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Hemorrhagic Complications ofAnticoagulant Treatment

The Seventh ACCP Conference onAntithrombotic and ThrombolyticTherapy

Mark N. Levine, MD, MSc, Chair; Gary Raskob, PhD;Rebecca J. Beyth, MD, MSc; Clive Kearon, MD, PhD; andSam Schulman, MD, PhD

This chapter about hemorrhagic complications ofanticoagulant treatment is part of the seventh ACCPConference on Antithrombotic and ThrombolyticTherapy: Evidence Based Guidelines. Bleeding is themajor complication of anticoagulant therapy. Thecriteria for defining the severity of bleeding variesconsiderably between studies, accounting in part forthe variation in the rates of bleeding reported. Themajor determinants of vitamin K antagonist-inducedbleeding are the intensity of the anticoagulant effect,underlying patient characteristics, and the length oftherapy. There is good evidence that vitamin Kantagonist therapy, targeted international normal-ized ratio (INR) of 2.5 (range, 2.0 to 3.0), is associ-ated with a lower risk of bleeding than therapytargeted at an INR > 3.0. The risk of bleedingassociated with IV unfractionated heparin (UFH) inpatients with acute venous thromboembolism (VTE)is < 3% in recent trials. This bleeding risk mayincrease with increasing heparin dosages and age(> 70 years). Low molecular weight heparin(LMWH) is associated with less major bleeding com-pared with UFH in acute VTE. UFH and LMWH arenot associated with an increase in major bleeding inischemic coronary syndromes, but are associatedwith an increase in major bleeding in ischemicstroke. Information on bleeding associated with thenewer generation of antithrombotic agents has be-gun to emerge. In terms of treatment decision mak-ing for anticoagulant therapy, bleeding risk cannotbe considered alone, ie, the potential decrease inthromboembolism must be balanced against the po-tential increased bleeding risk.

(CHEST 2004; 126:287S–310S)

Key words: anticoagulant; bleeding; complications; heparin

Abbreviations: AMS � anticoagulation management services;APTT � activated partial thromboplastin time; ASPECT � Anti-coagulants in the Secondary Prevention of Events in CoronaryThrombosis; CARS � Coumadin-Aspirin Reinfarction Study;CHAMP � Combination Hemotherapy and Mortality Preven-tion; CI � confidence interval; DVT � deep vein thrombosis;

INR � international normalized ratio; IST � InternationalStroke Trial; LMWH � low molecular weight heparin;NSAID � nonsteroidal anti-inflammatory drug; OR � odds ra-tio; RCT � randomized controlled trial; SPAF � Stroke Preven-tion in Atrial Fibrillation; SPIRIT � Stroke Prevention in Re-versible Ischemia Trial; SPORTIF � Stroke Prevention Using anOral Thrombin Inhibitor in Atrial Fibrillation; TIMI � Throm-bolysis in Myocardial Infarction; UFH � unfractionated heparin;VTE � venous thromboembolism; WARIS � Warfarin-AspirinReinfarction Study; WARSS � Warfarin-Aspirin RecurrentStroke Study

T he major complication of anticoagulant therapy isbleeding. In this review, the incidence of hemorrhage

in patients receiving oral anticoagulants or heparin and theclinical and laboratory risk factors that predispose tobleeding are discussed. The focus is on major bleeding andfatal bleeding. Details of the method used to selectrelevant articles can be found in the six previous sympo-sia1–6 of the American College of Chest Physicians and thechapter in this Supplement by Schunemann et al. Bleed-ing was generally classified as major if it was intracranial orretroperitoneal, if it led directly to death, or if it resultedin hospitalization or transfusion.1,2 However, there wasvariation between studies for the definition of bleeding.Although bleeding is the major side effect of anticoagulanttherapy, it should not be considered in isolation of poten-tial benefit, ie, reduction in thromboembolism. This chap-ter focuses on bleeding related to vitamin K antagonistsand heparins. In the section on vitamin K antagonists, riskfactors for bleeding are first considered, and then bleedingrates for specific clinical conditions are presented. Thesame format is used for heparins. Bleeding related to newantithrombotic agents is also briefly discussed in a chapterby Weitz et al in this Supplement. The search andeligibility criteria used for our review are described inTable 1.

1.0 Vitamin K Antagonists

1.1 Determinants of bleeding

The major determinants of oral vitamin K antagonist-induced bleeding are the intensity of the anticoagulanteffect, patient characteristics, the concomitant use ofdrugs that interfere with hemostasis, and the length oftherapy.

1.1.1 Intensity of anticoagulant effect

There is a strong relationship between the intensity ofanticoagulant therapy and the risk of bleeding that hasbeen reported in patients with deep vein thrombosis(DVT),7 tissue heart valves,8 mechanical heart valves,9–13

ischemic stroke,14 and atrial fibrillation.15–17 In random-ized clinical trials (RCTs) for these indications,7–10 thefrequency of major bleeding in patients randomly assignedto warfarin therapy at a targeted international normalizedratio (INR) of approximately 2.0 to 3.0 has been less thanhalf the frequency in patients randomly assigned to war-farin therapy at a targeted INR � 3.0. The intensity ofanticoagulant effect is probably the most important riskfactor for intracranial hemorrhage, independent of theindication for therapy, with the risk increasing dramati-

Reproduction of this article is prohibited without written permis-sion from the American College of Chest Physicians (e-mail:[email protected]).Correspondence to: Mark N. Levine, MD, MSc, Room 104, FirstFloor, Henderson Research Centre, 711 Concession St, Hamilton,Ontario L8V 1C3

www.chestjournal.org CHEST / 126 / 3 / SEPTEMBER, 2004 SUPPLEMENT 287S

Table 1—Question Definition and Eligibility Criteria: Risk Factors for Anticoagulant-Related Bleeding

Section Population Intervention or Exposure Outcomes MethodologyExclusionCriteria

1.1.1 Patients receiving oral anticoagulants(vitamin K antagonists)

Intensity of anticoagulanteffect

Any bleeding, major bleeding,intracranial bleeding, andfatal bleeding

RCTs, cohortstudies, casecontrol

None


Patient characteristics (age,gender, comorbidconditions: coronary arterydisease, congestive heartfailure, renal insufficiency,liver disease, malignancy,diabetes)


RCTs, cohortstudies

None


Concomitant drugs,antiplatelet drugs,acetaminophen, NSAIDs


RCTs, cohortstudies, casecontrol

None


Length (duration) of therapy Any bleeding, major bleeding,intracranial bleeding, andfatal bleeding

RCTs, cohortstudies

None


Bleeding risk models Any bleeding, major bleeding,intracranial bleeding, andfatal bleeding

Cohort studies None

1.2.1 Patients receiving long-term treatment forischemic cerebral vascular disease

Vitamin K antagonists Any bleeding, major bleeding,intracranial bleeding, andfatal bleeding

RCT None

1.2.2 Patients with prosthetic heart valves Vitamin K antagonists Any bleeding, major bleeding,intracranial bleeding, andfatal bleeding

RCT

1.2.3 Patients with atrial fibrillation Vitamin K antagonists, aspirin Any bleeding, major bleeding,intracranial bleeding, andfatal bleeding

RCT None

1.2.4 Coronary artery disease, myocardialinfarction, acute coronary syndromes,unstable angina, coronary artery bypassgraft surgery

Oral anticoagulants (includingvitamin K antagonists)


RCT None

1.2.5.1 Patients receiving long-term (� 4 wk)treatment for DVT

Vitamin K antagonists vsUFH, LMWH


RCT None

1.2.5.2 Patients receiving long-term treatment forDVT

Vitamin K antagonist, differentdurations


RCT None

1.2.5.3 Patients receiving long-term treatment forDVT

Vitamin K antagonist, differentintensities for extendedtreatment


RCT None

2.1 Patients with atrial fibrillation, venousthromboembolism

Oral direct thrombin inhibitors Any bleeding, major bleeding,intracranial and fatalbleeding

RCT None

3.1.1 Patients receiving heparins Heparin/dose response Any bleeding, major bleeding,intracranial and fatalbleeding

RCT None

3.1.2 Patients receiving heparins Method of administeringheparin

Any bleeding, major bleeding,intracranial and fatalbleeding

RCT None

3.1.3 Patients receiving heparins Patient risk factor Any bleeding, major bleeding,intracranial and fatalbleeding

RCT None

3.2.1.1 Patients with acute DVT or pulmonaryembolism

Initial therapy (5 to 7 d) withUFH or LMWH

Any bleeding, major bleeding,intracranial bleeding andfatal bleeding

RCT


Comparison of LMWHregimens


RCT None


� 3 mo of UFH or LMWH Any bleeding, major bleeding,intracranial and fatalbleeding

RCT None


Fondaparinux Any bleeding, major bleeding,intracranial and fatalbleeding

RCT None

3.3.1 Patients with acute stroke UFH, LMWH, vitamin Kantagonists, aspirin


RCT None

3.3.2 Patients with acute stroke UFH or LMWH vsantiplatelet agent


RCT None

3.4 Coronary artery disease, myocardialinfarction, acute coronary syndromes,unstable angina, coronary artery bypassgraft surgery

UFH, LMWH Any bleeding, major bleeding,intracranial bleeding andfatal bleeding

RCT None

288S Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

cally with an INR � 4.0 to 5.0.14,18,19 In a case-controlstudy, the risk of intracerebral hemorrhage doubled foreach increase of approximately 1 in the INR.19

In five randomized trials20 in patients with atrial fibril-lation, the annual incidence of major bleeding averaged1.3% in patients randomly assigned to warfarin therapy(targeted INR generally 2.0 to 3.0), compared with 1.0%in patients randomly assigned to treatment with placebo.In patients with atrial fibrillation, an INR of 2.5 (range, 2.0to 3.0) minimizes the risk of either hemorrhage or throm-boembolism.21,22 Among patients with antiphospholipidantibody syndrome and prior thrombosis, the annual rateof major bleeding was similar in patients treated withwarfarin at a targeted INR of 2.0 to 3.0, compared to thosetreated with warfarin at a targeted INR of 3.1 to 4.0 (3.0%vs 2.7%, respectively).23

Warfarin regimens (targeted INR � 2.0) have beeninvestigated and found to be safe in the primary preven-tion of thrombosis in patients with malignancy. In tworandomized trials in patients with malignancy, warfarintherapy, 1 mg/d of warfarin24 and 1 mg/d for 6 weeksfollowed by adjustment to an INR of 1.3 to 1.9,25 did notincrease the frequency of hemorrhage while still prevent-ing thrombosis.

Increased variation in the anticoagulant effect, mani-fested by variation in the INR, is associated with anincreased frequency of hemorrhage independent of themean INR.15,26,27 This effect is probably attributable toincreased frequency and degree of marked elevations inthe INR. Approaches to improve anticoagulant control(minimize INR fluctuations) could improve the safety andeffectiveness of vitamin K antagonists. Anticoagulationmanagement services (AMSs) or clinics and point-of-careINR testing are two such approaches. Two recent random-ized trials28,29 did not show a difference in quality ofanticoagulant control or bleeding between AMSs androutine medical care. Results from four observationalstudies30–33 showed AMSs were beneficial and associatedwith less bleeding than usual care.

