Long-Term Predictive Value of High-Sensitivity C-Reactive Protein for Cancer Mortality in Patients Undergoing Percutaneous Coronary Intervention

Hirohisa Endo; Tomotaka Dohi; Takehiro Funamizu; Jun Shitara; Hideki Wada; Shinichiro Doi; Ryo Naito; Hirokazu Konishi; Manabu Ogita; Hiroshi Iwata; Takatoshi Kasai; Shinya Okazaki; Kikuo Isoda; Kazunori Shimada; Katsumi Miyauchi; Hiroyuki Daida

doi:10.1253/circj.CJ-18-0962

Abstract

Background: High-sensitivity C-reactive protein (hs-CRP) is a well known risk factor for the development of cardiovascular disease and cancer. We investigated the long-term impact of hs-CRP on cancer mortality in patients with stable coronary artery disease (CAD).

Methods and Results: This study was a retrospective analysis of 2,867 consecutive patients who underwent percutaneous coronary intervention for stable CAD from 2000 to 2016. The patients were divided into 2 groups according to median hs-CRP. We then evaluated the association between baseline hs-CRP and both all-cause and cancer deaths. Median hs-CRP was 0.10 mg/dL (IQR, 0.04–0.27 mg/dL). The median follow-up period was 5.8 years (IQR, 2.3–10.0 years). There were 416 deaths (14.5%), including 149 cardiovascular deaths (5.2%) and 115 (4.0%) cancer deaths. On Kaplan-Meier analysis the higher hs-CRP group had a significantly higher incidence of both all-cause and cancer death (log-rank, P<0.001 and P=0.001, respectively). On multivariable analysis higher hs-CRP was significantly associated with higher risk of cancer death (HR, 1.74; 95% CI: 1.18–2.61, P=0.005).

Conclusions: Elevated baseline hs-CRP was significantly associated with cancer mortality in patients with stable CAD. Hs-CRP measurement may be useful for the identification of subjects with an increased risk of cancer death.

High-sensitivity C-reactive protein (hs-CRP) is a marker of acute-phase inflammatory response and had been reported to increase in several diseases, including cardiovascular disease;¹^–³ type 2 diabetes mellitus;⁴ and many types of cancer.⁵^,⁶ Recently, the role of inflammation in tumorigenesis had been widely accepted.⁷ Aggarwal et al reported that environmental factors, cigarette smoke, chronic infections, and the dietary factors linked to obesity might affect the development of cancer.⁸ In previous epidemiological studies, serum hs-CRP concentration was significantly associated with the incidence and mortality of cancer,⁵^,⁹^–¹¹ but these studies originated from Western countries.

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In contrast, the relationship between atherosclerosis and inflammation is well recognized.²^,³ Recent evidence suggested that anti-inflammatory therapy might reduce not only cardiovascular events, but also the occurrence of lung cancer.¹²^–¹⁴ The relevance of the association between cancer mortality and hs-CRP, however, remains unclear. The aim of the present study was therefore to evaluate cancer mortality in patients with stable coronary artery disease (CAD) after percutaneous coronary intervention (PCI).

Methods

Patients and Data Collection

The study flow is shown in Figure 1. This study was part of a retrospective analysis from a single-center prospective PCI registry of 4,584 patients who were enrolled from 2000 to 2016. Patients were excluded based on the following reasons: (1) acute coronary syndrome (n=1,431); (2) history of previous, suspected, or known malignancy (n=40); and (3) absence of hs-CRP data (n=246). The final number of patients in the study was 2,867 (63%). Patients were then divided into 2 groups according to median baseline hs-CRP: higher hs-CRP group, ≥0.1 mg/dL; lower hs-CRP group, <0.1 mg/dL.

Figure 1.

Flow chart of the study. hs-CRP, high-sensitivity C-reactive protein; PCI, percutaneous coronary intervention.

The demographic data, CAD risk factors, and medication at the time of PCI were collected from the institutional database. Blood samples were collected in the early morning after overnight fasting. Serum hs-CRP was measured before PCI on high-sensitivity latex turbidimetric immunoassay. Written informed consent for follow-up was obtained at the time of the initial procedure. This study was performed in accordance with the principles of the Declaration of Helsinki and with approval from the institutional review board.

