Impact of Body Composition Indices on Ten-year Mortality After Revascularization of Complex Coronary Artery Disease (From the Syntax Extended Survival Trial)

Numerous studies have demonstrated a paradoxical association between higher baseline body mass index (BMI) and lower long-term mortality risk after coronary revascularization, known as the “obesity paradox”, possibly relying on the single use of BMI. The current study is a post-hoc analysis of the SYNTAX Extended Survival (SYNTAXES) trial, which is the extended follow-up of the SYNTAX trial comparing percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) in patients with left-main coronary artery disease (LMCAD) or three-vessel disease (3VD). Patients were stratified according to baseline BMI and/or waist circumference (WC). Out of 1,800 patients, 1,799 (99.9%) and 1,587 (88.2%) had available baseline BMI and WC data, respectively. Of those, 1,327 (73.8%) patients had High BMI (≥25 kg/m2), whereas 705 (44.4%) patients had High WC (>102 cm for men or >88 cm for women). When stratified by both BMI and WC, 10-year mortality risk was significantly higher in patients with Low BMI/Low WC (adjusted hazard ratio [HR]: 1.65; 95% confidence interval [CI]: 1.09 to 2.51), Low BMI/ High WC (adjusted HR: 2.74; 95% CI: 1.12 to 6.69), or High BMI/High WC (adjusted HR: 1.59; 95% CI: 1.11 to 2.27) compared to those with High BMI/Low WC. In conclusion, the “obesity paradox” following coronary revascularization would be driven by low long-term mortality risk of the High BMI/Low WC group. Body composition should be assessed by the combination of BMI and WC in the appropriate evaluation of the long-term risk of obesity in patients with LMCAD or 3VD. Numerous studies have demonstrated a paradoxical association between higher baseline body mass index (BMI) and lower long-term mortality risk after coronary revascularization, known as the “obesity paradox”, possibly relying on the single use of BMI. The current study is a post-hoc analysis of the SYNTAX Extended Survival (SYNTAXES) trial, which is the extended follow-up of the SYNTAX trial comparing percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) in patients with left-main coronary artery disease (LMCAD) or three-vessel disease (3VD). Patients were stratified according to baseline BMI and/or waist circumference (WC). Out of 1,800 patients, 1,799 (99.9%) and 1,587 (88.2%) had available baseline BMI and WC data, respectively. Of those, 1,327 (73.8%) patients had High BMI (≥25 kg/m2), whereas 705 (44.4%) patients had High WC (>102 cm for men or >88 cm for women). When stratified by both BMI and WC, 10-year mortality risk was significantly higher in patients with Low BMI/Low WC (adjusted hazard ratio [HR]: 1.65; 95% confidence interval [CI]: 1.09 to 2.51), Low BMI/ High WC (adjusted HR: 2.74; 95% CI: 1.12 to 6.69), or High BMI/High WC (adjusted HR: 1.59; 95% CI: 1.11 to 2.27) compared to those with High BMI/Low WC. In conclusion, the “obesity paradox” following coronary revascularization would be driven by low long-term mortality risk of the High BMI/Low WC group. Body composition should be assessed by the combination of BMI and WC in the appropriate evaluation of the long-term risk of obesity in patients with LMCAD or 3VD. Obesity is a major health problem worldwide and contributes to progression of cardiovascular disease, including coronary artery disease (CAD), leading to poor prognosis.1Pischon T Boeing H Hoffmann K Bergmann M Schulze MB Overvad K van der Schouw YT Spencer E Moons KG Tjonneland A Halkjaer J Jensen MK Stegger J Clavel-Chapelon F Boutron-Ruault MC Chajes V Linseisen J Kaaks R Trichopoulou A Trichopoulos D Bamia C Sieri S Palli D Tumino R Vineis P Panico S Peeters PH May AM Bueno-de-Mesquita HB van Duijnhoven FJ Hallmans G Weinehall L Manjer J Hedblad B Lund E Agudo A Arriola L Barricarte A Navarro C Martinez C Quiros JR Key T Bingham S Khaw KT Boffetta P Jenab M Ferrari P Riboli E. General and abdominal adiposity and risk of death in Europe.N Engl J Med. 2008; 359: 2105-2120Crossref PubMed Scopus (1437) Google Scholar Nevertheless, numerous studies have demonstrated in patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) a paradoxical association between high baseline body mass index (BMI) and a low mortality risk, the so-called “obesity paradox”.2Lavie CJ McAuley PA Church TS Milani RV Blair SN. Obesity and cardiovascular diseases: implications regarding fitness, fatness, and severity in the obesity paradox.J Am Coll Cardiol. 