- Email: [email protected]
Impact of Body Mass Index on 5-Year Clinical Outcomes in Patients With ST–Segment Elevation Myocardial Infarction After Everolimus-Eluting or Bare-Metal Stent Implantation
Impact of Body Mass Index on 5-Year Clinical Outcomes in Patients With ST–Segment Elevation Myocardial Infarction After Everolimus-Eluting or Bare-Metal Stent Implantation Elisabetta Moscarella, MDa, Giosafat Spitaleri, MDa, Salvatore Brugaletta, MD, PhDa,*, Sara Sentí Farrarons, MDa, Alberto Pernigotti, MDa, Luis Ortega-Paz, MDa, Angel Cequier, MDb, Andrés Iñiguez, MDc, Antonio Serra, MDd, Pilar Jiménez-Quevedo, MDe, Vicente Mainar, MDf, Gianluca Campo, MDg, Maurizio Tespili, MDh, Peter den Heijer, MDi, Armando Bethencourt, MDj, Nicolás Vazquez, MDk, Marco Valgimigli, MD, PhDl, Patrick W. Serruys, MD, PhDm, and Manel Sabaté, MD, PhDa Patients with high body mass index (BMI) seem to have better outcomes after percutaneous coronary intervention than normal-weight patients. However, contrasting results have been reported on the “obesity paradox” in patients presenting with ST-elevation myocardial infarction (STEMI). The aim of our study was to investigate the impact of BMI on mortality in the population enrolled in the Evaluation of the Xience-V stent in Acute Myocardial INfArcTION (EXAMINATION) trial. The EXAMINATION trial randomized 1,498 patients with STEMI to a bare-metal stent or an everolimus-eluting stent. In this substudy patients were stratified into 3 groups according to BMI values: normal (BMI < 25 kg/m2), overweight (BMI = 25 to 29.9 kg/m2), and obese (BMI ≥ 30 kg/m2). The coprimary end points were the all-cause and cardiac deaths among the groups at the 5-year follow-up. BMI was available in 1,421 patients, divided in 401 (28.2%) normal, 702 (49.4%) overweight, and 318 (22.4%) obese. Obese patients were younger (p = 0.012) compared with the other groups, but with a worse cardiovascular risk profile. They were more frequently female (p <0.001) and with a higher rate of obesity-related co-morbidity conditions such as diabetes mellitus (p = 0.005), arterial hypertension (p <0.001), and hyperlipidemia (p = 0.001) compared with the other groups. At the 5-year follow-up, all-cause and cardiac deaths were less frequent in obese patients than in the other groups (p = 0.003 and p = 0.030, respectively). After adjustment for confounding variables, BMI was an independent predictor of all-cause death (hazard ratio 0.765, 95% confidence interval 0.599 to 0.979, p = 0.033), but not of cardiac death, without any interaction with the stent type. In conclusion, in patients with STEMI who underwent primary PCI, the long-term all-cause death rate decreased as BMI increased, confirming the obesity paradox, irrespective of the stent type. © 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;120:1460–1466)
a University Hospital Clínic, Cardiovascular Clinic Institute, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; bDepartment of Cardiology, University Hospital of Bellvitge, Barcelona, Spain; c Department of Cardiology, Hospital do Meixoeiro, Vigo, Spain; dDepartment of Cardiology, University Hospital of Sant Pau, Barcelona, Spain; eDepartment of Cardiology, University Hospital San Carlos, Madrid, Spain; fDepartment of Cardiology, Hospital General of Alicante, Alicante, Spain; gCardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Cona (FE), Italy and Maria Cecilia Hospital, GVM Care & Research, E.S.: Health Science Foundation, Cotignola, Italy; hDepartment of Cardiology, University Hospital Bolognini Seriate, Bergamo, Italy; iDepartment of Cardiology, Amphia Ziekenhuis, Breda, Netherlands; jDepartment of Cardiology, Hospital Son Espases, Palma de Mallorca, Spain; kDepartment of Cardiology, Hospital Juan Canalejo, A Coruña, Spain; lUniversity Hospital of Bern, Inselspital, Bern, Switzerland; and mInternational Centre of Circulatory Health, Imperial College London, London, United Kingdom. Manuscript received April 8, 2017; revised manuscript received and accepted July 21, 2017. See page 1465 for disclosure information. *Corresponding author: Tel: +34932279305; fax: +34932279305. E-mail address: [email protected] (S. Brugaletta).
0002-9149/© 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2017.07.040
The purpose of the present study was to investigate the impact of body mass index (BMI) on clinical outcomes and its interaction with the type of stent implanted in patients with ST-elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention (PCI) and enrolled in the Evaluation of the Xience-V stent in Acute Myocardial INfArcTION (EXAMINATION) trial.1 Methods This is a post hoc analysis study from the all-comer, multicenter, controlled, and randomized, EXAMINATION trial (NCT00828087). The detailed study design and the results of the EXAMINATION trial have been previously reported.1,2 All participating centers submitted and received the approval of their Medical Ethics Committee for the protocol and for the informed consent. The study was conducted in compliance with the protocol, the Declaration of Helsinki, and www.ajconline.org
Coronary Artery Disease/Impact of BMI on Mortality
applicable local requirements. All patients provided written informed consent. For this retrospective subgroup analysis, BMI was calculated using the following formula: BMI = body weight (in kilogram)/square of stature (height, in meter).3 The patients were stratified into 3 BMI groups4: normal (BMI <25 kg/m2), overweight (BMI 25 to 29.9 kg/m2), and obese (BMI ≥30 kg/m2). The coprimary end points were all-cause and cardiac deaths according to the Academic Research Consortium (ARC) criteria5 at 5 years’ follow-up. The secondary end points were any myocardial infarction (MI) (World Health Organization extended definition6), target-vessel myocardial infarction, any revascularization, target lesion revascularization, and stent thrombosis, as per ARC definitions,5 and major and minor bleeding, according to Thrombolysis in Myocardial Infarction (TIMI) classification.7 All clinical events were adjudicated by an independent Clinical Event Committee (Cardialysis, Rotterdam, The Netherlands). Clinical, angiographic, and procedural characteristics and 5-year outcomes were analyzed stratified by BMI group (normal vs overweight vs obese).
