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European Heart Journal Advance Access originally published online on August 4, 2006
European Heart Journal 2006 27(23):2755-2762; doi:10.1093/eurheartj/ehl182
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Weight-change as a prognostic marker in 12 550 patients following acute myocardial infarction or with stable coronary artery disease

Linn M.A. Kennedy1,*, Kenneth Dickstein2, Stefan D. Anker3, Margaret James4, Thomas J. Cook4, Krister Kristianson5 and Ronnie Willenheimer1

1 Department of Cardiology, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden
2 Cardiology Division, Stavanger University Hospital, University of Bergen, Norway
3 Division of Applied Cachexia Research, Department of Cardiology, Charité Campus Virchow Klinikum, Berlin, Germany
4 Merck & Co., Whitehouse Station, NJ, USA
5 Department of Clinical Pharmacology, Institution for Laboratory Medicine, Karolinska University Hospital, Huddinge, Sweden

Received 8 September 2005; revised 8 June 2006; accepted 14 July 2006; online publish-ahead-of-print 4 August 2006.

* *Corresponding author. Tel: +46 40 331000; fax: +46 40 336209. E-mail address: linn.kennedy{at}med.lu.se


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Aims To examine the prognostic importance of weight-change in patients with coronary artery disease (CAD), especially following acute myocardial infarction (AMI).

Methods and results In 4360 AMI patients (OPTIMAAL trial) without baseline oedema, we assessed 3-month weight-change, baseline body mass index (BMI), demographics, patient history, medication, physical examination, and biochemical analyses. Weight-change was defined as change >±0.1 kg/baseline BMI-unit. Patients were accordingly categorized into three groups; weight-loss, weight-stability, and weight-gain. Our findings were validated in 4012 AMI patients (CONSENSUS II trial) and 4178 stable CAD patients (79% with prior AMI, 4S trial). Median follow-up was 2.7 years, 3 months, and 4.4 years, respectively. In OPTIMAAL, 3-month weight-loss (vs. weight-stability) independently predicted increased all-cause death [n=471; hazard ratio (HR) 1.26; 95% CI 1.01–1.56; P=0.039] and cardiac death (n=299, HR 1.33, 95% CI 1.02–1.73, P=0.034). Weight-gain yielded risk similar to weight-stability (HR 1.07, P=0.592 and 0.97, P=0.866, respectively). In CONSENSUS II, 3-month weight-loss independently predicted increased mortality (HR 3.87, P=0.008). Weight-gain yielded risk similar to weight-stability (HR 1.11, P=0.860). In 4S, 1-year weight-loss independently predicted increased mortality (HR 1.44, P=0.004). Weight-gain conferred risk similar to weight-stability (HR 1.05, P=0.735).

Conclusion In patients following AMI or with stable CAD, weight-loss but not weight-gain was independently associated with increased mortality risk.

Key Words: Coronary artery disease • Acute myocardial infarction • Weight-change • Prognosis • Mortality


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgement
 References
 
High body mass index (BMI) is a significant risk factor for the development of cardiovascular disease and is associated with cardiovascular risk factors such as hypertension, insulin resistance, and dyslipidaemia,1,2 as well as increased risk of all-cause and cardiovascular death.3 Furthermore, obesity is associated with a variety of alterations in haemodynamic function, cardiac function, and morphology.4–6 Although many of these alterations are reversible with substantial weight-loss,5,7 the prognostic importance of weight-reduction in obese subjects in primary prevention is uncertain.8–20 Several studies have indicated that weight-loss is associated with increased mortality risk,8–10,12–14,16,18,19 despite efforts to exclude patients with silent pre-existing severe illness.12–14,19 Allison et al.17 showed in two population-based cohorts that weight-loss was associated with increased mortality risk, whereas fat loss was associated with decreased mortality risk during long-term follow-up.

The prognostic importance of obesity in patients with established coronary artery disease (CAD) is not well defined. Studies in patients undergoing percutaneous coronary intervention and in patients with acute myocardial infarction (AMI) have shown contradicting results.21–31 There is no available data on the prognostic impact of weight-change in patients with CAD. However, in patients with chronic heart failure (CHF), weight-loss was strongly associated with worse prognosis.32,33 We evaluated the prognostic importance of weight-change occurring within the first 3 months after an AMI in patients included in the OPTIMAAL trial.34–36 These results were validated by assessing the prognostic impact of weight-change in patients with AMI included in the CONSENSUS II trial,37 and in patients with stable CAD, 79% with prior AMI, included in the 4S trial.38


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgement
 References
 
Patients and trial design
In OPTIMAAL, 5477 patients at least 50 years of age with documented AMI, who showed signs or symptoms of heart failure, were enrolled within 10 days of onset of AMI symptoms.34–36 The primary endpoint was all-cause mortality. Other pre-specified endpoints included cardiac and cancer death. Patients were randomly assigned treatment with losartan or captopril. The 6090 patients in the CONSENSUS II trial had AMI and were randomized to treatment with enalapril or placebo.37 The 4444 patients included in the 4S trial had angina pectoris or previous AMI (79%) and received randomized treatment with simvastatin or placebo.38 All trials were approved by the respective Ethics Committees and were conducted in accordance with the Declaration of Helsinki.

