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Diabetes mellitus, glucose control parameters and platelet reactivity in ticagrelor treated patients
Thrombosis Research 143 (2016) 45–49
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Diabetes mellitus, glucose control parameters and platelet reactivity in ticagrelor treated patients Matteo Nardin a, Monica Verdoia a, Chiara Sartori a, Patrizia Pergolini b, Roberta Rolla b, Lucia Barbieri a, Alon Schaffer a, Giorgio Bellomo b, Harry Suryapranata c, Giuseppe De Luca a,⁎, on behalf of the Novara Atherosclerosis Study Group (NAS) a b c
Division of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont University, Novara, Italy Clinical Chemistry, Azienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont University, Novara, Italy Department of Cardiology, UMC St Radboud, Nijmegen, The Netherlands
a r t i c l e
i n f o
Article history: Received 24 February 2016 Received in revised form 21 April 2016 Accepted 25 April 2016 Available online 27 April 2016
a b s t r a c t Introduction: Despite the recent advances, prognostic difference between diabetic and non diabetic patients is still marked after an acute coronary syndrome. Diabetes mellitus and poor glycemic control represent well established pro-thrombotic conditions, as inadequate glycemic control can lead to impaired responsiveness to antiplatelet therapies. Among new antiplatelet agents, ticagrelor has provided more potent platelet inhibition, potentially offering benefits in reducing residual high-on treatment platelet reactivity. However, no study has so far investigated the relationship between diabetes mellitus and platelet reactivity in patients treated with ticagrelor after an acute coronary syndrome (ACS). Methods: In patients treated with acetylsalicylic acid (100–160 mg) and ticagrelor (90 mg twice a day) platelet reactivity was assessed at 30–90 days post-discharge for an ACS. Diabetic status was defined before discharge. Multiple-electrode aggregometry was used to assess platelet function. High residual platelet reactivity was defined as ADP-test results N417 AU ∗ min. Results: Diabetes was observed in 86 out of 224 patients (38.4%). Diabetes was significantly associated with older age, higher BMI, renal failure, hypertension, treatment with diuretics, higher levels of WBC, glycaemia, HbA1c, and lower levels of HDL-cholesterol. Platelet reactivity was higher in diabetic patients as compared to nondiabetic ones for all the different activating stimuli tested. A total of 29 patients (12.9%) displayed highresidual platelet reactivity with ticagrelor with an almost double rate in diabetics as compared to nondiabetics (18.8% vs 9.4%, p = 0.06; adjusted OR[95%CI] = 2.12[1.1–4.1], p = 0.025). A progressive increase of platelet reactivity was observed for higher HbA1c levels (r = 0.15, p = 0.029). Conclusion: The present study shows that diabetic patients display higher platelet reactivity despite dual antiplatelet therapy. In fact, diabetes mellitus emerged as independent predictor of high-residual platelet reactivity in post-ACS patients treated with ticagrelor. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction Diabetes mellitus still represents one of the main determinants of cardiovascular risk, accounting for about one third of patients admitted for an acute coronary syndrome (ACS) [1]. Moreover, despite the introduction of new-generation drug eluting stents, new implantation techniques and pharmacological strategies [2–4], diabetes is still associated with an increased rate of thrombotic complications and worse prognosis after percutaneous coronary revascularization (PCI), justifying a more aggressive management [5–7].
⁎ Corresponding author at: Ospedale “Maggiore della Carità”, Eastern Piedmont University, C.so Mazzini, 18, 28100 Novara, Italy. E-mail address: [email protected] (G. De Luca).
http://dx.doi.org/10.1016/j.thromres.2016.04.021 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
Enhanced platelet reactivity and reduced effectiveness of antiplatelet therapies play a central role in increasing the ischemic burden of diabetic patients, and especially among patients with inadequate glycemic control, where hyperglycemia, oxidative stress and enhanced inflammatory response can induce platelet activation. In fact, a higher rate of residual high-on treatment platelet reactivity (HRPR) has been shown in diabetic patients, as compared to non-diabetic patients, during clopidogrel treatment, thus negatively influencing cardiovascular outcomes [8,9]. Newly developed antiplatelet agents, inhibiting platelet P2Y12 receptor, have only partially overcome the phenomenon of impaired effectiveness observed with clopidogrel, providing a more powerful and predictable antiplatelet effect [10,11]. In particular, ticagrelor, a reversible, direct-acting P2Y12 blocker, has demonstrated in the PLATO-trial a reduction in major cardiovascular events among patients with
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diabetes that was consistent with the results in the overall cohort of patients [12,13]. However, a recent meta-analysis has suggested an association between diabetic status and platelet reactivity during ticagrelor maintenance therapy [14]. Therefore, the aim of the current study was to evaluate the relationship between diabetes mellitus, glucose control parameters and platelet reactivity, and the occurrence of HRPR in patients treated with ticagrelor after an acute coronary syndrome (ACS). 2. Methods We included patients admitted for an ACS to the Division of Cardiology, “Maggiore della Carità” Hospital, Eastern Piedmont University in Novara, Italy, from September 2013 to October 2014. Invasive treatment with coronary angiography and eventual coronary stenting was not a required inclusion criteria. All patients receiving at discharge dual antiplatelet therapy with ASA (100 to 160 mg daily) and ticagrelor (90 mg every 12 h) were scheduled for chemistry and platelet function tests evaluation at 30–90 days from discharge. The study was approved by our local Ethical Committee and informed consent was obtained by all patients. Main baseline clinical and angiographic data, together with the indication to dual antiplatelet therapy were recorded at discharge and included in a dedicated database, protected by password. Main cardiovascular risk factors were identified, hypertension was defined as systolic pressure N 140 mm Hg and/or diastolic pressure was N 90 mm Hg or if the individual was taking antihypertensive medications. The diagnosis of diabetes was based on previous history of diabetes treated with or without drug therapies, fasting glucose N126 g/dl or HbA1c N 6.5% at the moment of admission [15]. Compliance was assessed by medical interview. Exclusion criteria were patients' refusal or if the patient had given up ticagrelor therapy. 2.1. Biochemical measurements Blood samples were drawn in the early morning, following a fasting period of 12 h. Glucose, creatinine, glycosylated haemoglobin and lipid profile were determined as previously described [16]. Blood cells count was performed in a blood sample collected in tripotassium EDTA (7.2 mg) tubes. These blood samples were analysed within 2 h of venipuncture by automatic blood cells counter (A Sysmex XE-2100). 2.2. Platelet aggregation Platelet aggregation was determined by Multiplate electrical impedance aggregometry (MEA), within 1–2 h from the morning dose of ticagrelor. The aggregation tests were performed from 30 min to 2 h from blood collection [17]. Platelets aggregation was assessed after stimulation with arachidonic acid (0.5 mM) (ASPI test), collagen (3.2 μg/ml) (COL test), ADP (6.4 μM) with prostaglandin E1 and thrombin receptor activating peptide (TRAP-6; 30 μM). Results were expressed as arbitrary Aggregation Units (AU) and plotted against time, defining platelet function as the area under curve (AUC or AU ∗ min). HRPR for ticagrelor was defined for ADP test above 417 AU ∗ min (normal range: [417–1030]) [18]. The test was repeated in patients with HRPR to confirm the findings. The previously described cut-off value of 468 AU ∗ min was also applied for the definition of HRPR with Ticagrelor [19]. 2.3. Statistical analysis Statistical analysis was performed using SPSS 17.0 statistical package. Patients were grouped according to diabetic status. Continuous data were expressed as mean ± SD and non-numerical binary data as percentage. Analysis of variance and the chi-square test were used for continuous and non-numerical binary variables, respectively.