2014; 63: 1345-1354Crossref PubMed Scopus (379) Google Scholar, 3Gruberg L Weissman NJ Waksman R Fuchs S Deible R Pinnow EE Ahmed LM Kent KM Pichard AD Suddath WO Satler LF Lindsay Jr., J The impact of obesity on the short-term and long-term outcomes after percutaneous coronary intervention: the obesity paradox?.J Am Coll Cardiol. 2002; 39: 578-584Crossref PubMed Scopus (470) Google Scholar, 4Schwann TA Ramia PS Engoren MC Bonnell MR Goodwin M Monroe I Habib RH. Evidence and temporality of the obesity paradox in coronary bypass surgery: an analysis of cause-specific mortality.Eur J Cardiothorac Surg. 2018; 54: 896-903Crossref PubMed Scopus (4) Google Scholar, 5Ono M Chichareon P Tomaniak M Kawashima H Takahashi K Kogame N Modolo R Hara H Gao C Wang R Walsh S Suryapranata H da Silva PC Cotton J Koning R Akin I Rensing B Garg S Wykrzykowska JJ Piek JJ Jüni P Hamm C Steg PG Valgimigli M Windecker S Storey RF Onuma Y Vranckx P Serruys PW. The association of body mass index with long-term clinical outcomes after ticagrelor monotherapy following abbreviated dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: a prespecified sub-analysis of the GLOBAL LEADERS Trial.Clin Res Cardiol. 2020; 109: 1125-1139PubMed Google Scholar, 6Romero-Corral A Montori VM Somers VK Korinek J Thomas RJ Allison TG Mookadam F Lopez-Jimenez F. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies.Lancet. 2006; 368: 666-678Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar Although the exact biological and prognostic significance of the “obesity paradox” remains unclear thus far, one major hypothesis is that BMI itself would be a poor and indirect indicator of obesity-related cardiovascular risk since it does not necessarily reflect total body adiposity.7Iliodromiti S Celis-Morales CA Lyall DM Anderson J Gray SR Mackay DF Nelson SM Welsh P Pell JP Gill JMR Sattar N The impact of confounding on the associations of different adiposity measures with the incidence of cardiovascular disease: a cohort study of 296 535 adults of white European descent.Eur Heart J. 2018; 39: 1514-1520Crossref PubMed Scopus (78) Google Scholar Therefore, to combine BMI with other body composition indices such as waist circumference (WC) may achieve better predictive performance than single use of BMI, and may provide insights into the obesity paradox. The aim of the present subgroup analysis of the SYNTAX Extended Survival (SYNTAXES) study is to investigate the impact of body composition on very long-term clinical outcomes by using BMI and WC as two different anthropomorphic indices in patients with severe CAD who underwent PCI or CABG. The present study is a post-hoc subgroup analysis of the SYNTAXES study (NCT03417050), which was an investigator-driven extended 10-year follow-up of the SYNTAX trial (NCT00114972) beyond its original final follow-up of 5 years.8Serruys PW Morice MC Kappetein AP Colombo A Holmes DR Mack MJ Ståhle E Feldman TE van den Brand M Bass EJ Van Dyck N Leadley K Dawkins KD Mohr FW. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease.N Engl J Med. 2009; 360: 961-972Crossref PubMed Scopus (3050) Google Scholar,9Mohr FW Morice MC Kappetein AP Feldman TE Ståhle E Colombo A Mack MJ Holmes Jr., DR Morel MA Van Dyck N Houle VM Dawkins KD Serruys PW Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial.Lancet. 2013; 381: 629-638Abstract Full Text Full Text PDF PubMed Scopus (1138) Google Scholar In brief, the SYNTAX trial was a multicenter, randomized controlled trial done in 85 hospitals across 18 North American and European countries. A total of 1,800 patients with de novo three-vessel disease (3VD) and/or left main CAD (LMCAD), who were deemed eligible for both PCI and CABG based on clinical judgement and the consensus of a Heart Team, were enrolled and randomized in a 1:1 fashion either to receive PCI (n = 903) with a uniform use of TAXUS Express paclitaxel-drug eluting stents (Boston Scientific Corporation, Marlborough, MA, USA) or CABG (n = 897). Patients who had only one of the two revascularization options were excluded from randomization and were entered into nested registries for PCI or CABG. The main result of the SYNTAXES study has been already reported.10Thuijs D Kappetein AP Serruys PW Mohr FW Morice MC Mack MJ Holmes Jr., DR Curzen N Davierwala P Noack T Milojevic M Dawkins KD da Costa BR Jüni P Head SJ Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.Lancet. 