Preprocedural High-Sensitivity C-Reactive Protein Predicts Long-Term Outcome of Percutaneous Coronary Intervention

Abstract

Background: High-sensitivity C-reactive protein (hs-CRP) has been used to predict the risk of adverse cardiac events in patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). Less is known, however, about the association between hs-CRP and long-term outcome after PCI in the Japanese population.

Methods and Results: We studied 3,039 all-comer patients with CAD who underwent their first PCI and had data available for preprocedural hs-CRP at Juntendo University between 2000 and 2011. Patients were assigned to tertiles based on preprocedural hs-CRP concentration. We evaluated the incidence of major adverse cardiac events (MACE) including all-cause death, acute coronary syndrome (ACS), and target vessel revascularization (TVR). Patients with higher hs-CRP had a higher prevalence of current smoking, chronic kidney disease and ACS, and a lower prevalence of statin use. During a median follow-up period of 6.5 years, ongoing divergence in MACE with hs-CRP tertile was noted on Kaplan-Meier curves (hs-CRP <0.08 mg/L, 26.4%; 0.08–0.25 mg/L, 38.2%; >0.25 mg/L, 45.6%; log-rank P<0.001). After adjustment for established cardiovascular risk factors, hs-CRP was associated with higher incidence of MACE (hazard ratio [HR], 1.10; 95% CI: 1.04–1.16, P<0.001) and higher all-cause mortality (HR, 1.14; 95% CI: 1.06–1.22, P<0.001).

Conclusions: Preprocedural hs-CRP measurement is clinically useful for long-term risk assessment in Japanese patients with established CAD and undergoing PCI.

Inflammation plays a major role in the initiation and progression of atherosclerosis and the triggering of cardiovascular disease events.^1,2 Among several inflammation biomarkers, C-reactive protein (CRP) is widely used in the clinical setting to evaluate inflammatory disorders. Recently, the presence of low-grade inflammation has become detectable using high-sensitivity CRP (hs-CRP), which is now appreciated as a predictor of cardiovascular events.^3–6 Preprocedural hs-CRP elevation in patients who underwent percutaneous coronary intervention (PCI) has been shown to be associated with higher rates of adverse cardiac events.^7–9 Although several studies have been reported in Japan,^10–12 current knowledge of the importance of hs-CRP as a predictor for cardiovascular disease relies mainly on Western studies. Moreover, the question of whether hs-CRP remains a significant predictor of cardiovascular events for Asian patients with coronary artery disease (CAD), remains uncertain.

The aim of this study was therefore to investigate the value of preprocedural hs-CRP in very long-term outcome (>5 years) in patients with CAD who underwent PCI.

Methods

Subjects and Data Collection

The present study was a single-center, observational, retrospective cohort study. Among consecutive patients with CAD who underwent first PCI at Juntendo University Hospital between 2000 and 2011, we included only those patients for whom preprocedural hs-CRP was available. Patients with known malignancy and active inflammatory disease or without available preprocedural hs-CRP were excluded. Patients were divided into 3 groups according to preprocedural hs-CRP (<0.08, 0.08–0.25, and >0.25 mg/dL). In addition, patients were divided into 2 groups using 0.30 mg/dL as the cut-off point of hs-CRP.¹³

Demographic data, coronary risk factors, and medication were collected from the institutional database. Blood samples were collected in the early morning after overnight fasting, and blood pressure (BP) was measured on admission. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate <60 mL/min/1.73 m², calculated from the modification of the diet in renal disease equation modified with a Japanese coefficient using baseline serum creatinine.¹⁴ Patients with BP >140/90 mmHg or who were receiving anti-hypertensive drugs were regarded as hypertensive. Dyslipidemia was defined as low-density lipoprotein cholesterol (LDL-C) ≥140 mg/dL, high-density lipoprotein (HDL-C) ≤40 mg/dL, triglyceride (TG) ≥150 mg/dL, or current treatment with statins and/or lipid-lowering agents. Diabetes mellitus was defined as either hemoglobin A1c ≥6.5% or medication with insulin or oral hypoglycemic drugs. Written informed consent was obtained from all patients prior to PCI. This study was carried out in accordance with the Declaration of Helsinki and with approval from the institutional review board.

