Background
Primary percutaneous coronary intervention (PCI) is currently the standard care for patients with ST-segment elevation myocardial infarction (STEMI). Approximately 50% of these patients have multivessel disease and present worse clinical outcomes compared with those having single-vessel disease [
1,
2]. Although several previous small-scale randomized controlled trials (RCTs) and registries [
3‐
8] supported a conservative approach for nonculprit diseases, recent landmark RCTs have improved outcomes with immediate or staged complete revascularization [
9‐
12]. Accordingly, the latest European Society of Cardiology guideline upgraded the recommendation for nonculprit lesions revascularization during primary PCI or as a staged procedure over culprit-only PCI [
13].
Diabetes is a strong independent predictor of adverse cardiovascular events in patients with coronary artery disease (CAD) [
14‐
18]. Over recent decades, the prevalence of diabetes mellitus is dramatically increased from 108 million in 1980 to 451 million in 2017 [
19,
20]. Generally, diabetic patients are prone to a diffuse and rapidly progressive form of atherosclerosis. This increases the risk of unfavorable clinical outcomes after revascularization [
21,
22]. In this setting, diabetes might be an important consideration when choosing a revascularization strategy, i.e., staged complete revascularization or culprit-only PCI in patients with STEMI and multivessel disease.
Nevertheless, the relation between the effect of diabetes and different strategies remains underdetermined. These high-risk patients are generally underrepresented by RCTs, with a small proportion of diabetic patients enrolled [
9‐
12]. In a study conducted by Hamza et al. [
23], diabetic patients underwent complete revascularization with STEMI and multivessel disease were significantly associated with lower risk of adverse cardiovascular events than that in culprit-only PCI group. However, the limitations of their study were the small sample size and a short follow-up period of only 6 months. We therefore performed this study to compare the impact of diabetes status on long-term outcomes of patients with STEMI and multivessel disease after staged complete revascularization with that after culprit-only PCI.
Methods
Study design and population
The present report is a single-center, retrospective, observational study. The study design has been previously described [
24]. Briefly, a total of 1205 patients with STEMI and multivessel disease who underwent primary PCI within 12 h from symptom onset underwent staged complete revascularization or culprit-only PCI between January 2006 and December 2015 in our center. The local ethical committee approved the study, and the written informed consent was waived because of the retrospective enrollment. In addition, patient records were anonymized and deidentified before database merging and analysis.
Diabetes mellitus was diagnosed based on previous medical records as well as therapeutic status of glucose-lowering therapy, i.e., insulin, oral hypoglycemic agents, diet and exercise. Multivessel disease was defined as the presence of ≥ 70% angiographic stenosis in ≥ 1 nonculprit major coronary arteries (with diameter ≥ 2.5 mm). Exclusion criteria were single-vessel disease (n = 1390), left main disease (n = 40), concomitant chronic total occlusion (n = 307), rescue PCI (n = 116), immediate complete revascularization (n = 81), undergoing coronary artery bypass graft surgery (n = 97), receiving medical therapy only (n = 34), or being dead during hospitalization (n = 16).
Study procedures
All patients received loading doses of aspirin (300 mg), clopidogrel (600 mg) or ticagrelor (180 mg) before primary PCI. The culprit vessel was ascertained by evaluation of electrocardiographic changes, echocardiographic and angiographic findings. Primary PCI as well as the use of heparin, thrombus aspiration, and glycoprotein IIb/IIIa inhibitor were in compliance with the current guidelines and the operators’ routine practice [
13,
25]. After the procedure, aspirin (100 mg/day) and clopidogrel (75 mg/day) or ticagrelor (180 mg/day) were prescribed at the same time every day. Culprit-only PCI was defined as the treatment of the culprit vessel only at the time of primary PCI without revascularization of nonculprit vessels during the following 30 days after primary PCI. In the staged PCI group, revascularization of significant nonculprit lesions was performed within 30 days after the procedure, which was determined by the physicians and/or patients. Contrast-induced acute kidney injury was defined as an increase in serum creatinine of ≥ 25% compared with baseline values or as an absolute increase in serum creatinine of ≥ 0.5 mg/dL (44.2 mmol/L) within 72 h after PCI [
26,
27].