2019; 394: 1325-1334Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar Both SYNTAX and SYNTAXES trials were approved by the ethics committees at each investigating center, and all patients provided their written informed consent prior to participation in the SYNTAX trial. Follow-up was performed in accordance with local law and regulations of each participating institution and complied with the Declaration of Helsinki. Both BMI and WC measurements were collected at the time of randomization, prior to the index procedure. The patient's baseline BMI was calculated as weight in kilograms divided by height in meters squared. Patients were stratified according to their baseline BMI; Low BMI (<25 kg/m2) and High BMI (≥25 kg/m2) on the basis of World Health Organization and National Institutes of Health guidelines,11Jensen MD Ryan DH Apovian CM RF CM CA J TA for the of and obesity in a of the American of Heart Association on and The Obesity Am Coll Cardiol. 2014; 63: PubMed Scopus Google Scholar in which patients with BMI were as to kg/m2) or The patient's baseline WC was according to the of the National MJ AP Serruys PW Morice MC Y Van G G F Leadley K Dawkins KD Kappetein versus stents at in SYNTAX patients with or Surg. Full Text Full Text PDF PubMed Scopus Google Scholar in which WC was at the of the of the Patients were stratified according to their baseline WC at the time of Low WC cm for men or cm for and High WC (>102 cm for men or >88 cm for MD Ryan DH Apovian CM RF CM CA J TA for the of and obesity in a of the American of Heart Association on and The Obesity Am Coll Cardiol. 2014; 63: PubMed Scopus Google MJ AP Serruys PW Morice MC Y Van G G F Leadley K Dawkins KD Kappetein versus stents at in SYNTAX patients with or Surg. Full Text Full Text PDF PubMed Scopus Google Scholar patients were divided into according to both baseline BMI and baseline Low BMI/Low WC, Low BMI/High WC, High BMI/Low WC, and High BMI/High WC and were in an and The of the present study is death at was by using review and death Patients with were in the analysis and at the time of to or at 5 not in the SYNTAXES study for 10-year extended follow-up total of 5 patients in as and and compared using the as and and compared using or exact as is to the of events and was performed to the between A was between BMI and WC, and the was to the between BMI and WC. 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When stratified by both BMI and WC, and patients were as Low BMI/Low WC, Low BMI/High WC, High BMI/Low WC, and High BMI/High WC, The baseline in patients stratified by the combination of BMI and WC in and When compared to patients with High BMI/Low WC, patients with High BMI/High WC were had a higher of as as and had higher and had lower and had higher and had lower of had lower of and and was in of between patients with High BMI/Low WC and those with High BMI/High in patients stratified by BMI and = = = = mass index circumference artery LMCAD of total of coronary at antiplatelet therapy as or coronary artery bypass left main coronary artery left percutaneous coronary between PCI with and three-vessel in a as or coronary artery bypass left main coronary artery left percutaneous coronary between PCI with and three-vessel The of BMI and WC is in was a between BMI and WC The of the 10-year were to the incidence of death was significantly lower in patients with High BMI compared with those with low BMI, after was between and In patients with High WC had a significantly higher of death at compared with those with Low WC. The mortality risk in High WC Low WC was after and a WC was an of 10-year mortality in whereas BMI was not with the mortality risk hazard ratio for mortality at and obesity randomization or current disease, disease, disease, left clinical or of revascularization, disease or and SYNTAX as in BMI Low WC Low cm randomization or current disease, disease, disease, left clinical or of revascularization, disease or and SYNTAX as in in a When patients were divided into by both BMI and WC, patients with High BMI/Low WC the of death at by those with High BMI/High WC Low BMI/Low WC and Low BMI/High WC for the of death at were significantly higher in patients with Low BMI/Low WC, Low BMI/High WC, or High BMI/High WC compared to those with High BMI/Low WC 5 and the in the including different the of the The of risk for death at demonstrated that patients with higher BMI lower WC had lower mortality risk, and in patients with lower BMI higher WC had higher mortality risk of death at in HR: hazard CI: confidence as in between