RAUL A. BORRACCI1, 2, CARLOS A. INGINO2, JULIO MACIAS MIRANDA2
1Departamento de Cirugía Cardíaca, Hospital de Clínicas, Facultad de Medicina, Universidad de Buenos Aires, 2Departamento de Cardiología y Cirugía Cardíaca, ENERI-Sagrada Familia, Buenos Aires, Argentina
The relationship between higher body mass index (BMI), decreased morbidity and mortality is known as the “obesity paradox”, and has been described in cohorts of patients with hypertension, diabetes, heart failure, coronary and peripheral artery diseases, non-cardiac surgery, and end-stage renal disease. Here we investigated the relationship between BMI and short-term outcomes after adult cardiac surgery to explore the existence of an obesity paradoxical effect. A secondary objective was to perform an updated systematic review to further analyze the association between BMI and 30-day in-hospital mortality after cardiac surgery. A retrospective analysis was performed from a consecutive series of 1823 adult patients who underwent cardiac surgery, that were assigned to five BMI groups: normal weight (18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), class I obese (30-34.9 kg/m²), class II obese (35-39.9 kg/m²), and class III obese or morbidly obese (40-49.9 kg/m²). A systematic review search was performed including controlled trials and observational studies identified in MEDLINE, Embase, SCOPUS, and the Cochrane library (to the end of June 2017). In the present series, overweight and obese patients had similar or slightly lower in-hospital mortality rates after cardiac surgery compared with normal-weight individuals. Conversely, postoperative complication rates increased with higher BMI levels. Most studies included in the review showed that overweight and obese patients had at least the same mortality rate as normal-weight patients, or even a lower death risk. Pooled-data of the meta-analysis provided evidence on the association between higher BMI levels and a lower all-cause in-hospital mortality rate after cardiac surgery.
Key words: obesity, operative risk, cardiac surgery, meta-analysis
Asociación entre índice de masa corporal y resultados a corto plazo después de la cirugía cardíaca: estudio retrospectivo y metaanálisis. La relación entre mayor índice de masa corporal (IMC) y menor morbilidad y mortalidad se conoce como “paradoja de la obesidad”. Se ha descrito en cohortes de pacientes con hipertensión, diabetes, insuficiencia cardíaca, enfermedad coronaria y arterial periférica, cirugías no cardíacas y enfermedad renal en etapa terminal. Aquí se investigó la relación entre IMC y resultados a corto plazo después de cirugía cardíaca en adultos, y la manifestación de la paradoja de la obesidad. También se realizó una revisión sistemática sobre asociación entre IMC y mortalidad a 30 días de la cirugía cardíaca. Se hizo un análisis retrospectivo de una serie consecutiva de 1823 adultos con cirugía cardíaca, asignados a cinco grupos de IMC: peso normal (18.5-24.9 kg/m²), sobrepeso (25- 29.9 kg/m²), obesidad clase I (30-34.9 kg/m²), clase II (35-39.9 kg/m²), y clase III (40-49.9 kg/m²), y una búsqueda sistemática de ensayos controlados y estudios observacionales en MEDLINE, Embase, SCOPUS y Cochrane (hasta 30/6/2017). En la serie, las tasas de mortalidad hospitalaria fueron similares o ligeramente menores en pacientes con sobrepeso y obesidad comparados con aquellos de peso normal. Pero también las tasas de complicaciones postoperatorias aumentaron con el IMC. La mayoría de los estudios observacionales revisados mostraron que los pacientes con sobrepeso y obesidad tenían al menos similar tasa de mortalidad que aquellos con peso normal, o menor riesgo de muerte. Los datos combinados del metaanálisis evidenciaron asociación entre los niveles de IMC mayores y tasa de mortalidad hospitalaria más baja después de cirugía cardíaca.
