Abstract
Background
Stent thrombosis is a rare but deleterious event. Routine coronary angiography with percutaneous coronary intervention (PCI) is often deferred in the presence of laboratory markers of acute inflammation to prevent complications. The aim of this study was to investigate whether an acute inflammatory state is associated with an increased risk of early stent thrombosis.
Methods and Results
Within a prospective single‐center registry, the association between preprocedural acute inflammatory activation, defined as C‐reactive protein plasma levels >50 mg/L or a leukocyte count >12 g/L, and occurrence of early (≤30 days) stent thrombosis was evaluated. In total, 11 327 patients underwent PCI and of those, 6880 patients had laboratory results available. 49.6% of the study population received PCI for an acute coronary syndrome and 50.4% for stable ischemic heart disease. In patients with signs of acute inflammatory activation (24.9%), PCI was associated with a significantly increased risk for stent thrombosis (hazard ratio, 2.89; P<0.00001), independent of age, sex, kidney function, number and type of stents, presence of multivessel disease, choice of P2Y12 inhibitor, and clinical presentation. Elevated laboratory markers of acute inflammation were associated with the occurrence of stent thrombosis in both patients with acute coronary syndrome (hazard ratio, 2.63; P<0.001) and in patients with stable ischemic heart disease (hazard ratio, 3.57; P<0.001).
Conclusions
An acute inflammatory state at the time of PCI was associated with a significantly increased risk of early stent thrombosis. Evidence of acute inflammation should result in deferred PCI in elective patients, while future studies are needed for patients with acute coronary syndrome.
Keywords: coronary stent thrombosis, C‐reactive protein, inflammation, leukocyte count, PCI, stent
Subject Categories: Catheter-Based Coronary and Valvular Interventions, Percutaneous Coronary Intervention, Stent
Nonstandard Abbreviations and Acronyms
- BMS
bare‐metal stent
- DES
drug‐eluting stent
- SIHD
stable ischemic heart disease
Clinical Perspective.
What Is New?
Patients undergoing percutaneous coronary intervention for acute or stable atherosclerotic cardiovascular disease presenting with laboratory evidence of acute inflammation, defined as C‐reactive protein >50 mg/L or leukocyte count >12 g/L, are at strongly elevated risk of developing early stent thrombosis; this association was seen both in patients with stable ischemic heart disease and those with acute coronary syndromes.
What Are the Clinical Implications?
Further research is needed to confirm the herein reported findings to support a strategy of routine deferral of percutaneous coronary intervention in patients with stable ischemic heart disease and signs of acute inflammatory activation.
In addition, clinical trials testing additional antithrombotic, anti‐inflammatory, or other intensified treatment in patients with acute coronary syndrome with elevated inflammatory markers are strongly warranted.
Each year, more than 1 million percutaneous coronary interventions (PCIs) are performed in Europe and the United States alone. 1 , 2 A dreaded complication of PCI is the occurrence of stent thrombosis, an event associated with a high rate of morbidity and mortality. 3 Causes for stent thrombosis are manifold and include patient, procedural, device, as well as lesion characteristics. 4 Improvements in stent structure, drug coating, PCI techniques, as well as antithrombotic drugs have reduced the overall burden of stent thrombosis. 5 While inflammatory reactions to the implanted device have been described as a risk factor for in‐stent restenosis and possibly for stent thrombosis, 6 less is known about the influence of preprocedural inflammatory activation or infection on the occurrence of stent thrombosis.
While in current clinical practice, elective coronary angiography and PCI are often deferred in patients with laboratory or clinical signs of acute inflammation to prevent early procedure and device‐related complications, guideline recommendations for this setting are scarce because of a lack of high‐quality data. Therefore, we have investigated the association between laboratory signs of acute inflammation and infection and the occurrence of stent thrombosis within 30 days after PCI.
