Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events from the ...

Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events from the ...
Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding
  in Patients With Recent Cerebrovascular or Coronary Ischemic
                 Events (from the BRAVO Trial)
       Herbert D. Aronow, MD, MPHa,*, Robert M. Califf, MDb, Robert A. Harrington, MDb,
 Marc Vallee, MScb, Carmelo Graffagnino, MDc, Ashfaq Shuaib, MDd, Desmond J. Fitzgerald, MDe,
    J. Donald Easton, MDf, Frans Van de Werf, MD, PhDg, Hans-Christoph Diener, MD, PhDh,
 James Ferguson, MDi, Peter J. Koudstaal, MD, PhDj, Pierre Amarenco, MDk, Pierre Theroux, MDl,
    Stephen Davis, MDm, and Eric J. Topol, MDn, on behalf of the BRAVO Trial Investigators
                  Despite aspirin’s established role in the treatment of atherosclerotic vascular disease,
                  considerable controversy exists regarding its most effective dosing strategy. In a retrospec-
                  tive observational study, we examined the relation between prescribed aspirin dose (162 mg/day aspirin) and clinical outcome in 4,589 placebo-treated patients enrolled
                  in the Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion
                  (BRAVO) trial over a median follow-up of 366 days. Standard Cox regression analysis was
                  employed because propensity analysis was not feasible. Compared with lower aspirin doses,
                  higher doses were associated with lower unadjusted all-cause mortality (2.9 vs 1.6%,
                  respectively; log rank chi-square 8.6, p ⴝ 0.0034). Higher aspirin dose remained indepen-
                  dently predictive of lower all-cause mortality in a multivariable Cox proportional hazards
                  model (hazard ratio 0.64, 95% confidence interval 0.42 to 0.97, p ⴝ 0.037). However, there
                  was no significant difference in the incidence of the composite endpoint death, nonfatal
                  myocardial infarction, or nonfatal stroke (6.1% vs 6.2%, p ⴝ 0.74). Higher aspirin dose was
                  a significant independent predictor of any (hazard ratio 1.32, 95% confidence interval 1.12
                  to 1.55, p ⴝ 0.001) but not serious bleeding. In conclusion, our findings suggest that aspirin
                  doses of >162 mg/day may be more beneficial than those
1286                                    The American Journal of Cardiology (

