Prognostic role of C-reactive protein in very old patients with acute ischaemic stroke

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1 Journal of Internal Medicine 2005; 258: Prognostic role of C-reactive protein in very old patients with acute ischaemic stroke L. MASOTTI 1, E. CECCARELLI 2, S. FORCONI 3 & R. CAPPELLI 3 From the 1 Internal Medicine, Cecina Hospital, Livorno; 2 Centre of Physical Medicine and Rehabilitation, Campiglia M.ma, Livorno; and 3 Department of Internal, Cardiovascular and Geriatric Medicine, University of Siena, Siena, Italy Abstract. Masotti L, Ceccarelli E, Forconi S, Cappelli R (Cecina Hospital, Physical Medicine and Rehabilitation, Livorno; and University of Siena, Siena, Italy). Prognostic role of C-reactive protein in very old patients with acute ischaemic stroke. J Intern Med 2005; 258: Background and scope. Recent literature has demonstrated that inflammation contributes to all phases of atherosclerosis and brain damage caused by stroke. In acute phase of cerebrovascular diseases biochemical markers of inflammation, such as C- reactive protein (CRP), could represent an indicator of severity of stroke, but few studies have verified this hypothesis, especially in very old patients. The aim of this study was to evaluate the role of CRP on short- and long-term prognosis in 75-year old and over elderly patients with acute ischaemic stroke. Materials and methods. We retrospectively evaluated CRP values (nephelometric method), performed within 12 h from hospital admission, in 196 elderly patients (124 females and 72 males with mean age ± SD ± years), discharged with diagnosis of acute ischaemic stroke, 68 of them with atherothrombotic large vessel stroke, 38 with lacunar stroke and 90 with cardioembolic stroke. We studied the relationship between CRP values and short-term prognosis [30-day mortality, length of hospitalization (LOS) and physical disability measured by modified Rankin scale and long-term prognosis (12-month mortality and re-hospitalization)]. Results. Mean values of CRP were significantly higher in patients with cardioembolic stroke compared with atherothrombotic large vessel and lacunar stroke, in patients who died in the first 30 days from the acute event compared with survivors. LOS and physical disability score rose with increasing values of CRP for all subtypes of stroke. Higher CRP values were associated with the 12-month re-hospitalization for cerebrovascular events, whereas it did not influence the 12-month cumulative re-hospitalization and 12-month mortality. Conclusions. Elevation of CRP values at hospital admission could represent a negative prognostic index in elderly patients with ischaemic stroke, in particular, for short-term prognosis. Keywords: C-reactive protein, elderly, inflammation, prognosis, stroke. Introduction Much recent scientific evidence has assigned to inflammation a fundamental role in pathogenesis of atherosclerosis in all stages of this disease: starting, progression and thrombotic complications [1, 2]. Many reports have, in fact, provided that atherosclerosis could represent a chronic flogistic disorder and its exacerbations could determine acute cardiovascular and cerebrovascular events. C-reactive protein (CRP) is the prototype of acute phase of inflammation, so it is used as a biochemical marker in studies demonstrating the relationship between inflammation and atherosclerosis in all its manifestations [3, 4]. The role of CRP has been well established, with few discordant results [5], in terms of risk factor, severity of disease, prognosis and risk of recurrent cardiovascular events in coronary heart disease [2, 6 8] but in cerebrovascular disease the role of CRP Ó 2005 Blackwell Publishing Ltd 145

2 146 L. MASOTTI et al. remains unclear, especially in elderly patients. Many prospective studies such as the Framingham Study [9], the Cardiovascular Health Study [10], the Third National Health and Nutrition Examination Survey [11] and other analysis [12, 13] have demonstrated that high levels of CRP are an independent risk factor for future ischaemic cerebrovascular attacks; by contrast, the Leiden 85-Plus Study [14, 15] revealed that CRP is a nonspecific risk factor for fatal stroke in the elderly. In the acute phase of stroke inflammation contributes to brain damage proved by ischaemia [16]. The onset of cerebral ischaemia, in fact, determines an inflammatory cascade, especially mediated by an increase in local cytokines, adhesion molecules, acute phase proteins, macrophages and leucocytes. The strength of this response seems to be important for early and late clinical