Design of the present analysis
In post hoc analysis, we assessed the importance of relatively short-term weight-change to all-cause, cardiac, and cancer mortality. In OPTIMAAL and CONSENSUS II, weight-change was measured over the first 3 months, as body weight was reassessed at 3 months according to the protocol. In 4S, the 1-year weight-change was used, as body weight was not re-evaluated until 1 year after inclusion. In all trials, we analysed the impact of weight-change on mortality in univariable analysis, as well as after adjustment for baseline BMI, demographics, patient history, medication, physical examination, and biochemical analyses. Cardiac death was defined as death from AMI, progressive CHF and other cardiac causes, and sudden cardiac death. Patients with oedema at baseline were excluded from all analyses. Prior to data analysis, patients were categorized into four groups according to baseline BMI: underweight (<22 kg/m2), normal-weight (22–24.9 kg/m2), overweight (25.0–29.9 kg/m2), and obese (≥30 kg/m2). Weight-change was pre-defined as weight-gain or weight-loss from baseline of >0.1 kg per baseline BMI-unit. Consequently, for a patient with a BMI of 25 kg/m2, a change of >±2.5 kg was categorized as a weight-change. This corresponds to 3–3.5% change in total body-weight. Patients were accordingly divided into three groups with regard to weight-change: weight-loss, weight-stability, and weight-gain. In OPTIMAAL, patients with weight-loss were divided into those with moderate weight-loss (>0.1–0.2 kg/BMI-unit) and those with pronounced weight-loss (>0.2 kg/BMI-unit). The follow-up period began after obtaining the second body-weight assessment at approximately 3 and 12 months, and had a median length of 2.7 years (range 5–1363 days) in the OPTIMAAL trial, 82 days (range 1–147 days) in CONSENSUS II, and 4.4 years (range 2–1897 days) in the 4S trial.

Statistics
The value of weight-change category to predict endpoints was tested in uni- and multivariable time-to-event Cox proportional hazards models. Baseline covariates (including those listed on the left column of Table 1) were screened in univariable models for possible inclusion in a multivariable model. Covariates found to be significantly (P<0.05) associated with the respective endpoint were included in the corresponding multivariable model. The effect of baseline BMI-group was controlled for by including it as a stratification variable in the models. Hazard ratios (HR) and 95% CI were estimated for the effect of weight-gain or weight-loss relative to weight-stability. All statistical analyses were two-sided and a P-value<0.05 was considered as statistically significant. No formal adjustment for multiple testing was performed.


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  		Table 1 OPTIMAAL: baseline characteristics by 3-month weight-change group

 

   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgement
 References
 
OPTIMAAL trial
In OPTIMAAL, 4360 patients had baseline BMI data and 3-month weight measurements, and no baseline oedema. Of the patients with baseline BMI data, 367 died before the 3-month visit. Mean baseline BMI was 26.6 [standard deviation (SD) 3.9, range 13.2–49.4 kg/m2] and at 3 months it was 26.5 (SD 3.8, range 14.4–48.9 kg/m2). There were 382 (8.8%) underweight patients, 1146 (26.3%) normal-weight, 2059 (47.2%) overweight, and 773 (17.7%) obese patients. Weight-change data are given in Table 2. Among patients with weight-loss, 74% were overweight or obese and 20% were normal-weight at baseline. A 3-month weight-loss was found in 16% of the underweight patients, 19% of the normal-weight, 27% of the overweight, and in 31% of the obese patients. Of the 825 patients with weight-gain, 52% were overweight or obese at baseline. Table 1 shows the baseline characteristics of the four weight-change groups. There were some potentially important differences between the groups, adjusted for in multivariable analysis.


