Background Despite the use of warfarin, major systemic embolismremains an important complication in patients with heart-valvereplacement. Although the addition of antiplatelet agents hasthe potential to reduce this complication, their efficacy andsafety when given in combination with warfarin are uncertain.
Methods In a randomized, double-blind, placebo-controlled trial,we assessed the efficacy and safety of adding aspirin (100 mgper day) to warfarin treatment (target international normalizedratio, 3.0 to 4.5) in 370 patients with mechanical heart valvesor with tissue valves plus atrial fibrillation or a historyof thromboembolism.
Results A total of 186 patients were randomly assigned to aspirinand 184 to placebo, and they were followed for up to 4 years(average, 2.5). Major systemic embolism or death from vascularcauses occurred in 6 aspirin-treated patients (1.9 percent peryear) and 24 placebo-treated patients (8.5 percent per year)(risk reduction with aspirin, 77 percent; 95 percent confidenceinterval, 44 to 91 percent; P<0.001). Major systemic embolism,nonfatal intracranial hemorrhage, or death from hemorrhage orvascular causes occurred in 12 patients assigned to aspirin(3.9 percent per year) and 28 patients assigned to placebo (9.9percent per year) (risk reduction, 61 per cent; 95 percent confidenceinterval, 24 to 80 percent; P = 0.005); major systemic embolismor death from any cause occurred in 13 patients (4.2 percent)and 33 patients (11.7 percent), respectively (risk reduction,65 percent; 95 percent confidence interval, 33 to 82 percent;P<0.001); and death from all causes occurred in 9 patients(2.8 percent) and 22 patients (7.4 percent), respectively (riskreduction, 63 percent; 95 percent confidence interval, 19 to83 percent; P = 0.01). Bleeding occurred in 71 patients in theaspirin group (35.0 percent), as compared with 49 patients inthe placebo group (22.0 percent) (increase in risk, 55 percent;95 percent confidence interval, 8 to 124 percent; P = 0.02);major bleeding occurred in 24 and 19 patients, respectively(increase in risk, 27 percent; 95 percent confidence interval,-30 to 132 percent; P = 0.43).
Conclusions In patients with mechanical heart valves and high-riskpatients with prosthetic tissue valves, the addition of aspirinto warfarin therapy reduced mortality, particularly mortalityfrom vascular causes, together with major systemic embolism.Although there was some increase in bleeding, the risk of thecombined treatment was more than offset by the considerablebenefit.
Despite improvements in valve design, thromboembolism remainsa serious complication after heart-valve replacement. It isgenerally agreed that lifelong anticoagulant therapy is indicatedin all patients with mechanical valves and in patients withtissue valves (bioprostheses) if there is associated atrialfibrillation or previous thromboembolism. The recommendationfor relatively high-intensity anticoagulation is based on oneretrospective cohort study1 and on endorsements by the AmericanCollege of Chest Physicians2 and the British Society for Haematology3.
Despite the use of anticoagulants, major systemic embolism stilloccurs at a rate of about 2 to 3 percent per year4. To reducethe risk further, the addition of an antiplatelet agent hasbeen advocated. In one study,5 the addition of dipyridamoleto oral anticoagulants reduced the incidence of major systemicembolism from 14.3 percent to 1.3 percent per year, and a morerecent study6 reported that adding dipyridamole to oral anticoagulantsresulted in a small reduction in the risk of systemic thromboembolism,from 1.8 percent to 1.1 percent per year, in patients with newermechanical prostheses. On the basis of these data and the resultsof two other trials showing similar reductions in embolic events,7,8the combination of warfarin plus dipyridamole has been recommendedin patients with mechanical valves2. The routine use of dipyridamolein combination with anticoagulants is not widely prescribedas first-line treatment, however, because of severe side effectsof dipyridamole, including intractable headache, dizziness,nausea, flushing, and syncope.
