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European Heart Journal Advance Access originally published online on February 20, 2009
European Heart Journal 2009 30(7):857-865; doi:10.1093/eurheartj/ehp037
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease

Koon-Hou Mak1,*, Deepak L. Bhatt2, Mingyuan Shao3, Steven M. Haffner4, Christian W. Hamm5, Graeme J. Hankey6, S. Claiborne Johnston7, Gilles Montalescot8, Philippe Gabriel Steg9, Steven R. Steinhubl10, Keith A.A. Fox11 and Eric J. Topol12

1 Gleneagles Medical Centre, 6 Napier Road, No. 08-13, Singapore 258499, Singapore
2 VA Boston Healthcare System and Brigham and Women's Hospital, Boston, MA, USA
3 Cleveland Clinic, Cleveland, OH, USA
4 University of Texas Health Science Center, San Antonio, TX, USA
5 Kerckhoff Heart Center, Bad Nauheim, Germany
6 Royal Perth Hospital and School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia
7 University of California San Francisco, San Francisco, CA, USA
8 Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France
9 Hôpital Bichat-Claude Bernard, Paris, France
10 The Geisinger Clinic, Danville, PA, USA and The Medicines Company, Zurich, Switerland
11 University and Royal Infirmary of Edinburgh, Edinburgh, UK
12 Scripps Translational Research Institute, La Jolla, CA, USA

Received 14 June 2008; revised 16 December 2008; accepted 17 December 2008; online publish-ahead-of-print 20 February 2009.

* Corresponding author. Tel: +65 6476 0880, Fax: +65 6475 0880, Email: makheart{at}gmail.com

See page 752 for the editorial comment on this article (doi:10.1093/eurheartj/ehp081)


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Aims: We aimed to determine the relationship between body mass index (BMI) and cardiovascular events among individuals with or at-risk of atherothrombotic disease.

Methods and results: This was a prospective observational study of 15 532 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who were randomly assigned to clopidogrel or placebo, and followed-up for a median of 28 months for the occurrence of the primary endpoint (cardiovascular death, myocardial infarction, or stroke), all-cause mortality, and bleeding complications. Compared with the highest BMI quartile, the primary endpoint, cardiovascular, and all-cause mortality all occurred more frequently among patients in the lowest BMI quartile (about a third lower). The relationship between continuous BMI and adverse cardiovascular outcomes were presented as two linear spline terms with 29 kg/m2 as the cut-point for all-cause mortality. Lower BMI was associated with an increase in moderate and severe bleeding complications, largely accounted for by those receiving dual-antiplatelet agents with the highest tertile aspirin dose.

Conclusion: Adverse cardiovascular events and bleeding complications occurred more frequently among individuals with or at-risk for atherothrombotic disease and low BMI. Further studies should be directed to these patients to improve outcomes.

The CHARISMA trial is registered with ClinicalTrials.gov, NCT00050817 [ClinicalTrials.gov] .

Key Words: Aspirin • Cardiovascular • Clopidogrel • Myocardial infarction • Obesity • Stroke


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 References
 
Obesity predisposes to type II diabetes, hypertension, and cardiovascular diseases,1,2 and may compromise the gains in life-expectancy over the past decades.3 Commonly defined by the body mass index (BMI), several epidemiological studies reported a curvilinear relationship between mortality and BMI.4,5 However, this association may be confounded by other factors. After excluding smokers, among individuals with chronic illness in two cohorts of >1.5 million adult men and women, mortality was increased only among those with a higher BMI.6,7 Conversely, a meta-analysis of 40 studies involving 250 152 patients with coronary artery disease8 showed that low BMI (<20.0 kg/m2) was associated with total and cardiovascular mortality, which were 37% [95% confidence interval (CI), 32–43%] and 45% (95% CI, 16–81%), respectively, higher than in patients with normal BMI (20.0–24.9 kg/m2) after a mean follow-up of 3.8 years. Total and cardiovascular mortality was lowest among those who were overweight (BMI between 25.0 and 29.9 kg/m2).

One limitation of these epidemiological studies, which may explain the discrepancy between BMI and mortality in the general population and in patients with previous coronary artery disease, is that height and weight were reported by the participants and not directly measured in some of these investigations.6 We therefore aimed to explore the relationship between BMI, which was measured at baseline, and cardiovascular events in patients enrolled in the Clopdiogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 References
 
The study design9 and results10,11 of the CHARISMA trial have been previously published. Briefly, this was a multinational double-blind placebo-controlled randomized clinical trial that evaluated the efficacy of clopidogrel in approximately 15 600 patients with documented atherothrombotic disease, or with multiple risk factors for atherothrombosis who were receiving aspirin. After excluding those without BMI measurement, 15 532 individuals were included in this prospective observational study; 12 093 and 3274 had documented cardiovascular diseases and multiple risk factors, respectively. This status was unknown in 165 individuals. Aspirin was administered with and without clopidogrel in 7768 and 7764 participants, respectively. Patients underwent 6-monthly follow-up prospectively for a median of 28 months. The completeness of follow-up was 99.5%.

