Coronary heart disease (CHD) is the leading cause of mortality and morbidity worldwide [
Although their role in risk stratification remains to be fully determined, a substantial number of biomarkers can provide additional information beyond that provided by traditional risk factors to predict cardiovascular events [
The main objective of this study was to identify multivariate predictors of MACE in patients diagnosed with SCAD using a meta-analytical approach. Current guidelines were followed during the course of the present research, in particular the recent Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) amendment to the QUality Of Reporting Of Meta-analyses (QUOROM) statement and recommendations from the Cochrane Collaboration and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) [
MEDLINE, Cochrane Library, and BioMed Central were systematically screened in keeping with established methods [
The same two investigators independently and in a blinded fashion tabulated the data of all studies qualifying for the meta-analysis and also contacted the corresponding authors for additional information [
Continuous variables are reported as mean (SD) or median (range). Categorical variables are expressed as
Search strategy results are presented in Figure
Baseline characteristics of patients (
Variable | Value |
|
---|---|---|
Age (years) | 63.5 |
42 |
Female gender (%) | 26.6 |
42 |
Diabetes mellitus (%) | 23.2 |
42 |
Hypertension (%) | 58.7 |
42 |
Hyperlipidemia (%) | 63.8 |
24 |
Smoking (%) | 33.9 |
42 |
Family history (%) | 42.4 |
16 |
Alcohol use (%) | 29.5 |
3 |
Physically inactive (%) | 51.5 |
3 |
Prior stroke (%) | 9.05 |
6 |
Prior AMI (%) | 38.8 |
35 |
Prior CABG (%) | 11.8 |
22 |
Prior PCI (%) | 18.2 |
21 |
List of included studies with the number of patients involved and the type of treatment (PCI: percutaneous coronary angioplasty; CABG: coronary artery bypass graft; MT: medical therapy; ND: not reported data).
Study ID | Number of patients | Treatment |
---|---|---|
Aguilar et al., 2006 [ |
3319 | ND |
Arroyo-Espliguero et al., 2009 [ |
790 | PCI, MT |
Avanzas et al., 2005 [ |
297 | PCI, MT |
Bhatt et al., 2010 [ |
45227 | ND |
Borges et al., 2010, CABG [ |
136 | CABG |
Borges et al., 2010, MT [ |
110 | MT |
Borges et al., 2010, PCI [ |
146 | PCI |
Breeman et al., 2006 [ |
2928 | PCI, MT, CABG |
Carpeggiani et al., 2011 [ |
1442 | ND |
Chen et al., 2007 [ |
468 | ND |
Dart et al., 2007 [ |
7016 | ND |
Dibra et al., 2003 [ |
1152 | CABG, MT |
Eisen et al., 2008 [ |
361 | ND |
Eldrup et al., 2012 [ |
1090 | PCI, MT, CABG |
Chocron et al., 2008 [ |
2489 | ND |
Gehi et al., 2008 [ |
929 | PCI, MT, CABG |
Georgiadou et al., 2010 [ |
101 | ND |
Glaser et al., 2006 [ |
1457 | MT |
Harutyunyan et al., 2011 [ |
4372 | ND |
Hjemdahl et al., 2006 [ |
807 | ND |
Hueb et al., 2010 [ |
611 | MT |
Jeremias et al., 2008 [ |
7592 | PCI, MT, CABG |
Johansen et al., 2006 [ |
507 | PCI, MT, CABG |
Kaneko et al., 2013 [ |
747 | PCI |
Ku et al., 2011 [ |
981 | ND |
Leu et al., 2004 [ |
150 | PCI, MT, CABG |
Lopes et al., 2008 [ |
825 | ND |
Máchal et al., 2014 [ |
150 | PCI, MT, CABG |
Makino et al., 2010 [ |
626 | ND |
Momiyama et al., 2009 [ |
373 | PCI, MT |
Muzzarelli and Pfisterer, 2006 [ |
253 | PCI, MT, CABG |
Papa et al., 2008 [ |
422 | NF |
Park et al., 2014 [ |
203 | PCI, MT, CABG |
Pedersen et al., 2010 [ |
1025 | PCI, MT, CABG |
Povsic et al., 2015 [ |
1908 | MT |
Roman et al., 2010 [ |
178 | PCI, MT, CABG |
Rubulis et al., 2010 [ |
187 | ND |
Sabatine et al., 2007 [ |
3766 | ND |
Schnabel et al., 2010 [ |
1781 | ND |
Sinning et al., 2006 [ |
1806 | ND |
Cihan et al., 2010 [ |
2449 | PCI, MT, CABG |
Van Melle et al., 2010 [ |
839 | PCI, MT |
Wakabayashi et al., 2010 [ |
1944 | PCI, MT, CABG |
Zebrack et al., 2002 [ |
599 | ND |
Search strategy results.
In SCAD patients, the overall incidence of cardiovascular events was 7.8% (95% CI: 5.89%–9.66%). The incidence of MACE was 20.5% (95% CI: 14.2–22.8), all-cause death was 9.9% (95% CI: 5.2–15), CV death was 4.5% (95% CI: 3–5.1), MI was 6.2% (95% CI: 4.2–9), and unstable angina was 7.6% (95% CI: 5–13). Furthermore, 19.5% of patients (95% CI: 14.25–24.95) required repetition of revascularization (either surgery or PCI). An overview of the incidence of cardiovascular events is presented in Figure
Incidence of adverse cardiovascular events after a follow-up of 57 months. MACE: major adverse cardiac events.