Methods
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Study Population
This single‐center observational cohort study included consecutive patients ≥18 years of age from the coronary catheter laboratory registry of the Medical University of Vienna (CCLD‐MUW) who underwent coronary angiography with PCI. 7 PCI was performed by experienced interventional cardiologists according to local standards based on contemporary guidelines. The study is in line with the Declaration of Helsinki, was approved by the ethics committee of the Medical University of Vienna (institutional review committee), and all patients provided written informed consent.
Data Collection and Primary End Point
The CCLD‐MUW is a prospective registry, including all patients undergoing coronary angiography at the Medical University of Vienna/Vienna General Hospital, Austria. Registry data include baseline characteristics, comorbidities, angiographic characteristics, and laboratory results. Admission for acute coronary syndrome (ACS) was defined as an unscheduled admission for symptoms suggestive of ongoing myocardial ischemia (angina or angina equivalent) and was ultimately diagnosed as ST‐segment–elevation myocardial infarction (STEMI), non–ST‐segment–elevation myocardial infarction, or unstable angina according to the Universal Definition of Myocardial Infarction. 8
The primary end point was the occurrence of definite early stent thrombosis within 30 days after PCI, which was diagnosed based on the 2018 Academic Research Consortium‐2 consensus for standardized end point definitions for coronary intervention trials according to the discretion of the respective interventional cardiologist. 9 Follow‐up for survival was performed using the Austrian death registry. In addition, the electronic health registry of Vienna was screened for hospital admission within 30 days after primary PCI for all patients.
Laboratory Measurements
Preprocedural leukocyte count (upper limit of normal 10 g/L) and plasma levels of CRP (C‐reactive protein) >50 mg/L (upper limit of normal 5 mg/L) were obtained on the day of the intervention or the 24 hours prior by the central laboratory of the General Hospital of Vienna.
Statistical Analysis
Categorical variables are summarized as counts or percentages and are compared by the χ2 or by Fisher exact test as appropriate. Continuous variables are expressed as median (interquartile range). Unpaired variables were compared by Mann–Whitney test for 2 samples and by Kruskal–Wallis test for multiple samples. Concordance values (C‐index) were derived in order to determine statistically optimal as well as clinically practical cut‐off values for laboratory parameters that constitute inflammation. Highest C‐index values were observed in the range of CRP 25–50 mg/L and leukocytes of 10–12 g/L. In order to minimize false positive results within the range of highest C‐index values, significant inflammatory activation was defined by CRP >50 mg/L or leukocyte count >12 g/L (see Figure S1). Cox proportional hazard regression analysis was performed to assess the effect of inflammation on stent thrombosis. Variables that were clinically indicated or that were imbalanced between patients with and without stent thrombosis, as indicated by a P value <0.2 in the univariable analysis, were included in the analysis. Kaplan–Meier analysis (log‐rank test) was applied to verify the effect of inflammation on stent thrombosis. Two‐sided P values of <0.05 indicated statistical significance. SPSS 22.0 (IBM Corporation, Armonk, NY) and R version 4.23 (R Core Team, 2023) were used for all analyses.
Results
Baseline Characteristics
During the study period, 11 327 patients underwent coronary angiography and PCI for both stable and acute coronary disease, and 91 patients (0.8%) experienced a definite stent thrombosis within 30 days (Figure 1 for patient flowchart). Thirty‐day mortality was 22% in patients who experienced a stent thrombosis as compared with 2.8% in those without stent thrombosis (P<0.001). Preprocedural leukocyte counts and CRP plasma levels were available in 60.7% of the total cohort (n=6880) and in 95.6% of patients who experienced a stent thrombosis (n=87) during follow‐up. Table S1 gives a comparison of baseline characteristics of all patients in the registry and of the group of patients with available laboratory results. Laboratory results were more often available in patients with ACS as compared with patients with stable ischemic heart disease (SIHD) and elective procedures. Further analysis was performed in patients with inflammatory markers available. The Table shows the baseline characteristics of patients without (n=6793) and with definite early stent thrombosis (n=87; 1.3%). Median age was 63.6 (interquartile range, 54.1–72.5) years, and 4980 (72.4%) were male. 25.4% of patients had diabetes, 48.9% were smokers, and 71.2% of patients had arterial hypertension. Three thousand four hundred fifteen patients (49.6%) had an ACS, and 3465 (50.4%) were treated for SIHD (Tables S2 through S4).
