0
Special Report |

A European View on the North American Fifth Consensus on Antithrombotic Therapy* FREE TO VIEW

Marc Verstraete, MD; Colin R. M. Prentice, MD; Michel Samama, MD; Raymond Verhaeghe, MD; on behalf of a European Working Group
Author and Funding Information

Affiliations: *From the Center for Molecular and Vascular Biology (Drs. Verstraete and Verhaeghe), Katholieke Universiteit Leuven, Belgium; Division of Medicine (Dr. Prentice), University of Leeds, United Kingdom; and the Department of Hématologie-Biologie (Dr. Samana), Hôtel-Dieu de Paris, France. ,  A complete list of participants is located in the Appendix.

Correspondence to: Marc Verstraete, MD, Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Campus Gasthuisberg, O&N, Herestraat 49, 3000 Leuven, Belgium



Chest. 2000;117(6):1755-1770. doi:10.1378/chest.117.6.1755
Text Size: A A A
Published online

An American-Canadian group of experts have, in the November 1998 issue of CHEST, published for the fifth time their recommendations for antithrombotic therapy. This remarkable consensus document was the result of an extensive review of the literature by an interdisciplinary group. Considering the impact of this document on medical practice, also outside North America, a group of European experts reviewed in detail the fifth report, particularly the sections on clinical indications of antithrombotic treatment. The aim was not to indicate the many areas of agreement and to quote literature that has become available since publication of the last consensus documents, but rather to refer to the gray zones of uncertainty and limited number of divergent opinions.

The American College of Chest Physicians (ACCP) published in a supplement to the November 1998 issue of CHEST the conclusions of the Fifth Consensus Conference on Antithrombotic Therapy.1 This is a comprehensive document based on an exhaustive review of the literature as of April 1998, written by an interdisciplinary but essentially American-Canadian Group of about 90 experts.In this latest evolving consensus, the grading system, already used in the 1995 document, was modified to emphasize more strongly the concept of clinically important difference, and to build the benefit-to-risk ratio of a particular treatment into the grading system.

The North American initiative as well as the guidelines proposed for American practice were well received and can, in general, be recommended to European clinicians. At a discussion of this latest ACCP report, in Paris on January 21, 1999, French clinicians expressed some divergent views from the North American consensus on a selected number of indications for antithrombotic therapy. In the present report, the American-Canadian recommendations are critically discussed by a group of European experts in an effort to reach gradually a transatlantic if not a global consensus. The European participants in this endeavor are listed in the to this article.

The grading of the level of evidence of clinical trials is a milestone of progress, in that objective comparisons can now be made. One could make an argument that an A1 recommendation can be based on a single trial comprising a large, randomized, and placebo-controlled study. Alternatively, the case could be made that A1 grading should only be given when a second trial, virtually identical in design and treatment comparison, confirms the results of the first. This question needs to be resolved. As one could anticipate, the lower the grade, the greater was the divergence of opinion among our experts.

The European group has taken the opportunity to update the text in topics for which it believed that important publications have appeared since April 1998, the closing date of the North American Consensus. In general, only references that confirm or modify a recommendation have been included. It must be appreciated that the range of drugs and other treatments used in some situations is different from those used in Europe, owing to different customs and drug regulatory requirements.

Although there is an increasing willingness among clinicians to use anticoagulants during pregnancy, there is a paucity of evidence about the efficacy and safety of the ever-expanding number of antithrombotic agents for the prevention and treatment of maternal and fetal thrombotic disorders. The lack of controlled trials leads to low levels of evidence of the recommendations (mostly C2) in the chapter on the use of antithrombotic agents during pregnancy of the North American document.2 The European experts face the same limitation; therefore, their comments have to be taken as updated suggestions.

Main differences between the North American and European experts concern prophylaxis in pregnant women with thrombophilia or mechanical heart valves. Low-molecular-weight (LMW) heparins are used more often to treat pregnant women with thrombophilia in Europe than in North America. Oral anticoagulants are still used by European cardiologists to treat pregnant women with mechanical heart valves. LMW heparins are sometimes considered to be more expensive than unfractionated heparin (UH), but their advantages have to be taken into account, and cost varies from country to country.

Epidemiology

The exact incidence of venous thromboembolism during pregnancy is not well documented, but compared with nonpregnant fertile women < 35 years of age, it is at least 10 times higher.3In addition to the risk factors in pregnant women mentioned in the North American report, prothrombin G20210A polymorphism and probably hyperhomocysteinemia should be added to the list of thrombophilias.4

Prevention of Venous Thromboembolism in Pregnant Patients at Risk
During Pregnancy: The statement that prophylaxis with 5,000 IU of subcutaneous UH bid is effective is not fully shared by European experts. A dose of LMW heparin with a peak anticoagulant effect corresponding to 0.2 to 0.45 IU of anti-factor Xa per milliliter of plasma 3 h after subcutaneous injection seems to be effective and is also more practical for the patient (C1).5 LMW heparins are more often used in Europe in pregnant women because of simplicity, comfort, good cutaneous tolerance and supposed decreased risk of heparin-induced thrombocytopenia and osteoporosis. Their safety during pregnancy has been recently reviewed.6 The limited available evidence suggests that for the prevention of recurrent venous thromboembolism in women with a previous history of venous thrombosis, LMW heparin 50 IU of anti-factor Xa per kilogram (early pregnancy weight) subcutaneously once daily is generally adequate and safe. This dose is usually associated with a plasma peak of around 0.25 to 0.35 IU of anti-factor Xa per milliliter of plasma.5 However, there is concern that these doses of UH and LMW heparin may not be sufficient in very high-risk situations, for example, pregnant women with a previous history of venous thromboembolism associated with antiphospholipid antibodies or with severe thrombophilic defects, such as antithrombin III deficiency.

The doses of LMW heparin required during the third trimester are those in nonpregnant women of similar weight.78 A measurement of anti-factor Xa activity as well as weight-adjusted doses have been recommended (C2) in Europe in order to avoid insufficient anticoagulation.

In pregnant women with a history of previous venous thromboembolism secondary to a transient risk factor, clinical surveillance is proposed by the North American consensus group. By contrast, European clinicians prefer a pharmacological prophylaxis from the beginning of pregnancy or at least during the last trimester (C2). In these patients, screening for thrombophilia is compulsory. In the North American consensus document, the possibility of starting prophylaxis at a later stage in pregnancy is not considered.

For pregnant women with previous history of idiopathic thromboembolism or with thrombophilia but without previous personal thromboembolism, the North American consensus document lists three options: clinical surveillance, 5,000 IU UH bid, or adjusted-dose heparin to produce plasma levels of 0.1 to 0.2 IU of anti-factor Xa per milliliter of plasma throughout pregnancy.2 In the North American consensus, no difference is made among the genetic defects. The European clinicians consider that antithrombin III deficiency carries a higher thrombotic risk than protein C or S deficiency. The heterozygous factor V Leiden mutation and prothrombin polymorphism are usually associated with the lowest thrombotic risk. Accordingly, clinical surveillance is appropriate only for the latter two conditions in asymptomatic women without previous history of thromboembolism. Although there is no definite evidence, it may be prudent to use daily prophylaxis with LMW heparin in pregnant women from symptomatic kindreds with protein C or with antithrombin III deficiency, even in the absence of a previous thromboembolic episode (C2). In protein S deficiency, the same prophylaxis might be recommended in pregnant women with previous thrombosis only.

Treatment of Venous Thromboembolism in Pregnant Women

Although a full dose of UH by IV infusion for 5 to 10 days followed by an injection of the full dose after 9 to 12 h until term is the treatment of choice in the North American document,2 its duration at full doses is not accepted by all European experts. Some of them recommend a full therapeutic dose for 1 to 3 months, followed by a lower dose to limit the risk of osteoporosis. Full doses of heparin until delivery might be a lengthy treatment when the venous thrombosis occurs at the beginning of pregnancy. The severity of the thrombotic episode, its evolution during treatment, and its cause should probably also be considered in determining the duration of heparin treatment.

LMW heparin as an alternative to UH has been proposed and seems to offer some advantages,9 but there are no prospective clinical trials allowing general recommendations. Whether it should be given twice or once a day is still a matter of debate. Rare reports have used the second alternative.910 There is an agreement that the peak anti-factor Xa activity should be tested at least during the first month of LMW heparin treatment, then every month or trimester. However, the therapeutic range is uncertain,6 and standardization of anti-factor Xa activity measurement is essential. At present, LMW heparins, if used, should be administered bid to treat pregnant women with venous thromboembolism (C2). The dose should be adjusted to peak anti-factor Xa concentrations according to the instructions provided by the manufacturers of the LMW heparin used for nonpregnant patients.

Pregnant Women With Mechanical Heart Valves

As indicated in the North American consensus document,2 there are two approaches to anticoagulant therapy for pregnant women with mechanical heart valves. The first is to use UH throughout pregnancy, administered subcutaneously bid in doses adjusted to keep the mid-interval activated partial thromboplastin time (APTT) in the therapeutic range (at least twice the control), or an anti-factor Xa heparin concentration of 0.35 to 0.70 IU/mL plasma. However, some European experts are in favor of giving exclusively LMW heparin throughout pregnancy because of its comfort and better tolerance, although no firm data are available on the use of LMW heparin in this situation. It is difficult to make firm recommendations, except that all experts in North America and in Europe insist on the importance of planning the treatment together with the expectant couple.

The second approach is to use heparin until the 13th week, to switch to warfarin until the middle of the third trimester, and then to restart heparin treatment until delivery. This approach is encouraged by some experts because they consider it to be more effective than the first one.10

Pregnant Women With Antiphospholipid Antibodies

The North American recommendations are based on a high level of evidence (A1), and are generally accepted by the European experts, who agree with the combined treatment of heparin and aspirin. LMW heparin is used almost universally in Europe.1113

In general, this chapter14is received as a well-documented overview on antithrombotic prophylaxis, but a number of qualifications should be made. A general concern is how to translate data from studies with surrogate end points (eg, venography) into recommendations for daily practice in which clinical efficacy must prevail (eg, fatal and nonfatal pulmonary embolism and symptomatic deep vein thrombosis).15 Some studies using clinical end points cast some doubt on the figures usually given for the frequency of postoperative pulmonary embolism, and question the need of perioperative antithrombotic prophylaxis for all patients.16 However, most European experts agree with the North American consensus that aspirin is less effective than heparin as a prophylactic agent.

A further concern is that clinical thrombotic end points are nowadays much rarer than those recorded in historical literature. For instance Fender et al17 carried out a retrospective analysis of> 2,000 consecutive operations for hip replacement in the Trent region of the United Kingdom. There were only four definite fatal pulmonary emboli, an incidence of 0.2%. The near impossibility of carrying out controlled clinical trials in this situation is readily seen in the context of trials of equivalence, where a ≥ 0.5% difference is required between two treatments before equivalence is discarded.

