Correspondence
Warfarin and Aspirin after Heart-Valve Replacement
N Engl J Med 1994; 330:507-509February 17, 1994
- Article
To the Editor:
In a recent paper (Aug. 19 issue), Turpie et al. report a beneficial effect of adding aspirin to warfarin treatment for heart-valve recipients1. We question the interpretation of this study.
The risk of major embolism among patients who received both aspirin and warfarin was 1.6 percent per year, a figure higher than those from the literature for treatment with oral anticoagulants only. Bloomfield et al.2 found a 12-year cumulative risk of 8.8 percent, which corresponds to an annual incidence of about 0.8 percent (and not, as stated by Turpie et al., of 2 to 3 percent, which was apparently recalculated from the figures for total embolism). In a meta-analysis combining all literature we found a risk of 1.0 percent per year3. In our own center, which provides routine care to unselected patients, we found an incidence of major embolism of 0.6 percent per year4.
The risk of major bleeding was also higher than expected. The authors reported an incidence rate of major bleeding of 8.5 percent per year in the aspirin group and 6.6 percent per year in the placebo group (both aspirin and placebo were added to warfarin treatment). Recently, we have reported on bleeding complications in our anticoagulation clinic5. Here, in a routine situation, there was a much lower incidence rate of 2.7 percent per year. The figure that Turpie et al. report is exceptionally high, especially when one also considers that their study excluded 8 percent of patients because they had a contraindication to anticoagulants (which would not occur that frequently in a routine situation).
The high incidence of both embolic and bleeding complications in this study may not be surprising, however, when the poor anticoagulant control is taken into account. The intensity of anticoagulation was within the target range for only 40 percent of the time. This contrasts sharply with the situation in our center, in which this proportion was 77 percent5.
Thus, with well-monitored anticoagulant treatment, it is possible to achieve better results than Turpie et al. did with the addition of aspirin. We would therefore argue that physicians should first achieve the optimal level of anticoagulation, instead of adding aspirin to poorly controlled warfarin treatment, since the number of complications in the latter situation is unacceptably high.
5 ReferencesS.C. Cannegieter, M.D.
F.J.M. van der Meer, M.D.
E. Briet, M.D.
F.R. Rosendaal, M.D.
Leiden University Hospital, NL-2300 RC Leiden, the Netherlands1
Turpie AGG ,Gent M ,Laupacis A , et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 1993;329:524-529
Full Text | Web of Science | Medline2
Bloomfield P ,Wheatley DJ ,Prescott RJ ,Miller HC . Twelve-year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses. N Engl J Med 1991;324:573-579
Full Text | Web of Science | Medline3
Cannegieter SC, Rosendaal FR, Briet E. Thrombo-embolic and bleeding complications in patients with mechanical heart valve prostheses: review and meta-analysis. Circulation (in press).
4
Cannegieter SC ,Rosendaal FR ,Wintzen AR ,van der Meer FJM ,Briet E . The optimal intensity of oral anticoagulation therapy in patients with prosthetic heart valves. Thromb Haemost 1993;69:2363-2363 abstract.5
van der Meer FJ ,Rosendaal FR ,Vandenbroucke JP ,Briet E . Bleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch Intern Med 1993;153:1557-1562
CrossRef | Web of Science | Medline
To the Editor:
The use of a wide range of values for the international normalized ratio (INR) by Turpie et al. raises two important questions. First, was the benefit or risk of aspirin limited to certain INR ranges? Second, do the data indicate the appropriate level of anticoagulation for valve recipients? These questions might be answerable if the data were presented as incidence rates (number of events per number of patient-years) at different levels of anticoagulation. If this is not feasible, presenting the distribution of events according to the INR range might be helpful.
Since the INRs were below the desired range 49 percent of the time, aspirin may have been beneficial only when a “subtherapeutic” INR posed a high risk of thromboembolism. Alternatively, the increased risk of bleeding may have been limited to patients with INRs greater than 4.5 (which occurred 11 percent of the time). Such information may be useful in selecting candidates for combination therapy. Presenting incidence rates according to anticoagulation level could help resolve the controversy about the intensity of anticoagulation in such patients.
Henry I. Bussey, Pharm.D.
University of Texas Health Science Center, San Antonio, TX 78284-6220William D. Linn, Pharm.D.
Audie Murphy Veterans Affairs Medical Center, San Antonio, TX 78284To the Editor:
The benefits of combining oral aspirin and warfarin were well demonstrated in the recent report by Turpie et al. Although the risks were low, gastrointestinal hemorrhage still occurred twice as often in the aspirin group as in the placebo group. Furthermore, 7 percent of patients considered eligible for this study were excluded because of their inability to take aspirin.