Linear regression analysis was performed to compare glycemic control parameters and platelet reactivity at ADP-test. Multiple logistic regression analysis was performed to evaluate the relationship between glycemic status and HRPR after correction for baseline differences (all variables displaying a significant association with vitamin D levels at univariate analysis), that were entered in the model in block. Multiple linear regression analysis was conducted to evaluate the relationship between ADP test results and glycemic control (standardized beta coefficient) after correcting for significant continuous variables at univariate analysis. Partial correlation test was also performed for additional cross-validation. A p value b 0.05 was considered statistically significant. 3. Results Our population is represented by a total of 224 patients, including 86 (38.4%) diabetic patients. 3.1. Diabetic status and platelet reactivity Table 1 shows main baseline clinical features according to diabetic status. Diabetic patients were older (p = 0.05), with a higher BMI (p = 0.009), larger prevalence of renal failure (p = 0.016), hypertension (p = 0.02) and were more frequently receiving a chronic therapy with diuretics (p = 0.02). Diabetes mellitus directly related with White Blood Cells Count, glycaemia, HbA1c and HDL-cholesterol (p b 0.001, respectively). Platelet reactivity was higher in diabetic as compared to nondiabetic patients (p = 0.046 for ASPI test, p = 0.013 for COL test, p = 0.04 for TRAP test and p = 0.002 for ADP test, as in Table 1). A total 29 patients (12.9%) out of 224 displayed HRPR (ADP test ≥417 AU ∗ min) in treatment with ticagrelor, with an almost double rate of HRPR patients in the presence of diabetes mellitus, although such a marked absolute difference did not reach statistical significance (18.8% vs 9.4%, p = 0.06, Fig. 1). In fact, at multivariate analysis, after correction for baseline differences (age ≥ 75 years, BMI, renal failure, hypertension, diuretics, White Blood Cells Count, glycaemia, HbA1c and HDL-cholesterol), diabetes emerged as an independent predictor of HRPR with ticagrelor (OR[95%CI] = 2.12[1.1–4.1], p = 0.025). Results are shown in Table 2. At linear regression analysis, as displayed in Fig. 2A, a direct relationship was identified between platelet reactivity at ADP test and HbA1c (r = 0.15, p = 0.029), but not with fasting glycemia (r = 0.08, p = 0.20, Fig. 2B). The association between glycosylated haemoglobin and ADP test results were confirmed by partial regression analysis (beta = 0.142, p = 0.05). 4. Discussion The present study represents one of the largest cohorts of patients treated with Ticagrelor for a recent ACS, where the role of diabetes mellitus (DM) and glycemic control on platelet reactivity were assessed. Our main finding is that diabetes mellitus is independently associated with higher platelet reactivity. In addition, we have observed a significant linear association between HRPR and glycosylated haemoglobin levels, but not with fasting glycaemia. Diabetes mellitus represents a major public health concern, in particular for its progressively increasing prevalence and unfavorable cardiovascular prognosis. In fact, the improvements in the management of ACS and in revascularization strategies have proven largely unsatisfactory among diabetic patients, that still display a far higher risk of long-term mortality and acute ischemic events [20–22] as compared to non diabetics [23–26]. Platelet hyper-reactivity can be held responsible for a relevant part of the thrombotic risk increase among diabetic patients, thus explaining the great efforts accomplished to establish an optimal antiplatelet
M. Nardin et al. / Thrombosis Research 143 (2016) 45–49 Table 1 Baseline clinical characteristics according to diabetic status. Baseline clinical characteristics Age (mean ± SD) Age ≥ 75 years Male sex (%) BMI (mean ± SD) Hypercholesterolemia(%) Renal failure (%) Smokers (%) Active smokers Previous smoker Hypertension (%) History of MI (%) Previous PCI (%) Previous CABG (%) Previous CVA (%) Indication to angiography Unstable angina (%) NSTEMI (%) STEMI (%) Multivessel CAD (%) Concomitant medications ACE inhibitors(%) ARB (%) Beta blockers (%) Nitrates (%) Statins (%) Calcium antagonists (%) Diuretics (%) Biochemistry parameters (mean ± SD) Platelets (103/μl) WBC (103/μl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dL) Tryglicerides (mg/dl) Glycaemia (mg/dL) HbA1c (%) Creatinine (mg/dL) C-reactive protein (mg/dl) Uric acid (mg/dL) COL test (AUC; mean ± SD) ASPI test (AUC; mean ± SD) TRAP test (AUC; mean ± SD) ADP test (AUC; mean ± SD)
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Table 2 Multivariate analysis results of association between main baseline differences and HRPR at ADP-test.