Palabras clave: obesidad, riesgo operatorio, cirugía cardíaca, metaanálisis
Recibido: 8-I-2018 Aceptado: 30-V-2018
Dirección postal: Dr. Raúl A. Borracci, La Pampa 3030, 1428 Buenos Aires, Argentina
Obesity has been described as a risk factor for the development of coronary artery disease, stroke, cancer, renovascular disease, and other physical and psychological comorbidities1-5. Conversely, several other epidemiological and observational studies on different diseases have shown better outcomes and survival rates in overweight and obese patients than in those with normal body mass index (BMI)6. This counter-intuitive relationship between higher BMI and decreased morbidity and mortality is known as the “obesity paradox”7, and has been observed in patients with hypertension, diabetes, heart failure, coronary and peripheral artery diseases, non-cardiac surgery, and end-stage renal disease8-10. However, studies examining the association between obesity and adverse outcomes after cardiac surgery still remain controversial11-15. For instance, the EuroSCORE II model does not include BMI as a predictive variable for stratification of perioperative death risk16. Some studies have demonstrated that overweight and moderately obese patients have better early hospital outcomes in terms of mortality11, 12, 17, and a lower incidence of major adverse cardiac and cerebrovascular events12, 17, 18. Other studies have not found any clear protective effect of overweight and obesity on mortality or adverse events after cardiac surgery19-21; or they have even demonstrated a deleterious effect for sternal wound infection22-25, leg infection26, sternal dehiscence27, renal failure23, 28, atrial fibrillation26, 29, venous thromboembolism29, and pulmonary and gastrointestinal complications30. In general, studies with negative evidence for the “obesity paradox” have tended to include far fewer patients than reports with positive evidence, a difference possibly related to the power analysis of sample size. Nevertheless, outcomes from large samples may in turn exaggerate the clinical value of a statistical difference.
The aim of this study was to investigate the relationship between BMI and short-term outcomes after adult cardiac surgery and to explore the existence of an obesity paradoxical effect. A secondary objective was to perform an updated systematic review to further analyze the association between BMI and 30-day in-hospital mortality after cardiac surgery.
Materials and methods
A retrospective analysis was performed on prospectively collected data (ambispective design) from a consecutive series of 1823 adult patients who underwent different types of cardiac surgery at the Buenos Aires University Hospital and its associated clinics over a 6-year period (2011-2016). All types of on-pump and off-pump elective cardiac surgery were included, except transplantation and transcatheter aortic valve implantation. Baseline and operative data were prospectively collected in a clinical registry, which included the variables needed to estimate the operative risk mortality based on EuroSCORE II16. Additional information on other risk factors and comorbidities was added in the computerized database. In-hospital major postoperative complications (stroke, cardiac arrest, myocardial infarction, renal dialysis, permanent pacemaker implantation, ventricular arrhythmias, reoperation for bleeding, low cardiac output, sternal dehiscence, deep sternal wound infection or mediastinitis, sepsis, prolonged ventilation, and pneumonia), and in-hospital mortality were compared among various BMI groups after cardiac surgery. BMI was automatically recorded in the operation theatre before surgery. Postoperatively, patients were assigned to five BMI groups31: normal weight (18.5 to 24.9 kg/m.), overweight (25 to 29.9 kg/m.), class I obese (30 to 34.9 kg/m.), class II obese (35 to 39.9 kg/m.), and class III obese or morbidly obese (40 to 49.9 kg/m.). Underweight (BMI < 18.5 kg/m.) (n = 3) and class IV or “super obese” (BMI ≥ 50 kg/m.) (n = 1) groups were excluded from the study due to the low number of patients.
Baseline preoperative clinical variables and in-hospital outcome data were recorded and analyzed with the approval of the local Institutional Review Board which waived the need for a written informed consent.