The combination of aspirin in doses of up to 1200 mg per dayand anticoagulants has also been used after heart-valve replacement,with a significant reduction in embolic complications but anincreased risk of bleeding, especially gastrointestinal bleeding9,10.There is good evidence that the gastrointestinal irritationand hemorrhage with aspirin are dose-dependent with doses rangingfrom 100 to 1000 mg per day11. On the other hand, the antithromboticeffects of aspirin appear to be independent of the dose overthis range12. We therefore performed a placebo-controlled studyin high-risk patients with valve replacements who were receivinganticoagulant therapy with warfarin titrated to a targeted internationalnormalized ratio of 3.0 to 4.5, in order to determine the efficacyand safety of adding 100 mg of aspirin daily.
Methods
The study was approved by the institutional review board ateach of the three Canadian hospitals involved in the study andwas carried out from February 1987 through May 1991. Consecutivepatients with mechanical replacement valves or with tissue replacementvalves plus preoperative atrial fibrillation or a history ofthromboembolism were assessed for eligibility. Patients withreplacements in the aortic, mitral, or tricuspid positions (singlyor in combination) were potentially eligible, as were patientswho had concurrent coronary artery bypass graft surgery. Patientswere excluded if they were allergic to aspirin, had a contraindicationto either anticoagulant or antiplatelet therapy, were geographicallyinaccessible for follow-up, or were unwilling to give informedconsent.
The study was randomized, double-blind, and placebo-controlled.Patients were stratified according to center and according tothe type (mechanical or tissue) and site (aortic, mitral, ormultiple) of the qualifying replacement valve; they were assignedto treatment according to a computer-generated, randomized arrangement.
Left ventricular function was assessed by measuring ejectionfractions on two-dimensional echocardiography and by determiningthe presence of global hypokinesis or segmental-wall abnormalities.Substantial coronary artery disease was deemed to be presentif stenosis of more than 50 percent was detected in more thanone coronary artery on coronary angiography.
The majority of patients received low-dose heparin postoperatively(5000 units subcutaneously every eight hours) for prophylaxisagainst venous thrombosis, and heparin therapy was continuedfor three days after oral anticoagulant therapy was started.Patients were given anticoagulant therapy with warfarin as soonas they were able to take the medication orally (initial dose,10 mg per day, monitored to obtain an international normalizedratio of 3.0 to 4.5). When the dose of warfarin was stabilized,the international normalized ratio was measured at two-to-three-weekintervals. When the patients were given the initial dose ofwarfarin, they were randomly assigned to receive 100 mg of aspirinper day orally or an identical-appearing placebo. Aspirin wassupplied as delayed-release, enteric-coated 100-mg capsules(Astrix; Faulding Pharma, Salisbury, Australia). Warfarin sodiumwas prescribed as Coumadin (Du Pont Pharma, Mississauga, Ont.).
The main outcome events studied were death from vascular causes,major systemic embolism, valve thrombosis, and clinically importanthemorrhage. The patients were monitored routinely for theseevents during hospitalization and during follow-up at 3, 6,and 12 weeks and 6 months postoperatively. Thereafter, theywere seen every six months for the duration of the study. Afterdischarge from the hospital, they were instructed to reportat once any evidence of embolic or hemorrhagic complications.All events considered in the outcome assessments were majorand were verified and adjudicated by a group of experts whowere unaware of the treatment assignments in the study.
The causes of death were classified as hemorrhagic or nonhemorrhagic;the latter were subclassified as vascular or nonvascular. Vascularcauses were defined as cardiac or cerebrovascular, and deathfrom vascular causes included any death that was not clearlynonvascular. Major systemic embolism included cerebral embolism,defined as a neurologic deficit of sudden onset that persistedfor more than 24 hours with a computerized tomographic brainscan that was negative for primary intracranial hemorrhage;coronary artery embolism, defined as the occurrence of acutemyocardial infarction in the presence of coronary arteries knownto be normal; peripheral embolism, defined as the occurrenceof acute ischemia caused by an arterial embolism documentedby angiography or surgery; or valve thrombosis, defined as thedeposition of thrombus on the valve, documented by two-dimensionalechocardiography and resulting in hemodynamic dysfunction. Minorsystemic embolic events, such as transient ischemic attacks,were not counted as outcome events. Bleeding was classifiedas major or minor. Major bleeding was defined as overt hemorrhageassociated with a decrease of 20 g per liter or more in thehemoglobin level, the requirement for a transfusion of two ormore units of blood, or any intracranial, intraocular, intraarticular,or retroperitoneal bleeding. Bleeding was defined as minor ifit was overt but did not meet the other criteria for major bleeding.
