- Email: [email protected]
Usefulness of Mean Platelet Volume as a Biomarker for Long-Term Outcomes After Percutaneous Coronary Intervention
Usefulness of Mean Platelet Volume as a Biomarker for Long-Term Outcomes After Percutaneous Coronary Intervention Sandro Cadaval Goncalves, MD, PhDa, Marino Labinaz, MDa, Michel Le May, MDa, Chris Glover, MDa, Michael Froeschl, MDa, Jean-Francois Marquis, MDa, Edward O’Brien, MDa, Dino Shukla, MDa, Peter Ruchin, MBBSb,c, Dharmendra Sookur, MBChB, MDa, Andrew Ha, MDa, and Derek So, MD, MSca,* Larger size platelets have enhanced reactivity. The mean platelet volume (MPV) is a marker of platelet activation and is usually measured as part of blood testing. The aim of the present study was to investigate the utility of the MPV as a biomarker in prognosticating the long-term outcomes after percutaneous coronary intervention (PCI). The baseline MPV values from consecutive patients undergoing PCI were screened. Of the 1,432 patients, the composite primary end point of mortality or myocardial infarction at 1 year occurred in 80 (5.6%). The patients in the highest tertile (MPV >9.1 fL) had an increased frequency of the primary end point compared to those in the mid (8.1 to 9.1 fL) and lowest (<8.1 fL) tertiles (9.0%, 4.5%, and 3.5%, respectively; p <0.01). Logistic regression analysis demonstrated diabetes (odds ratio 2.44, 95% confidence interval 1.48 to 4.00) and highest tertile of MPV (odds ratio 2.42, 95% confidence interval 1.47 to 3.99) as the best predictors of adverse outcomes. In patients with acute coronary syndrome, the preprocedural MPV and troponin levels demonstrated a comparable predictive relation to the primary end point (receiver operator characteristics curve analysis, area under the curve 0.64, p ⴝ 0.01; and 0.63, p ⴝ 0.01, respectively). In conclusion, an elevated MPV was a strong independent predictor of long-term outcomes after PCI. The preprocedural MPV had prognostic value similar to that of troponin in patients with acute coronary syndrome. These findings could be of importance in the clinical evaluation of patients before PCI and the design of future studies assessing antiplatelet therapies. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:204 –209) Large platelets have enhanced reactivity compared with normal-size platelets.1,2 The mean platelet volume (MPV) has been associated with clinical and angiographic outcomes. Patients with a high MPV before balloon angioplasty have been more likely to develop restenosis.3 In patients undergoing primary percutaneous coronary intervention (PCI), a high MPV has been associated with impaired angiographic reperfusion and increased 6-month mortality.4 The predictive value of the MPV for clinical outcomes in undifferentiated patients undergoing PCI has not been investigated in the current era of drug-eluting stents and prolonged dual antiplatelet therapy. Unlike more expensive or time-consuming methods of assessing platelet function,5 the determination of platelet size by quantification of the MPV, using automated hemograms, is simple and inexpensive.6 The biologic rationale linking the MPV to clinical outcomes, along with its universal availability, have made it a promising indirect marker of platelet reactivity in the PCI setting. Our study sought to evaluate the effect of the
a
University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Wagga Wagga Base Hospital, Wagga Wagga, New South Wales, Australia; and cSt. Vincent’s Private Hospital, Sydney, New South Wales, Australia. Manuscript received July 10, 2010; manuscript received and accepted August 24, 2010. *Corresponding author: Tel: (613) 761-5387; fax: (613) 761-4338. E-mail address: [email protected] (D. So). b
0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.08.068
preprocedural MPV level on the long-term clinical outcomes in patients undergoing PCI for a variety of indications. Methods The present analysis was a cohort within the University of Ottawa Heart Institute PCI Registry. The registry has included patients treated at a tertiary cardiac center, with a referral base of 30 peripheral hospitals servicing a population of ⬎1 million. The study cohort included patients who had undergone PCI from December 1, 2003 to November 30, 2004. The patients were identified retrospectively from the registry and then followed prospectively for a 1-year period. The patients referred for elective and urgent PCI procedures, including primary PCI, were screened for the study. The patients were included if a baseline MPV measurement before PCI was available. The patients were excluded from the study if PCI had failed and they had undergone emergent coronary bypass surgery or if death had occurred during the index hospital admission. In the event that patients required more than one PCI during the study period, the entry date was recorded as the date of the index procedure. The study complied with the Declaration of Helsinki, and the Human Research Ethic Review Board of the University of Ottawa Heart Institute approved the study. Trained research nurses collected the data from the PCI reports and hospital charts during the study period. All pre-PCI medication and PCI-related data were documented. www.ajconline.org
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Table 1 Baseline characteristics according to mean platelet volume (MPV) tertile Characteristic
Age (years) Men Diabetes mellitus Current smoker Hypertension Hypercholesterolemia Previous aspirin Acute coronary syndrome History of heart failure Previous myocardial infarction Platelet count (⫻109/L) Hemoglobin (g/L) Creatinine (mol/L)
Total (n ⫽ 1,432)
62.8 ⫾ 11.5 1,043 (72.8%) 399 (27.9%) 228 (15.9%) 862 (60.2%) 1,024 (71.5%) 960 (67.0%) 1,102 (77.0%) 86 (6.0%) 354 (24.7%) 247 ⫾ 74.1 138.2 ⫾ 16.3 100.4 ⫾ 64.1
Tertile
p Value*
Lower (n ⫽ 460)
Mid (n ⫽ 492)
Upper (n ⫽ 480)
62.2 ⫾ 11.7 343 (74.6%) 111 (24.1%) 73 (15.9%) 268 (58.3%) 332 (72.2%) 312 (67.8%) 350 (76.1%) 23 (5.0%) 117 (25.4%) 261 ⫾ 75.4 137.7 ⫾ 17.0 100.3 ⫾ 75.7
62.3 ⫾ 11.2 360 (73.2%) 145 (29.5%) 83 (16.9%) 296 (60.2%) 350 (71.1%) 332 (67.5%) 365 (74.2%) 29 (5.9%) 119 (24.2%) 251 ⫾ 75.0 138.3 ⫾ 16.4 101.5 ⫾ 66.8
63.8 ⫾ 11.7 340 (70.8%) 143 (29.8%) 72 (15.0%) 298 (62.1%) 342 (71.2%) 316 (65.8%) 387 (80.6%) 34 (7.1%) 118 (24.6%) 228 ⫾ 68.0 138.6 ⫾ 15.6 99.4 ⫾ 47.1
0.061 0.428 0.095 0.728 0.489 0.928 0.783 0.051 0.402 0.092 0.001† 0.726 0.879
* Analyses done using chi-square test for categorical data or one-way analysis of variance for continuous data and Tukey’s post hoc test, as appropriate. Intergroup differences with Tukey’s test (p ⬍0.05); difference lies between tertiles 1 and 3 and 2 and 3.