We have recently observed that aspirin can be absorbed through the skin and cause marked and selective suppression of thromboxane biosynthesis1. The peak plasma aspirin level at three hours was 0.2 μg per milliliter, considerably lower than levels obtained with a low-dose oral aspirin tablet2.
The gastrointestinal toxicity of aspirin is dose-related, and gastrointestinal ulceration and bleeding probably represent a direct effect on the gastric mucosa. By circumventing the gastrointestinal tract and providing a high degree of platelet selectivity, the use of this route may avoid gastrointestinal bleeding. The advantages of combining warfarin and transdermal aspirin deserve further study.
2 ReferencesRudolph M. Keimowitz, M.D.
Gundersen Clinic, La Crosse, WI 54601Desmond J. Fitzgerald, F.R.C.P.I.
Center for Cardiovascular Science, Dublin, Ireland1
Keimowitz RM ,Pulvermacher G ,Mayo G ,Fitzgerald DJ . Transdermal modification of platelet function: a dermal aspirin preparation selectively inhibits platelet cyclooxygenase and preserves prostacyclin biosynthesis. Circulation 1993;88:556-561
Web of Science | Medline2
Clarke RJ ,Mayo G ,Price P ,FitzGerald GA . Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin. N Engl J Med 1991;325:1137-1141
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Cannegieter and colleagues state that the rates of major systemic embolism and hemorrhage in our study were higher than reported elsewhere. We disagree. Our rate of major systemic embolism (1.6 percent per patient-year) is well within the range (0.0 to 4.6 percent per patient-year) reported for embolic events in patients with mechanical valves who are treated with anticoagulants1.
It is difficult to compare bleeding rates across studies, because the criteria used to define major bleeding often differ and the published rates are highly variable. Our rate for major bleeding -- 6.6 percent per year in the patients treated with anticoagulants alone -- is consistent with the rates reported in a recent review of long-term anticoagulant therapy (e.g., 1.6 and 9.3 percent)2. In addition, it is unlikely that major bleeding in our study can be attributed to poor anticoagulant control, since only 11 percent of the patients had INRs above the target therapeutic range. Furthermore, the mean of the INRs immediately before the episodes of major bleeding was 3.4, as compared with an overall mean INR of 3.1.
In our study, the efficacy of adding aspirin to warfarin was dramatic, with a 65 percent reduction in the risk of major systemic embolism; such an effect is unlikely to be achieved with better anticoagulant control.
Some of the comments by Bussey and Linn are addressed above. In addition, it is worth noting that the mean of the INRs immediately before the occurrence of major systemic embolism was 2.8. The appropriate level of anticoagulation for valve recipients cannot be determined from our study. We are currently performing a trial in similar patients, all receiving 100 mg of aspirin daily, who have been randomly assigned to one of two intensities of anticoagulation (target INR, 2.0 to 2.5 or 3.0 to 3.5) to address this question. We agree with Keimowitz and Fitzgerald that combination therapy with warfarin and transdermal aspirin deserves further study.
2 ReferencesA.G.G. Turpie, M.B., Ch.B.
M. Gent, D.Sc.
McMaster University and Hamilton Civic Hospitals Research Centre, Hamilton, ON L8L 2X2, CanadaA. Laupacis, M.D.
University of Western Ontario, London, ON N6A 5C1, CanadaJ. Hirsh, M.D.
McMaster University and Hamilton Civic Hospitals Research Centre, Hamilton, ON L8L 2X2, Canada1
Stein PD ,Alpert JS ,Copeland J ,Dalen JE ,Goldman S ,Turpie AG . Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1992;102:Suppl:445S-455S
CrossRef | Web of Science | Medline2
Saour JN ,Sieck JO ,Mamo LAR ,Gallus AS . Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990;322:428-432
Full Text | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
N Asdaghi, D Manawadu, K Butcher. (2007) Therapeutic management of acute intracerebral haemorrhage. Expert Opinion on Pharmacotherapy 8:18, 3097-3116
CrossRef2
Richard J Kaplon, Delos M Cosgrove, A.Marc Gillinov, Bruce W Lytle, Eugene H Blackstone, Nicholas G Smedira. (2000) Cardiac valve replacement in patients on dialysis: influence of prosthesis on survival. The Annals of Thoracic Surgery 70:2, 438-441
CrossRef3
J. Galea, A. Manché, J. J. Goiti, T. J. Locke, G. A. Wilkinson, G. H. Smith. (1994) Omission of aspirin in patients following coronary artery bypass graft surgery. Journal of Clinical Pharmacy and Therapeutics 19:6, 381-386
CrossRef
