Current status of antithrombotic therapy in cardiovascular disease

Current

Status of Antithrombotic Therapy Cardiovascular Disease

in

Paul H. Rogers and Sol Sherry

T

HE introduction of heparin and the coumarins into clinical medicine representeda major therapeutic advance. Thesewere potent anticoagulants whose pharmacologic effects in vivo could be readily demonstrated, and they offered promise for the prevention and managementof a great many clinical problemsin which thrombosis and embolism appeared to play a primary or secondary role leading to seriousmorbidity and mortality. Yet, more than 30 yr later and after usage in millions of patients, considerable confusion exists as to their value under a variety of circumstances.Also, their effect in reducing the incidence of thromboembolism has not been evident, for if anything, the latter is more common today. This paradox can be traced to many factors suchaslack of use under circumstancesin which they are most effective, introduction of techniques and procedures that enhance the risk of thromboembolism, and an aging population at high risk of such complications. Experience with these agentshas taught us that anticoagulants are most useful in inhibiting those thrombi that are primarily composed of a fibrinred cell coagulum (coagulation thrombi) such as are found in venous and some intracardiac thrombi, whereasthey appear to be of relatively little value in preventing those thrombi composed primarily of platelet masses (platelet thrombi). This article representsan interpretative review and personalrecommendationsfor antithrombotic therapy in selected cardiovascular states. It also contains a brief commentary on the pathogenesis of thromboembolism and the pharmacologicprinciples behind the use of both anticoagulantsand antiplatelet agents.

From the Department of Medicine and the Specialized Center for Thrombosis Research, Temple University School of Medicine, Philadelphia, Pa. Reprint requests should be addressed to Dr. Sol Sherry, Department of Medicine, Temple University fiospital, Philadelphia, Pa. 19140. 0 1976 by Grune & Stratton, Inc.

Progress

in Cardiovascular

Diseases,

Vol.

XIX,

No.

PATHOPHYSIOLOGY THROMBOEMBOLISM

OF

A rational approach to antithrombotic therapy must be basedon plausible pathogenetic mechanisms. The body has a beautifully integrated system of checks and balances ‘hat allows for the fluidity of blood on the one hand but that is armed for prompt and appropriate responseto injury or hemorrhageon the other. A disturbancein this balance can lead to hemorrhage or inappropriate thrombosis. Platelets play a primary role in the arrest of bleeding from disrupted blood vessels.They have the unique capacity to adhere to denuded endothelium with its exposed subintimal collagen. Adherence may be readily reversible,but often stimulates the platelets to swell and expel cytoplasmic granules containing concentrated ADP and other substances,leading to a change in their surface characteristics and the subsequentaggregation of more platelets. A smaI1“white” thrombus nidus thus sealsthe endothelial disruption. In addition, platelets extrude factors (e.g., platelet factor III), which enhancescoagulation, and they alsoprovide a protective surfacewhere clotting factors become activated and local fibrin formation ensues.This fibrin stabilizes the platelet thrombus and then provides a surface conducive to further clotting from the passingblood; in the process,a platelet thrombus is then converted to a mixed thrombus. Coagulation,like platelets, provides a physiologic defense againsthemorrhage. The classicalconcept of the mechanisminvolved includes the activation of a seriesof clotting factors or procoagulantsthat act in sequenceleading to fibrin formation (Fig. I). Activation of this “cascade” may occur via art,extrinsic pathway (initiated by thromboplastic substancesliberated from traumatized tissue or disrupted blood vessels)or by the intrinsic system (initiated by contact with an abnormalsurface and accelerated by platelet phospholipids). Minute quantities of activated coagulation enzymes probably are constantly formed in or liberated into the circulation, but this is counterbalancedby several natural inhibitors (primarily antithrombin III).

3 (November/December),

1976

235

236

ROGERS

INTRINSIC

xp XI

'

>

XIa ANTITBROMBIN

*1x

t,

IX.3 I I I m *x

III

EXTRINSIC

ANTITHROMBIN

III >

VIII,

SYSTEM

*VII I I

i PLATELETS,

Xa I

Ca

f

m PROTHROMBIN

ANTITHROMSIN '

)

III

THROMBIN I ANTITHROMBIN

FIBRINOGEN

1.

SHERRY

SYSTEM

XII---+

Fig. heparin

AND

Simplified potentiation.

schema of The asterisks

intrinsic identify

and extrinsic factors that

coagulation are inhibited

When activation of the system predominates, fibrin forms, becomes further stabilized through crosslinking, and is organized into a network entrapping blood cells. All types of blood cells are present in the fully developed thrombus, but red cells form the bulk of it, giving the characteristic appearance of a red clot. There is a delicate balance between physiologic hemostasis and pathologic thrombosis. Vascular damage, stasis, and a hypercoagulable tendency are important predisposing factors to the pathologic state. Vascular injury readily activates platelets to stick and aggregate and is the most prominent factor in the pathogenesis of arterial thrombosis. Stasis is a common prerequisite for the development of a predominantly red thrombus; also along with turbulence, it is important in converting a platelet thrombus to a mixed or platelet-coagulation thrombus. A systemic hypercoagulable state is poorly defined, but seems to be important in certain groups of patients. Two types may be distinguished: 1) an increasedpredisposition to thrombosis by virtue of the presenceof hyperreactive platelets or of a preexisting imbalancein the coagulation system as in constitutional deficienciesin antithrombin III (the main plasmainhibitor to active coagulation enzymes), or excessesof factors V and VIII, or the presenceof certain abnormal fibrinogens (dysfibrinogenemias); and 2) statesin which activated factors are in the circulation fol-

>

FIBRIN

III

-+> THROMBIN,

systems. The heavy by coumarin drugs.

bands

XIII,

CROSS LINKED Ca indicate

principle

FIBRIN

sites

of

lowing trauma or necrosisbut are only capable of triggering thrombosis at a site of stasis(e.g., the postoperative state, following acute myocardial infarction, etc.). Thrombi can be categorized into three general types: platelet, coagulation, and intermediate or mixed; such a classification is useful in considering the rationale for various modes of therapy. Thrombi forming in the presence of rapid flow and high pressure(e.g., on arterial intimal lesions) tend to be composed primarily of platelets, whereas thrombi forming in areasof low pressure and slow flow, (e.g., in the veins) are primarily of the coagulation type. The latter is also common in atonic atria with their associatedstasis.Intermediate or mixed thrombi are commonly associated with those states in which rapid flow, turbulence, and static zones are present together. Thus, they are frequently observedon the endocardialsurface of transmurally infarcted myocardium and in association with stenotic arterial vessels. Predominantly white (platelet) thrombi are often preventable by therapy with drugsinhibiting platelet function. In contrast, anticoagulantslimit the progressionand recurrenceof coagulation thrombi. Mixed thrombi may be prevented either by anticoagulant therapy or antiplatelet agents depending on the factors involved, but combined antiplatelet and anticoagulation may be necessaryfor resistant cases.