outcomes [17]. However only few studies have provided information about the role of CRP in the acute phase of stroke, especially in very old patients. Against this background the aim of the present study was to evaluate the role of CRP values on short- and long-term prognosis in 75-year old and over elderly patients with acute ischaemic stroke. Materials and methods We conducted an observational, retrospective study on clinical data of elderly patients aged 75 and above admitted to our acute geriatric ward and discharged with diagnosis of ischaemic stroke ( and codes of International Classification of Diseases, 9th Revision, Clinical Modification, ICD-9-CM, Diagnosis Related Groups number 014) over a period of 4 years. In these patients we evaluated the association between CRP, performed in the first 12 h from hospital admission by the nephelometric method (Dade/Behring Diagnostics, Marburg, Germany; sensitivity mg dl )1, specificity 100%), and short- and long-term prognosis. In 284 patients discharged with a diagnosis of ischaemic stroke we excluded from the analysis 88 patients with a diagnosis of cancer in the previous 5 years (eight patients), chronic flogistic disorders (nine patients; of them two with rheumatoid arthritis, three with thyroiditis, one with cryoglobulinaemia, one with Sij}ogren syndrome and two with rheumatic polimyalgia), recent infectious diseases (13 patients), chronic liver (seven patients) or renal failure (12 patients) or with values of erythrocyte sedimentation rate (ESR) higher than 20 mm h )1 at hospital admission (38 patients). Our final study population refers to 196 patients (124 females and 72 males, with mean age ± years). Approximately 30% of patients came to our observation within 6 h from the onset of symptoms, 60% between 6 and 24 h, and 10% after 24 h. In all patients we performed brain computer tomography (BCT) in the first 72 h from hospital admission. In 129 patients we performed carotid Doppler ultrasonography; in 137 we performed B-mode echocardiography. The grade of carotid stenosis was quantified according to NASCET criteria [18, 19]. The subtype of stroke was atherothrombotic in 106 patients (68 with large vessel disease, 38 with lacunar disease, whereas 90 patients had a cardioembolic stroke). For subtype classification we used TOAST criteria [20, 21]. We followed 30-day mortality, length of hospitalization (LOS), physical disability at discharge performed by the modified Rankin scale [22] as outcomes of short-term prognosis and 12-month mortality and re-hospitalization as outcomes of longterm prognosis. As regards LOS we divided the patients into three groups: patients with LOS 12 days (71 patients, 36.2%), patients with LOS > 13 and <18 days (61 patients, 31.1%) and patients with LOS 19 days (64 patients, 32.7%). The choice of this LOS subdivision was made because of obtaining three homogeneous groups of patients for statistical analysis. The modified Rankin scale is a scale of levels (0 6) based on clinical evaluation for quantify progressive physical disability (see Appendix). Ethical approval was not needed for this study because only medical records were used. For statistical analysis we used the t-test for the differences of the means of independent samples and the correlation index of Pearson (r 2 ) for the relationship between CRP and prognostic parameters. P-value <0.05 and r 2 )1 )0.5 and were considered statistically significant. Results Table 1 summarizes the characteristics of the patients. In 34.6% of patients with previous

3 CRP IN ELDERLY STROKE PATIENTS 147 Table 1 Characteristics of patients (n ¼ 196) Sex 124 females/72 males Mean age ± SD ± years Risk factors for cerebrovascular diseases Hypertension 91 (46.4) Diabetes 32 (16.3) Hypercholesterolaemia 18 (9.1) Hyperuricaemia 31 (15.8) Smoke 36 (18.3) Obesity (BMI > 30) 67 (34.2) Carotid Doppler ultrasonography (performed in 129 patients) Stenosis 70% 9 (6.9) 51 69% 22 (17.0) 50% 88 (67.4) Normal 10 (7.7) Previous cerebrovascular attacks TIA 27 (13.7) Stroke 41 (20.9) Subtype of stroke Atherothrombotic 68 (34.7) Lacunar 38 (19.4) Cardioembolic 90 (45.9) Chronic atrial fibrillation 63 (32.1) Dilatative myocardiopathy 6 (3.3) Cardiac valvular disease 18 (9.3) Inter-atrial septum aneurysmal 2 (1.2) At home antithrombotic treatment None 142 (72.9) Aspirin 32 (16.6) Ticlopidine 7 (3.5) Indobufen 3 (1.5) Warfarin 6 (3.5) Unfractioned subcutaneous heparin 4 (2.0) Discharge disability Rankin score 2 19 (9.7) Cardioembolic stroke 14 (7.1) Atherothrombotic stroke 4 (2.0) Lacunar stroke 1 (0.5) Rankin score 3 54 (27.5) Cardioembolic stroke 26 (13.2) Atherothrombotic stroke 17 (8.6) Lacunar stroke 14 (7.1) Rankin score 4 45 (23.0) Cardioembolic stroke 18 (9.2) Atherothrombotic stroke 19 (9.7) Lacunar Stroke 8 (4.1) Rankin score 5 47 (24.0) Cardioembolic stroke 20 (10.2) Atherothrombotic stroke 17 (8.6) Lacunar stroke 10 (5.1) 30-day mortality (Rankin score 6) 31 (15.8) Cardioembolic stroke 12 (6.1) Atherothrombotic stroke 14 (7.2) Lacunar stroke 5 (2.5) Mean LOS ± SD ± days Cardioembolic stroke ± 7.93 days Atherothrombotic stroke ± days Lacunar stroke ± 7.84 days LOS 12 days 71 (36.2) Cardioembolic stroke 28 (14.1) Atherothrombotic stroke 23 (11.7) Table 1 Continued Lacunar stroke 20 (10.2) LOS days 61 (31.1) Cardioembolic stroke 30 (15.3) Atherothrombotic stroke 21 (10.6) Lacunar stroke 10 (5.1) LOS 19 days 64 (32.7) Cardioembolic stroke 32 (16.2) Atherothrombotic stroke 24 (12.1) Lacunar stroke 8 (4.0) 12-month mortality 23 (13.9) Cardioembolic stroke 11 (6.6) Atherothrombotic stroke 10 (6.1) Lacunar stroke 2 (1.2) 12-month re-hospitalization 80 (48.4) Cardioembolic stroke 42 (25.4) Atherothrombotic stroke 29 (17.5) Lacunar stroke 9 (5.5) Values are expressed as n (%), unless otherwise stated. TIA, transient ischaemic attack; LOS, length of hospitalization; BMI, body mass index. cerebrovascular events [transient ischaemic attack (TIA) or stroke], mean values of CRP were not significantly higher compared to patients without previous cerebrovascular attacks (5.44 vs mg dl )1, P ¼ 0.065). In patients treated at home with antithrombotic drugs mean values of CRP were lower with respect to the untreated patients (4.76 vs. 5.20, P ¼ 0.052). In patients with carotid stenosis 70% mean values of CRP (4.80 mg dl )1 ) were significantly higher compared to patients with stenosis 51 69% (3.49 mg dl )1, P ¼ 0.017) or stenosis 50% (2.97 mg dl )1, P ¼ 0.012). Moreover, mean values of CRP were significantly higher in patients with infarct at BCT performed in the first 72 h from hospital admission compared to patients without documented infarct (6.16 vs. 2.74, P ¼ ). Mean values of CRP were significantly higher in patients with cardioembolic stroke (5.44 mg dl )1 ) than in patients with atherothrombotic large vessel disease (3.36 mg dl )1, P ¼ ) and lacunar stroke (2.64 mg dl )1, P ¼ ). Thirty-one patients (15.8%, 17 females and 14 males), with mean age ± SD ± 5.95 years, died in the first 30 days from hospital admission. Of them 13/31 (42%) had had a previous cerebrovascular event. Mean LOS ± SD of patients who died was ± 8.21 days. In 21 of 31 patients (68%) brain CT demonstrated an ischaemic area in the first 72 h from hospital admission. Subtypes of stroke in

4 148 L. MASOTTI et al. CRP values (mg dl 1 ) p = Survivors Died p = p = p = CRP values (mg dl 1 ) Lacunar r 2 = 0.51 Large vessel r 2 = 0.62 Cardioembolic r 2 = Rankin score 2 Fig. 2 C-reactive protein (CRP) and disability. 0 Cardioembolic Large vessel Lacunar Total Groups Cardioembolic Large vessel Lacunar Total Survivors N Died N Fig. 1 C-reactive protein (CRP) and 30-day mortality. 196 died patients were: large vessel, 14 (45.2%), lacunar 5 (16.1%), and cardioembolic 12 (38.7%). Mean values of CRP were significantly higher in patients who died in the first 30 days from stroke compared with survivors (10.7 vs. 4.3 mg dl )1, P ¼ ), both for cardioembolic stroke (12.80 vs mg dl )1, P ¼ ) and atherothrombotic large vessel (4.53 vs mg dl )1, P ¼ 0.049) and lacunar stroke (7.11 vs mg dl )1, P ¼ 0.036) (Fig. 1). Figure 2 demonstrates the relationship between CRP and discharge disability. Disability increases with the increase in CRP values (r 2 ¼ 0.68), both for cardioembolic stroke (r 2 ¼ 0.74) and for atherothrombotic large vessel (r 2 ¼ 0.62) and lacunar stroke (r 2 ¼ 0.51). In patients with severe disability (Rankin score 5) mean values of CRP were significantly higher in cardioembolic stroke (17.43 mg dl )1 ) compared with atherothrombotic large vessel (7.26 mg dl )1, P ¼ ) and lacunar stroke (7.42 mg dl )1, P ¼ ) Total N Figure 3 shows the relationship between CRP values and LOS. Hospital stay was directly related to CRP values, both in cardioembolic stroke and in atherothrombotic large vessel and lacunar stroke; mean values of CRP were 3.59 mg dl )1 in patients with LOS 12 days (cardioembolic stroke 3.90 mg dl )1, atherothrombotic large vessel stroke 2.99 mg dl )1, lacunar stroke 2.57 mg dl )1 ), 4.48 mg dl )1 in patients with LOS > 13 and <18 days (cardioembolic stroke 6.47 mg dl )1, atherothrombotic large vessel stroke 3.46 mg dl )1, lacunar stroke 3.06 mg dl )1 ) and 6.27 mg dl )1 in patients with LOS 19 days (cardioembolic stroke 7.12 mg dl )1, atherothrombotic large vessel stroke 5.91 mg dl )1, lacunar stroke 4.43 mg dl )1 ). Mean LOS was >19 days in patients with a Rankin score 3, whilst it was <15 days in patients with a Rankin score 2 (P ¼ ). Twenty-three patients died after the first month from acute cerebrovascular event. We did not find significant differences in CRP values between this group of patients and the survivor patients (4.78 vs. CRP values (mg dl 1 ) < or = 12 days >13 and < 18 days > or = 19 days r 2 = 0.95 r 2 = 0.87 r 2 = 0.99 r 2 = 0.98 Lacunar Large vessel Cardioembolic Total hospital stay (day) Fig. 3 C-reactive protein (CRP) and length of hospitalization (LOS).

