Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events from the ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
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 those1286 The American Journal of Cardiology (www.AJConline.org)
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
Results
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 significantlyCoronary Artery Disease/BRAVO Aspirin Dose Substudy 1287
Figure 1. Frequency histogram of aspirin dose in overall cohort.
Table 2
1.00
Cause-specific mortality according to aspirin dose
0.99
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
0.97
Log Rank 8.6, p=0.0034 Cause of death 0.1159
Vascular 54 (80.6%) 24 (66.7%)
0.96
Nonvascular 13 (19.4%) 12 (33.3%)
Aspirin < 162 Aspirin >=162 Mode of death
0.95
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.
disease
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/day1288 The American Journal of Cardiology (www.AJConline.org)
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, orCoronary 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 cardiovascular1290 The American Journal of Cardiology (www.AJConline.org)
death, MI, or stroke in patients with stable double-bed 8. Topol EJ, Easton D, Harrington RA, Amarenco P, Califf RM, Graf-
vascular disease.18 fagnino C, Davis S, Diener HC, Ferguson J, Fitzgerald D, et al.
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.
lower dose aspirin therapy at preventing fatal atherothrom- 9. Topol EJ, Easton JD, Amarenco P, Califf R, Harrington R, Graf-
botic events. Given the discordance of existing data and the fagnino C, Davis S, Diener HC, Ferguson J, Fitzgerald D, et al. Design
resultant clinical equipoise these data engender, prospec- of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular
occlusion (BRAVO) trial. Am Heart J 2000;139:927–933.
tive, randomized controlled trials comparing higher with 10. Rubin DB. Estimating causal effects from large data sets using pro-
lower contemporary aspirin dosing regimens in patients pensity scores. Ann Intern Med 1997;127:757–763.
with clinically manifest atherosclerotic vascular disease ap- 11. Joffe MM, Rosenbaum PR. Invited commentary: propensity scores.
pear warranted. Am J Epidemiol 1999;150:327–333.
12. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition
of platelet thromboxane production by low-dose aspirin in healthy
1. Roderick PJ, Wilkes HC, Meade TW. The gastrointestinal toxicity of
subjects. J Clin Invest 1982;69:1366 –1372.
aspirin: an overview of randomised controlled trials. Br J Clin Phar-
13. Maree AO, Curtin RJ, Dooley M, Conroy RM, Crean P, Cox D,
macol 1993;35:219 –226.
2. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Baggish JS, Fitzgerald DJ. Platelet response to low-dose enteric-coated aspirin in
Bhatt DL, Topol EJ. Analysis of risk of bleeding complications after patients with stable cardiovascular disease. J Am Coll Cardiol 2005;
different doses of aspirin in 192,036 patients enrolled in 31 random- 46:1258 –1263.
ized controlled trials. Am J Cardiol 2005;95:1218 –1222. 14. FitzGerald GA, Oates JA, Hawiger J, Maas RL, Roberts LJ II, Lawson
3. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of JA, Brash AR. Endogenous biosynthesis of prostacyclin and throm-
randomised trials of antiplatelet therapy for prevention of death, myo- boxane and platelet function during chronic administration of aspirin
cardial infarction, and stroke in high risk patients. BMJ 2002;324: in man. J Clin Invest 1983;71:676 – 688.
71– 86. 15. Tantry U, Bliden KP, Gurbel PA, DiChiara J. Inconsistency in the
4. Kong DF, Hasselblad V, Kandzari DE, Newby LK, Califf RM. Seek- prevalence of platelet aspirin resistance as measured by COX-1 non-
ing the optimal aspirin dose in acute coronary syndromes. Am J specific assays in patients treated with 81, 162 and 325 mg aspirin.
Cardiol 2002;90:622– 625. J Am Coll Cardiol 2006;47:290A [Abstract].
5. ALDUSA Investigators. Aspirin at Low Dose in Unstable Angina pilot 16. Gurbel PA, Bliden KP, DiChiara J, Newcomer J, Weng W, Neerchal
study: report from the co-ordinating center. Unité de Pharmacologie NK, Gesheff T, Chaganti SK, Etherington A, Tantry US. Evaluation of
Clinique, Lyons: UPC, 1987. dose-related effects of aspirin on platelet function: results from the
6. O’Connor CM, Meese RB, McNulty S, Lucas KD, Carney RJ, Aspirin-Induced Platelet Effect (ASPECT) study. Circulation 2007;
LeBoeuf RM, Maddox W, Bethea CF, Shadoff N, Trahey TF, et al. A 115:3156 –3164.
randomized factorial trial of reperfusion strategies and aspirin dosing 17. Mehta SR. Clopidogrel in non–ST-segment elevation acute coronary
in acute myocardial infarction: the DUCCS-II Investigators. Am J syndromes. Eur Heart J 2006;8:G25–G30.
Cardiol 1996;77:791–797. 18. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE,
7. The Dutch TIA Trial Study Group. A comparison of two doses of Cacoub P, Cohen EA, Creager MA, Easton JD, et al. Clopidogrel and
aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic aspirin versus aspirin alone for the prevention of atherothrombotic
attack or minor ischemic stroke. N Engl J Med 1991;325:1261–1266. events. N Engl J Med 2006;354:1706 –1717.You can also read
