Mechanisms contributing to precipitation of unstable angina and acute myocardial infarction: Implications regarding therapy

CORONARY HEART DISEASE REVIEW

Mechanisms Contributing to Precipitation of Unstable Angina and Acute Myocardial Infarction: Implications Regarding Therapy STEPHEN E. EPSTEIN, MD, and SEBASTIAN T. PALMERI, MD

:linical and autopsy studies indicate that most paients who present with unstable angina or an acute nyocardial infarction (AMI) have significant mderlying coronary atherosclerosis. This review liscusses 4 mechanisms that may contribute to the )recipitation of these acute ischemic clinical synlromes: progression of atherosclerosis, acute corJnary thrombosis, coronary artery spasm, and )latelet aggregation. Numerous clinical trials using :hrombolytic agents early during AMI have shown he incidence of thrombosis to be at least 60%. )ther studies suggest that platelet aggregation requently contributes to the evolution of AMI from rustable angina and that spasm may occasionally )lay a similar role. The therapeutic implications of ~hese mechanisms are also considered in light of

their potential to restore coronary artery blood flow (vs conventional methods thought mainly to reduce myocardial oxygen demand) and thereby limit the infarct process. The role of vasodilators, thrombolyric agents, antiplatelet drugs and /3-adrenergic blocking drugs are discussed. Finally, therapeutic guidelines for the treatment of acutely ill patients are constructed that emphasize the need for a comprehensive yet time-efficient treatment strategy that uses nitrates, calcium channel-blocking drugs, streptokinase, heparin, aspirin and, in selected patients in an unstable condition, emergency percutaneous transluminal coronary angioplasty and coronary artery bypass grafting.

Mthough most patients with unstable angina or acute myocardial infarction (AMI) have severe coronary artery disease (CAD), considerable uncertainty remains as to the mechanisms that actually lead to these acute ischemic syndromes. This report is a review of the evidence relating to 4 proposed mechanisms: progression of atherosclerosis, thrombosis, coronary spasm and platelet aggregation. In addition, considering the clinical implications of these mechanisms, therapeutic guidelines are constructed for the treatment of patients who present with acute ischemic syndromes.

angina had coronary angiographic studies performed before (mean 44 months) and shortly after the onset of unstable symptoms. Progressive narrowing was found in about 75% of patients with unstable angina, as opposed to only 30% of a similar group of matched patients with stable angina. Whereas this report suggests that anatomic progression of CAD can contribute to the development of unstable angina, the results also demonstrate that a substantial percentage of patients have unstable symptoms without evidence of disease progression. Acute myocardial infarction: Most patients with transmural AMI have multivessel CAD and total or near-total occlusion of the coronary artery supplying the infarcted myocardium. These findings have been demonstrated both at necropsy2,a and by coronary angiographic studies of patients in the early hours after the onset of AMIJ-m However, the atheromatous lesion per se is generally not responsible for totally occluding the vessel. A thrombus is usually superimposed on the atheroma, transforming a severely but partially occluded artery into a totally occluded one. Thus, progression of the basic atheroma to total obstruction does

(Am J Cardiol 1984;54:1245-1252)

Progression of Atherosclerosis Unstable angina pectoris: The role of progression of atherosclerosis in the development of unstable angina was recently assessed in a study from the Montreal Heart Institute. 1 Thirty-eight patients with unstable From the National Head, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received June 15, 1984; revised manuscript received July 20, 1984, accepted July 23, 1984. Address for reprints: Stephen E. Epstein, MD, Chief, Cardiology Branch, Room 7B-15, Building 10, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20205. 1245

1246

UNSTABLEANGINA AND ACUTE MYOCARDIAL INFARCTION

not appear to be responsible for precipitating the acute clinical event. In support of this conclusion is the report of Kramer et al, 17 in which they analyzed the results of 62 patients who had undergone 2 catheterizations, between which they had had an MI. Thirty-five percent of the patients did not have disease progression. Bruschke et al is reported similar findings in their series of 256 patients with follow-up coronary arteriograms. Eight of their 30 patients (27%) who had repeat catheterizations with interim MIs had no significant disease progression. Hence, both unstable angina and AMI may occur without evidence of progression of the basic atherosclerotic lesion.

Thrombosis The thrombogenic hypothesis for progression of CAD holds that platelet and fibrin thrombi are sequentially deposited on the endothelium of the epicardial coronary arteries in a stuttering course. After each episode the thrombus organizes, retracts, and assumes the typical morphologic appearance of an atheromatous lesion. Ultimately, severe "atherosclerotic" CAD is observed, usually without overt evidence of thrombus formation. Progressively more severe coronary occlusion develops with each new episode of thrombus deposition until a thrombus totally obstructs the coronary artery. In this model, increasing severity of stenosis evolves in a stepwise fashion consequent to the acute deposition of thrombi, 1 or more of which may precipitate an acute ischemic event. Depending on several factors, including the severity of the underlying obstruction, the rate of its progression and the adequacy of collateral vessels, the patient could present clinically with either unstable angina or with AMI. Subsequently, recanalization or retraction of the clot could occur. This might constitute 1 mechanism leading to more stable symptoms, and might explain the finding that many patients have no apparent CAD progression after a period of unstable angina or AMI. Unstable angina pectoris: Evidence of a role for thrombosis in the production of unstable angina derives from several clinical studies. Vetrovec et a119 reported the results of 12 patients with unstable angina who were studied by coronary angiography within 5 days of having prolonged episodes of angina. Angiographic findings consistent with intracoronary thrombus were found in 11 of 13 ischemia-related vessels. More recently, Mandelkorn et al 2° found evidence of coronary thrombi in 4 of 9 patients with unstable angina, further suggesting the importance of thrombosis as a causative or complicating factor of unstable angina. Two intervention studies also suggest an important role of thrombosis in the evolution of unstable angina to AMI. In 1980, Lawrence et a121 treated 40 patients with unstable angina in a randomized, blinded trial that compared intravenous streptokinase and warfarin to warfarin therapy alone. At the end of their 6-month follow-up period, only I patient (5%) had died and none had had an MI in the group treated with streptokinase, whereas 4 patients (20%) had died and 4 had MIs during the same period in the group treated with warfarin alone. In 1981, Telford and Wilson 22 assessed the effects

