Use of the PFA-100™ closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: a systematic review and meta-analysis
2008; Elsevier BV; Volume: 6; Issue: 3 Linguagem: Inglês
10.1111/j.1538-7836.2008.02897.x
ISSN1538-7933
AutoresJean‐Luc Reny, Philippe de Moerloose, M. Dauzat, Pierre Fontana,
Tópico(s)Coronary Interventions and Diagnostics
ResumoSummaryBackground: PFA-100™ is a point-of-care assay that evaluates platelet reactivity in high-shear-stress conditions by measuring the closure time (CT) of a membrane aperture. When determined with a collagen/epinephrine cartridge (CEPI), the CT is usually prolonged by aspirin. Studies of the predictive value of a short PFA-100™CTCEPI for ischemic events in aspirin-treated patients have given variable results. Objectives: To conduct a systematic review and meta-analysis of studies on the clinical predictive value of a short PFA-100™CTCEPI in aspirin-treated cardiovascular patients. Patients and methods: Relevant studies were identified by scanning electronic databases. Studies were selected if they included aspirin-treated patients with symptomatic atherosclerosis, measured the PFA-100™CTCEPI, used a CT cut-off value to define aspirin ‘responders’ and ‘non-responders’, and reported ischemic events. Results: We selected seven non-prospective studies (1466 patients) and eight prospective studies (1227 patients). In non-prospective studies, the PFA-100™CTCEPI was performed after the ischemic clinical endpoint, and a publication bias was identified. In prospective studies, the global odds ratio (OR) for the recurrence of an ischemic event in ‘aspirin non-responders’ relative to ‘aspirin responders’ was 2.1 [95% confidence interval (CI) 1.4–3.4, P<0.001]. Pooled analysis with a random effect model revealed no heterogeneity (Q Cochran P =0.36 and I2 = 9.4%). Conclusions: A short PFA-100™CTCEPI is associated with increased recurrence of ischemic events in aspirin-treated cardiovascular patients. This finding needs to be confirmed in stable ischemic patients, and the PFA-100™CTCEPI cut-off needs to be refined in these patients. Background: PFA-100™ is a point-of-care assay that evaluates platelet reactivity in high-shear-stress conditions by measuring the closure time (CT) of a membrane aperture. When determined with a collagen/epinephrine cartridge (CEPI), the CT is usually prolonged by aspirin. Studies of the predictive value of a short PFA-100™CTCEPI for ischemic events in aspirin-treated patients have given variable results. Objectives: To conduct a systematic review and meta-analysis of studies on the clinical predictive value of a short PFA-100™CTCEPI in aspirin-treated cardiovascular patients. Patients and methods: Relevant studies were identified by scanning electronic databases. Studies were selected if they included aspirin-treated patients with symptomatic atherosclerosis, measured the PFA-100™CTCEPI, used a CT cut-off value to define aspirin ‘responders’ and ‘non-responders’, and reported ischemic events. Results: We selected seven non-prospective studies (1466 patients) and eight prospective studies (1227 patients). In non-prospective studies, the PFA-100™CTCEPI was performed after the ischemic clinical endpoint, and a publication bias was identified. In prospective studies, the global odds ratio (OR) for the recurrence of an ischemic event in ‘aspirin non-responders’ relative to ‘aspirin responders’ was 2.1 [95% confidence interval (CI) 1.4–3.4, P<0.001]. Pooled analysis with a random effect model revealed no heterogeneity (Q Cochran P =0.36 and I2 = 9.4%). Conclusions: A short PFA-100™CTCEPI is associated with increased recurrence of ischemic events in aspirin-treated cardiovascular patients. This finding needs to be confirmed in stable ischemic patients, and the PFA-100™CTCEPI cut-off needs to be refined in these patients. Aspirin is part of the first-line treatment regimen for atherothrombosis [1Fontana P. Reny J.L. New antiplatelet strategies in atherothrombosis and their indications.Eur J Vasc Endovasc Surg. 2007; 34: 10-7Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. The benefit of low-dose aspirin in