Clinicians frequently face the decision of aspirin and coumadin to continue aspirin when starting patients on warfarin. We performed a meta-analysis to characterize the tradeoffs involved in this common clinical dilemma. Multiple computerized databases toreference lists of relevant articles, conference proceedings, and queries of primary authors. Randomized trials comparing warfarin plus aspirin versus warfarin alone. Two reviewers independently extracted baseline data and aspirin and coumadin outcomes: Nine studies met the inclusion criteria.
Of the five that enrolled patients with mechanical heart valves, four used the same target INR in aspirin and coumadin groups, while one used a reduced target INR for the warfarin plus aspirin group, aspirin and coumadin. Pooling the results of the first four studies demonstrated that combination of warfarin plus aspirin significantly decreased thromboembolic events relative risk [RR], 0, aspirin and coumadin.
The one valve trial using a reduced INR in the warfarin plus aspirin group reported no difference in thromboembolic outcomes but found decreased major bleeding and a significant mortality benefit with combination therapy. Of the remaining trials, three evaluated a warfarin indication not routinely used in the United States post-myocardial infarctionand the only trial that considered atrial fibrillation was terminated early due to inadequate enrollment.
For mechanical heart valve patients, aspirin and coumadin, the benefits of continuing aspirin when starting warfarin therapy are clear. For other routine warfarin indications, there are not adequate data to guide this common clinical decision. Because of data demonstrating a lower risk of myocardial infarction MI and stroke, 1 — 3 the number of Americans taking daily aspirin is approaching 23 million.
Reasonable clinical arguments have been made for both approaches. On the one hand, proponents of aspirin and coumadin aspirin with warfarin therapy have hypothesized additive antithrombotic protection when both platelet function and coagulation factor activity are suppressed.
On the other hand, those warning against dual therapy have cautioned that the potential for increased bleeding would be unacceptably high, surely outweighing any theoretical benefits. In order to describe these tradeoffs quantitatively, we performed a systematic review and meta-analysis of any randomized trials comparing adjusted-dose warfarin plus aspirin versus adjusted-dose warfarin alone.
We aimed to characterize the efficacy and safety of the two treatment strategies by comparing thromboembolic, bleeding, and mortality outcomes in conditions in which these drugs might be used concomitantly. We used a Cochrane Optimized Medline Search Strategy see Appendix facilas and allergies to locate randomized, controlled trials involving warfarin or comparable oral vitamin K antagonists and aspirin published in English language journals between and October We manually reviewed the bibliographies of selected and related articles for any pertinent references overlooked by the computerized searches and explored national and international conference proceedings for abstracts of relevant work not yet published.
References identified by the computerized searches were imported into a computer database for review. Full text articles were obtained of references that either appeared to meet the inclusion criteria or could not be excluded by abstract and title review alone. Reviewers were not blinded to journal titles, aspirin and coumadin, author names, or institutional affiliations. For each study selected for the synthesis two reviewers independently extracted aspirin and coumadin data of interest.
If important pieces of data could not be located in a published report, efforts were made to contact the corresponding authors in order to obtain the missing details. Information was entered into a data collection aspirin and coumadin by each reviewer and then compared for consistency.
Disagreements were resolved via discussion, aspirin and coumadin. Statistical calculations were performed using Revman software. If a grouping of trial results was found to be heterogeneous using a P value cutoff of.
Absolute risk reductions for each endpoint by warfarin indication were manually calculated by subtracting the aspirin and coumadin event rates for each treatment group from the pooled event rates for each corresponding control group. Eight hundred twenty-five potential articles were initially located by the computerized searches.
As shown in Figure 1the majority of exclusions were made due to lack of randomization or missing treatment arms. Manual reference review led to the identification of one additional randomized trial.
A summary of the trials included in the synthesis is shown in Table 2. Five involved mechanical heart valve recipients, aspirin and coumadin, 121315 — 18 three were performed in post-myocardial infarction post-MI subjects, 19 — 21 and one had been conducted in atrial fibrillation patients at high risk for thromboembolic disease.
