Impact of Obesity and the Metabolic Syndrome on Response to Clopidogrel or Prasugrel and Bleeding Risk in Patients Treated After Coronary Stenting
2013; Elsevier BV; Volume: 113; Issue: 1 Linguagem: Inglês
10.1016/j.amjcard.2013.09.011
ISSN1879-1913
AutoresMathieu Pankert, Jacques Quilici, Anderson Diendonné Loundou, Valentine Verdier, Marc Lambert, Pierre Deharo, Guillaume Bonnet, Bénédicte Gaborit, Pierre‐Emmanuel Morange, René Valéro, Anne Dutour, Jean-Louis Bonnet, Marie‐Christine Alessi, Thomas Cuisset,
Tópico(s)Venous Thromboembolism Diagnosis and Management
ResumoThis study aimed to analyze the impact of body mass index (BMI) and the metabolic syndrome (MS) on responses to clopidogrel or prasugrel and bleeding risk after acute coronary syndrome. The study included 1,542 consecutive patients who underwent coronary stenting (287 clopidogrel 75 mg, 868 clopidogrel 150 mg, and 387 prasugrel 10 mg). Platelet reactivity was assessed 1 month after discharge using platelet reactivity index vasodilator stimulated phosphoprotein (PRI VASP). Three hundred thirty-six patients (21.8%) were obese (BMI ≥30), and we observed higher platelet reactivity associated with higher BMI across thienopyridine regimens. Incidence of high on-treatment platelet reactivity (PRI VASP >50%) was higher in obese than nonobese patients (p <0.05 for all regimens). Conversely, incidence of low on-treatment platelet reactivity with prasugrel therapy (PRI VASP <20%) was lower in obese than nonobese patients: 13% (12 of 93) versus 33% (97 of 294); odds ratio 0.30, 95% confidence interval 0.16 to 0.58; p <0.001. Accordingly, incidence of Bleeding Academic Research Consortium bleeding complications was higher in nonobese than in obese patients: 10% (119 of 1,206) versus 6% (20 of 336); odds ratio 1.7, 95% confidence interval 1.1 to 2.8; p = 0.03. This impaired response was only observed in obese patients with the MS, and obese with the MS had significantly higher platelet reactivity than other obese patients with all regimens (p 50%) was higher in obese than nonobese patients (p <0.05 for all regimens). Conversely, incidence of low on-treatment platelet reactivity with prasugrel therapy (PRI VASP <20%) was lower in obese than nonobese patients: 13% (12 of 93) versus 33% (97 of 294); odds ratio 0.30, 95% confidence interval 0.16 to 0.58; p <0.001. Accordingly, incidence of Bleeding Academic Research Consortium bleeding complications was higher in nonobese than in obese patients: 10% (119 of 1,206) versus 6% (20 of 336); odds ratio 1.7, 95% confidence interval 1.1 to 2.8; p = 0.03. This impaired response was only observed in obese patients with the MS, and obese with the MS had significantly higher platelet reactivity than other obese patients with all regimens (p 30), as well as any potential association with ischemic or hemorrhagic events, compared with nonobese patients. This study was also intended to assess the impact of the metabolic syndrome (MS) in obese patients regarding response to antiplatelet agent. Between July 2008 and December 2012, all patients who were admitted to our center for stable coronary artery disease or acute coronary syndrome (unstable angina, ST-segment elevation myocardial infarction, or non-ST-segment elevation myocardial infarction) and who underwent coronary angioplasty were consecutively enrolled. The patients were discharged with a maintenance dose of 75 mg of clopidogrel, 150 mg of clopidogrel, or 10 mg of prasugrel in combination with 75 mg of aspirin. The choice of the dual-therapy class was left to the physician's discretion. Patient's BMI was calculated using the standard weight/height2 formula. The patients were divided into 2 groups depending on BMI: obese (BMI ≥30) or nonobese (BMI <30). The obese population was further divided in groups according to the international obesity classification: class 1 obesity (30 kg/m2 ≤ BMI <34.9), class 2 (35 ≤ BMI <39.9), and class 3 (BMI ≥40). Patient inclusion criteria were admission for acute coronary syndrome or stable coronary artery disease; having undergone