Specific data about the clopidogrel response in elderly patients are lacking. The present study was performed to compare the platelet reactivity and clopidogrel response between patients aged >75 years and <75 years undergoing percutaneous coronary intervention for non–ST-segment elevation acute coronary syndrome. A total of 689 patients were enrolled, including 162 patients aged >75 years and 527 younger patients. All patients received a loading dose of 600 mg clopidogrel followed by 150 mg/day. Post-treatment platelet reactivity was assessed by adenosine diphosphate 10 μmol/L-induced platelet aggregation and the specific pharmacologic response to clopidogrel by the platelet reactivity index vasoactive stimulated phosphoprotein. High post-treatment platelet reactivity was defined as adenosine diphosphate 10 μmol/L-induced platelet aggregation >70%. Clinical events were recorded during 1 month of follow-up. The patients >75 years old had a greater rate of both ischemic and bleeding complications (p = 0.04 and p = 0.03, respectively). The post-treatment platelet reactivity in response to both the loading and the maintenance clopidogrel dose was greater in patients >75 years old than in the younger patients: 50 ± 17% versus 45 ± 17% (p = 0.002) and 57 ± 15% versus 53 ± 16% (p = 0.0005), respectively. The rate of high post-treatment platelet reactivity was significantly greater in patients aged >75 years after 600 mg and 150 mg clopidogrel: 14% versus 9% (p = 0.04) and 23% versus 15% (p = 0.02), respectively. In contrast, the pharmacologic response to clopidogrel was not impaired in patients >75 years after loading and maintenance doses: 43 ± 21% versus 46 ± 21% (p = 0.17) and 38 ± 18% versus 39 ± 18% (p = 0.55), respectively. In conclusion, patients aged >75 years have an impaired prognosis after acute coronary syndrome. They display greater post-treatment platelet reactivity. However, this greater platelet reactivity does not seem to be related to an impaired specific response to clopidogrel.
Dual antiplatelet therapy with aspirin and clopidogrel is currently the reference standard therapy for patients undergoing percutaneous coronary intervention (PCI) and/or after acute coronary syndrome (ACS). Several biologic studies have described a broad interindividual variability in the biologic response to clopidogrel. The clinical relevance of this biologic entity has been demonstrated in different clinical settings for both ischemic and bleeding complications. The mechanisms underlying this variability of response remain unclear and multifactorial. The elderly population is a specific population of growing concern in western countries that has been consistently underrepresented in randomized controlled trials. These patients have an impaired prognosis after ACS, including greater mortality, which might be related to platelet parameters. Recently, age has been proposed as a potential risk factor for greater platelet reactivity in clopidogrel-treated patients. However, in these studies, the clopidogrel response was assessed with a “nonspecific” test such as adenosine diphosphate (ADP)-induced light transmittance aggregometry and the VerifyNow assay (Accumetrics, San Diego, California), which analyze global platelet reactivity more than the specific pharmacologic response to clopidogrel, and focused only on the acute effect of the loading dose without an assessment during the steady state of maintenance therapy. The platelet reactivity index vasoactive stimulated phosphoprotein (PRI VASP) is recognized as the more specific pharmacologic test to assess the degree of P2Y12 receptor inhibition, and the effect of age on such a specific test remains unknown. In addition, a higher clopidogrel regimen for both loading and maintenance doses has been used to overcome the variability in the response. Recently, the clinical benefit of such doses has been suggested in patients undergoing PCI for ACS. Therefore, the present study was performed to compare the platelet reactivity and clopidogrel response between patients aged >75 years and <75 years undergoing PCI for non–ST-segment elevation ACS after high doses of clopidogrel, with loading dose of 600 mg and a maintenance dose of 150 mg/day.
