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Keywords:

  • Coronary artery disease;
  • gender;
  • human;
  • prognosis;
  • risk factor

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors contributions
  9. Address
  10. References

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 sufficient 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 3·4 years, with a registry-based extended follow-up after 9·1 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% confidence intervals]), age (1·04 per year [1·00;1·08], P = 0·041), female sex (0·33 [0·16;0·69], P = 0·001), fasting blood glucose (1.29 per mM [1.14; 1.46], P < 0·001), serum creatinine (1·02 per μM [1·00;1·03], P < 0·001) and leucocyte counts (1·21 per 106 cells/L [1·06;1·40], P = 0·008). 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.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors contributions
  9. Address
  10. References

Angina pectoris is a common condition with worrying symptoms 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 ß-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 to comparing the effects of the drugs on CV events, we examined a number of variables considered to have potential prognostic importance. They were chosen to reflect metabolic, atherothrombotic, psychosocial, electrophysiological and other factors related to coronary artery disease (Table 1).

Table 1. Previously analysed predictors of a nonfatal myocardial infarction or cardiovascular death during the double-blind study period of 3·4 years
 Median follow-up 3·4 yearsReferences
UnivariateMultivariate
  1. 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.

  2. Probability values for univariate and multivariate analyses during the double-blind study period of 3·4 years, as previously presented. Results presented for echocardiography were calculated for cardiovascular death only.

Demographic and history
Male sex< 0·001< 0·01 [3]
Age< 0·01< 0·05 [3]
History of hypertension< 0·01< 0·05 [3]
Previous myocardial infarction< 0·05ns [3]
History of congestive heart failure< 0·05ns [3]
Metabolic and haemostatic
Fasting blood glucose ≥ 6·1 mM< 0·001< 0·01 [4]
Diabetes mellitus< 0·001< 0·01 [2, 4]
Estimated creatinine clearance< 0·05< 0·05 [5]
VCAM0·05  [6]
tPA-antigen< 0·05< 0·05 [7]
PAI-1< 0·05< 0·05 [7]
Apolipoprotein A-1< 0·001< 0·05 [8]
HDL-cholesterol< 0·05  [8]
Triglycerides< 0·01  [8]
Fibrinogen< 0·001< 0·01 [9]
Leucocyte counts< 0·001< 0·05 [9]
ECG, LTER
ST depression at 2 min of rest< 0·001< 0·001 [10]
Maximal ST depression during exercise< 0·01< 0·01 [10]
Exercise duration (only in men)< 0·01< 0·001 [10]
ST depression during LTER< 0·05< 0·05 [11]
ST depression > 30 min during LTER< 0·05  [11]
Echocardiography
LVEDD< 0·001  [12]
LVESD< 0·001  [12]
LV mass index< 0·001  [12]
Left atrial diameter< 0·001  [12]
Autonomic function
Differential index< 0·0001< 0·001 [13]
SDNN< 0·001< 0·05 [13]
pNN50< 0·01< 0·05 [13]
Total power  0·007< 0·05 [14]
Low frequency  0·003< 0·05 [14]
High frequency< 0·001< 0·05 [14]
Normalized very low frequency< 0·001< 0·05 [14]
Normalized low frequency< 0·01< 0·05 [14]
Psychosocial
Sexual problems< 0·001 Unpublished
Tired< 0·01 Unpublished
Push myself hard in competition< 0·01 Unpublished
Have often chest pain< 0·01 Unpublished
Feel breathless on exercise< 0·01 Unpublished

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 population 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors contributions
  9. Address
  10. References

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 1987–1993 in the APSIS study [3]. Inclusion 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 confirm 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, significant valvular disease or severe congestive heart failure. Details have been described previously [3]. The median follow-up of the original APSIS study was 3·4 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 randomized treatment could be continued openly because there was no apparent prognostic benefit 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 metabolism [4], and haemostatic mechanisms and endothelial function [7]. Renal function was estimated by serum creatinine levels, for which values below 100 μM in women and 110 μM in men were considered normal, and by creatinine clearance, calculated according to the Cockroft–Gault formula [5].

