Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta-analysis
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Journal of Thrombosis and Haemostasis, 10: 512–520 DOI: 10.1111/j.1538-7836.2012.04635.x
ORIGINAL ARTICLE
Bleeding risk in randomized controlled trials comparing
warfarin and aspirin: a systematic review and meta-analysis
A. E. WARKENTIN,* M. P. DONADINI, F. A. SPENCER, W. LIM and M . C R O W T H E R
*Faculty of Medicine, University of Toronto, Toronto, ON; and Department of Medicine, McMaster University, Hamilton, ON, Canada
To cite this article: Warkentin AE, Donadini MP, Spencer FA, Lim W, Crowther M. Bleeding risk in randomized controlled trials comparing warfarin
and aspirin: a systematic review and meta-analysis. J Thromb Haemost 2012; 10: 512–20.
Introduction
Summary. Background: Warfarin and aspirin (acetylsalicylic
acid [ASA]) are the most commonly used anticoagulant and Anticoagulant and antiplatelet drugs are highly effective for the
antiplatelet drugs in the treatment of cardiovascular dis- prevention and treatment of thrombotic cardiovascular dis-
ease. Objectives: To provide a pooled estimate of the bleeding eases. Warfarin and aspirin (acetylsalicylic acid [ASA]) are the
risk from randomized controlled trials (RCTs) comparing most commonly used anticoagulant and antiplatelet agents for
warfarin and ASA at the dose ranges recommended in evidence- long-term prophylaxis in patients with atrial fibrillation,
based guidelines. Patients/Methods: Ovid MEDLINE, Em- myocardial infarction, peripheral artery disease, cerebrovascu-
base and the Cochrane Library, up to September 2011, were lar disease, heart failure, and heart valve replacement.
searched for RCTs comparing bleeding rates in adult patients Although they are highly effective, both ASA and warfarin
randomized to warfarin, target International Normalized Ratio can result in bleeding. Data on the risk of bleeding are
(INR) 2.0–3.5, and ASA, 50–650 mg daily, with at least surprisingly limited, perhaps because the reported rates vary as
3 months of follow-up. Pooled odds ratios (ORs) and associ- a result of study design and population, definition, site of
ated 95% confidence intervals (CIs) were calculated with the bleeding, and drug dosage. The annual incidence of major
inverse variance method and the random effects mod- bleeding in trials and cohort studies has been reported to be
el. Results: Four thousand four hundred and forty-two between 1.1% and 2.3% [1–5] in patients treated with warfarin
abstracts were screened, resulting in eight included studies for to achieve an International Normalized Ratio (INR) of 2.0–3.0
final analysis. A pooled estimate derived from the 2904 patients and between 1.1% and 1.5% in ASA-treated patients [2,3,6,7].
enrolled indicated a trend towards an increase in major bleeding These rates are derived from carefully selected patients; rates in
risk in those randomized to warfarin (OR 1.27; 95% CI 0.83– ÔunselectedÕ outpatients are likely to be higher, as demonstrated
1.94). The pooled OR for intracranial hemorrhage in patients in a recent nationwide registry, where the risks of bleeding were
treated with warfarin vs. ASA was 1.64 (95% CI 0.71–3.78), found to be 4.3% and 2.6% in patients receiving warfarin and
and that for extracranial major bleeding was 1.03 ASA, respectively [8]. Taken together, these studies suggest that
(95% CI 0.61–1.75). Minor bleeding, from a 1748-patient bleeding rates with warfarin are higher than those seen with
sample, was more common in warfarin patients (OR 1.50; ASA, but the difference between these bleeding rates is less than
95% CI 1.13–2.00). Conclusions: This meta-analysis failed to expected, given that ASA is a less potent anticoagulant than
find a statistically significant difference in major bleeding warfarin.
between warfarin, target INR 2.0–3.5, and ASA, 50–650 mg In clinical practice, the risk of bleeding related to warfarin is
daily. The trend towards increased bleeding with warfarin usually considered to be significantly higher than the risk
appears to be explained by an excess of intracranial bleeding in associated with ASA. However, a pooled estimate of the
warfarin patients. magnitude of this difference from direct comparison of
bleeding risk in trials that have randomized patients to
Keywords: aspirin, bleeding, meta-analysis, systematic review, warfarin vs. ASA within current therapeutic ranges has not
warfarin. been published, to our knowledge. To address this gap, we
performed a systematic review and meta-analysis of random-
ized controlled trials (RCTs) that enrolled adult patients with
any indication for long-term antithrombotic therapy and
Correspondence: Mark Crowther, Rm L301, St JosephÕs Hospital, randomized them to warfarin or ASA. Our objective was to
50 Charlton Ave East, Hamilton, L8N 4A6, ON, Canada.
compare the bleeding rates between these two groups of
Tel.: +1 905 521 6024; fax: +1 905 521 6090.
patients. Many studies have used ASA doses or warfarin INR
E-mail: crowthrm@mcmaster.ca
target ranges that are not used in modern clinical practice, so
Received 4 June 2011, accepted 4 January 2012 we sought to assess bleeding risks by use of the dose ranges
2012 International Society on Thrombosis and HaemostasisComparative bleeding risk: warfarin vs. aspirin 513
recommended in evidence-based guidelines: ASA 50– abstract selection phase, the article was discussed by the two
650 mg day)1 and INR range 2.0–3.5 [9–11]. We were also reviewers. If consensus could not be reached, a third reviewer
interested in, as a secondary question, what the bleeding risk (M.C.) could be consulted. Consultation with a third reviewer
was in trials that randomized patients to warfarin vs. warfarin could also be utilized for disagreements during the full-text
plus ASA (at equivalent warfarin targets in both treatment review.
arms, and within the same therapeutic ranges specified We included all studies meeting our inclusion criteria,
already). Prespecified secondary analyses of this study included irrespective of the efficacy outcome of the individual studies
an investigation of bleeding risk according to age (< 70 and and the indication for antithrombotic therapy, as it has been
‡ 70 years old) and clinical indication for therapy. previously reported that the therapeutic indication for anti-
thrombotic therapy does not significantly impact on bleeding
rates with long-term treatment [12].