    On December 12, 2000, BRAVO was terminated prema-                 Table 1
turely because of a statistically significant mortality excess        Patient characteristics (n ⫽ 4,589)
in lotrafiban-treated patients. Due to concern that lotrafiban        Variable                              Aspirin Dose (mg)          p Value
treatment might confound the relation between aspirin dose
                                                                                                       ⬍162               ⱖ162
and all-cause mortality, only placebo-treated patients were
                                                                                                    (n ⫽ 2,368)        (n ⫽ 2,221)
included in this substudy.
    In the main trial, patients were randomized to placebo or         Age (yrs)                   63 (55–71)            62 (53–70)      0.0061
1 of 2 doses of the oral glycoprotein IIb/IIIa receptor an-           Body mass index (kg/m2)     27 (24–29)            28 (25–31)     ⬍0.001
tagonist, lotrafiban, for an intended duration of 6 months to         Men                      1,681 (71.0%)         1,584 (71.3%)      0.8046
2 years. Aspirin use was mandated in all patients; however,           Caucasian                2,287 (96.6%)         2,003 (90.2%)     ⬍0.001
                                                                      Diastolic blood pressure    80 (70–85)            80 (70–82)     ⬍0.001
aspirin dose (75 to 325 mg/day) was left to investigator
                                                                          (mm Hg)
discretion and recorded at discharge. Treatment within 2              Systolic blood pressure    131 (120–150)         130 (120–144)    0.0082
days of enrollment with any drug that affected platelet                   (mm Hg)
activity, such as ticlopidine, clopidogrel, or dipyridamole,          Diabetes                   492 (20.8%)           550 (24.8%)      0.0013
was not permitted. Clopidogrel and ticlopidine were not               Former smoker              887 (37.5%)         1,014 (45.7%)     ⬍0.001
allowed during the trial except when administered after               Aspirin dose (mg)          100 (81–125)          325 (325–325)   ⬍0.001
revascularization procedures (n ⫽ 144) and typically not for          Hypertension             1,515 (64.0%)         1,540 (69.3%)     ⬍0.001
⬎30 days in that setting. Information on other concomitant            Peripheral vascular        101 (4.3%)            173 (7.8%)      ⬍0.001
medications used was not available.                                       disease
    BRAVO trial endpoints have been defined elsewhere.9               Previous MI                476 (20.1%)           454 (20.4%)      0.7747
                                                                      Previous heart failure     214 (9.0%)            190 (8.6%)       0.5643
The prespecified primary outcome in this substudy was
                                                                      Previous angina pectoris   403 (17.0%)           476 (21.4%)     ⬍0.001
all-cause mortality. Other secondary efficacy outcomes in-            Previous stroke            161 (6.8%)            182 (8.2%)       0.0724
cluded cause-specific mortality, nonfatal MI, nonfatal                Previous TIA               105 (4.4%)             97 (4.4%)       0.9123
stroke, urgent hospitalization, urgent revascularization, the         Previous percutaneous      231 (9.8%)            388 (17.5%)     ⬍0.001
composite endpoint death, MI, or stroke, and a composite of               transluminal
all-cause mortality, MI, stroke, hospitalization for recurrent            coronary angioplasty
ischemia, or urgent revascularization. Secondary safety out-          Previous coronary artery   184 (7.8%)            354 (15.9%)     ⬍0.001
comes included any bleeding (any adverse event due to                     bypass surgery
bleeding or Clinical Endpoint Committee-adjudicated intra-            Peripheral vascular        369 (15.6%)           368 (16.6%)      0.3631
cranial hemorrhage), serious bleeding (any serious adverse                disease
                                                                      Stroke                     516 (21.8%)           585 (26.3%)     ⬍0.001
event due to bleeding), need for whole or packed red blood
                                                                      TIA                        319 (13.5%)           304 (13.7%)      0.8308
cell transfusion, development of anemia, and other site-              MI                         652 (27.5%)           512 (23.1%)     ⬍0.001
specific bleeding.                                                    Unstable angina            653 (27.6%)           576 (25.9%)      0.2094
    Continuous variables are displayed as medians and in-
terquartile range (IQR). Wilcoxon rank-sum tests were uti-              Data presented as median (IQR) or n (%).
lized for comparisons of these data. Categorical variables
are shown as frequencies and percentages, and unadjusted              ity between aspirin dose and geographic region, it was not
comparisons of these data were made using chi-square test-            possible to simultaneously adjust for both in the same Cox
ing. Aspirin dose was categorized as ⬍162 or ⱖ162 mg/day              model.
so as to equally divide the study population. Unadjusted and
adjusted event-free survival was compared using log rank
chi-square testing and Cox proportional hazards regression
models, respectively. Variables were eligible for inclusion if        BRAVO randomized 4,590 patients to placebo; 1 patient, in
associated (p ⬍0.15) with the outcome of interest in unad-            whom aspirin dose was unknown, was excluded. Overall,
justed comparisons. Hazard ratio (HR) plots appear on a               2,207 patients qualified for enrollment because of recent
log10 scale. Attempts to develop a propensity model10,11 for          acute coronary syndrome (ACS): 1,018 with MI and 1,189
predicting aspirin dose were unsuccessful given its close             with unstable angina. Similarly, 1,649 patients qualified for
relation with geographic region of enrollment (lower aspirin          enrollment because of a recent ischemic neurologic syn-
doses were more frequently prescribed at non-North Amer-              drome: 590 with TIA and 1,059 with stroke. The remainder
ican sites). When geographic region was excluded, our                 had double-bed vascular disease; of these, 509 had periph-
propensity model was unable to discriminate well between              eral vascular disease and coronary disease, and 225 had
aspirin dose categories (c-statistic ⫽ 0.65). In contrast,            peripheral vascular disease and cerebrovascular disease. A
when geographic region was included, model discriminative             number of important differences existed between patients
capacity improved significantly (c ⫽ 0.87). However, when             treated with ⱖ162 compared with ⬍162 mg/day of aspirin
we attempted to match patients on the likelihood of receiv-           (Table 1).
ing ⬍162 versus ⱖ162 mg/day of aspirin using propensity                  The median overall aspirin dose at discharge was 160 mg
scores generated by the more discriminative model, our                (IQR 100 to 325). By design, patients were evenly distributed
study population was reduced from 4,589 to 1,594 (primary             across aspirin dose categories (⬍162 mg n ⫽ 2,368; ⱖ162 mg
events from 104 to 25). Propensity score matching is inap-            n ⫽ 2,221). Frequency of discharge aspirin dose is displayed in
propriate when such a large proportion of subjects cannot be          Figure 1. Aspirin dosing varied significantly by geographic
matched and therefore was abandoned. Given the collinear-             region. Median aspirin dose at discharge was significantly
Coronary Artery Disease/BRAVO Aspirin Dose Substudy                                                 1287