Specially trained research nurses performed an interview regarding psychosocial factors based on standardised questionnaires for the evaluation of psychosomatic symptoms, job strain, self-rated Type A behaviour including hostility, sleep disturbances and self-rated overall life satisfaction. Psychosomatic 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 stratification

For the purpose to stratify randomization for the double-blind treatment period in the APSIS study, a clinical risk stratification based on signs and symptoms was made, according to accepted clinical practice at the time of the study. Patients with vasospastic angina pectoris were classified as having low risk. Patients with effort-induced or mixed angina pectoris were classified according to three indicators of risk (age ≥ 60 years, electrocardiographic signs suggesting multivessel disease during exercise testing and clinical signs of left ventricular dysfunction).

Extended follow-up and definition 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 9·1 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]. Primary end points were CV death or nonfatal MI. CV death was predefined as a primary cause of death coded as 402, 404, 410–414 and 420–429 (ICD-9) or I10-I13, I20-I29, I30- I43, I44-I49, I50, I51 and I52 (ICD-10) and was always confirmed by two cardiologists. 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 first event was considered to be the time of the end point.

Statistical analysis and data management

Previously identified 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; demographic data (age, sex and waist circumference); laboratory variables (creatinine, estimated creatinine clearance, uric acid, leucocyte counts, fasting blood glucose, total, low-density lipoprotein (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 numbers 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; creatinine and estimated creatinine clearance, 808; uric acid, 787; leucocyte counts, 714; fasting blood glucose, 790; total cholesterol, 786; LDL- and HDL-cholesterol, 785; apolipoprotein 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 psychosocial and sexual problems).

Data are presented as mean values and standard deviations or odds ratios (per 1 unit change) with 95% confidence intervals, unless otherwise stated. We used Student's t-test and analysis of variance with the post hoc test proposed by Fisher after validation for normal distribution by the use of the Shapiro–Wilk test and log transformation of data or nonparametric tests for continuous data, as appropriate. We used the chi-square test or Fisher's exact test for variables in contingency tables. The Pearson correlation coefficient was used to test the independence between variables. Life table curves were calculated according to Kaplan–Meier 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 < 0·05 was considered significant.

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 confirms to CONSORT and STROBE statements [23].

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors contributions
  9. Address
  10. References

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 3·7 ± 4·5 years (3·9 ± 4·7 years in men and 3·3 ± 3·8 years in women). Medications at baseline aside of study drugs were acetylsalicylic acid (39%), long acting nitrates (52%), angiotensin-converting enzyme inhibitors (6%), lipid-lowering drugs (6%) and digoxin (3%); unfortunately, reliable data on medication during follow-up are not available. During the median follow-up of 9·1 years, 139 (17%) patients (18 women and 121 men) suffered either a nonfatal MI or CV death as a first 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 percutaneous coronary artery intervention (PCI) in 102 (12%) during the double-blind treatment period [3] (no information is available for the extended follow-up).

Table 2. Background characteristics of the entire study population
 AllMenWomen
  1. CABG, coronary artery bypass grafting; PCI, percutaneous coronary artery intervention; LDL and HDL, low-density and high-density lipoprotein.

  2. Mean values ± SD.

Number of subjects809561248
Age, years59 ± 759 ± 859 ± 7
Body mass index, kg/m226 ± 426 ± 326 ± 4
Systolic blood pressure, mmHg143 ± 21144 ± 21141 ± 20
Diastolic blood pressure, mmHg84 ± 1086 ± 1083 ± 10
Heart rate, beats/min65 ± 1264 ± 1266 ± 12
Left ventricular mass index, g/m298 ± 26104 ± 2587 ± 24
Active smokers, %222515
Previous smokers, %434831
Previous myocardial infarction, %16207
Previous CABG or PCI, %672
History of congestive heart failure, %767
History of hypertension, %272825
Diabetes mellitus, %9106
Fasting blood glucose, mM5·3 ± 1·65·4 ± 1·65·1 ± 1·4
Serum creatinine, μM97 ± 18102 ± 1787 ± 15
Total cholesterol, mM6·6 ± 1·26·6 ± 1·26·8 ± 1·3
LDL-cholesterol, mM4·6 ± 1·34·6 ± 1·04·7 ± 1·2
HDL-cholesterol, mM1·2 ± 0·31·1 ± 0·31·4 ± 0·3
Leucocyte counts, 106 cells/L6·0 ± 1·76·2 ± 1·75·6 ± 1·7