Endpoints

The endpoints were all-cause death and cancer death including gastrointestinal cancer, lung cancer, other solid cancers, and hematological malignancy. Cancer death was defined as the primary cause of death due to cancer, such as death due to underlying malignant disease itself, or complications of treatment for cancer. Clinical follow-up included review of medical charts, telephone contact, and questionnaires sent to the patients or their families. Mortality data were collected from the medical records of patients who died or who had been treated at the present institution, and the details and cause of death were collected from the questionnaires or in the other hospitals where the patients had been admitted.

Statistical Analysis

Continuous variables are expressed as mean±SD or median (IQR), depending on distribution. Categorical variables are expressed as percentage or frequency. Continuous variables were compared using one-way analysis of variance or Wilcoxon rank sum test, whereas categorical variables were compared using the chi-squared test. Unadjusted cumulative event rates were estimated using Kaplan-Meier curves. The association between hs-CRP and all-cause or cancer death after PCI was determined using multivariable Cox proportional hazard regression analysis. Age; history of cigarette smoking; chronic kidney disease (CKD), which was defined as estimated glomerular filtration rate <60 mL/min/1.73 m²; use of aspirin; use of statins, and hs-CRP ≥0.1 mg/dL had P<0.05 on univariate analysis and were selected as covariates in the multivariable analysis. Because of the non-normal distribution of hs-CRP, logarithmic transformation was used to perform Cox proportional hazard analysis, which included hs-CRP level as a continuous variable. Then, the hazard ratio (HR) and 95% CI were calculated. P<0.05 was considered to indicate statistical significance. All data were analyzed using JMP version 12.2 for Windows (SAS Institute, Cary, NC, USA).

Results

Baseline and Procedural Characteristics

The 2,867 patients had a mean age of 66.7±10.0 years, and 83.2% were men. Median hs-CRP was 0.10 mg/dL (IQR, 0.04–0.27 mg/dL). Baseline characteristics and medication data, stratified according to pre-procedural hs-CRP, are listed in Table 1. History of cigarette smoking, CKD, body mass index (BMI), and low-density lipoprotein-cholesterol were significantly higher in patients with higher hs-CRP, whereas high-density lipoprotein-cholesterol and use of statin were significantly higher in patients with lower hs-CRP.

Table 1. Baseline Clinical Characteristics and Medication

Variables	Entire cohort (n=2,867)	hs-CRP		P-value
Variables	Entire cohort (n=2,867)	<0.10 mg/dL (n=1,450)	≥0.10 mg/dL (n=1,417)	P-value
Clinical characteristics
hs-CRP (mg/dL)	0.10 (0.04–0.27)	0.04 (0.02–0.07)	0.28 (0.17–0.67)	<0.001
Age (years)	66.7±10.0	66.5±9.8	66.9±10.3	0.31
Male	2,384 (83.2)	1,197 (82.6)	1,187 (83.8)	0.38
BMI (kg/m²)	24.1±3.4	24.1±3.2	24.6±3.6	<0.001
Hypertension	2,119 (73.9)	1,052 (72.6)	1,067 (75.3)	0.094
Diabetes mellitus	1,316 (45.9)	653 (45.0)	663 (46.8)	0.35
Dyslipidemia	2,151 (75.0)	1,099 (75.8)	1,052 (74.2)	0.34
Smoking	1,867 (65.2)	888 (61.3)	979 (69.1)	<0.001
Current smoker	654 (22.8)	289 (20.0)	365 (25.8)	<0.001
Family history	832 (29.1)	446 (30.8)	386 (27.4)	0.04
Multi-vessel disease	1,743 (61.3)	863 (60.2)	880 (62.4)	0.23
TC (mg/dL)	175±36	173±35	177±37	0.003
LDL-C (mg/dL)	104±31	101±30	107±32	<0.001
HDL-C (mg/dL)	44±13	46±14	42±12	<0.001
TG (mg/dL)	136±83	133±92	139±72	0.04
HbA1c (%)	6.3±1.1	6.3±1.1	6.4±1.1	0.09
eGFR (mL/min/1.73 m²)	68±24	71±22	64±25	<0.001
CKD	891 (30.7)	364 (25.1)	518 (36.6)	<0.001
HD	195 (6.7)	64 (4.4)	130 (9.2)	<0.001
Medication
Aspirin	2,711 (95.3)	1,373 (95.5)	1,338 (95.2)	0.69
ACEI/ARB	1,392 (49.0)	687 (47.8)	705 (50.2)	0.20
β-blocker	1,481 (52.1)	751 (52.2)	730 (51.9)	0.87
Statin	1,849 (65.0)	995 (69.2)	854 (60.8)	<0.001
OHA	874 (30.5)	440 (30.3)	434 (30.6)	0.87
Insulin	207 (7.2)	108 (7.5)	99 (7.0)	0.63

