Platelet reactivity is not associated with recurrent cardiovascular events in men with a history of myocardial infarction: a cohort study

10:Bonten TN, Snoep JD, Roest M, Rosendaal FR, van der Bom JG. Platelet reactivity is not associated with recurrent cardiovascular events in men with a history of myocardial infarction: a cohort study. J Thromb Haemost 2012; 2616–8. Bonten TN, Snoep JD, Roest M, Rosendaal FR, van der Bom JG. Platelet reactivity is not associated with recurrent cardiovascular events in men with a history of myocardial infarction: a cohort study. J Thromb Haemost 2012; 2616–8. Cardiovascular disease is one of the leading causes of morbidity and mortality worldwide. In spite of improvements in secondary prevention over the past decades 20–40% of patients develop a recurrent event [1Roger V.L. Go A.S. Lloyd‐Jones D.M. Adams R.J. Berry J.D. Brown T.M. Carnethon M.R. Dai S. de Simone G. Ford E.S. Fox C.S. Fullerton H.J. Gillespie C. Greenlund K.J. Hailpern S.M. Heit J.A. Ho P.M. Howard V.J. Kissela B.M. Kittner S.J. et al.Heart disease and stroke statistics 2011 update.Circulation. 2011; 123: e18-209Crossref PubMed Scopus (0) Google Scholar]. Platelets are key players in the development of arterial thrombosis. Consequently, a cornerstone of secondary prevention comprises the inhibition of platelets [2Vandvik P.O. Lincoff A.M. Gore J.M. Gutterman D.D. Sonnenberg F.A. Alonso‐Coello P. Akl E.A. Lansberg M.G. Guyatt G.H. Spencer F.A. Primary and secondary prevention of cardiovascular disease.Chest. 2012; 141: e637S-68SAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Smith S.C. Allen J. Blair S.N. Bonow R.O. Brass L.M. Fonarow G.C. Grundy S.M. Hiratzka L. Jones D. Krumholz H.M. Mosca L. Pasternak R.C. Pearson T. Pfeffer M.A. Taubert K.A. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update.Circulation. 2006; 113: 2363-72Crossref PubMed Scopus (1535) Google Scholar]. According to international guidelines, classic risk factors are aggressively treated after a first cardiovascular event. Yet, other biological mechanisms may play a role in developing a recurrent event. Platelet characteristics, such as increased basal reactivity, have been proposed to be one of those mechanisms. At the occurrence of arterial thrombosis, platelets are activated and release granule contents into the vasculature, including chemokines which interact with other blood cells and the endothelium [4von Hundelshausen P. Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease.Circ Res. 2007; 100: 27-40Crossref PubMed Scopus (567) Google Scholar, 5Weber C. Platelets and chemokines in atherosclerosis: partners in crime.Circ Res. 2005; 96: 612-6Crossref PubMed Scopus (0) Google Scholar]. Three of these chemokines are NAP‐2 (neutrophil‐activating peptide‐2), which is an activation product of CXCL7 (CXC chemokine ligand 7, also known as precursor of beta‐thromboglobulin), CXCL4 (CXC chemokine ligand 4, also known as platelet factor 4) and RANTES (regulated on activation, normal T cell expressed and secreted), which modulates monocytes involved in the progression of atherosclerotic plaques [6von Hundelshausen P. Weber K.S.C. Huo Y. Proudfoot A.E.I. Nelson P.J. Ley K. Weber C. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium.Circulation. 2001; 103: 1772-7Crossref PubMed Google Scholar]. We measured NAP‐2, CXCL‐4 and RANTES because these markers were studied previously in relation to cardiovascular disease and serve as a marker of basal platelet activity [6von Hundelshausen P. Weber K.S.C. Huo Y. Proudfoot A.E.I. Nelson P.J. Ley K. Weber C. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium.Circulation. 2001; 103: 1772-7Crossref PubMed Google Scholar, 7Deuel T.F. Senior R.M. Chang D. Griffin G.L. Heinrikson R.L. Kaiser E.T. Platelet factor 4 is chemotactic for neutrophils and monocytes.Proc Natl Acad Sci U S A. 1981; 78: 4584-7Crossref PubMed Scopus (322) Google Scholar, 8Lane D.A. Ireland H. Wolff S. Ranasinghe E. Dawes J. Detection of enhanced in vivo platelet alpha‐granule release in different patient groups – comparison of beta‐thromboglobulin, platelet factor 4 and thrombospondin assays.Thromb Haemost. 1984; 52: 183-7Crossref PubMed Scopus (0) Google Scholar, 9Nassar T. Sachais B.S. Akkawi S. Kowalska M.A. Bdeir K. Leitersdorf E. Hiss E. Ziporen L. Aviram M. Cines D. Poncz M. Higazi A.A. 