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Risk prediction in stable angina pectoris

Thomas Kahan
*,
, Lennart Forslund

, Claes Held

, Inge Bj orkander
*,
, Ewa Billing

, Sven V. Eriksson
*,
,
Per N asman
**
, Nina Rehnqvist

and Paul Hjemdahl

*
Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm,
Sweden,

Department of Cardiology, Danderyd University Hospital Corp, Stockholm, Sweden,

Medical Products Agency,
Uppsala, Sweden,

Uppsala Clinical Research Centre, Department of Medical Sciences, Uppsala University, Uppsala,
Sweden,

Department of Medical Sciences, Uppsala University, Uppsala, Sweden,
**
Centre for Safety Research, The Royal
Institute of Technology KTH, Stockholm, Sweden,

The Swedish Council on Technology Assessment in Health Care (SBU),
Stockholm, Sweden,

Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska University Hospital (Solna),
Stockholm, Sweden
ABSTRACT
Background Although stable angina pectoris often carries a favourable prognosis, it remains important to
identify patients with an increased risk of cardiovascular (CV) complications. Many new markers of disease
activity and prognosis have been described. We evaluated whether common and easily accessible markers in
everyday care provide sufcient prognostic information.
Materials and methods The Angina Pectoris Prognosis Study in Stockholm treated 809 patients (248 women)
with stable angina pectoris with metoprolol or verapamil double blind during a median follow-up of 34 years,
with a registry-based extended follow-up after 91 years. Clinical and mechanistic variables, including lipids and
glucose, renal function, ambulatory and exercise-induced ischaemia, heart rate variability, cardiac and vascular
ultrasonography, and psychosocial variables were included in an integrated analysis. Main outcome measures
were nonfatal myocardial infarction (MI) and CV death combined.
Results In all, 139 patients (18 women) suffered a main outcome. Independent predictive variables were (odds
ratio [95% condence intervals]), age (104 per year [100;108], P = 0041), female sex (033 [016;069],
P = 0001), fasting blood glucose (1.29 per mM [1.14; 1.46], P < 0001), serum creatinine (102 per lM
[100;103], P < 0001) and leucocyte counts (121 per 10
6
cells/L [106;140], P = 0008). Smoking habits, lipids
and hypertension or a previous MI provided limited additional information. Impaired fasting glucose was as
predictive as manifest diabetes and interacted adversely with serum creatinine. Sexual problems were
predictive among men.
Conclusions Easily accessible clinical and demographic variables provide a good risk prediction in stable angina
pectoris. Impaired glucose tolerance and an elevated serum creatinine are particularly important.
Keywords Coronary artery disease, gender, human, prognosis, risk factor.
Eur J Clin Invest 2013; 43 (2): 141151
Introduction
Angina pectoris is a common condition with worrying symp-
toms and an increased risk of suffering cardiovascular (CV)
complications such as an acute myocardial infarction (MI) or
death. Although the long-term prognosis for patients with
stable angina pectoris is generally favourable [1,2], the
prognosis varies considerably depending on the severity of the
disease. Thus, it is important to have valid and clinically useful
markers for the prediction of CV risk of patients with stable
angina pectoris to identify high-risk patients in need of intense
preventive or therapeutic strategies at an early stage. Although
several prognostic markers for patients with coronary artery
disease have been described, and the search for new markers is
still very active, these markers are often sophisticated and not
always applicable in an ordinary clinical setting.
The Angina Prognosis Study in Stockholm (APSIS) study was
a prospective, randomised study comparing the effects of
treatment with the -blocker metoprolol and the heart rate
lowering calcium antagonist verapamil on prognosis in patients
with stable angina pectoris [3]. There was no overall difference
between the two drugs with regard to prognosis [3]. In addition
European Journal of Clinical Investigation Vol 43 141
DOI: 10.1111/eci.12025
ORIGINAL ARTICLE
to comparing the effects of the drugs on CV events, we exam-
ined a number of variables considered to have potential
prognostic importance. They were chosen to reect metabolic,
atherothrombotic, psychosocial, electrophysiological and other
factors related to coronary artery disease (Table 1).
Few studies have actually examined how patients with stable
angina pectoris are best evaluated in everyday clinical practice
regarding their risk of suffering major CV events. Thus, the
purpose of this long-term follow-up of the APSIS study popu-
lation was to compare the many different prognostic variables
that had been assessed to identify independent markers that are
useful in an ordinary clinical setting.