Data given as mean±SD, median (IQR) or n (%) . ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HD, hemodialysis; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; OHA, oral hypoglycemic agents; TC, total cholesterol; TG, triglycerides.

Clinical Outcomes

The median follow-up period was 5.8 years (IQR, 2.3–10.0 years). All-cause and cause-specific death data are listed in Table 2. There were 416 deaths (14.5%), including 149 cardiovascular deaths (5.2%) and 115 cancer deaths (4.0%). Of the 115 cancer deaths, 52.5% (n=60) were due to gastrointestinal cancer, and 20.9% (n=24) were due to lung cancer. Median period from index PCI to the time of cancer death was 4.7 years (IQR, 2.1–7.2 years).

Table 2. Deaths During the Follow-up Period

		hs-CRP (mg/dL)		P-value
	(n=2,867)	<0.10 mg/dL (n=1,450)	≥0.10 mg/dL (n=1,417)	P-value
All-cause death	416 (14.5)	145 (10.0)	271 (19.2)	<0.001
Cardiovascular death	149 (5.2)	57 (3.9)	92 (6.5)	0.002
Cancer death	115 (4.0)	40 (2.8)	75 (5.3)	<0.001
Lung cancer	24 (0.8)	7 (0.5)	17 (1.2)	0.03
Gastrointestinal cancer	60 (2.1)	23 (1.6)	37 (2.6)	0.054
Other cancer	31 (1.1)	10 (0.7)	21 (1.5)	0.04

Data given as n (%). hs-CRP, high-sensitivity C-reactive protein.

Compared with non-smokers, patients who were former or current cigarette smokers had significantly higher hs-CRP (0.11 mg/dL; IQR, 0.05–0.30 mg/dL vs. 0.09 mg/dL, IQR, 0.03–0.21 mg/dL; P<0.001) and significantly higher total number of cancer deaths during the follow-up period (90 deaths, 4.8% vs. 25 deaths, 2.5%; P=0.002). There was no significant interaction between hs-CRP and smoking status (P for interaction=0.35).

The cumulative incidences of all-cause, all-cancer, gastrointestinal cancer, and lung cancer deaths based on the Kaplan-Meier method are shown in Figure 2. Compared with the lower hs-CRP group, the higher hs-CRP group had a significantly higher incidence of cancer death (9.1% vs. 5.2%, log-rank P=0.001), and this trend was consistent for deaths from gastrointestinal and lung cancers.

Figure 2.

Time-to-event curves for mortality: (A) all-cause death; (B) cancer death; (C) gastrointestinal cancer death; and (D) lung cancer death according to median pre-procedural high-sensitivity C-reactive protein (hs-CRP).

The univariate Cox proportional hazard analysis for cancer death is given in Table 3. On unadjusted analysis, the relative risk for cancer death in patients with higher hs-CRP was 1.9-fold that in patients with lower hs-CRP (HR, 1.85; 95% CI: 1.27–2.34; P=0.001). Furthermore, age, history of cigarette smoking, prevalence of CKD, use of aspirin, and use of statins were significantly associated with cancer death.

Table 3. Univariate Cox Proportional Hazard Model for Cancer Death

Variables	HR	95% CI	P-value
Patient characteristics
Age (1-year increase)	1.06	1.04–1.09	<0.001
Male	1.30	0.78–2.32	0.33
BMI (1-kg/m² increase)	0.95	0.89–1.01	0.08
Dyslipidemia	0.69	0.47–1.04	0.08
History of cigarette smoking	1.96	1.28–3.12	0.002
Baseline laboratory findings
Log (hs-CRP) 1.0-unit increase	1.81	1.37–2.38	<0.001
hs-CRP >0.10 mg/dL	1.85	1.27–2.34	0.001
HDL-C (1-mg/dL increase)	0.99	0.97–1.001	0.07
eGFR (1-mL/min/1.73 m² increase)	0.99	0.99–1.002	0.11
CKD	1.49	1.02–2.16	0.04
Medication on discharge
Aspirin	0.39	0.21–0.83	0.02
Statin	0.63	0.44–0.92	0.02

HR, hazard ratio. Other abbreviations as in Table 1.