Diabetics n = 86
Non diabetics n = 138
67.19 (±10.91) 31.5 76.7 28.1 (±5.1) 64.7 24.4
64.25 (±11.5) 20.3 78.4 26.36 (±3.91) 58 11.5
28.2 17.6 82.4 22.4 30.6 14.1 8.2
33.8 24.5 67.6 21.7 25.2 7.9 4.2
35.3 38.3 26.4 69.6
32.1 32.4 35.5 60.7
0.27
58.1 22.1 86 45.3 86 26.7 36
63.3 12.2 90.6 38.1 90.6 16.5 21.6
0.48 0.06 0.29 0.33 0.29 0.09 0.02
238.91 (±77.26) 8.93 (±2.36) 37.1 (±9.5) 71.37 (±33.1) 134.87 (±81.74) 155.76 (±54.17) 7.4 (±1.42) 1.033 (±0.477) 0.53 (±0.93) 5.78 (±1.73) 460.92 (±160.24) 369.16 (±190.7) 1183.16 (±289.15) 315.55 (±159.21)
231.38 (±66.33) 7.54 (±2.01) 44 (±12.8) 75.72 (±27.18) 117.4 (±67.36) 101.38 (±13.48) 5.74 (±0.5) 0.981 (±0.572) 0.44 (±0.82) 5.96 (±1.95) 412.04 (±128.36) 318.54 (±178.76) 1099.73 (±296.86) 259.86 (±110.84)
p value 0.059 0.05 0.87 0.009 0.33 0.016 0.08
0.02 1 0.44 0.17 0.25 0.93
0.44 b0.001 b0.001 0.29 0.085 b0.001 b0.001 0.48 0.47 0.48 0.013 0.046 0.04 0.002
CAD = Coronary Artery Disease; MI = Myocardial Infarction; PCI = Percutaneous Coronary Interventions; CABG = Coronary Artery Bypass Graft; ACE = Angiotensin Converting Enzyme; ARB = Angiotensin Receptor Blockers; ASA = Acetylsalicylic Acid; LDL = LowDensity Lipoproteins.
treatment among these patients. Indeed, diabetes mellitus has been clearly demonstrated as a risk factor for HRPR despite dual antiplatelet therapy in the era of Clopidogrel [26–28].
Fig. 1. Bar graphs showing the prevalence of HRPR with ticagrelor at ADP test according to diabetes mellitus diagnosis.
Variable
OR
95% CI
p-Value
Diabetes mellitus HbA1c Age N 75 years Body mass index Hypertension Renal failure Diuretics treatment White blood cells HDL-cholesterol Glycaemia
2.12 1.33 2.93 1.01 3.1 0.28 1.59 1.04 1.02 1
1.1–4.1 1–1.9 1.0–8.2 0.9–1.1 0.64–15 0.1–1.2 0.6–4.5 0.9–1.3 1–1.1 0.98–1.01
0.025 0.09 0.043 0.88 0.16 0.09 0.38 0.68 0.29 0.65
A different scenario was hypothesized with newly developed antiplatelet agents such as prasugrel and ticagrelor, providing a more potent and predictable antiplatelet effect. However, while in the TRITON-TIMI 38 substudy, prasugrel offered greatest advantages for subjects with DM [1], in the PLATO [12], the clinical benefits of ticagrelor did not differ according to diabetic status. Moreover, a recent metaanalysis by Alexopulos et al. including the individual data of 445 patients treated with ticagrelor maintenance dose, stated that diabetes and age N 70 years were inversely associated to higher levels of platelet inhibition [14]. Contrastingly Laine et colleagues reported in 100 diabetic post-ACS patients that ticagrelor achieved a significantly lower platelet reactivity as compared to prasugrel loading dose, and the authors suggested that the potent antiplatelet effect of this drug could potentially overcome the higher platelet reactivity of diabetics [27]. Therefore, in presence of small studies and contrasting data, uncertainty still exists on the impact of DM and glycemic control on platelet function during ticagrelor treatment. In our study we included one of the largest cohorts of post-ACS patients treated with ticagrelor where platelet reactivity was assessed. Diabetic status was independently associated to higher platelet aggregation after adjustment for main confounders, with an almost double rate of HRPR among diabetic patients. DM also related with older age and metabolic disorders, that are known to increase thrombogenicity. However, after correction for all baseline confounders, we confirmed the independent association of diabetes mellitus with HRPR on ticagrelor in post-ACS patients. Moreover, the association between diabetic status and platelet reactivity was pointed up by the evidence of a positive correlation between platelet function and glycosylated haemoglobin, one of the most stable parameters evaluating the glucose control in patients with diabetes [28] [29]. A similar association for glucose control parameters had been previously reported by Singla et al. [30] in diabetic patients with HbA1c ≥ 7 g/dl and additionally, in agreement with our observation, Vivas et al. documented a significant reduction of aggregation in postACS patients receiving intensive glucose control treatment with insulin [31]. Indeed, hyperglycemia can impact on platelet function both directly and by modulating the release of pro-oxidant and inflammatory substances or by the glycation platelet surface proteins, with consequent amplification of platelet adhesion [32]. Unfortunately, all previous studies on glycemic parameters were conducted with clopidogrel, while in our population we firstly observed analogous results during treatment with ticagrelor. Indeed, in the PLATelet inhibition and patient Outcomes (PLATO) substudy focusing on 1036 diabetic patients, ticagrelor similarly reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with or without HbA1c above the median [13]. Nevertheless, present findings could shed new light on the still unsolved issue of high residual platelet reactivity among diabetics, even
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Fig. 2. Linear regressions showing the relationship between platelet reactivity at ADP test and HbA1c (A), and between platelet reactivity at ADP test and fasting glycemia (B).