ANTITHROMBOTIC

237

THERAPY

PHARMACOLOGIC PRINCIPLES THE USE OF ANTITHROMBOTIC

BEHIND AGENTS

Heparin Heparin, the first anticoagulant purified for clinical use, is a mucopolysaccharide probably produced by mast cells throughout the body but which is most concentrated in the lung, liver, and intestines.Commercialpreparationsin this country are produced from porcine intestines and bovine lung; whether significant differencesexist between these two types of preparationsin vivo is still controversial. The major anticoagulant action of heparin is to enhance and accelerate the activity of antithrombin III, a plasmaglobulin which is the major natural inhibitor of activated coagulation factors’ (Fig. 1). This inhibitor inhibits thrombin aswell as activated factors IX, X, and XI, enzymesof critical importance in the earlier stepsof the coagulation sequence.Since small amounts of the earlier coagulation enzymes(activated factors IX, X, XI) eventually lead to large amounts of thrombin, heparin in relatively low concentration can prevent the initiation of clotting, while much higher levelsare required to inhibit fibrin formation once thrombin hasbeenelaborated.This pharmacologicconsideration forms the basisfor the use of low-doseheparin for the primary prophylaxis of venous thromboembolismin high risk situations.’ Administration of heparin must be parenteral and is given by intravenous bolus, intravenous infusion, or subcutaneousinjection. Bolus therapy should be given every 4-6 hr, sincethe half-life of heparin in the circulation is l-2 hr; with subcutaneousadministration (becauseof slow absorption), the doseinterval may be increasedto 8-12 hr. As little as 10,000 units daily subcutaneouslycan be effective when used prophylactically, but 20,00060,000 units administeredintravenously daily, depending on mode of administration and kinetics of heparin clearance,are usually required to treat an establishedthromboembolism. The goal of anticoagulant therapy is to use enough drug to prevent thrombus propagation yet to limit the risk of a hemorrhagic complication. Since patient responseto a given doseof heparin is variable, severallaboratory testshave beenusedto help individualize dosage.The Lee-White clotting time has beenpopular in this regard but is a lessreliable and reproducible test than the activated partial thromboplastin time, which is currently the

test of choice (in somecentersan activated wholeblood clotting time is preferred). The value elf regulating heparin dosageusing these tests was not well defined until Basuet a1.3showedthat patients with recurrent thromboembolism, while receiving infusions of heparin, had partial thromboplastin times of less than 14 times the control value. Bleeding, which is the most seriouscomplication of heparin therapy and occurs in 5%-10% of patients, is not predictable (at present, monitoring is more important for assuringthe adequacy of anticoagulation than for avoiding bleeding), but certain risk factors have been identified. These include severehypertension, invasive proceduresor intramuscular injection, underlying lesions prone to hemorrhage, preexisting constitutional or acquired (including drug-induced) coagulation or platelet defects and prolonged periods of blood incoagulability (e.g., following intermittent mtravenous bolus therapy). In regard to the latter, recent studies indicate that constant infusions of heparin, so as to continuously maintain the activated partial thromboplastin time at approximately twice normal and to avoid long periods of incoagulability, is associatedwith a much lower incidence of bleedingcomplications.3,4 Consequently, when treating thromboembolism, one should adjust the heparin doseto maintain the partial thromboplastin time between 11 and 24 times control. The timing for testing patients is crucial, since extreme prolongation of test results will be found during the first 2 hr after a large bolus of heparin. Testing may be done at any time during constant infusion therapy but should be done within 1 hr before the next intravenous bolus or 2 hr before the next subcutaneousdose.When low doseheparin (i.e., 5000 units subcutaneously every 8-12 hr) is used, testing is usually unnecessary, sincesuch dosagedoesnot significantly affect the usualcoagulation assays. Coumarinsand Indanediones The isolation of the hemorrhagicfactor in sweet clover diseaseof cattle led to the development of two groups of oral anticoagulants, the indanediones and coumarins. The latter is predominantly usedin this country and further discussionwill be concerned primarily with warfarin (Coumadin@), the most popular coumarin. Oral anticoagulantsdo not have direct action on the coagulation system but inhibit the synthesisof

238

normal vitamin K-dependent clotting factors II (prothrombin), VII, IX, and X (Fig. 1). Antigenitally similar but inactive proteins are formed in an incompletely understood way. The levels of the normal procoagulants fall with therapy as a function of their half-life, which is shortest for factor VII and sequentially longer for factors IX, X, and II.5 Warfarin is well absorbed orally, thus offering a significant advantage over heparin for chronic therapy. The early practice of initiating anticoagulant therapy with a large loading dose is no longer necessary. O’Reilly and Aggele? reported that loading dose therapy caused rapid reduction of factor VII activity with prolongation of prothrombin time and danger of hemorrhage even though the levels of the other vitamin K-dependent factors were still relatively normal. Accordingly, therapy is now initiated with lo-15 mg of warfarin daily, and the subsequent maintenance dose is determined by prolongation of the prothrombin time. This dose usually ranges from 3 to 10 mg daily and is influenced by a complex interaction between vitamin K availability, hepatic function, plasma protein binding, and other drugs being used. Drug interactions are numerous, for various agents may influence binding, vitamin K metabolism, or hepatic functiom7 they should be considered whenever the maintenance dose of warfarin is unusual or changes significantly, or when a new medication is contemplated (physicians should keep a list of drug interactions for quick reference and patients should be advised to take only those prescription or nonprescription medications approved by the physician). Reliable periodic laboratory testing is mandatory when using oral anticoagulant therapy. The prothrombin time is a simple test that can be well standardized and is recommended. When therapy is initiated, the test is usually done daily, but can be decreased to once every 2-3 wk or longer in patients on a stable maintenance dose. The therapeutic objective is to maintain the prothrombin time from 1; to 24 times the control value in seconds; this range is effective in preventing thrombosis and is relatively free of hemorrhagic complications. Bleeding is by far the most important complication of oral anticoagulant therapy, occurring in lO%-20% of cases of prolonged therapy.*-” This figure varies considerably in different series depending on the degree and duration of anticoagula-

ROGERS

AND

SHERRY

tion as well as the population treated. In a Veterans Administration study of 999 patients anticoagulated for 1 mo, there were no deaths from hemorrhage; l1 however, in other long-term studies, there has been a 0.5%-1.0% mortality from hemorrhage. r2-r4 The most frequent sites of bleeding are urinary, gastrointestinal, nasopharyngeal, and cutaneous, but almost any site can be affected.“‘15 Intracerebral hemorrhage occurs infrequently but is the most common hemorrhagic cause of death in patients treated for cerebrovascular accidents. Most hemorrhagic complications are minor and transient and require adjustment of dosage rather than discontinuation of therapy. Contraindications to coumarin therapy are usually relative and their use must be weighed against the strength of the indication. Allergy is rarely a problem. Bleeding diathesis, active hemorrhage, recent severe head trauma, and uncontrolled hypertension are major contraindications. One should also withhold therapy in the presence of uncontrolled gastrointestinal or genitourinary bleeding, but a history of such in the past must be considered in light of the potential benefit of therapy. An acute cerebrovascular accident may be a good reason to withhold anticoagulants for up to a week, since a relatively bland cerebral infarct may be converted to an expanding hemorrhagic infarct by this therapy; embolic cerebrovascular accidents, while representing an indication for anticoagulation, nevertheless may pose a problem in this regard. Bacterial endocarditis commonly leads to cerebral emboli, but the associated vasculitis predisposes to hemorrhage with anticoagulation. Liver and renal disease are relative contraindications to anticoagulant therapy. Pericarditis unrelated to myocardial infarction is usually considered a contraindication since there is a fear of tamponade. However, the risk of tamponade is not increasedin patients with pericarditis associated with acute myocardial infarction;” its presence under this circumstance is not considered a contraindication to anticoagulation. Chronic anticoagulation on an ambulatory basis requires patient cooperation to minimize a hemorrhagic risk. Therefore, a psychotic or otherwise unreliable or uncooperative patient should not receive this therapy unless he can be strictly supervised by a reliable guardian. A physician prescribing such therapy should be well trained in its use, realizing the complexity of control as it re-

ANTITHROMBOTIC

lates to concurrent diseases, drug interactions, and laboratory tests. Finally, a reliable laboratory is essential since the usual therapeutic dose borders on the toxic hemorrhagic dose, and frequently must be checked by an appropriate laboratory test. Antiplatelet