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 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 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, 26 ± 3 kg/m2; blood pressure, 144 ± 21/85 ± 10 mmHg; heart rate, 65 ± 12 beats/min; left ventricular mass index, 100 ± 27 g/m2; 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, 5·36 ± 1·60 mM; serum creatinine, 97 ± 19 μM; total cholesterol, 6·7 ± 1·2 mM; LDL-cholesterol, 4·6 ± 1·1 mM; HDL-cholesterol, 1·2 ± 0·3 mM; and leucocyte counts 6·0 ± 1·6 106 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 provided independent prognostic information regarding the risk of suffering a nonfatal MI or CV death (Table 4).

Table 3. Background characteristics of the study population according to outcome
 Event-free survivalPrimary event
  1. CABG, coronary artery bypass grafting; PCI, percutaneous coronary artery intervention; LDL and HDL, low-density and high-density lipoprotein.

  2. Mean values ± SD. The primary outcome was nonfatal myocardial infarction or cardiovascular death combined.

Number of subjects670139
Age, years59 ± 662 ± 6
Body mass index, kg/m226 ± 326 ± 4
Systolic blood pressure, mmHg143 ± 20144 ± 22
Diastolic blood pressure, mmHg85 ± 1085 ± 10
Heart rate, beats/min65 ± 1165 ± 12
Left ventricular mass index, g/m298 ± 27108 ± 28
Active smokers, %2028
Previous smokers, %4342
Previous myocardial infarction, %1428
Previous CABG or PCI, %511
History of congestive heart failure, %610
History of hypertension, %2538
Diabetes mellitus, %717
Fasting blood glucose, mM5·2 ± 1·36·0 ± 2·3
Serum creatinine, μM96 ± 16104 ± 24
Total cholesterol, mM6·7 ± 1·26·7 ± 1·3
LDL-cholesterol, mM4·6 ± 1·14·6 ± 1·2
HDL-cholesterol, mM1·2 ± 0·31·1 ± 0·3
Leucocyte counts, 106 cells/L5·9 ± 1·66·6 ± 1·7
Table 4. Primary multivariate analysis of risk markers in the entire study cohort for a nonfatal myocardial infarction or cardiovascular death
 Odds ratio95% CI P
  1. CI, confidence interval.

  2. Data from 541 subjects; 93 had an endpoint. Odds ratios are given for 1 unit change (where appropriate). Multivariate analysis including clinical presentation 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).

Age, years1·041·00; 1·080·041
Female sex0·330·16; 0·690·001
Glucose, mM1·291·14; 1·46< 0·001
Serum creatinine, μM1·021·00; 1·03< 0·001
Leucocyte counts, 106 cells/L1·211·06; 1·400·008
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% confidence intervals) that fasting blood glucose (1·27 per mM [1·11; 1·45], P < 0·001), serum creatinine (1·02 per μM [1·00; 1·03], P = 0·004) and sexual problems (1·84 [1·02; 3·32], P = 0·042) provided independent prognostic information concerning a nonfatal MI or CV death.

image

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 significant difference between women and men, P < 0·001. (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 significant difference between nondiabetic patients with low blood glucose levels and the other two groups, P < 0·001. (c). Solid and hatched lines denote normal and elevated serum creatinine levels, respectively, where values below 100 μM in women and 110 μM in men were considered normal. There was a significant difference between the groups, P < 0·001.

Download figure to PowerPoint

In a corresponding multivariate analysis in women, 167 patients were included, but only 10 of them reached a primary endpoint. Leucocyte counts (1·80 per 106 cells/L [1·24; 2·06], P < 0·001) and serum creatinine (1·04 per μM [1·00; 1·08], P = 0·020) provided independent prognostic information among the women.