Materials and methods
Patients
In all, 1276 patients with a clinical history of stable angina
pectoris were referred to the Cardiovascular Research Centre at
Danderyd University Hospital, and 809 patients (248 women)
were included during 19871993 in the APSIS study [3]. Inclu-
sion criteria were age below 70 years and a typical history of
stable angina pectoris. When in doubt, additional examinations
(e.g. exercise test, perfusion scintigraphy and radiological or
gastrointestinal investigations) were performed to conrm the
diagnosis. Coronary angiography and other invasive methods
were not required for inclusion because the study focused on
the management of a general population of patients with
angina pectoris in everyday clinical practice. Exclusion criteria
included an acute MI within the past 3 years, anticipated need
for revascularisation within 1 month, signicant valvular dis-
ease or severe congestive heart failure. Details have been
described previously [3]. The median follow-up of the original
APSIS study was 34 years, with a minimum of 6 months. After
study termination (i.e. by 31 December 1993), the patients were
referred for usual care with the recommendation that the ran-
domized treatment could be continued openly because there
was no apparent prognostic benet of either drug [3].
Initially studied variables
Investigations performed at baseline and during the double-
blind treatment period according to the APSIS study protocol
included bicycle exercise testing [11,15]; 24-h ambulatory long-
term electrocardiographic registrations including analyses of
ST segment depression, arrhythmias and heart rate variability
within the time and frequency domains and by the differential
index [11,13,14,16,17]; and left ventricular dimensions and
systolic function by echocardiography [18]. Laboratory tests
included standard blood chemistry [7,9,19], glucose metabo-
lism [4], and haemostatic mechanisms and endothelial function
[7]. Renal function was estimated by serum creatinine levels,
for which values below 100 lM in women and 110 lM in men
Table 1 Previously analysed predictors of a nonfatal myo-
cardial infarction or cardiovascular death during the double-
blind study period of 34 years
Median follow-up
34 years
References Univariate Multivariate
Demographic and history
Male sex < 0001 < 001 [3]
Age < 001 < 005 [3]
History of hypertension < 001 < 005 [3]
Previous myocardial
infarction
< 005 ns [3]
History of congestive
heart failure
< 005 ns [3]
Metabolic and haemostatic
Fasting blood
glucose 61 mM
< 0001 < 001 [4]
Diabetes mellitus < 0001 < 001 [2,4]
Estimated creatinine
clearance
< 005 < 005 [5]
VCAM 005 [6]
tPA-antigen < 005 < 005 [7]
PAI-1 < 005 < 005 [7]
Apolipoprotein A-1 < 0001 < 005 [8]
HDL-cholesterol < 005 [8]
Triglycerides < 001 [8]
Fibrinogen < 0001 < 001 [9]
Leucocyte counts < 0001 < 005 [9]
ECG, LTER
ST depression at
2 min of rest
< 0001 < 0001 [10]
Maximal ST depression
during exercise
< 001 < 001 [10]
Exercise duration
(only in men)
< 001 < 0001 [10]
ST depression
during LTER
< 005 < 005 [11]
ST depression > 30 min
during LTER
< 005 [11]
Echocardiography
LVEDD < 0001 [12]
LVESD < 0001 [12]
142 2012 The Authors. European Journal of Clinical Investigation 2012 Stichting European Society for Clinical Investigation Journal Foundation
T. KAHAN ET AL. www.ejci-online.com
were considered normal, and by creatinine clearance, calcu-
lated according to the CockroftGault formula [5].
Specially trained research nurses performed an interview
regarding psychosocial factors based on standardised ques-
tionnaires for the evaluation of psychosomatic symptoms, job
strain, self-rated Type A behaviour including hostility, sleep
disturbances and self-rated overall life satisfaction. Psycho-
somatic symptoms were recorded using questions concerning
physical and psychological symptoms, such as sexual problems
and tiredness. Details and results have been presented [20,21].
Risk stratication
For the purpose to stratify randomization for the double-blind
treatment period in the APSIS study, a clinical risk stratication
based on signs and symptoms was made, according to accepted
clinical practice at the time of the study. Patients with vaso-
spastic angina pectoris were classied as having low risk.
Patients with effort-induced or mixed angina pectoris were
classied according to three indicators of risk (age 60 years,
electrocardiographic signs suggesting multivessel disease dur-
ing exercise testing and clinical signs of left ventricular
dysfunction).
Extended follow-up and denition of end points
An extended clinical follow-up was performed using complete
national registry data that were available until 31 December
1999, resulting in a median follow-up of 91 years (range, 78
147 months) [2]. Mortality data were based on the Swedish
National Death Registry, which provides complete data on
mortality and causes of death for all Swedish residents, and the
Swedish National Hospital Discharge Registry, which provides
reliable data on all hospitalizations for nonfatal MI [22]. Pri-
mary end points were CV death or nonfatal MI. CV death was
predened as a primary cause of death coded as 402, 404, 410
414 and 420429 (ICD-9) or I10-I13, I20-I29, I30- I43, I44-I49, I50,
I51 and I52 (ICD-10) and was always conrmed by two cardi-
ologists. An acute MI was considered to have occurred on the
date of a hospital admission resulting in a discharge diagnosis
of an acute MI (ICD-9 code 410 or ICD-10 code I20). For the
composite end point of CV death or MI, the date of the rst
event was considered to be the time of the end point.