of heparin on the development of transmural AMI in a randomized, blinded study of patients presenting with unstable angina pectoris. Heparin significantly decreased the frequency with which transmural MI occurred; 17% in the control group vs 3% in the group treated with heparin, suggesting an important role of coronary thrombosis in the evolution of unstable angina to AMI. Acute myocardial infarction: Numerous recent clinical trials using thrombolytic agents in patients during the first hours after the onset of AMI have shown the importance of thrombosis in the pathogenesis of AMI. 5-1e The incidence of thrombosis in AMI can be estimated to be no less than 60%. This is based on the percentage of patients in these trials who presented with total coronary occlusions and underwerit successful reperfusion with thrombolytic agents. The true incidence of thrombosis is probably actually higher, because some patients with an acute thrombus may not have responded to thrombolytic therapy, whereas others may have had spontaneous lysis before undergoing catheterization, and therefore would have presented with only subtotal occlusions and would have been excluded from this estimation.

Coronary Spasm Unstable angina: The role of coronary spasm as a contributing cause of unstable angina has been well documented. Beginning in 1973, several groups reported that in the absence of acute infarction, angina at rest associated with ST-segment elevation was almost always caused by large-vessel coronary spasm. 23-25 Bertrand et a126 performed coronary angiography with provocative testing in more than 1,000 patients and found that spasm could be provoked in 39% of the patients with typical angina at rest, and in 85% of the patients who had ST-segment elevation associated with their angina. 26 Acute myocardial infarction: Oliva and Breckinridge27 provided angiographic evidence indicating that spasm, superimposed on a severely stenotic lesion, may contribute to the total occlusion exhibited by some patients presenting with AMI. 27 Spasm also has been induced at catheterization in 20% of patients who had a transmural MI within 6 weeks of this study, as compared to only 6% of patients who had MIs more than 6 weeks before catheterization. 26 Data also have been published suggesting that unstable angina caused by coronary spasm can lead to AMI. 24,27-29 Finally, some patients who have had chest pain syndromes caused by coronary spasm documented at catheterization have subsequently had infarction in portions of myocardium supplied by the vessels that developed spasm. 28 It is unclear whether spasm in and of itself can cause sufficiently severe and prolonged ischemia so as to precipitate an acute transmural MI or whether spasm predisposes to the formation of thrombi or platelet aggregates, which then lead to prolonged total obstruction and infarction. Spasm may also be the result, and not the cause, of the acute thrombus or platelet aggregate. Finally, the incidence of reversible coronary artery spasm has been low in all of the recent thrombolytic

December 1, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54

rials. However, approximately 20% of the patients in ~t~ese studies have only subtotal lesions evident at the ime of angiography. Although it is possible that platelet ~ggregates had already deaggregated or a thrombus had /zed, since sublingual nitroglycerin is usually admin~tered before catheterization, coronary artery spasm annot be excluded as a possible precipitating cause or omplicating factor.

Platelet Aggregation Unstable angina: The possible clinical importance f platelets in patients presenting with unstable angina ,,,as shown in a large, randomized, multicenter Veterans ',.dministration clinical trial that compared control herapy to aspirin therapy (324 rag/day).3° During the -month follow-up period, 7% of the control group had ,~Is, as opposed to only 3.4% of the treated group. Death ,r MI occurred in 10% of the control subjects, compared ,~ith 5% of the patients treated with aspirin. Because a najor action of aspirin is to inhibit the aggregation of datelets, these results support the concept that the ormation of platelet aggregates plays an important role n the course of unstable angina and in the evolution of his syndrome to AMI. Experimental studies have also shown that platelet ~ggregates may form in the setting of a partially con~tricted coronary artery, which can lead to acute oclusion and ischemia. Folts et a131 produced partial oronary constriction in dogs and measured coronary low by placing flow probes proximal to the con,triction. In 25 of the 35 dogs (69%), repeated cycles |eveloped, characterized by spontaneous decreases in low and pressure distal to the constriction punctuated )y abrupt restorations of flow and pressure. When the togs were killed at the time of flow reduction, examiration of the coronary arteries revealed platelet aggre~,ates occluding the partially constricted artery. When tspirin was administered, the cyclic decreases in flow Jisappeared. Acute myocardial infarction: The Veterans Administration study3° provides clinical data that suggest ~hat platelets play an important role in the precipitation

S

Thromboxane

I

Over the past 10 to 15 years several experimental studies have revealed that therapeutic approaches designed to reduce myocardial oxygen demands may limit the extent of ischemic damage occurring during AMI. Nevertheless, skepticism has been expressed concerning the potential clinical benefit of interventions that solely reduce myocardial oxygen consumption.35,36 However, the realization that unstable angina or AMI may be precipitated by a potentially reversible decrease in coronary flow focuses attention on the development of interventions designed to limit infarct size by restoring flow. Figures 1 and 2 are diagrams of the complex interaction of the previously discussed dynamic factors, usually superimposed on severe underlying CAD, that may be involved in precipitating the acute ischemic syndromes. Thrombolytic and anticoagulant therapy: Recognition of the role of thrombosis in the precipitation of AMI has stimulated several trials designed to test the efficacy of thrombolytic agents for aborting the infarct process. Fletcher et al,37 in 1959, were the first to report the use of such agents in the setting of AMI. Since then NTG Ca Antagonists i'~'"~

T-

Vascular

t,

,nj.ry

~

Acute Ischemic Syndromes

THROMBUS

\ Fibrin

FIGURE 1. The interrelationship of dynamic mechanisms that may cause or contribute to the clinical presentation of acute ischemic syndromes,

\f Thrombin

Fibrinogen

I

"

I

i

/ ~, ~

,, F,=ee Deaggregation -' " n / i-,lasmlnoge ~ Activator

=mi-o

I THROMBUS, . . L / I ]"~Y

~ Fibrin

Vasodilatation

~ PGI2

/

Thromboxane "~.-.-l~..9[.-~ A2 ~ T ~ 1 PLATELET I ~ ~1~'I AGGREGATION r~ Prothrombin J Jf