239

THERAPY

Drugs

Several drugs that .alter platelet function offer promise as useful antithrombotic agents; they are administered orally and have acceptable therapeutic-to-toxic ratios. Aspirin prevents platelets from aggregating by irr-eversibly inhibiting the platelet ADP release reaction (presumably by interference with prostaglandin synthesis in the platelet). This effect is possible with doses (0.6-l .2 g daily) commonly used for analgesic purposes, and the action persists during the entire life span of the affected platelet. Dipyridamole is a phosphodiesterase inhibitor whose action in platelets is presumably to prevent the normal breakdown of cyclic AMP,16 interfering with the cells’ contractile mechanism. Originally introduced as a vasodilator for the treatment of angina, it subsequently was shown to limit experimentally induced platelet thromboembolism in animal models.“~‘* Platelet aggregation does not appear to be affected, and data concerning decreased platelet adhesiveness has been conflicting. l9 Sulfinpyrazone is a phenylbutazone analog originally introduced as a uricosuric agent that was popular in the treatment of gout until probenecid became available. Like aspirin, it inhibits the platelet release reaction but its mechanism may be different; the suggestion also has been made that it has a protective effect on vascular endothelium.20 Other drugs such as clofibrate, dextran, and hydroxychloroquine inhibit platelet function to a variable extent, but they have not evoked as much interest from an investigational standpoint as has aspirin, dipyridamole, and sulfinpyrazone. Antithrombotic therapy with agents such as aspirin, dipyridamole, and sulfinpyrazone needs less strict supervision than that required with heparin or the coumarins. Bleeding complications occur rarely unless patients have an underlying hemorrhagic tendency. Therefore, these agents should not be used in patients with problems such as hemophilia or von Willibrand’s disease. Allergic reactions, although uncommon, can occur with any of these agents. Dipyridamole often causes head-

aches that are dose-related. Aspirin and sulfinpyrazone are gastric irritants and thus are contraindicated when active peptic ulcer disease is present. Relatively common nonspecific gastrointestinal discomfort can be minimized by prescribing the drugs with food. Since sulfinpyrazone is a potent uricosuric agent, adequate fluid intake and occasionally alkalinzation of the urine is advisable to prevent uric acid nephropathy when uric acid levels are elevated. Also, acute gout is occasionally precipitated when patients with high uric acid levels are initially treated with a uricosuric agent. While minor complaints are frequent, serious reactions to antiplatelet agents are rare. However, one should remember that when antiplatelet agents, especially aspirin2’ are given in combination with anticoagulants, they may enhance the bleeding tendency associated with the latter’s use. ANTITHROMBOTIC CARDIOVASCULAR

THERAPY STATES

IN

CongestiveHeart Failure Patients with congestiveheart failure have more frequent problems with venous than arterial thromboembolism, probably related to stasisproduced by relatively high venous pressureand bed rest. The highest risk is associatedwith immobilization from heart failure; patients commonly develop deep venous thrombosis during the first week of hospitalization. The clinical diagnosisof pulmonary embolism in patients following admission for severe heart failure varies from 6% to 16%,22-25but in patients dying from heart failure, emboli are found in from 35% to 66% of autopsied patients.22a26-27Reasonable estimates are that 15%-25% of patients admitted to the hospital for treatment of heart failure will have a thromboembolic complication and a significant proportion (2%-3%) will die as a result of pulmonary embolism. The risk is even greater in patient with severe biventricular failure, prolonged bed rest, history of previous phlebitis, or low cardiac output syndrome. In 1952, Griffith and associates25 reported the benefit prophylactic anticoagulant therapy offers patients hospitalized for congestive heart failure. Their controlled study of 629 patients showed a reduction of from 16% to 2% in the clinical incidence of thromboembolism, and this was similar in patients with underlying rheumatic, hyperten-

240

sive , and coronary heart disease. Harvey and Finch24 found similar results with a reduction from 21% to 2% comparing a dicumoral treated with a control group. Mortality in this study was also decreased from 17% to 9% with treatment. Other trials have found a similar reduction in morbidity and mortality using anticoagulant ther22,23 apy. Recommendations. The available data indicate that anticoagulant therapy in patients with severe or intractable congestive heart failure is beneficial. In the acute setting, a short course of heparin or warfarin is effective; preliminary data suggest that low-dose heparin may be effective prophylaxis without as much hemorrhagic potential as full anticoagulation.28 However, in patients with chronic or recurrent biventricular failure, long-term therapy with an oral anticoagulant, (e.g., warfarin) is advisable, providing no contraindications are present.

Cardiomyopathy Primary heart muscle disease or cardiomyopathy includes many separate entities. A further gross subclassification separates “thin-walled” cardiomyopathy (such as that related to alcoholism) from “thick-walled” hypertrophic cardiomyopathy. Thromboembolism in these patients can be related to congestive heart failure and atria1 fibrillation as in any patient with cardiac disease, but there is an additional significant incidence of mural thrombosis and subsequent systemic embolization. In a group of 48 patients with alcoholic cardiomyopathy studied by McDonald et al.,29 thromboembolism was the most striking complication other than congestive heart failure. Twelve patients had pulmonary emboli that were not necessarily related to periods of bed rest, and there were three cerebral, two popliteal, and two renal emboli diagnosed clinically. Some of the patients received anticoagulants but the dose and duration varied. Of the 19 fatal cases, there were mural thrombi adherent to areas of endocardial thickening in five out of I4 autopsy cases. Pulmonary emboli were noted in seven, and evidence of renal emboli in three. A similar study of 57 patients with alcoholic cardiomyopathy by Demakis and associates3’ revealed that all seven of the patients who came to autopsy had mural thrombi. They also reported a similar incidence of thromboembolism in peripartum cardiomyopathy.31

ROGERS

AND

SHERRY

There are no randomized or controlled studies to prove the prophylactic efficacy of antithrombotic therapy in patients with cardiomyopathy. However, evidence gathered in patients with mural thromboembolism secondary to other forms of heart disease can be extrapolated to those with primary muscle disease. Recommendation. Since anticoagulation has been shown to inhibit venous and mural thromboembolism associated with other cardiovascular disorders, most moderate or severely affected cardiomyopathy patients should be maintained on chronic oral anticoagulant therapy. However, the data is insufficient to anticoagulate those with clinically mild disease unless they have other thromboembolic risk factors.

Rheumatic Disease Thromboembolism is a major cause of morbidity and mortality in chronic rheumatic heart disease, affecting at least 20% of patients.32 Deep venous thrombosis, pulmonary embolism, and systemic embolism are common complications; systemic embolization occurs more often with rheumatic than with other types of heart disease, especially when mitral stenosis is the predominant lesion. Patients with predominant aortic valve disease or mitral insufficiency are less frequently affected by systemic emboli.33-35 Of 194 patients who sustained an arterial embolus, Daley and associates36 found that 50 had pure mitral stenosis whereas only three had pure mitral insufficiency. Atria1 fibrillation and age are independent risk factors.31s36 Casella and associates3’ found that the mean age was 5 yr higher in those patients who had had an embolus; the incidence increased from 1.l% in the third to 38% in the seventh decade. The age of onset of the first overt embolus was most commonly the fourth decade but occurred occasionally in patients under 20 or over 70 yr of age.36 Clinical status is roughly correlated with most emboli occurring in class III and IV patients, although class I and II patients sustain emboli with significant and unpredictable frequency. Embolism at the time of valvulotomy or valve replacement is a disturbing complication occurring in from 6% to 10% of cases.38-40 Cerebral emboli are the most common systemic type, usually having a dramatic appearance with a highly mortality and morbidity.36,41y42 Less common are peripheral and visceral arterial emboli.

ANTITHROMBOTIC

THERAPY

Embolism is the primary cause of death in from 16% to 33% of patients who die of rheumatic heart disease;38-40 the mortality from the first systemic embolus is about 15%.32,38 Recurrent embolism frequently occurs within a year after the first episode, carrying a 42% mortality at this time.32,33,36

There is general agreement that anticoagulation markedly decreases the incidence of thromboembolism in a patient with rheumatic heart disease.33,43,44 The major therapeutic question is which group of patients has a risk of thromboembolism to counterbalance the risk of drug-related complications. Although stringently designed studies have not been performed, the data available are so impressive that most investigators do not feel that a controlled study of high-risk patients such as those with mitral stenosis and atria1 fibrillation can be justified. Recommendations. Patients with mitral stenosis should be maintained on chronic warfarin therapy if additional thromboembolic risk factors are present. These include age greater than 40 yr, recurrent or chronic atria1 fibrillation, congestive heart failure, shortened platelet survival, or severe symptoms. Anticoagulant prophylaxis in patients who have moderate mitral stenosis and no additional factors may be indicated, but the risk/benefit ratio is not as compelling in this group (contraindication to oral anticoagulation and physician familiarity with the therapy should be considered). Data to indicate that patients with rheumatic heart disease other than mitral stenosis should routinely be maintained on chronic anticoagulation are not available. Factors such as congestive heart failure and atria1 fibrillation should be considered independently and may give reason in the individual case to recommend this form of therapy.