cardiovascular patients is related to permanent inactivation of cyclooxygenase (COX)-1, which results in the inhibition of platelet thromboxane (Tx)A2 production, a major pathway amplifying platelet activation [2Patrono C. Garcia Rodriguez L.A. Landolfi R. Baigent C. Low-dose aspirin for the prevention of atherothrombosis.N Engl J Med. 2005; 353: 2373-83Crossref PubMed Scopus (1043) Google Scholar]. However, the inhibitory effect of aspirin on platelet reactivity varies among individuals, leading to the concept of ‘aspirin resistance’ [3Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance.Arterioscler Thromb Vasc Biol. 2004; 24: 1980-7Crossref PubMed Scopus (407) Google Scholar]. Specific pharmacodynamic resistance to aspirin, i.e. the inability of aspirin to inhibit COX-1-dependent TxA2 generation, is uncommon [4Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection.J Thromb Haemost. 2007; 5: S230-7Crossref PubMed Scopus (176) Google Scholar], as shown by studies of residual TxA2 production based on the measurement of serum or urinary levels of TxB2 (a stable TxA2 metabolite) or arachidonic acid-induced platelet aggregation [5Tantry U.S. Bliden K.P. Gurbel P.A. Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation.J Am Coll Cardiol. 2005; 46: 1705-9Crossref PubMed Scopus (307) Google Scholar, 6Faraday N. Yanek L.R. Mathias R. Herrera-Galeano J.E. Vaidya D. Moy T.F. Fallin M.D. Wilson A.F. Bray P.F. Becker L.C. Becker D.M. Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxygenase-1.Circulation. 2007; 115: 2490-6Crossref PubMed Scopus (150) Google Scholar]. In contrast, studies of platelet function based on non-specific tests dependent on other platelet amplification pathways or biological parameters suggest that aspirin leaves platelet reactivity globally intact in 20–30% of subjects [7Ivandic B.T. Giannitsis E. Schlick P. Staritz P. Katus H.A. Hohlfeld T. Determination of aspirin responsiveness by use of whole blood platelet aggregometry.Clin Chem. 2007; 53: 614-9Crossref PubMed Scopus (66) Google Scholar, 8Gum P.A. Kottke-Marchant K. Poggio E.D. Gurm H. Welsh P.A. Brooks L. Sapp S.K. Topol E.J. Profile and prevalence of aspirin resistance in patients with cardiovascular disease.Am J Cardiol. 2001; 88: 230-5Abstract Full Text Full Text PDF PubMed Scopus (814) Google Scholar]. Among these latter tests, the Platelet Function Analyzer (PFA)-100™ (Dade-Behring, Marburg, Germany) is of particular interest. This device implements a whole-blood test that evaluates platelet function in vitro in high-shear-rate conditions by measuring platelet occlusion of a membrane coated with platelet agonists. Aspirin usually prolongs the PFA-100™ closure time (CT) when the collagen/epinephrine (CEPI) cartridge is used, whereas conditions such as high von Willebrand factor (VWF) levels tend to shorten it [9Chakroun T. Gerotziafas G. Robert F. Lecrubier C. Samama M.M. Hatmi M. Elalamy I. In vitro aspirin resistance detected by PFA-100 closure time: pivotal role of plasma von Willebrand factor.Br J Haematol. 2004; 124: 80-5Crossref PubMed Scopus (123) Google Scholar]. As high-shear-stress conditions prevail in stenotic arteries, and as VWF is a marker of the cardiovascular risk [10Lip G.Y. Blann A. von Willebrand factor: a marker of endothelial dysfunction in vascular disorders?.Cardiovasc Res. 1997; 34: 255-65Crossref PubMed Scopus (414) Google Scholar], the PFA-100™CT could potentially serve to detect high residual platelet reactivity despite aspirin therapy, and thereby to predict the risk of ischemic events. However, recent studies have given conflicting results [11Gianetti J. Parri M.S. Sbrana S. Paoli F. Maffei S. Paradossi U. Berti S. Clerico A. Biagini A. Platelet activation predicts recurrent ischemic events after percutaneous coronary angioplasty: a 6 months prospective study.Thromb Res. 2006; 118: 487-93Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 12Atiemo A.D. Ng’alla L.S. Vaidya D. Williams M.S. Abnormal PFA-100 closure time is associated with increased platelet aggregation in patients presenting with chest pain.J Thromb Thrombolysis. 