|Year : 2018 | Volume
| Issue : 3 | Page : 130-136
Elevated high-sensitivity C-reactive protein after percutaneous coronary intervention in patients with stable coronary artery disease: A proof-of-concept study
Ahmed Bendary1, Bassel Wagdy2, Tarek Aboul Azm1, Osama Sanad1
1 Department of Cardiology, Benha Faculty of Medicine, Benha University, Benha, Egypt
2 Department of Cardiology, Al-Sahel Teaching Hospital, Ministry of Health, Cairo, Egypt
|Date of Web Publication||10-Sep-2018|
Dr. Ahmed Bendary
Department of Cardiology, Benha Faculty of Medicine, Benha University, Benha
Source of Support: None, Conflict of Interest: None
Objectives: Elevated levels of high-sensitivity C-reactive protein (hs-CRP) is associated with increased incidence of cardiovascular events. We aimed to investigate whether iatrogenic disruption of plaques by percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) would result in a meaningful rise in hs-CRP that could impact the short-term outcome. Methods and Results: From September 2017 to May 2018, we measured hs-CRP in 60 patients divided into three groups: Group I (20 patients with stable CAD undergoing elective PCI), Group II (20 patients with non-ST elevation-acute coronary syndromes undergoing PCI), and Group III (20 patients with stable and unstable CAD undergoing angiography without PCI). Samples for hs-CRP testing were withdrawn before the procedure, 6 and 24 h later. In Group I, levels increased from 2.4 ± 0.6 at baseline to 8.2 ± 1.7 mg/L 24 h later, P < 0.001. In Group II, levels increased from 7.7 ± 2.9 at baseline to 12.2 ± 3.5 mg/L 24 h later, P < 0.001. Group III showed no significant change. The median percentage change in Group I was significantly higher than both Groups II and III (239.09% [117.86–566.67] vs. 70.47% [−19.09–212.24] and 10.98% [−27.59–272.73], P < 0.001). No significant differences in baseline or 24-h hs-CRP levels were found between those who developed 30-day endpoints and those who did not. Conclusion: Iatrogenic disruption of plaques by PCI in stable CAD resulted in a significant rise of hs-CRP. However, this does not impact the short-term outcome.
Keywords: High-sensitivity C-reactive protein, percutaneous coronary intervention, stable coronary artery disease
|How to cite this article:|
Bendary A, Wagdy B, Azm TA, Sanad O. Elevated high-sensitivity C-reactive protein after percutaneous coronary intervention in patients with stable coronary artery disease: A proof-of-concept study. Res Cardiovasc Med 2018;7:130-6
|How to cite this URL:|
Bendary A, Wagdy B, Azm TA, Sanad O. Elevated high-sensitivity C-reactive protein after percutaneous coronary intervention in patients with stable coronary artery disease: A proof-of-concept study. Res Cardiovasc Med [serial online] 2018 [cited 2019 Jan 22];7:130-6. Available from: http://www.rcvmonline.com/text.asp?2018/7/3/130/240988
| Introduction|| |
Inflammation is an integral part of the atherosclerotic process and an essential triggering factor for various cardiovascular (CV) events. Many clinical studies have shown a relation between chronic inflammatory status and incident major adverse cardiac events (MACEs). Conventional risk factors for coronary artery disease (CAD), such as those in the Framingham risk score, have been the mainstay for risk stratification process for years; however, data point to the fact that about one-third of the patients with 0 or 1 risk factors develop CAD  and up to 40% of those whose low-density lipoprotein cholesterol (LDL-C) is average go on to have CV events. This highlighted the importance of having other tools for refinement of risk stratification, and biological markers of inflammation are among these emerging tools.
C-reactive protein (CRP), an acute-phase reactant secreted from hepatocytes, is a sensitive but nonspecific marker of inflammation or tissue damage in general. It has been shown to strongly correlate with both fatal and nonfatal coronary events. Unfortunately, recent evidence concluded that standard CRP assays suffice in the setting of active infection or acute inflammation in which there is extensive tissue damage. On the other hand, when it comes to the chronic setting and refinement of CV risk assessment process, high-sensitivity CRP (hs-CRP) provides acceptable sensitivity in detection of very low levels of this biomarker in apparently healthy individuals. Many studies supported the predictive value of hs-CRP for future CVD in both men and women. The case for the inflammatory hypothesis of CV disease and the role of hs-CRP as a maker or marker have been revived by recent data coming from CANTOS trial  which showed that the magnitude of the reduction in hs-CRP following a single dose of the interleukin-1ß monoclonal antibody can identify those with the largest reduction in MACEs. Moreover, a subanalysis of the landmark FOURIER trial pointed that patients with the highest levels of hs-CRP are those who are most likely to benefit from Evolocumab. In addition to its role as a marker for heightened CV risk, CRP has been also implicated in the pathogenesis of atherosclerosis by the recruitment of more monocytes and promotion of the uptake of LDL particles that form foam cells.
