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The frequency of aspirin resistance and its risk factors in patients with metabolic syndrome
International Journal of Cardiology 115 (2007) 391 – 396 www.elsevier.com/locate/ijcard
The frequency of aspirin resistance and its risk factors in patients with metabolic syndrome ☆ Goksel Kahraman ⁎, Tayfun Sahin, Teoman Kilic, Nart Zafer Baytugan, Aysen Agacdiken, Ertan Ural, Dilek Ural, Baki Komsuoglu Department of Cardiology, Kocaeli University, School of Medicine, Umuttepe, Yerleskesi, Eski Istanbul Yolu 10. km, 41380 Kocaeli, Turkey Received 1 July 2006; received in revised form 15 September 2006; accepted 21 October 2006 Available online 9 January 2006
Abstract Background: Although different populations were examined for the incidence of aspirin resistance, the frequency and related risk factors for aspirin resistance in patients with metabolic syndrome have not been reported yet. This study aimed to determine the frequency of aspirin resistance and its risk factors in patients with metabolic syndrome. Methods: We performed a cross-sectional study in 110 patients with metabolic syndrome. After one week of 100 mg/day aspirin, blood samples were obtained. Platelet function analyzer (PFA-100™) was used to determine the frequency of aspirin resistance. Endothelial functions, carotid intima media thickness, and the presence of plaques in the carotid arteries were evaluated for subclinical atherosclerosis and the levels of inflammatory markers were assessed as risk factors for aspirin resistance. The presence of subclinical atherosclerosis was defined as a maximum carotid intima media thickness of ≥ 0.9 mm and/or the presence of carotid atheroma. Results: Aspirin resistance was detected in 21.9% of the patients. In the multivariate analysis, hs-CRP levels (odds ratio [95% CI] = 2.8 [1.3– 5.9], p = 0.009), diastolic blood pressure, (0.9 [0.8–1.0], p = 0.007), and the presence of subclinical atherosclerosis (4.1 [1.4–12.2], p = 0.012) were statistically significant risk factors for aspirin resistance. Conclusions: We concluded that the frequency of aspirin resistance confirmed in this cohort of patients with metabolic syndrome was higher in patients with a lower diastolic blood pressure, higher hs-CRP levels and atherosclerotic changes in their carotid arteries. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Aspirin; Drug resistance; Metabolic syndrome; Risk factors
1. Introduction Metabolic syndrome is associated with a relative risk of 1.3 for all-cause mortality and 1.7 for cardiovascular disease in general population [1,2]. Low dose aspirin is recommended by several guidelines as a primary prevention strategy for metabolic syndrome patients with higher risk for cardiovascular events [3–5]. On the other hand, some studies showed that the anti-aggregant effect of aspirin could not be
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This study was supported by a grant from the Scientific Research Foundation of the Kocaeli University (46/2005). ⁎ Corresponding author. Tel.: +90 262 303 8484; fax: +90 262 303 8003. E-mail address: [email protected] (G. Kahraman). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.10.025
the same in all patients and thromboembolic events occurred in some patients who were under therapeutic doses of aspirin [6–9]. The absence of the expected anti-aggregant effect of aspirin is defined as aspirin resistance or aspirin insensitivity or unresponsiveness to aspirin. The incidence of aspirin resistance was reported as 8–45% in the literature [10]. Although different populations were examined for the incidence of aspirin resistance, the frequency and related risk factors for aspirin resistance in patients with metabolic syndrome have not been reported yet. In the present study, we investigated the frequency of aspirin resistance and subclinical inflammatory or non-inflammatory risk factors for this resistance in patients with metabolic syndrome who had no cardiovascular disease.
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2. Materials and methods 2.1. Study design, patients and protocol This was a cross-sectional follow-up study. 110 patients with diagnosis of metabolic syndrome according to the criteria of International Diabetes Federation [11] were included to the study between April 2005 and December 2005. The exclusion criteria were hypersensitivity to aspirin; the use of other non-steroidal anti-inflammatory drugs, ticlodipine, clopidogrel, dipiridamol, heparin or low molecular weight heparin; oral contraceptive agents; established coronary or peripheral arterial disease; platelet count lower than 140,000/ μL or higher than 450,000/μL; hemoglobin level lower than 8 g/dL; the presence of a myeloproliferative disease; the history of individual or familial bleeding diathesis; heparininduced thrombocytopenia; and hepatic or renal insufficiency. Subjects with major atherosclerotic plaques who represent clinical atherosclerosis in carotid arteries were also excluded from the study. All study patients were informed about study and gave written consent before study procedures. Local ethics committee of Kocaeli University Hospital approved the study protocol and informed consent form. This study was conducted in accordance with latest version of Helsinki Declaration. Aspirin with a dose of 100 mg/day was given to patients for one week before conducting the laboratory analysis. 2.2. Laboratory analysis Venous blood samples were taken after one-week treatment period. Aspirin resistance was evaluated with the use of platelet function analyzer (PFA-100™, Dade Behring), which is a semi-automatic analyzer for determining platelet function that reproduces in-vivo conditions [12]. For the analysis, citrated blood was passed through a capillary device, which stimulated in-vivo conditions of shear stress. PFA-100 gave a punctual lecture when blood flow stopped as a result of capillary occlusion which was due to the platelet adhesion and subsequent aggregation to the exposure of platelet agonists that covered the membrane of a disposable cartridge. The final point in which blood flow stopped was defined as the closure time. One-type cartridges which utilized a membrane that was covered with epinephrine were used. Platelet function was altered when collagen/epinephrine closure time was prolonged. However, prolongation of the collagen/epinephrine closure time was observed only with the effect of aspirin. In our laboratory, normal epinephrine closure time ranged between 88 and 186 s. If the collagen/epinephrine closure time was less than 187 s with 2.1% analytical variance, it was interpreted as aspirin resistance or aspirin insensitivity [13]. The following hematological, inflammatory, and biochemical risk factors which could be associated with aspirin resistance and subclinical atherosclerosis were evaluated: serum levels of high sensitive C-reactive protein (hs-CRP),