Methods
All patients admitted for non–ST-segment elevation ACS in our institution were eligible for the present prospective study if they had undergone successful coronary stenting. non–ST-segment elevation ACS was defined as clinical symptoms compatible with acute myocardial ischemia within 12 hours before admission and ≥1 of the following: a new finding of ST-segment changes, elevated cardiac biomarker levels, or coronary artery disease, as documented by a history of PCI or myocardial infarction. The exclusion criteria were a history of bleeding diathesis, persistent ST-segment elevation ACS, New York Heart Association class IV, PCI or coronary bypass grafting <3 months, contraindications to antiplatelet therapy, platelet count <100 g/L, creatinine clearance <25 ml/min, or the use of glycoprotein IIb/IIIa antagonists before the procedure. Patients received oral loading doses of 250 mg aspirin and 600 mg clopidogrel ≥12 hours before PCI. The initial platelet parameters were assessed 12 to 24 hours after the loading dose. PCI was performed within 24 hours after admission. Anticoagulation was obtained with unfractionnated heparin or 2.5 mg/day fondaparinux subcutaneously plus additional unfractionnated heparin during PCI. The use of a glycoprotein IIb/IIIa antagonist during PCI was allowed at the operator’s discretion. The patients were discharged with the following dual antiplatelet therapy: aspirin 75 mg and clopidogrel 150 mg/day. Platelet tests were performed 1 month after hospital discharge at clinical follow-up. Verbal compliance was also systematically checked during this consultation. The ethics committee of our institution approved the study protocol, and all patients gave written informed consent for participation. The blood samples for testing the platelet reactivity were drawn ≥12 hours after the loading dose of aspirin and clopidogrel and at the 1-month follow-up visit. The blood was immediately collected in Vacutainer tube containing 3.8% trisodium citrate, filled to capacity, and the blood-citrate mixture was centrifuged at 120 g for 5 minutes. The resulting platelet-rich plasma was kept at room temperature for use within 1 hour. The platelet count was determined in the platelet-rich plasma sample and adjusted to 2.5 × 10 8 /ml with homologous platelet-poor plasma. The platelets were stimulated with ADP (10 μmol/L), and aggregation was assessed with a PAP4 aggregometer (Biodata, Wellcome, Paris, France). Aggregation is expressed as the percentage of change in light transmittance from baseline, with platelet-poor plasma as the reference. In the present study, we report the data on the maximum intensity of ADP-induced platelet aggregation. ADP-induced platelet aggregation >70% was defined as high post-treatment platelet reactivity, as previously described, and was associated with a greater risk of ischemic complications. ADP-induced platelet aggregation <40% was defined as low post-treatment platelet reactivity and was associated with a greater risk of bleeding complications. To determine the VASP phosphorylation state of whole blood, we used a standardized flow cytometric assay (Platelet VASP, Diagnostica Stago [Biocytex], Asnières, France), which is an adaptation of the method of Schwarz et al. PRI VASP was calculated from the median fluorescence intensity (MFI) of samples incubated with prostaglandin E 1 (PGE 1 ) or prostaglandin E 1 and ADP according to the formula: PRI VASP = [(MFI (PGE1) − MFI (PGE1+ADP) /MFI PGE1 ] × 100. Clopidogrel resistance was defined as PRI VASP >50%, as previously proposed. The primary end point of the present study was the comparison of platelet reactivity (ADP-induced platelet aggregation) and clopidogrel response (PRI VASP) between patients aged >75 years and <75 years after loading and maintenance doses of clopidogrel. The secondary end point was the incidence of high post-treatment platelet reactivity (ADP-induced platelet aggregation >70%), low post-treatment platelet reactivity (ADP-induced platelet aggregation <40%), and clopidogrel resistance (PRI VASP >50%) between both groups of patients. Clinical follow-up was planned for all patients. The clinical end points were (1) the composite ischemic end point of cardiovascular death, stent thrombosis defined as the definite occurrence of a thrombotic event, according to the Academic Research Consortium classification, and recurrent ACS requiring urgent PCI; and (2) the occurrence of bleeding events according to the Academic Bleeding Consensus Definitions of type 1 and 2 or 3 or 5 (type 4 was not expected because no patient had undergone planned coronary artery bypass grafting). Statistical analysis was performed using the GraphPad Prism software, version 4.00 (GraphPad Software, La Jolla, California). Continuous variables are expressed as the mean ± SD. Categorical variables are expressed as frequencies and percentages. Comparisons between groups were made with the chi-square or Fisher exact test for categorical variables and nonparametric statistical testing for continuous variables. Values of p <0.05 were considered statistically significant.
Results