Atria1 Fibrillation The development of atria1 fibrillation in patients with mitral stenosis heralds a period of high risk for thromboembolism that is independent of age and functional class.34J37Y45Abernathy and Willis32 reviewed the literature related to thromboembolic complications of rheumatic heart disease and found atria1 fibrillation to be a risk factor independent of the severity of the valve lesion. Their autopsy review revealed that 87% of patients with atrial thrombosis had atria1 fibrillation. Patients with arterial emboli have an 82% incidence of atria1

241

fibrillation with an increased risk of embolism at the time of onset of atria1 fibrillation.32,33 Nonrheumatic heart disease with atria1 fibrillation is not clearly associated with a high incidence of atria1 thrombi unless there is cardiomegaly or congestive heart failure in addition.46 The majority of emboli occur within 1 yr of onset of atria1 fibrillation in patients with rheumatic disease, and there are frequent recurrences wfthin this year.33 This may be related in part to the frequent paroxysmal nature of the arrhythmia near its time of onset; thrombi form during the relative stasis associated with atria1 fibrillation and are dislodged by the return of forceful atria1 contraction. Artificial cardioversion is also associated with systemic embolization, which is usually delayed from 6 hr to 6 days after a successful conversion.46 There is similar risk using pharmacologic (e.g., digitalis and quinidine) or electrical cardioversion with an incidence varying from 2% to 6%.47-5’ Bjerkelund and Orning47 published the only large prospective trial evaluating the efficacy of anticoagulant therapy in preventing embolism after cardioversion. They followed the course of 228 patients admitted to their hospital on anticoagulants and that of 209 patients who were not on therapy when admitted. Although there were more patients in the treated group with previous emboli and/or mitral stenosis, this group had a 0.8% incidence of postcardioversion emboli, which was significantly less than the 5.3% incidence in the control group. This report has been questioned by some for such a high incidence of embolism in the controls. Korsgren and associates 52 also recommended anticoagulation after having no emboli complicate the course of 138 patients who were anticoagulated for at least 3 wk prior to attempted electrical cardioversion. Recommendations. Chronic anticoagulation is recommended for patients with sustained or paroxysmal atrial fibrillation who have mitral stenosis, cardiomegaly (especially left atria1 enlargement), or congestive heart failure. Prior to attempted elective cardioversion of patients in these categories, anticoagulation should be maintained for 2-3 wk. Emergency therapy for uncontrolled ventricular rate response to atria1 fibrillation should not be delayed for anticoagulation. The occasional patient with idiopathic, recent-onset atria1 fibrillation but no other evidence of heart disease (no evidence of cardiomegaly, valve disease, or heart failure) can

242

ROGERS

Table

1.

Coronary With

Thrombosis Coronary No.

Author Friedbergs” Foords5 Millers6

(yr)

of Patients

(1964)

Kurland58 Spain59

(1965) (1970)

Robert@ Chapmancl

*Sudden

TM13

SMI8

93(90)

50(20)

18(94)

20(10)

74(54) 303(91) 170(97)

9(O)

153(78) 315(87)

127(55) 200(54)

303(161

(I 972) (I 974)

Chandler62

(% Thrombosis)

Mlt

SD*

(I 939) (1948) (1951)

Ehrlichs7

Associated

Deaths

24(10)

(1974)

36(55)

death.

tMyocardial STransmural SSubendocardial

infarction, myocardial

unspecified infarction.

myocardial

type.

infarction.

be cardioverted without anticoagulation. In addition, patients who have coronary disease without hemodynamic decompensation need not be anticoagulated prior to attempted cardioversion. Acute Myocardial Infarction For many years following Herrick’s description in 1912 of patients dying of acute myocardial infarction, “coronary thrombosis” was considered the cause of acute coronary deaths.53 More recent studies have challenged this viewpoint. The incidence of thrombi varies greatly from one series to another (Table 1); this is in part related to autopsy technique, but the major determinant appears to be the mode of death: sudden death, subendocardial necrosis, or transmural infarction. Patients who have died suddenly or have focal areas of necrosis limited to the subendocardial half of their myocardium have a low incidence of coronary thrombosis (0%-20%). In contrast, the incidence in those patients dying with a transmural (more than half of the myocardial thickness involved) infarction is very high (90%-97%). Roberts and Buja6’ differ from others, however, in reporting only a 54% incidence of thrombi in patients dying of transmural infarction. The low incidence of coronary thrombosis in cases with sudden death or subendocardial necrosis is not surprising; arrhythmia probably causes most sudden deaths as well as mortality associated with subendocardial necrosis. This does not preclude the possibility, however, that platelet thromboemboli may cause ischemia and precipitate myocardial irritability.61a63 Thromboemboli of this type

AND

SHERRY

are not likely to be evident at death, since they can break up spontaneously or be rapidly lysed by the fibrinolytic system, which is enhanced both by epinephrine release and/or ischemia. As for transmural infarction, although the incidence of thrombosis is very high, its pathogenetic role remains controversial and is unlikely to be settled soon. The possibilities include the following: I) thrombosis causes the infarction; 2) thrombosis is a contributing factor in the pathogenesis (i.e., ischemia -+ subendocardial necrosis --+ thrombosis --+ development of transmural infarction); and 3) thrombosis is incidental and merely follows the completed infarction. Most investigators believe that thrombosis is pathogenetic and cite: the high incidence of thrombi in patients with transmural infarction; thrombosis is limited to the large epicardial vessel subtending the area of infarction, and is separated by l-2 cm from the infarcted muscle;6’ thrombi are often superimposed on ruptured or eroded plaques;61562,64 and the absence of thrombi at autopsy in some patients could be related either to subsequent resolution or incorporation into the arterial wall. The latter has been demonstrated to occur as early as 2 wk after infarction.65 Roberts,@j who has championed the view that thrombosis does not have a pathogenetic role in myocardial infarction, emphasizes: the absence of thrombi in a significant percentage of patients with transmural infarction; the presence of severe stenoses of the arteries subtending the infarction, which lead to an imbalance between myocardial oxygen supply and demand; and recent observations made with labeled fibrinogen. Erhardt et a1.67 administered 1251-fibrinogen to patients admitted to the hospital with acute transmural myocardial infarction. In seven patients who died, the radioactivity was diffusely present in coronary thrombi. He considered this as evidence that thrombosis results from rather than causes infarction, since a preformed thrombus would not have been labeled throughout. However, others have suggested that fibrinogen can perfuse a preexisting thrombus that may continue to grow and incorporate fibrinogen after the initial occlusion.62 While the significance of coronary thrombosis in the pathogenesis of myocardial infarction remains controversial, patients with acute infarcts are subject to a number of important thromboembolic events. These include both systemic and pulmo-

ANTITHROMBOTIC

THERAPY

Table

Author WrightT3 Greisman74 Tulloch75 Bresnick76

2.