Point-of-care testing with either patient self-testing orpatient self-management is another model for potentiallyimproving outcomes, as well as convenience. Patientself-testing provided better quality of anticoagulation con-trol compared to routine medical care in one trial34 (timein therapeutic range, 56% vs 32% [p � 0.001], and bleed-ing, 5.6% vs 12%, respectively [p � 0.05] after 6 months offollow-up), but no convincing difference compared withAMSs in two other studies.35,36 Similarly, studies of patientself-management report better quality of anticoagulantcontrol compared to routine medical care37–39 vsAMSs.40–42 Thus, no definite recommendations about theoptimal approach for maintaining anticoagulant controlcan be made.

1.1.2 Patient characteristics

The risk of major bleeding during warfarin therapy canbe related to specific comorbid conditions or patientcharacteristics. An increasing body of evidence supportsage as an independent risk factor for major bleeding.43–61

For example, Pengo et al60 evaluated the relationship of

age and other risk factors to the incidence of majorbleeding. Major bleeding occurred more frequently inpatients � 75 years of age (5.1%/yr) than in youngerpatients (1%/yr). Multivariate analysis indicated that age� 75 years was the only variable independently related toprimary bleeding (ie, bleeding unrelated to organic le-sion). Also, risk for intracranial hemorrhage may be in-creased among older patients, especially those � 75 yearsold when the INR is above therapeutic levels.19,20,43,62 Themechanism of how aging causes anticoagulant-relatedbleeding is not known.

A history of bleeding has been reported as a risk factorfor subsequent bleeding,63–65 but this observation has notbeen consistent.15,43,66 A history of nonbleeding pepticulcer disease, however, has not been associated withsubsequent GI bleeding.26,54,66

Other comorbid diseases have been associated withbleeding during warfarin therapy; these include treatedhypertension,46,47,49,51,67 cerebrovascular disease,43 isch-emic stroke,21,44 serious heart disease,43,48 and renal insuf-ficiency.26,43,63,64,68 The presence of malignancy was asignificant predictor of major bleeding in several stud-ies.54,56,57,64,66,69 In two of these studies,54,69 overanticoagu-lation was not the explanation for an increased risk ofbleeding, whereas in one study,69 the severity of the cancerwas identified as a risk factor. Another study68 did notconfirm that malignancy predisposed to bleeding, whileothers47,70 excluded patients with malignancies.

Although many other patient characteristics have beenassociated with bleeding during warfarin therapy, the datasupporting these findings are not compelling. For exam-ple, some studies noted an increased frequency of bleed-ing among women treated with warfarin,26,47,48,50,53 butothers have not.47,49,52,71,72 Although most experiencedclinicians believe that either alcoholism or liver diseaseincreases the risk of bleeding during long-term warfarintherapy, two studies46,47did not find such an association,whereas a large population-based study64 did.

Occult pathologic lesions may also precipitate warfarin-related bleeding. In one study,45 73% of adequatelyevaluated patients with a prothrombin time ratio � 1.5 atthe time of bleeding had an underlying pathologic lesion,compared to 16% of patients with a prothrombin timeratio � 1.5 (p � 0.05). However, pathologic lesions werefound to be associated with GI or genitourinary bleedingin 30% of patients with prothrombin time ratio � 2.5.

1.1.3 Concomitant drugs

Concomitant use of aspirin has been associated with ahigher frequency of bleeding, even in patients treated withwarfarin therapy with a mean INR of 1.5.73–76 In a largerandomized trial74 comparing the combination of low-dosewarfarin therapy and aspirin, 80 mg/d, to aspirin, 160mg/d, in patients with a history of myocardial infarction,the frequency of spontaneous major hemorrhage duringthe first year of therapy was increased to 1.4% in patientstreated with 3 mg of warfarin (INR � 2.0) and aspirin, 80mg/d, compared with 0.7% in patients treated with aspirin,160 mg/d (p � 0.01). In a large trial75 of primary preven-tion in persons at high risk for ischemic heart disease, the


rate of hemorrhagic stroke was 0.09%/yr in those treatedwith low-dose warfarin (target INR 1.5) plus aspirin, 75mg/d, 0.01%/yr with low-dose warfarin alone, and0.02%/yr with aspirin, and none in the placebo group.Similarly, in a trial76 that compared warfarin (INR, 1.5 to2.5) plus 81 mg of aspirin to 162 mg of aspirin alone inpatients after myocardial infarction, major bleeding wasmore common in the warfarin and aspirin group than inthe aspirin-only group (1.28 events vs 0.72 events/100person-years of follow-up, respectively; p � 0.001).

A number of medications can influence the anticoagu-lant response to vitamin K antagonists.77,78 A detaileddiscussion of such drug interactions is beyond the scope ofthis chapter. However, we will briefly consider the influ-ence of acetaminophen and nonsteroidal anti-inflamma-tory drugs (NSAIDs) on vitamin K antagonist anticoagu-lation.

Hylek et al79 reported that acetaminophen was associ-ated with excessive warfarin anticoagulation in a nestedcase-control study. Patients receiving warfarin with anINR � 6.0 were matched with control subjects with INRsbetween 1.7 and 3.3. On univariate analysis, acetamino-phen ingestion was associated with having an INR � 6.0,but no increase in bleeding. However, there were markeddifferences between the two populations. Patients weremore likely to have recently commenced a new medica-tion, eg, antibiotics; more likely to have an acute illness;more likely to have cancer; and had a decreased intake ofvitamin K-rich foods. On multivariable analyses, acetamin-ophen was no longer an independent predictor of exces-sive anticoagulation.

Johnsen et al80 conducted a population-based study inDenmark. Patients receiving oral anticoagulants wereidentified through a population-based prescription data-base, and were linked to a hospital discharge registry. Theincidence of upper GI bleeding with oral anticoagulantswas compared to the incidence in the general populationnot receiving oral anticoagulants. The standardized inci-dence ratio was 2.8 for oral anticoagulant alone, and 4.4for oral anticoagulant combined with acetaminophen.However, this type of design could not control for impor-tant confounders such as intercurrent illnesses such asinfection.

Gadisseur et al81 conducted a randomized trial in which31 patients receiving stable phenprocoumon therapy for 8weeks were randomized to paracetamol, 1,500 mg/d, 3,000mg/d, or placebo.81 These patients had no concurrentillnesses. After 1 week, there was a mean rise of 0.46 in theINR in both paracetamol groups compared to placebo. Atday 15, there was no difference between placebo and thelow dose of paracetamol and a mean rise of 0.22 INR inthe higher-dose paracetamol group. Hence, in this study,81

acetaminophen did not provoke clinically relevant changesin patients treated with low doses of paracetamol, andproduced very small changes at higher dose. Thus, at thisjuncture, the weight of evidence would indicate that anyimportant INR rise in patients receiving acetaminophen islikely as a result of concurrent illness necessitating theintake of this medication, and there is little evidence thatacetaminophen increases bleeding due to vitamin K an-tagonists.

It is well recognized that NSAIDs can be associatedwith upper GI bleeding.82 However, an important clinicalquestion is whether NSAIDs can increase the risk ofbleeding in patients receiving vitamin K antagonists. Al-though there are case reports83,84 that NSAIDs can pro-long the INR in patients receiving vitamin K antagonists,prospective studies85–87 have shown that NSAIDs do notinteract with vitamin K antagonists to prolong the INRexcessively.

Several studies have attempted to examine the relation-ship between NSAIDs and vitamin K antagonist-relatedbleeding. In one study,88 patients who bled while receivingcoumarin were identified from records of an outpatientanticoagulant clinic and hospital records. These patientswere sent a questionnaire on prior use of NSAIDs.88

Twelve percent of patients who bled had been receivingNSAIDs prior to the bleed. Although there was no controlpopulation of patients receiving coumarin who did notbleed, the authors concluded that the relative risk ofNSAID use with regard to bleeding complications was 5.8.Because of the limitations with the study design, thevalidity of the results is uncertain.

These same authors subsequently performed a nestedcase-control study89 in the same community to examinewhether Cox-2–selective NSAIDs are associated with lessbleeding complications in coumarin users compared withnonselective NSAIDs. They reported that Cox-2–selectiveNSAIDs are associated with less bleeding complicationsthan nonselective NSAIDs. However, the study89 had anumber of methodologic limitations, particularly in theselection of cases and control subjects.

In another study from Denmark, a pharmacologic da-tabase identified all prescriptions for NSAIDs in a specificcommunity from 1991 to 1995.90 This data were linked toa hospital database on admissions for GI bleeds. Thenumber of bleeds on NSAIDs was 3.6 times higher thanexpected in the general population not exposed toNSAIDs. Concurrent anticoagulant use increased the riskof bleeding to 11 times that expected. This type of studydesign is limited, however, by the retrospective nature andthe inability to identify important confounders that couldhave contributed to the bleeding.

Shorr et al91 performed a retrospective cohort study ofTennessee Medicaid enrollees aged � 65 years from 1984through 1986.91 The incidence of hospitalization for hem-orrhagic peptic ulcer disease in patients receiving antico-agulants was threefold the incidence for nonusers. Inpatients receiving oral anticoagulants, the risk of hospital-ization for hemorrhagic peptic ulcer disease was increaseda further threefold by the current use of NSAIDs. Thisstudy design is limited by a lack of adjustment for suchconfounders as duration of anticoagulant, intensity ofanticoagulant control, and concurrent medical illnesses.

In summary, the ideal design to address the question ofwhether NSAIDs increase bleeding on vitamin K antago-nists is a randomized trial. No such study has been done.To date, a number of observational studies have examinedthe question. Such studies, however, are subject to anumber of important biases. Hence, it is concluded that


the quality of evidence supporting any relationship be-tween NSAID use and bleeding on vitamin K antagonistsis weak.

1.1.4 Risk of bleeding and the length of timerelative to when anticoagulant therapy started

Four studies reported higher frequencies of bleedingearly in the course of therapy.26,46,47,54 In one of thesestudies,46 for example, the frequency of major bleedingdecreased from 3.0%/mo the first month of outpatientwarfarin therapy to 0.8%/mo during the rest of the firstyear of therapy, and to 0.3%/mo thereafter. Other descrip-tive studies92–95 have supported this observation, althoughsome studies67,96 have not.