The most common predictors of subsequent CV events in stable angina patients. Data are reported as OR median value, with lower/upper limit confidence interval.
Effect of length of follow-up (beta 0.07; 0.03–0.09), of optimal medical therapy (0.02; 0.01–0.04), of CABG (0.04; −0.01–−0.06), and of PCI (0.03; 0.02–0.07) on CV events.
This study demonstrates that (a) the incidence of cardiovascular events remains high in patients with stable coronary disease and (b) although we did not build a prediction model, we reported that simple, inexpensive, and readily available clinical and laboratory tests may be helpful in identifying patients at higher risk of developing subsequent events. Identification of high-risk individuals may enable initiation of timely and appropriate therapies to reduce cardiovascular symptoms and events. As recently stressed by the CALIBER study [
As a matter of fact, due to the great variability among patients with stable coronary disease, discerning when to intensify care and follow-up is still a trouble of physician experience and judgement. Our meta-analysis provides interesting information from an epidemiological point of view, revealing the most powerful predictors of cardiovascular events in patients with stable angina. This information is easily obtained and may provide a deeper insight into which patients with stable angina are really “stable.” Furthermore, this data may be used to help decide which patients should continue with optimal medical therapy or be referred for FFR-guided PCI.
LVEF at clinical presentation seems to be the most powerful index to recognize patients with higher risk of subsequent events. The prognostic significance of severely impaired left ventricular systolic function is well established in patients with heart failure, including those with coronary artery disease as the underlying aetiology [
Previous studies in a broad spectrum of heart failure patients reported that the relationship between LVEF and outcome was curvilinear with evidence that an ejection fraction of less than 45% was associated with a worse prognosis [
The American College of Cardiology-National Cardiovascular Data Registry, an angiographic registry, confirmed that, in stable angina patients, the risk-adjusted OR for significant CAD (i.e., >70% coronary stenosis) was reduced for women compared with men (OR: 0.34, 95% CI: 0.33–0.34), with black women having the lowest risk-adjusted odds compared with other females. Nevertheless, in this registry, white women had a 1.34-fold (95% CI: 1.21–1.48) higher risk-adjusted OR for mortality than white men with stable angina. The Authors explain this higher in-hospital mortality for white women with the lower utilization of elective coronary revascularization, aspirin, and glycoprotein IIb/IIIa inhibitors when compared with men [
In the extended follow-up of the Angina Prognosis Study In Stockholm (APSIS), men were at a 3- to 4-fold increased risk of MACE compared with female patients of a similar age. Interestingly, the event rate was greatly increased in a small subgroup of diabetic female patients. Thus, identifying and treating diabetes appear to be particularly important among female patients with CV disease, as, in the absence of diabetes, the CV mortality of female patients with stable angina pectoris seems to be similar to that of the general population [
When applying metaregression analysis on CV events with respect to the kind of therapy patients received (PCI, CABG, or OMT), we observed a trend of reduced events for PCI and a slight increase for CABG and OMT, but without statistical significance. This is in agreement with the current literature, as no evidence is available suggesting better outcomes for any of these therapies when compared to another. FFR-guided PCI, providing a functional rather than morphological assessment of stenosis, only promise some improvements in stable angina patients [
Smoking does not enter in our selection of risk factors, although it is a well-known and established risk factor. This is due to different classifications of smoking (former, current, or undetermined) in different studies. It is important to note that, in long-term registries such as the Angina Prognosis Study In Stockholm (APSIS), current smoking is an important and modifiable risk factor [
Finally, the term MACE, defined as “major adverse cardiac events” and commonly used as a composite endpoint in cardiovascular research, has no standard definition: including multiple types of clinical events of varying degrees of relatedness, validity, and utility of MACE could be questioned preferring separate endpoints that reflect both the safety and effectiveness of various treatment approaches [
Our study demonstrates that patients with stable angina pectoris at increased risk may be easily identified by assessing several common and important risk factors. In patients with increased risk, aggressive risk factor modification and medical therapy should be instituted and FFR-guided PCI considered if symptoms of angina are present. We found that ejection fraction, sex, diabetes mellitus, previous MI, and CRP independently predicted an increased risk during a cumulative five-year follow-up. Thus, these risk factors may identify patients in need of further angiographic investigation while a conservative strategy may be safely adopted in low-risk patients.
The main highlights of this paper are as follows: We performed a meta-analysis of studies in patients with stable angina to assess which variables predict prognosis. Thirty-eight reports were retained for meta-analysis, representing a total of 101,551 patients. Male sex, reduced EF, diabetes, prior AMI, and high C-reactive protein were the most powerful predictors of cardiovascular events. Metaregression revealed no interaction between the index treatment patients received (PCI, CABG, or OMT) and the incidence of MACE during follow-up. Simple and low-cost clinical features may help clinicians in identifying the most appropriate diagnostic and therapeutic approaches within the broad range of outpatients presenting with stable coronary artery disease.
The authors declare that they have no competing interests.