Follow-up and endpoints
Demographics, cardiovascular risk factors, clinical characteristics, laboratory data, angiographic and procedural details were collected from hospital databases and recorded in a computerized database. Follow-up information was obtained from the review of hospital charts, clinical visits or telephone interviews, which were conducted by trained reviewers. In order to record at least 2-year follow-up information about all patients, we extended the follow-up period to May 31, 2018.
The primary endpoint was major adverse cardiac and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction (MI), stroke, or unplanned revascularization. Secondary outcomes included the individual components of the primary endpoint as well as cardiac death, and the composite of cardiac death, MI or stroke. All deaths were considered to be cardiac-related unless a non-cardiac origin was documented. Diagnosis of MI was made according to fourth universal definition of MI [
28]. Stroke was defined as a new focal neurological deficit lasting > 24 h, which was confirmed by neurologists based on both clinical and radiographic criteria [
29]. Unplanned revascularization was repeat PCI or coronary artery bypass grafting of any vessels excluding staged PCI. In addition, all the endpoints were verified and adjudicated by an independent clinical events committee (XTS, HL and SZL).
Statistical analysis
Continuous variables were expressed as mean ± standard deviation or median (interquartile range), and were compared using the Student’s t test and Mann–Whitney U test according to different distributions. Categorical variables were expressed as number (percentage), and were compared using the Chi-square test or Fisher’s exact test. The Kaplan–Meier method was used to plot time-to-event curves, and differences were assessed using log-rank test. To find predictors of clinical events, Cox proportional hazard model analysis was conducted to provide adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Variables in Table
1 (without laboratory data) with P ≤ 0.1 at the univariate analysis were entered into multivariate Cox regression analysis. In particular, formal interaction testing was performed between diabetes status and revascularization treatment on all clinical outcomes.
Table 1
Baseline patient, angiographic and procedural characteristics according to diabetes status
Age (years) | 60 (51–68) | 60 (53–68) | 0.811 |
Male | 675 (80.9) | 280 (75.5) | 0.031 |
Current smoker | 467 (56.0) | 183 (49.3) | 0.032 |
Hypertension | 495 (59.4) | 242 (65.2) | 0.053 |
Dyslipidemia | 480 (57.6) | 230 (62.0) | 0.148 |
Previous myocardial infarction | 39 (4.7) | 26 (7.0) | 0.098 |
Previous PCI | 42 (5.0) | 28 (7.5) | 0.085 |
Previous stroke | 74 (8.9) | 44 (11.9) | 0.107 |
Peripheral vascular disease | 20 (2.4) | 16 (4.3) | 0.072 |
CKD in treatment | 16 (1.9) | 10 (2.7) | 0.392 |
OSAHS | 14 (1.7) | 2 (0.5) | 0.171 |
Heart rate (beats/min) | 76 (68–85) | 78 (70–85) | 0.101 |
Systolic blood pressure (mmHg) | 120 (108–130) | 120 (110–130) | 0.236 |
Laboratory data |
Peak troponin (μg/L) | 68 (28–102) | 73 (28–102) | 0.808 |
Peak CK (U/L) | 2101 (1124–3404) | 1977 (987–3347) | 0.204 |
Peak CK-MB (U/L) | 227 (120–305) | 173 (85–299) | < 0.001 |