                                                                                    Figure 1. Frequency histogram of aspirin dose in overall cohort.

                                                                                                                       Table 2
                                                                                                                       Cause-specific mortality according to aspirin dose

                                                                                                                       Variable                           Aspirin Dose (mg)              p Value

                                                                                                                                                     ⬍162                ⱖ162
         Freedom from Death

                              0.98                                                                                                                (n ⫽ 2,368)         (n ⫽ 2,221)

                                                                                                                       Death                   68/2,368 (2.9%)      36/2,221 (1.6%)      0.0034
                                         Log Rank 8.6, p=0.0034                                                        Cause of death                                                    0.1159
                                                                                                                        Vascular                       54 (80.6%)           24 (66.7%)
                                                                                                                        Nonvascular                    13 (19.4%)           12 (33.3%)
                                                                  Aspirin < 162         Aspirin >=162                  Mode of death
                                     0    50      100      150       200     250    300     350    400   450   500      Sudden                         12 (18.5%)            5 (13.9%)
                                                                    Days from Randomization                             Unwitnessed death               2 (3.1%)             3 (8.3%)
  Number at Risk
  Aspirin < 162 2354                     2312     2280    2262       2214    1978   1627   1218    988   621   397      MI                             17 (26.2%)            9 (25.0%)
  Aspirin >= 162 2209                    2175     2149    2130       2075    1915   1598   1264    986   698   393
                                                                                                                        Stroke                          5 (7.7%)             1 (2.8%)
                                                                                                                        Peripheral vascular             0                    1 (2.8%)
                       Figure 2. Unadjusted survival according to aspirin dose.
                                                                                                                        Heart failure                   7 (10.8%)            3 (8.3%)
                                                                                                                        Systemic                        2 (3.1%)             1 (2.8%)
greater in North American than non-North American patients                                                                 embolism
(325, IQR 325 to 325, vs 100, IQR 100 to 160, mg/day,                                                                   Other vascular                  8 (12.3%)            1 (2.8%)
respectively; p ⬍0.0001). In North American patients (n ⫽                                                               Nonvascular                    12 (18.5%)           12 (33.3%)
1,948), 1,677 were discharged on aspirin ⱖ162 mg/day, al-
though in non-North American patients (n ⫽ 2,641), only 544                                                              Data on cause of death and mode of death were not available for 1 and
                                                                                                                       3 patients, respectively, in the low-dose aspirin arm.
were in the higher aspirin dose category.
   The median duration of follow-up was 366 days (IQR
279 to 463). There were 104 deaths during follow-up: 36 in                                                             fatal MI or nonfatal stroke was observed. In a Cox propor-
those taking ⱖ162 and 68 in those taking ⬍162 mg/day of                                                                tional hazards regression model, higher aspirin dose was
aspirin. All-cause mortality was significantly greater in the                                                          independently predictive of lower all-cause mortality (HR
lower dose category (2.9% vs 1.6%; unadjusted HR com-                                                                  0.64, 95% CI 0.42 to 0.97, p ⫽ 0.037). Other independent
paring ⱖ162 to ⬍162 mg 0.552, 95% confidence interval                                                                  predictors of all-cause mortality appear in Figure 3.
[CI] 0.369 to 0.827; Figure 2). A breakdown of cause-                                                                     The incidence of the BRAVO trial primary composite
specific mortality according to aspirin dose appears in Table                                                          endpoint (death, MI, stroke, urgent revascularization, or
2. The majority of deaths occurring in both aspirin dose                                                               urgent hospitalization) was not significantly different be-
categories were vascular in etiology. No reduction in non-                                                             tween those discharged on ⱖ162 mg/day and ⬍162 mg/day
1288                                         The American Journal of Cardiology (