Figure 1. Patient flow chart.
ACS indicates acute coronary syndrome; CRP, C‐reactive protein; PCI, percutaneous coronary intervention; SIHD, stable ischemic heart disease; and ST, stent thrombosis.
Table 1.
Baseline Characteristics
| No early ST (n=6793) | Early ST (n=87) | P value | |
|---|---|---|---|
| Age, median (IQR) | 63.7 (54.2–72.6) | 60.5 (50.4–71.8) | 0.094 |
| Sex | 0.625 | ||
| Male, n (%) | 4915 (72.4%) | 65 (74.7%) | … |
| Female, n (%) | 1878 (27.6%) | 22 (25.3%) | … |
| BMI, kg/m2, median (IQR) | 27.3 (24.7–30.6) | 26.5 (24.2–30.5) | 0.577 |
| Smoker, n (%) | 3322 (48.9%) | 41 (47.1%) | 0.742 |
| Diabetes, n (%) | 1725 (25,4%) | 23 (26.4%) | 0.824 |
| Hypertension, n (%) | 4846 (71.3%) | 54 (62.1%) | 0.058 |
| Atrial fibrillation, n (%) | 316 (4.7%) | 3 (3.4%) | 0.436 |
| Family history of CAD, n (%) | 1400 (20.6%) | 12 (13.2%) | 0.118 |
| Previous myocardial infarction, n (%) | 1440 (21.2%) | 15 (17.2%) | 0.369 |
| Previous PCI, n (%) | 1158 (17.0%) | 16 (18.4%) | 0.741 |
| Previous CABG, n (%) | 542 (8.0%) | 3 (3.4%) | 0.120 |
| Total cholesterol, mg/dL, median (IQR) | 194.0 (160.5–229.0) | 183.5 (164.3–209.8) | 0.242 |
| HDL, mg/dL, median (IQR) | 43.0 (36.0–52.0) | 42.0 (33.0–50.0) | 0.105 |
| LDL, mg/dL, median (IQR)† | 117.4 (87.0–149.6) | 115.0 (98.6–139.0) | 0.795 |
| Triglycerides, mg/dL, median (IQR) | 136.0 (95.0–201.0) | 129.5 (91.5–187.0) | 0.500 |
| HbA1c, %, median (IQR) | 5.9 (5.6–6.5) | 5.8 (5.6–6.6) | 0.541 |
| Creatinine, mg/dL, median (IQR) | 1.02 (0.89–1.22) | 0.99 (0.85–1.33) | 0.461 |
| GFR (MDRD‐175), mL/kg per 1.73 m2, median (IQR) | 69.9 (54.7–82.5) | 75.5 (55.7–88.3) | 0.134 |
| Indication for PCI | 0.003* | ||
| SIHD, n (%) | 3435 (50.6%) | 30 (34.5%) | … |
| ACS, n % | 3358 (49.4%) | 57 (65.5%) | … |
| ACS type (n=3358/n=57) | <0.001* | ||
| STEMI, n (%) | 1792 (53.4%) | 45 (78.9%) | … |
| NSTEMI, n (%) | 1072 (31.9%) | 11 (19.3%) | … |
| Unstable AP, n (%) | 494 (14.7%) | 1 (1.8%) | … |
| Number of stents implanted, mean±SD | 1.6±1.0 | 2.1±1.4 | <0.001* |
| Stent type | 0.018 | ||
| Early‐generation DES‡, n(%) | 3526 (51.9%) | 53 (60.9%) | … |
| New‐generation DES§, n (%) | 2804 (41.3%) | 24 (27.6%) | … |
| BMS, n (%) | 463 (6.8%) | 10 (11.5%) | … |
| No. of coronary vessels diseased | 0.016* | ||
| Single‐vessel disease, n (%) | 2988 (44.0%) | 27 (31.0%) | … |
| Multivessel disease (>1 vessel), n (%) | 3805 (56.0%) | 60 (69.0%) | … |
| Aspirin, n (%) | 6454 (95.0%) | 84 (96.6%) | 0.511 |
| P2Y12 inhibitor | <0.001* | ||
| No/unknown, n (%) | 60 (0.9%) | 5 (5.8%) | … |
| Clopidogrel, n (%) | 5883 (85.9%) | 68 (78.2%) | … |
| Prasugrel, n (%) | 681 (10.0%) | 12 (13.8%) | … |
| Ticagrelor, n (%) | 219 (3.2%) | 2 (2.3%) | … |
ACS indicates acute coronary syndrome; AP, angina pectoris; BMI, body mass index; BMS, bare‐metal stent; CABG, coronary artery bypass graft; CAD, coronary artery disease; DES, drug‐eluting stent; GFR, glomerular filtration rate; HbA1c, hemoglobin A1c; HDL, high‐density lipoprotein; IQR, interquartile range; LDL, low‐density lipoprotein; MDRD, Modification of Diet in Renal Disease; NSTEMI, non–ST‐segment–elevation myocardial infarction; PCI, percutaneous coronary intervention; SIHD, stable ischemic heart disease; STEMI, ST elevation myocardial infarction; and ST, stent thrombosis.