despite the use of potent agents as ticagrelor. Thus, careful monitoring of these subgroups of patients at elevated cardiovascular risk could be suggested during antiplatelet maintenance therapy. About this topic, controversy still exists on the role and clinical management of HRPR, with the initial trials on tailoring antiplatelet therapy, such as GRAVITAS [33], and ARCTIC [34], providing no impact on outcomes. However, these trials based their definition of HRPR on Verifynow system, while the most recent MADONNA study has demonstrated the benefits of tailored therapy based on platelet reactivity assessment according to Multiple Electrode Analyzer (MEA), as in present study, suggesting its potentially larger utility in the prognostic stratification of patients [35]. However, future large randomized trials are certainly needed to confirm whether a tailored approach can improve the outcome among diabetic patients in the era of new ADP antagonists. 5. Limitations A first limitation can be considered the relatively small sample of our diabetic patients, displaying a numerical discrepancy with the non diabetic cohort, therefore potentially limiting the statistical power of our analysis. In fact, despite the large difference in the prevalence of HRPR, we observed a lack of statistical significance at univariate analysis, whereas significant results were achieved only at multivariate analysis, after the inclusion of several variables that may have caused an overfitting of the data based on our sample size. However, this represents nevertheless one of the largest study so far conducted on diabetes and HRPR in the era of ticagrelor. Moreover, the correlation between platelet reactivity and HbA1c was weak, accounting for only approximately 2% of the variation in platelet reactivity, even if it is statistically significant. However, hypoglycemic treatments and the stricter glycemic control among diabetic patients with a high cardiovascular risk could have conditioned a reduced range of HbA1c values, even though we did not consider glucose tolerance tests or the potential influence of hypoglycemic therapies, and in particular of the most recent oral drugs, whose anti-inflammatory and anti-thrombotic effects could have modulated platelet reactivity [36]. In addition, our results and patients with HRPR were not confirmed by the use of light transmission aggregometry, that still represents the gold standard for platelet aggregation. However, a good correlation between ADP-mediated IPA and ADP-LTA has already been reported [37]. Furthermore, we did not assess the levels of plasmatic Ticagrelor or pharmacokinetics data, however as Ticagrelor is a direct and reversible blocker of the ADP-receptor, we expect that baseline platelet reactivity, rather that pharmacokinetics, could have influenced our results, as suggested from previous studies [38]. Finally, the observational design of the study and the absence of asystematic follow-up of our patients cannot give us the definitely
opportunity to evaluate the impact of ticagrelor non-responsiveness on clinical outcome. Therefore, some caution should be certainly exercised in the interpretation of our results and additional larger studies are certainly needed to further confirm our findings and to assess the role of tailored antiplatelet therapy or dose adjustments in preventing thrombotic complications. 6. Conclusion The present study shows that diabetes mellitus is as independent predictor of high-residual platelet reactivity in post-ACS patients treated with ticagrelor. In addition, a linear association was observed between HRPR and glycosylated haemoglobin levels, a parameter of chronic glycemic control, but not with fasting glycaemia. Declaration of interest The authors report no conflicts of interest. Authors' contribution M Verdoia, MD 1) Conception and design; 2) Data collection; 3) Interpretation of the data; 4) Drafting of the article; 5) Final approval of the manuscript. M Nardin, MD; C Sartori, MD; L Barbieri, MD; A Schaffer, MD; 1) Interpretation of the data; 2) Data Collection; 3) Critical revision of the article for important intellectual content of the article; 4) Final approval of the manuscript. P Pergolini, MD; R Rolla, MD; G Bellomo, MD, PhD 1) Interpretation of the data; 2) Critical revision of the article for important intellectual content of the article; 3) Evaluation of platelet reactivity; 4) Final approval of the manuscript. H Suryapranata, MD, PhD, FACC, FESC; 1) Interpretation of the data; 2) Critical revision of the article for important intellectual content of the article; 3) Final approval of the manuscript. Giuseppe De Luca, MD, PhD 1) Conception and design; 2) Statistical analysis; 3) Interpretation of the data; 4) Drafting of the article; 5) Final approval of the manuscript; 6) Supervision. References [1] S.D. Wiviott, E. Braunwald, D.J. Angiolillo, S. Meisel, A.J. Dalby, F.W.A. Verheugt, et al., Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial I, Circulation 118 (16) (Oct 14, 2008) 1626–1636.
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[21] G. De Luca, M.T. Dirksen, C. Spaulding, H. Kelbæk, M. Schalij, L. Thuesen, et al., Time course, predictors and clinical implications of stent thrombosis following primary angioplasty. Insights from the DESERT cooperation, Thromb. Haemost. 110 (4) (Oct 2013) 826–833. [22] R. Klempfner, A. Elis, S. Matezky, G. Keren, A. Roth, A. Finkelstein, et al., Temporal trends in management and outcome of diabetic and non-diabetic patients with acute coronary syndrome (ACS): residual risk of long-term mortality persists: insights from the ACS Israeli Survey (ACSIS) 2000–2010, Int. J. Cardiol. 179 (Jan 20, 2015) 546–551. [23] C. Godino, D.Z. Parenti, D. Regazzoli, D. Rutigliano, L. Lucisano, G.M. Viani, et al., Oneyear outcome of biolimus eluting stent with biodegradable polymer in all comers: the Italian Nobori stent prospective registry, Int. J. Cardiol. 177 (1) (Nov 15, 2014) 11–16. [24] M.E. Farkouh, M. Domanski, L.A. Sleeper, F.S. Siami, G. Dangas, M. Mack, et al., Strategies for multivessel revascularization in patients with diabetes, N. Engl. J. Med. 367 (25) (Dec 20, 2012) 2375–2384. [25] A. Kapur, R.J. Hall, I.S. Malik, A.C. Qureshi, J. Butts, M. de Belder, et al., Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients. 1-year results of the CARDia (coronary artery revascularization in diabetes) trial, J. Am. Coll. Cardiol. 