The systematic review search strategy was performed using controlled trials and observational studies identified in MEDLINE, Embase, SCOPUS, and the Cochrane library (to the end of June 2017). Reference lists of primary studies, review articles, and previous meta-analyses were reviewed with no language, age or type of cardiac surgery restrictions. The inclusion criteria required studies to separately report mortality in normal, overweight and obese patients using traditional World Health Organization BMI categories. Studies comparing obese versus non-obese patients (i.e. normal and overweight patients grouped together), and studies published only in abstract form were excluded from the analysis. Articles were also excluded if the total number of deaths was < 3. Two reviewers (R.A.B. and C.A.I.) independently reviewed citations and performed data retrieval, and disagreements were resolved through consensus. No additional data were requested from the primary study authors. The primary endpoint was all-cause mortality. Odds ratios (OR) with 95% confidence intervals (95% CI) and forest plots were calculated with EPIDAT, Version 3.1 (Xunta de Galicia-PAHO/WHO) using fixed and random effect models. Heterogeneity among studies was examined using the c. test and the Higgins I. test (25%, 50%, and 75% I. values were interpreted as low, moderate, and high heterogeneity). A funnel plot was used as a graphical method to identify studies affecting heterogeneity, and the Begg test to assess publication bias.
Categorical data were expressed as absolute frequencies and percentages, and continuous variables as mean and standard deviation (SD). The Kolmogorov-Smirnov (K-S) goodness-of-fit test was used to analyze normal distributions. Univariate comparison of discrete variables was performed using c. or Yates’ corrected c. test. Analysis for linear trends in proportions for postoperative complications was done with c. test for trend. One-way analysis of variance (ANOVA) was used to compare more than two means and post hoc multiple comparisons were done with Tukey’s test assuming equal variances. The Snedecor F-test was used to assess variance equality. Observed-to-expected operative mortality ratios within groups was also calculated and compared with the c. test. A propensity-score analysis was used to adjust for preoperative and operative confounding factors in order to minimize baseline differences between the BMI groups. Characteristics independently associated with normal and overweight or obese patients after propensity-score matching were assessed in a multivariate binary logistic regression model with backward stepwise conditional method. Covariates used in the regression model included all the preoperative and operative variables, and final results were expressed as odds ratio (OR) with the associated 95% CI. Non-linear regression analysis and the corresponding coefficient of determination (R.) were used to find the best fit for postoperative complications and mortality rates between BMI groups. Statistical analysis was performed with IBM SPSS 23.0 Statistics (IBM Corporation, Armonk, NY). A 2-tailed p value ≤ 0.05 was considered statistically significant.
Classification and proportional distribution of patients based on preoperative BMI is shown in Table 1, where 22.7% (n = 413) was classified as obese, independently of class. For purpose analysis, all types of obesity were considered as a single group (aggregated BMI 30.0-49.9 kg/m.). Table 2 lists preoperative baseline characteristics of the BMI groups. Univariate analysis revealed younger age and higher rates of male sex and diabetes in overweight and obese patients compared with normal-weight individuals. Conversely, the normal-weight group showed higher rates of heart failure, pulmonary hypertension and heart valve endocarditis.
Distribution of operative variables and outcomes are shown in Table 3. Isolated coronary surgery and shorter cross-clamping time were more frequent in overweight and obese patients. Overall postoperative complications increased through BMI groups with a slight decrease in overweight patients (Table 3, Fig. 1). Postoperative ventricular arrhythmias were significantly more common in obese patients when complications were disaggregated.
In-hospital mortality rate was slightly higher in the normal-weight group than in the other BMI groups, though differences were not significant (normal versus overweight OR: 1.17, 95% CI: 0.70-1.95, p = 0.554; normal versus obese OR: 1.09, 95% CI: 0.59-2.00, p = 0.789) (Fig. 2). There was no statistical difference between observed and
expected mortality for each individual BMI group; nevertheless, the expected mortality risk according to EuroSCORE II was significantly different among BMI groups (ANOVA F = 2.98, p = 0.018; Tukey’s test p = 0.046 for post hoc comparison between normal and overweight groups), with the normal-weight group showing the highest expected risk.