Analyses of the entire study cohort according to glucose metabolism

A fasting glucose level above 6·0 mM was associated with a worsened prognosis (Fig. 1b). Among 87 patients with glucose > 6·0 mM, 35 had primary endpoints. A multivariate analysis of these patients showed that serum creatinine (1·05 per μM [1·01; 1·08], P = 0·006), sexual problems (4·26 [1·35; 13·44], P = 0·016) and CCS class (3·19 [1·13; 9·02, P = 0·030) 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 confirmed findings in the total study cohort. Thus, female sex (0·28 [0·12; 0·64], P < 0·001), leucocyte counts (1·27 per 106 cells/L [1·08; 1·49], P = 0·007) and age (1·06 per year [1·02; 1·11], P = 0·007) provided 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 creatinine (i.e. ≥ 100 μM in women and ≥ 110 μM in men) are illustrated in Fig. 1c. A multivariate analysis in 122 patients with elevated creatinine levels and 33 endpoints showed that diabetes (8·62 [2·15; 34·58], P < 0·001), leucocyte counts (1·55 per 106 cells/L [1·14; 2·11], P = 0·003), total cholesterol (0·56 per mM [0·36; 0·87], P = 0·016) and waist circumference (1·06 per cm [1·01; 1·12, P = 0·026) were independent predictors of CV death or MI.

Analyses in patients with normal serum creatinine levels (419 patients with 60 primary endpoints) largely confirmed findings made in the total study cohort. The results from such individuals with all variables available showed that female sex (0·22 [0·09; 0·52], P < 0·001), fasting glucose (1·20 per mM [1·03; 1·40], P = 0·006) and a history of an acute MI (2·29 [1·03; 1·40], P = 0·017) 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 missing 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 creatinine clearance, uric acid, fasting blood glucose, total, LDL- and HDL-cholesterol, apolipoprotein A-1 and triglycerides.

Multivariate analysis confirmed 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 CV death or MI.

Table 5. Secondary multivariate analysis of risk markers for a nonfatal myocardial infarction or cardiovascular death in the expanded subset of patients
 Odds ratio95% CI P
  1. CI, confidence interval.

  2. Data from 736 subjects; 139 had an endpoint. Odds ratios are given for 1 unit change (where appropriate). Multivariate analysis including clinical presentation 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.

Age, years1·041·01; 1·080·008
Female sex0·470·26; 0·86< 0·001
Glucose, mM1·301·16; 1·45< 0·001
Serum creatinine, μM1·011·00; 1·02< 0·001
Previous myocardial infarction1·721·06; 2·790·034
Smoking1·301·03; 1·640·036
Apolipoprotein A-1, g/L0·420·18; 1·000·041
History of hypertension1·541·00; 2·380·049

Further analyses of the expanded subset according to sex, glucose metabolism and serum creatinine are summarized in Table 6.

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 ratio95% CI P
  1. CI, confidence interval.

  2. 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 creatinine clearance, uric acid, fasting blood glucose, total, LDL- and HDL-cholesterol, apolipoprotein A-1 and triglycerides.

Sex
Men, 544 patients and 111 primary endpoints
Glucose, mM1·281·13; 1·44< 0·001
Previous myocardial infarction2·001·22; 3·290·003
Serum creatinine, μM1·021·00; 1·030·015
Smoking1·291·01; 1·650·038
Women, 234 patients and 17 primary endpoints
Glucose, mM1·461·14; 1·88< 0·001
Estimated creatinine clearance, mL/min0·960·92; 0·990·019
Glucose metabolism
Fasting glucose > 6·0 mM, 115 patients and 45 primary endpoints
Smoking1·871·12; 3·140·014
Estimated creatinine clearance, mL/min1·021·08; 1·050·015
CSS class2·531·04; 6·150·036
Fasting glucose ≤ 6·0 mM, 621 patients and 83 primary endpoints
Age, years1·061·02; 1·100·004
Female sex0·340·20; 0·76< 0·001
Apolipoprotein A-1, g/L0·270·09; 0·790·012
History of hypertension1·791·09; 3·000·021
Previous myocardial infarction2·001·22; 3·290·038
Smoking1·291·01; 1·650·038
Creatinine level
Elevated serum creatinine (≥ 100 μM in women, ≥ 110 μM in men), 169 patients and 41 primary endpoints
Glucose, mM1·571·24; 1·99< 0·001
Total cholesterol, μM0·590·41; 0·850·012
Waist circumference, cm1·101·04; 1·160·035
Normal serum creatinine (< 100 μM in women, < 110 μM in men), 567 patients and 83 primary endpoints
Female sex0·310·17; 0·59< 0·001
Age, years1·041·00; 1·080·012
Glucose, mM1·221·06; 1·390·002
History of hypertension1·801·07; 3·020·023
Previous myocardial infarction2·461·39; 4·350·039