†
The medications and dosages before PCI had been prescribed by the initial treating physician. The choice of stent and periprocedural antithrombotic therapy was at the discretion of the treating interventional cardiologist. A telephone interview was conducted 1 year after the index PCI. If a patient had been rehospitalized for possible cardiac symptoms, the records from the admitting hospital were obtained. For patients who had undergone repeat angiography or revascularization, the procedural reports and inhospital charts were evaluated for the outcomes. Explicit definitions for the data elements had been predetermined. Recurrent myocardial infarction was defined as ischemic symptoms with new or recurrent elevation of ST-segments in ⱖ2 contiguous leads and/or the elevation of cardiac biomarkers to ⬎2 times the upper limit of normal. Stent thrombosis included only angiographically or autopsy-confirmed cases ⱕ1 year after the index PCI procedure (Academic Research Consortium definite).7 Pretreatment with aspirin was defined as taking aspirin ⬎12 hours before PCI. Pretreatment with clopidogrel was defined as a cumulative dosage of the drug of ⱖ300 mg ⬎12 hours before PCI. For all patients, peripheral venous blood samples were used. The MPV measurements were determined from the first available blood sample within the preceding 2 weeks before PCI for elective patients. For nonelective patients, the MPV measurements were obtained from the admission blood work. All samples were obtained in standardized dipotassium ethylenedinitrotetraacetic acid (EDTA) tubes. The measurements were performed using automated hemograms (Bayer Advia 2120, Bayer Diagnostics, Tarrytown, New York). After the determination of the baseline MPV values, the study population was divided into tertiles according to the MPV. The primary outcome was a combined end point of all-cause mortality and nonfatal myocardial infarction at 1 year. For patients with ⬎1 myocardial infarction, only the first event was counted as an end point. Statistical analysis for the study was conducted using the Statistical Package for Social Sciences software, version 16.0 (SPSS, Chicago,
Illinois). The patients were separated into tertiles of MPV. The primary hypothesis, that patients with the highest MPV tertile would have a greater event rate than those in the other tertiles, was tested using a chi-square test and adjusted odds ratio (OR). All p values are reported as 2-tailed, with an accepted significance at ⱕ0.05. The ORs are reported with the 95% confidence intervals (CIs). The patient characteristics among the different tertiles of MPV were compared using the chi-square test. For continuous variables, Student’s t test or one-way analysis of variance and Tukey’s post hoc test was used. A logistic regression model to determine the predictors for the primary outcome was created. The covariates in the model included highest MPV tertile, age, gender, diabetes mellitus, previous myocardial infarction, hypertension, smoking, aspirin therapy, clopidogrel pretreatment, statin therapy, acute coronary syndrome (ACS), history of heart failure, platelet count, and creatinine on admission. Using the highest MPV tertile as the dependent variable, a separate regression analysis was conducted to establish the possible determinants of the MPV. Multiple separate logistic regression models were constructed using these variables to determine the influence of a high MPV in the subgroups of interest. To further delineate the role of MPV as a biomarker in patients with ACS, a receiver operating characteristic (ROC) curve was constructed to analyze the relation between the baseline MPV and death or myocardial infarction at 1 year. The same ROC curves were constructed for the pre-PCI troponin T and creatine kinase levels for patients with ACS. A logistic model using the previous variables, elevated troponin (⬎0.1 g/L), and elevated MPV was created for the patients with ACS. Results During the study period, 1,984 patients underwent PCI procedures. From the original cohort, 1,432 (72.2%) met the inclusion criteria and had MPV values available. The mean age of the cohort was 62.8 ⫾ 11.5 years, with 1,102 patients (77.0%) presenting with ACS. The division by tertile was as
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Table 2 Odds ratios (ORs) for highest tertile of mean platelet volume (MPV) by logistic regression analysis Characteristic Age (years) Male gender Diabetes mellitus Current smoker Hypertension Hypercholesterolemia Acute coronary syndrome History of heart failure Previous myocardial infarction Platelet count (⫻109/L) Hemoglobin (g/L) Creatinine (mol/L) Previous statin use Previous aspirin use Previous clopidogrel use
p Value
OR
95% CI
0.136 0.046 0.299 0.944 0.577 0.707 0.011 0.280 0.691 0.000 0.249 0.755 0.868 0.730 0.001
1.009 0.744 1.149 1.012 1.073 0.951 1.458 1.305 0.946 0.994 1.005 1.000 1.022 1.049 0.632
0.997–1.020 0.557–0.995 0.884–1.492 0.728–1.406 0.838–1.373 0.732–1.236 1.092–1.947 0.805–2.115 0.719–1.245 0.992–0.996 0.997–1.013 0.998–1.002 0.791–1.320 0.798–1.380 0.483–0.827
Figure 2. Incidence of primary end point by subgroup. Each subgroup stratified by upper tertile of MPV (⬎9.1 fL) versus 2 lower tertiles (ⱕ9.1 fL). F ⫽ female; M ⫽ male; DM ⫽ diabetes mellitus; HF ⫽ heart failure.
Figure 3. Adjusted ORs for composite primary end point of death or myocardial infarction by logistic regression analysis. Model variables included those significant on univariate analysis and those with face validity. MI ⫽ myocardial infarction; DM ⫽ diabetes mellitus; ASA ⫽ aspirin.