homocysteine, uric acid, fibrinogen, and microalbuminuria, hemogram, and all other biochemistry measurements. Serum levels of hs-CRP were measured with a rate nephelometric method (IMMAGE® Immunochemistry System, Beckman Coulter, USA). The measurement range in this method was 0.2–1440 mg/L and the reference range was b 7.44 mg/L. Values of hs-CRP ≥ 1.0 mg/dL were accepted as a risk factor for the development or the presence of subclinical atherosclerosis [14]. Homocysteine levels were analysed with chemiluminescent enzyme immumetric assay in Immulite 2000 analyzer. Hemogram, uric acid, fibrinogen, microalbuminuria and all other biochemistry measurements were carried out using standard methods. 2.3. Endothelial function and carotid intima media thickness Endothelial dysfunctions, increased carotid intima media thickness, and the presence of plaques in the carotid arteries were evaluated for subclinical atherosclerosis. All studies were performed using a high-resolution ultrasound system (Toshiba SSA-190A, Japan) equipped with a 7.5 MHz linear array transducer. An experienced cardiologist who was blinded to the laboratory profile of the patients performed the imaging. Flow-mediated and nitroglycerine-induced dilation of the brachial artery were evaluated according to the standard methods [15]. All measurements were performed between 08:00 and 10:00 am following a 10-hour fasting period. Carotid intima media thickness was measured both from the right and the left common carotid arteries. The measurements were performed from the far wall 10 mm proximal to the carotid bifurcation with 2D examination by a semiautomated, quick, safe, and reproducible computer program (M'ATH©). The presence of plaques in the common carotid artery, bifurcation, and internal carotid artery was evaluated in 2D views. Plaque was defined as a focal structure encroaching into at least 0.5 mm of the arterial lumen or 50% of the surrounding intima media or demonstrating a thickness of ≥ 1.5 mm from the media adventitia interface to the intima lumen interface. A carotid intima media thickness ≥ 0.9 mm and the presence of atheromatous plaques were defined as subclinical atherosclerosis [14]. 2.4. Statistical analysis Results were presented as mean ± standard deviation for continuous data or as percentages and numbers for categorical data. Normality tests were performed for all variables. Normally distributed continuous variables were analysed with two-tailed t-test and unequally distributed variables were compared by Mann–Whitney U test. Categorical data and proportions were analysed using χ2 test. Parameters significantly related with the presence of aspirin resistance were determined with binary forward logistic regression analysis. Statistical level of significance was defined as p b 0.05. SPSS-12.0 for Windows statistical software package program was used for statistical analysis.
G. Kahraman et al. / International Journal of Cardiology 115 (2007) 391–396 Table 2 Endothelial function and carotid intima media thickness characteristics
3. Results A total of 110 metabolic syndrome patients (72 females, age range 27–76 years) were included to the study. Aspirin resistance was defined in 24 (21.9%) of study patients. Patients with and without aspirin resistance were similar regarding gender distribution, age, body mass index, systolic blood pressure, and presence of diabetes or hypertension (Table 1). The mean diastolic blood pressure was significantly lower in patients with aspirin resistance ( p = 0.016). Serum hs-CRP and uric acid levels were higher in patients without aspirin resistance ( p = 0.019 and p = 0.05, respectively). The frequency of aspirin resistance was higher in patients with a hs-CRP level ≥ 1.0 mg/dL (56.3%) than in patients with a hs-CRP level b 1.0 mg/dL (16%) ( p = 0.001). Mean carotid intima media thickness was similar in both patients with or without aspirin resistance. On the other
Table 1 Demographic and clinical characteristics of patients Aspirin sensitive Aspirin resistant p (n = 86) (n = 24) Age (y) Female Current smokers Diabetes mellitus Hypertension Waist (cm) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse pressure (mmHg) Hemoglobin (g/dL) Hematocrit (%) Leukocytes (mm3) Platelet count (K × 103 μL) Mean platelet volume (fL) Collagen/epinephrine closure time (s) Fasting blood glucose (mg/dL) HDL cholesterol (mg/dL) Non-HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Total cholesterol/HDL cholesterol ratio Triglycerides (mg/dL) Creatinine (mg/dL) HbA1c (%) Uric acid (mg/dL) Fibrinogen (g/L) hs-CRP (mg/dL) hs-CRP ≥ 1 mg/dL Homocysteine (mmol/L) Microalbuminuria (mg/day)
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53 ± 9 56 (64%) 15 (17%) 39 (45%) 68 (78%) 101 ± 10 31.5 ± 5.1 137 ± 14
56 ± 11 16 (70%) 2 (9%) 8 (35%) 18 (78%) 102 ± 9 31.8 ± 6.2 132 ± 12
0.199 0.964 0.518 0.781 0.950 0.342 0.755 0.500
86 ± 8
82 ± 9
0.016
50 ± 10 13.4 ± 1.4 40.7 ± 3.9 7240 ± 1844 265,941 ± 77,116 9.6 ± 1.3 272 ± 36
55 ± 21 13.3 ± 1.6 40.4 ± 4.7 6862 ± 1563 243,500 ± 51,165 10.2 ± 2.2 139 ± 28
0.304 0.812 0.865 0.490 0.204
122 ± 34
118 ± 27
0.561
44 ± 8 159 ± 42
43 ± 7 155 ± 30
0.844 0.923
123 ± 38 4.7 ± 0.8
128 ± 37 4.79 ± 0.8
0.269 0.923
182 ± 94 0.9 ± 0.2 6.2 ± 1.1 4.5 ± 1.4 3.6 ± 0.7 0.49 ± 0.49 7 (8%) 11.7 ± 5.6 22 ± 36
142 ± 66 1.0 ± 0.4 6.3 ± 1.2 5.4 ± 1.9 3.7 ± 0.7 1.12 ± 1.43 9 (38%) 15.5 ± 9.9 35 ± 52
0.066 0.704 0.758 0.053 0.331 0.012 0.001 0.079 0.343
hs-CRP: high sensitive C-reactive protein.