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  		Table 2 OPTIMAAL: change from baseline in body-weight at 3 months by weight-change group

 
During follow-up, there were 471 deaths of which 299 were cardiac deaths. The crude event rates for all-cause mortality were: stable weight, 9.9%; weight-gain, 10.3%; weight-loss, 13.2%; moderate weight-loss, 12.4%; and pronounced weight-loss, 14.8%. The crude event rates for cardiac mortality were: stable weight, 6.4%; weight-gain, 6.2%; weight-loss, 8.5%; moderate weight-loss, 7.5%; and pronounced weight-loss, 10.1%. In univariable analysis, relative to weight-stability, patients with weight-loss had a significant 36% increase of all-cause and 35% increase of cardiac mortality hazard (Figure 1). Those with pronounced weight-loss had higher risk than patients with moderate weight-loss. Patients with weight-gain had risks similar to those with weight-stability. In univariable Cox proportional hazard analysis, increasing weight (as a continuous variable) was associated with a significantly lower all-cause (HR 0.97/kg, 95% CI 0.95–0.99, P=0.014) and cardiac mortality risk (HR 0.96/kg, 95% CI 0.94–0.99, P=0.007). Cancer deaths (n=62) ranged from 1.2 to 1.8% in the three groups. Weight-change showed no significant association with cancer death.


Figure 1821
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  		Figure 1 OPTIMAAL trial. Kaplan–Meier curves for all-cause (A) and cardiac (B) death for the four groups with regard to 3-month weight-change. Unbroken line, pronounced weight-loss; fine dotted line, moderate weight-loss; thick dotted line, weight-gain; broken line, stable weight. (A) All-cause death univariable HR, with weight-stability as reference: weight-gain, 1.038, 95% CI 0.810–1.328, P=0.7697; weight-loss, 1.365, 95% CI 1.111–1.678, P=0.0031; moderate weight-loss, 1.266, 95% CI 0.991–1.618, P=0.0588; pronounced weight-loss, 1.549, 95% CI 1.161–2.068, P=0.0029. (B) Cardiac death univariable HR, with weight-stability as reference: weight-gain, 0.966, 95% CI 0.704–1.326, P=0.8315; weight-loss, 1.352, 95% CI 1.045–1.749, P=0.0219; moderate weight-loss 1.196, 95% CI 0.876–1.633, P=0.2607; pronounced weight-loss, 1.642, 95% CI 1.156–2.332, P=0.0056.

 
Table 3 presents the multivariable models results. The covariate selection method resulted in the inclusion into the multivariable models of: age, pulse rate, serum creatinine, HDL-cholesterol (all-cause death only), haemoglobin (all-cause death only), history of AMI, history of hypercholesterolaemia (all-cause death only), history of CHF (cardiac death only), and in-hospital treatment with statins, thrombolytics, aspirin (all-cause death only), diuretics (all-cause death only), and beta-blockers (cardiac death only). A 3-month weight-loss was independently associated with increased risk of both all-cause and cardiac death and there was no significant interaction with baseline BMI group. This is also evident from the results presented in Figure 2A: in all baseline BMI groups, all-cause mortality was highest in patients with weight-loss, whereas weight-gain showed risks similar to weight-stability. When patients with weight-loss were divided into two groups, only pronounced weight-loss was significantly associated with increased risk (Table 3). Weight-gain showed approximately the same adjusted risk as weight-stability. The P-values for interaction between baseline BMI and weight-change were 0.562 for all-cause and 0.526 for cardiac death. In multivariable analysis, increasing weight (as a continuous variable) was associated with a non-significantly lower-adjusted all-cause (HR 0.98/kg, 95% CI 0.96–1.01, P=0.135) and a significantly lower-adjusted cardiac mortality risk (HR 0.97/kg, 95% CI 0.94–0.99, P=0.020).


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  		Table 3 Effect of weight changes on endpoints

 

Figure 1822
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  		Figure 2 Crude all-cause mortality (%) in the three weight-change groups by baseline BMI group: (A) OPTIMAAL trial, (B) CONSENSUS II trial, (C) 4S trial. White, weight-gain; grey, stable weight; black, weight-loss.

 
CONSENSUS II trial
Of the 6090 patients randomized in the CONSENSUS II trial, 4012 patients had baseline BMI and 3-month weight values, and no baseline oedema. Of the patients with baseline BMI data, 239 died before the 3-month visit. Of the 4012 patients included in the analysis, 11.4% were underweight, 29.4% normal-weight, 46.9% overweight, and 12.3% obese. Among the 528 (13.2%) patients with weight-loss, 66% were overweight or obese and 24% were normal-weight at baseline. A 3-month weight-loss was found in 11% of the underweight patients, 11% of the normal-weight, 13% of the overweight, and in 22% of the obese patients. Of the 996 (24.8%) patients with weight-gain, 50% were overweight or obese at baseline.