2007; https://doi.org/10.1007/s11239-007-0045-5Crossref Scopus (12) Google Scholar], and their statistical power is often limited by their small size. Here, we made a systematic review and quantified the clinical relevance of a short PFA-100™CTCEPI in aspirin-treated cardiovascular patients by performing a meta-analysis of prospective studies comparing the frequency of ischemic events in aspirin ‘responders’ and ‘non-responders’ identified on the basis of the PFA-100™CTCEPI. We scanned the MEDLINE, Web of Science and Cochrane Central Register of Controlled Trials databases for relevant studies. The search was confined to articles in English [13Moher D. Pham B. Klassen T.P. Schulz K.F. Berlin J.A. Jadad A.R. Liberati A. What contributions do languages other than English makeon the results of meta-analyses?.J Clin Epidemiol. 2000; 53: 964-72Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar] published up to July 2007 (Appendix). We also examined the reference lists of the studies thus identified, as well as meeting abstracts. To be included, studies had to: (i) involve aspirin-treated patients with symptomatic atherosclerosis; (ii) use the PFA-100™ device and CEPI cartridge to evaluate platelet function; (iii) use a PFA-100™CT cut-off value to define aspirin ‘responders’ and ‘non-responders’; and (iv) evaluate the occurrence or recurrence of arterial ischemic events as a prespecified endpoint. The reviewers were not blinded to the journal, authors, or institution of the publications, as this has been shown to be unnecessary [14Berlin J.A. Does blinding of readers affect the results of meta-analyses? University of Pennsylvania Meta-analysis Blinding Study Group.Lancet. 1997; 350: 185-6Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar]. To assess the specificity of the identified studies, we used a data collection form to abstract information from each report, regarding the year of publication, the duration and setting of the study, the study design, completeness of follow-up, blinding, case definition and matching of patients, total sample size, aspirin dosage, study population, and the PFA-100™CT cut-off used to define aspirin responsiveness. Absolute numbers of true positives (aspirin ‘non-responder’ patients with an ischemic event), true negatives (aspirin ‘responder’ patients without an ischemic event), false positives (aspirin ‘non-responder’ patients without an ischemic event) and false negatives (aspirin ‘responder’ patients with an ischemic event) were extracted from the articles to prepare 2 × 2 tables. When the control group of a non-prospective study included patients without atherosclerotic disease, only data for atherosclerotic controls were used. Two authors (J. L. Reny and P. Fontana) of this systematic review selected the studies and abstracted the data independently, and disagreements were resolved by discussion among all authors. Studies with retrospective, case-control or cross-sectional designs (referred to below as ‘non-prospective’) were analyzed separately from studies with a true prospective design, as defined elsewhere [15Rosner B.A. Fundamentals of Biostatistics. Thomson Brooks/Cole, 2006Google Scholar]. We pooled all the prospective studies for the determination of a global odds ratio (OR). The PFA-100™ [16Harrison P. Progress in the assessment of platelet function.Br J Haematol. 2000; 111: 733-44PubMed Google Scholar] is a Food and Drug Administration-approved device usually used to evaluate acquired and congenital platelet dysfunction [17Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction.J Lab Clin Med. 2001; 138: 152-63Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar]. The PFA-100™ device measures the time (CT) required for platelets to plug an aperture simulating an injured vessel, after platelet activation by relevant stimuli, namely collagen and epinephrine (CEPI), or collagen and ADP (CADP). The maximum possible CT is 300 s, values above 300 s corresponding to non-closure. Aspirin influences the CTCEPI value, whereas the CTCADP is unaffected [17Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction.J Lab Clin Med. 2001; 