Original Article
A Comparison of Aspirin with Placebo in Patients Treated with Warfarin after Heart-Valve Replacement
N Engl J Med 1993; 329:524-529August 19, 1993
- Abstract
Background
Despite the use of warfarin, major systemic embolism remains an important complication in patients with heart-valve replacement. Although the addition of antiplatelet agents has the potential to reduce this complication, their efficacy and safety 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 mg per day) to warfarin treatment (target international normalized ratio, 3.0 to 4.5) in 370 patients with mechanical heart valves or with tissue valves plus atrial fibrillation or a history of thromboembolism.
Results
A total of 186 patients were randomly assigned to aspirin and 184 to placebo, and they were followed for up to 4 years (average, 2.5). Major systemic embolism or death from vascular causes occurred in 6 aspirin-treated patients (1.9 percent per year) and 24 placebo-treated patients (8.5 percent per year) (risk reduction with aspirin, 77 percent; 95 percent confidence interval, 44 to 91 percent; P<0.001). Major systemic embolism, nonfatal intracranial hemorrhage, or death from hemorrhage or vascular causes occurred in 12 patients assigned to aspirin (3.9 percent per year) and 28 patients assigned to placebo (9.9 percent per year) (risk reduction, 61 per cent; 95 percent confidence interval, 24 to 80 percent; P = 0.005); major systemic embolism or 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 (risk reduction, 63 percent; 95 percent confidence interval, 19 to 83 percent; P = 0.01). Bleeding occurred in 71 patients in the aspirin group (35.0 percent), as compared with 49 patients in the 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-risk patients with prosthetic tissue valves, the addition of aspirin to warfarin therapy reduced mortality, particularly mortality from vascular causes, together with major systemic embolism. Although there was some increase in bleeding, the risk of the combined treatment was more than offset by the considerable benefit.
Media in This Article
Figure 1
Cumulative Risk of Major Systemic Embolism or Death from Vascular Causes.Figure 2
Cumulative Risk of Major Systemic Embolism, Nonfatal Intracranial Hemorrhage, Death from Hemorrhage, or Death from Vascular Causes.Article Activity
- Article
Despite improvements in valve design, thromboembolism remains a serious complication after heart-valve replacement. It is generally agreed that lifelong anticoagulant therapy is indicated in all patients with mechanical valves and in patients with tissue valves (bioprostheses) if there is associated atrial fibrillation or previous thromboembolism. The recommendation for relatively high-intensity anticoagulation is based on one retrospective cohort study1 and on endorsements by the American College of Chest Physicians2 and the British Society for Haematology3.
Despite the use of anticoagulants, major systemic embolism still occurs at a rate of about 2 to 3 percent per year4. To reduce the risk further, the addition of an antiplatelet agent has been advocated. In one study,5 the addition of dipyridamole to oral anticoagulants reduced the incidence of major systemic embolism from 14.3 percent to 1.3 percent per year, and a more recent study6 reported that adding dipyridamole to oral anticoagulants resulted in a small reduction in the risk of systemic thromboembolism, from 1.8 percent to 1.1 percent per year, in patients with newer mechanical prostheses. On the basis of these data and the results of two other trials showing similar reductions in embolic events,7,8 the combination of warfarin plus dipyridamole has been recommended in patients with mechanical valves2. The routine use of dipyridamole in combination with anticoagulants is not widely prescribed as first-line treatment, however, because of severe side effects of dipyridamole, including intractable headache, dizziness, nausea, flushing, and syncope.
The combination of aspirin in doses of up to 1200 mg per day and anticoagulants has also been used after heart-valve replacement, with a significant reduction in embolic complications but an increased risk of bleeding, especially gastrointestinal bleeding9,10. There is good evidence that the gastrointestinal irritation and hemorrhage with aspirin are dose-dependent with doses ranging from 100 to 1000 mg per day11. On the other hand, the antithrombotic effects of aspirin appear to be independent of the dose over this range12. We therefore performed a placebo-controlled study in high-risk patients with valve replacements who were receiving anticoagulant therapy with warfarin titrated to a targeted international normalized ratio of 3.0 to 4.5, in order to determine the efficacy and safety of adding 100 mg of aspirin daily.