0.396 b0.0001
Maximum IMT (mm) Maximum IMT ≥ 0.9 mm Carotid atheroma Subclinical atherosclerosis Baseline brachial artery diameter (mm) FMD increase in diameter (mm) FMD mean diameter (mm) FMD (%) NID (%)
Aspirin sensitive (n = 86)
Aspirin resistant (n = 24)
p
0.83 ± 0.11 23 (27%) 24 (28%) 35 (41%) 3.88 ± 0.51
0.89 ± 0.11 11 (46%) 13 (54%) 16 (67%) 3.98 ± 0.39
0.020 0.075 0.026 0.024 0.203
0.48 ± 0.18
0.44 ± 0.17
0.264
4.36 ± 0.51 12.9 ± 4.8 16.1 ± 5.3
4.40 ± 0.35 11.4 ± 5.4 14.1 ± 7.4
0.753 0.163 0.088
FMD: flow-mediated dilation; IMT: intima media thickness; NID: nitroglycerin-mediated dilation; Subclinical atherosclerosis: maximum IMT ≥0.9 mm and/or carotid atheroma.
hand, the number of patients with subclinical atherosclerosis was significantly higher in aspirin resistant group ( p = 0.024) (Table 2). The parameters of endothelial function which were flow-mediated dilation and nitroglycerine-induced dilation were similar in patients with or without aspirin resistance (Table 2). In the multivariate analysis, hs-CRP levels (odds ratio [95% CI] = 2.8 [1.3–5.9], p = 0.009), diastolic blood pressure, (0.9 [0.8–1.0], p = 0.007), and the presence of subclinical atherosclerosis (4.1 [1.4–12.2], p = 0.012) were statistically significant risk factors for aspirin resistance. 4. Discussion Metabolic syndrome is a complex disease, which might be related to progressive coronary and carotid atherosclerosis. Aspirin is recommended as a primary prevention strategy in patients with metabolic syndrome and high risk for cardiovascular events. However, aspirin resistance may emerge as an important problem in these patients who have a tendency for both inflammation and subclinical atherosclerosis. In this study, we demonstrated that the frequency of aspirin resistance was not low in patients with metabolic syndrome (21.9%). This finding suggested that 100 mg/day dose of aspirin might have not been provided its desirable effects in one out of every five patients with metabolic syndrome. The frequency of aspirin resistance in clinical studies might have been affected by the diagnostic method of aspirin resistance and the dose of aspirin studied. Because of the lack of a gold standard method for the diagnosis, different laboratory parameters for the detection of aspirin resistance were used in the previous studies [10]. Gum et al. investigated the effect of different diagnostic methods on the prevalence of aspirin resistance and reported a prevalence of 9.5% with PFA-100 device and 6% with optical platelet aggregation test in stable coronary artery disease patients
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who received 100 mg/day of aspirin [16]. In spite of this difference, the PFA-100 device that was used in this study has also been used in several other studies. The frequency of aspirin resistance detected with PFA-100 method was reported as 9.5–52% in patients with stable coronary artery disease, 10% in patients with peripheral artery disease, and 21.5% in patients with diabetes mellitus [17–19]. The frequency of aspirin resistance in our study group (21.9%) was consistent with those found in these previous studies. Due to the recommendation of low dose aspirin for primary prevention in patients with metabolic syndrome, the dose of aspirin was 100 mg/day in this study. Previous studies on the effects of different doses of aspirin on different populations showed that increasing aspirin dose decreased the frequency of aspirin resistance both in healthy subjects and in patients with stable coronary artery disease [20,21]. Gonzales-Conejero et al. reported that 33.3% of healthy subjects under the treatment of 100 mg/day of aspirin had aspirin resistance according to PFA-100 device and none of the subjects displayed aspirin resistance when the dose was increased up to 500 mg/day [20]. By using Ultegra Rapid PFA-ASA device, Lee et al. found that the efficacy of aspirin in patients with stable coronary artery disease was 68% when aspirin dose was 100 mg or lower, 83.3% when the dose was 150 mg and 100% when the dose was 300 mg [21]. On the other hand, possible effect of aspirin doses on antiaggregation and the frequency of drug resistance was conflicted with Antiplatelet Trialist Collaboration analysis [5]. In this meta-analysis, the comparison of 85, 160–352, and 500–1000 mg/day of aspirin revealed similar efficacy on decreasing vascular events. Literature review of other factors that could be related to aspirin resistance included female gender, age, smoking, hypertension, total and LDL cholesterol levels, diabetes mellitus, increased platelet turnover, use of ibuprofen, obesity, coronary artery disease and exercise [14,16,22–30]. Our study population differed from that of the former studies by the higher number of female patients. However, there was no significant difference regarding gender distribution between patients with or without aspirin resistance. Although our study population was also one decade younger than the patients of previous studies, no significant relation was found between age groups and the frequency of aspirin resistance. An interesting finding of our study was the lower diastolic blood pressure in aspirin resistant patients. Multivariate logistic regression analysis also revealed a relation between low diastolic blood pressure and aspirin resistance. Some previous studies reported a relationship between hypertension and aspirin resistance [21]. However, relation of aspirin resistance to low diastolic blood pressure which suggests increased pulse pressure and arterial stiffness especially in middle age adults have not been defined before. Arterial compliance, which can be affected from both diastolic blood pressure and other factors such as ventricular ejection, geometry of vascular system, heart rate, inflammation of the aorta, and arterial stiffness, is the major determinant of the
pulse pressure. Large randomised trials showed that patients with decreased diastolic blood pressure and related higher pulse pressure had increased risk of cardiovascular events [31,32]. A low diastolic blood pressure and a high pulse pressure as a consequence of both impaired arterial compliance and increased arterial stiffness might also trigger the shear stress and altered platelet functions especially in aspirin resistant patients. Although there was no statistically significant difference in pulse pressure values between patients with and without aspirin resistance, higher values were seen in aspirin resistant patients in our study (55 ± 21 vs. 50 ± 10 mm Hg). These findings suggested that a lower diastolic and a higher pulse pressure might increase the aggregation capacity of platelets by shear stress and this can be another pathway that affects development of aspirin resistance. Although anti-platelet therapy is commonly used for prophylaxis of atherothrombosis and there is growing evidence about the direct link between hs-CRP levels and development of atherothrombotic events, limited studies investigated the role of inflammation especially on individual's response to anti-platelet therapy [33–35]. With the hypothesis that acute inflammation could adversely affect PFA-100 results by elevating Von Willebrand factor levels, Homoncik et al. investigated the relationship between acute experimental systemic inflammation and PFA-100 results in 30 healthy volunteers. They observed a significant decrease of collagen/epinephrine