243

Trials

of Acute

Anticoagulant

on Mortality

(vr)

Patient5

(I 948)

800

+

0

175 154 250

+ + +

0 + -I-

430 920 362 800

+ 0 + +

+ 0 0 0

999

+

+

(1948) (1950) (1950)

Holten77 Smith78 Eastman79

(1951) (1951) (1957)

Hilden14 Va Coopll

(1961) (1973)

Prospective

Therapy

Randomized

nary embolism arising from endocardial mural thrombi and pulmonary embolism from complicating deep venous thrombosis. The majority (67%) of patients with transmural myocardial infarction develop endocardial mural thrombi in the area of infarction. 68 Systemic embolization from these thrombi is only a minor contributor to mortality after infarction but is a more important cause of morbidity, occurring in about 6% of patients who are not treated with anticoagulants.” Clinically diagnosed cerebral embolism occurs in about 4%, and peripheral, renal, and mesenteric is recognized less often. A larger percentage, however, can be demonstrated at autopsy but this is to be expected, since some emboli go unnoticed and patients with the largest infarcts and poorest prognoses are at highest risk of thromboembolic complications.6g’70 Venous thrombosis can be demonstrated in approximately 22% of patients after myocardial infarction when the sensitive iz51-fibrinogen testing is used28,71 and the incidence is much higher in those who go into shock or heart failure. The majority of these have occult calf vein thrombi that are of little clinical significance but extension to involve one or more deep veins occurs in approximately 20% of those with calf vein thrombi; this group is at significant risk of pulmonary embolism. The clinical diagnosis of pulmonary embolism in the setting of myocardial infarction is very difficult; often it is confused with recurrent infarction, angina pectoris, pneumonia, and heart failure. Therefore, observations on the clinical incidence of pulmonary emboli during life may be underestimated. In the past, when patients were immobilized for a month or so after a coronary event, embolism probably was more frequent. The 10% mortality rate from pulmonary embolism reported

After

concurrent Controls

Myocardial Double Blind

infarction Mortality

(%I

Control

Treated

+

24

15

0 +

35 41 13 36 25

9 23 19 23 14

42 25 11

20 23 IO

+ + 0 + + -t

by Woods and Barnes in 1941 is inaccurate today, 72 but there is still an overall clinical incidence of approximately 5%.6g,70 Thirty per cent of patients dying after myocardial infarction who do not receive anticoagulant therapy have pulmonary emboli found at autopsy,14 and these are often the primary or an important contributing cause of death; approximately one in 20 hospital deaths following an infarct can be ascribed to a pulmonary embolus. l1 Since most investigators still believe that coronary thrombosis is more than an incidental finding in acute infarction, and other thromboembolism is clearly an important clinical problem, various antithrombotic agents have been used in an attempt to modify the course of acute myocardial infarction both in terms of reducing mortality and for the pi-even tion of the thromboembolic complications. Effects of anticoagulation on mortality. In 1948, Wright and associates73 published the results of the American Heart Association-sponsored study that concluded that oral anticoagulant therapy markedly lowered mortality and morbidity when used for 6 wk following a “coronary thrombosis.” Other early trials agreed with these conclusions and little doubt was expressed for many years that anticoagulation reduced mortality. However, in recent years, a number of studies has failed to show a statistically significant improvement in mortality in patients receiving anticoagulant therapy, although, admittedly, a trend toward increased survival in most of the published studies is evident (Table 2). Furthermore, the earlier positive trials have been criticized severely. Gifford and Feinstein” wrote a critique of the methodology employed in the studies of anticoagulant therapy carried out prior to 1967. They reviewed 32 trials with attention to the fundamental

244

principles of trial design and found most of them deficient in randomization, blindness, and/or concurrent controls. Considering that the evidence in favor of anticoagulation for reducing mortality is shaky, at best, its use particularly in academic medical centers has waned considerably. However, two recent retrospective studies have added fuel to the controversy over the use of anticoagulant therapy for improving mortality following acute myocardial infarction. These epidemiologic reviews have more potential for bias than prospective controlled studies, but nevertheless are very interesting. Modan and associates’r reviewed the records of all patients hospitalized for acute myocardial infarction in Israel in 1966. There was a decrease in mortality from 27.3% to 8.2% in patients receiving heparin and/or coumarin anticoagulation. The care given to these patients differed from the usual care in the United States in that coronary intensive care units were not available. A second retrospective survey was on 1156 patients treated in Maryland hospitals from July 1966 to June 1967.82 The mortality rate was 21 times higher in control patients than in those who received anticoagulants. This difference persisted in university as well as community hospitals, whether or not intensive care units were used, and regardless of risk factors such as arrhythmia, congestive heart failure, and shock. There was an inverse correlation between the percentage of patients receiving such therapy and the total mortality in each hospital. The possibility that higher risk patients were systematically not anticoagulated is doubted by the authors but still remains a possibility. Unfortunately, for many reasons, it will be difficult to resolve the controversy over the effect of anticoagulation on the mortality associated with acute myocardial infarction due to the following factors. (1) A clinical trial, no matter how well planned or conducted, will not be free of criticism (at present it is impossible to conduct a perfect trial), and its conclusions can only be assigned a degree of probability of accuracy. Accordingly, any additional trial is unlikely to be accepted as definitive. (2) A carefully designed trial evaluating anticoagulants in acute myocardial infarction, must have accession limited to those patients who satisfy fairly rigid criteria for the presence of a transmural infarct. Meeting these criteria usually requires a period of observation, and such delays could elimi-

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nate the period during which anticoagulants have their greatest effect on mortality (should thrombosis play a secondary but intermediary role in determining the size and extent of many infarcts, this consideration could readily account for the differences reported in retrospective versus prospective studies). (3) Trials usually take several years to be completed and reported; accordingly the results of a study may no longer be applicable should new advances in therapy occur during or after the completion of the study. For example, early mobilization of the acutely infarcted patient practiced in recent years may have reduced significantly the incidence of pulmonary embolism; if so, then some of the benefits reported in the earlier trials may have been obviated by current procedures. Similarly, observations on anticoagulation made prior to the advent of coronary care units and their emphasis on aggressive patient care with modern technology and newer therapeutic agents also may have eliminated many of the deaths previously salvageable by anticoagulants. (4) As the mortality rate is lowered by newer advances, a logarithmic increase in the trial size is required to establish a significant difference. For example, if the mortality rate from an acute transmural infarction in coronary care units is now of the order of lo%, and 2% are due to a thromboembolic complication (20% of deaths), salvage of 80% of the latter by anticoagulants, i.e., a reduction in mortality from 10% to 8.4%, would probably require a trial size of lO,OOO-20,000 patients to establish an acceptable significance. Such a trial (10 to 20 times larger than that previously undertaken) would more than tax the logistic capabilities of any organization and is unlikely to be undertaken. Effects of anticoagulation on thromboembolic complications of acute infarction. Despite the lack of convincing evidence that anticoagulation reduces the mortality of acute infarction, ample justification exists for its use in reducing the morbidity of the illness, through the prevention of its secondary thromboembolic complications, i.e., pulmonary and systemic embolism. Heparin limits mural thrombi in animal models with myocardial infarction,83 and oral anticoagulation has also been shown to decrease the incidence of mural thrombi in patients after myocardial infarction.6g’70 In 1973, the results of the Veterans Administration cooperative clinical trialI were published; this study involved 999 patients

ANTITHROMBOTIC

THERAPY

randomly allocated to control and anticoagulated groups. The trial’s major effort was devoted to the identification of thromboembolic complications rather than focusing primarily on mortality, and it showed significantly fewer thromboemboli in patients treated with heparin and warfarin. There was a reduction in the incidence of strokes from 3.8% in controls to 0.8% in the treated group. Similar results were found clinically with other arterial and pulmonary embolism. Autopsy incidence of pulmonary embolism decreased from 32% to 0% in patients receiving anticoagulants. However, there was no significant decrease in congestive heart failure or recurrent myocardial infarction; and the overall mortality of 9.6% in treated was not significantly different from the 11.2% in the control group. Most of the trials completed since 1948 have found a similar although less accurately documented decreased incidence of thromboembolism in anticoagulated groups. Small subcutaneous doses of heparin (5000 units every 12 hr) have been shown to decrease venous thrombosis following myocardial infarction; however, since no evidence is available that this regimen will inhibit cardiac mural thromboembolism, this therapy cannot be recommended, as yet, as a substitute for conventional anticoagulation. There is also no good data to indicate that antiplatelet agents will reduce venous or mural thromboembolism in this group of patients. Recommendations. Currently available data suggest that full-dose anticoagulant therapy is beneficial after transmural myocardial infarction. This benefit is limited since the prognosis is in large part related to the size of the infarction, the extent of underlying chronic coronary atherosclerosis, and residual myocardial function. However, by preventing 80% of the thromboembolic complications, a small reduction in mortality and an even greater reduction in morbidity may be expected with therapy. In the setting of an uncomplicated transmural myocardial infarction, we suggest initiating oral anticoagulation at the time of admission with or without intravenous heparin for the first 48 hr, and continuing coumarin therapy for 30 days. This should limit mural thrombosis and should prevent most venous thromboembolism. Patients at highest risk (i.e., above age 60, history of previous infarction, the presence of large infarcts, associated shock or congestive failure), have even greater need for this therapy. If complications such as ventricular aneurysm, persistent heart