PCI; and receiving dual antiplatelet therapy on hospital discharge, which combined aspirin 75 mg with a maintenance dose of clopidogrel 75 mg, clopidogrel 150 mg, or prasugrel 10 mg. Patient exclusion criteria were antecedents of gastrointestinal or cerebral bleeding, creatinine clearance <25 ml/min according to the Cockcroft formula, or thrombocytopenia 50% as previously proposed12Cuisset T. Grosdidier C. Loundou A.D. Quilici J. Loosveld M. Camoin L. Pankert M. Beguin S. Lambert M. Morange P.E. Bonnet J.L. Alessi M.C. Clinical implications of very low on-treatment platelet reactivity in patients treated with thienopyridine: the POBA study (Predictor Of Bleedings with Antiplatelet drugs).JACC Cardiovasc Interv. 2013; 6: 854-863Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 14Cuisset T. Loosveld M. Morange P.E. Quilici J. Moro P.J. Saut N. Gaborit B. Castelli C. Beguin S. Grosdidier C. Fourcade L. Bonnet J.L. Alessi M.C. CYP2C19 *2 and *17 alleles have a significant impact on platelet response and bleeding risk in patients treated with prasugrel after acute coronary syndrome.JACC Cardiovasc Interv. 2012; 5: 1280-1287Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar and low on-treatment platelet reactivity (LTPR) as PRI VASP 102 cm for men and >88 cm for women), hypertriglyceridemia (triglycerides ≥1.7 mmol/L), low high-density lipoprotein cholesterol (<1 mmol/L for men and 50%) in obese versus nonobese patients and in different classes of obesity,•incidence of LTPR (PRI VASP <20%) in obese versus nonobese patients and in different classes of obesity, and•incidence of bleeding and ischemic events in obese versus nonobese patients. Statistical analyses were performed using PASW Statistics version 17.0 (SPSS Inc., Hong Kong). Continuous variables were reported as means and SD or as medians and range (according to their distribution), and categorical variables were reported as count and percentages. Univariate and multivariate analyses were performed using a logistic regression model. One-way analysis of variance was used for comparison between different groups. Odds ratios (ORs) were estimated with a 95% confidence interval (CI). Calibration of the logistic model was assessed using the Hosmer-Lemeshow goodness-of-fit test. For all tests, statistical significance was defined as p <0.05. During the study period, 1,542 patients were enrolled, of which 287 were treated with clopidogrel 75 mg, 868 with clopidogrel 150 mg, and 387 with prasugrel 10 mg. Among these patients, 24 (1.7%) were underweight (BMI <18.5), 521 (33.4%) normal weight, 661 (43%) overweight (26 ≤ BMI <30), and 336 (21.8%) were classified as obese (BMI ≥30). Of these, 264 (78.6%) were defined as class 1, 57 (17%) as class 2, and 15 (4.4%) as class 3. The clinical characteristics of the 2 patient groups are summarized in Table 1. The obese patients were significantly younger than the nonobese patients (62.5 ± 10 vs 65 ± 12 years, p <0.01). Likewise, hypertension was significantly more common in the obese patients (65% vs 55%, p <0.01), as were diabetes (47.6 vs 25.3%, p <0.01) and dyslipidemia (65.5 vs 52.4%, p <0.01), compared with nonobese patients. Metabolic characteristics of the 2 groups are summarized in Table 2. The obese patients displayed a higher degree of insulin resistance status than the nonobese patients did, as shown by significantly higher insulinemia, fasting glycemia, and glycated hemoglobin levels (p <0.01 for all). Similarly, triglyceride levels were significantly higher in obese patients (1.48 vs 1.18 g/L, p <0.01), as was lower high-density lipoprotein cholesterol (0.38 vs 0.42 g/L, p <0.01).Table 1Baseline clinical characteristicsVariable % or Mean ± SDNonobese Group (n = 1,206)Obese Group (n = 336)p (Mann-Whitney)Age (yrs)65 ± 1262.5 ± 10<0.01Female gender17.9%26.6%0.02Clinical presentation Stable angina pectoris12.8%10%NS NSTEMI24.7%33%<0.01 Unstable angina pectoris30.9%35.1%<0.01 STEMI31.8%21.6%<0.01CV risk factors Previous acute coronary syndrome33.8%45.1%0.02 Hypertension55%65%<0.01 Diabetes