                                                                           disease. In the Antithrombotic Trialists Collaboration
                                                                           (ATC) meta-analysis, the observed proportional reduction
                                                                           in events with aspirin therapy did not vary significantly
                                                                           across a range of daily aspirin doses. In a second meta-
                                                                           analysis, Kong et al4 observed that higher aspirin doses
                                                                           were associated with relatively less benefit than lower
                                                                           doses. However, neither meta-analysis included studies that
                                                                           directly compared different aspirin doses. Only 3 random-
                                                                           ized controlled trials have compared patients treated with
                                                                           different contemporary aspirin doses in a head-to-head fash-
                                                                           ion5–7; all failed to demonstrate a difference in outcome
                                                                           according to aspirin dose, however, they were largely un-
                                                                           derpowered to do so in patients with coronary disease. The
Figure 3. Independent predictors of all-cause mortality. PTCA ⫽ History
                                                                           only available comparative data to suggest that aspirin dose
of percutaneous transluminal coronary angioplasty.                         may influence clinical outcome after an acute ischemic
                                                                           event, are from a Clopidogrel in Unstable angina to prevent
                                                                           Recurrent Events (CURE) trial observational substudy of
of aspirin (Table 3). There was also no statistically signif-              12,562 patients in which higher aspirin doses (ⱖ200 mg/
icant difference in the incidence of the composite endpoint                day) were associated with a greater incidence of both isch-
death, nonfatal MI or nonfatal stroke in its component                     emic and hemorrhagic events than lower doses (⬍200 mg/
endpoints (excepting death) or in urgent hospitalization                   day). Our findings are congruent with CURE and other trial
when comparing those treated with ⱖ162 versus ⬍162                         data in supporting a relation between escalating aspirin dose
mg/day. Those taking ⱖ162 mg/day of aspirin were signif-                   and increased bleeding incidence. However, our data chal-
icantly more likely to undergo urgent revascularization than               lenge the notion that increasing aspirin dose has a neutral or
those who received ⬍162 mg/day.                                            negative effect on the incidence of ischemic events.
   Overall, any bleeding occurred in 603 patients during                       In a BRAVO trial preliminary analysis (lotrafiban- and
follow-up. The incidence of any bleeding was significantly                 placebo-treated patients included, n ⫽ 9,190), we observed
lower in patients who received ⬍162 mg/day than ⱖ162                       that aspirin doses ⬎162 mg/day were associated with a
mg/day of aspirin (Table 4). Serious bleeding was signifi-                 significant and independent 25% reduction in the hazard for
cantly less frequent in the lower dose aspirin category, as                all-cause mortality (HR 0.75, 95% CI 0.56 to 0.97, p ⫽
was anemia and use of whole blood or packed red blood cell                 0.03)8; this association was not statistically different from
transfusions. Most bleeding events were gastrointestinal,                  that observed in the present analysis in which our cohort
genitourinary, or due to epistaxis. There was no difference                was restricted to placebo-treated patients only. At the time
in the incidence of intracranial hemorrhage according to                   of that publication, we suspected that geographic region of
aspirin dose. In multivariable Cox proportional hazards                    enrollment confounded the association between lower aspi-
models, aspirin dose remained a significant independent                    rin dose and higher mortality. Specifically, patients enrolled
predictor of any, but not serious, bleeding (adjusted HR                   at non-North American sites were prescribed lower aspirin
comparing aspirin ⱖ162 with ⬍162 mg/day 1.32, 95% CI                       doses and had higher mortality than those enrolled at North
1.12 to 1.55, p ⫽ 0.001). Other significant and independent                American sites. However, when we stratified our results
predictors of any bleeding appear in Figure 4.                             according to geographic region, the relation between higher
                                                                           aspirin dose and lower all-cause mortality was also signif-
Discussion                                                                 icant in non-North American patients (1.29 vs 3.15% for
                                                                           ⱖ162 and ⬍162 mg aspirin, p ⫽ 0.0183).
In a retrospective observational study of placebo-treated                      Aspirin’s cardiovascular benefits are mediated primarily
patients from the BRAVO trial, we observed that when                       via irreversible acetylation of cyclooxygenase-1, inhibiting
compared with ⬍162 mg/day, aspirin doses ⱖ162 mg/day                       platelet thromboxane production. Near complete suppres-
were associated with a 1.3% absolute risk reduction and                    sion of platelet thromboxane synthesis can occur with doses
36% adjusted reduction in the hazard for all-cause mortality               as small as 30 mg in healthy subjects.12 However, some
over approximately 1 year. Although this study was non-                    patients with stable atherosclerotic cardiovascular disease
randomized and therefore hypothesis-generating, the ob-                    on low dose (enteric-coated) aspirin have persistent unin-
served absolute risk reduction translates into the need to                 hibited platelet cyclooxygenase activity as gauged by
treat 77 people with a recent ACS, ischemic neurological                   incomplete suppression of serum thromboxane levels.13
syndrome, or double-bed vascular disease with higher dose                  FitzGerald et al14 observed that when administered incre-
aspirin during 1 year to save 1 life. During the same inter-               mentally from 20 to 325 mg/day, aspirin resulted in a
val, aspirin doses ⱖ162 mg were associated with a 1.4%                     dose-dependent decrease in endogenous thromboxane pro-
increase in the absolute risk and 32% increase in the ad-                  duction as measured by urinary thromboxane metabolites;
justed hazard for any bleeding, but no significant increase in             furthermore, inhibition of platelet aggregation was not max-
the adjusted hazard for serious bleeding.                                  imal at lower doses. More recently, Tantry et al15observed
   These are the first data to suggest that higher aspirin                 a direct dose-dependent effect of aspirin on the inhibition of
doses are associated with less frequent fatal ischemic events              collagen-induced aggregation in a randomized trial of pa-
in patients with clinically manifest atherosclerotic vascular              tients with cardiovascular disease assigned to 81, 160, or
Coronary Artery Disease/BRAVO Aspirin Dose Substudy                                                 1289

