Comment on
Anti-platelet treatments in acute coronary syndrome: simplified network meta-analysis. [Int J Cardiol. 2011

Abbate, Antonio

Agostoni, Pierfrancesco

Biondi-Zoccai, Giuseppe

D'Ascenzo, Fabrizio

Modena, Maria Grazia

Giuseppe Biondi-Zoccai

Fabrizio D'Ascenzo

Antonio Abbate

Pierfrancesco Agostoni

Maria Grazia Modena

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International Journal of Cardiology

Agreement between adjusted indirect comparison and simplified network meta-analyses on prasugrel and ticagrelor (Reply to Passaro et al. — Int J Cardiol 2011)

BIONDI ZOCCAI, GIUSEPPE

Archivio della ricerca- Università di Roma La Sapienza

Agreement between adjusted indirect comparison and simplified network meta-analyses on prasugrel and ticagrelor (Reply to Passaro et al. - Int J Cardiol 2011)

Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

[4] Huikuri HV, Kervinen K, Niemelä M, et al. Effects of intracoronary injection ofmononuclear bone marrow cells on left ventricular function, arrhythmia riskproﬁle, and restenosis after thrombolytic therapy of acute myocardial infarction.Eur Heart J 2008;29:2723–32.[5] Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-celltransfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2006;367:113–21.[6] Li ZQ, Zhang M, Jing YZ, et al. The clinical study of autologous peripheral bloodstem cell transplantation by intracoronary infusion in patients with acutemyocardial infarction (AMI). Int J Cardiol 2007;115:52–6.[7] Kang HJ, Lee HY, Na SH, et al. 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All rights reserved.doi:10.1016/j.ijcard.2011.05.084Agreement between adjusted indirect comparison and simpliﬁed networkmeta-analyses on prasugrel and ticagrelor (Reply to Passaro et al.— Int J Cardiol 2011)☆Giuseppe Biondi-Zoccai a,⁎, Fabrizio D'Ascenzo b, Antonio Abbate c,Pierfrancesco Agostoni d, Maria Grazia Modena aa Division of Cardiology, University of Modena and Reggio Emilia, Modena, Italyb Division of Cardiology, University of Turin, Turin, Italyc VCU Pauley Heart Center, Richmond, VA, USAd Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlandsa r t i c l e i n f oArticle history:Received 22 May 2011Accepted 6 June 2011Available online 8 July 2011Keywords:Mixed treatment comparisonMeta-analysisNetwork meta-analysisPrasugrelSystematic reviewTicagrelorWe thank Passaro and colleagues for their interesting simpliﬁednetwork meta-analysis, [1] stemming from our recent adjustedindirect comparison meta-analysis comparing prasugrel versusticagrelor in patients with acute coronary syndromes [2].Indeed, network meta-analyses (i.e. mixed treatment compar-isons) and adjusted indirect comparisonmeta-analysis are very closelyrelated, as the latter may be considered a simpliﬁed network meta-analysis with a star shape [3]. Thus, the fact that Passaro et al. largelyconﬁrm the direction andmagnitude of effect of our own analysis, thussupporting its precision, accuracy, and validity, comes a no majorsurprise, but rather testiﬁes the consistency of these innovativestatistical approaches (Table 1) [4]. We have already endeavored inthis type of research study design in the past, focusing on ﬁrstgeneration drug-eluting stents, [5,6] second generation drug-elutingstents, [7] mechanical coronary recanalization after failed thrombo-lysis, [8] and antithrombotic agents for atrial ﬁbrillation, [9] and so farnone of our ﬁndings have been disproved by later trials or analyses.The discrepancy reported by Passero et al. in comparison to ourﬁndings on the safety end-point of major bleeding (odds ratio 0.70[95% conﬁdence interval 0.54–0.91] in our work versus risk ratio 0.72[0.50–1.04] in Passero et al.) might depend more on the deﬁnitionsused than on the statistical method. Indeed, we employed thestringent albeit insensitive Thrombolysis in Myocardial Infarction☆ Conﬂicts of interest: Dr. Biondi-Zoccai has lectured for Astra Zeneca, Bristol MyersSquibb, Sanoﬁ-Aventis; he has consulted for Astra Zeneca and Eli Lilly.⁎ Corresponding author at: Division of Cardiology, University of Modena and ReggioEmilia, Via Del Pozzo 71, 41124 Modena, Italy. Tel.: +39 059 422 57 83; fax: +39 059422 37 14.E-mail address: gbiondizoccai@gmail.com (G. Biondi-Zoccai).228 Letters to the Editor(TIMI) deﬁnition, and also distinguished coronary artery bypassgrafting (CABG)-related major bleeding from non-CABG-relatedmajor bleeding [2]. Conversely, they did not specify which deﬁnitionwas chosen for their analysis, and moreover it is unclear whether theydistinguished CABG-related from non-CABG-related major bleeding[1]. Thus, we cannot deﬁnitively address the purported discrepancybetween their ﬁndings and our own for major bleeding.They also appear to have overlooked other key end-points,including stent thrombosis, which remains in our opinion of utmostimportance, and which appeared signiﬁcantly less likely withprasugrel than with ticagrelor (odds ratio 0.63 [0.43–0.93],p_0.020 in our work) [2]. In addition, we could not ﬁnd details onthe statistical methods used to build their analytical network nor thestatistical package employed for computations. We guess they usedBayesian methods with non-informative priors and the WinBUGSpackage, [10] whereas we used ﬁxed-effect frequentist methods and afreeware package developed by the Meta-analysis and Evidence basedmedicine Training in Cardiology (METCARDIO) group [11]. Theaforementioned differences, as well as the simple impact of multipletesting and the use of risk ratios versus odds ratios might easilyexplain apparent discrepancies between the analyses.In conclusion, we remain positive that advanced statisticalapproaches, including adjusted indirect comparison meta-analysesand mixed treatment comparisons, will play an ever increasing role inshaping clinical research and practice. Thus, this scholarly debate onour recent adjusted indirect comparison meta-analysis comparingprasugrel and ticagrelor in acute coronary syndromes is more thanwelcome and stands as further proof of the need for externalrepetition and validation of any research endeavor.The authors of this manuscript have certiﬁed that they complywith the Principles of Ethical Publishing inthe International Journal ofCardiology (Shewan and Coats 2010;144:1–2).References[1] Passaro D, Fadda G, Maratea D, Messori A. Anti-platelet treatments in acutecoronary syndrome: simpliﬁed network meta-analysis. Int J Cardiol 2011;150:364–7.[2] Biondi-Zoccai G, Lotrionte M, Agostoni P, et al. Adjusted indirect comparisonmeta-analysis of prasugrel versus ticagrelor for patients with acute coronary syndromes.Int J Cardiol 2011;150:325–31.[3] Salanti G, Kavvoura FK, Ioannidis JP. Exploring the geometry of treatmentnetworks. Ann Intern Med 2008;148:544–53.[4] Biondi-Zoccai G, Landoni G, Modena MG. A journey into clinical evidence: fromcase reports to mixed treatment comparisons. HSR Proc Intensive CareCardiovascular Anesth 2011;3:93–6.[5] Biondi-Zoccai GG, Agostoni P, Abbate A, et al. Adjusted indirect comparison ofintracoronary drug-eluting stents: evidence from a metaanalysis of randomizedbare-metal-stent-controlled trials. Int J Cardiol 2005;100:119–23.[6] Biondi-Zoccai GG, Lotrionte M, Abbate A, et al. Direct and indirect comparisonmeta-analysis demonstrates the superiority of sirolimus- versus paclitaxel-elutingstents across 5854 patients. Int J Cardiol 2007;114:104–5.[7] Biondi-Zoccai G, Lotrionte M, Moretti C, et al. Percutaneous coronary interventionwith everolimus-eluting stents (Xience V): systematic review and direct-indirectcomparison meta-analyses with paclitaxel-eluting stents (Taxus) and sirolimus-eluting stents (Cypher). Minerva Cardioangiol 2008;56:55–65.[8] Testa L, van Gaal WJ, Biondi-Zoccai GG, et al. Repeat thrombolysis or conservativetherapy vs. rescue percutaneous coronary intervention for failed thrombolysis:systematic review and meta-analysis. QJM 2008;101:387–95.[9] Testa L, Zoccai GB, Porto I, et al. Adjusted indirect meta-analysis of aspirin pluswarfarin at international normalized ratios 2 to 3 versus aspirin plus clopidogrelafter acute coronary syndromes. Am J Cardiol 2007;99:1637–42.[10] Fryback DG, Stout NK, Rosenberg MA. An elementary introduction to Bayesiancomputing using WinBUGS. Int J Technol Assess Health Care 2001;17:98–113.[11] Meta-analysis and evidence based medicine Training in Cardiology (METCARDIO)indirect meta-analysis tool (ITC). Available from http://www.metcardio.org/macros/IMT.xls last accessed on 21 May 2011.0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.ijcard.2011.06.036Table 1Comparison of statistical results from Biondi-Zoccai et al.'s adjusted indirectcomparison meta-analysis [2] and Passero et al.'s network meta-analysis [1], bothcomparing prasugrel and ticagrelor in patients with acute coronary syndromes.*End-point Biondi-Zoccai et al.'sadjusted indirectcomparisonmeta-analysis [2]Passero et al.'ssimpliﬁednetworkmeta-analysis [1]Death, myocardial infarctionor strokeOR=1.02 (0.88–1.16) RR=1.04 (0.90–1.19)†Death OR=0.83 (0.65–1.05) RR=0.82 (0.65–1.04)Myocardial infarction OR=1.12 (0.94–1.33) NAStroke OR=1.18 (0.75–1.81) NAStent thrombosis OR=1.59 (1.08–2.32) NAMajor bleeding OR=0.70 (0.54–0.91) RR=0.72 (0.50–1.04)Major non-CABG-related bleeding OR=0.95 (0.69–1.32) NAMajor CABG bleeding OR=0.23 (0.09–0.58) NAMajor or minor bleeding OR=0.79 (0.65–0.96) NAMinor bleeding OR=0.93 (0.69–1.27) NADrug discontinuation OR=0.98 (0.84–1.13) NA*Reported with 95% conﬁdence intervals, with valuesb1.0 favoring ticagrelor, and N1.0favoring prasugrel; †death from cardiovascular causes; CABG = coronary artery bypassgrafting; NA = not available; OR = odds ratio; RR = risk ratio.229Letters to the Editor

Agreement between adjusted indirect comparison and simplified network meta-analyses on prasugrel and ticagrelor (Reply to Passaro et al. - Int J Cardiol 2011)

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