The relationship between red blood cell distribution width (rdw cv) and C Reactive protein (crp) with the clinical outcomes in non-ST Elevation Myocardial Infarction and unstable Angina Pectoris: A 6 months follow up study.


Abstract

Background and Aims: RDW CV is a marker of variation in size of rbc.RDW has been reported to be a predictor of cardiac events in CAD . CRP is a pentameric protein, an acute phase reactant and an independent marker of mortality in ACS . Here we hypothesized that RDW CV level on admission and CRP would be predictive of adverse outcomes in NSTEMI and uSAP patients.

Methods: 319 patients with ACS (240 males and 79 females) were prospectively analyzed. Patients were divided into two groups based on the fiftieth percentile of admission RDW CV levels. High RDW group (n=214) was defined as those patients having RDW levels of >14.0.Qualitative CRP positivity was observed in 113 patients.The relationship between RDW and CRP and primary endpoint (cardiovascular deaths), secondary end points (reinfarction, repeat TVR) and MACE were assessed. The median follow-up was 6 months.

Results: Patients in high RDW group were older (p=0.16), and included more females with history of HT, diabetes and MI. They had higher admission creatinine, Killip class >1,TIMI risk score, CPK-MB, peak creatinine Ldl and TLC and lower lvef . They had more killip>1 (p=0.020) in hospital and at 6-months followup had significantly increased mortality,reinfarction rates and hospitalization for heart failure.Patients with positive CRP and high RDW had significantly increased adverse outcomes.

Conclusion: Given the advantages of the RDW levels it may be used as a marker of cardiovascular risk management in NSTEMI and uSAP along with CRP and plan early invasive strategy.


Introduction

RDW CV is part of a routine CBC. It is a measurement of size variability in red blood cells. RDW is generally used for the differential diagnosis of anemia and hematological disorders. RDW has been shown to be a useful prognostic marker to identify patients with a higher risk of adverse cardiovascular outcomes in acute coronary syndromes (ACS). Accurate risk stratification in ACS is essential in deciding who should be treated immediately and whether to use more aggressive treatment strategies.1 The “width” in RDW is sometimes thought of as “misleading,” since it in fact is a measure of deviation of the volume of RBCs, and not directly the diameter. “Width” refers to the width of the volume curve (distribution width),not the width of the cells. Mathematically the RDW is calculated with the following formula:RDW CV= (Standard deviation of MCV ÷ mean MCV) × 100.Usually red blood cells are a standard size of about 11.5-14.5 μm. Higher RDW values indicate greater variation in size that is anisocytosis . Normal reference range in human red blood cells is 11–15%. Higher

RDW is associated with a poor prognosis in the setting of stable CAD, heart failure, acute MI, and stroke. Elevated RDW is a predictor of an increased risk of short-term adverse outcomes in patients with ACS. 2–6 The relationship of RDW with adverse outcomes in these patients is not completely understood. Inflammation, neurohormonal and adrenergic system activation may bring about changes in red blood cell maturation by disturbing the red cell membrane, thereby leading to increased RDW7. A correlation between RDW and inflammatory markers has also been reported (8) .“Red blood cells may represent a ‘real-time’ biomarker of an underlying abnormal pathophysiologic state.”

C-reactive protein (CRP) is a pentraxin acute-phase protein. CRP is a robust clinical marker because of its stability, reproducible results, and ease of assay. Patients with ACS have elevations in CRP in association with their presenting symptoms. Continued elevations in CRP portend increased risk of mortality despite currently available therapeutic strategies for ACS.CRP is a proven marker of inflammation in cardiac care and has a strong association with adverse clinical outcomes. CRP is a powerful marker of global risk and an independent marker of mortality in ACS, and therefore, it is useful for prognostication9.

