Effects of recombinant human erythropoietin on antiplatelet action of aspirin and clopidogrel in healthy subjects: Results of a double-blind, placebo-controlled randomized trial
Article Outline
Background
Recombinant human erythropoietin (rHuEpo) reduces myocardial injury in experimental ischemia and has been proposed as a cardioprotective agent for potential use in acute coronary syndromes. Its safety profile in clinical acute ischemic settings is uncertain because rHuEpo has been reported to increase platelet reactivity and the risk of thromboembolism in some disease populations. Whether prothrombotic effects of rHuEpo mitigate the effects of antiplatelet agents used in acute coronary syndrome patients is unknown.
Methods
Recombinant human erythropoietin 100, 200, 400 U/kg, or placebo was given intravenously once daily for 3 consecutive days in a double-blind randomized trial in 96 healthy subjects. A single oral dose of aspirin 325 mg or clopidogrel 300 mg was given immediately after the last dose of study drug. Bleeding time and in vitro high shear stress platelet function assays (PFA)–100 were determined before; 5 hours; and 1, 5, and 7 days after aspirin or clopidogrel.
Results
Recombinant human erythropoietin at doses of 100 and 200 U/kg did not alter bleeding time or PFA-100 closure times at any time point when compared with placebo. Recombinant human erythropoietin at a dose of 400 U/kg significantly blunted the post-aspirin increase in bleeding time when compared with placebo (P = .03) but did not alter post-clopidogrel bleeding times nor PFA closure times. The 400-U/kg dose did not change hematocrit but did significantly increase the platelet count at 5 days after study drug administration when compared with placebo (P = .014).
Conclusion
Short-term rHuEpo at doses up to 200 U/kg did not mitigate the effects of administration of aspirin or clopidogrel on either in vivo or in vitro measures of platelet function in healthy subjects. The 400-U/kg dose attenuated the effects of aspirin on bleeding time and increased the platelet count. Studies of the effects of rHuEpo on platelet function in patients with coronary artery disease are warranted to further characterize dose/safety profile.
Erythropoietin is a glycoprotein growth hormone produced primarily by the kidney that plays an important role in the homeostatic regulation of hematocrit.1 Its primary target organ is thought to be the bone marrow, where erythropoietin acts to suppress apoptosis in red blood cell precursors and promote release of mature erythrocytes into the circulation.2, 3 These actions of erythropoietin are mediated by a homodimeric transmembrane receptor linked to antiapoptotic signal transduction pathways mediated by Akt- and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT)-dependent mechanisms.4
Erythropoietin receptors have been identified in a wide array of tissues outside of the bone marrow, including adult human atrial and ventricular myocardium.5, 6, 7 The physiologic role of endogenous erythropoietin in the heart remains uncertain, but administration of a single large dose of exogenous erythropoietin has been shown to mitigate myocardial injury, reduce postischemic myocardial apoptosis, and improve ventricular function in experimental models of myocardial ischemia.8, 9, 10, 11
Concerns have been raised regarding application of these experimental findings to patients with acute coronary syndromes because administration of recombinant human erythropoietin (rHuEpo) is associated with increased platelet reactivity in healthy subjects and increased risk of thrombotic events in anemic patients with end-stage renal disease or cancer.12, 13, 14, 15, 16, 17 Recombinant human erythropoietin reverses uremic platelet dysfunction by poorly characterized mechanisms that appear to be at least partly independent of increased hematocrit.18 Increased platelet reactivity in the setting of acute coronary syndromes could increase risk of recurrent thrombosis with adverse clinical sequelae.
Potential clinical application of rHuEpo in acute coronary syndromes differs from its use in anemic populations; the proposed duration of therapy based on data from experimental models would be short (1-3 days), and the target population is routinely treated with aggressive antiplatelet therapy. There are few existing data on the effects of short-term administration of rHuEpo on platelet function, and no prior studies to determine whether rHuEpo may mitigate the effects of antiplatelet agents used in acute coronary syndrome patients. The aim of the current study was to determine the effects of ascending doses of rHuEpo versus placebo on in vivo and in vitro measures of platelet function after administration of aspirin or clopidogrel in healthy subjects. This double-blind, randomized study design was developed to identify a dose of rHuEpo that could be potentially applied in future clinical studies of patients with acute coronary syndromes.