mellitus25.3%47.6%<0.01 Smoker38.5%39%NS Dyslipidemia52.4%65.5%<0.01 Family history26%27%NS Ejection fraction (%)55 ± 855 ± 7NS Number of affected vessels1.71.8NSACS = acute coronary syndrome; CV = cardiovascular; LVEF = left ventricular ejection fraction; NS = non significant; NSTEMI = non-ST-segment elevation myocardial infarction; STEMI = ST-segment elevation myocardial infarction. Open table in a new tab Table 2Baseline biological characteristicsNonobese Group (n = 1,206)Obese Group (n = 336)p (Mann-Whitney)Fasting insulinemia (mIU/L)11.719.54<0.01Fasting glycemia (mmol/L)6.237.05<0.01C-reactive protein (mg/L)5.115.99<0.01Triglycerides (g/L)1.181.48<0.01Total cholesterol (g/L)1.51.49NSHDL cholesterol (g/L)0.420.38<0.01LDL cholesterol (g/L)0.850.82NSHbA1c (%)6.226.63<0.01Hemoglobin (g/dl)13.714.09NSPlatelets (g/L)250248NSCreatinine (mμmol/L)95.8894.120.03Fibrinogen (g/L)4.453.97NSHDL = high-density lipoprotein; LDL = low-density lipoprotein. Open table in a new tab ACS = acute coronary syndrome; CV = cardiovascular; LVEF = left ventricular ejection fraction; NS = non significant; NSTEMI = non-ST-segment elevation myocardial infarction; STEMI = ST-segment elevation myocardial infarction. HDL = high-density lipoprotein; LDL = low-density lipoprotein. Obese patients were classified according to MS, and we identified 66% obese patients with metabolic syndrome (n = 222) and 34% without metabolic syndrome (n = 114). The impact of BMI on thienopyridine responsiveness was analyzed using the PRI VASP method; results are summarized in Figure 1. On a clopidogrel 75 mg, clopidogrel 150 mg, or prasugrel 10 mg maintenance dose, the response to antiplatelet therapy was clearly and statistically correlated with BMI (p 50% in the obese than in the nonobese group regardless of the treatment regimen prescribed (clopidogrel 75 mg: 63% vs 38%, p <0.01; clopidogrel 150 mg: 61% vs 31%, p = 0.04; prasugrel 10 mg: 28% vs 4%, p <0.01). The superior efficacy of prasugrel was emphasized by a significantly lower HTPR rate than that observed in clopidogrel patients (p <0.01). LTPR (PRI VASP <20%) on prasugrel therapy was significantly more frequent in nonobese than in obese patients (OR 0.30, 95% CI 0.16 to 0.58, p <0.001). Interestingly, among the obese patients, we observed a strong impact of metabolic syndrome on response to thienopyridine with all regimens with significantly impaired response and higher platelet reactivity in obese with metabolic syndrome compared with obese without MS (Figure 3). Interestingly, obese patients without MS had no significant difference in platelet reactivity with all drugs compared with nonobese patients (Figure 3). This difference remains significant after adjustment with confounding variables including BMI. For all drug regimens, in multivariate analysis, metabolic syndrome was a stronger predictor of HTPR than obesity itself. Nine percent of patients (139 of 1,542) suffered from bleeding complications during 6-month follow-up, including 67 Bleeding Academic Research Consortium (BARC) 1, 52 BARC 2, and 20 BARC 3 bleedings, with 8 life-threatening and 3 intracranial bleeding events. No significant difference was observed for occurrence of stent thrombosis between obese and nonobese patients, nor was there a significant association between platelet reactivity and stent thrombosis. Conversely, statistically more bleeding episodes (as defined by the BARC classification) occurred in nonobese patients than in obese patients (6% [20 of 336] vs 10% [119 of 1,206], OR 1.7, 95% CI 1.1 to 2.8, p = 0.03). This may be accounted for by the fact that there were more hyper-responders in the nonobese group but more hyporesponders in the obese group. Indeed, in the entire population, patients with bleeding had lower PRI VASP values than patients without bleeding: 27% ± 17% versus 41% ± 19%, p 50% in obese and nonobese patients.