138: 152-63Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 18Poulsen T.S. Mickley H. Korsholm L. Licht P.B. Haghfelt T. Jorgensen B. Using the Platelet Function Analyzer-100 for monitoring aspirin therapy.Thromb Res. 2007; 120: 161-72Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. The reference range of the CEPI cartridge is based on values for 127 healthy unmedicated subjects, and is 85–165 s when blood is collected in tubes containing 0.129 m citrate (3.8%, package insert), and 82–105 s when blood is collected in tubes containing 0.105 m citrate (3.2%) [19Bock M. De Haan J. Beck K.H. Gutensohn K. Hertfelder H.J. Karger R. Heim M.U. Beeser H. Weber D. Kretschmer V. Standardization of the PFA-100(R) platelet function test in 105 mmol/l buffered citrate: effect of gender, smoking, and oral contraceptives.Br J Haematol. 1999; 106: 898-904Crossref PubMed Scopus (95) Google Scholar]. The characteristics of the patients were recorded as means and standard deviations for continuous variables, and counts and percentages for categorical variables. Comparisons were made with Student’s unpaired t-test for continuous variables. Relationships between continuous variables were assessed with simple linear regression. Groups of aspirin ‘responders’ and ‘non-responders’ were defined on the basis of the PFA-100™CTCEPI cut-off used in each study: aspirin ‘responders’ were reported to have a CTCEPI value greater than or equal to the cut-off, and aspirin ‘non-responders’ a CTCEPI value lower than or equal to the cut-off. The endpoint was the occurrence (non-prospective studies) or recurrence (prospective studies) of an arterial ischemic event. The results of each study were summarized in 2 × 2 tables. As in meta-analyses of therapeutic trials [20Leizorovicz A. Simonneau G. Decousus H. Boissel J.P. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis.BMJ. 1994; 309: 299-304Crossref PubMed Scopus (334) Google Scholar], given that there was no reason to favor a particular effect model, we used various methods based on both fixed and random effect models (combined logarithm of the odds ratio, Mantel–Haenszel, Cochran, and Peto). As the results obtained with the different methods were similar, only the ORs calculated with the logarithm of the OR are reported here, with the corresponding 95% confidence intervals (CIs). Association and heterogeneity tests were used for each analysis [21Cucherat M. Boissel J.P. Leizorovicz A. Haugh M.C. EasyMA: a program for the meta-analysis of clinical trials.Comput Methods Programs Biomed. 1997; 53: 187-90Crossref PubMed Scopus (116) Google Scholar]. Heterogeneity was considered to exist when the P-value of the heterogeneity test was 0.15 or less. Heterogeneity was also quantified with the I2 statistic [22Higgins J.P. Thompson S.G. Quantifying heterogeneity in a meta-analysis.Stat Med. 2002; 21: 1539-58Crossref PubMed Scopus (22176) Google Scholar]. The causes of heterogeneity were always sought. We assessed potential publication bias graphically, using funnel plots and distribution of the ORs according to the study sizes. A P-value of 0.05 or less in an association test was considered significant. Statistical analyses were performed using Stata (College Station, TX, USA) software release 7. The meta-analysis was implemented with EasyMA, a program for meta-analysis of clinical trials (available at http://www.spc.univ-lyon1.fr/easyma.dos/). The flowchart of the meta-analysis is shown in Fig. 1. The main reasons for excluding studies on the basis of the information contained in their abstracts were as follows: assessment of platelet function prior to surgery without ischemic endpoints; studies of biological effects of antiplatelet agents on platelet function without clinical endpoints; studies of the prevalence of low aspirin responsiveness without clinical endpoints; and studies of non-cardiovascular patients. On the basis of their abstracts, 26 studies met the selection criteria. Thorough evaluation of the 26 full articles led to the selection of 15 studies [11Gianetti J. Parri M.S. Sbrana S. Paoli F. Maffei S. Paradossi U. Berti S. Clerico A. Biagini A. Platelet activation predicts recurrent ischemic events after percutaneous coronary angioplasty: a 6 months prospective study.Thromb Res. 2006; 118: 487-93Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 12Atiemo A.D. Ng’alla L.S. Vaidya D. Williams M.S. Abnormal PFA-100 closure time is associated with increased platelet aggregation in patients presenting with chest pain.J Thromb Thrombolysis. 