Primary Endpoints

The primary endpoint was major adverse cardiac events (MACE), defined as a composite of all-cause death, acute coronary syndrome (ACS), and target vessel revascularization (TVR). Clinical follow-up included review of medical charts, telephone contact, and questionnaires sent to patients or their families. Mortality data were collected from the medical records of patients who died or who were treated at the present institution, and the details and cause of death were requested from other hospitals to which patients had been admitted. Mortality data were categorized as death from all-cause or cardiovascular death including CAD, cardiogenic shock, stroke, and sudden death. ACS was defined as acute myocardial infarction (AMI) and unstable angina. AMI was defined as ischemic symptoms, 2-fold increase in creatine kinase, or positive troponin T. Unstable angina was diagnosed in the presence of ischemic symptoms regardless of ST-T changes. TVR was considered to be ischemia driven if associated with stenosis of the target vessel diameter ≥75% with ischemic symptoms, or stenosis of the target vessel diameter ≥90% with or without documented ischemia.

Statistical Analysis

Quantitative data are presented as mean±SD or median (IQR). Categorical variables are presented as frequencies. Patients were assigned to tertiles based on preprocedural hs-CRP. Continuous variables across tertiles were compared using 1-way analysis of variance or Kruskal-Wallis test. Categorical variables (presented as frequencies) were compared using the chi-squared test. Unadjusted cumulative event rates were estimated using Kaplan-Meier curves and compared across tertiles. Effects of hs-CRP level on MACE after PCI were determined on multivariate Cox proportional hazard regression analysis. Variables with P<0.05 on univariate analysis (ACS, age, body mass index [BMI], CKD, diabetes, left ventricular ejection fraction [LVEF], multivessel disease, and use of statins) were included in multivariate analysis. hs-CRP was included in the multivariate model, and hazard ratios (HR) and 95% CI were calculated. P<0.05 was considered to indicate statistical significance. To assess whether the accuracy of predicting mortality would improve after adding hs-CRP into a baseline model with established risk factors (i.e., ACS, age, BMI, CKD, diabetes, LVEF, multivessel disease, and use of statins), we calculated the C-index and net reclassification improvement (NRI). The C-index is defined as the area under the receiver operating characteristic curve, and was compared for the baseline model and enriched models containing the established risk factors plus hs-CRP. NRI indicates relatively how many patients had improved accuracy of predicted probability for MACE. Differences were considered statistically significant at P<0.05. Statistical analysis was carried out using JMP version 12.0 (SAS Institute, Cary, NC, USA) and R version 3.2.3 (http://www.R-project.org/; R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline and Procedural Characteristics

Of the 3,579 patients who underwent PCI, preprocedural hs-CRP was available for 3,039 patients (84.9%; Figure 1). Clinical and procedural patient characteristics according to preprocedural hs-CRP tertile are shown in Tables 1,2. Patients in the highest hs-CRP level had a significantly higher incidence of current smoking, ACS and CKD, as well as higher baseline LDL and lower HDL on admission. Patients in the higher hs-CRP tertiles were less likely to be taking statins. In addition, reference vessel diameter was larger and LVEF was lower in patients in the higher hs-CRP tertiles.

Figure 1.

Study flow chart. hs-CRP, high-sensitivity C-reactive protein; PCI, percutaneous coronary intervention.

