Obesity and cardiovascular disease
Risk factor,paradox and impact of weight loss
Obesity has reached global epidemic proportions in
both adults and children and is associated with
numerous comorbidities, including hypertension
(HTN), type II diabetes mellitus, dyslipidemia,
obstructive sleep apnea and sleep-disordered
breathing, certain cancers, and major cardiovascular
Because of its maladaptive effects on various CV risk
factors and its adverse effects on CV structure and
function, obesity has a major impact on CV diseases,
such as heart failure (HF) , coronary heart disease
(CHD) , sudden cardiac death, and atrial fibrillation,
and is associated with reduced overall survival.
Recent evidence indicates that obesity is associated
with more morbidity than smoking, alcoholism, and
poverty, and if current trends continue, obesity may
soon overtake cigarette abuse as the leading cause of
preventable death in the world.
Adverse Effects of Obesity
A. Increases in insulin resistance
1) Glucose intolerance
2) Metabolic syndrome
3) Type 2 diabetes mellitus
1) Elevated total cholesterol
2) Elevated triglycerides
3) Elevated LDL cholesterol
4) Elevated non-HDL cholesterol
5) Elevated apolipoprotein-B
6) Elevated small, dense LDL particles
7) Decreased HDL cholesterol
8) Decreased apolipoprotein-A1
D. Abnormal left ventricular geometry
1) Concentric remodeling
2) Left ventricular hypertrophy
E. Endothelial dysfunction
F. Increased systemic
G. Systolic and diastolic
H. Heart failure
I. Coronary heart disease
J. Atrial fibrillation
K. Obstructive sleep
Despite this adverse association, numerous studies
have documented an obesity paradox in which
overweight and obese people with established CV
disease, including HTN, HF, CHD, and peripheral
arterial disease, have a better prognosis compared with
nonoverweight/ nonobese patients.
Obesity, HTN, and the obesity paradox
A total of 22,576 hypertensive patients with coronary artery
disease (follow up 61,835 patient years, mean age 66±9.8 years)
were randomized to blood pressure control according to the Sixth
JNC targets. Patients were classified into 5 groups according to
baseline BMI: less than 20 kg/m2 (thin), 20 to 25 kg/m2 (normal
weight), 25 to 30 kg/m2(overweight), 30 to 35 kg/m2 (class I
obesity), and 35 kg/m2 or more (class II-III obesity). The primary
outcome was first occurrence of death, nonfatal myocardial
infarction, or nonfatal stroke.
With patients of normal weight (BMI 20 to 25 kg/m2) as the
reference group, the risk of primary outcome was lower in the
overweight patients (adjusted hazard ratio [HR] 0.77, 95%
confidence interval [CI], 0.70-0.86, P<.001), class I obese patients
(adjusted HR 0.68, 95% CI, 0.59-0.78, P<.001), and class II to III
obese patients (adjusted HR 0.76, 95% CI, 0.65-0.88, P <.001).
Class I obese patients had the lowest rate of primary outcome and
death despite having smaller blood pressure reduction compared
with patients of normal weight at 24 months (17.5±21.9 mm
Hg/9.8±12.4 mm Hg vs 20.7±23.1 mm Hg / 10.6±12.5 mm Hg,
In a population with hypertension and coronary artery
disease, overweight and obese patients had a
decreased risk of primary outcome compared with
patients of normal weight, which was driven primarily
by a decreased risk of all-cause mortality.
Body mass index and prognosis in elderly
hypertensive patients: a report from the
European Working Party on High Blood
Pressure in the Elderly
Jaakko Tuomilehto, M.D., European Working Party on High Blood
Department of Epidemiology, National Public Health Institute,
In the current study of 800 elderly hypertensive
patients randomly assigned to active treatment, the
initial mean body mass index (BMI) was 26.7 kg/m2 in
560 women and 25.7 kg/m2 in 240 men.
During the trial, total mortality and cardiovascular
and noncardiovascular terminating events were
highest in the patients at the leanest BMI quintile. The
association between BMI and cardiovascular end
points was U-shaped, whereas noncardiovascular
mortality decreased with increasing BMI. The results
in the women were similar to those in the total group.
The U-shaped relation was confirmed with Cox's
proportional hazards model, controlling for age,
gender, systolic blood pressure, hemoglobin, serum
cholesterol, blood glucose, and cardiovascular
complications at entry.
