Author + information
- Received November 1, 2010
- Revision received July 26, 2011
- Accepted September 3, 2011
- Published online February 1, 2012.
- Ibrahim Akin, MD⁎,
- Ralph Tölg, MD†,
- Matthias Hochadel, PhD‡,
- Martin W. Bergmann, MD§,
- Ahmed A. Khattab, MD, PhD∥,
- Steffen Schneider, PhD‡,
- Jochen Senges, MD, PhD‡,
- Karl-Heinz Kuck, MD, PhD§,
- Gert Richardt, MD, PhD†,
- Christoph A. Nienaber, MD, PhD⁎,⁎ (, )
- DES.DE (German Drug-Eluting Stent) Study Group
- ↵⁎Reprint requests and correspondence:
Dr. Christoph A. Nienaber, Department of Internal Medicine I, Divisions of Cardiology, Pulmonology, and Intensive Care Medicine, Heart Center Rostock, Rostock School of Medicine, Ernst-Heydemann-straβe 6, 18057 Rostock, Germany
Objectives The aim of this study was to compare clinical outcomes among unselected patients stratified in categories of body mass index, who underwent percutaneous coronary intervention (PCI) with either sirolimus-eluting or paclitaxel-eluting stents.
Background Overweight and obesity are often considered risk factors for cardiovascular events. However, recent studies have associated obesity with better outcomes after PCI with bare-metal stents. Data from routine clinical practice using drug-eluting stents (DES) focusing on this “obesity paradox” are not available.
Methods We used data from DES.DE (German Drug-Eluting Stent) registry to compare in-hospital and 1-year outcomes among unselected patients undergoing PCI with DES implantation. Primary endpoints were the rate of major adverse cardiac and cerebrovascular events (MACCE) (defined as the composite of death, myocardial infarction, and stroke) and target vessel revascularization (TVR).
Results Between October 2005 and 2006, 1,436 normal weight, 2,839 overweight, and 1,531 obese patients treated with DES were enrolled at 98 sites. Baseline clinical parameters were more severe in overweight and obese patients; 1-year follow-up comparison between groups revealed similar rates of all-cause death (3.3% vs. 2.4% vs. 2.4%; p = 0.17), MACCE (7.1% vs. 5.6% vs. 5.5%; p = 0.09), and TVR in survivors (10.9% vs. 11.7% vs. 11.6%; p = 0.56) in normal weight individuals compared with overweight or obese patients. Such results persisted after risk-adjustment for heterogeneous baseline characteristics of groups and were independent of the types of DES.
Conclusions DES.DE revealed no evidence of “obesity paradox” in a routine clinical practice using DES.
Obesity is associated with significant morbidity and mortality, and is increasingly prevalent and growing in western societies, with two-thirds of the population being classified as overweight or obese (1). Overweight and obese individuals are at greater risk to develop coronary artery disease, primarily because of obesity-related conditions, such as diabetes mellitus, hypertension, and dyslipidemia (2). Although the impact of obesity on clinical outcomes after percutaneous coronary intervention (PCI) with bare-metal stents (BMS) has been investigated by several studies, the issue remains complex and controversial (3–7). Indeed, several studies have reported better clinical outcomes in overweight and obese subjects after PCI compared with normal and underweight subjects, an interaction termed “obesity paradox” (3–7). Our current analysis compares clinical outcomes after drug-eluting stent (DES) between normal weight, overweight, and obese patients in routine clinical practice followed ≥1 year in the large prospective multicenter DES.DE (German Drug-Eluting Stent) registry.