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Impact of BMI on response to thienopyridine assessed by PRI VASP (clopidogrel 75 mg, clopidogrel 150 mg, and prasugrel 10 mg) and impact of MS of obese patients, between obese patients with MS (Ob-MS) or without MS (Ob).View Large Image Figure ViewerDownload Hi-res image Download (PPT) In the present study, we observed a significant relation between BMI and the response to clopidogrel and prasugrel. Interestingly, these biological findings translate into clinical outcomes with a lower rate of bleedings in obese patients. In addition, in obese patients, the MS strongly affects response to P2Y12 blockers, suggesting a differing impact of each obesity class on platelet reactivity. 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O'Connor S.A. Abtan J. Kerneis M. Saint-Etienne C. Barthélémy O. Beygui F. Silvain J. Vicaut E. Montalescot G. ARCTIC InvestigatorsBedside monitoring to adjust antiplatelet therapy for coronary stenting.N Engl J Med. 2012; 367: 2100-2109Crossref PubMed Scopus (743) Google Scholar Several studies investigating platelet reactivity in patients treated with thienopyridines identified obesity as an important modulator of response to both clopidogrel16Sibbing D. von Beckerath O. Schömig A. Kastrati A. von Beckerath N. Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention.Am J Cardiol. 2007; 100: 203-205Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 17Cuisset T. Frere C. Quilici J. Morange P.E. Camoin L. Bali L. Lambert M. Juhan-Vague I. Alessi M.C. Bonnet J.L. Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response.Thromb Res. 2009; 123: 597-603Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar and prasugrel12Cuisset T. Grosdidier C. Loundou A.D. Quilici J. Loosveld M. Camoin L. Pankert M. Beguin S. Lambert M. Morange P.E. Bonnet J.L. Alessi M.C. Clinical implications of very low on-treatment platelet reactivity in patients treated with thienopyridine: the POBA study (Predictor Of Bleedings with Antiplatelet drugs).JACC Cardiovasc Interv. 2013; 6: 854-863Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 13Cayla G. Cuisset T. Silvain J. O'Connor S.A. Kerneis M. Castelli C. Quilici J. Bonnet J.L. Alessi M.C. Morange P.E. Collet J.P. Montalescot G. Prasugrel monitoring and bleeding in real world patients.Am J Cardiol. 2013; 111: 38-44Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar; this could suggest that treatment in this wide subgroup of patients should be optimized. Our present results are in line with impaired response in patients with high BMI and higher response and bleedings in nonobese patients. However, our results suggest than obesity is associated with impaired response to antiplatelet agents only if there is associated MS. Indeed, our study demonstrates that among obese patients defined by BMI, greater heterogeneity was observed regarding the impact of response to the drug. Obese patients without MS had a better response to thienopyridine compared with obese with MS and similar response to nonobese patients, indicating that metabolic status is a better correlate of platelet inhibition (PRI VASP) than BMI. Additional studies are required to understand precisely the complex underlying mechanisms that link metabolic status and platelet reactivity. One of the strategies proposed in previous studies16Sibbing D. von Beckerath O. Schömig A. Kastrati A. von Beckerath N. Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention.Am J Cardiol. 2007; 100: 203-205Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 17Cuisset T. Frere C. Quilici J. Morange P.E. Camoin L. Bali L. Lambert M. Juhan-Vague I. Alessi M.C. Bonnet J.L. Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response.Thromb Res. 2009; 123: 597-603Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar was to increase dose of clopidogrel in selected patients. However, our present study clearly shows that this strategy is ineffective in obese patients with same rate of HTPR for both 75 and 150 mg. This highlights the potential value of new P2Y12 blockers in this specific population. BMI could be integrated into daily practice to select the appropriate drug for a particular patient for an optimal balance of efficacy and safety. In recent years, obesity has become a major public health problem. According to the French ObEpi 2012 national obesity survey,29Charles M.A. Eschwège E. Basdevant A. Monitoring the obesity epidemic in France: the ObEpi surveys 1997–2006.Obesity. 