Methods
Study population
Ninety-six healthy subjects were studied. All subjects were normotensive nonsmokers without history of chronic illness or chronic medication use. Key exclusion criteria were hemoglobin >15 g/dL (for both sexes), <13 g/dL (male), or <12 g/dL (female); platelet count >400
000/μL or <150000/μL; active oral contraceptive drug use or pregnancy; and nonsteroidal anti-inflammatory drug or aspirin use within 1 week. The study protocol (www.clinicaltrials.gov) (Identifier NCT00368238) was approved by the Human Investigation Committee of Yale University. All subjects provided written informed consent.
Study protocol
The randomized, double-blind study protocol was designed to determine the effects of 3 consecutive days of study drug administration on platelet function over the subsequent 7 days after administration of either aspirin or clopidogrel (Figure 1). Eligible subjects were randomized to 3 doses of intravenous rHuEpo (100, 200, or 400 U/kg daily for 3 consecutive days) versus placebo (normal saline injection daily for 3 consecutive days). We selected this dosing regimen based on pharmacodynamic data in healthy subjects,19, 20 clinical experience in chronic anemia populations,4 a pilot study of rHuEpo in ischemic stroke patients,21 studies on apoptosis post myocardial infarction,22, 23 and studies in experimental ischemia.8, 9, 10, 11 The Yale Investigational Drug Service generated the randomization code and allocated study drug. For each dose of rHuEpo, 32 subjects were randomized to active drug or placebo in a 3:1 manner. This allocation scheme resulted in an equal number of subjects in each treatment group (n = 24) at the completion of the study. After the third dose of double-blind study drug, subjects were randomly assigned to receive a single open-label dose of aspirin 325 mg or clopidogrel 300 mg by mouth (n = 12 for each dose of rHuEpo and placebo).
Figure 1.
Schematic of randomized double-blind study design.
The primary outcome variables, bleeding time and platelet function assay (PFA) closure time, were determined before the first dose of study drug; immediately after the last dose of study drug; at 5 hours; and at 1, 5, and 7 days after administration of aspirin or clopidogrel. Complete blood count and vital signs were determined at the same time points. Serum erythropoietin levels and plasma markers of platelet activation (soluble P-selectin) and vascular endothelial cell activation (von Willebrand factor) were measured before the first dose and immediately after the last dose of study drug. Prothrombin time (PT), activated partial thromboplastin time (aPTT), International Normalized Ratio (INR), and fibrinogen levels were measured before the first dose of study drug and at 1 and 7 days after administration of aspirin or clopidogrel.
Bleeding time
Bleeding time was performed in a standardized fashion by one operator on the volar aspect of the forearm using a sterile, disposable automated incision device (Surgicutt Adult, Cardinal Health Inc, Montgomery, NY), as previously described.24 The precision in the laboratory for average bleeding times of 330 and 240 seconds is 9% (30 seconds) and 10% (24 seconds), respectively. Mean (±SD) bleeding time for our laboratory in healthy subjects is 300 ± 120 seconds.
Platelet function assay
In vitro platelet function, determined as closure time (seconds), was measured with the PFA-100 (Dade Behring Co LLC, Newark, DE) according to the manufacturer's instructions. Two cartridges were used to determine the closure time, each holding a membrane with a central aperture and coated with collagen and either epinephrine (PFA-EPI used for subjects assigned to aspirin) or adenosine diphosphate (PFA-ADP used for subjects assigned to clopidogrel). Each run was performed with a volume of 800 μL whole blood in each cartridge within 2 hours after blood sampling.
Laboratory studies
Complete blood cell count (ABX MICROS 60, CS/CT-16 Hematology Analyzer, Horiba ABX Diagnostic, Irvine, CA). Prothrombin time, aPTT, INR, and serum fibrinogen levels (Dade BCS instrument, Dade Behring Inc) were measured in the clinical laboratory at Yale New Haven Hospital. Serum erythropoietin (R & D Systems, Inc, Minneapolis, MN), plasma P-selectin (R & D Systems, Inc) levels, and plasma von Willebrand factor (Assaypro Inc, Brooklyn, NY) level were measured with commercially available enzyme-linked immunosorbent assays in the Yale General Clinical Research Center core laboratory.