A first comment is on the classification of level of risk. The North American document uses four levels of risk,14) whereas other consensus documents in Europe use only three. In principle, a fourth level should allow the prophylactic regimen to be better tailored to the patient’s needs. However, if LMW heparin is the preferred agent, as in many European centers, it is not clear if each risk level will indeed receive a different regimen of LMW heparin. Furthermore, the text remains to some extent vague as to the category in which an individual patient has to be classified, eg, with one vs multiple additional risk factors. Few trials indeed studied homogeneous groups of patients except for total hip and knee replacement. The reader gets the impression that all patients with inherited thrombophilia automatically fall into the highest risk category, whereas some differentiation may be justified.

Antithrombotic regimens to prevent venous thromboembolism are detailed in the North American consensus report,14) but the list is not complete, inasmuch as in Europe a wider range of LMW heparins are licensed (eg, boxol, parnaparin, reviparin). In Table 1 of the North American document,,14) the four levels of risk are not given; thus, it is difficult to relate the treatment regimens to those levels of risk given in Table 4 of the corresponding chapter of the document.14) The recommendations do not detail the LMW heparin regimens either; they suggest starting antithrombotic prevention 12 to 24 h after surgery in total hip replacement, which is clearly not standard European practice.

Because of its limited use, the coverage of dextran is brief. In renal insufficiency, it is only the 10% dextran-40 solution that should be used with caution. Rare anaphylactic responses can largely be avoided if the hapten principle dextran 1 is used.

It has been suggested in the North American consensus that aspirin is less effective than heparin as a prophylactic agent.14 However, a recent very large randomized trial of aspirin vs placebo in orthopedic patients has shown a 58% reduction in mortality in the aspirin-treated group compared with placebo.18 Heparin was not randomized in this trial and did not further reduce thromboembolism, but increased the amount of postoperative bleeding.

The evidence presented on the efficacy of elastic stockings in general surgery is meager and does not justify an A1 recommendation.

A hot issue is the duration of prophylaxis. The North American document14) lists the studies with prolonged LMW heparin prophylaxis, and points correctly to a significant risk of venographic thrombosis during the first postoperative month, even in patients with a normal venography at discharge. It is true that the incidence of symptomatic thromboembolism was low, and the document therefore calls for additional trials on out-of-hospital prophylaxis in which objectively documented symptomatic venous thromboembolism is the primary efficacy end point. For some, this seems like going back to the future, because most of this chapter is based on studies with surrogate end points. In addition, it may raise an ethical issue in some European countries that use prolonged prophylaxis, because a low risk of fatal pulmonary embolism still represents a not insignificant number of lives in view of the scale of orthopedic surgery. Others believe that the question is not settled, and trying to reach a consensus now may appear premature.

Sections that eventually might be added are discussions on contraindications of pharmacological prophylaxis because of a too-high bleeding risk and on conditions for which there are at present little or no data, eg, laparoscopic surgery, arthroscopy, and application of plaster casts. These issues occasionally lead to medicolegal discussion. The last North American recommendation addresses the risk of epidural or spinal hematoma with LMW heparin in patients who receive regional anesthesia or analgesia.14) Is caution only warranted with LMW heparin and not with other antithrombotic drugs?

The available data pertaining to very heterogenous medical groups do not support an A1 recommendation, although a recent publication is encouraging.19

Regarding orthopedic surgery, perhaps insufficient attention has been given to publications using clinical end points, and some question the degree of benefit of heparin to reduce fatal pulmonary embolism in orthopedic patients.20Further doubt on the A2 recommendation of heparin antithrombotic prophylaxis for hip fracture surgery is raised by the Cochrane database.21 Here, the conclusion is made that insufficient trials of good quality, using clinical end points, have been conducted to allow definite recommendations in favor of antithrombotic prophylaxis to be made.

The North American recommendations on the antithrombotic therapy of venous thromboembolism raise no fundamental disagreement.

A few points deserve attention to convert the recommendations into practical guidelines for daily use. For instance, the advice to prolong the APTT to a range that corresponds to a certain plasma heparin concentration (which in turn depends on the assay used) is universally valid. Conversion into a heparin nomogram for daily practice depends on the locally used APTT reagent, as explained in the chapter on heparin in the North American document. The substitution of LMW heparin for UH eliminates the problem of monitoring and meets with general support. European practice is probably a step ahead of the US Food and Drug Administration regulation: preparations other than enoxaparin are admitted as well, and pulmonary embolism is accepted as an indication for LMW heparin in a number of European countries. European doctors also have a larger choice of coumarin derivatives: phenprocoumon and acenocoumarol are prescribed as well as warfarin.

There is some concern about the North American recommendation to continue with a treatment dose of LMW heparin should oral anticoagulation be either inconvenient or contraindicated.22There is no evidence to support this recommendation (although this treatment has been prescribed during pregnancy). A few unquoted studies tested lower doses of LMW heparin after the initial phase, but the data are still too scarce to justify a grade A1 recommendation.25

Divergent views persist among Europeans experts on the optimal duration of therapy for certain categories of patients. For instance, one view holds that patients with congenital or acquired thrombophilia may need long-term to indefinite anticoagulant treatment after a first episode of thromboembolism if this event was not precipitated by an additional transient risk factor. The opposite view is that clinical trials should assess the cost-benefit ratio before treating patients indefinitely, even those with recurrent venous thromboembolism or a continuing risk factor, because the risk of recurrence varies with the thrombophilic state. In a trial that compared 6 months to 4 years of anticoagulant treatment after a second episode of venous thromboembolism, the benefit of long-term treatment was offset by an increased incidence of major bleeding.26 Thus, the current North American recommendation on the duration of treatment may also be a workable consensus in Europe.

Thrombolytic treatment evokes divergent comments. In Europe, its use in deep vein thrombosis is not generally advocated, except possibly in some cases of massive iliofemoral thrombosis. A prospective study found no difference in outcome between iliofemoral thrombosis and more distal thrombosis; therefore, the usefulness of thrombolysis in the former group may be questioned.27On the other hand, a more liberal use in pulmonary embolism has been advocated by some clinicians, eg, in patients with echocardiographic signs of right ventricular overload.28 The ACCP opinion22) that thrombolysis is highly individualized (with regard to clinicians as well as to patients) also prevails in Europe.

The guidelines published by the North American group comprehensively review the evidence from trials and risk stratification for atrial fibrillation (AF).29 Overall, the European experts agree with the recommendations, but the following items need to be addressed.

First, the evidence from epidemiologic data suggests that paroxysmal AF has an intermediate risk of stroke between chronic AF and sinus rhythm. However, trial data suggest that paroxysmal AF confers a similar risk of stroke to chronic AF.3031 It would be reasonable to assume that the risk of stroke in paroxysmal AF is related to the frequency and duration of paroxysms, and it is more likely that a patient with one short paroxysm of AF per year is at less risk compared to someone with long paroxysms of AF occurring every day: we may therefore be dealing with a wide spectrum of thromboembolic risk. Important risk factors are age of the patient, influence of underlying pathology, such as structural heart disease, and hypertension. Another difficulty arises because many patients have asymptomatic or“ silent” paroxysms. The precise risk to benefit ratio for thromboprophylaxis in patients with paroxysmal AF therefore remains unclear, although the current guidelines (including the North American guidelines) suggest treating patients with paroxysmal AF similar to patients with chronic AF.

In patients with very infrequent episodes of paroxysmal AF, the benefits of warfarin therapy may be significantly offset by its associated inconvenience and morbidity, and aspirin therapy may be a safer and reasonably effective option, at least for those patients aged< 75 years with no structural heart disease.3233 However, in patients aged > 75 years who have underlying structural heart disease and frequent paroxysms of AF or in patients with prior transient ischemic accidents or minor stroke, warfarin therapy is recommended until clearer risk stratification strategies are available for such patients.3435 Care is to be taken in the very elderly to balance the risk of anticoagulation, such as hemorrhage and noncompliance, with the possible benefit.

The North American guidelines29) summarize risk stratification schemes from the Atrial Fibrillation Investigators Study30 and the Stroke Prevention in Atrial Fibrillation-III trial.34,36 Their own recommendations29) appear to be a synthesis of both, and the role of echocardiography in risk stratification is not precise.

The North American recommendations should clearly emphasize that risk stratification can be performed using clinical guidelines in the majority of cases, with only a little refinement from echocardiography, as evident from recent reports.3738 The meta-analysis from the AF Investigators of 1,066 patients from three clinical trials also suggested that echocardiography refined clinical risk stratification, and that only moderate-to-severe left ventricular systolic dysfunction via two-dimensional transthoracic echocardiography independently predicted stroke risk.31 Contrary to previous reports, isolated left atrial dilatation on the echocardiogram was not an independent risk factor for increased stroke risk on multivariate analysis. Echocardiography is therefore useful in the small group of patients who have a low risk of stroke according to clinical risk factors. Only very rarely would clinicians need to proceed to transesophageal echocardiography to assist risk stratification, but in the Stroke Prevention in Atrial Fibrillation-III transesophageal echocardiography substudy, stroke and thromboembolism were correlated with dense spontaneous echocardiographic contrast, left atrial appendage thrombus, and complex aortic plaques.39

The European experts are in agreement with current recommendations of a minimum 3 weeks of warfarin therapy before cardioversion and 4 weeks after cardioversion.

The guidelines published by the North American group comprehensively review the evidence for antithrombotic therapy in valvular heart disease.40 Overall, the recommendations can be supported, but a small number of qualifications should be made. In the North American text reviewing evidence and recommendations, increased left atrial size is stated as a risk factor for stroke, especially in the presence of AF. The meta-analysis mentioned above, in 1,066 patients, found that only moderate-to-severe left ventricular systolic dysfunction via two-dimensional transthoracic echocardiography independently predicted stroke risk in nonvalvular AF. Contrary to previous reports, isolated left atrial dilatation on the echocardiogram was not an independent risk factor for increased stroke risk on multivariate analysis.31

Whether left atrial dilatation increases stroke risk in mitral valve disease needs to be clearly defined. Mitral annular calcification has not been identified on multivariate analysis as an independent risk factor for stroke and thromboembolism in AF,31 although the North American recommendations for anticoagulation in older subjects (ie, age > 75 years) seems reasonable.,29) The distinction between the relative stroke risk of mitral stenosis and mitral regurgitation is less clear. Mitral stenosis is associated with a high risk of stroke and systemic thromboembolism, especially if AF is present. However, there is some evidence that mitral regurgitation of sufficient severity may prevent the development of left atrial spontaneous echocardiographic contrast on transesophageal echocardiography and intracardiac thrombi, suggesting a protective effect of the regurgitant jet against thrombus formation (thrombogenesis).4142 Whether this translates into significant clinical differences with respect to antithrombotic therapy still needs some clarification.