During follow-up there were 57 deaths. The crude event rate for all-cause mortality was 3.0% in patients with weight-loss, 1.4% in those with weight-stability, and 0.6% among those with weight-gain. The multivariable model covariate selection for all-cause death resulted in the inclusion into the first multivariable model of: baseline loop diuretic use, systolic blood pressure, heart rate, body weight, age, creatinine, potassium, sodium, and total lactate dehydrogenase. However, due to few events, the three variables with the weakest association with mortality were not included in the second model, i.e. creatinine, potassium, and total lactate dehydrogenase were excluded (Table 3). Weight-loss over the first 3 months was independently associated with an adjusted 3.88 HR of all-cause death in the first model (Table 3). Weight-gain conferred adjusted risk similar to weight-stability in the first model. In the second multivariable model, weight-loss was still independently associated with an increased mortality, whereas weight-gain showed an adjusted 0.48 HR of mortality (Table 3). There was no significant interaction with baseline BMI group, which is also evident from the results presented in Figure 2B: all-cause mortality was highest in patients with weight-loss in all baseline BMI groups except the obesity group, and weight-gain showed similar or lower risk when compared with weight-stability across baseline BMI groups. Weight-gain (as a continuous variable) was associated with a significantly lower mortality risk in both univariable analysis (HR 0.96/kg, P<0.001) and in the second multivariable model (HR 0.97/kg, P=0.034).

4S trial
Of the 4444 patients randomized in the 4S trial, 4178 patients had baseline BMI and 1-year weight values, and no baseline oedema. Of the patients with baseline BMI data, 63 died before the 1-year visit. Of the 4178 patients included in the analysis, 8.3% were underweight, 33.1% normal-weight, 47.7% overweight, and 10.9% obese. Among the 815 (19.5%) patients with weight-loss, 62% were overweight or obese, and 31.5% were normal-weight at baseline. A 1-year weight-loss was found in 14.2% of the underweight patients, 18.6% of the normal-weight, 20% of the overweight, and in 24% of the obese patients. Of the 798 (19.1%) patients with weight-gain, 49% were overweight or obese at baseline.

During follow-up there were 343 deaths: 233 were coronary deaths, 13 were other cardiac deaths, and 55 were cancer deaths. The crude event rates for all-cause mortality were 11.7% in patients with weight-loss, 7.6% in those with weight-stability, and 7.1% among those with weight-gain. The corresponding figures were for coronary death 7.8, 5.2, and 4.7%, and for cancer death 2.0, 1.1, and 1.3%, respectively.

The multivariable model covariate selection for all-cause death resulted in the inclusion into the multivariable model of: age, gender, smoking status, haemoglobin, history of diabetes, hypertension and claudication, randomized treatment with simvastatin/placebo, and inclusion into the 4S trial due to AMI or not. Weight-loss over the first year was independently associated with an adjusted 45% increased hazard of all-cause death (Table 3). Weight-gain conferred adjusted risk similar to weight-stability. There was no significant interaction with baseline BMI group, which is also evident from the results presented in Figure 2C: in all baseline BMI groups, all-cause mortality was highest in patients with weight-loss, and weight-gain showed similar or lower risk when compared with weight-stability. The P-values for interaction between baseline BMI and weight-change were 0.898 for total mortality.

Weight-gain (as a continuous variable) was associated with a significantly lower mortality risk in both univariable (HR 0.96/kg, P=0.004) and multivariable analysis (HR 0.97/kg, P=0.029).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgement
 References
 
In patients following complicated AMI, included in OPTIMAAL, those with 3-month weight-loss had increased risk of all-cause and cardiac mortality over the following 2.7 years, compared with those with weight-stability, independent of baseline BMI and other covariates. The increased risk was particularly evident among patients with pronounced weight-loss and, thus, the risk appeared to be graded. Importantly, patients with weight-gain had risk similar to those with weight-stability in all baseline BMI groups. Our findings were confirmed by comparable analyses of the CONSENSUS II and 4S trials, in patients following AMI or with stable CAD. To the best of our knowledge, this is the first time the prognostic importance of weight-change has been assessed in a large study of patients with AMI or CAD.

The associations between weight-change and prognosis were remarkably consistent across the three studies, despite different time periods of weight-change, various periods of follow-up, and differences in the proportion of patients in the various baseline BMI groups and weight-change groups. Not only weight-change was of prognostic importance, but also baseline BMI; in accordance with prior reports by our group and others,23–26,28–31,39 in all three studies underweight patients had the highest mortality rate, as seen in Figure 2.