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Categorical variables were expressed as number and percentage and were compared by chi-square analysis or Fisher’s exact test, as appropriate. Continuous variables were expressed as mean ± standard deviation and were compared by analysis of variance test, as appropriate. All the analyses were stratified according to BMI groups. Event analyses were displayed using Kaplan-Meier plots and were compared with the log-rank test. A Cox model for all-cause and cardiac deaths was performed, correcting for those clinical variables that were significantly different among the groups: age, gender, systemic arterial hypertension, diabetes mellitus (DM), hyperlipidemia, everolimus-eluting stent implanted at the index procedure, and the clinical presentation (primary PCI <12 hours as reference). The interaction between the stent type and BMI was also tested either for all-cause or cardiac death. BMI was also used as a continuous variable to determine the specific shape of the association between BMI and all-cause mortality. A 2-sided p value of <0.05 was considered statistically significant. Statistical analyses were performed with SPSS statistical package 20.0 (SPSS Inc., Chicago, IL).
Table 1 Baseline characteristics Body Mass Index (Kg/m2) Variable
2
Body Mass Index (Kg/m ; mean±SD) Age (years, mean±SD) Man Xience Multilink Smoker Diabetes mellitus Arterial hypertension Hyperlipidemia Family history Previous Myocardial Infarction Previous percutaneous coronary intervention Previous coronary artery bypass graft Previous stroke Pre infarction angina pectoris Clinical condition Primary percutaneous coronary intervention (<12h) Rescue percutaneous coronary intervention Percutaneous coronary intervention after successful thrombolysis Late comer (>12h and <48h) Killip Class on admission I II III IV Infarct-related coronary artery Left main Left anterior descending Left circumflex Right coronary Saphenous vein graft Multivessel disease Ejection fraction, mean±SD Congestive heart Failure Cardiogenic shock Data are mean ± SD or n (%).
Total
<25
25–30
≥ 30
(n = 1421)
(n = 401)
(n = 702)
(n = 318)
27.34 ± 3.8 61.2 ± 12.3 1179 (83.0%) 708 (49.8%) 713 (50.2%) 1021 (71.9%) 249 (17.5%) 694 (48.9%) 632 (44.5%) 243 (17.1%) 77 (5.4%) 60 (4.2%) 7 (0.5%) 29 (2.0%) 411 (29.0%)
23.01 ± 1.8 62.21 ± 12.71 302 (76.3%) 197 (49.1%) 204 (50.9%) 283 (70.8%) 55 (13.8%) 176 (44.0%) 157 (39.2%) 70 (17.5%) 16 (4.0%) 9 (2.2%) 1 (0.2%) 8 (2.0%) 105 (26.3%)
27.4 ± 1.3 61.26 ± 11.99 619 (88.2%) 359 (51.1%) 343 (48.9%) 509 (72.5%) 121 (17.2%) 327 (46.6%) 307 (43.7%) 119 (17.0%) 37 (5.3%) 33 (4.7%) 4 (0.6%) 14 (2.0%) 201 (28.7%)
32.6 ± 2.6 59.49 ± 12.37 258 (81.1%) 152 (47.8%) 166 (52.2%) 229 (72.0%) 73 (23.0%) 191 (60.1%) 168 (52.8%) 54 (17.0%) 24 (7.5%) 18 (5.7%) 2 (0.6%) 7 (2.2%) 105 (33.0%)
1204 (84.8%) 91 (6.4%) 33 (2.3%) 92 (6.5%)
325 (81%) 26 (6.5%) 13 (3.2%) 37 (9.2%)
612 (87.3%) 42 (6.0%) 15 (2.1%) 32 (4.6%)
267 (84.0%) 23 (7.2%) 5 (15.2%) 23 (7.2%)
1270 (89.6%) 108 (7.6%) 21 (1.5%) 18 (1.3%)
358 (89.7%) 32 (8.0%) 5 (1.3%) 4 (1.0%)
629 (89.7%) 48 (6.8%) 11 (1.6%) 13 (1.9%)
283 (89.3%) 28 (8.8%) 5 (1.6%) 1 (0.3%)
5 (0.4%) 616 (43.3%) 201 (14.1%) 596 (41.9%) 3 (0.2%) 163 (11.5%) 52.0 ± 10.5 2 (0.1%) 18 (1.3%)
2 (0.5%) 171 (42.6%) 62 (15.5%) 165 (41.1%) 1 (0.2%) 44 (11.0%) 50.53 ± 11.06 1 (0.2%) 4 (1.0%)
2 (0.3%) 315 (44.9%) 83 (11.8%) 300 (42.7%) 2 (0.3%) 87 (12.4%) 51.53 ± 10.16 0 (0%) 13 (1.9%)
1 (0.3%) 130 (40.9%) 56 (17.6%) 131 (41.2%) 0 (0%) 32 (10.1%) 51.33 ± 9.88 1 (0.3%) 1 (0.3%)
P value
<0.001 0.012 <0.001 0.581 0.822 0.005 <0.001 0.001 0.344 0.110 0.053 0.710 0.974 0.140 0.043
0.442
0.417
0.520 0.427 0.366 0.106
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among the groups. The correlation between BMI and all cause mortality is shown in Figure 1. Figure 2 reports the KaplanMeier curves at the 5-year follow-up for all-cause and cardiac deaths. At Cox adjusted analysis (Table 4), BMI was an independent predictor of all-cause death together with age and clinical presentation (late comers). No significant interaction was found between BMI and the type of stent implanted. Only age emerged as an independent predictor of cardiac death.