1.1.5 Estimating bleeding risk

Models have been developed for estimating the risk formajor bleeding during vitamin K antagonist anticoagulanttherapy. These models are based on the identification ofindependent risk factors for warfarin-related bleeding,such as a history of stroke, history of GI bleeding, age� 65 years, and higher levels of anticoagula-tion.26,50,53,54,56,63,97 Such prediction rules can be useful inclinical practice because although physicians’ estimates ofrisk for anticoagulant-related bleeding are reasonably ac-curate during hospitalization, they are inaccurate duringlong-term outpatient therapy.63,97

Two prediction models have been developed and vali-dated in outpatients treated with warfarin. Beyth et al63

identified four independent risk factors for bleeding: age� 65 years, history of GI bleeding, history of stroke, andone or more of four specific comorbid conditions. Thismodel was validated in another cohort of patients treatedin another city; the cumulative incidence of major bleed-ing at 48 months was 53% in high-risk patients (three orfour risk factors), 12% in middle-risk patients (one or tworisk factors), and 3% in low-risk patients (no risk factors).Kuijer et al56 developed another prediction model basedon age, gender, and the presence of malignancy. Inpatients classified at high, middle, and low risk, thefrequency of major bleeding was 7%, 4%, and 1%, respec-tively, after 3 months of therapy. These prediction modelsshould not be the sole criterion for deciding whether toinitiate therapy, but should be used in conjunction withother assessments, such as the patient’s functional andcognitive status, likelihood of compliance to therapy, riskof thrombosis, and personal preference.98 Clinicians canuse these prediction models to help weigh the risks andbenefits of coumarin therapy, potentially adjusting theintensity, type, or length of therapy or the frequency ofINR monitoring. These assessments can be reviewed atthe initiation of therapy and periodically assessed through-out the course of coumarin treatment. In the future, teststhat assess the hepatic metabolism of coumarin, such asgenotyping for cytochrome P450 polymorphisms, mayhelp identify patients predisposed to bleeding duringcoumarin initiation.99

1.2 Risk of hemorrhage and clinical disorders

1.2.1 Ischemic cerebral vascular disease

Randomized trials have compared vitamin K antagonistswith a placebo or nontreatment group,100–105 a very-low-dose vitamin K antagonist group,106,107 or an antiplateletgroup,14,108–112 after an acute episode of ischemic cerebro-vascular disease of presumed arterial origin (for details ofearlier studies see Fourth ACCP Consensus Conferenceon Antithrombotic Therapy).4 In all but four of thesestudies,106–109,111 the intensity of vitamin K antagonist washigh (middle of prothrombin time target corresponded toan INR of � 4). Vitamin K antagonists were associatedwith increased bleeding in all of these studies, with afrequency of major bleeding (often intracerebral) varyingfrom 2 to 13% during a mean duration of follow-up of 6 to30 months. In addition to use of high intensities ofanticoagulation, unsuspected initial intracerebral hemor-rhage (pre-CT era), suboptimal control of hypertension,and initiation of anticoagulation in the setting of acutestroke may have contributed to high rates of bleeding inearly studies. However, there is recent evidence (seebelow) that ischemic stroke not due to cardioembolism isassociated with a much higher risk of anticoagulant-induced intracranial bleeding than strokes that are due toembolism (eg, with atrial fibrillation).108,113

Algra and colleagues112 combined the findings of fivestudies (approximately 4,000 patients) that compared vi-tamin K antagonists with antiplatelet therapy after tran-sient ischemic attack or minor stroke of presumed arterialorigin (approximately 4,000 patients) in a Cochrane sys-tematic review (updated 2002). The authors estimated arisk of major bleeding with vitamin K antagonists com-pared with antiplatelet therapy of 1.3 (95% confidenceinterval [CI], 0.8 to 2.0) for INR 1.4 to 2.8; 1.2 (95% CI,0.6 to 2.4) for INR 2.1 to 3.6; and 9.0 (95% CI, 3.9 to 21.0)for INR 3.0 to 4.5. As two studies14,109 (Stroke Preventionin Reversible Ischemia Trial [SPIRIT] and Warfarin-Aspirin Recurrent Stroke Study [WARSS]) accounted for86% of the patients in this review and were recentlypublished, they will be considered further.

In SPIRIT, 1,316 patients with a transient ischemiaattack or minor ischemic stroke were randomized toaspirin, 30 mg/d, or warfarin therapy at a targeted INR of3.0 to 4.5.14 There was a statistically significant increase inmajor bleeding associated with warfarin; 53 major bleed-ing complications (8.1%; 27 intracranial and 17 fatal) vs 6major bleeding complications (0.9%) with aspirin (3 intra-cranial and 1 fatal) during a mean follow-up of 14 months.Bleeding increased by a factor of 1.4 for each 0.5-Uincrease of the INR. Previous stroke has not been identi-fied as a risk factor for intracerebral bleeding in vitamin Kantagonist-treated patients with atrial fibrillation (INR, 1.4to 4.5)20,43,44,114 (see related section of this chapter and thechapter on “Antithrombotic Therapy in Atrial Fibrilla-tion”). An analysis of data from individual patients whowere allocated to vitamin K antagonist in the EuropeanAtrial Fibrillation Trial44 (stroke with atrial fibrillation;INR, 2.5 to 4.0) and in SPIRIT14 (stroke without atrialfibrillation; INR, 3.0 to 4.5) found that, independent of


other risk factors and achieved intensity of anticoagulation,risk of intracranial bleeding was at least 10 times higher ifstroke was not due to atrial fibrillation (hazard ratio of 19for intracranial, and only 1.9 for major extracranial bleed-ing).113

In the WARSS,109 2,206 patients were randomized to325 mg/d of aspirin or warfarin targeted to an INR of 1.4to 2.8 (mean achieved INR was 2.1) within 30 days of anischemic stroke (not including cardioembolism). Therewas a nonsignificant trend for an increase in major bleed-ing with warfarin (44 events vs 30 events; 7 events vs 4events associated with death), and a significant increase inminor bleeding (21% vs 13%) during 2 years of follow-up(the number of intracranial bleeds were not reported).109

The relative safety of oral anticoagulant therapy in theWARSS compared with the SPIRIT is consistent withintensity of anticoagulation having a major influence onrisk of bleeding in patients with ischemic stroke.

1.2.2 Prosthetic heart valves

Three meta-analyses115–117 on studies including onlypatients with prosthetic heart valves receiving long-termvitamin K antagonist therapy have been performed. Twoof the analyses aimed at evaluating risks and benefits of acombination of vitamin K antagonist and antiplatelet agentwith anticoagulant alone and included 5 studies115 and 10studies,116 respectively. In the meta-analysis by Cappelleriet al,115 the combined regimen increased the risk of anyhemorrhage by 65% and of major hemorrhage by 49%, butonly the former difference was statistically significant. Inthe meta-analysis by Massel and Little,116 the risk of major

hemorrhage was increased by the addition of antiplateletregimens (p � 0.033), but there was sufficient evidencethat 100 mg of aspirin compared to higher doses provideda safer combination. A meta-analysis by Pouleur andBuyse,117 based on six trials evaluating the efficacy andsafety of adding dipyridamole to anticoagulant therapy,showed that the risk of hemorrhage was identical in thetwo groups. The studies included in these analyses dif-fered regarding the targeted intensity of anticoagulation(in many of the studies based on a best guess of thereagents used to perform the prothrombin time), theantiplatelet agent (aspirin or dipyridamole), and the doseof aspirin (100 mg, 500 mg, or 1,000 mg), which increasesthe heterogeneity of the findings. These trials are de-scribed in greater detail below.

Bleeding rates in patients receiving different regimenswith long-term vitamin K antagonist therapy for prostheticheart valves have been reported from 14 randomizedclinical trials9–12,118–127 The targeted intensity of oral anti-coagulant therapy was not defined with the INR in thefirst five trials.118–122

In all nine randomized trials of long-term vitamin Kantagonist therapy in patients with mechanical heart valvessince 1990, the targeted intensity of anticoagulation wasreported using the INR.9–12,123–127 The rates of majorbleeding reported in these trials (Table 2) is, however,based on somewhat different definitions, and the timewithin the target INR range varied from 35 to 86%. In thestudy by Altman et al,10 major bleeding was not defined; inthe study by Pruefer et al,127 numerical data are notprovided by treatment group. In three trials,9,11,124 differ-

Table 2—Prosthetic Heart Valves

Study TreatmentNo. of Patients(Patient-Years)

Bleeding Events, %/yr

Major Fatal Intracranial

Saour et al9 Warfarin (INR 2.65) 122 (421) 1.0 0 0Warfarin (INR 9.0) 125 (436) 2.1 0.5 0.5

Turpie et al123 Warfarin (INR 3.0–4.5) plusplacebo

184 (462)* 4.1 0.7 0.7

Warfarin (INR 3.0–4.5) plus aspirin100 mg

186 (462)* 5.2 0.6 1.5

Altman et al125 Acenocoumarol (INR 2.0–3.0) plusaspirin 100 mg

207 (416) 3.6 0.5 0.2

Acenocoumarol (INR 2.0–3.0) plusaspirin 650 mg

202 (366) 5.2 0.3 0.3

Acar et al124 Acenocoumarol (INR 2.0–3.0) 188 (414) 4.1 0.2 0.5Acenocoumarol (INR 3.0–4.5) 192 (422) 5.5 0.2 0.7

Pengo et al11 Warfarin (INR 2.5–3.5) 104 (333) 1.2† 0 0.3Warfarin (INR 3.5–4.5) 101 (289) 3.8 0.3 0.3

Meschengieser et al12 Acenocoumarol (INR 2.5–3.5) plusaspirin 100 mg

258 (529) 1.1 0 0

Acenocoumarol (INR 3.5–4.5) 245 (471) 2.3 0.2 0.6Laffort et al126 Vitamin K antagonist (INR 2.5–3.5) 120 (120) 8.3‡ 3 0

Vitamin K antagonist (INR 2.5–3.5)plus aspirin 200 mg

109 (109) 19.2 3 0

*Approximate values estimated from mean follow-up.†p � 0.05.‡p � 0.02.


ent intensities of vitamin K antagonists were compared.Saour et al9 randomized patients to either warfarin therapyat a targeted INR of 2.65 or very-high-intensity warfarintherapy (targeted INR 9.0). The rate of major bleeding inthe former treatment arm was 3.3%, compared with 7.2%in the latter study arm during 3.5 years of follow-up(p � 0.27). In the trial conducted by Acar et al,124 380patients were randomized to treatment with acenocou-marol at a targeted INR of 2.0 to 3.0, or the samemedication at a targeted INR of 3.0 to 4.5. The rate ofmajor bleeding in the lower-intensity group was 9.0%compared with 12.0% in the higher-intensity group over2.2 years (p � 0.29). In a trial conducted by Pengo andcolleagues,11 205 patients were randomized to treatmentwith either warfarin or acenocoumarol at a targeted INRof 2.5 to 3.5 or the same medications at a targeted INR of3.5 to 4.5, and followed up for a mean of 3 years. The rateof major bleeding was 3.8% in the former group, com-pared with 11% in the latter group (p � 0.019). Thus, thepooled analysis of these trials indicates that by loweringthe intensity of anticoagulation, a rate difference for majorhemorrhage of 1.06 per 100 patient-years (95% CI, – 0.23to � 2.34) is achieved, when the results of these threetrials are pooled.