P≤0.05=significant.
LDL value calculated with Friedewald formula.
Early‐generation DES includes sirolimus‐ and paclitaxel‐eluting stents.
New‐generation DES includes everolimus‐ and zotarolimus‐eluting stents.
Definite Early Stent Thrombosis and Clinical Characteristics
Patients with ACS had a significantly higher rate of stent thrombosis (n=57; 1.7%) as compared with patients with SIHD (n=30; 0.9%; P<0.01). In addition, the incidence of stent thrombosis was significantly higher in ST‐segment–elevation myocardial infarction (2.4%) as compared with non–ST‐segment–elevation myocardial infarction (1.3%) and patients with unstable angina (0.3%; P<0.001), respectively (Table). Implantation of new‐generation drug‐eluting stents (DES) (everolimus‐ and zotarolimus‐eluting stents, n=2828) was associated with a significantly lower incidence of stent thrombosis (0.8%) as compared with early‐generation DES (sirolimus‐ and paclitaxel‐eluting stents, n=3579) or bare‐metal stents (BMS, n=473) with an incidence of early stent thrombosis of 1.5% and 2.1%, respectively (P=0.018).
Inflammatory Activation and Early Stent Thrombosis
1715 patients (24.9%) showed laboratory signs of inflammatory activation. Inflammatory activation was more common in patients with ACS (n=1152, 33.7%) as compared with patients with SIHD (n=563, 16.2%; P<0.00001). PCI in patients with a leukocyte count >12 g/L or CRP >50 mg/L was associated with a significantly increased risk for early stent thrombosis (hazard ratio [HR] 3.22 [95% CI, 2.12–4.90]; P<0.00001). Similar results were seen in patients with ACS (HR, 2.63 [95% CI, 1.56–4.44]; P<0.001) and in patients with SIHD (HR, 3.57 [95% CI, 1.72–7.41]; P<0.001; Figure 2). Early stent thrombosis occurred in 2.6% of patients with and in 0.8% of patients without signs of inflammatory activation (P<0.0001). The incidence of stent thrombosis in patients with ACS with and without signs of inflammation was 2.8% versus 1.1% (P<0.001) and in patients with SIHD with and without inflammation was 2.1% versus 0.6% (P=0.002). Similar results were seen when patients were stratified according type of stents. The incidence of stent thrombosis in patients with new‐generation DES with and without signs of inflammation was 1.7% versus 0.5% (P<0.001), in patients with early‐generation DES with and without inflammation was 3.0% versus 1.0% (P=0.004), and in patients with BMS was 4.5% versus 0.9% (P=0.017). Multivariable analysis showed that the increased risk for early stent thrombosis in patients with inflammatory activation was independent of age, sex, glomerular filtration rate, clinical presentation as ACS or SIHD, multivessel disease, P2Y12 inhibitor treatment, and number and type of stents (HR, 2.89 [95% CI, 1.86–4.48]; P<0.0001). If patients had an increase of both, leukocytes >12 g/L and CRP >50 mg/L, the rate of stent thrombosis further increased (Figure 3).