Results BMI calculation was available in 1,421 (95%) patients. According to BMI values, the patients were classified as follows: 401 (28.2%) normal, 702 (49.4%) overweight, and 318 (22.4%) obese (Table 1). Obese patients were younger compared with the other groups, but with a worse cardiovascular risk profile. These patients were more frequently female and with a higher rate of obesity-related co-morbidity conditions such as DM, arterial hypertension and hyperlipidemia compared with the other groups. The periprocedural characteristics are listed in Table 2. At the 5-year follow-up, allcause and cardiac deaths were both less frequently observed in the obese group than in the other groups, whereas no differences were noted for noncardiac death (Table 3). No significant differences were observed in terms of revascularization or definite or probable stent thrombosis
Discussion The main findings of our study can be summarized as follows: (1) all-cause death and cardiac death rates were less frequent in obese patients, confirming the obesity paradox; (2) however, when correcting for confounding factors, BMI remained an independent predictor of all-cause death but not
Table 2 Periprocedural characteristics Body Mass Index (Kg/m2) Total
<25
25–30
≥ 30
(n = 1421)
(n = 401)
(n = 702)
(n = 318)
878 (49.3%) 1119 (78.7%) 130 (9.1%) 102 (7.2%) 1315 (92.5%) 1346 (94.7%) 740 (52.1%) 1931.29 ± 2035.99 299.92 ± 2441.04 56.95 ± 99.3 926 (65.2%) 852 (60.7%) 1.39 ± 0.65 3.2 ± 0.45 27.51 ± 14.0 1324 (93.4%) 11 (0.7%)
227 (57.3%) 310 (77.3%) 40 (10.0%) 29 (7.2%) 368 (91.8%) 372 (92.8%) 192 (47.9%) 1964.99 ± 1870.90 224.17 ± 274.33 56.22 ± 114.7 254 (63.3%) 235 (58.6%) 1.36 ± 0.63 3.19 ± 0.44 27.37 ± 13.86 375 (93.8%) 3 (0.7%)
406 (58.0%) 550 (78.3%) 57 (8.1%) 53 (7.5%) 650 (92.6%) 675 (96.2%) 372 (53.0%) 1928.20 ± 2051.96 387.61 ± 3588.64 44.34 ± 95.89 455 (64.8%) 442 (62.9%) 1.41 ± 0.66 3.19 ± 0.46 28.01 ± 14.41 655 (93.6%) 8 (1.1%)
190 (59.7%) 259 (81.4%) 33 (10.4%) 20 (6.3%) 297 (93.4%) 299 (94.0%) 176 (55.3%) 1961.51 ± 2265.43 221.11 ± 257.56 50.79 ± 88.77 217 (68.2%) 175 (55.0%) 1.35 ± 0.63 3.22 ± 0.45 26.85 ± 13.67 294 (92.5%) 0 (0%)
Variable
Prethrombolysis in myocardial infarction flow 0 Unfractioned heparin Low molecular weight heparin Bivalirudin Aspirin Clopidogrel Glicoprotein IIb/IIIa inhibitor CK peak CK-MB peak Troponin peak Manual thrombectomy Direct stenting Number of stents implanted; mean±SD Maximum stent diameter mean±SD Total stent length, mean±SD Final Thrombolysis in myocardial infarction flow 3 Intra aortic balloon Pump
P value
0.966 0.377 0.406 0.769 0.710 0.044 0.109 0.959 0.654 0.215 0.377 0.031 0.262 0.556 0.454 0.643 0.387
Data are mean ± SD or n (%).
Table 3 Five-year outcomes Body Mass Index (Kg/m2) Variable
All-cause Death Cardiac death Non-cardiac death Myocardial Infarction Target vessel Myocardial Infarction Any revascularization Target lesion revascularization Definite/probable Stent thrombosis Major and minor Bleeding*
Total
<25
25–30
≥ 30
(n = 1421)
(n = 401)
(n = 702)
(n = 318)
142 (10.0%) 95 (6.7%) 47 (33.1%) 57 (4.0%) 41 (2.9%) 199 (14.0%) 82 (5.8%) 37 (2.6%) 94 (6.6%)
55 (13.7) 37 (9.2%) 18 (32.7%) 14 (3.5%) 11 (2.7%) 51 (12.7%) 19 (4.7%) 12 (3.0%) 28 (7.0%)
67 (9.5) 44 (6.3%) 23 (34.3%) 26 (3.7%) 18 (2.6%) 98 (14.0%) 41 (5.8%) 17 (2.4%) 46 (6.6%)
20 (6.3%) 14 (4.4%) 6 (30.0%) 17 (5.3%) 12 (3.8%) 50 (15.7%) 22 (6.9%) 8 (2.5%) 20 (6.3%)
* According to Thrombolysis In Myocardial Infarction (TIMI) classification.
P value
0.003 0.030 0.934 0.382 0.554 0.514 0.458 0.843 0.929
Coronary Artery Disease/Impact of BMI on Mortality
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Figure 1. BMI and all-cause death. Correlation between BMI values and all-cause death (odds ratio 0.894, 95% confidence interval, 0.851 to 0.939, p <0.001). Vertical dotted lines demarcate BMI groups: normal (BMI < 25 kg/m2), overweight (BMI = 25 to 29.9 kg/m2), and obese (BMI ≥ 30 kg/m2).
Figure 2. Five-year clinical outcomes. Kaplan-Meier curves at 5 years’ follow-up showing the incidence of the all-cause death and cardiac death between BMI groups.