Methods
The study was approved by the institutional review board at each of the three Canadian hospitals involved in the study and was carried out from February 1987 through May 1991. Consecutive patients with mechanical replacement valves or with tissue replacement valves plus preoperative atrial fibrillation or a history of thromboembolism were assessed for eligibility. Patients with replacements in the aortic, mitral, or tricuspid positions (singly or in combination) were potentially eligible, as were patients who had concurrent coronary artery bypass graft surgery. Patients were excluded if they were allergic to aspirin, had a contraindication to either anticoagulant or antiplatelet therapy, were geographically inaccessible for follow-up, or were unwilling to give informed consent.
The study was randomized, double-blind, and placebo-controlled. Patients were stratified according to center and according to the type (mechanical or tissue) and site (aortic, mitral, or multiple) of the qualifying replacement valve; they were assigned to treatment according to a computer-generated, randomized arrangement.
Left ventricular function was assessed by measuring ejection fractions on two-dimensional echocardiography and by determining the presence of global hypokinesis or segmental-wall abnormalities. Substantial coronary artery disease was deemed to be present if stenosis of more than 50 percent was detected in more than one coronary artery on coronary angiography.
The majority of patients received low-dose heparin postoperatively (5000 units subcutaneously every eight hours) for prophylaxis against venous thrombosis, and heparin therapy was continued for three days after oral anticoagulant therapy was started. Patients were given anticoagulant therapy with warfarin as soon as they were able to take the medication orally (initial dose, 10 mg per day, monitored to obtain an international normalized ratio of 3.0 to 4.5). When the dose of warfarin was stabilized, the international normalized ratio was measured at two-to-three-week intervals. When the patients were given the initial dose of warfarin, they were randomly assigned to receive 100 mg of aspirin per day orally or an identical-appearing placebo. Aspirin was supplied as delayed-release, enteric-coated 100-mg capsules (Astrix; Faulding Pharma, Salisbury, Australia). Warfarin sodium was 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 important hemorrhage. The patients were monitored routinely for these events during hospitalization and during follow-up at 3, 6, and 12 weeks and 6 months postoperatively. Thereafter, they were seen every six months for the duration of the study. After discharge from the hospital, they were instructed to report at once any evidence of embolic or hemorrhagic complications. All events considered in the outcome assessments were major and were verified and adjudicated by a group of experts who were 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. Vascular causes were defined as cardiac or cerebrovascular, and death from vascular causes included any death that was not clearly nonvascular. Major systemic embolism included cerebral embolism, defined as a neurologic deficit of sudden onset that persisted for more than 24 hours with a computerized tomographic brain scan that was negative for primary intracranial hemorrhage; coronary artery embolism, defined as the occurrence of acute myocardial infarction in the presence of coronary arteries known to be normal; peripheral embolism, defined as the occurrence of acute ischemia caused by an arterial embolism documented by angiography or surgery; or valve thrombosis, defined as the deposition of thrombus on the valve, documented by two-dimensional echocardiography and resulting in hemodynamic dysfunction. Minor systemic embolic events, such as transient ischemic attacks, were not counted as outcome events. Bleeding was classified as major or minor. Major bleeding was defined as overt hemorrhage associated with a decrease of 20 g per liter or more in the hemoglobin level, the requirement for a transfusion of two or more units of blood, or any intracranial, intraocular, intraarticular, or retroperitoneal bleeding. Bleeding was defined as minor if it was overt but did not meet the other criteria for major bleeding.
