Portal de Periódicos da CAPES

What the Clinical Event Committee Does Not See When It Comes to Stent Thrombosis

2016; Lippincott Williams & Wilkins; Volume: 9; Issue: 5 Linguagem: Inglês

10.1161/circinterventions.116.003861

1941-7632

Alexandra J. Lansky, Vivian G. Ng,

Antiplatelet Therapy and Cardiovascular Diseases

HomeCirculation: Cardiovascular InterventionsVol. 9, No. 5What the Clinical Event Committee Does Not See When It Comes to Stent Thrombosis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWhat the Clinical Event Committee Does Not See When It Comes to Stent Thrombosis Alexandra J. Lansky, MD and Vivian G. Ng, MD Alexandra J. LanskyAlexandra J. Lansky From the Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT. and Vivian G. NgVivian G. Ng From the Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT. Originally published9 May 2016https://doi.org/10.1161/CIRCINTERVENTIONS.116.003861Circulation: Cardiovascular Interventions. 2016;9:e003861In this issue of Circulation: Cardiovascular Interventions, Popma et al report important results from the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome (TRACER) trial that highlight the variability of stent thrombosis ascertainment between local investigators, the independent clinical event committee (CEC), and an angiographic core laboratory (ACL).1 Reported stent thrombosis rates in this cohort of patients with non–ST-segment–elevation acute coronary syndrome varied from 1.42% to 2.38% in the placebo arm and 1.53% to 2.24% in the treatment arm depending on how the ascertainment was made. Relative to the ACL (32.8%), local investigators over-reported (55.3%) stent thrombosis, whereas the CEC under-reported (21.6%) the stent thrombosis rate. The 3 groups agreed in just over half (53%) of cases, with only fair overall agreement (κ=0.32). Agreement was poor between local investigators and both CEC-adjudicated Academic Research Consortium (ARC)–definite stent thrombosis (κ=0.25) and ACL-identified stent thrombosis (κ=0.25). Of the comparisons, CEC-adjudicated ARC-definite stent thrombosis and ACL-identified stent thrombosis had the highest level of agreement, albeit still modest (κ=0.57). Although these inconsistencies in stent thrombosis reporting did not impact the overall results of the TRACER trial, these findings clearly have important implications for the safety reporting of novel pharmacological and device therapies and emphasize the need for standardized ascertainment methods in clinical trials.See Article by Popma et alStent thrombosis is a rare but devastating event after contemporary stent implantation,2–6 typically associated with large myocardial infarction or death.5–7 Although current generation drug-eluting stents have demonstrated significantly reduced stent thrombosis compared with first-generation drug-eluting stents, concerns persist in high-risk patient cohorts and with new technologies, such as bioresorbable coronary scaffolds.8–10 Likewise, some newer antiplatelet agents have demonstrated reductions in stent thrombosis rates while others (such as vorapaxar in the TRACER trial) have not. Therefore, reliable ascertainment of stent thrombosis remains imperative for device safety and pharmacological efficacy evaluations in clinical trials for an informed benefit risk assessment of novel therapies.Clinical definitions of stent thrombosis have varied in sensitivity and specificity as a result of the differing levels of evidence required to reach the diagnosis; criteria have ranged from the purely clinical (such as a myocardial infarction involving the target vessel territory)6,11 to requiring angiographic confirmation of thrombus.12,13 The ARC was a critical initiative that addressed the known variability in adverse event reporting by proposing standardizing end point definitions. ARC stent thrombosis definitions are stratified according to the degree of certainty (possible, probable, or definite),14 and ARC-defined definite stent thrombosis requires angiographic or autopsy confirmation of thrombosis in addition to clinical correlates (symptoms, ECG findings, or biomarkers). As a result, ARC-definite stent thrombosis is intended to have high specificity at the cost of sensitivity. In contrast, ARC-possible stent thrombosis is the most sensitive but least specific category and includes any unexplained death from 30 days after intracoronary stenting until the end of a trial's follow-up. Beyond stating the requirement for angiographic confirmation of thrombosis, the ARC guidance document is not prescriptive regarding the specific ascertainment methodology for angiographic thrombus confirmation, which arguably could rely on site reports, ACL reports (if available), or visual confirmation by CEC