Data on demographics, anthropometry, atherothrombotic risk factors, significant past history, and concomitant medications were obtained at enrolment by study coordinators. Body weight and height were measured at enrolment. Smoking status was categorized into three groups: current smokers (3143 subjects), former smokers (7578 subjects), and never smokers (4811 subjects). The primary efficacy endpoint of the CHARISMA trial was the first occurrence of cardiovascular death (including haemorrhagic death), MI, or stroke. The primary safety endpoint was severe bleeding as defined by the Global Utilization of Streptokinase and tissue-plasminogen activator for Occluded Coronary Arteries (GUSTO) criteria, which included fatal bleeding, primary intracranial haemorrhage, or bleeding causing haemodynamic compromise and requiring blood or fluid replacement, inotropic support, or surgical intervention.12 Moderate bleeding, as determined by the GUSTO criteria, captured bleeding that led to transfusion but that did not lead to haemodynamic compromise or intervention. These events were validated independently by the Cleveland Clinic Clinical Events Adjudication Committee, using pre-specified definitions, and were blinded to baseline BMI status. Other efficacy endpoints included all-cause mortality, cardiovascular death, MI, stroke, or repeat hospitalization for unstable angina, and transient ischaemic attack (TIA).

Statistical analysis
BMI was analysed as a categorical (quartile) and continuous (logarithm or linear spline transformed) variable. Baseline characteristics were compared among the BMI quartiles using Cochran-Armitage trend test for categorical variables and Spearman rank test for continuous variables. Differences for efficacy and safety endpoints among the BMI quartiles were assessed using a two-sided log-rank test and were plotted using cumulative Kaplan–Meier estimates of the event rates. Hazard ratios (HR) of the BMI quartiles and their associated 95% CI were estimated using Cox proportional hazards model, unadjusted or adjusted for cardiovascular risk factors including age, gender, smoking history (represented by dummy variables of current and former-smokers with referent never-smokers), diabetes mellitus, hypertension, and hypercholesterolaemia. For safety endpoints, the co-variates used for adjustment were age, diabetic nephropathy, hypertension, and diuretic use. The first quartile of BMI was used as the referent. Multivariable Cox models were created to assess the relationship of the continuous BMI (presented as linear spline terms) and cardiovascular events, after adjusting for age, gender, smoking history, diabetes mellitus, hypertension, and hypercholesterolaemia. These risk factors and BMI linear spline terms met the proportional hazards assumption by plotting the log of the negative log of their estimated survival distribution, log(–log(S(t))) vs. time. The linearity assumption was assessed and satisfied for all the continuous variables by plotting the logit of the events against the continuous variable. Although propensity score matching was performed, matching sample was not sufficiently large to be used for analysis. Propensity scores were entered into the final multivariable Cox models as an additional adjustment.

As the dose of aspirin was not standardized, it was adjusted for body weight for each patient and divided into tertiles, and endpoints were compared. In the trial, eight patients did not receive aspirin or the dose of aspirin was not recorded. For the aspirin group, the dose range was 0–4.584 mg/kg, with mean of 1.320 mg/kg and for the aspirin plus clopidogrel group, the dose range was 0–4.706 mg/kg, with mean of 1.318 mg/kg.

Subgroup analysis was performed to examine the effects of smoking, clopidogrel treatment, and primary prevention on the association of the continuous BMI and efficacy and safety endpoints. All analyses were performed using SAS software version 9.1.3 (SAS Institute Inc., Cary, NC, USA). A two-sided probability value of <0.05 was considered statistically significant.


   Results
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 Methods
 Results
Discussion
 Funding
 References
 
There were small but statistically significant differences in baseline characteristics among the BMI quartiles (Table 1). Patients with the lowest BMI quartile had the highest proportion of elderly, were more likely to smoke, and to have suffered from TIA or stroke. They were less likely to be a Caucasian, and to have suffered from hypertension, diabetes mellitus, hypercholesterolaemia, congestive heart failure, diabetic nephropathy, and previous MI. The proportion of patients treated with prior antiplatelet therapy was lowest among the highest BMI quartile. Those in the lowest BMI quartile were least likely to receive beta-blockers, angiotensin receptor blockers, angiotensin-converting enzyme-inhibitors, or statins (P-value for trend <0.0001).