Making recommendations on antithrombotic treatment in patients with prosthetic heart valves43is a difficult subject, as acknowledged in the first paragraph by the North American Consensus Group.44However, it is noted that the issue has not been addressed in terms of basic concepts. There is too much emphasis on reported rates of embolism, without discussion of the mechanisms involved in these predominantly cerebrovascular events. No mention is made of the prevention of valve thrombosis, the primary purpose of anticoagulation in these patients. Valve thrombosis is a much more serious and life-threatening event than most embolic events, although it occurs less frequently. Among patients receiving anticoagulation therapy, the incidence of valve thrombosis varies from 0 to 0.5%/yr in the aortic position and from 0 to 3%/yr in the mitral position.4547 Moreover, valve thrombosis rates give a much better indication of thrombogenicity of a particular prosthesis than embolic rates, which are heavily influenced by patient risk factors, eg, the presence of coronary artery, aortic or carotid artery disease, hypertension, diabetes, increased left ventricular mass, or cigarette smoking,48 a problem not discussed in the North American document. Unless the prevalence of these risk factors is known in a series of prosthetic valve patients, it is difficult to interpret data on embolism. The North American document assumes that all embolic events originate from the prosthesis, despite the fact that many other pathophysiologic mechanisms lead to cerebral infarction.47

The North American experts discuss primarily the problems associated with the St. Jude valve, by far the most common prosthetic valve used in the United States. However, in many other countries, the St. Jude valve is not the most commonly used valve. The article devotes little space to discussing tilting disk and caged-ball valves. It is assumed in this article that all prosthetic heart valves within a broad design category (for example, bileaflet or tilting disk) are equivalent in terms of thromboembolic risk. Examination of the prosthetic heart valve literature shows that this is not the case. Two obvious examples spring to mind. The Medtronic parallel bileaflet valve (Medtronic; Minneapolis, MN) was withdrawn before clinical trials were completed because of an unacceptably high incidence of valve thrombosis. It cannot therefore be assumed that all bileaflet valves are of equal thrombogenicity. Similarly, among tilting disk valves, there is a wide range of thrombogenicity. The Medtronic Hall valve has the lowest thrombogenicity on the basis of valve thrombosis rates, whereas the Lillehei-Kaster/Omniscience series of valves has the highest thrombogenicity. In the United Kingdom, the Omniscience valve was found to have an unacceptably high incidence of valve thrombosis when patients were treated with anticoagulants at the level recommended by the North American Consensus.48

Prominence is given to the article of Stein et al49 on the optimal international normalized ratio (INR), despite the facts that this article was based on an analysis of the literature in which most studies were uncontrolled and retrospective, that definitions of thromboembolic and bleeding events differed among studies, and that the sensitivity of North American thromboplastins used was not reported, shortcomings that invalidate the conclusions.

The article of Horstkotte et al50 is quoted on the basis that it was a prospective series. However, although the data may have been collected prospectively, the conversion to INR from the Quick test used in Germany during the period of observation was performed retrospectively, based on the assumption that each anticoagulant clinic had used the same thromboplastin reagent throughout a 12-year period. Furthermore, the separation of the patients into three groups was based on an average INR during a 12-year period, which seems unrealistic, especially when one takes into account the number of events, both thromboembolic and hemorrhagic, that occur while the patient is outside the therapeutic range.

In the very short paragraph on tilting disk valves, it is stated that Cannegieter and associates51 showed trends that suggested that an INR of 3.0 to 3.9 was optimal for tilting disk valves. The particular tilting disk valves in this series were predominantly Bjork-Shiley valves of different generations, and it has been shown that data from one type of tilting disk valve (particularly older-generation tilting disk valves) cannot be extrapolated to other tilting disk valves.48 The same reference in the North American Consensus is also used to support a statement that thromboembolic rates are higher with caged ball and caged disk valves. In fact, the number of caged ball and caged disk valves in this series was extremely small, so that it was impossible to demonstrate a significant difference between these types of prostheses and the other prostheses.

In general, the authors43 are too ready to recommend aspirin in addition to warfarin for risk factors for which there is no evidence of benefit, while appearing to diminish the importance of the increased risk of bleeding. The benefit of dipyridamole cannot be ignored, as is shown by two recent meta-analyses.5253

Patients with mechanical prosthetic heart valves who suffer systemic embolism despite adequate anticoagulation should first be investigated for a possible source of embolism before aspirin is simply added to their medication. Some European experts favor dipyridamole compared with low-dose aspirin in view of a lower bleeding risk. The relative efficacy of dipyridamole over aspirin in this indication is unclear.

This chapter was generally well received by the European reviewers.54 The statement is made that new trials of LMW heparins have been published since the fifth consensus document. This is unavoidable in periodic guidelines updates. Reference has also been made to the direct thrombin inhibitors, desirudin, and to long-term treatment with oral glycoprotein IIb/IIIa inhibitors.

Concerning the dosage of aspirin, the difference between Europe and United States arises from the formulation of low-dose aspirin. In the United States, the low-dose tablet contains 81 mg of acetylsalicylic acid, whereas in Europe, it is 75 mg. In patients with unstable coronary syndromes, ie, evolving myocardial infarction without persistent ST-segment elevation and unstable angina, 75 mg is an adequate, well-documented lowest dose. Also in chronic coronary artery disease, a dose of oral aspirin, 75 mg, is definitely the best documented dose concerning efficacy as well as safety. On the basis of the International Study on Infarct Survival-II results, aspirin, 150 mg, might be the lowest effective dose during the first month after myocardial infarction, either with or without initial thrombolysis.55

Regarding the effects of IV glycoprotein IIb/IIIa receptor blockers, it should be emphasized that effects have been obtained in patients with unstable angina, treated or not with invasive procedures. So far, a short-term treatment with an IV glycoprotein IIb/IIIa inhibitor agent in patients without early coronary angiography and revascularization has been associated with differences in long-term gains. Limited efficacy in a noninvasive setting was clearly demonstrated in the PURSUIT trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy), which is the largest ever performed in this setting.56The Platelet Receptor Inhibition for Ischemic Syndrome Management trial with tirofiban was conducted in patients with more severe unstable angina and resulted in a significant reduction of death and myocardial infarction at 7 days, 30 days, and at 6 months, with demonstrable effects in the noninvasive as well as invasive setting.57Therefore, the North American recommendation for the use of IV glycoprotein IIb/IIIa inhibitors should be modified to widen their indication. They are presently recommended for unstable angina of sufficient severity to warrant coronary care unit admission. The reason for coronary care unit admission is variable among hospitals and among countries, and there is no scientific basis for such a recommendation. The European reviewers propose that IV glycoprotein IIb/IIIa receptor inhibitors can be considered for patients hospitalized with unstable coronary syndromes and with refractory angina, together with conventional treatment with aspirin and heparin or LMW heparin, especially if early coronary angiography and revascularization procedures are planned or elevated troponin concentrations are present.58

In the recommendations of the treatment of unstable angina with anticoagulants, European investigators suggest that, so far, two LMW heparins, enoxaparin and dalteparin, can be considered to be the first choice rather than IV UH infusion (A1 level).5961 The comparison between enoxaparin and UH shows that the effects of enoxaparin are equivalent or better than IV UH. There are also fewer side effects with LMW heparins, especially thrombocytopenia. The time has come to recommend those LMW heparins, tested and proved superior to UH in this clinical setting, as the first choice in the unstable coronary syndrome.5961

Another questionable issue is the recommendation to maintain heparin treatment for at least 48 h in unstable coronary syndromes. In studies on heparin in addition to aspirin in unstable coronary syndromes, all the placebo-controlled trials of UH or LMW heparin have used at least 5 days of treatment. This recommendation is not refuted by other trials comparing 2 to 3 days treatment with LMW heparin vs UH.5960 In these trials, it is completely unknown whether the outcome of such a short-term treatment would be any better than placebo for more serious events, such as myocardial infarction and death. Thus, based on available evidence, the European reviewers propose that patients hospitalized with unstable angina or non-Q-wave myocardial infarction should, in addition to aspirin, be treated with LMW-heparin subcutaneously bid. Although the ideal treatment based on clinical trials is for 5 days or until a coronary procedure, if one is performed earlier, in practice, many patients are discharged from hospital after 2 to 3 days. If a coronary procedure is planned within the next few days or weeks, the LMW heparin treatment should be maintained until the procedure. As an alternative, conventional IV UH therapy can be used, which might be an advantage if the coronary procedure is planned within the initial 24 to 48 h after admission.

Regarding the prevention of deep vein thrombosis in myocardial infarction patients, it is stated in the North American Consensus document that there are no trials of IV low-dose heparin vs no heparin in myocardial infarction patients receiving aspirin and thrombolytic therapy.54) Much of the thrombotic prophylactic data are indeed old and based on the surrogate end points of labeled fibrinogen scanning or venography, and do not relate to real-life events. One can therefore question the strong recommendation54) that every patient with acute myocardial infarction should receive low-dose heparin therapy until ambulation.

Regarding patients with acute myocardial infarction, where no thrombolytic therapy has been given, the North American Consensus Group recommends low-dose UH treatment, 7,500 IU subcutaneously q12h, in addition to aspirin.54) There is very little evidence that treatment over and above standard aspirin, eg, subcutaneous heparin, is effective. Some of these patients will belong to the unstable coronary syndromes, which include non-Q-wave myocardial infarctions. Thus, in this subgroup, there is a clear indication on the basis of numerous trials for full-dose LMW heparin subcutaneously bid in addition to aspirin for ≥ 5 days.

In the primary prevention of thromboembolism in asymptomatic individuals > 50 years old and with at least one major atherothrombotic risk factor, aspirin, 75 mg qd, is also considered a reasonable proposition in Europe, but this should be strengthened by more clinical evidence. This recommendation is also based on the Hypertension Optimal Treatment trial consisting of 20,000 hypertensive individuals.62 A daily dose of aspirin, 75 mg, reduced myocardial infarction by 30% without increased risk of stroke. However, the primary aim should be to reduce the risk factors, such as raised cholesterol, high BP, or smoking habit. Concerning the use of low-intensity warfarin and its combination with aspirin for primary coronary prevention, the available evidence is fairly sparse at present.

The European reviewers agree with the North American recommendations on the use of thrombolytic drugs in acute myocardial infarction,63but have some reservations that the numerous subgroups described may somewhat confuse the practicing physician or busy cardiologist. The recommendation to start with IV β-blockade in the acute phase of myocardial infarction in all patients without contraindications is based on the International Study on Infarct Survival-II and Metoprolol in Acute Myocardial Infarction trials, in which the overall very low mortality rate renders the interpretation difficult.6465 In one trial, IV β-blockade was even harmful.66 One also wonders whether the use of angiotensin-converting enzyme inhibitors would not be limited to patients with congestive heart failure or hypertension, rather than recommended for all patients with myocardial infarction.