2007; https://doi.org/10.1007/s11239-007-0045-5Crossref Scopus (12) Google Scholar, 23Grundmann K. Jaschonek K. Kleine B. Dichgans J. Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.J Neurol. 2003; 250: 63-6Crossref PubMed Scopus (260) Google Scholar, 24Gum P.A. Kottke-Marchant K. Welsh P.A. White J. Topol E.J. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease.J Am Coll Cardiol. 2003; 41: 961-5Crossref PubMed Scopus (987) Google Scholar, 25Andersen K. Hurlen M. Arnesen H. Seljeflot I. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease.Thromb Res. 2003; 108: 37-42Abstract Full Text Full Text PDF Scopus (231) Google Scholar, 26Hobikoglu G.F. Norgaz T. Aksu H. Ozer O. Erturk M. Nurkalem Z. Narin A. High frequency of aspirin resistance in patients with acute coronary syndrome.Tohoku J Exp Med. 2005; 207: 59-64Crossref PubMed Scopus (43) Google Scholar, 27Pamukcu B. Oflaz H. Nisanci Y. The role of platelet glycoprotein IIIa polymorphism in the high prevalence of in vitro aspirin resistance in patients with intracoronary stent restenosis.Am Heart J. 2005; 149: 675-80Crossref PubMed Scopus (72) Google Scholar, 28Yilmaz M.B. Balbay Y. Caldir V. Ayaz S. Guray Y. Guray U. Korkmaz S. Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance.Thromb Res. 2005; 115: 25-9Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 29Marcucci R. Paniccia R. Antonucci E. Gori A.M. Fedi S. Giglioli C. Valente S. Prisco D. Abbate R. Gensini G.F. Usefulness of aspirin resistance after percutaneous coronary intervention for acute myocardial infarction in predicting one-year major adverse coronary events.Am J Cardiol. 2006; 98: 1156-9Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 30Malek L.A. Spiewak M. Filipiak K.J. Grabowski M. Szpotanska M. Rosiak M. Glowczynska R. Imiela T. Huczek Z. Opolski G. Persistent platelet activation is related to very early cardiovascular events in patients with acute coronary syndromes.Kardiol Pol. 2007; 65: 40-5PubMed Google Scholar, 31Poulsen T.S. Jorgensen B. Korsholm L. Bjorn Licht P. Haghfelt T. Mickley H. Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction.Thromb Res. 2007; 119: 555-62Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 32Linden M.D. Furman M.I. Frelinger 3rd, A.L. Fox M.L. Barnard M.R. Li Y. Przyklenk K. Michelson A.D. Indices of platelet activation and the stability of coronary artery disease.J Thromb Haemost. 2007; 5: 761-5Crossref PubMed Scopus (94) Google Scholar, 33Hobikoglu G.F. Norgaz T. Aksu H. Ozer O. Erturk M. Destegul E. Akyuz U. Unal Dai S. Narin A. The effect of acetylsalicylic acid resistance on prognosis of patients who have developed acute coronary syndrome during acetylsalicylic acid therapy.Can J Cardiol. 2007; 23: 201-6Abstract Full Text PDF PubMed Scopus (28) Google Scholar, 34Pamukcu B. Oflaz H. Onur I. Oncul A. Ozcan M. Umman B. Mercanoglu F. Meric M. Nisanci Y. Clinical relevance of aspirin resistance in patients with stable coronary artery disease: a prospective follow-up study (PROSPECTAR).Blood Coagul Fibrinolysis. 2007; 18: 187-92Crossref PubMed Scopus (41) Google Scholar, 35Pamukcu B. Oflaz H. Oncul A. Umman B. Mercanoglu F. Ozcan M. Meric M. Nisanci Y. The role of aspirin resistance on outcome in patients with acute coronary syndrome and the effect of clopidogrel therapy in the prevention of major cardiovascular events.J Thromb Thrombolysis. 