Re:RESOLVE could not verify the VERIFY study: response from Berry & Oldroyd
We write in response to the letter from Nijjer et al published in Heart on October 23rd 2013 subsequently removed and then reinstated in a revised form in October 1st 2014.
The original letter (published 15 Oct 2013) was in response to correspondence from Fan et al (University School of Medicine, Shanghai, China) commenting on a paper published online in Heart from the Davies group in Sept 2013 describing changes in iFR following percutaneous coronary intervention. Fan et al point out that the RESOLVE study of which ourselves, Nijjer and Davies are co-authors reported a "poor correlation" (their words) between iFR as first described by the Davies group in the ADVISE study and FFR, the use of which has been shown in two important randomised controlled trials to improve clinical outcomes in patients with stable ischaemic heart disease. At no point in their letter do Fan et al refer to the VERIFY study. Nevertheless, in the reply from Nijjer and Davies, after an opening paragraph of questionable relevance to the topic under discussion, they go on to make several claims about the VERIFY study, all of which are inaccurate and in our view, deliberately misleading.
1. "VERIFY when re-analysed independently using the validated iFR algorithms was not as originally presented and the findings of Berry et al. could not be substantiated"
All of the raw VERIFY data were provided to an independent core laboratory in the University of Columbia, New York and utilized in the RESOLVE analysis. In fact the correlation coefficient between iFR and FFR was 0.70 in VERIFY using the methodology described in the original ADVISE paper and 0.66 in RESOLVE (Fig 1a) using the proprietary Imperial College algorithm for which Davies holds the intellectual property and which has been licensed to Volcano Corporation (a multinational medical device company). In other words, if anything, the correlation is worse in RESOLVE not better. Furthermore we have the RESOLVE core lab analysis of the VERIFY dataset and the mean difference in iFR values between the two different methodologies is -0.007 which is less than the mean difference between repeated measures of either parameter and therefore represents no difference at all. It would appear that, in this case, it is not us who are 'entrenched into a cherished concept'.
2. "...the VERIFY authors paid little attention to the accuracy of their iFR wave free period and instead chose to define diastole to include a part of systole (Figure 1)..."
The sampling frequency of the physiological systems used to record coronary pressure data is generally 100Hz. This means individual data points can be recorded at 10ms intervals. The apparent discrepancy in the Figure referred to represents no more than 5ms and cannot possibly account for the differences between ADVISE and VERIFY. We have also reanalyzed the data after altering the end-point of the so-called "wave free period" by as much as 50ms and this makes no difference to the relationship between iFR and FFR.
3."Unique patient numbers appear overstated and misrepresented in the VERIFY manuscript"
Davies has confirmed to us that he believes the retrospective dataset used in VERIFY contains duplicate records. In fact the dataset includes 88 patients who had iFR and FFR measurements made before and after PCI and although this represents 2 data points for each of these patients, they are not duplicates. In any event the post PCI data from these patients was not included in the RESOLVE analysis (personal communication Dr Allen Jeremias).
Since the publication VERIFY, the iFR paradigm has changed. The "optimal" iFR treatment threshold recommended in ADVISE was 0.83, then it became 0.89, then 0.90 and now there is a hybrid protocol (0.86-0.93). Clearly, these changes are relevant to how individual patients might be treated with stents or bypass surgery or neither. One of the main results from VERIFY was that iFR was reduced by adenosine (see figure 3 in the original paper Berry C et al J Am Coll Cardiol 2013; 61: 1421-7. "iFR during rest and hyperaemia (with intravenous adenosine).
This result directly conflicts with ADVISE, the title page of which describes iFR as an "Adenosine-independent index of stenosis severity" which, patently, it is not. The hybrid approach now proposed is in fact dependent on using adenosine in a considerable proportion of patients. Our study was the first to show the adenosine dependence of iFR and this result has been replicated in several other studies (e.g. Redwood S et al British Cardiovascular Intervention Society 2014).
Finally, we wish to address the accusation that "... in the excitement and haste of rapidly reporting VERIFY, some oversights may have understandably occurred." In VERIFY, which was an international multicentre study, we met our timelines for data acquisition and reporting, but there was no excitement or haste. These assumptions, like several others before, are incorrect.
Conflict of Interest:
Prof Berry is a signatory to institutional agreements for consultancy and a research grant between the University of Glasgow and St Jude Medical. Prof Oldroyd has acted as a Consultant for Volcano Corp. and St Jude Medical.
RESOLVE could not verify the VERIFY study
'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 
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, an international collaboration that was necessary to resolve important questions raised by the VERIFY study. Although the final results of RESOLVE were to conclude that in independent hands the findings were similar to results by the ADVISE investigators [4-6], perhaps the most important message may have been missed. VERIFY, when re-analysed independently using the validated iFR algorithms, was not as originally presented and the VERIFY findings could not be substantiated. Now VERIFY, hailed as the death knell of iFR, stands alone, conflicting with every other iFR-FFR study in the field. How could this have occurred?
We suggest that in the excitement and haste of rapidly reporting VERIFY, some oversights may have understandably occurred.
First, the VERIFY authors may not have focussed on the accuracy of their iFR wave-free period and instead chose to define diastole as including a part of systole (clearly visible in Figure 1 of the VERIFY manuscript). 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 wave-free period.
Second, the number of individual patients in VERIFY appears to have been accidentally overstated. This means that some patients were included twice in the manuscript, potentially skewing the dataset.