The addition of aspirin to vitamin K antagonists hasbeen studied in four trials. In a blinded trial, Turpie etal123 compared warfarin (INR, 3.0 to 4.5) with warfarinplus 100 mg of aspirin. The rate of major bleeding was10.3% in the warfarin-alone group compared with 12.9%in the warfarin-plus-aspirin group after 2.5 years offollow-up (p � 0.43). Altman et al125 compared two differ-ent doses of aspirin (100 mg/d vs 650 mg/d) in patientsreceiving acenocoumarol at an INR of 2.0 to 3.0 followedup for an average of 24.1 months and 21.7 months,respectively. The rate of major bleeding in the lower-doseaspirin group was 7.2%, compared with 9.4% in thehigher-dose group (p � 0.4). Meschengieser et al12 com-pared acenocoumarol alone (INR, 3.5 to 4.5) with acombination of acenocoumarol at a lower intensity (INR,2.5 to 3.5) plus 100 mg of aspirin. The rate of majorbleeding was 4.5% in the monotherapy group, comparedwith 2.3% in the combination therapy group after amedian follow-up of 23 months (p � 0.27). The trial ofLaffort et al126 is unique in its homogeneity, since onlypatients with St. Jude Medical (St. Paul, MN) valveprosthesis in the mitral position were included. Treatmentwith vitamin K antagonists alone (INR, 2.5 to 3.5) wascompared with a combination of vitamin K antagonist andaspirin (200 mg/d) for 1 year, starting immediately aftersurgery. This may explain the high rate of major bleeding:8.3% with monotherapy, and 19.2% with the combination(p � 0.02).

The annual bleeding rates (percentage per year) regard-ing major, fatal, or intracranial hemorrhage are shown inTable 2. Cannegieter et al128 reported the results of aretrospective study in 1,608 patients who received vitaminK antagonist therapy for mechanical heart valves. The rateof intracranial and spinal bleeding was 0.57%/yr, and therate of major extracranial bleeding was 2.1%/yr. Cannegi-eter et al129 also published the results of a meta-analysis of46 studies (randomized trials and case series) of patients

who received vitamin K antagonists for mechanical valves.The incidence of major bleeding was 1.4%/yr.

1.2.3 Atrial fibrillation

The efficacy of warfarin in preventing stroke in patientswith nonvalvular atrial fibrillation has been consistentlydemonstrated in a number of RCTs and in meta-analysesof randomized trials.15–17,29,44,114,130–145 Overall, the rates ofwarfarin-related bleeding in these studies has been low(Table 3). Hart et al139 conducted a meta-analysis of sixtrials that compared adjusted-dose warfarin to placebo orcontrol. The rate of intracranial hemorrhage was 0.3%/yrwith warfarin and 0.1%/yr with placebo. This differencewas not statistically significant. The relative risk for majorextracranial hemorrhage was 2.4 (95% CI, 1.2 to 4.6), anabsolute increase of 0.3%/yr for warfarin patients. In theanalysis by Hart et al,139 five trials that compared adjusted-dose warfarin with aspirin were also examined. The rela-tive risk of intracranial hemorrhage for warfarin vs aspirinwas 2.1 (95% CI, 1.0 to 4.6).139

Segal et al138 conducted a meta-analysis of five trials thatcompared warfarin to placebo. The odds ratio (OR) formajor hemorrhage for patients receiving warfarin com-pared to placebo was 2.35 (95% CI, 1.20 to 4.24). The rateof major hemorrhage on placebo was 7 per 1,000 person-years, compared to 13 per 1,000 person-years receivingwarfarin.

More recently, two meta-analyses142,143 have evaluatedthe relative risks and benefits of oral anticoagulant therapyvs antiplatelet therapy in patients with atrial fibrillation.Oral anticoagulant therapy was associated with increasedmajor bleeding (1.45 OR,143 and 1.71 hazard ratio142); theincreased risk of oral anticoagulant therapy was offset byreduced nonfatal stroke (OR, 0.68),143 all strokes (hazardratio, 0.55),142 and all cardiovascular events (hazard ratio,0.71).142 The analysis by Taylor et al143 did not include theStroke Prevention in Atrial Fibrillation (SPAF) I andSPAF III studies15,131 or the European Atrial FibrillationTrial study.21 The analysis by van Walraven et al142 usedthe pooled individual patient data from all published trialscomparing oral anticoagulants with aspirin for atrial fibril-lation. Oral anticoagulant therapy was associated withincreased major bleeding (hazard ratio, 1.71; absoluteincrease, 0.9 events per 100 patient-years, p � 0.02); thecorresponding hazard ratios and absolute increases in ratesper 100 patient-years for all hemorrhagic stroke were 1.84and 0.2, (p � 0.19) and for fatal bleeding were 2.15 and0.2 (p � 0.32). This analysis concluded that treating 1,000patients with atrial fibrillation for 1 year with oral antico-agulants rather than aspirin would prevent 23 ischemicstrokes while causing nine additional major bleeds.142

Because � 50% of patients with atrial fibrillation are� 75 years old, the risk-benefit of oral anticoagulanttherapy in this clinical subgroup is of particular interest.One study (SPAF II)145 raised concern that the risk forwarfarin-related bleeding, especially intracranial hemor-rhage, may be increased substantially in patients � 75years old. The rate of major bleeding while receivingwarfarin was 2.3%/yr, compared with 1.1%/yr for patientsreceiving aspirin, 325 mg/d. However, the rate of major


warfarin-related bleeding was 4.2%/yr in patients � 75years old, compared with 1.7%/yr in younger patients; thecorresponding rates for intracranial bleeding were 1.8%/yrand 0.6%/yr, respectively. The reason why these rates aresubstantially higher than those observed in the otherclinical trials of warfarin in patients with atrial fibrillationis likely related to the intensity of anticoagulant therapy:virtually all intracranial hemorrhages in SPAF II, as in theother clinical trials, were associated with an INR � 3.0.145

In contrast, in the SPAF III trial (targeted INR, 2.0 to3.0), the mean age was 71 years and the rate of intracranialhemorrhage was 0.5%/yr.15

There have been two trials16,114,135 evaluating a fixed lowdose of warfarin (1.25 mg/d) in atrial fibrillation. Thesetrials were stopped early because of the SPAF III trial15

results that demonstrated that low-intensity warfarin

(ie, INR � 1.5) was insufficient for stroke prevention.The rates of major bleeding were low in these studies(Table 3).

The relative risk-benefit of warfarin therapy at a tar-geted INR of 1.5 to 2.1 compared with warfarin therapy ata targeted INR of 2.2 to 3.5 has been evaluated in arandomized trial in patients with atrial fibrillation.17 Majorbleeding occurred in 6 of 55 patients in the conventional-intensity group (rate, 6.6%/yr), compared with none of the60 patients (0%/yr) in the low-intensity group (p � 0.01).The six patients with major bleeding were all elderly(mean, 74 years) and older than the other 109 patientswithout major bleeding (mean, 66 years) [p � 0.01]. TheINR before bleeding was � 3.0 in four patients, and was3.1 and 3.6 in the remaining two patients, respectively.The annual rate of ischemic stroke was low in both the

Table 3—Atrial Fibrillation*

Study Treatment Patients, No.

Bleeding†

Major Fatal

Peterson et al132 Warfarin (INR 2.8–4.2) 335 NR 1 (0.3)Aspirin (75 mg) 336 NR 0Placebo 336 NR 0

Special report131 Warfarin (INR 2.0–3.5) 201 1.7 NRAspirin (325 mg) 192 0.9 NRPlacebo 195 1.2 NR

Boston130 Warfarin (INR 1.5–2.7) 212 8 (3.8) 1 (0.5)No medication 208 8 (3.8) 1 (0.5)

Connolly et al134 Warfarin (INR 2.0–3.0) 187 5 (2.7) 2 (1.1)Placebo 191 1 (0.5) 0

SPAF II145 Warfarin � 75 yr (INR 2.0–4.5) 358 1.7 NRAspirin � 75 yr 357 0.9 NRWarfarin � 75 yr (INR 2.0–4.5) 197 0.04 NRAspirin � 75 yr 188 1.6 NR

EAFT44 Warfarin (INR 2.5–4.0) 225 13 (5.8) 3 (1.3)Placebo 230 3 (1.3) 1 (0.4)Aspirin (300 mg) 404 6 (1.5) 2 (0.5)

Veterans Affairs133 Warfarin (INR 1.4–2.8) 260 6 (2.3) 0Placebo 265 4 (1.5) 1 (0.4)

SPAF III15 Warfarin (INR 1.2–1.5) plus aspirin (325 mg) 521 13 (2.4) 3 (0.6)Warfarin (INR 2.0–3.0) 523 12 (2.1) 2 (0.4)

Morocutti et al136 Warfarin (INR 2.0–3.5) 454 6.0 1.0Indobufen 462 1.0 0

Gullov et al16,114 Warfarin (INR 2.0–3.0) 170 1.1 0.3Warfarin (1.25 mg) 167 0.8 0Warfarin plus aspirin (1.25 mg and 300 mg) 171 0.3 0Aspirin (300 mg) 169 1.4 0.3

Pengo et al135 Warfarin (INR 2.0–3.0) 153 2.6 NRWarfarin (1.25 mg) 150 1.0 NR

Hellemons et al137 Phenprocoumon/acenocoumarol (INR 2.5–3.5) 131 0.5 NRPhenprocoumon/acenocoumarol (INR 1.1–1.6) 122 1.4 NRAspirin (150 mg) 141 1.4 NR

Yamaguchi17 Warfarin (INR 1.5–2.1) 60 0Warfarin (INR 2.2–3.5) 55 6 (6.6)‡ NR

Matcher et al29 Warfarin (INR 2.0–3.0) 572 6 0Warfarin (INR 2.0–3.0) 593 7 1

*Boston � Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators; SPAF � Stroke Prevention in Atrial Fibrillation; NR � notreported in publications.

†Data are presented as % per year or No. (%) unless otherwise indicated.‡p � 0.01.§p � 0.04.


conventional-intensity group (1.1%/yr) and in the low-intensity group (1.7%/yr); however, the 95% CIs for theserates overlap widely, and the study is too small to makedefinitive conclusions about the relative effectiveness ofthese two different intensities of anticoagulation.

A systematic review144 compared the rates of stroke,intracranial bleeding, and major bleeding from studies ofpatients treated in actual clinical practice with the pooleddata from RCTs. Patients in clinical practice were olderand had more comorbid conditions than the patients inclinical trials. Nevertheless, the rates of ischemic strokewere similar between clinical practice and the clinicaltrials (1.8 and 1.4 per 100 patient-years, respectively), aswere the corresponding rates of intracranial bleeding (0.1and 0.3 per 100 patient-years, respectively), and majorbleeding (1.1 and 1.3 per 100 patient-years, respective-ly).144 There was a higher rate of minor bleeding in clinicalpractice (12.0 per 100 patient-years) than in clinical trials(7.9 per 100 patient-years) [p � 0.002].