Figure 1. Incidence of death or myocardial infarction according to tertile of MPV. (A) Entire cohort. (B) Subgroup of patients with diabetes mellitus. (C) Subgroup of patients presenting with ACS.
follows: first tertile, MPV ⬍8.1 fL (n ⫽ 460); second tertile, MPV 8.1 to 9.1 fL (n ⫽ 492); and third tertile, MPV ⬎9.1 fL (n ⫽ 480). The baseline demographics of the study population stratified into MPV tertiles are listed in Table 1. With the exception of an expected inverse association with the platelet count, no significant differences were found for the baseline characteristics among the MPV tertiles. A trend was seen for patients with the highest tertile to be older and more prone to present with ACS. Subgroups stratified by gender, smoking status, hypertension, hypercholesterolemia, a history of heart failure, ACS, and a history of
myocardial infarction did not demonstrate significant differences in the mean MPV values. Logistic regression analysis demonstrated a previous use of clopidogrel to be inversely associated with the highest MPV tertile (OR 0.63, 95% CI 0.48 to 0.83, p ⫽ 0.001; Table 2). At 1 year of follow-up, 80 patients (5.6%) had died or experienced a myocardial infarction. In these patients, the mean baseline MPV was greater than that in those without a primary outcome (9.3 ⫾ 1.5 vs 8.7 ⫾ 1.3 fL, p ⬍0.001). When the 1-year incidence of outcomes was stratified by MPV tertile, the incidence of death or myocardial infarction was significantly more frequent with increasing MPV tertiles (Figure 1). Of the high-risk subgroups of patients with diabetes or ACS, those with the highest MPV tertile had an increased incidence of death and myocardial infarction compared to those with the lower 2 tertiles (Figure 1). The results of the univariate analysis of the primary end point by subgroup of interest are shown in Figure 2. In patients with diabetes, those with an elevated MPV had a threefold increase in the
Coronary Artery Disease/MPV and Outcomes After PCI
Figure 4. Adjusted ORs of highest tertile of MPV for primary end point in several subgroups using logistic regression models. Analysis for each subgroup also adjusted for age, female gender, smoking, hypertension, previous myocardial infarction, heart failure, diabetes, ACS, creatinine, platelet count, previous statin use, previous aspirin use, and previous clopidogrel use. DM ⫽ diabetes mellitus; HF ⫽ heart failure; MI ⫽ myocardial infarction.
Figure 5. ROC curve for MPV, troponin T, and creatine kinase to predict death or myocardial infarction at 1 year after PCI in patients presenting with ACS. AUC ⫽ area under curve; CK ⫽ creatine kinase.
event rate compared to those without an elevated MPV (17.5% vs 5.9%, p ⬍0.001). Patients with diabetes without an elevated MPV had an incidence of events similar to that of nondiabetic patients (5.9% vs 3.9%, respectively, p ⫽ 0.17). Comparable trends were present for patients with ACS versus those with stable angina. A high MPV value on admission (OR 2.42, 95% CI 1.47 to 3.99) and diabetes (OR 2.44, 95% CI 1.48 to 4.00) were the 2 independent variables demonstrating the strongest association with death or myocardial infarction at 1 year (Figure 3). Previous use of clopidogrel did not demonstrate an association with the primary outcome in the logistic regression model. The positive association of a high MPV with death or myocardial infarction at 1 year was consis-
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tently present for several subgroups on multivariate analysis (Figure 4). Stent thrombosis was documented in 9 patients (0.6%) of the entire cohort. No patient with stent thrombosis had the lowest MPV tertile; however, 3 patients in the second tertile and 6 in the highest tertile developed stent thrombosis (p ⫽ 0.05). The ROC curves for baseline MPV, creatine kinase, and troponin to the primary end point are shown in Figure 5. The area under the curve for each of the biomarkers, with the exception of baseline creatine kinase, was similar and predictive of death and myocardial infarction at 1 year. Multivariate analysis of the patients with ACS demonstrated elevated troponin and elevated MPV to be independent predictors of the primary end point (OR 1.95, 95% CI 1.14 to 3.36; and OR 2.48, 95% CI 1.44 to 4.27, respectively). Discussion The results of the present study have demonstrated an independent association between elevated MPV and the 1-year incidence of death or myocardial infarction in a large, unselected cohort of patients undergoing PCI in an era of prolonged dual antiplatelet therapy. A high MPV has been previously observed in patients with a history of smoking, diabetes mellitus, and ACS.8 –10 Among patients with acute myocardial infarction, high MPV values 6 months after infarction have been associated with increased subsequent ischemic events at 2 years.11 In patients undergoing percutaneous transluminal coronary angioplasty, the preprocedural MPV has been demonstrated to correlate with restenosis at 6 months.3 The admission MPV has also been demonstrated to be an independent predictor of impaired angiographic reperfusion and 6-month mortality after myocardial infarction treated with primary PCI.4 To our knowledge, the present study is the first and largest to show an association of elevated MPV with long-term PCI outcomes in the era of routine stenting and long-term dual antiplatelet therapy in undifferentiated patients undergoing PCI. After adjustment for multiple covariates, an elevated MPV remained a strong predictor of subsequent death and myocardial infarction at 1 year. Previously, the platelet count had been linked to mortality after ACS.12,13 The platelet count has also been shown to be inversely related to the MPV.6 In our study, the admission platelet count did not demonstrate an independent predictive value for the clinical outcomes on multivariate analysis when MPV was included in the model. Reticulated platelets, which tend to be larger, are reflective of enhanced turnover.14 Recently, the proportion of reticulated platelets in stable patients receiving dual antiplatelet therapy has been associated with increased adenosine diphosphate-induced reactivity.15 In that study, the regression analysis did not demonstrate MPV to have additive predictive value for the degree of reactivity in the context of a known percentage of reticulated platelets. However, that study had included 90 patients and was not sufficiently powered to determine differences in platelet function using the MPV. Moreover, routine quantification of reticulated platelets using flow cytometry would be expensive and impractical. The association of the MPV with the clinical outcomes in our study complements well with