Statistical analysis and data management
Previously identied relevant prognostic markers were
included in the multivariate analyses. The primary analysis was
performed on the total study cohort and included risk group;
angina class according to the Canadian Cardiovascular Society
(CCS); histories of a previous MI, hypertension or diabetes
mellitus; smoking; psychosocial and sexual problems; demo-
graphic data (age, sex and waist circumference); laboratory
variables (creatinine, estimated creatinine clearance, uric acid,
leucocyte counts, fasting blood glucose, total, low-density lipo-
protein (LDL) and high-density lipoprotein (HDL) cholesterol,
apolipoprotein A-1 and triglycerides); and heart rate variability
assessed by the differential index method. Also, the randomized
treatment (i.e. metoprolol or verapamil) was accounted for.
Some variables were not available for all subjects. The num-
bers of patients with data available were as follows: risk group,
809; CCS class, 803; histories of a previous MI, hypertension,
diabetes mellitus and tobacco use, 809, psychosocial and sexual
problems, 745; age and sex, 809; waist circumference, 792;
Table 1 Continued
Median follow-up
34 years
References Univariate Multivariate
LV mass index < 0001 [12]
Left atrial diameter < 0001 [12]
Autonomic function
Differential index < 00001 < 0001 [13]
SDNN < 0001 < 005 [13]
pNN50 < 001 < 005 [13]
Total power 0007 < 005 [14]
Low frequency 0003 < 005 [14]
High frequency < 0001 < 005 [14]
Normalized very
low frequency
< 0001 < 005 [14]
Normalized low
frequency
< 001 < 005 [14]
Psychosocial
Sexual problems < 0001 Unpublished
Tired < 001 Unpublished
Push myself hard
in competition
< 001 Unpublished
Have often
chest pain
< 001 Unpublished
Feel breathless
on exercise
< 001 Unpublished
VCAM, vascular cell adhesion molecule-1; tPA, tissue plasminogen activator;
PAI-1, plasminogen activator inhibitor-1; HDL, high-density lipoprotein; ECG,
electrocardiography; LTER, long-term ambulatory electrocardiography
recording; LVEDD and LVESD, left ventricular end systolic and end diastolic
diameter; LV, left ventricular; SDNN, standard deviation of normal-to-normal
beats; and pNN50, percentage of differences between adjacent RR intervals.
Probability values for univariate and multivariate analyses during the dou-
ble-blind study period of 34 years, as previously presented. Results pre-
sented for echocardiography were calculated for cardiovascular death only.
European Journal of Clinical Investigation Vol 43 143
RISK PREDICTION IN ANGINA PECTORIS
creatinine and estimated creatinine clearance, 808; uric acid,
787; leucocyte counts, 714; fasting blood glucose, 790; total
cholesterol, 786; LDL- and HDL-cholesterol, 785; apolipopro-
tein A-1, 780; triglycerides, 785; and heart rate variability, 723.
Thus, secondary analyses were performed in an expanded
subset of patients, in whom we excluded all variables resulting
in missing data in the multivariate analyses for more than 100
subjects (i.e. heart rate variability, leucocyte counts, and psy-
chosocial and sexual problems).
Data are presented as mean values and standard deviations
or odds ratios (per 1 unit change) with 95% condence inter-
vals, unless otherwise stated. We used Students t-test and
analysis of variance with the post hoc test proposed by Fisher
after validation for normal distribution by the use of the
ShapiroWilk test and log transformation of data or nonpara-
metric tests for continuous data, as appropriate. We used the
chi-square test or Fishers exact test for variables in contingency
tables. The Pearson correlation coefcient was used to test the
independence between variables. Life table curves were calcu-
lated according to KaplanMeier and compared using log-rank
tests. Cox regression analyses were used to identify predictive
factors. STATISTICA version 5.5 for PC (StatSoft, Tulsa, OK, USA)
and the SAS system for Windows 9.2 (SAS Institute Inc., Cary,
NC, USA) were used. A probability (P) value of < 005 was
considered signicant.
The Ethics Committee of the Karolinska Institute approved
the study and its extended follow-up. Informed consent was
obtained from each patient. Reporting of the study conrms to
CONSORT and STROBE statements [23].
Results
Primary analysis of the entire study cohort
General. In all, 809 patients were included, 248 (31%) women
and 561 (69%) men. Selected background characteristics are
presented in Table 2. The duration of angina pectoris was
37 45 years (39 47 years in men and 33 38 years in
women). Medications at baseline aside of study drugs were
acetylsalicylic acid (39%), long acting nitrates (52%), angio-
tensin-converting enzyme inhibitors (6%), lipid-lowering drugs
(6%) and digoxin (3%); unfortunately, reliable data on medi-
cation during follow-up are not available. During the median
follow-up of 91 years, 139 (17%) patients (18 women and 121
men) suffered either a nonfatal MI or CV death as a rst event.