InjirY

Proth

Fibrinogen

Therapeutic Implications

~ASA SPASM

PLATELET AGGREGATION

Thrombin

of AMI, especially in patients who initially present with unstable angina. There is additional experimental evidence suggesting that platelets may contribute to a worsening of ischemia and resulting necrosis in the setting of an acutely occluded coronary artery. Capurro et al32 showed that collateral blood flow increases more over the 4 hours after acute total coronary occlusion in dogs pretreated with aspirin than in control animals, although in a similar experimental model of fixed stenosis, there was no evidence that aspirin reduced infarct size. 33 Pretreatment of dogs with aspirin before acute coronary occlusion has been shown to reduce substantially the incidence of ventricular fibrillation, presumably by limiting the ischemia that might result from platelet aggregation.34

SPASM

Vascular

1247

Relief of Occlusion

t

Streptoklnase

Clot4peclfic Plumlnogen Activators

FIGURE 2. Several possible dynamic mechanisms that may cause acute ischemic syndromes, as well as both naturally occurring mechanisms and pharmacologic interventions that may relieve the degree of coronary obstruction. ASA = acetylsalicylic acid; Ca = calcium; NTG -nitroglycerin.

1248

UNSTABLEANGINA AND ACUTE MYOCARDIAL INFARCTION

TABLE I

Intracoronary Streptokinase: Acute Infarction Studies

Rentrop et al s Ganz et al e Gold et al 7 Markis et aP Merx et al 9 Mathey et a144 Schwarz et al ~° Anderson et al 11 Khaja et a112 Stack et a113 Smalling et a114 DeFeyter et a145 Alderman et al ~s

No. of Pts

Patient Selection

% with Total Occlusions

% Reperfused

29 20 30 9 204 41 27 24 20 24 136 42 15

-----C -R R C C C R

69 90 83 100 81 95 85 83 83 96 74 -100 °

76 95 68 100 81 73 70 95 60 62 73 74 73

Onset of Pain to Rx (hours)

Follow-Up Anticoagulation

% Restenosis

H,W H,W -N H,W H,W H H,A A H -A H

5 8 41 11 8 20 -0 -7 -13 --

5.6 2.6 <3 3.5 -1.4 3-4 2.7 5.4 4.4 -2-4 3.4

" Only patients with total occlusions of the infarct vessel were included. A = aspirin; C = consecutive series; H = heparin; N = none; R = randomized study; Rx = treatment with thrombolytic agent; ~V = warfarin; - - = data not reported.

T A B L E II

Intracoronary Streptokinase: Acute Infarction Studies

LV Ejection Fraction (%)

Rentrop et al 5 Mathey et al Reperfused44 Rx failures Schwarz et alm Reperfused Rx failures Anderson et al~ Rx patients Controls (aspirin) Khaja et a112 Rx patients Controls (aspirin) Stack et a113 Reperfused Rx failures Smalling et a114 Reperfused Rx failures Controls

Mortality (%) Early

Late

Follow-Up (wk)

Major Rx Complications

55

3.4

7.1

11

Femoral repairs, 2

37 34

47 26

0 27.3

0 --

1-3

VF,7

48 55

52 50

0 12.5

0 28.6

4

0

--

47 39

4.2 7.7

0 8.3

--

0

48 47

51 49

5 10

38 40

34 39

13.3 22.2

0 0

39 41 43

46 43 43

----

1.4 19 19.2

Pre-Rx

Post-Rx

51

0 11

41

Deaths, 2 ° Femoral repair, 1; transfusion, 1; VF/death, 1

8 26

Death, 1; CVA, 1; transfusions, 5

CVA = cerebrovascular accident; Rx -- treatment with thrombolyUc agent; VF = ventricular fibrillation; - - = information not reported; deaths = catheterization-related deaths.

T A B L E III

Intravenous Streptokinase: Acute Infarction Studies

European Working Party38 European Cooperative-39 Study Group Schroder et al is Spann et al 4° Neuhaus et a141 Ganz et a142 Alderman et a116

No. of Pts

Patient Selection (% )

% with Total Occlusions

357 155

R R

---

26 13 40 81 13

--

81 100 ° 100"

--R

% Reperfused ---

52 46 60 (96)1 62

100 °

Onset of Pain to Rx (hours)

Follow-Up Anticoagulation

8.9 <12

W --

---

W W W H,W H

9 13 -8 --

3.8 3.1 2.8 2.2 2.0

% Restenosis

• Only patients with total occlusion of the infarct-related vessel were included. 1 Patency assessed initially by clinical criteria. Abbreviations as in Table I.

there have been clinical trials using both intravenous (i.v.) 15,16,38-42and intracoronaryS-14,16,43-45thrombolytic agents in the treatment of AMI (Tables I to IV). These approaches have led to reperfusion in 60 to 96% of patients, with apparent reduction in myocardial ischemia

and injury, and preservation of left ventricular function. Although definitive data regarding the clinical role of thrombolytic therapy are as yet lacking, given the important causal role of thrombosis in the precipitation of AMI, it is highly likely that thrombolytic therapy will

December 1, 1984

f A B L E IV

THE AMERICAN JOURNAL OF CARDIOLOGY

Volume 54

1249

I n t r a v e n o u s S t r e p t o k l n a s e : A c u t e Infarction Studies

LVEF( % ) Pre-Rx

Mortality ( % )

Post-Rx

=uropean Working Party38 Streptokinase -I- warfarin Heparin + warfarin

Early

Late

m

19.0

m

27.4

Follow-Up Period (wk)

Major Rx Complications Cardiac rupture, 5; CVA, 2; bleeding, 7 Cardiac rupture, 5;

CVA, 2; bleeding, 2 uropean Cooperative Study 3s Streptokinase + warfarin Warfarin alone

--

11.6 17.8

15.6 30.6

26

54 56 58

7.5 ---

3.5 ---

16-108

58 41 --

--6.2

4 6 --

CVA, 2; Rx stopped, 5; transfusion, 1

-;chroder et al is Reperfused Rx failures

;pann et al4° ~leuhaus et a141 Reperfused Rx failures ~anz et a142

48 55

49

55 49

Cardiac rupture, 1

--

None

78

Cardiac rupture, 1;

HP

Cardiac rupture, 1;

VF, 6 CVA, 2; bleeding, 8; hypotension, 3

HP = hospital period; other abbreviations as in Table II.