The DES.DE registry design has been previously published (8). Briefly, the prospective multicenter German DES.DE registry was initiated in October 2005 as an observational registry by Deutsche Gesellschaft für Kardiologie (DGK, German Cardiac Society), Bundesverband Niedergelassener Kardiologen (BNK, German Society of Cardiologists in Private Practice) and Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte (ALKK, The Working Group of Leading Hospital Cardiologists) to analyze and evaluate the therapeutic principle of DES under routine clinical practice conditions in the context of the German Health System. Drug-eluting stents in DES.DE had to meet certain quality criteria constituted and confirmed by the DES.DE steering committee and were adopted from both European Society of Cardiology and American College of Cardiology/American Heart Association PCI guideline criteria for DES (9,10). In phase I of the registry (October 2005 to October 2006), only the 2 Food and Drug Administration–approved DES, Taxus, and Cypher, met all quality criteria of the registry. The interventional strategy, including choice of stent, use of intravascular ultrasound, and the choice of periprocedural adjunctive therapy, was at the discretion of the interventional operator regardless of clinical setting.
Data collection and follow-up
Data were collected via Internet platform by the Institut für Klinische Kardiologische Forschung (IKKF, Institute for Clinical Research) of the German Cardiac Society. The European Cardiology Audit and Registration Standard (CARDS) was adapted for both patient and lesion data. Written informed consent for processing of anonymous data at the Institut für Herzinfarktforschung (IHF, Heart Centre Ludwigshafen) and IKKF was required; both clinical and angiographic characteristics were collected at IKKF. Quantitative coronary angiography was performed on digitally stored pre- and post-intervention angiograms using the program installed on all catheterization laboratory–based workstations. Paper-based clinical follow-up and external telephone interviews by an independent contract research organization were performed at 3, 6, 9, and 12 months after initial stent placement. Relevant events and randomly selected angiograms were forwarded to 2 independent critical event committees for adjudication of stent thrombosis and validity (Online Appendix).
According to the World Health Organization and National Heart, Lung, and Blood Institute, the patient population was divided into normal weight (body mass index [BMI]: 18.5 to 24.9 kg/m2), overweight (BMI: 25 to 30 kg/m2), and obese groups (>30 kg/m2) (11,12). Primary objectives of the current survey on patients in DES.DE were prespecified as the occurrence of target-vessel revascularization (TVR) and major adverse cardiac and cerebrovascular events (MACCE) (defined as the composite of cardiac and noncardiac death, myocardial infarction [MI], and stroke). Myocardial infarction was either defined as ST-segment elevation myocardial infarction (STEMI) (ST-segment elevation ≥1 mm in 2 or more standard adjacent leads or ≥2 mm in 2 or more contiguous precordial leads, development of new left bundle branch block) or non–ST-segment elevation myocardial infarction (NSTEMI) (pathological increase of cardiac-specific enzymes with creatine kinase-myocardial band >1.5 times the normal limit, troponin T or I >99th percentile of the normal value). Acute coronary syndrome (ACS) was defined as STEMI, NSTEMI, or unstable angina according to the European Society of Cardiology or American College of Cardiology/American Heart Association guidelines (9,10). TVR includes repeat procedures, either PCI or coronary artery bypass graft (CABG), in the target vessel. In a number of major adverse cardiac events (MACE) definitions, different types of death (either cardiac or total death rate) and revascularization parameters, such as TVR have been used. Because the use of different definitions of MACE can cause confusion when comparing rates between trials, the steering committee decided to use only MACCE as defined in the previous text. Patients in the DES.DE registry were discouraged from undergoing routine angiography for follow-up; therefore, all reinterventions can be counted as clinically driven. Stent thrombosis was classified according to the definition proposed by the Academic Research Consortium (ARC) (13). Bleeding complications were categorized according to the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) classification; they were considered as major in case of severe or moderate bleeding, whereas they were considered minor in case of mild forms (14). Contrast-induced transient renal failure requiring single dialysis during index hospitalization was listed as an adverse event.