2008; 16: 2182-2186Crossref PubMed Scopus (176) Google Scholar nearly 7 million people in France are obese. This figure corresponds to 15% of the French population and represents an increase of >76% since 1997. Given the epidemic spread of obesity, clinical practitioners have to deal more frequently with this patient class. In addition to the many harmful effects that being overweight has on people's health in the long term, obesity defined as a BMI of ≥30 causes premature atherosclerosis, increases the risk of myocardial infarction and heart failure, and lowers life expectancy, mainly because of fatal cardiovascular events.19Calle E.E. Thun M.J. Petrelli J.M. Rodriguez C. Heath Jr., C.W. Body-mass index and mortality in a prospective cohort of U.S. adults.N Engl J Med. 1999; 341: 1097-1105Crossref PubMed Scopus (3047) Google Scholar, 20Berrington de Gonzalez A. Hartge P. Cerhan J.R. Flint A.J. Hannan L. MacInnis R.J. Moore S.C. Tobias G.S. Anton-Culver H. Freeman L.B. Beeson W.L. Clipp S.L. English D.R. Folsom A.R. Freedman D.M. Giles G. Hakansson N. Henderson K.D. Hoffman-Bolton J. Hoppin J.A. Koenig K.L. Lee I.M. Linet M.S. Park Y. Pocobelli G. Schatzkin A. Sesso H.D. Weiderpass E. Willcox B.J. Wolk A. Zeleniuch-Jacquotte A. Willett W.C. Thun M.J. Body-mass index and mortality among 1.46 million white adults.N Engl J Med. 2010; 363: 2211-2219Crossref PubMed Scopus (1614) Google Scholar Numerous factors have been shown to promote cardiovascular disease in obese patients, including metabolic dysregulation, arterial hypertension, dyslipidemia, and functional changes in the vascular endothelium. All these findings were observed in our patients, confirming the relevance of our data. Coronary artery disease is the primary cause of death in obese patients,19Calle E.E. Thun M.J. Petrelli J.M. Rodriguez C. Heath Jr., C.W. Body-mass index and mortality in a prospective cohort of U.S. adults.N Engl J Med. 1999; 341: 1097-1105Crossref PubMed Scopus (3047) Google Scholar, 20Berrington de Gonzalez A. Hartge P. Cerhan J.R. Flint A.J. Hannan L. MacInnis R.J. Moore S.C. Tobias G.S. Anton-Culver H. Freeman L.B. Beeson W.L. Clipp S.L. English D.R. Folsom A.R. Freedman D.M. Giles G. Hakansson N. Henderson K.D. Hoffman-Bolton J. Hoppin J.A. Koenig K.L. Lee I.M. Linet M.S. Park Y. Pocobelli G. Schatzkin A. Sesso H.D. Weiderpass E. Willcox B.J. Wolk A. Zeleniuch-Jacquotte A. Willett W.C. Thun M.J. Body-mass index and mortality among 1.46 million white adults.N Engl J Med. 2010; 363: 2211-2219Crossref PubMed Scopus (1614) Google Scholar who also develop the disease at an earlier age. In line with our observations, obese patients with MS should benefit from more aggressive and efficacious medical treatments, such as the most recent generation of P2Y12 inhibitors, which could result in fewer bleeding complications. In conclusion, BMI has a strong impact on the biological response to clopidogrel and prasugrel with a linear relationship existing between residual platelet reactivity under treatment and BMI. We also observed that in obese patients, there was a higher incidence of hyporesponders, along with a lower incidence of hyper-responders and bleeding events. However, this impaired response in obese patients was only observed in patients with MS, suggesting that not all types of obesity will alter response to thienopyridine. These results suggest potential benefits of tailored therapy based on BMI and the metabolic status of the patient, but this hypothesis needs to be tested in future clinical studies. The authors thank our nurse teams and technicians for assistance in executing this study, as well as the hematology laboratory at Conception Hospital for VASP analysis. The authors have no conflicts of interest to disclose.
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