrombolytic they require, is far from clear. More work needs to be done in order to clarify these points before thrombolysis can be recommended on a routine basis for patients who might otherwise now proceed to emergency revascularisation.

TABLE

1

Studies to date assessing the efficacy of various thrombolytics

in unstable angina.

Tie since last episode of chest pain

Treatment

Principal end points

Results

< 15.5 hr

130,000 u streptokinase i.c.

Improvement in patency of ischaemiarelated artery

Unsuccessful cases

< 5 days

190,000 u streptokinase i.c.

(a) Improvement in patency of ischaemiarelated artery (b) Reduction in frequency of angina

(a) Improvement in 10/13 (b) 6/9 experienced _1 angina for 48 hr post-infusion relative to 48 hr pre-infusion

“Most” within 24 hr

300,000 u streptokinase i.c.

Improvement in patency of ischaemiarelated artery

Improvement in 4/9

36 (incl. 8 with non Qwave infarction)

24 within 48 h

loo-300,000 streptokinase i.c.

Improvement in patency of ischaemiarelated artery

Improvement in 5/36

24

-C4 days

125 mg rt-PA i.v. over 12 hr

(a) Presence of subocclusive thrombosis postinfusion (b) Persistplacebo l/12 assigned to rt-PA

(a) 8/l 1

Authors

Study design

No. of patients

Rentrop et al. [32]

Open

5

Vetrovec et al. [33]

Open

13

Mandelkom et al. 1341

open

9

Ambrose et al. [35]

Open

Gold et al. [36]

Randomized placebocontrolled, double blind

u

ence of symptoms (observed up to 8 days)

in all

assigned to placebo, O/l 1 assigned to rt-PA (b) 6/11 assigned to

Gotoh et al. [12]

Open

(i) 21 with i.c. thrombus (ii) 14 with fixed narrowings only

Treatment given during symptoms

480,OOC 960.000 U urokinase i.c.

(a) Improvement in patency of ischaemiarelated artery (b) Relief of symptoms

(i) (a)&(h) Improve ment in 20/21 (ii) (a) Unsuccessful in all cases (b) Relief with _1in rate pressure product

De Zwaan et al. [37]

Open

(i) 21 (ii) 20

2-69 hrs

(i) 250,000 U streptokinase i.c. (ii) 100 mg rt-PA IV

Improvement in patency of ischaemiarelated artery

Improvement in (i) 11/21 and (ii) 11/20 but not necessarily associated with improvement in symptoms

U = units; i.c. = intracoronary;

i.v. = intravenous;

rt-PA = recombinant

tissue-type plasminogen activator.

b

The place of revascularization is now firmly established in those patients who fail to respond to medical therapy. Coronary angioplasty should be considered for those who have suitable lesions, and has been shown to produce acceptable results with respect to l-5 year mortality and morbidity [38-411, especially when compared with surgery. Such comparisons, however, should be interpreted cautiously, since no randomized study comparing the efficacy and long term results of the two forms of treatment has yet been carried out. In those whose lesions are unsuitable for angioplasty, coronary arterial bypass grafting should be considered. The results of surgery (as with angioplasty) have improved with increasing experience, but the long-term mortality is about the same as with medical therapy (except possibly in the subgroup with impaired left ventricular function who may be better off with an operation [7,42]. Should revascularisation be reserved solely for patients who remain refractory despite maximal medical therapy? Exercise testing should be performed after stabilisation in order to identify those individuals with a poor prognosis (such as those with a positive test as < 5 METS) [43] as they also may benefit from such interventions. Another group who may benefit from further investigation are those who continue to experience silent ischaemia observed on monitoring of the ST-segment although they are free from symptoms. Several studies have suggested that such patients have an adverse prognosis and more extensive coronary arterial disease than those who do not experience silent ischaernia [44,45]. It seems likely that such patients would also benefit from aggressive management. This cannot be routinely recommended until larger controlled studies have been performed to compare revascularization with medical therapy alone.

Conclusions

example, what initiates atherosclerotic plaque rupture? Which patients will benefit from thrombolytic therapy? The next few years should prove both to be an exciting time for clinicians and a beneficial one for our patients.

References 1 Levy

H. The natural

pectotis. 2 Wood

P. Acute

of changing

patterns

of angina

Med 1956:44:1123-1135.

and

subacute

coronary

insufficiency.

