Reduction in High-Sensitivity C-Reactive Protein Levels in Patients with Ischemic Stroke by Statin Treatment: Hs-CRP Sub-Study in J-STARS.
ABSTRACT: The pleiotropic effects of statins on recurrent stroke remain unclear. We investigated the effects of pravastatin on high-sensitivity C-reactive proteins (Hs-CRP) in ischemic stroke, and explored the impact of Hs-CRP on recurrent stroke and vascular events.This randomized open-label trial was ancillary to the J-STARS trial. One thousand and ninety-five patients with non-cardiogenic ischemic stroke were assigned to the pravastatin (n=545) or control groups (n=550). The primary and secondary endpoints were serum Hs-CRP reduction and stroke recurrence, including both ischemic and hemorrhagic ones, respectively. Onset of vascular events and each stroke subtype in relation to Hs-CRP levels were also determined.In the pravastatin treatment group, Hs-CRP levels (median 711 µg/L, IQR 344-1500) significantly decreased 2 months later (median 592 µg/L, IQR 301-1390), and they remained significantly lower until the end of the study. However, in the control group, baseline Hs-CRP levels were similar to those 2 months later. The reduction of Hs-CRP levels from the baseline to 2 months in the pravastatin group was statistically significant compared with the control (p=0.007). One SD increase in log-transformed Hs-CRP increased the risk of stroke recurrence (HR 1.17, 95% CI 0.97-1.40) and vascular events (HR 1.30, 95% CI 1.12-1.51). With an Hs-CRP cut-off of 1000 µg/L, higher Hs-CRP significantly increased the risk of recurrent stroke (HR 1.50, 95% CI 1.03-2.17)and vascular events (HR 1.68, 95% CI 1.23-2.29).In non-cardiogenic ischemic stroke, pravastatin treatment may reduce vascular inflammation as assessed by Hs-CRP, and higher Hs-CRP levels appeared to increase the risk of recurrent stroke and vascular events.
Project description:AIMS:To investigate the relative contribution of on-treatment low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) to the risk of recurrent stroke and transient ischemic attack (TIA) in patients with history of ischemic stroke. METHODS:A total of 1095 patients with non-cardioembolic ischemic stroke were randomized into two groups: control and patients receiving 10 mg of pravastatin per day. After excluding 18 patients who did not have baseline CRP data, the effects of LDL cholesterol and CRP on recurrent stroke and TIA were prospectively assessed in 1077 patients. RESULTS:During the follow-up of 4.9±1.4 years, there were 131 recurrent stroke or TIA cases. Patients with ontreatment LDL cholesterol ?120 mg/dL showed 29% reduction in recurrent stroke and TIA than those with LDL cholesterol ? 120 mg/dL (event rate 2.20 vs. 3.11 per 100 person-years, hazard ratio [HR] 0.71, 95% confidence interval (CI) 0.50-0.99, p?0.048). Patients with CRP ?1 mg/L had 32% reduction compared with that of patients with CRP ? 1 mg/L (event rate 2.26 vs. 3.40 per 100 person-years; HR 0.68, 95% CI 0.48-0.96, p?0.031). Although LDL cholesterol and CRP levels were not correlated in individual patients, those who achieved both LDL cholesterol ?120 mg/dL and CRP ?1 mg/L showed 51% reduction compared with that of patients with LDL cholesterol ? 120 mg/dL and CRP ? 1 mg/L (event rate 2.02 vs. 4.19 per 100 person-years; HR 0.49, 95% CI 0.31-0.79). CONCLUSIONS:The control of both LDL cholesterol and CRP levels appears to be effective for preventing recurrent stroke and TIA in patients with non-cardiogenic ischemic stroke.
Project description:Red cell distribution width (RDW), a measure of variability in size of circulating erythrocytes, is associated with arterial cardiovascular disease (CVD), but the underlying mechanism remains unclear. We aimed to investigate the impact of chronic inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) on this relationship, and explore whether RDW could be a mediator in the causal pathway between inflammation and arterial CVD. Baseline characteristics, including RDW and hs-CRP, were obtained from 5,765 individuals attending a population-based cohort study. We followed up participants from inclusion in the fourth survey of the Tromsø Study (1994/1995) until December 31, 2012. Multivariable Cox-regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for incident myocardial infarction (MI) and ischemic stroke across quintiles of hs-CRP and RDW. Subjects with hs-CRP in the highest quintile had 44% higher risk of MI (HR: 1.44, 95% CI: 1.14-1.80), and 64% higher risk of ischemic stroke (HR: 1.64, 95% CI: 1.20-2.24) compared with subjects in the lowest quintile. RDW mediated 7.2% (95% CI: 4.0-30.8%) of the association between hs-CRP and ischemic stroke. Subjects with RDW in the highest quintile had 22% higher risk of MI (HR: 1.22, 95% CI: 0.98-1.54) and 44% higher risk of ischemic stroke (HR: 1.44, 95% CI: 1.06-1.97) compared with subjects in the lowest quintile. These risk estimates were slightly attenuated after adjustments for hs-CRP. Our findings suggest that chronic inflammation is not a primary mechanism underlying the relationship between RDW and arterial CVD.