Methods
A protocol for assessment of study eligibility was drafted, and
Data extraction and study bias assessment
is available upon request from the authors. No study review
protocol is available for data extraction and data analysis. Two reviewers (A.E.W. and M.P.D.) independently per-
formed the data extraction, using an extraction sheet drafted
for the current study, and completed a bias assessment of
Data sources and searches
included articles utilizing the Cochrane Handbook for
We searched the Ovid MEDLINE (1948 to August week 4 Systematic Reviews of Interventions [13]. Data pertaining to
2011) and Ovid MEDLINE In-Process and Other Non- study inclusion criteria, such as target INR, ASA dosage, and
Indexed Citations (2 September 2011), Embase (1980–2011 duration of follow-up, were extracted, as were data pertaining
week 35) and the Cochrane Central Register of Controlled to factors such as number of patients enrolled in the study,
Trials (2011, issue 3) databases. The search strategies for these patient characteristics, clinical indication for antithrombotic
three databases were formulated by A.E.W., following consul- medication, bleeding definitions, bleeding outcomes in all
tation with a professional librarian. For a complete description patients and in specific subgroups, and number of patients
of search terms that were applied to each of these three assigned to the treatment arms of interest to the current
databases, see Appendix S1. The electronic search strategy was review (for a complete description, data extraction forms are
complemented by manually reviewing the reference lists of available from the authors upon request). Owing to hetero-
articles that were identified for full-text review, as well as geneity in across-study definitions for bleeding, major
through contact with content experts. bleeding events were counted as they were defined in each
study.
Discrepancies in the extracted data were resolved by
Study selection
consensus between the two reviewers.
The included studies, for the purposes of full-text review, The bias assessment of studies was conducted in accor-
satisfied the following criteria: (i) the study considered dance with that specified in the Cochrane Handbook for
patients prescribed warfarin with a target INR of 2.0–3.5 as Systematic Reviews of Interventions [13]. Studies were
compared with those precribed ASA at a dose of 50– assessed for selection bias, performance bias, detection bias,
650 mg day)1, or warfarin vs. warfarin plus ASA (with the attrition bias, and reporting bias. Selection bias assessment
same warfarin INR ranges and ASA dosages already involved analysis of random sequence generation and allo-
specified); (ii) the study was an RCT; (iii) adult patients were cation concealment. Performance bias assessment involved
enrolled; (iv) patient follow-up was carried out for at least the blinding of study participants and personnel. Detection
3 months; and (v) bleeding was an outcome ascertained in the bias assessment involved the blinding of study outcome
study. The study titles and abstracts were screened for study assessors. Attrition bias assessment involved an analysis of
inclusion, and if any of the five criteria were not satisfied, the the completeness of study outcome data. Reporting bias
study was excluded. If there was ambiguity as to whether each assessment involved an analysis of selective reporting of
criterion was satisfied, the abstract under consideration was study outcomes [13]. For each component of the analysis,
noted for full-text review. In addition, we excluded articles studies could receive a label of: low risk of bias; high risk of
that were not published in English, if the full-text article could bias; or unclear risk of bias. In an effort to avoid a possible
not be retrieved (online, from the library, or via interlibrary selection bias, all studies that were retrieved and subsequently
loan), and if other oral anticoagulants were used in addition analyzed with this bias assessment were ultimately included
to warfarin. If data from the same patients were published in in our final analysis.
multiple articles (i.e. duplicate data), data from the most
recent publication were used, unless the data were not
Data synthesis and analysis
extractable. The title and abstract review, and full-text review,
were performed in duplicate by two reviewers (A.E.W. and Pooled odds ratios (ORs) and associated 95% confidence
M.P.D.). If there was disagreement in the initial title and intervals (CIs) were calculated with the inverse variance
2012 International Society on Thrombosis and Haemostasis514 A. E. Warkentin et al
method for both major and minor bleeding in patients receiving
Results
warfarin vs. those receiving ASA. The analysis was performed
with Review Manager statistical software (REVMAN ver-
Study selection
sion 5.0; Copenhagen: The Nordic Cochrane Centre, The
Cochrane Collaboration, 2008). We identified 4442 studies with the electronic search strategy,
To explore between-study variability and the appropriate- and 47 of these were ultimately identified for full-text evaluation
ness of pooling the results from individual studies, the I2-test (Fig. 1). Of these 47 full-text articles, 40 studies were excluded
for heterogeneity was used. The I2-value expresses the for one or more of the following reasons: arms of treatment
percentage of between-study variability that is attributable to and/or INR range and/or ASA dosage were not appropriate
heterogeneity rather than chance. An I2-value of ‡ 60% (36 studies); duplicate data (two studies); and study was not an
suggests significant heterogeneity, indicating that a formal RCT (two studies). Therefore, seven studies remained for data
meta-analysis would be of limited value, given the amount of extraction and bias assessment. One additional article was
heterogeneity. To further reduce the impact of heterogeneity, identified from a manual review of study bibliographies. There
we chose to use a random effects model that would allow for were no additional eligible studies identified after communica-
heterogeneity and incorporate its impact in the meta-analysis. tion with four content experts. Therefore, eight studies were
Funnel plots of effect size against standard error were used to included in the systematic review and meta-analysis [14–21].