From June 2008 to January 2011, the present study included 689 consecutive patients undergoing coronary stenting for non–ST-segment elevation ACS, including 162 patients aged >75 years (23%) and 527 patients aged <75 years (77%). All patients received a loading dose of 600 mg of clopidogrel followed by a 150-mg/day maintenance dose for 1 month, with a low dose of aspirin. The baseline characteristics of the patients are summarized in Tables 1 and 2 . The mean age of the patients >75 years was 81 ± 4 years. The patient characteristics differed between those who were >75 years old and the younger patients, with a twofold increase in the proportion of women, greater degree of renal impairment, lower body mass index (25.9 ± 3.7 vs 27.4 ± 4.7 kg/m 2 , p = 0.0001), lower use of concomitant medications, such as β blockers and statins, and greater rate of calcium antagonists. The cardiovascular risk factors were also very different, with a lower incidence of familial history and smoking and greater rate of hypertension in patients >75 years. The procedural characteristics of patients aged >75 years differed also, with an expected lower use of drug-eluting stents, lower ejection fraction, and more diffuse coronary artery disease. The post-treatment platelet reactivity, as assessed by ADP-induced platelet aggregation, in response to both the loading dose and the maintenance dose was significantly greater in patients >75 years than in the younger patients (50 ± 17% vs 45 ± 17%, p = 0.002, and 57 ± 15% vs 53 ± 16%, p = 0.0005, respectively; Figure 1 ) . The rate of high post-treatment platelet reactivity was significantly greater in patients aged >75 years after both loading and maintenance doses (14% vs 9%, odds ratio 1.8, 95% confidence interval 1.05 to 3, p = 0.04, and 23% versus 15%, odds ratio 1.7, 95% confidence interval 1.25 to 2.7, p = 0.02, respectively; Figure 2 ) . The incidence of low post-treatment platelet reactivity, associated with bleeding risk at 1 month in patients receiving the 150-mg maintenance dose was significantly greater in the younger than in the older patients (24% vs 15%, odds ratio 2.1, 95% confidence interval 1.3 to 3.2, p = 0.01; Figure 3 ) . The pharmacologic response to clopidogrel assessed by PRI VASP was not impaired in patients >75 years old, neither after the loading dose nor after the maintenance dose (43 ± 21% vs 46 ± 21%, p = 0.17, and 38 ± 18% vs 39 ± 18%, p = 0.55, respectively; Figure 4 ) . Using the common threshold of PRI VASP >50% to define clopidogrel resistance, we observed a high rate of clopidogrel resistance in the whole population (48% patients after 600 mg and 34% of patients at 1 month with the 150-mg maintenance dose). The rate of clopidogrel resistance was not significantly greater in patients aged >75 years after 600 mg and 150 mg (42% vs 50%, p = 0.12, and 29% vs 36%, p = 0.13, respectively), with a trend toward a greater incidence of clopidogrel resistance in the younger patients than in the older patients ( Figure 5 ) . All patients attended the 1-month follow-up visit. Twenty-five cardiovascular ischemic events (4%) occurred in the whole population during follow-up, including 5 cardiovascular deaths, 6 cases of definite or probable stent thrombosis, and 14 recurrent ACS events. Recurrent ischemic events occurred more frequently in the patients aged >75 years than in the younger patients: 10 (6%) versus 15 (3%; p = 0.04). Regarding bleeding complications, no type 5 bleeding (fatal) occurred in the whole population. Pooling the Academic Research Consortium bleeding definitions for types 1, 2, and 3, 62 bleeding events (9%) occurred in the whole population. The bleeding event rate was significantly greater in patients aged >75 years than in patients <75 years: 20 (12%) versus 42 (8%; p = 0.03; Figure 6 ) .
| Characteristic | Age (years) | p Value | |
|---|---|---|---|
| >75 | <75 | ||
| Patients | 162 (23%) | 527 (77%) | |
| Age (years) | 81 ± 4 | 60 ± 9 | <0.0001 |
| Women | 50 (31%) | 84 (16%) | <0.0001 |
| Weight (kg) | 72 ± 12 | 80 ± 15 | <0.0001 |
| Body mass index (kg/m 2 ) | 25.9 ± 3.7 | 27.4 ± 4.7 | 0.0001 |
| Hypertension ⁎ | 118 (73%) | 281 (53%) | <0.0001 |
| Diabetes mellitus | 47 (29%) | 149 (28%) | 0.84 |
| Smoker | 18 (11%) | 238 (45%) | <0.0001 |
| Dyslipidemia † | 88 (54%) | 297 (56%) | 0.65 |
| Family history ‡ | 24 (15%) | 145 (28%) | 0.0008 |
| β Blockers | 102 (63%) | 384 (73%) | 0.02 |
| Angiotensin-converting enzyme inhibitors | 109 (67%) | 365 (69%) | 0.63 |
| Calcium antagonists | 28 (17%) | 56 (11%) | 0.03 |
| Proton pump inhibitors | 142 (88%) | 459 (87%) | 1.0 |
| Statins | 142 (88%) | 489 (92%) | 0.04 |
| Left ventricular ejection fraction (%) | 53 ± 9 | 55 ± 8 | 0.002 |
| Creatinine (μmol/L) | 94 ± 33 | 86 ± 27 | 0.04 |
⁎ Defined as documented and treated hypertension.
† Defined as documented and treated dyslipidemia.
‡ Previous myocardial infarction or sudden death in first-degree young relative (<55 years old for men and <65 years for women).
| Variable | Age (years) | p Value | |
|---|---|---|---|
| >75 | <75 | ||
| Patients | 162 (23%) | 527 (77%) | |
| Radial access | 148 (91%) | 480 (91%) | 1.0 |
| Drug-eluting stent | 38 (23%) | 283 (54%) | <0.0001 |
| Number of stents | 1.3 ± 0.6 | 1.2 ± 0.6 | 0.24 |
| Total stent length (mm) | 18 ± 9 | 19 ± 10 | 0.23 |
| Number of diseased vessels | 0.0001 | ||
| 1 | 45 (28%) | 245 (47%) | |
| 2 | 75 (46%) | 181 (34%) | |
| 3 | 42 (26%) | 101 (19%) | |
| Glycoprotein IIb/IIIa antagonists | 27 (20%) | 160 (31%) | 0.0006 |
| Left ventricular ejection fraction (%) | 53 ± 9 | 55 ± 8 | 0.002 |
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