Considering the fact that CRP may arise from within atherosclerotic plaques, helped by the local tissue injury at the site of mechanical plaque disruption that occurs during percutaneous coronary intervention (PCI), we thought that it may be interesting to study if PCI in stable CAD results in a meaningful elevation of hs-CRP level and if this elevation (if any) could affect 30-day outcome in those patients for whom PCI is done just for relief of symptoms.
| Methods|| |
In the period from September 2017 to May 2018, 60 patients were consecutively enrolled in this prospective observational study. The Institutional Review Board approved the design of the study, and all patients gave informed consents. The patients were divided into three groups.
Group I: Stable coronary artery disease undergoing percutaneous coronary intervention
This group included 20 consecutive patients with stable CAD undergoing PCI with drug-eluting stent (s) (DES) implantation. The strategy for PCI was complete revascularization during the index procedure. All patients in this group had anginal symptoms stable without marked change for ≥6 months together with a positive stress test. Any patients, who met the inclusion criteria but whose baseline hs-CRP was ≥3 mg/d, were excluded from the study because elevated hs-CRP per se is a marker for a higher risk of future MACEs. For this reason, patients with chronic arthropathies, renal failure, or malignant diseases were excluded as well.
Group II: Non-ST elevation-acute coronary syndrome undergoing percutaneous coronary intervention
This group included 20 consecutive patients admitted to the coronary care unit with a diagnosis of non-ST elevation-acute coronary syndrome (NSTE-ACS) and scheduled for an early invasive strategy for management with aim for complete revascularization during the index procedure. All patients had at least one of the followings; new onset (<1 month), typical effort angina, and/or resting pain together with dynamic ST-T wave changes in their electrocardiograms or positive troponin.
Group III: Coronary artery disease undergoing diagnostic coronary angiography (without percutaneous coronary intervention)
This group included 20 consecutive patients with stable and unstable CAD undergoing diagnostic coronary angiography only (without PCI).
All patients in the three groups were on guideline-directed medical therapy, and all women included in the study were not on any form of oral contraceptive pills or any hormonal replacement therapy. The treating physicians were blinded to the patients' laboratory data until the evaluation of all patients was complete, and the physician performing the hs-CRP assay was blinded to each patient's group allocation.
Diagnostic coronary angiography and percutaneous coronary intervention
All coronary angiographies were performed through the right femoral artery approach using standard 6F arterial introducers, sheaths, and catheters. PCI was done using the monorail technique and 6F guiding catheters in all patients. Xience™ DES (Abbott Vascular) was implanted in all patients after predilatation of the lesions (if indicated) using Sapphire™ (OrbusNeich) balloons. All treated lesions were de novo ones of native coronary arteries. PCI was performed in both Groups I and II by the same experienced independent operator who was blinded to the laboratory results of each patient.
Blood sampling and high-sensitivity C-reactive protein methodology
Venous blood samples were obtained using standard techniques at baseline, 6 h, and then, 24 h after each procedure. Sera were obtained by centrifugation of the blood for 10 min and then stored in several aliquots at −70°C until assayed. Highly sensitive CRP was measured using STAT-FAX reader using Accubind ELISA kits provided by Monbind Inc., Lake Forest, CA92630 USA. The kit was designed for the determination of hs-CRP in human in serum or plasma by microplate immunenzymatic assay. The analysis was done by an independent investigator who was blinded to each patient's study group allocation.
Thirty-day follow-up and endpoints
All patients were followed up at 30 days either by phone contact or personal interview. The endpoint was defined as a composite of CV mortality, recurrent hospitalization for ACS, and repeat urgent revascularization at 30 days' follow-up.
Statistical analysis and sample size calculation
Data management and statistical analysis were done using SPSS V.25 (IBM, Armonk, New York, United States). Numerical data were summarized using means and standard deviations whereas categorical data were summarized using numbers and percentages. For numeric variables, comparisons between three groups were done using the Kruskal–Wallis test. Angiographic data were compared between Groups I and II using the Mann–Whitney U test. Hs-CRP was compared between patients with and without MACE using the Mann–Whitney U test. Baseline hs-CRP was compared to its measurement after 24 h in each group using the Wilcoxon signed-rank test. Categorical data were compared using the Chi-square test or Fisher's exact if appropriate. All P values were two-sided. P < 0.05 was considered statistically significant.