display small-study effects that may arise from reporting bias, For the 47 full-text articles screened, there was perfect
differences in methodological quality, or true heterogeneity agreement between reviewers regarding inclusion and exclu-
among studies. Prespecified subgroup analyses were performed sion, except for one article that was deemed to be ambiguous
to evaluate the bleeding risk: (i) according to age (< 70 and by one of the reviewers. For this study, a third party (M.C.) was
‡70 years); and (ii) according to the clinical indication for consulted to resolve the ambiguity. This article was ultimately
antithrombotic therapy. excluded. [22]
A secondary analysis, specified a priori, was a comparison of
bleeding risk in studies that randomized patients to warfarin
Study characteristics
plus ASA vs. warfarin alone (with the same target INR in both
treatment arms, and the same prespecified INR range and ASA The main characteristics of the included studies are described in
dosages specified previously). Table 1. The patient population included atrial fibrillation in
Recods identified throgh
database screening
(n = 4442)
Duplicates removed (n = 767)
Records screened (n = 3675) Excluded (n = 3628)
Excluded (n = 40)
- Treatment arms and/or
Full-text articles assessed for INR range and/or ASA
eligibillity (n = 47) dosage not suitable (n =
36)
- Duplicate data (n = 2)
- Not an RCT (n = 2)
Articles identified through
full-text reference list
review (n = 1)
Studies included in meta-
analysis (n = 8)
Fig. 1. Study selection. ASA, aspirin (acetylsalicylic acid); INR, International Normalized Ratio; RCT, randomized controlled trial.
2012 International Society on Thrombosis and HaemostasisComparative bleeding risk: warfarin vs. aspirin 515
Table 1. Study and patient characteristics
Total no.
of patients Mean age Female/
(no. of (years) male (%) Mean Patients
First author, Indication for patients in (patients in (patients in ASA follow-up lost to Withdrawal/
year (study antithrombotic arms of arms of arms of INR dose duration follow-up, dropout*,
acronym) therapy interest) interest) interest) range (mg) (months) no. (%) no. (%)
Huynh, 2001 [14] UA/NSTEMI 135 67 20/80 2–2.5 80 13 3 (2) 12 (9)
and prior
CABG
Colli, 2007 [15] Aortic valve 69 70 14/86 2–3 100 3 NA 6 (8)
(WoA Epic) replacement
Gullov, 1999 [16] Atrial 677 (339) 73.2 38.9/61.1 2–3 300 NAà 0 170 (25.1)
(AFASAK 2) fibrillation
Rash, 2007 [17] Atrial 75 83§ 53/47 2–3 300 12 NA 11 (15)
(WASPO) fibrillation
Mant, 2007 [18] Atrial 973 81.5 45.4/54.6 2–3 75 32 8 (0.8) 279 (28.7)
(BAFTA) fibrillation
Cleland, 2004 [19] Chronic heart 279 (180) 64 25/75 2–3 300 27 NA NA
(WASH) failure
Cokkinos, 2006 Chronic heart 197 (114) 62 11/89 2–3 325 19 NA 3 (2)–
[20] (HELAS) failure
Massie, 2009 [21] Chronic heart 1587(1063) 63 15.2/84.8 2–3.5 162 23 76 (4.8)** 312 (19.7)
(WATCH) failure
ASA, acetylsalicylic acid; CABG, coronary artery bypass graft; INR, international normalized ratio; NA, not available; NSTEMI, non-ST-
elevation myocardial infarction; UA, unstable angina. *For withdrawal/dropout, all patients who stopped using the study drug or switched group
were counted. Seventy-five patients were initially enrolled, six of whom were withdrawn from final statistical analysis in the primary article. àThe
study was stopped prematurely, after 42 months. The mean duration of follow-up is not provided in the article describing the study. §This value
represents the mean of the reported median age in the primary article. –Only one of three patients belongs to one of the arms of interest. **Fifty
patients (4.7%) were lost to follow-up in the arms of interest. Two hundred and ten patients (19.8%) were withdrawn from study medication in
the arms of interest.
three studies [16–18], chronic heart failure in three studies [19– < 90 mmHg or a fall in Hb level below 9.7 g dL)1 in one
21], acute coronary syndrome in one study [14], and heart valve study [16].
replacement in one study [15]. The study sample sizes varied Five studies reported the frequency of minor bleeding
from 69 to 1587 patients. A total of 2948 patients were enrolled outcomes [14,16,17,19,21]. A formal minor bleeding definition
in the therapeutic arms relevant to the systematic review. ASA was, however, present in only two studies [14,16]. One study
dosage varied from 75 to 325 mg day)1; target INR ranges defined minor bleeding as all non-major bleeding events
were 2.0–2.5 in one study, 2.0–3.0 in six studies, and 2.0–3.5 in reported by the physician or patient [14], and one study
one study. The mean age varied from 62 to 83 years. Duration defined it as all non-major and non-threatening bleeds [16].
of follow-up varied among the included studies. For the purpose of the meta-analysis, we made an attempt to
Only one study included an additional arm assigned to differentiate intracranial from non-intracranial major bleeding
warfarin plus ASA at the same prespecified INR range and events. However, data on these events were reported only in
ASA dosage [14]. In four studies, other drugs or no treatment four studies [16,18,19,21]. After the authors of the other four
were used in additional arms not considered for the purpose of studies had been contacted, the relevant information was made
this meta-analysis: placebo or no treatment in two studies available for only one study [17].
