Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events from the ...
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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 (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 significantly
Coronary 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/day
1288 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, 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
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