Project description:BACKGROUND AND PURPOSE:Inflammation plays a critical role in the development of vascular disease, and increased levels of the inflammatory biomarkers, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), and high-sensitivity C-reactive protein (hs-CRP) have been shown to be associated with an increased risk for ischemic stroke. METHODS:In a prospective case-cohort (n=949) study in 12 762 apparently healthy, middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, we first examined whether Lp-PLA(2) and hs-CRP levels improved the area under the receiver operator characteristic curve (AUC) for 5-year ischemic stroke risk. We then examined how Lp-PLA(2) and hs-CRP levels altered classification of individuals into low-, intermediate-, or high-risk categories compared with traditional risk factors. RESULTS:In a model using traditional risk factors alone, the AUC adjusted for optimism was 0.732, whereas adding hs-CRP improved the AUC to 0.743, and adding Lp-PLA(2) significantly improved the AUC to 0.752. Addition of hs-CRP and Lp-PLA(2) together in the model improved the AUC to 0.761, and the addition of the interaction between Lp-PLA(2) and hs-CRP further significantly improved the AUC to 0.774. With the use of traditional risk factors to assess 5-year risk for ischemic stroke, 86% of participants were categorized as low risk (<2%); 11%, intermediate risk (2% to 5%); and 3%, high risk (>5%). The addition of hs-CRP, Lp-PLA(2), and their interaction to the model reclassified 4%, 39%, and 34% of the low-, intermediate- and high-risk categories, respectively. CONCLUSIONS:Lp-PLA(2) and hs-CRP may be useful in individuals classified as intermediate risk for ischemic stroke by traditional risk factors.
Project description:To compare the efficacy and safety of antiplatelet agents for the secondary prevention of ischemic stroke based on cytochrome P450 2C19 (CYP2C19) polymorphisms.This study was a prospective, multicenter, randomized, parallel-group, open-label, blind genotype trial. First time non-cardiogenic ischemic stroke patients were enrolled and screened within 30 days. Participants were randomized to receive either triflusal or clopidogrel for secondary stroke prevention. The primary outcome was the time from randomization to first recurrent ischemic stroke or hemorrhagic stroke.The required sample size was 1,080 but only 784 (73%) participants were recruited. In patients with a poor CYP2C19 genotype for clopidogrel metabolism (n=484), the risk of recurrent stroke among those who received triflusal treatment was 2.9% per year, which was not significantly different from those who received clopidogrel treatment (2.2% per year; hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.60-2.53). In the clopidogrel treatment group (n=393), 38% had good genotypes and 62% poor genotypes for clopidogrel metabolism. The risk of recurrent stroke in patients with a good CYP2C19 genotype was 1.6% per year, which was not significantly different from those with a poor genotype (2.2% per year; HR, 0.69; 95% CI, 0.26-1.79).Whilst there were no significant differences between the treatment groups in the rates of stroke recurrence, major vascular events, or coronary revascularization, the efficacy of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype status remains unclear.
Project description:Background:To compare the long-term clinical outcomes of different antihypertensive drugs in stable patients after acute hemorrhagic stroke (HS). Methods:From January 2001 to December 2013, patients with first-ever primary HS were identified in the National Health Insurance Research Database, Taiwan. Patients with traumatic intracerebral hemorrhage and secondary HS were excluded. Those with first-ever HS were recruited and classified into three groups: (1) angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB); (2) calcium channel blocker (CCB); and (3) other antihypertensive drugs (comparison) groups. Propensity score matching was used to balance the distribution of baseline characteristics, stroke severity, and medications between any two of the three groups. A validation study was performed using the databank of the Stroke Registry in Chang-Gung Healthcare System to reduce the bias. Primary outcomes were recurrent HS, ischemic stroke, any stroke, and all-cause mortality. Results:Compared to the comparison group, the ACEI/ARB group [35.4% versus 39.3%; hazard ratio (HR), 0.84; 95% confidence interval (CI), 0.74-0.95] and CCB group (33.0% versus 41.9%; HR, 0.72; 95% CI, 0.64-0.81) had a lower risk of all-cause mortality during long-term follow up. The CCB group had a similar risk of all-cause mortality to the ACEI/ARB group. Risks of recurrent HS, ischemic stroke, or any stroke were not different between the study groups. Conclusions:Antihypertensive drug class could be important to long-term outcomes in HS patients in addition to the target control of blood pressure. Both ACEIs/ARBs and CCBs are associated with lower risks of all-cause mortality. Our results may be applied to inform future research on hypertensive control in HS patients.
Project description:The aim of this study was to evaluate the diagnostic value of the serum biochemical markers high-sensitivity C-reactive protein (hs-CRP), D-dimer (DD) and fibrinogen (Fg) in differentiating etiological subtypes of ischemic stroke. This study was a retrospective case-only study, consecutively including patients with acute ischemic stroke. All patients were classified into subtypes using the TOAST classification system. A total of 317 patients were evaluated. Hs-CRP and DD levels were significantly different among the subtypes and were the highest in CE, followed by LAA and SAA; no significant difference between the subtypes was found for Fg. Hs-CRP > 6.96 mg/L was classified as the CE subtype, with a sensitivity of 41% and a specificity of 74%; DD > 791.30 ng/mL was classified as CE, with a sensitivity of 58% and a specificity of 78%. The combination of hs-CRP and DD classification as CE yielded a sensitivity of 65% and a specificity of 91%. DD > 791.30 ng/mL was considered an independent predictive factor of CE. Hs-CRP and DD could be useful for identifying the etiological subtypes of acute ischemic stroke, especially for predicting CE. The diagnostic value of DD was higher than that of hs-CRP.
Project description:Background Beyond the controlled setting of trials, scarce information exists on the burden, predictors, and outcomes associated with elevated hs CRP (high-sensitivity C-reactive protein) in "real-world" patients with myocardial infarction ( MI ). Methods and Results We included all-coming MI survivors undergoing hs CRP testing >30 days after an MI during routine health care in Stockholm, Sweden (2006-2011). hs CRP tests measured during hospitalization/emergency department visits, followed by antibiotics or indicative of acute illness, were excluded, together with patients with ongoing/recent cancer, chronic infections, or immunosuppression. Inflammation was defined over a 3-month baseline window and associated with subsequent death and major adverse cardiovascular events (composite of MI, ischemic stroke, or cardiovascular death). Included were 17 464 patients (63% men; mean age, 72.6 years) with a median hs CRP level of 2.2 (interquartile range, 1.0-6.0) mg/L and a median of 2.2 (interquartile range, 0.8-4.9) years since their MI . Most (66%) had hs CRP ≥2 mg/L, and 40% had hs CRP >3 mg/L. Lower hemoglobin, lower estimated glomerular filtration rate, and comorbidities (eg, heart failure, peripheral vascular disease, stroke, atrial fibrillation, diabetes mellitus, and rheumatoid diseases) were associated with higher odds of hs CRP ≥2 mg/L. Conversely, previous percutaneous coronary intervention, ongoing renin-angiotensin blockade, and statins were associated with lower hs CRP ≥2 mg/L odds. Patients with hs CRP ≥2 mg/L were at higher risk of major adverse cardiovascular events (n=3900; adjusted hazard ratio, 1.28; 95% CI, 1.18-1.38) and death (n=4138; adjusted hazard ratio, 1.42; 95% CI, 1.31-1.53). Results were robust across subgroups of patients and after exclusion of events occurring during the first 6 to 12 months. On a continuous scale, the association between hs CRP and outcomes was linear until hs CRP >5 mg/L, plateauing thereafter. Conclusions Most patients with MI exhibit elevated hs CRP levels. Besides identifying populations at high-inflammatory risk, this study extends the prognostic validity of this biomarker from trial evidence to real-world healthcare settings.
Project description:Ischemic strokes presenting with isolated acute vestibular syndrome (AVS) are not rare and still are challenging for diagnosis. In this retrospective study, we aimed to investigate the association of high-sensitivity C-reactive protein (hs-CRP) with stroke in patients with isolated AVS. A total of 217 patients with isolated AVS within 3 days of symptom onset were included. Serum hs-CRP levels were assessed within 24?hours of admission. The relationship between hs-CRP levels and stroke in patients with AVS were analyzed using univariate and multivariate models. The results showed that hs-CRP levels were significantly higher in infarction patients than that in noninfarction group. The stroke occurrence was increased with increasing quartile levels of hs-CRP. The highest quartile level of hs-CRP was associated with a higher occurrence of stroke compared with the lowest quartile group (adjusted odds ratio [OR], 4.099; 95% confidence interval [CI], 1.272-13.216; P?=?.018). We also found that male gender (adjusted OR, 5.635; 95% CI, 2.212-14.352; P?<?.001) and increased low-density lipoprotein cholesterol (LDL-C) (adjusted OR, 2.543; 95% CI, 1.175-5.505; P?=?.018) were independently associated with stroke in patients with AVS. In addition, using the receiver operating characteristic curve analysis, our study yielded a threshold value of hs-CRP at 1.82?mg/L, and demonstrated that combining hs-CRP with LDL-C improved the discriminatory ability to identify stroke patients with AVS (area under the curve of the combined model: 0.753; 95% CI?=?0.684-0.821; P?<?.001). Hs-CRP may be a useful indicator of stroke in patients with AVS. More attention should be paid to the patients with elevated hs-CRP level.
Project description:AIMS:The J-STARS study examined whether pravastatin (10 mg/day) reduces recurrence of stroke in non-cardioembolic ischemic stroke patients who were enrolled within 1 month to 3 years after initial stroke events (ClinicalTrials.gov, NCT00221104). The main results showed that the frequency of atherothrombotic stroke was low in pravastatin-treated patients, although no effect of pravastatin was found for the other stroke subtypes. We evaluated differences of early (within 6 months) or late (after 6 months) pravastatin treatment benefits on the incidence of stroke or transient ischemic attack (TIA), as well as atherothrombotic stroke and the other subtypes. METHODS:Subjects in the J-STARS study were classified into two cohorts, depending on whether they enrolled early (1 to 6 months) or late (6 months to 3 years) following initial stroke events. RESULTS:A total of 1578 patients (491 female, 66.2±8.5 years) were randomly assigned to either the pravastatin group (n=793; n=426 in the early cohort, n=367 in the late cohort) or the control group (n=785; n=417 in the early cohort, n=368 in the late cohort). During the follow-up of 4.9± 1.4 years, the rate of atherothrombotic stroke was lower in the pravastatin group compared to controls in the early cohort (0.24 vs. 0.88%/year, p=0.01) but not in the late cohort (0.17 vs. 0.39%/year, p=0.29). However, this difference of pravastatin effect on atherothrombotic stroke was not significantly interacted by the early or late cohort (p=0.59). The incidence rates of other stroke subtype were not different in between pravastatin and control groups despite the timing of entry. CONCLUSIONS:Pravastatin is likely to reduce atherothrombotic stroke in patients enrolled within 6 months after stroke onset. However, the clinical efficacy for prevention of recurrent stroke was not conclusive with earlier statin treatment.
Project description:In patients with TIA and ischemic stroke, we validated the total small vessel disease (SVD) score by determining its prognostic value for recurrent stroke.Two independent prospective studies were conducted, one comprising predominantly Caucasian patients with TIA/ischemic stroke (Oxford Vascular Study [OXVASC]) and one predominantly Chinese patients with ischemic stroke (University of Hong Kong [HKU]). Cerebral MRI was performed and assessed for lacunes, microbleeds, white matter hyperintensities (WMH), and perivascular spaces (PVS). Predictive value of total SVD score for risk of recurrent stroke was determined and potential refinements considered.In 2,002 patients with TIA/ischemic stroke (OXVASC n = 1,028, HKU n = 974, 6,924 patient-years follow-up), a higher score was associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio [HR] per unit increase: 1.32, 1.16-1.51, p < 0.0001; c statistic 0.61, 0.56-0.65, p < 0.0001) and intracerebral hemorrhage (ICH) (HR 1.54, 1.11-2.13, p = 0.009; c statistic 0.65, 0.54-0.76, p = 0.006). A higher score predicted recurrent stroke in SVD and non-SVD TIA/ischemic stroke subtypes (c statistic 0.67, 0.59-0.74, p < 0.0001 and 0.60, 0.55-0.65, p < 0.0001). Including burden of microbleeds and WMH and adjusting the cutoff of basal ganglia PVS potentially improved predictive power for ICH (c statistic 0.71, 0.60-0.81, phet = 0.45), but not for recurrent ischemic stroke (c statistic 0.60, 0.56-0.65, phet = 0.76) on internal validation.The total SVD score has predictive value for recurrent stroke after TIA/ischemic stroke. Prediction of recurrence in patients with nonlacunar events highlights the potential role of SVD in wider stroke etiology.