)ecome an increasingly important part of the therapeutic approach to the patient who has an AMI, and ~erhaps also to the patient with unstable angina. Of the 2 basic routes used to administer thrombolytic herapy, i.v. therapy is more practical, and has the ad'antage of requiring less delay before treatment is iniiated, because angiography is unnecessary. In addition, .v. therapy circumvents any concern regarding whether he correct coronary artery is being perfused with the ,hrombolytic agent, because ischemia might be the re,ult of multiple or distant occlusions. However, coronary ~rteriography and intracoronary streptokinase have the ~dvantages of precisely defining the coronary anatomy, md the local delivery of the thrombolytic agent may ~esult in higher success rates (Tables I and III). Finally, having already defined the patient's coronary anatomy, ~'uture treatment options, including percutaneous transluminal coronary angioplasty and coronary artery bypass grafting, can be carefully considered. More clot-specific thrombolytic agents, such as tissue plasminogen activator, are being tested. 46 Such agents have less effect on circulating plasminogen, and therefore are less likely to increase circulating levels of plasmin. As a result, many of the bleeding complications associated with streptokinase may be avoided. The effectiveness of heparin as a single agent in reducing infarct size or improving the survival rate has not been tested in well controlled studies. However, its efficacy in preventing the evolution of transmural infarction in patients with unstable angina has been clemonstrated.22 In addition, 10 to 20% of patients who have an AMI have clinical or laboratory evidence of infarct extension within the first week of the precipitating event.47-49 Therefore, a case can be made for administering anticoagulant therapy to patients who present with unstable angina or those with recurrent angina or persistent enzyme elevations after AMI. Also, heparin will probably play an important complementary role to thrombolytic therapy by inhibiting the formation of new thrombi subsequent to clot lysis. Vasodilators: Considerable experimental evidence exists suggesting that nitroglycerin can alter hemody-

namic and coronary flow characteristics to limit infarct size.5°-55 Furthermore, because large-vessel spasm may contribute to unstable angina, and probably predisposes some patients to the development of acute infarction, administration of nitroglycerin should constitute a primary approach to the treatment of these acute ischemic syndromes. Because calcium antagonists can be effective in relieving spasm unaffected by nitroglycerin,56 and because evidence exists suggesting that verapamil may reduce infarct size, 57,5s calcium antagonists should be considered whenever nitroglycerin is ineffective. Data supporting the usefulness of other vasodilators, such as nitroprusside, in reducing infarct size are inconclusive. In fact, some experimental and clinical studies suggest that nitroprusside may increase ischemic injury or mortality when administered early in the course of infarction.59~3 Although useful for the management of left ventricular failure and systemic hypertension complicating AMI, the routine administration of vasodilators, other than nitrates or calcium channel-blocking drugs, does not appear to be warranted during the early phases of acute infarction. Antiplatelet drugs: Experimental data suggest an important role of platelets in contributing to the degree of coronary obstruction in animals with either partial or total coronary artery obstruction.31,32,34Clinical trials have also shown that aspirin reduces the incidence of death and the development of AMI in patients with unstable angina. 3° The net effect of low-dose aspirin may be to inhibit platelet aggregation and the subsequent production of the potent vasoconstriction substance, thromboxane A2, without the undesired effect of irreversibly inhibiting production of prostacyclin, the potent vasodilator synthesized by endothelial cells,e4,65 However, no clinical studies have tested aspirin as a single agent in the treatment of AMI. Beta-adrcnergic blocking agents: By decreasing myocardial oxygen demands, ~3-adrenergic blocking agents may diminish ischemic injury that occurs during the early phase of AMI, especially if tachycardia is present. However, the results of clinical studies on the effects of these drugs on infarct size reduction are con-

1250

UNSTABLE ANGINA AND ACUTE MYOCARDIAL INFARCTION

flicting.35-36a In fact, if spasm contributes to the coronary obstruction and resulting acute ischemia, administration of ~-adrenergic blocking drugs could exacerbate the degree of ischemic injury by causing further coronary constriction. This may result either from their inhibition of ~2 (vasodilator) receptors located in the coronary circulation, or from baroreceptor-mediated vasoconstrictor reflexes triggered by the systemic hypotension these agents may produce. The potent negative inotropic properties of these drugs also make their use in the unstable patient potentially hazardous. Given the potential therapeutic advantage of treatment remedies designed to restore myocardial blood flow, and the fact that time is required to assess the efficacy of each intervention used, it would appear prudent in most cases not to delay thrombolytic therapy in order to initiate a trial of ~-blocking drugs. Although thrombus formation, spasm and platelet aggregation have been discussed as independent factors that contribute to acute ischemic syndromes, there are undoubtedly important interactions whereby the activation of one triggers the activation of another (Fig. 1 and 2). For example, platelet aggregation alters the clotting mechanisms to favor the deposition of fibrin, which ultimately results in the formation of a plateletfibrin thrombus. Platelet aggregation can also cause spasm through the release of thromboxane A2. Spasm itself may alter local vascular hemodynamics so as to predispose to platelet aggregation. Finally, by changing the stresses and geometry of the vessel wall, spasm may impair plaque integrity, and thereby predispose to the development of occlusive thrombi as a result of plaque rupture and hemorrhage.

ACUTE ISCHEMIC SYNDROMES

I

I Nitroglycerin [Iv]l !

Stable

Unstable

t

I

CaAntagonlst I i Stable

I

[ Ca Antag::"l'st Stable [P°] J I

J |

Unstable

+o°+...+,,I Uns~b.le__.. l

Coronary Arteriography I

I .,,.a,e+[Ion. sctlog] I

I NitroglycerinStreptokinase tic] I I

I

i

Reperfusion No reperfuslon I I ! i i l Stable Unstable Stable I

I Heperin/AsA I

I. . . . .

,..r,. _ _ _

,.J

t I PTCA/CABG ]

I .eta S,o ke.+ ] l

RISK STRATIFICATION FIGURE 3. Therapeutic guidelines for managing patients who present with acute ischemic syndromes. ASA = acetylsalicylic acid; Ca = calcium; CABG = coronary artery bypass graft; ic = intracoronary; iv = intravenous; po = orally; PTCA = percutaneous transluminal coronary angioplasty.

