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J Am Coll Cardiol, 2001; 37:569-578 © 2001 by the American College of Cardiology Foundation |
a Department of Medicine, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada
Manuscript received January 31, 2000; revised manuscript received September 6, 2000, accepted October 12, 2000.
Reprint requests and correspondence: Dr. David Massel, London Health Sciences Center, Room 205, Colborne Building, Victoria Campus, 375 South Street, London, Ontario, Canada, N6A 4G5
dmassel{at}lhsc.on.ca
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Abstract |
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The objective of this study was to compare the effectiveness and safety of adding dipyridamole or aspirin to warfarin among patients with prosthetic heart valves using meta-analytic techniques.
BACKGROUND
Patients with prosthetic heart valves are at increased risk for valve thrombosis and arterial thromboembolism. Oral anticoagulation alone, or the addition of antiplatelet drugs, has been used to minimize this risk. An important issue is the effectiveness and safety of the latter strategy.
METHODS
A combined MEDLINE and manual search was made for relevant articles from 1966 to November 1999. Standard meta-analysis techniques were used.
RESULTS
Ten studies involving 2,199 subjects met the inclusion criteria. Compared with anticoagulation alone, the addition of an antiplatelet agent reduced the risk of thromboembolic events (odds ratio [OR]: 0.41, p < 0.001) and total mortality (OR: 0.49, p < 0.001). The risk of major bleeding was increased when antiplatelet agents were added (OR: 1.50, p = 0.033). For major bleeding, the comparison of trials performed before and after 1990 (OR: 2.23 and 0.88, respectively) showed that the chi-square test for heterogeneity was significant (p = 0.025). The latter trials used low-dose aspirin, suggesting that the risk of bleeding may be lower with contemporary low-dose (100 mg daily) aspirin.
CONCLUSIONS
Adding antiplatelet therapy, especially low-dose aspirin, to warfarin decreases the risk of systemic embolism or death among patients with prosthetic heart valves. The risk of major bleeding is slightly increased with antiplatelet therapy. Nonetheless, the risk of bleeding appears to have diminished with the lower doses of aspirin used in the more recent trials, resulting in a favorable risk-to-benefit profile.
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As a means of improving the efficacy of antithrombotic therapy after cardiac valve implantation, anticoagulation has been augmented with an antiplatelet agent. Although the results of some of the trials have been encouraging, showing improved effectiveness with no substantial increase in bleeding risk, the results are far from consistent (6–17). Previous meta-analyses addressing the efficacy and safety of combined antiplatelet and oral anticoagulant for prosthetic valve management were potentially limited, having reviewed either English language trials, published data (18,19) or trials using dipyridamole (20) only.
We report a meta-analysis that includes data published in abstract form and clinical trial reports in any language. The goal of this study was to create a valid synthesis of all available, methodologically sound data to further assess the safety and efficacy of combined oral anticoagulant and antiplatelet therapy versus anticoagulant monotherapy in patients with prosthetic heart valves.
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Methods |
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Study eligibility. Studies were included in the meta-analysis if: 1) patients with prosthetic heart valves were enrolled, 2) there was a comparison of the addition of an antiplatelet agent to oral anticoagulation, 3) treatment groups were assigned through random allocation and 4) objective methods were used to assess for the development of major clinical outcomes or adverse consequences. Abstracts were included. Study quality, apart from the above, was not assessed. Reviewers were not blinded as to the author, journal or type of publication.
Data extraction. Two reviewers independently extracted data on three major outcomes: 1) rates of thromboembolism, 2) major hemorrhagic complications and 3) total mortality. The primary author’s definitions for the above were accepted. In addition, the following data were extracted from each study: mean follow-up, target INR or prothrombin time ratio, antiplatelet type and dose and whether the study was single- or double-blinded. Prosthetic valve type and position were not specifically reviewed because the original publications did not consistently examine the outcomes using these variables.