In general, there is a good correlation between the coronary patency rates at 90 min after start of thrombolytic treatment and 30-day mortality, except for the Reteplase vs Alteplase Patency Investigation During the Acute Myocardial Infarction-II trial,67 in which no difference in mortality was found for patients with either grade 2 or 3 angiographic coronary flow as defined by the study Thrombolysis in Myocardial Infarction.

In discussing the equivalence or absence of superiority in direct comparisons among thrombolytic agents, an introductory paragraph on the concept of equivalence would be desirable, and the upper boundary for equivalence or noninferiority needs to be specified. In a conventional equivalence trial, the starting point is the belief that treatments are identical, and the objective is to confirm this. There is no general agreement about what is acceptable as equivalence in the effect of treatments in myocardial infarction. In the first trial of thrombolytic agents in which equivalence was the declared end point (International Joint Efficacy Comparison of Thrombolytics),68equivalence was defined as the fatality rates of the two treatments being within 1%. On this basis, streptokinase and reteplase were equivalent. However, in the Continuous Infusion vs Double-Bolus Administration of Alteplase study69which compared two regimens of alteplase, equivalence was defined as the total mortality in the two groups being within 0.4%. In as much as a higher mortality was observed with the new, double-bolus regimen, equivalence could not be claimed (upper 95% boundary of equivalence, 0.49%, which exceeded the prespecified upper limit of 0.40%). The recent Assessment of the Safety and Efficacy of a New Thrombolytic Agent-II70and Intravenous mTPA for Treatment of Infarcting Myocardium Early-II71 trials were also equivalence or noninferiority trials that used a 1% absolute or 14% relative difference70and a ratio of 1.196 as upper limits71 of equivalence for 30-day mortality. There are clearly statistical problems here that need to be resolved in guidelines.

The chapter could also have included a final paragraph on the generality of the results of clinical trials, in which the mortality rate is so much lower than those observed in complete registers of all heart attack admissions.

In the North American document, the recommended dosage of aspirin in patients with coronary bypass graft is 325 mg/d started within 6 h of surgery (A1 level).72 It is stated that aspirin, 100 mg/d, was not consistently effective, referring to two small trials, one of which was negative and the other equivocal. However, the results in this context of a large trial have been ignored.72) In this trial, aspirin 50 mg tid, and aspirin 50 mg tid plus dipyridamole, were compared with placebo.73Occlusion rates were 14% (aspirin), 13% (aspirin plus dipyridamole), and 18% (placebo). The difference between aspirin and placebo approached statistical significance in a ratio estimate analysis, whereas multivariate analysis revealed a significant benefit (odds ratio, 0.73; 95% confidence intervals, 0.54 to 0.99). Furthermore, meta-analyses performed by the Antiplatelet Trialist’s Collaboration in these and other high-risk patients provided no evidence that low-dose aspirin is less effective than high-dose aspirin.74

For these reasons, the recommended dose of aspirin after coronary artery bypass surgery could be lowered to 75 mg qd. Aspirin is recommended for circa 1 year, as longer-term trials demonstrating benefit in terms of patency have not been conducted. Its continued use after 1 year in patients with saphenous vein to coronary artery grafts is justified on the grounds of the beneficial effect of aspirin in coronary artery disease. There is no unequivocal support for the use of coumarin anticoagulation, although the trials were too low-powered to exclude benefit in all patients and circumstances.75

Oral anticoagulants rather than aspirin, alone or in combination with aspirin, should be considered after coronary artery bypass surgery in patients in whom oral anticoagulants are simultaneously indicated, for example because of heart valve replacement or AF.

Recommending ticlopidine in patients who are allergic to aspirin is one option. Since the publication of the Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events study,76 clopidogrel instead of ticlopidin should now be recommended. Warfarin is another alternative, considering that several trials showed no differences comparing oral anticoagulants to either aspirin or aspirin plus dipyridamole.

Antithrombotic drugs showed no benefit with regard to patency of internal mammary artery (IMA) grafts, mainly due to their low occlusion rates. It is likely that this observation was biased by selection of patients and coronary arteries to be grafted. In an analysis of vein and IMA grafts,77 location of distal anastomosis and internal diameter of the grafted coronary artery were identified as independent predictors of graft occlusion rather than graft material (vein or IMA). Thus, apart from coronary heart diseases, antithrombotic drug therapy, preferably aspirin, should be recommended after IMA grafting.

Full agreement exists with the recommendations made by the North American consensus group,78 but a few qualifications are required.

First, it is reemphasized that the main aims of antithrombotic therapy are to prevent cardiovascular events and to retard local progression of the disease. These aims are not well demonstrated in patients with peripheral arterial occlusive disease. Particularly, the data on aspirin are poor in this category of patients: no single study with clinical end points yields significant results, and the reduction of vascular mortality, nonfatal stroke, and myocardial infarction was only 15.7% (not significant) in the Antiplatelet Trialist’s meta-analysis.74 One suggestion is to split this category: for patients with known cardiovascular or cerebrovascular disease (those who survived a myocardial infarction or stroke), the recommendation could remain at an A1 level; for the rest, a level of B2 is more appropriate. In addition, the data on aspirin are more scanty than that on ticlopidine, which received a B2 level recommendation. Not all the available data with ticlopidine are referred to in the consensus text, and it may well be that ticlopidine has better credentials than aspirin. Therefore, patients who do not tolerate aspirin or who experience a major cardiovascular event despite aspirin intake should be changed to ticlopidine, or preferably to clopidogrel, which has similar clinical efficacy but a better safety profile.,79 Of course, cost-benefit is another aspect that deserves further attention, and this applies as well for clopidogrel as for ticlopidine.

Intra-arterial thrombolysis for acute leg ischemia is practiced in a number of European centers with alteplase (recombinant tissue plasminogen activator [rtPA]) as well as with urokinase. The Surgery vs Thrombolysis for Ischemia of the Lower Extremity trial80 found no difference in efficacy and safety between rtPA and urokinase, but the summary table only retains urokinase as a B2 recommendation, which most probably corresponds to the US practice.

Newer data on prostaglandins and cilostazol published in the last 2 years will presumably be discussed in the next North American consensus conference. Although prostaglandins do have antiplatelet effects, their use in end-stage leg arterial disease is not intended to compete with aspirin. Defibrotide is an oligonucleotide endowed with antithrombotic properties and tested in Italy, but its effectiveness needs to be confirmed in further trials. Regarding trials with pentoxifylline, the end point was intermittent claudication, not thrombotic events.

This chapter is an impressive document, but is clearly written from a US perspective, with overwhelming emphasis on thrombolytic therapy using alteplase (rtPA).81 For European readers for whom rtPA use in acute stroke is not approved or even prohibited (eg, in France), the discussion may be less relevant.

Acute Treatment of Ischemic Stroke

A discussion on the heterogeneity of ischemic stroke would have probably been a better starting point for this chapter. Subtyping ischemic stroke is crucial to patient management. Which clinician can seriously admit that the benefits and risks of alteplase (rtPA) are similar in a young person with embolism from the heart to the middle cerebral artery, as in a frail hypertensive octogenerian with a lacunar infarct? A post hoc analysis on small subgroups of patients is inadequate to conclude that the benefits of rtPA are consistent regardless of age, stroke subtype, and stroke severity. The importance of subtyping is illustrated in the recently reported Pro-urokinase in Acute Cerebral Thromboembolism II study,82 which demonstrates benefit of thrombolysis for up to 6 h (thus far beyond the 3 h currently admitted) in patients with angiographically confirmed total occlusion of the middle cerebral artery.

With the present criteria, only 3 to 5% of patients admitted in most centers with ischemic stroke are candidates for thrombolytic therapy. The risk of intracranial hemorrhage increases if the criteria are violated; hence, thrombolytic treatment is better reserved for experienced stroke units. In addition, thrombolytic therapy in acute ischemic stroke is a rapidly moving field with new trials already reported (Standard Treatment with Activase to Reverse Stroke,83; Thrombolysis or Acute NonInterventional Therapy in Ischemic Stroke,84 and Pro-Urokinase in Acute Cerebral Thromboembolism II82) or even the published European Cooperative Acute Stroke Study II.85 The last mentioned study,85 a double-blind study of alteplase, 0.9 mg/kg, vs placebo within 6 h of stroke onset, enrolled 880 patients. CT excluded patients with signs of major infarction. The primary end point was the modified Rankin scale at 90 days, dichotomized for favorable and unfavorable outcome. A nonsignificant trend for a favorable outcome was obtained in alteplase-treated patients; shifting the dichotomy in a post hoc analysis eventually yielded a significant benefit of alteplase. Symptomatic intracranial bleeding occurred in 8.8% of alteplase-patients and in 3.4% of placebo-treated patients.

If thrombolysis is only to be used in a minority of patients, the available evidence suggests that aspirin should currently be the basic treatment for most patients with ischemic stroke. The International Stroke Trial86and the Chinese Acute Stroke Trial87 show that aspirin significantly decreases the risk of death and of early recurrence after a first ischemic stroke. By contrast, there is no evidence at present that heparin is effective in the treatment of acute ischemic stroke. Nevertheless, low-dose heparin or LMW heparin is frequently used in patients with hemiplegia or with restricted mobility of any cause to decrease the risk of venous thromboembolism, despite lack of documented clinical efficacy. The trials to support that practice are less numerous in stroke patients than in surgical patients, and studied surrogate end points only.

Cerebral venous thrombosis leads to a different type of stroke than arterial obstruction, and therefore deserves a separate discussion. So far, there is no indication at all that aspirin may be beneficial in this condition. Two randomized trials studied heparin therapy: heparin is safe, and the benefit of using it appears clinically relevant when the results of both trials are combined.8889

Prevention of Stroke

Aspirin is the only antiplatelet drug tested in primary prevention. It was not found to reduce the risk of stroke, although it did reduce the risk of myocardial infarction. In patients with AF, it decreases the risk of embolism by about 20%, far less than that achieved with oral anticoagulants, and is therefore reserved for those at low risk of embolism (see section on AF).

In Europe, expert opinions regarding the merits of individual antithrombotic agents in secondary stroke prevention vary as much as in North America. The juxtaposition of data from the European Stroke Prevention-II study,90 Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events trial,76 and Ticlopidine Aspirin Stroke Study trial91 in a single Figure is better avoided. It may be even misleading, as it suggests that the data were obtained from a direct comparison.