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Table 4 Multivariable model Adjusted Predictor of All Cause Death. Hazard Ratio
Stent implanted Body mass Index Age Sex Diabetes mellitus Hypercholesterolemia Hypertension Late comers (within 12-24h) Body mass Index *Treatment
1.116 0.765 1.096 0.843 0.997 0.952 1.036 1.212 1.011
P value
0.521 0.033 <0.001 0.397 0.987 0.784 0.843 0.018 0.965
95% Confidence interval Inferior
Superior
0.798 0.599 1.078 0.568 0.662 0.668 0.728 1.034 0.620
1.562 0.979 1.115 1.251 1.500 1.356 1.475 1.421 1.648
Adjusted Predictors of Cardiac Death Hazard Ratio
Stent implanted Body mass Index Age Sex Diabetes mellitus Hypercholesterolemia Hypertension Late comers (within 12-24h) Body mass Index *Treatment
0.919 0.773 1.106 0.823 1.080 0.965 1.208 1.164 1.177
P value
0.687 0.095 <0.001 0.425 0.754 0.873 0.401 0.133 0.591
95% Confidence interval Inferior
Superior
0.611 0.572 1.082 0.510 0.666 0.625 0.777 0.955 0.650
1.384 1.046 1.130 1.328 1.752 1.490 1.876 1.419 2.133
of cardiac death; and (3) no interaction was found between BMI and the type of stent implanted. Obesity is a widespread problem across all western countries,8,9 strongly associated with cardiovascular risk factors such as hypertension, DM, and dyslipidemia, and it is a wellestablished risk factor for the development of coronary artery disease and acute coronary syndromes.10,11 Nevertheless, an apparent paradoxical effect of BMI on the outcomes of patients with coronary artery disease, a phenomenon known as “obesity paradox,” has been reported: in patients who underwent PCI, BMI was inversely associated with worse outcomes, with obese and overweight participants having higher survival rates.12 Although the obesity paradox has been described for patients who underwent PCI for chronic total occlusion10 and for patients presenting with unstable angina or non–ST-elevation MI,13 whether BMI may impact the outcomes of patients with STEMI remains controversial. Some studies have shown the existence of an inverse relation between BMI and mortality in the STEMI setting.14–16 However, the protective BMI effect disappeared by correcting for confounders, thus weakening the hypothesis of a lower in-hospital17–19 or long-term20 mortality rate in the obese STEMI population. In our study, the prevalence of overweight and obesity in patients with STEMI was very high (72%), confirming obesity as an important European health problem. We found that BMI was an independent predictor of all-cause death, even after adjustment for potential confounding factors, but not of cardiac death. Age appeared instead as an independent predictor of both mortalities. Several possible
mechanisms may explain this phenomenon. A worse cardiovascular risk profile of obese patients (diabetes, hypertension, etc.) may be, for example, counterbalanced by their young age so that STEMI occurs early but with a lower cardiac mortality. The occurrence of STEMI in earlier stage in obese patients than in normal-weight patients has been already described.20 Young age may allow a more aggressive use of medications and procedures, a factor that may have a beneficial impact on cardiac mortality. Conversely, a better cardiovascular risk profile in the other BMI groups may be counterbalanced by advanced age: elderly patients exhibit poor clinical outcomes after acute MI, irrespective of the reperfusion technique, likely related to a higher risk of noncardiac death due to chronic diseases.21,22 This finding could eventually result in a lack of cardiac mortality difference among groups when confounding factors are taken into account. It has been shown that underweight patients with low BMI (<18.5 kg/m2) may have a worse prognosis after MI, due to cardiac cachexia, malnutrition, or depression.23 In our study, underweight patients were analyzed together within the normalBMI group because of the low prevalence of this condition (10 patients, 0.7%). However, potential confounding by cachexia in our analysis cannot be excluded. It is worth noting that our study included patients with STEMI who underwent different reperfusion therapies (primary PCI, rescue PCI, PCI after successful thrombolysis, and late comers within 12 to 24 hours) and that at Cox regression, late clinical presentation on admission also had an impact on mortality rates. In our study, obese patients presented more often earlier than other BMI groups (p = 0.043), which also may have influenced the long-term outcomes. Eventually, we look at the possible relation between BMI and the randomization effect of the stent implanted, as the long-term results from the EXAMINATION trial showed the superiority of the everolimus-eluting stent over the baremetal stent with respect to both patient-oriented composite end-point and device-oriented composite end-point, mainly driven by reductions in the rates of all-cause death, cardiac death, and target lesion revascularization.2 In our analysis, the inverse relation between BMI and mortality rate was maintained irrespective of the type of stent implanted, without any differences in terms of the number and the length of the stent implanted among the groups. The present study is a post hoc analysis of the EXAMINATION trial, not powered for clinical end points. BMI was calculated at the time of the index procedure but was not reevaluated during the follow-up. However, it has been shown that, in obese patients, there is only a small decrease in body weight in the first year after MI.24 Our analysis does not take into account the difference between peripheral versus abdominal obesity or waist circumference. Previous reports, however, showed that BMI maintained its predictive role on mortality irrespective of the obesity type.25 Finally, albeit small (5%), a potentially significant number of patients were excluded from the analysis because of missing data in the BMI calculation. No differences were shown in terms of end points between those patients included in and those excluded from our analysis (see the supplementary material). In patients presenting with STEMI who underwent PCI, the overall longterm mortality decreased as BMI increased, confirming a paradoxical obesity protection, even after adjustment for
Coronary Artery Disease/Impact of BMI on Mortality
confounding factors. BMI can be considered as an index of protective genetics and epigenetic factors decreasing the obese patients’ vulnerability to cardiovascular disease. However, the lack of impact of BMI on cardiac mortality suggests that multiple factors such as age or the time of presentation might be also implicated. Future studies are still needed to further clarify the BMI protection role. Perspectives Competency in medical knowledge: Obesity has a paradoxical protection role in overall mortality in patients presenting with STEMI who underwent PCI. Competency in patients care: The lack of a protective role in cardiac mortality when correcting for confounders suggests that other factors such as age or the time of clinical presentation might be also implicated.