Thromboembolic events were defined similarly in all five valve trials and typically included valve thromboses, systemic emboli, cerebrovascular emboli, and MIs occurring in the absence of significant coronary artery lesions. Transient ischemic attacks were included in four of the five trials, aspirin and coumadin. For the double-intervention trial, 18 thromboembolic event rates were low in both groups and essentially equivalent.
Again shown in Table 3major bleeding events were increased or equivalent with warfarin plus aspirin in all three of the single-intervention trials reporting this outcome 1315aspirin and coumadin, 16 pooled RR, 1, aspirin and coumadin. Conversely, aspirin and coumadin double-intervention trial 18 found fewer bleeding events in the combination therapy group.
The post-MI trials tracked subsequent cardiac events defined by clinical, electrocardiogram, and laboratory parameters. As shown in Table 4subsequent nonfatal MI rates were decreased with combination therapy in all three trials but none achieved statistical significance, aspirin and coumadin. As shown in Table 4the major bleeding outcomes were mixed. The single trial with identical INR targets in both treatment groups single intervention 19 reported a nonsignificant 3-fold increased risk of major bleeding for the combination therapy group, aspirin and coumadin.
The two aspirin and coumadin trials in which the target INRs were lower in the aspirin and coumadin plus aspirin groups 2021 suggested no clear difference in bleeding rates between the two treatment strategies pooled RR, 1. Two trials 1921 found nonsignificant increases in all-cause mortality with combination therapy whereas the remaining trial 20 showed no mortality difference. Combining the double-intervention trials 20aspirin and coumadin, 21 revealed a pooled risk of 1.
The single atrial fibrillation trial 22 evaluated elderly subjects at high risk for thromboembolic events average age approximately 74 years.
Thromboembolic events included aspirin and coumadin and hemorrhagic cerebrovascular accidents; MIs meeting clinical, electrocardiogram, and lab criteria; aspirin and coumadin systemic arterial emboli of cardiac origin affecting mesenteric, renal, splenic, or limb arteries, aspirin and coumadin. Major bleeding events included those requiring specific treatment such as transfusions or hospitalization. Though the trial was not adequately powered due to slow enrollment and subsequent early termination, thromboembolic and major bleeding rates were higher in the combined therapy group RR, 2.
The wide confidence intervals however, caution against drawing any major conclusions from the results. Despite the growing prevalence of aspirin use among patients starting warfarin, five of the nine randomized trials that specifically assessed the benefits and harms of combination warfarin plus aspirin therapy were restricted to patients with mechanical heart valves, aspirin and coumadin.
Three involved an indication rarely used in the United States routine post-MI and only one focused on patients with the most common chronic indication, atrial fibrillation. Mechanical heart valve patients have a clear overall benefit from combining aspirin with warfarin therapy.
Post-MI patients probably have a reduced risk of thromboembolic events but appear to have no decrease and perhaps an increase in overall mortality. Finally, because the atrial fibrillation trial was terminated early, there are no data from which to draw conclusions regarding this increasingly prevalent indication, aspirin and coumadin.
Though the efficacy and safety of combining warfarin and aspirin was reviewed in35 in its effort to be comprehensive the synthesis mixed trials addressing all three questions. Conversely, when previous investigators have focused specifically on aspirin and coumadin comparable to our own, 36 — 39 their reviews have been confined to mechanical heart valve trials. To our knowledge, our report is the first to focus on the tradeoffs of concomitant aspirin use in multiple adjusted-dose warfarin indications.
Nonetheless, our study is clearly limited by the small number of trials that fulfilled the inclusion criteria and the narrow scope of warfarin indications covered by the few qualifying trials, aspirin and coumadin. We did not have access to Excerpta Medica database but have no reason to believe that can you mix zoloft and ambien contains additional relevant trials not detected by our present search strategy.
While the initial study screening was performed by a single reviewer, our well-defined inclusion criteria made study selection straightforward and articles aspirin and coumadin presented any question were reviewed by both investigators prior to exclusion. Additional limitations might stem from the poor availability of information to assess study quality, and the variation in treatment regimens used in the studies.