Table 1

Baseline characteristics of study subjects

Low RDW <14%(n=214) % High RDW <14%(n=105) % p value
Age 56.0 10.2 (sd) 57.5 8.3(sd) 0.16 (NS)
BMI 27.4 3.0 (sd) 27.5 3.3(sd) 0.79 (NS)
Male 168 75.8 72 68.6 0.053 (NS)
HTN 130 60.7 76 73.2 0.022 (NS)
Timi 3.11 1.26 (sd) 3.99 1.43 (sd) <0.0001 (S)
Smoker 98 45.8 38 36.2 0.12 (NS)
DM 117 54.7 77 74.3 0.014 (NS)
Family H/o CAD 72 33.6 22 21.0 0.0260
Killip class >1 6 2.8 8 7.6 0.049 (S)
CRP positive 34 15.9 79 75.2 <0.0001 (S)

Despite the diversity in RDW research, few prospective studies have evaluated the relationship between the RDW and CRP with long term adverse outcomes in populations with NSTEMI and USAP. So we conducted the study “the association between RDW and CRP with the risk of in hospital outcomes and 6 months mortality and major adverse cardiovascular outcomes in patients with NSTEMI and USAP”.

Material and Methods

This crossectional prospective study included 329 patients who presented to the emergency/opd in department of cardiology at smsh jaipur with acute chest pain and diagnosed as NSTEMI and/or USAP from September 2013 to March 2014. 10 Patients were lost to follow up thus leaving data of 319 patients. Patient were assessed in hospital and at 6 months for study endpoints. Patients with known hematologic diseases such as haemolytic anemias, neoplastic metastases to the bone marrow, infections, autoimmune diseases, transfusions, iron replacement therapy, extracellular fluid increasing diseases (e.g. hypothyroidism and liver cirrhosis) were excluded from the study. The diagnosis of ACS was based on the criteria of the Joint European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/Word Heart Federation

Task definition .NSTEMI is defined by: electrocardiographic prominent t-wave inversion or st-segment depression and/or positive biomarkers of necrosis [e.g. Troponin, creatine kinase-MB (CK-MB)] and.USAP is defined as angina or equiv with 1/3 of features a)occurring at rest and >20 min b)severe chest pain c)crescendo pattern. At admission each patient was assessed by the medical history lifestyle and risk factors, TIMI score, hypertension, diabetes mellitus, hypercholesterolemia, smoking, bmi, anemia, left ventricular ejection fraction. RDW CV was obtained from the automated cbc using a coulter lh 780 hematology analyzer. CRP was also assessed qualitatively as negative and positive. All patients were followed after discharge using a standardized protocol that included telephone contacts, outpatient visits, and the recording of recurrent cardiac events.

The primary endpoint was cardiac death if related to MI, arrhythmia, refractory congestive heart failure, or sudden death. The secondary endpoints were reinfarction, revascularisation, stroke, or heart failure. Reinfarction is defined as an elevation in serum CK-MB levels of twice the upper limit of normal and ST-segment re-elevations. Hospitalization for heart failure is defined by the presence of new symptoms of dyspnea with pulmonary venous congestion on radiograph with interstitial or alveolar edema requiring hospitalization. Local ethics committee of our hospital provided approval for the study.

Table 2

Laboratory parameters

Low RDW (n=214) Low RDW (n=214)
Mean ±Std. Deviation Mean ±Std. Deviation P value
s.Creat(mg/dl) 1.0852 .31301 1.30 .77397 0.002 (S)
Hb(g/dl) 13.607 1.9237 12.90 1.8 0.72 (NS)
Rbs(mg/dl) 132.22 60.981 131.48 59.606 0.91 (NS)
Tlc(x109/l) 9.223 2.1814 15.30 4.0490 0.009 (NS)
cp mb(u/l) 37.88 29.912 55.16 40.900 0.0002 (S)
Ldl(mg/dl) 112.72 35.728 121.82 38.625 0.048 (S)
Lvef(%) 53.32 8.910 50.12 10.440 0.007 (S)

Table 3

Spearman Correlations

Variable r p value Significance
Age -0.78 0.16 not significant
BMI 0.061 0.27 not significant
Timi Score 0.22 <0.0001 significant
LVEF -0.14 0.011 significant

Figure 1

Correlation of CRP and Complications at 6 months

icfj.2015.2.27-g001.jpg

Study Protocol

The study population was divided into two groups based on the fiftieth percentile of admission RDW values. A high RDW group (n=105) and a low RDW group (n=214) were defined as having RDW levels of >14.0 and ≤14.0, respectively. Qualitative CRP positivity was observed in 113 patients. Complete blood counts and biochemical values were evaluated from blood samples obtained by antecubital vein puncture upon admission to the emergency department. Transthoracic echocardiography was performed on each patient immediately in the coronary care unit.