Data analysis
Continuous variables are presented as median and interquartile range (IQR). For all analyses, a 2-tailed P < .05 was used to infer statistical significance. Changes from pretreatment baseline values within groups were assessed with Friedman nonparametric test for repeated measures. Kruskal-Wallis test was performed to compare the changes from pretreatment baseline over time among the 4 groups to determine whether study drug modified the effect of aspirin or clopidogrel (kwallis command, Stata software version 8.0, Stata Corp, College Park, TX). When the Kruskal-Wallis test indicated a significant difference between groups, a rank sum test was performed to determine the level of significance for each dose of rHuEpo versus placebo. The differences in bleeding time responses between groups were also analyzed as a dichotomous variable with logistic regression models. The upper limit of the normal bleeding time for our laboratory (600 seconds) was used to define the groups. Based on previous estimates of the effects of aspirin and clopidogrel on bleeding time and 1-tailed α = .05, 12 subjects per treatment group provided >80% power to detect a 40% decrease in bleeding time in response to study drug administration.25, 26
Results
Study sample characteristics
Age, sex distribution, body size, pretreatment vital signs and hemoglobin concentration, and pre- and posttreatment serum erythropoietin levels are presented for each treatment group in Table I. Serum erythropoietin levels obtained after the last dose of study drug were significantly increased after administration of rHuEpo when compared with placebo (P < .001 for all individual comparisons with placebo and for linear trend across doses). Study drug was well tolerated in all subjects.
Table I. Study sample characteristics by treatment group (median [IQR])
| Placebo (n = 24) | rHuEpo 100 U/kg (n = 24) | rHuEpo 200 U/kg (n = 24) | rHuEpo 400 U/kg (n = 24) | |
|---|---|---|---|---|
| Age (y) | 25 (5) | 28 (6) | 24 (3) | 25 (5) |
| Sex (male/female) | 10/14 | 10/14 | 12/12 | 10/14 |
| BMI (kg/m2) | 24 (4) | 23 (5) | 24 (4) | 24 (5) |
| Systolic BP (mm Hg) | 117 (18) | 111 (15) | 118 (13) | 116 (16) |
| Diastolic BP (mm Hg) | 70 (8) | 71 (9) | 70 (9) | 68 (9) |
| Heart rate (min−1) | 68 (16) | 70 (13) | 68 (14) | 67 (16) |
| Hemoglobin (gm/dL) | 13.2 (2.4) | 13.6 (2.0) | 13.5 (1.9) | 13.8 (1.8) |
| Pre Rx EPO (mIU/mL) | 8 (3) | 9 (20) | 8 (6) | 7 (5) |
| Post-Rx EPO (mIU/mL) | 8 (5) | 1744 (721)⁎ | 4529 (2369)⁎ | 9506 (1501)⁎ |
⁎P < .001 versus placebo. |
Platelet function tests
Before administration of aspirin or clopidogrel, study drug administration for 3 consecutive days did not significantly change the bleeding time when compared with pretreatment baseline values (placebo from 405 [60] to 390 [75] seconds; rHuEpo 100 U/kg from 360 [60] to 390 [75] seconds; rHuEpo 200 U/kg from 405 [90] to 390 [75] seconds; and rHuEpo 400 U/kg from 390 [105] to 375 [120] seconds; all P values >.20). Bleeding time increased significantly after administration of aspirin 325 mg and clopidogrel 300 mg when compared with pretreatment values in all treatment groups (Figure 2, Table II, Table III, P < .01 for all comparisons). rHuEpo at the 100- and 200-U/kg doses did not significantly modify the bleeding time responses to aspirin or clopidogrel when compared with placebo. By contrast, rHuEpo at the 400-U/kg dose significantly decreased the bleeding time response at 5 hours after aspirin administration (median difference 90 seconds, P = .03) and 1 day after aspirin administration (median difference 90 seconds, P = .01) when compared with placebo. This dose of rHuEpo also significantly reduced the proportion of subjects with abnormal bleeding time after aspirin administration (Table II, P = .033). Recombinant human erythropoietin 400 U/kg did not alter the bleeding time response to clopidogrel when compared with placebo. PFA-EPI closure times after administration of aspirin and PFA-ADP closure times after administration of clopidogrel did not differ between treatment groups at any time point (Table II, Table III).
Figure 2.