dependent capillary obstruction time in patients whom inflammatory response was obtained. Although they concluded that acute systemic inflammation had a major impact on the results obtained by PFA-100 and might have confounded the interpretation of platelet function, the role of low grade inflammation–defined as a key mechanism for atherothrombosis–on platelet functions and aspirin responsiveness is still undetermined. According to our opinion, their data showed not only the impact of acute inflammation to PFA-100 results but also confirmed the acute effect of systemic inflammatory response to platelet functions and aspirin responsiveness. After this first pilot study, Ziegler et al. investigated the influence of serum hsCRP levels on efficiency of anti-platelet therapy in patients with peripheral arterial occlusive disease and found no difference between patients with and without elevated hsCRP levels regarding PFA-100 results [34]. However, patients who demonstrated a closure time below the cut-off value were excluded from this study. Nevertheless, hs-CRP measurements could be more interesting in those patients because the diminished response to aspirin might have been caused by a triggering effect of systemic inflammation in patients who demonstrated a closure time below the cut-off value [35]. In the present study, we evaluated hs-CRP levels both in patients with a closure time over and below our cutoff values for determining aspirin responsiveness and found a positive relationship between hs-CRP levels and aspirin resistance. This finding was also confirmed by the multivariate analysis results as hs-CRP levels had an odds ratio
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of 2.8 for aspirin resistance. In contrary, Homoncik et al. showed the negative correlation between acute inflammatory stimulus and PFA-100 [33]. Our findings suggested that chronic low grade inflammation may affect aspirin responsiveness and supported the idea that markers of inflammation can be useful for monitoring of individual's response to aspirin [36]. In spite of these interesting findings, the mechanism of development of aspirin response in patients with higher hsCRP levels was unclear in our study. The mechanism might have been the activation of cyclooxygenase-2 (COX-2) pathway, which could have been increased by inflammatory cytokines, endotoxins, and mitogens and has been accused as the most important source of prostaglandins in inflammation and cancer [37]. Induction of COX-2 enzyme might have been led to the production of thromboxane A2 (TxA2) or resulted in the synthesis of prostaglandin H2, which in turn could have been converted to TxA2 in aspirinated platelets, despite inhibition of COX-1. Hence, it was shown that particularly low dose aspirin resistance might appear when expression of COX-2 has increased [17]. High levels of hsCRP in patients unresponsive to aspirin 100 mg/day also suggested that increased aspirin doses might decrease aspirin resistance by decreasing hs-CRP levels. A small-scaled study showed that a significant decrease in hs-CRP levels was provided with the administration of aspirin 300 mg/day, whereas the same effect could not be observed by smaller doses [38,39]. In multivariate analysis, subclinical atherosclerosis defined as the presence of plaques or increased thickness of carotid intima media thickness ≥ 0.9 mm in the carotid arteries was significantly associated with aspirin resistance. It was claimed that increased carotid intima media thickness and/or the presence of atherosclerotic plaques and high levels of hs-CRP were markers of increased risk for future cardiovascular events in patients with metabolic syndrome. For those patients, aspirin may decrease the future risk for cardiovascular events. However, our findings that these markers were also associated with aspirin resistance and metabolic syndrome patients with higher cardiovascular risk had higher frequency of aspirin resistance suggested the importance of awareness of aspirin resistance especially during low dose aspirin administration. This study had some limitations. The frequency of aspirin resistance in patients with metabolic syndrome in this study was valid for the dose of 100 mg/day of aspirin and did not cover the other suggested doses of 150–325 mg/day. Platelet functions were evaluated only by using PFA-100. As it was not a clinical follow-up study, aspirin resistance was defined only biochemically and not clinically. Inflammation as well as further conditions might also have adversely influenced PFA-100 results. In conclusion, the frequency of aspirin resistance was considerably higher in this cohort of metabolic syndrome patients with lower diastolic blood pressure, higher serum hs-CRP levels, and atherosclerotic changes in their carotid
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arteries. These findings suggest that the anti-aggregant effect of low dose aspirin may be decreased or lost in these patients. Further studies which evaluate the possible risk factors for aspirin resistance in patients with metabolic syndrome will provide additional information for preventing future cardiovascular events. Acknowledgment We thank Sarper Erdogan, MD from the Department of Public Health, Kocaeli University School of Medicine, for statistical analysis. References [1] Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005;28:1769–78. [2] Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683–9. [3] U.S. Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med 2002;136:157–60. [4] Prevention of coronary heart disease in clinical practice: recommendations of the second joint task force of European and other societies on coronary prevention. Eur Heart J 1998;19:1434–503. [5] Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. [6] Helgason CM, Bolin KM, Hoff JA, et al. Development of AR in persons with previous ischemic stroke. Stroke 1994;25:2331–6. [7] Vejar M, Fragasso G, Hackett D, et al. Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina. Thromb Haemost 1990;63:163–8. [8] Mueller MR, Salat A, Strangl P, et al. Variable platelet response to lowdose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost 1997;78:1003–7. [9] Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirinresistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002;105:1650–5. [10] Sanderson S, Emery J, Baglin T, Kinmonth AL. Narrative review: AR and its clinical implications. Ann Intern Med 2005;142:370–80. [11] International Diabetes Federation. Worldwide definition of the metabolic syndrome; August 24 2005. Available at: http://www.idf.org/ webdata/docs/IDF_Metasyndrome_definition.pdf. Accessed. [12] Harrison P, Robinson M, Liesner R, et al. The PFA-100: a potential rapid screening tool for the assessment of platelet dysfunction. Clin Lab Haematol 2002;24:225–32. [13] Christiaens L, Macchi L, Herpin D, et al. Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Thromb Res 2003;108:115–9. [14] Guidelines Committee. 2003 European Society of Hypertension– European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–3. [15] Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257–65. [16] Gum PA, Marchant KK, Poggio ED, et al. Profile and prevalence of AR in patients with cardiovascular disease. Am J Cardiol 2001;88:230–5. [17] Poulsen TS, Kristensen SR, Atar D, Mickley H. A critical appraisal of the phenomenon of AR. Cardiology 2005;104:83–91.
