Background
Improved treatment of acute coronary syndrome with revascularization and modern medical drug therapy has reduced the short-term mortality rates and increased the number of coronary heart disease (CHD) patients in need of secondary prevention [
1]. In most European countries, primary care physicians are the key actors to coordinate and provide long-term CHD management [
1]. Efforts to support their clinical work is needed, as data from clinical practice in Europe have revealed poor risk factor control [
2] with only few improvements over time [
3]. Unhealthy lifestyle behaviour and low risk factor control is shown to contribute to the high risk of recurrent cardiovascular (CV) events observed in CHD patients [
4,
5].
The relative importance of different determinants of long-term disease progression need to be studied further, since most previous studies are based on registries [
4‐
6] with a limited number of clinical factors included. Data on lifestyle behaviour, participation in cardiac rehabilitation (CR) programs, and psychosocial factors have frequently been missing. In the recent EuroAspire IV registry study, CV comorbidities, low education and depressive symptoms were strongly and significantly associated with CV death or non-fatal myocardial infarction (MI), stroke or heart failure in an outpatient population, whereas lifestyle factors and control of lipids and blood pressure (BP) were not [
7].
The current prospective study aims to estimate the relative importance of preventable and potentially modifiable clinical and psychosocial factors associated with recurrent major adverse CV events (MACE) in an outpatient coronary population from routine clinical practice.
Results
Mean age at study inclusion was 63.6 (SD 9.6) years and 21% were females
(Table
1). The index coronary event was MI in 80% and stable or unstable CHD with angiography-verified stenosis in 20%. In all, 90% had been revascularized, 97% used at least one antiplatelet agent, 92% used a statin and 47% had participated in CR. Thirty percent (
n = 336) had coronary event(s) prior to the index event. Thirty-four percent were obese (BMI > 30 kg/m
2), 21% were current smokers, and 54% were former smokers. In all, 96% of the current smokers and 75% of the former smokers had been smoking for ≥20 years.
Table 1Baseline characteristics for the study population
Mean age at inclusion, mean ± SD | 63.6 ± 9.6 |
Females, n (%) | 237 (21.0) |
Low educationa, n (%) | 780 (70.3) |
Family history of coronary heart diseaseb, n (%) | 481 (42.5) |
ST-elevation infarction, n (%) | 335 (29.7) |
Non-ST-elevation infarction, n (%) | 561 (49.8) |
Stable or unstable angina, n (%) | 231 (20.4) |
Percutaneous coronary intervention, n (%) | 867 (77.3) |
Coronary artery bypass graft operation n (%) | 147 (9.6) |
No revascularization, n (%) | 108 (9.6) |
≥ 1 coronary event prior to index event, n (%) | 336 (29.8) |
Heart failure, n (%) | 148 (13.1) |
Atrial fibrillation, n (%) | 106 (9.4) |
Peripheral artery disease, n (%) | 100 (8.9) |
Stroke or transient ischemic attack, n (%) | 80 (7.1) |
Chronic kidney failure (eGFR< 60 mL/min/1.73m2), n (%) | 139 (13.4) |
Participation in cardiac rehabilitation, n (%) | 526 (46.7) |
Former smoking, n (%) | 603 (55.7) |
Current smoking, n (%) | 230 (21.2) |
Total cholesterol, mean ± SD | 4.0 ± 1.0 |
Low density lipoprotein cholesterol, mean ± SD | 2.1 ± 0.8 |
High density lipoprotein cholesterol, mean ± SD | 1.1 ± 0.3 |
Non-high density lipoprotein cholesterol, mean ± SD | 2.9 ± 0.9 |
Low physical activityc, n (%) | 472 (41.9) |
Physical inactivityc n (%) | 197 (18.0) |
Diabetes mellitus, n (%) | 189 (16.9) |
HbA1c in non-diabetic patients, mean ± SD | 5.8 ± 0.5 |
HbA1c in diabetic patients, mean ± SD | 7.6 ± 1.4 |
Systolic blood pressure mmHg, mean ± SD | 138 ± 19.0 |
Diastolic blood pressure mmHg, mean ± SD | 82 ± 8.8 |
Waist circumference cm, mean ± SD | 102.5 ± 12.3 |
Body Mass index in kg/m2, mean ± SD | 28.6 ± 4.5 |
C-reactive protein mg/l, mean ± SD | 2.5 ± 2.7 |
At least 1 antiplatelet agent, n (%) | 1096 (97.2) |
Statin treatment, n (%) | 1036 (91.9) |
Beta-blocker treatment, n (%) | 815 (72.3) |
ACE inhibitor or ARB treatment, n (%) | 561 (49.8) |
HADS Anxiety sum score, mean ± SD | 4.8 ± 3.2 |
HADS Depression sum score, mean ± SD | 3.9 ± 3.2 |
During a mean follow-up period of 4.2 (SD 0.4) years after study inclusion (mean time from index event to end of study was 5.7 (SD 0.9) years), 364 MACE events were observed in 240 (21 95% CI, 19–24%) patients, whereas 39 (3.4, 0.8% per year) died of CV causes. The distribution of composite endpoints is provided in Fig.