1.2.4 Ischemic heart disease

Anand and Yusuf146 conducted a meta-analysis of trialsevaluating vitamin K antagonists in patients with coronary

artery disease. Trials were stratified based on the intensityof the vitamin K antagonist and on the use of aspirin. In 16trials (10,056 patients) of high-intensity therapy (INR, 2.8to 4.8), the reduction in mortality and thromboemboliccomplications was offset by a sixfold increase (95% CI,4.4- to 8.2-fold) in major bleeding. For moderate-intensitytherapy (INR, 2 to 3) vs control (four trials; 1,365 pa-tients), the relative risk for major bleeding was 7.7 (95%CI, 3.3 to 18). For moderate-to-high-intensity therapy(INR � 2) vs aspirin (seven trials; 3,457 patients), therewas a relative risk of 2.4 (95% CI, 1.6 to 3.6) for increasein major bleeding. For low-intensity therapy (INR � 2.0)and aspirin vs aspirin alone (three trials; 8,435 patients),the relative risk for major bleeding was 1.3 (95% CI, 1.0 to1.8), with no significant reductions in mortality or cardio-vascular events.

There are 13 published randomized trials71,74,76,147–158 oflong-term oral anticoagulant therapy in patients with acutemyocardial infarction (Table 4). These 13 trials comparedthe following regimens: anticoagulant therapy was com-pared with placebo or control (n � 7)71,147–149,152–156; anti-coagulant therapy with aspirin (n � 1)150; anticoagulanttherapy with aspirin or placebo (n � 1)151; fixed low doses

Table 4—Ischemic Heart Disease*

Study Treatment Patients, No.

Bleeding†

Major Fatal

Sixty-plus148,149 Acenocoumarin (INR 2.2–5.0) 439 18 (4.1) 6 (1.4)Placebo 439 1 (0.2) 1 (0.2)

Group ER150 Oral anticoagulants‡ 652 21 (3.2) 8 (1.2)Aspirin (500 mg tid) 651 5 (0.8) 4 (0.6)

Breddin et al151 Phenprocoumon (INR 2.0–5.0) 320 NR 0Aspirin (500 mg tid) 317 NR 0Placebo 309 NR 0

Meuwissen et al71 Phenprocoumon (INR 1.9–5.0) 68 0 0Placebo 70 0 0

Loeliger et al152 Phenprocoumon (INR 2.0–5.0) 128 1 (0.8) 0Placebo 122 1 (0.8) 1 (0.8)

Bjerkelund153,154 Dicumarol (INR 1.3–2.1) 138 20 (14.5) 4 (2.9)No medication 139 5 (3.6) 1 (0.7)

Harvald et al155 Dicumarol (INR 1.5–2.1) 145 28 (19.3) 1 (0.7)Placebo 170 0 0

Smith et al147 Warfarin (INR 2.8–4.8) 607 13 (2.1) 3 (0.5)Placebo 607 0 0

ASPECT156 Nicoumalone/phenprocoumon (INR 2.8–4.8) 1,700 73 (4.3)§ 11 (0.6)§Placebo 1,704 19 (1.1) 0

CARS74 Warfarin 3 mg (INR 1.2)† plus aspirin 80 mg 3,382 75 (2.2) NRWarfarin 1 mg (INR 1.0)† plus aspirin 80 mg 2,082 42 (1.7) NRAspirin 160 mg 3,393 57 (1.5) NR

ASPECT-2157 Aspirin 336 3 (1) NRPhenprocoumon/acenocoumarol 325 3 (1) NRAspirin plus phenprocoumon/acenocoumarol 332 7 (2) NR

Fiore et al76 Warfarin (INR 1.5–2.5) plus aspirin 81 mg 2,522 0.72/100 patients per yr NRAspirin 162 mg 2,537 1.28/100 patients per yr NR

WARIS II158 Warfarin (INR 2.8–4.2) 1,216 0.68/patients per yr 5 (0.4)Aspirin 160 mg 1,206 0.17/patients per yr 0Warfarin (INR 2.0–2.5) plus aspirin 75 mg 1,208 0.57/patients per yr 6 (0.5)

*Sixty-plus � Sixty-Plus Reinfarction Study Research Group; see Table 3 for expansion of abbreviation.†Data are presented as No. (%) unless otherwise indicated.‡A number of different oral anticoagulants.§Median INR at 6 months of treatment. Warfarin was administered as a fixed dose (1 mg or 3 mg).


of warfarin (1 mg or 3 mg) combined with aspirin werecompared with aspirin alone (n � 1)74; anticoagulant ther-apy alone or combined with aspirin compared to aspirinalone (n � 2)157,158; and anticoagulant therapy with aspirincompared to aspirin (n � 1).76 The frequency of majorbleeding ranged from 0 to 10%, and fatal bleeding rangedfrom 0 to 2.9%.

Smith et al147 reported the results of a randomized trialthat renewed interest in the long-term use of oral antico-agulants after myocardial infarction. The targeted INRwas 2.8 to 4.8. Five patients in the warfarin group (0.8%)had intracranial hemorrhages, and three of these werefatal. Eight warfarin-treated patients (1.3%) experiencedmajor extracranial bleeds. There were no major bleeds inthe placebo group.

In a trial conducted by the Anticoagulants in theSecondary Prevention of Events in Coronary Thrombosis(ASPECT)-1 investigators, patients who had sustained amyocardial infarction were randomized to either oralanticoagulant therapy at a targeted INR of 2.8 to 4.8 orplacebo.156 The mean follow-up was 37 months. Seventy-three patients (4.3%) in the anticoagulant group experi-enced major bleeding, compared with 19 placebo-treatedpatients (1.1%). Three extracranial bleeds in the anticoag-ulant group were fatal; all were GI in origin. Cerebralhemorrhage was more common in patients who had beentreated with anticoagulants (n � 17; 1%), 8 of which werefatal, compared with 2 cerebral hemorrhages in placebo-treated patients, none of which were fatal. The rate ofmajor bleeding in the anticoagulant-treated group was1.5%/yr, compared with 0.2%/yr in the placebo-treatedgroup. This difference was statistically significant.

The Coumadin-Aspirin Reinfarction Study (CARS)74

compared long-term treatment using fixed low doses ofwarfarin (1 mg or 3 mg) combined with aspirin, 80 mg,to treatment with aspirin alone (160 mg) using arandomized, blinded study design. The median fol-low-up of the CARS was 14 months. The median INRvalues 4 weeks and 6 months after beginning treatmentwere 1.27 and 1.19, respectively, for patients receiving3 mg of warfarin with 80 mg of aspirin. Major hemor-rhage, including those related to invasive procedures,occurred in 75 patients (2.0%/yr) receiving 3 mg ofwarfarin with 80 mg of aspirin, 42 patients (1.7%/yr)receiving 1 mg of warfarin with 80 mg of aspirin, and 57patients (1.5%/yr) receiving aspirin alone. For sponta-neous major hemorrhage (not procedure related), an-nual rates were 1.4% in the group receiving 3 mg ofwarfarin plus 80 mg of aspirin, 1.0% in the groupreceiving 1 mg of warfarin plus 80 mg of aspirin, and0.74% in the group receiving 160 mg of aspirin alone.

The Combination Hemotherapy and Mortality Preven-tion (CHAMP) study76 compared the efficacy of warfarin(target INR, 1.5 to 2.5) with 81 mg of aspirin to 162 mg ofaspirin alone in patients after myocardial infarction whowere followed up for a median of 2.7 years. In theCHAMP study,76 major bleeding occurred more fre-quently in the combination therapy group than in theaspirin-alone group (1.28 events vs 0.72 events/100patient-years; p � 0.001).

The ASPECT-2 trial157 compared 80 mg of aspirin,

high-intensity (INR, 3.0 to 4.0) vitamin K antagonist, orcombination of 80 mg of aspirin and moderate-intensity(INR, 2.0 to 2.5) vitamin K antagonist in patients who hadsurvived acute coronary events; the median follow-up was12 months. Major bleeding rates were 1%, 1%, and 2% perpatient-year in the aspirin, warfarin, and combinationgroups, respectively. The frequency of minor bleeding was5%, 8%, and 15% per patient-years in the aspirin, warfa-rin, and combination groups, respectively.

The Warfarin-Aspirin Reinfarction Study (WARIS) II158

compared the efficacy and safety of warfarin (target INR,2.8 to 4.2), aspirin (160 mg), and the two combined (75 mgof aspirin with warfarin with target INR of 2.0 to 2.5) in along-term, randomized, unblinded multicenter study in-volving 3,606 patients after acute myocardial infarction(1,202 patients in each treatment group). The meanduration of follow-up in WARIS II was 4 years. Majornonfatal bleeding occurred in 0.62% of patients pertreatment-year in both warfarin groups, and in 0.17% ofpatients receiving aspirin (p � 0.001).

1.2.5 Venous thromboembolism

1.2.5.1. Heparins vs vitamin K antagonists. Linkins andcolleagues159 performed a meta-analysis of 33 prospectivestudies to determine how often major episodes of bleedingthat occurred during vitamin K antagonist therapy forvenous thromboembolism (VTE) were fatal (target INR,2.0 to 3.0). Most of the 10,757 patients included in theanalysis were initially treated with unfractionated heparin(UFH) or low molecular weight heparin (LMWH) andreceived vitamin K antagonists for 3 months.159 Of 275major bleeds, 37 bleeds were fatal, for an overall casefatality of 13%. Case fatality with intracranial bleeds was46%, and for major extracranial bleeds was 10%. Extracra-nial bleeds, which accounted for 81% of major bleedingepisodes, caused approximately two thirds of the deathsfrom bleeding. Although the risk of bleeding was higherduring the first 3 months of anticoagulant therapy thansubsequently, case fatality with major bleeding was similarduring the acute and long-term phases of treatment.159

There have been 16 randomized trials160–176 in patientswith VTE in which vitamin K antagonists were comparedwith various subcutaneous heparin regimens, usually overa 3-month period (Table 5). In one study,7 two intensitiesor vitamin K antagonist therapy were compared followinginitial heparin therapy (Table 5). Higher intensities ofanticoagulation (ie, INR, 2.6 to 4.4) were evaluated inearlier studies160–162 than in more recent trials (ie, INR,2.0 to 3.0).7,163–173,175,176 The higher-intensity regimenswere consistently associated with more total bleeding thanthe comparison study arms, with a similar trend for majorbleeding (Table 5). In the study7 that compared twointensities of oral anticoagulation, the frequency of totalbleeding was also substantially lower with the less-intenseregimen (4% vs 22%), without being associated with a lossof antithrombotic efficacy.

The 12 most recent of these studies163–173,175 comparedoral anticoagulant therapy at a targeted INR of 2.0 to 3.0anticoagulation with widely differing regimens of threeLMWH preparations (Table 5). The daily LMWH dose


was as low as 4,000 IU,163,167 to as high as 200 IU/kg,169,173

approximately a 3.5-fold difference. Two meta-analy-ses174,177 of studies that compared LMWH with vitaminK antagonist, each administered for 3 months after ini-tial heparin therapy, were performed. In the analysis byIorio and colleagues,177 which included seven stud-ies163–165,167–169,171 and a total of 1,379 patients, there was atrend toward less bleeding with long-term LMWH therapy(OR, 0.45; 95% CI, 0.2 to 1.1).177 Importantly, the relativefrequency of major bleeding with LMWH therapy was dosedependent, varying from an OR of approximately 0.2 at adose of approximately 4,000 IU/d, to an OR of approximately0.7 at a dose of approximately 12,000 IU/d (p � 0.03).