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The frequency of aspirin resistance and its risk factors in patients with metabolic syndrome ☆ Goksel Kahraman ⁎, Tayfun Sahin, Teoman Kilic, Nart Zafer Baytugan, Aysen Agacdiken, Ertan Ural, Dilek Ural, Baki Komsuoglu Department of Cardiology, Kocaeli University, School of Medicine, Umuttepe, Yerleskesi, Eski Istanbul Yolu 10. km, 41380 Kocaeli, Turkey Received 1 July 2006; received in revised form 15 September 2006; accepted 21 October 2006 Available online 9 January 2006
Abstract Background: Although different populations were examined for the incidence of aspirin resistance, the frequency and related risk factors for aspirin resistance in patients with metabolic syndrome have not been reported yet. This study aimed to determine the frequency of aspirin resistance and its risk factors in patients with metabolic syndrome. Methods: We performed a cross-sectional study in 110 patients with metabolic syndrome. After one week of 100 mg/day aspirin, blood samples were obtained. Platelet function analyzer (PFA-100™) was used to determine the frequency of aspirin resistance. Endothelial functions, carotid intima media thickness, and the presence of plaques in the carotid arteries were evaluated for subclinical atherosclerosis and the levels of inflammatory markers were assessed as risk factors for aspirin resistance. The presence of subclinical atherosclerosis was defined as a maximum carotid intima media thickness of ≥ 0.9 mm and/or the presence of carotid atheroma. Results: Aspirin resistance was detected in 21.9% of the patients. In the multivariate analysis, hs-CRP levels (odds ratio [95% CI] = 2.8 [1.3– 5.9], p = 0.009), diastolic blood pressure, (0.9 [0.8–1.0], p = 0.007), and the presence of subclinical atherosclerosis (4.1 [1.4–12.2], p = 0.012) were statistically significant risk factors for aspirin resistance. Conclusions: We concluded that the frequency of aspirin resistance confirmed in this cohort of patients with metabolic syndrome was higher in patients with a lower diastolic blood pressure, higher hs-CRP levels and atherosclerotic changes in their carotid arteries. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Aspirin; Drug resistance; Metabolic syndrome; Risk factors
1. Introduction Metabolic syndrome is associated with a relative risk of 1.3 for all-cause mortality and 1.7 for cardiovascular disease in general population [1,2]. Low dose aspirin is recommended by several guidelines as a primary prevention strategy for metabolic syndrome patients with higher risk for cardiovascular events [3–5]. On the other hand, some studies showed that the anti-aggregant effect of aspirin could not be
☆
This study was supported by a grant from the Scientific Research Foundation of the Kocaeli University (46/2005). ⁎ Corresponding author. Tel.: +90 262 303 8484; fax: +90 262 303 8003. E-mail address: [email protected] (G. Kahraman). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.10.025
the same in all patients and thromboembolic events occurred in some patients who were under therapeutic doses of aspirin [6–9]. The absence of the expected anti-aggregant effect of aspirin is defined as aspirin resistance or aspirin insensitivity or unresponsiveness to aspirin. The incidence of aspirin resistance was reported as 8–45% in the literature [10]. Although different populations were examined for the incidence of aspirin resistance, the frequency and related risk factors for aspirin resistance in patients with metabolic syndrome have not been reported yet. In the present study, we investigated the frequency of aspirin resistance and subclinical inflammatory or non-inflammatory risk factors for this resistance in patients with metabolic syndrome who had no cardiovascular disease.
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2. Materials and methods 2.1. Study design, patients and protocol This was a cross-sectional follow-up study. 110 patients with diagnosis of metabolic syndrome according to the criteria of International Diabetes Federation [11] were included to the study between April 2005 and December 2005. The exclusion criteria were hypersensitivity to aspirin; the use of other non-steroidal anti-inflammatory drugs, ticlodipine, clopidogrel, dipiridamol, heparin or low molecular weight heparin; oral contraceptive agents; established coronary or peripheral arterial disease; platelet count lower than 140,000/ μL or higher than 450,000/μL; hemoglobin level lower than 8 g/dL; the presence of a myeloproliferative disease; the history of individual or familial bleeding diathesis; heparininduced thrombocytopenia; and hepatic or renal insufficiency. Subjects with major atherosclerotic plaques who represent clinical atherosclerosis in carotid arteries were also excluded from the study. All study patients were informed about study and gave written consent before study procedures. Local ethics committee of Kocaeli University Hospital approved the study protocol and informed consent form. This study was conducted in accordance with latest version of Helsinki Declaration. Aspirin with a dose of 100 mg/day was given to patients for one week before conducting the laboratory analysis. 2.2. Laboratory analysis Venous blood samples were taken after one-week treatment period. Aspirin resistance was evaluated with the use of platelet function analyzer (PFA-100™, Dade Behring), which is a semi-automatic analyzer for determining platelet function that reproduces in-vivo conditions [12]. For the analysis, citrated blood was passed through a capillary device, which stimulated in-vivo conditions of shear stress. PFA-100 gave a punctual lecture when blood flow stopped as a result of capillary occlusion which was due to the platelet adhesion and subsequent aggregation to the exposure of platelet agonists that covered the membrane of a disposable cartridge. The final point in which blood flow stopped was defined as the closure time. One-type cartridges which utilized a membrane that was covered with epinephrine were used. Platelet function was altered when collagen/epinephrine closure time was prolonged. However, prolongation of the collagen/epinephrine closure time was observed only with the effect of aspirin. In our laboratory, normal epinephrine closure time ranged between 88 and 186 s. If the collagen/epinephrine closure time was less than 187 s with 2.1% analytical variance, it was interpreted as aspirin resistance or aspirin insensitivity [13]. The following hematological, inflammatory, and biochemical risk factors which could be associated with aspirin resistance and subclinical atherosclerosis were evaluated: serum levels of high sensitive C-reactive protein (hs-CRP),