7.
8. 9. 10.
11. 12.
Translational outlook: Further research is required to better understand this phenomenon and to better identify highmortality risk patients with STEMI, which may allow a more aggressive lifestyle and therapeutic intervention for secondary prevention after acute MI. Disclosures The authors report no relation with industry or other disclosures.
13.
14. 15.
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percutaneous coronary intervention: insights from the examination trial. Int J Cardiol 2015;179:73–78. 23. Knudtson MD, Klein BE, Klein R, Shankar A. Association with weight loss and subsequent mortality risk. Ann Epidemiol 2005;15:483– 491. 24. Fadl YY, Krumholz HM, Kosiborod M, Masoudi FA, Peterson PN, Reid KJ, Weintraub WS, Buchanan DM, Spertus JA. Predictors of weight
change in overweight patients with myocardial infarction. Am Heart J 2007;154:711–717. 25. Zeller M, Steg PG, Ravisy J, Lorgis L, Laurent Y, Sicard P, JaninManificat L, Beer JC, Makki H, Lagrost AC, Rochette L, Cottin Y, RICO Survey Working Group. Relation between Body Mass Index, waist circumference, and death after acute myocardial infarction. Circulation 2008;118:482–490.
a University Hospital Clínic, Cardiovascular Clinic Institute, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; bDepartment of Cardiology, University Hospital of Bellvitge, Barcelona, Spain; c Department of Cardiology, Hospital do Meixoeiro, Vigo, Spain; dDepartment of Cardiology, University Hospital of Sant Pau, Barcelona, Spain; eDepartment of Cardiology, University Hospital San Carlos, Madrid, Spain; fDepartment of Cardiology, Hospital General of Alicante, Alicante, Spain; gCardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Cona (FE), Italy and Maria Cecilia Hospital, GVM Care & Research, E.S.: Health Science Foundation, Cotignola, Italy; hDepartment of Cardiology, University Hospital Bolognini Seriate, Bergamo, Italy; iDepartment of Cardiology, Amphia Ziekenhuis, Breda, Netherlands; jDepartment of Cardiology, Hospital Son Espases, Palma de Mallorca, Spain; kDepartment of Cardiology, Hospital Juan Canalejo, A Coruña, Spain; lUniversity Hospital of Bern, Inselspital, Bern, Switzerland; and mInternational Centre of Circulatory Health, Imperial College London, London, United Kingdom. Manuscript received April 8, 2017; revised manuscript received and accepted July 21, 2017. See page 1465 for disclosure information. *Corresponding author: Tel: +34932279305; fax: +34932279305. E-mail address: [email protected] (S. Brugaletta).
0002-9149/© 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2017.07.040
The purpose of the present study was to investigate the impact of body mass index (BMI) on clinical outcomes and its interaction with the type of stent implanted in patients with ST-elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention (PCI) and enrolled in the Evaluation of the Xience-V stent in Acute Myocardial INfArcTION (EXAMINATION) trial.1 Methods This is a post hoc analysis study from the all-comer, multicenter, controlled, and randomized, EXAMINATION trial (NCT00828087). The detailed study design and the results of the EXAMINATION trial have been previously reported.1,2 All participating centers submitted and received the approval of their Medical Ethics Committee for the protocol and for the informed consent. The study was conducted in compliance with the protocol, the Declaration of Helsinki, and www.ajconline.org
Coronary Artery Disease/Impact of BMI on Mortality
applicable local requirements. All patients provided written informed consent. For this retrospective subgroup analysis, BMI was calculated using the following formula: BMI = body weight (in kilogram)/square of stature (height, in meter).3 The patients were stratified into 3 BMI groups4: normal (BMI <25 kg/m2), overweight (BMI 25 to 29.9 kg/m2), and obese (BMI ≥30 kg/m2). The coprimary end points were all-cause and cardiac deaths according to the Academic Research Consortium (ARC) criteria5 at 5 years’ follow-up. The secondary end points were any myocardial infarction (MI) (World Health Organization extended definition6), target-vessel myocardial infarction, any revascularization, target lesion revascularization, and stent thrombosis, as per ARC definitions,5 and major and minor bleeding, according to Thrombolysis in Myocardial Infarction (TIMI) classification.7 All clinical events were adjudicated by an independent Clinical Event Committee (Cardialysis, Rotterdam, The Netherlands). Clinical, angiographic, and procedural characteristics and 5-year outcomes were analyzed stratified by BMI group (normal vs overweight vs obese).
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Categorical variables were expressed as number and percentage and were compared by chi-square analysis or Fisher’s exact test, as appropriate. Continuous variables were expressed as mean ± standard deviation and were compared by analysis of variance test, as appropriate. All the analyses were stratified according to BMI groups. Event analyses were displayed using Kaplan-Meier plots and were compared with the log-rank test. A Cox model for all-cause and cardiac deaths was performed, correcting for those clinical variables that were significantly different among the groups: age, gender, systemic arterial hypertension, diabetes mellitus (DM), hyperlipidemia, everolimus-eluting stent implanted at the index procedure, and the clinical presentation (primary PCI <12 hours as reference). The interaction between the stent type and BMI was also tested either for all-cause or cardiac death. BMI was also used as a continuous variable to determine the specific shape of the association between BMI and all-cause mortality. A 2-sided p value of <0.05 was considered statistically significant. Statistical analyses were performed with SPSS statistical package 20.0 (SPSS Inc., Chicago, IL).