Therapeutic Guidelines The patient who presents with sustained or recurring angina at rest that is refractory to sublingual nitroglycerin should be considered unstable and in need of more aggressive therapy. The following guidelines are based on the pathophysiologic mechanisms and studies just discussed, and are aimed at limiting the ischemic or infarct process primarily by restoring myocardial blood flow (Fig. 3). Given the complex interaction of these mechanisms and the synergistic actions of the pharmacologic agents proposed, we must emphasize that a definitive guide to therapy cannot be developed at this time. Clearly, additional data are necessary regarding which subgroups of patients would be most responsive to different therapeutic approaches. Therefore, the outline we present should serve only a;~ a guide, to be modified as new data, drugs and interventions become available. Finally, it is important to consider that the specific approach used must be modified by the clinical setting as well as by local experience and resources. Because it is often difficult to distinguish unstable angina from AMI early in the patient's presentation, these ischemic syndromes are considered together. However, the proposed approach is not recommended for the patient with chronic stable angina that has only a mild change in its intensity, frequency or character; rather, it is intended for the patient with severe, sustained or recurrent angina associated with electrocardiographic changes. The recommended trials of nitrates and calcium channel-blocking agents should be conducted quickly to avoid any unnecessary delay in initiating possible thrombolytic therapy. Although not the subject of this study, routine measures such as mild analgesics and prophylactic antiarrhythmic therapy should also be used. Many patients will have taken 1 or more sublingual nitroglycerin tablets before they come to the hospital. Nevertheless, in the absence of hypotension, sublingual nitroglycerin should be immediately administered. If the patient's angina subsides, long-acting nitrates should be started. If the pain does not quickly remit, a trial of i.v. nitroglycerin should be promptly initiated while more aggressive therapy is being considered. If the patient's pain subsides and does not recur for 6 to 12 hours, the therapy should be switched to long-acting nitrates. If the patient's pain persists or recurs after a trial of i.v. nitroglycerin therapy, a calcium channel-blocking agent should be started in patients with no clinical evidence of congestive heart failure, heart block or hypotension, while preparations for invasive testing and treatment are completed. If the patient's pain subsides, maintenance calcium channel-blocking therapy should be started in addition to long-acting nitrates. At the same time, antiplatelet therapy with low-dose aspirin and anticoagulant therapy with heparin should be considered. This combination of antihemostatic agents appears to be well tolerated in several of the recent streptokinase trials.9,tt, 4t Caution must be used, however, because serious bleeding complications can

December 1, 1984

, , c c u r . 66,67 Long-term ~-blocking therapy may also be ~tarted at this time. If, on the other hand, the patient's condition remains , rustable after a therapeutic trial of nitroglycerin and ~, calcium channel-blocking drug, a prompt decision ~aust be made regarding more aggressive approaches. :f emergency coronary arteriography is neither desirable ~or feasible, and there are no contraindications to hrombolytic therapy, 68 i.v. thrombolytic therapy hould be considered. If thrombolytic therapy is initiated, it should be :tarted as early as possible. It would also appear prudent o insert a catheter into the pulmonary artery before tdministration of the thrombolytic agent. The hemofynamic information obtained may be useful in stabiizing the patient's condition. Careful insertion of the :atheter before initiation of thrombolytic therapy will dso minimize the likelihood of bleeding problems that ievelop from catheter insertion. If thrombolytic therapy ~s successful in ameliorating the patient's symptoms, it ;hould be followed by the administration of heparin and ow-dose aspirin for the remainder of the patient's hospital stay. If the patient is not helped by these interventions, transfer to a hospital equipped to procede with more definitive invasive testing and therapy should be considered. In hospitals that have catheterization facilities, patients whose condition remains unstable after nitrate and calcium antagonist therapy may undergo a more invasive diagnostic and therapeutic approach, including 30ronary arteriography. Intracoronary nitroglycerin and ~treptokinase, 5-18 percutaneous transluminal coronary mgioplasty 69-72 and emergency coronary artery bypass ~rafting6,9,11,73-78 are all reasonably safe and effective n selected patients when performed by experienced ~ersonnel. Nevertheless, the decision to proceed with :hese treatment modalities will have to be individualized for each patient, phy.~ician and facility. Despite the exciting potential for pharmacologic reversal of the dynamic mechanisms contributing to unstable angina and AMI, the efficacy of the therapeutic approaches we have discussed is still unproved. Furthermore, even if they are effective, there are still major limitations to the net benefit to be derived. Underlying atherosclerotic CAD is usually severe, with dynamic factors usually contributing only to a small but crucial final step that converts a severely narrowed coronary artery into one with critical stenosis. Therefore, it may become important to define precisely the coronary anatomy of patients who present with acute ischemic syndromes. In patients whose clinical course is stabilized with medical therapy, urgent definition of anatomy is probably unnecessary. In these patients, noninvasive testing to identify patients at high risk of recurrent cardiac events can be undertaken after 1 to 3 weeks. 79 However, in patients whose unstable course is not quickly relieved by pharmacologic therapy, urgent cardiac catheterization may be indicated. The catheterization results would identify those patients who have anatomic findings usually associated with a high risk of mortality, and would help to identify which of

THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54

1251

these patients are candidates for early balloon angioplasty or coronary bypass surgery. Acknowledgment: We thank June Moon for her secretarial assistance, as well as the many physicians whose advice we sought while developing the concepts expressed in this manuscript. References 1. Molse A, Tharoux P, Taaymans Y, Dascolngs B, Lesperance J, Waters DD, PelleUer GB, Bourassa MG. Unstable angina and progression of coronary atharosclerosis. N Engl J Mad 1983;309:685-689. 2. Roberts WC, Jones AA. Quantification of coronary arterial narrowing at necropsy in acute transmural myocardial infarction: analysis and comparison of findings in 27 patients and 22 controls. Circulation 1980;61: 786-790. 3. BuJa LM, Wlllarson Jr. Clinicopathologic correlates of acute ischemic heart disease syndromes. Am J Cardio11981;47:343-356. 4. DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897-902. 5. Renlrop P, Blanke H, Ksrsch KR, Kaiser H, Kostarlng H, Leltz K. Selective intracoronary thrombolysis in acute myocardial infarction and unstable angina pectoris. Circulation 1981;63:307-317. 6. Ganz W, Buchblnder N, Marcus H, Mondkar A, Maddahl J, Charuzl Y, O'Connor L, Shell W, Flshbaln MC, Kass R, Mlyamoto AL, Swan HJC. Intracoronary thrombolysis in evolving myocardial infarction. Am Heart J 1981;101:4-13. 7. Gold HK, Lelnbach RC, Buckley MJ, Aklns CW, Levlne FH, Austen WG. Intracoronary streptokinase in evolving infarction. Hosp Pract 1981; 16: 105-119. 8. Markls JE, Malagold M, Parker JA, Sllverman KJ, Barry WH, AIs AV, Paulln S, Grosoman W, Braunwald E. Myocardial salvage after lntracoronary thrombolysis with streptokinase in acute myocardial infarction. N Engl J Mad 1981;305:777-782. 9. Merx W, Dorr R, Rentrop P, Blanke H, Karach KR, Mathey DG, Kramer P, Rutach W, Schmutzler H. Evaluation of the effectiveness of intracoronary streptokinase infusion to acute myocardial infarction: postprocedure management and hospital course in 204 patients. Am Heart J 1981 ;102:1181-1187. 10. Schwarz F, Schuler G, Katus H, Mehmal HC, yon Olshausen K, Hofmann M, Hart'man HJ, KuMar W. Intracoronarythrombolysls in acute myocardial infarction: correlations among serum enzyme, scintigraphic and hemodynamic findings. Am J Cardiol 1982;50:32-38. 11. Anderson JL, Marshall HW, Bray BE, Lutz JR, Frederick PR, Yanowltz FG, Dalz FL, Klausner SC, Hagan AD. A randomized trial of intracoronary streptokinase in the treatment of acute myocardial infarction. N Engl J Med 1983;308:1312-1318. 12. KhaJaF, Walton JA, Bryurner JF, Lo E, Osterberger L, O'Neill WW, Cotter HT, Welso R, Lea T, Kurlan T, Goldberg AO, Pitt B, Goldsteln S. Intracoronary flbrlnolytic therapy in acute myocardial infarction. Report of a prospective randomized trial. N Engl J Med 1983;308:1305-1311. 13. Stack RS, Phillips III HR, Grlerson DS, Behar VS, Kong Y, Peter RH, Swain JL, Greenfield Jr JC. Functional improvement of jeopardized myocardium following intracoronary streptokinase infusion in acute myocardial infarction. J Clin Invest 1983;72:84-95. 14. Smalllng RW, Fuentes F, Matthews MW, Freund GC, Hicks CH, Redulo LA, Walker WE, Sterling RP, Gould KL. Sustained improvement in left ventricular function and mortality by intracoronary streptokinasa administration during evolving myocardial infarction. Circulation 1983;68: 131-138. 15. Schroder R, Blamlno G, von Leltner ER, Llnderer T, Bruggemann T, Heltz J, Vohrlnger H-F, Wegschelder K. Intravenous short-tarm infusion of streptokinase in acute myocardial infarction. Circulation 1983;67:538548. 16. Alderman EL, Jutzy KR, Berle LE, Miller RG, Friedman JP, Cregar WP, Ellastam M. Randomized comparison of intravenous versus intracoronary streptokinase for myocardial infarction. Am J Cardio11984;54:14-19. 17. Kramar JR, Malsuda Y, Mulligan JC, Aronow M, Proudflt WL Progression of coronary atharosclerosis. Circulation 1981;63:519-526. 18. Bruschke AVG, WlJers TS, Kolstars W, Landmann J. The anatomic evolution of coronary artery disease demonstrated by coronary arteriography in 256 nonoperated patients. Circulation 1981;63:527-536. 19. Velrovec GW, Lelnbach RC, Gold HK, Cowley MJ. Intracoronary thrombolysis in syndromes of unstable ischemia: angiographic and clinical results. Am Heart J 1982; 104:946-952. 20. Mandelkom JB, Wolf NM, Slngh S, Schechter JA, Kersh RI, Rodgers DIM, Workman MB, BanUvogllo LG, LaPorta SM, Malster SG. Intracoronary thrombus in nontransmural myocardial infarction and in unstable angina pectoris. Am J Cardiol 1983;52:1-6. 21. Lawrence JR, Shepherd Jr, Bone I, Rogen AS, Fulton WFM. Fibrinolytic therapy in unstable angina pectoris: a controlled clinical trial. Thromb Res 1980;17:767-777. 22. Telford AM, Wilson C. Trial of heparin vs. atanolol in prevention of myOcardial infarction in intermediate coronary syndrome. Lancet 1981;1: 1225-1228. 23. OIIva PB, Ports DE, Puss RG. Coronary arterial spasm in Prinzmatal angina. N Engl J Med 1973;288:745-751. 24. Maseri A, Mlmmo R, Chlerchla S, Marchesl C, Eng, Pesola A, L'Abbate A. Coronary artery spasm as a cause of acute myocardial ischemla in man. Chest 1975;68:625-633. 25. Maserl A, Severl S, De New M, L'Abbate A, Chlerchla S, Marzllll M,

1252

26.

27.

28.

29. 30.

31. 32. 33. 34. 35.

35a.

36.

36a. 37.

38. 39.

40.

41. 42. 43. 44.

45.

46.

47. 48. 49.

50.