Figure 2. Hazard ratios for early stent thrombosis.
BMS indicates bare‐metal stent; CRP, C‐reactive protein; DES, drug‐eluting stent; HR, hazard ratio; and Ref., reference category. Early‐generation DES include sirolimus‐ and paclitaxel‐eluting stents; new‐generation DES include everolimus‐ and zotarolimus‐eluting stents.
Figure 3. Early stent thrombosis rates in patients with increased CRP and elevated leukocyte count.
CRP indicates C‐reactive protein.
Inflammatory Activation and Time Until Stent Thrombosis
Figure 4 shows Kaplan–Meier curves for the occurrence of early stent thrombosis for the total cohort (P<0.00001), for patients with ACS (P<0.001), and for patients with SIHD (P<0.001). To assess whether the risk for stent thrombosis was mainly increased during the period of acute inflammatory activation or whether inflammatory activation at the time of PCI was also associated with stent thrombosis at a later phase, we performed a landmark analysis for the first 5 days (Figure 5A) and for the later period (Figure 5B), and we were able to show that inflammatory activation was associated with a higher rate of stent thrombosis in both the early (P<0.0001) and the later time period (P<0.0001).
Figure 4. Kaplan–Meier curves for early stent thrombosis according to presence of inflammatory activation.
Patients were stratified according the presence of significant inflammatory activation on the day of PCI (red) or no significant inflammatory activation (green). Kaplan–Meier survival curves for the total cohort (A), for patients with acute coronary syndromes (B), and for patients with stable ischemic heart disease (C). CRP indicates C‐reactive protein; and PCI, percutaneous coronary intervention.
Figure 5. Kaplan–Meier curves for early stent thrombosis according to the presence of inflammatory activation.
Landmark analysis for the first 5 days (A) and for the later period between day 5 and 30 (B) in patients with inflammatory activation (red) and without significant inflammatory activation (green).
Inflammatory Parameters, Infection, and Early Stent Thrombosis
At the time of PCI, median CRP levels and median leukocyte count were significantly higher in patients who had a stent thrombosis within 30 days as compared with patients without early stent thrombosis. Similar results were seen when patients were stratified according to clinical presentation at the time of PCI in patients with ACS and patients with SIHD (Figure 6). CRP levels in the fourth quartile were significantly associated with increased risk of early stent thrombosis in the total cohort (HR, 2.88 [95% CI, 1.52–5.44]; P=0.001; Figure 2) as well in patients with ACS (HR, 2.53 [95% CI, 1.17–5.50]; P<0.05) and with SIHD (HR, 4.11 [95% CI, 1.16–14.5]; P<0.05).
Figure 6. Plasma levels of C‐reactive protein and leukocyte count on the day of PCI according to the later occurrence of early stent thrombosis.
Boxplots for C‐reactive protein according to the occurrence of early stent thrombosis in the total cohort (A), in patients with acute coronary syndromes (B), and in patients with stable ischemic heart disease (C), as well as leukocyte count according to the occurrence of early stent thrombosis in the total cohort (D), in patients with acute coronary syndromes (E), and in patients with stable ischemic heart disease (F). PCI indicates percutaneous coronary intervention; and ST, stent thrombosis.
In addition, the highest quartile of leukocyte count was associated with increased risk of early stent thrombosis in the total cohort (HR, 5.49 [95% CI, 2.46–12.27]; P<0.0001; Figure 2), in patients with ACS (HR, 3.71 [95% CI, 1.50–9.19]; P<0.005), and in patients with SIHD (HR, 3.09 [95% CI, 1.12–8.50]; P<0.05).