Statistical analysis was performed using the SAS statistical package, version 9.1 (Cary, North Carolina). Demographic characteristics, pre-existing risk factors, procedure-related variables, and 1-year outcomes were summarized using mean and standard deviation for continuous variables, and frequency and percentage for categorical variables. Trends in baseline, procedural, and angiographic characteristics and in-hospital and follow-up data were assessed between normal weight, overweight, and obese patients by Cochran-Armitage test, whereas continuous variables were compared by 2-tailed Jonckheere-Terpstra test. Values of p < 0.05 were considered significant and were the result of 2-tailed tests. One-year event-free survival rates for MACCE and TVR were demonstrated by Kaplan-Meier curves and compared by log-rank test. The effect of BMI (per increase of 5 kg/m2) on MACCE during the follow-up period was evaluated by using multiple Cox regression to adjust for confounding parameters. The effect on TVR within 12 months was evaluated using multiple logistic regression, excluding patients who had died during follow-up, in order to account for the differential impact of risk factors between MACCE and TVR (8). The following variables were entered into a backward selection model for MACCE using a p value for removal of 0.05: female gender, age ≥75 years, BMI elevation of 5 kg/m2, current smoker, renal insufficiency, previous CABG, peripheral arterial disease, STEMI, impaired left ventricular function (ejection fraction <40%), heart failure. Similarly, in the multivariable model for TVR the following variables were entered: previous PCI, STEMI, unstable angina, impaired left ventricular function function (ejection fraction <40%), vessel diameter (<3 mm), and type C lesion.
Baseline characteristics and procedural outcomes
Between October 2005 and October 2006, 5,806 patients treated either with paclitaxel-eluting stents (PES) or sirolimus-eluting stents (SES) were enrolled at 98 sites in the prospective DES.DE registry. Analysis was based on 2,884 patients (49.7%) who received a PES, on 2,264 (39.0%) who were treated with SES, and on 658 patients (11.4%) who received both a PES and SES. Among these, 1,436 patients (24.7%) were classified as normal weight, 2,839 (48.9%) as overweight, and 1,531 (26.4%) as obese. Mean age was 65.2 ± 10.4 years, with older patients in the normal weight category as compared with overweight or obese groups (66.1 ± 11.0 vs. 65.5 ± 10.1 vs. 63.7 ± 10.7; p < 0.0001). Additionally, both overweight and obese subsets suffered from more severe comorbidity index with diabetes mellitus (21.5% vs. 29.2% vs. 46.9%; p < 0.0001). Conversely, smoking was less frequent in the obese and overweight groups (26.3% vs. 20.4% vs. 21.4%; p < 0.001) (Table 1).
Approximately one-third of all patients were admitted with ACS with no difference in the distribution of STEMI, NSTEMI, and unstable angina among subsets (Table 2); baseline demographics and descriptive data, such as previous CABG, previous PCI, and mild impairment of left ventricular function were also similar (Table 1).
Overall, 7,701 stents were implanted in 6,479 lesions of 5,806 patients (1.32 stents/patient and 1.19 stents/lesion) with a procedural success rate of 98.6%; stents were deployed in all PCI cases. The number of DES, both per patient and per lesion, was equally distributed among groups, with 1.31 stents/patient and 1.18 stents/lesion in the normal-weight subset, 1.33 stents/patient and 1.18 stents/lesion with overweight, and 1.33 stents/patient and 1.21 stents/lesion in obese patients, respectively. The diameter of stents used in obese patients was larger than that used for patients in the overweight and normal weight groups (Table 3).
The overall in-hospital MACCE rate was 2.4% in the normal weight, 2.2% in the overweight, and 1.6% in the obese groups (p = 0.10). Similarly, rates for MI and stroke, as well as for severe bleeding complications, were always low, with no differences between subsets. Conversely, in-hospital death rate trended slightly higher, with normal weight in 0.8% versus 0.5% and 0.3% (p = 0.05) (Table 4). Antithrombotic medication at discharge was similar, with dual antiplatelet therapy in over 99%, and combined dual antithrombotic and anticoagulation therapy in 2.7%.