Statistical analysis. All analyses were performed on the intention-to-treat basis. The statistical method used has been described in detail previously (24). A p value less than 0.05 (two-sided) was considered to be statistically significant. A "typical" odds ratio (OR) along with 95% confidence intervals (CI) were calculated for individual trials and for the summary results.
Chi-square tests of heterogeneity were used to assess the validity of combining trials. As these tests have low sensitivity for detecting heterogeneity, a more liberal level of statistical significance (p < 0.1) was assumed (25). If a test of heterogeneity was significant, a random-effect analysis was made and reported (26). In addition, for each outcome measure we also used the fixed-effects approach of Mantel Haenszel (27) and random-effects (26,28) models to estimate summary treatment effects for all studies combined. The number needed to treat to prevent one outcome event (NNT), and the expected benefit per 1,000 patients treated was estimated from fixed-effects models.
Sensitivity analyses. Sensitivity analyses were performed on all three outcome events. The impact of the following variables was assessed (predefined): studies published in English versus other languages, abstract versus full publication, the type of antiplatelet agent used (aspirin versus dipyridamole), whether the studies were double-blinded or not and the type of model used (29), that is, whether fixed- or random-effects.
Each study was deleted in turn to assess the impact of the individual studies on the overall results. A cumulative meta-analysis, based on chronological order, was performed to assess the robustness of treatment effects over time (30,31). To assess for the possibility of publication bias, we estimated the number of "missing and negative" trials that would have to exist and would nullify the results of the meta-analysis according to the methods of Rosenthal and L’Abbe (32,33).
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Results |
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Of the three main study outcomes, an arterial thromboembolic event (TE) was well defined and was the primary end point of all included trials. Definitions were similar and involved either transient or permanent cerebral ischemic injury or ultrasound or surgically confirmed other systemic arterial embolism. Reported data for major hemorrhagic complications of anticoagulant therapy with or without antiplatelet therapy were less consistent. Three original publications provided no data on bleeding (8,11,12). Data on bleeding for the Kasahara trial were abstracted from the dipyridamole meta-analysis that included unpublished data obtained from the registration file reviewed by the U.S. Food and Drug Administration (20). Data from the Rajah article was also available from the Pouleur meta-analysis but excluded from ours because the denominator from the active treatment groups was reported as 68 rather than 78 as in the original abstract (rendering the results somewhat suspect). The Meschengieser et al. (15) trial defined significant bleeding as that causing death, requiring transfusion or hospitalization. In the Turpie et al. (14) trial, major bleeding was defined as overt hemorrhage associated with 
20 g/L drop in the hemoglobin level, the requirement for transfusion of 2 units of blood or any intracranial, intraocular, intraarticular or retroperitoneal bleeding. Minor bleeding constituted either epistaxis, genitourinary bleeding or easy bruising. Two trials (7,9) did not distinguish between major and minor bleeding events. For this analysis, any intracerebral or gastroenteric bleeding event or episode of hemoptysis was taken to represent a significant hemorrhage in these two studies. One trial (6) reported only three nonfatal gastrointestinal bleeding events that were presumed to be significant.
Mortality data were explicit for nine trials and not provided in the original publication of the Kasahara trial (8); this data was abstracted from the dipyridamole meta-analysis (20) that included unpublished data (as above). One trial provided clear data on mortality associated with hemorrhage and thromboembolism but did not provide data on total deaths per treatment group (7).
Thromboembolic events. The results for the impact of antiplatelet agents on the risk of TE events are summarized in Table 2 and shown in Figure 1. Overall, antiplatelet agents reduced the risk of TE events with an OR of 0.41 (95% CI: 0.29 to 0.58, p < 0.001). The heterogeneity chi-square test was not significant (p = 0.79). This treatment effect corresponds to a relative risk reduction (RRR) of 57% (95% CI: 38% to 70%) and an NNT of 30 (95% CI: 19 to 62), both calculated using a fixed-effects model.