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previous findings supporting an independent role for larger platelets in adverse outcomes after PCI. Diabetes is a significant risk factor for adverse events after PCI.16 Patients with diabetes have enhanced platelet activation with a greater MPV than those without diabetes.9 It has previously been demonstrated that an increase in MPV is independent of glycemic control or the duration of diabetes.17 Our study confirmed greater average MPV values in patients with diabetes. We also demonstrated a marked increase in the adverse event rates in those with diabetes and a greater MPV. This finding establishes MPV as a powerful biomarker in risk stratification for patients with diabetes undergoing PCI. Additional studies are required to elucidate these potential mechanisms. Early clopidogrel administration before PCI has been shown to diminish postprocedural outcomes.18 Patients pretreated with clopidogrel had a lower MPV in our study. Logistic regression analysis also demonstrated previous treatment with clopidogrel to be inversely associated with a high MPV. A paucity of data is available about the effects of antiplatelet therapy on platelet size.19 In vitro studies have shown aspirin to have no effect on the MPV.20 In contrast, clopidogrel has been demonstrated to prevent increases in platelet size in an in vitro setting.21 The data from our study would suggest a possible role for clopidogrel in the inhibition of increased platelet size and its resulting sequelae. Whether this observation is a consequence of inhibiting platelet activation directly or preventing platelet turnover remains to be investigated. Clopidogrel unresponsiveness has been correlated with long-term ischemic outcomes after PCI.22–24 In our study, a trend was seen toward increased stent thrombosis among patients with the greater MPV tertiles. The role of MPV as a possible surrogate for clopidogrel responsiveness should be explored. The correlation between a high MPV and the long-term clinical outcomes after myocardial infarction has been previously described.5,7 Our data have confirmed this previous finding among patients with ACS who underwent PCI. Troponin is a well-established marker for adverse clinical events after PCI.25–27 In a cohort of patients undergoing PCI, Nageh et al25 demonstrated the baseline troponin level to be predictive of the 6-month major adverse cardiac events with an area under the curve of 0.68. In our study, the relation of troponin to the 1-year outcomes was comparable to the previous ROC analysis.25 In addition, the area under the curve for MPV mirrored the relation found for troponin. The independent predictive value of an elevated MPV from our study further supports the utility of this biomarker in patients with ACS who undergo PCI. Our study had some limitations. Because it was conducted retrospectively, the determination of the MPV was not standardized. Previously, it had been suggested that the MPV increases over time when exposed to EDTA.28,29 The variability in the amount of EDTA has also been hypothesized as a cause for the fluctuation in MPV size.19 However, our study represents the “real world” in which the MPV values are usually collected. In our hospital, standardized EDTA tubes are used for the blood collection for hemogram analysis. Also, the blood work for patients undergoing PCI is prioritized and usually processed within 1 hour of collection. The actual amount of increase in MPV over time has
been demonstrated to be ⬍0.5 fL if the samples have been analyzed within 2 hours of venopuncture.2 Although the MPV was associated with long-term outcomes, we were not able to determine the etiology of the elevated MPV. Quantification of the reticulated platelets or clopidogrel responsiveness could not be conducted because of our study design. Larger mechanistic studies linking MPV to these contributory factors might provide a better understanding of the role of MPV in post-PCI complications. MPV is unique compared to many conventional markers because the measurements can currently be done with automated hemograms.11 The complete blood count is routinely ordered for nearly all patients before PCI. Therefore, the MPV values will be already available for most patients undergoing PCI. Our data, from a large undifferentiated cohort, support the potential clinical utility of this test on a routine basis. 1. Kamath S, Blann AD, Lip GY. Platelet activation: assessment and quantification. Eur Heart J 2001;22:1561–1571. 2. Endler G, Klimesch A, Sunder-Plassmann H, Schillinger M, Exner M, Mannhalter C, Jordanova N, Christ G, Thalhammer R, Huber K, Sunder-Plassmann R. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 2002;117:399 – 404. 3. Yang A, Pizzulli L, Luderitz B. Mean platelet volume as marker of restenosis after percutaneous transluminal coronary angioplasty in patients with stable and unstable angina pectoris. Thromb Res 2006; 117:371–377. 4. Huczek Z, Kochman J, Filipiak KJ, Horszczaruk GJ, Grabowski M, Piatkowski R, Wilczynska J, Zielinski A, Meier B, Opolski G. Mean platelet volume on admission predicts impaired reperfusion and longterm mortality in acute myocardial infarction treated with primary percutaneous coronary intervention. J Am Coll Cardiol 2005;46:284 – 290. 5. Michelson AD. Methods for the measurement of platelet function. Am J Cardiol 2009;103(Suppl):20A–26A. 6. Boos CJ, Lip GY. Assessment of mean platelet volume in coronary artery disease—what does it mean? Thromb Res 2007;120:11–13. 7. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115: 2344 –2351. 8. Kario K, Matsuo T, Nakao K. Cigarette smoking increases the mean platelet volume in elderly patients with risk factors for atherosclerosis. Clin Lab Haematol 1992;14:281–287. 9. Papanas N, Symeonidis G, Maltezos E, Mavridis G, Karavageli E, Vosnakidis T, Lakasas G. Mean platelet volume in patients with type 2 diabetes mellitus. Platelets 2004;15:475– 478. 10. Pizzulli L, Yang A, Martin JF, Luderitz B. Changes in platelet size and count in unstable angina compared to stable angina or non-cardiac chest pain. Eur Heart J 1998;19:80 – 84. 11. Martin JF, Bath PM, Burr ML. Influence of platelet size on outcome after myocardial infarction. Lancet 1991;338:1409 –1411. 12. Mueller C, Neumann FJ, Hochholzer W, Trenk D, Zeller T, Perruchoud AP, Buettner HJ. The impact of platelet count on mortality in unstable angina/non-ST-segment elevation myocardial infarction. Am Heart J 2006;151:1214 –1217. 13. Sjauw KD, van der Horst IC, Nijsten MW, Nieuwland W, Zijlstra F. Value of routine admission laboratory tests to predict thirty-day mortality in patients with acute myocardial infarction. Am J Cardiol 2006;97:1435–1440. 14. Ault KA, Rinder HM, Mitchell J, Carmody MB, Vary CP, Hillman RS. The significance of platelets with increased RNA content (reticulated platelets): a measure of the rate of thrombopoiesis. Am J Clin Pathol 1992;98:637– 646. 15. Guthikonda S, Alviar CL, Vaduganathan M, Arikan M, Tellez A, DeLao T, Granada JF, Dong JF, Kleiman NS, Lev EI. Role of reticulated platelets and platelet size heterogeneity on platelet activity after
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dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease. J Am Coll Cardiol 2008;52:743–749. Champney KP, Veledar E, Klein M, Samady H, Anderson D, Parashar S, Wenger N, Vaccarino V. Sex-specific effects of diabetes on adverse outcomes after percutaneous coronary intervention: trends over time. Am Heart J 2007;153:970 –978. Hekimsoy Z, Payzin B, Ornek T, Kandogan G. Mean platelet volume in type 2 diabetic patients. J Diabetes Complications 2004;18:173– 176. Steinhubl SR, Berger PB, Brennan DM, Topol EJ. Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 2006;47:939 –943. Greisenegger S, Endler G, Hsieh K, Tentschert S, Mannhalter C, Lalouschek W. Is elevated mean platelet volume associated with a worse outcome in patients with acute ischemic cerebrovascular events? Stroke 2004;35:1688 –1691. Jagroop IA, Tsiara S, Mikhailidis DP. Mean platelet volume as an indicator of platelet activation: methodological issues. Platelets 2003; 14:335–336. Jagroop IA, Mikhailidis DP. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 2003;120:169 –170. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312–2317.