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  		Table 1 Baseline characteristics

 
Efficacy endpoints
The first occurrence of primary endpoint ranged from 6.2–8.1% (Table 2), with a step-wise decrease in events from the lowest to the highest BMI quartile (log-rank P = 0.0004) with the corresponding adjusted HR was 0.96 (95% CI, 0.90–1.01; P = 0.121). This relationship was also observed for cardiovascular mortality, non-fatal stroke, and all-cause mortality (Table 2 and Figure 1) but the association was lost in multivariable analysis (P = 0.204, 0.156, and 0.126, respectively).


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  		Table 2 Clinical efficacy outcomes

 

Figure 1
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  		Figure 1 Kaplan–Meier estimates of the cumulative incidence of all-cause mortality for the body mass index quartiles. Kaplan–Meier curves are truncated to 30 months because the estimated percentages beyond this time point becomes subject to large random error.

 
We found that continuous BMI could be presented as two linear spline terms. Likelihood ratio comparison (data not shown) showed that cut-off points for primary endpoint, cardiovascular and all-cause mortality were 31, 27, and 29 kg/m2, respectively. Figure 2A illustrates the linear spline transformation for all-cause mortality. These relationships were maintained in multivariable Cox regression models containing linear spline terms and traditional cardiovascular risk factors (Figure 2B and Table 3). For BMI lower than the spline cut-points, the hazard of the corresponding cardiovascular outcomes were reduced by 3%, 8%, and 5%, respectively, with one unit increase of BMI. This finding indicates that among individuals with low BMI, a rise in BMI was associated with a lower risk for adverse cardiovascular events. Conversely, among those with BMI higher than the cut-points, there was no significant association between the BMI linear spline and cardiovascular outcomes. Propensity scores, when used as a covariate in the multivariable Cox models, did not impact significantly on the BMI effect on the cardiovascular outcomes (data not shown). Likely, linear spline transformation appropriately represented the BMI data.


Figure 2
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  		Figure 2 Four-knot plot of estimated spline transformation and 95% confidence interval for the endpoint of unadjusted (A) and adjusted (B) all-cause mortality. The curve of the log hazard ratio against continuous body mass index (BMI) demonstrated that the continuous BMI data could be presented as two linear spline terms with the cut-point at about 29 kg/m2.

 

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  		Table 3 Multivariable Cox proportional hazards model for the cardiovascular outcomes

 
The relationship of a higher BMI associated with a lower occurrence of adverse cardiovascular outcome was consistent among various subgroups stratified by treatment and inclusion criteria groups (Figure 3). However, this relationship did not appear to be evident among non-smokers.


Figure 3
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  		Figure 3 Subgroup analysis for the efficacy endpoints and safety endpoints log-transformed body mass index (BMI) was applied in the unadjusted Cox proportional hazards models. Event rates for each subgroup were presented as number of events divided by the total number of patients in that subgroup (n/N). Hazard ratios are shown with their 95% CI. Heterogeneity tests showed no significant interaction between log BMI and subgroup variable, with the exception of smoking status in all-cause mortality (P = 0.006 for the interaction of log BMI and ever smoking).

 
Bleeding complications
Both severe and moderate bleeding complications occurred less frequently among those with higher BMI (log-rank P = 0.0206 and 0.0202, respectively) (Table 4). After adjusting for the risk factors, higher BMI remained associated with lower rate of severe bleeding (P = 0.026) but not for moderate bleeding (P = 0.079). Compared with the lowest quartile, the adjusted HR for severe bleeding complication was 0.68 (95% CI, 0.47–1.00; P = 0.049) for the highest quartile. Among those treated with aspirin alone, the rates of severe (1.1–1.5%) or moderate (1.2–1.4%) bleeding complications did not differ among the tertiles of weight-adjusted aspirin dose. For patients treated with dual anti-platelet agents, there was a trend towards a higher occurrence of severe bleeding complication among those receiving the highest compared with the lowest tertile of aspirin dose (2.1% vs. 1.4%; P = 0.062). However, the HR of primary intracranial haemorrhage was 3.56 (95% CI, 1.17–10.82; P = 0.017) in the highest compared with the lowest tertile of aspirin dose (0.5% vs. 0.2%). When analysed as a continuous variable, there was only a trend for lower rate of severe bleeding complication for individuals with higher BMI (HR = 0.478; 95% CI, 0.226–1.011; P = 0.053). This trend was observed for the smoking history, treatment, and inclusion criteria groups (Figure 3).