Table 4 lists the Cox proportional hazard analyses for all-cause and cancer deaths. In the adjusted model, higher pre-procedural hs-CRP was significantly associated with both all-cause death (HR, 1.74; 95% CI: 1.42–2.15; P<0.001) and cancer death (HR, 1.70; 95% CI: 1.15–2.53; P<0.01). Table 5 shows the results of multivariable Cox proportional hazard analysis, which included hs-CRP as a continuous variable. Even after adjusting for the other covariates, higher hs-CRP was significantly associated with a higher incidence of cancer death (HR, 1.71 per log hs-CRP 1.0 increase; 95% CI: 1.28–2.27; P<0.001). We also performed additional analyses by quartiles of hs-CRP to confirm the dose–response relationship (Supplementary Figure; Supplementary Table).

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

	All-cause death			Cancer death
	HR	95% CI	P-value	HR	95% CI	P-value
Unadjusted model
Low hs-CRP (<0.10 mg/dL)	Ref.	–	–	Ref.	–	–
High hs-CRP (≥0.10 mg/dL)	1.84	1.51–2.26	<0.001	1.85	1.27– 2.74	<0.01
Adjusted model
Low hs-CRP (<0.10 mg/dL)	Ref.	–	–	Ref.	–	––
High hs-CRP (≥0.10 mg/dL)	1.74	1.42–2.15	<0.001	1.70	1.15–2.53	<0.01

The covariates were age, BMI, CKD, diabetes mellitus, dyslipidemia, hypertension, use of aspirin, and use of statins for all-cause death and age, CKD, history of cigarette smoking, use of aspirin, and use of statins for cancer death. Covariates were added to the model if they were identified as significant predictors of all-cause death and cancer death on univariate analyses (P<0.05). Abbreviations as in Table 1.

Table 5. Multivariable Cox Proportional Hazard Model for Cancer Death

Variables	HR	95% CI	P-value
Log(hs-CRP) 1.0-unit increase	1.71	1.28–2.27	<0.001
Age (1-year increase)	1.07	1.05–1.09	<0.001
History of cigarette smoking	2.35	1.52–3.79	<0.001
CKD	1.06	0.72–1.56	0.76
Aspirin use	0.46	0.24–0.98	0.044
Statin use	0.74	0.51–1.08	0.12

Abbreviations as in Table 1.

Discussion

The major findings of the present study were as follows: (1) in 5.8 years of follow-up, cancer death accounted for almost one-third of all-cause deaths in patients with stable CAD following PCI; (2) the incidences of all-cause and cancer deaths were significantly higher in patients with higher pre-procedural hs-CRP (≥0.10 mg/dL) than in those with lower pre-procedural hs-CRP; and (3) on multivariable Cox hazard analysis, increased hs-CRP was significantly associated with cancer death in post-PCI patients.

To the best of our knowledge, this study was the first to demonstrate an association between serum hs-CRP and cancer mortality in Asian patients with CAD. The main findings were consistent with those of previous studies on both healthy subjects and cancer patients.¹⁵^–¹⁷ Several possible mechanisms of the association between chronic inflammation and cancer have been reported.¹⁸^,¹⁹ The clinical significance of elevated CRP as a marker of latent cancer and carcinogenesis, however, remains unclear. In this study, the median duration from PCI to cancer death was 4.7 years. Yachida and Iacobuzio-Donahue reported that even in pancreatic cancer, which is generally believed to be a high-grade malignancy, the period from pancreatic carcinogenesis to metastasis and death was >10 years.²⁰ Therefore, the cancer deaths observed in the present study were possibly influenced by both latent cancer at index PCI and chronic inflammation, which might have been involved in cancer development and progression.