The BMI level with the lowest risk was 28 to 29 kg/m2
for total mortality and cardiovascular terminating
events, 26 to 27 kg/m2 for cardiovascular mortality,
and 31 to 32 kg/m2 for noncardiovascular mortality.
BMI did not modify the favorable effects of drug
Obesity, HF, and the obesity paradox.
Body mass index and mortality in heart failure: A
Antigone Oreopoulos, MSca, Raj Padwal, MD, MScb, , , Kamyar Kalantar-Zadeh,
MD, MPH, PhDc, Gregg C. Fonarow, MD, FACCd, Colleen M. Norris, PhDe, Finlay
A. McAlister, MD, MScb
American Heart Journal
Volume 156, Issue 1, July 2008, Pages 13–22
In patients with chronic heart failure (CHF), previous
studies have reported reduced mortality rates in
patients with increased body mass index (BMI). The
potentially protective effect of increased BMI in CHF
has been termed the obesity paradox or reverse
epidemiology. This meta-analysis was conducted to
examine the relationship between increased BMI and
mortality in patients with CHF.
We searched the Cochrane Central Register of
Controlled Trials, MEDLINE, EMBASE, Scopus, and
Web of Science to identify studies with
contemporaneous control groups (cohort, case-control,
or randomized controlled trials) that examined the
effect of obesity on all-cause and cardiovascular
mortality. Two reviewers independently assessed
studies for inclusion and performed data extraction.
Nine observational studies met final inclusion criteria
(total n = 28,209). Mean length of follow-up was 2.7 years.
Compared to individuals without elevated BMI levels, both
overweight (BMI ∼25.0-29.9 kg/m2, RR 0.84, 95% CI
0.79-0.90) and obesity (BMI ∼≥30 kg/m2, RR 0.67, 95%
CI 0.62-0.73) were associated with lower all-cause
mortality. Overweight (RR 0.81, 95% CI 0.72-0.92) and
obesity (RR 0.60, 95% CI 0.53-0.69) were also associated
with lower cardiovascular mortality. In a risk-adjusted
sensitivity analysis, both obesity (adjusted HR 0.88, 95%
CI 0.83-0.93) and overweight (adjusted HR 0.93, 95% CI
0.89-0.97) remained protective against mortality.
Overweight and obesity were associated with lower allcause and cardiovascular mortality rates in patients
with CHF and were not associated with increased
mortality in any study.
An obesity paradox in acute heart failure:
Analysis of body mass index and inhospital
mortality for 108 927 patients in the Acute
Decompensated Heart Failure National
Gregg C. Fonarow, MDa, , , Preethi Srikanthan, MDa, Maria Rosa Costanzo, MDb,
Guillermo B. Cintron, MDc, Margarita Lopatin, MSd, for the ADHERE Scientific
Advisory Committee and Investigators
American Heart Journal
Volume 153, Issue 1, January 2007, Pages 74–8
The Acute Decompensated Heart Failure National
Registry was analyzed for acute HF hospitalizations in
263 hospitals in the United States from October 2001
through December 2004. Patients with documented
height and weight were divided into BMI (measured in
kilograms per square meter) quartiles. In hospital
mortality by BMI quartile for all the patients and for
those with reduced (n = 43 255) and preserved (n = 37
901) systolic function was assessed.
Body mass index quartiles in the 108 927 hospitalizations
were QI (16.0-23.6 kg/m2), QII (23.7-27.7 kg/m2), QIII
(27.8-33.3 kg/m2), and QIV (33.4-60.0 kg/m2). Patients in
the higher BMI quartiles were younger, had more diabetes,
and had a higher left ventricular ejection fraction. In
hospital mortality rates decreased in a near-linear fashion
across successively higher BMI quartiles. After adjustments
for age, sex, blood urea nitrogen, blood pressure,
creatinine, sodium, heart rate, and dyspnea at rest, BMI
quartile still predicted mortality risk. For every 5-U
increase in BMI, the odds of risk-adjusted mortality was
10% lower (95% CI 0.88-0.93, P < .0001).
Obesity, CHD, and the obesity paradox
Obesity plays a major role in adversely affecting major
CHD risk factors, including HTN, dyslipidemia, and
diabetes mellitus (DM), is the major component of
metabolic syndrome, and is probably an independent
risk factor for atherosclerosis and CHD events.