55 (5) (Feb 2, 2010) 432–440. [26] G. De Luca, M.T. Dirksen, C. Spaulding, H. Kelbæk, M. Schalij, L. Thuesen, et al., Impact of diabetes on long-term outcome after primary angioplasty: insights from the DESERT cooperation, Diabetes Care 36 (4) (Apr 2013) 1020–1025. [27] M. Laine, C. Frère, R. Toesca, J. Berbis, P. Barnay, M. Pansieri, et al., Ticagrelor versus prasugrel in diabetic patients with an acute coronary syndrome. A pharmacodynamic randomised study, Thromb. Haemost. 111 (2) (Feb 2014) 273–278. [28] R.J. Koenig, C.M. Peterson, R.L. Jones, C. Saudek, M. Lehrman, A. Cerami, Correlation of glucose regulation and hemoglobin AIc in diabetes mellitus, N. Engl. J. Med. 295 (8) (Aug 19, 1976) 417–420. [29] M.L. Larsen, M. Hørder, E.F. Mogensen, Effect of long-term monitoring of glycosylated hemoglobin levels in insulin-dependent diabetes mellitus, N. Engl. J. Med. 323 (15) (Oct 11, 1990) 1021–1025. [30] A. Singla, M.J. Antonino, K.P. Bliden, U.S. Tantry, P.A. Gurbel, The relation between platelet reactivity and glycemic control in diabetic patients with cardiovascular disease on maintenance aspirin and clopidogrel therapy, Am Heart J. 158 (5) (Nov 2009) 784.e1–784.e6. [31] D. Vivas, J.C. García-Rubira, E. Bernardo, D.J. Angiolillo, P. Martín, A. Calle-Pascual, et al., Effects of intensive glucose control on platelet reactivity in patients with acute coronary syndromes. Results of the CHIPS study (“Control de Hiperglucemia y Actividad Plaquetaria en Pacientes con Sindrome Coronario Agudo”), Heart 97 (10) (May 2011) 803–809. [32] G. Patti, C. Proscia, G. Di Sciascio, Antiplatelet therapy in patients with diabetes mellitus and acute coronary syndrome, Circ. J. 33–41 (2014). [33] M.J. Price, D.J. Angiolillo, P.S. Teirstein, E. Lillie, S.V. Manoukian, P.B. Berger, et al., Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the gauging responsiveness with a VerifyNow P2Y12 assay: impact on thrombosis and safety (GRAVITAS) trial, Circulation 124 (10) (Sep 6, 2011) 1132–1137. [34] J.-P. Collet, T. Cuisset, G. Rangé, G. Cayla, S. Elhadad, C. Pouillot, et al., Bedside monitoring to adjust antiplatelet therapy for coronary stenting, N. Engl. J. Med. 367 (22) (Nov 29, 2012) 2100–2109. [35] J.M. Siller-Matula, M. Francesconi, C. Dechant, B. Jilma, G. Maurer, G. Delle-Karth, et al., Personalized antiplatelet treatment after percutaneous coronary intervention: the MADONNA study, Int. J. Cardiol. 167 (5) (Sep 1, 2013) 2018–2023. [36] S. Genovese, G. De Berardis, A. Nicolucci, E. Mannucci, V. Evangelista, L. Totani, et al., Effect of pioglitazone versus metformin on cardiovascular risk markers in type 2 diabetes, Adv. Ther. 30 (2) (Feb 2013) 190–202. [37] R. Paniccia, E. Antonucci, N. Maggini, E. Romano, A.M. Gori, R. Marcucci, et al., Assessment of platelet function on whole blood by multiple electrode aggregometry in high-risk patients with coronary artery disease receiving antiplatelet therapy, Am. J. Clin. Pathol. 131 (6) (Jun 2009) 834–842. [38] M.J. Price, L. Clavijo, D.J. Angiolillo, G. Carlson, R. Caplan, R. Teng, et al., A randomised trial of the pharmacodynamic and pharmacokinetic effects of ticagrelor compared with clopidogrel in Hispanic patients with stable coronary artery disease, J. Thromb. Thrombolysis 39 (1) (Jan 2015) 8–14.
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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Diabetes mellitus, glucose control parameters and platelet reactivity in ticagrelor treated patients Matteo Nardin a, Monica Verdoia a, Chiara Sartori a, Patrizia Pergolini b, Roberta Rolla b, Lucia Barbieri a, Alon Schaffer a, Giorgio Bellomo b, Harry Suryapranata c, Giuseppe De Luca a,⁎, on behalf of the Novara Atherosclerosis Study Group (NAS) a b c
Division of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont University, Novara, Italy Clinical Chemistry, Azienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont University, Novara, Italy Department of Cardiology, UMC St Radboud, Nijmegen, The Netherlands
a r t i c l e
i n f o
Article history: Received 24 February 2016 Received in revised form 21 April 2016 Accepted 25 April 2016 Available online 27 April 2016
a b s t r a c t Introduction: Despite the recent advances, prognostic difference between diabetic and non diabetic patients is still marked after an acute coronary syndrome. Diabetes mellitus and poor glycemic control represent well established pro-thrombotic conditions, as inadequate glycemic control can lead to impaired responsiveness to antiplatelet therapies. Among new antiplatelet agents, ticagrelor has provided more potent platelet inhibition, potentially offering benefits in reducing residual high-on treatment platelet reactivity. However, no study has so far investigated the relationship between diabetes mellitus and platelet reactivity in patients treated with ticagrelor after an acute coronary syndrome (ACS). Methods: In patients treated with acetylsalicylic acid (100–160 mg) and ticagrelor (90 mg twice a day) platelet reactivity was assessed at 30–90 days post-discharge for an ACS. Diabetic status was defined before discharge. Multiple-electrode aggregometry was used to assess platelet function. High residual platelet reactivity was defined as ADP-test results N417 AU ∗ min. Results: Diabetes was observed in 86 out of 224 patients (38.4%). Diabetes was significantly associated with older age, higher BMI, renal failure, hypertension, treatment with diuretics, higher levels of WBC, glycaemia, HbA1c, and lower levels of HDL-cholesterol. Platelet reactivity was higher in diabetic patients as compared to nondiabetic ones for all the different activating stimuli tested. A total of 29 patients (12.9%) displayed highresidual platelet reactivity with ticagrelor with an almost double rate in diabetics as compared to nondiabetics (18.8% vs 9.4%, p = 0.06; adjusted OR[95%CI] = 2.12[1.1–4.1], p = 0.025). A progressive increase of platelet reactivity was observed for higher HbA1c levels (r = 0.15, p = 0.029). Conclusion: The present study shows that diabetic patients display higher platelet reactivity despite dual antiplatelet therapy. In fact, diabetes mellitus emerged as independent predictor of high-residual platelet reactivity in post-ACS patients treated with ticagrelor. © 2016 Elsevier Ltd. All rights reserved.
1. Introduction Diabetes mellitus still represents one of the main determinants of cardiovascular risk, accounting for about one third of patients admitted for an acute coronary syndrome (ACS) [1]. Moreover, despite the introduction of new-generation drug eluting stents, new implantation techniques and pharmacological strategies [2–4], diabetes is still associated with an increased rate of thrombotic complications and worse prognosis after percutaneous coronary revascularization (PCI), justifying a more aggressive management [5–7].