In the present study, the number of patients with a history of cigarette smoking and the proportion of current smokers were significantly higher in patients with higher hs-CRP than in those with lower hs-CRP; moreover, a history of cigarette smoking was an independent risk factor for cancer death. The Emerging Risk Factors Collaboration reported that hs-CRP was 1.3-fold higher in current smokers than in non-smokers,²¹ which was confirmed in the present study. In previous studies, former and current smokers had high inflammatory biomarkers, including hs-CRP,²²^,²³ and a negative correlation was found between CRP and arterial oxygen pressure in patients with chronic obstructive pulmonary disease (COPD).²⁴ Atherosclerotic patients with high hs-CRP often have multiple comorbidities, such as COPD, obesity, diabetes, and/or CKD. In particular, cigarette smoking is strongly associated with the development of both atherosclerosis and cancer. Careful long-term management and follow-up are required not only for cardiovascular disease, but also for systemic disease.

Aspirin (acetylsalicylic acid) is widely used for the prevention of cardiovascular disease. In several clinical trials, low-dose aspirin use reduced the incidence and mortality of several cancer types, especially colorectal cancer,²⁵^,²⁶ and statin use reduced systemic pro-inflammatory cytokines, CRP,²⁷ and the risk of development of several cancer types, including colorectal cancer,²⁸ hepatocellular carcinoma,²⁹ and breast cancer.³⁰ Furthermore, the interleukin (IL)-1β inhibitor, canakinumab, was recently reported to reduce the incidence and mortality of lung cancer.¹²^–¹⁴ These anti-inflammatory agents might have roles against carcinogenesis. The evidence for the mechanisms underlying such associations, however, is limited and remains controversial.³¹ Further research is needed to clarify the type of cancer that may respond to anti-inflammatory agents.

In the present study, the prevalence of CKD and hemodialysis were significantly higher in patients with higher hs-CRP than in those with lower hs-CRP. After adjustment by CKD, higher hs-CRP was significantly associated with cancer mortality. Lee et al compared the levels of inflammatory biomarkers, including CRP, tumor necrosis factor-α, and IL-6, between patients with and without CKD and showed that the CRP did not differ between CKD patients and non-CKD patients, even after adjustment for age and other co-factors.³² That study suggested that CRP is not an independent risk factor for CKD. In addition, Wong et al reported that the age-adjusted incidence and mortality of cancer were not significantly different between the CKD categories, except in those on hemodialysis.³³ Those findings were consistent with the present results. Future studies should investigate whether inflammatory markers can predict the incidence and mortality of cancer in patients with CKD.

Study Limitations

This study had several limitations. First, it was a retrospective observational study on patients with CAD; therefore, the association between hs-CRP and cancer death in the general population is not clear. It is important for cardiologists to pay attention to the occurrence of non-cardiac adverse events in addition to cardiovascular disease, when they treat the patients with elevated hs-CRP. Second, the collection of mortality data was based on review of the medical charts at the present hospital or on questionnaires from the patient families. Notably, 25 of 115 cases of cancer death were obtained via the questionnaires; although the majority of these cases had available detailed information on cancer type, cause of death, death date, and so on, in 3 cases the information on the primary site of cancer was lacking. It is possible that ambiguous points existed in the questionnaires declared by the patient families. Third, based on the medical charts, we excluded the patients with a history of previous, suspected, or known malignancy. We were unable, however, to obtain data on the prevalence of latent cancer at index PCI and the diagnosed date of cancer. Further longitudinal studies with larger populations are needed.

Conclusions

Elevated baseline hs-CRP was significantly associated with cancer mortality in patients with stable CAD, independent of other known risk factors, such as age, BMI, and history of cigarette smoking. Therefore, assessment of hs-CRP, which is a marker of chronic low-grade inflammation, may help identify subgroups with an increased risk of cancer death.

Acknowledgments

We wish to express our gratitude to the staff of the Department of Cardiovascular Medicine at Juntendo University. We also wish to thank Ms Yumi Nozawa for the data management.

Disclosures

H.D. has received scholarship funds from Astellas Pharma, Abbott Vascular Japan, Daiichi Sankyo Company, Takeda Pharmaceutical Company, and Merck Sharp and Dohme. The other authors declare no conflicts of interest.

Grants

None.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0962

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