The results of randomized trials in which patients withVTE were treated with less-intense oral anticoagulation(not part of primary comparison) following initial treat-ment with either UFH or LMWH generally have found anoverall frequency of major bleeding of approximately� 3% during 3 months of therapy,178 with higher ratesamong patients with cancer.170,173

1.2.5.2. Different durations of anticoagulation. Fourrandomized trials have compared 4 weeks179,180 or 6weeks181,182 with 3 months179,180 or 6 months,181,182 andthree studies have compared 3 months182–184 with 6months182,184 or 12 months183,184 of oral anticoagulation(INR, approximately 2.0 to 3.0) for the treatment of VTE.Following the initial phase of treatment during which allpatients were treated with anticoagulants, major bleedingoccurred infrequently without convincing evidence ofmore bleeding with the longer durations of therapy.179–183

Two randomized trials185,186 evaluated long-term oral an-ticoagulation for the prevention of recurrent VTE follow-ing an acute episode. Schulman et al185 randomized 227patients to regimens of either 6 months or 4 years ofanticoagulation (INR, 2.0 to 2.85) after a second episodeof VTE. Major bleeding occurred more frequently inpatients who were treated with long-term anticoagulation(2.4%/yr vs 0.7%/yr). Kearon et al186 randomized 162patients with a first episode of idiopathic VTE to remainon a regimen of warfarin (INR, 2.0 to 3.0), or to receive

Table 5—VTE

Study TreatmentNo. of

Patients

Bleeding (Approximately 3Months), No. (%)

Major Fatal

Bynum and Wilson160 Warfarin (INR 2.6–4.4) 24 4 (16.7) 0Heparin (5,000 U subcutaneous bid) 24 0 0

Hull et al161 Warfarin (INR 2.6–4.4) 33 4 (12.1) 0Heparin (5,000 U subcutaneous bid) 35 0 0

Hull et al162 Warfarin (INR 2.6–4.4) 53 3 (5.7) 0Heparin (approximately 10,000 U subcutaneous bid) 53 0 0

Hull et al7 Warfarin (INR 2.6–4.5) 49 2 (4.1) 0Warfarin (INR approximately 2.2) 47 2 (4.3) 0

Pini et al163 Warfarin (INR 2.7) 94 12 (12.8) 0Enoxaparin (4,000 IU subcutaneous qd) 93 3 (3.2) 0

Das et al164 Warfarin (INR 2.0–3.0) 55 0 0Dalteparin (5,000 IU subcutaneous qd) 50 0 0

Hamman166 Phenprocoumon (INR 2.0–3.0) 100 2 (2) Not availableDalteparin (5,000 IU subcutaneous qd) 100 0

Lopaciuk et al165 Acenocoumarol (INR 2.0–3.0) 95 2 (2.1) 0Nadroparin (85 IU/kg subcutaneous qd) 98 1 (1.0) 0

Gonzalez-Fajardo et al167 Warfarin (INR 2.0–3.0) 80 2 (2.5) 0Enoxaparin (4,000 IU subcutaneous qd) 85 1 (1.2) 0

Veiga et al168 Acenocoumarol (INR 2.0–3.0) 50 2 (4.0) 1Enoxaparin (4,000 IU subcutaneous qd) 50 1 (2.0) 0

Lopez-Beret et al169 Acenocoumarol (INR 2.0–3.0) 77 4.7 (5.2) 0Nadroparin (approximately 102 IU/kg subcutaneous bid) 81 0 0

Meyer et al170 Warfarin (INR 2.0–3.0) 75* 12 (16) 6Enoxaparin (150 IU/kg subcutaneous qd) 71* 5 (7.0) 0

Hull et al171 Warfarin (INR 2.0–3.0) 239 2 (0.8) Not reportedTinzaparin (175 IU/kg subcutaneous qd) 233 1 (0.4)

Hull et al172 Warfarin (INR 2.0–3.0) 368 17 (4.6) Not reportedTinzaparin (175 IU/kg subcutaneous qd) 369 12 (3.3)

Lee et al173 Warfarin (INR 2.0–3.0) 335* 12 (3.6)† 0Dalteparin (200 IU/kg subcutaneous qd first month) 338* 19 (5.6)† (0.3%)150 IU/kg subcutaneous qd second to sixth months

Kakkar175 Vitamin K antagonist (INR 2.0–3.0) 246 1 (0.4) 0Bemiparin 3,500 IU qd 111 1 (0.9) (0.9%)

*All patients had cancer.†Six-month follow-up.


placebo, for a further 2 years after an initial 3 months ofanticoagulation. Major bleeding occurred more frequentlyin patients who continued to receive anticoagulants(3.8%/yr vs 0%/yr).

A reasonable interpretation of the findings of thesestudies is that, for patients without a high risk of bleeding(ie, such as those entered in clinical trials), differences induration of anticoagulation do not translate into clinicallyimportant differences in frequencies of major bleedinguntil duration of therapy differs by a year or longer.

1.2.5.3. Different intensities of anticoagulation forextended treatment. The Extended Low-intensity Antico-agulation trial,61 which compared warfarin therapy withINR of 1.5 to 1.9 and INR of 2.0 to 3.0 for long-termprevention of recurrent unprovoked VTE in 738 patientswho had completed at least 3 months of initial treatmentwith an INR of 2.0 to 3.0, found no difference in thefrequency of major bleeding between the two groupsduring an average of 2.4 years of follow-up (INR, 1.5 to 1.9vs INR, 2.0 to 3.0: 1.1%/yr vs 0.9%/yr; hazard ratio, 1.2;95% CI, 0.4 to 3.0). The Prevention of Recurrent VenousThromboembolism trial,187 which compared warfarin ther-apy with INR of 1.5 to 2.0 and placebo in 508 patients whohad completed at least 3 months of warfarin treatmentwith an INR of 2.0 to 3.0, found no significant differencein the rate of major bleeding between the two groupsduring an average of 2.1 years of follow-up (INR, 1.5 to 2.0vs placebo: 0.9%/yr vs 0.4%/yr; hazard ratio, 2.5; 95% CI,0.5 to 13.0).

2.0 Oral Direct Thrombin Inhibitors2.1 Risk of hemorrhage and clinical disorders

The direct thrombin inhibitor ximelagatran has beencompared to warfarin in patients with nonvalvular atrialfibrillation in the Stroke Prevention Using an Oral Throm-bin Inhibitor in Atrial Fibrillation (SPORTIF) II trial.188

In SPORTIF II, 257 patients were randomized to receiveone of three twice-daily doses of ximelagatran (20 mg, 40mg, or 60 mg) or warfarin (INR, 2.0 to 3.0) for 3 months.There were no major bleeds in the ximelagatran group andone in the warfarin group. In the SPORTIF III trial,189

3,407 patients with nonvalvular atrial fibrillation receivedximelagatran, 36 mg bid, or warfarin (INR, 2.0 to 3.0). Therates of major bleeding were 1.3% and 1.8%, respectively.This difference was not statistically significant.

Oral direct thrombin inhibition with ximelagatran atdoses of 24 mg, 36 mg, 48 mg, or 60 mg bid plus 160 mg/dof aspirin was compared to 160 mg/d of aspirin alone in arecent multicenter blinded trial190 for secondary preven-tion of myocardial infarction. There were 1,883 patientsfollowed up for a 6-month treatment period. The rates ofmajor bleeding did not differ between treatment groups(1% for aspirin alone vs 2% for combined ximelagatrandoses), but patients in the combined ximelagatran groupswere three times more likely to stop therapy due tobleeding (hazard ratio, 3.35; 95% CI, 1.87 to 6.01). Inaddition, any bleeding (major and minor) was more fre-quent in the combined ximelagatran group (22%) com-pared to the aspirin-alone group (13%) [hazard ratio, 1.76;95% CI, 1.38 to 2.25].

Ximelagatran has been evaluated for both short-termand long-term treatment of VTE (Thrombin Inhibitors inVenous Thromboembolism studies).191,192 In the short-term treatment study,192 2,491 patients with acute DVTwere treated for 6 months with ximelagatran, 36 mg bid, orLMWH followed by vitamin K antagonist therapy (INR,2.0 to 3.0), using a blinded design. An “on-treatment”analysis suggested less major bleeding with ximelagatran(1.3% vs 2.2%; 95% CI for difference, –2.0 to � 0.2%);intention-to-treat analyses have not been reported forbleeding.192

In a long-term treatment study,191 18 months of ximel-agatran, 24 mg bid, was compared with placebo in 1,224patients with DVT or pulmonary embolism who hadcompleted 6 months of initial treatment with vitamin Kantagonists. There was no apparent increase of majorbleeding with ximelagatran (0.7%/yr; hazard ratio, 1.2;95% CI, 0.4 to 3.8).

3.0 Heparins

Heparin is usually administered in low doses by subcu-taneous injection to prevent venous thrombosis (prophy-lactic heparin), in higher doses to treat patients with acuteVTE or with acute coronary syndromes (therapeutic hep-arin), and in very high doses in patients during open-heartsurgery. In this chapter, we will discuss only bleedingassociated with therapeutic heparin (see the chapter byGeerts et al for a discussion of bleeding associated withprophylactic heparin). Heparin has the potential to inducebleeding by inhibiting blood coagulation, by impairingplatelet function,193 and by increasing capillary permeabil-ity.194 Heparin can also produce thrombocytopenia, butthis is rarely an important cause of bleeding.

3.1 Determinants of bleeding

3.1.1 Relationship between risk of bleedingand heparin dose/response

Since the anticoagulant response to heparin (measuredby a test of blood coagulation, eg, the activated partialthromboplastin time [APTT]) is influenced by the heparindose, it was not possible from reported studies to separatethe effects of these two variables (dose and laboratoryresponse) on hemorrhagic rates. To our knowledge, therehave been no randomized trials in patients with estab-lished VTE directly comparing different doses of heparin.In a study195 evaluating prophylaxis in patients with re-cent-onset traumatic spinal cord injuries, the incidence ofbleeding was significantly greater in patients randomizedto receive heparin adjusted to maintain the APTT at 1.5times control than compared with heparin, 5,000 U bid.The mean dose of heparin for the adjusted-dose regimenwas 13,200 U bid. Bleeding occurred in seven adjusted-dose patients compared with none in the fixed-dose group.

Subgroup analysis of randomized trials and prospectivecohort studies provide suggestive evidence for an associa-tion between the incidence of bleeding and the anticoag-ulant response. In the Urokinase Pulmonary EmbolismStudy,196 bleeding occurred in 20% of patients assigned toheparin in whom whole-blood clotting time was � 60 min,


compared to 5% of those whose whole-blood clotting timewas � 60 min (relative risk, 4.0). Norman and Provan197

reported five major bleeds in 10 patients whose APTT wasprolonged to more than twice the upper limit of theirtherapeutic range for at least 50% of their assays, but inonly 1 of 40 patients whose APTT remained therapeutic(relative risk, 20.0). Wilson et al198 described 80 nonsur-gical patients receiving heparin monitored by the whole-blood clotting time. Fifty-six percent who received “exces-sive heparin” bled, whereas only 16% who did not receiveexcessive heparin bled (relative risk, 3.5). Anand et al199

examined the relationship between the APTT and bleed-ing in 5,058 patients with acute coronary syndrome whoreceived IV heparin in the Organization to Assess Strate-gies for Ischemic Syndromes-2 trial. For every 10-s in-crease in the APTT, the major bleeding was increased by7% (p � 0.0004).