To further examine whether clinical signs of infection were associated with an increased risk of early stent thrombosis, we retrospectively analyzed the clinical records of 1500 patients, including all patients with early stent thrombosis (n=87) and a randomly selected group of patients without early stent thrombosis (n=1413) for the presence of urinary tract infection, pneumonia, sepsis, or other infections at the time of stent implantation. Interestingly, patients with pneumonia (n=46; HR, 2.63 (95% CI, 1.55–8.52); P<0.005) and even more pronounced patients with sepsis (n=12; HR, 12.83 [95% CI, 5.09–32.40]; P<0.00001) at time of PCI showed a high risk of acute stent thrombosis within 30 days (Figure 2).
Discussion
In this observational analysis including 6880 patients undergoing PCI for both ACS and SIHD, patients with laboratory signs of acute inflammatory activation had a >3‐fold rate of early stent thrombosis as compared with those without elevations of inflammatory markers. We used a combination of CRP values and leukocyte count to define an acute inflammatory state. The cut‐off values, defined as a leukocyte count >12 g/L or plasma levels of CRP >50 mg/L, were derived by calculating the C‐index for a range of values for CRP and leukocyte count, respectively. Importantly, the relative increase in risk for early stent thrombosis, defined as a definite stent thrombosis within 30 days of PCI, was even higher in patients with acute inflammation undergoing PCI for SIHD (2.1% versus 0.6%; HR, 3.57), a patient cohort that could routinely be rescheduled, as compared with patients undergoing PCI for ACS (2.8% versus 1.1%; HR, 2.63).
Stent thrombosis, albeit rare, is a dreaded complication of PCI accompanied by high morbidity and a mortality rate between 10% and 33%. 3 , 4 , 5 In our cohort, the occurrence of stent thrombosis was associated with a dramatically increased 30‐day mortality rate of 22%, as compared with only 2.8% in patients without stent thrombosis. Therefore, with millions of stents implanted each year worldwide, the prevention of stent thrombosis should represent a major clinical focus. Herein, the overall stent thrombosis rate was 0.8% in our total cohort and 1.3% in patients with preprocedural laboratory investigations available, which is comparable to rates published in the literature. 10 , 11 , 12 As expected, early stent thrombosis rates decreased from BMS to first‐generation and second‐generation DES. 4 , 6
Various factors have been causally implicated in the occurrence of stent thrombosis, including patient‐level factors such as the presence of diabetes, renal or malignant disease, active smoking status, presentation with myocardial infarction (MI) and premature cessation of antiplatelet therapy. Lesion‐level risk factors include the type of vessel as well as lesion type and location. Stent‐type and size are device‐level risk factors, and procedure‐level risk factors include peri‐interventional medication and complications during stent apposition. 4 , 13 In line with this, patients presenting with ACS were at higher risk for stent thrombosis in our cohort. Additional predictors of stent thrombosis included the presence of multivessel disease and the number of stents implanted. While presence of risk factors as outlined above are associated with the occurrence of stent thrombosis, only a fraction of such patients will actually experience a stent thrombosis. Additional systemic factors, such as presence of acute inflammation or infection, may be required to create such a prothrombotic milieu facilitating acute thrombosis of a recently implanted stent.