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High platelet reactivity is associated with myocardial infarction in premenopausal women: a population‐based case‐control study.J Thromb Haemost. 2010; 8: 906-13Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 13Cavusoglu E. Eng C. Chopra V. Clark L.T. Pinsky D.J. Marmur J.D. Low plasma RANTES levels are an independent predictor of cardiac mortality in patients referred for coronary angiography.Arterioscler Thromb Vasc Biol. 2007; 27: 929-35Crossref PubMed Scopus (0) Google Scholar, 14Smith C. Damås J.K. Otterdal K. Øie E. Sandberg W.J. Yndestad A. Waehre T. Scholz H. Endresen K. Olofsson P.S. Halvorsen B. Gullestad L. Frøland S.S. Hansson G.K. Aukrust P. Increased levels of neutrophil‐activating peptide‐2 in acute coronary syndromes: possible role of platelet‐mediated vascular inflammation.J Am Coll Cardiol. 2006; 48: 1591-9Crossref PubMed Scopus (0) Google Scholar, 15Sobel M. Salzman E.W. Davies G.C. Handin R.I. Sweeney J. Ploetz J. Kurland G. Circulating platelet products in unstable angina pectoris.Circulation. 1981; 63: 300-6Crossref PubMed Google Scholar, 16Taomoto K. Asada M. Kanazawa Y. Matsumoto S. Usefulness of the measurement of plasma beta‐thromboglobulin (beta‐TG) in cerebrovascular disease.Stroke. 1983; 14: 518-24Crossref PubMed Google Scholar, 17Rasi V. Ikkala E. Torstila I. Plasma thromboglobulin in acute myocardial infarction.Thromb Res. 1982; 25: 203-12Abstract Full Text PDF PubMed Google Scholar]. We hypothesized that increased basal activity of these platelet markers increase the risk of a recurrent cardiovascular event. In the present study, we studied the association between plasma concentrations of NAP‐2, CXCL4 and RANTES and the incidence of recurrent cardiovascular events in men with a history of a myocardial infarction (MI). A cohort study was performed among men who experienced a first MI between 1990 and 1996. Details of the study have been reported previously [18van der Krabben M.D. Rosendaal F.R. van der Bom J.G. Doggen C.J.M. Polymorphisms in coagulation factors and the risk of recurrent cardiovascular events in men after a first myocardial infarction.J Thromb Haemost. 2008; 6: 720-5Crossref PubMed Scopus (0) Google Scholar]. In short, patients were followed until 1st September 2004 to assess the occurrence of recurrent major arterial cardiovascular events (rMACE). Follow‐up information was collected from hospital files, general practitioners and patient questionnaires. The study was approved by the local ethics committee and all patients gave written informed consent. A blood sample was collected from each patient after the first event to determine levels of platelet markers (NAP‐2, CXCL4 and RANTES) using semi‐automated ELISA as described previously [12Snoep J.D. Roest M. Barendrecht A.D. De Groot P.G. Rosendaal F.R. van der Bom J.G. High platelet reactivity is associated with myocardial infarction in premenopausal women: a population‐based case‐control study.J Thromb Haemost. 2010; 8: 906-13Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19van Bladel E.R. Roest M. De Groot P.G. Schutgens R.E. Up‐regulation of platelet activation in hemophilia A.Haematologica. 2011; 96: 888-95Crossref PubMed Scopus (27) Google Scholar]. High levels of platelet reactivity were defined as levels above the 90th percentile. Continuous data are summarized as medians with interquartile range (IQR) and categorical data are presented as counts and percentages. Cox’s proportional hazard models were used to estimate hazard ratios for the occurrence of rMACE according to different concentrations of the platelet markers. Hazard ratios were adjusted for putative confounding factors in the relation between the platelet reactivity markers and rMACE. Sensitivity analyzes using continuous variables and different cut‐off points were performed. A total of 542 men were included in the cohort who experienced a first MI at a median age of 57 years (IQR 49–64), and for whom the median follow‐up time was 9.2 years (IQR 2.7–11.4). During follow‐up, 254 (47%) men developed at least one rMACE. The median time between first MI and blood sampling was 2.6 years (range 0.2–6 years), which did not differ between the patients with rMACE and no rMACE. Platelet reactivity markers