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The risk of major bleeding did not differ between trials using dipyridamole and aspirin (p = 0.19). Nonetheless, the risk of bleeding was higher in studies performed before 1990 as compared with the two more recent trials (OR: 2.23 vs. 0.88, p = 0.025) (14,15). The tests for heterogeneity comparing the two later aspirin trials with either the early aspirin or the early dipyridamole trials were statistically significant (p = 0.068 and 0.066, respectively), again suggesting that the risk of bleeding was less in the two most recent aspirin studies. When the above subgroup analyses were repeated with the Meschengieser et al. (15) trial excluded, there was less of an impact of pre-1990 versus post-1990 trials (OR: 2.29 vs. 1.28, p = 0.17), dipyridamole versus all aspirin trials (OR: 2.20 vs. 1.63, p = 0.49) or early and later aspirin trials (OR: 2.41 vs. 1.28, p = 0.23).
Additional sensitivity analyses and publication bias. There were no differences for any of the end points among trials published in English as compared with other languages, whether published as an abstract or as a manuscript or if double-blind methodology was used or not. The Kasahara study (8) was published in Japanese and only partial data were available; the analyses were repeated with this article excluded, and the results were unchanged. As a result, the addition of unpublished data (used in a previous meta-analysis [20]) did not alter the results apart from the inclusion of the Rajah unpublished data as described above. There was no impact on the end points of TE or death when each of the other trials was also excluded in turn.
Next, a series of hypothetical variances and observed minus expected mortalities (O to E), according to the method of Peto (24) were modeled for the Kasahara trial. This showed that 25 excess deaths in the antiplatelet group as compared with the controls would have had to occur to render the overall results of the meta-analysis conventionally statistically nonsignificant. The failure to report such a massive treatment-induced mortality excess was considered highly unlikely. Moreover, unpublished mortality data from the Kasahara study, which was included in the dipyridamole meta-analysis (20), showed that mortality was nonsignificantly reduced with dipyridamole. The possibility of publication bias was assessed by the methods of L’Abbe and Rosenthal (32,33). According to the method suggested by L’Abbe, it can be shown that more than 80 small negative trials (40 per group) or 11 larger negative trials (event rate 10%, 250 per group) would have to exist to nullify the results (32). Using the method of Rosenthal (33), it was estimated that 30 to 50 negative trials would have to exist in order to nullify the results of the meta-analysis for the outcomes of death and thromboembolic events, respectively.
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Discussion |
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Chesebro and colleagues (16) performed a randomized trial comparing warfarin and dipyridamole (400 mg daily) to warfarin and aspirin (500 mg daily) in patients with a prosthetic heart valve replacement. The risk of TE was slightly lower, but not statistically significant, among those allocated dipyridamole (0.5 vs. 1.8 per 100 patient-years). Bleeding rates were higher among those receiving concomitant aspirin as compared with dipyridamole (6.6 vs. 1.6 per 100 patient-years, p < 0.001). These results are discordant with ours and may reflect the dose of aspirin chosen; 500 mg in the Chesebro study (16) as compared with the lower risk of bleeding when 100 mg daily doses of aspirin (14,15) were used.
Aspirin effective but at less bleeding risk. The relative effectiveness and safety of aspirin may reflect patient selection, the degree of anticoagulation (target INR) sought or the dose of aspirin used. In the comparison of the aspirin trials, the risk of bleeding in the trials performed before 1990 (7,9) (that is, before the advent of widespread use of the standardized INR) was higher even though the target INR sought in the early trials was lower compared with the post-1990 trials (14,15) (Table 1). It is our postulate that the lower risk of bleeding in the more recent trials reflects the use of lower dose aspirin: 100 mg daily in the two contemporary trials compared with 500 to 1,000 mg daily in the earlier aspirin trials. Efficacy, on the other hand, did not appear to be dependent upon the degree of anticoagulation or dose of aspirin. In this regard, a more detailed discussion of some of the two later individual trials is in order.