1. The risk of recurrent MACE was significantly higher in patients with CHD prior to the index event compared to those without (age adjusted RR = 2.37, 95% CI 1.84–3.07,
p < 0.001).
The long-term risk of first MACE was significantly associated with increasing age, low education, former smoking, peripheral artery disease (PAD), chronic kidney failure and prior stroke, but not with gender in analyses adjusted for age and stratified by coronary events prior the index event
(Table
2, model 1). Of the potentially modifiable risk factors not taking statins, low or no physical activity, diabetes, non-participation in CR, higher systolic BP and higher anxiety and depression scores (HADS) were significantly associated with MACE. Current smoking vs. never smoking (RR 1.24, 95% CI 1.01–1.53,
p = 0.048) was also associated with MACE (data not shown). In multi-adjusted analyses (Table
2model 3), the strongest potentially modifiable predictors of MACE were not taking statins, physical inactivity and higher depression scores. Diabetes, non-participation in CR and higher anxiety score (HADS) were significantly associated with MACE after adjustments for coronary risk factors (Table
2, model 2), but became borderline significant after additional adjustments for CV comorbidity. In multi-adjusted sub-group analyses in patients with no CHD prior to the index event (
n = 791), LDL-cholesterol (RR 1.38 per mmol/L increase, 95% CI 1.13–1.68,
p = 0.002) was significantly associated with MACE. As no major changes in the estimates of the potentially modifiable factors were observed, study results for all MACE are presented in Additional file
1.
Table 2Risk of first recurrent cardiovascular event in coronary patients, estimated by Cox proportional hazard regression
Age per 10 years | 1.15 (1.00, 1.32) | 0.050 | 1.12 (0.96, 1.30) | 0.146 | 1.02 (0.87, 1.20) | 0.792 |
Male sex | 0.85 (0.63, 1.15) | 0.299 | 0.93 (0.67, 1.27) | 0.638 | 0.89 (0.64, 1.23) | 0.472 |
Low educationd | 1.68 (1.23, 2.31) | 0.001 | 1.58 (1.15, 2.11) | 0.005 | 1.51 (1.09, 2.09) | 0.014 |
Never smoking | 1 (reference) | 1 (reference) | 1 (reference) |
Former smoking | 1.54 (1.09, 2.19) | 0.017 | 1.51 (1.06, 2.16) | 0.024 | 1.46 (1.01, 2.10) | 0.043 |
Current smoking | 1.48 (0.97, 2.24) | 0.067 | 1.32 (0.86, 2.02) | 0.205 | 1.13 (0.73, 1.76) | 0.587 |
Adequate physical activitye | 1 (reference) | 1 (reference) | 1 (reference) |
Low physical activity | 1.36 (1.00, 1.85) | 0.051 | 1.37 (1.00, 1.87) | 0.049 | 1.35 (0.97, 1.87) | 0.071 |
Physical inactivity | 1.84 (1.29, 2.61) | 0.001 | 1.78 (1.23, 2.58) | 0.002 | 1.73 (1.18, 2.55) | 0.005 |
LDL cholesterol per mmol/L increase | 1.17 (1.00, 1.38) | 0.057 | 1.17 (0.99, 1.37) | 0.063 | 1.14 (0.97, 1.35) | 0.119 |
Diabetes mellitus | 1.64 (1.22, 2.19) | 0.001 | 1.47 (1.09, 2.00) | 0.013 | 1.35 (0.99, 1.84) | 0.061 |
Systolic blood pressure per 10 mmHg increase | 1.06 (0.99, 1.13) | 0.111 | 1.06 (0.99, 1.13) | 0.088 | 1.06 (0.99, 1.13) | 0.114 |
Waist circumference per 10 cm increase | 1.24 (1.00, 1.54) | 0.048 | 1.06 (0.84, 1.33) | 0.639 | 1.05 (0.83, 1.33) | 0.687 |
C-reactive protein per mg/L increase | 1.02 (0.98, 1.06) | 0.346 | | | | |
Not participating in cardiac rehabilitation | 1.42 (1.09, 1.86) | 0.010 | 1.32 (1.01, 1.74) | 0.045 | 1.29 (0.97, 1.70) | 0.077 |
Not taking statin | 2.08 (1.43, 3.03) | < 0.001 | 2.06 (1.33, 3.20) | 0.001 | 2.13 (1.36, 3.36) | 0.001 |
Heart failure | 1.21 (0.86, 1.69) | 0.281 | | | | |
Peripheral artery disease | 1.96 (1.39, 2.75) | < 0.001 | 1.78 (1.26, 2.52) | 0.001 | 1.73 (1.21, 2.49) | 0.003 |
Stroke or transient ischemic attack | 1.43 (0.94, 2.16) | 0.091 | 1.28 (0.84, 1.95) | 0.248 | 1.12 (0.72, 1.74) | 0.617 |
Chronic kidney failure (eGFR< 60 mL/min/1.73m2) | 1.84 (1.32,2.35) | < 0.001 | 1.62 (1.16, 2.27) | 0.005 | 1.52 (1.08, 2.14) | 0.016 |
HADS Anxiety sum per unit increase | 1.04 (1.01, 1.08) | 0.017 | 1.03 (1.00, 1.07) | 0.031 | 1.03 (1.00, 1.07) | 0.058 |
HADS Depression sum per unit increase | 1.06 (1.02, 1.10) | 0.002 | 1.05 (1.01, 1.09) | 0.045 | 1.04 (1.00, 1.09) | 0.028 |
