RESOLVE could not verify the VERIFY study

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Coronary revascularisation: Original article: Improvement in coronary haemodynamics after percutaneous coronary intervention: assessment using instantaneous wavefree ratio Sukhjinder S Nijjer, Sayan Sen, Ricardo Petraco, Rajesh Sachdeva, Florim Cuculi, Javier Escaned, Christopher Broyd, Nicolas Foin, Nearchos Hadjiloizou, Rodney A Foale, Iqbal Malik, Ghada W Mikhail, Amarjit S Sethi, Mahmud AlBustami, Raffi R Kaprielian, Masood A Khan, Christopher S Baker, Michael F Bellamy, Alun D Hughes, Jamil Mayet, Rajesh K Kharbanda, Carlo Di Mario, Justin E Davies Heart 2013;99:23 17401748 Published Online First: 18 September 2013 doi:10.1136/heartjnl2013304387

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RESOLVE could not verify the VERIFY study Sukhjinder S Nijjer, MRC Clinical Research Fellow and Cardiology Registrar

Ricardo Petraco, Sayan Sen, Darrel P Francis, Justin E Davies

Imperial College London

'The first step of scientific progress is both accepted knowledge and continual, instantaneous willingness to admit that what we believed true earlier was wrong and needing replacement...' Lance Gould [1] We thank Fan, Qi, He, Yang and Pijls for their continued interest in our work and physiology as a whole. Science thrives on experiments repeatable in independent hands. Dogma, on the other hand, discourages independent thought and when results are unexpected, an enormous scientific hiatus follows. Leaders unwilling to change, may feel obliged to further entrench into cherished concepts but this only makes the inevitable paradigm shift more unpleasant. Yang et al correctly point out the importance of RESOLVE[2], an international collaboration that was necessary to resolve important questions raised by the VERIFY study[3]. Although the final results of RESOLVE were to conclude that in independent hands the findings were similar to results by the ADVISE investigators [46], perhaps the most important message may have been missed. VERIFY, when reanalysed independently using the validated iFR algorithms, was not as originally presented and the findings of Berry et al. could not be substantiated. Now VERIFY, hailed as the death knell of iFR, stands alone, conflicting with every other iFRFFR study in the field.[7] How could this have occurred? It is now evident that in a fervour of excitement, serious oversights and amnesiac errors seem to have arisen. First, the VERIFY authors paid little attention to the accuracy of their iFR wavefree period and instead chose to define diastole as including a part of systole (clearly visible in Figure 1 of the VERIFY manuscript[3]). Whilst superficially appearing to be only a minor physiological transgression, the fundamental principles of iFR state that resistance is only stable and minimised over the cardiac cycle where waves are absent i.e. the wavefree period[4]. Second, unique patient numbers appear overstated, and misrepresented in the manuscript. This means that the same patients were included twice in the manuscript, potential seriously skewing the dataset. Third, and perhaps most worrying, Berry declared no conflict of interest when presenting VERIFY at ACC (2012) but had in fact broken the embargo by presenting first to stock market analysts. Together all of these factors led to the VERIFY study's reported accuracy of between 4960% being revised to 79.4% when independently reanalysed using the validated algorithms in RESOLVE. We urge Yang et al. to interpret the VERIFY dataset, and any other dataset which includes its data[8], with extreme caution. iFR and FFR are both indices of physiological stenosis severity. Both use pressure wire technology, but iFR as a resting measure does not require the administration of vasodilators such as adenosine. iFR can be measured at an instant at any time during the wavefree period, hence its name. The wavefree period provides a form of

natural hyperaemia, present in every beat. Adding external sources of vasodilatation will lower iFR value, but this does not alter the diagnostic accuracy as cutoffs also become lower.[9,10] Despite concerns that resting states are not possible in the catheter laboratory, ample evidence suggests otherwise[11]. Accordingly, postPCI assessment is possible and iFR is a dynamic measure of stenosis severity [12]. Whilst lesion classification disagreements may occur, all the evidence to date indicates that both measures are equally effective in agreeing with independent third measures of ischaemia.[7,9,13]. Whether differences between these indices are clinically important will be established in iFR clinical outcome studies such as FLAIR and SWEDEHEART.