Nevertheless, as with HTN and HF, many studies have
also reported an obesity paradox in CHD, including in
patients treated with revascularization.
Association of bodyweight with total mortality
and with cardiovascular events in coronary
artery disease: a systematic review of cohort
Abel Romero-Corral, MD, Victor M Montori, MD, Prof Virend K Somers,
MD, Josef Korinek, MD, Randal J Thomas, MD, Thomas G Allison, PhD,
Farouk Mookadam, MD, Francisco Lopez-Jimenez, MD.
Volume 368, Issue 9536, 19–25 August 2006, Pages 666–678
We selected cohort studies that provided risk estimates
for total mortality, with or without cardiovascular
events, on the basis of bodyweight or obesity measures
in patients with CAD, and with at least 6 months'
follow-up. CAD was defined as history of percutaneous
coronary intervention, coronary artery bypass graft, or
myocardial infarction. We obtained risk estimates for
five predetermined bodyweight groups: low, normal
weight (reference), overweight, obese, and severely
There were 40 studies with 250,152 patients that had a mean
follow-up of 3·8 years. Patients with a low body-mass index
(BMI) (ie, <20) had an increased relative risk (RR) for total
mortality (RR=1·37 [95% CI 1·32–1·43), and cardiovascular
mortality (1·45 [1·16–1·81]), overweight (BMI 25–29.9) had the
lowest risk for total mortality (0·87 [0·81–0·94]) and
cardiovascular mortality (0·88 [0·75–1·02]) compared with
those for people with a normal BMI. Obese patients (BMI 30–
35) had no increased risk for total mortality (0·93 [0·85–1·03])
or cardiovascular mortality (0·97 [0·82–1·15]). Patients with
severe obesity (≥35) did not have increased total mortality (1·10
[0·87–1·41]) but they had the highest risk for cardiovascular
mortality (1·88 [1·05–3·34]).
This study goal was to determine the impact of lean
mass index (LMI) and body fat (BF) on survival in
patients with coronary heart disease (CHD).
We studied 570 consecutive patients with CHD who
were referred to cardiac rehabilitation, stratified as
Low (25% in men and 35% in women) and High (25%
in men and 35% in women) BF and as Low (18.9
kg/m2 in men and 15.4 kg/m2 in women) and High
LMI, and followed for 3 years for survival.
Mortality is inversely related to LMI (p ‹ 0.0001). Mortality
was highest in the Low BF/Low LMI group (15%), which was
significantly higher than in the other 3 groups, and lowest in
the High BF/High LMI group (2.2%), which was significantly
lower than in the other 3 groups. In Cox regression analysis
as categoric variables, low LMI (hazard ratio [HR]: 3.1; 95%
confidence interval [CI]: 1.3 to 7.1) and low BF (HR: 2.6; 95%
CI: 1.1 to 6.4) predicted higher mortality, and as continuous
variables, high BF (HR: 0.91; 95% CI: 0.85 to 0.97) and high
LMI (HR: 0.81; 95% CI: 0.65 to 1.00) predicted lower
In patients with stable CHD, both LMI and BF predict
mortality, with mortality particularly high in those
with Low LMI/Low BF and lowest in those with High
LMI/High BF. Determination of optimal body
composition in primary and secondary CHD
prevention is needed.
The aim of this study was to investigate the impact of
morbid obesity (body mass index ≥40 kg/m2) on inhospital mortality and coronary revascularization
outcomes in patients presenting with acute myocardial
413,673 patients hospitalized with AMIs in 2009 were reviewed.
Morbidly obese patients constituted 3.7% of all patients with AMIs.
Analysis of the unadjusted data revealed that morbidly obese
patients compared with those not morbidly obese were more likely
to undergo any invasive cardiac procedures when presenting with
either ST-segment elevation myocardial infarction (97.4% vs
93.8%, p <0.0001) or noneST-segment elevation myocardial
infarction (85.5% vs 80.6%, p <0.0001). The unadjusted mortality
rate for morbidly obese patients with AMIs was 3.5%, compared
with 5.5% of those not obese (p <0.0001). After adjustment, lower
odds of mortality in those morbidly obese compared to those not
In conclusion, patients with morbid obesity had lower
odds of in-hospital mortality, compared to those not
morbidly obese, consistent with the phenomenon of
the “obesity paradox.”