Table 3
Incidence of secondary outcomes according to aspirin dose
                                                            Aspirin Dose (mg)                       p Value*               HR                  95% CI

                                                      ⬍162                    ⱖ162
                                                   (n ⫽ 2,368)             (n ⫽ 2,221)

BRAVO 1° Endpoint                                  391 (16.5%)             410 (18.5%)               0.13                 1.112             0.968–1.277
Death/MI/stroke                                    147 (6.2%)              135 (6.1%)                0.74                 0.961             0.760–1.213
MI                                                  48 (2.0%)               45 (2.0%)                0.94                 0.984             0.655–1.478
Stroke                                              48 (2.0%)               63 (2.8%)                0.10                 1.374             0.944–2.001
 Primary hemorrhagic                                 2 (4.2%)                4 (6.3%)
 Cerebral infarction                                42 (87.5%)              56 (88.9%)
 Retinal infarction                                  1 (2.1%)                2 (3.2%)
 Infarction–hemorrhagic conversion                   2 (4.2%)                1 (1.6%)
 Uncertain                                           1 (2.1%)                1 (1.6%)
Urgent hospitalization                             228 (9.6%)              230 (10.4%)               0.54                 1.06              0.882–1.273
Urgent revascularization                           175 (7.4%)              220 (9.9%)                0.0035               1.343             1.101–1.638

  One patient in the high dose aspirin group suffered both a cerebral and retinal infarction.
  * p Value derived from log rank testing.