were missing in 41 patients, of whom clinical characteristics did not differ from the non‐missing patients. For all platelet reactivity markers, patients with a level above the 90th percentile did not have an increased risk of developing an rMACE compared with patients with platelet reactivity markers below the 90th percentile. Adjustment for potential confounders did not change (CXCL4 and RANTES) or attenuated (NAP‐2) the risk estimates even further (Table 1). Changing the cut‐off points or using platelet reactivity as continuous variable did not affect the results.Table 1Hazard ratios for recurrent major arterial cardiovascular events (rMACE) in men with a first myocardial infarction (MI) according to platelet reactivity markersNo rMACE (n = 263)rMACE (n = 238)Hazard ratio (95% CI)UnadjustedFully adjusted*NAP‐2 < 90th percentile2402111 [ref.]1 [ref.] ≥ 90th percentile23271.3 (0.9–1.9)1.1 (0.8–1.7)CXCL4 < 90th percentile2392121 [ref.]1 [ref.] ≥ 90th percentile24261.2 (0.8–1.8)1.2 (0.8–1.8)RANTES < 90th percentile2392121 [ref.]1 [ref.] ≥ 90th percentile24261.2 (0.8–1.8)1.2 (0.8–1.8)Nap‐2: neutrophil activating peptide 2; CXCL4: CXC chemokine ligand 4; RANTES: regulated on activation, normal T cell expressed and secreted.*Adjusted for (at time of blood drawing): age, total cholesterol, systolic blood pressure, current smoking, C reactive protein and use of aspirin, oral anticoagulants, glucose‐lowering drugs, cholesterol‐lowering drugs. Open table in a new tab Nap‐2: neutrophil activating peptide 2; CXCL4: CXC chemokine ligand 4; RANTES: regulated on activation, normal T cell expressed and secreted. *Adjusted for (at time of blood drawing): age, total cholesterol, systolic blood pressure, current smoking, C reactive protein and use of aspirin, oral anticoagulants, glucose‐lowering drugs, cholesterol‐lowering drugs. Our findings in a cohort of men who survived a first MI do not confirm the notion that increased basal platelet reactivity increases the risk of recurrent cardiovascular events. This important negative finding contradicts previous studies which suggested that these inflammatory markers play a role in the development of first and recurrent cardiovascular events [12Snoep J.D. Roest M. Barendrecht A.D. De Groot P.G. Rosendaal F.R. van der Bom J.G. High platelet reactivity is associated with myocardial infarction in premenopausal women: a population‐based case‐control study.J Thromb Haemost. 2010; 8: 906-13Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 13Cavusoglu E. Eng C. Chopra V. Clark L.T. Pinsky D.J. Marmur J.D. Low plasma RANTES levels are an independent predictor of cardiac mortality in patients referred for coronary angiography.Arterioscler Thromb Vasc Biol. 2007; 27: 929-35Crossref PubMed Scopus (0) Google Scholar, 14Smith C. Damås J.K. Otterdal K. Øie E. Sandberg W.J. Yndestad A. Waehre T. Scholz H. Endresen K. Olofsson P.S. Halvorsen B. Gullestad L. Frøland S.S. Hansson G.K. Aukrust P. Increased levels of neutrophil‐activating peptide‐2 in acute coronary syndromes: possible role of platelet‐mediated vascular inflammation.J Am Coll Cardiol. 2006; 48: 1591-9Crossref PubMed Scopus (0) Google Scholar, 15Sobel M. Salzman E.W. Davies G.C. Handin R.I. Sweeney J. Ploetz J. Kurland G. Circulating platelet products in unstable angina pectoris.Circulation. 1981; 63: 300-6Crossref PubMed Google Scholar, 16Taomoto K. Asada M. Kanazawa Y. Matsumoto S. Usefulness of the measurement of plasma beta‐thromboglobulin (beta‐TG) in cerebrovascular disease.Stroke. 1983; 14: 518-24Crossref PubMed Google Scholar, 17Rasi V. Ikkala E. Torstila I. Plasma thromboglobulin in acute myocardial infarction.Thromb Res. 1982; 25: 203-12Abstract Full Text PDF PubMed Google Scholar]. Regarding the beta‐thromboglobulin NAP‐2, our findings are in line with the recent study of Berent et al. [20Berent R. Auer J. Franklin B. Schmid P. von Duvillard S.P. Platelet response to aspirin 50 and 100 mg in patients with coronary heart disease over a five‐year period.The American Journal of Cardiology. 