In the Turpie et al. double-blind randomized controlled trial (14), 186 patients were assigned to aspirin (100 mg/day delayed release, enteric coated) plus warfarin, and 184 were assigned to placebo plus warfarin. Patients were included if they had a mechanical prosthetic valve or tissue valves and atrial fibrillation or a history of thromboembolism. The target INR was 3.0 to 4.5. The primary end point (major embolism or death) was reduced among those assigned to aspirin (1.9% vs. 8.5% per year, p < 0.001). The stroke rate (1.3% vs. 4.2% per year, p = 0.027) and overall mortality (2.8% vs. 7.4%, p = 0.01) was reduced with aspirin. Furthermore, a composite outcome that could reflect net clinical benefit (major systemic embolism, nonfatal intracranial hemorrhage, death due to hemorrhage and vascular deaths) was also reduced with aspirin (3.9% per year vs. 9.9% per year, p = 0.005). Although the risk of bleeding was increased with aspirin, this was primarily due to minor bleeding including bruising, epistaxis and hematuria. Importantly, the risk of major hemorrhagic events did not differ significantly between groups (8.5% aspirin vs. 6.6% placebo, p = 0.43).
In the Meschengieser et al. trial (15), patients were randomized to either a high target INR (3.5 to 4.5; mean achieved 3.98) or a lower target INR (2.5 to 3.5; mean achieved 3.11) plus 100 mg of aspirin daily. The primary outcome events were rates of thromboembolism and bleeding. The rates of thromboembolism were similar at 2.8% and 2.7%, respectively. The risk of major bleeding (4.5% warfarin alone vs. 2.3% warfarin plus aspirin) and minor bleeding (17% warfarin alone vs. 14% warfarin plus aspirin) did not differ between groups but tended to favor the combination of low-dose aspirin and a lower target level of anticoagulation. Three intracranial hemorrhages occurred in the warfarin alone arm; none were seen in the combination arm. Therefore, the addition of low-dose aspirin with a lower level of anticoagulation was as effective, and possibly safer, as compared with a higher level of anticoagulation.
These results are consistent with the randomized trial by Altman et al. (17) who compared the effect of a low (INR 2.0 to 3.0) or high (INR 3.0 to 4.3) degree of anticoagulation in combination with dipyridamole (150 mg/day) and aspirin (660 mg/day) in patients with heart valve replacement. The rates of TE were similar between the low and high INR groups (1.92 vs. 4.94 per 100 patient-years, respectively) although there were very few events overall. The risk of bleeding, however, was less with the lower target INR (3.8 vs. 24.7 per 100 patient-years, p < 0.02). They concluded that a lower INR (2,3) used conjointly with platelet inhibitors was effective and safer than a higher target INR (17).
Improvements over previous meta-analyses. The first overview comparing rates of valve thrombosis, major embolism and bleeding was unable to show an advantage of the combination of aspirin and anticoagulation over anticoagulation alone; bleeding risk was increased, however (3). The studies included in the overview were not comparative randomized trials.
The meta-analyses performed by Fiore and colleagues (18) and Cappelleri and colleagues (19) were subject to bias through inclusion of English language only trials published as full manuscripts. The Fiore meta-analysis, published in abstract form only, included four trials comparing the use of aspirin as an adjunct to oral anticoagulation. The Cappelleri meta-analysis included five trials: four involving aspirin and one involving dipyridamole. Moreover, the study by Chesebro and colleagues (16) was included in both these meta-analyses but was excluded from ours, as patients treated with warfarin were only randomized to receive either aspirin or dipyridamole. Although a control group receiving warfarin alone was subsequently included in the analysis, patients were not randomized to warfarin alone or warfarin and either of the two antiplatelet regimens (16).