From the knowledge of an association between mortality-risk and obesity in healthy subjects, it would be anticipated that weight-loss from an initial state of obesity or overweight would be associated with decreased risk, when compared with stable or increased weight. However, we observed that the increased mortality risk associated with weight-loss was consistent across baseline BMI groups and a clear majority of those with weight-loss were overweight or obese at baseline. Thus, overweight/obese patients contributed the most to the increased risk associated with weight-loss. Moreover, around half of the patients with weight-gain were overweight or obese at baseline in all trials, and still there was no increased risk among those with weight-gain, when compared with those with weight-stability.

The reasons for weight-change in this study are unclear and the study design does not permit any assumptions of causality. Importantly, our findings do not preclude a benefit of weight-loss in response to exercise training as part of a cardiac rehabilitation program40 or in response to careful dietary advice.41 However, the consistently increased mortality risk associated with weight-loss in the present study indicates that weight-loss, at least in some of these patients, may be an ominous prognostic sign. In patients with advanced CHF, weight-loss resulting in cardiac cachexia is a common complication associated with poor prognosis.32,33,42 Evidence suggest that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder and that the wasting process is likely due to catabolic/anabolic imbalance. It is possible that the same mechanisms underlie weight-loss among patients with CAD without manifest CHF, indicating more severe disease as well as worse prognosis. Indeed, the fact that weight-loss was associated with increased risk of cardiac, but not cancer death in OPTIMAAL and 4S trials (not examined in CONSENSUS II due to too few deaths) indicates that the severity of the cardiac condition determines the prognosis. Thus, we propose that one important reason for the observed association between weight-loss and worse prognosis may be pronounced metabolic stress with neurohormonal and cytokine activation,43,44 causing weight-loss and increased mortality risk. All patients with oedema at baseline were excluded from the analyses in an attempt to eliminate weight-loss because of decreased oedema in patients with more severe CHF as a confounder. However, this does not preclude that more severe heart disease contributed to weight-loss and poor prognosis.

It is possible that weight-loss was associated with depression, known to affect survival adversely after AMI.45 We do not have data on depression in the present study. The association between weight-loss and increased mortality was independent of baseline smoking habits. However, theoretically, a larger proportion of patients in the weight-stability and weight-gain groups might have stopped smoking during follow-up, compared with the weight-loss group, contributing to the better prognosis in the former two groups. We do not have data on changes of smoking habits. However, this is an unlikely explanation to our findings; the baseline proportion of smokers among OPTIMAAL patients with weight-gain was two-fold when compared with those with weight-loss. Thus, there would have to be a very pronounced difference between the two groups in terms of patients who stopped smoking, to explain the difference in prognosis, especially since the increased risk associated with smoking remains for quite some time after discontinuing.

The limitations of the present study are mainly due to its post hoc nature. In multivariable analysis we could obviously adjust only for available variables. Therefore, variables not assessed in the study could potentially have affected the observed association between weight-loss and poor prognosis. It is important to remember that patients were somewhat selected, i.e. patients who died before the second body-weight assessment were obviously not included in the analysis.

In conclusion, in 4360 high-risk post AMI patients, 3-month weight-loss was independently associated with increased risk of all-cause and cardiac mortality during the following 2.7 years, compared with weight-stability. The risk increase was particularly evident among patients with pronounced weight-loss. The association between weight-loss and worse survival was confirmed by analyses of 4012 patients following AMI and 4178 patients with stable CAD, most of which had a prior AMI. Importantly, in all three trials, weight-gain conferred risk similar to weight-stability. Our results indicate that there is an independent association between short-term to intermediate-term weight-loss and mortality during short-term to long-term follow-up. The associations between weight-change and prognosis were consistent across baseline BMI-groups. Our findings expand the knowledge about the association between weight-change and prognosis in patients with stable CAD and following AMI and reinforce the need for a better understanding of the intricacies of weight-change among these patients. These associations and their causes should be further assessed in future investigations. We suggest that weight-loss in patients with established CAD should render every doctor's attention and underlying reasons should be explored.


   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
References
 
The OPTIMAAL, CONSENSUS II, and 4S trials were supported by grants from Merck & Co, who also participated in the collection of data in these trials. The authors' work was independent of the funder. L.M.A.K. received a research grant from the Swedish Heart-Lung Foundation. The work was performed at the Department of Cardiology, Malmö University Hospital.

Conflict of interest. M.J. and T.J.C. are employees at Merck & Co. K.K. was an employee at Merck & Co. (now retired), but otherwise there are no conflicts of interest with regard to this article.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 

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J. Wilding and N. Finer
Weight management and cardiovascular disease: implications of recent and ongoing clinical trials
The British Journal of Diabetes & Vascular Disease, July 1, 2008; 8(4): 170 - 176.
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