Br

Med J 1961;i:1779-1782. 3 Gazes

PC, Mobley

EM,

Faris

ties GB. Pre-infarctional

HM,

Duncan

(unstable)

M. Duncan

unstable

angina.

5 Krauss

KR.

B, Lutz

Lancet

Hutter

insufficiency:

Humph-

- a prospective

1973;48:331-337.

W. et al. Natural

history

of

1972;i:860-865.

AM,

course

RC,

angina

study - ten year follow up. Circulation 4 Fulton

De Sanctis

and

RW.

follow-up.

Acute

coronary

Circulation

1972;46

(suppl 1):66671. 6 Kannel WB, Feinleib

M. Natural

in the Framingham 7 Russell RO,

angina pectoris: pare surgical

history

RE,

national

N, et al. Unstable

cooperative

and medical

therapy.

study group

to com-

II. In-hospital

experi-

results in patients

and three vessel disease. Am J Cardiol R, AIAwadhi

son H, Contoy ble angina. DC.

R. Natural

history

prognosis

coronary

JW.

spontaneous 12 Gotoh

Br Heart

sessment attacks.

in ambulant

coronary

flow. Circulation of

monitoring. 15 Ambrose

BN,

rest

phology

DC.

Winters

JT.

of localized

correlation.

with

role of in-

angiographic

during ongoing

as-

angina1

I, Lazzari

Circulation

M, Maseti

A.

reduction

in

1980;61:759-768. W, Charuzi

nocturnal

Y,

angina:

Swan

HJC.

observations

and electrocardiographic

1979:59:955-968. SL,

Stem

and the pathogenesis Fallon

et al. The

angina;

haemodynamic

ris. J Am Co11 Cardiol 16 Levin

with stable

associated

at rest: primary

Ganz

and

Circulation JA.

morphology

0,

C, Simonetti

of events in angina J. Singh

changes

therapy

Sequence

Mechanism

patients

Raftery pressure.

1988;77:526-534.

S, Brunelh

14 Figueras

PMM, arterial

Am J Med 1966;41:947-961.

in unstable

and thrombolytic Circulation

6th

J 1983;50:85-91.

T, Katoh

thrombus

13 Chierchia

V. Cashman

pectoris.

K. Minamino

tracoronary

Morris

ed. The heart.

of continuous

Circulatory

angina

PF,

recognition,

1986;962.

recording

heart rate and ST segment 11 Roughgarden

Walter

disease:

In: Hurst JW.

10 Davies AB. BaIa Subramanian

angina pectoris.

CC.

heart

McGraw-Hill.

EB. Simultaneous

G, Johnof unsta-

J 1985;109:753-758.

and treatment.

ed. New York:

M, Tobin

and prognosis

King III SB, Fiesinger

Atherosclerotic

with one, two

1978;42:839-848.

AM, deBuitIeor

Am Heart

9 Hurst JW,

1972;29:154-163.

Kouchoukas

ence and initial follow-up 8 Mulcahy

of angina pectoris

Study. Am J Cardiol

Moraski

during continuous

Our understanding of the pathophysiology of unstable angina has progressed remarkably over the last decade. As a consequence, the making of therapeutic decisions now has a firmer foundation. It is likely that further developments will continue to be made and much has still to be learned: For

history

Ann Intern

A.

et al. Angiographic

of unstable

angina pecto-

1985;5:609-616. Significance coronary

of angiographic

stenoses:

1982;66:316-320.