Implantation of a coronary stent per se causes an inflammatory reaction, which can be quantified using circulating plasma CRP levels. 14 Persistent inflammatory activation after stent implantation as a response to endothelial injury has been implicated in the development of neo‐atherosclerosis, in‐stent restenosis, and late and very late stent thrombosis. 6 It is less clear, however, whether acute inflammatory activation or infection before PCI might induce a heightened activity of leukocytes, platelets, and the coagulation system, thereby causing or facilitating the occurrence of stent thrombosis via a mechanism called immunothrombosis. 15 Such conserved mechanisms are crucial in limiting localized infections, but when occurring systemically or pathologically they can cause various thrombotic vascular diseases. 16 One potential mechanism may be NETosis, the release of so‐called neutrophil extracellular traps (NETs) by neutrophils upon activation by platelets and inflammatory cytokines upstream of CRP. 17 Overactive NETosis may have detrimental effects in a variety of clinical scenarios such as atherothrombosis 18 and has been detected in coronary thrombi. 19 , 20
The COVID‐19 pandemic offered additional insights into the interplay between inflammation and infection and acute cardiovascular events, as patients with SARS‐CoV‐2 infection upon MI presentation showed dramatically increased rates of stent thrombosis. 21 Furthermore, influenza vaccination within 72 hours after acute MI reduced major adverse cardiovascular events, including stent thrombosis. 22
While in clinical practice it is common to defer elective procedures in light of acutely elevated markers of inflammation and infection, guideline recommendations for such an approach are scarce. Several observational studies have investigated a potential interplay between elevated inflammatory markers and the occurrence of stent thrombosis after PCI. In an Italian analysis of 83 patients undergoing PCI for unprotected left main disease using both bare‐metal and drug‐eluting stents, elevated preprocedural CRP levels (≥3 mg/L) and leukocytes were associated with an increased risk of death and acute MI during a 9‐month follow‐up. 23 The authors discussed that death after left main stenting in patients with elevated inflammation markers might have been related to stent thrombosis. Their findings are in line with results from a previous study conducted in >700 patients undergoing PCI, of whom ≈50% underwent PCI for acute MI. 24 Preprocedural CRP levels >3 mg/L were clearly associated with an increased risk of MI or death within 30 days after PCI. A subsequent French study specifically aimed at analyzing preprocedural elevated CRP levels (>4.6 mg/L) and the risk of stent thrombosis including 560 consecutive patients undergoing PCI with BMS. 25 As in previous studies, elevated preprocedural CRP was predictive of MI and death during a 1‐year follow‐up, but, surprisingly, not of stent thrombosis. In contrast, in a large (n=2691) cohort receiving DES for SIHD, 35% of patients were characterized by preprocedural CRP levels of >3 mg/L, and exhibited a >3‐fold increase in the risk of stent thrombosis during a median follow‐up of 3.9 years. 26 In yet another analysis including 301 patients with ST‐segment–elevation MI, the combination of elevated CRP (>2 mg/L) and the use of BMS was significantly predictive of the occurrence of stent thrombosis over a follow‐up period of 36 months. 27 All previous analyses used a very low cut‐off for CRP levels of either 2 or 3 mg/L, representing chronic, subclinical low‐grade inflammatory activation, within the normal range of CRP. Most of the aforementioned studies applied a long follow‐up window and event rates were low in the early phase after PCI because chronic low‐grade inflammatory activation represents a chronic risk factor for progression of atherosclerosis as opposed to an acute disruptive factor. It would, therefore, not be practical to use such mildly elevated CRP levels to defer PCI to a later date.
In the present analysis, we aimed to describe the risk associated with PCI in patients characterized by a transient, acute elevation in markers of inflammation and infection, which, to the best of our knowledge, has not been described yet. We have defined acute inflammatory activation as either plasma levels of CRP >50 mg/L or a leukocyte count of >12 g/L. These cut‐off values were derived by calculating the C‐index for a range of values for CRP and leukocyte count, respectively. Median CRP concentrations in young healthy adults were shown to be ≈0.8 mg/L, with 3 mg/L being the 90th centile and 10 mg/L the 99th centile. 28 Thus, a cut‐off of 50 mg/L represents clearly and acutely elevated CRP levels not explained by chronic inflammatory disease states. The reference range for leukocytes is usually given as between 4 and 10 g/L, depending on local laboratory, and any expansion of leukocytes is considered pathological. As such, we believe that we adequately identified patients with acute inflammatory/infectious states and excluded those with chronic low‐grade inflammation. Multivariable analysis suggested that the increased risk for early stent thrombosis seen in patients with laboratory signs of acute inflammation was independent of age, sex, kidney function, number and type of stents, presence of multivessel disease, choice of P2Y12 inhibitor, as well as the form of presentation (ACS versus SIHD). Importantly, clinical signs of infection including pneumonia and sepsis at the time of PCI were associated with a strongly increased risk of stent thrombosis, suggesting both acute (sterile) inflammatory activation as well as acute infections as drivers of increased laboratory signs of inflammation and stent thrombosis. In addition, it is well known that ACS is associated with an increase of inflammatory markers and as expected a significant higher proportion of patients with ACS showed signs of inflammation as compared with patients with SIHD. 29 , 30 While the risk of stent thrombosis in our cohort gradually decreased with the use of newer‐generation DES, the risk of early stent thrombosis was consistently 3‐ to 4‐fold elevated in patients with acute inflammation, underscoring the importance of our findings in contemporary clinical settings.