Statistical Analysis
The primary analysis of efficacy was based on the first occurrenceof an event in the composite outcome of major systemic embolismor death due to vascular causes; a composite outcome of majorsystemic embolism, nonfatal intracranial hemorrhage, death dueto hemorrhage, and death due to vascular causes was also analyzed.Other analyses of efficacy included major systemic embolismor death from any cause, death from a vascular cause, and deathfrom any cause. Events involving bleeding were analyzed separately.To allow for the variable duration of follow-up of individualpatients, the proportions of patients remaining event-free atany time after randomization were represented in survival curves,calculated by the Kaplan-Meier method13 and compared by theMantel-Haenszel test14. A proportional-hazards model containingan indicator variable for the treatment group was fitted withthe maximum-likelihood method of Cox15. The regression coefficientfor the treatment group and its associated standard error providea point estimate of risk reduction and a corresponding 95 percentconfidence interval. Analyses of efficacy are reported as annualizedrates. All tests of significance were two-sided.
Results
Patients
During the study period, 557 patients had heart-valve replacementsat the Hamilton Civic Hospitals, General Division, Hamilton,Ontario; the University Hospital, London, Ontario; or the Hotel-DieuHospital, Montreal. Eleven patients died early in the postoperativeperiod before they could be approached about participation inthe study. One hundred seventy-six patients who met the criteriafor inclusion also met one or more of the following criteriafor exclusion: contraindication to anticoagulants (42 patients),contraindication to aspirin (37), geographic inaccessibilityfor follow-up (25), medical need to continue aspirin treatment(6), and refusal of consent (66). The remaining 370 patients,who gave written informed consent to participate in the trial,were randomly assigned to receive 100 mg of aspirin per day(186 patients) or placebo (184 patients).
The groups were comparable with respect to important base-linecharacteristics (Table 1). Left ventricular function, as assessedby studying ejection fractions on two-dimensional echocardiography,was measured in 171 aspirin-treated patients (92 percent) and163 placebo-treated patients (89 percent); it was abnormal in68 and 62 of them (40 percent and 38 percent), respectively.Angiographically substantial coronary artery disease was foundin 50 of 150 aspirin-treated patients (33 percent) and 43 of157 patients given placebo (27 percent).
Table 1. Base-Line Characteristics of the Patients.
The patients were followed for a maximum of 4 years and a meanof 2 1/2 years; none were lost to follow-up.
Principal Outcome Events
Nine of the 186 patients in the aspirin group (4.8 percent)and 22 of the 184 patients in the placebo group (12.0 percent)died. Of these 31 deaths, 7 (3 in the aspirin group and 4 inthe placebo group) were classified as due to hemorrhage, 9 (4and 5, respectively) as not having a vascular cause, and 15(2 and 13, respectively) as having a vascular cause. Of thedeaths with vascular causes, five were sudden deaths (one inthe aspirin group and four in the placebo group), four weredue to acute myocardial infarction (all in the placebo group),three were due to acute heart failure (all in the placebo group),and three were due to acute ischemic stroke (one in the aspiringroup and two in the placebo group).
Five of the 186 patients in the aspirin group (2.7 percent)and 13 of the 184 patients in the placebo group (7.1 percent)had major systemic embolisms. Of these 18 embolic events, 16were cerebral (4 in the aspirin group and 12 in the placebogroup) and 2 (1 in each group) were peripheral. One patientin the placebo group who had a cerebral embolism also had avalve thrombosis; no patient with normal coronary arteries hada myocardial infarction. Six patients (three in each group)had fatal intracranial hemorrhages; one patient in the aspiringroup had a nonfatal intracranial hemorrhage before the fatalevent. In addition, there were five nonfatal intracranial hemorrhagesin four patients, all in the aspirin group.