Coronary angiography was performed on clinical grounds due
to unstable or incapacitating angina pectoris in 139 patients
(17%) with subsequent coronary artery bypass grafting or per-
cutaneous coronary artery intervention (PCI) in 102 (12%)
during the double-blind treatment period [3] (no information is
available for the extended follow-up).
A multivariate analysis of risk markers for a nonfatal MI or
CV death with complete and valid observations including
clinical presentation of the angina pectoris, CCS class, history of
a previous MI, hypertension, diabetes, history of smoking,
psychosocial and sexual problems, age, sex, waist circum-
ference, creatinine, estimated creatinine clearance, uric acid,
leucocyte counts, fasting blood glucose, total, LDL- and HDL-
cholesterol, apolipoprotein A-1, triglycerides and heart rate
variability provided data from 541 subjects, of whom 93 had
reached a primary endpoint. Their background characteristics
were comparable to the entire study cohort of 809 patients.
Thus, mean age was 59 7 years; body mass index,
Table 2 Background characteristics of the entire study popu-
lation
All Men Women
Number of subjects 809 561 248
Age, years 59 7 59 8 59 7
Body mass index, kg/m
2
26 4 26 3 26 4
Systolic blood
pressure, mmHg
143 21 144 21 141 20
Diastolic blood
pressure, mmHg
84 10 86 10 83 10
Heart rate, beats/min 65 12 64 12 66 12
Left ventricular
mass index, g/m
2
98 26 104 25 87 24
Active smokers, % 22 25 15
Previous smokers, % 43 48 31
Previous myocardial
infarction, %
16 20 7
Previous CABG or PCI, % 6 7 2
History of congestive
heart failure, %
7 6 7
History of hypertension, % 27 28 25
Diabetes mellitus, % 9 10 6
Fasting blood glucose, mM 53 16 54 16 51 14
Serum creatinine, lM 97 18 102 17 87 15
Total cholesterol, mM 66 12 66 12 68 13
LDL-cholesterol, mM 46 13 46 10 47 12
HDL-cholesterol, mM 12 03 11 03 14 03
Leucocyte counts, 10
6
cells/L 60 17 62 17 56 17
CABG, coronary artery bypass grafting; PCI, percutaneous coronary artery
intervention; LDL and HDL, low-density and high-density lipoprotein.
Mean values SD.
144 2012 The Authors. European Journal of Clinical Investigation 2012 Stichting European Society for Clinical Investigation Journal Foundation
T. KAHAN ET AL. www.ejci-online.com
26 3 kg/m
2
; blood pressure, 144 21/85 10 mmHg;
heart rate, 65 12 beats/min; left ventricular mass index,
100 27 g/m
2
; active smokers, 22%; and previous smokers,
43%; previous MI, 16%; history of congestive heart failure, 6%;
hypertension, 28%; or diabetes mellitus, 9%; fasting blood
glucose, 536 160 mM; serum creatinine, 97 19 lM; total
cholesterol, 67 12 mM; LDL-cholesterol, 46 11 mM;
HDL-cholesterol, 12 03 mM; and leucocyte counts 60 16
10
6
cells/L.
Selected background characteristics according to outcome are
given in Table 3. The results of the primary analysis showed
that increasing age, male sex and increasing baseline levels of
creatinine, fasting blood glucose and leucocyte counts all pro-
vided independent prognostic information regarding the risk of
suffering a nonfatal MI or CV death (Table 4).
Analyses of the entire study cohort according to sex. Men
had a worse prognosis than women (Fig. 1a). A multivariate
analysis in 374 men with 83 endpoints showed (odds ratios per
unit with 95% condence intervals) that fasting blood glucose
(127 per mM [111; 145], P < 0001), serum creatinine (102 per
lM [100; 103], P = 0004) and sexual problems (184 [102;
332], P = 0042) provided independent prognostic information
concerning a nonfatal MI or CV death.
In a corresponding multivariate analysis in women, 167
patients were included, but only 10 of them reached a primary
endpoint. Leucocyte counts (180 per 10
6
cells/L [124; 206],
P < 0001) and serum creatinine (104 per lM [100; 108],
P = 0020) provided independent prognostic information
among the women.
Analyses of the entire study cohort according to glucose
metabolism. A fasting glucose level above 60 mM was asso-
ciated with a worsened prognosis (Fig. 1b). Among 87 patients
with glucose > 60 mM, 35 had primary endpoints. A multi-
variate analysis of these patients showed that serum creatinine
(105 per lM [101; 108], P = 0006), sexual problems (426 [135;
1344], P = 0016) and CCS class (319 [113; 902, P = 0030)
provided independent prognostic information. Patients with
impaired fasting blood glucose had a similarly worsened
prognosis as those with diabetes mellitus (Fig. 1b).
