Lack of “obesity paradox” in patients presenting with ST-segment elevation myocardial infarction including cardiogenic shock: a multicenter German network registry analysis

In Europe, the prevalence of obesity ranges from 4.0 to 36.5 % 17] and it is also well known that obesity acts as an independent cardiovascular risk
factor for the development of coronary artery disease as well as general atherosclerosis
and is associated with increased overall morbidity and mortality 18], 19]. There is evidence that this increased risk is mediated through obesity-related co-morbidities
such as diabetes mellitus, hyperlipidemia, hypertension, increased insulin resistance,
enhanced free fatty acid turnover, and promotion of systemic inflammation 20]. However, despite this correlation there is an assumption of an inverse correlation
of obesity with mortality post PCI and less pronounced with a smaller need for repeat
revascularisation. This has been described as the “obesity paradox” 10], 21]. An analysis of 9,633 patients being stratified in normal weight (n?=?1,923), overweight
(n?=?4,813) and obese (n?=?2,897) undergoing PCI revealed a higher incidence of major
in-hospital complications, including cardiac death (1.0 % vs. 0.7 % vs. 0.4 %; p?=?0.001)
in normal weight than overweight and obese patients despite similar periprocedural
data. This was driven by overall mortality (10.6 % vs. 5.7 % vs. 4.9 %; p??0.0001).
Cardiac mortality (4.8 % versus 3.3 % versus 2.5 %; p??0.0001) was also significantly
higher in normal weight patients; whereas rates of MI and TVR were similar 10]. A large meta-analysis including 250,152 patients with established coronary artery
disease and a mean follow-up of 3.8 years supported these findings with increased
relative risk for overall mortality [RR 1.37 (95 % CI 1.32-1.43)], and cardiovascular
mortality [RR 1.45 (1.16-1.81)] after revascularization in normal weight patients
22]. These results persisted even after adjustment for potential confounders, including
age, arterial hypertension, diabetes, and left ventricular function. Another analysis
on patients with established coronary artery disease undergoing medical, interventional
or surgical treatment showed an “obesity paradox” after revascularisation irrespective
of the chosen strategy. In the whole cohort patients who were overweight or obese
were more likely to undergo revascularization procedures compared with those with
normal BMI, despite having lower risk coronary anatomy 23]. The underlying mechanism of the “obesity paradox” is speculative. Obesity is associated
with lower levels of plasma renin, epinephrine and high serum levels of low-density
lipoproteins that bind circulating lipopolysaccharides 24]. Coronary vessel diameters, as confirmed in out-patient cohorts, have been shown
to correlate with the increase in body weight; thus a smaller coronary artery size
in normal weight and lean patients could theoretically influence periprocedural outcome
25]. The relationship between obesity and survival is characterized in the literature
by a J- or U-shaped curve with increasing mortality in the very lean or severely obese
group 26], 27]; however, after adjustment for smoking and concurrent illness, the relationship has
always been linear 28], 29]. Contrasting with these findings our analysis of high-risk all-comers STEMI population
including patients with cardiogenic shock does not support the presence of an “obesity
paradox”. Although there is a trend for better one-year survival in obese patients,
this difference did not reach statistical significance. However, with access site
being femoral there might be more bleeding events in obese patients, which could be
avoided by radial access. Nevertheless, we think that the term “obesity paradox” might
predominantly reflect different degrees of bias that cannot be completely corrected
for by statistical means. Inherent bias in all obesity analyses result from the fact
that overweight and obese patients are usually younger and have larger culprit coronary
vessel diameters than normal weight counterparts. In general younger patients have
better clinical outcomes after acute MI regardless of reperfusion modality 30], 31]. Additionally, the presence of co-morbidities in obese and overweight younger patients
usually leads to more aggressive therapy of cardiovascular risk factors likely to
improve outcomes despite obesity 30], 31]. In a study of 130,139 patients hospitalized for coronary artery disease, higher
BMI was associated with increased use of standard medical therapies such as aspirin,
beta-blockers, renin-angiotensin inhibitors, and lipid lowering therapy, and an increased
likelihood of undergoing diagnostic catheterization and revascularization 32], 33]. The all-comer design of our registry with the majority of patients having had no
established coronary artery disease before the index STEMI reduces the influence of
potential confounders. Especially promotion of primary PCI in shock patients and after
resuscitation (significantly more frequent in obese and overweight patients) avoided
a severe pre-selection bias. Another point of discussion with respect to the obesity
paradox is that underweight patients may receive standard anti-coagulation doses that
are too high for their body size, making them more prone to post-procedural bleeding
complications, which could be ruled out in our cohort by weight-adjusted doses 3], 5]. In addition obesity was found to correlate with higher levels of factor VII, VIII,
fibrinogen and plasminogen activator inhibitor-1, which were all associated with increased
risk of thrombosis 34]. Accordingly prospective investigations have shown that overweight and obese patients
were more likely to suffer from suboptimal platelet response to clopidogrel and aspirin
treatment 35], 36]. In our cohort the use of GP IIb/IIIa inhibitor was high facing the nature of exclusively
high-risk STEMI patients. Furthermore obesity as well as STEMI is considered a low-grade
inflammatory state, as demonstrated by increased levels of the pro-inflammatory cytokines
interleukin-6 and tumor necrosis factor-alpha, and acute phase proteins such as C-reactive
protein 37]. This proinflammatory state may also directly and indirectly cause thrombosis by
oxidative stress and endothelial dysfunction 38]. Such findings could not be confirmed in our real-world setting with similar rates
of stent thrombosis in all subsets. Since low BMI may be a marker of severe systemic
illness 18], 39], we defined in a separate analysis the normal-weight group from 18.5 kg/m
²
-24.9 kg/m
²
and excluded 5 extremely underweight patients. However, this did not change the previous
findings with lack of an “obesity paradox”. A separate analysis of patients with cardiogenic
shock, which is associated with a prothrombic situation and systemic inflammation,
also revealed no statistical differences in clinical endpoints for all three groups.

Study limitation

The present study is an observational non-randomized study in which patients were
stratified according to their BMI at index-PCI. Thus, we had no information on intended
or unintended weight change, as well as on variables like physical inactivity and
socioeconomic factors which may have influenced the results. BMI is not as well correlated
to cardiovascular disease and death as waist circumference and waist-to-hip ratio,
which, however, were unavailable in our registries. Another limitation of our analysis
is the length of follow-up and small sample size that might result in lack of power
for meaningful conclusions but is reliable enough for hypothesis generation. An extended
follow-up may result in a cumulative detrimental effect of obesity and may even manifest
as increased late mortality and confirm the negative correlation of obesity with clinical
outcomes even in a setting of coronary revascularization. Additionally the access
site during PCI was femoral. With use of radial access site, bleeding events might
be reduced in overweight and obese patients, which might result in better clinical
outcomes as bleeding events correlate with overall mortality and myocardial infarction
rate.