[19,20]; clopidogrel in one study [21]; and fixed-dose warfarin
and fixed-dose warfarin plus ASA in one study [16].
Bias assessment
Major bleeding was defined in six studies, and differed across
the studies (Table 2). Among the criteria that defined major Only one of the eight included studies [20] was identified as low
bleeding, a need for transfusion was present in five studies risk of bias among all categories, as shown in Table 3. One
[14,17–19,21]; a fall in hemoglobin (Hb) level of ‡ 2 g dL)1 in additional study was identified as low risk in all but the random
three studies [14,17,21]; a fatal outcome in three studies sequence generation and allocation concealment categories, in
[16,18,21]; intracranial bleeding in two studies [17,18]; a need which insufficient information was provided to classify these
for surgical intervention in three studies [16,18,21]; an outcome items as low risk [14]. The remaining six studies all contained
of disability in one study [21]; an outcome of cardiopulmonary elements of high risk of bias with respect to blinding of
arrest or irreversible damage in one study [16]; and the presence participants/personnel [15–19,21]. This was because of the
of at least two characteristics including a request for more than unblinded nature of warfarin delivery in these trials. All studies
three red blood cell units, a systolic blood pressure of were identified as low risk in terms of selective reporting, and all
2012 International Society on Thrombosis and Haemostasis516 A. E. Warkentin et al
Table 2. Major bleeding definitions in the included studies
Components of major bleeding definition
Leading to
Fall in CP arrest or Potentially Definition
Hbof Transfusion Surgey Disability irreversible life- not
Study ‡ 2 g dL)1 required Intracranial required outcome damage* threatening Fatal available
Huynh, 2001 [14] 4 4 - - - - - - -
Colli, 2007 [15] - - - - - - - - 4
(WoA Epic)
Gullov, 1999 [16] - - - 4ৠ- 4à 4 4 -
(AFASAK 2)
Rash, 2007 [17] 4 4 4 - - - - - -
(WASPO)
Mant, 2007 [18] - 4 4 4 - - - 4 -
(BAFTA)
Cleland, 2004 - 4 - - - - - - -
[19] (WASH)
Cokkinos, 2006 - - - - - - - - 4
[20] (HELAS)
Massie, 2009 4 4– - 4 4 - - 4 -
[21] (WATCH)
CP, cardio-pulmonary; Hb, hemoglobin. *Myocardial infarction, stroke, blindness. Defined in the presence of at least two of the following:
> 3 U of red blood cells required; systolic blood pressure of < 90 mmHg; Hb < 6 mmol L)1 (9.7 g dL)1). àBleeding event defined as Ôlife-
threateningÕ. §Surgery or angiographic intervention required. –At least two units of packed red blood cells or whole blood.
Table 3. Study bias assessment
Random Blinding of Blinding of Incomplete
First author, year sequence Allocation participants/ outcome outcome Selective
(study acronym) generation concealment personnel assessment data reporting
Huynh, 2001 [14] Unclear risk Unclear risk Low risk Low risk Low risk Low risk
Colli, 2007 [15] (WoA Epic) Unclear risk Unclear risk High risk Unclear risk Unclear risk Low risk
Gullov, 1999 [16] (AFASAK 2) Low risk Low risk High risk Low risk Unclear risk Low risk
Rash, 2007 [17] (WASPO) Low risk Low risk High risk Unclear risk Unclear risk Low risk
Mant, 2007 [18] (BAFTA) Low risk Low risk High risk Low risk Unclear risk Low risk
Cleland, 2004 [19] (WASH) Low risk Low risk High risk Low risk Unclear risk Low risk
Cokkinos, 2006 [20] (HELAS) Low risk Low risk Low risk Low risk Low risk Low risk
Massie, 2009 [21] (WATCH) Low risk Low risk High risk Low risk Unclear risk Low risk
but two studies [14,15] were low risk for selection biases. Owing A distinction between intracranial hemorrhage and non-
to conservative estimation of risk in incomplete outcome data, intracranial major bleeding events was possible for only five
six of eight studies [15–19,21] were classified as unclear risk. studies [16–19,21] (2630 patients). The pooled OR for
Fully detailed bias assessments can be made available upon intracranial hemorrhage in patients treated with warfarin vs.
request to the authors. ASA was 1.64 (95% CI 0.71–3.78) (Fig. 4), and that for
extracranial major bleeding was 1.03 (95% CI 0.61–1.75)
(Fig. 5).