Table 4
Bleeding complications according to aspirin dose
                                   Aspirin Dose (mg)             p Value

                                 ⬍162             ⱖ162
                              (n ⫽ 2,368)      (n ⫽ 2,221)

Any bleeding                  264 (11.2%)      339 (15.3%)       ⬍0.0001
 Intracranial hemorrhage        4 (0.2%)         5 (0.2%)         0.67
 Gastrointestinal              81 (3.4%)       104 (4.7%)         0.03
 Genitourinary                 29 (1.2%)        62 (2.8%)         0.0001
 Epistaxis                     72 (3.0%)        98 (4.4%)         0.0139
 Retroperitoneal                   0                0              —
 Oral                          32 (1.4%)        32 (1.4%)         0.80
 Hematoma                      30 (1.3%)        36 (1.6%)         0.31
 Pericardial                       0                0              —             Figure 4. Independent predictors of any bleeding. CABG ⫽ coronary artery
 Pulmonary                      6 (0.3%)         6 (0.3%)         0.91           bypass graft surgery; HTN ⫽ hypertension.
 Ocular/retinal                12 (0.5%)         7 (0.3%)         0.31
 Gynecologic                    8 (0.3%)        14 (0.6%)         0.15
 Other uncategorized           18 (0.8%)        27 (1.2%)         0.12
Serious bleeding               56 (2.4%)        74 (3.3%)         0.0485
                                                                                 composite endpoint was not significantly reduced in patients
Anemia                         70 (3.0%)        97 (4.4%)         0.011          treated with higher aspirin doses given a statistically signif-
Packed red blood cell,         25 (1.1%)        43 (1.9%)         0.014          icant increase in the rate of urgent revascularization asso-
    platelet, fresh frozen                                                       ciated with higher aspirin doses. It is plausible that patients
    plasma, whole blood                                                          who were prescribed higher aspirin doses were more likely
    transfusion                                                                  to present for and undergo revascularization. Additionally,
Purpura                        49 (2.1%)       161 (7.2%)        ⬍0.0001
                                                                                 higher aspirin doses were not associated with fewer nonfatal
                                                                                 ischemic events. It is possible that higher aspirin doses
                                                                                 prevented fatal but not nonfatal stroke and MI; other ther-
325 mg/day of aspirin; further data from that laboratory                         apies for coronary artery disease, such as coronary artery
suggest that aspirin’s dose-dependent antiplatelet effects
                                                                                 bypass surgery, prevent death but not MI.
may also be mediated via noncyclooxygenase-1 pathways.16
                                                                                     Finally, dual antiplatelet therapy is now commonly pre-
   A number of limitations warrant mention. First, as this
study was not randomized, we cannot rule out the possibility                     scribed following ACS. It is unclear whether the survival
of residual bias and/or confounding. Second, the CI sur-                         benefits associated with higher aspirin doses in our study
rounding the HR point estimate for all-cause mortality was                       would be mitigated in the presence of concomitant thien-
broad, consistent with the relatively small number of fatal                      opyridine therapy. The ongoing Clopidogrel optimal load-
events. Third, we did not have information on changes in                         ing dose Usage to Reduce Recurrent EveNTs (CURRENT)
aspirin dose nor adherence to aspirin therapy after dis-                         trial will randomize patients with non–ST-elevation ACS
charge; such changes may have resulted in a less accurate                        managed with an early invasive strategy to aspirin 75 to 100
estimate of the association between aspirin dose and clinical                    versus ⬎300 mg/day and compare the risks for 30-day
outcome. Fourth, although we observed significantly fewer                        cardiovascular death, MI, or recurrent ischemia.17 Uncer-
deaths in patients treated with higher than lower dose aspi-                     tainty remains as to whether dual antiplatelet therapy is
rin therapy, the incidence of the BRAVO trial primary                            superior to aspirin monotherapy at reducing cardiovascular
1290                                            The American Journal of Cardiology (

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                                                                                  Randomized, double-blind, placebo-controlled, international trial of
   Despite these limitations, our findings suggest that aspi-                     the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular
rin doses of ⱖ162 mg/day may be more beneficial than                              disease. Circulation 2003;108:399 – 406.
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