5 CRP IN ELDERLY STROKE PATIENTS mg dl )1, P ¼ 0.14), both for cardioembolic stroke and for atherothrombotic large vessel and lacunar stroke. Eighty patients were re-hospitalized in the next 12 months. Table 2 reports the causes of re-hospitalization and the mean values of CRP for each cause. We did not find significant differences between CRP values of the total of re-hospitalized patients with respect to those who were not re-hospitalized (3.01 vs mg dl )1, P ¼ 0.18), whilst we found a significant difference in CRP values for the patients re-hospitalized for cerebrovascular attacks with respect to those who were not re-hospitalized (5.18 vs mg dl )1, P ¼ 0.032) and with respect to those who were re-hospitalized for noncerebrovascular causes (4.22 mg dl )1, P ¼ ). Twenty-one of 146 (14.3%) patients with a Rankin score 3 died of stroke after the first month compared with 2 of 19 (10.5%) patients with a Rankin score 2, whilst 72 of 146 (49.3%) patients with Rankin score 3 were re-hospitalized compared with 8 of 19 (42.1%) patients with a Rankin score 2. Discussion Studies regarding the role on CRP in stroke patients have been recently submitted to a meta-analysis. This report concludes that in primary prevention it is not possible to recommend measurement of CRP as a screening test for cerebrovascular diseases whilst in secondary prevention, CRP elevation adds to existing prognostic markers, but doubts remain as to whether specific therapeutic options are present [23]. Table 2 Causes of 12-month re-hospitalization Causes n (%) CRP (mg dl )1 ) Total 80 (100) 3.08 TIA/stroke 30 (37.5) 5.18 CHD 11 (13.7) 3.97 Fractures 11 (13.7) 3.11 Heart failure 10 (8) 0.42 GI bleedings 4 (5) 1.45 Others 14 (17.5) 1.27 CRP, C-reactive protein; TIA, transient ischemic attack; CHD, coronary heart disease; GI, gastrointestinal. Cerebrovascular events (5.18 mg dl )1 ) versus total other causes (4.22 mg dl )1 ), P ¼ We performed the present study to investigate whether CRP could be considered a negative prognostic predictor in acute ischaemic stroke in very old patients. We analysed the role of inflammation in very old ischaemic stroke patients. Reviewing the studies that considered the role of CRP in acute phase of stroke, our study enrolled the patients with higher mean age (>80 years). Apart from the limitations of the retrospective studies, we found that early, but not late, mortality, LOS and physical disability had a direct correlation with CRP values and that higher values of CRP at hospital admission are related to the recurrence of cerebrovascular diseases in the follow-up. Moreover, we observed a similar influence of CRP values on measured outcomes for the different subtypes of stroke. In agreement with other studies, the present analysis shows that in patients with previous cerebrovascular attacks an inflammatory process persists indicated by a higher CRP value in patients with positive anamnesis for TIA or stroke [24, 25]. Moreover, the lower CRP values in patients treated with antithrombotic drugs suggest that this group of drugs reduce inflammation [26, 27]. Many studies have analysed the relationship between CRP and carotid atherosclerosis. The main conclusions of these reports, except few discordant results [28], are that high levels of CRP are associated with intima media thickness, development of atherosclerotic plaques, their progression, rupture and cerebrovascular events, both in symptomatic than in asymptomatic carotid stenosis, and in surgically treated than in untreated carotid stenosis [29 36]. Our study in old patients confirms the relationship between CRP values and severity of carotid atherosclerosis in the acute phase of stroke. We found that higher values of CRP are associated with the presence of documented ischaemic damage of the brain in the first 72 h from hospital admission. A recent report analysed the relationship between inflammation and stroke by using a special contrast with a target for macrophages during magnetic resonance imaging of the brain, concluding that it is possible to monitor brain inflammation in stroke and its severity [37]. Other studies have showed a relationship between the size of stroke and the plasma levels of inflammation index [38, 39]. CRP values are higher in stroke compare than in TIA, and in haemorrhagic stroke than in

6 150 L. MASOTTI et al. ischaemic stroke. This fact could reflect that CRP is a marker of local severity of brain attack [40, 41]. We noticed a direct correlation between increasing values of CRP and increasing level of Rankin score. Previous reports showed similar results in younger patients with stroke by using other neurological scales but the evaluation of disability was marginal in these studies [32 45]. We demonstrate that higher values of CRP correlate with recurrence of cerebrovascular events. In our study we measured plasma CRP values at hospital admission. Other studies reported the influence of CRP on prognosis of stroke patients when measured in different moments of acute stroke phase, in particular, at hospital admission and discharge at the 12, 24 and 72 h. It seems that the more predictable value of CRP on outcomes is at hospital discharge, reflecting the persistent state of inflammation and therefore the high risk of recurrence [25, 43, 44, 46 48]. We observed some differences in CRP measurements in the different subtypes of stroke. Our findings in fact seem to demonstrate that higher levels of CRP are present in cardioembolic stroke patients, although CRP values seem to show the same influence on short- and long-term outcomes in all subtypes of stroke. Previous studies did not find a different pattern of CRP values in different subtypes of ischaemic stroke [43 45]. Further investigations should confirm these results. The vast body of literature about the relationship between inflammation and atherosclerosis with its complications has raised the question as to whether CRP and other inflammatory markers could become a target of therapy. In coronary artery disease two recent studies seem to demonstrate that therapy with statins and reducing levels of CRP could reduce the progression of atherosclerosis [49, 50]. In cerebrovascular disease the influence of some categories of drugs on atherosclerotic process modifying the acute phase of inflammation was studied. It was suggested that statins and angiotensin-converting enzyme inhibitors could be more effective in the presence of high CRP levels and that the efficacy of antiplatelet therapy, such as aspirin or clopidogrel, in secondary prevention could be related to the levels of inflammatory markers [23, 26, 27, 51]. This fascinating field of therapy in cerebrovascular diseases should be further investigated, but the road could be marked out. Conclusions Stroke is actually one of the main problems of health worldwide because of its high incidence, prevalence, mortality and residual disability. It is of utmost importance to select patients with high risk of negative outcomes and to address them through a more intensive pharmacological and rehabilitative approach. Our study, with the limitations of retrospective studies, confirms that in the acute phase of ischaemic stroke CRP could represent a prognostic marker in elderly patients. Further prospective studies are necessary to demonstrate this hypothesis. Conflict of interest statement No conflict of interest was declared. References 1 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: Pearson TA, Mensah GA, Alexander RW et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107: Jialal I, Devaraj S. Inflammation and atherosclerosis: the value of the high-sensitivity C-reactive protein assay as a risk marker. Am J Clin Pathol 2001; 116 (): S Ridker PM. High-sensitivity C-reactive protein and cardiovascular risk: rationale for screening and primary prevention. Am J Cardiol 2003; 21: 17K Danesh J, Wheeler JG, Hirschfield GM et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: de Maat MP, Bladhjerg EM, Drivsholm T, Borch-johnsen K, Moller-Jespersen J. Inflammation, thrombosis and atherosclerosis: results of the Glostrup study. J Thromb Haemost 2003; 1: Strandberg TE, Tilvis RS. C-reactive protein, cardiovascular risk factors, and mortality in a prospective study in the elderly. Arterioscler Thromb Vasc Biol 2000; 20: Rost N, Wolf P, Kase C et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framinghan study. Stroke 2001; 32: Cao JJ, Thach C, Manolio TA et al. C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation 2003; 108:

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