Statistical Analysis

Qualitative variables were expressed as percentages Quantitative variables were expressed as mean±sd. Correlations between RDW and other parameters were assessed using spearman’s rank correlation test. Comparison of parametric values between the two groups was performed using a two-tailed students’ t-test. Categorical variables were compared by the fisher’s exact test. P≤0.05 was taken as significant. Spss 20.0 version programme was used for all statistical analysis.

Results

The baseline characteristics of the two groups are summarized in Table 1.Compared with the low RDW group, the patients in the high RDW group were older and included more females. They were more likely to have a history of HTN, diabetes and MI. The high RDW group also had higher admission creatinine and Killip class >1. Other baseline characteristics were not statistically different between the two groups. They had significantly higher TIMI risk scores and also had less LVEF than the low RDW group(table 2).The patients with the higher RDW had significantly higher levels of CK-MB, peak creatinine, ldl and TLC .Other laboratory characteristics between the two groups were not statistically different (table 2).

Table 4 presents the in-hospital adverse outcomes in which killip class>1 was more in high RDW group(p=0.020).The high RDW group had significantly higher 6-month mortality compared with the low RDW group (P=0.008). The high RDW group also had significantly higher 6-months reinfarction rates and hospitalization for heart failure.Patients with positive CRP and high RDW taken together had significant killip class > 1 and at 6 months they had significant reinfarction rates, cv mortality and rehospitalisation for heart failure.

Discussion

The authors in the present study observed that a higher admission RDW level and positive CRP was associated with more adverse 6 months cardiovascular outcomes such as cardiovascular mortality, hospitalization for heart failure, and reinfarction in patients with NSTEMI and USAP. Red blood cell distribution width is a quantitative measure of the heterogeneity in the size of circulating erythrocytes. RDW CV can be measured routinely as part of daily automated CBC with no extra cost. Lappe et al.10 showed that RDW was associated with mortality in patients with stable angina pectoris. Wang et al.11 showed that elevated RDW could predict an increased risk of short term (1 month) adverse outcomes in patients with ACS. Azab et al.12 showed that RDW is an independent predictor of all-cause long-term mortality in NSTEMI patients. Borne et al.13 showed that RDW was associated with the incidence of first hospitalization because of heart failure among middle-aged patients.In our study, LVEF was less in the high RDW group than in the low RDW group. Follow up hospitalization for heart failure was significantly higher at 6 month in the high RDW group. In our study, the high RDW group was more likely to have a history of HTN, PCI and MI. Similar to other studies, high RDW was associated with a higher prevalence of cardiovascular risk factors in the present study14 also.Risk stratification is essential in the management of ACS. The TIMI and GRACE risk scores are valuable tools in risk stratification of ACS. In our study, RDW levels correlated well with the TIMI risk score. However, RDW has not been included in any risk scoring system yet.Inflammatory and neurohormonal activation could be one of the mechanism between elevated RDW and increased mortality15. Oxidative stress has long been proposed to be another indicator of the prognostic value of RDW. Red blood cells have a huge antioxidant capacity and serve as a primary oxidative sink, but they are prone to oxidative damage, which reduces cell survival and induces the release of juvenile erythrocytes into circulation in acute inflammatoty conditions like acs. Azab et al.12 hypothesized that elevated RDW could be an indication of altered red blood cell rheological properties that could lead to significant changes in blood flow and microcirculatory occlusion. Consequently, all these mechanisms – including chronic inflammatory state, neurohormonal activation, and an accelerated atherosclerotic process – may contribute toward adverse clinical outcomes and a poor prognosis in several cardiovascular diseases including acs.CRP has long been a marker of inflammation and is a robust clinical marker because of its stability, reproducible results, and ease of assay. Although it was originally proposed as a nonspecific marker of inflammation, several reports suggest that CRP may play a direct pathophysiological role in the development and progression of atherosclerosis16. Proposed mechanisms include induction of endothelial dysfunction,promotion of foam cell formation,inhibition of endothelial progenitor cell survival and differentiation, and activation of complement in atherosclerotic plaque intima and ischemic myocardium. There appears to be a bimodal CRP response among patients with ACS. In some patients, CRP may remain elevated for up to 3 months, whereas in others, CRP slowly declines during the hospital admission. A meta-analysis through 2001 found that elevated CRP at admission in patients with non–ST-elevation MI (NSTEMI) or unstable angina conferred a 1.5-fold increased risk of death or nonfatal MI at 30 days17. In our study also we found similar correlation between positive CRP and adverse clinical outcomes. Also when authors combined both markers together the adverse clinical outcomes correlated well with high RDW and positive CRP thus increasing the robustness of taking these two easily available markers together to stratify the patient.