Assessment of Efficacy
The composite outcome of major systemic embolism or death fromvascular causes occurred in 6 of 186 patients randomly assignedto aspirin (1.9 percent per year) as compared with 24 of 184patients randomly assigned to placebo (8.5 percent per year);this represents a reduction in risk of 77 percent (P<0.001),with a 95 percent confidence interval of 44 to 91 percent. Majorsystemic embolism, nonfatal intracranial hemorrhage, death dueto hemorrhage, or death due to vascular causes occurred in 12patients in the aspirin group (3.9 percent per year) and 28patients in the placebo group (9.9 percent per year) (risk reduction,61 percent; 95 percent confidence interval, 24 to 80 percent;P = 0.005); major systemic embolism or death from any causeoccurred in 13 patients in the aspirin group (4.2 percent peryear) and 33 patients in the placebo group (11.7 percent peryear) (risk reduction, 65 percent; 95 percent confidence interval,33 to 82 percent; P<0.001); and death from any cause occurredin 9 patients in the aspirin group (2.8 percent per year) and22 patients in the placebo group (7.4 percent per year) (riskreduction, 63 percent; 95 percent confidence interval, 19 to83 percent; P = 0.01). The annualized rates of these outcomesare shown in Table 2, together with the observed risk reductionsand 95 percent confidence intervals; the corresponding cumulativerisks are shown in Figure 1, Figure 2, Figure 3, and Figure 4.
Figure 4. Cumulative Risk of Death from All Causes.
There were 5 cases of major systemic embolism in the aspiringroup (1.6 percent per year) and 13 cases in the placebo group(4.6 percent per year) (risk reduction, 65 percent; 95 percentconfidence interval, 1 to 87 percent; P = 0.039), whereas therewere 4 cases of stroke in the aspirin group (1.3 percent peryear) and 12 cases in the placebo group (4.2 percent per year)(risk reduction, 70 percent; 95 percent confidence interval,7 to 90 percent; P = 0.027). Two patients in the aspirin groupdied of vascular causes (0.6 percent per year), as comparedwith 13 patients in the placebo group (4.4 percent per year)(risk reduction, 86 percent; 95 percent confidence interval,36 to 97 percent; P = 0.003).
Events and Clinical Characteristics
The frequency of major systemic embolism or death from vascularcauses in the patients is shown in Table 3 according to theposition of the valve replacement, the valve type or model,cardiac rhythm, concomitant coronary artery bypass graft surgery,and the presence of coronary artery disease or abnormal leftventricular function. There was no evidence that the benefitof aspirin depended on the valve position or type or on thepresence of coronary artery disease.
Table 3. Frequency of Major Systemic Embolism or Death from Vascular Causes in the Study Patients, According to Clinical Characteristics.
Hemorrhagic Complications
One hundred twenty patients had events involving bleeding, 71in the aspirin group (35 percent per year) and 49 in the placebogroup (22 percent per year). The higher risk of bleeding withaspirin than with placebo, an increase of 55 percent, was statisticallysignificant (P = 0.02) (95 percent confidence interval, 8 to124 percent). The difference between the two groups in ratesof bleeding was accounted for primarily by differences in minorbleeding events (such as hematuria, epistaxis, and bruising).
Major hemorrhagic events occurred in 43 patients, 24 in theaspirin group (8.5 percent per year) and 19 in the placebo group(6.6 percent per year). The increase of 27 percent in the riskof major hemorrhage with aspirin (95 percent confidence interval,-30 to 132 percent) was not statistically significant (P = 0.43).Thirty-three patients had major non-intracranial bleeding events(18, or 6.4 percent per year, in the aspirin group and 15, or5.2 percent per year, in the placebo group). These events weregastrointestinal (eight in the aspirin group and four in theplacebo group), genitourinary (five and none), retroperitoneal(two and one), surgical (two and one), due to hemarthrosis (noneand one), due to epistaxis (none and five), and due to othercauses (one and three).