Analyses in patients with a normal fasting glucose level (454
patients with 58 primary endpoints) largely conrmed ndings
in the total study cohort. Thus, female sex (028 [012; 064],
Table 3 Background characteristics of the study population
according to outcome
Event-free survival Primary event
Number of subjects 670 139
Age, years 59 6 62 6
Body mass index, kg/m
2
26 3 26 4
Systolic blood
pressure, mmHg
143 20 144 22
Diastolic blood
pressure, mmHg
85 10 85 10
Heart rate, beats/min 65 11 65 12
Left ventricular
mass index, g/m
2
98 27 108 28
Active smokers, % 20 28
Previous smokers, % 43 42
Previous myocardial
infarction, %
14 28
Previous CABG or PCI, % 5 11
History of congestive
heart failure, %
6 10
History of hypertension, % 25 38
Diabetes mellitus, % 7 17
Fasting blood glucose, mM 52 13 60 23
Serum creatinine, lM 96 16 104 24
Total cholesterol, mM 67 12 67 13
LDL-cholesterol, mM 46 11 46 12
HDL-cholesterol, mM 12 03 11 03
Leucocyte counts, 10
6
cells/L 59 16 66 17
CABG, coronary artery bypass grafting; PCI, percutaneous coronary artery
intervention; LDL and HDL, low-density and high-density lipoprotein.
Mean values SD. The primary outcome was nonfatal myocardial infarction
or cardiovascular death combined.
Table 4 Primary multivariate analysis of risk markers in the
entire study cohort for a nonfatal myocardial infarction or
cardiovascular death
Odds ratio 95% CI P
Age, years 104 100; 108 0041
Female sex 033 016; 069 0001
Glucose, mM 129 114; 146 < 0001
Serum creatinine, lM 102 100; 103 < 0001
Leucocyte counts, 10
6
cells/L 121 106; 140 0008
CI, condence interval.
Data from 541 subjects; 93 had an endpoint. Odds ratios are given for 1 unit
change (where appropriate). Multivariate analysis including clinical presen-
tation of angina pectoris, Canadian angina class, history of a previous
myocardial infarction, hypertension, diabetes, history of smoking,
psychosocial and sexual problems, age, sex, waist circumference, creatinine,
estimated creatinine clearance, uric acid, leucocyte counts, fasting blood
glucose, total, LDL- and HDL-cholesterol, apolipoprotein A-1, triglycerides,
and heart rate variability (differential index).
European Journal of Clinical Investigation Vol 43 145
RISK PREDICTION IN ANGINA PECTORIS
P < 0001), leucocyte counts (127 per 10
6
cells/L [108; 149],
P = 0007) and age (106 per year [102; 111], P = 0007) pro-
vided independent prognostic information concerning CV
death or MI.
Analyses of the entire study cohort according to creatinine
levels. The prognostic implications of an elevated serum cre-
atinine (i.e. 100 lM in women and 110 lM in men) are
illustrated in Fig. 1c. A multivariate analysis in 122 patients
with elevated creatinine levels and 33 endpoints showed that
diabetes (862 [215; 3458], P < 0001), leucocyte counts (155
per 10
6
cells/L [114; 211], P = 0003), total cholesterol (056 per
mM [036; 087], P = 0016) and waist circumference (106 per
cm [101; 112, P = 0026) were independent predictors of CV
death or MI.
Analyses in patients with normal serum creatinine levels (419
patients with 60 primary endpoints) largely conrmed ndings
made in the total study cohort. The results from such individ-
uals with all variables available showed that female sex (022
[009; 052], P < 0001), fasting glucose (120 per mM [103; 140],
P = 0006) and a history of an acute MI (229 [103; 140],
P = 0017) provided independent prognostic information.