homocysteine, uric acid, fibrinogen, and microalbuminuria, hemogram, and all other biochemistry measurements. Serum levels of hs-CRP were measured with a rate nephelometric method (IMMAGE® Immunochemistry System, Beckman Coulter, USA). The measurement range in this method was 0.2–1440 mg/L and the reference range was b 7.44 mg/L. Values of hs-CRP ≥ 1.0 mg/dL were accepted as a risk factor for the development or the presence of subclinical atherosclerosis [14]. Homocysteine levels were analysed with chemiluminescent enzyme immumetric assay in Immulite 2000 analyzer. Hemogram, uric acid, fibrinogen, microalbuminuria and all other biochemistry measurements were carried out using standard methods. 2.3. Endothelial function and carotid intima media thickness Endothelial dysfunctions, increased carotid intima media thickness, and the presence of plaques in the carotid arteries were evaluated for subclinical atherosclerosis. All studies were performed using a high-resolution ultrasound system (Toshiba SSA-190A, Japan) equipped with a 7.5 MHz linear array transducer. An experienced cardiologist who was blinded to the laboratory profile of the patients performed the imaging. Flow-mediated and nitroglycerine-induced dilation of the brachial artery were evaluated according to the standard methods [15]. All measurements were performed between 08:00 and 10:00 am following a 10-hour fasting period. Carotid intima media thickness was measured both from the right and the left common carotid arteries. The measurements were performed from the far wall 10 mm proximal to the carotid bifurcation with 2D examination by a semiautomated, quick, safe, and reproducible computer program (M'ATH©). The presence of plaques in the common carotid artery, bifurcation, and internal carotid artery was evaluated in 2D views. Plaque was defined as a focal structure encroaching into at least 0.5 mm of the arterial lumen or 50% of the surrounding intima media or demonstrating a thickness of ≥ 1.5 mm from the media adventitia interface to the intima lumen interface. A carotid intima media thickness ≥ 0.9 mm and the presence of atheromatous plaques were defined as subclinical atherosclerosis [14]. 2.4. Statistical analysis Results were presented as mean ± standard deviation for continuous data or as percentages and numbers for categorical data. Normality tests were performed for all variables. Normally distributed continuous variables were analysed with two-tailed t-test and unequally distributed variables were compared by Mann–Whitney U test. Categorical data and proportions were analysed using χ2 test. Parameters significantly related with the presence of aspirin resistance were determined with binary forward logistic regression analysis. Statistical level of significance was defined as p b 0.05. SPSS-12.0 for Windows statistical software package program was used for statistical analysis.
G. Kahraman et al. / International Journal of Cardiology 115 (2007) 391–396 Table 2 Endothelial function and carotid intima media thickness characteristics
3. Results A total of 110 metabolic syndrome patients (72 females, age range 27–76 years) were included to the study. Aspirin resistance was defined in 24 (21.9%) of study patients. Patients with and without aspirin resistance were similar regarding gender distribution, age, body mass index, systolic blood pressure, and presence of diabetes or hypertension (Table 1). The mean diastolic blood pressure was significantly lower in patients with aspirin resistance ( p = 0.016). Serum hs-CRP and uric acid levels were higher in patients without aspirin resistance ( p = 0.019 and p = 0.05, respectively). The frequency of aspirin resistance was higher in patients with a hs-CRP level ≥ 1.0 mg/dL (56.3%) than in patients with a hs-CRP level b 1.0 mg/dL (16%) ( p = 0.001). Mean carotid intima media thickness was similar in both patients with or without aspirin resistance. On the other
Table 1 Demographic and clinical characteristics of patients Aspirin sensitive Aspirin resistant p (n = 86) (n = 24) Age (y) Female Current smokers Diabetes mellitus Hypertension Waist (cm) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse pressure (mmHg) Hemoglobin (g/dL) Hematocrit (%) Leukocytes (mm3) Platelet count (K × 103 μL) Mean platelet volume (fL) Collagen/epinephrine closure time (s) Fasting blood glucose (mg/dL) HDL cholesterol (mg/dL) Non-HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Total cholesterol/HDL cholesterol ratio Triglycerides (mg/dL) Creatinine (mg/dL) HbA1c (%) Uric acid (mg/dL) Fibrinogen (g/L) hs-CRP (mg/dL) hs-CRP ≥ 1 mg/dL Homocysteine (mmol/L) Microalbuminuria (mg/day)
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53 ± 9 56 (64%) 15 (17%) 39 (45%) 68 (78%) 101 ± 10 31.5 ± 5.1 137 ± 14
56 ± 11 16 (70%) 2 (9%) 8 (35%) 18 (78%) 102 ± 9 31.8 ± 6.2 132 ± 12
0.199 0.964 0.518 0.781 0.950 0.342 0.755 0.500
86 ± 8
82 ± 9
0.016
50 ± 10 13.4 ± 1.4 40.7 ± 3.9 7240 ± 1844 265,941 ± 77,116 9.6 ± 1.3 272 ± 36
55 ± 21 13.3 ± 1.6 40.4 ± 4.7 6862 ± 1563 243,500 ± 51,165 10.2 ± 2.2 139 ± 28
0.304 0.812 0.865 0.490 0.204
122 ± 34
118 ± 27
0.561
44 ± 8 159 ± 42
43 ± 7 155 ± 30
0.844 0.923
123 ± 38 4.7 ± 0.8
128 ± 37 4.79 ± 0.8
0.269 0.923
182 ± 94 0.9 ± 0.2 6.2 ± 1.1 4.5 ± 1.4 3.6 ± 0.7 0.49 ± 0.49 7 (8%) 11.7 ± 5.6 22 ± 36
142 ± 66 1.0 ± 0.4 6.3 ± 1.2 5.4 ± 1.9 3.7 ± 0.7 1.12 ± 1.43 9 (38%) 15.5 ± 9.9 35 ± 52
0.066 0.704 0.758 0.053 0.331 0.012 0.001 0.079 0.343
hs-CRP: high sensitive C-reactive protein.