Anticoagulant Control
The mean international normalized ratios in the aspirin andplacebo groups were 3.0 and 3.1, respectively, and the averagedaily doses of warfarin were 5.8 and 5.5 mg. The internationalnormalized ratio was in the target range of 3.0 to 4.5 40 percentof the time. It was between 2.0 and 4.5 77 percent of the time,under 2.0 12 percent of the time, and over 4.5 11 percent ofthe time.
Discussion
In this double-blind, randomized, placebo-controlled trial,the administration of 100 mg of aspirin per day in patientsreceiving anticoagulation therapy with warfarin for heart-valvereplacement reduced the annual rate of the combined outcomeof major systemic embolism and vascular death from 8.5 percentto 1.9 percent. This represents a statistically significantreduction in relative risk of 77 percent. Since the additionof aspirin to warfarin therapy has the potential to increasethe risk of major bleeding, the combined end point of majorsystemic embolism, nonfatal intracranial hemorrhage, death fromhemorrhage, or death from vascular causes was studied. The annualizedrates of this combined end point were 3.9 percent for the aspiringroup and 9.9 percent for the placebo group; this representsa reduction in the relative risk of 61 percent and an absolutereduction of 6.0 percent per year. Thus, the net beneficialeffect of aspirin is considerable, even with the inclusion ofserious hemorrhagic events.
Several studies have shown a reduction in the risk of majorsystemic embolism in patients treated with warfarin and dipyridamole(300 to 400 mg per day)5,6,7,8. Previous studies have also demonstratedthat the addition of aspirin to oral anticoagulant therapy reducesthe risk of systemic embolism, but with a significant increasein the risk of bleeding. In the trial by Dale and colleagues,9aspirin (1000 mg per day) reduced the annual risk of systemicembolism from 9 percent to 2 percent, but the incidence of gastrointestinalbleeding was high in the combined-treatment group, includingone death from gastrointestinal hemorrhage. In a study by Altmanand colleagues,10 a combination of 500 mg of aspirin and oralanticoagulants reduced the risk of systemic embolism from 20percent to 5 percent, but with a significant increase, from2 percent to 7 percent, in the risk of gastrointestinal bleeding.In a comparison of warfarin alone, warfarin plus dipyridamole(400 mg per day), and warfarin plus aspirin (500 mg per day),Chesebro and colleagues6 found an excess of major bleeding complicationsin the warfarin-plus-aspirin group. Since the source of mostepisodes of major bleeding is gastrointestinal when aspirinis combined with coumarins and since the gastrointestinal sideeffects of aspirin are dose-related,12 the lower incidence ofserious hemorrhagic events with aspirin in our study as comparedwith the previous two studies may have been due to the lowerdose of aspirin used in our study.
The pharmacologic properties of the enteric-coated, slow-releasepreparation of aspirin may have contributed to its efficacyin reducing mortality from vascular causes and the incidenceof systemic embolism in our study. Such preparations, when givenin low doses, have been shown to acetylate platelet cyclooxygenasepredominantly in the portal circulation while preserving itin the endothelium of the systemic circulation, resulting inan inhibition of thromboxane production but leaving prostacyclinrelease relatively intact16,17,18,19.
Approximately 35 percent of our patients had evidence of ischemicheart disease on the basis of either abnormal focal left ventriculardysfunction or coronary angiography; 17 percent had concomitantcoronary bypass graft surgery. Patients with evidence of ischemicheart disease generally had higher rates of adverse outcomes,but both groups showed a benefit from the addition of aspirinto oral anticoagulants.