Although none of the studies were designed to comparethe effects on bleeding of either different doses of heparinor different levels of heparin response, there is a sugges-tion that bleeding is more likely to occur when an in vitrotest of coagulation is prolonged excessively, but thisevidence is by no means definitive. In addition, there isgood evidence that serious bleeding during heparin treat-ment can occur when the anticoagulant response is in thetherapeutic range. Finally, the results of Global Utilizationof Streptokinase and t-PA for Occluded Coronary ArteriesIIa and the Thrombolysis in Myocardial Infarction (TIMI)9A studies in patients with ischemic coronary syndromesindicated that a 20% increase in the IV heparin dose abovethe 1,000 U/h that was used in the Global Utilization ofStreptokinase and t-PA for Occluded Coronary Arteries Istudy increased the risk of intracranial bleeding whencombined with thrombolytic therapy.200,201

3.1.2 Relationship between risk of bleedingand method of administering heparin

The evidence for a relationship between the risk ofbleeding and the method of administering heparin comesfrom randomized trials in which UFH was either admin-istered by continuous IV infusion with intermittent IVinjection,198,202–206 continuous IV heparin with subcutane-ous heparin,207–210 continuous IV heparin for approxi-mately 10 days with a shorter course (4 to 5 days),211,212

continuous IV heparin and oral anticoagulants comparedwith oral anticoagulants alone,213 continuous IV heparinadministered on a weight-adjusted basis with a standardclinical approach (5,000-U bolus, 1,000 U/h),214 and con-tinuous IV heparin monitored using either the APTT ormonitored using a heparin assay.

In summary, there was an increased rate of majorbleeding with intermittent IV heparin compared withcontinuous IV infusion. Continuous IV heparin caused lessbleeding than intermittent IV heparin; continuous IVheparin and subcutaneous heparin were associated with asimilar amount of bleeding; and continuous IV heparin forapproximately 10 days and 5 days caused a similar amountof bleeding.

3.1.3 Relationship between the risk of bleedingand patient risk factors

There is good evidence that comorbid conditions,particularly recent surgery or trauma, are very impor-tant risk factors for heparin-induced bleeding.52,205,215

This association was demonstrated in the study by Hulland associates215 in patients with proximal vein throm-bosis. Patients without clinical risk factors for bleedingwere treated with a starting dose of 40,000 U of heparinby continuous infusion, while those with well-recog-nized risk factors for bleeding (recent surgery, trauma)received a starting dose of 30,000 U. Bleeding occurredin 1 of 88 low-risk patients (1%) who received 40,000 Uinitially and 12 of 111 high-risk patients (11%) whoreceived 30,000 U.

The concomitant use of aspirin was identified as a riskfactor in early retrospective studies216 and corroborated bySethi and associates.217 In their study in patients under-going aortocoronary bypass surgery, the preoperative useof aspirin caused excessive operative bleeding in patientswho receive very high doses of heparin as part of theroutine for bypass procedures. Although the concomitantuse of aspirin is associated with heparin-induced bleeding,this combination is used frequently in the initial treatmentof acute coronary artery syndromes without serious bleed-ing. The risk of heparin-associated bleeding increases withconcomitant thrombolytic therapy4 or GP IIb/IIIa antag-onists.218,219 In a retrospective analysis of 5,216 patientsundergoing percutaneous coronary intervention usingUFH, bleeding complications incrementally increased atall activated clotting times � 200 s.220

Renal failure and patient gender have also been impli-cated as risk factors for heparin-induced bleeding.221,222

The reported association with female gender has not beenconsistent among studies and remains in question.

Other studies221,223 have reported that older patientshad a higher risk of heparin-induced bleeding. In ananalysis of a randomized trial,224 age � 70 years wasassociated with a clinically important increased risk ofmajor bleeding.

3.2 Risk of hemorrhage and clinical disorder

3.2.1 VTE3.2.1.1. Initial therapy. Trials that have evaluated

acute treatment of VTE with different heparin regimenshave generally compared fixed-dose LMWH with adjust-ed-dose UFH administered IV225–237 (Table 6) or subcu-taneously229,238 (Table 7). The results of these studies havebeen combined in a number of meta-analysis.178,239,240 Inrelationship to major bleeding, the findings of thesestudies and meta-analysis can be summarized as follows.Overall, LMWH has generally been associated with lessbleeding than UFH (eg, OR, 0.60; 95% CI, 0.39 to0.93)240; however, this finding has been changing overtime. LMWH was associated with less bleeding than UFHin studies published before 1997 (OR, 0.53; 95% CI, 0.28to 0.98), but has been associated with a similar frequencyof bleeding in more recent studies (OR, 0.97; 95% CI, 0.52to 1.81).240 It is not clear if between study differences in


the relative frequency of bleeding with LMWH and UFHreflect differences in LMWH regimens, differences inUFH regimens, or occurred by chance.

3.2.1.2. Direct comparisons among LMWH regimens.Once-daily and twice-daily administration of the sameLMWH have been directly compared in six studies241–246

(the same total daily dose of LMWH has not always beencompared within studies). A meta-analysis247 of five of

these studies241–244,246 that had unconfounded compari-sons found no increase in major bleeding with once-dailytreatment (OR, 1.2; 95% CI, 0.4 to 3.2). Outpatient andinpatient administration of LMWH (three preparationswere used) was compared in a single study of 201 patients;two major bleeds occurred in each group.248 Tinzaparinand dalteparin, each administered once daily, have beencompared for outpatient treatment of VTE in a study of

Table 6—LMWH vs UFH for the Treatment of VTE

Study RegimensNo. of

PatientsMajor Bleeding,

No. (%)Fatal Bleeding,

No. (%)

Duroux225 Nadroparin subcutaneous bid (weight adjusted) 85 2 (2.4) 0IV heparin APTT ratio 1.5 to 2.0 81 4 (4.9) 0

Prandoni et al227 Nadroparin subcutaneous bid (weight adjusted) 85 1 (1) 0vsIV heparin APTT ratio 1.5 to 2.0 85 3 (4) 0

Hull et al228 (blinded) Tinzaparin 175 Xa U/kg subcutaneous qd vs 213 1 (0.5) 0IV heparin APTT ratio 1.5 to 2.5 219 11 (5.0) 2 (0.9)

Lopaciuk et al238 Nadroparin 92 Xa U/kg subcutaneous bid 74 0 0vssc heparin APTT ratio 1.5 to 2.5 72 1 (1) 0

Simonneau et al229 Enoxaparin 1 mg/kg subcutaneous bid 67 0 0vsIV heparin APTT ratio 1.5 to 2.5 67 0 0

Lindmarker et al230 Dalteparin 200 Xa U/kg subcutaneous qd 101 0 0vsIV heparin APTT ratio 1.5 to 3.0 103 0 0

Fiessinger et al231 Dalteparin 200 Xa U/kg subcutaneous qd 127 0 0vsIV heparin APTT ratio 1.5 to 3.0 133 2 (2) 0

Levine et al232* Enoxaparin 1 mg/kg subcutaneous bid 247 5 (2) 2 (0.8)vsIV heparin APTT 60 to 85 s 253 3 (1) 0

Koopman et al233* Nadroparin subcutaneous bid (weight adjusted) 202 1 (0.5) 0vsIV heparin APTT ratio 1.5 to 2.0 198 4 (2) 2 (1)

COLUMBUS Study234* Reviparin 3500 to 6300 Xa U subcutaneous bid (weight adjusted) 510 16 (3) 0vsIV heparin APTT ratio 1.5 to 2.5 511 12 (2) 2 (0.4)

Simonneau et al235† Tinzaparin 175 Xa U/kg subcutaneous qd 304 0 0vsIV heparin APTT ratio 2.0 to 3.0 308 1 (0.3) 1 (0.3)

Decousus et al236 Enoxaparin 1 mg/kg subcutaneous bid 195 7 (3.6) 1 (0.5)IV heparin APTT ratio 1.5 to 2.0 205 8 (3.9) 1 (0.5)

Kirchmaier et al237 Certoparin 8,000 IU subcutaneous bid 128 1 (0.8) 0IV certoparin 128 9 1 (0.8)IV heparin APTT ratio 2.0 to 3.0 131 4 0

Harenberg et al226 Certoparin 8,000 IU subcutaneous bid 265 4 (1.5) 0IV heparin APTT ratio 2.0 to 3.0 273 12 (4.5) 2 (0.7)

Breddin et al245 Reviparin 7,000–12,600 IU subcutaneous qd 388 1 (0.3) 0Reviparin 7,000–12,600 IU subcutaneous qd for 21 d 374 1 (0.3) 0IV heparin APTT ratio 1.5 to 2.5 375 2 (0.5) 0

Merli et al246 Enoxaparin 1 mg/kg subcutaneous bid 312 4 0Enoxaparin 1.5 mg/kg subcutaneous qd 298 5 1IV heparin APTT ratio 1.5 to 2.5 290 6 0

Reiss et al176 Certoparin 8,000 IU subcutaneous bid for 12 d 627 6 (1.0) 0IV heparin APTT ratio 1.5 to 2.5 593 5 (0.8) 0

Kakkar et al175 Bemiparin 115 IU/kg subcutaneous qd 126 0 0IU heparin APTT ratio 1.5 to 2.5 126 1 (0.8) 0

*Included home treatment with LMWH.†Pulmonary embolism.


497 patients; there was no difference in major bleeding(five bleeds with tinzaparin, and three bleeds with dalte-parin).249

3.2.1.3. Long-term treatment with UFH andLMWH. Trials of � 3 months of treatment with UFH orLMWH compared with oral anticoagulants have beendescribed earlier in this chapter (Table 5). In anotherstudy of 80 patients that compared 10,000 U of UFH with5,000 IU of dalteparin, with each administered subcuta-neously twice daily for 3 months after acute VTE, therewas no difference in the frequency of total bleeding and noepisodes of major bleeding in either group.250

3.2.1.4. Fondaparinux vs UFH or LMWH. The syn-thetic pentasaccharide fondaparinux has been evaluatedfor acute treatment of pulmonary embolism and DVT(Matisse studies).251,252 In the Matisse-PE trial,251 2,213patients were treated with a single subcutaneous dose offondaparinux (7.5 mg if 50 to 100 kg) or IV UFH (APTTratio, 1.5 to 2.5) for at least 5 days using an open-labeldesign. Major bleeding occurred in 1.3% of patientsreceiving fondaparinux, and in 1.1% of patients receivingUFH during the initial treatment period.251

In the Matisse-DVT trial,252 2,205 patients were treatedwith a single subcutaneous dose of fondaparinux (7.5 mg if50 to 100 kg) or twice-daily subcutaneous LMWH (enox-aparin, 1 mg/kg) for at least 5 days using a blinded design.Major bleeding occurred in 1.1% of patients receivingfondaparinux, and in 1.2% of patients receiving LMWHduring the initial treatment period.252

3.3 Ischemic cerebral vascular disease

3.3.1 Anticoagulants vs control

Approximately 20, mostly small, studies have comparedearly anticoagulant therapy with control in patients withacute ischemic stroke. The finding of studies that werepublished by 1999 (approximately 23,000 patients) werecombined in a Cochrane systematic review by Gubitz andcolleagues.253 The trials in this overview evaluated UFH,LMWH, heparinoid, oral anticoagulants, and directthrombin inhibitors administered in differing doses (eg,prophylactic doses for VTE; therapeutic doses for stroke)

and by different routes (eg, subcutaneously or IV). Inrelationship to bleeding, the review found that acuteanticoagulation had the following effects: (1) increasedsymptomatic intracranial bleeding approximately 2.5-fold(an excess of 9 per 1,000 patients), and (2) increased majorextracranial bleeding approximately threefold (an excess of9 per 1,000 patients). As the International Stroke Trial(IST),254 with � 19,000 patients, accounted for � 75% ofpatients in the analysis, it will be considered further.