The Warfarin vs Aspirin Reocclusion Stroke Study trial is not the only ongoing trial to investigate further the role of anticoagulants vs aspirin in secondary prevention. Also, the ongoing European and Australian Stroke Prevention in Reversible Ischemia Trial compares oral anticoagulation (INR, 2.0 to 3.0) with aspirin, 30 to 325 mg, or the combination of aspirin, 30 to 325 mg, and dipyridamole, 400 mg.

The section on the failure to prevent restenosis after coronary angioplasty is a useful review of the literature.92One can further add that a grade A2 trial with UH, 12,500 IU bid for 4 months, did not reveal any benefit in the 4 months angiographic minimal lumen diameters, compared to the no-heparin group.93

The recommendation to use aspirin and ticlopidine vs an aspirin plus warfarin approach already demonstrated in the Intracoronary Stenting and Antithrombotic Regimen trial94has been confirmed by the Full Anticoagulation vs Aspirin and Ticlopidin95and Multicenter Aspirin and Ticlopidine Trial After Intracoronary Stenting96trials. The Clopidogrel/Aspirin Stent International Cooperative Study97 showed no superiority of clopidogrel compared with ticlopidine after coronary stenting, but the finding of fewer side effects with clopidogrel confirms that it is to be preferred to ticlopidine.

This chapter is an excellent review of the difficult problem of antithrombotic and thrombolytic therapy in children.98 Most of the recommendations are also applicable to European countries.

The protocol for systemic heparin administration and adjustment for pediatric patients is applicable for APTT with an upper normal limit of 48 s. The APTT nomogram has to be adjusted according to the APTT reagent. A nomogram for APTT reagent with an upper normal limit of 42 s has been published.99

Two plausible explanations for the increased heparin requirement in young children are presented in the section on pharmacokinetics. A third one is the different ratio of extracellular to intracellular space in the newborn, because substances that act in the extracellular space require a relatively higher dose. When the dosage is calculated per kilogram of body weight, a newborn requires approximately double the quantity of a medication than does an adult. The converting factor from kilogram body weight to square meter body surface is 20 for an infant, approximately 30 for an older child, and approximately 40 for an adult. This led to dosage recommendations according to body surface.99

In the North American document, the use of warfarin for children is mentioned; in some European countries, other coumarin derivatives are used. The rather short half-life of warfarin compared with phenprocoumon allows corrections within a shorter period of time, but needs more controls and corrections of dose. A nomogram for phenprocoumon based on children’s’ body weight has been published.99 If anticoagulant therapy has to be reversed owing to life-threatening bleeding, particularly intracranial hemorrhage, the immediate application of a virus-inactivated prothrombin complex concentrate should be the first recommendation. The exclusive IV use of vitamin K1 is not capable of reversing the anticoagulant effect fast enough, and therefore may cause serious consequences.

The transfer of oral anticoagulants, such as warfarin, acenocoumarol, and phenprocoumon, into human milk is minimal. Some pediatricians nevertheless recommended a weekly oral supplement of 1 mg vitamin K1; occasional monitoring of the prothrombin time is advisable.

If thrombolytic therapy is performed using alteplase, a bolus injection should be administered. In case of severe bleeding complications during thrombolytic therapy, in particular if they are caused by a reduced fibrinogen, a commercially available, virus-inactivated fibrinogen concentrate is to be preferred over cryoprecipitate because of fewer side effects.

To treat children with a homozygous protein C deficiency, the use of protein C concentrates is preferred to fresh frozen plasma. Normal plasma levels of protein C can be achieved using small infusion volumes, whereas the use of fresh frozen plasma provides a bad recovery in relation to the volume infused. Furthermore, a long-term prophylaxis with a protein C concentrate in combination with an oral anticoagulant should be considered. This treatment regimen allows a milder anticoagulation (INR, 2.0 to 3.0) combined with a remarkably low incidence of complications (bleedings, thromboembolic complications, skin necrosis).

The best prophylaxis of thromboembolism is to recognize, avoid, and remove risk factors. This is particularly relevant in childhood, where risk factors could be found in 96% of thromboembolism (adults in only 30%); 84% had at least two risk factors, and 44% had more than three risk factors. Preventive measures are strict indications for central venous or arterial lines for example, or early cardiac surgery in cyanotic heart disease with high hematocrit. In some cases of lupus erythematodes, antiphospholipid antibody syndrome, carbohydrate deficiency, glycoprotein syndrome, secondary thrombocytosis after splenectomy and postsurgical immobilization of juveniles after puberty, antithrombotic prophylaxis has to be considered.

In many chapters, the benefit of treatment is given as a percentage reduction of the treatment to be tested against the comparator. This information can be misleading in that it does not define the effectiveness of treatment in the context of the disease being assessed. More useful for the practicing clinician is the expression of results in the format of the numbers needed to treat. This format indicates both the efficacy of the drug and also the number of clinical events in the population of patients to whom the drug is given.

There has been in the last year a gratifying increase in clinical trials leading to grade A recommendations (in 1986, 17 out of 72 recommendations were grade A level; in 1998, 91 out of 207 recommendations). Considering the many uncertainties that still prevail and the divergent opinions among experts, more clinical trials, independently designed, organized, and conducted, are needed. Although funding of pivotal trials can readily be obtained, this is far more difficult for subsequent confirmatory large-scale trials, and one may consider this to be the task of foundations or governmental agencies, possibly in conjunction with relevant pharmaceutical companies.

Members of the European Working Group include the following: P.R.F. Bell (Leicester, United Kingdom); M.E. Bertrand (Lille, France); D. Bergqvist (Uppsala, Sweden); H. Bounameaux (Genève, Switzerland); M.G. Bousser (Paris, France); H. Büller (Amsterdam, The Netherlands); E.G. Butchart (Cardiff, United Kingdom); S. Coccheri (Bologna, Italy); A. Cohen (London, United Kingdom); J. Conard (Paris, France); D. de Bono (Leicester, United Kingdom); C.D. Forbes (Dundee, United Kingdom); S. Haas (Münich, Germany); J. Hampton (Nottingham, United Kingdom); M. Hellgren (Göteborg, Sweden); P.J. Koudstaal (Rotterdam, The Netherlands); W. Kreuz (Frankfurt, Germany); B. Lämmle (Bern, Switzerland); K. Lechner (Wien, Austria); S. Levy (Marseille, France); G.Y.H. Lip (Birmingham, United Kingdom); G. Lowe (Glasgow, United Kingdom); J.P. Michel (Paris, France); G. Montalescot (Paris, France); R.S. More (London, United Kingdom); P. Petersen (Hvidovre, Denmark); M. Pfisterer (Basel, Switzerland); A. Planes (La Rochelle, France); M. Pini (Parma, Italy); P. Prandoni (Padova, Italy); C. Prentice (Leeds, United Kingdom); W. Robberecht (Leuven, Belgium); M. Samama (Paris, France); A.H. Sutor (Freiburg, Germany); M.L. Simoons (Rotterdam, The Netherlands); G.P. Taylor (London, United Kingdom); J. van der Meer (Groningen, The Netherlands); F. Van de Werf (Leuven, Belgium); C. Van Geet (Leuven, Belgium); J. van Gyn (Utrecht, The Netherlands); R. Verhaeghe (Leuven, Belgium); F.W.A. Verheugt (Nijmegen, The Netherlands), M. Verstraete (Leuven, Belgium); I. Walker (Glasgow, United Kingdom); and L. Wallentin (Uppsala, Sweden).

Abbreviations: ACCP = American College of Chest Physicians; AF = atrial fibrillation; APTT = activated partial thromboplastin time; IMA = internal mammary artery; INR = international normalized ratio; LMW = low-molecular-weight; rtPA = recombinant tissue plasminogen activator; UH = unfractionated heparin

Dalen, JE, Hirsh, J (1998) American College of Chest Physicians Conference on Antithrombotic Therapy.Chest114,439S-767S. [CrossRef] [PubMed]
 
Ginsburg, JS, Hirsh, J Use of antithrombotic agents during pregnancy.Chest1998;114,524S-530S. [CrossRef] [PubMed]
 
Nordstrõm, M, Lindblad, B, Bergqvist, D, et al A prospective study of the incidence of deep-vein thrombosis within a defined urban population.J Intern Med1992;232,155-160. [CrossRef] [PubMed]
 
Grandone, E, Margaglione, M, Colaizzo, D, et al Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations.Am J Obstet Gynecol1998;179,1324-1328. [CrossRef] [PubMed]
 
Blombäck, M, Bremme, K, Hellgren, M, et al Thromboprophylaxis with low molecular mass heparin, Fragmin (dalteparin), during pregnancy: a longitudinal safety study.Blood Coagul Fibrinolysis1998;9,1-9. [PubMed]
 
Sanson, BJ, Lensing, AWA, Prins, MH, et al Safety of low molecular weight heparin in pregnancy: a systematic review.Thromb Haemost1999;81,668-672. [PubMed]
 
Brennand, JE, Walker, ID, Greer, IA Anti-activated factor X profiles in pregnant women receiving antenatal thromboprophylaxis with Enoxaparin.Acta Hematol1999;101,53-55. [CrossRef]
 
Blombäck, M, Bremme, K, Hellgren, M, et al A pharmacokinetic study of dalteparin (Fragmin) during late pregnancy.Blood Coagul Fibrinolysis1998;9,343-350. [CrossRef] [PubMed]
 
Thomson, AJ, Walker, ID, Greer, IA Low molecular weight heparin for immediate management of thromboembolic disease in pregnancy [letter]. Lancet. 1998;;352 ,.:1904
 
Watson, WJ, Freeman, J, O’Brien, C, et al Embolic stroke in a pregnant patient with a mechanical heart valve on optimal heparin therapy.Am J Perinatol1996;13,371-372. [CrossRef] [PubMed]
 
Tam, WH, Wong, KS, Yuen, PM, et al Low molecular weight heparin and thromboembolism in pregnancy [letter]. Lancet. 1999;;353 ,.:932
 
Hunt, BJ, Doughty, HA, Majumdar, G, et al Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies.Thromb Haemost1997;77,39-43. [PubMed]
 
Dulitzki, M, Pauzner, R, Landevitz, P, et al Low molecular weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies.Obstet Gynecol1996;77,39-43
 
Clagett, GP, Andersson, FA, Geerts, W, et al Prevention of venous thromboembolism.Chest1998;114(suppl),531S-560S
 
Prentice, CRM Are symptomatic endpoints acceptable in venous thromboprophylactic studies?Haemostasis1998;28(suppl3),109-112
 
Warwick, D, Williams, MH, Bannister, GC Death and thromboembolic disease after total hip replacement: a series of 1162 cases with no routine chemical prophylaxis.J Bone Joint Surg Br1995;77,6-10. [PubMed]
 
Fender, D, Harper, WM, Thompson, JR, et al Mortality and fatal pulmonary embolism post primary total hip replacement: results from a regional hip register.J Bone Joint Surg Br1997;79,896-899. [CrossRef] [PubMed]
 
The Pulmonary Embolism Prevention (PEP) Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: the Pulmonary Embolism Prevention (PET) trial.Lancet2000;355,1295-1302. [CrossRef] [PubMed]
 
for the Prophylaxis in Medical Patients with Enoxaparin Study Group. Samama, MM, Cohen, AT, Darmon, JY, et al A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients.N Engl J Med1999;34,793-800
 
Murray, DW, Carr, AJ, Bulstrode, CJK Pharmacological thromboprophylaxis and total hip replacement.J Bone Joint Surg Br1995;77,3-5. [PubMed]
 
Handoll HHG, Farrar MJ, McBirnie J, et al. Prophylaxis using heparin, low molecular weight heparin and physical methods against deep vein thrombosis and pulmonary embolism in hip fracture surgery. Cochrane Library 1998; Issue 1. Oxford, UK: Update Software.
 