⁎ Corresponding author at: Ospedale “Maggiore della Carità”, Eastern Piedmont University, C.so Mazzini, 18, 28100 Novara, Italy. E-mail address: [email protected] (G. De Luca).
http://dx.doi.org/10.1016/j.thromres.2016.04.021 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
Enhanced platelet reactivity and reduced effectiveness of antiplatelet therapies play a central role in increasing the ischemic burden of diabetic patients, and especially among patients with inadequate glycemic control, where hyperglycemia, oxidative stress and enhanced inflammatory response can induce platelet activation. In fact, a higher rate of residual high-on treatment platelet reactivity (HRPR) has been shown in diabetic patients, as compared to non-diabetic patients, during clopidogrel treatment, thus negatively influencing cardiovascular outcomes [8,9]. Newly developed antiplatelet agents, inhibiting platelet P2Y12 receptor, have only partially overcome the phenomenon of impaired effectiveness observed with clopidogrel, providing a more powerful and predictable antiplatelet effect [10,11]. In particular, ticagrelor, a reversible, direct-acting P2Y12 blocker, has demonstrated in the PLATO-trial a reduction in major cardiovascular events among patients with
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diabetes that was consistent with the results in the overall cohort of patients [12,13]. However, a recent meta-analysis has suggested an association between diabetic status and platelet reactivity during ticagrelor maintenance therapy [14]. Therefore, the aim of the current study was to evaluate the relationship between diabetes mellitus, glucose control parameters and platelet reactivity, and the occurrence of HRPR in patients treated with ticagrelor after an acute coronary syndrome (ACS). 2. Methods We included patients admitted for an ACS to the Division of Cardiology, “Maggiore della Carità” Hospital, Eastern Piedmont University in Novara, Italy, from September 2013 to October 2014. Invasive treatment with coronary angiography and eventual coronary stenting was not a required inclusion criteria. All patients receiving at discharge dual antiplatelet therapy with ASA (100 to 160 mg daily) and ticagrelor (90 mg every 12 h) were scheduled for chemistry and platelet function tests evaluation at 30–90 days from discharge. The study was approved by our local Ethical Committee and informed consent was obtained by all patients. Main baseline clinical and angiographic data, together with the indication to dual antiplatelet therapy were recorded at discharge and included in a dedicated database, protected by password. Main cardiovascular risk factors were identified, hypertension was defined as systolic pressure N 140 mm Hg and/or diastolic pressure was N 90 mm Hg or if the individual was taking antihypertensive medications. The diagnosis of diabetes was based on previous history of diabetes treated with or without drug therapies, fasting glucose N126 g/dl or HbA1c N 6.5% at the moment of admission [15]. Compliance was assessed by medical interview. Exclusion criteria were patients' refusal or if the patient had given up ticagrelor therapy. 2.1. Biochemical measurements Blood samples were drawn in the early morning, following a fasting period of 12 h. Glucose, creatinine, glycosylated haemoglobin and lipid profile were determined as previously described [16]. Blood cells count was performed in a blood sample collected in tripotassium EDTA (7.2 mg) tubes. These blood samples were analysed within 2 h of venipuncture by automatic blood cells counter (A Sysmex XE-2100). 2.2. Platelet aggregation Platelet aggregation was determined by Multiplate electrical impedance aggregometry (MEA), within 1–2 h from the morning dose of ticagrelor. The aggregation tests were performed from 30 min to 2 h from blood collection [17]. Platelets aggregation was assessed after stimulation with arachidonic acid (0.5 mM) (ASPI test), collagen (3.2 μg/ml) (COL test), ADP (6.4 μM) with prostaglandin E1 and thrombin receptor activating peptide (TRAP-6; 30 μM). Results were expressed as arbitrary Aggregation Units (AU) and plotted against time, defining platelet function as the area under curve (AUC or AU ∗ min). HRPR for ticagrelor was defined for ADP test above 417 AU ∗ min (normal range: [417–1030]) [18]. The test was repeated in patients with HRPR to confirm the findings. The previously described cut-off value of 468 AU ∗ min was also applied for the definition of HRPR with Ticagrelor [19]. 2.3. Statistical analysis Statistical analysis was performed using SPSS 17.0 statistical package. Patients were grouped according to diabetic status. Continuous data were expressed as mean ± SD and non-numerical binary data as percentage. Analysis of variance and the chi-square test were used for continuous and non-numerical binary variables, respectively.