0.396 b0.0001
Maximum IMT (mm) Maximum IMT ≥ 0.9 mm Carotid atheroma Subclinical atherosclerosis Baseline brachial artery diameter (mm) FMD increase in diameter (mm) FMD mean diameter (mm) FMD (%) NID (%)
Aspirin sensitive (n = 86)
Aspirin resistant (n = 24)
p
0.83 ± 0.11 23 (27%) 24 (28%) 35 (41%) 3.88 ± 0.51
0.89 ± 0.11 11 (46%) 13 (54%) 16 (67%) 3.98 ± 0.39
0.020 0.075 0.026 0.024 0.203
0.48 ± 0.18
0.44 ± 0.17
0.264
4.36 ± 0.51 12.9 ± 4.8 16.1 ± 5.3
4.40 ± 0.35 11.4 ± 5.4 14.1 ± 7.4
0.753 0.163 0.088
FMD: flow-mediated dilation; IMT: intima media thickness; NID: nitroglycerin-mediated dilation; Subclinical atherosclerosis: maximum IMT ≥0.9 mm and/or carotid atheroma.
hand, the number of patients with subclinical atherosclerosis was significantly higher in aspirin resistant group ( p = 0.024) (Table 2). The parameters of endothelial function which were flow-mediated dilation and nitroglycerine-induced dilation were similar in patients with or without aspirin resistance (Table 2). In the multivariate analysis, hs-CRP levels (odds ratio [95% CI] = 2.8 [1.3–5.9], p = 0.009), diastolic blood pressure, (0.9 [0.8–1.0], p = 0.007), and the presence of subclinical atherosclerosis (4.1 [1.4–12.2], p = 0.012) were statistically significant risk factors for aspirin resistance. 4. Discussion Metabolic syndrome is a complex disease, which might be related to progressive coronary and carotid atherosclerosis. Aspirin is recommended as a primary prevention strategy in patients with metabolic syndrome and high risk for cardiovascular events. However, aspirin resistance may emerge as an important problem in these patients who have a tendency for both inflammation and subclinical atherosclerosis. In this study, we demonstrated that the frequency of aspirin resistance was not low in patients with metabolic syndrome (21.9%). This finding suggested that 100 mg/day dose of aspirin might have not been provided its desirable effects in one out of every five patients with metabolic syndrome. The frequency of aspirin resistance in clinical studies might have been affected by the diagnostic method of aspirin resistance and the dose of aspirin studied. Because of the lack of a gold standard method for the diagnosis, different laboratory parameters for the detection of aspirin resistance were used in the previous studies [10]. Gum et al. investigated the effect of different diagnostic methods on the prevalence of aspirin resistance and reported a prevalence of 9.5% with PFA-100 device and 6% with optical platelet aggregation test in stable coronary artery disease patients
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who received 100 mg/day of aspirin [16]. In spite of this difference, the PFA-100 device that was used in this study has also been used in several other studies. The frequency of aspirin resistance detected with PFA-100 method was reported as 9.5–52% in patients with stable coronary artery disease, 10% in patients with peripheral artery disease, and 21.5% in patients with diabetes mellitus [17–19]. The frequency of aspirin resistance in our study group (21.9%) was consistent with those found in these previous studies. Due to the recommendation of low dose aspirin for primary prevention in patients with metabolic syndrome, the dose of aspirin was 100 mg/day in this study. Previous studies on the effects of different doses of aspirin on different populations showed that increasing aspirin dose decreased the frequency of aspirin resistance both in healthy subjects and in patients with stable coronary artery disease [20,21]. Gonzales-Conejero et al. reported that 33.3% of healthy subjects under the treatment of 100 mg/day of aspirin had aspirin resistance according to PFA-100 device and none of the subjects displayed aspirin resistance when the dose was increased up to 500 mg/day [20]. By using Ultegra Rapid PFA-ASA device, Lee et al. found that the efficacy of aspirin in patients with stable coronary artery disease was 68% when aspirin dose was 100 mg or lower, 83.3% when the dose was 150 mg and 100% when the dose was 300 mg [21]. On the other hand, possible effect of aspirin doses on antiaggregation and the frequency of drug resistance was conflicted with Antiplatelet Trialist Collaboration analysis [5]. In this meta-analysis, the comparison of 85, 160–352, and 500–1000 mg/day of aspirin revealed similar efficacy on decreasing vascular events. Literature review of other factors that could be related to aspirin resistance included female gender, age, smoking, hypertension, total and LDL cholesterol levels, diabetes mellitus, increased platelet turnover, use of ibuprofen, obesity, coronary artery disease and exercise [14,16,22–30]. Our study population differed from that of the former studies by the higher number of female patients. However, there was no significant difference regarding gender distribution between patients with or without aspirin resistance. Although our study population was also one decade younger than the patients of previous studies, no significant relation was found between age groups and the frequency of aspirin resistance. An interesting finding of our study was the lower diastolic blood pressure in aspirin resistant patients. Multivariate logistic regression analysis also revealed a relation between low diastolic blood pressure and aspirin resistance. Some previous studies reported a relationship between hypertension and aspirin resistance [21]. However, relation of aspirin resistance to low diastolic blood pressure which suggests increased pulse pressure and arterial stiffness especially in middle age adults have not been defined before. Arterial compliance, which can be affected from both diastolic blood pressure and other factors such as ventricular ejection, geometry of vascular system, heart rate, inflammation of the aorta, and arterial stiffness, is the major determinant of the
pulse pressure. Large randomised trials showed that patients with decreased diastolic blood pressure and related higher pulse pressure had increased risk of cardiovascular events [31,32]. A low diastolic blood pressure and a high pulse pressure as a consequence of both impaired arterial compliance and increased arterial stiffness might also trigger the shear stress and altered platelet functions especially in aspirin resistant patients. Although there was no statistically significant difference in pulse pressure values between patients with and without aspirin resistance, higher values were seen in aspirin resistant patients in our study (55 ± 21 vs. 50 ± 10 mm Hg). These findings suggested that a lower diastolic and a higher pulse pressure might increase the aggregation capacity of platelets by shear stress and this can be another pathway that affects development of aspirin resistance. Although anti-platelet therapy is commonly used for prophylaxis of atherothrombosis and there is growing evidence about the direct link between hs-CRP levels and development of atherothrombotic events, limited studies investigated the role of inflammation especially on individual's response to anti-platelet therapy [33–35]. With the hypothesis that acute inflammation could adversely affect PFA-100 results by elevating Von Willebrand factor levels, Homoncik et al. investigated the relationship between acute experimental systemic inflammation and PFA-100 results in 30 healthy volunteers. They observed a significant decrease of collagen/epinephrine dependent capillary obstruction time in