Data synthesis
A sensitivity analysis was performed in two groups of trials
Major bleeding occurred in 69 of 1455 (4.7%; 95% CI 3.8–6.0) according to ASA dosage, in order to assess the robustness of
patients treated with warfarin and in 54 of 1449 (3.7%; the results. Considering only the RCTs that used ASA dosages
95% CI 2.9–4.8) patients treated with ASA (Fig. 2). The of < 300 mg [14,15,18,21], the pooled OR for major bleeding
pooled OR for major bleeding showed a non-statistically confirmed a non-statistically significant increased risk for
significant increase in major bleeding for patients receiving patients receiving warfarin vs. those receiving ASA (OR 1.25;
warfarin vs. those receiving ASA (OR 1.27; 95% CI 0.83– 95% CI 0.83–1.86). A similar result for the same comparison
1.94). was also obtained with consideration of the RCTs that used
The pooled OR for minor bleeding events (data available for ASA dosages equal to or greater than 300 mg [16,17,19,20]
five studies [14,16,17,19,21], 1748 patients) showed a signifi- (pooled OR 1.45; 95% CI 0.31–6.88).
cantly increased risk in patients treated with warfarin vs. ASA Funnel plots of effects size against standard error were
(OR 1.50; 95% CI 1.13–2.00) (Fig. 3). created for major and minor bleeding. The funnel plots
2012 International Society on Thrombosis and HaemostasisComparative bleeding risk: warfarin vs. aspirin 517
Warfarin ASA Odds ratio Odds ratio
Study or subgroup Events Total Events Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
Huynh et al, 2001 [14] 1 45 0 46 1.7% 3.13 [0.12–79.00]
Colli et al, 2007 [15] 3 34 1 35 3.3% 3.29 [0.32–33.31]
Gullov et al,1999 [16] 4 170 5 169 9.6% 0.79 [0.21–3.00]
Rash et al, 2007 [17] 0 36 3 39 2.0% 0.14 [0.01–2.87]
Mant et al, 2007 [18] 25 488 25 485 40.1% 0.99 [0.56–1.76]
Cleland et al, 2004 [19] 4 89 1 91 3.6% 4.24 [0.46– 38.66]
Cokkinos et al, 2006 [20] 4 53 0 61 2.1% 11.18 [0.59–212.70]
Massie et al, 2009 [21] 28 540 19 523 37.6% 1.45 [0.80–2.63]
Total (95% Cl) 1455 1449 100.0% 1.27 [0.83–1.94]
Total events 69 54
Heterogeneity: Tau2 = 0.03, Chi2 = 7.61, d.f. = 7 (P = 0.37); l 2 = 8%
Test for overall effect: Z = 1.09 (P = 0.28) 0.005 0.1 1 10 200
ASA Warfarin
Fig. 2. Risk of major bleeding in patients receiving warfarin or aspirin (acetylsalicylic acid) (ASA). CI, confidence interval; d.f., degrees of freedom; IV,
inverse variance.
Warfarin ASA Odds ratio Odds ratio
Study or subgroup Events Total Events Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
Huynh et al, 2001 [14] 10 45 2 46 3.2% 6.29 [1.29–30.57]
Gullov et al, 1999 [16] 42 170 26 169 22.7% 1.80 [1.05–3.11]
Rash et al, 2007 [17] 6 36 4 39 4.3% 1.75 [0.45–6.79]
Cleland et al, 2004 [19] 15 89 12 91 11.0% 1.33 [0.59–3.04]
Massie et al, 2009 [21] 155 540 123 523 58.9% 1.31 [0.99–1.72]
Total (95% Cl) 880 868 100.0% 1.50 [1.13–2.00]
Total events 228 167
Heterogeneity: Tau2 = 0.02; Chi2 = 4.57, d.f. = 4 (P = 0.33); l 2 = 12%
0.01 0.1 1 10 100
Test for overall effect: Z = 2.79 (P = 0.005)
ASA Warfarin
Fig. 3. Risk of minor bleeding in patients receiving warfarin or aspirin (acetylsalicylic acid) (ASA). CI, confidence interval; d.f., degrees of freedom; IV,
inverse variance.
Warfarin ASA Odds ratio Odds ratio
Study or subgroup Events Total Events Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
Gullov et al, 1999 [16] 2 170 1 169 12.0% 2.00 [0.18–22.27]
Rash et al, 2007 [17] 0 36 0 39 Not estimable
Mant et al, 2007 [18] 7 488 5 485 52.1% 1.40 [0.44–4.43]
Cleland et al, 2004 [19] 0 89 0 91 Not estimable
Massie et al, 2009 [21] 6 540 3 523 35.9% 1.95 [0.48–7.83]
Total (95% Cl) 1323 1307 100.0% 1.64 [0.71–3.78]
Total events 15 9
Heterogeneity: Tau2 = 0.00; Chi2 = 0.16, d.f. = 2 (P = 0.92); l 2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 1.17 (P = 0.24)
ASA Warfarin
Fig. 4. Risk of intracranial hemorrhage in patients receiving warfarin or aspirin (acetylsalicylic acid) (ASA). CI, confidence interval; d.f., degrees of
freedom; IV, variance.
Warfarin ASA Odds ratio Odds ratio
Study or subgroup Events Total Events Total Weight IV, Random, 95% Cl IV, Random, 95% Cl
Gullov et al, 1999 [16] 2 170 4 169 8.7% 0.49 [0.09–2.72]
Rash et al, 2007 [17] 0 36 3 39 3.0% 0.14 [0.01–2.87]
Mant et al, 2007 [18] 18 488 20 485 41.7% 0.89 [0.47–1.70]
Cleland et al, 2004 [19] 4 89 1 91 5.4% 4.24 [0.46–38.66]
Massie et al, 2009 [21] 22 540 16 523 41.2% 1.35 [0.70–2.59]
Total (95% Cl) 1323 1307 100.0% 1.03 [0.61–1.75]
Total events 46 44
Heterogeneity: Tau2 = 0.06; Chi2 = 4.78, d.f. = 4 (P = 0.31); l 2 = 16%
Test for overall effect: Z = 0.12 (P = 0.91) 0.01 0.1 1 10 100
ASA Warfarin
Fig. 5. Risk of extracranial major bleeding in patients receiving warfarin or aspirin (acetylsalicylic acid) (ASA). CI, confidence interval; d.f., degrees of
freedom; IV, inverse variance.