2011; 108: 644-50Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], in which no difference in the recurrence of cardiovascular events was found between patients with low and high beta‐thromboglobulin levels. A possible explanation for the absence of an association between platelet reactivity markers and recurrent cardiovascular events in our study is that our study population represented a group of stable patients with chronic cardiovascular disease, whereas patients in previous studies were studied in an acute setting [13Cavusoglu E. Eng C. Chopra V. Clark L.T. Pinsky D.J. Marmur J.D. Low plasma RANTES levels are an independent predictor of cardiac mortality in patients referred for coronary angiography.Arterioscler Thromb Vasc Biol. 2007; 27: 929-35Crossref PubMed Scopus (0) Google Scholar, 14Smith C. Damås J.K. Otterdal K. Øie E. Sandberg W.J. Yndestad A. Waehre T. Scholz H. Endresen K. Olofsson P.S. Halvorsen B. Gullestad L. Frøland S.S. Hansson G.K. Aukrust P. Increased levels of neutrophil‐activating peptide‐2 in acute coronary syndromes: possible role of platelet‐mediated vascular inflammation.J Am Coll Cardiol. 2006; 48: 1591-9Crossref PubMed Scopus (0) Google Scholar, 15Sobel M. Salzman E.W. Davies G.C. Handin R.I. Sweeney J. Ploetz J. Kurland G. Circulating platelet products in unstable angina pectoris.Circulation. 1981; 63: 300-6Crossref PubMed Google Scholar, 16Taomoto K. Asada M. Kanazawa Y. Matsumoto S. Usefulness of the measurement of plasma beta‐thromboglobulin (beta‐TG) in cerebrovascular disease.Stroke. 1983; 14: 518-24Crossref PubMed Google Scholar, 17Rasi V. Ikkala E. Torstila I. Plasma thromboglobulin in acute myocardial infarction.Thromb Res. 1982; 25: 203-12Abstract Full Text PDF PubMed Google Scholar]. However, platelet inflammatory markers might play a more dominant role in the development of cardiovascular events in stable patients with a low prevalence of classic risk factors [12Snoep J.D. Roest M. Barendrecht A.D. De Groot P.G. Rosendaal F.R. van der Bom J.G. High platelet reactivity is associated with myocardial infarction in premenopausal women: a population‐based case‐control study.J Thromb Haemost. 2010; 8: 906-13Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. A major strength of our study is the large sample size and long follow‐up, as platelet inflammatory markers may affect the vascular endothelium over a long period of time before a recurrent cardiovascular event takes place. Additionally, our results can be generalized to other men with a first MI, because our cohort was representative of a typical population of men who survived a first MI. A limitation of our study is that renal function, which affects the level of beta‐thromboglobulin [21Andrassy K. Deppermann D. Ritz E. Koderisch J. Seelig H. Different effects of renal failure on beta‐thromboglobulin and high affinity platelet factor 4 (HA‐PF4)‐concentrations.Thromb Res. 1980; 18: 469-75Abstract Full Text PDF PubMed Google Scholar], was not measured and could not be controlled for as a confounding factor. However, because renal function and beta‐thromboglobulin are inversely correlated, additionally controlling for the effect of renal function would only attenuate the hazard ratios. Unfortunately, owing to practical reasons, we did not measure soluble glycoprotein Ib (sGPIb) in the present study, whereas a previous study in premenopausal women found an association between high levels of sGPIb and MI [12Snoep J.D. Roest M. Barendrecht A.D. De Groot P.G. Rosendaal F.R. van der Bom J.G. High platelet reactivity is associated with myocardial infarction in premenopausal women: a population‐based case‐control study.J Thromb Haemost. 2010; 8: 906-13Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. In conclusion, we found that high platelet reactivity, as measured by CXCL4, NAP‐2 and RANTES, does not increase the risk of recurrent cardiovascular events in men who survived a first MI. The authors state that they have no conflict of interests. The authors thank the contributors to earlier phases of the Study of Myocardial Infarction Leiden: C.J.M. Doggen, M.D. van der Krabben and the cardiologists of the Departments of Cardiology, Leiden University Medical Center and Hospital Diaconessenhuis Leiden, the Netherlands. The original study, on which the present article is based, was supported by the Netherlands Heart Foundation (grant 92.345). We also thank P.G. de Groot and A.D. Barendrecht of the Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, the Netherlands, who provided the measurements of platelet reactivity markers for this study.