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  		Table 4 Bleeding complications

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
Among individuals with established or at risk for atherothrombotic disease, the occurrence of the primary endpoint showed a step-wise increment, with the highest event rate among patients in the lowest BMI quartile. Compared with the lowest BMI quartile, the HR for cardiovascular and all-cause mortality for those in the highest BMI quartile were 0.71 and 0.65, respectively. In a multivariable analysis, we found that BMI cut-points for the primary endpoint, cardiovascular, and all-cause mortality were 31, 27, and 29 kg/m2, respectively. Bleeding complications occurred more frequently among individuals with lowest BMI, particularly among those receiving dual-antiplatelet agents with the highest tertile of aspirin dose.

While in the general population, mortality is highest among those who are over- and under-weight,4,13,14 only those with the lowest BMI had higher mortality among patients with previous MI or who had undergone coronary revascularization procedures.4,15 In the Physicians' Health Study, in 5010 middle-aged and older men with previous MI or stroke who were followed-up for 5 years, the adjusted relative risk for all-cause mortality was 1.40 (95% CI, 1.06–1.85) among those with BMI <22.0 kg/m2 compared with subjects with BMI between 22.0 and 24.9 kg/m2.16 Similarly, in CHARISMA, where participants had established atherothrombotic disease or multiple cardiovascular risk factors, survival was the least among those with the lowest BMI quartile. These findings suggest that the relationship between obesity and mortality may differ between individuals with and without cardiovascular disease. Several pathophysiological mechanisms in obesity heighten the risk for vascular disease.2 Once the individual has suffered from MI or stroke, the metabolic reserve may somewhat ‘protect’ the obese from the insult and the potential for regeneration and repair.17 Conversely, compensatory capacity may be limited among those with low BMI. Other non-traditional risk factors, such as endothelial dysfunction,18 could have also accounted for this trend.

The disparities between obesity and outcome among different studies suggest that BMI may reflect adiposity poorly. In a large case–control study of 27 098 subjects, the association with MI was greater for waist-hip ratio than BMI.19 This relationship was consistent in different geographical regions and ethnic groups. Recently, this finding was corroborated by a cohort of 24 508 subjects prospectively followed for 9.1 years.20

The issue of obesity and mortality is further complicated by the fact that weight loss among obese individuals may be detrimental.21 When the illness is severe, individuals succumbed by losing weight, leading to a condition known as sarcopenia, which is associated with increased mortality.22 Despite these controversies, the American Heart Association undertook a pragmatic approach and issued a statement to caution obese individuals not have an unrealistic expectation for weight normalization. However, some weight loss may improve cardiovascular risk, cardiorespiratory fitness, and general well-being.2

Our finding of increased bleeding among individuals with lower BMI was consistent with the results from earlier studies on fibrinolytic therapy23 and undergoing percutaneous coronary intervention,15 whereby patients with lower body weight were more likely to suffer from bleeding complications. We found an increase in severe bleeding complications among patients with low BMI; especially for those receiving dual-antiplatelet agents and the aspirin dose at the highest tertile. This finding suggested that the risk of bleeding may be reduced by decreasing the dose of aspirin among those with lower BMI.

The strength of our study is that data have been prospectively collected from a rigorously conducted clinical trial with a large number of subjects, and the completeness of follow-up. A key limitation was that we used BMI as a measure for obesity, and its effect is modified by other atherosclerotic risk factors.24 Determinants of abdominal or central obesity may be better predictors of outcome.19 Unfortunately, waist circumference and waist-hip ratio were not ascertained in our study. Another limitation was that the duration of follow-up may not have been sufficiently long since some investigators felt that 15 years were needed to determine the full extent of cardiovascular mortality.25 However, this longer duration may be applicable for studies of individuals without established atherothrombotic disease. Other prognostic factors, such as haemoglobin level, left ventricular, and renal function, which might impact outcomes were not available in CHARISMA. We also did not have information on the use of stomach-protective agents, which might have impacted on the occurrence of bleeding.

In summary, the relationship between BMI and cardiovascular outcome is complex and may differ based on whether the patient does or does not have atherothrombosis, a subject requiring further investigation. Low BMI may be a marker for elevated risk of cardiovascular and bleeding events. Subsequent investigations should address these concerns to improve outcomes among patients with low BMI.


   Funding
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
Other than the funding by sanofi-aventis and Bristol-Myers Squibb for the original clinical trial, there is no funding for this manuscript.

Conflict of interest: D.L.B. has received research grants from Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, sanofi-aventis, and The Medicines Company; and has served as consultant/advisory board for Arena, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering Plough, Scios, Takeda, The Medicines Company, and Vertex. S.R.S. has received salary/employment from The Medicines Company and honoraria for consulting from sanofi-aventis, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, AstraZeneca, The Medicines Company, Portola, Cardax, Cogentus, and Arena.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 

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