In the IST, patients with acute ischemic stroke weretreated with aspirin (300 mg/d), subcutaneous heparin(5,000 U bid or 12,500 U bid), both, or neither (Table8).254 Heparin was associated with a dose-dependentincrease of both intracranial and extracranial bleeding (allmajor bleeds: control, 0.6%; heparin 5,000 U bid, 1.1%;heparin 12,500 U bid, 3.2%), which, at the higher dose,more than offset antithrombotic benefit. Patients who hadthe highest risk of recurrent ischemic stroke also had thehighest risk of intracerebral bleeding. For example, inpatients with acute ischemic stroke and atrial fibrillation,although the frequency of hemorrhagic stroke after 14days was 2.1% (32 of 1,557 patients) with heparin therapy(either dose) compared with 0.4% (7 of 1,612 patients)without heparin therapy, there was no difference in thecombined end point of recurrent ischemic or hemorrhagicstroke.

More recently, the Therapy Of Patients With AcuteStroke study255 compared four doses of a LMWH (cer-toparin) in 400 patients with ischemic stroke and found atrend to more major bleeding with the highest dosecompared to the three lower doses combined (9.0% vs2.0%).

3.3.2 Anticoagulants vs antiplatelet agents

Four trials254,256–258 have compared anticoagulants withantiplatelet agents in patients with acute ischemic stroke.UFH254,258 and LMWH256,257 in low doses254,258 or highdoses254,256,257 were compared with aspirin254,256,257 or as-pirin and dipyridamole.258 Three trials254,257,258 includedcardioembolic and noncardioembolic strokes, whereas onestudy256 was confined to cardioembolic strokes. The find-ings of these four studies, with data from � 16,000

Table 7—Risk of Intracranial and Major Extracranial Bleeding (14 Days) for Subcutaneous Heparin in AcuteIschemic Stroke*

Treatment Patients, No.

Bleeding, No. (%)

Total Intracranial Extracranial Fatal

Heparin 12,500 U bid plusaspirin 300 mg qd

2,430 75 (3.1) 42 (1.7) 33 (1.4) 10 (0.4)

Heparin 5,000 U bid plusaspirin 300 mg qd

2,431 39 (1.6) 19 (0.8) 20 (0.8) 9 (0.4)

Heparin 12,500 U bid 2,426 76 (3.2) 43 (1.8) 33 (1.4) 12 (0.5)Heparin 5,000 U bid 2,429 26 (1.1) 16 (0.7) 10 (0.4) 9 (0.4)Aspirin 300 mg qd 4,858 49 (1.0) 26 (0.5) 23 (0.5) 13 (0.3)Control 4,859 29 (0.6) 15 (0.3) 14 (0.3) 5 (0.1)

*From IST.254


patients (88% from the IST),254 have been combined in aCochrane systematic review by Berge and Sandercock.259

The review found that, compared to antiplatelet therapy,acute anticoagulation increased symptomatic intracranialhemorrhage 2.3-fold (an excess of 10 per 1,000 patients)and increased major extracranial hemorrhage 1.9-fold (anexcess of 5 per 1,000 patients treated). The increase inmajor bleeding with anticoagulants was mostly confined tohigh-dose regimens.259

3.4 Ischemic coronary syndromes

There have been two trials260,261 in which patients withischemic coronary artery disease were randomized totreatment with heparin or no heparin, one trial260 in whichheparin was compared with aspirin, and one trial262 inwhich high-dose heparin therapy was compared with alower dose of heparin. The results of these trials haveshown that heparin administered alone in patients withcoronary artery disease (without concurrent thrombolytictherapy) is not associated with an increased risk of majorbleeding.4

LMWH has been compared with a no-treatment controlor IV UFH in several trials in patients with unstable coronaryartery disease.263–266 For IV UFH, the rates of major bleedingrange from 0 to 6.3% during the initial 8 days of treatment,and from 0.3 to 3.2% during the long-term treatment phasebetween approximately 1 week and 3 months. For several ofthe trials, explicit data for the incidence of fatal bleeding werenot reported. The data in Table 8 support the inference thatLMWH does not result in an increased risk of major bleedingcompared with IV UFH. The absolute rates of major bleed-ing were higher in more recent trials267–269 than were ob-served in the initial large trials of LMWH.264,265 This is

probably due to inclusion in the more recent studies ofpatients who undergo cardiac catheterization or coronarybypass surgery; much of the major bleeding in these trials267–

269 was associated with invasive vascular procedures or coro-nary bypass surgery. In contrast, the earlier studies264,265

excluded patients for whom catheterization, angioplasty, orcoronary bypass surgery was planned. A meta-analysis270 ofrandomized trials comparing UFH or LMWH with placeboor untreated control, or comparing UFH with LMWH, forthe short-term and long-term management of patients withacute coronary syndrome without ST-segment elevationidentified 12 trials, involving a total of 17,157 patients.Long-term LMWH (� 7 days) was associated with a signif-icantly increased risk of major bleeding (OR, 2.26; 95% CI,1.63 to 3.14], p � 0.0001), which is equivalent to 12 majorbleeds per 1,000 patients treated. In a multicenter, blinded,placebo-controlled trial271 to examine the efficacy and safetyof twice-daily injections of weight-adjusted enoxaparin orplacebo for 14 days after stenting in patients at high risk forstent thrombosis, the groups had comparable rates of majorbleeding (3.3% for enoxaparin, and 1.6% for placebo;p � 0.08), but minor bleeding was increased with enoxaparin(25% vs 5.1%; p � 0.001).

Summary

Bleeding is the major complication of anticoagulanttherapy. The criteria for defining the severity of bleedingvaried considerably between studies, accounting in partfor the variation in the rates of bleeding reported. Sincethe last review, there have been several meta-analyses

Table 8—LMWH vs UFH for Acute Ischemic Coronary Syndromes*

Study RegimensTreatmentDuration

No. ofPatients

Major Bleeding,No. (%)

Fatal Bleeding,No. (%)

Gurfinkel et al263 ASA alone 5–7 d 73 0 0IV heparin APTT ratio 2.0 5–7 d 70 2 (2.9) 0Nadroparin 214 U/kg subcutaneous bid 5–7 d 68 0 0

FRISC264* Placebo subcutaneous bid 0–6 d 760 4 (0.5) 1 (0.1)Dalteparin 120 U/kg subcutaneous bid 0–6 d 746 6 (0.8) 0Placebo subcutaneous qd 6–45 d 614 2 (0.3) 0Dalteparin 7,500 U subcutaneous qd 6–45 d 619 2 (0.3) 0

Klein et al265 IV heparin APTT ratio 1.5 0–6 d 731 7 (1.0) Not reportedDalteparin 120 U/kg subcutaneous bid 0–6 d 751 8 (1.1) Not reportedPlacebo subcutaneous qd 6–45 d 565 2 (0.4) Not reportedDalteparin 7,500 U subcutaneous qd 6–45 d 567 3 (0.5) Not reported

TIMI IIA267 Enoxaparin 1.25 mg/kg subcutaneous q12h 14 d 321 21 (6.5) Not reportedEnoxaparin 1.0 mg/kg subcutaneous q12h 14 d 309 6 (1.9) Not reported

Cohen et al266 IV heparin APTT ratio 55 to 85 2–8 d 1,564 107 (6.8) Not reportedEnoxaparin 1.0 mg/kg subcutaneous q12h 2–8 d 1,607 102 (6.3) Not reported

FRISC II268 Placebo subcutaneous bid 3 mo 1,056 16 (1.5) Not reportedDalteparin 120 U/kg subcutaneous bid 3 mo 1,049 34 (3.2) Not reported

TIMI IIB269 IV heparin APTT ratio 1.5 to 2.5 8 d (hospital) 1,957 19 (1.0) 4 (0.2)Enoxaparin 1.0 mg/kg subcutaneous q12h 8 d (hospital) 1,953 29 (1.5) 4 (0.2)Placebo subcutaneous q12h 43 d 1,185 18 (1.5)Enoxaparin 40 mg or 60 mg subcutaneous qd 43 d 1,179 34 (2.9)

*FRISC � Fragmin During Instability in Coronary Artery Disease.


published on the rates of major bleeding in trials ofanticoagulants for atrial fibrillation, VTE, and ischemicheart disease.

The major determinants of vitamin K antagonist-in-duced bleeding are the intensity of the anticoagulanteffect, underlying patient characteristics, and the length oftherapy. There is good evidence that vitamin K antagonisttherapy at a targeted INR of 2.5 (range, 2.0 to 3.0), isassociated with a lower risk of bleeding than therapytargeted at an INR of � 3.0. There is no convincingevidence indicating that long-term secondary preventionof VTE with vitamin K antagonists targeted to INR valuesof 1.5 to 1.9 compared to INRs of 2.0 to 3.0 reduces thefrequency of bleeding.

There is some evidence to suggest that bleeding riskwith UFH increases with the heparin dosage and age(� 70 years). The risk of bleeding associated with IV UFHin patients with acute VTE is � 3% in recent trials.LMWH is associated with less major bleeding comparedwith UFH in acute VTE. UFH and LMWH are notassociated with an increase in major bleeding in ischemiccoronary syndromes, but extended administration ofLMWH in these patients is associated with increasedbleeding. Short-term treatment of ischemic stroke withtherapeutic-dose LMWH or UFH is associated with anincreased risk of major bleeding and intracranial bleeding.

Since the last review, information on bleeding associ-ated with the newer generation of antithrombotic agentshas begun to emerge. Long-term primary prevention ofatrial fibrillation and secondary prevention of myocardialinfarction and VTE with ximelagatran are associated witha low risk of bleeding. Acute treatment of VTE withfondaparinux is associated with a similar frequency ofbleeding as treatment with LMWH or UFH. In terms oftreatment decision making for anticoagulant therapy,bleeding risk cannot be considered alone, ie, the potentialdecrease in thromboembolism must be balanced againstthe potential increased bleeding risk.

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