Table 4

In hospital complications

In hospital complications Low RDW (n=214 % High RDW (n=105) % p value Significance
Killip >1 6 2.8 8 7.6 0.049 S
in Hospital mortality 3 1.4 1 1.0 0.76 NS
Re infarction 5 2.3 2 1.9 0.817 NS
tvr 0 0.0 1 1.0 0.57 NS
mace 7 3.3 3 2.9 0.84 NS
Vent arrythmias 3 1.4 2 1.9 0.73 NS
artial arrythmias 8 3.7 7 6.7 0.23 NS
cpr 3 1.4 2 1.9 0.73 NS

Table 5

CRP Positivity and correlation with complications at 6 months

Complications CRP Negative [n=206] % CRP Positive CRP Positive [n=113] % CRP Negative p value Significance
Stroke 2 1.0 1 0.9 0.93 NS
Reinfarction 4 1.9 12 10.6 0.023 S
CV Mortality 1 0.5 5 4.4 0.003 S
Heart failure hospitalization 2 1.0 8 7.1 0.013 S

Figure 2

Correlation of CRP positive and high RDW and complications at 6 months

icfj.2015.2.27-g002.jpg

Figure 3

Correlation of CRP positive and high RDW and in hospital complications

icfj.2015.2.27-g003.jpg

Table 6

Cases with CRP positives and High RDW correlated with complications

Outcomes CRP+RDW High [n=79] % CRP+RDW High Others [n=240] % Others p value Significance
killip class>1 12 15.2 2 0.8 <.001 S
inhostp mortality 1 1.3 3 1.3 0.99 NS
Re infarction 2 2.5 5 2.1 0.81 NS
tvr-taget vessal revascularization 0 0 1 0.4 0.56 NS
mace 2 2.5 8 3.3 0.72 NS
vent arrythmias 2 2.5 3 1.3 0.42 NS
atrial arrythmias 6 7.6 9 3.8 0.16 NS
CPR 2 2.5 3 1.3 0.42 NS
Stroke at 6 months 1 1.3 2 0.8 0.73 NS
reinfarction at 6 months 8 10.1 8 3.3 0.017 S
CV Mortality at 6 months 4 5.1 2 0.8 0.013 S
heart failure hospitilization 6 months 6 7.6 4 1.7 0.009 S

Table 7

Follow up complications at 6 months

Follow up complicaitons Low RDW (n=214) % High RDW (n=105) % p value Signi-ficance
Stroke 2 0.9 1 1.0 0.93 NS
Re infarction 5 2.3 11 10.4 0.0017 S
cvs mortality 1 0.004 5 0.047 0.008 S
Heart failure hostpitalization 2 0.0 8 0.0 0.0013 S

Study limitations

This is a single-center study. We did not assess other laboratory markers such as B-type natriuretic peptide, angiotensin II levels, erythropoietin, or markers of oxidative stress. Despite adjusting for multiple classical risk factors, there may have been residual confounding conditions and medications such as iron, folate, and vitamin B12 deficiency.we did only qualitative assessment of CRP as negative and positive and not measured quantitative values of CRP.

Conclusions

RDW CV is widely available to clinicians as part of CBC and thus incurs no additional costs. It correlates well with established inflammatory marker such as CRP in our study and when both combined we could stratify patients into high risk. Given the advantages of the RDW CV levels, it may be used as a marker of cardiovascular risk management in NSTEMI and USAP along with CRP and help in risk stratification and plan early invasive strategy. These associations will allow for the CBC (and in particular, RDW CV) to be utilized to great medical benefit for making novel diagnosis, for monitoring treatment plans and avoiding unnecessary or expensive tests in poor country like us where finance is always an issue.

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