Statistical Analysis
The primary analysis of efficacy was based on the first occurrence of an event in the composite outcome of major systemic embolism or death due to vascular causes; a composite outcome of major systemic embolism, nonfatal intracranial hemorrhage, death due to hemorrhage, and death due to vascular causes was also analyzed. Other analyses of efficacy included major systemic embolism or death from any cause, death from a vascular cause, and death from any cause. Events involving bleeding were analyzed separately. To allow for the variable duration of follow-up of individual patients, the proportions of patients remaining event-free at any time after randomization were represented in survival curves, calculated by the Kaplan-Meier method13 and compared by the Mantel-Haenszel test14. A proportional-hazards model containing an indicator variable for the treatment group was fitted with the maximum-likelihood method of Cox15. The regression coefficient for the treatment group and its associated standard error provide a point estimate of risk reduction and a corresponding 95 percent confidence interval. Analyses of efficacy are reported as annualized rates. All tests of significance were two-sided.
Results
Patients
During the study period, 557 patients had heart-valve replacements at the Hamilton Civic Hospitals, General Division, Hamilton, Ontario; the University Hospital, London, Ontario; or the Hotel-Dieu Hospital, Montreal. Eleven patients died early in the postoperative period before they could be approached about participation in the study. One hundred seventy-six patients who met the criteria for inclusion also met one or more of the following criteria for exclusion: contraindication to anticoagulants (42 patients), contraindication to aspirin (37), geographic inaccessibility for 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-line characteristics (Table 1Table 1
Base-Line Characteristics of the Patients.). Left ventricular function, as assessed by studying ejection fractions on two-dimensional echocardiography, was measured in 171 aspirin-treated patients (92 percent) and 163 placebo-treated patients (89 percent); it was abnormal in 68 and 62 of them (40 percent and 38 percent), respectively. Angiographically substantial coronary artery disease was found in 50 of 150 aspirin-treated patients (33 percent) and 43 of 157 patients given placebo (27 percent).The patients were followed for a maximum of 4 years and a mean of 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 in the placebo group) were classified as due to hemorrhage, 9 (4 and 5, respectively) as not having a vascular cause, and 15 (2 and 13, respectively) as having a vascular cause. Of the deaths with vascular causes, five were sudden deaths (one in the aspirin group and four in the placebo group), four were due 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 aspirin group 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, 16 were cerebral (4 in the aspirin group and 12 in the placebo group) and 2 (1 in each group) were peripheral. One patient in the placebo group who had a cerebral embolism also had a valve thrombosis; no patient with normal coronary arteries had a myocardial infarction. Six patients (three in each group) had fatal intracranial hemorrhages; one patient in the aspirin group had a nonfatal intracranial hemorrhage before the fatal event. In addition, there were five nonfatal intracranial hemorrhages in four patients, all in the aspirin group.
Assessment of Efficacy
The composite outcome of major systemic embolism or death from vascular causes occurred in 6 of 186 patients randomly assigned to aspirin (1.9 percent per year) as compared with 24 of 184 patients 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. Major systemic embolism, nonfatal intracranial hemorrhage, death due to hemorrhage, or death due to vascular causes occurred in 12 patients in the aspirin group (3.9 percent per year) and 28 patients 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 cause occurred in 13 patients in the aspirin group (4.2 percent per year) and 33 patients in the placebo group (11.7 percent per year) (risk reduction, 65 percent; 95 percent confidence interval, 33 to 82 percent; P<0.001); and death from any cause occurred in 9 patients in the aspirin group (2.8 percent per year) and 22 patients in the placebo group (7.4 percent per year) (risk reduction, 63 percent; 95 percent confidence interval, 19 to 83 percent; P = 0.01). The annualized rates of these outcomes are shown in Table 2Table 2
Outcome Analysis., together with the observed risk reductions and 95 percent confidence intervals; the corresponding cumulative risks are shown in Figure 1Figure 1Cumulative Risk of Major Systemic Embolism or Death from Vascular Causes., Figure 2Figure 2Cumulative Risk of Major Systemic Embolism, Nonfatal Intracranial Hemorrhage, Death from Hemorrhage, or Death from Vascular Causes., Figure 3Figure 3