Hyers, TM, Agnelli, G, Hull, RD, et al Antithrombotic therapy for venous thromboembolic disease.Chest1998;114(suppl),561S-578S
 
Monreal, M, Lafoz, E, Olive, A, et al Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contra-indications to coumarin.Thromb Haemost1994;71,7-11. [PubMed]
 
Pini, M, Aiello, S, Manotti, C, et al Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis.Thromb Haemost1994;72,191-197. [PubMed]
 
Lopaciuk, S, Bielska-Falda, H, Noszczyk, W, et al Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis.Thromb Haemost1999;81,26-31. [PubMed]
 
Schulman, S, Granqvist, S, Holmstrom, M, et al The duration of oral anticoagulant therapy after a second episode of venous thromboembolism.N Engl J Med1997;336,393-398. [CrossRef] [PubMed]
 
Prandoni, P, Lensing, AWA, Cogo, A, et al The long-term clinical course of acute deep venous thrombosis.Ann Intern Med1996;125,1-7. [PubMed]
 
Goldhaber, SZ Pulmonary embolism.N Engl J Med1998;399,93-94
 
Laupacis, A, Albers, GW, Dalen, JE, et al Antithrombotic therapy in atrial fibrillation.Chest1998;114(suppl),579S-589S
 
Atrial Fibrillation Investigators.. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.Arch Intern Med1994;154,1449-1457. [CrossRef] [PubMed]
 
Atrial Fibrillation Investigators.. Echocardiographic predictors of stroke in patients with atrial fibrillation.Arch Intern Med1998;158,1316-1320. [CrossRef] [PubMed]
 
Lip, GYH Thromboprophylaxis for atrial fibrillation.Lancet1999;353,4-6. [CrossRef] [PubMed]
 
Lip, GYH Does paroxysmal atrial fibrillation confer a paroxysmal thromboembolic risk?Lancet1997;349,1565-1566. [CrossRef] [PubMed]
 
SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators. Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III Study.JAMA1998;279,1673-1677
 
Sudlow, M, Thomson, R, Thwaites, B, et al Prevalence of atrial fibrillation and eligibility for anticoagulants in the community.Lancet1998;352,1167-1171. [CrossRef] [PubMed]
 
Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation-III randomised clinical trial.Lancet1996;348,633-638. [CrossRef] [PubMed]
 
The European Atrial Fibrillation Trial Study Group.. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke.Lancet1993;342,1255-1262. [PubMed]
 
Van Latum, JC, Koudstaal, PJ, van Kooten, F, et al Predictors of major vascular events in patients with a transient ischemic attack or nondisabling stroke and with nonrheumatic atrial fibrillation.Stroke1995;26,801-806. [CrossRef] [PubMed]
 
Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Transesophageal echocardiographic correlates of thromboembolism in high risk patients with nonvalvular atrial fibrillation.Ann Intern Med1998;128,639-647. [PubMed]
 
Salem, DN, Levine, HJ, Pauker, SG, et al Antithrombotic therapy in valvular heart disease.Chest1998;114(suppl),590S-601S
 
Maze, SS, Kotler, MN, Parry, WR Flow characteristics in the dilated left ventricle with thrombus: qualitative and quantitative Doppler analysis.J Am Coll Cardiol1989;13,873-881. [CrossRef] [PubMed]
 
Movsovitz, C, Movsowitz, HD, Jacobs, LE, et al Significant mitral regurgitation is protective against left atrial spontaneous echo contrast and thrombus as assessed by transesophageal echocardiography.J Am Soc Echocardiogr1993;6,107-114. [PubMed]
 
Stein, PD, Alpert, JS, Dalen, JE, et al Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.Chest1998;114(suppl),602S-610S
 
Dalen, JE, Hirsh, J Introduction: antithrombotic therapy—the evolving consensus: 1986 to 1988.Chest1998;114(suppl),439S-440S
 
Grunkemeier, GL, Starr, A, Rahimtoola, SH Prosthetic heart valve performance: long-term follow-up.Curr Probl Cardiol1992;17,331-406. [CrossRef]
 
Butchart, EG, Moreno de la Santa, P, Rooney, SJ, et al Arterial risk factors and ischemic cerebrovascular events after aortic valve replacement.J Heart Valve Dis1995;4,1-8. [PubMed]
 
Bamford, J, Sandercook, P, Dennis, M, et al Classification and natural history of clinically identifiable subtypes of cerebral infarction.Lancet1991;337,1521-1526. [CrossRef] [PubMed]
 
Butchart, EG Thrombogenicity, thrombosis and embolism. Butchart, EG Bodnar, E eds.Current issues in heart valve disease: thrombosis, embolism and bleeding1992,172-205 ICR Publishers. London, UK:
 
Stein, PD, Alpert, JS, Copeland, J, et al Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.Chest1992;102(suppl),445S-455S
 
Horstkotte, D, Schulte, HD, Bircks, W, et al Lower intensity anticoagulation therapy results in lower complication rates with the St. Jude medical prosthesis.J Thorac Cardiovasc Surg1994;107,1136-1145. [PubMed]
 
Cannegieter, SC, Rosendaal, FR, Wintzen, AR, et al Optimal oral anticoagulant therapy in patients with mechanical heart valves.N Engl J Med1995;333,11-17. [CrossRef] [PubMed]
 
Pouleur, H, Buyse, M Effects of dipyridamole in combination with anticoagulant therapy on survival and thromboembolic events in patients with prosthetic heart valves: a meta-analysis of the randomized trials.J Thorac Cardiovasc Surg1995;110,463-472. [CrossRef] [PubMed]
 
Cappelleri, JC, Fiore, L, Brophy, M, et al Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a meta-analysis.Am Heart J1995;130,547-552. [CrossRef] [PubMed]
 
Cairns, JA, Théroux, P, Lewis, HD, et al Antithrombotic agents in coronary artery disease.Chest1998;114(suppl),611S-633S
 
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.Lancet1988;ii,349-360
 
The PURSUIT Trial Investigators.. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes.N Engl J Med1998;339,436-443. [CrossRef] [PubMed]
 
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by unstable Signs and Symptoms (PRISM-Plus) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction.N Engl J Med1998;338,1488-1495. [CrossRef] [PubMed]
 
Hamm, CW, Heeschen, C, Goldmann, B, et al Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels.N Engl J Med1999;340,1623-1629. [CrossRef] [PubMed]
 
Cohen, M, Demers, C, Gurfinkel, EP, et al A comparison of low-molecular weight heparin with unfractionated heparin for unstable coronary artery disease.N Engl J Med1997;337,447-452. [CrossRef] [PubMed]
 
Antman, EM, McCabe, CH, Gurfinkel, EP, et al Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 11B study.Circulation1999;99,1593-1601. [CrossRef] [PubMed]
 
Fragmin, and Fast Revascularisation during Instable Artery Disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicentre study.Lancet1999;354,708-715. [CrossRef] [PubMed]
 
Hansson, L, Zanchetti, A, Carruthers, S, et al Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.Lancet1998;351,1755-1762. [CrossRef] [PubMed]
 
Cairns, JA, Kennedy, JW, Fuster, V Coronary thrombolysis.Chest1998;114(suppl),634S-657S
 
ISIS-1 (First International Study of Infarct Survival) Collaborative Study Group. Mechanisms for the early mortality reduction produced by beta-blockade started early in acute myocardial infarction: ISIS-1.Lancet1988;I,921-923
 
Olsson, G, Oden, A, Johanson, L, et al Prognosis after withdrawal of chronic postinfarction metoprolol treatment: a 2–7 year follow-up.Eur Heart J1988;9,365-372. [PubMed]
 
Pfisterer M, Cox JL, Granger CB, et al. Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience; global utilization of streptokinase and TPA (alteplase) for occluded coronary arteries. J Am Coll Cardiol 1098; 32:634–640.
 
Bode, C, Smalling, W, Berg, G, et al Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction.Circulation1996;94,891-898. [CrossRef] [PubMed]
 
International Joint Efficacy Comparison of Thrombolytics.. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence.Lancet1995;346,329-336. [CrossRef] [PubMed]
 
The Continuous Infusion Versus Double-Bolus Administration of Alteplase (COBALT) Investigators. A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction.N Engl J Med1997;337,1124-1130. [CrossRef] [PubMed]
 
Assessment of the Safety, and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial.Lancet1999;354,716-722. [CrossRef] [PubMed]
 
Antman, EM, Wilcox, RG, Giugliano, RP, et al Long-term comparison of lanoteplase and alteplase in ST elevation myocardial infarction: 6 months follow-up in InTIME II trial [abstract].Circulation1999;100,I-498
 
Stein, PD, Dalen, JE, Goldman, S, et al Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts.Chest1998;114(suppl),658S-665S
 
Sanz, G, Pajaron, A, Alegria, E, et al Prevention of early aortocoronary bypass occlusion by low-dose aspirin and dipyridamole.Circulation1990;182,765-773
 
Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy -III. Br Med J 1994; 308:81–106/159–168/235–246.
 