Time from symptom onset to PCI (h) | 5.0 (3.0–7.0) | 5.0 (3.5–8.0) | 0.009 |
Killip class III/IV | 74 (8.9) | 46 (12.4) | 0.059 |
Radial artery access | 295 (35.4) | 151 (40.7) | 0.077 |
No. narrowed coronary arteries | 0.778 |
Two | 580 (69.5) | 255 (68.7) | |
Three | 254 (30.5) | 116 (31.3) | |
Culprit vessel | 0.832 |
Left anterior descending | 325 (39.0) | 138 (37.2) | |
Left circumflex | 112 (13.4) | 50 (13.5) | |
Right | 397 (47.6) | 183 (49.3) | |
Non-culprit artery |
Left anterior descending | 370 (44.4) | 178 (48.0) | 0.245 |
Left circumflex | 453 (54.3) | 197 (53.1) | 0.696 |
Right | 266 (31.9) | 111 (29.9) | 0.495 |
Thrombus aspiration | 582 (69.8) | 234 (63.1) | 0.021 |
No-reflow phenomenon | 80 (9.6) | 37 (10.0) | 0.837 |
Intra-aortic balloon pump use | 83 (10.0) | 36 (9.7) | 0.894 |
Glycoprotein IIb/IIIa inhibitor use | 224 (26.9) | 91 (24.5) | 0.395 |
Temporary pacemaker | 20 (2.4) | 15 (4.0) | 0.116 |
Defibrillator | 43 (5.2) | 18 (4.9) | 0.824 |
Drug-eluting stent use | 809 (97.0) | 360 (97.0) | 0.975 |
Type of stent | 0.276 |
1st drug-eluting stent | 634 (76.0) | 265 (71.4) | |
2nd drug-eluting stent | 175 (21.0) | 95 (25.6) | |
Bare-mental stent | 2 (0.2) | 2 (0.5) | |
PTCA | 23 (2.8) | 9 (2.4) | |
Stent number | 1 (1–2) | 1 (1–2) | 0.137 |
Total stent length (mm) | 33 (24–48) | 30 (24–42) | 0.080 |
Minimum stent diameter (mm) | 3.00 (2.50–3.50) | 3.00 (2.50–3.50) | 0.338 |
Medications at discharge |
Aspirin | 833 (99.9) | 371 (100.0) | 1.000 |
P2Y12 receptor inhibitor | 834 (100.0) | 371 (100.0) | 1.000 |
ACEI/ARB | 617 (74.0) | 269 (72.5) | 0.592 |
β-blockers | 693 (83.1) | 331 (89.2) | 0.006 |
Statins | 826 (99.0) | 370 (99.7) | 0.289 |
Acute kidney injurya | 177 (21.3) | 74 (21.0) | 0.602 |
To adjust for potential confounders from the real world, a double 1:1 propensity score-matching analysis (staged PCI vs. culprit-only PCI groups) without replacement, on the basis of the nearest neighbor in terms of Mahalanobis distance with a caliper of 0.02, was performed in each subgroup of patients, i.e., nondiabetic and diabetic patients. To estimate the propensity score, a logistic regression model was used including variables of age, gender, current smoking, hypertension, previous MI, previous PCI, peripheral vascular disease, chronic kidney disease, time from symptom onset to PCI, heart rate, access site of PCI, Killip class III/IV, number of diseased vessels, culprit vessel of left anterior descending coronary artery, nonculprit vessel of left anterior descending coronary artery, thrombus aspiration, intra-aortic balloon pump, stent length, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and use of β-blockers. In addition, to assess the robustness of the results, long-term outcomes of patients undergoing staged PCI within 10 days were compared with those in culprit-only PCI group not undergoing revascularization of nonculprit vessels during the following 10 days after primary PCI in both nondiabetic and diabetic population.
Statistical analyses were conducted using SPSS 23.0 (SPSS Inc., Chicago, Illinois, USA) and STATA 12.0 (StataCorp, College Station, Texas, USA). A two-sided P value of < 0.05 was considered to indicate statistical significance.