Box plots of bleeding time (seconds) by treatment group before administration of aspirin (Pre-ASA, panel A) or clopidogrel (Pre-CLOP, panel B) and at listed time points after administration of aspirin (panel A) or clopidogrel (panel B). Box plots indicate median value (within box), interquartile range (upper and lower limits of box), values adjacent to 1.5 × IQR (whiskers), and individual data points outside this range. *P < .05 vs placebo. P, Placebo; E100, rHuEpo 100 U/kg; E200, rHuEpo 200 U/kg; E400, rHuEpo 400 U/kg.
Table II. Effects of study drug on bleeding time, and platelet function assay closure times (continuous variables reported as median (IQR)) before administration of aspirin and at listed time points after administration of aspirin
| Placebo (n = 12) | rHuEpo 100 U/kg (n = 12) | rHuEpo 200 U/kg (n = 12) | rHuEpo 400 U/kg (n = 12) | |
|---|---|---|---|---|
| BT (s) | ||||
| Pre aspirin | 375 (75) | 375 (75) | 350 (150) | 390 (150)⁎ |
| 5 h post | 735 (195) | 645 (165) | 645 (315) | 645 (210)⁎ |
| 1 d post | 555 (120) | 570 (150) | 510 (225) | 450 (135) |
| 5 d post | 450 (135) | 425 (105) | 450 (135) | 390 (135) |
| 7 d post | 390 (60) | 360 (30) | 390 (105) | 390 (135) |
| % BT >600 s | ||||
| Pre aspirin | 0 | 0 | 0 | 0 |
| 5 h post | 92 | 67 | 58 | 58 |
| 1 d post | 42 | 42 | 33 | 17 |
| 5 d post | 8 | 0 | 8 | 0 |
| 7 d post | 0 | 0 | 0 | 0 |
| PFA-EPI closure time (s) | ||||
| Pre aspirin | 132 (27) | 102 (28) | 120 (36) | 106 (23) |
| 5 h post | 290 (33) | 249 (153) | 291 (27) | 293 (45) |
| 1 d post | 253 (90) | 173 (172) | 291 (111) | 205 (178) |
| 5 d post | 142 (56) | 110 (45) | 146 (49) | 116 (19) |
| 7 d post | 130 (24) | 114 (54) | 133 (45) | 104 (33) |
⁎P < .05 versus placebo. |
Table III. Effects of study drug on bleeding time and platelet function assay closure times (continuous variables reported as median [IQR]) before administration of clopidogrel and at listed time points after administration of clopidogrel
| Placebo (n = 12) | rHuEpo 100 U/kg (n = 12) | rHuEpo 200 U/kg (n = 12) | rHuEpo 400 U/kg (n = 12) | |
|---|---|---|---|---|
| Bleeding time (s) | ||||
| Pre clopidogrel | 390 (90) | 390 (45) | 390 (45) | 375 (105) |
| 5 h post | 855 (435) | 705 (360) | 780 (205) | 780 (375) |
| 1 d post | 600 (155) | 585 (195) | 600 (90) | 525 (120) |
| 5 d post | 495 (120) | 465 (90) | 465 (60) | 435 (75) |
| 7 d post | 420 (150) | 390 (150) | 420 (45) | 420 (90) |
| % BT >600 s | ||||
| Pre clopidogrel | 0 | 0 | 0 | 0 |
| 5 h post | 75 | 92 | 92 | 75 |
| 1 d post | 67 | 50 | 58 | 25 |
| 5 d post | 25 | 8 | 0 | 8 |
| 7 d post | 8 | 0 | 0 | 0 |
| PFA-ADP closure time (s) | ||||
| Pre clopidogrel | 95 (29) | 83 (30) | 91 (29) | 94 (27) |
| 5 h post | 105 (29) | 79 (29) | 87 (11) | 107 (51) |
| 1 d post | 94 (15) | 80 (23) | 79 (25) | 87 (36) |
| 5 d post | 95 (27) | 75 (15) | 82 (29) | 83 (19) |
| 7 d post | 92 (29) | 74 (18) | 80 (29) | 84 (31) |
Secondary end points
Hematocrit did not change from pretreatment values in any treatment group and did not differ among treatment groups at any time point (Table IV). However, the platelet count increased significantly at 5 days after completion of rHuEpo 400 U/kg when compared with placebo (median difference 17000 cells/mm3, P = .014) and tended to be increased at 7 days after completion of rHuEpo 400U/kg when compared with placebo (median difference 20000 cells/mm3, P = .08). Systolic and diastolic blood pressure, PT, INR, aPTT, fibrinogen levels, von Willebrand factor levels, and P-selectin levels did not change from pretreatment values and did not differ among treatment groups at any time point (data not shown).