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23. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49:1505–1516. 24. Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, Ernst A, Sawhney NS, Schatz RA, Teirstein PS. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-ofcare assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008;29:992–1000. 25. Nageh T, Sherwood RA, Harris BM, Byrne JA, Thomas MR. Cardiac troponin T and I and creatine kinase-MB as markers of myocardial injury and predictors of outcome following percutaneous coronary intervention. Int J Cardiol 2003;92:285–293. 26. Fuchs S, Kornowski R, Mehran R, Lansky AJ, Satler LF, Pichard AD, Kent KM, Clark CE, Stone GW, Leon MB. Prognostic value of cardiac troponin-I levels following catheter-based coronary interventions. Am J Cardiol 2000;85:1077–1082. 27. Simoons ML, van den Brand M, Lincoff M, Harrington R, van der Wieken R, Vahanian A, Rutsch W, Kootstra J, Boersma E, Califf RM, Topol E. Minimal myocardial damage during coronary intervention is associated with impaired outcome. Eur Heart J 1999;20:1112–1119. 28. Bath PM, Butterworth RJ. Platelet size: measurement, physiology and vascular disease. Blood Coagul Fibrinolysis 1996;7:157–161. 29. Boos CJ, Balakrishnan B, Lip GY. The effects of coronary artery disease severity on time-dependent changes in platelet activation indices in stored whole blood. J Thromb Thrombolysis 2008;25:135– 140.
a
University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Wagga Wagga Base Hospital, Wagga Wagga, New South Wales, Australia; and cSt. Vincent’s Private Hospital, Sydney, New South Wales, Australia. Manuscript received July 10, 2010; manuscript received and accepted August 24, 2010. *Corresponding author: Tel: (613) 761-5387; fax: (613) 761-4338. E-mail address: [email protected] (D. So). b
0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.08.068
preprocedural MPV level on the long-term clinical outcomes in patients undergoing PCI for a variety of indications. Methods The present analysis was a cohort within the University of Ottawa Heart Institute PCI Registry. The registry has included patients treated at a tertiary cardiac center, with a referral base of 30 peripheral hospitals servicing a population of ⬎1 million. The study cohort included patients who had undergone PCI from December 1, 2003 to November 30, 2004. The patients were identified retrospectively from the registry and then followed prospectively for a 1-year period. The patients referred for elective and urgent PCI procedures, including primary PCI, were screened for the study. The patients were included if a baseline MPV measurement before PCI was available. The patients were excluded from the study if PCI had failed and they had undergone emergent coronary bypass surgery or if death had occurred during the index hospital admission. In the event that patients required more than one PCI during the study period, the entry date was recorded as the date of the index procedure. The study complied with the Declaration of Helsinki, and the Human Research Ethic Review Board of the University of Ottawa Heart Institute approved the study. Trained research nurses collected the data from the PCI reports and hospital charts during the study period. All pre-PCI medication and PCI-related data were documented. www.ajconline.org
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Table 1 Baseline characteristics according to mean platelet volume (MPV) tertile Characteristic
Age (years) Men Diabetes mellitus Current smoker Hypertension Hypercholesterolemia Previous aspirin Acute coronary syndrome History of heart failure Previous myocardial infarction Platelet count (⫻109/L) Hemoglobin (g/L) Creatinine (mol/L)
Total (n ⫽ 1,432)
62.8 ⫾ 11.5 1,043 (72.8%) 399 (27.9%) 228 (15.9%) 862 (60.2%) 1,024 (71.5%) 960 (67.0%) 1,102 (77.0%) 86 (6.0%) 354 (24.7%) 247 ⫾ 74.1 138.2 ⫾ 16.3 100.4 ⫾ 64.1
Tertile
p Value*
Lower (n ⫽ 460)
Mid (n ⫽ 492)
Upper (n ⫽ 480)
62.2 ⫾ 11.7 343 (74.6%) 111 (24.1%) 73 (15.9%) 268 (58.3%) 332 (72.2%) 312 (67.8%) 350 (76.1%) 23 (5.0%) 117 (25.4%) 261 ⫾ 75.4 137.7 ⫾ 17.0 100.3 ⫾ 75.7
62.3 ⫾ 11.2 360 (73.2%) 145 (29.5%) 83 (16.9%) 296 (60.2%) 350 (71.1%) 332 (67.5%) 365 (74.2%) 29 (5.9%) 119 (24.2%) 251 ⫾ 75.0 138.3 ⫾ 16.4 101.5 ⫾ 66.8
63.8 ⫾ 11.7 340 (70.8%) 143 (29.8%) 72 (15.0%) 298 (62.1%) 342 (71.2%) 316 (65.8%) 387 (80.6%) 34 (7.1%) 118 (24.6%) 228 ⫾ 68.0 138.6 ⫾ 15.6 99.4 ⫾ 47.1
0.061 0.428 0.095 0.728 0.489 0.928 0.783 0.051 0.402 0.092 0.001† 0.726 0.879
* Analyses done using chi-square test for categorical data or one-way analysis of variance for continuous data and Tukey’s post hoc test, as appropriate. Intergroup differences with Tukey’s test (p ⬍0.05); difference lies between tertiles 1 and 3 and 2 and 3.