Cumulative Risk of Major Systemic Embolism or Death., and Figure 4Figure 4
Cumulative Risk of Death from All Causes..There were 5 cases of major systemic embolism in the aspirin group (1.6 percent per year) and 13 cases in the placebo group (4.6 percent per year) (risk reduction, 65 percent; 95 percent confidence interval, 1 to 87 percent; P = 0.039), whereas there were 4 cases of stroke in the aspirin group (1.3 percent per year) 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 group died of vascular causes (0.6 percent per year), as compared with 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 vascular causes in the patients is shown in Table 3Table 3
Frequency of Major Systemic Embolism or Death from Vascular Causes in the Study Patients, According to Clinical Characteristics. according to the position 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 left ventricular function. There was no evidence that the benefit of aspirin depended on the valve position or type or on the presence of coronary artery disease.Hemorrhagic Complications
One hundred twenty patients had events involving bleeding, 71 in the aspirin group (35 percent per year) and 49 in the placebo group (22 percent per year). The higher risk of bleeding with aspirin than with placebo, an increase of 55 percent, was statistically significant (P = 0.02) (95 percent confidence interval, 8 to 124 percent). The difference between the two groups in rates of bleeding was accounted for primarily by differences in minor bleeding events (such as hematuria, epistaxis, and bruising).
Major hemorrhagic events occurred in 43 patients, 24 in the aspirin group (8.5 percent per year) and 19 in the placebo group (6.6 percent per year). The increase of 27 percent in the risk of 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, or 5.2 percent per year, in the placebo group). These events were gastrointestinal (eight in the aspirin group and four in the placebo group), genitourinary (five and none), retroperitoneal (two and one), surgical (two and one), due to hemarthrosis (none and one), due to epistaxis (none and five), and due to other causes (one and three).
Anticoagulant Control
The mean international normalized ratios in the aspirin and placebo groups were 3.0 and 3.1, respectively, and the average daily doses of warfarin were 5.8 and 5.5 mg. The international normalized ratio was in the target range of 3.0 to 4.5 40 percent of 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 of the time.
Discussion
In this double-blind, randomized, placebo-controlled trial, the administration of 100 mg of aspirin per day in patients receiving anticoagulation therapy with warfarin for heart-valve replacement reduced the annual rate of the combined outcome of major systemic embolism and vascular death from 8.5 percent to 1.9 percent. This represents a statistically significant reduction in relative risk of 77 percent. Since the addition of aspirin to warfarin therapy has the potential to increase the risk of major bleeding, the combined end point of major systemic embolism, nonfatal intracranial hemorrhage, death from hemorrhage, or death from vascular causes was studied. The annualized rates of this combined end point were 3.9 percent for the aspirin group and 9.9 percent for the placebo group; this represents a reduction in the relative risk of 61 percent and an absolute reduction of 6.0 percent per year. Thus, the net beneficial effect of aspirin is considerable, even with the inclusion of serious hemorrhagic events.
Several studies have shown a reduction in the risk of major systemic embolism in patients treated with warfarin and dipyridamole (300 to 400 mg per day)5-8. Previous studies have also demonstrated that the addition of aspirin to oral anticoagulant therapy reduces the risk of systemic embolism, but with a significant increase in the risk of bleeding. In the trial by Dale and colleagues,9 aspirin (1000 mg per day) reduced the annual risk of systemic embolism from 9 percent to 2 percent, but the incidence of gastrointestinal bleeding was high in the combined-treatment group, including one death from gastrointestinal hemorrhage. In a study by Altman and colleagues,10 a combination of 500 mg of aspirin and oral anticoagulants reduced the risk of systemic embolism from 20 percent to 5 percent, but with a significant increase, from 2 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 complications in the warfarin-plus-aspirin group. Since the source of most episodes of major bleeding is gastrointestinal when aspirin is combined with coumarins and since the gastrointestinal side effects of aspirin are dose-related,12 the lower incidence of serious hemorrhagic events with aspirin in our study as compared with the previous two studies may have been due to the lower dose of aspirin used in our study.