Secondary analysis of an expanded subset of
patients
Additional secondary analyses were performed in a subset of
patients, in whom we excluded all variables resulting in miss-
ing data in the multivariate analyses for more than 100 subjects,
that is, heart rate variability, leucocyte counts, and psychosocial
and sexual problems. In 736 subjects with 128 primary
endpoints, the following risk markers could be included in a
multivariate analysis: clinical presentation of angina pectoris,
CCS class, histories of a previous MI, hypertension, diabetes,
smoking, age, sex, waist circumference, creatinine, estimated
100
095
Women
090
085
P < 0001
080
075
500 0
070
2000 3000 2500 3500 4000 1500 1000
Men
Days
(a)
100
No diabetes and
glucose < 60 mmol/L
090
080
070
P < 0001
No diabetes and
glucose > 60 mmol/L
060
050
Diabetes
500 2000
Days
3000 2500 3500 4000 1500 1000 0
(b)
100
095
090
Normal creatinine
085
P < 0001
080
075
070
Elevated creatinine
500 2000
Days
3000 2500 3500 4000 1500 1000 0
(c)
Figure 1 Cumulative proportions of patients surviving without a cardiovascular death or an acute nonfatal myocardial infarction
(MI); o show complete events and + show censored events. (a) Hatched and solid lines denote women and men, respectively. There
was a signicant difference between women and men, P < 0001. (b) Solid, hatched and dotted lines denote fasting blood glucose
6 mM and no diabetes mellitus, known diabetes, and fasting blood glucose > 6 mM but no known diabetes, respectively. There
was a signicant difference between nondiabetic patients with low blood glucose levels and the other two groups, P < 0001. (c).
Solid and hatched lines denote normal and elevated serum creatinine levels, respectively, where values below 100 lM in women
and 110 lM in men were considered normal. There was a signicant difference between the groups, P < 0001.
146 2012 The Authors. European Journal of Clinical Investigation 2012 Stichting European Society for Clinical Investigation Journal Foundation
T. KAHAN ET AL. www.ejci-online.com
creatinine clearance, uric acid, fasting blood glucose, total,
LDL- and HDL-cholesterol, apolipoprotein A-1 and triglyce-
rides.
Multivariate analysis conrmed the independent prognostic
information for age, sex, fasting blood glucose and serum
creatinine (Table 5). In addition, a previous MI, smoking,
apolipoprotein A-1 and a history of hypertension provided
independent prognostic information concerning CVdeath or MI.
Further analyses of the expanded subset according to sex,
glucose metabolism and serum creatinine are summarized in
Table 6.
Discussion
This prospective study with a long follow-up (median,
91 years) shows that medically treated patients with stable
angina pectoris who underwent coronary angiography for
revascularization only when required have a good prognosis
[2], in agreement with the ndings of other studies [1]. Of note,
most patients with stable coronary artery disease have a simi-
larly favourable prognosis on medical therapy as after invasive
treatment [1, 24]. Although several markers may predict prog-
nosis over a few years in stable angina pectoris (Table 1), our
major nding is that a few readily available risk factors, that is,
age, sex, serum creatinine, blood glucose and leucocyte counts
are of considerable value when predicting long-term CV risk.
Smoking habits, lipids and a history of hypertension or MI
provide additional information. The present results in patients
with stable angina pectoris are much in agreement with nd-
ings in patients with a rst acute MI [25] and in the general
population [2628], suggesting that relatively few risk factors
are needed for risk prediction in ordinary health care. How-
ever, the clinical situation sometimes demands further investi-
gations, and such information can be of value for the diagnosis
and the choice of specic treatment for the individual patient.
Fasting blood glucose above 60 mM was associated with an
equally worsened prognosis as a diagnosis of type 2 diabetes.
This suggests that already an impaired fasting glucose
increases CV risk and that hyperglycemia per se rather than the
diagnosis of diabetes predicts outcome. Similar observations
have been made in hypertensive patients [29] and in patients at
high CV risk [30]. Of note, our results were based on a single
measurement, illustrating the strong prognostic power of fast-
ing blood glucose, and indicate that glucose is a continuous risk
factor beyond the threshold for diabetes. A glucose tolerance
test or assessment of haemoglobin A1c may have provided
even stronger prognostic information [31], but determination of
fasting glucose is a feasible and valuable prognostic marker
that can be assessed in every clinical setting.
Our ndings that CCS class, serum creatinine and sexual
problems (in men) predicted prognosis in patients with ele-
vated glucose levels may suggest that endothelial dysfunction
and atherosclerotic target organ damage (as reected by e.g.
angina pectoris, renal dysfunction and sexual problems) may
be of greater prognostic importance in patients with impaired
glucose tolerance or diabetes than in those with normal blood
glucose metabolism.
Elevated serum creatinine, assumed to reect renal dys-
function, was a marker for future CV events, in agreement with
ndings in patients with acute coronary artery disease [32].
Furthermore, a fasting blood glucose level above 6 mM was
associated with an eightfold increased risk for a future CV
event in patients with elevated serum creatinine levels. Thus,
the combination of impaired glucose tolerance or diabetes and
renal dysfunction appears to be particularly unfavourable in
patients with stable angina pectoris. Furthermore, in the cur-
rent study, risk prediction by serum creatinine was superior to
estimated creatinine clearance. We have previously shown that
estimated creatinine clearance provides risk prediction, partic-
ularly among men [5]. However, in the present multivariate
analyses, serum creatinine was a simple and useful marker for
CV risk in stable angina pectoris.