Discussion
During the 10-year study, diabetes was present in 30.8% of the patients with STEMI and multivessel disease who underwent primary PCI in our center. Multivariate analysis showed that diabetes mellitus was not independently associated with the primary endpoint of MACCE or the secondary outcomes at 5 years. Compared with culprit-only PCI, staged complete revascularization was associated with lower risks of MACCE, MI, unplanned revascularization and the composite of cardiac death, MI or stroke in nondiabetic patients. However, no significant difference was found between the two revascularization strategies in terms of all the outcomes in diabetic patients. Besides, significant interactions between diabetes status and treatment for MI, unplanned revascularization and the composite of cardiac death, MI or stroke at 5 years were found. Furthermore, these findings were demonstrated by propensity score-matching analysis.
Patients with STEMI and multivessel disease were associated with worse outcomes than those with single-vessel disease [
1,
2]. However, the management of nonculprit lesions has been fiercely debated for two decades until the recent publication of the landmark RCTs [
9‐
12]. The Preventative Angioplasty in Myocardial Infarction trial showed that preventive PCI of nonculprit lesions significantly reduced the risk of a composite endpoint of cardiac death, MI, and refractory angina at 23 months [
9]. The Complete Versus culprit-Lesion only PRimary PCI trial indicated that patients who received in-hospital complete revascularization had lower composite risk of all-cause death, recurrent MI, heart failure, and ischemia-driven revascularization at 1 year [
10]. In addition, the Third DANish Study of Optimal Acute Treatment of Patients with STEMI-PRImary PCI in MULTIvessel Disease and the Compare-Acute trials indicated significant benefit of immediate or complete revascularization regarding adverse cardiac events compared with culprit-only PCI [
11,
12]. Furthermore, the studies conducted by Cui et al. and Toyota et al. with 5-year information confirmed and extended the results of previous studies with short- or medium-term follow-up period [
24,
30].
Diabetes mellitus is both an important risk factor for the development of CAD [
20,
31] and a major determinant of poor clinical outcomes in patients with CAD [
14‐
18]. Patients with diabetes mellitus often have a high incidence of complex disease with smaller vessel size, longer lesion length, and higher plaque burden [
32]. The Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome Project which included 63,450 patients from 150 tertiary hospitals revealed that the prevalence of diabetes/possible diabetes was 36.8% in STEMI patients, which was a little higher than the finding of our study. In addition, diabetic/possible diabetic patients had 2.4-fold increased risk of in-hospital mortality and a twofold increased risk of a combination of cardiac death, recurrent MI, stent thrombosis or stroke compared with nondiabetic patients [
14]. Jung et al. [
15] reported that people with diabetes had a two- to sixfold higher risk of major adverse cardiac events than people without diabetes in South Korea. A report from Spain showed that patients with MI and diabetes had a significantly 15% higher in-hospital mortality than nondiabetic patients [
16]. A systematic review and meta-analysis with a total of 1,225,174 patients revealed an increased risk of early mortality (odds ratio 1.66, 95% CI 1.59 to 1.74) and 6–12-month mortality (odds ratio 1.86, 95% CI 1.75 to 1.97) in diabetic patients with acute coronary syndrome [
17]. Besides, Klempfner et al. [
18] enrolled 11, 472 patients with acute coronary syndrome found that diabetes was independently associated with a significantly increased mortality risk (39%) at 1 year compared with nondiabetic patients. Moreover, the incidence of ischemic events was consistently higher in diabetic patients after PCI or coronary artery bypass graft surgery [
21,
22]. The latest guideline has classified STEMI patients with diabetes as a special population and presented specific sections for the management of these patients in consideration of their extremely high risk [
13]. Therefore, diabetes status might be a major factor in the choice of revascularization strategy in patients with STEMI and multivessel disease.