245

failure, or atria1 fibrillation develop, anticoagulation may be needed for a longer period. Chronic Coronary Disease The acute and chronic effects of thrombosis in patients with chronic stable coronary disease are likely to be important in designing therapy for this condition; not only are such patients at high risk of acute coronary artery thromboembolism but such thrombi may contribute significantly to the arterial disease. All the components of a thrombus can be found in diseased arterial walls, and organized arterial thrombi can appear identical to a complicated atherosclerotic plaque.66 Coronary thrombi of different ages can often be found in a single artery with the oldest portions becoming incorporated into the vessel walhs4 this and other observations have lead some to conclude that the most logical explanation of atherosclerotic plaquing is the laying down and organization of thrombi.” Early reports by Wright and others led to the common practice of advising patients with coronary disease to take anticoagulants for the rest of their lives9 However, other investigators soon reported that this form of therapy offered no significant benefit, yet was frequently complicated by serious hemorrhage. A summary of the major trials testing long-term anticoagulation in patients with coronary heart disease is present in Table 3. In all of these, patients were randomly allocated to treatment or concurrent control group, but other desirable criteria for clinical trials were met to a variable extent. The results of these trials vary, with several showing a trend toward improved survival86V 877goand others showing no improvement.‘0~88~89 There is similar disagreement concerning the effect of anticoagulation on the incidence of reinfarction, angina pectoris, and congestive heart failure. Since platelet phenomena are considered to play an initiating role in the pathogenesis of artlerial thrombosis and possibly to atherogenesis as well, antiplatelet drugs have a theoretical advantage over anticoagulation in patients with chronic coronary artery disease. Clinical trials of antiplatelet agents have been limited in number and size. Blakely and Gent” in a randomized double-blind study of 2 11 elderly men with previous myocardial infarct,ion, found that there was significantly improved survival in the sulfinpyrazone-treated group, a finding that has not yet been confirmed. Elwood and as-

246

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Table

3. Trials

of Chronic

Anticoagulant

Therapy

on Mortality

After

Myocardial

Bjerkelund86 Harvald8’ Love1188 Loeligerlo Seaman89 Ebertgo

(vr)

(1957) (1962) (1967) (1967) (1969) (1969)

Patients

237 311 350

Follow-up

(yr)

735

sociates’* reported that men who took 200 mg of aspirin daily after a myocardial infarction had a trend toward improved longevity compared with those who did not take aspirin regularly. Several relatively small controlled studies have failed to show benefit from chronic dipyridamole therapy in patients with coronary heart disease.93-95 The Boston Collaborative Drug Surveillance Group96 analyzed the records of 13,898 patients admitted to 24 Boston hospitals in 1966 and 1972. They compared those with the diagnosis of acute myocardial infarction with those having other diagnoses and found a negative association between regular aspirin use and infarction. The data are consistent with the hypothesis that aspirin protects against the disease, but careful large prospective clinical trials with antiplatelet agents are needed to determine whether this hypothesis is correct. Such trials are currently under way; in this country, they include AMIS (Aspirin Myocardial Infarction Study); PARIS (Persantin-Aspirin Reinfarction Study); and ART (Anturane Reinfarction Trial). Recommendations. The value of long-term anticoagulation in patients with known chronic coronary disease is still being debated. However, evidence that this therapy reduces mortality or reinfarction is inadequate to recommend it in otherwise uncomplicated patients. Recent observations suggest that antiplatelet drugs might prove to be more effective than traditional anticoagulation. Large trials using sulfinpyrazone, aspirin, and/or dipyridamole are currently in progress, and will hopefully define ther role of these agents in patients with chronic coronary artery disease.

Aortocoronary Bypass Surgery In the past 10 yr, several surgical techniques have been developed in an attempt to supply blood to the ischemic myocardium. Implantation of internal mammary arteries into the myocardium has

2-8

(%)

Control

Treated

3

36 31 22

20 20 19

1 6

37

5 35

29

22

3-6 4-7

306 175

SHERRY

Infarction Mortality

Author

AND

7

not proved effective, but aortocoronary bypass with segments of saphenous veins has been more successful. This procedure yields relatively consistent relief of angina1 pain and improved blood flow past highly stenotic areas in the coronary vessels. Early patency of these grafts has been from 70% to 80% in most studies and is most related to surgical skill, size of the anastomosis, and caliber of the distal artery.97-1@’ Highly stenotic proximal vessels usually thrombose when they are successfully bypassed, a factor that is not critical as long as the bypass flow is sufficient for myocardial need. The long-term patency rate of coronary bypass grafts is uncertain. A report by Vlodner and Edwards,“’ of fibrotic intimal proliferation in six patients who died 3-9 mo postoperatively and graft thrombosis in four of these, greatly distressed cardiologists and surgeons involved in this procedure. Others quickly pointed out that obstruction is uncommon on follow-up angiography with a high patency rate at up to 5 yr.97-100 In addition, long-term experience with saphenous vein femoropopliteal artery bypass surgery has been extrapolated to the coronary bypass situation. Up to 95% of lower extremity bypass grafts, which are patent at 1 yr, have remained patent for up to 11 yr in the experience of Reichle and Tyson.“* For the most part, these patients have not received chronic antithrombotic therapy. Although peripheral and coronary artery bypasses are similar, coronary grafts have hemodynamics (e.g., flow predominantly in diastole and smaller distal vessels), which may make them more prone to degeneration and/or thrombosis. Preliminary studies by Steele and associateslo show that short platelet survival in patients having aortocoronary bypass surgery is associated with increased graft closure. Thus, there may be rationale for chronic antithrombotic therapy, although it has not yet been proven by proper prospective trials.

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Recommendations. We recommend anticoagulant therapy with low-dose heparin during the early period after coronary surgery to prevent venous thromboembolism. Although unproven, maintainance of these patients on antiplatelet drugs (i.e., 100 mg of dipyridamole plus 600 mg of aspirin, or 400-800 mg sulfinpyrazone daily) with the hope that progression of their underlying atherosclerosis and graft occlusion will be inhibited may be desirable. Prosthetic Heart Valves Thromboembolism has been the most frequent complication in patients who survive prosthetic valve replacement, occurring in up to half of those who had the early Starr-Edwards bali valves.‘04’105 The prime impetus for developing new valves has been this problem. However, low profile disc valves such as the Beall valve have not shown a clear-cut advantage over the newer ball valve models when the patients are maintained on anticoagulant therapy.106-10g A tilting disc such as the BjSrkShiley valve offers hemodynamic advantages over earlier valves but has been plagued by problems with massive valve thrombosis as well as peripheral embolism when anticoagulation is withheld.“’ Cloth-covered valves were designed to offer a less receptive site for thrombus formation but have not been totally successful.“‘-‘13 Indeed, small areas of platelet and fibrin thrombi can be found on most prostheses removed at reoperation or autopsy.‘0g Tissue valves such as the aortic porcine heterograft may be the only type that have a small risk of thromboembolism, since they have a hemodynamic pattern and surface similar to a normal valve. Initial observations have been promising with these but confirmation and long-term observations are still required. There have been no large prospective controlled clinical trials testing anticoagulant benefit in patients with prosthetic heart valves. However, available data from less ideal studies strongly indicate the benefit of chronic anticoagulation of all patients with prosthetic valves with the possible exception of the tissue prostheses. Gadboys and associates”’ reported that 5% of patients on sodium warfarin therapy had systemic embolism compared with 44% of patients who did not receive this therapy. Several other investigators have found that anticoagulated patients who sustain an embolus are likely to have had inadequate control of their dosage.‘04’“4-‘16