2012 International Society on Thrombosis and Haemostasis518 A. E. Warkentin et al
appeared symmetric, suggesting the absence of publication able to an increased risk of intracranial bleeding. The
bias or other reasons for small-study effects (Figs S1 and frequency of extracranial major bleeding was equivalent
S2). between warfarin and ASA.
Two prespecified subgroup analyses were performed The results of the secondary analysis based on age deserve
according to: (i) the mean age of the study participants; some consideration. We found a tendency for a higher risk of
and (ii) the clinical indication for antithrombotic therapy. bleeding related to warfarin than to ASA in patients younger
With regard to the secondary analysis based on patient age, than 70 years (OR 1.71; 95% CI 0.98–2.98), but not in those
the pooled ORs for major bleeding for patients receiving older than 70 years (OR 0.96; 95% CI 0.58–1.59). These
warfarin vs. ASA in studies that included patients with a findings coming from secondary analysis should be considered
mean age of < 70 years (four studies [14,19–21], 1492 with caution. Indeed, they may be attributable to chance, given
patients) or ‡ 70 years (four studies [15–18], 1456 patients) the small number of studies included in this secondary analysis.
were 1.71 (95% CI 0.98–2.98) and 0.96 (95% CI 0.58–1.59), Age has been described previously as a risk factor for bleeding
respectively. With regard to the secondary analysis based on in both patients treated with warfarin and those treated with
the clinical indication for antithrombotic therapy, and the ASA [3,4,8]. Additional data are needed to confirm or refute
risk of major bleeding related to warfarin vs. ASA in studies this finding.
that enrolled patients with atrial fibrillation (three studies This review does have limitations. First, there were
[16–18], 1387 patients) or with congestive heart failure (three relatively few RCTs comparing ASA, 50–650 mg day)1, and
studies [19–21], 1357 patients), the pooled ORs were 0.91 warfarin within an INR range of 2.0–3.5. Four of these
(95% CI 0.54–1.52) and 2.08 (95% CI 0.81–5.36), respec- studies were prematurely interrupted, because of slow enroll-
tively. ment of patients in all three congestive heart failure studies
Finally, the bleeding risk of warfarin plus ASA vs. warfarin [19–21], and for ethical reasons in the AFASAK-2 trial [16].
alone was only evaluated in one study that met our inclusion We excluded many older RCTs because they did not fulfill the
criteria [14]. In this study two of 44 (5%; 95% CI 0–16) prespecified criteria including the use of an INR target range
patients receiving warfarin and ASA experienced an episode of of 2.0–3.5. These issues resulted in fewer patients being
major bleeding, as compared with one of 45 (2%; 95% CI 0– available for the meta-analysis than we would have hoped, but
13) patients receiving warfarin (OR 2.10; 95% CI 0.18–23.98). we are confident that we identified all eligible studies. We
For the same comparison, minor bleeding events were expe- excluded observational studies, because we wished to present
rienced by nine of 44 (20%; 95% CI 11–35) patients and 10 of the most accurate estimate of bleeding risks by using a direct
45 (22%; 95% CI 12–36) patients, respectively (OR 0.90; comparison of warfarin and ASA. Second, the definition for
95% CI 0.33–2.48). major bleeding differed between studies. This heterogeneity,
which limits our ability to provide reliable estimates of
bleeding risk, argues strongly for the use of a standardized
Discussion
definition of major bleeding. The ISTH has established a
This systematic review provides a pooled analysis of the risk of definition for major bleeding in both medical and surgical
bleeding in RCTs that directly compared warfarin with ASA patients [23,24]; however, all of the studies included in this
using the INR and ASA dose ranges commonly used and systematic review were initiated before those definitions were
recommended by recent clinical practice guidelines [9–11]. published. We considered major bleeding and other types of
Interestingly, our meta-analysis showed a non-statistically bleeding as they were defined in each study and the meta-
significant increased risk of major bleeding in patients treated analysis compared the ORs calculated within each study, thus
with warfarin as compared with those treated with ASA allowing for a meaningful pooled estimate. This approach was
(OR 1.27; 95% CI 0.83–1.94). This observation may have also utilized in a similar meta-analysis [12]. Third, we were
clinical significance, insofar as clinicians will frequently switch particularly interested in intracranial hemorrhage, because of
patients with a perceived increased risk of bleeding from its high case-fatality rate [25] and its unique association with
warfarin therapy to ASA; the findings of this meta-analysis, antithrombotic therapies [26,27]. However, separate data for
along with considerations of the relative efficacy of ASA and intracranial and non-intracranial hemorrhage were available
warfarin, should be considered by clinicians when balancing for only five studies. Fourth, the risk of bleeding may vary
the risks and benefits of warfarin or ASA treatment. across different vitamin K antagonists, as a possible conse-
The results of our analysis of intracranial hemorrhage quence of significant differences in half-life. For this reason,
and non-intracranial major bleeding should be considered we decided to focus on warfarin only, even though we
with caution, as data were available for only five studies, acknowledge that the results may be less generalizable.
and only three of these studies [16,18,21] had estimable ORs However, our choice was made in order to provide more
for intracranial hemorrhage, owing to the lack of reported accurate and precise results. Finally, the patients enrolled in
bleeding events in the other two studies [17,19]. In addition, our analysis were selected because they were participants in
the CIs of the pooled ORs are wide. However, the results RCTs. Such patients probably have a lower risk of bleeding
seem to suggest that the trend towards increased major or other complications than unselected patients in the
bleeding in patients receiving warfarin was entirely attribut- community.