We believe that the herein described more than 3‐fold increased risk of early stent thrombosis in patients with laboratory signs of acute inflammation undergoing elective PCI for stable coronary disease indicates deferral of the procedure to a later time‐point. With a 22% mortality rate in the first 30 days in patients with stent thrombosis in our cohort, such a deferral may even constitute a life‐saving measure. In such situations it seems reasonable to search for infection or other remediable causes and follow up to assess for resolution and PCI indication. Our data further call for routine laboratory assessment in patients undergoing coronary angiography with the possibility of ad‐hoc PCI. In patients with ACS, however, especially in those presenting with ST‐segment–elevation MI, PCI represents a life‐saving intervention to restore blood flow and prevent heart failure and malignant arrhythmias. In the majority of cases, laboratory values will not be available at the time of PCI. Furthermore, signs of inflammation may be caused by the MI itself. Such patients may benefit from adjunct therapies such as additional antithrombotic or anti‐inflammatory treatment. Dedicated trials are warranted testing the hypothesis of reducing ischemic complications with more intense antiplatelet therapy, additional anticoagulatory therapy, or anti‐inflammatory agents, especially in patients with ACS with signs of inflammatory activation where intervention cannot be postponed.
Several limitations of the current analysis deserve discussion. Of the 11 337 patients undergoing coronary angiography and stent implantation, only 6880 patients (60.1%) had preprocedural CRP and leukocyte values available. The rate of stent thrombosis in the overall population was 0.8% as compared with 1.3% in the population with preprocedural inflammation markers available. Therefore, we cannot exclude the possibility that the availability of preprocedural laboratory values preselected higher‐risk patients. Patients with available laboratory markers were characterized by a higher rate of comorbidities but lower rates of pre‐existing cardiovascular diseases. Importantly, most patients who experienced a stent thrombosis had inflammatory parameters available for analysis. In addition, stent thrombosis rates are within a similar range as observed within clinical trials of that era. Only pre‐PCI levels of inflammatory markers were available in this registry. Thus it is unclear whether serial, post‐PCI sampling would result in more precise risk prediction. Because our findings stem from a single‐center registry, they warrant external confirmation. Despite multivariable modeling, we cannot rule out the possibility of residual, undetected confounding. Furthermore, measurement of routine CRP levels before elective PCI is not a routine approach in several countries, thus limiting the immediate clinical applicability of our findings.
Conclusions
In this retrospective registry analysis, preprocedural laboratory signs of an acute inflammatory state, defined as a leukocyte count >12 g/L or plasma levels of CRP >50 mg/L, were independently associated with a 3‐fold occurrence of definite stent thrombosis within 30 days of stent implantation. Importantly, this association was observed for both patients with ACS and patients undergoing elective PCI, in whom the more than 3‐fold increase in stent thrombosis rates should prompt deferral of coronary angiography and PCI.
Sources of Funding
Konstantin A. Krychtiuk is supported by the Max Kade Foundation. This work was supported by the Ludwig Boltzmann Institute for Cardiovascular Research.
Disclosures
None.
Supporting information
Tables S1–S4
Figure S1
This manuscript was sent to Jennifer Tremmel, MD, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.122.032300
For Sources of Funding and Disclosures, see page 11.
See Editorial by Cutlip.
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Associated Data
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Supplementary Materials
Tables S1–S4
Figure S1