Table 1 Baseline characteristics Body Mass Index (Kg/m2) Variable
2
Body Mass Index (Kg/m ; mean±SD) Age (years, mean±SD) Man Xience Multilink Smoker Diabetes mellitus Arterial hypertension Hyperlipidemia Family history Previous Myocardial Infarction Previous percutaneous coronary intervention Previous coronary artery bypass graft Previous stroke Pre infarction angina pectoris Clinical condition Primary percutaneous coronary intervention (<12h) Rescue percutaneous coronary intervention Percutaneous coronary intervention after successful thrombolysis Late comer (>12h and <48h) Killip Class on admission I II III IV Infarct-related coronary artery Left main Left anterior descending Left circumflex Right coronary Saphenous vein graft Multivessel disease Ejection fraction, mean±SD Congestive heart Failure Cardiogenic shock Data are mean ± SD or n (%).
Total
<25
25–30
≥ 30
(n = 1421)
(n = 401)
(n = 702)
(n = 318)
27.34 ± 3.8 61.2 ± 12.3 1179 (83.0%) 708 (49.8%) 713 (50.2%) 1021 (71.9%) 249 (17.5%) 694 (48.9%) 632 (44.5%) 243 (17.1%) 77 (5.4%) 60 (4.2%) 7 (0.5%) 29 (2.0%) 411 (29.0%)
23.01 ± 1.8 62.21 ± 12.71 302 (76.3%) 197 (49.1%) 204 (50.9%) 283 (70.8%) 55 (13.8%) 176 (44.0%) 157 (39.2%) 70 (17.5%) 16 (4.0%) 9 (2.2%) 1 (0.2%) 8 (2.0%) 105 (26.3%)
27.4 ± 1.3 61.26 ± 11.99 619 (88.2%) 359 (51.1%) 343 (48.9%) 509 (72.5%) 121 (17.2%) 327 (46.6%) 307 (43.7%) 119 (17.0%) 37 (5.3%) 33 (4.7%) 4 (0.6%) 14 (2.0%) 201 (28.7%)
32.6 ± 2.6 59.49 ± 12.37 258 (81.1%) 152 (47.8%) 166 (52.2%) 229 (72.0%) 73 (23.0%) 191 (60.1%) 168 (52.8%) 54 (17.0%) 24 (7.5%) 18 (5.7%) 2 (0.6%) 7 (2.2%) 105 (33.0%)
1204 (84.8%) 91 (6.4%) 33 (2.3%) 92 (6.5%)
325 (81%) 26 (6.5%) 13 (3.2%) 37 (9.2%)
612 (87.3%) 42 (6.0%) 15 (2.1%) 32 (4.6%)
267 (84.0%) 23 (7.2%) 5 (15.2%) 23 (7.2%)
1270 (89.6%) 108 (7.6%) 21 (1.5%) 18 (1.3%)
358 (89.7%) 32 (8.0%) 5 (1.3%) 4 (1.0%)
629 (89.7%) 48 (6.8%) 11 (1.6%) 13 (1.9%)
283 (89.3%) 28 (8.8%) 5 (1.6%) 1 (0.3%)
5 (0.4%) 616 (43.3%) 201 (14.1%) 596 (41.9%) 3 (0.2%) 163 (11.5%) 52.0 ± 10.5 2 (0.1%) 18 (1.3%)
2 (0.5%) 171 (42.6%) 62 (15.5%) 165 (41.1%) 1 (0.2%) 44 (11.0%) 50.53 ± 11.06 1 (0.2%) 4 (1.0%)
2 (0.3%) 315 (44.9%) 83 (11.8%) 300 (42.7%) 2 (0.3%) 87 (12.4%) 51.53 ± 10.16 0 (0%) 13 (1.9%)
1 (0.3%) 130 (40.9%) 56 (17.6%) 131 (41.2%) 0 (0%) 32 (10.1%) 51.33 ± 9.88 1 (0.3%) 1 (0.3%)
P value
<0.001 0.012 <0.001 0.581 0.822 0.005 <0.001 0.001 0.344 0.110 0.053 0.710 0.974 0.140 0.043
0.442
0.417
0.520 0.427 0.366 0.106
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among the groups. The correlation between BMI and all cause mortality is shown in Figure 1. Figure 2 reports the KaplanMeier curves at the 5-year follow-up for all-cause and cardiac deaths. At Cox adjusted analysis (Table 4), BMI was an independent predictor of all-cause death together with age and clinical presentation (late comers). No significant interaction was found between BMI and the type of stent implanted. Only age emerged as an independent predictor of cardiac death.