An “obesity paradox,” in which overweight and obese
individuals with established cardiovascular disease
have a better prognosis than normal weight subjects,
has been reported in a number of clinical cohorts, but
little is known about the effects of weight loss on the
obesity paradox and its association with health
Weight was determined in 3834 men at the time of a
clinically referred exercise test and again during a
clinical evaluation a mean of 7 years later. The
associations among weight changes, baseline fitness,
and other risk markers with cardiovascular and all
cause mortality were determined by Cox proportional
During the follow-up period, 314 subjects died (72 of
cardiovascular causes). In a multivariate analysis (including
baseline weight, weight change, exercise capacity, and
cardiovascular disease), weight gain was associated with lower
mortality and weight loss was associated with higher mortality (4%
higher per pound lost per year, P.001) compared with stable
weight. For all-cause mortality, the relative risks for the no change,
weight gain, and weight loss groups were 1.0 (referent), 0.64 (95%
confidence interval, 0.50-0.83), and 1.49 (95% confidence interval,
1.17-1.89), respectively (P.001). Those who died and exhibited
weight loss had a significantly higher prevalence of deaths due to
cancer and cardiovascular causes.
Weight loss was related to higher mortality and weight
gain was related to lower mortality when compared
with stable weight.
We sought to investigate the impact of body mass
index (BMI) on long-term all-cause mortality in
patients following first-time elective percutaneous
coronary intervention (PCI).
They used the Scottish Coronary Revascularisation Register to
undertake a cohort study of all patients undergoing elective PCI in
Scotland between April 1997 and March 2006 inclusive. they
excluded patients who had previously undergone revascularization.
There were 219 deaths within 5 years of 4880 procedures.
Compared with normal weight individuals, those with a BMI 27.5
and ,30 were at reduced risk of dying (HR 0.59, 95% CI 0.39–0.90,
95%, P : 0.014). There was no attenuation of the association after
adjustment for potential confounders, including age, hypertension,
diabetes, and left ventricular function (adjusted HR 0.59, 95% CI
0.39–0.90, P : 0.015), and there were no statistically significant
interactions. The results were unaltered by restricting the analysis
to events beyond 30 days of follow-up.
Among patients undergoing percutaneous intervention
for coronary artery disease, increased BMI was
associated with improved 5 year survival.
To find out the severity of coronary atherosclerosis and
its relationship to body structure and adiposity in
severely obese people with body mass index (BMI)
≥35.0 kg/m2 and to examine the incidence and
characteristic features of myocardial infarction and
other fatal coronary events in this population.
Forensic autopsy cases (n =166) with a BMI ≥35.0
kg/m2 examined in 1992 – 1998 were collected from
the files of the Department of Forensic Medicine,
University of Oulu, Finland.
Autopsy reports were analyzed, including data on age,
height, weight, abdominal subcutaneous fat thickness,
heart weight, coronary atherosclerosis, histopathology
and toxicology. Myocardial collagen and arteriolar
structure were examined by computerized image
In a large number of the severely obese individuals, the coronary arteries
were either lesion-free or only fatty streaks were observed (38% of men,
44% of women) and coronary thrombosis was rare (3.8% of men and 1.6%
of women). Cardiac causes of death predominated, cardiomyopathy being
the commonest. Myocardial infarction was the immediate cause of death
in 14.4% of men and 12.9% of the women, and it was associated with
increased heart size in men. Coronary atherosclerosis without any
infarction had been determined as the cause of death in 8.6% of the men
and 8.1% of the women. Abdominal subcutaneous fat thickness had a
significant negative association with the severity of coronary
atherosclerosis in the women, and a decrease in the arteriolar
media=lumen ratio with increasing BMI was observed in the men.
A considerable number of severely obese people have
only fatty streaks and no marked stenosis in their
coronary arteries, even at an advanced age. The large
amounts of subcutaneous adipose tissue in obese
women may provide some protection against coronary
lesion development, which could be an estrogen effect.
Myocardial infarction in severely obese men is
associated with cardiac hypertrophy.