Linear regression analysis was performed to compare glycemic control parameters and platelet reactivity at ADP-test. Multiple logistic regression analysis was performed to evaluate the relationship between glycemic status and HRPR after correction for baseline differences (all variables displaying a significant association with vitamin D levels at univariate analysis), that were entered in the model in block. Multiple linear regression analysis was conducted to evaluate the relationship between ADP test results and glycemic control (standardized beta coefficient) after correcting for significant continuous variables at univariate analysis. Partial correlation test was also performed for additional cross-validation. A p value b 0.05 was considered statistically significant. 3. Results Our population is represented by a total of 224 patients, including 86 (38.4%) diabetic patients. 3.1. Diabetic status and platelet reactivity Table 1 shows main baseline clinical features according to diabetic status. Diabetic patients were older (p = 0.05), with a higher BMI (p = 0.009), larger prevalence of renal failure (p = 0.016), hypertension (p = 0.02) and were more frequently receiving a chronic therapy with diuretics (p = 0.02). Diabetes mellitus directly related with White Blood Cells Count, glycaemia, HbA1c and HDL-cholesterol (p b 0.001, respectively). Platelet reactivity was higher in diabetic as compared to nondiabetic patients (p = 0.046 for ASPI test, p = 0.013 for COL test, p = 0.04 for TRAP test and p = 0.002 for ADP test, as in Table 1). A total 29 patients (12.9%) out of 224 displayed HRPR (ADP test ≥417 AU ∗ min) in treatment with ticagrelor, with an almost double rate of HRPR patients in the presence of diabetes mellitus, although such a marked absolute difference did not reach statistical significance (18.8% vs 9.4%, p = 0.06, Fig. 1). In fact, at multivariate analysis, after correction for baseline differences (age ≥ 75 years, BMI, renal failure, hypertension, diuretics, White Blood Cells Count, glycaemia, HbA1c and HDL-cholesterol), diabetes emerged as an independent predictor of HRPR with ticagrelor (OR[95%CI] = 2.12[1.1–4.1], p = 0.025). Results are shown in Table 2. At linear regression analysis, as displayed in Fig. 2A, a direct relationship was identified between platelet reactivity at ADP test and HbA1c (r = 0.15, p = 0.029), but not with fasting glycemia (r = 0.08, p = 0.20, Fig. 2B). The association between glycosylated haemoglobin and ADP test results were confirmed by partial regression analysis (beta = 0.142, p = 0.05). 4. Discussion The present study represents one of the largest cohorts of patients treated with Ticagrelor for a recent ACS, where the role of diabetes mellitus (DM) and glycemic control on platelet reactivity were assessed. Our main finding is that diabetes mellitus is independently associated with higher platelet reactivity. In addition, we have observed a significant linear association between HRPR and glycosylated haemoglobin levels, but not with fasting glycaemia. Diabetes mellitus represents a major public health concern, in particular for its progressively increasing prevalence and unfavorable cardiovascular prognosis. In fact, the improvements in the management of ACS and in revascularization strategies have proven largely unsatisfactory among diabetic patients, that still display a far higher risk of long-term mortality and acute ischemic events [20–22] as compared to non diabetics [23–26]. Platelet hyper-reactivity can be held responsible for a relevant part of the thrombotic risk increase among diabetic patients, thus explaining the great efforts accomplished to establish an optimal antiplatelet
M. Nardin et al. / Thrombosis Research 143 (2016) 45–49 Table 1 Baseline clinical characteristics according to diabetic status. Baseline clinical characteristics Age (mean ± SD) Age ≥ 75 years Male sex (%) BMI (mean ± SD) Hypercholesterolemia(%) Renal failure (%) Smokers (%) Active smokers Previous smoker Hypertension (%) History of MI (%) Previous PCI (%) Previous CABG (%) Previous CVA (%) Indication to angiography Unstable angina (%) NSTEMI (%) STEMI (%) Multivessel CAD (%) Concomitant medications ACE inhibitors(%) ARB (%) Beta blockers (%) Nitrates (%) Statins (%) Calcium antagonists (%) Diuretics (%) Biochemistry parameters (mean ± SD) Platelets (103/μl) WBC (103/μl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dL) Tryglicerides (mg/dl) Glycaemia (mg/dL) HbA1c (%) Creatinine (mg/dL) C-reactive protein (mg/dl) Uric acid (mg/dL) COL test (AUC; mean ± SD) ASPI test (AUC; mean ± SD) TRAP test (AUC; mean ± SD) ADP test (AUC; mean ± SD)
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Table 2 Multivariate analysis results of association between main baseline differences and HRPR at ADP-test.
Diabetics n = 86
Non diabetics n = 138
67.19 (±10.91) 31.5 76.7 28.1 (±5.1) 64.7 24.4
64.25 (±11.5) 20.3 78.4 26.36 (±3.91) 58 11.5
28.2 17.6 82.4 22.4 30.6 14.1 8.2
33.8 24.5 67.6 21.7 25.2 7.9 4.2
35.3 38.3 26.4 69.6
32.1 32.4 35.5 60.7
0.27
58.1 22.1 86 45.3 86 26.7 36
63.3 12.2 90.6 38.1 90.6 16.5 21.6
0.48 0.06 0.29 0.33 0.29 0.09 0.02
238.91 (±77.26) 8.93 (±2.36) 37.1 (±9.5) 71.37 (±33.1) 134.87 (±81.74) 155.76 (±54.17) 7.4 (±1.42) 1.033 (±0.477) 0.53 (±0.93) 5.78 (±1.73) 460.92 (±160.24) 369.16 (±190.7) 1183.16 (±289.15) 315.55 (±159.21)
231.38 (±66.33) 7.54 (±2.01) 44 (±12.8) 75.72 (±27.18) 117.4 (±67.36) 101.38 (±13.48) 5.74 (±0.5) 0.981 (±0.572) 0.44 (±0.82) 5.96 (±1.95) 412.04 (±128.36) 318.54 (±178.76) 1099.73 (±296.86) 259.86 (±110.84)
p value 0.059 0.05 0.87 0.009 0.33 0.016 0.08
0.02 1 0.44 0.17 0.25 0.93
0.44 b0.001 b0.001 0.29 0.085 b0.001 b0.001 0.48 0.47 0.48 0.013 0.046 0.04 0.002
CAD = Coronary Artery Disease; MI = Myocardial Infarction; PCI = Percutaneous Coronary Interventions; CABG = Coronary Artery Bypass Graft; ACE = Angiotensin Converting Enzyme; ARB = Angiotensin Receptor Blockers; ASA = Acetylsalicylic Acid; LDL = LowDensity Lipoproteins.
treatment among these patients. Indeed, diabetes mellitus has been clearly demonstrated as a risk factor for HRPR despite dual antiplatelet therapy in the era of Clopidogrel [26–28].
Fig. 1. Bar graphs showing the prevalence of HRPR with ticagrelor at ADP test according to diabetes mellitus diagnosis.