2012 International Society on Thrombosis and HaemostasisComparative bleeding risk: warfarin vs. aspirin 519
As noted previously, our results may be useful as a guide authors. Any queries (other than missing material) should be
for clinical practice. Clinicians frequently switch patients directed to the corresponding author for the article.
from warfarin to ASA as a result of a perception of
increased risk of bleeding; this switch is made on the
References
assumption that ASA is associated with a lower risk of
hemorrhage. Switching from warfarin to ASA has been 1 Ost D, Tepper J, Mihara H, Lander O, Heinzer R, Fein A. Duration of
shown to be associated with reduced efficacy in many anticoagulation following venous thromboembolism: a meta-analysis.
JAMA 2005; 294: 706–15.
clinical situations, particularly in those patients with atrial 2 Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of
fibrillation and additional risk factors for ischemic stroke antithrombotic therapy in atrial fibrillation: analysis of pooled data
[28]. The inability to demonstrate any difference in extra- from five randomized controlled trials. Arch Intern Med 1994; 154:
cranial major bleeding (OR 1.03; 95% CI 0.61–1.75) and the 1449–57.
failure to identify a reduced risk of bleeding in those 3 The Stroke Prevention in Atrial Fibrillation Investigators. Bleeding
during antithrombotic therapy in patients with atrial fibrillation. Arch
patients over 70 years of age (OR 0.96; 95% CI 0.58–1.59) Intern Med 1996; 156: 409–16.
suggest that the practice of switching from warfarin to ASA 4 Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, DÕAngelo A,
because ASA is less likely to be associated with bleeding Pengo V, Erba N, Moia M, Ciavarella N, Devoto G, Berrettini M,
should be re-evaluated. Musolesi S. Bleeding complication of anticoagulant treatment: an
In conclusion, this systematic review and meta-analysis inception-cohort, prospective collaborative study (ISCOAT). Lancet
1996; 348: 423–8.
comparing the bleeding risk associated with warfarin vs. ASA 5 Abdelhafiz AH, Wheeldon NM. Results of an open-label, prospective
in RCTs did not show a significant difference in major bleeding study of anticoagulant therapy for atrial fibrillation in an outpatient
risk between these two agents. Further study of this observa- anticoagulation clinic. Clin Ther 2004; 26: 1470–8.
tion is warranted, given this finding. 6 Gulløv AL, Koefoed BG, Petersen P, Pedersen TS, Andersen ED,
Godtfredsen J, Boysen G. Fixed minidose warfarin and aspirin alone
and in combination vs adjusted-dose warfarin for stroke prevention
Acknowledgements in atrial fibrillation: second Copenhagen Atrial Fibrillation,
Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158: 1513–
J. McKinnell acted in a guidance capacity for how to properly 21.
search the databases utilized in this investigation. She is a 7 Ng W, Wong WM, Chen WH, Tse HF, Lee PY, Lai KC, Li SW, Ng
professional librarian affiliated with the McMaster Health M, Lam KF, Cheng X, Lau CP. Incidence and predictors of upper
gastrointestinal bleeding in patients receiving low-dose aspirin for
Science Library (McMaster University). secondary prevention of cardiovascular events in patients with coro-
nary artery disease. World J Gastroenterol 2006; 12: 2923–7.
8 Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C,
Disclosure of Conflict of Interests Jørgensen C, Madsen JK, Hansen PR, Køber L, Torp-Pedersen C,
M. Crowther has sat on advisory boards for Leo Pharma, Gislason GH. Risk of bleeding in patients with acute myocardial
infarction treated with different combinations of aspirin, clopidogrel,
Pfizer, Bayer, BI, Alexion, and Artisan, has prepared educa- and vitamin K antagonists in Denmark: a retrospective analysis of
tional materials for Pfizer, Octapharm and CSL Behring, has nationwide registry data. Lancet 2009; 374: 1947–8.
provided expert testimony for Bayer, and holds a Career 9 Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen
Investigator award from the Heart and Stroke Foundation of KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB,
Ontario, and the Leo Pharma Chair in Thromboembolism Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK,
Adams CD, Anderson JL, Antman EM, Halperin JL et al. ACC/
Research at McMaster University. M. Crowther and F. A.
AHA/ESC 2006 Guidelines for the Management of Patients with
Spencer are Career Investigators of the Heart and Stroke Atrial Fibrillation: a report of the American College of Cardiology/
Foundation of Ontario. W. Lim is the recipient of the EJ American Heart Association Task Force on Practice Guidelines and
Moran Campbell Internal Career Award (McMaster Univer- the European Society of Cardiology Committee for Practice Guide-
sity). F. A. Spencer is affiliated with the Thrombosis and Ath- lines (Writing Committee to Revise the 2001 Guidelines for the
Management of Patients with Atrial Fibrillation): developed in col-
erosclerosis Research Institute (McMaster University). The laboration with the European Heart Rhythm Association and the
other authors state that they have no conflict of interest. Heart Rhythm Society. Circulation 2006; 114: e257–354.