†
The medications and dosages before PCI had been prescribed by the initial treating physician. The choice of stent and periprocedural antithrombotic therapy was at the discretion of the treating interventional cardiologist. A telephone interview was conducted 1 year after the index PCI. If a patient had been rehospitalized for possible cardiac symptoms, the records from the admitting hospital were obtained. For patients who had undergone repeat angiography or revascularization, the procedural reports and inhospital charts were evaluated for the outcomes. Explicit definitions for the data elements had been predetermined. Recurrent myocardial infarction was defined as ischemic symptoms with new or recurrent elevation of ST-segments in ⱖ2 contiguous leads and/or the elevation of cardiac biomarkers to ⬎2 times the upper limit of normal. Stent thrombosis included only angiographically or autopsy-confirmed cases ⱕ1 year after the index PCI procedure (Academic Research Consortium definite).7 Pretreatment with aspirin was defined as taking aspirin ⬎12 hours before PCI. Pretreatment with clopidogrel was defined as a cumulative dosage of the drug of ⱖ300 mg ⬎12 hours before PCI. For all patients, peripheral venous blood samples were used. The MPV measurements were determined from the first available blood sample within the preceding 2 weeks before PCI for elective patients. For nonelective patients, the MPV measurements were obtained from the admission blood work. All samples were obtained in standardized dipotassium ethylenedinitrotetraacetic acid (EDTA) tubes. The measurements were performed using automated hemograms (Bayer Advia 2120, Bayer Diagnostics, Tarrytown, New York). After the determination of the baseline MPV values, the study population was divided into tertiles according to the MPV. The primary outcome was a combined end point of all-cause mortality and nonfatal myocardial infarction at 1 year. For patients with ⬎1 myocardial infarction, only the first event was counted as an end point. Statistical analysis for the study was conducted using the Statistical Package for Social Sciences software, version 16.0 (SPSS, Chicago,
Illinois). The patients were separated into tertiles of MPV. The primary hypothesis, that patients with the highest MPV tertile would have a greater event rate than those in the other tertiles, was tested using a chi-square test and adjusted odds ratio (OR). All p values are reported as 2-tailed, with an accepted significance at ⱕ0.05. The ORs are reported with the 95% confidence intervals (CIs). The patient characteristics among the different tertiles of MPV were compared using the chi-square test. For continuous variables, Student’s t test or one-way analysis of variance and Tukey’s post hoc test was used. A logistic regression model to determine the predictors for the primary outcome was created. The covariates in the model included highest MPV tertile, age, gender, diabetes mellitus, previous myocardial infarction, hypertension, smoking, aspirin therapy, clopidogrel pretreatment, statin therapy, acute coronary syndrome (ACS), history of heart failure, platelet count, and creatinine on admission. Using the highest MPV tertile as the dependent variable, a separate regression analysis was conducted to establish the possible determinants of the MPV. Multiple separate logistic regression models were constructed using these variables to determine the influence of a high MPV in the subgroups of interest. To further delineate the role of MPV as a biomarker in patients with ACS, a receiver operating characteristic (ROC) curve was constructed to analyze the relation between the baseline MPV and death or myocardial infarction at 1 year. The same ROC curves were constructed for the pre-PCI troponin T and creatine kinase levels for patients with ACS. A logistic model using the previous variables, elevated troponin (⬎0.1 g/L), and elevated MPV was created for the patients with ACS. Results During the study period, 1,984 patients underwent PCI procedures. From the original cohort, 1,432 (72.2%) met the inclusion criteria and had MPV values available. The mean age of the cohort was 62.8 ⫾ 11.5 years, with 1,102 patients (77.0%) presenting with ACS. The division by tertile was as
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Table 2 Odds ratios (ORs) for highest tertile of mean platelet volume (MPV) by logistic regression analysis Characteristic Age (years) Male gender Diabetes mellitus Current smoker Hypertension Hypercholesterolemia Acute coronary syndrome History of heart failure Previous myocardial infarction Platelet count (⫻109/L) Hemoglobin (g/L) Creatinine (mol/L) Previous statin use Previous aspirin use Previous clopidogrel use
p Value
OR
95% CI
0.136 0.046 0.299 0.944 0.577 0.707 0.011 0.280 0.691 0.000 0.249 0.755 0.868 0.730 0.001
1.009 0.744 1.149 1.012 1.073 0.951 1.458 1.305 0.946 0.994 1.005 1.000 1.022 1.049 0.632
0.997–1.020 0.557–0.995 0.884–1.492 0.728–1.406 0.838–1.373 0.732–1.236 1.092–1.947 0.805–2.115 0.719–1.245 0.992–0.996 0.997–1.013 0.998–1.002 0.791–1.320 0.798–1.380 0.483–0.827
Figure 2. Incidence of primary end point by subgroup. Each subgroup stratified by upper tertile of MPV (⬎9.1 fL) versus 2 lower tertiles (ⱕ9.1 fL). F ⫽ female; M ⫽ male; DM ⫽ diabetes mellitus; HF ⫽ heart failure.
Figure 3. Adjusted ORs for composite primary end point of death or myocardial infarction by logistic regression analysis. Model variables included those significant on univariate analysis and those with face validity. MI ⫽ myocardial infarction; DM ⫽ diabetes mellitus; ASA ⫽ aspirin.