The Post Coronary Artery Bypass Graft Trial Investigators.. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in obstructive changes in saphenous-vein coronary-artery bypass grafts.N Engl J Med1997;336,153-162. [CrossRef] [PubMed]
 
Caprie Steering Committee.. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE).Lancet1996;348,1329-1339. [CrossRef] [PubMed]
 
van der Meer, J, Hillege, HL, van Gilst, WH, et al A comparison of internal mammary artery and saphenous vein grafts after coronary artery bypass surgery: no difference in one-year occlusion rates and clinical outcome.Circulation1994;90,2367-2374. [CrossRef] [PubMed]
 
Jackson, MR, Clagett, GP Antithrombotic therapy in peripheral arterial occlusive disease.Chest1998;114(suppl),660S-682S
 
Harker, LR, Boissel, JP, Pilgrin, AJ, et al Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE.Drug Saf1999;4,325-335
 
The STILE Investigators.. Results of a prospective randomised trial evaluating surgery versus thrombolysis for ischemia of the lower extremity: the STILE trial.Ann Surg1994;220,251-268. [CrossRef] [PubMed]
 
Albers, GW, Easton, JD, Sacco, RL, et al Antithrombotic and thrombolytic therapy for ischemic stroke.Chest1998;114(suppl),683S-698S
 
Furlan, AJ PROACT II: recombinant pro-urokinase (r-ProUK) in acute cerebral thromboembolism: initial trial results; the PROACT II investigators [abstract]. Stroke. 1999;;30 ,.:234
 
Albers, GW Prospective, monitored, multicenter, post-approval experience with intravenous t-PA for treatment of acute stroke: the Standard Treatment with Activase to Reverse Stroke (STARS) Study [abstract]. Stroke. 1999;;30 ,.:244
 
Clark, WM, Albers, GW The ATLANTIS rt-PA (alteplase) Acute Stroke Trial: final results [abstract]. Stroke. 1999;;30 ,.:234
 
Hacke, W, Kaste, M, Fieschi, C, et al Randomised double-blind trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II).Lancet1998;352,1245-1251. [CrossRef] [PubMed]
 
International Stroke Trial Collaborative Group.. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both or neither among 19,435 patients with acute ischemic stroke.Lancet1997;349,1569-1581. [CrossRef] [PubMed]
 
CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke.Lancet1997;349,1641-1649. [CrossRef] [PubMed]
 
Einhäupl, KM, Villringer, A, Meister, W, et al Heparin treatment in sinus venous thrombosis.Lancet1991;338,597-600. [CrossRef] [PubMed]
 
De Bruijn, SFTM, Stam, J Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis.Stroke1999;30,484-488. [CrossRef] [PubMed]
 
Diener, H, Cunha, L, Forbes, C, et al European Stroke Prevention Study 2: Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.J Neurol Sci1996;143,1-13. [CrossRef] [PubMed]
 
Hass, WK, Easton, JD, Adam, HP, Jr, et al A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients: the Ticlopidin Aspirin Stroke Study Group.N Engl J Med1989;321,501-507. [CrossRef] [PubMed]
 
Popma, JJ, Weitz, J, Bittle, JA, et al Antithrombotic therapy in patients undergoing coronary angioplasty.Chest1998;114(suppl),728S-741S
 
Brack, MJ, Ray, S, Chauhan, A, et al Results of a multicenter randomised trial investigating the effects of high dose unfractionated heparin on angiographic restenosis and clinical outcome: the Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial.J Am Coll Cardiol1995;26,947-954. [CrossRef] [PubMed]
 
Schomig, A, Neumann, FJ, Kastra, A, et al A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary stents.N Engl J Med1996;334,1084-1089. [CrossRef] [PubMed]
 
Bertrand, MF, Legrand, V, Boland, J, et al Randomised multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study.Circulation1998;98,1597-1603. [CrossRef] [PubMed]
 
Urban, P, Macaya, C, Rupprecht, H, et al Randomised evaluation of anticoagulant versus antiplatelet therapy after coronary stent implantation in high risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS).Circulation1998;98,2126-2132. [CrossRef] [PubMed]
 
Bertrand, ME, Rupprecht, HJ, Urban, P, et al Comparative safety of ticlopidine and clopidogrel in coronary stent patients: data from CLASICS [abstract].Circulation1999;100,I-620
 
Michelson, AD, Bovil, E, Monagle, P, et al Antithrombotic therapy in children.Chest1998;114(suppl),748S-769S
 
Sutor, AH, Massicotte, P, Leaker, M, et al Heparin therapy in pediatric patients.Semin Thromb Hemost1997;23,303-320. [CrossRef] [PubMed]
 

Figures

Tables

References

Dalen, JE, Hirsh, J (1998) American College of Chest Physicians Conference on Antithrombotic Therapy.Chest114,439S-767S. [CrossRef] [PubMed]
 
Ginsburg, JS, Hirsh, J Use of antithrombotic agents during pregnancy.Chest1998;114,524S-530S. [CrossRef] [PubMed]
 
Nordstrõm, M, Lindblad, B, Bergqvist, D, et al A prospective study of the incidence of deep-vein thrombosis within a defined urban population.J Intern Med1992;232,155-160. [CrossRef] [PubMed]
 
Grandone, E, Margaglione, M, Colaizzo, D, et al Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations.Am J Obstet Gynecol1998;179,1324-1328. [CrossRef] [PubMed]
 
Blombäck, M, Bremme, K, Hellgren, M, et al Thromboprophylaxis with low molecular mass heparin, Fragmin (dalteparin), during pregnancy: a longitudinal safety study.Blood Coagul Fibrinolysis1998;9,1-9. [PubMed]
 
Sanson, BJ, Lensing, AWA, Prins, MH, et al Safety of low molecular weight heparin in pregnancy: a systematic review.Thromb Haemost1999;81,668-672. [PubMed]
 
Brennand, JE, Walker, ID, Greer, IA Anti-activated factor X profiles in pregnant women receiving antenatal thromboprophylaxis with Enoxaparin.Acta Hematol1999;101,53-55. [CrossRef]
 
Blombäck, M, Bremme, K, Hellgren, M, et al A pharmacokinetic study of dalteparin (Fragmin) during late pregnancy.Blood Coagul Fibrinolysis1998;9,343-350. [CrossRef] [PubMed]
 
Thomson, AJ, Walker, ID, Greer, IA Low molecular weight heparin for immediate management of thromboembolic disease in pregnancy [letter]. Lancet. 1998;;352 ,.:1904
 
Watson, WJ, Freeman, J, O’Brien, C, et al Embolic stroke in a pregnant patient with a mechanical heart valve on optimal heparin therapy.Am J Perinatol1996;13,371-372. [CrossRef] [PubMed]
 
Tam, WH, Wong, KS, Yuen, PM, et al Low molecular weight heparin and thromboembolism in pregnancy [letter]. Lancet. 1999;;353 ,.:932
 
Hunt, BJ, Doughty, HA, Majumdar, G, et al Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies.Thromb Haemost1997;77,39-43. [PubMed]
 
Dulitzki, M, Pauzner, R, Landevitz, P, et al Low molecular weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies.Obstet Gynecol1996;77,39-43
 
Clagett, GP, Andersson, FA, Geerts, W, et al Prevention of venous thromboembolism.Chest1998;114(suppl),531S-560S
 
Prentice, CRM Are symptomatic endpoints acceptable in venous thromboprophylactic studies?Haemostasis1998;28(suppl3),109-112
 
Warwick, D, Williams, MH, Bannister, GC Death and thromboembolic disease after total hip replacement: a series of 1162 cases with no routine chemical prophylaxis.J Bone Joint Surg Br1995;77,6-10. [PubMed]
 
Fender, D, Harper, WM, Thompson, JR, et al Mortality and fatal pulmonary embolism post primary total hip replacement: results from a regional hip register.J Bone Joint Surg Br1997;79,896-899. [CrossRef] [PubMed]
 
The Pulmonary Embolism Prevention (PEP) Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: the Pulmonary Embolism Prevention (PET) trial.Lancet2000;355,1295-1302. [CrossRef] [PubMed]
 
for the Prophylaxis in Medical Patients with Enoxaparin Study Group. Samama, MM, Cohen, AT, Darmon, JY, et al A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients.N Engl J Med1999;34,793-800
 
Murray, DW, Carr, AJ, Bulstrode, CJK Pharmacological thromboprophylaxis and total hip replacement.J Bone Joint Surg Br1995;77,3-5. [PubMed]
 
Handoll HHG, Farrar MJ, McBirnie J, et al. Prophylaxis using heparin, low molecular weight heparin and physical methods against deep vein thrombosis and pulmonary embolism in hip fracture surgery. Cochrane Library 1998; Issue 1. Oxford, UK: Update Software.
 
Hyers, TM, Agnelli, G, Hull, RD, et al Antithrombotic therapy for venous thromboembolic disease.Chest1998;114(suppl),561S-578S
 
Monreal, M, Lafoz, E, Olive, A, et al Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contra-indications to coumarin.Thromb Haemost1994;71,7-11. [PubMed]
 
Pini, M, Aiello, S, Manotti, C, et al Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis.Thromb Haemost1994;72,191-197. [PubMed]
 
Lopaciuk, S, Bielska-Falda, H, Noszczyk, W, et al Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis.Thromb Haemost1999;81,26-31. [PubMed]
 
Schulman, S, Granqvist, S, Holmstrom, M, et al The duration of oral anticoagulant therapy after a second episode of venous thromboembolism.N Engl J Med1997;336,393-398. [CrossRef] [PubMed]
 
Prandoni, P, Lensing, AWA, Cogo, A, et al The long-term clinical course of acute deep venous thrombosis.Ann Intern Med1996;125,1-7. [PubMed]
 
Goldhaber, SZ Pulmonary embolism.N Engl J Med1998;399,93-94
 
Laupacis, A, Albers, GW, Dalen, JE, et al Antithrombotic therapy in atrial fibrillation.Chest1998;114(suppl),579S-589S
 
Atrial Fibrillation Investigators.. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.Arch Intern Med1994;154,1449-1457. [CrossRef] [PubMed]
 
Atrial Fibrillation Investigators.. Echocardiographic predictors of stroke in patients with atrial fibrillation.Arch Intern Med1998;158,1316-1320. [CrossRef] [PubMed]
 
Lip, GYH Thromboprophylaxis for atrial fibrillation.Lancet1999;353,4-6. [CrossRef] [PubMed]
 
Lip, GYH Does paroxysmal atrial fibrillation confer a paroxysmal thromboembolic risk?Lancet1997;349,1565-1566. [CrossRef] [PubMed]
 
SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators. Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III Study.JAMA1998;279,1673-1677
 
Sudlow, M, Thomson, R, Thwaites, B, et al Prevalence of atrial fibrillation and eligibility for anticoagulants in the community.Lancet1998;352,1167-1171. [CrossRef] [PubMed]
 
Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation-III randomised clinical trial.Lancet1996;348,633-638. [CrossRef] [PubMed]
 
The European Atrial Fibrillation Trial Study Group.. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke.Lancet1993;342,1255-1262. [PubMed]
 
Van Latum, JC, Koudstaal, PJ, van Kooten, F, et al Predictors of major vascular events in patients with a transient ischemic attack or nondisabling stroke and with nonrheumatic atrial fibrillation.Stroke1995;26,801-806. [CrossRef] [PubMed]
 
Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Transesophageal echocardiographic correlates of thromboembolism in high risk patients with nonvalvular atrial fibrillation.Ann Intern Med1998;128,639-647. [PubMed]
 