Table 1. Baseline Subject Clinical Characteristics

	Overall (n=3,039)	hs-CRP (mg/dL)			P-value
		Tertile 1 <0.08 (n=1,012)	Tertile 2 0.08–0.25 (n=1,007)	Tertile 3 >0.25 (n=1,020)
hs-CRP (mg/dL)	0.13 (0.05–0.39)	0.04 (0.02–0.05)	0.13 (0.10–0.21)	0.67 (0.39–1.46)	<0.0001
Age (years)	65.9±10.3	65.4±9.6	66.3±10.1	66.1±11.1	0.12
Male	2,508 (82.5)	838 (82.8)	836 (83.0)	834 (81.8)	0.73
BMI (kg/m2)	24.3±3.4	24.1±3.1	24.3±3.3	24.3±3.6	0.18
Hypertension	2,185 (71.9)	712 (70.4)	740 (73.5)	733 (71.9)	0.29
Diabetes	1,347 (44.3)	440 (43.5)	442 (43.9)	465 (45.6)	0.60
Dyslipidemia	2,203 (72.5)	757 (74.8)	740 (73.6)	706 (69.3)	0.01
Current smoker	793 (26.1)	229 (22.7)	251 (25.0)	313 (30.8)	0.0001
Family history	873 (28.8)	317 (31.4)	286 (28.5)	270 (26.6)	0.06
ACS presentation	822 (27.0)	162 (16.0)	262 (26.0)	398 (39.0)	<0.0001
Multivessel disease	1,751 (57.6)	583 (57.6)	584 (58.0)	584 (57.3)	0.94
SBP (mmHg)	134.5±22.7	135.2±22.9	133.8±22.7	134.5±22.6	0.39
DBP (mmHg)	72.8±13.4	73.3±13.2	72.8±13.2	72.4±13.8	0.38
TC (mg/dL)	182.0±38.3	178.5±35.7	184.4±38.9	183.1±39.9	0.002
LDL-C (mg/dL)	110.0±33.4	104.8±30.4	111.9±34.8	113.2±34.2	<0.0001
HDL-C (mg/dL)	44.4±13.1	46.2±13.8	44.6±12.4	42.4±12.8	<0.0001
TG (mg/dL)	134.9±85.2	133.4±82.5	138.0±76.9	133.2±95.2	0.36
FBG (mg/dL)	117.8±46.7	110.7±37.3	116.3±40.5	126.2±58.2	<0.0001
HbA1c (%)	6.34±1.22	6.32±1.19	6.28±1.12	6.42±1.35	0.03
eGFR (mL/min/1.73 m2)	68.4±23.6	71.7±29.5	67.5±22.3	66.1±27.2	<0.0001
CKD	923 (30.4)	226 (22.4)	322 (32.0)	375 (36.8)	<0.0001
HD	171 (5.6)	30 (3.0)	52 (5.2)	89 (8.7)	<0.0001

Data given as n (%), mean±SD or median (IQR) . ACS, acute coronary syndrome; BMI, body mass index; CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; HbA1c, hemoglobin A1c; HD, hemodialysis; HDL-C, high-density lipoprotein-cholesterol; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein-cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides.

Table 2. Medication, Angiographic and Procedural Characteristics

	Overall (n=3,039)	hs-CRP (mg/dL)			P-value
		Tertile 1 <0.08 (n=1,012)	Tertile 2 0.08–0.25 (n=1,007)	Tertile 3 >0.25 (n=1,020)
Aspirin	2,809 (93.5)	945 (94.5)	931 (93.8)	933 (92.4)	0.15
ACEI/ARB	1,561 (52.0)	496 (49.6)	506 (51.0)	559 (55.4)	0.03
β-blocker	1,500 (50.0)	499 (49.9)	511 (51.5)	490 (48.5)	0.42
OHA	835 (27.8)	293 (29.3)	269 (27.1)	273 (27.1)	0.45
Insulin	324 (10.7)	116 (11.5)	102 (10.1)	106 (10.4)	0.59
Statin	1,793 (59.7)	646 (64.6)	584 (58.9)	563 (55.7)	0.0002
LAD culprit coronary artery	1,420 (46.4)	493 (48.7)	464 (46.1))	463 (45.4)	0.29
Reference lumen diameter (mm)	2.9 (2.6–3.2)	2.8 (2.5–3.1)	2.9 (2.6–3.2)	2.9 (2.3–3.2)	<0.0001
MLD at baseline (mm)	0.4 (0.2–0.6)	0.4 (0.2–0.7)	0.4 (0.2–0.6)	0.4 (0.1–0.6)	0.05
MLD post-procedure (mm)	2.7 (2.4–3.1)	2.7 (2.4–3.0)	2.7 (2.4–3.1)	2.7 (2.4–3.1)	0.64
Stent size (mm)	3.0 (2.75–3.5)	3.0 (2.5–3.0)	3.0 (2.75–3.5)	3.0 (2.75–3.5)	<0.0001
DES	1,556 (51.2)	682 (67.4)	479 (47.6)	395 (38.7)	<0.0001
BMS	1,087 (35.8)	241 (23.8)	382 (37.9)	464 (45.5)	<0.0001
LVEF (%)	61.4±12.4	63.2±10.4	62.1±12.3	58.8±13.8	<0.0001