members.The classic angiographic appearance of thrombus is characterized by any combination of decreased contrast density, haziness, a filling defect, or convex contours with or without contrast staining or reduced flow. A semiquantitative classification of thrombus size has also been proposed.15 Previous validation studies of thrombus assessment are entirely consistent with the current report and have demonstrated only fair agreement between clinical centers and central core laboratories (κ=0.30), whereas ACL have substantial interobserver agreement for identifying thrombus (κ=0.7).16 Given the greater reliability and consistency of ACL thrombus assessment compared with clinical centers, ACL assessments (when available) should be an integral part of the source documents provided to the CEC for event adjudication, particularly when the CEC does not review angiograms directly—as was the case in TRACER.The results of Popma et al's study have important implications for the design and interpretation of clinical trials. This study demonstrated that the overall stent thrombosis rate reported by the local investigators (2.57% [182/7075]) was ≈2.5× that reported by the CEC (0.99% [71/7075]) and ≈1.5× the ACL rate (1.53% [108/7075]). Therefore, ARC-defined definite stent thrombosis rates reported in studies are not necessarily comparable unless similar evaluation methods and data sources are used. Although the higher stent thrombosis rates reported in registry studies compared with randomized trials are often attributed to higher risk patient populations, the findings of Popma et al indicate that the inherent overestimation of site-reported ST is also a contributor. In contrast, studies reporting only CEC-adjudicated ARC-definite stent thrombosis will have the lowest stent thrombosis rates because of the increased specificity and limitations in obtaining source documents, particularly when ACL analysis or direct review of angiograms do not inform the adjudication process. Furthermore, these findings have consequences for the design and powering of studies. Given that stent thrombosis is rare, the under-reporting by the CEC diminishes the likelihood of detecting significant differences between groups, and the results of the TRACER substudy underscore the critical nature of standardized ascertainment methods in addition to standardized definitions. It is clear from these data that ACL analysis is more sensitive for the detection of stent thrombosis than the CEC, which is to be expected given the CEC dependence on the quality and completeness of source documents. In 50% of the cases in which there was discordance between the ACL and CEC, the CEC did not have sufficient information to adjudicate ARC-definite stent thrombosis. Therefore, additional measures should be taken to improve CEC assessment of stent thrombosis:All clinical trials should include CEC adjudication of stent thrombosis according to ARC definitions in addition to any protocol-specific definitions to facilitate comparison between studies.The importance of complete documentation should be stressed at the site level, and all source documentation including angiograms must be made available to the CEC.When available, ACL analyses should be an integral input to CEC review and adjudication of all stent thrombosis and repeat revascularization.When ACL analyses are unavailable, the CEC should review the angiograms, and an interventional cardiologist or other clinician experienced in coronary angiography should be included in the adjudication team.This study from Popma et al enhances our understanding of the importance of the details of end point ascertainment and their impact on the design and interpretation of clinical trials. To improve the accuracy of stent thrombosis reporting in clinical trials, review of all available source documents, including the incorporation of ACL analyses and direct review of angiograms, should be a standard in the CEC adjudication process.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Alexandra J. Lansky, MD, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 1 Church St Suite 330, New Haven, CT 06520. E-mail [email protected].References1. Popma CJ, Sheng S, Korjian S, Daaboul Y, Chi G, Tricoci P, Huang Z, Moliterno DJ, White HD, van der Werf F, Harrington RA, Wallentin L, Held C, Armstrong PW, Aylward PE, Strony J, Mahaffey KW, Gibson CM. Lack of concordance between local investigators, angiographic core laboratory, and clinical event committee in the assessment of stent thrombosis: results from the TRACER angiographic substudy.Circ Cardiovasc Interv. 