Similarly, the aspirin doses ranged from 75 to 1, mg per aspirin and coumadin. Despite the diversity, however, no obvious relationship between the study outcomes and the INR ranges or aspirin doses was detected. In fact, the highest bleeding rates were seen in a trial using both a conservative target INR range and a modest aspirin dose. Admittedly, the primary aim of most trials evaluating warfarin and aspirin combinations has been to assess whether the addition of aspirin provides added protection in terms of the thrombosis risk for which the warfarin is indicated, without aspirin and coumadin to excessive bleeding.
While this question is different from asking whether it is safe to continue prophylactic aspirin for prevention of MI and stroke in celiac and arthritis requiring warfarin for alternative diagnoses i.
Though the inclusion criteria might require that subjects also meet defined criteria for prophylactic aspirin i. Because our review was specifically intended to address aspirin use in patients requiring warfarin, we considered carefully whether the post-MI trials were appropriate for the synthesis. Indeed in the United States, aspirin has been the traditional first-line prevention therapy following acute MI, whereas warfarin has been reserved for patients intolerant to aspirin, with left ventricular mural thrombus or high-risk anterior aspirin and coumadin motion abnormalities, aspirin and coumadin, or with recurrent thrombotic events on aspirin alone.
With the publication of the most recent post-MI trial, 20 however, it appears that our question may be relevant for this patient group as well.
Because both the warfarin plus aspirin and warfarin-only groups had fewer thromboembolic events compared to the aspirin-only group, attention is now being given to whether anticoagulation-based secondary prevention therapies should be more aggressively considered in this country.
For those clinicians and patients who choose to aspirin and coumadin on minimizing thromboembolic risk, these results suggest that combined warfarin plus aspirin therapy offers the best protection. On the other hand, for those who choose to focus on the broader overall mortality outcomes, the findings suggest that neither the addition of nor substitution with warfarin offers a mortality advantage over aspirin alone.
In the end, we are left with a striking lack of evidence regarding aspirin use in the most common warfarin indications. Unfortunately, the variations in outcomes among the conditions we were aspirin and coumadin to evaluate suggest that extrapolating from one warfarin indication to another may not be appropriate.
Nonetheless, with over 2 million people in the United States affected by atrial fibrillation and approachingnew cases per year, 40 the issues raised here will only become more relevant.
For now, decisions about the use of aspirin in most patients receiving warfarin will need to be individualized in the absence of adequate data. National Center for Biotechnology InformationU. J Gen Intern Med. Address correspondence and requests for reprints to Dr. Copyright by the Society of General Internal Medicine, aspirin and coumadin.
This article has been cited by other articles in PMC. Study Selection References identified by the computerized searches were imported into a computer database for review. Data Extraction For each study selected for the synthesis two reviewers independently extracted the data of interest. Data Synthesis Statistical calculations were performed using Revman software. Open in a separate window. Trial identification and selection process. RCT, randomized, controlled trial.
Study Characteristics A summary of the trials included in the synthesis is shown in Table 2. Mechanical Heart Valves Thromboembolic Events Thromboembolic events were defined similarly in all five valve trials and typically included valve thromboses, systemic emboli, cerebrovascular emboli, and MIs occurring in the absence of significant coronary artery lesions.
Post-myocardial Infarction Trials Subsequent Myocardial Infarction The post-MI trials tracked subsequent cardiac events defined by clinical, electrocardiogram, and laboratory parameters. All-cause Mortality Two trials 1921 found nonsignificant increases in all-cause mortality with combination therapy whereas the remaining trial 20 showed no mortality difference.
Atrial Fibrillation Trials Thromboembolic Events, Major Bleeding, and All-cause Mortality The single atrial fibrillation trial 22 evaluated elderly subjects at high risk for thromboembolic events average age approximately 74 years.
DISCUSSION Despite the growing prevalence of aspirin use among patients starting warfarin, five of the nine randomized trials that specifically assessed the benefits and harms of combination warfarin plus aspirin therapy were restricted to patients with mechanical heart valves. N Engl J Med. Collaborative overview of randomized trials of antiplatelet therapy, I: