Advertisement
Mayo Clinic Proceedings Home

Obesity Paradox in Pulmonary Embolism: Myth or Reality?

      Obesity, like smoking and hypertension, is a nonprovoking acquired risk factor and independent predictor of pulmonary embolism. In a population-based cohort study from the Emerging Risk Factors Collaboration in the United Kingdom,
      • Gregson J.
      • Kaptoge S.
      • Bolton T.
      • et al.
      Emerging Risk Factors Collaboration
      Cardiovascular risk factors associated with venous thromboembolism.
      older age, current smoking, and higher body mass index (BMI) were consistently associated with higher venous thromboembolic (VTE) risk. Adult BMI (calculated as weight in kilograms divided by height in meters squared) is strongly associated with VTE, especially adult waist circumference, even after adjusting for adult BMI, as is increasing weight gain from young adulthood, after adjusting for current BMI, among women but not men.
      • Hagan K.A.
      • Harrington L.B.
      • Kim J.
      • et al.
      Adiposity throughout the life course and risk of venous thromboembolism.
      Both malnutrition and obesity are risk factors associated with VTE in critically ill patients.
      • Reynolds P.M.
      • Van Matre E.T.
      • Wright G.C.
      • et al.
      Colorado Pulmonary Outcomes Research Group (CPOR)
      Evaluation of prophylactic heparin dosage strategies and risk factors for venous thromboembolism in the critically ill patient.
      Underweight is also associated with a higher mortality rate in patients with VTE. Obesity is associated not only with increased risk of VTE but also with recurrence of VTE. The increased risk of VTE in obese patients may be due in part to a chronic inflammatory state with increased activated protein C resistance.
      If obesity is associated with increased risk of VTE, it is not itself a clinical predictor of death. There are multiple clinical prediction rules including the Pulmonary Embolism Severity Index (PESI), the simplified PESI (sPESI), the European Society of Cardiology prognostic model, the Geneva prognostic score, the Aujesky 2006 prognostic model, the Global Registry of Acute Coronary Events pulmonary embolism risk score, the Hestia criteria, the Low-Risk Pulmonary Embolism Decision tool, the Prognosis in Pulmonary Embolism Score, the Davis 2007 prognostic model, and the Spanish score: none of them include weight as a variable capable of influencing outcome.
      • Kohn C.G.
      • Mearns E.S.
      • Parker M.W.
      • Hernandez A.V.
      • Coleman C.I.
      Prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate meta-analysis.
      In the current issue of Mayo Clinic Proceedings, Keller et al
      • Keller K.
      • Hobohm L.
      • Münzel T.
      • et al.
      Survival benefit of obese patients with pulmonary embolism.
      report a very large cohort, extracted from the German national database, of 345,831 adult inpatients in whom acute pulmonary embolism was diagnosed using an adapted version of the the International Statistical Classification of Diseases and Related Health Problems, 10th Revision,German Modification. Among them, 8.6% (29,817) were obese and 0.5% (1675) were underweight. Overall in-hospital mortality was 14.8% (51,226 patients). After adjustment for age, sex, comorbidities, and reperfusion therapy, a survival benefit was observed in obesity class I (BMI, 30-34 kg/m2) and obesity class II (BMI, 35-39 kg/m2), whereas underweight patients had a higher prevalence of cancer and higher mortality. In-hospital mortality followed a U-shape with lower mortality being conferred to patients with obesity classes I and II, and the shape of the curve was not influenced by the presence of cancer or heart failure. Do those findings constitute another example of the “obesity paradox”? The obesity paradox was first described in 1999 in patients undergoing hemodialysis; the authors reported that compared with normal-weight patients undergoing hemodialysis, the 1-year survival rate was significantly higher in the overweight patients and lower in the underweight patients.
      • Fleischmann E.
      • Teal N.
      • Dudley J.
      • May W.
      • Bower J.D.
      • Salahudeen A.K.
      Influence of excess weight on mortality and hospital stay in 1346 hemodialysis patients.
      The obesity paradox has been invoked subsequently in various conditions such as cardiovascular diseases, chronic obstructive lung diseases, and aging. The current findings are similar and indeed fit the hypothesis of the obesity paradox. It is interesting to note that in the obesity paradox and cardiovascular disease, for example, obesity is a risk factor for cardiovascular disease while at the same time being an apparent protector against poor outcome. The same pattern was noted in the study by Keller et al,
      • Keller K.
      • Hobohm L.
      • Münzel T.
      • et al.
      Survival benefit of obese patients with pulmonary embolism.
      with obesity being both a risk factor for VTE and an apparent protector against poor outcome. This phenomenon could be explained by the concept of collider stratification bias, in which conditioning on a variable (eg, pulmonary embolism) affected by exposure (eg, obesity) and outcome (pulmonary embolism is a known predictor of mortality) can introduce a spurious association between exposure (obesity is also a known predictor of mortality) and outcome and can even reverse the direction of association, making a harmful exposure appear protective.
      • Banack H.R.
      • Kaufman J.S.
      The obesity paradox: understanding the effect of obesity on mortality among individuals with cardiovascular disease.
      It can create an imbalance among unmeasured factors such a smoking between stratified groups. Smoking is a risk factor for pulmonary embolism, a predictor of poor outcome, and associated with less body weight. This scenario has been described as a “lean paradox,” in which those who smoke are actually leaner than and not as healthy as their nonsmoker counterparts.
      • Elagizi A.
      • Kachur S.
      • Lavie C.J.
      • et al.
      An overview and update on obesity and the obesity paradox in cardiovascular diseases.
      So, what can we learn from this study? Obesity (especially classes I and II) may not have so much a protective effect on in-hospital mortality of patients with acute pulmonary embolism but rather reflects the case of metabolically healthy obese individuals, a frequent and common finding in modern societies.
      • Elagizi A.
      • Kachur S.
      • Lavie C.J.
      • et al.
      An overview and update on obesity and the obesity paradox in cardiovascular diseases.
      Indeed, in the Global Anticoagulant Registry in the FIELD registry, a worldwide prospective observational study on VTE, the median BMI was 27.3 kg/m2 (interquartile range, 24.1-31.4 kg/m2), with 32.3% patients being classified as obese (BMI, ≥30 kg/m2) and 5.2% as underweight (BMI, <20 kg/m2).
      • Ageno W.
      • Haas S.
      • Weitz J.I.
      • et al.
      GARFIELD-VTE Investigators
      Characteristics and management of patients with venous thromboembolism: the GARFIELD-VTE Registry.
      The case of a metabolically healthy obese individual is further suggested by the finding that the lower mortality of obese patients with pulmonary embolism was limited to those aged 40 years and older, a benefit that may have been associated with a better metabolic reserve, less smoking, or less disease-associated weight loss.
      • Wang S.
      • Ren J.
      Obesity paradox in aging: from prevalence to pathophysiology.
      The study by Keller et al has several limitations. The use of the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, German Modification code may have underestimated the actual incidence of pulmonary embolism, and this study was limited to patients who were hospitalized. The causes (eg, provoked or unprovoked) of pulmonary embolism were not specified. When the weight was not available, the patient was attributed to the reference group. The presence of heart failure may have been confounded by underlying obstructive sleep apnea, obesity hypoventilation syndrome, atrial fibrillation, and/or congestive heart failure with preserved left ventricular function. The severity of pulmonary embolism was not specified, and the PESI score was used instead as a surrogate for severity. The outcome was, by design, all-cause in-hospital mortality, not any specific cause of mortality, and a composite of all causes of in-hospital death and need for invasive mechanical ventilation or cardiopulmonary resuscitation. The timing of cardiopulmonary resuscitation relative to the pulmonary embolism was not specified. The type of nonthrombolytic treatment (eg, classic or new oral anticoagulation) was not provided. The influence of smoking was not studied.
      Nevertheless, this is a large, contemporary study of hospitalized patients with acute pulmonary embolism. Whether its findings reflect a true obesity paradox or a lean paradox or are simply spurious and reflective of remaining unknown and/or unmeasured confounders, it raises new questions that will need to be explored further. At the end, obesity remains a risk factor for VTE, and obesity is globally associated with increased morbidity and mortality.

      References

        • Gregson J.
        • Kaptoge S.
        • Bolton T.
        • et al.
        • Emerging Risk Factors Collaboration
        Cardiovascular risk factors associated with venous thromboembolism.
        JAMA Cardiol. 2019; 4: 163-173
        • Hagan K.A.
        • Harrington L.B.
        • Kim J.
        • et al.
        Adiposity throughout the life course and risk of venous thromboembolism.
        Thromb Res. 2018; 172: 67-73
        • Reynolds P.M.
        • Van Matre E.T.
        • Wright G.C.
        • et al.
        • Colorado Pulmonary Outcomes Research Group (CPOR)
        Evaluation of prophylactic heparin dosage strategies and risk factors for venous thromboembolism in the critically ill patient.
        Pharmacotherapy. 2019; 39: 232-241
        • Kohn C.G.
        • Mearns E.S.
        • Parker M.W.
        • Hernandez A.V.
        • Coleman C.I.
        Prognostic accuracy of clinical prediction rules for early post-pulmonary embolism all-cause mortality: a bivariate meta-analysis.
        Chest. 2015; 147: 1043-1062
        • Keller K.
        • Hobohm L.
        • Münzel T.
        • et al.
        Survival benefit of obese patients with pulmonary embolism.
        Mayo Clin Proc. 2019; 94: 1960-1973
        • Fleischmann E.
        • Teal N.
        • Dudley J.
        • May W.
        • Bower J.D.
        • Salahudeen A.K.
        Influence of excess weight on mortality and hospital stay in 1346 hemodialysis patients.
        Kidney Int. 1999; 55 ([published correction appears in Kidney Int. 2000;57(2):760]): 1560-1567
        • Banack H.R.
        • Kaufman J.S.
        The obesity paradox: understanding the effect of obesity on mortality among individuals with cardiovascular disease.
        Prev Med. 2014; 62: 96-102
        • Elagizi A.
        • Kachur S.
        • Lavie C.J.
        • et al.
        An overview and update on obesity and the obesity paradox in cardiovascular diseases.
        Prog Cardiovasc Dis. 2018; 61: 142-150
        • Ageno W.
        • Haas S.
        • Weitz J.I.
        • et al.
        • GARFIELD-VTE Investigators
        Characteristics and management of patients with venous thromboembolism: the GARFIELD-VTE Registry.
        Thromb Haemost. 2019; 119: 319-327
        • Wang S.
        • Ren J.
        Obesity paradox in aging: from prevalence to pathophysiology.
        Prog Cardiovasc Dis. 2018; 61: 182-189

      Linked Article