UNSTABLEANGINA AND ACUTE MYOCARDIAL INFARCTION

Ballestra AM, Parodl O, Blaglni A, Dlstante A. "Variant" angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Am J Cardiol 1978;42:1019-1035. Bertrand ME, LaBlanche JM, TIImant PY, Thleuleux FA, Delforge MR, Carre AG, Asseman P, Borzln B, Llbersa C, Laurent JM. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary angiography. Circulation 1982;65:1299-1306. Oliva PB, Breckinrldge JC. Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation 1977;56:366-374. Maseri A, L'Abbate A, Baroldl G, Chlercbla S, Marzllll M, Ballestra AM, Severl S, Parodl O, Blaginl A, Dlstante A, Pesola A. Coronary vasospasm as a possible cause of myocardial infarction. N Engl J Med 1978;299: 1271-1277. Madlas JE. The syndrome of variant angina culminating in acute myocardial infarction. Circulation 1979;59:297-306. Lewis HD, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Dohedy JE, Schnaper HW, LeWlnler MM, Unares E, Pouget JM, Sabharwal SC, Chesler E, DeMota H. Protective effects of aspirin against acute myocardial infarction and death in man with unstable angina. N Engl J Med 1983;309:396-403. Foils JD, Crowell EB, Rowe GG. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 1976;54:365-370. Capurro NL, Marr KC, Aamodt R, Goldsteln RE, Epstein SE. Aspirininduced increase in collateral flow after acute coronary occlusion in dogs. Circulation 1979;59:744-747. Bonow RO, Llpaon LC, Sheehan FH, Capurro NL, Isner JM, Roberts WC, Goldstein RE, Epstein SE. Lack of effect of aspirin on myocardial infarct size in the dog. Am J Cardiol 1981;47:258-264. Moschos CB, Halder B, Dela Cruz Jr C, Lyons MM, Regan TJ. Antiarrhythmic effects of aspirin during nonthrombotic coronary occlusion, Circulation 1978;57:681-684. The International Collaborative Study Group. Reduction of infarct size with the early use of timolol in acute myocardial infarction. N Engl J Med 1984;310:9-15. Robeds R, Croft C, Gold HK, Hadwell TD, Jatte AS, Muller JE, Mullln SM, Parker C, Passamanl ER, Poole K, Raabe DS, Rude RE, Stone PH, Turl ZG, Sobel BE, Wlllerson Jr, Braunwald E, and the MILLS Study Group. Effect of propranolol on myocardial-infarct size in a randomized blinded Multicenter trial. N Engl J Med 1984;311:218-225. Frlshman WH, Furberg CD, Friedewald WT. B-adrenergic blockade for survivors of acute myocardial infarction. N Engl J Med 1984;310:830837. Rude RE, Muller JE, Braunwald E. Efforts to limit the size of myocardial infarcts. Ann Intern Med 1981;95:736-761. Fletcher A, Sherry S, AlkJaerslg N, SmymloUs F, Jlck S. Maintenance of a sustained thrombolytic state in man. II. Clinical observations on patients with myocardial infarctions and other thromboembolic disorders. J Clin Invest 1959;38:1111-1119. European Working Party. Streptokinase in recent myocardial infarction: a controlled multicenter trial. Brit Med J 1971;3:325-331. European Cooperative Study Group for Streptokinase Treatment in Acute Myocardial Infarction. Streptokinase in acute myocardial infarction. N Engl J Med 1979;301:797-802. Spann JF, Sherry S, Carabello BA, Mann RH, McCann WD, Gault JH, Gentzler RD, Roaenberg KM, Maurer AH, Denenberg BS, Warner HF, Rubln RN, Malmud LS, Comerota A. High-dose, brief intravenous streptokinase early in acute myocardial infarction. Am Heart J 1982;939945. Neuhaus KL, Tebbe U, Sauer G, Kreuzer H, Kosterlng H. High dose intravenous streptokinase in acute myocardial infarction. Clin Cardiol 1983;6:426-434. Ganz W, Geft I, Shah PK, Lew AS, Rodrlguez L, Weiss T, Maddahl J, Berman DS, Charuzl Y, Swan HJC. Intravenous streptokinase in evolving acute myocardial infarction. Am J Cardiol 1984;53:1209-1216. Boucek RJ, Murphy WP, Sommer LS, Voudoukls IJ. Segmental perfusion of the coronary arteries with fibrinolysin in man following a myocardial infarction. Am J Cardiol 1960;6:525-533. Mathey DG, Kuck KH, TIIsner V, Krebber HJ, Blelfleld W. Nonsurgical coronary artery recanalization in acute transmural myocardial infarction. Circulation 1981;63:489-497. De Feyter PJ, van Eenlge MJ, van der Wall EE, Bezemer PD, van Engelen CLJ, Funke-Kupper AJ, Kerkkamp HJJ, Vlsser FC, Roos JP. Effects of spontaneous and streptokinase-induced recanalization on left ventricular function after myocardial infarction. Circulation 1983;67:1039-1044. Van De Werf F, Ludbrook PA, Bergmann SR, Tiefenbrunn AJ, Fox KAA, De Geest H, Verstraete M, Collen D, Sobel BE. Coronary thrombolysis with tissue-type plasminogan activator in patients with evolving myocardial infarction. N Engl J Med 1984;310:609-613. Hutchlns GM, Bulkley BH. Infarct expansion versus extension: two different complications of acute myocardial infarction. Am J Cardiol 1978;41: 1127-1132. Marmot A, Sobel BE, Roberts R. Factors presaging early recurrent myocardial infarction ("Extension"). Am J Cardiol 1981;48:603-610. Baker JT, Bramlet DA, Lerster RM, Harrison DG, Roe CR, Cobb FR. Myocardial infarct extension: incidence and relationship to survival. Circulation 1982;65:918-923. Smllh ER, Redwood DR, McCarron WE, Epstein SE. Coronary artery occlusion in the conscious dog. Effects of alterations in arterial pressure produced by nitroglycerin, hemorrhage, and alpha-adrenergic agonists on the degree of myocardial ischemia. Circulation 1973;47:51-57.