10 Salem DN, OÕGara PT, Madias C, Pauker SG. Valvular and structural
heart disease: American College of Chest Physicians Evidence-Based
Supporting information Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 593S–629S.
11 Becker RC, Meade TW, Berger PB, Ezekowitz M, OÕConnor CM,
Additional Supporting Information may be found in the online
Vorchheimer DA, Guyatt GH, Mark DB, Harrington RA. The pri-
version of this article: mary and secondary prevention of coronary artery disease: American
Figure S1. Funnel plot for assessment of publication bias for College of Chest Physicians Evidence-Based Clinical Practice Guide-
major bleeding. lines (8th Edition). Chest 2008; 133: 776S–814S.
Figure S2. Funnel plot for assessment of publication bias for 12 Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin–oral
anticoagulant therapy compared with oral anticoagulant therapy alone
minor bleeding.
among patients at risk for cardiovascular disease: a meta-analysis of
Appendix S1. Supplemental materials. randomized trials. Arch Intern Med 2007; 167: 117–24.
Please note: Wiley-Blackwell are not responsible for the content 13 Higgins JPT, Altman DG, Sterne JAC (eds). Chapter 8: assessing risk
or functionality of any supporting materials supplied by the of bias in included studies. In: Higgins JPT, Green S (eds). Cochrane
2012 International Society on Thrombosis and Haemostasis520 A. E. Warkentin et al
Handbook for Systematic Reviews of Interventions, Version 5.1.0 (up- 21 Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JGF,
dated March 2011). The Cochrane Collaboration, 2011. Available Ezekowitz M, Jafri SM, Krol WF, OÕConnor CM, Schulman KA, Teo
from http://www.cochrane-handbook.org. K, Warren SR, for the WATCH Trial Investigators. Randomized trial
14 Huynh T, Théroux P, Bogaty P, Nasmith J, Solymoss S. Aspirin, of warfarin, aspirin, and clopidogrel in patients with chronic heart
warfarin, or the combination for secondary prevention of coronary failure: the Warfarin and Antiplatelet Therapy in Chronic Heart
events in patients with acute coronary syndromes and prior coronary Failure (WATCH) trial. Circulation 2009; 119: 1616–24.
artery bypass surgery. Circulation 2001; 103: 3069–74. 22 Powers PJ, Gent M, Jay RM, Julian DH, Turpie AG, Levine M, Hirsh
15 Colli A, Mestres CA, Castella M, Gherli T. Comparing warfarin to J. A randomized trial of less intense postoperative warfarin or aspirin
aspirin (WoA) after aortic valve replacement with the St Jude Medical therapy in the prevention of venous thromboembolism after surgery
EpicTM heart valve bioprosthesis: results of the WoA Epic Pilot Trial. for fractured hip. Arch Intern Med 1989; 149: 771–4.
J Heart Valve Dis 2007; 16: 667–71. 23 Schulman S, Kearon C. Definition of major bleeding in clinical
16 Gulløv AL, Koefoed BG, Petersen P. Bleeding during warfarin and investigations of antihemostatic medicinal products in non-surgical
aspirin therapy in patients with atrial fibrillation: the AFASAK 2 patients. J Thromb Haemost 2005; 3: 692–4.
Study. Arch Intern Med 1999; 159: 1322–8. 24 Schulman S, Angeras U, Bergqvist D, Eriksson B, Lassen MR, Fisher
17 Rash A, Downes T, Portner R, Yeo WW, Morgan N, Channer KS. A W. Definition of major bleeding in clinical investigations of antihe-
randomised controlled trial of warfarin versus aspirin for stroke pre- mostatic medicinal products in surgical patients. J Thromb Haemost
vention in octogenarians with atrial fibrillation (WASPO). Age Ageing 2010; 8: 202–4.
2007; 36: 151–6. 25 van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn
18 Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GYH, CJ. Incidence, case fatality, and functional outcome of intracerebral
Murray E, on behalf of the BAFTA investigators and the Midland haemorrhage over time, according to age, sex, and ethnic origin: a
Research Practices Network (MidReC). Warfarin versus aspirin for systematic review and meta-analysis. Lancet Neurol 2010; 9: 167–76.
stroke prevention in an elderly community population with atrial 26 Appelboam R, Thomas EO. Warfarin and intracranial haemorrhage.
fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Blood Rev 2009; 23: 1–9.
Study, BAFTA): a randomised controlled trial. Lancet 2007; 370: 493– 27 Toyoda K, Yasaka M, Nagata K, Nagao T, Gotoh J, Sakamoto T,
503. Uchiyama S, Minematsu K. Antithrombotic therapy influences loca-
19 Cleland JGF, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C, Prentice C, tion, enlargement, and mortality from intracerebral hemorrhage. The
Ford I, Trainer A, Poole-Wilson PA. The Warfarin/Aspirin Study in Bleeding with Antithrombotic Therapy (BAT) retrospective study.
Heart failure (WASH): a randomized trial comparing antithrombotic Cerebrovasc Dis 2009; 27: 151–9.
strategies for patients with heart failure. Am Heart J 2004; 148: 157–64. 28 Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, Lip
20 Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK, for the GY, Manning WJ. Antithrombotic therapy in atrial fibrillation:
HELAS investigators. Efficacy of antithrombotic therapy in chronic American College of Chest Physicians Evidence-Based Clinical Prac-
heart failure: the HELAS study. Eur J Heart Fail 2006; 8: 428–32. tice Guidelines (8th Edition). Chest 2008; 133: 546S–92S.
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