Figure 1. Incidence of death or myocardial infarction according to tertile of MPV. (A) Entire cohort. (B) Subgroup of patients with diabetes mellitus. (C) Subgroup of patients presenting with ACS.
follows: first tertile, MPV ⬍8.1 fL (n ⫽ 460); second tertile, MPV 8.1 to 9.1 fL (n ⫽ 492); and third tertile, MPV ⬎9.1 fL (n ⫽ 480). The baseline demographics of the study population stratified into MPV tertiles are listed in Table 1. With the exception of an expected inverse association with the platelet count, no significant differences were found for the baseline characteristics among the MPV tertiles. A trend was seen for patients with the highest tertile to be older and more prone to present with ACS. Subgroups stratified by gender, smoking status, hypertension, hypercholesterolemia, a history of heart failure, ACS, and a history of
myocardial infarction did not demonstrate significant differences in the mean MPV values. Logistic regression analysis demonstrated a previous use of clopidogrel to be inversely associated with the highest MPV tertile (OR 0.63, 95% CI 0.48 to 0.83, p ⫽ 0.001; Table 2). At 1 year of follow-up, 80 patients (5.6%) had died or experienced a myocardial infarction. In these patients, the mean baseline MPV was greater than that in those without a primary outcome (9.3 ⫾ 1.5 vs 8.7 ⫾ 1.3 fL, p ⬍0.001). When the 1-year incidence of outcomes was stratified by MPV tertile, the incidence of death or myocardial infarction was significantly more frequent with increasing MPV tertiles (Figure 1). Of the high-risk subgroups of patients with diabetes or ACS, those with the highest MPV tertile had an increased incidence of death and myocardial infarction compared to those with the lower 2 tertiles (Figure 1). The results of the univariate analysis of the primary end point by subgroup of interest are shown in Figure 2. In patients with diabetes, those with an elevated MPV had a threefold increase in the
Coronary Artery Disease/MPV and Outcomes After PCI
Figure 4. Adjusted ORs of highest tertile of MPV for primary end point in several subgroups using logistic regression models. Analysis for each subgroup also adjusted for age, female gender, smoking, hypertension, previous myocardial infarction, heart failure, diabetes, ACS, creatinine, platelet count, previous statin use, previous aspirin use, and previous clopidogrel use. DM ⫽ diabetes mellitus; HF ⫽ heart failure; MI ⫽ myocardial infarction.
Figure 5. ROC curve for MPV, troponin T, and creatine kinase to predict death or myocardial infarction at 1 year after PCI in patients presenting with ACS. AUC ⫽ area under curve; CK ⫽ creatine kinase.
event rate compared to those without an elevated MPV (17.5% vs 5.9%, p ⬍0.001). Patients with diabetes without an elevated MPV had an incidence of events similar to that of nondiabetic patients (5.9% vs 3.9%, respectively, p ⫽ 0.17). Comparable trends were present for patients with ACS versus those with stable angina. A high MPV value on admission (OR 2.42, 95% CI 1.47 to 3.99) and diabetes (OR 2.44, 95% CI 1.48 to 4.00) were the 2 independent variables demonstrating the strongest association with death or myocardial infarction at 1 year (Figure 3). Previous use of clopidogrel did not demonstrate an association with the primary outcome in the logistic regression model. The positive association of a high MPV with death or myocardial infarction at 1 year was consis-
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tently present for several subgroups on multivariate analysis (Figure 4). Stent thrombosis was documented in 9 patients (0.6%) of the entire cohort. No patient with stent thrombosis had the lowest MPV tertile; however, 3 patients in the second tertile and 6 in the highest tertile developed stent thrombosis (p ⫽ 0.05). The ROC curves for baseline MPV, creatine kinase, and troponin to the primary end point are shown in Figure 5. The area under the curve for each of the biomarkers, with the exception of baseline creatine kinase, was similar and predictive of death and myocardial infarction at 1 year. Multivariate analysis of the patients with ACS demonstrated elevated troponin and elevated MPV to be independent predictors of the primary end point (OR 1.95, 95% CI 1.14 to 3.36; and OR 2.48, 95% CI 1.44 to 4.27, respectively). Discussion The results of the present study have demonstrated an independent association between elevated MPV and the 1-year incidence of death or myocardial infarction in a large, unselected cohort of patients undergoing PCI in an era of prolonged dual antiplatelet therapy. A high MPV has been previously observed in patients with a history of smoking, diabetes mellitus, and ACS.8 –10 Among patients with acute myocardial infarction, high MPV values 6 months after infarction have been associated with increased subsequent ischemic events at 2 years.11 In patients undergoing percutaneous transluminal coronary angioplasty, the preprocedural MPV has been demonstrated to correlate with restenosis at 6 months.3 The admission MPV has also been demonstrated to be an independent predictor of impaired angiographic reperfusion and 6-month mortality after myocardial infarction treated with primary PCI.4 To our knowledge, the present study is the first and largest to show an association of elevated MPV with long-term PCI outcomes in the era of routine stenting and long-term dual antiplatelet therapy in undifferentiated patients undergoing PCI. After adjustment for multiple covariates, an elevated MPV remained a strong predictor of subsequent death and myocardial infarction at 1 year. Previously, the platelet count had been linked to mortality after ACS.12,13 The platelet count has also been shown to be inversely related to the MPV.6 In our study, the admission platelet count did not demonstrate an independent predictive value for the clinical outcomes on multivariate analysis when MPV was included in the model. Reticulated platelets, which tend to be larger, are reflective of enhanced turnover.14 Recently, the proportion of reticulated platelets in stable patients receiving dual antiplatelet therapy has been associated with increased adenosine diphosphate-induced reactivity.15 In that study, the regression analysis did not demonstrate MPV to have additive predictive value for the degree of reactivity in the context of a known percentage of reticulated platelets. However, that study had included 90 patients and was not sufficiently powered to determine differences in platelet function using the MPV. Moreover, routine quantification of reticulated platelets using flow cytometry would be expensive and impractical. The association of the MPV with the clinical outcomes in our study complements well with