Table IV. Hematocrit and platelet counts (median [IQR]) before and at listed time points after study drug administration
| Placebo (n = 24) | rHuEpo 100 U/kg (n = 24) | rHuEpo 200 U/kg (n = 24) | rHuEpo 400 U/kg (n = 24) | |
|---|---|---|---|---|
| Hematocrit (%) | ||||
| Before study drug | 40 (6) | 39 (7) | 40 (7) | 40 (4) |
| 5 h post | 41 (6) | 41 (7) | 41 (6) | 40 (6) |
| 1 d post | 40 (6) | 42 (6) | 42 (6) | 41 (6) |
| 5 d post | 40 (7) | 41 (8) | 41 (7) | 41 (4) |
| 7 d post | 39 (6) | 41 (6) | 41 (8) | 41 (6) |
| Platelet count (×103/mm3) | ||||
| Before study drug | 245 (56) | 253 (81) | 257 (98) | 255 (59) |
| 5 h post | 255 (54) | 244 (64) | 231 (98) | 260 (48) |
| 1 d post | 255 (62) | 262 (82) | 244 (91) | 257 (69) |
| 5 d post | 263 (59) | 272 (86) | 267 (119) | 275 (69) |
| 7 d post | 258 (59) | 267 (59) | 271 (91) | 274 (66) |
Discussion
The salient finding of the current study is that rHuEpo 400 U/kg given intravenously for 3 consecutive days attenuated the aspirin-induced increase in bleeding time and increased the platelet count when compared with placebo in nonanemic healthy subjects. This dose of rHuEpo did not modify the bleeding time response to clopidogrel, nor did it affect PFA closure times with either aspirin or clopidogrel. Lower doses of rHuEpo (100 and 200 U/kg) did not modify bleeding time, PFA closure times, nor any secondary outcome variables when compared with placebo.
To our knowledge, this is the first published study on the effect of short-term rHuEpo administration on the antiplatelet action of aspirin and clopidogrel in human subjects. Previous reports in chronic kidney disease patients consistently demonstrate that chronic rHuEpo treatment decreases bleeding time and increases in vitro measures of platelet reactivity,18, 27, 28, 29 but only 2 previous reports provide information on the potential interaction between aspirin and rHuEpo.30, 31 In an open-label study of 14 dialysis patients receiving chronic rHuEpo therapy adjusted to target hemoglobin 10 to 12 gm/dL, 4 to 8 weeks of treatment with aspirin 300 mg daily significantly decreased in vitro spontaneous platelet aggregation when compared with pretreatment values to a level that did not differ from normal controls.30 In a randomized, double-blind placebo-controlled crossover study of 137 anemic chronic dialysis patients, aspirin 30 mg daily for 3 months attenuated the rHuEpo-induced decrease in bleeding time when compared with placebo but did not increase bleeding time above pretreatment baseline and did not reduce the risk of thrombotic events.31 Baseline uremic platelet dysfunction in these 2 studies limits the relevance of these findings to the current healthy study sample and nonuremic patients with coronary artery disease. In an unpublished placebo-controlled randomized trial of 182 patients undergoing coronary artery bypass graft surgery, perioperative rHuEpo administration was associated with increased risk of postoperative thrombosis and death when compared with placebo despite the routine use of aspirin in these patients.32
The mechanisms that may contribute to the observed interaction between rHuEpo and aspirin cannot be directly discerned from our clinical study design. Increased hematocrit is thought to contribute to decreased bleeding time during chronic rHuEpo therapy in patients with uremic platelet dysfunction, but the prothrombotic effects of rHuEpo are at least partly independent of changes in red cell mass.28, 29, 33 In accord with previous studies in healthy subjects, hematocrit did not increase in response to short-term administration of rHuEpo in our subjects and therefore could not contribute to our findings.19, 20 Increased release of young platelets from bone marrow as manifested by increased circulating reticulated platelets, increased mean platelet volume, and increased platelet count may also contribute to the increased platelet reactivity in response to rHuEpo therapy.18, 34 The magnitude of the increase in platelet count observed in our subjects after rHuEpo 400 U/kg is consistent with a previous study in healthy subjects and may have contributed to the attenuation of the antiplatelet effects of aspirin.12 rHuEpo has also been reported to stimulate tyrosine kinase-dependent signal transduction pathways and increase basal and stimulated cytosolic calcium levels in platelets.33, 35, 36 Although changes in calcium homeostasis would be expected to modify antiplatelet effects of both aspirin and clopidogrel,37 we observed selective attenuation of aspirin-induced antiplatelet effects after rHuEpo. The putative mechanism for a selective interaction between rHuEpo and aspirin is unknown because a specific effect of rHuEpo on prostaglandin metabolism or signaling in platelets has not been reported. Alternatively the absence of a significant modification of post-clopidogrel bleeding time in our study may be related to the relatively small study sample and consequent limited power to detect smaller differences between treatment groups.