patients whom inflammatory response was obtained. Although they concluded that acute systemic inflammation had a major impact on the results obtained by PFA-100 and might have confounded the interpretation of platelet function, the role of low grade inflammation–defined as a key mechanism for atherothrombosis–on platelet functions and aspirin responsiveness is still undetermined. According to our opinion, their data showed not only the impact of acute inflammation to PFA-100 results but also confirmed the acute effect of systemic inflammatory response to platelet functions and aspirin responsiveness. After this first pilot study, Ziegler et al. investigated the influence of serum hsCRP levels on efficiency of anti-platelet therapy in patients with peripheral arterial occlusive disease and found no difference between patients with and without elevated hsCRP levels regarding PFA-100 results [34]. However, patients who demonstrated a closure time below the cut-off value were excluded from this study. Nevertheless, hs-CRP measurements could be more interesting in those patients because the diminished response to aspirin might have been caused by a triggering effect of systemic inflammation in patients who demonstrated a closure time below the cut-off value [35]. In the present study, we evaluated hs-CRP levels both in patients with a closure time over and below our cutoff values for determining aspirin responsiveness and found a positive relationship between hs-CRP levels and aspirin resistance. This finding was also confirmed by the multivariate analysis results as hs-CRP levels had an odds ratio
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of 2.8 for aspirin resistance. In contrary, Homoncik et al. showed the negative correlation between acute inflammatory stimulus and PFA-100 [33]. Our findings suggested that chronic low grade inflammation may affect aspirin responsiveness and supported the idea that markers of inflammation can be useful for monitoring of individual's response to aspirin [36]. In spite of these interesting findings, the mechanism of development of aspirin response in patients with higher hsCRP levels was unclear in our study. The mechanism might have been the activation of cyclooxygenase-2 (COX-2) pathway, which could have been increased by inflammatory cytokines, endotoxins, and mitogens and has been accused as the most important source of prostaglandins in inflammation and cancer [37]. Induction of COX-2 enzyme might have been led to the production of thromboxane A2 (TxA2) or resulted in the synthesis of prostaglandin H2, which in turn could have been converted to TxA2 in aspirinated platelets, despite inhibition of COX-1. Hence, it was shown that particularly low dose aspirin resistance might appear when expression of COX-2 has increased [17]. High levels of hsCRP in patients unresponsive to aspirin 100 mg/day also suggested that increased aspirin doses might decrease aspirin resistance by decreasing hs-CRP levels. A small-scaled study showed that a significant decrease in hs-CRP levels was provided with the administration of aspirin 300 mg/day, whereas the same effect could not be observed by smaller doses [38,39]. In multivariate analysis, subclinical atherosclerosis defined as the presence of plaques or increased thickness of carotid intima media thickness ≥ 0.9 mm in the carotid arteries was significantly associated with aspirin resistance. It was claimed that increased carotid intima media thickness and/or the presence of atherosclerotic plaques and high levels of hs-CRP were markers of increased risk for future cardiovascular events in patients with metabolic syndrome. For those patients, aspirin may decrease the future risk for cardiovascular events. However, our findings that these markers were also associated with aspirin resistance and metabolic syndrome patients with higher cardiovascular risk had higher frequency of aspirin resistance suggested the importance of awareness of aspirin resistance especially during low dose aspirin administration. This study had some limitations. The frequency of aspirin resistance in patients with metabolic syndrome in this study was valid for the dose of 100 mg/day of aspirin and did not cover the other suggested doses of 150–325 mg/day. Platelet functions were evaluated only by using PFA-100. As it was not a clinical follow-up study, aspirin resistance was defined only biochemically and not clinically. Inflammation as well as further conditions might also have adversely influenced PFA-100 results. In conclusion, the frequency of aspirin resistance was considerably higher in this cohort of metabolic syndrome patients with lower diastolic blood pressure, higher serum hs-CRP levels, and atherosclerotic changes in their carotid
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arteries. These findings suggest that the anti-aggregant effect of low dose aspirin may be decreased or lost in these patients. Further studies which evaluate the possible risk factors for aspirin resistance in patients with metabolic syndrome will provide additional information for preventing future cardiovascular events. Acknowledgment We thank Sarper Erdogan, MD from the Department of Public Health, Kocaeli University School of Medicine, for statistical analysis. References [1] Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005;28:1769–78. [2] Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683–9. [3] U.S. Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med 2002;136:157–60. [4] Prevention of coronary heart disease in clinical practice: recommendations of the second joint task force of European and other societies on coronary prevention. Eur Heart J 1998;19:1434–503. [5] Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. [6] Helgason CM, Bolin KM, Hoff JA, et al. Development of AR in persons with previous ischemic stroke. Stroke 1994;25:2331–6. [7] Vejar M, Fragasso G, Hackett D, et al. Dissociation of platelet activation and spontaneous myocardial ischemia in unstable angina. Thromb Haemost 1990;63:163–8. [8] Mueller MR, Salat A, Strangl P, et al. Variable platelet response to lowdose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost 1997;78:1003–7. [9] Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirinresistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002;105:1650–5. [10] Sanderson S, Emery J, Baglin T, Kinmonth AL. Narrative review: AR and its clinical implications. Ann Intern Med 2005;142:370–80. [11] International Diabetes Federation. Worldwide definition of the metabolic syndrome; August 24 2005. Available at: http://www.idf.org/ webdata/docs/IDF_Metasyndrome_definition.pdf. Accessed. [12] Harrison P, Robinson M, Liesner R, et al. The PFA-100: a potential rapid screening tool for the assessment of platelet dysfunction. Clin Lab Haematol 2002;24:225–32. [13] Christiaens L, Macchi L, Herpin D, et al. Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Thromb Res 2003;108:115–9. [14] Guidelines Committee. 2003 European Society of Hypertension– European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–3. [15] Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257–65. [16] Gum PA, Marchant KK, Poggio ED, et al. Profile and prevalence of AR in patients with cardiovascular disease. Am J Cardiol 2001;88:230–5. [17] Poulsen TS, Kristensen SR, Atar D, Mickley H. A critical appraisal of the phenomenon of AR. Cardiology 2005;104:83–91.
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