After adjusting by propensity score, a total of 806 patients for normal versus overweight comparison and 460 patients for normal versus obese comparison showed no systematic differences in the distribution of covariates.
Differences in in-hospital mortality rates were preserved, and complications rates became similar after propensity score-matched normal versus overweight groups were compared (mortality rate 4.2% versus 3.5%, OR: 1.22, 95% CI: 0.59-2.52, p = 0.583, and complications 8.4% versus 8.4%, OR: 1.00, 95% CI: 0.61-1.64, p = 1.000). Conversely, when comparing normal versus obese groups, differences in in-hospital mortality and complications rates were preserved after propensity score matching (mortality rate 3.5% versus 2.2%, OR: 1.62, 95% CI: 0.52-5.03, p = 0.399, and complications 6.5% versus 11.7%, OR: 0.52, 95% CI: 0.27-1.01, p = 0.052).
Out of 4410 initial independent references obtained through various search strategies comprising cardiac surgery and obesity, 30 eligible cohort observational studies were identified and included in the meta-analysis11, 12, 17-19, 22, 29, 31-53. When the data from our study before and after propensity score matching were included, the final meta-analysis population comprised 451 300 patients for the normal/overweight comparison (32 studies), and 289 214 patients for the normal/obese comparison (20 studies). The meta-analysis demonstrated the obesity paradox. Compared with overweight patients, the random observed global OR was 0.71 (95% CI, 0.66-0.77) for normal-weight individuals (Fig. 3.a), whereas compared with obese patients, the random observed global OR was 0.73 (95% CI, 0.65-0.83) for normal-weight patients (Fig. 3.b). Funnel plots revealed no evidence of publication bias in both mortality comparisons (Begg test Z = 0.60, p = 0.549 for overweight versus normal groups, and Z = 0.29, p = 0.770 for obese versus normal groups). Between-study heterogeneity was statistically significant in the analysis of both overweight versus normal-weight patients (I. = 61.0%, Q = 62.0, p = 0.0008) and in obese versus normal-weight patients (I. = 74.4%, Q = 44.3, p = 0.0009).
The initial unadjusted comparison of in-hospital mortality rates after cardiac surgery between the different BMI groups revealed the incipient reverse J-shaped distribution described in the obesity paradoxical effect, with overweight and class I obese patients showing the lowest mortalities. Nevertheless, the higher mortality rate found in patients with normal BMI can be easily explained by a greater expected risk according to EuroSCORE II. This expected risk was significantly higher than that predicted for the
other BMI groups, and even the observed-to-expected mortality ratio of the normal BMI cohort was closer to one. Therefore, this observation plus outcomes obtained from the propensity score analysis helped to question a clear obesity paradoxical effect on mortality when contrasting matched data of normal and overweight groups. Nonetheless, after propensity score analysis, obese patients presented a lower mortality rate compared with normal patients, but a higher complication rate. In short, relative to non-obese patients, overweight and obese individuals showed comparable or lower in-hospital mortality rates after cardiac surgery. On the contrary, the overall complication rates were similar in overweight and higher in obese patients compared with normal-weight individuals.
Evaluation relative to previous research becomes difficult because some studies bring together overweight and normal-weight patients in a single set of data20, 21, 23, 25, 28, 30, and adjustment by confounders was rarely done. The analysis of 4172 patients from the ARIAM registry21 demonstrated that after adjusting for severity and perfusion time, obese patients had mortality rate, complication rate, and length-of-stay similar to non-obese patients (BMI < 30 kg/m.). Ho el al.29 did not observe any “obesity paradox” in mortality rate assessment after adjusting data for the principal confounders. In a short series of 637 patients, obesity did not increase in-hospital mortality; however, it increased pulmonary and gastrointestinal complications after adjusting for age, sex, and comorbidities30. Conversely, in a cohort analysis with propensity score matching of 2440 patients, Stamou el al.11 communicated that overweight patients had a lower operative mortality than normal BMI patients (OR: 0.4, 95% CI: 0.2-0.9), whereas obese individuals had a comparable risk with respect to normal-weight patients.