REFERENCES 1 Gould KL, Johnson NP. Imaging in aortic stenosislet the data talk. JACC Cardiovasc Imaging 2012;5:1902. doi:10.1016/j.jcmg.2011.10.005 2 Allen Jeremias, Akiko Maehara, Philippe Genereux, et al. Multicenter Core Laboratory Comparison of the Instantaneous WaveFree Ratio and Resting Pd/Pa with Fractional Flow Reserve: The RESOLVE Study. J Am Coll Cardiol 2013;In Press. 3 Berry C, van't Veer M, Witt N, et al. VERIFY (VERification of Instantaneous WaveFree Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice): A Multicenter Study in Consecutive Patients. J Am Coll Cardiol 2013;61:14217. doi:10.1016/j.jacc.2012.09.065 4 Sen S, Escaned J, Malik IS, et al. Development and Validation of a New AdenosineIndependent Index of Stenosis Severity From Coronary WaveIntensity Analysis: Results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) Study. J Am Coll Cardiol 2012;59:1392402. doi:10.1016/j.jacc.2011.11.003 5 Petraco R, Escaned J, Sen S, et al. Classification performance of instantaneous wavefree ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry. EuroIntervention 2013;9:91101. doi:10.4244/EIJV9I1A14 6 Petraco R, Park JJ, Sen S, et al. Hybrid iFRFFR decisionmaking strategy: implications for enhancing universal adoption of physiologyguided coronary revascularisation. EuroIntervention J Eur Collab Work Group Interv Cardiol Eur Soc Cardiol 2013;8:115765. doi:10.4244/EIJV8I10A179 7 Sen S, Escaned J, Petraco R, et al. Reply to Letter to the Editor: iFR, Science, Size and Serendipity Can lightning strike twice? J Am Coll Cardiol Published Online First: 6 June 2013. doi:10.1016/j.jacc.2013.05.036 8 Johnson NP, Kirkeeide RL, Asrress KN, et al. Does the instantaneous wavefree ratio approximate the fractional flow reserve? J Am Coll Cardiol 2013;61:142835. doi:10.1016/j.jacc.2012.09.064 9 Sen S, Asrress KN, Nijjer S, et al. Diagnostic classification of the instantaneous wavefree ratio is equivalent to fractional flow reserve and is not improved with adenosine administration. Results of CLARIFY (Classification Accuracy of PressureOnly Ratios Against Indices Using Flow Study). J Am Coll Cardiol 2013;61:140920. doi:10.1016/j.jacc.2013.01.034 10 Sen S, Nijjer S, Petraco R, et al. Letter to the Editor: Instantaneous wavefree (iFR): Numerically different, but diagnostically superior to FFR? Is lower always better? J Am Coll Cardiol Published Online First: 20 May 2013. doi:10.1016/j.jacc.2013.03.076 11 Wilson RF, White CW. Intracoronary papaverine: an ideal coronary vasodilator for studies of the coronary circulation in conscious humans. Circulation 1986;73:44451. 12 Nijjer SS, Sen S, Petraco R, et al. Improvement in coronary haemodynamics after percutaneous coronary intervention: assessment using instantaneous wavefree ratio. Heart Published Online First: 18 September 2013. doi:10.1136/heartjnl2013304387 13 Van de Hoef T, Meuwissen M, Sen S, et al. Basal Stenosis Resistance Index And Instantaneous WaveFree Ratio Have The Same Diagnostic Performance As Fractional Flow Reserve To Detect Myocardial Ischemia Using Myocardial Perfusion Imaging. J Am Coll Cardiol 2013;61. doi:10.1016/S07351097(13)617568

Conflict of Interest: Dr Davies holds intellectual property pertaining the iFR technology ... less Submit response

Published 23 October 2013

Instantaneous Wavefree Ratio: a Word of Caution or Reliable Parameter? Changqing Yang

Guoxin Fan, Xiaolong Qi, Shisheng He,

Tongji Hospital, Tongji University School of Medicine Shanghai China

TO THE EDITOR: We take great interest in the paper1 by Nijjer et al. with regard to instantaneous wavefree ratio (iFR) assessing improvement in coronary haemodynamics after percutaneous coronary intervention (PCI). However, we have some concerns about the invasive, pressureonly index, iFR. iFR, a novel resting index without hyperemia, is calculated over five heartbeats as the ratio of distal to proximal coronary pressures during the diastolic. The assumption is that the resistance during a particular part of diastole will be as low as the average resistance during the complete heart cycle in hyperemia and not be influenced by adenosine infusion.2 Nevertheless, assumption is assumption, whilst numerical equation makes sense. Fluiddynamics equation elucidates that iFR is able to predict the severity of stenosis (e.g. a 70% long LAD stenosis) only when friction is the predominant cause of energy loss within the stenosis. 2 That is to say, a short 50% left main stenosis, in which separation and turbulent flow are responsible for the energy loss, creates a negligible resting gradient with an extremely large hyperemic gradient. In the recent Resolve registry3, a poor correlation was found between iFR and fractional flow reserve (FFR). Only if iFR was