Results BMI calculation was available in 1,421 (95%) patients. According to BMI values, the patients were classified as follows: 401 (28.2%) normal, 702 (49.4%) overweight, and 318 (22.4%) obese (Table 1). Obese patients were younger compared with the other groups, but with a worse cardiovascular risk profile. These patients were more frequently female and with a higher rate of obesity-related co-morbidity conditions such as DM, arterial hypertension and hyperlipidemia compared with the other groups. The periprocedural characteristics are listed in Table 2. At the 5-year follow-up, allcause and cardiac deaths were both less frequently observed in the obese group than in the other groups, whereas no differences were noted for noncardiac death (Table 3). No significant differences were observed in terms of revascularization or definite or probable stent thrombosis
Discussion The main findings of our study can be summarized as follows: (1) all-cause death and cardiac death rates were less frequent in obese patients, confirming the obesity paradox; (2) however, when correcting for confounding factors, BMI remained an independent predictor of all-cause death but not
Table 2 Periprocedural characteristics Body Mass Index (Kg/m2) Total
<25
25–30
≥ 30
(n = 1421)
(n = 401)
(n = 702)
(n = 318)
878 (49.3%) 1119 (78.7%) 130 (9.1%) 102 (7.2%) 1315 (92.5%) 1346 (94.7%) 740 (52.1%) 1931.29 ± 2035.99 299.92 ± 2441.04 56.95 ± 99.3 926 (65.2%) 852 (60.7%) 1.39 ± 0.65 3.2 ± 0.45 27.51 ± 14.0 1324 (93.4%) 11 (0.7%)
227 (57.3%) 310 (77.3%) 40 (10.0%) 29 (7.2%) 368 (91.8%) 372 (92.8%) 192 (47.9%) 1964.99 ± 1870.90 224.17 ± 274.33 56.22 ± 114.7 254 (63.3%) 235 (58.6%) 1.36 ± 0.63 3.19 ± 0.44 27.37 ± 13.86 375 (93.8%) 3 (0.7%)
406 (58.0%) 550 (78.3%) 57 (8.1%) 53 (7.5%) 650 (92.6%) 675 (96.2%) 372 (53.0%) 1928.20 ± 2051.96 387.61 ± 3588.64 44.34 ± 95.89 455 (64.8%) 442 (62.9%) 1.41 ± 0.66 3.19 ± 0.46 28.01 ± 14.41 655 (93.6%) 8 (1.1%)
190 (59.7%) 259 (81.4%) 33 (10.4%) 20 (6.3%) 297 (93.4%) 299 (94.0%) 176 (55.3%) 1961.51 ± 2265.43 221.11 ± 257.56 50.79 ± 88.77 217 (68.2%) 175 (55.0%) 1.35 ± 0.63 3.22 ± 0.45 26.85 ± 13.67 294 (92.5%) 0 (0%)
Variable
Prethrombolysis in myocardial infarction flow 0 Unfractioned heparin Low molecular weight heparin Bivalirudin Aspirin Clopidogrel Glicoprotein IIb/IIIa inhibitor CK peak CK-MB peak Troponin peak Manual thrombectomy Direct stenting Number of stents implanted; mean±SD Maximum stent diameter mean±SD Total stent length, mean±SD Final Thrombolysis in myocardial infarction flow 3 Intra aortic balloon Pump
P value
0.966 0.377 0.406 0.769 0.710 0.044 0.109 0.959 0.654 0.215 0.377 0.031 0.262 0.556 0.454 0.643 0.387
Data are mean ± SD or n (%).
Table 3 Five-year outcomes Body Mass Index (Kg/m2) Variable
All-cause Death Cardiac death Non-cardiac death Myocardial Infarction Target vessel Myocardial Infarction Any revascularization Target lesion revascularization Definite/probable Stent thrombosis Major and minor Bleeding*
Total
<25
25–30
≥ 30
(n = 1421)
(n = 401)
(n = 702)
(n = 318)
142 (10.0%) 95 (6.7%) 47 (33.1%) 57 (4.0%) 41 (2.9%) 199 (14.0%) 82 (5.8%) 37 (2.6%) 94 (6.6%)
55 (13.7) 37 (9.2%) 18 (32.7%) 14 (3.5%) 11 (2.7%) 51 (12.7%) 19 (4.7%) 12 (3.0%) 28 (7.0%)
67 (9.5) 44 (6.3%) 23 (34.3%) 26 (3.7%) 18 (2.6%) 98 (14.0%) 41 (5.8%) 17 (2.4%) 46 (6.6%)
20 (6.3%) 14 (4.4%) 6 (30.0%) 17 (5.3%) 12 (3.8%) 50 (15.7%) 22 (6.9%) 8 (2.5%) 20 (6.3%)
* According to Thrombolysis In Myocardial Infarction (TIMI) classification.
P value
0.003 0.030 0.934 0.382 0.554 0.514 0.458 0.843 0.929
Coronary Artery Disease/Impact of BMI on Mortality
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Figure 1. BMI and all-cause death. Correlation between BMI values and all-cause death (odds ratio 0.894, 95% confidence interval, 0.851 to 0.939, p <0.001). Vertical dotted lines demarcate BMI groups: normal (BMI < 25 kg/m2), overweight (BMI = 25 to 29.9 kg/m2), and obese (BMI ≥ 30 kg/m2).
Figure 2. Five-year clinical outcomes. Kaplan-Meier curves at 5 years’ follow-up showing the incidence of the all-cause death and cardiac death between BMI groups.