Complete clinical outcomes after a mean follow-up of 12.4 months were available in 97.1% of patients (Table 4); in 2.9%, the 1-year outcomes were not completed. No significant differences were noted between groups with respect to the incidence of MACCE-free survival and TVR-free survival (Figs 1 and 2)⇓. Similarly, no differences were noted in the rates of MI, stroke, and definite stent thrombosis (Table 4). Yet, compared with the obese and overweight groups, patients with normal weight had significantly higher rates of minor bleeding (57.2% versus 46.3% and 45.7%; p < 0.001) although antiplatelet therapy was similar. Subgroup analysis between outcomes after using SES or PES revealed no differences between both DES for primary endpoints MACCE and TVR, regardless of the BMI. With minor differences in baseline characteristics, subsequent multivariable analysis revealed no impact of overweight and obesity on primary endpoints at 1 year. After risk adjustment, rates for both MACCE and TVR remained similar between groups (Figs. 3 and 4)⇓⇓.
With growing recognition that obesity adversely influences traditional cardiovascular risk factors, such as hypertension, elevated plasma lipids, diabetes mellitus and metabolic syndrome, the American Heart Association defines obesity as a strong predictor for coronary artery disease (15). Increasing insulin resistance, enhanced free fatty acid turnover, elevated basal sympathetic tone, hypercoagulable blood, and promotion of systemic inflammation are pathophysiological changes by which obesity promotes the risk for coronary artery disease (16). Although obesity has traditionally been identified as independent marker for coronary events, recent studies have described an “obesity paradox” in patients undergoing PCI or CABG, reporting similar or lower post-operative mortality in obese patients compared with patients with normal weight (3–7). This so-called paradox has even been extended to conditions such as ACS and heart failure (17,18). Gruberg et al. (5) categorized 9,633 consecutive patients undergoing PCI in groups with BMI <24.9 kg/m2 (n = 1,923), BMI = 25 to 30 kg/m2 (n = 4,813), and BMI >30 kg/m2 (n = 2,897); despite similar angiographic success rates, normal BMI patients had a higher incidence of major in-hospital complications, including cardiac death (1.0% vs. 0.7% vs. 0.4%; p = 0.001) than overweight and obese patients. At 1 year, mortality was significantly higher in normal BMI patients compared with overweight or obese patients, both for overall (10.6% vs. 5.7% vs. 4.9%; p < 0.0001) and for cardiac mortality (4.8% vs. 3.3% vs. 2.5%; p < 0.0001), whereas rates of myocardial infarction and revascularization were similar despite a better baseline clinical profile with normal weight. A meta-analysis, including 250,152 patients with coronary artery disease and a mean follow-up of 3.8 years, suggested similar observations with a low BMI (<20 kg/m2) associated with an increased relative risk (RR) for overall mortality (RR: 1.37 [95% confidence interval (CI): 1.32 to 1.43]), and cardiovascular mortality (RR: 1.45 [95% CI: 1.16 to 1.81]), whereas overweight patients (BMI: 25 to 29.9 kg/m2) enjoyed a low risk for both overall (RR: 0.87 [95% CI: 0.81 to 0.94] and cardiac mortality (RR: 0.88 [95% CI: 0.75 to 1.02]) (19). Such findings were mirrored in registries with BMI of 27.5 to 30 kg/m2 leading to reduced risk of dying at 5 years (hazard ratio: 0.59, 95% CI: 0.39 to 0.90; p = 0.014) (20), underlining a protective notion of obesity. Other trials not supporting any protective notion of obesity are in fact corroborated by randomized data from TAXUS-IV (TAXUS IV-SR: Treatment of De Novo Coronary Disease Using a Single Paclitaxel-Eluting Stent) where overweight (BMI: 25 to 30 kg/m2) and obese (BMI >30 kg/m2) patients revealed higher 9-month restenosis rates (29.2% and 30.5%) than patients with normal weight (9.3%; p = 0.01) and higher MACE rates (20.8% and 23.2% vs. 11.1%; p = 0.02) with BMS, whereas no differences in restenosis and MACE with PES were noted at 1 year (21). Similar findings were reported in ARTS II (Arterial Revascularization Therapies Study II) trial, with similar rates for MACE after receiving SES regardless of obesity (22).