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors contributions
  9. Address
  10. References

This prospective study with a long follow-up (median, 9·1 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 findings of other studies [1]. Of note, most patients with stable coronary artery disease have a similarly favourable prognosis on medical therapy as after invasive treatment [[1], [24]]. Although several markers may predict prognosis over a few years in stable angina pectoris (Table 1), our major finding 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 findings in patients with a first acute MI [25] and in the general population [26-28], suggesting that relatively few risk factors are needed for risk prediction in ordinary health care. However, the clinical situation sometimes demands further investigations, and such information can be of value for the diagnosis and the choice of specific treatment for the individual patient.

Fasting blood glucose above 6·0 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 fasting 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 findings that CCS class, serum creatinine and sexual problems (in men) predicted prognosis in patients with elevated glucose levels may suggest that endothelial dysfunction and atherosclerotic target organ damage (as reflected 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 reflect renal dysfunction, was a marker for future CV events, in agreement with findings 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 current study, risk prediction by serum creatinine was superior to estimated creatinine clearance. We have previously shown that estimated creatinine clearance provides risk prediction, particularly among men [5]. However, in the present multivariate analyses, serum creatinine was a simple and useful marker for CV risk in stable angina pectoris.

Inflammation contributes to atherosclerotic disease, and various markers for increased inflammatory 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]. Unfortunately, high sensitivity CRP could not be measured in this 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 findings that erectile dysfunction may be a consequence of underlying endothelial dysfunction and a marker for CV disease, as reviewed elsewhere [34]. Patients with diabetes have impaired endothelial function. Accordingly, the relationship between sexual problems and a future CV event was much stronger in patients with elevated fasting blood glucose. However, autonomic dysfunction 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 pectoris experienced more stressful events and reported more sleep disturbances and psychosomatic symptoms than healthy control subjects [20]. Psychosocial factors and stress are associated 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 [37-39]. 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 sufficient 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 symptoms suggesting a need for prompt revascularisation and patients with a recent acute MI were excluded. Thus, our findings may not be applicable to all patients with stable coronary 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 confirmed our initial results, suggesting 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 reflect 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 defined 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 conclusion, 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 prognosis at a lower cost for the patient, which is important both for the patient and from a societal perspective [40, 41].

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors contributions
  9. Address
  10. References

The initial study was supported by the Swedish Heart Lung Foundation, the Swedish Medical Research Council, the Foundation of the Serafimer Hospital, the Swedish Society of Medicine, Karolinska Institutet, the Stockholm County Council, Knoll AG, Ludwigshafen, Germany, and AstraZeneca, Mölndal, Sweden. Karolinska Institutet supported the additional work in this report. The supporting sources had no involvement in the design, collection, analysis and interpretation of data, or writing of this or previous reports. The authors have no conflict of interests to declare.

Authors contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors contributions
  9. Address
  10. References

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 statistical evaluation. All authors participated in writing the paper.

Address

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors contributions
  9. Address
  10. References

Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, SE-182 88 Stockholm, Sweden (Thomas Kahan, Inge Björkander, Sven V Eriksson); Department of Cardiology, Danderyd University Hospital Corp, SE-182 88 Stockholm, Sweden (Thomas Kahan, Inge Björkander, Sven V Eriksson); Medical Products Agency, P.O. Box 26, SE-751 03 Uppsala, Sweden (Lennart Forslund); Uppsala Clinical Research Centre, Department of Medical Sciences, 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 Stockholm, Sweden (Per Näsman); 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 Hjemdahl).

References

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  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors contributions
  9. Address
  10. References
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