Inammation contributes to atherosclerotic disease, and
various markers for increased inammatory activity such as
high sensitivity CRP and leucocyte counts have been associated
with a worsened prognosis [33]. We found no prognostic
information in orosomucoid measurements, whereas leucocyte
counts were predictive, as reported previously [9]. Unfortu-
nately, high sensitivity CRP could not be measured in this
Table 5 Secondary multivariate analysis of risk markers for a
nonfatal myocardial infarction or cardiovascular death in the
expanded subset of patients
Odds ratio 95% CI P
Age, years 104 101; 108 0008
Female sex 047 026; 086 < 0001
Glucose, mM 130 116; 145 < 0001
Serum creatinine, lM 101 100; 102 < 0001
Previous myocardial infarction 172 106; 279 0034
Smoking 130 103; 164 0036
Apolipoprotein A-1, g/L 042 018; 100 0041
History of hypertension 154 100; 238 0049
CI, condence interval.
Data from 736 subjects; 139 had an endpoint. Odds ratios are given for 1 unit
change (where appropriate). Multivariate analysis including clinical presen-
tation of angina pectoris, Canadian angina class, history of a previous
myocardial infarction, hypertension, diabetes, history of tobacco use, age,
sex, waist circumference, creatinine, estimated creatinine clearance, uric
acid, fasting blood glucose, total, LDL- and HDL-cholesterol, apolipoprotein
A-1 and triglycerides.
European Journal of Clinical Investigation Vol 43 147
RISK PREDICTION IN ANGINA PECTORIS
Table 6 Secondary multivariate analyses of risk markers according to sex, glucose metabolism and creatinine levels for a nonfatal
myocardial infarction or cardiovascular death in the expanded subset of patients
Odds ratio 95% CI P
Sex
Men, 544 patients and 111 primary endpoints
Glucose, mM 128 113; 144 < 0001
Previous myocardial infarction 200 122; 329 0003
Serum creatinine, lM 102 100; 103 0015
Smoking 129 101; 165 0038
Women, 234 patients and 17 primary endpoints
Glucose, mM 146 114; 188 < 0001
Estimated creatinine clearance, mL/min 096 092; 099 0019
Glucose metabolism
Fasting glucose > 60 mM, 115 patients and 45 primary endpoints
Smoking 187 112; 314 0014
Estimated creatinine clearance, mL/min 102 108; 105 0015
CSS class 253 104; 615 0036
Fasting glucose 60 mM, 621 patients and 83 primary endpoints
Age, years 106 102; 110 0004
Female sex 034 020; 076 < 0001
Apolipoprotein A-1, g/L 027 009; 079 0012
History of hypertension 179 109; 300 0021
Previous myocardial infarction 200 122; 329 0038
Smoking 129 101; 165 0038
Creatinine level
Elevated serum creatinine ( 100 lM in women, 110 lM in men), 169 patients and 41 primary endpoints
Glucose, mM 157 124; 199 < 0001
Total cholesterol, lM 059 041; 085 0012
Waist circumference, cm 110 104; 116 0035
Normal serum creatinine (< 100 lM in women, < 110 lM in men), 567 patients and 83 primary endpoints
Female sex 031 017; 059 < 0001
Age, years 104 100; 108 0012
Glucose, mM 122 106; 139 0002
History of hypertension 180 107; 302 0023
Previous myocardial infarction 246 139; 435 0039
CI, condence interval.
Odds ratios are given per 1 unit change (where appropriate). Multivariate analysis including clinical presentation of angina pectoris, Canadian angina class
(CSS class), history of a previous myocardial infarction, hypertension, diabetes, history of smoking, age, sex, waist circumference, creatinine, estimated cre-
atinine clearance, uric acid, fasting blood glucose, total, LDL- and HDL-cholesterol, apolipoprotein A-1 and triglycerides.
148 2012 The Authors. European Journal of Clinical Investigation 2012 Stichting European Society for Clinical Investigation Journal Foundation
T. KAHAN ET AL. www.ejci-online.com
study, which is a potential limitation of the study. Indeed,
leucocyte counts provided valuable contributions to the risk
prediction also in the present long-term follow-up of the study,
especially among women and in patients with elevated serum
creatinine.
Sexual problems provided negative prognostic information
in men only. This is in agreement with ndings that erectile
dysfunction may be a consequence of underlying endothelial
dysfunction and a marker for CV disease, as reviewed else-
where [34]. Patients with diabetes have impaired endothelial
function. Accordingly, the relationship between sexual prob-
lems and a future CV event was much stronger in patients with
elevated fasting blood glucose. However, autonomic dysfunc-
tion can cause erectile dysfunction, is common in diabetic
patients and may also have contributed to this observation. We
have previously reported that patients with stable angina pec-
toris experienced more stressful events and reported more
sleep disturbances and psychosomatic symptoms than healthy
control subjects [20]. Psychosocial factors and stress are asso-
ciated with coronary artery disease and have been implicated in
the genesis of atherosclerotic disease [35,36]. However, our
results do not show that markers for psychosocial problems
provide independent prognostic information in patients with
stable angina pectoris.