BMI and WC in the risk of 10-year In the of risk for mortality at the of BMI and WC Patients with higher BMI lower WC of the had lower mortality risk and on the patients with lower BMI higher WC left of the had higher mortality risk at When stratified by of BMI or kg/m2) and WC or cm in men or or >88 cm in patients with High BMI/Low WC had the risk of death at whereas the risk was significantly higher in patients with Low BMI/Low WC, Low BMI/High WC, or High BMI/High WC. The in as in and When stratified by revascularization were either in PCI or CABG and The according to BMI or to or with combination of WC in and When compared to patients with low WC, patients with high WC had significantly higher of death at were in death those In BMI had a with WC BMI and WC and associations with mortality at When stratified by both BMI and WC, patients with High BMI/Low WC had the 10-year mortality which to the of High BMI be that the High BMI/Low WC patients have body mass including and than In patients with High BMI/Low WC were were on and had significantly lower of and compared to those with High BMI/High WC that the High BMI/High WC patients may be the with including and possibly to the outcomes compared to High BMI/Low WC AP de R of body in may provide obesity-related health 2019; Full Text Full Text PDF PubMed Scopus Google Scholar that was with in BMI from weight in patients undergoing N D R G S M A R R J P N V J impact of in patients undergoing percutaneous coronary intervention according to 2020; PubMed Scopus Google Scholar and in the all BMI the risk of major events was significantly higher in those with the of the obesity only by BMI. In the present the of WC was with an 10-year mortality risk, which was in with T K de D C AM M L C Y L Thomas R Somers VK Lopez-Jimenez F. obesity and in with coronary artery disease: a systematic review of the and analysis with Am Coll Cardiol. PubMed Scopus Google Scholar that WC has a better prognostic performance than BMI in CAD patients with Low BMI/Low WC had a significantly higher mortality at compared to those with High BMI/Low WC 5 and is that those and patients, as by higher higher of and higher in the compared to those with High BMI/Low WC Therefore, only one index was WC would not be to patients with a significantly higher 10-year mortality risk Low from the Therefore, for risk the use of BMI and WC other body composition should be in patients with T Boeing H Hoffmann K Bergmann M Schulze MB Overvad K van der Schouw YT Spencer E Moons KG Tjonneland A Halkjaer J Jensen MK Stegger J Clavel-Chapelon F Boutron-Ruault MC Chajes V Linseisen J Kaaks R Trichopoulou A Trichopoulos D Bamia C Sieri S Palli D Tumino R Vineis P Panico S Peeters PH May AM Bueno-de-Mesquita HB van Duijnhoven FJ Hallmans G Weinehall L Manjer J Hedblad B Lund E Agudo A Arriola L Barricarte A Navarro C Martinez C Quiros JR Key T Bingham S Khaw KT Boffetta P Jenab M Ferrari P Riboli E. General and abdominal adiposity and risk of death in Europe.N Engl J Med. 2008; 359: 2105-2120Crossref PubMed Scopus (1437) Google MD Ryan DH Apovian CM RF CM CA J TA for the of and obesity in a of the American of Heart Association on and The Obesity Am Coll Cardiol. 2014; 63: PubMed Scopus Google Scholar A of studies have that CAD patients had the mortality risk BMI CJ McAuley PA Church TS Milani RV Blair SN. Obesity and cardiovascular diseases: implications regarding fitness, fatness, and severity in the obesity paradox.J Am Coll Cardiol. 2014; 63: 1345-1354Crossref PubMed Scopus (379) Google Scholar, 3Gruberg L Weissman NJ Waksman R Fuchs S Deible R Pinnow EE Ahmed LM Kent KM Pichard AD Suddath WO Satler LF Lindsay Jr., J The impact of obesity on the short-term and long-term outcomes after percutaneous coronary intervention: the obesity paradox?.J Am Coll Cardiol. 2002; 39: 578-584Crossref PubMed Scopus (470) Google Scholar, 4Schwann TA Ramia PS Engoren MC Bonnell MR Goodwin M Monroe I Habib RH. Evidence and temporality of the obesity paradox in coronary bypass surgery: an analysis of cause-specific mortality.Eur J Cardiothorac Surg. 2018; 54: 896-903Crossref PubMed Scopus (4) Google Scholar, 5Ono M Chichareon P Tomaniak M Kawashima H Takahashi K Kogame N Modolo R Hara H Gao C Wang R Walsh S Suryapranata H da Silva PC Cotton J Koning R Akin I Rensing B Garg S Wykrzykowska JJ Piek JJ Jüni P Hamm C Steg PG Valgimigli M Windecker S Storey RF Onuma Y Vranckx P Serruys PW. The association of body mass index with long-term clinical outcomes after ticagrelor monotherapy following abbreviated dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: a prespecified sub-analysis of the GLOBAL LEADERS Trial.Clin Res Cardiol. 