The Pouleur et al. (20) meta-analysis comprised trials of dipyridamole only. It also included previously unpublished data, updated from the original publications, and a submission to the U.S. Federal Drug Agency. For the end points of TE and death, the results of our meta-analysis are in accord with theirs, and sensitivity analyses show that inclusion or exclusion of the unpublished data from published trials does not materially change our results or conclusions. The one discrepancy is for the end point of bleeding. Our meta-analysis suggests bleeding risk is increased with dipyridamole but theirs does not (OR: 2.2 vs. 1.001, respectively). The test of heterogeneity between the analyses is conventionally statistically significant (chi-square 3.968, p = 0.046). This may reflect our emphasis on major bleeding, whereas they included data on hemorrhagic events, whether fatal or not (20). The differences may also reflect the use of unpublished data. In this regard it is interesting to note that the bleeding risks for two of the studies (6,10) were qualitatively different in the Pouleur meta-analysis as compared with the original publications. In both original studies, the bleeding risk was slightly higher with dipyridamole; in the data used in the meta-analysis, the bleeding risk was lower. As such, our results may represent a more conservative estimate of bleeding risk.
In comparison with the above, our meta-analysis is more powerful, including data on 2,199 subjects from 10 trials and less subject to bias through inclusion of trials of any language, use of dipyridamole or aspirin and including publications as a manuscript or abstract. Furthermore, the robustness of our conclusions are reinforced through extensive sensitivity analyses which, among other things, included the impact of unpublished data, English language and other language publications (34) and whether double-blind methodology was used. None of these methodological factors impacted on our estimate of the effectiveness and safety of adjunctive antiplatelet therapy.
Potential limitations. Our analysis was not adjusted for study quality and, therefore, potentially at risk for this bias. A recent study found that the use of summary scores to identify trials of high methodological quality was problematic (35). Notwithstanding, it has also been shown that incorporation of studies of low methodological quality tend to show an increased estimate of benefit (36). However, our sensitivity analyses did not detect any effect of exclusion of individual trials (some of which were of lesser quality, for example the Rajah study [11], published as an abstract only) or a difference among double-blinded trials on the rates of thromboembolism or death prevention. We did not use blinded techniques during study selection or data abstraction as such procedures have not been found to be necessary (37). The possibility of publication bias in medical research is important but difficult to eliminate when performing a meta-analysis (23,38). To the present, unpublished data in meta-analyses remains controversial but should not be systematically excluded (39). Our analysis included all published data from the included randomized trials as well as some unpublished data obtained for an FDA submission and used in a previous meta-analysis (20). We were unable to verify this unpublished data. However, sensitivity analyses, excluding the unpublished data, did not alter our conclusions, except for the risk of major bleeding, as previously discussed.
We included trials that claimed to have used proper randomization techniques but did not seek to authenticate the veracity of these claims (40). Furthermore, although improper concealment of treatment allocation has been shown to be an important source of bias in RCTs (and therefore in meta-analyses based upon them), none of the included trials provided adequate information on this (41). Finally, although our study involved data on almost 2,200 subjects and the results for thromboembolism and death are highly statistically significant, there is the possibility of a type II error given the marginal degree of significance for the outcome of major bleeding. It can be shown that an individual trial of almost 3,200 subjects would be necessary to show a difference in the rate of bleeding from 5.0% to 7.4%, assuming a two-tailed alpha of 0.05 and 80% power. Pogue and Yusuf (42) have suggested that the sample size required for a meta-analysis should be at least as large as a single optimally powered RCT. As such, our analysis may be underpowered with respect to that end point only.
Clinical implications. Our results suggest that low-dose aspirin could be safely added to anticoagulation with an acceptable risk of bleeding and with the expectation that rates of death and thromboembolism would be reduced. Indeed, it is quite possible that outcomes would be improved with a more widespread use of aspirin as compared with existing guidelines (see Appendix). A survey performed by Ray and Turpie showed that low-dose aspirin was underused by North American cardiac surgeons. Only 21% of respondents routinely used aspirin in conjunction with anticoagulants (43). The two most common reasons for not using aspirin were the perceived increase in bleeding risk (49% of nonusers) or lack of proven benefit (23% of nonusers) (43). These concerns are unfounded and not in accord with the available trial and meta-analytic evidence.
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Appendix |
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