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previous findings supporting an independent role for larger platelets in adverse outcomes after PCI. Diabetes is a significant risk factor for adverse events after PCI.16 Patients with diabetes have enhanced platelet activation with a greater MPV than those without diabetes.9 It has previously been demonstrated that an increase in MPV is independent of glycemic control or the duration of diabetes.17 Our study confirmed greater average MPV values in patients with diabetes. We also demonstrated a marked increase in the adverse event rates in those with diabetes and a greater MPV. This finding establishes MPV as a powerful biomarker in risk stratification for patients with diabetes undergoing PCI. Additional studies are required to elucidate these potential mechanisms. Early clopidogrel administration before PCI has been shown to diminish postprocedural outcomes.18 Patients pretreated with clopidogrel had a lower MPV in our study. Logistic regression analysis also demonstrated previous treatment with clopidogrel to be inversely associated with a high MPV. A paucity of data is available about the effects of antiplatelet therapy on platelet size.19 In vitro studies have shown aspirin to have no effect on the MPV.20 In contrast, clopidogrel has been demonstrated to prevent increases in platelet size in an in vitro setting.21 The data from our study would suggest a possible role for clopidogrel in the inhibition of increased platelet size and its resulting sequelae. Whether this observation is a consequence of inhibiting platelet activation directly or preventing platelet turnover remains to be investigated. Clopidogrel unresponsiveness has been correlated with long-term ischemic outcomes after PCI.22–24 In our study, a trend was seen toward increased stent thrombosis among patients with the greater MPV tertiles. The role of MPV as a possible surrogate for clopidogrel responsiveness should be explored. The correlation between a high MPV and the long-term clinical outcomes after myocardial infarction has been previously described.5,7 Our data have confirmed this previous finding among patients with ACS who underwent PCI. Troponin is a well-established marker for adverse clinical events after PCI.25–27 In a cohort of patients undergoing PCI, Nageh et al25 demonstrated the baseline troponin level to be predictive of the 6-month major adverse cardiac events with an area under the curve of 0.68. In our study, the relation of troponin to the 1-year outcomes was comparable to the previous ROC analysis.25 In addition, the area under the curve for MPV mirrored the relation found for troponin. The independent predictive value of an elevated MPV from our study further supports the utility of this biomarker in patients with ACS who undergo PCI. Our study had some limitations. Because it was conducted retrospectively, the determination of the MPV was not standardized. Previously, it had been suggested that the MPV increases over time when exposed to EDTA.28,29 The variability in the amount of EDTA has also been hypothesized as a cause for the fluctuation in MPV size.19 However, our study represents the “real world” in which the MPV values are usually collected. In our hospital, standardized EDTA tubes are used for the blood collection for hemogram analysis. Also, the blood work for patients undergoing PCI is prioritized and usually processed within 1 hour of collection. The actual amount of increase in MPV over time has
been demonstrated to be ⬍0.5 fL if the samples have been analyzed within 2 hours of venopuncture.2 Although the MPV was associated with long-term outcomes, we were not able to determine the etiology of the elevated MPV. Quantification of the reticulated platelets or clopidogrel responsiveness could not be conducted because of our study design. Larger mechanistic studies linking MPV to these contributory factors might provide a better understanding of the role of MPV in post-PCI complications. MPV is unique compared to many conventional markers because the measurements can currently be done with automated hemograms.11 The complete blood count is routinely ordered for nearly all patients before PCI. Therefore, the MPV values will be already available for most patients undergoing PCI. Our data, from a large undifferentiated cohort, support the potential clinical utility of this test on a routine basis. 1. Kamath S, Blann AD, Lip GY. Platelet activation: assessment and quantification. Eur Heart J 2001;22:1561–1571. 2. Endler G, Klimesch A, Sunder-Plassmann H, Schillinger M, Exner M, Mannhalter C, Jordanova N, Christ G, Thalhammer R, Huber K, Sunder-Plassmann R. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 2002;117:399 – 404. 3. Yang A, Pizzulli L, Luderitz B. Mean platelet volume as marker of restenosis after percutaneous transluminal coronary angioplasty in patients with stable and unstable angina pectoris. Thromb Res 2006; 117:371–377. 4. Huczek Z, Kochman J, Filipiak KJ, Horszczaruk GJ, Grabowski M, Piatkowski R, Wilczynska J, Zielinski A, Meier B, Opolski G. Mean platelet volume on admission predicts impaired reperfusion and longterm mortality in acute myocardial infarction treated with primary percutaneous coronary intervention. J Am Coll Cardiol 2005;46:284 – 290. 5. Michelson AD. Methods for the measurement of platelet function. Am J Cardiol 2009;103(Suppl):20A–26A. 6. Boos CJ, Lip GY. Assessment of mean platelet volume in coronary artery disease—what does it mean? Thromb Res 2007;120:11–13. 7. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115: 2344 –2351. 8. Kario K, Matsuo T, Nakao K. Cigarette smoking increases the mean platelet volume in elderly patients with risk factors for atherosclerosis. Clin Lab Haematol 1992;14:281–287. 9. Papanas N, Symeonidis G, Maltezos E, Mavridis G, Karavageli E, Vosnakidis T, Lakasas G. Mean platelet volume in patients with type 2 diabetes mellitus. Platelets 2004;15:475– 478. 10. Pizzulli L, Yang A, Martin JF, Luderitz B. Changes in platelet size and count in unstable angina compared to stable angina or non-cardiac chest pain. Eur Heart J 1998;19:80 – 84. 11. Martin JF, Bath PM, Burr ML. Influence of platelet size on outcome after myocardial infarction. Lancet 1991;338:1409 –1411. 12. Mueller C, Neumann FJ, Hochholzer W, Trenk D, Zeller T, Perruchoud AP, Buettner HJ. The impact of platelet count on mortality in unstable angina/non-ST-segment elevation myocardial infarction. Am Heart J 2006;151:1214 –1217. 13. Sjauw KD, van der Horst IC, Nijsten MW, Nieuwland W, Zijlstra F. Value of routine admission laboratory tests to predict thirty-day mortality in patients with acute myocardial infarction. Am J Cardiol 2006;97:1435–1440. 14. Ault KA, Rinder HM, Mitchell J, Carmody MB, Vary CP, Hillman RS. The significance of platelets with increased RNA content (reticulated platelets): a measure of the rate of thrombopoiesis. Am J Clin Pathol 1992;98:637– 646. 15. Guthikonda S, Alviar CL, Vaduganathan M, Arikan M, Tellez A, DeLao T, Granada JF, Dong JF, Kleiman NS, Lev EI. Role of reticulated platelets and platelet size heterogeneity on platelet activity after
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