For detecting an effect size of 1 (Δ 1 standard deviation) with a two-sided statistical significance of 0.05, a sample size of 11 would have a power of 85%, based on a parametric t-test. As a nonparametric test with relative efficiency of 95% was expected, we increased our sample size to 20 (in each group). This has a power of 95% with a t-test and 90% for a nonparametric one.
| Results|| |
For the entire study population, the mean age was 53 ± 8 years. About 65% percent of them were males, 28% had DM, 35% were hypertensives, 43% were smokers, 30% had dyslipidemia, 25% were obese, 15% had a family history of premature CAD, 32% had a history of previously diagnosed CAD, and 13% had a history of PCI in other vessels. All patients were on maximally tolerated statin therapy (50% on rosuvastatin and 50% on atorvastatin) with mean duration of preprocedural therapy of 190 ± 56 days. The mean baseline ejection fraction calculated using Simpson's method was 54% ±6%, the mean baseline end-systolic volume was 50 ± 4 ml, and the mean baseline end-diastolic volume was 93 ± 11 ml. Between-group analysis showed no statistically significant differences in all baseline characteristics (including doses and duration of preprocedural statin therapy) in all the study three groups [Table 1].
Angiographic characteristics and percutaneous coronary intervention procedural details
For the entire study population, 47% had single-vessel disease, 32% had two-vessel disease, and 22% had three-vessel disease. For both Groups I and II, 60% has one stent implanted, 32% had two stents, and 8% had three stents. The mean average stent(s) diameter was 3.08 ± 0.34 mm, and the mean average stent(s) length was 27 ± 5 mm. We did not report any intraprocedural complications. Glycoprotein II b/III a inhibitor was not used in any case. All patients were preloaded with Clopidogrel (according to local protocols) with standard weight-adjusted dose of unfractionated heparin given during the procedure in both Groups I and II. Between-group analysis showed no statistically significant differences in all the study three groups as regard to angiographic characteristics and PCI procedural details except procedural times and total amount of contrast used which were significantly lower in Group III (patients who did not get PCI) compared to both Groups I and II [Table 2].
|Table 2: Angiographic characteristics and percutaneous coronary intervention procedural details*|
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High-sensitivity C-reactive protein data
Baseline hs-CRP levels were within the reference range in all patients in this group (mean 2.4 ± 0.6 mg/L). After stent(s) implantation, serum hs-CRP levels increased uniformly in all patients, and this increase was evident early (as soon as 6 h after the procedure). A 239.1% median percent increase in the levels of hs-CRP was observed 24 h after the procedure (range 117.86%–566.67%, P < 0.001). Mean hs-CRP levels 24 h after PCI increased to 8.2 ± 1.7 mg/L) [Figure 1] and [Figure 2].
|Figure 1: High-sensitivity C-reactive protein levels in Group I before and 24 h after percutaneous coronary intervention|
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|Figure 2: High-sensitivity C-reactive protein levels at baseline, 6 and 24 h after percutaneous coronary intervention in all the three groups. P value is for comparison between baseline and 24-h high-sensitivity C-reactive protein levels in each group|
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The mean baseline hs-CRP level was higher than the reference range in this group (mean 7.7 ± 2.9 mg/L). After stent(s) implantation, serum hs-CRP levels increased in all patients (except patient no. 18) but in a less uniform manner compared to Group I. This increase was also evident early (as soon as 6 h after the procedure). About 70.5% median percentage increase in the levels of hs-CRP was observed 24 h after the procedure (range−19.09%–212.24%, P < 0.001). Mean hs-CRP levels 24 h after PCI increased to 12.2 ± 3.5 mg/L [Figure 2] and [Figure 3].
|Figure 3: High-sensitivity C-reactive protein levels in Group II before and 24 h after percutaneous coronary intervention|
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The mean baseline hs-CRP level in this group was 3.2 ± 1.6 mg/L. Twenty-four hours after diagnostic coronary angiography, the mean hs-CRP level was 3.5 ± 1.3 mg/L. No statistically significant change in the levels of hs-CRP was noticed in this group when comparing values at baseline and 24 h after the procedure (median percentage change + 10.98% [range − 27.59%–272.73%, P = 0.197]) [Figure 2] and [Figure 4].
|Figure 4: High-sensitivity C-reactive protein levels in Group III before and 24 h after percutaneous coronary intervention|
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Of note, between-group analysis showed that median percentage change in hs-CRP levels after 24 h (from baseline) was significantly higher in Group I compared to both Groups II and III, and there was no significant difference in median percentage change when comparing Groups II and III [Table 3].
|Table 3: Percent change of high-sensitivity C-reactive protein after 24 h (from baseline) in study groups*|
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At 30 days follow-up, MACEs were reported in eight patients (13.3% of whole study population); in the form of one case CV mortality, three cases with repeat urgent revascularization, and four cases admitted due to recurrent ACS. There were no statistically significant differences in both baseline mean hs-CRP levels and levels at 24 h after the procedure when comparing those with and without MACEs [Table 4].