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Table 4 Multivariable model Adjusted Predictor of All Cause Death. Hazard Ratio
Stent implanted Body mass Index Age Sex Diabetes mellitus Hypercholesterolemia Hypertension Late comers (within 12-24h) Body mass Index *Treatment
1.116 0.765 1.096 0.843 0.997 0.952 1.036 1.212 1.011
P value
0.521 0.033 <0.001 0.397 0.987 0.784 0.843 0.018 0.965
95% Confidence interval Inferior
Superior
0.798 0.599 1.078 0.568 0.662 0.668 0.728 1.034 0.620
1.562 0.979 1.115 1.251 1.500 1.356 1.475 1.421 1.648
Adjusted Predictors of Cardiac Death Hazard Ratio
Stent implanted Body mass Index Age Sex Diabetes mellitus Hypercholesterolemia Hypertension Late comers (within 12-24h) Body mass Index *Treatment
0.919 0.773 1.106 0.823 1.080 0.965 1.208 1.164 1.177
P value
0.687 0.095 <0.001 0.425 0.754 0.873 0.401 0.133 0.591
95% Confidence interval Inferior
Superior
0.611 0.572 1.082 0.510 0.666 0.625 0.777 0.955 0.650
1.384 1.046 1.130 1.328 1.752 1.490 1.876 1.419 2.133
of cardiac death; and (3) no interaction was found between BMI and the type of stent implanted. Obesity is a widespread problem across all western countries,8,9 strongly associated with cardiovascular risk factors such as hypertension, DM, and dyslipidemia, and it is a wellestablished risk factor for the development of coronary artery disease and acute coronary syndromes.10,11 Nevertheless, an apparent paradoxical effect of BMI on the outcomes of patients with coronary artery disease, a phenomenon known as “obesity paradox,” has been reported: in patients who underwent PCI, BMI was inversely associated with worse outcomes, with obese and overweight participants having higher survival rates.12 Although the obesity paradox has been described for patients who underwent PCI for chronic total occlusion10 and for patients presenting with unstable angina or non–ST-elevation MI,13 whether BMI may impact the outcomes of patients with STEMI remains controversial. Some studies have shown the existence of an inverse relation between BMI and mortality in the STEMI setting.14–16 However, the protective BMI effect disappeared by correcting for confounders, thus weakening the hypothesis of a lower in-hospital17–19 or long-term20 mortality rate in the obese STEMI population. In our study, the prevalence of overweight and obesity in patients with STEMI was very high (72%), confirming obesity as an important European health problem. We found that BMI was an independent predictor of all-cause death, even after adjustment for potential confounding factors, but not of cardiac death. Age appeared instead as an independent predictor of both mortalities. Several possible
mechanisms may explain this phenomenon. A worse cardiovascular risk profile of obese patients (diabetes, hypertension, etc.) may be, for example, counterbalanced by their young age so that STEMI occurs early but with a lower cardiac mortality. The occurrence of STEMI in earlier stage in obese patients than in normal-weight patients has been already described.20 Young age may allow a more aggressive use of medications and procedures, a factor that may have a beneficial impact on cardiac mortality. Conversely, a better cardiovascular risk profile in the other BMI groups may be counterbalanced by advanced age: elderly patients exhibit poor clinical outcomes after acute MI, irrespective of the reperfusion technique, likely related to a higher risk of noncardiac death due to chronic diseases.21,22 This finding could eventually result in a lack of cardiac mortality difference among groups when confounding factors are taken into account. It has been shown that underweight patients with low BMI (<18.5 kg/m2) may have a worse prognosis after MI, due to cardiac cachexia, malnutrition, or depression.23 In our study, underweight patients were analyzed together within the normalBMI group because of the low prevalence of this condition (10 patients, 0.7%). However, potential confounding by cachexia in our analysis cannot be excluded. It is worth noting that our study included patients with STEMI who underwent different reperfusion therapies (primary PCI, rescue PCI, PCI after successful thrombolysis, and late comers within 12 to 24 hours) and that at Cox regression, late clinical presentation on admission also had an impact on mortality rates. In our study, obese patients presented more often earlier than other BMI groups (p = 0.043), which also may have influenced the long-term outcomes. Eventually, we look at the possible relation between BMI and the randomization effect of the stent implanted, as the long-term results from the EXAMINATION trial showed the superiority of the everolimus-eluting stent over the baremetal stent with respect to both patient-oriented composite end-point and device-oriented composite end-point, mainly driven by reductions in the rates of all-cause death, cardiac death, and target lesion revascularization.2 In our analysis, the inverse relation between BMI and mortality rate was maintained irrespective of the type of stent implanted, without any differences in terms of the number and the length of the stent implanted among the groups. The present study is a post hoc analysis of the EXAMINATION trial, not powered for clinical end points. BMI was calculated at the time of the index procedure but was not reevaluated during the follow-up. However, it has been shown that, in obese patients, there is only a small decrease in body weight in the first year after MI.24 Our analysis does not take into account the difference between peripheral versus abdominal obesity or waist circumference. Previous reports, however, showed that BMI maintained its predictive role on mortality irrespective of the obesity type.25 Finally, albeit small (5%), a potentially significant number of patients were excluded from the analysis because of missing data in the BMI calculation. No differences were shown in terms of end points between those patients included in and those excluded from our analysis (see the supplementary material). In patients presenting with STEMI who underwent PCI, the overall longterm mortality decreased as BMI increased, confirming a paradoxical obesity protection, even after adjustment for
Coronary Artery Disease/Impact of BMI on Mortality
confounding factors. BMI can be considered as an index of protective genetics and epigenetic factors decreasing the obese patients’ vulnerability to cardiovascular disease. However, the lack of impact of BMI on cardiac mortality suggests that multiple factors such as age or the time of presentation might be also implicated. Future studies are still needed to further clarify the BMI protection role. Perspectives Competency in medical knowledge: Obesity has a paradoxical protection role in overall mortality in patients presenting with STEMI who underwent PCI. Competency in patients care: The lack of a protective role in cardiac mortality when correcting for confounders suggests that other factors such as age or the time of clinical presentation might be also implicated.
7.
8. 9. 10.
11. 12.
Translational outlook: Further research is required to better understand this phenomenon and to better identify highmortality risk patients with STEMI, which may allow a more aggressive lifestyle and therapeutic intervention for secondary prevention after acute MI. Disclosures The authors report no relation with industry or other disclosures.
13.
14. 15.
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percutaneous coronary intervention: insights from the examination trial. Int J Cardiol 2015;179:73–78. 23. Knudtson MD, Klein BE, Klein R, Shankar A. Association with weight loss and subsequent mortality risk. Ann Epidemiol 2005;15:483– 491. 24. Fadl YY, Krumholz HM, Kosiborod M, Masoudi FA, Peterson PN, Reid KJ, Weintraub WS, Buchanan DM, Spertus JA. Predictors of weight
change in overweight patients with myocardial infarction. Am Heart J 2007;154:711–717. 25. Zeller M, Steg PG, Ravisy J, Lorgis L, Laurent Y, Sicard P, JaninManificat L, Beer JC, Makki H, Lagrost AC, Rochette L, Cottin Y, RICO Survey Working Group. Relation between Body Mass Index, waist circumference, and death after acute myocardial infarction. Circulation 2008;118:482–490.