51. Epstein SE, Borer JS, Kent KM, Redwood DR, Goldsteln RE, Levitt B. Protection of ischemic myocardium by nitroglycerin: experimental and clinical results. Circulation 1976;53:1:1-191-1-197. 52. Borer JS, Redwood DR, Levitt B, Cagln N, Blanchl C, Vallln H, Epstein SE. Reduction in myocardial ischemia with nitroglycerin or nitroglycerin plus phenylephrine administered during acute myocardial infarction. N Engl J Med 1975;293:1008-1012. 53. Come PC, Flaherty Jr, Baird MG, Rouleau JR, Weisfeldt ML, Green HL, Becker L, Pill B. Reversal by phenylephrine of the beneficial effects of intravenous nitroglycerin in patients with acute myocardial infarction. N Engl J Med 1975;293:1003-1007. 54. KIm YI, Williams JF. Large dose sublingual nitroglycerin in acute myocardial infarction: relief of chest pain and reduction of Q wave evolution. Am J Cardiol 1982;49:842-848. 55. Bussman W-D, Passok D, Seldel W, Kaltenbach M. Reduction of CK and CK-MB indexes of infarct size by intravenous nitroglycerin. Circulation 1981;63:615-622. 56. Hill JA, Feldman RL, Peplne CJ, ConU CR. Randomized double-blind comparison of nlfedipine and isosorbide dinitrate in patients with coronary arterial spasm. Am J Cardiol 1982;49:431-438. 57. Relmer KA, Lowe JE, Jennlngs RB. Effect of the calcium antagonist verapamil on necrosis following temporary coronary artery occlusion in dogs. Circulation 1977;55:581-587. 58. Bssarnan WD, Seher W, Grungraa M, Klepzlg H, Kaltenbach M. Reduction of CK and CK-MB indexes of infarct size by intravenous verapamil (abstr). Circulation 1982;66:1h11-2. 59. Epstein SE, Kent KM, Borer JS, Goldsteln RE, Smith HJ, Capurro NL. Vasodilators in the managementof acute myocardial infarction. Adv Cardiol 1978;22:138-146. 60. Pearlman AS, Engler RL, Goldstein RA, Kent KM, Epstein SE. Relative effects of nitroglycerin and nitroprusside during experimental acute myocardial ischemia. Eur J Cardiol 1980; 11:295-313. 61. Chlarlello M, Gold HK, Lelnbach RC, David MA, Maroko PR. Comparison between the effects of nitroprusside and nitroglycerin on ischemic injury during acute myocardial infarction. Circulation 1976;54:766-773. 62. Cohn JN, Francis GS, Archibald D, Trlstanl F, Fletcher F, Montero A, Clntron G, Clarke J, Hger D, Saunders R, Cobb F, Sm#h R, Leob H, Settle H. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure. N Engl J Med 1982;306:1129-1135. 63. Passamanl ER. Nitroprusside in myocardial infarction. N Engl J Med 1982;306:1168-1170. 64. Smith JB, Arakl H,.Lefer AM. Thromboxane A2, prostacyclin and aspirin: effects on vascular tone and platelet aggregation. Circulation 1980;62: suppl V:V-19-V-25. 65. Packhasm MA, Mustard JF. Pharmacology of platelet-affecting drugs. Circulation 1980;62:suppl V:V-26-V-41. 66. National Institutes of Health Concensus Development Conference. Thrombolytic therapy in thrombosis. Ann Intern Med 1980;93:141-144. 67. Koch-Wessr J, Sharma GVRK, Celia G, Parisl AF, Sasahara A/~. Medical intelligence drug therapy. N Engl J Med 1982;63:1268-1276. 68. Sharer KE, Santoro SA, Sobel BE, Jaffe AS. Monitoring activity of fibrinolytic agents. Am J Med 1984;76:879-886. 69. Meltzer RS, van den Brand M, Serruys PW, Florettl P, Hugenholtz PG. Sequential intracoronary streptokinase and transluminal angioplasty in unstable angina with evolving myocardial infarction. Am Heart J 1982; 104:1109-1111. 70. Goldberg S, Urban PL, Greenspon A, I~benthal M, Wallnsky P, Maroko P, Muza B, Harbord T, Calcagno J. Combination therapy for evolving myocardial infarction: intracoronary thrombolysis and percutaneous transluminal angioplasty. Am J Med 1982;72:994-997. 71. Myer J, Merx W, Schmltz H, Erbel R, Kiesslich T, Dorr R, Lamberlz H, Bethge C, Krebs W, Bardos P, Mlnale C, Messmer BJ, Effert S. Percutaneous transluminal coronary angioplasty immediately after intracoronary streptolysis of transmural myocardial infarction. Circulation 1982;66: 905-913. 72. Yasuno M, Salto Y, Ishlda M, Suzuki K, Endo S, Takahashl M. Effects of percutaneous transluminal coronary angioplasty: intracoronary thrombolysis with urokinase in acute myocardial infarction. Am J Cardiol 1984;53:1217-1220. 73. Berg R, Kendall RW, Duvolsin GE, Gangl JH, Rudy LW, Everhad FJ. Acute myocardial infarction: a surgical emergency. J Thorac Cardiovasc Surg 1975;70:432-439. 74. Bolookl H. Myocardial revascularization after acute myocardial infarction. Arch Surg 1976;111:1216-1224. 75. DeWood MA, Spres J, Notske RN, Lang HT, Shields JP, Simpson CS, Rudy LW, Grunwald R. Medical and surgical management of myocardial infarction. Am J Cardiol 1979;44:1356-1364. 75. Phillips SJ, Kongtahworn C, Zeff RH, Benson M, lannone L, Brown T, Gordon DF. Emergency coronary artery revascularization: a possible therapy for acute myocardial infarction. Circulation 1979;60:241-246. 77. Selinger SL, Berg R, Leonard JJ, Grunwald RP, O'Grady WP. Surgical treatment of acute evolving anterior myocardial infarction. Circulation 1981;64:supp111:11-28-11-33. 78. Phillips SJ, Zeff RH, Kongtahworn C, Skinner JR, lannone L, Brown TM, Wlckemeyor W, Gordon DF. Surgery for evolving myocardial infarction. JAMA 1982;248:1325-1328. 79. Epstein SE, Palmed ST, Patterson RE. Evaluation of patients after acute myocardial infarction: indications for cardiac catheterization and surgical intervention. N Engl J Med 1982;307:1487-1492.