Although the reduction in mortality and major systemic embolismis clearly important, the overall level of bleeding complicationswith warfarin remains a concern. A number of strategies maybe used to reduce this risk. Over the past decade, a numberof randomized trials in patients at risk of thromboembolismhave demonstrated that a less intense oral anticoagulant regimen(international normalized ratio, 2.0 to 3.0) is as effectiveas the more intense regimen (international normalized ratio,3.0 to 4.5), but with a marked reduction in bleeding20,21,22,23.In a study of patients with tissue replacement valves, therewas no difference in the frequency of major systemic embolismin the patients treated with less intense anticoagulation, butthere were significantly fewer bleeding complications21. Recently,two randomized trials have been reported in patients with mechanicalheart valves, in which two levels of oral anticoagulant therapyhave been compared. Saour and colleagues22 found no differencein the frequency of major embolic events in patients treatedwith high-intensity (international normalized ratio, 9.0) ascompared with low-intensity (international normalized ratio,2.65) oral anticoagulant therapy, but there was significantlyless bleeding in the low-intensity group. Altman and colleagues23compared low-intensity (international normalized ratio, 2.0to 2.99) with high-intensity (international normalized ratio,3.0 to 4.5) oral anticoagulants in patients who were also receiving660 mg of aspirin plus 75 mg of dipyridamole per day; they foundthat the frequency of embolic complications was low in bothgroups but that there were significantly fewer patients withbleeding complications in the low-intensity group than in thehigh-intensity group. Although our targeted international normalizedratio was 3.0 to 4.5, the mean ratio was 3.1 in the aspiringroup and 3.0 in the placebo group, with a comparable distributionof values in the two groups. It is likely that the mean ratioswere clustered in the lower part of the targeted range becauseof a conscious effort to adjust the dose to maintain low therapeuticvalues.
Our observation that a dose of 100 mg of aspirin per day iseffective in patients with prosthetic heart valves treated withoral anticoagulants is important from two standpoints. First,it has the potential to improve the care of patients with prostheticheart valves, and second, it raises the possibility that lowdoses of aspirin could provide added benefit in other thromboembolicdisorders, such as those occurring after a myocardial infarction,for which oral anticoagulants are effective24. An importantquestion that remains to be answered is whether a less intenseanticoagulant regimen (international normalized ratio, 2.0)plus low-dose aspirin would be as efficacious as the high-intensityregimen plus aspirin, but with a reduction in major bleeding.
Supported by a grant (T1367) from the Heart and Stroke Foundationof Ontario. Dr. Hirsh is a Distinguished Professor of the Heartand Stroke Foundation of Ontario. Dr. Laupacis was a CareerScientist of the Ontario Ministry of Health.
We are indebted to the following cardiac surgeons for allowingus to study patients under their care: B.W. Shragge, A.L. Parisi,and S. Brister (Hamilton); N. McKenzie, A. Menkis, R. Novick,and G. Guiardon (London); and I. Prieto (Montreal); to J.M.Turnbull (London) and J. Neemeh and M.S. Lemire (Montreal) fortheir assistance in the conduct of the trial; to D. Wright,J. Hoffman, and C. Rondeau, the study nurses responsible forrecruiting patients and carrying out the study; and to Mrs.Carol Burnett for assistance in the preparation of the manuscript.
Source Information
From the Departments of Medicine (A.G.G.T., J.H.), Clinical Epidemiology and Biostatistics (M.G., M.K.), and Surgery (J.G.), McMaster University and Hamilton Civic Hospitals Research Centre, Hamilton, Ont.; the Department of Medicine, University of Western Ontario and University Hospital, London, Ont. (A.L.); and the Departments of Medicine (Y.L.) and Surgery (F.B.), Hotel-Dieu Hospital, Montreal -- all in Canada.
Address reprint requests to Dr. Turpie at HGH-McMaster Clinic, Hamilton Civic Hospitals, General Division, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada.
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Warfarin and Aspirin after Heart-Valve Replacement
Cannegieter S.C., van der Meer F.J.M., Briet E., Rosendaal F.R., Bussey H. I., Linn W. D., Keimowitz R. M., Fitzgerald D. J., Turpie A.G.G., Gent M., Laupacis A., Hirsh J.
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Correspondence
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