As in other studies12, 19, 22, we found that overweight and obese patients were younger and with higher rates of male sex and diabetes compared with normal-weight patients. However, the higher rates of heart failure, pulmonary hypertension and valve endocarditis found in normal-weight patients had not been previously observed or considered.
Some considerations must be taken into account to evaluate the obesity paradox effect. Firstly, a normal BMI in a healthy person might be protective in a public health setting in which mortality is assessed in the long-term54. By contrast, an overweight or obese BMI might be protective in critical illnesses when comorbidities are frequent because mortality is high and is assessed in the short-term rather than years55-57. It is important to consider additional sources of bias for the “obesity paradox” phenomenon. Obese patients consistently undergo revascularization surgical procedures at a younger age than their non-obese counterparts and, consequently, may present with lower risk coronary anatomy58. Outcomes of the present study were consistent with this last observation, since obese patients were significantly younger, and coronary surgery was more common. On the other hand, the paradox may be due to selection bias if only a subgroup of the “healthiest” obese patients were selected for cardiac surgery59-60.
The present systematic review of observational studies suggested that overweight and obesity were associated with a neutral or beneficial effect on all-cause mortality after cardiac surgery. Meanwhile, pooled analysis of the 32 studies in the meta-analysis demonstrated a definite protective effect of overweight and obesity in general, on 30-day-in-hospital mortality rates post-cardiac surgery. Though moderate to high statistical heterogeneity was found in the analyses of overweight or obese versus normal-weight patients, nearly all studies reported a neutral or protective effect of higher BMI levels on mortality, providing supportive evidence that the summary effect sizes were the product of consistent results. Nevertheless, the pooled effect size found in the meta-analysis should be considered small (OR > 0.66)61.
Previously, two other meta-analyses reported similar outcomes. Oreopoulos et al.62 analyzed the effect of BMI only after coronary artery bypass grafting in 12 observational studies (nearly 75 000 patients). After coronary surgery, both overweight and obese patients had lower in-hospital mortality risks compared with normal-weight individuals (OR: 0.70, 95% CI: 0.63-0.77 and OR: 0.63, 95% CI: 0.56-0.71, respectively). Recently, Mariscalco et al.31 studied approximately 558 000 patients undergoing all types of cardiac surgery in 26 observational studies. They reported lower in-hospital mortality in overweight (OR: 0.79, 95% CI: 0.76-0.83), obese class I (OR: 0.81, 95% CI: 0.76-0.86) and obese class II (OR: 0.83; 95% CI: 0.74-0.94) patients relative to normal-weight individuals.
This study has some limitations. Since in most patients, BMI was calculated from self-reported weight and height, a systematic bias may arise when comparing with BMI calculated from objectively measured data. Nevertheless, in large studies54, self-reported and measured BMI differed on average by only 3%, with a 95% correlation coefficient between them. It is possible that overweight or obese patients with a more severe profile of comorbidities and considered at high risk for a cardiac operation were excluded from surgery. Isolated BMI used as a marker of obesity also has limitations, since other aspects of body composition such as visceral fat distribution were not explored in this study. Finally, early reductions in mortality observed in obese patients may not be sustained in the mid- and long-term.
In conclusion, this study showed that overweight and obese patients had similar or slightly lower in-hospital mortality rates after cardiac surgery compared with normal-weight individuals. Conversely, postoperative complication rates systematically increased with higher BMI levels. Most observational studies included in the systematic review showed that overweight and obese patients had at least the same mortality rate as normal-weight patients, or even a lower death risk. Pooled-data of the meta-analysis provided evidence on the association between higher BMI levels and a lower all-cause in-hospital mortality rate after cardiac surgery.
Conflict of interests: None to declare
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