247

Since there is a small but significant incidence of embolism, even with adequate anticoagulant control, investigators have studied platelet function in patients with prosthetic valves. Tests for adhesiveness and aggregation have not been abnormal, but platelet survival is significantly shortened with most types of valves.“7-11g Harker and Slichterl’g propose that platelets are selectively consumed by interaction with the prosthetic valves in an amount proportional to surface area. Studies by Steele et a1.“7P1’8 show that patients with a history of thromboembolism have shorter platelet survival than patients with the same type of prostheses who have not suffered from thromboembolism. Dipyridamole 400 mg daily improved shortened survival time toward normal,“” and sulfinpyrazone 400 mg daily had a similar effect.12’ Aspirin had little effect on platelet survival, but had a potentiating effect with dipyridamole, which permits the use of a lower dose of the latter.rlg In 1971, Sullivan and associates”’ reported a doubleblind controlled study in which dipyridamole or placebo was given to 163 patients surviving valve replacement; all patients also received anticoagulation with sodium warfarin. Within 1 yr, 14.3% of the placebo group suffered systemic emboli, whereas only 1.3% of the dipyridamole group had emboli, a statistically significant difference. There was no increase in bleeding complications using this combined therapy. Recommendations. In the absence of contraindications, chronic oral anticoagulation in all patients with synthetic prosthetic valves appears indicated. Indeed the inability to maintain this therapy in patients who are being considered for valve replacement is a relative contraindication to having the surgery. The newer heterograft valves offer promise in partially alleviating this problem. In addition, antiplatelet therapy with 100 mg dipyridamole plus 600 mg aspirin daily is recommended for patients who have an embolus while receiving oral anticoagulants, or in those who have valve models with a history of frequent thromboembolism.

Transient Cerebral Ischemia A transient ischemic attack is usually defined as an abrupt episode of focal neurologic symptom or sign lasting less than 24 hr with complete return of neurologic function. Tool and associates’22 found that 141 of 160 patients (88%) with transient ischemic attacks had lesions in one or more extra-

248

cranial arteries, most commonly the carotid. The mechanism of cerebral ischemia appears most often to be related to embolism from thrombotic material at the site of these lesions; such emboli may contain variable combinations of red blood cells, platelets, fibrin, and cholesterol. They usually follow the same vascular tributaries during repeated attacks and are harbingers of permanent cerebrovascular accidents, which occur in 25%-40% of patients within 5 yr after onset.‘23-‘27 Mortality in this group is about 6% per year with more patients dying of associated cardiac than cerebral disease.‘26’127 Anticoagulant therapy was empirically tried for this problem before arteriography defined the underlying lesion. Most reports indicate a significant decrease in the number of attacks in patients receiving oral anticoagulants.‘23’ 124,126,127Fisher 12* recorded a total number of more than 500 attacks in 15 control patients and only 20 attacks in 15 treated patients. Recurrence of transient ischemic attacks has been reported to occur in many patients who have had anticoagulant therapy withdrawn.‘29 Several investigators found a decreased rate of cerebral infarction in the anticoagulated group,124y127 but the data in general is inconclusive, and there is no impressive data to suggest that anticoagulant therapy improves mortality in these patients. Since platelet thromboemboli commonly precipitate transient ischemic attacks, drugs that suppress platelet function offer another possible way to decrease these episodes. In 1972, Evans13’ reported the result of a double-blind crossover trial using sulfinpyrazone on patients with amaurosis fugax, a type of transient ischemia resulting from microemboli to the retinal branches of the internal carotid artery. There was a 50% reduction in these episodes during the sulfinpyrazone treatment periods. Dyken and Oldrich’ found that 2 of 15 patients (13%) receiving aspirin had attacks while on therapy, whereas 9 of 11 (82%) who did not receive aspirin had attacks, yet there was no difference in the frequency of stroke or death in these groups. Acheson et a1.‘32 found no beneficial effects in patients with transient ischemic attacks using dipyridamole in a controlled double-blind fashion. This subject may be clarified by two large controlled double-blind multicenter trials: 1) a Canadian trial, now in its fourth year and nearing completion, which compares sulfinpyrazone alone,

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aspirin alone, sulfinpyrazone plus aspirin, with placebo in patients with transient ischemic attacks; and 2) an American trial sponsored by the National Institute of Neurological Diseases evaluating the effects of aspirin versus a placebo. Recommendations. Since no firm data is yet available showing that the natural history of patients with transient cerebral ischemia is altered by currently available therapy, no definitive recommendation can be made. However, we would suggest that symptomatic therapy be instituted for nonsurgical cases with sulfinpyrazone (400-800 mg) or aspirin 600 mg plus dipyridamole 100 mg daily. If these agents do not suppress the distressing episodes, then it appears reasonable to treat carefully selected, closely followed patients with oral anticoagulant therapy. Cerebrovascular Accidents Cerebral embolism. About 15% of patients with strokes have features suggesting cerebral embolism.133 Since the clinical distinction between thrombosis and embolism is often vague, the diagnosis of embolism can only be made when there is a predisposing factor present such as mitral stenosis, atria1 fibrillation, prosthetic heart valve or recent myocardial infarction, as discussed in the previous sections on rheumatic heart disease and mural thromboembolism. Anticoagulant therapy clearly decreases the recurrence of cerebral emboli. Carter’34 followed 130 patients with cerebral emboli originating from various sites for 6-12 yr. The recurrence rate of those who did not receive anticoagulant therapy was 65%, whereas only 16% of those who were anticoagulated had a recurrence, and survival was greater when anticoagulant therapy was used. Stroke-in-evolution. Thrombotic strokes not infrequently progress in a step-wise manner over a period of hours or days and are then known as “stroke-in-evolution.” If a partially occluding thrombus or a small totally occluding thrombus is present, spontaneous lysis can occur leaving no residual deficit or a small deficit. However, if an initially small occlusion initiates progressive thrombosis and occlusion of major vessels, then a large, less reversible cerebrovascular accident is likely to occur. Carter13’ randomized 80 patients with stroke-inevolution into a control group and a group treated

ANTITHROMBOTIC

249

THERAPY

with heparin and phenindione. With treatment, 77% improved and 5% died, which was significantly better than the 50% improvement and 20% mortality in the control group. It is possible that the reduction in death was related to the prevention of pulmonary embolism, which was the cause of death in three of five control patients. Baker and associates’24 found a similar reduction in mortality and progressive infarct in a randomized study of 128 patients. However, Fisher’s summary of a national cooperative study12’ found no improvement in survival, although there was a 50% reduction in progressive infarction in anticoagulated patients. None of these trials were blind, so observer bias may have influenced the decision about progression of neurologic abnormalities. “Completed” stroke. Thrombotic strokes are the largest category of cerebrovascular accidents having a high mortality and morbidity from neurologic residua and recurrent stroke. Therapy has been primarily aimed at preventing recurrent cerebral events in this group. Since 1956, several trials have assessed the influence of chronic anticoagulant therapy after presumed thrombotic stroke. Some studies have reported a trend toward increased survival and decreased recurrence,1363137 but the majority of trials have shown no benefit from this treatment.‘38”3g Cooperative trials from the Veterans Administration Hospitals and by Baker and associates found an even higher mortality in patients given anticoagulant, with mortality in large part due to intracerebral hemorrhage. 133a134 Hypertension predisposes to hemorrhage, and several investigators have commented that the high mortality may be related to inconsistent exclusion of even mildly hypertensive patients from anticoagulant trials.1343136,1383 14’ If all hypertensive patients are excluded, there is still a risk, since distinguishing primarily thrombotic from hemorrhagic strokes is often impossible. Hill et a1.‘38 observed the frequency of intracerebral hemorrhage in

hypertensive patients, so they excluded those with diastolic blood pressure above 100 mm Hg from their anticoagulant trial. Nevertheless, there were three intracerebral hemorrhages out of five fatal cerebrovascular accidents in the 66 patients in the treated group, whereas only one occurred in 65 control patients. Antiplatelet agents alone or in combination. with anticoagulant agents offer another potentially effective mode of therapy after a stroke. However, only limited studies have been completed concerning this question, which probably will remain unanswered, at least, until the current Canadian antiplatelet agent trial is complete. Recommendations. Chronic anticoagulant therapy is strongly indicated after a presumed cerebral embolus. Since there is a danger of converting a bland cerebral infarct to an expanding hemorrhagic one, therapy is usually withheld for several days to a week after the insult. Several trials suggest that there might be some improvement in survival and residual neurologic defects in patients with “strokein-evolution” who are treated early in their course. However, there are such great methodologic difficulties in these studies that a recommendation for anticoagulant therapy cannot be made. Patients with stable “completed” cerebrovascular accidents seem to be benefited by anticoagulation only for the prevention of stasis-related venous thromboembolism, a result that can probably be obtained with less complication by the use of low-dose heparin. We recommend maintaining low-dose heparin in patients with a recently “completed” stroke until they are fully mobilized. Antiplatelet agents are not likely to prevent recurrence in most patients with cerebral ernboli composed of mixed or predominantly red thrombus, i.e., from cardiac mural thrombi. However, they offer promise, although unproven, in decreasing the recurrence of cerebrovascular thrombosis in patients with a “completed” stroke.