Since clinical resistance to the antiplatelet agents is thought to be associated with increased risk of recurrent thrombotic events after coronary interventions, our findings have potential implications for the design of clinical trials of rHuEpo in patients with acute coronary syndromes.38, 39, 40 The 400 U/kg dose used in this study is comparable to that used in 2 pilot studies of erythropoietic agents in patients with ischemic stroke and acute myocardial infarction21, 41 and an ongoing randomized clinical trial in the United Kingdom registered on the www.clinicaltrials.gov Web site (identifier NCT0014905). Although no clinical thrombotic events were reported in the 2 pilot studies, the attenuation of the antiplatelet effects of aspirin observed after the 400-U/kg dose in our study, taken together with the known increased thrombotic risk associated with rHuEpo in anemic patients,14, 15, 16, 17 and the increased risk or adverse outcomes in the unpublished trial of post–coronary artery bypass graft patients,32 raises sufficient concern to suggest that clinical investigations of rHuEpo in acute coronary syndromes consider lower dosing ranges until additional data on the interaction of erythropoietin and aspirin are available.38, 42, 43 The 100 to 200 U/kg range utilized in the current study could be expected to be potentially efficacious; a study of experimental myocardial ischemia in rats indicates that doses as low as 150 U/kg provide cardioprotective effects if administered within 4 hours of the onset of ischemia.9
Several aspects of the study design provide caveats to our findings. Our findings in healthy subjects after administration of a single dose of aspirin or clopidogrel may not accurately reflect the effects of repeated doses of combination antiplatelet regimens routinely used in cardiovascular disease populations. We did not screen our normal study subjects for baseline antiplatelet drug resistance. With respect to clopidogrel, there is no consensus regarding clinical diagnostic testing approaches to reliably identify drug resistance.44 The estimated incidence of true biochemical aspirin resistance is low (<5%), but we cannot exclude the possibility that baseline aspirin resistance may have contributed to our findings. The randomized placebo-controlled study design should reduce the likelihood that baseline drug resistance or other unmeasured confounders would yield spurious findings. We used bleeding time as an in vivo measure of integrated platelet function and tissue hemostasis. The bleeding time takes into account intrinsic platelet receptor function, granule release, platelet interaction with von Willebrand factor and fibrinogen, and the platelet concentration itself.45 Since von Willebrand factor levels, fibrinogen, and thrombin-based clotting times did not change after any dose of rHuEpo when compared with placebo, our findings suggest that the change in the bleeding time values reflect changes in platelet-dependent hemostasis. Bleeding time has been previously used to assess the response to rHuEpo in uremic patients and the response to aspirin in cardiovascular disease populations, but its relation to risk of coronary arterial thrombosis has not been established.39 PFA closure times, which are closely correlated with in vitro optical platelet aggregometry measurements and have been tentatively linked to clinical outcomes in some disease populations, were not significantly altered by rHuEpo in our study.38, 39, 46 Additional confirmatory studies with optical platelet aggregometry are warranted. Nonetheless, our findings provide evidence of a possible negative interaction between short-term administration of rHuEpo and aspirin. Because experimental studies suggest a potential role of erythropoietin as a cardioprotective agent in acute ischemia, further studies to more fully characterize the interaction effects of rHuEpo with combined aspirin and clopidogrel treatment on platelet function in cardiovascular disease populations are warranted.
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This work was supported by grant-in-aid 0555844T from the American Heart Association Heritage Affiliate, National Institutes of Health HL K24-04024, and Division of Research Resources, the General Clinical Research Centers Program, National Institutes of Health MO1 RR00645.
PII: S0002-8703(07)00542-X
doi:10.1016/j.ahj.2007.06.036
© 2007 Published by Elsevier Inc.