mor-

histopathological

7 17 Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Circulation 1985;71:699-708. 18 Moise A, Thtroux P, Taeymans Y, et al. Unstable angina and progression of coronary atherosclerosis. N Engl J Med 1983;309:685-689. 19 Ambrose JA, Winters SL, Arora RR, et al. Angiographic evolution of coronary artery morphology in unstable angina. J Am Co11 Cardiol 1986;7:472-478. 20 Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med 1986;315:913-919. 21 Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986;315:983-989. 22 De Caterina R, Gazetti P, Mazzone A, Marzilli M, L’Abbate A. Platelet activation in angina at rest. Evidence by paired measurement of plasma beta-thromboglobulin and platelet factor 4. Eur Heart J 1988;9:913-922. 23 Kruskai JB, Commerford PJ, Franks JJ, Kirsch RE. Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease. N Engl J Med 1987;317: 1361-1365. 24 Theroux P, Latour JG, Leger-Gauthier C, De Lara J. Fibrinopeptide A and platelet factor levels in unstable angina pectoris. Circulation 1987;75:156-162. 25 Griffith TM, Lewis MJ, Newby AC, Henderson AM. Endothelium-derived relaxing factor. J Am Coll Cardiol 1988;12:797-806. 26 Badimon L, Badimon JJ, Galvez A, Chesebro JH, Fuster V. Influence of arterial damage and wall shear rate on platelet deposition. Arteriosclerosis 1986;6:312-320. 27 ThCrow P. A pathophysiologic basis for the clinical classification and management of unstable angina. Circulation 1987; 75 (suppl V):103-109. 28 Telford AM, Wilson C. Trial of heparin versus atenolol in prevention of myocardial infarction in intermediate coronary syndrome. Lancet 1981;i:1225-1228. 29 Lewis HD, Davis JW, Archibald DC, et al. Protective effects of aspirin against myocardial infarction and death in men with unstable angina. N Engl J Med 1983;309: 3966403. 30 Cairns JA, Gent M, Singer J, et al. Aspirin, sulphinpyrazone or both in unstable angina. N Engl J Med 1985;313: 1369-1375. 31 Lawrence JR, Shepherd JT, Bone I, Rogen AS, Fulton WFM. Fibrinolytic therapy in unstable angina pectoris: a controlled clinical trial. Thrombosis Res 1980;17:767-777. 32 Rentrop P, Blanke H, Karsch KR, Kaiser H, Kostering H, Leitz K. Selective intracoronary thrombolysis in acute myocardial infarction and unstable angina pectoris. Circulation 1981;63:307-317.

33 Vetrovec GW, Leinbach RC, Gold HK, Cowley MJ. Intracoronary thrombolysis in syndromes of unstable ischaemia: angiographic and clinical results. Am Heart J 1982;104:946-952. 34 Mandelkom JB, Wolf NM, Singh S, et al. Intracoronary thrombus in nontransmural myocardial infarction and in unstable angina pectoris. Am J Cardiol 1983;52:1-6. 35 Ambrose JA, Hjemdahl-Monsen C, Borrico S, et al. Quantitative and qualitative effects of intracoronary streptokinase in unstable angina and non-Q wave infarction. J Am Co11 Cardiol 1987;9:1156-1165. 36 Gold HK, Johns JA, Leinbach RC et al. A randomized, blinded, placebo-controlled trial of recombinant human tissue-type plasminogen activator in patients with unstable angina pectoris. Circulation 1987;75:1192-1199. 37 De Zwaan C, Bar FW, Janssen JHA, De Swart HB, Vermeer F, Wellens HJJ. Effects of thrombolytic therapy in unstable angina: clinical and angiographic results. J Am Co11 Cardiol 1981;12:301-309. 38 Steffenino G, Meier B, Fit-xi L, Rutishauser W. Follow up results of treatment of unstable angina by coronary angioplasty. Br Heart J 1987;57:416-419. 39 Leeman DE, McCabe CH, Faxon DP, et al. Use of percutaneous transluminal coronary angioplasty and bypass surgery despite improved medical therapy for unstable angina pectoris. Am J Cardiol 1988;61:38G_44G. 40 Sharma B, Wyeth RP, Kolath GS, Gimenez HJ, Franciosa JA. Percutaneous transluminal coronary angioplasty of one vessel for refractory unstable angina pectoris; efficacy in single and multivessel disease. Br Heart J 1988;59:280-286. 41 Talley JD, Hurst JW, King III SB, et al. Clinical outcome 5 years after attempted percutaneous transluminal coronary angioplasty in 427 patients. Circulation 1988;77:820-829. 42 Luchi RJ, Scott SM, Deupree RH, et al. Comparison of medical and surgical treatment for unstable angina pectoris. Results of a Veterans Administration Cooperative Study. N Engl J Med 1987;316:977-984. 43 Weiner DA, Ryan TJ, McCabe CH, et al. Prognostic importance of a clinical profile and exercise test in medically treated patients with coronary artery disease. J Am Co11 Cardiol 1984;3:772-779. 44 Nademanee K, Intarachot V, Josephson MA, Rieders D, Mody FV, Singh BN. Prognostic significance of silent myocardial ischaemia in patients with unstable angina. J Am Co11 Cardiol 1987;10:1-9. 45 Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenblith G. Silent ischaemia predicts infarction and death during two year follow-up of unstable angina. J Am Co11 Cardiol 1987:10:756-760.