Salem, DN, Levine, HJ, Pauker, SG, et al Antithrombotic therapy in valvular heart disease.Chest1998;114(suppl),590S-601S
 
Maze, SS, Kotler, MN, Parry, WR Flow characteristics in the dilated left ventricle with thrombus: qualitative and quantitative Doppler analysis.J Am Coll Cardiol1989;13,873-881. [CrossRef] [PubMed]
 
Movsovitz, C, Movsowitz, HD, Jacobs, LE, et al Significant mitral regurgitation is protective against left atrial spontaneous echo contrast and thrombus as assessed by transesophageal echocardiography.J Am Soc Echocardiogr1993;6,107-114. [PubMed]
 
Stein, PD, Alpert, JS, Dalen, JE, et al Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.Chest1998;114(suppl),602S-610S
 
Dalen, JE, Hirsh, J Introduction: antithrombotic therapy—the evolving consensus: 1986 to 1988.Chest1998;114(suppl),439S-440S
 
Grunkemeier, GL, Starr, A, Rahimtoola, SH Prosthetic heart valve performance: long-term follow-up.Curr Probl Cardiol1992;17,331-406. [CrossRef]
 
Butchart, EG, Moreno de la Santa, P, Rooney, SJ, et al Arterial risk factors and ischemic cerebrovascular events after aortic valve replacement.J Heart Valve Dis1995;4,1-8. [PubMed]
 
Bamford, J, Sandercook, P, Dennis, M, et al Classification and natural history of clinically identifiable subtypes of cerebral infarction.Lancet1991;337,1521-1526. [CrossRef] [PubMed]
 
Butchart, EG Thrombogenicity, thrombosis and embolism. Butchart, EG Bodnar, E eds.Current issues in heart valve disease: thrombosis, embolism and bleeding1992,172-205 ICR Publishers. London, UK:
 
Stein, PD, Alpert, JS, Copeland, J, et al Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.Chest1992;102(suppl),445S-455S
 
Horstkotte, D, Schulte, HD, Bircks, W, et al Lower intensity anticoagulation therapy results in lower complication rates with the St. Jude medical prosthesis.J Thorac Cardiovasc Surg1994;107,1136-1145. [PubMed]
 
Cannegieter, SC, Rosendaal, FR, Wintzen, AR, et al Optimal oral anticoagulant therapy in patients with mechanical heart valves.N Engl J Med1995;333,11-17. [CrossRef] [PubMed]
 
Pouleur, H, Buyse, M Effects of dipyridamole in combination with anticoagulant therapy on survival and thromboembolic events in patients with prosthetic heart valves: a meta-analysis of the randomized trials.J Thorac Cardiovasc Surg1995;110,463-472. [CrossRef] [PubMed]
 
Cappelleri, JC, Fiore, L, Brophy, M, et al Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a meta-analysis.Am Heart J1995;130,547-552. [CrossRef] [PubMed]
 
Cairns, JA, Théroux, P, Lewis, HD, et al Antithrombotic agents in coronary artery disease.Chest1998;114(suppl),611S-633S
 
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.Lancet1988;ii,349-360
 
The PURSUIT Trial Investigators.. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes.N Engl J Med1998;339,436-443. [CrossRef] [PubMed]
 
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by unstable Signs and Symptoms (PRISM-Plus) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction.N Engl J Med1998;338,1488-1495. [CrossRef] [PubMed]
 
Hamm, CW, Heeschen, C, Goldmann, B, et al Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels.N Engl J Med1999;340,1623-1629. [CrossRef] [PubMed]
 
Cohen, M, Demers, C, Gurfinkel, EP, et al A comparison of low-molecular weight heparin with unfractionated heparin for unstable coronary artery disease.N Engl J Med1997;337,447-452. [CrossRef] [PubMed]
 
Antman, EM, McCabe, CH, Gurfinkel, EP, et al Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 11B study.Circulation1999;99,1593-1601. [CrossRef] [PubMed]
 
Fragmin, and Fast Revascularisation during Instable Artery Disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicentre study.Lancet1999;354,708-715. [CrossRef] [PubMed]
 
Hansson, L, Zanchetti, A, Carruthers, S, et al Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.Lancet1998;351,1755-1762. [CrossRef] [PubMed]
 
Cairns, JA, Kennedy, JW, Fuster, V Coronary thrombolysis.Chest1998;114(suppl),634S-657S
 
ISIS-1 (First International Study of Infarct Survival) Collaborative Study Group. Mechanisms for the early mortality reduction produced by beta-blockade started early in acute myocardial infarction: ISIS-1.Lancet1988;I,921-923
 
Olsson, G, Oden, A, Johanson, L, et al Prognosis after withdrawal of chronic postinfarction metoprolol treatment: a 2–7 year follow-up.Eur Heart J1988;9,365-372. [PubMed]
 
Pfisterer M, Cox JL, Granger CB, et al. Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience; global utilization of streptokinase and TPA (alteplase) for occluded coronary arteries. J Am Coll Cardiol 1098; 32:634–640.
 
Bode, C, Smalling, W, Berg, G, et al Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction.Circulation1996;94,891-898. [CrossRef] [PubMed]
 
International Joint Efficacy Comparison of Thrombolytics.. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence.Lancet1995;346,329-336. [CrossRef] [PubMed]
 
The Continuous Infusion Versus Double-Bolus Administration of Alteplase (COBALT) Investigators. A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction.N Engl J Med1997;337,1124-1130. [CrossRef] [PubMed]
 
Assessment of the Safety, and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial.Lancet1999;354,716-722. [CrossRef] [PubMed]
 
Antman, EM, Wilcox, RG, Giugliano, RP, et al Long-term comparison of lanoteplase and alteplase in ST elevation myocardial infarction: 6 months follow-up in InTIME II trial [abstract].Circulation1999;100,I-498
 
Stein, PD, Dalen, JE, Goldman, S, et al Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts.Chest1998;114(suppl),658S-665S
 
Sanz, G, Pajaron, A, Alegria, E, et al Prevention of early aortocoronary bypass occlusion by low-dose aspirin and dipyridamole.Circulation1990;182,765-773
 
Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy -III. Br Med J 1994; 308:81–106/159–168/235–246.
 
The Post Coronary Artery Bypass Graft Trial Investigators.. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in obstructive changes in saphenous-vein coronary-artery bypass grafts.N Engl J Med1997;336,153-162. [CrossRef] [PubMed]
 
Caprie Steering Committee.. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE).Lancet1996;348,1329-1339. [CrossRef] [PubMed]
 
van der Meer, J, Hillege, HL, van Gilst, WH, et al A comparison of internal mammary artery and saphenous vein grafts after coronary artery bypass surgery: no difference in one-year occlusion rates and clinical outcome.Circulation1994;90,2367-2374. [CrossRef] [PubMed]
 
Jackson, MR, Clagett, GP Antithrombotic therapy in peripheral arterial occlusive disease.Chest1998;114(suppl),660S-682S
 
Harker, LR, Boissel, JP, Pilgrin, AJ, et al Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE.Drug Saf1999;4,325-335
 
The STILE Investigators.. Results of a prospective randomised trial evaluating surgery versus thrombolysis for ischemia of the lower extremity: the STILE trial.Ann Surg1994;220,251-268. [CrossRef] [PubMed]
 
Albers, GW, Easton, JD, Sacco, RL, et al Antithrombotic and thrombolytic therapy for ischemic stroke.Chest1998;114(suppl),683S-698S
 
Furlan, AJ PROACT II: recombinant pro-urokinase (r-ProUK) in acute cerebral thromboembolism: initial trial results; the PROACT II investigators [abstract]. Stroke. 1999;;30 ,.:234
 
Albers, GW Prospective, monitored, multicenter, post-approval experience with intravenous t-PA for treatment of acute stroke: the Standard Treatment with Activase to Reverse Stroke (STARS) Study [abstract]. Stroke. 1999;;30 ,.:244
 
Clark, WM, Albers, GW The ATLANTIS rt-PA (alteplase) Acute Stroke Trial: final results [abstract]. Stroke. 1999;;30 ,.:234
 
Hacke, W, Kaste, M, Fieschi, C, et al Randomised double-blind trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II).Lancet1998;352,1245-1251. [CrossRef] [PubMed]
 
International Stroke Trial Collaborative Group.. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both or neither among 19,435 patients with acute ischemic stroke.Lancet1997;349,1569-1581. [CrossRef] [PubMed]
 
CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke.Lancet1997;349,1641-1649. [CrossRef] [PubMed]
 
Einhäupl, KM, Villringer, A, Meister, W, et al Heparin treatment in sinus venous thrombosis.Lancet1991;338,597-600. [CrossRef] [PubMed]
 
De Bruijn, SFTM, Stam, J Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis.Stroke1999;30,484-488. [CrossRef] [PubMed]
 
Diener, H, Cunha, L, Forbes, C, et al European Stroke Prevention Study 2: Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.J Neurol Sci1996;143,1-13. [CrossRef] [PubMed]
 
Hass, WK, Easton, JD, Adam, HP, Jr, et al A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients: the Ticlopidin Aspirin Stroke Study Group.N Engl J Med1989;321,501-507. [CrossRef] [PubMed]
 
Popma, JJ, Weitz, J, Bittle, JA, et al Antithrombotic therapy in patients undergoing coronary angioplasty.Chest1998;114(suppl),728S-741S
 
Brack, MJ, Ray, S, Chauhan, A, et al Results of a multicenter randomised trial investigating the effects of high dose unfractionated heparin on angiographic restenosis and clinical outcome: the Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial.J Am Coll Cardiol1995;26,947-954. [CrossRef] [PubMed]
 
Schomig, A, Neumann, FJ, Kastra, A, et al A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary stents.N Engl J Med1996;334,1084-1089. [CrossRef] [PubMed]
 
Bertrand, MF, Legrand, V, Boland, J, et al Randomised multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study.Circulation1998;98,1597-1603. [CrossRef] [PubMed]
 
Urban, P, Macaya, C, Rupprecht, H, et al Randomised evaluation of anticoagulant versus antiplatelet therapy after coronary stent implantation in high risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS).Circulation1998;98,2126-2132. [CrossRef] [PubMed]
 
Bertrand, ME, Rupprecht, HJ, Urban, P, et al Comparative safety of ticlopidine and clopidogrel in coronary stent patients: data from CLASICS [abstract].Circulation1999;100,I-620
 
Michelson, AD, Bovil, E, Monagle, P, et al Antithrombotic therapy in children.Chest1998;114(suppl),748S-769S
 
Sutor, AH, Massicotte, P, Leaker, M, et al Heparin therapy in pediatric patients.Semin Thromb Hemost1997;23,303-320. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
Executive Summary*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
PubMed Articles
Guidelines
Guidelines on use of vena cava filters.
British Committee for Standards in Haematology | 9/25/2009
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543