The preventable and the potentially modifiable risk factors accounted for 66% (95% CI 49–77%) of the risk of MACE in population attributable fractions (PAF) analyses stratified for prior CHD at the index event and adjusted for age (Table
3). History of smoking (current and former) gave the highest contribution (27%), followed by low physical activity, not participating in CR (16%), diabetes (7%) and not taking statins (7%). By adding CV comorbidity, the PAF for all factors increased by only 2 to 68%. The PAF for all factors did not change after excluding patients with CV comorbidity (data not shown).
Table 3Attributable risk fraction associated with preventable and potentially modifiable risk factors
History of smoking | 27% | (5, 44) |
LDL cholesterol ≥1.8 mmol/L | −4% | (−23, 12) |
Low physical activitya | 21% | (5, 34) |
Diabetes mellitus | 7% | (1, 13) |
Blood pressure ≥ 140/90 (80) mmHg | 7% | (−6,19) |
Central obesityb | 11% | (−8, 28) |
Not participating in cardiac rehabilitation | 16% | (1, 28) |
Not taking statin | 7% | (4, 9) |
HADS Anxiety or Depression score ≥ 8 | 7% | (0, 15) |
All risk factors combined | 66% | (49, 77) |
Discussion
The risk of recurrent non-fatal CV events remained high in a chronic outpatient coronary population from routine clinical practice in Norway. Not taking statins, low or no physical activity and higher depression scores were the major potentially modifiable risk factors associated with MACE in multi-adjusted analysis. The comprehensive NOR-COR dataset, enables us to determine the relative importance of preventable and potentially modifiable factors that are regularly assessed in daily practice. Altogether, potentially preventable clinical and psychosocial factors predicted two out of three MACE in the present study. This emphasizes the great potential for reducing the patients` long-term residual CV mortality and morbidity risk by optimizing these factors.
The study population was < 80 years and most patients were revascularized and received the recommended drug treatment which is subsidized in Norway. Despite this, more than 2 out of 10 patients suffered a MACE during a 4 years follow-up period, and 16% had a non-fatal MI, stroke or CV death giving a yearly rate of 3.8%. Our results are in line with older data from the REACH registry reporting a prevalence of recurrent first CV death, MI and stroke of 4.5% per year (18% over 4 years) in patients with established CVD. In contrast, the EuroAspire IV register, with similar inclusion criteria, found a yearly rate of first CV death, MI and stroke of only 2.6% (5.1% over 2 years). However, EuroAspire IV had an inclusion rate of only 49% [
7] whereas 60% of the MACE were obtained by self-rapport questionnaires which may have underestimated the true prevalence. In line with our results, there was a yearly incidence of 1.1% CV deaths in EuroAspire IV. The high levels of MACE along with a low incidence of CV deaths found in both studies, most probably reflect effective management of recurrent non-fatal MACE.
Current smoking was not significantly associated with MACE compared to former and never smoking although a trend towards increased risk was observed. Former smoking, however, was prevalent and significantly associated with MACE. Even though former smoking may be regarded as a non-modifiable factor, it is a preventable risk factor in the CHD population. Smoking history combining former and current smoking, accounted for the highest attributable risk fraction (27%) for recurrent MACE. In line with our results, EuroAspire IV [
7], did not find a significant association between current smoking and MACE. Possible explanations might be a long history of smoking in those quitting prior to study inclusion and too short follow-up to see the effect of smoking cessation. The susceptibility of smoking also differs individually [
14], and those patients most susceptible to the negative effects of smoking, might to a larger extent have died prior to study inclusion. Smoking was significantly associated with increased risk of death, but not readmissions in a large Swedish registry study [
4]. Nevertheless, the benefit of smoking cessation in CHD prevention is strongly documented [
15].