2016; 9:e003114. doi: 10.1161/CIRCINTERVENTIONS.115.003114.LinkGoogle Scholar2. Tada T, Byrne RA, Simunovic I, King LA, Cassese S, Joner M, Fusaro M, Schneider S, Schulz S, Ibrahim T, Ott I, Massberg S, Laugwitz KL, Kastrati A. Risk of stent thrombosis among bare-metal stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: results from a registry of 18,334 patients.JACC Cardiovasc Interv. 2013; 6:1267–1274. doi: 10.1016/j.jcin.2013.06.015.CrossrefMedlineGoogle Scholar3. Räber L, Magro M, Stefanini GG, Kalesan B, van Domburg RT, Onuma Y, Wenaweser P, Daemen J, Meier B, Jüni P, Serruys PW, Windecker S. Very late coronary stent thrombosis of a newer-generation everolimus-eluting stent compared with early-generation drug-eluting stents: a prospective cohort study.Circulation. 2012; 125:1110–1121. doi: 10.1161/CIRCULATIONAHA.111.058560.LinkGoogle Scholar4. Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Gurbel PA, Xu K, Parise H, Kirtane AJ, Brodie BR, Mehran R, Stuckey TD; ADAPT-DES Investigators. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study.Lancet. 2013; 382:614–623. doi: 10.1016/S0140-6736(13)61170-8.CrossrefMedlineGoogle Scholar5. Schulz S, Schuster T, Mehilli J, Byrne RA, Ellert J, Massberg S, Goedel J, Bruskina O, Ulm K, Schömig A, Kastrati A. Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period.Eur Heart J. 2009; 30:2714–2721. doi: 10.1093/eurheartj/ehp275.CrossrefMedlineGoogle Scholar6. Cutlip DE, Baim DS, Ho KK, Popma JJ, Lansky AJ, Cohen DJ, Carrozza JP, Chauhan MS, Rodriguez O, Kuntz RE. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials.Circulation. 2001; 103:1967–1971.LinkGoogle Scholar7. Ong AT, Hoye A, Aoki J, van Mieghem CA, Rodriguez Granillo GA, Sonnenschein K, Regar E, McFadden EP, Sianos G, van der Giessen WJ, de Jaegere PP, de Feyter P, van Domburg RT, Serruys PW. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation.J Am Coll Cardiol. 2005; 45:947–953. doi: 10.1016/j.jacc.2004.09.079.CrossrefMedlineGoogle Scholar8. Cassese S, Byrne RA, Ndrepepa G, Kufner S, Wiebe J, Repp J, Schunkert H, Fusaro M, Kimura T, Kastrati A. Everolimus-eluting bioresorbable vascular scaffolds versus everolimus-eluting metallic stents: a meta-analysis of randomised controlled trials.Lancet. 2016; 387:537–544. doi: 10.1016/S0140-6736(15)00979-4.CrossrefMedlineGoogle Scholar9. Lipinski MJ, Escarcega RO, Baker NC, Benn HA, Gaglia MA, Torguson R, Waksman R. Scaffold thrombosis after percutaneous coronary intervention with ABSORB bioresorbable vascular scaffold: a systematic review and meta-analysis.JACC Cardiovasc Interv. 2016; 9:12–24. doi: 10.1016/j.jcin.2015.09.024.CrossrefMedlineGoogle Scholar10. Hoppmann P, Kufner S, Cassese S, Wiebe J, Schneider S, Pinieck S, Scheler L, Bernlochner I, Joner M, Schunkert H, Laugwitz KL, Kastrati A, Byrne RA. Angiographic and clinical outcomes of patients treated with everolimus-eluting bioresorbable stents in routine clinical practice: results of the ISAR-ABSORB registry.Catheter Cardiovasc Interv. 2016; 87:822–829. doi: 10.1002/ccd.26346.CrossrefMedlineGoogle Scholar11. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators.N Engl J Med. 1998; 339:1665–1671. doi: 10.1056/NEJM199812033392303.CrossrefMedlineGoogle Scholar12. Stone GW, Ellis SG, Cannon L, Mann JT, Greenberg JD, Spriggs D, O'Shaughnessy CD, DeMaio S, Hall P, Popma JJ, Koglin J, Russell ME; TAXUS V Investigators. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial.JAMA. 2005; 294:1215–1223. doi: 10.1001/jama.294.10.1215.CrossrefMedlineGoogle Scholar13. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE; SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.N Engl J Med. 2003; 349:1315–1323. doi: 10.1056/NEJMoa035071.CrossrefMedlineGoogle Scholar14. 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; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions.Circulation. 2007; 115:2344–2351. doi: 10.1161/CIRCULATIONAHA.106.685313.LinkGoogle Scholar15. Gibson CM, de Lemos JA, Murphy SA, Marble SJ, McCabe CH, Cannon CP, Antman EM, Braunwald E; TIMI Study Group. Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction: a TIMI 14 substudy.Circulation. 2001; 103:2550–2554.LinkGoogle Scholar16. Popma JJ, Lansky AJ, Yeh W, Kennard ED, Keller MB, Merritt AJ, DeFalco RA, Desai A, Pacera JH, Schnabel JF, Niedermeyer V, Baim DS, Detre KM. Reliability of the quantitative angiographic measurements in the New Approaches to Coronary Intervention (NACI) registry: a comparison of clinical site and repeated angiographic core laboratory readings.Am J Cardiol. 1997; 80(10A):19K–25K.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails May 2016Vol 9, Issue 5 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCINTERVENTIONS.116.003861PMID: 27162219 Originally publishedMay 9, 2016 Keywordsacute coronary syndromethrombosisstent thrombosisEditorialsdrug-eluting stentsPDF download Advertisement SubjectsStent