The pharmacologic properties of the enteric-coated, slow-release preparation of aspirin may have contributed to its efficacy in reducing mortality from vascular causes and the incidence of systemic embolism in our study. Such preparations, when given in low doses, have been shown to acetylate platelet cyclooxygenase predominantly in the portal circulation while preserving it in the endothelium of the systemic circulation, resulting in an inhibition of thromboxane production but leaving prostacyclin release relatively intact16-19.
Approximately 35 percent of our patients had evidence of ischemic heart disease on the basis of either abnormal focal left ventricular dysfunction or coronary angiography; 17 percent had concomitant coronary bypass graft surgery. Patients with evidence of ischemic heart disease generally had higher rates of adverse outcomes, but both groups showed a benefit from the addition of aspirin to oral anticoagulants.
Although the reduction in mortality and major systemic embolism is clearly important, the overall level of bleeding complications with warfarin remains a concern. A number of strategies may be used to reduce this risk. Over the past decade, a number of randomized trials in patients at risk of thromboembolism have demonstrated that a less intense oral anticoagulant regimen (international normalized ratio, 2.0 to 3.0) is as effective as the more intense regimen (international normalized ratio, 3.0 to 4.5), but with a marked reduction in bleeding20-23. In a study of patients with tissue replacement valves, there was no difference in the frequency of major systemic embolism in the patients treated with less intense anticoagulation, but there were significantly fewer bleeding complications21. Recently, two randomized trials have been reported in patients with mechanical heart valves, in which two levels of oral anticoagulant therapy have been compared. Saour and colleagues22 found no difference in the frequency of major embolic events in patients treated with high-intensity (international normalized ratio, 9.0) as compared with low-intensity (international normalized ratio, 2.65) oral anticoagulant therapy, but there was significantly less bleeding in the low-intensity group. Altman and colleagues23 compared low-intensity (international normalized ratio, 2.0 to 2.99) with high-intensity (international normalized ratio, 3.0 to 4.5) oral anticoagulants in patients who were also receiving 660 mg of aspirin plus 75 mg of dipyridamole per day; they found that the frequency of embolic complications was low in both groups but that there were significantly fewer patients with bleeding complications in the low-intensity group than in the high-intensity group. Although our targeted international normalized ratio was 3.0 to 4.5, the mean ratio was 3.1 in the aspirin group and 3.0 in the placebo group, with a comparable distribution of values in the two groups. It is likely that the mean ratios were clustered in the lower part of the targeted range because of a conscious effort to adjust the dose to maintain low therapeutic values.
Our observation that a dose of 100 mg of aspirin per day is effective in patients with prosthetic heart valves treated with oral anticoagulants is important from two standpoints. First, it has the potential to improve the care of patients with prosthetic heart valves, and second, it raises the possibility that low doses of aspirin could provide added benefit in other thromboembolic disorders, such as those occurring after a myocardial infarction, for which oral anticoagulants are effective24. An important question that remains to be answered is whether a less intense anticoagulant regimen (international normalized ratio, 2.0) plus low-dose aspirin would be as efficacious as the high-intensity regimen plus aspirin, but with a reduction in major bleeding.
Supported by a grant (T1367) from the Heart and Stroke Foundation of Ontario. Dr. Hirsh is a Distinguished Professor of the Heart and Stroke Foundation of Ontario. Dr. Laupacis was a Career Scientist of the Ontario Ministry of Health.
We are indebted to the following cardiac surgeons for allowing us 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) for their assistance in the conduct of the trial; to D. Wright, J. Hoffman, and C. Rondeau, the study nurses responsible for recruiting 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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