Physical inactivity (< 1 time/week) was a strong predictor of MACE. Low physical activity (< 30 min 2–3 times/week) was also associated with MACE after adjusting for other CV risk factors, but the association became borderline significant (
p = 0.071) after adjusting for CV comorbidity. The EuroAspire IV study did not find low physical activity to be significantly associated with MACE, but low physical activity was defined differently [
7]. However, several observational studies have identified physical inactivity as an important prognostic factor in CHD patients [
4,
16]. Other studies have found that the greatest effect on CHD prognosis was achieved by increasing the activity level from inactivity to low activity [
17,
18]. Therefore a larger effort should be made to help inactive patients become somewhat active, even though they may not reach guideline recommendations [
1].
A recent review found an effect of CR on the risk of new CV events even in the modern era of MI treatment [
19]. However, the population in RCT studies might differ from the general population with chronic CHD. We had a participation rate of 47% in CR, which is higher than the national average of 28% [
20]. Non-participation in CR was associated with MACE in analyses adjusted for age and CV risk factors. The effect of CR is thereby likely not only limited to the effect on risk factor control. Factors such as better medical adherence [
11] and effect on depressive symptoms [
21] might explain some of the additional effect. When adjusting for CV comorbidities, CR non-participation becomes borderline significant (
p = 0.077).
We found no significant association between higher LDL-cholesterol levels and MACE. This can be explained by the high prescription rate of statins and an average LDL-cholesterol level of 2.1 mmol/L at baseline. It is previously shown that the effect of LDL-cholesterol on cardiac prognosis in chronic CHD is most pronounced in those with levels above 2.6 mmol/L [
22]. However, increasing LDL-cholesterol level was significantly associated with recurrent MACE in the subgroup with one coronary event only. These patients are younger and have less comorbidity which may explain the relatively stronger effect on CV prognosis. Not taking a statin was the strongest determinant of recurrent MACE, and remained significant after adjusting for other risk factors and CV comorbidities. Taking statin treatment was also protective of recurrent CV events in EuroAspire IV [
7] and REACH [
5] registries. Thus, novel strategies to ensure prescription of and long-term adherence to statin therapy seems to be even more important than further LDL-cholesterol reduction in an outpatient CHD population. Muscular side-effects are the major cause of non-adherence/discontinuation of statins [
23]. Thus, further research into statin associated muscle symptoms and the identification of a biomarker is of vital importance [
23].
Several studies have found an “obesity paradox”, where overweight and moderately obese patients have better prognosis than those with normal weight [
24]. Increasing waist circumference was significantly associated with MACE, but not when adjusted for other CV risk factors. In line with our results, EuroAspire IV [
2] found a trend towards higher risk of MACE with increasing waist circumference. Diabetes, mainly type 2 (93%) was, associated with MACE in all adjusted analyses except from borderline significance (
p = 0.061) after adjusting for CV comorbidity. Systolic BP levels were significantly associated with MACE only in crude (1.07, 95% CI 1.00–1.15 per 10 mmHg,
p = 0.045), but not adjusted analyses, as observed in EuroAspire IV [
7]. In line with obesity, the effect of BP on MACE might have been partly modified through other risk factors like diabetes, CV comorbidity and increasing age.
Higher HADS sub-scores of both depression and anxiety were associated with increased risk of MACE in analyses adjusted for coronary risk factors, suggesting that the effect of these factors on MACE risk are not mediated through poor risk factor control alone. A wide range of mechanisms linking psychosocial factors to CHD have been identified, such as proinflammation, endothelial dysfunction and changes in the hypothalamic–pituitary-adrenal and autonomic nervous system [
25]. Even though treatment of depression so far has yielded limited and uncertain effect on prognosis [
26], depression and other psychosocial factors are important to address as they may act as barriers to both lifestyle changes and treatment adherence [
25,
27].
The NOR-COR population was consecutively recruited and the participation rate was high (83%). Socioeconomic status and mortality rate were in line with national data [
9]. Another strength of the study is that all MACE have been extracted from the hospital records by experienced cardiologists with only 14 out of 1127 patients being lost to follow-up. Since the hospital records are automatically linked to the Population Registry in Norway, no fatal cases are likely to have been overlooked. The present study has limitations. We may have missed some MACE occurring outside the catchment area of the participating hospitals. However, as hospital discharge reports are normally sent to the local hospital in Norway, the risk is low. By design, patients were included in NOR-COR 2–36 months after the index event, which may introduce a survival bias, as 160 patients had died between time of event and inclusion. These patients may have had even poorer risk factor control or more comorbidity than those included.
Although we have performed a comprehensive evaluation of determinants associated with recurrent MACE, data on additional potentially modifiable factors like fasting blood glucose, the use of metformin and pack years smoked are not available.
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