REFERENCES 1. Rosenberg RD: Actions and interactions of antithrombin and heparin. New Engl .I Med 292: 146, 1975 2. Wessler S, Yin ET: Theory and practice of minidose heparin in surgical patients. Circulation 47:671, 1973 3. Basu D, Gallus A, Hirsh .I, et al: A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. New Engl J Med 2871324, 1972

4. Martyn ministration 5. Bowie appearance studies in 1967 6. O’Reilly

DT, Janes JM: Continuous intravenous of heparin. Mayo Clin Proc 46:347, 1971

ad-

EJW, Thompson JH, Didisheim P, et al: Disrates of coagulation factors: Transfusion factor-deficient patients. Transfusion 7: 174, RA,

Aggeler

PM:

Studies

on

coumarin

250 anticoagulant drugs, initiation of warfarin therapy without a loading dose. Circulation 38: 169, 1968 7. Koch-Weser J, Sellers EM: Drug interactions with coumarin anticoagulants. New Engl J Med 285: 547, 197 1 8. Pastore BH, Resnick ME, Rodman T: Serious hemorrhagic complications of anticoagulant therapy. JAMA 180:117, 1962 9. Wright IS, Foley WT: Use of anticoagulants in the treatment of heart disease. Am J Med 3:718, 1947 10. Loeliger EA, Henson A, Kroes F, et al: A doubleblind trial of long-term anticoagulant treatment after myocardial infarction. Acta Med Stand 182:549, 1967 11. Ebert RV: Anticoagulants in acute myocardia1 infarction, results of a cooperative clinical trial. JAMA 225:124,1973 12. Nichol ES, Keyes JN, Borg JI, et al: Long-term anticoagulant therapy in coronary atherosclerosis. Am Heart J 55: 142, 1959 13. Wasserman AJ, Guttman LA, Yoe KB: Anticoagulants in acute myocardial infarction. Am Heart J 71:43, 1966 14. Hilden T, Iverson K, Raaschon F, et al: Anticoagulants in acute myocardial infarction. Lancet 2:327, 1961 15. Meltzer LE, Palmon F, Ferrigan M: Prothrombin levels and fatality rates in acute myocardial infarction. JAMA 187:985,1964 16. Mills DCB: Drugs that effect platelet behavior. Clin Haematol 1:295, 1972 17. Emmons PR, Harrison MJG, Honour AJ, et al: Effect of a pyrimidopyrimidine derivative on thrombus formation in the rabbit. Nature 208:255, 1965 18. Danese CA, Haimov M: Inhibition of experimentally arterial thrombosis in dogs with platelet deaggregating agents. Surgery 70:927, 1971 19. Weiss HJ: The pharmacology of platelet inhibition, in Spaet TH (ed): Progress in Hemostasis and Thrombosis, vol 1. New York, Grune & Stratton, 1972, p 199 20. Kaegi A, Pineo GF, Shimizu A: Arteriovenousshunt thrombosis: Prevention by suifinpyrazone. New Engl J Med 290:304, 1974 21. Kaneshiro MM, Mielke CH, Kasper CK, et al: Bleeding time after aspirin in disorders of intrinsic clotting. New Engl J Med 281:1039,1969 22. Anderson GM, Hull E: The effect of dicumarol upon the mortality and incidence of thromboembolic complications in congestive heart failure. Am Heart J 41:365, 1948 23. Wishart JH, Chapman CB: Dicumatol in congestive heart failure. New Engl J Med 239:701, 1948 24. Harvey WP, Finch CA: Dicumarol prophylaxis of thromboembolic disease in congestive heart failure. New Engl J Med 242:208,1950 25. Griffith GC, Strognell R, Levinson DC, et al: A study of the beneficial effects of anticoagulant therapy in congestive heart failure. Ann Intern Med 37:867, 1952 26. Kinsey D, White PD: Fever in congestive heart failure. Arch Intern Med 65: 163, 1940 27. Moran TJ: Autopsy incidence of pulmonary embolism in coronary heart disease. Ann Intern Med 32:949, 1950 28. Gallus AS, Hirsh J, Tuttle RJ, et al: Small sub-

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cutaneous doses of heparin in the prevention of venous thrombosis. New Engl J Med 288:545, 1973 29. McDonald CD, Burch GE, Walsh JJ: Prolonged bed rest in treatment of idiopathic cardiomyopathy. Am J Med 52:41, 1972 30. Demakis JG, Proskey A, Rahimtoola SH, et al: The natural course of alcoholic cardiomyopathy. Ann Intern Med 80:293,1974 31. Demakis JG, Shahbudin HR, Sutton GC, et al: Natural course of peripartum cardiomyopathy. Circulation 44: 1053, 1971 32. Abernathy WS, Willis PW: Thromboembolic complications of rheumatic heart disease. Cardiovasc Clin 5:131, 1973 33. Szekely P: Systemic embolization and anticoagulant prophylaxis in rheumatic heart disease. Br Med J 1: 1209, 1964 34. Coulshed N, Epstein EJ, McKendrick CS, et al: Systemic embolism in mitral valve disease. Br Heart J 32:26,1970 35. Keen G, Leveaux VM: Prognosis of cerebral embolism in rheumatic heart disease. Br Med J 2:91, 1958 36. Daley R, Mattingly, Holt CL, et al: Systemic arterial embolism in rheumatic heart disease. Am Heart J 42:566, 1951 37. Casella L, Abelmann WH, Ellis LB: Patients with mitral stenosis and systemic emboli. Arch Intern Med 114:773, 1964 38. Greenwood WF, Ardridge HE, McKelvey AD: Effect of mitral commissurotomy of duration of life, functional capacity, hemoptysis and systemic embolism. Am J Cardiol 11:348, 1963 39. Kellogg F, Liu CK, Fishman IW, et al: Systemic and pulmonary emboli before and after mitral commissurotomy. Circulation 24:263, 1961 40. Laws CL, Levine SA: Clinical notes on rheumatic heart disease with special reference to the cause of death. Am J Med Sci 186:833, 1953 41. Harris AW, Levine SA: Cerebral embolism in mitral steonsis. Ann Intern Med 15:637, 1941 42. Wood P: An appreciation of mitral stenosis. Br Med J 1: 1051, 1954 43. Wood JC, Conn HL: Prevention of systemic arterial embolism in chronic rheumatic heart disease by means of protracted anticoagulant therapy. Circulation 10:517, 1954 44. Foley WT, Wright IS: The use of anticoagulants. Med Clin North Am 41: 1339, 1956 45. Hay WE, Levine SA: Age and auricular fibrillation as independent factors in auricular mitral thrombosis formation. Am Heart J 24: 1, 1942 46. Askey JM: Embolism and atria1 fibrillation, the effect of restoration to normal rhythm with quinidine. Am J Cardiol9:491, 1962 47. Bjerkelund C, Orning OM: The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atria1 fibrillation. Am J Cardiol 23:2@8, 1969 48. Meltzer LE, Aytann, Yun DD, et al: Atria1 fibrillation treated with direct current countershock. ArchIntern Med 115:537, 1965 49. Morris JJ, Kong Y, North WC: Experience with

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