Together these factors led to the VERIFY study's reported accuracy of between 49-60% being revised to 79.4% when independently re-analysed using the validated algorithms in RESOLVE. We urge Yang et al. to interpret the VERIFY analysis, and any other analysis depending on it , 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 wave-free period, hence its name. The wave-free 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 cut-offs also become lower.[9,10] Despite concerns that resting states are not possible in the catheter laboratory, ample evidence suggests otherwise.
Accordingly, post-PCI assessment is possible and iFR is a dynamic measure of stenosis severity . Whilst lesion classification disagreements may occur, 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??5:190??2. doi:10.1016/j.jcmg.2011.10.005
2 Allen Jeremias, Akiko Maehara, Philippe Genereux, et al. Multicenter Core Laboratory Comparison of the Instantaneous Wave Free 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 Wave??Free 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 Adenosine??Independent Index of Stenosis Severity From Coronary Wave??Intensity Analysis: Results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) Study. J Am Coll Cardiol 2012 59:1392-402. doi:10.1016/j.jacc.2011.11.003
5 Petraco R, Escaned J, Sen S, et al. Classification performance of instantaneous wave??free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry. EuroIntervention 2013;9:91:101. doi:10.4244/EIJV9I1A146 Petraco R, Park JJ, Sen S, et al. Hybrid iFR??FFR decision??making strategy: implications for enhancing universal adoption of physiology guided coronary revascularisation. EuroIntervention J Eur Collab Work Group Interv Cardiol Eur Soc Cardiol 2013:8:1157-65. 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 wave free ratio approximate the fractional flow reserve? J Am Coll Cardiol 2013 61:1428-35. doi:10.1016/j.jacc.2012.09.064
9 Sen S, Asrress KN, Nijjer S, et al. Diagnostic classification of the instantaneous wave free ratio is equivalent to fractional flow reserve and is not improved with adenosine administration. Results of CLARIFY (Classification Accuracy of Pressure Only Ratios Against Indices Using Flow Study). J Am Coll Cardiol 2013:61:1409-20. doi:10.1016/j.jacc.2013.01.034
10 Sen S, Nijjer S, Petraco R, et al. Letter to the Editor: Instantaneous wave??free (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 1986:73:444-51.
12 Nijjer SS, Sen S, Petraco R, et al. Improvement in coronary haemodynamics after percutaneous coronary intervention: assessment using instantaneous wave free ratio. Heart Published Online First: 18 September 2013. doi:10.1136/heartjnl-2013-304387
13 Van de Hoef T, Meuwissen M, Sen S, et al. Basal Stenosis Resistance Index And Instantaneous Wave??Free 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/S0735-1097(13)61756-8
Conflict of Interest: Dr Davies holds intellectual property pertaining to the iFR technology
Instantaneous Wave-free 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 paper (1) by Nijjer et al with regard to instantaneous wave-free ratio (iFR) assessing improvement in coronary haemodynamics after percutaneous coronary intervention (PCI). However, we have some concerns about the invasive, pressure-only 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. Fluid-dynamics 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 registry (3), a poor correlation was found between iFR and fractional flow reserve (FFR). Only if iFR was <_0.82 as="in=" _24="of=" the="_1539="_1539"" patients="patients" could="could" hyperemia="hyperemia" be="be" omitted="omitted" to="to" achieve="achieve" a="a" _95="_95" certainty="certainty" making="making" correct="correct" decision="decision" whether="whether" or="or" not="not" revascularize.="revascularize." so="so" our="our" question="question" raised="raised" again="again" is="is" ifr="ifr" equivalent="equivalent" ffr="ffr" _4="_4" it="it" even="even" instantaneously="instantaneously" measured="measured" name="name" suggests="suggests" totally="totally" independent="independent" pharmacological="pharmacological" vasodilatation="vasodilatation" because="because" calculated="calculated" an="an" average="average" value="value" and="and" strongly="strongly" influenced="influenced" by="by" hyperemia.2="hyperemia.2" we="we" really="really" appreciate="appreciate" this="this" prospective="prospective" observational="observational" study="study" applying="applying" assess="assess" improvement="improvement" coronary="coronary" haemodynamics="haemodynamics" after="after" pci.="pci." found="found" that="that" change="change" intervention="intervention" _0.20="_0.20" _0.21="_0.21" was="was" similar="similar" _0.22="_0.22" _0.15="_0.15" p="p" surely="surely" based="based" on="on" data="data" presented="presented" might="might" used="used" objectively="objectively" document="document" following="following" pci="pci" manner="manner" ffr.1="ffr.1" however="however" may="may" have="have" highly="highly" variable="variable" measurement="measurement" clinical="clinical" practice="practice" almost="almost" unachievable="unachievable" create="create" true="true" resting="resting" condition="condition" obscure="obscure" determine="determine" what="what" extent="extent" some="some" present.="present.">
1 Nijjer SS, et al. Improvement in coronary haemodynamics after percutaneous coronary intervention: Assessment using instantaneous wave- free ratio. Heart. 2013
2. Pijls NH. Fractional flow reserve to guide coronary revascularization. Circ J. 2013; 77: 561-569.
3. A. J. Resolve: A multicenter study to evaluating the diagnostic accuracy of ifr compared to ffr. J Am Coll Cardiol. 2013;
4. Fan GX and Xu YW. Is the instantaneous wave-free ratio equivalent to fractional flow reserve? J Am Coll Cardiol. 2013; 62: 943.Conflict of Interest: None declared
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