Data given as n (%), mean±SD or median (IQR) . ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMS, bare metal stent; DES, drug-eluting stent; LAD, left anterior descending artery; LVEF, left ventricular ejection fraction; MLD, minimal lumen diameter; OHA, oral hypoglycemic agents.

Clinical Outcomes

The median follow-up period was 6.5 years (IQR, 3.4–9.5 years). In total, 903 MACE (29.7%) were identified, including 368 (12.1%) all-cause deaths, 263 (8.7%) ACS, and 432 (14.2%) TVR during follow-up. Cumulative incidence of MACE and all-cause death clearly increased with higher tertiles of hs-CRP (log-rank test, both P<0.0001; Figures 2,3).

Figure 2.

Kaplan-Meier cumulative incidence of major adverse cardiac events (MACE) vs. high-sensitivity C-reactive protein (hs-CRP) tertile (P<0.0001, log-rank test). MACE, all-cause death, acute coronary syndrome and target vessel revascularization.

Figure 3.

Kaplan-Meier cumulative incidence of all-cause death vs. high-sensitivity C-reactive protein (hs-CRP) tertile (P<0.0001, log-rank test).

Table 3 shows Cox proportional hazard analysis for MACE and all-cause death. On unadjusted Cox modeling, rates of MACE and all-cause death rose progressively with higher hs-CRP (both P<0.0001 for trend). Multivariate-adjusted HR also increased with rising hs-CRP, even after adjusting for these variables (P<0.0001 for trend). Furthermore, higher hs-CRP (≥0.30 mg/dL) was also associated with MACE (≥0.30 vs. <0.30 mg/L: HR, 1.33; 95% CI: 1.14–1.54; P=0.0002) and all-cause death (≥0.30 vs. <0.30 mg/L: HR, 1.67; 95% CI: 1.34–2.10; P<0.0001).

Table 3. Cox Proportional Hazard Model for MACE and All-Cause Death

	MACE				All-cause death
	HR	95% CI	P-value	P-value for trend	HR	95% CI	P-value	P-value for trend
Unadjusted model
Low tertile	Ref.	–	–	<0.0001	Ref.	–	–	<0.0001
Intermediate tertile	1.35	1.14–1.61	0.0006		2.11	1.54–2.93	<0.0001
High tertile	1.81	1.53–2.14	<0.0001		3.38	2.52–4.62	<0.0001
Adjusted model
Low tertile	Ref.	–	–	<0.0001	Ref.	–	–	<0.0001
Intermediate tertile	1.23	1.02–1.48	0.03		1.75	1.25–2.48	0.0009
High tertile	1.48	1.24–1.79	<0.0001		2.52	1.83–3.54	<0.0001

Adjusted-for variables were ACS, age, BMI, CKD, diabetes, LVEF, multivessel disease, and use of statins. These covariates were added to this model only if identified statistically as predictors of MACE and all-cause death (P<0.05). CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiac events. Other abbreviations as in Tables 1,2.