Variable
OR
95% CI
p-Value
Diabetes mellitus HbA1c Age N 75 years Body mass index Hypertension Renal failure Diuretics treatment White blood cells HDL-cholesterol Glycaemia
2.12 1.33 2.93 1.01 3.1 0.28 1.59 1.04 1.02 1
1.1–4.1 1–1.9 1.0–8.2 0.9–1.1 0.64–15 0.1–1.2 0.6–4.5 0.9–1.3 1–1.1 0.98–1.01
0.025 0.09 0.043 0.88 0.16 0.09 0.38 0.68 0.29 0.65
A different scenario was hypothesized with newly developed antiplatelet agents such as prasugrel and ticagrelor, providing a more potent and predictable antiplatelet effect. However, while in the TRITON-TIMI 38 substudy, prasugrel offered greatest advantages for subjects with DM [1], in the PLATO [12], the clinical benefits of ticagrelor did not differ according to diabetic status. Moreover, a recent metaanalysis by Alexopulos et al. including the individual data of 445 patients treated with ticagrelor maintenance dose, stated that diabetes and age N 70 years were inversely associated to higher levels of platelet inhibition [14]. Contrastingly Laine et colleagues reported in 100 diabetic post-ACS patients that ticagrelor achieved a significantly lower platelet reactivity as compared to prasugrel loading dose, and the authors suggested that the potent antiplatelet effect of this drug could potentially overcome the higher platelet reactivity of diabetics [27]. Therefore, in presence of small studies and contrasting data, uncertainty still exists on the impact of DM and glycemic control on platelet function during ticagrelor treatment. In our study we included one of the largest cohorts of post-ACS patients treated with ticagrelor where platelet reactivity was assessed. Diabetic status was independently associated to higher platelet aggregation after adjustment for main confounders, with an almost double rate of HRPR among diabetic patients. DM also related with older age and metabolic disorders, that are known to increase thrombogenicity. However, after correction for all baseline confounders, we confirmed the independent association of diabetes mellitus with HRPR on ticagrelor in post-ACS patients. Moreover, the association between diabetic status and platelet reactivity was pointed up by the evidence of a positive correlation between platelet function and glycosylated haemoglobin, one of the most stable parameters evaluating the glucose control in patients with diabetes [28] [29]. A similar association for glucose control parameters had been previously reported by Singla et al. [30] in diabetic patients with HbA1c ≥ 7 g/dl and additionally, in agreement with our observation, Vivas et al. documented a significant reduction of aggregation in postACS patients receiving intensive glucose control treatment with insulin [31]. Indeed, hyperglycemia can impact on platelet function both directly and by modulating the release of pro-oxidant and inflammatory substances or by the glycation platelet surface proteins, with consequent amplification of platelet adhesion [32]. Unfortunately, all previous studies on glycemic parameters were conducted with clopidogrel, while in our population we firstly observed analogous results during treatment with ticagrelor. Indeed, in the PLATelet inhibition and patient Outcomes (PLATO) substudy focusing on 1036 diabetic patients, ticagrelor similarly reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with or without HbA1c above the median [13]. Nevertheless, present findings could shed new light on the still unsolved issue of high residual platelet reactivity among diabetics, even
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M. Nardin et al. / Thrombosis Research 143 (2016) 45–49
Fig. 2. Linear regressions showing the relationship between platelet reactivity at ADP test and HbA1c (A), and between platelet reactivity at ADP test and fasting glycemia (B).
despite the use of potent agents as ticagrelor. Thus, careful monitoring of these subgroups of patients at elevated cardiovascular risk could be suggested during antiplatelet maintenance therapy. About this topic, controversy still exists on the role and clinical management of HRPR, with the initial trials on tailoring antiplatelet therapy, such as GRAVITAS [33], and ARCTIC [34], providing no impact on outcomes. However, these trials based their definition of HRPR on Verifynow system, while the most recent MADONNA study has demonstrated the benefits of tailored therapy based on platelet reactivity assessment according to Multiple Electrode Analyzer (MEA), as in present study, suggesting its potentially larger utility in the prognostic stratification of patients [35]. However, future large randomized trials are certainly needed to confirm whether a tailored approach can improve the outcome among diabetic patients in the era of new ADP antagonists. 5. Limitations A first limitation can be considered the relatively small sample of our diabetic patients, displaying a numerical discrepancy with the non diabetic cohort, therefore potentially limiting the statistical power of our analysis. In fact, despite the large difference in the prevalence of HRPR, we observed a lack of statistical significance at univariate analysis, whereas significant results were achieved only at multivariate analysis, after the inclusion of several variables that may have caused an overfitting of the data based on our sample size. However, this represents nevertheless one of the largest study so far conducted on diabetes and HRPR in the era of ticagrelor. Moreover, the correlation between platelet reactivity and HbA1c was weak, accounting for only approximately 2% of the variation in platelet reactivity, even if it is statistically significant. However, hypoglycemic treatments and the stricter glycemic control among diabetic patients with a high cardiovascular risk could have conditioned a reduced range of HbA1c values, even though we did not consider glucose tolerance tests or the potential influence of hypoglycemic therapies, and in particular of the most recent oral drugs, whose anti-inflammatory and anti-thrombotic effects could have modulated platelet reactivity [36]. In addition, our results and patients with HRPR were not confirmed by the use of light transmission aggregometry, that still represents the gold standard for platelet aggregation. However, a good correlation between ADP-mediated IPA and ADP-LTA has already been reported [37]. Furthermore, we did not assess the levels of plasmatic Ticagrelor or pharmacokinetics data, however as Ticagrelor is a direct and reversible blocker of the ADP-receptor, we expect that baseline platelet reactivity, rather that pharmacokinetics, could have influenced our results, as suggested from previous studies [38]. Finally, the observational design of the study and the absence of asystematic follow-up of our patients cannot give us the definitely
opportunity to evaluate the impact of ticagrelor non-responsiveness on clinical outcome. Therefore, some caution should be certainly exercised in the interpretation of our results and additional larger studies are certainly needed to further confirm our findings and to assess the role of tailored antiplatelet therapy or dose adjustments in preventing thrombotic complications. 6. Conclusion The present study shows that diabetes mellitus is as independent predictor of high-residual platelet reactivity in post-ACS patients treated with ticagrelor. In addition, a linear association was observed between HRPR and glycosylated haemoglobin levels, a parameter of chronic glycemic control, but not with fasting glycaemia. Declaration of interest The authors report no conflicts of interest. Authors' contribution M Verdoia, MD 1) Conception and design; 2) Data collection; 3) Interpretation of the data; 4) Drafting of the article; 5) Final approval of the manuscript. M Nardin, MD; C Sartori, MD; L Barbieri, MD; A Schaffer, MD; 1) Interpretation of the data; 2) Data Collection; 3) Critical revision of the article for important intellectual content of the article; 4) Final approval of the manuscript. P Pergolini, MD; R Rolla, MD; G Bellomo, MD, PhD 1) Interpretation of the data; 2) Critical revision of the article for important intellectual content of the article; 3) Evaluation of platelet reactivity; 4) Final approval of the manuscript. H Suryapranata, MD, PhD, FACC, FESC; 1) Interpretation of the data; 2) Critical revision of the article for important intellectual content of the article; 3) Final approval of the manuscript. Giuseppe De Luca, MD, PhD 1) Conception and design; 2) Statistical analysis; 3) Interpretation of the data; 4) Drafting of the article; 5) Final approval of the manuscript; 6) Supervision. References [1] S.D. Wiviott, E. Braunwald, D.J. Angiolillo, S. Meisel, A.J. Dalby, F.W.A. Verheugt, et al., Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial I, Circulation 118 (16) (Oct 14, 2008) 1626–1636.
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