2020; 109: 1125-1139PubMed Google Scholar, 6Romero-Corral A Montori VM Somers VK Korinek J Thomas RJ Allison TG Mookadam F Lopez-Jimenez F. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies.Lancet. 2006; 368: 666-678Abstract Full Text Full Text PDF PubMed Scopus (1119) Google Scholar a in the current study in the current patients with High WC had significantly higher mortality risk than those with Low WC that the with low Nevertheless, regarding the “obesity that the obesity paradox was present body CJ A D SM Milani Body composition and coronary disease obesity or a Full Text Full Text PDF PubMed Scopus Google Scholar or mass CJ A A SM Milani Body composition and in coronary disease: impact of mass index and body in the Am Coll Cardiol. PubMed Scopus Google Scholar on of BMI in patients with that WC not BMI association with cardiovascular outcomes after Y of body mass index and waist circumference with clinical outcomes following percutaneous coronary 2018; PubMed Scopus Google Scholar it has been that the obesity paradox was present by using WC in patients who had J S M P The in from the for in and in Heart J. PubMed Scopus Google Scholar or J The obesity paradox in men versus with J Cardiol. Full Text Full Text PDF PubMed Scopus Google Scholar In to study with very long-term follow-up those studies had only which may not be to obesity-related risk In of and/or confounding may the G L Onuma Y Garg S S van T N P Windecker S Serruys of body mass index on the of patients percutaneous coronary with J Cardiol. Full Text Full Text PDF PubMed Scopus Google CJ D R MA weight and obesity health Am Coll Cardiol. 2018; PubMed Scopus Google Scholar as an of the of and weight may a in the mortality risk obesity patients, and may to the PA Church TS CJ V Blair SN. The obesity fitness, and coronary Full Text Full Text PDF PubMed Scopus Google of on the obesity paradox in patients with J Cardiol. Full Text Full Text PDF PubMed Scopus Google Scholar studies with other measurements of body confounding such as the impact of a long-term on be in the Although the combination of BMI with WC be as a in into patient's body long-term a and prognostic risk by two to body The present study has including the of a randomized trial with of uniform by very long-term follow-up and high follow-up of for 10-year of 1,799 of the present study that is a post-hoc analysis of the SYNTAXES Although a of confounding the of other confounding be the of patients in study was than in other studies the association of BMI with mortality risk in in the Low BMI/High WC not be to the to the the significance of be a of on a with CAD or who were at of Therefore, it would be to the obesity paradox those CAD patients with better relying on body K Serruys PW V SJ Kappetein AP Head SJ Onuma Y Kent DM van and of the SYNTAX to between percutaneous and in patients with coronary artery disease: analysis of the multicentre randomised controlled SYNTAXES trial with cohort 2020; Full Text Full Text PDF PubMed Scopus Google Scholar BMI and WC were only at the time of BMI and WC on weight or the which have an impact on the clinical CJ D R MA weight and obesity health Am Coll Cardiol. 2018; PubMed Scopus Google Scholar would have been to by BMI and WC at a time to the patient's death or at of the 10-year the not other measurements of body composition or dual RJ M Body composition and 2008; PubMed Scopus Google Scholar than BMI and WC, which may have been to provide insights into the current the single in the SYNTAXES study was mortality is the and for patients which and all the obesity-related such as and and is an appropriate of In conclusion, stratified by a combination of BMI and WC, risk of death at was significantly higher in patients with Low BMI/Low WC, Low BMI/ High WC, or High BMI/High WC compared to those with High BMI/Low WC. I is for that the and by all and data, the of the and to all Serruys and Onuma the and and to all J. J. and Davierwala the and and to of the Noack and data, the and to and Takahashi and to of the Wykrzykowska and J. Piek and to of the and and to of the The the and participating in the SYNTAX and SYNTAXES Serruys from and the Hara a for from and a from for the Piek and from the Morice is a of and the Head to as of the Kappetein to as of the other have of to with with with with with with