Unfortunately, it remains undetermined whether diabetes has an effect on the outcomes of these patients who received staged complete revascularization or culprit-only PCI. Only a small number of patients with diabetes were included in previous RCTs and this high-risk group of patients were underrepresented [
9‐
12]. Hamza et al. enrolled 100 diabetic patients with STMEI and multivessel disease to randomly receive staged complete revascularization (n = 50) or culprit-only PCI (n = 50). After 6-month follow-up, they found that staged complete revascularization was significantly associated with a reduction in major adverse cardiac events (6% vs. 24%, P = 0.01), primarily due to reduction in ischemia-driven revascularization in the complete PCI group (2% vs. 12%; P = 0.047). However, their sample size was relatively small and the follow-up period was relatively short [
23]. Therefore, it is necessary to determine whether the effect of diabetes on clinical outcomes differs according to different revascularization strategies.
In this study, STEMI patients with and without diabetes mellitus showed similar risks of ischemic events. Furthermore, diabetes was not a predictor of the primary endpoint of MACCE or the secondary outcomes at 5 years in multivariate analysis, while the strategy of culprit-only PCI was an independent predictor of the less favorable outcomes in these patients. Patients with STEMI and multivessel disease was a higher-risk population in STEMI patients, thus the impact of revascularization strategy on prognosis is more important than the impact of diabetes status on prognosis in our study. Although with increased risk of perioperative events, early revascularization of nonculprit lesions can reduce ischemic burden, stabilize vulnerable plaque, and reduce the long-term incidence of ischemic events [
33]. Nonetheless, the comparable results between the diabetic and nondiabetic groups here could be partially explained, since data on the length of illness and details of antidiabetic therapy was not available in our study, which might have an effect on prognosis in diabetic patients. Actually, inappropriate antidiabetic therapy can significantly increase the risk of mortality [
34].
The most important finding of the present study might be that the interactions between diabetes status and revascularization assignment tended to be significant for the outcomes of MACCE, MI, unplanned revascularization, and the composite of cardiac death, MI or stroke at 5 years, which were confirmed by propensity score-matching analysis. In nondiabetic patients, the 5-year risks of MACCE, MI, unplanned revascularization, and the composite of cardiac death, MI or stroke were significantly lower in staged PCI group than those in culprit-only PCI group, whereas the incidences of all the outcomes were similar between the two revascularization strategies in diabetic patients. In other words, the strategy of staged complete revascularization lost its advantage in patients with diabetes and multivessel disease, which was contrary to the results of study conducted by Hamza et al. In clinical scenarios, the diffuse and rapidly progressive forms of CAD in diabetic patients may lead to more stent implantation characterized by longer length and smaller diameter, which is associated with worse outcomes. Although the new-generation drug-eluting stent has been widely used in clinical practice, the morbidity and mortality are still high in diabetic patients undergoing PCI and diabetes mellitus remains a risk factor for restenosis and stent thrombosis [
32,
35]. Considering the staged PCI of nonculprit vessels brings no additional benefits to diabetic patients with multivessel disease as compared with culprit-only PCI, it becomes even more important to choose an optimal hypoglycemic regimen in this population. Recently, several studies have found that the new antidiabetic drugs, i.e., sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists can lower blood glucose levels and mortality risks [
36‐
39]. Henceforward, these new types of drugs should be given a full consideration in the treatment of diabetic patients with STEMI and multivessel disease.
Limitations
There are several limitations of our study. First, as a single-center, nonrandomized study, our research is limited by unbalanced baseline characteristics and selection bias. Although we performed rigorous multivariable-adjusted analysis and propensity score-matching analysis, there might still be some unmeasured confounders. Second, our results were mainly derived from subgroup analysis of a cohort study, thus we might have inadequate statistical power to detect differences in clinical events in diabetic patients and the results should be interpreted as hypothesis generating. Moreover, the number of subjects with diabetes was modest (371), and possibly not all confounders were identified. Therefore, further larger-scale investigation in dedicated trials of diabetic patients is warranted. Third, the data on length of illness and details of antidiabetic therapy were not collected in the study. Finally, the significance of nonculprit lesions was routinely assessed on angiography other than ischemia testing, for example, fractional flow reserve or noninvasive physiological stress test for most patients.
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