Table 4 summarizes the multivariate Cox hazard regression analysis including hs-CRP as a continuous variable. Even after adjusting for other covariates, higher hs-CRP was significantly associated with higher incidence of MACE (per 1 mg/dL, HR, 1.10; 95% CI: 1.04–1.16; P=0.0004) and all-cause death (per 1 mg/dL, HR, 1.14; 95% CI: 1.06–1.22; P=0.0002).

Table 4. Multivariable Cox Proportional Hazard Model for MACE and All-Cause Death

	MACE			All-cause death
	HR	95% CI	P-value	HR	95% CI	P-value
hs-CRP (1-mg/dL increase)	1.10	1.04–1.16	0.0004	1.14	1.06–1.22	0.0002
ACS	1.59	1.37–1.85	<0.0001	1.62	1.28–2.03	<0.0001
Age (1-year increase)	1.02	1.01–1.03	<0.0001	1.06	1.05–1.08	<0.0001
BMI (1-kg/m2 increase)	0.97	0.95–0.99	0.02	0.97	0.94–1.02	0.11
CKD	1.21	1.04–1.41	0.01	1.53	1.22–1.92	0.0002
Diabetes	1.19	1.04–1.37	0.01	1.30	1.05–1.62	0.02
LVEF (1% increase)	1.00	0.990–1.001	0.14	0.98	0.97–0.99	<0.0001
Multivessel disease	1.15	0.998–1.338	0.05	1.23	0.98–1.55	0.08
Statin	0.68	0.59–0.79	<0.0001	0.57	0.46–0.71	<0.0001

Abbreviations as in Tables 1–3.

Model Discrimination

Adding hs-CRP to a baseline model with established risk factors improved the prediction of MACE (P=0.02) and all-cause death (P=0.002), as shown by the significant increase in the C-index (Table 5). Reclassification of patients was done using NRI. The addition of hs-CRP significantly improved the reclassification beyond the baseline model with established risk factors (MACE: NRI, 0.17; P<0.0001; all-cause death: NRI, 0.12; P=0.001; Table 5).

Table 5. Evaluation of Predictive Models for MACE and All-Cause Death

	C-index (95% CI)	P-value	NRI (95% CI)	P-value
MACE
Established risk factors	0.64 (0.62–0.67)	Ref.		Ref.
Established risk factors+hs-CRP	0.65 (0.63–0.67)	0.02	0.17 (0.10–0.24)	<0.0001
All-cause death
Established risk factor	0.72 (0.70–0.76)	Ref.		Ref.
Established risk factor+hs-CRP	0.73 (0.71–0.76)	0.002	0.12 (0.04–0.19)	0.001

Established risk factors included ACS, age, BMI, CKD, diabetes, LVEF, multivessel disease, and use of statins. NRI, net reclassification improvement. Other abbreviations as in Tables 1–3.

Discussion

The major findings of the present report are as follows: (1) high preprocedural hs-CRP was significantly associated with a higher incidence of MACE and all-cause death compared with lower hs-CRP; and (2) even after adjusting for important covariates, high preprocedural hs-CRP was strongly associated with increased MACE and mortality in patients undergoing PCI. We therefore believe that the association between preprocedural hs-CRP concentration and risk of future cardiovascular events seen in Western patients is also applicable to the Japanese population.

C-reactive protein is produced mainly in the liver in response to pro-inflammatory cytokines such as interleukin 6, and is widely used as an acute-phase reactant and non-specific marker of inflammation. As a downstream biomarker, CRP provides functional integration of overall upstream cytokine activation. CRP also may exert direct effects on vascular disease, including the binding and activation of complement.¹⁵ In addition to its role in triggering immunity in plaque deposition, in vitro studies have also indicated associations between CRP, inhibition of endothelial nitric oxide synthase, and impaired vasoreactivity.^16,17