Comparisons of the value of newer and traditional risk
markers have shown little additional prediction by including
the new markers [3739]. The present results support this
contention and show that traditional risk markers provide
excellent prediction of prognosis. Thus, in patients with stable
angina pectoris, a limited history from a routine outpatient visit
and a small standard blood test panel may provide sufcient
information to predict the future risk for an acute MI or a fatal
CV event.
This study has important limitations. We included patients
with a history of stable angina pectoris. Subjects with symp-
toms suggesting a need for prompt revascularisation and
patients with a recent acute MI were excluded. Thus, our
ndings may not be applicable to all patients with stable cor-
onary artery disease. Second, the study included 809 patients,
but the primary multivariate analysis with complete and valid
observations included data from fewer (541) subjects. Missing
results for certain variables in some patients may limit our
analyses and conclusions. However, additional secondary
analyses in 736 subjects conrmed our initial results, suggest-
ing independent prognostic information for age, sex, fasting
blood glucose, serum creatinine and leucocyte counts. Finally,
inherent in studies with a long-term follow-up, this study
population may not reect the clinical setting of today, given
the advance in cardiology over the years. This includes more
active secondary prevention with lifestyle advice and medical
therapy, and more active invasive treatment; the latter may,
however, be of limited importance in stable angina pectoris
[24].
The aim of health care is to provide health for as many as
possible and to use available resources in a rational and cost-
effective way. One way to optimize resource utilization is to
avoid unnecessary investigations and tests that may also
expose patients to unnecessary risks. Evidence-based medicine
is dened as the conscientious, explicit and judicious use of
current best evidence in making decisions about the care of
individual patients. Too much and detailed information may
actually be counterproductive in this respect [40]. In conclu-
sion, this study on stable angina pectoris suggests that few and
easily available risk markers (fasting blood glucose, serum
creatinine and leucocyte counts) are needed for risk prediction
in addition to age, sex and clinical history. When combined
with sound clinical judgement, we may provide a better prog-
nosis at a lower cost for the patient, which is important both for
the patient and from a societal perspective [40,41].
Acknowledgements
The initial study was supported by the Swedish Heart Lung
Foundation, the Swedish Medical Research Council, the Foun-
dation of the Seramer Hospital, the Swedish Society of Med-
icine, Karolinska Institutet, the Stockholm County Council,
Knoll AG, Ludwigshafen, Germany, and AstraZeneca,
M olndal, Sweden. Karolinska Institutet supported the addi-
tional work in this report. The supporting sources had no
involvement in the design, collection, analysis and interpreta-
tion of data, or writing of this or previous reports. The authors
have no conict of interests to declare.
Authors contributions
PH and NR were responsible for the study design. IB, EB, SVE,
CH, LF and TK performed the study. All authors contributed to
the analysis of study results. PN was responsible for the sta-
tistical evaluation. All authors participated in writing the
paper.
Address
Karolinska Institutet, Department of Clinical Sciences, Dande-
ryd Hospital, Division of Cardiovascular Medicine, SE-182 88
Stockholm, Sweden (Thomas Kahan, Inge Bj orkander, Sven V
Eriksson); Department of Cardiology, Danderyd University
Hospital Corp, SE-182 88 Stockholm, Sweden (Thomas Kahan,
Inge Bj orkander, Sven V Eriksson); Medical Products Agency,
P.O. Box 26, SE-751 03 Uppsala, Sweden (Lennart Forslund);
Uppsala Clinical Research Centre, Department of Medical Sci-
ences, Uppsala University, SE-751 85 Uppsala, Sweden (Claes
Held); Department of Medical Sciences, Uppsala University,
SE-751 85 Uppsala, Sweden (Ewa Billing); Centre for Safety
Research, The Royal Institute of Technology KTH, SE-100 44
European Journal of Clinical Investigation Vol 43 149
RISK PREDICTION IN ANGINA PECTORIS
Stockholm, Sweden (Per Nasman); The Swedish Council on
Technology Assessment in Health Care (SBU), SE-103 59
Stockholm, Sweden (Nina Rehnqvist); Department of Medicine
Solna, Clinical Pharmacology Unit, Karolinska University
Hospital (Solna), SE-171 76 Stockholm, Sweden (Paul Hjem-
dahl).
Correspondence to: Professor Thomas Kahan, Department of
Cardiology, Danderyd University Hospital Corp, SE-182 88
Stockholm, Sweden. Tel.: +46 8 123 568 61; fax: +46 8 755 0868;
e-mail: thomas.kahan@ds.se
Received 15 June 2012; accepted 7 November 2012
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