Results from DES.DE are unique, considering the impact of BMI on clinical outcomes after DES implantation in routine clinical practice. Compared with overweight and obese patients, those with normal body weight had similar rates of all-cause mortality and MACCE as well as TVR, MI, stroke, and stent thrombosis even after risk adjustment. Although our data challenge the so-called obesity paradox, the concept may actually be a misnomer, or may in fact not exist at all. Overweight and obese patients are usually younger, with larger culprit vessel diameter than normal weight counterparts; their comorbidity index is usually higher without any differences in the extent of coronary artery disease. Moreover, it is well established that younger patients have better clinical outcomes after acute MI regardless of reperfusion modality (23,24). Additionally, the presence of comorbidities in obese and overweight patients usually led to more aggressive therapy of cardiovascular risk factors likely to improve outcomes despite obesity (23,24). The relationship of obesity to long-term survival is complex, probably characterized by a J- or U-shaped curve, with increasing mortality in the very lean or severely obese group (25,26); however, when adjusted for smoking and concurrent illness, the relationship has always been linear (2,27,28). A low BMI may in fact be a marker of severe systemic illness, since low BMI is associated with a higher rate of noncardiac mortality (2,29). By defining the normal-weight group from 18.5 to 24.9 kg/m2, 16 extremely underweight patients were excluded because they were suffering from severe systemic illness. If patients with a BMI <18.5 kg/m2 were to be included, a significant difference in MACCE-free survival would emerge between groups (p = 0.04); a BMI of <25 kg/m2 (including the extremely underweight patients) would be associated with a MACCE-free survival of 90.2%, a BMI between 25 and 30 kg/m2 with 92%, and a BMI of >30 kg/m2 with 92.7% MACCE-free survival, respectively. No difference would be seen in TVR-free survival between groups (83.3% vs. 83.2% vs. 83.7%; p = 0.91).
Several prospective investigations have recently shown that subjects with BMI >25 kg/m2 were more likely to suffer from suboptimal platelet response to clopidogrel and aspirin treatment (30,31). Again, such findings could not be confirmed in the real-world setting of DES.DE, with similar rates of stent thrombosis in all subsets.
The present study suffers from the inherent limitation of an observational study. Potentially confounding variables such as physical inactivity, unintended weight loss, and socioeconomic factors were not analyzed, but may have influenced the results. Both severity of obesity were estimated by using the BMI as a momentum without any information on weight change. Apart from weight, both waist circumference and waist-to-hip ratio were unavailable; such alternative criteria for obesity may be more closely related to cardiovascular disease and death than BMI. Eventually any potential relation between obesity and survival may be lost the longer patients are followed. Yet, with extended follow-up, cumulative detrimental effect of obesity may even manifest as increased late mortality.
Data from DES.DE revealed no evidence of the “obesity paradox” in patients subjected to DES treatment in routine clinical practice with mortality, MI, stroke, stent thrombosis, MACCE, and TVR rates being independent of both BMI and choice of PES or SES. Prospective studies with long-term follow-up designed to confirm or refute the obesity paradox in the context of DES are required, focusing on fat distribution, central adiposity, temporal weight loss, and weight change.
For a complete list of investigators, please see the online version of this article.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- body mass index
- bare-metal stent(s)
- coronary artery bypass graft
- drug-eluting stent(s)
- major adverse cardiac and cerebrovascular event(s)
- major adverse cardiac event(s)
- myocardial infarction
- non–ST-segment elevation myocardial infarction
- percutaneous coronary intervention
- paclitaxel-eluting stent(s)
- relative risk
- sirolimus-eluting stent(s)
- ST-segment elevation myocardial infarction
- target vessel revascularization
- Received November 1, 2010.
- Revision received July 26, 2011.
- Accepted September 3, 2011.
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