Liuzzo et al first showed that elevation of CRP predicted poor outcome in patients with ACS in 1994.¹⁸ Since then, several studies have demonstrated an association between hs-CRP and risk of cardiovascular disease.^{2,4,6,19–22} In the Japanese population, Arima et al followed 2,589 patients without cardiovascular disease for 14 years and showed that hs-CRP was clearly associated with future CAD.²³ Several studies have shown that higher hs-CRP is associated with adverse cardiac events after PCI. Patti et al showed that the rates of periprocedural myocardial infarction after PCI were increased in patients with higher hs-CRP.²⁴ Sabatine et al followed 3,771 patients with stable CAD for 4.8 years and showed that baseline elevated hs-CRP after PCI was associated with worse prognosis.²⁵ Razzouk et al evaluated 8,834 patients with stable and unstable disease who underwent PCI, and found that preprocedural hs-CRP was predictive of mortality for both stable and unstable patients.⁹ The prevalence of ACS in the present study was approximately 27%, and preprocedural hs-CRP significantly improved prognostic information for MACE and mortality in long-term follow-up for both stable and unstable patients.

Median preprocedural hs-CRP level was 0.13 mg/dL in the present study, much lower than in Western populations.^7,9,25 Other studies of hs-CRP for primary prevention in the Japanese population have also noted lower hs-CRP compared with Western subjects.^11,23 hs-CRP varies greatly with ethnicity, with the highest level generally found in African-American populations, followed by Hispanic, South Asian, White, and East Asian patients.^26,27 Many differences are known to exist between Japanese and Western populations, not only in terms of genetics, but also with regard to food and lifestyle. These differences may also modulate hs-CRP level.

The present study has shown that hs-CRP is a clinically useful biomarker in predicting the risk of future cardiovascular events after PCI. A previous study showed that dexamethasone-eluting stents reduced CRP after PCI, and the number of adverse cardiac events during follow-up.²⁸ Elevated hs-CRP may mean that patients should postpone procedures and undergo aggressive medical therapy until lower hs-CRP is achieved. Aspirin and statins have been shown to indirectly decrease hs-CRP and could be used before procedures to reduce inflammation.^2,29 In particular, statin therapy reduced both LDL-C and CRP, along with the number of cardiovascular events.⁶ The question, however, of whether hs-CRP could be used as a therapeutic target marker for statin treatment remains contentious. Further investigation involving intensive treatment is necessary to clarify the potential of hs-CRP.

This study had several limitations. First, as a single-center, observational study of a small patient cohort, unknown confounding factors might have affected outcome regardless of analytical adjustments. The relatively small number of events may have contributed to the lack of statistically significant differences. Second, in some patients, high hs-CRP may have been related to infection. Information on active infection and sources of inflammation were unavailable in the present study, although we generally reschedule PCI when patients are being treated for active infection or malignant disease. Finally, although MI is recently diagnosed according to troponin level in the universal definition, we defined as a two-fold increase in creatine kinase or positive results for troponin T.

Conclusions

Elevated preprocedural serum hs-CRP was associated with long-term clinical outcome after PCI in the present study. As a result, hs-CRP could be a useful and strong predictor for long-term risk assessment in Japanese patients with established CAD who are scheduled to undergo PCI.

Acknowledgments

We are grateful to the staff of the Department of Cardiovascular Medicine at Juntendo University and the Department of Cardiology at Juntendo University Shizuoka Hospital. We also appreciate the assistance of Yumi Nozawa and Ayako Onodera.

Conflict of Interest

H.D. has received speakers’ Bureau/Honoraria from MSD, AstraZeneca, Kowa Pharmaceutical, Sanofi-Aventis, GlaxoSmithKline, Shionogi, Daiichi-Sankyo, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Pfizer, and Astellas Pharma, and research funds from Takeda Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Astellas Pharma, Novartis Pharma, MSD, Sanofi-Aventis, Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Pfizer, Kowa Pharmaceutical, Shionogi, AstraZeneca, Teijin, and Morinaga Milk Industry. K.M. has received speakers’ Bureau/Honoraria from MSD, AstraZeneca, Kowa Pharmaceutical, Sanofi-Aventis, Shionogi, Daiichi-Sankyo, Takeda Pharmaceutical, Pfizer, Astellas Pharma, and Novartis Pharma. The other authors report no conflicts of interest.

Funding

None.

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