2006; 22: 103-10Crossref PubMed Scopus (72) Google Scholar] meeting all our inclusion criteria. Eight studies were prospective and seven were non-prospective. The reasons for excluding the other 11 studies, of which nine were non-prospective, are given in Fig. 1. The study by Malek et al. [30Malek L.A. Spiewak M. Filipiak K.J. Grabowski M. Szpotanska M. Rosiak M. Glowczynska R. Imiela T. Huczek Z. Opolski G. Persistent platelet activation is related to very early cardiovascular events in patients with acute coronary syndromes.Kardiol Pol. 2007; 65: 40-5PubMed Google Scholar] was classified as non-prospective, despite a short follow-up period during index hospitalization, because, relative to admission, the median interval before the PFA-100™CTCEPI assay and before the ischemic endpoint was the same (6 days).Table 1Main characteristics of non-prospective studiesFirst author, yearATSDnMean age (years)Blinded assessment for biologists and cliniciansPFA-100™ during acute ischemiaCitrate concentration (%)Plasma VWF assayCTCEPI cut-off (s)Aspirin dose (mg day−1)Prevalence of ‘non-responders’ (%)OR (95% CI)Grundmann, 2003 [23Grundmann K. Jaschonek K. Kleine B. Dichgans J. Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.J Neurol. 2003; 250: 63-6Crossref PubMed Scopus (260) Google Scholar]Stroke5368BiologistsYesNANo1651002918 (0.99–327)Hobikoglu, 2005 [26Hobikoglu G.F. Norgaz T. Aksu H. Ozer O. Erturk M. Nurkalem Z. Narin A. High frequency of aspirin resistance in patients with acute coronary syndrome.Tohoku J Exp Med. 2005; 207: 59-64Crossref PubMed Scopus (43) Google Scholar]CAD20460NAYes3.8No170NA331.8 (1.0–3.3)Yilmaz, 2005 [28Yilmaz M.B. Balbay Y. Caldir V. Ayaz S. Guray Y. Guray U. Korkmaz S. Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance.Thromb Res. 2005; 115: 25-9Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]CAD2865YesNANANo193202 (mean)2813 (1.3–128)Pamukcu, 2005 [27Pamukcu B. Oflaz H. Nisanci Y. The role of platelet glycoprotein IIIa polymorphism in the high prevalence of in vitro aspirin resistance in patients with intracoronary stent restenosis.Am Heart J. 2005; 149: 675-80Crossref PubMed Scopus (72) Google Scholar]CAD20456NANA3.8No186100–300213.8 (1.8–8.0)Poulsen, 2007 [31Poulsen T.S. Jorgensen B. Korsholm L. Bjorn Licht P. Haghfelt T. Mickley H. Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction.Thromb Res. 2007; 119: 555-62Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]CAD29869BiologistsYes3.8Yes165150312.3 (1.3–4.1)Linden, 2007 [32Linden M.D. Furman M.I. Frelinger 3rd, A.L. Fox M.L. Barnard M.R. Li Y. Przyklenk K. Michelson A.D. Indices of platelet activation and the stability of coronary artery disease.J Thromb Haemost. 2007; 5: 761-5Crossref PubMed Scopus (94) Google Scholar]CAD58862CliniciansYes3.8No13081–325103.6 (1.8–7.3)Malek, 2007 [30Malek L.A. Spiewak M. Filipiak K.J. Grabowski M. Szpotanska M. Rosiak M. Glowczynska R. Imiela T. Huczek Z. Opolski G. Persistent platelet activation is related to very early cardiovascular events in patients with acute coronary syndromes.Kardiol Pol. 2007; 65: 40-5PubMed Google Scholar]CAD91NANAYes3.2No19075219.1 (2.0–41)ATSD, main atherosclerotic disease; CAD, coronary artery disease; NA, not available; VWF, von Willebrand factor; OR, odd ratio; CI, confidence interval. Open table in a new tab ATSD, main atherosclerotic disease; CAD, coronary artery disease; NA, not available; VWF, von Willebrand factor; OR, odd ratio; CI, confidence interval. All selected non-prospective studies involved patients with coronary artery disease, except one that included only patients with stroke as the qualifying event [23Grundmann K. Jaschonek K. Kleine B. Dichgans J. Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.J Neurol. 2003; 250: 63-6Crossref PubMed Scopus (260) Google Scholar]. Platelet reactivity was evaluated close to the acute ischemic event in five studies [23Grundmann K. Jaschonek K. Kleine B. Dichgans J. Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.J Neurol. 2003; 250: 63-6Crossref PubMed Scopus (260) Google Scholar, 26Hobikoglu G.F. Norgaz T. Aksu H. Ozer O. Erturk M. Nurkalem Z. Narin A. High frequency of aspirin resistance in patients with acute coronary syndrome.Tohoku J Exp Med. 2005; 207: 59-64Crossref PubMed Scopus (43) Google Scholar, 30Malek L.A. Spiewak M. Filipiak K.J. Grabowski M. Szpotanska M. Rosiak M. Glowczynska R. Imiela T. Huczek Z. Opolski G. Persistent platelet activation is related to very early cardiovascular events in patients with acute coronary syndromes.Kardiol Pol. 2007; 65: 40-5PubMed Google Scholar, 31Poulsen T.S. Jorgensen B. Korsholm L. Bjorn Licht P. Haghfelt T. Mickley H. Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction.Thromb Res. 2007; 119: 555-62Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 32Linden M.D. Furman M.I. Frelinger 3rd, A.L. Fox M.L. Barnard M.R. Li Y. Przyklenk K. Michelson A.D. Indices of platelet activation and the stability of coronary artery disease.J Thromb Haemost. 2007; 5: 761-5Crossref PubMed Scopus (94) Google Scholar]. Whether or not an acute ischemic event occurred close to the PFA-100™CTCEPI assay was not mentioned in two studies [27Pamukcu B. Oflaz H. Nisanci Y. The role of platelet glycoprotein IIIa polymorphism in the high prevalence of in vitro aspirin resistance in patients with intracoronary stent restenosis.Am Heart J. 2005; 149: 675-80Crossref PubMed Scopus (72) Google Scholar, 28Yilmaz M.B. Balbay Y. Caldir V. Ayaz S. Guray Y. Guray U. Korkmaz S. Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance.Thromb Res. 2005; 115: 25-9Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. The total number of patients in the non-prospective studies was 1466 (28–588 patients per study), and their mean ages ranged from 56 to 69 years. The aspirin doses ranged from 75 to 325 mg (not mentioned in one study [26Hobikoglu G.F. Norgaz T. Aksu H. Ozer O. Erturk M. Nurkalem Z. Narin A. High frequency of aspirin resistance in patients with acute coronary syndrome.Tohoku J Exp Med. 2005; 207: 59-64Crossref PubMed Scopus (43) Google Scholar]). The prevalence of aspirin ‘non-responders’ ranged from 10% to 22%, on the basis of PFA-100™CTCEPI cut-off values of 130–193 s. When measured (one study), the VWF level correlated with the PFA-100™CTCEPI [31Poulsen T.S. Jorgensen B. Korsholm L. Bjorn Licht P. Haghfelt T. Mickley H. Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction.Thromb Res. 2007; 119: 555-62Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. However, in the multivariate analysis of this latter study, the association between the PFA-100™CTCEPI and ischemic events was independent of the VWF level [31Poulsen T.S. Jorgensen B. Korsholm L. Bjorn Licht P. Haghfelt T. Mickley H. Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction.Thromb Res. 2007; 119: 555-62Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. The funnel plot representation for non-prospective studies (not shown) was in favor of a publication bias. Indeed, three small studies [23Grundmann K. Jaschonek K. Kleine B. Dichgans J. Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.J Neurol. 2003; 250: 63-6Crossref PubMed Scopus (260) Google Scholar, 28Yilmaz M.B. Balbay Y. Caldir V. Ayaz S. Guray Y. Guray U. Korkmaz S. Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance.Thromb Res. 2005; 115: 25-9Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 30Malek L.A. Spiewak M. Filipiak K.J. Grabowski M. Szpotanska M. Rosiak M. Glowczynska R. Imiela T. Huczek Z. Opolski G. Persistent platelet activation is related to very early cardiovascular events in patients with acute coronary syndromes.Kardiol Pol. 2007; 65: 40-5PubMed Google Scholar], with 53, 28 and 91 patients, respectively, reported high ORs (Table 1) that accounted for an asymmetric graphical representation. The total number of patients in the prospective studies was 1227 (47–325 patients per study), and their mean age ranged from 54 to 66 years. All selected prospective studies involved patients with coronary artery disease. Follow-up lasted 20 months on average, and ranged from 6 to 48 months. In one study, follow-up was limited to the index hospitalization [12Atiemo A.D. Ng’alla L.S. Vaidya D. Williams M.S. Abnormal PFA-100 closure time is associated with increased platelet aggregation in patients presenting with chest pain.J Thromb Thrombolysis. 2007; https://doi.org/10.1007/s11239-007-0045-5Crossref Scopus (12) Google Scholar]. The prevalence of aspirin ‘non-responders’ ranged from 9.5% to 49%, on the basis o
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