From 409 United States hospitals, 130,139
hospitalizations for CAD were identified with
documented height and weight. Patients were
stratified by BMI, with 3,305 (2.5%) underweight
(BMI <18.5 kg/m2), 34,697 (27%) of healthy weight
(BMI 18.5 to 24.9 kg/m2), 47,883 (37%) overweight
(BMI 25 to 29.9 kg/m2), 37,686 (29%) obese (BMI 30
to 39.9 kg/m2), and 6,568 (5%) extremely obese (BMI
As BMI increased, patients were significantly younger
but more likely to be men and have hypertension,
diabetes, and hyperlipidemia. Unadjusted in-hospital
mortality was highest in the underweight group
(10.4%) and significantly lower in the healthy weight
(5.4%), overweight (3.1%), obese (2.4%), and
extremely obese (2.9%) patients.
Higher BMI was associated with increased use of
standard medical therapies such as aspirin, blockers,
inhibitors of the renin-angiotensin system, and lipidlowering therapy in the hospital and at discharge. In
adjusted analyses, compared with the healthy-weight
group, overweight and obese patients were more likely
to undergo invasive procedures and had lower
mortality (p <0.01 for all odds ratios).
In conclusion, increasing BMI appears to be associated
with better use of guideline-recommended medical
treatment and invasive management of CAD, which
may explain the observed lower rates of in-hospital
We assessed 105 consecutive PH patients for clinical
and hemodynamic parameters, focusing on the
possible association between Body Mass Index (BMI)
and mortality. Follow-up period was 19 ±13 months.
Sixty-one patients (58%) had pre-capillary PH and 39
patients (37%) out-of-proportion post-capillary PH.
During follow-up period, 30 patients (29%) died.
Death was associated with reduced functional-class,
inverse-relation with BMI, higher pulmonary artery
and right atrial pressures, pulmonary vascular
resistance and signs of right ventricular failure.
In multivariate analysis, obesity (BMI 30 kg/m2), was
the variable most significantly correlated with
improved survival [H.R 0.2, 95% C.I 0.1e0.6; p =
0.004], even after adjustment for baseline
characteristics. Obese and very-obese (BMI ≥ 35
kg/m2) patients had significantly less mortality rates
during follow-up (12% and 8%, respectively) than nonobese patients (41%), p = 0.01.
Most studies that have evaluated the association
between the body-mass index (BMI) and the risks of
death from any cause and from specific causes have
been conducted in populations of European origin.
We performed pooled analyses to evaluate the
association between BMI and the risk of death among
more than 1.1 million persons recruited in 19 cohorts
in Asia. The analyses included approximately 120,700
deaths that occurred during a mean follow-up period
of 9.2 years.
In the cohorts of East Asians, including Chinese, Japanese, and
Koreans, the lowest risk of death was seen among persons with a
BMI (the weight in kilograms divided by the square of the height in
meters) in the range of 22.6 to 27.5. The risk was elevated among
persons with BMI levels either higher or lower than that range —
by a factor of up to 1.5 among those with a BMI of more than 35.0
and by a factor of 2.8 among those with a BMI of 15.0 or less. A
similar U-shaped association was seen between BMI and the risks
of death from cancer, from cardiovascular diseases, and from other
Weight loss is associated with short-term amelioration
and prevention of metabolic and cardiovascular risk,
but whether these benefits persist over time is
The prospective, controlled Swedish Obese Subjects Study involved
obese subjects who underwent gastric surgery and
contemporaneously matched, conventionally treated
obese control subjects. We now report follow-up data for subjects
(mean age, 48 years; mean body-mass index, 41) who had been
enrolled for at least 2 years (4047 subjects)
or 10 years (1703 subjects) before the analysis (January 1, 2004).
The follow-up rate for laboratory examinations was 86.6 percent at
2 years and 74.5 percent at 10 years.
After two years, the weight had increased by 0.1 percent in the control
group and had decreased by 23.4 percent in the surgery group (P<0.001).
After 10 years, the weight had increased by 1.6 percent and decreased by
16.1 percent, respectively (P<0.001). Energy intake was lower and the
proportion of physically active subjects higher in the surgery group than
in the control group throughout the observation period. Two- and 10-year
rates of recovery from diabetes, hypertriglyceridemia, low levels of highdensity lipoprotein cholesterol, hypertension, and hyperuricemia were
more favorable in the surgery group than in the control group, whereas
recovery from hypercholesterolemia did not differ between the groups.
The surgery group had lower 2- and 10-year incidence rates of diabetes,
hypertriglyceridemia, and hyperuricemia than the control group;
differences between the groups in the incidence of hypercholesterolemia
and hypertension were undetectable.