|Table 4: High-sensitivity C-reactive protein levels in those with and without major adverse cardiac events|
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| Discussion|| |
Despite its dramatic benefits in patients with ACS, PCI in patients with stable CAD does not provide a significant reduction in mortality or hard MACEs and is mainly performed for reduction of symptom burden. Even the latter benefit has been questioned recently. Therefore, there had been a great interest in studying the merits and demerits of this procedure that was greatly adopted by cardiologists since its invention. This becomes true if we realize that PCI is a procedure not without risk, with some commentators pointing out that PCI trades one problem (flow-limiting stenosis) for another problem having a metal cage exposed to blood platelets.
Considering that, the main aim of medical therapy in stable CAD is to stabilize vulnerable plaques to prevent any acute change that could lead to future coronary events, the fact that PCI itself induces iatrogenic mechanical disruption of these plaques makes sense and potentially contradicts with the aforementioned goal of medical therapy. Based on these facts, some research work has been carried out to study if PCI in stable CAD could lead to a clinically detectable systemic inflammatory response and if this might affect clinical outcome of those patients.
Our results add to the accumulating body of evidence confirming the role of iatrogenic plaque disruption in inducing a systemically detectable inflammatory response. We show that mechanical rupture of a stable atherosclerotic coronary plaque induced by elective stent implantation in a group of patients with stable CAD who are at low-risk (Group I) induces a marked increase in serum hs-CRP which was uniform in all patients and started early (as soon as 6 h after the procedure) persisting up to 24 h later. When stents were implanted in unstable plaques in a group of patients with NSTSE-ACS in whom the baseline hs-CRP level was already elevated (Group II), a further increase in hs-CRP was observed after PCI. In this group, the change in hs-CRP was less dramatic and less uniform than the change observed in the stable CAD group (median percent increase was 239.09% and 70.47%, respectively, P < 0.001). In a mixed group of patients (stable and unstable) who underwent coronary angiography without PCI (Group III), there was no significant change in levels of hs-CRP before and up to 24 h after the procedure. We found also that this observed increase in hs-CRP does not affect 30-days composite MACEs with the caveat that our study was not powered to detect differences in clinical endpoints [Table 4].
There is a general agreement in the literature that PCI leads to a meaningful rise in various inflammatory markers; however, data regarding the impact of this rise on short-term and long-term outcomes are conflicting, implying that this domain is still vivid for further clinical research. Almagor et al. found statistically significant elevation of CRP 20-h post-PCI in 12 patients with stable coronary disease (P < 0.002) and 12 patients with NSTE-ACS (P < 0.004); however, they did not follow-up their patients for clinical endpoints. Several studies have examined the predictive value of CRP levels after elective or emergent PCI with a positive prognostic impact. Buffon et al. found that preprocedural CRP is a significant predictor of both early and late outcomes during follow-up in 52 patients with stable CAD and 59 patients with ACS who underwent single-vessel PCI. Fournier et al. investigated the hs-CRP level after 1 month of bare-metal stent implantation. The 12-month event-free survival rate was greater when the hs-CRP level was ≤2.5 mg/L. Yun et al. enrolled 381 patients with ACS who underwent elective PCI and were followed up for 1 year, and they concluded that postprocedural hs-CRP elevation >3 mg/L was associated with higher MACEs. Chew et al. examined 272 patients who underwent PCI and were presented with New York Heart Association Class III-IV, with prior PCI and coronary artery bypass surgery (including patients with complex lesions and saphenous vein graft intervention). They concluded that the elevated baseline CRP is independently predictive of early (30 days) adverse outcome after PCI. On the contrary, similar to our findings, other studies failed to show any correlation between hs-CRP and recurrent events after elective or emergent PCI. No association between increased preprocedural hs-CRP and in-stent restenosis was found in the GENERATION study. Rittersma et al. also did not find any association or even trend between CRP concentration and angiographic restenosis in 345 patients who underwent nonurgent PCI. Youssef et al. showed a significant increase in hs-CRP levels after PCI in 41 patients with stable and unstable angina, with no prognostic impact on either short-term or long-term (2 years) follow-up.
The main limitation of the current study is lack of long-term follow-up.
| Conclusion|| |
Iatrogenic plaque disruption during elective PCI in stable CAD results in a systemically detectable significant rise in hs-CRP levels; however, this rise does not seem to have an impact on short-term outcome. We do recommend further studies using other inflammatory markers and long-term follow-up. This may give insights about the mechanisms of late events seen after PCI in stable CAD patients.
The proper handling and statistical analysis of data for this study by Dr. Mohamed Bendary are deeply acknowledged.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]