As compared with conventional therapy, bariatric
surgery appears to be a viable option for the treatment
of severe obesity, resulting in long-term weight loss,
improved lifestyle, and, except for
hypercholesterolemia, amelioration in risk factors that
were elevated at baseline.
Although gastric bypass surgery accounts for 80% of
bariatric surgery in the United States, only limited
long-term data are available on mortality among
patients who have undergone this procedure as
compared with severely obese persons from a general
In this retrospective cohort study, we determined the
long-term mortality (from 1984 to 2002) among 9949
patients who had undergone gastric bypass surgery
and 9628 severely obese persons who applied for
driver’s licenses. From these subjects, 7925 surgical
patients and 7925 severely obese control subjects were
matched for age, sex, and body-mass index. We
determined the rates of death from any cause and from
specific causes with the use of the National Death
During a mean follow-up of 7.1 years, adjusted long-term mortality from
any cause in the surgery group decreased by 40%, as compared with that
in the control group (37.6 vs. 57.1 deaths per 10,000 person-years,
P<0.001); cause-specific mortality in the surgery group decreased by 56%
for coronary artery disease (2.6 vs. 5.9 per 10,000 person-years, P =
0.006), by 92% for diabetes (0.4 vs. 3.4 per 10,000 person-years, P =
0.005), and by 60% for cancer (5.5 vs. 13.3 per 10,000 person-years,
P<0.001). However, rates of death not caused by disease, such as
accidents and suicide, were 58% higher in the surgery group than in the
control group (11.1 vs. 6.4 per 10,000 person-years, P = 0.04).
Long-term total mortality after gastric bypass surgery
was significantly reduced, particularly deaths from
diabetes, heart disease, and cancer. However, the rate
of death from causes other than disease was higher in
the surgery group than in the control group.
Obesity is associated with increased mortality. Weight
loss improves cardiovascular risk factors, but no
prospective interventional studies have reported
whether weight loss decreases overall mortality. In
fact, many observational studies suggest that weight
reduction is associated with increased mortality.
The prospective, controlled Swedish Obese Subjects
study involved 4047 obese subjects. Of these subjects,
2010 underwent bariatric surgery (surgery group) and
2037 received conventional treatment (matched
control group). We report on overall mortality during
an average of 10.9 years of follow-up. At the time of the
analysis (November 1, 2005), vital status was known
for all but three subjects (follow-up rate, 99.9%).
The average weight change in control subjects was less than
±2% during the period of up to 15 years during which weights
were recorded. Maximum weight losses in the surgical
subgroups were observed after 1 to 2 years: gastric bypass, 32%;
verticalbanded gastroplasty, 25%; and banding, 20%. After 10
years, the weight losses from baseline were stabilized at 25%,
16%, and 14%, respectively. There were 129 deaths in the control
group and 101 deaths in the surgery group. The unadjusted
overall hazard ratio was 0.76 in the surgery group (P = 0.04), as
compared with the control group, and the hazard ratio adjusted
for sex, age, and risk factors was 0.71 (P = 0.01). The most
common causes of death were myocardial infarction (control
group, 25 subjects; surgery group, 13 subjects) and cancer
(control group, 47; surgery group, 29).
Bariatric surgery for severe obesity is associated with
long-term weight loss and decreased overall mortality.
No obesity paradox for morbid obese patients
We examined the prevalence of morbid obesity (body
mass index [BMI] 40 kg/m2) among 227,044 patients
undergoing PCI and enrolled in the Blue Cross Blue
Shield of Michigan Cardiovascular Consortium registry
from 1998 to 2009.
The proportion of morbidly obese patients undergoing PCI
increased from 4.38% in 1998 to 8.36% in 2009.
Compared with overweight patients (BMI 25 to 30 kg/m2),
these patients had significantly increased vascular
complications (adjusted odds ratio [OR]: 1.31; 95% CI: 1.17
to 1.47; p < 0.0001), contrast-induced nephropathy
(adjusted OR: 1.89; 95% CI: 1.70 to 2.11; p < 0.0001),
nephropathy requiring dialysis (adjusted OR: 4.08; 95%
CI: 2.98 to 5.59; p < 0.0001), and mortality (adjusted OR:
1.63; 95% CI: 1.33 to 2.00; p < 0.0001).